2,2,2-trifluoro-N-methylethanamine;hydrochloride

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

Procedure: 133 mg (0.81 mmol) of N-ethyl-2,2,2-trifluoroethanamine hydrochloride were dissolved in 2 ml of DMF, 130 mg Amberlyst A-21 were added and the mixture was stirred at RT for 30 min. The mixture was filtered off and added to 100 mg (0.14 mmol, purity about 74%) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A), and the solution was stirred at RT overnight. The mixture was then warmed to 60° C. and stirred at this temperature overnight. In a separate flask, another 87 mg (0.54 mmol) of 2,2,2-trifluoro-N-methylethanamine hydrochloride were then dissolved in 0.5 ml of DMF, 88 mg of Amberlyst A-21 were added and the mixture was stirred at RT for 30 min. The mixture was filtered off and added to the first solution. The reaction mixture obtained was stirred at 100° C. for 4.5 h. The mixture was then diluted with a little water/THF and purified by preparative HPLC (acetonitrile/water+0.1% TFA). This gave 37 mg (41% of theory) of the target compound. 130 mg Amberlyst A-21 were added The mixture was filtered off the solution was stirred at RT overnight The mixture was then warmed to 60° C. stirred at this temperature overnight 88 mg of Amberlyst A-21 were added the mixture was stirred at RT for 30 min The mixture was filtered off added to the first solution The reaction mixture obtained was stirred at 100° C. for 4.5 h purified by preparative HPLC (acetonitrile/water+0.1% TFA)

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

Procedure: 41 mg (0.27 mmol) of 2,2,2-trifluoro-N-methylethanamine hydrochloride were dissolved in 2 ml of DMF, 40 mg of Amberlyst A-21 were added and the mixture was stirred at RT for 30 min. The mixture was filtered off and added to 100 mg (0.14 mmol, purity about 74%) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A), and the solution was stirred at RT overnight. In a separate flask, another 82 mg (0.54 mmol) of 2,2,2-trifluoro-N-methylethanamine hydrochloride were then dissolved in 0.5 ml of DMF, 80 mg of Amberlyst A-21 were added and the mixture was stirred at RT for 30 min. The mixture was filtered off and added to the first solution. The reaction mixture obtained was stirred at RT overnight. The mixture was then warmed to 60° C., and the reaction mixture was stirred at this temperature overnight, after which it was heated to 100° C. After stirring at 100° C. overnight, the mixture was diluted with a little water/THF and purified by preparative HPLC (acetonitrile/water+0.1% TFA). This gave 64 mg (74% of theory) of the target compound. 40 mg of Amberlyst A-21 were added The mixture was filtered off the solution was stirred at RT overnight 80 mg of Amberlyst A-21 were added the mixture was stirred at RT for 30 min The mixture was filtered off added to the first solution The reaction mixture obtained was stirred at RT overnight The mixture was then warmed to 60° C. the reaction mixture was stirred at this temperature overnight after which it was heated to 100° C After stirring at 100° C. overnight purified by preparative HPLC (acetonitrile/water+0.1% TFA)

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4′-methyl-5-((6-methylpyridin-3-yl)methylcarbamoyl)biphenyl-3-carboxylic acid (50 mg, 0.14 mmol) in N,N-dimethylformamide (1.5 mL) were added 2,2,2-trifluoro-N-methylethanamine hydrochloride (60 mg, 0.40 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (120 mg, 0.32 mmol) and N,N-diisopropylethylamine (0.50 mL, 2.87 mmol). The reaction mixture was stirred for 16 hours at 25° C. The reaction mixture was purified by preparative HPLC to afford the final product as a light yellow solid. The reaction mixture was purified by preparative HPLC

