Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[O:14][CH3:15].C(=O)([O-])[OH:17].[Na+].[I-].[Na+]>CS(C)=O>[CH3:15][O:14][C:7]1[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:6]=1[CH2:5][CH2:4][CH2:3][CH:2]=[O:17]
Reactant: O=C([O-])O
Reactant: COc1ccc(CCCCBr)c(OC)c1
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(CCCC=O)c(OC)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 42.5 %

Procedure:
A mixture of 1-(4-bromobutyl)-2,4-dimethoxybenzene (11.0 g, 40.2 mmol), sodium hydrogen carbonate (6.75 g, 80.3 mmol) and sodium iodide (9.03 g, 60.2 mmol) in DMSO (80 mL) was stirred at 105 C. for 1.5 h. The reaction mixture was allowed to cool to some extent after which ice water (240 mL) was added. The mixture was extracted with diethyl ether (2×200 mL), washed with brine (50 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (SiO2, hexane-EtOAc, 80:20) yielding the title compound as a colorless liquid (3.56 g): 1H NMR (CDCl3 -d) 9.74 (t, J=1.8 Hz, 1H), 7.00 (d, J=7.9 Hz, 1H), 6.45-6.40 (m, 2H), 3.79 (s, 3H), 3.79 (s, 3H), 2.59 (t, J=7.4 Hz, 2H), 2.44-2.39 (m, 2H), 1.90 (quintet, J=7.4 Hz, 2H); 13C NMR (CDCl3 -d) 202.91, 159.32, 158.28, 130.14, 121.90, 103.78, 98.44, 55.28, 55.16, 43.25, 28.80, 22.50; MS (EI, 70 eV): m/z (rel. int.) 208 (M+, 31), 164 (44), 151 (100), 121 (76), 91 (16).
Reaction SMILES: [CH3:1][C:2]1[NH:16][CH2:15][CH2:14][C:4]2=[C:5]3[C:10](=[N:11][C:3]=12)[CH:9]=[CH:8][C:7]([O:12][CH3:13])=[CH:6]3.[CH:17]1([C:20](Cl)=[O:21])[CH2:19][CH2:18]1>ClCCl>[CH2:1]=[C:2]1[C:3]2[NH:11][C:10]3[C:5](=[CH:6][C:7]([O:12][CH3:13])=[CH:8][CH:9]=3)[C:4]=2[CH2:14][CH2:15][N:16]1[C:20]([CH:17]1[CH2:19][CH2:18]1)=[O:21]
Reactant: COc1ccc2c(c1)=C1CCNC(C)=C1N=2
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Product: C=C1c2[nH]c3ccc(OC)cc3c2CCN1C(=O)C1CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 10-methoxyharmalan in anhydrous dichloromethane is added cyclopropylcarbonyl chloride. The solution becomes clear and is left to stir for 1 h at 0° C. After evaporation of the dichloromethane, the 1-methylene-2-cyclopropylcarbonyl-6-methoxy-1,2,3,4-tetrahydro-β-carboline is recovered by chromatography on silica (pet. ether/EtOAc; 50/50). (The product turns yellow in the light).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]3[C:17]([C:18]([O-:20])=O)=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.[NH3:21]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]3[C:17]([C:18]([NH2:21])=[O:20])=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1
Reactant: N
Reactant: COc1ccc(-c2nc3cccc(C(=O)[O-])c3[nH]2)cc1
Product: COc1ccc(-c2nc3cccc(C(N)=O)c3[nH]2)cc1
Temperature: 100 °C
Yield: 80 %

