Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[O:24]1[C:28]2[CH:29]=[CH:30][C:31](B(O)O)=[CH:32][C:27]=2[O:26][CH2:25]1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[O:24]1[C:28]2[CH:29]=[CH:30][C:31]([C:2]3[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=3[O:22][CH3:23])[C:5]([NH:7][C:8]3[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=3)=[O:6])=[CH:32][C:27]=2[O:26][CH2:25]1
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: COc1ccc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1-c1ccc2c(c1)OCO2

Procedure:
3-Bromo-4-methoxy-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 30.1, 60 mg, 0.154 mmol), benzo[d][1,3]dioxol-5-ylboronic acid (33.2 mg, 0.200 mmol), (Ph3P)4Pd (9 mg, 6.94 μmol), 2 M Na2CO3 (0.115 mL, 0.231 mmol), DME (2.4 mL) and water (0.8 mL) were subjected to MW irradiation at 150° C. for 10 min. The RM was filtered through a PL-Thiol MP SPE cartridge (StratoSpheres™, 6 mL), the cartridge was washed with MeOH (10 mL) and the combined filtrates were evaporated under reduced pressure to give the crude product was purified by preparative HPLC to afford the title compound. UPLC-MS (Condition 6) tR=2.37 min, m/z=432.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:4]=2[CH:3]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+].[F:28][C:29]1[CH:30]=[C:31](/[CH:36]=[CH:37]/B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:33]([F:35])[CH:34]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:28][C:29]1[CH:30]=[C:31](/[CH:36]=[CH:37]/[C:2]2[N:7]=[N:6][C:5]3[O:8][C:9]4[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=4[O:11][C:4]=3[CH:3]=2)[CH:32]=[C:33]([F:35])[CH:34]=1
Reactant: Clc1cc2c(nn1)Oc1ccccc1O2
Reactant: CC1(C)OB(/C=C/c2cc(F)cc(F)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Fc1cc(F)cc(/C=C/c2cc3c(nn2)Oc2ccccc2O3)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 95.2 %

Procedure:
Under an argon atmosphere, to 3-chloro[1,4]benzodioxino[2,3-c]pyridazine (500 mg) were added 1,2-dimethoxyethane (7.5 ml), 2M aqueous sodium carbonate solution (3.0 mL), 2-[(E)-2-(3,5-difluorophenyl)vinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (720 mg) and tetrakis(triphenylphosphine)palladium (130 mg). The reaction mixture was stirred at 100° C. for 3 hr and cooled to room temperature. Water was added, and the obtained solid was collected by filtration and dried under reduced pressure to give 3-[(E)-2-(3,5-difluorophenyl)vinyl][1,4]benzodioxino[2,3-c]pyridazine (700 mg).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:19]=[CH:18][CH:17]=[CH:16][C:5]2=[C:6]2[C:15]=1[O:14][C:13]1[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=1)[O:7]2>C(O)(=O)C.CO.[Zn]>[CH:16]1[C:5]2=[C:6]3[C:15](=[CH:2][N:3]=[C:4]2[CH:19]=[CH:18][CH:17]=1)[O:14][C:13]1[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=1)[O:7]3
Reactant: Clc1nc2ccccc2c2c1Oc1ccccc1O2
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: c1ccc2c(c1)Oc1cnc3ccccc3c1O2

Procedure:
Under an inert atmosphere, 1 mmol of 6-chloro-5-aza-7,12-dioxabenz[a]anthracene and 8 mmol of powdered zinc are brought to 50° C. in 5 ml of acetic acid for 8 hours. After cooling, the reaction mixture is diluted in methanol and then filtered through Celite. The residue is concentrated under vacuum, then washed with saturated sodium hydrogen carbonate solution and then extracted with chloroform. The organic phase is dried over magnesium sulfate and concentrated under vacuum. The crude mixture is chromatographed by flash chromatography on silica gel (eluent: ethyl acetate/petroleum ether).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].C1CCNCC1.[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28]>O1CCCC1>[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:28]
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3cccc(F)c3)c2)CC1
Reaction time: 0.08 h
Yield: 109.8 %

