Supporting Information. Design and Synthesis of 2-Arylbenzimidazoles and. Evaluation of Their Inhibitory Effect against. Chlamydia pneumoniae

Supporting Information Design and Synthesis of 2-Arylbenzimidazoles and Evaluation of Their Inhibitory Effect against Chlamydia pneumoniae Leena Keurulainen,, Olli Salin,, Antti Siiskonen,, Jan Marco Kern, Joni Alvesalo, Paula Kiuru, Matthias Maass, Jari Yli-Kauhaluoma, * Pia Vuorela,, * Division of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Helsinki, P.O. Box 56 (Viikinkaari 5 E), FI-00014 University of Helsinki, Finland, Pharmaceutical Sciences, Department of Biosciences, Åbo Akademi University, Biocity, Artillerigatan 6 A, FI-20520 Turku, Finland, Institute of Medical microbiology, Hygiene and Infectious Diseases, PMU University Hospital Salzburg, Muellner Hauptstr. 48, A-5020 Salzburg, Austria, Division of Pharmaceutical Biology, Faculty of Pharmacy, University of Helsinki, P.O. Box 56 (Viikinkaari 5 E), FI-00014 University of Helsinki, Finland Contents Syntheses and Characterization of Compounds Calculated Log P values References S2 S27 S28 S1

4-Methoxy-1,2-benzenediamine (1b). To a solution of 2-methoxy-2-nitroaniline (1.01 g, 6.01 mmol) in EtOH (42 ml) and EtOAc (42 ml) was added 10% Pd/C (0.12 g) in small portions and the solution was hydrogenated at room temperature for 5 h. The reaction mixture was filtered through a small pad of Celite, washed with EtOH, and eluent was evaporated in vacuo to give a dark solid (0.82 g, quant.), which was carried to the next step without further purification. 1 H NMR (300 MHz, DMSO-d 6 ) δ 6.41 (d, J 8.4 Hz, 1H), 6.16 (d, J 3.0 Hz, 1H), 5.96 (dd, J 2.9, 8.3 Hz, 1H), 4.49 (s, 2H), 3.98 (s, 2H), 3.57 (s, 3H). ( 1 H NMR was in agreement with reported data 1 ). R f = 0.19 (EtOAc : n-hexane = 1 : 2). 3-Nitro-N-[2-[(3-nitrobenzoyl)amino]-4-methoxyphenyl]benzamide (3). Synthesis according to the general procedure A using 1b (0.76 g, 5.5 mmol) as a starting compound gave bisamide 3 (2.21 g, 96%) as a purple powder. 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.61 (br s, 2H), 8.81 8.79 (m, 2H), 8.45 8.34 (m, 4H), 7.83 7.73 (m, 2H), 7.64 (d, J 9.0 Hz, 1H), 7.39 (d, J 3.0 Hz, 1H), 6.78 (dd, J 2.7, 8.7 Hz, 1H), 3.78 (s, 3H). R f = 0.26 (EtOAc : n-hexane = 1 : 1). 3-Nitro-N-[2-[(3-nitrobenzoyl)amino]-4-methylphenyl]benzamide (4). Synthesis according to the general procedure A using 4-methyl-1,2-diaminobenzene 1c (0.67 g, 5.5 mmol) as a starting compound gave bisamide 4 (2.16 g, 94%) as a light brown powder. 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.30 (s, 2H), 8.77 8.76 (m, 2H), 8.43 8.37 (m, 4H), 7.81 (t, J 8.1 Hz, 2H), 7.56 7.51 (m, 2H), 7.15 7.13 (m, 1H), 2.37 (s, 3H). R f = 0.49 (EtOAc : n-hexane = 1 : 1). 3-Nitro-N-[2-[(3-nitrobenzoyl)amino]-4-chlorophenyl]benzamide (5). Synthesis according to the general procedure A using 4-chloro-1,2-diaminobenzene 1d (0.78 g, 5.5 mmol) as a starting compound gave bisamide 5 (2.41 g, 99%) as a light yellow powder. 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.50 (s, 2H), 8.79 8.76 (m, 2H), 8.42 8.37 (m, 4H), 7.83 7.77 (m, 3H), 7.71 (d, J 8.7, Hz, 1H), 7.36 (dd, J 8.7, S2

2.1 Hz, 1H). R f = 0.49 (EtOAc : n-hexane = 1 : 1). 3-Nitro-N-[2-[(3-nitrobenzoyl)amino]-3-methylphenyl]benzamide (6). Synthesis according to the general procedure A using 3-methyl-1,2-diaminobenzene 1e (0.67 g, 5.5 mmol) as a starting compound gave bisamide 6 (2.22 g, 96%) as a light brown powder. 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.36 (s, 1H), 10.36 (s, 1H), 8.81 (t, J 1.7 Hz, 1H), 8.68 (t, J 2.0 Hz, 1H), 8.45 8.32 (m, 4H), 7.81 7.73 (m, 2H), 7.56 (d, J 6.9 Hz, 1H), 7.30 7.19 (m, 2H), 2.28 (s, 3H). R f = 0.42 (EtOAc : n-hexane = 1 : 1). 2-Methyl-N-[2-[(2-methyl-3-nitrobenzoyl)amino]phenyl]-3-nitrobenzamide (7). To the solution of 2-methyl-3-nitrobenzoic acid (2.17 g, 12.0 mmol, 1 equiv) in dry THF (20 ml) was added oxalyl chloride (1.12 ml, 13.2 mmol, 1.1 equiv) and a catalytic amount of DMF. The resulting solution was stirred for 1.5 h and reaction was completed by concentrating solution under reduced pressure to give yellow crystals as the crude acyl chloride (2.39 g). Synthesis according to the general procedure A using 1,2-diaminobenzene 1a (0.59 g, 5.50 mmol), and the acyl chloride (2.31 g, 11.6 mmol) prepared above gave bisamide 7 (2.18 g, 91%) as an off-white powder. 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.01 (s, 2H), 7.99 (d, J 8.4 Hz, 2H), 7.86 (d, J 7.8 Hz, 2H), 7.73 7.70 (m, 2H), 7.56 (t, J 8.0 Hz, 2H), 7.34 7.30 (m, 2H), 2.43 (s, 6H). R f = 0.38 (EtOAc : n-hexane = 1 : 1). 4-Methoxy-N-[2-[(4-methoxy-3-nitrobenzoyl)amino]phenyl]-3-nitrobenzamide (8). Following the procedure for the preparation of 7, the crude acyl chloride (2.55 g) was made from 4-methoxy-3- nitrobenzoic acid (2.37 g, 12.0 mmol, 1 equiv). Synthesis according to the general procedure A using 1,2-diaminobenzene 1a (0.59 g, 5.5 mmol) and the acyl chloride (2.49 g, 11.5 mmol) prepared above gave bisamide 8 (2.33 g, 91%) as an off-white powder. 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.17 (s, 2H), 8.48 (d, J 1.8 Hz, 2H), 8.25 (dd, J 8.9, 2.3 Hz, 2H), 7.66 7.63 (m, 2H), 7.50 (d, J 9.3 Hz, 2H), 7.31 7.28 (m, 2H), 4.00 (s, 6H). R f = 0.34 (EtOAc). S3

4-Nitro-N-[2-[(4-nitrobenzoyl)amino]phenyl]benzamide (9). Synthesis according to the general procedure A using 1,2-diaminobenzene 1a (0.59 g, 5.5 mmol) and 4-nitrobenzoyl chloride (2.14 g, 11.5 mmol) as starting compounds gave bisamide 9 (2.08 g, 93%) as a light yellow powder. 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.44 (br s, 2H), 8.36 (d, J 8.7 Hz, 4H), 8.20 (d, J 8.7 Hz, 4H), 7.70 7.67 (m, 2H), 7.31 7.28 (m, 2H). R f = 0.51 (EtOAc : n-hexane = 1 : 1). 2-[(3-Nitrobenzoyl)amino]phenyl 3-nitrobenzoate (10). Synthesis according to the general procedure A using 2-aminophenol (0.60 g, 5.5 mmol) as a starting compound gave 10 (2.16 g, 96%) as a light yellow powder. 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.59 (s, 1H), 8.78 (t, J 1.8 Hz, 1H), 8.61 (t, J 1.8 Hz, 1H), 8.54 8.47 (m, 2H), 8.40 8.37 (m, 1H), 8.27 (d, J 7.5 Hz, 1H), 7.85 (t, J 8.1 Hz, 1H), 7.76 (t, J 8.1 Hz, 1H), 7.72 7.69 (m, 1H), 7.52 7.48 (m, 1H), 7.44 7.39 (m, 2H). R f = 0.58 (EtOAc : n-hexane = 1 : 1). 5-Methoxy-2-(3-nitrophenyl)-1H-benzimidazole (12). Following the general procedure B, the product was synthesized from 3 (2.10 g, 4.81 mmol). Purification by flash chromatography on silica gel (EtOAc) gave 12 as a yellow powder (0.80 g, 62%). 1 H NMR (300 MHz, DMSO-d 6 ) δ 13.1 (br s, 1H), 8.95 (t, J 1.8 Hz, 1H), 8.56 8.53 (m, 1H), 8.30 8.26 (m, 1H), 7.82 (t, J 8.0 Hz, 1H), 7.53 (d, J 8.7 Hz, 1H), 7.10 (s, 1H), 6.88 (dd, J 8.9, 2.6 Hz, 1H), 3.82 (s, 3H). 13 C NMR (75 MHz, DMSO-d 6 ) δ 156.3, 148.6, 148.4, 132.1, 131.9, 130.6, 123.8, 120.5, 112.5, 55.5. LC-MS: [M + H] +, m/z 270 (t r = 4.4 min). R f = 0.32 (EtOAc : n-hexane = 1 : 1). 5-Methyl-2-(3-nitrophenyl)-1H-benzimidazole (13). Following the general procedure B, the product was synthesized from 4 (2.10 g, 5.00 mmol). Recrystallization from EtOH gave 13 as a yellow powder (0.75 g, 59%). Mp: 200 201 C (lit. 2 195 C). 1 H NMR (300 MHz, DMSO-d 6 ) δ 13.12 (s, 1H), 8.98 (t, J S4

