4,5-dichlorobenzene-1,2-diamine

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

Procedure: To the solution of 4,5-dichloro-benzene-1,2-diamine (25 g, 0.14 mol) in dry DMF (200 mL), was added CU (23 g, 0.14 mol) as the solid. The reaction solution was stirred at room temperature for 1 hour, then water (500 mL) was added. The precipitated solid was collected by filtration, washed with water, dried thoroughly to afford the titled compound (26.0 g, 90%). The crude product was used in the following reaction without further purification. The precipitated solid was collected by filtration washed with water dried thoroughly

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4,5-dichlorobenzene-1,2-diamine (1.0 g, 5.65 mmol), ethyl 2-oxo-2-(thiophen-2-yl)acetate (1.056 g, 5.73 mmol) and ethanol (8 ml) was stirred at 70° C. for 11 h, cooled to room temperature, filtered and washed with cold ethanol. The collected pale yellow solid was dried further (1.07 g) and used directly in next step. cooled to room temperature filtered washed with cold ethanol The collected pale yellow solid was dried further (1.07 g)

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

Procedure: 4,5-Dichloro-1,2-phenylenediamine (6.04 g, 34.1 mmol), cyclopropyl isothiocyanate (3.69 g, 37.2 mmol), 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate (20.1 g, 47.4 mmol) and pyridine (135 mL) were used according to general procedure I. The product was recrystallized from acetonitrile to afford 5.82 g (70%) of a yellow solid; m.p. 223-225° C. Anal. Calcd for C10H9Cl2N3: C, 49.61; H, 3.75; N, 17.36. Found: C, 49.53; H, 3.78; N, 17.12. The product was recrystallized from acetonitrile

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

Procedure: To a solution of 4,5-dichlorobenzene-1,2-diamine (3.0 g, 0.017 mol) and triethylamine (9.45 mL, 0.068 mol) in dichloromethane (120 mL) was added SOCl2 (4.92 mL, 0.068 mol) dropwise at room temperature. The resulting reaction mixture was heated to reflux for 20 h. The reaction mixture was then allowed to cool to room temperature, and quenched with water carefully. The resulting mixture was extracted with dichloromethane, dried over Na2SO4 and concentrated on a rotary evaporator to give a dark solid as the crude compound. The crude compound was purified by flash column chromatography (silica gel, CHCl3) to afford 5,6-dichlorobenzo[1,2,5]thiadiazole as an off-white crystalline solid (2.35 g, 68% yield). 1H NMR (CDCl3 500 MHz): δ: 8.19 (t, 2H, J=8.5 Hz). 13C NMR (CDCl3, 500 MHz): δ 153.07, 135.28, 121.51. Anal. calcd. for (C6H2Cl2N2S): C, 35.14; H, 0.98; N, 13.66. Found: C, 35.08; H, 1.01; H, 13.56. m.p: 108-110° C. The resulting reaction mixture was heated to reflux for 20 h quenched with water carefully The resulting mixture was extracted with dichloromethane dried over Na2SO4 concentrated on a rotary evaporator to give a dark solid as the crude compound The crude compound was purified by flash column chromatography (silica gel, CHCl3)

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 0.3 ml of 47% potassium hydroxide and 160 mmol of methyl acetoacetate in 20 ml of xylene are successively added to 150 mmol of 2-amino-4,5-dichloroaniline in 50 ml of xylene, stirred at 120° C. The whole mixture is brought to reflux for 4 hours, the water/methanol mixture formed being removed by means of a Dean and Stark apparatus. After addition of 26 ml of 47% potassium hydroxide and 17 ml of water, the aqueous phase is washed with xylene and then neutralized with acetic acid. The expected product crystallizes and is filtered off, washed and dried. to reflux for 4 hours being removed by means of a Dean and Stark apparatus After addition of 26 ml of 47% potassium hydroxide and 17 ml of water the aqueous phase is washed with xylene The expected product crystallizes is filtered off washed dried

