99073-88-8|Ethyl 2-bromo-6-benzothiazolecarboxylate| Ambeed

Structure of 99073-88-8

*Storage: {[sel_prStorage]}

*Shipping: {[sel_prShipping]}

4.5 *For Research Use Only !

{[proInfo.pro_purity]}

Cat. No.: {[proInfo.prAm]} Purity: {[proInfo.pro_purity]}

Change View

Size	Price	VIP Price	US Stock	Global Stock	In Stock
{[ item.pr_size ]}		Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate,item.pr_is_large_size_no_price, item.vip_usd) ]}

US Stock: ship in 0-1 business day
Global Stock: ship in 5-7 days

{[ item.pr_size ]}

In Stock

- +

Please Login or Create an Account to: See VIP prices and availability

US Stock: ship in 0-1 business day
Global Stock: ship in 2 weeks

Quality Control of [ 99073-88-8 ] Purity: 97% SDS Specification

COA

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

NMR

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

CNMR

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

HPLC

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

LC-MS

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

1-2 Day Shipping
High Quality
Technical Support

Product Details of [ 99073-88-8 ]

CAS No. :	99073-88-8
Formula :	C₁₀H₈BrNO₂S
M.W :	286.15
SMILES Code :	BrC1=NC2=C(S1)C=C(C=C2)C(=O)OCC
MDL No. :	MFCD08669850
InChI Key :	JQZQKEZCRZNJPC-UHFFFAOYSA-N
Pubchem ID :	12067225

Safety of [ 99073-88-8 ]

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

Computational Chemistry of [ 99073-88-8 ] Show Less

Physicochemical Properties

Num. heavy atoms	15
Num. arom. heavy atoms	9
Fraction Csp3	0.2
Num. rotatable bonds	3
Num. H-bond acceptors	3.0
Num. H-bond donors	0.0
Molar Refractivity	63.41
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	67.43 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.8
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	3.62
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	3.24
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.	2.35
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	3.96
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	3.19

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-4.14
Solubility	0.0207 mg/ml ; 0.0000723 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-4.72
Solubility	0.00541 mg/ml ; 0.0000189 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately 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	-4.3
Solubility	0.0144 mg/ml ; 0.0000504 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately 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	Yes
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	Yes
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	Yes
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.	-5.48 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)	2.42

Application In Synthesis of [ 99073-88-8 ]

* 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 [ 99073-88-8 ]

[ 99073-88-8 ] Synthesis Path-Downstream 1~35

1
[ 50850-93-6 ]
[ 99073-88-8 ]

Yield	Reaction Conditions	Operation in experiment
96%	With tert.-butylnitrite; copper(ll) bromide; In acetonitrile; at 20℃; for 1h;	Step 1: To a solution of tert-butyl nitrite (4.5 mL, 37.5 mmol) and copper(II) bromide (6.0 g, 27 mmol) in CH3CN(100 mL) at rt was added a mixture of ethyl 2-aminobenzo[d]thiazole-6-carboxylate (5.0 g, 22.5 mmol) in CH3CN (50mL). The reaction suspension was stirred at rt for 1 h. The resulting reaction mixture was quenched with 300 mL of 1 NHCl aqueous solution and extracted with CH2Cl2 (3x200 mL). The combined organic layers were dried over MgSO4,and concentrated under reduced pressure. The crude product was purified on a silica gel column using a mixture ofCH2Cl2-hexanes (4:1, v/v) as eluent to give ethyl 2-bromobenzo[d]thiazole-6-carboxylate as a white solid (6.2 g, 96%).1H NMR (300 MHz, CDCl3) delta 8.54 (d, J= 1.1 Hz, 1H), 8.16 (dd, J= 1.5, 8.7 Hz, 1H), 8.02 (d, J = 8.7 Hz, 1H), 4.43 (q, J=7.2 Hz, 2H), 1.43 (t, J= 7.2 Hz, 3H). LCMS (ESI) m/z 288, 286 (M+H)+.
89%	With tert.-butylnitrite; copper(ll) bromide; In acetonitrile; at 20℃; for 0.75h;	Add a solution of commercially available ethyl 2- aminobenzothiazole-6-carboxylate (10 g, 45 mmol) in acetonitrile (40 ML) to a solution of copper (II) bromide (12 G, 54 mmol) and tert-butyl nitrite (9 mL, 75 mmol) in acetonitrile (100 mL) at room temperature under nitrogen and stir for 45 min. Dilute the mixture with 1 N HCL (300 mL) and extract with methylene chloride (3 x 300 mL). Wash the combined organic extracts with water (300 mL), dry over MGS04, filter though a plug of silica gel and remove the solvents under reduced pressure to afford ethyl 2- bromobenzothiazole-6-carboxylate (Step 1) as an off-white solid (11.5 g, 89%): 1H NMR (CDC13) 5 1.40 (t, 3H), 4.40 (q, 2H), 8.00 (d, 1H), 8.20 (d, 1H), 8.60 (s, 1H).
		(195-4) Ethyl 2-bromo-1,3-benzothiazole-6-carboxylate was obtained from the compound of Example 195-3 in a similar manner to Example 125-2. 1H NMR (CDCl3, 400 MHz) delta 9.71 (brs, 1H), 9.16 (s, 1H), 8.56 (d, 1H, J=1.2 Hz), 8.24 (d, 1H, J=8.5 Hz), 8.09 (dd, 1H, J=8.5, 1.2 Hz), 7.19 (m, 1H), 6.95 (m, 1H), 6.39 (m, 1H).

