5-bromo-2-(2-methylpropoxy)benzonitrile

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

Procedure: 5-Bromo-2-isobutoxybenzonitrile and triisopropyl borate were dissolved in a mixed solvent of THF and toluene and an n-butyllithium-hexane solution was added dropwise to the solution at a temperature below −60° C. After the temperature was elevated to −20° C., 1M hydrochloric acid was added, followed by stirring at room temperature to obtain (3-cyano-4-isobutoxyphenyl)boronic acid. F: 220. an n-butyllithium-hexane solution was added dropwise to the solution at a temperature below −60° C was elevated to −20° C.

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

Procedure: 5-Bromo-2-isobutoxybenzonitrile and triisopropyl borate were dissolved in a mixed solvent of THF and toluene and an n-butyllithium-hexane solution was added dropwise to the solution at a temperature below −60° C. After the temperature was elevated to −20° C., 1M hydrochloric acid was added, followed by stirring at room temperature to obtain (3-cyano-4-isobutoxyphenyl)boronic acid. F: 220. an n-butyllithium-hexane solution was added dropwise to the solution at a temperature below −60° C was elevated to −20° C.

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

Procedure: 5-Bromo-2-hydroxybenzonitrile, isobutyl bromide, and potassium carbonate were heated at 80° C. in DMF in the presence of tetra-n-butylammonium bromide to obtain 5-bromo-2-isobutoxybenzonitrile. F: 254, 256.

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

Procedure: 5-Bromo-2-isobutoxybenzonitrile and triisopropyl borate were dissolved in a mixed solvent of THF and toluene and an n-butyllithium-hexane solution was added dropwise to the solution at a temperature below −60° C. After the temperature was elevated to −20° C., 1M hydrochloric acid was added, followed by stirring at room temperature to obtain (3-cyano-4-isobutoxyphenyl)boronic acid. F: 220. an n-butyllithium-hexane solution was added dropwise to the solution at a temperature below −60° C was elevated to −20° C.

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

Procedure: 5-Bromo-2-hydroxybenzonitrile, isobutyl bromide, and potassium carbonate were heated at 80° C. in DMF in the presence of tetra-n-butylammonium bromide to obtain 5-bromo-2-isobutoxybenzonitrile. F: 254, 256.

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a test tube-type reaction vessel (10 mL) were added ethyl 4-methylthiazole-5-carboxylate (85.5 mg, 0.5 mmol), 5-bromo-2-isobutoxybenzonitrile (127.1 mg, 0.5 mmol) obtained in Reference Example 3, a palladium species, a ligand, a base (1.0 mmol), an additive (0.15 mmol), and a solvent (1.7 mL). Thereafter, the reaction vessel was filled with nitrogen, heated to 120° C. under airtight seal, and the reaction mixture was stirred. After the reaction was complete, a portion of the reaction mixture was diluted with DMSO and the solution obtained was measured by HPLC. The total HPLC area % of the compounds A to D and TM was set as 100% and the calculated yield of the target material was computed from the HPLC area % of the target material. The results are shown in Table 10. obtained in Reference Example 3 Thereafter, the reaction vessel was filled with nitrogen seal the solution obtained

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

Procedure: A suspension of sodium hydride (1.64 g, a 60% suspension in mineral oil, 37.5 mmol) in N,N-dimethylformamide (50 mL) was cooled to 0° C. and thereafter 2-methyl-1-propanol (3.47 mL, 37.5 mmol) was added thereto in small portions. The reaction mixture was stirred at room temperature for 20 minutes. The mixture was cooled again to 0° C., 2-fluoro-5-bromobenzonitrile (5.00 g, 25.0 mmol) was added thereto in small portions, and thereafter the reaction mixture was stirred at room temperature for 15 hours. After the reaction was complete, water (100 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (3×100 mL). The organic phases were combined, washed with a saturated aqueous sodium chloride solution (2×50 mL), and thereafter dried over anhydrous sodium sulfate. After removing sodium sulfate by filtration, the solvent was concentrated under reduced pressure. The crude product obtained was purified by silica gel chromatography (hexane/ethyl acetate=9/1) to obtain the title compound (6.04 g). Yield, 95%. The mixture was cooled again to 0° C. in small portions, and thereafter the reaction mixture was stirred at room temperature for 15 hours was then extracted with ethyl acetate (3×100 mL) washed with a saturated aqueous sodium chloride solution (2×50 mL) dried over anhydrous sodium sulfate After removing sodium sulfate by filtration the solvent was concentrated under reduced pressure The crude product obtained was purified by silica gel chromatography (hexane/ethyl acetate=9/1)

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

Procedure: 5-Bromo-2-isobutoxybenzonitrile and triisopropyl borate were dissolved in a mixed solvent of THF and toluene and an n-butyllithium-hexane solution was added dropwise to the solution at a temperature below −60° C. After the temperature was elevated to −20° C., 1 M hydrochloric acid was added and the whole was stirred at room temperature to obtain (3-cyano-4-isobutoxyphenyl)boronic acid. F: 220. an n-butyllithium-hexane solution was added dropwise to the solution at a temperature below −60° C was elevated to −20° C.

