Name: 1142-20-7 | Cbz-Val-OH | (S)-2-(Benzyloxycarbonylamino)propanoic acid; L-Alanine, N-carboxy-, N-benzyl ester (6CI,7CI)
Brand: Ambeed
SKU: A278709
Rating: 4.0 (172 reviews)

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Structure of Cbz-Val-OH
CAS No.: 1142-20-7

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Synonyms: (S)-2-(Benzyloxycarbonylamino)propanoic acid; L-Alanine, N-carboxy-, N-benzyl ester (6CI,7CI); N-[(Benzyloxy)carbonyl]-L-alanine

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Quality Control of [ 1142-20-7 ] Purity: 98% SDS Specification

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Product Details of [ 1142-20-7 ]

CAS No. :	1142-20-7
Formula :	C₁₁H₁₃NO₄
M.W :	223.23
SMILES Code :	[C@@H](NC(OCC1=CC=CC=C1)=O)(C(=O)O)C
Synonyms :	(S)-2-(Benzyloxycarbonylamino)propanoic acid; L-Alanine, N-carboxy-, N-benzyl ester (6CI,7CI); N-[(Benzyloxy)carbonyl]-L-alanine
English Name :	((Benzyloxy)carbonyl)-L-alanine
MDL No. :	MFCD00002640
InChI Key :	TYRGLVWXHJRKMT-QMMMGPOBSA-N
Pubchem ID :	736104

Safety of [ 1142-20-7 ]

GHS Pictogram:
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Application In Synthesis of [ 1142-20-7 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Downstream synthetic route of [ 1142-20-7 ]

[ 1142-20-7 ] Synthesis Path-Downstream 1~55

1
[ 10065-72-2 ]
[ 1142-20-7 ]
[ 2483-51-4 ]

Yield	Reaction Conditions	Operation in experiment
73.1%		N-benzyloxycarbonyl-L-alanine (100 g, 0.45 mol) was dissolved in a dried N,N-dimethylformamide (3 L), and 1-hydroxylbenzotriazole (72.6 g, 0.54 mol) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (103.3 g, 0.54 mol) were added while stirring. After stirring for reaction for 1 hour, the mixture was subjected to an ice both until the temperature reached 0 C. L-alanine methyl ester (46.2 g, 0.45 mol) and N,N-diisopropyl ethylamine (173.8 g, 1.34 mol) dissolved in an N,N-dimethylformamide (1 L) solution were dropped into the mixture. After dropping, the mixture was stirred under ambient temperature for 10 hours and the solvents were removed by evaporation under reduced pressure. The crude product was dissolved in dichloromethane (2 L) and washed successively with saturated ammonia chloride solution, water and saturated sodium chloride solution. The organic phase was dried with anhydrous sodium sulfate and the solvents were removed by evaporation under reduced pressure. The crude product was re-crystallized by ethyl acetate/petroleum ether to obtain a pure product, which was a white solid I, i.e., Cbz-L-Ala-L-Ala-OMe (101 g; Yield, 73.1%).
73.1%		[0082] N-benzyloxycarbonyl-LAla (100g, 0.45mol) were dissolved in N,N-dimethylformamide (3L). 1-hydroxylbenzotriazole (HOBt, 72.6g, 0.54mol) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC, 103.3g, 0.54mol) were added when stirring. After reacting for 1 hour under stirring, the mixture was cooled to 0C in an ice bath and L-Ala methyl ester (46.2g, 0.45mol) and N,N-diisopropylethylamine (173.8g, 1.34mol) in the N,N-dimethylformamide solution (1L) was dropped into the mixture. After dropping, the mixture was stirred under ambient temperature for 10 hours. The solvents were removed by evaporation under reduced pressure. The crude product was dissolved in dichloromethane (2L) and washed subsequently by saturated ammonium chloride solution, water and saturated sodium chloride solution. The organic phase was dried by anhydrous sodium sulphate. After removing the solvents by evaporation under reduced pressure, the crude product was recrystallized to obtain a white solid I (101g, Yield 73.1%).
73.1%		N-benzyloxycarbonyl-L-alanine (100 g, 0.45 mol) was dissolved in a dried N,N-dimethylformamide (3 L), and 1-hydroxylbenzotriazole (72.6 g, 0.54 mol) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (103.3 g, 0.54 mol) were added while stirring. After stirring for reaction for 1 hour, the mixture was subjected to an ice bath until the temperature reached 0 C. L-alanine methyl ester (46.2 g, 0.45 mol) and N,N-diisopropyl ethylamine (173.8 g, 1.34 mol) dissolved in an N,N-dimethylformamide (1 L) solution were dropped into the mixture. After dropping, the mixture was stirred under ambient temperature for 10 hours and the solvents were removed by evaporation under reduced pressure. The crude product was dissolved in dichloromethane (2 L) and washed successively with saturated ammonia chloride solution, water and saturated sodium chloride solution. The organic phase was dried with anhydrous sodium sulfate and the solvents were removed by evaporation under reduced pressure. The crude product was re-crystallized by ethyl acetate/petroleum ether to obtain a pure product, which was a white solid I, i.e., Cbz-L-Ala-L-Ala-OMe (101 g; Yield, 73.1%).

References: [1]RSC Advances,2013,vol. 3,p. 16247 - 16250.
[2]Journal of Organic Chemistry,2010,vol. 75,p. 4812 - 4816.
[3]Journal of Enzyme Inhibition and Medicinal Chemistry,2020,vol. 35,p. 1387 - 1402.
[4]Patent: US2017/106094,2017,A1 .Location in patent: Paragraph 0041; 0042; 0043.
[5]Patent: EP3184540,2017,A1 .Location in patent: Paragraph 0080-0082; 0227-0228.
[6]Patent: US2019/135858,2019,A1 .Location in patent: Paragraph 0041-0043.
[7]Recueil des Travaux Chimiques des Pays-Bas,1968,vol. 87,p. 559 - 571.
[8]Journal of the American Chemical Society,1965,vol. 87,p. 611 - 619.
[9]Journal of Organic Chemistry,2015,vol. 80,p. 2874 - 2878.
[10]Journal of the American Chemical Society,2019,vol. 141,p. 12288 - 12295.

2
[ 1142-20-7 ]
[ CAS Unavailable ]
[ 33628-84-1 ]

Yield	Reaction Conditions	Operation in experiment
	(i) ClCO₂Et, Et₃N, (ii) /BRN= 3588822/, aq. Et₃N; Multistep reaction;

References: [1]Engelfried,C. et al. [Liebigs Annalen der Chemie, 1979, p. 973 - 985].

3
[ 1142-20-7 ]
[ 63060-94-6 ]
[ 98807-09-1 ]

References: [1]Journal of the Chemical Society,1964,p. 3965 - 3972.

4
[ 1142-20-7 ]
[ CAS Unavailable ]
[ 33628-84-1 ]

Yield	Reaction Conditions	Operation in experiment
75.6%	Stage #1: N-Cbz-Ala With benzotriazol-1-ol; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; Stage #2: methylamine In dichloromethane at 20℃; for 12h;	4.1.10. General procedure for preparation of compounds 10a,b,c,d,e,h,j,k General procedure: This procedure is illustrated for compound 10a. To a stirred solution of Z-glycine (250 mg, 1.2 mmol) in dichloromethane at 0 °C, dicyclohexylcarbodiimide (DCC) (296 mg, 1.44 mmol, 1.2 equiv) and hydroxybenzotriazole (HOBt) (195 mg, 1.44 mmol, 1.2 equiv) were added. The reaction mixture was maintained at 0 °C for 1 h, and then it was allowed to warm up to room temperature. The methylamine (112 mg, 3.6 mmol, 3 equiv) was added, and the reaction mixture was stirred for 12 h. The DCU was filtered, and the organic layer was washed with 5% citric acid solution (2×), saturated aqueous sodium bicarbonate (2×), and brine, dried and concentrated in vacuo, to afford a clear oil. The obtained residue was purified by flash column chromatography (EtOAc/hexane, 8:2), affording the title compound as a white solid. Yield 64%.
	(i) Et₂O, (ii) AcOH; Multistep reaction;
	With N-ethylmorpholine;; isobutyl chloroformate 1.) THF, -15 deg C, 5 min; 2.) THF/EtOH, -15 deg C to rt., 20 min; Yield given. Multistep reaction;

References: [1]Location in patent: experimental part Gaeta, Alessandra; Molina-Holgado, Francisco; Kong, Xiao L.; Salvage, Sarah; Fakih, Sarah; Francis, Paul T.; Williams, Robert J.; Hider, Robert C. [Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 3, p. 1285 - 1297].
[2]Smolikova,J. et al. [Collection of Czechoslovak Chemical Communications, 1971, vol. 36, p. 2474 - 2485].
[3]Blackburn, G. Michael; Lilley, Terence H.; Milburn, Peter J. [Journal of the Chemical Society, Faraday Transactions 1: Physical Chemistry in Condensed Phases, 1985, vol. 81, p. 2191 - 2206].

