Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[N+:16]([O-])=O)[N:7]=1)(=[O:3])[CH3:2]>CC(C)=O.[Ni]>[C:1]([O:4][CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[NH2:16])[N:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1ccc2c([N+](=O)[O-])cccc2n1
Agent: [Ni]
Solvent: CC(C)=O
Product: CC(=O)OCc1ccc2c(N)cccc2n1

Procedure:
Under hydrogen atmosphere, a solution that consists of 410 mg (1.67 mol) of 2-(acetoxymethyl)-5-nitroquinoline in 61 ml of acetone can be stirred in the presence of 410 mg of Raney nickel for 2 hours at room temperature. It is suctioned off on Celite and rewashed with acetone. After removal of the solvent and subsequent chromatography on silica gel with hexane-ethyl acetate (10–100%), 230 mg (64% of theory) of the product is obtained.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].I[CH3:14]>CN(C)C=O>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH3:14]
Reactant: CI
Reactant: Fc1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc2c(F)cccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 61.2 %

Procedure:
In an oven dried, nitrogen purged, 3 neck, 50 mL round bottom flask, 1.00 g (7.40 mmol) of 4-fluoroindole in 10 mL of dry dimethylformamide is reacted with 0.335 g (8.88 mmol) of 60% sodium hydride dispersed in mineral oil at room temperature for 4 h. 0.553 mL (8.88 mmol) of iodomethane is added and the reaction is allowed to stir at room temperature overnight, 15 h. The reaction is quenched with 50 mL of water, extracted 3×50 mL of ethyl acetate, dried (MgSO4), and concentrated. The crude product is purified by chromatography using hexanes:ethyl acetate as a solvent system to obtain 0.675 g of the title compound, 61% yield. MS, ES+=150.1; 1H NMR (DMSO-d6) δ 7.358-7.350 (d, J=3.083, 1H); 7.279-7.258 (d, J=8.368, 1H); 7.126-7.073 (m, 1H); 6.806-6.760 (m, 1H); 6.459-6.452 (d, J=3.083, 1H); 3.787 (s, 1H) ppm.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:12]2[CH:22]=[CH:21][C:15]([C:16]([N:18]([CH3:20])[CH3:19])=[O:17])=[CH:14][CH:13]=2)=[N:6][C:7]=1[C:8]([NH:10][NH2:11])=[O:9].[NH2:23][C:24]1[N:29]=[C:28]([C:30](O)=[O:31])[CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C.F[B-](F)(F)F.N1(OC(=[N+](C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:12]2[CH:13]=[CH:14][C:15]([C:16]([N:18]([CH3:19])[CH3:20])=[O:17])=[CH:21][CH:22]=2)=[N:6][C:7]=1[C:8]([NH:10][NH:11][C:30]([C:28]1[CH:27]=[CH:26][CH:25]=[C:24]([NH2:23])[N:29]=1)=[O:31])=[O:9]
Reactant: CN(C)C(=O)c1ccc(-c2cnc(N)c(C(=O)NN)n2)cc1
Reactant: Nc1cccc(C(=O)O)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc(-c2cnc(N)c(C(=O)NNC(=O)c3cccc(N)n3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-[5-amino-6-(hydrazinecarbonyl)pyrazin-2-yl]-N,N-dimethyl-benzamide (100 mg, 0.3163 mmol) and 6-aminopyridine-2-carboxylic acid (43.69 mg, 0.3163 mmol) in DMF (1.000 mL) weas treated with triethylamine (32.01 mg, 44.09 μL, 0.3163 mmol) then warmed slightly. The mixture was cooled to room temperature and then treated with (benzotriazol-1-yloxy-dimethylamino-methylene)-dimethyl-ammonium tetrafluoroborate (121.9 mg, 0.3796 mmol) and stirred at room temperature overnight. The mixture was poured dropwise onto water (5 ml) with rapid stirring, stirred at room temperature for 1 h then filtered to give a wet paste which was dried under high vacuum at 100° C. overnight. Used directly in the next step without purification.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([CH3:18])=[CH:5][CH:6]([S:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=1)[CH3:7].[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1>C1COCC1>[CH3:17][N:15]([CH3:16])[C:12]1[CH:13]=[CH:14][C:9]([S:8][CH:6]([CH3:7])[CH:5]=[C:4]([CH3:18])[CH2:3][OH:2])=[CH:10][CH:11]=1
Reactant: COC(=O)C(C)=CC(C)Sc1ccc(N(C)C)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(=CC(C)Sc1ccc(N(C)C)cc1)CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
To a solution of 4-(4-dimethylaminophenylsulfanyl)-2-methylpent-2-enoic acid methyl ester (0.279 g, 1.0 mmol) in dry THF (4 mL) at 0° C. was added dropwise a solution of di-isobutylaluminium hydride in toluene (1M, 3.0 mL, 3.0 mmol), under an atmosphere of argon. After stirring at 0° C. for one hour (TLC monitoring), the mixture was quenched by addition of methanol (0.5 mL: CAUTION), then water (0.3 mL), 5% aqueous sodium hydroxide solution (0.3 mL) and lastly 30% aqueous sodium potassium tartrate (4 mL). The mixture was stirred for 2 hours at 20° C., then extracted with diethyl ether (3×10 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and evaporated to give the title compound (0.22 g, 88%) as a colourless oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][CH2:6][CH2:7][OH:8])[CH3:4].Br[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[N:11]=1.O>CN(C)C=O>[Br:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([O:8][CH2:7][CH2:6][O:5][CH2:3][CH3:4])[N:11]=1
Reactant: CCOCCO
Reactant: Brc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCCOc1cccc(Br)n1

