Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([C:15](=[O:17])[NH2:16])[CH:14]=1)[NH:11][C:10]1[CH:9]=[C:8]([C:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:19]=3)[CH:7]=[CH:6][C:5]2=1.[CH:31]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][C:34]=1[CH3:42])=[O:32].C([O-])([O-])=O.[Na+].[Na+]>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>[C:15]([C:13]1[CH:14]=[C:2]([C:36]2[CH:37]=[CH:38][C:33]([CH:31]=[O:32])=[C:34]([CH3:42])[CH:35]=2)[CH:3]=[C:4]2[C:12]=1[NH:11][C:10]1[CH:9]=[C:8]([C:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[CH2:20][CH:19]=3)[CH:7]=[CH:6][C:5]2=1)(=[O:17])[NH2:16]
Reactant: Cc1cc(B(O)O)ccc1C=O
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc3c(c2)[nH]c2c(C(N)=O)cc(Br)cc23)CC1
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+]
Product: Cc1cc(-c2cc(C(N)=O)c3[nH]c4cc(C5=CCN(C(=O)OC(C)(C)C)CC5)ccc4c3c2)ccc1C=O
Reaction time: 4 h

Procedure:
To the reaction mixture above (483A) was added 4-formyl-3-methylphenylboronic acid (103 mg, 0.627 mmol), Pd(Ph3P)4 (11.14 mg, 9.64 μmol) and Na2CO3 (0.482 mL, 0.964 mmol). The mixture was stirred at 105 C for 4 hrs. The mixture was filtered and then purified using preparative HPLC to give titled product. MS (ESI) m/z 508.31 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:14](Cl)=[O:15])=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[O:17]1[CH2:21][CH2:20][C@H:19]([NH2:22])[CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Cl:1][C:2]1[C:3]([C:14]([NH:22][C@H:19]2[CH2:20][CH2:21][O:17][CH2:18]2)=[O:15])=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1
Reactant: N[C@H]1CCOC1
Reactant: O=C(Cl)c1noc(-c2ccc(Cl)cc2)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(N[C@H]1CCOC1)c1noc(-c2ccc(Cl)cc2)c1Cl
Reaction time: 48 h

Procedure:
A mixture of 4-chloro-5-(4-chlorophenyl)isoxazole-3-carbonyl chloride (24 mg, 0.087 mmol), (S)-tetrahydrofuran-3-amine (13 μL, 0.13 mmol), and potassium carbonate (36 mg, 0.261 mmol) in dichloromethane (1 mL) was stirred for 48 hours. The volatiles were removed in vacuo, and the residue was purified by silica gel chromatography, eluting with dichloromethane 5% methanol in dichloromethane to afford the title compound: (19.1 mg, 0.059 mmol). MS (ESI) m/z (M+H+): 327.2/329.2.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.Cl.[CH3:8][N:9]1[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1.[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.C(N(CC)CC)C.[OH-].[Na+]>C1COCC1.O.CN(C=O)C>[CH3:8][N:9]1[CH2:10][CH2:11][CH:12]([C:15]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])[CH2:13][CH2:14]1
Reactant: C1CCNC1
Reactant: CN1CCC(C(=O)O)CC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CN1CCC(C(=O)N2CCCC2)CC1
Temperature: 5 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
Add oxalyl chloride (5.08 mL, 0.058 mol) dropwise to a suspension of 1-methyl-4-carboxypiperidine HCl (10 g, 0.056 mol) in THF (100 mL) in the presence of a catalytic amount of DMF (0.1 mL) at room temperature. Stir for 1 hr. and then heat the mixture at reflux until gas emission stops (about 1 hr.). Cool the white suspension to 5° C. and add a solution of pyrrolidine (7.92 g, 0.111 mol) and triethylamine (16.9 g, 0.167 mol) dropwise over 30 min at a temperature between 5 and 13° C. Stir the suspension for 30 min. at 10° C. and then warm to room temperature. Quench the reaction mixture by adding 30% NaOH (20 mL, 0.2 mol) and water (10 mL). Decant the aqueous layer and extract with THF (200 mL). Combine the organic layers, dry over Na2CO3, and evaporate under vacuum at 40° C. Solubilize the resulting oil in cyclohexane (200 mL). Evaporate under reduced pressure at 40° C. to give a white solid (11 g). Heat the white solid (11 g) under reflux in cyclohexane (50 mL) until completely dissolved. Cool the solution to room temperature and stir at room temperature for 2 hr. Filter the suspension wash the crystals with cyclohexane (10 mL). Dry the white crystals under reduced pressure at 40° C. to provide the title intermediate (7.76 g, 75% yield).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH2:8][CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11])=[O:5])#[N:2].C=O.N1CCCC[CH2:17]1.O>C(OC(=O)C)CCC>[C:1]([C:3](=[CH2:17])[C:4]([O:6][CH2:7][CH2:8][CH2:9][Si:10]([CH3:11])([CH3:13])[CH3:12])=[O:5])#[N:2]
Reactant: C1CCNCC1
Reactant: C[Si](C)(C)CCCOC(=O)CC#N
Agent: C=O
Solvent: CCCCOC(C)=O
Solvent: O
Product: C=C(C#N)C(=O)OCCC[Si](C)(C)C

