4-fluoro-2-isothiocyanato-1-methylbenzene

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

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

Procedure: A mixture of the crude N-ethyl glycine (11.5 g), 5-fluoro-2-methylphenyl-isothiocyanate (10.42 g), triethyl amine (12.5 g) and chloroform (300 mL) was heated at reflux for 6 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate (500 mL) and washed with water (500 mL). The organic phase was evaporated to dryness. The residue was dissolved in ethanol (50 mL), then diluted with diethyl ether (200 mL). The solution was saturated with hydrogen chloride. The mixture was filtered. The solid was discarded. The filtrate was evaporated to dryness. The residue was dissolved in diethyl ether (300 mL) and washed with water (200 mL). The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization from ethanol afforded the title compound (6.5 g) as a pink solid, m.p. 98°-100° C. Anal. Calcd. for. C12H13F N2O S: C, 57.13; H, 5.19; N, 11.10. Found: C, 56.88; H, 5.17; N, 11.05. Mass spectrum (EI, M.+) m/z 252. was heated at reflux for 6 hours The solvent was evaporated The residue was dissolved in ethyl acetate (500 mL) washed with water (500 mL) The organic phase was evaporated to dryness The residue was dissolved in ethanol (50 mL) diluted with diethyl ether (200 mL) The mixture was filtered The filtrate was evaporated to dryness The residue was dissolved in diethyl ether (300 mL) washed with water (200 mL) The organic phase was dried over anhydrous sodium sulfate evaporated to dryness Crystallization from ethanol

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

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

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

Procedure: A mixture of the crude N-ethyl glycine (11.5 g), 5-fluoro-2-methylphenylisothiocyanate (10.42 g), triethylamine (12.5 g) and chloroform (300 mL) was heated at reflux for 6 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate (500 mL) and washed with water (500 mL). The organic phase was evaporated to dryness. The residue was dissolved in ethanol (50 mL), then diluted with diethyl ether (200 mL). The solution was saturated with hydrogen chloride. The mixture was filtered. The solid was discarded. The filtrate was evaporated to dryness. The residue was dissolved in diethyl ether (300 mL) and washed with water (200 mL). The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization from ethanol afforded the title compound (6.5 g) as a pink solid, m.p. 98°-100° C. Anal. Calcd. for. C12H13F N2O S: C, 57.13; H, 5.19; N, 11.10. Found: C, 56.88; H, 5.17; N, 11.05. Mass spectrum (EI, M.+) m/z 252. was heated at reflux for 6 hours The solvent was evaporated The residue was dissolved in ethyl acetate (500 mL) washed with water (500 mL) The organic phase was evaporated to dryness The residue was dissolved in ethanol (50 mL) diluted with diethyl ether (200 mL) The mixture was filtered The filtrate was evaporated to dryness The residue was dissolved in diethyl ether (300 mL) washed with water (200 mL) The organic phase was dried over anhydrous sodium sulfate evaporated to dryness Crystallization from ethanol

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

Procedure: 5-Fluoro-2-methylphenyl isothiocyanate (16.7 g; 0.1 mol) was added dropwise to aqueous ethylamine (120 mL of 70% solution). The mixture was stirred for 2 hour at ambient temperature. Excess ethylamine was removed under a stream of nitrogen. The residue was diluted with water. The solids were collected by filtration, washed with water and dried. The solid was dissolved in ether and washed with water. The organic phase was dried over anhydrous magnesium sulfate then evaporated to dryness to give N-(5-fluoro-2-methylphenyl)-N′-ethylthiourea (18.5 g), m.p. 93–95° C. Mass spectrum; (El, M.+) m/z 212. 1H-NMR (DMSO-d6; 300 MHz): δ 9.01 (br s, 1H), 7.66 (br s, 1H), 7.25–7.18 (m, 2H), 6.96 (m, 1H), 3.45 (m, 2H), 2.13 (s, 3H), and 1.09 ppm (t, 3H). Excess ethylamine was removed under a stream of nitrogen The residue was diluted with water The solids were collected by filtration washed with water dried The solid was dissolved in ether washed with water The organic phase was dried over anhydrous magnesium sulfate then evaporated to dryness

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

Procedure: A mixture of the crude N-ethyl glycine (11.5 g), 5-fluoro-2-methylphenyl-isothiocyanate (10.42 g), triethyl amine (12.5 g) and chloroform (300 mL) was heated at reflux for 6 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate (500 mL) and washed with water (500 mL). The organic phase was evaporated to dryness. The residue was dissolved in ethanol (50 mL), then diluted with diethyl ether (200 mL). The solution was saturated with hydrogen chloride. The mixture was filtered. The solid was discarded. The filtrate was evaporated to dryness. The residue was dissolved in diethyl ether (300 mL) and washed with water (200 mL). The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization from ethanol afforded the title compound (6.5 g) as a pink solid, m.p. 98°-100° C. Anal. Calcd. for. C12H13F N2O S: C, 57.13; H, 5.19; N, 11.10. Found: C, 56.88; H, 5.17; N, 11.05. Mass spectrum (EI, M.+) m/z 252. was heated at reflux for 6 hours The solvent was evaporated The residue was dissolved in ethyl acetate (500 mL) washed with water (500 mL) The organic phase was evaporated to dryness The residue was dissolved in ethanol (50 mL) diluted with diethyl ether (200 mL) The mixture was filtered The filtrate was evaporated to dryness The residue was dissolved in diethyl ether (300 mL) washed with water (200 mL) The organic phase was dried over anhydrous sodium sulfate evaporated to dryness Crystallization from ethanol

