1-(bromomethyl)-4-methylsulfanylbenzene

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: A solution of 1-(bromomethyl)-4-(methylsulfanyl)benzene (prepared according to D. D. M. Wayner, D. R. Arnold, Can J. Chem., 1984, 62, 1164) (2.54 g, 11.7 mmol) in THF (10 mL) was added dropwise to a slurry of Riecke® Zinc in THF (22.8 mL of a commercial suspension [5 g Zn/100 mL], 17.5 mmol) under nitrogen. During this time the temperature rose steadily to 35° C. After allowing the black slurry to cool to room temperature over 30 min bis(triphenylphosphine)nickel (II) chloride (762 mg, 1.17 mmol) was added followed by a solution of methyl 3-chloroisonicotinate (prepared according to J. Epsztajn, M. W. Plotka, A. Grabowska, Synth. Commun., 1997, 27, 1075) (1.0 g, 5.83 mmol) in THF (10 mL), dropwise, taking care to keep the temperature below 30° C. After the addition was complete the reaction was allowed to cool to room temperature over 1 h before being quenched by the addition of sat. NH4Cl (aq) (20 mL) while cooling with an ice bath. The mixture was filtered through Celite®, washing well with EtOAc (3×20 mL), the organic layer was separated, dried (MgSO4) and evaporated to give a brown oil. The residue was purified by column chromatography [SiO2; EtOAc:pentane, 1:3 increasing polarity to EtOAc:pentane, 1:1 and then to (EtOAc:MeOH:NH4OH, 95:5:0.5):pentane, 1:1] to give the title compound as an orange oil; δH (CDCl3, 400 MHz) 2.43 (3H, s), 3.82 (3H, s), 4.30 (2H, s), 7.05 (2H, d), 7.18 (2H, d), 7.67 (1H, br), 8.59 (2H, br); MS m/z (TS+) 274 (MH+). rose steadily to 35° C was added prepared the temperature below 30° C After the addition before being quenched by the addition of sat. NH4Cl (aq) (20 mL) while cooling with an ice bath The mixture was filtered through Celite® washing well with EtOAc (3×20 mL) the organic layer was separated dried (MgSO4) evaporated to give a brown oil The residue was purified by column chromatography [SiO2

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

Procedure: To a suspension of 4-methylthiobenzyl bromide (5.6 g. 25.8 mmol), thiotetronic acid (3.0 g, 25.8 mmol) in dioxane (50 ml), was added aqueous potassium hydroxide (25.8 mL). The mixture was stirred at temperatures in the range of 65°-70° C. for 3 hours. Then, the mixture was cooled to room temperature, poured into H20, acidified with HCl (2N) and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography on acid washed (5% H3PO4 in MeOH) silica gel (eluting solvent hexane/EtOAc 1/3) gave a white solid (1.72 g, 26.5%): m.p. 206°-208° C. poured into H20 extracted with EtOAc The organic extracts were dried over MgSO4 Evaporation and purification by flash chromatography on acid washed (5% H3PO4 in MeOH) silica gel (eluting solvent hexane/EtOAc 1/3)

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

Procedure: To a suspension of 4-methylthiobenzyl bromide (5.6 g. 25.8 mmol), thiotetronic acid (3.0 g, 25.8 mmol) in dioxane (50 ml), was added aqueous potassium hydroxide (25.8 mL). The mixture was stirred at temperatures in the range of 65°-70° C. for 3 hours. Then, the mixture was cooled to room temperature, poured into H20, acidified with HCl (2N) and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography on acid washed (5% H3PO4 in MeOH) silica gel (eluting solvent hexane/EtOAc 1/3) gave a white solid (1.72 g, 26.5%): m.p. 206°-208° C. poured into H20 extracted with EtOAc The organic extracts were dried over MgSO4 Evaporation and purification by flash chromatography on acid washed (5% H3PO4 in MeOH) silica gel (eluting solvent hexane/EtOAc 1/3)

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

Procedure: Using 0.22 g of 4-(methylthio)benzyl bromide, 3 ml of N,N-dimethylformamide, 0.05 g of sodium hydride (60% in oil), and 0.17 g of (3,3,3-trifluoropropyl)malononitrile, and according to the process described in the Production Example 26, there was obtained 0.15 g of 2-(4-(methylthio)benzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (34)).

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

Procedure: A solution of 1-(bromomethyl)-4-(methylsulfanyl)benzene (prepared according to D. D. M. Wayner, D. R. Arnold, Can J. Chem., 1984, 62, 1164) (2.54 g, 11.7 mmol) in THF (10 mL) was added dropwise to a slurry of Riecke® Zinc in THF (22.8 mL of a commercial suspension [5 g Zn/100 mL], 17.5 mmol) under nitrogen. During this time the temperature rose steadily to 35° C. After allowing the black slurry to cool to room temperature over 30 min bis(triphenylphosphine)nickel (II) chloride (762 mg, 1.17 mmol) was added followed by a solution of methyl 3-chloroisonicotinate (prepared according to J. Epsztajn, M. W. Plotka, A. Grabowska, Synth. Commun., 1997, 27, 1075) (1.0 g, 5.83 mmol) in THF (10 mL), dropwise, taking care to keep the temperature below 30° C. After the addition was complete the reaction was allowed to cool to room temperature over 1 h before being quenched by the addition of sat. NH4Cl (aq) (20 mL) while cooling with an ice bath. The mixture was filtered through Celite®, washing well with EtOAc (3×20 mL), the organic layer was separated, dried (MgSO4) and evaporated to give a brown oil. The residue was purified by column chromatography [SiO2; EtOAc:pentane, 1:3 increasing polarity to EtOAc:pentane, 1:1 and then to (EtOAc:MeOH:NH4OH, 95:5:0.5):pentane, 1:1] to give the title compound as an orange oil; δH (CDCl3, 400 MHz) 2.43 (3H, s), 3.82 (3H, s), 4.30 (2H, s), 7.05 (2H, d), 7.18 (2H, d), 7.67 (1H, br), 8.59 (2H, br); MS m/z (TS+) 274 (MH+). rose steadily to 35° C was added prepared the temperature below 30° C After the addition before being quenched by the addition of sat. NH4Cl (aq) (20 mL) while cooling with an ice bath The mixture was filtered through Celite® washing well with EtOAc (3×20 mL) the organic layer was separated dried (MgSO4) evaporated to give a brown oil The residue was purified by column chromatography [SiO2

