2-(bromomethyl)-1-chloro-4-methoxybenzene

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

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

Procedure: The parent compound was obtained as a white solid in comparable yields according to the procedures described above for the preparation of N-methyl-N-(2-methyl-naphthalen-1-ylmethyl)-6-morpholin-4-yl-4-o-tolyl-nicotinamide (Example 19) using 2-chloro-5-methoxy-benzyl bromide instead of 1-chloromethyl-2-methylnaphthalene in step b). The parent compound was obtained as a white solid in comparable yields

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

Procedure: The parent compound was obtained as a white solid in comparable yields according to the procedures described above for the preparation of N-methyl-N-(2-methyl-naphthalen-1-ylmethyl)-6-morpholin-4-yl-4-o-tolyl-nicotinamide (Example 19) using 2-chloro-5-methoxy-benzyl bromide instead of 1-chloromethyl-2-methylnaphthalene in step b). The parent compound was obtained as a white solid in comparable yields

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

Procedure: To the 2-(bromomethyl)-1-chloro-4-methoxybenzene (3.79 g, 16.09 mmol) in anhydrous ethanol (30 mL) at room temperature, 6-methyl-2-sulfanylpyrimidin-4-ol (2.28 g, 16.09 mmol) was added. Triethylamine (1.79 g, 17.7 mmol) was then added. The reaction mixture was stirred overnight at room temperature. The reaction progress was monitored by LCMS. The solvent was evaporated, and the crude residue was suspended in water and sonicated. The white precipitated product was filtered off and washed with water, ether, and ethyl acetate to provide the 2-{[(2-chloro-5-methoxyphenyl)methyl]sulfanyl}-6-methylpyrimidin-4-ol as a white solid (4.05 g, 85% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.20 (s, 3H), 3.71 (s, 3H), 4.39 (s, 2H), 5.99 (bs, 1H), 6.88 (d, J=8.9 Hz, 1H), 7.19 (s, 1H), 7.38 (d, J=8.9 Hz, 1H). The solvent was evaporated sonicated The white precipitated product was filtered off washed with water, ether, and ethyl acetate

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

Procedure: To a solution of the 1-chloro-4-methoxy-2-methylbenzene (2.0 g, 12.77 mmol) in anhydrous carbon tetrachloride (50 mL), NBS (2.29 g, 12.98 mmol) and benzoyl peroxide (0.154 g, 0.64 mmol) was added. The reaction mixture was heated to reflux overnight. Then, the reaction mixture was cooled to room temperature and filtered. The filtrate was evaporated to provide crude 2-(bromomethyl)-1-chloro-4-methoxybenzene, which was used for the next step without any further purification; 1H NMR (400 MHz, DMSO-d6): δ 3.74 (s, 3H), 4.66 (s, 2H), 7.01 (d, J=8.9 Hz, 1H), 7.19 (s, 1H), 7.38 (d, J=8.9 Hz, 1H). The reaction mixture was heated to reflux overnight filtered The filtrate was evaporated

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

Procedure: To the 2-(bromomethyl)-1-chloro-4-methoxybenzene (3.79 g, 16.09 mmol) in anhydrous ethanol (30 mL) at room temperature, 6-methyl-2-sulfanylpyrimidin-4-ol (2.28 g, 16.09 mmol) was added. Triethylamine (1.79 g, 17.7 mmol) was then added. The reaction mixture was stirred overnight at room temperature. The reaction progress was monitored by LCMS. The solvent was evaporated, and the crude residue was suspended in water and sonicated. The white precipitated product was filtered off and washed with water, ether, and ethyl acetate to provide the 2-{[(2-chloro-5-methoxyphenyl)methyl]sulfanyl}-6-methylpyrimidin-4-ol as a white solid (4.05 g, 85% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.20 (s, 3H), 3.71 (s, 3H), 4.39 (s, 2H), 5.99 (bs, 1H), 6.88 (d, J=8.9 Hz, 1H), 7.19 (s, 1H), 7.38 (d, J=8.9 Hz, 1H). The solvent was evaporated sonicated The white precipitated product was filtered off washed with water, ether, and ethyl acetate

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

Procedure: To a solution of the 1-chloro-4-methoxy-2-methylbenzene (2.0 g, 12.77 mmol) in anhydrous carbon tetrachloride (50 mL), NBS (2.29 g, 12.98 mmol) and benzoyl peroxide (0.154 g, 0.64 mmol) was added. The reaction mixture was heated to reflux overnight. Then, the reaction mixture was cooled to room temperature and filtered. The filtrate was evaporated to provide crude 2-(bromomethyl)-1-chloro-4-methoxybenzene, which was used for the next step without any further purification; 1H NMR (400 MHz, DMSO-d6): δ 3.74 (s, 3H), 4.66 (s, 2H), 7.01 (d, J=8.9 Hz, 1H), 7.19 (s, 1H), 7.38 (d, J=8.9 Hz, 1H). The reaction mixture was heated to reflux overnight filtered The filtrate was evaporated

