Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]([CH2:19][O:20][CH2:21][CH:22]=[CH2:23])([CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:7][CH3:8])[CH:2]=[CH2:3].[Cl:24][SiH:25]([Cl:27])[Cl:26]>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[Cl:24][Si:25]([CH2:23][CH2:22][CH2:21][O:20][CH2:19][C:6]([CH2:5][O:4][CH2:1][CH2:2][CH2:3][Si:25]([Cl:27])([Cl:26])[Cl:24])([CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:7][CH3:8])([Cl:27])[Cl:26]
Reactant: Cl[SiH](Cl)Cl
Reactant: C=CCOCC(CC)(COCC=C)COCCCCCCCC
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Product: CCCCCCCCOCC(CC)(COCCC[Si](Cl)(Cl)Cl)COCCC[Si](Cl)(Cl)Cl
Temperature: 55 °C
Yield: 60 %

Procedure:
A 1 L, 3-neck flask equipped with magnetic stirrer, pot thermometer and condenser was charged with 3,3-diallyloxymethyl-5-oxa-tridecane (200 g) prepared in Example 4. After heating to 50-60° C., 30 ml of trichlorosilane was added followed by 1 ml of 2.5% chloroplatinic acid solution. Once initiation was observed, a total of 178.8 g of trichlorosilane was added at a rate to maintain reaction temperature at 70-100° C. After the addition was complete, the mixture was maintained at 80-90° C. for 2 hours. The mixture was distilled. The product was isolated in 60% yield, b.p. 220-222 C./0.9 mm; density 1.135; 1HNMR (C6D6): 0.90(m, 6H), 1.13(m, 4H), 1.26(m, 10H), 1.58(m, 8H), 3.10(t, 4H), 3.32(s, 2H), 3.38(t, 4H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[CH2:32]([NH:34][C:35]1[C:36]([NH2:48])=[CH:37][C:38]([S:41]([C:44]([F:47])([F:46])[F:45])(=[O:43])=[O:42])=[CH:39][CH:40]=1)[CH3:33]>C(#N)C>[CH2:32]([NH:34][C:35]1[CH:40]=[CH:39][C:38]([S:41]([C:44]([F:45])([F:46])[F:47])(=[O:42])=[O:43])=[CH:37][C:36]=1[NH:48][C:12](=[O:14])[CH2:11][C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=1)[CH3:33]
Reactant: CCNc1ccc(S(=O)(=O)C(F)(F)F)cc1N
Reactant: CS(=O)(=O)c1ccc(CC(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCNc1ccc(S(=O)(=O)C(F)(F)F)cc1NC(=O)Cc1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-methylsulfonylphenylacetic acid (100 mg, 0.467 mmol) in acetonitrile was added 1-hydroxybenzotriazole (76 mg, 0.56 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carboiimide hydrochloride (108 mg, 0.56 mmol), triethylamine (0.143 mL, 1.03 mmol) and N1-ethyl-4-[(trifluoromethyl)sulfonyl]benzene-1,2-diamine (125 mg, 0.467 mmol). The mixture was stirred at room temperature for overnight. The reaction was extracted with ethyl acetate, washed with water and brine, dried, concentrated and recrystallized from ethyl acetate to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ9.54 (br s, 1H, NH), 7.88 (d, J=8.3 Hz, 2H), 7.75 (d, J=2.1 Hz, 1H), 7.64 (dd, 1H), 7.61 (d, J=8.3 Hz, 2H), 6.90 (d, J=9.0 Hz, 1H), 6.70 (t, J=5.2 Hz, 1H, NH), 3.86 (s, 2H, CH2), 3.31 (s, 3H, CH3), 3.29 (m, 2H, NCH2CH3), 1.20 (t, J=7.1 Hz, 3H, NCH2CH3). MS 465 [M++1].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([O:11][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CCCCCCCCCCBr
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCOc1ccc([N+](=O)[O-])c(C)c1
Temperature: 115 °C
Reaction time: 48 h
Yield: 100 %

Procedure:
To a solution of 3-methyl-4-nitrophenol (45 g, 0.294 mol) in dimethylformamide (270 mL) there were added 1-bromodecane (65 g, 0.294 mol) and potassium carbonate (121.8 g, 0.882 mol). The reaction mixture was heated to 115° C. and stirred at that temperature for 48 hours. The reaction mixture was cooled and poured into water (4 L), stirred for 0.5 hour and extracted with two portions of ethyl acetate (1.5 L and 600 mL). The combined organic extracts were washed with 5% aqueous solution sodium bicarbonate (1 L), water (1 L and 0.5 L), dried over sodium sulfate and concentrated to give the crude product (90 g, 0.294 mol, 100% yield). This product was used in the next step without purification.
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].[C:5]([Si:9]([CH3:12])([CH3:11])Cl)([CH3:8])([CH3:7])[CH3:6].N1C=CN=C1>CN(C)C=O.C(OCC)(=O)C>[Br:1][CH2:2][CH2:3][O:4][Si:9]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:12])[CH3:11]
Reactant: OCCBr
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCBr
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.9 %

Procedure:
2-Bromoethanol (3.44 g, 27.53 mmol), t-butyldimethylchlorosilane (4.23 g, 28.07 mmol), and imidazole (3.97 g, 58.31 mmol) was dissolved in dimethylformamide (20 ml) and the solution was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate and washed with water and then with saturated brine, and dried over magnesium sulfate. Insoluble solids were removed by filtration, and then the filtrate was concentrated under reduced pressure to obtain t-butyldimethylsilyl 2-bromoethyl ether (6.05 g) as crude product. The crude product (1.83 g), 2-phenylimidazole (1.11 g, 7.70 mmol), and potassium carbonate (1.50 g, 10.9 mmol) was added in dimethylformamide (10 ml), and the mixture was heated at 80° C. for 10 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and then with saturated brine, and dried over sodium sulfate. Insoluble solids were removed by filtration and the filtrate was evaporated under reduced pressure. The resulting oil was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain the title compound as pale yellow oil (1.16 g, yield: 50%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH:24]3[S:28][C:27](=[O:29])[NH:26][C:25]3=[O:30])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1.[CH3:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1>>[O:29]=[C:27]1[NH:26][C:25](=[O:30])[CH:24]([CH2:23][C:20]2[CH:19]=[CH:18][C:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][N:9]([CH3:8])[C:36](=[O:37])[C:35]4[CH:39]=[CH:40][C:32]([CH3:31])=[CH:33][CH:34]=4)[CH:12]=3)=[CH:22][CH:21]=2)[S:28]1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CNCc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(=O)N(C)Cc2cccc(-c3ccc(CC4SC(=O)NC4=O)cc3)c2)cc1

Procedure:
In a manner similar to that of Example 37(e), by reacting 500 mg (1.1 mmol) of 5-(3′-methylaminomethylbiphenyl-4-ylmethyl)thiazolidine-2,4-dione trifluoroacetate with 170 μl (1.25 mmol) of 4-methylbenzoyl chloride, and after purification, 350 mg (70%) of N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-4, N-dimethylbenzamide are obtained in the form of a white solid with a melting point of 198° C.
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH:21]([N:43]1C(=O)C2=CC=CC=C2C1=O)[CH2:22][O:23][C:24]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].O.NN>C(O)(C)C>[CH2:1]([O:19][CH2:20][CH:21]([NH2:43])[CH2:22][O:23][C:24]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCOCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CC(C)O
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOCC(N)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 70 °C
Yield: 84.2 %

Procedure:
In 50 ml of isopropylalcohol was dissolved 6.4 g of 3-octadecyloxy-2-phthalimido-1-trityloxypropane, and 4 ml of hydrazine hydrate was added to the solution. The mixture was heated at 70° C. for 1 hour, and concentrated under reduced pressure. Ethyl acetate was added to the residue and the insoluble matter was filtered off. The filtrate was concentrated to dryness and purified by silica gel chromatography (eluent: n-hexane-ethyl acetate=3:1) to give 4.41 g (84%) of the desired compound as a pale brown solid.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][C:15]([C:19](O)=[O:20])=[CH:14][C:13]=3[CH:22]=2)=[CH:5][CH:4]=1.[CH3:24][N:25]([CH2:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1)[CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>CN(C)C=O>[CH3:1][N:2]([CH3:23])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][C:15]([C:19]([NH:37][C:36]4[CH:38]=[CH:39][C:33]([CH2:32][N:25]([CH:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)[CH3:24])=[CH:34][CH:35]=4)=[O:20])=[CH:14][C:13]=3[CH:22]=2)=[CH:7][CH:8]=1
Reactant: CN(C)c1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCO3)cc1
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)c1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCO3)cc1
Temperature: 25 °C
Yield: 28.2 %

Procedure:
To a solution of 7—(4-dimethylaminophenyl)-2,3-dihydro-1-benzoxepine-4-carboxylic acid (0.15 g), 4—(N-methyl-N-(tetrahydropyran-4-yl)aminomethyl)aniline (0.11 g) and triethylamine (0.2 ml) in dimethylformamide (15 ml) was added diethyl cyano-phosphate (0.11 ml) under ice-cooling, and the mixture was stirred under nitrogen atmosphere at room temperature over night. The solvent was evaporated, and the residue was purified with silica gel column (methanol/ethyl acetate/triethylamine) to give crude crystals, which were recrystallized from ethyl acetate-hexane to give 7—(4-dimethylaminophenyl)-N-(4—((N-tetrahydropyran-4-yl-N-methylamino)methyl)phenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 149) (0.07 g) as pale brown crystals.
Reaction SMILES: [CH3:1][N:2]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=2)=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:3]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH2:7]2)[CH:4]1[C:10](O)=[O:11].CCN=C=NCCCN(C)C.C1C=CC2[N:53]([OH:54])N=NC=2C=1.NO>CN(C=O)C.C(OCC)(=O)C>[OH:54][NH:53][C:10]([C@@H:4]1[C@H:3]([N:2]([CH3:1])[S:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[CH:20][CH:21]=2)(=[O:14])=[O:15])[C@@H:8]2[CH2:9][C@H:5]1[CH2:6][CH2:7]2)=[O:11]
Reactant: On1nnc2ccccc21
Reactant: CN(C1C2CCC(C2)C1C(=O)O)S(=O)(=O)c1ccc(OCc2ccc3ccccc3n2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: NO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN([C@@H]1[C@H]2CC[C@H](C2)[C@@H]1C(=O)NO)S(=O)(=O)c1ccc(OCc2ccc3ccccc3n2)cc1
Reaction time: 20 h
Yield: 50 %

Procedure:
To a solution of 3-{methyl-[4-(quinolin-2-ylmethoxy)-benzenesulfonyl]-amino}-bicyclo[2.2.1]heptane-2-carboxylic acid (125 mg, 0.268 mmol) in DMF (1 mL) were added EDCI (103 mg, 0.536 mmol), HOBT (72.5 mg, 0.536 mmol) and hydroxylamine (50% in water, 82 μL, 1.34 mmol) at room temperature. The mixture was stirred for 20 h, diluted with ethyl acetate (5 mL), and washed with water (3×3 mL) and brine (3 mL). The organic layer was concentrated and the residue was purified by RP-HPLC to give (1R,2S,3R,4S)-N-hydroxy-3-(methyl{[4-(quinolin-2-ylmethoxy)phenyl]sulfonyl}amino)bicyclo[2.2.1]heptane-2-carboxamide (50% yield). MS (ESI) [M+H] 482.2
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([CH:16]=O)=[CH:14][N:15]=3)[CH:12]=2)[CH:2]=1.[CH3:18][NH:19][NH2:20].[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[CH3:18][N:19]([S:27]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:29])=[O:28])[N:20]=[CH:16][C:13]1[N:11]2[CH:12]=[C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH:8]=[CH:9][C:10]2=[N:15][CH:14]=1
Reactant: O=Cc1cnc2ccc(-c3cccnc3)cn12
Reactant: CNN
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCO
Product: CN(N=Cc1cnc2ccc(-c3cccnc3)cn12)S(=O)(=O)c1ccccc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
To a solution of 6-(pyridin-3-yl)imidazo[1,2-a]pyridine-3-carbaldehyde (Intermediate 1, 70 mg, 0.31 mmol) in ethanol (3 mL) was added methyl hydrazine (17 mg, 0.47 mmol) at RT. The reaction was heated at 85° C. for 3 h. Ethanol was evaporated. Pyridine (2 mL) was added to this residue, followed by addition of benzene sulfonylchloride (83 mg, 0.47 mmol). The reaction mixture was stirred at RT overnight. Pyridine was evaporated. Water was added to this residue and extracted with dichloromethane. Organic layer was dried over sodium sulfate and evaporated. The crude product was purified by column chromatography (silica gel, 1.5% methanol in chloroform) to obtain the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]([CH:12]=[C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=3)[NH:15][C:14]2=[O:23])=[C:9]([CH3:11])[CH:10]=1)=[O:5])C.[OH-].[K+]>CO.C(O)C>[Cl:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:23])[C:13]2=[CH:12][C:8]1[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:10][C:9]=1[CH3:11]
Reactant: CCOC(=O)c1cc(C)c(C=C2C(=O)Nc3ccc(Cl)cc32)[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: Cc1cc(C(=O)O)[nH]c1C=C1C(=O)Nc2ccc(Cl)cc21
Yield: 72.3 %

Procedure:
A mixture of 5-(5-chloro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (1.3 g, 4 mmol) and potassium hydroxide in methanol (25 mL) and ethanol (25 mL) was heated to reflux for overnight. Insoluble materials were removed by filtration and the mixture was neutralized with 6N hydrochloric acid to give 0.876 g (70%) of the title compound.
Reaction SMILES: [S:1]1[C:5]2[CH2:6][N:7]([C:10](=[O:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:8][CH2:9][C:4]=2[CH:3]=[CH:2]1.[CH3:23][NH:24][CH3:25].[CH2:26]=O>C(O)(=O)C>[CH3:23][N:24]([CH2:26][C:2]1[S:1][C:5]2[CH2:6][N:7]([C:10](=[O:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:8][CH2:9][C:4]=2[CH:3]=1)[CH3:25]
Reactant: C=O
Reactant: CNC
Reactant: O=C(CCCCCc1ccccc1)N1CCc2ccsc2C1
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(s1)CN(C(=O)CCCCCc1ccccc1)CC2
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of 0.503 g (1.548 mmol) of 1-(5,7-dihydro-4H-thieno[2,3-c]pyridin-6-yl)-6-phenylhexan-1-one in 20 ml of acetic acid, 0.17 g (1.9 mmol) of 50% aqueous dimethylamine and 0.15 g (1.9 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 3 hours. Additionally, 0.5 g (5.5 mmol) of 50% aqueous dimethylamine and 0.5 g (6.2 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 6 hours. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with aqueous sodium hydroxide and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=4/1) to yield the desired product.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:37][CH2:38][C:39]#[CH:40]>>[N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:29]=[CH:30][C:31]([C:32]([NH:37][CH2:38][C:39]#[CH:40])=[O:33])=[CH:35][CH:36]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: C#CCN
Reactant: O=C(O)c1ccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Product: C#CCNC(=O)c1ccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Yield: 100.8 %

