[ CAS No. 1448189-30-7 ] {[proInfo.proName]}

Name: 1448189-30-7|(4-(4-Methylthiazol-5-yl)phenyl)methanamine|95%
Brand: Ambeed
SKU: A933581
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Quality Control of [ 1448189-30-7 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 1448189-30-7 ]

SDS Specification

Alternatived Products of [ 1448189-30-7 ]

Product Details of [ 1448189-30-7 ]

CAS No. :	1448189-30-7	MDL No. :	MFCD28965258
Formula :	C₁₁H₁₂N₂S	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	PCZXZPOWHWJXDZ-UHFFFAOYSA-N
M.W :	204.29	Pubchem ID :	89689879
Synonyms :

Calculated chemistry of [ 1448189-30-7 ] Expand+

Physicochemical Properties

Num. heavy atoms :	14
Num. arom. heavy atoms :	11
Fraction Csp3 :	0.18
Num. rotatable bonds :	2
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	60.19
TPSA :	67.15 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.22 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.15
Log Po/w (XLOGP3) :	1.87
Log Po/w (WLOGP) :	2.43
Log Po/w (MLOGP) :	1.25
Log Po/w (SILICOS-IT) :	3.74
Consensus Log Po/w :	2.29

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.73
Solubility :	0.377 mg/ml ; 0.00184 mol/l
Class :	Soluble
Log S (Ali) :	-2.9
Solubility :	0.256 mg/ml ; 0.00125 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-4.25
Solubility :	0.0115 mg/ml ; 0.0000562 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.39

Safety of [ 1448189-30-7 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P264-P271-P280-P302+P352-P304+P340-P305+P351+P338-P312-P332+P313-P337+P313-P362-P403+P233-P405-P501	UN#:	N/A
Hazard Statements:	H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 1448189-30-7 ]

* 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.

Upstream synthesis route of [ 1448189-30-7 ]
Downstream synthetic route of [ 1448189-30-7 ]

[ 1448189-30-7 ] Synthesis Path-Upstream 1~1

1
[ 1448189-30-7 ]
[ 1448189-80-7 ]

Reference： [1] Patent: US2017/8904, 2017, A1,
[2] Patent: US2017/281784, 2017, A1,
[3] Journal of Medicinal Chemistry, 2018, vol. 61, # 2, p. 583 - 598
[4] Patent: US2018/125821, 2018, A1,
[5] Patent: US2016/45607, 2016, A1,

[ 1448189-30-7 ] Synthesis Path-Downstream 1~109

1
[ 1448189-30-7 ]
[ 13726-69-7 ]
[ 1448191-54-5 ]

Yield	Reaction Conditions	Operation in experiment
98%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; for 15h;	(3.S,4R)-tert-bvfiy 4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyI) pyrrolidine- 1-carboxylate (25',4R)-l-(rt-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (366 mg, 1.58 mmol, 1 equiv.) was dissolved in 15 mL DMF and charged with EDC (380 mg, 2.0mmol 1.3 equiv,), and HOBt (310 mg, 2.0 mmol, 1.5 equiv) after 5 minutes of stirring (4-(4- methylthiazol-5-yl)phenyl)methanamine (325 mg, 1.58 mmol, 1 equiv) was added. Upon stirring for 15 h the reaction was diluted with 25 mL EtOAc, and washed with 25 mL brine (2X), followed by 25 mL Sat. NaHC03 (2X). The organic layer was concentrated down to yield 650 mg (98 % yield) of the product as a yellow oil 1H NMR (400 MHz, CDC13) delta 8.67 (s, 1H), 7.43 - 7.29 (m, 4H), 4.49 (d, J= 16.7 Hz, 4H), 3.51 (dd, J= 1 1.0, 4.7 Hz, 2H), 2.61 - 2.45 (m, 4H), 2.03 (d, J = 7.4 Hz, 2H), 1.42 (s, 9H).TLC: (9:1 DCM:MeOH (0.5 N NH3)) Ry=0.20; MS (ESI) 417.5 (M+H)+.
98%		(2S,4R)-tert-butyl 4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl) pyrrolidine-1-carboxylate (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (366 mg, 1.58 mmol, 1 equiv.) was dissolved in 15 mL DMF and charged with EDC (380 mg, 2.0 mmol 1.3 equiv,), and HOBt (310 mg, 2.0 mmol, 1.5 equiv) after 5 minutes of stirring (4-(4-methyl thiazol-5-yl)phenyl)methanamine (325 mg, 1.58 mmol, 1 equiv) was added. Upon stirring for 15 h the reaction was diluted with 25 mL EtOAc, and washed with 25 mL brine (2), followed by 25 mL Sat. NaHCO3 (2). The organic layer was concentrated down to yield 650 mg (98% yield) of the product as a yellow oil. 1H NMR (400 MHz, CDCl3) delta 8.67 (s, 1H), 7.43-7.29 (m, 4H), 4.49 (d, J=16.7 Hz, 4H), 3.51 (dd, J=11.0, 4.7 Hz, 2H), 2.61-2.45 (m, 4H), 2.03 (d, J=7.4 Hz, 2H), 1.42 (s, 9H). TLC: (9:1 DCM:MeOH (0.5 N NH3)) Rf=0.20; MS (ESI) 417.5 (M+H)+.
95%		To a solution of preparative compound (2) (340 mg, 1.66 mmol, 1 equiv.) in DMF was added Boc-Hyp- OH (383 mg, 1.66 mmol, 1 equiv.) and the solution was stirred at room temperature. DIPEA (4 equiv.) was added drop-wise, and the mixture was stirred for 5 min at room temperature. HATU (1.1 equiv.) was added, and the mixture was stirred at room temperature for another 30 min. Water was added, and the mixture was extracted with ethyl acetate (3 x). The combined organic phases were washed with brine (x2), dried over MgS04 ,and evaporated under reduced pressure to give the corresponding crude, which was purified by flash column chromatography purification to yield desired preparative compound (3) as a yellow solid (658 mg, 1.58 mmol, 95%) that matched the reported spectral data. MS (ESI): [M + 1] calculated 418.2; observed 418.2.

