1-N-BOC-1,2-CIS-CYCLOHEXYLDIAMINE

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

Procedure: To the solution of 3,5-dichloropyrazine-2-carbonitrile (2.00 g, 11.5 mmol) in 30 mL NMP were added tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (2.71 g, 12.6 mmol) and DIEA (4.07 mL, 13.8 mmol). The mixture was stirred at RT for 1.5 h. To it was poured 300 mL water. After stirring vigorously for 2 h, the solid was isolated by filtration, washed with water and dried in vacuum oven for overnight to afford tert-butyl (1S,2R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)cyclohexylcarbamate in quantitative yield. After stirring vigorously for 2 h the solid was isolated by filtration washed with water dried in vacuum oven for overnight

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

Procedure: A solution of 3,5-dichloropyrazine-2-carbonitrile (100 mg, 0.574 mmol), tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (123 mg, 0.574 mmol) and DIEA (0.150 mL, 0.862 mmol) in NMP (3 mL) was stirred at room temperature for 20 h. HOAc (0.3 mL) was added. Then, water was added to induce precipitation. The precipitate was collected, dried on vacuum to give tert-butyl (1S,2R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)cyclohexylcarbamate (165 mg). A mixture of tert-butyl (1S,2R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)cyclohexylcarbamate (80 mg, 0.227 mmol), 3-(2H-1,2,3-triazol-2-yl)aniline (50 mg, 0.312 mmol), K2CO3 (60 mg, 0.434 mmol), BINAP (20 mg, 0.032 mmol) and Pd(OAc)2 (10 mg, 0.044 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 100 C for 20 h. Water and EtOAc were added. Organic phase was separated. The aqueous phase was extracted with EtOAc again. The combined organic phases were dried over Na2SO4, concentrated in vacuo to give a crude tert-butyl (1S,2R)-2-(6-(3-(2H-1,2,3-triazol-2-yl)phenylamino)-5-cyanopyrazin-2-ylamino)cyclohexylcarbamate (170 mg). The crude tert-butyl (1S,2R)-2-(6-(3-(2H-1,2,3-triazol-2-yl)phenylamino)-5-cyanopyrazin-2-ylamino)cyclohexylcarbamate (170 mg) was dissolved in TFA (4 mL). After being stirred at room temperature for 2 h, the mixture was concentrated in vacuo. The residue was purified by HPLC to give 3-(3-(2H-1,2,3-triazol-2-yl)phenylamino)-5-((1R,2S)-2-aminocyclohexylamino)pyrazine-2-carbonitrile (28 mg). precipitation The precipitate was collected dried on vacuum

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

Procedure: A solution of 1.96 g of 4-chloro-2-ethoxycarbonyl-6-methoxyquinazoline in 70 mL of toluene was combined with 1.58 g of cis-2-tert-butoxycarbonylaminocyclohexylamine and 0.74 g of triethylamine, and heated under reflux for 15 hours. After concentrating, the mixture was combined with water, extracted with chloroform, and dried. After the solvent was distilled off, the residue was purified by column chromatography on silica gel (chloroform) to obtain 2.70 g of the desirable compound. heated under reflux for 15 hours After concentrating extracted with chloroform dried After the solvent was distilled off the residue was purified by column chromatography on silica gel (chloroform)

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

Procedure: A solution of 1.96 g of 4-chloro-2-ethoxycarbonyl-6-methoxyquinazoline in 70 mL of toluene was combined with 1.58 g of cis-2-tert-butoxycarbonylaminocyclohexylamine and 0.74 g of triethylamine, and heated under reflux for 15 hours. After concentrating, the mixture was combined with water, extracted with chloroform, and dried. After the solvent was distilled off, the residue was purified by column chromatography on silica gel (chloroform) to obtain 2.70 g of the desirable compound. heated under reflux for 15 hours After concentrating extracted with chloroform dried After the solvent was distilled off the residue was purified by column chromatography on silica gel (chloroform)

