Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[C:5]2[OH:13].N1C=CC=CC=1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][C:7](=[O:12])[CH:6]=[C:5]([O:13][S:26]([C:23]3[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=3)(=[O:28])=[O:27])[C:4]=2[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=c1cc(O)c2cc(Cl)ccc2o1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Oc2cc(=O)oc3ccc(Cl)cc23)cc1
Reaction time: 1 h
Yield: 89.8 %

Procedure:
6-Chloro-4-hydroxycoumarin (25.4 mmol, 5.0 g) is suspended in DCM (50 mL) and pyridine (63.3 mmol, 5.1 mL) is added. The mixture is cooled in an ice bath and p-toluenesulfonyl chloride (26.8 mmol, 5.1 g) is added. The ice bath is removed and the compound slowly dissolves and a solid is deposited (pyridine HCl). After 1 hr the mixture is transferred to a separatory funnel, HCl (2 M) is added, and a solid is formed. The organic layer is removed and the solid-containing aqueous layer is filtered to remove the precipitate. The filtrate is washed with DCM and the combined organic layers are washed with H2O, NaHCO3 (sat.), H2O, and brine. The extract is then dried over MgSO4 and is evaporated. The residue is triturated with Et2O to give the title compound (8.0 g, 90%) as a cream solid. 1H NMR (CDCl3, 400 MHz) δ 7.91 (2H, d, J=8 Hz), 7.54 (1H, d, J=2 Hz), 7.51 (1H, dd, J=2, 9 Hz), 7.42 (2H, d, J=8 Hz), 7.26 (1H, d, J=9 Hz), 6.38 (1H, s), 2.49 (3H, s); LCMS (MeCN—H2O, Luna 3μC18(2) 30×4.6 mm; MS (ESI, Pos.) calcd for C16H11ClO5S m/z [M+H]=351 found [no mass ion detected].
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)([O-])=O>[Pd].C(O)C>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2
Reactant: O=[N+]([O-])c1cccc2[nH]ccc12
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc2[nH]ccc12
Reaction time: 2 h
Yield: 100 %

Procedure:
A mixture of the 4-nitroindole (10.0 mmol), 10% palladium on carbon (20% by weight), and absolute ethanol (50 mL) was shaken under a hydrogen atmosphere (3 atm) for 2 hours. The resulting reaction mixture was filtered through Celite®, and the filtrate was evaporated under reduced pressure to afford the corresponding 4-aminoindole, which was used directly (assumed 100% yield) in the next step below.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4](=[O:12])[C:5]2[CH:10]=[N:9][N:8]([CH3:11])[C:6]=2[N:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][CH2:22][CH2:23]Br>CN(C)C=O>[CH3:11][N:8]1[C:6]2[N:7]=[C:2]3[N:3]([C:4](=[O:12])[C:5]=2[CH:10]=[N:9]1)[CH2:23][CH2:22][CH2:21][CH2:20][S:1]3
Reactant: BrCCCCBr
Reactant: Cn1ncc2c(=O)[nH]c(S)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1ncc2c(=O)n3c(nc21)SCCCC3
Temperature: 80 °C
Reaction time: 6 h
Yield: 22 %

