Scifinder®: 1. Single Step

SciFinder® Page 1
1. Single Step
90%
Overview
Steps/Stages Notes
green chemistry-catalyst, chemoselective,
1.1 R:Cyclopentene, C:1221406-59-2, S:PhMe, 12 h, 120°C regioselective, Schlenk tube used, mechanism
studied, Reactants: 2, Reagents: 1, Catalysts:
1, Solvents: 1, Steps: 1, Stages: 1, Most
stages in any one step: 1
References
Deaminative and Decarboxylative Catalytic
Alkylation of Amino Acids with Ketones
By Kalutharage, Nishantha and Yi, Chae S.
From Angewandte Chemie, International
Edition, 52(51), 13651-13655; 2013
Reaction Protocol
Step 1
Products 1-Phenyl-3-pentanone, 90%, CAS RN:20795-51-1
Reactants L-Phenylglycine, CAS RN:2935-35-5
Methyl ethyl ketone, CAS RN:78-93-3
Reagents Cyclopentene, CAS RN:142-29-0
Catalysts Ruthenium(1+), carbonylhydro(η6-benzene)(tricyclohexylphosphine)-, tetrafluoroborate(1-) (1:1), CAS
RN:1221406-59-2
Solvents Toluene, CAS RN:108-88-3
Procedure 1. In a glove box, dissolve 2-butanone (1.0 mmol), (S)-phenylglycine (1.2 mmol), cyclopentene (7 mg,
10 mol %) and cationic ruthenium hydride complex (3 mol %) in toluene (2 mL) in a 25 mL Schlenk
tube equipped with a Teflon stopcock and a magnetic stirring bar.
2. Bring the tube out of the glove box.
3. Stir the reaction mixture in an oil bath set at 120 °C for 12 hours.
4. Take the reaction tube out of the oil bath.
5. Cool the reaction to room temperature.
6. Filter the reaction mixture.
7. Purify the product through a short silica gel column (280-400 mesh; CH2Cl2, 10 mL).
Transformation Reduction of the C-N Bond/ Deamination
1H NMR (400 MHz, CDCl3) δ 7.31-7.28 (m, 2H), 7.20-7.17 (m, 3H), 2.92 (t, J = 7.6 Hz, 2H), 2.73 (t, J = 7.6 Hz,
2H), 2.40 (q, J = 7.5 Hz, 2H), 1.06 (t, J = 7.5 Hz, 3H) ppm.
13C NMR 13C{1H} NMR (100 MHz, CDCl ) δ 208.0, 134.3, 129.3, 128.4, 126.7, 35.9, 31.9, 30.6, 22.7 ppm.
3
Mass Spec GC-MS M/z = 162 (M+).
CAS Method 3-544-CAS-9467685
Number
CASREACT ®: Copyright © 2018 American Chemical Society. All Rights Reserved. CASREACT contains reactions
from CAS and from: ZIC/VINITI database (1974-1999) provided by InfoChem; INPI data prior to 1986; Biotransformations
database compiled under the direction of Professor Dr. Klaus Kieslich; organic reactions, portions copyright 1996-2006
John Wiley & Sons, Ltd., John Wiley and Sons, Inc., Organic Reactions Inc., and Organic Syntheses Inc. Reproduced
under license. All Rights Reserved.
2. 2 Steps
SciFinder® Page 2
[Step 2.1]
Overview
Steps/Stages Notes
1) stereoselective, 2) stereoselective,
1.1 R:LiAlH4, S:THF Reactants: 2, Reagents: 3, Solvents: 4, Steps:
2, Stages: 4, Most stages in any one step: 2
1.2 R:NaOH, S:H2O
2.1 S:Benzene References
Asymmetric addition of n-butyllithium to
2.2 R:NaBH4, S:EtOH aldehydes: new insights into the reactivity and
enantioselectivity of the chiral amino ether
accelerated reaction
By Granander, Johan et al
From Tetrahedron, 58(23), 4717-4725; 2002
Reaction Protocol
Step 1
No Protocol for this Step.
Step 2
3. Single Step
90%
Overview
Steps/Stages Notes
SciFinder® Page 3
aerobic, optimization study, optimized on
1.1 R: reagent, optimized on additive, optimized on
solvent, optimized on temperature, Reactants:
2, Reagents: 3, Solvents: 1, Steps: 1, Stages:
1, Most stages in any one step: 1
References
Metal-Free sp3 C-H Functionalization:
PABS/I2-Promoted Synthesis of
Polysubstituted Oxazole Derivatives from
Arylethanones and 2-Amino-2-alkyl/arylacetic
Acid
R:I2, R:O2, S:DMSO, 5 h, 100°C By Hu, Ting et al
From Synlett, 26(20), 2866-2869; 2015
Reaction Protocol
Step 1
4. Single Step
85%
Overview
Steps/Stages Notes
alternative preparation shown,
1.1 R:I2, S:C5H5N, 12 h, 120°C chemoselective, pressure vessel used, green
chemistry, Reactants: 2, Reagents: 1,
Solvents: 1, Steps: 1, Stages: 1, Most stages
in any one step: 1
References
Molecular Iodine-Mediated Chemoselective
Synthesis of Multisubstituted Pyridines
through Catabolism and Reconstruction
Behavior of Natural Amino Acids
By Xiang, Jia-Chen et al
From Organic Letters, 18(1), 24-27; 2016
Experimental Procedure
SciFinder® Page 4
General/Typical Procedure: General procedure for the synthesis of 3 and 5 (3a and 5a as an example)
3a: A mixture of glycine 1a (2.0 mmol), acetophenone 2a (2.0 mmol), I2 (2.0 mmol), in pyridine (2.0
mL) was stirred at 120°C for 12 hours in a pressure vessel. Then added 50 mL water and 30 mL
saturated brine solution to the mixture and extracted with EtOAc 3 times (3 × 50 mL). The extract was
washed with 10% Na2S2O3 solution, dried over anhydrous Na2SO4 and concentrated under reduced
pressure. The crude product was purified by column chromatography on alkaline aluminum oxide
(eluent: n-hexane /EtOAc=50/1), The product 3a as White crystalline solid (168 mg, 73%). 2,6-
diphenylpyridine (3a) 2,4,6-triphenylpyridine (3q) Pale yellow solid (261 mg, 85%). Mp = 136-138 °C;
1H NMR (300 MHz, CDCl ) δ 8.27-8.15 (m, 4H), 7.89 (s, 2H), 7.73-7.77 (m, 2H), 7.45-7.55(m, 9H). 13C
3
NMR (75 MHz, CDCl3) δ 157.46, 150.27, 139.44, 139.00, 129.11, 129.08, 129.00, 128.70, 127.18,
127.16, 117.18. IR (KBr): 1604.8217, 1594.08, 1577.98, 1550.14, 1493.32, 1446.48, 1399.63,
1072.97, 1029.93, 869.90, 758.63, 738.25, 691.96, 634.06, 610.85, 575.69. HRMS (ESI): m/z [M+H]+
calcd for C23H18N: 308.1435; found: 308.1434.
Reaction Protocol
Step 1
5. Single Step
80%
Overview
Steps/Stages Notes
alternative preparation shown, no solvent,
1.1 R:O2, C:Cu(CF3SO3)2, 20 h, 100°C, 1 atm; 100°C → rt Reactants: 2, Reagents: 1, Catalysts: 1, Steps:
References
Copper-Catalyzed Formal C-N Bond
Cleavage of Aromatic Methylamines:
Assembly of Pyridine Derivatives
By Huang, Huawen et al
From Journal of Organic Chemistry, 78(8),
3774-3782; 2013
SciFinder® Page 5
General/Typical Procedure: General Procedure for the Synthesis of 2,4,6-Trisubstituted Pyridines. To
a 25 mL pressure tube was added a mixture of ketone 1 (2 mmol), benzylamine 2 (1.2 mmol)
andCu(OTf)2 (36 mg, 0.1 mmol), successively. Subsequently, the tube was evacuated with a vacuum
pump, filled with oxygen (1 atm) and sealed with Teflon stopper. The mixture was stirred at 100 °C for
20 h. Upon completion, the crude product was cooled to room temperature and then directly separated
by flash column chromatography on silica gel to give the pure product 3. Pyridines 3ja and 3ka were
prepared using toluene (0.5 mL) as the solvent for convenience of stirring. Pyridines 3la and 3ma were
obtained at 80 °C for 8 h. Asymmetrical pyridines 4a d were synthesized according to this procedure
using two different ketones (1 mmol for each). 2,4,6-Triphenylpyridine (3aa).10 Table 4. Pyridine
Synthesis via Cleavage of C C and C N Bonds a Entry 5 2,4,6-Triphenylpyridine (3aa).10 Yield 80%. 1H
NMR (400 MHz, CDCl3) δ 8.22 (d, J = 7.1 Hz, 4H), 7.91 (s, 2H), 7.77 (d, J = 7.0 Hz, 2H), 7.57 7.43 (m,
9H); 13C NMR (101 MHz, CDCl3) δ 157.5, 150.3, 139.5, 139.0, 129.1, 129.1, 129.0, 128.7, 127.2,
127.2, 117.2; HRMS (ESI) calc. C23H17N [M + H]+ 308.1434, found 308.1442.
Reaction Protocol
Step 1
6. Single Step
79%
Overview
Steps/Stages Notes
References
Edition, 52(51), 13651-13655; 2013
Reaction Protocol
Step 1
Products Dihydrochalcone, 79%, CAS RN:1083-30-3
Acetophenone, CAS RN:98-86-2
RN:1221406-59-2
SciFinder® Page 6
Procedure 1. In a glove box, dissolve amino acid (1.2 mmol), ketone (1.0 mmol), cyclopentene (0.1 mmol) and
cationic ruthenium hydride complex (3 mol %) in toluene (2 mL) in a 25 mL Schlenk tube equipped with
a Teflon stopcock and a magnetic stirring bar.
5. Cool the reaction mixture to room temperature.
6. Open the tube to air.
7. Filter the resulting solution through a short silica gel column by eluting with CH2Cl2 (10 mL).
8. Analyze the filtrate by GC and GC-MS.
9. Isolate the pure product by a simple column chromatography on silica gel (280-400 mesh,
hexane/EtOAc = 40:1 to 1:1).
Scale milligram
1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 7.9 Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.7 Hz, 2H), 7.31-
7.18 (m, 5H), 3.30 (t, J = 7.7 Hz, 2H), 3.07 (t, J = 7.7 Hz, 2H) ppm.
13C NMR 13C{1H} NMR (100 MHz, CDCl ) δ 196.9, 138.8, 134.3, 130.7, 126.2, 126.1, 126.0, 125.6, 123.7, 27.6,
3
27.5 ppm.
Number
7. Single Step
42%
Overview
Steps/Stages Notes
aerobic, Reactants: 2, Reagents: 3, Solvents:
1.1 R: 1, Steps: 1, Stages: 1, Most stages in any one
step: 1
References
Acid
By Hu, Ting et al
R:I2, R:O2, S:DMSO, 5 h, 100°C From Synlett, 26(20), 2866-2869; 2015
Reaction Protocol
Step 1

SciFinder® Page 7
8. 3 Steps
[Step 2.1] [Step 3.2]
Overview
Steps/Stages Notes
1) stereoselective, 2) stereoselective, 3)
1.1 R:LiAlH4, S:THF stereoselective, Reactants: 3, Reagents: 4,
1.2 R:NaOH, S:H2O in any one step: 3
2.1 S:Benzene
References
2.2 R:NaBH4, S:EtOH Asymmetric addition of n-butyllithium to
aldehydes: new insights into the reactivity and
3.1 R:NaH, S:THF enantioselectivity of the chiral amino ether
3.2
3.3 S:H2O By Granander, Johan et al
Reaction Protocol
Step 1
Step 2
Step 3
SciFinder® Page 8
9. Single Step
88%
Overview
Steps/Stages Notes
References
Edition, 52(51), 13651-13655; 2013
Reaction Protocol
Step 1
Products 1-Phenyl-3-heptanone, 88%, CAS RN:19969-04-1
2-Hexanone, CAS RN:591-78-6
RN:1221406-59-2
Procedure 1. In a glove box, dissolve an amino acid (1.2 mmol), a ketone (1.0 mmol), cyclopentene (0.1 mmol)
and cationic ruthenium hydride complex (3 mol %) in toluene (2 mL) in a 25 mL Schlenk tube equipped
with a Teflon stopcock and a magnetic stirring bar.
Scale milligram
1H NMR (400 MHz, CDCl3) δ 7.22-7.02 (m, 5H), 2.79 (t, J = 8.1 Hz, 2H), 2.62 (t, J = 8.1 Hz, 2H), 2.28 (t, J = 7.5
Hz, 2H), 1.44 (p, J = 7.5 Hz, 2H), 1.18 (sextet, J = 7.5 Hz, 2H), 0.78 (t, J = 7.5 Hz, 1H) ppm.
13C NMR 13C{1H} NMR (100 MHz, CDCl ) δ 210.7, 141.6, 128.9, 128.8, 126.5, 44.7, 43.2, 30.2, 26.3, 22.8, 14.3
3
ppm.
Number
SciFinder® Page 9
10. 3 Steps
[Step 2.1] [Step 3.2]
Overview
Steps/Stages Notes
2.1 S:Benzene
References
3.2
Reaction Protocol
Step 1
Step 2
Step 3
SciFinder® Page 10
11. 2 Steps
[Step 2.1]
Overview
Steps/Stages Notes
Reactants: 2, Reagents: 5, Solvents: 3, Steps:
1.1 R:NaBH4, S:THF, rt → 0°C 2, Stages: 5, Most stages in any one step: 4
1.2 R:I2, S:THF, 40 min, 0°C; 18 h, reflux; reflux → rt References
Dual Catalyst System for Asymmetric
1.3 R:MeOH, rt; 30 min, rt Alternating Copolymerization of Carbon
Dioxide and Cyclohexene Oxide with Chiral
1.4 R:KOH, S:H2O, 4 h, rt Aluminum Complexes: Lewis Base as
Catalyst Activator and Lewis Acid as
2.1 R:Na2SO4, S:MeOH, 1 h, rt; 12 h, rt Monomer Activator
By Nishioka, Kiyoshi et al
From Macromolecules (Washington, DC,
United States), 45(20), 8172-8192; 2012
Step 1
General/Typical Procedure: (S)-2-Amino-1-propanol (L-alaninol).7 NaBH4 (6.92 g, 183 mmol) was
suspended in dry THF (200 mL) in a 500-mL two-necked round-bottomed flask fitted with a reflux
condenser and a dropping funnel under dry nitrogen. L-Alanine (6.76 g, 76 mmol) was added to the
solution, and the mixture was then cooled to 0 °C in an ice bath. While a solution of iodine (19.3 g, 76
mmol) in dry THF (50 mL) was dropwise added over 40 min, a vigorous evolution of gas was
observed. After the evolution of gas ceased, the mixture was heated under reflux for 18 h. The mixture
was cooled to room temperature, and methanol was then added cautiously until the mixture became
clear. The clear solution was stirred for 30 min and concentrated under reduced pressure to leave a
white paste. After the white paste was dissolved in KOH aq (20%, 150 mL) over 4 h under stirring, the
solution was washed with CH2Cl2 (150 mL) three times. The combined organic layers were dried over
Na2SO4 and concentrated under reduced pressure to leave a yellow liquid. The residue was distilled to
afford a compound. (S)-2-Amino-2-phenylethanol (L-phenylglycinol). Recrystallization from toluene to
give white crystals in 79% yield. [α]D 28 +29° (c 0.8, 1 M HCl aq) [lit.8 [α]D 19 +33° (c 0.75, 1 M HCl aq)].
Mp 73- 76 °C (lit.8 75-78 °C). 1H NMR (CDCl3): δ 7.34-7.25 (m, 5H), 4.23 (s, 1H), 3.75-3.71 (d, 1H),
3.57- 3.52 (t, 1H), 2.20-2.01 (br, 3H). IR (KBr, cm-1): 3420, 3405, 3325, 3150, 3110, 3065, 3028, 2939,
2920, 2895, 2850, 2690, 1601, 1499, 1472, 1462, 1360, 1052, 1040, 935, 800, 775, 703.
Step 2
General/Typical Procedure: 4-((S)-1-Hydroxy-3-methylbutan-2-ylimino)pent-2-en-2-ol (2cH2).50
Na2SO4 (2.5 g) was added to acetylacetone (1.0 g, 10 mmol) in methanol (10 mL) in a 100-mL two-
necked roundbottomed flask equipped with a dropping funnel. (S)-2-Amino-3-methyl-1-butanol (1.03 g,
10.0 mmol) in methanol (20 mL) was added dropwise over 1 h while the solution turned yellow, and the
resulting mixture was then stirred for 12 h at room temperature. After dilution with CH2Cl2 (10 mL), the
mixture was filtered and concentrated to dryness under reduced pressure to leave a yellow solid. The
residue was purified by silica gel column chromatography with ethyl acetate/ hexane (2/3, vol/vol) to
afford a compound. 4-((S)-2-Hydroxy-1-phenylethylimino)pent-2-en-2-ol (2gH2). This was purified by
recrystallization from ethanol to afford a white crystal (88% yield). [α]D -878° (c 1.6, CHCl3). 1H NMR
(CDCl3): δ 11.43 (br, 1H), 7.37-7.28 (m, 5H), 5.03 (s, 1H), 4.73-4.68 (m, 1H), 3.87-3.78 (m, 2H), 3.25-
3.21 (t, 1H), 2.07 (s, 3H), 1.87 (s, 3H). 13C NMR (CDCl3): δ 195.4, 163.9, 139.3, 128.9, 128.6, 127.7,
126.5, 96.4, 67.2, 60.1, 28.5, 19.4. FAB-MS m/z: 220 [for C13H18NO2 [M + H]+].
Reaction Protocol
Step 1
Products (+)-Phenylglycinol, 79%, CAS RN:20989-17-7
SciFinder® Page 11
Reagents Sodium borohydride, CAS RN:16940-66-2
Iodine, CAS RN:7553-56-2
Methanol, CAS RN:67-56-1
Potassium hydroxide, CAS RN:1310-58-3
Solvents Tetrahydrofuran, CAS RN:109-99-9
Water, CAS RN:7732-18-5
Procedure 1. Suspend NaBH4 (6.92 g, 183 mmol) in dry THF (200 mL) in a 500-mL two-necked round-bottomed
flask fitted with a reflux condenser and a dropping funnel under dry nitrogen.
2. Add corresponding amino acid (76 mmol) to the solution.
3. Cool the mixture to 0 °C in an ice bath.
4. Add a solution of iodine (19.3 g, 76 mmol) in dry THF (50 mL) dropwise to the mixture over 40 min.
5. Observe a vigorous evolution of gas at the same time.
6. Heat the mixture under reflux for 18 hours after the evolution of gas ceased.
7. Cool the mixture to room temperature.
8. Add methanol cautiously to the mixture until the mixture become clear.
9. Stir the clear solution for 30 min.
10. Concentrate the solution under reduced pressure to obtain a white paste.
11. Dissolve the white paste in KOH aq (20%, 150 mL) over 4 hours under stirring.
12. Wash the solution with CH2Cl2 (150 mL) three times.
13. Dry the combined organic layers over Na2SO4.
14. Concentrate the organic layers under reduced pressure to obtain a yellow liquid.
15. Distill the residue.
16. Recrystallize the residue from toluene to afford (S)-2-amino-2-phenylethanol.
1H NMR (CDCl3): δ7.34-7.25 (m, 5H), 4.23 (s, 1H), 3.75-3.71 (d, 1H), 3.57- 3.52 (t, 1H), 2.20-2.01 (br, 3H)
IR (KBr, cm-1): 3420, 3405, 3325, 3150, 3110, 3065, 3028, 2939, 2920, 2895, 2850, 2690, 1601, 1499,
1472, 1462, 1360, 1052, 1040, 935, 800, 775, 703
[α]D20 [α]D28 +29° (c 0.8, 1 M HCl aq)
MP 73- 76 °C
State white crystals
Number
Step 2
Products (βS)-β-[(3-Hydroxy-1-methyl-2-buten-1-ylidene)amino]benzeneethanol, 88%, CAS RN:1403239-82-6
Reactants (+)-Phenylglycinol, CAS RN:20989-17-7
Acetylacetone, CAS RN:123-54-6
Reagents Sodium sulfate, CAS RN:7757-82-6
Solvents Methanol, CAS RN:67-56-1
Procedure 1. Add Na2SO4 (2.5 g) to acetylacetone (10 mmol) in methanol (10 mL) in a 100-mL two-necked
round-bottomed flask equipped with a dropping funnel.
2. Add (S)-2-amino-2-phenylethanol (10.0 mmol) in methanol (20 mL) dropwise to the mixture over 1
hour, while the solution turns to yellow.
3. Stir the resulting mixture for 12 hours at room temperature.
4. Dilute the mixture with CH2Cl2 (10 mL).
5. Filter the mixture.
6. Concentrate the filtrate to dryness under reduced pressure to obtain a yellow solid.
7. Purify the residue by recrystallization from ethanol to afford 4-((S)-2-hydroxy-1-
phenylethylimino)pent-2-en-2-ol.
1H NMR (CDCl3): δ 11.43 (br, 1H), 7.37-7.28 (m, 5H), 5.03 (s, 1H), 4.73-4.68 (m, 1H), 3.87-3.78 (m, 2H), 3.25-
3.21 (t, 1H), 2.07 (s, 3H), 1.87 (s, 3H)
13C NMR (CDCl3): δ 195.4, 163.9, 139.3, 128.9, 128.6, 127.7, 126.5, 96.4, 67.2, 60.1, 28.5, 19.4
[α]D20 [α]D -878° (c 1.6, CHCl3)
Mass Spec FAB-MS: 220 [for C13H18NO2 [M + H]+]
State white crystal
Number
SciFinder® Page 12
12. Single Step
94%
Overview
Steps/Stages Notes
step: 1
References
Acid
By Hu, Ting et al
Reaction Protocol
Step 1
13. Single Step
95%
Overview
Steps/Stages Notes
SciFinder® Page 13
step: 1
References
Acid
By Hu, Ting et al
Reaction Protocol
Step 1
14. 5 Steps
[Step 2.1] [Step 4.2]
Overview
Steps/Stages Notes
1.1 R:LiAlH4, S:THF 5, Stages: 6, Most stages in any one step: 2
2.1 R:C5H5N, S:THF References
Stereoselective aldol reactions with chiral
3.1 R:KOH, S:H2O, S:MeOH secondary acetamides
By Devant, Ralf and Braun, Manfred
4.1 R:BuLi
From Chemische Berichte, 119(7), 2191-207;
4.2 1986
5.1 R:KOH, S:H2O, S:MeOH
Reaction Protocol
SciFinder® Page 14
Step 1
Step 2
Step 3
Step 4
Step 5
15. 4 Steps
[Step 2.1] [Step 4.2]
Overview
Steps/Stages Notes
4.1 R:BuLi
4.2 1986
Reaction Protocol
SciFinder® Page 15
Step 1
Step 2
Step 3
Step 4
16. Single Step
87%
Overview
Steps/Stages Notes
step: 1
References
Acid
By Hu, Ting et al
Reaction Protocol
Step 1
17. Single Step
SciFinder® Page 16
70%
Overview
Steps/Stages Notes
sealed tube used, optimization study,
1.1 R:t-BuOOH, C:I2, S:AcNMe2, S:H2O, 4 h, 25°C; 25°C → 60°C; 4 optimized on catalyst, reagent and
h, 60°C temperature, Reactants: 2, Reagents: 1,
Catalysts: 1, Solvents: 2, Steps: 1, Stages: 1,
Most stages in any one step: 1
References
Metal-free synthesis of polysubstituted
oxazoles via a decarboxylative cyclization
from primary α-amino acids
By Li, Yunfeng et al
From Sustainable Chemical Processes, 1,
8/1-8/6, 6 pp.; 2013
Reaction Protocol
Step 1
18. 3 Steps
[Step 2.1] [Step 3.1]
Overview
SciFinder® Page 17
Steps/Stages Notes
1.1 R:NaBH4, S:THF, rt → 0°C 3, Stages: 6, Most stages in any one step: 4
1.2 R:I2, S:THF, 40 min, 0°C; 18 h, reflux; reflux → rt References
Dual Catalyst System for Asymmetric
1.3 R:MeOH, rt; 30 min, rt Alternating Copolymerization of Carbon
Dioxide and Cyclohexene Oxide with Chiral
1.4 R:KOH, S:H2O, 4 h, rt Aluminum Complexes: Lewis Base as
2.1 R:Na2SO4, S:MeOH, 1 h, rt; 12 h, rt Monomer Activator
3.1 S:THF, -30°C; -30°C → rt; 2.5 h, rt By Nishioka, Kiyoshi et al
United States), 45(20), 8172-8192; 2012
Step 1
3.57- 3.52 (t, 1H), 2.20-2.01 (br, 3H). IR (KBr, cm-1): 3420, 3405, 3325, 3150, 3110, 3065, 3028, 2939,
2920, 2895, 2850, 2690, 1601, 1499, 1472, 1462, 1360, 1052, 1040, 935, 800, 775, 703.
Step 2
General/Typical Procedure: 4-((S)-1-Hydroxy-3-methylbutan-2-ylimino)pent-2-en-2-ol (2cH2).50
Na2SO4 (2.5 g) was added to acetylacetone (1.0 g, 10 mmol) in methanol (10 mL) in a 100-mL two-
necked roundbottomed flask equipped with a dropping funnel. (S)-2-Amino-3-methyl-1-butanol (1.03 g,
10.0 mmol) in methanol (20 mL) was added dropwise over 1 h while the solution turned yellow, and the
resulting mixture was then stirred for 12 h at room temperature. After dilution with CH2Cl2 (10 mL), the
mixture was filtered and concentrated to dryness under reduced pressure to leave a yellow solid. The
residue was purified by silica gel column chromatography with ethyl acetate/ hexane (2/3, vol/vol) to
afford a compound. 4-((S)-2-Hydroxy-1-phenylethylimino)pent-2-en-2-ol (2gH2). This was purified by
recrystallization from ethanol to afford a white crystal (88% yield). [α]D -878° (c 1.6, CHCl3). 1H NMR
(CDCl3): δ 11.43 (br, 1H), 7.37-7.28 (m, 5H), 5.03 (s, 1H), 4.73-4.68 (m, 1H), 3.87-3.78 (m, 2H), 3.25-
3.21 (t, 1H), 2.07 (s, 3H), 1.87 (s, 3H). 13C NMR (CDCl3): δ 195.4, 163.9, 139.3, 128.9, 128.6, 127.7,
126.5, 96.4, 67.2, 60.1, 28.5, 19.4. FAB-MS m/z: 220 [for C13H18NO2 [M + H]+].
Step 3
General/Typical Procedure: Complex [2bAlMe]2.41 After 2bH2 (0.16 g, 1.0 mmol) was dissolved in dry
THF (10 mL) in a 50-mL two-necked roundbottomed flask equipped with a three-way stopcock under
dry nitrogen, the mixture was cooled at -30 °C. Me3Al (0.12 mL, 1.2 mmol) was carefully added to the
solution by a hypodermic syringe in a nitrogen stream. After gas evolution ceased, the resulting
mixture was allowed to warm to room temperature and then stirred for 2.5 h. The volatile components
were then removed under reduced pressure to leave a white solid. The crude product was purified by
recrystallization form THF/hexane to afford a compound. Complex [2gAlMe]2. 90% yield as a colorless
crystal. Complexe [2gAlMe]2 was synthesized according to the similar procedure to [2bAlMe]2. 1H
NMR (CDCl3): δ 7.50-7.20 (m, 10H), 5.21 (s, 2H), 4.70-4.39 (m, 2H), 3.90-3.61 (m, 4H), 3.10-2.99 (t,
2H), 2.00 (s, 6H), 1.80 (s, 3H), -0.99 (s, 3H), -1.10 (s, 3H). Crystal data: Empirical formula:
C28H36Al2N2O4; Formula weight: 518.55; Temperature: 100(2) K; Wavelength: 0.71073 Å ; Crystal
system: Orthorhombic; Space group: P212121; Unit cell dimensions: a = 9.0425(15) Å ; α: = 90°; b: =
14.736(2) Å ; β: = 90°; c: = 20.513(3) Å ; γ = 90° ; Volume: 2733.4(8); Å 3; Z: 4; Density (calculated):
1.260 Mg/m3; Absorption coefficient: 0.142 mm-1; F(000): 1104; Crystal size: 0.50 × 0.25 × 0.23 mm3.
Reaction Protocol
Step 1
SciFinder® Page 18
IR (KBr, cm-1): 3420, 3405, 3325, 3150, 3110, 3065, 3028, 2939, 2920, 2895, 2850, 2690, 1601, 1499,
1472, 1462, 1360, 1052, 1040, 935, 800, 775, 703
[α]D20 [α]D28 +29° (c 0.8, 1 M HCl aq)
MP 73- 76 °C
Number
Step 2
Products (βS)-β-[(3-Hydroxy-1-methyl-2-buten-1-ylidene)amino]benzeneethanol, 88%, CAS RN:1403239-82-6
Acetylacetone, CAS RN:123-54-6
Reagents Sodium sulfate, CAS RN:7757-82-6
Procedure 1. Add Na2SO4 (2.5 g) to acetylacetone (10 mmol) in methanol (10 mL) in a 100-mL two-necked
round-bottomed flask equipped with a dropping funnel.
2. Add (S)-2-amino-2-phenylethanol (10.0 mmol) in methanol (20 mL) dropwise to the mixture over 1
hour, while the solution turns to yellow.
3. Stir the resulting mixture for 12 hours at room temperature.
4. Dilute the mixture with CH2Cl2 (10 mL).
5. Filter the mixture.
6. Concentrate the filtrate to dryness under reduced pressure to obtain a yellow solid.
7. Purify the residue by recrystallization from ethanol to afford 4-((S)-2-hydroxy-1-
phenylethylimino)pent-2-en-2-ol.
1H NMR (CDCl3): δ 11.43 (br, 1H), 7.37-7.28 (m, 5H), 5.03 (s, 1H), 4.73-4.68 (m, 1H), 3.87-3.78 (m, 2H), 3.25-
3.21 (t, 1H), 2.07 (s, 3H), 1.87 (s, 3H)
13C NMR (CDCl3): δ 195.4, 163.9, 139.3, 128.9, 128.6, 127.7, 126.5, 96.4, 67.2, 60.1, 28.5, 19.4
[α]D20 [α]D -878° (c 1.6, CHCl3)
State white crystal
Number
Step 3
Products Aluminum, bis[µ-[4-[[(1R)-2-(hydroxy-κO:κO)-1-phenylethyl]imino-κN]-2-pentanonato(2-)-
κO]]dimethyldi-, stereoisomer, 90%, CAS RN:1403239-72-4
SciFinder® Page 19
Reactants (βS)-β-[(3-Hydroxy-1-methyl-2-buten-1-ylidene)amino]benzeneethanol, CAS RN:1403239-82-6
Trimethylaluminum, CAS RN:75-24-1
Procedure 1. Dissolve 4-((S)-2-hydroxy-1-phenylethylimino)pent-2-en-2-ol (1.0 mmol) in dry THF (10 mL) in a 50-
mL two-necked round-bottomed flask equipped with a three-way stopcock under dry nitrogen.
2. Cool the mixture at -30 °C.
3. Add Me3Al (0.12 mL, 1.2 mmol) carefully to the solution by a hypodermic syringe in a nitrogen
stream.
4. Allow the resulting mixture to warm to room temperature after the gas evolution ceased.
5. Stir the mixture for 2.5 hours.
6. Remove the volatile components under reduced pressure to obtain a white solid.
7. Purify the crude product by recrystallization form THF/hexane to afford the product.
1H NMR (CDCl3): δ 7.50-7.20 (m, 10H), 5.21 (s, 2H), 4.70-4.39 (m, 2H), 3.90-3.61 (m, 4H), 3.10-2.99 (t, 2H),
2.00 (s, 6H), 1.80 (s, 3H), -0.99 (s, 3H), -1.10 (s, 3H)
Crystal Empirical formula: C28H36Al2N2O4; Formula weight: 518.55; Temperature: 100(2) K; Wavelength:
Structure Data 0.71073 Å ; Crystal system: Orthorhombic; Space group: P212121; Unit cell dimensions: a = 9.0425(15)
Å ; α: = 90°; b: = 14.736(2) Å ; β: = 90°; c: = 20.513(3) Å ; γ = 90° ; Volume: 2733.4(8); Å 3; Z: 4;
Density (calculated): 1.260 Mg/m3
State colorless crystal
Number
19. Single Step
86%
Overview
Steps/Stages Notes
green chem., selective for intramolecular
1.1 R:t-BuOOH, C:I2, S:H2O, S:AcNMe2, 18 h, 80°C oxidative decarboxylative amination, sealed
tube used, Reactants: 2, Reagents: 1,
References
Metal-free intramolecular oxidative
decarboxylative amination of primary α-amino
acids with product selectivity
By Yan, Yizhe and Wang, Zhiyong
From Chemical Communications (Cambridge,
United Kingdom), 47(33), 9513-9515; 2011
Reaction Protocol
Step 1
Products 4-Ethyl-2-phenylquinazoline, 86%, CAS RN:68674-67-9
SciFinder® Page 20
Reactants DL-Phenylglycine, CAS RN:2835-06-5
1-(2-Aminophenyl)-1-propanone, CAS RN:1196-28-7
Reagents tert-Butyl hydroperoxide, CAS RN:75-91-2
Catalysts Iodine, CAS RN:7553-56-2
Solvents Water, CAS RN:7732-18-5
Dimethylacetamide, CAS RN:127-19-5
Procedure 1. Heat corresponding benzoquinone (0.2 mmol), phenylglycine (0.3 mmol), I2 (25.4 mg, 0.1 mmol)
and TBHP (55 µL of 70 % aqueous solution, 0.4 mmol) in DMA (0.5 mL) at 80 °C for 18 hours in a
sealed tube.
2. Monitor the completion of the reaction by TLC.
3. Purify the residue by column chromatography over silica gel to obtain 4-ethyl-2-phenylquinazoline.
Transformation Addition of Amines to Aldehydes, Ketones or Thiocarbonyls
1H NMR (300 MHz, CDCl3) δ (ppm) 8.68-8.64 (m, 2 H), 8.13-8.06(m, 2 H), 7.88-7.81 (m, 1 H), 7.60-7.48 (m, 4
H), 3.38 (q, J = 7.5 Hz, 2 H), 1.54 (t, J =7.5 Hz, 3 H)
13C NMR (75 MHz, CDCl3) δ (ppm) 172.2, 160.2, 150.7, 138.6, 133.4,130.5, 129.5, 128.7, 128.6, 126.9, 124.6,
122.4, 27.8, 12.5
HRMS calc. C16H14N2: 234.1157, found:234.1156
State light yellow solid
Number
20. Single Step
88%
Overview
Steps/Stages Notes
1.1 R:I2, S:DMSO, 45 min, 110°C 1, Stages: 2, Most stages in any one step: 2
1.2 15 min, 100°C
References
One-pot total synthesis: the first total
synthesis of chiral alkaloid pimprinol A and
the facile construction of its natural congeners
from amino acids
By Xiang, Jiachen et al
Reaction Protocol
Step 1

SciFinder® Page 21
21. Single Step
90%
Overview
Steps/Stages Notes
References
Edition, 52(51), 13651-13655; 2013
Reaction Protocol
Step 1
Products 1-(4-Methoxyphenyl)-3-phenyl-1-propanone, 90%, CAS RN:5739-38-8
4'-Methoxyacetophenone, CAS RN:100-06-1
RN:1221406-59-2
Scale milligram
1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 9.0 Hz, 2H), 7.26-7.11 (m, 5H), 6.86 (d, J = 9.0 Hz, 2H), 3.79 (s, 3H),
3.30 (t, J = 8.0 Hz, 2H), 2.99 (t, J = 8.0 Hz, 2H) ppm.
3
40.1, 30.3 ppm.
SciFinder® Page 22
Number
22. Single Step
85%
Overview
Steps/Stages Notes
step: 1
References
Acid
By Hu, Ting et al
Reaction Protocol
Step 1
23. Single Step
58%
Overview
Steps/Stages Notes
SciFinder® Page 23
in-situ generated key intermediate (α iodinated
1.1 R:Oxone, C:I2, S:DMSO, rt → 95°C; 2-4 h, 95°C compound), Reactants: 2, Reagents: 1,
References
Direct Synthesis of 2,5-Disubstituted
Oxazoles through an Iodine-Catalyzed
Decarboxylative Domino Reaction
By Xu, Wei et al
6065-6074; 2013
General/Typical Procedure: General Experimental Procedure 1 for Preparation of 2-Alkyl-5-aryl
Oxazoles from Aryl Ketones. A solution of the corresponding acetophenone 1 (0.40 mmol, 1 equiv),
the α-amino acid (1.2 mmol, 3 equiv), Oxone (1.2 mmol, 3 equiv), and iodine (0.08 mmol, 0.2 equiv) in
DMSO (3 mL) was heated to 95 °C. The resulting mixture was stirred at 95 °C until the starting
material was completely converted. The reaction mixture was allowed to cool to rt and then treated
with saturated aqueous solutions of Na2S2O3 and NaHCO3. The aqueous phase was extracted with
EtOAc (3 times), and the combined organic layers were dried over anhydrous Na2SO4, filtered, and
concentrated. The residue was purified by flash column chromatography on silica gel. 2-Isopropyl-5-
phenyloxazole (3a): Prepared from acetophenone and valine following general experimental procedure
1. 2-Phenyl-5-(4-methoxyl)oxazole (3i): Prepared from 4-methoxyacetophenone and phenylglycine
following general experimental procedure 1; yield, 58 mg (58%), pale yellow solid; eluent, petroleum
ether/ethyl acetate (8:1). mp 77.0-78.0 °C; 1H NMR (400 MHz, CDCl3) δ 8.09 (dt, J = 8.3, 2.2 Hz, 2H),
7.65-7.63 (m, 2H), 7.48-7.46 (m, 3H), 7.32 (s, 1H), 6.98-6.95 (m, 2H), 3.84 (s, 3H); 13C NMR (101
MHz, CDCl3) δ 160.5, 159.7, 151.2, 130.0, 128.7, 127.5, 126.1, 125.7, 121.8, 120.8, 114.3, 55.3; IR
(neat) 2973, 1498, 1300, 1250, 1021, 951, 823, 772, 705, 614 cm-1; MS (ESI) m/z [M]+ 251.1.
Reaction Protocol
Step 1
24. 2 Steps
[Step 2.1]
SciFinder® Page 24
Overview
Steps/Stages Notes
1) pressure vessel used, control experiments,
1.1 R:I2, 6 h, 110°C 2) alternative preparation shown,
chemoselective, pressure vessel used, control
2.1 R:I2, S:C5H5N, 12 h, 110°C experiments, green chemistry, Reactants: 3,
Reagents: 1, Solvents: 1, Steps: 2, Stages: 2,
References
Step 1
For reaction 1. Acetophenone was treated with 1.0 equivalent of I2 in the absence of an amino acid in
pyridine under the standard condition for 6 h. This reaction produced 1-(2-oxo-2-phenylethyl)pyridin-1-
ium iodide (A) as a undissolved product in excellent yield. (Figure S1 a)
Step 2
Given that the generation of the pyridinium ylide equivalent A would be an inevitable part of this
reaction and pyridine was found to be critical to the success of this transformation, it seemed
reasonable to assume that a pyridinium ylide was formed as a crucial intermediate during this reaction.
The formation of 3q in 71% yield from the reaction of amino acid 1q with A in the absence of
acetophenone provided further proof of this idea. However, that the yield of this reaction was lower
than that of the reaction shown in Scheme 3, which indicated that acetophenone played another role in
the transformation. (Figure S1 b) 2,4,6-triphenylpyridine (3q) Mp = 136-138 °C; 1H NMR (300 MHz,
CDCl3) δ 8.27-8.15 (m, 4H), 7.89 (s, 2H), 7.73-7.77 (m, 2H), 7.45-7.55(m, 9H). 13C NMR (75 MHz,
CDCl3) δ 157.46, 150.27, 139.44, 139.00, 129.11, 129.08, 129.00, 128.70, 127.18, 127.16, 117.18. IR
(KBr): 1604.8217, 1594.08, 1577.98, 1550.14, 1493.32, 1446.48, 1399.63, 1072.97, 1029.93, 869.90,
758.63, 738.25, 691.96, 634.06, 610.85, 575.69. HRMS (ESI): m/z [M+H]+ calcd for C23H18N:
308.1435; found: 308.1434.
Reaction Protocol
Step 1
Step 2
SciFinder® Page 25
25. Single Step
55%
Overview
Steps/Stages Notes
sealed tube used, Reactants: 2, Reagents: 1,
1.1 R:t-BuOOH, C:I2, S:AcNMe2, S:H2O, 4 h, 25°C; 25°C → 60°C; 4 Catalysts: 1, Solvents: 2, Steps: 1, Stages: 1,
h, 60°C Most stages in any one step: 1
References
8/1-8/6, 6 pp.; 2013
Reaction Protocol
Step 1
26. Single Step
98%
Overview
Steps/Stages Notes
SciFinder® Page 26
step: 1
References
Acid
By Hu, Ting et al
Reaction Protocol
Step 1
27. Single Step
97%
Overview
Steps/Stages Notes
step: 1
References
Acid
By Hu, Ting et al
Reaction Protocol
Step 1
SciFinder® Page 27
28. Single Step
92%
Overview
Steps/Stages Notes
step: 1
References
Acid
By Hu, Ting et al
Reaction Protocol
Step 1
29. Single Step
82%
Overview
Steps/Stages Notes
SciFinder® Page 28
step: 1
References
Acid
By Hu, Ting et al
Reaction Protocol
Step 1
30. Single Step
74%
Overview
Steps/Stages Notes
References
By Xu, Wei et al
6065-6074; 2013
SciFinder® Page 29
1. 2-Phenyl-5-(2-naphthyl)oxazole (3s): Prepared from 2-acetylnaphthalene and phenylglycine
following general experimental procedure 1; yield, 80 mg (74%), pale yellow solid; eluent, petroleum
ether/ethyl acetate (8:1). mp 100.0-102.0 °C; 1H NMR (400 MHz, CDCl3) δ 8.18-8.16 (m, 3H), 7.91-
7.83 (m, 3H), 7.76 (dd, J = 8.5, 1.7 Hz, 1H), 7.55-7.47 (m, 6H); 13C NMR (101 MHz, CDCl3) δ 161.2,
151.3, 133.3, 133.0, 130.3, 128.8, 128.7, 128.2, 127.8, 127.4, 126.7, 126.4, 126.3, 125.2, 123.9,
122.8, 122.0; IR (neat) 3091, 1562, 1485, 1137, 973, 891, 857, 819, 744 706, 618 cm-1; MS (EI) m/z
271.1 (100) [M]+.bul., 243.2 (22) [M - CH2N]+.bul., 127.1 (12) [M - C9H6NO]+.bul..
Reaction Protocol
Step 1
31. Single Step
50%
Overview
Steps/Stages Notes
References
By Xu, Wei et al
6065-6074; 2013
SciFinder® Page 30
1. 2-Phenyl-5-(1-naphthyl)oxazole (3t): Prepared from 1-acetylnaphthalene and phenylglycine
following general experimental procedure 1; yield, 54 mg (50%); pale yellow solid; eluent, petroleum
ether/ethyl acetate (15:1). mp 113.0-114.0 °C; 1H NMR (400 MHz, CDCl3) δ 8.39 (d, J = 8.4 Hz, 1H),
8.20-8.17 (m, 2H), 7.92 (t, J = 8.3 Hz, 2H), 7.84 (dd, J = 7.2, 1.1 Hz, 1H), 7.63-7.49 (m, 7H); 13C NMR
(101 MHz, CDCl3) δ 161.5, 150.5, 133.8, 130.4, 130.0, 129.5, 128.8, 128.7, 127.4, 127.1, 126.7, 126.4,
126.3, 126.2, 125.3, 125.3, 124.8; IR (neat) 3053, 1589, 1485, 1397, 1233, 1119, 990, 925, 839, 767,
703, 684, 655, 623, 601 cm-1; MS (EI) m/z 271.1 (100) [M]+.bul., 243.2 (25) [M - CH2N]+.bul..
Reaction Protocol
Step 1
32. Single Step
80%
Overview
Steps/Stages Notes
References
Edition, 52(51), 13651-13655; 2013
Reaction Protocol
Step 1
Products 1-(4-Methoxyphenyl)-2-methyl-3-phenyl-1-propanone, 80%, CAS RN:96519-77-6
4'-Methoxypropiophenone, CAS RN:121-97-1
RN:1221406-59-2
SciFinder® Page 31
Transformation Decarboxylation of Aliphatic Acids
Reduction of the C-N Bond/ Deamination
Scale milligram
1H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 8.9 Hz, 2H), 7.31-7.14 (m, 5H), 6.91 (d, J = 8.9 Hz, 2H), 3.86 (s, 3H),
3.75-3.65 (m, 1H), 3.15 (dd, J = 13.7, 6.5 Hz, 1H), 2.68 (dd, J = 13.7, 6.5 Hz, 1H), 1.19 (d, J = 6.7 Hz,
3H) ppm;.
3
42.3, 39.4, 17.6 ppm.
Number
33. Single Step
74%
Overview
Steps/Stages Notes
chemoselective, pressure vessel used, green
1.1 R:I2, S:C5H5N, 12 h, 120°C chemistry, Reactants: 2, Reagents: 1,
in any one step: 1
References
SciFinder® Page 32
diphenylpyridine (3a) 2,4,6-tris(4-fluorophenyl)pyridine (3t) White crystalline solid (266 mg, 74%); Mp =
221-223 °C; 1H NMR (600 MHz, CDCl3) δ 8.14-8.17 (m, 4H), 7.76 (s, 2H), 7.68-7.70 (m, 2H), 7.17-7.25
(m, 6H). 13C NMR (150 MHz, CDCl3) δ 164.49, 162.84, 156.53, 149.40, 135.39, 134.90, 128.89 (d, J =
8.2 Hz), 116.77-116.52 (m), 116.47, 116.16 (d, J = 21.7 Hz), 115.71, 115.57. IR (KBr): 1657.21,
1609.47, 1548.24, 1511.14, 1426.63, 1384.49, 1295.00, 1223.88, 1155.84, 1098.10, 1011.84, 821.11,
780.34, 581.27, 554.64, 515.05, 439.32. MS: m/z [M] calcd for C23H14F3N, found: 361.22.
Reaction Protocol
Step 1
34. Single Step
86%
Overview
Steps/Stages Notes
References
United Kingdom), 47(33), 9513-9515; 2011
Reaction Protocol
Step 1
Products 4-(1-Methylethyl)-2-phenylquinazoline, 86%, CAS RN:93330-81-5
1-(2-Aminophenyl)-2-methyl-1-propanone, CAS RN:27309-55-3
SciFinder® Page 33
sealed tube.
3. Purify the residue by column chromatography over silica gel to obtain 4-isopropyl-2-
phenylquinazoline.
1H NMR (300 MHz, CDCl3) δ (ppm) 8.70-8.66 (m, 2 H), 8.17-8.07 (m,2 H), 7.87- 7.80 (m, 1 H), 7.59-7.48 (m, 4
H), 4.00-3.90 (m, 1 H), 1.52 (s, 3 H), 1.50 (s,3 H)
13C NMR (75 MHz, CDCl3) δ (ppm) 175.6, 151.1, 138.7, 133.2, 130.5, 129.7,128.7, 128.6, 126.7, 124.2, 121.8,
31.3, 21.9
HRMS calc. C17H16N2: 248.1313, found: 248.1317
State yellow solid
Number
35. Single Step
Overview
Steps/Stages Notes
buffered soln., Reactants: 2, Reagents: 2,
1.1 R:C16H33N+Me3 •Cl-, R:EDTA, C:87251-90-9, S:H2O Catalysts: 1, Solvents: 1, Steps: 1, Stages: 1,
References
Nonenzymic transamination of phenylglycine
with 2-oxoglutaric acid mediated by a micellar
pyridoxal model
By Kondo, Hiroki et al
From Chemistry Letters, (12), 2013-16; 1988
Reaction Protocol
Step 1

