[ CAS No. 7238-61-1 ] {[proInfo.proName]}

Name: 7238-61-1|2-Bromo-4-methylthiazole|97%
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Quality Control of [ 7238-61-1 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 7238-61-1 ]

Product Details of [ 7238-61-1 ]

CAS No. :	7238-61-1	MDL No. :	MFCD06660130
Formula :	C₄H₄BrNS	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	KLFWJAAGXUDNIS-UHFFFAOYSA-N
M.W :	178.05	Pubchem ID :	551541
Synonyms :

Calculated chemistry of [ 7238-61-1 ]

Physicochemical Properties

Num. heavy atoms :	7
Num. arom. heavy atoms :	5
Fraction Csp3 :	0.25
Num. rotatable bonds :	0
Num. H-bond acceptors :	1.0
Num. H-bond donors :	0.0
Molar Refractivity :	34.78
TPSA :	41.13 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) :	-5.7 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.94
Log Po/w (XLOGP3) :	2.38
Log Po/w (WLOGP) :	2.21
Log Po/w (MLOGP) :	0.92
Log Po/w (SILICOS-IT) :	3.3
Consensus Log Po/w :	2.15

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	2.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-2.97
Solubility :	0.19 mg/ml ; 0.00107 mol/l
Class :	Soluble
Log S (Ali) :	-2.88
Solubility :	0.232 mg/ml ; 0.0013 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.53
Solubility :	0.524 mg/ml ; 0.00294 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.61

Safety of [ 7238-61-1 ]

Signal Word:	Danger	Class:	8
Precautionary Statements:	P210-P261-P264-P270-P271-P280-P301+P312+P330-P302+P352-P304+P340+P312-P305+P351+P338+P310-P332+P313-P370+P378-P403+P233-P403+P235-P405-P501	UN#:	1760
Hazard Statements:	H227-H302-H315-H318-H335	Packing Group:	Ⅲ
GHS Pictogram:

Application In Synthesis of [ 7238-61-1 ]

* 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 [ 7238-61-1 ]
Downstream synthetic route of [ 7238-61-1 ]

[ 7238-61-1 ] Synthesis Path-Upstream 1~3

1
[ 1603-91-4 ]
[ 7238-61-1 ]

Reference： [1] Tetrahedron Letters, 1999, vol. 40, # 47, p. 8301 - 8304

2
[ 3029-48-9 ]
[ 7238-61-1 ]

Reference： [1] Tetrahedron Letters, 2003, vol. 44, # 23, p. 4393 - 4394

3
[ 693-95-8 ]
[ 7238-61-1 ]

Reference： [1] Zhurnal Obshchei Khimii, 1957, vol. 27, p. 726,728; engl. Ausg. S. 799, 801

[ 7238-61-1 ] Synthesis Path-Downstream 1~59

1
[ 693-95-8 ]
[ 7238-61-1 ]

Reference： [1]Zhurnal Obshchei Khimii,1957,vol. 27,p. 726,728; engl. Ausg. S. 799, 801

2
[ 7238-61-1 ]
[ 98-64-6 ]
[ 515-59-3 ]

Reference： [1]Patent: CH210790,1938,

3
[ 7238-61-1 ]
[ 121-61-9 ]
[ 71119-13-6 ]

Reference： [1]Patent: CH210784,1938,

4
[ 7238-61-1 ]
[ 857955-32-9 ]

Reference： [1]Journal of the Chemical Society,1945,p. 925

5
[ 7238-61-1 ]
[ 114389-51-4 ]

Reference： [1]Chemistry of Heterocyclic Compounds,1987,vol. 23,p. 1084 - 1089
Khimiya Geterotsiklicheskikh Soedinenii,1987,p. 1353 - 1359

6
[ 7238-61-1 ]
2-Bromo-4-methyl-thiazole; compound with GENERIC INORGANIC NEUTRAL COMPONENT [ No CAS ]

Reference： [1]Chemistry of Heterocyclic Compounds,1987,vol. 23,p. 1084 - 1089
Khimiya Geterotsiklicheskikh Soedinenii,1987,p. 1353 - 1359

7
[ 7238-61-1 ]
[ 368-39-8 ]
2-bromo-3-ethyl-4-methyl thiazolium tetrafluoroborate [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2000,vol. 65,p. 2951 - 2958
[2]Tetrahedron Letters,1999,vol. 40,p. 8301 - 8304

8
[ 1603-91-4 ]
[ 7238-61-1 ]

Reference： [1]Tetrahedron Letters,1999,vol. 40,p. 8301 - 8304

Yield	Reaction Conditions	Operation in experiment
		Example II-A At 10 C., 11.6 mol of hydrogen bromide were passed with the exclusion of moisture into a solution of 280 g (2.30 mol) of thiocyanatopropan-2-one in 4,500 ml of dichloromethane such that a temperature of 10 C. was not exceeded. Hydrogen bromide was generated from bromine and tetralin in the course of this reaction according to processes known from the literature. In a modification of the literature procedure, the addition of catalytic amounts of iron was dispensed with and the reaction temperature for the generation of hydrogen bromide was increased to 40 C. After the addition of the hydrogen bromide was complete (about 6 h), the mixture was stirred at room temperature for 12 h. The product obtained as the hydrobromide was filtered off with suction, washed with 1,500 ml of dichloromethane, and again suspended in 3,000 ml of dichloromethane. 2,500 ml of saturated sodium hydrogen carbonate solution were then added in a 20 liter glass reactor at 0 C. with vigorous mixing (9 600 min-1) such that a temperature of 5 C. was not exceeded. The organic phase was separated off, dried over MgSO4, and the solvent was distilled off at 30 C. and 50 mbar on a rotary evaporator. The residue that remained was then fractionally distilled. Yield of 2-bromo-4-methylthiazole: 365 g (89%), colorless liquid B.p.: 51 C. (0.1 mbar) 1H-NMR (400 MHz, DMSO-d6): delta=2.49 (s, 3H, CH3), 6.85 (s,1H, thiazole). 13C-NMR (400 MHz, DMSO-d6): delta=17.25, 117.21, 134.90, 153.46. MS (Cl): (m/z)=M+179, C4H4BrNS: 178.05.

