(3S,5S)-3,5-dimethylmorpholine

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

Procedure: A mixture of methyl 2-chlorobenzoxazole-4-carboxylate (620 mg, 2.96 mmol) and (3S,5S)-3,5-dimethylmorpholine (341 mg, 2.96 mmol) and potassium carbonate (1.0 g, 7.4 mmol), in DMF (15 mL), was stirred in a 35° C. oil bath. After 17 h, the reaction mixture was cooled to ambient temperature, diluted with H2O (50 mL) and extracted with EtOAc (2×30 mL). The combined organic layers were washed with H2O (3×20 mL), brine (20 mL), dried (Na2SO4), and concentrated under reduced pressure. Methyl 2-((3 S,5S)-3,5-dimethylmorpholino)benzoxazole-4-carboxylate (770 mg, 89%) was obtained as an amber oil. 1H NMR consistent. extracted with EtOAc (2×30 mL) The combined organic layers were washed with H2O (3×20 mL), brine (20 mL) dried (Na2SO4) concentrated under reduced pressure

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

Procedure: A mixture of methyl 2-chlorobenzoxazole-4-carboxylate (620 mg, 2.96 mmol) and (3S,5S)-3,5-dimethylmorpholine (341 mg, 2.96 mmol) and potassium carbonate (1.0 g, 7.4 mmol), in DMF (15 mL), was stirred in a 35° C. oil bath. After 17 h, the reaction mixture was cooled to ambient temperature, diluted with H2O (50 mL) and extracted with EtOAc (2×30 mL). The combined organic layers were washed with H2O (3×20 mL), brine (20 mL), dried (Na2SO4), and concentrated under reduced pressure. Methyl 2-((3 S,5S)-3,5-dimethylmorpholino)benzoxazole-4-carboxylate (770 mg, 89%) was obtained as an amber oil. 1H NMR consistent. extracted with EtOAc (2×30 mL) The combined organic layers were washed with H2O (3×20 mL), brine (20 mL) dried (Na2SO4) concentrated under reduced pressure

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

Procedure: To a solution of (3S,5S)-3,5-dimethylmorpholine (115 mg, 1.0 mmol) in DMF (2 mL) was added HATU (380 mg, 1.0 mmol), DIPEA (260 mg, 2.0 mmol), and 6-aminonicotinic acid (138 mg, 1.0 mmol) at room temperature. After stirring for 18 h, the reaction mixture was filtered and purified with Combiflash (A: 1‰NH4HCO3/water, B: acetonitrile) to afford 324a (80 mg, 34%) as a yellow solid. MS (ESI): 236.1 (M+H). the reaction mixture was filtered purified with Combiflash (A: 1‰NH4HCO3/water, B

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

Procedure: To a solution of (3S,5S)-3,5-dimethylmorpholine (115 mg, 1.0 mmol) in DMF (2 mL) was added HATU (380 mg, 1.0 mmol), DIPEA (260 mg, 2.0 mmol), and 6-aminonicotinic acid (138 mg, 1.0 mmol) at room temperature. After stirring for 18 h, the reaction mixture was filtered and purified with Combiflash (A: 1% NH4HCO3/water, B: acetonitrile) to afford 324a (80 mg, 34%) as a yellow solid. MS (ESI): 236.1 (M+H). the reaction mixture was filtered purified with Combiflash (A: 1% NH4HCO3/water, B

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

Procedure: To a solution of (3S,5S)-3,5-dimethylmorpholine (115 mg, 1.0 mmol) in DMF (2 mL) was added HATU (380 mg, 1.0 mmol), DIPEA (260 mg, 2.0 mmol), and 6-aminonicotinic acid (138 mg, 1.0 mmol) at room temperature. After stirring for 18 h, the reaction mixture was filtered and purified with Combiflash (A: 1% NH4HCO3/water, B: acetonitrile) to afford 324a (80 mg, 34%) as a yellow solid. MS (ESI): 236.1 (M+H). the reaction mixture was filtered purified with Combiflash (A: 1% NH4HCO3/water, B

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

Procedure: A mixture of methyl 2-chlorobenzoxazole-4-carboxylate (620 mg, 2.96 mmol) and (3S,5S)-3,5-dimethylmorpholine (341 mg, 2.96 mmol) and potassium carbonate (1.0 g, 7.4 mmol), in DMF (15 mL), was stirred in a 35° C. oil bath. After 17 h, the reaction mixture was cooled to ambient temperature, diluted with H2O (50 mL) and extracted with EtOAc (2×30 mL). The combined organic layers were washed with H2O (3×20 mL), brine (20 mL), dried (Na2SO4), and concentrated under reduced pressure. Methyl 2-((3 S,5S)-3,5-dimethylmorpholino)benzoxazole-4-carboxylate (770 mg, 89%) was obtained as an amber oil. 1H NMR consistent. extracted with EtOAc (2×30 mL) The combined organic layers were washed with H2O (3×20 mL), brine (20 mL) dried (Na2SO4) concentrated under reduced pressure

