1,2-dibromopropane

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

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

Procedure: A solution of 12.6 g of (2-trifluoromethyl-phenyl)-acetonitrile and 7.6 ml of 1,2-dibromopropane in 36 ml ether were added slowly through a dropping funnel to a suspension of 3.62 g of sodium hydride in 85 ml DMSO at 0° C. After addition, the ice-water bath was allowed to warm up to room temperature slowly and the reaction mixture was stirred at room temperature overnight. The reaction was carefully quenched with isopropyl and H2O. The suspension became clear. The organic layer was separated, and the aqueous layer was extracted twice with ether. The combined organic extracts were combined, dried and concentrated by evaporation in a vacuum. The residue was purified by column chromatography on silica-gel (EtOAc-hexane 2%-4%) to yield 8.5 g of product as a white solid. After addition The reaction was carefully quenched with isopropyl and H2O The organic layer was separated the aqueous layer was extracted twice with ether dried concentrated by evaporation in a vacuum The residue was purified by column chromatography on silica-gel (EtOAc-hexane 2%-4%)

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

Procedure: A solution of 12.6 g of (2-trifluoromethyl-phenyl)-acetonitrile and 7.6 ml of 1,2-dibromopropane in 36 ml ether were added slowly through a dropping funnel to a suspension of 3.62 g of sodium hydride in 85 ml DMSO at 0° C. After addition, the ice-water bath was allowed to warm up to room temperature slowly and the reaction mixture was stirred at room temperature overnight. The reaction was carefully quenched with isopropyl and H2O. The suspension became clear. The organic layer was separated, and the aqueous layer was extracted twice with ether. The combined organic extracts were combined, dried and concentrated by evaporation in a vacuum. The residue was purified by column chromatography on silica-gel (EtOAc-hexane 2%-4%) to yield 8.5 g of product as a white solid. After addition The reaction was carefully quenched with isopropyl and H2O The organic layer was separated the aqueous layer was extracted twice with ether dried concentrated by evaporation in a vacuum The residue was purified by column chromatography on silica-gel (EtOAc-hexane 2%-4%)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirring solution of 4-iodophenol (15 g, 70 mmol) and K2CO3 (12.4 g, 90 mmol) in DMF (30 mL) was added 1,2-dibromopropane (7.8 mL, 90 mmol) over a period of 1 hr. The solution was heated at 50° C. and stirred overnight under Ar. Water (500 mL) was added and the reaction mixture was extracted with dichloromethane, dried over Na2SO4, filtered and the solvent evaporated under reduced pressure. Purified on silica gel chromatography, eluted with 10% ethyl acetate in hexanes to give the title compound as a white solid (10 g, 29 mmol). the reaction mixture was extracted with dichloromethane dried over Na2SO4 filtered the solvent evaporated under reduced pressure Purified on silica gel chromatography eluted with 10% ethyl acetate in hexanes

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-(4-(2-Isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (C34a)(0.16 g, 0.42 mmol), 1-(2-ethyl-5-methylphenyl)thiourea (CA41) (0.081 g, 0.42 mmol), and cesium carbonate (0.13 g, 0.39 mmol) in acetonitrile (1.9 mL) was stirred at room temperature for 3 hours. The reaction was diluted with butanone (2 mL) and potassium carbonate (0.12 g, 0.83 mmol) and 1,2-dibromopropane (0.090 mL, 0.83 mmol) were added. The reaction was heated to 60° C. for 6 hours. The reaction was diluted with water and extracted with dichloromethane (2×) and the organic layers were filtered through a phase separator and concentrated. Purification by flash column chromatography using 0-100% ethyl acetate/B, where B=1:1 dichloromethane/hexanes, as eluent provided the title compound as a yellow oil (0.034 g, 13%). were added extracted with dichloromethane (2×) the organic layers were filtered through a phase separator concentrated Purification by flash column chromatography

