Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)NC(=O)N(Br)C1=O.[CH:12]1([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]([O:25][CH:26]([CH3:28])[CH3:27])[CH:16]=2)[CH2:14][CH2:13]1.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C>[Br:1][C:24]1[C:15]([CH:12]2[CH2:14][CH2:13]2)=[CH:16][C:17]([O:25][CH:26]([CH3:28])[CH3:27])=[C:18]([CH:23]=1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: O=c1[nH]c(=O)n(Br)c(=O)n1Br
Reactant: COC(=O)c1ccc(C2CC2)cc1OC(C)C
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)c(C2CC2)cc1OC(C)C
Temperature: 90 °C
Reaction time: 1 h
Yield: 158.2 %

Procedure:
Dibromoisocyanuric acid (3.99 g) was added at room temperature to a DMF (80 mL) solution of methyl 4-cyclopropyl-2-isopropoxybenzoate (5.43 g), and the mixture was stirred at 90° C. for 1 hour in a nitrogen atmosphere. An aqueous sodium thiosulfate solution was added to the reaction mixture at room temperature, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (6.89 g).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.Cl.[N:10]([O-])=O.[Na+].[Cl:14][Sn]Cl>O>[ClH:14].[NH:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[N:7][CH:6]=1)[NH2:10]
Reactant: Cc1ccc(N)cn1
Reactant: O=N[O-]
Reactant: Cl[Sn]Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1ccc(NN)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
To a 0° C. solution of 6-methylpyridin-3-amine (12 g, 0.11 mol) in cone HCl (40 mL) was added a solution of NaNO2 (7.7 g, 110 mmol) in water (30 mL) and the resulting mixture was stirred at 0° C. for 1 h. A solution of SnCl2 (50 g, 0.22 mol) in cone HCl (60 mL) was added at 0° C. The reaction solution was warmed to RT and stirred for 2 hours. The precipitate was collected by filtration to provide 5-hydrazinyl-2-methylpyridine hydrochloride (10 g, 57% yield) which was used without further purification.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.[C:10]([O:14][C:15]([N:17]1[C@H:22]([CH2:23][NH2:24])[C@@H:21]2[CH2:25][C@H:18]1[CH2:19][CH2:20]2)=[O:16])([CH3:13])([CH3:12])[CH3:11].CCN(C(C)C)C(C)C>C1COCC1>[C:10]([O:14][C:15]([N:17]1[C@H:22]([CH2:23][NH:24][C:3](=[O:5])[C:2]([F:1])([F:8])[F:9])[C@@H:21]2[CH2:25][C@H:18]1[CH2:19][CH2:20]2)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1CN
Reactant: CCOC(=O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1CNC(=O)C(F)(F)F

Procedure:
Ethyl trifluoroacetate (12.2 mmol, 1.30 eq) is added to a solution of (1R,3S,4S)-3-aminomethyl-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (9.42 mmol, 1.00 eq) and DIPEA (14.1 mmol, 1.50 eq) in THF (25 mL). After 50 min the mixture is concentrated in vacuo, diluted with TBME (100 mL) and washed twice with aq. citric acid (5%) and water respectively. The organic layer is dried over MgSO4 and concentrated in vacuo to give a crude product which is used without further purification. LC-MS (basic): tR=0.95 min; [M+H]+=323.2.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][NH2:8])[CH:5]=[CH:4][N:3]=[CH:2]1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: NCCn1ccnc1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Product: O=S(=O)(NCCn1ccnc1)c1ccc(Br)cc1

