Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].[CH3:14][S:15]([N:18]1[CH2:23][CH2:22][CH:21](OS(C)(=O)=O)[CH2:20][CH2:19]1)(=[O:17])=[O:16]>C(O)C.CO>[CH3:14][S:15]([N:18]1[CH2:23][CH2:22][CH:21]([S:1][C:2]2[N:7]3[CH:8]=[CH:9][N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:20][CH2:19]1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)OC1CCN(S(C)(=O)=O)CC1
Reactant: Sc1cccc2nccn12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CS(=O)(=O)N1CCC(Sc2cccc3nccn23)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 37.1 %

Procedure:
To a suspension of 5-mercaptoimidazo[1,2-a]pyridine (1.50 g, 10 moles) in ethanol (100 ml) was added a solution of 4.1M sodium methylate (2.44 ml, 10 mmoles) in methanol and the mixture was stirred at room temperature for 10 minutes. To the reaction mixture was added 1-methylsulfonyl-4-methylsulfonyloxypiperidine (2.83 g, 11 mmoles) at room temperature and the mixture was heated under reflux for 14 hours. After the solvent was distilled off, the residue was dissolved in chloroform, which was washed in turn with an aqueous 1N sodium hydroxide solution and water and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by column chromatography [eluent:ethyl acetate/ethanol (10:1)] to obtain 1.27 g of the desired product (40.8%, light brown solid).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([CH3:22])[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH2:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCOC(C)=O.[C:29]([OH:32])(=[S:31])[CH3:30]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([CH3:22])[CH:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][S:31][C:29](=[O:32])[CH3:30])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(O)=S
Reactant: C=C(C(=O)OCC)C(C)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CSC(C)=O)C(C)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 45 °C

Procedure:
TEA (86 μL, 0.617 mmol) was added to a solution of 4-(2ethoxycarbonyl-1-methyl-allyl)-piperidine-1-carboxylic acid tert-butyl ester (0.18 g, 0.59 mmol) in thioacetic acid (2 mL) at 0° C. After stirring for 6 h more thioacetic acid (2 mL) was added and the mixture was stirred at 45° C. over night. EtOAc was added and the mixture was washed with water, saturated NaHCO3 and brine, dried and concentrated under reduced pressure. The crude was purified by flash chromatography (toluene/EtOAc, 5:1→1:1) to slightly unpure 4-(3-acetylsulfanyl-2-ethoxycarbonyl-1-methyl-propyl)-piperidine-1-carboxylic acid tert-butyl ester (0.17 g, 75%).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25](C(F)(F)F)[CH:26]=1)[CH2:6][N:7]([CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1I)[C:8](=[O:11])[O:9][CH3:10].[C:33]([Cu])#[N:34].[NH4+].[OH-]>CN(C=O)C>[CH3:10][O:9][C:8](=[O:11])[N:7]([CH2:6][C:5]1[CH:24]=[C:25]([C:2]([F:32])([F:31])[F:1])[CH:26]=[C:3]([C:2]([F:31])([F:1])[F:32])[CH:4]=1)[CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[C:33]#[N:34]
Reactant: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1I
Reactant: N#C[Cu]
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1C#N
Temperature: 25 °C