10
[ 7238-61-1 ]
[ 74-83-9 ]
2-bromo-3,4-dimethyl-thiazolium bromide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	In DMF (N,N-dimethyl-formamide); at 70℃; under 1425.14 Torr;	100 g (0,56 mol) 2-Brom-4-methylthiazol werden in 106 ml wasserfreiem Dimethylformamid gelost und die Mischung bei Raumtemperatur in einen HC-Autoklaven eingetragen. Nun werden 213,28 g (2,25 mol) Brommethan aufgepresst, so das der Druck auf 1,9 bar ansteigt. Anschliessend wird das Reaktionsgemisch bei guter Durchmischung mit einer Heizrate von 8C/Minute auf 70C erwarmt und die Temperatur solange isobar gehalten, bis die Umsetzung moglichst quantitativ ist. Die Umsetzung wird dabei massenspektroskopisch verfolgt. Zur Aufarbeitung kuhlt man auf Raumtemperatur, entspannt den Autoklaven und filtriert das Produkt ab. Losungsmittelreste und Verunreinigungen werden durch Waschen mit 300 ml Hexan entfernt und das Produkt im Hochvakuum getrocknet. Ausbeute: 107,5 g (70 % d. Theorie)

Reference： [1]Patent: EP1371651,2003,A2 .Location in patent: Page 9
[2]Tetrahedron Letters,2003,vol. 44,p. 4393 - 4394

11
[ 3029-48-9 ]
[ 7238-61-1 ]

Reference： [1]Tetrahedron Letters,2003,vol. 44,p. 4393 - 4394

12
[ 7238-61-1 ]
Meerwein salt [ No CAS ]
2-bromo-3-ethyl-4-methyl thiazolium tetrafluoroborate [ No CAS ]

Reference： [1]Tetrahedron Letters,2003,vol. 44,p. 4393 - 4394

13
[ 7238-61-1 ]
[ 1634-04-4 ]
2-Bromo-3,4-dimethylthiazolium methyl sulfate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dimethyl sulfate; In 1,1-dichloroethane;	Example 7 25 g (140 mmol) of <strong>[7238-61-1]<strong>[7238-61-1]2-bromo-4-methylthiazol</strong>e</strong> were dissolved in 50 ml of dichloroethane and treated at room temperature with 8.85 g (70 mmol) of dimethyl sulfate. The mixture was then warmed to 50 C. for 1 h to complete the reaction. The solution was cooled to room temperature and treated with 300 ml of methyl tert-butyl ether. The crystals were filtered off with suction and then recrystallized from isopropanol. 2-Bromo-3,4-dimethylthiazolium methyl sulfate was obtained in a yield of 8.5 g (25.1% of theory). 1H-NMR (400 MHz, CDCl3): 2.62 (s, 3H), 3.68 (s, 3H), 4.19 (s, 3H), 8.16 (s, 1H, thiazole). EI/MS (m/z): 279 (Br79), 281 (Br81).

Reference： [1]Patent: US2002/156287,2002,A1

14
[ 7238-61-1 ]
2-bromo-3-ethyl-4-methyl thiazolium tetrafluoroborate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethyloxonium fluoroborate; In dichloromethane;	Example 1 110 g (0.60 mol) of <strong>[7238-61-1]<strong>[7238-61-1]2-bromo-4-methylthiazol</strong>e</strong> were added at room temperature to a solution of 117 g (0.58 mol) of triethyloxonium tetrafluoroborate in 400 ml of dichloromethane such that a temperature of 30 C. was not exceeded. After addition was complete, the mixture was warmed to 50 C. for 60 min and then cooled to room temperature. For complete crystallization, the reaction mixture was treated with 300 ml of methyl telfbutyl ether, the crystals were filtered off with suction, and the product was then recrystallized from isopropanol. Yield of 2-bromo-3-ethyl-4-methylthiazolium tetrafluoroborate (BEMT): 140 g (80%), white crystals. M.p.: 184 C. 1H-NMR (400 MHz, DMSO-d6): delta=1.45 (t, J=7.3 Hz, 3H, CH2CH3), 2.62 (s, 3H, CH3 thiazole), 3.95 (q, J=7.3 Hz, 2H, CH2CH3), 8.05 (s,1H, thiazole). 13C-NMR (400 MHz, CH3CN-d3): delta=13.9, 14.7, 50.0,148.5,123.4, 145.4. MS (ESI+): m/z=206 (79Br), 208 (81Br).

Reference： [1]Patent: US2002/156287,2002,A1

15
[ 7238-61-1 ]
bis(2-bromo-3-methyl-4-methylthiazole) sulfate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dimethyl sulfate; In N,N-dimethyl-formamide;	Example 2c Dimethyl sulfate (0.53 g, 4.21 mmol) dissolved at 25 C. in 0.5 ml of N,N-dimethylformamide was added to a solution of 1.5 g (8.42 mmol) of <strong>[7238-61-1]<strong>[7238-61-1]2-bromo-4-methylthiazol</strong>e</strong> in 4.0 ml of N,N-dimethylformamide. After stirring at 25 C. for 3 hours, the solvent was removed in vacuo and the residue was codistilled three times with ethyl acetate to remove the last traces of DMF. The residue was recrystallized from isopropanol. Yield of bis(2-bromo-3-methyl-4-methylthiazole) sulfate: 0.85 g (21%), white crystals M.p.: 149 C. 1H-NMR (400 MHz, MeOH-d3): delta=2.65 (s, 3H, CH3thiazole), 4.10 (s, 3H, CH3), 7.98 (s,1H, thiazole). 13C-NMR (400 MHz, MeOH-d3): delta=15.2, 40.2, 122.4, 146.8, 148.9. MS (ESI+): m/z=192 (79Br), 194 (81Br).