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

Procedure: 133 mg (0.81 mmol) of N-ethyl-2,2,2-trifluoroethanamine hydrochloride were dissolved in 2 ml of DMF, 130 mg Amberlyst A-21 were added and the mixture was stirred at RT for 30 min. The mixture was filtered off and added to 100 mg (0.14 mmol, purity about 74%) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-ylmethyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A), and the solution was stirred at RT overnight. The mixture was then warmed to 60° C. and stirred at this temperature overnight. In a separate flask, another 87 mg (0.54 mmol) of 2,2,2-trifluoro-N-methylethanamine hydrochloride were then dissolved in 0.5 ml of DMF, 88 mg of Amberlyst A-21 were added and the mixture was stirred at RT for 30 min. The mixture was filtered off and added to the first solution. The reaction mixture obtained was stirred at 100° C. for 4.5 h. The mixture was then diluted with a little water/THF and purified by preparative HPLC (acetonitrile/water+0.1% TFA). This gave 37 mg (41% of theory) of the target compound. 130 mg Amberlyst A-21 were added The mixture was filtered off the solution was stirred at RT overnight The mixture was then warmed to 60° C. stirred at this temperature overnight 88 mg of Amberlyst A-21 were added the mixture was stirred at RT for 30 min The mixture was filtered off added to the first solution The reaction mixture obtained was stirred at 100° C. for 4.5 h purified by preparative HPLC (acetonitrile/water+0.1% TFA)

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

Procedure: 41 mg (0.27 mmol) of 2,2,2-trifluoro-N-methylethanamine hydrochloride were dissolved in 2 ml of DMF, 40 mg of Amberlyst A-21 were added and the mixture was stirred at RT for 30 min. The mixture was filtered off and added to 100 mg (0.14 mmol, purity about 74%) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A), and the solution was stirred at RT overnight. In a separate flask, another 82 mg (0.54 mmol) of 2,2,2-trifluoro-N-methylethanamine hydrochloride were then dissolved in 0.5 ml of DMF, 80 mg of Amberlyst A-21 were added and the mixture was stirred at RT for 30 min. The mixture was filtered off and added to the first solution. The reaction mixture obtained was stirred at RT overnight. The mixture was then warmed to 60° C., and the reaction mixture was stirred at this temperature overnight, after which it was heated to 100° C. After stirring at 100° C. overnight, the mixture was diluted with a little water/THF and purified by preparative HPLC (acetonitrile/water+0.1% TFA). This gave 64 mg (74% of theory) of the target compound. 40 mg of Amberlyst A-21 were added The mixture was filtered off the solution was stirred at RT overnight 80 mg of Amberlyst A-21 were added the mixture was stirred at RT for 30 min The mixture was filtered off added to the first solution The reaction mixture obtained was stirred at RT overnight The mixture was then warmed to 60° C. the reaction mixture was stirred at this temperature overnight after which it was heated to 100° C After stirring at 100° C. overnight purified by preparative HPLC (acetonitrile/water+0.1% TFA)

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

Procedure: A mixture of 3-(6-benzene sulfonyl-6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)cyclopentylamine (200 mg, 520 μmol) and triethylamine (333 μL, 2.39 mmol) in DCM (3 mL) was added dropwise to a stirred solution of triphosgene (121 mg, 400 μmol) in DCM (3 mL) and stirred at ambient temperature for 1 hour. A solution of the free base of methyl (2,2,2-trifluoroethyl) amine hydrochloride (240 mg, 1.60 mmol) in DCM (2 mL) was added dropwise and after 1 hour the reaction was quenched with a saturated solution of sodium bicarbonate. After standing for 2 days and organic phase was dried using a phase separator cartridge and purified by column chromatography on silica gel (gradient: 0 to 100% ethyl acetate in cyclohexane) to afford 80 mg (29%) of racemic trans 3-[3-(6-benzenesulfonyl-6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-cyclopentyl]-1-methyl-1-(2,2,2-trifluoro-ethyl)-urea as a gum. LCMS (Method B, ESI): RT=3.70 min, m+H=522.4. was quenched with a saturated solution of sodium bicarbonate After standing for 2 days organic phase was dried purified by column chromatography on silica gel (gradient: 0 to 100% ethyl acetate in cyclohexane)