2-fluoro-3-methylaniline

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

Procedure: In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine (0.2 g, 0.45 mmol) obtained in Example 128, step 2 and 2-fluoro-3-methylaniline (0.085 g, 0.68 mmol), the title compound (0.2 g, 85%) was obtained.

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

Procedure: In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine (0.2 g, 0.45 mmol) obtained in Example 128, step 2 and 2-fluoro-3-methylaniline (0.085 g, 0.68 mmol), the title compound (0.2 g, 85%) was obtained.

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

Procedure: In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine (100 mg, 0.24 mmol) obtained in Example 19, step 4 and 2-fluoro-3-methylaniline (46 mg, 0.36 mmol), the title compound (120 mg, 99%) was obtained.

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

Procedure: At 0° C., dimethyl acetylenedicarboxylate (8.70 mL, 70.4 mmol) was added dropwise to a solution 2-fluoro-3-methylaniline (7.34 g, 58.7 mmol) in MeOH (58.7 mL). After stirring at room temperature overnight, the reaction mixture was concentrated to dryness. The residue was purified by silica gel flash chromatography (gradient 0-60% EtOAc/Hexanes) to give (E)-dimethyl 2-(2-fluoro-3-methylphenylimino)succinate (7-14, 14.59 g, 93%). LRMS m/z (M+H)+ 268.3 found, 268.1 required. the reaction mixture was concentrated to dryness The residue was purified by silica gel flash chromatography (gradient 0-60% EtOAc/Hexanes)

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

Procedure: At 0° C., dimethyl acetylenedicarboxylate (8.70 mL, 70.4 mmol) was added dropwise to a solution 2-fluoro-3-methylaniline (7.34 g, 58.7 mmol) in MeOH (58.7 mL). After stirring at room temperature overnight, the reaction mixture was concentrated to dryness. The residue was purified by silica gel flash chromatography (gradient 0-60% EtOAc/Hexanes) to give (E)-dimethyl 2-(2-fluoro-3-methylphenylimino)succinate (7-14, 14.59 g, 93%). LRMS m/z (M+H)+ 268.3 found, 268.1 required. the reaction mixture was concentrated to dryness The residue was purified by silica gel flash chromatography (gradient 0-60% EtOAc/Hexanes)

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

Procedure: 3-Amino-2-fluorotoluene (4.89 g, 39.1 mmol), dimethyl 2-oxobutanedioate (6.26 g, 39.1 mmol), and TosicAcid (0.223 g, 1.172 mmol) were heated at reflux under Dean-Stark conditions for 1 hour. The solvent was removed in vacuo and the residue purified by column chromatography on a silica gel column, eluting with EtOAc/hexane (0-15%) to afford Dimethyl(2E)-2-[(2-fluoro-3-methylphenyl)imino]butanedioate (7-6, 5.48 g, 53% yield) as a clear oil, LCMS shows the compound is 100% pure, LRMS m/z (M+H)+ 268.2 found, 268.1 required. at reflux under Dean-Stark conditions for 1 hour The solvent was removed in vacuo the residue purified by column chromatography on a silica gel column eluting with EtOAc/hexane (0-15%)

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

Procedure: The product is prepared according to the procedure described in Example 5, using 260 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 250 mg of 2-fluoro-3-methylaniline in place of the 2,4-difluoroaniline. 208 mg of N-(2-fluoro-3-methylphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following: The product is prepared

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 6-Bromo-2-fluoro-3-methylaniline (9.00 g, 44.1 mmol), which had been obtained in Reference example 4(4a), was dissolved in a 1:1 mixture (130 mL) of N,N-dimethyl formamide and methanol, and added with [1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloride-dichloromethane complex (10.8 g, 13.2 mmol) and N,N-diisopropylethylamine (23 mL, 132.3 mmol). The mixture was vigorously stirred at 85° C. for 2 hours under a carbon monoxide atmosphere. The reaction solution was cooled to room temperature, added with ethyl acetate and water, filtered using Millicup (registered trademark)-LH, and washed with ethyl acetate. The filtered solution was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane/ethyl acetate=4/1) to give the title compound as a colorless solid (5.70 g, yield 71%). The reaction solution was cooled to room temperature filtered washed with ethyl acetate The filtered solution was extracted with ethyl acetate The organic layer was washed with saturated brine dried over anhydrous magnesium sulfate The solvent was distilled off under reduced pressure The residue was purified by silica gel chromatography (n-hexane/ethyl acetate=4/1)

Conditions: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared from 2-fluoro-3-methylaniline via 2-mercapto-7-methyl-1,3-benzothiazole as described for 2,5-dichloro-1,3-benzothiazole except that in the first step the reaction mixture was heated to 180° C. for 24 h in a sealed tube.

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 6-Bromo-2-fluoro-3-methylaniline (9.00 g, 44.1 mmol), which had been obtained in Reference example 6 (6a), was dissolved in 1:1 mixture (130 mL) of N,N-dimethyl formamide and methanol, and added with [1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloride-dichloromethane complex (10.8 g, 13.2 mmol) and N,N-diisopropylethylamine (23 mL, 132.3 mmol). The mixture was vigorously stirred at 85° C. for 2 hours under a carbon monoxide atmosphere. The reaction solution was cooled to room temperature, added with ethyl acetate and water, filtered using Millicup (registered trademark)-LH, and washed with ethyl acetate. The filtered solution was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane/ethyl acetate=4/1) to give the title compound as a colorless solid (5.70 g, yield 71%). The reaction solution was cooled to room temperature filtered washed with ethyl acetate The filtered solution was extracted with ethyl acetate The organic layer was washed with saturated brine dried over anhydrous magnesium sulfate The solvent was distilled off under reduced pressure The residue was purified by silica gel chromatography (n-hexane/ethyl acetate=4/1)

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

Procedure: The product is prepared according to the procedure described in Example 5, using 260 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 250 mg of 2-fluoro-3-methylaniline in place of the 2,4-difluoroaniline. 208 mg of N-(2-fluoro-3-methylphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following: The product is prepared

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

Procedure: In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine (0.2 g, 0.45 mmol) obtained in Example 128, step 2 and 2-fluoro-3-methylaniline (0.085 g, 0.68 mmol), the title compound (0.2 g, 85%) was obtained.