[ CAS No. 777-12-8 ] {[proInfo.proName]}

Name: 777-12-8|6-(Trifluoromethyl)benzo[d]thiazol-2-amine|98%
Brand: Ambeed
SKU: A619089
Price: 14.0 USD
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Quality Control of [ 777-12-8 ]

COA NMR CNMR HPLC LC-MS

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Product Citations

Novel amides of mycophenolic acid and some heterocyclic derivatives as immunosuppressive agents

Walczak, Juliusz Maksymilian ; Iwaszkiewicz-Grzes, Dorota ; Ziomkowska, Michalina , et al. J. Enzym. Inhib. Med. Ch.,2022,37(1):2725-2741. DOI: 10.1080/14756366.2022.2127701 PubMed ID: 36189734

Abstract: The group of 18 new amide derivatives of mycophenolic acid (MPA) and selected heterocyclic amines was synthesised as potential immunosuppressive agents functioning as inosine-5′-monophosphate dehydrogenase (IMPDH) uncompetitive inhibitors. The synthesis of 14 of them employed uronium-type activating system (TBTU/HOBt/DIPEA) while 4 of them concerned phosphonic acid anhydride method (T3P/Py) facilitating amides to be obtained in moderate to excellent yields without the need of phenolic group protection. Most of optimised protocols did not require complicated reaction work-ups, including chromatographic, solvent-consuming methods. The biological activity assay was performed on the T-Jurkat cell line and peripheral mononuclear blood cells (PBMCs) which are both dedicated for antiproliferative activity determination. Each of designed derivatives was characterised by reduced cytotoxicity and benzoxazole analogue (A2) revealed the most promising activity. Subsequently, an observed structure-activity relationship was discussed.

Keywords: Mycophenolic acid ; amide derivatives ; heterocycles ; benzoxazole ; IMPDH inhibition

Purchased from AmBeed: 934-32-7 ; 1477-42-5 ; 5464-79-9 ; 5464-79-9 ; 136-95-8 ; 95-24-9 ; 533-30-2 ; 1123-93-9 ; 6285-57-0 ; 15864-32-1 ; 29927-08-0 ; 348-40-3 ; 58-63-9 ; 4570-41-6 ; 24280-93-1 ; 2536-91-6 ; 19952-47-7 ; 1747-60-0 ; 777-12-8 ; 58-63-9 ; 75985-45-4 ; 63837-12-7 ...More

Product Details of [ 777-12-8 ]

CAS No. :	777-12-8	MDL No. :	MFCD00269597
Formula :	C₈H₅F₃N₂S	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	WEDYEBJLWMPPOK-UHFFFAOYSA-N
M.W :	218.20	Pubchem ID :	2735955
Synonyms :

Calculated chemistry of [ 777-12-8 ] Expand+

Physicochemical Properties

Num. heavy atoms :	14
Num. arom. heavy atoms :	9
Fraction Csp3 :	0.12
Num. rotatable bonds :	1
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	49.03
TPSA :	67.15 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.56 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.79
Log Po/w (XLOGP3) :	2.92
Log Po/w (WLOGP) :	4.06
Log Po/w (MLOGP) :	2.32
Log Po/w (SILICOS-IT) :	3.38
Consensus Log Po/w :	2.89

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.44
Solubility :	0.0788 mg/ml ; 0.000361 mol/l
Class :	Soluble
Log S (Ali) :	-3.99
Solubility :	0.0223 mg/ml ; 0.000102 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.5
Solubility :	0.0682 mg/ml ; 0.000313 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.02

Safety of [ 777-12-8 ]

Signal Word:	Danger	Class:	6.1
Precautionary Statements:	P261-P264-P270-P271-P280-P301+P310+P330-P302+P352-P304+P340+P312-P305+P351+P338-P332+P313-P337+P313-P403+P233-P405-P501	UN#:	2811
Hazard Statements:	H300-H315-H319-H335	Packing Group:	Ⅱ
GHS Pictogram:

Application In Synthesis of [ 777-12-8 ]

* 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.

Upstream synthesis route of [ 777-12-8 ]
Downstream synthetic route of [ 777-12-8 ]

[ 777-12-8 ] Synthesis Path-Upstream 1~7

1
[ 455-14-1 ]
[ 333-20-0 ]
[ 777-12-8 ]

Reference： [1] Synlett, 2012, vol. 23, # 15, p. 2219 - 2222
[2] Journal of Organic Chemistry, 2017, vol. 82, # 18, p. 9312 - 9320
[3] Journal of Pharmaceutical Sciences, 1994, vol. 83, # 10, p. 1425 - 1432
[4] Journal of Medicinal Chemistry, 1999, vol. 42, # 15, p. 2828 - 2843
[5] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 23, p. 5561 - 5565

2
[ 455-14-1 ]
[ 1147550-11-5 ]
[ 777-12-8 ]

Reference： [1] Journal of Organic Chemistry, 2018, vol. 83, # 19, p. 12129 - 12142
[2] J. Gen. Chem. USSR (Engl. Transl.), 1963, vol. 33, p. 2240 - 2245[3] Zhurnal Obshchei Khimii, 1963, vol. 33, p. 2301 - 2307
[4] European Journal of Medicinal Chemistry, 2018, vol. 148, p. 477 - 486

3
[ 1736-72-7 ]
[ 777-12-8 ]

Reference： [1] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 16, p. 5678 - 5682
[2] Journal of Medicinal Chemistry, 2016, vol. 59, # 21, p. 9814 - 9824

4
[ 90774-69-9 ]
[ 777-12-8 ]

Reference： [1] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 16, p. 5678 - 5682

5
[ 455-14-1 ]
[ 540-72-7 ]
[ 777-12-8 ]

Reference： [1] Patent: US2832761, 1954, ,
[2] Patent: US2822359, 1954, ,
[3] Patent: US2865909, 1954, ,
[4] Patent: US2857372, 1954, ,
[5] European Journal of Organic Chemistry, 2011, # 19, p. 3421 - 3429

6
[ 455-14-1 ]
[ 777-12-8 ]

Reference： [1] Journal of Medicinal Chemistry, 2016, vol. 59, # 21, p. 9814 - 9824

7
[ 777-12-8 ]
[ 159870-86-7 ]

Yield	Reaction Conditions	Operation in experiment
92%	Stage #1: With tert.-butylnitrite; copper dichloride In acetonitrile at 20℃; for 0.166667 h; Stage #2: at 65℃; for 0.5 h; Stage #3: With hydrogenchloride In water; acetonitrile	In a three-necked flask fitted with a condenser, a suspension of copper II chloride (370 mg, 2.75 mmol) in acetonitrile (5 mL) was treated with tert-butyl nitrite (0.41 mL, 3.44 mmol) and stirred at rt for 10 minutes. A solution of 2-amino-6-trifluoromethylbenzthiazole (500 mg, 2.29 mmol) in acetonitrile (1 mL) was then added dropwise. The mixture was heated at 65° C. for 30 minutes, then cooled and diluted with an excess of 1 N aqueous hydrochloric acid solution. The mixture was extracted with ethyl acetate. The organic phase was separated, dried (MgSO4), and concentrated under reduced pressure. An orange semi-solid (501 mg, 92percent) was obtained and used without further purification. 1H NMR (300 MHz, CDCl3) δ 8.10-8.05 (m, 2H), 7.74 (d, 1H); LC-MS m/z 238.2 (MH+), ret. time 3.76 min TLC Rf=0.50 (9:1 hexanes/ethyl acetate).

Reference： [1] Patent: US2004/224997, 2004, A1, . Location in patent: Page 30
[2] Patent: WO2007/39176, 2007, A1, . Location in patent: Page/Page column 67-68

[ 777-12-8 ] Synthesis Path-Downstream 1~109

1
[ 455-14-1 ]
[ 540-72-7 ]
[ 777-12-8 ]

Reference： [1]Patent: US2832761,1954,
[2]European Journal of Organic Chemistry,2011,p. 3421 - 3429

2
[ 777-12-8 ]
[ 91-99-6 ]
[ 2193-90-0 ]

Reference： [1]Journal of general chemistry of the USSR,1963,vol. 33,p. 2240 - 2245
Zhurnal Obshchei Khimii,1963,vol. 33,p. 2301 - 2307

3
[ 777-12-8 ]
[ 121-69-7 ]
[ 3879-63-8 ]

Reference： [1]Journal of general chemistry of the USSR,1963,vol. 33,p. 2240 - 2245
Zhurnal Obshchei Khimii,1963,vol. 33,p. 2301 - 2307

4
[ 70-23-5 ]
[ 777-12-8 ]
ethyl-7-trifluoromethylimidazo<2,1-b>benzothiazole-2-carboxylate [ No CAS ]

Reference： [1]Il Farmaco,1993,vol. 48,p. 31 - 43
[2]European Journal of Pharmaceutical Sciences,2001,vol. 14,p. 209 - 216

5
[ 638-07-3 ]
[ 777-12-8 ]
ethyl-7-trifluoromethylimidazo<2,1-b>benzothiazole-2-acetate [ No CAS ]

Reference： [1]Il Farmaco,1993,vol. 48,p. 31 - 43

6
[ 777-12-8 ]
[ 131105-90-3 ]

Reference： [1]Journal of Medicinal Chemistry,1991,vol. 34,p. 108 - 122

7
[ 777-12-8 ]
[ 131106-70-2 ]

Yield	Reaction Conditions	Operation in experiment
46%	With isopentyl nitrite; In tetrahydrofuran; for 0.5h;Reflux;	[00180] To a solution of 6-(trifluoromethyl)benzothiazol-2-amine ( 1) (2.00 g, 9.17 mmol) in 20 mL of THF was added isoamyl nitrite (3.22 g, 27.5 mmol). The mixture was heated to reflux for 30 min, quenched with water, and extracted with ethyl acetate. The organic extract was dried over Na2S04and concentrated under reduced pressure. The crude material was purified by silica gel chromatography to afford 860 mg (46%) of the title compound as a yellow solid. NMR (400 MHz, CDC13) delta 9.16 (s, 1H), 8.26 (m, 2H), 7.78 (d, J= 1.2 Hz, 1H).
43.2%	With isopentyl nitrite; In tetrahydrofuran; for 1.5h;Inert atmosphere; Reflux;	6-(Trifluoromethyl)benzo[d]thiazol-2-amine (6.8 g, 31.16 mmol)was dissolved in THF (60 mL) under N2. Isoamyl nitrite (8.03 g,68.55 mmol) was added dropwise and the mixture was refluxed for1.5 h. Then the mixture was poured into ice-H2O (60 mL) andextracted with EtOAc. The organic layer was washed by saturatedaqueous NaCl and dried over Na2SO4. It was then concentrated andpurified via flash chromatography on silica gel to get 6 g (Yield43.2%) of 6-(trifluoromethyl)benzo[d]thiazole (21n) as a yellow oil.ES-LCMS m/z: 204.0 (MH).

Reference： [1]European Journal of Organic Chemistry,2011,p. 3421 - 3429
[2]Patent: WO2015/197861,2015,A1 .Location in patent: Paragraph 00179-00180
[3]European Journal of Medicinal Chemistry,2019,vol. 183
[4]Journal of Medicinal Chemistry,1991,vol. 34,p. 108 - 122

8
[ 455-14-1 ]
[ 333-20-0 ]
[ 777-12-8 ]

Yield	Reaction Conditions	Operation in experiment
	With bromine; In acetic acid;Cooling with ice;	General procedure: A mixture of 0.1 mol of 4?substituted aniline and 0.1 mol ofPotassium thiocyanate (KCNS) in 100 ml glacial acetic acid (AcOH) was cooled inan ice bath and stirred for 10 to 20 min, and then 0.1 mol bromine in glacialacetic acid was added dropwise at such a rate to keep the temperature below 10C throughout the addition. Theprogress of the reaction was monitored by Thin Layer Chromatography usingtoluene: acetone (8:2) solvent system. The reaction mixture was stirredat room temperature for 2 to 4 hrs, the hydrobromide (HBr) salt thus separatedout was filtered, washed with acetic acid, dried, dissolved in hot water and basified to pH 11.0 with ammonia solution (NH4OH)and the resulting precipitate was filtered, washed with water and dried to getthe desired product 2a-q.

