methyl 2-bromo-3-phenylpropanoate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A -78° C. solution of N-(benzyloxyacetyl)morpholine (1 g, 8.5 mmol) in THF (25 mL) was treated with potassium bis(trimethylsilyl)amide (17 mL of a 0.5M solution). After stirring for 10 min at -78° C., a solution of methyl 2-bromo-3-phenylpropionate (8.5 mmol) in THF (5 mL) was added dropwise. Stirring at -78° C. for 30 min was followed by warming to 0° C. The reaction was then distributed between ether and brine solution. The organic layer was washed with brine and dried over MgSO4. Evaporation and flash chromatography on silica gel gave the desired product in 63% yield. Stirring at -78° C. for 30 min by warming to 0° C The organic layer was washed with brine dried over MgSO4 Evaporation and flash chromatography on silica gel

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A -78° C. solution of N-(benzyloxyacetyl)morpholine (1 g, 8.5 mmol) in THF (25 mL) was treated with potassium bis(trimethylsilyl)amide (17 mL of a 0.5M solution). After stirring for 10 min at -78° C., a solution of methyl 2-bromo-3-phenylpropionate (8.5 mmol) in THF (5 mL) was added dropwise. Stirring at -78° C. for 30 min was followed by warming to 0° C. The reaction was then distributed between ether and brine solution. The organic layer was washed with brine and dried over MgSO4. Evaporation and flash chromatography on silica gel gave the desired product in 63% yield. Stirring at -78° C. for 30 min by warming to 0° C The organic layer was washed with brine dried over MgSO4 Evaporation and flash chromatography on silica gel

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A -78° C. solution of N-(benzyloxyacetyl)morpholine (1 g, 8.5 mmol) in THF (25 mL) was treated with potassium bis(trimethylsilyl)amide (17 mL of a 0.5M solution). After stirring for 10 min at -78° C., a solution of methyl 2-bromo-3-phenylpropionate (8.5 mmol) in THF (5 mL) was added dropwise. Stirring at -78° C. for 30 min was followed by warming to 0° C. The reaction was then distributed between ether and brine solution. The organic layer was washed with brine and dried over MgSO4. Evaporation and flash chromatography on silica gel gave the desired product in 63% yield. Stirring at -78° C. for 30 min by warming to 0° C The organic layer was washed with brine dried over MgSO4 Evaporation and flash chromatography on silica gel

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A -78° C. solution of N-(benzyloxyacetyl)morpholine (1 g, 8.5 mmol) in THF (25 mL) was treated with potassium bis(trimethylsilyl)amide (17 mL of a 0.5M solution). After stirring for 10 min at -78° C., a solution of methyl 2-bromo-3-phenylpropionate (8.5 mmol) in THF (5 mL) was added dropwise. Stirring at -78° C. for 30 min was followed by warming to 0° C. The reaction was then distributed between ether and brine solution. The organic layer was washed with brine and dried over MgSO4. Evaporation and flash chromatography on silica gel gave the desired product in 63% yield. Stirring at -78° C. for 30 min by warming to 0° C The organic layer was washed with brine dried over MgSO4 Evaporation and flash chromatography on silica gel

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A -78° C. solution of N-(benzyloxyacetyl)morpholine (1 g, 8.5 mmol) in THF (25 mL) was treated with potassium bis(trimethylsilyl)amide (17 mL of a 0.5M solution). After stirring for 10 min at -78° C., a solution of methyl 2-bromo-3-phenylpropionate (8.5 mmol) in THF (5 mL) was added dropwise. Stirring at -78° C. for 30 min was followed by warming to 0° C. The reaction was then distributed between ether and brine solution. The organic layer was washed with brine and dried over MgSO4. Evaporation and flash chromatography on silica gel gave the desired product in 63% yield. Stirring at -78° C. for 30 min by warming to 0° C The organic layer was washed with brine dried over MgSO4 Evaporation and flash chromatography on silica gel

