Tert-butyl 5-bromo-2-methylbenzylcarbamate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1,1-Dimethylethyl [(5-bromo-2-methylphenyl)methyl]carbamate (2.7 g, 9.0 mmol), Pd(OAc)2 (81 mg, 0.36 mmol), dicyclohexyl [2′-(methyloxy)-1,1′-binaphthalen-2-yl]phosphane (216 mg, 0.45 mmol) and K3PO4 (2.5 g, 11.7 mmol) were dissolved in dioxane (50 mL). The mixture was heated at 80° C. for 30 min, and then [3-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)phenyl]boronic acid (3.1 g, 11.7 mmol) was added. The mixture reaction was stirred at reflux for two days. The solvent was removed under reduced pressure, then diluted with CH2Cl2 (100 mL). The organic layer was washed with water (30 mL), brine (30 mL), and dried over Na2SO4. After removing the solvent, 3.6 g of the crude product 1,1-dimethylethyl {[3′-({[(1,1-dimethylethyl)-(dimethyl)silyl]oxy}methyl)-4-methyl-3-biphenylyl]methyl}carbamate was obtained (yield: 90%). The mixture reaction at reflux for two days The solvent was removed under reduced pressure diluted with CH2Cl2 (100 mL) The organic layer was washed with water (30 mL), brine (30 mL) dried over Na2SO4 After removing the solvent

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a clear solution of 1,1-dimethylethyl [(5-bromo-2-methylphenyl)methyl]carbamate (923 mg, 3.01 mmol) in DCM (10 mL) was added 4N HCl in dioxane (3 mL). Solid precipitated out from the solution after 30 min. The mixture was stirred at RT for another 1 h. It was then concentrated under vacuum to get rid of solvent. The resulting residue was re-dissolved in DCM. Et3N (1.5 mL, 10.3 mmol) was added followed by 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-carbonyl]benzoic acid (1000 mg, 2.05 mmol) and HBTU (933 mg, 2.46 mmol). The mixture was stirred at RT overnight. The reaction was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were then washed with water followed by the brine wash. The organic layer was then concentrated under vacuum to give a crude residue. It was then purified with CombiFlash chromatography, eluting with 0 to 10% methanol in DCM to obtain N-[(5-bromo-2-methylphenyl)methyl]-N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide as a solid (1.4 g, 98%). LC-MS m/z 634 (M+H)+. Solid precipitated out from the solution after 30 min It was then concentrated under vacuum to get rid of solvent The mixture was stirred at RT overnight The reaction was quenched with saturated NaHCO3 extracted with DCM twice The combined organic layers were then washed with water wash The organic layer was then concentrated under vacuum to give a crude residue It was then purified with CombiFlash chromatography eluting with 0 to 10% methanol in DCM

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a clear solution of 1,1-dimethylethyl [(5-bromo-2-methylphenyl)methyl]carbamate (923 mg, 3.01 mmol) in DCM (10 mL) was added 4N HCl in dioxane (3 mL). Solid precipitated out from the solution after 30 min. The mixture was stirred at RT for another 1 h. It was then concentrated under vacuum to get rid of solvent. The resulting residue was re-dissolved in DCM. Et3N (1.5 mL, 10.3 mmol) was added followed by 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-carbonyl]benzoic acid (1000 mg, 2.05 mmol) and HBTU (933 mg, 2.46 mmol). The mixture was stirred at RT overnight. The reaction was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were then washed with water followed by the brine wash. The organic layer was then concentrated under vacuum to give a crude residue. It was then purified with CombiFlash chromatography, eluting with 0 to 10% methanol in DCM to obtain N-[(5-bromo-2-methylphenyl)methyl]-N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide as a solid (1.4 g, 98%). LC-MS m/z 634 (M+H)+. Solid precipitated out from the solution after 30 min It was then concentrated under vacuum to get rid of solvent The mixture was stirred at RT overnight The reaction was quenched with saturated NaHCO3 extracted with DCM twice The combined organic layers were then washed with water wash The organic layer was then concentrated under vacuum to give a crude residue It was then purified with CombiFlash chromatography eluting with 0 to 10% methanol in DCM