Procedure:
1.7 g of 60% oily sodium hydride was suspended in 20 ml of N,N-dimethylformamide, followed by adding a solution of 10 ml of N,N-dimethylformamide containing 4.1 ml of 2-ethoxyethanol thereto with stirring under ice-cooling. After stirring for 20 minutes, a solution of 10 ml of N,N-dimethylformamide containing 5 g of 2,6-dibromopyridine was added thereto and the mixture was further stirred at room temperature for one hour. Then, water was added thereto, and the mixture was extracted with ethyl acetate. The organic phase was further washed with brine, dried over anhydrous sodium sulfate and the solvent was removed. The residue was subjected to silica gel column chromatography using 5% ethyl acetate/hexane as an eluent for separation and purification, to give 4.8 g of the target compound.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[F:7][C:8]1[CH:9]=[C:10]([OH:15])[CH:11]=[CH:12][C:13]=1[F:14].[CH3:16][O:17][C:18](=[O:27])/[CH:19]=[C:20](\[NH:22][C:23](=[O:26])[CH2:24]Br)/[CH3:21]>CC(C)=O>[F:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][C:13]=1[F:14])[O:15][CH2:24][C:23]([NH:22]/[C:20](/[CH3:21])=[CH:19]\[C:18]([O:17][CH3:16])=[O:27])=[O:26]
Reactant: COC(=O)/C=C(/C)NC(=O)CBr
Reactant: Oc1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)/C=C(/C)NC(=O)COc1ccc(F)c(F)c1
Temperature: 25 °C
Yield: 59.6 %

Procedure:
To a suspension of K2CO3 (1.38 g, 10.0 mmol) in acetone (50 mL) were added 3,4-difluorophenol (0.78 g, 6.00 mmol) and (Z)-methyl-3-(2-bromoacetamido)but-2-enoate (1.18 g, 5.00 mmol) and the mixture was refluxed for 5 h. The mixture was cooled to rt and filtered and the filtrate was concentrated in vacuo. To the residue was added DCM (100 mL) and the mixture was washed with water (100 mL×2) and brine (100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=5:1) to give the title compound as a white solid (0.85 g, 59%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.[CH2:21]([O:23][C:24](=[O:29])[CH2:25][C:26](Cl)=[O:27])[CH3:22].CC[O-].[Na+]>C1C=CC=CC=1.O>[CH2:21]([O:23][C:24]([C:25]1[C:26](=[O:27])[N:11]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[C:5]2[C:6]([C:8]=1[CH3:9])=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:29])[CH3:22]
Reactant: CCOC(=O)CC(=O)Cl
Reactant: COc1ccc(CNc2ccc(Cl)cc2C(C)=O)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)c1c(C)c2cc(Cl)ccc2n(Cc2ccc(OC)cc2)c1=O
Temperature: 80 °C
Yield: 83.5 %

