[ CAS No. 464192-28-7 ] {[proInfo.proName]}

Name: 464192-28-7|2-Bromo-5-formylthiazole|98%
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Quality Control of [ 464192-28-7 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 464192-28-7 ]

CAS No. :	464192-28-7	MDL No. :	MFCD03788567
Formula :	C₄H₂BrNOS	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	DJUWIZUEHXRECB-UHFFFAOYSA-N
M.W :	192.03	Pubchem ID :	2773259
Synonyms :

Calculated chemistry of [ 464192-28-7 ]

Physicochemical Properties

Num. heavy atoms :	8
Num. arom. heavy atoms :	5
Fraction Csp3 :	0.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	35.2
TPSA :	58.2 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) :	-6.21 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.14
Log Po/w (XLOGP3) :	1.77
Log Po/w (WLOGP) :	1.72
Log Po/w (MLOGP) :	-0.1
Log Po/w (SILICOS-IT) :	3.0
Consensus Log Po/w :	1.5

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.54
Solubility :	0.551 mg/ml ; 0.00287 mol/l
Class :	Soluble
Log S (Ali) :	-2.61
Solubility :	0.471 mg/ml ; 0.00245 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.1
Solubility :	1.53 mg/ml ; 0.00798 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.42

Safety of [ 464192-28-7 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H317-H319	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 464192-28-7 ]

* 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 [ 464192-28-7 ]
Downstream synthetic route of [ 464192-28-7 ]

[ 464192-28-7 ] Synthesis Path-Upstream 1~8

1
[ 464192-28-7 ]
[ 1679-18-1 ]
[ 721920-84-9 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 24, p. 7216 - 7221

2
[ 464192-28-7 ]
[ 411235-57-9 ]
[ 877385-86-9 ]

Reference： [1] Journal of Medicinal Chemistry, 2017, vol. 60, # 1, p. 290 - 306

3
[ 687636-93-7 ]
[ 464192-28-7 ]

Yield	Reaction Conditions	Operation in experiment
61%	With manganese(IV) oxide In chloroform at 20℃; for 72 h;	MnO₂ (3.8 g, 37.10 mmol) was added to a solution of (2-bromothiazol-5-yl)methanol (1.44 g,7.42 mmol) in CHCl₃ (20 mL). The resulting mixture was stirred at RT for 3 days. Then the solution was filtered through celite and concentrated, yielding 2-bromothiazole-5-carbaldehyde(870 mg, 61 percent) as a white solid.¹H-NMR (400 MHz, CDCl₃): δ(ppm): 9.95 (s, 1 H), 8.16 (s, 1 H).¹³C-NMR (IOO MHz, CDCl₃): δ(ppm): 180.93, 150.47, 145.48, 142.91. <n="63"/>MS (ESI): m/z : 192.31 ([MH⁺]).

Reference： [1] Patent: WO2008/61795, 2008, A2, . Location in patent: Page/Page column 61-62

4
[ 1003-61-8 ]
[ 464192-28-7 ]

Reference： [1] Patent: WO2004/37818, 2004, A1, . Location in patent: Page 69
[2] Patent: US2011/190299, 2011, A1, . Location in patent: Page/Page column 20

5
[ 464192-28-7 ]
[ 687636-93-7 ]

Yield	Reaction Conditions	Operation in experiment
25%	Stage #1: at 0 - 20℃; for 4 h; Inert atmosphere Stage #2: With hydrogenchloride In waterInert atmosphere Stage #3: With sodium hydroxide In waterInert atmosphere	2-Bromothiazole-5-carbaldehyde (3.00 g, 15.62 mmol) and methanol (50 mL) were combined. The mixture was cooled to 0 °C under nitrogen and sodium borohydride (0.591 g, 15.62 mmol) was added portion wise. Stirring was continued at this temperature for 2 hours. The reaction was then warmed to room temperature and stirred for two additional hours. The solvent was concentrated and saturated aqueous NH₄C1 was added to the residue. The acidity was first adjusted to pH~6 using 1 M aqueous HC1 followed by adjusting the pH~10 by the addition of 1 M aqueous NaOH. The mixture was extracted with ethyl acetate. The organic layer was then washed with brine, dried with sodium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel eluting with ethyl acetate/hexane (10percent to 25percent) to give the title compound as a light yellow oil. MS (DCI+) m/z 194, 196 (M+H)⁺.

Reference： [1] Patent: WO2012/87833, 2012, A1, . Location in patent: Page/Page column 125-126
[2] Journal of Medicinal Chemistry, 2007, vol. 50, # 25, p. 6303 - 6306
[3] Patent: WO2004/37818, 2004, A1, . Location in patent: Page 69 - 70
[4] Patent: WO2007/75749, 2007, A2, . Location in patent: Page/Page column 25; 37-39
[5] Patent: WO2009/77990, 2009, A1, . Location in patent: Page/Page column 92
[6] Patent: US2006/293364, 2006, A1, . Location in patent: Page/Page column 23; 42
[7] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 9, p. 2721 - 2724

6
[ 464192-28-7 ]
[ 128796-39-4 ]
[ 447406-52-2 ]

Yield	Reaction Conditions	Operation in experiment
21%	With sodium carbonate In 1,4-dioxane; water for 20 h; Heating / reflux	A mixture of 2-bromo-5-formylthioazole (525 mg, 2.73 mmol), (4-trifluoromethyl)phenylboronic acid (519 mg, 2.73 mmol), tetrakis(triphenylphosphine)palladium(0) (95 mg, 0.082 mmol) and 2 N aqueous Na₂CO₃(5.5 mL, 10.94 mmol) were refluxed in dioxane (8 mL) for 20 h. It was cooled and partitioned between EtOAc and water. After separating layers, the organic phase was washed with water and brine. It was dried over Na₂SO₄and concentrated under reduced pressure. The crude product was purified by column chromatography eluting with EtOAc/Hexane. The title compound was obtained in yellow solids (145 mg, 21percent).

Reference： [1] Patent: US2007/244094, 2007, A1, . Location in patent: Page/Page column 51-52

7
[ 464192-28-7 ]
[ 1765-93-1 ]
[ 914348-80-4 ]

Yield	Reaction Conditions	Operation in experiment
88%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; sodium carbonate In ethanol; toluene at 85℃; for 6 h; Inert atmosphere	To a solution of 2-bromothiazole-5-carbaldehyde (5.0 g, 26.04 mmol) in toluene (150 mL) and ethanol (75 mL) was added (4-fluorophenyl)boronic acid (7.29 g, 52.08 mmol), 2M sodium carbonate solution (73.58 mL), Pd(PPh₃)₄ (1.5 g, 1.3 mmol) under argon atmosphere. The resulting mixture was heated at 85°C for 6 h. The reaction mixture was concentrated under reduced pressure, the residue was diluted with water (150 mL), and extracted with ethyl acetate (5 x 500 mL). The organic layer was dried over Na₂S0₄, filtered and concentrated under reduced pressures to obtain crude product. The crude product was purified by Combiflash® chromatography (Mobile phase: 10percent ethyl acetate in hexane) to give 2-(4- fluorophenyl)thiazole-5-carbaldehyde as off-white solid (200 mg, 88percent yield). IH NMR (400 MHz, DMSO-d₆): δ 10.06 (s, IH), 8.74 (s, IH), 8.14-8.11 (m, 2H), 7.39 (t, 2H); LC-MS m/z calculated for [M+H]⁺ 208.02, found 207.9

Reference： [1] Patent: WO2013/49559, 2013, A1, . Location in patent: Page/Page column 52

8
[ 464192-28-7 ]
[ 768-35-4 ]
[ 914348-84-8 ]

Yield	Reaction Conditions	Operation in experiment
54%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; sodium carbonate In ethanol; water; toluene at 120℃; for 4 h; Inert atmosphere	Step 1 : 2-(3-fluorophenyl)thiazole-5-carbaldehyde: To a solution of 2-bromothiazole-5-carbaldehyde (0.6 g , 3.125 mmol) in toluene (2 mL) and ethanol (1 mL) was added 4-fluorophenyl boronic acid (0.524 g, 3.75 mmol), 2 M solution of aq. a₂C0₃. The reaction mixture degassed with argon, tetrakis (0.180 g, 0.156 mmol) was added, the reaction mixture was again degassed with argon for 10 min, and heated to 120°C for 4 h. The reaction mixture was evaporated under vacuum to remove ethanol, the reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (50 mL) and dried over sodium sulphate, filtered and evaporated under reduced pressure to obtain crude product. The crude product was purified by Biotage Isolera® One chromatography (using 6percent ethyl acetate and hexane) to give 2-(3-fluorophenyl)thiazole-5-carbaldehyde (0.350 g, 54percent yield); ^XH NMR (400 MHz, DMSO-d₆): ? 8.78 (s, 1H), 7.90 (dd, 2H), 7.61 (q, 1H); 7.44 (t, 1H); LC-MS m/z calcd for [M+H]⁺ 208.02, found 208.0.

Reference： [1] Patent: WO2013/49565, 2013, A1, . Location in patent: Page/Page column 31

[ 464192-28-7 ] Synthesis Path-Downstream 1~70

1
[ 464192-28-7 ]
[ 128796-39-4 ]
[ 447406-52-2 ]

Yield	Reaction Conditions	Operation in experiment
21%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; for 20h;Heating / reflux;	A mixture of 2-bromo-5-formylthioazole (525 mg, 2.73 mmol), (4-trifluoromethyl)phenylboronic acid (519 mg, 2.73 mmol), tetrakis(triphenylphosphine)palladium(0) (95 mg, 0.082 mmol) and 2 N aqueous Na2CO3 (5.5 mL, 10.94 mmol) were refluxed in dioxane (8 mL) for 20 h. It was cooled and partitioned between EtOAc and water. After separating layers, the organic phase was washed with water and brine. It was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography eluting with EtOAc/Hexane. The title compound was obtained in yellow solids (145 mg, 21%).

