Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[OH:11].[C:12](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[O:11][CH3:12]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1cccc(Br)c1O
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1c(Br)cccc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 89.8 %

Procedure:
2-Bromo-6-nitro-phenol 1b (46.55 g, 0.214 mol) was dissolved in 500 mL of acetone followed by addition of potassium carbonate (35.36 g, 0.26 mol) and iodomethane (20.1 mL, 0.32 mol). The reaction mixture was heated to reflux at 70° C. for 40 hours. The reaction mixture was concentrated under reduced pressure and diluted with 1300 mL of ethyl acetate and 500 mL of water. The aqueous layer was extracted with ethyl acetate (300 mL×2). The combined organic extracts were washed with 4 M hydrochloric acid and saturated sodium bicarbonate solution and then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 1-bromo-2-methoxy-3-nitro-benzene 1c (44.59 g, yield 90.0%) as a brown solid.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[Cl:8][C:9]1[CH:34]=[CH:33][C:12]2[N:13]3[C:17]([CH2:18][NH:19][CH2:20][C:11]=2[CH:10]=1)=[N:16][N:15]=[C:14]3[CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[CH2:23][CH2:22]1.N1C=CC=CC=1>ClCCl>[NH3:2].[CH3:1][N:2]([CH3:7])[S:3]([N:19]1[CH2:18][C:17]2[N:13]([C:14]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)[CH2:23][CH2:22]3)=[N:15][N:16]=2)[C:12]2[CH:33]=[CH:34][C:9]([Cl:8])=[CH:10][C:11]=2[CH2:20]1)(=[O:5])=[O:4]
Reactant: Clc1ccc2c(c1)CNCc1nnc(C3CCN(c4ccccn4)CC3)n1-2
Reactant: CN(C)S(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(C)S(=O)(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2C2CCN(c3ccccn3)CC2)C1
Product: N
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.3 %

Procedure:
Dimethylsulphamoyl chloride (0.12 ml, 1.08 mmol) was added to a solution of the amine from example 4 (140 mg, 0.36 mmol) and pyridine (90 μl, 1.08 mmol) in dichloromethane (8 ml), and the reaction mixture was stirred at room temperature for 18 hours. TLC analysis showed that starting material remained, so additional dimethylsulphamoyl chloride (0.08 ml, 0.72 mmol) was added and the mixture was stirred for a further 24 hours. The mixture was washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulphate, and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (95:5:0.5) as eluant, to afford the title compound as a pale yellow gum (120 mg).
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[N:4][CH:3]=1.[CH2:7]([O:9][C:10]([Sn](CCCC)(CCCC)CCCC)=[CH2:11])[CH3:8].[F-].[K+]>CN(C=O)C.O.C(OCC)C>[CH2:10]([O:9][C:7]([C:2]1[S:6][CH:5]=[N:4][CH:3]=1)=[CH2:8])[CH3:11]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Brc1cncs1
Agent: [F-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: C=C(OCC)c1cncs1
Temperature: 70 °C
Reaction time: 0.67 h
Yield: 83.1 %

Procedure:
A mixture of 3.28 g (20.0 mmol) of 5-bromothiazole (for synthesis see H. C. Beyerman, P. H. Berben, J. S. Bontekoe, Rec. Trav. Chim. 1954, 73, 325), 7.43 mL (22.0 mmol) of (1-ethoxyvinyl)tributyltin, and 284 mg (0.404 mmol) of PdCl2 (PPh3)2 in 40 mL of DMF was heated at 70° C. for 30 h. The reaction mixture was cooled to 0° C. and 40 mL of a solution of potassium fluoride in water and 40 mL of diethyl ether were added. After stirring for 40 min the precipitate was faltered off and the aqueous and organic phases separated. The aqueous phase was re-extracted with 4×40 mL of diethyl ether. The combined ether phases were washed with 2×75 mL of water, 1×100 mL of brine, dried (MgSO4) and the solvent removed in vacuo. Flash chromatography (silica gel, 20% ethyl acetate-hexanes) afforded 2.58 g (83%) of the title compound as a yellow oil: 1H NMR (400 MHz, CDCl3) δ8.65 (s, 1H), 7.80 (s, 1H), 4.61 (d, 1H, J=3 Hz), 4.24 (d, 1H, J=3 Hz), 3.91 (q, 2H, J=7 Hz), 13.9 (t, 3H, J=7 Hz).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].OS(O)(=O)=O.[CH3:15]O>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:15])=[O:8]
Reactant: CO
Reactant: O=C(O)CCCCCBr
Agent: O=S(=O)(O)O
Product: COC(=O)CCCCCBr