Procedure:
A solution of 2 (0.20 g, 1.18 mmol) in 3 mL of anhydrous benzene was treated with ethyl-3-chloro-3-oxopropionate (165 μL, 0.20 g, 1.30 mmol). The reaction mixture was heated to 80° C. for 1 h. The reaction was allowed to cool to room temperature and was concentrated in vacuo. The resulting oil was dissolved in 3 mL of ethanol, treated with NaOEt (40.0 mg, 0.59 mmol). The suspension was heated to 80° C. for 10 min, allowed to cool to room temperature, and diluted with H2O. The resulting white precipitate was filtered to give 3 (0.38 g, 80%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 7.69 (d, J=2.3 Hz, 1H), 7.39 (dd, J=2.3, 9 Hz, 1H), 7.26 (d, J=9 Hz, 1H), 7.15 (d, J=8.6 Hz, 2H), 6.81 (d, j=8.6 Hz, 2H), 5.47 (br S, 2H), 4.46 (q, J=7.2 Hz, 2H), 3.75 (s, 3H), 2.46 (s, 3H), 1.43 (t, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([OH:14])[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]#[N:33])=[CH:17][CH:16]=2)[C@H:10]([O:34][CH2:35][C@H:36]2[CH2:40][O:39][C:38]([CH3:42])([CH3:41])[O:37]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:44][C:45]1[CH:46]=[C:47]([O:55][CH3:56])[C:48]2[C:53]([CH:54]=1)=[CH:52][CH:51]=[CH:50][CH:49]=2>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([O:14][CH2:44][C:45]2[CH:46]=[C:47]([O:55][CH3:56])[C:48]3[C:53](=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH:54]=2)[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]#[N:33])=[CH:17][CH:16]=2)[C@H:10]([O:34][CH2:35][C@H:36]2[CH2:40][O:39][C:38]([CH3:42])([CH3:41])[O:37]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)[C@@H](c2ccc(OCCCOc3ccccc3C#N)cc2)[C@H](OC[C@H]2COC(C)(C)O2)C1
Reactant: COc1cc(CCl)cc2ccccc12
Product: COc1cc(CO[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H](OC[C@H]3COC(C)(C)O3)[C@@H]2c2ccc(OCCCOc3ccccc3C#N)cc2)cc2ccccc12

Procedure:
In analogy to the procedure described in example 1) (f) the (3S,4R,5R)-4-[4-[3-(2-cyano-phenoxy)-propoxy]-phenyl]-3-[(4S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-5-hydroxy-piperidine-1-carboxylic acid tert-butyl ester was reacted with 3-chloromethyl-1-methoxy-naphthalene [example 1 (α)] to yield the (3S,4R,5R)-4-[4-[3-(2-cyano-phenoxy)-propoxy]-phenyl]-3-[(4S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester as colorless oil; MS: 753 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6])=[CH2:2].S(Cl)([Cl:14])=O>>[CH:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([Cl:14])=[O:6])=[CH2:2]
Reactant: O=S(Cl)Cl
Reactant: C=Cc1ccccc1C(=O)O
Product: C=Cc1ccccc1C(=O)Cl

Procedure:
Reaction of 2-ethenylbenzoic acid with thionyl chloride affords 2-ethenylbenzoyl chloride, which on reaction with diethylamine, affords 2-ethenyl-N,N-diethylbenzamide. Reaction of the latter with s-butyl lithium and reaction of the resulting lithium salt with sulfur dioxide followed by sodium hydroxylamine-O-sulfonate affords 2-ethenyl-6-aminosulfonyl-N,N-diethylbenzamide, which, on heating in glacial acetic acid, affords 4-ethenylsaccharin.
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7]1>CN(C)C=O>[O:6]1[C:10]2[CH:11]=[CH:12][C:13]([S:1]([Cl:5])(=[O:3])=[O:2])=[CH:14][C:9]=2[O:8][CH2:7]1
Reactant: O=S(=O)(Cl)Cl
Reactant: c1ccc2c(c1)OCO2
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1ccc2c(c1)OCO2
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 16.3 %

