Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:13])(=O)[CH2:2][C:3]1[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:5]([OH:7])=O.[Br:14][CH2:15][CH2:16]O.[C:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][C:28]([O:30][CH2:31][CH2:32][Br:33])=[O:29])([OH:20])=[O:19].P(Cl)(Cl)(Cl)(Cl)[Cl:35]>C1C=CC=CC=1.S(=O)(=O)(O)O>[C:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][C:28]([O:30][CH2:31][CH2:32][Br:33])=[O:29])([OH:20])=[O:19].[Br:14][CH2:15][CH2:16][C:1]1[O:13][C:5]([C:4]2[C:3]([C:2]=1[Cl:35])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:7]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(O)Cc1ccccc1C(=O)O
Reactant: OCCBr
Agent: O=C(Cc1ccccc1C(=O)O)OCCBr
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: O=c1oc(CCBr)c(Cl)c2ccccc12
Yield: 46 %

Procedure:
2-Bromoethyl 2-carboxyphenylacetate was prepared from heating 10 g of homophthalic acid (56 mmole) and 21 g of 2-bromoethanol (167 mmole) in 175 ml of benzene with a few drops of conc. sulfuric acid at 90°-110° C. for two hours, yield 64%. TLC shows that it is a pure compound. The cyclization of 2-bromoethyl 2-carboxyphenylacetate with PCl5 was performed by a previous method with modification (Tirodkar, and Usgaonkar, Indian. J. Chem. 7, pp 114-1116 (1969)). 1.15 g of 2-bromoethyl 2-carboxyphenylacetate was heated with 2.1 g of PCl5 in 90 ml of benzene at 70° C. for 2 hrs. The benzene was removed and the residue triturated with petroleum ether. The crude product was purified by silica gel column chromatography with methylene chloride as an eluent to give 560 mg of 3-(bromoethyl)-4-chloroisocoumarin (yield, 46%). IR and NMR spectra show it was the desired product. 100 mg of 3-bromoethyl-4-chloroisocoumarin (0.3 mmole) was heated with 60 mg of thiourea (0.8 mmole) in 5 ml of THF at 70° C. for 2 days to give a yellow solid, 50 mg (yield, 40%), m.p. 167°-169° C. (dec); one spot on TLC, RF=0.7 (Butanol:acetic acid:water=6:1:5); NMR spectrum (d6 -DMSO), δ9.1 (2b, 4H), 7.5-8.1 (m, 4H), 4.6 (t, 2H), 3.6 (t, 2H); mass spectrum (FAB+), m/e=299 (M+ -Br). Anal. Calc. for C12H12N2O3Br1Cl1S2 : C, 37.96; H, 3.19; N, 7.38. Found: C, 37.81; H, 3.28; N, 7.71.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]([S:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][CH2:48][O:49][CH2:50][CH2:51][O:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][O:58][CH2:59][CH2:60][OH:61])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C=CC=CC=1>C(Cl)Cl>[C:12]([S:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][CH2:48][O:49][CH2:50][CH2:51][O:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCOCCOCCOCCOCCOCCOCCCCCCCCCCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCOCCOCCOCCCCCCCCCCCSC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
p-Toluenesulfonyl chloride (900 mg, 4.7 mmol) was added to a solution of alcohol 4 (910 mg, 1.28 mmol) dissolved in 12 mL of CH2Cl2 and 2 mL of pyridine at 0° C. The solution was warmed to room temperature and stirred for 16 hours. The reaction mixture was rinsed with brine (2×30 mL) and H20 (2×30 mL), and then the organics were dried over MgSO4. After the solvent was evaporated, the crude residue was purified by flash chromatography (gradient, 1:1 hexanes/EtOAc to EtOAc) to afford 1.01 g (91%) of pure 5. 1H NMR (CDCl3, 400 MHz) d 7.79 (d, J=8.0 Hz, 2 H), 7.40 (d, J=7.8 Hz, 6 H), 7.33 (d, J=8.0 Hz, 2 H), 7.26 (t, J=7.8 Hz, 6 H), 7.19 (t, J=7.8 Hz, 3 H), 4.15 (t, J=4.8 Hz, 2 H), 3.67 (t, J=5.2 Hz, 2 H), 3.64-3.54 (br m, 20 H), 3.43 (t, J=6.8 Hz, 2 H), 2.45 (s, 3 H), 2.12 (t, J=7.2 Hz, 2 H), 1.56 (m, 2 H), 1.42-0.90 (br, 16 H).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH3:8][CH:9]([CH2:11][CH2:12][CH2:13][C@H:14]([C@@H:16]1[C@:34]2([CH3:35])[C@H:19]([C@H:20]3[C@H:31]([CH2:32][CH2:33]2)[C@:29]2([CH3:30])[C:23]([CH2:24][C@H:25]([CH2:27][CH2:28]2)[OH:26])=[CH:22][CH2:21]3)[CH2:18][CH2:17]1)[CH3:15])[CH3:10].N1C=CC=CC=1>C(Cl)Cl>[C:1]([OH:6])(=[O:7])[CH2:2][CH2:3][C:4]([OH:26])=[O:5].[CH3:10][CH:9]([CH2:11][CH2:12][CH2:13][C@H:14]([C@@H:16]1[C@:34]2([CH3:35])[C@H:19]([C@H:20]3[C@H:31]([CH2:32][CH2:33]2)[C@:29]2([CH3:30])[C:23]([CH2:24][C@H:25]([CH2:27][CH2:28]2)[OH:26])=[CH:22][CH2:21]3)[CH2:18][CH2:17]1)[CH3:15])[CH3:8].[CH3:10][CH:9]([CH2:11][CH2:12][CH2:13][C@H:14]([C@@H:16]1[C@:34]2([CH3:35])[C@H:19]([C@H:20]3[C@H:31]([CH2:32][CH2:33]2)[C@:29]2([CH3:30])[C:23]([CH2:24][C@H:25]([CH2:27][CH2:28]2)[OH:26])=[CH:22][CH2:21]3)[CH2:18][CH2:17]1)[CH3:15])[CH3:8]
Reactant: O=C1CCC(=O)O1
Agent: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(O)CCC(=O)O
Temperature: 80 °C