5
[ 1142-20-7 ]
[ 74-88-4 ]
[ 21691-41-8 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium hydride In tetrahydrofuran at 0 - 20℃; for 7h; Inert atmosphere;	Synthesis of 4-2 To a solution of 4-1 (500 mg, 2.24 mmol) and NaH (270 mg, 6.72 mmol) in dry THF (5.0 mL) was added CH3I(791 μL, 12.7 mmol) at 0 and the mixture was stirred for 7 hr at room temperature. The reaction wasquenched by addition of water and the aqueous layer was washed with ethyl acetate. After adjustment of pHto 2 by 1N HCl aq., the product was extracted with ethyl acetate. The solvent was removed by evaporation togive 4-2 (540 mg, quant) as yellow oil.
91%	With sodium hydride In tetrahydrofuran for 24h; Ambient temperature;
90%	With sodium hydride In tetrahydrofuran at 60℃; for 12h;

	(i) NaH, THF, DMF, (ii) /BRN= 969135/, (iii) aq. NaOH; Multistep reaction;
	(i) NaH, THF, (ii) /BRN= 969135/; Multistep reaction;
	(i) NaH, THF, DMF, (ii) NaOH, MeOH; Multistep reaction;

References: [1]Nakamura, Noriaki; Uchinomiya, Shohei; Inoue, Kazuya; Ojida, Akio [Molecules, 2020, vol. 25, # 9].
[2]Blackburn, G. Michael; Lilley, Terence H.; Milburn, Peter J. [Journal of Solution Chemistry, 1986, vol. 15, # 2, p. 99 - 108].
[3]Stodulski, Maciej; Mlynarski, Jacek [Tetrahedron Asymmetry, 2008, vol. 19, # 8, p. 970 - 975].
[4]Coggins,J.R.; Benoiton,N.L. [Canadian Journal of Chemistry, 1971, vol. 49, p. 1968 - 1971].
[5]Cheung,S.T.; Benoiton,N.L. [Canadian Journal of Chemistry, 1977, vol. 55, p. 906 - 910].
[6]Keroulas,H. et al. [Bulletin de la Societe Chimique de France, 1975, p. 793 - 799].

6
[ 1142-20-7 ]
[ 2491-20-5 ]
[ 2483-51-4 ]

Yield	Reaction Conditions	Operation in experiment
90%	With N-[2-(4-sulphonatephenylamino)-4-methoxy-1,3,5-triazin-6-yl]-4-methylmorpholinium inner salt; sodium hydrogencarbonate; In water; for 5h;Product distribution / selectivity;	Example 19. A round-bottomed flask was charged with Z-Ala-OH (0.223 g, 0.001 mol), H-Ala-OMe x HCl (0.140 g, 0.001 mol), SPMT x 5H2O (0.471 g, 0.001 mol) and NaHCO3 (0.168 g, 0.002 mol). Water (10 ml) was added to the flask and the mixture was stirred using a magnetic stirrer. During the reaction, a formation of white precipitate was observed. After 5 hours, the precipitate was filtered off and dried in the air. Z-Ala-Ala-OMe (0.278 g, 90% yield) was obtained in the form of a white powder, having the m.p. of 93-94C (lit. 106-108C). The results of NMR analysis of the obtained compound are as follows: 1H NMR (acetone-d6) δ = 1.341 (d, J = 7 Hz, CH3, 3H); δ = 1.380 (d, J = 7 Hz, CH3, 3H); 3.673 (s, CH3, 3H); 4.240 (dp, J = 7.25 Hz, J = 2 Hz, CH, 1H); 4.435 (dp, J = 7.5 Hz, J = 1 Hz, CH, 1H); 5.077 (d, J = 1.5 Hz, CH2, 2H); 6.482 (m, NH, 1H); 7.267-7.417 (m, CArH, 5H); 7.536 (m, NH, 1H) [ppm].
52%	With 4-methyl-morpholine; isobutyl chloroformate; In tetrahydrofuran; at 0 - 20℃;	General procedure: To a solution of ((benzyloxy)carbonyl)-L-phenylalanine (0.72 g, 2.4 mmol, 1.0 eq) andN-methylmorpholine (0.97 g, 9.6 mmol, 4.0 eq) in anhydrous THF was added isobutylchloroformate (0.49 g, 3.6 mmol, 1.5 eq) at 0 C. The methyl L-alaninate hydrochloride(0.33 g, 2.4 mmol, 1.0 eq) was then added and the reaction was allowed to warm slowly toroom temperature overnight. The next day the reaction mixture was diluted with EtOAc(25 mL) and washed in succession with 1.0 M HCl (50 mL), 5% sodium carbonate solution(50 mL), brine (50 mL), then dried over sodium sulfate before filtering and concentrating invacuo. The residue was recrystallized in a DCM:Hexanes solution and filtered, yielding12g as a white crystalline solid (0.61 g, 1.6 mmol, 66%).

References: [1]Patent: EP2407460,2012,A1 .Location in patent: Page/Page column 9.
[2]Journal fur praktische Chemie (Leipzig 1954),1984,vol. 326,p. 35 - 40.
[3]Chem,2021,vol. 7,p. 3144 - 3156.
[4]Chemical and Pharmaceutical Bulletin,1990,vol. 38,p. 2997 - 3003.
[5]Molecules,2021,vol. 26.
[6]Journal of the Chemical Society. Perkin transactions I,1972,vol. 8,p. 1015 - 1020.
[7]Analytical Chemistry,1993,vol. 65,p. 1861 - 1867.

7
[ 1142-20-7 ]
[ 60789-87-9 ]
[ 153647-49-5 ]

Yield	Reaction Conditions	Operation in experiment
88%	With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane for 0.5h;

References: [1]Wijkmans, Jac C. H. M.; Boom, Jacques H. van; Bloemhoff, Wim [Tetrahedron Letters, 1993, vol. 34, # 44, p. 7123 - 7126].

8
[ 1142-20-7 ]
[ 57296-03-4 ]
[ 3401-36-3 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine In acetonitrile for 5h;

References: [1]Takeda, Kazuyoshi; Sawada, Izumi; Suzuki, Akira; Ogura, Haruo [Tetrahedron Letters, 1983, vol. 24, # 41, p. 4451 - 4454].

9
[ 1142-20-7 ]
[ 6331-09-5 ]
[ 64532-72-5 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; dicyclohexyl-carbodiimide In dichloromethane at 0℃; for 4h;

References: [1]Ueda, Toshihisa; Saito, Morinobu; Kato, Tetsuo; Izumiya, Nobuo [Bulletin of the Chemical Society of Japan, 1983, vol. 56, # 2, p. 568 - 572].

10
[ 1142-20-7 ]
[ 115491-90-2 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
	With 4-methyl-morpholine In acetonitrile Ambient temperature;

References: [1]Denarie, Michel; Grenouillat, Denis; Malfroot, Thierry; Senet, Jean-Pierre; Sennyey, Gerard; Wolf, Patrick [Tetrahedron Letters, 1987, vol. 28, # 47, p. 5823 - 5826].

11
[ 1142-20-7 ]
[ 120418-31-7 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
	In nitromethane for 0.0833333h; Ambient temperature;

References: [1]Saha, Ashis K.; Schultz, Peter; Rapoport, Henry [Journal of the American Chemical Society, 1989, vol. 111, # 13, p. 4856 - 4859].

12
[ 1142-20-7 ]
[ 54680-72-7 ]
[ 88576-85-6 ]

Yield	Reaction Conditions	Operation in experiment
75%	With chloroformic acid ethyl ester; triethylamine In tetrahydrofuran

References: [1]Fittkau, Siegfried; Jahreis, Guenther [Journal fur praktische Chemie (Leipzig 1954), 1984, vol. 326, # 1, p. 48 - 53].