SciFinder® Page 34
36. Single Step
51%
Overview
Steps/Stages Notes
References
8/1-8/6, 6 pp.; 2013
Reaction Protocol
Step 1
37. 6 Steps
[Step 2.1] [Step 4.2]

SciFinder® Page 35
[Step 6.1]
Overview
Steps/Stages Notes
4.1 R:BuLi
4.2 1986
5.1 R:KOH, S:H2O, S:MeOH
6.1
Reaction Protocol
Step 1
Step 2
Step 3
Step 4
Step 5
Step 6
38. Single Step
SciFinder® Page 36
99%
Overview
Steps/Stages Notes
step: 1
References
Acid
By Hu, Ting et al
Reaction Protocol
Step 1
39. Single Step
95%
Overview
Steps/Stages Notes
SciFinder® Page 37
step: 1
References
Acid
By Hu, Ting et al
Reaction Protocol
Step 1
40. Single Step
93%
Overview
Steps/Stages Notes
step: 1
References
Acid
By Hu, Ting et al
Reaction Protocol
Step 1
41. Single Step
SciFinder® Page 38
96%
Overview
Steps/Stages Notes
alternative condition may be used, Reactants:
1.1 R:KOH, S:Me2CHOH, 2 h, 55-60°C 2, Reagents: 1, Solvents: 1, Steps: 1, Stages:
References
Technical improvement in the manufacture of
Dane salt, especially (D)-(-)α-phenylglycine or
(D)-(-)-α-4-hydroxyphenylglycine Dane salt
(ethyl or methyl potassium or sodium) at self-
controlled temperature
By Bhagavanta, Hanamapure Basagonda
From Indian Pat. Appl., 2008CH00216, 01
Jun 2012
Reaction Protocol
Step 1
42. Single Step
94%
Overview
Steps/Stages Notes
SciFinder® Page 39
incremental addition of agent, Reactants: 2,
1.1 R:NaOH, S:Me2CHOH, 30 min, rt; 2 h, rt Reagents: 1, Solvents: 1, Steps: 1, Stages: 1,
References
Jun 2012
Reaction Protocol
Step 1
43. 5 Steps (Converging)
Overview
Steps/Stages Notes
SciFinder® Page 40
paraformaldehyde used as reactant,
1.1 R: incremental addition of paraformaldehyde and
ammonium salt, catalyst prepared and used,
94% ee, Michael addition, stereoselective,
Reactants: 5, Reagents: 6, Catalysts: 1,
in any one step: 2
References
Enantioselective synthesis of quaternary ∆4-
R:F3CCO2H, S:THF, 2 h, reflux; reflux → rt; overnight, reflux and ∆5-dehydroprolines based on a two-step
formal [3+2] cycloaddition of α-aryl and α-
1.1 alkyl isocyano(thio)acetates with vinyl ketones
R:HClO4, S:H2O, 0°C; 12 h, rt
By Odriozola, Amaiur et al
1.2 R:K2CO3, S:H2O, pH 9 From Chemistry - A European Journal,
2.1 2 h, 70°C 23(52), 12758-12762; 2017
3.1 R:POCl3, R:i-Pr2NH, S:CH2Cl2, 1.5 h, -30°C

4.1 C:2127845-78-5, S:CH2Cl2, 36 h, rt
Reaction Protocol
Sequence 1
Step 1
Sequence 2
Step 1
Sequence 2
Step 2
Sequence 2
Step 3
Sequence 2
Step 4
44. Single Step
SciFinder® Page 41
76%
Overview
Steps/Stages Notes
References
Edition, 52(51), 13651-13655; 2013
Reaction Protocol
Step 1
Products 1,2,3-Triphenyl-1-propanone, 76%, CAS RN:4842-45-9
2-Phenylacetophenone, CAS RN:451-40-1
RN:1221406-59-2
Scale milligram
1H NMR (400 MHz, CDCl3) δ 7.85-7.30 (m, 6H), 7.21-6.96 (m, 9H), 4.73 (t, J = 7.4 Hz, 1H), 3.49 (dd, J = 13.8,
7.8 Hz, 1H), 2.99 (dd, J = 13.8, 7.8 Hz, 1H) ppm.
13C NMR 13C{1H} NMR (100 MHz, CDCl ) δ 199.3, 139.7, 139.0, 132.8, 129.1, 129.0, 128.8, 128.6, 128.4,
3
128.2, 128.2, 127.1, 126.1, 55.9, 40.1 ppm.
Number
SciFinder® Page 42
45. Single Step
Overview
Steps/Stages Notes
key step, Reactants: 2, Reagents: 2, Solvents:
1.1 R:KOH, S:MeOH 2, Steps: 1, Stages: 2, Most stages in any one
step: 2
1.2 R:AcOH, S:PhMe, S:MeOH
References
Preparation of phenylglycine enamine salts
(Dane salts) as intermediates for β-lactam
antibiotics
By Ban, Karoly et al
From PCT Int. Appl., 9101969, 21 Feb 1991
Reaction Protocol
Step 1
46. 2 Steps
[Step 2.1]
Overview
SciFinder® Page 43
Steps/Stages Notes
1.1 R:NH3, S:H2O, 30 min, -20°C 2, Stages: 2, Most stages in any one step: 1
2.1 R:NaOMe, S:MeOH, 60 min, 60°C References
Process for preparation of sodium (R)-α-((3-
methoxy-1-methyl-3-oxo-1-
propenyl)amino)cyclohexa-1,4-diene-1-
acetate
By Yao, Fengming et al
From Faming Zhuanli Shenqing, 105017049,
04 Nov 2015
Reaction Protocol
Step 1
Step 2
47. 4 Steps
[Step 2.1]
[Step 4.1]
Overview
Steps/Stages Notes
SciFinder® Page 44
4) catalyst prepared and used, 95% ee,
1.1 R:HClO4, S:H2O, 0°C; 12 h, rt Michael addition, stereoselective, Reactants:
4, Reagents: 4, Catalysts: 1, Solvents: 2,
1.2 R:K2CO3, S:H2O, pH 9 Steps: 4, Stages: 5, Most stages in any one
2.1 2 h, 70°C step: 2
3.1 R:POCl3, R:i-Pr2NH, S:CH2Cl2, 1.5 h, -30°C References

4.1 C:2127845-78-5, S:CH2Cl2, 36 h, rt Enantioselective synthesis of quaternary ∆4-
and ∆5-dehydroprolines based on a two-step
alkyl isocyano(thio)acetates with vinyl ketones
From Chemistry - A European Journal,
23(52), 12758-12762; 2017
Reaction Protocol
Step 1
Step 2
Step 3
Step 4
48. 6 Steps
[Step 2.1]
[Step 4.1]
SciFinder® Page 45
Overview
Steps/Stages Notes
1.1 R:HClO4, S:H2O, 0°C; 12 h, rt Michael addition, stereoselective, 6) 94% ee,
stereoselective, Reactants: 4, Reagents: 7,
1.2 R:K2CO3, S:H2O, pH 9 Catalysts: 2, Solvents: 3, Steps: 6, Stages: 8,
2.1 2 h, 70°C Most stages in any one step: 2

5.1 R:HCl, S:H2O, S:EtOH, rt; 1 h, rt formal [3+2] cycloaddition of α-aryl and α-
5.2 R:NH4OH, S:H2O, pH 9-10 By Odriozola, Amaiur et al
6.1 R:H2, C:Pd, S:EtOH, 16 h, rt 23(52), 12758-12762; 2017
Reaction Protocol
Step 1
Step 2
Step 3
Step 4
Step 5
Step 6
49. 5 Steps
[Step 2.1]
SciFinder® Page 46
[Step 4.1]
Overview
Steps/Stages Notes
2.1 2 h, 70°C step: 2

5.1 C:AgF, C:DBU, S:CH2Cl2, 5 h, rt and ∆5-dehydroprolines based on a two-step
23(52), 12758-12762; 2017
Reaction Protocol
Step 1
Step 2
Step 3
Step 4
Step 5
50. 5 Steps
SciFinder® Page 47
[Step 2.1]
[Step 4.1]
Overview
Steps/Stages Notes
2.1 2 h, 70°C step: 2

23(52), 12758-12762; 2017
Reaction Protocol
Step 1
Step 2
Step 3
Step 4
Step 5

SciFinder® Page 48
51. 2 Steps
[Step 2.1]
Overview
Steps/Stages Notes
1) stereoselective, 2) stereoselective,
1.1 R:LiAlH4, S:THF Reactants: 2, Reagents: 3, Solvents: 4, Steps:
1.2 R:NaOH, S:H2O
2.1 S:Benzene References
Asymmetric addition of n-butyllithium to
2.2 R:NaBH4, S:EtOH aldehydes: new insights into the reactivity and
enantioselectivity of the chiral amino ether
By Granander, Johan et al
Reaction Protocol
Step 1
Step 2
52. 2 Steps
[Step 2.1]
SciFinder® Page 49
Overview
Steps/Stages Notes
2) regioselective, bicarbonate stage 2,
1.1 R:SOCl2, S:MeOH Reactants: 3, Reagents: 3, Solvents: 4, Steps:
1.2 R:NH4OH, S:H2O
References
1.3 R:LiAlH4, S:THF Structure-activity relationship of
1.4 S:EtOH dihydroimidazo-, dihydropyrimido,
2.1 S:EtOH, heated tetrahydrodiazepino-[2,1-b]-thiazoles, and -
2.2 S:H2O, neutralized benzothiazoles as an acylation catalyst
By Okamoto, Sentaro et al
From Tetrahedron Letters, 55(11), 1909-
1912; 2014
Reaction Protocol
Step 1
Products 2-Imidazolidinethione, 4-phenyl-, (4R)-, CAS RN:1580490-75-0
Reactants (-)-Phenylglycine, CAS RN:875-74-1
Carbon disulfide, CAS RN:75-15-0
Reagents Thionyl chloride, CAS RN:7719-09-7
Ammonium hydroxide, CAS RN:1336-21-6
Lithium aluminum hydride, CAS RN:16853-85-3
Tetrahydrofuran, CAS RN:109-99-9
Ethanol, CAS RN:64-17-5
Procedure 1. Obtain chiral 2-phenyl substituted nonbenzo analogues from a-bromoacetophenone and (R)-4-
phenylimidazolidine-2-thione and (R)-4-phenylimidazolidine-2-thione.
Number
Step 2
Products Imidazo[2,1-b]thiazole, 5,6-dihydro-3,6-diphenyl-, (6R)-, 38%, CAS RN:1580490-39-6
Reactants 2-Imidazolidinethione, 4-phenyl-, (4R)-, CAS RN:1580490-75-0
Phenacyl bromide, CAS RN:70-11-1
Solvents Ethanol, CAS RN:64-17-5
Procedure 1. Obtain chiral 2-phenyl substituted nonbenzo analogue from a-bromoacetophenone and (R)-4-
Number
53. Single Step
SciFinder® Page 50
90%
Overview
Steps/Stages Notes
step: 1
References
Acid
By Hu, Ting et al
Reaction Protocol
Step 1
54. 3 Steps
[Step 3.1]
Overview
Steps/Stages Notes
SciFinder® Page 51
3) H-Y Zeolite used as catalyst, Reactants: 3,
1.1 R:SOCl2, 30 h, cooled Reagents: 2, Solvents: 2, Steps: 3, Stages: 4,
1.2 16 h, reflux Most stages in any one step: 2
2.1 R:NH3, S:H2O, 16 h, rt References
3.1 S:MeOH, 24 h, reflux Imidazolinone derivatives as CGRP receptor
antagonists
By Selnick, Harold G. et al
From PCT Int. Appl., 2010077752, 08 Jul
2010
Step 1
3-phenyl-1,4-diazaspiro[4.5]dec-3-en-2-one. Step A. 2-amino-2-phenylacetamide hydrochloride. To
ice-chilled methanol (300 mL) under argon, thionyl chloride (50 mL, 660 mmol) was carefully added
dropwise over 30min. Then, phenylglycine (50 g, 330 mmol) was added. The ice-bath was removed
and the reaction mixture was heated to reflux for 16h. The reaction was then evaporated under
reduced pressure. Diethyl ether (200 mL) was added followed by filtration to give the product provided
as the hydrochloride salt. 1H NMR (DMSO-d6, 400 MHz) δ: 9.24 (s, 3H), 7.49~7.51 (m, 2H), 7.40~7.41
(m, 3H), 5.20 (s, 1H), 3.65 (s, 3H).
Step 2
Step B. 2-amino-2-phenylacetamide hydrochloride. Phenylglycine methyl ester hydrochloride from
Step A. (64 g, 317 mmol) was dissolved in ammonia (150 mL) and stirred at room temperature under
argon for 16h. The reaction mixture was extracted with DCM (200 mL × 3), dried over Na2SO4 and
evaporated under reduced pressure to a white solid which was dried under reduced pressure to afford
The product. 1H NMR: (DMSO-d6, 400 MHz) δ: 7.50 (s, 1H), 7.19~7.48 (m, 5H), 7.02 (s, 1H), 4.28 (s,
1H).
Step 3
Step C. 3-phenyl-1,4-diazaspiro[4.5]decan-2-one. To the product of step B above (0.5 g, 3.3 mmol) in
methanol was added cyclohexanone (0.32 g, 3.3 mmol) and H-Y Zeolizes (1.0 g), and the mixture
stirred under reflux for 24 h under argon. The reaction was allowed to cool to room temperature and
was filtered and the solid washed well with methanol. The filtrate was evaporated to afford the title
compound as a white solid, after trituration with hexane (0.52 g, yield: 68%). 1H NMR (DMSO-d6, 400
MHz) δ: 8.57 (s, 1H), 7.36-7.46 (m, 2H), 7.20~7.33 (m, 3H), 4.55 (d, J = 11.6 Hz, 1H), 3.34 (d, J = 12
Hz, 1H), 1.35-1.92 (m, 10H).
Reaction Protocol
Step 1
Step 2
Step 3
55. 4 Steps
SciFinder® Page 52
[Step 3.1]
Overview
Steps/Stages Notes
3) H-Y Zeolite used as catalyst, Reactants: 3,
1.1 R:SOCl2, 30 h, cooled Reagents: 4, Solvents: 3, Steps: 4, Stages: 6,
1.2 16 h, reflux Most stages in any one step: 2
antagonists
4.1 R:Bromosuccinimide, S:CH2Cl2, 16 h, rt
4.2 R:NaHCO3, S:H2O, 1 h, rt From PCT Int. Appl., 2010077752, 08 Jul
2010
Step 1
(m, 3H), 5.20 (s, 1H), 3.65 (s, 3H).
Step 2
1H).
Step 3
Step C. 3-phenyl-1,4-diazaspiro[4.5]decan-2-one. To the product of step B above (0.5 g, 3.3 mmol) in
methanol was added cyclohexanone (0.32 g, 3.3 mmol) and H-Y Zeolizes (1.0 g), and the mixture
stirred under reflux for 24 h under argon. The reaction was allowed to cool to room temperature and
was filtered and the solid washed well with methanol. The filtrate was evaporated to afford the title
compound as a white solid, after trituration with hexane (0.52 g, yield: 68%). 1H NMR (DMSO-d6, 400
MHz) δ: 8.57 (s, 1H), 7.36-7.46 (m, 2H), 7.20~7.33 (m, 3H), 4.55 (d, J = 11.6 Hz, 1H), 3.34 (d, J = 12
Hz, 1H), 1.35-1.92 (m, 10H).
SciFinder® Page 53
Step 4
Step D. 3-phenyl-1,4-diazaspiro[4.5]dec-3-en-2-one. From Step C above (3 g, 13 mmol) was dissolved
in DCM and was stirred at room temperature for 16h under argon atmosphere with N-
Bromosuccinimide (2.3 g, 13 mmol). A solution of saturated sodium bicarbonate was added and
stirring continued for 1h at room temperature. The organic layer was separated, dried and evaporated
under reduced pressure to yield the the product as a white solid after trituration with hexane (2.8 g,
yield: 96.5%). 1H NMR (DMSO-d6, 400 MHz) δ: 10.20 (s, 1H), 8.28 (t, J = 8 Hz,2H), 7.44-7.52 (m, 3H),
1.44-1.75 (m, 10H).
Reaction Protocol
Step 1
Step 2
Step 3
Step 4
56. Single Step
85%
Overview
Steps/Stages Notes
References
United Kingdom), 47(33), 9513-9515; 2011
Reaction Protocol
SciFinder® Page 54
Step 1
Products 4-(1,1-Dimethylethyl)-2-phenylquinazoline, 85%, CAS RN:1229609-94-2
1-(2-Aminophenyl)-2,2-dimethyl-1-propanone, CAS RN:65374-14-3
Procedure 1. Heat corresponding benzoquinone (0.2 mmol), phenylglycine ( 0.3 mmol), I2 (25.4 mg, 0.1 mmol)
sealed tube.
3. Purify the residue by column chromatography over silica gel to obtain 4-tert-butyl-2-
phenylquinazoline.
1H NMR (400 MHz, CDCl3) δ (ppm) 8.70-8.66 (m, 2 H), 8.44 (dd, J1 =8.8 Hz, J2 = 0.8 Hz, 1 H), 8.11 (dd, J1 =
8.4 Hz, J2 = 0.4 Hz, 1 H), 7.82-7.78 (m, 1 H),7.55-7.48 (m, 4 H), 1.72 (s, 9 H)
13C NMR (100 MHz, CDCl3) δ (ppm) 176.5, 159.0,152.2, 138.7, 132.4, 130.52, 130.48, 128.7, 128.6, 126.6,
125.7, 121.7, 40.7, 30.8
State yellow solid
Number
Overview
SciFinder® Page 55
Steps/Stages Notes
1.1 R:F3CCO2H, R:i-Pr2NH, S:THF, 6 h, reflux; overnight, reflux paraformaldehyde used, incremental addition
of paraformaldehyde, Michael addition,
1.1 R:NaOH, S:H2O, S:MeCN, 0°C; 2 h, 0°C; 0°C → rt; 1 h, rt Reactants: 4, Reagents: 5, Catalysts: 1,
2.1 R:DCC, S:CH2Cl2, 0°C; 0°C → rt; 20 h, rt in any one step: 2
3.1 C:916665-69-5, S:CH2Cl2, rt
References
3.2 R:HCl, S:H2O, rt Enantioselective Construction of
Tetrasubstituted Stereogenic Carbons
through Bronsted Base Catalyzed Michael
Reactions: α'-Hydroxy Enones as Key Enoate
Equivalent
By Badiola, Eider et al
From Journal of the American Chemical
Society, 136(51), 17869-17881; 2014
Sequence 1
Step 1
METHOD B: Commercially available 3-hydroxy-3-methyl-2-butanone (1 equiv., 5.3 mL, 50 mmol) and
paraformaldehyde (2 equiv., 3 g, 100 mmol) were added to a solution of iPr2NH (2 equiv., 14.0 mL, 100
mmol) and TFA (2.5 equiv., 9.6 mL, 125 mmol) in THF (250 mL). The mixture was refluxed and
paraformaldehyde (2 equiv., 3 g, 100 mmol) was added every 2 h three times. The mixture was stirred
at reflux overnight and then was cooled to room temperature. CH2Cl2 (100 mL) was added and the
mixture was washed with 1N HCl (75 mL), 1N NaOH (75 mL) and brine (75 mL), and the organic layer
was dried over MgSO4. The solvent was removed under reduced pressure (230 mbar/bath 40 °C). The
residue was purified by flash column chromatography on silica gel (eluent: diethyl ether) to give
product. 4-hydroxy-4-methylpent1-en-3-one (1), Yield: 5.0 g, 44.5 mmol, 89%, colorless oil. b.p. 45°C
(13 mmHg); IR (neat, cm-1) 3445 (OH), 1693 (C=O); 1H NMR (CDCl3) δ 6.73 (dd, 1H, CH, J = 9.5 Hz,
J' = 16.8 Hz), 6.50 (dd, 1H, HCH, J = 2.2 Hz, J' = 16.8 Hz), 5.82 (dd, 1H, HCH, J = 2.2 Hz, J' = 10.3
Hz), 1.38 (s, 6H, 2CH3); 13C NMR (CDCl3) δ 202.3, 131.1, 128.8, 75.4, 26.1.
Sequence 2
Step 1
Procedure Unavailable
Step 2
Step 3
Reaction Protocol
Sequence 1
Step 1
Products 4-Hydroxy-4-methyl-1-penten-3-one, 89%, CAS RN:22082-43-5
Reactants 3-Hydroxy-3-methyl-2-butanone, CAS RN:115-22-0
Formaldehyde, CAS RN:50-00-0
Reagents Trifluoroacetic acid, CAS RN:76-05-1
Diisopropylamine, CAS RN:108-18-9
Procedure 1. Add commercially available 3-hydroxy-3-methyl-2-butanone ( 1 equiv., 5.3 mL, 50 mmol ) and
paraformaldehyde ( 2 equiv., 3 g, 100 mmol ) to a solution of iPr2NH ( 2 equiv., 14.0 mL, 100 mmol )
and TFA ( 2.5 equiv., 9.6 mL, 125 mmol ) in THF ( 250 mL ) .
2. Reflux the mixture and add paraformaldehyde ( 2 equiv., 3 g, 100 mmol ) every 2 hours three times.
3. Stir the mixture at reflux overnight and cool to room temperature.
4. Add CH2Cl2 ( 100 mL ) and wash the mixture with 1N HCl ( 75 mL ) , 1N NaOH ( 75 mL ) and brine (
75 mL ) , and dry the organic layer over MgSO4.
5. Remove the solvent under reduced pressure ( 230 mbar/bath 40 °C ) .
6. Purify the residue by flash column chromatography on silica gel ( eluent: diethyl ether ) to obtain
product.
Scale gram
1H NMR ( CDCl3 ) δ 6.73 ( dd, 1H, CH, J = 9.5 Hz, J' = 16.8 Hz ) , 6.50 ( dd, 1H, HCH, J = 2.2 Hz, J' = 16.8 Hz )
, 5.82 ( dd, 1H, HCH, J = 2.2 Hz, J' = 10.3 Hz ) , 1.38 ( s, 6H, 2CH3 ) ;
13C NMR ( CDCl3 ) δ 202.3, 131.1, 128.8, 75.4, 26.1.
IR ( neat, cm-1 ) 3445 ( OH ) , 1693 ( C=O ) ;
SciFinder® Page 56
BP 45°C ( 13 mmHg ) ;
State colorless oil
Number
Sequence 2
Step 1
Products α-(Benzoylamino)benzeneacetic acid, 80%, CAS RN:29670-63-1
Benzoyl chloride, CAS RN:98-88-4
Reagents Sodium hydroxide, CAS RN:1310-73-2
Acetonitrile, CAS RN:75-05-8
Procedure 1. Dissolve D, L-Phenylglycine ( 1.51 g, 10 mmol ) and NaOH ( 1.62 g, 40 mmol ) in H2O/CH3CN (
75/25, 0.3 M ) .
2. Cool to 0 °C, benzoyl chloride ( 1.22 mL, 10.5 mmol ) dropwise at this temperature.
3. Stir the mixture for additional 2 hours at 0 °C.
4. Allow the mixture to warm to room temperature and stir for one additional hour.
5. Remove all volatiles under reduced pressure, add concentrated HCl to cause precipitation.
6. Filter the mixture and wash the filter cake with ice-cold diethylether.
Scale gram
1H NMR ( 300 MHz, CDCl3 ) , δ: 7.86 - 7.77 ( m, 2H ) , 7.57 - 7.32 ( m, 8H ) , 7.08 ( d, J = 7.0 Hz, 1H ) , 5.80 ( d,
J = 6.7 Hz, 1H ) .
State white solid
Number
Sequence 2
Step 2
Products 2,4-Diphenyl-5(4H)-oxazolone, 62%, CAS RN:28687-81-2
Reactants α-(Benzoylamino)benzeneacetic acid, CAS RN:29670-63-1
Reagents Dicyclohexylcarbodiimide, CAS RN:538-75-0
Solvents Dichloromethane, CAS RN:75-09-2
Procedure 1. Suspend N-benzoyl-D, L-phenylglycine ( 1.28 g, 5 mmol ) in CH2Cl2 ( 50 mL, 10 mL/mmol ) .
2. Cool the mixture to 0 °C and add DCC ( 1.08 g, 5.25 mmol, 1.05 equiv. ) portionwise.
3. Allow the mixture to warm to room temperature and stir for additional 20 hours at this temperature.
4. Filter a precipitate and concentrate the filtrate in vacuo.
5. Purify the product by silica gel column chromatography using hexane/ethyl acetate ( 95:5 ) .
Scale milligram
1H NMR ( 300 MHz, CDCl3 ) , δ: 8.24 - 7.94 ( m, 2H ) , 7.67 - 7.49 ( m, 3H ) , 7.48 - 7.34 ( m, 5H ) , 5.53 ( s, 1H
).
13C NMR ( 75 MHz, CDCl3 ) , δ: 176.4, 162.8, 133.6, 133.3, 129.1, 129.1, 128.9, 128.8, 128.3, 127.6, 127.4,
127.0, 68.3.
Mass Spec UPLC-DAD-QTOF: C15H12NO2 [M+H]+ calcd.: 238.0863, found: 238.0860.
MP 104-105 °C.
State yellow solid
Number
Sequence 2
Step 3
Products 5(4H)-Oxazolone, 4-(4-hydroxy-4-methyl-3-oxopentyl)-2,4-diphenyl-, CAS RN:1639968-09-4
Reactants 2,4-Diphenyl-5(4H)-oxazolone, CAS RN:28687-81-2
4-Hydroxy-4-methyl-1-penten-3-one, CAS RN:22082-43-5
Reagents Hydrochloric acid, CAS RN:7647-01-0
Catalysts N-[3,5-Bis(trifluoromethyl)phenyl]-N'-[2-(dimethylamino)ethyl]thiourea, CAS RN:916665-69-5
SciFinder® Page 57
Procedure 1. Add the achiral thiourea catalyst to a mixture of azlactone ( 1 eq., 0.2 mmol ) and the α'-hidroxy
enone ( 1.5 eq., 0.3 mmol ) in dichloromethane ( 0.4 mL ) at room temperature.
2. Stir the mixture at the same temperature, until consumption of the azlactone ( monitor by 1H-NMR )
.
3. Quench the reaction mixture with 1M HCl ( 10 mL ) and extract the aqueous layer with CH2Cl2 ( 3 ×
20 mL ) .
4. Dry the combined organic layers over MgSO4, filter and evaporate the solvent under reduced
pressure.
5. Purify the crude by flash column chromatography on silica gel to obtain the product.
Number
Overview
Steps/Stages Notes
SciFinder® Page 58
1.1 R:HBr, R:NaNO2, S:H2O, 0°C; 2.5 h, rt paraformaldehyde used, incremental addition
of paraformaldehyde, Michael addition,
2.1 R:H2SO4, S:MeOH, 1 h, reflux Reactants: 5, Reagents: 6, Catalysts: 1,
3.1 R:C5H5N, rt → 110°C; 3 h, 100-110°C in any one step: 2
3.2 S:EtOH, 30 min, rt
References
1.1 R:F3CCO2H, R:i-Pr2NH, S:THF, 6 h, reflux; overnight, reflux Enantioselective Construction of
2.1 C:Et3N, 0°C Tetrasubstituted Stereogenic Carbons
Equivalent
Society, 136(51), 17869-17881; 2014
Sequence 1
Step 1
The corresponding amino acid (40 mmol, 1 equiv.) is solubilized in 48% HBr (40 mL) and 36 mL water.
The reaction mixture is cooled to 0 °C and a solution of NaNO2 (4.4 g, 64 mmol, 1.6 equiv.) in 10 mL
water was added dropwise. The mixture was stirred for 2.5 h at room temperature, then concentrated
to remove acid vapor, and extracted with Et2O (4 × 10 mL). The organic layers were washed with
water, brine, dried over MgSO4, and concentrated under reduced pressure. α-bromophenylacetic acid.
Step 2
Step 3
General/Typical Procedure: A mixture of the corresponding α-bromo methyl ester (1.1 equiv.),
thioamide (1 equiv.) and pyridine (1 equiv.) was stirred under argon and slowly heated to 100-110 °C
until the mixture solidified. After 3 h, ethanol (15 mL) was added and the mixture was stirred at room
temperature for 30 min. After filtration the crude product was washed with ethanol. 2,5-Diphenylthiazol-
4-ol (25f). The title compound 25f was prepared from methyl 2-bromo-2-phenylacetate (2.5 g, 11
mmol) and thioamide (1.4 g, 10 mmol) according to the general procedure B. The resulting solid was
washed with ethanol. Yellow solid; yield: 1.9 g, 7.7 mmol, 77%. m. p. 214-216 °C. 1H NMR (300 MHz,
CDCl3), δ: 8.01 - 7.90 (m, 2H), 7.89 - 7.79 (m, 2H), 7.54 - 7.32 (m, 6H). 13C NMR (75 MHz, CDCl3), δ:
145.8, 141.4, 129.8, 128.8, 128.5, 127.1, 126.4, 126.1, 125.5, 109.5. UPLC-DAD-QTOF: C15H12NOS
[M+H]+ calcd.:254.0640, found:254.0647.
Sequence 2
Step 1
METHOD B: Commercially available 3-hydroxy-3-methyl-2-butanone (1 equiv., 5.3 mL, 50 mmol) and
paraformaldehyde (2 equiv., 3 g, 100 mmol) were added to a solution of iPr2NH (2 equiv., 14.0 mL, 100
mmol) and TFA (2.5 equiv., 9.6 mL, 125 mmol) in THF (250 mL). The mixture was refluxed and
paraformaldehyde (2 equiv., 3 g, 100 mmol) was added every 2 h three times. The mixture was stirred
at reflux overnight and then was cooled to room temperature. CH2Cl2 (100 mL) was added and the
mixture was washed with 1N HCl (75 mL), 1N NaOH (75 mL) and brine (75 mL), and the organic layer
was dried over MgSO4. The solvent was removed under reduced pressure (230 mbar/bath 40 °C). The
residue was purified by flash column chromatography on silica gel (eluent: diethyl ether) to give
product. 4-hydroxy-4-methylpent1-en-3-one (1), Yield: 5.0 g, 44.5 mmol, 89%, colorless oil. b.p. 45°C
(13 mmHg); IR (neat, cm-1) 3445 (OH), 1693 (C=O); 1H NMR (CDCl3) δ 6.73 (dd, 1H, CH, J = 9.5 Hz,
J' = 16.8 Hz), 6.50 (dd, 1H, HCH, J = 2.2 Hz, J' = 16.8 Hz), 5.82 (dd, 1H, HCH, J = 2.2 Hz, J' = 10.3
Hz), 1.38 (s, 6H, 2CH3); 13C NMR (CDCl3) δ 202.3, 131.1, 128.8, 75.4, 26.1.
Step 2
To a mixture of the corresponding 4-hydroxy-4-methylpent-1-en-3-one (1 equiv., 0.3 mmol) and enone
2 (3.0/1.5 equiv., 0.6/0.45 mmol), in dichloromethane (0.9 mL) at 0 °C, the catalyst TEA (20 mol%,
0.06 mmol, 38 mg) was added. The resulting suspension was stirred at the same temperature, until
consumption of the thiazolone (monitored by 1H-NMR). Then, 3 mL of methanol and 0.6 mL of HF
48% were added at the corresponding temperature and the mixture was warmed to room temperature
and stirred for 45 min. The reaction was treated at 0 °C with saturated aqueous solution of NaHCO3
until neutralization. The product was extracted from the aq. phase with CH2Cl2 and the combined
organic phases were dried with MgSO4. Evaporation of the solvent under reduced pressure gave the
crude product, which was purified by flash column chromatography (eluting with hexane/ethyl acetate
80/20). 5-(4-Hydroxy-4-methyl-3-oxopentyl)-2,5-diphenylthiazol-4(5H)-one (27f) (racemic).
Reaction Protocol
Sequence 1
Step 1
Products Bromophenylacetic acid, CAS RN:4870-65-9
SciFinder® Page 59
Reagents Hydrogen bromide, CAS RN:10035-10-6
Sodium nitrite, CAS RN:7632-00-0
Procedure 1. Solubilize the amino acid ( 40 mmol, 1 equiv. ) in 48% HBr ( 40 mL ) and 36 mL water.
2. Cool the reaction mixture to 0 °C and add a solution of NaNO2 ( 4.4 g, 64 mmol, 1.6 equiv. ) in 10
mL water dropwise.
3. Stir the mixture for 2.5 hours at room temperature, concentrate to remove acid vapor and extract
with Et2O ( 4 × 10 mL ) .
4. Wash the organic layers with water, brine.
5. Dry over MgSO4 and concentrate under reduced pressure.
Number
Sequence 1
Step 2
Products Benzeneacetic acid, α-bromo-, methyl ester, CAS RN:3042-81-7
Reactants Bromophenylacetic acid, CAS RN:4870-65-9
Reagents Sulfuric acid, CAS RN:7664-93-9
Procedure 1. Treat the α-bromoacid with a solution of concentrated sulphuric acid ( 30 µL/mmol ) in methanol ( 2
mL/mmol ) and reflux for one hour.
2. Cool the solution to room temperature and concentrate in vacuo.
3. Add Et2O and wash the organic layer with 5% aqueous solution of NaHCO3 and brine.
4. Dry over MgSO4 and concentrate in vacuo.
Number
Sequence 1
Step 3
Products 2,5-Diphenyl-4-thiazolol, 77%, CAS RN:59484-42-3
Reactants Benzeneacetic acid, α-bromo-, methyl ester, CAS RN:3042-81-7
Thiobenzamide, CAS RN:2227-79-4
Reagents Pyridine, CAS RN:110-86-1
Procedure 1. Stir a mixture of the methyl 2-bromo-2-phenylacetate ( 2.5 g, 11 mmol ) , thioamide ( 1.4 g, 10 mmol
) and pyridine ( 1 equiv. ) under argon and heat slowly to 100-110 °C until solidifying the mixture.
2. Add ethanol ( 15 mL ) , after 3 hours and stir the mixture at room temperature for 30 minutes.
3. Filter and wash the crude product with ethanol.
Scale gram
1H NMR ( 300 MHz, CDCl3 ) , δ: 8.01 - 7.90 ( m, 2H ) , 7.89 - 7.79 ( m, 2H ) , 7.54 - 7.32 ( m, 6H ) .
13C NMR ( 75 MHz, CDCl3 ) , δ: 145.8, 141.4, 129.8, 128.8, 128.5, 127.1, 126.4, 126.1, 125.5, 109.5.
Mass Spec UPLC-DAD-QTOF: C15H12NOS [M+H]+ calcd.:254.0640, found:254.0647.
MP 214-216 °C.
State yellow solid
Number
Sequence 2
Step 1
Products 4-Hydroxy-4-methyl-1-penten-3-one, 89%, CAS RN:22082-43-5
Reactants 3-Hydroxy-3-methyl-2-butanone, CAS RN:115-22-0
Formaldehyde, CAS RN:50-00-0
Reagents Trifluoroacetic acid, CAS RN:76-05-1
Diisopropylamine, CAS RN:108-18-9
SciFinder® Page 60
Procedure 1. Add commercially available 3-hydroxy-3-methyl-2-butanone ( 1 equiv., 5.3 mL, 50 mmol ) and
paraformaldehyde ( 2 equiv., 3 g, 100 mmol ) to a solution of iPr2NH ( 2 equiv., 14.0 mL, 100 mmol )
and TFA ( 2.5 equiv., 9.6 mL, 125 mmol ) in THF ( 250 mL ) .
2. Reflux the mixture and add paraformaldehyde ( 2 equiv., 3 g, 100 mmol ) every 2 hours three times.
3. Stir the mixture at reflux overnight and cool to room temperature.
4. Add CH2Cl2 ( 100 mL ) and wash the mixture with 1N HCl ( 75 mL ) , 1N NaOH ( 75 mL ) and brine (
75 mL ) , and dry the organic layer over MgSO4.
5. Remove the solvent under reduced pressure ( 230 mbar/bath 40 °C ) .
6. Purify the residue by flash column chromatography on silica gel ( eluent: diethyl ether ) to obtain
product.
Scale gram
1H NMR ( CDCl3 ) δ 6.73 ( dd, 1H, CH, J = 9.5 Hz, J' = 16.8 Hz ) , 6.50 ( dd, 1H, HCH, J = 2.2 Hz, J' = 16.8 Hz )
, 5.82 ( dd, 1H, HCH, J = 2.2 Hz, J' = 10.3 Hz ) , 1.38 ( s, 6H, 2CH3 ) ;
13C NMR ( CDCl3 ) δ 202.3, 131.1, 128.8, 75.4, 26.1.
IR ( neat, cm-1 ) 3445 ( OH ) , 1693 ( C=O ) ;
BP 45°C ( 13 mmHg ) ;
State colorless oil
Number
Sequence 2
Step 2
Products 4(5H)-Thiazolone, 5-(4-hydroxy-4-methyl-3-oxopentyl)-2,5-diphenyl-, CAS RN:1639968-03-8
Reactants 4-Hydroxy-4-methyl-1-penten-3-one, CAS RN:22082-43-5
2,5-Diphenyl-4-thiazolol, CAS RN:59484-42-3
Catalysts Triethylamine, CAS RN:121-44-8
Procedure 1. Add the catalyst TEA ( 20 mol%, 0.06 mmol, 38 mg ) to a mixture of 4-hydroxy-4-methylpent-1-en-3-
one ( 1 equiv., 0.3 mmol ) and enone ( 3.0/1.5 equiv., 0.6/0.45 mmol ) , in dichloromethane ( 0.9 mL )
at 0 °C.
2. Stir the resulting suspension at the same temperature, until consumption of the thiazolone ( monitor
by 1H-NMR ) .
3. Add 3 mL of methanol and 0.6 mL of HF 48% at the corresponding temperature.
4. Warm the mixture to room temperature and stir for 45 minutes.
5. Treat the reaction at 0 °C with saturated aqueous solution of NaHCO3 until neutralization.
6. Extract the product from the aqueous phase with CH2Cl2 and dry the combined organic phases with
MgSO4.
7. Evaporate the solvent under reduced pressure to obtain the crude product.
8. Purify by flash column chromatography ( eluting with hexane/ethyl acetate 80/20 ) .
Number
59. Single Step
78%
SciFinder® Page 61
Overview
Steps/Stages Notes
chemoselective, pressure vessel used, green
1.1 R:I2, S:C5H5N, 12 h, 120°C chemistry, Reactants: 2, Reagents: 1,
in any one step: 1
References
diphenylpyridine (3a) 4-(2-chlorophenyl)-2,6-diphenylpyridine (3r) Yellow oil (266 mg, 78%); 1H NMR
(600 MHz, CDCl3) δ 8.19 (d, J = 7.8 Hz, 4H), 7.78 (s, 2H), 7.56 -7.53 (m, 1H), 7.49-7.52 (m, 4H), 7.42-
7.45 (m, 3H), 7.40-7.36 (m, 2H). 13C NMR (150 MHz, CDCl3) δ 156.81, 148.62, 139.20, 138.40,
132.24, 130.87, 130.26, 129.69, 129.10, 128.68, 127.12, 119.51. IR (KBr): 3060.14, 1684.99, 1602.66,
1544.21, 1475.48, 1443.16, 1397.74, 1262.86, 1033.15, 880.37, 804.19, 755.84, 690.72, 629.38.
HRMS (ESI): m/z [M+H]+ calcd for C23H17NCl: 342.1048; found: 342.1044.
Reaction Protocol
Step 1
60. Single Step
96%
Overview
Steps/Stages Notes
SciFinder® Page 62
exothermic, Reactants: 2, Reagents: 1,
1.1 R:KOH, S:Me2CHOH, rt → 60°C; 2 h, 55-60°C Solvents: 1, Steps: 1, Stages: 1, Most stages
in any one step: 1
References
Jun 2012
Reaction Protocol
Step 1
61. Single Step
97%
Overview
Steps/Stages Notes
1.1 R:KOH, S:MeOH, S:PhMe, 80°C; reflux 1, Stages: 2, Most stages in any one step: 2
1.2 S:Me2CHOH, 2 h, 0-5°C
References
Method for preparing phenylglycine Dane salt
By Sun, Haiquan
10 Mar 2010
Reaction Protocol
Step 1
62. Single Step
SciFinder® Page 63
96%
Overview
Steps/Stages Notes
Dane salt formation; neutralization at 40-50°
1.1 R:KOH, S:Me2CHOH for ∼20 min; condensation under reflux for 1 h,
1.2 1, Stages: 2, Most stages in any one step: 2
References
Method for preparation of protected amino
acid salts
By Arai, Toshiaki et al
From Jpn. Kokai Tokkyo Koho, 2001348365,
18 Dec 2001
Example 1 D-(-)Phenyl glycine 151.2 g (1.0 mol), 96% potassium hydroxide 57.0 g (0.98
mol),isopropanol (containing ~3% moisture) 1200 ml were added to a 2L four-necked flask, heated to
40~50°C internal temperature and stirred for ~20 minutes. While measuring the pH by pH meter
{manufactured by Radio East Asia Co., Ltd., portable digital pH meter HM-10P,electrode;
GST142C}potassium hydroxide (~1.5 g) was slowly added and completely dissolved. When a
neutralization curve was drawn (as shown in figure 1),polarization potential inflection point
(neutralization point) could be found, addition of D-phenylglycine and potassium hydroxide were
adjusted to this polarization potential inflection point and potassium salt was synthesized. Further,
ethyl acetoacetate 136.6 g (1.05 mol) was added in to the solution obtained and refluxed for 1 hour.
Then, it was cooled to 25°C, precipitated crystals were collected by filtration, washed with isopropanol
450 ml. Primary crystals of potassium (-)-N-(1-ethoxycarbonylpropen-2-yl)-α-amino-α-phenyl acetate
(yield 89%) were obtained. Filtrate and washings were concentrated under normal pressure,
isopropanol 1200 ml was distilled off, residual liquid was cooled to below 25°C,preciptated crystals
were washed with isopropanol 60 ml to obtain secondary crystals (yield 7%). Both primary and
secondary crystals were dried under reduced pressure to obtain 289.3 g crystals (yield 96%).
Reaction Protocol
Step 1
63. Single Step
SciFinder® Page 64
85%
Overview
Steps/Stages Notes
1.1 R:KOH, S:EtOH, heated 1, Stages: 2, Most stages in any one step: 2
1.2 S:EtOH, 1 h, reflux
References
Preparation of spiro and dispiro 1,2,4-
trioxolanes antimalarials
By Vennerstrom, Jonathan L. et al
2009
Step 1. In a 50 ml flask fitted with a reflux condenser (capped with a CaCl2 drying tube) were placed
L(+)-phenylglycine (3.02 g, 20 mmol), KOH (1.45 g, 22 mmol), and absolute ethanol (15 ml). The
mixture was heated until the solution became clear. A solution of ethyl acetoacetate (3.0 g, 23 mmol)
in ethanol (6 ml) was added. The reaction mixture was refluxed for 1 h, cooled to rt, and concentrated
to about 10 mL The precipitate was collected by filtration and washed with cold ethanol to give
potassium L(+)-phenylglycine Dane salt (4.7 g, 85%) as a white powder. 1H NMR (500 MHz, DMSO-
d6) δ 1.16 (t, J=7.0 Hz, 3H), 1.60 (s, 3H), 3.99 (q, J=7.0 Hz, 2H), 4.23 (s, 1H), 4.67 (d, J=6.4 Hz, 1H),
7.15-7.26 (m, 5H) and 9.56 (d, J=6.4 Hz, 1H).
Reaction Protocol
Step 1
64. Single Step
80%
Overview
SciFinder® Page 65
Steps/Stages Notes
1.1 R:KOH, S:EtOH, heated Solvents: 1, Steps: 1, Stages: 2, Most stages
1.2 S:EtOH, 1 h, reflux in any one step: 2
References
Preparation of spiro and dispiro 1,2,4-
trioxolanes antimalarials
By Vennerstrom, Jonathan L. et al
2009
Step 1. In a 50 ml flask fitted with a reflux condenser (capped with a CaCl2 drying tube) were placed D(
)-phenylglycine (3.02 g, 20 mmol), KOH (1.45 g, 22 mmol), and absolute ethanol (15 ml). The mixture
was heated until the solution became clear. A solution of ethyl acetoacetate (3.0 g, 23 mmol) in
ethanol (6 ml) was added. The reaction mixture was refluxed for 1 h, cooled to rt, and concentrated to
about 10 mL The precipitate was collected by filtration and washed with cold ethanol to give potassium
D( )-phenylglycine Dane salt (4.4 g, 80%) as a white powder. 1H NMR (500 MHz, DMSO-d6) δ 1.16 (t,
J=7.0 Hz, 3H), 1.60 (s, 3H), 3.99 (q, J=7.0 Hz, 2H), 4.23 (s, 1H), 4.67 (d, J=6.4 Hz, 1H), 7.15-7.26 (m,
5H) and 9.56 (d, J=6.4 Hz, 1H).
Reaction Protocol
Step 1
65. Single Step
80%
Overview
Steps/Stages Notes
1.1 R:Dicyclohexylamine, S:H2O, S:MeOH, S:EtOH 1, Stages: 1, Most stages in any one step: 1
References
Synthesis and conformational studies in 1-
ethoxy-2-propene (AE)-protected dipeptides
By Panse, G. T. et al
From Indian Journal of Chemistry, Section B:
Organic Chemistry Including Medicinal
Chemistry, 26B(6), 507-10; 1987
Reaction Protocol
Step 1