Reference： [1]Angewandte Chemie - International Edition,2019,vol. 58,p. 12246 - 12251
Angew. Chem.,2019,vol. 131,p. 12374 - 12379,6
[2]Patent: US2007/244094,2007,A1 .Location in patent: Page/Page column 51-52

2
[ 637-81-0 ]
[ 464192-28-7 ]
[ 881888-41-1 ]

Yield	Reaction Conditions	Operation in experiment
45%	With potassium ethoxide; In ethanol; dichloromethane; N,N-dimethyl-formamide; at 0 - 20℃; for 18h;	2-Azido-3-(2-bromo-4-thiazolyl)propenoic acid ethyl ester Add slowly to a solution of potassium ethoxide (30 ml, 24% w:w, 3 eq. of EtOK) a slurry of 2-bromo-4-thiazolylcarboxyaldehyde (3.87 gm, 30 mol) and 2-azidoacetate ethyl ester (11.5 gm, 3 esq.) in a mixed solvent of ethanol (150 ml) DMF (5 ml) and methylene chloride (DCM, 20 ml) at 0 C. over 15-20 minutes. Stir the final mixture overnight (18 hr) at room temperature, quench the reaction with ammonium chloride and remove the ethanol (~50 ml) on a rotary evaporator. Extract the aqueous mixture with DCM (3*250 ml portions), wash the organic phase with brine and dry over MgSO4. Filter and concentrate the filtrate, and purify the crude mixture (12.2 gm) by flash chromatography [ISCO, SiO2, 120 gm cartridge, elute with methanol: DCM (0-5%)] to afford the title compound (3.6 gm, 45%). LCMS: retention time=3.68 min, (M+)=302.98

Reference： [1]Patent: US2007/299112,2007,A1 .Location in patent: Page/Page column 14

3
[ 110-85-0 ]
methyl 2-bromo-1,3-thiazole-5-carboxylate [ No CAS ]
[ 464192-28-7 ]
methyl 2-bromothiazole-5-caboxylate [ No CAS ]
[ 726185-68-8 ]

Yield	Reaction Conditions	Operation in experiment
79.8%	With potassium carbonate; In acetonitrile;	Method D To a solution of methyl 2-bromothiazole-5-carboxylate 1 (5.00 g, 22.50 mmol) in acetonitrile (50 ml) were added piperazine 6 (2.32 g, 26.97 mmol) and potassium carbonate (6.22 g, 45.05 mmol) under a N2 atmosphere. The reaction mixture was heated to reflux at 80 C. for 10 h. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using silica gel to give 2-piperazin-1-yl-thiazole-5-carboxylic acid methyl ester 7 as a solid (4.10 g, 79.8%). HPLC: 92% (Rt=3.883 min). 1H NMR (CDCl3, 200 MHz), delta: 7.88 (1H, s), 3.89 (3H, s), 3.55 (4H, t, J=6.0 Hz), 2.98 (4H, t, J=6.0 Hz). MS (m/z): 228 (M+1).

Reference： [1]Patent: US2005/250784,2005,A1

4
[ 464192-28-7 ]
[ 57260-71-6 ]
[ 354587-77-2 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In acetonitrile; at 80℃; for 16h;	A flask was charged with 2-bromo-5-formylthiazole (150 mg, 0.78 mmol, 1.00 equiv), ACN (40 ml), K2C03 (269 mg, 1.95 mmol, 2.50 equiv), and tert-butyl piperazine-l-carboxylate (174 mg, 0.94 mmol, 1.20 equiv). The reaction mixture was stirred at 80 C for 16 h. The resulting solution was cooled to room temperature and ACN was removed in vacuo. The crude mixture was dissolved in EtOAc (20 mL) and diluted with brine (10 mL satd. aq. NaCl). The solution was extracted with EtOAc (3 x 20 mL), dried over Na2S04, filtered through celite and concentrated to tert-butyl 4-(5-formylthiazol-2-yl)piperazine-l-carboxylate (83 mg, 36% crude) 1H NMR (400 MHz, Chloroform-i ) delta 9.71 (s, 1H), 7.86 (s, 1H), 3.82 - 3.42 (m, 8H), 1.48 (s, 9H).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 5995 - 5999
[2]Patent: WO2019/46318,2019,A1 .Location in patent: Paragraph 00192

5
[ 110-89-4 ]
[ 464192-28-7 ]
1-[(2-bromo-1,3-thiazol-5-yl)methyl]piperidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Intermediate 271 -[(2-bromo-1 ,3-thiazol-5-yl)methyl2-Bromo-5-formylthiazole (198 mg, 1 .034 mmol, available from Fluorochem) was mixed with acetic acid (0.148 mL, 2.58 mmol) and Piperidine (0.128 mL, 1.292 mmol), dissolved in Dichloromethane (DCM) (9.5 mL) and stirred under nitrogen for 30 minutes, sodium triacetoxyborohydride (41 1 mg, 1 .938 mmol) was added and the reaction was allowed to stir under nitrogen for 45 minutes. A second sample of sodium triacetoxyborohydride (41 1 mg, 1 .938 mmol) was added and the reaction was left to stir under nitrogen for 4.5 days. The reaction was loaded onto a 5g SCX-column, eluting with MeOH (40 mL) followed by 2M MeOH/NH3 (40 mL). Product-containing fractions were evaporated to dryness to give a yellow solid. This was partitoned between sodium bicarbonate (20 mL) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc (70 mL) and the organic fractions were combined, washed (brine (50 mL)), dried (sodium sulfate), filtered and evaporated to dryness to give a yellow solid (214 mg). This was purified on a 25+S Biotage silica column, eluting with DCM:2M MeOH/NH3 (1 :0 to 49:1 , 22CV). Product-containing fractions were evaporated to dryness to give a dark yellow solid (134 mg)LCMS (Method C): Rt = 0.47, MH+ = 263
		2-Bromo-5-formylthiazole (198 mg, 1.034 mmol, available from Fluorochem) was mixed with acetic acid (0.148 mL, 2.58 mmol) and Piperidine (0.128 mL, 1.292 mmol), dissolved in Dichloromethane (DCM) (9.5 mL) and stirred under nitrogen for 30 minutes. sodium triacetoxyborohydride (411 mg, 1.938 mmol) was added and the reaction was allowed to stir under nitrogen for 45 minutes. A second sample of sodium triacetoxyborohydride (411 mg, 1.938 mmol) was added and the reaction was left to stir under nitrogen for 4.5 days. The reaction was loaded onto a 5 g SCX-column, eluting with MeOH (40 mL) followed by 2M MeOH/NH3 (40 mL). Product-containing fractions were evaporated to dryness to give a yellow solid. This was partitioned between sodium bicarbonate (20 mL) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc (70 mL) and the organic fractions were combined, washed (brine (50 mL)), dried (sodium sulfate), filtered and evaporated to dryness to give a yellow solid (214 mg). This was purified on a 25+S Biotage silica column, eluting with DCM:2M MeOH/NH3 (1:0 to 49:1, 22 CV). Product-containing fractions were evaporated to dryness to give a dark yellow solid (134 mg)LCMS (Method C): Rt=0.47, MH+=263

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 5325 - 5329
[2]Patent: WO2011/54841,2011,A1 .Location in patent: Page/Page column 51
[3]Patent: US2012/208798,2012,A1 .Location in patent: Page/Page column 22

6
[ 464192-28-7 ]
[ 219735-99-6 ]
[ 960605-20-3 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 47; The mixture of <strong>[219735-99-6]2-chloro-4-methoxyphenyl boronic acid</strong> (372 mg), 2-bromo-5- formylthiazole(576 mg), sodium bicarbonate (6 mL, 1 M), dioxane (6 mL) and palladium tetrakistriphenylphosphine (30 mg) was heated at 1000C for 4 hours. The mixture was filtered through celite and diluted with ethyl acetate (100 mL) and washed with water (100 mL) followed by brine (50 mL). The organic fraction was dried with sodium sulfate and concentrated in vacuo to give the coupled product as a brown solid. To a solution of trimethyl phosphonoacetate (146 mg) in 5 mL of THF was added n-butyllithium (0.59 mL, 1.6 M in hexane) at O0C. The resulting solution was stirred at this temperature for 30 min. To this solution was added a THF solution (5 mL) of the above intermediate aldehyde (170 mg). The mixture was slowly warmed to rt and stirred for 2 hours. After quenching the mixture was water, the mixture was extracted with ethyl acetate, dried with sodium sulfate and concentrated in vacuo to give the enoate as a brown oily solid. To this enoate (83 mg) was added 5 mL of EPO <DP n="53"/>THF:MeOH:water (3:1:1) followed by LiOH (2 mL, 1 M). The mixture was stirred at rt for 5 hours. After acidified with concentrated HCl until pH = 4, the slurry was extracted with 30% isopropanol in chloroform, dried with sodium sulfate and concentrated in vacuo to give the enoic acid as a yellow solid. To this enoic acid (100 mg) was added toluene (5 mL) and thionyl chloride (2 mL). The mixture was heated to reflux for 1 hour and the solvent was distilled off under reduced pressure. The residue was taken up with toluene (5 mL) and to it was added anthranilic acid methyl ester (74 mg). The resulting mixture was heated to reflux for additional 1 hour. The solvent was removed and the residue was taken up with DMSO (6 mL). Only part of solid dissolved, the remaining solid was filtered and LC-MS showed it was mainly the desired compound, which was taken up with methanol (18 mL). To this mixture was added tosyl hydrazide (500 mg). The mixture was heated at reflux. After one day, an additional 300 mg of tosyl hydrazide was added. After two and a half days, the resulting mixture was concentrated and dissolved in acetone. The solution was directly purified by biotage (5%-25% ethyl acetate in petroleum ether) to give the anthranilide methyl ester as an oily solid. This methyl ester was dissolved in 5 mL of THF:MeOH: water (3:1:1) followed by LiOH (3 mL, 1 M). The mixture was stirred at rt for 4 hours. After Gilson purification, the acid was obtained as a white solid. To this methyl ether derivative was added 5 mL of dichloromethane and 0.23 mL of borontribromide (0.23 mL, IN in dichloromefhane) at O0C. After stirring at RT for 2h, the reaction was quenched by water at O0C. The mixture was concentrated in vacuo and then dissolved by DMSO. The DMSO solution was purified by Gilson to give Example 47 as a white solid. IH NMR (acetone-d6, 500 MHz) delta 11.42 (s, IH), 8.56 (d, IH), 8.07 (d, IH), 7.77 (d, IH), 7.70 (s, IH), 7.56 (t, IH), 7.15 (t, IH), 6.95 (d, IH), 6.84 (dd, IH), 3.34 (t, 2H), 2.88 (t, 2H); LCMS m/z 401 (M-I), 403 (M++l).

