1-bromo-2-isocyanatoethane

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

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: To a solution of N-(5-chloropyridin-2-yl)-2-[((4-((methylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide (0.70 g, 1.4 mmol) in THF (10 mL) at 0° C. was added 2-bromoethylisocyanate (0.63 mL, 4.2 mmol) and the mixture stirred at ambient temperature. After 30 minutes, the mixture was cooled, concentrated in vacuo and the residue dissolved in DMF (4 mL). Pyrrolidine (0.50 g, 7.0 mmol) was added. The reaction was stirred for 1 hour and poured into water and ethyl acetate. The ethyl acetate layer was dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 0.050 g of N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-(pyrrolidin-1-yl)ethyl)ureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide; NMR (DMSO-d6 /TFA) 10.9 (s, 1), 9.6 (m,1), 9.4 (s, 1), 8.3 (d, 1), 8.1 (d, 1), 7.9 (dd, 1), 7.5 (s, 1), 7.4 (s, 1), 7.3 (s, 1), 4.4 (s, 2), 3.9 (s, 3), 3.6 (m, 2), 3.4 (m, 2), 3.2 (m, 2), 3.0 (m, 2), 2.9 (s, 3), 2 (m, 2), 1.8 (m, 2) ppm. the mixture was cooled concentrated in vacuo the residue dissolved in DMF (4 mL) The reaction was stirred for 1 hour The ethyl acetate layer was dried over MgSO4 concentrated in vacuo Purification by flash chromatography on silica gel

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

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

Procedure: To a solution of N-(2-mercaptobenzoyl)-β-alaninamide (0.90 g, 4.0 mmol) in DMF (20 ml) was added 2-bromoethyl isocyanate (0.91 g, 6.0 mmol). The reaction mixture was stirred for 6 h. The solvent was evaporated to dryness, and the residue was treated with ethyl ether (20 ml) with vigorous stirring. The precipitate obtained was filtered, washed with water and dried over CaCl2. Yield: 87%. 1H NMR (DMSO-d6): 2.36 (t, 2H, CH2), 3.42 (q, 2H, CH2), 3.54 (s, 4H, 2CH2), 6.88 (brs, 1H, NH2), 7.36-7.66 (m, 5H, Ar—H, NH2), 8.26 (t, 1H, NH), 8.66 (brs, 1H, NH). The solvent was evaporated to dryness the residue was treated with ethyl ether (20 ml) with vigorous stirring The precipitate obtained was filtered washed with water dried over CaCl2

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

Procedure: To a solution of N-(2-mercaptobenzoyl)-β-alaninamide (0.90 g, 4.0 mmol) in DMF (20 ml) was added 2-bromoethyl isocyanate (0.91 g, 6.0 mmol). The reaction mixture was stirred for 6 h. The solvent was evaporated to dryness, and the residue was treated with ethyl ether (20 ml) with vigorous stirring. The precipitate obtained was filtered, washed with water and dried over CaCl2. Yield: 87%. 1H NMR (DMSO-d6): 2.36(t, 2H, CH2), 3.42(q, 2H, CH2), 3.54(s, 4H, 2CH2), 6.88(brs, 1H, NH2), 7.36-7.66(m, 5H, Ar—H, NH2), 8.26(t, 1H, NH), 8.66(brs, 1H, NH). The solvent was evaporated to dryness the residue was treated with ethyl ether (20 ml) with vigorous stirring The precipitate obtained was filtered washed with water dried over CaCl2

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

Procedure: To a solution of N-(2-mercaptobenzoyl)-β-alaninamide (0.90 g, 4.0 mmol) in DMF (20 ml) was added 2-bromoethyl isocyanate (0.91 g, 6.0 mmol). The reaction mixture was stirred for 6 h. The solvent was evaporated to dryness, and the residue was treated with ethyl ether (20 ml) with vigorous stirring. The precipitate obtained was filtered, washed with water and dried over CaCl2. Yield: 87%. 1H NMR (DMSO-d6): 2.36(t, 2H, CH2), 3.42(q, 2H, CH2), 3.54(s, 4H, 2CH2), 6.88(brs, 1H, NH2), 7.36-7.66(m, 5H, Ar—H, NH2), 8.26(t, 1H, NH), 8.66(brs, 1H, NH). The solvent was evaporated to dryness the residue was treated with ethyl ether (20 ml) with vigorous stirring The precipitate obtained was filtered washed with water dried over CaCl2