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: In an analogous manner to the stepwise sequence outlined in intermediate 19, starting from 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20) and 2,6-difluoro-phenol and alkylating with 2-bromo-3-phenyl-propionic acid methyl ester (Intermediate 13) afforded 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-phenyl-propionic acid as a white solid (555.8 mg, 96% for the final step); ES+-HRMS m/e calcd for C19H14N2O4F2 [M+H+] 373.0995, found 373.0994. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.28-3.37 (m, 1H), 3.44 (dd, J=14.3, 4.7 Hz, 1H), 5.64 (dd, J=11.1, 4.7 Hz, 1H), 5.96 (d, J=2.7 Hz, 1H), 7.09-7.25 (m, 5H), 7.30-7.41 (m, 2H), 7.41-7.52 (m, 1H), 8.19 (d, J=2.7 Hz, 1H), 13.24 (br s, 1H).

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

Procedure: In an analogous manner to the stepwise sequence outlined in intermediate 19, starting from 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20) and 2,6-difluoro-phenol and alkylating with 2-bromo-3-phenyl-propionic acid methyl ester (Intermediate 13) afforded 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-phenyl-propionic acid as a white solid (555.8 mg, 96% for the final step); ES+-HRMS m/e calcd for C19H14N2O4F2 [M+H+] 373.0995, found 373.0994. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.28-3.37 (m, 1H), 3.44 (dd, J=14.3, 4.7 Hz, 1H), 5.64 (dd, J=11.1, 4.7 Hz, 1H), 5.96 (d, J=2.7 Hz, 1H), 7.09-7.25 (m, 5H), 7.30-7.41 (m, 2H), 7.41-7.52 (m, 1H), 8.19 (d, J=2.7 Hz, 1H), 13.24 (br s, 1H).

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A -78° C. solution of N-(benzyloxyacetyl)morpholine (1 g, 8.5 mmol) in THF (25 mL) was treated with potassium bis(trimethylsilyl)amide (17 mL of a 0.5M solution). After stirring for 10 min at -78° C., a solution of methyl 2-bromo-3-phenylpropionate (8.5 mmol) in THF (5 mL) was added dropwise. Stirring at -78° C. for 30 min was followed by warming to 0° C. The reaction was then distributed between ether and brine solution. The organic layer was washed with brine and dried over MgSO4. Evaporation and flash chromatography on silica gel gave the desired product in 63% yield Stirring at -78° C. for 30 min by warming to 0° C The organic layer was washed with brine dried over MgSO4 Evaporation and flash chromatography on silica gel

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A -78° C. solution of N-(benzyloxyacetyl)morpholine (1 g, 8.5 mmol) in THF (25 mL) was treated with potassium bis(trimethylsilyl)amide (17 mL of a 0.5M solution). After stirring for 10 min at -78° C., a solution of methyl 2-bromo-3-phenylpropionate (8.5 mmol) in THF (5 mL) was added dropwise. Stirring at -78° C. for 30 min was followed by warming to 0° C. The reaction was then distributed between ether and brine solution. The organic layer was washed with brine and dried over MgSO4. Evaporation and flash chromatography on silica gel gave the desired product in 63% yield. Stirring at -78° C. for 30 min by warming to 0° C The organic layer was washed with brine dried over MgSO4 Evaporation and flash chromatography on silica gel

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A -78° C. solution of N-(benzyloxyacetyl)morpholine (1 g, 8.5 mmol) in THF (25 mL) was treated with potassium bis(trimethylsilyl)amide (17 mL of a 0.5M solution). After stirring for 10 min at -78° C., a solution of methyl 2-bromo-3-phenylpropionate (8.5 mmol) in THF (5 mL) was added dropwise. Stirring at -78° C. for 30 min was followed by warming to 0° C. The reaction was then distributed between ether and brine solution. The organic layer was washed with brine and dried over MgSO4. Evaporation and flash chromatography on silica gel gave the desired product in 63% yield. Stirring at -78° C. for 30 min by warming to 0° C The organic layer was washed with brine dried over MgSO4 Evaporation and flash chromatography on silica gel