isocyanomethylbenzene

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

Procedure: To a solution of 7.2 g (29.48 mmol) (2-amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester (Example 73, intermediate g) in 75 ml methanole, 2.48 g (35.37 mmol) cyclopropanecarbaldehyde (commercially available) were added. After stirring for 5 min. at room temperature the solution was treated with 4.62 g (29.5 mmol) 4-chlorobenzoic acid (commercially available), followed by an addition of 3.6 ml (29.47 mmol) benzylisocyanide (commercially available). The formed solution was stirred at room temperature for 23 h, then 36.85 ml (147 mmol) 4 M hydrochloric acid in dioxane were added dropwise over 5 min. The resulting suspension was stirred for 23 h, then poured onto 500 ml saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, and evaporated. The residue was purified by silica gel column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane:ethyl acetate (100:0 to 50:50). Light yellow solid (99%). MS (Turbo Spray): m/z=452.1 [M+H]. The formed solution was stirred at room temperature for 23 h The resulting suspension was stirred for 23 h The aqueous layer was extracted three times with ethyl acetate The combined organic layers were washed with water and brine dried over magnesium sulfate filtered evaporated The residue was purified by silica gel column chromatography eluting with a gradient of heptane:ethyl acetate (100:0 to 50:50)

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

Procedure: To a solution of 5.0 g (20.47 mmol) (2-amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester (Example 73, intermediate g) in 50 ml methanol, 2.21 g (22.57 mmol) cyclopentanecarbaldehyde (commercially available) were added. After stirring for 5 min. at room temperature, 3.2 g (20.5 mmol) p-chlorobenzoic acid and 2.5 ml (20.47 mmol) benzyl isocyanide (commercially available) were added. After stirring for 19 h, 38.38 ml (153.52 mmol) 4 M hydrochloric acid in dioxane were added dropwise over 5 min. After 5 h the solution was poured on 500 ml saturated aqueous sodium bicarbonate solution and the phases were separated. The organic layer was extracted three times with ethyl acetate and the combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, and evaporated. The residue was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 50:50). Light yellow foam (97%). MS (Turbo Spray): m/z=480.1 [M+H]. After stirring for 19 h the phases were separated The organic layer was extracted three times with ethyl acetate the combined organic layers were washed with water and brine dried over magnesium sulfate filtered evaporated The residue was purified by silica gel chromatography eluting with a gradient of n-heptane:ethyl acetate (100:0 to 50:50)

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

Procedure: To a solution of 3.8 g (15.56 mmol) (2-amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester (Example 73, intermediate g) in 38 ml methanol, 2.54 g (17.12 mmol) 4,4-difluorocyclohexanone (commercially available) were added. After stirring for 5 min. at room temperature the solution was treated with 2.44 g (15.58 mmol) p-chlorobenzoic acid, followed by an addition of 1.9 ml (15.56 mmol) benzyl isocyanide (commercially available). To the viscous slurry 12 ml methanol were added and the reaction for 22.5 h. Then 19.45 ml (77.80 mmol) 4M hydrochloric acid in dioxane were added dropwise over 5 min. After 4.5 h another 19.45 ml (77.80 mmol) 4M hydrochloric acid in dioxane were added. After 24 h, the suspension was poured onto 300 ml aqueous saturated sodium bicarbonate solution and the phases were separated. The aqueous layer was extracted three times with ethyl acetate and the organic layers were washed with brine, dried over magnesium sulfate, filtered, and evaporated. The residue was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane:ethyl acetate (100:0 to 50:50). Light yellow solid (76%). MS (Turbo Spray): m/z=530.2 [M+H]. the reaction for 22.5 h After 24 h the phases were separated The aqueous layer was extracted three times with ethyl acetate the organic layers were washed with brine dried over magnesium sulfate filtered evaporated The residue was purified by silica gel chromatography eluting with a gradient of heptane:ethyl acetate (100:0 to 50:50)

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

Procedure: To the solution of 1.5 g (6.145 mmol) 2-amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester (Example 73, intermediate g), 1.080 g (6.145 mmol) 4-chloro-2-methyl-benzoic acid (commercially available), 985.5 ul (7.375 mmol) cyclohexenecarbaldehyde (commercially available) and 763.5 ul (6.145 mmol) benzyl isocyanide (commercially available) were dissolved in 15 ml methanol and the light brown solution was stirred at room temperature overnight. Then 15.00 ml (60.0 mmol) 4M hydrochloric acid in dioxane (commercially available) were added and the reaction mixture was stirred at room temperature for 4.5 h and then evaporated. The residue was taken up in ethyl acetate and aqueous saturated sodium bicarbonate solution, the phases were separated, the organic phase extracted a second time with ethyl acetate and the combined organic layers washed with water and brine to give, after evaporation, the compound as yellow foam which was pure enough for the next step without further purification. MS (ESI): m/z=508.02 (M+). the reaction mixture was stirred at room temperature for 4.5 h evaporated aqueous saturated sodium bicarbonate solution, the phases were separated the organic phase extracted a second time with ethyl acetate the combined organic layers washed with water and brine to give after evaporation the compound as yellow foam which was pure enough for the next step without further purification