Procedure:
3-trimethylsilylpropyl 2-cyanoacetate (31.84 g, 0.16 moles) prepared as described in Example 1, was added dropwise over 10 minutes to a stirred solution of paraformaldehyde (4.8 g, 0.16 moles formaldehyde) and piperidine (0.12 g) in n-butylacetate at 70° C. The mixture was heated under reflux in a Dean-Stark apparatus until the quantitative amount of water expected from formaldehyde condensation had been collected (2.8 g). The mixture was allowed to cool and phosphorous pentoxide (0.57 g), p-toluenesulfonic acid (1.09 g) and 1,4-hydroquinone (2.18g) were added. The solvent was removed by distillation under reduced pressure to yield a viscous, orange/yellow coloured liquid. The liquid was fractionated under reduced pressure to give crude monomer (16.80 g b.p. 150°-180° C. at 0.7-10 mbar). Vacuum distillation of the crude material onto a catalytic quantity of methanesulfonic acid and 1,4-hydroquinone (10-4 g) afforded the pure product 3-trimethylsilylpropyl 2-cyanoacrylate as a slightly yellow coloured reactive liquid (12.45 g, 37%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=2)=[O:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].Br.[Br:32][CH2:33][CH2:34][NH2:35].C(N(CC)CC)C>C1COCC1>[Br:32][CH2:33][CH2:34][NH:35][S:27]([C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:18](=[O:19])[CH2:17][CH2:16][C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:8]=2)=[CH:22][CH:23]=1)(=[O:29])=[O:28]
Reactant: NCCBr
Reactant: CC(C)(C)c1cc(CCC(=O)Nc2ccc(S(=O)(=O)Cl)cc2)cc(C(C)(C)C)c1O
Agent: Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(CCC(=O)Nc2ccc(S(=O)(=O)NCCBr)cc2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 20 h
Yield: 51.6 %

Procedure:
To a stirred suspension of 4-[3-(3,5-di-tert-butyl-4-hydroxy-phenyl)-propionylamino]-benzenesulfonyl chloride (4.38 g, 0.0097 mol) and 2-bromoethylamine hydrobromide (2.11 g, 0.0103 mol) in THF (30 g) at 0-2° C. under nitrogen was added dropwise a solution of triethylamine (2.01 g, 0.0199 mol) in THF (9 g). When addition was complete, the reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was filtered and the filtrate was spin evaporated in vacuo. The residue was chromatographed over silica (toluene/acetone 75:25) to give 2.7 g of N-[4-(2-bromoethylsulfamoyl)-phenyl]-3-(3,5-di-tert-butyl -4-hydroxy-phenyl)-propionamide as a white crystalline solid, mp 153-155° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([SH:12])[CH:6]=[CH:5]2.F[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([C:22]([F:23])([F:25])[F:24])[CH:15]=1)[CH:6]=[CH:5]2
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Reactant: Sc1ccc2cc(Br)ccc2c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: N#Cc1ccc(Sc2ccc3cc(Br)ccc3c2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 6-bromonaphthalene-2-thiol (956 mg) and 4-fluoro-2-trifluoromethyl benzonitrile (756 mg) in dimethylformamide (15 ml), at ambient temperature, was treated dropwise with triethylamine (504 mg). After stirring at ambient temperature for 3 hours the reaction mixture was diluted with ethyl acetate (100 ml), washed with water (3×25 ml) and brine (25 ml), dried (MgSO4) and evaporated to give a yellow oil. Crystallisation from methanol (20 ml) gave 4-(6-bromonaphth-2-ylthio)-2-trifluoromethylbenzonitrile (1.176 g, mp 114-116° C.;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:27])[C:10]2([NH:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([Cl:8])[CH:7]=1)[C:9]([C:10]1([NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1)=[O:27]
Reactant: Cc1ccc(S(=O)(=O)NC2(C(O)c3cc(Cl)cc(Cl)c3)CCCCC2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC2(C(=O)c3cc(Cl)cc(Cl)c3)CCCCC2)cc1
Reaction time: 6 h

