N-methoxy-N,3-dimethylbutanamide

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dissolve 2-bromo-5-(tert-butyldimethylsilyloxymethyl)pyridine (1.99 g, 6.583 mmol, prepared by following the procedure described in J. Org. Chem. 2004, 69, 250-262) in anhydrous THF (20 mL). Cool the solution to −78° C., add n-BuLi (4.32 mL, 6.912 mmol, 1.6M solution in hexane) and stir at this temperature for 40 min. Add slowly a solution of N-methoxy-N-methyl-3-methyl-butyramide (0.955 g, 6.583 mmol) in anhydrous THF (5 mL). Stir the mixture for 2 h at −78° C. and then allow the mixture to warm to room temperature. Add brine and extract the aqueous layer twice with EtOAc. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (19:1) to give the desired intermediate as yellow oil (890 mg, 44%). GC-MS m/z: 307 (M+). prepared Stir the mixture for 2 h at −78° C. to warm to room temperature Add brine and extract the aqueous layer twice with EtOAc Dry the combined organic extracts over Na2SO4 filter concentrate in vacuo Purify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (19:1)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dissolve 2-bromo-5-(tert-butyldimethylsilyloxymethyl)pyridine (1.99 g, 6.583 mmol, prepared by following the procedure described in J. Org. Chem. 2004, 69, 250-262) in anhydrous THF (20 mL). Cool the solution to −78° C., add n-BuLi (4.32 mL, 6.912 mmol, 1.6M solution in hexane) and stir at this temperature for 40 min. Add slowly a solution of N-methoxy-N-methyl-3-methyl-butyramide (0.955 g, 6.583 mmol) in anhydrous THF (5 mL). Stir the mixture for 2 h at −78° C. and then allow the mixture to warm to room temperature. Add brine and extract the aqueous layer twice with EtOAc. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (19:1) to give the desired intermediate as yellow oil (890 mg, 44%). GC-MS m/z: 307 (M+). prepared Stir the mixture for 2 h at −78° C. to warm to room temperature Add brine and extract the aqueous layer twice with EtOAc Dry the combined organic extracts over Na2SO4 filter concentrate in vacuo Purify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (19:1)

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: The reaction and treatment were carried out in the same manner as in Example 36-b) using N-methoxy-N-methyl-3-methylbutanamide and 3-methylbenzyl magnesium chloride to obtain a title compound as a light yellow oily substance. The reaction and treatment

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

Procedure: The reaction and treatment were carried out in the same manner as in Example 36-b) using N-methoxy-N-methyl-3-methylbutanamide and 3-methylbenzyl magnesium chloride to obtain a title compound as a light yellow oily substance. The reaction and treatment

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

Procedure: The reaction and treatment were carried out in the same manner as in Example 36-b) using N-methoxy-N-methyl-3-methylbutanamide and 4-methylbenzyl magnesium chloride to obtain a title compound as a light yellow oily substance. The reaction and treatment

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

Procedure: The reaction and treatment were carried out in the same manner as in Example 36-b) using N-methoxy-N-methyl-3-methylbutanamide and 4-methylbenzyl magnesium chloride to obtain a title compound as a light yellow oily substance. The reaction and treatment

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

Procedure: A few drops of a solution of 5-bromobenzo[b]thiophene (2 g; prepared in a manner similar to that described in Example 21) in tetrahydrofuran (10 ml) was added under nitrogen to a mixture of magnesium turnings (0.24 g), tetrahydrofuran (2 ml) and a few small crystals of iodine, heat was applied to initiate the reaction, then the remainder of the bromobenzo[b]thiophene solution was added at reflux temperature over 10 minutes. When the addition was complete, the mixture was heated under reflux for 1 hour, then a solution of N-methoxy-N,3-dimethylbutyramide (1.43 g) in tetrahydrofuran (10 ml) was added. The mixture was heated under reflux for 1 hour, cooled to ambient temperature, then quenched by the addition of 2M hydrochloric acid (25 ml) and stirred at ambient temperature for 5 minutes. The majority of the tetrahydrofuran was removed in vacuo, then water (25 ml) was added to the residue and the product was extracted into ethyl acetate (2×25 ml). The extracts were washed with water (25 ml) and saturated aqueous sodium chloride solution (25 ml), dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography over silica using petroleum ether (b.p. 60-80° C.) followed by a 95:5 mixture of petroleum ether (b.p. 60-80° C.) and ethyl acetate as eluants. Appropriate fractions were combined and the solvents removed in vacuo to give 1-(benzo[b]thiophen-5-yl)-3-methylbutan-1-one (1.25 g) as an off-white solid which was used without further purification. prepared in a manner similar to the reaction at reflux temperature over 10 minutes When the addition the mixture was heated under reflux for 1 hour The mixture was heated under reflux for 1 hour quenched by the addition of 2M hydrochloric acid (25 ml) The majority of the tetrahydrofuran was removed in vacuo water (25 ml) was added to the residue the product was extracted into ethyl acetate (2×25 ml) The extracts were washed with water (25 ml) and saturated aqueous sodium chloride solution (25 ml) dried (MgSO4) the solvent removed in vacuo The residue was purified by flash chromatography over silica followed by a 95:5 mixture of petroleum ether (b.p. 60-80° C.) and ethyl acetate as eluants the solvents removed in vacuo

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

Procedure: The preparation is carried out analogously to Example 29a from 6-bromo-2-phenyl-benzoxazole and N-methoxy-3,N-dimethyl-butyramide.

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

Procedure: Prepared starting from N-Methoxy-3,N-dimethyl-butyramide in an analogous fashion to 6-(1,1-difluoro-butyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (see Preparations 264 and 116. MS: [M+H]+=255. Prepared

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dissolve 2-bromo-5-(tert-butyldimethylsilyloxymethyl)pyridine (1.99 g, 6.583 mmol, prepared by following the procedure described in J. Org. Chem. 2004, 69, 250-262) in anhydrous THF (20 mL). Cool the solution to −78° C., add n-BuLi (4.32 mL, 6.912 mmol, 1.6M solution in hexane) and stir at this temperature for 40 min. Add slowly a solution of N-methoxy-N-methyl-3-methyl-butyramide (0.955 g, 6.583 mmol) in anhydrous THF (5 mL). Stir the mixture for 2 h at −78° C. and then allow the mixture to warm to room temperature. Add brine and extract the aqueous layer twice with EtOAc. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (19:1) to give the desired intermediate as yellow oil (890 mg, 44%). GC-MS m/z: 307 (M+). prepared Stir the mixture for 2 h at −78° C. to warm to room temperature Add brine and extract the aqueous layer twice with EtOAc Dry the combined organic extracts over Na2SO4 filter concentrate in vacuo Purify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (19:1)