(3-bromo-4-chlorophenyl)methanamine

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

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 3-bromo-4-chlorobenzamide (1.6 g, 6.8 mmol) in THF (10 mL) was added borane dimethyl sulfide complex (1.36 mL, 13.6 mmol) at room temperature. The mixture was then heated to 60° C. for 8 days. The solvent was pumped off and the reaction cautiously quenched with ethanol. When bubbling ceased, 1N HCl was added until the pH was ˜2. The mixture was stirred at 50° C. for 4 h. The mixture was partitioned between EtOAc and water. The aqueous phase was washed 3× with EtOAc. The aqueous phase was then adjusted to pH 10 with 2N NaOH and extracted 3× with EtOAc. The combined organics phases were washed with brine, dried over anhydrous Na2SO4, filtered, and evaporated to afford the title compound as a clear oil. LC-MS m/z 219.6 (M+H)+, 1.41 min (ret time). the reaction cautiously quenched with ethanol When bubbling 1N HCl was added until the pH was ˜2 The mixture was partitioned between EtOAc and water The aqueous phase was washed 3× with EtOAc extracted 3× with EtOAc The combined organics phases were washed with brine dried over anhydrous Na2SO4 filtered evaporated

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 (1,000 mg, 2.210 mmol), 1-(3-bromo-4-chlorophenyl)methanamine (487 mg, 2.210 mmol), HBTU (1,006 mg, 2.65 mmol) and Et3N (1.540 mL, 11.05 mmol) in DCM was stirred at room temperature over the weekend. The reaction 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 with flash chromatography eluting with 0 to 100% ethyl acetate in hexane (product came out at 100% ethyl acetate in hexane). The product fractions were combined to give N-[(3-bromo-4-chlorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-pyridinedicarboxamide (1,100 mg, 41%). LC-MS m/z 654.4 (M+H)+, 0.93 min (ret time). The reaction 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 with flash chromatography eluting with 0 to 100% ethyl acetate in hexane (product

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 (1,000 mg, 2.210 mmol), 1-(3-bromo-4-chlorophenyl)methanamine (487 mg, 2.210 mmol), HBTU (1,006 mg, 2.65 mmol) and Et3N (1.540 mL, 11.05 mmol) in DCM was stirred at room temperature over the weekend. The reaction 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 with flash chromatography eluting with 0 to 100% ethyl acetate in hexane (product came out at 100% ethyl acetate in hexane). The product fractions were combined to give N-[(3-bromo-4-chlorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-pyridinedicarboxamide (1,100 mg, 41%). LC-MS m/z 654.4 (M+H)+, 0.93 min (ret time). The reaction 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 with flash chromatography eluting with 0 to 100% ethyl acetate in hexane (product

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

Procedure: A mixture of 1-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]cyclopropanecarboxylic acid (600 mg, 1.444 mmol), HBTU (657 mg, 1.733 mmol), Et3N (1006 μL, 7.22 mmol) and 1-(3-bromo-4-chlorophenyl)methanamine (350 mg, 1.589 mmol) in DCM was stirred at room temperature overnight. 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 with a Gilson HPLC (acidic conditions: 0.1% TFA in the solvents), eluting with 10 to 70% CH3CN in water at a flow rate of 20 mL/min. The product fractions were combined and washed with saturated NaHCO3 and extracted with ethyl acetate twice. The combined organic layers were dried over sodium sulfate, filtered and then concentrated under vacuum to give N1-[(3-bromo-4-chlorophenyl)methyl]-N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,1-cyclopropanedicarboxamide (20 mg, 2.24%). LC-MS m/z 617 M+, 0.92 min (ret time). 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 with a Gilson HPLC (acidic conditions 0.1% TFA in the solvents), eluting with 10 to 70% CH3CN in water at a flow rate of 20 mL/min washed with saturated NaHCO3 extracted with ethyl acetate twice The combined organic layers were dried over sodium sulfate filtered concentrated under vacuum

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

Procedure: A mixture of 1-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]cyclopropanecarboxylic acid (600 mg, 1.444 mmol), HBTU (657 mg, 1.733 mmol), Et3N (1006 μL, 7.22 mmol) and 1-(3-bromo-4-chlorophenyl)methanamine (350 mg, 1.589 mmol) in DCM was stirred at room temperature overnight. 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 with a Gilson HPLC (acidic conditions: 0.1% TFA in the solvents), eluting with 10 to 70% CH3CN in water at a flow rate of 20 mL/min. The product fractions were combined and washed with saturated NaHCO3 and extracted with ethyl acetate twice. The combined organic layers were dried over sodium sulfate, filtered and then concentrated under vacuum to give N1-[(3-bromo-4-chlorophenyl)methyl]-N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,1-cyclopropanedicarboxamide (20 mg, 2.24%). LC-MS m/z 617 M+, 0.92 min (ret time). 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 with a Gilson HPLC (acidic conditions 0.1% TFA in the solvents), eluting with 10 to 70% CH3CN in water at a flow rate of 20 mL/min washed with saturated NaHCO3 extracted with ethyl acetate twice The combined organic layers were dried over sodium sulfate filtered concentrated under vacuum

