, 106 µmol) are added. Reaction mixture was heated under argon at 80°C for 6h. Reaction mixture was cooled down to room temperature, diluted with EtOAc, washed with brine, dried over Na 2 SO 4 and evaporated. Crude product was purified by flash chromatography using as eluent a mixture of DCM/cyclohexane and then DCM/MeOH, to give 281 mg of a white powder (47 %), 60 mmol) were added in 5 mL of dry and degassed DMF. Then, PdCl 2 (dppf) 2 (68 mg, 53 µmol) and CuI, vol.20

. Hz,

, 254 mg, 448 µmol), and 5 mL of a mixture dry Et 2 O/dry THF (1:1). Iodomethane (27.7 µL, 1.345 mmol) was then added, and reaction mixture was stirred at room temperature. After 1h30 and 4h, iodomethane (27.7 µL, 1.345 mmol) was added again. Reaction mixture was then evaporated to dryness. Residue was triturated in Et 2 O, filtrated, and the residue was purified by preparative HPLC (ammonium formate buffer, pH 3.8) to give the titled product as a brown residue (55 mg, 17%), a 25 mL flask were added, vol.3

, In a 5 mL flask were added N-(3,4-dimethoxy-phenyl)-2-[3-(4-fluoro-phenyl)-isothioureido]-N-methyl-propionamide (26c) (75 mg, 180 µmol), K 2 CO 3 (26 mg, 188 µmol), sodium iodide (14 mg, 93 µmol), and 1 mL of acetonitrile (QS 0.2 M). The suspension was stirred at room temperature for 10 min, and 2-(bromomethyl)-1,3-difluorobenzene (40 mg, 193 µmol) was then added. The suspension was stirred at room temperature for 16 hours. The medium was then evaporated, residue was dissolved in EtOAc, washed with water and brine, vol.3

. Mhz, Cl 2 ): ? (ppm) 1.22 (d, J = 6.4 Hz, 3H), 3.25 (s, 3H), 3.63 (s, 3H)

, 6-Difluoro-benzylsulfanyl)-3-(4-fluoro-phenyl)-5-methyl-3H-imidazol-4-yl]-(3,4-dimethoxy-phenyl)-methyl-amine

, 90 mmol), and T3P® in EtOAc (266 µL, 0.45 mmol) were then added. Half of the mixture was heated with microwave at 150°C for 10 min. The expected product was observed, starting material has disappeared, but unfortunately, reaction mixture was dirty. The other half of the reaction mixture was heated at reflux for 45 hours. T3P® (3 eq) and DIEA (6 eq) were added after 4, 19, and 24 hours. T3P® (1.5 eq) and DIEA (3 eq) were added after 42 hours. Reaction mixture was then diluted with EtOAc, washed with water, a saturated aqueous solution of NaHCO 3 , and brine. Organic phase was then dried over Na 2 SO 4 and evaporated

, CDCl 3 ): ? (ppm) 2.11 (s, 3H, CH 3 ),2.87 (s, 3H

1. Hz and ). Ar, .83 (m, 3H, Ar), 6.93-6.97 (m, 4H, Ar), 7.19 (m, 1H, Ar). 13 C NMR (75 MHz, vol.6, pp.6-76

. Hz, , vol.162

, 4-dimethoxy-N-methylaniline (3a) (500 mg, 2.99 mmol), 6 mL of EtOAc, (2R)-2-(tert-butoxycarbonylamino)-6-(9H-fluoren-9-ylmethoxycarbonylamino)hexanoic acid (1681.33 mg, 3.59 mmol), DIEA (1.57 mL, 8.97 mmol) and T3P® (2.64 mL, 4.49 mmol). The reaction mixture was then stirred at 50°C for 1 hour. The reaction mixture was diluted in EtOAc, washed with a saturated aqueous solution of NaHCO 3 and with brine, and the organic phase was dried over MgSO 4 and evaporated to dryness to give 1.85 g of the titled compound as dark red oil, leading to a quantitative yield, vol.3

