Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[C:3]=1[F:11].[C:12](O)(=[O:16])[C:13](O)=[O:14]>Cl>[Cl:1][C:2]1[C:3]([F:11])=[C:4]2[C:5](=[CH:6][C:7]=1[F:8])[NH:9][C:13](=[O:14])[C:12](=[O:16])[NH:10]2
Reactant: O=C(O)C(=O)O
Reactant: Nc1cc(F)c(Cl)c(F)c1N
Agent: Cl
Product: O=c1[nH]c2cc(F)c(Cl)c(F)c2[nH]c1=O
Temperature: 25 °C
Yield: 81.7 %

Procedure:
A mixture of 230 mg (1.29 mmol) of 4-chloro-3,5-difluoro-1,2-phenylenediamine and 125 mg (1.38 mmol) of oxalic acid in 4 mL of 2N HCl was refluxed for 3 h and cooled to room temperature. The mixture was filtered, washed with water, and dried to leave a brown solid (245 mg, 82%); mp >250° C.; 1H NMR (DMSO-d6), 6.921 (d, 1, J=9.61), 12.143 (s, 1), 12.168 (s, 1). MS, 232 (M+, 100), 204 (80), 176 (40), 149 (70), 171 (80). HRMS calcd for C8H335ClF2N2O2, 231.9848, found 231.9851.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:18]([OH:19])[C@@H:17]([CH2:20][O:21][C:22](=[O:38])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[O:16][C@@H:11]([O:12][CH2:13][CH:14]=[CH2:15])[C@@H:10]1[NH:39][C:40](=[O:56])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.C1C=CC=CC=1.N12CCN(CC1)CC2>C(Cl)(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].CC(C)=O.O>[CH2:1]([O:8][C@H:9]1[C@H:18]([OH:19])[C@@H:17]([CH2:20][O:21][C:22](=[O:38])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[O:16][C@@H:11]([O:12][CH:13]=[CH:14][CH3:15])[C@@H:10]1[NH:39][C:40](=[O:56])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCO[C@@H]1O[C@H](COC(=O)CCCCCCCCCCCCCCC)[C@@H](O)[C@H](OCc2ccccc2)[C@H]1NC(=O)CCCCCCCCCCCCCCC
Agent: [Rh]
Agent: C1CN2CCN1CC2
Agent: [Cl-]
Solvent: O
Solvent: CC(C)=O
Solvent: CCO
Product: CC=CO[C@@H]1O[C@H](COC(=O)CCCCCCCCCCCCCCC)[C@@H](O)[C@H](OCc2ccccc2)[C@H]1NC(=O)CCCCCCCCCCCCCCC

Procedure:
To 500 mg. of Compound 6 in a mixture of 2.0 ml. of ethanol, benzene and water (7:3:1) 40 mg. of tris(triphenylphosphine)rhodium(I) chloride and 15 mg. of 1,4-diazabicyclo-[2.2.2]octane were added. The reaction mixture was heated under reflux overnight. Thin layer chromatography (5% acetone in CHCl3) showed the reaction to be complete. The reaction was conducted in the general manner described by Corey et al, in J. Org. Chem., 38 (1973) 3224 and P. A. Gent et al, J. Chem. Soc., Chem. Commun., (1974) 277-278. A high yield of Compound 7 was obtained.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[N:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][CH:15]=[C:16]([NH:18][C:19](=[O:37])[NH:20][C:21]3[N:26]=[C:25]([CH2:27][N:28]4[CH2:32][CH2:31][CH2:30][CH:29]4[C:33](OC)=[O:34])[CH:24]=[CH:23][CH:22]=3)[N:17]=2)=[CH:9][CH:8]=1>C1COCC1>[OH:34][CH2:33][CH:29]1[CH2:30][CH2:31][CH2:32][N:28]1[CH2:27][C:25]1[N:26]=[C:21]([NH:20][C:19]([NH:18][C:16]2[N:17]=[C:13]([C:10]3[CH:9]=[CH:8][N:7]=[CH:12][CH:11]=3)[S:14][CH:15]=2)=[O:37])[CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)C1CCCN1Cc1cccc(NC(=O)Nc2csc(-c3ccncc3)n2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Nc1cccc(CN2CCCC2CO)n1)Nc1csc(-c2ccncc2)n1
Reaction time: 8 h