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

Procedure: A solution of 391 mg of 4-chloro-2-(4-chlorostyryl)-6-methoxyquinazoline, 379 mg of cis-2-(tert-butoxycarbonyl)aminocyclohexylamine, and 358 mg of triethylamine in 20 mL of toluene was combined with a catalytic amount of 4-dimethylaminopyridine, and heated under reflux for 20 hours. After distilling the reaction solution off, the residue was combined with water, extracted with chloroform, dried over magnesium sulfate, and concentrated. The residue was purified by column chromatography on silica gel (chloroform:methanol=50:1) to obtain 580 mg of the desirable compound. heated under reflux for 20 hours After distilling the reaction solution off, the residue extracted with chloroform dried over magnesium sulfate concentrated The residue was purified by column chromatography on silica gel (chloroform:methanol=50:1)

Conditions: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a 10 mL sealed cap glass vial, 4,6-dichloro-2-(2,4-dimethoxybenzyl)-7-fluoro-1,1-dimethyl-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (50 mg, 0.125 mmol) and tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (53.2 mg, 0.250 mmol) were dissolved in ACN (2 mL). N-ethyldiisopropylamine (0.033 mL, 0.188 mmol) was added, the cap was sealed, and the reaction mixture heated at 95° C. for 72 h. The reaction mixture was subsequently purified by preparative HPLC and basified to give the title compound as a light yellow solid (40 mg, 55%). [M+H] calc'd for C29H38ClFN4O5, 578.1. found, 577.4. In a 10 mL sealed the cap was sealed The reaction mixture was subsequently purified by preparative HPLC

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred suspension of tert-butyl 4,6-dichloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (12.5 g, 38.9 mmol) in 2-propanol (72 mL) was added a solution of tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (10.01 g, 46.7 mmol) in DMSO (12.00 mL) and DIPEA (8.84 mL, 50.6 mmol). The reaction mixture was heated to 90° C. for 16 h at which point it was cooled to 50° C. and water (50 mL) was added dropwise to give a precipitate. The suspension was stirred at 50° C. for 1 h then cooled to RT. The suspension was reheated to 50° C. for 15 min and cooled to RT for two more cycles. The solids were subsequently filtered and washed with isopropanol (20 mL) and dried on a filter to give the title compound (9.538 g, 49%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.18-1.76 (br m, 26H), 3.83 (br s, 1H), 4.12 (br s, 1H), 4.72 (s, 2H), 6.71 (d, J=7.58 Hz, 1H), 7.22 (d, J=6.32 Hz, 1H). was cooled to 50° C. to give a precipitate then cooled to RT The suspension was reheated to 50° C. for 15 min cooled to RT for two more cycles The solids were subsequently filtered washed with isopropanol (20 mL) dried on a filter

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred suspension of tert-butyl 4,6-dichloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (12.5 g, 38.9 mmol) in 2-propanol (72 mL) was added a solution of tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (10.01 g, 46.7 mmol) in DMSO (12.00 mL) and DIPEA (8.84 mL, 50.6 mmol). The reaction mixture was heated to 90° C. for 16 h at which point it was cooled to 50° C. and water (50 mL) was added dropwise to give a precipitate. The suspension was stirred at 50° C. for 1 h then cooled to RT. The suspension was reheated to 50° C. for 15 min and cooled to RT for two more cycles. The solids were subsequently filtered and washed with isopropanol (20 mL) and dried on a filter to give the title compound (9.538 g, 49%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.18-1.76 (br m, 26H), 3.83 (br s, 1H), 4.12 (br s, 1H), 4.72 (s, 2H), 6.71 (d, J=7.58 Hz, 1H), 7.22 (d, J=6.32 Hz, 1H). was cooled to 50° C. to give a precipitate then cooled to RT The suspension was reheated to 50° C. for 15 min cooled to RT for two more cycles The solids were subsequently filtered washed with isopropanol (20 mL) dried on a filter