Procedure:
A mixture of 4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and (piperidinomethyl)-polystyrene (50 mg, 0.130 mmol) in tetrahydrofuran (1 mL) was allowed to stand for 5 min. 3-fluorobenzoyl chloride (28 μL, 0.229 mmol) and tetrahydrofuran (1 mL) were added to the reaction mixture. The reaction mixture was mixed for 18 h at ambient temperature. The reaction mixture was filtered and the filter cake was rinsed with methanol. Glacial acetic acid (0.5 mL) was added to the filtrate solution and allowed to stand for 5 min. This mixture was poured over a Varian Mega Bond Elut™ strong cation exchange column. The column was rinsed with methanol to remove impurities, then treated with a 7M ammonia in methanol to elute the product from the column. The solvent was evaporated to give 43 mg (>100%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][C:7](=[O:13])[CH:6]=[CH:5]2.[C:14](OC(=O)C)(=[O:16])[CH3:15].C(O[Na])(C)=O>O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:14](=[O:16])[CH3:15])[O:8][C:7](=[O:13])[CH:6]=[CH:5]2
Reactant: Cc1cc2ccc(=O)oc2cc1O
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)O[Na]
Solvent: O
Product: CC(=O)Oc1cc2oc(=O)ccc2cc1C

Procedure:
To prepare the alkylangelicins with an alkyl group in the 4'-position of the furan ring, the suitable umbelliferones, (I), (II), (III) were acetylated and the 7-acetoxycoumarins thus obtained were submitted to the Fries rearrangement. The 8-acetylumbelliferones were converted into the ethyl esters of the 7-(8-acetylcoumarinyl)oxyacetic acids, which were then hydrolized and cyclized yielding the desired 4'-methylangelicins. In such a manner a mixture of 6-methyl-7-hydroxycoumarin (I) (10.0 g), acetic anhydride (40 ml) and anhydrous AcONa (4.0 g) was refluxed for 1 h. To the reaction mixture an equal volume of H2O was cautiously added and the whole was refluxed for 10 min. The mixture was diluted with H2O (300 ml), chilled and the precipitate was collected by filtration, washed several times with H2O, dried and crystallized from MeOH, yielding the 6-methyl-7-acetoxycoumarin (XXII) (10.0 g; m.p. 147° C.). ##STR28##
Reaction SMILES: [CH:1]([N:4]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[C:5](=[O:21])[CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:3])[CH3:2].C(OC([N:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[C:38]1[CH2:46][C:47]([O:54][CH3:55])([C:51](Cl)=[O:52])[C:48](Cl)=[O:49])=O)(C)(C)C>C1COCC1>[NH:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[C:38]1[CH2:46][C:47]1([O:54][CH3:55])[C:48](=[O:49])[N:7]([CH2:6][C:5]([N:4]([CH:1]([CH3:3])[CH3:2])[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[O:21])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:51]1=[O:52]
Reactant: COC(Cc1cc2ccccc2n1C(=O)OC(C)(C)C)(C(=O)Cl)C(=O)Cl
Reactant: COc1ccc(N(C(=O)CNc2ccccc2Nc2ccccc2)C(C)C)cc1
Solvent: C1CCOC1
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3cc4ccccc4[nH]3)(OC)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Yield: 12.2 %