Procedure:
As mentioned in the general procedure (I), 6-bromohexanoic acid (15 g, 76.9 mmol, 1 equiv) was dissolved in methanol (150 mL), and a catalytic amount of conc.H2SO4 (2 mL) was added and the reaction was carried out. The product was taken to next step without column purification. Yield 14.8 g (92%). 1H NMR (400 MHz, CDCl3): δ 3.66 (s, 3H), 3.42-3.38 (m, 2H), 2.32 (t, J=7.2 Hz, 2H), 1.90-1.83 (m, 2H), 1.68-1.61 (m, 2H), 1.50-1.44 (m, 2H). 13C NMR (100 MHz, CDCl3); δ 173.9, 51.5, 33.8, 33.4, 32.3, 27.6, 24.0. EI/MS m/z (r.i.) 211(M+2, 98), 210(M+1, 8), 209(M+, 100), 178(16), 161(33), 129(51), 97(28), 87(9), 74(23), 69(23).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([S:15][CH3:16])[S:5][C:6]=1[C:7](=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>C1(C)C=CC=CC=1>[CH3:19][N:20]([CH3:22])/[CH:21]=[C:8](/[C:7]([C:6]1[S:5][C:4]([S:15][CH3:16])=[N:3][C:2]=1/[N:1]=[CH:19]/[N:20]([CH3:22])[CH3:21])=[O:14])\[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)CC(=O)c1sc(SC)nc1N
Solvent: Cc1ccccc1
Product: CCOC(=O)/C(=C\N(C)C)C(=O)c1sc(SC)nc1/N=C/N(C)C

Procedure:
A mixture of EXAMPLE 1A (8.8 g) and N,N-dimethyl-formamide dimethyl acetal (15.1 g) in toluene (170 mL) at 110° C. was stirred for 3 hours, concentrated to half volume, cooled, and filtered. 1H NMR (300 MHz, CDCl3) δ 8.40 (s, 1H), 7.42 (s, 1H), 3.99 (q, 2H), 3.05 (d, 6H), 2.92 (b, 6H), 2.65 (s, 3H), 1.04 (t, 3H).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[CH2:15](OCC)C.[C-:20]#[N:21].[K+]>O>[C:20]([CH:13]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:6]([CH3:15])[C:5]2[C:14]1=[CH:1][CH:2]=[CH:3][CH:4]=2)#[N:21]
Reactant: [C-]#N
Reactant: CCOCC
Reactant: c1ccc2nc3ccccc3cc2c1
Agent: [K+]
Solvent: O
Product: CN1c2ccccc2C(C#N)c2ccccc21
Reaction time: 0.5 h
Yield: 75 %

Procedure:
A solution of 10.0 g (43.5 mmol) of acridine chloromethylate [A. Kaufmann et al, Ber. Dt. Chem. Ges. 42, 1999 (1909)]in 100 ml of water is covered with a layer of 200 ml of diethyl ether, and a solution of 3.13 g (48.0 mmol) of potassium cyanide in 20 ml of water is added. After about 30 minutes, the ether phase is separated off, the mixture is concentrated to 50 ml on a vacuum rotary evaporator and the product which has precipitated is filtered off. Crystallization of the crude product from ethanol gives 7.10 g (75%) of 9-cyano-9,10-dihydro-10-methyl-acridine, melting point 141°-143° C. (compound (106), Table 1).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH2:31][O:32][CH3:33])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1>>[CH:34]1([C:37]([NH:1][C@H:2]2[CH2:3][CH2:4][C@H:5]([NH:8][C:9]([C:11]3[C:15]4[N:16]=[CH:17][N:18]=[C:19]([C:20]5[C:28]6[O:27][CH2:26][O:25][C:24]=6[CH:23]=[CH:22][C:21]=5[O:29][CH2:30][CH2:31][O:32][CH3:33])[C:14]=4[NH:13][CH:12]=3)=[O:10])[CH2:6][CH2:7]2)=[O:38])[CH2:36][CH2:35]1
Reactant: O=C(Cl)C1CC1
Reactant: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c[nH]c13)OCO2
Product: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)C5CC5)CC4)c[nH]c13)OCO2