Procedure:
When 1H-imidazole-1-ethanamine was treated with 4-bromobenzenesulfonyl chloride by the procedure of Example 20, the compound of this example, mp 165°-167° C., was obtained.
Reaction SMILES: [CH:1]1([C:5]2[C:13]([C:14]3[NH:18][C:17]([O:19][CH3:20])=[N:16][N:15]=3)=[CH:12][C:8]([C:9](N)=[O:10])=[C:7]([CH3:21])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.N([O-])=[O:23].[Na+]>C(O)(C(F)(F)F)=O>[CH:1]1([C:5]2[C:13]([C:14]3[NH:18][C:17]([O:19][CH3:20])=[N:16][N:15]=3)=[CH:12][C:8]([C:9]([OH:23])=[O:10])=[C:7]([CH3:21])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COc1nnc(-c2cc(C(N)=O)c(C)cc2C2CCC2)[nH]1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COc1nnc(-c2cc(C(=O)O)c(C)cc2C2CCC2)[nH]1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4-cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzamide (compound 89.8, 0.1 g, 0.33 mmol) in TFA (5 mL) at 0° C., was added NaNO2 (46 mg, 0.66 mmol). The mixture was stirred at 0° C. for 1 hour, then at room temperature for 2 hours. The mixture was concentrated under reduced pressure and the residue was partitioned between EtOAc and brine. The aqueous layer was extracted with EtOAc and the combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure to yield 0.1 g (theoretical) of the title compound as a clear oil. m/z (ES+) 288 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:6]=1[Cl:12].N1C=CC=CC=1.[C:20]1([O:26][C:27](Cl)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1.C(OC(=O)C)C>[CH3:2][O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([NH:11][C:27]([O:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:28])[CH:8]=[CH:7][C:6]=1[Cl:12]
Reactant: COC(=O)c1cc(N)ccc1Cl
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)c1cc(NC(=O)Oc2ccccc2)ccc1Cl
Temperature: 25 °C
Yield: 52.3 %

Procedure:
To a stirred mixture of 5-amino-2-chloro-benzoic acid methyl ester hydrochloride (1.110 g, 5.0 mmol) and pyridine (0.79 g, 10.0 mmol) in anhydrous THF (15 mL) at 0° C. was added phenylchloroformate (0.95 g, 6.0 mmol). After warming to room temperature, the reaction mixture was diluted with ethylacetate (50 mL), washed sequentially with 10% HCl, water and brine and dried over sodium sulfate. Removal of solvent under vacuum and purification of the product by flash chromatography (10% ethyl acetate in hexanes) yielded 0.8 g (53%) of a colorless solid. 1H NMR (300 MHz, DMSO-d6) δ3.9 (s, 3H), 7.0 (br s, 1H), 7.18 (m, 2H), 7.4 (m, 3H), 7.6 (m, 1H), 7.9 (d, J=2.5 Hz, 1H). Mass Spectrum (M−H): 3:1 ratio of 304 and 306.
Reaction SMILES: [C-:1]#[N:2].[Na+].Br[CH2:5][CH2:6][CH:7]=[C:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>CN(C)P(N(C)C)(N(C)C)=O>[C:9]1([C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][CH2:6][CH2:5][C:1]#[N:2])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: BrCCC=C(c1ccccc1)c1ccccc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: N#CCCC=C(c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 80 %

Procedure:
To a stirred solution of 73.g (1.5 mol) of sodium cyanide in 1 liter of hexamethylphosphoramide at ambient temperature was added over a 1 hour period a solution of 290. g (1 mol) of 4-bromo-1,1-diphenyl-1-butene in 0.5 liters of hexamethylphosphoramide. The mixture was stirred overnight, poured into 2 liters of water and extracted with 3×1 liters of ether. The ether extracts were combined, washed with 3×0.5 liters of Water, 0.5 liters of brine, and dried over sodium sulfate. The resulting crude solid was recrystallized from isopropyl ether to give 190 .g (80%) of 5,5-diphenyl-4-pentenenitrile as a white solid (mp 64°-66° C.) .
Reaction SMILES: CN(C)C=O.CS([O:10][CH2:11][CH2:12][C:13]([CH3:17])=[C:14]([F:16])[F:15])(=O)=O.[CH:18]1([O:23][C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][N:25]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1.C(=O)([O-])O.[Na+]>O>[CH:18]1([O:23][C:24]2[CH:32]=[CH:31][C:27]([C:28]([O:10][CH2:11][CH2:12][C:13]([CH3:17])=[C:14]([F:16])[F:15])=[O:29])=[CH:26][N:25]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C(O)c1ccc(OC2CCCC2)nc1
Reactant: CC(CCOS(C)(=O)=O)=C(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(CCOC(=O)c1ccc(OC2CCCC2)nc1)=C(F)F
Temperature: 100 °C
Reaction time: 3 h
Yield: 70.7 %

