2-methoxyacetonitrile

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

Procedure: To a stirred mixture of 2-Amino-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid ethyl ester (2.0 g, 0.0088 mol) and methoxyacetonitrile (1.3 ml, 0.0177 mol) in 1,4-dioxane (200 nml), dry HCl gas was purged for 30-45 minutes at 0-5° C. The reaction mixture was then warmed to room temperature and stirred for about 20 h under inert atmosphere. After completion of the reaction, the mixture was quenched with the addition of crushed ice (˜200 g). The aqueous layer was then extracted well with ethyl acetate (2×250 ml). Combined organic layers was washed with brine solution (100 ml) dried over anhydrous Na2SO4 and concentrated under vacuum to get crude 2-Methoxymethyl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-ol as brown colored solid which was forwarded as such for the next step. Yield: (2 g, 90%); 1H NMR (400 MHz, DMSO) δ ppm=12.27 (s, 1H), 4.28 (s, 2H), 3.31 (s, 3H), 2.87-2.84 (m, 2H), 2.74-2.71 (m, 2H), 1.81-1.73 (m, 4H); LCMS: [M+H]=251.1. was purged for 30-45 minutes at 0-5° C After completion of the reaction the mixture was quenched with the addition of crushed ice (˜200 g) The aqueous layer was then extracted well with ethyl acetate (2×250 ml) Combined organic layers was washed with brine solution (100 ml) dried over anhydrous Na2SO4 concentrated under vacuum

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

Procedure: To a stirred mixture of 2-Amino-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid ethyl ester (2.0 g, 0.0088 mol) and methoxyacetonitrile (1.3 ml, 0.0177 mol) in 1,4-dioxane (200 nml), dry HCl gas was purged for 30-45 minutes at 0-5° C. The reaction mixture was then warmed to room temperature and stirred for about 20 h under inert atmosphere. After completion of the reaction, the mixture was quenched with the addition of crushed ice (˜200 g). The aqueous layer was then extracted well with ethyl acetate (2×250 ml). Combined organic layers was washed with brine solution (100 ml) dried over anhydrous Na2SO4 and concentrated under vacuum to get crude 2-Methoxymethyl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-ol as brown colored solid which was forwarded as such for the next step. Yield: (2 g, 90%); 1H NMR (400 MHz, DMSO) δ ppm=12.27 (s, 1H), 4.28 (s, 2H), 3.31 (s, 3H), 2.87-2.84 (m, 2H), 2.74-2.71 (m, 2H), 1.81-1.73 (m, 4H); LCMS: [M+H]=251.1. was purged for 30-45 minutes at 0-5° C After completion of the reaction the mixture was quenched with the addition of crushed ice (˜200 g) The aqueous layer was then extracted well with ethyl acetate (2×250 ml) Combined organic layers was washed with brine solution (100 ml) dried over anhydrous Na2SO4 concentrated under vacuum

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

Procedure: A solution (about 100 mL) of 3,4-dichlorophenylmagnesium bromide in diethyl ether was prepared from a mixture of magnesium (flakes) (2.07 g) in diethyl ether (100 mL) and 1-bromo-3,4-dichlorobenzene (17.5 g). A solution of methoxyacetonitrile (5.0 g) in diethyl ether (10 mL) was added dropwise to a solution of 3,4-dichlorophenylmagnesium bromide in diethyl ether under ice-cooling, and the resulting mixture was stirred under ice-cooling for 20 min. The reaction mixture was quenched with water, the mixture was acidified with 1 N hydrochloric acid, and the mixture was stirred under ice-cooling for 15 min. The reaction mixture was extracted with ethyl acetate, the organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated to give a pale-yellow oil. The oil was purified by silica gel column chromatography (eluent; hexane:ethyl acetate (19:1-1:1)) to give the title compound (10.5 g). cooling cooling for 20 min The reaction mixture was quenched with water the mixture was stirred under ice- cooling for 15 min The reaction mixture was extracted with ethyl acetate the organic layer was washed with water and brine dried over anhydrous magnesium sulfate the solvent was evaporated to give a pale-yellow oil The oil was purified by silica gel column chromatography (eluent; hexane:ethyl acetate (19:1-1:1))

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

Procedure: A solution of 35.5 g (0.50 mol) of methoxyacetonitrile in 29 ml (23 g, 0.50 mol) of ethanol and 30 ml of absolute diethylether was cooled to 0° C. and over 1 hour 22.5 g (0.62 mol) of hydrogen chloride gas was introduced, whilst towards the end of the introduction of gas the reaction product crystallised out. To complete the precipitation 130 ml of diethylether were added and the colourless needles were filtered off. was introduced, whilst towards the end of the introduction of gas the reaction product crystallised out the precipitation 130 ml of diethylether were added the colourless needles were filtered off

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

Procedure: 2-Methoxyacetonitrile (1.0 g, 14.1 mmol) was dissolved in anhydrous ethanol (28.1 mL) under an atmosphere of Ar. The solution was cooled to 0° C., saturated with HCl gas, stirred for 6 h, allowed to warm to RT, and stirred for 6 h. The solvent was removed in vacuo to afford ethyl 2-methoxyacetimidate hydrochloride (1.0 g, 44.0%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 4.42 (q, J=7.0 Hz, 2H), 4.31 (s, 2H), 3.36 (s, 3H), 1.32 (t, J=7.0 Hz, 3H). stirred for 6 h The solvent was removed in vacuo

