diethyl propanediimidate;dihydrochloride

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

Procedure: To a cooled mixture of 5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazole-3-carboxylic acid (3.71 g, 10.0 mmol), diethyl ether and N,N-dimethylformamide (3.0 ml) is added oxalyl chloride (1.52 g, 12.0 mmol). The mixture is allowed to warm to room temperature and stirred overnight. The mixture is allowed to settle and the supernatant is decanted and concentrated in vacuo. The residue is taken up in methylene chloride and added dropwise to a stirred mixture of diethyl malonimidate dihydrochloride (2.31 g, 10.0 mmol), diisopropylethylamine (10 ml) and methylene chloride at −40° C. over one hour. The resultant mixture is allowed to warm to room temperature, diluted with methylene chloride, washed with water, 10% aqueous hydrochloric acid and water, dried over anhydrous magnesium sulfate and concentrated in vacuo to afford the title compound as a white solid (0.410 g, 8.31%, mp 197-200° C.) which is identified by NMR spectral analysis. the supernatant is decanted concentrated in vacuo to warm to room temperature washed with water, 10% aqueous hydrochloric acid and water dried over anhydrous magnesium sulfate concentrated in vacuo

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

Procedure: To a cooled mixture of 5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazole-3-carboxylic acid (3.71 g, 10.0 mmol), diethyl ether and N,N-dimethylformamide (3.0 ml) is added oxalyl chloride (1.52 g, 12.0 mmol). The mixture is allowed to warm to room temperature and stirred overnight. The mixture is allowed to settle and the supernatant is decanted and concentrated in vacuo. The residue is taken up in methylene chloride and added dropwise to a stirred mixture of diethyl malonimidate dihydrochloride (2.31 g, 10.0 mmol), diisopropylethylamine (10 ml) and methylene chloride at −40° C. over one hour. The resultant mixture is allowed to warm to room temperature, diluted with methylene chloride, washed with water, 10% aqueous hydrochloric acid and water, dried over anhydrous magnesium sulfate and concentrated in vacuo to afford the title compound as a white solid (0.410 g, 8.31%, mp 197-200° C.) which is identified by NMR spectral analysis. the supernatant is decanted concentrated in vacuo to warm to room temperature washed with water, 10% aqueous hydrochloric acid and water dried over anhydrous magnesium sulfate concentrated in vacuo

Conditions: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Triethylamine (6 ml) was added over 5 minutes to a stirred suspension of diethyl malonimidate dihydrochloride (5 g) in ethanol (50 ml). Phenylhydrazine (2.1 ml) was added, then the mixture was stirred at ambient temperature for 4 hours and at 95° C. for 30 minutes. The solvent was removed in vacuo, and the residue was partitioned between ethyl acetate (100 ml) and water (50 ml). The organic layer was separated, washed with water (50 ml), dried (MgSO4), and the solvent was removed in vacuo. The residue was purified by flash chromatography over silica using a 19:1 mixture of dichloromethane and methanol as eluant, appropriate fractions were combined, and the solvents were removed in vacuo to give 3,5-diamino-1-phenylpyrazole as a red-brown oil (0.76 g). The solvent was removed in vacuo the residue was partitioned between ethyl acetate (100 ml) and water (50 ml) The organic layer was separated washed with water (50 ml) dried (MgSO4) the solvent was removed in vacuo The residue was purified by flash chromatography over silica using a 19:1 mixture of dichloromethane and methanol as eluant the solvents were removed in vacuo

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

Procedure: The following components were reacted according to General Procedure 1, above: 3-nitro-1,2-phenylenediamine (0.50 g; 3.26 mmoles) 2,3-diaminobenzoic acid (0.40 g; 3.26 mmoles), diethyl malonimidate dihydrochloride (1.1 eq.; 0.83 g; 3.60 mmoles) and acetic acid (25 mL). The crude mixture of three compounds was then reduced according to General Procedure 2, above. The crude solid was taken up in 10 mL of dilute HCl, purified by preparative HPLC (2 to 40% acetonitrile (with 0.1% TFA) over 60 minutes) and converted to the HCl salt by three freeze drying cycles with dilute HCl. This procedure gave 0.103 g of pure 2-[(4-amino-1H-benzimidazol-2-yl)methyl]-1H-benzimidazole-4-carboxylic acid dihydrochloride in 8% yield. It had MS: m/z=308.2 [M+1] amu and gave one peak on HPLC at both 210 and 280 nm (10.20 minutes using the JWTFACN gradient). The following components were reacted The crude mixture of three compounds purified by preparative HPLC (2 to 40% acetonitrile (with 0.1% TFA) over 60 minutes) drying cycles with dilute HCl

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

Procedure: The following components were reacted according to General Procedure 1, above: 3-nitro-1,2-phenylenediamine (0.50 g; 3.26 mmoles) 3,4-diaminobenzoic acid (0.40 g; 3.26 mmoles), diethyl malonimidate dihydrochloride (1.1 eq.; 0.83 g; 3.60 mmoles) and acetic acid (25 mL). The crude mixture of three compounds was then reduced according to General Procedure 2, above. The crude solid product was taken up in 10 mL of dilute HCl, purified by preparative HPLC (2 to 40% acetonitrile (with 0.1% TFA) over 60 minutes) and converted to the HCl salt by three freeze drying cycles with dilute HCl. This procedure gave 0.213 g of pure 2-[(4-amino-1H-benzimidazol-2-yl)methyl]-1H-benzimidazole-5-carboxylic acid dihydrochloride in 17% yield. It had MS: m/z=308.2 [M+1] amu and gave one peak on HPLC at both 210 and 280 nm (10.20 minutes using the JWTFACN gradient). The following components were reacted The crude mixture of three compounds purified by preparative HPLC (2 to 40% acetonitrile (with 0.1% TFA) over 60 minutes) drying cycles with dilute HCl

