t-Butyl2-iodobenzoate

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

Procedure: 2-Iodobenzoic acid (10.06 g, 40.56 mmol) was converted to 2-iodobenzoic chloride by reacting with oxalyl chloride (5.34 mL, 60.84 mmol) in methylene chloride (100 mL), initiated by a drop DMF. The solvent and excess oxalyl chloride were removed by rotary evaporation. To a 250 mL one neck round bottom flask was charged t-butanol with THF (50 mL) and then cooled to −78 C. A solution of n-butyl lithium in hexanes (2.5 M, 24.3 mL) was added, followed by the solution of 2-iodobenzoic chloride in THF (50 mL). The resulting reaction mixture was stirred at −78 C for 20 min and then at rt for 2 hours. The reaction was quenched by water and worked up. The product was purified by flash chromatography to afford the title compound as a white solid. The solvent and excess oxalyl chloride were removed by rotary evaporation To a 250 mL one neck round bottom flask was charged t-butanol with THF (50 mL) cooled to −78 C A solution of n-butyl lithium in hexanes (2.5 M, 24.3 mL) was added The resulting reaction mixture at rt for 2 hours The reaction was quenched by water The product was purified by flash chromatography

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 0.149 g (0.35 mmol) of the product of Step G and 0.132 g (0.43 mmol) of t-butyl 2-iodobenzoate in 1 mL of anhydrous DMF was added 5 mg of bis(triphenylphosphine)palladium(II) chloride. The mixture was degassed, flushed with nitrogen, then magnetically stirred under a nitrogen atmosphere for 12 hours at 100° C. The reaction mixture was cooled to room temperature, then partitioned between EtOAc and water. The organic layer was extracted, separated, dried (MgSO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 50% EtOAc-hexane. Evaporation of the purified fractions and drying in vacuo afforded 0.111 g (73%) of the title compound as an off-white amorphous solid. The mixture was degassed flushed with nitrogen The reaction mixture was cooled to room temperature partitioned between EtOAc and water The organic layer was extracted separated dried (MgSO4) filtered evaporated The residue was purified on a silica gel flash chromatography column eluted with 50% EtOAc-hexane Evaporation of the purified fractions drying in vacuo

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 0.149 g (0.35 mmol) of the product of Step G and 0.132 g (0.43 mmol) of t-butyl 2-iodobenzoate in 1 mL of anhydrous DMF was added 5 mg of bis(triphenylphosphine)palladium(II) chloride. The mixture was degassed, flushed with nitrogen, then magnetically stirred under a nitrogen atmosphere for 12 hours at 100° C. The reaction mixture was cooled to room temperature, then partitioned between EtOAc and water. The organic layer was extracted, separated, dried (MgSO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 50% EtOAc-hexane. Evaporation of the purified fractions and drying in vacuo afforded 0.111 g (73%) of the title compound as an off-white amorphous solid. The mixture was degassed flushed with nitrogen The reaction mixture was cooled to room temperature partitioned between EtOAc and water The organic layer was extracted separated dried (MgSO4) filtered evaporated The residue was purified on a silica gel flash chromatography column eluted with 50% EtOAc-hexane Evaporation of the purified fractions drying in vacuo

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

Procedure: Using N-(morpholin-2-yl methyl)-2-(4-chlorophenyl)-4-methylthiazole-5-carboxamide (120 mg, 0.341 mmol) and tert-butyl 2-iodobenzoate (104 mg, 0.341 mmol), the same procedure was followed as in Example 58 to give 113 mg (63%) of the desired compound as a pale yellow amorphous product.

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

Procedure: Using N-(morpholin-2-yl methyl)-2-(4-chlorophenyl)-4-methylthiazole-5-carboxamide (120 mg, 0.341 mmol) and tert-butyl 2-iodobenzoate (104 mg, 0.341 mmol), the same procedure was followed as in Example 58 to give 113 mg (63%) of the desired compound as a pale yellow amorphous product.

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

Procedure: 2-Iodobenzoic acid (10.06 g, 40.56 mmol) was converted to 2-iodobenzoic chloride by reacting with oxalyl chloride (5.34 mL, 60.84 mmol) in methylene chloride (100 mL), initiated by a drop DMF. The solvent and excess oxalyl chloride were removed by rotary evaporation. To a 250 mL one neck round bottom flask was charged t-butanol with THF (50 mL) and then cooled to −78 C. A solution of n-butyl lithium in hexanes (2.5 M, 24.3 mL) was added, followed by the solution of 2-iodobenzoic chloride in THF (50 mL). The resulting reaction mixture was stirred at −78 C for 20 min and then at rt for 2 hours. The reaction was quenched by water and worked up. The product was purified by flash chromatography to afford the title compound as a white solid. The solvent and excess oxalyl chloride were removed by rotary evaporation To a 250 mL one neck round bottom flask was charged t-butanol with THF (50 mL) cooled to −78 C A solution of n-butyl lithium in hexanes (2.5 M, 24.3 mL) was added The resulting reaction mixture at rt for 2 hours The reaction was quenched by water The product was purified by flash chromatography

