Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=C([CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)C#N.Cl.[C:17]([OH:20])(=[O:19])[CH3:18]>>[CH3:3][C:2]1[CH:1]=[C:18]([CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:17]([OH:20])=[O:19]
Reactant: Cc1cc(C#N)ccc1N1CCOCC1
Reactant: CC(=O)O
Agent: Cl
Product: Cc1cc(C(=O)O)ccc1N1CCOCC1
Yield: 91 %

Procedure:
To a solution of 3-methyl-4-morpholinobenzonitrile (1.0 g, 4.9 mmol) in glacial acetic acid (10 mL) was added a 20% aqueous hydrochloric acid solution (60 mL) and the reaction was heated at reflux for 35 h. The acetic acid was evaporated in vacuo and the remaining water solution was alkalized with 2 M aqueous sodium hydroxide solution to pH 8. The solution was washed, twice, with chloroform and the water phase was adjusted to pH 4 with a 2 M aqueous hydrochloric acid solution. The product was filtered off and dried in vacuo to afford 1.0 g (91% yield) of the title compound as white crystals: mp 220-221° C.; EIMS (70 eV) m/z (relative intensity) 221 (100, M+).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.CS(C)=O.[O:16]1[CH:18]2[CH2:19][CH:20]=[CH:21][CH:17]12>O1CCCC1.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>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH:20]3[CH2:21][CH:17]([OH:16])[CH:18]=[CH:19]3)[N:3]=[C:2]([I:1])[C:10]=12
Reactant: C1=CC2OC2C1
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Nc1ncnc2c1c(I)nn2C1C=CC(O)C1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 61.4 %

Procedure:
A mixture of tetrakis(triphenylphosphine)palladium(0) (0.04 g, 0.03 mmol), 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.30 g, 1.14 mmol) and dimethyl sulfoxide (3 mL) was stirred at ambient temperature in the dark for 2 minutes and cooled to 0° C. A solution of 2,4a-dihydro-1aH-cyclopenta[b]oxirene (0.14 g, 1.72 mmol) in tetrahydrofuran (3 mL) was added into the mixture at 0° C. and stirred at 0° C. for 3 hours. The mixture was stirred at ambient temperature overnight and purified by preparative HPLC to yield 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-cyclopenten-1-ol (0.24 g, 0.70 mmol) as a white solid: RP-HPLC (Hitachi HPLC, Hypersil C18, 5 μm, 100A, 250×4.6 mm; 25%-100% acetonitrile—0.05M ammonium acetate over 10 min, 1 mL/min) Rt 4.23 min. MS: MH+ 344.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])/[C:5](/[O:16][CH2:17][CH3:18])=[CH:6]/[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)[CH3:2].Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])[O:25][C:26]=1[CH3:27]>>[CH2:1]([O:3][C:4](=[O:19])/[C:5](/[O:16][CH2:17][CH3:18])=[CH:6]/[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:21][C:22]1[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[Cl:34])[O:25][C:26]=1[CH3:27])[CH:11]=[CH:10]2)[CH3:2]
Reactant: CCOC(=O)/C(=C/c1ccc2[nH]ccc2c1)OCC
Reactant: Cc1oc(-c2ccccc2Cl)nc1CCl
Product: CCOC(=O)/C(=C/c1ccc2c(ccn2Cc2nc(-c3ccccc3Cl)oc2C)c1)OCC

Procedure:
In analogy to the procedures described in examples 36a) and 36b), (Z)-2-ethoxy-3-(1H-indol-5-yl)-acrylic acid ethyl ester [preparation 1a)] was reacted with 4-chloromethyl-2-(2-chloro-phenyl)-5-methyl-oxazole to give (Z)-3-{1-[2-(2-chloro-phenyl)-5-methyl-oxazol-4-ylmethyl]-1H-indol-5-yl}-2-ethoxy-acrylic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:23]([O:25][C:26]([C:28]1[CH:29]=[N:30][C:31](Cl)=[C:32]([N+:35]([O-:37])=[O:36])[C:33]=1[NH2:34])=[O:27])[CH3:24]>C1(C)C=CC=CC=1>[CH2:23]([O:25][C:26]([C:28]1[CH:29]=[N:30][C:31]([N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:32]([N+:35]([O-:37])=[O:36])[C:33]=1[NH2:34])=[O:27])[CH3:24]
Reactant: CCOC(=O)c1cnc(Cl)c([N+](=O)[O-])c1N
Reactant: c1ccc(CNCc2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc(N(Cc2ccccc2)Cc2ccccc2)c([N+](=O)[O-])c1N
Temperature: 25 °C
Yield: 103.3 %