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl 6-chloro-4-cyano-2-(1-ethyl-1H-pyrazol-4-yl)nicotinate (201 mg, 0.691 mmol) in DMF (1 mL) was added DIPEA (0.242 mL, 1.383 mmol) and tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (237 mg, 1.106 mmol). The reaction mixture was stirred at 100° C. overnight, after which the solvent was removed, and the resulting crude material was diluted in MeOH (5.0 mL) and purified via reverse phase preparative HPLC. The collected fractions were collected and ACN was removed via rotary evaporation. The resulting aq solution was neutralized with saturated aq NaHCO3 and washed with EtOAc (2×200 mL), dried over Na2SO4, and filtered. The organic phase was stripped to dryness via rotary evaporation to yield the title compound (62 mg, 19%). [M+H] calc'd for C24H32N6O4, 469. found, 469. after which the solvent was removed the resulting crude material was diluted in MeOH (5.0 mL) purified via reverse phase preparative HPLC The collected fractions were collected ACN was removed via rotary evaporation washed with EtOAc (2×200 mL) dried over Na2SO4 filtered The organic phase was stripped to dryness via rotary evaporation

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

Procedure: A solution of ethyl 4-(1,5-dimethyl-1H-pyrazol-4-yl)-6-methyl-2-(methylsulfonyl)pyrimidine-5-carboxylate (0.07 g, 0.207 mmol), tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (0.089 g, 0.414 mmol) and Et3N (0.115 mL, 0.827 mmol) in DMA (3 mL) was heated in a sealed tube at 90° C. for 8 h. The reaction mixture was poured slowly onto ice to yield a pale yellow precipitate, which was isolated by vacuum filtration, washed with water, and dried under vacuum to give the title compound. [M+H] calc'd for C24H36N6O4, 473. found, 473. The reaction mixture was poured slowly onto ice to yield a pale yellow precipitate which was isolated by vacuum filtration washed with water dried under vacuum

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

Procedure: A solution of ethyl 4-(1,5-dimethyl-1H-pyrazol-4-yl)-6-methyl-2-(methylsulfonyl)pyrimidine-5-carboxylate (0.07 g, 0.207 mmol), tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (0.089 g, 0.414 mmol) and Et3N (0.115 mL, 0.827 mmol) in DMA (3 mL) was heated in a sealed tube at 90° C. for 8 h. The reaction mixture was poured slowly onto ice to yield a pale yellow precipitate, which was isolated by vacuum filtration, washed with water, and dried under vacuum to give the title compound. [M+H] calc'd for C24H36N6O4, 473. found, 473. The reaction mixture was poured slowly onto ice to yield a pale yellow precipitate which was isolated by vacuum filtration washed with water dried under vacuum

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

Procedure: A mixture of methyl 6-chloro-4-cyano-2-(3-(methylsulfonyl)phenylamino)nicotinate (162.8 mg, 0.445 mmol), tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (111.6 mg, 0.521 mmol) and Et3N (0.1 mL, 0.717 mmol) in THF (6 mL) and DMF (6.00 mL) was stirred at 60° C. for 12 h. After the mixture was cooled, saturated aq NaHCO3 (30 mL) was added and the mixture was extracted with EtOAc (2×30 mL). The organic layers were washed with saturated aq NaHCO3 (15 mL), water (15 mL) and brine (15 mL), were dried over anhydrous Na2SO4, and filtered through SiO2. The filtrate was concentrated under reduced pressure and the residue was washed with IPE to give the title compound as a yellow solid (182.2 mg, 75%). 1H-NMR (CDCl3) δ ppm 1.42-1.67 (m, 15H), 1.84-1.91 (m, 2H), 3.07 (s, 3H), 3.95-3.97 (m, 4H), 4.16-4.17 (m, 1H), 4.77 (s, 1H), 6.24 (s, 1H), 7.48-7.51 (m, 1H), 7.58-7.61 (m, 1H), 7.77-7.78 (m, 1H), 8.41 (s, 1H), 10.99 (s, 1H), 1H not detected. After the mixture was cooled the mixture was extracted with EtOAc (2×30 mL) The organic layers were washed with saturated aq NaHCO3 (15 mL), water (15 mL) and brine (15 mL) were dried over anhydrous Na2SO4 filtered through SiO2 The filtrate was concentrated under reduced pressure the residue was washed with IPE