Procedure:
A solution of 0.76 g (2.0 mmol) of N-isopropyl-N-(4-methoxy-phenyl)-2-(2-phenylamino-phenylamino) acetamide, prepared as in Intermediate 43, in 10 mL of THF is added dropwise to a solution of 1.0 g (2.4 mmol) of 2-(N-tert-butoxycarbonyl-1H-indol-2-ylmethyl)-2-methoxy-malonyl dichloride in 35 mL of THF. The brown solution is heated at reflux for 1 d. After removal of THF in vacuo the residue is diluted with 100 mL of 1N HCl and extracted with EtOAc (×2). the organic extract is washed with 1N HCl, brine, sat. NaHCO3 and brine, dried over MgSO4 and concentrated in vacuo to a brown foam. Purification by silica gel flash chromatography (30-50% EtOAc/petroleum ether) followed by reverse phase C-18 MPLC (70-80% methanol/H2O) gave 0.15 g of the title compound as a white powder: 1H NMR (d6 -DMSO 300 MHz) δ10.78 (s,1H), 7.57 (d, 1H, J=6), 7.5-6.9 (m, 16H), 6.69 (d, 1H, J=8), 4.82 (m, 1H), 4.26 (m, 2H), 3.79 (s, 3H), 3.56 (q, 2H, J=16), 0.99 (t, 6H, J=7); low resolution MS (FAB) m/e 617 (MH+).
Reaction SMILES: [CH2:1]([N:8]([CH2:12][Si](C)(C)C)[CH2:9]OC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:17][C:18]([F:32])([F:31])[O:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22](/[CH:26]=[CH:27]/[N+:28]([O-:30])=[O:29])[CH:21]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([N:8]1[CH2:9][C@@H:27]([N+:28]([O-:30])=[O:29])[C@H:26]([C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([O:19][C:18]([F:17])([F:31])[F:32])[CH:21]=2)[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])/C=C/c1cccc(OC(F)(F)F)c1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])[C@@H]1CN(Cc2ccccc2)C[C@H]1c1cccc(OC(F)(F)F)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
N-benzyl-1-methoxy-N-[(trimethylsilyl)methyl]methanamine was added to a solution of 1-trifluoromethoxy-3-((E)-2-nitro-vinyl)-benzene (6.00 g; 35.90 mmol) in DCM (50 ml). The reaction solution was cooled to 0° C., TFA (0.30 ml; 3.95 mmol) was added dropwise, and stirred overnight at RT. The reaction solution was washed with H2O and brine, dried over MgSO4, filtered, and concentrated. The crude material was purified via Biotage (340 g column) eluting with 5% EtOAc in hexane to provide the desired product 5.5 g, yield 51%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:28][C:29]1[CH:30]=[C:31]([CH:34]=[C:35]([F:37])[CH:36]=1)[CH2:32]Cl>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:32][C:31]2[CH:30]=[C:29]([F:28])[CH:36]=[C:35]([F:37])[CH:34]=2)=[CH:4][CH:3]=1
Reactant: Fc1cc(F)cc(CCl)c1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Product: O=C1OC2(CCN(C(=O)c3cn(Cc4cc(F)cc(F)c4)c4cc(Cl)ccc34)CC2)c2ccccc21

Procedure:
Following the general procedure III as described above, the acylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 16 above) with commercially available 3,5-difluorobenzyl chloride gave the title compound. ES-MS m/e (%): 507.4 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][N:8]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([C:30]1[CH:31]=[CH:32][C:33]([O:37][CH3:38])=[C:34]([OH:36])[CH:35]=1)[S:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)[CH2:7][CH2:6]2.S(C1C=CC(C)=CC=1)(O[CH2:43][CH2:44][Cl:45])(=O)=O.[H-].[Na+]>CC(=O)CC>[Cl:45][CH2:44][CH2:43][O:36][C:34]1[CH:35]=[C:30]([CH:21]([S:22][C:23]2[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:9]2)[CH:31]=[CH:32][C:33]=1[O:37][CH3:38]
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Reactant: COc1ccc(C(CCCCCCN2CCc3cc(OC)c(OC)cc3C2)Sc2ccc(C)cc2)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: COc1cc2c(cc1OC)CN(CCCCCCC(Sc1ccc(C)cc1)c1ccc(OC)c(OCCCl)c1)CC2
Temperature: 25 °C