, 99 mmol) and TFA (2.56 mL, 33.42 mmol) were dissolved in 5 (ppm) 1.73-1.89 (m, 1H), vol.1

, In a 50 mL flask were added methyl 2-(bromomethyl)-1,3-difluoro-benzene (419.82 mg, 2.03 mmol), K 2 CO 3 (308.3 mg, 2.23 mmol) and 10.2 mL of acetonitrile. The suspension was stirred at room temperature for 10 min, and methyl (4S)-5-(3,4-dimethoxy-N-methyl-anilino)-4-[(4-fluorophenyl)carbamothioylamino]-5-oxo-pentanoate (28c) (940 mg, 2.03 mmol) was then added at the reaction mixture and it was stirred at room temperature overnight. The medium was then evaporated

. Mgso4, The crude was evaporated to dryness to give 1.05 g of the desired product as dark oil, leading to a 87% yield

, CDCl 3 ): ? (ppm) 1.93 (brs, 2H), 2.29 (brs, 2H), vol.3

, 6-difluorophenyl)methylsulfanyl]-5-(3,4-dimethoxy-N-methyl-anilino)-1-(4-fluorophenyl)imidazol-4-yl]propanoate (28). In a 100 mL flask, Methyl, vol.3, issue.2

-. , 6-difluorophenyl)methylsulfanyl]-N-(4-fluorophenyl)carbonimidoyl]amino]-5-(3,4-dimethoxy-N-methyl-anilino)-5-oxo-pentanoate, vol.5

, The medium was stirred at 80°C for 24 hours. The reaction mixture was diluted in EtOAc and washed with water, brine, and dried over MgSO 4 and evaporated to dryness. The conversion was not complete. The residue was dissolved in 17 mL of EtOAc, DIEA (1.88 mL, 10.21 mmol), and 17 mL of EtOAc

. Etoac, 70/30) to give 265 mg of the desired product with the starting material. The crude was again dissolved in EtOAc and T3P® (0.6 mL, 1.018 mmol), DIEA (0.376 mL, vol.2, p.35

, CDCl 3 ): ? (ppm) 2.67-2.72 (m, 4H), 2.85 (s, 3H), 3.62 (s, 3H), 3.79 (s, 3H)

, Hz, 1H), 6.72 (d, J = 8.7 Hz, 1H), 6.77 (t, J = 7.7 Hz, 2H), 6.87-6.92 (m, 4H)

, 4-dimethoxy-N-methyl-anilino)-1-(4-fluorophenyl)imidazol-4-yl]propanoic acid (29)

. Mhz,

, J = 23.0 Hz), 129.1 (d, J = 8.9 Hz), vol.129, pp.175-183

, 4-dimethoxy-N-methyl-anilino)-1-(4-fluorophenyl)imidazol-4-yl]butyl-trimethyl-ammonium;formate (30)

. Iodomethane, 59 µL, 0.3 mmol) and DIEA

, mmol) were added at the reaction mixture and it was stirred at room temperature overnight. The reaction mixture was evaporated to dryness, a 5 mL flask was diluted 4, 2665.

, Vanessa Hoguet are recipients of a doctoral fellowship of the French Ministère de la Recherche. NMR acquisitions were done at the Laboratoire d'Application de Résonance Magnétique Nucléaire (LARMN)

. Etoac,

D. Dcm,

, DIEA, diisopropylethylamine; DIO, diet-induced obese

. Dme, N. Dmf, and N. ,

. Dmso,

, EtOH, ethanol; eq, equivalent; GI, gastrointestinal

, GLP-1, Glucagon Like Peptide-1

. Gp-bar1, G-protein coupled bile acid receptor 1

H. Hfd, Fat Diet

. Meoh and . Pbs,

, THF, tetrahydrofuran; TLC, thin layer chromatography. T3P, 1-Propylphosphonic acid cyclic anhydride

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