Procedure:
To a solution of Example 5 dissolved in DMF (1.5 mL) was added CuCN (20 mg, 0.22 mmol) and the resultant mixture was heated at 100° C. for 16 h. The reaction was cooled to room temperature, poured into NH4OH (10 mL) and extracted with EtOAC (4×30 mL). The combined organic extracts were washed with H2O and brine (10 mL each), dried over MgSO4, filtered and concentrated in vacuo. Purification by flash chromatography (0 to 25% EtOAc/hexanes) afforded the title compound as a colorless oil. LCMS=485 (M+1)+. 1H NMR (CDCl3, 500 MHz): δ 7.81 (s, 1H), 7.78 (d, J=7.7 Hz, 1H), 7.67-7.31 (m, 4H), 4.82 (br s, 2H), 4.72 (s, 2H), 3.91 (s, 3H).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[NH:21][C:20](=[O:22])[C@H:19]([CH:23]([CH3:25])[CH3:24])[NH:18][C:17](=[O:26])[C@@H:16]([NH:27][C:28]([C:30]2[NH:31][CH:32]=[CH:33][CH:34]=2)=[O:29])[CH2:15][C:14]2=[CH:35][CH:36]=[C:11]([CH:12]=[CH:13]2)[O:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=O.CC(C[AlH]CC(C)C)C.CCOC(C)=O>C(Cl)Cl>[CH:3]([C@H:5]1[NH:21][C:20](=[O:22])[C@H:19]([CH:23]([CH3:25])[CH3:24])[NH:18][C:17](=[O:26])[C@@H:16]([NH:27][C:28]([C:30]2[NH:31][CH:32]=[CH:33][CH:34]=2)=[O:29])[CH2:15][C:14]2=[CH:13][CH:12]=[C:11]([CH:36]=[CH:35]2)[O:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:2]
Reactant: COC(=O)[C@@H]1CCCCOc2ccc(cc2)C[C@H](NC(=O)c2ccc[nH]2)C(=O)N[C@@H](C(C)C)C(=O)N1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)[C@@H]1NC(=O)[C@@H](NC(=O)c2ccc[nH]2)Cc2ccc(cc2)OCCCC[C@@H](C=O)NC1=O
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Ester 51 (45 mg) was dissolved in DCM (6 mL) under an atmosphere of argon. The reaction was cooled to −78° C. To the resultant solution DIBAL (0.5 mL) was added dropwise. This was stirred for 2 h before being allowed to warm to rt overnight. The reaction mixture was partitioned between EtOAc and 1M hydrochloric acid. The aqueous phase was extracted again with EtOAc and the combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. Purification was achieved using flash chromatography, eluting with a gradient of 1/1 EtOAc/(50/70) petroleum ether to EtOAc to yield a light brown solid, 14 mg, 33%. Rf=0.25 (1/1 EtOAc/(50/70) petroleum ether).
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:21])[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5].C(=O)=O.[H][H].[ClH:27]>C(O)C.C(OCC)(=O)C.[Pd]>[ClH:27].[ClH:27].[CH3:1][O:2][N:3]([CH3:21])[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: CON(C)C(=O)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Agent: O=C=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CON(C)C(=O)C1CCN(c2ccc(N)cc2)CC1
Yield: 100 %

Procedure:
A solution of 1-(4-nitro-phenyl)-piperidine-4-carboxylic acid methoxy-methyl-amide (approximately 0.20 g, 0.8 mmol) in ethanol/ethyl acetate (1:1, 30 mL) and concentrated hydrochloric acid (1 mL) is degassed with dry ice. Palladium on carbon (10%, 35 mg) is added and the mixture is shaken for two hours under 40 psi of hydrogen. The mixture is filtered through a pad of diatomaceous earth and concentrated under reduced pressure to give 1-(4-amino-phenyl)-piperidine-4-carboxylic acid methoxy-methyl-amide dihydrochloride (0.30 g, >100%).
Reaction SMILES: [CH2:1]([O:4]C(=O)NC1CC(=O)OC1OCC)[CH:2]=C.[O:17]=[C:18]1[O:22][CH:21]([O:23][CH2:24][CH2:25]C2C=CC=CC=2)[CH:20]([NH:32][C:33]([CH:35]2[CH2:39][CH2:38][CH2:37][N:36]2[C:40](=[O:54])[CH:41]([NH:43][C:44](=[O:53])[C:45]2[CH:50]=[CH:49][C:48]([NH2:51])=[C:47]([Cl:52])[CH:46]=2)[CH3:42])=[O:34])[CH2:19]1>>[CH2:24]([O:23][CH:21]1[CH:20]([NH:32][C:33]([CH:35]2[CH2:39][CH2:38][CH2:37][N:36]2[C:40](=[O:54])[CH:41]([NH:43][C:44](=[O:53])[C:45]2[CH:50]=[CH:49][C:48]([NH:51][C:1](=[O:4])[CH3:2])=[C:47]([Cl:52])[CH:46]=2)[CH3:42])=[O:34])[CH2:19][C:18](=[O:17])[O:22]1)[CH3:25]
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Reactant: C=CCOC(=O)NC1CC(=O)OC1OCC
Product: CCOC1OC(=O)CC1NC(=O)C1CCCN1C(=O)C(C)NC(=O)c1ccc(NC(C)=O)c(Cl)c1

