ethyl (3S)-3-(4-hydroxyphenyl)hex-4-ynoate

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of ethyl(3S)-3-(4-hydroxyphenyl)hex-4-ynate (0.350 g, 1.5 mmol) in acetonitrile (25 mL) is added potassium carbonate (0.621 g, 4.5 mmol) and 1′-[4-(bromomethyl)benzyl]spiro[indene-1,4′-piperidine] (0.77 g, 2.1 mmol). The reaction mixture is heated for 16 hours at 90° C. The mixture is concentrated, diluted with water, and extracted with EtOAc (2×200 mL). The combined extracts are washed with water (50 mL), brine (50 mL), dried over sodium sulfate, filtered, and concentrated to dryness to give the title compound (0.3 g, 38%). ESI/MS m/z 520 (M+H)+. The mixture is concentrated diluted with water extracted with EtOAc (2×200 mL) The combined extracts are washed with water (50 mL), brine (50 mL) dried over sodium sulfate filtered concentrated to dryness

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

Procedure: To a solution ethyl (3S)-3-(4-hydroxyphenyl)hex-4-ynoate (0.1 g, 0.43 mmol) and 1,4-bis(bromomethyl)benzene (0.227 g, 0.861 mmol) in DMF (5 mL) is added Cs2CO3 (0.28 g, 0.861 mmol) at 0° C. The reaction mixture is allowed to warm to room temperature over 2 h. The reaction mixture is diluted with water (25 mL) and extracted with EtOAc (3×10 mL). The combined organic layer is washed with water (10 mL×3) and saturated brine solution (10 mL), dried, filtered, and evaporated to dryness. The crude product is purified by silica gel chromatography, eluting with hexane:ethyl acetate (9.0:1.0) to give the title compound (0.1 g, 55.9%). ESI/MS m/z (M+H)+ 415.4. extracted with EtOAc (3×10 mL) The combined organic layer is washed with water (10 mL×3) and saturated brine solution (10 mL) dried filtered evaporated to dryness The crude product is purified by silica gel chromatography eluting with hexane:ethyl acetate (9.0:1.0)

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

Procedure: To a 0° C. solution of (3S)-3-(4-hydroxyphenyl)hex-4-ynoic acid (2.7 g, 13.2 mmol) in ethanol (135 mL) is added sulfuric acid (2.7 mL) and the mixture is heated at reflux for 4 hours, concentrated, diluted with water, and extracted with EtOAc (2×100 mL). The combined extracts are washed with saturated brine, dried over sodium sulfate, filtered, and concentrated to yellow oil (2.1 g, 68%). 1H NMR (400 MHz, CDCl3) δ 7.23 (d, J=8.0 Hz, 2H), 6.76 (d, J=8.0 Hz, 2H), 4.9 (bs, 1H), 4.11 (q, J=6.8 Hz, 2H), 4.04 (m, 1H), 2.60-2.75 (m, 2H), 1.82 (s, 3H), 1.21 (t, J=6.8 Hz, 3H). the mixture is heated at reflux for 4 hours concentrated diluted with water extracted with EtOAc (2×100 mL) The combined extracts are washed with saturated brine dried over sodium sulfate filtered concentrated to yellow oil (2.1 g, 68%)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of ethyl(3S)-3-(4-hydroxyphenyl)hex-4-ynate (0.350 g, 1.5 mmol) in acetonitrile (25 mL) is added potassium carbonate (0.621 g, 4.5 mmol) and 1′-[4-(bromomethyl)benzyl]spiro[indene-1,4′-piperidine] (0.77 g, 2.1 mmol). The reaction mixture is heated for 16 hours at 90° C. The mixture is concentrated, diluted with water, and extracted with EtOAc (2×200 mL). The combined extracts are washed with water (50 mL), brine (50 mL), dried over sodium sulfate, filtered, and concentrated to dryness to give the title compound (0.3 g, 38%). ESI/MS m/z 520 (M+H)+. The mixture is concentrated diluted with water extracted with EtOAc (2×200 mL) The combined extracts are washed with water (50 mL), brine (50 mL) dried over sodium sulfate filtered concentrated to dryness

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

Procedure: To a solution ethyl (3S)-3-(4-hydroxyphenyl)hex-4-ynoate (0.1 g, 0.43 mmol) and 1,4-bis(bromomethyl)benzene (0.227 g, 0.861 mmol) in DMF (5 mL) is added Cs2CO3 (0.28 g, 0.861 mmol) at 0° C. The reaction mixture is allowed to warm to room temperature over 2 h. The reaction mixture is diluted with water (25 mL) and extracted with EtOAc (3×10 mL). The combined organic layer is washed with water (10 mL×3) and saturated brine solution (10 mL), dried, filtered, and evaporated to dryness. The crude product is purified by silica gel chromatography, eluting with hexane:ethyl acetate (9.0:1.0) to give the title compound (0.1 g, 55.9%). ESI/MS m/z (M+H)+ 415.4. extracted with EtOAc (3×10 mL) The combined organic layer is washed with water (10 mL×3) and saturated brine solution (10 mL) dried filtered evaporated to dryness The crude product is purified by silica gel chromatography eluting with hexane:ethyl acetate (9.0:1.0)

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

Procedure: To a solution ethyl (3S)-3-(4-hydroxyphenyl)hex-4-ynoate (0.1 g, 0.43 mmol) and 1,4-bis(bromomethyl)benzene (0.227 g, 0.861 mmol) in DMF (5 mL) is added Cs2CO3 (0.28 g, 0.861 mmol) at 0° C. The reaction mixture is allowed to warm to room temperature over 2 h. The reaction mixture is diluted with water (25 mL) and extracted with EtOAc (3×10 mL). The combined organic layer is washed with water (10 mL×3) and saturated brine solution (10 mL), dried, filtered, and evaporated to dryness. The crude product is purified by silica gel chromatography, eluting with hexane:ethyl acetate (9.0:1.0) to give the title compound (0.1 g, 55.9%). ESI/MS m/z (M+H)+ 415.4. extracted with EtOAc (3×10 mL) The combined organic layer is washed with water (10 mL×3) and saturated brine solution (10 mL) dried filtered evaporated to dryness The crude product is purified by silica gel chromatography eluting with hexane:ethyl acetate (9.0:1.0)

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

Procedure: To a 0° C. solution of (3S)-3-(4-hydroxyphenyl)hex-4-ynoic acid (2.7 g, 13.2 mmol) in ethanol (135 mL) is added sulfuric acid (2.7 mL) and the mixture is heated at reflux for 4 hours, concentrated, diluted with water, and extracted with EtOAc (2×100 mL). The combined extracts are washed with saturated brine, dried over sodium sulfate, filtered, and concentrated to yellow oil (2.1 g, 68%). 1H NMR (400 MHz, CDCl3) δ 7.23 (d, J=8.0 Hz, 2H), 6.76 (d, J=8.0 Hz, 2H), 4.9 (bs, 1H), 4.11 (q, J=6.8 Hz, 2H), 4.04 (m, 1H), 2.60-2.75 (m, 2H), 1.82 (s, 3H), 1.21 (t, J=6.8 Hz, 3H). the mixture is heated at reflux for 4 hours concentrated diluted with water extracted with EtOAc (2×100 mL) The combined extracts are washed with saturated brine dried over sodium sulfate filtered concentrated to yellow oil (2.1 g, 68%)

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

Procedure: To a 0° C. solution of (3S)-3-(4-hydroxyphenyl)hex-4-ynoic acid (2.7 g, 13.2 mmol) in ethanol (135 mL) is added sulfuric acid (2.7 mL) and the mixture is heated at reflux for 4 hours, concentrated, diluted with water, and extracted with EtOAc (2×100 mL). The combined extracts are washed with saturated brine, dried over sodium sulfate, filtered, and concentrated to yellow oil (2.1 g, 68%). 1H NMR (400 MHz, CDCl3) δ 7.23 (d, J=8.0 Hz, 2H), 6.76 (d, J=8.0 Hz, 2H), 4.9 (bs, 1H), 4.11 (q, J=6.8 Hz, 2H), 4.04 (m, 1H), 2.60-2.75 (m, 2H), 1.82 (s, 3H), 1.21 (t, J=6.8 Hz, 3H). the mixture is heated at reflux for 4 hours concentrated diluted with water extracted with EtOAc (2×100 mL) The combined extracts are washed with saturated brine dried over sodium sulfate filtered concentrated to yellow oil (2.1 g, 68%)

