(1R,2R)-2-aminocyclohexan-1-ol

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

Procedure: To a yellow suspension of 1.50 g 5-bromo-6-(4-chloro-phenyl)-3-trifluoromethyl-pyrazine-2-carboxylic acid in 11 ml dichloromethane was added drop wise 0.608 g 1-chloro-N,N, 2-trimethylpropenylamine and the resulting the yellow solution was stirred at room temperature for 30 min. The resulting orange solution was added dropwise to a cooled (ice bath) solution of 0.522 g (1R,2R)-2-amino-cyclohexanol and 0.7868 g ethyldiisopropylamine in 10 ml ethyl acetate. This red solution was stirred at room temperature for 90 min. To the red solution was added 30 ml 10% aqueous citric acid solution. The layers were separated and the organic layer was purified by chromatography on silica gel with a gradient of heptane: ethyl acetate=1:1 to ethyl acetate to yield 1.56 g of the title compound as yellow crystals. MS (M−H) at 479.0 and 476.0. The resulting orange solution was added dropwise to This red solution was stirred at room temperature for 90 min The layers were separated the organic layer was purified by chromatography on silica gel with a gradient of heptane

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

Procedure: N-(3-Formyl-8-methylquinolin-7-yl)-4-(tetrahydrofuran-2-ylmethoxy)benzamide (1.0 g) obtained in Reference Example 2% and trans-2-aminocyclohexanol (546 mg) were suspended in 1-methyl-2-pyrrolidone (20 mL) and acetic acid (7.0 mL) and the mixture was stirred at room temperature for 3 hr. Sodium triacetoxyborohydride (2.35 g) was added and the mixture was stirred at room temperature for 3 hr. 1N Aqueous sodium hydroxide solution was added to quench the reaction and basify the mixture. The mixture was partitioned and extracted with ethyl acetate, the organic layer was added to a solution of citric acid (4.0 g) in water (40 mL)-dimethyl sulfoxide (20 mL), and the mixture was washed with ethyl acetate. 1N Aqueous sodium hydroxide solution was added to the aqueous layer, and the mixture was partitioned and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained solid was recrystallized from ethyl acetate-diisopropyl ether to give the title compound (395 mg, yield 32%) as a colorless solid. to quench the reaction The mixture was partitioned extracted with ethyl acetate the organic layer was added to a solution of citric acid (4.0 g) in water (40 mL)-dimethyl sulfoxide (20 mL) the mixture was washed with ethyl acetate 1N Aqueous sodium hydroxide solution was added to the aqueous layer the mixture was partitioned extracted with ethyl acetate The organic layer was washed with saturated brine dried over anhydrous magnesium sulfate the solvent was evaporated under reduced pressure The obtained solid was recrystallized from ethyl acetate-diisopropyl ether

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

Procedure: A mixture of 4-bromophenylboronic acid (1.7 g, 8.1 mmol), nickel iodide (102 mg, 0.32 mmol), solid sodium hexamethyldisilazide (1.6 g, 8.1 mmol) and trans-2-aminocyclohexanol (49.0 mg, 0.32 mmol) was sealed in a microwave vial, diluted with dry i-PrOH (7 mL), and evacuated/backfilled with N2 three times. The reaction mixture was stirred at room temperature for 5 minutes, treated with a solution of 3-iodotetrahydrofuran (800 mg, 4.04 mmol) in i-PrOH (1 mL) and evacuated/backfilled with N2. The reaction mixture was subjected to microwave irradiation at 80° C. for 20 minutes. The cooled reaction mixture was poured into 0.3N HCl (30 mL) and extracted with heptane/EtOAc (2:1, 3×20 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give a yellow solid. The crude material was purified by flash chromatography (0-5% EtOAc/Heptane) to give the title compound (471 mg, 51% yield) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J=8.39 Hz, 2H), 7.11 (d, J=8.39 Hz, 2H), 4.09 (t, J=8.00 Hz, 1H), 4.04 (td, J=8.39, 4.69 Hz, 1H), 3.89 (q, J=8.00 Hz, 1H), 3.65-3.70 (m, 1H), 3.34 (quin, J=7.66 Hz, 1H), 2.35 (dtd, J=12.37, 7.77, 7.77, 4.68 Hz, 1H), 1.94 (dq, J=12.37, 8.04 Hz, 1H). was sealed in a microwave vial irradiation at 80° C. for 20 minutes The cooled reaction mixture extracted with heptane/EtOAc (2:1, 3×20 mL) The combined organic layers were dried over Na2SO4 concentrated in vacuo to give a yellow solid The crude material was purified by flash chromatography (0-5% EtOAc/Heptane)