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 6303 - 6306
[2]Patent: WO2006/57922,2006,A2 .Location in patent: Page/Page column 51-52

7
[ 464192-28-7 ]
[ 687636-93-7 ]

Yield	Reaction Conditions	Operation in experiment
64%	With sodium tetrahydroborate; In methanol; at 0℃; for 5h;	Under N2 protection,The compound 2-bromothiazole-5-carbaldehyde (2.0 g, 10.5 mmol) was dissolved in anhydrous methanol (40 mL) and cooled to 0 C.Sodium borohydride (0.6 g, 15.7 mmol) was slowly added.The reaction was stirred at 0 C for 5.0 h.The reaction was quenched by adding distilled water (2 mL), and the reaction mixture was concentrated.The residue is separated by column chromatography (eluent:DCM/MeOH (v/v) = 100/1),1.3 g of a pale yellow solid were obtained in a yield: 64%.
25%		2-Bromothiazole-5-carbaldehyde (3.00 g, 15.62 mmol) and methanol (50 mL) were combined. The mixture was cooled to 0 C under nitrogen and sodium borohydride (0.591 g, 15.62 mmol) was added portion wise. Stirring was continued at this temperature for 2 hours. The reaction was then warmed to room temperature and stirred for two additional hours. The solvent was concentrated and saturated aqueous NH4C1 was added to the residue. The acidity was first adjusted to pH~6 using 1 M aqueous HC1 followed by adjusting the pH~10 by the addition of 1 M aqueous NaOH. The mixture was extracted with ethyl acetate. The organic layer was then washed with brine, dried with sodium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel eluting with ethyl acetate/hexane (10% to 25%) to give the title compound as a light yellow oil. MS (DCI+) m/z 194, 196 (M+H)+.
	With sodium tetrahydroborate; In methanol; at 10 - 20℃; for 3.25h;	Intermediate 103 (16.34 g, 0.086 mol) was dissolved in methanol (300 mL) and cooled to 10C. Sodium borohydride (1.63 g, 0.043 mol) was added portionwise over 15 min. The cooling bath was removed and the reaction allowed to warm to room temperature and stirred for 3 hours. The solvent was evaporated. Water (100 mL) was added followed by 1N HCI (200 mL). Ethyl acetate (450 mL) was added and the phases were separated. The organic layer was washed with brine (450 mL), dried (MgS04) and concentrated to give a brown liquid. The crude product was purified by chromatography on silica, using cyclohexane-ethyl acetate (80: 20 v/v) as eluent to give the title compound. 'H NMR (CDCI3) : 8 7.4 (1H, s), 4.82 (2H, d), 2.96 (1H, t)

		EXAMPLE 4; Commercially available 2-bromo-5-formylthiazole (5 g, 26 mmol) in tetrahydrofuran (50 mL) was cooled to 0 0C. To this solution was added portionwise, sodium <n="39"/>borohydride (1.23 g, 32 mmol), and the reaction mixture was stirred for 1 h at 0 0C, and then allowed to warm to room temperature and stirred for another hour. Upon reaction completion, water (100 ml) was added and the mixture was allowed to stir for 30 minutes. The reaction mixture was concentrated in vacuo and purified via flash chromatography (Biotage 40M). To the corresponding thiazole-alcohol (3.87 g, 20 mmol) in CH2Cl2 (10OmL) at 0 0C was added carbon tetrabromide (13.2 g, 40 mmol) and triphenylphosphine (10 g, 40 mmol). The reaction mixture was allowed to stir at room temperature for 1 h. The mixture was concentrated in vacuo and purified via flash chromatography (Biotage 40 M). To a pre-cooled (0 0C) solution containing commercially available ethyl N-(diphenylmethylene) glycinate (2.87 g, 10.7 mmol) in tetrahydrofuran (18 mL), was added potassium tert-butoxide (1.2 g, 10.7 mmol) in tetrahydrofuran (25 mL). The reaction mixture was stirred at this temperature for 30 minutes and cooled to -78 0C. To this pre-cooled (-780C ) solution was added the thiazolyl bromide (1.83g, 7.1 mmol) in tetrahydrofuran (8 mL). The reaction mixture was stirred at this temperature for 30 minutes, and then allowed to stir at room temperature for 1 h. A saturated solution of ammonium chloride (40 mL) was then added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The organic layers were combined, dried over sodium sulfate, concentrated in vacuo, and purified by flash chromatography (Biotage 40M). To the corresponding Schiff base (3.17 g, 7.1 mmol) was added concentrated hydrochloric acid (9 mL), and the reaction mixture was allowed to stir for 1 h at room temperature. Following the completion of the reaction, the aqueous layer was washed 3 times with ethyl acetate (2OmL), and the aqueous layer was concentrated in vacuo. Without further purification, the amine (1.99g, 7.16 mmol) in CH2Cl2 (100 mL) was treated with triethylamine ( 2.89g, 29 mmol) and di- tert-butyl dicarbonate (3.1g, 14.3 mmol). The reaction mixture was stirred for 12 h at room temperature. Upon reaction completion, a saturated solution of sodium bicarbonate (100 mL) was added, and the mixture was allowed to stir for 30 minutes. The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (2 x 50 mL). The organic layers were combined, dried over sodium sulfate, concentrated in vacuo, and purified by flash chromatography (Biotage 40 M). To the amino acid (0.82g, 2.1 mmol) in toluene (20 mL) was added (2- chloro-4-methoxyphenyl)boronic acid ( 0.81 g, 4.3 mmol), tetrakis-triphenylphosphine palladium (0.12 g, 0.1 mmol), and potassium carbonate (0.89 g, 6.4 mmol). The reaction mixture was heated to 100 0C for 12 h. Following the reaction completion, the mixture was concentrated in vacuo and purified via flash chromatography (Biotage 40M). To the desired amino acid (0.57g, 1.3 mmol) in tetrahydrofuran (6 mL) was added water (6 mL), methanol (1 mL), and lithium hydroxide (0.12 g, 5.2 mmol). The biphasic reaction mixture was allowed to stir at room temperature for 12 h. The mixture was concentrated in vacuo, diluted with 10 mL of water, cooled to 0 0C and acidified with concentrated HCl to a pH of 3. The acidic solution was extracted three times with ethyl acetate (10 mL), and the organic extracts were dried with sodium sulfate and concentrated in vacuo. Without further purification, the carboxylic acid (0.14 g, 0.33 mmol) in tetrahydrofuran (5 mL) at -20 0C was treated with 4-methylmorpholine (0.067 g, 0.67 mmol), followed by the dropwise addition of isobutyl chloroformate (0.045 g, 0.33 mol). The reaction mixture was stirred for 10 minutes, followed by the <n="40"/>addition of ethyl-2-aminobenzoate (0.11 g, 0.67 mmol). The mixture was stirred at -20 0C for 2 h and then room temperature for 12 h. Following the reaction completion, the precipitate was filtered off and the filtrate was concentrated in vacuo and purified via flash chromatography (Biotage 40S). To the purified anthranilic acid derivative (18 mg, 33 mmol) in CH2Cl2 (3 xnL) at 0 0C, was added borontribromide (IM, 0.33 mmol). The mixture was allowed to stir at 0 0C for 10 minutes and then room temperature for 1 h. Following the reaction completion, water (10 mL) was added, and the Triphasic mixture was stirred for 10 minutes. The reaction mixture was then concentrated in vacuo, diluted with 10 mL of water, cooled to 0 0C and basified with sodium hydroxide to a pH of 14. The basic reaction mixture was allowed to stir for 12 h at room temperature. The mixture was concentrated in vacuo and then diluted with water (2 mL). The aqueous solution was acidified with concentrated hydrochloric acid (pH= 3) and then purified by reverse phase HPLC (Gilson) to provide the de...
	With sodium tetrahydroborate; In methanol; at 0 - 25℃;Inert atmosphere;	In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), commercially available 2-bromo-thiazole-5-carbaldehyde (2.100 g, 10.94 mmol) was dissolved in MeOH (50 ml_). NaBH4 (535 mg, 13.58 mmol) was added portionwise at 0 0C and the reaction mixture stirred at rt for 1 h. Water (50 ml.) was added and the mixture extracted with EA (3 x 50 ml_). The combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a yellow solid. TLC: rf (1 :1 hept-EA) = 0.31. LC-MS-conditions 01 : tR = 0.56 min; [M+AcCN+H]+ = 234.84.
		To the commercially available thiazole bromo aldehyde (4.97 g) shown in Scheme 10, in 200 mL of methanol was added NaBH4 (0.98 g) in portions at 0 C. The mixture was stirred for 2 h and concentrated. The residue was suspended in saturated NH4Cl solution (200 mL) to adjust the pH to 6. The mixture was then basified by NaOH (aq) to pH 11 before the extraction with ethyl acetate (4×200 mL). The combined organic fractions were dried with sodium sulfate and concentrated to give the alcohol.

Reference： [1]Patent: CN104744446,2019,B .Location in patent: Paragraph 1729; 1743-1745
[2]Patent: WO2012/87833,2012,A1 .Location in patent: Page/Page column 125-126
[3]Journal of Medicinal Chemistry,2007,vol. 50,p. 6303 - 6306
[4]Patent: WO2004/37818,2004,A1 .Location in patent: Page 69 - 70
[5]Patent: WO2007/75749,2007,A2 .Location in patent: Page/Page column 25; 37-39
[6]Patent: WO2009/77990,2009,A1 .Location in patent: Page/Page column 92
[7]Patent: US2006/293364,2006,A1 .Location in patent: Page/Page column 23; 42
[8]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 2721 - 2724

8
[ 1003-61-8 ]
[ 464192-28-7 ]

Yield	Reaction Conditions	Operation in experiment
69.13%	With tert.-butylnitrite; copper(I) bromide; In acetonitrile; at 25℃; for 5h;Inert atmosphere;	Under N2 protection,250mLIn a two-necked flask, tert-butyl nitrite (4.8 g, 47 mmol) and copper bromide (8.2 g, 40 mmol) and anhydrous acetonitrile (180 mL) were added, and the mixture was stirred at 25 C for 0.5 h.The compound <strong>[1003-61-8]2-aminothiazole-5-carbaldehyde</strong> (4.0 g, 31 mmol) was dissolved in anhydrous acetonitrile (30 mL) and slowly added dropwise to the above solution.The reaction was stirred at 25 C for 12.0 h. concentrate,Add ethyl acetate (200 mL),The organic layer was washed once with saturated brine (60 mL).Dry anhydrous sodium sulfate (20g), concentrated,4.12 g of a red solid were obtained in a yield: 69.13%.
	With tert.-butylnitrite; copper(ll) bromide; In acetonitrile; at 20℃; for 4h;	2-Amino-1, 3-THIAZOLE-5-CARBOXALDEHYDE (13.78 g, 0.108 mol, 1 eq) in acetonitrile (200 mL) (SLURRY) was added portionwise to a stirred suspension of CuBr2 (36.03 g, 0.129 mol) and t-butyl nitrite (19 mL, 0.161 mL) in acetonitrile (550 mL). The reaction was stirred at room temperature for 4 hours then evaporated to give a solid. This was treated with ethyl acetate (400 mL) and 2M HCI (400 mL). Water (200 mL), brine (100 mL) and ethyl acetate (200 mL) were added. The phases were separated. The aqueous phase was extracted with ethyl acetate (250 mL). The combined organic layers were dried (MGS04) and evaporated to give the title compound. 'H NMR (CDCI3) : 8 9.97 (1H, s), 8.19 (1H, s)
		Compounds 85 and 86 were synthesized by using the materials that have a substituent corresponding to these compounds, according to the following production scheme.