67%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 25℃; for 1h;	Combine HATU (5.3g, 14mmol), DIPEA (4.6ml, 28mmol) and(2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (2.15 g, 9.3 mmol) was added to a solution of compound 39 (1.9 g, 9.3 mmol) in DMF (15 ml) .After stirring at 25C for 1 hour, DMF was spin-dried under reduced pressure, and extracted with ethyl acetate and saturated aqueous NaHCO 3 solution.The organic layer was separated, washed with brine, and dried over Na 2 SO 4.The solvent was spin-dried under reduced pressure, and the residue was purified by silica gel column chromatography (MeOH:CH2Cl2=4:96) to obtain 40 as a white solid (2.6 g, 6.2 mmol, 67%):
56%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃;	[0404] Step 1: synthesis of tert-butyl (2S,4R)-4-hydroxy-2-({ [4-(4-methyl-l,3-thiazol-5- yl)phenyl]methyl}carbamoyl)pyrrolidine-l-carboxylate (J)[0405] To a stirred solution of (2S,4R)-l-[(tert-butoxy)carbonyl]-4-hydroxypyrrolidine-2-carboxylic acid (I, 2.7 g, 11.7 mmol) in N,N-dimethylformamide (20 mL) was added DIEA (2.52 g, 19.50 mmol), HATU (4.47 g, 11.76 mmol) and [4-(4-methyl-l,3-thiazol-5- yl)phenyl]methanamine (H, 2.0 g, 9.79 mmol) at rt. The resulting mixture was stirred at rt overnight, LC-MS indicated formation of the desired product. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (50 mL x 3). The organic layers were combined, washed with saturated aqueous solution of sodium chloride (50 mL), dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel chromatography (eluent: dichloromethane/methanol (v:v = 20: 1)) to give J (yield: 56%) as a yellow solid.
56%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃;	To a stirred solution of (2S,4R)-1-[(tert-butoxy)carbonyl]-4-hydroxypyrrolidine-2-carboxylic acid (2.7 g, 11.68 mmol) in N,N-dimethylformamide (20 mL) was added DIEA (2.52 g, 19.50 mmol), HATU (4.47 g, 11.76 mmol) and <strong>[1448189-30-7][4-(4-methyl-1,3-thiazol-5-yl)phenyl]methanamine</strong> (2 g, 9.79 mmol) at rt. The resulting mixture was stirred at rt overnight, at which time LC-MS indicated completion of reaction. The reaction mixture was diluted by 20 mL of water and extracted with ethyl acetate (50 mL*3). The organic layers were combined, washed with saturated aqueous solution of sodium chloride (50 mL), dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel chromatography (eluent: dichloromethane/methanol (v:v=20:1)) to give the titled compound (yield: 56%) as a yellow solid.
56%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃;	To a stirred solution of (2S,4R)-l-[(tert-butoxy)carbonyl]-4-hydroxypyrrolidine-2- carboxylic acid (2.7 g, 11.68 mmol) in N,N-dimethylformamide (20 mL) was added DIPEA (2.52 g, 19.50 mmol), HATU (4.47 g, 11.76 mmol) and [4-(4-methyl-l,3-thiazol-5- yl)phenyl]methanamine (2 g, 9.79 mmol) at rt. The resulting mixture was stirred at rt overnight, at which time LC-MS indicated completion of reaction. The reaction mixture was diluted with 20 mL of water and extracted with ethyl acetate (50 mL x 3). The organic layers were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel column chromatography (eluent: dichloromethane/methanol (v:v = 20:1)) to give the titled compound (yield: 56%) as a yellow solid.
56%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃;	To a stirred solution of (2S,4R)-1-[(tert-butoxy)carbonyl]-4-hydroxypyrrolidine-2-carboxylic acid (I, 2.7 g, 11.7 mmol) in N,N-dimethylformamide (20 mL) was added DIEA (2.52 g, 19.50 mmol), HATU (4.47 g, 11.76 mmol) and <strong>[1448189-30-7][4-(4-methyl-1,3-thiazol-5-yl)phenyl]methanamine</strong> (H, 2.0 g, 9.79 mmol) at rt. The resulting mixture was stirred at rt overnight, LC-MS indicated formation of the desired product. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (50 mL*3). The organic layers were combined, washed with saturated aqueous solution of sodium chloride (50 mL), dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel chromatography (eluent: dichloromethane/methanol (v:v=20:1)) to give J (yield: 56%) as a yellow solid.
56%	With N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate;	Step 3: Preparation of tert-butyl (2S,4R)-4-hydroxy-2-([[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]carbamoyl)pyrrolidine-1-carboxylate To a stirred solution of (2S,4R)-1-[(tert-butoxy)carbonyl]-4-hydroxypyrrolidine-2-carboxylic acid (2.7 g, 11.68 mmol) in N,N-dimethylformamide (20 mL) was added DIPEA (2.52 g, 19.50 mmol), HATU (4.47 g, 11.76 mmol) and <strong>[1448189-30-7][4-(4-methyl-1,3-thiazol-5-yl)phenyl]methanamine</strong> (2 g, 9.79 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight, at which time LC-MS indicated completion of reaction. The reaction mixture was diluted with 20 mL of water and extracted with ethyl acetate (50 mL*3). The organic layers were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel column chromatography (eluent: dichloromethane/methanol (v:v=20:1)) to give the titled compound (yield: 56%) as a yellow solid.
30%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 0 - 20℃; for 12h;	A solution of (2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-pyrrolidine-2-carboxylic acid (3.36 g, 14.5 mmol, CAS13726-69-7) in DMF (50 mL) was cooled to 0 C. Then, DIPEA (5.13 g, 39.7 mmol), [4-(4-methylthiazol-5-yl) phenyl]methanamine (2.70 g, 13.2 mmol) and HATU (6.03 g, 15.9 mmol) were added. Finally, the mixture was allowed to warm to rt and stirred for 12 hours. On completion, the reaction mixture was concentrated under reduced pressure to remove the DMF. The residue was diluted with water (50 mL) and extracted with DCM (3×60 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by reverse phase flash (0.1% NH3-H2O in water) column to give the title compound (1.70 g, 30% yield) as a yellowish solid. 1H NMR (400 MHz, MeOD-d4) delta 8.91 (s, 1H), 7.48-7.40 (m, 4H), 4.74-4.25 (m, 4H), 3.66-3.56 (m, 1H), 3.54-3.43 (m, 1H), 2.48 (s, 3H), 2.31-2.20 (m, 1H), 2.08-1.98 (m, 1H), 1.54-1.25 (m, 9H); LC-MS (ESI+) m/z 418.0 (M+H)+.
24%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 25℃;	Into a 50-mL round-bottom flask, was placed (2S,4R)-l-[(tert-butoxy)carbonyl]-4- hydroxypyrrolidine-2-carboxylic acid (2.7 g, 11.68 mmol, 1.20 equiv) in N,N- dimethylformamide (30 mL), DIEA (2.52 g, 19.50 mmol, 1.20 equiv), HATU (4.47 g, 11.76 mmol, 1.20 equiv), [4-(4-methyl-l,3-thiazol-5-yl)phenyl]methanamine (2 g, 9.79 mmol, 1.00 equiv). The resulting solution was stirred overnight at 25C. The reaction was then quenched by the addition of 20 mL of water and extracted with 3x20 mL of ethyl acetate. The organic layers combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1). This resulted in 1 g (24%) of tert-butyl (2S,4R)-4-hydroxy-2-([[4-(4-methyl-l,3-thiazol-5- yl)phenyl]methyl]carbamoyl)pyrrolidine-l-carboxylate as a yellow solid.
24%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 25℃;	Into a 50-mL round-bottom flask, was placed (2S,4R)-1-[(tert-butoxy)carbonyl]-4- hydroxypyrrolidine-2-carboxylic acid (2.7 g, 11.68 mmol, 1.20 equiv) in N,N- dimethylformamide (30 mL), DIEA (2.52 g, 19.50 mmol, 1.20 equiv), HATU (4.47 g, 11.76 mmol, 1.20 equiv), <strong>[1448189-30-7][4-(4-methyl-1,3-thiazol-5-yl)phenyl]methanamine</strong> (2 g, 9.79 mmol, 1.00 equiv). The resulting solution was stirred overnight at 25C. The reaction was then quenched by the addition of 20 mL of water and extracted with 3x20 mL of ethyl acetate. The organic layers combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1). This resulted in 1 g (24%) of tert-butyl (2S,4R)-4-hydroxy-2-([[4-(4-methyl-1,3-thiazol-5- yl)phenyl]methyl]carbamoyl)pyrrolidine-1-carboxylate as a yellow solid.

Reference： [1]Angewandte Chemie - International Edition,2012,vol. 51,p. 11463 - 11467
[2]Patent: WO2013/106646,2013,A2 .Location in patent: Page/Page column 119-120
[3]Patent: US2016/45607,2016,A1 .Location in patent: Paragraph 0270; 0271
[4]Journal of Medicinal Chemistry,2014,vol. 57,p. 8657 - 8663
[5]Patent: WO2016/146985,2016,A1 .Location in patent: Page/Page column 79
[6]Chemical Communications,2019,vol. 55,p. 1821 - 1824
[7]Patent: CN111233661,2020,A .Location in patent: Paragraph 0234-0235; 0251-0253
[8]Patent: WO2016/118666,2016,A1 .Location in patent: Paragraph 0399; 0404; 0405
[9]Patent: US2017/8904,2017,A1 .Location in patent: Paragraph 0376; 0379
[10]Patent: WO2017/30814,2017,A1 .Location in patent: Paragraph 00194; 00197
[11]Patent: US2017/281784,2017,A1 .Location in patent: Paragraph 0191; 0194
[12]Patent: US2018/125821,2018,A1
[13]Journal of Medicinal Chemistry,2018,vol. 61,p. 583 - 598
[14]Patent: US2019/192668,2019,A1 .Location in patent: Paragraph 2358; 2361
[15]Patent: WO2020/113233,2020,A1 .Location in patent: Paragraph 00962; 001409; 001414-001415
[16]Patent: WO2019/195609,2019,A2 .Location in patent: Paragraph 00591-00592
[17]Patent: WO2020/51564,2020,A1 .Location in patent: Paragraph 1089; 1090

2
[ 1448189-32-9 ]
[ 1448189-30-7 ]
[ 1448189-33-0 ]