Procedure:
To a solution of 4.25 g of anhydrous N,N-dimethylformamide at 0° C. under nitrogen was added 7.84 g of sulfuryl chloride, whereupon a solid formed. After stirring for 15 minutes, 6.45 g of 1,3-benzodioxole was added, and the mixture heated at 100° C. for 2 hours. The reaction was cooled, poured into ice water, extracted with methylene chloride, dried over magnesium sulfate, filtered and concentrated to give 7.32 g of crude material as a black oil. This was chromatographed on silica gel using 20% methylene chloride/hexane to afford 1.9 g of (1,3-benzodioxol-5-yl)sulfonyl chloride.
Reaction SMILES: Cl.[CH:2]([Si:5]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[O:6][CH2:7][CH2:8][C@@H:9]([CH3:24])[CH2:10][C@@H:11]1[N:16]=C(OC)[C@@H](C(C)C)N=[C:12]1[O:22][CH3:23])([CH3:4])[CH3:3].[OH-:31].[Na+]>O1CCCC1>[NH2:16][C@@H:11]([CH2:10][C@H:9]([CH3:24])[CH2:8][CH2:7][O:6][Si:5]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:2]([CH3:4])[CH3:3])[C:12]([O:22][CH3:23])=[O:31]
Reactant: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1C[C@H](C)CCO[Si](C(C)C)(C(C)C)C(C)C
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)[C@@H](N)C[C@H](C)CCO[Si](C(C)C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
100 ml of 0.5N hydrochloric acid are added to a solution of 10.0 g of 3,6-dihydro-3(S)-[4-triisoproylsilyloxy-2(S)-methylbutyl]-6(R)-isopropyl-2,5-dimethoxypyrazine in 100 ml of tetrahydrofuran and the mixture is stirred at room temperature for 40 min. The reaction mixture is brought to pH 9 by addition of 1N sodium hydroxide solution and then extracted with methylene chloride. The combined organic phase is filtered through cotton wool and concentrated. The crude product is purified by FC over 900 g of silica gel with a 500:10:1 mixture of methylene chloride, methanol and 25% ammonia solution. In addition to the re-isolated starting material, this gives the title compound: Rf (methylene chloride-methanol-concentrated ammonia: (140:10:1))=0.34.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:20])[C:5]([Cl:19])=[C:6]([O:8][C:9]2[C:10]([F:18])=[C:11]([CH2:16][NH2:17])[CH:12]=[CH:13][C:14]=2[Cl:15])[CH:7]=1.[C:21]([Zn]C#N)#[N:22].CN(C=O)C>C(O)CC.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>[NH2:17][CH2:16][C:11]1[C:10]([F:18])=[C:9]([O:8][C:6]2[CH:7]=[C:2]([CH:3]=[C:4]([F:20])[C:5]=2[Cl:19])[C:21]#[N:22])[C:14]([Cl:15])=[CH:13][CH:12]=1
Reactant: N#C[Zn]C#N
Reactant: NCc1ccc(Cl)c(Oc2cc(Br)cc(F)c2Cl)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCO
Solvent: CN(C)C=O
Product: N#Cc1cc(F)c(Cl)c(Oc2c(Cl)ccc(CN)c2F)c1
Temperature: 120 °C
Yield: 89.8 %