13
[ 1142-20-7 ]
[ 66674-16-6 ]

Yield	Reaction Conditions	Operation in experiment
100%	Stage #1: N-Cbz-Ala With 4-methyl-morpholine; isobutyl chloroformate In tetrahydrofuran at -15℃; for 0.25h; Stage #2: With sodium tetrahydroborate In tetrahydrofuran; water at -15℃; for 1h;
90%	Stage #1: N-Cbz-Ala With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In ethyl acetate at 0℃; for 0.166667h; Stage #2: With sodium tetrahydroborate In water; ethyl acetate at 0℃; for 0.366667h;	General procedure for the reduction of carboxylic acids to alcohols using T3P-NaBH₄: General procedure: To a solution of carboxylic acid (10 mmol) in THF (10 mL), DIPEA (11 mmol, 1.42 mL) and 50% T3P in EtOAc (20 mmol, 6.36 mL) were added at 0 °C and the solution was stirred for about 10 min. Then aqueous solution of NaBH4 (10 mmol, 388 mg in 0.3 mL of H2O) was added to the reaction mixture at the same temperature and the reaction was allowed to stir till the completion of the reaction as indicated by TLC. After the completion of the reaction, the solvent was evaporated and the crude alcohol was extracted into EtOAc and the organic phase was washed with 5% citric acid (10 mL × 2), 5% Na2CO3 (10 mL × 2), water, and brine solution. The product was isolated after the evaporation of solvent under reduced pressure and dried over anhydrous Na2SO4.
88%	Stage #1: N-Cbz-Ala With 4-methyl-morpholine; isobutyl chloroformate In 1,2-dimethoxyethane at -15℃; Stage #2: With sodium tetrahydroborate In 1,2-dimethoxyethane; water at 15℃;

	With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 25℃;
	Stage #1: N-Cbz-Ala With triethylamine; isobutyl chloroformate In tetrahydrofuran Stage #2: With sodium tetrahydroborate In water
	Multi-step reaction with 2 steps 1: 95 percent / KHCO₃ / dimethylformamide / 4 h / Ambient temperature 2: 95 percent / LiBH₄ / tetrahydrofuran; ethanol
	Multi-step reaction with 2 steps 1: 2.33 g / diethyl ether 2: 67 percent / lithium borohydride / tetrahydrofuran / 1 h / Ambient temperature
	Multi-step reaction with 2 steps 1: N-methylmorpholine / tetrahydrofuran / -10 °C 2: NaBH₄/MeOH / 0.33 h / 0 °C
	Multi-step reaction with 2 steps 1: diethyl ether 2: LiBH₄ / tetrahydrofuran
	Stage #1: N-Cbz-Ala With 4-methyl-morpholine; isobutyl chloroformate In 1,2-dimethoxyethane at -15 - 20℃; Inert atmosphere; Stage #2: With sodium tetrahydroborate In 1,2-dimethoxyethane; water at -15℃; for 1h; Inert atmosphere;
	Multi-step reaction with 2 steps 1: 4-methyl-morpholine / 1,2-dimethoxyethane / 20 °C 2: sodium tetrahydroborate; water / -15 °C
	Multi-step reaction with 2 steps 1: 4-methyl-morpholine / tetrahydrofuran / 0.25 h / -15 °C / Inert atmosphere 2: sodium tetrahydroborate / methanol; water / 0.25 h / -15 °C / Inert atmosphere
	Multi-step reaction with 2 steps 1: dicyclohexyl-carbodiimide / tetrahydrofuran / 1 h / 0 °C 2: sodium tetrahydroborate / water; tetrahydrofuran / 0.08 h / 0 °C
	Multi-step reaction with 2 steps 1: 4-methyl-morpholine / tetrahydrofuran / -15 °C 2: sodium tetrahydroborate
	Multi-step reaction with 3 steps 1: dichloromethane / 1 h / 0 °C / Schlenk technique; Inert atmosphere 2: diisobutylaluminium hydride / dichloromethane / 0.75 h / -78 °C / Schlenk technique; Inert atmosphere 3: sodium tetrahydroborate / methanol / 0.33 h / 0 °C / Inert atmosphere; Schlenk technique
	Stage #1: N-Cbz-Ala With 4-methyl-morpholine; chloroformic acid ethyl ester In tetrahydrofuran at -15℃; for 0.25h; Stage #2: With sodium tetrahydroborate In tetrahydrofuran for 0.5h; Stage #3: With water In tetrahydrofuran for 0.25h;
	Stage #1: N-Cbz-Ala With N-ethyl-N,N-diisopropylamine; isobutyl chloroformate Stage #2: With sodium tetrahydroborate; water
	With methanol; sodium tetrahydroborate; methyl chloroformate In tetrahydrofuran at -15℃;

References: [1]Dola, Vasantha Rao; Soni, Awakash; Agarwal, Pooja; Ahmad, Hafsa; Raju, Kanumuri Siva Rama; Rashid, Mamunur; Wahajuddin, Muhammad; Srivastava, Kumkum; Haq; Dwivedi; Puri; Katti [Antimicrobial Agents and Chemotherapy, 2017, vol. 61, # 3].
[2]Location in patent: experimental part Nagendra; Madhu; Vishwanatha; Sureshbabu, Vommina V. [Tetrahedron Letters, 2012, vol. 53, # 38, p. 5059 - 5063].
[3]Magar, Pratibha; Parravicini, Oscar; Štěpánková, Šárka; Svrčková, Katarina; Garro, Adriana D.; Jendrzejewska, Izabela; Pauk, Karel; Hošek, Jan; Jampílek, Josef; Enriz, Ricardo D.; Imramovský, Aleš [International Journal of Molecular Sciences, 2021, vol. 22, # 17].
[4]Guindon; Slassi; Ghiro; Bantle; Jung [Tetrahedron Letters, 1992, vol. 33, # 30, p. 4257 - 4260].
[5]Tully, David C.; Liu, Hong; Alper, Phil B.; Chatterjee, Arnab K.; Epple, Robert; Roberts, Michael J.; Williams, Jennifer A.; Nguyen, Khanhlinh T.; Woodmansee, David H.; Tumanut, Christine; Li, Jun; Spraggon, Glen; Chang, Jonathan; Tuntland, Tove; Harris, Jennifer L.; Karanewsky, Donald S. [Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 7, p. 1975 - 1980].
[6]Wyslouch, Aleksandra; Lisowski, Marek; Pedyczak, Artur; Siemion, Ignacy Z. [Tetrahedron Asymmetry, 1992, vol. 3, # 11, p. 1401 - 1410].
[7]Kanamoto; Nagai; Hase; et al. [Chemical and Pharmaceutical Bulletin, 1983, vol. 31, # 1, p. 135 - 143].
[8]Kokotos, George [Synthesis, 1990, p. 299 - 301].
[9]Mijovic,M.P.V.; Walker,J. [Journal of the Chemical Society, 1960, p. 909 - 916].
[10]Shi, Haibin; Liu, Kai; Leong, Wendy W.Y.; Yao, Shao Q. [Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 14, p. 3945 - 3948].
[11]Brouwer, Arwin J.; Ceylan, Tarik; Jonker, Anika M.; Linden, Tima Van Der; Liskamp, Rob M.J. [Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 7, p. 2397 - 2406].
[12]Sleebs, Brad E.; Nguyen, Nghi H.; Hughes, Andrew B. [Synlett, 2013, vol. 24, # 6, p. 747 - 751].
[13]Jadhav, Sandip V.; Misra, Rajkumar; Singh, Sumeet K.; Gopi, Hosahudya N. [Chemistry - A European Journal, 2013, vol. 19, # 48, p. 16256 - 16262].
[14]Madhu, Chilakapati; Panguluri, Nageswara Rao; Sureshbabu, Vommina V. [Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2014, vol. 53, # 7, p. 858 - 864].
[15]Ivkovic, Jakov; Lembacher-Fadum, Christian; Breinbauer, Rolf [Organic and Biomolecular Chemistry, 2015, vol. 13, # 42, p. 10456 - 10460].
[16]Santhosh; Durgamma; Shekharappa; Sureshbabu, Vommina V. [Organic and Biomolecular Chemistry, 2018, vol. 16, # 26, p. 4874 - 4880].
[17]Current Patent Assignee: UNIVERSITY OF VIRGINIA - WO2005/115150, 2005, A2 Location in patent: Page/Page column 75.
[18]Xu, Shuheng; Cui, Sunliang [Organic Letters, 2021, vol. 23, # 13, p. 5197 - 5202].

14
[ 6530-41-2 ]
[ 1142-20-7 ]

Yield	Reaction Conditions	Operation in experiment
98%	With tetrabutyl ammonium fluoride In N,N-dimethyl-formamide Ambient temperature;

References: [1]Namikoshi, Michio; Kundu, Bijoy; Rinehart, Kenneth L. [Journal of Organic Chemistry, 1991, vol. 56, # 18, p. 5464 - 5466].

