tert-butyl N-amino-N-ethylcarbamate

Conditions: temp:35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (Z)-N,N-dicyclopropyl-4-(4,4-dimethoxy-1-(methylthio)-3-oxobut-1-enylamino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 101A, 160 mg, 0.312 mmol) and tert-butyl 1-ethylhydrazinecarboxylate (125 mg, 0.780 mmol) in acetic acid (2 mL) wan stirred at 35° C. overnight. Solvent was evaporated and the crude product was purified by flash chromatography on silica gel using an automated ISCO system (40 g column, eluting with 2-8% methanol/dichloromethane). (Z)-tert-Butyl 2-(1-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)-4,4-dimethoxy-3-oxobut-1-enyl)-1-ethylhydrazinecarboxylate (195 mg, 0.312 mmol, 100% yield) was obtained as a yellow solid. Solvent was evaporated the crude product was purified by flash chromatography on silica gel using an automated ISCO system (40 g column, eluting with 2-8% methanol/dichloromethane)

Conditions: temp:35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (Z)-N,N-dicyclopropyl-6-ethyl-1-methyl-4-(1-(methylthio)-3-oxobut-1-enylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 74B, 70 mg, 0.155 mmol) and tert-butyl 1-ethylhydrazinecarboxylate (49.6 mg, 0.309 mmol) in acetic acid (1 mL) wan stirred at 35° C. for 4 h (monitored by LC/MS until no starting material left). Formic acid (1 mL) was added and the reaction mixture stirred at 60° C. for 6 h. The solvent was evaporated and the crude product was purified by flash chromatography on silica gel using an automated ISCO system (12 g column, eluting with 2-10% methanol/dichloromethane). The material was further purified by preparative HPLC to afford N,N-dicyclopropyl-6-ethyl-4-(1-ethyl-5-methyl-1H-pyrazol-3-ylamino)-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (38 mg, 53.4% yield) as an off-white solid. left) the reaction mixture stirred at 60° C. for 6 h The solvent was evaporated the crude product was purified by flash chromatography on silica gel using an automated ISCO system (12 g column, eluting with 2-10% methanol/dichloromethane) The material was further purified by preparative HPLC

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

Procedure: Methylhydrazine (1.415 mL, 26.9 mmol) was added to a solution of tert-butyl 1,3-dioxoisoindolin-2-yl(ethyl)carbamate (example 74A, 5.2 g, 17.91 mmol) in THF (40 mL) at 0° C. and the reaction mixture was stirred at room temperature overnight. A white precipitate formed and was filtered off through a pad of Celite, The filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate (50 ml) and extracted with 1N HCl (3×30 ml), the acid layer was washed with ethyl acetate (50 ml) and basified to pH 10 by addition of 20% NaOH. The basic solution was then extracted with ethyl acetate (3×50 ml) and the combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give tert-butyl 1-ethylhydrazinecarboxylate (2.5 g, 87% yield) as colorless oil. A white precipitate formed was filtered off through a pad of Celite The filtrate was concentrated in vacuo The residue was dissolved in ethyl acetate (50 ml) extracted with 1N HCl (3×30 ml) the acid layer was washed with ethyl acetate (50 ml) basified to pH 10 by addition of 20% NaOH The basic solution was then extracted with ethyl acetate (3×50 ml) the combined organic layers were washed with brine dried over magnesium sulfate filtered concentrated in vacuo

Conditions: temp:35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (Z)-N,N-dicyclopropyl-4-(4,4-dimethoxy-1-(methylthio)-3-oxobut-1-enylamino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 101A, 160 mg, 0.312 mmol) and tert-butyl 1-ethylhydrazinecarboxylate (125 mg, 0.780 mmol) in acetic acid (2 mL) wan stirred at 35° C. overnight. Solvent was evaporated and the crude product was purified by flash chromatography on silica gel using an automated ISCO system (40 g column, eluting with 2-8% methanol/dichloromethane). (Z)-tert-Butyl 2-(1-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)-4,4-dimethoxy-3-oxobut-1-enyl)-1-ethylhydrazinecarboxylate (195 mg, 0.312 mmol, 100% yield) was obtained as a yellow solid. Solvent was evaporated the crude product was purified by flash chromatography on silica gel using an automated ISCO system (40 g column, eluting with 2-8% methanol/dichloromethane)

