1-ethynyl-2-(trifluoromethyl)benzene

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

Procedure: The title compound was synthesized according to the procedure described for the preparation of Example 160 using 83 (100 mg, 0.43 mmol) and 2-ethynyl-α,α,α-trifluorotoluene (0.09 mL, 0.65 mmol) to provide 254 (18 mg, 12% yield) as a tan solid. LC-MS (M+H=365 obsd.=365). 1H NMR (400 MHz, d6-DMSO): δ 9.62 (d, 1H), 8.50 (d, 1H), 8.41 (dd, 1H), 8.08 (d, 1H), 7.95 (d, 1H), 7.86 (m, 2H), 7.74 (m, 2H), 7.39 (d, 1H). The title compound was synthesized

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

Procedure: Prepared as described for 3,4-bis(benzyloxy)-6-(phenylethynyl)pyridazine (Intermediate 2) from 3,4-bis(benzyloxy)-6-chloropyridazine (Intermediate 1) and 1-ethynyl-2-(trifluoromethyl)benzene in quantitative yield. Prepared

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

Procedure: 60 mg (0.21 mmol) of the compound from Example 122A were dissolved in 2 ml of acetonitrile, 14 mg (0.21 mmol) of sodium azide were added and the mixture was stirred at RT for 1 h. 0.4 mg (0.002 mmol) of copper(II) acetate monohydrate and 43 mg (0.25 mmol) of 1-ethynyl-2-(trifluoro-methyl)benzene were then added. The resulting mixture was stirred at RT for 20 h. For work-up, 10 ml of ethyl acetate were added and the mixture was washed twice with in each case 5 ml of water. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified chromatographically [Method 19]. This gave 48 mg (45% of theory) of the target compound. The resulting mixture was stirred at RT for 20 h the mixture was washed twice with in each case 5 ml of water The organic phase was dried over sodium sulfate filtered concentrated under reduced pressure The crude product was purified chromatographically [Method 19]

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

Procedure: To a solution of [(3aR,4R,6R,6aR)-6-(6-iodo-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl sulfamate (0.200 g, 0.402 mmol) in DMF (7 mL) was added DIPEA (0.176 mL, 1.01 mmol), 1-ethynyl-2-trifluoromethyl-benzene (0.224 mL, 1.61 mmol), CuI (0.0191 g, 0.101 mmol), and Pd(PPh3)2Cl2 (0.0282 g, 0.0402 mmol). The mixture was stirred at r.t. for 50 min, diluted with DCM (25 mL) and washed with saturated aq EDTA.Na2 (3×25 mL). The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography (15 to 50% EtOAc/DCM) to isolate the title compound (0.185 g, 85%). washed with saturated aq EDTA The combined organics were washed with brine dried over Na2SO4 filtered concentrated The crude product was purified by flash chromatography (15 to 50% EtOAc/DCM)

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

Procedure: Ethyl 1-(4-fluorophenyl)-2-((2-(trifluoromethyl)phenyl)ethynyl)-1H-imidazole-5-carboxylate (46) was prepared in a similar manner as that described for the synthesis of compound 42 using ethyl 1-(4-fluorophenyl)-2-iodo-1H-imidazole-5-carboxylate (38) (900 mg, 2.5 mmol), 1-ethynyl-2-(trifluoromethyl)benzene (0.42 mL, 3.0 mmol), PdCl2(PPh3)2 (88 mg, 0.13 mmol), copper (I) iodide (23 mg, 0.13 mmol), diisopropyl amine (7 mL), and THF (50 mL).

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

Procedure: Ethyl 1-(4-fluorophenyl)-2-((2-(trifluoromethyl)phenyl)ethynyl)-1H-imidazole-5-carboxylate (46) was prepared in a similar manner as that described for the synthesis of compound 42 using ethyl 1-(4-fluorophenyl)-2-iodo-1H-imidazole-5-carboxylate (38) (900 mg, 2.5 mmol), 1-ethynyl-2-(trifluoromethyl)benzene (0.42 mL, 3.0 mmol), PdCl2(PPh3)2 (88 mg, 0.13 mmol), copper (I) iodide (23 mg, 0.13 mmol), diisopropyl amine (7 mL), and THF (50 mL).