2.0 Hz, 1H), 8.61 8.56 (m, 1H), 8.30 (ddd, J 8.2, 2.3, 1.0 Hz, 1H), 7.83 (t, J 8.0 Hz, 1H), 7.47 (d, J 30.5 Hz, 2H), 7.07 (d, J 7.9 Hz, 1H), 2.37 (m, 3H). 13 C NMR (75 MHz, DMSO-d 6 ) δ 148.7, 148.3, 132.3, 132.0, 131.9, 130.6, 124.2, 124.0, 120.7, 118.7 (br), 111.3 (br), 21.3. LC-MS: [M + H] +, m/z 254 (t r = 4.5 min). R f = 0.48 (EtOAc : n-hexane = 1 : 1). 5-Chloro-2-(3-nitrophenyl)-1H-benzimidazole (14). Following the general procedure B, the product was synthesized from 5 (2.20 g, 5.00 mmol). Recrystallization from EtOH/EtOAc (1 : 1) gave 14 as a purple powder (0.56 g, 47%). Mp: 243 C (lit. 3 187 C). 1 H NMR (300 MHz, DMSO-d 6 ) δ 13.44 (s, 1H), 8.97 (t, J 2.0 Hz, 1H), 8.58 8.55 (m, 1H), 8.32 (ddd, J 8.3, 2.1, 1.1 Hz, 1H), 7.83 (t, J 8.1 Hz, 1H), 7.65 (br s, 2H), 7.25 (dd, J 8.4, 1.8 Hz, 1H). 13 C NMR (75 MHz, DMSO-d 6 ) δ 150.4, 148.3, 132.6, 131.2, 131.0, 127.3 (br), 124.5, 122.9 (br), 121.0, 112.9 (br). LC-MS: [M + H] +, m/z 274 (t r = 6.4 min). R f = 0.53 (EtOAc : n-hexane = 1 : 1). 4-Methyl-2-(3-nitrophenyl)-1H-benzimidazole (15). Following the general procedure B, the product was synthesized from 6 (2.10 g, 5.00 mmol). Recrystallization from EtOH gave 15 as yellow crystals (0.99 g, 78%). Mp: 196 C. 1 H NMR (300 MHz, CD 3 OD) δ 9.03 (s, 1H), 8.51 (d, J 8.4 Hz, 1H), 8.34 (d, J 8.4 Hz, 1H), 7.79 (t, J 8.3 Hz, 1H), 7.46 (d, J 7.8 Hz, 1H), 7.21 7.16 (m, 1H), 7.08 (d, J 7.5 Hz, 1H), 2.64 (s, 3H). 13 C NMR (75 MHz, DMSO-d 6 ) δ 150.3, 133.6, 133.1, 131.5, 125.4, 125.0, 124.5, 122.6, 17.1. R f = 0.48 (EtOAc : n-hexane = 1 : 1). 2-(2-Methyl-3-nitrophenyl)-1H-benzimidazole (16). Following the general procedure B, the product was synthesized from 7 (2.17 g, 5.00 mmol). Recrystallization from EtOH/H 2 O gave 16 as a brownish powder (0.63 g, 56%). Mp: 224 225 C. 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.12 8.06 (m, 2H), 7.79 7.74 (m, 2H), 7.69 (t, J 8.0 Hz, 1H), 7.44 7.39 (m, 2H), 2.59 (s, 3H). 13 C NMR (75 MHz, DMSO-d 6 ) δ 151.4, 148.7, 135.9, 134.6, 131.1, 130.2, 127.4, 125.9, 124.0, 115.0, 16.2. LC-MS: [M + H] +, m/z 254 (t r S5

= 3.6 min). R f = 0.19 (EtOAc : n-hexane = 1 : 1). 2-(4-Methoxy-3-nitrophenyl)-1H-benzimidazole (17). Following the general procedure B, the product was synthesized from 8 (2.33 g, 5.00 mmol). Recrystallization from EtOH gave 17 as a green-yellow powder (0.34 g, 31%). Mp: 225 227 C. 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.69 (d, J 2.1 Hz, 1H), 8.46 (dd, J 8.9, 2.5 Hz, 1H), 7.63 7.57 (m, 3H), 7.26 7.21 (m, 2H), 4.02 (s, 3H). 13 C NMR (75 MHz, DMSO-d 6 ) δ 153.3, 149.1, 139.2, 138.9 (br), 132.4, 123.1, 122.6, 122.3, 115.2, 57.1. LC-MS: [M + H] +, m/z 270 (t r = 3.9 min). R f = 0.20 (EtOAc : n-hexane = 1 : 1). 2-(4-Nitrophenyl)-1H-benzimidazole (18). Following the general procedure B, the product was synthesized from 9 (2.03 g, 5.00 mmol). Recrystallization from MeOH gave 18 as yellow crystals (0.55 g, 46%). Mp: 319 C (lit. 4 318 321 C). 1 H NMR (300 MHz, DMSO-d 6 ) δ 13.29 (s, 1H), 8.41 (s, 4H), 7.73 (d, J 7.5 Hz, 1H), 7.59 (d, J 6.9 Hz, 1H), 7.29 7.24 (m, 2H). 13 C NMR (75 MHz, DMSO-d 6 ) δ 149.0, 147.8, 143.8, 136.0, 135.2, 127.4 (2C), 124.3 (2C), 123.6, 122.3, 119.5, 111.8. ( 1 H NMR and 13 C NMR were in agreement with reported data 5 ). LC-MS: [M + H] +, m/z 240 (t r = 4.4 min). R f = 0.58 (EtOAc : n-hexane = 1 : 1). 2-(3-Nitrophenyl)-1,3-benzoxazole (19). Compound 10 (4.07 g, 10.0 mmol, 1 equiv) and p-tsa (3.80 g, 20.0 mmol, 2 equiv) were refluxed in p-xylene according to the general procedure B. Reaction mixture was partitioned between EtOAc and saturated NaHCO 3 solution. Recrystallization from EtOAc gave 19 as purple crystals (0.13 g, 42%). Mp: 207 C. 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.87 (t, J 2.1 Hz, 1H), 8.61 (d, J 8.1 Hz, 1H), 8.47 (dd, J 8.6, 2.3 Hz, 1H), 7.96 7.85 (m, 3H), 7.54 7.44 (m, 2H). ( 1 H NMR was in with reported data 6 ). 13 C NMR (75 MHz, DMSO-d 6 ) δ 160.3, 150.4, 148.3, 141.2, 133.2, 131.3, 127.9, 126.3, 126.3, 125.3, 121.7, 120.3, 111.3. LC-MS: [M + H] +, m/z 241 (t r = 7.5 min). R f = 0.77 (EtOAc : n-hexane = 1 : 1). S6

1-Methyl-2-(3-nitrophenyl)benzimidazole (20). To a solution of 11 (2.39 g, 10.0 mmol, 1 equiv) in DMF (70 ml) was added K 2 CO 3 (1.38 g, 10.0 mmol, 1 equiv) and iodomethane (9.68 ml, 11.0 mmol, 1.1 equiv). The resulting mixture was stirred for 19 h, and reaction was quenched by addition of water (600 ml). The resulting precipitate was filtered off and washed with water (2 30 ml). Recrystallization from EtOH gave 20 as beige crystals (2.38 g, 94%). Mp: 162 163 C (lit. 7 151 154 C). 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.66 (t, J 1.8 Hz, 1H), 8.39 (dd, J 8.4, 1.5 Hz, 1H), 8.33 (d, J 7.8 Hz, 1H), 7.88 (t, J 7.8 Hz, 1H), 7.70 (dd, J 20.1, 7.5 Hz, 2H), 7.37 7.26 (m, 2H), 3.95 (s, 3H). 13 C NMR (75 MHz, DMSO-d 6 ) δ 150.7, 148.0, 142.3, 136.7, 135.4, 131.7, 130.4, 124.2, 123.9, 122.9, 122.3, 119.3, 110.8, 31.7. LC-MS: [M + H] +, m/z 254 (t r = 3.9 min). R f = 0.61 (EtOAc : n-hexane = 1 : 1). 1-tert-Butyl-2-(3-nitrophenyl)benzimidazole (21). A suspension of 11 (1.20 g, 5.00 mmol, 1 equiv), Cs 2 CO 3 (3.26 g, 10.0 mmol, 2 equiv) and (t-boc) 2 O (1.42 g, 6.51 mmol, 1.3 equiv) in dry acetonitrile (80 ml) was stirred for 1 h under an argon atmosphere. Reaction mixture was filtered and evaporated in vacuo. The resulting residue was dissolved to EtOAc (70 ml), washed with water (70 ml) and brine (70 ml), dried over anhydrous Na 2 SO 4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on SiO 2 (EtOAc : n-hexane = 1 : 2) to give 21 as light yellow crystals (1.60 g, 94%). 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.58 (t, J 2.0 Hz, 1H), 8.38 (ddd J 8.4, 2.3, 0.9 Hz, 1H), 8.21 8.17 (m, 1H), 8.07 8.04 (m, 1H), 7.84 7.78 (m, 2H), 7.51 7.40 (m, 2H), 1.37 (s, 9H). 13 C NMR (75 MHz, DMSO-d 6 ) δ 151.0, 147.7, 147.2, 142.1, 136.1, 133.8, 133.4, 129.6, 125.5, 124.6, 124.4, 124.2, 120.0, 114.9, 85.6, 27.2 (3C). R f = 0.41 (EtOAc : n-hexane = 1 : 3). 1-tert-Butyl-5-methoxy-2-(3-nitrophenyl)benzimidazole (22). Following the procedure for the preparation of 21 by using 12 (0.25 g, 0.91 mmol), Cs 2 CO 3 (0.59 g, 1.8 mmol, 2 equiv) and (t-boc) 2 O (0.26 g, 1.2 mmol, 1.3 equiv) as starting materials in dry acetonitrile. The crude product was purified by S7

