Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]#[C:3][CH3:4].[N+](=[C:7]([C:12]([O:14][CH3:15])=[O:13])[C:8]([O:10][CH3:11])=[O:9])=[N-]>FC1C(F)=C(F)C(F)=C(F)C=1F.[Hg]>[CH3:1][C:2]1[C:7]([C:12]([O:14][CH3:15])=[O:13])([C:8]([O:10][CH3:11])=[O:9])[C:3]=1[CH3:4]
Reactant: COC(=O)C(=[N+]=[N-])C(=O)OC
Reactant: CC#CC
Agent: [Hg]
Solvent: Fc1c(F)c(F)c(F)c(F)c1F
Product: COC(=O)C1(C(=O)OC)C(C)=C1C
Reaction time: 100 h
Yield: 46.2 %

Procedure:
A nitrogen-degassed solution of 37.5 grams (0.69 mole) of 2-butyne and 20.0 grams (0.13 mole) of dimethyl diazomalonate in approximately 325 grams of hexafluorobenzene was photolyzed for approximately 100 hours, at 0° C.-5° C., employing a 100-watt Hanovia mercury lamp in a manner similar to that described in Example XCVI Part A. Similar workup of the reaction mixture afforded 10.8 grams (0.06 mole) of dimethyl 2,3-dimethyl-2-cyclopropene-1,1-dicarboxylate. NMR analysis of the product indicated the following:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:14])[C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.Cl[C:16]1[C:25]2[C:20](=[CH:21][C:22]([F:27])=[CH:23][C:24]=2[F:26])[N:19]=[C:18]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[C:17]=1[CH3:34].Cl.O1CCOCC1>CN1C(=O)CCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([NH:14][C:16]2[C:25]3[C:20](=[CH:21][C:22]([F:27])=[CH:23][C:24]=3[F:26])[N:19]=[C:18]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[C:17]=2[CH3:34])[C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1N1CCCCC1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(Br)cnc1N1CCCCC1
Reaction time: 4 h

Procedure:
5-Bromo-2-(piperidin-1-yl)pyridin-3-amine (0.0537 g, 0.210 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (0.0632 g, 0.217 mmol), and hydrochloric acid, 4.0M in 1,4-dioxane (0.05 mL, 0.200 mmol) were stirred in NMP (0.50 mL) then microwaved at 150° C. After an additional 4 h, the reaction was diluted with EtOAc and washed once with satd aq. sodium bicarbonate and once with brine. After drying over anhydrous sodium sulfate, filtration, and concentration, the brown residue was purified with silica gel chromatography (0-40% EtOAc in hexanes) to yield mostly N-(5-bromo-2-(piperidin-1-yl)pyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine. Mass Spectrum (ESI) m/e=510.2 (M+1).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:16]([O:20][C:21](=[O:47])[CH:22]([N:36]1[C:40](=[O:41])[C:39]2=[CH:42][CH:43]=[CH:44][CH:45]=[C:38]2[C:37]1=[O:46])[CH:23]1[NH:27][CH:26]([C:28]([OH:30])=[O:29])[C:25]2([CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[S:24]1)([CH3:19])([CH3:18])[CH3:17].Cl>CN(C)C=O>[CH2:1]([O:30][C:28]([CH:26]1[C:25]2([CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[S:24][CH:23]([CH:22]([N:36]2[C:40](=[O:41])[C:39]3=[CH:42][CH:43]=[CH:44][CH:45]=[C:38]3[C:37]2=[O:46])[C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:47])[NH:27]1)=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)C(C1NC(C(=O)O)C2(CCCCC2)S1)N1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C(C1NC(C(=O)OCc2ccccc2)C2(CCCCC2)S1)N1C(=O)c2ccccc2C1=O
Reaction time: 8 h
Yield: 82.7 %