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 0.3 ml of 47% potassium hydroxide and 160 mmol of methyl acetoacetate in 20 ml of xylene are successively added to 150 mmol of 2-amino-4,5-dichloroaniline in 50 ml of xylene, stirred at 120° C. The whole mixture is brought to reflux for 4 hours, the water/methanol mixture formed being removed by means of a Dean and Stark apparatus. After addition of 26 ml of 47% potassium hydroxide and 17 ml of water, the aqueous phase is washed with xylene and then neutralized with acetic acid. The expected product crystallizes and is filtered off, washed and dried. to reflux for 4 hours being removed by means of a Dean and Stark apparatus After addition of 26 ml of 47% potassium hydroxide and 17 ml of water the aqueous phase is washed with xylene The expected product crystallizes is filtered off washed dried

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: An adaptation of the method of Burrell et al., J. Chem. Soc. Perkin I. 2707 (1973), was used. A mixture of 4,5-dichloro-1,2-phenylenediamine (354 mg, 2.00 mmol; Aldrich Co.) and ethyl thiooxamate (333 mg, 2.50 mmol; Aldrich Co.) in 5 mL of ethanol was heated to reflux. The resulting brown solution was stirred under reflux for 10 h. The resulting brown suspension was cooled down to 25° C. A brown precipitate appeared. The mixture was vacuum filtered and the brown solid was washed with EtOH (5×2 mL) and dried in vacuum at 60° C. overnight to yield 92 mg (20%) of 6,7-dichloro-3-aminoquinoxalin-2(1H)-one: mp dec.>350° C. 1H NMR (300 MHz, DMSO-d6) δ 12.261 (br s, 1H, NH), 7.421 (s, 1H, H-5), 7.252 (s, 1H, H-8). Mass: calcd. for C8H5Cl2N3O (M+) M/z 228.9810, found 228.9820. was heated to reflux under reflux for 10 h filtered the brown solid was washed with EtOH (5×2 mL) dried in vacuum at 60° C. overnight

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

Procedure: A mixture of 528 mg (2.98 mmol) of 4,5-dichloro-1,2-phenylenediamine and 448 mg (2.98 mmol) of benzoylformic acid in 8 mL of ethanol was refluxed overnight. It was filtered, washed by water, and dried to leave 760 mg (87%) of solid. 1H NMR (DMSO-d6), 7.465-7.536 (m, 4), 8.088 (s, 1), 8.256-8.282 (m, 2) 12.683 (s, 1). was refluxed overnight It was filtered washed by water dried

Conditions: temp:135.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4,5-Dichlorobenzene-1,2-diamine (5.018 g, 28.4 mmol) was dissolved in HCl solution (4 M solution) (25 ml) at r.t. and delta-valerolactone (5.3 ml, 56.7 mmol) was added slowly. The reaction was heated to 135° C. for 2 hrs then slowly cooled to r.t. The reaction was quenched by the addition of sat. NaHCO3 solution (200 ml) until the pH was 8. The mixture was extracted with EtOAc (3×100 ml) and the combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to give the crude product as a brown solid which was triturated with ether (100 ml) to give the pure product as a purple solid (6.383 g, 87%): MS (ESI+) for C11H12Cl2N2O m/z 259.1 [M+H]+; LC purity 89% (ret. time, 1.23 min); 1H NMR (500 MHz, CDCl3) δ 7.56 (s, 2H), 3.55 (t, J=6.38 Hz, 2H), 2.86 (t, J=7.57 Hz, 2H), 1.84 (quin, J=7.68 Hz, 2H), 1.43-1.69 (m, 2H). then slowly cooled to r.t The reaction was quenched by the addition of sat. NaHCO3 solution (200 ml) until the pH was 8 The mixture was extracted with EtOAc (3×100 ml) the combined organic layers were dried over MgSO4 filtered concentrated in vacuo to give the crude product as a brown solid which was triturated with ether (100 ml)

