(3R)-3-methylmorpholine;hydrochloride

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

Procedure: A solution of 2-chloro-1-methyl-2′-phenyl-1H-[4,4′]bipyrimidinyl-6-one (149 mg, 0.50 mmol), (3R)-3-Methyl-morpholine hydrochloride (83 mg, 0.82 mmol), and diisopropylethylamine (0.313 ml, 1.8 mmol) in N,N-dimethylformamide (2.0 ml) was stirred at 80° C. Water was added to the solution and the precipitate was filtered, washed with water and diethyl ether, and dried to afford 1-methyl-2-((3R)-3-methyl-morpholin-4-yl)-2′-phenyl-1H-[4,4′]bipyrimidinyl-6-one (162 mg, quant.). the precipitate was filtered washed with water and diethyl ether dried

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

Procedure: A solution of 2-chloro-3-methyl-6-(pyrimidin-4-yl)-3H-pyrimidin-4-one (0.32 g, 1.44 mmol), (3R)-3-methylmorpholine hydrochloride (0.4 g, 2.9 mmol) and triethylamine (0.9 g, 8.9 mmol) in tetrahydrofuran (20 ml) was stirred for 10 hours at 100° C. The solution was partitioned between water and chloroform, and the organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; 5-10% methanol in chloroform) to afford 3-methyl-2-((3R)-3-methylmorpholin-4-yl)-6-(pyrimidin-4-yl)-3H-pyrimidin-4-one (0.31 g, 1.08 mmol, 75%) as white crystals. The solution was partitioned between water and chloroform the organic layer was washed with brine dried over magnesium sulfate concentrated under reduced pressure The residue was purified by silica gel column chromatography (eluent; 5-10% methanol in chloroform)

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

Procedure: A solution of 2-chloro-3-methyl-6-(pyrimidin-4-yl)-3H-pyrimidin-4-one (0.32 g, 1.44 mmol), (3R)-3-methylmorpholine hydrochloride (0.4 g, 2.9 mmol) and triethylamine (0.9 g, 8.9 mmol) in tetrahydrofuran (20 ml) was stirred for 10 hours at 100° C. The solution was partitioned between water and chloroform, and the organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; 5-10% methanol in chloroform) to afford 3-methyl-2-((3R)-3-methylmorpholin-4-yl)-6-(pyrimidin-4-yl)-3H-pyrimidin-4-one (0.31 g, 1.08 mmol, 75%) as white crystals. The solution was partitioned between water and chloroform the organic layer was washed with brine dried over magnesium sulfate concentrated under reduced pressure The residue was purified by silica gel column chromatography (eluent; 5-10% methanol in chloroform)

Conditions: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 6.0 g (19.2 mmol) 2,6-dichloro-N-(4-fluorobenzyl)-4-methyl-pyridine-3-carboxylic amide (synthesized according to the methods described in section a) of example 2), 3.9 g (28.7 mmol) (R)-3-methylmorpholine hydrochloride, 13.0 ml (76.6 mmol) and NMP (18.4 ml) was heated in the MW to 180° C. for 16 h. After cooling to RT the mixture was partiotionated between EtOAc and a 2M aq. NaOH sol. The organic layer was separated, dried over MgSO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 1:1) provided 1.4 g (3.7 mmol, 20%) 2-chloro-N-(4-fluorobenzyl)-4-methyl-6-[(3R)-3-methylmorpholino]-pyridine-3-carboxylic amide. synthesized After cooling to RT the mixture a 2M aq. NaOH sol. The organic layer was separated dried over MgSO4 concentrated in vacuo Purification of the residue by CC (hexane/EtOAc 1:1)