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-(4-(2-Isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (C34a)(0.16 g, 0.42 mmol), 1-(2-ethyl-5-methylphenyl)thiourea (CA41) (0.081 g, 0.42 mmol), and cesium carbonate (0.13 g, 0.39 mmol) in acetonitrile (1.9 mL) was stirred at room temperature for 3 hours. The reaction was diluted with butanone (2 mL) and potassium carbonate (0.12 g, 0.83 mmol) and 1,2-dibromopropane (0.090 mL, 0.83 mmol) were added. The reaction was heated to 60° C. for 6 hours. The reaction was diluted with water and extracted with dichloromethane (2×) and the organic layers were filtered through a phase separator and concentrated. Purification by flash column chromatography using 0-100% ethyl acetate/B, where B=1:1 dichloromethane/hexanes, as eluent provided the title compound as a yellow oil (0.034 g, 13%). were added extracted with dichloromethane (2×) the organic layers were filtered through a phase separator concentrated Purification by flash column chromatography

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

Procedure: 1,2-Bis(4'-methoxyphenyl-amino)-propane, applied as starting substance, is obtained with a yield of 32.7% by reacting 4-methoxyaniline with 1,2-dibromopropane as described by McKay and Tarlton (loc. cit.). The compound melts at 82°-84° C. is obtained with a yield of 32.7%

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

Procedure: Methyl-2-thiophenecarbodithioate (47 g, 0.27 mol) in methanol (250 ml) at 0-5° C., was stirred and treated with powdered hydroxylamine hydrochloride (20 g) and followed by dropwise addition of triethylamine (50 ml) in methanol (50 ml) over 2 hours, to prepare a reaction mixture. Additional hydroxylamine hydrochloride (5 g) and triethylamine (10 ml) was added consecutively to the reaction mixture and after 45 minutes, the reaction mixture turned yellow (from red). 1,2-Dibromopropane (26 ml) was then added to the yellow reaction mixture, followed by addition of triethylamine (75 ml). The resultant new reaction mixture was refluxed for 4 hours and then left overnight at ambient temperature. The methanol was removed from the reaction mixture to leave a residue. Water was added to the residue which was then extracted into ethyl acetate, washed with dilute hydrochloric acid (2N, 100 ml), water, and dried (MgSO4). The ethyl acetate was then removed to leave a brown oil which was crystallized with cyclohexane to produce two crops of 5,6-dihydro-6-methyl-3-(2-thienyl)-1,4,2-oxadiazine (11.7 g and 3.7 g, mp 70-72° C.) Found: C 48.90, H 4.66, N 7.17, C8H9NOS2 requires C 48.24, H 4.52, N 7.07 to prepare a reaction mixture The resultant new reaction mixture was refluxed for 4 hours The methanol was removed from the reaction mixture to leave a residue was then extracted into ethyl acetate washed with dilute hydrochloric acid (2N, 100 ml), water dried (MgSO4) The ethyl acetate was then removed to leave a brown oil which was crystallized with cyclohexane

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

Procedure: A solution of isopropylmagnesium chloride [prepared by the reaction of magnesium (2.4 g) and 2-chloropropane (10 ml) in tetrahydrofuran (30 ml)] was added dropwise under argon at -20° C. to a solution of 3-chloropropan-1-ol (9.45 g) in tetrahydrofuran (100 ml). Magnesium (3.6 g) was added and the mixture was allowed to stand for twenty minutes and was then heated under reflux in the presence of 1,2-dibromopropane for 40 minutes. 1-(4-Chlorophenyl)cyclobutanecarbonitrile (8 g) was added and the mixture was heated under reflux for 16 hours. The mixture was cooled and the supernatant liquid decanted from excess magnesium metal and treated with sodium borohydride (3 g) and propan-2-ol (100 ml). The mixture was heated under reflux for 5 hours. The reaction mixture was cooled, added to water and excess concentrated hydrochloric acid was added. The resulting solution was washed with toluene, basified and extracted with toluene. The extracts were dried and evaporated to give a residue which was distilled in a Buchi Kugelrohr apparatus (140°/0.4 mm) to give 4-amino-4-[1-(4-chlorophenyl)-cyclobutyl]butan-1-ol. to stand for twenty minutes was then heated the mixture was heated under reflux for 16 hours The mixture was cooled the supernatant liquid decanted from excess magnesium metal treated with sodium borohydride (3 g) and propan-2-ol (100 ml) The mixture was heated under reflux for 5 hours The reaction mixture was cooled added to water and excess concentrated hydrochloric acid was added The resulting solution was washed with toluene extracted with toluene The extracts were dried evaporated to give a residue which was distilled in a Buchi Kugelrohr apparatus (140°/0.4 mm)