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

Procedure: The title compound was prepared from (1R,2R)-2-aminocyclohexanol and 4-(3-(5-(2-(2,2-dimethylpyrrolidin-1-yl)ethylcarbamoyl)-2-fluorophenylcarbamoyl)imidazo[1,2-a]pyridin-7-yl)-2-fluorobenzoic acid (step 3) analogously to Example 7.3 step 2;

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

Procedure: Treat 2-chloro-1,7-bis(phenylmethyl)purin-6-one with trans-2-aminocyclohexanol as described in Preparative Example 5 to give the title compound, a tan foam. FAB MS: M+1=430.

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

Procedure: Treat 2-chloro-1,7-bis(phenylmethyl)purin-6-one with trans-2-aminocyclohexanol as described in Preparative Example 5 to give the title compound, a tan foam. FAB MS: M+1=430.

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

Procedure: A mixture of 4-bromophenylboronic acid (1.7 g, 8.1 mmol), nickel iodide (102 mg, 0.32 mmol), solid sodium hexamethyldisilazide (1.6 g, 8.1 mmol) and trans-2-aminocyclohexanol (49.0 mg, 0.32 mmol) was sealed in a microwave vial, diluted with dry i-PrOH (7 mL), and evacuated/backfilled with N2 three times. The reaction mixture was stirred at room temperature for 5 minutes, treated with a solution of 3-iodotetrahydrofuran (800 mg, 4.04 mmol) in i-PrOH (1 mL) and evacuated/backfilled with N2. The reaction mixture was subjected to microwave irradiation at 80° C. for 20 minutes. The cooled reaction mixture was poured into 0.3 N HCl (30 mL) and extracted with heptane/EtOAc (2:1, 3×20 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give a yellow solid. The crude material was purified by flash chromatography (0-5% EtOAc/Heptane) to give the title compound (471 mg, 51% yield) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J=8.39 Hz, 2H), 7.11 (d, J=8.39 Hz, 2H), 4.09 (t, J=8.00 Hz, 1H), 4.04 (td, J=8.39, 4.69 Hz, 1H), 3.89 (q, J=8.00 Hz, 1H), 3.65-3.70 (m, 1H), 3.34 (quin, J=7.66 Hz, 1H), 2.35 (dtd, J=12.37, 7.77, 7.77, 4.68 Hz, 1H), 1.94 (dq, J=12.37, 8.04 Hz, 1H). was sealed in a microwave vial irradiation at 80° C. for 20 minutes The cooled reaction mixture extracted with heptane/EtOAc (2:1, 3×20 mL) The combined organic layers were dried over Na2SO4 concentrated in vacuo to give a yellow solid The crude material was purified by flash chromatography (0-5% EtOAc/Heptane)