Procedure:
Starting from trans-4-[5-(2-methoxy-ethoxy)-benzo[1,3]dioxol-4-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A185) and cyclopropanecarbonyl chloride the title compound was obtained as colorless solid.
Reaction SMILES: [C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[CH3:12]OC(OC)N(C)C.CC1C=CC(S(O)(=O)=O)=CC=1.Cl.[Cl:32][C:33]1[CH:34]=[C:35]([NH:40][NH2:41])[CH:36]=[CH:37][C:38]=1[F:39]>CCOC(C)=O>[C:8]([O:7][C:1]([C:2]1[CH:12]=[N:41][N:40]([C:35]2[CH:36]=[CH:37][C:38]([F:39])=[C:33]([Cl:32])[CH:34]=2)[C:3]=1[CH3:5])=[O:6])([CH3:11])([CH3:10])[CH3:9]
Reactant: NNc1ccc(F)c(Cl)c1
Reactant: COC(OC)N(C)C
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)OC(C)(C)C)cnn1-c1ccc(F)c(Cl)c1
Temperature: 130 °C
Reaction time: 16 h
Yield: 99.4 %

Procedure:
To a mixture of tert-butyl acetoacetate (1.1 mL, 6.8 mmol) and dimethylformamide-dimethylacetal (1.0 mL, 7.6 mmol) in a microwave tube is added a catalytic amount of TsOH. The yellow solution is heated at 130° C. in the microwave for 15 min. The resultant dark red solution is then cooled to room temperature, concentrated in vacuo and dissolved in acetonitrile (5.0 mL). Triethylamine (2.5 mL) is added followed by 3-chloro-4-fluorophenylhydrazine hydrochloride (1.3 g, 6.8 mmol). The dark reddish brown solution is stirred at room temperature for 16 hours. The reaction is diluted with EtOAc (75 mL) and washed with water (7×50 mL). The combined organic phases are dried over MgSO4, filtered and concentrated in vacuo to afford 1-(3-chloro-4-fluoro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid tert-butyl ester as a dark brown oil (2.1 g, 100%) which is used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8]1)=[O:5].Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH2:13]([N:10]1[CH2:11][CH2:12][CH:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[C:23]([F:24])[CH:22]=[CH:21][CH:20]=3)[NH:1][C:26]2=[O:28])[CH2:8][CH2:9]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1c(F)cccc1C(=O)NC1CCN(Cc2ccccc2)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=c1[nH]c2c(F)cccc2c(=O)n1C1CCN(Cc2ccccc2)CC1
Yield: 258.9 %

Procedure:
To a solution of 2-amino-N-(1-benzylpiperidin-4-yl)-3-fluorobenzamide (750 mg, 2.29 mmol) in dichloromethane (30.0 mL) at 0° C. was added triphosgene (227 mg, 0.33 equiv.) as a solution in dichloromethane (5 mL). The ice bath was removed and the reaction heated at reflux for 6 h. The reaction was concentrated, dissolved in ethyl acetate, washed with saturated sodium bicarbonate, then water, then brine, dried over magnesium sulfate, and concentrated to give 700 mg of a white solid. The crude product was purified by flash chromatography to give 205 mg (25%) as a white solid. Mass spec.: 354.13 (MH)+.
Reaction SMILES: [CH2:1]=[C:2]([CH:4]=[CH:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[CH:16]([CH2:17][CH2:18][CH2:19][CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].[H][H].C(OCC)(=[O:32])C>C(O)(=O)C.[Pt]=O>[CH3:8][C@@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C:12](=[C:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C@H:16]([CH2:17][C@@H:18]([OH:32])[CH2:19][CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)[CH2:6][CH2:5][CH2:4][CH:2]([CH3:3])[CH3:1]
Reactant: [H][H]
Reactant: CCOC(C)=O
Reactant: C=C(C)C=CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4CCCC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CC(C)CCC[C@@H](C)[C@H]1CCC2=C3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@@]21C

Procedure:
50 g of cholestadiene were dissolved in 800 ml of dry ethyl acetate to which 30 ml of acetic acid had previously been added and after addition of 1.5 g of platinum oxide the mixture was transferred to an autoclave of 2 1 volume. Hydrogenation was carried out at 50° C. and 10 atm hydrogen pressure and was complete after 24 h. After reaction was complete, the catalyst was filtered off, the solvent was concentrated in a rotary evaporator and the doristerol obtained was recrystallized from ethanol. Yield: 42.5 g (88.5%). The purity of the substance was confirmed with the aid of 1H-NMR and 13C-NMR spectroscopy. 17 g of 4-(propen-2-oxy)benzoyl chloride and 32 g of doristerol were dissolved in 200 ml of dry toluene and heated to reflux for 15 h. The solvent was then distilled off and the residue was recrystallized from ethanol; yield: 44.9 g (99%), m.p. 92° C. (n*105i).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[C:18]([O:20][CH3:21])=[O:19].C(OCC)C>C1COCC1>[CH3:21][O:20][C:18]([NH:9][CH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:19]
Reactant: COC(=O)Cl
Reactant: NCCc1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)NCCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To a stirred solution of phenethylamine (75.2 mL, 0.6 mol) and triethylamine (83 mL, 0.6 mol) in THF (500 mL) was added slowly methyl chloroformate (46.2 mL, 0.6 mol) dissolved in THF (50 mL). After the reaction was stirred for an additional 1 h at room temperature, diethyl ether (2 L) and 1 N HC1 (800 mL) was added. The organic layer was washed with water, dried (MgSO4), and concentrated in vacuo to give a clear oil of pure title compound (102 g, 95%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[S:8]1(=[O:24])=[O:23].[CH3:25][CH:26]1[CH2:31][NH:30][CH2:29][CH:28]([CH3:32])[NH:27]1>>[CH3:25][CH:26]1[NH:27][CH:28]([CH3:32])[CH2:29][N:30]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[S:8]2(=[O:24])=[O:23])[CH2:31]1
Reactant: O=S1(=O)N(CCCCCBr)c2ccccc2N1c1ccccc1F
Reactant: CC1CNCC(C)N1
Product: CC1CN(CCCCCN2c3ccccc3N(c3ccccc3F)S2(=O)=O)CC(C)N1
Yield: 99.5 %

Procedure:
In an analogous manner as described in general procedure V, 1-(5-bromopentyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.07 g, 0.18 mmol) was treated with 2,6-Dimethyl-piperazine (0.06 g, 0.54 mmol) to provide 0.08 g (88%) of 1-[5-(3,5-dimethylpiperazin-1-yl)pentyl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide. MS (ES) m/z 447.0;
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:6][C:5]=1[N+:17]([O-:19])=[O:18].[OH-].[Na+].Cl.N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:32]>O1CCOCC1.C(Cl)Cl>[N+:17]([C:5]1[CH:6]=[C:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:8]=[CH:9][C:4]=1[C:3]([F:32])=[O:2])([O-:19])=[O:18]
Reactant: COC(=O)c1ccc(C(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Reactant: Fc1nc(F)nc(F)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)c1ccc(C(=O)F)c([N+](=O)[O-])c1
Reaction time: 6 h

Procedure:
To a stirred solution of the above di-ester ((7), 7.28 g, 26 mmol) in dioxane (100 mL) was added aq. 1N NaOH (30 mL). The reaction was stirred for 6 h, acidified with aq. 1N HCl (30 mL), extracted with ethyl acetate, washed with brine, dried (MgSO4) and evaporated under reduced pressure to give the corresponding acid which was used as is in the next reaction. To a stirred solution of the above acid (6.68 g, 25 mMol) under Ar in dry CH2Cl2 (75 mL) was added pyridine (2.1 mL, 25 mMol) followed by cyanuric fluoride (1.56 mL, 17 mMol). After stirring for 2 h the reaction became a thick suspension. The reaction was then evaporated under reduced pressure, taken up in ether (150 mL) and filtered through a pad of celite to remove insoluble materials. The filtrate was washed with cold water, dried (MgSO4), filtered and evaporated under reduced pressure to give the crude acid fluoride (8) as a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]=O)[CH:6]=[CH:5][N:4]=1.[C:11]([OH:17])(=[O:16])[CH2:12][C:13]([OH:15])=O.C(O[CH2:21][CH3:22])=O.[H-].[Na+]>>[CH:13]([CH:12]([CH2:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=1)[C:11]([O:17][CH2:21][CH3:22])=[O:16])=[O:15]
Reactant: CCOC=O
Reactant: COc1cc(C=O)ccn1
Reactant: O=C(O)CC(=O)O
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(C=O)Cc1ccnc(OC)c1

Procedure:
Condensation of 2-methoxypyridine-4-carboxaldehyde with malonic acid with subsequent esterification and hydrogenation at 344 kPa and formylation of the product with ethyl formate and sodium hydride gave ethyl 2-formyl-3-(2-methoxy-4-pyridyl)propionate as an oil.
Reaction SMILES: O1CC1[CH2:3][C:4]12[O:10][CH:5]1[CH:6]=CC=[CH:9]2.[CH2:12]([CH2:14][NH2:15])[OH:13]>O>[OH:13][CH2:12][CH2:14][NH:15][CH2:6][CH:5]([OH:10])[CH:4]([CH3:3])[CH3:9]
Reactant: NCCO
Reactant: C1=CC2OC2(CC2CO2)C=C1
Solvent: O
Product: CC(C)C(O)CNCCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The above compound could be made in the same manner as Example 1 using the appropriate epoxide: 1 eq. of (2,3-Epoxypropyl)benzene oxide and 4 eq. ethanol amine The above compound could be made in the following manner: stirred at room temperature overnight. The solution could be poured into water and the water is extracted with dichloromethane. The combined dichloromethane layers could be washed with brine and concentrated.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:13]=2)=[N:5][C:4]([NH2:25])=[N:3]1.CC1C=CC(S(Cl)(=O)=[O:34])=CC=1.CC1C=CC(S(NC2N=C(NCCC[O:57][C:58]3C=[CH:62][CH:61]=[C:60](CN4CCCCC4)[CH:59]=3)N(C)N=2)(=O)=O)=CC=1>>[CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:13]=2)=[N:5][C:4]([NH:25][C:62]([C:61]2[O:57][CH:58]=[CH:59][CH:60]=2)=[O:34])=[N:3]1
Reactant: Cn1nc(N)nc1NCCCOc1cccc(CN2CCCCC2)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)Nc2nc(NCCCOc3cccc(CN4CCCCC4)c3)n(C)n2)cc1
Product: Cn1nc(NC(=O)c2ccco2)nc1NCCCOc1cccc(CN2CCCCC2)c1

Procedure:
The triazole (A) (2.00 g) and 4-methylbenzenesulphonic acid, chloride (1.22 g) was 4-methyl-N-[1-methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-1H-1,2,4-triazol-3-yl]benzenesulphonamide (1.58 g) m.p. 100.5°-102°.
Reaction SMILES: [CH:1]1([NH:7][S:8](Cl)(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:12]([NH2:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(N(CC)CC)C.C([O-])([O-])=O.[Na+].[Na+]>ClCCl>[CH:1]1([NH:7][S:8]([NH:28][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)NC1CCCCC1
Reactant: CCCCCCCCCCCCCCCCN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCNS(=O)(=O)NC1CCCCC1
Temperature: 0 °C
Reaction time: 5 h
Yield: 78.5 %

Procedure:
A solution of 13.6 g of the cyclohexylsulfamoyl chloride (69 mmol) in 100 mL of dichloromethane is added under argon atmosphere to a solution of 1-hexadecylamine (19.9 g, 82 mmol) and triethylamine (47.5 mL, 340 mmol) in 300 mL of dichloromethane. The reaction mixture is stirred 5 hours at 0° C., neutralized with an aqueous Na2CO3 solution and concentrated under reduced pressure. The residue is taken up in dichloromethane (800 mL). The organic components are successively washed with diluted hydrochloric aqueous solution, NaHCO3 aqueous solution and brine, dried (Na2SO4), and concentrated under reduced pressure. The residue is suspended in ether, filtered through Büchner, and the precipitate is washed two times with 100 ml of ether to yield a white powder of N-cyclohexyl-N′-hexadecylsulfamide (21.8 g, 79%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[F:15][C:16]([F:26])([F:25])[O:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:24][C:21]2[CH:22]=[CH:23][C:18]([O:17][C:16]([F:15])([F:25])[F:26])=[CH:19][CH:20]=2)=[C:3]([C:11]([F:14])([F:13])[F:12])[CH:4]=1)([O-:10])=[O:9]
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=[N+]([O-])c1ccc(Oc2ccc(OC(F)(F)F)cc2)c(C(F)(F)F)c1
Temperature: 95 °C
Yield: 92.8 %

