(3-bromo-4-methoxyphenyl)methanamine

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

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Bromo-4-(methyloxy)benzonitrile (2.12 g, 10 mmol), THF (30 mL), and 1.5 M borane in THF (30 mL, 45 mmols) were combined and stirred under argon at reflux, Then additional 1.5 M borane in THF (30 mL, 45 mmols) was added and refluxing was continued. THF (30 mL), and 1.5 M borane in THF (30 mL, 45 mmols) was again added and the mixture refluxed for a total of ten days to drive the reaction to completion. Reaction worked up by the cautious addition of ethanol followed by 1N HCl until the pH was 2. The mixture was then heated to 50° C. for 4 h. The solvents were pumped off and the residue partitioned between EtOAc and water. The aqueous phase was washed 3× with EtOAc, and adjusted to pH 10 by the addition of 2.5 N NaOH. The aqueous phase was extracted 3× with EtOAc. The combined organic phases were dried over anhydrous Na2SO4, filtered and evaporated to give the title compound. at reflux refluxing the mixture refluxed for a total of ten days the reaction to completion Reaction the residue partitioned between EtOAc and water The aqueous phase was washed 3× with EtOAc adjusted to pH 10 by the addition of 2.5 N NaOH The aqueous phase was extracted 3× with EtOAc The combined organic phases were dried over anhydrous Na2SO4 filtered evaporated

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 {[3-bromo-4-(methyloxy)phenyl]-methyl}amine (343 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-(methyloxy)phenyl]methyl}-N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,1-cyclopropanedicarboxamide (100 mg, 11.29%). LC-MS m/z 613 M+, 0.83 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:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Bromo-4-(methyloxy)benzonitrile (2.12 g, 10 mmol), THF (30 mL), and 1.5 M borane in THF (30 mL, 45 mmols) were combined and stirred under argon at reflux, Then additional 1.5 M borane in THF (30 mL, 45 mmols) was added and refluxing was continued. THF (30 mL), and 1.5 M borane in THF (30 mL, 45 mmols) was again added and the mixture refluxed for a total of ten days to drive the reaction to completion. Reaction worked up by the cautious addition of ethanol followed by 1N HCl until the pH was 2. The mixture was then heated to 50° C. for 4 h. The solvents were pumped off and the residue partitioned between EtOAc and water. The aqueous phase was washed 3× with EtOAc, and adjusted to pH 10 by the addition of 2.5 N NaOH. The aqueous phase was extracted 3× with EtOAc. The combined organic phases were dried over anhydrous Na2SO4, filtered and evaporated to give the title compound. at reflux refluxing the mixture refluxed for a total of ten days the reaction to completion Reaction the residue partitioned between EtOAc and water The aqueous phase was washed 3× with EtOAc adjusted to pH 10 by the addition of 2.5 N NaOH The aqueous phase was extracted 3× with EtOAc The combined organic phases were dried over anhydrous Na2SO4 filtered evaporated

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Bromo-4-(methyloxy)benzonitrile (2.12 g, 10 mmol), THF (30 mL), and 1.5 M borane in THF (30 mL, 45 mmols) were combined and stirred under argon at reflux, Then additional 1.5 M borane in THF (30 mL, 45 mmols) was added and refluxing was continued. THF (30 mL), and 1.5 M borane in THF (30 mL, 45 mmols) was again added and the mixture refluxed for a total of ten days to drive the reaction to completion. Reaction worked up by the cautious addition of ethanol followed by 1N HCl until the pH was 2. The mixture was then heated to 50° C. for 4 h. The solvents were pumped off and the residue partitioned between EtOAc and water. The aqueous phase was washed 3× with EtOAc, and adjusted to pH 10 by the addition of 2.5 N NaOH. The aqueous phase was extracted 3× with EtOAc. The combined organic phases were dried over anhydrous Na2SO4, filtered and evaporated to give the title compound. at reflux refluxing the mixture refluxed for a total of ten days the reaction to completion Reaction the residue partitioned between EtOAc and water The aqueous phase was washed 3× with EtOAc adjusted to pH 10 by the addition of 2.5 N NaOH The aqueous phase was extracted 3× with EtOAc The combined organic phases were dried over anhydrous Na2SO4 filtered evaporated