Yield	Reaction Conditions	Operation in experiment
88%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 4 - 20℃; for 19h;	(2S,4R)-4-(tert-butoxy)-l-(2-(3-methylisoxazol-5-yl)acetyl)-N-(4-(4-methylthiazol-5- yl)benz l)pyrrolidine-2-carboxamide (2S,4R)-4-(tert-butoxy)-l-(2-(3-methylisoxazol-5-yl)acetyl)pyrrolidine-2-carboxylic acid (53.7 mg, 0.173 mmol, 1.3 eq), <strong>[1448189-30-7](4-(4-methylthiazol-5-yl)phenyl)methanamine</strong> (27.2 mg, 0.133 mmol, 1 eq), EDC (33.2 mg, 0.173 mmol, 1.3 eq), and HOBt (23.4 mg, 0.173 mmol, 1.3 eq) were dissolved in DMF (3.5 mL) at 4C. DIPEA (0.07 mL, 0.4 mmol, 3 eq) was added, and the solution was allowed to slowly warm to room tmeprature. After 19 hours, the mixture was poured into brine and extracted four times with EtOAc. The organic layer was dried with sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (1 to 5% MeOH/DCM) gave a colorless oil (58.1 mg, 0.117 mmol, 88%). *H NMR (400 MHz, CDC13) delta 8.67 (s, 1H), 7.42 - 7.27 (m, 5H), 6.06 (s, 1H), 4.69 (dd, J= 8.4, 2.6 Hz, 1H), 4.59 - 4.35 (m, 3H), 3.82 - 3.71 (m, 3H), 3.34 (dd, J= 9.9, 6.3 Hz, 1H), 2.59 - 2.46 (m, 4H), 2.25 (s, 3H), 1.91 (dd, J= 8.2, 4.4 Hz, 1H), 1.25 - 1.14 (m, 9H). 13C NMR (101 MHz, CDC13) delta 170.70, 167.35, 165.30, 160.24, 150.42, 148.59, 138.09, 131.74, 131.05, 129.66, 127.85, 104.19, 74.48, 70.02, 59.12, 54.20, 43.25, 35.59, 33.49, 28.38, 16.19, 11.57. MS (ESI) 497.4 (M+H).
88%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 4 - 20℃; for 19h;	(2S,4R)-4-(tert-butoxy)-1-(2-(3-methylisoxazol-5-yl)acetyl)pyrrolidine-2-carboxylic acid (53.7 mg, 0.173 mmol, 1.3 eq), <strong>[1448189-30-7](4-(4-methylthiazol-5-yl)phenyl)methanamine</strong> (27.2 mg, 0.133 mmol, 1 eq), EDC (33.2 mg, 0.173 mmol, 1.3 eq), and HOBt (23.4 mg, 0.173 mmol, 1.3 eq) were dissolved in DMF (3.5 mL) at 4 C. DIPEA (0.07 mL, 0.4 mmol, 3 eq) was added, and the solution was allowed to slowly warm to room temperature. After 19 hours, the mixture was poured into brine and extracted four times with EtOAc. The organic layer was dried with sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (1 to 5% MeOH/DCM) gave a colorless oil (58.1 mg, 0.117 mmol, 88%). 1H NMR (400 MHz, CDCl3) delta 8.67 (s, 1H), 7.42-7.27 (m, 5H), 6.06 (s, 1H), 4.69 (dd, J=8.4, 2.6 Hz, 1H), 4.59-4.35 (m, 3H), 3.82-3.71 (m, 3H), 3.34 (dd, J=9.9, 6.3 Hz, 1H), 2.59-2.46 (m, 4H), 2.25 (s, 3H), 1.91 (dd, J=8.2, 4.4 Hz, 1H), 1.25-1.14 (m, 9H). 13C NMR (101 MHz, CDCl3) delta 170.70, 167.35, 165.30, 160.24, 150.42, 148.59, 138.09, 131.74, 131.05, 129.66, 127.85, 104.19, 74.48, 70.02, 59.12, 54.20, 43.25, 35.59, 33.49, 28.38, 16.19, 11.57. MS (ESI) 497.4 (M+H).
88%	With benzotriazol-1-ol; 1,2-dichloro-ethane; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 4 - 20℃; for 19h;	(2S,4R)-4-(tert-hutoxy)- 1 .(2(3.methylisoxazol..5 .yl)acetyi)pyrroiidine.2. carboxylic acid (53.7 ng, 0.173 mmoi, 1.3 eq), (4-(4-methyithiazol-5-yl)phenyi)methanamine (27.2 mg, 0.133 mrnoi, I eq), EDC (33.2 mg. 0.173 rnmol, 1 .3 eq), and HOBt (23.4 rug, 0.173 mmol, 1.3 eq) were dissolved in DMF (3.5 mL) at 4C. DIPEA (0.07 mL, 0.4 mmol, 3 eq) was added, and the solution was allowed to slowly warm to room tmeprature. After 19 hours, the mixture was poured into brine and extracted four times with EtOAc. The organic layer was dried with sodium sulfate, filtered and concentrated under reduced pressul?e. Purification by column chromatography (1 o 5% MeOH/DCM) gave a colorless oil (58.1 rug, 0.117 mrnol, 88%). ?H NMR (400 MHz, CDCI3) oe 8,67 (s, IH), 7.42 7,27 (in, SF1), 6.06 (s, lI-I), 4.69 (dd, J = 8.4, 2.6 Hz, IF1), 4.59 4.35 (in, 3H), 3.82 3.71 (m, 3H), 3.34 (dd, J = 9,9, 6.3 I-Iz, 111), 2.59 -2.46 (m. 4H), 2.25 (s, 3H), 1.91 (dd, .1= 8.2, 4.4 Hz, IH), 1.25 - 1.14 (m, 9H). ?3C NMR (101 MHz, CDC13) oe 170.70, 167.35, 165.30, 160.24, 150.42. 148.59, 138.09, 131.74, 131.05, 129.66, 127.85, 104.19, 74.48, 70.02. 59.12, 54.20, 43.25, 35.59. 33.49, 28.38, 16.19,11.57. MS (ES1) 497.4 (M+H).

Reference： [1]Angewandte Chemie - International Edition,2012,vol. 51,p. 11463 - 11467
[2]Patent: WO2013/106646,2013,A2 .Location in patent: Page/Page column 91-92
[3]Patent: US2014/356322,2014,A1 .Location in patent: Paragraph 0270
[4]Patent: WO2016/149668,2016,A1 .Location in patent: Paragraph 00545; 00548; 00549

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[ 1448189-28-3 ]
[ 1448189-30-7 ]

Reference： [1]Angewandte Chemie - International Edition,2012,vol. 51,p. 11463 - 11467
[2]Patent: WO2013/106646,2013,A2
[3]Patent: US2014/356322,2014,A1
[4]Patent: US2016/45607,2016,A1

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[ 1448189-30-7 ]

Yield	Reaction Conditions	Operation in experiment
89%	With tetrabutyl ammonium fluoride; In tetrahydrofuran; acetonitrile; at 20℃; for 24h;	(4-(4-methylthiazol-5-yl)phenyl)methanamine 2-(trimethylsilyl)ethyl 4-(4-methylthiazol-5-yl)benzylcarbamate (51.8 mg, 0.149 mmol, 1 eq) was dissolvd in acetonittile (6 mL) at room temperature. A one molar solution of tetrabutylammonium fluoride in THF (0.45 mL, 0.45 mmol, 3 eq) was added and the solution was stirred for 24 hours. The mixture was concentrated under reduced pressure. Purification by column chromatography (0.5 to 4% 0.5N N (MeOH)/DCM) gave a light yellow oil (27.2 mg, 0.133 mmol, 89%). NMR (500 MHz, MeOD) delta 8.87 (s, 1H), 7.44 (s, 4H), 3.85 (s, 2H), 2.47 (s, 3H). I3C NMR (126 MHz, MeOD) delta 152.77, 149.07, 143.63, 133.42, 131.46, 130.49, 129.05, 46.23, 15.79. MS (ESI) 205.0 (M+H).
89%	With tetrabutyl ammonium fluoride; In tetrahydrofuran; acetonitrile; at 20℃; for 24h;	2-(trimethylsilyl)ethyl 4-(4-methylthiazol-5-yl)benzylcarbamate (51.8 mg, 0.149 mmol, 1 eq) was dissolved in acetonitrile (6 mL) at room temperature. A one molar solution of tetrabutylammonium fluoride in THF (0.45 mL, 0.45 mmol, 3 eq) was added and the solution was stirred for 24 hours. The mixture was concentrated under reduced pressure. Purification by column chromatography (0.5 to 4% 0.5N NH3 (MeOH)/DCM) gave a light yellow oil (27.2 mg, 0.133 mmol, 89%). 1H NMR (500 MHz, MeOD) delta 8.87 (s, 1H), 7.44 (s, 4H), 3.85 (s, 2H), 2.47 (s, 3H). 13C NMR (126 MHz, MeOD) delta 152.77, 149.07, 143.63, 133.42, 131.46, 130.49, 129.05, 46.23, 15.79. MS (ESI) 205.0 (M+H).
89%	With tetrabutyl ammonium fluoride; In tetrahydrofuran; acetonitrile; at 20℃; for 24h;	(4-(4-methylthiazol-5-yl)phenyl)methanamine 2-(trimethylsilyl)ethyl 4-(4-methylthiazol-5-yl)benzylcarbamate (51.8 mg, 0.149 mmol, 1 eq) was dissolved in acetonitrile (6 mL) at room temperature. A one molar solution of tetrabutylammonium fluoride in THF (0.45 mL, 0.45 mmol, 3 eq) was added and the solution was stirred for 24 hours. The mixture was concentrated under reduced pressure. Purification by column chromatography (0.5 to 4% 0.5N NH3 (MeOH)/DCM) gave a light yellow oil (27.2 mg, 0.133 mmol, 89%). 1H NMR (500 MHz, MeOD) delta 8.87 (s, 1H), 7.44 (s, 4H), 3.85 (s, 2H), 2.47 (s, 3H). 13C NMR (126 MHz, MeOD) delta 152.77, 149.07, 143.63, 133.42, 131.46, 130.49, 129.05, 46.23, 15.79. MS (ESI) 205.0 (M+H).

