Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]2[C@H:13]([NH:16][C:17](=[O:29])[C@@H:18]([N:23]3[CH2:28][CH2:27]O[CH2:25][CH2:24]3)[CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:14][CH2:15][C@H:10]2[CH2:9]1)C1C=CC=CC=1.[CH:30]1([S:33](Cl)(=[O:35])=[O:34])[CH2:32][CH2:31]1.FC(F)(F)C1C=C(S(Cl)(=O)=O)C=CC=1>>[CH:30]1([S:33]([N:8]2[CH2:12][C@H:11]3[C@H:13]([NH:16][C:17](=[O:29])[C@@H:18]([N:23]4[CH2:24][CH2:25][CH2:27][CH2:28]4)[CH2:19][CH:20]([CH3:21])[CH3:22])[CH2:14][CH2:15][C@H:10]3[CH2:9]2)(=[O:35])=[O:34])[CH2:32][CH2:31]1
Reactant: CC(C)C[C@@H](C(=O)N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21)N1CCOCC1
Reactant: O=S(=O)(Cl)C1CC1
Agent: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Product: CC(C)C[C@@H](C(=O)N[C@@H]1CC[C@H]2CN(S(=O)(=O)C3CC3)C[C@H]21)N1CCCC1

Procedure:
The title compound was prepared by substituting (2S)-N-[(3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-yl]-4-methyl-2-pyrrolidin-1-ylpentanamide from Example 250 for (S)-N-((3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-yl)-4-methyl-2-morpholinopentanamide and cyclopropanesulfonyl chloride for 3-(trifluoromethyl)benzene-1-sulfonyl chloride in the procedures described in Example 319: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.14 (d, J=7.3 Hz, 1H), 4.33-4.40 (m, 1H), 3.82 (dd, J=9.9, 2.6 Hz, 1H), 3.57 (dd, J=9.9, 7.0 Hz, 1H), 3.41 (dd, J=9.6, 7.0 Hz, 1H), 3.22 (dd, J=9.6, 3.2 Hz, 1H), 3.16 (dd, J=9.2, 5.1 Hz, 1H), 2.60-2.70 (m, 7H), 2.04 (dq, J=11.9, 5.9 Hz, 1H), 1.79-1.97 (m, 3H), 1.56-1.67 (m, 6H), 1.33-1.40 (m, 1H), 1.16-1.23 (m, 2H), 0.99 (d, J=6.3 Hz, 3H), 0.92 (d, J=6.4 Hz, 3H), 0.86-0.92 (m, 2H); MS (ESI+) m/z 398 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:10])[C:7]=1[CH2:8]O.S(Br)([Br:13])=O>C(Cl)Cl.CN(C=O)C>[Br:13][CH2:8][C:7]1[C:2]([F:1])=[CH:3][N:4]=[CH:5][C:6]=1[F:10]
Reactant: OCc1c(F)cncc1F
Reactant: O=S(Br)Br
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Fc1cncc(F)c1CBr
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
(3,5-Difluoro-4-pyridyl)methanol (6.11 g, 42.11 mmol) was dissolved in CH2Cl2 (140 mL). At 0° C. Thionyl bromide (3.589 mL, 46.32 mmol) was added slowly, then 1 drop of DMF was added: the solution turned yellow with gas evolution. The reaction mixture was stirred at rt for 1.5 h. It was quenched with 10 ml water. The pH was made basic (pH=9) with aq NaHCO3. The water layer was extracted 3 times with CH2Cl2. The combined organic layers were washed with brine. The organic phase was dried with Na2SO4, filtrated and the filtrate evaporated. The desired product was obtained as a brown liquid (9.68 g, lacrimator).
