1235406-42-4|tert-Butyl thiazol-4-ylcarbamate| Ambeed

Structure of 1235406-42-4

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Quality Control of [ 1235406-42-4 ] Purity: 98% SDS Specification

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Product Details of [ 1235406-42-4 ]

CAS No. :	1235406-42-4
Formula :	C₈H₁₂N₂O₂S
M.W :	200.26
SMILES Code :	O=C(OC(C)(C)C)NC1=CSC=N1
MDL No. :	MFCD18800853
InChI Key :	NNPOFSOQPYVUDW-UHFFFAOYSA-N
Pubchem ID :	53241636

Safety of [ 1235406-42-4 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 1235406-42-4 ] Show Less

Physicochemical Properties

Num. heavy atoms	13
Num. arom. heavy atoms	5
Fraction Csp3	0.5
Num. rotatable bonds	4
Num. H-bond acceptors	3.0
Num. H-bond donors	1.0
Molar Refractivity	52.36
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	79.46 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.09
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	1.85
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.3
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	0.67
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	1.77
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.74

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.27
Solubility	1.08 mg/ml ; 0.0054 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-3.14
Solubility	0.145 mg/ml ; 0.000725 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-2.25
Solubility	1.13 mg/ml ; 0.00562 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	No
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	Yes
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.21 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	2.67

Application In Synthesis of [ 1235406-42-4 ]

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

Downstream synthetic route of [ 1235406-42-4 ]

[ 1235406-42-4 ] Synthesis Path-Downstream 1~35

1
[ 766-98-3 ]
[ 1258934-68-7 ]
[ 1235406-42-4 ]
[ 1258934-72-3 ]
[ 1258934-71-2 ]

References: [1]Synthesis,2010,p. 3152 - 3162.
[2]Synthesis,2010,p. 3152 - 3162.

2
[ 766-98-3 ]
[ 1258934-68-7 ]
[ 1235406-42-4 ]
[ 1258934-71-2 ]

References: [1]Synthesis,2010,p. 3152 - 3162.

3
[ 3973-08-8 ]
[ 75-65-0 ]
[ 1235406-42-4 ]

Yield	Reaction Conditions	Operation in experiment
94%	With diphenyl phosphoryl azide; triethylamine; In tert-butyl alcohol; for 16h;Inert atmosphere; Reflux;	5.80 ml (41.84 mmol) of triethylamine and subsequently, with ice-bath cooling, 9.10 ml (42.19 mmol) of diphenyl azidophosphate are introduced into a solution of 4.85 g (37.55 mmol) of 4-thiazolecarboxylic acid in 180 ml of tert-butanol under nitrogen, and the reaction mixture is heated under reflux for 16 h. The solvent is removed in vacuo, the residue is taken up in dichloromethane and washed twice with water and saturated NaCl solution. The organic phase is dried over sodium sulfate, evaporated in vacuo, and the residue is purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 1/1), giving 7.07 g (35.30 mmol, 94%) of tert-butyl N-(1,3-thiazol-4-yl)carbamate as beige crystals; ESI-MS: m/e: 201 ([M+H]+).
69.1%	With diphenyl phosphoryl azide; triethylamine; at 10℃; for 16h;Reflux;	To a stirred solution of compound 1a (159 g, 1.2 mol) and triethylamine (167 mL, 1.2 mol) in t BuOH (1 L) was added DPPA (343 g, 1.2 mol) drop wise at 10oC and the mixture was heated to reflux for 16 hrs. The mixture was concentrated and purified by column (PE: EtOAc = 20:1~5:1) to give compound 2a (170 g, 69.1%) as a white solid. 1H NMR CDCl3, 400 MHz ^ 8.60 (s, 1 H), 8.56 (bs, 1 H), 7.31 (bs, 1 H) 1.56 (s, 9 H).
69%	With diphenyl phosphoryl azide; triethylamine; In tert-butyl alcohol; at 10℃; for 16h;Reflux;	To a stirred solution of compound 17 (159 g, 1.2 mol) and triethylamine (167 mL, 1 .2 mol) in t- BuOH (1 L) was added DPPA (343 g, 1 .2 mol) drop wise at 10°C and the mixture was heated to reflux for 16 hrs. The mixture was concentrated and purified by column (PE: EtOAc = 20:1 -5:1 ) to give compound 18 (170 g, 69percent>) as a white solid. (0558) 1 H NMR CDCIs, 400 MHz: ppm delta 8.60 (s, 1 H), 8.56 (bs, 1 H), 7.31 (bs, 1 H) 1.56 (s, 9 H).