15
[ 66674-16-6 ]
[ 1142-20-7 ]

Yield	Reaction Conditions	Operation in experiment
95%	With jones' reagent In acetone at 0℃; for 3h;
	Stage #1: (S)-(-)-N-(benzyloxycarbonyl)alaninol With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; water; sodium bromide; sodium hydroxide In 1,2-dichloro-ethane; acetone at -20 - 20℃; Stage #2: With sodium hypochlorite In 1,2-dichloro-ethane; acetone at 20℃;

References: [1]Kashima, Choji; Harada, Kazuo; Fujioka, Yoko; Maruyama, Tatsuya; Omote, Yoshimori [Journal of the Chemical Society. Perkin transactions I, 1988, p. 535 - 540].
[2]Qiu, Jia; Xu, Yougen; Su, Shimin; Gao, Yadong; Yu, Peiyuan; Ruan, Zhixiong; Liao, Kuangbiao [Chinese Journal of Chemistry, 2023, vol. 41, # 2, p. 143 - 150].

16
[ 1142-20-7 ]
[ 62492-58-4 ]
[ 62492-62-0 ]

Yield	Reaction Conditions	Operation in experiment
	With dicyclohexyl-carbodiimide In dichloromethane; acetone

References: [1]Kolbah; Blazevic; Hannoun; et al. [Helvetica Chimica Acta, 1977, vol. 60, # 1, p. 265 - 283].

17
[ 1125-88-8 ]
[ 1142-20-7 ]
[ 171860-41-6 ]

Yield	Reaction Conditions	Operation in experiment
71.9%	With boron trifluoride diethyl etherate In diethyl ether at -15℃; for 96h;
60%	With boron trifluoride diethyl etherate In diethyl ether at -78 - 20℃; for 120h;
60%	With boron trifluoride diethyl etherate In diethyl ether at -78 - 20℃; Inert atmosphere;	1 4.1.1 (2S,4S)-Benzyl-4-methyl-5-oxo-2-phenyloxazolidine-carboxylate 1 Properly dried Z-(S)-alanine (22.3 g, 100 mmol) and benzaldehyde dimethyl acetal (14.4 mL, 95.9 mmol) in diethyl ether (500 mL) were cooled to -78 °C followed by the dropwise addition of BF3·Et2O (60.2 mL, 489 mmol) under a nitrogen atmosphere. The reaction mixture was then allowed to warm to room temperature and stirred until completion of the reaction as monitored by TLC. The reaction mixture was treated with saturated aqueous NaHCO3 at 0 °C, initially in small portions until strong bubbling ceased, and then the mixture was extracted with Et2O (3 * 150 mL). The combined organic phase was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under vacuum and the predominant cis-isomer was obtained from the crude mixture by silica gel column chromatography using ethyl acetate in hexane (1:4) as the eluent. The compound was further crystallised from diethyl ether/hexane to yield compound 1 (18.66 g, 60% yield) as white crystalline solid: mp 53-54 °C; 1H NMR (400 MHz, CDCl3) δ = 1.56 (d, J = 6.9 Hz, 3H), 4.45 (q, J = 6.9 Hz, 1H), 5.11-5.21 (m, 2H), 6.64 (s, 1H), 7.25-7.40 (m, 10H); 13C NMR (100 MHz, CDCl3) δ = 18.2, 52.2, 67.9, 89.1, 126.3, 126.6, 128.1, 128.5, 128.6, 128.8, 129.8, 135.4, 136.9, 153.4, 172.5; FTIR (KBr): ν = 3352, 1800, 1717, 763 cm-1; HRMS (ESI-TOF) calculated for [C18H17NO4+H]+ 312.1230, found 312.1229.