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

Procedure: To a solution of (S)-ethyl 3-(4-hydroxyphenyl)hex-4-ynoate (WO05/086661) (0.2 g, 0.87 mmol) in DMF (20 mL) is added Cs2CO3 (0.84 g, 2.59 mmol) and 6-(chloromethyl)-2-(2,6-dimethylphenyl)-[1,2,4]triazolo[1,5-a]pyridine (0.187 g, 0.69 mmol). The reaction mixture is stirred at room temperature for 16 hours. The reaction mixture is poured into ice cold water and extracted with EtOAc (3×50 mL). The combined organic extracts are washed with water (2×50 mL), brine (50 mL), dried over anhydrous Na2SO4, filtered, and evaporated to dryness. The crude material is purified by combiflash silica gel chromatography eluting with 13% EtOAc in hexane to give the title compound as colourless liquid (0.225 g, 55%). LCMS m/z 468 (M+H)+. The reaction mixture is poured into ice cold water extracted with EtOAc (3×50 mL) The combined organic extracts are washed with water (2×50 mL), brine (50 mL) dried over anhydrous Na2SO4 filtered evaporated to dryness The crude material is purified by combiflash silica gel chromatography eluting with 13% EtOAc in hexane

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

Procedure: To a solution of (S)-ethyl 3-(4-hydroxyphenyl)hex-4-ynoate (WO05/086661) (0.2 g, 0.87 mmol) in DMF (20 mL) is added Cs2CO3 (0.84 g, 2.59 mmol) and 6-(chloromethyl)-2-(2,6-dimethylphenyl)-[1,2,4]triazolo[1,5-a]pyridine (0.187 g, 0.69 mmol). The reaction mixture is stirred at room temperature for 16 hours. The reaction mixture is poured into ice cold water and extracted with EtOAc (3×50 mL). The combined organic extracts are washed with water (2×50 mL), brine (50 mL), dried over anhydrous Na2SO4, filtered, and evaporated to dryness. The crude material is purified by combiflash silica gel chromatography eluting with 13% EtOAc in hexane to give the title compound as colourless liquid (0.225 g, 55%). LCMS m/z 468 (M+H)+. The reaction mixture is poured into ice cold water extracted with EtOAc (3×50 mL) The combined organic extracts are washed with water (2×50 mL), brine (50 mL) dried over anhydrous Na2SO4 filtered evaporated to dryness The crude material is purified by combiflash silica gel chromatography eluting with 13% EtOAc in hexane

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

Procedure: To a stirred solution of (S)-ethyl 3-(4-hydroxyphenyl)hex-4-ynoate (1.4 g, 6.09 mmol) in DMF, is added cesium carbonate (5.9 g, 18.1 mmol) and 2-bromo-6-(chloromethyl)-[1,2,4]triazolo[1,5-a]pyridine (1.5 g, 6.09 mmol) and the reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is quenched with ice cold water and extracted with EtOAc (2×200 mL). The organic extract is washed with brine (2×30 mL), dried over sodium sulphate, and concentrated. The crude material is purified by silica gel chromatography (combiflash purifier 10 g redisep column) eluting with 25% EtOAc in hexane to give the title compound as a yellow sticky oil (1.4 g, 54%). LCMS m/z 442 (M+H)+. The reaction mixture is quenched with ice cold water extracted with EtOAc (2×200 mL) The organic extract is washed with brine (2×30 mL) dried over sodium sulphate concentrated The crude material is purified by silica gel chromatography (combiflash purifier 10 g redisep column) eluting with 25% EtOAc in hexane

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

Procedure: To a stirred solution of (S)-ethyl 3-(4-hydroxyphenyl)hex-4-ynoate (1.4 g, 6.09 mmol) in DMF, is added cesium carbonate (5.9 g, 18.1 mmol) and 2-bromo-6-(chloromethyl)-[1,2,4]triazolo[1,5-a]pyridine (1.5 g, 6.09 mmol) and the reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is quenched with ice cold water and extracted with EtOAc (2×200 mL). The organic extract is washed with brine (2×30 mL), dried over sodium sulphate, and concentrated. The crude material is purified by silica gel chromatography (combiflash purifier 10 g redisep column) eluting with 25% EtOAc in hexane to give the title compound as a yellow sticky oil (1.4 g, 54%). LCMS m/z 442 (M+H)+. The reaction mixture is quenched with ice cold water extracted with EtOAc (2×200 mL) The organic extract is washed with brine (2×30 mL) dried over sodium sulphate concentrated The crude material is purified by silica gel chromatography (combiflash purifier 10 g redisep column) eluting with 25% EtOAc in hexane