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

Procedure: 10.0 g (40.94 mmol) (2-amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester were dissolved in 60 ml methanol, then 5.91 ml (49.13 mmol) cyclohexylcarbaldehyde (commercially available) were added. After stirring for 5 min. at room temperature the solution was treated with 7.50 g (40.94 mmol) 2,6-dimethoxynicotinic acid commercially available), followed by an addition of 5.0 ml (40.94 mmol) benzylisocyanide (commercially available). From the clear, light brown and slightly warm solution a suspension formed within a few minutes. After 3 h another ml methanol were added. After stirring for 20 h, 51.18 ml (205 mmol) of a 1M hydrochloric acid solution in dioxane were added dropwise over 5 min. The resulting solution was stirred at room temperature for 29 h, then poured onto 500 ml saturated aqueous sodium bicarbonate solution and the layers were separated. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated to dryness. The resulting solid was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with n-heptane:tert-butyl methyl ether (1:1) as eluant. Off-white foam (72%). MS (Turbo Spray) m/z=521.5 [M+H]. 5.91 ml (49.13 mmol) cyclohexylcarbaldehyde (commercially available) were added From the clear, light brown and slightly warm solution a suspension formed within a few minutes After stirring for 20 h The resulting solution was stirred at room temperature for 29 h the layers were separated The aqueous layer was extracted three times with ethyl acetate The combined organic layers were washed with water and brine dried over magnesium sulfate filtered treated with silica gel evaporated to dryness The resulting solid was purified by silica gel chromatography eluting with n-heptane:tert-butyl methyl ether (1:1) as eluant

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

Procedure: The compound was synthesized starting from 3-(4-methyl-1H-imidazol-1-yl)propyl amine 0.250 g (1.8 mmol), benzaldehyde 0.182 ml (1.8 mmol), benzylisonitrile 0.220 ml (1.8 mmol) pyridiniumchloride 0.210 g (1.8 mmol) and KOCN 0.150 g (1.8 mmol) as described in method 1. The compound was synthesized

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

Procedure: The compound was synthesized starting from (3-(5-methyl-1H-imidazol-1-yl)propyl)amine 0.278 g (2 mmol), benzaldehyde 0.202 ml (2 mmol), benzylisonitrile 0.245 ml (2 mmol) pyridiniumchloride 0.231 g (2 mmol) and KOCN 0.165 g (2 mmol) as described in method 1. The compound was synthesized

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

Procedure: The compound was synthesized starting from 3-(1H-imidazol-1-yl)propylamine 1.0 g (7.98 mmol), benzaldehyde 0.807 ml (7.98 mmol), benzylisonitrile 0.972 ml (7.98 mmol), pyidiniumchloride 0.920 and KOCN 0.648 g (7.98 mmol) as described in method 1. The compound was synthesized

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

Procedure: The compound was synthesized starting from 5-aminobenzimidazole 1.331 g (10 mmol), benzaldehyde 1.02 ml (10 mmol), benzyl isonitrile 1.22 ml (10 mmol) and KOCN 0.84 g (10 mmol) as described in method 1. The compound was synthesized

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

Procedure: To a solution of (2-amino-5-fluoro-phenyl)-carbamic acid tert-butyl ester (4.0 g, 17.68 mmol, 1.0 equiv; prepared as described in M. J. Bamford, M. J. Alberti, N. Bailey, S. Davies, D. K. Dean, A. Gaiba, S. Garland, J. D. Harling, D. K. Jung, T. A. Panchal, C. A. Parr, J. G. Steadman, A. K. Talde, J. T. Townsend, D. M. Wilson, J. Witherington Bioorg. Med. Chem. Lett. 2005, 15, 3402-3406) in methanol (50 mL) was added cyclohexanecarbaldehyde (1.98 g, 2.13 mL, 17.68 mmol, 1.0 equiv; [2043-61-0]) and the mixture stirred at rt. After 30 min, (R)-methoxy-phenyl-acetic acid (2.94 g, 17.68 mmol, 1.0 equiv; [CAS RN 3966-32-3]) and isocyanomethyl-benzene (2.07 g, 2.15 mL, 17.68 mmol, 1.0 equiv; [931-53-3]) were added and stirring continued at rt for 2 h. A solution of 4 M HCl in dioxane (18 mL) was added and the reaction mixture stirred at rt overnight. The solution was concentrated by evaporation under reduced pressure, the pH adjusted to 9 by addition of a solution of 1 M NaHCO3 and the aqueous layer extracted with dichloromethane. The combined organic phases were dried over MgSO4 and concentrated by evaporation under reduced pressure. The crude material was purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane (+1% triethylamine)/ethyl acetate to give 5.9 g (69%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.25 (t, J=7.5 Hz, 3H), 1.41 (t, J=7.5 Hz, 3H), 3.43 (s, 3H), 4.01 (q, J=7.5 Hz, 2H), 4.26 (q, J=7.5 Hz, 2H), 5.05 (s, 1H), 6.43-6.48 (m, 2H). MS (ISP): 486.4 [M+H]+. prepared stirring continued at rt for 2 h the reaction mixture stirred at rt overnight The solution was concentrated by evaporation under reduced pressure the pH adjusted to 9 by addition of a solution of 1 M NaHCO3 the aqueous layer extracted with dichloromethane The combined organic phases were dried over MgSO4 concentrated by evaporation under reduced pressure The crude material was purified by silica column chromatography eluting with a gradient of heptane (+1% triethylamine)/ethyl acetate