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

Procedure: 5-Bromo-2-hydroxybenzonitrile, isobutyl bromide, and potassium carbonate were heated at 80° C. in DMF in the presence of tetra-n-butylammonium bromide to obtain 5-bromo-2-isobutoxybenzonitrile. F: 254, 256.

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a test tube-type reaction vessel (60 mL) were added ethyl 4-methylthiazole-5-carboxylate (2.14 g, 12.5 mmol), 5-bromo-2-isobutoxybenzonitrile (2.54 g, 10.0 mmol) obtained in the Reference Example 1, and a solvent (7.6 mL), a palladium compound (0.025 mmol), a ligand (0.10 mmol), a base (21.0 mmol), carboxylic acid (0.10 mmol), an additive (0.10 mmol), and a reducing agent (0.10 mmol) listed in the Table 10. Thereafter, the reaction vessel was filled with nitrogen gas and sealed air-tight and the mixed solution was heated to 140° C. and stirred for 24 hours. After the completion of the reaction, a portion of the reaction solution was diluted with xylene and DMSO and the resulting solution was analyzed by HPLC measurement. The total HPLC area % of the compound A to D and TM was adjusted to 100%, the calculated yield of the subject material was computed from each HPLC area %. Calculation of the calculated yield from the HPLC area % of subject material was carried out by applying corresponding numbers in the following calculation formula. Yield (%) of TM=total amount of TM (mol)/[{total amount of A (mol)+total amount of C (mol)×2+total amount of TM (mol)}]×100 Total amount of each compound (mol)=HPLC area value (mAU) of each compound/HPLC area value (mAU/mol) per mol of each compound obtained in the Reference Example 1 Thereafter, the reaction vessel was filled with nitrogen gas sealed air-tight After the completion of the reaction Calculation of the calculated yield from the HPLC area % of subject material Yield (%) of TM=total amount of TM (mol)/[{total amount of A (mol)+total amount of C (mol)×2+total amount of TM (mol)

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a test tube-type reaction vessel (60 mL) were added ethyl 4-methylthiazole-5-carboxylate (2.14 g, 12.5 mmol), 5-bromo-2-isobutoxybenzonitrile (2.54 g, 10.0 mmol) obtained in the Reference Example 1 and xylene (7.6 mL). After adding compounds listed in the Table 9 as a palladium compound (0.025 mmol), a ligand (0.10 mmol), a base (21.0 mmol), a carboxylic acid (0.10 mmol), and an additive (1.0 mmol), the reaction vessel was filled with nitrogen gas and sealed air-tight. The reaction mixture was heated to 140° C. and stirred for 24 hours. After the completion of the reaction, a part of the reaction solution was diluted with xylene and DMSO and the resulting solution was analyzed by HPLC measurement. The total HPLC area % of the compound A to D and TM (TM means target compound) was adjusted to 100%, the calculated yield of the subject material was calculated from each HPLC area %. Calculation of the yield from the HPLC area % of the subject material was carried out by applying corresponding numbers in the following calculation formula. Yield (%) of TM=total amount of TM (mol)/[{total amount of A (mol)+total amount of C (mol)×2+total amount of TM (mol)}]×100 Total amount of each compound (mol)=HPLC area value (mAU) of each compound/HPLC area value (mAU/mol) per mol of each compound After adding compounds sealed air-tight After the completion of the reaction Calculation of the yield from the HPLC area % of the subject material Yield (%) of TM=total amount of TM (mol)/[{total amount of A (mol)+total amount of C (mol)×2+total amount of TM (mol)

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: After cooling a suspension of sodium hydride (1.64 g, 60% suspension in mineral oil, 37.5 mmol) in N,N-dimethylformamide (50 mL) to 0° C., 2-methyl-1-propanol (3.47 mL, 37.5 mmol) was added stepwise. And the reaction mixture was stirred at 25° C. for 20 minutes. Again, the reaction mixture was cooled to 0° C., 2-fluoro-5-bromobenzonitrile (5.00 g, 25.0 mmol) was added stepwise to the reaction mixture and the mixture was stirred at 25° C. for 15 hours. After the completion of the reaction, water (100 mL) was added and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layer was washed with saturated brine (2×50 mL), and dried over sodium sulfate anhydrous. After removing sodium sulfate by filtration, the solvent was evaporated under reduced pressure, and the resulting crude compound was purified on silica-gel chromatography (hexane/ethyl acetate=9/1) to obtain the titled compound (6.04 g). Yield: 95%. After cooling Again, the reaction mixture was cooled to 0° C. the mixture was stirred at 25° C. for 15 hours was added the mixture was extracted with ethyl acetate (3×100 mL) The combined organic layer was washed with saturated brine (2×50 mL) dried over sodium sulfate anhydrous After removing sodium sulfate by filtration the solvent was evaporated under reduced pressure the resulting crude compound was purified on silica-gel chromatography (hexane/ethyl acetate=9/1)