[ CAS No. 27532-96-3 ] {[proInfo.proName]}

Name: 27532-96-3|H-Gly-OtBu.HCl|98%
Brand: Ambeed
SKU: A207246
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2D 3D

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Quality Control of [ 27532-96-3 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 27532-96-3 ]

Product Details of [ 27532-96-3 ]

CAS No. :	27532-96-3	MDL No. :	MFCD00058255
Formula :	C₆H₁₄ClNO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	-
M.W :	167.63	Pubchem ID :	-
Synonyms :	Glycine tert-butyl ester hydrochloride	Chemical Name :	H-Gly-OtBu.HCl

Calculated chemistry of [ 27532-96-3 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.83
Num. rotatable bonds :	3
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	41.95
TPSA :	52.32 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.62 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	0.99
Log Po/w (WLOGP) :	1.09
Log Po/w (MLOGP) :	0.75
Log Po/w (SILICOS-IT) :	0.01
Consensus Log Po/w :	0.57

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-1.31
Solubility :	8.3 mg/ml ; 0.0495 mol/l
Class :	Very soluble
Log S (Ali) :	-1.68
Solubility :	3.52 mg/ml ; 0.021 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-0.79
Solubility :	27.2 mg/ml ; 0.163 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.16

Safety of [ 27532-96-3 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 27532-96-3 ]

* 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.

Upstream synthesis route of [ 27532-96-3 ]
Downstream synthetic route of [ 27532-96-3 ]

[ 27532-96-3 ] Synthesis Path-Upstream 1~4

1
[ 13139-15-6 ]
[ 27532-96-3 ]
[ 32991-17-6 ]

Reference： [1] Angewandte Chemie - International Edition, 2018, vol. 57, # 30, p. 9456 - 9460[2] Angew. Chem., 2018, vol. 130, # 30, p. 9600 - 9604,5

2
[ 27532-96-3 ]
[ 6456-74-2 ]

Reference： [1] Patent: WO2009/55696, 2009, A1, . Location in patent: Page/Page column 75-76
[2] Journal of Organic Chemistry, 2013, vol. 78, # 22, p. 11404 - 11413

3
[ 1013-88-3 ]
[ 27532-96-3 ]
[ 81477-94-3 ]

Yield	Reaction Conditions	Operation in experiment
83.1%	at 20℃; for 20 h;	tert-Butyl 2-(diphenymethyleneamino)acetate[0072] A solution of benzophenone imine (106.2 g; 587 mmol) and tert-butyl2-aminoacetate hydrochloride (98.3 g; 587 mmol) in dichloromethane (1 L; HPLC grade) was stirred at ambient temperature for 20 hours. The reaction mixture was partitioned between dichloromethane (0.5 L) and water (1.5 L) and the layers were separated. The aqueous phase was extracted with dichloromethane (0.5 L) and the combined organic layers were dried (MgSO₄), filtered and concentrated in vacuo to give a slightly off-white solid. The resulting solid was triturated with n-hexane to give 141 g (83.1percent) of the title product as a white solid. ¹H-NMR (CDCl₃, 400 MHz) δ 7.62 (d, 2H, ArH), 7.21-7.42 (m, 6H, ArH), 7.13 (d, 2H, ArH), 4.05 (s, 2H, CH₂), 1.41 (s, 9H, C(CH₃)₃); ¹³C-NMR (CDCl₃, 100 MHz) δ 171.5, 169.8, 139.4, 136.2, 130.4, 128.8, 128.7, 128.6, 128.0.127.7, 81.4, 56.3, 28.1.

Reference： [1] Organic Letters, 2015, vol. 17, # 18, p. 4498 - 4501
[2] Synlett, 2016, vol. 27, # 9, p. 1403 - 1407
[3] Chemistry - A European Journal, 2012, vol. 18, # 12, p. 3773 - 3779
[4] Journal of Medicinal Chemistry, 2016, vol. 59, # 7, p. 3515 - 3531
[5] Journal of Organic Chemistry, 1982, vol. 47, # 13, p. 2663 - 2666
[6] Patent: US6410580, 2002, B1,
[7] Patent: US6277987, 2001, B1,
[8] Journal of the American Chemical Society, 2012, vol. 134, # 34, p. 14011 - 14018
[9] Chemistry - A European Journal, 2010, vol. 16, # 4, p. 1153 - 1157
[10] Patent: WO2011/22429, 2011, A2, . Location in patent: Page/Page column 19
[11] Tetrahedron Letters, 2003, vol. 44, # 14, p. 2881 - 2883
[12] Tetrahedron Letters, 2004, vol. 45, # 39, p. 7197 - 7199

4
[ 24424-99-5 ]
[ 27532-96-3 ]
[ 111652-20-1 ]

Yield	Reaction Conditions	Operation in experiment
100%	Stage #1: With triethylamine In toluene at 60℃; for 0.5 h; Stage #2: for 6 h;	Example 1 (examples of the reaction formula (1)) [of 13] The glycine T-butyl ester hydrochloride 9 (10.0g, 59 . 7mmol) in toluene (46.2 ml) was maintained in suspension at 60 °C, and added triethylamine (6.51g, 64 . 3mmol), stirred for 0.5 hours. Furthermore, the di-tert-butyl dicarbonate (10.0g, 45 . 9mmol) in toluene (11.6 ml) was added dropwise in the reaction mixture, and to reacted for 6 hours. Furthermore, after adding water (30 ml), the organic layer was separated. Then, the solvent was distilled off from the organic layer by n-hexane, obtaining N-Boc-glycine T-butyl ester 10 (10.6g, 45 . 9mmol, yield 100percent). The structure of the product was confirmed through ¹H-NMR analysis.

Reference： [1] Patent: CN103068795, 2016, B, . Location in patent: Paragraph 0119; 0120; 0121; 0122; 0123; 0124
[2] Synthesis, 1987, # 3, p. 223 - 225
[3] The Journal of organic chemistry, 2002, vol. 67, # 24, p. 8291 - 8298

[ 27532-96-3 ] Synthesis Path-Downstream 1~88

1
[ 27532-96-3 ]
[ 2602-85-9 ]
[ 29782-02-3 ]

Reference： [1]Helvetica Chimica Acta,1970,vol. 53,p. 1011 - 1030

2
[ 1013-88-3 ]
[ 27532-96-3 ]
[ 81477-94-3 ]

Yield	Reaction Conditions	Operation in experiment
91%	In dichloromethane;	A. Benzhydrylideneaminoacetic Acid t-Butyl Ester A solution of glycine t-butyl ester hydrochloride (10 g, 59.65 mmol) in 250 mL of di-chloromethane is treated with benzophenoneimine (10.8 g, 59.6 mmol) at RT. After 16 h, the mixture is washed with brine, dried over anhydrous MgSO4 and concentrated to give benzhydrylideneaminoacetic acid t-butyl ester as a white solid (16.1 g, 91%).
91%	In dichloromethane;	A. Benzhydrylideneaminoacetic acid t-butyl ester A solution of glycine t-butyl ester hydrochloride (10 g, 59.65 mmol) in 250 mL of dichloromethane is treated with benzophenoneimine (10.8 g, 59.6 mmol) at RT. After 16 h, the mixture is washed with brine, dried over anhydrous MgSO4 and concentrated to give benzhydrylideneaminoacetic acid t-butyl ester as a white solid (16.1 g, 91%).
83.1%	In dichloromethane; at 20℃; for 20h;	tert-Butyl 2-(diphenymethyleneamino)acetate[0072] A solution of benzophenone imine (106.2 g; 587 mmol) and tert-butyl2-aminoacetate hydrochloride (98.3 g; 587 mmol) in dichloromethane (1 L; HPLC grade) was stirred at ambient temperature for 20 hours. The reaction mixture was partitioned between dichloromethane (0.5 L) and water (1.5 L) and the layers were separated. The aqueous phase was extracted with dichloromethane (0.5 L) and the combined organic layers were dried (MgSO4), filtered and concentrated in vacuo to give a slightly off-white solid. The resulting solid was triturated with n-hexane to give 141 g (83.1%) of the title product as a white solid. 1H-NMR (CDCl3, 400 MHz) delta 7.62 (d, 2H, ArH), 7.21-7.42 (m, 6H, ArH), 7.13 (d, 2H, ArH), 4.05 (s, 2H, CH2), 1.41 (s, 9H, C(CH3)3); 13C-NMR (CDCl3, 100 MHz) delta 171.5, 169.8, 139.4, 136.2, 130.4, 128.8, 128.7, 128.6, 128.0.127.7, 81.4, 56.3, 28.1.

Reference： [1]Organic Letters,2015,vol. 17,p. 4498 - 4501
[2]Synlett,2016,vol. 27,p. 1403 - 1407
[3]Chemistry - A European Journal,2012,vol. 18,p. 3773 - 3779
[4]Journal of Medicinal Chemistry,2016,vol. 59,p. 3515 - 3531
[5]Journal of Organic Chemistry,1982,vol. 47,p. 2663 - 2666
[6]Patent: US6410580,2002,B1
[7]Patent: US6277987,2001,B1
[8]Journal of the American Chemical Society,2012,vol. 134,p. 14011 - 14018
[9]Chemistry - A European Journal,2010,vol. 16,p. 1153 - 1157
[10]Patent: WO2011/22429,2011,A2 .Location in patent: Page/Page column 19
[11]Tetrahedron Letters,2003,vol. 44,p. 2881 - 2883
[12]Tetrahedron Letters,2004,vol. 45,p. 7197 - 7199
[13]Advanced Synthesis and Catalysis,2019
[14]Organic Letters,2020,vol. 22,p. 120 - 125

3
[ 24424-99-5 ]
[ 27532-96-3 ]
[ 111652-20-1 ]

Yield	Reaction Conditions	Operation in experiment
100%		Example 1 (examples of the reaction formula (1)) [of 13] The glycine T-butyl ester hydrochloride 9 (10.0g, 59 . 7mmol) in toluene (46.2 ml) was maintained in suspension at 60 C, and added triethylamine (6.51g, 64 . 3mmol), stirred for 0.5 hours. Furthermore, the di-tert-butyl dicarbonate (10.0g, 45 . 9mmol) in toluene (11.6 ml) was added dropwise in the reaction mixture, and to reacted for 6 hours. Furthermore, after adding water (30 ml), the organic layer was separated. Then, the solvent was distilled off from the organic layer by n-hexane, obtaining N-Boc-glycine T-butyl ester 10 (10.6g, 45 . 9mmol, yield 100%). The structure of the product was confirmed through 1H-NMR analysis.

