Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[N:33][CH:34]=[C:35](F)[CH:36]=5)[C:31]([CH3:39])=[CH:30][C:29]4=[O:40])[CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1.[CH3:41][O-:42].[Na+].CO.O.C(Cl)(Cl)Cl>CO>[O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[N:33][CH:34]=[C:35]([O:42][CH3:41])[CH:36]=5)[C:31]([CH3:39])=[CH:30][C:29]4=[O:40])[CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: C[O-]
Reactant: Cc1cc(=O)n(CCN2CCC(N(Cc3cc4c(cn3)OCCO4)C(=O)OC(C)(C)C)CC2)c2cc(F)cnc12
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CO
Product: COc1cnc2c(C)cc(=O)n(CCN3CCC(N(Cc4cc5c(cn4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 72 mg of tert-butyl (2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(7-fluoro-4-methyl-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate in 2.5 mL of methanol, 77 mg of a 28% sodium methoxide/methanol solution was added at room temperature, and the mixture was heated under reflux while stirring for 2 hours. After cooling to room temperature, water and chloroform were added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by basic silica gel column chromatography using an eluent of chloroform to obtain 82 mg of tert-butyl (2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(7-methoxy-4-methyl-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a light brown oily substance.
Reaction SMILES: [N+](=[CH2:3])=[N-].[OH:4][CH:5]1[CH2:9][CH2:8][CH:7]([CH:10]=[CH:11][CH:12]([OH:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:6]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26]>C(OCC)C>[OH:4][CH:5]1[CH2:9][CH2:8][CH:7]([CH:10]=[CH:11][CH:12]([OH:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:6]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:3])=[O:26]
Reactant: C=[N+]=[N-]
Reactant: CCCCCC(O)C=CC1CCC(O)C1CCCCCCC(=O)O
Solvent: CCOCC
Product: CCCCCC(O)C=CC1CCC(O)C1CCCCCCC(=O)OC
Reaction time: 18 h
Yield: 72 %

Procedure:
A solution of diazomethane (0.327 g.) in dry diethyl ether (10 ml.) was added to a solution of 7-[2-hydroxy-5-(3-hydroxy-1-octenyl)cyclopentyl]heptanoic acid (0.4 g.) [prepared as described in Example 1] in dry diethyl ether (10 ml.). The resulting solution was allowed to stand at ambient temperature for 18 hours, during which time a solid precipitated. The solid was removed by filtration and the filtrate evaporated. The remaining traces of ether were removed from the residue by pumping under high vacuum to give methyl 7-[2-hydroxy-5-(3-hydroxy-1-octenyl)cyclopentyl]heptanoate (0.3 g., 72%). (Found: C, 70.8; H, 10.6. C21H38O4 requires C, 71.25; H, 10.72%) νmax 1730 cm-1, 980 cm-1 (liquid film). N.M.R. (approximately 10% solution in deuterochloroform) 0.92δ (triplet J=5c/s, terminal CH3) 1.7, 1.4δ (overlapping multiplets, cyclic and chain CH2), 2.38δ (triplet J=6.5c/s, CH2C=0), 2.70δ (broad singlet, --OH), 3.76δ (singlet --COOCH3), 4.32, 4.15 and 4.00δ (overlapping multiplets, cis and trans ##EQU7## 5.62δ (multiplet, ##EQU8##
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[C:3]([OH:5])=[O:4].[CH3:15][C:16]([CH3:18])=O.S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O>[C:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:2]1[C:3](=[O:5])[O:4][C:16]([CH3:18])([CH3:15])[O:1]1)([OH:14])=[O:13]
Reactant: O=C(O)CCCCCCC(O)C(=O)O
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC1(C)OC(=O)C(CCCCCCC(=O)O)O1