SciFinder® Page 66
66. Single Step
Overview
Steps/Stages Notes
1.1 R:NaOH, R:AcOH, S:EtOH 1, Stages: 1, Most stages in any one step: 1
References
antibiotics
Reaction Protocol
Step 1
67. Single Step
Overview
Steps/Stages Notes
SciFinder® Page 67
1.1 R:AcONa, S:EtOH 1, Stages: 1, Most stages in any one step: 1
References
antibiotics
Reaction Protocol
Step 1
68. Single Step
Overview
Steps/Stages Notes
1.1 Reactants: 2, Steps: 1, Stages: 1, Most stages
in any one step: 1
References
D-2-Phenylglycine enamine salts
By Lonyai, Peter et al
From Hung. Teljes, 32333, 30 Jul 1984
Reaction Protocol
Step 1
69. Single Step
SciFinder® Page 68
50%
Overview
Steps/Stages Notes
1.1 R:NaOH, C:CuSO4, S:H2O, rt → 50°C; 30 min, 50°C; 50°C → Solvents: 3, Steps: 1, Stages: 5, Most stages
0°C in any one step: 5
References
1.2 R:NaOH, S:H2O, S:MeOH, overnight, rt
Discovery of Nanomolar Dengue and West
1.3 R:8-Quinolinol, S:Me2CO, 3 h, rt Nile Virus Protease Inhibitors Containing a 4-
Benzyloxyphenylglycine Residue
1.4 R:NaOH, S:H2O, basify By Behnam, Mira A. M. et al
From Journal of Medicinal Chemistry, 58(23),
1.5 R:HCl, S:H2O 9354-9370; 2015
A solution of the amino acid (1 equiv) in 1 M NaOH (1 equiv) and a solution of CuSO4·5H2O (0.67
equiv) in water (10 mL) were warmed to 50 °C under stirring. Both solutions were combined, and the
reaction mixture was stirred for 30 min at 50 °C. After cooling on an ice water bath, the blue precipitate
of the amino acid Cu-complex separated immediately. The precipitate was isolated, washed with
water, and dried. The Cu-complex was dissolved in methanol (25 mL) and 1 M NaOH (1 equiv). The
corresponding benzyl or phenacyl bromide (1.1 equiv) was added, and the mixture was stirred at room
temperature overnight. The insoluble Cu-complex of the resulting ether was collected by filtration,
washed with MeOH, and then with water to remove excess of the unreacted starting material. Finally, 1
M HCl (2 equiv) was added to release the product from the Cu-complex. The precipitated product was
washed with water and dried under reduced pressure.34 The crude product was used for subsequent
synthetic steps without further purification. An alternative workup using 8-quinolinol37 was employed to
obtain 21a due to the solubility of the Cu-product complex after acidification. To the resulting solution,
8-hydroxyquinoline (0.5 equiv) in acetone was added, and the mixture was stirred at room temperature
for 3 h. The solution was alkalized with 1 M NaOH, and the green precipitate of copper 8-
hydroxyquinolate was removed by filtration. Acetone was evaporated under reduced pressure, and the
solution was acidified using 1 M HCl. After lyophilization, the solid was dissolved in EtOH/ ACN (1:1) to
allow the removal of the insoluble NaCl by filtration. The solvent was evaporated. The amino acid
product, without further purification. (4-Phenacyloxy)-D-phenylglycine (21a). Compound 21a was
obtained according to the general procedure from (4-hydroxy)-D-phenylglycine (502 mg, 3 mmol) and
2-bromoacetophenone (657 mg, 3.3 mmol). A brown solid (484 mg, 50% yield). 1H NMR (300 MHz,
DMSO-d 6/NaOD) δ 7.93 7.78 (m, 2H), 7.36 (dd, J = 8.2, 1.2 Hz, 1H), 7.29 7.17 (m, 2H), 6.72 (d, J =
8.5 Hz, 2H), 6.04 (d, J = 8.4 Hz, 2H), 4.45 (s, 1H), 3.74 (s, 2H). 13C NMR (APT, 75 MHz, DMSO-d 6/
NaOD) δ 200.37, 178.70, 169.42, 131.18, 130.03, 129.11, 128.77, 127.21, 127.19, 126.34, 126.32,
125.71, 117.84, 73.81, 60.80. HRMS (ESI): m/z [M H] calcd for C16H14NO4, 284.0928; found,
284.0929.
Reaction Protocol
Step 1
70. Single Step
SciFinder® Page 69
43%
Overview
Steps/Stages Notes
References
8/1-8/6, 6 pp.; 2013
Reaction Protocol
Step 1
71. 3 Steps
[Step 3.1]
Overview
Steps/Stages Notes
SciFinder® Page 70
3) H-Y Zeolite used as catalyst stage 1,
1.1 R:SOCl2, 30 h, cooled Reactants: 3, Reagents: 4, Solvents: 3, Steps:
1.2 16 h, reflux 3, Stages: 6, Most stages in any one step: 3
antagonists
2010
Step 1
(m, 3H), 5.20 (s, 1H), 3.65 (s, 3H).
Step 2
1H).
Step 3
To the product of step B above (0.5 g, 3.3 mmol) in methanol was added cyclohexanone (0.32 g, 3.3
mmol) and H-Y Zeolizes (1.0 g), and the mixture stirred under reflux for 24 h under argon. The reaction
was allowed to cool to room temperature and was filtered and the solid washed well with methanol.
The filtrate was evaporated to afford the title compound as a white solid, after trituration with hexane.
From Step C above (3 g, 13 mmol) was dissolved in DCM and was stirred at room temperature for 16h
under argon atmosphere with N-Bromosuccinimide (2.3 g, 13 mmol), A solution of saturated sodium
bicarbonate was added and stirring continued for 1h at room temperature. The organic layer was
separated, dried and evaporated under reduced pressure. Intermediate 10-b. 1H NMR (DMSO-d6, 400
MHz) δ: 8.27 (t, J=8.4 Hz, 2H), 7.40-7.52 (m, 3H), 1.50-1.89 (m, 12H).
Reaction Protocol
Step 1
Step 2
Step 3
72. Single Step
SciFinder® Page 71
66%
Overview
Steps/Stages Notes
References
8/1-8/6, 6 pp.; 2013
Reaction Protocol
Step 1
73. Single Step
64%
Overview
Steps/Stages Notes
References
8/1-8/6, 6 pp.; 2013
SciFinder® Page 72
Reaction Protocol
Step 1
74. 4 Steps
[Step 2.1]
[Step 4.1]
Overview
Steps/Stages Notes
2.1 2 h, 70°C step: 2

23(52), 12758-12762; 2017
Reaction Protocol
Step 1
Step 2

SciFinder® Page 73
Step 3
Step 4
75. Single Step
89%
Overview
Steps/Stages Notes
step: 1
References
Acid
By Hu, Ting et al
Reaction Protocol
Step 1
76. 4 Steps
SciFinder® Page 74
[Step 2.1]
[Step 4.1]
Overview
Steps/Stages Notes
2.1 2 h, 70°C step: 2

23(52), 12758-12762; 2017
Reaction Protocol
Step 1
Step 2
Step 3
Step 4

SciFinder® Page 75
77. 5 Steps
[Step 2.1]
[Step 4.1]
Overview
Steps/Stages Notes
2.1 2 h, 70°C step: 2

5.1 R:NaIO4, S:MeOH, S:H2O, 4 h, rt formal [3+2] cycloaddition of α-aryl and α-
23(52), 12758-12762; 2017
Reaction Protocol
Step 1
Step 2
Step 3

SciFinder® Page 76
Step 4
Step 5
78. Single Step
84%
Overview
Steps/Stages Notes
step: 1
References
Acid
By Hu, Ting et al
Reaction Protocol
Step 1
79. Single Step
SciFinder® Page 77
95%
Overview
Steps/Stages Notes
green chem.-waste redn., Reactants: 2,
1.1 R:K2CO3, 4 h, 50°C Reagents: 1, Steps: 1, Stages: 1, Most stages
in any one step: 1
References
Synthesis of phenylglycine derivatives
By Li, Zhongxin et al
28 Jan 2009
Reaction Protocol
Step 1
Overview
Steps/Stages Notes
SciFinder® Page 78
96% ee, Reactants: 5, Reagents: 9, Catalysts:
References
2.1 2 h, 70°C 23(52), 12758-12762; 2017

4.1 C:2127845-78-5, S:CH2Cl2, 36 h, rt
5.1 R:HCl, S:H2O, S:EtOH, rt; 1 h, rt
5.2 R:NH4OH, S:H2O, pH 9-10
6.1 R:H2, C:Pd, S:EtOH, 16 h, rt

Reaction Protocol
Sequence 1
Step 1
Sequence 2
Step 1
Sequence 2
Step 2
Sequence 2
Step 3
Sequence 2
Step 4
Sequence 2
Step 5
Sequence 2
Step 6

SciFinder® Page 79
Overview
Steps/Stages Notes
in any one step: 2
References
2.1 2 h, 70°C 23(52), 12758-12762; 2017

4.1 C:2127845-78-5, S:CH2Cl2, 36 h, rt
5.1 C:AgF, C:DBU, S:CH2Cl2, 5 h, rt
Reaction Protocol
Sequence 1
Step 1
Sequence 2
Step 1

SciFinder® Page 80
Sequence 2
Step 2
Sequence 2
Step 3
Sequence 2
Step 4
Sequence 2
Step 5
Overview
Steps/Stages Notes
SciFinder® Page 81
in any one step: 2
References
2.1 2 h, 70°C 23(52), 12758-12762; 2017

4.1 C:2127845-78-5, S:CH2Cl2, 36 h, rt
5.2 R:NH4OH, S:H2O, pH 9-10

Reaction Protocol
Sequence 1
Step 1
Sequence 2
Step 1
Sequence 2
Step 2
Sequence 2
Step 3
Sequence 2
Step 4
Sequence 2
Step 5
SciFinder® Page 82
Overview
Steps/Stages Notes
in any one step: 2
References
2.1 2 h, 70°C 23(52), 12758-12762; 2017

4.1 C:2127845-78-5, S:CH2Cl2, 36 h, rt
Reaction Protocol
Sequence 1
Step 1
Sequence 2
Step 1
Sequence 2
Step 2

SciFinder® Page 83
Sequence 2
Step 3
Sequence 2
Step 4
84. 2 Steps
[Step 2.1]
Overview
Steps/Stages Notes
1) sealed tube used (stage 2), 2) alternative
1.1 R:Et3N, S:CH2Cl2, cooled preparation shown, Schlenk tube used,
1.2 R:NH3, S:H2O, S:Me2CHOH, 10 h, 90°C Solvents: 4, Steps: 2, Stages: 3, Most stages
in any one step: 2
2.1 R:AcOH, R:t-BuOOH, C:Bu4N+ •I-, S:H2O, S:DMSO, 10 h, 90°C
References
n-Bu4NI-catalyzed selective dual amination of
sp3 C-H bonds: oxidative domino synthesis of
imidazo[1,5-c]quinazolines on a gram-scale
By Zhao, Dan et al
United Kingdom), 50(33), 4302-4304; 2014
Reaction Protocol
Step 1
SciFinder® Page 84
Products 4-Methyl-2-phenylquinazoline, 76%, CAS RN:1806-66-2
Reactants 2'-Aminoacetophenone, CAS RN:551-93-9
Reagents Triethylamine, CAS RN:121-44-8
Ammonia, CAS RN:7664-41-7
Isopropanol, CAS RN:67-63-0
Procedure 1. Cool a solution of 2-aminoacetophenone derivatives (20 mmol) and triethylamine (3.3 mL, 1.2 equiv)
in dichloromethane (DCM) (60 mL) in an ice-water bath.
2. Add chloride to above solution dropwise.
3. Monitor the progress of the reaction by TLC.
4. Wash the solution with diluted hydrochloric acid, saturated NaHCO3, brine upon completion
5. Dry over anhydrous Na2SO4.
6. Concentrate the organic phase in vacuo to obtain amide as an intermediate without further
purification.
7. Add amide, 25% ammonia water (20 mL) and isopropanol (20 mL) to a 250 mL sealed tube.
8. Locate the tube in a preheated 90 °C oil bath and stir for 10 h.
10. Wash with diluted hydrochloric acid, saturated NaHCO3, brine.
11. Dry over anhydrous Na2SO4.
12. Concentrate in vacuo.
13. Purify the residue by chromatography on silica gel with an eluent of petroleum ether and ethyl
acetate to obtain 4-methyl-2-phenylquinazoline.
1H NMR (300 MHz, CDCl3) δ 8.63 (dd, J = 7.9, 1.8 Hz, 2H), 8.09 (d, J = 8.3 Hz, 2H), 7.87 (ddd, J = 8.5, 6.9, 1.3
Hz, 1H), 7.64 - 7.45 (m, 4H), 3.02 (s, 3H).
13C NMR (75 MHz, CDCl3) δ 168.1, 160.0, 150.2 138.2, 133.4, 130.3, 129.1, 128.48, 128.52, 126.7, 124.8,
122.8, 21.9.
Mass Spec MS (ESI): 221.00 [M+H]+.
MP 84 - 85 °C
State white solid
Number
Step 2
Products 3,5-Diphenylimidazo[1,5-c]quinazoline, 65%, CAS RN:1591671-89-4
Reactants 4-Methyl-2-phenylquinazoline, CAS RN:1806-66-2
DL-Phenylglycine, CAS RN:2835-06-5
Reagents Acetic acid, CAS RN:64-19-7
tert-Butyl hydroperoxide, CAS RN:75-91-2
Catalysts Tetrabutylammonium iodide, CAS RN:311-28-4
Dimethyl sulfoxide, CAS RN:67-68-5
Procedure 1. Stir a mixture of 4-methylquinazoline (0.3 mmol), benzylamine (0.6 mmol), n-Bu4NI (0.06 mmol),
TBHP (1.2 mmol, 70% in water) and acetic acid (0.9 mmol) in 2 mL DMSO in a Schlenk tube at 90 °C.
2. Stir the reaction for 10 h.
3. Cool the reaction mixture to the room temperature.
4. Extract the reaction mixture by ethyl acetate (3x5 mL).
5. Wash the organic phase with brine.
6. Dry over anhydrous Na2SO4 and concentrate in vacuo.
7. Purify the residue by chromatography on silica gel with an eluent of petroleum ether and ethyl
acetate to obtain 3,5-diphenylimidazo[1,5-c]quinazoline
1H NMR (300 MHz, CDCl3) δ 8.13 - 8.05 (m, 1H), 8.04 (s, 1H), 7.95 - 7.88 (m, 1H), 7.60 - 7.53 (m, 2H), 7.34 (d,
J = 7.4 Hz, 2H), 7.23 - 6.97 (m, 8H).
13C NMR (100 MHz, CDCl3) δ 146.2, 142.7, 138.1, 133.8, 131.4, 130.3, 129.9, 129.2, 128.6, 128.5, 128.2, 128.0,
127.7, 127.4, 121.7, 120.6, 119.3.
HRMS (ESI) m/z calcd for C22H16N3 [M+H]+ 322.1339, found 322.1338.
MP 142 - 145 °C
Number
SciFinder® Page 85
85. 3 Steps
[Step 2.1] [Step 3.2]
Overview
Steps/Stages Notes
2.1 S:Benzene
References
3.2
Reaction Protocol
Step 1
Step 2
Step 3
86. 2 Steps
SciFinder® Page 86
[Step 2.2]
Overview
Steps/Stages Notes
1.1 R:Dicyclohexylamine, S:H2O, S:MeOH, S:EtOH 2, Stages: 3, Most stages in any one step: 2
2.1 R:ClCO2Et, S:CH2Cl2 References
Synthesis and conformational studies in 1-
2.2 R:Et3N, S:CH2Cl2 ethoxy-2-propene (AE)-protected dipeptides
By Panse, G. T. et al
From Indian Journal of Chemistry, Section B:
Organic Chemistry Including Medicinal
Chemistry, 26B(6), 507-10; 1987
Reaction Protocol
Step 1
Step 2
87. Single Step
47%
Overview
Steps/Stages Notes
SciFinder® Page 87
References
8/1-8/6, 6 pp.; 2013
Reaction Protocol
Step 1
88. Single Step
85%
Overview
Steps/Stages Notes
1.1 R:Cyclopentene, C:1221406-59-2, S:PhMe, 12 h, 120°C regioselective, stereoselective, Schlenk tube
used, mechanism studied, >20:1 dr,
in any one step: 1
References
Edition, 52(51), 13651-13655; 2013
Reaction Protocol
Step 1
Products Cyclohexanone, 5-methyl-2-(phenylmethyl)-, trans-, 85%, CAS RN:84624-36-2
(RS)-3-Methylcyclohexanone, CAS RN:591-24-2
RN:1221406-59-2
SciFinder® Page 88
Scale milligram
1H NMR (600 MHz, CDCl3) δ 7.30-7.23 (m, 2H), 7.21-7.13 (m, 3H), 3.24 (dd, J = 14.0, 4.6 Hz, 1H), 2.47 (ddddd,
J = 12.9, 9.0, 4.6, 1.4, 1.3 Hz, 1H), 2.43-2.33 (m, 2H), 2.09-1.96 (m, 1H), 1.93-1.76 (m, 1H), 1.38-1.22
(m, 2H), 1.01 (d, J = 6.3 Hz, 3H) ppm;.
13C NMR 13C{1H} NMR (150 MHz, CDCl ) δ 212.0, 140.5, 129.1, 128.2, 125.9, 51.6, 50.5, 35.7, 35.2, 33.9, 32.4,
3
22.3 ppm.
Number
89. Single Step
83%
Overview
Steps/Stages Notes
1.1 R:Cyclopentene, C:1221406-59-2, S:PhMe, 12 h, 120°C regioselective, stereoselective, Schlenk tube
used, mechanism studied, >20:1 dr,
in any one step: 1
References
Edition, 52(51), 13651-13655; 2013
Reaction Protocol
SciFinder® Page 89
Step 1
Products rel-(2R,6R)-2-Methyl-6-(phenylmethyl)cyclohexanone, 83%, CAS RN:29478-34-0
2-Methylcyclohexanone, CAS RN:583-60-8
RN:1221406-59-2
Scale milligram
1H NMR (600 MHz, CDCl3) δ 7.30-7.23 (m, 2H), 7.21-7.13 (m, 3H), 3.23 (dd, J = 13.9, 5.0 Hz, 1H), 2.55 (ddddd,
J = 13.9, 12.9, 8.6, 5.1, 5.0, 1.3 Hz, 1H), 2.48-2.35 (m, 2H), 1.84-1.75 (m, 1H), 1.66 (qt, J = 13.8, 3.8
Hz, 1H), 1.34 (pt, J = 12.9, 3.8 Hz, 2H), 1.03 (d, J = 6.3 Hz, 3H) ppm;.
13C NMR 13C{1H} NMR (150 MHz, CDCl ) δ 213.8, 140.8, 129.1, 128.2, 125.9, 52.7, 45.7, 37.4, 35.5, 34.7, 25.6,
3
25.5 ppm.
Number
90. Single Step
63%
Overview
Steps/Stages Notes
SciFinder® Page 90
References
By Xu, Wei et al
6065-6074; 2013
1. 2-Phenyl-5-(2,5-dimethylphenyl)oxazole (3j): Prepared from 2,5-dimethylacetophenone and
phenylglycine following general experimental procedure 1; yield, 62 mg (63%), white solid; eluent,
petroleum ether/ethyl acetate (15:1). mp 79.0-80.0 °C; 1H NMR (400 MHz, CDCl3) δ 8.14 (dd, J = 8.0,
1.7 Hz, 2H), 7.59 (s, 1H), 7.52-7.46 (m, 3H), 7.34 (s, 1H), 7.18 (d, J = 7.7 Hz, 1H), 7.09 (dd, J = 7.7,
1.3 Hz, 1H), 2.50 (s, 3H), 2.41 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 160.7, 150.9, 135.7, 131.8,
131.2, 130.2, 129.2 128.8, 127.4, 127.2, 127.0, 126.2, 126.0, 21.4, 21.0; IR (neat) 2921, 1538, 1494,
1445, 1066, 963, 811, 772, 704, 687 cm-1; HRMS (ESI) m/z calcd for C17H15NO [M + H]+ 250.1226,
found 250.1225.
Reaction Protocol
Step 1
91. Single Step
44%
Overview
Steps/Stages Notes
SciFinder® Page 91
1.1 R:Et3N, S:H2O, S:Benzene Solvents: 2, Steps: 1, Stages: 1, Most stages
in any one step: 1
References
Conversion of homochiral amines, β-amino
alcohols and α-amino acids to their chiral 2-
substituted pyrrole derivatives
By Demir, Ayhan S. et al
From Journal of the Chemical Society, Perkin
Transactions 1, (10), 1162-1167; 2001
Reaction Protocol
Step 1
92. Single Step
52%
Overview
Steps/Stages Notes
References
8/1-8/6, 6 pp.; 2013
Reaction Protocol
Step 1
93. 6 Steps
SciFinder® Page 92
[Step 2.1] [Step 5.1]
Overview
Steps/Stages Notes
5) stereoselective, resoln. step, 6) resoln. step,
1.1 R:NaBH4, S:EtOH, 0-10°C; overnight, rt Reactants: 3, Reagents: 8, Solvents: 3, Steps:
1.2 R:H2O, 15 min, rt
References
2.1 R:HBr, S:H2O, S:EtOH, overnight, reflux Dutch resolution: Separation of enantiomers
with families of resolving agents. A status
3.1 R:NaOH, S:H2O, overnight, 50°C, pH 10; 50°C → rt report
By Kellogg, Richard M. et al
3.2 R:HCl, S:H2O, rt, pH 6
From Synthesis, (10), 1626-1638; 2003
4.1 R:H2O2, S:H2O, S:AcOH, < 32°C
4.2 R:Me2S, 0°C
5.1 R:HCl, S:H2O, heated; overnight, rt

6.1 S:H2O, 60°C
6.2 R:NH4OH, S:H2O, 60°C, pH 7; 2 h, 0°C
Step 1
Reduction of Acetophenones to Alcohols 13a-c; General Procedure To a suspension of NaBH4 (5.8 g;
0.16 mol) in EtOH (120 mL) was added at 0 °C the acetophenone (0.32 mol) (in case of the p-Br
acetophenone this was a solution in EtOH) dropwise, while maintaining the temperature below 10 °C.
After addition is complete, the reaction mixture was stirred overnight at r.t. After addition of water (100
mL), the mixture was stirred at r.t. for 15 min. The reaction mixture was extracted with Et2O (3 × 100
mL). The combined ether layers were washed with brine, dried over Na2SO4, and concentrated to give
a compound. 1-Phenylethanol (13a), colorless liquid, yield 98%. 1H NMR (CDCl3): δ = 1.54 (d, 3 H),
2.98 (br s, 1 H), 4.91 (q, 1 H), 7.32-7.45 (m, 5 H). 13C NMR: δ = 25.1 (q), 70.2 (d), 125.5 (d), 127.4 (d),
128.5 (d), 145.9 (s).
SciFinder® Page 93
Step 2
Formation of Thiourea Salts 14a-c; General Procedure A mixture of the alcohol 12 (0.10 mol), thiourea
(0.10 mol), 48% HBr (40 mL) and EtOH (50 mL) was refluxed overnight. After cooling to r.t., the
reaction mixture was concentrated in vacuo, yielding a white solid or a syrup, depending on the
substituent. This crude salt was used without further purification. Compound 14a.
Step 3
Hydrolysis of the Thiourea Salts 14 to the Thiols 15a-c; General Procedure The thiourea salt 14 (0.10
mol) was dissolved or suspended in water (50 mL) and heated to 50 °C. To this mixture was added
dropwise 33% NaOH solution until no more cloudiness developed upon addition and the pH had risen
to 10. The reaction mixture was stirred overnight at 50 °C. After cooling to r.t., 30% HCl was added
until pH 6. The reaction mixture was extracted with Et2O (3 × 100 mL). The combined organic layers
were washed with brine, dried over Na2SO4 and concentrated to a liquid. NOTE: the thiols have a
distinct odor. 1-Phenylethanethiol (15a), yield 75%. 1H NMR: δ = 1.67 (d, 3 H), 4.23 (q, 1 H), 7.35 (m, 5
H). 13C NMR: δ = 25.9 (q), 38.5 (d), 126.2 (d), 127.0 (d), 128.5 (d), 144.8 (s).
Step 4
Oxidation of Thiols 15a-c to 12a-c General procedure The thiol 15 (36 mmol) was dissolved in HOAc
(120 mL). H2O2 (110 mL, 30%, 2 equiv) was added dropwise, at such a rate that the temperature
remained below 32 °C. Beware of the induction time of the reaction; the temperature rise does not
follow the addition immediately. After addition was complete and the thiol has reacted (according to
TLC), Me2S was added at 0 °C until no more peroxides were present, as shown by a peroxide test.
The reaction mixture was concentrated in vacuo (during evaporation the peroxide test was also
applied), yielding an oil. This residue was suspended in H2O (ca. 80 mL) and 33% NaOH was added
until pH 7. The water layer was washed with Et2O (3 × 75 mL) and concentrated in vacuo to yield the
sodium sulfonate, which was dried in vacuo at 60 °C. 1-Phenylethanesulfonic Acid (12a), yield 77%.
1H NMR (DMSO): δ = 1.51 (d, 3 H), 3.83 (q, 1 H), 7.27 (m, 5 H), 11.5 (br s, 1 H). 13C NMR (DMSO): δ
= 17.5 (q), 59.9 (d), 126.6 (d), 127.6 (d), 128.9 (d), 139.9 (s).
Step 5
Resolution of 12a13a Sulfonate (50 g; 0.24 mol) was dissolved in 10% HCl (150 mL). L-4-
Hydroxyphenylglycine (40.1 g, 0.24 mol) was added together with 10% HCl (450 mL) and the mixture
was heated until a clear solution was obtained. The mixture was allowed to crystallize at r.t. overnight.
The resulting crystals were removed by filtration under suction, washed with ice water. The salt was
recrystallized from 10% HCl and a little MeOH to afford 22.8 g (27%) of a white solid. White solid, yield
30.3 g, 36%. [α]D-83.9 (c 1, MeOH); HPLC (Ultron ES OVM, 20 mM KH2PO4-CH3CN, 95:5): 87% ee.
Step 6
The salt was suspended in H2O (25 mL) and heated to 60 °C until a clear solution was obtained. NH3
(6 N) was added until pH 7. The mixture was stirred at 0 °C for 2 h. The resulting solid was removed by
filtration and the filtrate was passed over Amberlite IR-120. The column was eluted with H2O. The
eluent was concentrated in vacuo and stripped with toluene to obtain free sulfonic acid. Yield 14.5 g.
HPLC: 98% ee.
Reaction Protocol
Step 1
Step 2
Step 3
Step 4
Step 5
Step 6

SciFinder® Page 94
94. 5 Steps
[Step 2.1] [Step 5.1]
Overview
Steps/Stages Notes
5) stereoselective, resoln. step, Reactants: 3,
1.1 R:NaBH4, S:EtOH, 0-10°C; overnight, rt Reagents: 7, Solvents: 3, Steps: 5, Stages: 8,
1.2 R:H2O, 15 min, rt
References
From Synthesis, (10), 1626-1638; 2003
4.1 R:H2O2, S:H2O, S:AcOH, < 32°C
4.2 R:Me2S, 0°C
5.1 R:HCl, S:H2O, heated; overnight, rt

Step 1
Reduction of Acetophenones to Alcohols 13a-c; General Procedure To a suspension of NaBH4 (5.8 g;
0.16 mol) in EtOH (120 mL) was added at 0 °C the acetophenone (0.32 mol) (in case of the p-Br
acetophenone this was a solution in EtOH) dropwise, while maintaining the temperature below 10 °C.
After addition is complete, the reaction mixture was stirred overnight at r.t. After addition of water (100
mL), the mixture was stirred at r.t. for 15 min. The reaction mixture was extracted with Et2O (3 × 100
mL). The combined ether layers were washed with brine, dried over Na2SO4, and concentrated to give
a compound. 1-Phenylethanol (13a), colorless liquid, yield 98%. 1H NMR (CDCl3): δ = 1.54 (d, 3 H),
2.98 (br s, 1 H), 4.91 (q, 1 H), 7.32-7.45 (m, 5 H). 13C NMR: δ = 25.1 (q), 70.2 (d), 125.5 (d), 127.4 (d),
128.5 (d), 145.9 (s).
Step 2
Formation of Thiourea Salts 14a-c; General Procedure A mixture of the alcohol 12 (0.10 mol), thiourea
(0.10 mol), 48% HBr (40 mL) and EtOH (50 mL) was refluxed overnight. After cooling to r.t., the
reaction mixture was concentrated in vacuo, yielding a white solid or a syrup, depending on the
substituent. This crude salt was used without further purification. Compound 14a.
SciFinder® Page 95
Step 3
Hydrolysis of the Thiourea Salts 14 to the Thiols 15a-c; General Procedure The thiourea salt 14 (0.10
mol) was dissolved or suspended in water (50 mL) and heated to 50 °C. To this mixture was added
dropwise 33% NaOH solution until no more cloudiness developed upon addition and the pH had risen
to 10. The reaction mixture was stirred overnight at 50 °C. After cooling to r.t., 30% HCl was added
until pH 6. The reaction mixture was extracted with Et2O (3 × 100 mL). The combined organic layers
were washed with brine, dried over Na2SO4 and concentrated to a liquid. NOTE: the thiols have a
distinct odor. 1-Phenylethanethiol (15a), yield 75%. 1H NMR: δ = 1.67 (d, 3 H), 4.23 (q, 1 H), 7.35 (m, 5
H). 13C NMR: δ = 25.9 (q), 38.5 (d), 126.2 (d), 127.0 (d), 128.5 (d), 144.8 (s).
Step 4
Oxidation of Thiols 15a-c to 12a-c General procedure The thiol 15 (36 mmol) was dissolved in HOAc
(120 mL). H2O2 (110 mL, 30%, 2 equiv) was added dropwise, at such a rate that the temperature
remained below 32 °C. Beware of the induction time of the reaction; the temperature rise does not
follow the addition immediately. After addition was complete and the thiol has reacted (according to
TLC), Me2S was added at 0 °C until no more peroxides were present, as shown by a peroxide test.
The reaction mixture was concentrated in vacuo (during evaporation the peroxide test was also
applied), yielding an oil. This residue was suspended in H2O (ca. 80 mL) and 33% NaOH was added
until pH 7. The water layer was washed with Et2O (3 × 75 mL) and concentrated in vacuo to yield the
sodium sulfonate, which was dried in vacuo at 60 °C. 1-Phenylethanesulfonic Acid (12a), yield 77%.
1H NMR (DMSO): δ = 1.51 (d, 3 H), 3.83 (q, 1 H), 7.27 (m, 5 H), 11.5 (br s, 1 H). 13C NMR (DMSO): δ
= 17.5 (q), 59.9 (d), 126.6 (d), 127.6 (d), 128.9 (d), 139.9 (s).
Step 5
Resolution of 12a13a Sulfonate (50 g; 0.24 mol) was dissolved in 10% HCl (150 mL). L-4-
Hydroxyphenylglycine (40.1 g, 0.24 mol) was added together with 10% HCl (450 mL) and the mixture
was heated until a clear solution was obtained. The mixture was allowed to crystallize at r.t. overnight.
The resulting crystals were removed by filtration under suction, washed with ice water. The salt was
recrystallized from 10% HCl and a little MeOH to afford 22.8 g (27%) of a white solid. White solid, yield
30.3 g, 36%. [α]D-83.9 (c 1, MeOH); HPLC (Ultron ES OVM, 20 mM KH2PO4-CH3CN, 95:5): 87% ee.
Reaction Protocol
Step 1
Step 2
Step 3
Step 4
Step 5
95. Single Step
SciFinder® Page 96
97%
Overview
Steps/Stages Notes
alternative solvent and conditions may be
1.1 R:KOH, S:Me2CHOH, rt → 55°C; 2 h, 55-56°C; 30 min, 56°C → - used, exothermic, Reactants: 2, Reagents: 1,
5°C Solvents: 1, Steps: 1, Stages: 1, Most stages
in any one step: 1
References
Jun 2012
Reaction Protocol
Step 1
96. Single Step
95%
Overview
Steps/Stages Notes
SciFinder® Page 97
in any one step: 1
References
28 Jan 2009
Reaction Protocol
Step 1
97. Single Step
97%
Overview
Steps/Stages Notes
stereoselective, first step assumed, Reactants:
1.1 R:NaOH, S:MeOH, rt → reflux 2, Reagents: 1, Solvents: 1, Steps: 1, Stages:
1.2 1 h, reflux 2, Most stages in any one step: 2
References
Contributions to the synthesis and the
evaluation of amoxicillin. 2. Synthesis of
amoxicillin trihydrate
By Vlase, A. et al
From Roumanian Biotechnological Letters,
10(3), 2197-2203; 2005
Reaction Protocol
Step 1
98. Single Step
SciFinder® Page 98
91%
Overview
Steps/Stages Notes
step: 1
References
Acid
By Hu, Ting et al
Reaction Protocol
Step 1
99. Single Step
97%
Overview
Steps/Stages Notes
SciFinder® Page 99
key step, Reactants: 2, Reagents: 1, Solvents:
1.1 R:KOH, S:MeOH 2, Steps: 1, Stages: 2, Most stages in any one
1.2 S:MeCN step: 2
References
Preparation of phenylglycine enamines (Dane
salts) as intermediates for β-lactam antibiotics
Reaction Protocol
Step 1
100. Single Step
85%
Overview
Steps/Stages Notes
1.1 R:KOH, S:MeOH, reflux Solvents: 1, Steps: 1, Stages: 2, Most stages
1.2 1 h, reflux in any one step: 2
References
By Vlase, A. et al
10(3), 2197-2203; 2005
Reaction Protocol
Step 1
101. Single Step
SciFinder® Page 100
86%
Overview
Steps/Stages Notes
1.1 R:KOH, S:MeOH 1, Stages: 1, Most stages in any one step: 1
References
Preparation of 5-arylhydantoins as
hydroxyphenylglycine intermediates
By Yasuda, Hiroshi
From Eur. Pat. Appl., 647630, 12 Apr 1995
Reaction Protocol
Step 1
102. Single Step
95%
Overview
Steps/Stages Notes
1.1 S:MeOH Classification: Addition-Elimination; N-
Alkylation; # Conditions: MeCOCH2CO2Me;
MeOH Rf 30mn; # Comments: reactant and
product are sodium salts, Reactants: 2,
in any one step: 1
References
Derivatives of 6-aminopenicillanic acid. XI.
α-Amino-p-hydroxybenzylpenicillin
By Nayler, J. H. C. et al
From Journal of the Chemical Society
[Section] C: Organic, (10), 1920-2; 1971
Reaction Protocol
Step 1
Overview
Steps/Stages Notes
in any one step: 2
References
2.1 2 h, 70°C 23(52), 12758-12762; 2017