flash chromatography on SiO 2 (EtOAc : n-hexane = 1 : 3) to give partially separating, faster, and slower eluting part of the product (50 : 50) as off-white crystals, combined products (0.27 g, 82%). Faster eluting 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.54 (t, J 2.1 Hz, 1H), 8.36 (ddd, J 8.3, 2.4, 1.0 Hz, 1H), 8.16 (dt, J 7.8, 1.4 Hz, 1H), 7.80 (t, J 8.0 Hz, 1H), 7.68 (d, J 8.7 Hz, 1H), 7.56 (d, J 2.1 Hz, 1H), 7.04 (dd, J 8.7, 2.4 Hz, 1H), 3.86 (s, 3H), 1.38 (s, 9H). 13 C NMR (75 MHz, DMSO-d 6 ) δ 157. 8, 149.8, 147.7, 147.2, 136.3, 136.0, 134.3, 133.9, 129.5, 124.3, 123.9, 120.6, 113.3, 98.6, 85.6, 55.6, 27.1 (3C). R f = 0.31 (EtOAc : n-hexane = 1 : 3). Slower eluting: 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.57 (t, J 2.0 Hz, 1H), 8.37 (ddd, J 8.2, 2.5, 1.0 Hz, 1H), 8.18 (dt, J 7.8, 1.2 Hz, 1H), 7.92 (d, J 9.3 Hz, 1H), 7.81 (t, J 8.0 Hz, 1H), 7.33 (d, J 2.7 Hz, 1H), 7.08 (dd, J 9.2, 2.6 Hz, 1H), 3.84 (s, 3H), 1.37 (s, 9H). 13 C NMR (75 MHz, DMSO-d 6 ) δ 157.0, 151.3, 147.6, 147.2, 143.0, 136.1, 133.8, 129.5, 127.6, 124.4, 124.1, 115.3, 114.4, 102.7, 85.5, 55.6, 27.1 (3C). R f = 0.22 (EtOAc : n-hexane = 1 : 3). 3-(5-Methyl-1H-benzimidazol-2-yl)aniline (24). According to the general procedure C compound 13 (0.63 g, 2.5 mmol) in EtOH/EtOAc (75 ml, 2 : 1) was hydrogenated (Pd/C 0.05 g) for 3 h to give 24 as a beige crude product (0.54 g, 97%), which was used without further purification. 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.47 (br s, 1H), 7.45 7.33 (m, 3H), 7.56 (d, J 7.5 Hz, 1H), 7.16 (t, J 7.5 Hz, 1H), 6.99 (d, J 8.1 Hz, 1H), 6.67 (d, J 7.8 Hz, 1H), 5.38 (br s, 2H), 2.41 (s, 3H). R f = 0.45 (EtOAc). General procedure D The mixture of the nitro compound (1 equiv) and SnCl 2 2H 2 O (5 equiv) in EtOH was refluxed for 30 min. The reaction mixture was allowed to cool to room temperature and 10% NaOH solution was added in small portions in an ice-water bath until the mixture became strongly alkaline (ph > 11). The resulting mixture was extracted with EtOAc and the combined extracts were washed with brine, dried over anhydrous Na 2 SO 4, filtered and evaporated in vacuo to give the aniline. S8

3-(5-Chloro-1H-benzimidazol-2-yl)aniline (25). Compound 14 (1.35 g, 4.93 mmol) was reduced according to the general procedure D. The crude product was purified with Biotage purification system (EtOAc : n-hexane = 7 : 3) to give a light orange solid 25 (0.49 g, 41%). 1 H NMR (300 MHz, DMSOd 6 ) δ 12.89 (s, 1H), 7.76 7.50 (m, 2H), 7.41 (s, 1H), 7.28 7.15 (m, 3H), 6.70 (dd, J 7.5, 1.8 Hz, 1H), 5.33 (s, 2H). 13 C NMR (75 MHz, DMSO-d 6 ) δ 153.5, 149.1, 130.2, 129.4, 126.1, 122.1, 115.8, 114.0, 111.9. LC-MS: [M + H] +, m/z 244 (t r = 3.5 min). R f = 0.59 (EtOAc). 3-(4-Methyl-1H-benzimidazol-2-yl)aniline (26). According to the general procedure C compound 15 (0.24 g, 0.95 mmol) in EtOH/EtOAc (24 ml, 2 : 1) was hydrogenated (Pd/C 0.02 g) for 3 h to give the light brown crude product 26 (0.21 g, 100%), which was carried to the next step without further purification. 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.60 and 12.41 (2 s, 1H, tautomers), 7.46 (t, J 1.8 Hz, 1H), 7.30 (br s, 1H), 7.17 (t, J 7.7 Hz, 1H), 7.06 (t, J 7.5 Hz, 1H), 6.97 6.95 (m, 1H), 6.69 6.65 (m, 1H), 5.29 (s, 2H), 2.56 (s, 3H). R f = 0.24 (EtOAc : n-hexane = 1 : 1). 3-(1H-Benzimidazol-2-yl)-2-methylaniline (27). According to the general procedure C, a solution of compound 16 (0.25 g, 0.99 mmol) in EtOH/EtOAc/MeOH (175 ml, 2 : 1 : 1) was hydrogenated (Pd/C 0.02 g) for 3 h, and purified with Biotage purification system (EtOAc : n-hexane = 1 : 1) to give an offwhite solid 27 (0.17 g, 81%). 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.45 (s, 1H), 7.64 (br s, 1H), 7.48 (br s, 1H), 7.18 (d, J 4.8 Hz, 2H), 7.04 (t, J 7.7 Hz, 1H), 6.84 (d, J 7.8 Hz, 1H), 6.77 (d, J 7.8 Hz, 1H), 5.06 (s, 2H), 2.25 (s, 3H). 13 C NMR (75 MHz, DMSO-d 6 ) δ 152.2, 147.3, 136.7, 128.9, 126.2, 122.8, 120.4, 118.2, 116.0, 114.7, 14.4. LC-MS: [M + H] +, m/z 224 (t r = 3.5 min). R f = 0.53 (EtOAc). 5-(1H-Benzimidazol-2-yl)-2-methoxyaniline (28). According to the general procedure C, compound 17 (0.42 g, 1.6 mmol) in EtOH (50 ml) was hydrogenated (Pd/C 0.02 g) for 3 h to give the crude product. Recrystallization from MeOH gave 28 as yellow crystals (0.27 g, 71%). Mp: 113 C. 1 H NMR S9

(300 MHz, DMSO-d 6 ) δ 12.57 (s, 1H), 7.58 7.41 (m, 3H), 7.34 (dd, J 8.4, 2.4 Hz, 1H), 7.15 7.12 (m, 2H), 6.94 (d, J 8.4 Hz, 1H), 4.93 (s, 2H), 3.84 (s, 3H). 13 C NMR (75 MHz, DMSO-d 6 ) δ 152.2, 147.9, 143.9, 137.9, 122.9, 121.5, 118.3, 114.8, 111.9, 110.9, 110.4, 55.4. LC-MS: [M + H] +, m/z 240 (t r = 2.9 min). R f = 0.49 (EtOAc). 4-(1H-Benzimidazol-2-yl)aniline (29). Compound 18 (0.73 g, 3.1 mmol) was reduced according to the general procedure D to give 29 as a light yellow crude product (0.50 g, 78%), which was carried without further purification to the next step. 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.42 (s, 1H), 7.86 7.82 (m, 2H), 7.48 (d, J 22.2 Hz, 2H), 7.13 7.08 (m, 2H), 6.68 6.64 (m, 2H), 5.59 (s, 2H). ( 1 H NMR was in agreement with reported data 8 ). R f = 0.49 (EtOAc). 3-(1,3-Benzoxazol-2-yl)aniline (30). Compound 19 (0.87 g, 3.6 mmol) was reduced according to the general procedure D to give a dark violet crude product 30 (0.71 g, 93%), which was carried to the next step without further purification. 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.79 7.74 (m, 2H), 7.45 7.33 (m, 4H), 7.23 (t, J 7.7 Hz, 1H), 6.80 (ddd, J 8.0, 2.3, 1.1 Hz, 1H), 5.49 (s, 2H). R f = 0.47 (EtOAc : n-hexane = 1 : 1). 3-(1-Methylbenzimidazol-2-yl)aniline (31). Compound 20 (2.38 g, 9.40 mmol) was reduced according to the general procedure D to give an off-white crude product 31 (1.47 g, 70%), which was carried to the next step without further purification. 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.66 7.63 (m, 1H), 7.59 7.56 (m, 1H), 7.30 7.17 (m, 3H), 7.04 (t, J 1.8 Hz, 1H), 6.93 (d, J 7.2 Hz, 1H), 6.72 (dd, J 8.1, 2.1 Hz, 1H), 5.33 (s, 2H), 3.85 (s, 3H). R f = 0.26 (EtOAc). 4-(1-tert-Butylbenzimidazol-2-yl)aniline (32). According to the general procedure C, compound 21 (1.53 g, 4.51 mmol) in EtOH/EtOAc (27 ml, 2 : 1) was hydrogenated (Pd/C 0.09 g) for 5 h to give the S10