Reference： [1]Synlett,2012,vol. 23,p. 2219 - 2222
[2]Journal of Organic Chemistry,2017,vol. 82,p. 9312 - 9320
[3]Journal of Pharmaceutical Sciences,1994,vol. 83,p. 1425 - 1432
[4]Journal of Medicinal Chemistry,1999,vol. 42,p. 2828 - 2843
[5]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 5561 - 5565

9
[ 777-12-8 ]
[ 70-11-1 ]
[ 182554-22-9 ]

Reference： [1]Il Farmaco,1996,vol. 51,p. 483 - 491
[2]RSC Advances,2016,vol. 6,p. 67086 - 67095

10
[ 777-12-8 ]
[ 86691-07-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 5678 - 5682
[2]European Journal of Organic Chemistry,2011,p. 3421 - 3429
[3]Patent: WO2015/197861,2015,A1
[4]European Journal of Medicinal Chemistry,2019,vol. 183

11
[ 1736-72-7 ]
[ 777-12-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 5678 - 5682
[2]Journal of Medicinal Chemistry,2016,vol. 59,p. 9814 - 9824

12
[ 777-12-8 ]
(3-methyl-7-trifluoromethyl-4H-benzo[1,4]thiazin-2-yl)-phenyl-methanone [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 5678 - 5682

13
[ 777-12-8 ]
(3-chloro-phenyl)-(3-methyl-7-trifluoromethyl-4H-benzo[1,4]thiazin-2-yl)-methanone [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 5678 - 5682

14
[ 777-12-8 ]
(4-chloro-phenyl)-(3-methyl-7-trifluoromethyl-4H-benzo[1,4]thiazin-2-yl)-methanone [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 5678 - 5682

15
[ 777-12-8 ]
(4-bromo-phenyl)-(3-methyl-7-trifluoromethyl-4H-benzo[1,4]thiazin-2-yl)-methanone [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 5678 - 5682

16
[ 777-12-8 ]
phenyl-(3-phenyl-7-trifluoromethyl-4H-benzo[1,4]thiazin-2-yl)-methanone [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 5678 - 5682

17
[ 90774-69-9 ]
[ 777-12-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 5678 - 5682

18
[ 777-12-8 ]
2-imino-3-(2-ethylsulphinylethyl)-6-trifluoromethylbenzothiazoline [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 2828 - 2843

19
[ 777-12-8 ]
[ 182554-32-1 ]

Reference： [1]Il Farmaco,1996,vol. 51,p. 483 - 491

20
[ 777-12-8 ]
(2-Phenyl-7-trifluoromethyl-benzo[d]imidazo[2,1-b]thiazol-3-yl)-acetic acid [ No CAS ]

Reference： [1]Il Farmaco,1996,vol. 51,p. 483 - 491

21
[ 777-12-8 ]
[ 182554-26-3 ]

Reference： [1]Il Farmaco,1996,vol. 51,p. 483 - 491

22
[ 777-12-8 ]
Trimethyl-(2-phenyl-7-trifluoromethyl-benzo[d]imidazo[2,1-b]thiazol-3-ylmethyl)-ammonium; iodide [ No CAS ]

Reference： [1]Il Farmaco,1996,vol. 51,p. 483 - 491

23
[ 777-12-8 ]
10-(trifluoromethyl)-7-thia-2,5-diazatricyclo[6.4.0.0²^,⁶]dodeca-1⁽⁸⁾,3,5,9,11-pentaene-4-carboxylic acid [ No CAS ]

Reference： [1]Il Farmaco,1993,vol. 48,p. 31 - 43

24
[ 777-12-8 ]
(7-Trifluoromethyl-benzo[d]imidazo[2,1-b]thiazol-2-yl)-acetic acid [ No CAS ]

Reference： [1]Il Farmaco,1993,vol. 48,p. 31 - 43

25
[ 777-12-8 ]
[ 110704-57-9 ]

Reference： [1]Journal of Medicinal Chemistry,1991,vol. 34,p. 108 - 122

26
[ 777-12-8 ]
[ 110704-28-4 ]

Reference： [1]Journal of Medicinal Chemistry,1991,vol. 34,p. 108 - 122

27
[ 777-12-8 ]
[ 96232-04-1 ]

Reference： [1]Journal of Medicinal Chemistry,1991,vol. 34,p. 108 - 122

28
[ 777-12-8 ]
[ 131106-03-1 ]

Reference： [1]Journal of Medicinal Chemistry,1991,vol. 34,p. 108 - 122

29
[ 777-12-8 ]
2-(2-imino-6-trifluoromethyl-3-benzothiazolinyl)ethanol bromhydrate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol;	the procedure is as in the example 6, starting with 2-amino-6-trifluoromethylbenzothiazole (17.9 g), ethanol (50 cc) and 2-bromoethanol. 2-(2-imino-6-trifluoromethyl-3-benzothiazolinyl)ethanol bromhydrate (10.5 g) is obtained. 2-amino-6-trifluoromethylbenzothiazole may be prepared according to the method described in U.S. Pat. No. 2,822,359.

Reference： [1]Patent: US5260297,1993,A

30
[ 777-12-8 ]
[ 79455-63-3 ]
N-(6-trifluoromethylbenzothiazol-2-yl)-2-chloro-6-fluorobenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; dmap; In water;	EXAMPLE 2 STR7 At 0 to 5° C., 2-chloro-6-fluorobenzoyl chloride (1.93 g) was added dropwise to a solution composed of 2-amino-6-trifluoromethylbenzothiazole (2.18 g), pyridine (30 ml) and 4-dimethylaminopyridine (0.1 g). The reaction mixture was stirred at room temperature (20 to 30° C.) for one day, and then the pyridine was evaporated. Water was added to the residue, and the mixture was stirred. The resulting crystals were collected by filtration, and thoroughly washed with water. Recrystallization from ethanol gave the desired N-(6-trifluoromethylbenzothiazol-2-yl)-2-chloro-6-fluorobenzamide (2.5 g). mp. 265°-270° C.

Reference： [1]Patent: US4675331,1987,A

31
[ 777-12-8 ]
[ 18063-02-0 ]
N-(6-trifluoromethylbenzothiazol-2-yl)-2,6-difluorobenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran;	EXAMPLE 1 STR6 At 0 to 5 C., 2,6-difluorobenzoyl chloride (1.77 g) was added dropwise to a solution composed of 2-amino-6-trifluoromethylbenzothiazole (2.18 g), tetrahydrofuran (30 ml) and triethylamine (1.1 g). The reaction mixture was stirred at 30 to 40 C. for 5 hours, and then tetrahydrofuran was evaporated. The solid residue was washed with water and recrystallized from ethanol to give the desired N-(6-trifluoromethylbenzothiazol-2-yl)-2,6-difluorobenzamide (2.8 g). mp. 256-257 C.

Reference： [1]Patent: US4675331,1987,A

Yield	Reaction Conditions	Operation in experiment
28%	With bromine; acetic acid; at 0 - 20℃;	General procedure: [190] Preparation 1. 6-trifluoromethoxybenzo[d]thiazol-2-amine[191] Ammonium thiocyanate (1.70 g, 22.30 mmol) was added to a solution of 4-(trifluoromethoxy)aniline (3.54 g, 20.00 mmol) in acetic acid (30 mL). The reaction mixture was cooled to 0?10 ?. A solution of bromine (1.10 mL, 22.00 mmol) in acetic acid (5 mL) was added dropwise to the reaction mixture, which was then stirred at room temperature overnight. The resulting solid was filtered, and then dissolved in water. The aqueous layer was basified to pH 11-12 with solid sodium carbonate. The resulting solid was filtered, washed with water, and then dried in vacuo to give the titled compound (2.84 g) as a white solid. The product was used in the subsequent step without further purification (Yield: 61percent).
28%	With bromine; acetic acid; In water; at 0 - 20℃;	General procedure: Preparation 1. 6-trifluoromethoxybenzo[d]thiazol-2-amine Ammonium thiocyanate (1.70 g, 22.30 mmol) was added to a solution of 4-(trifluoromethoxy)aniline (3.54 g, 20.00 mmol) in acetic acid (30 mL). The reaction mixture was cooled to 0-10° C. A solution of bromine (1.10 mL, 22.00 mmol) in acetic acid (5 mL) was added dropwise to the reaction mixture, which was then stirred at room temperature overnight. The resulting solid was filtered, and then dissolved in water. The aqueous layer was basified to pH 11-12 with solid sodium carbonate. The resulting solid was filtered, washed with water, and then dried in vacuo to give the titled compound (2.84 g) as a white solid. The product was used in the subsequent step without further purification (Yield: 61percent).
		The more preferred compounds are:2-aminobenzothiazole,2-amino-6-methylbenzothiazole,2-amino-4-methylbenzothiazole,2-amino-6-trifluoromethylbenzothiazole,2-amino-4-trifluoromethylbenzothiazole,2-amino-5-trifluoromethylbenzothiazole,2-amino-6-trifluoromethoxybenzothiazole,2-amino-6-ethoxybenzothiazole,2-amino-6-nitrobenzothiazole,...

With sulfuric acid; ammonium bromide; at 100℃; for 0.75h;

General procedure: 5,6-Dichloro-1,3-benzothiazol-2-amine To a solution of (3,4-dichlorophenyl)thiourea (1.00 g, 4.52 mmol) in concentrated sulfuric acid (2.3 mL) was added ammonium bromide (438 mg, 4.52 mmol) and the solution heated at 100°C for 45 min. The reaction was allowed to cool to room temperature, then ice/water (34 mL) was added and the solution basified with N(aq). The resulting precipitate was sonicated and then collected by filtration to afford the title compound as a 50percent mixture with the 6,7 dichloro isomer which was taken into the next stage without further purification (1.30g, 48percent purity, 31percent yield); m/z = 218.8 (MH)+.

33
[ 777-12-8 ]
6-Trifluoromethyl-2-trifluoroacetylaminobenzothiazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		a) 6-Trifluoromethyl-2-trifluoroacetylaminobenzothiazole Starting from 2-amino-6-trifluoromethylbenzothiazole (6.54 g, 30 mmol), the title compound was obtained as white crystals (7.4 g, yield: 78percent) in the same manner as described in Example 1 (d). Melting point: 200-202°C.

Reference： [1]Patent: EP1043319,2000,A1

34
[ 777-12-8 ]
[ 122-04-3 ]
[ 1048025-73-5 ]

Reference： [1]European Journal of Medicinal Chemistry,2008,vol. 43,p. 1519 - 1524

35
[ 777-12-8 ]
[ 708-06-5 ]
[ 1220777-80-9 ]

Reference： [1]Magnetic Resonance in Chemistry,2010,vol. 48,p. 210 - 218

36
[ 777-12-8 ]
[ 1202889-55-1 ]
[ 1233698-65-1 ]

Yield	Reaction Conditions	Operation in experiment
32.7%		4-(6-Chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation B; 100 mg, 0.265 mmol) was diluted with dichloromethane (5 mL) followed by the addition of oxalyl chloride in dichloromethane (2M) (146 muL, 0.292 mmol) and dimethylformamide (1 drop). After stirring for 30 minutes a small aliquot was diluted with methanol for 5 minutes. Thin layer chromatography of this aliquot showed complete conversion to methyl ester. 6- (Trifluoromethyl)benzo[d]thiazol-2-amine (63.7 mg, 0.292 mmol) and diisopropyl ethylamine (116 muL, 0.664 mmol) were added and the reaction was stirred at 35°C for 1 hour. The reaction was loaded directly onto a Biotage 25 cartridge and eluted with 5percent ethyl acetate/hexanes to 70percent ethyl acetate/hexanes to yield ethyl 6-chloro-7-(4-(6- (trifluoromethyl)benzo[d]thiazol-2-ylcarbamoyl)phenoxy)chroman-4-carboxylate (50 mg, 0.0867 mmol, 32.7 percent yield).