Procedure:
In 120 ml of dimethylformamide was dissolved 6.0 g (32.9 mmol) of 4,5-dihydro-6-mercapto-1-methylpyrazolo[3,4-d]pyrimidin-4(1H)-one [Helv. Chim. Acta, 42, 349 (1959)], and 13.7 g (98.8 mmol) of potassium carbonate and 5.90 ml (49.4 mmol) of 1,4-dibromobutane were added to the solution, followed by stirring at 80° C. for 6 hours. After evaporation of the solvent, the residue was subjected to partition between chloroform and water, and the chloroform layer was concentrated to dryness under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with chloroform to give 1.71 g (22%) of Compound 45. The compound was recrystallized from ethanol for purification.
Reaction SMILES: [CH2:1]([N:3]([CH2:24][CH3:25])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)[CH2:13][CH2:14]O)=[CH:8][CH:7]=1)=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:46].O>C(#N)C>[Br:46][CH2:14][CH2:13][CH:12]([C:9]1[CH:10]=[CH:11][C:6]([C:4](=[O:5])[N:3]([CH2:24][CH3:25])[CH2:1][CH3:2])=[CH:7][CH:8]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1
Reactant: BrC(Br)(Br)Br
Reactant: CCN(CC)C(=O)c1ccc(C(CCO)c2cccc(OC)c2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Product: CCN(CC)C(=O)c1ccc(C(CCBr)c2cccc(OC)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
3-(4-Diethylcarbamoylphenyl)-1-hydroxy-3-(3-methoxyphenyl)propane (215 mg) was dissolved in acetonitrile (4 ml), added with triphenylphosphine (304 mg) and carbon tetrabromide (385 mg) under ice cooling and stirred at room temperature for 30 minutes. The reaction mixture was added with water (5 ml) and extracted twice with dichloromethane (5 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate=2:1) to obtain 189 mg of the title compound. Yield: 74%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[CH2:10](Cl)[CH:11]=[CH2:12]>C(O)(C)C.[OH-].[Na+].C(OCC)C>[CH2:12]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([CH3:9])[CH:4]=1)[CH:11]=[CH2:10]
Reactant: C=CCCl
Reactant: Cc1cc(O)ccc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(C)O
Product: C=CCOc1ccc(Br)c(C)c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
To a dark yellow solution of 4-bromo-3-methyl-phenol (4.68 g, 25 mmol) in isopropanol (60 mL) and 3 N aq. NaOH (20 mL), allylchloride (8.18 g, 107 mmol) is added. The mixture is stirred at 70° C. for 3 h before it is cooled to rt, diluted with diethyl ether and washed with 1 N aq. NaOH solution (275 mL) and 1 M aq. HCl solution (70 mL) followed by brine (70 mL). The org. extract is dried over MgSO4, filtered, concentrated and dried to give crude 4-allyloxy-1-bromo-2-methyl-benzene (5.67 g) as a yellow oil; LC-MS: tR=0.59 min; [M+1]+=not detectable; 1H NMR (CDCl3): δ 2.38 (s, 3H), 4.52 (dt, J=5.3, 1.5 Hz, 2H), 5.29-5.34 (m, 1H), 5.39-5.46 (m, 1H), 6.00-6.11 (m, 1H), 6.65 (dd, J=8.8, 3.0 Hz, 1H), 6.83 (d, J=3.0 Hz, 1H), 7.41 (d, J=8.5 Hz, 1H).
Reaction SMILES: [F:1][C:2]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]2[CH:3]1[CH:4]([OH:9])[CH2:5][C:6]2=[O:8].[C:15]([Si:19]([CH3:22])([CH3:21])Cl)([CH3:18])([CH3:17])[CH3:16].CN(C)C=O.N1C=CN=C1>O>[F:1][C:2]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:3]2[CH:7]1[CH:6]([O:8][Si:19]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:22])[CH3:21])[CH2:5][C:4]2=[O:9]
Reactant: CCOC(=O)C1(F)C2C(=O)CC(O)C21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(F)C2C(=O)CC(O[Si](C)(C)C(C)(C)C)C21
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.7 %

