2-chloro-1-fluoro-4-iodobenzene

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: A mixture of 3-chloro-4-fluoroiodobenzene (5.00 g), copper(I) iodide (74.3 mg), triphenylphosphine (256 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (404 mg), propargyl alcohol (1.27 ml), diisopropylethylamine (13.6 ml) and tetrahydrofuran (80 ml) was stirred at room temperature for 8 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-80:20) to give the object product (3.20 g) as a brown oil. the mixture was extracted with ethyl acetate washed with saturated brine dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-80:20)

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

Procedure: In analogy to the procedure described in Example 31F], 2-chloro-1-fluoro-4-iodobenzene and (3-diethylamino-pyrrolidin-1-yl)-[5-(3-ethynyl-phenyl)-4-methyl-1H-pyrazol-3-yl]-methanone (Example 31E]) gave the title compound in 68% yield light yellow foam. MS: 479.2 (MH+, 1 Cl).

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

Procedure: To a 50 ml of isopropyl alcohol solution containing 15.0 g of 3(S)-aminopyrrolidine-1-carboxylic acid tert-butyl ester (80.5 mmol) and 24.8 g of 2-chloro-1-fluoro-4-iodobenzene (96.7 mmol) were added 1.54 g of copper (I) iodide (8.1 mmol), 9.0 ml of ethylene glycol (10.1 mmol) and 34.2 g of potassium phosphate (161 mmol), and heated under reflux under a nitrogen atmosphere for 46 hours. The reaction solution was cooled to room temperature and filtered using Celite. The substance remained in the filter was washed with ethyl acetate and the filtrate was concentrated under reduced pressure together with the washings, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1). The solvent was distilled off under reduced pressure, and the residue was recrystallized from diethyl ether to thereby obtain 15.9 g of white powdery 3(S)-(3-chloro-4-fluorophenylamino)pyrrolidine-1-carboxylic acid tert-butyl ester. heated under reflux under a nitrogen atmosphere for 46 hours filtered was washed with ethyl acetate the filtrate was concentrated under reduced pressure together with the washings the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1) The solvent was distilled off under reduced pressure the residue was recrystallized from diethyl ether

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

Procedure: To a 50 ml of isopropyl alcohol solution containing 15.0 g of 3(S)-aminopyrrolidine-1-carboxylic acid tert-butyl ester (80.5 mmol) and 24.8 g of 2-chloro-1-fluoro-4-iodobenzene (96.7 mmol) were added 1.54 g of copper (I) iodide (8.1 mmol), 9.0 ml of ethylene glycol (10.1 mmol) and 34.2 g of potassium phosphate (161 mmol), and heated under reflux under a nitrogen atmosphere for 46 hours. The reaction solution was cooled to room temperature and filtered using Celite. The substance remained in the filter was washed with ethyl acetate and the filtrate was concentrated under reduced pressure together with the washings, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1). The solvent was distilled off under reduced pressure, and the residue was recrystallized from diethyl ether to thereby obtain 15.9 g of white powdery 3(S)-(3-chloro-4-fluorophenylamino)pyrrolidine-1-carboxylic acid tert-butyl ester. heated under reflux under a nitrogen atmosphere for 46 hours filtered was washed with ethyl acetate the filtrate was concentrated under reduced pressure together with the washings the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1) The solvent was distilled off under reduced pressure the residue was recrystallized from diethyl ether

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

Procedure: Add bis(triphenylphosphine)palladium (II) dichloride (64 mg, 0.091 mmol), copper (I) iodide (35 mg, 0.18 mmol), and 3-chloro-5-ethynylpyridine, (prepared as described in PREPARATION 27), (250 mg, 1.8 mmol) to a solution of 2-chloro-1-fluoro -4-iodobenzene (560 mg, 2.2 mmol) in triethylamine (3.8 mL, 27 mmol) and heat at 60° C. for 5 h. Cool to room temperature and concentrate. Purify by silica gel chromatography, eluting with 50:50 to 100:0 dichloromethane:hexanes, followed by a second silica gel chromatography, eluting with 100:0 to 90:10 hexanes:ethyl acetate, to give the title compound as a white solid (340 mg, 70%). Cool to room temperature concentrate Purify by silica gel chromatography eluting with 50:50 to 100:0 dichloromethane eluting with 100:0 to 90:10 hexanes

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

Procedure: Add bis(triphenylphosphine)palladium (II) dichloride (110 mg, 0.15 mmol), copper (I) iodide (57 mg, 0.30 mmol), and 3-ethynyl-5-methoxypyridine, (prepared as described in PREPARATION 10), (400 mg, 3.0 mmol) to a solution of 2-chloro-1-fluoro-4-iodobenzene (0.46 mL, 3.6 mmol) in triethylamine (6.3 mL, 45.0 mmol) and heat at 60° C. for 5 h. Cool to room temperature and concentrate. Purify the residue by silica gel chromatography, eluting with a gradient of 100:0 to 80:20 dichloromethane:ethyl acetate, followed by a second silica gel chromatography, eluting with 67:33 to 60:40 hexanes:ethyl acetate, to give the title compound as a white solid (730 mg, 93%). Cool to room temperature concentrate Purify the residue by silica gel chromatography eluting with a gradient of 100:0 to 80:20 dichloromethane eluting with 67:33 to 60:40 hexanes

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Stir 5-trimethylsilanylethynyl-nicotinonitrile (300 mg, 1.5 mmol), (prepared essentially as described in PREPARATION 3), 2-chloro-1-fluoro-4-iodobenzene (390 mg, 1.5 mmol), bis(triphenylphosphine)palladium (II) dichloride (50 mg, 0.08 mmol) and copper (I) iodide (20 mg, 0.15 mmol) in triethylamine (15 mL) under nitrogen and cool to −78° C. Add a 1 M solution of tetrabutylammonium fluoride (1.5 mL) in tetrahydrofuran and warm to room temperature and then heat at 70° C. until complete by thin layer chromatography. Concentrate and purify the residue by silica gel chromatography, eluting with hexanes:ethyl acetate, and then recrystallize from hexanes:ethyl acetate to give the title compound (120 mg, 31%). (prepared essentially warm to room temperature heat at 70° C. until complete by thin layer chromatography Concentrate purify the residue by silica gel chromatography eluting with hexanes ethyl acetate, and then recrystallize from hexanes

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

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