Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]3([CH2:30][CH2:31][CH2:32][C:33]([O:35]C)=[O:34])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:18][CH2:17]2)[C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)=[O:10])=[N:6][CH:7]=1.[OH-].[Na+].O.C(O)(=O)C>CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]3([CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:18][CH2:17]2)[C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)=[O:10])=[N:6][CH:7]=1
Reactant: COC(=O)CCCC1(CCN2CCC(N(C(=O)c3ccco3)c3ccc(C)cn3)CC2)CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CCCC(=O)O)CCCCC3)CC2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.2 %

Procedure:
To a solution of methyl 4-[1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]butyrate (210 mg) in methanol (10 mL) was added a 3N aqueous sodium hydroxide solution (1.4 mL) at room temperature. After stirring the solution at room temperature for 3 hours, a 3N aqueous sodium hydroxide solution (0.7 mL) was added thereto at room temperature. The solution was stirred at room temperature for 2 hours. Water (5 mL) and acetic acid (0.36 mL) were then added to the solution and it was concentrated under reduced pressure to distill off the methanol. The solution was extracted with 20% ethanol/chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (180 mg).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:12][N:11]([C:13]3[N:18]=[C:17]([C:19]([OH:21])=O)[CH:16]=[CH:15][CH:14]=3)[CH2:10][CH2:9][C:7]=2[N:8]=1.[CH:22]([C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28])([CH3:24])[CH3:23]>>[CH:22]([C:25]1[CH:26]=[C:27]([NH:28][C:19](=[O:21])[C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([N:11]3[CH2:10][CH2:9][C:7]4[N:8]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=4[CH2:12]3)[N:18]=2)[CH:29]=[CH:30][CH:31]=1)([CH3:24])[CH3:23]
Reactant: CC(C)c1cccc(N)c1
Reactant: CSc1ncc2c(n1)CCN(c1cccc(C(=O)O)n1)C2
Product: CSc1ncc2c(n1)CCN(c1cccc(C(=O)Nc3cccc(C(C)C)c3)n1)C2

Procedure:
In a manner similar to that described in Example 108, a mixture of 6-[2-(methylthio)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-6-yl]pyridine-2-carboxylic acid and 3-isopropylaniline were converted to the title compound (560 mg).
Reaction SMILES: C(OC([NH:11][C@H:12]([C:14]1[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:16][CH:15]=1)[CH3:13])=O)C1C=CC=CC=1>C(O)C.C(O)(=O)C.[C].[Pd]>[NH2:11][C@H:12]([C:14]1[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])=[CH:16][CH:15]=1)[CH3:13]
Reactant: C[C@H](NC(=O)OCc1ccccc1)c1ccc(C(=O)OC(C)(C)C)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: C[C@H](N)c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
To a stirred solution of tert-butyl 4-((1S)-1-{[(benzyloxy)carbonyl]amino}ethyl)benzoate (step 2, 3.48 g, 9.8 mmol) in a mixture of ethanol (25 mL) and acetic acid (25 mL) was added 10% palladium-carbon (400 mg). The mixture was stirred at room temperature for 2 h under hydrogen atmosphere. The palladium catalyst was removed by filtration and washed with ethanol (100 mL). The filtrate was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (200 mL) and saturated sodium bicarbonate aqueous solution (200 mL). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (200 mL). The combined organic extracts were washed with brine (200 mL) and dried (sodium sulfate), and concentrated to give 2.02 g (93%) of the title compounds as white solids: 1H-NMR (CDCl3) δ 7.95 (2H, d, J=8.3 Hz), 7.39 (2H, d, J=8.3 Hz), 4.22–4.12 (1H, dq, J=7.3, 6.6 Hz), 1.80 (2H, br.s), 1.58 (9H, s), 1.38 (3H, d, J=6.6 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[C:9]2OS(C(F)(F)F)(=O)=O)([O-:3])=[O:2].[CH2:22]([Sn](CCCC)(CCCC)C=C)[CH2:23]CC.[Cl-].[Li+]>O1CCOCC1.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>[N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[C:9]2[CH:22]=[CH2:23])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc2c(OS(=O)(=O)C(F)(F)F)ccnc12
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: C=Cc1ccnc2c([N+](=O)[O-])cccc12
Reaction time: 1 h
Yield: 64.1 %

