2,4-dichlorobenzenethiol

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:

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

Procedure: Sodium carbonate (13.8 g) is added to a solution of 1,2-dichloro-3-nitrobenzene (19.29 g) and 2,4-dichlorothio-phenol (17.9 g) in xylene (250 ml), and the resulting mixture is heated for 5 hours at reflux temperature. The precipitate is separated by filtration, washed with xylene and the combined organic phases are concentrated. The resultant residue is mixed with petroleum ether and stirred for 1 hour at room temperature. Following this, the crystalline material is suction filtered and washed with petroleum ether, and any remaining solvent is removed in a vacuum. Yield: 25.6 g of colourless crystals (76.6%). the resulting mixture is heated for 5 hours at reflux temperature The precipitate is separated by filtration washed with xylene the combined organic phases are concentrated The resultant residue is mixed with petroleum ether filtered washed with petroleum ether any remaining solvent is removed in a vacuum

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

Procedure: Following the procedure described in Example 11, Step A, the title compound was prepared using 2-fluoro-4-[5-(2-morpholin-4-yl-ethyl)-imidazol-1-ylmethyl]-benzonitrile (0.15 g, 0.477 mmol) and 2,4-dichlorothiophenol (0.086 g, 0.477 mmol).

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

Procedure: A mixture of 11.78 g of 2,4-dichlorothiophenol and 12.0 g of potassium hydroxide in 50 ml of acetone was stirred and heated to reflux. 11.77 g of ethyl 2-bromopropionate were added gradually and the mixture was heated under reflux for 22 hours. After cooling to room temperature, the mixture was filtered and the filtrate was evaporated to dryness. The residue was taken up in 400 ml of diethyl ether and the solution was washed with 400 ml of water and 400 ml of 10% sodium carbonate solution, dried over anhydrous sodium sulfate and evaporated to dryness. A solution of the residue in a mixture of 30 ml of ethanol and 17 ml of 10% potassium hydroxide solution was heated under reflux for 21 hours. The solution was evaporated to dryness and the residue was dissolved in 50 ml of water. The resulting solution was washed twice with 50 ml of diethyl ether each time and then acidified with concentrated hydrochloric acid and extracted twice with 150 ml of ethyl acetate each time. The combined organic extracts were washed twice with 200 ml of water each time, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was recrystallized from diethyl ether to give 4.08 g of 2(RS)-(2,4-dichlorophenyl-thio)propionic acid in the form of a yellow solid of melting point 95°-98° C. heated to reflux the mixture was heated under reflux for 22 hours the mixture was filtered the filtrate was evaporated to dryness the solution was washed with 400 ml of water and 400 ml of 10% sodium carbonate solution dried over anhydrous sodium sulfate evaporated to dryness A solution of the residue in a mixture of 30 ml of ethanol and 17 ml of 10% potassium hydroxide solution was heated under reflux for 21 hours The solution was evaporated to dryness the residue was dissolved in 50 ml of water The resulting solution was washed twice with 50 ml of diethyl ether each time extracted twice with 150 ml of ethyl acetate each time The combined organic extracts were washed twice with 200 ml of water each time dried over anhydrous sodium sulfate evaporated to dryness The residue was recrystallized from diethyl ether

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

Procedure: A mixture of 11.78 g of 2,4-dichlorothiophenol and 12.0 g of potassium hydroxide in 50 ml of acetone was stirred and heated to reflux. 11.77 g of ethyl 2-bromopropionate were added gradually and the mixture was heated under reflux for 22 hours. After cooling to room temperature, the mixture was filtered and the filtrate was evaporated to dryness. The residue was taken up in 400 ml of diethyl ether and the solution was washed with 400 ml of water and 400 ml of 10% sodium carbonate solution dried over anhydrous sodium sulfate and evaporated to dryness. A solution of the residue in a mixture of 30 ml of ethanol and 17 ml of 10% potassium hydroxide solution was heated under reflux for 21 hours. The solution was evaporated to dryness and the residue was dissolved in 50 ml of water. The resulting solution was washed twice with 50 ml of diethyl ether each time and then acidified with concentrated hydrochloric acid and extracted twice with 150 ml of ethyl acetate each time. The combined organic extracts were washed twice with 200 ml of water each time, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was recrystallized from diethyl ether to give 4.08 g of 2(RS)-(2,4-dichlorophenyl-thio)propionic acid in the form of a yellow solid of melting point 95°-98° C. heated to reflux the mixture was heated under reflux for 22 hours the mixture was filtered the filtrate was evaporated to dryness the solution was washed with 400 ml of water and 400 ml of 10% sodium carbonate solution dried over anhydrous sodium sulfate evaporated to dryness A solution of the residue in a mixture of 30 ml of ethanol and 17 ml of 10% potassium hydroxide solution was heated under reflux for 21 hours The solution was evaporated to dryness the residue was dissolved in 50 ml of water The resulting solution was washed twice with 50 ml of diethyl ether each time extracted twice with 150 ml of ethyl acetate each time The combined organic extracts were washed twice with 200 ml of water each time dried over anhydrous sodium sulfate evaporated to dryness The residue was recrystallized from diethyl ether