Procedure:
To a stirred solution of N-{1-[(3,5-dichloro-phenyl)-hydroxy-methyl]-cyclohexyl}4-methyl-benzenesulfonamide in CH2Cl2 (4 mL) was added Dess-Martin reagent. The mixture was stirred for 6 hours and saturated aqueous NaHCO3 (5 mL) and solid Na2S2O3 (ca. 1 g) were added. After stirring for 30 min, the mixture was applied to a 10 mL Chem Elut cartridge and allowed to stand for 5 min. The cartridge was eluted with CH2Cl2 (25 mL) and the eluate was evaporated to leave the intended ketone (102 mg) as an oil. The crude product was dissolved in CH2Cl2 (4 mL) and stirred with PS-TsNHNH2 resin (100 mg, 0.28 mmol) for 3 hours. The mixture was filtered and washed with CH2Cl2 (5 mL), ether (5 mL), and CH2Cl2 (5 mL). The filtrate was evaporated to leave N-[1-(3,5-dichloro-benzoyl)-cyclohexyl]4-methyl-benzenesulfonamide (98 mg) as an oil. 1H NMR (500 MHz, CDCl3) δ(ppm): 7.8 (s, 2H), 7.6 (d, 2H), 7.4 (s, 1H), 7.2 (d, 2H), 5.75 (s, 1H), 2.35 (s, 3H), 1.9 (m, 2H), 1.8 (m, 2H), 1.4 (m, 3H), 1.3 (m, 2H), 1.2 (m, 1H).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[NH2:11][C:12]1[C:17]([CH2:18][O:19][CH3:20])=[C:16]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:15]([C:28](OC)=[O:29])=[C:14]([CH:32]([CH3:34])[CH3:33])[N:13]=1.C1(C)C=CC=CC=1.O>C(OCC)(=O)C>[NH2:11][C:12]1[C:17]([CH2:18][O:19][CH3:20])=[C:16]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:15]([CH2:28][OH:29])=[C:14]([CH:32]([CH3:34])[CH3:33])[N:13]=1
Reactant: COCc1c(N)nc(C(C)C)c(C(=O)OC)c1-c1ccc(F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COCc1c(N)nc(C(C)C)c(CO)c1-c1ccc(F)cc1
Reaction time: 1 h

Procedure:
140 ml (210 mmol) of a 1.5 M solution of diisobutylaluminum hydride are added dropwise at 78° C. to -75° C. under argon to a solution of 23.1 g (70 mmol) of the compound of Example 30 in 1 1 of toluene and the mixture is stirred at this temperature for 1 h. While it is allowed to warm, 40 ml of water and 50 ml of ethyl acetate are added dropwise, kieselguhr is added, filtered off with suction and washed with ethyl acetate. The aqueous phase is extracted with ethyl acetate, and the combined organic phases are washed with saturated NaCl solution and dried over sodium sulphate. The solution is concentrated to dryness and the residue is thoroughly stirred in ether.
Reaction SMILES: [CH3:1][NH:2][C:3](SC)=[CH:4][N+:5]([O-:7])=[O:6].[F:10][C:11]([F:23])([F:22])[C:12]1[CH:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([NH:20][NH2:21])[CH:13]=1>C(O)C>[CH3:1][NH:2][C:3]([NH:21][NH:20][C:14]1[CH:13]=[C:12]([C:11]([F:23])([F:22])[F:10])[CH:17]=[C:16]([O:18][CH3:19])[N:15]=1)=[CH:4][N+:5]([O-:7])=[O:6]
Reactant: CNC(=C[N+](=O)[O-])SC
Reactant: COc1cc(C(F)(F)F)cc(NN)n1
Solvent: CCO
Product: CNC(=C[N+](=O)[O-])NNc1cc(C(F)(F)F)cc(OC)n1
Temperature: 25 °C
Yield: 27.7 %