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1,1-Dimethylethyl [(5-bromo-2-methylphenyl)methyl]carbamate (2.7 g, 9.0 mmol), Pd(OAc)2 (81 mg, 0.36 mmol), dicyclohexyl[2′-(methyloxy)-1,1′-binaphthalen-2-yl]phosphane (216 mg, 0.45 mmol) and K3PO4 (2.5 g, 11.7 mmol) were dissolved in dioxane (50 mL). The mixture was heated at 80° C. for 30 min, and then [3-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)phenyl]boronic acid (3.1 g, 11.7 mmol) was added. The mixture reaction was stirred at reflux for two days. The solvent was removed under reduced pressure, then diluted with CH2Cl2 (100 mL). The organic layer was washed with water (30 mL), brine (30 mL), and dried over Na2SO4. After removing the solvent, 3.6 g of the crude product 1,1-dimethylethyl {[3′-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-4-methyl-3-biphenylyl]methyl}carbamate was obtained. Yield: 90%. The mixture reaction at reflux for two days The solvent was removed under reduced pressure diluted with CH2Cl2 (100 mL) The organic layer was washed with water (30 mL), brine (30 mL) dried over Na2SO4 After removing the solvent

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1,1-Dimethylethyl [(5-bromo-2-methylphenyl)methyl]carbamate (2.7 g, 9.0 mmol), Pd(OAc)2 (81 mg, 0.36 mmol), dicyclohexyl [2′-(methyloxy)-1,1′-binaphthalen-2-yl]phosphane (216 mg, 0.45 mmol) and K3PO4 (2.5 g, 11.7 mmol) were dissolved in dioxane (50 mL). The mixture was heated at 80° C. for 30 min, and then [3-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)phenyl]boronic acid (3.1 g, 11.7 mmol) was added. The mixture reaction was stirred at reflux for two days. The solvent was removed under reduced pressure, then diluted with CH2Cl2 (100 mL). The organic layer was washed with water (30 mL), brine (30 mL), and dried over Na2SO4. After removing the solvent, 3.6 g of the crude product 1,1-dimethylethyl {[3′-({[(1,1-dimethylethyl)-(dimethyl)silyl]oxy}methyl)-4-methyl-3-biphenylyl]methyl}carbamate was obtained (yield: 90%). The mixture reaction at reflux for two days The solvent was removed under reduced pressure diluted with CH2Cl2 (100 mL) The organic layer was washed with water (30 mL), brine (30 mL) dried over Na2SO4 After removing the solvent

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a clear solution of 1,1-dimethylethyl [(5-bromo-2-methylphenyl)methyl]carbamate (923 mg, 3.01 mmol) in DCM (10 mL) was added 4N HCl in dioxane (3 mL). Solid precipitated out from the solution after 30 min. The mixture was stirred at RT for another 1 h. It was then concentrated under vacuum to get rid of solvent. The resulting residue was re-dissolved in DCM. Et3N (1.5 mL, 10.3 mmol) was added followed by 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-carbonyl]benzoic acid (1000 mg, 2.05 mmol) and HBTU (933 mg, 2.46 mmol). The mixture was stirred at RT overnight. The reaction was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were then washed with water followed by the brine wash. The organic layer was then concentrated under vacuum to give a crude residue. It was then purified with CombiFlash chromatography, eluting with 0 to 10% methanol in DCM to obtain N-[(5-bromo-2-methylphenyl)methyl]-N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide as a solid (1.4 g, 98%). LC-MS m/z 634 (M+H)+. Solid precipitated out from the solution after 30 min It was then concentrated under vacuum to get rid of solvent The mixture was stirred at RT overnight The reaction was quenched with saturated NaHCO3 extracted with DCM twice The combined organic layers were then washed with water wash The organic layer was then concentrated under vacuum to give a crude residue It was then purified with CombiFlash chromatography eluting with 0 to 10% methanol in DCM

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1,1-Dimethylethyl [(5-bromo-2-methylphenyl)methyl]carbamate (2.7 g, 9.0 mmol), Pd(OAc)2 (81 mg, 0.36 mmol), dicyclohexyl[2′-(methyloxy)-1,1′-binaphthalen-2-yl]phosphane (216 mg, 0.45 mmol) and K3PO4 (2.5 g, 11.7 mmol) were dissolved in dioxane (50 mL). The mixture was heated at 80° C. for 30 min, and then [3-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)phenyl]boronic acid (3.1 g, 11.7 mmol) was added. The mixture reaction was stirred at reflux for two days. The solvent was removed under reduced pressure, then diluted with CH2Cl2 (100 mL). The organic layer was washed with water (30 mL), brine (30 mL), and dried over Na2SO4. After removing the solvent, 3.6 g of the crude product 1,1-dimethylethyl {[3′-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-4-methyl-3-biphenylyl]methyl}carbamate was obtained. Yield: 90%. The mixture reaction at reflux for two days The solvent was removed under reduced pressure diluted with CH2Cl2 (100 mL) The organic layer was washed with water (30 mL), brine (30 mL) dried over Na2SO4 After removing the solvent