[ CAS No. 133046-46-5 ] {[proInfo.proName]}

Name: 133046-46-5|Ethyl 2-(trifluoromethyl)thiazole-4-carboxylate|97%
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COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 133046-46-5 ]

CAS No. :	133046-46-5	MDL No. :	MFCD10568298
Formula :	C₇H₆F₃NO₂S	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	WFUNYBAJYAWHLX-UHFFFAOYSA-N
M.W :	225.19	Pubchem ID :	20079591
Synonyms :

Calculated chemistry of [ 133046-46-5 ]

Physicochemical Properties

Num. heavy atoms :	14
Num. arom. heavy atoms :	5
Fraction Csp3 :	0.43
Num. rotatable bonds :	4
Num. H-bond acceptors :	6.0
Num. H-bond donors :	0.0
Molar Refractivity :	43.2
TPSA :	67.43 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.95 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.31
Log Po/w (XLOGP3) :	2.43
Log Po/w (WLOGP) :	3.49
Log Po/w (MLOGP) :	1.13
Log Po/w (SILICOS-IT) :	3.3
Consensus Log Po/w :	2.53

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.77
Solubility :	0.385 mg/ml ; 0.00171 mol/l
Class :	Soluble
Log S (Ali) :	-3.49
Solubility :	0.0731 mg/ml ; 0.000324 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.67
Solubility :	0.483 mg/ml ; 0.00214 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.71

Safety of [ 133046-46-5 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 133046-46-5 ]

* 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 [ 133046-46-5 ]
Downstream synthetic route of [ 133046-46-5 ]

[ 133046-46-5 ] Synthesis Path-Upstream 1~6

1
[ 354-38-1 ]
[ 70-23-5 ]
[ 133046-46-5 ]

Yield	Reaction Conditions	Operation in experiment
40%	With Lawessons reagent In tetrahydrofuranReflux	A solution of 2,2,2-trifluoroacetamide (14.24 g, 1 eq.) and Lawesson's reagent (30.6 g, 0.6 eq.) in THF (120 mL) was stirred at reflux for 18 hrs. The mixture was cooled, ethyl bromopyruvate (16 mL, 1 eq.) was added and the reaction refluxed for weekend. The reaction was cooled, evaporated in vacuum, and the resulting crude material extracted with dichloromethane and washed with water. The organic layer was dried over Na₂SO₄, filtered, and concentrated to give an orange oil. The oil was purified by chromatography on a silica gel (petroleum ether/dichloromethane) to yield compound 251 in 40percent yield. ¹H NMR- 161 -SDI-18153v₂ (DMSO-J₆, 400 MHz): δ (ppm) 1.32 (t, J= 7.10 Hz, 3H), 4.34 (q, J= 7.10 Hz, 2H), 8.9 (s,IH); 1¹9T NMR (DMSO-J₆, 376 MHz): δ (ppm) -60.29 (s, 3F); MS (ESI, EI⁺): m/z = 225.9(MH⁺).
32%	Stage #1: With Lawessons reagent In tetrahydrofuran for 18 h; Reflux Stage #2: for 18 h; Reflux	A mixture of 2,2,2-trifluoroacetamide (7.12g, 63 mmol) and Lawesson's reagent (15.3 g, 37.8 mmol) in THF (60 mL) was heated at reflux for 18 hours. The reaction was then cooled down to RT and treated with ethyl bromopyruvate (8.0 mL, 63 mmol). The reaction was stirred at reflux for an additional 18 hours, then concentrated under vacuum and diluted with ethyl acetate. This mixture was washed with water (IX) and brine (IX), dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (8X1 1 cm, toluene, then second time with 120g silica gel, hexane/ethyl acetate) to give the title material (4.47g, 32percent) as a pale yellow solid. ¹H NMR (CDCl₃, 400 MHz) δ 8.37 (s, 1H), 4.45 (q, J= 7.0 Hz, 2H), 1.41 (t, J= 7.0 Hz, 1H).