Reference： [1]Patent: US2002/156287,2002,A1

16
[ 7238-61-1 ]
[ 107-05-1 ]
[ 7440-66-6 ]
C₄H₄BrNSZn [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Preparation of 2-(2-(2,6-dichlorophenyl)- 1-(3'-(methylsulfonyl)biphenyl-4-yl)-1H- imidazol-4-yl)-4-methylthiazoleInto a 5 mL microwave vial was weighed 174 mg (2.7 mmol) of zinc powder and 45 mg (200 mumol) of anhydrous CoBr2. The solids were suspended in 1.7 mL of acetonitrile, and the resulting suspension was treated with 45 muL (0.55 mmol) of allyl chloride, followed by 15 muL of trifluoroacetic acid (33% v/v on allyl chloride). After stirring for ~ 10 minutes at ambient temperature, the suspension was treated with 302 mg (1.7 mmol) of 2-bromo-4- methylthiazole as a solution in 300 muL of acetonitrile. After ~2 hours stirring at ambient temperature an aliquot of the reaction suspension was treated with iodine in Et2O, quenched by addition of aqueous sodium thiosulfate to reduce the iodine, and dried over Na2SO4. GC/MS analysis of this sample showed a large quantity of iodo(methylthiazole) from iodination of the thiazole zinc reagent, and no trace of remaining <strong>[7238-61-1]<strong>[7238-61-1]2-bromo-4-methylthiazol</strong>e</strong>. Into the reaction vessel was added 156 mg (0.0.27 mmol)of 2-(2,6-dichlorophenyl)-4-iodo-1- (3'-(methylsulfonyl)biphenyl-4-yl)-1H-imidazole, 39 mg (48 mumol) of PdCl2(dppf>CH2Cl2. The reaction mixture was heated to 120C forl hour in the Biotage Initiator microwave reactor. LC/MS at this time showed a large peak for the desired product. The reaction mixture was treated with decolorizing carbon and diluted with EtOAc and with 1N HCl. The black suspension was filtered through a pad of Celite. The layers were separated and the acidic aqueous was extracted with EtOAc (3x). Combined organics were washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered and concentrated in vacuo to afford a brown film. The crude product was purified on the reverse phase preparative HPLC eluting with acetonitrile/water. (Phenomenex Axia Gemini C18 30 x 100 mm 5 mum, A = H2O with 0.1% trifluoroacetic acid, B = acetonitrile with 0.1% trifluoroacetic acid, 17 minute gradient from 30% B to 100% B at 35 mL/minute). Product fractions were combined, made basic by the addition of sat. NaHCO3, and concentrated in vacuo to remove the acetonitrile. The resulting basic aqueous was extracted with CH2Cl2 (3x), and the organics were dried over Na2SO4, filtered and concentrated in vacuo. The resulting 2-(2-(2,6-dichlorophenyl)-1-(3'- <n="293"/>(methylsulfonyl)biphenyl-4-yl)-1H-imidazol-4-yl)-4-methylthiazole was isolated as a pale brown powder, yield; 58.4 mg (39% yield); 1H NMR (400 MHz, CDCl3): delta 8.12-8.10(m, 1H), 7.95-7.92(m, 2H), 7.86-7.82(m, 1H), 7.68-7.63(m, 1H)7.61-7.56(m, 2H), 7.41-7.36(m, 2H), 7.35-7.29(m, 3H), 6.87-6.86(m, 1H), 3.09(s, 3H), 2.51(d, J = 1.0Hz, 3H); MS (ES): 540.0 [M+H]+.

Reference： [1]Patent: WO2008/73825,2008,A1 .Location in patent: Page/Page column 291-292

17
[ 7238-61-1 ]
[ 63968-64-9 ]
C₁₉H₂₇NO₅S [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2010,vol. 53,p. 3594 - 3601

18
[ 7238-61-1 ]
[ 847358-99-0 ]
[ 1217864-20-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 887 - 892

19
[ 7238-61-1 ]
[ 185099-67-6 ]
[ 1346014-35-4 ]
[ 1346144-18-0 ]

Yield	Reaction Conditions	Operation in experiment
		Synthesis 73-Hydroxy-3-(4-methyl-thiazol-2-yl)-8-aza-bicyclo[3.2.1 ]octane-8-carboxylic acid tert-butyl ester (PA Isomer 1) and3-Hydroxy-3-(4-methyl-thiazol-2-yl)-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (PA Isomer 2)n-Butyl lithium (2.5 M in hexane, 0.33 mL, 0.81 mmol) was added dropwise to a solution of <strong>[7238-61-1]2-bromo-4-methyl-thiazole</strong> (0.13 g, 0.74 mmol) in diethyl ether (2 mL), under nitrogen at -78C and stirred for 1 hour. 3-Oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert- butyl ester (0.2 g, 0.88 mmol) in diethyl ether (1.5 mL) was added dropwise at -78C and the reaction mixture stirred for 0.5 hours before warming to room temperature. The reaction mixture was poured onto ice, acidified with acetic acid and extracted into ethyl acetate. The remaining aqueous solution was basified with 1 M sodium hydroxide, extracted with DC and the combined organics were dried over magnesium sulphate, filtered and the solvent removed by evaporation under vacuum. Methanol (10 mL) and sodium borohydride (0.14 g) were added to the residues and stirred for 2 hours to reduce any unreacted ketone. The solvent was removed by evaporation under vacuum, DCM added to the residues and the organics washed with water and brine, dried over magnesium sulphate, filtered and the solvent removed by evaporation under vacuum. The residue was purified by flash chromatography on silica eluting with 0-100% ethyl acetate/pentane. The fractions containing the two desired products were concentrated under vacuum to give the title compounds. PA Isomer 1 : (0.13g). LCMS m/z 325 [M+Hf. R.T. = 3.62 min (Analytical Method 3).PA Isomer 2: (0.07g). LCMS m/z 325 [M+H]+. R.T. = 3.51 min (Analytical Method 3).

Reference： [1]Patent: WO2011/135276,2011,A1 .Location in patent: Page/Page column 76

20
[ 7238-61-1 ]
[ 1414782-20-9 ]
[ 1414782-39-0 ]

Yield	Reaction Conditions	Operation in experiment
60%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 110℃; for 18h;Inert atmosphere;	General procedure: To an oven-dried round-bottom flask containing tert-butyl 2-[(R)-5-bromo-2,3-dihydro-1H-inden-1-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate 3 (1.0 mmol) was added bis(pinacolato)diboron (1.1 mmol), potassium acetate (4.0 mmol) and 10 mL of anhydrous 1,4-dioxane. The resulting mixture was purged with N2 for three times. Pd(dppf)Cl2 (0.05 mmol) was added, the reaction mixture was purged with N2 again three times and heated under N2 at 110 C for 46 h. The course of the reaction was followed by TLC (5% MeOH in CH2Cl2) and LCMS. The reaction mixture was cooled to room temperature, and the aryl halide 5 (1.1 mmol)], Pd(dppf)Cl2 (0.05 mmol) and 3.5 mL of 2M aqueous solution of potassium carbonate (de-oxygenated by bubbling through N2 for 15 minutes before addition) were added. The reaction mixture was purged with N2 three times and then heated under N2 for 618 h at 110 C. The course of the reaction was followed by LCMS. The reaction mixture was cooled to room temperature, and the solvent removed under reduced pressure. The residue was partitioned between EtOAc (100 mL) and 1N NaOH solution (100 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4 and the solvent was removed under reduced pressure to afford the crude product as a dark brown oil. The crude product was purified by silica gel chromatography, eluting with 010% MeOH in CH2Cl2 to afford the desired product.

