Name: 5198-88-9|2-Bromothiazole-4-carboxylic acid|97%
Brand: Ambeed
SKU: A103142
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Yield	Reaction Conditions	Operation in experiment
		b) 2-bromothiazole-4-carboxylic Acid To a stirring suspension of the compound of Example 3(a) (32.11 g, 0.127 mol) in 16% HBr (aq) (400 mL) at 0 C. a solution of NaNO2 (9.11 g, 0.132 mol) in water (16 mL) was added. After stirring for 35 min, CuBr (20.6 g, 0.144 mol) was added followed by additional 16% Hbr(aq) (150 mL). The mixture was heated at 70 C. for 1 h and immediately filtered. The filtrate was saturated with NaCl and extracted with ethyl acetate (2*500 mL). The organic phases were combined, dried (MgSO4), filtered and concentrated to a brown solid. This was combined with solid collected by filtration and used without further purification or characterization in the next step.

2
C₁₈H₃₁N₃O₄SSi*C₂HF₃O₂ [ No CAS ]
[ 5198-88-9 ]
methyl 2-{(S)-1-[2-(2-bromothiazole-4-carbonylamino)-(R)-3-(tert-butyldimethylsiloxy)butanoylamino]-(Z)-propenyl}thiazole-4-carboxylate [ No CAS ]

Reference： [1]Synlett,2006,p. 3033 - 3036

3
[ 5198-88-9 ]
[ 16450-41-2 ]
diethyl N-(2-bromo-4-thiazolylcarbonyl)-L-glutamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
2.7 g (84%)	With 2-(Dimethylamino)pyridine; thionyl chloride; triethylamine;N-methyl-acetamide; In dichloromethane; benzene;	To a 100 mL 14/20 round bottom flask under a nitrogen atmosphere was charged 1.7 g (8.17 mmmol) of <strong>[5198-88-9]2-bromo-4-thiazolecarboxylic acid</strong> in 17 mL of benzene, followed by the addition of 2.4 mL (33 mmol) of thionyl chloride, and a catalytic amount of dimethylformamide. The reaction was heated to reflux for 2 hours The volatiles were removed in vacuo, and this residue was then dissolved in 20 mL of methylene chloride and added dropwise to an ice-bath cooled mixture of 2.06 g (8.58 mmol) of L-glutamic acid diethyl ester, 2.39 mL (10.1 mmol) of triethylamine, and 10 mg of dimethylaminopyridine in 30 mL of methylene chloride. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 2 hours The reaction was diluted with methylene chloride, washed with 0.5 N hydrochloric acid, water, 5% sodium bicarbonate, water, dried over sodium sulfate, and removed in vacuo. The crude residue was purified using silica gel flash chromatography eluding with 3:1 chloroform/ether to give 2.7 g (84%) of diethyl N-(2-bromo-4-thiazolylcarbonyl)-L-glutamate as a yellow oil. Rf =0.43 (3:1 chloroform/ether). 1H NMR (300 MHz, DMSO-d6) delta 1.14 (q, J=7.1 Hz, 6H), 1.98-2.18 (m, 2H), 2.35 (t, J=7.3 Hz, 2H), 3.97-4.11 (m, 4H), 4.37-4.50 (m, 1H), 8.28 (d, J=5.9 Hz, 1H), 8.73 (d, J=7.7 Hz, 1H) Anal. Cal'd for C13 H17 BrN2 O5 S: C, 39.71; H, 4.36; N, 7.12. Found: C, 39.84; H, 4.29; N, 7.36.

Reference： [1]Patent: US6066639,2000,A

4
[ 100367-77-9 ]
[ 5198-88-9 ]

Yield	Reaction Conditions	Operation in experiment
2.7 g (94%)	In sodium hydroxide;	The starting material can be prepared as follows. To a 100 mL 24/40 round bottom flask was charged 3.25 g (13.8 mmol) of 2-bromo-4-thiazolecarboxylic acid ethyl ester (Helv. Chim. Acta, 1942, 25, 1073) dissolved in 20 mL of 1N sodium hydroxide. The reaction was stirred at room temperature for 3 h, cooled down in an ice bath and acidified to pH 2 with SN hydrochloric acid. The white precipitate was filtered, washed with 20 mL cold water, and dried in a vacuum oven to give 2.7 g (94%) of 2-bromo-4-thiazolecarboxylic acid. m.p. 227-229 C., Rf =0.16 (20% methanol/chloroform). 1H NMR (300 MHz, DMSO-d6) delta 8.43 (s, 1H). Anal. Cal'd for C4 H2 BrNO5 S: C, 23.10; H, 0.97; N, 6.73. Found: C, 23.42; H, 0.97; N, 6.51.
		Intermediate 3: 2-Bromo-thiazole-4-carboxylic acid To a solution of 2-bromo-thiazole-4-carboxylic acid ethyl ester (Combi-Blocks, Inc., San Diego, Calif.; 5 g, 21.2 mmol) in MeOH (25 mL) and water (25 mL) was added LiOH (0.56 g, 23.3 mmol). After stirring for 4 h at reflux temperature, MeOH was evaporated in vacuo. To the residue was added more water, the mixture was acidified to pH 2 with concentrated HCl (3 mL), and extracted with EtOAc. The combined extracts were evaporated to give 2-bromo-thiazole-4-carboxylic acid which was used without further purification. The compounds of the present invention were preferably prepared by methods A to F:
		Example 57A »\|00427] 2-bromothiazole-4-carboxylic acid\|00428] Ethyl 2-bromothiazole-4-carboxylate (600 mg, 2.54 mmol) was suspended in ethanol (15 mL). Sodium hydroxide (7.5 mL, 1 M) was added and the reaction mixture was stirred at 35 0C for 0.5 hours. The reaction mixture was acidified to pH ~ 3 with 1 M HCl, then diluted with water (100 mL) and extracted with ethyl acetate (2 x 50 mL). The organic extracts were combined, washed with brine (100 mL), dried (sodium sulfate), filtered and concentrated to provide the title compound. MS (APCI) m/z = 208/210 (M+H)+.

		Ethyl 2-bromothiazole-4-carboxylate (97 mg, 0.409 mmol) was dissolved in a solvent mixture of ethanol (15 mL) and water (7.5 mL) and treated with aqueous <n="173"/>sodium hydroxide (2.50 M, 2.54 mL). The mixture was stirred at 35 C for 30 minutes, and then partitioned between ethyl acetate (100 mL) and HCl (1.0 M, 100 mL). The organic phase was dried (sodium sulfate) and concentrated to afford the carboxylic acid as a white solid. To a solution of this material in pyridine (5 mL) were added 4-aminopyridine (46.1 mg, 0.490 mmol), HOBt (78 mg, 0.511 mmol), DMAP (10.0 mg, 0.082 mmol) and EDAC (117 mg, 0.613 mmol). The reaction mixture was stirred at room temperature for 18 hours then filtered through a frit The filtrate was concentrated in vacuo and purified by preparative HPLC [Waters Nova- Pak HR Cl 8 6mum 60A Prep-Pak cartridge column (40 x 100 mm), 10%-100% gradient of acetonitrile in 10 mM aqueous ammonium acetate over 12 minutes at a flow rate of 70 mL/minute] to provide the titled compound: 1H NMR (400 MHz, methanol-D4) delta ppm 7.83 - 7,90 (m, 2 H), 840 (s, 1 H), 8.43 - 8.46 (m, 2 H). MS (ESI) m/z = 284/286 (M+H)+.
	With lithium hydroxide; In tetrahydrofuran; water; at 20℃; for 3h;	Step 2: Preparation of 2-bromothiazole-4-carboxylic acid To a solution of ethyl 2-bromothiazole-4-carboxylate (18.0 g, 76.0 mmol) in THF (90 mL) and H2O (90 mL) was added LiOH (4.8 g, 114 mmol). The mixture was stirred at r,t for 3 hr and extracted with EtOAc (2*150 mL). The aqueous layer was separated, adjusted to pH 2-3 with satd. aq. NH4Cl, and filtered. The solid was collected and dried under high vacuum to afford 2-bromothiazole-4-carboxylic acid. LC-MS: m/z 206 (M-H)-.
	With water; lithium hydroxide; In tetrahydrofuran; at 20℃; for 3h;	Step 2: Preparation of 2-bromothiazole-4-carboxylic acid. To a solution of ethyl 2- bromothiazole-4-carboxylate (18.0 g, 76.0 mmol) in TTEIF (90 mL) and 1120 (90 mL) was added LiOH (4.8 g, 114 mmol). The mixture was stirred at r,t for 3 hr and extracted with EtOAc (2 x 150 mL).The aqueouslayer was separated, adjusted to pH 2-3 with satd. aq. NH4C1, and filtered. The solid was collected and dried under high vacuum to afford 2-bromothiazole-4-carboxylic acid. LC-MS: m/z 206 (M-H).
70 g	With sodium tetrahydroborate; ethanol; at 50℃; for 5.5h;Reflux; Inert atmosphere;	This compound was prepared according to the procedure described in documents WO2013/163279 and Tetrahedron Lett. 1991, 32, 4263. NaBH4 (32.0 g, 0.845 mol) was added portionwise to a solution of ethyl 2-bromothiazole-4-carboxylate (100.0 g, 0.424 mol) in EtOH (800 mL) over 0.5 h at <50C with stirring. The suspension was heated under reflux for 5 h. The mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was dissolved in CH2CI2 (500 mL) and the resulting solution was washed with saturated aqueous NaHCO, (300 mL><3) and brine (300 mLx 1), dried over anhydrous Na2S04 and concentrated to dryness to afford the corresponding alcohol (70 g).

