Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[C@@H:6]([CH3:21])[C:7]([S:18]([CH3:20])=O)=[C:8]2[C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[CH3:3].[CH2:22]([O:25][C:26]([N:28]1[CH2:32][C@@H](S)[CH2:30][C@H:29]1[CH2:34][O:35][CH2:36][CH2:37][F:38])=[O:27])[CH:23]=[CH2:24].CC(N(C)C)=O>CN(C)C=O>[CH2:22]([O:25][C:26]([N:28]1[CH2:32][C@@H:20]([S:18][C:7]2[C@H:6]([CH3:21])[C@H:5]3[N:9]([C:10](=[O:11])[C@@H:4]3[C@H:2]([OH:1])[CH3:3])[C:8]=2[C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[CH2:30][C@H:29]1[CH2:34][O:35][CH2:36][CH2:37][F:38])=[O:27])[CH:23]=[CH2:24]
Reactant: C=CCOC(=O)C1=C(S(C)=O)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reactant: C=CCOC(=O)N1C[C@@H](S)C[C@H]1COCCF
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](COCCF)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.2 %

Procedure:
To a mixture of allyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-methylsulfinyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (150 mg) and silica gel (300 mg) in N,N-dimethylformamide (1.5 ml) was added a solution of (2S,4S)-1-allyloxycarbonyl-2-(2-fluoroethoxymethyl)-4-mercaptopyrrolidine (150 mg) i dimethylacetamide (1.45 g). The mixture was stirred for 2 hours at ambient temperature. Silica gel was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography to afford allyl (4R,5S,6S)-3-[(2S,4S)-1-allyloxycarbonyl-2-(2-fluoroethoxymethyl)pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (160 mg).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([CH2:12][O:13][CH2:14][O:15][CH3:16])=[N:6][C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)[CH3:2].[CH:17]1([CH:22]=O)[CH2:21][CH2:20][CH2:19][CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH:17]1([CH2:22][N:3]([CH2:1][CH3:2])[C:4]2[C:5]([CH2:12][O:13][CH2:14][O:15][CH3:16])=[N:6][C:7]([O:10][CH3:11])=[CH:8][CH:9]=2)[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CCNc1ccc(OC)nc1COCOC
Reactant: O=CC1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCN(CC1CCCC1)c1ccc(OC)nc1COCOC
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.5 %

Procedure:
A solution of N-ethyl-6-methoxy-2-[(methoxymethoxy)methyl]pyridin-3-amine (7.20 g, 31.8 mmol) and cyclopentanecarbaldehyde (3.75 g, 38.2 mmol) in 1,2-dichloroethane (240 mL) was added with sodium triacetoxyborohydride (8.75 g, 41.3 mmol), and the mixture was stirred at room temperature for 12 hours. The reaction mixture was added with water, and extracted with chloroform. The organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:1) to obtain N-(cyclopentylmethyl)-N-ethyl-6-methoxy-2-[(methoxymethoxy)methyl]pyridin-3-amine (8.39 g, 86%) as pale yellow oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([NH2:29])(=O)C.B(F)(F)F.CCOCC>C1(C)C(C)=CC=CC=1>[CH2:19]([O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:10]1[N:29]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[O:8][CH:9]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(COCc1ccccc1)c1ccccc1OCc1ccccc1
Reactant: CC(N)=O
Agent: FB(F)F
Solvent: Cc1ccccc1C
Solvent: CCOCC
Product: c1ccc(COc2ccccc2-c2coc(-c3ccccc3)n2)cc1
Yield: 29.3 %