Procedure:
Prepared from (2-ethoxy-5-oxo-tetrahydro-furan-3-yl)-carbamic acid allyl ester and 97b following the method used for 98a. The title compound was isolated as a white solid (51 mg, 18% yield). 1H-NMR (500 MHz, 1:1 CDCl3:CD3OD) δ 1.08-1.35 (m, 3H), 1.35-1.55 (m, 3H), 1.75-2.44 (m, 4H), 2.26 (s, 3H), 2.44-3.07 (m, 2H), 3.48-3.97 (m, 2H), 4.18-4.92 (m, 5H), 5.32 (d, 0.4H), 5.47 (d, 0.1H), 5.58 (d, 0.4H), 5.64 (d, 0.1H), 7.70-8.35 (m, 3H). Analytical HPLC 10.37, 10.54 min. LC-MS (ES+) m/e=509.2 (M+H+).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][NH:8]1)=[N+:2]=[N-:3].[CH:13](OCC)=[S:14]>CCOCC>[CH:13]([N:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]1[CH2:6][CH2:5][CH2:4][N:1]=[N+:2]=[N-:3])=[S:14]
Reactant: [N-]=[N+]=NCCCC1CCCCN1
Reactant: CCOC=S
Solvent: CCOCC
Product: [N-]=[N+]=NCCCC1CCCCN1C=S
Reaction time: 8 h

Procedure:
To a solution of 2-(3'-azidopropyl)-piperidine (1.8 g) in ether (10 ml) was added ethyl thioformate (1.5 ml). The solution was kept at 4° C. overnight and evaporated to leave an oil which was purified by chromatograpy on silica gel. The IR-spectrum (CHCl3) showed strong bands at 2950, 2100, 1485, 1445 and 1250 cm-1.
Reaction SMILES: Cl[C:2]1[CH:12]=[C:6]2[N:7]([CH3:11])[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:13])[N:3]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:27]=[CH:28][C:29]=1[Cl:30])[O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][OH:26])=[CH:21][CH:20]=1>>[Cl:14][C:15]1[CH:16]=[C:17]([CH:27]=[CH:28][C:29]=1[Cl:30])[O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][O:26][C:2]2[CH:12]=[C:6]3[N:7]([CH3:11])[CH2:8][CH2:9][CH2:10][N:5]3[C:4](=[O:13])[N:3]=2)=[CH:21][CH:20]=1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: OCc1ccc(Oc2ccc(Cl)c(Cl)c2)cc1
Product: CN1CCCn2c1cc(OCc1ccc(Oc3ccc(Cl)c(Cl)c3)cc1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one and (4-(3,4-dichlorophenoxy)phenyl)methanol.
Reaction SMILES: O.[C:2]1([CH3:13])[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]=[CH:11][CH3:12])=[CH:4][CH:3]=1>[Pt].CCCCCCC>[CH3:13][C:2]1[CH:7]=[CH:6][C:5]2[CH:8]=[CH:9][CH:10]=[C:11]([CH3:12])[C:4]=2[CH:3]=1
Reactant: CC=CCCc1ccc(C)cc1
Agent: [Pt]
Solvent: CCCCCCC
Solvent: O
Product: Cc1ccc2cccc(C)c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Deionized water (500 parts) was added to H mordenite (15 parts) made by Tosoh Corporation, silica (270 parts), and alumina sol (21 parts) containing 70 weight percent alumina as a binder, and the mixture was thoroughly stirred at room temperature. After shaping of the slurry with an extruder, the shaped article was dried at 110° C. and then calcined at 350° C. for 3 hours to prepare a catalyst. After this catalyst was packed into a cylindrical stainless-steel cyclization reactor, 5-(p-tolyl)-2-pentene prepared by the preceding step was fed at a rate of 10 parts/hr while nitrogen was fed at a rate of 250 parts/min to complete a cyclization reaction at a temperature of 170° C. under normal pressure. The molar ratio of the diluent solvent to the raw material was 11. After the cyclization reaction, the reaction solution was fed to a cylindrical stainless-steel dehydrogenation reactor filled with 40 parts of 1%-platinum/activated charcoal catalyst (made by N.E. CHEMCAT). The reaction temperature was 280° C. During the dehydrogenation reaction, n-heptane as the diluent solvent was also fed at a rate of 20 parts/hr. After the reaction, the solution was fed to a glass distillation column under a reduced pressure of 19 kPa to recover n-heptane. The residual reaction solution after the removal of n-heptane was fed to a glass distillation column under a reduced pressure of 13 kPa to separate low-boiling-point components at a rate of 0.05 parts/hr and high-boiling-point components at a rate of 0.3 parts/hr and to isolate 9.4 parts of 1,7-DMN with a purity of 98% from a middle plate of the distillation column.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[N+:12]([O-])=O)[CH3:2]>[Pd].C(O)C>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[NH2:12])[CH3:2]
Reactant: CCOC(=O)Cc1ccncc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)Cc1ccncc1N
Yield: 111.8 %