Reference： [1]Patent: WO2010/75200,2010,A1 .Location in patent: Page/Page column 163

37
[ 777-12-8 ]
[ 1314518-69-8 ]

Reference： [1]European Journal of Organic Chemistry,2011,p. 3421 - 3429

38
[ 777-12-8 ]
[ 1314518-77-8 ]

Reference： [1]European Journal of Organic Chemistry,2011,p. 3421 - 3429

39
[ 777-12-8 ]
[ 1314518-62-1 ]

Reference： [1]European Journal of Organic Chemistry,2011,p. 3421 - 3429

40
[ 777-12-8 ]
[ 132740-43-3 ]
[ 1334127-09-1 ]

Yield	Reaction Conditions	Operation in experiment
	With n-butyllithium; In tetrahydrofuran; hexane; at 20℃;	General Procedure: To the residue was added dry tetrahydrofuran (THF, 1.5 ml). It was added dropwise to a solution of n-buthyllithium (0.80 mmol, 1.6 M in n-Hexane) deprotonated amine (0.80 mmol) in 1.5 ml tetrahydrofuran and stirred at room temperature overnight. The reaction solution was added to a vigorous stirred water to give the solid crude urea. The solid was filtered off and recrystallised from methanol or ethanol.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 5610 - 5615

41
[ 777-12-8 ]
[ 56651-60-6 ]
[ 1334127-11-5 ]

Yield	Reaction Conditions	Operation in experiment
	With n-butyllithium; In tetrahydrofuran; hexane; at 20℃;	General Procedure: To the residue was added dry tetrahydrofuran (THF, 1.5 ml). It was added dropwise to a solution of n-buthyllithium (0.80 mmol, 1.6 M in n-Hexane) deprotonated amine (0.80 mmol) in 1.5 ml tetrahydrofuran and stirred at room temperature overnight. The reaction solution was added to a vigorous stirred water to give the solid crude urea. The solid was filtered off and recrystallised from methanol or ethanol.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 5610 - 5615

42
[ 777-12-8 ]
[ 1357099-42-3 ]
[ 1379509-98-4 ]

Yield	Reaction Conditions	Operation in experiment
81%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;	General procedure: To a solution of 2-aminobenzothiazole (150 mg, 1 mmol) in dichloromethane (20 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (210 mg, 1.1 mmol) and 1-hydroxy-1,2,3-benzotriazole (HOBt) (13.5 mg, 0.1 mmol). Then compound 8 (402 mg, 1 mmol) was added and the reaction mixture was stirred at room temperature for 14 h and the reaction was monitored by TLC. After completion of reaction, water was added to reaction mixture and extracted with dichloromethane (2 .x. 30 ml). The organic layer was dried with Na2SO4 and evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate and hexane (1:1) as solvent system to obtain the pure product 9a as yellow solid. (449 mg, 84percent yield);
80%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 25℃; for 24h;	Nl-[6-(trifluoromethyl)-l,3-benzothiazol-2-yl]-2-{2-methoxy-5-[(.pound.)-3-oxo-3-(3,4,5- trimethoxyphenyl)-. -propenyljphenoxy} acetamide (9i) To a solution of 6-(trifluoromethyl)-2-aminobenzothiazole (218 mg, 1.0 mmol) in dichloromethane (20 mL) was added l -Ethyl-3-(3-Dimethylaminopropyl)carbodiimide (EDC) (191 mg, 1 .0 mmol) and 1 -hydroxy- 1 ,2, 3 -benzotriazole (HOBt) (13.5 mg, 0.1 mmol). Then added 2-{2-methoxy-5-[(.pound.)-3-oxo-3-(3,4,5-trimethoxy phenyl)- l -propenyFJphenoxy} acetic acid (2) (402 mg, 0.1 mmol) and the reaction mixture was stirred at a temperature of 25 °C for 24h and the reaction was monitored by TLC. Then to this water is added and extracted with dichloromethane. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate and hexane as solvent system to obtain the pure product (9i) (480 mg, 80percent yield) NMR (CDC13): delta 10.74 (br s, 1 H), 8.1 1 (s, 1 H), 7.87 (d, 1 H, J = 8.3 Hz), 7.64-7.74 (m, 2H), 7.28-7.40 (m, 3H), 7.22 (s, 2H), 6.99 (d, 1H, J = 8.3 Hz), 4.84 (s, 2H), 4.09 (s, 3H), 3.95 (s, 6H), 3.91 (s, 3H); ESIMS:603 (M+l )+.
80%		To a solution of 6-(trifluoromethyl)-2-aminobenzothiazole (218 mg, 1.0 mmol) in dichloromethane (20 mL) was added 1-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide (EDC) (191 mg, 1.0 mmol) and 1-hydroxy-1,2,3-benzotriazole (HOBt) (13.5 mg, 0.1 mmol). Then added 2-{2-methoxy-5-[(E)-3-oxo-3-(3,4,5-trimethoxy phenyl)-1-propenyl]phenoxy}acetic acid (2) (402 mg, 0.1 mmol) and the reaction mixture was stirred at a temperature of 25° C. for 24 h and the reaction was monitored by TLC. Then to this water is added and extracted with dichloromethane. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate and hexane as solvent system to obtain the pure product (9i) (480 mg, 80percent yield) 1H NMR (CDCl3): delta 10.74 (br s, 1H), 8.11 (s, 1H), 7.87 (d, 1H, J=8.3 Hz), 7.64-7.74 (m, 2H), 7.28-7.40 (m, 3H), 7.22 (s, 2H), 6.99 (d, 1H, J=8.3 Hz), 4.84 (s, 2H), 4.09 (s, 3H), 3.95 (s, 6H), 3.91 (s, 3H); ESIMS: 603 (M+1)+.

Reference： [1]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 3480 - 3492
[2]Patent: WO2012/104857,2012,A1 .Location in patent: Page/Page column 28; 29
[3]Patent: US2013/317231,2013,A1 .Location in patent: Paragraph 0182

43
[ 777-12-8 ]
[ 1392443-96-7 ]
[ 1392442-05-5 ]

Yield	Reaction Conditions	Operation in experiment
80%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 25℃; for 24h;	To a solution of 6-(trifluoromethyl)-2-aminobenzothiazole (218 mg, 1.0 mmol) in dichloromethane (20 mL) was added l-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide (EDC) (191 mg, 1.0 mmol) and 1 -hydroxy- 1 ,2, 3 -benzotriazole (HOBt) (13.5 mg, 0.1 mmol). Then added 2-{5-[l-acetyl-3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-lH-5-pyrazolyl]-2- methoxyphenoxy}aceticacid (3) (458 mg, 0.1 mmol) and the reaction mixture was stirred at a temperature of 25 °C for 24h and the reaction was monitored by TLC. Then to this water is added and extracted with dichloromethane. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate and hexane as solvent system to obtain the pure product (lOi) (528 mg, 80percent yield). NMR (CDC13): 8 10,82 (br s, 1H), 8.11 (s, 1H), 7.88 (d, 1H, J = 7.9 Hz), 7.67-7.70 (m, 1H), 6.98-7.02 (dd, lH, J = 7.9, 1.6 Hz), 6.96 (s, 2H), 6.90-6.94 (m, 2H), 5.51-5.56 (dd, l H, J = 1 1.9, 3.9 Hz), 4.79 (s, 2H), 3.99 (s, 3H), 3.91 (s, 6H), 3.89 (s, 3H), 3.71-3.79 (dd, lH, J = 11.9, 17.5 Hz), 3.10-3.15 (dd, 1H, J= 17.5, 4.7 Hz), 2.43 (s, 3H); ESIMS:659 (M+l)+.
80%		To a solution of 6-(trifluoromethyl)-2-aminobenzothiazole (218 mg, 1.0 mmol) in dichloromethane (20 mL) was added 1-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide (EDC) (191 mg, 1.0 mmol) and 1-hydroxy-1,2,3-benzotriazole (HOBt) (13.5 mg, 0.1 mmol). Then added 2-{5-[1-acetyl-3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-5-pyrazolyl]-2-methoxyphenoxy}acetic acid (3) (458 mg, 0.1 mmol) and the reaction mixture was stirred at a temperature of 25° C. for 24 h and the reaction was monitored by TLC. Then to this water is added and extracted with dichloromethane. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate and hexane as solvent system to obtain the pure product (10i) (528 mg, 80percent yield). 1H NMR (CDCl3): delta 10.82 (br s, 1H), 8.11 (s, 1H), 7.88 (d, 1H, J=7.9 Hz), 7.67-7.70 (m, 1H), 6.98-7.02 (dd, 1H, J=7.9, 1.6 Hz), 6.96 (s, 2H), 6.90-6.94 (m, 2H), 5.51-5.56 (dd, 1H, J=11.9, 3.9 Hz), 4.79 (s, 2H), 3.99 (s, 3H), 3.91 (s, 6H), 3.89 (s, 3H), 3.71-3.79 (dd, 1H, J=11.9, 17.5 Hz), 3.10-3.15 (dd, 1H, J=17.5, 4.7 Hz), 2.43 (s, 3H); ESIMS: 659 (M+1)+.

Reference： [1]Patent: WO2012/104857,2012,A1 .Location in patent: Page/Page column 30; 31
[2]Patent: US2013/317231,2013,A1 .Location in patent: Paragraph 0188

44
[ 777-12-8 ]
[ 763903-09-9 ]
[ 1392441-94-9 ]

Yield	Reaction Conditions	Operation in experiment
80%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 25℃; for 24h;	To a solution of 6-(trifluoromethyl)-2-aminobenzothiazole (218 mg, 1.0 mmol) in dichloromethane (20 mL) was added l-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide (EDC) (191 mg, 1.0 mmol) and l-hydroxy-l,2,3-benzotriazole (HOBt) (13.5 mg, 0.1 mmol). Then added 2-{2-methoxy-5-[( )-2-(3,4.5-trimethoxyphenyl)-l -ethenyl]phenoxy}aceticacid (1) (374 mg, 0.1 mmol) and the reaction mixture was stirred at a temperature of 25 °C for 24h and the reaction was monitored by TLC. Then to this water is added and extracted with dichloromethane. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate and hexane as solvent system to obtain the pure product (8i) (450 mg, 80percent yield) NMR (CDC13): delta 8.12 (s, 1H), 7.93 (d, 1H, J = 8.4 Hz), 7.69-7.75 (m, 1H), 7.01-7.06 (dd, 1H, J = 8.3, 1.7 Hz), 6.95 (d, 1H, J = 1.7 Hz), 6.85 (d, 1H, J = 8.3 Hz), 6.43-6.53 (m, 1H), 4.68 (s, 2H), 3.99 (s, 3H), 3.83 (s, 3H), 3.70 (s, 6H); ESIMS:575 (M+l)+.
80%		To a solution of 6-(trifluoromethyl)-2-aminobenzothiazole (218 mg, 1.0 mmol) in dichloromethane (20 mL) was added 1-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide (EDC) (191 mg, 1.0 mmol) and 1-hydroxy-1,2,3-benzotriazole (HOBt) (13.5 mg, 0.1 mmol). Then added 2-{2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)-1-ethenyl]phenoxy}acetic ac id (1) (374 mg, 0.1 mmol) and the reaction mixture was stirred at a temperature of 25° C. for 24 h and the reaction was monitored by TLC. Then to this water is added and extracted with dichloromethane. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate and hexane as solvent system to obtain the pure product (8i) (450 mg, 80percent yield) 1H NMR (CDCl3): delta 8.12 (s, 1H), 7.93 (d, 1H, J=8.4 Hz), 7.69-7.75 (m, 1H), 7.01-7.06 (dd, 1H, J=8.3, 1.7 Hz), 6.95 (d, 1H, J=1.7 Hz), 6.85 (d, 1H, J=8.3 Hz), 6.43-6.53 (m, 1H), 4.68 (s, 2H), 3.99 (s, 3H), 3.83 (s, 3H), 3.70 (s, 6H); ESIMS: 575 (M+1)+.