Procedure:
A stirred mixture of 10.2 g. of 2-hydroxynonanedioic acid, 50 ml. of acetone, 75 ml. of petroleum ether (b.p. 30°-55° C.), and 0.25 ml. of sulfuric acid is heated at reflux for 7 hours with azeotropic removal of water. The stirred mixture is treated with 0.59 g. of sodium carbonate and diluted with petroleum ether. The solution is decanted from solid and concentrated to give 9.4 g. of oil; pmr (CDCl3) δ 1.58 and 1.63 (gem-dimethyl group).
Reaction SMILES: B.C1C[O:5]CC1.CC(=CC)C.[CH3:12][O:13][CH2:14][CH2:15][C:16]([CH3:25])([CH2:22][CH:23]=[CH2:24])[C:17]([O:19][CH2:20][CH3:21])=[O:18].P([O-])([O-])([O-])=O.OO>C1COCC1.[Cl-].[Na+].O>[OH:5][CH2:24][CH2:23][CH2:22][C:16]([CH2:15][CH2:14][O:13][CH3:12])([CH3:25])[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: C1CCOC1
Reactant: C=CCC(C)(CCOC)C(=O)OCC
Agent: B
Agent: CC=C(C)C
Agent: O=P([O-])([O-])[O-]
Solvent: O
Product: CCOC(=O)C(C)(CCCO)CCOC
Temperature: 25 °C
Reaction time: 1 h
Yield: 39 %

Procedure:
BH3.THF (1 M in THF, 16.5 ml, 1.1 eq.) was added dropwise to a stirred solution of 2-methyl-2-butene (1.75 ml, 1.1 eq.) in dry THF (15 ml) at 0° C. An hour later, a cold solution of ethyl 2-(2-methoxyethyl)-2-methylpent-4-enoate (3.00 g, 1 eq.) in THF (15 ml) was rapidly added. After the reaction mixture had been stirred at room temperature for 1 h, it was quenched with MeOH at 0° C., and then buffer (pH 7, 0.5 M phosphate solution, 18 ml) and H2O2 (30% in water, 18.4 ml, 12 eq.) were added. The reaction mixture was stirred at room temperature for 14 h, poured into brine and extracted with ether. The combined organic phase was washed with saturated aqueous Na2S2O3 solution, water and brine, dried over Na2SO4, and concentrated. Silica gel chromatography using 5-50% ether-DCM yields the title compound (3.27 g, 39%).
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]([F:15])([F:14])[F:13])=[C:9]([C:16](Cl)=[O:17])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:19][C:20]([F:33])([F:32])[C:21]1[CH:22]=[C:23]([NH2:31])[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1.C(N(CC)C(C)C)(C)C.Cl.C([O-])(O)=O.[Na+]>ClCCl>[F:19][C:20]([F:32])([F:33])[C:21]1[CH:22]=[C:23]([NH:31][C:16]([C:9]2[CH:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[O:11][C:10]=2[C:12]([F:15])([F:14])[F:13])=[O:17])[CH:24]=[C:25]([C:27]([F:28])([F:30])[F:29])[CH:26]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(Cl)c1cc(-c2ccccc2)oc1C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(-c2ccccc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.1 %

Procedure:
An excess of 5-phenyl-2-trifluoromethyl-furan-3-carbonyl chloride (1 g, 3.6 mmol) was added to a solution of 3,5-bis-trifluoromethyl-phenylamine (0.758 g, 3.3 mmol) and N,N-diisopropylethylamine (0.58 mL) in dichloromethane (50 mL). After stirring at room temperature for 1 day, the reaction underwent an aqueous acidic (dilute HCl, 2×30 mL) and basic (dilute NaHCO3, 2×30 mL) workup followed by washing with brine (saturated NaCl, 2×30 mL), drying over MgSO4, and concentration. The crude compound was purified by passing through a silica gel plug eluting with ethyl acetate/hexanes (2:1) to afford the title compound (1.42 g, 92% yield). ES-MS negative Q1 (m/z) 466.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]1[N:10]=[N:11][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=3)[CH2:17][CH2:16]2)=[CH:13][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:27][C:23]1[CH:22]=[C:21]([N:18]2[CH2:17][CH2:16][N:15]([C:12]3[N:11]=[N:10][C:9]([O:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:14][CH:13]=3)[CH2:20][CH2:19]2)[CH:26]=[CH:25][CH:24]=1
Reactant: Oc1ccccc1
Reactant: Cc1cccc(N2CCN(c3ccc(Cl)nn3)CC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cccc(N2CCN(c3ccc(Oc4ccccc4)nn3)CC2)c1
Temperature: 150 °C
Yield: 60 %