4.1 C:2127845-78-5, S:CH2Cl2, 36 h, rt
Reaction Protocol
Sequence 1
Step 1

Sequence 2
Step 1
Sequence 2
Step 2
Sequence 2
Step 3
Sequence 2
Step 4
104. 3 Steps
[Step 3.1]
Overview
Steps/Stages Notes
3) Michael addition, Reactants: 3, Reagents: 3,
1.1 R:NaOH, S:H2O, S:MeCN, 0°C; 2 h, 0°C; 0°C → rt; 1 h, rt Catalysts: 1, Solvents: 3, Steps: 3, Stages: 4,
2.1 R:DCC, S:CH2Cl2, 0°C; 0°C → rt; 20 h, rt
3.1 C:916665-69-5, S:CH2Cl2, rt References
Enantioselective Construction of
3.2 R:HCl, S:H2O, rt Tetrasubstituted Stereogenic Carbons
Equivalent
Society, 136(51), 17869-17881; 2014
Reaction Protocol
Step 1
Products α-(Benzoylamino)benzeneacetic acid, 80%, CAS RN:29670-63-1
Reagents Sodium hydroxide, CAS RN:1310-73-2
Acetonitrile, CAS RN:75-05-8
Procedure 1. Dissolve D, L-Phenylglycine ( 1.51 g, 10 mmol ) and NaOH ( 1.62 g, 40 mmol ) in H2O/CH3CN (
75/25, 0.3 M ) .
2. Cool to 0 °C, benzoyl chloride ( 1.22 mL, 10.5 mmol ) dropwise at this temperature.
3. Stir the mixture for additional 2 hours at 0 °C.
4. Allow the mixture to warm to room temperature and stir for one additional hour.
5. Remove all volatiles under reduced pressure, add concentrated HCl to cause precipitation.
6. Filter the mixture and wash the filter cake with ice-cold diethylether.
Scale gram
1H NMR ( 300 MHz, CDCl3 ) , δ: 7.86 - 7.77 ( m, 2H ) , 7.57 - 7.32 ( m, 8H ) , 7.08 ( d, J = 7.0 Hz, 1H ) , 5.80 ( d,
J = 6.7 Hz, 1H ) .
State white solid
Number
Step 2
Products 2,4-Diphenyl-5(4H)-oxazolone, 62%, CAS RN:28687-81-2
Reactants α-(Benzoylamino)benzeneacetic acid, CAS RN:29670-63-1
Reagents Dicyclohexylcarbodiimide, CAS RN:538-75-0
Procedure 1. Suspend N-benzoyl-D, L-phenylglycine ( 1.28 g, 5 mmol ) in CH2Cl2 ( 50 mL, 10 mL/mmol ) .
2. Cool the mixture to 0 °C and add DCC ( 1.08 g, 5.25 mmol, 1.05 equiv. ) portionwise.
3. Allow the mixture to warm to room temperature and stir for additional 20 hours at this temperature.
4. Filter a precipitate and concentrate the filtrate in vacuo.
5. Purify the product by silica gel column chromatography using hexane/ethyl acetate ( 95:5 ) .
Scale milligram
1H NMR ( 300 MHz, CDCl3 ) , δ: 8.24 - 7.94 ( m, 2H ) , 7.67 - 7.49 ( m, 3H ) , 7.48 - 7.34 ( m, 5H ) , 5.53 ( s, 1H
).
13C NMR ( 75 MHz, CDCl3 ) , δ: 176.4, 162.8, 133.6, 133.3, 129.1, 129.1, 128.9, 128.8, 128.3, 127.6, 127.4,
127.0, 68.3.
Mass Spec UPLC-DAD-QTOF: C15H12NO2 [M+H]+ calcd.: 238.0863, found: 238.0860.
MP 104-105 °C.
State yellow solid
Number
Step 3
Products 5(4H)-Oxazolone, 4-(4-hydroxy-4-methyl-3-oxopentyl)-2,4-diphenyl-, CAS RN:1639968-09-4
Reactants 2,4-Diphenyl-5(4H)-oxazolone, CAS RN:28687-81-2
Reagents Hydrochloric acid, CAS RN:7647-01-0
Catalysts N-[3,5-Bis(trifluoromethyl)phenyl]-N'-[2-(dimethylamino)ethyl]thiourea, CAS RN:916665-69-5
Procedure 1. Add the achiral thiourea catalyst to a mixture of azlactone ( 1 eq., 0.2 mmol ) and the α'-hidroxy
enone ( 1.5 eq., 0.3 mmol ) in dichloromethane ( 0.4 mL ) at room temperature.
2. Stir the mixture at the same temperature, until consumption of the azlactone ( monitor by 1H-NMR )
.
3. Quench the reaction mixture with 1M HCl ( 10 mL ) and extract the aqueous layer with CH2Cl2 ( 3 ×
20 mL ) .
4. Dry the combined organic layers over MgSO4, filter and evaporate the solvent under reduced
pressure.
5. Purify the crude by flash column chromatography on silica gel to obtain the product.
Number
105. 4 Steps
[Step 2.1] [Step 3.1]
[Step 4.1]
Overview
Steps/Stages Notes
4) Michael addition, Reactants: 4, Reagents: 4,
1.1 R:HBr, R:NaNO2, S:H2O, 0°C; 2.5 h, rt Catalysts: 1, Solvents: 3, Steps: 4, Stages: 5,
2.1 R:H2SO4, S:MeOH, 1 h, reflux
References
3.1 R:C5H5N, rt → 110°C; 3 h, 100-110°C Enantioselective Construction of
3.2 S:EtOH, 30 min, rt Tetrasubstituted Stereogenic Carbons
4.1 C:Et3N, 0°C through Bronsted Base Catalyzed Michael
Equivalent
Society, 136(51), 17869-17881; 2014
Step 1
The corresponding amino acid (40 mmol, 1 equiv.) is solubilized in 48% HBr (40 mL) and 36 mL water.
The reaction mixture is cooled to 0 °C and a solution of NaNO2 (4.4 g, 64 mmol, 1.6 equiv.) in 10 mL
water was added dropwise. The mixture was stirred for 2.5 h at room temperature, then concentrated
to remove acid vapor, and extracted with Et2O (4 × 10 mL). The organic layers were washed with
water, brine, dried over MgSO4, and concentrated under reduced pressure. α-bromophenylacetic acid.
Step 2
Step 3
General/Typical Procedure: A mixture of the corresponding α-bromo methyl ester (1.1 equiv.),
thioamide (1 equiv.) and pyridine (1 equiv.) was stirred under argon and slowly heated to 100-110 °C
until the mixture solidified. After 3 h, ethanol (15 mL) was added and the mixture was stirred at room
temperature for 30 min. After filtration the crude product was washed with ethanol. 2,5-Diphenylthiazol-
4-ol (25f). The title compound 25f was prepared from methyl 2-bromo-2-phenylacetate (2.5 g, 11
mmol) and thioamide (1.4 g, 10 mmol) according to the general procedure B. The resulting solid was
washed with ethanol. Yellow solid; yield: 1.9 g, 7.7 mmol, 77%. m. p. 214-216 °C. 1H NMR (300 MHz,
CDCl3), δ: 8.01 - 7.90 (m, 2H), 7.89 - 7.79 (m, 2H), 7.54 - 7.32 (m, 6H). 13C NMR (75 MHz, CDCl3), δ:
145.8, 141.4, 129.8, 128.8, 128.5, 127.1, 126.4, 126.1, 125.5, 109.5. UPLC-DAD-QTOF: C15H12NOS
[M+H]+ calcd.:254.0640, found:254.0647.
Step 4
To a mixture of the corresponding 4-hydroxy-4-methylpent-1-en-3-one (1 equiv., 0.3 mmol) and enone
2 (3.0/1.5 equiv., 0.6/0.45 mmol), in dichloromethane (0.9 mL) at 0 °C, the catalyst TEA (20 mol%,
0.06 mmol, 38 mg) was added. The resulting suspension was stirred at the same temperature, until
consumption of the thiazolone (monitored by 1H-NMR). Then, 3 mL of methanol and 0.6 mL of HF
48% were added at the corresponding temperature and the mixture was warmed to room temperature
and stirred for 45 min. The reaction was treated at 0 °C with saturated aqueous solution of NaHCO3
until neutralization. The product was extracted from the aq. phase with CH2Cl2 and the combined
organic phases were dried with MgSO4. Evaporation of the solvent under reduced pressure gave the
crude product, which was purified by flash column chromatography (eluting with hexane/ethyl acetate
80/20). 5-(4-Hydroxy-4-methyl-3-oxopentyl)-2,5-diphenylthiazol-4(5H)-one (27f) (racemic).
Reaction Protocol
Step 1
Products Bromophenylacetic acid, CAS RN:4870-65-9
Reagents Hydrogen bromide, CAS RN:10035-10-6
Sodium nitrite, CAS RN:7632-00-0
Procedure 1. Solubilize the amino acid ( 40 mmol, 1 equiv. ) in 48% HBr ( 40 mL ) and 36 mL water.
2. Cool the reaction mixture to 0 °C and add a solution of NaNO2 ( 4.4 g, 64 mmol, 1.6 equiv. ) in 10
mL water dropwise.
3. Stir the mixture for 2.5 hours at room temperature, concentrate to remove acid vapor and extract
with Et2O ( 4 × 10 mL ) .
4. Wash the organic layers with water, brine.
5. Dry over MgSO4 and concentrate under reduced pressure.
Number
Step 2
Products Benzeneacetic acid, α-bromo-, methyl ester, CAS RN:3042-81-7
Reactants Bromophenylacetic acid, CAS RN:4870-65-9
Reagents Sulfuric acid, CAS RN:7664-93-9
Procedure 1. Treat the α-bromoacid with a solution of concentrated sulphuric acid ( 30 µL/mmol ) in methanol ( 2
mL/mmol ) and reflux for one hour.
2. Cool the solution to room temperature and concentrate in vacuo.
3. Add Et2O and wash the organic layer with 5% aqueous solution of NaHCO3 and brine.
4. Dry over MgSO4 and concentrate in vacuo.
Number
Step 3
Products 2,5-Diphenyl-4-thiazolol, 77%, CAS RN:59484-42-3
Reactants Benzeneacetic acid, α-bromo-, methyl ester, CAS RN:3042-81-7
Thiobenzamide, CAS RN:2227-79-4
Reagents Pyridine, CAS RN:110-86-1
Procedure 1. Stir a mixture of the methyl 2-bromo-2-phenylacetate ( 2.5 g, 11 mmol ) , thioamide ( 1.4 g, 10 mmol
) and pyridine ( 1 equiv. ) under argon and heat slowly to 100-110 °C until solidifying the mixture.
2. Add ethanol ( 15 mL ) , after 3 hours and stir the mixture at room temperature for 30 minutes.
3. Filter and wash the crude product with ethanol.
Scale gram
1H NMR ( 300 MHz, CDCl3 ) , δ: 8.01 - 7.90 ( m, 2H ) , 7.89 - 7.79 ( m, 2H ) , 7.54 - 7.32 ( m, 6H ) .
13C NMR ( 75 MHz, CDCl3 ) , δ: 145.8, 141.4, 129.8, 128.8, 128.5, 127.1, 126.4, 126.1, 125.5, 109.5.
Mass Spec UPLC-DAD-QTOF: C15H12NOS [M+H]+ calcd.:254.0640, found:254.0647.
MP 214-216 °C.
State yellow solid
Number
Step 4
Products 4(5H)-Thiazolone, 5-(4-hydroxy-4-methyl-3-oxopentyl)-2,5-diphenyl-, CAS RN:1639968-03-8
Reactants 2,5-Diphenyl-4-thiazolol, CAS RN:59484-42-3
Catalysts Triethylamine, CAS RN:121-44-8
Procedure 1. Add the catalyst TEA ( 20 mol%, 0.06 mmol, 38 mg ) to a mixture of 4-hydroxy-4-methylpent-1-en-3-
one ( 1 equiv., 0.3 mmol ) and enone ( 3.0/1.5 equiv., 0.6/0.45 mmol ) , in dichloromethane ( 0.9 mL )
at 0 °C.
2. Stir the resulting suspension at the same temperature, until consumption of the thiazolone ( monitor
by 1H-NMR ) .
3. Add 3 mL of methanol and 0.6 mL of HF 48% at the corresponding temperature.
4. Warm the mixture to room temperature and stir for 45 minutes.
5. Treat the reaction at 0 °C with saturated aqueous solution of NaHCO3 until neutralization.
6. Extract the product from the aqueous phase with CH2Cl2 and dry the combined organic phases with
MgSO4.
7. Evaporate the solvent under reduced pressure to obtain the crude product.
8. Purify by flash column chromatography ( eluting with hexane/ethyl acetate 80/20 ) .
Number
106. Single Step
96%
Overview
Steps/Stages Notes
in any one step: 1
References
28 Jan 2009
Reaction Protocol
Step 1
107. Single Step
85%
Overview
Steps/Stages Notes
References
United Kingdom), 47(33), 9513-9515; 2011
Reaction Protocol
Step 1
Products 4-Butyl-2-phenylquinazoline, 85%, CAS RN:197163-72-7
1-(2-Aminophenyl)-1-pentanone, CAS RN:61485-11-8
sealed tube.
3. Purify the residue by column chromatography over silica gel to obtain 4-butyl-2-phenylquinazoline.
1H NMR (300 MHz, CDCl3) δ (ppm) 8.66-8.62 (m, 2 H), 8.13-8.05 (m,2 H), 7.87-7.81 (m, 1 H), 7.59-7.48 (m, 4
H), 3.33 (t, J = 7.5 Hz, 2 H), 2.00-1.94 (m, 2H), 1.54 (q, J = 7.5 Hz, 2 H), 1.02 (t, J = 7.5 Hz, 3 H)
13C NMR (75 MHz, CDCl3) δ (ppm) 171.6, 160.2, 150.8, 138.6, 133.3, 130.4, 129.5, 128.7, 128.6, 126.8, 124.7,
122.6, 34.4, 30.8, 22.9,14.1
State yellow solid
Number
108. Single Step
81%
Overview
Steps/Stages Notes
1.1 S:EtOH, 4 h, reflux Reactants: 2, Solvents: 1, Steps: 1, Stages: 1,
References
Synthesis of
thioxotetrahydropyrimidinecarboxylic acids
By Filimonov, S. I. et al
From Izvestiya Vysshikh Uchebnykh
Zavedenii, Khimiya i Khimicheskaya
Tekhnologiya, 53(4), 83-86; 2010
Reaction Protocol
Step 1
109. Single Step
55%
Overview
Steps/Stages Notes
References
8/1-8/6, 6 pp.; 2013
Reaction Protocol
Step 1
110. 3 Steps
[Step 2.1] [Step 3.2]
Overview
Steps/Stages Notes
2.1 S:Benzene
References
3.2
Reaction Protocol
Step 1
Step 2
Step 3
111. Single Step
97%
Overview
Steps/Stages Notes
alternative solvent and conditions may be
1.1 R:KOH, S:Me2CHOH, rt → 55°C; 2 h, 55-56°C; 30 min, 56°C → - used, exothermic, Reactants: 2, Reagents: 1,
5°C Solvents: 1, Steps: 1, Stages: 1, Most stages
in any one step: 1
References
Jun 2012
Reaction Protocol
Step 1
112. Single Step
97%
Overview
Steps/Stages Notes
1.1 R:K2CO3, S:MeOH, S:PhMe, 80°C; reflux 1, Stages: 2, Most stages in any one step: 2
1.2 S:Me2CHOH, 2 h, 0-5°C
References
Method for preparing phenylglycine Dane salt
By Sun, Haiquan
10 Mar 2010
Reaction Protocol
Step 1
113. Single Step
91%
Overview
Steps/Stages Notes
stereoselective, yield depends on isolation
1.1 R:NaOH, S:MeOH, heated procedure, Reactants: 2, Reagents: 1,
1.2 1 h, reflux Solvents: 1, Steps: 1, Stages: 2, Most stages
in any one step: 2
References
By Vlase, A. et al
10(3), 2197-2203; 2005
Reaction Protocol
Step 1
114. Single Step
92%
Overview
Steps/Stages Notes
1.1 C:Pd, S:H2O, 18 h, 140°C Reactants: 2, Catalysts: 1, Solvents: 1, Steps:
References
Method for preparation of quinazolines with
amino acids and o-nitroacetophenones
By Tang, Lin
23 Mar 2016
Reaction Protocol
Step 1
115. Single Step
85%
Overview
Steps/Stages Notes
stereoselective, yield depends on isolation
1.1 R:KOH, S:MeOH, heated procedure, Reactants: 2, Reagents: 1,
1.2 1 h, reflux Solvents: 1, Steps: 1, Stages: 2, Most stages
in any one step: 2
References
By Vlase, A. et al
10(3), 2197-2203; 2005
Reaction Protocol
Step 1
116. Single Step
89%
Overview
Steps/Stages Notes
1.1 C:Pd, S:H2O, 24 h, 140°C thermal, green chemistry, reusable catalyst,
alternative preparation shown, Reactants: 2,
References
Heterogeneous Palladium-Catalyzed
Hydrogen-Transfer Cyclization of
Nitroacetophenones with Benzylamines:
Access to C-N Bonds
By Tang, Lin et al
From ChemCatChem, 8(23), 3565-3569;
2016
Reaction Protocol
Step 1

117. Single Step
88%
Overview
Steps/Stages Notes
step: 1
References
Acid
By Hu, Ting et al
Reaction Protocol
Step 1
118. Single Step
Overview
Steps/Stages Notes
1.1 R:Et3N, R:S, S:EtOH, 16 h, reflux 1, Stages: 5, Most stages in any one step: 5
1.2 R:HCl, S:H2O, 16 h, reflux References
Preparation of fused bicyclic and tricyclic
1.3 R:POCl3, 3 h, 55-65°C pyrimidine compounds as tyrosine kinase
inhibitors
1.4 R:NaHCO3, S:H2O By Hsieh, Hsing-Pang et al
1.5 S:BuOH, 16 h, 80°C
From U.S. Pat. Appl. Publ., 20100120805, 13
May 2010
General/Typical Procedure: To a mixture of cyclohexanone (1.18 g), malononitrile (0.66 g), and
sulphur (0.40 g) in absolute ethanol (3 ml) was added triethylamine (2 mL). After refluxed for 16 h, the
reaction mixture was concentrated and the residue was partitioned between water and ethyl acetate.
The organic layer was concentrated and the crude compound was purified by silica gel column
chromatography using a mixture of hexanes:ethyl acetate (4:1), to give the title compound (0.94 g,
44%). To a mixture of 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl cyanide (0.9 g) and formic acid
(10 mL) was added 0.1 mLconc. HCl. After refluxed for 16 h, the reaction mixture was cooled and
water (20 mL) was added. The precipitate was collected by filtration and washed thoroughly with water
and hexanes to give the title compound (0.8 g, 77%). A mixture of 3,4,5,6,7,8-
hexahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-one (0.8 g) and POCl3 (10 mL) was heated at 55-65°C.
for 3 h. Water was then added followed by sodium bicarbonate. The resulting mixture was extracted
with ethyl acetate. The organic layer was concentrated and the crude compound was purified by silica
gel column chromatography using a mixture of hexanes: ethyl acetate (20:1), to give the title
compound (0.52 g, 60%). A mixture of 4-chloro-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine (1
g) and S-2-amino-2-phenyl-ethanol (0.672 g, 1.1 eq) in n-butanol (1 mL) was heated at 80°C. for 16 h.
The reaction mixture was concentrated and the residue was partitioned between water and
dichloromethane. The organic layer was washed with brine, dried over MgSO4 and concentrated. The
crude compound was purified by silica gel column chromatography using a mixture of
dichloromethane:methanol (30:1), to give the title compound (0.88 g). Compound 20. LC-MS (ESI) m/z
326.0 (M+H)+.
Reaction Protocol
Step 1
119. 4 Steps
[Step 2.1]
[Step 4.1]
Overview
Steps/Stages Notes
2.1 2 h, 70°C step: 2

23(52), 12758-12762; 2017
Reaction Protocol
Step 1
Step 2
Step 3
Step 4
120. 6 Steps
[Step 2.1]
[Step 4.1]
Overview
Steps/Stages Notes
1.2 R:K2CO3, S:H2O, pH 9 Solvents: 3, Steps: 6, Stages: 8, Most stages
2.1 2 h, 70°C in any one step: 2

6.1 R:H2, C:Pd, S:EtOH, 16 h, rt 23(52), 12758-12762; 2017
Reaction Protocol
Step 1
Step 2
Step 3
Step 4
Step 5

Step 6
121. 5 Steps
[Step 2.1]
[Step 4.1]
Overview
Steps/Stages Notes
2.1 2 h, 70°C step: 2

5.1 C:AgF, C:DBU, S:CH2Cl2, 5 h, rt and ∆5-dehydroprolines based on a two-step
23(52), 12758-12762; 2017
Reaction Protocol
Step 1
Step 2
Step 3

Step 4
Step 5
122. 5 Steps
[Step 2.1]
[Step 4.1]
Overview
Steps/Stages Notes
2.1 2 h, 70°C step: 2

23(52), 12758-12762; 2017
Reaction Protocol
Step 1
Step 2

Step 3
Step 4
Step 5
123. 5 Steps
[Step 2.1] [Step 5.1]
Overview
Steps/Stages Notes
1.2 R:H2O, 15 min, rt
References
From Synthesis, (10), 1626-1638; 2003
4.1 R:H2O2, S:H2O, S:AcOH, < 32°C
4.2 R:Me2S, 0°C
5.1 R:HCl, S:H2O

Step 1
General/Typical Procedure: Reduction of Acetophenones to Alcohols 13a-c; General Procedure To a
suspension of NaBH4 (5.8 g; 0.16 mol) in EtOH (120 mL) was added at 0 °C the acetophenone (0.32
mol) (in case of the p-Br acetophenone this was a solution in EtOH) dropwise, while maintaining the
temperature below 10 °C. After addition is complete, the reaction mixture was stirred overnight at r.t.
After addition of water (100 mL), the mixture was stirred at r.t. for 15 min. The reaction mixture was
extracted with Et2O (3 × 100 mL). The combined ether layers were washed with brine, dried over
Na2SO4, and concentrated to give a compound. 1-p-Tolylethanol (13b) Yield: 98%. 1H NMR: δ = 1.14
(d, 3 H), 1.60 (br s, 1 H), 2.02 (s, 3 H), 4.54 (q, 1 H), 6.83 (d, 2 H), 6.93 (d, 2 H). 13C NMR: δ = 20.8
(q), 24.8 (q), 70.0 (d), 125.2 (d), 129.0 (d), 137.0 (s), 142.8 (s).
Step 2
General/Typical Procedure: Formation of Thiourea Salts 14a-c; General Procedure A mixture of the
alcohol 12 (0.10 mol), thiourea (0.10 mol), 48% HBr (40 mL) and EtOH (50 mL) was refluxed
overnight. After cooling to r.t., the reaction mixture was concentrated in vacuo, yielding a white solid or
a syrup, depending on the substituent. This crude salt was used without further purification. Compound
14b.
Step 3
General/Typical Procedure: Hydrolysis of the Thiourea Salts 14 to the Thiols 15a-c; General Procedure
The thiourea salt 14 (0.10 mol) was dissolved or suspended in water (50 mL) and heated to 50 °C. To
this mixture was added dropwise 33% NaOH solution until no more cloudiness developed upon
addition and the pH had risen to 10. The reaction mixture was stirred overnight at 50 °C. After cooling
to r.t., 30% HCl was added until pH 6. The reaction mixture was extracted with Et2O (3 × 100 mL). The
combined organic layers were washed with brine, dried over Na2SO4 and concentrated to a liquid.
NOTE: the thiols have a distinct odor. 1-p-Tolylethanethiol (15b) Yield: 87%. 1H NMR: δ = 1.64 (d, 3
H), 2.32 (s, 4 H), 4.19 (q, 1 H), 7.11 (d, 2 H), 7.24 (d, 2 H). 13C NMR: δ = 20.8 (q), 25.9 (q), 38.2 (d),
126.1 (d), 129.2 (d), 136.7 (s), 142.8 (s).
Step 4
General/Typical Procedure: Oxidation of Thiols 15a-c to 12a-c General procedure The thiol 15 (36
mmol) was dissolved in HOAc (120 mL). H2O2 (110 mL, 30%, 2 equiv) was added dropwise, at such a
rate that the temperature remained below 32 °C. Beware of the induction time of the reaction; the
temperature rise does not follow the addition immediately. After addition was complete and the thiol
has reacted (according to TLC), Me2S was added at 0 °C until no more peroxides were present, as
shown by a peroxide test. The reaction mixture was concentrated in vacuo (during evaporation the
peroxide test was also applied), yielding an oil. This residue was suspended in H2O (ca. 80 mL) and
33% NaOH was added until pH 7. The water layer was washed with Et2O (3 × 75 mL) and
concentrated in vacuo to yield the sodium sulfonate, which was dried in vacuo at 60 °C. 1-p-
Tolylethanesulfonic Acid (12b) Yield was not determined, since traces of DMSO remained. 1H NMR
(D2O): δ = 1.74 (d, 3 H), 4.24 (q, 1 H), 7.34 (d, 2 H), 7.44 (d, 2 H).
Step 5
Sulfonate 12b (140.7 g, 0.63 mol) was suspended in 10% HCl (200 mL). L-4-Hydroxyphenylglycine
(105.2 g, 0.63 mol) was added and heated until a clear solution was obtained. The mixture was
allowed to crystallize at r.t. overnight. The resulting crystals were removed by filtration under suction,
washed with ice water. HPLC showed unfortunately no base line separation. The salt was
recrystallized from 10% HCl-MeOH to afford 15.1 g (6.5%). White solid, yield 39.3 g, 17%. 85% ee,
[α]D -74.2 (c = 0.5, MeOH).
Reaction Protocol
Step 1
Step 2
Step 3
Step 4