crude product. Column chromatography on SiO 2 (EtOAc : n-hexane = 1 : 1) gave 32 as off-white crystals (1.10 g, 81%). 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.96 7.93 (m, 1H), 7.74 7.71 (m, 1H), 7.43 7.34 (m, 2H), 7.14 (t, J 7.7 Hz, 1H), 6.81 (s, 1H), 6.76 6.69 (m, 2H), 5.29 (s, 2H), 1.37 (s, 9H). 13 C NMR (75 MHz, DMSO) δ 154.0, 148.3, 148.1, 142.1, 133.4, 132.3, 128.4, 124.7, 124.2, 119.7, 116.5, 114.9, 114.4, 113.9, 85.0, 27.0. R f = 0.20 (EtOAc : n-hexane = 1 : 2). 4-(1-tert-Butyl-5-methoxybenzimidazol-2-yl)aniline (33). According to the general procedure C, compound 22 (0.75 g, 2.03 mmol) in EtOH/EtOAc (12 ml, 2 : 1) was hydrogenated (Pd/C 0.04 g) for 5 h to give the crude product. Column chromatography on SiO 2 (EtOAc : n-hexane = 1 : 1) gave 33 as partially separating parts of product, a faster eluting yellowish solid and slower eluting (50 : 50) white crystals, combined (0.61 g, 88%). Faster eluting: 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.61 (d, J 8.7 Hz, 1H), 7.46 (d, J 2.7 Hz, 1H), 7.12 (t, J 8.0 Hz, 1H), 6.98 (dd, J 8.7, 2.7 Hz, 1H), 6.78 (t, J 1.8 Hz, 1H), 6.73 6.66 (m, 2H), 5.26 (s, 2H), 3.83 (s, 3H), 1.37 (s, 9H). 13 C NMR (75 MHz, DMSO- d 6 ) δ 157.3, 152.9, 148.2, 136.3, 134.2, 132.6, 128.4, 120.2, 116.2, 114.6, 114.4, 112.8, 98.0, 84.9, 55.6, 27.0. R f = 0.14 (EtOAc : n-hexane = 1 : 2). Slower eluting: 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.80 (d, J 9.0 Hz, 1H), 7.25 (d, J 2.1 Hz, 1H), 7.11 (t, J 7.8 Hz, 1H), 6.99 (dd, J 8.9, 2.6 Hz, 1H), 6.78 6.78 (m, 1H), 7.73 6.67 (m, 2H), 5.26 (s, 2H), 3.80 (s, 3H), 1.35 (s, 9H). 13 C NMR (75 MHz, DMSO-d 6 ) δ 156.8, 154.4, 148.2, 148.1, 143.0, 132.4, 128.4, 127.6, 116.5, 114.8, 114.4, 113.4, 102.6, 84.8, 55.5, 27.0. R f = 0.09 (EtOAc : n-hexane = 1 : 2). General procedure F A solution of carboxylic acid (1.20 mmol, 1.2 equiv), oxalyl chloride (100 µl, 1.20 mmol) and one drop of DMF in anhydrous THF (2-5 ml) was stirred for 1 h. A solution of 23 (0.21 g, 1.0 mmol, 1 equiv) in anhydrous THF and TEA (210 µl, 1.5 mmol, 1.5 equiv) was added to the mixture. After stirring for appropriate time, the reaction mixture was concentrated under reduced pressure and the residue was partitioned between water (100 ml) and EtOAc (50 ml). The aqueous layer was separated and S11

extracted with EtOAc (50 ml) and the combined organic phases were washed with saturated NaHCO 3 (50 ml) and brine (50 ml), dried over anhydrous Na 2 SO 4, filtered, and the filtrate was evaporated in vacuo to give the product. General procedure G To a solution of carboxylic acid (1.20 mmol, 1.2 equiv) in anhydrous THF (2 ml) was added oxalyl chloride (100 µl, 1.20 mmol, 1.2 equiv) and one drop of DMF. The resulting solution was stirred for 1 h. A solution of 32 (0.31 g, 1.0 mmol, 1 equiv) or 33 (0.34 g, 1.0 mmol, 1 equiv) in anhydrous THF (4 ml) and TEA (170 µl, 1.2 mmol, 1.2 equiv) were added to the reaction mixture. After 30 min, THF was evaporated, and the residue was dissolved in EtOAc (70 ml). Washing with saturated NaHCO 3 (70 ml) and brine (50 ml), and drying over anhydrous Na 2 SO 4 gave the amide. A mixture of this t-bocprotected compound (0.5 mmol, 1 equiv) in DCM (2 ml) and TFA (0.5 ml) was stirred for 4 h at room temperature. Evaporation, dissolving the residue to EtOAc (40 ml), washing with 1 M NaOH solution (40 ml), water (40 ml) and brine (40 ml), drying with anhydrous Na 2 SO 4, filtration and evaporation to dryness gave the crude product. N-[3-(1H-Benzimidazol-2-yl)phenyl]thiophene-3-carboxamide (35). According to the general procedure F 3-thiophenecarboxylic acid (0.15 g, 1.2 mmol) was dissolved in THF (2 ml). After addition of 23 (0.21 g, 1.0 mmol) in THF (8 ml) the resulting mixture was stirred for 1 h. The crude product was recrystallized from MeOH to give 34 as white crystals (0.10 g, 30%). Mp: 132 137 C. 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.93 (s, 1H), 10.25 (s, 1H), 8.66 (s, 1H), 8.45 (dd, J 1.7, 2.6 Hz, 1H), 7.91 7.85 (m, 2H), 7.71 7.67 (m, 3H), 7.56 7.50 (m, 2H), 7.25 7.17 (m, 2H). 13 C NMR (75 MHz, DMSO-d 6 ) δ 161.0, 151.2, 143.8, 139.6, 137.6, 135.0, 130.6, 129.9, 129.3, 127.2, 127.0, 122.6, 121.7, 121.4, 118.8, 118.7, 111.4. LC-MS: [M + H] +, m/z 320 (t r = 4.2 min). FT-IR (KBr, cm -1 ): 3269, 1656, 1563, 1262, 738. R f = 0.26 (EtOAc : n-hexane = 1 : 1). HRMS (EI): calcd for C 18 H 13 N 3 OS 319.0779; S12

found 319.0780. N-[3-(1H-Benzoimidazol-2-yl)-phenyl]-2-(2-thienyl)acetamide (36). After stirring a mixture of 23 (0.21 g, 1.0 mmol), TEA and 2-thienylacetyl chloride (140 µl, 1.1 mmol) in THF (10 ml) for 30 min and extracting according to the general procedure E, the resulting crude product was purified by flash chromatography on SiO 2 (DCM : MeOH, 2%) and recrystallized from EtOH/H 2 O to give 36 as brownish crystals (0.12 g, 36%). Mp: 221 C. 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.91 (s, 1H), 10.41 (s, 1H), 8.53 (t, J 1.7 Hz, 1H), 7.82 (d, J 8.1 Hz, 1H), 7.67 7.42 (m, 4H), 7.42 7.40 (m, 1H), 7.21 7.19 (m, 2H), 7.03 6.98 (m, 2H), 3.93 (s, 2H). 13 C NMR (75 MHz, DMSO-d 6 ) δ 168.2, 151.1, 143.7, 139.6, 137.0, 135,0, 130.7, 129.4, 126.7, 126.4, 125.1, 122.5, 121.7, 121.3, 120.6, 118.9, 117.5, 111.4, 37.6. LC-MS: [M + H] +, m/z 334 (t r = 4.3 min). FT-IR (KBr, cm -1 ): 3102, 2925, 2851, 1648, 1527, 746. R f = 0.19 (EtOAc : n-hexane = 1 : 1). N-[3-(1H-Benzimidazol-2-yl)phenyl]furan-2-carboxamide (37). According to the general procedure F furan-2-carboxylic acid (0.13 g, 1.2 mmol) was dissolved in THF (2 ml). After addition of 23 (0.21 g, 1.0 mmol) in THF (7 ml) the resulting mixture was stirred for 30 min. The crude product was purified with Biotage purification system (EtOAc : n-hexane = 1 : 1) to give 37 as a white powder (0.10 g, 33%). 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.92 (s, 1H), 10.37 (s, 1H), 8.66 (t, J 1.8 Hz, 1H), 7.97 7.97 (m, 1H), 7.87 7.84 (m, 2H), 7.66 7.50 (m, 3H), 7.42 (d, J 3.6 Hz, 1H), 7.22 7-20 (m, 2H), 6.73 (dd, J 1.7, 3.5 Hz, 1H). 13 C NMR (75 MHz, DMSO-d 6 ) δ 156.3, 151.1, 147.3, 145.9, 143.7, 139.1, 135.0, 130.6, 129.3, 122.5, 121.8, 121.6, 118.8, 114.8, 114.9, 112.2, 111.4. LC-MS: [M + H] +, m/z 304 (t r = 3.8 min). FT-IR (KBr, cm -1 ): 3054, 1664, 1307, 743. R f = 0.16 (EtOAc : n-hexane = 1 : 1). S13