Reference： [1]Angewandte Chemie - International Edition,2012,vol. 51,p. 11463 - 11467
[2]Patent: WO2013/106646,2013,A2 .Location in patent: Page/Page column 88-89
[3]Patent: US2014/356322,2014,A1 .Location in patent: Paragraph 0260; 0265
[4]Patent: US2016/45607,2016,A1 .Location in patent: Paragraph 0262; 0263

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[ 1448189-30-7 ]
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Reference： [1]Angewandte Chemie - International Edition,2012,vol. 51,p. 11463 - 11467
[2]Patent: WO2013/106646,2013,A2
[3]Patent: US2014/356322,2014,A1
[4]Patent: US2016/45607,2016,A1
[5]Chemical Communications,2019,vol. 55,p. 1821 - 1824

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[ 1418120-86-1 ]

Reference： [1]Angewandte Chemie - International Edition,2012,vol. 51,p. 11463 - 11467
[2]Patent: WO2013/106646,2013,A2
[3]Patent: US2014/356322,2014,A1

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[ 1448189-30-7 ]
[ 1418120-88-3 ]

Reference： [1]Angewandte Chemie - International Edition,2012,vol. 51,p. 11463 - 11467

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[ 1418120-90-7 ]

Reference： [1]Angewandte Chemie - International Edition,2012,vol. 51,p. 11463 - 11467

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[ 1448189-30-7 ]
[ 1418120-94-1 ]

Reference： [1]Angewandte Chemie - International Edition,2012,vol. 51,p. 11463 - 11467
[2]Patent: US2014/356322,2014,A1

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[ 1448189-30-7 ]
[ 1418120-96-3 ]

Reference： [1]Angewandte Chemie - International Edition,2012,vol. 51,p. 11463 - 11467
[2]Patent: WO2013/106646,2013,A2
[3]Patent: US2014/356322,2014,A1

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[ 1418120-92-9 ]

Reference： [1]Angewandte Chemie - International Edition,2012,vol. 51,p. 11463 - 11467

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[ 1418120-52-1 ]

Reference： [1]Angewandte Chemie - International Edition,2012,vol. 51,p. 11463 - 11467
[2]Patent: WO2016/149668,2016,A1

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[ 623-00-7 ]
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Reference： [1]Angewandte Chemie - International Edition,2012,vol. 51,p. 11463 - 11467
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 8657 - 8663
[3]Patent: US2014/356322,2014,A1
[4]Patent: WO2016/118666,2016,A1
[5]Patent: WO2016/146985,2016,A1
[6]Patent: US2017/8904,2017,A1
[7]Chemistry - A European Journal,2017,vol. 23,p. 13875 - 13878
[8]Patent: US2017/281784,2017,A1
[9]Journal of Medicinal Chemistry,2018,vol. 61,p. 583 - 598
[10]Patent: WO2017/30814,2017,A1
[11]Patent: US2018/125821,2018,A1
[12]Patent: US2016/45607,2016,A1
[13]Patent: CN109678852,2019,A
[14]Chemical Communications,2019,vol. 55,p. 1821 - 1824
[15]Patent: US2019/192668,2019,A1
[16]Patent: WO2019/195609,2019,A2
[17]Patent: WO2020/51564,2020,A1
[18]Patent: CN111233661,2020,A
[19]Patent: WO2020/113233,2020,A1

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[ 1448189-30-7 ]

Yield	Reaction Conditions	Operation in experiment
73%	With methanol; sodium tetrahydroborate; cobalt(II) chloride; for 1.5h;	Alternate Route: 4-bromobenzonitrile (5.1 g, 28 mmol, 1 eq), 4-methylthiazole (5.56 g, 56 mmol, 2 eq) potassium acetate (5.5 g, 56 mmol, 2 eq), palladium (II) acetate (63 mg, 0.28 mmol, 1 mol %) were dissolved in dimethylacetamide and stirred under argon. (CITE JOC, 2009, 74, 1179) The mixture was heated to 150 C. and stirred for 19 hours, then diluted with 500 mL EtOAc, and washed 4 times with 300 mL water. The first wash was then back extracted with 300 mL EtOAc, and then washed 4 times with 100 mL water. The combined organic layer was dried over sodium sulfate, filtered and concentrated under vacuum to give a beige solid (5.55 g, 27.7 mmol, 99%) that matched the reported spectral data.[8] The solid was then dissolved in MeOH (280 mL) and cooled to 4 C. Cobalt chloride (9.9 g, 41.6 mmol, 1.5 eq) was added, followed by the slow, portionwise addition of sodium borohydride (5.2 g, 139 mmol, 5 eq), which was accompanied by vigorous bubbling. After 90 minutes, the reaction was quenched by the addition of water and ammonium hydroxide. The mixture was extracted 4 times with chloroform, and purified by column chromatography (10 to 30% 0.5M NH3 (MeOH)/DCM) to give a darker oil (4.12 g, 20.2 mmol, 73%).
73%	With methanol; sodium tetrahydroborate; cobalt(II) chloride; at 4℃; for 1.5h;	Alternate Route: 4-bromobenzonitrile (5.1 g, 28 mmol, 1 eq), 4-methylthiazole (5.56 g, 56 mmol, 2 eq) potassium acetate (5.5 g, 56 mmol, 2 eq), palladium (II) acetate (63 mg, 0.28 mmol, 1 mol %) were dissolved in dimethylacetamide and stirred under argon (J. Org. Chem. 2009, 74:1179). The mixture was heated to 150 C. and stirred for 19 hours, then diluted with 500 mL EtOAc, and washed 4 times with 300 mL water. The first wash was then back extracted with 300 mL EtOAc, and then washed 4 times with 100 mL water. The combined organic layer was dried over sodium sulfate, filtered and concentrated under vacuum to give a beige solid (5.55 g, 27.7 mmol, 99%) that matched the reported spectral data. The solid was then dissolved in MeOH (280 mL) and cooled to 4 C. Cobalt chloride (9.9 g, 41.6 mmol, 1.5 eq) was added, followed by the slow, portionwise addition of sodium borohydride (5.2 g, 139 mmol, 5 eq), which was accompanied by vigorous bubbling. After 90 minutes, the reaction was quenched by the addition of water and ammonium hydroxide. The mixture was extracted 4 times with chloroform, and purified by column chromatography (10 to 30% 0.5M NH3 (MeOH)/DCM) to give a darker oil (4.12 g, 20.2 mmol, 73%).
56%	With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 60℃; for 3.16h;Inert atmosphere;	Step 2: Synthesis of [4-(4-methyl-l,3-thiazol-5-yl)phenyl]methanamine (H)[0403] To a stirred solution of 4-(4-methyl-l,3-thiazol-5-yl)benzonitrile (G, 35.0 g, 174.8 mmol) in tetrahydrofuran (1000 mL) was added LiAlH4(20.0 g, 526.3 mmol) in portions at 0C in 10 min under a nitrogen atmosphere. The resulting solution was then stirred at 60 C for 3h. LC-MS indicated formation of the desired product. The reaction was then cooled to 0C, quenched by the addition water (20 mL, added slowly), aq. solution of NaOH(15%, 20 mL) and water (60 mL). The resulting mixture was then extracted with ethyl acetate (300 mL x 2). The organic layers were combined, washed with saturated aqueous solution of sodium chloride (100 mL), dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel chromatography (eluent:dichloromethane/methanol (v:v = 10: 1)) to give H (yield: 56%) as a yellow oil.