Procedure:
A mixture of 8-nitro-4-(trifluoromethanesulfonyloxy)quinoline (6.0 g), tri-n-butyl(vinyl)tin (6.49 g), tetrakis(triphenylphosphine)palladium(0) (1.08 g) and lithium chloride (2.37 g) in dioxane (120 ml) was refluxed for 1.5 hours. The mixture was concentrated in vacuo, and ethyl acetate (200 ml) was added to the residue. The mixture was stirred for 1 hour, and insoluble material was filtered off. The residue was purified by flash chromatography (ethyl acetate-n-hexane) to give 8-nitro-4-vinylquinoline (2.39 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:14]N1C(=O)CCC1=O.[C:22]1([P:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br-:14].[CH2:8]([O:7][C:5]([C:4]1[CH:10]=[CH:11][C:12]([CH2:13][P+:28]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:2]([F:1])[CH:3]=1)=[O:6])[CH3:9]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)c1ccc(C)c(F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(F)c1
Product: [Br-]
Temperature: 100 °C
Reaction time: 16 h
Yield: 83.7 %

Procedure:
To a solution of ethyl 3-fluoro-4-methylbenzoate (8.586 g, 47.13 mmol) in carbon tetrachloride (70 ml) were added N-bromosuccinimide (8.388 g, 47.13 mmol) and 2,2′-azobisisobutyronitrile (309.6 mg, 1.885 mmol), and the mixture was stirred at 90° C. for 30 mins and at 100° C. for 16 hrs. The reaction mixture was cooled to 0° C., and the precipitated solid was filtered off and washed twice with hexane. The filtrate and washing solution were combined, and the mixture was washed twice with water and once with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in toluene (30 ml), and triphenylphosphine (9.891 g, 37.71 mmol) was added. The mixture was heated under reflux for 40 mins and cooled to room temperature. The precipitate was collected by filtration, and dried under reduced pressure to give [4-(ethoxycarbonyl)-2-fluorobenzyl](triphenyl)phosphonium bromide (16.52 g, yield 67.0%) as a white solid.
Reaction SMILES: C([Cl:4])(=O)C.Cl.[CH2:6]([C:13]1[S:17][N:16]([CH:18]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]2)[CH2:15][N:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CO>[ClH:4].[CH2:6]([C:13]1[S:17][N:16]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH2:15][N:14]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CN=C(Cc3ccccc3)S2)CC1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CO
Product: c1ccc(CC2=NCN(C3CCNCC3)S2)cc1
Reaction time: 0.17 h
Yield: 121.4 %

Procedure:
Acetyl chloride (0.2 mL, 2.8 mmol) was added to 2 mL of methanol and stirred for 10 min. This solution of HCl in methanol was added to 46 mg of 4-(5-benzyl-1,2,4-thiadiazol-2-yl)-1-t-butyoxycarbonyl-pieridine (step B) and stirred for 1 hr. The reaction mixture was concentrated and the residue was diluted with EtOAc and concentrated again to isolate 46 mg of the title compound which was sufficiently pure for use in the next step.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:6][N:7]1[CH2:12][CH2:11][O:10][C@@H:9]([CH2:13][NH:14][C:15](=[O:18])[CH2:16]Cl)[CH2:8]1.[CH2:23]([O:25][C:26]([C:28]1[N:29]=[C:30]([SH:33])[S:31][CH:32]=1)=[O:27])[CH3:24].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:6][N:7]1[CH2:12][CH2:11][O:10][C@@H:9]([CH2:13][NH:14][C:15](=[O:18])[CH2:16][S:33][C:30]2[S:31][CH:32]=[C:28]([C:26]([O:25][CH2:23][CH3:24])=[O:27])[N:29]=2)[CH2:8]1
Reactant: CCOC(=O)c1csc(S)n1
Reactant: O=C(CCl)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1csc(SCC(=O)NC[C@H]2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The resultant product (776 mg) of (1-2) and the resultant product (379 mg) of (1-3) were dissolved in dimethylformamide (6 mL), potassium carbonate (829 mg) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent. The solvent was evaporated from the eluent to give the title compound (850 mg) as a pale-yellow oil.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:19]1[CH:20]=[C:21]([O:25][CH3:26])[CH:22]=[CH:23][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu].[N+](C1C=CC=CC=1)([O-])=O>[C:1]1([N:7]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cccc(I)c1
Reactant: c1ccc(Nc2ccc3ccccc3c2)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1cccc(N(c2ccccc2)c2ccc3ccccc3c2)c1
Yield: 67.3 %

