2-[2-[4-fluoro-2-(trifluoromethyl)phenoxy]ethylamino]ethanol

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

Procedure: 5-(4-Methyl-1H-imidazol-1-yl)-6-oxo-1,6-dihydropyridine-2-carboxylic acid, 0.7 hydrobromide salt (P1) (201 mg, 0.729 mmol) and 2-({2-[4-fluoro-2-(trifluoromethyl)phenoxy]ethyl}amino)ethanol (C36) (214 mg, 0.801 mmol) were combined with dichloromethane (15 mL) and N,N-diisopropylethylamine (0.508 mL, 2.92 mmol), and the mixture was stirred for 5 minutes at room temperature. O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 97%, 857 mg, 2.19 mmol) was added in one portion, and the reaction was stirred for an additional 16 hours. Water (50 mL) was added, and the mixture was extracted with dichloromethane (3×50 mL). The combined organic layers were washed sequentially with saturated aqueous sodium bicarbonate solution (50 mL), water (50 mL) and saturated aqueous sodium chloride solution (50 mL), then dried over magnesium sulfate and concentrated in vacuo. Purification was carried out twice using silica gel chromatography (Gradient #1: 0% to 20% methanol in dichloromethane; Gradient #2: 0% to 70% [10% 2 N ammonia in methanol/90% ethyl acetate] in ethyl acetate) to afford the title compound as a white solid. Yield: 268 mg, 0.595 mmol, 82%. LCMS m/z 451.0 (M+1). 1H NMR (400 MHz, CD3OD) δ 2.24 (d, J=0.9 Hz, 3H), 3.90-3.95 (m, 2H), 4.01 (dd, J=5.1, 5.1 Hz, 2H), 4.32-4.37 (m, 4H), 7.21-7.26 (m, 1H), 7.25 (d, J=7.8 Hz, 1H), 7.30-7.32 (m, 1H), 7.32-7.39 (m, 2H), 7.76 (d, J=7.8 Hz, 1H), 8.30 (d, J=1.3 Hz, 1H). the reaction was stirred for an additional 16 hours the mixture was extracted with dichloromethane (3×50 mL) The combined organic layers were washed sequentially with saturated aqueous sodium bicarbonate solution (50 mL), water (50 mL) and saturated aqueous sodium chloride solution (50 mL) dried over magnesium sulfate concentrated in vacuo Purification

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

Procedure: A mixture of 1-(2-bromoethoxy)-4-fluoro-2-(trifluoromethyl)benzene (C35) (600 mg, 2.09 mmol) and 2-aminoethanol (2.20 mL, 52.4 mmol) was heated to 80° C. for 1.5 hours. The reaction was allowed to cool to room temperature, diluted with ethyl acetate (75 mL) and washed with aqueous sodium hydroxide solution (1 N, 4×50 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to provide the title compound as a white solid. Yield: 550 mg, 2.06 mmol, 99%. LCMS m/z 268.1 (M+1). 1H NMR (400 MHz, CD3OD) δ 2.80 (br dd, J=5.5, 5.4 Hz, 2H), 3.04 (dd, J=5.4, 5.2 Hz, 2H), 3.68 (br dd, J=5.6, 5.4 Hz, 2H), 4.20 (dd, J=5.3, 5.3 Hz, 2H), 7.22 (br dd, J=8.8, 4.2 Hz, 1H), 7.30-7.37 (m, 2H). to cool to room temperature washed with aqueous sodium hydroxide solution (1 N, 4×50 mL) The organic layer was dried over magnesium sulfate concentrated under reduced pressure