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

Procedure: A mixture of 4-bromophenylboronic acid (1.7 g, 8.1 mmol), nickel iodide (102 mg, 0.32 mmol), solid sodium hexamethyldisilazide (1.6 g, 8.1 mmol) and trans-2-aminocyclohexanol (49.0 mg, 0.32 mmol) was sealed in a microwave vial, diluted with dry i-PrOH (7 mL), and evacuated/backfilled with N2 three times. The reaction mixture was stirred at room temperature for 5 minutes, treated with a solution of 3-iodotetrahydrofuran (800 mg, 4.04 mmol) in i-PrOH (1 mL) and evacuated/backfilled with N2. The reaction mixture was subjected to microwave irradiation at 80° C. for 20 minutes. The cooled reaction mixture was poured into 0.3 N HCl (30 mL) and extracted with heptane/EtOAc (2:1, 3×20 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give a yellow solid. The crude material was purified by flash chromatography (0-5% EtOAc/Heptane) to give the title compound (471 mg, 51% yield) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J=8.39 Hz, 2H), 7.11 (d, J=8.39 Hz, 2H), 4.09 (t, J=8.00 Hz, 1H), 4.04 (td, J=8.39, 4.69 Hz, 1H), 3.89 (q, J=8.00 Hz, 1H), 3.65-3.70 (m, 1H), 3.34 (quin, J=7.66 Hz, 1H), 2.35 (dtd, J=12.37, 7.77, 7.77, 4.68 Hz, 1H), 1.94 (dq, J=12.37, 8.04 Hz, 1H). was sealed in a microwave vial irradiation at 80° C. for 20 minutes The cooled reaction mixture extracted with heptane/EtOAc (2:1, 3×20 mL) The combined organic layers were dried over Na2SO4 concentrated in vacuo to give a yellow solid The crude material was purified by flash chromatography (0-5% EtOAc/Heptane)

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

Procedure: The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and trans-(±)-2-aminocyclohexanol. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.11-1.93 (m, 18H) 3.32 (s, 1H) 3.45 (m, 1H) 3.64 (m, 1H) 3.95 (s, 3H) 4.07 (t, J=13.39 Hz, 2H) 4.48 (m, 1H) 4.64 (br. s., 1H) 7.49 (d, J=8.0 Hz, 1H) 7.55 (s, 1H) 7.90 (s, 1H) 8.03 (d, J=8.08 Hz, 1H) 8.22 (s, 1H) 8.28 (d, J=8.34 Hz, 1H). [M+H] calculated for C28H36F2N6O4, 559. found 559. as described in the General procedure for amide bond synthesis The final compound was purified by reverse phase HPLC to give the free base

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

Procedure: The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and trans-(±)-2-aminocyclohexanol. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.11-1.93 (m, 18H) 3.32 (s, 1H) 3.45 (m, 1H) 3.64 (m, 1H) 3.95 (s, 3H) 4.07 (t, J=13.39 Hz, 2H) 4.48 (m, 1H) 4.64 (br. s., 1H) 7.49 (d, J=8.0 Hz, 1H) 7.55 (s, 1H) 7.90 (s, 1H) 8.03 (d, J=8.08 Hz, 1H) 8.22 (s, 1H) 8.28 (d, J=8.34 Hz, 1H). [M+H] calculated for C28H36F2N6O4, 559. found 559. as described in the General procedure for amide bond synthesis The final compound was purified by reverse phase HPLC to give the free base

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

Procedure: 3,5-difluorophenylboronic acid (2.0 equiv.), (1R,2R)-2-aminocyclohexanol (0.06 equiv.), NaHMDS (2.0 equiv.), and nickel(II) iodide (0.06 equiv.) were dissolved in 2-propanol (0.35 M). The mixture was degassed with N2, stirred at rt for 10 min and then a solution of 3-iodooxetane (1.0 equiv.) in 2-Propanol (0.70 M) was added. The mixture was sealed and heated at 80° C. in the microwave for 20 min. The mixture was filtered through celite, eluting with EtOH and concentrated. The crude residue was purified by ISCO SiO2 chromatography eluting with 0-100% EtOAc in Heptanes to afford 3-(3,5-difluorophenyl)oxetane in 63% yield. 1H NMR (400 MHz, <cdcl3>) δ 6.88-6.96 (m, 2H), 6.72 (tt, J=2.20, 8.95 Hz, 1H), 5.08 (dd, J=6.26, 8.22 Hz, 2H), 4.71 (t, J=6.26 Hz, 2H), 4.14-4.24 (m, 1H). The mixture was degassed with N2 The mixture was sealed heated at 80° C. in the microwave for 20 min The mixture was filtered through celite eluting with EtOH concentrated The crude residue was purified by ISCO SiO2 chromatography eluting with 0-100% EtOAc in Heptanes

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

Procedure: Trans-2-amino-cyclohexanol (Aldrich) is treated with triphosgene in methylene chloride (⅓ equivalent). To the resulting solution, excess ammonium hydroxide is added to give after work up the title compound.