Procedure:
({3-[(5-bromo-2-chloro-3-fluorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)amine (3.00 g, 7.83 mmol) was combined with dicyanozinc (0.460 g, 3.92 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.453 g, 0.392 mmol) in n-propanol (15 mL) and heated at 120° C. for 25 min in a microwave reactor under an inert atmosphere. DMF (8 mL) was added and the reaction mixture was again heated at 120° C. for 90 min in a microwave reactor at which time LC-MS indicated complete conversion. The reaction mixture was concentrated to remove the n-propanol, diluted with EtOAc, washed four times with saturated aqueous NaHCO3, dried over MgSO4, filtered and concentrated to dryness. The residue was purified on 80 g silica gel eluted successively with EtOAc followed by 0 to 10% CH3OH/DCM to give 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-4-chloro-5-fluorobenzonitrile (1.16 g, 3.52 mmol, 45.0% yield) as a pale yellow oil which crystallized on standing. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.92 (dd, J=8.65, 1.51 Hz, 1H), 7.47-7.58 (m, 2 H), 7.25 (s, 1H), 3.77 (s, 2H), 1.93 (br. s., 2H). LC-MS (ES−) m/z 326.96, 329.05 [M−1]. LC-MS (ES+) m/z 329.00, 330.96 [M+H].
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.[NH:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.C(=O)([O-])[O-].[K+].[K+]>[Cu].O>[N:11]1([C:2]2[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: c1c[nH]cn1
Reactant: O=[N+]([O-])c1cccc(I)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=[N+]([O-])c1cccc(-n2ccnc2)c1
Temperature: 200 °C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
A mixture of 1-iodo-3-nitrobenzene (90 g, 0.36 mol), imidazole (54 g, 0.79 mol), potassium carbonate (54 g, 0.39 mol) and finely divided copper powder (1 g) is heated to 200° C. The melt is stirred for 2 hours under nitrogen. During the reaction water vapor is trapped by molecular sieves, placed between the reation vessel and the condenser. Following the reaction the mixture is cooled to 100° C. and water is added. The mixture is allowed to cool to room temperature and the crude product is filtered off and dried. Recrystallization from toluene (200-250 ml) affords pure 3-(1-imidazolyl)nitrobenzene (54.2 g, 79%). Mp 101-102° C.
Reaction SMILES: [OH-].[Na+].CO.C([O:7][C:8]([C:10]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:13][S:12][C:11]=1[N:23]1[C:31](=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]1=[O:33])=[O:9])C.Cl>O>[O:32]=[C:31]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](=[O:33])[N:23]1[C:11]1[S:12][CH:13]=[C:14]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[C:10]=1[C:8]([OH:9])=[O:7]
Reactant: CCOC(=O)c1c(-c2ccc(OC)cc2)csc1N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(-c2csc(N3C(=O)c4ccccc4C3=O)c2C(=O)O)cc1

Procedure:
To a solution of NaOH (1.4 mmol) in a 1:1 mixture of methanol:H2O (6 mL) is added 2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-4-(4-methoxyphenyl)-thiophene-3-carboxylic acid ethyl ester (0.7 mmol, Example 20, Part C). The mixture is heated to reflux for 90 min, then diluted with water (12 mL), chilled in an ice bath, and acidified with concentrated HCl. The product that precipitates is collected by filtration, washed with water, and dried, affording the desired compound.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[N:31]1([CH2:6][CH2:7][C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:18]=[CH:19][C:20]([C:23]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[O:24])=[CH:21][CH:22]=4)=[CH:13][C:11]=3[CH:12]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cc3)ccc2o1
Reactant: C1CCNCC1
Product: O=C(c1ccc(-c2ccc3oc(CCN4CCCCC4)cc3c2)cc1)N1CCOCC1

Procedure:
The product from Example 23D and piperidine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ 7.82 (m, 1H), 7.73 (d, J=8.1, 2H), 7.54 (m, 2H), 7.51 (d, J=8.1 Hz, 2H), 6.77 (s, 1H), 3.32-3.8 (m, 14H), 3.07 (m, 2H), 1.5-2.1 (m, 6H); MS (DCI) m/z 419 (M+H)+;
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:8][C:9]=1[N:10]([C:17]([C@H:19]1[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]1)=[O:18])[CH:11]1[CH2:16][CH2:15][S:14][CH2:13][CH2:12]1)=[O:4].C(OO)(=O)C1C(=CC=CC=1)C(O)=[O:36].[Mg]>CCO.O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:8][C:9]=1[N:10]([C:17]([C@H:19]1[CH2:20][CH2:21][C@H:22]([CH3:25])[CH2:23][CH2:24]1)=[O:18])[CH:11]1[CH2:16][CH2:15][S:14](=[O:36])[CH2:13][CH2:12]1)=[O:4]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCSCC1
Reactant: O=C(O)c1ccccc1C(=O)OO
Agent: [Mg]
Solvent: O
Solvent: CCO
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCS(=O)CC1
Reaction time: 24 h