Reference： [1]Patent: CN103068795,2016,B .Location in patent: Paragraph 0119; 0120; 0121; 0122; 0123; 0124
[2]Synthesis,1987,p. 223 - 225
[3]Journal of Organic Chemistry,2002,vol. 67,p. 8291 - 8298

4
[ 1676-75-1 ]
[ 27532-96-3 ]
[ 132866-45-6 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,1993,vol. 41,p. 1965 - 1970

5
[ 65-86-1 ]
[ 27532-96-3 ]
Ort-Gly-O-t-Bu [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1980,vol. 23,p. 913 - 918

6
[ 5891-45-2 ]
[ 27532-96-3 ]
[ 103673-94-5 ]

Reference： [1]Journal of Medicinal Chemistry,1994,vol. 37,p. 3294 - 3302

7
[ 27532-96-3 ]
[ 86060-81-3 ]
[ 186097-61-0 ]

Reference： [1]Archiv der Pharmazie,1996,vol. 329,p. 498 - 502

8
[ 27532-96-3 ]
[ 14997-58-1 ]
[ 189280-51-1 ]

Reference： [1]Journal of Organic Chemistry,1997,vol. 62,p. 3285 - 3290

9
[ 27532-96-3 ]
[ 98632-91-8 ]
[ 210818-40-9 ]
[ 210818-41-0 ]

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 2631 - 2635

10
[ 27532-96-3 ]
[ 142855-80-9 ]
[ 403736-50-5 ]

Reference： [1]Bioorganic and medicinal chemistry,2001,vol. 9,p. 3231 - 3241

11
[ 5545-52-8 ]
[ 27532-96-3 ]
[ 475101-71-4 ]

Reference： [1]Journal of Carbohydrate Chemistry,2007,vol. 26,p. 61 - 82
[2]Il Farmaco,2003,vol. 58,p. 787 - 793

12
[ 122889-11-6 ]
[ 27532-96-3 ]
[ 675882-22-1 ]

Reference： [1]Il Farmaco,2003,vol. 58,p. 787 - 793

13
[ 27532-96-3 ]
[(3,5-bis-benzyloxy-pyridine-2-carbonyl)-amino]-acetic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%		To a solution of 3,5-bis-benzyloxy-pyridine-2-carboxylic acid, 2, (2.36 g, 6.36 mmol) in DMF (20 mL) at room temperature under N2 is added I-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide (EDCI) (1.83 g, 9.54 mmol) and 1-hydroxybenzo-triazole (HOBt) (0.086 g, 0.64 mmol). The mixture is stirred for 15 minutes after which time <strong>[27532-96-3]glycine tert-butyl ester hydrochloride</strong> (1.60 g, 9.54 mmol) and diisopropylethylamine (DIPEA) (3.32 ml, 19.08 mmol) are added. The resulting solution is stirred at room temperature for 48 hours then concentrated under reduced pressure. The resulting brown oil is purified over silica (EtOAc) to afford 3.04 g (99% yield) of the desired compound as a yellow solid. 1H NMR (250 MHz, CDCl3) delta ppm 8.19 (1H, t, J=5.2 Hz), 8.01-8.08 (2H, m), 7.27-7.54 (9H, m), 6.97 (1H, d, J=2.4 Hz), 5.24 (2H, s), 5.13 (2 H, s), 4.17 (2 H, d, J=5.2 Hz), 1.51 (9H, s). HPLC-MS: m/z 449 [M+H]+.

Reference： [1]Patent: US2007/299086,2007,A1 .Location in patent: Page/Page column 31

14
[ 27532-96-3 ]
[ 1694-92-4 ]
[ 552847-32-2 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium hydrogencarbonate; In tetrahydrofuran; at 0 - 20℃; for 16h;	To a stirred solution of <strong>[27532-96-3]glycine tert-butyl ester hydrochloride</strong> (1.05g, 6.26mmol) in anhydrous tetrahydrofuran (32mL) was added NaHCO3 (2.11g, 25.12mmol). The suspension was cooled at 0C and a solution of 2-nitrobenzenesulfonyl chloride (1.392g, 6.34mmol) in anhydrous tetrahydrofuran (60mL) was added. After stirring for 16hat room temperature, the mixture was filtered and the solvent was removed under vacuum to give the desired compound 7 as a white amorphous powder (1.98g, 100%). TLC: Rf=0.70 (silica gel, CH2Cl2). 1H NMR (300MHz, CDCl3): delta=1.31 (s, 9H, 3×CH3), 3.89 (d, J=5.7Hz, 2H, CH2), 6.02 (t, J=5.7Hz, 1H, NH), 7.68-7.78 (m, 2H, 2×CH), 7.89-7.97 (m 1H, CH), 8.04-8.12 (m, 1H, CH) ppm.
17.6 g	With 4-methyl-morpholine; In dichloromethane; at 20℃; for 2.5h;Cooling with ice;	To a suspension of fe/f-butyl glycinate hydrochloride (10.0 g, 60 mmol) in CH2CI2 (120 mL) was added 2-nitrobenzenesulfonyl chloride (13.2 g, 60 mmol). The mixture was cooled in an ice-bath, and N- methylmorpholine (16.3 mL, 15.0 g, 150 mmol) was added dropwise during a period of 30 min. The mixture was stirred at rt for 2 h, washed with dilute NaHC03 solution (2 x 50 mL), water (50 mL), brine (50 mL), dried (MgS04), and concentrated to provide colorless crystals (17.6 g). LC/MS m/z: 334.17 (M+NH4)+, 633.1 1 (2M+H)+, 650.18 (2M+Na)+

Reference： [1]Tetrahedron,2018,vol. 74,p. 4272 - 4287
[2]Organic Letters,2007,vol. 9,p. 1635 - 1638
[3]Patent: WO2016/160677,2016,A1 .Location in patent: Page/Page column 144

15
[ 27532-96-3 ]
[ 100-52-7 ]
[ 64923-12-2 ]

Yield	Reaction Conditions	Operation in experiment
87%	With magnesium sulfate; triethylamine; In dichloromethane; at 20℃; for 19h;	A slurry of <strong>[27532-96-3]glycine tert-butyl ester hydrochloride</strong> (10.04 g, 59.9 mmol), dichloromethane (100 mL), benzaldehyde (6.07 mL, 59.9 mmol), triethylamine (8.35 mL, 59.9mmol), and magnesium sulfate (14.42 g, 120 mmol) was stirred at room temperature. After 19 h, the sluffy was filtered, concentrated, toluene added (30 mL), and filtered again. The filtrate was concentrated to a minimal volume, pipet filtered through a kimwipe with minimal toluene rinse, then concentrated, giving the title compound (11.429 g, 52.1 mmol, 87 % yield). 1 H NMR (400 MHz, DMSO-d6) d 8.34 (d, /= 1.3 Hz, 1H), 7.76 (dd, /= 7.5, 2.1 Hz, 2H), 7.54 - 7.39 (m, 3H), 4.31 (d, /= 1.3 Hz, 2H), 1.44 (s, 9H); MS (ESI+) m/z 220 (M+H)+.
		A mixture of <strong>[27532-96-3]glycine tert-butyl ester hydrochloride</strong> (6.95 g, 41.5 mmol) and magnesium sulfate (5.67 g, 47.1 mmol) in CH2Cl2 (60 mL) was treated with triethylamine (5.78 mL, 41.5 mmol), stirred for 15 minutes, treated with benzaldehyde (3.82 mL, 37.7 mmol) and stirred at room temperature overnight. The mixture was filtered to remove the solids and the solids were washed with CH2Cl2. The combined filtrates were washed with water (20 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (?15 mL). The combined CH2Cl2 layers were dried (MgSO4), filtered and concentrated (room temperature water bath) to provide the title compound. 1H NMR (400 MHz, CDCl3) delta ppm 8.27 (s, 1H), 7.80-7.76 (m, 2H), 7.47-7.37 (m, 3H), 4.31 (s, 2H), 1.50 (s, 9H); MS (ESI+) m/z 220 (M+H)+.

Reference： [1]Journal of Organic Chemistry,2020,vol. 85,p. 7620 - 7632
[2]Patent: WO2019/193062,2019,A1 .Location in patent: Paragraph 0246
[3]Tetrahedron,2007,vol. 63,p. 6587 - 6602
[4]Patent: WO2007/13698,2007,A1 .Location in patent: Page/Page column 88
[5]Patent: US2018/99931,2018,A1 .Location in patent: Paragraph 2064

16
[ 27532-96-3 ]
[ 146803-41-0 ]
[(2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)propylamino]acetic acid tert-butyl ester [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 5627 - 5643

17
[ 27532-96-3 ]
[ 111717-08-9 ]

Reference： [1]Synthesis,1987,p. 223 - 225
[2]Tetrahedron,1988,vol. 44,p. 5403 - 5414

18
[ 27532-96-3 ]
[ 598-21-0 ]
[ 1309945-41-2 ]

Yield	Reaction Conditions	Operation in experiment
93%		Zu 50 g (296,5 mmol) Glycin-tert.-butylester Hydrochloridsalz und 90 g (889,5 mmol) Triethylamin in 500 ml Methylenchlorid tropft man bei 0C 77,8 g (385,5 mmol) Brom-Essigsurebromid zu. Dabei hlt man die Temperatur zwischen 0C - 5C. Man gibt 1000 ml 5 %ige aqu. Salzsure zu und trennt die organische Phase ab. Die organische Phase wird noch einmal mit 500 ml 5 %iger aqu. Salzsure extrahiert, ber Magnesiumsulfat getrocknet und im Vakuum zur Trockne eingedampft. Der Rckstand wird aus Diisopropylether/n-Hexan umkristallisiert. Ausbeute: 30,5 g (61 % d. Th.) Elementaranalyse: ber. C 38,11 H 5,60 N 5,56 Br 31,69 ; gef. C 37,92 H 5,76 N 5,38 Br 31,42 .