N-[3-(1H-Benzimidazol-2-yl)phenyl]furan-3-carboxamide (38). According to the general procedure F furan-3-carboxylic acid (0.13 g, 1.2 mmol) was dissolved in THF (2 ml). After addition of 23 (0.21 g, 1.0 mmol) in THF (11 ml) the resulting mixture was strirred for 30 min. Extraction provided the crude product, which was purified with Biotage purification system (EtOAc : n-hexane = 9 : 11) to give 38 as an off-white powder (0.19 g, 64%). 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.93 (s, 1H), 10.13 (s, 1H), 8,60 (t, J 1,8 Hz, 1H), 8.45 (m, 1H), 7.91 7.81 (m, 3H), 7.68 7.65 (m, 1H), 7.56 7.50 (m, 2H), 7.25 7.17 (m, 2H), 7.06 (dd, J 1.8, 0.6 Hz, 1H). 13 C NMR (75 MHz, DMSO-d 6 ) δ 160.5, 151.1, 146.1, 144.3, 139.5, 130.6, 129.3, 122.9, 122.2 (br), 121.5, 121.4, 118.6, 111.1 (br), 109.3. LC-MS: [M + H] +, m/z 304 (t r = 3.8 min,). FT-IR (KBr, cm -1 ): 3306, 1650, 1564, 744. R f = 0.20 (EtOAc : n-hexane = 1 : 1). N-[3-(1H-Benzimidazol-2-yl)phenyl]-1-methylpyrrole-2-carboxamide (39). According to the general procedure F 1-methyl-2-pyrrolecarboxylic acid (0.15 g, 1.2 mmol) was dissolved in THF (2 ml), and after addition of 23 (0.21 g, 1.0 mmol) in THF (10 ml) the resulting mixture was stirred for 45 min. Extraction gave the crude product which was purified with Biotage purification system (EtOAc : n- hexane = 2 : 3) and (EtOAc : n-hexane = 3 : 7 1 : 1) to give 39 as yellowish powder (0.11 g, 34%). 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.90 (s, 1H), 9.93 (s, 1H), 8.67 8.66 (m, 1H), 7.82 (dd, J 1.7, 7.7 Hz, 2H), 7.60 (br s, 2H), 7.49 (t, J 8.0 Hz, 1H), 7.24 7.19 (m, 2H), 7.13 (dd, J 3.8, 1.7 Hz, 1H), 7.04 (t, J 2.0 Hz, 1H), 6.11 (dd, J 3.8, 2.6 Hz, 1H), 3.90 (s, 3H). 13 C NMR (75 MHz, DMSO-d 6 ) δ 159.9, 151.3, 143.8, 140.0, 135.0, 130.5, 129.1, 125.2, 122.5, 121.7, 121.5, 120.9, 118.8, 118.4, 114.0, 111.4, 106.9, 36.5. LC-MS: [M + H] +, m/z 317 (t r = 4.2 min). FT-IR (KBr, cm -1 ): 3429, 3062, 1670, 744. R f = 0.30 (EtOAc : n-hexane = 1 : 1). N-[3-(1H-Benzimidazol-2-yl)phenyl]thiazole-4-carboxamide (40). According to the general procedure F 4-thiazolecarboxylic acid (0.15 g, 1.2 mmol) was dissolved in THF (5 ml). TEA (420 µl, S14

3.0 mmol, 3 equiv) was added to the solution and after addition of 23 (0.21 g, 1.0 mmol) in THF (12 ml) the resulting mixture was stirred for 30 min. Extraction F gave the crude product which was purified with Biotage purification system (EtOAc : n-hexane = 1 : 1 2 : 1) to give 40 as a white powder (0.16 g, 50%). 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.92 (s, 1H), 10.50 (s, 1H), 9.30 (d, J 2.1 Hz, 1H), 8.77 (t, J 1.8 Hz, 1H), 8.55 (d, J 1.8 Hz, 1H), 7.91 7.86 (m, 2H), 7.68 (d, J 7.2 Hz, 1H), 7.56 7.50 (m, 2H), 7.23 7.19 (m, 2H). 13 C NMR (75 MHz, DMSO-d 6 ) δ 159.3, 155.2, 151.2, 150.6, 143.8, 139.0, 135.1, 130.6, 129.2, 125.8, 122.5, 122.1, 121.9, 121.7, 118.9, 111.4. LC-MS: [M + H] +, m/z 321 (t r = 3.6 min). FT-IR (KBr, cm -1 ): 3382, 3079, 1678, 1563, 1298, 742. R f = 0.61 (EtOAc). N-[3-(1H-Benzimidazol-2-yl)phenyl]benzamide (41). After stirring a mixture of 23 (0.21 g, 1.0 mmol), TEA and benzoyl chloride (130 µl, 1.1 mmol, 1.1 equiv) in THF (10 ml) for 30 min and extracting according to the general procedure E, the resulting crude product was recrystallized from MeOH to give 41 as light brown crystals (0.09 g, 29%). Mp: 132 133 C (lit. 9 139 C ). 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.93 (s, 1H), 10.45 (s, 1H), 8.73 (t, J 1.7 Hz, 1H), 8.05 8.02 (m, 2H), 7.88 (dd, J 8.1, 1.8 Hz, 2H), 7.69 7.54 (m, 6H), 7.25 7.17 (m, 2H). 13 C NMR (75 MHz, DMSO-d 6 ) δ 165.7, 151.2, 143.8, 139.8, 135.1, 134.7, 131.7, 130.6, 129.3, 128.5 (2C), 127.7 (2C), 122.6, 121.9, 121.7, 121.6, 118.9, 111.4. FT-IR (KBr, cm -1 ): 3228, 1657, 1552, 1265, 741. LC-MS: [M + H] +, m/z 314 (t r = 4.4 min). R f = 0.31 (EtOAc : n-hexane = 1 : 1). N-[3-(1H-Benzimidazol-2-yl)phenyl]-3-methylbenzamide (42). According to the general procedure F 3-methylbenzoic acid (0.16 g, 1.2 mmol) was dissolved in THF (2 ml). After addition of 23 (0.21 g, 1.0 mmol) in THF (10 ml) the resulting mixture was strirred for 30 min. The product was purified with Biotage purification system (DCM : MeOH, 1%) and recrystallized from acetonitrile to give 42 as offwhite crystals (71 mg, 23%). Mp: 220 221 C. 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.93 (s, 1H), 10.40 S15

(s, 1H), 8.71 8.71 (m, 1H), 7.90 7.81 (m, 4H), 7.65 7.51 (m, 3H), 7.45 7.43 (m, 2H), 7.23 7.21 (m, 2H), 2.42 (s, 3H). 13 C NMR (75 MHz, DMSO-d 6 ) δ 165.7, 151.2, 143.8, 139.8, 137.8, 135.1, 134.7, 132.3, 130.6, 129.2, 128.8, 128.4, 128.2, 124.9, 122.5, 121.8, 121.7, 121.5, 118.8, 118.8, 111.4, 21.0. LC-MS: [M + H] +, m/z 328 (t r = 4.9 min). FT-IR (KBr, cm -1 ): 2924, 2855, 1650, 1553, 1303, 1229, 740. R f = 0.34 (EtOAc : n-hexane = 1 : 1). HRMS (EI): calcd for C 21 H 17 N 3 O 327.1372; found 327.1389. N-[3-(1H-Benzimidazol-2-yl)phenyl]-3-trifluoromethylbenzamide (43). According to the general procedure F 3-trifluoromethylbenzoic acid (0.23 g, 1.2 mmol) was dissolved in THF (2 ml). After addition of 23 (0.21 g, 1.0 mmol) in THF (10 ml) the resulting mixture was stirred for 30 min. Recrystallization from MeOH/H 2 O gave 43 as an off-white powder (0.27 g, 71%). Mp: 245 C. 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.95 (s, 1H), 10.67 (s, 1H), 8.70 (t, J 1.8 Hz, 1H), 8.38 (s, 1H), 8.33 (d, J 8.1 Hz, 1H), 8.00 (s, J 8.1 Hz, 1H), 7.94 7.89 (m, 2H), 7.82 (t, J 7.7 Hz, 1H), 7.67 7.66 (m, 1H), 7.59 7.53 (m, 2H), 7.28 7.17 (m, 2H). 13 C NMR (75 MHz, DMSO-d 6 ) δ 164.1, 151.1, 143.8, 139.4, 135.5, 135.1, 132.0, 130.7, 129.8, 129.3, 129.2 (q, J CF 31.9 Hz), 128.3 (q, J CF 3.7 Hz), 124.3 (q, J CF 3.8 Hz), 124.0 (q, J CF 271.0 Hz), 122.6, 121.9, 121.8, 121.7, 119.0, 118.9. LC-MS: [M + H] +, m/z 382 (t r = 5.4 min). FT-IR (KBr, cm -1 ): 3302, 1667, 1556, 741. R f = 0.31 (EtOAc : n-hexane = 1 : 1). HRMS (EI): calcd for C 21 H 14 F 3 N 3 O 381.1089; found 381.1102. N-[3-(1H-Benzimidazol-2-yl)phenyl]-3-chlorobenzamide (44). According to the general procedure F 3-chlorobenzoic acid (0.19 g, 1.2 mmol) was dissolved in THF (2 ml). After addition of 23 (0.21 g, 1.0 mmol) in THF (10 ml) the resulting mixture was stirred for 30 min. Recrystallization from MeOH gave the product 44 as an off-white powder (0.12 g, 33%). Mp: 122 125 C. 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.93 (s, 1H), 10.55 (s, 1H), 8.70 (s, 1H), 8.09 (t, J 1.8 Hz, 1H), 8.00 7.98 (m, 1H), 7.89 (d, J 8.7 Hz, 2H), 7.71 7.66 (m, 2H), 7.63 7.52 (m, 3H), 7.26 7.17 (m, 2H). 13 C NMR (75 MHz, DMSO-d 6 ) δ 164.1, 151.1, 143.9, 139.5, 136.7, 135.1, 133.3, 131.6, 130.7, 130.5, 129.3, 127.5, 126.6, 122.6, 121.8, S16