Procedure:
A mixture of 1.9 parts of phenol, 2.9 parts of 3-chloro-6-[4-(3-methylphenyl)-1-piperazinyl]pyridazine and 2.76 parts of potassium carbonate was stirred and heated for 7 hours in an oil bath at 150° C. After cooling, water was added. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from a mixture of 2-propanol and 2,2'-oxybispropane. The product was filtered off and dried, yielding 2 parts (60%) of 3-[4-(3-methylphenyl)-1-piperazinyl]-6-phenoxypyridazine; mp. 123.4° C. (compound 264).
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:10](=O)[C:11]1[CH:16]=[CH:15][C:14]([C:17](F)(F)[F:18])=[CH:13][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[N+]([O-])(O)=O.[N+]([O-])(O)=O.[F:31][C:32]1[CH:33]=[C:34]([NH:44][C:45]([NH2:47])=[NH:46])[CH:35]=[CH:36][C:37]=1[N:38]1[CH:42]=[C:41]([CH3:43])[N:40]=[CH:39]1>>[F:31][C:32]1[CH:33]=[C:34]([NH:44][C:45]2[N:47]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][F:18])=[CH:13][CH:12]=3)[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][N:46]=2)[CH:35]=[CH:36][C:37]=1[N:38]1[CH:42]=[C:41]([CH3:43])[N:40]=[CH:39]1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1cn(-c2ccc(NC(=N)N)cc2F)cn1
Solvent: O=[N+]([O-])O
Product: CCOC(=O)c1cnc(Nc2ccc(-n3cnc(C)c3)c(F)c2)nc1-c1ccc(CF)cc1

Procedure:
The title compound was prepared from crude ethyl 3-dimethylamino-2-(4-trifluoromethyl-benzoyl)-acrylate (142 mg, 0.45 mmol) and N-[3-fluoro-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (121 mg, 0.34 mmol) using in analogous manner the procedure described in example 28b). Obtained as a pale-yellow solid (128 mg, 78%). Mp 219-221° C.
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[S:14]1[C:18](B(O)O)=[CH:17][C:16]2[CH:22]=[CH:23][CH:24]=[CH:25][C:15]1=2.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.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>[S:14]1[C:18]([C:2]2[C:3]([O:12][CH3:13])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=2)[CH:7]=[O:8])=[CH:17][C:16]2[CH:22]=[CH:23][CH:24]=[CH:25][C:15]1=2
Reactant: OB(O)c1cc2ccccc2s1
Reactant: COc1cc(OC)c(C=O)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(OC)c(-c2cc3ccccc3s2)cc1C=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 79.6 %

Procedure:
Ex-6A: 5-Bromo-2,4-dimethoxybenzaldehyde (4.9 g, 20.0 mmol) was dissolved in ethylene glycol dimethyl ether (50 mL). Tetrakis(triphenylphosphine)palladium(0) (2.32 g, 2 mmol) was added, and the mixture was stirred at room temperature under nitrogen for 5 min. Benzo[b]thiophene-2-boronic acid (4.27 g, 24 mmol) and sodium carbonate solution (2 M, 20 mL) were added. The mixture was stirred at reflux under nitrogen for 24 hours. Upon cooling to room tempaerature, it was poured into water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and evaporated. Silica gel chromatography (hexane/ethyl acetate 2:1 then 1:1) gave 4.75 g (83%) of the desired 5-(benzo[b]thien-2-yl)-2,4-dimethoxybenzaldehyde.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4](Cl)[CH:3]=1.[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.F[P-](F)(F)(F)(F)F.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1
Reactant: Oc1ccccc1
Reactant: O=C(O)c1ccc(Br)cc1Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc(Br)cc1Oc1ccccc1
Yield: 100.7 %