Reference： [1] Patent: WO2011/17389, 2011, A1, . Location in patent: Page/Page column 161-162
[2] Patent: WO2013/163279, 2013, A1, . Location in patent: Paragraph 00141
[3] Patent: US2015/18328, 2015, A1, . Location in patent: Paragraph 1206
[4] Patent: WO2015/3640, 2015, A1, . Location in patent: Page/Page column 265

2
[ 70-23-5 ]
[ 133046-46-5 ]

Yield	Reaction Conditions	Operation in experiment
21%	Stage #1: With Lawessons reagent In tetrahydrofuran for 18 h; Heating / reflux Stage #2: for 18 h; Heating / reflux	A solution of 2,2,2 -trifluoroacetamide (7.12 g, 63 mmol) and Lawesson's Reagent (15.3 g, 37.8 mmol) in THF (anhydrous, 60 ml) was stirred at reflux for 18 hrs. The reaction mixture was cooled then ethyl bromopyruvate (8 ml, 63 mmol) added, and refluxed for 18 hrs. The reaction was cooled, evaporated in vacuo, and the resulting crude material extracted into ethyl acetate and washed with water. The organic fraction was dried (MgSO^, and condensed to give a yellow/orange oil. The residue was purified by flash column chromatography on silica (eluent: 15percent ethyl acetate in hexane) to provide the title EPO <DP n="45"/>compound as a clear oil (3 g, 21 percent). ¹H NMR δ (400MHz, CDCl₃) δ 8.39 (1 H, s), 4.47 (2 H, q, J7.1), 1.42 (3 H, t, /7.2).

Reference： [1] Patent: WO2006/122200, 2006, A1, . Location in patent: Page/Page column 43-44

3
[ 19172-47-5 ]
[ 354-38-1 ]
[ 70-23-5 ]
[ 133046-46-5 ]

Yield	Reaction Conditions	Operation in experiment
21%	Stage #1: for 18 h; Heating / reflux Stage #2: for 18 h; Heating / reflux	A solution of 2,2, 2-trifluoroacetamide (7.12 g, 63 mmol) and Lawesson's Reagent (15.3 g, 37.8 mmol) in THF (anhydrous, 60 ml) was stirred at reflux for 18 h. The reaction mixture was cooled, then ethyl bromopyruvate (8 ml, 63 mmol) added, and refluxed for 18 h. The reaction was cooled, evaporated in vacuo, and the resulting crude material extracted into ethyl acetate and washed with water. The organic fraction was dried over MgSO4, and condensed to givea yellow/orange oil. The residue was purified by flash column chromatography on silica eluting with 15 percent ethyl acetate in hexane to provide the title compound as a clear oil (3 g, 21 percent). 1H NMR (400MHz,CDCI3)8 8.39(1H, s), 4.47 (2H, q, J7. 1), 1.42 (3H, t, J7.2).

Reference： [1] Patent: US2013/289238, 2013, A1, . Location in patent: Page/Page column
[2] Patent: WO2005/49613, 2005, A1, . Location in patent: Page/Page column 50

4
[ 100367-77-9 ]
[ 133046-46-5 ]

Reference： [1] Science, 2018, vol. 360, # 6392, p. 1010 - 1014

5
[ 70-23-5 ]
[ 421-52-3 ]
[ 133046-46-5 ]

Reference： [1] Patent: WO2006/120481, 2006, A2, . Location in patent: Page/Page column 19

6
[ 133046-46-5 ]
[ 915030-08-9 ]

Yield	Reaction Conditions	Operation in experiment
93%	Stage #1: With lithium hydroxide In tetrahydrofuran; methanol at 20℃; for 1 h; Stage #2: Acidic conditions	Ethyl 2-(trifluoromethyl)thiazole-4-carboxylate (400 mg, 1.176 mmol) was dissolved in THF/methanol mixture (9: 1) and 1M lithium hydroxide (3.55 ml, 3.55 mmol) was added slowly. The reaction mixture was stirred at RT for 1 hour, pH was adjusted to 2 and the reaction mixture was extracted three times with ethyl acetate. Ethyl acetate phases were combined, dried and evaporated to dryness. Yield 93 percent. m/z [197.1+1]
77%	Stage #1: at 80℃; for 16 h; Stage #2: With hydrogenchloride In methanol; water at 0℃;	A mixture of Description 26 (2.82 g, 12.5 mmol) and potassium hydroxide (1.7 g, 30 mmol), in methanol (2 ml) and water (7 ml) was heated at 8O⁰C for 16h. The reaction was cooled, poured onto ice and acidified to pH 2 using cone, hydrochloric acid before extracting into ethyl acetate. The organic layer was dried (MgSO₄) and evaporated to give the title compound as a white solid (1.9 g, 77percent). ¹HNMR (500MHz, DMSO) δ 8.84 (1 H, s).