Procedure:
To a stirred solution of 5.57 g of 5-[7-(3,4-dihydro-6,7-dimethoxy-2(1H) -isoquinolinyl)-1-[(4-methylphenyl) thio]heptyl ]-2-methoxyphenol and 2.0 mL of 2-chloroethyl tosylate in 50 mL of 2-butanone is added 0.44 g of 60% sodium hydride in oil. The solution is heated to reflux for 48 hours and then cooled to room temperature. The solution is partitioned between chloroform and brine and the organic layer dried. The solvent is removed at reduced pressure and the residue chromatographed on silica gel with a gradient elution going from hexane to chloroform to methyl alcohol. The desired fractions are concentrated, dissolved in diethyl ether and passed through a short hydrous magnesium silicate pad. The solvent is removed at reduced pressure to afford 1.6 g of the desired product as a light tan gum. MS(CI): m/z 598(M+H+) and 474(M-(TolSH)+H+). Calcd for C34H44ClNSO4 : C=68.26, H=7.41, N=2.34, Cl=5.93, S=5.36 Found C=68.41, H=7.01, N=2.12, Cl=5.71, S=5.15
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:15][CH:16]=[CH:17][C:18]=2[CH2:19][OH:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N2CCN(CC2)C1.[S:29](Cl)([C:32]1[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=1)(=[O:31])=[O:30]>C(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:15][CH:16]=[CH:17][C:18]=2[CH2:19][O:20][S:29]([C:32]2[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2occc2CO)CC1
Agent: C1CN2CCN1CC2
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCc2ccoc2C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 48.6 %

Procedure:
4-(3-Hydroxymethylfuran-2-yl)piperidine-1-carboxylic acid t-butyl ester (0.3 g, 1.1 mmol, 1.0 eq.) was dissolved in DCM (5.7 mL). The mixture was cooled to 0° C. and DABCO (132 mg, 1.2 mmol, 1.1 eq.) was added, followed by TsCl (224 mg, 1.2 mmol, 1.1 eq.). The mixture was stirred at 0° C. for 90 minutes, then diluted with EtOAc (500 mL) and washed with water (2×250 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation to yield the title compound (233 mg), which was used without further purification.
Reaction SMILES: [H-].[Na+].[S:3]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:7][C:6]=2[CH:5]=[CH:4]1.[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15]Cl.Cl>C1COCC1.C1(C)C=CC=CC=1>[CH:18]1[CH:19]=[CH:20][C:13]([Cl:12])=[C:14]([CH2:15][N:8]2[CH2:7][C:6]3[CH:5]=[CH:4][S:3][C:11]=3[CH2:10][CH2:9]2)[CH:17]=1
Reactant: ClCc1ccccc1Cl
Reactant: c1cc2c(s1)CCNC2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Clc1ccccc1CN1CCc2sccc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (0.42 g, 8.6 mmole) in THF (5.0 ml) is added a solution of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine (1.0 g, 7.2 mmole), prepared, for example, as described in Example 4B, in THF (10 ml). The mixture is stirred under a nitrogen atmosphere at room temperature for 30 minutes and o-chlorobenzyl chloride (1.74 g, 10.8 mmole) is added. After stirring at room temperature for 90 minutes, toluene (15 ml) is added and the mixture is heated to reflux for 15 to 20 hours. Disappearance of starting material is confirmed by TLC. The mixture is then cooled to room temperature and acidified with 40 ml 1N hydrochloric acid. The organic layer is separated. The aqueous layer is extracted with 50 ml of toluene. The aqueous layer is then separated and basified with dilute aqueous sodium hydroxide to pH 13-14. The product is extracted into methylene chloride (3×40 ml). The methylene chloride extracts are washed (1×50 ml water) and (1×50 ml salt solution) then dried over anhydrous magnesium sulfate and concentrated to give the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:24])([C:18]3[N:22]([CH3:23])[N:21]=[CH:20][N:19]=3)[C:16](=O)[C:15]3[C:14]([C:26]([O:28]CC)=O)=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9]2)=[CH:4][CH:3]=1.O.[NH2:32][NH2:33]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:9][C:10]3[C:15]4[C:16](=[N:32][NH:33][C:26](=[O:28])[C:14]=4[CH:13]=[CH:12][CH:11]=3)[C:17]2([CH3:24])[C:18]2[N:22]([CH3:23])[N:21]=[CH:20][N:19]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cccc2c1C(=O)C(C)(c1ncnn1C)C(c1ccc(F)cc1)N2
Reactant: NN
Solvent: CO
Solvent: O
Product: Cn1ncnc1C1(C)c2n[nH]c(=O)c3cccc(c23)NC1c1ccc(F)cc1
Yield: 54 %