Conditions: temp:35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (Z)-N,N-dicyclopropyl-6-ethyl-1-methyl-4-(1-(methylthio)-3-oxobut-1-enylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 74B, 70 mg, 0.155 mmol) and tert-butyl 1-ethylhydrazinecarboxylate (49.6 mg, 0.309 mmol) in acetic acid (1 mL) wan stirred at 35° C. for 4 h (monitored by LC/MS until no starting material left). Formic acid (1 mL) was added and the reaction mixture stirred at 60° C. for 6 h. The solvent was evaporated and the crude product was purified by flash chromatography on silica gel using an automated ISCO system (12 g column, eluting with 2-10% methanol/dichloromethane). The material was further purified by preparative HPLC to afford N,N-dicyclopropyl-6-ethyl-4-(1-ethyl-5-methyl-1H-pyrazol-3-ylamino)-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (38 mg, 53.4% yield) as an off-white solid. left) the reaction mixture stirred at 60° C. for 6 h The solvent was evaporated the crude product was purified by flash chromatography on silica gel using an automated ISCO system (12 g column, eluting with 2-10% methanol/dichloromethane) The material was further purified by preparative HPLC

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

Procedure: Methylhydrazine (1.415 mL, 26.9 mmol) was added to a solution of tert-butyl 1,3-dioxoisoindolin-2-yl(ethyl)carbamate (example 74A, 5.2 g, 17.91 mmol) in THF (40 mL) at 0° C. and the reaction mixture was stirred at room temperature overnight. A white precipitate formed and was filtered off through a pad of Celite, The filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate (50 ml) and extracted with 1N HCl (3×30 ml), the acid layer was washed with ethyl acetate (50 ml) and basified to pH 10 by addition of 20% NaOH. The basic solution was then extracted with ethyl acetate (3×50 ml) and the combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give tert-butyl 1-ethylhydrazinecarboxylate (2.5 g, 87% yield) as colorless oil. A white precipitate formed was filtered off through a pad of Celite The filtrate was concentrated in vacuo The residue was dissolved in ethyl acetate (50 ml) extracted with 1N HCl (3×30 ml) the acid layer was washed with ethyl acetate (50 ml) basified to pH 10 by addition of 20% NaOH The basic solution was then extracted with ethyl acetate (3×50 ml) the combined organic layers were washed with brine dried over magnesium sulfate filtered concentrated in vacuo

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of tert-butyl 3-(diethoxymethyl)-6-fluoro-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate (1.3 g, 3.0 mmol) in ethanol (10.4 mL) was added hydrochloric acid (11.1 mL of 4 M, 44.6 mmol) (4 M in dioxane). The reaction mixture was allowed to stir at 25° C. for 2 hours. The solvent was removed under vacuum, and the obtained solid was azeotroped with ethanol (3×30 mL). The resulting beige-white solid was fully dissolved in ethanol (10.40 mL) at 25° C. prior to the addition of tert-butyl N-amino-N-ethyl-carbamate (571.2 mg, 3.6 mmol). The solution was allowed to stir at 25° C. overnight. To the thick beige-white slurry that formed was added hydrochloric acid (3.7 mL of 4 M in dioxane, 14.9 mmol). The mixture was heated at 60° C. to yield a clear yellow solution. After 1 hour at 60° C., a thick white slurry developed. The slurry was allowed to slowly cool to 25° C. over 4 hours, and solids were collected by vacuum filtration. The cake was rinsed with a 10% solution of EtOH in hexanes (2×). Residual solvent was further removed under reduced pressure providing 1-ethyl-8-fluoro-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] hydrochloride (880 mg, 82%). ESI-MS m/z talc. 287.1, found 288.1 (M+1)+. Retention time 0.79 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 7.52 (dd, J=9.4, 2.8 Hz, 1H), 7.47 (s, 1H), 7.26-7.13 (m, 2H), 5.24 (s, 1H), 4.47 (q, J=7.2 Hz, 2H), 3.30-3.12 (m, 4H), 2.18-2.01 (m, 4H), 1.37 (t, J=7.2 Hz, 3H). The solvent was removed under vacuum the obtained solid was azeotroped with ethanol (3×30 mL) The resulting beige-white solid was fully dissolved in ethanol (10.40 mL) at 25° C. to stir at 25° C. overnight To the thick beige-white slurry that formed The mixture was heated at 60° C. to yield a clear yellow solution After 1 hour at 60° C. to slowly cool to 25° C. over 4 hours solids were collected by vacuum filtration The cake was rinsed with a 10% solution of EtOH in hexanes (2×) Residual solvent was further removed under reduced pressure

