4-bromo-1-iodo-2-methylbenzene

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:

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

Procedure: Synthesised by analogous methods to Intermediate 5a, using 4-bromo-2-methyl-iodobenzene at Stage 2 of Scheme 4. m/z 500 [M+H]+.

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

Procedure: The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and 5-bromo-2-iodotoluene in analogy to Example 1a): MS (ISP): 473.9 (M+H)+ and 373.9 ((M-Boc)+H)+.

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

Procedure: The title compound was prepared from 5-bromo-2-iodotoluene and 5-fluoropyridine-3-boronic acid in analogy to Example 1b): MS (ISP): 265.8 and 267.9 (M+H)+.

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a vial with zinc dust (2.77 g, 42.4 mmol) in anhydrous THF (15 mL) under nitrogen was added 1,2-dibromoethane (0.24 mL, 2.83 mmol), then the suspension was stirred at 65° C. for 3 min. After cooling to ambient temperature, chloro(trimethyl)silane (0.36 mL, 2.83 mmol) was added and the mixture was stirred at room temperature for 30 min. Then, a solution of tert-butyl 3-iodoazetidine-1-carboxylate (8.00 g, 28.3 mmol) in THF (10 mL) was added and the mixture was stirred for 45 min. P(2-furyl)3 (1.31 g, 5.7 mmol) and tris(dibenzylidene acetone)dipalladium (0) (2.59 g, 2.83 mmol) were added to a separate vial, dissolved in THF (5 mL) and stirred under nitrogen at ambient temperature for 10 min, then the mixture and 5-bromo-2-iodotoluene (4.84 mL, 33.9 mmol) in THF (10 mL) were added to the organozine reagent solution. The mixture was then placed in a 65° C. oil bath for 2 h. The reaction mixture was allowed to cool to room temperature and then was poured into water. The mixture was extracted with EtOAc, and the organic layer was concentrated in vacuo. Purification by chromatography on silica gel (0 to 50% EtOAc in hexanes, then 50 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 271.8 [M-t-Bu+2H]+; 1H NMR (500 MHz, acetone-d6) δ 7.40-7.30 (m, 3 H),4.23 (br, 2 H),3.99 (m, 1 H),3.91 (m, 2 H),2.21 (s, 3 H),1.42 (s, 9 H). After cooling to ambient temperature the mixture was stirred at room temperature for 30 min the mixture was stirred for 45 min stirred under nitrogen at ambient temperature for 10 min was then placed in a 65° C. for 2 h to cool to room temperature The mixture was extracted with EtOAc the organic layer was concentrated in vacuo Purification by chromatography on silica gel (0 to 50% EtOAc in hexanes

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

Procedure: To a solution of 4-bromo-1-iodo-2-methylbenzene (148 mg, 0.5 mmol) in THF (10 mL) at −25° C. was added isopropylmagnesium bromide (0.5 mL, 0.5 mmol) and stirred 3 h. Succinic anhydride (55 mg, 0.55 mmol) was added and the reaction was stirred 18 h. The mixture was quenched with water (10 mL) and washed with 1N NaOH (10 mL), 1N HCl (10 mL), brine (10 mL) and dried (MgSO4). The organic layer was concentrated in vacuo and the residue purified by flash chromatography (0-100% EtOAc/Hexane) to afford 55A (42 mg, 31%) as a crystalline solid. 1H NMR (400 MHz, CDCl3) δ ppm 0.98 (t, 3 H) 2.42 (q, 2 H) 2.73 (t, 2 H) 4.10 (t, 2 H) 6.82 (d, 1 H) 7.02 (d, 1 H) 7.09 (t, 2 H) 7.15 (t, 1 H) 7.36 (d, 1 H) 7.58-7.63 (m, 1 H). the reaction was stirred 18 h The mixture was quenched with water (10 mL) washed with 1N NaOH (10 mL), 1N HCl (10 mL), brine (10 mL) dried (MgSO4) The organic layer was concentrated in vacuo the residue purified by flash chromatography (0-100% EtOAc/Hexane)

