(3-bromo-5-chlorophenyl)methanamine

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

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

Procedure: Step G4. A mixture of 2-(3-Bromo-5-chlorobenzyl)isoindoline-1,3-dione (5.1 g, 14.6 mmol) and hydrazine monohydrate (0.8 g, 16 mmol) in ethanol (150 mL) was refluxed for 4 hours. Upon cooling to room temperature, a white solid precipitated. The solid was filtered and washed with ethanol, then dried in vacuum. 1H NMR (DMSO-d6) showed that the white solid is a mixture of 3-bromo-5-chlorobenzylamine and 2,3-dihydrophthalazine-1,4-dione. This material was used in subsequent steps without further purification. was refluxed for 4 hours a white solid precipitated The solid was filtered washed with ethanol dried in vacuum a mixture of 3-bromo-5-chlorobenzylamine and 2,3-dihydrophthalazine-1,4-dione This material was used in subsequent steps without further purification

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

Procedure: To 3-bromo-5-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 7 days. The solvent was pumped off and the reaction cautiously quenched with ethanol. When the 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 layer 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 dried over anhydrous Na2SO4, filtered, and evaporated to give the title compound as a clear oil. LC-MS m/z 219.7 (M+H)+, 1.42 min (ret time). the reaction cautiously quenched with ethanol 1N HCl was added until the pH was ˜2 The mixture was partitioned between EtOAc and water The aqueous layer was washed 3× with EtOAC extracted 3× with EtOAc The combined organics phases were dried over anhydrous Na2SO4 filtered evaporated

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

Procedure: To 3-bromo-5-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 7 days. The solvent was pumped off and the reaction cautiously quenched with ethanol. When the 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 layer 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 dried over anhydrous Na2SO4, filtered, and evaporated to give the title compound as a clear oil. LC-MS m/z 219.7 (M+H)+, 1.42 min (ret time). the reaction cautiously quenched with ethanol 1N HCl was added until the pH was ˜2 The mixture was partitioned between EtOAc and water The aqueous layer was washed 3× with EtOAC extracted 3× with EtOAc The combined organics phases were dried over anhydrous Na2SO4 filtered evaporated

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

Procedure: To 3-bromo-5-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 7 days. The solvent was pumped off and the reaction cautiously quenched with ethanol. When the 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 layer 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 dried over anhydrous Na2SO4, filtered, and evaporated to give the title compound as a clear oil. LC-MS m/z 219.7 (M+H)+, 1.42 min (ret time). the reaction cautiously quenched with ethanol 1N HCl was added until the pH was ˜2 The mixture was partitioned between EtOAc and water The aqueous layer was washed 3× with EtOAC extracted 3× with EtOAc The combined organics phases were dried over anhydrous Na2SO4 filtered evaporated

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 (677 mg, 1.5 mmol) was suspended in dichloromethane (DCM) (50 ml), and HBTU (569 mg, 1.5 mmol) was added, followed sequentially by 3-bromo-5-chlorobenzylamine (331 mg, 1.5 mmol), and TEA (0.418 mL, 3.0 mmol). The reaction mixture was stirred overnight under argon at room temperature to give a clear-colorless solution. The solvent was removed on a rotovap and the residue was partitioned between ethyl acetate (100 mL) and 1N NaOH (20 mL). The phases were separated and the organic phase was washed 2× with 1N NaOH (20 mL), and then 1× with brine (20 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. The crude product was taken up in dichloromethane and absorbed on Isolute® Sorbent and purified by CombiFlash on a 40 g silica column eluted with 0-10% DCM/MeOH to give the title compound as white solid. LC-MS m/z 652.9 (M+H)+, 2.08 min (ret time); mp 109-112° C.; analytical HPLC shows 97.6% purity, (ret time 13.921 min). to give a clear-colorless solution The solvent was removed on a rotovap the residue was partitioned between ethyl acetate (100 mL) and 1N NaOH (20 mL) The phases were separated the organic phase was washed 2× with 1N NaOH (20 mL) The organic layer was dried over anhydrous Na2SO4 filtered concentrated to give the crude product absorbed on Isolute® Sorbent purified by CombiFlash on a 40 g silica column eluted with 0-10% DCM/MeOH