Reference： [1]Patent: CN104744446,2019,B .Location in patent: Paragraph 1729; 1741-1742
[2]Patent: WO2004/37818,2004,A1 .Location in patent: Page 69
[3]Patent: US2011/190299,2011,A1 .Location in patent: Page/Page column 20

9
[ 464192-28-7 ]
[ 860625-20-3 ]
[ 1201411-17-7 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;tetrakis(triphenylphosphine)palladium (0); In 1,4-dioxane; water;	Example 249 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-(1-pyrrolidinylmethyl)-1,3-thiazol-2-yl]-1H-indole-7-carboxamide trifluoroacetate To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide (500 mg, 1.1 mmol) in dioxane (12 mL) and H2O (4 mL) was added <strong>[464192-28-7]2-bromo-1,3-thiazole-5-carbaldehyde</strong> (634 mg, 3.3 mmol), potassium carbonate (898 mg, 8.8 mmol) and tetrakis(triphenylphosphine)palladium(0) (210 mg, 0.181 mmol). Reaction was run in the microwave at 150 C. for 20 min. Aqueous work-up performed to give crude product. The reaction was then repeated in the microwave at 150 C. for 30 min to give 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-1,3-thiazol-2-yl)-1H-indole-7-carboxamide.
	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 150℃; for 0.833333h;Microwave irradiation;	Example 249: 3-ri-(ethylsulfonyl)-4-piperidinyl1-545-(l-pyrrolidinylmethyl)-1 ,3- thiazol-2-yll-1 H-indole-7-carboxamide trifluoroacetate;To a solution of 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 /-/-indole-7-carboxamide (500 mg, 1.1 mmol) in dioxane (12 ml_) and H2O (4 ml_) was added 2-bromo-1 ,3-thiazole-5-carbaldehyde (634 mg, 3.3 mmol), potassium carbonate (898 mg, 8.8 mmol) and tetrakis(triphenylphosphine)palladium(0) (210 mg, 0.181 mmol). Reaction was run in the microwave at 150 C for 20 min. Aqueous work-up performed to give crude product. The reaction was then repeated in the microwave at 150 C for 30 min to give 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl- 1 ,3-thiazol-2-yl)-1 /-/-indole-7-carboxamide.

Reference： [1]Patent: US2009/143372,2009,A1
[2]Patent: WO2007/5534,2007,A2 .Location in patent: Page/Page column 235

10
[ 464192-28-7 ]
[ 81290-20-2 ]
[ 929028-45-5 ]

Yield	Reaction Conditions	Operation in experiment
48%	With cesium fluoride; In 1,2-dimethoxyethane; at 20℃; for 2h;	A solution (0.52 M) of 2-bromo-5-formylthiazole and CsF (0.2 eq.) in DME was treated with TMSCF3(2.0 eq.) and the resulting solution was stirred at RT for 2 h. Then, the reaction mixture was quenched with water and stirred at RT for 15 min. The aqueous solution was extracted with EtOAc several times and the combined organic layers were dried and concentrated to give a residue that was purified by flash chromatography on silica gel (petroleum ether/EtOAc 20: 1 to 3: 1) to yield (48%) the title compound as a yellow solid.1H NMR (300 MHz, CDCl3, 300K) delta 4.04 (d, J= 5.9 Hz, IH), 5.32 (m, IH), 7.59 (s, IH); MS (ES+)C5H3BrF3NOS requires: 261, 263, found: 262, 264 (M+H)+.
		EXAMPLE 9; 2.2.2-Trinuoro-l-r2-(2-naphthvn-1.3-thiazol-5-yllethanone alpha3) StepJj_l-(2-Bromo-l,3-thiazol-5-yl)-2,2,2-trifluoroethanol (Il)A solution (0.52 M) of 2-bromo-5-formylthiazole (1.0 eq.) and CsF (0.2 eq.) in DME was treated with CF3SiMe3 (2.0 eq.) and then stirred for 2 h at RT. The reaction mixture was quenched by adding water and stirred for 15 min. Then, it was diluted with EtOAc and the organic phase was separated. The aqueous phase was extracted twice with EtOAc. The combined organic phase was dried (Na2SO4) and solvents were removed under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 5-25% EtOAc/petroleum ether to afford the title compound as a yellow solid. 1H NMR (300 MHz, CDCl3, 300K) delta 4.04 (IH, d, J = 5.9 Hz), 5.32 (IH, dq, J = 5.9 Hz, J = 5.9 Hz), 7.59 (IH, s). MS (ES+) C5H3BrF3NOS requires: 261/263, found: 262/264 (M+H)+

Reference： [1]Patent: WO2007/29035,2007,A2 .Location in patent: Page/Page column 57; 73-74
[2]Patent: WO2007/93827,2007,A1 .Location in patent: Page/Page column 49

11
[ 464192-28-7 ]
[ 941572-43-6 ]
[ 941572-44-7 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 150℃; for 0.0833333h;Microwave irradiation;	D15 (250mg, 0.95mmol), sodium carbonate (401 mg, 3.79mmol), 2-bromo-1 ,3- thiazole-5-carboxaldehyde (182mg, 0.95mmol) and tefra/wstriphenylphosphine Pd(O) <n="30"/>(55mg, 0.047mmol) in 1 :1 aqueous 1 ,2-dimethoxyethane (4ml) was heated in a microwave reactor at 15O0C for 5min and the solvent was then removed in vacuo. The residue was partitioned between water and DCM and the organic phase was dried and concentrated to give the crude product as an oil which was purified on silica (0-100% diethyl ether/pet, ether gradient) to give the title compound as a yellow solid (85mg). deltaH (CDCI3) 1.96 (4H1 m), 3.28 (4H, m), 4.00 (4H, s), 7.13 (1 H1 m), 8.42 (1 H, dd), 8.44 (1 H, s), 8.48 (1 H1 dd), 10.10 (1 H, s). MS (ES): MH+ 332.

Reference： [1]Patent: WO2007/65669,2007,A1 .Location in patent: Page/Page column 28

12
[ 96-50-4 ]
[ 464192-28-7 ]
[ 1029087-76-0 ]

Yield	Reaction Conditions	Operation in experiment
51%		A solution of <strong>[464192-28-7]2-bromothiazole-5-carbaldehyde</strong> (150 mg, 0.78 mmol) and 2-amino-thiazole (78 mg, 0.78 mmol) in toluene (7 mL) and 3A molecules sieves were stirred at reflux overnight. The strong yellow solution of the corresponding imine was then poured over NaBH4 (147 mg, 3.9 mmol) in hot EtOH (50 mL). The colorless solution was filtered, concentrated and purified by column chromatography (30% AcOEt/PE) yielding iV-((2-bromothiazol-5-yl)methyl)thiazol- 2-amine (110 mg, 51%) as a solid.1H-NMR (400 MHz, CD3OD/CDC13): delta(ppm): 7.33 (s, IH) 6.95 (d, J= 3.7 Hz, IH), 6.40 (d, J = 3.7 Hz, IH), 4.49 (s, 2H), 2.9 (bs, IH).13C-NMR (100 MHz, CD3OD/CDC13): delta(ppm): 169.00, 140.64, 139.95, 138.38, 136.27,107.53, 41.29.MS (ESI): m/z : 276.30 ([MH+]).

Reference： [1]Patent: WO2008/61795,2008,A2 .Location in patent: Page/Page column 61-62

13
[ 687636-93-7 ]
[ 464192-28-7 ]

Yield	Reaction Conditions	Operation in experiment
91%	With Dess-Martin periodane; In dichloromethane; at 0 - 20℃; for 2h;	Into a 500-mL round-bottom flask, was placed <strong>[687636-93-7](2-bromothiazol-5-yl)methanol</strong> (20 g, 103 mmol), DCM (200 mL). This was followed by the addition of Dess-Martin reagent (46 g, 103 mmol) in portions at 0C. The resulting solution was stirred for 2 h at RT and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:20 to 1:10). This resulted in 18 g (91%) of the title compound as awhite solid. MS-ESI: 193.9, 191.9 (M+1).
61%	With manganese(IV) oxide; In chloroform; at 20℃; for 72h;	MnO2 (3.8 g, 37.10 mmol) was added to a solution of <strong>[687636-93-7](2-bromothiazol-5-yl)methanol</strong> (1.44 g,7.42 mmol) in CHCl3 (20 mL). The resulting mixture was stirred at RT for 3 days. Then the solution was filtered through celite and concentrated, yielding 2-bromothiazole-5-carbaldehyde(870 mg, 61 %) as a white solid.1H-NMR (400 MHz, CDCl3): delta(ppm): 9.95 (s, 1 H), 8.16 (s, 1 H).13C-NMR (IOO MHz, CDCl3): delta(ppm): 180.93, 150.47, 145.48, 142.91. <n="63"/>MS (ESI): m/z : 192.31 ([MH+]).

Reference： [1]Patent: WO2019/79119,2019,A1 .Location in patent: Page/Page column 462
[2]Patent: WO2008/61795,2008,A2 .Location in patent: Page/Page column 61-62

14
[ 464192-28-7 ]
[ 90965-06-3 ]
[ 1076224-13-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 5209 - 5212

15
[ 464192-28-7 ]
[ 959616-35-4 ]
[ 1173896-21-3 ]

Yield	Reaction Conditions	Operation in experiment
55%		To a solution of Intermediate 29 (210 mg) in 1,2-dichloroethane (8 ml) was added <strong>[464192-28-7]2-bromo-1,3-thiazole-5-carbaldehyde</strong> (80 mg, from COMBI-BLOCKS). After stirring for a few minutes, sodium triacetoxyborohydride (278 mg) was added. The reaction was stirred at room temperature overnight and more NaBH(OAc)3 was added in several portions until starting material was not detected by LCMS. The solvent was removed to dryness under vacuum and the residue was dissolved in CH2Cl2. The mixture was washed with saturated NaHCO3, brine, dried over Na2SO4, and concentrated under vacuum. The residue obtained was purified by column chromatography on silica gel using CH2Cl2/MeOH 9:1 as eluent to give 110 mg (55%) of the title compound. 1H-NMR (delta, ppm, CDCl3): 8.28 (d, 1 H), 7.84 (d, 1 H), 7.38 (s, 1 H), 7.20 (s, 1 H), 6.74 (d, 1 H), 4.36 (t, 2H), 3.99 (bd, 2H), 3.98 (s, 3H), 2.97 (bd, 2H), 2.65 (t, 2H), 2.60-2.48 (m, 1 H), 2.19 (bt, 2H), 1.89 (bd, 2H), 1.47-1.30 (m, 2H). [ES MS] m/z 478 (MH+).