Procedure:
4-Bromo-2-chloro-benzoic acid (10 g, 42 mmol), phenol (4.19 g, 44 mmol), tetrakisacetonitrilecopper hexafluorophosphate (3.95 g, 10.6 mmol), and cesium carbonate (27.6 g, 85 mmol) were added to a 1 L 3-neck round bottom flask equipped with a mechanical stirrer, reflux condenser, and containing toluene (350 mL). The reaction was refluxed overnight under nitrogen with stirring. After cooling, ethyl acetate (200 mL) was added and the reaction was acidified with aqueous 2N HCI. The organic phase was separated, dried (MgSO4), and filtered. The filtrate was concentrated to afford 4-bromo-2-phenoxybenzoic acid (12.4 g) that was used in subsequent reactions without further purification.
Reaction SMILES: Cl.[CH2:2]([O:9][NH2:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.O=C1CCC(=O)N1[O:25][C:26](=O)[CH2:27][CH:28]([C:34](=[O:56])[NH:35][CH:36]([C:40]([N:42]1[CH2:46][CH2:45][CH2:44][CH:43]1[CH2:47][O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:41])[CH:37]([CH3:39])[CH3:38])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>CN(C)C=O>[CH2:2]([O:9][NH:10][C:26](=[O:25])[CH2:27][CH:28]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:34]([NH:35][CH:36]([C:40]([N:42]1[CH2:46][CH2:45][CH2:44][CH:43]1[CH2:47][O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:41])[CH:37]([CH3:39])[CH3:38])=[O:56])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCCCCC(CC(=O)ON1C(=O)CCC1=O)C(=O)NC(C(=O)N1CCCC1COCc1ccccc1)C(C)C
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCC(CC(=O)NOCc1ccccc1)C(=O)NC(C(=O)N1CCCC1COCc1ccccc1)C(C)C

Procedure:
The coupling of fragment A and B is comprised of the following steps: (a) a solution of 14 in dimethylformide or any suitable solvent is treated with triethylamine followed by a solution of 8 in dimethylformamide or any suitable solvent to yield 3-(1-(2-(S)-benzyloxymethylpyrrolidine-1-carbonyl)-2-(S)-methylpropyl-carbamoyl)-octanoic acid tert-butyl ester 15; (b) treatment of 15 in dichloromethane with trifluoroacetic acid to yield 3-(1-(2-benzyloxymethyl-pyrrolidine-1-carbonyl)-2-methyl-propyl carbamoyl)-octanoic acid 16; (c) treatment of a solution 16 and hydroxysuccinamide 7 with dicyclohexylcarbodiimide or any suitable imide to afford 3-(1-(2-benzyloxymethyl-pyrrolidine-1-carbonyl)-2-methylpropylcarbamoyl)-octanoic acid 2,5-dioxo-pyrrolidin-1-yl ester 17; (d) fragment C is introduced by treatment of a suspension of O-benzylhydroxyamine hydrochloride 18 in dimethylformamide with triethylamine followed by a solution of 17 in dimethylformamide to afford N4-benzyloxy-N 1-(1-(2-benzyloxymethyl-pyrrolidine-1-carbonyl)-2-methyl-propyl)-2-pentyl-succinamide 19. (f) hydrogenating 19 with hydrogen gas and palladium hydroxide in activated carbon wherein actinonin 1 is thereby formed (Scheme 4, FIG. 3C).
Reaction SMILES: [I-].[NH2:2][N+:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([O:14][CH2:15][CH3:16])(=[O:13])[C:10]#[C:11][CH3:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O.C(OCC)(=O)C.CCCCCC>[CH3:12][C:11]1[C:10]([C:9]([O:14][CH2:15][CH3:16])=[O:13])=[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][N:3]2[N:2]=1
Reactant: CC#CC(=O)OCC
Reactant: N[n+]1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1c(C)nn2ccccc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 36724.2 %