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

Procedure: To a solution of 2-(3-Chloro-pyrazin-2-yl)-2-methyl-propionic acid ethyl ester (0.70 g) in acetonitrile (7.0 ml) was added 1-ethynyl-2-trifluoromethylbenzene (0.781 g) and caesium carbonate (“Cs2CO3”) (2.99 g) and nitrogen bubbled through the solution for 20 min. To this solution was added as 4,5-(bisdiphenylphosphino)-9,9-dimethylxanthene (“Xantphos”) (0.133 g) and (1,1′-bis(diphenylphosphino)-ferrocene)dichloro palladium(2) (0.125 g) and the reaction mixture heated to reflux for 30 min. The reaction mixture was cooled to ambient temperature then filtered and concentrated. The residue was purified by chromatography on silica gel (eluent 5-95% ethyl acetate in isohexane) to give 2-methyl-2-(3-phenylethynyl-pyrazin-2-yl)-propionic acid ethyl ester (compound B1 of Table B) (0.52 g). bubbled through the solution for 20 min To this solution was added as 4,5-(bisdiphenylphosphino)-9,9-dimethylxanthene (“Xantphos”) (0.133 g) and (1,1′-bis(diphenylphosphino)-ferrocene)dichloro palladium(2) (0.125 g) the reaction mixture heated to reflux for 30 min then filtered concentrated The residue was purified by chromatography on silica gel (eluent 5-95% ethyl acetate in isohexane)

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

Procedure: The title compound was prepared in analogy to example 10 step A from 4-chloro-2-iodoaniline (500 mg, 1.97 mmol) and 1-ethynyl-2-(trifluoromethyl)benzene (330 μl, 2.37 mmol). Off white solid. Rf 0.3 (1:9 Ethyl acetate:heptane) as an intense blue spot under UV light.

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

Procedure: 1-{6-chloro-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylic acid ethyl ester (100 mg, 0.317 mmol), Pd(PPh3)2Cl2 (12 mg, 0.017 mmol) and copper(I)iodide (5 mg, 0.026 mmol) were dissolved in diisopropylethylamine and stirred for 2 min. o-ethynyl-trifluoromethylbenzene (100 ul, 0.072 mmol) was added and the mixture stirred under N2 at 70° C. for 18 hours. The yellow suspension turned black. After cooling to room temperature, the reaction mixture was diluted with chloroform (12 ml), passed through a celite plug and concentrated under vacuo. Purification by Flash Chromatography (0-30% Ethyl acetate/Hexanes) gave Compound Dl. Yield 35%. 1H NMR 400 MHz CDCl3 δ (ppm): 8.58 (s, 1H); 7.78 (d, 1H); 7.71 (d, 1H); 7.56 (m, 2H); 4.16 (m, 2H); 4.01 (d, 2H); 3.21 (m, 2H); 2.63 (m, 1H); 2.03 (m, 2H); 1.84 (m, 2H); 1.26 (t, 3H). LCMS (ESI) m/z 449 (M+H+, 100%) was added After cooling to room temperature concentrated under vacuo Purification by Flash Chromatography (0-30% Ethyl acetate/Hexanes) gave Compound Dl

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

Procedure: The title compound was synthesized according to the procedure described for the preparation of Example 160 using 83 (100 mg, 0.43 mmol) and 2-ethynyl-α,α,α-trifluorotoluene (0.09 mL, 0.65 mmol) to provide 254 (18 mg, 12% yield) as a tan solid. LC-MS (M+H=365 obsd.=365). 1H NMR (400 MHz, d6-DMSO): δ 9.62 (d, 1H), 8.50 (d, 1H), 8.41 (dd, 1H), 8.08 (d, 1H), 7.95 (d, 1H), 7.86 (m, 2H), 7.74 (m, 2H), 7.39 (d, 1H). The title compound was synthesized

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

Procedure: Prepared as described for 3,4-bis(benzyloxy)-6-(phenylethynyl)pyridazine (Intermediate 2) from 3,4-bis(benzyloxy)-6-chloropyridazine (Intermediate 1) and 1-ethynyl-2-(trifluoromethyl)benzene in quantitative yield. Prepared

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

Procedure: 60 mg (0.21 mmol) of the compound from Example 122A were dissolved in 2 ml of acetonitrile, 14 mg (0.21 mmol) of sodium azide were added and the mixture was stirred at RT for 1 h. 0.4 mg (0.002 mmol) of copper(II) acetate monohydrate and 43 mg (0.25 mmol) of 1-ethynyl-2-(trifluoro-methyl)benzene were then added. The resulting mixture was stirred at RT for 20 h. For work-up, 10 ml of ethyl acetate were added and the mixture was washed twice with in each case 5 ml of water. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified chromatographically [Method 19]. This gave 48 mg (45% of theory) of the target compound. The resulting mixture was stirred at RT for 20 h the mixture was washed twice with in each case 5 ml of water The organic phase was dried over sodium sulfate filtered concentrated under reduced pressure The crude product was purified chromatographically [Method 19]