Reference： [1]Patent: EP2080761,2009,A1 .Location in patent: Page/Page column 43

16
[ 464192-28-7 ]
[ 75-24-1 ]
[ 875548-59-7 ]

Yield	Reaction Conditions	Operation in experiment
	In n-heptane; dichloromethane; at 0℃;Inert atmosphere;	In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of commercially available <strong>[464192-28-7]2-bromo-thiazole-5-carbaldehyde</strong> (1.80 g, 9.37 mmol) in CH2CI2 (70.0 mL) was treated at 0 0C with trimethylaluminum (46.0 mL of a 1 M solution in heptane, 46 mmol). The reaction mixture was then stirred at 0 0C <n="99"/>for 45 min. CH2CI2 (100.0 ml.) followed by sat. aq. NH4CI (100 ml.) was then added. The mixture was then treated with 1 N HCI (50 ml.) and the aq. layer was extracted with CH2CI2 (150 ml_). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a yellow oil. TLC: rf (1 :2 hept-EA) = 0.40. LC-MS-conditions 02: tR = 0.70 min; [M+AcCN+H]+ = 249.17.

Reference： [1]Patent: WO2009/77990,2009,A1 .Location in patent: Page/Page column 97-98

17
[ 464192-28-7 ]
[ 74-89-5 ]
C₅H₅BrN₂S [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 1287 - 1291

18
[ 464192-28-7 ]
[ 2386-64-3 ]
[ 1194056-21-7 ]

Yield	Reaction Conditions	Operation in experiment
42%		2-Bromo-thiazole-5-carbaldehyde (1.00 g, 5.21 mmol) was dissolved in THF (10 ml). A solution of ethylmagnesium bromide (3 M in diethylether, 5.00 mL, 15.0 mmol) was added. The mixture was stirred for 18 h. The reaction was poured into sat. ammonium chloride solution/ice (100 mL) and diluted with ethyl acetate (100 ml). The organic phase was separated, washed with sodium bicarbonate solution (100 mL), dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography eluting with a gradient of 0-100% ethyl acetate in hexanes provided l-(2-bromo-thiazol-5-yl)-propan-l- ol (480 mg, 42%). Unreacted 2-Bromo-thiazole-5-carbaldehyde (465 mg, 46%) was also obtained.

Reference： [1]Patent: WO2009/137338,2009,A1 .Location in patent: Page/Page column 79

19
[ 464192-28-7 ]
[ 925-90-6 ]
[ 1194056-21-7 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; diethyl ether; for 18h;	To a solution of <strong>[464192-28-7]2-bromo-thiazole-5-carbaldehyde</strong> (1.00 g, 5.21 mmol) in THF (10 niL) was added a 3 M solution of ethylmagnesium bromide (5.00 rnL, 15.0 mmol) in diethyl ether. The mixture was stirred for 18 hours. The reaction was poured into saturated aqueous ammonium chloride (100 mL) containing crushed ice and diluted with EtOAc (100 mL). The organic phase was separated, washed with saturated aqueous sodium bicarbonate solution (100 mL), dried over sodium sulfate, filtered and concentrated. The compound was purified by silica gel chromatography eluting with a gradient of 0-100% ethyl acetate in hexanes provided l-(2-bromo-thiazol-5-yl)-propan-l-ol.
		Example 11: Synthesis of (5)-l-(2-Methanesulfonyl-thiazol-5-yl)-propylamine hydrochloride (11); To a solution of 2-bromo-thiazole-5-carboxaldehyde (1.00 g, 5.21 mmol) in THF (10 mL) is added a 3 M solution of ethylmagnesium bromide (5.00 mL, 15.0 mmol) in diethyl ether. After 18 hours, the reaction is poured into saturated aqueous ammonium chloride (100 mL) containing crushed ice and diluted with EtOAc (100 mL). The organic phase is separated, washed with saturated aqueous sodium bicarbonate solution (100 mL), dried over sodium sulfate, filtered and concentrated. The compound is purified by silica gel chromatography eluting using a gradient of 0- 100% EtOAc in hexanes to provide l-(2-bromo-thiazol-5-yl)-propan-l-ol.

Reference： [1]Patent: WO2010/36632,2010,A1 .Location in patent: Page/Page column 186
[2]Patent: WO2011/56440,2011,A1 .Location in patent: Page/Page column 50

20
[ 123-75-1 ]
[ 464192-28-7 ]
[ 1242446-37-2 ]

Yield	Reaction Conditions	Operation in experiment
37%	With sodium cyanoborohydride; acetic acid; In methanol; at 20℃; for 1.5h;	To a solution of <strong>[464192-28-7]2-bromothiazole-5-carbaldehyde</strong> (37; 3.0 g, 15.6 mmol), pyrrolidine (1.77 g, 24.9 mmol) and acetic acid (1.5 g, 24.9 mmol) in MeOH (60 mL) was added NaCNBH3 (1.56 g, 24.9 mmol) in portions over 30 min at room temperature, then stirred for 1 h. Ethyl acetate (100 mL) was added and the mixture was washed with water, dried over MgSO4, and concentrated. The residue was purified by silica gel column (petroleum ether: ethyl acetate 3:1) to afford 2-bromo- 5-(pyrrolidin-l-ylmethyl)thiazole 38 as a yellow oil (870 mg , 37%). MS calcd for C8HnBrN2S: 247.2; found: 248 [M+l].

Reference： [1]Patent: WO2010/101949,2010,A1 .Location in patent: Page/Page column 121

21
[ 464192-28-7 ]
[ 822-36-6 ]
[ 1231192-09-8 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 1h;	5-ethynyl-2-(4-methyl-1H-imidazol-1-yl)-1,3-thiazole. A mixture of 2-bromo-1,3-uuazole-5-carbaldehyde (10 mg, 0.068 mmol), 4-methyl-1H-imidazole (7.23 mg,0.088mmol), potassium carbonate (28.1 mg, 0.203 mmol) and DMF (5 ml) were heated at 1100C for 1h. The mixture was purified on silica gel (EtOAc/hexane 8:2) to afford 2-(4-methyl-1H-imidazol-1-yl)-1,3-thiazole-5-carbaldehyde (38.4 mg, 0.199 mmol) as a yellow solid. This aldehyde (38.4 mg, 0.199 mmol) and anhydrous potassium carbonate (110 mg, 0.795 mmol) were placed in a 25-ml flask and placed on high vacuum for 10 min. Under N2, anhydrous MeOH (2 ml) was added. To the suspension was added dimethyl (1-diazo-2- oxopropyl) phosphonate (40 mul, 0.256 mmol). The reaction was stirred at rt for 22 h. The mixture was diluted with DCM, washed with water, dried over sodium sulfate, concentrated to afford crude product, which was used in next step directly. MS calc'd 190.0 (MH+), exp 190.0 (MH+).

Reference： [1]Patent: WO2010/71741,2010,A1 .Location in patent: Page/Page column 30; 31

22
[ 464192-28-7 ]
[ 191162-40-0 ]
[ 1248681-42-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 20℃;Inert atmosphere;	Production Example 1; 2-( 1 -Methyl- lH-indol-2-yl)- 1 ,3-thiazole-5-carbaldehyde; A dimethoxyethane solution (15 mL) of commercially available ( 1 -methyl- lH-indol- 2-yl)boronic acid (328 mg), commercially available 2-bromo-l,3-thiazole-5-carbaldehyde (300 mg), tetrakis(triphenylphosphine)palladium(0) (181 mg), and 1 M sodium carbonate aqueous solution (4.7 mL) was stirred overnight at room temperature in a nitrogen atmosphere. The dimethoxyethane was distilled off under reduced pressure, and the resulting residue was extracted with chloroform, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 3:2) to give the title compound (160 mg) as a pale yellow solid.
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 20℃;Inert atmosphere;	A dimethoxyethane solution (15 mL) of commercially available (1-methyl-1H-indol-2-yl)boronic acid (328 mg), commercially available <strong>[464192-28-7]2-bromo-1,3-thiazole-5-carbaldehyde</strong> (300 mg), tetrakis(triphenylphosphine)palladium(0) (181 mg), and 1 M sodium carbonate aqueous solution (4.7 mL) was stirred overnight at room temperature in a nitrogen atmosphere. The dimethoxyethane was distilled off under reduced pressure, and the resulting residue was extracted with chloroform, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:2) to give the title compound (160 mg) as a pale yellow solid.

Reference： [1]Patent: WO2010/117085,2010,A1 .Location in patent: Page/Page column 19
[2]Patent: US2012/22078,2012,A1 .Location in patent: Page/Page column 10

23
[ 464192-28-7 ]
[ 3462-97-3 ]
[ 936845-76-0 ]
[ 936845-77-1 ]

Yield	Reaction Conditions	Operation in experiment
30%; 19%		To a solution of (4-methoxy-benzyl)-triphenyl-phosphonium chloride (1.8 g, 4.0 mmol) in anhydrous DMF (30 mL) was added 'BuOK (0.68 g, 6.0 mmol). The solution was stirred for 30 min before adding solution of <strong>[464192-28-7]2-bromothiazole-5-carbaldehyde</strong> (0.69 g, 3.6 mmol) in DMF (10 niL). The mixture was stirred overnight. The solvent was removed in vacuo and the residue was suspended in EtOAc (100 mL) and washed with brine (2 x 50 mL). The aqueous was extracted with EtOAc (2 x 50 mL). The combined organic phase was dried (Na2SO4) and concentrated. The residue was purified by flash column (SiO2/5% hexanes in EtOAc) to afford the title intermediate with cis (320 mg, 30%) and trans (200 mg, 19%) isomers.[0093] 1H NMR (500 MHz, DMSO-d6) (cis): d 3.79 (s, 3H), 6.75 (d, J= 6.5 Hz, 2H), 6.98 (d, J= 8.7 Hz, 2H), 7.21 (d, J= 8.7 Hz, 2H), 7.70 (s, IH). 1H NMR (500 MHz, DMSO-d6) (trans): d 3.32 (s, 3H), 6.93 (d, J= 16.3 Hz, IH), 6.95 (d, J= 8.7 Hz, 2H), 7.30 (d, J= 16.3 Hz, IH), 7.52 (d, J= 8.7 Hz, 2H), 7.68 (s, IH).

Reference： [1]Patent: WO2007/56023,2007,A2 .Location in patent: Page/Page column 34-35

24
[ 464192-28-7 ]
[ 2767-70-6 ]
2-bromo-5-[2-(4-nitro-phenyl)-vinyl]-thiazole [ No CAS ]
2-bromo-5-[2-(4-nitro-phenyl)-vinyl]-thiazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of (4-nitro-benzyl)-triphenyl-phosphonium bromide (1.6 g, 3.4 mmol) in anhydrous DMF (20 mL) was added 'BuOK (0.40 g, 3.6 mmol). The solution was stirred for 30 min before adding solution of <strong>[464192-28-7]2-bromo-thiazole-5-carbaldehyde</strong> (0.50 g, 2.6 mmol) in DMF (10 mL). The mixture was stirred overnight and poured into water. The mixture was extracted with EtOAc (2 x 40 mL) and the combined organic extracts washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the residue purified by flash column on silica gel (hexanes to 15% EtOAc/hexanes) to afford title intermediate as a mixture of cis/trans isomers (0.25 g, 31%).

Reference： [1]Patent: WO2007/56023,2007,A2 .Location in patent: Page/Page column 64

25
[ 464192-28-7 ]
[ 72311-12-7 ]
5-(3-methoxystyryl)-2-bromothiazole [ No CAS ]
5-(3-methoxystyryl)-2-bromothiazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of (3-methoxy-benzyl)-triphenyl-phosphonium bromide (2.0 g, 4.8 mmol) in anhydrous DMF (30 mL) was added (Bu0K (0.77 g, 6.9 mmol). The solution was stirred for 30 min before adding solution of <strong>[464192-28-7]2-bromothiazole-5-carbaldehyde</strong> (0.77 g, 4.0 mmol) in DMF (10 mL). The mixture was stirred overnight. The solvent was removed in vacuo and the residue suspended in EtOAc (100 mL) and washed with brine (2 x 50 mL). The aqueous was extracted with EtOAc (2 x 50 mL). The combined organic phase was dried (Na2SO4) and concentrated. The residue was purified by flash column (SiO2/40% hexanes in EtOAc) to afford the title intermediate (1.2 g, 98%) as a mixture of cis and trans isomers.

Reference： [1]Patent: WO2007/56023,2007,A2 .Location in patent: Page/Page column 41

26
[ 464192-28-7 ]
[ 936845-79-3 ]
5-(2-(2-bromothiazol-5-yl)vinyl)-1H-indole [ No CAS ]
5-(2-(2-bromothiazol-5-yl)vinyl)-1H-indole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of intermediate 8 (1.16 g, 2 mmol) in anhydrous DMF (30 mL) was added 1BuOK (0.34 g, 3.0 mmol). The solution was stirred for 30 min before adding solution of <strong>[464192-28-7]2-bromothiazole-5-carbaldehyde</strong> (0.39 g, 2.0 mmol) in DMF (10 mL). The mixture was stirred overnight. The benzoyl group was removed during the reaction. The solvent was removed in vacuo and the residue suspended in EtOAc (100 mL) and washed with brine (2 x 50 mL). The aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic phase was dried (Na2SO4) and concentrated. The residue was purified by flash column (SiO2/5% hexanes in EtOAc) to afford the title intermediate as a mixture of cis and trans isomers (160 mg, 13%).

Reference： [1]Patent: WO2007/56023,2007,A2 .Location in patent: Page/Page column 39

27
[ 464192-28-7 ]
[ 1679-18-1 ]
[ 721920-84-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 7216 - 7221
[2]Organic Letters,2019

28
[ 464192-28-7 ]
[ 36282-40-3 ]
[ 1255940-25-0 ]

Reference： [1]Journal of Medicinal Chemistry,2010,vol. 53,p. 8176 - 8186

29
[ 464192-28-7 ]
[ 536-74-3 ]
[ 396082-02-3 ]

Yield	Reaction Conditions	Operation in experiment
93%	With triethylamine;bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; In tetrahydrofuran; at 20℃; for 18.0833h;	Example 2052-Phenylethynyl-thiazole-5-carbaldehyde; Example 205 was prepared via the Scheme 3, step a, using standard Sonogashira coupling between 2-Bromo-5-formylthiazole (49) and phenylacetylene, as follows: To a round bottom flask was added 2-bromo-5-formylthiazole (3.83 g, 19.9 mmol, purchased from Frontier Scientific, Inc.), THF (100 mL) and triethylamine (20 mL). To the solution was successively added CuI (228 mg, 1.20 mmol), PdCl2(PPh3)2 (420 mg, 0.60 mmol) and a solution of phenylacetylene (2.24 g, 21.9 mmol) in THF (20 mL) over a period of about 5 minutes. The reaction was then stirred at room temperature for 18 hours. The volatiles were removed under reduced pressure, the residue transferred to a 1.0-L separatory funnel with EtOAc (200 mL) and saturated aqueous sodium bicarbonate (300 mL) and extracted. The layers were separated and the aqueous layer was extracted again with EtOAc (2×100 mL). The combined organic layers were then washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient ranging from 5% to 50% EtOAc in hexanes to afford the titled compound, 2-phenylethynyl-thiazole-5-carbaldehyde, (3.94 g, 93%) as an orange solid.

Reference： [1]Patent: US2011/92475,2011,A1 .Location in patent: Page/Page column 52

30
[ 464192-28-7 ]
[ 1301198-32-2 ]
[ 1301198-70-8 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium hydrogencarbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; at 20 - 100℃; for 20h;Inert atmosphere;	Intermediate 1061 -Methylethyl [(2S,4/?)-1 -acetyl-6-(5-formyl-1 ,3-thiazol-2-yl)-2-methyl-1 ,2,3,4- tetrahydro-4-quinolinyl]carbamate1 -Methylethyl [(2S,4R)-1 -acetyl-2-methyl-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)- 1 ,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Intermediate 52) (108 mg, 0.259 mmol), 2-bromo-1 ,3-thiazole-5-carbaldehyde (74.7 mg, 0.389 mmol), sodium bicarbonate (32.7 mg, 0.389 mmol) and tetrakis(triphenylphosphine)palladium(0) (30.0 mg, 0.026 mmol) were stirred at 100C in 1 ,2-dimethoxyethane (DME) (4 mL) under nitrogen for 16 h then cooled to room temperature. A saturated NaHC03 aqueous solution (1 mL) was added and the resulting mixture was stirred at 100C for 4h then cooled to room temperature and concentrated in vacuo. The residue was dissolved in DCM and the organic phase was filtered through celite then concentrated in vacuo to give 1 -methylethyl [(2S,4R)-1 -acetyl-6-(5-formyl-1 ,3-thiazol-2-yl)-2-methyl-1 ,2,3,4-tetrahydro-4- quinolinyl]carbamate (104 mg, 0.259 mmol, 100%) which was used in the next step without further purification. LCMS (method G): Retention time 0.91 min, [M+H]+ = 402.0
	With sodium hydrogencarbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; at 100℃; for 20h;Inert atmosphere;	1-Methylethyl [(2S,4R)-1-acetyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Intermediate 52) (108 mg, 0.259 mmol), <strong>[464192-28-7]2-bromo-1,3-thiazole-5-carbaldehyde</strong> (74.7 mg, 0.389 mmol), sodium bicarbonate (32.7 mg, 0.389 mmol) and tetrakis(triphenylphosphine)palladium(0) (30.0 mg, 0.026 mmol) were stirred at 100 C. in 1,2-dimethoxyethane (DME) (4 mL) under nitrogen for 16 h then cooled to room temperature. A saturated NaHCO3 aqueous solution (1 mL) was added and the resulting mixture was stirred at 100 C. for 4 h then cooled to room temperature and concentrated in vacuo. The residue was dissolved in DCM and the organic phase was filtered through celite then concentrated in vacuo to give 1-methylethyl [(2S,4R)-1-acetyl-6-(5-formyl-1,3-thiazol-2-yl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (104 mg, 0.259 mmol, 100%) which was used in the next step without further purification. LCMS (method G): Retention time 0.91 min, [M+H]+=402.0

Reference： [1]Patent: WO2011/54841,2011,A1 .Location in patent: Page/Page column 99
[2]Patent: US2012/208798,2012,A1 .Location in patent: Page/Page column 45

31
[ 464192-28-7 ]
[ 753-90-2 ]
[ 1253116-32-3 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In 1,4-dioxane;Reflux;	Compounds 102 and 103 were synthesized by using the materials that have a substituent corresponding to these compounds, according to the following production scheme.

Reference： [1]Patent: US2011/190299,2011,A1 .Location in patent: Page/Page column 21

32
[ 464192-28-7 ]
C₁₀H₁₀N₂O₂S [ No CAS ]
[ 1253208-84-2 ]

Yield	Reaction Conditions	Operation in experiment
	With piperidine; In ethanol;Reflux;	Compounds 85 and 86 were synthesized by using the materials that have a substituent corresponding to these compounds, according to the following production scheme.

Reference： [1]Patent: US2011/190299,2011,A1 .Location in patent: Page/Page column 20; 53

33
[ 464192-28-7 ]
[ 352-13-6 ]
[ 1332855-91-0 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of <strong>[464192-28-7]2-bromothiazole-5-carbaldehyde</strong> (14 g) in THF (300 mL) was added dropwise 1M (4-fluorophenyl)magnesium bromide/THF solution (80 mL) at -78 C., and the mixture was stirred for 1 hr. Saturated aqueous ammonium chloride solution was added, and the mixture was allowed to cool to room temperature, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried, and concentrated. Trifluoroacetic acid (100 mL) and triethylsilane (58 mL) were added to the obtained residue, and the mixture was stirred for 100 min at 75 C. The mixture was allowed to cool to room temperature and concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:50-1:9) to give the object compound (16.8 g) described in the above-mentioned scheme.1H-NMR (CDCl3) delta: 7.31-7.29 (m, 1H), 7.21-7.14 (m, 2H), 7.05-6.98 (m, 2H), 4.07 (s, 2H).

Reference： [1]Patent: US2012/108564,2012,A1 .Location in patent: Page/Page column 23

34
[ 464192-28-7 ]
[ 768-35-4 ]
[ 914348-84-8 ]

Yield	Reaction Conditions	Operation in experiment
54%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 120℃; for 4h;Inert atmosphere;	Step 1 : 2-(3-fluorophenyl)thiazole-5-carbaldehyde: To a solution of <strong>[464192-28-7]2-bromothiazole-5-carbaldehyde</strong> (0.6 g , 3.125 mmol) in toluene (2 mL) and ethanol (1 mL) was added 4-fluorophenyl boronic acid (0.524 g, 3.75 mmol), 2 M solution of aq. a2C03. The reaction mixture degassed with argon, tetrakis (0.180 g, 0.156 mmol) was added, the reaction mixture was again degassed with argon for 10 min, and heated to 120C for 4 h. The reaction mixture was evaporated under vacuum to remove ethanol, the reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (50 mL) and dried over sodium sulphate, filtered and evaporated under reduced pressure to obtain crude product. The crude product was purified by Biotage Isolera One chromatography (using 6% ethyl acetate and hexane) to give 2-(3-fluorophenyl)thiazole-5-carbaldehyde (0.350 g, 54% yield); XH NMR (400 MHz, DMSO-d6): ? 8.78 (s, 1H), 7.90 (dd, 2H), 7.61 (q, 1H); 7.44 (t, 1H); LC-MS m/z calcd for [M+H]+ 208.02, found 208.0.