Procedure:
To a 250-ml Parr flask was added 0.30 g (1.4 mmol) of 3-nitro-4-pyridineacetic acid ethyl ester, 50 mg of 10% palladium on charcoal and 100 mL of ethanol. The mixture was subjected to hydrogenation using a Parr hydrogenator at 40 PSI for 15 min. The mixture was filtered through celite, and the filtrate was concentrated to give an oil which crystallised under a high vacuum to afford 0.282 g of the title compound as a yellow solid. 1H NMR (DMSO-d6): δ 1.15 (t, J=7.2 Hz, 3H), 3.52 (s, 2H), 4.05 (q, J=7.2 Hz, 2H), 5.11 (s, 2H), 6.89 (d, J=4.8 Hz, 1H), 7.67 (d, J=4.8 Hz, 1H), 7.92 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:33]#[C:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:8][C:9]=1[N:10]([C:24]([C@H:26]1[CH2:31][CH2:30][C@H:29]([CH3:32])[CH2:28][CH2:27]1)=[O:25])[CH:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1)=[O:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:33]#[C:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[CH:8][C:9]=1[N:10]([C:24]([C@H:26]1[CH2:27][CH2:28][C@H:29]([CH3:32])[CH2:30][CH2:31]1)=[O:25])[CH:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]1)=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product from step IV (5.198 g) is dissolved in 30 mL of CH2Cl2 and treated with 20 mL of trifluoroacetic acid. The mixture is stirred at room temperature overnight, then it is evaporated to dryness, obtained residue is redissolved in CH2Cl2 and washed with aqueous NaHCO3 and brine. Organic fraction is separated, dried over Na2SO4, and concentrated to give 5.340 g of crude 5-(3,3-dimethyl-but-1-ynyl)-3-[(trans-4-methyl-cyclohexanecarbonyl)-(piperidin-4-yl)amino]-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](O)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].P(Br)(Br)([Br:29])=O>C1(C)C=CC=CC=1>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([Br:29])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Br)(Br)Br
Reactant: CCCCOC(=O)c1nc(O)c2cc(SC3CCCCC3)ccc2c1O
Solvent: Cc1ccccc1
Product: CCCCOC(=O)c1nc(Br)c2cc(SC3CCCCC3)ccc2c1O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74 %

Procedure:
To a mixture of 7-cyclohexylsulfanyl-1,4-dihydroxy-isoquinoline-3-carboxylic acid butyl ester (2.95 g, 7.87 mmol) in toluene (40 mL) was added POBr3 (3.38 g, 11.8 mmol) was refluxed for 3 h. Reaction mixture was cooled to 0° C. and quenched with saturated NaHCO3 aqueous solution (100 mL). It was stirred for 15 min., and then was extracted with EtOAc. Organic layer was washed with brine, dried over MgSO4, filtered and concentrated to provide the title compound 2.55 g (5.82 mmol), which was used directly to the next reaction without further purification. 1H NMR (200 MHz) CDCl3, δ in ppm: 11.85 (s, 1H), 8.23 (d, J=8.8 Hz, 1H), 8.05 (s, 1H), 7.65 (d, J=8.5 Hz, 1H), 4.47 (t, J=7.0 Hz, 2H), 3.46 (br S, 1H), 2.10 (br m, 2H), 1.85-1.42 (m, 12H), 0.99 (t, J=7.1 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C:11]2[CH:12]=[N:13][CH:14]=[C:15]([F:17])[CH:16]=2)[C:5]([N+:18]([O-])=O)=[CH:4][CH:3]=1.[Cl-].[NH4+]>CO.O.[Fe]>[NH2:18][C:5]1[C:6]([NH:10][C:11]2[CH:12]=[N:13][CH:14]=[C:15]([F:17])[CH:16]=2)=[C:7]([C:2]([F:1])=[CH:3][CH:4]=1)[C:8]#[N:9]
Reactant: N#Cc1c(F)ccc([N+](=O)[O-])c1Nc1cncc(F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: N#Cc1c(F)ccc(N)c1Nc1cncc(F)c1
Yield: 61.5 %