Procedure:
A mixture of ethyl 2-(4-fluorophenyl)-3-methyl-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (80 mg, 0.19 mmol) in 85% hydrazine monohydrate (5 mL) and methanol (1 mL) was stirred under reflux overnight. The resulting solution was cooled and filtered, washed the cake by methanol (2 mL) to obtain a white solid, dried in vacuum at 55° C. to obtain the title compound (40 mg, yield 54%). LC-MS (ESI) m/z: 377 (M+1)+; 1H-NMR (400 MHz, DMSO-d) δ (ppm): 1.83 (s, 3H), 2.86 (s, 3H), 4.61 (s, 1H), 6.88-6.92 (m, 2H), 7.11-7.169 (t, J=8.8 Hz, 2H), 7.19-7.22 (d, J=8.0 Hz, 1H), 7.41 (s, 1H), 7.47-7.49 (m, 1H), 7.60-7.64 (t, J=8.0 Hz, 1H), 7.72 (s, 1H), 12.40 (s, 1H).
Reaction SMILES: [N:1]([CH:4]([C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([Cl:13])=[C:8]([I:14])[C:7]=1[O:15][CH3:16])[CH3:5])=[N+]=[N-].CP(C)C>O1CCCC1.O>[Cl:13][C:9]1[C:10]([Cl:12])=[CH:11][C:6]([CH:4]([NH2:1])[CH3:5])=[C:7]([O:15][CH3:16])[C:8]=1[I:14]
Reactant: COc1c(C(C)N=[N+]=[N-])cc(Cl)c(Cl)c1I
Agent: CP(C)C
Solvent: C1CCOC1
Solvent: O
Product: COc1c(C(C)N)cc(Cl)c(Cl)c1I
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 71.4 %

Procedure:
A solution of 1-(1-azidoethyl)-4,5-dichloro-3-iodo-2-methoxybenzene (3.3 g, 8.9 mmol) in tetrahydrofuran (20 mL) and water (6.4 mL) was treated with 1.0 M trimethylphosphine in tetrahydrofuran (11 mL, 11 mmol) and stirred at 20° C. for 1.5 hours. The reaction mixture was concentrated, diluted with ethyl acetate and extracted with 1 M HCl (2×). The combined aqueous layers were neutralized with solid sodium bicarbonate, and extracted with ethyl acetate (2×). The combined organic extracts were washed with brine, dried with magnesium sulfate, filtered, and concentrated to give the desired product (2.2 g, 72%). This material was used without further purification. LCMS for C9H8Cl2IO (M−NH2)+: m/z=328.9, 330.9. Found: 328.8, 330.8.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO.O>[CH2:12]([NH:19][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCc1ccccc1
Reactant: ClCCCOc1cccnc1
Solvent: O
Solvent: CO
Product: c1ccc(CNCCCOc2cccnc2)cc1
Temperature: 120 °C
Yield: 2.2 %

