1,3-dichloro-2-fluorobenzene

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

Procedure: A mixture of 3-[2-(4-hydroxy-phenyl)-morpholin-4-yl]-propionic acid tert-butyl ester (200 mg; 0.65 mmol), 2,6-dichlorofluorobenzene (107.35 mg; 0.65 mmol) and K2CO3 (134.9 mg; 0.98 mmol), in DMF (10 mL) was heated at 100° C., for 2 days. After cooling to RT the mixture was diluted with Et2O and washed with water (3 times). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (Et2O) to afford 3-{2-[4-(2,6-dichloro-phenoxy)-phenyl]-morpholin-4-yl}-propionic acid tert-butyl ester: (150.00 mg). washed with water (3 times) The combined organic layers were dried (Na2SO4) filtered concentrated in vacuo The residue was purified by column chromatography (Et2O)

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

Procedure: A mixture of 3-[2-(4-hydroxy-phenyl)-morpholin-4-yl]-propionic acid tert-butyl ester (200 mg; 0.65 mmol), 2,6-dichlorofluorobenzene (107.35 mg; 0.65 mmol) and K2CO3 (134.9 mg; 0.98 mmol), in DMF (10 mL) was heated at 100° C., for 2 days. After cooling to RT the mixture was diluted with Et2O and washed with water (3 times). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (Et2O) to afford 3-{2-[4-(2,6-dichloro-phenoxy)-phenyl]-morpholin-4-yl}-propionic acid tert-butyl ester: (150.00 mg). washed with water (3 times) The combined organic layers were dried (Na2SO4) filtered concentrated in vacuo The residue was purified by column chromatography (Et2O)

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

Procedure: A solution of 4-(4-benzyl-morpholin-2-yl)-2-chloro-phenol (0.50 g; 1.56 mmol), 2,6-dichlorofluorobenzene (0.26 g; 1.56 mmol) and K2CO3 (0.32 g; 2.35 mmol) in DMF (10 mL) was heated at 100° C. for three days. After cooling to RT, the mixture was diluted with EtOAc and washed with water (3×). The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, CH2Cl2/MeOH 99.5:0.5) to afford 4-Benzyl-2-[3-chloro-4-(2,6-dichloro-phenoxy)-phenyl]-morpholine (0.35 g). washed with water (3×) The organic layer was dried (MgSO4) filtered concentrated in vacuo The residue was purified by column chromatography (SiO2, CH2Cl2/MeOH 99.5:0.5)

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

Procedure: A mixture of 3-[2-(4-hydroxy-phenyl)-morpholin-4-yl]-propionic acid tert-butyl ester (200 mg; 0.65 mmol), 2,6-dichlorofluorobenzene (107.35 mg; 0.65 mmol) and K2CO3 (134.9 mg; 0.98 mmol), in DMF (10 mL) was heated at 100° C., for 2 days. After cooling to RT the mixture was diluted with Et2O and washed with water (3 times). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (Et2O) to afford 3-{2-[4-(2,6-dichloro-phenoxy)-phenyl]-morpholin-4-yl}-propionic acid tert-butyl ester: (150.00 mg). washed with water (3 times) The combined organic layers were dried (Na2SO4) filtered concentrated in vacuo The residue was purified by column chromatography (Et2O)

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

Procedure: A mixture of 3-[2-(4-hydroxy-phenyl)-morpholin-4-yl]-propionic acid tert-butyl ester (200 mg; 0.65 mmol), 2,6-dichlorofluorobenzene (107.35 mg; 0.65 mmol) and K2CO3 (134.9 mg; 0.98 mmol), in DMF (10 mL) was heated at 100° C., for 2 days. After cooling to RT the mixture was diluted with Et2O and washed with water (3 times). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (Et2O) to afford 3-{2-[4-(2,6-dichloro-phenoxy)-phenyl]-morpholin-4-yl}-propionic acid tert-butyl ester: (150.00 mg). washed with water (3 times) The combined organic layers were dried (Na2SO4) filtered concentrated in vacuo The residue was purified by column chromatography (Et2O)