Reference： [1] Patent: WO2011/51540, 2011, A1, . Location in patent: Page/Page column 140-141
[2] Patent: WO2006/122200, 2006, A1, . Location in patent: Page/Page column 44
[3] Patent: US2009/131431, 2009, A1, . Location in patent: Page/Page column 148
[4] Patent: WO2007/36733, 2007, A1, . Location in patent: Page/Page column 222-223
[5] Patent: WO2009/147188, 2009, A1, . Location in patent: Page/Page column 110

[ 133046-46-5 ] Synthesis Path-Downstream 1~39

1
[ 354-38-1 ]
[ 70-23-5 ]
[ 133046-46-5 ]

Yield	Reaction Conditions	Operation in experiment
40%	With Lawessons reagent; In tetrahydrofuran;Reflux;	A solution of <strong>[354-38-1]2,2,2-<strong>[354-38-1]trifluoroacetamide</strong></strong> (14.24 g, 1 eq.) and Lawesson's reagent (30.6 g, 0.6 eq.) in THF (120 mL) was stirred at reflux for 18 hrs. The mixture was cooled, ethyl bromopyruvate (16 mL, 1 eq.) was added and the reaction refluxed for weekend. The reaction was cooled, evaporated in vacuum, and the resulting crude material extracted with dichloromethane and washed with water. The organic layer was dried over Na2SO4, filtered, and concentrated to give an orange oil. The oil was purified by chromatography on a silica gel (petroleum ether/dichloromethane) to yield compound 251 in 40% yield. 1H NMR- 161 -SDI-18153v2 (DMSO-J6, 400 MHz): delta (ppm) 1.32 (t, J= 7.10 Hz, 3H), 4.34 (q, J= 7.10 Hz, 2H), 8.9 (s,IH); 119T NMR (DMSO-J6, 376 MHz): delta (ppm) -60.29 (s, 3F); MS (ESI, EI+): m/z = 225.9(MH+).
32%		A mixture of <strong>[354-38-1]2,2,2-<strong>[354-38-1]trifluoroacetamide</strong></strong> (7.12g, 63 mmol) and Lawesson's reagent (15.3 g, 37.8 mmol) in THF (60 mL) was heated at reflux for 18 hours. The reaction was then cooled down to RT and treated with ethyl bromopyruvate (8.0 mL, 63 mmol). The reaction was stirred at reflux for an additional 18 hours, then concentrated under vacuum and diluted with ethyl acetate. This mixture was washed with water (IX) and brine (IX), dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (8X1 1 cm, toluene, then second time with 120g silica gel, hexane/ethyl acetate) to give the title material (4.47g, 32%) as a pale yellow solid. 1H NMR (CDCl3, 400 MHz) delta 8.37 (s, 1H), 4.45 (q, J= 7.0 Hz, 2H), 1.41 (t, J= 7.0 Hz, 1H).
		Step 1: Preparation of ethyl 2-(trifluoromethyl)thiazole-4-carboxylate To a solution of <strong>[354-38-1]2,2,2-<strong>[354-38-1]trifluoroacetamide</strong></strong> (1.42 g, 12.6 mmol) in dry THF (60 mL) was added Lawesson's reagent (3.06 g, 7.56 mmol). The reaction mixture was heated at reflux for 18 hr and then cooled, followed by addition of ethyl 3-bromo-2-oxopropanoate (1.6 mL, 12.6 mmol). The mixture was refluxed for another 18 hr and then cooled to r.t. The resulting mixture was partitioned between EtOAc and water. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated and purified by standard methods to afford ethyl 2-(trifluoromethyl)thiazole-4-carboxylate. 1H NMR (400 MHZ, CDCl3) delta 8.42 (s, 1H) 4.47 (q, J=7.1 Hz, 2H), 1.45 (t, J=7.2 Hz, 3H). LC-MS: m/z 226 (M+H)+.