		(195-4) Ethyl 2-bromo-1,3-benzothiazole-6-carboxylate was obtained from the compound of Example 195-3 in a similar manner to Example 125-2. 1H NMR (CDCl3, 400MHz) delta 9.71 (brs, 1H), 9.16 (s, 1H), 8.56 (d, 1H, J=1.2Hz), 8.24 (d, 1H, J=8.5Hz), 8.09 (dd, 1H, J=8.5, 1.2Hz), 7.19 (m, 1H), 6.95 (m, 1H), 6.39 (m, 1H).
	With tert.-butylnitrite; copper(ll) bromide; In acetonitrile; at 0 - 20℃; for 2.16667h;Inert atmosphere;	EXAMPLE 1; 2-[l-(3,4,5-Tribromobenzyl)-lH-L2,3-triazol-4-yl]-L3-benzothiazole-6-carboxylic acid Step 1: Ethyl 2-bromo-L3-benzothiazole-6-carboxylateA suspension Of CuBr2 (1.20 g, 5.40 mmol) in anhydrous acetonitrile (15 niL) was purged with nitrogen. The mixture was cooled in an ice-bath and treated with t- BuONO (696 mg, 6.75 mmol). After further stirring for 10 min at about 0 to 5 0C, the mixture was reacted with 2-amino-l,3-benzothiazole-6-carboxylate (1.0 g, 4.5 mmol). The cooling bath was removed and the reaction mixture was stirred at room temperature for 2 h. The mixture was then diluted with water (30 mL) and extracted with ether (100 mL x 2). The combined organic phase was filtered to removed copper salts, then washed with water (20 mL) and brine (20 mL), dried over Na2SO4 and concentrated to afford the title compound.1H NMR (CDCl3, 400 MHz): delta 8.54 (d, IH), 8.16 (dd, IH), 8.02 (d, IH), 4.42 (q, 2H), 1.42 (t, 3H).
	With tert.-butylnitrite; copper(ll) bromide; In acetonitrile; at 65℃; for 2h;	STEP A: Ethyl 2-aminobenzothiazole-6-carboxylate (8.91 g) and CuBr2 (13.43 g) were combined in acetonitrile (300 mL). To the resulting deep green solution was added tert-butylnitrite (7.14 mL). The resulting mixture was heated to ~65 C for two hours, then concentrated to ~50 mL. The resulting concentrate was diluted with water (250 mL) and extracted with EtOAc (2*250 mL). The resulting yellow solution was concentrated to yield ethyl 2-bromobenzo[d]thiazole-6-carboxylate as a yellow solid. 1H NMR delta 8.55 (s, 1H), 8.16 (dd, 1H, J=8.6, 1.7 Hz), 8.03 (d, 1H, J=8.3 Hz), 4.43 (q, 2H, J=7.1 Hz), 1.43 (t, 3H, J=7.1 Hz). MS: 286.0 (M+H).
	With tert.-butylnitrite; copper(ll) bromide; In acetonitrile; at 20℃; for 14h;Cooling with ice;	To the solution of ethyl 2-aminobenzo[d]thiazole-6-carboxylate (8.0 g, 36.0 mmol) and CuBr2 (16.07 g, 72.0 mmol) in acetonitrile (200 mL), tert-butyl nitrite (7.42 mL, 72.0 mmol) was added on ice bath. The reaction mixture was stirred at room temperature for 14 h. The solvent was removed under reduced pressure and to the residue ethyl acetate (200 mL) and NH4Cl solution (200 mL) were added. The organic phase was washed with brine (100 mL) and NH4Cl solution (100 mL), dried over Na2SO4, filtered and the solvent evaporated under reduced pressure. Yield: 8.0 g (78%); pale brown solid. (0862) 1H NMR (400 MHz, DMSO-d6): d 1.36 (t, J = 7.1 Hz, 3H), 4.37 (q, J = 7.1 Hz, 2H), 8.10 (s, 2H), 8.82 (s, 1H) ppm.

References: [1]Patent: EP2766359,2016,B1 .Location in patent: Paragraph 0319.
[2]Patent: WO2004/63155,2004,A1 .Location in patent: Page 148-149.
[3]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 1874 - 1879.
[4]Yakugaku Zasshi/Journal of the Pharmaceutical Society of Japan,1958,vol. 78,p. 437.
Chem.Abstr.,1958,p. 14589.
[5]Patent: US2003/181496,2003,A1 .
[6]Patent: EP1479384,2004,A1 .
[7]Patent: WO2010/37225,2010,A1 .Location in patent: Page/Page column 42.
[8]Patent: US2011/152287,2011,A1 .Location in patent: Page/Page column 21.
[9]Patent: WO2020/48949,2020,A1 .Location in patent: Page/Page column 98.

2
[ 99073-88-8 ]
[ 108-00-9 ]
2-(2-dimethylamino-ethylamino)-benzothiazole-6-carboxylic acid ethyl ester [ No CAS ]

References: [1]Yakugaku Zasshi/Journal of the Pharmaceutical Society of Japan,1958,vol. 78,p. 437.
Chem.Abstr.,1958,p. 14589.

3
[ 99073-88-8 ]
[ 109-55-7 ]
2-(3-dimethylamino-propylamino)-benzothiazole-6-carboxylic acid ethyl ester [ No CAS ]

References: [1]Yakugaku Zasshi/Journal of the Pharmaceutical Society of Japan,1958,vol. 78,p. 437.
Chem.Abstr.,1958,p. 14589.

4
[ 99073-88-8 ]
[ 20291-99-0 ]
[ 290363-57-4 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 1219 - 1223.
[2]Chemical and Pharmaceutical Bulletin,2003,vol. 51,p. 697 - 701.

5
[ 99073-88-8 ]
[ 214337-23-2 ]
[ 628725-92-8 ]

References: [1]Journal of Medicinal Chemistry,2003,vol. 46,p. 4428 - 4449.

6
[ 99073-88-8 ]
(2S)-2-[(3aS,6S,6aR)-4-(6-ethylcarboxylate-1,3-benzothiazol-2-yl)-6-methyl-5-oxohexahydropyrrolo[3,2-b]pyrrol-1(2H)-yl]carbonyl}-N-(4-isopropylphenyl)pyrrolidine-1-carboxamide [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2003,vol. 46,p. 4428 - 4449.

7
[ 99073-88-8 ]
2-[(3S,3aR,6aS)-3-Methyl-2-oxo-4-((S)-pyrrolidine-2-carbonyl)-hexahydro-pyrrolo[3,2-b]pyrrol-1-yl]-benzothiazole-6-carboxylic acid ethyl ester; compound with trifluoro-acetic acid [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2003,vol. 46,p. 4428 - 4449.

8
[ 99073-88-8 ]
[ 290363-43-8 ]

References: [1]Chemical and Pharmaceutical Bulletin,2003,vol. 51,p. 697 - 701.
[2]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 1219 - 1223.

9
[ 99073-88-8 ]
[ 290363-29-0 ]

References: [1]Chemical and Pharmaceutical Bulletin,2003,vol. 51,p. 697 - 701.
[2]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 1219 - 1223.

10
[ 99073-88-8 ]
[ 625080-89-9 ]

References: [1]Chemical and Pharmaceutical Bulletin,2003,vol. 51,p. 697 - 701.

11
[ 99073-88-8 ]
N-[1-(3,4-dichlorobenzyl)piperidin-4-yl]-(6-methylcarbamoyl-2-benzothiazolylthio)acetamide [ No CAS ]

References: [1]Chemical and Pharmaceutical Bulletin,2003,vol. 51,p. 697 - 701.

12
[ 99073-88-8 ]
N-[1-(3,4-dichlorobenzyl)piperidin-4-yl]-(6-carbamoyl-2-benzothiazolylthio)acetamide [ No CAS ]

References: [1]Chemical and Pharmaceutical Bulletin,2003,vol. 51,p. 697 - 701.

13
[ 99073-88-8 ]
N-[1-(3,4-dichlorobenzyl)piperidin-4-yl]-(6-dimethylcarbamoyl-2-benzothiazolylthio)acetamide [ No CAS ]

References: [1]Chemical and Pharmaceutical Bulletin,2003,vol. 51,p. 697 - 701.

14
[ 99073-88-8 ]
N-[1-(3,4-dichlorobenzyl)piperidin-4-yl]-[6-(3-pyridylmethyl)carbamoyl-2-benzothiazolylthio]acetamide [ No CAS ]

References: [1]Chemical and Pharmaceutical Bulletin,2003,vol. 51,p. 697 - 701.

15
[ 99073-88-8 ]
N-[1-(3,4-dichlorobenzyl)piperidin-4-yl]-[6-(2-pyridylmethyl)carbamoyl-2-benzothiazolylthio]acetamide [ No CAS ]

References: [1]Chemical and Pharmaceutical Bulletin,2003,vol. 51,p. 697 - 701.

16
[ 99073-88-8 ]
N-[1-(3,4-dichlorobenzyl)piperidin-4-yl]-(6-benzylcarbamoyl-2-benzothiazolylthio)acetamide [ No CAS ]

References: [1]Chemical and Pharmaceutical Bulletin,2003,vol. 51,p. 697 - 701.