Procedure:
(6-Fluoro-2-(5-fluoropyridin-3-ylamino)-3-nitrobenzonitrile (1.73 g, 6.26 mmol), iron powder (712 mg, 12.5 mmol), and ammonium chloride (966 mg, 18.8 mmol) in methanol (40 mL) and water (12 mL) were heated at 90° C. for 1 h. The reaction mixture was filtered and the filtrate concentrated in vacuo. The residue was dissolved in water and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% EtOAc in cyclohexane) to yield the title compound as brown solid (948 mg, 61%). 1H NMR 400 MHz δ (CDCl3): 8.05 (1H, d, J=2.4 Hz), 8.03-7.99 (1H, m), 7.01 (1H, d, J=2.1 Hz), 6.99 (1H, s), 6.59 (1H, dt, J=10.2, 2.4 Hz), 5.78 (1H, br s), 3.84 (2H, br s).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:7][C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.C(O[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23])C>CC#N>[N+:22]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:16]=1[NH:1][CH2:2][C:3]1[O:7][C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1)([O-:24])=[O:23]
Reactant: NCc1ccc(CCC(=O)O)o1
Reactant: CCOc1ccncc1[N+](=O)[O-]
Solvent: CC#N
Product: O=C(O)CCc1ccc(CNc2ccncc2[N+](=O)[O-])o1

Procedure:
The desired compound was prepared by heating a solution in CH3CN of 5-aminomethyl-2-carboxyethylfuran with 4-ethoxy-3-nitropyridine.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH:9]([O:10][C:11](=[O:13])[CH3:12])[CH:8]=[CH:7][S:6]1)=[O:4].S(Cl)(Cl)(=O)=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[O:10][C:11](=[O:13])[CH3:12])=[O:4]
Reactant: COC(=O)C1SC=CC1OC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: O=S(=O)(Cl)Cl
Product: COC(=O)c1sccc1OC(C)=O
Yield: 79 %

Procedure:
20.2 Parts of 3-acetoxydihydrothiophene-2-carboxylic acid methyl ester are reacted with 6.75 parts by volume of sulfuryl chloride in 150 parts by volume of CCl4 at 0° C. for one hour. The end product is isolated from the reaction mixture by the method described in Example 14c). 15.8 parts (79% of theory) of 3-acetoxythiophene-2-carboxylic acid methyl ester of boiling point 84°-86° C./0.04 mbar are obtained.
Reaction SMILES: [C:1]([OH:12])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[C:8]([OH:10])(=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12]
Reactant: O=C(O)CCCCCCC(=O)O
Reactant: Nc1ccccc1
Solvent: Cc1ccccc1
Product: O=C(O)CCCCCCC(=O)Nc1ccccc1

Procedure:
Suberic acid (Compound 1, 174.2 g, 1.0 mole), aniline (Compound 2, 85.8-94.9 g), and toluene (0.1-0.2 L) are combined, heated to reflux and refluxed for a minimum of 60 hours. The reaction is quenched at reflux by adjusting the pH to ≧11 with 10% sodium hydroxide solution. The aqueous phase is separated. The organic layer is combined with toluene (0.11-0.13 L) and water (0.3-0.4 L), and the aqueous layer is separated. The aqueous layers from the extractions and toluene (0.11-0.13 L) are combined, settled, and then separated. The aqueous layer is extracted twice with toluene (0.2-0.3 L) at 60-70° C. The aqueous layer is adjusted at 20-30° C. to a pH of 5.8-6.2, using hydrochloric acid and 10% sodium hydroxide solution as needed. The batch is filtered, washed with chilled water (0.2-0.3 L) and then washed with chilled isopropanol. The wet cake is dried at a maximum of 65° C. under vacuum to yield suberanilic acid.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:10]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:8]=[CH:7][C:6]=2[C@H]2CN(C(OC(C)(C)C)=O)[CH2:18][C@H:4]2[NH:3]1.Cl.O1CCO[CH2:29][CH2:28]1>C(OCC)C>[CH2:28]([N:3]([CH2:4][CH3:18])[C:2](=[O:1])[C:11]1[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=1[C:12]([F:13])([F:14])[F:15])[CH3:29]
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2c3cccc(C(F)(F)F)c3C(=O)N[C@@H]2C1
Agent: Cl
Solvent: CCOCC
Product: CCN(CC)C(=O)c1ccccc1C(F)(F)F
Reaction time: 4 h
Yield: 85 %