Procedure:
3.46 g of 2-benzyloxy-1-(2-benzyloxy-phenyl)-ethanone according to step (c) are refluxed with 2.95 g of acetamide and 0.9 ml of boron trifluoride etherate in 100 ml of anhydrous xylene over 20 hours. After the solution obtained has been cooled and washed with water it is dried over sodium sulphate, the solvent is distilled off in vacuo and the residue remaining is chromatographed on silica gel (toluene). In addition to re-isolated educt, 1 g (31%) of the target compound is isolated.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.F[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21]#[N:22])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CC(C)C(N)=O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([C:21]#[N:22])=[CH:13][CH:12]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(O)cc1
Reactant: N#Cc1ccc(F)c2ccccc12
Agent: CC(C)C(N)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: N#Cc1ccc(Oc2ccc(C=O)cc2)c2ccccc12
Temperature: 120 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
4-Hydroxybenzaldehyde (300 mg, 2.46 mmol) was dissolved in dimethylacetoamide (8.0 mL), and 4-fluoro-naphthalene-1-carbonitrile (463 mg, 0.420 mmol) and cesium carbonate (1.20 g, 3.69 mmol) were sequentially added thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at 120° C. for 2 hours. After the temperature of the reaction solution was returned to room temperature, water was added thereto, and the organic matter was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, then dried over anhydrous sodium sulfate and filtered. Then, the solvent was distilled off under reduced pressure, whereby a crude product was obtained. This crude product was purified by silica gel column chromatography (hexane:ethyl acetate=95:5 to 70:30 (v/v)), whereby the objective title compound was obtained (515 mg, yield: 77%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]2[CH2:15][O:14][C:13](=[O:16])[C:12]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[C:6]([F:10])[C:7]=1[S:8][CH3:9].[OH2:23].[OH2:24].O.O.O.O.C(OO)(=O)C1C(=CC=CC=1)C(O)=O.O.O.O.O.O.O.O.C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=O.[Mg+2]>ClCCl.CO>[F:1][C:2]1[CH:3]=[C:4]([C:11]2[CH2:15][O:14][C:13](=[O:16])[C:12]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:5]=[C:6]([F:10])[C:7]=1[S:8]([CH3:9])(=[O:24])=[O:23]
Reactant: O
Reactant: CSc1c(F)cc(C2=C(c3ccccc3)C(=O)OC2)cc1F
Agent: O=C(O)c1ccccc1C(=O)OO
Agent: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CO
Product: CS(=O)(=O)c1c(F)cc(C2=C(c3ccccc3)C(=O)OC2)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
Unpurified 4-[3,5-difluoro-4-(methylthio)-phenyl]-3-phenylfuran-2(5H)-one (8.9 g, 27 mmol) and magnesum monoperoxyphthalate hexahydrate (17.2 g, 27 mmol) were combined in a mixture of dichloromethane (200 mL) and methanol (60 mL), and stirred overnight at room temperature. The slurry was poured into water, and extracted with dichloromethane (1×200 mL, 2×50 mL). The combined extracts were washed with water and dilute sodium bicarbonate, and the aqueous sodium bicarbonate wash extracted with dichloromethane (50 mL). The combined extracts were dried with magnesium sulfate, filtered and concentrated. The residue was treated again with magnesium monoperoxyphthalate hexahydrate (8.5 g., 25 mmol), in a mixture of dichloromethane (120 mL) and methanol (30 mL), stirring overnight at room temperature. The reaction mixture was poured into water, and extracted with dichloromethane (2×200 mL). The combined extracts were washed with dilute ammonium chloride (100 mL), and dilute sodium chloride (100 mL), dried with magnesium sulfate, and concentrated to give 6.7 g yellow solids. The crude product was dissolved in dichloromethane (20 mL), and crystallized by adding a mixture of 40% ethyl acetate/60% hexanes (15 mL). The product was filtered, and the filtrate purified by silica gel chromatography using 40% ethyl acetate/60% hexanes to give a total of 5.3 g yellow solids (56%). The 4-[3,5-difluoro-4-(methylsulfonyl)phenyl]-3-phenylfuran-2(5H)-one was recrystallized from ethyl acetate to give white solids. MP 203.5-203.8° C. 1H NMR (CDCl3/400 MHz) 7.35-7.44 (m, 5H), 6.97 (d, 2H, J=9.0), 5.11 (s, 2H), 3.29 (s, 3H). ESHRMS m/z 351.0536 (M+H+, Calcd 351.0502). Anal. Calcd for C17H12F2O4S: C, 58.28; H, 3.45; Found: C, 57.69; H, 3.72.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:44])[CH:4]([N:12]1[C:18](=[O:19])[CH:17]([NH:20][C:21](=[O:39])[CH:22](Br)[CH2:23][CH2:24][CH2:25][CH2:26][N:27]2[C:31](=[O:32])[C:30]3=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]3[C:28]2=[O:37])[CH2:16][C:15]2[CH:40]=[CH:41][CH:42]=[CH:43][C:14]=2[CH2:13]1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:45][O:46][C:47]1[CH:54]=[CH:53][C:50]([CH2:51][SH:52])=[CH:49][CH:48]=1>>[CH3:1][NH:2][C:3](=[O:44])[CH:4]([N:12]1[C:18](=[O:19])[CH:17]([NH:20][C:21](=[O:39])[CH:22]([S:52][CH2:51][C:50]2[CH:53]=[CH:54][C:47]([O:46][CH3:45])=[CH:48][CH:49]=2)[CH2:23][CH2:24][CH2:25][CH2:26][N:27]2[C:31](=[O:32])[C:30]3=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]3[C:28]2=[O:37])[CH2:16][C:15]2[CH:40]=[CH:41][CH:42]=[CH:43][C:14]=2[CH2:13]1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COc1ccc(CS)cc1
Reactant: CNC(=O)C(Cc1ccccc1)N1Cc2ccccc2CC(NC(=O)C(Br)CCCCN2C(=O)c3ccccc3C2=O)C1=O
Product: CNC(=O)C(Cc1ccccc1)N1Cc2ccccc2CC(NC(=O)C(CCCCN2C(=O)c3ccccc3C2=O)SCc2ccc(OC)cc2)C1=O