Procedure:
2.8 g of (1RS,4SR,5SR,6RS)ethyl 6-fluoro-4-hydroxy-2-oxobicyclo[3.1.0]hexane-6-carboxylate and 2.5 g of t-butyldimethylchlorosilane were dissolved into 14 ml of N,N-dimethylformamide. 1.0 g of imidazole was further added thereto with ice-cooling, and this was stirred at room temperature for one day. The reaction solution was poured into water, and extracted with n-hexane-ethyl acetate (1:9). The obtained organic layer was washed with, in sequence, water and a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. After filtering off the desiccant, concentration of the filtrate was carried out under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel (made by Wako Pure Chemical Industries Ltd.), eluent: hexane-ethyl acetate=15:1), yielding 3.8 g of (1RS,4SR,5SR,6RS)ethyl 6-fluoro-4-t-butyldimethylsilyloxy-2-oxobicyclo[3.1.0]hexane-6-carboxylate. The proton NMR and mass spectrograph data are shown below.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[CH:13]=[CH:14][CH:15]=2)[CH2:6][CH2:5]1.[C:22]1([CH:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:29](Cl)=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[C:32]1([CH:28]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:29]([NH:1][CH2:2][CH2:3][N:4]2[CH2:9][CH2:8][CH:7]([C:10]3[CH:11]=[C:12]([NH:16][C:17](=[O:21])[CH:18]([CH3:19])[CH3:20])[CH:13]=[CH:14][CH:15]=3)[CH2:6][CH2:5]2)=[O:30])[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCN)CC2)c1
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCNC(=O)C(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 (THF) and Scheme AT using N-{3-[1-(2-aminoethyl)-4-piperidinyl]phenyl}-2-methylpropanamide and diphenylacetyl chloride: ESMS m/e: 484.2 (M+H)+.
Reaction SMILES: C[N:2]([CH2:4][C@@H:5]1[CH2:8][C@H:7]([C:9]2[N:13]3[CH:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]3=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)[N:10]=2)[CH2:6]1)C.N>>[NH2:2][CH2:4][CH:5]1[CH2:6][CH:7]([C:9]2[N:13]3[CH:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]3=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)[N:10]=2)[CH2:8]1
Reactant: CN(C)C[C@H]1C[C@@H](c2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)nccn32)C1
Agent: N
Product: NCC1CC(c2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)nccn23)C1

Procedure:
Prepared according to the procedure described above for cis-3-(3-dimethylaminomethylcyclobutyl)-1-(4-phenoxyphenyl)-imidazo[1,5-a]pyrazin-8-ylamine, except using ammonia.
Reaction SMILES: [C:1]1([N:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]Br)=[CH:18][CH:17]=1>CN(C)C=O>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:9]2[CH2:10][CH2:11][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]2=[O:12])=[CH:18][CH:17]=1
Reactant: BrCCCCCOc1ccc(Br)cc1
Reactant: O=C1NCCN1c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1N(CCCCCOc2ccc(Br)cc2)CCN1c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-phenyl-2-imidazolidinone (0.10 g, 0.62 mmol) dissolved in 10 mL dimethylformamide cooled in an ice bath was added NaH (60% dispersion in mineral oil, 27.0 mg, 0.68 mmol). The mixture was stirred at room temperature for 30 minutes; then cooled in ice bath. 1-Bromo-4-[(5-bromopentyl)oxy] benzene (0.20 g, 0.62 mmol) was added, and the mixture was stirred at room temperature for additional 4 hours. The reaction was quenched with MeOH, and the solvents were pumped off. Saturated aqueous NH4Cl and dichloromethane (15 mL) were added to the residue. The dichloromethane layer was separated and dried over MgSO4, filtered, evaporated, and purified by column chromatography (ethyl acetate:MeOH=10:1) to give the product (i.e., Compound 9) as a yellow solid (0.19 g, 77%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8](Cl)=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH2:19]([O:26][C:27]([N:29]1[CH2:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C>[OH:14][C:13]1[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:7]([C:8]([N:32]2[CH2:33][CH2:34][CH2:35][N:29]([C:27]([O:26][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:28])[CH2:30][CH2:31]2)=[O:9])=[CH:11][C:12]=1[C:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: O=C(OCc1ccccc1)N1CCCNCC1
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Solvent: CC#N
Product: CC(C)(C)c1cc(C(=O)N2CCCN(C(=O)OCc3ccccc3)CC2)cc(C(C)(C)C)c1O
Reaction time: 6 h