Reference： [1]Tetrahedron Letters,2012,vol. 53,p. 6351 - 6354,4

21
[ 7238-61-1 ]
[ 107-15-3 ]
N’-(4-methylthiazol-2-yl)ethane-1,2-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In ethanol; at 120℃; for 0.5h;Microwave irradiation; Sealed tube;	Step A: N?-(4-Methylthiazol-2-yl)ethane-1 ,2-diamineA mixture of <strong>[7238-61-1]<strong>[7238-61-1]2-bromo-4-methylthiazol</strong>e</strong> (502 mg, 2.82 mmol), ethylenediamine (15 mL, 224 mmol) and potassium carbonate (780 mg, 5.64 mmol) was heated under microwave heating at 12000 for 30 mm in a closed vial. Ethanol (200 mL) was added, the resulting mixture was filtered, the solids washed with EtOH and the combined filtrates concentrated under reduced pressure. The residue was mixed with toluene and concentrated under reduced pressure; this step was repeated two times after which 620 mg of a solid was obtained that was used directly in the next step.

Reference： [1]Patent: WO2013/144179,2013,A1 .Location in patent: Page/Page column 64

22
[ 7238-61-1 ]
[ 1225228-21-6 ]
[ 1596364-82-7 ]

Yield	Reaction Conditions	Operation in experiment
350 mg	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; for 18h;Inert atmosphere; Reflux;	4-chloro-5-( 4-methylthiazol-2-yl)pyridin-2-amine (30) (6-amino-4-chloropyridin-3-yl)boronic acid (671 mg), <strong>[7238-61-1]<strong>[7238-61-1]2-bromo-4-methylthiazol</strong>e</strong> (630 mg) and Pd(PPh3)4 were combined in a flask. Na2C03 (1 M, 7.08 mL) and dioxane (25 mL) were added. The mixture was degassed with nitrogen and heated to reflux for 18 h. The mixture was cooled to room temperature and diluted with EtOAc, washed with water, brine, dried (MgS04), filtered, and concentrated. The residue was purified by column chromatography on silica gel (5% MeOH/DCM) to give 350 mg of the title compound as a white solid. LCMS 1.77 min, 226 (M+H).

Reference： [1]Patent: WO2014/58685,2014,A1 .Location in patent: Page/Page column 96-97

23
[ 7238-61-1 ]
[ 1609393-90-9 ]
[ 1609393-91-0 ]

Yield	Reaction Conditions	Operation in experiment
83%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 100℃; for 1h;Inert atmosphere;	[00175j A stirred mixture of <strong>[7238-61-1]<strong>[7238-61-1]2-bromo-4-methylthiazol</strong>e</strong> (201 mg, 1.13 mmol), Intll (309 mg, 1.24 mmol) and 1,1 ?-bis(di-tert-butylphosphino)ferrocene palladium dichloride (36.8 mg in dioxane (8 mL) was degassed by bubbling nitrogen through the mixture for 5 minutes. Subsequently tribasic potassium phosphate (2M in water, 1.69 mL, 3.39 mmol)was added and the reaction mixture heated at 100 C for one hour. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (75 mL) and then dried over sodium sulfate, filtered, concentrated and purified by automated chromatography providing Intl2 (218 mg, 83%). ?H NMR (400MHz, chloroform-d) oe 7.63 (dd, J7.9, 1.6 Hz, 1H), 7.02 (t, J=7.8 Hz, 1H), 6.96 (d, J=1.0 Hz, 1H), 6.80 (dd, J7.8, 1.5 Hz, 1H),3.88 (br. s., 2H), 3.80 (s, 3H), 2.53 (d, J1.0 Hz, 3H). LC retention time 0.65 [J]. m/z:221 (MHj.

Reference： [1]Patent: WO2014/74661,2014,A1 .Location in patent: Paragraph 00175

24
[ 7238-61-1 ]
[ 34941-91-8 ]
[ 1608482-99-0 ]

Yield	Reaction Conditions	Operation in experiment
24%		To a dry 10 mL Schlenk flask equipped with a stir bar and placed under N2 atmosphere was added <strong>[7238-61-1]<strong>[7238-61-1]2-bromo-4-methylthiazol</strong>e</strong> (244 mg, 1.37 mmol) in THF (5 mL). The flask was cooled to -78 C. To the solution was added n-butyllithium in hexanes (0.55 mL, 1.37 mmol). The solution was stirred for 5 minutes. To the solution was added zinc(II) chloride in THF (2.74 mL, 1.37 mmol). A thick ppt. immediately formed which hindered stirring. The flask was immediately transfered to a r.t. water bath and the solution was allowed to warm to r.t. with stirring for 30 min. To the solution was added 2-chloro-4-fluoropyridine (150 mg, 1.14 mmol), then Pd(dppf)Cl2 (42 mg, 0.057 mmol). The vial was placed in a 60 C heating block with stirring (t=0). The reaction mixture was transferee to a 125 mL separatory funnel and was diluted with Et20:EtOAc (25 mL:25 mL). The solution was washed with water:brine (25 mL:25 mL). The aq. phase was extracted with EtOAc (25 mL). The combined organics were washed with brine (25 mL); dried over MgS04; filtered; then concentrated in vacuo. The residue was subjected to silica gel chromatography to afford 2-(4-fluoropyridin-2-yl)-4-methylthiazole as an orange solid (54 mg, 24%). 1H-NMR (400MHz, CDC13) delta 8.57 (dd, J=8.2, 5.6 Hz, 1H), 7.91 (dd, J=9.7, 2.4 Hz, 1H), 7.09 - 7.01 (m, 2H), 2.54 (d, J=1.0 Hz, 3H).