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

Procedure: 4-Chloro-2,5-difluorobenzaldehyde (0.177 g, 1.0 mmol) and (3S,5S)-3,5-dimethylmorpholine (0.167 g, 1.10 mmol) were dissolved in dichloromethane (10 mL). Sodium triacetoxyborohydride (0.307 g, 1.45 mmol) was added and the mixture was stirred under argon atmosphere at RT for 20 h. The mixture was diluted with dichloromethane and washed with NaHCO3 (aq). The organic phase was dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica eluting with gradients of ammonia in methanol and dichloromethane. The fractions containing product were pooled and evaporated to give (3S,5S)-4-(4-chloro-2,5-difluorobenzyl)-3,5-dimethylmorpholine (0.118 g, 43%) as a liquid. washed with NaHCO3 (aq) The organic phase was dried (MgSO4) evaporated The residue was purified by column chromatography on silica eluting with gradients of ammonia in methanol and dichloromethane The fractions containing product evaporated

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

Procedure: 4-Bromo-3-fluorobenzaldehyde (0.250 g, 1.23 mmol) and (3S,5S)-3,5-dimethylmorpholine (0.205 g, 1.35 mmol) were dissolved in dichloromethane (10 mL). Sodium triacetoxyborohydride (0.378 g, 1.79 mmol) was added and the mixture was stirred under argon atmosphere at RT for 20 h. The mixture was diluted with dichloromethane and washed with NaHCO3 (aq). The organic phase was dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica eluting with gradients of ammonia in methanol and dichloromethane. The fractions containing product were pooled and evaporated to give (3S,5S)-4-(4-bromo-3-fluorobenzyl)-3,5-dimethylmorpholine (0.113 g, 30%) as a liquid. washed with NaHCO3 (aq) The organic phase was dried (MgSO4) evaporated The residue was purified by column chromatography on silica eluting with gradients of ammonia in methanol and dichloromethane The fractions containing product evaporated

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

Procedure: To a solution of (3S,5S)-3,5-dimethylmorpholine (115 mg, 1.0 mmol) in DMF (2 mL) was added HATU (380 mg, 1.0 mmol), DIPEA (260 mg, 2.0 mmol), and 6-aminonicotinic acid (138 mg, 1.0 mmol) at room temperature. After stirring for 18 h, the reaction mixture was filtered and purified with Combiflash (A: 1% NH4HCO3/water, B: acetonitrile) to afford 324a (80 mg, 34%) as a yellow solid. MS (ESI): 236.1 (M+H). the reaction mixture was filtered purified with Combiflash (A: 1% NH4HCO3/water, B

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

Procedure: To a solution of (3S,5S)-3,5-dimethylmorpholine (115 mg, 1.0 mmol) in DMF (2 mL) was added HATU (380 mg, 1.0 mmol), DIPEA (260 mg, 2.0 mmol), and 6-aminonicotinic acid (138 mg, 1.0 mmol) at room temperature. After stirring for 18 h, the reaction mixture was filtered and purified with Combiflash (A: 1‰NH4HCO3/water, B: acetonitrile) to afford 324a (80 mg, 34%) as a yellow solid. MS (ESI): 236.1 (M+H). the reaction mixture was filtered purified with Combiflash (A: 1‰NH4HCO3/water, B

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

Procedure: To a solution of (3S,5S)-3,5-dimethylmorpholine (115 mg, 1.0 mmol) in DMF (2 mL) was added HATU (380 mg, 1.0 mmol), DIPEA (260 mg, 2.0 mmol), and 6-aminonicotinic acid (138 mg, 1.0 mmol) at room temperature. After stirring for 18 h, the reaction mixture was filtered and purified with Combiflash (A: 1% NH4HCO3/water, B: acetonitrile) to afford 324a (80 mg, 34%) as a yellow solid. MS (ESI): 236.1 (M+H). the reaction mixture was filtered purified with Combiflash (A: 1% NH4HCO3/water, B

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

Procedure: A mixture of methyl 2-chlorobenzoxazole-4-carboxylate (620 mg, 2.96 mmol) and (3S,5S)-3,5-dimethylmorpholine (341 mg, 2.96 mmol) and potassium carbonate (1.0 g, 7.4 mmol), in DMF (15 mL), was stirred in a 35° C. oil bath. After 17 h, the reaction mixture was cooled to ambient temperature, diluted with H2O (50 mL) and extracted with EtOAc (2×30 mL). The combined organic layers were washed with H2O (3×20 mL), brine (20 mL), dried (Na2SO4), and concentrated under reduced pressure. Methyl 2-((3 S,5S)-3,5-dimethylmorpholino)benzoxazole-4-carboxylate (770 mg, 89%) was obtained as an amber oil. 1H NMR consistent. extracted with EtOAc (2×30 mL) The combined organic layers were washed with H2O (3×20 mL), brine (20 mL) dried (Na2SO4) concentrated under reduced pressure