hex-5-ynenitrile

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

Procedure: This product was prepared from benzenesulfonic acid 4-cyano-2-methoxy-phenyl ester and 5-hexynenitrile following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane/EtOAc 8:2; yield (70 mg, 62%); 1H NMR δ (CDCl3): 7.52 (d, J=8.34 Hz, 1H), 7.21 (d, J=8.22 Hz, 1H), 7.11 (s, 1H), 3.81 (s, 3H), 2.69 (t, J=7.25 Hz, 2H), 2.58 (t, J=7.22 Hz, 2H), 1.99 (p, J=7.12 Hz, 2H); LCMS m/z: 224. yield (70 mg, 62%)

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

Procedure: To a solution of the title compound of Example 5 (0.35 g), CuI (0.042 g), and Pd(PPh3)2Cl2 (0.012 g) in 10 mL diethylamine is added 5-hexynenitrile (0.085 mL). The reaction is stirred overnight. The reaction is then partitioned between ethyl acetate and water. The organic layer is washed twice with water, dried over MgSO4, filtered, and adsorbed onto silica. A Biotage Flash 40S (eluent 3% MeOH:CH2Cl2) affords the desired product. The product is recrystallized from CH2Cl2 --MeOH/hexanes. A second crop of crystals is obtained by concentration of the filtrate. The total yield of the title compound is 0.21 g. The reaction is then partitioned between ethyl acetate and water The organic layer is washed twice with water dried over MgSO4 filtered

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

Procedure: To a solution of the title compound of Example 5 (0.35 g), CuI (0.042 g), and Pd(PPh3)2Cl2 (0.012 g) in 10 mL diethylamine is added 5-hexynenitrile (0.085 mL). The reaction is stirred overnight. The reaction is then partitioned between ethyl acetate and water. The organic layer is washed twice with water, dried over MgSO4, filtered, and adsorbed onto silica. A Biotage Flash 40S (eluent 3% MeOH:CH2Cl2) affords the desired product. The product is recrystallized from CH2Cl2 --MeOH/hexanes. A second crop of crystals is obtained by concentration of the filtrate. The total yield of the title compound is 0.21 g. The reaction is then partitioned between ethyl acetate and water The organic layer is washed twice with water dried over MgSO4 filtered

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

Procedure: To a solution of the title compound of Example 5 (0.35 g), CuI (0.042 g), and Pd(PPh3)2Cl2 (0.012 g) in 10 mL diethylamine is added 5-hexynenitrile (0.085 mL). The reaction is stirred overnight. The reaction is then partitioned between ethyl acetate and water. The organic layer is washed twice with water, dried over MgSO4, filtered, and adsorbed onto silica. A Biotage Flash 40S (eluent 3% MeOH:CH2Cl2) affords the desired product. The product is recrystallized from CH2Cl2 --MeOH/hexanes. A second crop of crystals is obtained by concentration of the filtrate. The total yield of the title compound is 0.21 g. The reaction is then partitioned between ethyl acetate and water The organic layer is washed twice with water dried over MgSO4 filtered

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

Procedure: To a solution of 3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl trifluoromethanesulfonate (3.03 g, 6.13 mmol), copper iodide (176 mg, 0.920 mmol) and hex-5-ynenitrile (2.86 g, 30.7 mmol) in tetrahydrofuran (30 ml)-triethylamine (10 ml) was added dichlorobistriphenylphosphinepalladium (431 mg, 0.613 mmol), and the mixture was stirred under an argon atmosphere at 80° C. for 10 min. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give black crystals. The crystals were recrystallized from ethyl acetate-n-hexane to give tert-butyl {[6-(5-cyanopent-1-yn-1-yl)-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methyl}carbamate (2.56 g, yield 84%) as white crystals. Subsequently, tert-butyl {[6-(5-cyanopent-1-yn-1-yl)-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methyl}carbamate (2.56 g, 5.17 mmol) and 10% palladium-carbon (550 mg) were suspended in a mixed solvent of ethanol (200 ml)-tetrahydrofuran (35 ml) and the mixture was stirred under a hydrogen atmosphere at room temperature for 3.5 hrs. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give tert-butyl {[6-(5-cyanopentyl)-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methyl}carbamate (2.37 g, yield 92%) as white crystals. washed with saturated aqueous ammonium chloride solution dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure to give black crystals The crystals were recrystallized from ethyl acetate-n-hexane

