Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C@:10]([CH2:28][OH:29])([CH2:11][C:12]3[CH:20]=[N:19][N:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:13]=3[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH2:33][CH3:34]>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C@:10]([CH2:28][O:29][CH2:33][CH3:34])([CH2:11][C:12]3[CH:20]=[N:19][N:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:13]=3[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(C(=O)OC(C)(C)C)C2
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A solution of (R)-1-(4-fluorophenyl)-4a-hydroxymethyl-1,4,4a,5,7,8-hexahydro-1,2,6-triazacyclopenta[b]naphthalene-6-carboxylic acid tert-butyl ester (0.25 g) in tetrahydrofuran (2.5 mL) under argon at room temperature was treated sequentially with sodium hydride (0.072 g, 60% dispersion in mineral oil) and iodoethane (0.15 mL), and the resulting mixture was stirred at 50° C. for 2 hour. The solution was cooled to room temperature, diluted with ethyl acetate, washed with saturated aqueous ammonium chloride solution, water and brine, and dried over sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (9:1 by volume), to afford the title compound as an amber gum (0.21 g). LCMS (Method E): 428 (M+H)+, Retention time 4.7 minutes.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C([N:15]1[C@@H:20]2[C@H:21]([C:23]([OH:25])=[O:24])[CH2:22][C@@:16]1([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C@H:17]([O:26][CH2:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=1)[CH2:18][CH2:19]2)C1C=CC=CC=1>[Pd].C(O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:41][C:38]([F:39])([F:40])[C:30]1[CH:29]=[C:28]([CH2:27][O:26][C@@H:17]2[CH2:18][CH2:19][C@@H:20]3[NH:15][C@@:16]2([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:22][C@H:21]3[C:23]([OH:25])=[O:24])[CH:33]=[C:32]([C:34]([F:36])([F:37])[F:35])[CH:31]=1
Reactant: O=C(O)[C@@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 110.7 %

Procedure:
A mixture of (1R*,2R*,5S*,6R*)-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octan-6-carboxylic acid trifluoroacetate (Example 53; 2.7 g, 4 mmol), 10% palladium on charcoal (500 mg) and ethanol (30 ml) was stirred under hydrogen atmosphere (1 atm) at +40° C. for 20 minutes. The reaction mixture was cooled to room temperature, flushed with nitrogen gas and filtered through a pad of Celite™. The filtrate was concentrated to give the title compound (2.6 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]=[C:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1.[H][H]>[Pt](=O)=O.CO>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1
Reactant: CCOC(=O)N1CCC(=Nc2c(C)cccc2C)CC1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CO
Product: CCOC(=O)N1CCC(Nc2c(C)cccc2C)CC1

Procedure:
A mixture of 45 parts of ethyl 4-[(2,6-dimethylphenyl)-imino]-1-piperidinecarboxylate, 0.3 parts of platinum dioxide in 160 parts of methanol is hydrogenated at normal pressure and at a temperature between 24° and 35° C. After the calculated amount of hydrogen is taken up, hydrogenation is stopped. The catalyst is filtered off and the filtrate is evaporated. The oily residue is distilled, to yield 30 parts of the oily free base of ethyl 4-[(2,6-dimethylphenyl)amino]-1-piperidinecarboxylate; bp. 148°-153° C. at 0.01 mm. pressure. From this distillate, the hydrochloride salt is prepared in the usual manner in 1,1'-oxybisethane. The precipitated solid salt is filtered off and dried, yielding 28.5 parts of ethyl 4-[(2,6-dimethylphenyl)amino]-1-piperidinecarboxylate hydrochloride; mp. 195.5° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)[CH2:5][C:6]([OH:8])=O.O.ON1C2C=CC=CC=2N=N1.[N:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[CH:32][CH:31]=1>C(#N)C>[CH3:1][O:2][C:3](=[O:18])[CH:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)[CH2:5][C:6](=[O:8])[N:39]1[CH2:40][CH2:41][N:36]([C:33]2[CH:34]=[CH:35][N:30]=[CH:31][CH:32]=2)[CH2:37][CH2:38]1
Reactant: COC(=O)C(CC(=O)O)Cc1ccc(OC)cc1
Reactant: c1cc(N2CCNCC2)ccn1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: COC(=O)C(CC(=O)N1CCN(c2ccncc2)CC1)Cc1ccc(OC)cc1
Reaction time: 0.17 h
Yield: 89.9 %

Procedure:
To a solution of 2-(4-methoxybenzyl)succinic acid 1-methyl ester (3 g) in acetonitrile (60 ml) were added HOBt (1-hydroxy-1H-benzotriazole monohydrate) (1.84 g) and 1-ethyl-3-(3-dimethylamgnopropyl)carbodiide hydrochloride (2.76 g) and the solution was stirred for 10 minutes. To the solution was added 1-(4-pyridyl)-piperazine (1.96 g) and the solution was stirred for 30 minutes at room temperature. The reaction mixture was concentrated and the concentrate was made basic with an aqueous solution of sodium hydrogen carbonate to give an alkaline solution, which was extracted with ethyl acetate twice. The extract was washed with saturated brine and dried over Na2SO4. The solution was concentrated under reduced pressure and recrystallized from ethyl acetate/hexane to give the titled compound (4.25 g) as colorless needles.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)[CH3:2].[H-].[Na+].[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25](Cl)[N:24]=1>CN(C=O)C>[Cl:22][C:23]1[N:24]=[C:25]([NH:14][CH:11]2[CH2:10][CH2:9][N:8]([CH2:7][C:6]3[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=3)[CH2:13][CH2:12]2)[CH:26]=[CH:27][CH:28]=1
Reactant: Clc1cccc(Cl)n1
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cc(CN2CCC(Nc3cccc(Cl)n3)CC2)ccc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 2 %

Procedure:
To a solution of 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (39.7 mg, 0.15 mmol, 1.2 equiv; intermediate A1) in dry DMF (1.5 mL) under Ar was added sodium hydride (6.6 mg, 0.15 mmol, 1.2 equiv; 55% free-flowing powder moistened with oil) and the reaction mixture stirred at rt. After 2 h, 2,6-dichloro-pyridine (18.5 mg, 0.125 mmol, 1.0 equiv; commercially available) was added and the mixture heated by microwave irradiation to 140° C. for 1 h. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 1.1 mg (2%) of the title compound. MS (ISP): 376.3 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[O:9])=[C:6]([CH3:13])[CH:5]=1)(=[O:3])[CH3:2].[Cl:14][C:15]1[CH:16]=[C:17]([C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])[CH:18]=[C:19]([Cl:21])[CH:20]=1.C(N(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:16]=[C:17]([C:22]([OH:27])([C:23]([F:24])([F:25])[F:26])[CH2:2][C:1]([C:4]2[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[O:9])=[C:6]([CH3:13])[CH:5]=2)=[O:3])[CH:18]=[C:19]([Cl:21])[CH:20]=1
Reactant: CC(=O)c1ccc(C(N)=O)c(C)c1
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Solvent: CCCCN(CCCC)CCCC
Solvent: Cc1ccccc1
Product: Cc1cc(C(=O)CC(O)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(N)=O
Temperature: 60 °C
Reaction time: 25 h
Yield: 78.3 %

Procedure:
0.35 g of 4-acetyl-2-methylbenzoic acid amide, 0.49 g of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 1.72 g of toluene and 0.19 g of tri-n-butylamine were fed and the mixture was stirred for 25 hours at 60° C. The mixture was left to cool to room temperature and the slurry-state reaction solution was filtered under reduced pressure, and the solid was washed with a small amount of toluene. 0.65 g of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-methylbenzoic acid amide as a light yellow solid was obtained by drying under reduced pressure.
Reaction SMILES: [Br:1][C:2]1[C:3](O)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.N1C2C(=CC=CC=2)C=CC=1.O=P(Cl)(Cl)[Cl:24]>O>[Br:1][C:2]1[C:3]([Cl:24])=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnc(O)c(Br)c1
Solvent: c1ccc2ncccc2c1
Solvent: O
Product: O=[N+]([O-])c1cnc(Cl)c(Br)c1
Temperature: 100 °C
Yield: 82.7 %

