1-BOC-4-BROMO-1H-INDAZOLE

To a solution of 4-bromoindazole (1.0 g, 5.07 mmol) in DCM (20 ml) was added TEA (0.85 ml, 6.1 mmol) and DMAP (0.062 g, 0.50 mmol) at rt. Boc anhydride (1.28 ml, 5.58 mmol) was added drop wise to the reaction mixture at rt. The reaction mixture was stirred at rt for 2.5 h. The resulting reaction mixture was poured in to water (30 ml) and extracted with DCM (2 x 30 ml). The combined organic phase was dried over NaGeneral procedure: tert-Butyl 3-bromo 1H-indazole-1-carboxylate (0.5 mmol), Na2CO3(0.5 mmol), boronic acid (1.0 mmol), Pd(PPh3)2Cl2 (1 mol%), and 1, 4-dioxane: ethanol = 4:1 (5 mL) were added to10 mL vial. The vial was sealed with a crimp cap and placed in a Biotage initiator microwave cavity. After thereaction vial was irradiated at 140 C for 30 min, themicrowave reactor was cooled with air. Product was separatedwith ethyl acetate and saturated aqueous NH4Cl solution.The organic layer was dried with anhydrous sodiumsulfate, filtered, and concentrated. Products were purifiedby silica gel column chromatography using a hexane: ethylacetate = 4:1.General procedure: tert-Butyl 3-bromo 1H-indazole-1-carboxylate (0.5 mmol), Na2CO3(0.5 mmol), boronic acid (1.0 mmol), Pd(PPh3)2Cl2 (1 mol%), and 1, 4-dioxane: ethanol = 4:1 (5 mL) were added to10 mL vial. The vial was sealed with a crimp cap and placed in a Biotage initiator microwave cavity. After thereaction vial was irradiated at 140 C for 30 min, themicrowave reactor was cooled with air. Product was separatedwith ethyl acetate and saturated aqueous NH4Cl solution.The organic layer was dried with anhydrous sodiumsulfate, filtered, and concentrated. Products were purifiedby silica gel column chromatography using a hexane: ethylacetate = 4:1.General procedure: tert-Butyl 3-bromo 1H-indazole-1-carboxylate (0.5 mmol), Na2CO3(0.5 mmol), boronic acid (1.0 mmol), Pd(PPh3)2Cl2 (1 mol%), and 1, 4-dioxane: ethanol = 4:1 (5 mL) were added to10 mL vial. The vial was sealed with a crimp cap and placed in a Biotage initiator microwave cavity. After thereaction vial was irradiated at 140 C for 30 min, themicrowave reactor was cooled with air. Product was separatedwith ethyl acetate and saturated aqueous NH4Cl solution.The organic layer was dried with anhydrous sodiumsulfate, filtered, and concentrated. Products were purifiedby silica gel column chromatography using a hexane: ethylacetate = 4:1.General procedure: tert-Butyl 3-bromo 1H-indazole-1-carboxylate (0.5 mmol), Na2CO3(0.5 mmol), boronic acid (1.0 mmol), Pd(PPh3)2Cl2 (1 mol%), and 1, 4-dioxane: ethanol = 4:1 (5 mL) were added to10 mL vial. The vial was sealed with a crimp cap and placed in a Biotage initiator microwave cavity. After thereaction vial was irradiated at 140 C for 30 min, themicrowave reactor was cooled with air. Product was separatedwith ethyl acetate and saturated aqueous NH4Cl solution.The organic layer was dried with anhydrous sodiumsulfate, filtered, and concentrated. Products were purifiedby silica gel column chromatography using a hexane: ethylacetate = 4:1.To a stirred solution of tert-butyl 4-bromo-lH-indazole-l-carboxylate (0.3 g, 1.01 mmol) and tert-butyl (4-methoxybenzyl)(5-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)thiazol-2-yl)carbamate (0.67 g, 1.515 mmol) in toluene:water (9: 1, 10 ml) was added Na2C03(0.21 g, 2.02 mmol) at rt. The reaction mixture was degassed for 20 min at rt. Pd(dppf)Cl2(0.074 g, 0.101 mmol) was added to the reaction mixture at rt. The reaction mixture was heated at 105C for 1 h. The resulting reaction mixture was allowed to cool at rt, poured into water (20 ml) and extracted with EtOAc (2 x 20 ml). The combined organic phase was separated, dried over Na2S04, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (7-20% EtOAc in hexane) yielding tert-butyl 4-(2-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)thiazol-5-yl)-lH- indazole-l-carboxylate (0.44 g, 0.819 mmol). LCMS: Method C, 3.27 min, MS: ES+ 537.53.Step a. To a stirred solution of 4-bromo-lH-indazole (3.00 g, 15.22 mmol) in DCM (30 ml) were added DMAP (0.18 g, 1.52 mmol), TEA (1.84 g, 18.27 mmol) and BOC anhydride (3.7 ml, 16.75 mmol) at rt. The reaction mixture stirred at rt for 3 h, poured into water (100 ml) and extracted with DCM (3 x 30 ml). The combined organic phase was collected, dried over Na2S04, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (20% EtOAc in hexane) yielding a mixture in approximately 60:40 ratio of regio-isomers tert-butyl 4-bromo-lH-indazole-l-carboxylate and tert-butyl 4- bromo-2H-indazole-2-carboxylate (3.2 g, 10.77 mmol). LCMS: Method A, 2.50 min, 2.61 min, MS: ES+ 297.14.A. tert-Butyl 4-bromo-1H-indazole-1-carboxylate; To a solution of 4-bromo indazole (1.2 g, 5.6 mmol, ) in THF (15 mL) was added DMAP (0.068g, 0.56mmol) followed by BOC-anhydride (1.8 g, 8.4 mmol) and this was stirred at rt. for 5 h. THF was evaporated and the residue was extracted with dichloromethane (3 X 75ml_) which was washed successively with potassium hydrogen sulfate(10%) solution (10 mL X2), followed by water (10 mL), dried over sodium sulfate and concentrated in vacuo to give a gum which was purified on a Biotage- S silica gel column using hexane/ethyl acetate (80-100%) to give a colorless foam.To a solution of 4-bromoindazole (1.0 g, 5.07 mmol) in DCM (20 ml) was added TEA (0.85 ml, 6.1 mmol) and DMAP (0.062 g, 0.50 mmol) at rt. Boc anhydride (1.28 ml, 5.58 mmol) was added drop wise to the reaction mixture at rt. The reaction mixture was stirred at rt for 2.5 h. The resulting reaction mixture was poured in to water (30 ml) and extracted with DCM (2 x 30 ml). The combined organic phase was dried over Na2S04, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (15-20% EtOAc in hexane) yielding tert-butyl 4- bromo-lH-indazole-l-carboxylate (1.5 g, 5.06 mmol). LCMS: Method C, 2.601 min, MS: ES+ 297.19; NMR (400 MHz, DMSO-d6) delta ppm: 8.20 (s, 1 H), 8.15 (d, J=8.0 Hz, 1 H), 7.47 (dd, J=0.8 Hz, 7.6 Hz, 1 H), 7.37 - 7.41 (m, 1 H), 1.74 (s, 9 H).

Molecular Weight:297.15
XLogP3:3.5
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:296.01604
Monoisotopic Mass:296.01604
Topological Polar Surface Area:44.1
Heavy Atom Count:17
Complexity:303
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes