2-chloro-N-(2-methoxyethyl)acetamide

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a three-necked 2L round bottom flask fitted with two 500 mL addition funnels, containing 56.4 g (39.8 mL, 0.50 mole) chloroacetyl chloride in 400 mL dichloromethane and 20 g (0.50 mole) sodium hydroxide in 400 mL water, respectively, and a water-oooled condenser, was placed 35.7 g (41.3 mL, 0.48 mole) 2-methoxyethylamine, 100 mL water, 100 mL dichloro-methane. The reaction vessel was cooled to 0° C. by a salt-ice bath. The organic and aqueous solutions were allowed to add slowly, ~0.25mL per minute, to the reaction mixture. During the addition the pH of the water phase of the reaction was monitored and the rate of addition of the alkali solution adjusted so as to maintain pH=12. When the addition was complete, the mixture was allowed to warm to room temperature and stir overnight. The organic layer was removed by siphon and dried with magnesium sulfate for four hours. The mixture was filtered through #4 filter paper on a large Buchner funnel and the sulfate washed with 2×100 mL fresh dichloromethane. The combined filtrates were then placed in 2L round bottomed flask and the mixture distilled at 1 torr. Fractions collected from 55° C. to 60° C. were combined and analyzed by NMR. Yield 31.1 g (43% based on starting 2-methoxyethylamine). TLC (silica on glass, 2% methanol in dichloromethane) Rf =0.40. 1H(δ,CDCl,) 3.28(s,3H), 3.40(m,4H), 3.97(s,2H), 6.92(br, 1H). 13C{1H} (δ, CDCl3) 39.27, 42.32, 58.60, 70.54, 166.22. respectively, and a water-oooled condenser, was placed to add slowly the rate of addition of the alkali solution to maintain pH=12 When the addition to warm to room temperature The organic layer was removed by siphon dried with magnesium sulfate for four hours The mixture was filtered through #4 filter paper on a large Buchner funnel the sulfate washed with 2×100 mL fresh dichloromethane the mixture distilled at 1 torr Fractions collected from 55° C. to 60° C.

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a three-necked 2L round bottom flask fitted with two 500 mL addition funnels, containing 56.4 g (39.8 mL, 0.50 mole) chloroacetyl chloride in 400 mL dichloromethane and 20 g (0.50 mole) sodium hydroxide in 400 mL water, respectively, and a water-oooled condenser, was placed 35.7 g (41.3 mL, 0.48 mole) 2-methoxyethylamine, 100 mL water, 100 mL dichloro-methane. The reaction vessel was cooled to 0° C. by a salt-ice bath. The organic and aqueous solutions were allowed to add slowly, ~0.25mL per minute, to the reaction mixture. During the addition the pH of the water phase of the reaction was monitored and the rate of addition of the alkali solution adjusted so as to maintain pH=12. When the addition was complete, the mixture was allowed to warm to room temperature and stir overnight. The organic layer was removed by siphon and dried with magnesium sulfate for four hours. The mixture was filtered through #4 filter paper on a large Buchner funnel and the sulfate washed with 2×100 mL fresh dichloromethane. The combined filtrates were then placed in 2L round bottomed flask and the mixture distilled at 1 torr. Fractions collected from 55° C. to 60° C. were combined and analyzed by NMR. Yield 31.1 g (43% based on starting 2-methoxyethylamine). TLC (silica on glass, 2% methanol in dichloromethane) Rf =0.40. 1H(δ,CDCl,) 3.28(s,3H), 3.40(m,4H), 3.97(s,2H), 6.92(br, 1H). 13C{1H} (δ, CDCl3) 39.27, 42.32, 58.60, 70.54, 166.22. respectively, and a water-oooled condenser, was placed to add slowly the rate of addition of the alkali solution to maintain pH=12 When the addition to warm to room temperature The organic layer was removed by siphon dried with magnesium sulfate for four hours The mixture was filtered through #4 filter paper on a large Buchner funnel the sulfate washed with 2×100 mL fresh dichloromethane the mixture distilled at 1 torr Fractions collected from 55° C. to 60° C.

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a three-necked 2L round bottom flask fitted with two 500 mL addition funnels, containing 56.4g (39.8 mL, 0.50 mole) chloroacetyl chloride in 400 mL dichloromethane and 20g (0.50 mole) sodium hydroxide in 400 mL water, respectively, and a water-cooled condenser, was placed 35.7g (41.3 mL, 0.48 mole) 2-methoxyethylamine, 100 mL water, 100 mL dichloro-methane. The reaction vessel was cooled to 0° C. by a salt-ice bath. The organic and aqueous solutions were allowed to add slowly, ~0.25 mL per minute, to the reaction mixture. During the addition the pH of the water phase of the reaction was monitored and the rate of addition of the alkali solution adjusted so as to maintain pH=12. When the addition was complete, the mixture was allowed to warm to room temperature and stir overnight. The organic layer was removed by siphon and dried with magnesium sulfate for four hours. The mixture was filtered through #4 filter paper on a large Buchner funnel and the sulfate washed with 2×100 mL fresh dichloromethane. The combined filtrates were then placed in 2L round bottomed flask and the mixture distilled at 1 torr. Fractions collected from 55° C. to 60° C. were combined and analyzed by NMR. Yield 31.1g (43% based on starting 2-methoxyethylamine). TLC (silica on glass, 2% methanol in dichloromethane) Rf =0.40. 1H(δ,CDC13) 3.28(s,3H), 3.40(m,4H), 3.97(s,2H), 6.92(br, 1H). 13C{1H} (δ, CDCl3) 39.27, 42.32, 58.60, 70.54, 166.22. to add slowly the rate of addition of the alkali solution to maintain pH=12 When the addition to warm to room temperature The organic layer was removed by siphon dried with magnesium sulfate for four hours The mixture was filtered through #4 filter paper on a large Buchner funnel the sulfate washed with 2×100 mL fresh dichloromethane the mixture distilled at 1 torr Fractions collected from 55° C. to 60° C.

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a three-necked 2L round bottom flask fitted with two 500 mL addition funnels, containing 56.4 g (39.8 mL, 0.50 mole) chloroacetyl chloride in 400 mL dichloromethane and 20 g (0.50 mole) sodium hydroxide in 400 mL water, respectively, and a water-oooled condenser, was placed 35.7 g (41.3 mL, 0.48 mole) 2-methoxyethylamine, 100 mL water, 100 mL dichloro-methane. The reaction vessel was cooled to 0° C. by a salt-ice bath. The organic and aqueous solutions were allowed to add slowly, ~0.25mL per minute, to the reaction mixture. During the addition the pH of the water phase of the reaction was monitored and the rate of addition of the alkali solution adjusted so as to maintain pH=12. When the addition was complete, the mixture was allowed to warm to room temperature and stir overnight. The organic layer was removed by siphon and dried with magnesium sulfate for four hours. The mixture was filtered through #4 filter paper on a large Buchner funnel and the sulfate washed with 2×100 mL fresh dichloromethane. The combined filtrates were then placed in 2L round bottomed flask and the mixture distilled at 1 torr. Fractions collected from 55° C. to 60° C. were combined and analyzed by NMR. Yield 31.1 g (43% based on starting 2-methoxyethylamine). TLC (silica on glass, 2% methanol in dichloromethane) Rf =0.40. 1H(δ,CDCl,) 3.28(s,3H), 3.40(m,4H), 3.97(s,2H), 6.92(br, 1H). 13C{1H} (δ, CDCl3) 39.27, 42.32, 58.60, 70.54, 166.22. respectively, and a water-oooled condenser, was placed to add slowly the rate of addition of the alkali solution to maintain pH=12 When the addition to warm to room temperature The organic layer was removed by siphon dried with magnesium sulfate for four hours The mixture was filtered through #4 filter paper on a large Buchner funnel the sulfate washed with 2×100 mL fresh dichloromethane the mixture distilled at 1 torr Fractions collected from 55° C. to 60° C.

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

Procedure: Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-chloro-N-(2-methoxyethyl)acetamide (14 mg) according to an analogous synthetic method to Example 567 and purified by LC-MS, the title compound (3.5 mg) was obtained. purified by LC-MS

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

Procedure: The preparation of N-[2-(cyclopent-2-enyl)phenyl]-N-(2-methoxyethyl)-2-chloroacetamide was conducted in a fashion analogous to example 2. Reaction of 30.00 g (188.4 mmol) of 2-(cyclopent-2-enyl)aniline, 75.75 g (750 mmol}of triethylamine, and 70.91 g (750 mmol) of 2-chloroethyl methyl ether at 100° C. in a closed, 500 mL flask for 56 hr. afforded ca. 40 g of a crude product consisting of, in part, 90.05 wt % of N-(2-methoxyethyl)-2-(cyclopent-2-enyl)aniline and 7.24 wt % of 2-(cyclopent-2-enyl)aniline. Acylation of this material with 2-chloroacetyl chloride provided ca. 50 g of a product consisting of, in part, 89.35 wt % of N-[2- cyclopent-2-enyl)phenyl]-N-(2-methoxyethyl)-2-chloroacetamide and 8.84 wt % of N-[2-(cyclopent-2-enyl)phenyl]-2-chloroacetamide. This material was purified by column chromatograph then bulb-to-bulb distillation (bp 165-175°C/1 mm/Hg). This material was purified by column chromatograph bulb-to-bulb distillation (bp 165-175°C/1 mm/Hg)