Procedure:
To a cooled (0-5° C.) mixture of 3-bromo-2-hydroxy-5-nitropyridine (47.0 g, 0.214 mol) and quinoline (13.7 g, 0.107 mol) was added POCl3 (26.0 mL, 0.278 mol) dropwise over ˜10 min (the mixture was difficult to stir initially but became less viscous as the reaction progressed and the mixture warmed). After stirring at 120° C. for 3.5 h, the mixture was cooled to 100° C. and water (90 mL) was added. The resulting mixture was stirred vigorously while cooling to 0-5° C. The product was collected by filtration, washed with water and dried in vacuo at 45° C. to give 3-bromo-2-chloro-5-nitropyridine (42.0 g, 82% yield). 1H NMR (CD3OD) δ 9.19 (d, J=2.4 Hz, 1H), 8.93 (d, J=2.4 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6]Cl.[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]=[O:16])=[N:13][CH:14]=1.[H-].[Na+].O>CN(C=O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]=[O:16])=[N:13][CH:14]=1
Reactant: O=Cc1ccc(O)cn1
Reactant: COCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOCOc1ccc(C=O)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
##STR94## A. Methoxyethoxymethyl chloride (MEM) (19 g, 153 mmol) was added to a solution of 5-hydroxy-2-pyridinecarboxaldehyde (18.4 g, 149 mmol)in 300 ml DMF. NaH (6.3 g of 60% oil dispersion, 158 mmol) were added in portions while cooling the mixture to maintain 20°-30° C. The mixture was stirred an additional 1 hour at 25° C. 5 ml water were added, most of the solvent was evaporated, and water was added to the residue. The mixture was extracted with EtOAc. The extracts were dried over Na2SO4, filtered, and evaporated to a residue. The residue was chromatographed on silica gel eluting with EtOAc-hexanes (35:65) to obtain 5-[(2-methoxyethoxy)methoxy]-2-pyridinecarboxaldehyde: C10H13NO4 (211.22); 1H-NMR (CDCl3) δ 10.01 (s,1), 8.52 (d,1), 7.93 (d,1), 7.49 (m,1), 5.39 (s,2), 3.80 (m,2), 3.53 (m,2), 3.32 (s,3).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH:10]=[CH:11][C:12]2[CH:13]=[C:14](/[CH:17]=[CH:18]/[C:19]([O:21][CH3:22])=[O:20])[S:15][CH:16]=2)[N:9]=1)(=[O:3])[CH3:2]>C(OCC)(=O)C.C(O)(=O)C.[C].[Pd]>[C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]2[CH:13]=[C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[S:15][CH:16]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)/C=C/c1cc(C=Cc2csc(NC(C)=O)n2)cs1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)CCc1cc(CCc2csc(NC(C)=O)n2)cs1
Yield: 83 %