Step 5
124. Single Step
93%
Overview
Steps/Stages Notes
step: 1
References
Acid
By Hu, Ting et al
Reaction Protocol
Step 1
125. Single Step
37%
Overview
Steps/Stages Notes
1.1 R:NaOH, C:CuSO4, S:H2O, rt → 50°C; 30 min, 50°C; 50°C → Solvents: 2, Steps: 1, Stages: 3, Most stages
0°C in any one step: 3
References
1.2 R:NaOH, S:H2O, S:MeOH, overnight, rt
Discovery of Nanomolar Dengue and West
1.3 R:HCl, S:H2O Nile Virus Protease Inhibitors Containing a 4-
Benzyloxyphenylglycine Residue
By Behnam, Mira A. M. et al
From Journal of Medicinal Chemistry, 58(23),
9354-9370; 2015
General/Typical Procedure: General Procedure for the Synthesis of (4-Hydroxy)-phenyl-glycine Ethers.
A solution of the amino acid (1 equiv) in 1 M NaOH (1 equiv) and a solution of CuSO4·5H2O (0.67
equiv) in water (10 mL) were warmed to 50 °C under stirring. Both solutions were combined, and the
reaction mixture was stirred for 30 min at 50 °C. After cooling on an ice water bath, the blue precipitate
of the amino acid Cu-complex separated immediately. The precipitate was isolated, washed with
water, and dried. The Cu-complex was dissolved in methanol (25 mL) and 1 M NaOH (1 equiv). The
corresponding benzyl or phenacyl bromide (1.1 equiv) was added, and the mixture was stirred at room
temperature overnight. The insoluble Cu-complex of the resulting ether was collected by filtration,
washed with MeOH, and then with water to remove excess of the unreacted starting material. Finally, 1
M HCl (2 equiv) was added to release the product from the Cu-complex. The precipitated product was
washed with water and dried under reduced pressure.34 The crude product was used for subsequent
synthetic steps without further purification. (4-Benzyloxy)-L-phenylglycine (3a). Compound 3a was
obtained according to the general procedure from (4-hydroxy)-L-phenylglycine (1003 mg, 6 mmol) and
benzyl bromide (0.78 mL, 6.6 mmol). [4-(4-Bromo)phenacyloxy]-D-phenylglycine (22a). Compound
22a was obtained according to the general procedure from (4- hydroxy)-D-phenylglycine (1003 mg, 6
mmol) and 2,4'-dibromo acetophenone (2001 mg, 6.6 mmol). A yellow solid (900 mg, 37% yield). 1H
NMR (300 MHz, DMSO-d 6/NaOD) δ 7.56 (d, J = 8.5 Hz, 2H), 7.30 (d, J = 8.5 Hz, 2H), 7.21 (d, J = 8.6
Hz, 2H), 6.89 (d, J = 8.6 Hz, 2H), 3.95 (s, 2H), 3.74 (s, 1H). 13C NMR (APT, 75 MHz, DMSO-d
6/NaOD) δ 204.39, 173.99, 157.78, 133.50, 131.38, 130.18, 129.93, 127.46, 127.25, 126.81, 117.90,
114.31, 73.22, 60.34. HRMS (ESI): m/z [M H] calcd for C16H13BrNO4, 362.0033; found, 362.0022.
Reaction Protocol
Step 1
126. 2 Steps
[Step 2.1]
Overview
Steps/Stages Notes
1.1 C:H2O, C:H2SO4, 6 h, 65°C 2) product obtained as mixture of cis and trans
isomers, Reactants: 3, Reagents: 3, Catalysts:
1.2 R:NaHCO3, S:H2O 2, Solvents: 2, Steps: 2, Stages: 4, Most
2.1 R:Na+ •(AcO)3BH-, S:ClCH2CH2Cl, 23 h, rt
References
2.2 R:H2O Preparation of oxazolidinone compounds and
derivatives thereof as inhibitors of tankyrase
By Bregman, Howard et al
From PCT Int. Appl., 2013134079, 12 Sep
2013
Step 1
Step 1: (S)-Methyl 2-amino-2-phenylacetate. A catalytic amount of concentrated sulfuric acid (0.1 mL)
was added to a 50 mL round bottom flask containing a solution of (S)-2-amino-2-phenylacetic acid
(commercially available from Sigma-Aldrich, Milwaukee, WI) (1.0 g, 6.6 mmol) in MeOH (10 mL). The
resulting mixture was heated at 65°C for 6 hours. The solvent was removed under reduced pressure,
and the mixture was quenched with aqueous NaHCO3 and extracted with EtOAc. The organic layer
was dried over Na2SO4, filtered, and concentrated. Yield: (0.8 g, 74.0%) as a white solid. 1H NMR (300
MHz, CDCl3) δ: 7.37-7.32 (m, 5H), 4.62 (s, 1H), 3.70 (s, 3H).
Step 2
Step 2: (S)-Methyl 2-((4-hydroxycyclohexyl)amino)-2-phenylacetate. (S)-(+)-2-Phenylglycine methyl
ester (commercially available from Sigma-Aldrich, Milwaukee, WI, 433 g, 2.146 mol) was added to a
solution of 4-hydroxycyclohexanone (245 g, 2.146 mol) in DCE (8.5 L). Sodium triacetoxyborohydride
was added (910 g, 4.292 mol), and the mixture was stirred at room temperature under nitrogen for 23
hours. Water (3 L) was added to quench the reaction, and the organic layer was separated. The
aqueous phase was extracted with DCM (4 L×2) and the organic layers were combined, dried, filtered
and concentrated. The residue was purified by column chromatography (gradient elution with 100%
DCM to DCM/MeOH=25:1). Yield: (197 g, 35%) (mixture of cis and trans). m/z (ESI) 264 (M+H)+.
Reaction Protocol
Step 1
Step 2
Overview
Steps/Stages Notes
literature preparation, literature preparation,
1.1 R:NaH, S:THF, S:DMSO, 15 min, 0°C alternative reaction conditions shown,
1.2 S:THF, 15 min, 0°C; 2 h, 0°C regioselective, stereoselective, molecular
sieves used, Reactants: 4, Reagents: 5,
1.3 R:H2O, 0°C Catalysts: 1, Solvents: 3, Steps: 4, Stages: 6,
1.1 R:NaBH4, R:I2, S:THF, reflux
References
2.1 R:Et3N, S:CH2Cl2, rt One-Pot Synthesis of Oxazolidine Derivatives
3.1 C:BF3-Et2O, S:CH2Cl2, 2 h, rt by [3+2]-Annulation Reactions of 1-Tosyl-2-
phenyl/alkylaziridines with Aryl Epoxides
By Pandey, Ashok Kumar and Banerjee,
Prabal
From Asian Journal of Organic Chemistry,
5(3), 360-366; 2016
Reaction Protocol
Sequence 1
Step 1
Products α-Methylstyrene oxide, 90%, CAS RN:2085-88-3
Reactants Trimethylsulfonium iodide, CAS RN:2181-42-2
Acetophenone, CAS RN:98-86-2
Reagents Sodium hydride, CAS RN:7646-69-7
Dimethyl sulfoxide, CAS RN:67-68-5
Procedure 1. Charge a two-neck, round-bottom flask with NaH (0.25 g, 10.42 mmol).
2. Wash paraffin oil of NaH with dry hexane.
3. Subject the flask at 0 °C.
4. Add dry DMSO to the mixture.
5. Add THF (1:1, 40 ml) followed by addition of trimethylsulfonium iodide (3.17 g, 10.42 mmol) to the
cooled reaction mixture.
6. Stir the reaction mixture for 15 minutes at 0 °C.
7. Add THF solution of acetophenone (4.17 mmol) dropwise to the mixture over 15 minutes.
8. Monitor the reaction by TLC for 2 hours.
9. After completion of reaction, quench the mixture with ice cold water.
10. Extract the aqueous reaction mixture with diethyl ether.
11. Wash the organic layer three to four times with water.
12. Dry the organic layer over anhydrous Na2SO4.
13. Evaporate the solvent on rotary evaporator at reduced pressure in cold water.
14. Subject the crude product to the cycloaddition reaction.
Scale milligram
1H NMR 400 MHz: δ (ppm) 7.21-7.39 (m, 5H), 2.91 (d, J = 5.4 Hz, 1H), 2.74 (d, J = 5.4 Hz, 1H), 1.65 (s, 3H).
Number
Sequence 2
Step 1
Sequence 2
Step 2
Sequence 2
Step 3
Products Oxazolidine, 3-[(4-methylphenyl)sulfonyl]-5-phenyl-2-[(1S)-1-phenylethyl]-, (2S,5R)-, 87%, CAS
RN:1865745-90-9
Oxazolidine, 3-[(4-methylphenyl)sulfonyl]-5-phenyl-2-[(1R)-1-phenylethyl]-, (2S,5R)-, 87%, CAS
RN:1865745-91-0
Reactants (2S)-1-[(4-Methylphenyl)sulfonyl]-2-phenylaziridine, CAS RN:149769-84-6
α-Methylstyrene oxide, CAS RN:2085-88-3
Catalysts Boron trifluoride etherate, CAS RN:109-63-7
Procedure 1. Charge a round-bottom flask containing a magnetic stirrer bar with 2-methyl-2-phenyloxirane (0.22
mmol), 2-phenyl-1-tosylaziridine (0.19 mmol), 4Å molecular sieves (200 wt%) and BF3OEt2 (50 mol%)
under a nitrogen atmosphere.
2. Add dry dichloromethane to the mixture.
3. Stir the reaction mixture at room temperature.
4. Monitor the reaction by TLC for 2 hours.
5. After completion, filter the mixture through Celite.
6. Evaporate the solvent under reduced pressure.
7. Purify the product by flash column chromatography on silica.
Scale milligram
1H NMR 400 MHz, CDCl3 δ = 7.82 (d, J = 8.1 Hz, 2H), 7.32-7.29 (m, 5 H), 7.27-7.22 (m, 5H), 6.92 (d, J = 8.1
Hz, 2H), 5.37 (d, J = 4.2 Hz, 1 H), 3.92 (dd, J = 10.1, 5.3 Hz, 1 H), 3.69 (dd, J =11.9, 5.3 Hz, 1 H), 3.31
(td, J =11.2, 4.2 Hz, 1 H), 2.49 (dd, J =11.9, 10.1 Hz, 1 H), 2.5 (s, 3H), 1.49 ppm (d, J = 2.1 Hz, 3H).
13C NMR 100 MHz, CDCl3 δ = 17.0, 21.7, 45.1, 53.5, 78.7, 94.8, 126.6, 126.9, 127.9, 128.5, 128.6, 128.8, 129.7,
130.6, 135.2, 136.4, 140.3, 144.5 ppm.
IR Neat: νmax = 3062, 3030, 2924, 2854, 1597, 1494, 1417, 1379, 1163, 1090, 991, 815, 756, 697, 663
cm-1.
[α]D20 [α]20D = -24.22° (c = 2.4, CHCl3).
HRMS ESI m/z: calcd for C24H25NNaO3S: 430.1447 [M+Na]+ found: 430.1485.
Rf 0.55, EtOAc/hexane = 1:10 (v/v).
State viscous liquid.
Number
128. 4 Steps
[Step 2.1]
[Step 4.1]
Overview
Steps/Stages Notes
1.1 R:Et3N, R:S, S:EtOH, 16 h, reflux 4, Stages: 5, Most stages in any one step: 2
2.1 R:HCl, S:H2O, 16 h, reflux References
Preparation of fused bicyclic and tricyclic
3.1 R:POCl3, 3 h, 55-65°C pyrimidine compounds as tyrosine kinase
inhibitors
3.2 R:NaHCO3, S:H2O By Hsieh, Hsing-Pang et al
4.1 S:BuOH, 16 h, 80°C
From U.S. Pat. Appl. Publ., 20100120805, 13
May 2010
Step 1
2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-ylcyanide (step a): To a mixture of cyclohexanone (1.18
g), malononitrile (0.66 g), and sulphur (0.40 g) in absolute ethanol (3 ml) was added triethylamine (2
mL). After refluxed for 16 h, the reaction mixture was concentrated and the residue was partitioned
between water and ethyl acetate. The organic layer was concentrated and the crude compound was
purified by silica gel column chromatography using a mixture of hexanes:ethyl acetate (4:1), to give the
title compound (0.94 g, 44%). 2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-ylcyanide, Yield (0.94 g,
44%).
Step 2
3,4,5,6,7,8-Hexahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-one (step b): To a mixture of 2-amino-
4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl cyanide (0.9 g) and formic acid (10 mL) was added 0.1
mLconc. HCl. After refluxed for 16 h, the reaction mixture was cooled and water (20 mL) was added.
The precipitate was collected by filtration and washed thoroughly with water and hexanes to give the
title compound (0.8 g, 77%). 3,4,5,6,7,8-Hexahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-one, Yield (0.8
g, 77%). 1H NMR (300 MHz, CDCl3): δ 7.91 (s, 1H), 3.03-3.00 (m, 2H), 2.80-2.77 (m, 2H), 1.89-1.83
(m, 4H).
Step 3
4-Chloro-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine (step c): A mixture of 3,4,5,6,7,8-
hexahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-one (0.8 g) and POCl3 (10 mL) was heated at 55-65°C.
for 3 h. Water was then added followed by sodium bicarbonate. The resulting mixture was extracted
with ethyl acetate. The organic layer was concentrated and the crude compound was purified by silica
gel column chromatography using a mixture of hexanes: ethyl acetate (20:1), to give the title
compound (0.52 g, 60%). 4-Chloro-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-djpyrimidine, Yield (0.52 g,
60%). 1H NMR (300 MHz, CDCl3): δ 8.69 (s, 1H), 3.10-3.07 (m, 2H), 2.88-2.86 (m, 2H), 1.89-1.92 (m,
4H). LC-MS (ESI) m/z 225.3 (M+H).
Step 4
General/Typical Procedure: S-2-Phenyl-2-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-
ylamino)-ethanol (Compound 1, step d): A mixture of 4-chloro-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-
d]pyrimidine (1 g) and S-2-amino-2-phenyl-ethanol (0.672 g, 1.1 eq) in n-butanol (1 mL) was heated at
80°C. for 16 h. The reaction mixture was concentrated and the residue was partitioned between water
and dichloromethane. The organic layer was washed with brine, dried over MgSO4 and concentrated.
The crude compound was purified by silica gel column chromatography using a mixture of
dichloromethanemethanol (30:1), to give the title compound (0.88 g). Compound 18. 1H NMR (300
MHz, CDCl3): δ 9.00 (s, 1H), 7.22-7.31 (m, 5H), 5.78 (s, 1H), 2.78-3.07 (m, 4H), 1.84-2.01 (m, 4H).
Reaction Protocol
Step 1
Step 2
Step 3
Step 4
129. Single Step
95%
Overview
Steps/Stages Notes
References
Edition, 52(51), 13651-13655; 2013
Reaction Protocol
Step 1
Products 2,3-Dihydro-2-(phenylmethyl)-1H-inden-1-one, 95%, CAS RN:16307-30-5
1-Indanone, CAS RN:83-33-0
RN:1221406-59-2
Scale milligram
1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 7.7 Hz, 1H), 7.42-7.27 (m, 7H), 3.41 (dd, J = 14.0, 4.4 Hz, 1H), 3.17
(dd, J = 17.2, 7.7 Hz, 1H), 3.01 (dddd, J = 10.5, 7.7, 4.4, 4.0 Hz, 1H), 2.86 (dd, J = 17.2, 4.0 Hz, 1H),
2.66 (dd, J = 14.0, 10.5 Hz, 1H) ppm.
13C NMR 13C{1H} NMR (100 MHz, CDCl ) δ 207.8, 153.6, 139.6, 136.5, 134.8, 128.9, 128.5, 127.4, 126.6,
3
126.3, 124.0, 48.9, 37.0, 32.1 ppm.
Number
130. Single Step
Overview
Steps/Stages Notes
H-Y Zeolite used as catalyst stage 4,
1.1 R:SOCl2, S:MeOH, 30 min, cooled Reactants: 2, Reagents: 4, Solvents: 3, Steps:
antagonists
2010
General/Typical Procedure: To ice-chilled methanol (300 mL) under argon, thionyl chloride (50 mL,
660 mmol) was carefully added dropwise over 30min. Then, phenylglycine (50 g, 330 mmol) was
added. The ice-bath was removed and the reaction mixture was heated to reflux for 16h. The reaction
was then evaporated under reduced pressure. Diethyl ether (200 mL) was added followed by filtration.
Phenyl glycine methyl ester hydrochloride from Step A. (64 g, 317 mmol) was dissolved in ammonia
(150 mL) and stirred at room temperature under argon for 16h. The reaction mixture was extracted
with DCM (200 mL × 3), dried over Na2SO4 and evaporated under reduced pressure. To the product of
step B above (0.5 g, 3.3 mmol) in methanol was added cyclohexanone (0.32 g, 3.3 mmol) and H-Y
Zeolizes (1.0 g), and the mixture stirred under reflux for 24 h under argon. The reaction was allowed to
cool to room temperature and was filtered and the solid washed well with methanol. The filtrate was
evaporated. From Step C above (3 g, 13 mmol) was dissolved in DCM and was stirred at room
temperature for 16h under argon atmosphere with N-Bromosuccinimide (2.3 g, 13 mmol), A solution of
saturated sodium bicarbonate was added and stirring continued for 1h at room temperature. The
organic layer was separated, dried and evaporated under reduced pressure. Intermediate 10-c. 1H
NMR (DMSO-d6, 400 MHz) 0δ: 7.72-7.75 (m, 1H), 7.33-7.35 (m, 1H), 7.23-7.29 (m, 2H), 2.38 (s, 3H),
1.46-1.75 (m, 10H).
Reaction Protocol
Step 1
131. 2 Steps
[Step 2.1]
Overview
Steps/Stages Notes
2) H-Y zeolites, Reactants: 2, Reagents: 2,
1.1 R:SOCl2, S:MeOH, 30 min, cooled; 3 h, reflux; cooled Solvents: 3, Steps: 2, Stages: 3, Most stages
in any one step: 2
1.2 R:NH4OH, S:H2O, overnight, rt
2.1 S:EtOH, 24 h, reflux; reflux → rt; 4 d, rt References
Preparation of N-phenyl-2-oxo-1,4-
diazaspiro[4.5]dec-3-en-1-yl acetamide
derivatives and their use as glycine
transporter inhibitors
By Coulton, Steven et al
2007
Step 1
2-Amino-2-[4-(methyloxy)phenyl]acetamide.To an ice-cold suspension of 4-methoxyphenylglycine
(3.77g; 0.021mol) in methanol was added thionyl chloride dropwise over 30min. After complete
addition, the reaction mixture was heated at reflux for 3h, cooled and evaporated. The resulting solid
was dissolved in 0.88 ammonia (100ml) and stirred at room temperature overnight. The reaction was
extracted twice with DCM and the organic phases separated with a Phase-Separation cartridge and
evaporated under reduced pressure to afford the title product (0045g; 12%) as a white solid. 1H NMR
(CDCl3) δ: 1.77 (2H, br s), 3.80 (3H, s), 4.50 (1H, s), 5.52 (1H, s), 6.83 (1H, s), 6.87 - 6.91 (2H, m),
7.33 - 7.36 (2H, m).
Step 2
General/Typical Procedure: 3-{4-Chlorophenyl)-1,4-diazaspiro[4.5]decan-2-one. To 2-amino-2-(4-
chlorophenyl)acetamide D2 (10.00g; 54.3mmol) in methanol (500ml) was added cyclohexanone
(5.62ml; 54.3mmol) and H-Y zeolites (10.00g) and the mixture stirred under reflux for 24h. The
reaction was allowed to cool to room temperature and after 4 days was filtered and the solid washed
well with methanol. The filtrate wasevaporated to afford the title product (12.91g; 90%) as a white
solid. The title compound (1.92g; 56%) was obtained from 2-amino-2-[4-(methyloxy)phenyl]acetamide
D8 (2.50g; 1.39mmol), cyclopentanone (1.24ml; 1.39mmol) and H-Y zeolites (5g) in ethanol (200ml) in
a similar manner to that described in D3. Mass Spectrum (Electrospray LC/MS): Found 247 (MH+).
C14H18N2O2 requires 246. Ret. time 1.28/1.33 min.
Reaction Protocol
Step 1
Step 2
132. 3 Steps
[Step 2.1]
Overview
Steps/Stages Notes
in any one step: 2
2.1 S:EtOH, 24 h, reflux; reflux → rt; 4 d, rt References
3.1 R:Bromosuccinimide, S:CH2Cl2, overnight, rt diazaspiro[4.5]dec-3-en-1-yl acetamide
3.2 R:NaHCO3, S:H2O, 0.5 h, rt transporter inhibitors
2007
Step 1
7.33 - 7.36 (2H, m).
Step 2
solid. The title compound (1.92g; 56%) was obtained from 2-amino-2-[4-(methyloxy)phenyl]acetamide
D8 (2.50g; 1.39mmol), cyclopentanone (1.24ml; 1.39mmol) and H-Y zeolites (5g) in ethanol (200ml) in
a similar manner to that described in D3. Mass Spectrum (Electrospray LC/MS): Found 247 (MH+).
C14H18N2O2 requires 246. Ret. time 1.28/1.33 min.
Step 3
General/Typical Procedure: 3-{4-Chlorophenyl)-1,4-diazaspiro[4.5]dec-3-en-2-one. N-
Bromosuccinimide (8.69g; 48.81mmol) was added in one portion to a stirred solution of 3-(4-
chlorophenyl)-1,4-diazaspiro[4.5]decan-2-one D3 (12.91g; 48.81mmol) in DCM (400ml) and the
mixture stirred overnight at room temperature. Saturated aqueous sodium bicarbonate (500ml) was
added and the mixture stirred for 0.5h.The layers were separated and the aqueous extracted with
DCM (300ml). The combined organics were dried (Na2SO4) and the solvent removed under reduced
pressure at 45°C. The residual solid was partitioned between DCM (500ml) and saturated aqueous
sodium bicarbonate (500ml) and stirred overnight at room temperature. The aqueous layer was
extracted with DCM (300ml) and the organic layers combined, dried(Na2SO4) and the solvent removed
under reduced pressure to afford the title product (10.25g; 80%) as a pale yellow solid. The title
product (1.92g; 100%) was obtained from 3-[4-(methyloxy)phenyl]-1,4-diazaspiro[4.4]nonan-2-one D15
(1.92g; 7.8mmol) and N-bromosuccinimide (1.40g; 7.8mmol) in DCM (150ml) using a method similar to
that described in D4. 1H NMR(CDCl3) inter alia δ: 1.80 - 2.20 (8H, m), 3.87 (3H, s), 6.94 - 6.97 (2H, m),
7.98 (1H, br s), 8.36 - 8.40 (2H, m). Mass Spectrum (Electrospray LC/MS): Found 245 (MH+).
C14H16N2O2 requires 244. Ret. time 2.45 min.
Reaction Protocol
Step 1
Step 2
Step 3
133. Single Step
85%
Overview
Steps/Stages Notes
tube used, optimized on
oxidant,catalyst,solvent,temperature,reaction
time, optimization study, mechanism studied,
in any one step: 1
References
United Kingdom), 47(33), 9513-9515; 2011
Reaction Protocol
Step 1
Products 2,4-Diphenylquinazoline, 85%, CAS RN:31730-65-1
Reactants 2-Aminobenzophenone, CAS RN:2835-77-0
Procedure 1. Heat (2-aminophenyl)(phenyl)methanone (39.4 mg, 0.2 mmol), phenylglycine (45.3 mg, 0.3 mmol),
I2 (25.4 mg, 0.1 mmol) and TBHP (55 µL of 70 % aqueous solution, 0.4 mmol) in DMA (0.5 mL) at 80
°C for 18 hours in a sealed tube.
3. Purify the residue by column chromatography over silica gel to obtain the product.
Scale milligram
1H NMR (300 MHz, CDCl3) δ (ppm) 8.72-8.68 (m, 2 H), 8.15 (d, J= 8.8 Hz, 1 H), 7.92-7.86 (m, 3 H), 7.61-7.50
(m, 7 H)
128.6,127.0, 121.8
State light yellow solid
Number
134. Single Step
78%
Overview
Steps/Stages Notes
References
United Kingdom), 47(33), 9513-9515; 2011
Reaction Protocol
Step 1
Products 4-Cyclopropyl-2-phenylquinazoline, 78%, CAS RN:1229609-96-4
(2-Aminophenyl)cyclopropylmethanone, CAS RN:136832-46-7
sealed tube.
3. Purify the residue by column chromatography over silica gel to obtain 4-cyclopropyl-2-
phenylquinazoline.
1H NMR (300 MHz, CDCl3) δ (ppm) 8.61-8.57 (m, 2 H), 8.27 (d, J = 8.4Hz, 1 H), 8.05 (d, J = 8.4 Hz, 1 H), 7.86-
7.79 (m, 1 H), 7.58-7.45 (m, 4 H), 2.83-2.74 (m,1 H), 1.57-1.51 (m, 2 H), 1.28-1.21 (m, 2 H)
13C NMR (75 MHz, CDCl3) δ (ppm) 172.1,159.9, 150.4, 138.6, 133.2, 130.3, 129.3, 128.53, 128.47, 126.6,
124.4, 123.0, 13.0, 12.2
State yellow solid
Number
135. Single Step
22%
Overview
Steps/Stages Notes
1.1 R:t-BuOK, S:MeOH, 15 min, rt 1, Stages: 2, Most stages in any one step: 2
1.2 R:YbCl3, S:MeOH, rt; overnight, rt References
New amino acid ligated yttrium hydroxy
clusters
By Thielemann, Dominique T. et al
From Dalton Transactions, 39(29), 6661-
6666; 2010
Reaction Protocol
Step 1
Products Yttrium, tetrakis[µ-[α-(amino-κN)benzeneacetato-κO:κO]]hexakis(1,3-diphenyl-1,3-propanedionato-
κO1,κO3)tetra-µ3-hydroxy-µ4-hydroxypenta-, 22%, CAS RN:1243985-83-2
Dibenzoylmethane, CAS RN:120-46-7
Reagents Potassium tert-butoxide, CAS RN:865-47-4
Ytterbium chloride, CAS RN:10361-91-8
Procedure 1. Stir a solution of KOtBu (1.168 g, 9.89 mmol, 3 eq.) in 20 mL of methanol.
2. Add the α-amino acids (2.64 mmol, 0.8 eq.) D-phenyl glycine (399 mg) to the above mixture.
3. Add dibenzoylmethane (905 mg, 3.96 mmol, 1.2 eq.) to the above mixture, which turn its colour from
colourless to pale yellow.
4. Stir the above mixture for 15 min, .
5. Add a solution of [YCl3·(H2O)6] (1.00 g, 3.30 mmol, 1 eq.) in 20 mL of methanol dropwise to the
above mixture.
6. Form a flaky white precipitate.
7. Stir the reaction overnight at room temperature.
8. Filter off the precipitate, wash with methanol (3 x 20 mL) and air-dry.
9. Extract the resulting yellow solids of compounds with 20 mL of dichloromethane.
10. Filter the solution and cool to -80 °C to obtain the product.
Transformation Coordination of a Metal to Carbon and Heteroatom
Scale milligram
1H NMR (CDCl3 , 400 MHz): δ5.29 (2H, s, CH2Cl2), 6.15 (4H, t, J = 10.3 Hz, CH (PhGly)), 6.23 (4H, s, CH
(Ph2acacbas)), 6.42 (2H, s, CH (Ph2acacap)), 6.71 (10H, m, Ph), 6.84 (8H, m, Ph), 7.04 (10H, m, Ph),
7.11 (10H, m, Ph), 7.16 (10H, m, Ph), 7.36 (12H, m, Ph), 7.62 (20H, m, Ph), 7.82 (8H, br s, NH2)
13C NMR (CDCl3, 400 MHz): δ60.7 (α-CH), 95.3 (CH (Ph2acac)), 127.2 (Ar-C), 127.4 (Ar-C), 127.7 (Ar-C), 128.2
(Ar-C), 129.0 (Ar- C), 130.7 (p-Ar-C), 131.1 (p-Ar-C), 140.0 (i-Ar-C), 141.6 (i-Ar- C), 180.7 (carboxyl-
C), 182.4, 183.5, 185.7 (CO (Ph2acacap/bas))
IR [cm-1]: 3348, 3285, 3060, 1593, 1552, 1517, 178, 1453, 1395, 1311, 1024, 1009, 943, 597
[α]D 20 [α]20 = 754.92 (CH2Cl2, c = 0.60)
Crystal C122H103N4O25Y5·3(CH2Cl2), M = 2724.41, orthorhombic, a = 18.175(5) AË , b = 19.080(5) AË , c =
Structure Data 33.846(5) AË , V = 11737(5) AË 3, T = 200(2) K, space group P212121, Z = 4, µ(Mo-Ka) = 2.657 mm-1,
82578
Elemental C122H103N4O25Y5·CH2Cl2 (2554.60) Calcd: C 57.83, H 4.14 N 2.19. Found: C 57.76, H 4.25, N 1.87
Analysis
Raman [cm-1]: 3055, 1594 (νCO), 1487, 1439, 1288, 1283, 1175, 1059, 1004, 998, 939, 780, 669, 604, 396.
C122H103N4O25Y5·CH2Cl2 (2554.60)
State single crystals
Number
Overview
Steps/Stages Notes
in any one step: 2
References
2.1 2 h, 70°C 23(52), 12758-12762; 2017

4.1 C:2127845-78-5, S:CH2Cl2, 36 h, rt
Reaction Protocol
Sequence 1
Step 1
Sequence 2
Step 1
Sequence 2
Step 2

Sequence 2
Step 3
Sequence 2
Step 4
137. 2 Steps
[Step 2.1]
Overview
Steps/Stages Notes
1.1 R:NaBH4, S:THF, rt → 0°C Solvents: 3, Steps: 2, Stages: 5, Most stages
in any one step: 4
1.2 R:I2, S:THF, 40 min, 0°C; 18 h, reflux; reflux → rt
References
1.3 R:MeOH, rt; 30 min, rt Dual Catalyst System for Asymmetric
Alternating Copolymerization of Carbon
1.4 R:KOH, S:H2O, 4 h, rt Dioxide and Cyclohexene Oxide with Chiral
2.1 C:HCO2H, S:PhMe, 48 h, reflux Aluminum Complexes: Lewis Base as
Monomer Activator
United States), 45(20), 8172-8192; 2012
Step 1
3.57- 3.52 (t, 1H), 2.20-2.01 (br, 3H). IR (KBr, cm-1): 3420, 3405, 3325, 3150, 3110, 3065, 3028, 2939,
2920, 2895, 2850, 2690, 1601, 1499, 1472, 1462, 1360, 1052, 1040, 935, 800, 775, 703.
Step 2
3-((S)-2-Hydroxy-1-phenylethylimino)-1,3-diphenylprop-1-en-1-ol (2hH2).76 L-Phenylglycinol (2.19 g,
10.0 mmol) and dibenzoylmethane (2.24 g, 10.0 mmol) were dissolved in toluene (50 mL) in a 100-mL
round-bottomed flask equipped with a reflux condenser. After one drop of formic acid was added to
this solution, the mixture was heated under reflux for 48 h. The mixture was concentrated under
reduced pressure to leave a yellow oil. The crude oil was purified by silica gel column chromatography
with ethyl acetate to afford a compound. Yellow viscous oil, yield 1.65 g, 48%. [α]D -366° (c 1.8,
CHCl3). 1H NMR (CDCl3): δ 12.16-11.98 (br, 1H), 7.91-7.85 (d, 2H), 7.42-7.11 (m, 13H), 5.75 (s, 1H),
4.67-4.58 (m, 1H), 4.04- 3.90 (br, 1H), 3.87-3.81 (m, 2H). 13C NMR (CDCl3): δ 188.9, 167.4, 140.1,
139.6, 135.4, 130.9, 129.5, 128.8, 128.4, 128.3, 127.8, 127.6, 127.2, 126.5, 94.6, 67.4. FAB-MS m/z:
344 [for C23H22NO2 [M + H]+].
Reaction Protocol
Step 1
IR (KBr, cm-1): 3420, 3405, 3325, 3150, 3110, 3065, 3028, 2939, 2920, 2895, 2850, 2690, 1601, 1499,
1472, 1462, 1360, 1052, 1040, 935, 800, 775, 703
[α]D20 [α]D28 +29° (c 0.8, 1 M HCl aq)
MP 73- 76 °C
Number
Step 2
Products Benzeneethanol, β-[(3-hydroxy-1,3-diphenyl-2-propen-1-ylidene)amino]-, (βS)-, 48%, CAS
RN:1403239-83-7
Catalysts Formic acid, CAS RN:64-18-6
Procedure 1. Dissolve L-phenylglycinol (2.19 g, 10.0 mmol) and dibenzoylmethane (2.24 g, 10.0 mmol) in toluene
(50 mL) in a 100-mL round-bottomed flask equipped with a reflux condenser.
2. Add one drop of formic acid to this solution.
3. Heat the mixture under reflux for 48 hours.
4. Concentrate the mixture under reduced pressure to obtain a yellow oil.
5. Purify the crude oil by silica gel column chromatography with ethyl acetate to afford 3-((S)-2-
hydroxy-1-phenylethylimino)-1,3-diphenylprop-1-en-1-ol.
Scale gram
1H NMR (CDCl3): δ 12.16-11.98 (br, 1H), 7.91-7.85 (d, 2H), 7.42-7.11 (m, 13H), 5.75 (s, 1H), 4.67-4.58 (m, 1H),
4.04- 3.90 (br, 1H), 3.87-3.81 (m, 2H)
13C NMR (CDCl3): δ 188.9, 167.4, 140.1, 139.6, 135.4, 130.9, 129.5, 128.8, 128.4, 128.3, 127.8, 127.6, 127.2,
126.5, 94.6, 67.4
[α]D20 [α]D -366° (c 1.8, CHCl3)
State yellow viscous oil
Number
Overview
Steps/Stages Notes
literature preparation, no experimental detail,
1.1 R:AcCl, S:MeOH, 2 min, 0°C Dean-Stark conditions used (stage 2),
1.2 24 h, rt Reactants: 3, Reagents: 5, Catalysts: 2,
1.1 in any one step: 2
2.1 R:NaBH4, S:MeOH, 10 min, rt; 1 h, rt References
2.2 C:p-MeC6H4SO3H, S:Benzene, 7 h, reflux
Pyrrolidine and thiazole derivatives with
3.1 R:NaOH, S:H2O, S:MeOH, 2 d, rt metallo-β-lactamase inhibitory properties
By Bateson, John Hargreaves and Best,
4.1 R:Cl(O=)CC(=O)Cl, C:DMF, S:CH2Cl2, 30 min, rt Desmond John
From PCT Int. Appl., 9840056, 17 Sep 1998
4.2 R:Et3N, S:CH2Cl2, rt; 1 h, rt
Reaction Protocol
Sequence 1
Step 1
Sequence 2
Step 1

Sequence 2
Step 2
Sequence 2
Step 3
Sequence 2
Step 4
139. Single Step
45%
Overview
Steps/Stages Notes
green chem., sealed tube used, product
1.1 R:(NH4)2S2O8, C:I2, S:H2O, S:AcNMe2, 80°C depends on oxidant, alternative preparation
shown, Reactants: 2, Reagents: 1, Catalysts:
References
United Kingdom), 47(33), 9513-9515; 2011
Reaction Protocol
Step 1
Products 4-Phenylquinazoline, 45%, CAS RN:17629-01-5
Reactants 2-Aminobenzophenone, CAS RN:2835-77-0
Reagents Ammonium persulfate, CAS RN:7727-54-0
Procedure 1. Heat (2-aminophenyl)(phenyl)methanone (0.2 mmol), phenylglycine (0.3 mmol), I2 ( 0.1 mmol) and
ammonium persulfate in DMA (0.5 mL) at 80 °C in a sealed tube.
3. Purify by column chromatography over silica gel to obtain 4-phenylquinazoline.
1H NMR (400 MHz, CDCl3) δ (ppm) 9.39 (s, 1 H), 8.24 (d, J = 8.8 Hz, 2 H), 7.95-7.90 (m, 1 H), 7.82-7.76 (m, 2
H), 7.64-7.56 (m, 4 H)
123.3
State needle-like solid
Number
140. 4 Steps
[Step 2.1]
[Step 4.1]
Overview
Steps/Stages Notes
2.1 2 h, 70°C step: 2

23(52), 12758-12762; 2017
Reaction Protocol
Step 1
Step 2
Step 3
Step 4
141. Single Step
77%
Overview
Steps/Stages Notes
1.1 S:MeOH, -78°C → rt; 3-48 h, rt reaction may also run at reflux temperature,
conversion-40%, Reactants: 4, Solvents: 1,
Steps: 1, Stages: 1, Most stages in any one
step: 1
References
A method for the synthesis of amino acid
derivatives
By Mjalli, Adnan M. M.
2000
Reaction Protocol
Step 1
142. Single Step
85%
Overview
Steps/Stages Notes
1.1 C:1967791-32-7, S:H2O, S:MeOH, 5 d, 20°C alternative reaction conditions shown,
Reactants: 2, Catalysts: 1, Solvents: 2, Steps:
References
Preparation of chiral pyridoxamine
compounds as catalysts for synthesizing
chiral amino acids
By Zhao, Baoguo et al
16 Nov 2016
Reaction Protocol
Step 1
143. 2 Steps
[Step 2.1]
Overview
Steps/Stages Notes
1.2 R:NH4OH, S:H2O
References
1912; 2014
Reaction Protocol
Step 1
Number
Step 2
Products Imidazo[2,1-b]thiazole, 5,6-dihydro-3-(4-methoxyphenyl)-6-phenyl-, (6R)-, 44%, CAS RN:1580490-40-
9
4-Methoxyphenacyl bromide, CAS RN:2632-13-5
Number
144. Single Step
85%
Overview
Steps/Stages Notes
1.1 C:1967791-37-2, S:H2O, S:MeOH, 6 d, 20°C catalyst prepared and used, 63% e.e,
stereoselective, Reactants: 2, Catalysts: 1,
in any one step: 1
References
Asymmetric transamination of α-keto acids
catalyzed by chiral pyridoxamines
By Lan, Xiaoyu et al
From Organic Letters, 18(15), 3658-3661;
2016
Reaction Protocol
Step 1
145. 2 Steps
[Step 2.1]
Overview
Steps/Stages Notes
2) H-Y zeolites used, Reactants: 2, Reagents:
1.1 R:SOCl2, S:MeOH, 30 min, cooled; 3 h, reflux; cooled 2, Solvents: 1, Steps: 2, Stages: 3, Most
1.2 R:NH3, overnight, rt
2.1 S:MeOH, overnight, reflux; reflux → rt References
derivatives as glycine transporter inhibitors
2007
Step 1
Description 45: 2-Amino-2-[4-(methyloxy)phenyl]acetamide To an ice-cold suspension of 4-
methoxyphenylglycine (3.77g; 0.021 mol) in methanol was added thionyl chloride dropwise over
30min. After complete addition, the reaction mixture was heated at reflux for 3h, cooled and
evaporated. The resulting solid was dissolved in 0.88 ammonia (100ml) and stirred at room
temperature overnight. The reaction was extracted twice with DCM and the organic phases separated
with a Phase-Separation cartridge and evaporated under reduced pressure to afford the title product
(0.45g; 12%) as a white solid. 2-Amino-2-[4-(methyloxy)phenyl]acetamide, yield (0.45g; 12%). 1H NMR
(CDCl3) δ : 1.77 (2H, br s), 3.80 (3H, s), 4.50 (1H, s), 5.52 (1H, s), 6.83 (1H, s), 6.87 - 6.91 (2H, m),
7.33 - 7.36 (2H, m).
Step 2
General/Typical Procedure: Description 3: 3-[4-(Trifluoromethyl)phenyl]-1,4-diazaspiro[4.5]decan-2-
one To 2-amino-2-[4-(trifluoromethyl)phenyl]acetamide D2 (8.92g; 40.9mmol), in methanol (350ml)
was added cyclohexanone (4.24ml; 40.9mmol) and H-Y zeolites (8.92g) under argon and the mixture
refluxed overnight. After cooling to room temperature and chilling in an ice-bath the reaction mixture
was filtered. The solid was washed with methanol and 20 the filtrate evaporated under reduced
pressure to afford the title compound (10.59g; 86%) Description 46: 3-[4-(Methyloxy)phenyl]-1,4-
diazaspiro[4.5]decan-2-one The title compound (0.420g; 65%) was obtained from 2-amino-2-[4-
(methyloxy)phenyl]acetamide D45 (0.450g; 2.5mmol), cyclohexanone (0.245g; 2.5mmol) and H-Y
zeolites (1g) in methanol (20ml) in a similar manner to that described in D3. 1H NMR (CDCl3) δ : 1.44-
1.57 (4H, m), 1.71 - 1.73 (6H, m), 2.11 (1H, br s), 3.80 (3H, s), 4.64 (1H, s), 6.55 (1H, br s), 6.89 - 6.92
(2H, m), 7.36 - 7.40 (2H, m).
Reaction Protocol
Step 1
Step 2
146. 2 Steps
[Step 2.1]
Overview
Steps/Stages Notes
1.1 R:SOCl2, S:MeOH, 30 min, cooled; 3 h, reflux 2, Solvents: 1, Steps: 2, Stages: 3, Most
2.1 S:MeOH, 24 h, reflux; reflux → rt; 4 d, rt References
Preparation of diazaspirodecenyl-
diazaspiroundecenyl- and diazaspirononenyl
acetamides as GlyT1 transporter inhibitors for
the treatment of psychosis
By Dean, Anthony William and Porter,
Roderick Alan
From PCT Int. Appl., 2007014762, 08 Feb
2007
Step 1
Description 12: 2-Amino-2-[4-(methyloxy)phenyl]acetamide: To an ice-cold suspension of 4-
(0.45g; 12%) as a white solid. 1H NMR (CDCl3) δ: 1.77 (2H, br s), 3.80 (3H, s), 4.50 (1H, s), 5.52 (1H,
s), 6.83 (1H, s), 6.87 - 6.91 (2H, m), 7.33 - 7.36 (2H, m).
Step 2
General/Typical Procedure: Description 8: 3-(4-Chlorophenyl)-1,4-diazaspiro[4.5]decan-2-one: To 2-
amino-2-(4-chlorophenyl)acetamide D7 (10.00g; 54.3mmol) in methanol (500ml) was added
cyclohexanone (5.62ml; 54.3mmol) and H-Y zeolites (10.00g) and the mixture stirred under reflux for
24h. The reaction was allowed to cool to room temperature and after 4 days was filtered and the solid
washed well with methanol. The filtrate was evaporated. Description 13: 3-[4-(Methyloxy)phenyl]-1,4-
diazaspiro[4.5]decan-2-one, yield 0.420g, 65%. 1H NMR (CDCl3) δ: 1.44 - 1.57 (4H, m), 1.71 - 1.73
(6H, m), 2.11 (1H, br s), 3.80 (3H, s), 4.64 (1H, s), 6.55 (1H, br s), 6.89 - 6.92 (2H, m), 7.36 - 7.40 (2H,
m).
Reaction Protocol
Step 1
Step 2
147. 2 Steps
[Step 2.1]
Overview
Steps/Stages Notes
in any one step: 2
2007
Step 1
7.33 - 7.36 (2H, m).
Step 2
3-[4-(Methyloxy)phenyl]-1,4-diazaspiro[4.5]decan-2-one. The title compound (0.420g; 65%) was
obtained from 2-amino-2-[4-(methyloxy)phenyl]acetamide D8 (0.450g; 2.5mmol), cyclohexanone
(0.245g; 2.5mmol) and H-Y zeolites (1g) in methanol (20ml) in a similar manner to that described in
D3. 1H NMR (CDCl3) δ: 1.44 - 1.57 (4H, m), 1.71 - 1.73 (6H, m), 2.11 (1H, br s), 3.80 (3H, s), 4.64 (1H,
s), 6.55 (1H, br s), 6.89 - 6.92 (2H, m), 7.36 - 7.40 (2H, m).
Reaction Protocol
Step 1
Step 2
148. 2 Steps
[Step 2.1]
Overview
Steps/Stages Notes
2) H-Y zeolites used as catalyst, Reactants: 2,
1.1 R:SOCl2, S:MeOH, cooled; 30 min, cooled; 3 h, reflux Reagents: 2, Solvents: 1, Steps: 2, Stages: 3,
2.1 S:MeOH, 24 h, reflux References
Preparation of 1-(2-aryl-2-oxoethyl)-3-phenyl-
1,4-diazaspiro[4.5]dec-3-en-2-one derivatives
as glycine transporter inhibitors
By Branch, Clive Leslie et al
From PCT Int. Appl., 2007116061, 18 Oct
2007
Step 1
as a white solid, yield 0.45g, 12%. 1H NMR (CDCl3) δ: 1.77 (2H, br s), 3.80 (3H, s), 4.50 (1 H, s), 5.52
(1 H, s), 6.83 (1 H, s), 6.87 - 6.91 (2H, m), 7.33 - 7.36 (2H, m).
Step 2
amino-2-(4-chlorophenyl)acetamide D2 (10.0Og; 54.3mmol) in methanol (500ml) was added
cyclohexanone (5.62ml; 54.3mmol) and H-Y zeolites (10.0 g) and the mixture stirred under reflux for
washed well with methanol. The filtrate was evaporated to afford the title product as a white solid. 3-
[4-(Methyloxy)phenyl]-1,4-diazaspiro[4,5]decan-2-one, yield 0.420g; 65%. 1H NMR (CDCl3) δ: 1.44 -
1.57 (4H, m), 1.71 - 1.73 (6H, m), 2.1 1 (1 H, br s), 3.80 (3H, s), 4.64 (1 H, s), 6.55 (1 H, br s), 6.89 -
6.92 (2H, m), 7.36 - 7.40 (2H, m).
Reaction Protocol
Step 1
Step 2
149. 2 Steps
Overview
Steps/Stages Notes
1.1 S:MeOH, -78°C → rt; 3-48 h, rt 1) reaction may also run at reflux temperature,
conversion-40%, 2) procedure resubjected
2.1 R:H2, C:Pd(OH)2, S:MeOH, rt three times, Reactants: 4, Reagents: 1,
References
derivatives
2000
Reaction Protocol
Step 1
Step 2
150. Single Step
76%
Overview
Steps/Stages Notes
in any one step: 1
References
2016
Reaction Protocol
Step 1
151. Single Step
75%
Overview
Steps/Stages Notes
1.1 C:1852468-17-7, S:H2O, S:MeOH, 2 d, 25°C Reactants: 2, Catalysts: 1, Solvents: 2, Steps:
References
Pyridoxal catalyst and synthesis method and
application thereof
16 Dec 2015
Reaction Protocol
Step 1
152. Single Step
Overview
Steps/Stages Notes
References
chiral amino acids
16 Nov 2016
Reaction Protocol
Step 1
153. Single Step
Overview
Steps/Stages Notes
References
chiral amino acids
16 Nov 2016
Reaction Protocol
Step 1
154. 3 Steps
[Step 2.1]
Overview
Steps/Stages Notes
1.1 R:SOCl2, S:MeOH, 30 min, cooled; 3 h, reflux; cooled 4, Solvents: 3, Steps: 3, Stages: 5, Most
3.2 R:NaHCO3, S:H2O, rt By Coulton, Steven et al
2007
Step 1
7.33 - 7.36 (2H, m).
Step 2
(2H, m), 7.36 - 7.40 (2H, m).
Step 3
General/Typical Procedure: Description 4: 3-[4-(Trifluoromethyl)phenyl]-1,4-diazaspiro[4.5]dec-3-en-2-
one N-Bromosuccinimide (6.32g; 35.5mmol; 1 eq) was added to 3-[4-(trifluoromethyl)phenyl]-1,4-
diazaspiro[4.5]decan-2-one D3 (10.59g; 35.5mmol) in DCM (200ml) and the reaction stirred overnight
at room temperature under argon. Saturated aqueous sodium bicarbonate (150ml) was added and the
mixture stirred, the organic layer was then separated and the aqueous extracted with DCM. The
combined DCM extracts were dried with Na2SO4, filtered and evaporated under reduced pressure to
afford the title product (5g). Additional washing of the filtered Na2SO4 with methanol-DCM several
times afforded further title product, giving 10.69g in total. Description 47: 3-[4-(Methyloxy)phenyl]-1,4-
diazaspiro[4.5]dec-3-en-2-one The title product (406mg; 100%) was obtained from 3-[4-
(methyloxy)phenyl]-1,4-diazaspiro[4.5]decan-2-one D46 (400mg; 1.54mmol) and N-bromosuccinimide
(275mg; 1.55mmol) in DCM (20ml) using a method similar to that described in D4. 1H NMR (CDCl3) δ :
1.40 - 1.75 (6H, m), 1.85 - 2.00 (4H, m), 3.87 (3H, s), 6.94 - 6.98 (2H, m), 8.18 (1H, brs), 8.37-8.40
(2H, m).
Reaction Protocol
Step 1
Step 2
Step 3

155. 3 Steps
[Step 2.1]
Overview
Steps/Stages Notes
1.1 R:SOCl2, S:MeOH, 30 min, cooled; 3 h, reflux 4, Solvents: 3, Steps: 3, Stages: 5, Most
Preparation of diazaspirodecenyl-
3.1 R:Bromosuccinimide, S:CH2Cl2, overnight, rt diazaspiroundecenyl- and diazaspirononenyl
3.2 R:NaHCO3, S:H2O, 0.5 h, rt the treatment of psychosis
Roderick Alan
2007
Step 1
(0.45g; 12%) as a white solid. 1H NMR (CDCl3) δ: 1.77 (2H, br s), 3.80 (3H, s), 4.50 (1H, s), 5.52 (1H,
s), 6.83 (1H, s), 6.87 - 6.91 (2H, m), 7.33 - 7.36 (2H, m).
Step 2
amino-2-(4-chlorophenyl)acetamide D7 (10.00g; 54.3mmol) in methanol (500ml) was added
cyclohexanone (5.62ml; 54.3mmol) and H-Y zeolites (10.00g) and the mixture stirred under reflux for
washed well with methanol. The filtrate was evaporated. Description 13: 3-[4-(Methyloxy)phenyl]-1,4-
diazaspiro[4.5]decan-2-one, yield 0.420g, 65%. 1H NMR (CDCl3) δ: 1.44 - 1.57 (4H, m), 1.71 - 1.73
(6H, m), 2.11 (1H, br s), 3.80 (3H, s), 4.64 (1H, s), 6.55 (1H, br s), 6.89 - 6.92 (2H, m), 7.36 - 7.40 (2H,
m).
Step 3
General/Typical Procedure: Method 2: N-Bromosuccinimide (8.69g; 48.81 mmol) was added in one
portion to a stirred solution of 3-(4-chlorophenyl)-1,4-diazaspiro[4.5]decan-2-one D8 (12.91g; 48.81
mmol) in DCM (400ml) and the mixture stirred overnight at room temperature. Saturated aqueous
sodium bicarbonate (500ml) was added and the mixture stirred for 0.5h. The layers were separated
and the aqueous extracted with DCM (300ml). The combined organics were dried (Na2SO4) and the
solvent removed under reduced pressure at 45°C. The residual solid was partitioned between DCM
(500ml) and saturated aqueous sodium bicarbonate (500ml) and stirred overnight at room
temperature. The aqueous layer was extracted with DCM (300ml) and the organic layers combined,
dried (Na2SO4) and the solvent removed under reduced pressure. Description 14: 3-[4-
(Methyloxy)phenyl]-1,4-diazaspiro[4.5]dec-3-en-2-one, yield 406mg, 100%. 1H NMR (CDCl3) δ: 1.40 -
1.75 (6H, m), 1.85 - 2.00 (4H, m), 3.87 (3H, s), 6.94 - 6.98 (2H, m), 8.18 (1H, br s), 8.37 - 8.40 (2H, m).
Reaction Protocol
Step 1
Step 2
Step 3
156. 3 Steps
[Step 2.1]
Overview
Steps/Stages Notes
in any one step: 2
3.2 R:NaHCO3, S:H2O, 0.5 h, rt transporter inhibitors
2007
Step 1
7.33 - 7.36 (2H, m).
Step 2
3-[4-(Methyloxy)phenyl]-1,4-diazaspiro[4.5]decan-2-one. The title compound (0.420g; 65%) was
obtained from 2-amino-2-[4-(methyloxy)phenyl]acetamide D8 (0.450g; 2.5mmol), cyclohexanone
(0.245g; 2.5mmol) and H-Y zeolites (1g) in methanol (20ml) in a similar manner to that described in
D3. 1H NMR (CDCl3) δ: 1.44 - 1.57 (4H, m), 1.71 - 1.73 (6H, m), 2.11 (1H, br s), 3.80 (3H, s), 4.64 (1H,
s), 6.55 (1H, br s), 6.89 - 6.92 (2H, m), 7.36 - 7.40 (2H, m).
Step 3
3-[4-{Methyloxy)phenyl]-1,4-diazaspiro[4.5]dec-3-en-2-one. The title product (406mg; 100%)was
obtained from 3-[4-(methyloxy)phenyl]-1,4-diazaspiro[4.5]decan-2-one D9 (400mg; 1.54mmol) and N-
bromosuccinimide (275mg; 1.55mmol) in DCM (20ml) using a method similar to that described in D4.
1H NMR (CDCl ) δ: 1.40 - 1.75 (6H, m), 1.85 - 2.00 (4H, m), 3.87 (3H, s), 6.94 - 6.98 (2H, m), 8.18
3
(1H, br s), 8.37 - 8.40 (2H, m).
Reaction Protocol
Step 1
Step 2
Step 3
157. 3 Steps
[Step 2.1]
Overview
Steps/Stages Notes
1.1 R:SOCl2, S:MeOH, cooled; 30 min, cooled; 3 h, reflux Reagents: 4, Solvents: 3, Steps: 3, Stages: 5,
2.1 S:MeOH, 24 h, reflux References
Preparation of 1-(2-aryl-2-oxoethyl)-3-phenyl-
3.1 R:Bromosuccinimide, S:CH2Cl2, overnight, rt 1,4-diazaspiro[4.5]dec-3-en-2-one derivatives
3.2 R:NaHCO3, S:H2O, 0.5 h, rt By Branch, Clive Leslie et al
2007
Step 1
as a white solid, yield 0.45g, 12%. 1H NMR (CDCl3) δ: 1.77 (2H, br s), 3.80 (3H, s), 4.50 (1 H, s), 5.52
(1 H, s), 6.83 (1 H, s), 6.87 - 6.91 (2H, m), 7.33 - 7.36 (2H, m).
Step 2
amino-2-(4-chlorophenyl)acetamide D2 (10.0Og; 54.3mmol) in methanol (500ml) was added
cyclohexanone (5.62ml; 54.3mmol) and H-Y zeolites (10.0 g) and the mixture stirred under reflux for
washed well with methanol. The filtrate was evaporated to afford the title product as a white solid. 3-
[4-(Methyloxy)phenyl]-1,4-diazaspiro[4,5]decan-2-one, yield 0.420g; 65%. 1H NMR (CDCl3) δ: 1.44 -
1.57 (4H, m), 1.71 - 1.73 (6H, m), 2.1 1 (1 H, br s), 3.80 (3H, s), 4.64 (1 H, s), 6.55 (1 H, br s), 6.89 -
6.92 (2H, m), 7.36 - 7.40 (2H, m).
Step 3
General/Typical Procedure: Description 4: 3-(4-Chlorophenyl)-1,4-diazaspiro[4.5]dec-3-en-2-one: N-
Bromosuccinimide (8.69g; 48.81 mmol) was added in one portion to a stirred solution of 3-(4-
chlorophenyl)-1,4-diazaspiro[4.5]decan-2-one D3 (12.91g; 48.81 mmol) in DCM (400ml) and the
added and the mixture stirred for 0.5h. The layers were separated and the aqueous extracted with
extracted with DCM (300ml) and the organic layers combined, dried (Na2SO4) and the solvent
removed under reduced pressure to afford the title product as a pale yellow solid. 3-[4-
(Methyloxy)phenyl]-1,4-diazaspiro[4.5]dec-3-en-2-one, yield 406 mg, 100%. 1H NMR (CDCl3) δ: 1.40 -
1.75 (6H, m), 1.85 - 2.00 (4H, m), 3.87 (3H, s), 6.94 - 6.98 (2H, m), 8.18 (1 H, br s), 8.37 - 8.40 (2H,
m).
Reaction Protocol
Step 1
Step 2
Step 3
158. Single Step
38%
Overview
Steps/Stages Notes
1.1 C:1827505-09-8, S:H2O, S:THF, 3 d, 20°C ee 66%, stereoselective, Reactants: 2,
References
Preparation of chiral pyridoxal compounds
useful as catalyst for asymmetric biomimetic
transamination of α-keto acids
16 Dec 2015
Reaction Protocol
Step 1
159. Single Step
56%
Overview
Steps/Stages Notes
in any one step: 1
References
2016
Reaction Protocol
Step 1
160. 4 Steps
[Step 2.1]
Overview
Steps/Stages Notes
2) H-Y zeolites used, 4) regioselective,
1.1 R:SOCl2, S:MeOH, 30 min, cooled; 3 h, reflux; cooled Reactants: 2, Reagents: 5, Solvents: 3, Steps:
3.2 R:NaHCO3, S:H2O, rt By Coulton, Steven et al
4.1 R:Br2, S:CH2Cl2, 1.5 h, rt; 5 h, reflux; 88 h, cooled From PCT Int. Appl., 2007104775, 20 Sep
2007
Step 1
7.33 - 7.36 (2H, m).
Step 2
(2H, m), 7.36 - 7.40 (2H, m).
Step 3
General/Typical Procedure: Description 4: 3-[4-(Trifluoromethyl)phenyl]-1,4-diazaspiro[4.5]dec-3-en-2-
one N-Bromosuccinimide (6.32g; 35.5mmol; 1 eq) was added to 3-[4-(trifluoromethyl)phenyl]-1,4-
diazaspiro[4.5]decan-2-one D3 (10.59g; 35.5mmol) in DCM (200ml) and the reaction stirred overnight
at room temperature under argon. Saturated aqueous sodium bicarbonate (150ml) was added and the
mixture stirred, the organic layer was then separated and the aqueous extracted with DCM. The
combined DCM extracts were dried with Na2SO4, filtered and evaporated under reduced pressure to
afford the title product (5g). Additional washing of the filtered Na2SO4 with methanol-DCM several
times afforded further title product, giving 10.69g in total. Description 47: 3-[4-(Methyloxy)phenyl]-1,4-
diazaspiro[4.5]dec-3-en-2-one The title product (406mg; 100%) was obtained from 3-[4-
(methyloxy)phenyl]-1,4-diazaspiro[4.5]decan-2-one D46 (400mg; 1.54mmol) and N-bromosuccinimide
(275mg; 1.55mmol) in DCM (20ml) using a method similar to that described in D4. 1H NMR (CDCl3) δ :
1.40 - 1.75 (6H, m), 1.85 - 2.00 (4H, m), 3.87 (3H, s), 6.94 - 6.98 (2H, m), 8.18 (1H, brs), 8.37-8.40
(2H, m).
Step 4
Description 48: 3-[3-Bromo-4-(methyloxy)phenyl]-1,4-diazaspiro[4.5]dec-3-en-2-one Bromine (0.25ml;
4.86mmol) was added to a stirred solution of 3-[4-(methyloxy)phenyl]-1,4-diazaspiro[4.5]dec-3-en-2-
one D47 (1.21g, 4.69mmol) in DCM (30ml) and the mixture stirred at room temperature for 1.5h then
heated at reflux for 5h. The mixture was cooled and stirring continued for 88h. Evaporation under
reduced pressure, trituration with toluene (30ml) and evaporation under reduced pressure gave a pale
yellow solid (1.7g). Purification of a 500mg portion by MDAP gave the title compound (0.17g). 3-[3-
Bromo-4-(methyloxy)phenyl]-1,4-diazaspiro[4.5]dec-3-en-2-one, yield (0.17g). Mass Spectrum
(Electrospray LC/MS): Found 337 (MH+). C15H1779BrN2O2.requires 336. Ret. time 3.00 min.
Reaction Protocol
Step 1
Step 2
Step 3
Step 4
161. Single Step
38%
Overview
Steps/Stages Notes
References
application thereof
16 Dec 2015
Reaction Protocol
Step 1
162. 2 Steps
Overview
Steps/Stages Notes
1.1 C:1967791-37-2, S:H2O, S:MeOH, 6 d, 20°C 1) catalyst prepared and used, 64% e.e,
2.1 stereoselective, 2) no experimental detail,
References
2016
Reaction Protocol
Step 1
Step 2
163. 2 Steps
Overview
Steps/Stages Notes
References
2016
Reaction Protocol
Step 1