Step 1: Preparation of ethyl 2-(truoromethyl)thiazole-4-carboxylate. To a solution of 2,2,2- [354-38-1]trifluoroacetamide(1 .42 g, 12.6 mmol) in dry THF(60 mL) was added Lawesson?s reagent (3.06 g,7.56 mmol). The reaction mixture was heated atreflux for 18 hr and then cooled, followed by addition ofethyl 3-bromo-2-oxopropanoate (1.6 mL, 12.6 mmol).The mixture was refluxed for another 18 hr and then cooled to r.t.. The resulting mixture was partitioned between EtOAc and water. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated andpurified by standard methods to afford ethyl 2-(trifluoromethyl)thiazole-4-carboxylate.?HNMR (400MHz,CDC13) 8.42 (s, 111) 4.47 (q, J=7.1 Hz, 211), 1.45 (t, J 7.2 Hz, 3H). LC-MS:m/z 226 (M+H).

Reference： [1]Patent: WO2011/17389,2011,A1 .Location in patent: Page/Page column 161-162
[2]Patent: WO2013/163279,2013,A1 .Location in patent: Paragraph 00141
[3]Patent: US2015/18328,2015,A1 .Location in patent: Paragraph 1206
[4]Patent: WO2015/3640,2015,A1 .Location in patent: Page/Page column 265

2
[ 133046-46-5 ]
[ 133046-47-6 ]

Yield	Reaction Conditions	Operation in experiment
	With diisobutylaluminium hydride; In tetrahydrofuran; dichloromethane; at -78℃; for 2h;	Diiosbutyl aluminium hydride (1M in dichloromethane, 25.2 ml, 25.2 mmol) was added dropwise to a solution of Description 35 (2.83 g, 12.6 mmol) in THF (anhydrous, 40 ml)at-78 C. This was allowed to stir at-78 OC for 1 h then a further equivalent of diisobutyl aluminium hydride(1M in dichloromethane, 12 ml, 12 mmol) was added and the solution stirred at-78 oC for another hour. Methanol (20 ml) was added to the solution and allowed to warm to room temperature. The reaction was evaporated in vacuo, extracted into diethyl ether, washed with aqueous sodium potassium tartrate (200 ml), then aqueous ammonium chloride (200 ml). The diethyl ether layer was dried overMgS04, evaporated in vacuo to give the crude alcohol product as a light yellow oil (2.9 g). Bromine(-800ul) was added dropwise to a light yellow solution of the crude alcohol (2 g, 11 mmol) and triphenyl phosphine (3.15 g, 12 mmol) in N, Ndimethylformamide (anhydrous, 20 ml) at 0 oC until the colour persisted. This was then stirred at RT for 1 h. The solution was extracted into ethyl acetate, washed with water, dried overMgS04, evaporated in vacuo to give a yellow solid. This was purified by flash column chromatography on silica eluting with 10 % ethyl acetate in hexane to give the title compound as a yellow oil (1.64 g,61 %). 'H NMR (400 MHz, DMSO) 8 8.24 (1H, s), 4.84 (2H, s).
		Di-isobutyl aluminium hydride (1 M in dichloromethane, 25.2 ml, 25.2 mmol) was added dropwise to a solution of Description 15 (2.83 g, 12.6 mmol) in THF (40 ml) at -78 0C. The reaction was allowed to stir at -78 0C for 1 h then a further equivalent of diisobutyl aluminium hydride (1 M in dichloromethane, 12 ml, 12 mmol) was added and the solution stirred at -78 0C for another hour. Methanol (20 ml) was added and the solution allowed to warm to room temperature. The reaction was evaporated in vacuo, extracted into diethyl ether, washed with aqueous sodium potassium tartrate (200 ml), then aqueous ammonium chloride (200 ml). The diethyl ether layer was dried over MgSO4, evaporated in vacuo to give the crude alcohol product as a light yellow oil (2.9 g). 1H NMR (400 MHz, CDCl3) delta 7.49 (1 H, s), 4.85 (2 H, s). M/z (ES+) 184 (MH-H+).