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2.[F:18][C:19]([F:34])([F:33])[C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1>>[F:18][C:19]([F:33])([F:34])[C:20]1[CH:21]=[C:22]([CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=1)[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2
Reactant: BrC=C1c2ccccc2CCc2ccccc21
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: FC(F)(F)c1cc(C=C2c3ccccc3CCc3ccccc32)cc(C(F)(F)F)c1

Procedure:
Combine 5-bromomethylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (0.5 g, 1.75 mmol) and 3,5-bis (trifluoromethyl)phenyl boronic acid (0.449 g, 1.75 mmol) using procedures essentially as described in Example 219, below. Pass through a plug of silica gel equilibrated with hexanes. Concentrate the filtrate to give the title product. Analysis for C24H16F6: Calcd: C, 68.90 H, 3.85. Found: C, 68.64 H, 3.80. HPLC (ISO80-10M)) t=5.64 min (98%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][C:5]([CH2:14][N:15](C)[C@@H:16]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]([OH:19])=O)=[C:6]([CH:12]=[O:13])[O:7]2.[CH3:25][O:26][C:27](=[O:35])[C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[N:30][CH:29]=1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O>[CH3:25][O:26][C:27](=[O:35])[C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:17](=[O:19])[C@@H:16]([N:15]2[CH2:14][C:5]3[CH2:4][C:3]4[C:2]([Cl:1])=[CH:11][CH:10]=[CH:9][C:8]=4[O:7][C:6]=3[C:12]2=[O:13])[CH2:20][CH:21]([CH3:22])[CH3:23])=[N:30][CH:29]=1
Reactant: CC(C)C[C@@H](C(=O)O)N(C)CC1=C(C=O)Oc2cccc(Cl)c2C1
Reactant: COC(=O)c1ccc(N)nc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc(NC(=O)[C@H](CC(C)C)N2CC3=C(Oc4cccc(Cl)c4C3)C2=O)nc1
Yield: 28.4 %

Procedure:
A solution of (S)-2-[(5-chloro-2-formyl-4H-chromen-3-ylmethyl)-methyl-amino]-4-methyl-pentanoic acid (300 mg, 2.1 mmol) (Example 3, Step 1), commercially available 6-amino-nicotinic acid methyl ester (163 mg, 1.07 mmol), N-ethyl-N-dimethyaminopropyl carbodiimide hydrochloride (EDCI. HCl) (190 mg, 0.98 mmol), and N-hydroxybenzotriazole (HOBt) (132 mg, 0.982 mmol) in methylene chloride (15 mL) was stirred for 16 hours at 25° C. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue, upon silica gel flash chromatography using hexane-ethyl acetate gradient elution, afforded 6-[(S)-2-(8-chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl-pentanoylamino]-nicotinic acid methyl ester (143 mg, 3%), as a white solid. 1H NMR (DMSO-d6) δ: 11.36 (s, 1H), 8.87 (s, 1H), 8.29 (dd, J=8.8, 2.0 Hz, 1H), 8.15 (d, J=8.8 Hz, 1H), 7.18-7.39 (m, 2H), 7.09 (dd, J=6.8, 2.0 Hz, 1H), 5.09 (dd, J=10.8, 4.4 Hz, 1H), 4.43 (d, J=19.1 Hz, 1H), 4.08 (d, J=19.1 Hz, 1H), 3.86 (s, 3H), 3.75 (s, 2H), 1.78-1.92 (m, 1H), 1.63-1.76 (m, 1H), 1.47 (br. s., 1H), 0.93 (t, J=5.9 Hz, 6H).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:24])[CH3:23])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.C([Li])CCC.[N:32]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[CH:36]=1)=[C:33]=[S:34]>O1CCCC1>[C:37]1([CH3:41])[CH:38]=[CH:39][CH:40]=[C:35]([NH:32][C:33]([N:21]([C:18]2[CH:19]=[CH:20][C:15]([C:12]3[N:13]=[CH:14][N:10]([C:7]4[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:25])[F:26])=[CH:9][CH:8]=4)[N:11]=3)=[CH:16][CH:17]=2)[C:22](=[O:24])[CH3:23])=[S:34])[CH:36]=1
Reactant: Cc1cccc(N=C=S)c1