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

Procedure: Potassium t-butoxide (1.1 g) was added to a solution of 2,4-dichlorothiophenol (1.8 g) in N,N-dimethylformamide (DMF) (5 mL). The mixture was stirred at room temperature for 10 minutes and then 6-chloro-2H-pyridazin-3-one (1.31 g) was added. The reaction mixture was stirred at 100° C. for five hours. The mixture was then cooled to room temperature, poured into water (20 mL) and 20% potassium hydroxide (5 mL) was added. The resulting dark solution was extracted with ethyl acetate (2×10 mL). The aqueous layer was collected and the pH was adjusted to 3 with concentrated hydrochloric acid. The solution was then extracted with ethyl acetate (3×10 mL). The ethyl acetate layer was collected, dried over anhydrous sodium sulfate, filtered and evaporated to obtain a crude product, which was purified by silica gel chromatography (1:1 ethyl acetate/hexane as eluent) to afford 6-(2,4-dichloro-phenylsulfanyl)-2H-pyridazin-3-one (418 mg, 15%); NMR 6.88 (d, 1H), 7.10 (d, 1H), 7.24(dd, 1H), 7.48 (d, 1H), 7.52 (d, 1H). The reaction mixture was stirred at 100° C. for five hours The mixture was then cooled to room temperature was added The resulting dark solution was extracted with ethyl acetate (2×10 mL) The aqueous layer was collected The solution was then extracted with ethyl acetate (3×10 mL) The ethyl acetate layer was collected dried over anhydrous sodium sulfate filtered evaporated to obtain a crude product, which was purified by silica gel chromatography (1:1 ethyl acetate/hexane as eluent)

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

Procedure: The title compound was prepared by the procedures described in Example 1 substituting 2,4-dichlorothiophenol with 2-bromothiophenol, 2-chlorobenzaldehyde with 3,4-dichlorobenzaldehyde, and 6-amino-1-hexanol with 1-(3-aminopropyl)-2-pyrrolidinone. 1H-NMR (DMSO-d6, 300 MHz) δ 8.12 (t, J=5.9 Hz, 1H), 7.81 (m, 2H), 7.52 (dd, J=8.1, 2.0 Hz, 1H), 7.44 (dt, J=7.5, 1.4, 1H), 7.34 (dt, J=7.5, 2.0, 1H), 7.39 (d, J=15.8 Hz, 1H), 7.28 (dd, J=7.6, 1.9 Hz, 1H), 7.05 (d, J=8.1 Hz, 1H), 6.67 (d, J=15.8 Hz, 1H), 4.02 (d, J=0.7 Hz, 1H), 3.29-3.35 (m, 2H), 3.11-3.25 (m, 4H), 2.21 (t, J=8.1 Hz, 1H), 1.94 (m, 2H), 1.64 (m, 2H), MS(APCI) (M+H)+ at mV/z 493, 495, 497, 499.

