(3-fluorophenyl)boronic acid

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

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

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

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

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

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

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

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

Procedure: The title compound was prepared from a Suzuki coupling of 4-Methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (intermediate Example 1g) with 3-fluoro-phenylboronic acid under the conditions described in Example 1; 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.89-1.00 (m, 6H), 1.58 (dt, J=13.39, 6.63 Hz, 1H), 1.78 (ddd, J=13.76, 7.34, 7.03 Hz, 1H), 2.01-2.13 (m, 1H), 3.82 (t, J=7.83 Hz, 1H), 7.05-7.13 (m, 1H), 7.32 (dd, J=10.03, 1.47 Hz, 1H), 7.36-7.47 (m, 2H), 7.52-7.61 (m, 2H), 7.66-7.76 (m, 5H); Calcd for C25H22F4O2 (M+Na) 453.16, Found 453.

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

Procedure: A mixture of [3-[2-[1-(5-bromothiazole-2-yl)-4-pyrrolidine-1-ylpiperidine-4-yl]ethoxy]-5-chlorophenyl]acetic acid (60 mg), 3-fluorophenyl boronic acid (32 mg), tetrakis (triphenylphosphine) palladium (13 mg), 1M sodium carbonate (0.55 mL) and dimethylformamide (1 mL) was reacted with a microwave reaction device at 180° C. for 5 minutes. The insoluble material was filtrated. To the filtrate was added formic acid. The solvent was evaporated under reduced pressure and the residue was purified by high performance liquid chromatography to give the title compound (14.4 mg). Yield: 24%. was reacted with a microwave reaction device at 180° C. for 5 minutes The insoluble material was filtrated To the filtrate was added formic acid The solvent was evaporated under reduced pressure the residue was purified by high performance liquid chromatography

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: tert-Butyl 2-(2-(3-fluorophenyl)-5-hydroxy-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamido)acetate. To a mixture of tert-butyl 2-(2-chloro-5-hydroxy-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamido)acetate (100 mg, 1 eq., Method 10), Pd(dppf)Cl2 (0.05 eq.), 3-fluorophenylboronic acid (3.0 eq., available from Aldrich (Milwaukee, Wis.)) in degassed dioxane (4 mL) was added degassed aqueous Na2CO3 (2M, 3 eq.) in a sealed tube. The mixture was stirred overnight at 80° C. The mixture was then cooled to room temperature and diluted with water. The phases were separated and extracted with more CH2Cl2. The combined organic phases were washed with water and brine, dried over Na2SO4 and concentrated. The residue was dissolved in DMA and purified on reversed phase HPLC to give the title compound (48 mg, 41%) as a light brown solid. C21H21FN4O5 (428.4). APCI-MS: 429 ([M+H]+), 373 ([M-(t-Bu)+H]+). 1H-NMR (DMSO-d6): δ 10.21 (br s, 1H), 9.39 (s, 1H), 8.40 (d, J=7.8, 1H), 8.25 (d, J=9.3, 1H), 7.66 (q, J=8.1, 1H), 7.49 (dt, J=8.5, 2.5, 1H), 4.13 (d, J=5.7, 2H), 3.55 (s, 3H), 1.46 (s, 9H). was added The mixture was then cooled to room temperature The phases were separated extracted with more CH2Cl2 The combined organic phases were washed with water and brine dried over Na2SO4 concentrated The residue was dissolved in DMA purified on reversed phase HPLC

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a reaction vessel charged with 4 mL of toluene and 1 mL of water, was added 45 mg (0.072 mmol) of 4-[3-[6-(5-bromo-4′-dimethylamino-biphenyl-3-yloxy)-hexyl]-2-(2-carboxy-ethyl)-phenoxy]-butyric acid, 3-fluorophenylboronic acid (20 mg, 0.144 mmol), and potassium phosphate (35.9 mg, 0.144 mmol). This mixture was put under an atmosphere of nitrogen and 4.16 mg of tetrakis(triphenylphosphine)palladium(0) was added. This mixture was stirred and was heated overnight at 90° C. At this time, analysis of an aliquot by LC-MS, indicated the formation of the desired product. To the reaction mixture was added 2N HCl to effect pH=˜6. The aqueous phase was thrice extracted with ethyl acetate. The combined organic phases were dried with MgSO4, filtered and washed with ethyl acetate. The filtrate was concentrated in vacuo to provide a solid which was purified by preparative HPLC to provide 46 mg of product. Example 57 was characterized by low resolution mass spectrometry where signals corresponding to the following were observed: ES(+)=598+Na, ES(−)=597. Example 57 was also characterized by high resolution mass spectrometry where signals corresponding to the following were observed: m/e calculated for C37H39FO6 598.273068; found compatible with (M+Na)1+=621.2624.

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

Procedure: A similar procedure as described in Example 12, step 3 was used, starting from 1-iodo-3-methoxy-5-nitro-benzene (1.03 g, 3.69 mmol) and 3-fluoro-phenylboronic acid (800 mg, 5.72 mmol) to afford 3′-fluoro-5-methoxy-3-nitro-biphenyl (745 mg, 82%) as an amorphous white solid: EI(+)-HRMS m/e calculated for C13H10FNO3 (M)+ 247.0645, found 247.0645.