2,5-dibromobenzaldehyde

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

Procedure: 5 g (18.5 mmol) of 2,5-dibromobenzaldehyde, 3 mL (27.7 mmol) of 2-aminothiophenol, and 2.35 g (9.25 mmol) of iodine (I2) were dissolved in 100 mL of DMF. The solution was reacted at 100° C. for 1 hour. The acquired reactant was purified through a column, obtaining 4.64 g (Y=68%) of a white solid. The solution was reacted at 100° C. for 1 hour The acquired reactant was purified through a column obtaining 4.64 g (Y=68%) of a white solid

Conditions: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Methoxyphenylhydrazine hydrochloride (1 g) was suspended in 1M aqueous NaOH solution and extracted with ether. The organic phase was dried (MgSO4), filtered and concentrated to dryness to give 3-methoxyphenylhydrazine. 2,5-Dibromobenzaldehyde (1 g) and N-methylpyrrolidone (3.7 ml) were added and the mixture was heated under microwave conditions to 160° C. for 10 min. K2CO3 (1.015 g), CuI (36 mg) and trans-N,N′-dimethyl-cyclohexane-1,2-diamine (53 mg) were added and the mixture was heated under microwave conditions to 160° C. for 40 min. CuI (18 mg) and trans-N,N′-dimethyl-cyclohexane-1,2-diamine (26 mg) were added and the mixture was heated under microwave conditions to 160° C. for 20 min. The mixture was filtered and the filtrate was concentrated. The product was purified by chromatography (SiO2, CH2Cl2/MeOH 100:0=>95:5) to give the title compound (659 mg) as a yellow oil. MS (m/e)=303.0 [M+H+]. the mixture was heated under microwave conditions to 160° C. for 40 min the mixture was heated under microwave conditions to 160° C. for 20 min The mixture was filtered the filtrate was concentrated The product was purified by chromatography (SiO2, CH2Cl2/MeOH 100:0=>95:5)

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

Procedure: In analogy to Example 187, step 1, 4-methoxyphenylhydrazine was reacted with 2,5-dibromobenzaldehyde to give the title compound as a light brown solid. MS (m/e)=303.0 [M+H+].

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

Procedure: In analogy to Example 187, step 1, 2-methoxyphenylhydrazine was reacted with 2,5-dibromobenzaldehyde to give the title compound as a brown oil. MS (m/e)=303.2 [M+H+].

Conditions: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Methoxyphenylhydrazine hydrochloride (1 g) was suspended in 1 M aqueous NaOH solution and extracted with ether. The organic phase was dried (MgSO4), filtered and concentrated to dryness to give 3-methoxyphenylhydrazine. 2,5-Dibromobenzaldehyde (1 g) and N-methylpyrrolidone (3.7 ml) were added and the mixture was heated under microwave conditions to 160° C. for 10 min. K2CO3 (1.015 g), Cul (36 mg) and trans-N,N′-dimethyl-cyclohexane-1,2-diamine (53 mg) were added and the mixture was heated under microwave conditions to 160° C. for 40 min. Cul (18 mg) and trans-N,N′-dimethyl-cyclohexane-1,2-diamine (26 mg) were added and the mixture was heated under microwave conditions to 160° C. for 20 min. The mixture was filtered and the filtrate was concentrated. The product was purified by chromatography (SiO2, CH2Cl2/MeOH 100:0=>95:5) to give the title compound (659 mg) as a yellow oil. MS (m/e)=303.0 [M+H+]. the mixture was heated under microwave conditions to 160° C. for 40 min the mixture was heated under microwave conditions to 160° C. for 20 min The mixture was filtered the filtrate was concentrated The product was purified by chromatography (SiO2, CH2Cl2/MeOH 100:0=>95:5)

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

Procedure: To a mixed solution of toluene (2250 ml) and distilled water (250 ml) at 0° C. is added finely ground potassium phosphate tribasic (699.23 g, 3.29 mol) portionwise over 10 minutes. This mixture is then allowed to warm to room temperature, followed by the addition of 2,5-dibromobenzaldehyde (235.0 g, 890 mmol) and cyclopropylboronic acid (68.92 g, 801 mmol). After stirring at room temperature for 50 minutes under a blanket of nitrogen tetrakis(triphenylphosphine)palladium (102.89 g, 89 mmol) is added over 10 minutes, washing residual solid with toluene (50 ml). The reaction mixture is then stirred at 80° C. for 22 hours, followed by cooling to room temperature and addition of distilled water (500 ml). The mixture is filtered through a pad of silica (washing with additional ethyl acetate) and the aqueous phase is extracted with ethyl acetate (2×300 ml). The combined organic extracts are washed with brine (500 ml), dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on silica gel (iso-hexane/ethyl acetate as eluant) followed by distillation under reduced pressure to afford 5-bromo-2-cyclopropylbenzaldehyde as a yellow oil. To a mixed solution of toluene (2250 ml) and distilled water (250 ml) at 0° C. is added over 10 minutes washing residual solid with toluene (50 ml) by cooling to room temperature addition of distilled water (500 ml) The mixture is filtered through a pad of silica (washing with additional ethyl acetate) the aqueous phase is extracted with ethyl acetate (2×300 ml) The combined organic extracts are washed with brine (500 ml) dried with anhydrous magnesium sulfate concentrated under reduced pressure The residue is purified by chromatography on silica gel (iso-hexane/ethyl acetate as eluant) followed by distillation under reduced pressure