56%	With thionyl chloride; zinc(II) chloride In tetrahydrofuran at 0℃; for 4h;
48%	With thionyl chloride; zinc(II) chloride In tetrahydrofuran for 4h;
47.04%	With boron trifluoride diethyl etherate In diethyl ether at -78 - 25℃; for 24h;	30.1 Step 1: A solution of (2S)-2-(benzyloxycarbonylamino)propanoic acid (5 g, 22.40 mmol, 1 eq), dimethoxymethylbenzene (3.41 g, 22.40 mmol, 3.38 mL, 1 eq) in Et2O (35.30 g, 476.26 mmol, 50.00 mL, 21.26 eq) was added BF3.Et2O (19.07 g, 134.39 mmol, 16.59 mL, 6 eq) at - 78 °C. The mixture was warmed to 25 °C and stirred at 25 °C for 24 hr under N2atmosphere. The reaction mixture was slowly added to cooled saturated aqueous NaHCO3(1000 mL) and stirred for 30 min, then the organic layers was washed H2O, dried with MgSO4. The solvent was removed in vacuo to get a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=20/1 to 10/1) and recrystallization with (Et2O: PE=1:2). The mixture was filtered and the filter cake was concentrated under reduced pressure to give compound benzyl (2S,4S)-4-methyl-5-oxo-2-phenyl-oxazolidine- 3-carboxylate (12 g, 37.77 mmol, 47.04% yield, 98% purity) as colorless crystals.
47.04%	With boron trifluoride diethyl etherate In diethyl ether at -78 - 25℃; for 24h;	30.1 Step 1: A solution of (2S)-2-(benzyloxycarbonylamino)propanoic acid (5 g, 22.40 mmol, 1 eq), dimethoxymethylbenzene (3.41 g, 22.40 mmol, 3.38 mL, 1 eq) in Et2O (35.30 g, 476.26 mmol, 50.00 mL, 21.26 eq) was added BF3.Et2O (19.07 g, 134.39 mmol, 16.59 mL, 6 eq) at - 78 °C. The mixture was warmed to 25 °C and stirred at 25 °C for 24 hr under N2atmosphere. The reaction mixture was slowly added to cooled saturated aqueous NaHCO3(1000 mL) and stirred for 30 min, then the organic layers was washed H2O, dried with MgSO4. The solvent was removed in vacuo to get a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=20/1 to 10/1) and recrystallization with (Et2O: PE=1:2). The mixture was filtered and the filter cake was concentrated under reduced pressure to give compound benzyl (2S,4S)-4-methyl-5-oxo-2-phenyl-oxazolidine- 3-carboxylate (12 g, 37.77 mmol, 47.04% yield, 98% purity) as colorless crystals.
46%	With thionyl chloride; zinc(II) chloride In tetrahydrofuran at -15 - 0℃; for 4h; Inert atmosphere;	9.1 Example 9 (1): 400 g of Cbz-L-alanine is dissolved in 2 L of tetrahydrofuran,Add 314 g of benzaldehyde dimethyl acetal and pass a nitrogen replacement system.The ice salt bath was cooled to -15 ° C, and 213.4 g of thionyl chloride was added dropwise.The control temperature is lower than 0 ° C, and the mixture is stirred until the temperature reaches -15 ° C.244g of anhydrous zinc chloride was added in batches, and the temperature was controlled below 0 °C.After stirring for 4 hours, 2 L of water was added to quench the reaction.Then extracted with 1.2 L of ethyl acetate.The organic phase is washed sequentially with water and a saturated sodium bicarbonate solution until neutral.Dry over anhydrous sodium sulfate, concentrate and recrystallize with 600 mL of isopropyl ether and 400 mL of petroleum ether.Filtration and drying gave 257 g of intermediate 4, and the hydrogen spectrum is shown in Figure 4.White solid,The yield was 46%.
43%	Stage #1: benzaldehyde dimethyl acetal; N-Cbz-Ala With thionyl chloride In tetrahydrofuran at 0℃; for 0.166667h; Stage #2: With zinc(II) chloride In tetrahydrofuran at 0℃; for 4h;	1 Step 1: Synthesis of benzyl (2S,4S)-4-methyl-5-oxo-2-phenyloxazolidine-3-carboxylate To a mixture of ((benzyloxy)carbonyl)-L-alanine (25 g, 111.99 mmol) and (dimethoxymethyl)benzene (71.38 mL, 115.35 mmol) in THF (180 mL) was added SOCl2 (8.94 g, 123.19 mmol) in one portion at 0 °C. The mixture was stirred for 10 min before ZnCl2 (5.77 mL, 123.26 mmol) was added to the solution, then the mixture was stirred at 0 °C for 4 h. The reaction mixture was quenched by dropwise addition of cold H2O and adjusted to pH = 5 with sat. NaHCO3, then extracted with EtOAc (2 x 100 mL). The organic phase was washed with a aq. sat. NaHCO3 (30 mL) and brine (30 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (1→10% EtOAc/pet. ether) to afford product (15 g, 43% yield).
43%	Stage #1: benzaldehyde dimethyl acetal; N-Cbz-Ala With thionyl chloride In tetrahydrofuran at 0℃; for 0.166667h; Stage #2: With zinc(II) chloride In tetrahydrofuran at 0℃; for 4h;	Step 1: Synthesis of benzyl (2S,4S)-4-methyl-5-oxo-2-phenyloxazolidine-3-carboxylate To a mixture of ((benzyloxy)carbonyl)-L-alanine (25 g, 111.99 mmol) and (dimethoxymethyl)benzene (71.38 mL, 115.35 mmol) in THF (180 mL) was added SOCl2 (8.94 g, 123.19 mmol) in one portion at 0° C. The mixture was stirred for 10 min before ZnCl2 (5.77 mL, 123.26 mmol) was added to the solution, then the mixture was stirred at 0° C. for 4 h. The reaction mixture was quenched by dropwise addition of cold H2O and adjusted to pH=5 with sat. NaHCO3, then extracted with EtOAc (2*100 mL). The organic phase was washed with a aq. sat. NaHCO3(30 mL) and brine (30 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (1→10% EtOAc/pet. ether) to afford product (15 g, 43% yield).
	With boron trifluoride diethyl etherate In diethyl ether at -15℃; for 96h;
	With thionyl chloride; zinc(II) chloride In tetrahydrofuran at 0℃; for 0.333333h;
	With thionyl chloride; zinc(II) chloride In tetrahydrofuran at 0℃;
	Stage #1: benzaldehyde dimethyl acetal; N-Cbz-Ala With thionyl chloride In tetrahydrofuran at 0℃; for 0.5h; Stage #2: With zinc(II) chloride In tetrahydrofuran at 0℃; for 3h;	23.2 Step 2 Step 2. Thionyl chloride (3.27 mL, 44.8 mmol) was added to the stirring mixture of CBz-L-alanine 23-2 (10.0 g, 44.8 mmol) and benzaldehyde dimelthyl acetal (6.73 mml, 44.8 mmol) in dry THF at 0 °C. After it was stirred for 30 min, anhydrous ZnCl2 (6.11 g, 44.8 mmol) was added. The mixture was stirred at 0 °C for 3 h and antoher 0.2 equiv. of ZnCl2/SOCl2 was then added. The mixture was then quenched with water (below 10°C) and extracted with MTBE (150 mL x 3). The organic layer was dried over Na2S04 and purified by column on silica gel to give compound 23-4. NMR (400 MHz, CDC13) δ 7.41-7.39 (m, 10 H), 6.65 (s, 1 H), 5.18-5.16 (m, 2 H), 4.47-4.52 (m, 1 H), 1.63-1.57 (m, 3 H).
53 %	Stage #1: benzaldehyde dimethyl acetal; N-Cbz-Ala With thionyl chloride In tetrahydrofuran at 0℃; Stage #2: With zinc(II) chloride In tetrahydrofuran at 0℃;	Step 1: Synthesis of benzyl (2S,4S)-4-methyl-5-oxo-2-phenyloxazolidine-3-carboxylate To a solution of ((benzyloxy)carbonyl)-L-alanine (5 g, 22.40 mmol) and (dimethoxymethyl)benzene (3.51 g, 23.07 mmol) in THF (36 mL ) was added SOCb (2.93 g, 24.64 mmol) in one portion at 0 °C. The mixture was stirred for 10 min and then ZnCL (1.15 mL , 24.64 mmol) was added. The mixture was then stirred at 0 °C for 4 h. The reaction mixture was quenched by the dropwise addition of cold H2O, adjusted to pH 5 with sat. NaHCC>3, then extracted with EtOAc (2 x 30 mL ). The organic phase was washed with a sat. aq. NaHCC>3 (30 mL ) and brine (30 mL ), dried with anhydrous Na2S O4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0→20% EtOAc/pet. ether) to afford the product (3.7 g, 53% yield) as an oil.
53 %	Stage #1: benzaldehyde dimethyl acetal; N-Cbz-Ala With thionyl chloride In tetrahydrofuran at 0℃; Stage #2: With zinc(II) chloride In tetrahydrofuran at 0℃;	Step 1. Synthesis of benzyl (2S,4S)-4-methyl-5-oxo-2-phenyloxazolidine-3-carboxylate To a solution of ((benzyloxy)carbonyl)-L-alanine (5 g, 22.40 mmol) and (dimethoxymethyl)benzene (3.51 g, 23.07 mmol) in THF (36 mL) was added SOCI2 (2.93 g, 24.64 mmol) in one portion at 0 °C. The mixture was stirred for 10 min and then ZnCL (1 .15 mL, 24.64 mmol) was added. The mixture was then stirred at 0 °C for 4 h. The reaction mixture was quenched by the dropwise addition of cold H2O, adjusted to pH 5 with sat. NaHCO3, then extracted with EtOAc (2 x 30 mL). The organic phase was washed with a sat. aq. NaHCO3 (30 mL) and brine (30 mL), dried with anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0→20% EtOAc/pet. ether) to afford the product (3.7 g, 53% yield) as an oil.
53 %	Stage #1: benzaldehyde dimethyl acetal; N-Cbz-Ala With thionyl chloride In tetrahydrofuran at 0℃; Stage #2: With zinc(II) chloride In tetrahydrofuran at 0℃;	Step 1: Synthesis of benzyl (2S,4S)-4-methyl-5-oxo-2-phenyloxazolidine-3-carboxylate To a solution of ((benzyloxy)carbonyl)-L-alanine (5 g, 22.40 mmol) and (dimethoxymethyl)benzene (3.51 g, 23.07 mmol) in THF (36 mL ) was added SOCb (2.93 g, 24.64 mmol) in one portion at 0 °C. The mixture was stirred for 10 min and then ZnCL (1.15 mL , 24.64 mmol) was added. The mixture was then stirred at 0 °C for 4 h. The reaction mixture was quenched by the dropwise addition of cold H2O, adjusted to pH 5 with sat. NaHCC>3, then extracted with EtOAc (2 x 30 mL ). The organic phase was washed with a sat. aq. NaHCC>3 (30 mL ) and brine (30 mL ), dried with anhydrous Na2S O4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0→20% EtOAc/pet. ether) to afford the product (3.7 g, 53% yield) as an oil.
53 %	Stage #1: benzaldehyde dimethyl acetal; N-Cbz-Ala With thionyl chloride In tetrahydrofuran at 0℃; Stage #2: With zinc(II) chloride In tetrahydrofuran at 0℃;	Step 1. Synthesis of benzyl (2S,4S)-4-methyl-5-oxo-2-phenyloxazolidine-3-carboxylate To a solution of ((benzyloxy)carbonyl)-L-alanine (5 g, 22.40 mmol) and (dimethoxymethyl)benzene (3.51 g, 23.07 mmol) in THF (36 mL) was added SOCI2 (2.93 g, 24.64 mmol) in one portion at 0 °C. The mixture was stirred for 10 min and then ZnCL (1 .15 mL, 24.64 mmol) was added. The mixture was then stirred at 0 °C for 4 h. The reaction mixture was quenched by the dropwise addition of cold H2O, adjusted to pH 5 with sat. NaHCO3, then extracted with EtOAc (2 x 30 mL). The organic phase was washed with a sat. aq. NaHCO3 (30 mL) and brine (30 mL), dried with anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0→20% EtOAc/pet. ether) to afford the product (3.7 g, 53% yield) as an oil.
53 %	Stage #1: benzaldehyde dimethyl acetal; N-Cbz-Ala With thionyl chloride In tetrahydrofuran at 0℃; Stage #2: With zinc(II) chloride In tetrahydrofuran at 0℃;	14.1 Step 1: Synthesis of benzyl (2S,4S)-4-methyl-5-oxo-2-phenyloxazolidine-3-carboxylate To a solution of ((benzyloxy)carbonyl)-L-alanine (5 g, 22.40 mmol) and (dimethoxymethyl)benzene (3.51 g, 23.07 mmol) in THF (36 mL) was added SOCI (2.93 g, 24.64 mmol) in one portion at 0 °C. The mixture was stirred for 10 min and then ZnCh (1 .15 mL, 24.64 mmol) was added. The mixture was then stirred at 0 °C for 4 h. The reaction mixture was quenched by the dropwise addition of cold H O, adjusted to pH 5 with sat. NaHCC, then extracted with EtOAc (2 x 30 mL). The organic phase was washed with a sat. aq. NaHC03 (30 mL) and brine (30 mL), dried with anhydrous Na2S04, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 20% EtOAc/pet. ether) to afford the product (3.7 g, 53% yield) as an oil.
53 %	Stage #1: benzaldehyde dimethyl acetal; N-Cbz-Ala With thionyl chloride In tetrahydrofuran at 0℃; Stage #2: With zinc(II) chloride In tetrahydrofuran at 0℃;	14.1 Step 1: Synthesis of benzyl (2S,4S)-4-methyl-5-oxo-2-phenyloxazolidine-3-carboxylate To a solution of ((benzyloxy)carbonyl)-L-alanine (5 g, 22.40 mmol) and (dimethoxymethyl)benzene (3.51 g, 23.07 mmol) in THF (36 mL) was added SOCI (2.93 g, 24.64 mmol) in one portion at 0 °C. The mixture was stirred for 10 min and then ZnCh (1 .15 mL, 24.64 mmol) was added. The mixture was then stirred at 0 °C for 4 h. The reaction mixture was quenched by the dropwise addition of cold H O, adjusted to pH 5 with sat. NaHCC, then extracted with EtOAc (2 x 30 mL). The organic phase was washed with a sat. aq. NaHC03 (30 mL) and brine (30 mL), dried with anhydrous Na2S04, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 20% EtOAc/pet. ether) to afford the product (3.7 g, 53% yield) as an oil.