Procedure:
Succinic anhydride (1.55 gm, 15.5 mmol) was added to a solution of cholesterol (5 gm, 12.9 mmol) in pyridine (10 ml). After heating at 80° C. for 3 h, the reaction mixture was diluted with DCM and the organic phase was washed with 10% HCl (50 ml) followed by a water wash (50 ml). The organic phase was separated, dried over Na2SO4 to obtain cholesterol hemisuccinate as white solid. The solid was recrystallized from DCM and hexane (5.78 gm, 92% yield, and melting point 176-178° C.). 1H NMR (300 MHz, CDCl3): δ 5.47 (d, vinylic-H, J=5.0), 4.70-4.60 (m, 1H), 2.75-2.65 (m, 4H), 2.38-2.35 (d, 7H), 2.20-1.80 (m, 12H), 1.60-1.40 (m, 12H), 0.78-0.75 (m, 3H).
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:12]([CH3:32])[C:13](=[O:31])[C:14]2[C:19]([C:20]=1[N:21]([C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([CH3:30])[CH:24]=1)[CH3:22])=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].O.Cl.O>C1COCC1.CO>[C:1]([O:5][CH:6]([C:11]1[N:12]([CH3:32])[C:13](=[O:31])[C:14]2[C:19]([C:20]=1[N:21]([C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([CH3:30])[CH:24]=1)[CH3:22])=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(OC(C)(C)C)c1c(N(C)c2ccc(C)c(C)c2)c2ccccc2c(=O)n1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1ccc(N(C)c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3ccccc23)cc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.4 %

