tert-butyl 2-(2-hydroxyethyl)pyrrolidine-1-carboxylate

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

Procedure: To a stirred solution of LAH (0.94 g, 24.69 mmol) in dry THF (100 mL) was added solution of compound 36 (3.0 g 12.34 mmol) in THF (40 mL) at 0° C. and stirred at rt for 16 hours. The reaction mixture was quenched with brine solution and filtered through a Celite® bed. The organic layer was dried over anhydrous Na2SO4 and evaporated. The crude was purified by Combiflash® chromatography eluting with 2-3% of methanol-DCM to provide liquid compound 37. The reaction mixture was quenched with brine solution filtered through a Celite® bed The organic layer was dried over anhydrous Na2SO4 evaporated The crude was purified by Combiflash® chromatography eluting with 2-3% of methanol-DCM

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

Procedure: To a stirred solution of LAH (0.94 g, 24.69 mmol) in dry THF (100 mL) was added solution of compound 36 (3.0 g 12.34 mmol) in THF (40 mL) at 0° C. and stirred at rt for 16 hours. The reaction mixture was quenched with brine solution and filtered through a Celite® bed. The organic layer was dried over anhydrous Na2SO4 and evaporated. The crude was purified by Combiflash® chromatography eluting with 2-3% of methanol-DCM to provide liquid compound 37. The reaction mixture was quenched with brine solution filtered through a Celite® bed The organic layer was dried over anhydrous Na2SO4 evaporated The crude was purified by Combiflash® chromatography eluting with 2-3% of methanol-DCM

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

Procedure: To a stirred solution of LAH (0.94 g, 24.69 mmol) in dry THF (100 mL) was added solution of compound 36 (3.0 g 12.34 mmol) in THF (40 mL) at 0° C. and stirred at rt for 16 hours. The reaction mixture was quenched with brine solution and filtered through a Celite® bed. The organic layer was dried over anhydrous Na2SO4 and evaporated. The crude was purified by Combiflash® chromatography eluting with 2-3% of methanol-DCM to provide liquid compound 37. The reaction mixture was quenched with brine solution filtered through a Celite® bed The organic layer was dried over anhydrous Na2SO4 evaporated The crude was purified by Combiflash® chromatography eluting with 2-3% of methanol-DCM

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

Procedure: Tert-butyl 2-(2-hydroxyethyl)pyrrolidine-1-carboxylate (260 mg, 1.2 mmol), triphenyl phosphine (310 mg, 1.2 mmol) and diethyl azodicarboxylate (0.19 mmol, 1.2 mmol) were added to a tetrahydrofuran solution (6 ml) of 6-({4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-yl}oxy)pyridin-3-ol (200 mg, 0.60 mmol) obtained in Example 6, and the reaction solution was stirred at room temperature for 30 minutes. The reaction solution was diluted with chloroform, the organic layer was washed with water and saturated saline water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=96:4) and amine-type silica gel column chromatography (hexane:ethyl acetate=50:50) to obtain tert-butyl 2-(2-{[6-({4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-yl}oxy)pyridin-3-yl]oxy}ethyl)pyrrolidine-1-carboxylate (290 mg, yield: 90.5%) as a pale yellow amorphous solid. the organic layer was washed with water and saturated saline water dried over anhydrous sodium sulfate concentrated under reduced pressure The obtained residue was purified by silica gel column chromatography (chloroform:methanol=96:4) and amine-type silica gel column chromatography (hexane:ethyl acetate=50:50)

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

Procedure: Tert-butyl 2-(2-hydroxyethyl)pyrrolidine-1-carboxylate (260 mg, 1.2 mmol), triphenyl phosphine (310 mg, 1.2 mmol) and diethyl azodicarboxylate (0.19 mmol, 1.2 mmol) were added to a tetrahydrofuran solution (6 ml) of 6-({4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-yl}oxy)pyridin-3-ol (200 mg, 0.60 mmol) obtained in Example 6, and the reaction solution was stirred at room temperature for 30 minutes. The reaction solution was diluted with chloroform, the organic layer was washed with water and saturated saline water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=96:4) and amine-type silica gel column chromatography (hexane:ethyl acetate=50:50) to obtain tert-butyl 2-(2-{[6-({4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-yl}oxy)pyridin-3-yl]oxy}ethyl)pyrrolidine-1-carboxylate (290 mg, yield: 90.5%) as a pale yellow amorphous solid. the organic layer was washed with water and saturated saline water dried over anhydrous sodium sulfate concentrated under reduced pressure The obtained residue was purified by silica gel column chromatography (chloroform:methanol=96:4) and amine-type silica gel column chromatography (hexane:ethyl acetate=50:50)

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

Procedure: To a stirred solution of LAH (0.94 g, 24.69 mmol) in dry THF (100 mL) was added solution of compound 36 (3.0 g 12.34 mmol) in THF (40 mL) at 0° C. and stirred at rt for 16 hours. The reaction mixture was quenched with brine solution and filtered through a Celite® bed. The organic layer was dried over anhydrous Na2SO4 and evaporated. The crude was purified by Combiflash® chromatography eluting with 2-3% of methanol-DCM to provide liquid compound 37. The reaction mixture was quenched with brine solution filtered through a Celite® bed The organic layer was dried over anhydrous Na2SO4 evaporated The crude was purified by Combiflash® chromatography eluting with 2-3% of methanol-DCM