References: [1]Location in patent: experimental part Long, Ya-Qiu; Xue, Ting; Song, Yan-Li; Liu, Zu-Long; Huang, Shao-Xu; Yu, Qiang [Journal of Medicinal Chemistry, 2008, vol. 51, # 20, p. 6371 - 6380].
[2]Hutton, Craig A.; Bartlett, Paul A. [Journal of Organic Chemistry, 2007, vol. 72, # 18, p. 6865 - 6872].
[3]Tiwari, Vinay Shankar; Murugula, Raghavendra; Yadav, Shyam Raj; Haq, Wahajul [Tetrahedron Asymmetry, 2016, vol. 27, # 17-18, p. 865 - 871].
[4]Location in patent: scheme or table Dungan, Victoria J.; Ortin, Yannick; Mueller-Bunz, Helge; Rutledge, Peter J. [Organic and Biomolecular Chemistry, 2010, vol. 8, # 7, p. 1666 - 1673].
[5]Kapadia; Spero; Eriksson [Journal of Organic Chemistry, 2001, vol. 66, # 5, p. 1903 - 1905].
[6]Current Patent Assignee: SENDA BIOSCIENCES - WO2021/252640, 2021, A1 Location in patent: Paragraph 00150-00151.
[7]Current Patent Assignee: SENDA BIOSCIENCES - WO2021/252640, 2021, A1 Location in patent: Paragraph 00150-00151.
[8]Current Patent Assignee: KANGHUA SHANGHAI NEW DRUG R D - CN109206331, 2019, A Location in patent: Paragraph 0036.
[9]Current Patent Assignee: REVOLUTION MEDICINES - WO2021/108683, 2021, A1 Location in patent: Page/Page column 172.
[10]Current Patent Assignee: REVOLUTION MEDICINES - US2021/130326, 2021, A1 Location in patent: Paragraph 1667-1668.
[11]Akaji, Kenichi; Kuriyama, Naohiro; Kiso, Yoshiaki [Journal of Organic Chemistry, 1996, vol. 61, # 10, p. 3350 - 3357].
[12]Eriksson, Magnus; Napolitano, Elio; Xu, Jinghua; Kapadia, Suresh; Byrne, Denis; Nummy, Laurence; Grinberg, Nelu; Shen, Sherri; Lee, Heewon; Farina, Vittorio [Chimia, 2006, vol. 60, # 9, p. 566 - 573].
[13]Coe, Diane M; Perciaccante, Rossana; Procopiou, Panayiotis A [Organic and biomolecular chemistry, 2003, vol. 1, # 7, p. 1106 - 1111].
[14]Current Patent Assignee: GENENTECH - WO2015/95227, 2015, A2 Location in patent: Page/Page column 110; 111.
[15]Current Patent Assignee: REVOLUTION MEDICINES - WO2022/235866, 2022, A1 Location in patent: Page/Page column 5553-54.
[16]Current Patent Assignee: REVOLUTION MEDICINES - WO2022/235870, 2022, A1 Location in patent: Page/Page column 209.
[17]Current Patent Assignee: REVOLUTION MEDICINES - WO2022/235866, 2022, A1 Location in patent: Page/Page column 5553-54.
[18]Current Patent Assignee: REVOLUTION MEDICINES - WO2022/235870, 2022, A1 Location in patent: Page/Page column 209.
[19]Current Patent Assignee: REVOLUTION MEDICINES - WO2022/251292, 2022, A1 Location in patent: Page/Page column 766.
[20]Current Patent Assignee: REVOLUTION MEDICINES - WO2022/251292, 2022, A1 Location in patent: Page/Page column 766.

18
[ 1142-20-7 ]
[ 4375-15-9 ]
[ 210702-63-9 ]

Yield	Reaction Conditions	Operation in experiment
90%	With dicyclohexyl-carbodiimide

References: [1]He; Foxman; Snider [Journal of the American Chemical Society, 1998, vol. 120, # 25, p. 6417 - 6418].

19
[ 1142-20-7 ]
[ 71810-97-4 ]
[ 374756-15-7 ]

Yield	Reaction Conditions	Operation in experiment
50%	Stage #1: N-Cbz-Ala With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; Stage #2: D-alaninamide hydrochloride With triethylamine In tetrahydrofuran at 20℃; Further stages.;

References: [1]Sutton; Clardy [Journal of the American Chemical Society, 2001, vol. 123, # 41, p. 9935 - 9946].

20
[ 1142-20-7 ]
[ 22263-68-9 ]
[ 799783-05-4 ]

Yield	Reaction Conditions	Operation in experiment
98%	Stage #1: N-Cbz-Ala; ethyl 2-<<1(S)-phenylethyl>amino>acetate With dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 16h; Stage #2: With hydrogen In ethanol for 12h;

References: [1]Hernandez, Fernando; Morales, Viviana; Buenadicha, Felix L.; Soellhuber, Monica; Avendano, Carmen [Tetrahedron Asymmetry, 2004, vol. 15, # 19, p. 3045 - 3058].

21
[ 1142-20-7 ]
[ 74410-26-7 ]
[ 416899-37-1 ]

Yield	Reaction Conditions	Operation in experiment
0.685 g	With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; triethylamine In dichloromethane for 6h;

References: [1]Zeng, Huaqiang; Yang, Xiaowu; Flowers II, Robert A.; Gong, Bing [Journal of the American Chemical Society, 2002, vol. 124, # 12, p. 2903 - 2910].

22
[ 1142-20-7 ]
[ 2483-51-4 ]

References: [1]Synthesis,2004,p. 80 - 86.
[2]Chemical and pharmaceutical bulletin,1989,vol. 37,p. 46 - 49.
[3]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,1991,vol. 30,p. 1129 - 1130.
[4]Molecules,2019,vol. 24.
[5]Green Chemistry,2021,vol. 23,p. 848 - 855.

23
[ 1142-20-7 ]
[ 613688-34-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: isobutyl chloroformate; 4-methylmorpholine / CH₂Cl₂; diethyl ether / 0.75 h / -10 °C 1.2: 75 percent / CH₂Cl₂ / 7 h / 20 °C 2.1: 68 percent / Rh₂(OAc)4 / CH₂Cl₂ / 15 h / -40 - 20 °C
	Multi-step reaction with 3 steps 1: N,N-dimethyl-formamide; oxalyl dichloride / Schlenk technique 2: tetrahydrofuran; diethyl ether / 3 h / 0 - 20 °C / Inert atmosphere; Schlenk technique 3: dirhodium tetraacetate / dichloromethane / 0 - 20 °C / Schlenk technique

References: [1]Hanessian, Stephen; Fu, Jian-Min [Canadian Journal of Chemistry, 2001, vol. 79, # 11, p. 1812 - 1826].
[2]Ishida, Naoki; Shimamoto, Yasuhiro; Yano, Takaaki; Murakami, Masahiro [Journal of the American Chemical Society, 2013, vol. 135, # 51, p. 19103 - 19106].

24
[ 1142-20-7 ]
[ 33628-84-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: SOCl₂ / 1 h / 0 °C 2: 1.9 g / ethanol

References: [1]Polonski, T. [Tetrahedron, 1985, vol. 41, # 3, p. 611 - 616].

