tert-butyl N-(3-amino-3-phenylpropyl)carbamate

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

Procedure: NH2NH2 (1.8 mL, 57.7 mmol) was added to a THF/MeOH (1:1, 30 mL) solution of 1,1-dimethylethyl[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropyl]carbamate (2.2 g, 5.79 mmol) and stirred at 50° C. in a sealed system. After 12 hours, the solids were filtered, washing with methanol. The filtrate was concentrated and purified by column chromatography using 5% MeOH in CHCl3 containing 1% NH4OH to give the title compound (1.1 g, 76%) as a white solid: LC-MS (ES) m/z=251 (M+H)+. the solids were filtered washing with methanol The filtrate was concentrated purified by column chromatography

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

Procedure: NH2NH2 (1.8 mL, 57.7 mmol) was added to a THF/MeOH (1:1, 30 mL) solution of 1,1-dimethylethyl[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropyl]carbamate (2.2 g, 5.79 mmol) and stirred at 50° C. in a sealed system. After 12 hours, the solids were filtered, washing with methanol. The filtrate was concentrated and purified by column chromatography using 5% MeOH in CHCl3 containing 1% NH4OH to give the title compound (1.1 g, 76%) as a white solid: LC-MS (ES) m/z=251 (M+H)+. the solids were filtered washing with methanol The filtrate was concentrated purified by column chromatography

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

Procedure: NH2NH2 (1.8 mL, 57.7 mmol) was added to a THF/MeOH (1:1, 30 mL) solution of 1,1-dimethylethyl[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropyl]carbamate (2.2 g, 5.79 mmol) and stirred at 50° C. in a sealed system. After 12 hours, the solids were filtered, washing with methanol. The filtrate was concentrated and purified by column chromatography using 5% MeOH in CHCl3 containing 1% NH4OH to give the title compound (1.1 g, 76%) as a white solid: LC-MS (ES) m/z=251 (M+H)+. the solids were filtered washing with methanol The filtrate was concentrated purified by column chromatography

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

Procedure: (3-{4-[6-(2-Morpholin-4-yl-ethylamino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-pyrimidin-2-ylamino}-3-phenyl-propyl)-carbamic acid tert-butyl ester was prepared from [3-(2-methane sulfonyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine (from Example 11 supra) and (3-amino-3-phenyl-propyl)-carbamic acid tert-butyl ester (from Example 2 supra) by following the method in Example 61.

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A sealed tube was charged with {4-[3-(3-bromo-phenyl)-1-trityl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (from Example 43 supra) (500 mg, 0.686 mmol), (3-amino-3-phenyl-propyl)-carbamic acid tert-butyl ester (from Example 2 supra) (258 mg, 1.03 mmol), DavePhos (54 mg, 0.137 mmol), K2CO3 (142 mg, 1.03 mmol), Pd2(dba)3 (31 mg, 0.0343 mmol) and 1,4-dioxane (14 mL). This mixture was stirred at 120° C. for 15 hours under an atmosphere of N2. The mixture was cooled and filtered; the filtrate was evaporated under reduced pressure to give the crude product. It was purified by chromatography (silica gel, 200-300 mesh, dichloromethane:MeOH, 200:1 to 50:1), then by prep-HPLC to give (4-{3-[3-(3-tert-butoxycarbonylamino-1-phenyl-propylamino)-phenyl]-1-trityl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino}-cyclohexyl)-carbamic acid tert-butyl ester. (Yield 63 mg, 10.2%). The mixture was cooled filtered the filtrate was evaporated under reduced pressure to give the crude product It was purified by chromatography (silica gel, 200-300 mesh, dichloromethane:MeOH, 200:1 to 50:1)

Conditions: temp:132.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A sealed tube was charged with [3-(6-bromo-pyridin-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine (from Example 32 supra) (500 mg, 0.936 mmol), (3-amino-3-phenyl-propyl)-carbamic acid tert-butyl ester (from Example 2 supra) (328 mg, 1.31 mmol), Pd2(dba)3 (54 mg, 0.094 mmol), DavePhos (74 mg, 0.187 mmol), K2CO3 (181 mg, 1.31 mmol) and dioxane (20 mL). The mixture was stirred at 132° C. under an atmosphere of N2 for 7.5 hours. After cooling to room temperature, the mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 14 g, 100-200 mesh, eluting with dichloromethane:MeOH, 80:1) to give crude product which was further purified by prep-HPLC to afford (3-{6-[6-(2-morpholin-4-yl-ethylamino)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-pyridin-2-ylamino}-3-phenyl-propyl)-carbamic acid tert-butyl ester. (Yield 147 mg, 16%). After cooling to room temperature the mixture was filtered concentrated under reduced pressure The residue was purified by column chromatography (silica gel, 14 g, 100-200 mesh, eluting with dichloromethane:MeOH, 80:1) to give crude product which was further purified by prep-HPLC