Reference： [1]Patent: EP946525,2004,B1 .Location in patent: Page 15

19
[ 27532-96-3 ]
[ 98-74-8 ]
[ 34596-92-4 ]

Yield	Reaction Conditions	Operation in experiment
81%	With pyridine; at 0 - 20℃; for 18h;Inert atmosphere;	Step 1: Synthesis of tert-butyl 2-(4-nitrophenylsulfonamido) acetate [00378] A round bottom flask equipped with a stir bar and under nitrogen was charged with <strong>[27532-96-3]glycine tert-butyl ester hydrochloride</strong> (20 g, 119.76 mmol) and pyridine (260 mL). The mixture was cooled to 0 C at which time 4-nitrobenzenesulfonyl chloride (28.98 g, 131.74 mmol) was added portion-wise maintaining the mixture below 10 C. The reaction was then allowed to warm to room temperature. After 18 h at room temperature, the reaction mixture was poured into water (1000 mL). A precipitate formed which was filtered and dried under vacuum to give tert-butyl 2-(4-nitrophenylsulfonamido) acetate (30.8 g, 97.46 mmol, 81% yield) as a yellow solid. 1H MR (CDC13) delta: 8.36-8.34 (m, 2H), 8.07-8.05 (m, 2H), 5.23 (br s, 1H), 3.75-3.74 (d, J= 5.6 Hz, 2H), 1.35 (s, 9H).
	With pyridine;	Glycine tert-butyl ester hydrochloride is reacted with 4-nitrobenzenesulfonyl chloride in pyridine, to give tert-butyl 2-[(4-nitrophenyl)sulfonyl]amino}acetate.
	In pyridine; hexane; ethyl acetate;	Reference Example 1 N-[(4-Nitrophenyl)sulfonyl]glycine t-butyl ester STR454 4-Nitrobenzenesulfonyl chloride (46.3 g) was added to a solution of glycine t-butyl ester hydrochloride (35 g) in pyridine (200 ml). The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated. The residue was washed with water and then a mixture of hexane and ethyl acetate (9:1) and dried to give the title compound (61.4 g) having the following physical data. TLC: Rf 0.18 (Hexane: Ethyl acetate=4:1).

	In pyridine; hexane; ethyl acetate;	Reference example 1 N-[(4-Nitrophenyl)sulfonyl]glycine t-butyl ester 4-Nitrobenzenesulfonyl chloride (46.3 g) was added to a solution of glycine t-butyl ester hydrochloride (35 g) in pyridine (200 ml). The mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated. The precipitated crystals was washed with water and then a mixture of hexane and ethyl acetate (9:1) and dried to give the title compound (61.4 g) having the following physical data. TLC: Rf 0.18 (Hexane: Ethyl acetate=4:1).
	With triethylamine; In dichloromethane; for 18h;Inert atmosphere; Sealed tube;	Glycine tert-butyl ester hydrochloride (2.5 g, 14.9 mmol) was sealed in a flask with stir bar under nitrogen and dissolved with DCM (60 mL) before triethylamine (4.26 mL, 30.6 mmol) was added. 4-Nitrobenzene-1-sulfonyl chloride (3.64 g, 16.4 mmol) was sealed under nitrogen in a separate flask and dissolved with DCM (16.4 mL, 14.9 mmol). The resulting solution was added by syringe over 5 min. to the solution of <strong>[27532-96-3]glycine tert-butyl ester hydrochloride</strong>, and the reaction was stirred for 18 h. The reaction was quenched by pouring it onto half-saturated aq. NaHCO3 (100 mL). It was then diluted with more DCM and water, the layers were separated, and the organic layer was washed again with aq. NaHCO3, then brine. The organics were dried over MgSO4, filtered, and concentrated to give the desired product as a white solid (4.73 g, 100%). LRMS (ESI-) (M-H): 315.24.

Reference： [1]Patent: WO2016/106284,2016,A2 .Location in patent: Paragraph 00378
[2]Patent: EP1422224,2004,A1 .Location in patent: Page 35
[3]Patent: US6022893,2000,A
[4]Patent: US6177466,2001,B1
[5]Patent: US2014/94462,2014,A1 .Location in patent: Paragraph 1269

20
[ 14051-46-8 ]
[ 27532-96-3 ]
t-butyl ([4-(5H-dibenzo[a,d][7]annulen-5-ylidene)-1-piperidinyl]-carbonyl}amino)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%		0307] 475 mg (2.93 mmol) of N,N'-carbonyldiimidazole was dissolved in 10 ml of anhydrous tetrahydrofuran. 0.45 ml (3.29 mmol) of triethylamine was added to the obtained solution, and they were stirred at room temperature for 10 minutes. The reaction mixture was cooled with ice, and 460 mg (2.74 mmol) of t-butyl aminoacetate hydrochloride was added dropwise to the mixture during a period of about 10 minutes, and they were stirred at room temperature for 1 hour. After cooling with ice, 500 mg (1.83 mmol) of 4-(5H-dibenzo[a,d][7]annulen-5-ylidene)piperidine was added to the resultant mixture, and they were stirred at room temperature overnight. Water was added to the reaction mixture. After extracting with ethyl acetate followed by drying over anhydrous magnesium sulfate, the product was concentrated under reduced pressure. The residue thus obtained was purified by the silica gel chromatography (dichloromethane:methanol=95:5 to 2:3) to obtain the title compound. [0308] Yield: 752 mg (1.75 mmol), 95% MS (ESI, m/z) 431 (M+H)+ 1H-NMR (CDCl3): 1.46 (9H, s), 2.12-2.20 (2H, m), 2.28-2.33 (2H, m), 3.01-3.09 (2H, m), 3.52-3.59 (2H, m), 3.90 (2H, d), 4.91 (1H, br t).

Reference： [1]Patent: US2004/167118,2004,A1 .Location in patent: Page 24

21
[ 17609-52-8 ]
[ 27532-96-3 ]
[ 439088-73-0 ]

Yield	Reaction Conditions	Operation in experiment
94%		[(2R)-[(BENZYLOXY)] carbonyl] amino} (phenyl) acetic acid (Z- (R)-Phg-OH) (10 g, 35.0 mmol) and tert-butylglycine hydrochloride (6.3 g, 37.4 mmol) was dissolved in DCM (200 ml) with 2,6-lutidine (8.2 ml, 70.4 mmol). After stirring 5 minutes at [0C] TBTU (12.4 g, 38.6 mmol) was added and stirring was continued 1 hours 30 minutes at [0C] and 3 hours 45 minutes at room temperature. The reaction mixture was washed with water (2 x 100 [ML),] dried (magnesium sulphate) and purified with flash chromatography (DCM: EtOAc 7: [1->5] : 1) to give the title compound (13 g, 94 %). NMR (500 MHz) : 1.45 (s, 9 [H),] 3.84 (d, 1 H), 4.00 (dd, 1 H), 5.10 (m, 2 H), 5. 28 (br s, 1 H), 6.13 (br s, 1 H), 6.23 (br s, 1 H), 7.30-7. 44 (m, 10 H).

Reference： [1]Patent: WO2004/5247,2004,A1 .Location in patent: Page 106

22
[ 27532-96-3 ]
[ 75833-38-4 ]
tert-Butyl [(6-cyano-2-pyrimidinyl)amino]acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%	With triethylamine; at 20℃; for 18h;	Reference Example 108 tert-Butyl [(6-cyano-2-pyrimidinyl)amino]acetate 2-Chloro-6-cyanopyrimidine (2.09 g, 15.0 mmol), glycine tert-butyl ester hydrochloride salt (2.52 g, 15.0 mmol) and triethylamine (2.38 ml, 17.0 mmol) were dissolved in DMF (30 ml), and the mixture was stirred at room temperature for 18 hrs.. The reaction mixture was combined with ethyl acetate and water.. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.. The solvent was evaporated to give the titled compound (1.07 g, 45 %) as pale yellow crystals.1H-NMR (CDCl3) delta: 1.49 (9H, s), 4.08 (2H, d, J = 5.6 Hz), 5.90 (1H, br s), 6.88 (1H, d, J = 4.7 Hz), 8.46 (1H, d, J = 4.7 Hz). IR(KBr): 3261, 2984, 2243, 1734, 1601, 1570, 1535, 1417, 1367, 1228, 1155, 848, 733 cm-1.

Reference： [1]Patent: EP1424336,2004,A1 .Location in patent: Page 217

23
[ 27532-96-3 ]
[ 156130-41-5 ]
[ 762300-05-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	With benzotriazol-1-ol; triethylamine; dicyclohexyl-carbodiimide; In tetrahydrofuran; at 20℃; for 60h;	To a suspension of (alphaR,3R,4S)-4-(3-hydroxyphenyl)-3,4-dimethyl-alpha-(phenylmethyl)-1-piperidinepropanoic acid (13) (4 g, 0.88 mmol), <strong>[27532-96-3]glycine tert-butyl ester hydrochloride</strong> (2 g, 11.96 mmol, 1.1 eq) and hydroxybenzotriazole (1.62 g, 11.96 mmol, 1.1 eq) in anhydrous tetrahydrofuran (35 mL) was added under nitrogen triethylamine (1.67 mL, 11.96 mmol, 1.1 eq) followed by a solution of dicyclohexylcarbodiimide (2.47 g, 11.96 mmol, 1.1 eq) in anhydrous tetrahydrofuran (15 mL) (Scheme 3). The reaction mixture was stirred at room temperature for 60 h, cooled to 0 C. for 30 minutes and filtered. The filtrate was concentrated under vacuum and ethyl acetate (100 mL) was added. The solution was washed with and saturated aqueous solution of sodium carbonate (100 mL) and brine (100 mL). The organic layer was dried over sodium sulfate, filtered and placed in a fridge overnight to allow residual traces of dicyclohexylurea to precipitate. The suspension was then filtered and the filtrate was concentrated to give compound 14b as yellow foam (6 g, 100%). Mass spectral analysis: m/z=481 (M+H)+