56%	With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 60℃; for 3h;Inert atmosphere;	To a stirred solution of <strong>[122957-57-7]4-(4-methyl-1,3-thiazol-5-yl)benzonitrile</strong> (35 g, 174.77 mmol) in tetrahydrofuran (1000 mL) was added LiAlH4 (20 g, 526.32 mmol) in portions at 0 C. in 10 min under a nitrogen atmosphere. The resulting solution was then stirred at 60 C. for 3 h, at which time LC-MS indicated completion of reaction. The reaction was cooled to 0 C., then quenched by the addition water (20 mL, added slowly), aq. solution of NaOH (15%, 20 mL) and water (60 mL). The resulting mixture was then extracted with ethyl acetate (300 mL*2). The organic layers were combined, washed with saturated aqueous solution of sodium chloride (100 mL), dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel chromatography (eluent: dichloromethane/methanol (v:v=10:1)) to give the titled compound (yield: 56%) as a yellow oil.
56%	With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 60℃; for 3.16667h;Inert atmosphere;	To a stirred solution of 4-(4-methyl-l,3-thiazol-5-yl)benzonitrile (35 g, 174.77 mmol) in tetrahydrofuran (1000 mL) was added LiAlIL; (20 g, 526.32 mmol) in portions at 0C in 10 min under a nitrogen atmosphere. The resulting mixture was then stirred at 60 C for 3h, at which time LC-MS indicated completion of reaction. The mixture was cooled to 0C, then quenched by the addition of water (20 mL, added slowly), aq. solution of NaOH (15%, 20 mL) and water (60 mL). The resulting mixture was then extracted with ethyl acetate (300 mL x 2). The organic layers were combined, washed with brine (100 mL), dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel column chromatography (eluent: dichloromethane/methanol (v:v = 10: 1)) to give the titled compound (yield: 56%) as a yellow oil.
56%	With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 60℃; for 3.17h;Inert atmosphere;	To a stirred solution of <strong>[122957-57-7]4-(4-methyl-1,3-thiazol-5-yl)benzonitrile</strong> (G, 35.0 g, 174.8 mmol) in tetrahydrofuran (1000 mL) was added LiAlH4 (20.0 g, 526.3 mmol) in portions at 0 C. in 10 min under a nitrogen atmosphere. The resulting solution was then stirred at 60 C. for 3 h. LC-MS indicated formation of the desired product. The reaction was then cooled to 0 C., quenched by the addition water (20 mL, added slowly), aq. solution of NaOH(15%, 20 mL) and water (60 mL). The resulting mixture was then extracted with ethyl acetate (300 mL*2). The organic layers were combined, washed with saturated aqueous solution of sodium chloride (100 mL), dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel chromatography (eluent: dichloromethane/methanol (v:v=10:1)) to give H (yield: 56%) as a yellow oil.
56%	With lithium aluminium tetrahydride;	Step 2: Preparation of [4-(4-methyl-1,3-thiazol-5-yl)phenyl]methanamine To a stirred solution of <strong>[122957-57-7]4-(4-methyl-1,3-thiazol-5-yl)benzonitrile</strong> (35 g, 174.77 mmol) in tetrahydrofuran (1000 mL) was added LiAlH4 (20 g, 526.32 mmol) in portions at 0 C. in 10 minutes under a nitrogen atmosphere. The resulting mixture was then stirred at 60 C. for 3 hours, at which time LC-MS indicated completion of reaction. The mixture was cooled to 0 C., then quenched by the addition of water (20 mL, added slowly), aq. solution of NaOH (15%, 20 mL) and water (60 mL). The resulting mixture was then extracted with ethyl acetate (300 mL*2). The organic layers were combined, washed with brine (100 mL), dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel column chromatography (eluent: dichloromethane/methanol (v:v=10:1)) to give the titled compound (yield: 56%) as a yellow oil.
56%	With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 60℃; for 3.16667h;	Into a 3-L 3 -necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 4-(4-methyl-l,3-thiazol-5-yl)benzonitrile (35 g, 174.77 mmol, LOO equiv) in tetrahydrofuran (1000 mL). This was followed by the addition of LiAltL (20 g, 526.32 mmol, 3.00 equiv) in portions at 0C in 10 minutes. The resulting solution was stirred for 3 hours at 60C in an oil bath. The reaction was cooled to 0C with a water/ice bath, then quenched by the addition of 20 mL of water, 20mL of NaOH (15%) and 60 mL of water. The resulting solution was diluted with 200 mL of ethyl acetate. The solids were filtered out. The filtrate was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (10:1). This resulted in 20 g (56%) of [4-(4-methyl-l,3-thiazol-5-yl)phenyl]methanamine as yellow oil.
56%	With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 60℃; for 3.16667h;Inert atmosphere;	Into a 3-L 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed <strong>[122957-57-7]4-(4-methyl-1,3-thiazol-5-yl)benzonitrile</strong> (35 g, 174.77 mmol, 1.00 equiv) in tetrahydrofuran (1000 mL). This was followed by the addition of LiAlH4 (20 g, 526.32 mmol, 3.00 equiv) in portions at 0C in 10 min. The resulting solution was stirred for 3 h at 60C in an oil bath. The reaction was cooled to 0C with a water/ice bath, then quenched by the addition of 20 mL of water, 20mL of NaOH (15%) and 60 mL of water. The resulting solution was diluted with 200 mL of ethyl acetate. The solids were filtered out. The filtrate was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (10:1). This resulted in 20 g (56%) of [4-(4-methyl-1,3-thiazol-5-yl)phenyl]methanamine as yellow oil.
37%	With sodium tetrahydroborate; cobalt(II) chloride; In methanol; at 20℃; for 1.5h;Cooling with ice;	Compound 38 (5.0 g, 25 mmol) was dissolved in methanol (125 ml), CoCl 2 (4.5 g, 35 mmol) was added under ice bath conditions and then NaBH 4 (3.8 g, 100 mmol) was added portionwise.Stir at room temperature for 90 minutes, add ammonia and water to quench the reaction, and filter the reaction solution with diatomaceous earth.The celite was washed with DCM:MeOH:TEA=10:1:0.1 solvent, and the obtained filtrate was saturated withSodium bicarbonate aqueous solution and DCM:MeOH=10:1 solvent extraction, spin-dry the solvent under reduced pressure and pass through silica gel column chromatography(Ethyl acetate followed by DCM:MeOH=10:1) The residue was purified to give a yellow oil 39 (1.9 g, 9.3 mmol, 37% yield):
29%	With sodium tetrahydroborate; cobalt(II) chloride; In methanol; at 0℃; for 1.5h;	To a solution of 4-bromobenzonitrile (1.5 g, 8.24 mmol, 1 equiv.) and Pd(OAc)2 (2 mg, 0.08mmol, 0.1mol%) in DMAc (8mL) were added KOAc (1.62g, 16.5 mmol, 2 equiv.) and 4-methylthiazole (1.63 g, 1.49 mL, 16.5 mmol, 2 equiv.). The resulting mixture was heated to 150 C and stirred overnight. The mixture was diluted with water and extracted with DCM (3x). The combined organic phases were dried over MgS04 and evaporated under reduced pressure to give the corresponding cyano derivate as a beige solid (1.67 g, 7.99 mmol, 97%) that matched the reported spectral data. A solution of the cyano-derivate product (270mg, 1.3mmol, 1 equiv.) in methanol (15mL) was cooled to 0C. CoCl (282 mg, 2.2 mmol, 1.5 equiv.) was added, followed by portion-wise addition of NaBH4 (274 mg, 7.2 mmol, 5 equiv.). The resulting mixture was stirred for 90 min, the reaction was quenched with water and ammonium hydroxide, and the mixture was extracted with chloroform (6x). The combined organic phases were dried over MgS04 and evaporated under reduced pressure to give a dark-brown oil which was purified by flash column chromatography to yield the desired product, preparative compound (4) as a yellow oil (76.5 mg, 0.40 mmol, 29% (isolated)) that matched the reported spectral data.
23.3%	With sodium tetrahydroborate; cobalt(II) chloride; In methanol; at 0 - 20℃; for 12.5h;	To a solution of <strong>[122957-57-7]4-(4-methylthiazol-5-yl)benzonitrile</strong> (14.7 g, 73.4 mmol) in MeOH (460 mL) was added dichlorocobalt (14.3 g, 110 mmol) and the mixture was cooled to 0 C. Then, NaBH4 (13.9 g, 367 mmol) was added in portions over 0.5 hour. Finally, the mixture was allowed to warm to rt and stirred for 12 hours. On completion, the reaction mixture was quenched with NH3.H2O (20 mL, 30 wt %), then diluted with water (100 mL) and extracted with DCM (3×80 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by reverse phase flash column (0.1% NH3.H2O in water) to give the title compound (3.50 g, 23.3% yield) as a yellowish oil. LC-MS (ESI+) m/z 205.1 (M+H)+.
	With hydrogen; ammonium hydroxide; In methanol; at 25℃;	<strong>[122957-57-7]4-(4-methylthiazol-5-yl)benzonitrile</strong> (2.0 g) was added to a 50 ml three-necked flask.Add 15ml of methanol to dissolve,Join Raney Nickel,Replace with hydrogen 3 times, add ammonia water,Stir at 25 C overnight, detect by TLC, and complete the reaction.Filtration and concentration under reduced pressure gave the title compound.