121.8, 121.7, 118.9, 111.4. LC-MS: [M + H] +, m/z 348 (t r = 5.1 min). FT-IR (KBr, cm -1 ): 3285, 1663, 1558, 1260, 739. R f = 0.34 (EtOAc : n-hexane = 1 : 1). N-[3-(1H-Benzimidazol-2-yl)phenyl]-3-fluorobenzamide (45). According to the general procedure F 3-fluorobenzoic acid (0.17 g, 1.2 mmol) was dissolved in THF (2 ml). After addition of 23 (0.21 g, 1.0 mmol) in THF (10 ml) the resulting mixture was stirred for 30 min. Recrystallization from MeOH/H 2 O twice gave 45 as an off-white powder (0.12 g, 36%). Mp: 135 139 C. 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.59 (s, 1H), 8,75 (s, 1H), 7.95 7.84 (m, 4H), 7.70 7.57 (m, 4H), 7.51 7.45 (m, 1H), 7.32 7.27 (m, 2H). 13 C NMR (75 MHz, DMSO-d 6 ) δ 164.3 (d, J CF 2.6 Hz), 162.0 (d, J 243.0 Hz), 150.7, 139.6, 138.0, 136.9 (d, J 6.8 Hz), 130.7 (d, J CF 8.3 Hz), 129.5, 129.3, 124.0 (d, J CF 2.8 Hz), 122.9, 122.6, 122.2, 119.1, 118.7 (d, J CF 24.1 Hz), 115.0, 114.6 (d, J CF 22.8 Hz). LC-MS: [M + H] +, m/z 332 (t r = 4.6 min). FT-IR (KBr, cm -1 ): 3063, 1662, 1588, 739. R f = 0.29 (EtOAc : n-hexane = 1 : 1). N-[3-(1H-Benzimidazol-2-yl)phenyl]-3-methoxybenzamide (46). According to the general procedure F 3-methoxybenzoic acid (0.18 g, 1.2 mmol) was dissolved in THF (2 ml). After addition of 23 (0.21 g, 1.0 mmol) in THF (10 ml) the resulting mixture was stirred for 30 min. The crude product was recrystallized from 2-propanol/MeOH (3 : 2) to give 46 as white crystals (0.10 g, 28%). Mp: 121 C. 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.94 (s, 1H), 10.43 (s, 1H), 8.71 (t, J 1.7 Hz; 1H), 7.09 7.87 (m, 2H), 7.68 7.45 (m, 6H), 7.23 7.17 (m, 3H), 3.86 (s, 3H). 13 C NMR (75 MHz, DMSO-d 6 ) δ 165.3, 159.2, 151.2, 143.8, 139.7, 136.1, 135.1, 130.6, 129.6, 129.2, 122.6, 121.9, 121.7, 121.6, 120.0, 118.9, 118.9, 117.5, 112.9, 111.4, 55.4. LC-MS: [M + H] +, m/z 344 (t r = 4.6 min). FT-IR (KBr, cm -1 ): 3274, 1650, 1243, 1040, 739. R f = 0.27 (EtOAc : n-hexane = 1 : 1). S17

Methyl 3-N-[3-(1H-benzimidazol-2-yl)carbamoyl]benzoate (47). According to the general procedure F 3-(methoxycarbonyl)benzoic acid (0.22 g, 1.2 mmol) was dissolved in THF (3 ml). After addition of 23 (0.21 g, 1.0 mmol) in THF (12 ml) the resulting mixture was stirred for 1 h. The crude product was purified with Biotage purification system (EtOAc : n-hexane = 1 : 1) to give 47 as a white powder (0.10 g, 27%). 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.94 (s, 1H), 10.67 (s, 1H), 8.71 (t, J 1.7 Hz, 1H), 8.62 (t, J 1.5 Hz, 1H), 8.30 (d, J 8.1 Hz, 1H), 8.19 (d, J 7.8 Hz, 1H), 7.93 7.89 (m, 2H), 7.73 (t, J 7.7 Hz, 1H), 7.67 (d, J 6.6 Hz, 1H), 7.55 (t, J 8.0 Hz, 2H), 7.24 7.21 (m, 2H), 3.93 (s, 3H). 13 C NMR (75 MHz, DMSO-d 6 ) δ 165.8, 164.7, 151.1, 143.8, 139.5, 135.2, 135.1, 132.5, 132.2, 130.7, 129.9, 129.3, 129.2, 128.4, 122.6, 121.9, 121.8, 119.0, 118.9, 111.4, 52.5. LC-MS: [M + H] +, m/z 372 (t r = 4.7 min). FT-IR (KBr, cm -1 ): 3333, 1713, 1653, 1305, 1252, 741. R f = 0.20 (EtOAc : n-hexane = 1 : 1). N-[3-(1H-Benzimidazol-2-yl)phenyl]-2-methylbenzamide (48). General procedure F. 2- methylbenzoic acid (0.16 g, 1.2 mmol) was dissolved in THF (2 ml). After addition of 23 (0.21 g, 1.0 mmol) in THF (12 ml) the resulting mixture was stirred for 30 min. The crude product was purified with Biotage purification system (DCM : MeOH, 5%) and recrystallized from acetonitrile to give 48 as white crystals (0.16 g, 49%). Mp: 148 150 C. 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.92 (s, 1H), 10.48 (s, 1H), 8.74 (s, 1H), 7.86 (d, J 7.5 Hz, 1H), 7.74 7.66 (m, 2H), 7.54 7.49 (m, 3H), 7.44 7.39 (m, 1H), 7.35 7.30 (m, 2H), 7.22 7.20 (m, 2H), 2.43 (s, 3H). 13 C NMR (75 MHz, DMSO-d 6 ) δ 168.1, 151.3, 143.8, 139.9, 137.1, 135.4, 135.1, 130.8, 130.6, 129.7, 129.3, 127.3, 125.7, 122.6, 121.7, 121.6, 121.3, 118.9, 118.1, 111.4, 19.4. LC-MS: [M + H] +, m/z 328 (t r = 4,5 min). FT-IR (KBr, cm -1 ): 3295, 3058, 1657, 1304, 739. R f = 0.37 (EtOAc : n-hexane = 1 : 1). HRMS (EI): calcd for C 21 H 17 N 3 O 327.1372; found 327.1389. N-[3-(1H-Benzimidazol-2-yl)phenyl]-2-trifluoromethylbenzamide (49). According to the general procedure G, 2-(trifluoromethyl)benzoic acid (0.23 g, 1.2 mmol) and 32 (0.31 g, 1.0 mmol) were used S18

as starting materials. Final product was purified with Biotage purification system (DCM: MeOH, 1%) to give 49 as a white solid (13 mg, 6%). 1 H NMR (300 MHz, DMSO- d 6 ) δ 13.00 (s, 1H), 10.67 (s, 1H), 8.70 (t, J 1.7 Hz, 1H), 8.39 (s, 1H), 8.34 (d, J 8.1 Hz, 1H), 8.00 (d, J 7.8 Hz, 1H), 7.94 7.89 (m, 2H), 7.82 (t, J 7.8 Hz, 1H), 7.62 7.54 (m, 3H), 7.25 7.19 (m, 2H). 13 C NMR (75 MHz, DMSO- d 6 ) δ 164.1, 151.1, 143.8, 139.4, 135.5, 135.0, 132.0, 130.6, 129.8, 129.4, 129.2 (q, J CF 31.9 Hz), 128.3 (q, J CF 3.4 Hz), 124.3 (q, J CF 3.8 Hz), 122.6 (q, J CF 270.8 Hz), 122.2, 121.9, 121.9, 119.0, 111.4. LC-MS: [M + H] +, m/z 382 (t r = 5.4 min). FT-IR (KBr, cm -1 ): 3268, 1665, 1552, 742. R f = 0.27 (EtOAc : n-hexane = 1 : 1). N-[3-(1H-Benzimidazol-2-yl)phenyl]-2-methoxybenzamide (50). According to the general procedure G 2-methoxybenzoic acid (0.18 g, 1.2 mmol) and 32 (0.31 g, 1.0 mmol) were used as starting materials. Biotage purification (DCM : MeOH 1%) gave 50 as a white solid (61 mg, 36%). 1 H NMR (300 MHz, DMSO- d 6 ) δ 12.93 (s, 1H), 10.30 (s, 1H), 8.67 (s, 1H), 7.87 (d, J 7.8 Hz, 1H), 7.78 (d, J 8.4 Hz, 1H), 7.69 (dd, J 7.5, 1.5 Hz, 1H), 7.61 (br s, 2H), 7.56 7.49 (m, 2H), 7.24 7.20 (m, 3H), 7.09 (t, J 7.5 Hz, 1H), 3.94 (s, 3H). 13 C NMR (75 MHz, DMSO- d 6 ) δ 164.7, 156.6, 151.2, 139.6, 132.2, 130.7, 129.7, 129.3, 124.8, 122.1, 121.5, 121.3, 120.5, 118.1, 112.0, 56.0. FT-IR (KBr, cm -1 ): 3339, 3052, 1653, 1558, 1232, 744. LC-MS: [M + H] +, m/z 344 (t r = 4.8 min). R f = 0.17 (EtOAc : n-hexane = 1 : 1). N-[3-(1H-Benzimidazol-2-yl)phenyl]acetamide (51). Following the procedure E, a mixture of 23 (0.21 g, 1.0 mmol), TEA, and acetyl chloride (85 µl, 1.2 mmol) in THF (12 ml) was stirred for 50 min. The crude product was recrystallized from MeOH to give 51 as yellowish crystals (0.06 g, 24%). Mp: 296 C (lit. 9 288 C). 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.88 (s, 1H), 10.12 (s, 1H), 8.50 (s, 1H), 7.79 (d, J 7.5 Hz, 1H), 7.67 7.64 (m, 2H), 7.54 7.44 (m, 2H), 7.24 7.16 (m, 2H), 2.09 (s, 3H). 13 C NMR (75 MHz, DMSO-d 6 ) δ 168.5, 151.2, 143.8, 139.9, 135.0, 130.7, 129.3, 122.5, 121.7, 120.9, 120.4, 118.9, S19

