N'-hydroxybenzenecarboximidamide

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 13.6 g. (0.1 mole) benzamide oxime in 625 milliliters dioxane is treated dropwise with 19.8 g. (0.1 mole) 2-chloroformyl benzoic acid methyl ester in 200 milliliters dioxane. This mixture is then refluxed for one hour, cooled slightly and treated with 3.3 milliliters of boron trifluoride etherate. The reaction mixture is refluxed for 18 hours. The resulting residue is cooled and filtered to remove a small amount of solid. The filtrate is evaporated in vacuo and the resulting oil is dissolved in ether, washed with water, 10 percent sodium carbonate, water and then brine. The ether solution is dried over anhydrous magnesium sulfate decolorized with charcoal filtered to remove the charcoal and the filtrate evaporated in vacuo to give o-(3-phenyl-1,2,4-oxadiazol-5-yl)-benzoic acid methyl ester. This mixture is then refluxed for one hour cooled slightly The reaction mixture is refluxed for 18 hours The resulting residue is cooled filtered to remove a small amount of solid The filtrate is evaporated in vacuo the resulting oil is dissolved in ether washed with water, 10 percent sodium carbonate, water The ether solution is dried over anhydrous magnesium sulfate filtered to remove the charcoal the filtrate evaporated in vacuo

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

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

Procedure: CDl (0.98 g, 6.1 mmol) was added to a solution of 5-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoic acid (1.89 g, 5.5 mmol) in DMF (15 ml) and stirred under nitrogen for 1.5 h. Benzamidoxime (0.91 g, 6.1 mmol) was added and the mixture stirred at 110° C. overnight. The reaction mixture was partitioned between EtOAc and 2M HCl. The organic layer was separated, washed with brine, dried (MgSO4) and evaporated. The crude product was crystallised from methanol and then further purified using the Companion™ system and a gradient elution from cyclohexane to EtOAc. Product containing fractions were combined and evaporated to give the title compound as a white solid (850 mg). the mixture stirred at 110° C. overnight The reaction mixture was partitioned between EtOAc and 2M HCl The organic layer was separated washed with brine dried (MgSO4) evaporated The crude product was crystallised from methanol further purified a gradient elution from cyclohexane to EtOAc Product containing fractions evaporated

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

Procedure: CDl (0.98 g, 6.1 mmol) was added to a solution of 5-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoic acid (1.89 g, 5.5 mmol) in DMF (15 ml) and stirred under nitrogen for 1.5 h. Benzamidoxime (0.91 g, 6.1 mmol) was added and the mixture stirred at 110° C. overnight. The reaction mixture was partitioned between EtOAc and 2M HCl. The organic layer was separated, washed with brine, dried (MgSO4) and evaporated. The crude product was crystallised from methanol and then further purified using the Companion™ system and a gradient elution from cyclohexane to EtOAc. Product containing fractions were combined and evaporated to give the title compound as a white solid (850 mg). the mixture stirred at 110° C. overnight The reaction mixture was partitioned between EtOAc and 2M HCl The organic layer was separated washed with brine dried (MgSO4) evaporated The crude product was crystallised from methanol further purified a gradient elution from cyclohexane to EtOAc Product containing fractions evaporated

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl 5-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoate (74 mg, 0.2 mmol) and benzamidoxime (30 mg, 0.22 mmol) were suspended in dry EtOH (1 ml) and ethanolic sodium ethoxide (21% by wt., 0.111 ml, 0.3 mmol) was added. The mixture was gently warmed until solids were dissolved and then heated in the microwave reactor at 140° C. for 10 min. The mixture was then partitioned between EtOAc and 2M HCl and the organic phase dried (Na2SO4) and evaporated. MDAP afforded the pure title compound (40.7 mg). The mixture was gently warmed until solids were dissolved The mixture was then partitioned between EtOAc and 2M HCl the organic phase dried (Na2SO4) evaporated

