2-bromo-N-propan-2-ylacetamide

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

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

Procedure: A solution of tert-butyl 5-(2-(3-hydroxyphenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.3 g, 0.66 mmol), N-isopropylbromoacetamide (0.132 g, 0.726 mmole), and K2CO3 (0.183 g, 1.32 mmole) in DMF (3.6 mL) was heated overnight at 30° C. The crude product was poured onto ice-water (ca. 50 mL) and the suspension was stirred for approximately 0.5 h, filtered and dried (Na2SO4). The crude product was recrystallized from absolute EtOH (10 mL) to afford tert-butyl 5-(2-(3-(2-(isopropylamino)-2-oxoethoxy)-phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.160 g, mmol, 45%). filtered dried (Na2SO4) The crude product was recrystallized from absolute EtOH (10 mL)

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 4 mL vial equipped with a magnetic stir bar were added 4-bromo-3,5-dimethyl-1H-pyrazole (50 mg, 0.286 mmol), 2-bromo-N-isopropylacetamide (51.4 mg, 0.286 mmol), K2CO3 (118 mg, 0.857 mmol), and acetonitrile (2 mL). The contents of the vial were stirred to give a white suspension. The vial was heated in a sand bath to 70° C. for 24 hours. The reaction mixture was subsequently partitioned between water (10 mL) and ethyl acetate (15 mL). The layers were separated, and the aqueous layer was back-extracted with ethyl acetate (15 mL). The combined organic layers were concentrated to give the title compound as a white solid, which was used without further purification (80 mg). To a 4 mL vial equipped with a magnetic stir bar to give a white suspension The reaction mixture was subsequently partitioned between water (10 mL) and ethyl acetate (15 mL) The layers were separated the aqueous layer was back-extracted with ethyl acetate (15 mL) The combined organic layers were concentrated

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

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

Procedure: A solution of tert-butyl 5-(2-(3-hydroxyphenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.3 g, 0.66 mmol), N-isopropylbromoacetamide (0.132 g, 0.726 mmole), and K2CO3 (0.183 g, 1.32 mmole) in DMF (3.6 mL) was heated overnight at 30° C. The crude product was poured onto ice-water (ca. 50 mL) and the suspension was stirred for approximately 0.5 h, filtered and dried (Na2SO4). The crude product was recrystallized from absolute EtOH (10 mL) to afford tert-butyl 5-(2-(3-(2-(isopropylamino)-2-oxoethoxy)-phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.160 g, mmol, 45%). filtered dried (Na2SO4) The crude product was recrystallized from absolute EtOH (10 mL)

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 4 mL vial equipped with a magnetic stir bar were added 4-bromo-3,5-dimethyl-1H-pyrazole (50 mg, 0.286 mmol), 2-bromo-N-isopropylacetamide (51.4 mg, 0.286 mmol), K2CO3 (118 mg, 0.857 mmol), and acetonitrile (2 mL). The contents of the vial were stirred to give a white suspension. The vial was heated in a sand bath to 70° C. for 24 hours. The reaction mixture was subsequently partitioned between water (10 mL) and ethyl acetate (15 mL). The layers were separated, and the aqueous layer was back-extracted with ethyl acetate (15 mL). The combined organic layers were concentrated to give the title compound as a white solid, which was used without further purification (80 mg). To a 4 mL vial equipped with a magnetic stir bar to give a white suspension The reaction mixture was subsequently partitioned between water (10 mL) and ethyl acetate (15 mL) The layers were separated the aqueous layer was back-extracted with ethyl acetate (15 mL) The combined organic layers were concentrated