25
[ CAS Unavailable ]
[ 1125-88-8 ]
[ 1142-20-7 ]
[ 143564-89-0 ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride In tetrahydrofuran; hexane; water	1.1 Preparation of cis-3-carbobenzyloxy-4-methyl-2-phenyloxazolidinone Step 1 Preparation of cis-3-carbobenzyloxy-4-methyl-2-phenyloxazolidinone SOCl2 (0.65 ml, 8.96 mmol) was added to a stirring solution of (S)-N-carbobenzyloxy alanine (2.0 g. 8.96 mmol) and benzaldehyde dimethyl acetal (1.34 ml, 8.96 mmol) in dry THF (15 ml) at 0° C. After stirring for 5 min, anhydrous ZnCl2 (1.22 g, 8.96 mmol) was added and the reaction mixture was stirred at this temperature for 3 h. At this stage, 0.2 eq. each of SOCl2 (0.13 ml) and anhydrous ZnCl2 (0.25 g) were added and the reaction mixture was stirred for 1 h. The reaction was followed by silica gel TLC (20% ethyl acetate/hexane, Rf ~0.5). The reaction mixture was quenched by dropwise addition of water so that the reaction temperature did not exceed 10° C. It was extracted with ethyl acetate. The organic extract was washed with water until almost neutral, washed with sat. NaHCO3 solution, water and finally dried over anhydrous Na2 SO4. Evaporation of the solvent furnished a light yellow oil that solidified on stirring with 18 ml of hexane. The product was filtered and dried under reduced pressure (1.81 g, 65%, 29:1 cis/tans by NMR). The product was purified by crystallization from ethanol/water to give colorless needles, mp 52° C.-53° C. (1.46 g, 52.3%>50:1 cis by NMR).

References: [1]Current Patent Assignee: BOEHRINGER INGELHEIM PHARMACEUTICALS INC - US6043376, 2000, A.

26
[ 1142-20-7 ]
[ 2011-66-7 ]
[ 58662-82-1 ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride; sodium hydrogencarbonate; In tetrahydrofuran; Petroleum ether;	(a) 53.6 g of carbobenzoxy-L-alanine are dissolved in 400 ml of dry tetrahydrofuran, the solution is treated dropwise with 30 g of thionyl chloride while cooling with ice and the mixture is stirred for 1 hour in the cold. A solution of 54 g (0.2 mol) of <strong>[2011-66-7]2-amino-5-nitro-2'-chlorobenzophenone</strong> in 150 ml of dry tetrahydrofuran is subsequently added dropwise thereto rapidly, whereupon the mixture is stirred at room temperature for 24 hours. The solution obtained is concentrated, the residue is treated with ice and 10 percent sodium bicarbonate solution and extracted with methylene chloride. The organic solution is dried over sodium sulphate and evaporated. The residue is treated with dry ether, left to crystallize for 1 hour and then filtered while rinsing with ether/petroleum ether (1:1). After drying, there is obtained (S)-benzyl-[1-[[2-(o-chlorobenzoyl)-4-nitrophenyl]carbamoyl]ethyl]carbamate of melting point 143-145; [alpha]25 D =18 (1 percent solution in methylene chloride).

References: [1]Patent: US4474777,1984,A .

27
[ 1142-20-7 ]
[ 2338-18-3 ]
phenylmethyl [2-[(2,3-dihydro-1H-inden-2-yl)amino]-1R-methyl-2-oxoethyl]carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 20 phenylmethyl [2-[(2,3-dihydro-1H-inden-2-yl)amino]-1R-methyl-2-oxoethyl]carbamate STR29 (Z-(D)Ala-NH-2Indane) The title compound was prepared from Z-(D)Alanine (10 g, 44.8 mmol) and 2-amino indane hydrochloride (7.6 g, 44.8 mmol) by the method of Example 8. After workup, the crude solid was washed liberally with Et2 O to give 12.35 g of the white solid title material.

References: [1]Patent: US4822775,1989,A .

28
[ 1142-20-7 ]
[ 2011-66-7 ]
[ 80080-94-0 ]

Yield	Reaction Conditions	Operation in experiment
	With phosphorus pentachloride; In tetrahydrofuran; toluene;	82 g of carbobenzoxy-L-alanine are dissolved in 100 ml of absolute tetrahydrofuran, the solution is cooled to -40 C and treated with 80 g of phosphorus pentachloride. The mixture is stirred at -30 C for 20 minutes and subsequently added to a shaken solution of 80 g of <strong>[2011-66-7]2-amino-5-nitro-2'-chlorobenzophenone</strong> in 100 ml of absolute tetrahydrofuran. The solution is concentrated on a rotary evaporator at 50-60 C, treated twice with toluene and evaporated each time. By crystallisation of the residue from ether, there is obtained (-)-benzyl-[1-[{2-(o-chlorobenzoyl)4-nitrophenyl}carbamoyl]-ethyl]carbamate which melts at 147 C and exhibits a rotation of [alpha]25D =-18.2 (in methylene chloride, 1%).

References: [1]Patent: US4031078,1977,A .

29
[ 1142-20-7 ]
[ 90071-62-8 ]
[ 960326-30-1 ]

Yield	Reaction Conditions	Operation in experiment
90%	With benzotriazol-1-ol; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 20℃; for 8h;
85%	With benzotriazol-1-ol; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 20℃;	Synthesis of cyclo(-L-Am7(S-)-D-Am7(S-)-L-Ala-D-Pro-) (1) To a cold solution of Z-L-Ala-OH (2.847 g, 12.75 mmol) and H-DPro-OtBu (1.82 g, 10.63 mmol) in DMF (22 mL), HOBtH2O (1.628 g, 10.63 mmol) and DCC (2.64 g, 12.75 mmol) were added. The mixture was stirred overnight at room temperature. After completion of the reaction, DMF was removed by evaporation. The residue was dissolved in ethyl acetate (AcOEt) and filtered. Then it was washed with 10% citric acid, 4% NaHCO3 and brine, respectively. The AcOEt solution was dried over anhydrous MgSO4 and concentrated to remain an solid substance which was purified by silica gel chromatography using 1% methanol in chloroform (v/v) to yield Z-L-Ala-D-Pro-OtBu (3.388 g, 85%) as solid. To a solution of protected dipeptide (0.941 g, 2.50 mmol) in acetic acid (13 mL), Pd-C (125 mg) was added and the mixture was stirred under hydrogen atmosphere overnight. The reaction was monitored by TLC and HPLC. After completion of the reaction, Pd-C was filtered off and the acetic acid was evaporated. Then the residue was dissolved in AcOEt and was washed with saturated Na2CO3 solution. The AcOEt solution was dried over anhydrous Na2CO3 and concentrated to remain dipeptide free amine, H-L-Ala-D-Pro-OtBu (0.517 g, 85%). To a cold solution of Boc-D-Ab7-OH (0.694 g, 2.13 mmol) and free amine (0.517 g, 2.13 mmol) in DMF (5 mL), HOBtH2O (0.328 g, 2.13 mmol) and DCC (0.530 g, 2.56 mmol) were added and was stirred for 5 h on ice-bath. The product Boc-D-Ab7-L-Ala-D-Pro-OtBu was obtained in a similar manner as described earlier as white foam (0.880 g, 75%). The protected tripeptide (0.880 g, 1.6 mmol) was dissolved in 4 M HCl/dioxane (4 mL) in ice bath and was kept for 30 min at room temperature. After completion of the reaction, HCl/dioxane was removed by evaporation and the residue was dissolved in AcOEt. The solution was washed with saturated Na2CO3 solution and dried over anhydrous Na2CO3. The AcOEt solution was filtered and concentrated to remain free amine H-D-Ab7-L-Ala-D-Pro-OtBu (0.570 g, 1.27 mmol, 79%) which was condensed with Boc-L-Ab7-OH (0.412 g, 1.27 mmol) according to the method described earlier and the fully protected crude linear tetrapeptide was purified by silica gel chromatography using 1% methanol in chloroform (v/v) to yield Boc-L-Ab7-D-Ab7-L-Ala-DPro-OtBu (0. 570 g, 60%) as white foam. The protected tetrapeptide (0.555 g, 0.73 mmol) was dissolved in TFA (3 mL) on ice bath and kept for 3 h at room temperature. After evaporation of TFA, the residue was solidified using ether and petroleum ether to yield TFA salt of the linear tetrapeptide (0.500 g, 99%). The TFA salt of linear tetrapeptide, TFAH-L-Ab7-D-Ab7-L-Val-D-Pro-OH (0.500 g, 0.72 mmol), HATU (0.410 g, 1.08 mmol) and DIEA (0.313 mL, 1.8 mmol) were added in separate five portions to DMF (180 mL) in every 10 min interval with stirring. After completion of the cyclization reaction, the reaction was quenched by adding a small amount of acetic acid and DMF was evaporated and the residue was dissolved in AcOEt. Then solution was washed with 10%) citric acid, 4% NaHCO3 and brine, respectively. The AcOEt solution was dried over anhydrous MgSO4 and concentrated to remain an foamy substance, which was purified by silica gel chromatography using 1% methanol in chloroform (v/v) to yield cyclic tetrapeptide, cyclo(-L-Ab7-DAb7-L-Ala-D-Pro-) (0.260 g, 62%, HPLC: rt 6.72 min). To a solution of cyclic tetrapeptide (0.240 g, 0.41 mmol) in DMF (3 mL), KSAc (0.137 g, 1.23 mmol) was added and was stirred for 7 h at room temperature. DMF was evaporated and the residue was dissolved in AcOEt. Then it was washed with 10% citric acid and brine, respectively. The AcOEt solution was dried over anhydrous MgSO4 and concentrated to remain crude substance, which was purified by silica gel chromatography using 1% methanol in chloroform(v/v) to yield cyclo(-L-Am7(Ac)-D-Am7(Ac)-L-Ala-D-Pro-) (0.200 g, 85%, HPLC: rt 6.50 min) as heavy oil. The thio ester compound (0.145 g, 0.25 mmol) was dissolved in DMF (3 mL) and passed Ar to remove air. Then methyl amine in methanol (0.255 mL, 2.50 mmol) was added and stirred for 2 h at room temperature. After completion of the reaction, methylamine was evaporated and the residue was dissolved in DMF (50). Iodine in ethanol (0.064 g, 0.25 mmol) was added dropwise and stirred for 30 min at room temperature. After evaporation of DMF, The oxidized peptide was purified by LH-20 gel filtration with DMF as eluent. The cyclo(-L-Am7(S-)-D-Am7(S-)-L-Ala-D-Pro-) (1) (0.034 g, 0.07 mmol, 28%, HPLC: rt 5.33 min) was obtained as solid. HR-FABMS,[M+H]+ 485.2278 for C22H37N4O4S2 (calcd 485.2256). 1HNMR (500 MHz, CDCl3): dH 7.12 (d, J = 5.5 Hz, 1H), 6.42 (d,J = 10 Hz, 1H), 6.14 (d, J = 10 Hz, 1H), 4.89-4.98 (m, 1H), 4.71 (d,J = 7.5 Hz, 1H), 4.41-4.50 (m, 2H), 3.91-4.00 (m, 1H), 3.49-3.56 (m, 1H), 2.58-2.81 (m, 4H), 2.26-2.43 (m, 2H), 2.18 (t, J = 10 Hz,1H), 1.90-2.00 (m, 1H), 1.74-1.88 (m, 3H), 1.59-1.74 (m, 4H),1.26-1.54 (m, 12H).
80%	With 1-hydroxybenzotriazol-hydrate; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 20℃; for 8h;