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl 5-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoate (74 mg, 0.2 mmol) and benzamidoxime (30 mg, 0.22 mmol) were suspended in dry EtOH (1 ml) and ethanolic sodium ethoxide (21% by wt., 0.111 ml, 0.3 mmol) was added. The mixture was gently warmed until solids were dissolved and then heated in the microwave reactor at 140° C. for 10 min. The mixture was then partitioned between EtOAc and 2M HCl and the organic phase dried (Na2SO4) and evaporated. MDAP afforded the pure title compound (40.7 mg). The mixture was gently warmed until solids were dissolved The mixture was then partitioned between EtOAc and 2M HCl the organic phase dried (Na2SO4) evaporated

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

Procedure: To a solution of phenylacetic acid (2.04 g) in 50 mL of DMF was added carbonyldiimidazole (2.7 g). The mixture was stirred for 20 min and then benzene amidoxime (2.04 g) was added. The resulting mixture was stirred for 20 min at r.t. and 18 h at 75 ° C. After cooling, the reaction mixture was poured in to 50 mL of water and extracted with 2×50 mL of 1:1 hexane/EtOAc. The extract was dried over MgSO4 and filtered. The filtrate was concentrated and the residue was purified by silica gel chromatography, eluting with 1:5 EtOAc/hexane to give 2 g of the title compound as a yellow syrup. The resulting mixture was stirred for 20 min at r.t. and 18 h at 75 ° C After cooling extracted with 2×50 mL of 1:1 hexane/EtOAc The extract was dried over MgSO4 filtered The filtrate was concentrated the residue was purified by silica gel chromatography eluting with 1:5 EtOAc/hexane

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

Procedure: A mixture of benzamidoxime (270 parts) carbon disulphide (152 parts), 5-normal sodium methoxide (40 parts) and ethanol (200 parts) were heated at reflux for 16 hours. The solution was evaporated to dryness and the residue washed with 3-normal hydrochloric acid to give 5-mercapto-3-phenyl-1,2,4-thiadiazole (152 parts, 39% yield), melting point 147°-148° C. were heated at reflux for 16 hours The solution was evaporated to dryness the residue washed with 3-normal hydrochloric acid

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

Procedure: To a stirring solution of 4-((N-(2-(tert-butoxy)-2-oxoethyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)methyl)benzoic acid INT-37 (129 mg, 0.22 mmol) and 4-methylmorpholine (52.0 μL, 0.47 mmol) in dioxane (2 mL) was added isobutyl chloroformate (28.0 μL, 0.22 mmol). After 1 h, the reaction mixture was added to a stirring solution of N′-hydroxybenzimidamide (32.0 mg, 0.24 mmol) in DMF (2 mL). After a further 1 h, the reaction mixture was heated to 120° C. for 1 h. The reaction mixture was allowed to cool to room temperature then poured onto citric acid (50 mL, 0.1 M aqueous solution) and extracted with EA(2×20 mL). The combined organic extracts were washed with NaHCO3 (20 mL), dried over MgSO4 and the solvents evaporated. The crude material was purified by column chromatography (EA/isohexanes). The isolated material was dissolved in DCM (2 mL) and treated with TFA (2 mL). After 2 h, the solvents were concentrated and the residue purified by preparative HPLC to afford 19 mg (14%) of 2-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(3-phenyl-1,2,4-oxadiazol-5-yl)benzyl)benzamido) acetic acid 368 as a white solid. LCMS-ESI (m/z) calculated for C34H27F3N4O6: 644; found 645 [M+H]+, tR=7.56 min (Method 9). 1H NMR (400 MHz, DMSO) δ 12.85 (s, 1H), 10.34 (s, 1H), 8.22-8.16 (m, 2H), 8.15-8.08 (m, 2H), 7.81-7.49 (m, 7H), 7.49-7.29 (m, 3H), 7.29-7.05 (m, 2H), 4.78 (s, 1H), 4.71 (s, 1H), 4.05 (s, 1H), 3.98 (s, 1H), 3.91-3.77 (s, 5H). After a further 1 h to cool to room temperature then poured onto citric acid (50 mL, 0.1 M aqueous solution) extracted with EA(2×20 mL) The combined organic extracts were washed with NaHCO3 (20 mL) dried over MgSO4 the solvents evaporated The crude material was purified by column chromatography (EA/isohexanes) The isolated material was dissolved in DCM (2 mL) treated with TFA (2 mL) After 2 h the solvents were concentrated the residue purified by preparative HPLC