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

Procedure: To a solution of (2-amino-5-fluoro-phenyl)-carbamic acid tert-butyl ester (4.0 g, 17.68 mmol, 1.0 equiv; prepared as described in M. J. Bamford, M. J. Alberti, N. Bailey, S. Davies, D. K. Dean, A. Gaiba, S. Garland, J. D. Harling, D. K. Jung, T. A. Panchal, C. A. Parr, J. G. Steadman, A. K. Talde, J. T. Townsend, D. M. Wilson, J. Witherington Bioorg. Med. Chem. Lett. 2005, 15, 3402-3406) in methanol (50 mL) was added cyclohexanecarbaldehyde (1.98 g, 2.13 mL, 17.68 mmol, 1.0 equiv; [2043-61-0]) and the mixture stirred at rt. After 30 min, (R)-methoxy-phenyl-acetic acid (2.94 g, 17.68 mmol, 1.0 equiv; [CAS RN 3966-32-3]) and isocyanomethyl-benzene (2.07 g, 2.15 mL, 17.68 mmol, 1.0 equiv; [931-53-3]) were added and stirring continued at rt for 2 h. A solution of 4 M HCl in dioxane (18 mL) was added and the reaction mixture stirred at rt overnight. The solution was concentrated by evaporation under reduced pressure, the pH adjusted to 9 by addition of a solution of 1 M NaHCO3 and the aqueous layer extracted with dichloromethane. The combined organic phases were dried over MgSO4 and concentrated by evaporation under reduced pressure. The crude material was purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane (+1% triethylamine)/ethyl acetate to give 5.9 g (69%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.25 (t, J=7.5 Hz, 3H), 1.41 (t, J=7.5 Hz, 3H), 3.43 (s, 3H), 4.01 (q, J=7.5 Hz, 2H), 4.26 (q, J=7.5 Hz, 2H), 5.05 (s, 1H), 6.43-6.48 (m, 2H). MS (ISP): 486.4 [M+H]+. prepared stirring continued at rt for 2 h the reaction mixture stirred at rt overnight The solution was concentrated by evaporation under reduced pressure the pH adjusted to 9 by addition of a solution of 1 M NaHCO3 the aqueous layer extracted with dichloromethane The combined organic phases were dried over MgSO4 concentrated by evaporation under reduced pressure The crude material was purified by silica column chromatography eluting with a gradient of heptane (+1% triethylamine)/ethyl acetate

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

Procedure: To a mixture of (2-amino-4,5-difluoro-phenyl)-carbamic acid tent-butyl ester (1.00 g, 4 mmol, 1.0 equiv) and (S)-alpha-methoxyphenylacetic acid (0.68 g, 1.0 equiv., [CAS RN 26164-26-1]) in methanol (25 mL) were added cyclohexanecarbaldehyde (0.459 g, 4 mmol, 1.0 equiv; [2043-61-0]) and benzyl isonitrile (0.48 g, 1.0 equiv., 4 mmol, CAS RN 10340-91-7). The mixture was stirred overnight at room temperature. A solution of 4 M HCl in dioxane (3 mL) was added, and the reaction mixture stirred at room temperature overnight. The mixture was partitioned between water (100 ml) and ethyl acetate (100 ml). The phases were separated and the aqueous phase extracted with ethyl acetate (2×50 ml), the combined organic phases washed with brine, dried over sodium sulfate and evaporated under reduced pressure to afford the title compound as an orange gum (2.16 g, quant., mixture of diastereomers) that was used without further purification. MS (ISP): 504.1 [M+H]+. the reaction mixture stirred at room temperature overnight The mixture was partitioned between water (100 ml) and ethyl acetate (100 ml) The phases were separated the aqueous phase extracted with ethyl acetate (2×50 ml) the combined organic phases washed with brine dried over sodium sulfate evaporated under reduced pressure