Procedure:
Prepare by the method of Example 3.2 using 2-(4-(2-bromo-6-phthalimidohexanoyl-amino)-3-oxo-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl)-3-phenyl-propionic acid, N-methyl amide and p-methoxybenzylmercaptan to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH2:12][C:13]([OH:15])=O.CN1CCCCC1.C(OC(Cl)=O)C(C)C.Cl.[CH3:32][NH:33][O:34][CH3:35]>C(Cl)Cl>[CH3:35][O:34][N:33]([CH3:32])[C:13](=[O:15])[CH2:12][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[CH3:1]
Reactant: CNOC
Reactant: Cc1ccc2ccccc2c1CC(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCCCC1
Solvent: ClCCl
Product: CON(C)C(=O)Cc1c(C)ccc2ccccc12
Temperature: -78 °C

Procedure:
(2-Methyl-naphthalen-1-yl)-acetic acid (3.55 g, 17.8 mmol) was stirred with N-methylpiperidine (2.48 mL, 21.4 mmol) in CH2Cl2 in an argon-purged, round-bottom flask. The mixture was chilled to −78° C. Isobutylchloroformate (2.53 mL, 19.5 mmol) was added via syringe. The reaction was stirred at −78° C. for twenty minutes and then a mixture of N,O-dimethylhydroxylamine hydrochloride (2.08 g, 21.3 mmol) and N-methylpiperidine (2.67 mL, 22.0 mmol) in CH2Cl2 (2 mL) was added via syringe. The reaction was stirred at −78° C. for five minutes and was then allowed to warm to room temperature. The reaction was quenched with 1N HCl (˜5 mL) and was diluted with H2O. The dilution was extracted three times with EtOAc. The organic extracts were combined, washed with brine solution, dried over Na2SO4, filtered through celite, and concentrated to give N-methoxy-N-methyl-2-(2-methyl-naphthalen-1-yl)-acetamide in quantitative yield. 1H NMR (300 MHz) CDCl3 δ 7.94 (d, J=8.8 Hz, 1H), 7.80 (d, J=8.7 Hz, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.44 (m, 2H), 7.34 (d, J=8.2 Hz, 1H), 4.26 (s, 2H), 3.67 (s, 3H), 3.23 (s, 3H), 2.51 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:9]([OH:11])=[O:10])=[N:6][C:7]=1[CH3:8].S(Cl)([Cl:14])=O.[CH3:16]O>>[ClH:14].[CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:9]([O:11][CH3:16])=[O:10])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1ncc(C(=O)O)nc1C
Reactant: CO
Reactant: O=S(Cl)Cl
Product: COC(=O)c1cnc(C)c(C)n1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5,6-dimethylpyrazine-2-carboxylic acid (580 mg, 3.82 mmol) in methanol (20 mL) was added thionyl chloride (1.82 g, 15.3 mmol) slowly at 0° C. and the mixture was stirred for 2 h and then heated to reflux for 16 h. The reaction was then cooled to r.t. and concentrated to give the crude product as a yellow solid (700 mg). MS (ESI): m/z 167.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[CH:16]=2)=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[N:6]=1.[C:22](Cl)(=[O:24])[CH3:23].C(=O)([O-])O.[Na+].CN(C)[C:33](=[O:35])[CH3:34]>CN(C)C1C=CN=CC=1>[C:22]([NH:21][C:17]1[CH:16]=[C:15]([C:4]2[S:3][C:2]([NH:1][C:33](=[O:35])[CH3:34])=[N:6][C:5]=2[C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[CH:20]=[CH:19][N:18]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: COc1ccc(-c2nc(N)sc2-c2ccnc(N)c2)cc1
Reactant: CC(=O)N(C)C
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccc(-c2nc(NC(C)=O)sc2-c2ccnc(NC(C)=O)c2)cc1
Temperature: 70 °C
Reaction time: 14 h
Yield: 58 %