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

Procedure: A mixture of tert-butyl 1-ethylhydrazinecarboxylate (320 mg, 2.0 mmol) and benzyl 3-(hydroxymethylene)-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate (770 mg, 2.0 mmol) in dichloroethane (5 mL) was allowed to stir at 25° C. with TFA (78 μL, 1.0 mmol) for 2 h. Once LC/MS analysis showed complete imine formation, more TFA was added to deprotect the hydrazine and cyclize the product. The reaction was diluted with dichloromethane, and aqueous sodium bicarbonate was added with stirring. The layers were separated and the organics were further washed with saturated aqueous sodium bicarbonate and brine. The organics were dried over sodium sulfate and evaporated to dryness. The crude material was purified by column chromatography (0-100% ethyl acetate in hexanes) to afford benzyl 1-ethyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxylate (530 mg, 65%). ESI-MS m/z calc. 403.2, found 404.7 (M+1)+; Retention time: 1.94 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J=7.6 Hz, 1H), 7.40-7.29 (m, 4H), 7.29-7.19 (m, 2H), 7.10-6.99 (m, 2H), 5.16 (s, 2H), 4.47 (q, J=7.3 Hz, 2H), 4.15-3.95 (m, 2H), 3.45-3.26 (m, 2H), 2.15-2.03 (m, 2H), 1.88-1.78 (m 2H), 1.54 (t, J=7.3 Hz, 4H). was added was added The layers were separated the organics were further washed with saturated aqueous sodium bicarbonate and brine The organics were dried over sodium sulfate evaporated to dryness The crude material was purified by column chromatography (0-100% ethyl acetate in hexanes)

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

Procedure: tert-Butyl 1,3-dioxoisoindolin-2-yl(ethyl)-carbamate (790 mg, 2.7 mmol) in THF (16 mL) was cooled to 0° C. and methylhydrazine (250 μL, 4.8 mmol) was added. The reaction mixture was warmed to room temperature and was stirred until all starting material was consumed. The mixture was filtered through a pad of Celite and the solvent was evaporated. The residue was purified by column chromatography (0-10% methanol in dichloromethane) to afford tert-butyl 1-ethylhydrazinecarboxylate (320 mg, 74%). Retention time: 1.13 minutes (3 min run). was consumed The mixture was filtered through a pad of Celite the solvent was evaporated The residue was purified by column chromatography (0-10% methanol in dichloromethane)

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

Procedure: tert-Butyl 1,3-dioxoisoindolin-2-yl(ethyl)-carbamate (790 mg, 2.7 mmol) in THF (16 mL) was cooled to 0° C. and methylhydrazine (250 μL, 4.8 mmol) was added. The reaction mixture was warmed to room temperature and was stirred until all starting material was consumed. The mixture was filtered through a pad of Celite and the solvent was evaporated. The residue was purified by column chromatography (0-10% methanol in dichloromethane) to afford tert-butyl 1-ethylhydrazinecarboxylate (320 mg, 74%). Retention time: 1.13 minutes (3 min run). was consumed The mixture was filtered through a pad of Celite the solvent was evaporated The residue was purified by column chromatography (0-10% methanol in dichloromethane)