Procedure:
A mixture of 13.4 g (0.05 mol) of 3,5-di-tert.-butyl-4-hydroxybenzoyl chloride and 12.4 g (0.053 mol) of 1-benzyloxycarbonylhomopiperazine in 200 ml of acetonitrile is heated under reflux, with stirring, for 6 hour. The solvent is then removed by distillation under reduced pressure, the residue is partitioned between methylene chloride and dilute hydrochloric acid, and the organic phase is separated off and washed with saturated brine. After drying over sodium sulfate and removal of the solvent by distillation under reduced pressure, the crystalline residue is digested with hot diisopropyl ether, filtered off with suction, washed with diisopropyl ether and dried.
Reaction SMILES: [C:1]([C:6]1[C:15](=O)[C:14]2[C:9](=[C:10]([O:17][CH3:18])[CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].P(Cl)(Cl)([Cl:21])=O>C(Cl)(Cl)Cl>[Cl:21][C:15]1[C:14]2[C:9](=[C:10]([O:17][CH3:18])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[C:1](=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cccc2c(=O)c(C(=O)C(C)C)c[nH]c12
Solvent: ClC(Cl)Cl
Product: COc1cccc2c(Cl)c(C(=O)C(C)C)cnc12
Yield: 71 %

Procedure:
3-Isobutyryl-8-methoxy-4(1H)-quinolone (8.31 g, 0.034 mol) was heated under reflux in a mixture of phosphorus oxychloride (20 ml) and chloroform (30 ml) for 30 minutes. The mixture was evaporated and the residue was partitioned between dichloromethane and sodium hydrogen carbonate solution. The organic solution was washed with sodium hydrogen carbonate solution, water and brine, dried, filtered and evaporated to give 4-chloro-3-isobutyryl-8-methoxyquinoline as a brown oil (6.4 g, 71%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[N:5]([CH2:7][CH2:8][O:9]C2CCCCO2)[CH:6]=1.O1CCCC1.Cl>C(OCC)(=O)C>[Br:1][C:2]1[N:3]=[C:4]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[N:5]([CH2:7][CH2:8][OH:9])[CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(Br)cn2CCOC2CCCCO2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2nc(Br)cn2CCO)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
Combine tert-butyl 4-(4-bromo-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (5.00 g, 10.91 mmol), tetrahydrofuran (150 mL), and 1 M aqueous hydrochloric acid (50 mL); let stir overnight at room temperature. Dilute with ethyl acetate. Wash with excess 1M aqueous sodium hydroxide, followed by saturated aqueous sodium chloride. Dry the organics over anhydrous magnesium sulfate, filter, and concentrate in vacuo to give the title compound as a yellow foam (3.84 g, 94%). MS (ES) m/z=376 [M]+.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[NH:16][N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O[CH:29]1[CH2:32][C:31](=[CH:33][CH2:34][CH3:35])[CH2:30]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[N:16]([CH:29]3[CH2:32][C:31](=[CH:33][CH2:34][CH3:35])[CH2:30]3)[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ncnc2[nH]nc(-c3ccc(Oc4ccccc4)cc3)c12
Reactant: CCC=C1CC(OS(C)(=O)=O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC=C1CC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Yield: 67.3 %

Procedure:
A solution of 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.743 g, 0.00245 mol) in N,N-dimethylformamide (20 mL) was reacted with 3-propylidenecyclobutyl methanesulfonate (0.699 g, 0.00367 mol) and cesium carbonate (0.866 g, 0.00367 mol) at 70° C. for three days. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with water (2×20 mL) and brine (20 mL). The organic layer was dried over magnesium sulfate and the solvent was removed in vacuo. The residue was purified by flash column chromatography on silica using dichloromethane/methanol (98:2). The solvent was removed in vacuo to give 3-(4-phenoxyphenyl)-1-(3-propylidenecyclobutyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.655 g, 0.00165 mol) as a tan solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[S:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=1)(=[O:25])=[O:24]>>[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[S:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([N:10]2[CH2:9][CH2:8][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:12][CH2:11]2)=[O:31])=[CH:28][CH:27]=1)(=[O:25])=[O:24]
Reactant: O=C(O)c1ccc(S(=O)(=O)c2ccc3ccccc3c2)cc1
Reactant: c1cc(N2CCNCC2)ccn1
Product: O=C(c1ccc(S(=O)(=O)c2ccc3ccccc3c2)cc1)N1CCN(c2ccncc2)CC1
Yield: 32 %