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

Procedure: A solution of 1-(bromomethyl)-4-(methylsulfanyl)benzene (prepared according to D. D. M. Wayner, D. R. Arnold, Can J. Chem., 1984, 62, 1164) (2.54 g, 11.7 mmol) in THF (10 mL) was added dropwise to a slurry of Riecke® Zinc in THF (22.8 mL of a commercial suspension [5 g Zn/100 mL], 17.5 mmol) under nitrogen. During this time the temperature rose steadily to 35° C. After allowing the black slurry to cool to room temperature over 30 min bis(triphenylphosphine)nickel (II) chloride (762 mg, 1.17 mmol) was added followed by a solution of methyl 3-chloroisonicotinate (prepared according to J. Epsztajn, M. W. Plotka, A. Grabowska, Synth. Commun., 1997, 27, 1075) (1.0 g, 5.83 mmol) in THF (10 mL), dropwise, taking care to keep the temperature below 30° C. After the addition was complete the reaction was allowed to cool to room temperature over 1 h before being quenched by the addition of sat. NH4Cl (aq) (20 mL) while cooling with an ice bath. The mixture was filtered through Celite®, washing well with EtOAc (3×20 mL), the organic layer was separated, dried (MgSO4) and evaporated to give a brown oil. The residue was purified by column chromatography [SiO2; EtOAc:pentane, 1:3 increasing polarity to EtOAc:pentane, 1:1 and then to (EtOAc:MeOH:NH4OH, 95:5:0.5):pentane, 1:1] to give the title compound as an orange oil; δH (CDCl3, 400 MHz) 2.43 (3H, s), 3.82 (3H, s), 4.30 (2H, s), 7.05 (2H, d), 7.18 (2H, d), 7.67 (1H, br), 8.59 (2H, br); MS m/z (TS+) 274 (MH+). rose steadily to 35° C was added prepared the temperature below 30° C After the addition before being quenched by the addition of sat. NH4Cl (aq) (20 mL) while cooling with an ice bath The mixture was filtered through Celite® washing well with EtOAc (3×20 mL) the organic layer was separated dried (MgSO4) evaporated to give a brown oil The residue was purified by column chromatography [SiO2

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

Procedure: The compound was synthesized starting from N-(pentan-2-yl)benzimidazol-5-amine (102 mg; 0.5 mmol; 1 eq.), 4-methylthiobenzylbromide (120 mg; 0.55 mmol; 1.1 eq.) and K2CO3 (76 mg; 0.55 mmol; 1.1 eq.) according to method 6; Yield: 0.038 g (22.4%); MS m/z: 340.3 [M+H]+; 1H-NMR (400 MHz, DMSO d6): δ 0.85-0.89 (m, 3H); 1.12 (d, 3H, 3J=6.6 Hz); 1.33-1.47 (m, 3H); 1.61-1.68 (m, 1H); 2.40 (s, 3H); 3.92-3.94 (m, 1H, CH3—N—CH—C3H7); 4.30 (s, 2H); 6.77-6.79 (m, 2H); 7.13-7.15 (m, 2H); 7.23-7.25 (m, 2H); 7.31-7.33 (m, 1H); 7.90 (s, 1H); 11.90 (br s, 1H); HPLC (METHOD [A]): rt 16.75 min (85.6%) The compound was synthesized rt 16.75 min (85.6%)

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

Procedure: The compound was synthesized starting from N-isobutyl-benzimidazol-5-amine (95 mg; 0.5 mmol; 1 eq.), 4-methylthiobenzylbromide (120 mg; 0.55 mmol; 1.1 eq.) and K2CO3 (76 mg; 0.55 mmol; 1.1 eq.) according to method 6; Yield: 0.066 g (40.6%); MS m/z: 326.4 [M+H]+; 1H-NMR (400 MHz, DMSO d6): δ 0.92 (d, 6H, 3J=6.6 Hz); 2.01-2.08 (m, 1H); 2.41 (s, 3H); 3.21 (d, 2H, 3J=7.1 Hz); 4.53 (s, 2H); 6.68 (br s, 1H); 6.70 (dd, 1H, 3J=2.1 Hz, 3J=8.7 Hz); 7.13-7.18 (m, 4H); 7.34 (d, 1H, 3J=8.7 Hz); 7.90 (s, 1H); 11.91 (br s, 1H); HPLC (METHOD [A]): rt 16.40 min (99.5%) The compound was synthesized rt 16.40 min (99.5%)