Procedure:
To a mixture of methyl 2-(4-((3,4-dimethylphenyl)(methyl)amino)-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)-2-hydroxyacetate (90 mg, 0.237 mmol) and amberlyst 15 resin (45 mg, 0.237 mmol) in DCM (3 mL) at −70° C. was bubbled a stream of isobutylene until the volume doubles. The tube was sealed, and the reaction was stirred at room temperature for 10 hours. The mixture was filtered through a short pad of silica gel, washed with DCM and EtOAc, and the filtrate was concentrated. The mixture was purified on silica using EtOAc/hexanes 0-40% to give the intermediate methyl ester as an off-white solid (41.6 mg, 39%). 1H NMR (400 MHz, CDCl3) δ ppm 8.56-8.44 (m, 1 H), 7.59-7.42 (m, 3 H), 7.26-7.14 (m, 1 H), 7.05-6.93 (m, 1 H), 6.03-5.82 (m, 2 H), 3.74-3.67 (m, 7 H), 3.33 (s, 4 H), 2.23-2.12 (m, 6 H), 1.38-1.22 (m, 4 H), 1.12-1.00 (m, 9 H); ES-LCMS: 437.4 (M+1). To a solution of methyl 2-(tert-butoxy)-2-(4-((3,4-dimethylphenyl)(methyl)amino)-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)acetate (41.6 mg) in THF (3.0 mL) and MeOH (1 mL) was added a solution of LiOH/water (1.183 mL, 1.183 mmol). The mixture was stirred at room temperature for 18 hours. The mixture was cooled to 0° C. and 1N HCl/water was added to pH˜3 and the mixture was purified by reverse phase HPLC on a C18 column using MeCN/water 10-90% containing 0.05% TFA to provide the title compound as an off-white solid (19.5 mg, 19%). 1H NMR (400 MHz, CDCl3) ppm 8.58-8.42 (m, 1 H), 7.62-7.45 (m, 2 H), 7.21-7.12 (m, 1 H), 7.02-6.58 (m, 2 H), 6.02 (s, 1 H), 3.79-3.63 (m, 3 H), 3.41 (s, 3 H), 2.30-2.07 (m, 6 H), 1.27-1.08 (m, 9 H); ES-LCMS: 423.4 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH:12]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11]2=[O:16])(C)(C)C.[C:18]([OH:24])([C:20]([F:23])([F:22])[F:21])=[O:19]>C(Cl)Cl>[F:21][C:20]([F:23])([F:22])[C:18]([OH:24])=[O:19].[NH2:7][CH:8]1[CH2:13][CH:12]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11]2=[O:16]
Reactant: CC(C)(C)OC(=O)NC1CC2CCC1CC2=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CC2CCC1CC2=O
Temperature: 25 °C
Yield: 91.5 %