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 6166 - 6190
[2]Chemistry - A European Journal,2008,vol. 14,p. 2322 - 2339
[3]Journal of Medicinal Chemistry,2018,vol. 61,p. 10875 - 10894
[4]Synthetic Communications,2013,vol. 43,p. 2876 - 2882
[5]Patent: US6066639,2000,A
[6]Patent: US2007/167622,2007,A1 .Location in patent: Page/Page column 11
[7]Patent: WO2008/118742,2008,A1 .Location in patent: Page/Page column 67
[8]Patent: WO2008/58096,2008,A2 .Location in patent: Page/Page column 171-172
[9]European Journal of Organic Chemistry,2013,p. 6404 - 6419
[10]Patent: US2015/18328,2015,A1 .Location in patent: Paragraph 1233
[11]Patent: WO2015/3640,2015,A1 .Location in patent: Page/Page column 270
[12]Patent: WO2019/99977,2019,A2 .Location in patent: Paragraph 00191; 00192

5
[ 5198-88-9 ]
[ 98215-44-2 ]

Yield	Reaction Conditions	Operation in experiment
	With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; for 4h;	To a solution of 2-bromothiazole-5-carboxylic acid (752 mg, 3.62 mmol) in DCM (10 mL) was slowly added oxalyl chloride (0.38 mL, 4.34 mmol) and then DMF (1 drop). The mixture was stirred for 4 hours, following which the organics were removed in vacuo, and the residues azeotroped with toluene (10 mL). The crude material was dissolved in DCM (10 mL) and slowly added to a stirred suspension of azetidine hydrochloride (404 mg, 4.34 mmol) and triethylamine (1.8 mL, 13 mmol) in DCM (25 mL). The mixture was stirred at RT for 2 hours before the organics were removed in vacuo. The residue was partitioned between ethyl acetate (50 mL) and water (25 mL), the organic layer washed with brine (25 mL), dried (MgSO4) and evaporated to a residue which was chromatographed on silica, eluting with 40% ethyl acetate in zso-hexane, to give the desired compound (500 mg). 1R NMR delta (CDCl3): 2.3 (m, 2H), 4.15 (m, 2H), 4.6 (m, 2H) and 8.0 (s, IH); m/z 249 (M+H)+.

Reference： [1]Patent: WO2007/7041,2007,A1 .Location in patent: Page/Page column 145

6
[ 5198-88-9 ]
[ 918445-37-1 ]
[ 918445-38-2 ]

Yield	Reaction Conditions	Operation in experiment
98%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In dichloromethane; at 20℃; for 18h;	To a mixture of 4,6-dimethoxy-N2-((1 -((2-(trimethylsilyl)ethoxy)methyl)-1 H- imidazol-2-yl)methyl)pyrimidine-2,5-diamine (Intermediate 108, 494 mg, 1.3 mmol), <strong>[5198-88-9]2-bromothiazole-4-carboxylic acid</strong> (Intermediate 41 , 272 mg, 1.3 mmol) and triethylamine (0.37 ml, 2.6 mmol) in dichloromethane (20 ml) was added HBTU (0.5 g, 1.3 mmol). The reaction was stirred at ambient temperature for 18 h. The solvent was removed in vacuo and then the mixture divided between ethyl acetate (50 ml) and dilute hydrochloric acid (0.1 M, 50 ml). The organic layer was washed with saturated sodium hydrogen carbonate solution (50 ml), brine (20 ml), dried (MgSO4) and the solvent was removed in vacuo. The crude product was then purified by column chromatography (SiO2; methanol-dichloromethane 1-19) to afford the title compound as a pale yellow oil (0.73 g, 98 %); m/z 572.02 (MH+).

Reference： [1]Patent: WO2007/582,2007,A1 .Location in patent: Page/Page column 38; 84

7
[ 5198-88-9 ]
[ 918445-43-9 ]
[ 918445-44-0 ]

Yield	Reaction Conditions	Operation in experiment
89%	With triethylamine; HATU; In dichloromethane; at 20℃; for 18h;	To a mixture of 1 -(5-amino-4,6-dimethoxypyrimidin-2-yl)imidazolidin-2-one (Intermediate 114, 0.86g, 3.6mmol), <strong>[5198-88-9]2-bromothiazole-4-carboxylic acid</strong>(Intermediate 41 , 0.75 g, 3.6 mmol), triethylamine (1.0 ml, 7.16 mmol) and dichloromethane (40 ml) was added HATU (1.4 g, 3.8 mmol). The reaction was stirred at ambient temperature for 18h. The solvent was removed in vacuo and then the mixture divided between ethyl acetate (50 ml) and dilute hydrochloric acid (0.1 M, 50 ml). The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (50 ml), brine (20 ml), dried (MgSO4) and the solvent was removed in vacuo. The crude product was then purified by column chromatography (silica; methanol- dichloromethane 1-19) to afford the title compound as a pale yellow oil (1.4 g, 89 %); m/z 430.94 (MH+).

Reference： [1]Patent: WO2007/582,2007,A1 .Location in patent: Page/Page column 38; 86

8
[ 5198-88-9 ]
[ 767-92-0 ]
[ 944275-16-5 ]

Yield	Reaction Conditions	Operation in experiment
86%	With N-ethyl-N,N-diisopropylamine; bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate; In dichloromethane; at 20℃;	Step 1. (2-Bromo-thiazol-4-yl)-(octahvdro-guinolin-1-yl)-methanone A solution of <strong>[5198-88-9]2-bromo-thiazole-4-carboxylic acid</strong> (Intermediate 3; 21.2 mmol), decahydroquinoline (3.54 g, 25.4 mmol), DIPEA (7.4 mL, 42.4 mmol), and PyBrop (11.9 g, 25.4 mmol) in dry DCM (70 mL) was stirred overnight at room temperature. The mixture was extracted with DCM and water three times. The combined DCM extracts were evaporated, and the residue was chromatographed on silica, eluding with EtOAc/Hexane (0-10% gradient) to give (2-bromo-thiazol-4-yl)-(octahydro-quinolin-1-yl)-methanone (6.0 g, 86%).

Reference： [1]Patent: US2007/167622,2007,A1 .Location in patent: Page/Page column 15-16

9
[ 5198-88-9 ]
[ 504-03-0 ]
[ 944275-19-8 ]

Yield	Reaction Conditions	Operation in experiment
86%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 1h;	Step 1. (2-Bromo-thiazol-4-yl)-(2,6-dimethyl-piperidin-1-yl)-methanone A solution of <strong>[5198-88-9]2-bromothiazole-4-carboxylic acid</strong> (Intermediate 3; 2 g, 9.6 mmol), 2,6-dimethylpiperidine (1.18 mL, 8.8 mmol), HATU (4.18 g, 11.0 mmol) and DIEA (2.1 mL, 12.1 mmol) in DMF (10 mL) was stirred at room temperature for 1 h. Ethyl acetate (20 mL) was added and the solution was washed with 0.2 M HCl (2*10 mL), water (10 mL), and brine (10 mL), then it was dried (MgSO4), filtered, evaporated, and purified by flash column chromatography (10-40% ethyl acetate/hexanes) to give (2-bromo-thiazol-4-yl)-(2,6-dimethyl-piperidin-1-yl)-methanone (2.3 g, 86%) as a white solid.