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a scintillation vial was combined 40 mg (0.06 mmol) of 3-fluoro-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-2-(2,2,2-trifluoro-acetylamino)-benzamide, 165 mg (0.092 mmol) of 2-bromo-N-isopropyl-acetamide, 17 mg (0.12 mmol) of potassium carbonate, and 0.5 mL N,N-dimethylformamide. The vial was heated in a heating block at 60° C. for 19 hours. 5.5 mg (0.03 mmol) 2-bromo-N-isopropyl-acetamide and 8.5 mg (0.06 mmol) potassium carbonate were added. Additionally, 9.0 mg (0.06 mmol) of sodium iodide was added and the reaction was heated to 60° C. for another 72 hours. The reaction was allowed to cool to room temperature and salts were filtered off. The crude filtrate was diluted with 0.5 mL methanol and 150 μL of a 50% w/v potassium hydroxide aqueous solution was added. The reaction was stirred 1 hour at room temperature. The solution was neutralized by adding acetic acid dropwise and then the reaction was concentrated to dryness. The resulting residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (containing 10% methanol) and hexanes. The clean fractions were concentrated and then lyophilized overnight to afford 13.3 mg (0.003 mmol, 43% yield) of 3-fluoro-2-[(isopropylcarbamoyl-methyl)-amino]-5-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide as a pale yellow powder. 1H NMR (500 MHz, CD3OD) δ 8.42 (s, br., 1H), 8.18 (d, 1H), 7.65 (s, 1H), 7.58 (dd, 1H), 7.45 (dd, 1H), 7.31 (t, 1H), 7.25 (d, 1H), 7.13 (d, 1H), 7.06 (t, 1H), 4.02 (m, 1H), 3.85 (s, 3H), 3.84 (s, 2H), 3.15 (s, br., 3H), 3.04 (s, br., 3H), 1.16 (d, 6H); MS: m/z 504.1 (M+H+). the reaction was heated to 60° C. for another 72 hours to cool to room temperature salts were filtered off The crude filtrate was diluted with 0.5 mL methanol and 150 μL of a 50% w/v potassium hydroxide aqueous solution was added by adding acetic acid dropwise the reaction was concentrated to dryness The resulting residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (containing 10% methanol) and hexanes The clean fractions were concentrated lyophilized overnight

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a scintillation vial was combined 40 mg (0.06 mmol) of 3-fluoro-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-2-(2,2,2-trifluoro-acetylamino)-benzamide, 165 mg (0.092 mmol) of 2-bromo-N-isopropyl-acetamide, 17 mg (0.12 mmol) of potassium carbonate, and 0.5 mL N,N-dimethylformamide. The vial was heated in a heating block at 60° C. for 19 hours. 5.5 mg (0.03 mmol) 2-bromo-N-isopropyl-acetamide and 8.5 mg (0.06 mmol) potassium carbonate were added. Additionally, 9.0 mg (0.06 mmol) of sodium iodide was added and the reaction was heated to 60° C. for another 72 hours. The reaction was allowed to cool to room temperature and salts were filtered off. The crude filtrate was diluted with 0.5 mL methanol and 150 μL of a 50% w/v potassium hydroxide aqueous solution was added. The reaction was stirred 1 hour at room temperature. The solution was neutralized by adding acetic acid dropwise and then the reaction was concentrated to dryness. The resulting residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (containing 10% methanol) and hexanes. The clean fractions were concentrated and then lyophilized overnight to afford 13.3 mg (0.003 mmol, 43% yield) of 3-fluoro-2-[(isopropylcarbamoyl-methyl)-amino]-5-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide as a pale yellow powder. 1H NMR (500 MHz, CD3OD) δ 8.42 (s, br., 1H), 8.18 (d, 1H), 7.65 (s, 1H), 7.58 (dd, 1H), 7.45 (dd, 1H), 7.31 (t, 1H), 7.25 (d, 1H), 7.13 (d, 1H), 7.06 (t, 1H), 4.02 (m, 1H), 3.85 (s, 3H), 3.84 (s, 2H), 3.15 (s, br., 3H), 3.04 (s, br., 3H), 1.16 (d, 6H); MS: m/z 504.1 (M+H+). the reaction was heated to 60° C. for another 72 hours to cool to room temperature salts were filtered off The crude filtrate was diluted with 0.5 mL methanol and 150 μL of a 50% w/v potassium hydroxide aqueous solution was added by adding acetic acid dropwise the reaction was concentrated to dryness The resulting residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (containing 10% methanol) and hexanes The clean fractions were concentrated lyophilized overnight