Procedure:
The acetate salt of methyl (2-(4'-methoxyphenyl)benzimidazole-4-carboxylate was dissolved in excess liquid ammonia and heated at 100° C. in a sealed pressure vessel at 40 atmospheres overnight. The ammonia was allowed to evaporate, and the solid residue was collected and washed with ice cold water (3×5 ml). Recrystallisation from aqueous methanol afforded the title compound (226.4 mg, 80%); mp 261-263° C.; Found: C, 66.07; H, 4.23; N, 15.29. C15H13N3O2. 0.2CH3OH requires C, 66.70; H, 5.08; N, 15.35; vmax /cm-1 3321.47, 3140.72, 1656.23, 1608.25, 1421.43, 1242.55; δH (d6DMSO, 200 MHz) 3.96 (3H, s, OMe), 7.23-7.27 (2H, d, J=8.6, Ph-3/3'H), 7.37-7.45 (1H, t, Ar-5H), 7.78-7.82 (1H, d, Ar-4H), 7.87 (1H, br s, Imz-H), 7.93-7.96(1H, d, Ar-6H), 8.27-8.31 (2H, d, J=8.6, Ph-2/2'H), 9.4-9.5 (1H, br s, --CONH), 13.3-13.4 (1H, br s, --CONH); m/z (EI) 267 (M+), 249, 222, 206, 77, 32.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]4[NH:25][C:24]([CH2:26][CH3:27])=[N:23][C:20]4=3)[O:15][CH2:14]2)(=O)=O)=CC=1.[NH:28]1[CH2:33][CH:32]=[C:31]([C:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[NH:36][CH:35]=2)[CH2:30][CH2:29]1>CS(C)=O.C(OCC)(=O)C>[NH:36]1[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:34]([C:31]2[CH2:32][CH2:33][N:28]([CH2:12][CH:13]3[O:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]5[NH:25][C:24]([CH2:26][CH3:27])=[N:23][C:20]5=4)[O:15][CH2:14]3)[CH2:29][CH:30]=2)=[CH:35]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: CCc1nc2c3c(ccc2[nH]1)OC[C@H](COS(=O)(=O)c1ccc(C)cc1)O3
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCc1nc2c3c(ccc2[nH]1)OCC(CN1CC=C(c2c[nH]c4ccccc24)CC1)O3
Temperature: 80 °C
Yield: 58.1 %

Procedure:
A mixture of 0.84 g (2.2 mmole) of [(8R)-2-ethyl-7,8-dihydro-3H-6,9-dioxa-1,3-diaza-cyclopenta[a]naphthalen-8-yl]methyl 4-methylbenzenesulfonate and 1.5 g (7.60 mmole) of 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole in 10.0 mL of DMSO was heated at 80° C. under nitrogen for 6 hours. The reaction was allowed to come to room temperature, diluted to 500 mL with ethyl acetate, washed with 400 mL portions of saturated aqueous sodium bicarbonate, water and saturated brine, dried over sodium sulfate, filtered and evaporated in vacuum. The residue was column chromatographed on silica gel with 0-3% methanol in chloroform as eluant and the product fractions concentrated in vacuum to give 0.53 g of the desired compound as the free base. Recrystallization from ethanol with the addition of one equivalent of fumaric acid gave 0.46 g of the (S)-enantiomer of the title compound as a pale yellow solid fumarate, m.p. 231-232° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:15][C:16](=[O:20])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1>>[CH3:1][O:2][C:3]1[C:4]([NH:15][C:16]([N:32]2[CH2:31][CH2:30][N:29]([C:26]3[CH:25]=[CH:24][C:23]([O:22][CH3:21])=[CH:28][CH:27]=3)[CH2:34][CH2:33]2)=[O:20])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2
Reactant: CCOC(=O)Nc1nc2ccc(OC)cc2nc1OC
Reactant: COc1ccc(N2CCNCC2)cc1
Product: COc1ccc(N2CCN(C(=O)Nc3nc4ccc(OC)cc4nc3OC)CC2)cc1
Yield: 87 %