Reference： [1]Patent: WO2005/49613,2005,A1 .Location in patent: Page/Page column 51
[2]Patent: WO2006/120481,2006,A2 .Location in patent: Page/Page column 19

3
[ 70-23-5 ]
[ 133046-46-5 ]

Yield	Reaction Conditions	Operation in experiment
21%		A solution of 2,2,2 -trifluoroacetamide (7.12 g, 63 mmol) and Lawesson's Reagent (15.3 g, 37.8 mmol) in THF (anhydrous, 60 ml) was stirred at reflux for 18 hrs. The reaction mixture was cooled then ethyl bromopyruvate (8 ml, 63 mmol) added, and refluxed for 18 hrs. The reaction was cooled, evaporated in vacuo, and the resulting crude material extracted into ethyl acetate and washed with water. The organic fraction was dried (MgSO^, and condensed to give a yellow/orange oil. The residue was purified by flash column chromatography on silica (eluent: 15% ethyl acetate in hexane) to provide the title EPO <DP n="45"/>compound as a clear oil (3 g, 21 %). 1H NMR delta (400MHz, CDCl3) delta 8.39 (1 H, s), 4.47 (2 H, q, J7.1), 1.42 (3 H, t, /7.2).

Reference： [1]Patent: WO2006/122200,2006,A1 .Location in patent: Page/Page column 43-44

4
[ 133046-46-5 ]
[ 133046-48-7 ]
[ 133046-47-6 ]

Yield	Reaction Conditions	Operation in experiment
43%; 19%	With diisobutylaluminium hydride; In dichloromethane; at -78℃; for 1h;	Diisobutyl aluminium hydride (IM in dichloromethane, 16.7 ml, 16.7 mmol) was added dropwise to a solution of Description 26 (1.88 g, 8.37 mmol) in anhydrous dichloromethane (10 ml) at -78 0C. The reaction was stirred at -78 0C for lhr, and then excess aq. 2Nu hydrochloric acid was added and the reaction allowed to warm to room temperature. The reaction was extracted into ethyl acetate (x 5) and the organic layer washed with water and saturated aqueous NH4Cl, then dried (MgSO4) and evaporated.Purification by flash column chromatography on silica (eluent: 25% ethyl acetate in hexane) gave the title compound as a pale yellow solid (650 mg, 43%) 1H NMR (400 MHz, DMSO) delta 10.01 (1 H, s), 9.07 (1 H, s). (Additionally, some of the corresponding alcohol (19 %) was isolated).

Reference： [1]Patent: WO2006/122200,2006,A1 .Location in patent: Page/Page column 47

5
[ 133046-46-5 ]
[ 915030-08-9 ]

Yield	Reaction Conditions	Operation in experiment
93%		Ethyl 2-(trifluoromethyl)thiazole-4-carboxylate (400 mg, 1.176 mmol) was dissolved in THF/methanol mixture (9: 1) and 1M lithium hydroxide (3.55 ml, 3.55 mmol) was added slowly. The reaction mixture was stirred at RT for 1 hour, pH was adjusted to 2 and the reaction mixture was extracted three times with ethyl acetate. Ethyl acetate phases were combined, dried and evaporated to dryness. Yield 93 %. m/z [197.1+1]
77%		A mixture of Description 26 (2.82 g, 12.5 mmol) and potassium hydroxide (1.7 g, 30 mmol), in methanol (2 ml) and water (7 ml) was heated at 8O0C for 16h. The reaction was cooled, poured onto ice and acidified to pH 2 using cone, hydrochloric acid before extracting into ethyl acetate. The organic layer was dried (MgSO4) and evaporated to give the title compound as a white solid (1.9 g, 77%). 1HNMR (500MHz, DMSO) delta 8.84 (1 H, s).
		Ethyl 2-(trifluoromethyl)-1,3-thiazole-4-carboxylate (80 mg) in ethanol (1 ml) was treated with 2N sodium hydroxide (0.706 ml) and the solution stirred at room temperature for 18 h. 2M Hydrochloric acid (0.54 ml) was added and the mixture blown down to dryness. The residue was dried under vacuum over phosphorous pentoxide and was then suspended in dry dichloromethane (1 ml) and treated at room temperature with oxalyl chloride (0.032 ml) and DMF (1 drop). The mixture was stirred at room temperature for 30 mins and then added dropwise to a solution of Intermediate 16 (98 mg) in acetonitrile (2 ml) and the mixture was stirred at room temperature for 22 h. The mixture was diluted with dichloromethane (15 ml), washed with brine (2×15 ml) and blown down to dryness. The residue was purified by mass directed autoprep HPLC followed by SPE cartridge (5 g, aminopropyl) eluting with methanol. The eluent was blown down to dryness to give Example 339 as a brown gum (96 mg). LCMS showed MH+=483; TRET=2.57 min.