Reactant: CC(=O)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)N(C(=S)Nc1cccc(C)c1)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To N-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acetamide in tetrahydrofuran (1.1 mL) cooled to −78° C. was added n-butyllithium (2.5 M, 0.13 mL). The reaction was stirred for 1 hour. 1-Isothiocyanato-3-methylbenzene was added and the solution was slowly warmed to 0° C. over 1 hour. The mixture was quenched with aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was purified via radial chromatography using a 97:3 chloroform/methanol mixture as eluent providing the title compound as a tan solid (0.062 g, 55%).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:36])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:35])[CH2:33]Cl)[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:53][O:54][C:55]1[CH:63]=[CH:62][C:58]([CH2:59][NH:60][CH3:61])=[CH:57][CH:56]=1>C(Cl)Cl.CN(C=O)C>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:36])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:35])[CH2:33][N:60]([CH2:59][C:58]4[CH:62]=[CH:63][C:55]([O:54][CH3:53])=[CH:56][CH:57]=4)[CH3:61])[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccnc(NC(=O)CCl)c3)c3ccccc23)cc1
Reactant: CNCc1ccc(OC)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN(C)CC(=O)Nc2cc(COc3ccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(C)cc4)c4ccccc34)ccn2)cc1
Temperature: 55 °C
Reaction time: 12 h
Yield: 12.3 %

Procedure:
To a solution of N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-chloroacetamide (Intermediate B) (50 mg, 0.08 mmol) in DCM (1.0 mL), DMF (0.2 mL) and DIPEA (17.5 μl, 0.10 mmol) was added N-(4-methoxybenzyl)-N-methylamine (15.5 μl, 0.09 mmol) The reaction mixture was stirred at 55° C. for 12 hr. The crude reaction mixture was purified by column chromatography (12 g, 0-10% MeOH in DCM, gradient elution). Product fractions were concentrated in vacuo and the residue triturated with a mixture of diethyl ether, DCM and iso-hexane (2:1:2, 5.0 mL) to afford N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-((4-methoxybenzyl)(methyl)amino) acetamide (Example 14) as a white solid (7 mg, 11%): m/z 713 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.27 (9H, s), 2.25 (3H, s), 2.39 (3H, s), 3.22 (2H, s), 3.59 (2H, s), 3.72 (3H, s), 5.38 (2H, s), 6.35 (1H, s), 6.90 (2H, m), 7.01 (1H, m), 7.27 (3H, m), 7.35 (2H, m), 7.43 (2H, m), 7.64-7.55 (3H, m), 7.94 (1H, m), 8.37-8.28 (3H, m), 8.58 (1H, s), 8.79 (1H, s), 9.97 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:30])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]2[N:23]=C(C3C=NC=CN=3)C=[CH:20][N:19]=2)=[CH:12][CH:11]=1.N1C=CN=CC=1C(=O)C.[CH3:40][C:41]1[N:42]=[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][N:44]2[C:49]=1[C:50](=O)[CH3:51]>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:30])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]2[N:23]=[C:50]([C:49]3[N:44]4[CH:45]=[CH:46][CH:47]=[CH:48][C:43]4=[N:42][C:41]=3[CH3:40])[CH:51]=[CH:20][N:19]=2)=[CH:12][CH:11]=1
Reactant: Nc1ccccc1NC(=O)c1ccc(CNc2nccc(-c3cnccn3)n2)cc1
Reactant: CC(=O)c1c(C)nc2ccccn12
Agent: CC(=O)c1cnccn1
Product: Cc1nc2ccccn2c1-c1ccnc(NCc2ccc(C(=O)Nc3ccccc3N)cc2)n1

Procedure:
Title compound was obtained according to the scheme 6 similarly to the compound 26a (Example 29) using instead of 1-pyrazin-2-yl-ethanone as the starting material the ketone 333 (Table 11). Characterization of the title compound is provided in the Table 12.