Procedure:
8.5 g. (0.05 mole) of benzyl bromide are first added all at once and then 3.43 g. (0.034 mole) of triethylamine are added to a solution of 12 g. (0.026 mole) of tert-butyl-4-carboxy-alphaphthalimido-1-thia-3-azaspiro[4.5]decane-2-acetate in 130 ml. of anhydrous dimethylformamide. The reaction mixture is left to stand overnight at ambient temperature and then it is poured on to ice and 10 ml. of 6N hydrochloric acid are added followed by extraction with benzene. The organic phase is first washed with a 5% aqueous solution of sodium hydrogen carbonate and then with water, dried over anhydrous sodium sulfate, filtered and finally evaporated to dryness. After recrystallization from a mixture of diethyl ether and hexane (50/50), 12 g. (0.0215 mole) of tert-butyl 4-benzyloxycarbonyl-alpha-phthalimido-1-thia-3-azaspiro[4.5]decane-2-acetate are obtained. Yield: 82.7%. M.P. 165°-166° C.
Reaction SMILES: [CH3:1]OC1C(OC)=CC2NC(=O)CN=C(C3C=CC=CC=3)C=2C=1.[CH2:23]([O:25][C:26]1[C:43]([O:44][CH3:45])=[CH:42][C:29]2[C:30]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[N:31][CH2:32][C:33](=[O:35])[NH:34][C:28]=2[CH:27]=1)[CH3:24].C1(=O)OCCO1.IC>>[CH2:23]([O:25][C:26]1[C:43]([O:44][CH3:45])=[CH:42][C:29]2[C:30]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[N:31][CH2:32][C:33](=[O:35])[N:34]([CH3:1])[C:28]=2[CH:27]=1)[CH3:24]
Reactant: COc1cc2c(cc1OC)C(c1ccccc1)=NCC(=O)N2
Reactant: CCOc1cc2c(cc1OC)C(c1ccccc1)=NCC(=O)N2
Solvent: CI
Solvent: O=C1OCCO1
Product: CCOc1cc2c(cc1OC)C(c1ccccc1)=NCC(=O)N2C
Yield: 69 %

Procedure:
By replacing in the example 7,8-dimethoxy-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one (XXIIaa) by 8-ethoxy-7-methoxy-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (XXIIam), and ethylene carbonate by iodomethane, and proceeding in the same manner, the abovenamed product is obtained. Yield: 69%. M: 138–140° C. 1H-NMR (CDCl3, 200 MHz): d 1.54 (t, 3H, CH3), 3.38 (s, 3H, NCH3), 3.74 (s, 3H, OCH3), 4.18 (q, 2H, —OCH2), 4.29 (AB system, ? d=0.98, JAB=10.5, 2H, —CH2), 6.70 (s, 1H Ar), 6.77 (s, 1H Ar), 7.39–7.43 (m, 3H Ar), 7.63–7.68 (m, 3H Ar).
Reaction SMILES: [C:1]1(=[O:17])[N:5]([CH2:6][CH2:7][S:8](Cl)(=[O:10])=[O:9])[C:4](=[O:12])[C:3]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:2]12.[I:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>>[C:4]1(=[O:12])[N:5]([CH2:6][CH3:7])[C:1](=[O:17])[C:2]2=[CH:16][CH:15]=[CH:14][CH:13]=[C:3]12.[I:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][SH:8](=[O:10])=[O:9])=[CH:21][CH:20]=1
Reactant: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)Cl
Reactant: Nc1ccc(I)cc1
Product: CCN1C(=O)c2ccccc2C1=O
Product: O=[SH](=O)Nc1ccc(I)cc1

Procedure:
Prepared according to general method A from 2-phthalimidoethanesulfonyl chloride (1.50 g) and 4-iodoaniline (2.70 g). Yield: 1.56 g (56%). 1H-NMR (CDCl3) δ (ppm) 10.14 (s, 1H), 7.83 (s, 4H), 7.63 (d, J=8.7 Hz, 2H), 7.00 (d, J=8.8 Hz, 2H), 3.94 (t, J=7.1 Hz, 2H), 3.94-3.44 (m, 2H).
Reaction SMILES: [CH2:1]([NH2:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:20]([OH:28])(=[O:27])[C:21]([CH2:23][C:24](O)=[O:25])=[CH2:22].[NH2:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][OH:35]>>[OH:35][CH2:34][CH2:33][O:32][CH2:31][CH2:30][NH3+:29].[CH2:1]([N:19]1[C:24](=[O:25])[CH2:23][CH:21]([C:20]([O-:28])=[O:27])[CH2:22]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: NCCOCCO
Reactant: CCCCCCCC/C=C\CCCCCCCCN
Reactant: C=C(CC(=O)O)C(=O)O
Product: CCCCCCCC/C=C\CCCCCCCCN1CC(C(=O)[O-])CC1=O
Product: [NH3+]CCOCCO
Yield: 101 %