Procedure:
To a solution of 4-[2-amino-4-(4-methoxyphenyl)-1,3-thiazol-5-yl]-2-pyridylamine (0.40 g, 1.4 mmol) and 4-dimethylaminopyridine (0.055 g, 0.45 mmol) in N,N-dimethylacetamide (10 mL) was added acetyl chloride (0.3 mL, 4.2 mmol), and the mixture was stirred for 14 hours at 70° C. An aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and extracted with ethyl acetate. The extracts were washed with brine, then, dried and concentrated. The crude crystal was recrystallized from ethanol to obtain a title compound (0.30 g, yield 58%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18](=[N:26][C:27]#[N:28])OC4C=CC=CC=4)[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.Cl.[CH2:30]([NH2:32])[CH3:31]>C(O)(C)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18](=[N:26][C:27]#[N:28])[NH:32][CH2:30][CH3:31])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: N#CN=C(Oc1ccccc1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1
Reactant: CCN
Agent: Cl
Solvent: CC(C)O
Product: CCNC(=NC#N)N1CCN(c2ccnc3cc(Cl)ccc23)CC1

Procedure:
7-Chloro-4-[4-(cyanimino(phenoxy)methyl)piperazin-1-yl]quinoline (0.39 g, 1.0 mmol), ethylamine hydrochloride (1.68 g, 20.6 mmol), and diaza[2.2.2]bicyclooctane (2.24 g, 20.0 mmol) in isopropanol (20 mL) are heated in a sealed tube for 4 h at 110° C. The reaction mixture is concentrated, and the residue is suspended in EtOAc. Washing with water, drying (MgSO4), and removing the solvent leads to a colorless solid, which is washed with hot ether to yield the title product.
Reaction SMILES: [CH2:1]([OH:9])[CH:2]=[CH:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].[CH2:10]=[CH:11][CH:12]=[CH2:13].[P]>[Rh]>[CH2:8]=[C:7]([CH2:10][CH:11]=[CH:12][CH3:13])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2][CH2:1][OH:9]
Reactant: C=CCCCC=CCO
Reactant: C=CC=C
Agent: [Rh]
Agent: [P]
Product: C=C(CC=CC)CCCC=CCO

Procedure:
7-methylene-2,9-undecadiene-1-ol was prepared from 2,7-octadiene-1-ol and butadiene by employing a catalyst which had an atomic ratio of trivalent phosphorus to rhodium of 3.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([NH2:7])[S:4][N:3]=1.N1C=CC=CC=1.Cl[C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[O:16].O>O1CCCC1>[CH3:1][C:2]1[N:6]=[C:5]([NH:7][C:15](=[O:16])[O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])[S:4][N:3]=1
Reactant: Cc1nsc(N)n1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1nsc(NC(=O)OCC(Cl)(Cl)Cl)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
To a solution of 3-methyl-1,2,4-thiadiazol-5-amine (1.00 g, 8.68 mmol) and pyridine (0.850 ml, 10.4 mmol) in tetrahydrofuran (30 ml) was added 2,2,2-trichloroethyl chloroformate (1.44 ml, 10.4 mmol) with ice-cooling and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. Hexane was poured to the residue and a solid was collected by filtration to obtain the desired product (1.84 g, 72.8%).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.ON1C2C=CC=CC=2N=N1.[F:43][C:44]1[CH:49]=[C:48]([F:50])[CH:47]=[CH:46][C:45]=1[CH2:51][C:52]([OH:54])=O.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[F:43][C:44]1[CH:49]=[C:48]([F:50])[CH:47]=[CH:46][C:45]=1[CH2:51][C:52]([N:24]([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][S:18][C:9]1[NH:10][C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:54]
Reactant: CCCCCCCNCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reactant: O=C(O)Cc1ccc(F)cc1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCN(CCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1)C(=O)Cc1ccc(F)cc1F
Reaction time: 2.5 h
Yield: 88 %

