[(2S)-2,3-dihydro-1H-indol-2-yl]methanol

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

Procedure: To a cold (0° C.) solution of (S)-indolin-2-ylmethanol (4.60 mmol, 1.2 equiv.) and triethylamine (2.5 equiv.) in dichloromethane (20 ml) was added dropwise 4-methoxy-2,6-dimethylbenzenesulfonyl chloride (3.83 mmol, 1.0 equiv.) in dichloromethane (5 ml) and the reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with dichloromethane, washed successively with water and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the crude product was purified by silica gel column chromatography. Yield: 72%. washed successively with water and brine dried over sodium sulfate The solvent was evaporated under reduced pressure the crude product was purified by silica gel column chromatography

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

Procedure: To a solution of (S)-indoline-2-carboxylic acid (9.2 mmol, 1.0 equiv.) in THF (18 ml) was added dropwise BH3-DMS solution (18.4 mmol, 2 equiv.) and the reaction mixture was heated to reflux for 12 h. The mixture was quenched with methanol (7.5 ml) and conc. HCl (2.5 ml) with cooling and was then refluxed for additional 2 h. The solvent was evaporated and the residue was basified with 40% NaOH solution and extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate and the solvent was evaporated under reduced pressure to give the crude product which was purified by silica gel column chromatography. Yield: 87%. the reaction mixture was heated to reflux for 12 h The mixture was quenched with methanol (7.5 ml) and conc. HCl (2.5 ml) with cooling was then refluxed for additional 2 h The solvent was evaporated extracted with dichloromethane The organic layer was washed with brine dried over sodium sulfate the solvent was evaporated under reduced pressure

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

Procedure: To a cold (0° C.) solution of (S)-indolin-2-ylmethanol (4.60 mmol, 1.2 equiv.) and triethylamine (2.5 equiv.) in dichloromethane (20 ml) was added dropwise 4-methoxy-2,6-dimethylbenzenesulfonyl chloride (3.83 mmol, 1.0 equiv.) in dichloromethane (5 ml) and the reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with dichloromethane, washed successively with water and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the crude product was purified by silica gel column chromatography. Yield: 72%. washed successively with water and brine dried over sodium sulfate The solvent was evaporated under reduced pressure the crude product was purified by silica gel column chromatography

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

Procedure: To a solution of (S)-indoline-2-carboxylic acid (9.2 mmol, 1.0 equiv.) in THF (18 ml) was added dropwise BH3-DMS solution (18.4 mmol, 2 equiv.) and the reaction mixture was heated to reflux for 12 h. The mixture was quenched with methanol (7.5 ml) and conc. HCl (2.5 ml) with cooling and was then refluxed for additional 2 h. The solvent was evaporated and the residue was basified with 40% NaOH solution and extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate and the solvent was evaporated under reduced pressure to give the crude product which was purified by silica gel column chromatography. Yield: 87%. the reaction mixture was heated to reflux for 12 h The mixture was quenched with methanol (7.5 ml) and conc. HCl (2.5 ml) with cooling was then refluxed for additional 2 h The solvent was evaporated extracted with dichloromethane The organic layer was washed with brine dried over sodium sulfate the solvent was evaporated under reduced pressure

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

Procedure: To a cold (0° C.) solution of (S)-indolin-2-ylmethanol (4.60 mmol, 1.2 equiv.) and triethylamine (2.5 equiv.) in dichloromethane (20 ml) was added dropwise 4-methoxy-2,6-dimethylbenzenesulfonyl chloride (3.83 mmol, 1.0 equiv.) in dichloromethane (5 ml) and the reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with dichloromethane, washed successively with water and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the crude product was purified by silica gel column chromatography. Yield: 72%. washed successively with water and brine dried over sodium sulfate The solvent was evaporated under reduced pressure the crude product was purified by silica gel column chromatography

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

Procedure: To a solution of (S)-indoline-2-carboxylic acid (9.2 mmol, 1.0 equiv.) in THF (18 ml) was added dropwise BH3-DMS solution (18.4 mmol, 2 equiv.) and the reaction mixture was heated to reflux for 12 h. The mixture was quenched with methanol (7.5 ml) and conc. HCl (2.5 ml) with cooling and was then refluxed for additional 2 h. The solvent was evaporated and the residue was basified with 40% NaOH solution and extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate and the solvent was evaporated under reduced pressure to give the crude product which was purified by silica gel column chromatography. Yield: 87%. the reaction mixture was heated to reflux for 12 h The mixture was quenched with methanol (7.5 ml) and conc. HCl (2.5 ml) with cooling was then refluxed for additional 2 h The solvent was evaporated extracted with dichloromethane The organic layer was washed with brine dried over sodium sulfate the solvent was evaporated under reduced pressure

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

Procedure: 4-Methoxy-2,6-dimethylbenzenesulfonic acid chloride (3.83 mmol, 1.0 eq) in DCM (5 ml) was added dropwise to a cooled (0° C.) solution of (S)-indolin-2-ylmethanol (4.60 mmol, 1.2 eq) and triethylamine (2.5 eq) in DCM (20 ml) and the mixture was stirred for 2 h at room temperature. The reaction mixture was diluted with DCM and washed with water and saturated sodium chloride solution. It was dried over sodium sulfate and concentrated to small volume under vacuum. The crude product was processed by column chromatography. Yield: 72% washed with water and saturated sodium chloride solution It was dried over sodium sulfate concentrated to small volume under vacuum

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

Procedure: BH3-DMS solution (18.4 mmol, 2 eq) was added dropwise to a solution of (S)-indoline-2-carboxylic acid (9.2 mmol, 1.0 eq) in THF (18 ml) and the mixture was refluxed for 12 h. Methanol (7.5 ml) and concentrated HCl (2.5 ml) were added to the reaction mixture with cooling, then refluxing was continued for a further 2 hours. The solvent was removed under vacuum and the residue made alkaline with 40% NaOH solution and extracted with DCM. The organic phase was washed with saturated sodium chloride solution, dried (Na2SO4) and concentrated to small volume under vacuum. The crude product was processed by column chromatography. Yield: 87% the mixture was refluxed for 12 h with cooling refluxing The solvent was removed under vacuum extracted with DCM The organic phase was washed with saturated sodium chloride solution dried (Na2SO4) concentrated to small volume under vacuum

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: tert-Butyl 2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-4-(trifluoromethylsulfonyloxy)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (250 mg, 0.45 mmol, example 69c) was dissolved in DMF (2 mL). (S)-indolin-2-ylmethanol (67.3 mg, 0.45 mmol) was added and the reaction mixture was heated at 85° C. overnight. The reaction was allowed to reach room temperature, the solvent was evaporated under reduced pressure and the crude was purified by flash column chromatography using dichloromethane and methanol as eluent and gave (S)-tert-butyl 4-(2-(hydroxymethyl)indolin-1-yl)-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (65.3 mg, 26.2%). MS (ES+) m/z 554.4 (M+H)+ to reach room temperature the solvent was evaporated under reduced pressure the crude was purified by flash column chromatography

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (S)-Indolin-2-ylmethanol (25.5 mg, 0.17 mmol) was added to a solution of 6-methyl-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl trifluoromethanesulfonate (80 mg, 0.17 mmol, Example 9a) in DMSO (1 mL). The reaction was heated to 80° C. for 2 h. The solution was allowed to cool down, filtered and the product was purified on preparative HPLC to give (S)-(1-(6-methyl-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)indolin-2-yl)methanol (22.00 mg, 27.6%). MS (ESI+)/(ESI−) m/z 468/466 to cool down filtered the product was purified on preparative HPLC