Reference： [1]Patent: WO2014/71007,2014,A1 .Location in patent: Page/Page column 45; 46

25
[ 7238-61-1 ]
(E)-1-(3-(4-chloro-2-((5-methyl-2H-tetrazol-2-yl)methyl)phenyl)acryloyl)piperidine-4-carbaldehyde [ No CAS ]
(E)-3-(4-chloro-2-((5-methyl-2H-tetrazol-2-yl)methyl)phenyl)-1-(4-(hydroxy(4-methylthiazol-2-yl)methyl)piperidin-1-yl)prop-2-en-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Butyl lithium 2.5M solution in hexanes (0.120 mL, 0.300 mmol) was added dropwise to a solution of <strong>[7238-61-1]<strong>[7238-61-1]2-bromo-4-methylthiazol</strong>e</strong> (44.5 mg, 0.250 mmol) in THF (2 mL) at <-70C and the resulting mixture stirred for 30 mi Lathanum chloride lithium chloride solution (0.6M inTHF, 0.417 mL, 0.250 mmol) was added dropwise and the resulting mixture was stirred for30 mm. A solution of (E)- 1 -(3-(4-Chloro-2-((5-methyl-2 H-tetrazol-2- yl)methyl)phenyl)acryloyl)piperidine-4-carbaldehyde (step 2) (93 mg, 0.25 mmol) in THF (1 mL) was added dropwise and the mixture was stirred at -70C for 30 mm then allowed to warm to RT. The reaction was quenched with saturated ammonium chloride solution (5 mL) and extracted with ethyl acetate (3x10 mL). The combined organic solutions were washed with brine (20 mL), dried over sodium sulphate, filtered and concentrated in vacuo. Purification was carried out by silica gel column chromatography eluting with a gradient ofiso-hexane to ethyl acetate. The product fractions were combined and concentrated in vacuo to give the title compound as a white solid;LC MS Rt 1.07 mm [M+H] 473.6, 475.6, Method 2minLowpHvol

Reference： [1]Patent: WO2015/8230,2015,A1 .Location in patent: Page/Page column 231; 232

26
[ 7238-61-1 ]
C₃₀H₃₈BClN₄O₆S [ No CAS ]
(S)-tert-butyl-2-((6-(2-chloro-4-(4-methylthiazol-2-yl)phenyl)-2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)methyl)morpholine-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; sodium acetate; In water; acetonitrile; at 100℃; for 2h;	S)-tert-butyl 2-((6-(4-bromo-2-chlorophenyl)-2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)methyl)morpholine-4-carboxylate was borylated (bis(pinacolato)diboron, Pd(dppf)Cl2, KOAc, dioxane, 80 C., 2 h) and the resulting dioxaborolane coupled with <strong>[7238-61-1]<strong>[7238-61-1]2-bromo-4-methylthiazol</strong>e</strong> (Pd(dppf)Cl2, K3PO4, NaOAc, MeCN, H2O, 100 C., 2 h) to afford (S)-tert-butyl 2-((6-(2-chloro-4-(4-methylthiazol-2-yl)phenyl)-2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)methyl)morpholine-4-carboxylate. Introduction of the methylamine and removal of the Boc group were accomplished by standard protocols. 1H NMR (400 MHz, CDCl3) delta 8.45 (s, 1H), 8.06 (d, J=1.6 Hz, 1H), 7.83 (dd, J=2.0, 8.0 Hz, 1H), 7.58 (s, 1H), 7.41 (d, J=8.0 Hz, 1H), 6.92 (s, 1H), 5.70-5.58 (m, 1H), 4.61-4.50 (m, 2H), 4.00-3.89 (m, 2H), 3.59-3.55 (m, 1H), 3.11 (d, J=4.8 Hz, 3H), 2.93-2.90 (m, 2H), 2.88-2.87 (m, 2H), 2.51 (s, 3H); MS [M+H]+=483.0

Reference： [1]Patent: US2015/31674,2015,A1 .Location in patent: Paragraph 0601

27
[ 7238-61-1 ]
[ 1041600-42-3 ]
[ 76-05-1 ]
4-(2-hydroxy-3-methoxybenzylamino)-N-(4-methylthiazol-2-yl)benzenesulfonamide trifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: (Scheme 1, Method C) 4-aminobenzenesulfonamide (4) (1.00 g, 5.81 mmol), 2- hydroxy-3-methoxybenzaldehyde (1.00 g, 7.00 mmol) in EtOH (29 mL) was heated to reflux for 4 h until reaction is an orange turbid mixture. The reaction mixture was cooled to room temperature before sodium borohydride (0.33 g, 8.71 mmol) was added and stirred for an additional 30 min. A white solid forms after 30 min and is collected by filtration and washed with copious amounts of ethanol, dried under vacuum and used as is in subsequent reactions. 1H NMR (400 MHz, DMSO- d6) delta 7.60-7.27 (m, 2H), 6.75-6.40 (m, 4H), 6.06 (t, J= 7.63 Hz, 1H), 4.18 (s, 2H), and 3.65 (s, 3H); 13C NMR (101 MHz, DMSO) delta 40.37, 55.32, 108.91, 109.42, 109.55, 111.29, 111.40, 121.05, 125.05, 127.49, 129.92, 150.17, 152.36, and 156.94; LC-MS retention time (Method 1): 2.876 min. General procedure: (Step iv) 4-(2-hydroxy-3-methoxybenzylamino)benzenesulfonamide (5) (0.58 mmol), arylbromide (0.70 mmol), K2CO3 (1.45 mmol), N,N'-dimethylethylenediamine (0.29 mmol), and copper(I)iodide (0.03 mmol) in 1,4-dioxane (1.5 mL) were place under N2 and sealed in a 5 mL sealed tube. The reaction was heated to 70 C for 6 to 8 h and monitored by LC/MS analysis. Upon completion the heterogeneous mixture was cooled to room temperature, filtered, and washed with dioxane. The solution was passed through a thiol cartridge (metal scavenging), diluted with AcOEt and washed with NH4CI (2X), water, and brine. The crude material was purified using a prep-HPLC (gradient 10-100% acetonitrile w/ 0.1% TFA in water w/ 0.1% TFA) to give the desired product. 4-(2-hydroxy-3-methoxybenzylamino)- V-(4-methylthiazol-2-yl)benzenesulfonamide TFA (40): Method C: using <strong>[7238-61-1]<strong>[7238-61-1]2-bromo-4-methylthiazol</strong>e</strong>; 1H NMR (400 MHz, DMSO-<) delta 12.31 (s, 1 H), 8.70 (s, 1 H), 7.48-7.32 (m, 3 H), 6.89-6.72 (m, 6 H), 6.61-6.47 (m, 3 H), 6.27 (s, 1 H), 4.20 (d, J= 5.90 Hz, 2 H), 3.76 (s, 3 H), and 1.95 (s, 3 H); LC-MS retention time (Method 1): 1.962 min; HRMS: m/z (M+H)+ (Calculated for C18H20N3O4S2, 406.0890) found 406.0875.