Procedure:
4.7 g of N-methyl-1-methylthio-2-nitroetheneamine, 6.6 g of crude 4-trifluoromethyl-6-methoxy-2-pyridylhydrazine (Intermediate No. 71) and 35 ml of ethanol were stirred for about 5.5 hours under heating and refluxing and then cooled to room temperature, whereupon precipitated crystals were collected by filtration. The crystals obtained by filtration were washed with a small amount of methanol and then dried to obtain 2.7 g of N-methyl-1-(2-(4-trifluoromethyl-6-methoxy-2-pyridyl)hydrazino)-2-nitroetheneamine (Compound No. 98) having a melting point of 193° C. (decomposed).
Reaction SMILES: Cl.[C:2]([CH2:5][CH:6]([OH:23])[CH2:7][NH:8][CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[CH:15]=2)[CH2:10]1)(O)=[O:3].C[Si](N[Si](C)(C)C)(C)C>C1(C)C(C)=CC=CC=1>[CH3:20][O:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:21][CH3:22])[CH2:10][CH:9]([N:8]1[CH2:7][CH:6]([OH:23])[CH2:5][C:2]1=[O:3])[CH2:18][CH2:17]2
Reactant: COc1cc2c(cc1OC)CC(NCC(O)CC(=O)O)CC2
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Solvent: Cc1ccccc1C
Product: COc1cc2c(cc1OC)CC(N1CC(O)CC1=O)CC2
Reaction time: 24 h
Yield: 71 %

Procedure:
To N-(3-carboxy-2-hydroxypropyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-2-napthylamine hydrocloride (ST 576, prepared as described in the Italian patent application 47652A/88) (1 g, 2.89 mmoles) in xylene (40 mL), 1.2 mL HMDS and TMSCI (few drops) were added. The resulting mixture was refluxed under stirring for 24 hours. Xylene was evaporated, the residue was taken up with EtOH (40 mL) and 1N HCl in isopropanol (1 mL) was added thereto. After 5 minutes, NaHCO3 was added till neutrality, the mixture was filtered and the filtrate evaporated. The residue was chromatographed on silica gel using EtOAc--MeOH (95:5) as eluant. 600 mg of the title compound were obtained. Yield 71%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[F:10][C:11]([F:15])([F:14])[CH2:12]I.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH2:12][C:11]([F:15])([F:14])[F:10])[CH:4]=1
Reactant: FC(F)(F)CI
Reactant: COc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(OCC(F)(F)F)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
A suspension of 5.00 g of 3-methoxy phenol, 10.0 g of 2,2,2-trifluoroethyl iodide and 20.0 g of cesium carbonate in DMF (15 ml) was stirred at 80° C. for two hours. The solution was added with water and extracted with Et2O; the organic layer was washed in saturated brine, then, was dried in MgSO4, the drying agent was separated by filtration and solvent was evaporated under reduced pressure obtained 6.60 g of the title compound.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[C:19]([CH3:20])=[CH:18][C:12]2[CH:13]([CH3:17])[C:14](=[O:16])[O:15][C:11]=2[CH:10]=1)C1C=CC=CC=1.[H][H]>O1CCOCC1.[Pd]>[NH2:8][C:9]1[C:19]([CH3:20])=[CH:18][C:12]2[CH:13]([CH3:17])[C:14](=[O:16])[O:15][C:11]=2[CH:10]=1
Reactant: Cc1cc2c(cc1N(Cc1ccccc1)Cc1ccccc1)OC(=O)C2C
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Product: Cc1cc2c(cc1N)OC(=O)C2C

Procedure:
4 g of 6-dibenzylamino-3,5-dimethylbenzofuran-2(3H)-one are dissolved in 40 ml of dioxane and reduction is carried out at room temperature, under normal pressure, with hydrogen and with 0.4 g of palladium-on-carbon. The mixture is then filtered, and the filtrate is concentrated to dryness by evaporation and recrystallised from methanol. In this manner 6-amino-3,5-dimethylbenzofuran-2(3H)-one having a melting point of 123°-124° C. is obtained.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH2:13]Br)[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][N:22]([CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH2:13][N:22]([CH2:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=2)[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: COC(=O)c1cc(CBr)cc(CBr)c1
Reactant: c1ccc(CNCc2ccccn2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(CN(Cc2ccccn2)Cc2ccccn2)cc(CN(Cc2ccccn2)Cc2ccccn2)c1