Reaction SMILES: C[N:2]([CH:4]=[C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[CH2:14][O:15][Si](C(C)(C)C)(C)C)[NH:7][C:6]1=[O:23])[CH3:3].Cl.[CH3:25][NH:26][S:27](=[O:36])([C:29]1[CH:34]=[CH:33]C(N)=[CH:31][CH:30]=1)=[O:28]>C(O)C>[OH:15][CH2:14][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:13]=1[C:5](=[CH:4][NH:2][C:3]1[CH:33]=[CH:34][C:29]([S:27]([NH:26][CH3:25])(=[O:36])=[O:28])=[CH:30][CH:31]=1)[C:6](=[O:23])[NH:7]2
Reactant: CNS(=O)(=O)c1ccc(N)cc1
Reactant: CN(C)C=C1C(=O)Nc2cccc(CO[Si](C)(C)C(C)(C)C)c21
Agent: Cl
Solvent: CCO
Product: CNS(=O)(=O)c1ccc(NC=C2C(=O)Nc3cccc(CO)c32)cc1
Temperature: 25 °C
Yield: 39.3 %

Procedure:
A solution of 1.2 g (3.7 mmol) of 3-methylsulfanyl-4-(t-butyidimethylsilyloxy)methyl-1,3-dihydro-indol-2-one in THF (25 mL) was stirred with saturated ammonium chloride solution (20 mL), and activated zinc dust (5 g) was added. The mixture was stirred for 60 h at rt. The organic phase was separated, dried over MgSO4 and concentrated to give 1,16 g of impure 4-(t-butyidimethylsilyloxy)methyl-1,3dihydro-indol-2-one as an off-white solid: 1H NMR (DMSO-d6): δ 0.11 (s, 6H), 0.86 (s, 9H), 3.42 (s, 2H), 4.67 (s, 2H), 6.74 (d, J=7.7 Hz, 1H), 6.95 (d, J=7.7 Hz, 1H), 7.18 (t J=7.7 Hz, 1H), 10.40 (s, 1H). A solution of 0.64 g (2.3 mmol) of 4-(t-butyldimethylsilyloxy)methyl-1,3-dihydro-indol-2-one in DMF dimethylacetal (5 mL) was heated to 100° C. for 1 h. The excesss DMF dimethylacetal was removed under high vacuum, and the resulting dark oil was chromatographed on silica gel, eluting with EtOAc, to give 0.34 g (44%) of 3-dimethylaminomethylene-4-(t-butyidimethyl-silyloxy)methyl-1,3-dihydro-indol-2one as a white solid: 1H NMR (DMSO-d6): δ −0.03 (s, 6H), 0.81 (s, 9H), 3.29 (s, 6H), 4.64 (s, 2H), 6.66 (d, J=7.3 Hz, 1H), 6.73 (d, J=7.3 Hz, 1H), 6.79 (t, J=7.3 Hz, 1H), 7.76 (s, 1H), 9.97 (s, 1H)); APCI−MS m/z 333 (M+1)+. A solution of 0.115 g (0.34 mmol) of 3-dimethylaminomethylene-4-(t-butyidimethylsilyloxy)methyl-1,3dihydro-indol-2-one in ethanol (10 mL) was treated with 0.076 g (0.34 mmol) N-methylsulfanilamide hydrochloride. The solution was refluxed for 0.5 h and cooled to rt. The resulting yellow precipitate was isolated by filtration, washed with ethanol and dried to yield 0.048 g (38%) of the title compound: 1H NMR (DMSO-d6): δ 2.37 (d, J=5.0 Hz, 3H), 4.67 (s, 2H), 5.3 (bs, 1H), 6.78 (d, J=7.5 Hz, 1H), 6.93 (d, J=7.5 Hz, 1H), 6.99 (t, J=7.5 Hz, 1H), 7.33 (q, J=5.0 Hz, 1H), 7.44 (d, J=8.6 Hz, 2H), 7.71 (d, J=8.6 Hz, 2H), 8.32 (d, J=12.2 Hz, 1H), 10.67 (s, 1H), 11.26 (d, J=12.2 Hz, 1H); APCI−MS m/z 358 (M−1)−. Anal. Calcd for C17H17N3O4S: C, 56.81, H, 4.77; N, 11.69, S, 8.92. Found C, 56.89, H, 4.81; N, 11.70; S, 8.84.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5]Br.[OH:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:16][CH:17]=1
Reactant: BrCCCCBr
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1ccc(OCCCCBr)cc1

Procedure:
A mixture of 1,4 dibromobutane (50 ml), methyl 4-hydroxy-benzoate (15.2 g, 0.1 mole), potassium carbonate (40 g) in 2-butanone (500 ml) was refluxed for 24 hours. The mixture was filtered, solvent removed and the residue was chromatographed on silica gel eluted with chloroform/petrol and recrystallised from pentane to give methyl 4-(4-bromobutyloxy)benzoate (19.26 g).