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

Procedure: The same procedure was used as described for the preparation of example 365, but without addition of tetrabutylammonium iodide. Starting materials: N-(3-Iodo-benzyloxy)-2-[(pyridin-4-ylmethyl)-amino]-benzamide (see example 361) and 5-cyano-1-pentyne (Aldrich). as described for the preparation of example 365

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

Procedure: Argon was passed through a solution of 45 ml of 3-bromopyridine and 49.61 g of 5-hexynenitrile in 500 ml of dichloromethane and 150 ml of dry triethylamine for 15 minutes and 3.0 g of bis(triphenylphosphine)palladium dichloride and 0.45 g of cuprous iodide were added. The reaction flask was evacuated and refilled with argon and was heated to reflux for 12 hours. The resulting mixture was diluted with 1 L of dichloromethane and washed with 2×300 ml of water, 1×300 ml brine, dried over potassium carbonate and concentrated. The residue was distilled to afford 62.82 g (79%) of 6-(3-pyridinyl)-5-hexynenitrile as a yellow oil, bp 140°-170° C./0.2 mm., suitable for use in the next step. A portion was purified by chromatography over silica gel eluting with 1:1 ethyl acetate-hexane containing 1% triethylamine and was redistilled to give an analytical sample of 6-(3-pyridinyl)-5-hexynenitrile. The reaction flask was evacuated refilled with argon was heated to reflux for 12 hours The resulting mixture was diluted with 1 L of dichloromethane washed with 2×300 ml of water, 1×300 ml brine dried over potassium carbonate concentrated The residue was distilled

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

Procedure: To a solution of 3-(4-iodo-phenyl)-4-hydroxy-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carbonitrile (60 mg, 0.15 mmol) in 1.5 mL DMF was added diethylamine (0.16 mL, 1.5 mmol), followed by copper(I) iodide (trace), Pd(PPh3)Cl2 (3.5 mg, 0.005 mmol), and triphenylphosphine (12 mg, 0.04 mmol). The resulting mixture was stirred at rt for 5 min, after which hex-5-ynenitrile (50 μL, 0.5 mmol) was added. The reaction was then heated to 90° C. using microwave reactor for 20 min, filtered, concentrated and purified by reverse phase HPLC to give the titled compound. MS (ESI) m/e 358 (M−H)+; 1H NMR (300 MHz, DMSO-d6): δ 1.82–1.91 (m, 2H), 2.56 (t, J=7.12 Hz, 2H), 2.65 (t, J=7.12 Hz, 2H), 6.67 (s, 1H), 7.31 (d, J=8.48 Hz, 2H) 7.43 (d, J=8.48, 2H), 10.80 (s, 1H). The reaction was then heated to 90° C. for 20 min filtered concentrated purified by reverse phase HPLC

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

Procedure: This product was prepared from benzenesulfonic acid 4-cyano-2-methoxy-phenyl ester and 5-hexynenitrile following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane/EtOAc 8:2; yield (70 mg, 62%); 1H NMR δ (CDCl3): 7.52 (d, J=8.34 Hz, 1H), 7.21 (d, J=8.22 Hz, 1H), 7.11 (s, 1H), 3.81 (s, 3H), 2.69 (t, J=7.25 Hz, 2H), 2.58 (t, J=7.22 Hz, 2H), 1.99 (p, J=7.12 Hz, 2H); LCMS m/z: 224. yield (70 mg, 62%)