Conditions: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 6.0 g (19.2 mmol) 2,6-dichloro-N-(4-fluorobenzyl)-4-methyl-pyridine-3-carboxylic amide (synthesized according to the methods described in section a) of example 2), 3.9 g (28.7 mmol) (R)-3-methylmorpholine hydrochloride, 13.0 ml (76.6 mmol) and NMP (18.4 ml) was heated in the MW to 180° C. for 16 h. After cooling to RT the mixture was partiotionated between EtOAc and a 2M aq. NaOH sol. The organic layer was separated, dried over MgSO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 1:1) provided 1.4 g (3.7 mmol, 20%) 2-chloro-N-(4-fluorobenzyl)-4-methyl-6-[(3R)-3-methylmorpholino]-pyridine-3-carboxylic amide. synthesized After cooling to RT the mixture a 2M aq. NaOH sol. The organic layer was separated dried over MgSO4 concentrated in vacuo Purification of the residue by CC (hexane/EtOAc 1:1)

Conditions: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 6.0 g (19.2 mmol) 2,6-dichloro-N-(4-fluorobenzyl)-4-methyl-pyridine-3-carboxylic amide (synthesized according to the methods described in section a) of example 2), 3.9 g (28.7 mmol) (R)-3-methylmorpholine hydrochloride, 13.0 ml (76.6 mmol) and NMP (18.4 ml) was heated in the MW to 180° C. for 16 h. After cooling to RT the mixture was partiotionated between EtOAc and a 2M aq. NaOH sol. The organic layer was separated, dried over MgSO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 1:1) provided 1.4 g (3.7 mmol, 20%) 2-chloro-N-(4-fluorobenzyl)-4-methyl-6-[(3R)-3-methylmorpholino]-pyridine-3-carboxylic amide. synthesized After cooling to RT the mixture a 2M aq. NaOH sol. The organic layer was separated dried over MgSO4 concentrated in vacuo Purification of the residue by CC (hexane/EtOAc 1:1)

Conditions: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Chloro-6-((R)-3-methyl-morpholin-4-yl)-9H-purine (1.02 g, 4 mmol), diisopropylethylamine (1.40 mL, 8 mmol), and (R)-3-methylmorpholin hydrochloride (826 mg, 6 mmol) were stirred in 2-butanol (5 mL) in a closed microwave tube under argon at 50° C., until all ingredients were dissolved. The reaction was then stirred at 180° C. for 100 hours. The reaction mixture was then cooled to room temperature and diluted with 200 mL of CH2Cl2. were dissolved The reaction mixture was then cooled to room temperature

Conditions: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Chloro-6-((R)-3-methyl-morpholin-4-yl)-9H-purine (1.02 g, 4 mmol), diisopropylethylamine (1.40 mL, 8 mmol), and (R)-3-methylmorpholin hydrochloride (826 mg, 6 mmol) were stirred in 2-butanol (5 mL) in a closed microwave tube under argon at 50° C., until all ingredients were dissolved. The reaction was then stirred at 180° C. for 100 hours. The reaction mixture was then cooled to room temperature and diluted with 200 mL of CH2Cl2. were dissolved The reaction mixture was then cooled to room temperature

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2,6-Dichloro-9H-purine (2.36 g, 12.5 mmol), (R)-3-methylmorpholin hydrochloride (1.89 g, 13.8 mmol), and diisopropylethylamine (5.46 mL, 31.3 mmol) were dissolved in 15 mL of isopropanol, and the reaction mixture was stirred for 18 hours at 75° C. The reaction mixture was then diluted with 200 mL of CH2Cl2. The organic solvents were washed with aqueous Na2CO3, followed by water and brine. Drying over Na2SO4, filtering and concentration under reduced pressure gave a residue, which was purified by column chromatography (150 g SiO2, CH2Cl2/EtOH/aq NH3 in a ratio of 96/4/0.1) to give the product as a solid (2.87 g, 91%). The organic solvents were washed with aqueous Na2CO3 Drying over Na2SO4 filtering concentration under reduced pressure gave a residue, which was purified by column chromatography (150 g SiO2, CH2Cl2/EtOH/aq NH3 in a ratio of 96/4/0.1)