Procedure:
To a solution of N-[5-(4,5-diphenyl-1H-imidazol-2-ylthio)pentyl]-1-heptanamine (2.2 g, 0.005 mol), 1-hydroxybenzotriazole hydrate (0.81 g, 0.006 mol), and 2,4-difluorophenylacetic acid (1.12 g, 0.0065 mol) in N,N-dimethylformamide (50 mL) at 0° was added, portionwise as a solid, dicyclohexylcarbodiimide (1.24 g, 0.006 mol). The reaction mixture was stirred at 0° for 2.5 hours, then at ambient temperature for 72 hours. The solids were filtered and washed with chloroform. The filtrate was concentrated under vacuum and the residue (5.2 g) was chromatographed with 7:3 hexane-ethyl acetate. The resulting solid was triturated with hexane to give the title compound (2.59 g, 0.0044 mol) as a yellow oil. 1H NMR (CDCl3) δ7.6-7.0(m,11H), 6.8-6.5(m,2H), 3.7(d,2H,J=13.7Hz), 3.5(t,2H,J=6.4Hz), 3.4-3.0(m,3H), 2.9(t,2 H,J=6.1Hz), 1.8-1.1(m,17H), 0.9(t,3H,J=6.6Hz).
Reaction SMILES: [Cl:1][Si](C)(C)C.[CH3:6][C:7]([CH3:15])([CH3:14])[C:8](=[O:13])[CH2:9][C:10](=[O:12])[CH3:11].CS(C)=O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C.O>[Cl:1][CH:9]([C:8](=[O:13])[C:7]([CH3:15])([CH3:14])[CH3:6])[C:10](=[O:12])[CH3:11]
Reactant: CC(=O)CC(=O)C(C)(C)C
Reactant: C[Si](C)(C)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: O
Solvent: CC#N
Solvent: CS(C)=O
Product: CC(=O)C(Cl)C(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.4 %

Procedure:
Chlorotrimethylsilane (26.8 ml, 0.21 mol) was added dropwise to a stirred pale yellow solution of tetrabutylammonium bromide (1.13 g, 3.50 mmol) in dry acetonitrile (100 ml) at room temperature under nitrogen. The resulting solution was cooled in ice and 5,5-dimethylhexane-2,4-dione (10.0 g, 70.4 mmol) and then dry dimethylsulphoxide (14.7 ml, 0.21 mol) were added dropwise over 5 minutes producing a yellow solution which was allowed to warm slowly to room temperature with stirring over 3 hours. The mixture was diluted with water (1000 ml) and stirred for 10 min and then extracted with ether (1×500 ml, 2×250 ml). The combined ether layers were dried over magnesium sulphate, filtered and concentrated under reduced pressure to leave a yellow oil. The crude product was purified by distillation under reduced pressure to provide the title compound (10.0 g) as a pale yellow oil, b.p. 220–225° C./60 mmHg.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1.[Cl:22][CH2:23][CH2:24][N:25]=[C:26]=[O:27].C(N(CC)CC)C>O1CCCC1>[Cl:22][CH2:23][CH2:24][NH:25][C:26]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1)=[O:27]
Reactant: O=C=NCCCl
Reactant: CN1C(=O)CN=C(c2ccccc2F)c2cc(N)ccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1C(=O)CN=C(c2ccccc2F)c2cc(NC(=O)NCCCl)ccc21
Reaction time: 8 h