Procedure:
LiAlH4 (3 mg, 0.079 mmol) was added to a solution of methyl 1-{6-[3-(2-pyridin-4-yl-thiazol-4-yl)ureido]-pyridin-2-ylmethyl}-pyrrolidine-2-carboxylate (15 mg, 0.034 mmol, Example 77) in THF (5 mL) at RT and the resulting mixture was stirred for 8 h. A precipitate formed and was collected. The solid was dissolved in CHCl3 (5 mL) and washed with saturated NaHCO3 solution (5 mL). The aqueous layer was adjusted to pH 7 with 1N HCl and extracted with CHCl3. The organics were combined, dried over MgSO4 and concentrated in vacuo to give a pale yellow solid. MS m/z: 411.1 (M+H). Calc'd for C20H22N6O2S-410.50.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][C:15]=2[C:23]([F:26])([F:25])[F:24])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.[Cl:56][C:57]1[CH:68]=[CH:67][C:60]2[NH:61][C:62]([C@@H:64]([NH2:66])[CH3:65])=[N:63][C:59]=2[CH:58]=1>CN1C(=O)CCC1>[C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:66][C@H:64]([C:62]3[NH:61][C:60]4[CH:67]=[CH:68][C:57]([Cl:56])=[CH:58][C:59]=4[N:63]=3)[CH3:65])=[O:20])=[CH:16][C:15]=2[C:23]([F:26])([F:24])[F:25])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)O)cc2C(F)(F)F)CC1
Reactant: C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCCC1=O
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C(F)(F)F)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1f from 4-(4-N-Boc-piperazin-1-yl)-3-trifluoromethyl-benzoic acid, TBTU, NMM and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethylamine in NMP and subsequent purification by chromatography on silica gel (eluant: petroleum ether/ethyl acetate=50:50).
Reaction SMILES: [C:1]([C:4]1(C(OC)=O)[CH2:9][CH2:8][CH:7]([C:10]([O:12][CH3:13])=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl.O>CO>[C:1]([CH:4]1[CH2:9][CH2:8][CH:7]([C:10]([O:12][CH3:13])=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COC(=O)C1CCC(C(C)=O)(C(=O)OC)CC1
Agent: Cl
Solvent: CO
Solvent: O
Product: COC(=O)C1CCC(C(C)=O)CC1

Procedure:
Dimethyl 1-acetylcyclohexane-1,4-dicarboxylate (23.3 g.) was added to a solution of concentrated hydrochloric acid (253 ml.) in methanol (126 ml.). After refluxing for 10 hours the reaction mixture was poured into water and then extracted with dichloromethane. The organic phase was then washed with saturated sodium bicarbonate solution and brine. After drying over anhydrous magnesium sulphate the solvent was removed under reduced pressure to give methyl 4-acetylcyclohexanecarboxylate as a colourless oil. This was purified by distillation (b.p. 138°-145°/14 mmHg). Nuclear Magnetic Resonance spectrum (NMR) was as follows: 3.60, 3H, s; 2.6-1.2, 13H, m.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]1[C:8](=[O:26])[N:9]([CH3:25])[C:10](=[O:24])[N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C:12]=1[CH3:13].[C:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)#[N:28].C(=O)([O-])[O-].[Na+].[Na+].O>O1CCCC1.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>[CH3:25][N:9]1[C:8](=[O:26])[C:7]([C:6]2[CH:5]=[CH:4][S:3][C:2]=2[C:32]2[CH:33]=[CH:34][C:29]([C:27]#[N:28])=[CH:30][CH:31]=2)=[C:12]([CH3:13])[N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C:10]1=[O:24]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Cc1c(-c2ccsc2Br)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
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: O
Solvent: C1CCOC1
Product: Cc1c(-c2ccsc2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Yield: 91.9 %