Procedure:
Using an analogous procedure to that described in Example 1, N-(4-pyridyl)piperazine was reacted with 4-(2-naphthylsulphonyl)benzoic acid to give 1-[4-(2-naphthylsulphonyl)benzoyl]-4-(4-pyridyl)piperazine in 32% yield;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[NH2:21][CH:22]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23]1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:21][CH:22]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23]2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)C1

Procedure:
Prepared according to the procedure described for example 70 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (3.0 g, 8.5 mmol) 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (3.5 g, 9.3 mmol) and tert-butyl 3-aminopyrrolidine-1-carboxylate (1.86 g, 0.52 mmol). The title compound was obtained as a solid (3.1 g, 70% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.98 (2H, s), 8.91 (1H, m), 8.52 (1H, s), 4.29 (1H, m), 3.49 (1H, m), 3.30 (1H, m), 3.15 (1H, m), 2.06 (1H, m), 2.03 (1H, m), 1.83 (1H, m), 1.40 (9H, s).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:21][C@@H:20]2[C@:15]([CH3:23])([CH:16]=[CH:17][C:18](=[O:22])[NH:19]2)[C@@H:14]2[C@@H:3]1[C@H:4]1[C@:11]([CH3:24])([CH2:12][CH2:13]2)[C@@H:7]([C:8](=[O:10])[CH3:9])[CH2:6][CH2:5]1.[CH2:25]([Mg]Br)[CH3:26].[Cl-].[NH4+]>O1CCCC1.CCOCC>[CH3:1][C@H:2]1[CH2:21][C@@H:20]2[C@:15]([CH3:23])([CH:16]=[CH:17][C:18](=[O:22])[NH:19]2)[C@@H:14]2[C@@H:3]1[C@H:4]1[C@:11]([CH3:24])([CH2:12][CH2:13]2)[C@@H:7]([C@:8]([CH2:25][CH3:26])([OH:10])[CH3:9])[CH2:6][CH2:5]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3[C@@H](C)C[C@H]4NC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC[C@](C)(O)[C@H]1CC[C@H]2[C@@H]3[C@@H](C)C[C@H]4NC(=O)C=C[C@]4(C)[C@H]3CC[C@@]21C
Temperature: 25 °C
Yield: 48.5 %

Procedure:
To a solution of 100 mg (0.303 mmol) 7β-methyl-5α-4-azapregn-1-ene-3,20-dione in 10 ml dry tetrahydrofuran at -40° C. under N2 was added 15 eq ethylmagnesium bromide (4.5 mmol) in ether. The reaction was stirred and allowed to warm to RT over 18 hours. Aqueous ammonium chloride (5 ml) was added and the solvents were evaporated. The residue was partitioned between methylene chloride and water. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated. The product was purified via HPLC on a 19×300 mm 8 micron silica column using 5% isopropanol/hexane at 20 ml/min to yield 53 mg (0.147 mmol, 49% yield) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.Cl[C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=1.[H-].[Na+]>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=2)[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: O=C(Cc1ccc(F)cc1)c1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccncc1)C(c1ccc(F)cc1)c1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 65 %