Procedure:
To 5 ml of N,N-dimethylformamide were dissolved 0.42 g (2.1 mmol) of 4,4-difluoro-3-methyl-3-butenyl methanesulfonate and 0.42 g (2.0 mmol) of 6-cyclopentyloxynicotinic acid, followed by the addition of 0.35 g (4.2 mmol) of sodium hydrogencarbonate and stirring at 100° C. for 3 hours. The reaction liquid was then poured in water and extracted with diethyl ether. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (diisopropyl ether: hexane=1:7) to obtain 0.44 g (yield: 70%) of 4,4-difluoro-3-methyl-3-butenyl 6-cyclopentyloxynicotinate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[NH:23][N:24]=[C:25]([O:26][CH2:27][CH2:28][N:29]4C(=O)C5C(=CC=CC=5)C4=O)[C:18]=23)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.O.NN>C(O)C>[NH2:29][CH2:28][CH2:27][O:26][C:25]1[C:18]2[C:19](=[N:20][CH:21]=[N:22][C:17]=2[NH:16][C:4]2[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=3)=[C:2]([Cl:1])[CH:3]=2)[NH:23][N:24]=1
Reactant: O=C1c2ccccc2C(=O)N1CCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 68.7 %

Procedure:
A mixture of 2-{2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)oxy]ethyl}-1H-isoindole-1,3(2H)-dione (prepared as described in Example 90/350 mg, 0.65 mmol) and hydrazine monohydrate (63111) in ethanol (2 ml) was refluxed overnight. After evaporation of the solvent, the crude material was purified by preparative HPLC (column beta-basic, Hypercil 5 μm, 21×100 mm) eluting with a mixture of water and acetonitrile containing 2g/l of ammonium carbonate (gradient) to give the title compound (184 mg, 69%); NMR Spectrum: 2.94 (t, 2H), 4.25 (t, 2H), 5.29 (s, 2H), 7.23 (d, 1H), 7.37 (t, 1H), 7.53-7.58 (m, 2H), 7.85-7.90 (m, 2H), 8.26 (s, 1H), 8.60 (br s, 2H). Mass Spectrum: 412 (MH+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](CC(O)=O)=[CH:2]1.S(Cl)([Cl:12])=O.ON1C(=O)C[CH2:17][C:16]1=[O:21].C(N(C(C)C)CC)(C)C>CO.O1CCOCC1>[S:1]1[CH:2]=[CH:3][CH:4]=[C:5]1[CH2:17][C:16]([Cl:12])=[O:21].[S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: O=C(O)Cc1ccsc1
Reactant: O=C1CCC(=O)N1O
Reactant: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: C1COCCO1
Product: O=C(Cl)Cc1cccs1
Product: c1ccsc1