Procedure:
(5-Oxo-bicyclo[2.2.2]oct-2-yl)-carbamic acid tert-butyl ester (Preparation 75, 279 g, 1.17 mol, 1.0 eq) was taken up in DCM (450 mL). TFA (416 mL, 5.60 mol, 4.8 eq) was added dropwise. On addition, the reaction warms to reflux while much gas evolves. The reaction mixture was kept at reflux temperature for 1 hour after which it was allowed to cool to room temperature overnight. The mixture was concentrated and the residue was taken up in DCM (50 mL) and then tert-butyl methyl ether (1.3 L) was added which resulted in a brown suspension. The solids were collected by filtration (P3) and were washed with tert-butyl methyl ether. The latter was dried in vacuo (40° C.) to furnish title compound as an off-white solid (272 g, 1.07 mol, 92%).
Reaction SMILES: [NH2:1][C:2](=[N:4][C:5]([C:7]1[CH:8]=[C:9]([CH:22]2[CH2:27][CH2:26][N:25](C(OCC3C=CC=CC=3)=O)[CH2:24][CH2:23]2)[N:10]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:11]=1[CH3:12])=[O:6])[NH2:3].C(Cl)(Cl)[Cl:39]>C(O)C.[Pd]>[ClH:39].[ClH:39].[NH2:3][C:2]([NH2:1])=[N:4][C:5]([C:7]1[CH:8]=[C:9]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[N:10]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:11]=1[CH3:12])=[O:6]
Reactant: Cc1c(C(=O)N=C(N)N)cc(C2CCN(C(=O)OCc3ccccc3)CC2)n1CCc1ccc(F)cc1
Reactant: ClC(Cl)Cl
Agent: [Pd]
Solvent: CCO
Product: Cc1c(C(=O)N=C(N)N)cc(C2CCNCC2)n1CCc1ccc(F)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A 230 mg portion of benzyl 4-{4-{[(diaminomethylene)amino]carbonyl}-1-[2-(4-fluorophenyl)ethyl]-5-methyl-1H-pyrrol-2-yl}piperidine-1-carboxylate was dissolved in 5 ml of ethanol, 45 mg of 10% palladium-activated carbon was added, followed by stirring at room temperature for 5 hours under an atmosphere of hydrogen. After adding chloroform to the reaction liquid, the insoluble matter was separated by celite filtration, and the filtrate was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (Chromatorex (registered trademark), methanol:chloroform=10:90). The resulting product was dissolved in 3 ml of ethanol, and 0.269 ml of 4 M hydrogen chloride/ethyl acetate was added under ice-cooling, followed by stirring overnight at room temperature. The resulting solid was collected by filtration to obtain 95 mg of N-(diaminomethylene)-1-[2-(4-fluorophenyl)ethyl]-2-methyl-5-piperidin-4-yl-1H-pyrrole-3-carboxamide dihydrochloride as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](=O)[CH3:9])[CH:3]=1.O.[NH2:12][NH2:13]>CO>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](/[C:8](=[N:12]\[NH2:13])/[CH3:9])[CH:3]=1
Reactant: NN
Reactant: CC(=O)c1cc(Br)ccn1
Solvent: O
Solvent: CO
Product: C/C(=N/N)c1cc(Br)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring solution of 1-(4-bromopyridin-2-yl)ethanone (2.4 g, 12 mmol) in MeOH (40 mL) was added hydrazine monohydrate (2.9 mL, 60 mmol) in one portion. After stirring at room temperature for 2 hours, the mixture was concentrated to afford the product. 1H NMR (400 MHz, CDCl3) δ 8.34 (d, J=5.3 Hz, 1H), 8.14 (d, J=1.8 Hz, 1H), 7.33 (dd, J=5.3, 1.8 Hz, 1H), 5.66 (br s, 2H), 2.23 (s, 3H).
Reaction SMILES: Cl.[CH2:2]([NH:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:14]=O.[CH3:16][C:17]1[C:18]2[CH2:31][CH2:30][CH2:29][C:28](=[O:32])[C:19]=2[C:20]2[CH2:21][CH2:22][C:23](=[O:27])[NH:24][C:25]=2[CH:26]=1>C(OC(=O)C)(=O)C>[CH2:2]([N:9]([CH2:14][CH:29]1[C:28](=[O:32])[C:19]2[C:20]3[CH2:21][CH2:22][C:23](=[O:27])[NH:24][C:25]=3[CH:26]=[C:17]([CH3:16])[C:18]=2[CH2:31][CH2:30]1)[CH2:10][CH2:11][CH2:12][CH3:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1cc2c(c3c1CCCC3=O)CCC(=O)N2
Reactant: CCCCNCc1ccccc1
Reactant: C=O
Agent: Cl
Solvent: CC(=O)OC(C)=O
Product: CCCCN(Cc1ccccc1)CC1CCc2c(C)cc3c(c2C1=O)CCC(=O)N3

Procedure:
N-Benzyl-N-butylamine hydrochloride (12 g), 6 ml of 37% formalin, 40 ml of acetic anhydride and 11.5 g of 6-methyl-1,2,3,4,7,8,9,10-octahydro-benzo[f]quinoline-3,10-dione are allowed to react and post-treated in the same manner of Example 1. The obtained crystals are recrystallized from isopropanol to give 13.2 g of 9-(N-benzyl-N-butylaminomethyl)-6-methyl-1,2,3,4,7,8,9,10-octahydro-benzo[f]quinoline-3,10-dione as colorless needles, melting at 190°-193° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].C([O-])([O-])=O.[K+].[K+].[C:30]([C:34]1[CH:39]=[CH:38][C:37]([SH:40])=[CH:36][CH:35]=1)([CH3:33])([CH3:32])[CH3:31]>CN(C=O)C.O>[C:30]([C:34]1[CH:35]=[CH:36][C:37]([S:40][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=3)=[CH:4][C:3]=2[N+:21]([O-:23])=[O:22])=[CH:38][CH:39]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)c1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ccc(Sc2ccc(NC(=O)c3cccc(C(F)(F)F)c3)cc2[N+](=O)[O-])cc1
Temperature: 80 °C

Procedure:
The product from Example 242a (600 mg, 1.828 mmol) was dissolved in DMF (20 ml) to which K2CO3 (505 mg, 3.656 mmol), and 4-tert-Butyl-benzenethiol (304 mg, 1.828 mmol) were added. This reaction mixture was then heated to 80° C. for 1 hr. At this time the reaction mixture was cooled to room temperature, diluted with water, and the title compound collected by filtration (311 mg, 35%)
Reaction SMILES: I[CH2:2][CH3:3].[CH2:4]=[C:5]1[CH2:8][CH:7]([C:9]([OH:11])=[O:10])[CH2:6]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:4]=[C:5]1[CH2:8][CH:7]([C:9]([O:11][CH2:2][CH3:3])=[O:10])[CH2:6]1
Reactant: C=C1CC(C(=O)O)C1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=C1CC(C(=O)OCC)C1
Reaction time: 16 h

Procedure:
Iodoethane (7.5 mL, 93.0 mol) was added at rt to a mixture of 3-methylenecyclobutanecarboxylic acid (10.0 g, 80.0 mmol) and cesium carbonate (56.0 g, 170.0 mmol) in anhydrous N,N-dimethylformamide (500.00 mL) under an atmosphere of nitrogen. The reaction was stirred for 16 hr then partitioned between diethyl ether (1 L) and brine (1 L). The aqueous layer was extracted with diethyl ether (3×500 mL) and the combined organic phases washed with water (2×1L), dried over sodium sulfate, filtered and concentrated in vacuo to yield desired product 1H NMR (400 MHz, CDCl3) δ ppm 1.26 (t, 3H), 2.71-3.27 (m, 5H), 4.15 (q, J=7.07 Hz, 2H) and 4.53-4.96 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[O:30]([C:37]1[CH:42]=[CH:41][C:40](O)=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:29][C:40]2[CH:41]=[CH:42][C:37]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:38][CH:39]=2)[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(Br)cc3)CC2)c1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3ccc(Oc4ccccc4)cc3)c3ccc(Br)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-bromophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-phenoxyphenol: ESMS m/e: 626.6 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=4)[CH:15]=3)[CH:10]=[CH:9]2)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:33][NH2:34].O>CS(C)=O>[CH3:33][NH:34][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=4)[CH:15]=3)[CH:10]=[CH:9]2)[N:5]=[CH:6][N:7]=1
Reactant: O=[N+]([O-])c1cccc(-c2ccc3ccn(-c4cc(Cl)ncn4)c3c2)c1
Reactant: CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CNc1cc(-n2ccc3ccc(-c4cccc([N+](=O)[O-])c4)cc32)ncn1
Temperature: 100 °C
Reaction time: 15 h
Yield: 98 %

Procedure:
1-(6-Chloropyrimidin-4-yl)-6-(3-nitrophenyl)-1H-indole (200 mg, 0.57 mmol) and potassium carbonate (788 mg, 7.5 mmol) were dissolved in DMSO (5 mL). Methylamine hydrochloride (192 mg, 2.85 mmol) was added at room temperature. The reaction mixture was stirred at 100° C. for 15 hours. After cooling to room temperature, water was added and the reaction mixture was stirred for 1 hour. Thus prepared solid was filtered, washed with water, and dried in the air. N-Methyl-6-(6-(3-nitrophenyl)-1H-indol-1-yl)pyrimidin-4-amine (193 mg) was yielded as white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=1[F:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C([CH2:26][CH3:27])(CC)C([O-])([O-])[O-])C.[N-:28]=[N+:29]=[N-:30].[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:26]([CH3:27])=[N:30][N:29]=[N:28]2)=[CH:11][C:10]=1[F:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1ccc(OCc2ccccc2)c(F)c1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1nnnn1-c1ccc(OCc2ccccc2)c(F)c1
Reaction time: 3 h