Procedure:
A mixture of 43.8 g (0.2 mol) of phenyl-β-naphthylamine, 46.8 g (0.2 mol) of m-iodoanisol, 27.6 g (0.2 mol) of anhydrous potassium carbonate, 2 g of copper powder and 300 ml of nitrobenzene was heated under reflux for 15 hours. The inorganic substances were filtered off and the nitrobenzene was distilled off. The residue obtained was then processed by column chromatography to obtain 43.8 g of phenyl-β-naphthyl-3-methoxyphenylamine.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].Br[CH2:37][CH2:38][CH2:39][F:40]>>[F:40][CH2:39][CH2:38][CH2:37][O:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]
Reactant: FCCCBr
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)cc1O
Product: COc1cc2c(cc1OC)C(Cc1ccc(OC)c(OCCCF)c1)N(CC(=O)NCc1ccccc1)CC2

Procedure:
prepared by reaction of 2-[1-(3-hydroxy-4-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with 1-bromo-3-fluoro-propane
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[N:11][C:12]([N+:15]([O-])=O)=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O.[Cl-].[Ca+2].[Cl-]>C(O)C>[NH2:15][C:12]1[N:11]=[CH:10][C:9]([O:8][C:6]2[CH:5]=[CH:4][C:3]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:2]([F:1])[CH:7]=2)=[CH:14][CH:13]=1
Reactant: O=C(Nc1ccc(Oc2ccc([N+](=O)[O-])nc2)cc1F)OCc1ccccc1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: Nc1ccc(Oc2ccc(NC(=O)OCc3ccccc3)c(F)c2)cn1
Temperature: 25 °C
Yield: 76.5 %

Procedure:
To a solution of benzyl {2-fluoro-4-[(6-nitropyridin-3-yl)oxy]phenyl}carbamate (40 g, 104.3 mmol) in ethanol (1020 mL)/water (180 mL) were added reduced iron (29.1 g, 521.7 mmol) and calcium chloride (5.8 g, 52.2 mmol), and the mixture was heated under reflux for 8 hr. The reaction mixture was cooled to room temperature, filtered through celite, and washed with ethanol. The solvent was evaporated under reduced pressure, water (200 mL) was added to the residue, and the mixture was extracted with ethyl acetate (800 mL). The organic layer was washed with water and saturated brine in this order, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, hexane/ethyl acetate (=3/1) was added, and the precipitate was collected by filtration to give the title compound (28.2 g, 76%).
Reaction SMILES: Cl.[CH3:2][C:3]1[NH:4]C=CN=1.[NH2:8][C:9]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:10]=1[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])=O.C(=O)(O)[O-:26].[Na+]>C(CN)O>[NH2:8][C:9]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:10]=1[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])=[N:4][CH2:3][CH2:2][OH:26]
Reactant: Cc1ncc[nH]1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1F
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: NCCO
Product: Nc1ccc(Cl)cc1C(=NCCO)c1ccccc1F

Procedure:
A mixture of 40 g of 2-methylimidazole hydrochloride and of 90 g of 2-amino-5-chloro-2'-fluoro-benzophenone in 240 ml of ethanolamine is heated at 135° for 2 hours. After cooling, the reaction mixture is poured into an aqueous sodium bicarbonate solution. The mixture is extracted with ether, the organic phase is washed repeatedly with water and is dried over sodium sulphate, and the solvent is evaporated to dryness. The residual oil is chromatographed on a silica column, elution being carried out with a 50/50 mixture of cyclohexane and ethyl acetate.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[C:38]1([CH2:44][CH2:45][CH2:46][NH2:47])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH3:35][O:34][C:23]1[CH:22]=[C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:47][CH2:46][CH2:45][CH2:44][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])[CH:26]=[CH:25][C:24]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]
Reactant: COc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1ccccc1C
Reactant: NCCCc1ccccc1
Product: COc1cc(C(=O)N2Cc3ccc(C(=O)NCCCc4ccccc4)n3Cc3ccccc32)ccc1-c1ccccc1C