Reference： [1]Patent: US2007/167622,2007,A1 .Location in patent: Page/Page column 17

10
[ 100367-77-9 ]
[ 83553-47-3 ]
[ 944275-17-6 ]
[ 5198-88-9 ]

Yield	Reaction Conditions	Operation in experiment
		Step 2. Mixture of 2-iodo-thiazole-4-carboxylic acid ethyl ester and 2-bromo-thiazole-4-carboxylic acid A solution of lithium hydroxide (3.27 g, 136.5 mmol) in water (65 mL) was added to a solution of the mixture of 2-iodo-thiazole-4-carboxylic acid ethyl ester and 2-bromo-thiazole-4-carboxylic acid ethyl ester (from Step 1; 10.8 g) in tetrahydrofuran (100 mL). The mixture was stirred at room temperature for 2.5 hours. At this time, the reaction mixture was concentrated in vacuo, followed by addition of water (100 mL). The resultant solution was acidified to pH 1 with 1 M HCl. A white solid was formed. The aqueous suspension was extracted with ethyl acetate (3*250 mL). The combined organic extracts were washed with water (250 mL) and brine (250 mL). The combined organic extracts were dried over MgSO4, filtered and then concentrated in vacuo to give a mixture of 2-iodo-thiazole-4-carboxylic acid ethyl ester and 2-bromo-thiazole-4-carboxylic acid (11.5 g). This material was used in the next step without further purification.

Reference： [1]Patent: US2007/167622,2007,A1 .Location in patent: Page/Page column 16-17

11
[ 5198-88-9 ]
[ 1001413-13-3 ]
[ 1001411-30-8 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 6535 - 6544

12
[ 5198-88-9 ]
[ 170017-74-0 ]
[ 1023298-53-4 ]

Yield	Reaction Conditions	Operation in experiment
72%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 80℃; for 3h;	Example 8; Preparation of Compound 8 EPO <DP n="85"/>8Step 1 - Preparation of Intermediate Compound ATo a solution of <strong>[5198-88-9]2-bromo-thiazole-4-carboxylic acid</strong> (2.0 mmol, 0.42 g) in DMF (10 ml_) was added lambda/,lambda/-diisopropylethylamine (3.0 mmol, 0.52 mL) followed by HATU (2.0 mmol, 0.76 g). To the resulting solution was added 4-(2-aminophenyl)- piperazine-1 -carboxylic acid te/t-butyl ester (2.0 mmol, 0.56 g) and the resulting reaction was heated to 80 C and allowed to stir at this temperature for 3 hours, after which time the reaction mixture was cooled to room temperature, then concentrated in vacuo Xo provide a crude residue. The crude residue was purified using flash flash column chromatography on silica gel using Hexane/EtOAc (4.5/1 ) as eluent to provide Compound A as a yellow solid (72%, 0.67 g). 1H NMR (400 MHz, CDCI3) delta 10.38 (S1 1 H), 8.49 (dd, J= 8.0, 1.2 Hz, 1 H), 8.14 (s, 1 H), 7.23-7.10 (m, 3 H), 3.72 (br s, 4H), 2.89-2.87 (m, 4H), 1.50 (s, 9H). HPLC-MS retention time = 2.39 min. m/z 467.05 (M+H).
72%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 80℃; for 3h;	Example 1; Preparation of Intermediate Compound A; To a solution of <strong>[5198-88-9]2-bromo-thiazole-4-carboxylic acid</strong> (2.0 mmol, 0.42 g), N1N- diisopropylethylamine (3.0 mmol, 0.52 mL) and HATU (2.0 mmol, 0.76 g) in DMF (10 mL) was added 4-(2-aminophenyl)-piperazine-1 -carboxylic acid fe/t-butyl ester (2.0 mmol, 0.56 g). The reaction mixture was stirred at 80 C for 3 h, and then concentrated in vacuo. The resulting residue was purified using flash column chromatography on silica gel (eluent: Hexane:EtOAc (4.5:1)) to provide Compound A as a yellow solid (0.67 g , 72%). 1H NMR (400 MHz, CDCI3) delta 10.38 (s, 1 H), 8.49 (dd, J = 8.0, 1.2 Hz, 1 H), 8.14 (s, 1 H), 7.23-7.10 (m, 3 H), 3.72 (br s, 4H), 2.89-2.87 (m, 4H), 1.50 (s, 9H). HPLC-MS RT= 2.39 min, mass calculated for formula C19H23BrN4O3S 466.07, observed LCMS m/z 467.05 (M+H).
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 80℃; for 15h;	Example 5Preparation of Compound 5To a solution of 2-bromo-thiazole-5-carboxylic acid (0.050 mmol, 10 mg), lambda/,lambda/-diisopropylethylamine (0.20 mmol, 26 mg) and HATU (0.050 mmol, 19 mg) in DMF (1 ml_) was added 4-(2-aminophenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.10 mmol, 28 mg). The resulting reaction was heated to 80 0C and allowed to stir at this temperature for 15 hours, after which time the reaction mixture was cooled to room temperature and concentrated in vacuo. The resulting residue was reacted with TFA (0.5 ml_) for 10 minutes. The TFA solution was then concentrated in vacuo Xo provide a crude residue which was purified using reverse phase HPLC to provide Compound 5.

With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 15h;

General procedure: To a solution of <strong>[5198-88-9]2-bromo-thiazole-4-carboxylic acid</strong> (0.78 mmol, 0.16 g), DIEA (1.5 mmol, 0.26 mL) and HATU (0.78 mmol, 0.30 g) in DMF (4 mL) was added 4-(3-amino-pyridin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.78 mmol, 0.22 g). The reaction mixture was stirred at room temperature for about 15 h, and then concentrated in vacuo. The resulting residue was purified using column chromatography on silica gel (eluent: EtOAc) to provide the title compound as a yellow solid (0.23 g, 63% yield).

Reference： [1]Patent: WO2008/54701,2008,A1 .Location in patent: Page/Page column 83-84; 125-126
[2]Patent: WO2008/54749,2008,A1 .Location in patent: Page/Page column 120
[3]ACS Medicinal Chemistry Letters,2012,vol. 3,p. 123 - 128
[4]Patent: WO2008/54702,2008,A1 .Location in patent: Page/Page column 114
[5]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 2590 - 2594

13
[ 5198-88-9 ]
(E)-(tert-butoxy)-N',N-bis(propan-2-yl)methanimidamide [ No CAS ]
[ 947407-89-8 ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane; for 18h;Heating / reflux;	Example 46; Preparation of Compound 46A46ATo a solution of 2-bromo-4-thiazole carboxylic acid (1.00 g, 4.81 mmol) in dichloromethane (25 ml_) is added 2-tert-butyl-1 ,3-diisopropylisourea (29 mmol, 8.8 g). The resulting solution is heated to reflux and stirred at reflux for 18 hours. After 18 hours, the precipitate is filtered out via a fine frit and the solute reduced in vacuo. The residue is taken up in dichloromethane and Compound 46A is purified via silica gel chromatography. 1H NMR (400 MHz, DMSO) delta 8.40 (s, 1 H), 1.51 (s, 9H).

Reference： [1]Patent: WO2008/54701,2008,A1 .Location in patent: Page/Page column 107

14
[ 5198-88-9 ]
[ 1023594-61-7 ]
[ 1023594-68-4 ]

Yield	Reaction Conditions	Operation in experiment
28%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 80℃; for 3h;	Example 19; Preparation of Compound 19A EPO <DP n="94"/>To a premixed solution of <strong>[5198-88-9]2-bromo-thiazole-4-carboxylic acid</strong> (2.0 mmol, 0.42 g), lambda/,lambda/-diisopropylethylamine (3.0 mmol, 0.52 ml_) and HATU (2.0 mmol, 0.76 g) in DMF (3 ml_) was added [1-(2-amino-phenyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (2.0 mmol, 0.60 g). The reaction mixture was stirred at 80 C for 3 h, and then concentrated in vacuo. The resulting residue was purified using column chromatography on silica gel (eluent: Hexane: EtOAc (4:1)) to provide Compound 19A as a yellow solid (0.27 g , 28%). HPLC-MS RT= 2.30 min, mass calculated for formula C20H25BrN4O3S 480.08, observed LCMS m/z 481.00 (M+H).

Reference： [1]Patent: WO2008/54701,2008,A1 .Location in patent: Page/Page column 92-93

15
[ 5198-88-9 ]
[ 1023594-69-5 ]
[ 1023592-97-3 ]

Yield	Reaction Conditions	Operation in experiment
	With HATU; In N,N-dimethyl-formamide; at 20℃; for 18h;	Example 31; Preparation of Compound 31 A EPO <DP n="102"/>3OA 31 AA solution of <strong>[5198-88-9]2-bromothiazole-4-carboxylic acid</strong> (2.40 mmol. 500 mg), compound 3OA (2.52 mmol, 627 mg) and HATU (2.52 mmol, 959 mg) in DMF (20 ml.) is allowed to stir at room temperature for 18 hours. The mixture was concentrated in vacuo and purified via silica gel chromatography. Compound 31 A was then recrystallized from methanol and ether and filtered to afford an off-white solid. 1H NMR (400 MHz, DMSO) delta 10.03-10.00 (s, 1 H), 8.48 (s, 1 H), 8.34-8.30 (dd, J = 7.8,1.6 Hz, 1 H), 7.27-7.22 (dd, J = 7.4,1.6 Hz, 1 H), 7.20-7.11 (m, 2H), 3.13- 3.04 (m, 2H), 2.90-2.82 (m, 2H), 2.54-2.45 (m, 5H), 2.15-2.06 (m, 2H).

Reference： [1]Patent: WO2008/54701,2008,A1 .Location in patent: Page/Page column 100-101

16
[ 5198-88-9 ]
[ 1023299-64-0 ]

Yield	Reaction Conditions	Operation in experiment
95%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 2.16667h;	Example 79; Preparation of Compound 79A; To a solution of 2-bromo thiazole-5 carboxylic acid (0.57 mmol) and HATU (0.68 mmol) in 1 mL of DMF, was added DIPEA (3 equvalents, 1.6 mmol) and the resulting reaction was stirred for 10 minutes at room temperature. To the reaction mixture was then added a solution of compound 78B (0.57 mmol) in 0.5mL of DMF and the resulting reaction was stirred at room temperature for an additional 2 hours. The reaction mixture was then concentrated in vacuo and the residue obtained was purified using preparative liquid chromatography (5-10% methanol in dichloromethane) to provide 0.54 mmol (95%) of compound 79A.

Reference： [1]Patent: WO2008/54749,2008,A1 .Location in patent: Page/Page column 201

17
[ 5198-88-9 ]
[ 1023298-54-5 ]
[ 1023298-72-7 ]

Yield	Reaction Conditions	Operation in experiment
63%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20 - 80℃; for 15 - 72h;Product distribution / selectivity;	To a solution of <strong>[5198-88-9]2-bromo-thiazole-4-carboxylic acid</strong> (0.78 mmol, 0.16 g), N1N- diisopropylethylamine (1.5 mmol, 0.26 mL) and HATU (0.78 mmol, 0.30 g) in DMF (10 mL) was added 4-(3-amino-pyridin-4-yl)-piperazine-1-carboxylic acid te/t-butyl ester (0.78 mmol, 0.22 g). The reaction mixture was heated to 80 C and allowed to stir at this temperature for about 15 hours, after which time the reacton mixture was cooled to room temperature and concentrated in vacuo. The resulting crude residue was purified using flash column chromatography on silica gel (eluent: ethyl acetate) to provide Compound B as a yellow solid. HPLC-MS RT= 1.40 min, mass calculated for formula C18H22BrN5O3S 467.06, observed LCMS m/z 468.05 (M+H).; Example 47; Preparation of Intermediate Compounds 47A-47C; Following the method described in Example 46, utilizing 2-bromo-thiazole-4- carboxylic acid and the indicated amines, intermediate compounds 47A-47C were made.; Example 46; Preparation of Intermediate Compound 46A; To a solution of compound 43A (1.1 g, 5.2 mmol) in DMF (10 ml.) was added lambda/,lambda/-diisopropylethylamine (2.7 ml, 15.4 mmol) and HATU (2.2 g, 5.6 mmol) in DMF (10 mL) was added aniline (1.5 g, 5.2 mmol) from Preparative Example 10. The reaction mixture was stirred at room temperature for 72 h and then concentrated in vacuo. The crude residue was taken up in EtOAc (50 mL) and sat. aq NaHCO3 (2 ml.) was added. The layers were separated and the organic layer was washed with sat. aq. NaHCO3 (1 x 2 mL) and brine (1 x 2 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified using preparative thin-layer chromatography using a 40:1 mixture of CH2CI2ZMeOH as eluent to provide 1.9 g (75% yield) of compound 46A as a light yellow solid as the title compound. LC-MS [M+H] = 483.2; 89% purity.
63%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 15h;	To a solution of <strong>[5198-88-9]2-bromo-thiazole-4-carboxylic acid</strong> (0.78 mmol, 0.16 g), DIEA (1.5 mmol, 0.26 mL) and HATU (0.78 mmol, 0.30 g) in DMF (4 mL) was added 4-(3-amino-pyridin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.78 mmol, 0.22 g). The reaction mixture was stirred at room temperature for about 15 h, and then concentrated in vacuo. The resulting residue was purified using column chromatography on silica gel (eluent: EtOAc) to provide the title compound as a yellow solid (0.23 g, 63% yield). Mass calculated for formula C18H22BrN5O3S 467.06, observed LCMS m/z for (M+H)+ 468.05. 1H NMR (600 MHz, CD3OD) delta 9.26 (s, 1H),8.38 (s, 1H), 8.25 (d, J = 6.0 Hz, 1H), 7.21 (d, J = 6.0 Hz, 1H), 3.70 (br s, 4H), 3.06 (t, J = 4.8 Hz,4H), 1.49 (s, 9H). 13C NMR (150 MHz, CD3OD) delta ?159.0, 156.3, 151.9, 150.4, 146.8, 142.6,138.5, 130.5, 129.6, 116.2, 81.6, 51.5, 28.7.

Reference： [1]Patent: WO2008/54749,2008,A1 .Location in patent: Page/Page column 131; 154; 155
[2]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 2590 - 2594

18
[ 5198-88-9 ]
[ 156-87-6 ]
[ 1025468-31-8 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 4h;	To a solution of 2-bromothiaz le-4-carboxylic acid (500mg, 2.4mmol), and 3- aminopropan-1-ol (247mul, 4.8mmol) in CH2Cl2 (15ml) was added iV-(3-dimethylaminopropyl)- 30 N'-ethylcarbodiimide hydrochloride (690mg, 3.6mmol), 1-hydroxybenzotriazole (486mg, EPO <DP n="44"/>3.6mmol), and diisopropylethylamine (627mul, 3.6 mmol). The resulting mixture was stirred at room temperature for 4 hours. The mixture was washed with water, IN HCl, sat. NaHCO3, sat. NaCl, dried over Na2SO4, filtered and evaporated to give the title compound. 1HNMR (500 MHz, CDCl3) delta: 8.08 (s, IH), 7.55 (br s, IH), 3.70 (q, J = 5.7, 2H), 3.63 (q, J = 6.4, 2H), 3.13 (t, 5 J = 6.2, IH), 1.82 (m, 2H).

