4-chloro-2-fluoro-1-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:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of n-BuLi (1.6 M in hexanes, 4.68 mmol, 2.93 mL) in dry THF was slowly added 4-chloro-2-fluoro-1-iodo-benzene 19a (3.9 mmol, 1.0 g) at −78° C. under N2. The mixture was stirred for 1 h at −78° C. and ethyl trifluoroacetate 18b (0.51 mL, 4.29 mmol) was added. The reaction was allowed to warm to room temperature overnight and was quenched with saturated aqueous NH4Cl solution. The mixture was extracted with EtOAc. The organic extracts were concentrated and purified by flash column chromatography (silica gel, 15% EtOAc/hexanes) to give compound 19b. at −78° C. to warm to room temperature overnight was quenched with saturated aqueous NH4Cl solution The mixture was extracted with EtOAc The organic extracts were concentrated purified by flash column chromatography (silica gel, 15% EtOAc/hexanes)

Conditions: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 5-(2-chloro-4-fluorophenyl)-1,3-dimethyl-1H-pyrazol-4-amine (i.e. the product of Step F) (7.07 g, 23.8 mmol), 4-chloro-2-fluoroiodobenzene (256 μL, 2.0 mmol), sodium tert-butoxide (0.192 g, 2.0 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (0.117 g, 0.16 mmol) in toluene (5 mL) was heated at 180° C. in a Biotage Initiator™ microwave apparatus for 1 h. The resulting material was purified by flash chromatography on a silica gel (40 g), Varian Bond Elute SI® column (30% ethyl acetate in hexanes as eluant) to provide the title compound, a compound of the present invention, as a dark purple/brown oil (164 mg). The resulting material was purified by flash chromatography on a silica gel (40 g), Varian Bond Elute SI® column (30% ethyl acetate in hexanes as eluant)

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

Procedure: To a solution of n-BuLi (1.6 M in hexanes, 2.93 mL, 4.68 mmol) in dry THF was slowly added 4-chloro-2-fluoro-1-iodo-benzene 11h (31.0 g, 0.9 mmol) at −78° C. under N2. The mixture was stirred for 1 h at −78° C. and ethyl trifluoroacetate 11b (0.51 mL, 4.29 mmol) was added. The reaction was allowed to warm to room temperature overnight and was quenched with saturated aqueous NH4Cl solution. The mixture was extracted with EtOAc. The organic extracts were concentrated and purified by flash column chromatography (silica gel, 15% EtOAc/hexanes) to give compound 11i. at −78° C. to warm to room temperature overnight was quenched with saturated aqueous NH4Cl solution The mixture was extracted with EtOAc The organic extracts were concentrated purified by flash column chromatography (silica gel, 15% EtOAc/hexanes)

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

Procedure: To a solution of n-BuLi (1.6 M in hexanes, 4.68 mmol, 2.93 mL) in dry THF was slowly added 4-chloro-2-fluoro-1-iodo-benzene 67h (3.9 mmol, 1.0 g) at −78° C. under N2. The mixture was stirred for 1 h at −78° C. and ethyl trifluoroacetate 67b (0.51 mL, 4.29 mmol) was added. The reaction was allowed to warm to room temperature overnight and was quenched with saturated aqueous NH4Cl solution. The mixture was extracted with EtOAc. The organic extracts were concentrated and purified by flash column chromatography (silica gel, 15% EtOAc/hexanes) to give compound 67i. at −78° C. to warm to room temperature overnight was quenched with saturated aqueous NH4Cl solution The mixture was extracted with EtOAc The organic extracts were concentrated purified by flash column chromatography (silica gel, 15% EtOAc/hexanes)