Procedure:
265 g of oleylamine, 130 g of itaconic acid and 105 g of 2-(2-aminoethoxy)ethanol were used to obtain 485 g of N-oleyl-5-oxopyrrolidine-3-carboxylic acid 2-(2-hydroxyethoxy)ethylammonium salt with
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:14]([NH2:20])[CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1.[C:21]([NH:24][C:25]1[CH:35]=[CH:34][CH:33]=[C:27]2[C:28]([O:30][C:31](=O)[C:26]=12)=[O:29])(=[O:23])[CH3:22].C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:14]([N:20]3[C:31](=[O:30])[C:26]4[C:27](=[CH:33][CH:34]=[CH:35][C:25]=4[NH:24][C:21](=[O:23])[CH3:22])[C:28]3=[O:29])[CH2:15][S:16]([CH3:19])(=[O:17])=[O:18])[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1
Reactant: CC(=O)Nc1cccc2c1C(=O)OC2=O
Reactant: COc1ccc(C(N)CS(C)(=O)=O)cc1OCC1CC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(C(CS(C)(=O)=O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)cc1OCC1CC1
Yield: 21.2 %

Procedure:
To a solution of 1-(3-cyclopropylmethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethylamine (1.0 g, 3.3 mmol) in acetic acid (10 mL), was added 3-acetamido-phthalic anhydride (1.37 g, 6.7 mmol) and sodium acetate (0.54 g, 6.7 mmol). The mixture was heated at reflux temperature overnight. The solvent was removed in vacuo. The resulted oil was extracted with ethyl acetate (50 mL) and water (30 mL). The organic layer was washed with water (30 mL×2) and brine (30 mL) and dried over magnesium sulfate. The solvent was removed in vacuo and the resulted oil was purified by silica gel column to give N-{2-[1-(3-cyclopropylmethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide as a white solid (340 mg, 21%): mp 102-104° C.; 1H NMR (CDCl3) δ 0.35-0.37 (m, 2H, c-CH2), 0.62-0.67 (m, 2H, c-CH2), 0.88-0.93 (m, 2H, c-CH2), 1.25-1.32 (m, 1H, c-CH), 2.25 (s, 3H, CH3), 2.87 (s, 3H, CH3), 3.75 (dd, J=4, 15 Hz, 1H, CHH), 3.83-3.85 (m, 5H, OCH2+OCH3), 4.53 (dd, J=10, 15 Hz, 1H, CH2), 5.85 (dd, J=4, 10 Hz, 1H, NCH), 6.84 (d, J=8 Hz, 1H, Ar), 7.07-7.10 (m, 2H, Ar), 7.45 (d, J=5 Hz, 1H, Ar), 7.62 (t, J=8 Hz, 1H, Ar), 8.72 (d, J=8 Hz, 1H, Ar), 9.45 (s, 1H, NHCO); 13C NMR (CDCl3) δ 1.6, 3.2, 3.3, 24.7, 41.4, 48.3, 54.2, 55.8, 73.9, 111.5, 113.1, 115.0, 118.0, 120.3, 124.7, 129.1, 130.9, 135.9, 137.2, 148.6, 149.8, 167.2, 169.0, 169.3. Analy. Calculated for C24H26N2O7S: C, 59.25; H, 5.39; N, 5.76. Found: C, 59.00; H, 5.36; N, 5.55.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][N:6]([CH2:17][CH3:18])[C:7]1[CH:8]=[N:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=1)[CH2:3][OH:4].C([O-])([O-])=O.[K+].[K+].[N:25]#[C:26]Br.C(OC(=O)C)C>C1COCC1.O>[NH2:25][C:26]1[O:4][CH2:3][C@H:2]([CH2:5][N:6]([CH2:17][CH3:18])[C:7]2[CH:8]=[N:9][C:10]([C:13]([F:16])([F:14])[F:15])=[CH:11][CH:12]=2)[N:1]=1
Reactant: CCN(C[C@H](N)CO)c1ccc(C(F)(F)F)nc1
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCN(C[C@H]1COC(N)=N1)c1ccc(C(F)(F)F)nc1
Reaction time: 1 h
Yield: 46.3 %

