5-BROMO-2-CHLOROPYRAZINE

A mixture of Pd(dppf)Cl2 (15.13 g, 20.68 mmol), CS2CO3 (269.49 g, 827.17 mmol), 3-fluoro-5-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-2-(2, 2, 2- trifluoroethoxy)pyridine (141.18 g, 439.69 mmol) and 2-bromo-5-chloro-pyrazine (80 g, 413.59 mmol) in l, 4-Dioxane (1 L) and Water (150 mL) under N2 was stirred at 35 C for 2 hours. After cooling to room temperature, to the mixture was added water (300 mL) and the mixture was filtered through Celite. After separating, the organic phase was washed with brine (300 mL), dried over anhydrous Na2S04, filtered and concentrated to give the crude product. The crude product was re-dissolved in EA/PE = 1/3 (500 mL) and then filtered through silica gel mat. The cake was washed with EA/PE = 1/3 (500 mL). The combined organic phase was concentrated to give a residue as oil. To the oil was added PE (500 mL) slowly and some solid was obtained. The solid was collected and dried in oven to give the product (100 g, 242.4 mmol, 58% yield) as a solid. LCMS Rt= 1.28 min in 2.0 min chromatography, 10-80AB, MS ESI calcd. for C11H7CIF4N3O [M+H]+308.0, found 307.9.A mixture of 2-bromo-5-chloro-pyrazine (800 mg, 4.14 mmol), 3-fluoro-5-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-2-[l- (trifluoromethyl)cyclobutoxy]pyridine (1642.99 mg, 4.55 mmol), CS2CO3(4042.64 mg, 12.41 mmol), Pd(dppf)Cl2(60.52 mg, 0.08 mmol) in l, 4-dioxane (12 mL) and H2O (4 mL) was stirred at 50 C for 8 hours. After cooling to room temperature, the reaction mixture was concentrated to remove solvent, diluted with water (20 mL), and extracted with EtOAc (20 mL x 2). The combined organic phase was washed with brine (40 mL), dried over Na2S04and concentrated to give a crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 10%) to give the product as a solid, which was confirmed by LCMS Rt= 1.01 min in 1.5 min chromatography, MS ESI calcd. for C14H11CIF4N3O [M+H]+348.1, found 347.9.A mixture of 2-bromo-5-chloro-pyrazine (2 g, 10.34 mmol), 3-fluoro-5-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-2-[(lR)-2, 2, 2-trifluoro-l- methyl-ethoxy]pyridine (3.12 g, 9.31 mmol), Pd(dppf)Cl2 (1.13 g, 1.55 mmol) and CS2CO3 (6.74 g, 20.68 mmol) in l, 4-dioxane (100 mL) and water (10 mL) was stirred under N2 at 50 C for 5 hours. After cooling to room temperature, the mixture was diluted with EtOAc (10 mL), filtered with silica gel, eluted with EtOAc (20 mL) and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 20%) to give the product (2500 mg, 7.21 mmol, 70% yield) as a solid. 'H NMR (400MHz, CDCI3) dH= 8.77 (d, 1H), 8.64 (d, 1H), 8.53 (d, 1H), 8.08 (dd, 1H), 6.00 - 5.83 (m, 1H), 1.59 (d, 3H).A mixture of 2-bromo-5-chloro-pyrazine (1 g, 5.17 mmol), 3-fluoro-5-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-2-[(lS)-2, 2, 2-trifluoro-l- methyl -ethoxy ] pyridine (1.73 g, 5.17 mmol), CS2CO3 (3.37 g, 10.34 mmol) and Pd(dppf)Cl2 (567.41 mg, 0.78 mmol) in l, 4-Dioxane (100 mL) and Water (10 mL) was stirred at 55 C under N2 for 5 hours. From LCMS, desired MS was observed and no starting material was remained. The solution was cooled to room temperature and concentrated to give a residue. To the residue was added water (50 mL), extracted with EtOAc (50 mL x 2). The combined organic phase was washed with water (50 mL), brine (50 mL x 2), dried over anhydrous Na2S04, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography column on silica gel (EtOAc in PE = 0% to 5%) to give the product (1.4 g, 4.35 mmol, 84% yield) as a solid. 'H NMR (DMSO-c, 400MHz) 5H= 9.18 (s, 1H), 8.91 - 8.74 (m, 2H), 8.46 (dd, 1H), 6.05 - 5.99 (m, 1H), 1.53 (d, 3H).A mixture of 2-bromo-5-chloro-pyrazine (2 g, 10.34 mmol), 3-fluoro-5-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-2-(2, 2, 2-trifluoro-l, l- dimethyl-ethoxy)pyridine (3.61 g, 10.34 mmol), CS2CO3 (6.74 g, 20.68 mmol) andPd(dppf)Cl2 (1.13 g, 1.55 mmol) in l, 4-Dioxane (80 mL) and Water (8 mL) was stirred at 55 C under N2 for 5 hours. The mixture was cooled to room temperature and concentrated to give a residue. To the residue was added water (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic phase was washed with water (50 mL), brine (50 mL x 2), dried over anhydrous Na2S04, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography column on silica gel (EtOAc in PE = 0% to 5% to 10%) to give the product (2.3 g, 5.45 mmol) as a solid. 