Procedure:
To a solution of 5-(2-bromothiophen-3-yl)-3,6-dimethyl-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 200) (17.0 mg), 4-cyanophenylboronic acid (11.2 mg) and sodium carbonate (20.2 mg) in tetrahydrofuran (1.0 ml)/water (0.2 ml) was added tetrakis(triphenylphosphine)palladium (4.4 mg) and the resulting mixture was stirred with heating under reflux for twelve hours. To the reaction mixture was added water (10 ml) and the resulting mixture was extracted with ethyl acetate (10 ml×2). The organic layer was washed with saturated saline (10 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 4-[3-[3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]thiophen-2-yl]benzonitrile (16.4 mg).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]([NH2:15])=[S:14])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.Cl[CH:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)[C:18](=O)[CH3:19].C(N(CC)C(C)C)(C)C.ClC(Cl)=O>C(O)C>[Cl:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[CH2:21][C:17]1[S:14][C:13]([NH:12][C:9]2[CH:8]=[CH:7][C:6]([N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)=[CH:11][CH:10]=2)=[N:15][C:18]=1[CH3:19]
Reactant: NC(=S)Nc1ccc(-n2cncn2)cc1
Reactant: CC(=O)C(Cl)Cc1cccc(Cl)c1
Agent: O=C(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1nc(Nc2ccc(-n3cncn3)cc2)sc1Cc1cccc(Cl)c1
Temperature: 170 °C

Procedure:
A suspension of 55 mg (0.25 mmol) 4-(1,2,4-triazol-1-yl)phenylthiourea, of 60 mg (0.28 mmol) 3-chloro-4-(3-chlorophenyl)-2-butanone and of 65 mg (0.5 mmol) N,N-diisopropyl ethyl amine in ethanol (2.5 ml) was refluxed over night. The same amount of chloro ketone was added and the reaction was heated to reflux over night. Again 1.1 equivalent of chloro ketone was added and the reaction was heated for 10 minutes in a microwave oven to 170° C. The solvent was evaporated and the residue was purified on silica gel with methylene chloride/methanol 19/1 yielding 27 mg (28%) [5-(3-chloro-benzyl)-4-methyl-thiazol-2-yl]-(4-[1,2,4]triazol-1-yl-phenyl)-amine as a yellow solid. MS ISP (m/e): 382.1 (100) (M+H)+. 1H NMR (CDCl3, 250 MHz): δ (ppm)=8.48 (s, 1H), 8.09 (s, 1H), 7.60 (d, 2H), 7.46 (d, 2H), 7.25-7.18 (m, 3H), 7.09 (d, 1H), 3.96 (s, 2H), 2.29 (s, 3H).
Reaction SMILES: [CH:1]1([C:4]2[CH2:5][CH:6]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:13][CH2:12]3)[C:7](=[O:10])[NH:8][N:9]=2)[CH2:3][CH2:2]1>C(#N)C.[Cu](Cl)Cl>[CH:1]1([C:4]2[CH:5]=[C:6]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:13][CH2:12]3)[C:7](=[O:10])[NH:8][N:9]=2)[CH2:3][CH2:2]1
Reactant: O=C1NN=C(C2CC2)CC1C1CCN(C(=O)OCc2ccccc2)CC1
Agent: Cl[Cu]Cl
Solvent: CC#N
Product: O=C(OCc1ccccc1)N1CCC(c2cc(C3CC3)n[nH]c2=O)CC1
Temperature: 90 °C
Reaction time: 18 h
Yield: 40.2 %

Procedure:
Copper(II) chloride (anhydrous; 101 mg, 0.75 mmol) was added to a solution of benzyl 4-(6-cyclopropyl-3-oxo-2,3,4,5-tetrahydropyridazine-4-yl)piperidine-1-carboxylate (134 mg, 0.38 mmol) in acetonitrile (16 mL). The reaction mixture was heated to 90° C. After 18 h, the mixture was cooled to ambient temperature and concentrated. Dichloromethane was added to the concentrated mixture, followed by hydrochloric acid (1 N in water). The mixture was extracted with dichloromethane (3×) and the combined organic extracts were dried over magnesium sulfate and concentrated. Purification by silica gel chromatography (100% dichloromethane→90% dichloromethane/methanol) gave the title compound (54 mg). MS 354.1 (M+1).
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[F:20][C:21]([F:30])([F:29])[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:19]=[CH:18][C:15]([CH2:16][O:28][C:25]3[CH:26]=[CH:27][C:22]([C:21]([F:20])([F:29])[F:30])=[CH:23][CH:24]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(CBr)cc2)CC1
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCC[C@H]1CC[C@H](c2ccc(COc3ccc(C(F)(F)F)cc3)cc2)CC1