Procedure:
The title compound was prepared in the manner of Example 36 from 2,2,2-trichloro-1-{10-[(2-methoxy-2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 35 and 3-phenylpropylamine. Purification was performed using HPLC with a normal phase column. Elution with a mixture of etoxynonafluorobutane and methanol gave the title compound in 87% yield, m.p. 191° C. MS [(+)ESI, m/z]: 570 [M+H]+
Reaction SMILES: [N+:1]([CH2:4][CH:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1)([O-])=O.[ClH:16]>C(O)C.[Ni]>[ClH:16].[CH:12]1[C:9]2[CH2:10][CH2:11][CH:5]([CH2:4][NH2:1])[CH2:6][CH2:7][C:8]=2[CH:15]=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])CC1CCc2ccccc2CC1
Agent: [Ni]
Agent: Cl
Solvent: CCO
Product: NCC1CCc2ccccc2CC1
Reaction time: 12 h
Yield: 41.3 %

Procedure:
A mixture of 7-(nitromethyl)-6,7,8,9-tetrahydro-5H-benzo[α][7]annulene (Description 27; 48.6 g, 0.24 mol) and Ra—Ni (50 g) in ethanol (600 ml) was hydrogenated at 60 psi for 12 hours. An additional charge of Ra—Ni (50 g) was added and the mixture was hydrogenated until GC analysis indicated the reaction was complete. The resulting mixture was filtered over Celite™ and washed with ethanol (200 ml). The filtrate was treated with concentrated HCl (35 ml, 0.42 mol) and concentrated under reduced pressure. The product was then slurried in tert-butyl methyl ether (100 ml) and cooled between 0 and 5° C., filtered and washed with tert-butyl methyl ether (100 ml) and dried to give the title compound (21 g, 42%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][CH2:27][C:28](O)=[O:29])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[NH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][CH2:27][C:28]([NH:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:29])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCC(=O)O)c[nH]c34)no2)cc1Cl
Reactant: CCOC(=O)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNC(=O)CCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Temperature: 40 °C
Reaction time: 3 h
Yield: 55.6 %

Procedure:
To a solution of 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoic acid (E1) (150 mg), ethyl glycinate (73 mg) and HATU (402 mg) in DCM (20 mL) was added DIPEA (0.2 mL). The reaction was stirred at 40° C. for 3 h. The reaction mixture was cooled to room temperature and partitioned between DCM (25 mL) and water (25 mL). The organic phase was washed with water, dried over sodium sulphate and evaporated in vacuo to afford the crude product ethyl N-{3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoyl}glycinate as an off-white solid (D125) (100 mg), which was used directly in the next step. MS (ES): C26H27ClN4O5 requires 510; found 511.2 (M+H+).
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1)=O.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C1(C)C=CC=CC=1>[N:19]1([CH:1]=[C:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH2:5][CH2:4]2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: C1CCNCC1
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)N1CCC(=CN2CCCCC2)CC1

Procedure:
To a solution of benzyl 4-formylpiperidine-1-carboxylate (22.35 g) in toluene (300 mL) was added piperidine (11.55 g). The mixture was stirred at reflux under a Dean-Stark trap overnight. The mixture was then concentrated under vacuum and the residue was used directly in the next step.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][CH:9]2[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10]2)=[CH:3][CH:2]=1.C(O)(=O)C>[Pt].CCOC(C)=O>[NH:1]1[CH2:2][CH2:3][CH:4]([CH2:7][O:8][CH:9]2[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10]2)[CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CC(OCc2ccncc2)C1
Agent: [Pt]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(OCC2CCNCC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
tert-Butyl 3-(pyridin-4-ylmethoxy)azetidine-1-carboxylate (4.8 g) was mixed with acetic acid (25 ml) and EtOAc (25 ml), and 10% platinum/carbon was added thereto under argon atmosphere, followed by stirring at room temperature overnight under hydrogen atmosphere of 1 atm. The reaction mixture was filtered using Celite as a filtration adjuvant, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain tert-butyl 3-(piperidin-4-ylmethoxy)azetidine-1-carboxylate (4.8 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=O)=[N:6][CH:7]=1.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].N1CCCCC1>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:11][C:12]([OH:14])=[O:13])=[N:6][CH:7]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(Br)cn1
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1ccc(Br)cn1
Temperature: 100 °C
Reaction time: 1 h
Yield: 53.8 %