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 (677 mg, 1.5 mmol) was suspended in dichloromethane (DCM) (50 ml), and HBTU (569 mg, 1.5 mmol) was added, followed sequentially by 3-bromo-5-chlorobenzylamine (331 mg, 1.5 mmol), and TEA (0.418 mL, 3.0 mmol). The reaction mixture was stirred overnight under argon at room temperature to give a clear-colorless solution. The solvent was removed on a rotovap and the residue was partitioned between ethyl acetate (100 mL) and 1N NaOH (20 mL). The phases were separated and the organic phase was washed 2× with 1N NaOH (20 mL), and then 1× with brine (20 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. The crude product was taken up in dichloromethane and absorbed on Isolute® Sorbent and purified by CombiFlash on a 40 g silica column eluted with 0-10% DCM/MeOH to give the title compound as white solid. LC-MS m/z 652.9 (M+H)+, 2.08 min (ret time); mp 109-112° C.; analytical HPLC shows 97.6% purity, (ret time 13.921 min). to give a clear-colorless solution The solvent was removed on a rotovap the residue was partitioned between ethyl acetate (100 mL) and 1N NaOH (20 mL) The phases were separated the organic phase was washed 2× with 1N NaOH (20 mL) The organic layer was dried over anhydrous Na2SO4 filtered concentrated to give the crude product absorbed on Isolute® Sorbent purified by CombiFlash on a 40 g silica column eluted with 0-10% DCM/MeOH

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

Procedure: To 3-bromo-5-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 7 days. The solvent was pumped off and the reaction cautiously quenched with ethanol. When bubbling ceased, 1N HCl was added until pH was ˜2. The mixture was stirred at 50° C. for 4 h. The mixture was partitioned between EtOAc and water. The aqueous was washed 3× with ethyl acetate. The aqueous was then adjusted to pH 10 with 2N NaOH and extracted 3× with EtOAc. The combined organics phases were dried over anhydrous Na2SO4, filtered, and concentrated to give the title compound as a clear oil. LC-MS m/z 219.7 (M+H)+, 1.42 min (ret time). the reaction cautiously quenched with ethanol When bubbling 1N HCl was added until pH was ˜2 The mixture was partitioned between EtOAc and water The aqueous was washed 3× with ethyl acetate extracted 3× with EtOAc The combined organics phases were dried over anhydrous Na2SO4 filtered concentrated

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

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

Procedure: Step G4. A mixture of 2-(3-Bromo-5-chlorobenzyl)isoindoline-1,3-dione (5.1 g, 14.6 mmol) and hydrazine monohydrate (0.8 g, 16 mmol) in ethanol (150 mL) was refluxed for 4 hours. Upon cooling to room temperature, a white solid precipitated. The solid was filtered and washed with ethanol, then dried in vacuum. 1H NMR (DMSO-d6) showed that the white solid is a mixture of 3-bromo-5-chlorobenzylamine and 2,3-dihydrophthalazine-1,4-dione. This material was used in subsequent steps without further purification. was refluxed for 4 hours a white solid precipitated The solid was filtered washed with ethanol dried in vacuum a mixture of 3-bromo-5-chlorobenzylamine and 2,3-dihydrophthalazine-1,4-dione This material was used in subsequent steps without further purification

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

Procedure: Step G4. A mixture of 2-(3-Bromo-5-chlorobenzyl)isoindoline-1,3-dione (5.1 g, 14.6 mmol) and hydrazine monohydrate (0.8 g, 16 mmol) in ethanol (150 mL) was refluxed for 4 hours. Upon cooling to room temperature, a white solid precipitated. The solid was filtered and washed with ethanol, then dried in vacuum. 1H NMR (DMSO-d6) showed that the white solid is a mixture of 3-bromo-5-chlorobenzylamine and 2,3-dihydrophthalazine-1,4-dione. This material was used in subsequent steps without further purification. was refluxed for 4 hours a white solid precipitated The solid was filtered washed with ethanol dried in vacuum a mixture of 3-bromo-5-chlorobenzylamine and 2,3-dihydrophthalazine-1,4-dione This material was used in subsequent steps without further purification

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

Procedure: To 3-bromo-5-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 7 days. The solvent was pumped off and the reaction cautiously quenched with ethanol. When the 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 layer 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 dried over anhydrous Na2SO4, filtered, and evaporated to give the title compound as a clear oil. LC-MS m/z 219.7 (M+H)+, 1.42 min (ret time). the reaction cautiously quenched with ethanol 1N HCl was added until the pH was ˜2 The mixture was partitioned between EtOAc and water The aqueous layer was washed 3× with EtOAC extracted 3× with EtOAc The combined organics phases were dried over anhydrous Na2SO4 filtered evaporated