Reference： [1]Patent: US2004/186135,2004,A1 .Location in patent: Page/Page column 19-20; 24

24
[ 27532-96-3 ]
[ 393105-53-8 ]
tert-Butyl 2-[(2{-1-benzyl-5-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}-2-oxoacetyl)amino]acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With benzotriazol-1-ol; triethylamine; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃; for 2h;	tert-Butyl 2-[(2{-1-benzyl-5-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}-2-oxoacetyl)amino]acetate To an ice-cooled solution of <strong>[393105-53-8]2-{1-benzyl-5-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}-2-oxoacetic acid</strong> (1.47 g, 3.35 mmol) in methylene chloride (25 mL) was added 1-hydroxybenzotriazole hydrate (0.771 g, 5.03 mmol). The reaction mixture was stirred for few minutes in an ice bath. Triethylamine (0.47 mL, 3.4 mmol), and glycine tert-butyl ester hydrochloride (0.573 g, 3.42 mmol) were added. After stirring for five more minutes in the ice bath, dicyclohexylcarbodiimide (0.88 g, 4.27 mmol) was added. The reaction mixture was then stirred at room temperature for 2 hours under nitrogen. The mixture was filtered. The insoluble matter was washed with ethyl acetate. The combined filtrate was evaporated to dryness. The residue was partitioned in ethyl acetate and 2N hydrochloric acid. The organic phase was washed with brine and evaporated to dryness. The residue was purified by flash chromatography (Biotage apparatus) using 2.5-12.5% ethyl acetate in hexane to yield the title compound as a yellow solid (1.47 g, 80%), mp 167-168 C. Mass spectrum (-ESI, [M-H]-) m/z 551.7; 1HNMR (500 MHz, DMSO-d6): delta9.05 (s, 1H), 9.0 (t, 1H, J=6.0 Hz), 8.5 (d, 1H, J=1.5 Hz), 7.75-7.8 (m, 2H), 7.7 (d, 1H, J=8.4 Hz), 7.6 (dd, 1H, J=8.6 Hz and 1.8 Hz), 7.45 (d, 1H, J=8.1 Hz), 7.3-7.35 (m, 5H), 5.65 ppm (s, 2H), 3.9 (d, 2H, J=6.1 Hz), and 1.45 ppm (s, 9H).

Reference： [1]Patent: US2004/116504,2004,A1 .Location in patent: Page 9

25
[ 858104-20-8 ]
[ 27532-96-3 ]
[ 858104-00-4 ]

Yield	Reaction Conditions	Operation in experiment
95%		Method 13; N-[4-((2R, 3R)-1-(4-fluorophenyl)-3-[2-(4-methoxyphenyl)-2-oxoethyl] thio}-4- oxoazetidin-2-yl) phenoxy] acetyl} glycine; A mixture of [4- ((2R,3R)-1-(4-fluorophenyl)-3-[2-(4-methoxyphenyl)-2-oxoethyl]thio}-4- oxoazetidin-2-yl) phenoxy] acetic acid (0.150g, 0.30 mmol), tert-butyl glycinate hydrochloride (0.0635 g, 0.38 mmol) and N-methylmorpholine (0.10 ml, 0.91 mmol) in DCM (2ml) was stirred at room temperature. TBTU (0.128 g, 0.40 mmol) was added and the mixture was stirred overnight. Trifluoroacetic acid (4.0 ml) was added and after 2 h the solvent was removed under reduced pressure. The residue was purified by preparative HPLC on a Kromasil C8-column using 35% MeCN in 0. 1M ammonium acetate buffer as eluent. The solvent was removed under reduced pressure and 0.159 g (95 %) of the title product was obtained. M/z 553.02.

Reference： [1]Patent: WO2005/61452,2005,A1 .Location in patent: Page/Page column 134

26
2-benzyl-3-[4a-(3-hydroxy-phenyl)-10a-methyl-3,4,4a,5,10,10a-hexahydro-1H-benzo[g]isoquinolin-2-yl]-propionic acid [ No CAS ]
[ 27532-96-3 ]
C₃₆H₄₄N₂O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With N-ethyl-N,N-diisopropylamine; HATU; In DMF (N,N-dimethyl-formamide); at 0 - 20℃; for 16h;	To a cold (0 C.) solution of <strong>[27532-96-3]glycine tert-butyl ester hydrochloride</strong> (0.050 g, 0.296 mmol, 1.5 eq) in anhydrous dimethylformamide (5 mL) was added successively diisopropylethylamine (0.18 mL, 1 mmol, 5 eq) and a solution of 30 (0.090 g, 0.198 mmol, 1 eq) in anhydrous dimethylformamide (1 mL). To this stirred solution was added under argon a solution of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (0.112 g, 0.296 mmol, 1.5 eq) in anhydrous dimethylformamide (1 mL). The mixture was stirred at room temperature under argon for 16 hours and concentrated in vacuo. The residue was partitioned between an aqueous saturated solution of sodium bicarbonate (30 mL) and chloroform (30 mL). The aqueous layer was further extracted with chloroform (30 mL) and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (eluent:dichloromethane/methanol=99:1) affording the desired t-butyl ester 31 (0.103 g, 91%); [M+H]+ 569. To a stirred solution of 31 (0.093 g, 0.181 mmol, 1 eq) in dioxane (2.5 mL) was added a solution of a 4N aqueous solution of HCl (2.5 mL) drop wise. A white precipitate formed after 20 minutes. To the suspension was added a 1N aqueous solution of HCl (1 mL). The clear solution was stirred at room temperature for 16 hours. A 12N aqueous solution of HCl (1 mL) was added to the reaction mixture, which was stirred for an additional 16 hours at room temperature. The mixture was concentrated in vacuo. The crude product was purified by preparative HPLC [Genesis C18 column (Jones Chromatography), eluent: 10-50% acetonitrile in water (+0.1% TFA), tR=30min)] affording the title compound 32 (Example 8) (0.064 g, 58%); [M+H]+ 513.

Reference： [1]Patent: US2005/203123,2005,A1 .Location in patent: Page/Page column 28

27
[ 27532-96-3 ]
[ 87001-32-9 ]
[ 329041-19-2 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In DMF (N,N-dimethyl-formamide); at 0 - 25℃; for 12h;	Example 2 ; Preparation of a Compound of Formula I, According to General Scheme 2, Wherein X is Carbon, R3, R4, R7, and R8 are Hydrogen, R1 is Hydroxy, and R2, R5, and R6 are as Above Example of a Preparation of a Compound of Formula XV, Step 13, Scheme 2 ; [4-Benzyloxybenzenesulfonylamino]-acetic acid tert-butyl ester ; To a mixture of glycine tert butyl ester hydrochloride salt (compound of formula XIV, 50 g, 300 mmol) and dimethylformamide (400 ml) at about 0C was added triethylamine (127 ml, 885 mmol) and 4-benzyloxybenzenesulfonyl chloride (102 g, 357 mmol). After stirring for about 1 hour, the mixture was warmed to a temperature of about 20 C. to about 25 C., and stirred for about an additional 12 hours. The mixture was diluted with 1M hydrochloric acid, extracted twice with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Trituration of the residue with ether-hexane afforded 91 g of [4-Benzyloxybenzenesulfonylamino]-acetic acid tert-butyl ester (compound of formula XV) as a colorless solid.
	With triethylamine; In N-methyl-acetamide;	Example of a preparation of a compound of formula XV, Step 13, Scheme 2 [4-Benzyloxybenzenesulfonylamino]-acetic acid tert-butyl ester To a mixture of glycine tertbutyl ester hydrochloride salt (compound of formula XIV, 50 g, 300 mmol) and dimethylformamide (400 ml) at about 0C was added triethylamine (127 ml, 885 mmol) and 4-benzyloxybenzenesulfonyl chloride (102 g, 357 mmol). After stirring for about 1 hour, the mixture was warmed to a temperature of about 20C to about 25C, and stirred for about an additional 12 hours. The mixture was diluted with 1M hydrochloric acid, extracted twice with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo.Trituration of the residue with ether-hexane afforded 91 g of [4-Benzyloxybenzenesulfonylamino]-acetic acid tert-butyl ester (compound of formula XV) as a colorless solid.

Reference： [1]Patent: US2005/227997,2005,A1 .Location in patent: Page/Page column 37
[2]Patent: EP1081137,2001,A1

28
[ 329-15-7 ]
[ 27532-96-3 ]
[ 868842-48-2 ]

Yield	Reaction Conditions	Operation in experiment
100%	With triethylamine; In dichloromethane; at 0 - 20℃; for 20.5h;	Step A: (4-Trifluoromethylbenzoylamino)acetic acid tert-butyl ester To a solution of 4-trifluoromethylbenzoyl chloride (15.0 mL, 0.1 mol) and <strong>[27532-96-3]glycine tert-butyl ester hydrochloride</strong> (17.8 g, 0.1 mol) in dichloromethane (200.0 mL) at 0 C, was added triethylamine (29.6 mL, 0.2 mol) and the reaction mixture was stirred at 0 C. for 30 min and warmed to room temperature for 3-20 h. The mixture was washed with water, 1N hydrochloric acid and water. The organic layer was separated, dried over sodium sulfate, filtered and the filtrate was concentrated in vacuo to give 28.7 g of the desired product as a white solid (100%), which was used without further purification.

Reference： [1]Patent: US2005/250819,2005,A1 .Location in patent: Page/Page column 10

29
[ 939-80-0 ]
[ 27532-96-3 ]
[ 247132-58-7 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In ethanol;	Step 6 N-(4-Cyano-2-nitrophenyl)glycine tert-Butyl Ester To a solution of <strong>[939-80-0]4-chloro-3-nitrobenzonitrile</strong> (33.87 g) and glycine tert-butyl ester hydrochloride (55.98 g) in ethanol (400 ml) was added triethylamine (77.6 ml), and the mixture was stirred at room temperature for 15 hours and then at 50 C. for 3 hours. After completion of the reaction, the solvent was evaporated and the obtained residue was extracted with ethyl acetate. The extract was washed with 10% aqueous citric acid solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The obtained residue was washed with diisopropyl ether and collected by filtration to give the title compound (38.419 g). 1H-NMR (delta ppm, CDCl3) 1.53 (s, 9H), 4.03 (d, J=5.0 Hz, 2H), 6.75 (d, J=8.9 Hz, 1H), 7.64 (dd, J=2.0, 8.9 Hz, 1H), 8.55 (d, J=2.0 Hz, 1H), 8.81 (brs, 1H).