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

Procedure: A mixture of the crude N-ethyl glycine (11.5 g), 5-fluoro-2-methylphenyl-isothiocyanate (10.42 g), triethyl amine (12.5 g) and chloroform (300 mL) was heated at reflux for 6 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate (500 mL) and washed with water (500 mL). The organic phase was evaporated to dryness. The residue was dissolved in ethanol (50 mL), then diluted with diethyl ether (200 mL). The solution was saturated with hydrogen chloride. The mixture was filtered. The solid was discarded. The filtrate was evaporated to dryness. The residue was dissolved in diethyl ether (300 mL) and washed with water (200 mL). The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization from ethanol afforded the title compound (6.5 g) as a pink solid, m.p. 98°-100° C. Anal. Calcd. for. C12H13F N2O S: C, 57.13; H, 5.19; N, 11.10. Found: C, 56.88; H, 5.17; N, 11.05. Mass spectrum (EI, M.+) m/z 252. was heated at reflux for 6 hours The solvent was evaporated The residue was dissolved in ethyl acetate (500 mL) washed with water (500 mL) The organic phase was evaporated to dryness The residue was dissolved in ethanol (50 mL) diluted with diethyl ether (200 mL) The mixture was filtered The filtrate was evaporated to dryness The residue was dissolved in diethyl ether (300 mL) washed with water (200 mL) The organic phase was dried over anhydrous sodium sulfate evaporated to dryness Crystallization from ethanol

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

Procedure: A mixture of glycinamide hydrochloride (4.42 g), 5-fluoro-2-methylphenylisothiocyanate (6.68 g), triethyl amine (4.1 g), and chloroform (150 mL) was stirred at ambient temperature for 18 hours. The precipitate was collected by filtration, washed with chloroform and air dried to give 2-[3-(5-Fluoro-2-methylphenyl)-thioureido]acetamide (7.6 g), m.p. 172°-174° C. (dec.). This compound was used without further purification in the next paragraph. The precipitate was collected by filtration washed with chloroform and air dried

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

Procedure: A mixture of glycinamide hydrochloride (4.42 g), 5-fluoro-2-methylphenyl-isothiocyanate (6.68 g), triethyl amine (4.1 g), and chloroform (150 mL) was stirred at ambient temperature for 18 hours. The precipitate was collected by filtration, washed with chloroform and air dried to give 2-[3-(5-Fluoro-2-methylphenyl)-thioureido]-acetamide (7.6 g), m.p. 172°-174° C. (dec.). This compound was used without further purification in the next paragraph. The precipitate was collected by filtration washed with chloroform and air dried

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

Procedure: In methanol (50 ml), 5-fluoro-2-methylphenyl isothiocyanate (2.00 g, 12.0 mmol) was added to methyl 4-amino-3-hydroxyphenylacetate (2.17 g, 12.0 mmol) and the resulting mixture was stirred at room temperature for 27 hours. Mercuric oxide (yellow) (3.12 g, 14.4 mmol) was added to the reaction mixture, followed by stirring at 70° C. for 4 hours. After cooling to room temperature, the reaction mixture was filtered through Celite, followed by washing with methanol. The filtrate was distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from chloroform/ethyl acetate (10/1) eluate fractions, methyl (2-(5-fluoro-2-methylphenylamino)-6-benzoxazolyl)acetate (1.73 g, 46%) was obtained as a brown oil. by stirring at 70° C. for 4 hours After cooling to room temperature the reaction mixture was filtered through Celite by washing with methanol The filtrate was distilled under reduced pressure to remove the solvent The residue was purified by chromatography on a silica gel column, whereby from chloroform/ethyl acetate (10/1) eluate fractions

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

Procedure: Under stirring at 0° C., a solution of 5-fluoro-2-methylaniline (1.23 g, 9.84 mmol) in methylene chloride (10 ml) was added dropwise to a mixture of calcium carbonate (2.46 g, 24.6 mmol) and thiophosgene (750 μl, 9.84 mmol) in a methylene chloride/water (1/1, 40 ml) mixture. After completion of the dropwise addition, the reaction mixture was stirred further at 0° C. for 35 minutes. The reaction mixture was poured in ice-1N HCR, followed by extraction with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent to give 5-fluoro-2-methylphenyl isothiocyanate (1.45 g, 88%) as a brown oil. After completion of the dropwise addition the reaction mixture was stirred further at 0° C. for 35 minutes followed by extraction with chloroform The extract was washed with saturated brine dried over anhydrous sodium sulfate distilled under reduced pressure to remove the solvent