Procedure:
A mixture of 0.03 m of p-(trans-4-pentylcyclohexyl)-benzyl bromide (obtainable from p-(trans-4-pentylcyclohexyl)-benzoic acid), 0.03 m of p-(trifluoromethyl)-phenol, 0.03 m of potassium carbonate and 40 ml of DMF are warmed to 120° while stirring under the exclusion of air and, after cooling, worked up as usual. p-(Trifluoromethyl)-phenyl p-(trans-4-pentylcyclohexyl)benzyl ether is obtained.
Reaction SMILES: [O:1]=[C:2]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2)[CH2:3][CH2:4][CH2:5]Cl.N1C=CC=CC=1.[C:24]1([C:30]2([C:36](=[O:38])[CH3:37])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[O:1]=[C:2]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2)[CH2:3][CH2:4][CH2:5][N:33]1[CH2:32][CH2:31][C:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:36](=[O:38])[CH3:37])[CH2:35][CH2:34]1
Reactant: O=C1CCc2cc(C(=O)CCCCl)ccc2N1
Reactant: CC(=O)C1(c2ccccc2)CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)C1(c2ccccc2)CCN(CCCC(=O)c2ccc3c(c2)CCC(=O)N3)CC1
Reaction time: 7 h

Procedure:
2.6 Grams of 6-(1-oxo-4-chlorobutyl)-3,4-dihydro-carbostyril, 12 g of pyridine and 2.7 g of 4-phenyl-4-acetyl-piperidine were mixed in 30 ml of dimethylformamide and stirred at 70°-80° C. for 7 hours. The reaction mixture was poured into 100 ml of 5%-sodium hydrogencarbonate aqueous solution and the organic layer was extracted with chloroform then the chloroform layer was washed with water, dried and chloroform was removed by distillation. The residue thus obtained was recrystallized from ethanol to obtain 6-[1-oxo-4-(4-phenyl-4-acetyl-1-piperidyl)butyl]-3,4-dihydrocarbostyril in light yellow plate-like crystals. Yield: 2.1 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[C:10]=2[C:20]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)=[O:21])=[CH:5][CH:4]=1.[Br:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]Br.C([O-])([O-])=O.[K+].[K+]>CC(=O)CC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[C:10]=2[C:20]([C:22]2[CH:23]=[CH:24][C:25]([O:28][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][Br:29])=[CH:26][CH:27]=2)=[O:21])=[CH:7][CH:8]=1
Reactant: BrCCCCCCCCBr
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OCCCCCCCCBr)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
750 mg (1.92 mmol) of [2-(4-Methoxyphenyl)-6-methoxybenzo[b]thien-3-yl][4-hydroxyphenyl]methanone, 5.23 g (19.2 mmol) of 1,8-dibromooctane, and 2.66 mg (19.2 mmol) of K2CO3 were combined in 150 mL of 2-butanone. The reaction mixture was stirred and heated to reflux under a nitrogen atmosphere. The reaction was allowed to proceed for three hours, cooled to ambient temperature, and filtered. The solvent was removed by evaporation in vacuo to a yellow oil. The crude product was further purified by chromatography on a silica gel column eluted with a linear gradient begining with hexane and ending with hexane-EtOAc (5:1) (v/v). The desired fractions were determined by tlc, combined, and evaporated to dryness. This yielded 1.28 g (114%; some EtOAc was present in the solid) of the title compound as a yellow, amorphous powder.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:15]([O-:17])=[O:16])[CH:8]=2)[N:3]=1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O>[NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([NH:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:15]([O-:17])=[O:16])[CH:8]=2)[N:3]=1
Reactant: NCc1ccccc1
Reactant: N#Cc1c(N)nc2ccc([N+](=O)[O-])cc2c1Cl
Solvent: O
Product: N#Cc1c(N)nc2ccc([N+](=O)[O-])cc2c1NCc1ccccc1
Temperature: 55 °C
Reaction time: 1.5 h

Procedure:
A mixture of 7 g of 2-amino-3-cyano-4-chloro-6-nitroquinoline and 30 mL of benzylamine was stirred at 55° C. for 1.5 hours. The reaction mixture is poured onto 30 mL of water. The precipitated material is filtered off, washed with water to give 7 g of the title compound, m.p.: 280-283° C. LC-MS: MH+ 2320; Ret. time: 5.19 minutes.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:23]=[CH:22][CH:21]=[CH:20][C:6]=1[C:7]([NH:9][C:10]1[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13])=[O:8])(=[O:3])[CH3:2].[C:24]([O:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30](Cl)=[O:31])(=[O:26])[CH3:25]>>[C:1]([O:4][C:5]1[CH:23]=[CH:22][CH:21]=[CH:20][C:6]=1[C:7]([NH:9][C:10]1[CH:18]=[C:17]([NH:19][C:30](=[O:31])[C:29]2[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=2[O:27][C:24](=[O:26])[CH3:25])[CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccccc1C(=O)Nc1cc(N)ccc1C(=O)O
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Product: CC(=O)Oc1ccccc1C(=O)Nc1ccc(C(=O)O)c(NC(=O)c2ccccc2OC(C)=O)c1