17
[ 99073-88-8 ]
[ 128796-39-4 ]
[ 729591-59-7 ]

Yield	Reaction Conditions	Operation in experiment
27%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; for 19h;Heating / reflux;	Heat a degassed solution of ethyl 2-bromobenzothiazole-6- carboxylate (Step 1, 7.75 G, 27.1 mmol), tetrakis (TRIPHENYLPHOSPHINE) palladium (0) (1.7 g, 1.5 mmol), 4- (trifluoromethyl) phenylboronic acid (6.2 g, 32.6 mmol) and 2 M aqueous sodium carbonate solution (120 mL) in DME (90 mL) at reflux under nitrogen for 19 h. Dilute the cooled mixture with 1 N NAOH (1.2 L) and extract with methylene chloride (2 x 500 ML). Dry the combined organic extracts over MGS04, remove the solvents under reduced pressure and purify the residue by flash column chromatography on silica gel, eluting with hexanes/ethyl acetate (98: 2), to afford ethyl 2- (4-trifluoromethylphenyl) benzothiazole-6-carboxylate as a white solid (2.62 g, 27%) : 1H NMR (CDC13) 5 1.40 (t, 3H), 4.40 (q, 2H), 7.80 (d, 2H), 8.10 (d, 1H), 8.20 (m, 3H), 8.60 (s, 1H).

References: [1]Patent: WO2004/63155,2004,A1 .Location in patent: Page 149.

Yield	Reaction Conditions	Operation in experiment
		(195-2) Under nitrogen atmosphere, a solution of the compound of Example 195-1 (3.09 g) and copper (II) bromide (10.8 g) in CH3CN (200 mL) was cooled to 0 C., and thereto was added dropwise isobutyl nitrite (6.27 g), and the mixture was stirred at 0 C. for 10 minutes, and stirred at room temperature for 2 hours. Water was added to the mixture, and the mixture was extracted twice with Et2O. The organic layer was washed with water, and dried over MgSO4. The solvent was evaporated under reduced pressure to give a crude ethyl 2-bromo-1,3-benzo-thiazole-6-carboxylate (8.16 g).
		(195-2) Under nitrogen atmosphere, a solution of the compound of Example 195-1 (3.09 g) and copper (II) bromide (10.8 g) in CH3CN (200 mL) was cooled to 0C, and thereto was added dropwise isobutyl nitrite (6.27 g), and the mixture was stirred at 0C for 10 minutes, and stirred at room temperature for 2 hours. Water was added to the mixture, and the mixture was extracted twice with Et2O. The organic layer was washed with water, and dried over MgSO4. The solvent was evaporated under reduced pressure to give a crude ethyl 2-bromo-1,3-benzothiazole-6-carboxylate (8.16 g).

19
[ 99073-88-8 ]
[ 19989-64-1 ]

Yield	Reaction Conditions	Operation in experiment
42%	With sodium formate;Pd(PPh3)4; In DMSO (100 ML)-CH3CN; water;	Under nitrogen atmosphere, to a solution of this compound (4.00 g) in DMSO (100 mL)-CH3CN (100 mL) were added successively Pd(PPh3)4(485 mg) and sodium formate (4.76 g), and the mixture was stirred at 100 C. for 75 minutes. The solvent was evaporated under reduced pressure, and thereto was added water, and the mixture was extracted four times with Et2O, and dried over MgSO4. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (hexane/ethyl acetate=10/1) to give ethyl 1,3-benzothiazole-6-carboxylate (1.21 g, 42%). 1H NMR (CDCl3, 400 MHz) delta 9.15 (s, 1H), 8.71 (dd, 1H, J=1.6, 0.5 Hz), 8.21 (dd, 1H, J=8.6, 1.6 Hz), 8.17 (dd, 1H, J=8.6, 0.5 Hz), 4.44 (q, 2H, J=7.1 Hz), 1.44 (t, 3H, J=7.1 Hz).
42%	With sodium formate;Pd(PPh3)4; In DMSO (100 ML)-CH3CN; water;	Under nitrogen atmosphere, to a solution of this compound (4.00 g) in DMSO (100 mL)-CH3CN (100 mL) were added successively Pd(PPh3)4 (485 mg) and sodium formate (4.76 g), and the mixture was stirred at 100C for 75 minutes. The solvent was evaporated under reduced pressure, and thereto was added water, and the mixture was extracted four times with Et2O, and dried over MgSO4. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (hexane/ethyl acetate = 10/1) to give ethyl 1,3-benzothiazole-6-carboxylate (1.21 g, 42 %). 1H NMR (CDCl3, 400MHz) delta 9.15 (s, 1H), 8.71 (dd, 1H, J=1.6, 0.5Hz), 8.21 (dd, 1H, J=8.6, 1.6Hz), 8.17 (dd, 1H, J=8.6, 0.5Hz), 4.44 (q, 2H, J=7.1Hz), 1.44 (t, 3H, J=7.1Hz).

References: [1]Patent: US2003/181496,2003,A1 .
[2]Patent: EP1479384,2004,A1 .