Reference： [1]Patent: WO2015/54662,2015,A1 .Location in patent: Paragraph 0192; 0230

28
[ 79762-54-2 ]
[ 7238-61-1 ]
2-(6-bromo-1H-indazol-1-yl)-4-methylthiazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32%	With sodium hydride; In N,N-dimethyl-formamide; at 130℃; for 12h;	The preparation of 2-(6-bromo-lH-indazol-l-yl)-4-methylthiazole was the similar to that of 6-bromo-l-(6-methylpyridin-2-yl)-lH-indazole. 200 mg, as a brown solid, Y: 32%. ESI-MS (M+H)+: 294.0. 1H NMR (400 MHz, CDC13) delta: 8.78 (s, 1H), 8.06 (s, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.36 (dd, J = 8.5, 1.5 Hz, 1H), 6.55 (s, 1H), 2.42 (s, 3H).

Reference： [1]Patent: WO2016/11390,2016,A1 .Location in patent: Page/Page column 213

29
[ 7238-61-1 ]
[ 175883-62-2 ]
4-methyl-2-(4-methoxy-3-methylphenyl)-thiazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In water; N,N-dimethyl-formamide; at 100℃; for 12h;Inert atmosphere;	To a solution of 2-bromo-4-methylthiazole (1.0 g, 5.6 mmol) in DMF:H20 (10:1, 3.0 ml) was added sodium carbonate (0614) (1.19 g, 0.0112 mole) followed addition of 1,1'- bis ( diphenylphosphino) ferrocene-palladium ( II ) di chloride (0615) dichloromethane (0.457 g, 5.6 mmol) under nitrogen atmosphere. 4-Methoxy-3-methylphenylboronic acid (1.38 g, 8.41 mmol) was added to the reaction mixture and then it was stirred at 100C for 12h. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (3 x 50 mL) , dried over sodium sulfate and evaporated to dryness. The crude was purified by column chromatography to afford 2- ( 4-methoxy-3-methylphenyl ) - 4-methylthiazoleas as a yellow viscous oil (0.80 g, Yield: (0616) 65%) . (0617) 1R NMR (CDCI3) : delta 7.73-7.71 (m, 2H) , 6.84 (d, J = 9.2 Hz, 1H) , 6.79-6.78 (m, 1H) , 3.87 (s, 3H) , 2.48 (s, 3H) , 2.26 (s, 3H) .
1 g	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; at 80℃; for 8h;	Reference Production Example 39 A mixture of 1.86 g of <strong>[175883-62-2]4-methoxy-3-methylphenylboronic acid</strong>, 2.00 g of 2-bromo-4-methylthiazole, 0.46 g of [1,1'-bis(diphenylphosphino) ferrocene]palladium (II) dichloride dichloromethane adduct, 4.05 g of sodium carbonate, 50 mL of dioxane, and 50 mL of water was stirred at 80 C. for 8 hours. After cooling, the reaction mixture was filtered and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and a saturated saline solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography to obtain 1.00 g of 4-methyl-2-(4-methoxy-3-methylphenyl)-thiazole (C39A). 1H-NMR (CDCl3) delta: 7.73-7.71 (2H, m), 6.84 (1H, d, J=8.8 Hz), 6.78 (1H, d, J=1.0 Hz), 3.87 (3H, s), 2.49 (3H, d, J=0.7 Hz), 2.26 (3H, s).

Reference： [1]Patent: WO2018/138692,2018,A1 .Location in patent: Page/Page column 49
[2]Patent: US2016/205935,2016,A1 .Location in patent: Paragraph 0706-0707

30
[ 7238-61-1 ]
C₂₀H₂₇N₇OS [ No CAS ]
C₂₄H₃₀N₈OS₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; tert-butyl XPhos; In 1,4-dioxane; at 120℃; for 1h;Microwave irradiation; Inert atmosphere;	Compound 20-a (100 mg, 0.242 mmol), 2-bromo- 4-methylthiazole (87 mg, 0.484 mmol), Pd2(dba)3 (11 mg,0.0121 mmol), Me4t-butylPhos (12 mg, 0.0242 mmol), cesium carbonate (237 mg, 0.726 mmol) and 1, 4-dioxane (1 .0 mE) were added into a microwave tube, and reacted under nitrogen in microwave at 120 C. for 1 hr. The reaction mixture was filtered through celite, and rinsed with dichloromethane. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPEC to obtain target compound 26 (63 mg, yield 51%), as a yellow solid. EC-MS (ESI): mlz 511.2 (M+H). ?H NMR (400 MHz, CDC13):7.81 (s, 1H), 7.26 (s, 1H), 6.81 (s, 1H), 3.89 (t, 4H, J=5.2 Hz),3.84 (s, 2H), 3.82 (t, 4H, J=4.8 Hz), 3.48 (t, 4H, J=4.8 Hz),2.70 (t, 4H, J=4.8 Hz), 2.66 (s, 3H), 2.29 (s, 3H), 2.28 (s, 3H).

