7-bromo-5-methoxy-1-benzofuran

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

Procedure: A mixture of the product from Step C (3.6 g, 16 mmol), methylboronic acid (1.4 g, 24 mmol), Pd(dppf)2Cl2 (0.65 g, 0.8 mmol) and Cs2CO3 (13.0 g, 40 mmol) in 1,4-dioxane (50 mL) and H2O (10 mL) was refluxed for 3 hrs under N2 atmosphere. The reaction was cooled to room temperature and filtered through a celite pad. The filtrate was diluted with EtOAc (200 mL) and washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica column chromatography (eluted with PE) to afford the title compound (1.0 g, 38%) as an oil. 1H-NMR (600 MHz, CDCl3) δ 7.63 (d, J=1.6 Hz, 1H), 6.92 (d, J=2.1 Hz, 1H), 6.76 (s, 1H), 6.73 (d, J=1.8 Hz, 1H), 3.86 (s, 3H), 2.53 (s, 3H) ppm. was refluxed for 3 hrs under N2 atmosphere filtered through a celite pad The filtrate was diluted with EtOAc (200 mL) washed with brine (50 mL) dried over anhydrous sodium sulfate concentrated under reduced pressure The residue was purified by silica column chromatography (eluted with PE)

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

Procedure: To a mixture of the product from step B (2.7 g, 8.5 mmol) in toluene (10 mL) was added PPA (1.0 mL). The reaction was heated at 70° C. for 1 hr. The reaction was cooled to room temperature. The mixture was diluted with EtOAc (200 mL) and the water phase was adjusted to pH 7-8 by NaOH (2 mol/L). The organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica column chromatography (eluted with PE) to afford the title compound (0.27 g, 16%) as an oil. 1H-NMR (600 MHz, CDCl3) δ 7.68 (d, J=2.1 Hz, 1H), 7.13 (d, J=2.2 Hz, 1H), 7.04 (d, J=2.3 Hz, 1H), 6.79 (d, J=2.1 Hz, 1H), 3.86 (s, 3H) ppm. was added PPA (1.0 mL) The reaction was cooled to room temperature The organic phase was washed with brine (50 mL) dried over anhydrous sodium sulfate concentrated under reduced pressure The residue was purified by silica column chromatography (eluted with PE)

Conditions: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dissolve 7-bromo-5-methoxybenzofuran (6.0 g, 26.43 mmol), bis(dibenzylideneacetone)palladium (1.32 g, 2.3 mmol) and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (2.7 g, 6.86 mmol) in anhydrous tetrahydrofuran (36 mL), add freshly prepared 2-ethoxy-2-oxoethylzinc bromide in tetrahydrofuran (66 mL). Heat at 50-60° C. for 5 h. Cool and filter mixture through celite and evaporate to a thick red-brown oil (30 g). Purify by flash chromatography using a gradient of ethyl acetate in hexanes yields the pure compound as a thick yellow oil (6.2 g, quant). ESMS m/z (relative intensity) 235.2 (M++H+, 10), 161.1 (M+−CO2Et+H+, 100). Cool filter mixture through celite evaporate to a thick red-brown oil (30 g) Purify by flash chromatography

Conditions: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dissolve 7-bromo-5-methoxybenzofuran (6.0 g, 26.43 mmol), bis(dibenzylideneacetone)palladium (1.32 g, 2.3 mmol) and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (2.7 g, 6.86 mmol) in anhydrous tetrahydrofuran (36 mL), add freshly prepared 2-ethoxy-2-oxoethylzinc bromide in tetrahydrofuran (66 mL). Heat at 50-60° C. for 5 h. Cool and filter mixture through celite and evaporate to a thick red-brown oil (30 g). Purify by flash chromatography using a gradient of ethyl acetate in hexanes yields the pure compound as a thick yellow oil (6.2 g, quant). ESMS m/z (relative intensity) 235.2 (M++H+, 10), 161.1 (M+−CO2Et+H+, 100). Cool filter mixture through celite evaporate to a thick red-brown oil (30 g) Purify by flash chromatography

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

Procedure: Beginning with 4.0 gm (17.6 mMol) 5-methoxy-7-bromobenzofuran and 3.94 gm (19.4 mMol) 1-benzyl-3-methyl-4-oxo-piperidine, 3.33 gm (54%) of the desired compound were recovered essentially as described in EXAMPLE 3.

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

Procedure: A mixture of the product from Step C (3.6 g, 16 mmol), methylboronic acid (1.4 g, 24 mmol), Pd(dppf)2Cl2 (0.65 g, 0.8 mmol) and Cs2CO3 (13.0 g, 40 mmol) in 1,4-dioxane (50 mL) and H2O (10 mL) was refluxed for 3 hrs under N2 atmosphere. The reaction was cooled to room temperature and filtered through a celite pad. The filtrate was diluted with EtOAc (200 mL) and washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica column chromatography (eluted with PE) to afford the title compound (1.0 g, 38%) as an oil. 1H-NMR (600 MHz, CDCl3) δ 7.63 (d, J=1.6 Hz, 1H), 6.92 (d, J=2.1 Hz, 1H), 6.76 (s, 1H), 6.73 (d, J=1.8 Hz, 1H), 3.86 (s, 3H), 2.53 (s, 3H) ppm. was refluxed for 3 hrs under N2 atmosphere filtered through a celite pad The filtrate was diluted with EtOAc (200 mL) washed with brine (50 mL) dried over anhydrous sodium sulfate concentrated under reduced pressure The residue was purified by silica column chromatography (eluted with PE)

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

Procedure: To a mixture of the product from step B (2.7 g, 8.5 mmol) in toluene (10 mL) was added PPA (1.0 mL). The reaction was heated at 70° C. for 1 hr. The reaction was cooled to room temperature. The mixture was diluted with EtOAc (200 mL) and the water phase was adjusted to pH 7-8 by NaOH (2 mol/L). The organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica column chromatography (eluted with PE) to afford the title compound (0.27 g, 16%) as an oil. 1H-NMR (600 MHz, CDCl3) δ 7.68 (d, J=2.1 Hz, 1H), 7.13 (d, J=2.2 Hz, 1H), 7.04 (d, J=2.3 Hz, 1H), 6.79 (d, J=2.1 Hz, 1H), 3.86 (s, 3H) ppm. was added PPA (1.0 mL) The reaction was cooled to room temperature The organic phase was washed with brine (50 mL) dried over anhydrous sodium sulfate concentrated under reduced pressure The residue was purified by silica column chromatography (eluted with PE)

Conditions: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dissolve 7-bromo-5-methoxybenzofuran (6.0 g, 26.43 mmol), bis(dibenzylideneacetone)palladium (1.32 g, 2.3 mmol) and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (2.7 g, 6.86 mmol) in anhydrous tetrahydrofuran (36 mL), add freshly prepared 2-ethoxy-2-oxoethylzinc bromide in tetrahydrofuran (66 mL). Heat at 50-60° C. for 5 h. Cool and filter mixture through celite and evaporate to a thick red-brown oil (30 g). Purify by flash chromatography using a gradient of ethyl acetate in hexanes yields the pure compound as a thick yellow oil (6.2 g, quant). ESMS m/z (relative intensity) 235.2 (M++H+, 10), 161.1 (M+−CO2Et+H+, 100). Cool filter mixture through celite evaporate to a thick red-brown oil (30 g) Purify by flash chromatography