Reference： [1]Angewandte Chemie - International Edition,2012,vol. 51,p. 11463 - 11467
[2]Patent: US2014/356322,2014,A1 .Location in patent: Paragraph 0266
[3]Patent: US2016/45607,2016,A1 .Location in patent: Paragraph 0264; 0265
[4]Patent: WO2016/118666,2016,A1 .Location in patent: Paragraph 0399; 0402; 0403
[5]Patent: US2017/8904,2017,A1 .Location in patent: Paragraph 0376; 0378
[6]Patent: WO2017/30814,2017,A1 .Location in patent: Paragraph 00194; 00196
[7]Patent: US2017/281784,2017,A1 .Location in patent: Paragraph 0191; 0193
[8]Patent: US2018/125821,2018,A1
[9]Patent: WO2019/195609,2019,A2 .Location in patent: Paragraph 00589-00590
[10]Patent: WO2020/51564,2020,A1 .Location in patent: Paragraph 1087; 1088
[11]Patent: CN111233661,2020,A .Location in patent: Paragraph 0234-0235; 0248-0250
[12]Journal of Medicinal Chemistry,2014,vol. 57,p. 8657 - 8663
[13]Patent: WO2016/146985,2016,A1 .Location in patent: Page/Page column 78; 79
[14]Chemical Communications,2019,vol. 55,p. 1821 - 1824
[15]Patent: US2019/192668,2019,A1 .Location in patent: Paragraph 2358; 2360
[16]Chemistry - A European Journal,2017,vol. 23,p. 13875 - 13878
[17]ACS Medicinal Chemistry Letters,2014,vol. 5,p. 23 - 28
[18]Journal of Medicinal Chemistry,2018,vol. 61,p. 583 - 598
[19]Patent: CN109678852,2019,A .Location in patent: Paragraph 0077; 0079; 0082; 0083

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[ 1448187-20-9 ]

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[2]Patent: US2014/356322,2014,A1

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[ 1448186-85-3 ]

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[2]Patent: US2014/356322,2014,A1

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[ 1448189-30-7 ]
[ 1448187-01-6 ]

Reference： [1]Patent: WO2013/106646,2013,A2
[2]Patent: WO2013/106646,2013,A2
[3]Patent: US2014/356322,2014,A1
[4]Patent: US2014/356322,2014,A1
[5]Patent: US2014/356322,2014,A1
[6]Patent: US2014/356322,2014,A1
[7]Patent: US2014/356322,2014,A1

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[ 1448189-47-6 ]

Reference： [1]Patent: WO2013/106646,2013,A2
[2]Patent: US2014/356322,2014,A1
[3]Patent: US2014/356322,2014,A1
[4]Journal of Medicinal Chemistry,2018,vol. 61,p. 583 - 598

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[ 1448189-49-8 ]

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[2]Patent: US2014/356322,2014,A1
[3]Patent: US2014/356322,2014,A1

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(2S,4R)-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide hydrochloride [ No CAS ]

Reference： [1]Patent: WO2013/106646,2013,A2
[2]Patent: WO2017/30814,2017,A1
[3]Patent: US2019/192668,2019,A1

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[ 1448187-61-8 ]

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[ 1448187-25-4 ]

Reference： [1]Patent: WO2013/106646,2013,A2
[2]Patent: US2014/356322,2014,A1

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(2S,4R)-1-((S)-2-aminopropanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride [ No CAS ]

Reference： [1]Patent: WO2013/106646,2013,A2
[2]Patent: US2014/356322,2014,A1
[3]Patent: US2014/356322,2014,A1
[4]Patent: US2014/356322,2014,A1

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[2]Patent: US2014/356322,2014,A1

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Reference： [1]Patent: WO2013/106646,2013,A2
[2]Patent: US2014/356322,2014,A1
[3]Journal of Medicinal Chemistry,2018,vol. 61,p. 583 - 598
[4]Patent: US2016/45607,2016,A1

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[2]Patent: US2014/356322,2014,A1

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[2]Patent: US2014/356322,2014,A1

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[2]Patent: US2014/356322,2014,A1
[3]Patent: US2014/356322,2014,A1
[4]Patent: US2014/356322,2014,A1

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[2]Patent: US2014/356322,2014,A1

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[2]Patent: US2014/356322,2014,A1

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Reference： [1]Patent: WO2013/106646,2013,A2
[2]Patent: US2014/356322,2014,A1
[3]Patent: US2014/356322,2014,A1
[4]Patent: US2014/356322,2014,A1

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Reference： [1]Patent: WO2013/106646,2013,A2
[2]Patent: US2014/356322,2014,A1

35
[ 1448189-30-7 ]
[ 1448187-35-6 ]

Reference： [1]Patent: WO2013/106646,2013,A2
[2]Patent: US2014/356322,2014,A1

36
[ 1448189-30-7 ]
[ 1448187-37-8 ]

Reference： [1]Patent: WO2013/106646,2013,A2

37
[ 1448189-30-7 ]
(2S,4R)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)-1-((S)-morpholine-3-carbonyl)pyrrolidine-2-carboxamide hydrochloride [ No CAS ]

Reference： [1]Patent: WO2013/106646,2013,A2

38
[ 1448189-30-7 ]
[ 1448188-74-6 ]

Reference： [1]Patent: WO2013/106646,2013,A2
[2]Patent: US2014/356322,2014,A1

39
[ 1448189-30-7 ]
[ 1448189-79-4 ]

Reference： [1]Patent: WO2013/106646,2013,A2
[2]Patent: US2014/356322,2014,A1

40
[ 1448189-30-7 ]
[ 1448187-31-2 ]

Reference： [1]Patent: WO2013/106646,2013,A2
[2]Patent: US2014/356322,2014,A1

41
[ 1448189-30-7 ]
tert-butyl 4-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-1-oxopropan-2-yl)piperazine-1-carboxylate [ No CAS ]
tert-butyl 4-((R)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-1-oxopropan-2-yl)piperazine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2013/106646,2013,A2

42
[ 1448189-30-7 ]
[ 1448187-29-8 ]

Reference： [1]Patent: WO2013/106646,2013,A2
[2]Patent: US2014/356322,2014,A1

43
[ 1448189-30-7 ]
[ 1448189-84-1 ]

Reference： [1]Patent: WO2013/106646,2013,A2
[2]Patent: US2014/356322,2014,A1

44
[ 1448189-30-7 ]
[ 1448187-92-5 ]

Reference： [1]Patent: WO2013/106646,2013,A2
[2]Patent: US2014/356322,2014,A1

45
[ 1448189-32-9 ]
[ 1448189-30-7 ]
[ 1418120-52-1 ]

Reference： [1]Patent: WO2013/106646,2013,A2
[2]Patent: US2014/356322,2014,A1

46
[ 693-95-8 ]
[ 623-00-7 ]
[ 1448189-30-7 ]