Procedure:
To a solution of 2-(4-fluorophenyl)-1-(pyridin-4-yl)ethanone (4.0 g, 18.6 mmol) [prepared as described in Example 1 above] and 2-chloro-3-nitropyridine (6.50 g, 41.13 mmol) in dimethylformamide (50 ml) at 0° C. was added sodium hydride (1.65 g, 41 mmol, 60% in oil) under an argon atmosphere. The reaction mixture was warmed to room temperature and stirred for an hour. The reaction mixture was quenched with water and the product was extracted into ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo to give a dark brown oil. Purification by flash column chromatography (10% to 50% ethyl acetate/hexanes gradient) gave 2-(4-fluorophenyl)-2-(3-nitropyridin-2-yl)-1-(pyridin-4-yl)ethanone as a brown oil (4.08 g).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([N:13]1[CH2:17][C@@H:16]([C:18]2([C:21]([O:23]CC)=[O:22])[CH2:20][CH2:19]2)[C@H:15]([OH:26])[CH2:14]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(OC)(O[CH3:31])(=O)=O.O>O1CCCC1>[CH2:3]([O:10][C:11]([N:13]1[CH2:14][C@H:15]([O:26][CH3:31])[C@@H:16]([C:18]2([C:21]([OH:23])=[O:22])[CH2:20][CH2:19]2)[CH2:17]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COS(=O)(=O)OC
Reactant: CCOC(=O)C1([C@@H]2CN(C(=O)OCc3ccccc3)C[C@H]2O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CO[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1C1(C(=O)O)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Under a nitrogen atmosphere, 60% sodium hydride (0.149 g, 3.73 mmol) was suspended in anhydrous tetrahydrofuran (20 ml) to which, after cooling to 0° C., was subsequently added dropwise a dry tetrahydrofuran (20 ml) solution of 1-benzyloxycarbonyl-3-(S)-hydroxy-4-(R)-(1-ethoxycarbonylcyclopropyl)pyrrolidine (0.98 g, 2.92 mmol) over a period of 5 minutes. After 15 minutes of stirring in an ice bath, dimethyl sulfate (0.441 ml, 4.66 mmol) was added dropwise to the reaction solution which was cooled in the ice bath. The reaction solution was stirred at room temperature for 4 hours and then mixed with water (0.5 ml), followed by evaporating tetrahydrofuran under reduced pressure. The thus obtained residue was dissolved in ethanol (40 ml), and a 1 M sodium hydroxide aqueous solution (8.76 ml) was added dropwise to the resulting solution at room temperature. The reaction solution was heated under reflux for 2 hours and then ethanol was evaporated under reduced pressure. The resulting residue was cooled in an ice bath, acidified by adding dropwise a 1 M hydrochloric acid aqueous solution (15 ml) and then extracted with ethyl acetate (50 ml×3). All of the organic layers were combined, washed with a 1 N hydrochloric acid aqueous solution (50 ml) and saturated brine (50 ml) and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 0.935 g (quantitative) of the title compound as a colorless amorphous substance.
Reaction SMILES: [F:1][C:2]1[CH:31]=[C:30]([N+:32]([O-])=O)[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[CH:16][N:15]=3)[S:13][C:6]=12.[NH4+].[Cl-]>[Fe].CCO.O>[F:1][C:2]1[CH:31]=[C:30]([CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][N:21]4[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]4)=[CH:16][N:15]=3)[S:13][C:6]=12)[NH2:32]
Reactant: CN1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc([N+](=O)[O-])cc5F)c4s3)nc2)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CN1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(N)cc5F)c4s3)nc2)CC1
Yield: 100 %

Procedure:
To a solution of 401 (306 mg, 0.64 mmol) and NH4Cl (30 mg, 0.54 mmol) in 2:1 EtOH/water (10.5 mL) was added iron powder (304 mg, 5.43 mmol) and the suspension was heated to reflux for 1 hour. The reaction mixture was filtered through celite and concentrated to provide title compound 396, that was used without further purification (343 mg, 100% yield). MS (m/z): (M+1) 450.0 (100%).