Step 2
164. 2 Steps
Overview
Steps/Stages Notes
References
2016
Reaction Protocol
Step 1
Step 2
165. Single Step
38%
Overview
Steps/Stages Notes
1.1 C:1827505-09-8, S:H2O, S:THF, 3 d, rt 66% ee, stereoselective, Reactants: 2,
References
Chiral Pyridoxal-Catalyzed Asymmetric
Biomimetic Transamination of α-Keto Acids
By Shi, Limin et al
2015
Reaction Protocol
Step 1
Products L-Leucine, 38%, CAS RN:61-90-5
Benzophenone, CAS RN:119-61-9
Reactants 2,2-Diphenylglycine, CAS RN:3060-50-2
4-Methyl-2-oxovaleric acid, CAS RN:816-66-0
Catalysts 5-[[(2S)-2-[Bis([1,1':3',1''-terphenyl]-5'-yl)[(triethylsilyl)oxy]methyl]-1-pyrrolidinyl]carbonyl]-3-hydroxy-2-
methyl-4-pyridinecarboxaldehyde, CAS RN:1827505-09-8
Procedure 1. Add pyridoxal (0.020 mmol), 4- (naphthalen-1-yl) -2-oxobutanoic acid (0.20 mmol), 2, 2-
diphenylglycine (0.22 mmol), THF (1.4 mL), and H2O (0.6 mL) to a 5-mL vial equipped with stirrer bar.
2. Stir the mixture at room temperature for 3 d.
3. Transfer the reaction mixture to a 25-mL eggplant-shaped flask.
4. Add Methanol (15 mL) and add silica gel (0.50 g).
5. Remove the solvent via rotary evaporator under reduced pressure at 25 ° C.
6. Submit the residue to flash chromatography (silica gel, EtOH / ethyl acetate / 25-28% ammonia
solution = 100:58:16).
Transformation Reductive Alkylation of Ammonia or Amines
1H NMR (600 MHz, D2O with 2 equiv. of KOH) δ 3.17 (dd, J = 8.4, 6.0 Hz, 1H), 1.62-1.52 (m, 1H), 1.42-1.34 (m,
1H), 1.32-1.25 (m, 1H), 0.82 (d, J = 6.6 Hz, 3H), 0.81 (d, J = 6.6 Hz, 3H);
13C NMR (150 MHz, D2O with 2 equiv. of KOH) δ 184.4, 54.5, 44.2, 24.3, 22.4, 21.3;
IR (KBr) 3423, 2954, 1612, 1586, 1513, 1411 cm-1;
[α]D 20 = +16.0 (c 0.11, 1.0 M HCl)
Enantiomeric 66%
Excess
HRMS m/z Calcd. for C6H14NO2 (M + H)+ : 132.1025; Found: 132.1031.
MP 212-216 ° C;
State white solid
Number
166. 2 Steps
[Step 2.1]
Overview
Steps/Stages Notes
1.1 R:NaBH4, S:THF 2, Stages: 5, Most stages in any one step: 4
2.1 S:MeOH, 24 h, rt
References
2.2 R:NaBH4, S:THF, 273K N-[(S)-1-(3,5-Dimethyl-2-
hydroxyphenyl)ethyl]-N-[(R)-2-hydroxy-1-
2.3 R:HCl, S:H2O phenylethyl]ammonium chloride
By Zhang, Guangyou et al
2.4 R:NaOH, neutralized
From Acta Crystallographica, Section E:
Structure Reports Online, 64(1), o240-o241,
o240/1-o240/9; 2008
Reaction Protocol
Step 1
Step 2
167. Single Step
Overview
Steps/Stages Notes
H-Y Zeolite used as catalyst stage 4,
1.1 R:SOCl2, S:MeOH, 30 min, cooled Reactants: 2, Reagents: 4, Solvents: 3, Steps:
antagonists
2010
General/Typical Procedure: To ice-chilled methanol (300 mL) under argon, thionyl chloride (50 mL,
660 mmol) was carefully added dropwise over 30min. Then, phenylglycine (50 g, 330 mmol) was
added. The ice-bath was removed and the reaction mixture was heated to reflux for 16h. The reaction
was then evaporated under reduced pressure. Diethyl ether (200 mL) was added followed by filtration.
Phenyl glycine methyl ester hydrochloride from Step A. (64 g, 317 mmol) was dissolved in ammonia
(150 mL) and stirred at room temperature under argon for 16h. The reaction mixture was extracted
with DCM (200 mL × 3), dried over Na2SO4 and evaporated under reduced pressure. To the product of
step B above (0.5 g, 3.3 mmol) in methanol was added cyclohexanone (0.32 g, 3.3 mmol) and H-Y
Zeolizes (1.0 g), and the mixture stirred under reflux for 24 h under argon. The reaction was allowed to
cool to room temperature and was filtered and the solid washed well with methanol. The filtrate was
evaporated. From Step C above (3 g, 13 mmol) was dissolved in DCM and was stirred at room
temperature for 16h under argon atmosphere with N-Bromosuccinimide (2.3 g, 13 mmol), A solution of
saturated sodium bicarbonate was added and stirring continued for 1h at room temperature. The
organic layer was separated, dried and evaporated under reduced pressure. Intermediate 10-e. 1H
NMR (DMSO-d6, 400 MHz) δ: 7.67-7.69 (m, 1H), 7.15-7.36 (m, 3H), 2.35 (s, 3H), 1.56-1.88 (m, 12H).
Reaction Protocol
Step 1
168. Single Step
Overview
Steps/Stages Notes
1.1 S:MeOH, -78°C → rt; 3-48 h, rt reaction may also run at reflux temperature,
prophetic reaction, Reactants: 4, Solvents: 1,
step: 1
References
derivatives
2000
Reaction Protocol
Step 1
169. Single Step
93%
Overview
Steps/Stages Notes
1.1 R:(t-Bu-O)2, C:Cu(CF3SO3)2, C:I2, S:PhMe, rt; rt → 120°C; 10 h, Catalysts: 2, Solvents: 1, Steps: 1, Stages: 1,
120°C Most stages in any one step: 1
References
Synthesis of 1,3-Disubstituted Imidazo[1,5-
a]pyridines from Amino Acids via Catalytic
Decarboxylative Intramolecular Cyclization
By Wang, Huiqiao et al
3681-3687; 2016
Reaction Protocol
Step 1
170. 3 Steps
[Step 3.1]
Overview
Steps/Stages Notes
1.1 R:SOCl2, S:MeOH, 45 min, cooled Solvents: 2, Steps: 3, Stages: 4, Most stages
1.2 cooled; 48 h, 40°C; 40°C → rt in any one step: 2
2.1 R:NH3, 64 h, rt References
3.1 S:EtOH, 24 h, reflux; reflux → rt; 4 d, rt Preparation of N-phenyl-2-oxo-1,4-
2007
Step 1
Methyl amino(4-chlorophenyl)acetate. To ice-chilled methanol (300ml) under argon was carefully
added dropwise thionylchloride (15.44ml;0.217mol) over 45min.4-Chlorophenylglycine (26.26g; 0.141
mol) was added, ice cooling removed and the reaction mixture warmed to 40°C; the reaction was
stirred at 40°C for 48h. After cooling to room temperature, the reaction was evaporated under reduced
pressure. Re-evaporation from methanol afforded a white solid which was triturated with diethyl ether
(ca. 700ml) and then stored at ca. 4°C for 64h, filtered, washed with diethyl ether and dried in vacuo to
afford the title product as the hydrochloride salt (33.40g; 100%). 1H NMR (d6-DMSO) δ: 3.72 (3H, s),
5.36 (1H, s), 7.53 - 7.58 (4H, m), 9.07 (3H, s). Mass Spectrum (Electrospray LC/MS): Found 200
(MH+). C9H10CINO2 requires 199. Ret.time 1.32 min.
Step 2
2-Amino-2-(4-chlorophenyl)acetamide. Methyl amino(4-chlorophenyl)acetate D1 as the hydrochloride
salt (33.40g; 0.14mol) was dissolved in 0.88 ammonia (500ml; ca. 7.4mol) and stirred at room
temperature for 64h. The reaction mixture was extracted with DCM (300ml ×6),the extracts dried
(Na2SO4) and evaporated under reduced pressure to a white solid, which was dried under reduced
pressure to afford the title product (22.45g; 86%). 1H NMR (CDCl3) δ: 1.82 (2H, br s), 4.53 (1H, s),
5.49 (1H, br s), 6.92 (1H, br s), 7.32 - 7.39 (4H, m).
Step 3
solid. The title compound (combined yield from 2 crops 1.635g; 56%) was obtained from 2-amino-2-[4-
(chloro)phenyl]acetamide D2 (2.40g; 13mmol), cyclopentanone (1.15ml; 13mmol) and H-Y zeolites
(3.13g) in ethanol (140ml) in a similar manner to that described in D3. After removal of solvent, final
compound was obtained by trituration with ethanol to give title compound 1.45g). A second crop
(0.185g) was obtained from the ethanol mother liquors. 1H NMR (CDCl3) inter alia δ: 1.66 - 2.00 (8H,
m), 2.30 (1H, m), 4.64 (1H, m), 6.54(1H, s), 7.35 (2H, d) 7.45 (2H, d).
Reaction Protocol
Step 1
Step 2
Step 3
171. 4 Steps
[Step 3.1]
Overview
Steps/Stages Notes
3.1 S:EtOH, 24 h, reflux; reflux → rt; 4 d, rt Preparation of N-phenyl-2-oxo-1,4-
4.1 R:Bromosuccinimide, S:CH2Cl2, overnight, rt derivatives and their use as glycine
4.2 R:NaHCO3, S:H2O, 0.5 h, rt By Coulton, Steven et al
2007
Step 1
Step 2
5.49 (1H, br s), 6.92 (1H, br s), 7.32 - 7.39 (4H, m).
Step 3
solid. The title compound (combined yield from 2 crops 1.635g; 56%) was obtained from 2-amino-2-[4-
(chloro)phenyl]acetamide D2 (2.40g; 13mmol), cyclopentanone (1.15ml; 13mmol) and H-Y zeolites
(3.13g) in ethanol (140ml) in a similar manner to that described in D3. After removal of solvent, final
compound was obtained by trituration with ethanol to give title compound 1.45g). A second crop
(0.185g) was obtained from the ethanol mother liquors. 1H NMR (CDCl3) inter alia δ: 1.66 - 2.00 (8H,
m), 2.30 (1H, m), 4.64 (1H, m), 6.54(1H, s), 7.35 (2H, d) 7.45 (2H, d).
Step 4
General/Typical Procedure: 3-{4-Chlorophenyl)-1,4-diazaspiro[4.5]dec-3-en-2-one. N-
Bromosuccinimide (8.69g; 48.81mmol) was added in one portion to a stirred solution of 3-(4-
chlorophenyl)-1,4-diazaspiro[4.5]decan-2-one D3 (12.91g; 48.81mmol) in DCM (400ml) and the
added and the mixture stirred for 0.5h.The layers were separated and the aqueous extracted with
extracted with DCM (300ml) and the organic layers combined, dried(Na2SO4) and the solvent removed
under reduced pressure to afford the title product (10.25g; 80%) as a pale yellow solid. The title
product (1.05; 72%) after recrystallisation from ethanol, was obtained from 3-(4-chlorophenyl)-1,4-
diazaspiro[4.4]nonan-2-one D18 (1.48g; 5.90mmol) and N-bromosuccinimide (1.05g; 5.90mmol) in
DCM (50ml) using a method similar to that described in D4. 1H NMR (CDCl3) inter alia δ: 1.86 - 2.14
(8H, m), 7.43 (2H, d) and 8.37 (2H, m).
Reaction Protocol
Step 1
Step 2
Step 3
Step 4
172. Single Step
89%
Overview
Steps/Stages Notes
References
Edition, 52(51), 13651-13655; 2013
Reaction Protocol
Step 1
Products 3,4-Dihydro-2-(phenylmethyl)-1(2H)-naphthalenone, 89%, CAS RN:27019-08-5
1-Tetralone, CAS RN:529-34-0
RN:1221406-59-2
Scale milligram
1H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 7.8 Hz, 1H), 7.45 (dt, J = 7.1, 1.2 Hz, 1H), 7.32-7.19 (m, 7H), 3.48 (dd,
J = 13.4, 3.7 Hz, 1H), 2.95-2.89 (m, 2H), 2.74-2.59 (m, 1H), 2.62 (dd, J = 13.4, 9.6 Hz, 1H), 2.09 (dq, J
= 13.4, 4.4 Hz, 1H), 1.84-1.70 (m, 1H) ppm;.
13C NMR (100 MHz, CDCl3) δ 201,7, 144.0, 140.1, 133.2, 129.7, 128.7, 128.4, 127.5, 126.5, 126.1, 103.6, 49.5,
35.7, 28.6, 27.6 ppm.
Number
173. Single Step
50%
Overview
Steps/Stages Notes
References
8/1-8/6, 6 pp.; 2013
Reaction Protocol
Step 1
174. Single Step
95%
Overview
Steps/Stages Notes
in any one step: 1
References
28 Jan 2009
Reaction Protocol
Step 1

175. Single Step
98%
Overview
Steps/Stages Notes
stereoselective, catalyst prepared and used,
1.1 R:AcOH, C:1990535-88-0, S:H2O, S:MeOH, 20 h, rt 92%ee, Reactants: 2, Reagents: 1, Catalysts:
References
Enzyme-inspired axially chiral pyridoxamines
armed with a cooperative lateral amine chain
for enantioselective biomimetic
transamination
By Liu, Yong Ethan et al
Society, 138(34), 10730-10733; 2016
Reaction Protocol
Step 1
176. Single Step
94%
Overview
Steps/Stages Notes
References
transamination
Society, 138(34), 10730-10733; 2016
Reaction Protocol
Step 1
177. Single Step
61%
Overview
Steps/Stages Notes
References
16 Dec 2015
Reaction Protocol
Step 1
178. Single Step
80%
Overview
Steps/Stages Notes
in any one step: 1
References
2016
Reaction Protocol
Step 1
179. Single Step
52%
Overview
Steps/Stages Notes
References
16 Dec 2015
Reaction Protocol
Step 1
180. Single Step
72%
Overview
Steps/Stages Notes
in any one step: 1
References
2016
Reaction Protocol
Step 1
181. Single Step
Overview
Steps/Stages Notes
References
chiral amino acids
16 Nov 2016
Reaction Protocol
Step 1
182. Single Step
Overview
Steps/Stages Notes
References
chiral amino acids
16 Nov 2016
Reaction Protocol
Step 1
183. Single Step
Overview
Steps/Stages Notes
References
chiral amino acids
16 Nov 2016
Reaction Protocol
Step 1
184. Single Step
Overview
Steps/Stages Notes
References
chiral amino acids
16 Nov 2016
Reaction Protocol
Step 1

185. Single Step
51%
Overview
Steps/Stages Notes
References
16 Dec 2015
Reaction Protocol
Step 1
186. Single Step
37%
Overview
Steps/Stages Notes
References
16 Dec 2015
Reaction Protocol
Step 1
187. Single Step
29%
Overview
Steps/Stages Notes
References
16 Dec 2015
Reaction Protocol
Step 1
188. Single Step
52%
Overview
Steps/Stages Notes
References
By Shi, Limin et al
2015
Reaction Protocol
Step 1
Products 4-Ethyl-L-norleucine, 52%, CAS RN:134055-71-3
4-Ethyl-2-oxohexanoic acid, CAS RN:190963-49-6
solution = 100:58:16).
6H), 0.75 (t, J = 7.2 Hz, 6H);
13C NMR (150 MHz, D2O with 2 equiv. of KOH) δ 184.4, 54.5, 38.8, S-40 36.4, 25.0, 24.3, 9.9, 9.7.
IR (KBr) 3423, 2964, 1583, 1520, 1407, 1324 cm-1;
[α]D 20 = +10.5 (c 0.13, 1.0 M KOH)
Enantiomeric 78%
Excess
MP 215-220 ° C;
State white solid
Number
189. Single Step
Overview
Steps/Stages Notes
stereoselective, ee (90%), Reactants: 2,
1.1 R:AcOH, C:1990535-88-0, S:H2O, S:MeOH, 20 h, 20°C Reagents: 1, Catalysts: 1, Solvents: 2, Steps:
References
Catalyzer of chiral biaryl skeleton
pyridoxylamine class and synthetic method
and application thereof
16 Nov 2016
Reaction Protocol
Step 1
190. Single Step
Overview
Steps/Stages Notes
References
16 Nov 2016
Reaction Protocol
Step 1
191. Single Step
61% (50:50)
61% (50:50)
Overview
Steps/Stages Notes
References
By Shi, Limin et al
2015
Reaction Protocol
Step 1
Products Octanoic acid, 2-amino-4-ethyl-, (2S,4S)-, 61%, CAS RN:1827505-58-7
Octanoic acid, 2-amino-4-ethyl-, (2S,4R)-, 61%, CAS RN:1827505-61-2
4-Ethyl-2-oxooctanoic acid, CAS RN:1470364-87-4
solution = 100:58:16).
10H), 0.85-0.71 (m, 6H);
13C NMR (150 MHz, D2O with 2 equiv. of KOH) δ 184.7, 184.6, 54.91, 54.89, 39.7, 39.6, 35.3, 35.2, 32.6, 32.0,
28.3, 28.1, 25.9, 25.1, 22.7, 13.74, 13.73, 10.2, 10.0;
IR (KBr) 3424, 2929, 1605, 1405, 1340 cm-1;
[α]D 20 = +1.0 (c 0.27, 1.0 M HCl)
Enantiomeric : 79%
Excess
MP 210-214 ° C;
State white solid
Number
192. Single Step
51%
Overview
Steps/Stages Notes
References
By Shi, Limin et al
2015
Reaction Protocol
Step 1
Products (2S)-2-Amino-4-propylheptanoic acid, 51%, CAS RN:1827505-56-5
2-Oxo-4-propylheptanoic acid, CAS RN:1827505-92-9
solution = 100:58:16).
10H), 0.78 (t, J = 6.6 Hz, 6H);
13C NMR (100 MHz, D2O with 2 equiv. of KOH) δ 184.6, 54.9, 40.1, 35.9, 35.2, 33.4, 19.2, 19.0, 14.1, 14.0;
IR (KBr) 3393, 3196, 2955, 1667, 1608, 1400 cm-1;
[α]D20 = +3.9 (c 0.33, 1.0 M HCl)
Enantiomeric 76%
Excess
MP 212-216 ° C;
State white solid
Number
193. Single Step
47%
Overview
Steps/Stages Notes
in any one step: 1
References
2016
Reaction Protocol
Step 1
194. Single Step
33%
Overview
Steps/Stages Notes
References
application thereof
16 Dec 2015
Reaction Protocol
Step 1
195. Single Step
28%
Overview
Steps/Stages Notes
References
application thereof
16 Dec 2015
Reaction Protocol
Step 1
196. 2 Steps
Overview
Steps/Stages Notes
References
2016
Reaction Protocol
Step 1
Step 2
197. 2 Steps
Overview
Steps/Stages Notes
References
2016
Reaction Protocol
Step 1

Step 2
198. 2 Steps
Overview
Steps/Stages Notes
References
2016
Reaction Protocol
Step 1
Step 2
199. Single Step
37%
Overview
Steps/Stages Notes
References
By Shi, Limin et al
2015
Reaction Protocol
Step 1
Products (2S)-2-Amino-4,4-dimethylpentanoic acid, 37%, CAS RN:57224-50-7
4,4-Dimethyl-2-oxopentanoic acid, CAS RN:34906-87-1
solution = 100:58:16).
1H NMR (400 MHz, D2O with 2 equiv. of KOH) δ 3.18 (dd, J = 6.4, 6.0 Hz, 1H), 1.58 (dd, J = 14.0, 6.4 Hz, 1H),
1.23 (dd, J = 14.0, 6.0 Hz, 1H), 0.79 (s, 9H);
13C NMR (150 MHz, D2O with 2 equiv. of KOH) δ 183.3, 53.9, 48.4, 29.5, 28.9;
IR (KBr) 3393, 2957, 1582, 1506, 1336 cm-1;
[α]D 20 = +6.0 (c 0.22, 1.0 M HCl)
Enantiomeric 67%
Excess
MP 208-210 ° C;
State white solid
Number
200. Single Step
29%
Overview
Steps/Stages Notes
1.1 C:1827505-09-8, S:H2O, S:THF, 3 d, rt alternative preparation shown, 66% ee,
in any one step: 1
References
By Shi, Limin et al
2015
Reaction Protocol
Step 1
Products (2S)-2-Aminodecanoic acid, 29%, CAS RN:84277-81-6
2-Oxodecanoic acid, CAS RN:333-60-8
solution = 100:58:16).
12H), 0.73 (t, J = 6.6 Hz, 3H);
13C NMR (150 MHz, D2O with 2 equiv. of KOH) δ 183.9, 56.0, 34.7, 31.1, 28.7, 28.5, 28.4, 24.9, 22.0, 13.4;
IR (KBr) 3405, 2954, 2918, 1582, 1514, 1411, 1353 cm-1;
[α]D20 = +24.5 (c 0.10, 1.0 M KOH)
Enantiomeric 66%
Excess
MP 220-222 ° C;
State white solid
Number
201. 2 Steps
[Step 2.1]
Overview
Steps/Stages Notes
1.1 R:NaOEt, S:EtOH Solvents: 2, Steps: 2, Stages: 3, Most stages
in any one step: 2
1.2
2.1 C:AcONa, S:AcOH References
Implementation of alpha-amino acids as chiral
synthons in the synthesis of pharmaceutically
significant N-pyrrolylacetic acids
By Bijev, Atanas T. et al
From Bulgarian Chemical Communications,
33(2), 173-179; 2001
Reaction Protocol
Step 1
Step 2
202. 3 Steps
[Step 3.1]
Overview
Steps/Stages Notes
1.1 R:SOCl2, S:MeOH, 45 h, cooled; 48 h, 40°C; 40°C → rt 3, Solvents: 2, Steps: 3, Stages: 4, Most
1.2 R:HCl, S:H2O
References
2.1 R:NH3, 64 h, rt Preparation of diazaspirodecenones and
3.1 S:MeOH, 24 h, reflux; reflux → rt; 4 d, rt diazaspirononenones as GlyT1 transporter
inhibitors for treating neurological and
neuropsychiatric disorders
By Marshall, Howard Robert
From PCT Int. Appl., 2008092879, 07 Aug
2008
Step 1
Description 1 : Methyl amino(4-chlorophenyl)acetate. To ice-chilled methanol (300ml) under argon was
carefully added dropwise thionyl chloride (15.44ml; 0.217mol) over 45min. 4-Chlorophenylglycine
(26.26g; 0.141 mol) was added, ice cooling removed and the reaction mixture warmed to 40°C. The
reaction was stirred at 40°C for 48h. After cooling to room temperature, the reaction was evaporated
under reduced pressure. Re-evaporation from methanol afforded a white solid which was triturated
with diethyl ether (ca. 700ml) and then stored at ca. 4°C for 64h, filtered, washed with diethyl ether and
dried in vacuo to afford the title product as the hydrochloride salt (33.40g; 100%). 1H NMR (d6-DMSO)
δ: 3.72 (3H, s), 5.36 (1 H, s), 7.53 - 7.58 (4H, m), 9.07 (3H, s). Mass Spectrum (Electrospray LC/MS):
Found 200 (MH+). C9H10 35ClNO2 requires 199. Ret. time 1.32 min.
Step 2
Description 2: 2-Amino-2-(4-chlorophenyl)acetamide. Methyl amino(4-chlorophenyl)acetate D1 as the
hydrochloride salt (33.40g; 0.14mol) was dissolved in 0.88 ammonia (500ml; ca. 7.4mol) and stirred at
room temperature for 64h. The reaction mixture was extracted with DCM (300ml x6), the extracts dried
5.49 (1H, br s), 6.92 (1H, br s), 7.32 - 7.39 (4H, m).
Step 3
Description 3: 3-(4-Chlorophenyl)-1,4-diazaspiro[4.5]decan-2-one. To 2-amino-2-(4-
well with methanol. The filtrate was evaporated to afford the title product (12.91g; 90%) as a white
solid. 1H NMR (CDCl3) δ: 1.44 - 1.57 (4H, m), 1.66 - 1.76 (6H, m), 2.21 (1 H, s), 4.69 (1 H, s), 6.80 (1
H, s), 7.32 -7.35 (2H, m), 7.45 - 7.49 (2H, m).
Reaction Protocol
Step 1
Step 2
Step 3
203. 3 Steps
[Step 3.1]
Overview
Steps/Stages Notes
1.1 S:MeOH, 40 h, reflux 3) H-Y zeolites used, Reactants: 3, Reagents:
1.2 C:HCl, S:H2O, 8 h, reflux; 16 h, rt 2, Catalysts: 1, Solvents: 3, Steps: 3, Stages:
1.3 R:NaHCO3, S:H2O
References
2.1 R:NH4OH, S:H2O, 3.5 d, rt Preparation of diazaspirodecenones and
3.1 S:EtOH, 6 h, reflux; overnight, rt diazaspirononenones as GlyT1 transporter
By Coulton, Steven and Porter, Roderick Alan
2008
Step 1
Description 6. Methyl amino{4-[(methyloxy)methyl]phenyl}acetate. A stirred solution of amino[4-
(bromomethyl)phenyl]acetic acid hydrobromide (Tetrahedron 1977, 33(20), 2715) (5.0g, 0.015mol) in
methanol (120ml) was heated under argon at reflux with stirring for 40 hours. Conversion of
bromomethyl to methoxymethyl was complete and approx. 55:45 mixture of acid:methyl ester was
present. The mixture was treated with conc. HCl acid (4ml) and heated at reflux for 8 hours, followed
by 16 hours at room temperature. The reaction mixture was concentrated under vacuum to approx.
15ml, then the residue treated with sat. NaHCO3 solution (80ml) and extracted with ether (2 ×60ml).
The combined extract was dried (Na2SO4) and concentrated under vacuum to give the title compound
a pale yellow oil (1.1g). Extraction of the aqueous with dichloromethane (3 × 60ml), combining the
extracts and concentrating under vacuum afforded a further batch of title compound as a colourless oil
(1.5g). Mass Spectrum (Electrospray LC/MS): Found 210 (MH+) very weak. C11H15NO3 requires 209.
Ret. time 1.16 min. 1H NMR δ (CDCl3; 400MHz): 2.03 (2H, br s), 3.38 (3H, s), 3.67 (3H, s), 4.44 (2H,
s), 4.62 (1H, s), 7.30-7.40 (4H, m).
Step 2
Description 7. 2-Amino-2-{4-[(methyloxy)methyl]phenyl}acetamide. METHOD A. A mixture of methyl
amino{4-[(methyloxy)methyl]phenyl}acetate (2.6g, 0.012mol, Description 6) and 0.88 ammonia solution
(60ml) was stirred well at room temperature for 3.5 days producing a colourless solution. This was
extracted with dichloromethane (6 × 50ml) and the combined extract dried (Na2SO4) and concentrated
under vacuum to give the title compound as a white solid (1.34g, 56%). Concentration of the aqueous
under vacuum afforded a further batch of title compound as a white solid (0.86g, 36%). Mass
Spectrum (Electrospray LC/MS): Found 195 (MH+) very weak. C10H14N2O2 requires 194. Ret. time
0.63 min. 1H NMR δ (CDCl3; 400MHz): 1.83 (2H, br s), 3.38 (3H, s), 4.44 (2H, s), 4.52 (1H, s), 5.91
(1H, br s), 6.88 (1H, br s), 7.33 (2H, d), 7.41 (2H, d).
Step 3
Description 10. 3-{4-[(Methyloxy)methyl]phenyl}-1,4-diazaspiro[4.4]nonan-2-one. A stirred solution of
2-amino-2-{4-[(methyloxy)methyl]phenyl}acetamide (450 mg, 2.317 mmol, Description 7, Method A) in
ethanol (20 ml) was treated with cyclopentanone (0.215 ml, 2.433 mmol) followed by Zeolite HY
(product CBV400 from Zeolyst, Oosterhorn, Netherlands) (700mg) and then heated at reflux for a total
of 6 hours, plus overnight at room temperature. The mixture was allowed to cool, filtered through
Kieselguhr and the filtrate concentrated under vacuum. The residue was crystallised from a mixture of
dichloromethane (2ml) and ether (8ml) to give the title compound as a white solid (270mg). Mass
Spectrum (Electrospray LC/MS): Found 261 (MH+) weak. C15H20N2O2 requires 260. Ret. time 1.24
min. 1H NMR δ (CDCl3; 400MHz): 1.60-1.85 (6H, m), 1.85-2.00 (2H, m), 2.25 (1H, br s), 3.73 (3H, s),
4.46 (2H, s), 4.65 (1H, s), 6.87 (1H, br s), 7.34 (2H, d), 7.46 (2H, d).
Reaction Protocol
Step 1
Step 2
Step 3

204. 3 Steps
[Step 3.1]
Overview
Steps/Stages Notes
1.1 R:SOCl2, S:MeOH, 45 min, cooled 2, Solvents: 2, Steps: 3, Stages: 4, Most
1.2 0°C → 40°C; 48 h, 40°C; 40°C → rt stages in any one step: 2
2.1 R:NH3, S:NH3, 64 h, rt References
3.1 S:MeOH, 24 h, reflux; reflux → rt; 4 d, rt Preparation of diazaspirodecenyl-
Roderick Alan
2007
Step 1
Description 6: Methyl amino(4-chlorophenyl)acetate: To ice-chilled methanol (300ml) under argon was
(26.26g; 0.141 mol) was added, ice cooling removed and the reaction mixture warmed to 40°C; the
δ: 3.72 (3H, s), 5.36 (1H, s), 7.53 - 7.58 (4H, m), 9.07 (3H, s). Mass Spectrum (Electrospray LC/MS):
Found 200 (MH+). C9H1035ClNO2 requires 199. Ret. time 1.32 min.
Step 2
Description 7: 2-Amino-2-(4-chlorophenyl)acetamide: Methyl amino(4-chlorophenyl)acetate D6 as the
5.49 (1H, br s), 6.92 (1H, br s), 7.32 - 7.39 (4H, m).
Step 3
Description 8: 3-(4-Chlorophenyl)-1,4-diazaspiro[4.5]decan-2-one: To 2-amino-2-(4-
well with methanol. The filtrate was evaporated. 3-(4-Chlorophenyl)-1,4-diazaspiro[4.5]decan-2-one as
a white solid, yield 12.91g, 90%. 1H NMR (CDCl3) δ: 1.44 - 1.57 (4H, m), 1.66 - 1.76 (6H, m), 2.21 (1H,
s), 4.69 (1H, s), 6.80 (1H, s), 7.32 - 7.35 (2H, m), 7.45 - 7.49 (2H, m).
Reaction Protocol
Step 1
Step 2
Step 3
205. 3 Steps
[Step 3.1]
Overview
Steps/Stages Notes
3.1 S:MeOH, 24 h, reflux; reflux → rt; 4 d, rt Preparation of N-phenyl-2-oxo-1,4-
2007
Step 1
Step 2
5.49 (1H, br s), 6.92 (1H, br s), 7.32 - 7.39 (4H, m).
Step 3
3-{4-Chlorophenyl)-1,4-diazaspiro[4.5]decan-2-one. To 2-amino-2-(4-chlorophenyl)acetamide D2
(10.00g; 54.3mmol) in methanol (500ml) was added cyclohexanone (5.62ml; 54.3mmol) and H-Y
zeolites (10.00g) and the mixture stirred under reflux for 24h. The reaction was allowed to cool to room
temperature and after 4 days was filtered and the solid washed well with methanol. The filtrate
wasevaporated to afford the title product (12.91g; 90%) as a white solid. 1H NMR (CDCl3) δ: 1.44 -
1.57 (4H, m), 1.66 - 1.76 (6H, m), 2.21 (1H, s), 4.69 (1H, s), 6.80 (1H, s), 7.32 - 7.35 (2H, m), 7.45 -
7.49 (2H, m).
Reaction Protocol
Step 1
Step 2
Step 3
206. 3 Steps
[Step 3.1]
Overview
Steps/Stages Notes
1.1 R:SOCl2, S:MeOH, 45 min, cooled Reagents: 2, Solvents: 2, Steps: 3, Stages: 4,
1.2 48 h, 40°C; 40°C → rt Most stages in any one step: 2
3.1 S:MeOH, 24 h, reflux Preparation of 1-(2-aryl-2-oxoethyl)-3-phenyl-
2007
Step 1
Description 1 : Methyl amino(4-chlorophenyl)acetate hydrochloride: To ice-chilled methanol (300ml)
under argon was carefully added dropwise thionyl chloride (15.44ml; 0.217mol) over 45min. 4-
Chlorophenylglycine (26.26g; 0.141 mol) was added, ice cooling removed and the reaction mixture
warmed to 40°C; the reaction was stirred at 40°C for 48h. After cooling to room temperature, the
reaction was evaporated under reduced pressure. Re-evaporation from methanol afforded a white
solid which was triturated with diethyl ether (ca. 700ml) and then stored at ca. 4°C for 64h, filtered,
washed with diethyl ether and dried in vacuo to afford the title product as the hydrochloride salt, yield
33.40g; 100%. 1H NMR (d6-DMSO) δ: 3.72 (3H, s), 5.36 (1 H, s), 7.53 - 7.58 (4H, m), 9.07 (3H, s).
Mass Spectrum (Electrospray LC/MS): Found 200 (MH+). C9H1035ClNO2 requires 199. Ret. time 1.32
min.
Step 2
(Na2SO4) and evaporated under reduced pressure to afford a white solid, which was dried under
reduced pressure to afford the title product, yield 22.45g; 86%. 1H NMR (CDCl3) δ: 1.82 (2H, br s),
4.53 (1 H, s), 5.49 (1 H, br s), 6.92 (1 H, br s), 7.32 - 7.39 (4H, m).
Step 3
chlorophenyl)acetamide D2 (10.0Og; 54.3mmol) in methanol (500ml) was added cyclohexanone
(5.62ml; 54.3mmol) and H-Y zeolites (10.0 g) and the mixture stirred under reflux for 24h. The reaction
was allowed to cool to room temperature and after 4 days was filtered and the solid washed well with
methanol. The filtrate was evaporated to afford the title product as a white solid. 3-(4-Chlorophenyl)-
1,4-diazaspiro[4.5]decan-2-one, yield 12.91g, 90%. 1H NMR (CDCl3) δ: 1.44 - 1.57 (4H, m), 1.66 - 1.76
(6H, m), 2.21 (1 H, s), 4.69 (1 H, s), 6.80 (1 H, s), 7.32 - 7.35 (2H, m), 7.45 - 7.49 (2H, m).
Reaction Protocol
Step 1
Step 2
Step 3