Reference： [1]Patent: WO2008/57336,2008,A2 .Location in patent: Page/Page column 42-43

19
[ 5198-88-9 ]
[ 98946-18-0 ]
[ 947407-89-8 ]

Yield	Reaction Conditions	Operation in experiment
82%	With boron trifluoride diethyl etherate; In tetrahydrofuran; dichloromethane; at 20℃; for 16h;	[0122] Tert-butyl 2,2,2-trichloroacetimidate (17.20 ml, 96 mmol, 2 eq) was added to a stirred suspension of <strong>[5198-88-9]2-bromothiazole-4-carboxylic acid</strong> (10 g, 48.1 mmol, 1 eq) in dichloromethane (DCM) (100 mL) and tetrahydrofuran (THF) (50 mL), followed by dropwise addition of BF3?OEt2 (0.938 ml, 7.40 mmol, 10 mol%). The mixture was stirred at room temperature for 16 h, concentrated, quenched slowly with a saturated bicarbonate solution, and extracted with ethyl acetate. The organic layer was washed with saturated bicarbonate and brine, then dried, and the crude product was purified in a Biotage (Charlotte, NC) flash system eluting with 5-30% ethyl acetate in hexanes over 12 column volumes. The product fraction was concentrated to provide tert-butyl <strong>[5198-88-9]2-bromothiazole-4-carboxylate</strong> 1 as a white solid (10.4 g, 82%).
82%	With boron trifluoride diethyl etherate; In tetrahydrofuran; dichloromethane; at 20℃; for 16h;	[0127] tert-butyl 2,2,2-trichloroacetimidate (17.20 ml, 96 mmol, 2 eq) was added to a stirred suspension of <strong>[5198-88-9]2-bromothiazole-4-carboxylic acid</strong> (10 g, 48.1 mmol, 1 eq) in dichloromethane (DCM) (100 mL) and tetrahydrofuran (THF) (50 mL), followed by dropwise addition of BF3- OEt2 (0.938 ml, 7.40 mmol, 10 mol ). The mixture was stirred at room temperature for 16 h, concentrated, quenched slowly with a saturated bicarbonate solution, and extracted with ethyl acetate. The organic layer was washed with saturated bicarbonate and brine, then dried, and the crude product was purified in a Biotage (Charlotte, NC) flash system eluting with 5-30% ethyl acetate in hexanes over 12 column volumes. The product fraction was concentrated to provide tert-butyl <strong>[5198-88-9]2-bromothiazole-4-carboxylate</strong> 1 as a white solid (10.4 g, 82%).

Reference： [1]Patent: WO2016/109559,2016,A2 .Location in patent: Paragraph 0121; 0122
[2]Journal of Medicinal Chemistry,2017,vol. 60,p. 9184 - 9204
[3]Patent: WO2018/5807,2018,A1 .Location in patent: Paragraph 0127
[4]Chemistry - A European Journal,2008,vol. 14,p. 2322 - 2339

20
[ 5198-88-9 ]
[ 5680-80-8 ]
[ 1032582-86-7 ]

Reference： [1]Chemistry - A European Journal,2008,vol. 14,p. 2322 - 2339

21
[ 5198-88-9 ]
[ 28144-70-9 ]
[ 1160288-86-7 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃; for 144h;	a) Preparation of Intermediate V.1 N-[2-(Aminocarbonyl)phenyl]-2-bromo-4-thiazolecarboxamide (Intermediate V.1) 2-Bromo-4-thiazolecarboxylic acid (1 g), HATU (2.01 g) and 2-aminobenz-amide (0.65 g) are introduced into N,N-dimethylformamide (DMF) (20 ml). The mixture is cooled with an ice bath, and N,N-diisopropylethylamine (0.90 ml) is added. The reaction mixture is stirred at room temperature for 6 days, poured into ice-water and allowed to thaw with stirring, and the precipitated solid is filtered off with suction, washed twice with water, twice with diethyl ether and dried in vacuo. Intermediate V.1 is obtained as a solid (1.4 g). C11H8BrN3O2S, M=326.2. 1H-NMR (300 MHz, D6-DMSO): delta=7.20 (m, 1H), 7.56 (m, 1H), 7.79 (s, 1H), 7.84 (m, 1H), 8.30 (s, 1H), 8.47 (m, 1H), 8.67 (m, 1H), 12.9 (s, 1H).
	With O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 144h;	2-Bromo-4-thiazolecarboxylic acid (1 g), HATU (2.01 g) and 2-aminobenzamide (0.65 g) are introduced into N,N-dimethylformamide (DMF) (20 ml). The mixture is cooled with an ice bath, and N,N-diisopropylethylamine (0.90 ml) is added. The reaction mixture is stirred at room temperature for 6 days, poured into ice-water and allowed to thaw with stirring, and the precipitated solid is filtered off with suction, washed twice with water, twice with diethyl ether and dried in vacuo. Intermediate VI.1 is obtained as a solid (1.4 g).C11H8BrN3O2S, M=326.2. 1H-NMR (300 MHz, D6-DMSO): delta=7.20 (m, 1H), 7.56 (m, 1H), 7.79 (s, 1H), 7.84 (m, 1H), 8.30 (s, 1H), 8.47 (m, 1H), 8.67 (m, 1H), 12.9 (s, 1H).
	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 0 - 20℃; for 144h;	a) Preparation of intermediate III.2 N-[2-(Aminocarbonyl)phenyl]-2-bromo-4-thiazolecarboxamide 2-Bromo-4-thiazolecarboxylic acid (1 g), HATU (2.01 g) and 2-aminobenzamide (0.65 g) are introduced into N,N-dimethylformamide (DMF) (20 ml). The mixture is cooled with an ice bath, and N,N-diisopropylethylamine (0.90 ml) is added. The reaction mixture is stirred at room temperature for 6 days, poured into ice-water and allowed to thaw with stirring, and the precipitated solid is filtered off with suction, washed twice with water, twice with diethyl ether and dried in vacuo. Intermediate III.2 is obtained as a solid (1.4 g). C11H8BrN3O2S, M=326.2. 1H-NMR (300 MHz, D6-DMSO): delta=7.20 (m, 1H), 7.56 (m, 1H), 7.79 (s, 1H), 7.84 (m, 1H), 8.30 (s, 1H), 8.47 (m, 1H), 8.67 (m, 1H), 12.9 (s, 1H).

Reference： [1]Patent: US2009/163486,2009,A1 .Location in patent: Page/Page column 10
[2]Patent: US2009/203715,2009,A1 .Location in patent: Page/Page column 15
[3]Patent: US2009/149517,2009,A1 .Location in patent: Page/Page column 9

22
[ 5198-88-9 ]
[ 57260-71-6 ]
[ 1169698-65-0 ]

Yield	Reaction Conditions	Operation in experiment
91%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 2h;	2- bromothiazole-4-carboxylic acid (1.31 g, 6.3 mmol) was combined with tert-hutyl piperazine-1- carboxylate (1.2 g, 6.3 mmol) in DCM (15 mL), and then stirred at 2O0C. until it formed a clear solution. Nl-((ethylimino)methylene)-N3,N3-dimethylpropane-l,3-diamine hydrochloride (1.2 g, 6.3 mmol) was then added, and the reaction was stirred at 200C. for 2 hours. The reaction was concentrated in vacuum, before transferring it to a separation funnel with ethyl acetate. The organic layer was washed with saturated NaHCCh, water, NH4CI, and then with brine. After drying the organic layer with MgSO1J, it was concentrated in vacuum to yield compound 72 (2.2g, 91%) as a light yellow solid. 1H NMR (500 MHz, DMSO-d6) delta 8.16 (IH, s), 3.61 (4H, m), 3.38 (4H, m), 1.42 (9H, s) ppm; LCMS-ESI (POS), M/Z, M+1-C3H9: Found 320.0.

Reference： [1]Patent: WO2009/85185,2009,A1 .Location in patent: Page/Page column 71

23
[ 5198-88-9 ]
[ 1023298-99-8 ]
[ 1187056-44-5 ]

Yield	Reaction Conditions	Operation in experiment
99.9%	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃;	To a mixture of (S)-tert-butyl 1-(3-aminopyridin-4-yl)piperidin-3-ylcarbamate (1.04 g, 5.00 mmol) and <strong>[5198-88-9]2-bromothiazole-4-carboxylic acid</strong> (1.46 g, 5.00 mmol) in Methylene chloride (10 mL, 200 mmol) was added N,N-Diisopropylethylamine (3.48 mL, 20.0 mmol) and N,N,N',N'-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (2.28 g, 6.00 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was then concentrated and the residue was purified on silica eluting with 0 to 5% MeOH in DCM with 1% NH4OH (2.41 g, 99.9%). ESIMS m/z=484.1 (M+1).
	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; for 60h;	A solution containing 1 eq each of (S)-tert-butyl 1-(3-aminopyridin-4-yl)piperidin-3-ylcarbamate, <strong>[5198-88-9]2-bromothiazole-4-carboxylic acid</strong>, HOAT and EDC in DMF, at a concentration of 0.5 M, was stirred for 60 hours. The solution was diluted with EtOAc and was washed with H2O (4×), NaCl(sat.), was dried over MgSO4, was filtered and the volatiles were removed in vacuo yielding (S)-tert-butyl 1-(3-(2-bromothiazole-4-carboxamido)pyridin-4-yl)piperidin-3-ylcarbamate, LCMS (m/z): 416.1 (MH+); LC Rt=1.95 min.
	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; for 60h;	A solution containing 1 eq each of (S)-tert-butyl l -(3-aminopyridin-4- yl)piperidin-3-ylcarbamate, <strong>[5198-88-9]2-bromothiazole-4-carboxylic acid</strong>, HOAT and EDC in DMF, at a concentration of 0.5 M, was stirred for 60 hours. The solution was diluted with EtOAc and was washed with H2O (4x), NaCl(Sat.), was dried over MgSO4, was filtered and the volatiles were removed in vacuo yielding (S)-tert-butyl l-(3-(2- 0 bromothiazole-4-carboxamido)pyridin-4-yl)piperidin-3-ylcarbamate, LCMS (m/z): 416.1 (MH+); LC Rt = 1 .95 min.