Procedure:
Dibenzylamine (1.95 mL, 10 mmol), triethylamine (1.37 mL, 10 mmol), 4-amino-6-chloro-5-nitro-pyridine-3-carboxylic acid ethyl ester (2.45 g, 10 mmol) and toluene (73 mL) were combined and heated at reflux over night. The reaction mixture was cooled to room temperature and filtered through a short column of silica gel (eluting first with dichloromethane then ethyl acetate). The organics were concentrated to provide 10 as a yellow oil (4.2 g). 1H NMR (400 MHz, d6-DMSO) δ: 1.28 (t, J=7.1 Hz, 3H), 4.25 (q, J=7.1 Hz, 2H), 4.60 (s, 4H), 7.14-7.31 (m, 10H), 8.35 (s, br, 2H), 8.54 (s, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:4]=[C:5](Br)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:15][N:16](C)C=O>O.ClCCl>[CH3:1][N:2]([CH3:14])[C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[C:15]#[N:16]
Reactant: CN(C)c1cc(Br)cc(C(F)(F)F)c1
Reactant: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CN(C)c1cc(C#N)cc(C(F)(F)F)c1

Procedure:
To a solution of 3-dimethylamino-5-trifluoromethylbromobenzene (7.3 g) in N,N-dimethylformamide (20 mL) is added cuprous cyanide (2.7 g) and the reaction heated at reflux for 12 hours. The reaction is diluted with water (40 mL) and dichloromethane is added. The dichloromethane fraction is washed with concentrated ammonium hydroxide, then water. The solution is dried over anhydrous magnesium sulfate, filtered and concentrated to give a yellow solid which is recrystallized from hexanes to give a yellow solid, (4.7 g).
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1)([OH:3])=O.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH2:24][NH2:25].ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.Cl.CN(C)CCCN=C=NCC>>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH2:24][NH:25][C:1]([CH2:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1)=[O:3]
Reactant: O=C(O)Cc1cccc(CC(=O)O)c1
Reactant: COc1ccccc1CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1CCNC(=O)Cc1cccc(CC(=O)O)c1
Yield: 30.5 %

Procedure:
Prepared from (3-carboxymethyl-phenyl)-acetic acid (2.00 g), 2-(2-methoxy-phenyl)-ethylamine (1.60 g), 1-hydroxybenzotriazole (1.40 g), Hunigs base (1.8 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.00 g), using the method of Example 44 (step a), to give 1.03 g of the sub-titled compound as a white solid.
Reaction SMILES: CCN(CC)CC.[Cl:8][C:9]1[N:14]=[C:13](Cl)[CH:12]=[CH:11][N:10]=1.[NH2:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([CH3:26])=[CH:20]2>CCO>[Cl:8][C:9]1[N:14]=[C:13]([NH:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21]([CH3:26])=[CH:20]3)[CH:12]=[CH:11][N:10]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc2cc(Nc3ccnc(Cl)n3)ccc2[nH]1
Yield: 80 %

Procedure:
Et3N (1 mmol) was added to a solution of 2,4-dichloropyrimidine (1 mmol) and 5-amino-2-methylindole (1 mmol) in 5 ml EtOH. The reaction mixture was refluxed for 5 hours. After removal of the solvent in vacuo and addition of H2O, the mixture was extracted with EtOAc. The organic layers were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated in vacuo. The resulting residue was purified by column chromatography to give N-(2-chloropyrimidin-4-yl)-2-methyl-1H-indol-5-amine in a yield of 80%.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][CH2:5][C:6]([F:9])([F:8])[F:7].C(N(CC)CC)C.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>ClCCl>[Cl:1][CH2:2][CH2:3][N:4]([CH2:5][C:6]([F:9])([F:8])[F:7])[C:18](=[O:19])[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: FC(F)(F)CNCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Oc1ccccc1)N(CCCl)CC(F)(F)F
Temperature: 0 °C