Procedure:
In the first set of experiments, amine and carboxylic acid terminated thiophene intermediates were prepared (FIG. 4) and subsequently coupled with carbohydrate moieties. In the second set, the distance between thiophene and carbohydrate was extended by iminothiolane hydrochloride (compound 30) and a thiol was generated after extension. (The reaction conditions specified in FIG. 4(a) are as follows: cat. DIPEA/CHCl3, r.t., 95% yield; FIG. 4(b) are as follows: CHCl3 (highly diluted), r.t., overnight, 83-96% yield; FIG. 4(c) are as follows: BOC-ON, Et3N/CHCl3, r.t., 52% yield; FIG. 4(d)(i) are as follows: 3-(3-Thienyl)acrylic acid (compound 19), HOBt/EDC, DIPEA, CHCl3, r.t., 6 h, 93% yield; FIG. 4(d)(ii) are as follows: 30% TFA/CH2Cl2, r.t., 3 h, 93% yield; FIG. 4(d)(iii) are as follows: 1 M NaOH, quantitative). These thiols were prepared in situ and coupled with compounds 2 or 5 by Michael type addition to give another set of thiophene-carbohydrate monomers. The two types of carbohydrate moieties are summarized in FIG. 5 and FIG. 6. Commercially available 3-thiopheneacetic acid (compound 6) (Acros Organics, Fisher Scientific, Pittsburgh, Pa.) was converted into the corresponding methyl ester (compound 7) in 88% yield by thionyl chloride in methanol. Thiopheneacetyl chloride (compound 8) was prepared in situ, by thionyl chloride in dioxane. Direct addition of N-hydroxysuccinimide (NHS) in the presence of diisopropylethylamine (DIPEA) at 0° C. afforded thiophene active ester (compound 9) in 75% overall yield. Compound 9 was stable under dry conditions and could be prepared in bulk quantities.
Reaction SMILES: [CH:1]([Li])([CH2:3]C)[CH3:2].[CH2:6]([C:10]1[N:14](CC2C=CC(C3C=CC=CC=3C3NN=NN=3)=CC=2)[N:13]=[C:12]([CH2:33][C:34](=O)[CH2:35][CH2:36][CH3:37])[N:11]=1)[CH2:7][CH2:8][CH3:9].C(Br)C1C=CC=CC=1.C1C[O:50]CC1>>[CH2:6]([C:10]1[NH:14][N:13]=[C:12]([C:33](=[O:50])[CH2:34][C:35]2[CH:36]=[CH:37][CH:3]=[CH:1][CH:2]=2)[N:11]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCc1nc(CC(=O)CCC)nn1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: C1CCOC1
Reactant: [Li]C(C)CC
Agent: BrCc1ccccc1
Product: CCCCc1nc(C(=O)Cc2ccccc2)n[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
Under nitrogen, 7.3 mmol of sec-butyl lithium was added dropwise to 2.0 g (6.1 mmol) of the Sem-protected 5-butyl-3-(dimethoxymethyl)-1H-1,2,4-triazole from Example 30 in 100 ml of anhydrous THF at −78° C. The reaction was stirred for 1 h and then quenched with 0.87 ml (7.3 mmol) of benzyl bromide. The reaction was allowed to warm to ambient temperature and stir overnight. The THF was removed in vacuo; the residue dissolved in methylene chloride, washed with water and dried (MgSO4). The methylene chloride was removed in vacuo. The residue was dissolved in 10 ml of ethanol and 10 ml of 3M HCl and stirred at reflux for 2.5 h. The solvents were removed in vacuo. The residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate solution, and dried (MgSO4). Silica gel chromatography (Waters Prep 500A) using ethyl acetate/hexane (35:65) gave 460 mg (31%) of 5-butyl-3-(phenylacetyl)-1H-1,2,4-triazole: NMR (CDCl3) δ 0.92 (t, J=8 Hz, 3H), 1.31–1.55 (m, 2H), 1.70–1.83 (m, 2H), 2.88 (t, J=8 Hz, 2H), 4.39 (s, 2H), 7.21–7.38 (m, 5H). Following General Procedure A, 440 mg (1.8 mmol) of this material was reacted with 1.8 mmol of the alkylating reagent prepared in step 1 of Example 3. The crude product was dissolved in 10 ml of acetic acid/water (9:1) and stirred at ambient temperature for 4 days. The solvent was removed in vacuo; the residue dissolved in dilute base and washed with toluene. The water was acidified and extracted with ethyl acetate. Purification by reverse phase chromatography (Waters Delta Prep 3000) using acetonitrile/water (45:55) gave 50 mg (5%) of 5-[4′-[[5-butyl-3-(phenylacetyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole as the colorless TFA salt: NMR (DMSO-d6) δ 0.86 (t, J=8 Hz, 3H), 1.23–1.38 (m, 2H), 1.52–1.65 (m, 2H), 2.80 (t, J=8 Hz, 2H), 4.32 (s, 2H), 5.52 (s, 2H), 7.11 (d, J=8 Hz, 2H), 7.19 (d, J=8 Hz, 2H), 7.23–7.35 (m, 5H), 7.52–7.63 (m, 2H), 7.65–7.74 (m, 2H); MS (FAB) m/e (rel intensity) 478 (100), 244 (8), 235 (8), 207 (34), 192 (12); HRMS. Calc'd for M+H: 478.2355. Found: 478.2414.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C@H:2]([CH3:4])[OH:3].I[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>CCOCC>[CH2:7]([O:6][C:1](=[O:5])[CH:2]([O:3][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH3:10])[CH3:4])[CH3:8]
Reactant: CCCCCCCCCCCCI
Reactant: CCOC(=O)[C@H](C)O
Solvent: CCOCC
Product: CCCCCCCCCCCCOC(C)C(=O)OCC
Reaction time: 50 h
Yield: 25.7 %