Reference： [1]Patent: US6562828,2003,B1

30
[ 886041-96-9 ]
[ 27532-96-3 ]
[ 886042-62-2 ]

Yield	Reaction Conditions	Operation in experiment
100%		Step 1: Tert-butyl N-/2-[3-cvclohexyl-l-(2.2-dimethoxyethyl)-6-(methoxycarbonyl)-lH-indol-2- y/ J benzyl fslycinate; To a solution of methyl 3-cyclohexyl-l-(2,2-dimethoxyethyl)-2-(2-formylphenyl)-lH -indole-6- carboxylate (prepared as described in Example 20, Step 2) in DCE (0.09 M), tert-butyl glycinate hydrochloride salt (1.5 eq)was added followed by NaBH(OAc)3 (3 eq). The solution was stirred at RT for 2 days. The reaction was quenched with aqueous NaHCO3 and extracted with EtOAc (x2). The combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as a viscous oil (quantitative); MS (ES+) m/z 565 (M+H)+

Reference： [1]Patent: WO2006/46030,2006,A2 .Location in patent: Page/Page column 60

31
[ 367-86-2 ]
[ 27532-96-3 ]
[ 877628-58-5 ]

Yield	Reaction Conditions	Operation in experiment
79%	With sodium hydrogencarbonate; In dimethyl sulfoxide; at 50 - 100℃;	A mixture of 4-fluoro-3-nitrobenzotrifluoride (209 mg, 1 mmol), glycineester hydrochloride (201 mg, 1 .2 mmol) and NaHCO3 (128 mg, 2 mmol) in dry DMSO(1 ml) is stirred overnight at 50 or 65 C. In case the reaction is not complete a furtherheating at 85C to 100C for 3 h is necessary. The reaction is then cooled to rt andwater is added. The yellow to orange solid formed is filtered over a fritted funnel,rinsed thoroughly with water and dried under high vacuum. This yields the titlecompound (254 mg) in 79% as a yellow solid: ?R = 1.08 min (LC-3), ESI-MS (pos.):m/z 403.2 [M+2AcCN]+, m/z 321.56 [M+H]+, 'H-NMR (DMSO-d6): 5 (ppm) 1.44 (s,9H, ffiu), 4.23 (d, 2H, NHQkCOz), 7.08 (d, 1H, Har0m), 7.80 (dd, 1H, Ramm), 8.34 (br.s, lH,Harom),8.65(t, 1H,NH).

Reference： [1]Patent: WO2006/21418,2006,A1 .Location in patent: Page/Page column 162
[2]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 4660 - 4664

32
[ 858105-70-1 ]
[ 27532-96-3 ]
[ 912953-27-6 ]

Yield	Reaction Conditions	Operation in experiment
93%	With triethylamine; In 1,4-dioxane; at 100℃; for 6h;	b) 1 ,1-Dimethylethyl Lambda/-[4-nitro-4'-(trifluoromethyl)-3-biphenylyl]glycinateA mixture of 1 ,1-dimethylethyl glycinate hydrochloride (1.20 g, 7.16 mmol), 3- fluoro-4-nitro-4'-(trifluoromethyl)biphenyl (1.00 g, 3.51 mmol), triethylamine (1.00 mL, 7.17 mmol) and dioxane (10 mL) was stirred at 100 0C under argon for 6 h, then cooled and partitioned between water and ethyl acetate. The extracts were washed with water and brine, dried (MgSO4), then the solvent removed under reduced pressure and the residue chromatographed (silica gel, 5-30% ethyl acetate/ hexane) to give the title compound (1.29 g, 93%) as a solid. 1 H NMR (400MHz, D6-DMSO) delta 8.46 (br t, J = 5.3 Hz, 1 H), 8.22 (d, J = 8.9 Hz, 1 H), 8.00 (d, J = 8.2 Hz, 2H), 7.88 (d, J = 8.3 Hz, 2H), 7.19 (d, J = 1.8 Hz, 1 H), 7.11 (dd, J = 8.9, 1.8 Hz, 1 H), 4.34 (d, J = 5.4 Hz, 2H), 1.46 (s, 9H).

Reference： [1]Patent: WO2006/113432,2006,A2 .Location in patent: Page/Page column 45

33
ethyl (4R)-6-(bromomethyl)-4-(4-cyanophenyl)-2-oxo-1-[3-(trifluoromethyl)-phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate [ No CAS ]
[ 27532-96-3 ]
[ 1150267-52-9 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium carbonate; In acetonitrile; at 160℃; for 0.333333h;Microwave irradiation;	Intermediate 17A mixture of Intermediate 5 (1.00 g, 1.97 mmol), glycine terf-butyl ester hydrochloride (330 mg, 1.97 mmol) and potassium carbonate (410 mg, 2.95 mmol) in acetonitrile (20 ml) was heated at 160C for 20 min in the microwave. The mixture was filtered and evaporated. The residue was taken up into EtOAc 20 (150 ml) and the solution was washed with 10% aqueous citric acid (100 ml) and water (50 mi), dried (Na2SO4) and evaporated to give the pure product. Yield: quantitative LC-MS (Method 2): Rt = 3.59/3.76 min, m/z = 457 [M+H-tBu]+
49%	With triethylamine; In tetrahydrofuran; at 60℃; for 17h;	Intermediate 5 (6.00 g, 11.81 mmol), <strong>[27532-96-3]glycine tert-butyl ester hydrochloride</strong> (2.37 g, 14.17 mmol) and triethylamine (6.5 ml) in THF (100 ml) were heated at 600C for 17 h. After cooling, the mixture was filtered and the filtrate evaporated. The crude mixture was separated using a CombiFlash companion (80 g cartridge) eluting with 50-100% EtOAc in pentane. The desired product was obtained as an orange glass. Yield: 2.99 g (49%) LC-MS (Method 2): Rt = 3.62 min, m/z = 513 [M+H]+

Reference： [1]Patent: WO2009/60158,2009,A1 .Location in patent: Page/Page column 19
[2]Patent: WO2009/60206,2009,A1 .Location in patent: Page/Page column 54

34
[ 1148547-19-6 ]
[ 27532-96-3 ]
[ 1148547-20-9 ]

Yield	Reaction Conditions	Operation in experiment
86%		A mixture of 6-(2-chlorophenyl)-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4- dihydropyrazine-2-carboxylic acid (0.409 g, 1 mmol) and 1,1-carbonyl diimidazole (0.243 g, 1.5 mmol) in DMF (5 ml) was stirred at RT for 50 min. To this solution was added tert- <n="44"/>butyl glycinate hydrochloride (0.335 g, 2 mmol) followed by Et3N (0.416 ml, 3 mmol) and after 2h at RT the reaction mixture was partitioned between ethyl acetate (300 ml) and water (50 ml). The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel flash chromatography (0-2% methanol in DCM) to give tert-butyl lambda/-({6-(2-chlorophenyl)-5-methyl-3-oxo-4-[3- (trifluoromethyl)phenyl]-3,4-dihydropyrazin-2-yl}carbonyl)glycinate (0.45 g, 86%).1H NMR (400 MHz, DMSOd6) delta 9.44 (t, J= 5.1 Hz, IH); 8.05 (m, IH); 7.96 (d, J= 7.2Hz, IH); 7.91-7.82 (m, 2H); 7.66-7.62 (m, IH); 7.53-7.49 (m, 3H); 3.97 (d, J= 5.8 Hz, 2H); 1.83 (s, 3H); 1.42 (s, 9H). APCI-MS m/z: 522.0 [MH+].

Reference： [1]Patent: WO2009/58076,2009,A1 .Location in patent: Page/Page column 41-43

35
[ 27532-96-3 ]
[ 113749-54-5 ]
[ 1167995-18-7 ]

Yield	Reaction Conditions	Operation in experiment
85%		To the compound (4 g, 15.55 iranol) of Example 1 were added CH2Cl2 (60 ml) and H-GIy-OtBu-HCl (2.61 g, 15.55 mmol) , and the mixture was cooled to 0C. To the mixture were added EDC*HCl <n="58"/>(3.28 g, 17.11 ?nnol) , HOBt (2.52 g, 18.66 irimol) and NEt3 (3.30 g, 32.66 mmol) , and the mixture was allowed to warm to room temperature and stirred for 13 hr. Tap water was added to the reaction solution and the mixture was extracted with chloroform. The organic layer was washed twice with tap water and once with saturated brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (chloroform-kappa:hloroform:methanol=200:l-»100:l-»50:l->30:l) to give the title compound, yield 4.90 g, 85%, yellow solid, melting point 94-950C.1H NMR (200 MHz, CDCl3): delta = 1.45 (s, 9 H), 3.36 (s, 2 H), 3.90 (s, 4 H), 3.98(d, 2 H, J = 5.7 Hz), 7.16 (ddd, 2 H, J = 1.1, 4.8, 7.5 Hz), 7.37 (dm, 2 H, J =7.9 Hz), 7.63 (ddd, 2 H, J = 1.8, 7.5, 7.6 Hz), 8.55 (ddd, 2 H, J = 0.9, 1.8, 4.8 Hz), 8.89 (t, 1 H, J = 5.6 Hz) .