Procedure:
Into a 500-mL round-bottom flask, was placed (2-chloroethyl)(2,2,2-trifluoroethyl)amine (15 g, 92.85 mmol, 1.00 equiv), a solution of triethylamine (16.4 g, 162.07 mmol, 1.75 equiv) in dichloromethane (200 mL). This was followed by the addition of phenyl chloroformate (20.3 g, 129.66 mmol, 1.40 equiv) dropwise with stirring at 0° C. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 100 mL of 1M HCl. The resulting mixture was washed with 2×100 mL of sodium bicarbonate (sat.). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with petroleum ether. This resulted in 10 g (22%) of phenyl N-(2-chloroethyl)-N-(2,2,2-trifluoroethyl)carbamate as light yellow oil. (ES, m/z): 283 [M+H]+
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17]([OH:19])=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Cl.Cl.[NH2:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=2)[CH2:25][CH2:24]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(N(CC)CC)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17]([NH:22][CH:23]3[CH2:28][CH2:27][N:26]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=4)[CH2:25][CH2:24]3)=[O:19])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(C2CCC(CC(=O)O)CC2)cc1
Reactant: NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(C2CCC(CC(=O)NC3CCN(Cc4ccc(Cl)c(Cl)c4)CC3)CC2)cc1
Reaction time: 12 h
Yield: 58.3 %

Procedure:
[4-(4-Acetylphenyl)cyclohexyl]acetic acid (2.0 g) and 4-amino-1-(3,4-dichlorobenzyl)piperidine dihydrochloride (2.5 g) were suspended in DMF (50 mL), and triethylamine (2.1 mL), EDC hydrochloride (1.6 g) and HOBt (1.3 g) were added to the suspension. The suspension was stirred for 12 hrs. The reaction mixture was washed with water and then saturated brine and dried, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to crystallize to give the title compound (2.2 g) as a white solid. melting point: 168° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:21](O)=[O:22])[NH:3]1.[C:24]1([CH:30]([NH2:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([CH:30]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:37][C:21]([C@H:11]2[CH2:10][CH2:9][C@H:8]3[C@H:7]4[C@H:16]([CH2:15][CH2:14][C@:12]23[CH3:13])[C@:17]2([CH3:20])[C:4]([NH:3][C:2](=[O:1])[CH2:19][CH2:18]2)=[CH:5][CH2:6]4)=[O:22])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Product: C[C@]12CC[C@H]3[C@@H](CC=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)NC(c1ccccc1)c1ccccc1
Yield: 59 %

Procedure:
The title compound was prepared in a yield of 59% in a similar manner to that described in Example 1 by reacting 3-oxo-4-azaandrost-5-ene-17β-carboxylic acid and diphenylmethylamine.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Cl[CH2:18][CH:19]([OH:21])[CH3:20]>>[OH:21][CH:19]([CH3:20])[CH2:18][N:3]1[C:4]2[C:9](=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2)[CH:10]=[C:2]1[CH3:1]
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: CC(O)CCl
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(C)O

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 120) and 1-chloro-2-propanol: 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J=8.5 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 6.59 (s, 1H), 4.20 (m, 1H), 4.12 (m, 2H), 2.52 (s, 3H), 1.33 (d, J=6.1 Hz, 3H); MS (ES) m/z 283 (M+1).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:13]([NH:15][C@H:16]([C:22]([O:24][CH3:25])=[O:23])[CH2:17][O:18][CH2:19][CH:20]=C)=[O:14].CSC.C(Cl)Cl.C[OH:40]>>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:13]([NH:15][C@H:16]([C:22]([O:24][CH3:25])=[O:23])[CH2:17][O:18][CH2:19][CH:20]=[O:40])=[O:14]
Reactant: CO
Reactant: C=CCOC[C@H](NC(=O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O)C(=O)OC
Solvent: CSC
Solvent: ClCCl
Product: COC(=O)[C@H](COCC=O)NC(=O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
Dissolve N-[2-(1,3-dihydro-1,3-dioxo- 2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-O-2-propenyl-L-serine, methyl ester (13 g, 29.8 mmol) in methylene chloride /methanol (10:1, 220 mL). Cool to -78° C. and sparge with a mixture of ozone/oxygen for approximately 10 minutes until a blue color persists. Sparge with nitrogen for 10 minutes at -78° C. to remove excess ozone. Treat with methylsulfide (60 mL, 0.82 mol) and allow to warm to room temperature. Stir at room temperature for 2.5 hours, evaporate the solvent in vacuo and dissolve the residue in ethyl acetate (200 mL). Wash with water, saturated sodium chloride, dry (MgSO4) and evaporate the solvent in vacuo to give the intermediate N-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3phenylpropyl]-O-2-oxoethyl-L-serine, methyl ester as a foam (13.6 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([S:9][C:10]#N)[CH:5]=[CH:4][C:3]=1[NH:12][C:13](=[O:21])[C@:14]([OH:20])([CH3:19])[C:15]([F:18])([F:17])[F:16].[S-2].[Na+].[Na+].[CH3:25][N:26]([CH3:36])[C:27]([C:29]1[CH:34]=[CH:33]C(I)=[CH:31][CH:30]=1)=[O:28]>CN(C=O)C.O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([S:9][C:10]2[CH:33]=[CH:34][C:29]([C:27](=[O:28])[N:26]([CH3:36])[CH3:25])=[CH:30][CH:31]=2)[CH:5]=[CH:4][C:3]=1[NH:12][C:13](=[O:21])[C@:14]([OH:20])([CH3:19])[C:15]([F:18])([F:17])[F:16]
Reactant: CN(C)C(=O)c1ccc(I)cc1
Reactant: C[C@@](O)(C(=O)Nc1ccc(SC#N)c(Cl)c1Cl)C(F)(F)F
Agent: [Na+]
Agent: [S-2]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc(Sc2ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c2Cl)cc1
Temperature: 50 °C

