2-(5-bromo-1-benzofuran-2-yl)ethanol

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

Procedure: The product from Example 4A (241 mg, 1.0 mmol), 4-cyanophenylboronic acid (221 mg, 1.5 mmol), tetrakis(triphenylphosphine) palladium (0) (57.5 mg, 0.05 mmol), 2-(dicyclohexyl phosphino)biphenyl (35.0 mg, 0.10 mmol), and sodium carbonate (160 mg, 1.5 mmol) were combined in 1,2-dimethoxyethane (16 mL) and water (6 mL) and heated at 80° C. overnight. The mixture was allowed to cool to room temperature and diluted with ethyl acetate (30 mL). The mixture was washed with 5% NaHCO3, 25% brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to dryness. The residue was purified by silica gel column chromatography to provide 197 mg (75%) of the title compound. An analytical sample was crystallized from diethyl ether; mp; MS-DCl-NH3: 281 (M+NH4)+; 1H-NMR (CDCl3) δ 7.68 (5H, m), 7.51 (1H, d, J=8.5Hz), 7.44 (1H, dd, J=8.5, 1.9 Hz), 6.57 (1H, s), 4.02 (2H, q, J=5.8 Hz), 3.07 (2H, t, J=5.8Hz) 1.70 (1H, t, J=5.8Hz), 13C-NMR (CDCl3) δ 156.9, 154.6, 145.8, 133.9, 132.2, 129.3, 127.6, 122.8, 119.0, 118.8, 111.2, 110.2, 103.7, 60.7, 32.3. The mixture was washed with 5% NaHCO3, 25% brine dried over anhydrous Na2SO4 filtered the filtrate was concentrated to dryness The residue was purified by silica gel column chromatography

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

Procedure: The product from Example 4A (241 mg, 1.0 mmol), 4-cyanophenylboronic acid (221 mg, 1.5 mmol), tetrakis(triphenylphosphine) palladium (0) (57.5 mg, 0.05 mmol), 2-(dicyclohexyl phosphino)biphenyl (35.0 mg, 0.10 mmol), and sodium carbonate (160 mg, 1.5 mmol) were combined in 1,2-dimethoxyethane (16 mL) and water (6 mL) and heated at 80° C. overnight. The mixture was allowed to cool to room temperature and diluted with ethyl acetate (30 mL). The mixture was washed with 5% NaHCO3, 25% brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to dryness. The residue was purified by silica gel column chromatography to provide 197 mg (75%) of the title compound. An analytical sample was crystallized from diethyl ether; mp; MS-DCl-NH3: 281 (M+NH4)+; 1H-NMR (CDCl3) δ 7.68 (5H, m), 7.51 (1H, d, J=8.5Hz), 7.44 (1H, dd, J=8.5, 1.9 Hz), 6.57 (1H, s), 4.02 (2H, q, J=5.8 Hz), 3.07 (2H, t, J=5.8Hz) 1.70 (1H, t, J=5.8Hz), 13C-NMR (CDCl3) δ 156.9, 154.6, 145.8, 133.9, 132.2, 129.3, 127.6, 122.8, 119.0, 118.8, 111.2, 110.2, 103.7, 60.7, 32.3. The mixture was washed with 5% NaHCO3, 25% brine dried over anhydrous Na2SO4 filtered the filtrate was concentrated to dryness The residue was purified by silica gel column chromatography

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The product from Example 4A (1.21 g, 5.0 mmol), 4-dimethylaminopyridine (0.06 g, 0.5 mmol), and triethylamine (1.5 mL, 10.5 mmol) were combined in dichloromethane (20 mL) stirred briefly and treated with para-toluenesulfonyl chloride (1.91 g, 10.0 mmol) in dichloromethane (2 mL) over about 5 minutes. After stirring at about 22° C. for 3 hours, the mixture was then washed with saturated NaHCO3 solution (20 mL, 2×), brine (20 mL), dried over Na2SO4, and distilled to dryness. The residue in acetonitrile (˜5 mL) was heated at 50° C. to effect dissolution, allowed to cool to room temperature slowly, and then cooled to about 0° C. The slurry was filtered and the obtained solid dried under reduced pressure at 40° C. to provide the title compound (0.95 g, 48% yield). MS-DCI (M+NH4)+ observed m/z at 412, 414; 1H NMR (CDCl3 at 400 MHz) δ 2.38 (s, 3H), 3.11 (m, 2H), 4.35 (m, 2H), 6.35 (m, 1H), 7.1-7.18 (m, 3H), 7.27 (dd, 1H), 7.56 (d, 1H), 7.64-7.67 (m, 2H); 13C NMR (CDCl3 at 100 MHz) δ 21.9, 28.8, 67.1, 103.7, 112.0, 115.5, 122.9, 126.3, 127.4, 129.4, 130.1, 132.3, 144.4, 153.0, 154.2 with 2 peaks overlapping. After stirring at about 22° C. for 3 hours the mixture was then washed with saturated NaHCO3 solution (20 mL, 2×), brine (20 mL) dried over Na2SO4 distilled to dryness dissolution to cool to room temperature slowly cooled to about 0° C The slurry was filtered the obtained solid dried under reduced pressure at 40° C.

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The product from Example 3A (14.95 g, 50 mmol), palladium(ll) acetate (0.11 g, 0.5 mmol), triphenylphosphine (0.26 g, 1.0 mmol), and copper(I) iodide (0.19 g, 1.0 mmol) were combined in isopropyl acetate (100 mL). Nitrogen gas was bubbled through the reaction mixture for about 15 minutes. The mixture was treated with 3-butyn-1-ol (5.6 mL, 75.0 mmol) stirred briefly and then treated with diisopropylamine (42 mL, 300 mmol) slowly over about 10 minutes. After stirring for 2 hours at about 22° C., the mixture was heated at about 60° C. for about 6 hours and then cooled to about 22° C. The reaction mixture was filtered through a pad of Celite® (˜5 g) and the Celite® was washed with isopropyl acetate (˜30 mL). The filtrate was washed with saturated NaHCO3 solution (100 mL, 2×), 10% Na2S2O3 solution (100 mL, 2×), brine (50 mL), dried over Na2SO4, and distilled to dryness. The residue was purified by silica gel column chromatography to provide the title compound (8.7 g, 72% yield). MS DCl (M+NH4)+ m/z at 258,260; 1H NMR(CDCl3at 400 MHz) δ 3.03 (m, 2H), 3.98 (m, 2H), 6.45 (m, 1H), 7.25-7.32 (m, 2H), 7.60 (d, 1H); 13C NMR (CDCl3 at 100 MHz) δ 32.2, 60.6, 103.0, 112.1, 115.4, 122.8, 126.1, 130.4, 153.1, 157.0. Nitrogen gas was bubbled through the reaction mixture for about 15 minutes After stirring for 2 hours at about 22° C. cooled to about 22° C The reaction mixture was filtered through a pad of Celite® (˜5 g) the Celite® was washed with isopropyl acetate (˜30 mL) The filtrate was washed with saturated NaHCO3 solution (100 mL, 2×), 10% Na2S2O3 solution (100 mL, 2×), brine (50 mL) dried over Na2SO4 distilled to dryness The residue was purified by silica gel column chromatography