207. 3 Steps
[Step 2.1] [Step 3.1]
Overview
Steps/Stages Notes
1.1 R:NaBH4, S:THF, rt → 0°C Solvents: 3, Steps: 3, Stages: 6, Most stages
in any one step: 4
1.2 R:I2, S:THF, 40 min, 0°C; 18 h, reflux; reflux → rt
References
1.3 R:MeOH, rt; 30 min, rt Dual Catalyst System for Asymmetric
Alternating Copolymerization of Carbon
1.4 R:KOH, S:H2O, 4 h, rt Dioxide and Cyclohexene Oxide with Chiral
2.1 C:HCO2H, S:PhMe, 48 h, reflux Aluminum Complexes: Lewis Base as
3.1 S:THF, -30°C; -30°C → rt; 2.5 h, rt Catalyst Activator and Lewis Acid as
Monomer Activator
United States), 45(20), 8172-8192; 2012
Step 1
3.57- 3.52 (t, 1H), 2.20-2.01 (br, 3H). IR (KBr, cm-1): 3420, 3405, 3325, 3150, 3110, 3065, 3028, 2939,
2920, 2895, 2850, 2690, 1601, 1499, 1472, 1462, 1360, 1052, 1040, 935, 800, 775, 703.
Step 2
3-((S)-2-Hydroxy-1-phenylethylimino)-1,3-diphenylprop-1-en-1-ol (2hH2).76 L-Phenylglycinol (2.19 g,
10.0 mmol) and dibenzoylmethane (2.24 g, 10.0 mmol) were dissolved in toluene (50 mL) in a 100-mL
round-bottomed flask equipped with a reflux condenser. After one drop of formic acid was added to
this solution, the mixture was heated under reflux for 48 h. The mixture was concentrated under
reduced pressure to leave a yellow oil. The crude oil was purified by silica gel column chromatography
with ethyl acetate to afford a compound. Yellow viscous oil, yield 1.65 g, 48%. [α]D -366° (c 1.8,
CHCl3). 1H NMR (CDCl3): δ 12.16-11.98 (br, 1H), 7.91-7.85 (d, 2H), 7.42-7.11 (m, 13H), 5.75 (s, 1H),
4.67-4.58 (m, 1H), 4.04- 3.90 (br, 1H), 3.87-3.81 (m, 2H). 13C NMR (CDCl3): δ 188.9, 167.4, 140.1,
139.6, 135.4, 130.9, 129.5, 128.8, 128.4, 128.3, 127.8, 127.6, 127.2, 126.5, 94.6, 67.4. FAB-MS m/z:
344 [for C23H22NO2 [M + H]+].
Step 3
General/Typical Procedure: Complex [2bAlMe]2.41 After 2bH2 (0.16 g, 1.0 mmol) was dissolved in dry
THF (10 mL) in a 50-mL two-necked roundbottomed flask equipped with a three-way stopcock under
dry nitrogen, the mixture was cooled at -30 °C. Me3Al (0.12 mL, 1.2 mmol) was carefully added to the
solution by a hypodermic syringe in a nitrogen stream. After gas evolution ceased, the resulting
mixture was allowed to warm to room temperature and then stirred for 2.5 h. The volatile components
were then removed under reduced pressure to leave a white solid. The crude product was purified by
recrystallization form THF/hexane to afford a compound. Complex [2hAlMe]2. 80% yield as a colorless
powder. Complexe [2hAlMe]2 was synthesized according to the similar procedure to [2bAlMe]2. 1H
NMR (CDCl3): δ 8.00-7.97 (d, 4H), 7.60-7.01 (m, 26H), 5.86 (s, 2H), 4.67-4.59 (m, 4H), 3.90-3.81 (m,
4H), -0.88 (s, 3H), -0.97 (s, 3H).
Reaction Protocol
Step 1
IR (KBr, cm-1): 3420, 3405, 3325, 3150, 3110, 3065, 3028, 2939, 2920, 2895, 2850, 2690, 1601, 1499,
1472, 1462, 1360, 1052, 1040, 935, 800, 775, 703
[α]D 20 [α]D28 +29° (c 0.8, 1 M HCl aq)
MP 73- 76 °C
Number
Step 2
Products Benzeneethanol, β-[(3-hydroxy-1,3-diphenyl-2-propen-1-ylidene)amino]-, (βS)-, 48%, CAS
RN:1403239-83-7
Catalysts Formic acid, CAS RN:64-18-6
Procedure 1. Dissolve L-phenylglycinol (2.19 g, 10.0 mmol) and dibenzoylmethane (2.24 g, 10.0 mmol) in toluene
(50 mL) in a 100-mL round-bottomed flask equipped with a reflux condenser.
2. Add one drop of formic acid to this solution.
3. Heat the mixture under reflux for 48 hours.
4. Concentrate the mixture under reduced pressure to obtain a yellow oil.
5. Purify the crude oil by silica gel column chromatography with ethyl acetate to afford 3-((S)-2-
hydroxy-1-phenylethylimino)-1,3-diphenylprop-1-en-1-ol.
Scale gram
1H NMR (CDCl3): δ 12.16-11.98 (br, 1H), 7.91-7.85 (d, 2H), 7.42-7.11 (m, 13H), 5.75 (s, 1H), 4.67-4.58 (m, 1H),
4.04- 3.90 (br, 1H), 3.87-3.81 (m, 2H)
13C NMR (CDCl3): δ 188.9, 167.4, 140.1, 139.6, 135.4, 130.9, 129.5, 128.8, 128.4, 128.3, 127.8, 127.6, 127.2,
126.5, 94.6, 67.4
[α]D20 [α]D -366° (c 1.8, CHCl3)
State yellow viscous oil
Number
Step 3
Products Aluminum, bis[µ-[3-[[(1R)-2-(hydroxy-κO:κO)-1-phenylethyl]imino-κN]-1,3-diphenyl-1-propanonato(2-)-
κO]]dimethyldi-, stereoisomer, 80%, CAS RN:1403239-73-5
Reactants Benzeneethanol, β-[(3-hydroxy-1,3-diphenyl-2-propen-1-ylidene)amino]-, (βS)-, CAS RN:1403239-83-7
Trimethylaluminum, CAS RN:75-24-1
Procedure 1. Dissolve 3-((S)-2-hydroxy-1-phenylethylimino)-1,3-diphenylprop-1-en-1-ol (1.0 mmol) in dry THF (10
mL) in a 50-mL two-necked round-bottomed flask equipped with a three-way stopcock under dry
nitrogen.
2. Cool the mixture at -30 °C.
3. Add Me3Al (0.12 mL, 1.2 mmol) carefully to the solution by a hypodermic syringe in a nitrogen
stream.
4. Allow the resulting mixture to warm to room temperature after the gas evolution ceased.
5. Stir the mixture for 2.5 hours.
6. Remove the volatile components under reduced pressure to obtain a white solid.
7. Purify the crude product by recrystallization form THF/hexane to afford the product.
1H NMR (CDCl3): δ 8.00-7.97 (d, 4H), 7.60-7.01 (m, 26H), 5.86 (s, 2H), 4.67-4.59 (m, 4H), 3.90-3.81 (m, 4H), -
0.88 (s, 3H), -0.97 (s, 3H)
State colorless powder
Number
208. 4 Steps
[Step 3.1]
Overview
Steps/Stages Notes
1.1 R:SOCl2, S:MeOH, 45 h, cooled; 48 h, 40°C; 40°C → rt 5, Solvents: 3, Steps: 4, Stages: 6, Most
1.2 R:HCl, S:H2O
References
2.1 R:NH3, 64 h, rt Preparation of diazaspirodecenones and
3.1 S:MeOH, 24 h, reflux; reflux → rt; 4 d, rt diazaspirononenones as GlyT1 transporter
4.1 R:Bromosuccinimide, S:CH2Cl2, overnight, rt neuropsychiatric disorders
By Marshall, Howard Robert
4.2 R:NaHCO3, S:H2O, 0.5 h, rt
2008
Step 1
Description 1 : Methyl amino(4-chlorophenyl)acetate. To ice-chilled methanol (300ml) under argon was
(26.26g; 0.141 mol) was added, ice cooling removed and the reaction mixture warmed to 40°C. The
δ: 3.72 (3H, s), 5.36 (1 H, s), 7.53 - 7.58 (4H, m), 9.07 (3H, s). Mass Spectrum (Electrospray LC/MS):
Found 200 (MH+). C9H10 35ClNO2 requires 199. Ret. time 1.32 min.
Step 2
Description 2: 2-Amino-2-(4-chlorophenyl)acetamide. Methyl amino(4-chlorophenyl)acetate D1 as the
5.49 (1H, br s), 6.92 (1H, br s), 7.32 - 7.39 (4H, m).
Step 3
Description 3: 3-(4-Chlorophenyl)-1,4-diazaspiro[4.5]decan-2-one. To 2-amino-2-(4-
well with methanol. The filtrate was evaporated to afford the title product (12.91g; 90%) as a white
solid. 1H NMR (CDCl3) δ: 1.44 - 1.57 (4H, m), 1.66 - 1.76 (6H, m), 2.21 (1 H, s), 4.69 (1 H, s), 6.80 (1
H, s), 7.32 -7.35 (2H, m), 7.45 - 7.49 (2H, m).
Step 4
Description 4: 3-(4-Chlorophenyl)-1,4-diazaspiro[4.5]dec-3-en-2-one . N-Bromosuccinimide (8.69g;
48.81 mmol) was added in one portion to a stirred solution of 3-(4-chlorophenyl)-1 ,4-
diazaspiro[4.5]decan-2-one D3 (12.91g; 48.81 mmol) in DCM (400ml) and the mixture stirred overnight
at room temperature. Saturated aqueous sodium bicarbonate (500ml) was added and the mixture
stirred for 0.5h. The layers were separated and the aqueous extracted with DCM (300ml). The
combined organics were dried (Na2SO4) and the solvent removed under reduced pressure at 45°C.
The residual solid was partitioned between DCM (500ml) and saturated aqueous sodium bicarbonate
(500ml) and stirred overnight at room temperature. The aqueous layer was extracted with DCM
(300ml) and the organic layers combined, dried (Na2SO4) and the solvent removed under reduced
pressure to afford the title product (10.25g; 80%) as a pale yellow solid. 1H NMR (CDCl3) δ: 1.51 - 1.70
(6H, m), 1.91 - 1.99 (4H, m), 7.42 - 7.49 (2H, m), 8.36 - 8.39 (2H, m), 8.88 (1 H, s).
Reaction Protocol
Step 1
Step 2
Step 3
Step 4
209. 4 Steps
[Step 3.1]
Overview
Steps/Stages Notes
1.3 R:NaHCO3, S:H2O
References
3.1 S:EtOH, 6 h, reflux; overnight, rt diazaspirononenones as GlyT1 transporter
4.1 R:Bromosuccinimide, S:CH2Cl2, 45 min, rt neuropsychiatric disorders
4.2 R:NaHCO3, S:H2O, 20 min, rt
2008
Step 1
s), 4.62 (1H, s), 7.30-7.40 (4H, m).
Step 2
(1H, br s), 6.88 (1H, br s), 7.33 (2H, d), 7.41 (2H, d).
Step 3
Description 10. 3-{4-[(Methyloxy)methyl]phenyl}-1,4-diazaspiro[4.4]nonan-2-one. A stirred solution of
2-amino-2-{4-[(methyloxy)methyl]phenyl}acetamide (450 mg, 2.317 mmol, Description 7, Method A) in
ethanol (20 ml) was treated with cyclopentanone (0.215 ml, 2.433 mmol) followed by Zeolite HY
(product CBV400 from Zeolyst, Oosterhorn, Netherlands) (700mg) and then heated at reflux for a total
of 6 hours, plus overnight at room temperature. The mixture was allowed to cool, filtered through
Kieselguhr and the filtrate concentrated under vacuum. The residue was crystallised from a mixture of
dichloromethane (2ml) and ether (8ml) to give the title compound as a white solid (270mg). Mass
Spectrum (Electrospray LC/MS): Found 261 (MH+) weak. C15H20N2O2 requires 260. Ret. time 1.24
min. 1H NMR δ (CDCl3; 400MHz): 1.60-1.85 (6H, m), 1.85-2.00 (2H, m), 2.25 (1H, br s), 3.73 (3H, s),
4.46 (2H, s), 4.65 (1H, s), 6.87 (1H, br s), 7.34 (2H, d), 7.46 (2H, d).
Step 4
Description 11. 3-{4-[(Methyloxy)methyl]phenyl}-1,4-diazaspiro[4.4]non-3-en-2-one. A stirred solution
of 3-{4-[(methyloxy)methyl]phenyl}-1,4-diazaspiro[4.4]nonan-2-one (355 mg, 1.364 mmol, Description
10) in dichloromethane (20 ml) at room temperature under argon was treated with solid N-
bromosuccinimide (243 mg, 1.364 mmol) and maintained at room temperature for 45 minutes. The
orange solution was treated with saturated NaHCO3 solution (15ml) and stirred well. The orange colour
was quickly lost. After 20 minutes the dichloromethane layer was separated, dried (Na2SO4) and
concentrated under vacuum to leave a pale brown solid (302mg), containing the title compound, as the
major component. This was used directly in the next step. Mass Spectrum (Electrospray LC/MS):
Found 259 (MH+). C15H18N2O2 requires 258. Ret. time 2.31 min. 1H NMR δ (CDCl3; 400MHz): 1.90-
2.20 (8H, m), 3.41 (3H, s), 4.53 (2H, s), 7.43 (2H, d), 8.37 (2H, d), 9.08 (1H, br s).
Reaction Protocol
Step 1
Step 2
Step 3
Step 4

210. 4 Steps
[Step 3.1]
Overview
Steps/Stages Notes
1.1 R:SOCl2, S:MeOH, 45 min, cooled 4, Solvents: 4, Steps: 4, Stages: 6, Most
1.2 0°C → 40°C; 48 h, 40°C; 40°C → rt stages in any one step: 2
3.1 S:MeOH, 24 h, reflux; reflux → rt; 4 d, rt Preparation of diazaspirodecenyl-
4.1 R:Bromosuccinimide, S:CH2Cl2, overnight, rt acetamides as GlyT1 transporter inhibitors for
4.2 R:NaHCO3, S:H2O, 0.5 h, rt By Dean, Anthony William and Porter,
Roderick Alan
2007
Step 1
Description 6: Methyl amino(4-chlorophenyl)acetate: To ice-chilled methanol (300ml) under argon was
(26.26g; 0.141 mol) was added, ice cooling removed and the reaction mixture warmed to 40°C; the
δ: 3.72 (3H, s), 5.36 (1H, s), 7.53 - 7.58 (4H, m), 9.07 (3H, s). Mass Spectrum (Electrospray LC/MS):
Found 200 (MH+). C9H1035ClNO2 requires 199. Ret. time 1.32 min.
Step 2
5.49 (1H, br s), 6.92 (1H, br s), 7.32 - 7.39 (4H, m).
Step 3
well with methanol. The filtrate was evaporated. 3-(4-Chlorophenyl)-1,4-diazaspiro[4.5]decan-2-one as
a white solid, yield 12.91g, 90%. 1H NMR (CDCl3) δ: 1.44 - 1.57 (4H, m), 1.66 - 1.76 (6H, m), 2.21 (1H,
s), 4.69 (1H, s), 6.80 (1H, s), 7.32 - 7.35 (2H, m), 7.45 - 7.49 (2H, m).
Step 4
Method 2: N-Bromosuccinimide (8.69g; 48.81 mmol) was added in one portion to a stirred solution of
3-(4-chlorophenyl)-1,4-diazaspiro[4.5]decan-2-one D8 (12.91g; 48.81 mmol) in DCM (400ml) and the
added and the mixture stirred for 0.5h. The layers were separated and the aqueous extracted with
extracted with DCM (300ml) and the organic layers combined, dried (Na2SO4) and the solvent
removed under reduced pressure. 3-(4-Chlorophenyl)-1,4-diazaspiro[4.5]dec-3-en-2-one as a pale
yellow solid, yield 10.25g, 80%. 1H NMR (CDCl3) δ: 1.51 - 1.70 (6H, m), 1.91 - 1.99 (4H, m), 7.42 -
7.49 (2H, m), 8.36 - 8.39 (2H, m), 8.88 (1H, s).
Reaction Protocol
Step 1
Step 2
Step 3
Step 4
211. 4 Steps
[Step 3.1]
Overview
Steps/Stages Notes
3.1 S:MeOH, 24 h, reflux; reflux → rt; 4 d, rt Preparation of N-phenyl-2-oxo-1,4-
4.1 R:Bromosuccinimide, S:CH2Cl2, overnight, rt derivatives and their use as glycine
4.2 R:NaHCO3, S:H2O, 0.5 h, rt By Coulton, Steven et al
2007
Step 1
Step 2
5.49 (1H, br s), 6.92 (1H, br s), 7.32 - 7.39 (4H, m).
Step 3
3-{4-Chlorophenyl)-1,4-diazaspiro[4.5]decan-2-one. To 2-amino-2-(4-chlorophenyl)acetamide D2
(10.00g; 54.3mmol) in methanol (500ml) was added cyclohexanone (5.62ml; 54.3mmol) and H-Y
zeolites (10.00g) and the mixture stirred under reflux for 24h. The reaction was allowed to cool to room
temperature and after 4 days was filtered and the solid washed well with methanol. The filtrate
wasevaporated to afford the title product (12.91g; 90%) as a white solid. 1H NMR (CDCl3) δ: 1.44 -
1.57 (4H, m), 1.66 - 1.76 (6H, m), 2.21 (1H, s), 4.69 (1H, s), 6.80 (1H, s), 7.32 - 7.35 (2H, m), 7.45 -
7.49 (2H, m).
Step 4
3-{4-Chlorophenyl)-1,4-diazaspiro[4.5]dec-3-en-2-one. N-Bromosuccinimide (8.69g; 48.81mmol) was
added in one portion to a stirred solution of 3-(4-chlorophenyl)-1,4-diazaspiro[4.5]decan-2-one D3
(12.91g; 48.81mmol) in DCM (400ml) and the mixture stirred overnight at room temperature. Saturated
aqueous sodium bicarbonate (500ml) was added and the mixture stirred for 0.5h.The layers were
separated and the aqueous extracted with DCM (300ml). The combined organics were dried (Na2SO4)
and the solvent removed under reduced pressure at 45°C. The residual solid was partitioned between
DCM (500ml) and saturated aqueous sodium bicarbonate (500ml) and stirred overnight at room
temperature. The aqueous layer was extracted with DCM (300ml) and the organic layers combined,
dried(Na2SO4) and the solvent removed under reduced pressure to afford the title product (10.25g;
80%) as a pale yellow solid. 1H NMR (CDCl3) δ: 1.51 - 1.70 (6H, m), 1.91 - 1.99 (4H, m), 7.42 - 7.49
(2H, m), 8.36 - 8.39 (2H, m), 8.88 (1H, s).
Reaction Protocol
Step 1
Step 2

Step 3
Step 4
212. 4 Steps
[Step 3.1]
Overview
Steps/Stages Notes
1.1 R:SOCl2, S:MeOH, 45 min, cooled Reagents: 4, Solvents: 4, Steps: 4, Stages: 6,
1.2 48 h, 40°C; 40°C → rt Most stages in any one step: 2
3.1 S:MeOH, 24 h, reflux Preparation of 1-(2-aryl-2-oxoethyl)-3-phenyl-
4.1 R:Bromosuccinimide, S:CH2Cl2, overnight, rt as glycine transporter inhibitors
4.2 R:NaHCO3, S:H2O, 0.5 h, rt
2007
Step 1
Description 1 : Methyl amino(4-chlorophenyl)acetate hydrochloride: To ice-chilled methanol (300ml)
under argon was carefully added dropwise thionyl chloride (15.44ml; 0.217mol) over 45min. 4-
Chlorophenylglycine (26.26g; 0.141 mol) was added, ice cooling removed and the reaction mixture
warmed to 40°C; the reaction was stirred at 40°C for 48h. After cooling to room temperature, the
reaction was evaporated under reduced pressure. Re-evaporation from methanol afforded a white
solid which was triturated with diethyl ether (ca. 700ml) and then stored at ca. 4°C for 64h, filtered,
washed with diethyl ether and dried in vacuo to afford the title product as the hydrochloride salt, yield
33.40g; 100%. 1H NMR (d6-DMSO) δ: 3.72 (3H, s), 5.36 (1 H, s), 7.53 - 7.58 (4H, m), 9.07 (3H, s).
Mass Spectrum (Electrospray LC/MS): Found 200 (MH+). C9H1035ClNO2 requires 199. Ret. time 1.32
min.
Step 2
(Na2SO4) and evaporated under reduced pressure to afford a white solid, which was dried under
reduced pressure to afford the title product, yield 22.45g; 86%. 1H NMR (CDCl3) δ: 1.82 (2H, br s),
4.53 (1 H, s), 5.49 (1 H, br s), 6.92 (1 H, br s), 7.32 - 7.39 (4H, m).
Step 3
chlorophenyl)acetamide D2 (10.0Og; 54.3mmol) in methanol (500ml) was added cyclohexanone
(5.62ml; 54.3mmol) and H-Y zeolites (10.0 g) and the mixture stirred under reflux for 24h. The reaction
was allowed to cool to room temperature and after 4 days was filtered and the solid washed well with
methanol. The filtrate was evaporated to afford the title product as a white solid. 3-(4-Chlorophenyl)-
1,4-diazaspiro[4.5]decan-2-one, yield 12.91g, 90%. 1H NMR (CDCl3) δ: 1.44 - 1.57 (4H, m), 1.66 - 1.76
(6H, m), 2.21 (1 H, s), 4.69 (1 H, s), 6.80 (1 H, s), 7.32 - 7.35 (2H, m), 7.45 - 7.49 (2H, m).
Step 4
Description 4: 3-(4-Chlorophenyl)-1,4-diazaspiro[4.5]dec-3-en-2-one: N-Bromosuccinimide (8.69g;
48.81 mmol) was added in one portion to a stirred solution of 3-(4-chlorophenyl)-1,4-
diazaspiro[4.5]decan-2-one D3 (12.91g; 48.81 mmol) in DCM (400ml) and the mixture stirred overnight
at room temperature. Saturated aqueous sodium bicarbonate (500ml) was added and the mixture
stirred for 0.5h. The layers were separated and the aqueous extracted with DCM (300ml). The
combined organics were dried (Na2SO4) and the solvent removed under reduced pressure at 45°C.
The residual solid was partitioned between DCM (500ml) and saturated aqueous sodium bicarbonate
(500ml) and stirred overnight at room temperature. The aqueous layer was extracted with DCM
(300ml) and the organic layers combined, dried (Na2SO4) and the solvent removed under reduced
pressure to afford the title product as a pale yellow solid. 3-(4-Chlorophenyl)-1,4-diazaspiro[4.5]dec-3-
en-2-one, 10.25g; 80% 1H NMR (CDCl3) δ: 1.51 - 1.70 (6H, m), 1.91 - 1.99 (4H, m), 7.42 - 7.49 (2H,
m), 8.36 - 8.39 (2H, m), 8.88 (1 H, s).
Reaction Protocol
Step 1
Step 2
Step 3
Step 4
213. 4 Steps
[Step 2.1]
[Step 4.1]
Overview
Steps/Stages Notes
2.1 2 h, 70°C step: 2

23(52), 12758-12762; 2017
Reaction Protocol
Step 1
Step 2
Step 3
Step 4
214. Single Step
64%
Overview
Steps/Stages Notes
References
8/1-8/6, 6 pp.; 2013
Reaction Protocol
Step 1
Overview
Steps/Stages Notes
literature preparation, no experimental detail,
1.1 R:AcCl, S:MeOH, 2 min, 0°C Dean-Stark conditions used (stage 2),
1.2 24 h, rt Reactants: 3, Reagents: 5, Catalysts: 2,
1.1 in any one step: 2
2.1 R:NaBH4, S:MeOH, 10 min, rt; 1 h, rt References
2.2 C:p-MeC6H4SO3H, S:Benzene, 7 h, reflux
Pyrrolidine and thiazole derivatives with
3.1 R:NaOH, S:H2O, S:MeOH, 8 h, rt metallo-β-lactamase inhibitory properties
By Bateson, John Hargreaves and Best,
4.1 R:Cl(O=)CC(=O)Cl, C:DMF, S:CH2Cl2, 30 min, rt Desmond John
From PCT Int. Appl., 9840056, 17 Sep 1998
4.2 R:Et3N, S:CH2Cl2, rt; 1 h, rt
Reaction Protocol
Sequence 1
Step 1
Sequence 2
Step 1
Sequence 2
Step 2
Sequence 2
Step 3
Sequence 2
Step 4
216. Single Step
95%
Overview
Steps/Stages Notes
in any one step: 1
References
28 Jan 2009
Reaction Protocol
Step 1
217. Single Step
82%
Overview
Steps/Stages Notes
1.2 15 min, 100°C
References
from amino acids
Reaction Protocol
Step 1
218. Single Step
73%
Overview
Steps/Stages Notes
in any one step: 1
References
diphenylpyridine (3a) 2,6-di(9H-fluoren-3-yl)-4-phenylpyridine (3v) Pale yellow solid (352 mg, 73%); Mp
= 259-261 °C; 1H NMR (600 MHz, CDCl3) δ 8.44 (s, 2H), 8.23 (d, J = 7.8 Hz, 2H), 7.91-7.96 (m, 4H),
7.86 (d, J = 7.8 Hz, 2H), 7.80 (d, J = 7.8 Hz, 2H), 7.60 (d, J = 7.2 Hz, 2H), 7.56 (t, J = 7.2 Hz, 2H), 7.50
(t, J = 7.2 Hz, 1H), 7.42 (t, J = 7.8 Hz, 2H), 7.35 (t, J = 7.8 Hz, 2H), 4.04 (s, 4H). 13C NMR (100 MHz,
CDCl3) δ 157.22, 143.78, 143.63, 142.77, 141.08, 138.58, 136.99, 129.06, 127.19, 126.95, 126.72,
126.25, 125.01, 124.01, 120.18, 119.94, 117.34, 37.19. IR (KBr): 1592.61, 1542.79, 1450.03, 1400.59,
1300.18, 1218.87, 1075.97, 951.76, 867.60, 836.24, 760.84, 734.01, 694.47. HRMS (ESI): m/z [M+H]+
calcd for C37H26N: 484.2063; found: 484.2060.
Reaction Protocol
Step 1
219. Single Step
36%
Overview
Steps/Stages Notes
in any one step: 1
References
diphenylpyridine (3a) 2-(9H-fluoren-3-yl)-4,6-diphenylpyridine (3qv) Yellow solid (142 mg, 36%); Mp =
202-204 °C; 1H NMR (600 MHz, CDCl3) δ 8.41 (s, 1H), 8.20-8.22 (m, 3H), 7.92 (s, 1H), 7.90-7.85 (m,
2H), 7.83 (d, J = 7.2 Hz, 1H), 7.75 (d, J = 7.2 Hz, 2H), 7.57 (d, J = 7.2 Hz, 1H), 7.52 (t, J = 7.2 Hz, 4H),
7.43-7.47 (m, 2H), 7.39 (t, J = 7.2 Hz, 1H), 7.32 (t, J = 7.2 Hz, 1H), 3.99 (s, 2H). 13C NMR (150 MHz,
CDCl3) δ 157.62, 157.47, 150.12, 143.85, 143.76, 142.58, 141.29, 139.61, 139.03, 138.03, 129.07,
129.01, 128.94, 128.69, 127.16, 126.94, 125.09, 127.05, 123.74, 120.20, 119.97, 117.09, 116.98,
37.03. IR (KBr): 1637.13, 1385.02, 1301.83, 1184.90, 1148.57, 1044.88, 1014.89, 967.12, 763.17,
687.85, 620.55, 564.01. HRMS (ESI): m/z [M+H]+ calcd for C30H21N: 396.1747; found: 396.1753.
Reaction Protocol
Step 1

220. 3 Steps
[Step 2.1]
[Step 3.1]
Overview
Steps/Stages Notes
1.1 C:H2O, C:H2SO4, 6 h, 65°C 2) product obtained as mixture of cis and trans
isomers, Reactants: 4, Reagents: 4, Catalysts:
1.2 R:NaHCO3, S:H2O 2, Solvents: 4, Steps: 3, Stages: 6, Most
2.1 R:Na+ •(AcO)3BH-, S:ClCH2CH2Cl, 23 h, rt
References
2.2 R:H2O Preparation of oxazolidinone compounds and
3.1 S:96-47-9, S:THF, 1 h, 0°C; 0°C → rt; 2.5 h, rt derivatives thereof as inhibitors of tankyrase
By Bregman, Howard et al
3.2 R:NH4Cl, S:H2O, 0°C
2013
Step 1
Step 1: (S)-Methyl 2-amino-2-phenylacetate. A catalytic amount of concentrated sulfuric acid (0.1 mL)
was added to a 50 mL round bottom flask containing a solution of (S)-2-amino-2-phenylacetic acid
(commercially available from Sigma-Aldrich, Milwaukee, WI) (1.0 g, 6.6 mmol) in MeOH (10 mL). The
resulting mixture was heated at 65°C for 6 hours. The solvent was removed under reduced pressure,
and the mixture was quenched with aqueous NaHCO3 and extracted with EtOAc. The organic layer
was dried over Na2SO4, filtered, and concentrated. Yield: (0.8 g, 74.0%) as a white solid. 1H NMR (300
MHz, CDCl3) δ: 7.37-7.32 (m, 5H), 4.62 (s, 1H), 3.70 (s, 3H).
Step 2
Step 2: (S)-Methyl 2-((4-hydroxycyclohexyl)amino)-2-phenylacetate. (S)-(+)-2-Phenylglycine methyl
ester (commercially available from Sigma-Aldrich, Milwaukee, WI, 433 g, 2.146 mol) was added to a
solution of 4-hydroxycyclohexanone (245 g, 2.146 mol) in DCE (8.5 L). Sodium triacetoxyborohydride
was added (910 g, 4.292 mol), and the mixture was stirred at room temperature under nitrogen for 23
hours. Water (3 L) was added to quench the reaction, and the organic layer was separated. The
aqueous phase was extracted with DCM (4 L×2) and the organic layers were combined, dried, filtered
and concentrated. The residue was purified by column chromatography (gradient elution with 100%
DCM to DCM/MeOH=25:1). Yield: (197 g, 35%) (mixture of cis and trans). m/z (ESI) 264 (M+H)+.
Step 3
Step 3: (S)-4-((2-Hydroxy-2-methyl-1-phenylpropyl)amino)cyclohexanol. A solution of
methylmagnesium bromide in 2-methyltetrahydrofuran (3.2 M, 935 mL, 2.992 mol) was added over 1
hour to an ice-cooled solution of (S)-methyl 2-((4-hydroxycyclohexyl)amino)-2-phenylacetate (197 g,
0.748 mol) in anhydrous THF (2 L). The resulting mixture was allowed to warm to room temperature
slowly under nitrogen and stirred for 2.5 hours. The mixture was poured into a well stirred mixture of
ice water and saturated aqueous ammonium chloride. The mixture was extracted with EtOAc (3 L×3),
and the organic layers were combined, dried, filtered and concentrated. Yield: (184 g, 93%). m/z (ESI)
264 (M+H)+.
Reaction Protocol
Step 1
Step 2
Step 3
221. 3 Steps
[Step 3.1]
Overview
Steps/Stages Notes
1.3 R:NaHCO3, S:H2O
References
3.1 S:EtOH, rt → reflux; 72 h, reflux; reflux → rt diazaspirononenones as GlyT1 transporter
2008
Step 1
s), 4.62 (1H, s), 7.30-7.40 (4H, m).
Step 2
(1H, br s), 6.88 (1H, br s), 7.33 (2H, d), 7.41 (2H, d).
Step 3
Description 8. 3-{4-[(Methyloxy)methyl]phenyl}-1,4-diazaspiro[4.5]decan-2-one. In a 4L round-
bottomed flask 2-amino-2-{4-[(methyloxy)methyl]phenyl}acetamide (30.5g, 157 mmol, Description 7,
Method B) was dissolved in ethanol 2.4 L to give a yellow solution. Cyclohexanone (15.41 g, 157
mmol) was added followed by 44 g of zeolite HY (product CBV400 from Zeolyst, Oosterhorn ,
Netherlands). The mixture was heated to reflux and allowed to stir at this temperature for 72h, then it
was cooled to room temperature, filtered and evaporated under vacuum to obtain 30g of crude
material that was triturated under magnetic stirring with 250 ml of a mixture of pentane/diethyl ether
95/5 to afford 27.5 g (61.3%) of title product as a white solid. 1H NMR (CDCl3) δ: 1.40-1.8 (10H, m),
2.15 (1H, broad s), 3.38 (3H, s), 4.48 (2H, s), 4.78 (1H, broad s), 6.58 (1H, broad s), 7.35 (2H, d) , 7.48
(2H,d).
Reaction Protocol
Step 1
Step 2
Step 3
222. 4 Steps
[Step 3.1]
Overview
Steps/Stages Notes
1.1 S:MeOH, 40 h, reflux 3) H-Y zeolites used, 4) in the dark, Reactants:
1.2 C:HCl, S:H2O, 8 h, reflux; 16 h, rt 3, Reagents: 4, Catalysts: 1, Solvents: 4,
1.3 R:NaHCO3, S:H2O step: 3
2.1 R:NH4OH, S:H2O, 3.5 d, rt References
3.1 S:EtOH, rt → reflux; 72 h, reflux; reflux → rt Preparation of diazaspirodecenones and
diazaspirononenones as GlyT1 transporter
4.1 R:Bromosuccinimide, S:CH2Cl2, 20 min, rt; 30 min, rt inhibitors for treating neurological and
4.2 R:Na2SO3, S:H2O, 15 min, rt By Coulton, Steven and Porter, Roderick Alan
4.3 R:NaHCO3, S:H2O, S:CH2Cl2 From PCT Int. Appl., 2008092872, 07 Aug
2008
Step 1
s), 4.62 (1H, s), 7.30-7.40 (4H, m).
Step 2
(1H, br s), 6.88 (1H, br s), 7.33 (2H, d), 7.41 (2H, d).
Step 3
Description 8. 3-{4-[(Methyloxy)methyl]phenyl}-1,4-diazaspiro[4.5]decan-2-one. In a 4L round-
bottomed flask 2-amino-2-{4-[(methyloxy)methyl]phenyl}acetamide (30.5g, 157 mmol, Description 7,
Method B) was dissolved in ethanol 2.4 L to give a yellow solution. Cyclohexanone (15.41 g, 157
mmol) was added followed by 44 g of zeolite HY (product CBV400 from Zeolyst, Oosterhorn ,
Netherlands). The mixture was heated to reflux and allowed to stir at this temperature for 72h, then it
was cooled to room temperature, filtered and evaporated under vacuum to obtain 30g of crude
material that was triturated under magnetic stirring with 250 ml of a mixture of pentane/diethyl ether
95/5 to afford 27.5 g (61.3%) of title product as a white solid. 1H NMR (CDCl3) δ: 1.40-1.8 (10H, m),
2.15 (1H, broad s), 3.38 (3H, s), 4.48 (2H, s), 4.78 (1H, broad s), 6.58 (1H, broad s), 7.35 (2H, d) , 7.48
(2H,d).
Step 4
Description 9. 3-{4-[(Methyloxy)methyl]phenyl}-1,4-diazaspiro[4.5]dec-3-en-2-one. METHOD A.
Reaction was carried out in flask covered with aluminium foil, protected from light. To a solution of 3-
{4-[(methyloxy)methyl]phenyl}-1,4-diazaspiro[4.5]decan-2-one (15.4g, 56.1 mmol, Description 8) in
DCM (300ml), a solution of N-bromosuccinimide (11g, 61.7 mmol) in DCM (300ml) was added
dropwise in 20min. The mixture was stirred at room temperature for 30min. A solution of Na2SO3 (6g in
300ml of H2O) was then added and the resulting mixture was stirred for 15min. A sat sol of NaHCO3
(400ml) was added and the mixture diluted with DCM (400ml). The organic phase was washed with
HCl acid (2N, 2×200ml), dried over Na2SO4 and concentrated in vacuum to give the title material
(10.6g, 69.3%) as white solid. 1H NMR (CDCl3) δ: 1.50-2.10 (10H, m), 3.43 (3H, s), 4.55 (2H, s), 7.45
(2H, d), 8.00 (1H, broad s), 8.41 (2H, d).
Reaction Protocol
Step 1
Step 2
Step 3
Step 4
Overview
Steps/Stages Notes
1.1 S:MeCN, 1 h, reflux Wolff-Kischner Reduction, Friedel-Crafts
Reaction, Wolff-Kischner Reduction,
2.1 R:Et3N, S:MeCN, 1 h, reflux stereoselective, prophetic reaction, Gabriel
synthesis, Reactants: 6, Reagents: 20,
1.1 R:KOH, R:N2H4, S:(CH2OH)2, rt → reflux Catalysts: 1, Solvents: 10, Steps: 18, Stages:
2.1 R:AlCl3, S:Benzene, S:PhNO2, 2 h, reflux; cooled
References
2.2 R:HCl, S:H2O, acidify Antagonists of the magnesium binding defect
as therapeutic agents and methods for
3.1 R:KOH, R:N2H4, S:(CH2OH)2, rt → reflux treatment of abnormal physiological states
By Wells, Ibert Clifton
4.1 R:H2SO4, R:HNO3, S:H2O, 1 h, 90°C From PCT Int. Appl., 2002011714, 14 Feb
2002
5.1 R:Zn, rt; cooled
5.2 R:NaOH, S:H2O, neutralized
5.3 R:HCl, S:H2O
6.1 R:H2SO4, R:NaNO2, S:H2O, 0°C

7.1 S:H2O, 2 h, reflux
8.1 R:AcOH, R:AcOOH, S:H2O, 4 h, 25-30°C; 1 h, 30-35°C; 8 h, <
40°C; 4 d, rt
9.1 S:Ac2O, 100°C
10.1 R:NH3
11.1 R:CH2N2, S:CHCl3
11.2 R:Na, S:EtOH
12.1 R:SOCl2, reflux
13.1 R:K phthalimide, S:DMF, 1 h, 30-50°C
13.2 R:N2H4, S:H2O, S:EtOH, 2 h, reflux

14.1 S:PhMe, 100°C
14.2 R:NH3, R:Na
15.1 R:H2, C:PtO2, S:EtOH
16.1 R:ClCO2CH2Ph, S:MeCN, 1 h, reflux
16.2 R:ClCO2Et, R:Et3N, S:MeCN, 1 h, reflux

