(3-bromo-4-fluorophenyl)methanamine

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

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

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

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

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

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

Conditions: temp:15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To two vials which each contained a solution of [(3-bromo-4-fluorophenyl)methyl]amine hydrochloric salt (0.601 g, 2.5 mmol) in p-dioxane/H2O (15/5 mL) was each added {3-[(4-{[(1,1-dimethylethyl)oxy]carbonyl}-1-piperazinyl)methyl]phenyl}boronic acid (1.2 g, 3.75 mmol), Pd(PPh3)4 (145 mg, 0.125 mmol), and K2CO3 (1.38 g, 10 mmol). The resulting mixture was heated in a microwave machine at about 15° C. for about 15 mins. The organic layer of both vials was separated, combined, concentrated and purified by CombiFlash chomatograph to afford 1.98 g (99%) of the title compound. LC-MS m/z 400 (M+H)+. The organic layer of both vials was separated concentrated purified by CombiFlash chomatograph

Conditions: temp:15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To two vials which each contained a solution of [(3-bromo-4-fluorophenyl)methyl]amine hydrochloric salt (0.601 g, 2.5 mmol) in p-dioxane/H2O (15/5 mL) was each added {3-[(4-{[(1,1-dimethylethyl)oxy]carbonyl}-1-piperazinyl)methyl]phenyl}boronic acid (1.2 g, 3.75 mmol), Pd(PPh3)4 (145 mg, 0.125 mmol), and K2CO3 (1.38 g, 10 mmol). The resulting mixture was heated in a microwave machine at about 15° C. for about 15 mins. The organic layer of both vials was separated, combined, concentrated and purified by CombiFlash chomatograph to afford 1.98 g (99%) of the title compound. LC-MS m/z 400 (M+H)+. The organic layer of both vials was separated concentrated purified by CombiFlash chomatograph

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

Procedure: A mixture of 6-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-pyridinecarboxylic acid (900 mg, 1.989 mmol), 1-(3-bromo-4-fluorophenyl)methanamine (406 mg, 1.989 mmol), HBTU (905 mg, 2.387 mmol) and Et3N (1.386 mL, 9.94 mmol) in DCM was stirred at room temperature overnight. The reaction did not go to completion overnight. An additional equivalent of each reagent was added and the reaction stirred over the weekend. The reaction mixture was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were washed with brine and then concentrated under vacuum to give the crude residue. It was then purified using flash chromatography eluting with 0 to 100% ethyl acetate in hexane (product came out at 100% ethyl acetate in hexane). However, this product batch was not pure. It was purified with a Gilson HPLC. Product crashed out from the HPLC solution. The solid was filtered to obtain N-[(3-bromo-4-fluorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-pyridinedicarboxamide (120 mg) as a solid. The mother liquor was purified with a Gilson HPLC to obtain another batch of N-[(3-bromo-4-fluorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-pyridinedicarboxamide (160 mg). LC-MS m/z 638.4 (M+H)+, 0.89 min (ret time). did not go to completion overnight An additional equivalent of each reagent was added the reaction stirred over the weekend The reaction mixture was quenched with saturated NaHCO3 extracted with DCM twice The combined organic layers were washed with brine concentrated under vacuum to give the crude residue It was then purified eluting with 0 to 100% ethyl acetate in hexane (product It was purified with a Gilson HPLC The solid was filtered

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

Procedure: A mixture of 6-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-pyridinecarboxylic acid (900 mg, 1.989 mmol), 1-(3-bromo-4-fluorophenyl)methanamine (406 mg, 1.989 mmol), HBTU (905 mg, 2.387 mmol) and Et3N (1.386 mL, 9.94 mmol) in DCM was stirred at room temperature overnight. The reaction did not go to completion overnight. An additional equivalent of each reagent was added and the reaction stirred over the weekend. The reaction mixture was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were washed with brine and then concentrated under vacuum to give the crude residue. It was then purified using flash chromatography eluting with 0 to 100% ethyl acetate in hexane (product came out at 100% ethyl acetate in hexane). However, this product batch was not pure. It was purified with a Gilson HPLC. Product crashed out from the HPLC solution. The solid was filtered to obtain N-[(3-bromo-4-fluorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-pyridinedicarboxamide (120 mg) as a solid. The mother liquor was purified with a Gilson HPLC to obtain another batch of N-[(3-bromo-4-fluorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-pyridinedicarboxamide (160 mg). LC-MS m/z 638.4 (M+H)+, 0.89 min (ret time). did not go to completion overnight An additional equivalent of each reagent was added the reaction stirred over the weekend The reaction mixture was quenched with saturated NaHCO3 extracted with DCM twice The combined organic layers were washed with brine concentrated under vacuum to give the crude residue It was then purified eluting with 0 to 100% ethyl acetate in hexane (product It was purified with a Gilson HPLC The solid was filtered

Conditions: temp:15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To two vials which each contained a solution of [(3-bromo-4-fluorophenyl)methyl]amine hydrochloric salt (0.601 g, 2.5 mmol) in p-dioxane/H2O (15/5 mL) was each added {3-[(4-{[(1,1-dimethylethyl)oxy]carbonyl}-1-piperazinyl)methyl]phenyl}boronic acid (1.2 g, 3.75 mmol), Pd(PPh3)4 (145 mg, 0.125 mmol), and K2CO3 (1.38 g, 10 mmol). The resulting mixture was heated in a microwave machine at about 15° C. for about 15 mins. The organic layer of both vials was separated, combined, concentrated and purified by CombiFlash chomatograph to afford 1.98 g (99%) of the title compound. LC-MS m/z 400 (M+H)+. The organic layer of both vials was separated concentrated purified by CombiFlash chomatograph

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

Procedure: A solution of 4-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-4-oxobutanoic acid (1.0 g, 2.478 mmol), 1-(3-bromo-4-fluorophenyl)methanamine (0.648 g, 2.69 mmol), HATU (1.065 g, 2.8 mmol) and triethylamine (0.781 mL, 5.6 mmol) in dichloromethane (45 mL) was stirred overnight at room temperature. The reaction mixture was diluted with DCM, washed with saturated NaHCO3, water and saturated NaCl, and dried over Na2SO4. The organic layer was evaporated to give a pale amber residue. The residue was triturated with a small amount of DCM, then sonicated to give a uniform mixture. A white solid was collected and dried to afford N-[(3-bromo-4-fluorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}butanediamide (1.08 g, 73.9%) as a crystalline solid. LC-MS m/z 589.1 (M+H)+, 0.79 min (ret time). washed with saturated NaHCO3, water and saturated NaCl dried over Na2SO4 The organic layer was evaporated to give a pale amber residue The residue was triturated with a small amount of DCM sonicated to give a uniform mixture A white solid was collected dried