Reference： [1]Patent: US2011/59961,2011,A1 .Location in patent: Page/Page column 56-57
[2]Patent: US2010/216839,2010,A1 .Location in patent: Page/Page column 57
[3]Patent: WO2009/109576,2009,A1 .Location in patent: Page/Page column 116

24
[ 5198-88-9 ]
[ 1187056-55-8 ]
[ 1187056-47-8 ]

Yield	Reaction Conditions	Operation in experiment
	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; for 17h;	A solution containing 1 eq each of tert-butyl(1S,3R,5S)-3-(3-aminopyridin-4-yl)-5-methylcyclohexylcarbamate, <strong>[5198-88-9]2-bromothiazole-4-carboxylic acid</strong>, HOAT and EDC in DMF, at a concentration of 0.3 M, was stirred for 17 hours. The solution was diluted with EtOAc and was washed with H2O (4×), NaCl(sat.), was dried over MgSO4, was filtered and the volatiles were removed in vacuo yielding tert-butyl (1S,3R,5S)-3-(3-(2-bromothiazole-4-carboxamido)pyridin-4-yl)-5-methylcyclohexylcarbamate, LCMS (m/z): 495.1/497.1 (MH+); LC Rt=3.17 min.
	With hydroxyazabenzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 17h;	A solution of tert-butyl ((l S,3R,5S)-3-(3-aminopyridin-4-yl)-5- methylcyclohexyl)carbamate (1.0 eq.), <strong>[5198-88-9]2-bromothiazole-4-carboxylic acid</strong> (1.2 eq.), HO AT (1.2 eq.) and EDC (1.20) in DMF (0.2 M) was stirred at RT for 17 h. The solution was then diluted with EtOAc and washed subsequenetly with water, IN NaOH then saturated brine solution. The organic phase was dried with magnesium sulfate and concentrated in vaccuo to yield the product tert-butyl ((l S,3R,5S)-3-(3-(2-bromothiazole- 4-carboxamido)pyridin-4-yl)-5-methylcyclohexyl)carbamate as a pale yellow oil which was utilised without further purification. LC/MS = 495.0/497.0 (MH+), Rt = 0.90 min.
	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; for 17h;	A solution containing 1 eq each of tert-butyl (lS,3R,5S)-3-(3- aminopyridin-4-yl)-5-methylcyclohexylcarbamate, <strong>[5198-88-9]2-bromothiazole-4-carboxylic acid</strong>, HOAT and EDC in DMF, at a concentration of 0.3 M, was stirred for 17 hours. The solution was diluted with EtOAc and was washed with H2O (4x), NaCl(sat.), was dried over MgSO4, was filtered and the volatiles were removed in vacuo yielding tert-butyl (lS,3R,5S)-3-(3-(2-bromothiazole-4-carboxamido)pyridin-4-yl)-5- methylcyclohexylcarbamate, LCMS (m/z): 495.1/497.1 (MH+); LC R1 = 3.17 min

Reference： [1]Patent: US2010/216839,2010,A1 .Location in patent: Page/Page column 59
[2]Patent: WO2014/33630,2014,A1 .Location in patent: Page/Page column 78
[3]Patent: WO2009/109576,2009,A1 .Location in patent: Page/Page column 119

25
[ 5198-88-9 ]
[ 1052713-65-1 ]
[ 1187056-46-7 ]

Yield	Reaction Conditions	Operation in experiment
	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; for 60h;	A solution containing 1 eq each of tert-butyl(3R,4R)-1-(3-aminopyridin-4-yl)-4-(tert-butyldimethylsilyloxy)piperidin-3-ylcarbamate, <strong>[5198-88-9]2-bromothiazole-4-carboxylic acid</strong>, HOAT and EDC in DMF, at a concentration of 0.5 M, was stirred for 60 hours. The solution was diluted with EtOAc and was washed with H2O (4×), NaCl(sat.), was dried over MgSO4, was filtered and the volatiles were removed in vacuo yielding tert-butyl(3R,4R)-1-(3-(2-bromothiazole-4-carboxamido)pyridin-4-yl)-4-(tert-butyldimethylsilyloxy)piperidin-3-ylcarbamate, LCMS (m/z): 612.2/614.2 (MH+); LC Rt=4.26 min.
	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; for 60h;	A solution containing 1 eq each of tert-butyl (3R,4R)-l-(3-aminopyridin-4-yl)-4-(tert-butyldimethylsilyloxy)piperidin-3-ylcarbamate, 2-bromothiazole-4- carboxylic acid, HOAT and EDC in DMF, at a concentration of 0.5 M, was stirred for 60 hours. The solution was diluted with EtOAc and was washed with H2O (4x), NaCl(Sat ), was dried over MgSO4, was filtered and the volatiles were removed in vacuo yielding <n="120"/>tert-butyl (3R,4R)-l-(3-(2-bromothiazole-4-carboxamido)pyridin-4-yl)-4-(tert- butyldimethylsilyloxy)piperidin-3-ylcarbamate, LCMS (m/z): 612.2/614.2 (MH+); LC Rt = 4.26 min.

Reference： [1]Patent: US2010/216839,2010,A1 .Location in patent: Page/Page column 59
[2]Patent: WO2009/109576,2009,A1 .Location in patent: Page/Page column 118-119

26
[ 1336-21-6 ]
[ 5198-88-9 ]
[ 848501-94-0 ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride;N,N-dimethyl-formamide; In dichloromethane; ethyl acetate;	Step 2: 2-Bromo-1,3-thiazole-4-carboxamide To a suspension of <strong>[5198-88-9]2-bromo-1,3-thiazole-4-carboxylic acid</strong> (3.82 g, 18.4 mmol) and a catalytic amount of DMF in CH2Cl2 (100 mL) at 0 C. was slowly added thionyl chloride (14 mL of a 2M solution in CH2Cl2). The resulting mixture was stirred for 12 h at the room temperature and then heated to reflux for 1 h. The mixture was concentrated to dryness in vacuo. The white solid obtained was taken up in ethyl acetate, added to a pre-cooled (0 C.) 9-10% aqueous ammonium hydroxide solution (90 ml) and stirred for 1 h at 0 C. The organic layer was separated and the aqueous phase was extracted twice with ethyl acetate. The combined ethyl acetate solution was washed with brine, dried over magnesium sulfate and concentrated in vacuo, affording the title compound was obtained as an off-white solid. 1H NMR (400 MHz, DMSO-d6) delta ppm 7.60 (s, 1H), 7.82 (s, 1H), 8.22 (s, 1H).
	With thionyl chloride;N,N-dimethyl-formamide; In dichloromethane; ethyl acetate;	Step 2: 2-Bromo-1,3-thiazole-4-carboxamide To a suspension of <strong>[5198-88-9]2-bromo-1,3-thiazole-4-carboxylic acid</strong> (3.82 g, 18.4 mmol) and a catalytic amount of DMF in CH2Cl2 (100 mL) at 0 C. was slowly added thionyl chloride (14 mL of a 2M solution in CH2Cl2). The resulting mixture was stirred for 12 h at the room temperature and then heated to reflux for 1 h. The mixture was concentrated to dryness in vacuo. The white solid obtained was taken up in ethyl acetate, added to a pre-cooled (0 C.) 9-10% aqueous ammonium hydroxide solution (90 ml) and stirred for 1 h at 0 C. The organic layer was separated and the aqueous phase was extracted twice with ethyl acetate. The combined ethyl acetate solution was washed with brine, dried over magnesium sulfate and concentrated in vacuo, affording the title compound was obtained as an off-white solid. 1H NMR (400 MHz, DMSO-d6) delta ppm 7.60 (s, 1H), 7.82 (s, 1H), 8.22 (s, 1H).