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[C:3]([C:4]([OH:6])=[O:5])=[CH:7][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:9][CH:10]=2)=[CH:18][CH:17]=1
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)O)c1
Reactant: OB(O)c1ccc(Cl)cc1
Product: CS(=O)(=O)c1ccc(-c2ccc(Cl)cc2)c(C(=O)O)c1

Procedure:
Prepared in analogy to Example B25 from 2-Iodo-5-methanesulfonyl-benzoic acid (example B19(b)) and 4-chloro-benzeneboronic acid. Light brown solid. MS (m/e): 309.1 ([M−H], 100%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24](Br)=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11].[O:26]1[CH2:31][CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH2:28][CH2:27]1.C([O-])(=O)C.[K+].O1CCOCC1>CO.O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([C:29]3[CH2:30][CH2:31][O:26][CH2:27][CH:28]=3)=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: O=C(c1ccc(Oc2ncccc2Br)cc1)c1nc2ccccc2[nH]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: O=C(c1ccc(Oc2ncccc2C2=CCOCC2)cc1)c1nc2ccccc2[nH]1
Temperature: 100 °C

Procedure:
A clear 150 ml pressure tube was charged with (1H-benzo[d]imidazol-2-yl)(4-(3-bromopyridin-2-yloxy)phenyl)methanone (1.5 g, 3.80 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.959 g, 4.57 mmol), Bis-[4-(di-tert-butylphosphino)-N,N-dimethylbenzenamine]Palladium dichloride (2.69 g, 3.80 mmol), potassium acetate (0.373 g, 3.80 mmol), Dioxane (9 mL) and Water (1.000 mL). The reaction flask was flushed with nitrogen and capped. The reaction was heated to 100° C. for 16 hours. The reaction was then cooled down to RT and partitioned with ethyl acetate (50 ml) and water (50 ml). The organic layer was washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate and then filtered. The volatile were reduced to a smaller volume and the solid that precipitated out was filtered off. The cake obtained was suspended in hot MeOH, filtered and dried to give (1H-benzo[d]imidazol-2-yl)(4-(3-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yloxy)phenyl)methanone as a yellow solid. MS (ESI, pos. ion) m/z: 397.9 (M+1).
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]([OH:20])=O)[CH:15]=[CH:14][C:12]=2[N:13]=1)[CH2:6][CH2:7][CH3:8].[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1O.[OH-].[Na+]>CN1CCCC1=O>[CH2:5]([C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]3[O:20][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=3)[CH:15]=[CH:14][C:12]=2[N:13]=1)[CH2:6][CH2:7][CH3:8]
Reactant: CCCCc1nc2ccc(C(=O)O)cc2[nH]1
Reactant: Nc1ccccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O=S(Cl)Cl
Product: CCCCc1nc2ccc(-c3nc4ccccc4o3)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1.43 g (12 mMol) of thionyl chloride are added dropwise at 10° C. with stirring to a suspension of 2.52 g (10 mMol) of 2-n-butyl-benzimidazole-5-carboxylic acid in 15 ml of N-methylpyrrolidinone. The mixture is stirred for a further 15 minutes at ambient temperature, then 1.31 g (11 mMol) of 2-aminophenol are added and the mixture is heated to 140° C. for 2 hours. The mixture is then poured onto about 50 g of ice and 5 ml of 30% sodium hydroxide solution are added with stirring. The crude product precipitated is suction filtered and purified by column chromatography (300 g of silica gel; eluant: methylene chloride+3% ethanol).