Reference： [1]European Journal of Medicinal Chemistry,2012,vol. 56,p. 166 - 178
[2]Patent: WO2012/104857,2012,A1 .Location in patent: Page/Page column 26; 27
[3]Patent: US2013/317231,2013,A1 .Location in patent: Paragraph 0174

45
[ 777-12-8 ]
[ 898748-31-7 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 5514 - 5540

46
[ 777-12-8 ]
[ 1135869-08-7 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 5514 - 5540

47
[ 3946-32-5 ]
[ 777-12-8 ]
[ 1526909-84-1 ]

Yield	Reaction Conditions	Operation in experiment
70%		CDI (230 mg, 1.4 mmol) was dissolved in DCM and suberic acid monomethyl ester (0.25 ml, 1.4mmol) was added. The mixture was stirred for 10 min, a solution of 6-chlorobenzo[d]thiazol-2-amine (180 mg) in DMF (2 ml) was added. The reaction mixture stirred for 24h at 50-60°C. DCM was evaporated under reduced pressure, then the mixture was poured into 50 ml of cold water. The precipitate appeared was filtered and washed, dried at 70°C to obtain a white solid.

Reference： [1]Medicinal Chemistry,2013,vol. 9,p. 1051 - 1057

48
[ 3946-32-5 ]
[ 777-12-8 ]
[ 1526909-80-7 ]

Reference： [1]Medicinal Chemistry,2013,vol. 9,p. 1051 - 1057

49
[ 777-12-8 ]
[ 36449-75-9 ]
[ 1579990-97-8 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2755 - 2772

50
[ 777-12-8 ]
[ 5416-93-3 ]
[ 1579990-98-9 ]

Yield	Reaction Conditions	Operation in experiment
50%	In tetrahydrofuran; at 110℃; for 1h;Microwave irradiation;	Example 2: General procedure for synthesis of compounds 24 and 46. (0108) (0109) General methodology: In a microwave vial benzothiazole derivative and the corresponding isocyanate is added in each case. Next, THF is added as solvent. The vial is introduced into the microwave reactor and heated to the temperature for the time indicated in each case. After the reaction time, ethyl acetate (50 mL) and water (50 mL) is added. The organic phase is dried over anhydrous MgS04 and the solvent is removed under reduced pressure. The obtained residue was purified by flash column chromatography using Isolera One equipment, in all cases a mixture of hexane and ethyl acetate as eluent was used. N-(6-trifluoromethylbenzothiazole-2-yl)-N'-(4-methoxyphenyl)urea (46): (0111) Reagents: 1-isocianato-4-methoxybenzene (170.9 mg, 1.2 mmol), 2-amino-6-trifluoromethylbenzothiazole (250 mg, 1.2 mmol) and 0.4 mL of THF. Reaction conditions: 1 hour under microwave irradiation at 110°C. Purification by flash column chromatography using hexane/ethyl acetate (3:1) to obtain a white solid. Yield: 208.7 mg, 50percent. Mp: 194°C-196°C 1H NMR (300 MHz, DMSO-d6) delta: 10.97 (s, 1 H), 8.99 (s, 1 H), 8.39 (s, 1 H), 7.79 (d, J = 8.4 Hz, 1 H), 7.72 - 7.62 (m, 1 H), 7.41 (d, J = 8.9 Hz, 2H), 6.91 (d, J = 9.0 Hz, 2H), 3.72 (s, 3H). 13C NMR (75 MHz, DMSO-d6) delta: 162.6, 160.8, 155.4, 151.8, 132.3, 131.1, 125.3 (d, J = 39.6 Hz), 124.8 (d, J = 242.6 Hz), 122.8 (d, J = 2.7 Hz), 120.9 (2C), 119.5 (d, J = 4.2 Hz), 119.5, 114.1 (2C), 55.2. HPLC purity: >99percent. MS (ES) m/z: 368 [M+H]+. Elemental analysis (C16H12F3N3O2S): Theoretical percentC 52.31, percentH 3.29, percentN 11.44. Found percentC 50.27, percentH 4.08, percentN 11.54.

Reference： [1]Patent: EP2949651,2015,A1 .Location in patent: Paragraph 0108-0109; 0111
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 2755 - 2772

51
[ 777-12-8 ]
[ 41904-39-6 ]
[ 1579991-01-7 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2755 - 2772

52
[ 777-12-8 ]
[ 25026-34-0 ]
[ 1579991-05-1 ]

Yield	Reaction Conditions	Operation in experiment
95%	at 150℃; for 0.0833333h;Microwave irradiation;	General procedure: Amide formation: (0088) The acid chloride (1 eq) formed on the corresponding 2-aminobenzothiazole (1 eq) is added introduced in a microwave vial. The vial is introduced in the microwave reactor and heated to the temperature for the time indicated in each case. Dichloromethane (50 mL) is added and extracted with a 0.1 M HCl (50 mL) solution. Next, the organic phase is washed with saturated NaHC03 solution (50 mL) and then with saturated NaCl (50 mL) solution. The organic phase is dried over anhydrous MgS04 and the solvent removed under reduced pressure. The residue obtained was purified by flash column chromatography using Isolera One equipment. In all cases a mixture of hexane and ethyl acetate was used as eluent. All the acid chlorides required for the synthesis of the amide derivatives were synthesised in situ except: 2-(4-chlorophenyl)acetyl chloride, 2-(2,5-dimethoxyphenyl)acetyl chloride and 2-phenylbutanoyl chloride, which were purchased directly from the company Sigma Aldrich. N-(6-trifluoromethylbenzothiazole-2-yl)-2-(4-chlorophenyl)acetamide (1): Reagents: 2-(4-chlorophenyl)acetyl chloride (216.7 mg, 1.1 mmol) and 2-amino-6-trifluoromethylbenzothiazole (250 mg, 1.14 mmol). Reaction conditions: 5 min under microwave irradiation at 150°C. Purification by flash column chromatography using hexane/ethyl acetate (3:1) to obtain a white solid. Yield: 404.1 mg, 95percent. Mp: 135°C-137°C 1H NMR (300 MHz, DMSO-d6) delta: 12.84 (s, 1 H), 8.48 (s, 1 H), 7.90 (d, J = 8.5 Hz, 1 H), 7.73 (d, J = 8.4 Hz, 1 H), 7.49 - 7.27 (m, 4H), 3.87 (s, 2H). 13C NMR (75 MHz, DMSO-d6) delta: 170.4, 161.1, 151.2, 134.0, 133.4, 132.0, 131.3, 128.1, 124.5 (d, J = 272.0 Hz), 123.7 (d, J = 31.8 Hz), 122.9 (d, J = 3.9 Hz), 120.9, 1 19.9 (d, J = 4.3 Hz) 41.0. HPLC purity: >99percent. ESI-MS (m/z): 371 [M+H]+. Elemental analysis (C16H10ClF3N2OS): Theoretical percentC 51.83, percentH 2.72, percentN 7.56, percentS 8.64; Found percentC 52.00, percentH 2.71, percentN 7.55, percentS 8.49.

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2755 - 2772
[2]Patent: EP2949651,2015,A1 .Location in patent: Page/Page column 0088-0089

53
[ 777-12-8 ]
[ 28033-63-8 ]
[ 1579991-06-2 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2755 - 2772

54
[ 777-12-8 ]
[ 21615-34-9 ]
[ 1579990-96-7 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2755 - 2772

55
[ 777-12-8 ]
[ 51512-09-5 ]
[ 1579991-04-0 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2755 - 2772

56
[ 777-12-8 ]
[ 6834-42-0 ]
[ 1579991-07-3 ]

Yield	Reaction Conditions	Operation in experiment
26%	at 110℃; for 0.25h;Microwave irradiation;	General procedure: Amide formation: (0088) The acid chloride (1 eq) formed on the corresponding 2-aminobenzothiazole (1 eq) is added introduced in a microwave vial. The vial is introduced in the microwave reactor and heated to the temperature for the time indicated in each case. Dichloromethane (50 mL) is added and extracted with a 0.1 M HCl (50 mL) solution. Next, the organic phase is washed with saturated NaHC03 solution (50 mL) and then with saturated NaCl (50 mL) solution. The organic phase is dried over anhydrous MgS04 and the solvent removed under reduced pressure. The residue obtained was purified by flash column chromatography using Isolera One equipment. In all cases a mixture of hexane and ethyl acetate was used as eluent. All the acid chlorides required for the synthesis of the amide derivatives were synthesised in situ except: 2-(4-chlorophenyl)acetyl chloride, 2-(2,5-dimethoxyphenyl)acetyl chloride and 2-phenylbutanoyl chloride, which were purchased directly from the company Sigma Aldrich N-(6-trifluoromethylbenzothiazole-2-yl)-2-(3-methoxyphenyl)acetamide (6): (0092) Reagents: 2-(3-methoxyphenyl)acetyl chloride (211.7 mg, 1.2 mmol), 2-amino-6-trifluoromethylbenzothiazole (250 mg, 1.2 mmol) and THF (1 mL). Reaction conditions: 15 min under microwave irradiation at 110°C. Purification by flash column chromatography using hexane/ethyl acetate (3:1) to obtain a white solid. Yield: 108.1 mg, 26percent. Mp: 154°C-156°C 1H NMR (400 MHz, DMSO-d6) delta: 12.83 (s, 1 H), 8.48 (s, 1 H), 7.90 (d, J = 8.5 Hz, 1 H), 7.73 (dd, J = 8.5, 1.5 Hz, 1 H), 7.25 (t, J = 7.9 Hz, 1 H), 6.92 (m, 2H), 6.84 (dd, J = 7.9, 2.2 Hz, 1 H), 3.82 (s, 2H), 3.74 (s, 2H). 13C NMR (101 MHz, DMSO-d6) delta: 171.2, 161.8, 160.0, 152.0, 136.5, 132.7, 130.2, 125.2 (d, J = 271.8 Hz), 124.4 (d, J = 31.9 Hz), 123.6 (d, J = 3.6 Hz), 122.2, 121.6, 120.6 (d, J = 4.1 Hz), 115.9, 113.0, 55.7, 42.6. HPLC purity: 98percent. MS (ES) m/z: 367 [M+H]+. Elemental Analysis (C17H13F3N2O2S): Theoretical percentC 55.73, percentH 3.58, percentN 7.65, percentS 8.75; Found percentC 55.80, percentH 3.41, percentN 7.66, percentS 9.02.N, 9.02percent S.

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2755 - 2772
[2]Patent: EP2949651,2015,A1 .Location in patent: Page/Page column 0088; 0092

57
[ 777-12-8 ]
[ 2003-14-7 ]
[ 1579991-08-4 ]

Yield	Reaction Conditions	Operation in experiment
42%	at 110℃; for 0.333333h;Microwave irradiation;	General procedure: Amide formation: (0088) The acid chloride (1 eq) formed on the corresponding 2-aminobenzothiazole (1 eq) is added introduced in a microwave vial. The vial is introduced in the microwave reactor and heated to the temperature for the time indicated in each case. Dichloromethane (50 mL) is added and extracted with a 0.1 M HCl (50 mL) solution. Next, the organic phase is washed with saturated NaHC03 solution (50 mL) and then with saturated NaCl (50 mL) solution. The organic phase is dried over anhydrous MgS04 and the solvent removed under reduced pressure. The residue obtained was purified by flash column chromatography using Isolera One equipment. In all cases a mixture of hexane and ethyl acetate was used as eluent. All the acid chlorides required for the synthesis of the amide derivatives were synthesised in situ except: 2-(4-chlorophenyl)acetyl chloride, 2-(2,5-dimethoxyphenyl)acetyl chloride and 2-phenylbutanoyl chloride, which were purchased directly from the company Sigma Aldrich N-(6-trifluoromethylbenzothiazole-2-yl)-2-(3-(trifluoromethyl)phenyl)acetamide (13): (0099) Reagents: 2-(3-(trifluoromethyl)phenyl)acetyl chloride (253.8 mg, 1.2 mmol), 2-amino-6-trifluoromethylbenzothiazole (250 mg, 1.2 mmol) and THF (0.5 mL). Reaction conditions: 20 min under microwave irradiation at 110°C. Purification by flash column chromatography using hexane/ethyl acetate (1:1) to obtain a white solid. Yield: 194.4 mg, 42percent. Mp: 138-140 °C 1H NMR (400 MHz, DMSO-d6) delta: 12.87 (s, 1 H), 8.48 - 8.43 (m, 1 H), 7.88 (d, J = 8.5 Hz, 1H), 7.74 - 7.51 (m, 5H), 3.99 (s, 2H). 13C NMR (101 MHz, DMSO-d6) delta: 170.9, 161.7, 151.9, 136.4, 134.5, 132.7, 130.1, 129.7 (d, J = 31.5 Hz.), 126.9 (d, J = 3.9 Hz), 125.2 (d, J = 271.8 Hz), 124.9 (d, J = 272.1 Hz), 124.4 (d, J = 3.8 Hz), 124.4 (d, J = 31.8 Hz), 123.6 (d, J = 4.0 Hz), 121.7, 120.6 (d, J = 4.4 Hz), 41.9. HPLC purity: 96percent. MS (ES) m/z: 405 [M+H]+.