Reference： [1]Patent: WO2013/49565,2013,A1 .Location in patent: Page/Page column 31

35
[ 464192-28-7 ]
[ 914672-66-5 ]
2-(1H-pyrazol-3-yl)thiazole-5-carbaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
33%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 100℃; for 1h;Inert atmosphere;	Step 1 : 2-(lH-pyrazol-3-yl) thiazole-5-carbaldehyde To a solution of <strong>[464192-28-7]2-bromothiazole-5-carbaldehyde</strong> (0.8 g, 4.16 mmol) in toluene (6 mL) and EtOH (5 mL), tert-butyl 3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole-l-carboxylate (1.8 g, 6.2 mmol), 2M a2C03 (6.2 mL, 12.4 mmol) and Pd(PPli3)4 (0.45 mg, 0.4 mmol) were added under argon. The mixture was degassed, heated to 100C, stirred for 1 h. After completion of the reaction, by monitoring with TLC (5% MeOHYDCM), the resulting mixture was filtered with Celite reagent and the filtrate was separated. This filtrate was concentrated, extracted with EtOAc (2x 100 mL), washed with water (100 mL), dried over Na2S04 and concentrated in vacuo. The resulting residue was purified by Biotage Isolera One column purifier (silica gel 100-200 microns) using 3% methanol in dichloromethane and isolated as yellow color solid (0.25 g, 33% yield).1H MR (400 MHz, DMSO-d6): ? 13.49 (brs, IH), 10.03 (s, IH), 8.60 (s, IH), 8.55 (s, IH), 8.09(s, IH); LC-MS m/z calcd for [M+H]+, 180.02; found, 180.1.

Reference： [1]Patent: WO2013/49565,2013,A1 .Location in patent: Page/Page column 33

36
[ 464192-28-7 ]
[ 5720-07-0 ]
[ 38401-67-1 ]

Yield	Reaction Conditions	Operation in experiment
87.7%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 60℃; for 5h;Inert atmosphere;	leTo a stirred solution of 5-bromothiophene-2-carbaldehyde (1 g, 5.2 mmol) in toluene (40 mL) and ethanol (20 mL) was added (4-methoxyphenyl)boronic acid (1.59 g, 10.4 mmol), 2M Na2C03 (14.7 mL), and Pd(PPh3)4 (60 mg, 0.05 mmol). The reaction was purged with argon and heated at 60C for about 5 h. The reaction mixture was concentrated, diluted with water (100 mL), and extracted with ethyl acetate (2 x 200 mL). The combined organic extracts were washed with brine solution (20 mL), the organic layer was dried over Na2S04 and concentrated under vacuum to obtain crude product. The crude product was purified by flash chromatography (silica gel, 60-120 ?) using 10% ethyl acetate in hexane eluent to afford 5-(4- methoxyphenyl)thiophene-2-carbaldehyde as off white solid (1 g, 87.7% yield). lH NMR (400 MHz, DMSO-d6): ? 9.85 (s, IH), 7.97 (d, IH), 7.73 (d, 2H), 7.61 (d, IH), 7.02 (d, 2H), 3.98 (s, 3H); LC-MS m/z calcd for [M+H]+ 219.04, found 219.3.

Reference： [1]Patent: WO2013/49565,2013,A1 .Location in patent: Page/Page column 35-36

37
[ 464192-28-7 ]
[ 1765-93-1 ]
[ 914348-80-4 ]

Yield	Reaction Conditions	Operation in experiment
88%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; toluene; at 85℃; for 6h;Inert atmosphere;	To a solution of 2-bromothiazole-5-carbaldehyde (5.0 g, 26.04 mmol) in toluene (150 mL) and ethanol (75 mL) was added (4-fluorophenyl)boronic acid (7.29 g, 52.08 mmol), 2M sodium carbonate solution (73.58 mL), Pd(PPh3)4 (1.5 g, 1.3 mmol) under argon atmosphere. The resulting mixture was heated at 85C for 6 h. The reaction mixture was concentrated under reduced pressure, the residue was diluted with water (150 mL), and extracted with ethyl acetate (5 x 500 mL). The organic layer was dried over Na2S04, filtered and concentrated under reduced pressures to obtain crude product. The crude product was purified by Combiflash chromatography (Mobile phase: 10% ethyl acetate in hexane) to give 2-(4- fluorophenyl)thiazole-5-carbaldehyde as off-white solid (200 mg, 88% yield). IH NMR (400 MHz, DMSO-d6): delta 10.06 (s, IH), 8.74 (s, IH), 8.14-8.11 (m, 2H), 7.39 (t, 2H); LC-MS m/z calculated for [M+H]+ 208.02, found 207.9

Reference： [1]Patent: WO2013/49559,2013,A1 .Location in patent: Page/Page column 52

38
[ 269410-08-4 ]
[ 464192-28-7 ]
[ 1369336-35-5 ]

Yield	Reaction Conditions	Operation in experiment
54%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; toluene; at 70℃; for 4h;Inert atmosphere;	Step 1: 2-(lH-Pyrazol-4-yl)thiazole-5-carbaldehyde To a solution of <strong>[464192-28-7]2-bromothiazole-5-carbaldehyde</strong> (500 mg, 2.6 mmol) in toluene (15 mL) and ethanol (7 mL) was added 4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole (606 mg, 3.1 mmol), 2M sodium carbonate solution (7.3 mL) and Pd(PPh3)4 (30 mg, 0.02 mmol). The reaction mixture was purged with argon for 15 min and the resulting mixture was heated at 70C for 4 h. The reaction mixture was concentrated, diluted with water (100 mL), and extracted with ethyl acetate (2 x 200 mL). The combined extracts were washed with brine solution (20 mL), dried over Na2S04, filtered and concentrated to under vacuum to obtain crude product. The crude product was purified by flash chromatography (60-120 mu; 50% ethyl acetate in hexane) to afford 2-(lH-pyrazol-4-yl)thiazole-5-carbaldehyde as yellow solid (250 mg, 54% yield). 1H NMR (400 MHz, DMSO-d6): delta 13.49 (br s, 1H), 10.00 (s, 1H), 8.61(s, 1H), 8.55(s, 1H), 8.09 (s, 1H); LC-MS m/z calculated for [M+H]+ 180.02, found 180.1.

Reference： [1]Patent: WO2013/49559,2013,A1 .Location in patent: Page/Page column 70; 71

39
[ 464192-28-7 ]
[ 78-81-9 ]
[ 1445720-47-7 ]

Yield	Reaction Conditions	Operation in experiment
80%		N-((2-Bromothiazol-5-yl)methyl)-2-methylpropan- 1 -amine To a mixture of <strong>[464192-28-7]2-bromothiazole-5-carbaldehyde</strong> (1 g; 5.20 mmol) and sodium triacetoxyborohydride (3.5 g, 15.6 mmol) in dichloroethane (25 mL) was added 2- methylpropan-1 -amine (0.93 mL, 9.37 mmol) and acetic acid (312 mg, 16.6 mmol), and the reaction was stirred at ambient temperature for 2 hours. The reaction was then treated with 1 N aqueous NaOH, extracted with EtOAc (x3) , dried with MgS04 and concentrated to give N-[(2- bromothiazol-5-yl)methyl]-2-methyl-propan-l-amine (1.04 g, 80% yield) The product was used without further purification. LCMS (m/z) ES+249 [M+l]+.

Reference： [1]Patent: WO2013/92939,2013,A1 .Location in patent: Page/Page column 39

40
[ 464192-28-7 ]
[ 867-13-0 ]
(E)-ethyl 3-(2-bromo-1,3-thiazol-5-yl)acrylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%		General procedure: To a stirred solution of triethyl phosphonoacetate (24.4 mmol) in THF (30 mL) at 0oC was added sodium hydride (24.4 mmol) portionwise. The mixture was stirred for 1 h before addition of aldehyde (12.2 mmol). The reaction mixture was allowed to warm to r.t. and stirred for 17 h, before quenching with water (50 mL) and extracting into EtOAc (2 x 50 mL). The organic layers were combined and washed with water (2 x 50 mL), dried (MgS04), filtered and concentrated.

Reference： [1]Patent: WO2014/14900,2014,A1 .Location in patent: Paragraph 00161; 00189

41
[ 464192-28-7 ]
[ 659742-21-9 ]
2-(6-methylpyridin-3-yl)thiazole-5-carbaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
41%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,2-dimethoxyethane; water; at 110℃; for 0.333333h;Microwave irradiation;	Intermediate 11: 2-(6-methyl pyridin-3-yl)thiazole-5-carbaldehyde A mixture of <strong>[464192-28-7]2-bromothiazole-5-carbaldehyde</strong> (400 mg, 2.08 mmol), (6-methylpyridin-3- yl)boronic acid (428 mg, 3.12 mmol, 1.5 equiv), [1,1?-bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with dichloromethane (170 mg,0.21 mmol, 0.1 equiv) and 2.0 M aqueous sodium carbonate (5.2 mL, 10.4 mmol, 5 equiv) in1,2-dimethoxyethane (6.9 mL) was heated in a microwave reactor at 110 00 for 20 minutes.The reaction was then diluted with ethyl acetate (50 mL) and water (50 mL). The layers wereseparated and the aqueous layer was extracted with ethyl acetate (2 x 25 mL). The combinedorganic extracts were washed with saturated aqueous sodium chloride (30 mL), dried overNa2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc) provided 2-(6- methylpyridin-3-yl)thiazole-5-carbaldehyde (0.176 g, brown solid) in 41% yield. 1H NMR (400 MHz, ODd3) oe 10.08 (5, 1H), 9.15 (d, J = 2.0 Hz, 1H), 8.47 (5, 1H), 8.19 (dd, J = 8.1, 2.4 Hz, 1 H), 7.31 (d, J = 8.3 Hz, 1 H), 2.66 (5, 3H). MS m/z 205.0 (M + H) Rt-0.36 mm.
41%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,2-dimethoxyethane; water; at 110℃; for 0.333333h;Microwave irradiation;	A mixture of <strong>[464192-28-7]2-bromothiazole-5-carbaldehyde</strong> (400 mg, 2.08 mmol), (6-methylpyridin-3- yl)boronic acid (428 mg, 3.12 mmol, 1.5 equiv), [1,1?-bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with dichloromethane (170 mg,0.21 mmol, 0.1 equiv) and 2.0 M aqueous sodium carbonate (5.2 mL, 10.4 mmol, 5 equiv) in1,2-dimethoxyethane (6.9 mL) was heated in a microwave reactor at 110 00 for 20 minutes.The reaction was then diluted with ethyl acetate (50 mL) and water (50 mL). The layers wereseparated and the aqueous layer was extracted with ethyl acetate (2 x 25 mL). The combinedorganic extracts were washed with saturated aqueous sodium chloride (30 mL), dried overNa2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc) provided 2-(6- methylpyridin-3-yl)thiazole-5-carbaldehyde (0.176 g, brown solid) in 41% yield. 1H NMR (400 MHz, ODd3) oe 10.08 (5, 1H), 9.15 (d, J = 2.0 Hz, 1H), 8.47 (5, 1H), 8.19 (dd, J = 8.1, 2.4 Hz, 1 H), 7.31 (d, J = 8.3 Hz, 1 H), 2.66 (5, 3H). MS m/z 205.0 (M + H) Rt-0.36 mm.