References: [1]Shivashimpi, Gururaj M.; Amagai, Satoshi; Kato, Tamaki; Nishino, Norikazu; Maeda, Satoko; Nishino, Tomonori G.; Yoshida, Minoru [Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 24, p. 7830 - 7839].
[2]Hoque, Md. Ashraful; Islam, Md. Nurul; Islam, Md. Shahidul; Kato, Tamaki; Nishino, Norikazu; Ito, Akihiro; Yoshida, Minoru [Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 15, p. 3850 - 3855].
[3]Nishino, Norikazu; Shivashimpi, Gururaj M.; Soni, Preeti B.; Bhuiyan, Mohammed P.I.; Kato, Tamaki; Maeda, Satoko; Nishino, Tomonori G.; Yoshida, Minoru [Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 1, p. 437 - 445].

30
[ 1142-20-7 ]
[ 473797-71-6 ]
[ 1193377-27-3 ]

Yield	Reaction Conditions	Operation in experiment
34%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane Inert atmosphere;

References: [1]Location in patent: experimental part Lawandi, Janice; Toumieux, Sylvestre; Seyer, Valentine; Campbell, Philip; Thielges, Sabine; Juillerat-Jeanneret, Lucienne; Moitessier, Nicolas [Journal of Medicinal Chemistry, 2009, vol. 52, # 21, p. 6672 - 6684].

31
[ 1142-20-7 ]
[ 73101-74-3 ]
[ 1254122-50-3 ]

References: [1]Tetrahedron,2010,vol. 66,p. 8189 - 8195.

32
[ 1142-20-7 ]
[ 22203-98-1 ]
[ 1121627-36-8 ]

Yield	Reaction Conditions	Operation in experiment
32%	With dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at -10℃; for 4h;
	With dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at -15℃;

References: [1]Imramovsky, Ales; Vinsova, Jarmila; Ferriz, Juana Monreal; Buchta, Vladimir; Jampilek, Josef [Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 2, p. 348 - 351].
[2]Location in patent: scheme or table Imramovsky, Ales; Pesko, Matus; Kralova, Katarina; Vejsova, Marcela; Stolarikova, Jirina; Vinsova, Jarmila; Jampilek, Josef [Molecules, 2011, vol. 16, # 3, p. 2414 - 2430].

33
[ 1142-20-7 ]
[ 1821-39-2 ]
[ 1352436-66-8 ]

Yield	Reaction Conditions	Operation in experiment
83%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; Inert atmosphere;	4.2.1. General procedure A (13a-e) General procedure: The N-protected amino acid 12a-e (1 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.2 mmol), HOBt (1.2 mmol), DIPEA (4.75 mmol) and 2-propylaniline (1.2 mmol) were suspended in anhydrous DMF (5 mL). The reaction mixture was stirred at rt overnight under nitrogen. 1 M HCl (50 mL) was added and the mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with 1 M HCl (50 mL), brine (50 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel to yield 13a-e.

References: [1]Location in patent: experimental part Heng, Sabrina; Tieu, William; Hautmann, Stephanie; Kuan, Kevin; Pedersen, Daniel Sejer; Pietsch, Markus; Gütschow, Michael; Abell, Andrew D. [Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 24, p. 7453 - 7463].

34
[ 1142-20-7 ]
[ 78603-91-5 ]

References: [1]Applied Organometallic Chemistry,2015,vol. 29,p. 661 - 667.

35
[ 1125-88-8 ]
[ 1142-20-7 ]
[ 135923-86-3 ]
[ 171860-41-6 ]

Yield	Reaction Conditions	Operation in experiment
60%	With boron trifluoride diethyl etherate In diethyl ether at -78 - 20℃; Inert atmosphere;

References: [1]Yadav, Shyam Raj; Tiwari, Vinay Shankar; Haq, Wahajul [Chirality, 2015, vol. 27, # 9, p. 619 - 624].

36
[ 616224-38-5 ]
[ 1142-20-7 ]
[ 1890230-89-3 ]

Yield	Reaction Conditions	Operation in experiment
75%	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0℃; for 15h;	Representative example for 4-9: Preparation of methyl4-[[(2R)-2-(benzyloxycarbonylamino)-3-methyl-butanoyl]amino]-3-(methylamino)benzoate (7) General procedure: Toa solution of Z-D-Val-OH (0.98 g,3.88 mmol) in DMF (6 ml), methyl 4-amino-3-(methylamino)benzoate [1] (0.7 g,3.88 mmol) in DMF (2ml) was added at 0 oC. Subsequently, HOAt (0.79 g,5.82 mmol) and WSCI*HCl (1.12 g,5.82 mmol) were added to the former solution at 0 oC and stirred for15 h. The reaction mixture was quenched with saturated NH4Cl (10 ml)and extracted with EtOAc (100 ml). The combined extracts were washed with waterand brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 1.4 g of 7.

References: [1]Teno, Naoki; Gohda, Keigo; Yamashita, Yukiko; Otsubo, Tadamune; Yamaguchi, Masafumi; Wanaka, Keiko; Tsuda, Yuko [Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 9, p. 2259 - 2261].

37
[ 1142-20-7 ]
[ 68858-20-8 ]
[ 35661-60-0 ]
[ 35661-39-3 ]
N-(9-fluorenylmethoxycarbonyl)-(L)-5-hydroxy-norvaline-1-allyl ester [ No CAS ]
[ 73731-37-0 ]
[ 77128-73-5 ]
C₄₉H₇₂N₈O₁₂ [ No CAS ]