2,4-difluoro-N'-hydroxybenzenecarboximidamide

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

Procedure: A solution of 5-(8-chloro-3-ethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoic acid (0.05 g, 0.16 mmol) in DMSO (1 ml) was treated with CDl (0.029 g, 0.18 mmol) and the mixture stirred at room temperature for 1 h. Subsequently, the mixture was treated with 2,4-difluorobenzamidoxime (0.03 g, 0.18 mmol) and then heated to 120° C. for 30 min. The product was purified from the crude mixture using MDAP. Product-containing fractions were evaporated using a stream of nitrogen and the resulting colourless gum triturated in ether and dried to reveal the title compound as a white solid (50 mg, 70%). heated to 120° C. for 30 min The product was purified from the crude mixture Product-containing fractions were evaporated the resulting colourless gum triturated in ether dried

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

Procedure: A solution of 5-(8-chloro-3-ethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoic acid (0.05 g, 0.16 mmol) in DMSO (1 ml) was treated with CDl (0.029 g, 0.18 mmol) and the mixture stirred at room temperature for 1 h. Subsequently, the mixture was treated with 2,4-difluorobenzamidoxime (0.03 g, 0.18 mmol) and then heated to 120° C. for 30 min. The product was purified from the crude mixture using MDAP. Product-containing fractions were evaporated using a stream of nitrogen and the resulting colourless gum triturated in ether and dried to reveal the title compound as a white solid (50 mg, 70%). heated to 120° C. for 30 min The product was purified from the crude mixture Product-containing fractions were evaporated the resulting colourless gum triturated in ether dried

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

Procedure: To a solution of 2,4-difluoro-N′-hydroxybenzimidamide 5.2 (3.52 g, 33% purity, max. 7.2 mmol) and pyridine (2.32 mL, 28.7 mmol) in anhydrous CH2Cl2 under N2 was added ethyl chlorooxoacetate (1.27 g, 9.32 mmol) dropwise over 5 min at RT. The mixture was stirred under reflux. After 1 h30, the rxn mixt. was concentrated and purified on silica gel using CH2Cl2, furnishing 1.414 g of title product 5a as colorless oil. Yield: 1.414 g (78%). LCMS: P=94%, rt=4.21 nm, m/z=255, 277 (M+Na). under reflux was concentrated purified on silica gel

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

Procedure: To a solution of 2,4-difluoro-N′-hydroxybenzimidamide 5.2 (3.52 g, 33% purity, max. 7.2 mmol) and pyridine (2.32 mL, 28.7 mmol) in anhydrous CH2Cl2 under N2 was added ethyl chlorooxoacetate (1.27 g, 9.32 mmol) dropwise over 5 min at RT. The mixture was stirred under reflux. After 1 h30, the rxn mixt. was concentrated and purified on silica gel using CH2Cl2, furnishing 1.414 g of title product 5a as colorless oil. Yield: 1.414 g (78%). LCMS: P=94%, rt=4.21 nm, m/z=255, 277 (M+Na). under reflux was concentrated purified on silica gel

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

Procedure: 90.0 mg (0.242 mmol) of 1-[(3-hydroxyazetidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 101A) and 47.3 (0.266 mmol) of 2,4-difluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 35.2 mg (27% of theory).

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

Procedure: 100 mg (0.244 mmol) of 1-[(4-cyanopiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 100A) and 46.2 mg (0.269 mmol) of 2,4-difluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 63.9 mg (47% of theory).

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

Procedure: 100 mg (0.250 mmol) of 1-[(4-hydroxypiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 99A) and 47.3 (0.275 mmol) of 2,4-difluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 52.1 mg (38% of theory).

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

Procedure: 80 mg (0.22 mmol) of 5-(4-ethylphenyl)-1-[(4-hydroxypiperidin-1-yl)carbonyl]piperidine-3-carboxylic acid (Example 59A) and 60 mg (0.33 mmol) of 2,4-difluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 2. Yield: 69 mg (60% of theory)

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

Procedure: 80 mg (0.20 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 44A) and 38 mg (0.22 mmol, 1.1 eq.) of 2,4-difluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 52 mg (48% of theory)

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

Procedure: 69 mg (0.20 mmol) of 5-(4-ethylphenyl)-1-(morpholin-4-ylcarbonyl)piperidine-3-carboxylic acid (Example 38A) and 38 mg (0.22 mmol, 1.1 eq.) of 2,4-difluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 47 mg (47% of theory)

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

Procedure: A solution of 5-(8-chloro-3-ethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoic acid (0.05 g, 0.16 mmol) in DMSO (1 ml) was treated with CDl (0.029 g, 0.18 mmol) and the mixture stirred at room temperature for 1 h. Subsequently, the mixture was treated with 2,4-difluorobenzamidoxime (0.03 g, 0.18 mmol) and then heated to 120° C. for 30 min. The product was purified from the crude mixture using MDAP. Product-containing fractions were evaporated using a stream of nitrogen and the resulting colourless gum triturated in ether and dried to reveal the title compound as a white solid (50 mg, 70%). heated to 120° C. for 30 min The product was purified from the crude mixture Product-containing fractions were evaporated the resulting colourless gum triturated in ether dried

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

Procedure: To a solution of 2,4-difluoro-N′-hydroxybenzimidamide 5.2 (3.52 g, 33% purity, max. 7.2 mmol) and pyridine (2.32 mL, 28.7 mmol) in anhydrous CH2Cl2 under N2 was added ethyl chlorooxoacetate (1.27 g, 9.32 mmol) dropwise over 5 min at RT. The mixture was stirred under reflux. After 1 h30, the rxn mixt. was concentrated and purified on silica gel using CH2Cl2, furnishing 1.414 g of title product 5a as colorless oil. Yield: 1.414 g (78%). LCMS: P=94%, rt=4.21 nm, m/z=255, 277 (M+Na). under reflux was concentrated purified on silica gel