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a scintillation vial was combined 40 mg (0.06 mmol) of 3-fluoro-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-2-(2,2,2-trifluoro-acetylamino)-benzamide, 165 mg (0.092 mmol) of 2-bromo-N-isopropyl-acetamide, 17 mg (0.12 mmol) of potassium carbonate, and 0.5 mL N,N-dimethylformamide. The vial was heated in a heating block at 60° C. for 19 hours. 5.5 mg (0.03 mmol) 2-bromo-N-isopropyl-acetamide and 8.5 mg (0.06 mmol) potassium carbonate were added. Additionally, 9.0 mg (0.06 mmol) of sodium iodide was added and the reaction was heated to 60° C. for another 72 hours. The reaction was allowed to cool to room temperature and salts were filtered off. The crude filtrate was diluted with 0.5 mL methanol and 150 μL of a 50% w/v potassium hydroxide aqueous solution was added. The reaction was stirred 1 hour at room temperature. The solution was neutralized by adding acetic acid dropwise and then the reaction was concentrated to dryness. The resulting residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (containing 10% methanol) and hexanes. The clean fractions were concentrated and then lyophilized overnight to afford 13.3 mg (0.003 mmol, 43% yield) of 3-fluoro-2-[(isopropylcarbamoyl-methyl)-amino]-5-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide as a pale yellow powder. 1H NMR (500 MHz, CD3OD) δ 8.42 (s, br., 1H), 8.18 (d, 1H), 7.65 (s, 1H), 7.58 (dd, 1H), 7.45 (dd, 1H), 7.31 (t, 1H), 7.25 (d, 1H), 7.13 (d, 1H), 7.06 (t, 1H), 4.02 (m, 1H), 3.85 (s, 3H), 3.84 (s, 2H), 3.15 (s, br., 3H), 3.04 (s, br., 3H), 1.16 (d, 6H); MS: m/z 504.1 (M+H+). the reaction was heated to 60° C. for another 72 hours to cool to room temperature salts were filtered off The crude filtrate was diluted with 0.5 mL methanol and 150 μL of a 50% w/v potassium hydroxide aqueous solution was added by adding acetic acid dropwise the reaction was concentrated to dryness The resulting residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (containing 10% methanol) and hexanes The clean fractions were concentrated lyophilized overnight

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

Procedure: A solution of tert-butyl 5-(2-(3-hydroxyphenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.3 g, 0.66 mmol), N-isopropylbromoacetamide (0.132 g, 0.726 mmole), and K2CO3 (0.183 g, 1.32 mmole) in DMF (3.6 mL) was heated overnight at 30° C. The crude product was poured onto ice-water (ca. 50 mL) and the suspension was stirred for approximately 0.5 h, filtered and dried (Na2SO4). The crude product was recrystallized from absolute EtOH (10 mL) to afford tert-butyl 5-(2-(3-(2-(isopropylamino)-2-oxoethoxy)-phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.160 g, mmol, 45%). filtered dried (Na2SO4) The crude product was recrystallized from absolute EtOH (10 mL)

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

Procedure: A solution of tert-butyl 5-(2-(3-hydroxyphenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.3 g, 0.66 mmol), N-isopropylbromoacetamide (0.132 g, 0.726 mmole), and K2CO3 (0.183 g, 1.32 mmole) in DMF (3.6 mL) was heated overnight at 30° C. The crude product was poured onto ice-water (ca. 50 mL) and the suspension was stirred for approximately 0.5 h, filtered and dried (Na2SO4). The crude product was recrystallized from absolute EtOH (10 mL) to afford tert-butyl 5-(2-(3-(2-(isopropylamino)-2-oxoethoxy)-phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.160 g, mmol, 45%). filtered dried (Na2SO4) The crude product was recrystallized from absolute EtOH (10 mL)

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