4-amino-2-methylbenzonitrile

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

Procedure: N-(4-Cyano-3-methylphenyl)-2-methylacrylamide was prepared as described in Example 1 starting from 4-amino-2-methylbenzonitrile and methacryloyl chloride.

Conditions: temp:92.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Methyl-4-nitrobenzonitrile (1.0 g, 6 mmol) was dissolved in acetic acid (15 ml). Water (3.75 ml) was added and the mixture was heated between 90-95° C. Iron powder (2.5 g) was added during 1.5 hours and the resulting mixture was heated for 1 hour. Other portion of water (3.75 ml) was added and the heating was continued for additional 2 hours. The solution was allowed to cool to room temperature and the mixture was diluted with water (100 ml) and extracted with ethyl acetate (4×40 ml). The organic phase was washed with 5% NaHCO3 (1×50 ml) and water (1×50 ml), dried over Na2SO4 and evaporated. The crude product was used without further purifications. 1H NMR (DMSO-d6): 2.28 (3H, s), 6.04 (2H, bs), 6.44 (1H, m), 6.48 (1H, m), 7.31 (1H, m). the resulting mixture was heated for 1 hour to cool to room temperature extracted with ethyl acetate (4×40 ml) The organic phase was washed with 5% NaHCO3 (1×50 ml) and water (1×50 ml) dried over Na2SO4 evaporated

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

Procedure: N-(4-Cyano-3-methylphenyl)-2-methylacrylamide was prepared as described in Example 1 starting from 4-amino-2-methylbenzonitrile and methacryloyl chloride.

Conditions: temp:92.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Methyl-4-nitrobenzonitrile (1.0 g, 6 mmol) was dissolved in acetic acid (15 ml). Water (3.75 ml) was added and the mixture was heated between 90-95° C. Iron powder (2.5 g) was added during 1.5 hours and the resulting mixture was heated for 1 hour. Other portion of water (3.75 ml) was added and the heating was continued for additional 2 hours. The solution was allowed to cool to room temperature and the mixture was diluted with water (100 ml) and extracted with ethyl acetate (4×40 ml). The organic phase was washed with 5% NaHCO3 (1×50 ml) and water (1×50 ml), dried over Na2SO4 and evaporated. The crude product was used without further purifications. 1H NMR (DMSO-d6): 2.28 (3H, s), 6.04 (2H, bs), 6.44 (1H, m), 6.48 (1H, m), 7.31 (1H, m). the resulting mixture was heated for 1 hour to cool to room temperature extracted with ethyl acetate (4×40 ml) The organic phase was washed with 5% NaHCO3 (1×50 ml) and water (1×50 ml) dried over Na2SO4 evaporated

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

Procedure: The coupling of (S)-2-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-6-(5-bromo-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate K) and 4-amino-2-methyl-benzonitrile according to procedure B followed by deprotection yielded the title compound as a white solid. MS (ESI): m/z=394.1 [M+H]+.

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

Procedure: In the synthesis of the compound of example 160, the procedure was as in the preparation of the compound of example 158: 2-methyl-4-nitrobenzonitrile was reduced with hydriodic acid (analogously to the procedure for the synthesis of compound 63.4) to 4-amino-2-methylbenzonitrile (160.3; 1H NMR: 7.3, d, 1H, 6.48, s, 1H, 6.42, d, 1H, 6.02, s, 2H; 227, s, 3H). The aniline 160.3 was converted with standard methods using tert-butyl 2-amino-2-methylpropionate hydrochloride and phosgene (solution in toluene) to compound 160.1 (4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-methylbenzonitrile; 1H NMR: 8.7, s, 1H, 7.88, d, 1H, 7.55, s, 1H; 7.44, d, 1H, 1.4, s, 3H), which was in turn reacted with 2-bromo-1-bromomethyl-4-fluorobenzene to give 160.2 (4-[3-(2-bromo-4-fluorobenzyl)-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl]-2-methylbenzonitrile; molecular weight 429.04 (C20H17BrFN3O2);