Procedure:
Methyl 3,5-bis(bromomethyl)-benzoate (500 mg, 1.6 mmol) and di-(2-picolyl)-amine (800 mg, 725 μL, 4 mmol) were dissolved in ACN followed by the addition of dry K2CO3 (1.1 g, 7.9 mmol). The reaction mixture was refluxed overnight under reflux condenser equipped with a CaCl2 tube. The reaction mixture was filtered and filtrate was evaporated under reduced pressure. Yellow residue was purified by flash chromatography (Al2O3 neutral, firstly AcOEt was used to elute impurities and then MeOH/AcOEt=1:9 (v/v)) affording a pure product as a yellow oil. Yield: 850 mg (95%). 1H NMR (500 MHz, CDCl33) δ 8.51 (m, 4H), 7.94 (d, J=1.5 Hz, 2H), 7.70 (s, 1H), 7.61 (m, 8H), 7.12 (m, 4H), 3.92 (s, 3H), 3.81 (s, 8H), 3.73 (s, 4H). 13C NMR (101 MHz, CDCl3) δ 197.9, 167.1, 159.5, 148.9, 139.7, 136.2, 133.8, 130.2, 128.7, 122.8, 121.9, 60.1, 58.2, 52.0. MS (ESI, m/z): calculated: 558.7 observed: 559.5 [M+H]+.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3]1.C(N(CC)CC)C.Cl[C:21]1[N:26]=[C:25]([NH2:27])[C:24]([N+:28]([O-:30])=[O:29])=[CH:23][CH:22]=1.O>C(#N)C>[NH2:27][C:25]1[N:26]=[C:21]([N:2]2[CH2:7][CH2:6][CH2:5][C@@H:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3]2)[CH:22]=[CH:23][C:24]=1[N+:28]([O-:30])=[O:29]
Reactant: CCOC(=O)[C@@H]1CCCNC1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)[C@@H]1CCCN(c2ccc([N+](=O)[O-])c(N)n2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.7 %

Procedure:
To a solution of (R)-ethyl piperidine-3-carboxylate hydrochloride salt (1.2 g, 6.21 mmol) in acetonitrile (20 mL) was added triethylamine (2.61 mL, 18.64 mmol). The mixture was stirred for 10 min at room temperature. 6-Chloro-3-nitropyridin-2-amine (753 mg, 4.31 mmol) was added and the reaction mixture was stirred at 80° C. for 3 h. The mixture was cooled to room temperature and water was added. The mixture was extracted with ethyl acetate. The organics were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford (R)-ethyl 1-(6-amino-5-nitropyridin-2-yl)piperidine-3-carboxylate (1.1 g). MS (ES+APCI) (M+H) 295.2.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][OH:19])[CH2:14][CH2:13]1.[H-].[Na+]>CS(C)=O>[CH3:11][N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][O:19][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: CN1CCC(CO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN1CCC(COc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 40 °C
Reaction time: 2 h
Yield: 69.4 %

Procedure:
To a mixture of p-chloro nitrobenzene (6.0 g, 38 mmol) and 1-methyl-4-piperidinemethanol (4.91 g, 38 mmol) in anhydrous DMSO (60 mL) was added NaH (1.82 g, 45.6 mmol) in small portions at room temperature under N2-atmosphere. After the addition was complete the reaction mixture was warmed at 40° C. and stirred for another 2 h. The reaction was quenched with water, and the product was extracted with EtOAc. The organic layer was washed with brine and dried over Na2SO4. The crude product was recrystallized from ether to yield 6.6 g (69%) of the title compound as an orange solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.59-1.72 (m, 2H) 1.92 (d, J=11.37 Hz, 3 H) 2.19 (t, J=11.49 Hz, 2H) 2.44 (s, 3H) 3.09 (d, J=11.12 Hz, 2H) 3.93 (d, J=5.31 Hz, 2 H) 6.93 (d, J=9.2 Hz, 2H) 8.20 (d, J=9.6 Hz, 2H); [M+H] calc'd for C13H19N2O3, 251.2; found, 251.4.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]2[CH:25]=[CH:24][C:12]([C:13]([NH:15][C@H:16]([C:21]([OH:23])=[O:22])[CH2:17][CH2:18][S:19][CH3:20])=O)=[C:11]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])[CH:10]=2)[CH:2]=1>C(O)CCC.OS(O)(=O)=O>[CH2:2]([O:23][C:21](=[O:22])[C@H:16]([CH2:17][CH2:18][S:19][CH3:20])[NH:15][CH2:13][C:12]1[CH:24]=[CH:25][C:9]([CH:8]=[CH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:10][C:11]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH3:32])[CH2:3][CH2:4][CH3:5]
Reactant: CSCC[C@H](NC(=O)c1ccc(C=Cc2cccnc2)cc1-c1ccccc1C)C(=O)O
Agent: O=S(=O)(O)O
Solvent: CCCCO
Product: CCCCOC(=O)[C@H](CCSC)NCc1ccc(C=Cc2cccnc2)cc1-c1ccccc1C
Yield: 86 %

