2-[tert-butyl(dimethyl)silyl]oxyethanamine

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:; See reaction.notes.procedure_details.

Procedure: 1-(4-((1-(tert-Butoxycarbonyl)piperidin-3-yl)methylamino)-6-(5-cyanopyrazin-2-ylamino)pyridin-3-yl)-1H-pyrrole-3-carboxylic acid (80 mg, 0.154 mmol) was dissolved in DMF (1.5 mL). 2-(tert-Butyldimethylsilyloxy)ethanamine (41 mg, 0.230 mmol), N-ethyldiisopropylamine (30 mg, 0.230 mmol), 1-hydroxy benzotriazole hydrate (31 mg, 0.230 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (44 mg, 0.23 mmol) were added to the solution and the reaction mixture was stirred for 14 h at room temperature. The solution was partitioned between dichloromethane and water. The two phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried (Na2SO4) and evaporated to give tert-butyl 3-((5-(3-(2-(tert-butyldimethylsilyloxy)ethylcarbamoyl)-1H-pyrrol-1-yl)-2-(5-cyanopyrazin-2-ylamino)pyridin-4-ylamino)methyl)piperidine-1-carboxylate (80 mg, 78%) which was used in the next step without purification. The solution was partitioned between dichloromethane and water The two phases were separated the aqueous phase was extracted with dichloromethane The combined organic phases were dried (Na2SO4) evaporated

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

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

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

Procedure: To a stirred solution of 1,2,4-trifluoro-5-nitrobenzene (0.5 g, 0.0028 mol) in acetonitrile (5 ml) was added DIPEA (0.98 ml, 0.0056 mol) and 2-(tert-butyldimethylsilyloxy)ethanamine (0.49 g, 0.0028 mol) was added portion wise under cooling condition with constant stirring. The reaction mixture was allowed to stir at room temperature for 4 h. The reaction was concentrated and diluted with water (20 ml) and extracted with ethyl acetate (3×25 ml). The combined organic layers were washed with brine dried over Na2SO4 and concentrated in vacuo and purified by column chromatography on silica gel to afford the desired product N-ethyl-4,5-difluoro-2-nitroaniline. (37 as yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 8.37 (bs, 1H), 8.13-8.17 (dd, J=8.4, 8.4 Hz, 1H), 7.21-7.27 (dd, J=7.2, 7.2 Hz, 1H), 3.8-3.82 (t, J=5.2 Hz, 2H) 3.45-3.49 (m, 2H), 0.84 (s, 9H), 0.021 (s, 6H). MS (M+1=333). was added portion wise under cooling condition with constant stirring The reaction was concentrated diluted with water (20 ml) extracted with ethyl acetate (3×25 ml) The combined organic layers were washed with brine dried over Na2SO4 concentrated in vacuo purified by column chromatography on silica gel

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

Procedure: Ethanolamine (2.00 g, 32.7 mmol) was dissolved in DMF (15 mL) followed by addition of imidazole (1.11 g, 16.4 mmol) and tert-butyldimethylsilyl chloride (2.46 g, 16.4 mmol), and then the mixture was stirred at room temperature for 12 hours. Water and an aqueous saturated sodium hydrogencarbonate solution were added to the reaction mixture in that order, and then the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=10/1) to give 2-(tert-butyldimethylsilyloxy)ethylamine (1.59 g; yield 56%). the mixture was extracted with ethyl acetate The organic layer was washed with a saturated saline solution dried over anhydrous sodium sulfate the solvent was evaporated under reduced pressure The resulting residue was purified by silica gel column chromatography (chloroform/methanol=10/1)

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

Procedure: Ethanolamine (2.00 g, 32.7 mmol) was dissolved in DMF (15 mL) followed by addition of imidazole (1.11 g, 16.4 mmol) and tert-butyldimethylsilyl chloride (2.46 g, 16.4 mmol), and then the mixture was stirred at room temperature for 12 hours. Water and an aqueous saturated sodium hydrogencarbonate solution were added to the reaction mixture in that order, and then the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=10/1) to give 2-(tert-butyldimethylsilyloxy)ethylamine (1.59 g; yield 56%). the mixture was extracted with ethyl acetate The organic layer was washed with a saturated saline solution dried over anhydrous sodium sulfate the solvent was evaporated under reduced pressure The resulting residue was purified by silica gel column chromatography (chloroform/methanol=10/1)

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

Procedure: 1-(4-((1-(tert-Butoxycarbonyl)piperidin-3-yl)methylamino)-6-(5-cyanopyrazin-2-ylamino)pyridin-3-yl)-1H-pyrrole-3-carboxylic acid (80 mg, 0.154 mmol) was dissolved in DMF (1.5 mL). 2-(tert-Butyldimethylsilyloxy)ethanamine (41 mg, 0.230 mmol), N-ethyldiisopropylamine (30 mg, 0.230 mmol), 1-hydroxy benzotriazole hydrate (31 mg, 0.230 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (44 mg, 0.23 mmol) were added to the solution and the reaction mixture was stirred for 14 h at room temperature. The solution was partitioned between dichloromethane and water. The two phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried (Na2SO4) and evaporated to give tert-butyl 3-((5-(3-(2-(tert-butyldimethylsilyloxy)ethylcarbamoyl)-1H-pyrrol-1-yl)-2-(5-cyanopyrazin-2-ylamino)pyridin-4-ylamino)methyl)piperidine-1-carboxylate (80 mg, 78%) which was used in the next step without purification. The solution was partitioned between dichloromethane and water The two phases were separated the aqueous phase was extracted with dichloromethane The combined organic phases were dried (Na2SO4) evaporated