Procedure:
Using the method in Example 172, 4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and 3-aminopropyne (17 mg, 0.30 mmol, 0.6M in DMF) were combined to give 54 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 536 [M+H]+.
Reaction SMILES: C([N:4]1[CH2:8][CH:7]([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[CH:6]([CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)[CH2:5]1)C=C.CC#N>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].O>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH:18]2[CH2:17][CH2:16][N:15]([CH2:14][CH:6]3[CH:7]([C:9]4[CH:13]=[CH:12][S:11][CH:10]=4)[CH2:8][NH:4][CH2:5]3)[CH2:20][CH2:19]2)=[CH:22][CH:23]=1
Reactant: C=CCN1CC(CN2CCC(c3ccc(F)cc3)CC2)C(c2ccsc2)C1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Product: Fc1ccc(C2CCN(CC3CNCC3c3ccsc3)CC2)cc1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A mixture of 0.48 g (0.26 mmol) of 1-allyl-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(RS)-(3-thienyl)pyrrolidine and 0.067 g (0.072 mmol) of Wilkinson's catalyst [Rh(PPh)3Cl] in 20 mL of an 85% solution of CH3CN and water was heated to 90° C. and stirred for 3 h. The reaction mixture was cooled to rt and concentrated. The residue was partitioned between EtOAc and water. The organic fraction was washed with sat. NaHCO3, dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by chomatography (silica, CHCl3: MeOH: NH3, 90: 10:1) to give the title compound. 1H NMR CDCl3) δ7.28 (d of d, 1H, J=3.0, 4.8 Hz), 7.15-7.17 (m, 2H), 6.95-7.02 (m, 4H), 3.31-3.38 (m, 2H), 2.85-3.03 (m, 5H), 2.35-2.48 (m, 5H), 1.95-2.02 (m, 2H), 1.61-1.78 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH2:10][C:11]([OH:13])=O)[C:6]=2[C:14]=1[F:15].[NH2:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2([C:31]#[N:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1)[CH3:18].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC#N.O>[C:31]([C:25]1([C:22]2[CH:21]=[CH:20][C:19]([CH:17]([NH:16][C:11](=[O:13])[CH2:10][N:7]3[C:6]4[C:14]([F:15])=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[N:9]=[CH:8]3)[CH3:18])=[CH:24][CH:23]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)#[N:32]
Reactant: CC(N)c1ccc(C2(C#N)CCCCC2)cc1
Reactant: O=C(O)Cn1cnc2ccc(F)c(F)c21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: CC(NC(=O)Cn1cnc2ccc(F)c(F)c21)c1ccc(C2(C#N)CCCCC2)cc1

Procedure:
N-{1-[4-(1-Cyanocyclohexyl)phenyl]ethyl}-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamide is synthesized according to example 5 by mixing (6,7-difluoro-1H-benzimidazol-1-yl)acetic acid (233 mg, 1.10 mmol) prepared according to scheme 2, 1-[4-(1-aminoethyl)phenyl]cyclohexanecarbonitrile (250 mg, 1.10 mmol) prepared according to scheme 11, Et3N (111 mg, 1.10 mmol, 0.153 mL) and HATU (418 mg, 1.10 mmol) in MeCN (10.0 mL). The product is purified by HPLC: Gilson prep pumps, Flow rate: 30 ml/min, Column: Gemini (5μ) 21.2×50 mm, Mobile phase: A=water (10 mM NH4CO3) B=MeCN, (336 mg, 0.796 mmol, 72%). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.38 (d, J=7.03 Hz, 3H) 1.23-1.35 (m, 1H) 1.51-1.69 (m, 2H) 1.69-1.78 (m, 1H) 1.77-1.89 (m, 4H) 1.99-2.09 (m, 2H) 4.87-5.00 (m, 1H) 5.07 (s, 2H) 7.14-7.28 (m, 1H) 7.37 (d, J=8.40 Hz, 2H) 7.42-7.53 (m, 3H) 8.19 (s, 1H) 8.83 (d, J=7.81 Hz, 1H); MS [M+H], calcd: 424.0. found: 423.3.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:10]1(C)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([Mg]Cl)(C)(C)C.ClC1C=CC=CC=1>CC1(P(C(C)(C)C)C(C)(C)C)C(C2C=CC=CC=2)(C2C=CC=CC=2)C1.O.C1COCC1>[C:10]1([C:2]2[NH:1][C:9]3[C:4]([CH:3]=2)=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ccccc1
Reactant: c1ccc2[nH]ccc2c1
Agent: CC(C)(C)P(C(C)(C)C)C1(C)CC1(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: Clc1ccccc1
Solvent: O
Product: c1ccc(-c2cc3ccccc3[nH]2)cc1
Temperature: 5 °C
Yield: 96 %