		Example 339 W-[1 ,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1 H- pyrazolo[3,4-b]pyridin-5-yl]methyl}-2-(trifluoromethyl)-1,3-thiazole-4-carboxamideEthyl 2-(trifluoromethyl)-1,3-thiazole-4-carboxylate (80mg) in ethanol (1ml) was treated with 2N sodium hydroxide (0.706ml) and the solution stirred at room temperature for 18h. 2M Hydrochloric acid (0.54ml) was added and the mixture blown down to dryness. EPO <DP n="224"/>The residue was dried under vacuum over phosphorous pentoxide and was then suspended in dry dichloromethane (1ml) and treated at room temperature with oxalyl chloride (0.032ml) and DMF (1 drop). The mixture was stirred at room temperature for 30mins and then added dropwise to a solution of Intermediate 16 (98mg) in acetonitrile (2ml) and the mixture was stirred at room temperature for 22h. The mixture was diluted with dichloromethane (15ml), washed with brine (2 x 15ml) and blown down to dryness. The residue was purified by mass directed autoprep HPLC followed by SPE cartridge (5g, aminopropyl) eluting with methanol. The eluent was blown down to dryness to give Example 339 as a brown gum (96mg). LCMS showed MH+ = 483; TRET = 2.57min.
		Intermediate 502-(Trifluoromethyl)-1 ,3-thiazole-4-carboxylic acid A mixture of ethyl 2-(trifluoromethyl)-1 ,3-thiazole-4-carboxylate (278mg) in ethanol (3.5ml) was added 2M sodium hydroxide solution (2.4ml) and the mixture stirred at RT for 1 h. The mixture was acidified by the addition of 2M hydrochloric acid solution (2.5ml) and the mixture blown to dryness. The residue was treated with water (2ml) and extracted with ethyl acetate (3x5ml). The combined organic extracts were dried over sodium sulphate and evaporated to give the title compound (168mg) as a beige solid. 1H NMR (DMSO) delta 8.84 (s, 1 H)

Reference： [1]Patent: WO2011/51540,2011,A1 .Location in patent: Page/Page column 140-141
[2]Patent: WO2006/122200,2006,A1 .Location in patent: Page/Page column 44
[3]Patent: US2009/131431,2009,A1 .Location in patent: Page/Page column 148
[4]Patent: WO2007/36733,2007,A1 .Location in patent: Page/Page column 222-223
[5]Patent: WO2009/147188,2009,A1 .Location in patent: Page/Page column 110

6
[ 70-23-5 ]
[ 421-52-3 ]
[ 133046-46-5 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; for 18h;Heating / reflux;	A solution of 2,2,2 -trifluoroacetamide (7.12 g, 63 mmol) and Lawesson's Reagent (15.3 g, 37.8 mmol) in THF (60 ml) was stirred at reflux for 18 h. The reaction mixture was cooled, ethyl bromopyruvate (8 ml, 63 mmol) added and the reaction refluxed for 18 h. The reaction was cooled, evaporated in vacuo, and the resulting crude material extracted into ethyl acetate and washed with water. The organic fraction was dried over MgSO4 and condensed to give a yellow/orange oil. The oil was purified by flash column chromatography on silica eluting with 15 % ethyl acetate in hexane to provide the title compound as a clear oil (3 g, 21 %). 1H NMR (400 MHz, CDCl3) delta 8.39 (1 H, s), 4.47 (2 H, q, J7.1), 1.42 (3 H, t, J7.2).