'H NMR (400 MHz, CDCI3) dH= 8.77 (d, 1H), 8.64 (d, 1H), 8.53 (d, 1H), 8.05 (dd, 1H), 1.88 (s, 6H). LCMS R, = 0.96 min in 1.5 min chromatography, MS ESI calcd. for Ci3HnClF4N30 [M+H]+336.0, found 335.9.A mixture of 5-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2- yl)-2-[(lR)-2, 2, 2-trifluoro-l-methy l-ethoxy]pyridine (200 g, 630.7 mmol), 2-bromo-5- chloro-pyrazine (122 g, 630.7 mmol) , Pd(dppf)Cl2(46.15 g, 63.07 mmol) and CS2CO3(513.7 g, 1.58 mol) in l, 4-dioxane (2000 mL) and water (500 mL) was stirred at 50C for 2 hours under N2. After cooling to 25 C, the mixture was separated and the organic phase was concentrated to remove most of dioxane. The residue was poured into water (1 L) and the mixture was extracted with EtOAc (800 mL x 2). The combined organic phase was washed with water (500 mL) and brine (500 mL), dried over anhydrous Na2S04, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 1% to 3% to 20%) to give the product (122 g, 401.75 mmol, 64% yield) as a solid. 'H NMR (400MHz, CDCl3) dH= 8.77 - 8.73 (m, 2H), 8.63 (d, 1H), 8.26 (dd, 1H), 6.96 (d, 1H), 5.93 - 5.82 (m, 1H), 1.54 (d, 3H).A mixture of 2-bromo-5-chloro-pyrazine (4 g, 20.68 mmol), 2-benzyloxy-5-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)pyridine (7.08 g, 22.75 mmol), CS2CO3 (l3.47g, 4l.36mmol) and Pd(dppf)Cl2 (1.51 g, 2.07 mmol) in l, 4-dioxane (50mL) and water (lOmL) was stirred at 50 C under N2 for 3 hours. After cooling to room temperature, the mixture was filtered and concentrated to give a residue. To the residue was added water (100 mL), extracted with EtOAc (150 mL x 2). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2S04, filtered and concentrated to give the crude product. The crude product was filtered through silica gel (~ 50 g) and eluted with DCM (150 mL x 3). The filtrate was concentrated to give the impure product. The impure product was triturated from /-Pi O (15 mL) to give the product of (4 g, 13.44 mmol, 65% yield) as a solid. LCMS Rt= 1.03 min in 1.5 min chromatography, 5-95AB, MS ESI calcd. for Ci6H13ClN30 [M+H]+298.1, found 297.9.A mixture of 2-bromo-5-chloro-pyrazine (4 g, 20.68 mmol), 2-benzyloxy-3-fluoro-5-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)pyridine (6.81 g, 20.68 mmol), CS2CO3 (13.47 g, 41.36 mmol) and Pd(dppf)Cl2 (2.27 g, 3.1 mmol) in 1, 4- dioxane (30 mL) and water (3 mL) was stirred at 50 C under N2 for 16 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated. Water (50 mL) was added and the aqueous layer was extracted with EtOAc (50 mL x 2). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2S04, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 15% to 30%) to give the product (5.5 g, 17.42 mmol, 84% yield) as a solid. 'H NMR (400MHz, DMSO-r) dH= 9.15 (s, 1H), 8.85 (s, 1H), 8.77 (s, 1H), 8.37 (d, 1H), 7.52 - 7.46 (m, 2H), 7.44 - 7.32 (m, 3H), 5.51 (s, 2H).A mixture of 5-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2- yl)-2-[(lS)-2, 2, 2-trifluoro-l-methyl-ethoxy]pyridine (600 mg, 1.89 mmol), 2-bromo-5- chloro-pyrazine (329.39 mg, 1.7 mmol), Pd(dppf)Cl2 (207.67 mg, 0.28 mmol) and CS2CO3 (1232.88 mg, 3.78 mmol) in l, 4-Dioxane (15 mL) and Water (1.5 mL) was stirred at 60 C for 5 hours under N2. After cooling to room temperature, the mixture was concentrated to give the residue. The residue was diluted with FLO (20 mL), and the mixture was extracted with EtOAc (30 mL x 2). The combined organic phase was washed with water (20 mL) and brine (20 mL), dried over Na2S04, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 3%) to give the product (350 mg, 1.15 mmol, 61% yield) as an oil. LCMS Rt= 0.95 min in 1.5 min chromatography, 5-95 AB, MS ESI calcd. for C i HioCIFiN iO [M+H]+304.0, found 304.1.A mixture of 5-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2- yl)-2-[l-(trifluoromethyl)cyclobutoxy]pyridine (2.1 g, 6.12 mmol), 2-bromo-5-chloro- pyrazine (1.18 g, 6.12 mmol), Pd(dppf)Cl2(671.68 mg, 0.92 mmol) and CS2CO3(3.99 g, 12.24 mmol) in l, 4-Dioxane (20 mL) and Water (2 mL)was stirred at 60 C for 6 hours under N2. After cooling to room temperature, the mixture was concentrated to give the residue. The residue was diluted with H2O (20 mL), and the mixture was extracted with EtOAc (20 mL x 2). The combined organic phase was washed with water (20 mL) and brine (40 mL), dried over Na2S04, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 1% to 10%) to give the product (1.5 g, 4.263mmol, 70% yield) as an oil. 'H NMR (CDCI3, 400MHz) 5H = 8.80 - 8.72 (m, 2H), 8.63 (d, 1H), 8.25 (dd, 1H), 6.91 (d, 1H), 3.01 - 2.83 (m, 2H), 2.78 - 2.62 (m, 2H), 2.18 - 1.84 (m, 2H).

Molecular Weight:193.43
XLogP3:1.6
Hydrogen Bond Acceptor Count:2
Exact Mass:191.90899
Monoisotopic Mass:191.90899
Topological Polar Surface Area:25.8
Heavy Atom Count:8
Complexity:80.4
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes