Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2]/[C:3](=[CH:7]\[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:17][C:18]1[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=1[CH3:23])[CH:12]=[CH:11]2)/[C:4]([OH:6])=[O:5].[H][H]>CO.ClCCl.[Pd]>[CH3:1][O:2][CH:3]([CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:17][C:18]1[N:19]=[C:20]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:21][C:22]=1[CH3:23])[CH:12]=[CH:11]2)[C:4]([OH:6])=[O:5]
Reactant: CO/C(=C\c1ccc2c(ccn2Cc2nc(-c3ccccc3)oc2C)c1)C(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: COC(Cc1ccc2c(ccn2Cc2nc(-c3ccccc3)oc2C)c1)C(=O)O
Yield: 60.9 %

Procedure:
A suspension of 80 mg of (Z)-2-methoxy-3-[1-(5-methyl-2-phenyl-oxazol-4-ylmethyl)-1H-indol-5-yl]-acrylic acid in 5 ml of methanol and 2 ml of dichloromethane and 30 mg of Pd/C 10%) was hydrogenated at 22° C. and 1 bar until hydrogen uptake ceased (3 h). The mixture was filtered, the filtrate evaporated and the residue was purified by preparative HPLC (RP-18, CH3CN/H2O, gradient) to give 49 mg of the title compound as a yellow oil. MS: (M−H)− 389.1.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][N:8]1[C@@H:11]([CH3:12])[C@@H:10]([CH2:13]/[CH:14]=[CH:15]/[Sn](CCCC)(CCCC)CCCC)[C:9]1=[O:29].Br[C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1.[OH-].[NH4+].[Cl-].[Na+]>CN(C)C=O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][N:8]1[C@@H:11]([CH3:12])[C@@H:10]([CH2:13]/[CH:14]=[CH:15]/[C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)[C:9]1=[O:29]
Reactant: Cc1ccc(Br)cc1
Reactant: CCCC[Sn](/C=C/C[C@H]1C(=O)N(OC2CCCCO2)[C@H]1C)(CCCC)CCCC
Agent: Cl[Pd]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cc1ccc(/C=C/C[C@H]2C(=O)N(OC3CCCCO3)[C@H]2C)cc1
Temperature: 80 °C
Yield: 67.1 %

Procedure:
To a solution of (3R,4S)-1-(2-tetrahydropyranyloxy)-3-((2E)-3-tributylstannyl-2-propene-1-yl)-4-methylazetidin-2-one (400 mg, 0.78 mmol) in 1 mL of dimethylformamide is added 4-bromotoluene (180 mg, 0.93 mmol) and triphenyphosphine palladium (II) dichloride (27 mg, 0.04 mmol). The resulting solution is heated at 80° C. for 18 h, then 1 mL ammonium hydroxide is added. The reaction mixture is poured into saturated sodium chloride solution (20 mL) and extracted wit 1:1 ethyl acetate/hexane (50 mL). The combined organic layers were dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography (elution with 3:1 hexanes-ethyl acetate) to provide (3R,4S)-1-(2-tetrahydropyranyloxy)-3-((2E)-3-(4-methylphenyl)-2-propene-1-yl)-4-methylazetidin-2-one as an oil (165 mg, 67% yield).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][S:13]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[C:23]([CH3:38])[N:24]([C:26]3[CH:27]=[C:28]4[C:33](=[C:34]([CH3:36])[CH:35]=3)[NH:32][C:31](=[O:37])[CH:30]=[CH:29]4)[CH:25]=2)=[CH:17][CH:16]=1)=[O:14].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH3:12][S:13]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[C:23]([CH3:38])[N:24]([C:26]3[CH:27]=[C:28]4[C:33](=[C:34]([CH3:36])[CH:35]=3)[NH:32][C:31](=[O:37])[CH:30]=[CH:29]4)[CH:25]=2)=[CH:17][CH:16]=1)(=[O:9])=[O:14]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(-n2cc(-c3ccc(S(C)=O)cc3)nc2C)cc2ccc(=O)[nH]c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(-n2cc(-c3ccc(S(C)(=O)=O)cc3)nc2C)cc2ccc(=O)[nH]c12

Procedure:
meta-Chloroperbenzoic acid (0.11 g) was added to a stirred solution of 6-(4-[4-methylsulphinylphenyl]-2-methyl-imidazol-1-yl)-8-methyl-2-(1H)-quinolone (0.14 g) in dichloromethane (20 cm3) at room temperature. After 30 minutes the mixture was poured into saturated sodium carbonate solution (30 cm3) and extracted with dichloromethane (3×30 cm3). The combined and dried (MgSO4) extracts were evaporated in vacuo to give a residue which was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with methanol:dichloromethane, 1:19 by volume. Collection and evaporation of appropriate fractions afforded a solid which was recrystallised from ethyl acetate to give the title compound, m.p. 345°-7° (0.06 g).
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[CH:7]=1.[C-:12]#[N:13].[Na+].C(Cl)Cl>CS(C)=O>[C:12]([CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[CH:7]=1)#[N:13]
Reactant: [C-]#N
Reactant: ClCc1cc2ccccc2o1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: N#CCc1cc2ccccc2o1
Reaction time: 1 h

Procedure:
Compound 5 (117 g) was added dropwise to a stirring suspension of sodium cyanide (37.64 g) in dimethyl sulfoxide (100 ml). The reactor was placed from time to time into an ice bath in order to keep the reaction temperature between 20° C. and 45° C. Addition lasted 60 minutes. The reaction mixture was stirred for another 16 hours, then poured into methylene chloride (500 ml), washed with water (500 ml, then 2×250 ml), and evaporated to dryness. A small sample was purified on a silica gel column, eluting with dichloromethane/hexanes (50:50 v/v).
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(N(C(C)C)CC)(C)C.[C:19](Br)([CH3:22])([CH3:21])[CH3:20].[Cl-].[NH4+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.[O-]S(C(F)(F)F)(=O)=O.[Zn+2].[O-]S(C(F)(F)F)(=O)=O>[C:19]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a mixture of indole (5 g, 42.7 mmol), zinc triflate (9.3 g, 25.6 mmol), and tetrabutylammonium iodide (7.9 g, 21.4 mmol) in anhydrous toluene (120 mL) was added diisopropylethylamine (8.2 mL, 47 mmol) at room temperature under a blanket of nitrogen. After the reaction was stirred 15 minutes at room temperature, the reaction mixture was treated with tert-butyl bromide (2.5 mL, 21.7 mmol). The reaction solution was stirred at room temperature under nitrogen for 3 hours, then poured into a saturated aqueous solution of ammonium chloride (150 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over magnesium sulfate, concentrated, and the residue was purified via flash column chromatography (silica, 10% ethyl acetate in hexane) to afford 3-tert-butyl-1H-indole as a white solid. MS (ES) m/z 174.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N:25]=[C:26]=[S:27])[CH:20]=1>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][C:4]([C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])=[CH:3][C:2]=1[NH:1][C:26]([NH:25][C:21]1[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=1)=[S:27]
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Reactant: S=C=Nc1cccnc1
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NC(=S)Nc1cccnc1
Yield: 95.2 %

Procedure:
Prepared according to the procedure described for Example 60 using 3-amino-4-methoxy-N-phenyl-benzamide (0.972 g, 4.00 mmol) and 3-pyridyl isothiocyanate (0.565 g, 4.15 mmol). Trituration in hexanes/ethyl acetate (3:2) gave the product (1.441 g); m.p. 178-179° C.
Reaction SMILES: [C:1]([C:3](=[N:15][O:16][CH2:17][CH2:18][CH3:19])[C:4]([N:10]1[CH:14]=[N:13][CH:12]=[N:11]1)=[N:5][O:6][CH2:7][CH2:8][CH3:9])#[N:2].C(=O)([O-])[O-:21].[K+].[K+].OO.S([O-])([O-])(=S)=S.[Na+].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CO>[C:1]([C:3](=[N:15][O:16][CH2:17][CH2:18][CH3:19])[C:4]([N:10]1[CH:14]=[N:13][CH:12]=[N:11]1)=[N:5][O:6][CH2:7][CH2:8][CH3:9])(=[O:21])[NH2:2]
Reactant: O=C([O-])[O-]
Reactant: CCCON=C(C#N)C(=NOCCC)n1cncn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: OO
Agent: [Br-]
Solvent: CO
Product: CCCON=C(C(N)=O)C(=NOCCC)n1cncn1
Reaction time: 10 h
Yield: 646.5 %

Procedure:
To 5 ml of a methanol solution containing 1.06 g (4.0 mmol) of the 1-[2-cyano-1,2-bis(n-propoxyimino)ethyl]-1H-1,2,4-triazole produced in Example 23 were added, at room temperature, 65 mg (0.20 mmol) of tetrabutylammonium bromide, 55 mg (0.40 mmol) of potassium carbonate and 1.8 g (16 mmol) of an aqueous 30 wt. % hydrogen peroxide solution, followed by stirring for 10 hours. To the reaction mixture was added sodium dithiosulfate, followed by stirring for 10 minutes. The reaction mixture was concentrated under reduced pressure. The resulting crystal was washed with an aqueous citric acid solution, cold water and isopropyl ether in this order to obtain 0.73 g (yield: 64%) of a title compound.
Reaction SMILES: [NH2:1][C@:2]1([C@H:10]([CH3:12])[OH:11])[O:7][C:5](=[O:6])[C:4]([OH:8])=[C:3]1[O-:9].[NH:13]1CCC[C@H]1C(Cl)=O>N1C=CC=CC=1>[NH:13]1[CH2:10][CH2:2][CH2:3][C@H:4]1[C:5]([OH:7])=[O:6].[NH2:1][C@:2]1([C@H:10]([CH3:12])[OH:11])[O:7][C:5](=[O:6])[C:4]([OH:8])=[C:3]1[O-:9]
Reactant: O=C(Cl)[C@@H]1CCCN1
Agent: C[C@H](O)[C@@]1(N)OC(=O)C(O)=C1[O-]
Solvent: c1ccncc1
Product: O=C(O)[C@@H]1CCCN1

Procedure:
6-Deoxyamino ascorbate (5 mmoles) is reacted with prolyl chloride (7 mmoles) in dry pyridine and worked up by the method as described above and crystallized from ethanol.
Reaction SMILES: O=[C:2]([CH3:19])[CH2:3][O:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])[CH2:7][CH2:6]1.[CH3:20][CH:21]([NH2:29])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>C1C=CC=CC=1>[CH3:20][CH:21]([NH:29][CH:2]([CH3:19])[CH2:3][O:4][CH:5]1[CH2:6][CH2:7][CH:8]([C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:12])[CH2:9][CH2:10]1)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(=O)COC1CCC(C(=O)c2ccccc2)CC1
Reactant: CC(N)Cc1ccccc1
Solvent: c1ccccc1
Solvent: O
Product: CC(COC1CCC(C(=O)c2ccccc2)CC1)NC(C)Cc1ccccc1

Procedure:
4-(2-oxo-propoxy)-cyclohexanophenone (0.02 mole) and α-methyl-phenethylamine (0.02 mole) are then heated in benzene solution. The water formed is removed by means of a Dean-Stark apparatus.
Reaction SMILES: C(O[C:4]1([O:14]CC)[NH:8][C:7](=[O:9])[C:6]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:5]12)C.Cl.[O:18]1CC[CH2:20][CH2:19]1>>[O:14]=[C:4]1[C:5]2[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:7](=[O:9])[N:8]1[CH2:20][CH:19]=[O:18]
Reactant: C1CCOC1
Reactant: CCOC1(OCC)NC(=O)c2ccccc21
Agent: Cl
Product: O=CCN1C(=O)c2ccccc2C1=O
Temperature: 75 °C

Procedure:
To a solution of phthalimide diethylacetal (15 g) in tetrahydrofuran (THF) (30 mL) was added 10% aqueous HCl (18 mL). After heating at 75° C. for 5 hrs, the solution was allowed to cool to room temperature, and ethyl acetate was separated and dried over magnesium sulfate (MgSO4). The solution was filtered and evaporated to provide 11.2 g of the titled compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([F:15])=[CH:10][CH:9]=2)=[O:4].O[Li].O.COC(C)(C)C.[ClH:25]>CO.C1COCC1.O>[ClH:25].[F:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[CH:7]=[N:6][C:5]([C:3]([OH:4])=[O:2])=[CH:14]2
Reactant: COC(=O)c1cc2cc(F)ccc2cn1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: O=C(O)c1cc2cc(F)ccc2cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1 g of the resulting crude 6-fluoro-isoquinoline-3-carboxylic acid methyl ester is dissolved in 20 ml of MeOH/THF (1:1) and slowly mixed at 5° with a solution of 510 mg of LiOH hydrate in 10 ml of water. The resulting solution is stirred at room temperature overnight and poured into a solution consisting of 50 ml of MeOtBu, 10 ml of water and 7 ml of 2N aqu. HCl. The precipitate is filtered off and washed with MeOtBu.
Reaction SMILES: [C@@H:1]1([N:13]2[C:22]3[N:21]=[CH:20][N:19]=[C:17]([NH2:18])[C:16]=3[N:15]=[CH:14]2)[O:12][C@H:6]([CH:7]([C:9]([OH:11])=[O:10])[OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3]>C(O)CCC>[CH2:1]([O:10][C:9]([CH:7]([OH:8])[C@H:6]1[O:12][C@@H:1]([N:13]2[C:22]3[N:21]=[CH:20][N:19]=[C:17]([NH2:18])[C:16]=3[N:15]=[CH:14]2)[C@H:2]([OH:3])[C@@H:4]1[OH:5])=[O:11])[CH2:2][CH2:4][CH3:6]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](C(O)C(=O)O)[C@@H](O)[C@H]1O
Solvent: CCCCO
Product: CCCCOC(=O)C(O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O
Yield: 54 %

Procedure:
In an analogous manner, by the reaction of free adenosine-5'-carboxylic acid with ethanol, there is obtained adenosine-5'-carboxylic acid ethyl ester in a yield of 78% of theory (m.p. 204°-205° C.) and by the reaction of free adenosine-5'-carboxylic acid with n-butanol, there is obtained adenosine-5'-carboxylic acid n-butyl ester in a yield of 54% of theory (m.p. 167° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[O:8][C:7](=[O:16])[CH:6]=1.[CH3:22][O:23][CH2:24]OC.O=P(Cl)(Cl)Cl.CN(C)C=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:22][O:23][CH3:24])[CH:13]=2)[O:8][C:7](=[O:16])[CH:6]=1
Reactant: COCOC
Reactant: O=c1cc(Oc2c(Cl)cccc2Cl)c2cc(O)ccc2o1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COCOc1ccc2oc(=O)cc(Oc3c(Cl)cccc3Cl)c2c1
Temperature: 25 °C
Yield: 38 %

Procedure:
A mixture of 4-(2,6-dichlorophenoxy)-6-hydroxycoumarin (1.2 g, 32 mmole), dimethoxymethane (0.565 g, 7.4 mmole), POCl3 (0.74 g, 4.8 mmole) and dimethylformamide (0.43 g, 5.94 mmole) in toluene is heated at 90°-100° C. for 4 hours, cooled to room temperature, poured onto ice water and filtered. The filtercake is dried and recrystallized from acetonitrile/water to afford the title product, 0.45 g (38% yield), mp 302°-305° C. (dec), identified by 1HNMR, 13 CNMR and IR analyses.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:13][C:14]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]3[CH:39]=[CH:38][C:28]([CH2:29][P:30](=[O:37])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])=[CH:27][CH:26]=3)[N:15]=2)=[C:6]2[C:10]=1[CH2:9][N:8]([CH3:11])[C:7]2=[O:12].[C:40]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)(=[O:42])[CH3:41].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[C:40]([N:43]1[CH2:48][CH2:47][N:46]([C:2]2[CH:3]=[CH:4][C:5]([NH:13][C:14]3[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]4[CH:39]=[CH:38][C:28]([CH2:29][P:30](=[O:37])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])=[CH:27][CH:26]=4)[N:15]=3)=[C:6]3[C:10]=2[CH2:9][N:8]([CH3:11])[C:7]3=[O:12])[CH2:45][CH2:44]1)(=[O:42])[CH3:41]
Reactant: CC(=O)N1CCNCC1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)c4c3C(=O)N(C)C4)n2)cc1)OCC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(N4CCN(C(C)=O)CC4)c4c3C(=O)N(C)C4)n2)cc1)OCC
Temperature: 100 °C
Reaction time: 8 h
Yield: 19.5 %