Procedure:
To a stirred solution of 3-[(trans-4-methyl-cyclohexanecarbonyl)-(tetrahydro-thiopyran-4-yl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (57 mg, 0.124 mmol)in EtOH (1.2 mL) from step 2 was added magnesium monoperoxyphthalic acid (29.6 mg, 0.06 mmol) in one portion, stirred for 24 h. Reaction mixture was diluted with water, extracted with EtOAc. The combined organic solution was washed with brine, dried, and concentrated. Purification of the residue on Preparative TLC using 5% MeOH-DCM gave 3-[(trans-4-methyl-cyclohexanecarbonyl)-(1-oxo-tetrahydro-thiopyran-4-yl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (30 mg, 51%). NMR 1H (CDCl3, 400 MHz, For major isomer): 7.66-7.6 (m, 2H), 7.5-7.4 (m, 3H), 7.09 (s, 1H), 4.84-4.76 (t, 1H), 3.85 (s, 3H), 3.4-1.2 (m), 0.772 (d, J=6.6, 3H), 0.74-0.56 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][CH2:10][CH2:11][O:12][C:7]=2[C:6]([C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.[Cl:16][S:17](O)(=[O:19])=[O:18]>>[CH3:1][O:2][C:3]1[C:8]2[O:9][CH2:10][CH2:11][O:12][C:7]=2[C:6]([C:13]([OH:15])=[O:14])=[CH:5][C:4]=1[S:17]([Cl:16])(=[O:19])=[O:18]
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccc(C(=O)O)c2c1OCCO2
Product: COc1c(S(=O)(=O)Cl)cc(C(=O)O)c2c1OCCO2
Temperature: 25 °C
Yield: 98 %

Procedure:
1045 cm3 of chlorosulfonic acid were introduced into a balloon flask provided with an agitator, a thermometer and a condenser and then, in portions, 110 g of 8-methoxy-1,4-benzodioxane-5-carboxylic acid were added with the temperature being maintained at from 5°-10°C. The mixture was agitated at ambient temperature and then poured on ice. The precipitate was dried off, washed and dried. 159 g of 8-methoxy-7-chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid were obtained. (yield: 98%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]3[O:23][CH2:24][O:25][C:19]=3[CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:26]>C(OCC)(=O)C>[ClH:26].[CH2:24]1[O:23][C:20]2[CH:21]=[CH:22][C:17]([S:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)(=[O:16])=[O:15])=[CH:18][C:19]=2[O:25]1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc3c(c2)OCO3)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc2c(c1)OCO2)N1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-tert-butoxycarbonyl-4-(3,4-methylenedioxybenzenesulfonyl)piperazine (0.5g) in ethyl acetate (2 ml) was added 4 N HCl in ethyl acetate (10 ml), and the mixture was stirred at room temperature for 30 minutes. The precipitated crystals were filtered to give 3,4-methylenedioxybenzenesulfonylpiperazine hydrochloride (0.39g). To a solution of the crystals (100 mg) in dichloromethane (3 ml) were added triethylamine (0.05 ml), 4-methyl-2-(4-pyridyl)thiazole-5-carboxylic acid (74 mg) and WSC (70 mg), and the mixture was stirred at room temperature for 2 hours and concentrated. To the residue was added water, and the solution was extracted with ethyl acetate. The extract was washed with water, dried (MgSO4) and concentrated to give the title compound as crystals (90 mg). The crystals were filtered and washed with ether. NMR (CDCl3): 2.48(3H, s), 3.07(4H, m), 3.75(4H, m), 6.12(2H, s), 6.93(1H, d, J=8.2 Hz), 7.17(2H, s), 7.31(1H, d, J=8.2 Hz), 7.74(2H, d, J=6.2 Hz), 8.71(2H, d, J=6.2 Hz). IR(KBr):1626, 1479, 1427, 1342, 1250 cm1.