Yield	Reaction Conditions	Operation in experiment
73%		Alternate Route: 4-bromobenzonitrile (5.1 g, 28 mmol, 1 eq), 4-methylthiazole (5.56 g, 56 mmol, 2 eq) potassium acetate (5.5 g, 56 mmol, 2 eq), palladium (II) acetate (63 mg, 0.28 mmol, 1 mol %) were dissolved in dimethylacetamide and stirred under argon. (CITE JOC, 2009, 74, 1 179) The mixture was heated to 150 C and stirred for 19 hours, then diluted with 500 mL EtOAc, and washed 4 times with 300 mL water. The first wash was then back extracted with 300 mL EtOAc, and then washed 4 times with 100 mL water. The combined organic layer was dried over sodium sulfate, filtered and concentrated under vacuum to give a beige solid (5.55 g, 27.7 mmol, 99%) that matched the reported spectral data.[S] The solid was then dissolved in MeOH (280 mL) and cooled to 4 C. Cobalt chloride (9.9 g, 41.6 mmol, 1.5 eq) was added, followed by the slow, portionwise addition of sodium borohydride (5.2 g, 139 mmol, 5 eq), which was accompanied by vigorous bubbling. After 90 minutes, the reaction was quenched by the addition of water and ammonium hydroxide. The mixture was extracted 4 times with chloroform, and purified by column chromatography (10 to 30% 0.5M NH3 (MeOH)/DCM) to give a darker oil (4.12 g, 20.2 mmol, 73%).

Reference： [1]Patent: WO2013/106646,2013,A2 .Location in patent: Page/Page column 89

47
[ 1448189-34-1 ]
[ 1448189-30-7 ]
[ 1418120-52-1 ]

Reference： [1]ACS Medicinal Chemistry Letters,2014,vol. 5,p. 23 - 28

48
[ 1448189-30-7 ]
[ 108-24-7 ]
[ 1485065-66-4 ]

Reference： [1]ACS Medicinal Chemistry Letters,2014,vol. 5,p. 23 - 28

49
[ 1448189-30-7 ]
[ 33996-33-7 ]
[ 1448187-20-9 ]

Reference： [1]ACS Medicinal Chemistry Letters,2014,vol. 5,p. 23 - 28

50
[ 1448189-30-7 ]
[ 1448189-90-9 ]

Reference： [1]Patent: US2014/356322,2014,A1
[2]Patent: WO2016/118666,2016,A1
[3]Patent: US2017/8904,2017,A1
[4]Patent: US2017/281784,2017,A1
[5]Journal of Medicinal Chemistry,2018,vol. 61,p. 583 - 598
[6]Patent: US2018/125821,2018,A1
[7]Patent: US2016/45607,2016,A1
[8]Patent: WO2019/195609,2019,A2
[9]Patent: WO2020/113233,2020,A1

51
[ 1448189-30-7 ]
[ 1448187-21-0 ]

Reference： [1]Patent: US2014/356322,2014,A1

52
[ 1448189-30-7 ]
[ 1448187-22-1 ]

Reference： [1]Patent: US2014/356322,2014,A1

53
[ 1448189-30-7 ]
(2S,4R)-1-[(2S)-2-aminopropanoyl]-4-hydroxy-N-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide hydrochloride [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 583 - 598

54
[ 1448189-30-7 ]
[ 1448189-71-6 ]

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 583 - 598

55
[ 1448189-30-7 ]
[ 1448189-72-7 ]

Reference： [1]Patent: US2014/356322,2014,A1

56
[ 1448189-30-7 ]
(2S,4R)-4-hydroxy-1-((S)-3-methyl-2-(methylamino)butanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride [ No CAS ]

Reference： [1]Patent: US2014/356322,2014,A1

57
[ 1448189-30-7 ]
[ 1448189-74-9 ]

Reference： [1]Patent: US2014/356322,2014,A1

58
[ 1448189-30-7 ]
(2S,4R)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)-1-((S)-morpholine-3-carbonyl)pyrrolidine-2-carboxamide hydrochloride [ No CAS ]

Reference： [1]Patent: US2014/356322,2014,A1

59
[ 1448189-30-7 ]
[ 1448189-80-7 ]

Reference： [1]Patent: US2017/8904,2017,A1
[2]Patent: US2017/281784,2017,A1
[3]Journal of Medicinal Chemistry,2018,vol. 61,p. 583 - 598
[4]Patent: US2018/125821,2018,A1
[5]Patent: US2016/45607,2016,A1

60
[ 1448189-30-7 ]
[ 1448188-79-1 ]

Reference： [1]Patent: US2014/356322,2014,A1

61
[ 1448189-30-7 ]
tert-butyl 4-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-1-oxopropan-2-yl)piperazine-1-carboxylate [ No CAS ]

Reference： [1]Patent: US2014/356322,2014,A1

62
[ 1448189-30-7 ]
[ 1448187-82-3 ]

Reference： [1]Patent: US2014/356322,2014,A1
[2]Patent: US2014/356322,2014,A1
[3]Patent: US2014/356322,2014,A1

63
[ 1448189-30-7 ]
[ 1448187-85-6 ]

Reference： [1]Patent: US2014/356322,2014,A1
[2]Patent: US2014/356322,2014,A1
[3]Patent: US2014/356322,2014,A1

64
[ 1448189-30-7 ]
[ 1448187-89-0 ]

Reference： [1]Patent: US2014/356322,2014,A1
[2]Patent: US2014/356322,2014,A1
[3]Patent: US2014/356322,2014,A1

65
[ 1448189-30-7 ]
[ 1448187-90-3 ]

Reference： [1]Patent: US2014/356322,2014,A1
[2]Patent: US2014/356322,2014,A1
[3]Patent: US2014/356322,2014,A1

66
[ 1448189-30-7 ]
[ 1448189-03-4 ]

Reference： [1]Patent: US2014/356322,2014,A1

67
[ 1448189-30-7 ]
[ 1448189-04-5 ]

Reference： [1]Patent: US2014/356322,2014,A1

68
[ 1448189-30-7 ]
[ 1448189-12-5 ]

Reference： [1]Patent: US2014/356322,2014,A1

69
[ 1448189-30-7 ]
[ 1448189-17-0 ]

Reference： [1]Patent: US2014/356322,2014,A1

70
[ 1448189-30-7 ]
[ 1448191-49-8 ]

Reference： [1]Patent: US2014/356322,2014,A1

71
[ 1448189-30-7 ]
[ 1448189-27-2 ]

Reference： [1]Patent: US2014/356322,2014,A1

72
[ 1448189-30-7 ]
(2S,4R)-1-(3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylic acid [ No CAS ]
(2S,4R)-1-(3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 8657 - 8663

73
[ 1448189-30-7 ]
[ 1448188-58-6 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 8657 - 8663

74
[ 1448189-30-7 ]
C₂₇H₃₇N₅O₅S [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 8657 - 8663

75
[ 1448189-30-7 ]
(2S,4R)-1-((S)-2-((S)-2-acetamido-4-methylpentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 8657 - 8663

76
[ 1448189-30-7 ]
(2S,4R)-1-((S)-2-((S)-2-acetamido-3-phenylpropanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 8657 - 8663

77
[ 1448189-30-7 ]
(2S,4R)-1-((S)-2-((S)-2-acetamido-3,3-dimethylbutanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 8657 - 8663

78
[ 1448189-30-7 ]
(2S,4R)-1-((S)-2-((S)-2-acetamido-2-phenylacetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 8657 - 8663

79
[ 1448189-30-7 ]
2-acetyl-N-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazo-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 8657 - 8663

80
[ 1448189-30-7 ]
(2S,4R)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide trifluoroacetic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 8657 - 8663
[2]Patent: WO2016/146985,2016,A1

81
[ 1448189-30-7 ]
[ 1448188-62-2 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 8657 - 8663
[2]Patent: WO2016/146985,2016,A1

82
[ 1448189-30-7 ]
tert-butyl ((S)-2-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazole-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-2-oxo-1-phenylethyl)carbamate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 8657 - 8663

83
[ 1448189-30-7 ]
tert-butyl ((S)-2-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxo-1-phenylethyl)carbamate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 8657 - 8663

84
[ 1448189-30-7 ]
C₂₄H₂₆N₄O₃S*C₂HF₃O₂ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 8657 - 8663

85
[ 1448189-30-7 ]
(S)-tert-butyl 2-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazole-5-yl)benzyl)carbamoyl)pyrrolidin-1-carbonyl)pyrrolidine-1-carboxylate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 8657 - 8663