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

Procedure: A mixture 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) and 1-[3-bromo-4-(methyloxy)phenyl]methanamine (0.581 g, 2.69 mmol), HATU (1.065 g, 2.8 mmol) and triethylamine (0.781 ml, 5.6 mmol) was stirred in dichloromethane (45 mL) at room temperature overnight. The reaction mixture was diluted with DCM, washed with saturated NaHCO3, followed by saturated NaCl. The organic layer was dried over Na2SO4 and then evaporated to dryness which gave, initially, a glassy gum, but which then appeared to crystallize. The residue was taken up in a small amount of MeOH and sonicated for a while. A crystalline white solid formed and was collected and dried to afforded N-{[3-bromo-4-(methyloxy)phenyl]methyl}-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}butanediamide (804 mg, 53.9%) as a white solid. LC-MS m/z 601.3 (M+H)+, 0.77 min (ret time). washed with saturated NaHCO3 The organic layer was dried over Na2SO4 evaporated to dryness which gave to crystallize sonicated for a while A crystalline white solid formed was collected dried

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

Procedure: A mixture 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) and 1-[3-bromo-4-(methyloxy)phenyl]methanamine (0.581 g, 2.69 mmol), HATU (1.065 g, 2.8 mmol) and triethylamine (0.781 ml, 5.6 mmol) was stirred in dichloromethane (45 mL) at room temperature overnight. The reaction mixture was diluted with DCM, washed with saturated NaHCO3, followed by saturated NaCl. The organic layer was dried over Na2SO4 and then evaporated to dryness which gave, initially, a glassy gum, but which then appeared to crystallize. The residue was taken up in a small amount of MeOH and sonicated for a while. A crystalline white solid formed and was collected and dried to afforded N-{[3-bromo-4-(methyloxy)phenyl]methyl}-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}butanediamide (804 mg, 53.9%) as a white solid. LC-MS m/z 601.3 (M+H)+, 0.77 min (ret time). washed with saturated NaHCO3 The organic layer was dried over Na2SO4 evaporated to dryness which gave to crystallize sonicated for a while A crystalline white solid formed was collected dried

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

Procedure: A mixture of 3-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-3-oxopropanoic acid (0.6 g, 1.541 mmol), 1-[3-bromo-4-(methyloxy)phenyl]methanamine (0.389 g, 1.8 mmol), HATU (0.760 g, 2.0 mmol), and triethylamine (0.599 ml, 4.3 mmol) in dichloromethane (40 mL) was stirred overnight at room temperature to give a pale yellow solution. The reaction mixture was diluted with DCM, washed with saturated NaHCO3 and then saturated NaCl. The organic layer was dried over Na2SO4, evaporated to dryness which gave viscous syrup. The viscous syrup was chromatographed on an 80 g Combi-Flash Column in silica with DCM-MeOH (0-8%). The product from this purification was placed on a Chromatotron Plate (2000μ) silica eluting with DCM-MeOH (3.5%) to give N-{[3-bromo-4-(methyloxy)phenyl]methyl}-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}propanediamide (800 mg, 88%). LC-MS m/z 587.3 (M+H)+, 0.83 min (ret time). to give a pale yellow solution washed with saturated NaHCO3 The organic layer was dried over Na2SO4 evaporated to dryness which gave viscous syrup The viscous syrup was chromatographed on an 80 g Combi-Flash Column in silica with DCM-MeOH (0-8%) The product from this purification