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].O[CH:8]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][S:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=1)[CH2:9][C:10]([O:12]C(C)(C)C)=[O:11]>FC(F)(F)C([O-])=O>[C:4]([CH2:3][CH2:2][S:1][CH:8]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][S:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:39])([F:38])[F:40])[CH:32]=1)[CH2:9][C:10]([OH:12])=[O:11])([OH:6])=[O:5]
Reactant: CC(C)(C)OC(=O)CC(O)c1ccccc1CCCCCCCSc1cccc(C(F)(F)F)c1
Reactant: O=C(O)CCS
Agent: O=C([O-])C(F)(F)F
Product: O=C(O)CCSC(CC(=O)O)c1ccccc1CCCCCCCSc1cccc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
To trifluoroacetate acid (20 ml), cooled to 0° C., was added 3-mercaptopropionic acid (0.26 ml, 3 mmoles) followed by t-butyl 3-hydroxy-3-[2-(7-(3-trifluoromethylphenylthio)heptyl)phenyl]propanoate. The reaction mixture was stirred for 1 hour and evaporated. The resulting residue was diluted with carbon tetrachloride and washed with ice water. The organic layer was dried over sodium sulfate, filtered and evaporated. The resulting oil was flash chromatographed to give the desired product, -log KB value 6.8.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[NH:22][C:21]3=[O:29])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH2:15][CH2:16][CH:17]([N:20]3[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[N:22]([S:38]([CH3:37])(=[O:40])=[O:39])[C:21]3=[O:29])[CH2:18][CH2:19]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(N2CCC(n3c(=O)n(S(C)(=O)=O)c4ccccc43)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
One (1) g of 1-[1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one (cf. International Publication WO 96/13262) and 0.53 ml of triethylamine were suspended in 30 ml of chloroform. To the suspension 0.29 ml of methanesulfonyl chloride was added, followed by 2 hours' stirring at room temperature. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction liquid, which was then extracted with chloroform. The extract was dried over sodium sulfate, concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform, chloroform/methanol=19/1) to give 860 mg of 1-[1-(1-(tert-butoxycarbonyl)piperidin-4-yl)piperidin-4-yl]-3-(methylsulfonyl)-1,3-dihydro-2H-benzimidazol-2-one. The product was dissolved in 25 ml of trifluoroacetic acid, stirred for 30 minutes at room temperature and then the trifluoroacetic acid was distilled off. To the residue ether and chloroform were added and whereby obtained crystals were recovered by filtration, to give 860 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([CH2:14][CH2:15][NH:16][C:17]([C:19]3[N:20]=[CH:21][NH:22][CH:23]=3)=[O:18])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([CH2:14][CH2:15][NH:16][C:17]([C:19]3[N:20]=[CH:21][N:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[CH:23]=3)=[O:18])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1)c1c[nH]cn1
Reactant: Brc1ccccn1
Product: O=C(NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1)c1cn(-c2ccccn2)cn1

Procedure:
The title compound was synthesized from 1H-Imidazole-4-carboxylic acid {2-[5-(3,4-dichlorophenyl)furan-2-yl]ethyl}amide of Example 15 and 2-bromopyridine by the method described by A. K. Verma et al. Tetrahedron Lett. 48 (2007) 4207. Purification by flash chromatography using CH2Cl2/MeOH as a gradient eluent (100:0-99.9:0.1) gave a product which was triturated in EtOAc at RT to afford the desired product. 1H NMR (400 MHz, DMSO-d6): 2.96 (2H, t), 3.59 (2H, m), 6.35 (1H, d), 7.03 (1H, d), 7.44 (1H, m), 7.63 (2H, s), 7.84 (1H, s), 7.95 (1H, distorted d), 8.05 (1H, m), 8.33 (1H, t), 8.43 (1H, d), 8.54 (1H, m), 8.64 (1H, d, 4J=1.1 Hz).