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

Procedure: To a solution of 4-bromo-1-iodo-2-methylbenzene (148 mg, 0.5 mmol) in THF (10 mL) at −25° C. was added isopropylmagnesium bromide (0.5 mL, 0.5 mmol) and stirred 3 h. Succinic anhydride (55 mg, 0.55 mmol) was added and the reaction was stirred 18 h. The mixture was quenched with water (10 mL) and washed with 1N NaOH (10 mL), 1N HCl (10 mL), brine (10 mL) and dried (MgSO4). The organic layer was concentrated in vacuo and the residue purified by flash chromatography (0-100% EtOAc/Hexane) to afford 55A (42 mg, 31%) as a crystalline solid. 1H NMR (400 MHz, CDCl3) δ ppm 0.98 (t, 3 H) 2.42 (q, 2 H) 2.73 (t, 2 H) 4.10 (t, 2 H) 6.82 (d, 1 H) 7.02 (d, 1 H) 7.09 (t, 2 H) 7.15 (t, 1 H) 7.36 (d, 1 H) 7.58-7.63 (m, 1 H). the reaction was stirred 18 h The mixture was quenched with water (10 mL) washed with 1N NaOH (10 mL), 1N HCl (10 mL), brine (10 mL) dried (MgSO4) The organic layer was concentrated in vacuo the residue purified by flash chromatography (0-100% EtOAc/Hexane)

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

Procedure: KF (870 mg, 15 mmol), n-Bu4NCl (2.77 g, 10 mmol), Pd(dba)2 (145 mg, 0.25 mmol), molecular sieves (4 Ang, 200 mg, activated balls), 5-bromo-2-iodo-1-methylbenzene (1.49 g, 5 mmol), trimethyl(vinyl)silane (2.7 mL, 20 mmol), and toluene (10 mL) were added to a pressure vessel and sparged with Ar. The vial was sealed and microwaved at 170° C. for 30 min. The mixture was cooled to ambient temperature, diluted with hexanes, filtered and concentrated. The crude oil was purified by flash chromatography (100% hexanes) to yield 30A (750 mg, 76%) as a clear oil. 1H NMR (400 MHz, CDCl3) δ ppm 2.31 (s, 3 H) 5.31 (dd, J=10.99, 1.10 Hz, 1 H) 5.62 (dd, J=17.59, 1.10 Hz, 1 H) 6.84 (dd, J=17.04, 10.99 Hz, 1 H) 7.26-7.35 (m, 3 H). sparged with Ar The vial was sealed microwaved at 170° C. for 30 min diluted with hexanes filtered concentrated The crude oil was purified by flash chromatography (100% hexanes)

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

Procedure: Under an argon atmosphere 39.6 mL (39.6 mmol; 1M in hexane) of lithium-hexamethyldisilazane was added to a suspension of 145 mg (0.65 mmol) of palladium (II) acetate and 875 mg (2.22 mmol) of 2-dicyclohexylphosphino-2-(N,N-dimethylamino)biphenyl in 40 mL of toluene and the reaction solution was stirred for 10 minutes at RT. Then the mixture was cooled to −10° C. and combined with 3.30 mL (24.5 mmol) of tert-butyl acetate (dried over basic Alox). 4.00 mL (22.2 mmol) of 4-bromo-1-iodo-2-methylbenzene were quickly added at −10° C. and the reaction solution was heated to RT. After the reaction was complete, the reaction solution was diluted with water and EtOAc. The organic phase was separated off, washed with aqueous ammonium chloride solution and water, and dried over magnesium sulfate. After the desiccant and solvent had been eliminated, the residue was purified by chromatography (silica gel, PE/EtOAc 9:1). Yield: 2.0 g (32% of theoretical; 45% content of product according to 1H-NMR); C13H17BrO2 (M=285.177). Then the mixture was cooled to −10° C. the reaction solution was heated to RT The organic phase was separated off washed with aqueous ammonium chloride solution and water dried over magnesium sulfate the residue was purified by chromatography (silica gel, PE/EtOAc 9:1)