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 3-bromo-4-chlorobenzamide (1.6 g, 6.8 mmol) in THF (10 mL) was added borane dimethyl sulfide complex (1.36 mL, 13.6 mmol) at room temperature. The mixture was then heated to 60° C. for 8 days. The solvent was pumped off and the reaction cautiously quenched with ethanol. When bubbling ceased, 1N HCl was added until the pH was ˜2. The mixture was stirred at 50° C. for 4 h. The mixture was partitioned between EtOAc and water. The aqueous phase was washed 3× with EtOAc. The aqueous phase was then adjusted to pH 10 with 2N NaOH and extracted 3× with EtOAc. The combined organics phases were washed with brine, dried over anhydrous Na2SO4, filtered, and evaporated to afford the title compound as a clear oil. LC-MS m/z 219.6 (M+H)+, 1.41 min (ret time). the reaction cautiously quenched with ethanol When bubbling 1N HCl was added until the pH was ˜2 The mixture was partitioned between EtOAc and water The aqueous phase was washed 3× with EtOAc extracted 3× with EtOAc The combined organics phases were washed with brine dried over anhydrous Na2SO4 filtered evaporated

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 3-bromo-4-chlorobenzamide (1.6 g, 6.8 mmol) in THF (10 mL) was added borane dimethyl sulfide complex (1.36 mL, 13.6 mmol) at room temperature. The mixture was then heated to 60° C. for 8 days. The solvent was pumped off and the reaction cautiously quenched with ethanol. When bubbling ceased, 1N HCl was added until the pH was ˜2. The mixture was stirred at 50° C. for 4 h. The mixture was partitioned between EtOAc and water. The aqueous phase was washed 3× with EtOAc. The aqueous phase was then adjusted to pH 10 with 2N NaOH and extracted 3× with EtOAc. The combined organics phases were washed with brine, dried over anhydrous Na2SO4, filtered, and evaporated to afford the title compound as a clear oil. LC-MS m/z 219.6 (M+H)+, 1.41 min (ret time). the reaction cautiously quenched with ethanol When bubbling 1N HCl was added until the pH was ˜2 The mixture was partitioned between EtOAc and water The aqueous phase was washed 3× with EtOAc extracted 3× with EtOAc The combined organics phases were washed with brine dried over anhydrous Na2SO4 filtered evaporated

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

Procedure: In a 100 mL round-bottomed flask was added 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-chlorophenyl)methanamine (0.595 g, 2.7 mmol), HATU (1.065 g, 2.8 mmol) and triethylamine (0.641 ml, 4.6 mmol) in dichloromethane (35 mL) to give a yellow suspension. The mixture was stirred overnight at room temperature. The reaction was quenched with saturated NaHCO3 and diluted with DCM. The organic layer were separated, then washed with water followed by saturated NaCl. The organic layer was dried over Na2SO4 and evaporated to a small volume, about 15 mL, from which a crystalline solid appeared which was collected, washed very sparingly with DCM and dried to give N-[(3-bromo-4-chlorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}butanediamide (1 g, 66.6%) as a solid. LC-MS m/z 605.5 (M+H)+, 0.75 min (ret time). to give a yellow suspension The reaction was quenched with saturated NaHCO3 diluted with DCM The organic layer were separated washed with water The organic layer was dried over Na2SO4 evaporated to a small volume, about 15 mL, from which a crystalline solid was collected washed very sparingly with DCM dried

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

Procedure: A solution of 3-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-3-oxopropanoic acid (600 mg, 1.541 mmol), 1-(3-bromo-4-chlorophenyl)methanamine (397 mg, 1.8 mmol), HATU (760 mg, 2.0 mmol), and triethylamine (0.488 ml, 3.5 mmol) in 25 mL of DCM was stirred at room temperature overnight. The reaction mixture was diluted with DCM, washed with saturated NaHCO3, water and saturated NaCl. The organic layer was dried over Na2SO4 and evaporated to a pale amber residue. This was purified on 80 g. Combi-Flash column with DCM [0-8% MeOH] to give N-[(3-bromo-4-chlorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}propanediamide. LC-MS m/z 591.2 (M+H)+, 0.84 min (ret time). washed with saturated NaHCO3, water and saturated NaCl The organic layer was dried over Na2SO4 evaporated to a pale amber residue This was purified on 80 g

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

Procedure: A solution of 3-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-3-oxopropanoic acid (600 mg, 1.541 mmol), 1-(3-bromo-4-chlorophenyl)methanamine (397 mg, 1.8 mmol), HATU (760 mg, 2.0 mmol), and triethylamine (0.488 ml, 3.5 mmol) in 25 mL of DCM was stirred at room temperature overnight. The reaction mixture was diluted with DCM, washed with saturated NaHCO3, water and saturated NaCl. The organic layer was dried over Na2SO4 and evaporated to a pale amber residue. This was purified on 80 g. Combi-Flash column with DCM [0-8% MeOH] to give N-[(3-bromo-4-chlorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}propanediamide. LC-MS m/z 591.2 (M+H)+, 0.84 min (ret time). washed with saturated NaHCO3, water and saturated NaCl The organic layer was dried over Na2SO4 evaporated to a pale amber residue This was purified on 80 g

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

Procedure: 3-[({[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]benzoic acid (0.564 g, 1.25 mmol), [(3-bromo-4-chlorophenyl)methyl]amine (0.275 g, 1.25 mmol, HBTU (0.474 g, 1.25 mmol), and TEA (0.348 mL, 2.5 mmol) were combined in CH2Cl2 (30 mL). The mixture was stirred overnight at room temperature. The reaction mixture was concentrated to dryness. Residue taken up in EtOAc, washed with 1 N NaOH, brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product. It was purified further using CombiFlash on a 40 g column eluted with 0-10% MeOH/CH2Cl2 to give the title compound as a white solid. LC-MS m/z 652.9 (M+H)+, 1.91 min (ret time); mp 115-117° C.; analytical HPLC shows 98.4% purity, (ret time 13.689 min). The reaction mixture was concentrated to dryness washed with 1 N NaOH, brine dried over anhydrous Na2SO4 filtered concentrated to give the crude product It was purified further using CombiFlash on a 40 g column eluted with 0-10% MeOH/CH2Cl2