60.6%	With diphenyl phosphoryl azide; triethylamine; at 0 - 90℃;	2.1 tert-butyl thiazo 1-4-ylcarbamate DPPA (1.19 g, 4.34 mmol) was added dropwise to a mixture of thiazole-4- carboxylic acid (0.5 g, 3.87 mmol) and triethylamine (0.44 g, 4.30 mmol) in tert-BuOH (50 mL) at 0 C -5 C. The mixture was heated to 90 C for overnight. The solvent was evaporated in vacuo, the residue was diluted with water and extracted with EA (3 x 20 mL). The combined organic phase was washed with brine, dried with Na2S04, concentrated under reduced pressure to give crude product. The crude product was purified by column chromatography on silica gel (EA/heptane=l/10) to give the title compound (0.47 g, 2.35 mmol, 60.6%) as a white solid. LC-MS : m/z 201 (M+H), RT=1.28 min; 1H NMR (400 MHz, CDC13): delta = 8.59 (d, J =2.4 Hz, 2H), 7.31 (s, 1H), 1.54 (s, 9H).
51.5%	With diphenylphosphoranyl azide; triethylamine; In tert-butyl alcohol; at 90 - 100℃; for 72h;	Thiazol-4-carboxylic acid (5.0 g, 38.8 mmol) was dissolved in t-BuOH (100 mL), and then TEA (8.1 mL, 1.5 eq.) and DPPA (7.1 mL, 1.5 eq.) were added thereto. While maintaining the internal temperature at 90 to 100C, the reaction mixture was stirred for 3 days, and then the completion of the reaction was confirmed by TLC. The product was concentrated under reduced pressure, distilled water (50 mL) was added, and extracted twice with EA (100 mL). MgSO4 was added to the organic layer, which was stirred, dried and then filtered. The filtrate was concentrated under reduced pressure, and the residue was added to a small amount of EA and slurried. The resulting solid was filtered to obtain a white title compound (4.0 g, 51.5%). 1H NMR (MeOD): 8.73(s, 1H), 7.24(s, 1H), 1.52(s, 9H)
27%	With diphenyl phosphoryl azide; triethylamine; at 100℃; for 17h;	A mixture of thiazole-4-carboxylic acid (8.16 g, 63.2 mmol) and triethylamine (9.7 mL, 70 mmol) in tert-butanol (320 mL) was treated with diphenyl phosphoryl azide (15 mL, 70 mmol) and heated gradually in an oil bath to 100 C. and stirred for 17 h. Once cooled, the crude reaction mixture was concentrated under reduced pressure to remove most of the volatiles. The residue was transferred to a 1.0-L separatory funnel with ethyl acetate (300 mL) and the organic layer was washed with water (2×200 mL) and brine (2×100 mL). The organic layer was then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified silica gel chromatography, eluting from 0% to 50% ethyl acetate in heptanes. The resultant gummy solid was triturated with heptanes, filtered, washed with heptanes and dried under high vacuum to afford tert-butyl thiazol-4-ylcarbamate (3.42 g, 27%) as a white solid. 1H NMR (300 MHz, CDCl3) delta 1.54 (s, 9H), 7.30 (br. s, 1H), 8.33 (br. s, 1H), 8.58 (d, J=2.3 Hz, 1H). [M-C4H8+H]+=145.1.
	With diphenyl phosphoryl azide; triethylamine; for 18h;Reflux;	Thiazole-4-carboxylic acid (6.46 g, 50.0 mmol) was slurried in terf-butyl alcohol (280 mL). Triethylamine (7.68 mL, 55.1 mmol) and diphenylphosphonic azide (1 1 .9 mL, 55.1 mmol) were added and the reaction mixture heated at reflux for 18 hours. The reaction mixture was concentrated in vacuo and the residue dissolved in ethyl acetate. The organics were washed successively with water, 5% aqueous citric acid solution, water, saturated aqueous sodium bicarbonate and brine. The organic phase was dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography (ISCO column, hexanes to ethyl acetate gradient elution) then triturated with 20% terf-butyl methyl ether in hexanes. The solid was collected by filtration and dried in vacuo to afford the title compound as a white solid (6.48 g).1 HNMR (CDCIs): delta 1 .46 (s, 9H), 7.23 (m, 1 H), 8.89 (d, 1 H).LCMS Rt = 1 .46 min MS m/z 201 [MH]+
	With diphenylphosphoranyl azide; triethylamine; In tert-butyl alcohol; at 100℃; for 8h;Inert atmosphere;	[0168] To a solution of 40-1 (8.9 g, 68 mmol), Et3N (7.8 g, 76 mmol) in t-BuOH (100 mL) was added DPPA (21 g, 77 mmol), then the mixture was stirred for 8 h under N2 at 100 C. Aftercooled to room temperature, the solvent was removed in vacuo. The residue was dissolved in CH2CI2 and the organic layer was washed with water and brine, dried over Na2504. The crudeproduct was purified by column chromatography on silica gel (PE: EtOAc = 4:1) to give 40-2. ?H NMR (400 MHz CDCI3) 5 8.87 (brs, 1H), 8.61?8.62 (m, 1H), 7.26?7.27 (m, 1H), 1.54 (s, 9H).
	With diphenyl phosphoryl azide; triethylamine; at 100℃; for 8h;Inert atmosphere;	To a solution of 40-1 (8.9 g, 68 mmol), Et3N (7.8 g, 76 mmol) in t-BuOH (100 mL) was added DPPA (21 g, 77 mmol), then the mixture was stirred for 8 h under N2at 100 C. After cooled to room temperature, the solvent was removed in vacuo. The residue was dissolved in CH2CI2 and the organic layer was washed with water and brine, dried over Na2504. The crude product was purified by column chromatography on silica gel (PE: EtOAc = 4:1) to give 40-2. 1H NMR (400 MHz CDCl3) 5 8.87 (brs, 1H), 8.61?8.62 (m, 1H), 7.26?7.27 (m, 1H), 1.54 (s, 9H).