Reference： [1]Patent: WO2006/120481,2006,A2 .Location in patent: Page/Page column 19

7
[ 19172-47-5 ]
[ 354-38-1 ]
[ 70-23-5 ]
[ 133046-46-5 ]

Yield	Reaction Conditions	Operation in experiment
32%	In tetrahydrofuran;	2A. Ethyl 2-(trifluoromethyl)thiazole-4-carboxylate A mixture of <strong>[354-38-1]2,2,2-<strong>[354-38-1]trifluoroacetamide</strong></strong> (7.12 g, 63 mmol) and Lawesson's reagent (15.3 g, 37.8 mmol) in THF (60 mL) was heated at reflux for 18 hours. The reaction was then cooled down to RT and treated with ethyl bromopyruvate (8.0 mL, 63 mmol). The reaction was stirred at reflux for an additional 18 hours, then concentrated under vacuum and diluted with ethyl acetate. This mixture was washed with water (1) and brine (1), dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (8*11 cm, toluene, then second time with 120 g silica gel, hexane/ethyl acetate) to give the title material (4.47 g, 32%) as a pale yellow solid. 1H NMR (CDCl3, 400 MHz) delta 8.37 (s, 1H), 4.45 (q, J=7.0 Hz, 2H), 1.41 (t, J=7.0 Hz, 1H).
21%		A solution of 2,2, 2-<strong>[354-38-1]trifluoroacetamide</strong> (7.12 g, 63 mmol) and Lawesson's Reagent (15.3 g, 37.8 mmol) in THF (anhydrous, 60 ml) was stirred at reflux for 18 h. The reaction mixture was cooled, then ethyl bromopyruvate (8 ml, 63 mmol) added, and refluxed for 18 h. The reaction was cooled, evaporated in vacuo, and the resulting crude material extracted into ethyl acetate and washed with water. The organic fraction was dried over MgSO4, and condensed to givea yellow/orange oil. The residue was purified by flash column chromatography on silica eluting with 15 % ethyl acetate in hexane to provide the title compound as a clear oil (3 g, 21 %). 1H NMR (400MHz,CDCI3)8 8.39(1H, s), 4.47 (2H, q, J7. 1), 1.42 (3H, t, J7.2).

Reference： [1]Patent: US2013/289238,2013,A1 .Location in patent: Page/Page column
[2]Patent: WO2005/49613,2005,A1 .Location in patent: Page/Page column 50

8
[ 133046-46-5 ]
5-[(2-chlorophenyl)methyl]sulfonamido}-2-(trifluoromethyl)-1,3-thiazole-4-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2014/198849,2014,A1

9
[ 133046-46-5 ]
C₁₄H₁₂ClF₃N₂O₄S₂ [ No CAS ]

Reference： [1]Patent: WO2014/198849,2014,A1

10
[ 133046-46-5 ]
ethyl 5-bromo-2-(trifluoromethyl)thiazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51%		A solution of <strong>[133046-46-5]ethyl 2-(trifluoromethyl)thiazole-4-carboxylate</strong> (1.3 g, 5.78 mmol) in THF (5 mL) was dropwised to the solution of LDA (5.8 mL, 11.56 mmol) in THF (10 mL) at -78 C under N2.The mixture was stirred for 45 minutes at same temperature. To this, a solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (5.58 g, 17.34 mmol) in THF (5 mL) was dropwised and warmed to room temperature, stirred for 2 hours. The reaction was quenched with saturated ammonium chloride solution. Water was added and the mixture was extracted with EA (x3). The organic layer was combined, dried and concentrated. The residue was purified via silica gel chromatography (petroleum ether-ethyl acetate) to give the desired compound as yellow oil (900 mg, 51%). ESI MS m/z = 549.5 [M+H]+.
250 mg		Intermediate 48 DIPA (0.35ml_, 2.5mmol) was dissolved in dry tetrahydrofuran (5m L) and cooled to - 78C under nitrogen. To this, n-butyllithium (1.6M in hexanes; 1 .56ml_, 2.5mmol) was added over 5 minutes and stirred for 2 minutes. The solution was warmed to room temperature then cooled to -78C. To this, a solution of ethyl 2- (trifluoromethyl)thiazole-4-carboxylate [133046-46-5] (450mg, 2.0mmol) in dry tetrahydrofuran (4ml_) was added over 5 minutes and stirred at the same temperature for 45 minutes. To this, a solution of 1 ,2-dibromotetrachloroethane (980mg, 3.0mmol) in dry tetrahydrofuran (3ml_) was added over 5 minutes and warmed to room temperature over 2 hours. The reaction was quenched with saturated ammonium chloride solution. The mixture was diluted with water and extracted with dichloromethane. The organic layer was dried with MgS04, filtered and concentrated in vacuo to dryness. The residue was purified by chromatography on silica eluting with 0-25% ethyl acetate/cyclohexane. The fractions containing the desired product were combined and the solvents removed by evaporation in vacuo to give Intermediate 48 (250mg) as an off white solid. 1 H NMR (CDCIs) delta: 4.47 (2H, q), 1 .44 (3H, t)