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

Procedure: 3-(4-(2-Isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (C34a)(0.16 g, 0.42 mmol), 1-(2-ethyl-5-methylphenyl)thiourea (CA41) (0.081 g, 0.42 mmol), and cesium carbonate (0.13 g, 0.39 mmol) in acetonitrile (1.9 mL) was stirred at room temperature for 3 hours. The reaction was diluted with butanone (2 mL) and potassium carbonate (0.12 g, 0.83 mmol) and 1,2-dibromopropane (0.090 mL, 0.83 mmol) were added. The reaction was heated to 60° for 6 hours. The reaction was diluted with water and extracted with dichloromethane (2×) and the organic layers were filtered through a phase separator and concentrated. Purification by flash column chromatography using 0-100% ethyl acetate/B, where B=1:1 dichloromethane/hexanes, as eluent provided the title compound as a yellow oil (0.034 g, 13%). were added The reaction was heated to 60° for 6 hours extracted with dichloromethane (2×) the organic layers were filtered through a phase separator concentrated Purification by flash column chromatography

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To (E)-N-(2-isopropylphenyl)-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)hydrazinecarbothioamide (300 mg, 0.572 mmol) and potassium carbonate (316 mg, 2.29 mmol) in butanone (4 ml) was added 1,2-dibromopropane (0.072 ml, 0.686 mmol). The reaction was heated to 85° C. overnight. The reaction was determined to be complete by LCMS. The reaction mixture was diluted with DCM and washed with water. The aqueous layer was extracted with DCM. The organic layers were poured through a phase separator and concentrated. Purification by flash column chromatography provided a yellow solid. The solid was recrystallized from MeOH. The solid was filtered, washed with MeOH, and dried to provide the title compound as a yellow solid which was dissolved in acetone and concentrated (3×). The light yellow solid was collected and dried under to provide the title compound as a 1:1 mixture of rotational diastereoisomers (75.1 mg, 0.133 mmol, 23%): mp 201-204° C.; 1H NMR of mixture (400 MHz, CDCl3) δ 8.56 (s, 2H), 8.18 (dd, J=10.8, 7.4 Hz, 6H), 7.84-7.73 (m, 8H), 7.45-7.30 (m, 8H), 7.30-7.23 (m, 2H), 7.20 (d, J=6.7 Hz, 1H), 7.12 (dd, J=7.8, 1.2 Hz, 1H), 4.43-4.33 (m, 1H), 4.16 (dd, J=12.6, 6.3 Hz, 1H), 3.48 (dt, J=13.3, 6.7 Hz, 1H), 3.37 (dd, J=10.8, 6.2 Hz, 1H), 3.24 (dt, J=13.7, 6.9 Hz, 1H), 3.08-2.92 (m, 3H), 1.33-1.16 (m, 18H); ESIMS m/z 566 (M+H). washed with water The aqueous layer was extracted with DCM The organic layers were poured through a phase separator concentrated Purification by flash column chromatography provided a yellow solid The solid was recrystallized from MeOH The solid was filtered washed with MeOH dried

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

Procedure: A solution of 12.6 g of (2-trifluoromethyl-phenyl)-acetonitrile and 7.6 ml of 1,2-dibromopropane in 36 ml ether were added slowly through a dropping funnel to a suspension of 3.62 g of sodium hydride in 85 ml DMSO at 0° C. After addition, the ice-water bath was allowed to warm up to room temperature slowly and the reaction mixture was stirred at room temperature overnight. The reaction was carefully quenched with isopropyl and H2O. The suspension became clear. The organic layer was separated, and the aqueous layer was extracted twice with ether. The combined organic extracts were combined, dried and concentrated by evaporation in a vacuum. The residue was purified by column chromatography on silica-gel (EtOAc-hexane 2%-4%) to yield 8.5 g of product as a white solid. After addition The reaction was carefully quenched with isopropyl and H2O The organic layer was separated the aqueous layer was extracted twice with ether dried concentrated by evaporation in a vacuum The residue was purified by column chromatography on silica-gel (EtOAc-hexane 2%-4%)