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

Procedure: 2-Methoxyacetonitrile (1.0 g, 14.1 mmol) was dissolved in anhydrous ethanol (28.1 mL) under an atmosphere of Ar. The solution was cooled to 0° C., saturated with HCl gas, stirred for 6 h, allowed to warm to RT, and stirred for 6 h. The solvent was removed in vacuo to afford ethyl 2-methoxyacetimidate hydrochloride (1.0 g, 44.0%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 4.42 (q, J=7.0 Hz, 2H), 4.31 (s, 2H), 3.36 (s, 3H), 1.32 (t, J=7.0 Hz, 3H). stirred for 6 h The solvent was removed in vacuo

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

Procedure: To 25 g (281 mmole) of methoxyacetonitrile in 100 ml of diethyl ether at reflux was added 250 ml (250 mmole) of 1.0M 4-chlorophenyl magnesium bromide in diethyl ether. After refluxing for 30 minutes the reaction mixture was hydrolyzed with a solution of 30 ml of concentrated sulfuric acid in 100 ml of water. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, concentrated in vacuo, and dissolved in hexanes. The insolubles were filtered away and the resultant solution was concentrated and distilled yielding a clear liquid. bp 105°-115° C. at 1 torr. The oil solidified on standing. After refluxing for 30 minutes the reaction mixture The organic layer was washed with water and brine dried over anhydrous magnesium sulfate concentrated in vacuo dissolved in hexanes The insolubles were filtered away the resultant solution was concentrated distilled yielding a clear liquid

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Hydrochloric acid gas is bubbled through a solution of methoxyacetonitrile (26 g, 0.37 mol) in EtOH (22 mL) and diethyl ether (118 mL), which is chilled to −10° C. for twenty minutes. The reaction vessel is capped and stirred for 17 hours at ambient temperature. The mixture is cooled to −10° C. The solid that forms is collected by filtration, washed with diethyl ether and air dried to afford 2-methoxy-acetimidic acid ethyl ester hydrochloride (49.3 g, 87%) as a solid. The reaction vessel is capped The mixture is cooled to −10° C The solid that forms is collected by filtration washed with diethyl ether and air dried

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

Procedure: A solution of 35.5 g (0.50 mol) of methoxyacetonitrile in 29 mL (23 g, 0.50 mol) of ethanol and 30 mL of absolute diethylether was cooled to 0° C. and over 1 hour 22.5 g (0.62 mol) of hydrogen chloride gas was introduced, whilst towards the end of the introduction of gas the reaction product crystallized out. To complete the precipitation 130 mL of diethylether were added and the colorless needles were filtered off. Yield: 66.4 g (86% of theory); melting point: 117° C.-118° C. was introduced, whilst towards the end of the introduction of gas the reaction product crystallized out the precipitation 130 mL of diethylether were added the colorless needles were filtered off

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Hydrochloric acid gas is bubbled through a solution of methoxyacetonitrile (26 g, 0.37 mol) in EtOH (22 mL) and diethyl ether (118 mL), which is chilled to −10° C. for twenty minutes. The reaction vessel is capped and stirred for 17 hours at ambient temperature. The mixture is cooled to −10° C. The solid that forms is collected by filtration, washed with diethyl ether and air dried to afford 2-methoxy-acetimidic acid ethyl ester hydrochloride (49.3 g, 87%) as a solid. The reaction vessel is capped The mixture is cooled to −10° C The solid that forms is collected by filtration washed with diethyl ether and air dried

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

Procedure: A solution of 35.5 g (0.50 mol) of methoxyacetonitrile in 29 mL (23 g, 0.50 mol) of ethanol and 30 mL of absolute diethylether was cooled to 0° C. and over 1 hour 22.5 g (0.62 mol) of hydrogen chloride gas was introduced, whilst towards the end of the introduction of gas the reaction product crystallized out. To complete the precipitation 130 mL of diethylether were added and the colorless needles were filtered off. Yield: 66.4 g (86% of theory); melting point: 117° C.-118° C. was introduced, whilst towards the end of the introduction of gas the reaction product crystallized out the precipitation 130 mL of diethylether were added the colorless needles were filtered off

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

Procedure: A solution of 35.5 g (0.50 mol) of methoxyacetonitrile in 29 ml (23 g, 0.50 mol) of ethanol and 30 ml of absolute diethylether was cooled to 0° C. and over 1 hour 22.5 g (0.62 mol) of hydrogen chloride gas was introduced, whilst towards the end of the introduction of gas the reaction product crystallised out. To complete the precipitation 130 ml of diethylether were added and the colourless needles were filtered off. Yield: 66.4 g (86% of theory), Melting point: 117-118° C. was introduced, whilst towards the end of the introduction of gas the reaction product crystallised out the precipitation 130 ml of diethylether were added the colourless needles were filtered off