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

Procedure: In the synthesis of the compound of example 160, the procedure was as in the preparation of the compound of example 158: 2-methyl-4-nitrobenzonitrile was reduced with hydriodic acid (analogously to the procedure for the synthesis of compound 63.4) to 4-amino-2-methylbenzonitrile (160.3; 1H NMR: 7.3, d, 1H, 6.48, s, 1H, 6.42, d, 1H, 6.02, s, 2H; 227, s, 3H). The aniline 160.3 was converted with standard methods using tert-butyl 2-amino-2-methylpropionate hydrochloride and phosgene (solution in toluene) to compound 160.1 (4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-methylbenzonitrile; 1H NMR: 8.7, s, 1H, 7.88, d, 1H, 7.55, s, 1H; 7.44, d, 1H, 1.4, s, 3H), which was in turn reacted with 2-bromo-1-bromomethyl-4-fluorobenzene to give 160.2 (4-[3-(2-bromo-4-fluorobenzyl)-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl]-2-methylbenzonitrile; molecular weight 429.04 (C20H17BrFN3O2);

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

Procedure: In the synthesis of the compound of example 160, the procedure was as in the preparation of the compound of example 158: 2-methyl-4-nitrobenzonitrile was reduced with hydriodic acid (analogously to the procedure for the synthesis of compound 63.4) to 4-amino-2-methylbenzonitrile (160.3; 1H NMR: 7.3, d, 1H, 6.48, s, 1H, 6.42, d, 1H, 6.02, s, 2H; 227, s, 3H). The aniline 160.3 was converted with standard methods using tert-butyl 2-amino-2-methylpropionate hydrochloride and phosgene (solution in toluene) to compound 160.1 (4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-methylbenzonitrile; 1H NMR: 8.7, s, 1H, 7.88, d, 1H, 7.55, s, 1H; 7.44, d, 1H, 1.4, s, 3H), which was in turn reacted with 2-bromo-1-bromomethyl-4-fluorobenzene to give 160.2 (4-[3-(2-bromo-4-fluorobenzyl)-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl]-2-methylbenzonitrile; molecular weight 429.04 (C20H17BrFN3O2);

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

Procedure: (2R)-3-Bromo-2-hydroxy-2-methylpropionic acid (1.52 g, 8.3 mmol) was dissolved in 35 ml of dry THF and 0.5 ml of dry DMA was added. Solution was cooled to 0° C. and thionyl chloride (0.8 ml; 10.8 mmol) was added dropwise. The solution was allowed to heat up to room temperature and stirred for 2 hours at room temperature. 4-Cyano-3-methylaniline (1.07 g, 8.1 mmol) was added in 5 ml of dry THF and reaction refluxed for 2 hours. THF was evaporated, the residue dissolved in 40 ml of CH2Cl2 and washed with 50 ml of 1% NaHCO3 and then with 4×25 ml of water. The organic phase was evaporated and residue was dried under reduced pressure at 40° C. overnight to give 2.24 g of crude product which was crystallized from 5 ml of toluene (75° C. then cooled to room temperature and to 0° C.), filtered and washed with 5 ml of ice cold toluene. The precipitate was dried under reduced pressure overnight at 40° C. to give 1.54 g of the product. to heat up to room temperature reaction refluxed for 2 hours THF was evaporated the residue dissolved in 40 ml of CH2Cl2 washed with 50 ml of 1% NaHCO3 The organic phase was evaporated residue was dried under reduced pressure at 40° C. overnight to give 2.24 g of crude product which was crystallized from 5 ml of toluene (75° C. then cooled to room temperature and to 0° C.), filtered washed with 5 ml of ice cold toluene The precipitate was dried under reduced pressure overnight at 40° C.

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

Procedure: N-(4-Cyano-3-methylphenyl)-2-methylacrylamide was prepared as described in Example 1 starting from 4-amino-2-methylbenzonitrile and methacryloyl chloride.

Conditions: temp:92.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Methyl-4-nitrobenzonitrile (1.0 g, 6 mmol) was dissolved in acetic acid (15 ml). Water (3.75 ml) was added and the mixture was heated between 90-95° C. Iron powder (2.5 g) was added during 1.5 hours and the resulting mixture was heated for 1 hour. Other portion of water (3.75 ml) was added and the heating was continued for additional 2 hours. The solution was allowed to cool to room temperature and the mixture was diluted with water (100 ml) and extracted with ethyl acetate (4×40 ml). The organic phase was washed with 5% NaHCO3 (1×50 ml) and water (1×50 ml), dried over Na2SO4 and evaporated. The crude product was used without further purifications. 1H NMR (DMSO-d6): 2.28 (3H, s), 6.04 (2H, bs), 6.44 (1H, m), 6.48 (1H, m), 7.31 (1H, m). the resulting mixture was heated for 1 hour to cool to room temperature extracted with ethyl acetate (4×40 ml) The organic phase was washed with 5% NaHCO3 (1×50 ml) and water (1×50 ml) dried over Na2SO4 evaporated