Procedure:
Ethyl N-(3,6-dimethoxyquinoxalin-2-yl)carbamate and 1-(4-methoxyphenyl)piperazine were reacted by the same way with the example 148 to obtain the titled compound (yield, 87%). 1H NMR (300 MHz, CDCl3): δ 3.12-3.15 (m, 4H), 3.74-3.76 (m, 7H), 3.89 (s, 3H), 4.11 (s, 3H), 6.83-6.93 (m, 4H), 7.12-7.13 (m, 2H), 7.33 (s, 1H), 7.72-7.75 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]([CH3:25])[C:10]=1[CH:26](O)[CH2:27][CH:28]=[CH2:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SiH](CC)(CC)CC.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]([CH3:25])[C:10]=1[CH2:26][CH2:27][CH:28]=[CH2:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCC(O)c1c(C)c(OCc2ccccc2)c(C)c(C)c1OCc1ccccc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCCc1c(C)c(OCc2ccccc2)c(C)c(C)c1OCc1ccccc1
Reaction time: 1.25 h
Yield: 99.1 %

Procedure:
1-(2,5-Bis(benzyloxy)-3,4,6-trimethylphenyl)but-3-en-1-ol (3.7 g, 9.4 mmol) was dissolved into 10 mL CH2Cl2 and treated with Et3SiH (12 mL, 94.4 mmol.). To this clear, colorless solution was added trifluoroacetic acid (TFA) (10.5 mL, 142 mmol) neat over 3 minutes which darkened the solution and exothermed. The reaction vessel was placed in a room temperature water bath and let stir for 1.25 h. The reaction was concentrated to yellow oil via rotary evaporation and the residue dissolved in 100 mL methyl t-butyl ether (MTBE). To this was added 50 mL 2.5 M K2CO3, the layers separated and the aqueous phase extracted 3×50 mL MTBE. The combined organics were washed with 50 mL saturated aqueous NaCl, dried over Na2SO4 and concentrated to give 1-(2,5-bis(benzyloxy)-3,4,6-trimethylphenyl)-3-butene, (3.6 g) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ=7.51 (d, 4 H), 7.44-7.35 (m, 6 H), 5.90 (m, 1 H), 5.06 (d, 1 H), 4.97 (d, 1 H), 4.78 (s, 2 H), 4.74 (s, 2 H), 2.74 (m, 2 H), 2.27-2.24 (m, 9 H) ppm.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([N+:11]([O-])=O)[CH:3]=1>C(O)(=O)C.O.[Fe]>[NH2:11][C:4]1[CH:3]=[C:2]([Br:1])[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[CH:5]=1
Reactant: O=[N+]([O-])c1cc(Br)c2c(c1)CCO2
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Nc1cc(Br)c2c(c1)CCO2
Yield: 74.1 %

Procedure:
7-Bromo-5-nitro-2,3-dihydrobenzofuran (2 g) was suspended in acetic acid (5 ml) and water (12 ml). Iron powder (3.5 g) was added and the mixture was heated at reflux for 3hr. The cooled mixture was cooled and filtered through celite. The filtrate was concentrated and azeotroped with toluene. The residue was purified by chromatography on silica using 10% ethyl acetate in hexane as eluent to afford the title compound (1.3 g) as an oil. 1H NMR (250 MHz, CDCl3) δ 3.22 (2H, t, J=7.5 Hz), 3.38 (2H, br s), 4.58 (2H, t, J=8 Hz), 6.51-6.53 (1H, m), 6.63-6.64 (1H, m).
Reaction SMILES: [O:1]([C:8]1[S:9][C:10]([CH2:13][OH:14])=[CH:11][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16]1([CH3:29])[C@@H:18]([CH:19]=[C:20]2[CH2:24][CH2:23][S:22][C:21]2=[O:25])[C@H:17]1[C:26](Cl)=[O:27].N1C=CC=CC=1.Cl>C1C=CC=CC=1>[CH3:15][C:16]1([CH3:29])[C@@H:18]([CH:19]=[C:20]2[CH2:24][CH2:23][S:22][C:21]2=[O:25])[C@H:17]1[C:26]([O:14][CH2:13][C:10]1[S:9][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:12][CH:11]=1)=[O:27]
Reactant: CC1(C)[C@H](C(=O)Cl)[C@@H]1C=C1CCSC1=O
Reactant: OCc1cnc(Oc2ccccc2)s1
Agent: Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC1(C)[C@H](C(=O)OCc2cnc(Oc3ccccc3)s2)[C@@H]1C=C1CCSC1=O
Temperature: 20 °C
Reaction time: 24 h
Yield: 43.4 %

Procedure:
2.1 g of (2-phenoxy-5-thiazolyl)-methanol were added to a solution of 2.44 g of (1R,3S) 2,2-dimethyl-3[(dihydro-2-oxo-3-(2H)-thienylidene)-methyl]-cyclopropane-1-carboxylic acid chloride [described in French Pat. No. 70-21682] in 50 ml of benzene and 3 ml of pyridine were added thereto dropwise at 0° C. The mixture was stirred at 20° C. for 24 hours and was then poured into aqueous 2N hydrochloric acid solution. The decanted organic phase was dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with benzene. The product was crystallized from ethyl acetate to obtain 1.8 g of (2-phenoxy-5-thiazolyl)-methyl (1R,3S) 2,2-dimethyl-3-[(dihydro-2-oxo-3-(2H)-thienylidene)-methyl]-cyclopropane-1-carboxylate.
Reaction SMILES: Cl[CH2:2][O:3][C:4]([NH:6][C:7]([CH3:28])([CH3:27])[CH2:8][O:9][C:10](=[O:26])[C@H:11]([CH:23]([CH3:25])[CH3:24])[NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])=[O:5].[I-:29].[Na+]>CC(C)=O>[I:29][CH2:2][O:3][C:4]([NH:6][C:7]([CH3:28])([CH3:27])[CH2:8][O:9][C:10](=[O:26])[C@H:11]([CH:23]([CH3:25])[CH3:24])[NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])=[O:5]
Reactant: [I-]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(C)(C)NC(=O)OCCl
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(C)(C)NC(=O)OCI
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To a solution of 2-(N-(chloromethoxycarbonyl)-amino)-2-methyl-1-(N-benzyloxycarbonyl-L-valyloxy)propane (1.05 g, 2.53 mmole) in dry acetone (20 ml) was added sodium iodide (1.8 g, 12 mmole) and the mixture was stirred for 36 hours at room temperature. The mixture was evaporated under reduced pressure and ethyl acetate and water were added. The organic phase was washed with 10% sodium thiosulfate solution and water. The organic phase was dried with sodium sulfate and evaporated under reduced pressure. Yield: 1.04 g=81%
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1)[CH2:6][CH:7]1[C:11](=C)[CH2:10][CH2:9][C:8]1([CH:16]([CH3:18])[CH3:17])[C:13]([NH2:15])=[O:14].[O:28]=[O+][O-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[F:24][C:22]([F:23])([F:25])[C:20]1[CH:19]=[C:5]([CH:4]=[C:3]([C:2]([F:26])([F:27])[F:1])[CH:21]=1)[CH2:6][CH:7]1[C:11](=[O:28])[CH2:10][CH2:9][C:8]1([CH:16]([CH3:18])[CH3:17])[C:13]([NH2:15])=[O:14]
Reactant: C=C1CCC(C(N)=O)(C(C)C)C1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=[O+][O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)C1(C(N)=O)CCC(=O)C1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