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2755 - 2772
[2]Patent: EP2949651,2015,A1 .Location in patent: Page/Page column 0088; 0090; 0099

58
[ 777-12-8 ]
[ 4693-91-8 ]
[ 1579991-09-5 ]

Yield	Reaction Conditions	Operation in experiment
44%	at 110℃; for 0.166667h;Microwave irradiation;	General procedure: Amide formation: (0088) The acid chloride (1 eq) formed on the corresponding 2-aminobenzothiazole (1 eq) is added introduced in a microwave vial. The vial is introduced in the microwave reactor and heated to the temperature for the time indicated in each case. Dichloromethane (50 mL) is added and extracted with a 0.1 M HCl (50 mL) solution. Next, the organic phase is washed with saturated NaHC03 solution (50 mL) and then with saturated NaCl (50 mL) solution. The organic phase is dried over anhydrous MgS04 and the solvent removed under reduced pressure. The residue obtained was purified by flash column chromatography using Isolera One equipment. In all cases a mixture of hexane and ethyl acetate was used as eluent. All the acid chlorides required for the synthesis of the amide derivatives were synthesised in situ except: 2-(4-chlorophenyl)acetyl chloride, 2-(2,5-dimethoxyphenyl)acetyl chloride and 2-phenylbutanoyl chloride, which were purchased directly from the company Sigma AldrichN-(6-trifluoromethylbenzothiazole-2-yl)-2-(4-methoxyphenyl)acetamide (3): (0090) Reagents: 2-(4-methoxyphenyl)acetyl chloride (21 1.7 mg, 1.2 mmol), 2-amino-6-trifluoromethylbenzothiazole (250 mg, 1.2 mmol) and THF (1 mL). Reaction conditions: 10 min under microwave irradiation at 110°C. Purification by flash column chromatography using hexane/ethyl acetate (3:1) to obtain a yellow solid. Yield: 184.8 mg, 44percent. Mp: 133°C-134°C 1H NMR (300 MHz, DMSO-d6) delta: 12.79 (s, 1 H), 8.47 (s, 1 H), 7.90 (d, J = 8.5 Hz, 1 H), 7.73 (d, J = 8.5 Hz, 1 H), 7.26 (d, J = 8.6 Hz, 2H), 6.89 (d, J = 8.7 Hz, 2H), 3.77 (s, 2H), 3.72 (s, 3H). 13C NMR (75 MHz, DMSO-d6) delta: 171.0, 161.1, 158.3, 151.3, 132.0, 130.4, 126.3, 124.5 (d, J = 272.2 Hz), 123.7 (d, J = 31.9 Hz), 122.9 (d, J = 3.7 Hz), 120.9, 119.8 (d, J = 4.3 Hz), 113.9, 55.0, 40.9. HPLC purity: >99percent. MS (ES) m/z: 367 [M+H]+. Elemental analysis (C17H13F3N2O2S): Theoretical percentC 55.73, percentH 3,58, percentN 7,65, percentS 8.75; Found percentC 55.48, percentH 3.31, percentN 7.44, percentS 8,97.

Reference： [1]Patent: EP2949651,2015,A1 .Location in patent: Page/Page column 0088; 0090
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 2755 - 2772

59
[ 777-12-8 ]
[ 103-80-0 ]
[ 1579991-10-8 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2755 - 2772

60
[ 777-12-8 ]
[ 6831-55-6 ]
[ 1579991-11-9 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2755 - 2772

61
[ 777-12-8 ]
[ 6831-55-6 ]
[ 1579991-13-1 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2755 - 2772

62
[ 777-12-8 ]
[ 52711-92-9 ]
[ 1579991-14-2 ]

Yield	Reaction Conditions	Operation in experiment
31%	at 150℃; for 0.116667h;Microwave irradiation;	General procedure: Amide formation: (0088) The acid chloride (1 eq) formed on the corresponding 2-aminobenzothiazole (1 eq) is added introduced in a microwave vial. The vial is introduced in the microwave reactor and heated to the temperature for the time indicated in each case. Dichloromethane (50 mL) is added and extracted with a 0.1 M HCl (50 mL) solution. Next, the organic phase is washed with saturated NaHC03 solution (50 mL) and then with saturated NaCl (50 mL) solution. The organic phase is dried over anhydrous MgS04 and the solvent removed under reduced pressure. The residue obtained was purified by flash column chromatography using Isolera One equipment. In all cases a mixture of hexane and ethyl acetate was used as eluent. All the acid chlorides required for the synthesis of the amide derivatives were synthesised in situ except: 2-(4-chlorophenyl)acetyl chloride, 2-(2,5-dimethoxyphenyl)acetyl chloride and 2-phenylbutanoyl chloride, which were purchased directly from the company Sigma Aldrich. N-(6-trifluoromethylbenzothiazole-2-yl)-2-(2,5-dimethoxyphenyl)acetamide (29): (0105) Reagents: 2-(2,5-dimethoxyphenyl)acetyl chloride (246 mg, 1.2 mmol), 2-amino-6-trifluoromethylbenzothiazole (250 mg, 1.2 mmol). Reaction conditions: 7 min under microwave irradiation at 150°C. Purification by flash column chromatography using hexane/ethyl acetate (3:1) to obtain a beige solid. Yield: 141.7 mg, 31percent. Mp. 146°C-147°C 1H NMR (300 MHz, DMSO-d6) 5: 8.26 (d, J = 24.7 Hz, 1 H), 7.63 (dd, J = 32.9, 7.4 Hz, 2H), 6.82 (dd, J = 30.0, 9.1 Hz, 3H), 3.68 (s, 8H). 13C NMR (75 MHz, DMSO-d6) delta: 174.0, 165.95, 152.9, 152.6, 151.5, 132.5, 125.9, 121.9 (d, J = 2.25 Hz), 121.6 (d, J = 37.2 Hz), 119.2, 118.8 (d, J = 3.6 Hz), 117.4, 111.7 (2C), 56.0, 55.3, 38.4. HPLC purity: >99percent. MS (ES) m/z: 397 [M+H]+.

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2755 - 2772
[2]Patent: EP2949651,2015,A1 .Location in patent: Page/Page column 0088; 0105

63
[ 777-12-8 ]
[ 39053-78-6 ]
[ 1579991-15-3 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2755 - 2772

64
[ 777-12-8 ]
[ 39053-78-6 ]
[ 1579991-16-4 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2755 - 2772

65
[ 777-12-8 ]
[ 23860-35-7 ]
[ 1579991-17-5 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2755 - 2772

66
[ 7065-46-5 ]
[ 777-12-8 ]
[ 1579991-18-6 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2755 - 2772

67
[ 873302-27-3 ]
[ 777-12-8 ]
5-hydroxy-2-phenyl-7-(4-(6-(trifluoromethyl)benzo[d]thiazol-2-ylamino)butoxy)-4H-chromen-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%	In acetonitrile;Reflux;	General procedure: In a flask charged with 50 mL of CH3CN was added2.5 mmol of compound 5 andappropriate benzothiazole derivatives (2a-r,1.5 eq.) and the reaction mixture was refluxed for 10-38 h until the completeconsumption of starting material as detected by TLC.After the completion of the reaction, the reactionmixture was treated with ice and the resulting solid was filtered and washedwith water (2 x 25 mL). The residue was purifiedby a silica gel column chromatography andwas eluted with dichloromethane: methanol (40:1) to afford correspondingproducts 6a-r in 49-82% of yields.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 5561 - 5565

68
[ 777-12-8 ]
[ 2909-38-8 ]
N-(6-trifluoromethylbenzothiazole-2-yl)-N'-(3-chlorophenyl)urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
10%	In tetrahydrofuran; at 110℃; for 3.5h;Microwave irradiation;	Example 2: General procedure for synthesis of compounds 24 and 46. (0108) (0109) General methodology: In a microwave vial benzothiazole derivative and the corresponding isocyanate is added in each case. Next, THF is added as solvent. The vial is introduced into the microwave reactor and heated to the temperature for the time indicated in each case. After the reaction time, ethyl acetate (50 mL) and water (50 mL) is added. The organic phase is dried over anhydrous MgS04 and the solvent is removed under reduced pressure. The obtained residue was purified by flash column chromatography using Isolera One equipment, in all cases a mixture of hexane and ethyl acetate as eluent was used. N-(6-trifluoromethylbenzothiazole-2-yl)-N'-(3-chlorophenyl)urea (24): (0110) Reagents: 1-isocianato-3-chlorobenzene (175.8 mg, 1.2 mmol), 2-amino-6-trifluoromethylbenzothiazole (250 mg, 1.2 mmol) and THF (0.4 mL). Reaction conditions: 3 hours and 30 min under microwave irradiation at 110°C. Purification by flash column chromatography using hexane/ethyl acetate (3:1) to obtain a white solid. Yield: 43.2 mg, 10percent. Mp: 222°C-223°C 1H NMR (500 MHz, DMSO-d6) delta: 11.16 (s, 1 H), 9.38 (s, 1 H), 8.41 (s, 1 H), 7.73 (s, 1 H), 7.69 (dd, J = 8.5, 1.9 Hz, 1 H), 7.38 (s, 1 H), 7.35 (t, J = 7.9 Hz, 2H), 7.11 (d, J = 8.5 Hz, 1H). 13C NMR (126 MHz, DMSO-d6) delta: 162.6, 152.0, 140.3, 133.7, 131.0, 125.0 (q, J = 271.7 Hz), 123.6 (d, J = 31.8 Hz), 123.5, 123.4 (d, J = 2.5 Hz), 120.1 (d, J = 4.3 Hz), 118.8, 117.9. HPLC purity: >99percent. MS (ES) m/z: 372 [M+H]+.

Reference： [1]Patent: EP2949651,2015,A1 .Location in patent: Paragraph 0108-0110

69
[ 777-12-8 ]
2-(3,4-dimethoxybenzyl)-6-(trifluoromethyl)benzo[d]thiazole [ No CAS ]

Reference： [1]Patent: WO2015/197861,2015,A1

70
[ 777-12-8 ]
2-iodo-6-(trifluoromethyl)-1,3-benzothiazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With diiodomethane; isopentyl nitrite; In N,N-dimethyl-formamide; at 60℃; for 0.5h;	Step 1, Method 12: 2-Iodo-6-(trifluoromethyl)-l,3-benzothiazole[0190] To a solution of 6-(trifluoromethyl)-l,3-benzothiazol-2-amine (200 mg, 0.92 mmol) in dry N,N-dimethylformamide (7 mL), diiodomethane (3.69 mL, 45.83 mmol) and 3-methylbutyl nitrite (3.69 mL, 27.5 mmol) were added and the mixture heated at 60 °C for 30 minutes. The volatile solvents were evaporated, water (20 mL) added and the mixture extracted with dichloromethane (2 x 10 mL). The combined organic layers were washed with water (5 x 10 mL), dried over sodium sulphate, filtered and concentrated. Purification by FCC (silica, 0-100percent dichloromethane in heptane) gave the title compound 224 mg (74percent yield) as a white powder. Tr(METCR1278) = 2.24 min, (ES+) (M+H)+330.