Procedure:
(R)-N[2,3-Dichloro-4-thiocyanatophenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Method 39) (0.5 g) as a solution in DMF was treated with a solution of sodium sulphide (403 mg) in water (2 ml) and the mixture was heated at 50° C. for 1 hour. The reaction mixture was then treated with a solution of N,N-dimethylcarbamoyl-4-iodobenzene (0.455 g) in DMF (5 ml), followed by cuprous oxide (0.121 g). The reaction mixture was heated at 150° C. for 4.5 hours under an argon atmosphere. The reaction mixture was quenched with water (100 ml), and DCM was added (100 ml) and the mixture was filtered through diatomaceous earth. The aqueous layer was separated and washed with DCM (3×50 ml). The organic extracts were combined and dried. The volatile material was removed by evaporation, and the product was purified by chromatography using a Mega Bond Elut column (20 g silica) eluting with 0-5% MeOH/DCM to yield the title compound as a white solid. (0.53 g) 80%. NMR: 1.60 (s, 3H), 2.95 (d, 6H), 7.30 (d, 1H); 7.30-7.50 (m, 4H), 7.85 (s, 1H), 7.90 (d, 1H), 9.90 (s, 1H); m/z: 479.
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:11].[O-:12][S:13]([O-:15])=[O:14].[Na+].[Na+].O>CCO>[CH3:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[S:13]([OH:15])(=[O:14])=[O:12]
Reactant: O=S([O-])[O-]
Reactant: Cc1cccc([N+](=O)[O-])c1F
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cccc([N+](=O)[O-])c1S(=O)(=O)O
Yield: 205.9 %

Procedure:
In a similar fashion using route 39 general procedure 95, 2-fluoro-3-nitrotoluene (2.5 g 16.1 mmol) in EtOH (60 ml) and Na2SO3 (4.61 g, 36.58 mmol) in EtOH: water (40 ml: 50 ml) at 70° C. for 16 h gave the title compound (7.2 g) which was used in the next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]=[CH:6][N:7]([CH2:9][CH2:10][CH2:11][NH:12][C:13]([CH3:23])([CH3:22])[CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:8]=1.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:22][C:13]([NH:12][CH2:11][CH2:10][CH2:9][N:7]1[CH:8]=[C:4]([CH2:3][CH2:2][NH:1][S:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:32])=[O:31])[N:5]=[CH:6]1)([CH3:23])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(COc1ccccc1)NCCCn1cnc(CCN)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: CC(C)(COc1ccccc1)NCCCn1cnc(CCNS(=O)(=O)c2ccccc2)c1