117.4, 111.4, 24.1. LC-MS: [M + H] +, m/z 252 (t r = 2.9 min). FT-IR (KBr, cm -1 ): 3274, 2786, 1671, 1592, 1449, 1267, 746. R f = 0.29 (EtOAc). N-[3-(1H-Benzimidazol-2-yl)phenyl]-2,2-dimethylpropanamide (52). After stirring a mixture of 23 (0.21 g, 1.0 mmol), TEA and 2,2-dimethylpropanoyl chloride (135 µl, 1.1 mmol) in THF (10 ml) for 30 min and extracting according to the general procedure E, the resulting crude product was recrystallized from MeOH/H 2 O to give 52 as light brown crystals (0.11 g, 37%). Mp: 257 258 C. 1 H NMR (300 MHz, CD 3 OD) δ 8.21 (t, J 1.7 Hz, 1H), 7.83 7.81 (m, 1H), 7.69 7.66 (m, 1H), 7.61 (br s, 2H), 7.50 (t, J 7.7 Hz, 1H), 7.29 7.24 (m, 2H), 1.34 (s, 9H). 13 C NMR (75 MHz, CD 3 OD) δ 180.0, 153.7, 141.1, 132.0, 131.0, 125.2, 124.0, 124.3, 121.7, 113.1, 119.6 (br), 113.1 (br), 41.1, 28.3 (3C). LC-MS: [M + H] +, m/z 294 (t r = 4.2 min). FT-IR (KBr, cm -1 ): 3340, 3054, 1654, 1558, 1450, 1302, 744. R f = 0.37 (EtOAc : n-hexane = 1 : 1). N-[3-(1H-Benzimidazol-2-yl)phenyl]cyclohexanecarboxamide (53). According to the general procedure G, cyclohexanecarboxylic acid (0.15 g, 1.2 mmol) and 32 (0.31 g, 1.0 mmol) were used as starting materials. Final product was purified with Biotage purification system (EtOAc : n-hexane = 1 : 1). Recrystallization from acetonitrile gave 53 as a white solid (48 mg, 30%). Mp: 242 243 C. 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.88 (s, 1H), 10.00 (s, 1H), 8.56 (s, 1H), 7.79 (d, J 7.5 Hz, 1H), 7.66 7.63 (m, 2H), 7.52 7.54 (m, 1H), 7.45 (t, J 8.0 Hz, 1H), 7.21 7.19 (m, 2H), 2.41 2.33 (m, 1H), 1.86 1.65 (m, 5H), 1.50 1.15 (m, 5H). 13 C NMR (75 MHz, DMSO- d 6 ) δ 174.5, 151.2, 143.8, 140.0, 135.1, 130.6, 129.2, 122.5, 121.6, 120.8, 120.5, 118.8, 117.5, 111.4, 44.9, 29.1 (2C), 25.4, 25.2 (2C). LC-MS: [M + H] +, m/z 320 (t r = 4.8 min). FT-IR (KBr, cm -1 ): 3284, 2926, 2854, 1657, 1562, 1250, 742. R f = 0.30 (EtOAc : n-hexane = 1 : 1). HRMS (EI): calcd for C 20 H 21 N 3 O 319.1685; found 319.1685. N-[3-(5-Methoxy-1H-benzimidazol-2-yl)phenyl]thiophene-2-carboxamide (54). To a solution of 33 (0.34 g, 1.0 mmol, 1 equiv) in anhydrous THF (5 ml) was added 2-thiophenecarbonyl chloride (160 µl, S20

1.1 mmol, 1.1 equiv) and TEA (150 µl, 1.1 ml, 1.1 equiv). After 1 h the reaction was continued according to the general procedure G. Final product was purified with Biotage purification system (DCM : MeOH, 1%) to give 54 as a white powder (30 mg, 18%). 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.79 (s, 1H), 10.43 (s, 1H), 8.59 8.58 (m, 1H), 8.12 8.10 (m, 1H), 7.90 7.88 (m, 1H), 7.86 7.82 (m, 2H), 7.55 7.49 (m, 2H), 7.28 7.24 (m, 1H), 7.17 7.01 (m, 1H), 6.86 6.83 (m, 1H), 3.82 (2 s, 3H). 13 C NMR (75 MHz, DMSO) δ 161.3, 160.4, 160.0, 139.9, 139.3, 132.1, 130.8, 129.3, 128.2, 121.2, 118.2, 111.3 (br), 94.4 (br), 55.4. LC-MS: [M + H] +, m/z 350 (t r = 4.5 min). FT-IR (KBr, cm -1 ): 3072, 1637, 1269, 792. R f = 0.26 (EtOAc : n-hexane = 1 : 1). N-[3-(5-Methyl-1H-benzimidazol-2-yl)phenyl]thiophene-2-carboxamide (55). After stirring a mixture of 24 (0.22 g, 1.0 mmol), TEA, and 2-thiophenecarbonyl chloride (120 µl, 1.1 mmol) in THF (10 ml) for 30 min and extracting according to the general procedure E, the resulting crude product was purified with Biotage purification system (DCM : MeOH, 1%) to give 55 as a white powder (0.13 g, 39%). 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.80 (br s, 1H), 10.44 (s, 1H), 8.62 (t, J 1.5 Hz, 1H), 8.12 (dd, J 3.9, 0.9 Hz, 1H), 7.89 7.85 (m, 3H), 7.53 (t, J 8.0 Hz, 1H), 7.43 (d, J 26.2 Hz, 2H), 7.25 (dd, J 5.0, 4.0 Hz, 1H), 7.05 7.02 (m, 1H), 2.43 (s, 3H). 13 C NMR (75 MHz, DMSO-d 6 ) δ 160.0, 150.8, 140.0, 139.4, 132.2, 131.4, 130.8, 129.3, 128.2, 123.7, 121.6, 121.5, 118.7, 21.4. LC-MS: [M + H] +, m/z 334 (t r = 4.7 min). FT-IR (KBr, cm -1 ): 2911, 1639, 1553, 1296, 790. R f = 0.33 (EtOAc : n-hexane = 1 : 1). HRMS (EI): calcd for C 19 H 15 N 3 OS 333.0936; found 333.0932. N-[3-(5-Chloro-1H-benzimidazol-2-yl)phenyl]thiophene-2-carboxamide (56). After stirring a mixture of 25 (0.24 g, 1.0 mmol), TEA, and 2-thiophenecarbonyl chloride (120 µl, 1.1 mmol) in THF (10 ml) for 30 min and extracting according to the general procedure E, the resulting crude product was recrystallized from MeOH to give 56 as an off-white powder (0.05 g, 14%). Mp: 250 251 C. 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.69 (s, 1H), 8.75 (t, J 1.8 Hz, 1H), 8.18 (dd, J 3.9, 1.2 Hz, 1H), 8.02 7.99 (m, 1H), 7.94 7.90 (m, 2H), 7.81 (d, J 1.8 Hz, 1H), 7.76 (d, J 8.7 Hz, 1H), 7.66 (t, J 8.1 Hz, 1H), 7.47 S21

(dd, J 8.6, 2.0 Hz, 1H), 7.26 (dd, J 5.0, 3.8 Hz, 1H). 13 C NMR (75 MHz, DMSO-d 6 ) δ 160.2, 151.0, 139.7, 139.6, 140.0, 133.7, 132.4, 129.9, 129.7, 128.8, 128.3, 126.0, 124.8, 124.2, 122.9, 119.4, 115.8, 114.3. LC-MS: [M + H] +, m/z 354 (t r = 5.8 min). FT-IR (KBr, cm -1 ): 3325, 2635, 1644, 1567, 1262. R f = 0.33 (EtOAc : n-hexane = 1 : 1). HRMS (EI): calcd for C 18 H 12 ClN 3 OS 353.0390; found 353.0406. N-[3-(4-Methyl-1H-benzimidazol-2-yl)phenyl]thiophene-2-carboxamide (57). After stirring a mixture of 26 (68 mg, 0.30 mmol, 1 equiv), TEA (62 µl, 0.45 mmol, 1.5 equiv) and 2- thiophenecarbonyl chloride (48 µl, 0.33 mmol, 1.1 equiv) in THF (3 ml) for 30 min and extracting according to the general procedure E, the resulting crude product was purified with Biotage purification system (DCM : MeOH, 1%) and recrystallized from EtOH/H 2 O to give 57 as a light yellow powder (26 mg, 15%). Mp: 148 150 C. 1 H NMR (300 MHz, CD 3 OD) δ 8.41 (t, J 1.5 Hz, 1H), 7.96 (dd, J 3.6, 1.2 Hz, 1H), 7.88 (dt, J 7.8, 1.2 Hz, 1H), 7.83 7.78 (m, 1H), 7.75 (dd, J 4.7, 1.1 Hz, 1H), 7.56 (t, J 8.1 Hz, 1H), 7.46 (d, J 8.1 Hz, 1H), 7.22 7.45 (m, 2H), 7.11 7.08 (m, 1H), 2.64 (s, 3H). 13 C NMR (75 MHz, CD 3 OD) δ 162.9, 152.6, 140.5, 140.5, 139.5, 138.5, 132.8, 131.1, 130.7, 130.4, 129.1, 125.0, 125.5, 124.3, 124.2, 120.9, 113.6, 17.1. LC-MS: [M + H] +, m/z 334 (t r = 4.7 min). FT-IR (KBr, cm -1 ): 3288, 1655, 1550, 757. R f = 0.21 (EtOAc : n-hexane = 1 : 1). N-[3-(1H-Benzimidazol-2-yl)-2-methylphenyl]thiophene-2-carboxamide (58). After stirring a mixture of 27 (0.22 g, 1.0 mmol), TEA and 2-thiophenecarbonyl chloride (120 µl, 1.1 mmol) in THF (20 ml) for 30 min and extracting according to the general procedure E, the resulting crude product was recrystallized from MeOH to give 58 as white crystals (0.05 g, 14%). Mp: 183 185 C. 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.40 (s, 1H), 8.11 (dd, J 3.9, 1.2 Hz, 1H), 7.89 7.84 (m, 3H), 7.74 7.66 (m, 2H), 7.62 7.52 (m, 3H), 7.25 (dd, J 5.0, 3.8 Hz, 1H), 2.39 (s, 3H). 13 C NMR (75 MHz, DMSO-d 6 ) δ 160.3, 149.0, 139.3, 137.4, 134.6, 132.0, 131.9, 131.3, 129.7, 129.1, 128.2, 126.5, 125.8, 125.0, 114.3, 15.6. LC-MS: [M + H] +, m/z 334 (t r = 3.8 min). FT-IR (KBr, cm -1 ): 2924, 2854, 1627, 1529, 1296, 747. R f = S22