Procedure:
To a stirred mixture of (S)-2-amino-3-[ethyl-(6-trifluoromethyl-pyridin-3-yl)-amino]-propan-1-ol (0.04 g, 0.15 mmol) and K2CO3 (0.025 g, 0.18 mmol) in THF (2 ml) under an argon atmosphere was added a solution of cyanogen bromide (0.025 g, 0.18 mmol) in THF (1 ml). The mixture was stirred for 1 hour, then ethylacetate and water were added. The aqueous phase was back extracted with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (SiO2, EtOAc/MeOH=9:1) to give the title compound as white solid (0.02 g, 46%), MS (ISP): 289.0 ([M+H]+).
Reaction SMILES: [F:1][C:2]([F:16])([C:6]([F:15])([F:14])[C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9])[CH2:3][CH2:4][OH:5].N1C=CC=CC=1.[Cl-].[C:24]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]CC)(=[O:30])/[CH:25]=[CH:26]\[C:27]([O-])=[O:28].C(OCC)(=O)C>C(Cl)(Cl)Cl>[C:24]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])(=[O:30])/[CH:25]=[CH:26]\[C:27]([O:5][CH2:4][CH2:3][C:2]([F:16])([F:1])[C:6]([F:14])([F:15])[C:7]([F:12])([F:13])[C:8]([F:9])([F:10])[F:11])=[O:28]
Reactant: OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCCCCCCCCCCCOC(=O)/C=C\C(=O)[O-]
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCCCCCCCCCOC(=O)/C=C\C(=O)OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 1 h
Yield: 17 %

Procedure:
3,3,4,4,5,5,6,6,6-Nonafluorohexanol (164.6 g, 623 mmol) and pyridine (49.3 mL, 623 mmol) were dissolved in chloroform (280 mL), and the mixture was added dropwise with monododecyl maleate chloride (155.8 g, 566 mmol), while the internal temperature was kept at 20° C. or lower on an ice bath. After completion or the addition, the mixture was stirred for 1 hour and added with ethyl acetate. The organic phase was washed with 1 mol/L aqueous hydrochloric acid and a saturated sodium chloride aqueous solution. Then, the organic layer was collected, and the organic solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/chloroform=10/0 to 7/3 (v/v)) to obtain the target compound (48.2 g, yield: 18%).
Reaction SMILES: [C:1]([N:11]1[CH2:16][CH2:15][C:14]([OH:25])([CH2:17][NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13][CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(N(CC)CC)C.ClCCl.[C:36](Cl)(Cl)=[O:37]>C1(C)C=CC=CC=1>[C:19]1([N:18]2[CH2:17][C:14]3([CH2:13][CH2:12][N:11]([C:1]([O:3][CH2:4][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=4)=[O:2])[CH2:16][CH2:15]3)[O:25][C:36]2=[O:37])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(OCc1ccccc1)N1CCC(O)(CNc2ccccc2)CC1
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)N1CCC2(CC1)CN(c1ccccc1)C(=O)O2
Yield: 50.7 %

Procedure:
To a mixture of 2.2 g 1-carbobenzyloxy-4-hydroxy-4-anilinomethylpiperidine, 3 ml triethylamine and 20 ml dichloromethane is added a solution of 3 g phosgene in 25 ml toluene. After 30 minutes the mixture is washed with 100 ml, 1 N hydrochloric acid. Removal of solvent by evaporation followed by recrystallization from diethyl ether-hexane affords 1.2 g of 3-phenyl-8-carbobenzyloxy-1-oxa-3,8-diazaspiro[4.5]decan-2-one, mp 100°-102°.
Reaction SMILES: [CH3:1]C(N)CC.CN(C)CCCN.CN(C)[CH2:15][CH2:16][CH2:17][NH:18][C:19]1[C:24]2[CH:25]=[N:26][C:27]3[N:31]([CH2:32][CH3:33])[N:30]=[CH:29][C:28]=3[C:23]=2[N:22]2[N:34]=[CH:35][N:36]=[C:21]2[N:20]=1>>[CH2:32]([N:31]1[C:27]2[N:26]=[CH:25][C:24]3[C:19]([NH:18][CH:17]([CH3:1])[CH2:16][CH3:15])=[N:20][C:21]4[N:22]([N:34]=[CH:35][N:36]=4)[C:23]=3[C:28]=2[CH:29]=[N:30]1)[CH3:33]
Reactant: CCn1ncc2c1ncc1c(NCCCN(C)C)nc3ncnn3c12
Reactant: CCC(C)N
Agent: CN(C)CCCN
Product: CCC(C)Nc1nc2ncnn2c2c1cnc1c2cnn1CC
Yield: 78 %

Procedure:
By substituting 1-methylpropylamine for the 3-dimethylaminopropylamine in the procedure of Example 1 (c), 8-ethyl-N-(1-methylpropyl)-8H-pyrazolo[4',3':5,6]pyrido[3,4-e]-[1,2,4]triazolo[1,5-a]pyrimidin-5-amine is obtained, yield 78%; m.p. 228°-230° (methanol).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]#[N:11])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>>[Br-:24].[C:10]([C:9]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])([CH2:2][CH2:3]1)[CH2:8][CH2:7]2)#[N:11]
Reactant: N#CC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Reactant: CCCCCCCCCBr
Product: CCCCCCCCC[N+]12CCC(C(C#N)(c3ccccc3)c3ccccc3)(CC1)CC2
Product: [Br-]
Yield: 78 %

Procedure:
Following the general procedure outlined in Example 2, 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)acetonitrile (0.0495 g, 0.164 mmol) and 1-bromononane (0.050 mL, 0.262 mmol) in 2CH3CN/3CHCl3 (4.0 mL) were reacted to give the desired product (0.0652 g, 78.6%). EI-MS m/z 429 (M+) Rt (2.55 min).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)[S:9]1(=[O:33])=[O:32].Cl>ClCCl.O1CCOCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[S:9]1(=[O:33])=[O:32]
Reactant: Cc1ccccc1N1c2ccccc2N(CCN2CCN(C(=O)OC(C)(C)C)CC2)S1(=O)=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1ccccc1N1c2ccccc2N(CCN2CCNCC2)S1(=O)=O
Yield: 91.4 %

Procedure:
In an analogous manner as general procedure II, step 2, a solution of tert-butyl 4-{2-[3-(2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl}piperazine-1-carboxylate (0.22 g, 0.47 mmol) in dichloromethane (10 mL) was treated with hydrogen chloride (3.0 mL of a 4 M solution in dioxane), resulting in a white precipitate that was evaporated and dried under vacuum to provided 1-(2-methylphenyl)-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (0.16 g, 92%) as a white solid:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][CH:9]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([N+:33]([O-])=O)[CH:28]=3)[CH:20]=2)[C:10]2[S:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:4][CH2:3]1.O.O.[Sn](Cl)Cl>C(O)C.ClCCl.[OH-].[Na+]>[S:11]1[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=[C:10]1[CH:9]([O:8][CH:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)[C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=1)[O:25][CH2:26][C:27]1[CH:28]=[C:29]([NH2:33])[CH:30]=[CH:31][CH:32]=1
Reactant: CN1CCC(OC(c2cccc(OCc3cccc([N+](=O)[O-])c3)c2)c2nc3ccccc3s2)CC1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: CN1CCC(OC(c2cccc(OCc3cccc(N)c3)c2)c2nc3ccccc3s2)CC1

Procedure:
A suspension of 2-{(1-methylpiperidin-4-yloxy)[3-(3-nitro-benzyloxy)phenyl]-methyl}benzothiazole (example 196, 55 mg) and tin(II) chloride dihydrate (250 mg) in ethanol (2 mL) is refluxed for 1 h. The cooled mixture is diluted with dichloromethane and aqueous 1N sodium hydroxide. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure to afford 3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxymethyl}-phenylamine which is then converted into its oxalate salt in acetone to give 3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxymethyl}-phenylamine, oxalate as an orange solid. TLC of the base (eluent: CH2Cl2/MeOH/NH4OH 95/5/0.5): Rf=0.14.
Reaction SMILES: C1(CCCN)C=CC=CC=1.[CH2:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][N:12]1[C:20]([NH:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][N:24]=1)=[O:21].[CH2:32]1[C:40]2[C:35](=[CH:36]C=CC=2)[CH2:34][N:33]1C(NC1C=CC(C(O)=O)=CC=1)=O>>[CH3:34][CH:35]([CH3:36])[CH2:40][CH2:32][NH:33][C:27]([C:26]1[CH:30]=[CH:31][C:23]([NH:22][C:20]([N:12]2[CH2:11][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)=[O:21])=[N:24][CH:25]=1)=[O:29]
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)nc1
Agent: NCCCc1ccccc1
Product: CC(C)CCNC(=O)c1ccc(NC(=O)N2Cc3ccccc3C2)nc1

Procedure:
The title compound was prepared as described in Example 1C, substituting 3-methylbutan-1-amine for 3-phenylpropan-1-amine and 6-(isoindoline-2-carboxamido)nicotinic acid for 4-(isoindoline-2-carboxamido)benzoic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.24 (s, 1H), 8.73 (d, J=2.4 Hz, 1H), 8.42 (t, J=5.5 Hz, 1H), 8.13 (dd, J=8.8, 2.4 Hz, 1H), 7.99 (d, J=8.7 Hz, 1H), 7.25-7.37 (m, 4H), 4.71-4.95 (bs, 4H), 3.24-3.32 (m, 2H), 1.57-1.68 (m, 1H), 1.43 (q, J=7.1 Hz, 2H), 0.91 (d, J=6.6 Hz, 6H); MS (ESI(+)) m/e 353 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N+:10]([O-])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-:15].[K+].[K+]>C(OC(=O)C)(=O)C.C(OCC)(=O)C.C(Cl)(Cl)Cl>[C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([OH:15])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [O-][n+]1ccc(-c2ccccc2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: Oc1cc(-c2ccccc2)ccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-phenylpyridine-1-oxide (2.00 g, 0.012 mol) in acetic anhydride (6 mL) was heated at reflux for 48 hours. The reaction mixture was cooled to ambient temperature, diluted with ethyl acetate (80 mL) and washed with saturated aqueous sodium bicarbonate (2×15 mL) and brine (15 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in methanol (20 mL) and potassium carbonate (0.32 g, 0.002 mol) was added to the solution. The reaction mixture was stirred at ambient temperature for 1 hour, then diluted with chloroform (100 mL) and filtered through Celite. The filtrate was concentrated in vacuo. The residue was dissolved in a mixture of methanol/chloroform 1/10 (30 mL). The title compound was precipitated with the addition of hexanes (30 mL) as a white solid which was collected by filtration (1.20 g, 60%): 1H NMR (300 MHz, DMSO-d6) δ 7.66-7.62 (m, 2H), 7.48-7.37 (m, 4H), 6.51 (d, J=1.2 Hz, 1H), 6.44 (dd, J=6.7, 1.8 Hz, 1H); MS (ES+) m/z 172.5 (M+1).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](=[O:31])[N:11]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1)[CH2:12][C:13]1[O:14][C:15]([CH3:18])=[CH:16][CH:17]=1)[CH2:2]2.[CH2:32]([Br:35])[CH:33]=[CH2:34]>C(Cl)(Cl)Cl.C(#N)C>[Br-:35].[CH2:34]([N+:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[C@@H:3]([O:9][C:10](=[O:31])[N:11]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1)[CH2:12][C:13]1[O:14][C:15]([CH3:18])=[CH:16][CH:17]=1)[CH2:2]2)[CH:33]=[CH2:32]
Reactant: C=CCBr
Reactant: COc1ccc(CCN(Cc2ccc(C)o2)C(=O)O[C@H]2CN3CCC2CC3)cc1OC
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: C=CC[N+]12CCC(CC1)[C@@H](OC(=O)N(CCc1ccc(OC)c(OC)c1)Cc1ccc(C)o1)C2
Product: [Br-]
Temperature: 25 °C
Reaction time: 21 h
Yield: 94.9 %