Procedure:
3-[4-(2-Aminoethyl)imidazol-1-yl]-N-(1,1-dimethyl-2-phenoxyethyl)propylamine (2.05 g) was reacted with benzenesulphonyl chloride (1.15 g) in a similar manner to Example 55 to give N-(2-{1-[3-(1,1-dimethyl-2-phenoxyethylamino)propyl]imidazol-4-yl}ethyl]benzenesulphonamide, as an oil. The compound contained 7% of N-(2-{1-[3-(1,1-dimethyl-2-phenoxyethylamino)propyl]imidazol-5-yl}ethyl]benzenesulphonamide, by 1H nmr and 13C nmr. These compounds may be separated by HPLC.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH:25]([CH3:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C1CCCCC=1.B(Br)(Br)Br.ClCCl>>[CH3:26][CH:25]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]1[S:9]([C:6]1[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=1)(=[O:11])=[O:10]
Reactant: COc1ccc(S(=O)(=O)N2c3ccccc3-c3ccccc3C2C)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: C1=CCCCC1
Product: CC1c2ccccc2-c2ccccc2N1S(=O)(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
A stirred suspension of 5-[(4-methoxyphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine (0.73 g, 2.0 mmol) and cyclohexene (3.28 g, 40 mmol) was treated at room temperature under nitrogen with a solution of 1.0 M boron tribromide in dichloromethane (12 mL, 12 mmol). After stirring for approximately four hours at room temperature, the reaction was quenched with methanol (20 mL) and diluted with dichloromethane. The mixture was washed sequentially with an aqueous potassium carbonate solution, a saturated, aqueous sodium chloride solution, and water. The organic phase was dried over anhydrous sodium sulfate, filtered through a short column of silica gel, and eluted with ethyl acetate. The ethyl acetate phase was evaporated in vacuo to a crude residue (1.0 g). The crude residue was purified by preparative chromatography on a Biotage® 40 Mi column of pre-packed silica gel (90 g) with gradient elution of between 10% to 30% methyl tert-butyl ether in hexane at a flow rate of 50 mL/min and afforded, after evaporation of the solvent, a colorless oil. Crystallization of the colorless oil from a mixture of diethyl ether-hexane yielded the title compound (0.525 g, 1.5 mmol, 75%) as a homogeneous, colorless, crystalline solid,
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[O:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[CH2:30][CH:29]1[CH2:37]O.C(P(CCCC)CCCC)CCC.N(/C(N1CCCCC1)=O)=N\C(N1CCCCC1)=O>C(OCC)(=O)C.O1CCCC1>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:37][CH:29]2[CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:28]2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: OCC1Cc2ccccc2O1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(/N=N/C(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCc1nc(C)n(CC2Cc3ccccc3O2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.22 g), 2,3-dihydro-1-benzofuran-2-ylmethanol (1.02 g), tributylphosphine (2.1 mL), 1,1′-[(E)-diazene-1,2-diyldicarbonyl]dipiperidine (1.72 g) and tetrahydrofuran (60 mL) was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, and the insoluble solid was filtered off. The solvent of the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless viscous substance (0.86 g, 52%).
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]([CH2:23][C:24]2[S:28][C:27]3[CH:29]=[CH:30][C:31]([CH2:33][CH3:34])=[CH:32][C:26]=3[CH:25]=2)[CH:14]=1.[CH2:35]([O:42][CH:43]1[CH:48]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:47]([O:57][CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[CH:46]([CH2:65][O:66][CH2:67][C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[O:45][C:44]1=[O:74])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[Cl-].[NH4+]>C1COCC1>[CH2:35]([O:42][C@@H:43]1[C@H:48]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C@@H:47]([O:57][CH2:58][C:59]2[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=2)[C@@H:46]([CH2:65][O:66][CH2:67][C:68]2[CH:69]=[CH:70][CH:71]=[CH:72][CH:73]=2)[O:45][C:44]1([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]([CH2:23][C:24]2[S:28][C:27]3[CH:29]=[CH:30][C:31]([CH2:33][CH3:34])=[CH:32][C:26]=3[CH:25]=2)[CH:14]=1)[OH:74])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C1OC(COCc2ccccc2)C(OCc2ccccc2)C(OCc2ccccc2)C1OCc1ccccc1
Reactant: CCc1ccc2sc(Cc3cc(Br)c4ccccc4c3)cc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCc1ccc2sc(Cc3cc(C4(O)O[C@H](COCc5ccccc5)[C@H](OCc5ccccc5)[C@@H](OCc5ccccc5)[C@H]4OCc4ccccc4)c4ccccc4c3)cc2c1
Reaction time: 0.08 h
Yield: 0.1 %

Procedure:
In a nitrogen stream, an n-butyllithium hexane solution (1.6 M, 0.83 ml, 1.33 mmol) was added dropwise to a solution of 2-(4-bromonaphtalen-2-ylmethyl)-5-ethylbenzo-[b]thiophene (460 mg, 1.21 mmol) in THF (15 ml) at −78° C. The reaction mixture was stirred at the same temperature for five minutes and to this solution, a solution of 3,4,5-trisbenzyloxy-6-benzyloxymethyltetrahydro-pyran-2-one (844 mg, 1.57 mmol) in THF (5 ml) was added dropwise. The reaction solution was stirred at −78° C. for five minutes and a saturated ammonium chloride aqueous solution was added to stop the reaction. The reaction mixture was extracted with ethyl acetate and the organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:9)] to obtain the title compound (1.06 mg, 100%).