Procedure:
The 3-chloro-1-(3-pyridyloxy)propane (0.65 g, 3.78 mmol) was dissolved in methanol (20 mL) and added to a mixture of benzylamine (13.5 mL) in water (20 mL) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 120° C. (oil bath temperature) for 3 h. After cooling, the mixture was concentrated by rotary evaporation, and saturated NaCl solution (25 mL) was added to the residue. The mixture was acidified to pH 1 with 10% HCl solution and extracted with CHCl3 (2×35 mL) to remove impurities. The aqueous phase was basified to pH 10 with 100% NaOH solution, and the mixture was extracted with chloroform (4×50 mL). The combined chloroform extracts were dried (MgSO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give a brown oil. The oil was concentrated by vacuum distillation to remove excess benzylamine (bp 85° C. at 15 mm Hg). The remaining residue (0.483 g) was purified by column chromatography on silica gel (25g) eluting with CH3OH—NH4OH (50:1, v/v). Fractions containing the product (Rf 0.39) were combined and concentrated on a rotary evaporator. The residue was re-chromatographed on silica gel (10 g). Fractions containing the product were combined and concentrated on a rotary evaporator. The residue was dissolved in CHCL3 and the CHCL3 solution was dried (MgSO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 20 mg (2.2%) of a light-brown oil. The compound exhibits a Ki of 3000 nM. The compound exhibits neurotransmitter release of 29 percent.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[CH3:9].C1C(=O)N([Br:17])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.O>C(Cl)(Cl)(Cl)Cl>[Br:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:9][Br:17])=[C:2]([Cl:1])[CH:7]=1
Reactant: Cc1ccc(Br)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cc(Br)ccc1CBr
Yield: 55.3 %

Procedure:
5.0 g of 2-chloro-4-bromotoluene are dissolved in 120 ml of CCl4. 4.3 g of NBS and 1.6 g of AIBN are added. The mixture is heated at reflux for 15 hours, water is added, the two phases are separated and then extraction is carried out with CH2Cl2. Purification is carried out by chromatography on a silica column eluted with petroleum ether. 3.8 g of liquid are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[C:21]([CH3:28])=[C:20]([CH3:29])[C:19]=2[OH:30])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:33]I.O>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[C:21]([CH3:28])=[C:20]([CH3:29])[C:19]=2[O:30][CH3:33])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1
Reactant: CI
Reactant: COC(=O)CCCCCC(c1ccc(F)cc1)c1c(O)c(C)c(C)c2c1CCCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCCCC(c1ccc(F)cc1)c1c2c(c(C)c(C)c1OC)CCCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of methyl 7-(4-fluorophenyl)-7-(2-hydroxy-3,4-dimethyl-5,6,7,8-tetrahydronaphthyl)heptanoate (0.5 g) in dimethylformamide (1 ml) was added to a mixture of 60% sodium hydride (51 mg) and dimethylformamide (2 ml) at 0° C. The reaction mixture was stirred at room temperature for 30 minutes. Methyl iodide (82 ml) was added dropwise and the mixture was stirred at the same temperature for 2 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography to obtain methyl 7-(4-fluorophenyl)-7-(2-methoxy-3,4-dimethyl-5,6,7,8-tetrahydronaphthyl)heptanoate (0.4 g) (Compound 58). The physical properties and spectrum data thereof are shown in Tables 3 and 4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([SH:22])[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[C:23]1(C)C=CC(S(OCCOS(C2C=CC(C)=CC=2)(=O)=O)(=O)=O)=C[CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]3[C:11]([S:22][CH2:23][CH2:24]3)=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2nc(S)[nH]c2-c2ccc(OC)cc2)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc3n(c2-c2ccc(OC)cc2)CCS3)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 61.7 %

Procedure:
A mixture of 46.8 g (0.15 mole) of 4,5-bis(p-methoxyphenyl)-2-mercaptoimidazole, 55.5 g (0.15 mole) of ethylene glycol di-p-toluenesulfonate [Helv. Chim Acta 29 1675 (1946); Chem Abs. 41 1641 g] and 45.5 g (0.33 mole) potassium carbonate in 500 ml dimethylformamide was stirred at room temperature for 3 days. The mixture was poured into ice water and the precipitated product was collected and washed with water. Recrystallization from 1200 ml ethanol gave 31.3 g (61%) of product, m.p. 155°-8°.