Procedure:
4.2 g (0.015 M) of 7-amino-5-(o-fluorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one are heated at reflux for 3 hours in 80 ml of absolute tetrahydrofuran with 3.5 ml of chloroethylisocyanate and a catalytic amount of triethylamine. The mixture is left to stand at room temperature overnight. The solution is concentrated on a steam-bath and the residue is crystallised from ethyl acetate. There is obtained 1-(2-chloroethyl)-3-[5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]urea which melts at 240° C. with decomposition.
Reaction SMILES: COC1C=CC([C:9]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[C:17](OC)[C:11]=3[CH:10]=2)=CC=1.COC1C=C(C=C(OC)C=1OC)C(Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-].O>C(Cl)Cl.CCOC(C)=O>[S:13]1[CH:9]=[CH:10][C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]1=2
Reactant: COc1ccc(-c2cc3c(OC)cccc3s2)cc1
Agent: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: c1ccc2sccc2c1
Reaction time: 18 h
Yield: 6.8 %

Procedure:
To a well stirred solution of 2-(4′-methoxyphenyl)-4-methoxybenzo[b]thiophene (0.200 g, 0.74 mmol) and 3,4,5-trimethoxybenzoyl chloride (0.1 84 g, 0.74 mmol) in CH2Cl2 (7 mL) was added AlCl3 (0.200 g, 1.48 mmol) portion-wise over a 15 minute period. After 18 h, water was added, and the product was isolated initially with CH2Cl2 and subsequently by extraction with EtOAc. The organic layers were separately washed sequentially with NaHCO3 and brine and then dried over MgSO4. Purification by flash chromatography (silica gel, 70:30 hexane/EtOAc) afforded benzo[b]thiophene (0.023 g, 0.05 mmol, 7%) as a white solid. Recrystallization (Ethanol/hexane/CH2Cl2)yielded a highly pure crystalline sample. 1H-NMR (CDCl3, 360 MHz) δ7.80 (d, J=8.4 Hz, 1H, ArH), 7.73 (d, J=8.8 Hz, 2H, ArH), 7.66 (s, 1H, ArH), 7.02 (s, 2H, ArH), 6.96 (d, J=8.8 Hz, 2H, ArH), 6.70 (d, J=8.3 Hz, 1H, arH), 4.08 (s, 3H, —OCH3), 3.95 (s, 3H, —OCH3), 3.91 (s, 6H, —OCH3), 3.87 (S, 3H, —OCH3), HRMS (EI) M+ calcd for C26H24O6S 464.1294, found 464.1310. Anal. Calcd for C26H24O6S: C, 67.23; H, 5.21; S, 6.90. Found C, 67.19; H, 5.26; S, 6.87. Compound 13A shows an inhibition of tubulin polymerization >40 μM. Biological activity of compound 13A is shown in Table 19.
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH3:29])[CH2:4][CH2:5][CH2:6][NH:7][C:8]([NH:10][C:11]1[CH:16]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][C:19]=2[CH3:27])[CH:14]=[CH:13][N:12]=1)=[O:9])[CH3:2].[Cl-].[NH4+].O.C(OCC)(=O)C>C(O)C.[Fe]>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][C:15]2[CH:14]=[CH:13][N:12]=[C:11]([NH:10][C:8]([NH:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:28][CH3:29])[CH2:1][CH3:2])=[O:9])[CH:16]=2)=[C:19]([CH3:27])[CH:20]=1
Reactant: CCN(CC)CCCNC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cc2C)ccn1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCN(CC)CCCNC(=O)Nc1cc(Oc2ccc(N)cc2C)ccn1
Temperature: 90 °C
Yield: 15 %

Procedure:
To a solution of 1-(3-diethylaminopropyl)-3-[4-(2-methyl-4-nitrophenoxy)pyridin-2-yl]urea (794 mg) in ethanol (50 ml) were added electrolytic iron powder (442 mg), ammonium chloride (847 mg) and water (10 ml), followed by stirring to heat at 90° C. for 1 hr. The reaction mixture was cooled down to room temperature, and filtered to remove an insoluble portion. The filtrate was concentrated under a reduced pressure to give a residue, which was then supplied with ethyl acetate (100 ml), washed with a saturated aqueous solution of sodium hydrogencarbonate, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:1 to 1:2, ethyl acetate, and then ethyl acetate:methanol=20:1 to 10:1) to provide the titled compound (110 mg, 15%).