Reference： [1]Patent: WO2009/84737,2009,A1 .Location in patent: Page/Page column 56-57

36
[ 27532-96-3 ]
[ 19771-63-2 ]
tetrahydrothiazolo[3,4-a]pyrazine-3,5,8-trione [ No CAS ]

Reference： [1]Patent: US2005/129635,2005,A1 .Location in patent: Page/Page column 14

37
[ 952059-69-7 ]
[ 27532-96-3 ]
[ 1151802-40-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 6307 - 6312

38
[ 764-67-0 ]
[ 27532-96-3 ]
[ 1101135-91-4 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 0 - 20℃;	General procedure: To a stirred solution of 2-hydroxyhexadecanoic acid (1.0 mmol) and hydrochloride amino component (1.0 mmol) in CH2Cl2 (10 mL), Et3N (0.3 mL, 2.2 mmol) and subsequently 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (WSCI) (0.21 g, 1.1 mmol) and 1-hydroxybenzotriazole (HOBt) (0.14 g, 1.0 mmol) were added at 0 C. The reaction mixture was stirred for 1 h at 0 C and overnight at room temperature. The solvent was evaporated under reduced pressure and EtOAc (20 mL) was added. The organic layer was washed consecutively with brine, 1 N HCl, brine, 5% NaHCO3, and brine, dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by column chromatography using CH2Cl2/MeOH 99:1 as eluent.

Reference： [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 735 - 743

39
[ 764-67-0 ]
[ 27532-96-3 ]
tert-butyl 2-(2-oxohexadecanamido)acetate [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 735 - 743

40
[ 55854-46-1 ]
[ 27532-96-3 ]
[ 1312952-19-4 ]

Yield	Reaction Conditions	Operation in experiment
80%	With triethylamine; In 1,4-dioxane; water; at 20℃;	5-bromothiophene-2-sulfonyl chloride 8 (500 mg, 2.21 mmol) was added to a solution of glycine tert-butyl ester hydrochloride (372 mg, 2.21 mmol) in H2O (2.20 mL) and dioxane (2.20 mL) containing Et3N (0.61 mL, 4.42 mmol). The reaction was stirred overnight at room temperature, then dioxane was evaporated and the residue was taken up with EtOAc and washed (3×) with water and brine. Organic layers were then collected, dried over Na2SO4, and evaporated in vacuo. The crude was purified by flash chromatography using an Isolute Si (II) cartridge (n-hexane/EtOAc 8:1) and a yellow solid was obtained (568 mg, 1.77 mmol, 80% yield). 1H NMR (CDCl3) delta: 1.43 (s, 9H); 3.78 (d, J = 5.3 Hz, 2H); 5.14 (t, J = 5.3 Hz, 1H); 7.08-7.10 (m, 1H); 7.38-7.40 (m, 1H).

Reference： [1]European Journal of Medicinal Chemistry,2011,vol. 46,p. 2617 - 2629

41
[ 35661-40-6 ]
[ 27532-96-3 ]
Fmoc-L-Phe-Gly-OtBu [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0℃; for 4h;	[COMPARATIVE EXAMPLE 6] (Synthesis Process F): Preparation of [6Psi7,CSNH]MS10 (Compound No. 166) Tyr-Asn-Trp-Asn-Ser-PhePsi(CSNH)Gly-Leu-Arg-Phe-NH2 In 10 mL of DMF, 503 mg of HCl H-Gly-OBu was dissolved and 1162 mg of Fmoc-Phe, 608 mg of HOBt, 1874 mg of PyBOP and 784 muL of DIEA were added at 0C, followed by stirring for 4 hours. The solvent was concentrated and the concentrate was dissolved in AcOEt. The solution was then washed with 1N HCl aq. solution, satd. NaHCO aq. solution and then satd. NaCl aq. solution. After drying over NaSO, the solvent was concentrated and diethyl ether-petroleum ether was added to give 1.48 g (yield 99%) of Fmoc-PheGly-OBu as the precipitate. After 250 mg of the product was dissolved in 10 mL of toluene, 404 mg of Lawesson's reagent was added to the solution, followed by stirring at 80C for 2 hours. The solvent was concentrated and the concentrate was dissolved in AcOEt. The solution was then washed with 1N HCl aq. solution, satd. NaHCO aq. solution and then satd. NaCl aq. solution. After drying over NaSO, the solvent was concentrated and the concentrate was purified by flush column chromatography. Diethyl ether-petroleum ether was added to the eluate to give 207 mg (yield 80%) of Fmoc-PhePsi(CSNH)Gly-OBu as the precipitate. To 103 mg of the product, TFA/HO (95/5) was added and the mixture was stirred for an hour. After the solvent was concentrated, diethyl ether was added to give 82.4 mg (yield 90%) of Fmoc-PhePsi(CSNH)Gly-OH as the precipitate. Using Fmoc-Phe-PAL resin, which was prepared by introducing Fmoc-Phe into commercially available PAL resin, the peptide chain was extended on ABI 433A and 80 mg of Fmoc-LeuArg(Pbf)Phe-PAL resin thus extended was subjected to Fmoc deprotection. Then 35 mg of Fmoc-PhePsi(CSNH)Gly-OH, 47 mg of PyBrop, 14 mg of HOAt and 35 muL of DIEA were added to the resin, followed by shaking for 15 hours. After the resin washed, the peptide chain was extended on ABI 433A to give Boc-Tyr(Bu)Asn(Trt)Trp(Boc)Asn(Trt)Ser(Bu)PhePsi(CSNH)GlyLeuArg(Pbf)Phe-PA L resin. To 15 mg of the product, 200 muL of TFA/PhSMe/m-cresol/TIS/EDT (85/5/5/2.5/2.5) was added, followed by stirring for 2 hours. Diethyl ether was added to the reaction solution, the resulting precipitate was centrifuged and the supernatant was removed. This procedure was repeated for washing. The residue was extracted with an aqueous acetic acid solution and the extract was filtered to remove the resin. Then, linear density gradient elution (60 minutes) was performed with eluants A/B: 77/23-57/43 using: 0.1% TFA in water and eluant B: 0.1% TFA-containing acetonitrile on preparative HPLC using YMC D-ODS-5-ST S-5 120A column (20 x 150 mm). The fractions containing the product were collected and lyophilized to give 1.0 mg of white powders. Mass spectrum (M+H)+ 1318.7 (Calcd. 1318.6) Elution time on HPLC: 20.8 min Elution conditions: Column: Wakosil-II 5C18 HG (4.6 x 100 mm) Eluant: linear density gradient elution with eluants A/B = 100/0-30/70, using 0.1% TFA in water as eluant A and acetonitrile containing 0.1% TFA (35 mins.) Flow rate: 1.0 ml/min.

Reference： [1]Patent: EP2113513,2016,B1 .Location in patent: Paragraph 0244
[2]Journal of Organic Chemistry,2011,vol. 76,p. 6518 - 6524
[3]Chemistry - A European Journal,2014,vol. 20,p. 3077 - 3083

42
[ 27532-96-3 ]
[ 112-67-4 ]
[ 1206591-90-3 ]

Yield	Reaction Conditions	Operation in experiment
94%	With triethylamine; In chloroform; at 20℃; for 15.1667h;Cooling with ice;	Gly-tBu.HCl (8.82 g, 52.6 mmol) and palmitoyl chloride (15.2 ml, 50.1 mmol) were dissolved in 200 ml of chloroform and, to the resultant while cooled with ice with stirring, triethylamine (14.6 ml, 105 mmol) was added dropwise over 10 minutes. Subsequently, the resultant was left to gradually reach room temperature and was stirred for 15 hours. Water was added thereto for separation, and then an organic phase was washed with a saturated saline solution and dried over magnesium sulfate. After concentrated under reduced pressure, the residue was washed with hexane and was filtered to obtain 17.4 g (94%) of a desired compound as a colorless solid. 1H-NMR (300 MHz DMSO-d6 deltappm): 8.09 (1H, t, J=6.3 Hz), 3.67 (2H, d, J=6.3 Hz), 2.09 (2H, t, J=7.8 Hz), 1.48 (21-1, m), 1.39 (9H, s), 1.23 (24H, brs), 0.85 (3H, t, J=6.9 Hz). MS (EI) m/z: 314.3 (M+-Boc+H)
94%	With triethylamine; In chloroform; at 20℃; for 15.167h;Cooling with ice;	<Synthesis of N-Palmitoyl-Gly-OtBu> (0223) Gly-tBu?HCl (8.82 g, 52.6 mmol) and palmitoyl chloride (15.2 ml, 50.1 mmol) were dissolved in 200 ml of chloroform. Triethylamine (14.6 ml, 105 mmol) was added dropwise to the solution with stirring while cooling with ice over 10 minutes, and then the reaction solution was allowed to gradually reach room temperature and stirred for 15 hours. Water was added, and then the water was separated. Then, the organic phase was washed with a saturated saline solution and dried over magnesium sulfate. After concentration under reduced pressure, the residue was washed with hexane and filtered to give 17.4 g (94%) of a target compound as a colorless solid. (0224) 1H-NMR (300 MHz, DMSO-d6, delta ppm): 8.09 (1H, t, J=6.3 Hz), 3.67 (2H, d, J=6.3 Hz), 2.09 (2H, t, J=7.8 Hz), 1.48 (2H, m), 1.39 (9H, s), 1.23 (24H, brs), 0.85 (3H, t, J=6.9 Hz). (0225) MS (EI) m/z: 314.3 (M+-Boc-1, bp).