86
[ 1448189-30-7 ]
C₂₁H₂₆N₄O₃S*C₂HF₃O₂ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 8657 - 8663

87
[ 1448189-30-7 ]
(2S,4R)-1-((S)-2-acetamido-2-phenylacetyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 8657 - 8663

88
[ 1448189-30-7 ]
(2S,4R)-tert-butyl 4-hydroxy-2-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)carbamoyl)pyrrolidin-1-yl)carbonyl)pyrrolidine-1-carboxylate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 8657 - 8663

89
[ 1448189-30-7 ]
C₂₁H₂₆N₄O₄S*C₂HF₃O₂ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 8657 - 8663

90
[ 1448189-30-7 ]
[ 1448191-64-7 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 8657 - 8663

91
[ 1448189-30-7 ]
C₂₂H₂₈N₄O₃S*C₂HF₃O₂ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 8657 - 8663

92
[ 1448189-30-7 ]
tert-butyl (1-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 8657 - 8663

93
[ 1448189-30-7 ]
[ 1448189-98-7 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 8657 - 8663
[2]Patent: US2014/356322,2014,A1
[3]Patent: WO2016/118666,2016,A1
[4]Patent: WO2016/146985,2016,A1
[5]Patent: US2017/8904,2017,A1
[6]Patent: US2017/281784,2017,A1
[7]Journal of Medicinal Chemistry,2018,vol. 61,p. 583 - 598
[8]Patent: WO2017/30814,2017,A1
[9]Patent: US2018/125821,2018,A1
[10]Patent: US2016/45607,2016,A1
[11]Chemical Communications,2019,vol. 55,p. 1821 - 1824
[12]Patent: US2019/192668,2019,A1
[13]Patent: WO2019/195609,2019,A2
[14]Patent: CN111233661,2020,A
[15]Patent: WO2020/113233,2020,A1

94
[ 1448189-30-7 ]
C₂₈H₄₁N₅O₄S*C₂HF₃O₂ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 8657 - 8663

95
[ 1448189-30-7 ]
(2S,4R)-1-((S)-3,3-dimethyl-2-((2,2,2-trifluoroacetyl)-l4-azaneyl)butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 8657 - 8663
[2]Patent: WO2016/146985,2016,A1

96
[ 1448189-30-7 ]
[ 1448187-60-7 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 8657 - 8663

97
[ 1448189-30-7 ]
(2S,4R)-1-((S)-2-((S)-2-acetamido-2-phenylacetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 8657 - 8663

98
[ 1448189-30-7 ]
tert-butyl ((S)-1-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 8657 - 8663
[2]Patent: WO2016/146985,2016,A1

99
[ 1448189-30-7 ]
C₃₁H₃₉N₅O₄S*C₂HF₃O₂ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 8657 - 8663

100
[ 1448189-30-7 ]
tert-butyl ((S)-1-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-3,3-dimethyl-1-oxobutan-2-yl)carbamate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 8657 - 8663

101
[ 1448189-30-7 ]
C₂₈H₄₁N₅O₄S*C₂HF₃O₂ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 8657 - 8663

102
[ 1448189-30-7 ]
tert-butyl 3-(((S)-2-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamoyl)-3,4-dihydroisoquinoline-2-(1H)-carboxylate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 8657 - 8663

103
[ 1448189-30-7 ]
(2S,4R)-1-((2S,4R)-1-acetyl-4-hydroxypyrrolidine-2-carbonyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 8657 - 8663

104
[ 1448189-30-7 ]
C₃₂H₃₉N₅O₄S*C₂HF₃O₂ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 8657 - 8663

105
[ 1448189-30-7 ]
C₂₅H₃₅N₅O₄S*C₂HF₃O₂ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 8657 - 8663

106
[ 1448189-30-7 ]
tert-butyl (S)-1-((S)-1-((2S,4R)-4-hydroxy-2-(4-(4-methylthiazol-5-yl)benzylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylamino)-1-oxopropan-2-ylcarbamate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 8657 - 8663

107
[ 1448189-30-7 ]
[ 13726-69-7 ]
(2S,4R)-tert-butyl 4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%		(2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (366 mg, 1.58 mmol, 1 equiv.) was dissolved in 15 mL DMF and charged with EDC (380 mg, 2.0 mmol 1.3 equiv,), and HOBt (310 mg, 2.0 mmol, 1.5 equiv) after 5 minutes of stirring <strong>[1448189-30-7](4-(4-methylthiazol-5-yl)phenyl)methanamine</strong> (325 mg, 1.58 mmol, 1 equiv) was added. Upon stirring for 15 h the reaction was diluted with 25 mL EtOAc, and washed with 25 mL brine (2×), followed by 25 mL Sat. NaHCO3 (2×). The organic layer was concentrated down to yield 650 mg (98% yield) of the product as a yellow oil. 1H NMR (400 MHz, CDCl3) delta 8.67 (s, 1H), 7.43-7.29 (m, 4H), 4.49 (d, J=16.7 Hz, 4H), 3.51 (dd, J=11.0, 4.7 Hz, 2H), 2.61-2.45 (m, 4H), 2.03 (d, J=7.4 Hz, 2H), 1.42 (s, 9H).TLC: (9:1 DCM:MeOH (0.5 N NH3)) Rf=0.20; MS (ESI) 417.5 (M+H)+.

Reference： [1]Patent: US2014/356322,2014,A1 .Location in patent: Paragraph 0290; 0291

108
[ 26177-44-6 ]
[ 1448189-30-7 ]

Reference： [1]Patent: US2014/356322,2014,A1

109
[ 1448189-30-7 ]
[ 87691-27-8 ]
tert-butyl (2S,4S)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 25℃; for 2h;pH > 9;	To a solution of (4-(4-methylthiazol-5-yl)phenyl)methanamine (500 mg, 2.43 mmol, 1 eq.) in DCM was added (2S,4S)-l -(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (565 mg, 2.43 mmol, 1 eq.) and l -[Bis(dimemylamino)memylene]-lH-l ,2,3-triazolo[4,5-b]pyridinium-3-oxidhexafl phosphate (HATU) (827 mg, 2.68 mmol, 1.1 eq.). After the pH of the reaction was adjusted to >9 by addition of NN-diisopropylethyl amine (1.70 ml, 9.72 mmol, 4 eq.) the reaction was stirred for 2 h at 25 C. The reaction mixture was washed with water and the organic phase then dried over MgS04. After removing the solvent in vacuum the residue was purified by flash column chromatography using a gradient of 10% to 70% Acetone in Hexane. Yield: 587 mg (58%); -NMR (CDC13, 400 MHz) 1.45 (s, 9H), 2. 14-2.23 (m, 1 H), 2.34-2.39 (m, 1 H), 2.51 (s, 3H), 3.44-3.53 (m, 2H), 4.40-4.46 (m, 4H), 4.58 (dd, 1 H, J(HH)= 7.08 Hz, J(HH)= 14.9 Hz), 7.32-7.39 (m, 4 H), 7.51-7.54 (m, 1 H), 8.67 (s, 1 H); UC-NMR (CDC13, 101 MHz) delta 12.7, 28.4, 35.9, 55.9, 57.2, 59.7, 70.9, 81.0, 127.8, 129.7, 131.2, 137.7, 148.7, 150.4, 155.9, 162.8, 173.5; HRMS m/z calc. for C2iH28N304S [M+H4] 418.1795, found 418.1786.

Reference： [1]Patent: WO2016/146985,2016,A1 .Location in patent: Page/Page column 80; 81
[2]Chemical Communications,2019,vol. 55,p. 1821 - 1824

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[ 28241-62-5 ]

4-Methyl-5-phenylthiazol-2-amine

Similarity: 0.82

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Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 1448189-30-7 ] {[proInfo.proName]}

Quality Control of [ 1448189-30-7 ]

Related Doc. of [ 1448189-30-7 ]

Product Details of [ 1448189-30-7 ]

Calculated chemistry of [ 1448189-30-7 ] Expand+

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 1448189-30-7 ]

Application In Synthesis of [ 1448189-30-7 ]

[ 1448189-30-7 ] Synthesis Path-Upstream 1~1

[ 1448189-30-7 ] Synthesis Path-Downstream 1~109

Similar Product of [ 1448189-30-7 ]

Related Parent Nucleus of [ 1448189-30-7 ]

Thiazoles

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Similar Product of
[ 1448189-30-7 ]

Related Parent Nucleus of
[ 1448189-30-7 ]