0.11 (EtOAc : n-hexane = 1 : 1). N-[5-(1H-Benzimidazol-2-yl)-2-methoxyphenyl]thiophene-2-carboxamide (59). The mixture of 28 (0.24 g, 1.0 mmol), TEA, and 2-thiophenecarbonyl chloride (120 µl, 1.1 mmol) in THF (10 ml) was stirred for 30 min. Extraction according to the general procedure E gave the crude product, which was recrystallized from MeOH to give 59 as yellow crystals (0.14 g, 40%). Mp: 246 248 C. 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.79 (s, 1H), 8.52 (d, J 2.1 Hz, 1H), 8.18 (dd, J 8.7, 2.1 Hz, 1H), 8.07 (d, J 3.6 Hz, 1H), 7.88 (d, J 4.8 Hz, 1H), 7.71 7.68 (m, 2H), 7.42 7.37 (m, 3H), 7.25 7.22 (m, 1H), 3.96 (s, 3H). 13 C NMR (75 MHz, DMSO-d 6 ) δ 160.1, 155.2, 149.5, 139.3, 134.8, 132.1, 129.5, 128.3, 126.9, 126.1, 124.6, 124.2, 117.8, 114.2, 112.5, 56.3. LC-MS: [M + H] +, m/z 350 (t r = 4.2 min). FT-IR (KBr, cm -1 ): 3398, 2926, 1639, 1382, 1017, 735. R f = 0.51 (EtOAc : n-hexane = 1 : 1). N-[3-(5-Methoxy-1H-benzimidazol-2-yl)phenyl]thiophene-3-carboxamide (60). According to the general procedure G 3-thiophenecarboxylic acid (50 mg, 0.36 mmol, 1.2 equiv), oxalyl chloride (30 µl, 0.36 mmol, 1.2 equiv) and 33 (0.10 g, 0.30 mmol, 1 equiv) were used as starting materials. Extraction and deprotection according to the general procedure G (0.2 mmol) gave the crude product. It was purified with Biotage purification system (DCM : MeOH, 1%), and recrystallized from MeOH to produce 60 as white crystals (12 mg, 16%). Mp: 134 136 C. 1 H NMR (300 MHz, CD 3 OD) δ 8.28 (t, J 1.7 Hz, 1H), 8.25 (dd, J 3.0, 1.3 Hz, 1H), 7.87 7.72 (m, 2H), 7.65 (dd, J 5.1, 1.3 Hz, 1H), 7.56 7.41 (m, 3H), 7.07 (s, 1H), 6.89 (dd, J 8.8, 2.4 Hz, 1H), 3.83 (s, 3H). 13 C NMR (75 MHz, CD 3 OD) δ 164.0, 158.4, 152.6, 140.5, 138.7, 131.8, 130.6, 128.0, 127.6, 123.8, 123.5, 120.2, 113.8, 56.2. LC-MS: [M + H] +, m/z 350 (t r = 4.5 min). FT-IR (KBr, cm -1 ): 3104, 1649, 1555, 739. R f = 0.15 (EtOAc : n-hexane = 1 : 1). HRMS (EI): calcd for C 19 H 15 N 3 O 2 S 349.0885; found 349.9877. N-[3-(1-Methylbenzimidazol-2-yl)phenyl]thiophene-2-carboxamide (61). After stirring the mixture S23

of 31 (0.25 g, 1.1 mmol), TEA, and 2-thiophenecarbonyl chloride (120 µl) in THF (10 ml) for 1 h and after extraction according to the general procedure E, the resulting powder was recrystallized from MeOH to give 61 as light orange crystals (0.23 g, 70%). Mp: 220 C. 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.47 (s, 1H), 8.28 (m, 1H), 8.09 (dd, J 1.1, 3.8 Hz, 1H), 7.95 (dt, J 7.5, 2.1 Hz, 1H), 7.89 (dd, J 1.2, 4.8 Hz, 1H), 7.72 7.54 (m, 4H), 7.36 7.24 (m, 3H), 3.94 (s, 3H). 13 C NMR (75 MHz, DMSO-d 6 ) δ 160.1, 152.7, 142.4, 139.8, 139.1, 136.7, 132.2, 130.5, 129.4, 129.1, 128.2, 124.3, 122.4, 122.0, 121.3, 121.2, 119.0, 110.6, 31.8. LC-MS: [M + H] +, m/z 334 (t r = 4.2 min). FT-IR (KBr, cm -1 ): 3066, 1647, 1552, 1298, 755. R f = 0.15 (EtOAc : n-hexane = 1 : 1). N-[3-(1H-Benzimidazol-2-yl)phenyl]benzenesulfonamide (62). After stirring the mixture of 23 (0.21 g, 1.0 mmol), TEA, and benzenesulfonyl chloride (150 µl, 1.2 mmol) for 24 h, another portion of benzenesulfonyl chloride (40 µl, 0.3 mmol) was added and the mixture was stirred for additional 18 h. Extracting according to the general procedure E gave the crude product, which was recrystallized from EtOH to give 62 as a light brown powder (0.18 g, 51%). Mp: 269 270 C. 1 H NMR (300 MHz, DMSOd 6 ) δ 10.83 (s, 1H), 8.05 (t, J 1.5 Hz, 1H), 8.00 (d, J 8.1 Hz, 1H), 7.87 7.79 (m, 4H), 7.64 7.51 (m, 6H), 7.35 (dd, J 1.4, 8.3 Hz, 1H). 13 C NMR (75 MHz, DMSO-d 6 ) δ 148.6, 148.2, 139.2, 139.0, 133.2, 132.5, 130.6, 129.4, 128.5, 127.7, 126.7, 125.8, 125.5, 124.9, 124.5, 124.0, 119.2, 114.2. LC-MS: [M + H] +, m/z 350 (t r = 4.4 min). FT-IR (KBr, cm -1 ): 3328, 2923, 1339, 1162, 742. R f = 0.30 (EtOAc : n- hexane = 1 : 1). N-[3-(1,3-Benzoxazol-2-yl)phenyl]thiophene-2-carboxamide (63). After stirring the mixture of 30 (0.21 g, 1.0 mmol), TEA and 2-thiophenecarbonyl chloride (120 µl, 1.1 mmol) in THF (5 ml) for 45 min and extracting according to the general procedure E, the resulting crude product was recrystallized from MeOH to give 63 as purple crystals (0.22 g, 69%). Mp: 207 C. 1 H NMR (300 MHz, DMSO-d 6 ) δ S24

10.52 (s, 1H), 8.70 (t, J 1.7 Hz, 1H), 8.11 (dd, J 1.2, 3.6 Hz, 1H), 8.03 8.00 (m, 1H), 7.96 7.90 (m, 2H), 7.85 7.81 (m, 2H), 7.61 (t, J 8.0 Hz, 1H), 7.48 7.40 (m, 2H), 7.27 (dd, J 3.6, 5.0 Hz, 1H). 13 C NMR (75 MHz, DMSO-d 6 ) δ 162.1, 160.2, 150.2, 147.5, 139.7, 132.3, 129.8, 129.5, 128.2, 126.8, 125.6, 125.0, 123.3, 122.4, 119.9, 118.7, 111.0. LC-MS: [M + H] +, m/z 321 (t r = 7.4 min). FT-IR (KBr, cm -1 ): 3312, 1637, 1560, 1263, 747. R f = 0.42 (EtOAc : n-hexane = 1 : 2). N-[4-(1H-Benzimidazol-2-yl)phenyl]thiophene-2-carboxamide (64). After stirring the mixture of 29 (0.21 g, 1.0 mmol), TEA, and 2-thiophenecarbonyl chloride (120 µl, 1.1 mmol) in THF (10 ml) for 30 min and extracting according to the general procedure E, the resulting crude product was recrystallized from MeOH to give 64 as a light yellow powder (0.13 g, 41%). Mp: 349 350 C. 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.87 (s, 1H), 10.44 (s, 1H), 8.18 8.15 (m, 2H), 8.07 (dd, J 3.5, 1.0 Hz, 1H), 7.94 7.89 (m, 3H), 7.60 7.57 (m, 2H), 7.26 (dd, J 3.8, 5.0 Hz, 1H), 7.21 7.17 (m, 2H). 13 C NMR (75 MHz, DMSO-d 6 ) δ 160.0, 154.4 (br), 151.1, 143.9 (br), 140.2, 139.8, 134.8 (br), 132.2, 129.4, 128.2, 127.0 (2C), 125.4, 122.0, 120.3, 118.0 (br), 111.2 (br) (2C). LC-MS: [M + H] +, m/z 320 (t r = 4.2 min). FT-IR (KBr, cm -1 ): 3244, 1643, 1535, 1278, 745. R f = 0.68 (EtOAc). 3-(1H-Imidazol-2-yl)aniline (66). According to the general procedure D, 2-(3-nitrophenyl)imidazole 65, synthesized according to Voss et al. 10, (0.60 g, 3.2 mmol) in EtOH (50 ml) was hydrogenated (Pd/C 0.06 g) for 5.5 h to give 66 as a light brown crude product (0.50 g, quant.), which was used without further purification. 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.28 (br s, 1H), 7.20 6.92 (m, 5H), 6.57 6.50 (m, 1H), 5.14 (br s, 2H). R f = 0.20 (DCM : MeOH = 9 : 1). N-[3-(1H-Imidazol-2-yl)phenyl]thiophene-2-carboxamide (67). Following the procedure E, a mixture of 66 (0.16 g, 1.0 mmol), TEA and 2-thiophenecarbonyl chloride (120 µl, 1.1 mmol) in THF (10 ml) S25