Reference： [1]Patent: US2012/35108,2012,A1 .Location in patent: Page/Page column 8
[2]Patent: US9265833,2016,B2 .Location in patent: Page/Page column 23

43
[ 364-74-9 ]
[ 27532-96-3 ]
[ 877628-72-3 ]

Yield	Reaction Conditions	Operation in experiment
77%	With sodium hydrogencarbonate; In dimethyl sulfoxide; at 80℃;Inert atmosphere;	A suspension of <strong>[364-74-9]2,5-difluoronitrobenzene</strong> (1.8 g, 11.3 mmol), tert-butyl glycinate hydrochloride (1.99 g, 11.9 mmol, 1.05 eq.) and NaHCO3 (1.45 g, 22.6 mmol, 2 eq.) in DMSO (20 mL) is stirred overnight at 80C. After cooling, water (250 mL) is added and the precipitated orange solid is filtered over a Buechner funnel. It is rinsed thoroughly with water and dried under high-vacuum to afford 2.36 g (8.73 mmol, 77%) of the title compound as an orange solid.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 4660 - 4664

44
[ 117-78-2 ]
[ 27532-96-3 ]
[ 1385833-76-0 ]

Reference： [1]Chemical Communications,2012,vol. 48,p. 7595 - 7597
[2]Chemical Communications,2013,vol. 49,p. 1169 - 1171

45
[ 1402796-38-6 ]
[ 27532-96-3 ]
[ 1402798-65-5 ]

Yield	Reaction Conditions	Operation in experiment
87%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 1h;	Compound 37 (0.1 g, 0.17 mmol) was dissolved in methylene chloride (3 mL). tert- Butyl 2-aminoacetate HCl (37 mg, 0.22 mmol), diisopropylethylamine (0.09 mL, 0.51 mmol) and hydroxybenzotriazole (46 mg, 0.34 mmol) were added dropwise to the obtained solution, and stirred at room temperature 10 minutes. l-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (66 mg, 0.34 mmol) was added dropwise to the reaction mixture, and then stirred at room temperature for 1 hour. After the completion of the reaction, the reaction mixture was diluted with methylene chloride, and washed with water and brine. The organic layers were collected, dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by MPLC (Si02, 20%-30% Hexane/ EtOAc), thus obtaining Compound 342 (0.1 g, 87%) as white solid.1H NMR (400 MHz, CDC13); atropisomer mixture; delta 7.82 (d, 1 H, J= 4.7 Hz), 7.73 - 7.70 (m, 2.5 H), 7.65 (dd, 0.5 H, J= 8.6, 2.3 Hz), 7.53, 7.47 (2d, 1 H, J= 2.4 Hz), 6.86 (t, 1 H, J= 8.6 Hz), 6.67 - 6.60 (m, 1 H), 5.56 (dd, 1 H, J= 16.3, 8.1 Hz), 4.12 - 4.03 (m, 2 H), 3.99 - 3.92 (m, 2 H), 3.80, 3.77 (2s, 3 H), 3.47, 3.32 (2d, 1 H, J= 14.8 Hz), 2.45 - 2.00 (m, 2 H), 1.90 (brs, 2 H), 1.48 - 1.44 (m, 11 H), 1.00 (dd, 6 H, J= 11.0, 2.3 Hz), 0.41, 0.34 (2d, 3 H, J= 6.5 Hz); MS (ESI) m/z 699.1 (M++H).
		tert-butyl 2-(3-(2-(((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidin-3-yl)methyl)-4,4-dimethylcyclohex-1-enyl)-4-methoxybenzamido)acetate Compound 37 (0.1 g, 0.17 mmol) was dissolved in methylene chloride (3 mL). tert-Butyl2-aminoacetate?HCl (37 mg, 0.22 mmol), diisopropylethylamine (0.09 mL, 0.51 mmol) and hydroxybenzotriazole (46 mg, 0.34 mmol) were added dropwise to the obtained solution, and stirred at room temperature 10 minutes. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (66 mg, 0.34 mmol) was added dropwise to the reaction mixture, and then stirred at room temperature for 1 hour. After the completion of the reaction, the reaction mixture was diluted with methylene chloride, and washed with water and brine. The organic layers were collected, dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by MPLC (SiO2, 20%-30% Hexane/EtOAc), thus obtaining Compound 342 (0.1 g, 87%) as white solid. 1H NMR (400 MHz, CDCl3); atropisomer mixture; delta7.82 (d, 1H, J=4.7 Hz), 7.73-7.70 (m, 2.5H), 7.65 (dd, 0.5H, J=8.6, 2.3 Hz), 7.53, 7.47 (2d, 1H, J=2.4 Hz), 6.86 (t, 1H, J=8.6 Hz), 6.67-6.60 (m, 1H), 5.56 (dd, 1H, J=16.3, 8.1 Hz), 4.12-4.03 (m, 2H), 3.99-3.92 (m, 2H), 3.80, 3.77 (2s, 3H), 3.47, 3.32 (2d, 1H, J=14.8 Hz), 2.45-2.00 (m, 2H), 1.90 (brs, 2H), 1.48-1.44 (m, 11H), 1.00 (dd, 6H, J=11.0, 2.3 Hz), 0.41, 0.34 (2d, 3H, J=6.5 Hz); MS (ESI) m/z 699.1 (M++H).

Reference： [1]Patent: WO2012/141487,2012,A2 .Location in patent: Page/Page column 137
[2]Patent: US2014/31335,2014,A1 .Location in patent: Paragraph 0547; 0548

46
[ 1460302-12-8 ]
[ 27532-96-3 ]
[ 1460302-25-3 ]

Yield	Reaction Conditions	Operation in experiment
78%	With 1-hydroxy-7-aza-benzotriazole; N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 4℃; for 3h;	.2: Amide coupling of a macrocyclic carboxylic acid with an amine and HATU A soln of a macrocyxclic carboxylic acid (0.12 mmol), an amine (1 .2 equiv.), HATU (1 .5 equiv.) and HOAt (1 .5 equiv.) in DMF (0.5 mL) was treated at 4C with i-Pr2NEt (3.0 equiv.). The mixture was stirred at 4C for 2 h. The mixture was distributed between CH2CI2 and 1 M aq. HCI soln. The organic phase was washed (sat. aq. NaCI soln), dried (Na2S04), filtered and concentrated. Purification of the crude product by chromatography (FC, normal phase or reversed phase prep. HPLC) afforded a macrocyclic amide.
78%	With 1-hydroxy-7-aza-benzotriazole; N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; at 4℃; for 3h;	General procedure: A soln of a macrocyxclic carboxylic acid (0.12 mmol), an amine (1.2 equiv.), HATU (1.5 equiv.) and HOAt (1.5 equiv.) in DMF (0.5 mE) was treated at 4 C. with i-Pr2NEt (3.0 equiv.). The mixture was stirred at 4 C. for 2 h. The mixture was distributed between CH2C12 and 1 M aq. HC1 soln. The organic phase was washed (sat. aq. NaC1 soln), dried (Na2504), filtered and concentrated. Purification of the crude product by chromatography (FC, normal phase or reversed phase prep. HPEC) afforded a macrocyclic amide. tert-butyl 2-([(9S,14S)-9,15-dimethyl-1 1 ,16-dioxo-7-oxa-10,15-diazatricyclo[15.3.1. 12?6]docosa-1 (21),2(22),3,5,17,19-hexaen-14-yl]carbonyl}amino)acetate

Reference： [1]Patent: WO2013/139697,2013,A1 .Location in patent: Page/Page column 182; 215
[2]Patent: US2015/51183,2015,A1 .Location in patent: Paragraph 0824; 0825; 0848

47
[ 6940-50-7 ]
[ 27532-96-3 ]
[ 1534328-69-2 ]

Reference： [1]Journal of the American Chemical Society,2014,vol. 136,p. 874 - 877
[2]Angewandte Chemie - International Edition,2019,vol. 58,p. 9948 - 9953
Angew. Chem.,2019,vol. 131,p. 10053 - 10058,6

48
[ 3518-65-8 ]
[ 27532-96-3 ]
[ 1569296-85-0 ]

Yield	Reaction Conditions	Operation in experiment
73%	With triethylamine; In dichloromethane; at 0 - 18℃; for 16h;	tert-Butyl [(chloromethyl)sulfonyl]amino}acetate (14). A solution of glycine teut-butyl esterhydrochloride (600 mg, 3.58 mmol) and triethylamine (1.0 mL, 7.16 mmol) in anhydrous DCM (20 mL) was cooled to 0 C and then a solution of chloromethylsulfonyl chloride (0.33 mL, 3.58 mmol) in DCM (10 mL) was added dropwise at 0 C. The reaction mixture was warmed to 18 C and stirred for 16 h. It was diluted with DCM (150 mL), washed with H20 (3 X 50 mL), washed with brine (50 mL),dried and the solvent was evaporated to give ester 14 (641 mg, 73%) as a tan oil which was used without further purification: 1H NMR 6 8.15 (t,J 6.1 Hz, 1 H, NH), 4.89 (s, 2 H, CH2C1), 3.74 (d,J6.1 Hz, 2 H, CH2NH), 1.42 [s, 9 H, C(CH3)3]; 13C NMR 6 168.7, 81.2, 55.8, 44.5, 27.6 (3); MS m/ Qviltb, 100%).

Reference： [1]Patent: WO2014/30142,2014,A2 .Location in patent: Page/Page column 33
[2]Journal of Medicinal Chemistry,2018,vol. 61,p. 1241 - 1254

49
[ 56962-11-9 ]
[ 27532-96-3 ]
[ 1427753-47-6 ]

Yield	Reaction Conditions	Operation in experiment
613 mg		Preparation Example 73 To a solution of <strong>[56962-11-9]2-chloro-4-hydroxybenzaldehyde</strong> (400 mg) in dichloromethane (4.00 mL) were added anhydrous magnesium sulfate (615 mg) and tert-butyl glycinate hydrochloride (679 mg), followed by stirring at room temperature overnight. The reaction mixture was filtered, and then the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (12.0 mL), and sodium borohydride (193 mg) was added thereto, followed by stirring at room temperature for 2 hours. To the reaction mixture were added water and ethyl acetate, and the organic layer was extracted. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain tert-butyl N-(2-chloro-4-hydroxybenzyl)glycinate (613 mg).