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

Procedure: Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-chloro-N-(2-methoxyethyl)acetamide (14 mg) according to an analogous synthetic method to Example 567 and purified by LC-MS, the title compound (3.5 mg) was obtained. purified by LC-MS

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

Procedure: Following general procedure A, methyl hydrogen fumarate (MHF) (0.50 g, 3.84 mmol) dissolved in NMP was reacted at ca. 55° C. with N-(2-methoxyethyl) chloroacetamide (0.69 g, 4.60 mmol) in the presence of CsHCO3 (0.89 g, 4.61 mmol) to afford 0.07 g (8% yield) of the title compound (5) as a white solid after purification by mass-guided preparative HPLC and lyophilization. 1H NMR (CDCl3, 400 MHz): δ 6.94-6.92 (m, 2H), 6.46 (br s, 1H), 4.68 (s, 2H), 3.83 (s, 3H), 3.52-3.46 (m, 4H), 3.36 (s, 3H). MS (ESI): m/z 245.98 (M+H)+.

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

Procedure: Following general procedure A, methyl hydrogen fumarate (MHF) (0.50 g, 3.84 mmol) dissolved in NMP was reacted at ca. 55° C. with N-(2-methoxyethyl)chloroacetamide (0.69 g, 4.60 mmol) in the presence of CsHCO3 (0.89 g, 4.61 mmol) to afford 0.07 g (8% yield) of the title compound (5) as a white solid after purification by mass-guided preparative HPLC and lyophilization. 1H NMR (CDCl3, 400 MHz): δ 6.94-6.92 (m, 2H), 6.46 (br s, 1H), 4.68 (s, 2H), 3.83 (s, 3H), 3.52-3.46 (m, 4H), 3.36 (s, 3H). MS (ESI): m/z 245.98 (M+H)+.

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

Procedure: Following general procedure A, methyl hydrogen fumarate (MHF) (0.50 g, 3.84 mmol) dissolved in NMP was reacted at ca. 55° C. with N-(2-methoxyethyl)chloroacetamide (0.69 g, 4.60 mmol) in the presence of CsHCO3 (0.89 g, 4.61 mmol) to afford 0.07 g (8% yield) of the title compound (5) as a white solid after purification by mass-guided preparative HPLC and lyophilization. 1H NMR (CDCl3, 400 MHz): δ 6.94-6.92 (m, 2H), 6.46 (br s, 1H), 4.68 (s, 2H), 3.83 (s, 3H), 3.52-3.46 (m, 4H), 3.36 (s, 3H). MS (ESI): m/z 245.98 (M+H)+.

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

Procedure: Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-chloro-N-(2-methoxyethyl)acetamide (14 mg) according to an analogous synthetic method to Example 567 and purified by LC-MS, the title compound (3.5 mg) was obtained. purified by LC-MS

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a three-necked 2L round bottom flask fitted with two 500 mL addition funnels, containing 56.4g (39.8 mL, 0.50 mole) chloroacetyl chloride in 400 mL dichloromethane and 20g (0.50 mole) sodium hydroxide in 400 mL water, respectively, and a water-cooled condenser, was placed 35.7g (41.3 mL, 0.48 mole) 2-methoxyethylamine, 100 mL water, 100 mL dichloro-methane. The reaction vessel was cooled to 0° C. by a salt-ice bath. The organic and aqueous solutions were allowed to add slowly, ~0.25 mL per minute, to the reaction mixture. During the addition the pH of the water phase of the reaction was monitored and the rate of addition of the alkali solution adjusted so as to maintain pH=12. When the addition was complete, the mixture was allowed to warm to room temperature and stir overnight. The organic layer was removed by siphon and dried with magnesium sulfate for four hours. The mixture was filtered through #4 filter paper on a large Buchner funnel and the sulfate washed with 2×100 mL fresh dichloromethane. The combined filtrates were then placed in 2L round bottomed flask and the mixture distilled at 1 torr. Fractions collected from 55° C. to 60° C. were combined and analyzed by NMR. Yield 31.1g (43% based on starting 2-methoxyethylamine). TLC (silica on glass, 2% methanol in dichloromethane) Rf =0.40. 1H(δ,CDC13) 3.28(s,3H), 3.40(m,4H), 3.97(s,2H), 6.92(br, 1H). 13C{1H} (δ, CDCl3) 39.27, 42.32, 58.60, 70.54, 166.22. to add slowly the rate of addition of the alkali solution to maintain pH=12 When the addition to warm to room temperature The organic layer was removed by siphon dried with magnesium sulfate for four hours The mixture was filtered through #4 filter paper on a large Buchner funnel the sulfate washed with 2×100 mL fresh dichloromethane the mixture distilled at 1 torr Fractions collected from 55° C. to 60° C.