Procedure:
4-Benzyloxy-3-fluoro-phenylamine as a solution in acetic acid (50 ml) was heated to 75° under nitrogen. Triethylorthoacetate (10.3 ml) was added. After a further 45 min at this temperature, sodium azide (7.8 g) was added portionwise. Heating was continued for a further 3 h, the reaction cooled overnight and poured into sodium bicarbonate solution (8%, ca. 500 ml), extracted with dichloromethane (3×100 ml), dried (Na2SO4) and evaporated. The residue was purified by FCC with (dichloromethane/methanol (995:5)) to give the title compound as a solid (4.6 g). T.l.c. (Dichloromethane/methanol (995:5)), Rf 0.45.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH2:6].[C:8]([C:11]1[CH:42]=[C:41]2[C:14]([CH2:15][C:16]3[C:20]([C:21](=[O:34])[CH:22]([C:32]#[N:33])[C:23]([NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:24])=[N:19][N:18]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:17]=32)=[CH:13][CH:12]=1)(O)=[O:9].C1(N=C=NC2CCCCC2)CCCCC1.CN(CCO)C>C(#N)C.C(N(CC)CC)C>[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH:6][C:8]([C:11]1[CH:42]=[C:41]2[C:14]([CH2:15][C:16]3[C:20]([C:21](=[O:34])[CH:22]([C:32]#[N:33])[C:23](=[O:24])[NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[N:19][N:18]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:17]=32)=[CH:13][CH:12]=1)=[O:9]
Reactant: COC(=O)CN
Reactant: N#CC(C(=O)Nc1ccccc1)C(=O)c1nn(-c2ccccc2)c2c1Cc1ccc(C(=O)O)cc1-2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)CCO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)CNC(=O)c1ccc2c(c1)-c1c(c(C(=O)C(C#N)C(=O)Nc3ccccc3)nn1-c1ccccc1)C2
Temperature: 25 °C
Yield: 45.2 %

Procedure:
Glycine methyl ester hydrochloride (0.7 g) suspended in anhydrous acetonitrile (250 ml) is treated with triethylamine (0.56 g) under stirring at room temperature. To the suspension first 3-(7-carboxy-1,4-dihydro-1-phenyl-indeno[1,2-c]pyrazole-3-yl)-2-cyano-3-oxo-N-phenyl-propanamide (2.3 g) and the dicyclohexylcarbodiimide (1.25 g) are added. The reaction mixture is kept under stirring at room temperature for 4 hours and then is basified to pH 8 by adding dimethylaminoethanol. The precipitate is filtered, washed with acetonitrile and then eliminated. The organic solution is concentrated in vacuo to a small volume, diluted with water, acidified to pH 2 with 1N HCl and then basified to pH 8 with 1N NaOH. The obtained precipitate is filtered, washed with water, dissolved in chloroform and washed with 1N HCl and then with water until neutral. The organic solution is evaporated in vacuo to dryness and the residue is purified over a SiO2 column using CHCl3 /methanol 90/10 as eluent. Final crystallization from CH2Cl 2 /ethyl acetate yields 1.2 g of pure N-[1,4-dihydro-1-phenyl-3-(2-phenylcarbamoyl-cyano-acetyl)indeno[1,2-c]pyrazol-7-yl] carbonyl-glycine methyl ester.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14].[C:16]([O-:19])(=[O:18])[CH3:17].[Na+]>C(O)(=O)C.O>[C:16]([O:19][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14])(=[O:18])[CH3:17]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1CCl
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)OCc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 60 h
Yield: 97.9 %

Procedure:
2 g (8.348 mmol) of 1-chloromethyl-2-nitro-4-trifluoromethylbenzene are added, at a temperature in the region of 20° C., under an argon atmosphere, to 20 g (244 mmol) of sodium acetate in solution in 100 cm3 of acetic acid. After stirring for 60 hours at a temperature in the region of 100° C., the reaction mixture is diluted with 200 cm3 of water and then extracted with 2 times 300 cm3 of dichloromethane. The organic phases are combined, washed with 100 cm3 of water, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure (2.7 kPa), to give 2.15 g of 2-nitro-4-trifluoromethylbenzyl acetate in the form of an orange oil;
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][O:30][C:31]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:32]=1[CH:33]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:33][C:32]3[CH:35]=[C:36]([O:39][CH3:40])[CH:37]=[CH:38][C:31]=3[O:30][CH3:29])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: COc1ccc(OC)c(C=O)c1
Product: COc1ccc(OC)c(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 2,5-dimethoxy-benzaldehyde according to the procedure of Example 66. MS (ES) m/z 529.1.