References: [1]Synthesis,2010,p. 3152 - 3162.
[2]Patent: US2012/252759,2012,A1 .Location in patent: Page/Page column 22.
[3]Journal of Medicinal Chemistry,2017,vol. 60,p. 7029 - 7042.
[4]Patent: WO2018/210659,2018,A1 .Location in patent: Page/Page column 165-166.
[5]Patent: WO2019/57660,2019,A1 .Location in patent: Page/Page column 221.
[6]Patent: WO2014/41175,2014,A1 .Location in patent: Page/Page column 57.
[7]Patent: EP3375782,2018,A1 .Location in patent: Paragraph 0049; 0152; 0154.
[8]Patent: US2016/95858,2016,A1 .Location in patent: Paragraph 3923; 3924.
[9]Patent: WO2012/4706,2012,A2 .Location in patent: Page/Page column 47-48.
[10]Patent: WO2015/77905,2015,A1 .Location in patent: Paragraph 0168.
[11]Patent: WO2015/80988,2015,A1 .Location in patent: Paragraph 0168.

4
[ 1235406-42-4 ]
[ 1258934-68-7 ]

Yield	Reaction Conditions	Operation in experiment
86%	With N-iodo-succinimide; In 1,2-dichloro-ethane; at 83℃; for 2h;	To a solution of <strong>[1235406-42-4]tert-butyl thiazol-4-ylcarbamate</strong> (2.50 g, 12.4 mmol, 1.0 eq) in 1,2-dichloroethane (120 mL), N-iodosuccinimide (3.00 g, 13.3 mmol, 1.07 eq) was added. The resulting suspension was heated at 83 C. until the starting material was consumed (TLC, 2 h), during which it became a red solution. After cooling to room temperature, saturated aqueous Na2S203 and water were added and the layers were separated. The aqueous layer was extracted with CH2Cl2 and the combined organics were dried over MgSO4, decolorized with activated charcoal, filtered through Celite, and evaporated to provide tert-butyl (5-iodothiazol-4-yl)carbamate (3.67 g, 95% purity, 86% yield) as a pale yellow solid. Reactions run at higher concentration resulted in lower yield and purity. 1H NMR (400 MHz, Chloroform-d) delta 8.87 (s, 1H), 6.48 (s, 1H), 1.53 (s, 9H).
85%	With N-iodo-succinimide; In 1,2-dichloro-ethane; for 2h;Reflux;	1033 mg (4.59 mmol) of N-iodosuccinimide are introduced into a solution of 800 mg (3.99 mmol) of <strong>[1235406-42-4]tert-butyl N-(1,3-thiazol-4-yl)carbamate</strong> in 40 ml of dichloroethane, and the reaction mixture is heated under reflux for 2 h. After cooling, the mixture is washed twice with water and with saturated sodium thiosulfate solution. The combined organic phases are dried over sodium sulfate, evaporated in vacuo, and the residue is purified by flash chromatography on silica gel (eluent: cyclohexane/ethyl acetate 8/2 to 1/1), giving 1.19 g (3.43 mmol, 85%) of tert-butyl N-(5-iodo-1,3-thiazol-4-yl)carbamate as white crystals after crystallisation from diethyl ether; ESI-MS: m/e: 327 ([M+H]+).
75%	With N-iodo-succinimide; In 1,2-dichloro-ethane; at 20℃; for 5h;	To a stirred solution of compound 2a (90 g, 1.35 mol) in DCE (1200 mL) was added NIS (135 g, 1.74 mol) portion wise at 20oC and stirred for 5 hrs. The mixture was washed with brine (200 mL), aq. Na2SO3 (200 mL), dried over Na2SO4, filtered, concentrated and purified by column (PE:EtOAc = 20:1~5:1) to give compound 3a (110 g, 75.0%) as a white solid. 1H NMR CDCl3, 400 MHz ^ 8.79 (s, 1 H), 6.53 (bs, 1 H), 1.54 (s, 9 H).