Procedure:
To a suspension of 1-aminopyridinium iodide (125 g, 0.56 mmol) in N,N-dimethylformamide (1.2 L) were added ethyl 2-butynoate (54.0 g, 0.48 mmol) and potassium carbonate (79 g, 0.36 mmol) and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with water (500 mL), ethyl acetate (500 mL) and hexane (500 mL), and the precipitated solid was collected by filtration, and washed with water (500 mL). The filtrate was extracted with a mixed solvent (1.5 L×2) of ethyl acetate/hexane (1:1) and dried over anhydrous magnesium sulfate, and the insoluble material was filtered off. The residue obtained by concentration of the filtrate and the solid collected by filtration in the above were combined, washed with diethyl ether (25 mL) and hexane (25 mL) and dried to give the title compound (36.0 g, 37%) as a white solid. The washing solution was concentrated, and the obtained residue was washed with diethyl ether (10 mL) and hexane (10 mL) and dried to give a second crop (11.0 g, 11%) of the title compound as a white solid. The washing solution of the second crop was concentrated, and the obtained residue was purified using a pad (elution solvent: ethyl acetate/hexane=1/1) with silica gel and activated carbon in 2 layers, washed with diethyl ether (5.0 mL) and hexane (5.0 mL) and dried to give a third crop (6.5 g, 7%) of the title compound as a white solid (total yield 55%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.C([Li])CCC.[Si](N=C=S)(N=C=S)(N=C=S)[N:18]=[C:19]=[S:20].C(N)=S>C1C=CC=CC=1.O>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([C:19](=[S:20])[NH2:18])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: S=C=N[Si](N=C=S)(N=C=S)N=C=S
Reactant: Cc1cnc2c(c1)CCCC2
Agent: NC=S
Agent: [Li]CCCC
Solvent: O
Solvent: c1ccccc1
Product: Cc1cnc2c(c1)CCCC2C(N)=S
Reaction time: 0.5 h

Procedure:
A solution of 3-methyl-5,6,7,8-tetrahydroquinoline (1.43 g, 0.01 mole) in benzene (20 ml) was treated with n-butyl-lithium (15% w/w, 4.5 ml, 0.01 mole) and the solution was allowed to stand at room temperature for 0.5 hours. The solution was then treated with a suspension of silicon tetraisothiocyanate (1.3 g, 0.005 mole) in benzene (5 ml) at 0° C. After 10 minutes, water (50 ml.) was added to the solution of 3-methyl-5,6,7,8-tetrahydroquinoline-8-(N-lithio-N-(tri-isothiocyanato) silyl)thiocarboxamide causing hydrolysis to 3-methyl-5,6,7,8-tetrahydroquinoline-8-(N-tri-isothiocyanato)silyl) thiocarboxamide and subsequent hydrolysis to the title compound, and the mixture was stirred for 0.5 h at room temperature and then acidified with conc. HCl. The aqueous layer was separated, washed with ethyl acetate and the pH was adjusted to 10 with solid Na2CO3. The basic mixture was extracted with ethyl acetate (3 × 50 ml) and the combined organic extracts were dried (MgSO4), filtered and evaporated. The residue was triturated with n-hexane to give 3-methyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide (0.2 g, 10%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.C1C(=O)N([Br:16])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][Br:16])=[N:6][CH:7]=1
Reactant: Cc1ccc(Br)cn1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(Br)cn1
Temperature: 50 °C

Procedure:
To a mixture of 5-bromo-2-methylpyridine (46.5 g, 0.27 mol) in CCl4 (800 mL) was added NBS (53 g, 0.297 mol) and benzoylperoxide (4.7 g) and refluxed for 2 h in presence of light. The reaction mixture was cooled to 50° C. and filtered off the solid succinimide. The filtrate was concentrated and the crude 5-bromo-2-bromomethylpyridine was used for next reaction.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:3]1>C1C=CC=CC=1.O.C(OCC)(=O)C.[Fe]>[NH2:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[C:2]([CH3:20])([CH3:1])[CH:3]=[C:4]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC1(C)C=C(c2ccccc2)c2cc([N+](=O)[O-])ccc21
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccccc1
Product: CC1(C)C=C(c2ccccc2)c2cc(N)ccc21
Yield: 98.7 %