20
[ 99073-88-8 ]
potassium hydrosulfide [ No CAS ]
ethyl 2-mercaptobenzo[d]thiazole-6-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In hydrogenchloride; ethanol; ethyl acetate;	Step 3 6-Ethoxycarbonyl-2-mercaptobenzothiazole The crude <strong>[99073-88-8]2-bromo-6-ethoxycarbonylbenzothiazole</strong> (1.90 g, 6.64 mmol) from Step 2 was suspended in absolute ethanol (35 mL) and treated with potassium hydrogen sulfide (0.96 g, 13.3 mmol). The mixture was placed under a nitrogen atmosphere, stirred, and heated in an oil bath at 80 C. The benzothiazole starting material gradually went into solution. After heating for 30 minutes,the mixture was cooled in an ice bath, treated with IN hydrochloric acid (13.5 mL), and evaporated under vacuum. The residue was partitioned between ethyl acetate (100 mL) and water (100 mL) and the aqueous phase extracted with more ethyl acetate (50 mL). The combined ethyl acetate solution was washed with brine (50 mL), dried over sodium sulfate, filtered and evaporated under vacuum to a yellow-tan solid (1.56 g). This material was triturated with diethyl ether and dried under vacuum to provide 6-ethoxycarbonyl-2-mercaptobenzothiazole (1.14 g) as a pale tan powder. 1 H NMR (DMSO-d6, 500 MHz) delta1.31 (t, CH3), 3.33 (br s, SH), 4.30(q, CH2), 7.35 (d, H-4), 7.94 (d, H-5), and 8.29 (s, H-7). 13 C NMR (DMSO-d6, 125.7 MHz) delta14.1, 60.9, 112.1,123.2, 125.5, 128.4, 129.7, 144.6, 165.0, and 191.8.
	With hydrogenchloride; In ethanol; ethyl acetate;	Step 3 6-Ethoxycarbonyl-2-mercaptobenzothiazole The crude <strong>[99073-88-8]2-bromo-6-ethoxycarbonylbenzothiazole</strong> (1.90 g, 6.64 mmol) from Step 2 was suspended in absolute ethanol (35 mL) and treated with potassium hydrogen sulfide (0.96 g, 13.3 mmol). The mixture was placed under a nitrogen atmosphere, stirred, and heated in an oil bath at 80 C. The benzothiazole starring material gradually went into solution. After hearing for 30 minutes, the mixture was cooled in an ice bath, treated with 1N hydrochloric acid (13.5 mL), and evaporated under vacuum. The residue was partitioned between ethyl acetate (100 mL) and water (100 mL) and the aqueous phase extracted with more ethyl acetate (50 mL). The combined ethyl acetate solution was washed with brine (50 mL), dried over sodium sulfate, filtered and evaporated under vacuum to a yellow-tan solid (1.56 g). This material was triturated with diethyl ether and dried under vacuum to provide 6-ethoxycarbonyl-2-mercaptobenzothiazole (1.14 g) as a pale tan powder. 1 H NMR (DMSO-d6, 500 MHz) delta1.31 (t, CH3), 3.33 (br s, SH), 4.30(q, CH2), 7.35 (d, H-4), 7.94 (d, H-5), and 8.29 (s, H-7). 13 C NMR (DMSO-d6, 125.7 MHz) delta14.1, 60.9, 112.1,123.2, 125.5, 128.4, 129.7, 144.6, 165.0, and 191.8.

References: [1]Patent: US5498777,1996,A .
[2]Patent: US5538964,1996,A .

21
potassium, hydrogen sulfide [ No CAS ]
[ 99073-88-8 ]
6-ethoxycarbonyl-2-thioxo-2,3-dihydrobenzothiazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In ethanol; ethyl acetate;	Step 3 6-Ethoxycarbonyl-2-thioxo-2,3-dihydrobenzothiazole The crude <strong>[99073-88-8]2-bromo-6-ethoxycarbonylbenzothiazole</strong> (1.90 g, 6.64 mmol) from Step 2 was suspended in absolute ethanol (35 mL) and treated with potassium, hydrogen sulfide (0.96 g, 13.3 mmol). The mixture was placed under a nitrogen atmosphere, stirred, and heated in an oil bath at 80 C. The benzothiazole starting material gradually went into solution. After heating for 20 minutes, the mixture was cooled in an ice bath, treated with 1N hydrochloric acid (13.5 mL), and evaporated under vacuum. The residue was partitioned between ethyl acetate (100 mL) and water (100 mL) and the aqueous phase extracted with more ethyl acetate (50 mL). The combined ethyl acetate solution was washed with brine (50 mL), dried over sodium sulfate, filtered and evaporated under vacuum to a yellow-tan solid (1.56 g). This material was triturated with ether and dried under vacuum to provide 6-ethoxycarbonyl-2-thioxo-2,3-dihydrobenzothiazole (1.14 g) as a pale tan powder. 1 H NMR (DMSO-d6, 500 MHz) delta1.31 (t, CH3), 4.30 (q, CH2), 7.35 (d, H-4), 7.94 (d, H-5), and 8.29 (s, H-7). 13 C NMR (DMSO-d6, 125.7 MHz) delta14.1, 60.9, 112.1, 123.2, 125.5, 128.4, 129.7, 144.6, 165.0, and 191.8.