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

Procedure: The following components were reacted according to General Procedure 1, above: 3-nitro-1,2-phenylenediamine (0.5 g; 3.26 mmoles), 3-methyl-1,2-phenylenediamine (0.4 g; 3.26 mmoles), diethyl malonimidate dihydrochloride (1.1 eq.; 0.83 g; 3.60 mmoles) and acetic acid (25 mL). The crude mixture of three compounds was then reduced according to General Procedure 2, above. The crude solid product was taken up in 10 mL of dilute HCl, purified by preparative HPLC (15 to 75% acetonitrile (with 0.1% TFA) over 60 minutes) and converted to the HCl salt by three freeze drying cycles with dilute HCl. This procedure gave 0.42 g of pure 2-[(4-methyl-1H-benzimidazol-2-yl)methyl]-1H-benzimidazol-4-ylamine dihydrochloride in 37% yield. It had MS: m/z=278.2 [N+1] amu and gave one peak on HPLC at both 210 and 280 nm (12.01 minutes using the JWTFACN gradient). The following components were reacted The crude mixture of three compounds purified by preparative HPLC (15 to 75% acetonitrile (with 0.1% TFA) over 60 minutes) drying cycles with dilute HCl

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

Procedure: The following components were reacted according to General Procedure 1, above: 3-nitro-1,2-phenylenediamine (0.50 g; 3.26 mmoles), 3-fluoro-1,2-phenylenediamine (0.41 g; 3.26 mmoles), diethyl malonimidate dihydrochloride (1.1 eq.; 0.83 g; 3.60 mmoles) and acetic acid (25 mL). The crude mixture of three compounds was then reduced according to General Procedure 2, above. The crude solid product was taken up in 10 mL of dilute HCl, purified by preparative HPLC (25 to 75% acetonitrile (with 0.1% TFA) over 50 minutes) and converted to the HCl salt by three freeze drying cycles with dilute HCl. This procedure gave 0.208 g of pure 2-[(4-fluoro-1H-benzimidazol-2-yl)methyl]-1H-benzimidazol-4-ylamine dihydrochloride in 18% yield. It had MS: m/z=282.2 [M+1] amu and gave one peak on HPLC at both 210 and 280 nm (12.99 minutes using the JWTFACN gradient). The following components were reacted The crude mixture of three compounds purified by preparative HPLC (25 to 75% acetonitrile (with 0.1% TFA) over 50 minutes) drying cycles with dilute HCl

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

Procedure: To a flame-dried 100 mL round-bottom flask equipped with a stir bar and a reflux condenser were added 4-chloro-1,2-phenylenediamine (1 g; 7.0 mmoles), 3-nitro-1,2-phenylenediamine (1.07 g; 7.0 mmoles), diethyl malonimidate dihydrochloride (1.62 g; 7.0 mmoles) and ultra pure acetic acid (ca. 35 mL; from Aldrich) under a nitrogen atmosphere. The mixture was refluxed for 2 hours and then cooled to room temperature, and the acetic acid was removed (via roto-vap). The residue was suspended and sonicated (ca. 5 minutes) in 0.5 M HCl, and the remaining precipitate was removed by filtration and dried (P2O5 and high-vacuum). This procedure gave 0.8 g of the desired 2-[(5-chloro-1H-benzimidazol-2-yl)methyl]4-nitro-1H-benzimidazole as a dark brown solid in 35% yield. It gave one major peak by HPLC and had mass spec (FB+): m/z=328.0 [M+]. To a flame-dried 100 mL round-bottom flask equipped with a stir bar and a reflux condenser The mixture was refluxed for 2 hours the acetic acid was removed (via roto-vap) sonicated (ca. 5 minutes) in 0.5 M HCl the remaining precipitate was removed by filtration dried (P2O5 and high-vacuum)

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

Procedure: To a cooled mixture of 5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazole-3-carboxylic acid (3.71 g, 10.0 mmol), diethyl ether and N,N-dimethylformamide (3.0 ml) is added oxalyl chloride (1.52 g, 12.0 mmol). The mixture is allowed to warm to room temperature and stirred overnight. The mixture is allowed to settle and the supernatant is decanted and concentrated in vacuo. The residue is taken up in methylene chloride and added dropwise to a stirred mixture of diethyl malonimidate dihydrochloride (2.31 g, 10.0 mmol), diisopropylethylamine (10 ml) and methylene chloride at −40° C. over one hour. The resultant mixture is allowed to warm to room temperature, diluted with methylene chloride, washed with water, 10% aqueous hydrochloric acid and water, dried over anhydrous magnesium sulfate and concentrated in vacuo to afford the title compound as a white solid (0.410 g, 8.31%, mp 197-200° C.) which is identified by NMR spectral analysis. the supernatant is decanted concentrated in vacuo to warm to room temperature washed with water, 10% aqueous hydrochloric acid and water dried over anhydrous magnesium sulfate concentrated in vacuo