2,2,2-trifluoro-N-(2,2,2-trifluoroethyl)ethanamine

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

Procedure: Under a nitrogen atmosphere, a solution of 5-bromo-6-(cyclopropylmethoxy)-pyridine-2-carboxylic acid methyl ester (Example 114 a, 1 g, 3.5 mmol), bis(2,2,2-trifluoroethyl)amine (1.90 g, 10 mmol), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (CAN 98327-87-8, 0.435 g, 1 mmol), tris(dibenzylideneacetone) dipalladium (CAN 51364-51-3, 0.32 g, 0.35 mmol) and cesium carbonate (CAN 534-17-8, 3.4 g, 10 mmol) in toluene (50 mL) was reacted overnight at 110° C. The reaction mixture was concentrated under reduced pressure, dissolved in water, extracted with ethyl acetate (50 mL), the aqueous layer was adjusted to pH 2 with conc. HCl, then extracted with ethyl acetate (3×50 mL), washed with brine (2×50 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 10 g, 20% ethyl acetate in petroleum ether) to yield the title compound (0.5 g, 29.7%) as a yellow oil; MS: m/e=387.1 [M+H]+. The reaction mixture was concentrated under reduced pressure dissolved in water extracted with ethyl acetate (50 mL) extracted with ethyl acetate (3×50 mL) washed with brine (2×50 mL) dried over Na2SO4 concentrated under reduced pressure The residue was purified by column chromatography (silica gel, 10 g, 20% ethyl acetate in petroleum ether)

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

Procedure: Under a nitrogen atmosphere, a solution of 5-bromo-6-(cyclopropylmethoxy)-pyridine-2-carboxylic acid methyl ester (Example 114 a, 1 g, 3.5 mmol), bis(2,2,2-trifluoroethyl)amine (1.90 g, 10 mmol), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (CAN 98327-87-8, 0.435 g, 1 mmol), tris(dibenzylideneacetone) dipalladium (CAN 51364-51-3, 0.32 g, 0.35 mmol) and cesium carbonate (CAN 534-17-8, 3.4 g, 10 mmol) in toluene (50 mL) was reacted overnight at 110° C. The reaction mixture was concentrated under reduced pressure, dissolved in water, extracted with ethyl acetate (50 mL), the aqueous layer was adjusted to pH 2 with conc. HCl, then extracted with ethyl acetate (3×50 mL), washed with brine (2×50 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 10 g, 20% ethyl acetate in petroleum ether) to yield the title compound (0.5 g, 29.7%) as a yellow oil; MS: m/e=387.1 [M+H]+. The reaction mixture was concentrated under reduced pressure dissolved in water extracted with ethyl acetate (50 mL) extracted with ethyl acetate (3×50 mL) washed with brine (2×50 mL) dried over Na2SO4 concentrated under reduced pressure The residue was purified by column chromatography (silica gel, 10 g, 20% ethyl acetate in petroleum ether)

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

Procedure: 4-Fluoro-3-nitrobenzoic acid (2.50 g, 13.5 mmol) was refluxed in a 2:1 mixture of CH2Cl2/SOCl2 (150 mL) for 5 h. The solvent was concentrated and the residue was dissolved in CH2Cl2 (50 mL). Another CH2Cl2 solution (50 mL) of diisopropylethylamine (DIPEA) (3.50 mL, 20.3 mmol) and bis(2,2,2-trifluoroethyl)amine (4.90 g, 27.0 mmoL) was then added dropwise to the cold stirring solution (0° C.) of the acid chloride. The solution was stirred at RT overnight. The solution was then washed with 5% KHSO4 solution, saturated NaHCO3 solution, and brine and dried over anhydrous MgSO4. The product was purified by flash chromatography on silica gel using 3:1/HEX:EtOAc. Yield: 3.08 g (66%); 1H NMR (CDCl3) 4.17 (brs, 4H), 7.40 (t, J=8.59 Hz, 1H), 7.66 (m, 2H), 8.10 (d, J=6.84 Hz, 1H). The solvent was concentrated the residue was dissolved in CH2Cl2 (50 mL) The solution was then washed with 5% KHSO4 solution, saturated NaHCO3 solution, and brine dried over anhydrous MgSO4 The product was purified by flash chromatography on silica gel using 3:1/HEX

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

Procedure: 4-Fluoro-3-nitrobenzoic acid (2.50 g, 13.5 mmol) was refluxed in a 2:1 mixture of CH2Cl2/SOCl2 (150 mL) for 5 h. The solvent was concentrated and the residue was dissolved in CH2Cl2 (50 mL). Another CH2Cl2 solution (50 mL) of diisopropylethylamine (DIPEA) (3.50 mL, 20.3 mmol) and bis(2,2,2-trifluoroethyl)amine (4.90 g, 27.0 mmoL) was then added dropwise to the cold stirring solution (0° C.) of the acid chloride. The solution was stirred at RT overnight. The solution was then washed with 5% KHSO4 solution, saturated NaHCO3 solution, and brine and dried over anhydrous MgSO4. The product was purified by flash chromatography on silica gel using 3:1/HEX:EtOAc. Yield: 3.08 g (66%); 1H NMR (CDCl3) 4.17 (brs, 4H), 7.40 (t, J=8.59 Hz, 1H), 7.66 (m, 2H), 8.10 (d, J=6.84 Hz, 1H). The solvent was concentrated the residue was dissolved in CH2Cl2 (50 mL) The solution was then washed with 5% KHSO4 solution, saturated NaHCO3 solution, and brine dried over anhydrous MgSO4 The product was purified by flash chromatography on silica gel using 3:1/HEX