Procedure:
To a mixture of 1,1-dimethyl-5-nitro-3-phenyl-1H-indene (0.56 g, 2.11 mmol) in 5 mL of benzene was added 33% ferric chloride (1 mL) and 4 mL of water. The mixture was stirred at reflux and iron powder (1.00 g, 5.28 mmol) was added in four portions during 2 hours. The resulting mixture was stirred at reflux for additional 18 hours. The mixture was diluted with 20 mL of water and 20 mL of ethyl acetate, and filtered through a pad of celite. The filtrate was extracted with ethyl acetate (20 mL×3). The combined extracts were dried over magnesium sulfate to give 0.49 g (98% yield) of the crude title compound which was not further purified and used in the next reaction; 1H-NMR (CDCl3) δ 1.37 (s, 6H), 6.40 (s, 1H), 6.71 (dd, J=2.0, 7.9 Hz, 1H), 6.93 (d, J=2.0 Hz, 1H), 7.19 (d, J=7.9 Hz, 1H), 7.36-7.58 (m, 5H); MS m/e 236 (MH+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].[CH3:12][C:13]([O:16][C:17](ON=C(C1C=CC=CC=1)C#N)=[O:18])([CH3:15])[CH3:14].C(N(CC)CC)C>O.CC(C)=O>[C:13]([O:16][C:17]([C:4]1[C:3]([CH2:2][NH2:1])=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])=[O:18])([CH3:15])([CH3:14])[CH3:12]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: NCc1cccc(C(=O)O)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)c1c(CN)cccc1C(=O)O
Yield: 64.2 %

Procedure:
The title compound was prepared according to a modification of standard procedures previously reported in the literature (Itoh, Hagiwara, and Kamiya (1975) Tett. Lett., 4393). 3-Aminomethylbenzoic acid (hydrochloride salt) (3.0 g, 16.0 mmol) was dissolved in 60 ml H2O. To this was added a solution of Boc-ON (4.33 g, 17.6 mmol) in 60 ml acetone followed by triethylamine (5.56 ml, 39.9 mmol). The solution turned yellow and the pH was adjusted to 9 (wet pH paper) by adding an additional 1.0 ml (7.2 mmol) triethylamine. The solution was stirred overnight at room temperature at which time the acetone was removed under reduced pressure and the remaining aqueous layer was washed three times with ether. The aqueous layer was then acidified to pH 2 with 2N HCl and then extracted three times with ethyl acetate. The combined organic layers were washed three times with H2O, dried over anhydrous magnesium sulfate, and evaporated to dryness under reduced pressure. The material was recrystallized from ethyl acetate/hexane to give two crops of the title compound (2.58 g, 64%) as an off-white solid. mp 123°-125° C.; 1H NMR (CDCl3) 1.47 (s, 9H), 4.38 (br s, 2H), 4.95 (br s, 1H), 7.45 (t, 1H), 7.55 (d, 1H), 8.02 (d, 2H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:17]1([CH:23]([NH2:34])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:1]1([CH2:7][CH2:8][C:9]([NH:11][CH2:12][C:13](=[O:15])[NH:34][CH:23]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:31])([F:32])[F:33])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CNC(=O)CCc1ccccc1
Reactant: NC(c1ccccc1)c1ccccc1C(F)(F)F
Agent: Cl
Product: O=C(CCc1ccccc1)NCC(=O)NC(c1ccccc1)c1ccccc1C(F)(F)F

Procedure:
Prepared in analogy to example 1.1 from mmol (3-phenyl-propionylamino)-acetic acid (CA [56613-60-6]) and rac-C-phenyl-C-(2-trifluoromethyl-phenyl)-methylamine hydrochloride (CA [49703-62-0]).