References: [1]Patent: US5496816,1996,A .

22
[ 50850-93-6 ]
[ 7789-45-9 ]
[ 99073-88-8 ]

Yield	Reaction Conditions	Operation in experiment
	With tert.-butylnitrite; In acetonitrile;	Step 2 2-Bromo-6-ethoxycarbonylbenzothiazole A mixture of copper(II) bromide (2.70 g, 12.09 mmol) and anhydrous acetonitrile (50 mL) was purged with nitrogen, cooled in an ice bath, treated with tert-butyl nitrite (1.8 mL, 15.13 mmol), stirred 10 minutes at 0-5 C., and then treated with solid 2-amino-6ethoxycarbonylbenzothiazole (2.24 g, 10.08 mmol). The cooling bath was removed and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (300 mL) and extracted with ether (2*100 mL). The extracts were filtered to remove copper salts, then washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, filtered and evaporated under vacuum to provide crude 2-bromo-6-ethoxycarbonylbenzothiazole (1.90 g) as an orange-tan solid. 1 H NMR (CDCl3, 500 MHz) delta1.42 (t, CH3), 4.42 (q, CH2), 8.02 (d, H-4), 8.15 (dd, H-5), and 8.53 (d, H-7). 13 C NMR (CDCl3, 125.7 MHz) delta14.3, 61.5, 122.5, 122.9, 127.8, 137.2, 142.3, 155.0, and 156.7.
	With tert.-butylnitrite; In acetonitrile;	Step 2 2-Bromo-6-ethoxycarbonylbenzothiazole A mixture of copper(II) bromide (2.70 g, 12.09 mmol) and anhydrous acetonitrile (50 mL) was purged with nitrogen, cooled in an ice bath, treated with tert-butyl nitrite (1.8 mL, 15.13 mmol), stirred 10 minutes at 0-5 C., and then treated with solid 2-amino-6 -ethoxycarbonylbenzothiazole (2.24 g, 10.08 mmol). The cooling bath was removed and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (300 mL) and extracted with diethyl ether (2*100 mL). The extracts were filtered to remove copper salts, then washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, filtered and evaporated under vacuum to provide crude 2-bromo-6-ethoxycarbonylbenzothiazole (1.90 g) as an orange-tan solid. 1 H NMR (CDCl3, 500 MHz) delta1.42 (t, CH3), 4.42 (q, CH2), 8.02(d, H-4), 8.15 (dd, H-5), and 8.53 (d, H-7). 13 C NMR (CDCl3, 125.7 MHz) delta14.3, 61.5, 122.5, 122.9, 127.8, 137.2, 142.3, 155.0, and 165.7.
	With tert.-butylnitrite; In acetonitrile;	Step 2 2-Bromo-6-ethoxycarbonylbenzothiazole A mixture of copper(II) bromide (2.70 g, 12.09 mmol) and anhydrous acetonitrile (50 mL) was purged with nitrogen, cooled in an ice bath, treated with tert-butyl nitrite (1.8 mL, 15.13 mmol), stirred 10 minutes at 0-5 C., and then treated with solid 2-amino-6 ethoxycarbonylbenzothiazole (2.24 g, 10.08 mmol). The cooling bath was removed and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (300 mL) and extracted with diethyl ether (2*100 mL). The extracts were filtered to remove copper salts, then washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, filtered and evaporated under vacuum to provide crude 2-bromo-6-ethoxycarbonylbenzothiazole (1.90 g) as an orange-tan solid. 1 H NMR (CDCl3, 500 MHz) delta1.42 (t, CH3), 4.42 (q, CH2), 8.02(d, H-4), 8.15 (dd, H-5), and 8.53 (d, H-7). 13 C NMR (CDCl3, 125.7 MHz) delta14.3, 61.5, 122.5, 122.9, 127.8, 137.2, 142.3, 155.0, and 165.7.

References: [1]Patent: US5496816,1996,A .
[2]Patent: US5498777,1996,A .
[3]Patent: US5538964,1996,A .