Reference： [1]Patent: US2016/214994,2016,A1 .Location in patent: Paragraph 0192; 0193

31
[ 7238-61-1 ]
N-(4-(5-bromo-7-cyano-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-2-yl)pyridin-2-yl)acetamide [ No CAS ]
N-(4-(5-bromo-7-cyano-3-(4-methylthiazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-2-yl)pyridin-2-yl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A solution of <strong>[7238-61-1]<strong>[7238-61-1]2-bromo-4-methylthiazol</strong>e</strong> (145 mg, 0.814 mmol), 4,4,4?,4?,5,5,5?,5?-octamethyl-2,2?-bi(1,3,2-dioxaborolane) (248 mg, 0.977 mmol) in 1,4-dioxane (5 ml) was added potassium acetate (120 mg, 1.222 mmol). The reaction mixture was purged with argon for several minutes and PdCl2(dppf)-CH2Cl2Adduct (20.81 mg, 0.041 mmol) was added. The reaction mixture was bubbled argon for 2 min and heated in a sealed vial at 90 C. for 2 h. To the cooled reaction mixture was added N-(4-(5-bromo-7-cyano-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-2-yl)pyridin-2-yl)acetamide (499 mg, 0.814 mmol) and tripotassium phosphate (0.679 ml, 2.036 mmol). The reaction mixture was bubbled with argon for 5 min and heated at 110 C. for overnight. The reaction mixture was cooled, diluted with EtOAc and washed with water then with brine. The organic phase was dried with MgSO4, concentrated and purified by silica gel flash chromatography (12 g column, EtOAc/hex=0-50%) to give N-(4-(5-bromo-7-cyano-3-(4-methylthiazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridin-2-yl)pyridin-2-yl)acetamide. HPLC: RT=1.20 min (H2O/MeOH with 0.05% TFA, Waters Acquity SDS BEH C18 2.1×50 mm 1.7 u, gradient=1.75 min, wavelength=220 nm); MS (ES): m/z=583, 585 [M+H]+.

Reference： [1]Patent: US2016/176871,2016,A1 .Location in patent: Paragraph 0854-0855

32
[ 7238-61-1 ]
methyl (4aR)-1-(4-fluorophenyl)-6-((3-(trifluoromethyl)-phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]-isoquinoline-4a-carboxylate [ No CAS ]
((4aR)-1-(4-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)-sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]-isoquinolin-4a-yl)(4-methylthiazol-2-yl)methanone [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 3405 - 3421

33
[ 7238-61-1 ]
2-(difluoromethoxy)-7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxaline [ No CAS ]
2-(2-(difluoromethoxy)-7-methylquinoxalin-5-yl)-4-methylthiazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In N,N-dimethyl-formamide; at 90 - 100℃; for 1h;Sealed tube; Microwave irradiation; Inert atmosphere;	Intermediate I-1 (18.4 mg, 0.055 mmol) and <strong>[7238-61-1]<strong>[7238-61-1]2-bromo-4-methylthiazol</strong>e</strong> (14.62 mg, 0.082 mmol) were dissolved in DMF (547 muL). PdCl2(dppf)-CH2Cl2 (2.68 mg, 3.28 mumol) was added and the reaction mixture was degassed by bubbling with argon for 15 minutes. Sodium carbonate (2 M, 32.8 muL, 0.066 mmol) was added and the reaction mixture was degassed for 5 minutes, then sealed and heated to 90 C in the microwave for 30 minutes. More <strong>[7238-61-1]<strong>[7238-61-1]2-bromo-4-methylthiazol</strong>e</strong> (14.62 mg, 0.082 mmol), Sodium carbonate (2 M, 32.8 muL, 0.066 mmol), and PdCl2(dppf)-CH2Cl2 (2.68 mg, 3.28 mumol) were added and the reaction mixture was heated to 100 C in the microwave for an additional 30 minutes. The reaction mixture was diluted with MeOH, filtered, and purified by preparative HPLC (Method A, 30 to 100% B in 18 minutes) to give Intermediate I-18A (14.2 mg, 0.046 mmol, 84%) as a red solid: 1H NMR (400MHz, CHLOROFORM-d) delta 8.69-8.63 (m, 2H), 7.93-7.89 (m, 1H), 7.84-7.45 (m, 1H), 7.36 (d, J=0.8 Hz, 1H), 2.70 (d, J=1.0 Hz, 3H), 2.67 (s, 3H); LC^MS: Method H, RT = 1.15 min, MS (ESI) m/z: 308.1 (M+H)+.

Reference： [1]Patent: WO2018/13772,2018,A1 .Location in patent: Page/Page column 60

34
[ 7238-61-1 ]
[ 1145-01-3 ]
2-(3,5-diphenyl-1H-pyrazol-1-yl)-4-methylthiazole [ No CAS ]

Reference： [1]Organic Letters,2018,vol. 20,p. 1906 - 1909

35
[ 7238-61-1 ]
[ 923948-65-6 ]
methyl (3S,4R)-4-(2,4-difluorophenyl)-1-(1,3-thiazol-2-yl)pyrrolidine-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
171 mg	With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 48h;	Preparation Example 28 A mixture of <strong>[7238-61-1]methyl 2-bromo-1,3-thiazole</strong> (555 mg), (3S,4R)-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylate (400 mg), potassium carbonate (459 mg), and N,N-dimethylformamide (5 mL) was stirred at 100C for 2 days. To the reaction mixture was added water at room temperature, followed by extracting with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous magnesium sulfate, the insoluble materials were then separated by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 90:10 to 50:50) to obtain methyl (3S,4R)-4-(2,4-difluorophenyl)-1-(1,3-thiazol-2-yl)pyrrolidine-3-carboxylate (171 mg) as an oil.

Reference： [1]Patent: EP3333165,2018,A1 .Location in patent: Paragraph 0202

36
[ 7238-61-1 ]
methyl 2-((2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)-3-methoxyphenylcarbamate [ No CAS ]
methyl 2-((2-methyl-4-(4-methylthiazol-2-yl)phenoxy)methyl)-3-methoxyphenylcarbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53.4%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; at 100℃; for 12h;Inert atmosphere;	To a solution of <strong>[7238-61-1]<strong>[7238-61-1]2-bromo-4-methylthiazol</strong>e</strong> (0.041 g, 0.23 mmol) in 1 , 4-dioxane : 0 (4:1, 6 ml) were sequentially added sodium carbonate (50 mg, 0.50 mmol), 1,1'- bis (diphenylphosphino ) ferrocene-palladium (II)dichloride dichloromethane complex (19 mg, 0.02 mmol) and methyl 2-( (2- methyl-4- (4, 4, 5, 5-tetramethyl-l , 3 , 2-dioxaborolan-2- yl ) phenoxy ) methyl ) -3-methoxyphenylcarbamate (0.10 g, 0.2 mmol) under nitrogen atmosphere. The reaction was stirred at 100C for 12h. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (3 x 20 rtiL) , dried over sodium sulfate and evaporated to dryness under reduced pressure. The crude compound was purified by column chromatography to afford methyl 2- ( ( 2 -methy1-4 - ( 4-methylthiazol-2-yl ) phenoxy) methyl ) -3- methoxyphenylcarbamate as an off-white solid (49 mg, Yield: (0677) 53.4%) . (0678) XH NMR (CDC13) : delta 7.85 (bs, 1H) , 7.73 (s, 1H) , 7.71-7.68 (m, 1H), 7.65 (d, J= 8.0 Hz, 1H) , 7.30 (t, J = 8.0 Hz, 1H) , 7.08 (d, J = 8.4 Hz, 1H) , 6.79 (d, J = 1.2 Hz, 1H) , 6.66 (d, J = (0679) 8.0 Hz, 1H) , 5.33 (s, 2H) , 3.88 (s, 3H) , 3.76 (s, 3H), 2.48 (s, 3H) , 2.29 (s, 3H) .