Reference： [1]Patent: WO2016/33460,2016,A1 .Location in patent: Paragraph 0190

71
[ 777-12-8 ]
4-[6-(trifluoromethyl)-1,3-benzothiazol-2-yl]pyridine-3-carbonitrile [ No CAS ]

Reference： [1]Patent: WO2016/33460,2016,A1

72
[ 777-12-8 ]
[ 29568-33-0 ]
5-chloro-2-methoxy-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 48h;	[0152] 5-Chloro-2-methoxybenzoic acid (535.0 mg, 2.864 mmol) was dissolved in DCM (15.0 mL), followed by the addition of catalytic amount of DMF (40 .iL) and oxalyl chloride (0.30 mL, 3.437 mmol) respectively. The reaction was allowed to stir at rt for 30 mm and concentrated in vacuo. The residue was re-dissolved in TIIF (10.0 mL), and Hunig?s base (0.50 mL, 2.864 mmol) and 6-(trifluoromethyl)benzo[d]thiazol-2-ammne (500.0 mg, 2.29 1 mmol) were added. The mixture was stirred at rt for 48 hours before it was filtered. The filter cake was washed with diethyl ether and DCM to give 5-chloro-2-methoxy-N-(6-(trifluoromethyl)benzo[d]thiazol-2- yl)benzamide (710.5 mg, 80percent yield). This compound (400.0 mg, 1.034 mmol) was then mixed with pyridinium chloride (4.000 g). The mixture was heated to 210 °C, stirred for 15 minutes and cooled down to rt. The resulting solid was suspended in water and filtered. The filter cake was washed with diethyl ether to give 5-chloro-2-hydroxy-N-(6-(trifluoromethyl)benzo[d]thiazol-2- yl)benzamide 31 (219.1 mg, 57percent yield). ?H NMR (300 MHz, DMSO-d6) 6 8.56 (d, J = 2.2 Hz, 1H), 7.93 (dd, J = 6.2, 4.0 Hz, 2H), 7.84 ?7.72 (m, 1H), 7.55 (dt, J = 8.8, 2.4 Hz, 1H), 7.10 (dd, J = 9.0, 2.0 Hz, 1H). MS (ESI) exact mass calculated for [M+H] (C15H9C1F3N2025) requires m/z 373.0, found m/z 372.7.

Reference： [1]Patent: WO2016/81599,2016,A1 .Location in patent: Paragraph 0152

73
[ 777-12-8 ]
10-(trifluoromethyl)benzo[4',5']thiazolo[2',3':2,3]imidazo[4,5-c]cinnoline [ No CAS ]

Reference： [1]RSC Advances,2016,vol. 6,p. 67086 - 67095

74
[ 777-12-8 ]
C₂₄H₂₃F₃N₄O₄S [ No CAS ]

Reference： [1]RSC Advances,2016,vol. 6,p. 67086 - 67095

75
[ 777-12-8 ]
[ 108-24-7 ]
N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)acetamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 9814 - 9824

76
[ 455-14-1 ]
[ 777-12-8 ]

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 9814 - 9824

77
[ 777-12-8 ]
[ 1877-71-0 ]
C₁₇H₁₁F₃N₂O₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;	<strong>[777-12-8]6-(trifluoromethyl)benzo[d]thiazol-2-amine</strong> (commercially available or prepared according to Step 1 and 2 of Example 1) (1 eq), 3-(methoxycarbonyl)benzoic acid (1.05eq) and DIPEA (5 eq) were dissolved in DMF (2 ml). HI3TU(1.2 eq) was added and the reaction were stirred overnightat ambient temperature before extraction with ethylacetate,washed thoroughly 2 times with dilute acid and dried. Thecrude product, methyl 3-((6-(trifluoromethyl)benzo[d]thi-azol-2-yl)carbamoyl)benzoate, was isolated by evaporationof the solvent under reduced pressure.

Reference： [1]Patent: US2017/7583,2017,A1 .Location in patent: Paragraph 0092; 0093

78
[ 777-12-8 ]
[ 103-71-9 ]
C₁₅H₁₀F₃N₃OS [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane; at 20℃; for 16h;Inert atmosphere;	Phenyl isocyanate (107 mg, 0.9 nmol) was addedto a solution of 2-amino-6-fluorobenzothiazole (100mg, 0.6mmol) in dry DCM under argon. The reaction was allowedto proceed at R.T. for 16 hours before the product wasisolated by filtration.

Reference： [1]Patent: US2017/7583,2017,A1 .Location in patent: Paragraph 0100; 0101

79
[ 777-12-8 ]
[ 104-88-1 ]
4-chloro-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide [ No CAS ]

Reference： [1]Chemical Communications,2017,vol. 53,p. 1478 - 1481

80
[ 777-12-8 ]
[ 51676-76-7 ]
C₁₅H₈ClF₃N₄O₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.72 g		1.09g (0.005 mol) 2-amino-6-trifluoromethylbenzothiazole was dissolved in 10 mL of N,N-dimethylformamide, 0.4 g (0.01 mol) of sodium hydroxide was added with stirring, After 10 minutes, 1.26 g (0.005 mol) of 2,6-dichloro-3,5-dinitrotoluene was added thereto ,The reaction was continued at room temperature for 5 hours. After completion of the TLC monitoring reaction, the reaction solution was poured into 50 mL of saturated brine and extracted with ethyl acetate. The organic phase was extracted with anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was subjected to column chromatography (eluent ethyl acetate and petroleum ether (Boiling range 60-90 ° C) in a volume ratio of 1:10) to give 0.72 g of compound 3571, Yellow solid. Melting point 136-138 ° C.

Reference： [1]Patent: CN104177310,2016,B .Location in patent: Paragraph 0139; 0140; 0141; 0142

81
[ 777-12-8 ]
3-(3,4-dimethoxyphenyl)-1H-pyrazole-5-carbaldehyde [ No CAS ]
(E)-N-[(3-(3,4-dimethoxyphenyl)-1H-pyrazol-5-yl)methylene]-6-(trifluoromethyl)benzo[d]thiazol-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	In ethanol; for 6h;Reflux;	To 3-subtituted phenyl-1H-pyrazole-5-carbaldehydes 11(a-d) (1 mmol) obtained in the above step was added substituted 2-amino benzothiazoles (1.0 mmol) in ethanol and heated to reflux for 6 h. The completion of reaction was confirmed by TLC in ethyl acetate and hexane solvent system. The product so obtained was filtered and washed twice with ethanol. Futher these solid products were recrystallized in ethanol to get pure conjugates of pyrazole and benzothiazole amine (12a-12q) in good yields (Scheme-I). #10;

Reference： [1]Asian Journal of Chemistry,2017,vol. 29,p. 1029 - 1034

82
[ 777-12-8 ]
3-(benzo[d][1,3]dioxol-5-yl)-1H-pyrazole-5-carbaldehyde [ No CAS ]
(E)-N-[(3-(benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-5-yl)methylene]-6-(trifluoromethyl)benzo[d]thiazol-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	In ethanol; for 6h;Reflux;	To 3-subtituted phenyl-1H-pyrazole-5-carbaldehydes 11(a-d) (1 mmol) obtained in the above step was added substituted 2-amino benzothiazoles (1.0 mmol) in ethanol and heated to reflux for 6 h. The completion of reaction was confirmed by TLC in ethyl acetate and hexane solvent system. The product so obtained was filtered and washed twice with ethanol. Futher these solid products were recrystallized in ethanol to get pure conjugates of pyrazole and benzothiazole amine (12a-12q) in good yields (Scheme-I). #10;

Reference： [1]Asian Journal of Chemistry,2017,vol. 29,p. 1029 - 1034

83
[ 777-12-8 ]
[ 102-36-3 ]
1-(3,4-dichlorophenyl)-3-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)urea [ No CAS ]

Reference： [1]ChemMedChem,2017,vol. 12,p. 1045 - 1054

84
[ 777-12-8 ]
3-chloro-2-fluorophenylisocyanate [ No CAS ]
1-(3-chloro-2-fluorophenyl)-3-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)urea [ No CAS ]

Reference： [1]ChemMedChem,2017,vol. 12,p. 1045 - 1054

85
[ 777-12-8 ]
[ 50528-86-4 ]
1-(2-chloro-5-(trifluoromethyl)phenyl)-3-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)urea [ No CAS ]

Reference： [1]ChemMedChem,2017,vol. 12,p. 1045 - 1054

86
[ 777-12-8 ]
[ 16588-69-5 ]
1-(4-chloro-2-(trifluoromethyl)phenyl)-3-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)urea [ No CAS ]

Reference： [1]ChemMedChem,2017,vol. 12,p. 1045 - 1054

87
[ 85-44-9 ]
[ 777-12-8 ]
2-(6-trifluoromethylbenzothiazol-2-yl)-1H-isoindole-1,3(2H)-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54.1%	With acetic acid; for 7h;Reflux; Inert atmosphere;	A mixture of phthalic anhydride (0.339 g, 2.289 mmol) and 2-amino-6-trifluoromethylbenzothiazole (0.5 g, 2.291 mmol) in acetic acid (20 mL) was refluxed for 7 hours under an atmosphere of nitrogen. After removing solvent, the residues were recrystallized with acetone to afford product 59 (431.0 mg, 54.1 percent) as white needle crystals: mp 279.0-28 1.5 °C; 1H NMR (DMSO-d6)delta 8.70 (s, 1H, C7?-H). 8.23 (d, 1H, C4?-H), 8.12-8.09 (m, 2H, C5,6-H), 8.02-7.99 (m, 2H, C4,7-H) and 7.88 (d, 1H, C5?-H); 13C NMR (DMSO-d6)delta 168.7, 160.0, 155.9, 140.1, 137.1,135.4, 130.0, 129.5, 128.7, 127.6, 127.3 and 124.5 ppm; MS (CI/CH4), m/z 348 (M+)

Reference： [1]Patent: WO2017/59062,2017,A1 .Location in patent: Page/Page column 31

88
[ 777-12-8 ]
[ 108-94-1 ]
3-(trifluoromethyl)-7,8,9,10-tetrahydrobenzo[d]benzo[4,5]imidazo[2,1-b]thiazole [ No CAS ]

Reference： [1]Green Chemistry,2017,vol. 19,p. 4294 - 4298

89
[ 777-12-8 ]
5-chloro-3-cyclopropyl-2-methoxybenzoic acid [ No CAS ]
5-chloro-3-cyclopropyl-2-hydroxy-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
26%		To a stirred solution of 5-chloro-3-cyclopropyl-2-methoxybenzoic acid(120mg, 0.S3mmol) and HBTU (243mg, 0.64mmol) in DMF (5m1) was added DIPEA(277u1, 1.S9mmol). The mixture was stirred for lOmins and then <strong>[777-12-8]6-(trifluoromethyl)benzo[d]thiazol-2-amine</strong> (92mg, 0. 42mmol) was added. The resultingreaction was heated at 120 °C for 24hs. After cooled to rt, the mixture was separated between EA and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification by column chromatography gave the title compound as a yellow solid (45mg, 26percent). ?H NIVIR (300 MHz, Chloroform-d) 8.11 (s, 1H), 7.70 -7.63(m, 2H), 6.98 (d, J = 3.0 Hz, 1H), 6.71 (d, J = 3.0 Hz, 1H), 2.20-2.10 (m, 1H), 1.05-1.00 (m, 2H), 0.70-0.65 (m, 2H). MS (ESI) [M+H]requires m/z 413.03, found m/z 413.15.

Reference： [1]Patent: WO2017/201313,2017,A1 .Location in patent: Paragraph 0214

90
[ 777-12-8 ]
5-chloro-3-isopropyl-2-methoxybenzoic acid [ No CAS ]
5-chloro-2-hydroxy-3-isopropyl-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
22%		To a stirred solution of 5-chloro-3-isopropyl-2-methoxybenzoic acid (90mg, 0.395mmo1) and HBTU (180mg, 0.474mmo1) in DMF (5m1) was added DIPEA (206u1, 1.l85mmol). The mixture was stirred for lOmins and then 6- (trifluoromethyl)benzo[d]thiazol-2-amine (86mg, 0.3 95mmol) was added. The resulting reaction was heated at 120 °C for 24hs. After cooled to rt, the mixture was separated between EA and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification by column chromatography gave the title compound as a yellow solid (35mg, 22percent). ?H NMR (300 MHz, Chloroform-d) 8.17 (s, 1H), 7.66 (s, 2H), 7.50 (d, J = 2.5 Hz, 1H), 7.34 (d, J = 1.7 Hz, 1H), 3.51 - 3.35 (m, 1H), 1.28 (d, J = 6.9 Hz, 6H). MS (ESI) [M+H]requires m/z 415.05, found m/z 415.05.

