Carbamic acid, [(1R,2S)-2-aminocyclohexyl]-, 1,1-dimethylethyl ester (9CI)

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

Procedure: A solution of 710 mg of 2,4-dichloro-6-methoxyquinazoline in 20 mL of methylene chloride was combined with 471 mg of triethylamine and 750 mg of (1S,2R)-2-tert-butoxycarbonylaminocyclohexylamine, and stirred at room temperature for 48 hours. After concentrating, the mixture was combined with water, extracted with methylene chloride, and dried. After solvent was distilled off, the residue was purified by column chromatography on silica gel (chloroform:methanol 20:1) to obtain 1.20 g of the desirable compound. After concentrating extracted with methylene chloride dried After solvent was distilled off the residue was purified by column chromatography on silica gel (chloroform:methanol 20:1)

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

Procedure: A solution of 710 mg of 2,4-dichloro-6-methoxyquinazoline in 20 mL of methylene chloride was combined with 471 mg of triethylamine and 750 mg of (1S,2R)-2-tert-butoxycarbonylaminocyclohexylamine, and stirred at room temperature for 48 hours. After concentrating, the mixture was combined with water, extracted with methylene chloride, and dried. After solvent was distilled off, the residue was purified by column chromatography on silica gel (chloroform:methanol 20:1) to obtain 1.20 g of the desirable compound. After concentrating extracted with methylene chloride dried After solvent was distilled off the residue was purified by column chromatography on silica gel (chloroform:methanol 20:1)

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

Procedure: Aqueous sodium hydroxide (50%, 10 g, 0.125 mole, 5.7 eq) was added to a solution of cis-tert-butyl 2-(2,2,2-trifluoroacetamido)cyclohexylcarbamate in EtOH (about 21.9 mmol). An exotherm from 20 to 37° C. was observed and a fine white slurry formed. The reaction mixture was stirred overnight, during which further solids precipitated out of solution. The solvent volume was concentrated under reduced pressure to about 10 to 15 mL and then IPAc (40 mL) and water (30 mL) were added to form a clean bi-phasic solution. Following phase separation the aqueous phase was extracted with IPAc (15 mL) and the organic extracts were combined and washed with water (15 mL) to give the title compound as a crude racemic product in IPAc. from 20 to 37° C. a fine white slurry formed precipitated out of solution The solvent volume was concentrated under reduced pressure to about 10 to 15 mL IPAc (40 mL) and water (30 mL) were added to form a clean bi-phasic solution Following phase separation the aqueous phase was extracted with IPAc (15 mL) washed with water (15 mL)

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

Procedure: Crude cis-tert-butyl 2-(1,3-dioxoisoindolin-2-yl)cyclohexylcarbamate (3.90 g) was dissolved in toluene (20 mL) and charged to a round bottom flask. Hydrazine hydrate (0.70 mL) was added and the mixture was heated to 80° C. for 2 h whereupon TLC analysis indicated the reaction was complete. The reaction was cooled to RT and the solids were filtered and washed with toluene (2×5 mL). The filtrates were washed with 2 N NaOH aq (10 mL) and phase separated. The aqueous phase was extracted with toluene (2×5 mL) and the combined organic extracts were washed with 10% HOAc aq (2×10 mL). The combined aqueous washes were basified with 2 N NaOH aq (13 mL). The product was extracted with IPAc (2×10 mL) and the combined organic extracts were washed with water (5 mL). The organic phase was concentrated to dryness to give 0.78 g of crude product. The oil was re-dissolved in IPAc (12 mL), heated to about 75° C., and maleic acid (423 mg) was added. Precipitation of solids occurred immediately and the thick mixture was diluted with IPAc (5 mL). The slurry was cooled to RT and allowed to stand for 20 min. The solids were filtered, washed with IPAc (10 mL), and dried to give a maleic acid salt of the title compound as white crystalline solid (730 mg, 44%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.34-1.42 (m, 2H), 1.50 (s, 9H), 1.50-1.64 (m, 6H), 3.22 (m, 1H), 3.83 (br s, 1H), 6.02 (s, 2H), 6.86 (d, J=7.5 Hz, 1H), 7.68 (br s, 3H). charged to a round bottom flask The reaction was cooled to RT the solids were filtered washed with toluene (2×5 mL) The filtrates were washed with 2 N NaOH aq (10 mL) and phase separated The aqueous phase was extracted with toluene (2×5 mL) the combined organic extracts were washed with 10% HOAc aq (2×10 mL) The product was extracted with IPAc (2×10 mL) the combined organic extracts were washed with water (5 mL) The organic phase was concentrated to dryness to give 0.78 g of crude product The oil was re-dissolved in IPAc (12 mL) heated to about 75° C. Precipitation of solids the thick mixture was diluted with IPAc (5 mL) The slurry was cooled to RT The solids were filtered washed with IPAc (10 mL) dried