Reference： [1]Patent: WO2019/67864,2019,A1 .Location in patent: Page/Page column 332-333
[2]Patent: WO2014/198849,2014,A1 .Location in patent: Page/Page column 124; 125

11
[ 133046-46-5 ]
N1,N5-bis (3,3-difluorocyclobutyl)-biguanide [ No CAS ]
N2,N4-bis(3,3-difluorocyclobutyl)-6-(2-(trifluoromethyl)thiazol-4-yl)-1,3,5-triazine-2,4-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium methylate; In methanol; at 20℃; for 48h;	General procedure: Step 3: Preparation of N2,N4-bis(3,3-difluorocyclobutyl)-6-(4-(trifluoromethyl) thiazol-2-yl)-1,3,5-triazine-2,4-diamine To a mixture of N1,N5-bis(3,3-difluoro cyclobutyl)-biguanide (60 mg, 0.22 mmol) in MeOH (5 mL) were added <strong>[133046-46-5]ethyl 2-(trifluoromethyl)thiazole-4-carboxylate</strong> (58.5 mg, 0.26 mmol) and NaOMe (23.7 mg, 0.44 mmol). The reaction mixture was then stirred at r.t. for 48 hr then partitioned between EtOAc and H2O. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, and concentrated and purified by standard methods to afford the N2,N4-bis(3,3-difluorocyclobutyl)-6-(4-(trifluoromethyl)thiazol-2-yl)-1,3,5-triazine-2,4-diamine. 1H NMR (400 MHz, CDCl3) delta 7.83 (d, J=5.2 Hz, 1H), 7.01-6.74 (m, 1H), 5.74-5.43 (m, 2H), 4.45-4.32 (m, 2H), 3.11-3.04 (m, 4H), 2.63-2.48 (m, 4H). LC-MS: m/z 443 (M+H)+.
	With sodium methylate; In methanol; at 20℃; for 48h;	Step 3: Preparation of N-bis(3,3-duorocyclobutyl)-6-(4-(trfluoromethyl)thiazol-2-yl)- 1,3,5-triazine-2,4-diamine. To a mixture of N?,N5-bis(3,3-difluorocyclobutyl)-biguanide (60 mg,0.22 mmol) in MeOH (5 mL) were added <strong>[133046-46-5]ethyl 2-(trifluoromethyl)thiazole-4-carboxylate</strong> (58.5 mg, 0.26 mmol) and NaOMe (23.7 mg, 0.44 mmol). The reaction mixture was then stirred at r.t. for 48 hr then partitioned between EtOAc and 1120.The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, and concentrated and purified by standard methods to afford the N2,N4-bis(3 ,3 -difluorocyclobutyl)-6-(4-(trifluoromethyl)thiazol-2-yl)- 1,3,5 -triazine2,4-diamine.?H NMR (400 MHz, CDC13) 7.83 (d, J= 5.2 Hz, 111), 7.01-6.74 (m, 111), 5.74-5.43 (m, 2 H), 4.45-4.32 (m, 211), 3.11-3.04 (m, 411), 2.63-2.48 (m, 411). LC-MS: m/z 443 (M+H).

Reference： [1]Patent: US2015/18328,2015,A1 .Location in patent: Paragraph 1208; 1219-1220
[2]Patent: WO2015/3640,2015,A1 .Location in patent: Page/Page column 265; 266

12
[ 133046-46-5 ]
(R)-4-(7-(2,4-dimethoxybenzyl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2-(trifluoromethyl)thiazole [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 3060 - 3082

13
[ 133046-46-5 ]
(R)-(8-methyl-3-(2-(trifluoromethyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 3060 - 3082

14
[ 133046-46-5 ]
(R)-4-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2-(trifluoromethyl)thiazole [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 3060 - 3082

15
[ 133046-46-5 ]
2-(trifluoromethyl)thiazole-4-carbohydrazide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 3060 - 3082

16
[ 133046-46-5 ]
[ 630-25-1 ]
ethyl 5-bromo-2-(trifluoromethyl)thiazole-4-carboxylate [ No CAS ]