75%

With N-iodo-succinimide; In 1,2-dichloro-ethane; at 20℃; for 5h;

To a stirred solution of compound 18 (90 g, 1 .35 mol) in DCE (1200 mL) was added NIS (135 g, 1 .74 mol) portion wise at 20C and stirred for 5 hrs. The mixture was washed with brine (200 mL), aq. Na2S03 (200 mL), dried over Na2S04, filtered, concentrated and purified by column (petroleum ether (PE):ethyl acetate(EtOAc) = 20:1 -5:1 ) to give compound 19 (1 10 g, 75%) as a white solid. (0562) H NMR CDCIs, 400 MHz: ppm delta 8.79 (s, 1 H), 6.53 (bs, 1 H), 1.54 (s, 9 H).

References: [1]Patent: US2020/109154,2020,A1 .Location in patent: Paragraph 0392; 0395; 0398-0400.
[2]Synthesis,2010,p. 3152 - 3162.
[3]Patent: US2012/252759,2012,A1 .Location in patent: Page/Page column 22.
[4]Patent: WO2018/210659,2018,A1 .Location in patent: Page/Page column 166.
[5]Patent: WO2019/57660,2019,A1 .Location in patent: Page/Page column 221-222.

5
[ 220227-21-4 ]
[ 1235406-42-4 ]
[ 1235406-62-8 ]

Yield	Reaction Conditions	Operation in experiment
68%		EXAMPLE 293 Synthesis of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-2,5-difluoro-//-(thiazol-4- yl)benzenesulfonamide 2,2,2-trifluoroacetate Step 1. Preparation of te/f-butyl thiazol-4-yl((2,4,5-trifluorophenyl)sulfonyl)carbamate To a solution of terf-butyl thiazol-4-ylcarbamate (1.47 g, 7.35 mmol) in anhydrous tetrahydrofuran (10 mL) was added a 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (10.3 mL, 10.3 mmol) at -78 C. The reaction mixture was allowed to warm to ambient temperature and stirred for 1 h. The reaction mixture was then cooled to -78 C, and a solution of 2,4,5- trifluorobenzenesulfonyl chloride (1.22 mL, 8.82 mmol) in anhydrous tetrahydrofuran (10 mL) was added to it. The reaction mixture was allowed to warm to ambient temperature and stirred for 3 h. The mixture was diluted with ethyl acetate (50 mL), washed with saturated ammonium chloride (2 chi 30 mL), brine (2 chi 30 mL), dried over anhydrous sodium sulfate, and filtered. Concentration of the filtrate in vacuo and purification of the residue by column chromatography, eluting with a gradient of 0 to 50% of ethyl acetate in hexanes, provided the title compound as a colorless solid (2.0 g, 68% yield): MS (ES+) m/z 395.0 (M + 1).
64%		To a solution of terf-butyl 1 ,3-thiazol-4-ylcarbamate (Preparation 3, 28.94 g, 145 mmol) in anhydrous tetrahydrofuran (600 mL) at -70 C, under an atmosphere of nitrogen was added lithium 1 , 1 ,1 ,3,3,3-hexamethyldisilazan-2-ide (1 M in tetrahydrofuran , 145 mL, 1 45 mmol ) d rop-wise. The reaction mixture was allowed to warm to ambient temperature and stirred for 1 hour before cooling to -70 C once again. A solution of 2, 4, 5-trifluro benzenesulfonyl chloride (40 g, 173 mmol) in tetrahydrofuran (80 mL) was added drop-wise and then th e reaction m ixtu re was slowly warmed to am b ient temperature and stirred for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution before concentrating in vacuo. The crude residue was purified by silica gel column chromatography (0% to 15% ethyl acetate in hexanes gradient elution) to afford the title compound as white solid (37 g, 64%).1 H NMR (400 MHz, CDCI3): delta 1 .35 (s, 9H), 7.07-7.1 3 (m, 1 H), 7.52 (s, 1 H), 8.00-8.06 (m, 1 H), 8.78 (s, 1 H).LCMS Rt= 3.46 minutes. MS m/z 395 [MH]+
62%		A solution of ferf-butyl thiazol-4-ylcarbamate (3.46 g, 17.3 mmol) in tetrahydrofuran (150 mL) at -78 C was treated with lithium 6/'s(trimethylsilyl)amide (1.0 M solution in tetrahydrofuran, 20.8 mL, 20.8 mmol). The resulting mixture was stirred at -78 C for 0.5 h, allowed to warm to ambient temperature and stirred for a further 0.5 h. The reaction mixture was cooled to -78 C and treated with a solution of 2,4,5- trifluorobenzene-1-sulfonyl chloride (3.99 g, 17.3 mmol) in tetrahydrofuran (30 mL). The resulting mixture was stirred at -78 C for 4 h, allowed to warm to ambient temperature and stirred for a further 16 h. The reaction mixture was diluted with ethyl acetate (300 mL) and washed with saturated aqueous ammonium chloride (2 x 150 mL) and brine (2 x 150 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with a gradient of ethyl acetate in hexanes to afford terf-butyl thiazol-4-yl((2,4,5- trifluorophenyl)sulfonyl)carbamate as a beige solid in 62% yield (4.23 g): 1H NMR (300 MHz, CDCI3) 6 8.79-8.75 (m, 1 H), 8.06-7.96 (m, 1 H), 7.53-7.48 (m, 1H), 7.15-7.04 (m, 1 H), 1.34 (s, 9H); MS (ES+) m/z 394.7 (M + 1).

References: [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 7029 - 7042.
[2]Patent: WO2017/201468,2017,A1 .Location in patent: Page/Page column 375-376.
[3]Patent: WO2012/4706,2012,A2 .Location in patent: Page/Page column 74.
[4]Patent: WO2013/64984,2013,A1 .Location in patent: Page/Page column 137-138.
[5]ACS Medicinal Chemistry Letters,2016,vol. 7,p. 277 - 282.

6
[ 1235406-42-4 ]
[ 13656-57-0 ]
[ 1235406-85-5 ]

Yield	Reaction Conditions	Operation in experiment
67%		EXAMPLE 38 Synthesis of (S)-4-((1-benzylpyrrolidin-3-yl)(methyl)amino)-5-chloro-2-fluoro-//-(thiazol- 4-yl)benzenesulfonamide 2,2,2-trifluoroacetate Step 1. Preparation of terf-butyl ((5-chloro-2,4-difluorophenyl)sulfonyl)(thiazol-4- yl)carbamate To a solution of terf-butyl thiazol-4-ylcarbamate (160.0 g, 799.0 mmol) in anhydrous tetrahydrofuran (1500 mL) was added lithium bis(trimethylsilyl)amide (1 M solution in tetrahydron, 1120 mL) at -78 C. The reaction mixture was warmed to 5 C, stirred for 30 minutes, and cooled to -78 C. To it was then added dropwise a solution of 5-chloro-2,4-difluorobenzenesulfonyl chloride (355.3 g, 1440 mmol) in anhydrous tetrahydrofuran (500 mL) at -78 C. The reaction mixture was allowed to warm to ambient temperature and stirred for 12h. To it was then added saturated ammonium chloride (200 mL), and the mixture was extracted with ethyl acetate (3 chi 1000 mL). The combined organic phase was washed with brine (3 chi 1000 mL), dried over anhydrous sodium sulfate, and filtered. Concentration of the filtrate in vacuo and trituration of the residue with methanol (500 mL) provided the title compound as a colorless solid (220.0 g, 67% yield): H NMR (400MHz, DMSO-cfe) £9.14 (d, J = 2.2 Hz, 1 H), 8.25 (t, J = 7.6 Hz, 1 H), 8.06-7.94 (m, 2H), 1.28 (s, 9H); MS (ES+) m/z 310.8 (M - 99), 312.8 (M - 99).
31.8%		Under N2 protection,Z-0-2 (8.0 g, 0.04 mol)Was dissolved in dry THF (80 ml)The mixture was cooled to -78 C,LiHMDS (IM, 48 ml, 0.048 mol)Of THF solution.After the dropwise addition,The mixture is in-78 C,Stir for 0.5 h.The reaction solution was slowly warmed to room temperature,Stir for 1h,Then cooled to -78 C,5-Chloro-2,4-difluorobenzenesulfonyl chloride (11.11 g, 0.048 mol)In THF (50 ml) was added dropwise to the above reaction solution.The mixture was stirred at -78 & lt; 0 &After stirring for 1 h, the temperature was raised to room temperature,And stirred at room temperature for 16 h.To the reaction solution was added saturated aqueous ammonium chloride solution (250 ml) and extracted with ethyl acetate (3 x 100 ml) to combine the organic phases,Washed with saturated brine (200 ml)dry,40 C spin dry.Crude column (100-200 mesh silica gel), eluent as petroleum ether: ethyl acetate = (4: 1),To give Z-0-3 (5.11 g, yield: 31.8%)As a white solid. ESI-MS (M + Na) +: 434.0, purity: 95.9% (UV214).
		To a solution of thiazol-4-yl-carbamic acid te/t-butyl ester (Preparation 3, 503 mg, 2.51 mmol) in tetrahydrofuran (5.0 ml_) cooled to -78 C was added lithium hexamethyldisilazide (1 .0 M in tetrahydrofuran, 2.76 ml_, 2.76 mmol). The reaction mixture was stirred for 30 minutes at ambient temperature then cooled to -78 C. A sol ution of 5-chloro-2,4-difluorobenzenesulfonyl chloride (620.5 mg, 2.51 mmol) in tetrahydrofuran (5.0 ml_) was added slowly via a syringe. After the addition was complete, the reaction mixture was allowed to warm gradually to ambient temperature. After 24 hours, the reaction mixture was poured into saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo onto diatomaceous earth. The residue was purified by automated silica gel flash chromatography (0% to 5% ethyl acetate in dichloromethane gradient elution) to afford the title compound as a white solid (733 mg).1 HNMR (de-DMSO): delta 1 .40 (s, 9H), 7.10 (m, 1 H), 7.52 (m, 1 H), 8.25 (t, 1 H), 8.80 (m, 1 H).LCMS Rt = 1 .70 min MS m/z 31 1 [M(-Boc)H]+

		[0169] To a solution of 40-2 (1.0 g, 4.9 mmol) in 20 mL of THE was added LiHMDS (5.8 mL, 5.8mmol) at -78 C, and the mixture was stirred for 1 h under N2at room temperature. After beingcooled back to -78 C, a solution of 19-4(1.1 g, 4.5 mmol) in 2 mL of THE was added to the above solution. Then the mixture was warmed to room temperature and stirred for 1 h. The reaction was quenched with NH4CI and extracted with EtOAc. The organic layer was washed with water and brine, dried over Mg504, filtered and concentrated. The crude product was purified bycolumn chromatography on silica gel (PE: EtOAc = 8:1) to give 7-1. ?H NMR (400 MHz CDCI3) S8.80 (d, J = 2.0 Hz, 1H), 8.23 (t, J = 7.6 Hz, 1H), 7.53 (d, J = 2.0 Hz, 1H), 7.09 (t, J = 8.4 Hz, 1H), 1.37 (s, 9H). MS m/z (Mi-H): 411
		To a solution of 40-2 (1.0 g, 4.9 mmol) in 20 mL of THE was added LiHMDS (5.8 mL, 5.8 mmol) at -78 C, and the mixture was stirred for 1 h under N2at room temperature. After being cooled back to -78 C, a solution of 19-4 (1.1 g, 4.5 mmol) in 2 mL of THE was added to the above solution. Then the mixture was warmed to room temperature and stirred for 1 h. The reaction was quenched with NH4CI and extracted with EtOAc. The organic layer was washed with water and brine, dried over Mg504, filtered and concentrated. The crude product was purified by column chromatography on silica gel (PE: EtOAc = 8:1) to give 7-1. ?H NMR (400 MHz CDCl3) 5 8.80 (d, J = 2.0 Hz, 1H), 8.23 (t, J = 7.6 Hz, 1H), 7.53 (d, J = 2.0 Hz, 1H), 7.09 (t, J = 8.4 Hz, 1H), 1.37 (s, 9H). MS m/z (M+H): 411

References: [1]Patent: WO2017/201468,2017,A1 .Location in patent: Page/Page column 144.
[2]Journal of Medicinal Chemistry,2017,vol. 60,p. 7029 - 7042.
[3]Patent: CN106243003,2016,A .Location in patent: Paragraph 0130; 0131; 0133.
[4]Patent: WO2012/4706,2012,A2 .Location in patent: Page/Page column 48.
[5]Patent: WO2015/77905,2015,A1 .Location in patent: Paragraph 0169.
[6]Patent: WO2015/80988,2015,A1 .Location in patent: Paragraph 0169.

7
[ 1235406-42-4 ]
[ 1354819-07-0 ]

References: [1]Patent: WO2012/4706,2012,A2 .

8
[ 1235406-42-4 ]
[ 1354819-09-2 ]

References: [1]Patent: WO2012/4706,2012,A2 .

9
[ 1235406-42-4 ]
[ 1354819-28-5 ]

References: [1]Patent: WO2012/4706,2012,A2 .

10
[ 1235406-42-4 ]
[ 1354819-12-7 ]

References: [1]Patent: WO2012/4706,2012,A2 .

11
[ 1235406-42-4 ]
[ 1354819-30-9 ]

References: [1]Patent: WO2012/4706,2012,A2 .

12
[ 1235406-42-4 ]
[ 1354819-13-8 ]

References: [1]Patent: WO2012/4706,2012,A2 .

13
thiazole-4-carbonyl azide [ No CAS ]
[ 75-65-0 ]
[ 1235406-42-4 ]

Yield	Reaction Conditions	Operation in experiment
67%	In toluene; for 2h;Reflux;	Step B: A mixture of thiazole-4-carbonyl azide (860 mg, 5.5 mmol) and 2-methylpropan-2-ol (0.62 mL) in toluene (20 mL) was heated under reflux for 2 h. The mixture was concentrated under reduced pressure and partitioned between water and EtOAc. The organic layer was concentrated under reduced pressure to afford tert- butyl thiazol-4-ylcarbamate (740 mg, 67%). 1H NMR (300 MHz, DMSO-t/6) delta 10.21 (br s, 1H), 8.89 (s, 1H), 7.23 (br s, 1H), 1.46 (s, 9H).

References: [1]Patent: WO2012/30914,2012,A1 .Location in patent: Page/Page column 80-89.