Reference： [1]Patent: WO2014/141153,2014,A1 .Location in patent: Page/Page column 46
[2]Patent: WO2014/141104,2014,A1 .Location in patent: Page/Page column 111

42
[ 464192-28-7 ]
[(2-chloro-phenyl)-methoxy-methyl]-phosphonic acid diethyl ester [ No CAS ]
2-bromo-5-[2-(2-chloro-phenyl)-2-methoxy-vinyl]-thiazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.33 g	With n-butyllithium; In tetrahydrofuran; hexane; at -60 - -10℃; for 3h;Inert atmosphere;	Svnthesis45 2-Bromo-5-[2-(2-chl thoxy-vinyl]-thiazole To a solution of [(2-chloro-phenyl)-methoxy-methyl]-phosphonic acid diethyl ester (2.5 mmol, 0.73 g) in THF (5 mL) was slowly added a 2.5 M solution of n-butyl lithium in hexanes (2.5 mmol, 1.0 mL) at -78 C, under nitrogen. The mixture was stirred for 20 minutes and then treated with a solution of <strong>[464192-28-7]2-bromo-thiazole-5-carbaldehyde</strong> (2.3 mmol, 0.44 g) in THF (5 mL). The mixture was stirred for 1 hour at below -60 C before slowly warming to -10 C (over 30 minutes). The reaction was stirred for a further 1.5 hours, warmed to room temperature and quenched with saturated aqueous ammonium chloride (50 mL). The mixture was extracted into ethyl acetate (100 mL), washed with brine (50 mL), dried and evaporated under reduced pressure. The crude product was purified by flash column chromatography eluting with 0 to 20% ethyl acetate / cyclohexane. Fractions were pooled and evaporated under reduced pressure to give the title compound (mixture of E and Z isomers) as a yellow liquid. Yield: 0.33 g, 60%. LCMS, analytical method 1 , mixture of E and Z isomers TR= 5.05 mins and 5.40 mins, ES positive ion Ml+H = 330.00/332.00.

Reference： [1]Patent: WO2015/25172,2015,A1 .Location in patent: Page/Page column 124

43
[ 464192-28-7 ]
[ 201802-67-7 ]
C₂₂H₁₆N₂OS [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; for 24h;Inert atmosphere; Reflux;	General procedure: Under argon atmosphere, a mixture of <strong>[464192-28-7]2-bromothiazole-5-carbaldehyde</strong> (0.39 g, 2.00 mmol), 4-(diphenylamino)phenylboronic acid (0.87 g, 3.00 mmol), [Pd(PPh3)4] (0.12 g, 0.10 mmol), cesium carbonate (1.95 g, 6.00 mmol), dioxane (40 mL) and deionized water (4 mL) was degassed for 10 min and heated to reflux for 24 h. The mixture was then cooled to the room temperature and extracted with chloroform. The resulting organic layer was washed thoroughly by brine and then dried with anhydrousNa2SO4 and filtered. After purified by column chromatography over silica gel using hexane and dichloromethane (v/v 1:2), compound 4 was obtained in a yield of 0.62 g (87%) as orange solid. Mp: 128-130 C. Main FTIR absorptions (KBr pellets, cm-1): 3440 (m), 3070 (w), 2815 (w), 1668 (s), 1585 (s), 1487 (m), 1406 (s), 1329 (s), 1223 (m), 1149 (s), 837 (m), 760 (w), 698 (m), 639 (w), 537 (w), 499 (w). 1H NMR (300 MHz, CDCl3) delta: 10.00 (s, 1H), 8.36 (s, 1H), 7.87-7.82 (dt, J=9.0 Hz, 2.7 Hz, 2H), 7.35=7.30 (m, 4H), 7.18-7.11 (m, 6H), 7.07-7.03 (dt, J=9.0 Hz, 2.7 Hz, 2H). 13C NMR (75 MHz,CDCl3) delta: 181.9, 175.5, 152.6, 151.2, 146.4, 137.6, 129.5, 128.3, 125.7, 125.0, 124.5, 120.8. EI-TOF-MS (m/z): calcd for [C22H16N2OS]+ 356.1 (100%), 357.1 (25.6%), 358.1 (4.5%), found 355.8 (100%), 354.8(63.9%), 356.8 (7.8%). Anal. Calcd for C22H16N2OS: C, 74.13, H, 4.52,N, 7.86%. Found: C, 74.25, H, 4.78, N, 7.90%.

Reference： [1]Tetrahedron,2015,vol. 71,p. 3966 - 3975

44
[ 419536-33-7 ]
[ 464192-28-7 ]
C₂₂H₁₄N₂OS [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; for 24h;Inert atmosphere; Reflux;	General procedure: Under argon atmosphere, a mixture of <strong>[464192-28-7]2-bromothiazole-5-carbaldehyde</strong> (0.39 g, 2.00 mmol), 4-(diphenylamino)phenylboronic acid (0.87 g, 3.00 mmol), [Pd(PPh3)4] (0.12 g, 0.10 mmol), cesium carbonate (1.95 g, 6.00 mmol), dioxane (40 mL) and deionized water (4 mL) was degassed for 10 min and heated to reflux for 24 h. The mixture was then cooled to the room temperature and extracted with chloroform. The resulting organic layer was washed thoroughly by brine and then dried with anhydrousNa2SO4 and filtered. After purified by column chromatography over silica gel using hexane and dichloromethane (v/v 1:2), compound 4 was obtained in a yield of 0.62 g (87%) as orange solid.

Reference： [1]Tetrahedron,2015,vol. 71,p. 3966 - 3975

45
[ 854952-58-2 ]
[ 464192-28-7 ]
C₂₂H₁₄N₂OS [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57%	With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; for 24h;Inert atmosphere; Reflux;	General procedure: Under argon atmosphere, a mixture of <strong>[464192-28-7]2-bromothiazole-5-carbaldehyde</strong> (0.39 g, 2.00 mmol), 4-(diphenylamino)phenylboronic acid (0.87 g, 3.00 mmol), [Pd(PPh3)4] (0.12 g, 0.10 mmol), cesium carbonate (1.95 g, 6.00 mmol), dioxane (40 mL) and deionized water (4 mL) was degassed for 10 min and heated to reflux for 24 h. The mixture was then cooled to the room temperature and extracted with chloroform. The resulting organic layer was washed thoroughly by brine and then dried with anhydrousNa2SO4 and filtered. After purified by column chromatography over silica gel using hexane and dichloromethane (v/v 1:2), compound 4 was obtained in a yield of 0.62 g (87%) as orange solid.

Reference： [1]Tetrahedron,2015,vol. 71,p. 3966 - 3975

46
[ 464192-28-7 ]
[ 124-40-3 ]
[ 1005-28-3 ]

Yield	Reaction Conditions	Operation in experiment
1.42 g	With potassium carbonate; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃; for 1.5h;	To a solution of <strong>[464192-28-7]2-bromothiazole-5-carbaldehyde</strong> (2g) in DMF (20m1) was added at 2MMe2NH in THF (6.8m1) and K2C03 (4.3g). The reaction mixture was stirred at rt for 1.5h.After filtration was the mixture diluted with sat. aq. NH4CI and EA, the layers were separatedand the aq. phase was extracted with EA. The combined org. layers were dried overMgSO4, filtrated off and evaporated in vacuo. The crude was purified by CC (BuechiSepacore, 20g cartridge, solvent A: Heptane, solvent B: EA, gradient in %B: 1 to 10, flowrate: 20 mI/mm) to afford 1.42g of a yellowish solid. LC-MS (A): tR = 0.54 mm; [M+H]:157.22.

Reference： [1]Patent: WO2015/75025,2015,A1 .Location in patent: Page/Page column 86

47
[ 464192-28-7 ]
[ 107-21-1 ]
2-bromo-5-(1,3-dioxolan-2-yl)thiazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
3.42 g	With toluene-4-sulfonic acid; In toluene; for 2h;Inert atmosphere; Reflux; Dean-Stark;	To a solution of 2-bromo-1 ,3-thiazole-5-carboxaldehyde (5g) in toluene (60 mL) were added ethylene glycol anhydrous (4 mL) and PTSA (326 mg). The reaction mixture was stirred under reflux for 2h with a Dean-Stark apparatus. The mixture was diluted with 20% Na2CC>3 in water and EA, the layers were separated and the aq. phase was washed with EA. The combined org. layers were washed with sat. aq. NaCI, dried over Na2S04, filtrated off and evaporated in vacuo. The crude was purified by CC (Buchi Sepacore, 50g cartridge, solvent A: Heptane, solvent B: EA, gradient in %B: 0 to 2, flow rate: 30 mL/min) to afford 3.42g of a yellow oil. LC-MS (A) tR = 0.68 min; [M+H]+: 235.33.

Reference： [1]Patent: WO2015/75023,2015,A1 .Location in patent: Page/Page column 118

48
[ 464192-28-7 ]
[ 497-06-3 ]
2-bromo-5-(1,3-dioxolan-2-yl)thiazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With toluene-4-sulfonic acid; In toluene; for 3h;Reflux; Dean-Stark;	Example A.17 a) Preparation of Intermediate (20a) A mixture of <strong>[464192-28-7]2-bromo-5-formyl-1,3-thiazole</strong> (0.384 g, 2 mmol, leq), ptoluensulfonic acid (0.03 1 g, 0.16 mmol, 0.08 eq) and ethylenglycol (0.334 mL, 6 mmol,eq) in dry toluene (12 mL) was refluxed using a Dean-Stark apparatus for 3 h. Then thesolvent was removed and the residue purified by flash chromatography over silica gel (100% Petroleum ether - 20/80 EtOAc/Petroleum ether), yielding intermediate 20a (0.33 g, yield 70%) as a colourless oil.

Reference： [1]Patent: WO2015/118019,2015,A1 .Location in patent: Page/Page column 42; 43

49
[ 637-81-0 ]
[ 464192-28-7 ]
ethyl 2-azido-3-(2-bromothiazol-5-yl)acrylate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 3165 - 3186

50
[ 464192-28-7 ]
[ 4433-63-0 ]
[ 933683-87-5 ]