A solution of 3,5-bis(trifluoromethyl)benzyl 3-methylene-1-isopropylcyclopentane-carboxamide (910 mg, 2.31 mmol) in dichloromethane (50 mL) was cooled to −78° C. and a stream of ozone was passed through until the permanent blue color indicated complete consumption of the olefin. The excess ozone was purged with a stream of nitrogen, and triphenylphosphine (729 mg, 2.78 mmol) was added. The cooling bath was removed, and the reaction mixture was allowed to stir at ambient temperature overnight. The solvent was removed in vacuo, the residue was purified by column chromatography (silica gel, ethyl acetate:hexane/1:2) to give 760.7 mg (83%) of the desired product. 1H NMR (500 MHz, CDCl3): 7.81 (s, 1H), 7.74 (s, 2H), 6.16 (bs, 1H), 6.61 (m, 2H), 2.78 (bd, J=18.07 Hz, 1H), 2.40 to 2.20 (bm, 4H), 2.08-1.98 (m, 2H), 0.99 (d, J=6.86 Hz, 3H), 0.97 (d, J=6.87 Hz, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:15]([C:16]2[C:25]3[C:20](=[CH:21][C:22]([OH:26])=[CH:23][CH:24]=3)[N:19]=[CH:18][CH:17]=2)=[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][N:9]2[N:8]=1.CN(C=O)C.Br[CH2:33][CH2:34][CH2:35][Cl:36].C(=O)([O-])[O-].[Cs+].[Cs+]>CO>[Cl:36][CH2:35][CH2:34][CH2:33][O:26][C:22]1[CH:21]=[C:20]2[C:25]([C:16]([C:15]3[C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[N:8][N:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=34)=[CH:17][CH:18]=[N:19]2)=[CH:24][CH:23]=1
Reactant: Oc1ccc2c(-c3c(-c4ccccn4)nn4ccccc34)ccnc2c1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CO
Product: ClCCCOc1ccc2c(-c3c(-c4ccccn4)nn4ccccc34)ccnc2c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
4-(2-Pyridin-2-yl-pyrazolo[1,5-a]pyridin-3-yl)-quinolin-7-ol in a solution of DMF and MeOH is treated with 1-bromo-3-chloropropane (3 equiv) and cesium carbonate (2 equiv). The reaction is heated to 60° C. and stirred overnight. The reaction is then purified on silica gel column (see Prep. 77) chromatography to afford the desired product.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([CH2:24][C:25]#[N:26])(=[O:23])=[O:22])=[CH:17][CH:16]=1.O>C(O)C>[C:1]([C:5]1[CH:6]=[C:7](/[CH:8]=[C:24](/[S:21]([C:18]2[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=2)(=[O:23])=[O:22])\[C:25]#[N:26])[CH:10]=[CH:11][C:12]=1[OH:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#CCS(=O)(=O)c1ccc(F)cc1
Reactant: CC(C)(C)c1cc(C=O)ccc1O
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1cc(/C=C(\C#N)S(=O)(=O)c2ccc(F)cc2)ccc1O
Yield: 82.2 %