Reference： [1]Patent: EP2757093,2014,A1 .Location in patent: Paragraph 0206

50
[ 5070-13-3 ]
[ 27532-96-3 ]
[N-(tert-butyl-glycyl)-carbamoyl]-p-nitrophenol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With dmap; In tetrahydrofuran; dichloromethane; at 20℃; for 3h;	Example 7 Synthesis of 3,4',5-tri-[N-(glycyl)-carbamoyl]-resveratrol: [N-(tert-butyl-glycyl)-carbamoyl]-p-nitrophenol (23; tBuOGly-PNPC): A solution of <strong>[27532-96-3]glycine tert-butyl ester hydrochloride</strong> (1.0 g, 4.0 mmol, 1 eq.) and DMAP (0.7 g, 4.0 mmol, 1 eq.) in CH2Cl2 (10 mL) was added dropwise to a solution of bis (4-nitrophenyl) carbonate (1.8 g, 4.0 mmol, 1 eq.) and DMAP (0.7 g, 4.0 mmol, 1 eq.) in THF (20 mL), and the mixture was stirred at room temperature for 3 hours. The resulting mixture was diluted in CH2Cl2 (150 mL) and washed with 0.5 N HCl (3 * 100 mL). The organic layer was dried over MgSO4 and filtered. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography using chloroform:acetone:hexane 3:1:6 as eluent to afford 1.26 g of 23 (72 % yield). 1H-NMR (250 MHz, CDCl3) delta (ppm): 1.49 (s, 9H, 3 * -C-CH3), 3.95 (d, 2H, -CH2-, 3JH-H = 5.25 Hz), 5.71 (t, 1 H, -NH-, 3JH-H = 5.25 Hz), 7.31 (d, 2H, 2 * Ar-H, 3JH-H = 9.25 Hz), 8.23 (d, 2H, 2 * Ar-H, 3JH-H = 9.25 Hz); 13C-NMR (250 MHz, CDCl3) delta (ppm): 168.4, 155.7, 153.0, 144.8, 125.1, 122.0, 82.8, 43.4, 28.0; ESI-MS (ion trap): m/z 297 [M+H]+.

Reference： [1]Patent: EP2774915,2014,A1 .Location in patent: Paragraph 0078-0080
[2]Journal of Agricultural and Food Chemistry,2018,vol. 66,p. 8124 - 8131

51
[ 373-49-9 ]
[ 27532-96-3 ]
C₂₂H₄₁NO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
49%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃;	(9Z)-Hexadec-9-enoic acid (1 .5 g, 5.91 mmol) was dissolved in 1 :2 DMF/THF (total volumel O ml). To this solution, DMAP (0.87 g, 7.09 mmol), EDC (1 .36 g, 7.09 mmol), and Gly-O'Bu.HCI (1 .98 g, 1 1 .81 mmol) was added and the reaction was stirred at room temperature overnight. The reaction is represented in the following scheme: After completion of the reaction, the mixture was pumped dry and washed with Dl- H2O three times (5 ml/each). The final product was purified with column chromatography to provide 1060 mg of the desired product in 49% yield. The structure was characterized by 1 H NMR. 1 H NMR (500 MHz, CDCI3): delta 8.1 1 (t, J = 6.0 Hz, 1 H), 5.34-5.30 (m, 2H), 3.67 (d, J = 6.0 Hz, 2H), 2.09 (t, J = 7.4 Hz, 2H), 2.00-1 .96 (m, 4H), 1 .51 -1 .46 (m, 2H), 1 .39 (s, 9H), 1 .30-1 .24 (m, 16 H), 0.85 (t, J = 6.9 Hz, 3H).

Reference： [1]Patent: WO2014/143620,2014,A1 .Location in patent: Page/Page column 34; 35

52
[ 1552-94-9 ]
[ 27532-96-3 ]
C₁₇H₂₁NO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃;	5-Phenylpenta-2,4-dienoic acid (0.2 g, 1 .15 mmol) was dissolved in 1 :2 DMF/THF (total volume is 5 ml). To this solution, DMAP (0.25 g, 2.07 mmol), EDC (0.4 g, 2.07 mmol), and Gly-O'Bu.HCI (0.23 g, 1 .38 mmol) were added and the reaction was stirred at room temperature overnight. The reaction is represented in the following scheme: After completion of the reaction, the mixture was pumped dry and washed with Dl- H2O three times (5 ml/each). The final product was purified with column chromatography to provide 220 mg of the desired product in 67% yield. The structure was characterized by 1 H NMR. 1 H NMR (500 MHz, DMSO-D6): delta 8.42 (t, J = 6.0 Hz, 1 H), 7.56 (d, J = 7.4 Hz, 2H), 7.37 (t, J = 7.4 Hz, 2H), 7.30 (t, J = 7.4 Hz, 1 H), 7.25-7.20 (m, 1 H), 7.10-7.03 (m, 1 H), 6.96 (d, J = 15.6 Hz, 1 H), 6.22 (d, J = 15.0 Hz, 1 H), 3.82 (d, J = 6.0 Hz, 2H), 1 .41 (s, 9H).

Reference： [1]Patent: WO2014/143620,2014,A1 .Location in patent: Page/Page column 36; 37

53
[ 779-89-5 ]
[ 27532-96-3 ]
C₁₆H₁₈F₃NO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃;	3-(Trifluoromethyl)cinnamic acid (0.2 g, 0.93 mmol) was dissolved in 1 :2 DMF/THF (total volume 4 ml). To this solution, DMAP (0.17 g, 1 .4 mmol), EDC (0.27 g, 1 .4 mmol), and Gly-O'Bu.HCI (0.23 g, 1 .38 mmol) was added and the reaction was stirred at room temperature overnight. The reaction is represented by the following scheme: After completion of the reaction, the mixture was pumped dry and washed with Dl- H2O three times (5 ml/each). The final product was purified with column chromatography to provide 210 mg of the desired product in 69percent yield. The structure was characterized by 1 H NMR. 1 H NMR (500 MHz, DMSO-D6): delta 8.45 (t, J = 6.0 Hz, 1 H), 7.93 (s, 1 H), 7.89 (d, J = 7.8 Hz, 1 H), 7.72 (d, J = 7.8 Hz, 1 H), 7.65 (t, J = 7.8 Hz, 1 H), 7.54 (d, J = 15.9 Hz, 1 H), 6.87 (d, J = 15.9 Hz, 1 H), 3.87 (d, J = 6.0 Hz, 2H), 1 .41 (s, 9H). The resulting t- butyl ester (0.1 g) was dissolved in 1 :1 DCM/TFA solution (DCM/TFA (total volume 1 .5 ml). The mixture was stirred at room temperature for 2 h to obtain compound 16 for the next step of the synthesis.

Reference： [1]Patent: WO2014/143620,2014,A1 .Location in patent: Page/Page column 43; 44

54
(2E,11Z)-octadeca-2,11-dienoic acid [ No CAS ]
[ 27532-96-3 ]
C₂₄H₄₃NO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃;	Compound 5 (0.2 g, 1 .15 mmol) was dissolved in 1 :2 DMF/THF (total volume is 5 ml). To this solution, 4-N,N-dimethylaminopyridine (DMAP) (0.25g, 2.07 mmol), 1 - Ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (0.40 g, 2.07 mmol), and Gly-O'Bu.HCI (0.23 g, 1 .38 mmol) were added and the reaction was stirred at room temperature overnight. After completion of the reaction, the mixture was pumped dry and washed with DI-H2O three times (5 ml/each). The product was purified by column chromatography on a column of silica gel to afford 220 mg of the homogeneous product in 67% yield. The structure was characterized by 1H NMR: 1 H NMR (500 MHz, CDCI3): delta 6.85 (dt, J1 = 15.3 Hz, J2 = 7.0 Hz, 1 H), 5.92 (br, 1 H), 5.81 (d, J = 15.3 Hz, 1 H), 5.35-5.33 (m, 2H), 4.0 (d, J = 5.0 Hz, 2H), 2.19-2.14 (m, 2H), 2.02-1 .99 (m, 4H), 1 .47 (s, 9H), 1 .46-1 .40 (m, 2 H), 1 .33-1 .25 (m, 16H), 0.88 (t, J = 6.9 Hz, 3H).
67%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃;	Example 10 d) Synthesis of N-[(2E,1 1Z)-octadeca-2,1 1-dienoyl]glycine 18 Compound 17(0.2 g, 1.15 mmol) was dissolved in 1:2 DMFITHF (total volume is 5 ml). To this solution, 4-N,N-dimethylaminopyridine (DMAP) (0.25g, 2.07 mmol), 1 -Ethyl-3-(3?-dimethylaminopropyl)carbodiimidehydrochloride (EDC) (0.40 g, 2.07 mmol), and GlyOtBu.HCl (0.23 g, 1 .38 mmol) were added and the reaction was stirred at room temperature overnight. After completion of the reaction, the mixture was pumped dry and washed with DI-H20 three times (5 mI/each). The product was purified by column chromatography on silica gel to afford 220 mg of thehomogeneous product in 67% yield. The structure was characterized by1H NMR: 1H NMR (500 MHz, CDCI3): 6 6.85 (dt, J1 = 15.3 Hz, J2 = 7.0 Hz,1H), 5.92 (br, 1H), 5.81 (d, J= 15.3 Hz, 1H), 5.35-5.33 (m, 2H), 4.0 (d, J=5.0 Hz, 2H), 2.19-2.14 (m, 2H), 2.02-1.99 (m, 4H), 1.47 (5, 9H), 1.46-1.40(m, 2 H), 1.33-1.25 (m, 16H), 0.88 (t, J= 6.9 Hz, 3H).

Reference： [1]Patent: WO2014/143620,2014,A1 .Location in patent: Page/Page column 32; 33
[2]Patent: WO2015/130890,2015,A1 .Location in patent: Page/Page column 70

55
C₅H₄ClNO₄S₂ [ No CAS ]
[ 27532-96-3 ]
C₁₁H₁₆N₂O₆S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With triethylamine; In dichloromethane; at 20℃; for 1h;	[00288j Synthesis of compound 1.5. Into a 100-mL 3-necked round-bottom flask, were placed compound 1.4 (2.2 g, 9.10 mmol, 1.00 equiv), dichloromethane (30 mL), 2-[(2- aminoacetyl)oxy]-2-methylpropyl (1.5 g, 11.52 mmol, 1.27 equiv), and Et3N (1.84 g, 18.18 mmol, 2.00 equiv). Reaction was stirred for 1 hour at room temperature. The resulting mixture was concentrated under vacuum. The crude was purified using flash column chromatography to furnish 3 g (98%) of compound 1.5.

Reference： [1]Patent: WO2014/182950,2014,A1 .Location in patent: Paragraph 00284; 00288

56
[ 18711-13-2 ]
[ 27532-96-3 ]
tert-butyl2-amino-2-(4,7-dichloro-3-hydroxy-2-oxoindolin-3-yl)acetate 2,2,2-trifluoroacetate [ No CAS ]