14
[ 1241914-72-6 ]
[ 1235406-42-4 ]
[ 1362690-47-8 ]

Yield	Reaction Conditions	Operation in experiment
50%		Step C: To (4-chloroquinazolin-2-yl)(4-fluorophenyl)methanone from Example 1 Step A (250 mg, 0.87 mmol) in DMF (20 mL) at 0 C under argon was added 60% sodium hydride/mineral oil (38 mg, 1 mmol), and the mixture was stirred for 10 min. tert-Butyl thiazol-4-ylcarbamate (315 mg, 1.5 mmol) in DMF (10 mL) was added slowly, and the mixture was stirred for 30 min at rt. Additional 60% sodium hydride/mineral oil (42 mg, 1.05 mmol) was added and the mixture was stirred at rt for 2 h. The mixture was partitioned between water and EtOAc, and the organic layer was dried over Na2S04 and concentrated under reduced pressure. The residue was purified by silica gel chromatography 0-25% EtOAc/hexanes to afford tert-butyl 2-(4-fluorobenzoyl)quinazolin-4-yl(thiazol-4-yl)carbamate (200 mg, 50%). LCMS (ESI) m/z 451 (M + H)+

References: [1]Patent: WO2012/30914,2012,A1 .Location in patent: Page/Page column 81.

15
[ 1235406-42-4 ]
[ 1258934-71-2 ]

References: [1]Patent: US2012/252759,2012,A1 .

16
[ 1235406-42-4 ]
[ 1258934-81-4 ]

References: [1]Patent: US2012/252759,2012,A1 .

17
[ 1235406-42-4 ]
[ 1258934-82-5 ]

References: [1]Patent: US2012/252759,2012,A1 .

18
[ 287172-65-0 ]
[ 1235406-42-4 ]
tert-butyl [(5-bromo-2,4-difluorophenyl)sulfonyl]-1,3-thiazol-4-ylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Preparation 38 Tert-butyl[(5-bromo-2,4-difluorophenyl)sulfonyl]1,3-thiazol-4-ylcarbamate To a solution of thiazole-4-yl-carbamic acid tert-butyl ester (WO201004707, 1650 mg, 8.23 mmol) in THF (29.3 mL) was added LiHMDS (8.23 mL, 8.23 mmol) at 0 C. After stirring for 1 hour at this temperature, the reaction mixture was cooled to -78 C. and 2,4-difluoro-5-bromobenzenesulfonamide (2000 mg, 6.86 mmol) in THF (5.0 mL) was added. The mixture was allowed to warm to room temperature over 18 hours. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution (60 mL) and extracted into DCM. The organic layer was collected, dried over MgSO4 and concentrated in vacuo. The residue was dissolved in DCM (10 mL), TFA (10 mL) was added and the reaction mixture stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and purified using silica gel column chromatography eluting with 50:50 EtOAc:Heptane to afford the title compound as a white solid (2.08 g, 85%). 1H NMR (400 MHz, DMSO-d6): delta ppm 1.35 (s, 9H), 7.10 (s, 1H), 7.75 (m, 1H), 8.10 (m, 1H), 8.90 (m, 1H), 11.45 (br s, 1H).

References: [1]Patent: US2014/315933,2014,A1 .Location in patent: Paragraph 0531; 0532; 0533.

19
[ 1235406-42-4 ]
tert-butyl (5-chloro-2-fluoro-4-(((hexahydro-1H-pyrrolizin-7a-yl)methyl)amino)phenyl)sulfonyl(thiazol-4-yl)carbamate [ No CAS ]

References: [1]Patent: WO2015/77905,2015,A1 .
[2]Patent: WO2015/80988,2015,A1 .

20
[ 220227-21-4 ]
[ 1235406-42-4 ]
C₃₇H₃₇ClF₂N₄O₁₀S₂ [ No CAS ]

References: [1]ACS Medicinal Chemistry Letters,2016,vol. 7,p. 277 - 282.

21
[ 1235406-42-4 ]
tert-butyl N-[2-[[6-tert-butyl-2-(2,4,6-trimethylphenoxy)pyridine-3-carbonyl]sulfamoyl]thiazol-4-yl]carbamate [ No CAS ]

References: [1]Patent: US2016/95858,2016,A1 .

22
[ 1235406-42-4 ]
tert-butyl N-(2-sulfamoyl-1,3-thiazol-4-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%		A solution of <strong>[1235406-42-4]tert-butyl thiazol-4-ylcarbamate</strong> (1.50 g, 7.49 mmol) in methyl tert-butyl ether (35 mL) was cooled in an ice bath and treated slowly with iso-propylmagnesium chloride (11 mL of a 2.0 M solution in THF, 22 mmol). A voluminous white solid appeared. After 20 minutes in the ice bath, sulfur dioxide was gently bubbled into the reaction mixture for 5 minutes then the reaction mixture was stirred at room temperature for 1 h. The crude reaction mixture was concentrated under reduced pressure to remove most of the volatiles and the solid obtained was suspended in water (80 mL) and cooled in an ice bath. Sodium acetate (3.40 g, 41.5 mmol) and hydroxylamine-O-sulfonic acid (3.39 g. 30.0 mmol) were successively added. The ice-bath was removed and the reaction was left to stir at room temperature for 45 h. The reaction mixture was transferred to a separatory funnel and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with 5% aqueous sodium bicarbonate (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting from 0% to 75% ethyl acetate in heptanes, to provide 1.2 g of a solid that was contaminated with iso-propylsulfonamide. The solid was dissolved in methanol (3 mL) and water (2 mL) was added dropwise with stirring. The precipitate was filtered, washed with water and dried under high vacuum to afford tert-butyl N-(2-sulfamoyl-1,3-thiazol-4-yl)carbamate (0.90 g, 43%) as a white solid. 1H NMR (300 MHz, DMSO-d6) delta 1.46 (s, 9H), 7.56 (s, 2H), 9.12 (s, 1H), 9.24 (s, 1H). [M-C4H8+H]+=224.0.