Procedure:
A mixture of Diethyl [4-({4-[(7-bromo-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzyl]phosphonate (50.0 mg, 0.0796 mmol), 1-acetylpiperazine (0.510 g, 3.98 mmol), bis(dibenzylideneacetone)palladium(0) (9.15 mg, 0.0159 mmol), and Cs2CO3 (77.8 mg, 0.239 mmol) in 1,4-dioxane (5 mL) was evacuated and purged with N2 three times and stirred at 100° C. overnight. The crude mixture was passed through a Thiol-SPE cartridge to remove Pd and subsequently purified by MDP to isolate the title compound (10.5 mg, 20% yield). 1H NMR (400 MHz, CD3OD) δ=1.28 (t, J=7.1 Hz, 6 H), 2.17 (s, 3 H), 3.04-3.10 (m, 2 H), 3.11-3.15 (m, 2 H), 3.19 (s, 3 H), 3.23 (d, J=21.5 Hz, 2 H), 3.68-3.73 (m, 2 H), 3.73-3.79 (m, 2 H), 4.02-4.14 (m, 4 H), 4.54 (s, 2 H), 7.15 (d, J=8.8 Hz, 1 H), 7.38 (dd, J=8.6, 2.5 Hz, 2 H), 7.53 (d, J=8.1 Hz, 2 H), 8.34 (s, 1 H), 8.52 (br. s., 1 H).
Reaction SMILES: [C:1]1([N:7]2[C:25](=[O:26])[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[CH:15][C:16]([N:19]5[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]5)=[N:17][C:18]=4[C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:27]1(N2CCNCC2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:1]1([N:7]2[C:25](=[O:26])[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[CH:15][C:16]([N:19]5[CH2:20][CH2:21][N:22]([C:27]6[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=6)[CH2:23][CH2:24]5)=[N:17][C:18]=4[C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1c2c[nH]c3ccc(N4CCNCC4)nc3c-2nn1-c1ccccc1
Reactant: c1ccc(N2CCNCC2)cc1
Product: O=c1c2c[nH]c3ccc(N4CCN(c5ccccc5)CC4)nc3c-2nn1-c1ccccc1

Procedure:
The title compound was prepared following the procedure described for 6a using 1-phenylpiperazine instead of piperazine. 1H-NMR (DMSO-d6) δ (ppm): 2.80 (4H, br), 3.11 (1H, m), 3.80 (1H, dd, J=11.44, 2.75 Hz), 4.39 (1H, J=11.53 Hz), 4.41 (1H, J=11.53 Hz), 7.14 (1H, tt, J=7.42, 1.09 Hz), 7.36 (6H, m), 7.52 (2H, m), 7.83 (1H, d, J=9.34 Hz), 8.16 (2H, m), 8.54 (1H, s). m/z 423.5 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].I[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[F-].[K+].Cl>CN(C)C=O>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CCCCCCCCI
Reactant: N#Cc1ccc(O)cc1F
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(C#N)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 111.6 %