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

Procedure: A solution of 4-(4-benzyl-morpholin-2-yl)-2-chloro-phenol (0.50 g; 1.56 mmol), 2,6-dichlorofluorobenzene (0.26 g; 1.56 mmol) and K2CO3 (0.32 g; 2.35 mmol) in DMF (10 mL) was heated at 100° C. for three days. After cooling to RT, the mixture was diluted with EtOAc and washed with water (3×). The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, CH2Cl2/MeOH 99.5:0.5) to afford 4-Benzyl-2-[3-chloro-4-(2,6-dichloro-phenoxy)-phenyl]-morpholine (0.35 g). washed with water (3×) The organic layer was dried (MgSO4) filtered concentrated in vacuo The residue was purified by column chromatography (SiO2, CH2Cl2/MeOH 99.5:0.5)

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

Procedure: The same method as in Example 3 was conducted using 7-methyl-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepin-4-ol (Reference Example 19) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2,6-dichloro-1-fluorobenzene instead of 1,3-difluorobenzene to give the objective compound. to give the objective compound

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

Procedure: A mixture of 3-[2-(4-hydroxy-phenyl)-morpholin-4-yl]-propionic acid tert-butyl ester (200 mg; 0.65 mmol), 2,6-dichlorofluorobenzene (107.35 mg; 0.65 mmol) and K2CO3 (134.9 mg; 0.98 mmol), in DMF (10 mL) was heated at 100° C., for 2 days. After cooling to RT the mixture was diluted with Et2O and washed with water (3 times). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (Et2O) to afford 3-{2-[4-(2,6-dichloro-phenoxy)-phenyl]-morpholin-4-yl}-propionic acid tert-butyl ester: (150.00 mg). washed with water (3 times) The combined organic layers were dried (Na2SO4) filtered concentrated in vacuo The residue was purified by column chromatography (Et2O)

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

Procedure: A solution of 4-(4-benzyl-morpholin-2-yl)-2-chloro-phenol (0.50 g; 1.56 mmol), 2,6-dichlorofluorobenzene (0.26 g; 1.56 mmol) and K2CO3 (0.32 g; 2.35 mmol) in DMF (10 mL) was heated at 100° C. for three days. After cooling to RT, the mixture was diluted with EtOAc and washed with water (3×). The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, CH2Cl2/MeOH 99.5:0.5) to afford 4-Benzyl-2-[3-chloro-4-(2,6-dichloro-phenoxy)-phenyl]-morpholine (0.35 g). washed with water (3×) The organic layer was dried (MgSO4) filtered concentrated in vacuo The residue was purified by column chromatography (SiO2, CH2Cl2/MeOH 99.5:0.5)

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

Procedure: A mixture of 3-[2-(4-hydroxy-phenyl)-morpholin-4-yl]-propionic acid tert-butyl ester (200 mg; 0.65 mmol), 2,6-dichlorofluorobenzene (107.35 mg; 0.65 mmol) and K2CO3 (134.9 mg; 0.98 mmol), in DMF (10 mL) was heated at 100° C., for 2 days. After cooling to RT the mixture was diluted with Et2O and washed with water (3 times). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (Et2O) to afford 3-{2-[4-(2,6-dichloro-phenoxy)-phenyl]-morpholin-4-yl}-propionic acid tert-butyl ester: (150.00 mg). washed with water (3 times) The combined organic layers were dried (Na2SO4) filtered concentrated in vacuo The residue was purified by column chromatography (Et2O)

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

Procedure: A solution of 4-(4-benzyl-morpholin-2-yl)-2-chloro-phenol (0.50 g; 1.56 mmol), 2,6-dichlorofluorobenzene (0.26 g; 1.56 mmol) and K2CO3 (0.32 g; 2.35 mmol) in DMF (10 mL) was heated at 100° C. for three days. After cooling to RT, the mixture was diluted with EtOAc and washed with water (3×). The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, CH2Cl2/MeOH 99.5:0.5) to afford 4-Benzyl-2-[3-chloro-4-(2,6-dichloro-phenoxy)-phenyl]-morpholine (0.35 g). washed with water (3×) The organic layer was dried (MgSO4) filtered concentrated in vacuo The residue was purified by column chromatography (SiO2, CH2Cl2/MeOH 99.5:0.5)