References: [1]Patent: US2016/95858,2016,A1 .Location in patent: Paragraph 3925; 3926.

23
[ 1235406-42-4 ]
perfluorophenyl 5-(2-methoxy-4-(trifluoromethyl)phenyl)naphthalene-2-sulfonate [ No CAS ]
tert-butyl (5-(2-methoxy-4-(trifluoromethyl)phenyl)naphthalen-2-yl)sulfonyl(thiazol-4-yl)carbamate [ No CAS ]

References: [1]ACS Medicinal Chemistry Letters,2016,vol. 7,p. 1062 - 1067.

24
[ 874801-46-4 ]
[ 1235406-42-4 ]
tert-butyl ((4-bromo-3-chlorophenyl)sulfonyl)(thiazol-4-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%		To a solution of <strong>[1235406-42-4]tert-butyl thiazol-4-ylcarbamate</strong> (26.50 g, 132.33 mmol) in THF (300 mL) at -78 C, under nitrogen, was added 1 M solution of lithium bis(trimethylsilyl)amide in THF (185 mL, 185 mmol) dropwise. The mixture was warmed to 0 C and stirred for 1 h. The mixture was added dropwise a solution of 4-bromo-3-chlorobenzenesulfonyl chloride (49.88 g, 172.03 mmol) in THF (200 mL) at -78 C. The resulting mixture was stirred at 20 C for 3 h and then quenched with saturated aqueous sodium bicarbonate (100 mL) and water (300 mE). The mixture was extracted with EtOAc (3 x 300 mL) and the combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resdiue was triturated with MeOH (200 mL) to give the title compound as a colorless solid (35.00 g, 58% yield).MS (ES+) m/z: 476.9 (M + 23). 1H NMR (300 MHz, CDCl3) (5 8.82 (d, J = 2.0 Hz, 1H), 8.25 (a, J = 4.0 Hz, 1H), 7.95-7.89 (m, 1H), 7.87-7.83 (m, 1H), 7.58 (d, J = 4.0 Hz, 1H), 1.38 (s, 9H).
58%		EXAMPLE 225 Synthesis of (f?)-4-((1 -benzyl-3-methylpyrrolidin-3-yl)amino)-3-chloro-//-(thiazol-4- yl)benzenesulfonamide formate To a mixture of te/f-butyl thiazol-4-ylcarbamate (26.5 g, 132.3 mmol) in anhydrous tetrahydrofuran (300 mL) was added a 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (185.3 mL, 185.3 mmol) at -78 C. The reaction mixture was allowed to warm to 0 C and stirred for 1 h. After cooling the reaction mixture to -78 C, a solution of 4-bromo-3-chlorobenzenesulfonyl chloride (49.88 g, 172.0 mmol) in anhydrous tetrahydrofuran (200 mL) was added to it. The reaction mixture was allowed to warm to ambient temperature, stirred for 3 h, and then quenched by addition of saturated sodium bicarbonate solution (100 mL). The mixture was diluted with water (300 mL) and extracted with ethyl acetate (3 chi 300 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, and filtered. Concentration of the filtrate in vacuo and trituration of the residue in methanol (200 mL) provided the title compound as a colorless solid (35.0 g, 58% yield): H NMR (400 MHz, CDCI3) 8.85-8.78 (d, J = 2.0 Hz, 1 H), 8.28-8.21 (d, J = 4.0 Hz, 1 H), 7.95-7.89 (m, 1 H), 7.87-7.83 (m, 1 H), 7.59-7.55 (d, J = 4.0 Hz, 1 H), 1.38 (s, 9H); MS (ES+) m/z 352.9 (M - 99), 354.9 (M - 99).

References: [1]Patent: WO2017/58821,2017,A1 .Location in patent: Page/Page column 149; 150.
[2]Patent: WO2017/201468,2017,A1 .Location in patent: Page/Page column 265.

25
[ 1235406-42-4 ]
C₂₃H₂₀Cl₂FN₅O₅S₂ [ No CAS ]

References: [1]Patent: CN106243003,2016,A .

26
[ 1235406-42-4 ]
tert-butyl [(5-chloro-2-fluoro-4-{2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]-4-(trifluoromethyl)phenoxy}phenyl)sulfonyl]-1,3-thiazol-4-yl-carbamate [ No CAS ]