Procedure:
To dry dimethylformamide (200 mL) were added 2-fluoro-4-hydroxybenzonitrile (13.71 g, 100 mmol), 1-iodooctane (28.82 g, 120 mmol) and potassium fluoride (11.6 g, 200 mmol). This mixture was stirred at room temperature for 16 h, and then at 50° C. for 2 h and then at 90° C. for 2 h. The mixture was then poured into wet-ice (400 g) and 37% HCl (10 mL). The resulting solution was extracted with diethyl ether (3×200 mL). The ether layer was washed with water (2×200 mL) and dried over Na2SO4. After filtration, rotary evaporation gave the crude desired intermediate 2-fluoro-4-n-octyloxybenzonitrile (27.83 g). This liquid intermediate was then added, over a 5-10 min period at 3-13° C. to a flask containing LiAlH(OEt)3 [which had been freshly prepared from LiAlH4 (5.03 g, 0.1326 mol) and ethyl acetate (15.24 g, 0.1730 mol) at 3-8° C. in diethyl ether (130 mL)]. The reaction mixture was stirred at 5° C. for 75 min and 5 N H2SO4 aqueous solution (120 mL) was added dropwise with cooling. After separation, the aqueous layer was extracted with diethyl ether (2×100 mL) and the combination extracts were washed with water (2×100 mL). Standard work-up procedures afforded crude 2-fluoro-4-n-octyloxybenzaldehyde (26.07 g). The crude material was then mixed with N-tert-butylhydroxylamine (8.6 g, 96.4 mmol), molecular sieves (50 g, 4 A) and silica gel (10 g) in chloroform (250 mL). The mixture was stirred at room temperature for 23 h and refluxed for 3 h under argon gas. The mixture was then filtered and rotary evaporated to give a residue which was purified by column chromatography over silica gel eluted with hexanes/ethyl acetate (4:1, v:v). The title compound (12.90 g) was obtained in 39.9% overall yield as a slightly yellowish solid. m.p. 35.6° C. (Rf=0.36 on a silica gel plate using hexanes/EtOAc, 4:1, v:v, as the eluant).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH:5]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=1[NH:28][C:29](=[O:39])[CH2:30][N:31]1[CH2:36][CH2:35][NH:34][CH:33]([CH2:37][OH:38])[CH2:32]1.C(N(CC)CC)C>CN(C)C=O>[F:12][C:9]1[CH:10]=[CH:11][C:6]([CH:5]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:4][CH2:3][CH2:2][N:34]2[CH2:35][CH2:36][N:31]([CH2:30][C:29]([NH:28][C:22]3[C:23]([CH3:27])=[CH:24][CH:25]=[CH:26][C:21]=3[Cl:20])=[O:39])[CH2:32][CH:33]2[CH2:37][OH:38])=[CH:7][CH:8]=1
Reactant: Fc1ccc(C(CCCI)c2ccc(F)cc2)cc1
Reactant: Cc1cccc(Cl)c1NC(=O)CN1CCNC(CO)C1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cccc(Cl)c1NC(=O)CN1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)C(CO)C1
Temperature: 70 °C
Reaction time: 4 h
Yield: 33.1 %

Procedure:
A mixture of 7.4 parts of 1,1'-(4-iodobutylidene)bis[4-fluorobenzene], 5.5 parts of N-(2-chloro-6-methylphenyl)-3-(hydroxymethyl)-1-piperazineacetamide, 4.0 parts of N,N-diethylethanamine and 68 parts of N,N-dimethylformamide was stirred for 4 hours at about 70° C. The reaction mixture was cooled overnight to room temperature and the solvent was evaporated. The residue was taken up in trichloromethane. The organic phase was washed with water, dried, filtered and evaporated. The oily residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The oily residue solidified on triturating in 2,2'-oxybispropane. The product was filtered off and dried, yielding 3.21 parts (33.1%) of 4-[4,4-bis(4-fluorophenyl)butyl]-N-(2-chloro-6-methylphenyl)-3-(hydroxymethyl)-1-piperazineacetamide; mp. 149.8° C. (compound 51).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][CH2:20][NH:21]3)=[CH:16][CH:15]=2)=[O:13])=[CH:7][C:6]=1[F:24])[CH3:2].[F:26][C:27]1[CH:28]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][CH2:20][N:21]3[S:33]([C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([F:26])[CH:28]=3)(=[O:35])=[O:34])=[CH:16][CH:15]=2)=[O:13])=[CH:7][C:6]=1[F:24])[CH3:2]
Reactant: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)NCCC3)cc1F
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(F)c2)CCC3)cc1F

Procedure:
2-Fluoro-4-{[1-(3-fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid, m/z (ES+): 473.24 (M+H+.), was prepared in analogy to example 40, steps 1 to 5. Step 2 was performed using 4-amino-2-fluorobenzoic acid ethyl ester and yielded 2-fluoro-4-[(quinoline-7-carbonyl)-amino]-benzoic acid ethyl ester, which was reduced to 2-fluoro-4-[(1,2,3,4-tetrahydro-quinoline-7-carbonyl)-amino]-benzoic acid ethyl ester in step 3. Step 4 was performed using 3-fluoro-benzenesulfonyl chloride, yielding 2-fluoro-4-{[1-(3-fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 5.