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

Procedure: To a solution of the 1-chloro-4-methoxy-2-methylbenzene (2.0 g, 12.77 mmol) in anhydrous carbon tetrachloride (50 mL), NBS (2.29 g, 12.98 mmol) and benzoyl peroxide (0.154 g, 0.64 mmol) was added. The reaction mixture was heated to reflux overnight. Then, the reaction mixture was cooled to room temperature and filtered. The filtrate was evaporated to provide crude 2-(bromomethyl)-1-chloro-4-methoxybenzene, which was used for the next step without any further purification; 1H NMR (400 MHz, DMSO-d6): δ 3.74 (s, 3H), 4.66 (s, 2H), 7.01 (d, J=8.9 Hz, 1H), 7.19 (s, 1H), 7.38 (d, J=8.9 Hz, 1H). The reaction mixture was heated to reflux overnight filtered The filtrate was evaporated

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium cyanide (10.4 g) was added portionwise to a stirred solution of the above benzyl bromide (25 g) in a 2:1 mixture of ethanol and water (250 ml). The mixture was stirred for one hour at 50° C., poured into water and extracted with ether. The extract gave 2-chloro-5-methoxy-phenylacetonitrile (m.p. 62°-65° C.). 10M Boranemethylsulphide complex (11.3 ml) was added dropwise under nitrogen to a refluxing solution of the above phenylacetonitrile (18.6 g) in tetrahydrofuran (150 ml). The mixture was heated under reflux for 2 hours and dilute hydrochloric acid was added dropwise and the acidified mixture heated at 95° C. for one hour. The cooled mixture was washed with ether, basified with dilute sodium hydroxide solution and extracted with ether. The extract yielded 2 -chloro-5-methoxyphenethylamine as a yellow oil. extracted with ether

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium cyanide (10.4 g) was added portionwise to a stirred solution of the above benzyl bromide (25 g) in a 2:1 mixture of ethanol and water (250 ml). The mixture was stirred for one hour at 50° C., poured into water and extracted with ether. The extract gave 2-chloro-5-methoxy-phenylacetonitrile (m.p. 62°-65° C.). 10M Boranemethylsulphide complex (11.3 ml) was added dropwise under nitrogen to a refluxing solution of the above phenylacetonitrile (18.6 g) in tetrahydrofuran (150 ml). The mixture was heated under reflux for 2 hours and dilute hydrochloric acid was added dropwise and the acidified mixture heated at 95° C. for one hour. The cooled mixture was washed with ether, basified with dilute sodium hydroxide solution and extracted with ether. The extract yielded 2 -chloro-5-methoxyphenethylamine as a yellow oil. extracted with ether

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

Procedure: Methyl iodide (110 g was added dropwise to a stirred solution of 4-chloro-3-methylphenol (100 g) and potassium carbonate (194 g) in acetone (500 ml). The mixture was stirred for 1.5 hours. Methyl iodide (142 g) was added and the mixture stirred for a further hour. Solvent was removed by evaporation and the residue partitioned between water and ethyl acetate. The organic layer yielded an oil which was heated under reflux for 2 hours with N-bromosuccinimide (119 g) and benzoyl peroxide (1 g) in carbon tetrachloride (250 ml). The mixture was cooled, filtered and the filtrate concentrated to give a residue which was distilled under high vacuum. The fractions collected between 88° and 94° C./0.4 mbar were recrystallised from petroleum ether (b.p. 60°-80° C.) to give 2-chloro-5-methoxy benzyl bromide, m.p. 51°-52° C. the mixture stirred for a further hour Solvent was removed by evaporation the residue partitioned between water and ethyl acetate The organic layer yielded an oil which was heated The mixture was cooled filtered the filtrate concentrated to give a residue which was distilled under high vacuum The fractions collected between 88° and 94° C./0.4 mbar were recrystallised from petroleum ether (b.p. 60°-80° C.)

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

Procedure: The parent compound was obtained as a white solid in comparable yields according to the procedures described above for the preparation of N-methyl-N-(2-methyl-naphthalen-1-ylmethyl)-6-morpholin-4-yl-4-o-tolyl-nicotinamide (Example 19) using 2-chloro-5-methoxy-benzyl bromide instead of 1-chloromethyl-2-methylnaphthalene in step b). The parent compound was obtained as a white solid in comparable yields