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of tert-butyl 3-(diethoxymethyl)-6-fluoro-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate (1.3 g, 3.0 mmol) in ethanol (10.4 mL) was added hydrochloric acid (11.1 mL of 4 M, 44.6 mmol) (4 M in dioxane). The reaction mixture was allowed to stir at 25° C. for 2 hours. The solvent was removed under vacuum, and the obtained solid was azeotroped with ethanol (3×30 mL). The resulting beige-white solid was fully dissolved in ethanol (10.40 mL) at 25° C. prior to the addition of tert-butyl N-amino-N-ethyl-carbamate (571.2 mg, 3.6 mmol). The solution was allowed to stir at 25° C. overnight. To the thick beige-white slurry that formed was added hydrochloric acid (3.7 mL of 4 M in dioxane, 14.9 mmol). The mixture was heated at 60° C. to yield a clear yellow solution. After 1 hour at 60° C., a thick white slurry developed. The slurry was allowed to slowly, cool to 25° C. over 4 hours, and solids were collected by vacuum filtration. The cake was rinsed with a 10% solution of EtOH in hexanes (2×). Residual solvent was further removed under reduced pressure providing 1-ethyl-8-fluoro-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]hydrochloride (880 mg, 82%). ESI-MS m/z calc. 287.1. found 288.1 (M+1)+. Retention time 0.79 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 7.52 (dd, J=9.4, 2.8 Hz, 1H), 7.47 (s, 1H), 7.26-7.13 (m, 2H), 5.24 (s, 1H), 4.47 (q, J=7.2 Hz, 2H), 3.30-3.12 (m, 4H), 2.18-2.01 (m, 4H), 1.37 (t, J=7.2 Hz, 3H). The solvent was removed under vacuum the obtained solid was azeotroped with ethanol (3×30 mL) The resulting beige-white solid was fully dissolved in ethanol (10.40 mL) at 25° C. to stir at 25° C. overnight To the thick beige-white slurry that formed The mixture was heated at 60° C. to yield a clear yellow solution After 1 hour at 60° C. cool to 25° C. over 4 hours solids were collected by vacuum filtration The cake was rinsed with a 10% solution of EtOH in hexanes (2×) Residual solvent was further removed under reduced pressure

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

Procedure: A mixture of tert-butyl 1-ethylhydrazinecarboxylate (320 mg, 2.0 mmol) and benzyl 3-(hydroxymethylene)-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate (770 mg, 2.0 mmol) in dichloroethane (5 mL) was allowed to stir at 25° C. with TFA (78 μL, 1.0 mmol) for 2 h. Once LC/MS analysis showed complete imine formation, more TFA was added to deprotect the hydrazine and cyclize the product. The reaction was diluted with dichloromethane, and aqueous sodium bicarbonate was added with stirring. The layers were separated and the organics were further washed with saturated aqueous sodium bicarbonate and brine. The organics were dried over sodium sulfate and evaporated to dryness. The crude material was purified by column chromatography (0-100% ethyl acetate in hexanes) to afford benzyl 1-ethyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxylate (530 mg, 65%). ESI-MS m/z calc. 403.2. found 404.7 (M+1)+; Retention time: 1.94 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J=7.6 Hz, 1H), 7.40-7.29 (m, 4H), 7.29-7.19 (m, 2H), 7.10-6.99 (m, 2H), 5.16 (s, 2H), 4.47 (q, J=7.3 Hz, 2H), 4.15-3.95 (m, 2H), 3.45-3.26 (m, 2H), 2.15-2.03 (m, 2H), 1.88-1.78 (m 2H), 1.54 (t, J=7.3 Hz, 4H). was added was added The layers were separated the organics were further washed with saturated aqueous sodium bicarbonate and brine The organics were dried over sodium sulfate evaporated to dryness The crude material was purified by column chromatography (0-100% ethyl acetate in hexanes)