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

Procedure: To a solution of 4,5-dichlorobenzene-1,2-diamine (3.0 g, 0.017 mol) and triethylamine (9.45 mL, 0.068 mol) in dichloromethane (120 mL) was added SOCl2 (4.92 mL, 0.068 mol) dropwise at room temperature. The resulting reaction mixture was heated to reflux for 20 h. The reaction mixture was then allowed to cool to room temperature, and quenched with water carefully. The resulting mixture was extracted with dichloromethane, dried over Na2SO4 and concentrated on a rotary evaporator to give a dark solid as the crude compound. The crude compound was purified by flash column chromatography (silica gel, CHCl3) to afford 5,6-dichlorobenzo[1,2,5]thiadiazole as an off-white crystalline solid (2.35 g, 68% yield). 1H NMR (CDCl3 500 MHz): δ: 8.19 (t, 2H, J=8.5 Hz). 13C NMR (CDCl3, 500 MHz): δ 153.07, 135.28, 121.51. Anal. calcd. for (C6H2Cl2N2S): C, 35.14; H, 0.98; N, 13.66. Found: C, 35.08; H, 1.01; H, 13.56. m.p: 108-110° C. The resulting reaction mixture was heated to reflux for 20 h quenched with water carefully The resulting mixture was extracted with dichloromethane dried over Na2SO4 concentrated on a rotary evaporator to give a dark solid as the crude compound The crude compound was purified by flash column chromatography (silica gel, CHCl3)

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

Procedure: Triethyl orthoacetate (4.6 g, 1 eq) was added drop wise to a refluxing mixture of 4,5-dichloro-1,2-phenylenediamine (5 g, 1 eq) and a catalytic amount of p-toluenesulfonic acid in toluene (40 mL). The mixture was refluxed for 3 hrs and 5.7 g black solid was collected after evaporation of the solvents under reduced pressure and used directly in the following step without further purification. ESI-MS (m/z) calcd (found): 200.0 (201.1) for [M+H]+. To the crude 5,6-dichloro-2-methyl-benzoimidazole (5.7 g, 1 eq) (see FIG. 9) and grinded potassium hydroxide (4.8 g, 3 eq) in acetone (50 mL) was added iodomethane (5.2 g, 1.4 eq) drop wise and the mixture was stirred overnight. The solvent was evaporated under reduced pressure and the residue was partitioned between dichloromethane (200 mL) and water (200 mL). The aqueous phase was washed two times with dichloromethane (200 mL) and the combined organic phase was dried over Na2SO4 and evaporated to dryness. The crude product was recrystallized from ethyl acetate. 5.5 g product was collected as pale flakes with 90.6% yield for two steps. 1H NMR: (CDCl3) 2.55 (s, 3H), 3.63 (s, 3H), 7.28 (s, 1H), 7.68 (s, 1H). 13C NMR: (CDCl3): 13.82, 30.05, 110.20, 120.00, 125.58, 125.75, 134.97, 141.83, 153.93. ESI-MS (m/z) calcd (found): 214.0 (215.1) for [M+H]+. The mixture was refluxed for 3 hrs 5.7 g black solid was collected after evaporation of the solvents under reduced pressure used directly in the following step without further purification The solvent was evaporated under reduced pressure the residue was partitioned between dichloromethane (200 mL) and water (200 mL) The aqueous phase was washed two times with dichloromethane (200 mL) the combined organic phase was dried over Na2SO4 evaporated to dryness The crude product was recrystallized from ethyl acetate 5.5 g product was collected as pale flakes with 90.6% yield for two steps

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

Procedure: The compound was prepared in a manner analogous to 2,6-dichloro-N-[3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide (Example 94E), however using 4-(2,6-difluoro-benzoylamino)-1H-pyrazole-3-carboxylic acid (Example 16D) and 4,5-dichloro-1,2-phenylene diamine to give N-[3-(5,6-dichloro-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-2,6-difluoro-benzamide (29 mg) as a beige solid. (LC/MS: Rt 3.53, [M+H]+ 408.02).