Procedure:
{4-[2-(pyrid-3-yl)ethenyl]-2-(2-methylphenyl)benzoyl}methionine (138 mg, 0.30 mmol) was heated at 100° C. for 2 hours in n-butanol (5 mL) with 1 drop of H2SO4. The reaction was evaporated to dryness, partitioned between ethyl acetate and 5% NaHCO3, washed with water and brine, and dried over Na2SO4 to provide the title compound in 86% yield. 1H NMR (CDCl3, 300 MHz) δ 0.92 (t, 3H), 1.35 (m, 2H), 1.60 (m, 2H), 1.86 (m, 1H), 2.1 (m, 9H), 4.08 (m, 2H), 4.62 (m, 1H), 5.97 (d, 1H), 7.18-8.04 (m, 1H), 8.53 (s, 1H), 8.77 (s, 1H). MS m/e 503 (M+H)+.
Reaction SMILES: [CH3:1][NH:2]CCNC.I[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[C@@H:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[CH2:22][N:23]([CH3:25])[CH3:24].[C-]#N.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.[Cu]I>[CH3:24][N:23]([CH2:22][C@@H:18]1[CH2:19][CH2:20][CH2:21][C@H:17]1[C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[C:8]([C:1]#[N:2])[CH:9]=2)[NH:13][CH:12]=1)[CH3:25]
Reactant: CN(C)C[C@@H]1CCC[C@H]1c1c[nH]c2ccc(I)cc12
Reactant: CNCCNC
Agent: [Cu]I
Agent: [C-]#N
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CN(C)C[C@@H]1CCC[C@H]1c1c[nH]c2ccc(C#N)cc12
Temperature: 125 °C
Yield: 82.6 %

Procedure:
N,N′-dimethylethylenediamine (5.66 mL, 53 mMol) was added to a mixture of trans [2-(5-iodo-1H-indol-3-yl)-cyclopentylmethyl]-dimethylamine (19.4 g, 53 mMol), sodium cyanide (3.1 g, 63 mMol), and copper(I) iodide (1 g, 5.3 mMol) in deoxygenated anhydrous toluene (50 mL). The resulting mixture was heated in an oil bath to 125° C. under N2 for ˜18 h. The reaction was cooled to 50° C., diluted with ethyl acetate (400 mL), and heated to reflux for 5 min. The resulting suspension was transferred to a separatory funnel and washed with aqueous NaHCO3 (400 mL and twice with 200 mL). Every aqueous layer was extracted with ethyl acetate (50 mL) to make sure no product was left in aqueous layer. The combined organic layers were dried over MgSO4. Solvent was removed in vacuo to give the crude product which was purified by silica gel chromatography using dichloromethane/2.0 M ammonia in methanol (100/0 to 93/7) as the eluent, to give trans 3-(2-dimethylaminomethyl-cyclopentyl)-1H-indole-5-carbonitrile (11.7 g, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=1.[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:24]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:26])=[O:25])[CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH:16]=1
Reactant: CN1CC=C(c2c[nH]c3ccc(Cl)cc23)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: CCOCC
Product: CN1CC=C(c2cn(S(=O)(=O)c3ccccc3)c3ccc(Cl)cc23)CC1
Yield: 76.2 %

Procedure:
from 5-chloro-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (Example 4d, 25 mg, 0.10 mmol) and phenylsulfonyl chloride (26.4 mg, 0.15 mmol). The HCl salt (29.5 mg, 70%) was prepared from the crude product using 1M HCl in ether; m.p 245-8° C., HRMS-FAB+ for C20H19N2O2SCl.HCl, calculated MH+ (--HCl): 387.09341; found: 387.09262.