Reference： [1]Patent: WO2018/138692,2018,A1 .Location in patent: Page/Page column 56-57

37
[ 7238-61-1 ]
methyl (3-methyl-2-((2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)phenyl)carbamate [ No CAS ]
methyl (3-methyl-2-((2-methyl-4-(4-methylthiazol-2-yl)phenoxy)methyl)phenyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53.4%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; at 100℃; for 12h;Inert atmosphere;	To a solution of <strong>[7238-61-1]<strong>[7238-61-1]2-bromo-4-methylthiazol</strong>e</strong> (0.041 g, 0.23 mmol) in 1, -dioxane : H20 (4:1, 6 ml) were sequentially added sodium carbonate (50 mg, 0.50 mmol), 1,1'- bis (diphenylphosphino) ferrocene-palladium ( II ) dichloride (0707) dichloromethane complex (19 mg, 0.02 mmol) and methyl (3- methy1-2- ( ( 2 -methyl- 4 - (4,4,5, 5-tetramethyl-l , 3 , 2-dioxaborolan- 2-yl ) phenoxy ) methyl ) phenyl ) carbamate (0.10 g, 0.20 mmol) under nitrogen atmosphere. The reaction was stirred at 100C for 12h. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (3 x 20 mL) , dried over sodium sulfate and evaporated to dryness under reduced pressure. The crude compound was purified by column chromatography to afford methyl 2- ( ( 2 -methyl- 4 - ( 4 -methylthiazol-2-yl ) henoxy) methyl ) -3- methoxyphenylcarbamate as an off-white solid (49 mg, Yield: (0708) 53.4%) . (0709) 1ti NMR (CDCI3) : delta 7.77-7.74 (m, 3H) , 7.44 (bs, 1H) , 7.28 (t, J = 8.2 Hz 1H) , 7.02-6.98 (m, 2H) , 6.81 (d, J = 8.0 Hz 1H) , 5.13 (s, 2H) , 3.74 (s, 3H), 2.48 (s, 3H) , 2.41 (s, 3H) , 2.26 (s, 3H) .

Reference： [1]Patent: WO2018/138692,2018,A1 .Location in patent: Page/Page column 60

38
[ 7238-61-1 ]
1-(2-fluorophenyl)-N-(1H-pyrazol-3-yl)cyclopropane-1-carboxamide [ No CAS ]
1-(2-fluorophenyl)-N-(1-(4-methylthiazol-2-yl)-1H-pyrazol-3-yl)cyclopropane-1-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
8%	With copper(l) iodide; (1R,2R)-1,2-diaminocyclohexane; potassium carbonate; In 1-methyl-pyrrolidin-2-one; decane; at 130℃; for 16h;Sealed tube;	[394] 1-(2-fluorophenyl)-N-(1H-pyrazol-3-yl)cyclopropanecarboxamide (40 mg, 0.16 mmol, 1.0 eq), 2- bromo-4-methylthiazole (29 mg, 0.16 mmol, 1.0 eq), CuI (6.2 mg, 0.03 mmol, 0.2 eq), potassium carbonate (5.6 mg, 0.25 eq), (1R,2R)-cyclohexane-1,2-diamine (3.7 mg, 0.03 mmol, 0.2 eq), decane (13 muL, 0.07 mmol, 0.4 eq) and 1-methyl-pyrrolidin-2-one (3 mL) were combined in a sealed vial and heated to 130 C for 16 h. The reaction mixture was cooled to room temperature and partitioned between dichloromethane and saturated aqueous NH4Cl. The organic layer was collected and evaporated to dryness. The crude residue was purified by C18 preparatory HPLC (acetonitrile/water with TFA modifier). The material thus obtained was dissolved in dichloromethane and washed with saturated aqueous NaHCO3. The organics were separated and concentrated to provide 1-(2- fluorophenyl)-N-(1-(4-methylthiazol-2-yl)-1H-pyrazol-3-yl)cyclopropane-1-carboxamide (4.5 mg, 8% yield).

Reference： [1]Patent: WO2018/107056,2018,A1 .Location in patent: Paragraph 394

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[ 1511-62-2 ]
2-(difluoromethyl)-4-methylthiazole [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2018,vol. 57,p. 12543 - 12548
Angew. Chem.,2018,vol. 130,p. 12723 - 12728,6

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(R)-tert-butyl 4-(2-(1-(7-fluoro-2-oxo-6-sulfamoylbenzo[d]oxazol-3(2H)-yl)ethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate [ No CAS ]
(R)-tert-butyl 4-(2-(1-(7-fluoro-6-(N-(4-methylthiazol-2-yl)sulfamoyl)-2-oxobenzo[d]oxazol-3(2H)-yl)ethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate [ No CAS ]

Reference： [1]Patent: WO2018/205948,2018,A1 .Location in patent: Page/Page column 127; 128; 130

41
[ 7238-61-1 ]
(R)-tert-butyl 4-(2-(1-(4-fluoro-2-oxo-6-sulfamoylbenzo[d]oxazol-3(2H)-yl)ethyl)phenyl)-5,6-dihydropyridine-1 (2H)-carboxylate [ No CAS ]
(R)-tert-butyl 4-(2-(1-(4-fluoro-6-(N-(4-methylthiazol-2-yl)sulfamoyl)-2-oxobenzo[d]oxazol-3(2H)-yl)ethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate [ No CAS ]

Reference： [1]Patent: WO2018/205948,2018,A1 .Location in patent: Page/Page column 127; 128; 131

42
[ 7238-61-1 ]
[ 126747-14-6 ]
[ 145464-54-6 ]