Reference： [1]Patent: US2010/113512,2010,A1
[2]Patent: US2011/124559,2011,A1

27
[ 170235-26-4 ]
[ 5198-88-9 ]

Yield	Reaction Conditions	Operation in experiment
	With lithium hydroxide; In tetrahydrofuran;	Step 1: 2-Bromo-1,3-thiazole-4-carboxylic Acid A mixture of methyl 2-bromo-1,3-thiazole-4-carboxylate (4.2 g, 18.9 mmol), THF (120 mL) and 1N lithium hydroxide (50 mL) was heated at 70 C. for 1 h. The organic solvent was removed in vacuo. The residual aqueous solution was cooled to 0-5 C. and acidified to pH1 with 1N HCl solution. The tile compound was obtained by filtration, as a white solid. 1H NMR (400 MHz, DMSO-d6) delta ppm 8.43 (s, 1H) 13.30 (s, 1H).
	With lithium hydroxide; In tetrahydrofuran;	Step 1: 2-Bromo-1,3-thiazole-4-carboxylic Acid A mixture of methyl 2-bromo-1,3-thiazole-4-carboxylate (4.2 g, 18.9 mmol), THF (120 mL) and 1N lithium hydroxide (50 mL) was heated at 70 C. for 1 h. The organic solvent was removed in vacuo. The residual aqueous solution was cooled to 0-5 C. and acidified to pH1 with 1N HCl solution. The tile compound was obtained by filtration, as a white solid. 1H NMR (400 MHz, DMSO-d6) delta ppm 8.43 (s, 1H) 13.30 (s, 1H).
	With lithium hydroxide; In tetrahydrofuran; at 70℃; for 1h;	A mixture of methyl 2-bromo-1,3-thiazole-4-carboxylate (4.2 g, 18.9 mmol), THF (120 mL) and 1N lithium hydroxide (50 mL) was heated at 70 C. for 1 h. The organic solvent was removed in vacuo. The residual aqueous solution was cooled to 0-5 C. and acidified to pH1 with 1N HCl solution. The tile compound was obtained by filtration, as a white solid.

Reference： [1]Patent: US2010/113512,2010,A1
[2]Patent: US2011/124559,2011,A1
[3]Patent: CN102516115,2016,B .Location in patent: Paragraph 0368; 0369

28
[ 504-24-5 ]
[ 5198-88-9 ]
[ 1026136-69-5 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 20℃; for 18h;	Ethyl <strong>[5198-88-9]2-bromothiazole-4-carboxylate</strong> (97 mg, 0.409 mmol) was dissolved in a solvent mixture of ethanol (15 mL) and water (7.5 mL) and treated with aqueous <n="173"/>sodium hydroxide (2.50 M, 2.54 mL). The mixture was stirred at 35 C for 30 minutes, and then partitioned between ethyl acetate (100 mL) and HCl (1.0 M, 100 mL). The organic phase was dried (sodium sulfate) and concentrated to afford the carboxylic acid as a white solid. To a solution of this material in pyridine (5 mL) were added 4-aminopyridine (46.1 mg, 0.490 mmol), HOBt (78 mg, 0.511 mmol), DMAP (10.0 mg, 0.082 mmol) and EDAC (117 mg, 0.613 mmol). The reaction mixture was stirred at room temperature for 18 hours then filtered through a frit The filtrate was concentrated in vacuo and purified by preparative HPLC [Waters Nova- Pak HR Cl 8 6mum 60A Prep-Pak cartridge column (40 x 100 mm), 10%-100% gradient of acetonitrile in 10 mM aqueous ammonium acetate over 12 minutes at a flow rate of 70 mL/minute] to provide the titled compound: 1H NMR (400 MHz, methanol-D4) delta ppm 7.83 - 7,90 (m, 2 H), 840 (s, 1 H), 8.43 - 8.46 (m, 2 H). MS (ESI) m/z = 284/286 (M+H)+.

Reference： [1]Patent: WO2008/58096,2008,A2 .Location in patent: Page/Page column 171-172

29
[ 5198-88-9 ]
[ 3920-40-9 ]
[ 1160288-85-6 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; at 20℃; for 20.0h;	A mixture of 2-bromothiazole-4-carboxylic acid (891 mg), <strong>[3920-40-9]4-amino-1-methyl-1H-pyrazole-3-carboxamide</strong> (600 mg) and HATU (1.95 g) in DMF (5 ml) and ethyldiisopropylamine (1.5 ml) is stirred at room temperature for 20 h and then poured into ice-water. The precipitated solid is filtered off, washed twice with water and three times each with diethyl ether and ethyl acetate and dried in vacuo (889 mg).C9H8BrN5O2S (329.0), LC-MS (ZQ): Rt=0.87, m/z=330 [M+H]+. 1H-NMR (300 MHz, D6-DMSO): 3.88 (s, 3H), 7.45 (br. s., 1H), 7.70 (br. s., 1H), 8.31 (s, 1H), 8.41 (s, 1H), 11.0 (s, 1H).

Reference： [1]Patent: US2009/149517,2009,A1 .Location in patent: Page/Page column 8

30
[ 5198-88-9 ]
C₇H₈NPol [ No CAS ]
C₁₁H₈BrN₂OPolS [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With bis-(2-oxo-3-oxazolidinyl)phosphoryl chloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 24h;Product distribution / selectivity;	Synthesis of 7V-benzyl-2-(pyrimidin-4-ylamino)thiazole-4-carboxamide (Thiazovivin); [0205] Benzyl amine was loaded to 4-formyl-3,5-dimethoxyphenoxymethyl functionalized polystyrene resin (PAL) via reductive amination to give PAL-benzyl amine resin. See, Ding, S.; Grey, N. S. Wu, X.; Ding, Q.; Schultz, P. G. J. Am. Chem. Soc. 2002, 124, 1594-1596. A reaction flask containing PAL-benzyl amine resin (200 mg, 0.2 mmol),<strong>[5198-88-9]2-bromothiazole-4-carboxylic acid</strong> (83 mg, 0.4 mmol), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl) (153 mg, 0.6 mmol) and diisopropylethylamine (0.17 mL, 1 mmol) in DMF (3 mL) was shaken for 24 hr at room temperature. The resin was washed with methanol, dichloromethane and dried in vacuo to give PAL resin-Lambda/-benzyl-2-bromothiazole-4-carboxamide, which was then added to a flame-dried reaction vial, followed by 4-aminopyrimidine (95 mg, 1 mmol), Pd2(dba)3 (46 mg, 0.05 mmol), Xantphos (87 mg, 0.15 mmol) and NaO1Bu (192 mg, 2 mmol). The vial was sure safe capped and degassed, then charged with argon and anhydrous dioxane (1.5 mL). The reaction was shaken for 24 hours at 90 0C. The resin was washed with sodium diethyldithiocarbamate solution (0.05 M in DMF), methanol and dichloromethane and dried in vacuo. The resin was subsequently cleaved with cleavage cocktail TFAiCH2Cl2IH2O (45:55:5) (2 mL) for 2 hr. The resin was filtered, the filtrate was collected and evaporated in vacuo to give the crude which was then purified by HPLC to give the title compound (30 mg, 48%). 7V-Benzyl-2-(pyrimidin-4-ylamino)thiazole-4-carboxamide[0206] Exact mass calculated for Ci5Hi3N5OS: 311.1, found LCMS m/z = 334.1 (M+Na+).[0207] 1H NMR (400 MHz, J6-DMSO) 4.49 (d, J= 6.3 Hz, 2H), 5.76 (s, IH), 7.21-7.27 (m, 2H), 7.30-7.34 (m, 4H), 7.85 (s, IH), 8.45 (t, J= 6.3 Hz, IH), 8.51 (d, J= 6.1 Hz, IH), 8.94 (s, IH).