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

Procedure: To a solution of N-(5-chloropyridin-2-yl)-2-[((4-((methylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide (0.70 g, 1.4 mmol) in THF (10 mL) at 0° C. was added 2-bromoethylisocyanate (0.63 mL, 4.2 mmol) and the mixture stirred at ambient temperature. After 30 minutes, the mixture was cooled, concentrated in vacuo and the residue dissolved in DMF (4 mL). Pyrrolidine (0.50 g, 7.0 mmol) was added. The reaction was stirred for 1 hour and poured into water and ethyl acetate. The ethyl acetate layer was dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 0.050 g of N-(5-chloropyridin-2-yl)-2-[((4-((N'-methyl-N'-(2-(pyrrolidin-1-yl)ethyl)ureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide; NMR (DMSO-d6 /TFA) 10.9 (s, 1), 9.6 (m,1), 9.4 (s, 1), 8.3 (d, 1), 8.1 (d, 1), 7.9 (dd, 1), 7.5 (s, 1), 7.4 (s, 1), 7.3 (s, 1), 4.4 (s, 2), 3.9 (s, 3), 3.6 (m, 2), 3.4 (m, 2), 3.2 (m, 2), 3.0 (m, 2), 2.9 (s, 3), 2 (m, 2), 1.8 (m, 2) ppm. the mixture was cooled concentrated in vacuo the residue dissolved in DMF (4 mL) The reaction was stirred for 1 hour The ethyl acetate layer was dried over MgSO4 concentrated in vacuo Purification by flash chromatography on silica gel

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

Procedure: An ice-cooled solution of 302 mg (0.99 mmol) of the compound from Example 101A in 10 ml of dichloromethane was admixed dropwise with 99 μl (1.09 mmol) of 2-bromoethyl isocyanate. After 10 minutes, the ice bath was removed and the mixture was stirred for a further 5 min. All of the volatile components were removed on a rotary evaporator. The residue was taken up in 5 ml of anhydrous THF and admixed, with ice cooling, with 44 mg of sodium hydride (60% in mineral oil, 1.09 mmol). After 2 h, 1 ml of 1M hydrochloric acid was added and the reaction mixture was freed from the solvent on a rotary evaporator. The aqueous residue was dissolved in DMSO and purified by preparative HPLC [Method 23]. The product fraction was freed from the solvents on a rotary evaporator. Drying of the residue in an HV gave 210 mg (38% of theory) of the title compound. the ice bath was removed All of the volatile components were removed on a rotary evaporator After 2 h the reaction mixture was freed from the solvent on a rotary evaporator The aqueous residue was dissolved in DMSO purified by preparative HPLC [Method 23] The product fraction was freed from the solvents on a rotary evaporator Drying of the residue in an HV

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

Procedure: To a solution of 5.5 mg (1RS,3SR)-6-(1,1-difluoro-methoxy)-1-(3-hydroxy-phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-beta-carboline-3-carboxylic acid methyl ester in 10 ml 2-butanon are added 132 μl bromoethyl isocyanate. The mixture is heated to reflux for 30 h. An aqueous solution of sodium bicarbonate is added and the mixture is extracted with ethyl acetate. The organic layer is washed with brine and dried with magnesium sulfate. The solvent is removed at reduced pressure. After column chromatography (silica gel; toluene, ethyl acetate 4:1) and trituration with diisopropylether, 550 mg (61%) of the title compound are obtained as a colorless solid. MS: m/z (MH+)=519.9/522.0 The mixture is heated to reflux for 30 h the mixture is extracted with ethyl acetate The organic layer is washed with brine dried with magnesium sulfate The solvent is removed at reduced pressure

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of 1.66 g (5.39 mmol) (1RS,3SR)-6-Chloro-1-(3-hydroxy-phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-beta-carboline-3-carboxylic acid methyl ester in 20 ml 2-butanon are added 490 μl 2-bromoethyl isocyanate. After heating the mixture to reflux for 4 h, additional 490 μl 2-bromoethyl isocyanate are added and the mixture is heated to reflux over night. The solvent is removed at reduced pressure and the residue is dissolved in 20 ml dimethyl formamide. The mixture is stirred at 80° C. for 15 h. The solvent is removed at reduced pressure and the residue is dissolved in ethyl acetate. Water is added and the organic layer is dried with magnesium sulfate. The solvent is removed at reduced pressure and the residue is suspended in a mixture of toluene and ethyl acetate (4:1). The suspension is filtered. 1.35 g (62%) of the title compound are obtained as the precipitate. m.p.: 262-264° C., MS: m/z (MH+)=488.0/490.0 After heating the mixture to reflux for 4 h the mixture is heated to reflux over night The solvent is removed at reduced pressure the residue is dissolved in 20 ml dimethyl formamide The solvent is removed at reduced pressure the residue is dissolved in ethyl acetate Water is added the organic layer is dried with magnesium sulfate The solvent is removed at reduced pressure the residue is suspended in a mixture of toluene and ethyl acetate (4:1) The suspension is filtered