16.3 S:PhMe, 100°C
16.4 R:NH3, R:Na
Sequence 1
Step 1
0.12 Mole of each of the commercial available compounds, benzylchloroformate (20.5 gm.) and L-
phenylglycine (18.1 gm.), are dissolved in 200 ml of acetonitrile and heated under reflux for 1 hour to
form 0.11 mole, i.e., carbobenzyloxy (°CBZ") L-phenylglycine. Yield 90%.
Step 2
To this solution is added 0.23 mole (20 gm.) of triethylamine, 0.1 mole (10.9 gm.) of ethyl and 50 ml of
acetonitrile. Heating under reflux is continued for another hour, and then the solution is disted to
dryness. The residue which contains the mixed anhydride, CBZ-NH-CH(C6H5)-COO-COOC2H5
(approximately 0.1 mole) is dissolved in 200 ml of toluene. Final product.
Sequence 2
Step 1
Reaction (b): Synthesis of n-butylbenzene. (Wolff-Kischner Reduction). The product from Reaction (a)
is mixed with 200 ml of ethylene glycol, 10 gm. of KOH and 0.15 mole (5 gm.) of hydrazine. The
mixture is heated to reflux temperature while being stirred, and the water evolved is collected. When
the evolution of water ceases, the mixture is cooled, diluted with 200 ml of disted water, and steam
disted. The distate is extracted three times with 100 ml portions of benzene, and after the combined
extracts are dried over anhydrous Na2SO4, the benzene is removed by distation. The product, n-
butylbenzene, is crystallized from absolute ethanol. n-butylbenzene. m.p. 88°C.
Step 2
Reaction (a): Synthesis of n-butyrophenone. (FriedeCrafts Reaction). 0.1 Mole 10.7 gm.) of n-butyryl
chloride, 0.2 mole (16 gm.) of benzene, and 0.2 mole (27 gm.) of anhydrous AlCl3 are added to 100 ml
of nitrobenzene, and the mixture heated under reflux for 2 hours. The mixture is then cooled, acidified
with conc. HCl, diluted with 200 ml disted water and steam disted. The aqueous phase of the distate is
discarded, and the organic phase is dried with anhydrous Na2SO4. The solvents are then removed by
distation, and the residue of n-butyrophenone is used without further purification. Reaction (c):
Synthesis of para-n-butylbutyrophenone. Reaction (a) is repeated using 0.1 mole (13.4 gm.) of n-butyl
benzene, prepared in Reaction (b) supra and 0.1 mole (10.7 gm.) of n-butyryl chloride. The crude
reaction product is isolated as was the product in Reaction (a).
Step 3
butylbenzene, is crystallized from absolute ethanol. Reaction (d): Synthesis of 1.4-di-n-butylbenzene.
Reaction (b) is repeated using the approximately 0.1 mole of product from Reaction (c) as the starting
material. The reaction product, 1,4-di-n-butylbenzene, is crystallized from absolute ethanol and the
structure confirmed by NMR spectroscopsy.
Step 4
Reaction (e): Synthesis of 2,5-di-n-butynitrobenzene. 0.1 Mole (19.1 gm.) of 1,4- di-n-butylbenzene
prepared in Reaction (d) is dissolved in 60 ml of a 1:2 (v:v) mixture of conc. HNO3 and conc. H2SO4.
The solution is stirred, while its temperature is maintained at 90°C, for one hour. The solution becomes
yellow indicating that the reaction has occurred. The product is not isolated. 2,5-di-n-butynitrobenzene
Step 5
Reaction (f): Synthesis of 2,5-di-n-butylaniline. To the reaction mixture from Reaction (e) 0.4 mole (26
gm.) of powdered zinc is slowly added while the stirring is continued. The yellow color fades as the
reaction comes to completion. The reaction mixture is cooled, diluted with 400 ml of disted water, and
the acid content neutralized by the addition of an excess of 10 M NaOH. The reaction product is
extracted into diethyl ether, and the combined ether extracts are washed with disted water. From the
ether solution, the hydrochloride of the reaction product slowly precipitates after the addition of 10 ml
of conc. HCl and by ching the mixture. The recovered product is pure 2,5-di-n-butylaniline
hydrochloride as indicated by GLC of the free base. 2,5-di-n-butylaniline hydrochloride
Step 6
Reaction (g): Synthesis of 2,5-di-n-butylbenzene diazoriium salt. 0.1 Mole (24.0 gm.) of 2,5-di-n-
butylaniline hydrochloride prepared in Reaction (f) is dissolved in 130 ml 3 M H2SO4 and the mixture
cooled to 0 °C. by surrounding it with crushed ice. To the ched solution, 0.12 mole of NaNO2 (8.3 gm.)
is slowly added with stirring which is continued until starch-iodide paper turns blue. 2,5-di-n-
butylbenzene diazoriium salt.
Step 7
Reaction (h): Synthesis of 2,5-di-n-butylphenol. The solution from Reaction (g) is diluted with an equal
volume of disted water so as to adjust the H2SO4 concentration to approximately 1.5 M, and this
solution is heated under reflux for 2 hours. The 2,5-di-n- butylphenol thus formed is removed from this
reaction mixture by steam distation and is extracted from the distate with benzene. The benzene is
disted, and the residue analyzed by GLC and GLC-MS. 2,5-di-n-butylphenol.
Step 8
Reaction (i): Synthesis of cis,cis-1,3-butadiene-1,4-di-n-butYl,4-dicarboxylic acid. 0.33 Mole of
peracetic acid (63 gm., 56 ml of 40% peracetic acid) is added to a 250 ml, two necked reaction flask
fitted with a condenser, a dropping funnel and a magnetic stirrer. The flask is immersed in a water bath
maintained at 25°-30°C. While the peracetic acid is being stirred, a cold solution of 2,5-di-n-butylphenol
(0.1 mole, 20.6 gm., from Reaction (h)) in 75 ml of glacial acetic acid is added dropwise over a period
of 4 hours. The temperature of the reaction mixture is maintained between 30°-35°C. Solid material
begins to separate from the solution and when the addition of the phenol is complete, the mixture is
stirred for one hour and then is allowed to stand for 8 hours while its temperature is kept below 40°C.
After the mixture has remained at room temperature for 4 days, the crude product is obtained by
suction filtration. cis,cis-1,3-butadiene-1 t4-di-n-butYl,4-dicarboxylic acid.
Step 9
Reaction (j): Synthesis of mixed acetyl anhydrides of trans,trans-1,3-butadiene-1,4-di-n-butYl,4-
dicarboxylic acid. The product obtained in Reaction (i) is dissolved in 50 ml of acetic anhydride with
heating and stirring and to this solution is added 0.25 mole (20 gm.) of acetyl chloride. The
temperature of this stirred solution is maintained at 100°C. under reflux conditions until hydrogen
chloride is no longer evolved. Under these conditions, the cis,cis-isomer is converted to the
trans,trans-isomer and the double anhydride is formed. After the mixture has cooled, it is lyophilized to
dryness. Final product
Step 10
Reaction (k): Synthesis of trans,trans-1,3-butadiene-1,4-di-n-butYl-carboxy4-carboxamide. The crude
product of Reaction (j) is dissolved in 200 ml of anhydrous ammonia in a Dewar flask and the excess
ammonia is allowed to evaporate. The residue consists of a mixture of ammonium dicarboxylate,
diamide, monoamide-mono ammonium carboxylate, acetamide and ammonium acetate and is
dissolved in hot water. This solution is poured onto a 5.0 x 100 cm. column of anion exchange resin in
the acetate form maintained at 100°C. Hot water and then hot 0.01 M NaCl is used to elute the
adsorbed materials. The order of elution is monitored by determination of the pH of successive 25 ml
fractions of eluate. The desired substance, trans,trans-1,3-butadiene-1,4-di-n-butYl-carboxy4-
carboxamide is the second material to be eluted by the 0.01 NaCl. The fractions of eluate which
contain this material as the sodium salt, are combined and, after passage through a cation exchange
column in the hydrogen form, are lyophilized to dryness. The dicarboxylate and diamide forms of the
starting material obtained from the anion exchange column are reworked to increase the yield of the
desired product. trans,trans-1,3-butadiene-1,4-di-n-butYl-carboxy4-carboxamide
Step 11
carboxamide. 0.1 Mole of the product of Reaction (k) is dissolved in chloroform and 0.11 mole (4.6
gm.) of diazomethane (CH2N2) in chloroform is added. The yellow color of the diazomethane quickly
fades, indicating that the methyl ester has formed. Excess diazomethane is removed by the addition of
a few drops of glacial acetic acid to form methyl acetate. The chloroform is removed by distation to
dryness and the residue is dissolved in absolute ethanol. 0.50 Mole of sodium beads is added to this
solution, and after the evolution of hydrogen subsides, the solution is diluted with disted water and
extracted exhaustively with methylene chloride. The combined extracts are dried with anhydrous
Na2SO4 and the volume is reduced by distation to about 100 ml. To this solution of trans,trans-1,3-
butadiene-1,4-di-n-butYl-hydroxymethy4-carboxamide thus obtained trans,trans-1,3-butadiene-1,4-di-
n-butYl-hydroxymethy4-carboxamide.
Step 12
To this solution of trans,trans-1,3-butadiene-1,4-di-n-butYl-hydroxymethy4-carboxamide thus obtained,
0.1 mole of thionyl chloride (SOCl2, 8 gm.) is added and the solution is heated under reflux until the
evolution of SO2 and hydrogen chloride ceases. The target product is obtained as the residue by
evaporating the solution to dryness. Final product.
Step 13
Reaction (m): Synthesis of trans,trans-1,3-butadiene-1,4-di-n-butYl-aminomethy4-carboxamide.
(Gabriel Synthesis). 0.1 Mole (26.8 gm.) of the product from Reaction (1) is dissolved in 200 ml of
dimethylformamide and 0.1 mole (18.5 gm) of potassium phthalimide is then added. The mixture is
stirred and warmed to between 30° and 50°C. for one hour. After the formed KCl is removed by
filtration, 0.5 mole (16 gm.) of hydrazine, together with sufficient 95% ethanol to form a solution, is
added and the solution refluxed for 2 hours. The reaction mixture is cooled, diluted generously with
disted water, and extracted exhaustively with 50 ml portions of toluene. 15 ML of conc. HCl are added
to the combined toluene extracts, the combination thoroughly mixed, and allowed to stand at 5°C. The
hydrochloride of the named product forms slowly, is isolated by filtration, and is twice recrystallised by
repeating the process of forming the hydrochloride. It is characterized and its structure confirmed by
NMR spectroscopy of the free base. trans,trans-1,3-butadiene-1,4-di-n-butYl-aminomethy 4-
carboxamide.
Step 14
To the resulting toluene solution of the mixed anhydride is added a toluene solution of 0.1 mole of the
trans,trans-1,3-butadiene-1,4-di-n-butYl-aminomethy4-carboxamide prepared in Reaction (m). The
resulting solution is heated at 100°C. and stirred until the evolution of CO2 ceases indicating that the
substituted amide of CBZ-L-phenylglycine has formed. The toluene is then removed from the reaction
mixture by distation in vacuo, and the residue is dissolved in liquid ammonia in a Dewar flask. To this
solution 4.6 gm. of sodium beads are added, and the ammonia is allowed to evaporate. The residue is
taken up in the minimum volume of boiling glacial acetic acid horn which the named product
crystallizes and is recovered by filtration. It is washed with small volumes of cold glacial acetic acid, air
dried, and characterized by infra red and NMR spectroscosopy (X= trans, trans >C=CH--HC==C<, R1=
H, R2- H, R3= n-butyl, R4= n-butyl, R5= H, R6= R7--(CH2)n--HC(NH2)--CO--, where R7= phenyl, n= 0).
N-(2,5-di-n-buty2,4-trans,trans-pentadiene-5-carboxamide)-L-phenylglycinamide.
Step 15
Reaction (o): Synthesis of 5-aminomethy8-dodecane carboxamide (the perhydro-1,3-butadiene-based
intermediate). 0.1 Mole (23.8 gm.) of trans,trans-1,3-butadiene-l,4-di-n- butYl-aminomethy4-
carboxamide from Reaction (m) is dissolved in the minimum volume of 95% ethanol and subjected,
with shaking, to hydrogen gas at atmospheric pressure in the presence of 50 mg. of Adams platinum
oxide catalyst. The reduction is quantitative as reflected by the volume of hydrogen consumed (0.2
mole). 5-aminomethy8-dodecane carboxamide (quantitative).
Step 16
General/Typical Procedure: Reaction (n): Synthesis ofN-(2,5-di-n-buty2,4-trans,trans-pentadiene-5-
carboxamide)-L-phenYlglvcinamide (the named trans,trans-1,3-butadiene based compound of the
above Formula). 0.12 Mole of each of the commercial available compounds, benzylchloroformate (20.5
gm.) and L-phenylglycine (18.1 gm.), are dissolved in 200 ml of acetonitrile and heated under reflux for
I hour to form 0.11 mole, i.e. 90% yield, of carbobenzyloxy (°CBZ") L-phenylglycine. To this solution is
added 0.23 mole (20 gm.) of triethylamine, 0.1 mole (10.9 gm.) of ethyl and 50 ml of acetonitrile.
Heating under reflux is continued for another hour, and then the solution is disted to dryness. The
residue which contains the mixed anhydride, CBZ-NH-CH(C6H5)-COO-COOC2H5 (approximately 0.1
mole) is dissolved in 200 ml of toluene. This solution is washed three times with 50 ml of disted water
and dried with anhydrous Na2SO4. To the resulting toluene solution of the mixed anhydride is added a
toluene solution of 0.1 mole of the trans,trans-1,3-butadiene-1,4-di-n-butYl-aminomethy4-carboxamide
prepared in Reaction (m). The resulting solution is heated at 100°C. and stirred until the evolution of
CO2 ceases indicating that the substituted amide of CBZ-L-phenylglycine has formed. The toluene is
then removed from the reaction mixture by distation in vacuo,and the residue is dissolved in liquid
ammonia in a Dewar flask. To this solution 4.6 gm. of sodium beads are added, and the ammonia is
allowed to evaporate. The residue is taken up in the minimum volume of boiling glacial acetic acid horn
which the named product crystallizes and is recovered by filtration. It is washed with small volumes of
cold glacial acetic acid, air dried, and characterized by infra red and NMR spectroscosopy (X= trans,
trans >C=CH - HC==C<, R1= H, R2- H, R3= n-butyl, R4= n-butyl, R5= H, R6= R7-(CH2)n--HC(NH2)--
CO--, where R7= phenyl, n= 0). This mixture is converted to the racemic mixture of the four possible
optical isomers of N-(5-methylene-8-dodecane carboxamide)-L-phenylglycinamide by repetition of
Reaction (n) (X= >C*H(CH2)2HC*<, R1= H, R2= H, R3= n-butyl, R4= n-butyl, R5= H, R6= R7--(CH2)n--
HC(NH2)--CO-, where R7= phenyl, n= 0). The specific L-, D-isomer (amino acid convention) can be
obtained after resolving the mixture of four isomers produced supra.
Reaction Protocol
Sequence 1
Step 1
Sequence 1
Step 2
Sequence 2
Step 1
Sequence 2
Step 2
Sequence 2
Step 3
Sequence 2
Step 4

Sequence 2
Step 5
Sequence 2
Step 6
Sequence 2
Step 7
Sequence 2
Step 8
Sequence 2
Step 9
Sequence 2
Step 10
Sequence 2
Step 11
Sequence 2
Step 12
Sequence 2
Step 13
Sequence 2
Step 14
Sequence 2
Step 15
Sequence 2
Step 16

Overview
Steps/Stages Notes
1.1 R:KOH, R:N2H4, S:(CH2OH)2, rt → reflux Catalysts: 1, Solvents: 10, Steps: 17, Stages:
References
2002
5.3 R:HCl, S:H2O

40°C; 4 d, rt
9.1 S:Ac2O, 100°C
10.1 R:NH3
11.2 R:Na, S:EtOH

14.1 S:PhMe, 100°C
14.2 R:NH3, R:Na
15.1 R:H2, C:PtO2, S:EtOH

Sequence 1
Step 1
Step 2
Sequence 2
Step 1
Step 2
Step 3
Step 4
Step 5
Step 6
Step 7
Step 8
Step 9
Step 10
Step 11
Step 12
Step 13
carboxamide.
Step 14
Step 15
Reaction (o): Synthesis of 5-aminomethy8-dodecane carboxamide (the perhydro-1,3-butadiene-based
intermediate). 0.1 Mole (23.8 gm.) of trans,trans-1,3-butadiene-l,4-di-n- butYl-aminomethy4-
carboxamide from Reaction (m) is dissolved in the minimum volume of 95% ethanol and subjected,
with shaking, to hydrogen gas at atmospheric pressure in the presence of 50 mg. of Adams platinum
oxide catalyst. The reduction is quantitative as reflected by the volume of hydrogen consumed (0.2
mole). 5-aminomethy8-dodecane carboxamide (quantitative).
Reaction Protocol
Sequence 1
Step 1

Sequence 1
Step 2
Sequence 2
Step 1
Sequence 2
Step 2
Sequence 2
Step 3
Sequence 2
Step 4
Sequence 2
Step 5
Sequence 2
Step 6
Sequence 2
Step 7
Sequence 2
Step 8
Sequence 2
Step 9
Sequence 2
Step 10
Sequence 2
Step 11

Sequence 2
Step 12
Sequence 2
Step 13
Sequence 2
Step 14
Sequence 2
Step 15
Overview
Steps/Stages Notes
1.1 R:KOH, R:N2H4, S:(CH2OH)2, rt → reflux Solvents: 10, Steps: 16, Stages: 22, Most
References
2002
5.3 R:HCl, S:H2O

40°C; 4 d, rt
9.1 S:Ac2O, 100°C
10.1 R:NH3
11.2 R:Na, S:EtOH

14.1 S:PhMe, 100°C
14.2 R:NH3, R:Na
Sequence 1
Step 1
Step 2
Sequence 2
Step 1
Step 2
Step 3
Step 4
Step 5
Step 6
Step 7
Step 8
Step 9
Step 10
Step 11
Step 12
Step 13
carboxamide.
Step 14
Reaction Protocol
Sequence 1
Step 1
Sequence 1
Step 2

Sequence 2
Step 1
Sequence 2
Step 2
Sequence 2
Step 3
Sequence 2
Step 4
Sequence 2
Step 5
Sequence 2
Step 6
Sequence 2
Step 7
Sequence 2
Step 8
Sequence 2
Step 9
Sequence 2
Step 10
Sequence 2
Step 11
Sequence 2
Step 12

Sequence 2
Step 13
Sequence 2
Step 14
226. Single Step
85%
Overview
Steps/Stages Notes
1.1 R:KOH, S:MeOH 1, Stages: 3, Most stages in any one step: 3
1.2 S:MeOH
References
1.3
Synthesis of cephalosporin-type antibiotics by
coupling of their β-lactam nucleus and
racemic amino acid side chains using a
clathration-induced asymmetric
transformation
By Kemperman, Gerardus J. et al
From European Journal of Organic
Chemistry, (10), 1817-1820; 2001
Reaction Protocol
Step 1

227. 2 Steps
[Step 2.1]
Overview
Steps/Stages Notes
1.2 R:NH4OH, S:H2O
References
1912; 2014
Reaction Protocol
Step 1
Number
Step 2
Products Benzenamine, 4-[(6R)-5,6-dihydro-6-phenylimidazo[2,1-b]thiazol-3-yl]-N,N-dimethyl-, 40%, CAS
RN:1580490-42-1
2-Bromo-1-[4-(dimethylamino)phenyl]ethanone, CAS RN:37904-72-6
Number
228. Single Step
68%
Overview
Steps/Stages Notes
References
transamination
Society, 138(34), 10730-10733; 2016
Reaction Protocol
Step 1
229. Single Step
99%
Overview
Steps/Stages Notes
step: 1
References
Acid
By Hu, Ting et al
Reaction Protocol
Step 1
230. 5 Steps
[Step 2.1] [Step 5.1]
Overview
Steps/Stages Notes
1.2 R:H2O, 15 min, rt
References
From Synthesis, (10), 1626-1638; 2003
4.1 R:H2O2, S:H2O, S:AcOH, < 32°C
4.2 R:Me2S, 0°C
5.1 R:HCl, S:H2O

Step 1
General/Typical Procedure: Reduction of Acetophenones to Alcohols 13a-c; General Procedure To a
suspension of NaBH4 (5.8 g; 0.16 mol) in EtOH (120 mL) was added at 0 °C the acetophenone (0.32
mol) (in case of the p-Br acetophenone this was a solution in EtOH) dropwise, while maintaining the
temperature below 10 °C. After addition is complete, the reaction mixture was stirred overnight at r.t.
After addition of water (100 mL), the mixture was stirred at r.t. for 15 min. The reaction mixture was
extracted with Et2O (3 × 100 mL). The combined ether layers were washed with brine, dried over
Na2SO4, and concentrated to give a compound. 1-(4-Bromophenyl)ethanol (13c)26. 1H NMR: δ = 1.40
(d, 3 H), 4.80 (q, 1 H), 7.20 (d, 2 H), 7.42 (d, 2 H). 13C NMR: δ = 25.0 (q), 69.6 (d), 121.0 (s), 127.0 (d),
131.4 (d), 144.7 (s).
Step 2
General/Typical Procedure: Formation of Thiourea Salts 14a-c; General Procedure A mixture of the
alcohol 12 (0.10 mol), thiourea (0.10 mol), 48% HBr (40 mL) and EtOH (50 mL) was refluxed
overnight. After cooling to r.t., the reaction mixture was concentrated in vacuo, yielding a white solid or
a syrup, depending on the substituent. This crude salt was used without further purification. Compound
14c.
Step 3
General/Typical Procedure: Hydrolysis of the Thiourea Salts 14 to the Thiols 15a-c; General Procedure
The thiourea salt 14 (0.10 mol) was dissolved or suspended in water (50 mL) and heated to 50 °C. To
this mixture was added dropwise 33% NaOH solution until no more cloudiness developed upon
addition and the pH had risen to 10. The reaction mixture was stirred overnight at 50 °C. After cooling
to r.t., 30% HCl was added until pH 6. The reaction mixture was extracted with Et2O (3 × 100 mL). The
combined organic layers were washed with brine, dried over Na2SO4 and concentrated to a liquid.
NOTE: the thiols have a distinct odor. 1-(4-Bromophenyl)ethanethiol (15c) Yield: 64%. 1H NMR: δ =
1.80 (d, 3 H), 4.12 (q, 1 H), 7.19 (d, 2 H), 7.38 (d, 2 H). 13C NMR: δ = 25.7 (q), 37.9 (d), 120.6 (s),
128.0 (d), 131.6 (d), 144.8 (s).
Step 4
General/Typical Procedure: Oxidation of Thiols 15a-c to 12a-c General procedure The thiol 15 (36
mmol) was dissolved in HOAc (120 mL). H2O2 (110 mL, 30%, 2 equiv) was added dropwise, at such a
rate that the temperature remained below 32 °C. Beware of the induction time of the reaction; the
temperature rise does not follow the addition immediately. After addition was complete and the thiol
has reacted (according to TLC), Me2S was added at 0 °C until no more peroxides were present, as
shown by a peroxide test. The reaction mixture was concentrated in vacuo (during evaporation the
peroxide test was also applied), yielding an oil. This residue was suspended in H2O (ca. 80 mL) and
33% NaOH was added until pH 7. The water layer was washed with Et2O (3 × 75 mL) and
concentrated in vacuo to yield the sodium sulfonate, which was dried in vacuo at 60 °C. 1-(4-
Bromophenyl)ethanesulfonic Acid 12c Yield: 87%. 1H NMR (D2O): δ = 1.75, 4.00 (q, 1 H), 7.23 (d, 2
H), 7.39 (d, 2 H), (d, 3 H). 13C NMR (D2O): δ = 15.5 (q), 60.0 (d), 121.2 (s), 130.4 (d), 131.2 (d), 136.3
(s).
Step 5
Resolution of 12c Sulfonate 12c (2.0 g; 7 mmol) was suspended in 10% HCl (40 mL). L-p-
Hydroxyphenylglycine (1.16 g, 7 mmol) was added and heated until a clear solution was obtained. The
mixture was allowed to crystallize at r.t. overnight. The resulting crystals were removed by filtration
under suction, washed with ice water. [α]D -64.6 (c = 0.5, MeOH). Unfortunately no HPLC-method
could be devised to determine the ee. Due to low yield this salt was suspended in water (5 mL) and
heated to 60 °C. Ammonia (6 N) was added until pH 7. The mixture was stirred at 0 °C for 2 h. The
resulting solid was removed by filtration and the filtrate was passed over Amberlite IR-120. The column
was eluted with H2O. The eluent was concentrated in vacuo and stripped with toluene to obtain 50 mg
of free sulfonic acid, which still contained some H2O. White solid, yield 0.45 g, 15%.
Reaction Protocol
Step 1
Step 2
Step 3
Step 4
Step 5
231. Single Step
87%
Overview
Steps/Stages Notes
1.2 15 min, 100°C
References
from amino acids
Reaction Protocol
Step 1

232. Single Step
53%
Overview
Steps/Stages Notes
in any one step: 1
References
2016
Reaction Protocol
Step 1
233. Single Step
Overview
Steps/Stages Notes
References
16 Nov 2016
Reaction Protocol
Step 1
234. 2 Steps
Overview
Steps/Stages Notes
References
2016
Reaction Protocol
Step 1
Step 2
235. 7 Steps
[Step 2.1]
[Step 4.1] [Step 6.1]
Overview
Steps/Stages Notes

6.1 S:MeOH, S:Me(CH2)4Me, rt; 2 h, rt alkyl isocyano(thio)acetates with vinyl ketones
23(52), 12758-12762; 2017
7.2 R:NH4OH, S:H2O, pH 9-10
Reaction Protocol
Step 1

Step 2
Step 3
Step 4
Step 5
Step 6
Step 7
236. 6 Steps
[Step 2.1]
[Step 4.1] [Step 5.2]
Overview
Steps/Stages Notes

23(52), 12758-12762; 2017
6.2 R:NH4OH, S:H2O, pH 9-10
Reaction Protocol
Step 1
Step 2
Step 3
Step 4
Step 5
Step 6
237. 6 Steps
[Step 2.1]
[Step 4.1] [Step 6.1]
Overview
Steps/Stages Notes
2.1 2 h, 70°C step: 2

23(52), 12758-12762; 2017
Reaction Protocol
Step 1
Step 2
Step 3
Step 4
Step 5
Step 6
238. 5 Steps
[Step 2.1]
[Step 4.1] [Step 5.2]
Overview
Steps/Stages Notes
2.1 2 h, 70°C step: 2

23(52), 12758-12762; 2017
Reaction Protocol
Step 1
Step 2
Step 3
Step 4

Step 5
239. Single Step
76%
Overview
Steps/Stages Notes
stereoselective, Strecker reaction, Reactants:
1.1 R:AcOH, S:H2O, S:MeOH, 96 h, rt 3, Reagents: 1, Solvents: 2, Steps: 1, Stages:
References
Chirality transfer using (R)-phenylglycine
amide: a key technology for the synthesis of
enantiopure amines
By De Lange, Ben et al
From PharmaChem, 1(7/8), 29-32; 2002
Reaction Protocol
Step 1
240. 2 Steps
[Step 2.1]
Overview
Steps/Stages Notes
1.1 S:Benzene 1) paraformaldehyde used, 2) regioselective,
2.1 S:Ac2O Reactants: 4, Solvents: 2, Steps: 2, Stages: 2,
References
1,3-dipolar cycloadditions of new mesoionic
compounds. Synthesis of 1H-pyrrolo[1,2-
c]thiazoles, pyrrolizines and 5,6,7,8-
tetrahydroindolizines
By Dalla Croce, Piero and La Rosa, Concetta
From Heterocycles, 55(10), 1843-1857; 2001
Reaction Protocol
Step 1
Step 2
241. Single Step
71%
Overview
Steps/Stages Notes
1.1 R:I2, S:C5H5N, 12 h, 110°C chemoselective, pressure vessel used, control
experiments, green chemistry, Reactants: 2,
Reagents: 1, Solvents: 1, Steps: 1, Stages: 1,
References
Given that the generation of the pyridinium ylide equivalent A would be an inevitable part of this
reaction and pyridine was found to be critical to the success of this transformation, it seemed
reasonable to assume that a pyridinium ylide was formed as a crucial intermediate during this reaction.
The formation of 3q in 71% yield from the reaction of amino acid 1q with A in the absence of
acetophenone provided further proof of this idea. However, that the yield of this reaction was lower
than that of the reaction shown in Scheme 3, which indicated that acetophenone played another role in
the transformation. (Figure S1 b) 2,4,6-triphenylpyridine (3q) Mp = 136-138 °C; 1H NMR (300 MHz,
CDCl3) δ 8.27-8.15 (m, 4H), 7.89 (s, 2H), 7.73-7.77 (m, 2H), 7.45-7.55(m, 9H). 13C NMR (75 MHz,
CDCl3) δ 157.46, 150.27, 139.44, 139.00, 129.11, 129.08, 129.00, 128.70, 127.18, 127.16, 117.18. IR
(KBr): 1604.8217, 1594.08, 1577.98, 1550.14, 1493.32, 1446.48, 1399.63, 1072.97, 1029.93, 869.90,
758.63, 738.25, 691.96, 634.06, 610.85, 575.69. HRMS (ESI): m/z [M+H]+ calcd for C23H18N:
308.1435; found: 308.1434.
Reaction Protocol
Step 1
242. 2 Steps
[Step 2.1]
Overview
Steps/Stages Notes
1.1 R:SOCl2, S:MeOH, 30 min, cooled; 2 h, 5°C; 16 h, rt 2, Solvents: 2, Steps: 2, Stages: 3, Most
1.2 R:NH4OH, S:H2O, 16 h, rt
2.1 S:MeOH, 24 h, reflux; reflux → rt References
2007
Step 1
General/Typical Procedure: Description 15: Methyl amino(3-chlorophenyl)acetate To amino(3-
chlorophenyl)acetic acid (5.0g; 26.95mmol) suspended in methanol (30ml) and stirred at ice-bath
temperature under argon was added dropwise thionyl chloride (30ml) over 30min. After stirring for a
further 2h at 5°C and at room temperature for 16h, the reaction solution was evaporated under
reduced pressure. Trituration of the residue with diethylether afforded the title compound as a ca. 1:1
mixture with amino(3-chlorophenyl)acetic acid (6.16g). Description 16: 2-Amino-2-(3-
chlorophenyl)acetamide Methyl amino(3-chlorophenyl)acetate D15 (6.16g) was dissolved in
concentrated ammonia solution (75ml) and stirred at room temperature for 16h. The reaction was
extracted with DCM (x2) and the extracts dried, evaporated and triturated with hexane to afford the title
compound (1.527g; 31% from amino(3-chlorophenyl)acetic acid). 2-Amino-2-(3-
chlorophenyl)acetamide, yield (1.527g; 31%). 1H NMR (d6-DMSO) δ : 2.22 (2H, br s), 4.31 (1H, s),
7.09 (1H, br s), 7.28 - 7.39 (3H, m), 7.48 (1H, s), 7.51 (1H, brs).
Step 2
General/Typical Procedure: Description 10: 3-{4-[(Trifluoromethyl)oxy]phenyl}-1,4-diazaspiro[4.5]
decan-2-one To 2-amino-2-{4-[(trifluoromethyl)oxy]phenyl}acetamide D9 (3.70g; 15.81mmol) in
methanol (200ml) was added cyclohexanone (1.549ml; 15.81mmol) and H-Y zeolites (6.00g) and the
mixture stirred under reflux for 24h under argon. The reaction was allowed to cool to room temperature
and was filtered and the solid washed well with methanol. The filtrate was evaporated to afford the title
product (3.88g; 50%) as a white solid, after trituration with hexane. Description 17: 3-(3-Chlorophenyl)-
1,4-diazaspiro[4.5]decan-2-one The title compound (1.49g; 68%) was prepared from 2-amino-2-(3-
chlorophenyl)acetamide D16 (1.52g; 8.26mmol) and cyclohexanone (0.81 Og; 8.26mmol) in methanol
(100ml) with H-Y zeolites (3.5g) in a similar manner to the procedure of D10. 1H NMR(d6-DMSO) δ :
1.22 - 1.43 (2H, m), 1.48 - 1.70 (8H, m), 3.58 (1H, d), 4.60 (1H, d), 7.29-7.40 (2H, m), 7.47 (1H, d),
7.51 (1H, s), 8.68 (1H,s).
Reaction Protocol
Step 1
Step 2

243. 3 Steps
[Step 3.1]
Overview
Steps/Stages Notes
1.1 R:HCl, S:H2O, S:MeOH, rt; 4 h, reflux 2, Solvents: 3, Steps: 3, Stages: 3, Most
2.1 R:NH4OH, S:H2O, 18 h, rt
3.1 S:EtOH, 18 h, reflux References
Preparation of spiro-condensed imidazolone
derivatives inhibiting the glycine transporter
By Blunt, Richard et al
From PCT Int. Appl., 2009034061, 19 Mar
2009
Step 1
Description 20. Methyl amino(3-bromophenyl)acetate A stirred suspension of amino(3-
bromophenyl)acetic acid (D19) (3.0g) in methanol (50 ml) at room temperature under argon was
treated with cone HCl acid (4ml) and then heated at reflux temperature for 4 hours. The solution was
concentrated under vacuum to approx 10ml volume then added carefully to excess sat. NaHCO3
solution (100ml), treated with EtOAc (100ml) and shaken well. As significant insoluble material was
present, the mixture was filtered and the EtOAc layer isolated from the filtrate, dried (Na2SO4) and
concentrated under vacuum to leave the title compound as a pale yellow oil (2.4g). 1H NMR (CDCl3) δ:
1.90 (2H, br s), 3.71 (3H, s), 4.59 (1H, s), 7.25 (1H, m), 7.31 (1H, d), 7.43 (1H, d), 7.57 (1H, s).
Step 2
Description 21. 2-Amino-2-(3-bromophenyl)acetamide A mixture of methyl amino(3-
bromophenyl)acetate (D20) (2.35g) in 0.88 NH3 solution (50ml) at room temperature under argon was
stirred well for 18 hours affording a homogeneous solution, which was then extracted with DCM (3 x
30ml) and the extract dried (Na2SO4) and concentrated under vacuum to leave the title compound as a
white solid (1.51g). 1H NMR (D6-DMSO) δ: 2.23 (2H, s), 4.30 (1H, s), 7.08 (1H, s), 7.26 (1H, m), 7.40-
7.46 (2H, m), 7.51 (1H, s), 7.60 (1H, s).
Step 3
Description 22. 3-(3-Bromophenyl)-1,4-diazaspiro[4.5]decan-2-one A stirred mixture of 2-amino-2-(3-
bromophenyl)acetamide (D21) (1.5g) in ethanol (60ml) at room temperature under argon was treated
with cyclohexanone (0.713ml, 6.88mmol) followed by H-Y Zeolites (2.0g, 6.55mmol) and then heated
under reflux for 18 hours. The reaction mixture was allowed to cool, filtered through Kieselguhr and the
filtrate concentrated under vacuum. The residue was triturated with Et2O (50ml) and the solid filtered
off and dried under vacuum to afford the title compound as a white solid (1.52g). Mass Spectrum
(LC/MS): Found 309/311 (MH+). Ret. time 1.99 min. 1H NMR (CDCl3) δ: 1.35-1.60 (4H, m), 1.60-1.82
(6H, m), 2.22 (1H, d), 4.69 (1H, d), 71.13-7.32 (2H, m), 7.40-7.50 (2H, m), 7.71 (1H, s).
Reaction Protocol
Step 1
Step 2
Step 3
244. 3 Steps
[Step 2.1]
Overview
Steps/Stages Notes
1.1 R:SOCl2, S:MeOH, 30 min, cooled; 2 h, 5°C; 16 h, rt 4, Solvents: 3, Steps: 3, Stages: 5, Most
1.2 R:NH4OH, S:H2O, 16 h, rt
2.1 S:MeOH, 24 h, reflux; reflux → rt References
3.1 R:Bromosuccinimide, S:CH2Cl2, 16 h, rt diazaspiro[4.5]dec-3-en-1-yl acetamide
3.2 R:NaHCO3, S:H2O, 1 h, rt By Coulton, Steven et al
2007
Step 1
General/Typical Procedure: Description 15: Methyl amino(3-chlorophenyl)acetate To amino(3-
chlorophenyl)acetic acid (5.0g; 26.95mmol) suspended in methanol (30ml) and stirred at ice-bath
temperature under argon was added dropwise thionyl chloride (30ml) over 30min. After stirring for a
further 2h at 5°C and at room temperature for 16h, the reaction solution was evaporated under
reduced pressure. Trituration of the residue with diethylether afforded the title compound as a ca. 1:1
mixture with amino(3-chlorophenyl)acetic acid (6.16g). Description 16: 2-Amino-2-(3-
chlorophenyl)acetamide Methyl amino(3-chlorophenyl)acetate D15 (6.16g) was dissolved in
concentrated ammonia solution (75ml) and stirred at room temperature for 16h. The reaction was
extracted with DCM (x2) and the extracts dried, evaporated and triturated with hexane to afford the title
compound (1.527g; 31% from amino(3-chlorophenyl)acetic acid). 2-Amino-2-(3-
chlorophenyl)acetamide, yield (1.527g; 31%). 1H NMR (d6-DMSO) δ : 2.22 (2H, br s), 4.31 (1H, s),
7.09 (1H, br s), 7.28 - 7.39 (3H, m), 7.48 (1H, s), 7.51 (1H, brs).
Step 2
General/Typical Procedure: Description 10: 3-{4-[(Trifluoromethyl)oxy]phenyl}-1,4-diazaspiro[4.5]
decan-2-one To 2-amino-2-{4-[(trifluoromethyl)oxy]phenyl}acetamide D9 (3.70g; 15.81mmol) in
methanol (200ml) was added cyclohexanone (1.549ml; 15.81mmol) and H-Y zeolites (6.00g) and the
mixture stirred under reflux for 24h under argon. The reaction was allowed to cool to room temperature
and was filtered and the solid washed well with methanol. The filtrate was evaporated to afford the title
product (3.88g; 50%) as a white solid, after trituration with hexane. Description 17: 3-(3-Chlorophenyl)-
1,4-diazaspiro[4.5]decan-2-one The title compound (1.49g; 68%) was prepared from 2-amino-2-(3-
chlorophenyl)acetamide D16 (1.52g; 8.26mmol) and cyclohexanone (0.81 Og; 8.26mmol) in methanol
(100ml) with H-Y zeolites (3.5g) in a similar manner to the procedure of D10. 1H NMR(d6-DMSO) δ :
1.22 - 1.43 (2H, m), 1.48 - 1.70 (8H, m), 3.58 (1H, d), 4.60 (1H, d), 7.29-7.40 (2H, m), 7.47 (1H, d),
7.51 (1H, s), 8.68 (1H,s).
Step 3
General/Typical Procedure: Description 11: 3-{4-[(Trifluoromethyl)oxy]phenyl}-1,4-diazaspiro[4.5]dec-
3-en-2-one 3-{4-[(Trifluoromethyl)oxy]phenyl}-1,4-diazaspiro[4.5] decan-2-one D10 (3.880g;
12.36mmol) was dissolved in DCM (80 ml) and stirred at room temperature for 16 hours under an
atmosphere of argon with N-bromosuccinimide (2.216g; 12.36mmol). A solution of saturated sodium
hydrogen carbonate (100ml) was then added and stirring continued for 1 hour at room temperature.
The organic layer was separated, dried (MgSO4) and evaporated at reduced pressure to yield the title
compound as a yellow solid after trituration with hexane (3.25g; 84%). Description 18: 3-(3-
Chlorophenyl)-1,4-diazaspiro[4.5]dec-3-en-2-one The title compound (1.363g, 91%) was prepared
from 3-(3-chlorophenyl)-1,4-diazaspiro[4.5]decan-2-one D17 (1.49g; 5.64mmol) and N-
bromosuccinimide (1.011g; 5.64mmol) in DCM (30ml) by a similar procedure to that described in D11.
1H NMR (d - DMSO) δ : 1.40 - 1.88 (10H, m), 7.58 (1H, t), 7.64 (1H, m), 8.28 (1H, d), 8.37 (1H,
6
s),10.34(1H,brs).
Reaction Protocol
Step 1
Step 2
Step 3
245. Single Step
80%
Overview
Steps/Stages Notes
References
United Kingdom), 47(33), 9513-9515; 2011
Reaction Protocol
Step 1
Products 4-Hexadecyl-2-phenylquinazoline, 80%, CAS RN:1229609-93-1
1-(2-Aminophenyl)-1-heptadecanone, CAS RN:1229609-90-8
sealed tube.
3. Purify the residue by column chromatography over silica gel to obtain 4-hexadecyl-2-
phenylquinazoline.
1H NMR (400 MHz, CDCl3) δ (ppm) 8.66-8.63 (m, 2 H), 8.12-8.06 (m,2 H), 7.86- 7.81 (m, 1 H), 7.58-7.48 (m, 4
H), 3.32 (t, J = 7.6 Hz, 2 H), 2.00-1.94 (m, 2H), 1.53-1.47 (m, 2 H), 1.42-1.36 (m, 2 H), 1.26-1.20 (m,
22 H), 0.88 (t, J = 6.4 Hz, 3 H)
13C NMR (100 MHz, CDCl3) δ (ppm) 171.6, 160.2, 150.9, 138.6, 133.3, 130.4, 129.6, 128.7, 128.6,126.8, 124.7,
122.7, 34.7, 32.1, 29.85, 29.82, 29.74, 29.67, 29.5, 28.7, 22.8, 14.2
HRMS calc. C30H42N2:430.3348, found: 430.3345
State yellow solid
Number
246. 4 Steps
[Step 3.1]
Overview
Steps/Stages Notes
1.1 R:HCl, S:H2O, S:MeOH, rt; 4 h, reflux 4, Solvents: 4, Steps: 4, Stages: 5, Most
2.1 R:NH4OH, S:H2O, 18 h, rt
3.1 S:EtOH, 18 h, reflux References
Preparation of spiro-condensed imidazolone
4.1 R:Bromosuccinimide, S:CH2Cl2, 18 h, rt derivatives inhibiting the glycine transporter
By Blunt, Richard et al
4.2 R:NaHCO3, S:H2O, 2 h
From PCT Int. Appl., 2009034061, 19 Mar
2009
Step 1
Description 20. Methyl amino(3-bromophenyl)acetate A stirred suspension of amino(3-
bromophenyl)acetic acid (D19) (3.0g) in methanol (50 ml) at room temperature under argon was
treated with cone HCl acid (4ml) and then heated at reflux temperature for 4 hours. The solution was
concentrated under vacuum to approx 10ml volume then added carefully to excess sat. NaHCO3
solution (100ml), treated with EtOAc (100ml) and shaken well. As significant insoluble material was
present, the mixture was filtered and the EtOAc layer isolated from the filtrate, dried (Na2SO4) and
concentrated under vacuum to leave the title compound as a pale yellow oil (2.4g). 1H NMR (CDCl3) δ:
1.90 (2H, br s), 3.71 (3H, s), 4.59 (1H, s), 7.25 (1H, m), 7.31 (1H, d), 7.43 (1H, d), 7.57 (1H, s).
Step 2
Description 21. 2-Amino-2-(3-bromophenyl)acetamide A mixture of methyl amino(3-
bromophenyl)acetate (D20) (2.35g) in 0.88 NH3 solution (50ml) at room temperature under argon was
stirred well for 18 hours affording a homogeneous solution, which was then extracted with DCM (3 x
30ml) and the extract dried (Na2SO4) and concentrated under vacuum to leave the title compound as a
white solid (1.51g). 1H NMR (D6-DMSO) δ: 2.23 (2H, s), 4.30 (1H, s), 7.08 (1H, s), 7.26 (1H, m), 7.40-
7.46 (2H, m), 7.51 (1H, s), 7.60 (1H, s).
Step 3
Description 22. 3-(3-Bromophenyl)-1,4-diazaspiro[4.5]decan-2-one A stirred mixture of 2-amino-2-(3-
bromophenyl)acetamide (D21) (1.5g) in ethanol (60ml) at room temperature under argon was treated
with cyclohexanone (0.713ml, 6.88mmol) followed by H-Y Zeolites (2.0g, 6.55mmol) and then heated
under reflux for 18 hours. The reaction mixture was allowed to cool, filtered through Kieselguhr and the
filtrate concentrated under vacuum. The residue was triturated with Et2O (50ml) and the solid filtered
off and dried under vacuum to afford the title compound as a white solid (1.52g). Mass Spectrum
(LC/MS): Found 309/311 (MH+). Ret. time 1.99 min. 1H NMR (CDCl3) δ: 1.35-1.60 (4H, m), 1.60-1.82
(6H, m), 2.22 (1H, d), 4.69 (1H, d), 71.13-7.32 (2H, m), 7.40-7.50 (2H, m), 7.71 (1H, s).
Step 4
Description 23. 3-(3-Bromophenyl)-1,4-diazaspiro[4.5]dec-3-en-2-one A stirred solution of 3-(3-
bromophenyl)-1,4-diazaspiro[4.5]decan-2-one (D22) (1.50g) in dichloromethane (35ml) at room
temperature under argon was treated with N-bromosuccinimide (0.907g, 5.09mmol) and maintained at
room temperature for 18 hours producing a yellow heterogeneous mixture. This was diluted with DCM
(35ml), treated with 5% NaHCO3 solution (60ml) and stirred well for 2 hours. At this stage the yellow
colour had been lost and a precipitate was present. The solid was filtered off, washed with water and
DCM and dried under vacuum to afford the title compound as a white solid (1.25g). Mass Spectrum
(LC/MS): Found 307/309 (MH+). Ret. time 2.76 min. 1H NMR (D6-DMSO) δ: 1.40-1.85 (10H, m), 7.48
(1H, t), 7.77 (1H, m), 8.31 (1H, m), 8.50 (1H, s), 10.32 (1H, br s).
Reaction Protocol
Step 1
Step 2
Step 3
Step 4
247. Single Step
82%
Overview
Steps/Stages Notes
in any one step: 1
References
2016
Reaction Protocol
Step 1
248. Single Step
Overview
Steps/Stages Notes
References
chiral amino acids
16 Nov 2016
Reaction Protocol
Step 1

249. Single Step
92%
Overview
Steps/Stages Notes
1.1 R:(t-Bu-O)2, C:Cu(CF3SO3)2, C:I2, S:PhMe, rt; rt → 120°C; 10 h, Catalysts: 2, Solvents: 1, Steps: 1, Stages: 1,
120°C Most stages in any one step: 1
References
Synthesis of 1,3-Disubstituted Imidazo[1,5-
a]pyridines from Amino Acids via Catalytic
Decarboxylative Intramolecular Cyclization
By Wang, Huiqiao et al
3681-3687; 2016
Reaction Protocol
Step 1
250. 2 Steps
Overview
Steps/Stages Notes
References
2016
Reaction Protocol
Step 1
Step 2

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3.1 R:POCl3, R:i-Pr2NH, S:CH2Cl2, 1.5 h, -30°C

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