Procedure:
To a solution of (±)-cis-tert-butyl 5-oxo-6-(trifluoromethyl)-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate (50 mg, 0.14 mmol) in 1 mL of 1,4-dioxane was added 4 mL of 4 N HCl in dioxane. The reaction was allowed to stir for 4 h and then was diluted with diethyl ether. A solid slowly settled out of solution. The solvents were decanted and the remaining solid was triturated twice with diethyl ether and dried in vacuo to afford 35 mg (85%) of the title compound of Example 1 as an off-white solid. 1H NMR (DMSO-D6): δ 9.8 (broad s, 1H), 9.6 (broad s, 1H), 8.15 (s, 1H), 7.86 (d, 1H, J=7.1 Hz), 7.78-7.70 (m, 2H), 4.40-4.38 (m, 1H), 3.75-3.67 (m, 2H), 3.55-3.52 (m, 1H), 3.45-3.37 (m, 1H), 3.10-3.05 (m, 1H). LRMS (ESI): 257.16 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:10][C:9]2([C:17](=O)[CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[NH2:33][NH2:34]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:34][N:33]=[C:17]([CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:21][CH2:20]3)[C:9]2([OH:10])[C:11]2[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)C2(c3ccncc3)OC2c2ccc(F)cc2)CC1
Reactant: NN
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(CC2=NNC(c3ccc(F)cc3)C2(O)c2ccncc2)CC1
Temperature: 25 °C
Yield: 53.9 %

Procedure:
To a solution of 1,1-dimethylethyl 4-[2-[3-(4-fluorophenyl)-2-(4-pyridinyl)oxiranyl]-2-oxoethyl]-1-piperidinecarboxylate prepared in step 4 of this Example (3.45 g, 7.8409 mmol) in ethanol (15 mL), anhydrous hydrazine (0.50 mL, 15.6818 mmol) was added. The reaction was heated to reflux overnight. The reaction solution was cooled to room temperature and ethanol was removed under reduced pressure. The resulting residue was taken into ethyl acetate, washed with water and brine, and dried over MgSO4. After filtration the solvent was removed under reduced pressure. The crude residue was purified by chromatography (silica gel, 2:1-1:1-1:2 hexane/ethyl acetate) to give 1,1-dimethylethyl 4-[[5-(4-fluorophenyl)-4,5-dihydro-4-hydroxy-4-(4-pyridinyl)-1H-pyrazol-3-yl]methyl]-1-piperidinecarboxylate (1.9187 g, 53.9%). This intermediate (1.8611 g, 4.0993 mmol) was dissolved in dry methylene chloride (40 mL) and treated with Martin sulfurane dehydrating reagent (4.13 g, 6.1490 mmol). The reaction solution was stirred at room temperature under N2 overnight, then diluted with ethyl acetate, washed with 1N sodium hydroxide solution, water and brine, dried over MgSO4. After filtration the solvents were removed. The resulting crude pruduct mixture was purified by flash chromatoghaphy (silica gel, 2:1-1:1-1:2 Hexane/ethyl acetate) to give 1,1-dimethylethyl 4-[[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]methyl]-1-piperidinecarboxylate (0.6964 g, 39%).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:26])[CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[Cl:25])=[CH:7][C:6]=1[Cl:27].[CH3:28][O:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[Cl:27][C:6]1[CH:7]=[C:8]([NH:11][C:12](=[O:26])[CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[Cl:25])[CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][N:33]1[CH2:34][CH2:35][CH:30]([O:29][CH3:28])[CH2:31][CH2:32]1
Reactant: O=C(COc1ccc(C(F)(F)F)cc1Cl)Nc1ccc(OCCBr)c(Cl)c1
Reactant: COC1CCNCC1
Product: COC1CCN(CCOc2ccc(NC(=O)COc3ccc(C(F)(F)F)cc3Cl)cc2Cl)CC1

Procedure:
Prepared analogously to Example 145 starting from N-[4-(2-bromo-ethoxy)-3-chloro-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide (Z28b) and 4-methoxy-piperidine.