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

Procedure: To a solution of (3R)-3-methylmorpholine hydrochloride (122 mg, 0.887 mmol, Tyger Scientific, Ewing, USA) and triethylamine (0.124 mL, 0.887 mmol) in methanol (2 mL) was added formaldehyde (37% aqueous) (0.066 mL, 0.887 mmol). The reaction mixture was stirred at room temperature for 2 hours before the addition of 4-(trifluoromethyl)phenyl isocyanide (152 mg, 0.887 mmol) and trimethylsilylazide (0.118 mL, 0.887 mmol). The reaction mixture was stirred at room temperature overnight (approximately 18 hours) and the solvent removed under vacuum. The residue was purified by MDAP. Fractions containing the desired compound were combined and the solvent removed. The residue was partitioned between saturated NaHCO3 (2 mL) and DCM (5 ml). The organic layer was collected via a hydrophobic frit and the solvent removed under a stream of argon. The compound was dissolved in a minimum of diethyl ether before the addition of 1N HCl in diethyl ether (2 mL) leading to precipitation. The ether was decanted and the precipitate dried under vacuum to yield the title compound as a pale yellow solid (105 mg). the solvent removed under vacuum The residue was purified by MDAP Fractions containing the desired compound the solvent removed The residue was partitioned between saturated NaHCO3 (2 mL) and DCM (5 ml) The organic layer was collected via a hydrophobic frit the solvent removed under a stream of argon The compound was dissolved in a minimum of diethyl ether before the addition of 1N HCl in diethyl ether (2 mL) leading to precipitation The ether was decanted the precipitate dried under vacuum

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

Procedure: To a solution of (3R)-3-methylmorpholine hydrochloride (122 mg, 0.887 mmol, Tyger Scientific, Ewing, USA) and triethylamine (0.124 mL, 0.887 mmol) in methanol (2 mL) was added formaldehyde (37% aqueous) (0.066 mL, 0.887 mmol). The reaction mixture was stirred at room temperature for 2 hours before the addition of 4-(trifluoromethyl)phenyl isocyanide (152 mg, 0.887 mmol) and trimethylsilylazide (0.118 mL, 0.887 mmol). The reaction mixture was stirred at room temperature overnight (approximately 18 hours) and the solvent removed under vacuum. The residue was purified by MDAP. Fractions containing the desired compound were combined and the solvent removed. The residue was partitioned between saturated NaHCO3 (2 mL) and DCM (5 ml). The organic layer was collected via a hydrophobic frit and the solvent removed under a stream of argon. The compound was dissolved in a minimum of diethyl ether before the addition of 1N HCl in diethyl ether (2 mL) leading to precipitation. The ether was decanted and the precipitate dried under vacuum to yield the title compound as a pale yellow solid (105 mg). the solvent removed under vacuum The residue was purified by MDAP Fractions containing the desired compound the solvent removed The residue was partitioned between saturated NaHCO3 (2 mL) and DCM (5 ml) The organic layer was collected via a hydrophobic frit the solvent removed under a stream of argon The compound was dissolved in a minimum of diethyl ether before the addition of 1N HCl in diethyl ether (2 mL) leading to precipitation The ether was decanted the precipitate dried under vacuum

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

Procedure: A solution of (3R)-3-methylmorpholine hydrochloride (52.4 mg, 0.381 mmol), 5-(chloromethyl)-1-[3-(trifluoromethyl)phenyl]-1H-tetrazole (50 mg, 0.190 mmol, commercially available from Otava, Kiev, Ukraine) and di-isopropylethylamine (0.067 mL, 0.381 mmol) in acetonitrile (1.5 mL) was heated to 120° C. for 15 minutes in a microwave reactor. The reaction mixture was allowed to cool and the solvent removed under vacuum. The residue was purified by MDAP and fractions containing the desired product were combined and the solvent removed. The residue was dissolved in a minimum of diethyl ether before the dropwise addition of 1N HCl in diethyl ether (3 mL) leading to precipitation. The solvent was removed under a stream of argon and the residue triturated with diethyl ether then dried under vacuum to yield the title compound as a white solid (46 mg). to cool the solvent removed under vacuum The residue was purified by MDAP and fractions containing the desired product the solvent removed The residue was dissolved in a minimum of diethyl ether before the dropwise addition of 1N HCl in diethyl ether (3 mL) leading to precipitation The solvent was removed under a stream of argon the residue triturated with diethyl ether then dried under vacuum