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

Procedure: To a solution of n-BuLi (1.6 M in hexanes, 4.68 mmol, 2.93 mL) in dry THF was slowly added 4-chloro-2-fluoro-1-iodo-benzene 67h (3.9 mmol, 1.0 g) at −78° C. under N2. The mixture was stirred for 1 h at −78° C. and ethyl trifluoroacetate 67b (0.51 mL, 4.29 mmol) was added. The reaction was allowed to warm to room temperature overnight and was quenched with saturated aqueous NH4Cl solution. The mixture was extracted with EtOAc. The organic extracts were concentrated and purified by flash column chromatography (silica gel, 15% EtOAc/hexanes) to give compound 67i. at −78° C. to warm to room temperature overnight was quenched with saturated aqueous NH4Cl solution The mixture was extracted with EtOAc The organic extracts were concentrated purified by flash column chromatography (silica gel, 15% EtOAc/hexanes)

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

Procedure: The title compound was prepared according to the procedure described in Example-3 using 5-(2-chloro-6-fluorophenyl)-2-(4-ethynylphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate-2, 0.100 g, 0.319 mmol), 4-chloro-2-fluoro-1-iodobenzene (0.123 g, 0.479 mmol), TBAF (0.201 g, 0.638 mmol), bis(triphenylphosphine)palladium(II) chloride (0.020 g, 0.028 mmol) and DMSO (3.0 ml). The obtained crude product was purified with column chromatography on silica gel eluting with 1.0% MeOH:DCM to afford 0.045 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 7.38 (d, J=8.4 Hz, 1H), 7.50 (t, J=8.7 Hz, 1H), 7.57-7.70 (m, 6H), 8.02 (d, J=8.7 Hz, 2H), 12.74 (br s, 1H). MS (m/z): 442.38 (M+). The title compound was prepared The obtained crude product was purified with column chromatography on silica gel eluting with 1.0% MeOH

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

Procedure: To a solution of 4-chloro-2-fluoro-1-iodobenzene (2.0 g, 7.8 mmol) in DMSO (10 mL) was added ethynyl(trimethyl)silane (1.14 g, 11.0 mmol), copper iodide (0.029 g, 0.15 mmol), bis(triphenylphosphine) palladium(II) chloride (0.218 g, 0.3 mmol) and TEA (1 mL). The reaction mass was stirred at RT for 4-5 h. The reaction mass quenched in water, passed through celite bed and extracted with ethyl acetate and concentrated to afford 1.0 g of desired product. The reaction mass quenched in water extracted with ethyl acetate concentrated

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

Procedure: To a solution of 4-chloro-2-fluoro-1-iodobenzene (2.0 g, 7.8 mmol) in DMSO (10 mL) was added ethynyl(trimethyl)silane (1.14 g, 11.0 mmol), copper iodide (0.029 g, 0.15 mmol), bis(triphenylphosphine) palladium(II) chloride (0.218 g, 0.3 mmol) and TEA (1 mL). The reaction mass was stirred at RT for 4-5 h. The reaction mass quenched in water, passed through celite bed and extracted with ethyl acetate and concentrated to afford 1.0 g of desired product. The reaction mass quenched in water extracted with ethyl acetate concentrated

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

Procedure: To a solution of n-BuLi (1.6 M in hexanes, 4.68 mmol, 2.93 mL) in dry THF was slowly added 4-chloro-2-fluoro-1-iodo-benzene 67h (3.9 mmol, 1.0 g) at −78° C. under N2. The mixture was stirred for 1 h at −78° C. and ethyl trifluoroacetate 67b (0.51 mL, 4.29 mmol) was added. The reaction was allowed to warm to room temperature overnight and was quenched with saturated aqueous NH4Cl solution. The mixture was extracted with EtOAc. The organic extracts were concentrated and purified by flash column chromatography (silica gel, 15% EtOAc/hexanes) to give compound 67i. at −78° C. to warm to room temperature overnight was quenched with saturated aqueous NH4Cl solution The mixture was extracted with EtOAc The organic extracts were concentrated purified by flash column chromatography (silica gel, 15% EtOAc/hexanes)