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

Procedure: A mixture of 4,6-dichloro-2-(2,4-dimethoxybenzyl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (316 mg, 0.851 mmol) and cis-tert-butyl 2-aminocyclohexylcarbamate (365 mg, 1.703 mmol) and DIPEA (0.743 mL, 4.26 mmol) in ACN (2 mL) was stirred at 85° C. for 3 d. The resulting crude material was reconstituted in MeOH (1 mL) and purified by preparative HPLC. The fractions were collected and stripped to dryness via rotary evaporation to yield the title compound (161 mg, 34%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.35 (br s, 10H), 1.58 (br s, 2H), 1.76 (br s, 2H), 3.71-3.90 (m, 11H), 4.33 (br s, 2H), 4.51 (br s, 2H), 6.43-6.72 (m, 3H), 6.87 (br s, 1H), 7.07 (br s, 1H). [M+H] calc'd for C27H34ClFN4O5, 549. found, 549. purified by preparative HPLC The fractions were collected stripped to dryness via rotary evaporation

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

Procedure: A mixture of 4,6-dichloro-2-(2,4-dimethoxybenzyl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (316 mg, 0.851 mmol) and cis-tert-butyl 2-aminocyclohexylcarbamate (365 mg, 1.703 mmol) and DIPEA (0.743 mL, 4.26 mmol) in ACN (2 mL) was stirred at 85° C. for 3 d. The resulting crude material was reconstituted in MeOH (1 mL) and purified by preparative HPLC. The fractions were collected and stripped to dryness via rotary evaporation to yield the title compound (161 mg, 34%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.35 (br s, 10H), 1.58 (br s, 2H), 1.76 (br s, 2H), 3.71-3.90 (m, 11H), 4.33 (br s, 2H), 4.51 (br s, 2H), 6.43-6.72 (m, 3H), 6.87 (br s, 1H), 7.07 (br s, 1H). [M+H] calc'd for C27H34ClFN4O5, 549. found, 549. purified by preparative HPLC The fractions were collected stripped to dryness via rotary evaporation

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

Procedure: To a mixture of 4,6-dichloro-2-(2,4-dimethoxybenzyl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (200 mg, 0.539 mmol) and tert-butyl (1R,2S)-2-aminocyclohexylcarbamate (173 mg, 0.808 mmol) in ACN (5 mL) was added N,N-diisopropylethylamine (0.141 mL, 0.808 mmol). The reaction mixture was heated in a sealed vial at 100° C. for several hours after which additional amine (0.5 eq) was added. The mixture was heated overnight and the solvent was subsequently removed in vacuo. The residue was dispersed in DMSO and MeOH (1/1) and the resulting mixture was filtered. The filtrate was purified via preparative HPLC. The fractions were collected and dried in vacuo to give the title compound as a tan solid (60.7 mg, 21%). [M+H] calc'd for C27H34ClFN4O5, 550. found, 550 was added The mixture was heated overnight the solvent was subsequently removed in vacuo The residue was dispersed in DMSO MeOH (1/1) and the resulting mixture was filtered The filtrate was purified via preparative HPLC The fractions were collected dried in vacuo

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

Procedure: To a mixture of 4,6-dichloro-2-(2,4-dimethoxybenzyl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (200 mg, 0.539 mmol) and tert-butyl (1R,2S)-2-aminocyclohexylcarbamate (173 mg, 0.808 mmol) in ACN (5 mL) was added N,N-diisopropylethylamine (0.141 mL, 0.808 mmol). The reaction mixture was heated in a sealed vial at 100° C. for several hours after which additional amine (0.5 eq) was added. The mixture was heated overnight and the solvent was subsequently removed in vacuo. The residue was dispersed in DMSO and MeOH (1/1) and the resulting mixture was filtered. The filtrate was purified via preparative HPLC. The fractions were collected and dried in vacuo to give the title compound as a tan solid (60.7 mg, 21%). [M+H] calc'd for C27H34ClFN4O5, 550. found, 550 was added The mixture was heated overnight the solvent was subsequently removed in vacuo The residue was dispersed in DMSO MeOH (1/1) and the resulting mixture was filtered The filtrate was purified via preparative HPLC The fractions were collected dried in vacuo