Procedure:
5-Bromo-pyridin-2-carbaldehyde (2.0 g, 10.6 mmol), malonic acid (2.5 g, 24.2 mmol), and piperidine (0.9 mL, 9.0 mmol) were added to pyridine (6.5 mL). The reaction mixture was stirred at 100° C. for 1 hour and then concentrated under reduced pressure. Distilled water was added to the reaction mixture, which was then filtered. The resulting solid was dried under reduced pressure to give 1.3 g of the titled compound as a brown solid.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH2:19])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:20][C:21]1[C:25]([C:26](O)=[O:27])=[CH:24][NH:23][N:22]=1>>[NH2:20][C:21]1[C:25]([C:26]([NH:19][CH2:18]/[CH:17]=[CH:16]\[CH2:15][O:14][C:10]2[CH:9]=[C:8]([CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:13]=[CH:12][N:11]=2)=[O:27])=[CH:24][NH:23][N:22]=1
Reactant: NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: Nc1n[nH]cc1C(=O)O
Product: Nc1n[nH]cc1C(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Yield: 38 %

Procedure:
Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine and 3-amino-4-pyrazolecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 172°-174° C., in a 38% yield.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]([N:13]1[CH:17]=[N:16][N:15]=[CH:14]1)[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1.[O:18]([C:26]1[CH:27]=[C:28]([SH:32])[CH:29]=[CH:30][CH:31]=1)[Si](C(C)(C)C)(C)C.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.O>[OH:18][C:26]1[CH:27]=[C:28]([S:32][CH2:2][CH2:3][N:4]([N:13]2[CH:17]=[N:16][N:15]=[CH:14]2)[C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=2)[CH:29]=[CH:30][CH:31]=1
Reactant: N#Cc1ccc(N(CCBr)n2cnnc2)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(N(CCSc2cccc(O)c2)n2cnnc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 4-[(2-bromo-ethyl)-[1,2,4]triazol-4-yl-amino]-benzonitrile (CAB02148=CAB03031, 146 mg, 0.50 mmol), 3-(tert-butyl-dimethylsiloxy)-thiophenol (240 mg, 1.0 mmol) and potassium carbonate (276 mg, 2.0 mmol) in DMF (10 mL) was stirred for 48 hours at room temperature. The mixture was transferred into a separation funnel and ethyl acetate (50 mL) and water (50 mL) were added. The organic layer was separated, washed with brine (30 mL), dried over sodium sulphate and concentrated under reduced pressure. The residue was crystallised from methanol. Yield: 93 mg (55%) to colourless crystals. 1H-NMR (400 MHz, d6-DMSO) δ=3.14 (t, J=7.0 Hz, 2H), 4.02 (t, J=7.0 Hz, 2M, 6.53 (d, J=9.0 Hz, 2H), 6.62 (ddd, J=7.8, 2.0, 0.8 Hz, 1H), 6.70-6.72 (m, 2H), 7.10 (dd, J=7.8, 7.8, 1H), 7.70 (d, J=9.0 Hz, 2H), 8-94 (s, 2H), 9.60 (s, 1H, —OH). 13C-NMR (100 MHz, d6-DMSO) δ=29.53, 52.46, 102.38, 112.86, 113.57, 115.36, 119.00, 130.11, 133.94, 135.82, 143.50, 150.71, 157.90, 169.59. LRMS (FAB+): 338.2 (100, [M+H]+). Found: C, 60.6; H, 4.53; N, 20.8%; C17H15N5OS (337.4) requires C, 60.52; H, 4.48; N, 20.76%.