Procedure:
[PdCl(π-allyl)]2 (15.6 mg, 0.1 mol %) and cBRIDP (60.2 mg, 0.4 mol %) were placed into a 50 mL, two-necked, round bottomed flask equipped a gas inlet, and the flask was evacuated and filled with nitrogen. Subsequently, to the mixture was added dehydrated THF (11 mL) to prepare a catalyst solution. A 200 mL, four-necked, round-bottomed flask equipped with a Teflon® coated magnetic stirring bar, condenser, dropping funnel, thermometer, and a gas inlet was evacuated and filled with nitrogen. Indole (5.0 g, 42.7 mmol, 1.0 equivalent) and dehydrated toluene (55 mL) were charged into the flask, and the mixture was cooled to 5° C. using an ice bath. To the mixture was added a THF solution of tert-butylmagnesium chloride (tBuMgCl) (1.02 mol/L, 46.0 mL, 47.0 mmol, 1.1 equivalents) (containing 42.0 mL of THF) dropwise via the dropping funnel at such a rate that the temperature of the reaction solution was kept at 15° C. or lower. Subsequently, to the solution were added chlorobenzene (4.8 mL, 47.0 mmol, 1.1 equivalents) and the catalyst solution (11 mL) successively, and the solution was stirred for 15 minutes under reflux. After cooling the reaction mixture to room temperature, to the mixture were added water (30 mL) and the aqueous layer was separated off. The organic layer was concentrated under reduced pressure to give oily residue, which was purified by silica gel column chromatography (eluent: n-hexane/toluene) to afford 7.9 g of phenylindole as a viscous oil.
Reaction SMILES: CS[C:3]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:10][CH:9]=1)([CH3:7])[C:4]([OH:6])=[O:5].O.C(OCC)C>C(O)(=O)C.[Zn]>[CH2:14]([C:11]1[CH:10]=[CH:9][C:8]([CH:3]([CH3:7])[C:4]([OH:6])=[O:5])=[CH:13][CH:12]=1)[CH:15]([CH3:17])[CH3:16]
Reactant: CSC(C)(C(=O)O)c1ccc(CC(C)C)cc1
Agent: [Zn]
Solvent: O
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Yield: 100.8 %

Procedure:
α-Methylthio-α-(p-isobutylphenyl)propionic acid (387 mg) was dissolved in 3 ml of acetic acid, and 200 mg of zinc powder was added. The mixture was heated under reflux for 2 hours. Furthermore, 200 mg of zinc powder was added, and the mixture was heated under reflux for 18 hours. The zinc powder which agglomerated was pulverized, and the mixture was again heated under reflux for 20 hours. Water (30 ml) and 20 ml of diethyl ether were added, and the insoluble matter was separated by filtration. Then, conc. hydrochloric acid was added to adjust the pH of the mixture to 1, and it was extracted four times with 20 ml of diethyl ether. The organic layer was washed with 10 ml of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the diethyl ether and acetic acid. Thus, 319 mg of α-(p-isobutylphenyl)propionic acid was obtained as an oil which crystallized soon. Recrystallization from hexane afforded colorless crystals having a melting point of 74° to 76° C. The IR and NMR spectra of this product were identical with those of the authentic sample.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])/[C:3](/[NH2:10])=[CH:4]/[C:5]([O:7]CC)=O.[Cl:13][C:14]1[C:25]([C:26](=[O:31])[NH:27][CH:28]([CH3:30])[CH3:29])=[CH:24][C:17]([NH:18][C:19](=O)[O:20]CC)=[C:16]([F:32])[CH:15]=1>>[CH:28]([NH:27][C:26](=[O:31])[C:25]1[CH:24]=[C:17]([N:18]2[C:5](=[O:7])[CH:4]=[C:3]([C:2]([F:1])([F:11])[F:12])[NH:10][C:19]2=[O:20])[C:16]([F:32])=[CH:15][C:14]=1[Cl:13])([CH3:30])[CH3:29]
Reactant: CCOC(=O)Nc1cc(C(=O)NC(C)C)c(Cl)cc1F
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Product: CC(C)NC(=O)c1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl

Procedure:
Analogously to the procedure described in Example 1, starting from ethyl 4,4,4-trifluoro-3-aminocrotonate and ethyl 4-chloro-2-fluoro-5-(N-isopropylcarbamoyl)-carbanilate there is obtained N-isopropyl-2-chloro-5-[3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1(2H)-pyrimidinyl]-4-fluorobenzamide, m.p. 234°-239° C.