3-fluoro-2-(fluoromethyl)-2-methylpropanoic acid

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred solution of Intermediate 209B (28.1 mg, 0.204 mmol) in toluene (2 mL) at RT under nitrogen was added TEA (0.043 mL, 0.305 mmol), DPPA (0.047 mL, 0.204 mmol) and the solution was heated at 70° C. and stirred for 2 h. The reaction mass was cooled to RT and to it was added Intermediate 185B (30 mg, 0.102 mmol) in THF (1 mL) was added and the reaction mixture was stirred at RT for 12 h. The reaction mass was diluted with ethyl acetate (25 mL), the organic layer was separated, washed with a 10% aqueous solution of NaHCO3, water, brine dried over Na2SO4, filtered, and the filtrate evaporated. The crude compound was purified by preparative HPLC to afford Compound 209 as pale yellow solid (11 mg, 24% yield). The HPLC Retention times 1.963 min. and 1.968 min. (Methods J and K respectively); MS(ES): m/z=430.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.85 (dd, J=7.31, 2.16 Hz, 1H), 7.64-7.73 (m, 1H), 7.42-7.52 (m, 1H), 7.15-7.30 (m, 2H), 6.62 (s, 1H), 4.73 (s, 2H), 4.64 (s, 2H), 4.52 (s, 2H), 4.14 (s, 2H), 3.84 (s, 2H), 1.31 (t, J=2.07 Hz, 3H). The reaction mass was cooled to RT and to it was added the reaction mixture was stirred at RT for 12 h the organic layer was separated washed with a 10% aqueous solution of NaHCO3, water, brine dried over Na2SO4 filtered the filtrate evaporated The crude compound was purified by preparative HPLC

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred solution of Intermediate 209B (28.1 mg, 0.204 mmol) in toluene (2 mL) at RT under nitrogen was added TEA (0.043 mL, 0.305 mmol), DPPA (0.047 mL, 0.204 mmol) and the solution was heated at 70° C. and stirred for 2 h. The reaction mass was cooled to RT and to it was added Intermediate 185B (30 mg, 0.102 mmol) in THF (1 mL) was added and the reaction mixture was stirred at RT for 12 h. The reaction mass was diluted with ethyl acetate (25 mL), the organic layer was separated, washed with a 10% aqueous solution of NaHCO3, water, brine dried over Na2SO4, filtered, and the filtrate evaporated. The crude compound was purified by preparative HPLC to afford Compound 209 as pale yellow solid (11 mg, 24% yield). The HPLC Retention times 1.963 min. and 1.968 min. (Methods J and K respectively); MS(ES): m/z=430.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.85 (dd, J=7.31, 2.16 Hz, 1H), 7.64-7.73 (m, 1H), 7.42-7.52 (m, 1H), 7.15-7.30 (m, 2H), 6.62 (s, 1H), 4.73 (s, 2H), 4.64 (s, 2H), 4.52 (s, 2H), 4.14 (s, 2H), 3.84 (s, 2H), 1.31 (t, J=2.07 Hz, 3H). The reaction mass was cooled to RT and to it was added the reaction mixture was stirred at RT for 12 h the organic layer was separated washed with a 10% aqueous solution of NaHCO3, water, brine dried over Na2SO4 filtered the filtrate evaporated The crude compound was purified by preparative HPLC

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

Procedure: To a stirred solution of Intermediate 209A (0.300 g, 1.314 mmol) in EtOAc (5 mL) was added 10% Pd/C (0.140 g, 0.131 mmol). The reaction mixture was stirred for 12 h under an atmosphere of hydrogen (15 psi). The reaction mixture was then filtered through a pad of CELITE® and the cake was washed with EtOAc. The filtrate was concentrated under reduced pressure to afford Intermediate 209B as a yellow liquid (160 mg, 88%). The crude product was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.02 (bs, 1H), 4.40-4.66 (m, 4H), 1.06-1.20 (m, 3H). The reaction mixture was then filtered through a pad of CELITE® the cake was washed with EtOAc The filtrate was concentrated under reduced pressure

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred solution of Intermediate 209B (28.1 mg, 0.204 mmol) in toluene (2 mL) at RT under nitrogen was added TEA (0.043 mL, 0.305 mmol), DPPA (0.047 mL, 0.204 mmol) and the solution was heated at 70° C. and stirred for 2 h. The reaction mass was cooled to RT and to it was added Intermediate 185B (30 mg, 0.102 mmol) in THF (1 mL) was added and the reaction mixture was stirred at RT for 12 h. The reaction mass was diluted with ethyl acetate (25 mL), the organic layer was separated, washed with a 10% aqueous solution of NaHCO3, water, brine dried over Na2SO4, filtered, and the filtrate evaporated. The crude compound was purified by preparative HPLC to afford Compound 209 as pale yellow solid (11 mg, 24% yield). The HPLC Retention times 1.963 min. and 1.968 min. (Methods J and K respectively); MS(ES): m/z=430.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.85 (dd, J=7.31, 2.16 Hz, 1H), 7.64-7.73 (m, 1H), 7.42-7.52 (m, 1H), 7.15-7.30 (m, 2H), 6.62 (s, 1H), 4.73 (s, 2H), 4.64 (s, 2H), 4.52 (s, 2H), 4.14 (s, 2H), 3.84 (s, 2H), 1.31 (t, J=2.07 Hz, 3H). The reaction mass was cooled to RT and to it was added the reaction mixture was stirred at RT for 12 h the organic layer was separated washed with a 10% aqueous solution of NaHCO3, water, brine dried over Na2SO4 filtered the filtrate evaporated The crude compound was purified by preparative HPLC

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

Procedure: To a stirred solution of Intermediate 209A (0.300 g, 1.314 mmol) in EtOAc (5 mL) was added 10% Pd/C (0.140 g, 0.131 mmol). The reaction mixture was stirred for 12 h under an atmosphere of hydrogen (15 psi). The reaction mixture was then filtered through a pad of CELITE® and the cake was washed with EtOAc. The filtrate was concentrated under reduced pressure to afford Intermediate 209B as a yellow liquid (160 mg, 88%). The crude product was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.02 (bs, 1H), 4.40-4.66 (m, 4H), 1.06-1.20 (m, 3H). The reaction mixture was then filtered through a pad of CELITE® the cake was washed with EtOAc The filtrate was concentrated under reduced pressure