2-methyl-2-pyrrolidin-1-ylpropanal

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under an argon atmosphere, pyrrolidine (3.55 g, 0.05 mole) was dissolved in ethyl ether (50 ml). Triethylamine (5.06 g, 0.05 mole) was added and the solution cooled to and maintained at 0° C. 2-Methylacryloyl chloride (5.22 g, 0.05 mole), dissolved in ethyl ether (50 ml) was added to the reaction and the solution stirred overnight. Water (50 ml) was added, the layers were separated and the aqueous layer extracted with ethyl ether. The extracts were concentrated and the resulting product dried (6.77 g). The structure was confirmed by NMR. the solution cooled to and was added to the reaction the layers were separated the aqueous layer extracted with ethyl ether The extracts were concentrated the resulting product dried (6.77 g)

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

Procedure: To a mixture of (S)-3-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-3-oxopropanenitrile (285 mg, 0.60 mmol), 2-methyl-2-pyrrolidin-1-yl-propanal (719 mg, 5.1 mmol) and pyrrolidine (0.23 mL, 2.8 mmol) in DCM (6 mL) at room temperature was added chloro(trimethyl)silane (0.23 mL, 1.8 mmol). After stirring 90 min, the solution was diluted with sat. NaHCO3 and extracted with DCM. The organic layers were combined, dried (MgSO4), filtered and concentrated. The crude material was purified by Isolera (10 g column:0%-15% iPrOH/DCM) to obtain 270 mg of (S)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methyl-4-(pyrrolidin-1-yl)pent-2-enenitrile. MS (pos. ion) m/z: 595 (M+1). extracted with DCM dried (MgSO4) filtered concentrated The crude material was purified by Isolera (10 g column:0%-15% iPrOH/DCM)

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

Procedure: To a solution of 2-methylpropanal (5.6 mL, 61.8 mmol) in DCM (75 mL) cooled with an ice bath was added bromine (3.2 mL, 61.8 mmol) dropwise. After 1 hr, the solution was evaporated, stirred in DCM (8 ml) at room temperature and pyrrolidine (0.94 mL, 11.26 mmol) was added. After stirring 4 h, the mixture was diluted with brine and the layers separated. The organic layer was washed with 1M HCl and then the aqueous layer was basified with KOH to pH=10-11. This was then extracted with DCM and the organic layers were combined, dried (MgSO4), filtered and concentrated to isolate 2-methyl-2-pyrrolidin-1-yl-propanal oil as an oil. the solution was evaporated After stirring 4 h the layers separated The organic layer was washed with 1M HCl This was then extracted with DCM dried (MgSO4) filtered concentrated

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

Procedure: To a mixture of (S)-3-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-3-oxopropanenitrile (285 mg, 0.60 mmol), 2-methyl-2-pyrrolidin-1-yl-propanal (719 mg, 5.1 mmol) and pyrrolidine (0.23 mL, 2.8 mmol) in DCM (6 mL) at room temperature was added chloro(trimethyl)silane (0.23 mL, 1.8 mmol). After stirring 90 min, the solution was diluted with sat. NaHCO3 and extracted with DCM. The organic layers were combined, dried (MgSO4), filtered and concentrated. The crude material was purified by Isolera (10 g column:0%-15% iPrOH/DCM) to obtain 270 mg of (S)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methyl-4-(pyrrolidin-1-yl)pent-2-enenitrile. MS (pos. ion) m/z: 595 (M+1). extracted with DCM dried (MgSO4) filtered concentrated The crude material was purified by Isolera (10 g column:0%-15% iPrOH/DCM)

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

Procedure: To a solution of 2-methylpropanal (5.6 mL, 61.8 mmol) in DCM (75 mL) cooled with an ice bath was added bromine (3.2 mL, 61.8 mmol) dropwise. After 1 hr, the solution was evaporated, stirred in DCM (8 ml) at room temperature and pyrrolidine (0.94 mL, 11.26 mmol) was added. After stirring 4 h, the mixture was diluted with brine and the layers separated. The organic layer was washed with 1M HCl and then the aqueous layer was basified with KOH to pH=10-11. This was then extracted with DCM and the organic layers were combined, dried (MgSO4), filtered and concentrated to isolate 2-methyl-2-pyrrolidin-1-yl-propanal oil as an oil. the solution was evaporated After stirring 4 h the layers separated The organic layer was washed with 1M HCl This was then extracted with DCM dried (MgSO4) filtered concentrated

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under an argon atmosphere, pyrrolidine (3.55 g, 0.05 mole) was dissolved in ethyl ether (50 ml). Triethylamine (5.06 g, 0.05 mole) was added and the solution cooled to and maintained at 0° C. 2-Methylacryloyl chloride (5.22 g, 0.05 mole), dissolved in ethyl ether (50 ml) was added to the reaction and the solution stirred overnight. Water (50 ml) was added, the layers were separated and the aqueous layer extracted with ethyl ether. The extracts were concentrated and the resulting product dried (6.77 g). The structure was confirmed by NMR. the solution cooled to and was added to the reaction the layers were separated the aqueous layer extracted with ethyl ether The extracts were concentrated the resulting product dried (6.77 g)