23
[ 496786-98-2 ]
[ 99073-88-8 ]
[ 945400-75-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In tetrahydrofuran; water;Heating / reflux;	A mixture of 2-bromo-l,3-benzothiazole-6-carboxylic acid ethyl ester (See WO 95/25108) (0.74 g, 2.57 mmol), 4-[5-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl-piperazine-l- carboxylic acid tert-butyl ester (1.0 g, 2.57 mmol), sodium carbonate (0.820 g, 7.71 mmol) and Pd(dppf)Cl2DCM (0.094 g, 0.13 mmol) in THF/water (9:1, 15 mL) was stirred at reflux o.n. Additional Pd(dppf)Cl2DCM (20 mg) was added and the reaction was refluxed for one more day. The r.m. was concentrated in vacuo and to the residue was added DCM and water. The aqueous layer was extracted three times with DCM, dried (MgSO4), filtered and evaporated in vacuo. The product was purified by flash column chromatography (35% ethyl acetate in hexane), giving the title compound (0.85 g) as a solid. 1H NMR delta 8.83 (d, 1 H) 8.73 (s, 1 H) 8.19 (dd, 1 H) 8.04 (s, 2 H) 7.00 (d, 1 H) 4.36 (q, 2 H) 3.65 - 3.72 (m, 4 H) 3.42 - 3.50 (m, 4 H) 1.43 (s, 9 H) 1.36 (t, 3 H); MS m/z (M+H) 469.

References: [1]Patent: WO2007/86800,2007,A1 .Location in patent: Page/Page column 58.

24
[ 99073-88-8 ]
[ 214337-28-7 ]

Yield	Reaction Conditions	Operation in experiment
99%	With diisobutylaluminium hydride; In dichloromethane; toluene; at -78℃; for 2.08333h;	To a solution of ethyl 2-bromobenzo[djthiazole- 6-carboxylate (1.00 g, 3.49 mmol) in DCM (17 ml) at -78 C was added DIBAL-H in toluene(7.5 ml, 7.5 mmol, 1.0 M) slowly over 5 mm and the resulting mixture was stirred at -78 C for 2 h. The reaction was quenched at -78 C with 1 M Rochelle salt (10 mL) and allowed to warm to rt over 30 mm. The aqueous layer was extracted with 1:10 IPAIDCM (3 x 10 mL) and the combined organics were dried over MgSO4, filtered, and concentrated. The title compound was 1Solated as a pale yellow solid (841 mg, 99%). MS (ES+) C8H6BrNOSrequires: 243, found: 244 [M+Hf?. ?H NMR (600 MHz, Chloroform-d) oe 7.96 (d, J = 8.4 Hz,1H), 7.85 (s, 1H), 7.45 (dd, J= 8.4, 1.6 Hz, 1H), 4.83 (d, J= 5.8 Hz, 2H), 1.81 (t, J 5.9 Hz,1H)
80%	With diisobutylaluminium hydride; In dichloromethane; at -78℃; for 2h;	Step 2: To a solution of ethyl 2-bromobenzo[d]thiazole-6-crboxylate (5.0 g, 17.5 mmol) from Step 1 of thisExample in anhydrous CH2Cl2 was added DIBAL-H (1.0 M in CH2Cl2, 36.7 mL, 36.7 mmol) slowly at -78 C. The solutionwas stirred at -78 C for 2 h. The resulting mixture was quenched with 10 mL of saturated aq sodium potassium tartrateat -78 C. After slowly warming to 0 C, the mixture was further treated with 50 mL of saturated aq sodium potassiumtartrate and stirred at rt for 2 h. The aqueous layer was separated and extracted with CH2Cl2 (3 x 100 mL). The combinedorganic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The crude productwas purified on a silica gel column using a mixture of EtOAc-hexanes (2:3, v/v) as eluent to give (2-bromobenzo[d]thiazol-6-yl)methanol as a white solid (3.4 g, 80%). 1H NMR (300 MHz, CDCl3) delta 7.96 (d, J = 8.3 Hz, 1H), 7.85 (s, 1H), 7.45(dd, J= 1.4, 8.4 Hz, 1H), 4.83 (s, 2H), 1.86 (br s, 1H). LCMS (ESI) m/z 244, 246 (M+H)+.
69%	With lithium triethylborohydride; In tetrahydrofuran; at 0℃; for 1h;	Intermediate 308A (0.85 g, 2.97 mmol) was dissolved in THF (20 mL) and cooledto 0 C. 1.0 M Super-Hydride in THF (6.54 mL, 6.54 mmol) was added dropwise to thiscooled solution. After stirring at 0 C for 1 h, the reaction was quenched with saturated ammonium chloride and then diluted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (24g, 5-60% EtOAc/Hexanes, 18 mm) to give Intermediate 308B (0.5 g, 2.048 mmol, 69.0 % yield) as a white solid. LC-MS. Method A, RT = 1.54 mm, MS (ESI)m/z: 244.0 and 246.0 (M+H). ?HNMR(500IVIHz, CHLOROFORM-d) 7.93 (d, J=8.5 Hz, 1H), 7.70 (d, J0.8 Hz, 1H), 7.39 (dd, J=8.4,1.5 Hz, 1H), 5.08 (s, 2H).

References: [1]Patent: WO2018/81276,2018,A1 .Location in patent: Page/Page column 112.
[2]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 1874 - 1879.
[3]Patent: EP2766359,2016,B1 .Location in patent: Paragraph 0322.
[4]Patent: WO2018/13774,2018,A1 .Location in patent: Page/Page column 715; 716.