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

Procedure: To a stirring solution of 4-((N-(2-(tert-butoxy)-2-oxoethyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)methyl)benzoic acid INT-37 (129 mg, 0.22 mmol) and 4-methylmorpholine (52.0 μL, 0.47 mmol) in dioxane (2 mL) was added isobutyl chloroformate (28.0 μL, 0.22 mmol). After 1 h, the reaction mixture was added to a stirring solution of N′-hydroxybenzimidamide (32.0 mg, 0.24 mmol) in DMF (2 mL). After a further 1 h, the reaction mixture was heated to 120° C. for 1 h. The reaction mixture was allowed to cool to room temperature then poured onto citric acid (50 mL, 0.1 M aqueous solution) and extracted with EA(2×20 mL). The combined organic extracts were washed with NaHCO3 (20 mL), dried over MgSO4 and the solvents evaporated. The crude material was purified by column chromatography (EA/isohexanes). The isolated material was dissolved in DCM (2 mL) and treated with TFA (2 mL). After 2 h, the solvents were concentrated and the residue purified by preparative HPLC to afford 19 mg (14%) of 2-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(3-phenyl-1,2,4-oxadiazol-5-yl)benzyl)benzamido) acetic acid 368 as a white solid. LCMS-ESI (m/z) calculated for C34H27F3N4O6: 644; found 645 [M+H]+, tR=7.56 min (Method 9). 1H NMR (400 MHz, DMSO) δ 12.85 (s, 1H), 10.34 (s, 1H), 8.22-8.16 (m, 2H), 8.15-8.08 (m, 2H), 7.81-7.49 (m, 7H), 7.49-7.29 (m, 3H), 7.29-7.05 (m, 2H), 4.78 (s, 1H), 4.71 (s, 1H), 4.05 (s, 1H), 3.98 (s, 1H), 3.91-3.77 (s, 5H). After a further 1 h to cool to room temperature then poured onto citric acid (50 mL, 0.1 M aqueous solution) extracted with EA(2×20 mL) The combined organic extracts were washed with NaHCO3 (20 mL) dried over MgSO4 the solvents evaporated The crude material was purified by column chromatography (EA/isohexanes) The isolated material was dissolved in DCM (2 mL) treated with TFA (2 mL) After 2 h the solvents were concentrated the residue purified by preparative HPLC

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

Procedure: A solution of benzamide oxime (24.92%) in 2-methyl THF (67.53 g, 124 mmoles) was charged to a 500 mL flask, followed by DI water (20.0 g), 55% aqueous tetrabutylammonium hydroxide (0.94 g), and 50% sodium hydroxide (0.96 g, 12 mmoles). To this mixture was added 2-thiophenecarbonyl chloride (17.77 g, 120 mmoles) and 50% sodium hydroxide (9.60 g, 120 mmoles) simultaneously over 30 minutes while heating to about 70° C. The reaction was complete is less than one hour. The temperature was reduced to 60° C., and the pH of the aqueous phase was neutralized to 7.61, and was drained off to waste. A hot solution of 1.25 g of Morwet D-425 in 100 ml DI water was added to the mixture, and the 2-phase mixture was heated to distill off the 2-methyltetrahydrofuran/water azeotrope (boiling point 71° C.). Additional water (150 ml) was pumped into the reactor flask over about 15 minutes, once the 2-methyltetrahydrofuran began to distill out. While maintaining good agitation, the pot temperature reached 100.5° C. (vapor temperature 97° C.). The slurry was cooled and filtered using a coarse glass frit. The scale was scraped off the agitator and combined with the wet cake; the scale was only about 3% of total product. The combined wet cake was washed with hot DI water (3×50 ml) and suction-dried for 5 minutes to give a 3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole wet cake, 34.80 g. The loss on drying of the wet cake was 20.13%. The assay of the dried 3-phenyl-5-(thiophen-2-yl)-1,2,4-oxadiazole was 96.12%, and the residual chloride was <200 ppm. The reaction was complete is less than one hour was reduced to 60° C. the 2-phase mixture was heated to distill off the 2-methyltetrahydrofuran/water to distill out While maintaining good agitation reached 100.5° C. (vapor temperature 97° C.) The slurry was cooled filtered The combined wet cake was washed with hot DI water (3×50 ml) suction-dried for 5 minutes