Reference： [1]Patent: WO2010/65721,2010,A1 .Location in patent: Page/Page column 55

31
[ 5198-88-9 ]
[ 71018-04-7 ]
[ 1262975-71-2 ]

Reference： [1]Chemistry - A European Journal,2010,vol. 16,p. 14083 - 14093

32
[ 5198-88-9 ]
[ 170911-92-9 ]
[ 1314119-12-4 ]

Reference： [1]ACS Medicinal Chemistry Letters,2011,vol. 2,p. 632 - 637

33
[ 5198-88-9 ]
[ 1350918-02-3 ]
[ 1365174-19-1 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃;	Preparation of Int- 6; lnt-5 lnt-8a; A mixture of 2-bromothiazole-4-carboxyIic acid (180 mg, 0.87 mmol), Int~5 (352 mg, 0.87 mmol), 2-(7-aza-lH-benzotriazole-l-yl)-l ,1,3,3 -tetramethyluromum hexafluorophosphate (HATU) (354 mg, 0.96 mmol) and N,N-diisopropylethylamine (0.31 ml, 1.74 mmol) were stirred in N,N-dimethylformamide (5 ml) at r.t. overnight. Water and ethyl acetate were added and layers were separated. The separated organic layer was washed with water, dried (MgSO*?) and filtered. Solvents were removed in vacuum and chromatographic purification (ethyl acetate - hexane) gave Int-8a as white solid.

Reference： [1]Patent: WO2012/36974,2012,A1 .Location in patent: Page/Page column 50

34
[ 5198-88-9 ]
[ 1374113-51-5 ]
[ 1374113-36-6 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃;	A mixture of <strong>[5198-88-9]2-bromothiazole-4-carboxylic acid</strong> (0.11 g, 0.53 mmol), lnt-5 (0.20 g, 0.53 mmol), 2-(7-aza-lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (HATU) (242 mg, 0.64 mmol) and N,N-diisopropylethylamme (0.14 ml, 0.80 mmol) were stirred in N,N- dimethylformamide (5 ml) at r.t. overnight. Water and ethyl acetate were added and layers were separated. The separated organic layer was washed with water, dried (MgS04) and filtered. Solvents were removed in vacuum and chromatographic purification (ethyl acetate - hexane) gave Int-8b as white solid

Reference： [1]Patent: WO2012/58174,2012,A1 .Location in patent: Page/Page column 32; 33

35
[ 5198-88-9 ]
[ 3144-09-0 ]
[ 1353560-14-1 ]

Yield	Reaction Conditions	Operation in experiment
89%		2-Bromo-1,3-thiazole-4-carboxylic acid (0.8 g, 3.85 mmol) was initially charged in tetrahydrofuran (10 ml). N,N'-Carbonyldiimidazole (0.94 g, 5.77 mmol) was added and the reaction mixture was heated under reflux for 1 h. Methanesulphonamide (0.55 g, 5.77 mmol) was added and, after 10 min, 1,8-diazabicyclo[5.4.0]undec-7-ene (0.88 g, 5.77 mmol). The reaction mixture was stirred at room temperature for 16 h and then the solvent was removed under reduced pressure. The residue was taken up in water and acidified with hydrochloric acid. The precipitated product was filtered off with suction. The aqueous phase was extracted with dichloromethane; the organic phase was dried over sodium sulphate and filtered, and the solvent was removed under reduced pressure. This gave a total of 1.0 g (89% of theory) of 2-bromo-N-(methylsulphonyl)-1,3-thiazole-4-carboxamide.HPLC-MS: LogP(HCOOH): 0.83; mass (m/z): 284.9 (M+H)+;1H NMR (d6-DMSO): 3.33 (s, 3H), 8.61 (s, 1H), 12.00 (s, 1H)

Reference： [1]Patent: US2012/165345,2012,A1 .Location in patent: Page/Page column 37-38

36
[ 5198-88-9 ]
[ 1009692-04-9 ]
[ 1420834-43-0 ]

Yield	Reaction Conditions	Operation in experiment
< 80%		3-[(2-bromo-thiazole-4-carbonyl)-annino]-3-o-tolyl-propionic acid methyl ester100mg (0,48mnnol) of 2-bromo-l ,3-thiazole-4-carboxylic acid are dissolved in 10 ml of DMF, N-ethylmorpholine (122 mg, 2,2Eq) and TOTU (174mg, 1 .1 Eq) are added and the mixture is stirred at RT for 5 minutes. Then 93mg (1 Eq) of methyl 3-amino-3-(2- methylphenyl)propanoate are added and the mixture is stirred overnight. The solvent is removed in vacuo and the residue subjected to preparative HPLC delivering 3-[(2- bromo-thiazole-4-carbonyl)-amino]-3-o-tolyl-propionic acid methyl ester yields in yields below 80%
< 80%		3-[(2-bromo-thiazole-4-carbonyl)-annino]-3-o-tolyl-propionic acid methyl ester100mg (0,48mnnol) of 2-bromo-l ,3-thiazole-4-carboxylic acid are dissolved in 10 ml of DMF, N-ethylmorpholine (122 mg, 2,2Eq) and TOTU (174mg, 1 .1 Eq) are added and the mixture is stirred at RT for 5 minutes. Then 93mg (1 Eq) of methyl 3-amino-3-(2- methylphenyl)propanoate are added and the mixture is stirred overnight. The solvent is removed in vacuo and the residue subjected to preparative HPLC delivering 3-[(2- bromo-thiazole-4-carbonyl)-amino]-3-o-tolyl-propionic acid methyl ester yields in yields below 80%
< 80%		3-[(2-bromo-thiazole-4-carbonyl)-amino]-3-o-tolyl-propionic acid methyl ester 100 mg (0.48 mmol) of <strong>[5198-88-9]2-bromo-1,3-thiazole-4-carboxylic acid</strong> are dissolved in 10 ml of DMF, N-ethylmorpholine (122 mg, 2.2 Eq) and TOTU (174 mg, 1.1 Eq) are added and the mixture is stirred at RT for 5 minutes. Then 93 mg (1 Eq) of methyl 3-amino-3-(2-methylphenyl)propanoate are added and the mixture is stirred overnight. The solvent is removed in vacuo and the residue subjected to preparative HPLC delivering 3-[(2-bromo-thiazole-4-carbonyl)-amino]-3-o-tolyl-propionic acid methyl ester yields in yields below 80%

< 80%

Step 1: [0295] 3-[(2-bromo-thiazole-4-carbonyl)-amino]-3-o-tolyl-propionic Acid Methyl Ester <strong>[5198-88-9]2-bromo-1,3-thiazole-4-carboxylic acid</strong> are dissolved in 10 ml of DMF, N-ethylmorpholine (122 mg, 2,2Eq) and TOTU (174 mg, 1.1Eq) are added and the mixture is stirred at RT for 5 minutes. Then 93 mg (1 Eq) of methyl 3-amino-3-(2-methylphenyl)propanoate are added and the mixture is stirred overnight. The solvent is removed in vacuo and the residue subjected to preparative HPLC delivering 3-[(2-bromo-thiazole-4-carbonyl)-amino]-3-o-tolyl-propionic acid methyl ester yields in yields below 80%

Reference： [1]Patent: WO2013/14204,2013,A2 .Location in patent: Page/Page column 56
[2]Patent: WO2013/14205,2013,A1 .Location in patent: Page/Page column 49; 50
[3]Patent: US2013/53416,2013,A1 .Location in patent: Paragraph 0318
[4]Patent: US2013/53402,2013,A1 .Location in patent: Paragraph 0294; 0295; 0296

37
[ 5198-88-9 ]
[ 1023299-09-3 ]
[ 1023299-32-2 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 15h;	General procedure: To a solution of <strong>[5198-88-9]2-bromo-thiazole-4-carboxylic acid</strong> (0.78 mmol, 0.16 g), DIEA (1.5 mmol, 0.26 mL) and HATU (0.78 mmol, 0.30 g) in DMF (4 mL) was added 4-(3-amino-pyridin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.78 mmol, 0.22 g). The reaction mixture was stirred at room temperature for about 15 h, and then concentrated in vacuo. The resulting residue was purified using column chromatography on silica gel (eluent: EtOAc) to provide the title compound as a yellow solid (0.23 g, 63% yield).