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

Procedure: (±)-cis-N-tert-Butoxycarbonyl-1,2-cyclohexanediamine (3.78 g) was dissolved in acetonitrile (80 ml), and to the solution triethylamine (2.44 ml) and benzyl bromide (2.10 ml) were added, and the mixture was stirred at room temperature for 13 hours. The solvent was distilled off under reduced pressure, dichloromethane and water was added to the residue to separate an organic layer. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (hexane:ethyl acetate=1:1) to obtain the title compound (3.08 g) as a pale orange oil. The solvent was distilled off under reduced pressure, dichloromethane and water was added to the residue to separate an organic layer The organic layer was dried over anhydrous sodium sulfate concentrated under reduced pressure The residue was purified by flash column chromatography on silica gel (hexane:ethyl acetate=1:1)

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

Procedure: (±)-cis-N-tert-Butoxycarbonyl-1,2-cyclohexanediamine (3.78 g) was dissolved in acetonitrile (80 ml), and to the solution triethylamine (2.44 ml) and benzyl bromide (2.10 ml) were added, and the mixture was stirred at room temperature for 13 hours. The solvent was distilled off under reduced pressure, dichloromethane and water was added to the residue to separate an organic layer. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (hexane:ethyl acetate=1:1) to obtain the title compound (3.08 g) as a pale orange oil. The solvent was distilled off under reduced pressure, dichloromethane and water was added to the residue to separate an organic layer The organic layer was dried over anhydrous sodium sulfate concentrated under reduced pressure The residue was purified by flash column chromatography on silica gel (hexane:ethyl acetate=1:1)

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

Procedure: Aqueous sodium hydroxide (50%, 10 g, 0.125 mole, 5.7 eq) was added to a solution of cis-tert-butyl 2-(2,2,2-trifluoroacetamido)cyclohexylcarbamate in EtOH (about 21.9 mmol). An exotherm from 20 to 37° C. was observed and a fine white slurry formed. The reaction mixture was stirred overnight, during which further solids precipitated out of solution. The solvent volume was concentrated under reduced pressure to about 10 to 15 mL and then IPAc (40 mL) and water (30 mL) were added to form a clean bi-phasic solution. Following phase separation the aqueous phase was extracted with IPAc (15 mL) and the organic extracts were combined and washed with water (15 mL) to give the title compound as a crude racemic product in IPAc. from 20 to 37° C. a fine white slurry formed precipitated out of solution The solvent volume was concentrated under reduced pressure to about 10 to 15 mL IPAc (40 mL) and water (30 mL) were added to form a clean bi-phasic solution Following phase separation the aqueous phase was extracted with IPAc (15 mL) washed with water (15 mL)

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

Procedure: Crude cis-tert-butyl 2-(1,3-dioxoisoindolin-2-yl)cyclohexylcarbamate (3.90 g) was dissolved in toluene (20 mL) and charged to a round bottom flask. Hydrazine hydrate (0.70 mL) was added and the mixture was heated to 80° C. for 2 h whereupon TLC analysis indicated the reaction was complete. The reaction was cooled to RT and the solids were filtered and washed with toluene (2×5 mL). The filtrates were washed with 2 N NaOH aq (10 mL) and phase separated. The aqueous phase was extracted with toluene (2×5 mL) and the combined organic extracts were washed with 10% HOAc aq (2×10 mL). The combined aqueous washes were basified with 2 N NaOH aq (13 mL). The product was extracted with IPAc (2×10 mL) and the combined organic extracts were washed with water (5 mL). The organic phase was concentrated to dryness to give 0.78 g of crude product. The oil was re-dissolved in IPAc (12 mL), heated to about 75° C., and maleic acid (423 mg) was added. Precipitation of solids occurred immediately and the thick mixture was diluted with IPAc (5 mL). The slurry was cooled to RT and allowed to stand for 20 min. The solids were filtered, washed with IPAc (10 mL), and dried to give a maleic acid salt of the title compound as white crystalline solid (730 mg, 44%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.34-1.42 (m, 2 H), 1.50 (s, 9 H), 1.50-1.64 (m, 6 H), 3.22 (m, 1 H), 3.83 (br s, 1 H), 6.02 (s, 2 H), 6.86 (d, J=7.5 Hz, 1 H), 7.68 (br s, 3 H). charged to a round bottom flask The reaction was cooled to RT the solids were filtered washed with toluene (2×5 mL) The filtrates were washed with 2 N NaOH aq (10 mL) and phase separated The aqueous phase was extracted with toluene (2×5 mL) the combined organic extracts were washed with 10% HOAc aq (2×10 mL) The product was extracted with IPAc (2×10 mL) the combined organic extracts were washed with water (5 mL) The organic phase was concentrated to dryness to give 0.78 g of crude product The oil was re-dissolved in IPAc (12 mL) heated to about 75° C. Precipitation of solids the thick mixture was diluted with IPAc (5 mL) The slurry was cooled to RT The solids were filtered washed with IPAc (10 mL) dried