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

Procedure: 2-Iodobenzoic acid (10.06 g, 40.56 mmol) was converted to 2-iodobenzoic chloride by reacting with oxalyl chloride (5.34 mL, 60.84 mmol) in methylene chloride (100 mL), initiated by a drop DMF. The solvent and excess oxalyl chloride were removed by rotary evaporation. To a 250 mL one neck round bottom flask was charged t-butanol with THF (50 mL) and then cooled to −78 C. A solution of n-butyl lithium in hexanes (2.5 M, 24.3 mL) was added, followed by the solution of 2-iodobenzoic chloride in THF (50 mL). The resulting reaction mixture was stirred at −78 C for 20 min and then at rt for 2 hours. The reaction was quenched by water and worked up. The product was purified by flash chromatography to afford the title compound as a white solid. The solvent and excess oxalyl chloride were removed by rotary evaporation To a 250 mL one neck round bottom flask was charged t-butanol with THF (50 mL) cooled to −78 C A solution of n-butyl lithium in hexanes (2.5 M, 24.3 mL) was added The resulting reaction mixture at rt for 2 hours The reaction was quenched by water The product was purified by flash chromatography

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 0.149 g (0.35 mmol) of the product of Step G and 0.132 g (0.43 mmol) of t-butyl 2-iodobenzoate in 1 mL of anhydrous DMF was added 5 mg of bis(triphenylphosphine)palladium(II) chloride. The mixture was degassed, flushed with nitrogen, then magnetically stirred under a nitrogen atmosphere for 12 hours at 100° C. The reaction mixture was cooled to room temperature, then partitioned between EtOAc and water. The organic layer was extracted, separated, dried (MgSO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 50% EtOAc-hexane. Evaporation of the purified fractions and drying in vacuo afforded 0.111 g (73%) of the title compound as an off-white amorphous solid. The mixture was degassed flushed with nitrogen The reaction mixture was cooled to room temperature partitioned between EtOAc and water The organic layer was extracted separated dried (MgSO4) filtered evaporated The residue was purified on a silica gel flash chromatography column eluted with 50% EtOAc-hexane Evaporation of the purified fractions drying in vacuo

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

Procedure: The title compound was prepared following the procedure described for intermediate 1 substituting tert-butyl 2-iodobenzoate with 2-bromo-5-fluropyridine. 1H NMR (500 MHz, CDCl3) δ 9.83 (s, 1H), 8.52 (d, J=2.9 Hz, 1H), 7.86 (d, J=8.2 Hz, 2H), 7.67-7.70 (m, 1H), 7.42-7.46 (m, 1H), 7.29 (d, J=8.2 Hz, 2H), 3.0 (t, J=7.6 Hz, 2H), 2.82 (t, J=7.3 Hz, 2H).

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanol (37.9 mmol), tert-butyl 2-iodobenzoate (11.5 g, 37.9 mmol), sodium carbonate (10 g, 94.8 mmol), 1,1′-bis(diphenylphosphino)ferroncene-palladium dichloride dichloromethane complex (1:1), DMF (170 mL) and water (22 mL) was heated at 80° C. under nitrogen overnight. The reaction mixture was cooled to RT, poured into water, and the product was extracted with EtOAc-Hexanes (1:1). The combined organic extracts were washed with water and brine, dried (Na2SO4) and concentrated, and the residue was purified on silica gel (Hexane/EtOAc, from 2/1 to 1/1) to afford tert-butyl 4′-(3-hydroxypropyl)biphenyl-2-carboxylate. The reaction mixture was cooled to RT the product was extracted with EtOAc-Hexanes (1:1) The combined organic extracts were washed with water and brine dried (Na2SO4) concentrated the residue was purified on silica gel (Hexane/EtOAc, from 2/1 to 1/1)

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

Procedure: 2-Iodobenzoic acid (10.06 g, 40.56 mmol) was converted to 2-iodobenzoic chloride by reacting with oxalyl chloride (5.34 mL, 60.84 mmol) in methylene chloride (100 mL), initiated by a drop DMF. The solvent and excess oxalyl chloride were removed by rotary evaporation. To a 250 mL one neck round bottom flask was charged t-butanol with THF (50 mL) and then cooled to −78 C. A solution of n-butyl lithium in hexanes (2.5 M, 24.3 mL) was added, followed by the solution of 2-iodobenzoic chloride in THF (50 mL). The resulting reaction mixture was stirred at −78 C for 20 min and then at rt for 2 hours. The reaction was quenched by water and worked up. The product was purified by flash chromatography to afford the title compound as a white solid. The solvent and excess oxalyl chloride were removed by rotary evaporation To a 250 mL one neck round bottom flask was charged t-butanol with THF (50 mL) cooled to −78 C A solution of n-butyl lithium in hexanes (2.5 M, 24.3 mL) was added The resulting reaction mixture at rt for 2 hours The reaction was quenched by water The product was purified by flash chromatography

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 0.149 g (0.35 mmol) of the product of Step G and 0.132 g (0.43 mmol) of t-butyl 2-iodobenzoate in 1 mL of anhydrous DMF was added 5 mg of bis(triphenylphosphine)palladium(II) chloride. The mixture was degassed, flushed with nitrogen, then magnetically stirred under a nitrogen atmosphere for 12 hours at 100° C. The reaction mixture was cooled to room temperature, then partitioned between EtOAc and water. The organic layer was extracted, separated, dried (MgSO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 50% EtOAc-hexane. Evaporation of the purified fractions and drying in vacuo afforded 0.111 g (73%) of the title compound as an off-white amorphous solid. The mixture was degassed flushed with nitrogen The reaction mixture was cooled to room temperature partitioned between EtOAc and water The organic layer was extracted separated dried (MgSO4) filtered evaporated The residue was purified on a silica gel flash chromatography column eluted with 50% EtOAc-hexane Evaporation of the purified fractions drying in vacuo