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

Procedure: 4-Fluoro-3-nitrobenzoic acid (2.50 g, 13.5 mmol) was refluxed in a 2:1 mixture of CH2Cl2/SOCl2 (150 mL) for 5 h. The solvent was concentrated and the residue was dissolved in CH2Cl2 (50 mL). Another CH2Cl2 solution (50 mL) of diisopropylethylamine (DIPEA) (3.50 mL, 20.3 mmol) and bis(2,2,2-trifluoroethyl)amine (4.90 g, 27.0 mmoL) was then added dropwise to the cold stirring solution (0° C.) of the acid chloride. The solution was stirred at RT overnight. The solution was then washed with 5% KHSO4 solution, saturated NaHCO3 solution, and brine and dried over anhydrous MgSO4. The product was purified by flash chromatography on silica gel using 3:1/HEX:EtOAc. Yield: 3.08 g (66%); 1H NMR (CDCl3) 4.17 (brs, 4H), 7.40 (t, J=8.59 Hz, 1H), 7.66 (m, 2H), 8.10 (d, J=6.84 Hz, 1H). The solvent was concentrated the residue was dissolved in CH2Cl2 (50 mL) The solution was then washed with 5% KHSO4 solution, saturated NaHCO3 solution, and brine dried over anhydrous MgSO4 The product was purified by flash chromatography on silica gel using 3:1/HEX

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

Procedure: 4-Fluoro-3-nitrobenzoic acid (2.50 g, 13.5 mmol) was refluxed in a 2:1 mixture of CH2Cl2/SOCl2 (150 mL) for 5 h. The solvent was concentrated and the residue was dissolved in CH2Cl2 (50 mL). Another CH2Cl2 solution (50 mL) of diisopropylethylamine (DIPEA) (3.50 mL, 20.3 mmol) and bis(2,2,2-trifluoroethyl)amine (4.90 g, 27.0 mmol) was then added dropwise to the cold stirring solution (0° C.) of the acid chloride. The solution was stirred at rt overnight. The solution was then washed with 5% KHSO4 solution, saturated NaHCO3 solution, brine and dried over anhydrous MgSO4. The crude product was purified by flash chromatography using 3:1/hexanes:EtOAc to afford the title product. Yield: 3.08 g (66%). 1H NMR (400 MHz, CDCl3) δ 4.17 (brs, 4H), 7.40 (t, J=8.59 Hz, 1H), 7.66 (m, 2H), 8.10 (d, J=6.84 Hz, 1H). The solvent was concentrated the residue was dissolved in CH2Cl2 (50 mL) The solution was then washed with 5% KHSO4 solution, saturated NaHCO3 solution, brine dried over anhydrous MgSO4 The crude product was purified by flash chromatography

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

Procedure: Under a nitrogen atmosphere, a solution of 5-bromo-6-(cyclopropylmethoxy)-pyridine-2-carboxylic acid methyl ester (Example 114 a, 1 g, 3.5 mmol), bis(2,2,2-trifluoroethyl)amine (1.90 g, 10 mmol), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (CAN 98327-87-8, 0.435 g, 1 mmol), tris(dibenzylideneacetone) dipalladium (CAN 51364-51-3, 0.32 g, 0.35 mmol) and cesium carbonate (CAN 534-17-8, 3.4 g, 10 mmol) in toluene (50 mL) was reacted overnight at 110° C. The reaction mixture was concentrated under reduced pressure, dissolved in water, extracted with ethyl acetate (50 mL), the aqueous layer was adjusted to pH 2 with conc. HCl, then extracted with ethyl acetate (3×50 mL), washed with brine (2×50 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 10 g, 20% ethyl acetate in petroleum ether) to yield the title compound (0.5 g, 29.7%) as a yellow oil; MS: m/e=387.1 [M+H]+. The reaction mixture was concentrated under reduced pressure dissolved in water extracted with ethyl acetate (50 mL) extracted with ethyl acetate (3×50 mL) washed with brine (2×50 mL) dried over Na2SO4 concentrated under reduced pressure The residue was purified by column chromatography (silica gel, 10 g, 20% ethyl acetate in petroleum ether)

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

Procedure: Under a nitrogen atmosphere, a solution of 5-bromo-6-(cyclopropylmethoxy)-pyridine-2-carboxylic acid methyl ester (Example 114 a, 1 g, 3.5 mmol), bis(2,2,2-trifluoroethyl)amine (1.90 g, 10 mmol), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (CAN 98327-87-8, 0.435 g, 1 mmol), tris(dibenzylideneacetone) dipalladium (CAN 51364-51-3, 0.32 g, 0.35 mmol) and cesium carbonate (CAN 534-17-8, 3.4 g, 10 mmol) in toluene (50 mL) was reacted overnight at 110° C. The reaction mixture was concentrated under reduced pressure, dissolved in water, extracted with ethyl acetate (50 mL), the aqueous layer was adjusted to pH 2 with conc. HCl, then extracted with ethyl acetate (3×50 mL), washed with brine (2×50 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 10 g, 20% ethyl acetate in petroleum ether) to yield the title compound (0.5 g, 29.7%) as a yellow oil; MS: m/e=387.1 [M+H]+. The reaction mixture was concentrated under reduced pressure dissolved in water extracted with ethyl acetate (50 mL) extracted with ethyl acetate (3×50 mL) washed with brine (2×50 mL) dried over Na2SO4 concentrated under reduced pressure The residue was purified by column chromatography (silica gel, 10 g, 20% ethyl acetate in petroleum ether)