Procedure:
A mixed solution composed of 44.3 g of 1-chloro-4-nitro-2-trifluoromethylbenzene, 98 mL of N,N-dimethylacetamide, 35 g of 4-trifluoromethoxyphenol, and 20.4 g of potassium carbonate was stirred with heating at 90 to 100° C. for 3 hr. This reaction solution was concentrated under the reduced pressure. Ethyl acetate was then added to and dissolved in the residue, and the solution was washed with brine. The solution was then concentrated under the reduced pressure. n-Hexane was added to the residue, and the precipitated crystals were collected by filtration to give 66.9 g of 4-nitro-1-(4-trifluoromethoxyphenoxy)-2-trifluoromethylbenzene (yield 92.7%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[CH3:9][C:10]1[CH:23]=[CH:22][C:13]([CH:14]=[C:15]([C:19]([O-:21])=[O:20])[C:16]([O-:18])=O)=[CH:12][CH:11]=1.Cl.[CH2:25](N(CC)CC)[CH3:26]>C(O)C>[CH2:25]([O:21][C:19]([CH:15]1[C:16](=[O:18])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][CH:14]1[C:13]1[CH:12]=[CH:11][C:10]([CH3:9])=[CH:23][CH:22]=1)=[O:20])[CH3:26]
Reactant: CCN(CC)CC
Reactant: Cc1ccc(C=C(C(=O)[O-])C(=O)[O-])cc1
Reactant: Nc1ccccc1S
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1C(=O)Nc2ccccc2SC1c1ccc(C)cc1
Yield: 979.1 %

Procedure:
A mixture of 32 g of o-aminothiophenol, 65.6 g of p-methylbenzalmalonate and 1.4 g of triethylamine hydrochloride was heated at about 180° C. until no further ethanol was distilled out (for about 3 hours). The resulting reaction mixture was worked up in the same manner as described in Reference Example 2 (a) and the crystals thus obtained was recrystallized from chloroform-petroleum ether to obtain 34 g of 2,3-dihydro-3-ethoxycarbonyl-2-(p-tolyl)-1,5-benzothiazepin-4(5H)-one as light yellow needles having a melting point of 185° C.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[CH2:12]([S:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][N:18]=1)[CH:13]([CH3:15])[CH3:14].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:12]([S:16][C:17]1[N:18]=[CH:19][C:20]([C:23]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:24]=2)=[CH:21][CH:22]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: COC(=O)c1ccccc1S
Reactant: CC(C)CSc1ccc(C#N)cn1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)CSc1ccc(-c2nc(=O)c3ccccc3s2)cn1
Yield: 24.4 %

Procedure:
A mixture of methyl thiosalicylate (1.01 g, 6.0 mmol), 2-isobutylthio-5-cyanopyridine (1.03 g, 5.0 mmol), triethylamine (0.98 ml, 7.0 mmol) and toluene (10 ml) was refluxed under nitrogen atmosphere for 20 hrs. The reaction mixture was concentrated. The residue was subjected to a silica gel column chromatography, eluted with ethyl acetate-hexane (2:1, v/v) and recrystallized from ethyl acetate-isopropylether to give the titled compound (0.40 g, 23%).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14]([N:16]1[CH2:20][CH2:19][C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25](I)[CH:24]=2)([O:21][CH3:22])[CH2:17]1)=[O:15])[CH3:12]>>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([S:1][C:27]2[CH:28]=[C:23]([C:18]3([O:21][CH3:22])[CH2:19][CH2:20][N:16]([C:14]([O:13][CH2:11][CH3:12])=[O:15])[CH2:17]3)[CH:24]=[CH:25][CH:26]=2)=[CH:3][CH:4]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(S)cc1
Reactant: CCOC(=O)N1CCC(OC)(c2cccc(I)c2)C1
Product: CCOC(=O)N1CCC(OC)(c2cccc(Sc3ccc(C(C)=O)cc3)c2)C1
Yield: 24 %

Procedure:
Using an analogous procedure to that described in Example 10, 4'-mercaptoacetophenone was reacted with 1-ethoxycarbonyl-3-(3-iodophenyl)-3-methoxypyrrolidine to give 3-[3-(4-acetylphenylthio)phenyl]-1-ethoxycarbonyl-3-methoxypyrrolidine as a gum in 24% yield.