Procedure:
47.0 g of ethyl L-(+)-lactate and 88.4 g of 1-iodododecane were added into a flask and mixed under nitrogen gas stream. 42.1 g of freshly synthesized Ag2O was added in 3 hours. After the mixture was left standing at room temperature for 50 hours, it was heated on a water bath at 60°-70° C. for 4 hours. The mixture was diluted with 200 ml of ether, subjected to filtration and then ether was evaporated. The residue was washed with 100 ml of aqueous 5% KOH, then dried over anhydrous Na2SO4 and subjected to vacuum distillation. The fractions of 169° C./9 mmHg were collected to obtain 22 g of (-)-ethyl-2-dodecyloxypropionate. Optical rotation [α]D23° =-42°.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[O:14])=[O:7].[C:15]1(=O)NCCCCC1>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:15][C:9]1=[O:14])=[O:7]
Reactant: O=C1CCCCCN1
Reactant: O=C1CCCCN1C(=O)c1ccco1
Product: O=C1CCCCCN1C(=O)c1ccco1

Procedure:
Synthesized as for N-(2-furoyl)valerolactam (Example IX) using caprolactam (Aldrich) in place of valerolactam.
Reaction SMILES: C1(C)C=CC(S([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][N:13]([CH:17]=[O:18])[CH2:12]2)(=O)=O)=CC=1.[C:20]([O-])(=[S:22])[CH3:21].[K+]>CN(C)C=O>[C:20]([O:10][CH:11]1[CH2:16][CH2:15][CH2:14][N:13]([CH:17]=[O:18])[CH2:12]1)(=[S:22])[CH3:21]
Reactant: CC([O-])=S
Reactant: Cc1ccc(S(=O)(=O)OC2CCCN(C=O)C2)cc1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=S)OC1CCCN(C=O)C1
Yield: 21 %

Procedure:
A solution of 1-formyl-3-piperidinyl p-toluenesulfonate (1.12 g., 0.007 mole) and potassium thioacetate (0.91 g., 0.008 mole) in 10 ml. dimethylformamide was heated at 70° C. under nitrogen for 20 hours. The reaction mixture was diluted with 150 ml. ethyl acetate and the resulting solution was washed with four 50 ml. portions of water and 50 ml. brine, dried over anhydrous sodium acetate and concentrated in vacuo. The residue was chromatographed on silica gel (125 g.) eluting with 4:1 ethyl acetate-hexane to yield 0.16 g. (21% yield) of the title compound. NMR (CDCl3): 1.13-2.3 (c) and 2.32 (s) (total 7H); 2.84-4.0 (c, 5H); and 7.9 (d, 1H)ppm.
Reaction SMILES: CC1C=CC(S([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17](CC#N)[CH:18]=3)[CH:13]=[CH:12]2)(=O)=O)=CC=1.[OH-:23].[Na+].[CH2:25]([OH:27])[CH3:26]>>[NH:11]1[C:19]2[C:14](=[CH:15][C:16]([CH2:26][C:25]([OH:23])=[O:27])=[CH:17][CH:18]=2)[CH:13]=[CH:12]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3ccc(CC#N)cc32)cc1
Reactant: [OH-]
Reactant: CCO
Agent: [Na+]
Product: O=C(O)Cc1ccc2[nH]ccc2c1
Yield: 68 %

Procedure:
A solution of 1-(4-methylphenylsufonyl)indole-6-acetonitrile (9.5 g) in ethanol (58 ml) was treated with 20% (w/v) sodium hydroxide (58 ml) and heated to reflux for 2.5 hr. The ethanol was evaporated and the aqueous residue was slowly acidified at 0° with concentrated hydrochloric acid. The white precipitate was collected by filtration, washed with water and dried under vacuum to give indole-5-acetic acid (4.1 g, 68%) as an ivory powder: NMR (250 MHz, DMSO-d6): 3.57(s, 2H, ArCH2), 9.65(dd, 1H, H6 -indole), 7.40(s, 1H, H4 -indole).
Reaction SMILES: [N:1]1([C:6]2[CH:17]=[CH:16][C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.N1C=CC=CC=1.[CH3:24][O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>ClCCl>[CH3:24][O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:15][CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:9]2[CH:16]=[CH:17][C:6]([N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)=[CH:7][CH:8]=2)=[O:31])=[CH:28][CH:27]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: NCCCCOc1ccc(-n2ccnc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(C(=O)NCCCCOc2ccc(-n3ccnc3)cc2)cc1
Temperature: -10 °C
Reaction time: 18 h

Procedure:
A solution of 2.3 g of 4-[4-(1H-imidazol-1-yl)phenoxy]butaneamine (Example 2) in 50 ml of dichloromethane containing 2 ml of pyridine is treated with 2.0 g of 4-methoxybenzoyl chloride. The reaction mixture is allowed to stand at room temperature for 18 hours, and is then heated at reflux for one hour. The volatiles are removed in vacuo. The residue is partitioned between 100 ml of dichloromethane and 100 ml of water. The dichloromethane layer is dried over Na2SO4, and then heated to gentle boiling. Hexane is then added to turbidity and the mixture cooled at -10° C. A tacky precipitate results and crystals develop in the supernatant solvent. These are collected, washed with hexane, and dried in vacuo at room temperature; m.p. 125°-126° C.; yield, 0.4 g.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:25]#[N:26].[Br:27][C:28]1[C:33]([OH:34])=[C:32]2[O:35][CH2:36][O:37][C:31]2=[CH:30][CH:29]=1>>[Br:27][C:28]1[C:33]([O:34][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:25]#[N:26])=[C:32]2[O:35][CH2:36][O:37][C:31]2=[CH:30][CH:29]=1
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1OCCCN1CCN(C)CC1
Reactant: Oc1c(Br)ccc2c1OCO2
Product: COc1cc2c(Oc3c(Br)ccc4c3OCO4)c(C#N)cnc2cc1OCCCN1CCN(C)CC1
Yield: 52 %

Procedure:
Using an analogous procedure to that described in Example 14, 4chloro-3-cyano-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline was reacted with 6-bromo-2,3-methylenedioxyphenol to give the title compound as a solid in 52% yield; NMR Spectrum: (DMSOd6 and CF3CO2D) 2.25-2.4 (m, 2H), 2.95 (s, 3H), 3.24-4.0 (m, 8H), 3.48 (m, 2H), 3.98 (s, 3H), 4.35 (m, 2H) 6.02 (s, 1H), 6.08 (s, 1H), 6.92 (d, 1H), 7.25 (d, 1H), 7.6 (d, 2H), 8.9 (s, 1H); Mass Spectrum: M+H+ 555 and 557.
Reaction SMILES: [C:1]([C:8]1[NH:9][CH:10]=[CH:11][N:12]=1)([C:3]1[NH:4][CH:5]=[CH:6]N=1)=O.[Br:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([S:24](O)=O)[CH:18]=[CH:17]2.[C:27](OCC)(=O)[CH3:28]>CN(C)C=O>[N:4]1[CH:3]=[CH:1][C:8]([N:9]2[CH2:10][CH2:11][N:12]([S:24][C:19]3[CH:18]=[CH:17][C:16]4[C:21](=[CH:22][CH:23]=[C:14]([Br:13])[CH:15]=4)[CH:20]=3)[CH2:28][CH2:27]2)=[CH:6][CH:5]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CCOC(C)=O
Reactant: O=S(O)c1ccc2cc(Br)ccc2c1
Solvent: CN(C)C=O
Product: Brc1ccc2cc(SN3CCN(c4ccncc4)CC3)ccc2c1
Reaction time: 8 h

Procedure:
Carbonyl diimidazole (324 mg) was added to a solution of 6-bromonaphthalene-2-sulphinic acid (658 mg) in dimethylformamide (10 ml). After stirring at ambient temperature for one hour N-4-(4-pyridyl)piperazine (326 mg) was added as a solid in one portion and stirring continued at ambient temperature overnight. The reaction mixture was poured into ethyl acetate (100 ml), washed with water (3×25 ml), brine (25 ml), dried (MgSO4) and evaporated to give a yellow oil which was purified by chromatography on silica gel (Mega Bond Elut column) using an increasing concentration of methanol in dichloromethane (up to 5% methanol) as eluant to give an oil which on trituration with diethyl ether gave a white solid 1-(4-pyridyl)-4-(6-bromonaphtalene-2-sulphenyl)piperazine (170 mg), m.p. 200-202° C.; microanalysis, found: C, 54.9; H, 4.4; N, 10.1; C19H18BrN3OS requires: C, 54.9; H, 4.3; N, 10.1; NMR: 2.9-3.0(m,2H); 3.1-3.3(m,2H); 3.35-3.5(m,4H); 6.8(dd,2H); 7.7-7.8(m,2H); 8.1-8.2(m,4H); 8.3(s,1H); 8.35(d,1H); MS: m/z 416 (MH)+.