25
[ 99073-88-8 ]
[ 1066-54-2 ]
[ 1220449-28-4 ]

Yield	Reaction Conditions	Operation in experiment
	With copper(l) iodide; triethylamine;bis-triphenylphosphine-palladium(II) chloride; In toluene; at 20 - 60℃;Inert atmosphere;	Step 2: Ethyl 2-[(trimethylsilyl)ethynyl]-L3-benzothiazole-6-carboxylateTo a stirred solution of ethyl 2-bromo-l,3-benzothiazole-6-carboxylate (880 mg, 3.07 mmol) and ethynyltrimethylsilane (453 mg, 4.61 mmol) in toluene (15 mL) and TEA (5 mL) was added CuI (117 mg, 0.61 mmol), Pd(PPh3)2Cl2 (216 mg, 0.31 mmol) and PPh3 (81 mg, 0.31 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at 60 0C for 4 h. After cooling, the mixture was filtered and the solid was washed with EtOAc (200 mL). The combined organic phase was concentrated. The crude residue was purified by silica gel column chromatography (PE / EA = 50:1) to afford the title compound.1H NMR (CDCl3, 400 MHz): delta 8.58 (d, IH), 8.1 1 (dd, IH), 8.01 (d, IH), 4.36 (q, 2H), 1.42 (t, 3H), 0.32 (s, 9H).

References: [1]Patent: WO2010/37225,2010,A1 .Location in patent: Page/Page column 42.

26
[ 99073-88-8 ]
[ 98-80-6 ]
[ 19989-70-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 120℃; for 0.416667h;Microwave irradiation;	A mixture of ethyl 2- bromo-benzothiazole-6-carboxylate Iw (300 mg, 1.05 mmol), phenylboronic acid Ix (192 mg, 1.57 mmol), K2CO3 (188 mg, 1.36 mmol) and Pd(dppf)Cl2.CH2Cl2 (43 mg, 0.05 mmol) in dioxane (2 mL) and H2O (0.4 ml) was heated at 120 0C for 25 min under microwave. The reaction mixture was diluted with CH2Cl2, washed with H2O, dried over Na2SO4, and concentrated. Purification by flash column chromatography (silica gel, 15% EtO Ac/heptane) gave Iy (220 mg).
	With potassium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 120℃; for 0.416667h;Microwave;	A. Ethyl 2-phenyl-benzothiazole-6-carboxylate, 26b. A mixture of ethyl 2-bromo-benzothiazole-6-carboxylate 26a (300 mg, 1.05 mmol), phenylboronic acid 10b (192 mg, 1.57 mmol), K2CO3 (188 mg, 1.36 mmol) and Pd(dppf)Cl2.CH2Cl2 (43 mg, 0.05 mmol) in dioxane (2 mL) and H2O (0.4 ml) was heated at 120 C. for 25 min under microwave. The reaction mixture was diluted with CH2Cl2, washed with H2O, dried over Na2SO4, and concentrated. Purification by flash column chromatography (silica gel, 15% EtOAc/heptane) gave 26b (220 mg).
	With potassium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 120℃; for 0.416667h;microwave irradiation;	A mixture of ethyl 2-bromo-benzothiazole-6-carboxylate 26a (300 mg, 1.05 mmol), phenylboronic acid 10b (192 mg, 1.57 mmol), K2CO3 (188 mg, 1.36 mmol) and Pd(dppf)Cl2.CH2Cl2 (43 mg, 0.05 mmol) in dioxane (2 mL) and H2O (0.4 ml) was heated at 120 C. for 25 min under microwave. The reaction mixture was diluted with CH2Cl2, washed with H2O, dried over Na2SO4, and concentrated. Purification by flash column chromatography (silica gel, 15% EtOAc/heptane) gave 26b (220 mg).

With potassium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; dichloromethane; water; at 120℃; for 0.416667h;microwave irradiation;

A mixture of ethyl 2-bromo-benzothiazole-6-carboxylate 20d (300 mg, 1.05 mmol), phenylboronic acid (192 mg, 1.57 mmol), K2CO3 (188 mg, 1.36 mmol) and Pd(dppf)Cl2.CH2Cl2 (43 mg, 0.05 mmol) in dioxane (2 mL) and H2O (0.4 mL) was heated at 120 C. for 25 min in a microwave reactor. The reaction mixture was diluted with CH2Cl2, washed with H2O, dried over Na2SO4, and concentrated. Purification by flash column chromatography (silica gel, 15% EtOAc/heptane) gave compound 20e (220 mg).

References: [1]Patent: WO2010/124082,2010,A1 .Location in patent: Page/Page column 76.
[2]Patent: US2012/58986,2012,A1 .Location in patent: Page/Page column 35.
[3]Patent: US2012/77797,2012,A1 .Location in patent: Page/Page column 35.
[4]Patent: US2012/101081,2012,A1 .Location in patent: Page/Page column 50.

27
[ 99073-88-8 ]
[ 1312763-08-8 ]