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

Procedure: (2-Bromophenyl)[2-chloro-4-(2-carboxy-E-ethenyl)phenyl]sulfide was prepared by the procedures described in Example 1 substituting 2,4 dichlorothiophenol with 2-bromothiophenol, 2-chlorobenzaldehyde with 3,4 dichlorobenzaldehyde. 1-(3-aminopropyl)-5-((S)-thexyldimethylsilyloxymethyl)-2-pyrrolidinone (0.2818 g, 0.8959 mmol) was added to a solution of this cinnamic acid (0.3312 g, 0.8959 mmol), 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride (0.3435 g, 1.79 mmol), and 1-hydroxybenzotriazole hydrate (0.1816 g, 1.34 mmol) in DMF (4.0 mL). After stirring for 12 hours the reaction mixture was diluted with EtOAc (250 mL), extracted with sat. NH4Cl (1×75 mL), extracted with H2O (2×75 mL), rinsed with brine (75 mL), and dried over Na2SO4. The resultant thexyldimethylsilyl alcohol was purified by flash chromatography (EtOAc) on silica gel (0.4974 g, 83%). Tetrabutylammonium fluoride (0.68 mL of 1.0 M solution in THF) was added dropwise to a solution of this protected alcohol (0.4544 g, 0.682 mmol) in THF (1.7 mL). After 2 hours the reaction was diluted with EtOAc (50 mL) and extracted with sat. NH4Cl (1×25 mL), extracted with H2O (2×25 mL), rinsed with brine (25 mL), and dried over Na2SO4. Flash chromatography (EtOAc →9:1 CH2Cl2:MeOH) on silica gel yielded the title compound (0.3144 g, 88%). 1H-NMR (DMSO-d6, 300 MHz) δ 8.14 (t, J=5.5 Hz, 1H), 7.81 (m, 2H), 7.53 (dd, J=8.3, 1.7 Hz, 1H), 7.44 (dt, J=7.7, 1.5, 1H), 7.40 (dt, J=7.7, 1.8, 1H), 7.39 (d, J=15.6 Hz, 1H), 7.28 (dd, J=7.7, 1.8 Hz, 1H), 7.05 (d, J=8.1 Hz, 1H), 6.67 (d, J=15.6 Hz, 1H), 4.84 (t, J=5.1 Hz, 1H), 2.94-3.62 (m, 8H), 1.54-2.29 (m, 6H), MS(APCI) (M+H)+ at m/z 523, 525, 527, 529. extracted with sat. NH4Cl (1×75 mL) extracted with H2O (2×75 mL) rinsed with brine (75 mL) dried over Na2SO4 The resultant thexyldimethylsilyl alcohol was purified by flash chromatography (EtOAc) on silica gel (0.4974 g, 83%) extracted with sat. NH4Cl (1×25 mL) extracted with H2O (2×25 mL) rinsed with brine (25 mL) dried over Na2SO4

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

Procedure: (2-Bromophenyl)[2-chloro-4-(2-carboxy-E-ethenyl)phenyl]sulfide was prepared by the procedures described in Example 1 substituting 2,4 dichlorothiophenol with 2-bromothiophenol, 2-chlorobenzaldehyde with 3,4 dichlorobenzaldehyde. 1-(3-aminopropyl)-5-((S)-thexyldimethylsilyloxymethyl)-2-pyrrolidinone (0.2818 g, 0.8959 mmol) was added to a solution of this cinnamic acid (0.3312 g, 0.8959 mmol), 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride (0.3435 g, 1.79 mmol), and 1-hydroxybenzotriazole hydrate (0.1816 g, 1.34 mmol) in DMF (4.0 mL). After stirring for 12 hours the reaction mixture was diluted with EtOAc (250 mL), extracted with sat. NH4Cl (1×75 mL), extracted with H2O (2×75 mL), rinsed with brine (75 mL), and dried over Na2SO4. The resultant thexyldimethylsilyl alcohol was purified by flash chromatography (EtOAc) on silica gel (0.4974 g, 83%). Tetrabutylammonium fluoride (0.68 mL of 1.0 M solution in THF) was added dropwise to a solution of this protected alcohol (0.4544 g, 0.682 mmol) in THF (1.7 mL). After 2 hours the reaction was diluted with EtOAc (50 mL) and extracted with sat. NH4Cl (1×25 mL), extracted with H2O (2×25 mL), rinsed with brine (25 mL), and dried over Na2SO4. Flash chromatography (EtOAc →9:1 CH2Cl2:MeOH) on silica gel yielded the title compound (0.3144 g, 88%). 1H-NMR (DMSO-d6, 300 MHz) δ 8.14 (t, J=5.5 Hz, 1H), 7.81 (m, 2H), 7.53 (dd, J=8.3, 1.7 Hz, 1H), 7.44 (dt, J=7.7, 1.5, 1H), 7.40 (dt, J=7.7, 1.8, 1H), 7.39 (d, J=15.6 Hz, 1H), 7.28 (dd, J=7.7, 1.8 Hz, 1H), 7.05 (d, J=8.1 Hz, 1H), 6.67 (d, J=15.6 Hz, 1H), 4.84 (t, J=5.1 Hz, 1H), 2.94-3.62 (m, 8H), 1.54-2.29 (m, 6H), MS(APCI) (M+H)+ at m/z 523, 525, 527, 529. extracted with sat. NH4Cl (1×75 mL) extracted with H2O (2×75 mL) rinsed with brine (75 mL) dried over Na2SO4 The resultant thexyldimethylsilyl alcohol was purified by flash chromatography (EtOAc) on silica gel (0.4974 g, 83%) extracted with sat. NH4Cl (1×25 mL) extracted with H2O (2×25 mL) rinsed with brine (25 mL) dried over Na2SO4