Procedure:
The reaction mixture of 178.0 mg of 3-t-butyl-4-hydroxybenzaldehyde and 219.0 mg of (4-fluorobenzenesulphonyl)acetonitrile in 2.0 mL of ethanol containing 0.01 mL piperidine was refluxed for 4 h and cooled down. To the above reaction mixture was added water and then the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. The resulting residue was purified on silica gel column eluting with ethyl acetate-hexane (1:6) to give 295.0 mg of the titled compound.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([N+:7]([O-])=O)[C:4](O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)=[CH:3][CH:2]=1.O[CH:23]1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H:24]1O>>[NH:7]1[C:5]2[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=2)[CH:24]=[CH:23]1
Reactant: O=[N+]([O-])c1ccccc1O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reactant: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O
Product: c1ccc2[nH]ccc2c1

Procedure:
Principle of Step 1: ONPG substituting for lactose is metabolized with β-galactosidase. At 44.5° C. E. coli grow and utilize ONPG and produce indole. β-galactoside turns the medium yellow. In the yellow colored medium, both fecal coliforms and E. coli are present. In samples which do not have a yellow color, there are no fecal coliforms and E. coli.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:40]=[CH:39][C:7]2[CH2:8][CH2:9][CH2:10][CH:11]([N:13]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:14][C@H:15]([O:24][Si:25]([CH2:30][CH3:31])([CH2:28][CH3:29])[CH2:26][CH3:27])[CH2:16][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:12][C:6]=2[CH:5]=1.[CH2:41](I)[CH3:42].C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:41]([O:3][C:4]1[CH:40]=[CH:39][C:7]2[CH2:8][CH2:9][CH2:10][CH:11]([N:13]([C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[CH2:14][C@H:15]([O:24][Si:25]([CH2:28][CH3:29])([CH2:26][CH3:27])[CH2:30][CH3:31])[CH2:16][O:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:12][C:6]=2[CH:5]=1)[CH3:42]
Reactant: CCI
Reactant: CC[Si](CC)(CC)O[C@H](COc1ccccc1)CN(C(=O)OC(C)(C)C)C1CCCc2ccc(O)cc2C1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc2c(c1)CC(N(C[C@@H](COc1ccccc1)O[Si](CC)(CC)CC)C(=O)OC(C)(C)C)CCC2
Reaction time: 0.5 h

Procedure:
Under nitrogen, to a suspension of sodium hydride (60% in oil, 12 mg) in N,N-dimethylformamide (2 ml) was dropwise added N-(3-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]-tert-butoxycarbonylamine (150 mg) in N,N-dimethylformamide (1 ml) at 5° C., and the mixture was stirred at the same temperature for 30 minutes. To this one was added ethyl iodide (27 μl), and the mixture was stirred at room temperature for 2 hours. The resulting mixture was poured into saturated aqueous sodium hydrogencarbonate, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=20:1) to give N-(3-ethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]-tert-butoxycarbonylamine (130 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:18][C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=3)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[C:8]([CH3:29])[C:7]=2[CH:30]=1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:18][C:19]3[CH:28]=[CH:27][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=3)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[C:8]([CH3:29])[C:7]=2[CH:30]=1
Reactant: CCCCCCC(Nc1ccc(C(=O)OC)cc1)c1oc2ccc(OC)cc2c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCCCC(Nc1ccc(C(=O)O)cc1)c1oc2ccc(OC)cc2c1C
Reaction time: 8 h
Yield: 90.3 %

Procedure:
To a mixture of methyl 4-{[1-(5-methoxy-3-methyl-1-benzofuran-2-yl)heptyl]amino}benzoate (1.17 g) synthesized above, tetrahydrofuran (20 mL) and ethanol (20 mL) was added 1N aqueous sodium hydroxide solution (20.0 mL), and the mixture was stirred overnight with heating under reflux, and concentrated under reduced pressure. The residue was dissolved is in water (20 mL), and 1N hydrochloric acid (20.0 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (1.02 g, 90%) as a pale-brown solid.
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][C:4]([S:7][CH2:8][C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:3][CH:2]=1.[BH4-].[Na+].O.Cl>C(O)(C)C>[C:1]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:6]=[CH:5][C:4]([S:7][CH2:8][CH:9]([OH:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(=O)CSc1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CCOC(=O)C(O)CSc1ccc(-c2ccccc2)cc1
Reaction time: 2 h
Yield: 24.1 %

Procedure:
To a stirred suspension of ethyl 3-(4-biphenylylthio)-2-oxopropionate (1.44 g, 0.0048 mole) in isopropanol (24 ml) was added sodium borohydride (0.18 g, 0.0048 mole). After 2 hrs., water (75 ml) and 2 N HCl (0.5 ml) were added. The mixture was extracted with methylene chloride (2×150 ml). The contents of the combined extracts, after drying (Na2SO4) and concentration, were chromatographed on silica gel (120 g) using 1,1,1-trichloroethane as eluting solvent to obtain 0.35 g (24%) of ethyl 3-(4-biphenylylthio)lactate, m.p. 101.5°-102° C.
Reaction SMILES: [CH3:1][C:2]([CH2:8][CH:9]([CH3:11])[CH3:10])=[C:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[CH3:12][Li].O>CCOCC>[CH3:1][C:2]([C:3]1[CH2:7][CH:6]=[CH:5][CH:4]=1)([CH3:12])[CH2:8][CH:9]([CH3:11])[CH3:10]
Reactant: [Li]C
Reactant: CC(CC(C)C)=C1C=CC=C1
Solvent: O
Solvent: CCOCC
Product: CC(C)CC(C)(C)C1=CC=CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 80 %