Procedure:
By the procedure similar to that described in Example 23, 2-(2'-acetoxybenzamido)-4-aminobenzoic acid and 2-acetoxybenzoylchloride were allowed to react and were treated to obtain crude crystals. Recrystallization from methanol-water gave 2,4-bis(2'-acetoxybenzamido)-benzoic acid having a melting point between 194° - 195°C. The product wass confirmed to be identical to that obtained in Example 18.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[CH:9][CH:8]=1)[NH2:5].[C:22]1([C:28]2[CH:42]=[CH:41][C:31]([C:32]([CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][C:35]3=O)=[O:33])=[CH:30][CH:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH3:1][O:2][C:3](=[O:21])[CH:4]([NH:5][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[C:32]([C:31]1[CH:30]=[CH:29][C:28]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:42][CH:41]=1)=[O:33])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Reactant: O=C1CCCCC1C(=O)c1ccc(-c2ccccc2)cc1
Product: COC(=O)C(Cc1ccc(O)cc1)Nc1ccccc1C(=O)c1ccc(-c2ccccc2)cc1
Yield: 32.3 %

Procedure:
The title compound (830 mg) was prepared from 1.83 g (5.7 mmol) O-benzyl-L-tyrosine methyl ester and 1.59 g (5.7 mmol) of 2-(4-phenylbenzoyl)cyclohexanone (Child, R. G. et.al. J. Pharm Sci 1977, 66(4), 466-76) according to the method of Intermediate 23 followed by purification via silica gel chromatography eluting with 1/9 EtOAc/hexanes: Low resolution MS (Cl) m/e 452 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:13][CH2:14]S(C)(=O)=O)[CH2:9]1)=[O:7].I.[NH:33]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]=[C:34]1[C:42]([CH:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)=[O:43]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:47]2[CH2:48][CH2:49][CH:44]([C:42]([C:34]3[NH:33][C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=4[N:35]=3)=[O:43])[CH2:45][CH2:46]2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCS(C)(=O)=O)(c3ccccc3)C2)cc(OC)c1OC
Reactant: O=C(c1nc2ccccc2[nH]1)C1CCNCC1
Agent: I
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)c4nc5ccccc5[nH]4)CC3)(c3ccccc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 6.6.2 using 1-(3,4,5-trimethoxy-benzoyl)-3-phenyl-3-(2-methanesulfonyl-ethyl)-pyrrolidine and 4-(1 H-benzoimidazole-2-carbonyl)-piperidine hydroiodide salt to give the title compound: mp; 108.0-111.0° C.; Rf=0.28 (silica gel, 5/1 ethyl acetate/methanol) Elemental Analysis calculated for C35H40N4O5·0.30 H2O: C 69.82; H 6.80; N 9.30; Found: C 69.90; H 6.79; N 9.22.
Reaction SMILES: [CH3:1][CH2:2][Mg+].[Br-].I[C:6]1[CH:13]=[C:12]([O:14][C:15]2[N:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][N:16]=2)[CH:11]=[CH:10][C:7]=1[C:8]#[N:9]>C1COCC1.[Cl-].[Cl-].[Zn+2]>[CH2:1]([C:6]1[CH:13]=[C:12]([O:14][C:15]2[N:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][N:16]=2)[CH:11]=[CH:10][C:7]=1[C:8]#[N:9])[CH3:2]
Reactant: N#Cc1ccc(Oc2ncc([N+](=O)[O-])cn2)cc1I
Reactant: CC[Mg+]
Agent: [Br-]
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CCc1cc(Oc2ncc([N+](=O)[O-])cn2)ccc1C#N
Reaction time: 1 h