Reference： [1]Patent: WO2017/201313,2017,A1 .Location in patent: Paragraph 0218

91
[ 777-12-8 ]
C₉H₆ClNO₃ [ No CAS ]
5-chloro-3-cyano-2-hydroxy-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62 mg		To a stirred solution of methyl 5-chloro-3-cyano-2-methoxybenzoate (86mg, 0.382mmo1) in MeOH (3m1) was added 2.0 ml iN KOH solution. The resulting mixture was stirred at 60°C overnight. The solvent was evaporated out and 4N HC1 in dioxane (lml) was added to the residue. The mixture was stirred for another 10mm before it was concentrated and dried under vacumn. To this residue was added HBTU (172mg, 0.456mmo1), DMF (3m1) and DIPEA (330u1, 1.9 mmol). The mixture was stirred for lOmins and then <strong>[777-12-8]6-(trifluoromethyl)benzo[d]thiazol-2-amine</strong> (83mg, 0.3 8mmol) was added. The resulting reaction was heated at 120 °C for 24hs. After cooled to rt, the mixture was separated between EA and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification by column chromatography gave the 5-chloro-3-cyano-2- hydroxy-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)b enzamide as a yellow solid (62mg, 42percent). ?H NMR (300 IVIHz, Acetone-d6) 8.31 (dt, J = 1.6, 0.9 Hz, 1H), 7.85 (d, J = 3.0 Hz, 1H), 7.79 -7.65 (m, 2H), 7.14 (d, J = 3.0 Hz, 1H). MS (ESI) [M+H] requires m/z 398.00, found m/z 397.95.

Reference： [1]Patent: WO2017/201313,2017,A1 .Location in patent: Paragraph 0236

92
[ 777-12-8 ]
C₁₁H₁₃ClO₅ [ No CAS ]
5-chloro-2-hydroxy-3-((methoxymethoxy)methyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2yl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
37 mg		To a stirred solution of methyl 5-chloro-2-methoxy-3-((methoxymethoxy)methyl)benzoate (122mg, 0.445mmo1) in MeOH (5m1) was added 2.2 ml iN KOH solution. The resulting mixture was stirred at 60°C overnight. After cooled to rt, the reaction was partitioned between EA and 2percent citric acid. The EA layer was washed with brine, dried over Na2504 and concentrated in vacuo. To this residue was added HBTU (98mg, 0.258mmo1), DMF (3m) and DIPEA (187u, 1.075 mmo). The mixture was stirred for lOmins and then 6-(trifluoromethy)benzo[d]thiazo-2-amine (47mg, 0.2l5mmo) was added. The resuting reaction was heated at 120 °C for 24hs. After cooed to rt, the mixture was separated between EA and water. The organic ayer was washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification by coumn chromatography gave the 5- choro-2-hydroxy-3 -((methoxymethoxy)methy)-N-(6-(trifluoromethy)benzo[d]thiazo -2y)benzamide as a yeow soid (37mg, 39percent). ?H NMR (400 MHz, Choroform-d) 8.16 (s, 1H), 7.99 (d, J = 2.5 Hz, 1H), 7.91 (d, J = 6.1 Hz, 1H), 7.72 (d, J = 6.1 Hz, 1H), 7.48 (d, J =2.5 Hz, 1H), 4.80 (s, 2H), 4.78 (s, 2H), 3.47 (s, 3H). MS (ESI) [M+Na] requires m/z 469.02, found m/z 468.55.

Reference： [1]Patent: WO2017/201313,2017,A1 .Location in patent: Paragraph 0238

93
[ 777-12-8 ]
C₉H₈Cl₂O₂ [ No CAS ]
5-chloro-2-methoxy-3-methyl-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
120 mg	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 48h;	5-chloro-2-methoxy-3-methylbenzoic acid (220mg, 1.lmmol) was dissolved in dichloromethane (5.0 mL), followed by the addition of catalytic amount of dimethylformamide (3 drops) and oxalyl chloride (114 uL, 1 .32mmol) respectively. The reaction was allowed to stir at room temperature for 30 mm and concentrated in vacuo. Theresidue was redissolved in tetrahydrofuran (8.0 mL), and Hunig? s base (230uL, 1.31 mmol) and <strong>[777-12-8]6-(trifluoromethyl)benzo[d]thiazol-2-amine</strong> (240mg, 1.1 mmol) were added. The mixture was stirred at room temperature for 48 hours before silica gel was added to quench the reaction. Solvent was evaporated and the resulting residue was purified via silica gel columnchromatography to yield 5 -chloro-2-methoxy-3 -methyl-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide (120 mg, 28percent yield). ?H NMR (300 IVIFIz, acetone-cl6) 11.60 (s, 1H), 8.45 (s, 1H), 7.96 (d, J = 8.5 Hz, 1H), 7.88?7.72 (m, 2H), 7.57 (d, J = 2.8 Hz, 1H), 4.00 (s, 3H), 2.43 (s, 3H). MS (ESI) [M+H]requires m/z 401.03, found m/z 400.75.

Reference： [1]Patent: WO2017/201313,2017,A1 .Location in patent: Paragraph 0164; 0167

94
[ 777-12-8 ]
C₁₃H₁₈ClNO₃*ClH [ No CAS ]
5-chloro-3-(3-(dimethylamino)propyl)-2-methoxy-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50 mg		To a stirred solution of methyl 5-chloro-3-(3-(dimethylamino)propyl)-2- methoxybenzoate (90mg, 0.32mmol) in MeOH (5m1) was added 1.5m1 iN KOH solution. The resulting mixture was stirred at rt overnight. The solvent was evaporated out and 4N HC1 in dioxane (lml) was added to the residue. The mixture was stirred for another 10mm before it was concentrated and dried under vacuum. To this residue was added HBTU (144mg, 0.38mmol), DMF (3m1) and DIPEA (275u1, 1.S8mmol). The mixture was stirred for lOmins and then 6 (trifluoromethyl)benzo[d]thiazol-2-amine (69mg, 0.32mmol) was added. The resulting reaction was heated at 80 °C for 24hs. After cooled to rt, the mixture was separated between EA and water. The organic layer was washed with brine, dried over Na2504 and concentrated in vacuo. Purification by column chromatography gave the title compound as a pale yellow solid (50mg, 34percent). MS (ESI) [M+H]requires m/z 472.1, found m/z 471.6.

Reference： [1]Patent: WO2017/201313,2017,A1 .Location in patent: Paragraph 0252; 0253

95
[ 777-12-8 ]
C₁₁H₁₄ClNO₃*ClH [ No CAS ]
5-chloro-3-((dimethylamino)methyl)-2-hydroxy-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
15 mg		To a stirred solution of methyl 5-chloro-3-((dimethylamino)methyl)-2- methoxybenzoate (94mg, 0.365mmo1) in MeOH (5m1) was added 1.83m1 iN KOH solution. The resulting mixture was stirred at 60°C overnight. The solvent was evaporated out and 4N HC1 in dioxane (lml) was added to the residue. The mixture was stirred for another 10mm before it was concentrated and dried under vacuum. To this residue was added HBTU (166mg, 0.438mmo1), DMF (5m1) and DIPEA (318u1, 1.825mmo1). The mixture was stirred for 1 Omins and then 6 (trifluoromethyl)benzo[d]thiazol-2-amine (80mg, 0.3 6Smmol) was added. The resulting reaction was heated at 120 °C for 24hs. After cooled to rt, the mixture was separated between EA and water. The organic layer was washed with brine, dried over Na2504 and concentrated in vacuo. Purification by column chromatography gave the title compound as a yellow solid (15mg, 10percent). ?HNMR (300 IVIHz, Chloroform-d) 8.13 (dd, J = 4.3, 2.3 Hz, 2H), 7.87 (d, J = 8.5 Hz, 1H), 7.68 (d, J = 8.6 Hz, 1H), 7.18 (d, J = 2.7 Hz, 1H),3.94 (s, 2H), 2.60 (s, 6H). MS (ESI) [M+H] requires m/z 430.06., found m/z 429.70.

Reference： [1]Patent: WO2017/201313,2017,A1 .Location in patent: Paragraph 0257

96
[ 777-12-8 ]
C₁₂H₁₆ClNO₃*ClH [ No CAS ]
5-chloro-3-(2-(dimethylamino)ethyl)-2-methoxy-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a stirred solution of methyl 5-chloro-3-(2-(dimethylamino)ethyl)-2- methoxybenzoate (88mg, 0.324mmol) in methanol (5ml) was added IN potassium hydroxide (91mg, 1.62mmol, 1.62ml) solution. The mixture was heated at 60°C overnight. IN HC1 was added to adjust the PH to 1. The mixture was concentrated in vacuo. The residue was dissolved in dimethylformamide (3ml). N,N,N',N'-Tetramethyl-0-(lH-benzotriazol-l- yl)uronium hexafluorophosphate (71mg, 0.324mmol) was added followed by N,N- diisopropylethylamine (282ul, 1.62mmol). The resulting mixture was stirred at room temperature for 15mins, then <strong>[777-12-8]6-(trifluoromethyl)benzo[d]thiazol-2-amine</strong> (71mg, 0.324mmol) was added. The resulting mixture was stirred at 100°C overnight. Saturated ammonium chloride solution was added and extracted with ethyl acetate for two times. The combined ethyl acetate layer was dried over Na2S04 and concentrated under reduced pressure. The residue was purified via silica gel column chromatography to give title compound as a yellow powder (34mg, 23percent). 1H NMR (300 MHz, Chloroform-i ) delta 8.16 (s, 1H), 8.05 (d, J = 2.7 Hz, 1H), 7.91 (d, J = 8.6 Hz, 1H), 7.71 (dd, J = 8.5, 2.0 Hz, 1H), 7.50 (d, J = 2.7 Hz, 1H), 3.97 (s, 3H), 2.99 - 2.93 (m, 2H), 2.75 - 2.66 (m, 2H), 2.43 (s, 6H). MS (ESI) [M+H]+requires m/z 458.08, found m/z 458.15.

Reference： [1]Patent: WO2017/201313,2017,A1 .Location in patent: Paragraph 0174

97
[ 777-12-8 ]
5-chloro-2-methoxy-3-(2-(methylsulfonamido)ethyl)benzoic acid [ No CAS ]
5-chloro-2-hydroxy-3-(2-(methylsulfonamido)ethyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
38%		5 -Chloro-2-methoxy-3 -(2-(methyl sulfonamido)ethyl)benzoic acid (101mg,0.329mmo1) was dissolved in dimethylformamide (3m1). N,N,N?,N?-Tetramethyl-O-(lHbenzotriazol-1-yl)uronium hexafluorophosphate (149mg, 0.394mmo1) was added followed by N,N-diisopropylethylamine (172u1, 0.98mmol). The resulting mixture was stirred at room temperature for 1 Smins, then 6-(trifluoromethyl)b enzo[d]thiazol-2-amine (86mg, 0.394mmo1) was added. The resulting mixture was stirred at 110°C overnight. Saturatedammonium chloride solution was added and extracted with ethyl acetate for two times. The combined ethyl acetate layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified via silica gel column chromatography to give 5-Chloro-2- hydroxy-3 -(2-(methyl sulfonamido)ethyl)-N-(6-(trifluoromethyl)b enzo[d]thiazol-2-yl)benzamide 3 as a yellow powder (55mg, 38percent). ?H NIVIR (300 MHz, acetone-cl6) 8.43 (s, 1H), 8.13 (d, J = 2.6 Hz, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.84 (d, J = 6.9 Hz, 1H), 7.49 (d, J =2.6 Hz, 1H), 3.46 (t, J = 7.0 Hz, 2H), 2.99 (t, J = 7.0 Hz, 2H), 2.91 (s, 3H). MS (ESI) [M+Na]requires m/z 516.00, found m/z 515.75.