Procedure:
0.300 g (0.7 mmol) of [2-(3,4-Dimethoxyphenyl)ethyl]-(5-methylfuran-2-ylmethyl)carbamic acid (3R)-1-azabicyclo[2.2.2]oct-3-yl ester were dissolved in 5 ml of CHCl3 and 3.5 ml of acetonitrile. To this solution 0.30 ml (0.423 g, 3.5 mmol) of allyl bromide were added and the mixture was stirred during 21 hours at room temperature under N2 atmosphere. Solvents were evaporated. The residue was treated with ether several times to obtain an oil, which was redissolved in CHCl3 and evaporated to dryness to give 0.365 g (94.8%) of the title product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[C:11]([C:13]([OH:15])=O)[N:12]=2)=[C:4]([F:16])[CH:3]=1.[CH:17]([NH:20][N:21]=[C:22]([NH2:24])[CH3:23])([CH3:19])[CH3:18].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[C:11]([C:13]([N:24]=[C:22]([NH:21][NH:20][CH:17]([CH3:19])[CH3:18])[CH3:23])=[O:15])[N:12]=2)=[C:4]([F:16])[CH:3]=1
Reactant: CC(N)=NNC(C)C
Reactant: O=C(O)c1c[nH]c(-c2ccc(Br)cc2F)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(=NC(=O)c1c[nH]c(-c2ccc(Br)cc2F)n1)NNC(C)C

Procedure:
Scheme 11 shows the synthesis of 5-(2-(4-bromo-2-fluorophenyl)-1H-imidazol-4-yl)-1-isopropyl-3-methyl-1H-1,2,4-triazole V from 4-bromo-2-fluorobenzimidamide hydrochloride 12. 3-Chloro-2-oxopropanoic acid and 12 are reacted with base to give 2-(4-bromo-2-fluorophenyl)-1H-imidazole-4-carboxylic acid 30. Alternatively, 3-bromo-2-oxopropanoic acid can be reacted with 12 to give 30. Reaction of 30 with N′-isopropylacetohydrazonamide 6 and coupling reagent HBTU (N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate, 0-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, CAS Ref No. 94790-37-1) in DMF gives intermediate, 2-(4-bromo-2-fluorophenyl)-N-(1-(2-isopropylhydrazinyl)ethylidene)-1H-imidazole-4-carboxamide 31 which need not be isolated and cyclizes upon heating to give V. Alternatively, 5-(2-(4-chloro-2-fluorophenyl)-1H-imidazol-4-yl)-1-isopropyl-3-methyl-1H-1,2,4-triazole 44, the chloro version of V, can be prepared from 4-chloro-2-fluorobenzonitrile 38 (Scheme 15)
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[C:9]1([CH2:19][N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1>C(O)C>[C:9]1([CH2:19][N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O-:6])=[O:5]
Reactant: O=C(O)/C=C/C(=O)O
Agent: c1ccc2c(Cn3ccnc3)cccc2c1
Solvent: CCO
Product: O=C([O-])/C=C/C(=O)O
Reaction time: 0.17 h

Procedure:
A solution of fumaric acid (0.21 g) in hot ethanol (10 ml) was added to a solution of 1-(1-naphthylmethyl)imidazole (0.4 g) in ethanol (5 ml). After boiling for 10 minutes, the solution was evaporated under reduced pressure to afford a white solid. Recrystallisation of the solid from ethanol afforded 1-(1-naphthylmethyl)imidazole, hydrogen fumarate, m.p. 159°-161° C.