A solution of (E)-3-(tetrahydro-pyran-4-yl)-acrylic acid (prepared as described in PCT Publication WO 2005/101989 (A2,A3), 0.200 g, 1.28 mmol) in dry CH2Cl2 (5 mL) was treated with oxalyl chloride (0.110 mL, 0.00128 mol) and DMF (1 drop) at room temperature for 1 h. The volatiles were evaporated in vacuo (water bath temperature <30° C.). At the same time, a suspension of NaH (78.8 mg, 1.97 mmol, 60% dispersion in oil) in dry THF (3 mL) was treated portionwise with 3-nitro-2′-trifluoromethyl-biphenyl-4-ylamine (278 mg, 0.985 mmol, prepared as in STEP A above) and stirred at room temperature for 30 min. The residue was taken up in dry THF (2 mL) and slowly added to the NaH mixture. The resulting mixture was stirred at room temperature overnight, quenched with saturated aqueous NH4Cl (20 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 24-g Sepra Si 50 SPE column (Isco system: flow rate=20 mL/min; eluting with EtOAc/hexane, 5:95, v/v over 5 min and 5:95 to 40:60, v/v over 25 min) to yield (E)-N-(3-nitro-2′-trifluoromethyl-biphenyl-4-yl)-3-(tetrahydro-pyran-4-yl)-acrylamide as a yellow solid.