Procedure:
To a solution of 8.00 g (54.0 mmol) of 6-methyl-6-isobutylfulvene in 30 ml of ether, 54.0 ml (61.6 mmol) of an ether solution of methyllithium was dropwise added in a nitrogen atmosphere with ice cooling, followed by stirring at room temperature for 4 days. Then, 30 ml of water was added. The separated organic phase was washed with water and a saturated saline solution, then dried over magnesium sulfate and filtered. From the filtrate, the solvent was removed under reduced pressure to obtain a liquid. The liquid was subjected to vacuum distillation (120° C./25 mmHg) to obtain 7.10 g (43.2 mmol) of a light yellow liquid (yield: 80%)
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:30])=[CH:4][C:5]2[N:11]([C:12](=[O:23])[CH2:13][N:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][OH:22])[CH2:16][CH2:15]3)[C:10]3[N:24]=[CH:25][CH:26]=[CH:27][C:9]=3[C:8](=O)[NH:7][C:6]=2[CH:29]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:32]>N1C=CC=CC=1>[CH3:1][C:2]1[C:3]([CH3:30])=[CH:4][C:5]2[N:11]([C:12](=[O:23])[CH2:13][N:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][OH:22])[CH2:16][CH2:15]3)[C:10]3[N:24]=[CH:25][CH:26]=[CH:27][C:9]=3[C:8](=[S:32])[NH:7][C:6]=2[CH:29]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: Cc1cc2c(cc1C)N(C(=O)CN1CCN(CCO)CC1)c1ncccc1C(=O)N2
Solvent: c1ccncc1
Product: Cc1cc2c(cc1C)N(C(=O)CN1CCN(CCO)CC1)c1ncccc1C(=S)N2

Procedure:
In the manner given in Example 1, 8,9-dimethyl-6,11-dihydro-11-[[4-(2-hydroxyethyl)piperazino]acetyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one is reacted with phosphorus pentasulfide in pyridine to give 8,9-dimethyl-6,11-dihydro-11-[[4-(2-hydroxyethyl)piperazino]acetyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-thione.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[O:14][CH2:15][CH3:16])=[CH:11][CH:10]=[CH:9][C:8]=2[NH:17][C:18](=[O:27])[C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:26])(O)=[O:2].Cl.C([N:31]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.N>CN(C)C=O.O>[C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[O:14][CH2:15][CH3:16])=[CH:11][CH:10]=[CH:9][C:8]=2[NH:17][C:18](=[O:27])[C:19]1[C:20]([Cl:26])=[CH:21][CH:22]=[CH:23][C:24]=1[Cl:25])(=[O:2])[NH2:31]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCOc1c(C(=O)O)cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1c(C(N)=O)cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
To a solution of 3-carboxy-8-(2,6-dichlorobenzoylamino)-4-ethoxyquinoline (153 mg) in dimethylformamide were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (109 mg) and 1-hydroxybenzotriazole (76.5 mg), and the mixture was stirred for 2 hours at ambient temperature. To the mixture was added conc. ammonia solution (0.2 ml) with stirring, and the mixture was stirred for 6 hours at ambient temperature. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated ammonium chloride solution, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from ethanol to give 3-carbamoyl-8-(2,6-dichlorobenzoylamino)-4-ethoxyquinoline (128.3 mg).