Procedure:
In a flamed 2-necked flask, under N2, to a solution of ZnCl2 (0.82 mL of a 0.5 M solution on THF, 0.41 mmol) in 1.0 mL of THF, cooled at −15° C., EtMgBr (0.41 mL of a 1.0 M solution in THF, 0.41 mmol) was slowly added and the reaction mixture was stirred at that temperature for 1 h. Then Pd(tBu3P)2 (7.0 mg, 0.03 mmol) was added, followed by 2-iodo-4-[(5-nitro-2-pyrimidinyl)oxy]benzonitrile (Intermediate 121, 50.0 mg) in THF (1.0 mL) and the reaction mixture was stirred at −15° C. for 1 h and then the NaCl/ice bath was removed. After 2 hours at r.t. additional 3.5 mg (0.015 mmol) of (tBu3P)2 were added. The reaction was quenched with NH4Cl (saturated aqueous solution) and extracted with EtOAc (three times). The collected organic were dried over Na2SO4, filtered and evaporated. The residue obtained was charged on a silica gel column and eluted with Cyclohexane/EtOAc (from 100:0 to 90:10 Cyclohexane/EtOAc, plateau at 90:10) affording 25 mg of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2OCC[O:10]2)=[CH:5][N:4]=1)#[N:2].Cl>O1CCCC1>[C:1]([C:3]1[N:4]=[CH:5][C:6]([CH:9]=[O:10])=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(C2OCCO2)cn1
Agent: Cl
Solvent: C1CCOC1
Product: N#Cc1ccc(C=O)cn1
Temperature: 50 °C
Reaction time: 13 h
Yield: 101.7 %

Procedure:
2-Cyano-5-(1,3-dioxolan-2-yl)pyridine (478 mg, 2.71 mmol) was dissolved in tetrahydrofuran (5.0 mL). To this, 1N hydrochloric acid (5.0 mL) was added under a nitrogen atmosphere at room temperature and the mixture was stirred at the same temperature for 16 hours and successively at 50° C. for 13 hours. Then, the reaction mixture was neutralized with a saturated aqueous sodium bicarbonate solution, and extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and thereby 6-cyano-3-pyridinecarboxaldehyde (364 mg, yield: 100%) was obtained.
Reaction SMILES: [H-].[Na+].[CH:3](=[C:5](/[C:10]1[CH:35]=[C:34]2[C:13]([NH:14][C:15]3[C:16]2=[CH:17][CH:18]=[C:19]2[C:27]=3[NH:26][C:25]3[C:20]2=[CH:21][C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:23][CH:24]=3)=[CH:12][CH:11]=1)\[CH:6]=[CH:7]/[CH:8]=C)\[CH3:4].C1OCCOCCOCCOCCOC1.[Br:51][C:52]1[CH:60]=[CH:59][CH:58]=[CH:57][C:53]=1[C:54](Cl)=[O:55]>C1COCC1>[Br:51][C:52]1[CH:60]=[CH:59][CH:58]=[CH:57][C:53]=1[C:54]([N:26]1[C:27]2[C:19](=[CH:18][CH:17]=[C:16]3[C:34]4[C:13](=[CH:12][CH:11]=[C:10]([C:5]5[CH:6]=[CH:7][CH:8]=[CH:4][CH:3]=5)[CH:35]=4)[NH:14][C:15]3=2)[C:20]2[C:25]1=[CH:24][CH:23]=[C:22]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:21]=2)=[O:55]
Reactant: O=C(Cl)c1ccccc1Br
Reactant: C=C/C=C\C(=C/C)c1ccc2[nH]c3c(ccc4c5cc(-c6ccccc6)ccc5[nH]c43)c2c1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(c1ccccc1Br)n1c2ccc(-c3ccccc3)cc2c2ccc3c4cc(-c5ccccc5)ccc4[nH]c3c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.1 g (52.5 mmol) of NaH (60% in mineral oil) are dissolved in 500 ml of THF under a protective atmosphere. 20 g (50 mmol) of 3-[(Z)-1-eth-(E)-ylidenepenta-2,4-dienyl]-8-phenyl-11,12-dihydro-11,12-diazaindeno[2,1-a]-fluorene and 11.5 g (52.5 mmol) of 15-crown-5 dissolved in 200 ml of THF are added. After 1 h at room temperature, a solution of 12 g (55 mmol) of 2-bromobenzoyl chloride in 250 ml of THF is added dropwise. The reaction mixture is stirred at room temperature for 18 h. After this time, the reaction mixture is poured onto ice and extracted three times with dichloromethane. The combined organic phases are dried over Na2SO4 and evaporated. The residue is extracted with hot toluene and recrystallised from toluene/n-heptane. The yield is 22 g (75%).