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

Procedure: 5 g (18.5 mmol) of 2,5-dibromobenzaldehyde, 3 mL (27.7 mmol) of 2-aminothiophenol, and 2.35 g (9.25 mmol) of iodine (I2) were dissolved in 100 mL of DMF. The solution was reacted at 100° C. for 1 hour. The acquired reactant was purified through a column, obtaining 4.64 g (Y=68%) of a white solid. The solution was reacted at 100° C. for 1 hour The acquired reactant was purified through a column obtaining 4.64 g (Y=68%) of a white solid

Conditions: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Methoxyphenylhydrazine hydrochloride (1 g) was suspended in 1M aqueous NaOH solution and extracted with ether. The organic phase was dried (MgSO4), filtered and concentrated to dryness to give 3-methoxyphenylhydrazine. 2,5-Dibromobenzaldehyde (1 g) and N-methylpyrrolidone (3.7 ml) were added and the mixture was heated under microwave conditions to 160° C. for 10 min. K2CO3 (1.015 g), CuI (36 mg) and trans-N,N′-dimethyl-cyclohexane-1,2-diamine (53 mg) were added and the mixture was heated under microwave conditions to 160° C. for 40 min. CuI (18 mg) and trans-N,N′-dimethyl-cyclohexane-1,2-diamine (26 mg) were added and the mixture was heated under microwave conditions to 160° C. for 20 min. The mixture was filtered and the filtrate was concentrated. The product was purified by chromatography (SiO2, CH2Cl2/MeOH 100:0=>95:5) to give the title compound (659 mg) as a yellow oil. MS (m/e)=303.0 [M+H+]. the mixture was heated under microwave conditions to 160° C. for 40 min the mixture was heated under microwave conditions to 160° C. for 20 min The mixture was filtered the filtrate was concentrated The product was purified by chromatography (SiO2, CH2Cl2/MeOH 100:0=>95:5)

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

Procedure: The compounds in TABLE 1 were prepared using the chemistry described in EXAMPLES 1, 4, 5 and 6 or with following modifications: 1) EXAMPLES 47 to 50 (where R1=R21) were prepared as described in EXAMPLE 1 substituting 4-bromo-4′-(trifluoromethoxy)biphenyl-3-carbaldehyde with 2,5-dibromobenzaldehyde; 2) EXAMPLES 117 to 133 were prepared as described in EXAMPLE 1 substituting methyl 2-amino-5-bromobenzoate with methyl 5-amino-2-bromobenzoate; 3) EXAMPLES 111 to 113 were prepared from the intermediate from EXAMPLE 1 Step H using the procedure described in EXAMPLE 42A/42B. The compounds in TABLE 1 were prepared 1) EXAMPLES 47 to 50 (where R1=R21) were prepared 2) EXAMPLES 117 to 133 were prepared

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

Procedure: 5 g (18.5 mmol) of 2,5-dibromobenzaldehyde, 3 mL (27.7 mmol) of 2-aminothiophenol, and 2.35 g (9.25 mmol) of iodine were dissolved in 100 mL of DMF. The solution was reacted at 100° C. for 1 hour. The obtained reactant was purified through a column, obtaining 4.64 g (Y=68%) of a white solid. The solution was reacted at 100° C. for 1 hour The obtained reactant was purified through a column obtaining 4.64 g (Y=68%) of a white solid

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

Procedure: In analogy to Example 187, step 1, 4-methoxyphenylhydrazine was reacted with 2,5-dibromobenzaldehyde to give the title compound as a light brown solid. MS (m/e)=303.0 [M+H+].

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

Procedure: In analogy to Example 187, step 1, 2-methoxyphenylhydrazine was reacted with 2,5-dibromobenzaldehyde to give the title compound as a brown oil. MS (m/e)=303.2 [M+H+].