Reference： [1]Patent: WO2017/201313,2017,A1 .Location in patent: Paragraph 0178

98
[ 777-12-8 ]
5-chloro-2-(trifluoromethyl)-1H-benzo[d]imidazole-7-carboxylic acid [ No CAS ]
5-chloro-2-(trifluoromethyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)-1H-benzo[d]imidazole-7-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
38%		To a stirred solution of 5-chloro-2-(trifluoromethyl)-1H-benzo[d]imidazole-7-carboxylic acid (60mg, 0.23 mmol) was added N,N,N? ,N? -Tetramethyl - O-( 1 H-benzotriazol -1 -yl)uronium hexafluorophosphate (121mg, 0.3 2mmol) and N,Ndiisopropylethylamine (278u1, 1.6mmol). The mixture was stirred for lOmins and then 6- (trifluoromethyl)benzo[d]thiazol-2-amine (54mg, 0 .2Smmol) was added. The resulting reaction was heated at 80 °C for 2hs. After cooled to room temperature, the mixture was separated between ethyl acetate and saturated ammonium chloride solution. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification by column chromatography gave 5 -chloro-2-(trifluoromethyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2- yl)-1H-benzo[d]imidazole-7-carboxamide 8 as a pale yellow solid (40mg, 3 8percent). ?H NIVIR (500 IVIHz, acetone-cl6) 7.95 (s, 1H), 7.74 (s, 1H), 7.60 (s, 1H), 7.50 (d, J = 8.3 Hz, 1H), 7.42 (s, 0.5H), 7.30 (d, J = 8.3 Hz, 1H), 6.97 (s, 0.5H). MS (ESI) exact mass calculated for [M+H] requires m/z 465.0, found m/z 464.7.

Reference： [1]Patent: WO2017/201313,2017,A1 .Location in patent: Paragraph 0186

99
[ 777-12-8 ]
1-bromo-5-methoxy-2,4-bis(trifluoromethyl)benzene [ No CAS ]
N-(5-methoxy-2,4-bis(trifluoromethyl)phenyl)-6-(trifluoromethyl)benzo[d]thiazol-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%	With dmap; potassium phosphate; palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; molybdenum hexacarbonyl; In 1,4-dioxane; at 120℃; for 0.5h;Inert atmosphere; Microwave irradiation;	A mixture of 1 -bromo-5 -methoxy-2,4-bi s(trifluoromethyl)benzene (45mg, 0. l4mmol), Mo(CO)6 (111mg, 0.42mmol), <strong>[777-12-8]6-(trifluoromethyl)benzo[d]thiazol-2-amine</strong> (92mg, 0.42mmol), K3P04 (149mg, 0.7Ommol), 4-dimethylaminopyridine (34mg, 0.28mmol), palladium(II) acetate (4mg, 0.Ol4mmol) and Xantphos (16mg, 0.O28mmol) in dioxane (3m1) was microwaved at 120°C under nitrogen for 30mins. Saturated ammonium chloride solution was added and extracted with ethyl acetate for two times. The combined organic layer was dried over sodium sulfate, concentrated in vacuo. Purification by column chromatography gave the title compound as a white solid (42mg, 63percent). ?H NMR (400 MHz, Chloroform-cl) 8.37 (s, 1H), 8.02 ? 7.96 (m, 1H), 7.83 (s, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.70? 7.63 (m, 1H), 4.05 (s, 3H).

Reference： [1]Patent: WO2017/201313,2017,A1 .Location in patent: Paragraph 0190

100
[ 777-12-8 ]
C₁₀H₅ClF₆O₂ [ No CAS ]
5-methoxy-2,4-bis(trifluoromethyl)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
290 mg	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 48h;	5-methoxy-2,4-bis(trifluoromethyl)benzoic acid (400mg, 1.39mmol) was dissolved in dichloromethane (5.0 mL), followed by the addition of catalytic amount of dimethylformamide (3 drops) and oxalyl chloride (143 uL, 1.67mmol) respectively. Thereaction was allowed to stir at room temperature for 30 mm and concentrated in vacuo. The residue was re-dissolved in tetrahydrofuran (8.0 mL), and Hunig?s base (291uL, 1.67 mmol) and 6-(trifluoromethyl)benzo[d]thiazol -2-amine (244mg, 1.12 mmol) were added. The mixture was stirred at room temperature for 48 hours before silica gel was added to quench the reaction. Solvent was evaporated and the resulting residue was purified via silica gel column chromatography to yield the title compound as a white solid (290 mg, 53percent yield). ?H NIVIR (500 MHz, acetone-cl6) 8.48 (s, 1H), 8.05 (s, 1H), 7.98 ? 7.91 (m, 2H), 7.79 (dd, J = 8.5, 1.4 Hz, 1H), 4.16 (s, 3H). MS (ESI) exact mass calculated for [M+H] requires m/z489.03, found m/z 488.60.

Reference： [1]Patent: WO2017/201313,2017,A1 .Location in patent: Paragraph 0193

101
[ 777-12-8 ]
5-chloro-2-methoxy-3-ethylbenzoic acid [ No CAS ]
5-chloro-3-ethyl-2-hydroxy-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%		102031 5 -chloro-2-methoxy-3 -ethylbenzoic acid (100mg, 0 .467mmo1) was dissolved in DMF (5m1). HBTU (2 13mg, 0.56 immol) was added followed by DIPEA (244u1, 1.4Ommol). The resulting mixture was stirred at rt for l5mins, then 6- (trifluoromethyl)benzo[d]thiazol-2-amine (102mg, 0 .467mmo1) was added. The resulting mixture was stirred at 120°C for 24h. Saturated NH4C1 solution was added and extracted with EA for two times. The combined EA layer was dried over Na2504 and concentrated under reduced pressure. The residue was purified via silica gel column chromatography to give title compound as a yellow powder (115mg, 62percent). ?H NIVIR (300 IVIFIz, Acetone-d6) 8.40 (s, 1H), 8.10 (s, 1H), 7.90 (d, J = 8.7 Hz, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.39 (s, 1H), 2.72 (q, J=9.OHz, 2H), 1.24 (t, J = 9.0 Hz, 3H). MS (ESI) [M+H]requires m/z 401.03, found m/z400.6.

Reference： [1]Patent: WO2017/201313,2017,A1 .Location in patent: Paragraph 0203

102
[ 777-12-8 ]
[ 22901-09-3 ]
N-(isochroman-1-yl)-6-(trifluoromethyl)benzo[d]thiazol-2-amine [ No CAS ]
2-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)-3,4-dihydroisoquinolin-1(2H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%; 18%	With acetic acid; at 80℃; for 4h;	General procedure: Mixture of 2-(2-bromoethyl)benzaldehyde 1 (0.1g, 0.0047 mmol) and 4-methoxybenzo[d]thiazol-2-amine 2b (0.102 g, 0.0056 mmol) in 3.0 mL of acetic acid was stirred at 80 oC for 4 h, after cooling to room temperature, the reaction mixture was poured into saturated aqueous NaHCO3, and the resulting mixture was extracted with EtOAc three times. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford pure isochroman 3b (0.107g, 73percent) and isoquinolinone 10b (0.029g, 20percent).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 196 - 201

103
[ 672883-68-0 ]
[ 777-12-8 ]
3-(cyclopropylmethoxy)-4-(difluoromethoxy)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.64 g	With potassium carbonate; In benzene; for 6h;Reflux;	4.1.1.8 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)benzamide 4h Obtained from the reaction of 2h with 3, white solid, yield 72percent (0.64?gm), mp 160-161?°C. 1HNMR (400?MHz, DMSO-d6) delta 10.34 (s, 1H, NH exchanged with D2O), 7.74 (m, 1H, Ar H), 7.54 (m, 1H, Ar H), 7.39 (s, 1H, CHF2), 7.26 (d, J?=?8.16, 1H, Ar H), 7.19 (d, J?=?8.48, 1H, Ar H), 3.93 (d, J?=?6.92, 2H, CH2), 1.23 (m, 1H, CH), 0.55 (m, 2H, 2 CH), 0.36 (m, 2H, 2 CH). 13C NMR (100?MHz, DMSO-d6) delta 170.53, 166.92, 149.86, 143.82, 133.98, 130.29, 129.11, 128.75, 126.10, 124.84, 122.75, 120.56, 119.44, 116.88, 115.18, 114.31, 73.58, 10.36, 3.48. IR (KBr) upsilonmax?cm-1: 3294 (NH), 1654 (C=O). Elemental analysis calcd (percent) for C20H15F5N2O3S (458.40): C, 52.40; H, 3.30; N, 6.11. Found: C, 552.67; H, 3.67; N, 6.39.

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 148,p. 477 - 486

104
[ 777-12-8 ]
[ 100-52-7 ]
(E)-1-phenyl-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)methanimine [ No CAS ]

Reference： [1]Chemistry - A European Journal,2018,vol. 24,p. 3117 - 3121

105
[ 777-12-8 ]
[ 100-52-7 ]
(S,E)-2-(phenyl((6-(trifluoromethyl)benzo[d]thiazol-2-yl)amino)methyl)but-2-enal [ No CAS ]

Reference： [1]Chemistry - A European Journal,2018,vol. 24,p. 3117 - 3121

106
[ 777-12-8 ]
2-((4-oxo-3-phenyl-3,4,6,7-tetrahydrothieno[3,2-d]pyrimidin-2-yl)thio)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)acetamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 4087 - 4102

107
[ 777-12-8 ]
2-((3-benzyl-4-oxo-3,4,6,7-tetrahydrothieno[3,2-d]pyrimidin-2-yl)thio)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)acetamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 4087 - 4102

108
[ 777-12-8 ]
2-((3-(4-methoxybenzyl)-4-oxo-3,4,6,7-tetrahydrothieno[3,2-d]pyrimidin-2-yl)thio)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)-acetamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 4087 - 4102

109
[ 777-12-8 ]
2-((3-(2,3-dimethoxybenzyl)-4-oxo-3,4,6,7-tetrahydrothieno[3,2-d]pyrimidin-2-yl)thio)-N-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)acetamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 4087 - 4102

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Technical Information

• 1,4-Addition of an Amine to a Conjugated Enone • 1,4-Addition of an Amine to a Conjugated Enone • Alkyl Halide Occurrence • Amides Can Be Converted into Aldehydes • Amine Synthesis from Nitriles • Amine Synthesis from Nitriles • Amines Convert Acyl Chlorides into Amides • Amines Convert Esters into Amides • An Alkane are Prepared from an Haloalkane • Azide Reduction by LiAlH4 • Azide Reduction by LiAlH4 • Basicity of Amines • Buchwald-Hartwig C-N Bond and C-O Bond Formation Reactions • Chan-Lam Coupling Reaction • Chichibabin Reaction • Diazotization Reaction • DIBAL Attack Nitriles to Give Ketones • Enamine Formation • Formation of an Amide from an Amine and a Carboxylic Acid • Formation of an Amide from an Amine and a Carboxylic Acid • Friedel-Crafts Alkylation of Benzene with Haloalkanes • Hemiaminal Formation from Amines and Aldehydes or Ketones • Hemiaminal Formation from Amines and Aldehydes or Ketones • Hofmann Elimination • Hofmann Rearrangement • Hydride Reductions • Hydrolysis of Imines to Aldehydes and Ketones • Imine Formation from Amines and Aldehydes or Ketones • Leuckart-Wallach Reaction • Mannich Reaction • Methylation of Ammonia • Methylation of Ammonia • Nitrosation of Amines • Peptide Bond Formation with DCC • Petasis Reaction • Preparation of Amines • Preparation of LDA • Reactions of Amines • Reduction of an Amide to an Amine • Reduction of an Amide to an Amine • Reductive Amination • Reductive Amination • Ring Opening of Azacyclopropanes • Ring Opening of Azacyclopropanes • Ring Opening of Oxacyclobutanes • Specialized Acylation Reagents-Vilsmeier Reagent • Strecker Synthesis • Synthesis of 2-Amino Nitriles • Ugi Reaction

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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. 777-12-8 ] {[proInfo.proName]}

Quality Control of [ 777-12-8 ]

Related Doc. of [ 777-12-8 ]

Product Citations

Product Details of [ 777-12-8 ]

Calculated chemistry of [ 777-12-8 ] Expand+

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 777-12-8 ]

Application In Synthesis of [ 777-12-8 ]

[ 777-12-8 ] Synthesis Path-Upstream 1~7

[ 777-12-8 ] Synthesis Path-Downstream 1~109

Technical Information

Related Functional Groups of [ 777-12-8 ]

Fluorinated Building Blocks

Amines

Trifluoromethyls

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 777-12-8 ]