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

Procedure: A mixture of 3-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-3-oxopropanoic acid (0.6 g, 1.541 mmol), 1-[3-bromo-4-(methyloxy)phenyl]methanamine (0.389 g, 1.8 mmol), HATU (0.760 g, 2.0 mmol), and triethylamine (0.599 ml, 4.3 mmol) in dichloromethane (40 mL) was stirred overnight at room temperature to give a pale yellow solution. The reaction mixture was diluted with DCM, washed with saturated NaHCO3 and then saturated NaCl. The organic layer was dried over Na2SO4, evaporated to dryness which gave viscous syrup. The viscous syrup was chromatographed on an 80 g Combi-Flash Column in silica with DCM-MeOH (0-8%). The product from this purification was placed on a Chromatotron Plate (2000μ) silica eluting with DCM-MeOH (3.5%) to give N-{[3-bromo-4-(methyloxy)phenyl]methyl}-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}propanediamide (800 mg, 88%). LC-MS m/z 587.3 (M+H)+, 0.83 min (ret time). to give a pale yellow solution washed with saturated NaHCO3 The organic layer was dried over Na2SO4 evaporated to dryness which gave viscous syrup The viscous syrup was chromatographed on an 80 g Combi-Flash Column in silica with DCM-MeOH (0-8%) The product from this purification

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]-5-methylbenzoic acid (0.931 g, 2 mmol) was partially dissolved in the dichloromethane (DCM) (50 mL), and then HBTU (0.758 g, 2.000 mmol) was added followed sequentially by {[3-bromo-4-(methyloxy)phenyl]methyl}amine (0.432 g, 2.000 mmol) and TEA (0.558 mL, 4.00 mmol). The mixture was allowed to stir under argon overnight at room temperature. The solvent was removed on a rotavap to give the crude product. The residue was taken up in EtOAc (100 mL) and washed 3× with water (50 mL), 1× with brine, dried over anhydrous Na2SO4 filtered and the solvent concentrated. The residue was taken up in methylene chloride and absorbed on Isolute® Sorbent and purified by CombiFlash on an 80 g silica column eluted with 0-10% DCM/MeOH to give the title compound as a white solid. LC-MS m/z 663.0 (M+H)+, 0.91 min (ret time); mp 123-126° C.; analytical HPLC shows 97.6% purity, (ret time 13.411 min). The solvent was removed on a rotavap to give the crude product washed 3× with water (50 mL), 1× with brine dried over anhydrous Na2SO4 filtered the solvent concentrated absorbed on Isolute® Sorbent purified by CombiFlash on an 80 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 (0.564 g, 1.25 mmol), {[3-bromo-4-(methyloxy)phenyl]methyl}amine (0.27 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 solvents were concentrated, and the residue taken up in EtOAc, washed with 1N NaOH, brine, dried and concentrated to give the crude product which was purified using CombiFlash on a 40 g column eluted with 0-10% MeOH/CH2Cl2 to afford the title compound as a white solid. LC-MS m/z 649.5 (M+H)+, 1.76 min (ret time); mp 130-132° C.; analytical HPLC shows 100% purity, (ret time 12.776 min). The solvents were concentrated washed with 1N NaOH, brine dried concentrated to give the crude product which was purified eluted with 0-10% MeOH/CH2Cl2

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Bromo-4-(methyloxy)benzonitrile (2.12 g, 10 mmol), THF (30 mL), and 1.5 M borane in THF (30 mL, 45 mmols) were combined and stirred under argon at reflux. The additional 1.5 M borane in THF (30 mL, 45 mmols) and reflux continued. THF (30 mL), and 1.5 M borane in THF (30 mL, 45 mmols) was again added and the mixture refluxed for a total of ten days to drive the reaction to completion. The reaction was worked up by the cautious addition of ethanol followed by 1N HCl until the pH was 2. This mixture was then heated to 50° C. for 4 h. The solvents were pumped off, and the residue partitioned between EtOAc and water. The aqueous phase was washed 3× with EtOAc and adjusted to pH 10 by the addition of 2.5 N NaOH. The aqueous phase was extracted 3× with EtOAc. The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated to give the title compound. LC-MS m/z 198.7 (M−NH2), 0.99 min (ret time). at reflux the mixture refluxed for a total of ten days the reaction to completion the residue partitioned between EtOAc and water The aqueous phase was washed 3× with EtOAc adjusted to pH 10 by the addition of 2.5 N NaOH The aqueous phase was extracted 3× with EtOAc The combined organic phases were dried over anhydrous Na2SO4 filtered concentrated