5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole

To a solution of 5-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)thiazole (200 mg, 0.95 mmol) and 2, 4-dichloropyrimidine (95 mg, 0.63 mmol) in dioxane (5 mL) and H20 (1 mL) was added NHC- Pd (20 mg, 0.06 mmol) and K2C03 (174 mg, 1.26 mmol) at room temperature under N2. The mixture was stirred at 1 l0C for 3h in microwave. The solution was diluted with DCM (50 mL) and washed with brine (20 mL). The organic layer was dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by prep- TLC (Petroleum Ether/Ethyl Acetate = 1/1) to give 5-(2- chloropyrimidin-4-yl)thiazole (40 mg, 35%). MS Calcd.: 197, MS Found: 198 ([M+H]+).To a mixture of 5-(4, 4, 5, 5-tetramethyl-1 , 3, 2-dioxaborolan-2-yl)-1 , 3- thiazole (848 mg, 4.02 mmol) and fe/f-butyl 4-(3-chloropyrazin-2-yl)piperazine-1 - carboxylate (1.00 g, 3.35 mmol) in toluene (35 ml_) were added water (5 ml_) and sodium carbonate (1.06 g, 10.0 mmol), followed by [1 , 1?- bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (245 mg, 0.335 mmol). The reaction vessel was then sealed and heated at 100 C for 16 hours. After removal of solvents in vacuo, the residue was purified via chromatography on silica gel (Gradient: 0% to 90% ethyl acetate in petroleum ether) to afford the product as a yellow oil. Yield: 500 mg, 1.44 mmol, 43%. LCMS m/z 348.1 [M+H]+. 1H NMR (400 MHz, CDCIs) d 9.0- 8.8 (br s, 1 H), 8.8-8.6 (br s, 1 H), 8.23 (d, J=2.4 Hz, 1 H), 8.17 (d, J=2.4 Hz, 1 H), 3.68- 3.57 (br m, 4H), 3.24-3.14 (br m, 4H), 1.48 (s, 9H).DMF (100 mL) was degased by vacuum/nitrogen filling cycles. 3-Bromo-4-nitropyridine (4.01 g, 19.74 mmol), 5-(4, 4, 5, 5-tetramethyl-1 , 3, 2-dioxaborolan-2-yl)thiazole (5 g, 23.69 mmol), cesium fluoride (7.50 g, 49.3 mmol), copper(l) iodide (0.376 g, 1.974 mmol) and Pd(Ph3P)4 (1.140 g, 0.987 mmol) were added and the crude was heated at 90C for 18 h. The reaction was cooled to room temperature and diluted with ethyl acetate. The organic phase was washed several times with water and brine, dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica using a Biotage Isolera system employing dichloromethane/methanol (98/2) to afford the desired product (3.80 g, 93 %). (0176) 1H NMR (400 MHz, DMSO-d6) d 9.32 (s, 1 H), 9.02 (s, 1 H), 8.96 (d, 1 H), 8.16 (s, 1 H), 8.08 (d, 1 H).General procedure: Aryl bromide (0.1 mmol, 1.0 eq.) and the corresponding boronicacid/boronic acid pinacol ester (0.2 mmol, 2.0 eq.) were placed in around-bottom flask, followed by DME (5.0 mL) and Na2CO3 aqueoussolution (2.0 M, 2.5 mL). The solution was degassed before additionof Pd(dppf)Cl2eCH2Cl2 (0.02 mmol, 0.2 eq.) in one portion. Thesolution was degassed again and heated at 95 C for 12 h. Theaqueous layer was extracted with ethyl acetate. The combinedorganic layers were dried over anhydrous sodium sulfate andconcentrated in vacuo. The residue was purified by flash columnchromatography to afford the desired product.A mixture of 5-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)thiazole (604 mg, 3.03 mmol), 3-bromo-5-chloro-l-methyl-lH-pyrrolo[2, 3-b]pyridine (372 mg, 1.52 mmol), CS2CO3 (0.8 M in water, 6 mL) and Pd(/-Bu3P)2 (77 mg, 0.152 mmol) in dioxane (8 mL) was stirred at 100 C for 15 h under N2 atmosphere. The color of the mixture was black. Crude LCMS showed the starting material was consumed completely and the purity of the desired product is 10% (Rt = 0.695 min; MS Calc'd: 249.0; MS Found: 249.9 [M+H]+). The reaction mixture was diluted with ethyl acetate (20 mL), dried over Na2S04, filtered and concentrated. The residue was purified by Combi Flash (50% EtOAc in pentane) to afford 5-(5-chloro-l- methyl-lH-pyrrolo[2, 3-b]pyridin-3-yl)thiazole(35.0 mg, yield: 9%) as a yellow solid. NMR (400 MHz, CDCh) d 3.94 (3H, s), 7.24 (1H, d, J= 3.2 Hz), 7.81-7.84 (2H, m), 8.34 (1H, d, J= 2.0 Hz), 8.56 (1H, d, J= 2.0 Hz).A mixture of trans-N-(6-chloro-2, 7-naphthyridin-3-yl)-4-(dimethylamino) cyclohexane-1-carboxamide (CLXXX) (40 mg, 0.12 mmol), A degassedmixture of a solution of benzyl ((R)-4-(4-bromo-2-fluorophenyl)- 1 -((5)-i -(4-chloro-3 -(5-(difluoromethyl)- 1-1 , 2, 4-triazol- 1 -yl)phenyl)-2-((( 1-(trifluoromethyl)cyclopropyl)carbamoyl)oxy)ethyl)-4-neopentyl-5 -oxoimidazolidin-2-ylidene)carbamate (30 mg, 0.033 mmol) in dioxane (1 mL), 5-(4, 4, 5, 5 -tetramethyl- 1 , 3, 2-dioxaborolan-2-yl)thiazole (14 mg, 0.067 mmol), tetrakis(triphenylphosphine)palladium(0) (7.7 mg, 7.0 umol) and potassium carbonate (23 mg, 0.17 mmol) and water (0.20 mL) was stirred at 100 C for 0.5 h. The reaction mixture was cooled to rt and treated with saturated aqueous NH4C1 and EtOAc. After stirring for 10 mm, the layers were separated and theaqueous layer was further extracted with EtOAc. The combined organic layers were washed with saturated aqueous NH4C1 and then with brine, dried (over Na2SO4), filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (0-100% EtOAc/hexanes) to afford the desired product.To a solution of 5-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)thiazole (10.00 g, 47.37 mmol, 1.00 eq) in MeOH (50.00 mL) was added KHF2 (4.5 M, 31.58 mL in water, 3.00 eq). The mixture was stirred at 25 C for 3 hours. TLC indicated reactant 1 was consumed completely. The mixture was concentrated under reduced pressure. The mixture was washed with EtOAc (50 mL) and filtered. The filter cake was dried under reduced pressure to give the crude product. The crude product was washed with MeOH (20 mL) and filtered. The filtrate was concentrated under reduced pressure to afford compound potassium trifluoro(thiazol-5-yl)borate (2.95 g, 15.44 mmol, 32.60% yield, 100% purity) was obtained as a white solid. MS (ESI) m/z 134.0 [M-KF+H] + 1H MR (400MHz, ACETONITRILE-d3) 8.73 (s, 1H), 7.67 (s, 3H) 19F MR (377MHz, ACETONITRILE-d3) -135.88 (br dd, J=44.8, 90.6 Hz, 3F) 11B NMR (128MHz, ACETONITRILE-d3) 1.86, 2.39 (q, J=45.9 Hz, IB)