Procedure:
Methyl (2E)-3-(4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]vinyl}thiophen-2-yl)acrylate (3.000 g, 8.971 mmol) was dissolved in ethyl acetate (400 ml) and acetic acid (100 ml). 20% Palladium carbon was added, and the mixture was hydrogenated at room temperature under an atmospheric pressure. After the completion of the reaction, the catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (FUJI SILYSIA CHEMICAL LTD. BW-300SP, 100 g, ethyl acetate:hexane=2:3) to give methyl 3-(4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}thiophen-2-yl)propionate (2.521 g, 7.449 mmol, yield 83.0%) as a pale-yellow solid.
Reaction SMILES: [CH:1](=[C:5]1[CH2:10][CH2:9][CH:8]([CH:11]2[CH2:16][CH2:15][CH:14]([CH:17]=[CH2:18])[CH2:13][CH2:12]2)[CH2:7][CH2:6]1)[CH2:2][CH:3]=[CH2:4].[FH:19].C(=O)([O-])O.[Na+]>ClCCl.N1C=CC=CC=1>[CH2:1]([C:5]1([F:19])[CH2:6][CH2:7][CH:8]([CH:11]2[CH2:12][CH2:13][CH:14]([CH:17]=[CH2:18])[CH2:15][CH2:16]2)[CH2:9][CH2:10]1)[CH2:2][CH:3]=[CH2:4]
Reactant: F
Reactant: C=CCC=C1CCC(C2CCC(C=C)CC2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CCCC1(F)CCC(C2CCC(C=C)CC2)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
20.6 g of 4'-but-3-enylidene-4-vinylbicyclohexyl in 40 ml of dichloromethane were cooled to -25° C. 7.523 ml of a 70% solution of hydrogen fluoride in pyridine were then added dropwise with stirring, and the mixture was stirred at -25° C. for 30 minutes and then at RT for a further 8 hours. The reaction solution was poured into a suspension of 40 g of sodium hydrogencarbonate and 800 g of ice-water. The mixture was extracted with three times 150 ml of hexane. The combined organic extracts were washed once with 50 ml of sodium chloride solution, dried using sodium sulphate, filtered and evaporated to a residue. Crystallization from pentane at -25° C. gave 4-but-3-enyl-4-fluoro-4'-vinylbicyclohexyl (C 13 SmB 37 N 80 I, Δn=0.049, Δε=-1.8, viscosity=13 mm2).
Reaction SMILES: [NH2:1][NH2:2].Cl[C:4]1[N:5]=[N:6][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:8][CH:9]=1>>[NH:1]([C:4]1[N:5]=[N:6][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)[NH2:2]
Reactant: NN
Reactant: Clc1ccc(-c2ccncc2)nn1
Product: NNc1ccc(-c2ccncc2)nn1

Procedure:
The reaction of hydrazine with 3-chloro-6-(4-pyridinyl)pyridazine to produce 3-hydrazino-6-(4-pyridinyl)-pyridazine is carried out by heating the reactants at about 60° l C. to 100° C. in a suitable solvent, preferably but optionally under an inert atmosphere. The reaction is preferably run at about 75° C. to 85° C. and is conveniently and preferably run by heating the reactants in refluxing isopropyl alcohol, preferably under nitrogen. Other suitable solvents include dioxane, ethanol, 2-methoxyethanol, or the like. Optionally, the reaction can be run in the absence of a solvent.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]([Cl:16])[N:7]=1)C.[NH3:18].CO>>[Cl:16][C:8]1[N:7]=[C:6]([CH2:5][C:4]([NH2:18])=[O:3])[C:15]2[C:10]([CH:9]=1)=[CH:11][CH:12]=[CH:13][CH:14]=2
Reactant: N
Reactant: CCOC(=O)Cc1nc(Cl)cc2ccccc12
Solvent: CO
Product: NC(=O)Cc1nc(Cl)cc2ccccc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
(3-chloro-isoquinolin-1-yl)-acetic Acid Ethyl Ester (2.5 g, 10 mmol) is dissolved in 4N NH3/MeOH (50 ml). The solution is transferred into an autoclave and kept at 120° C. for 48 hours. After cooling to RT the solvent is removed and the resulting crude product is purified on silica gel using methylene chloride (100%)→ methylene chloride/methanol (95/5) as eluent, affording 2-(3-chloro-isoquinolin-1-yl)-acetamide as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][C:14]1[N:19]=[C:18]([Sn](CCCC)(CCCC)CCCC)[CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=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[Pd]Cl>[Cl:12][C:10]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:13])[N:19]=2)[CH:11]=1
Reactant: Clc1cc(Cl)c2cccnc2n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(C)n1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1cccc(-c2cc(Cl)c3cccnc3n2)n1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A solution of 1.69 g (8.47 mmol) 2,4-dichloro-[1,8]naphthyridine and 3.24 g (8.47 mmol) 6-methyl-2-(tributylstannyl)-pyridine in 8.5 ml toluene was heated to 80° C. under nitrogen. Then 178 mg (0.254 mmol) bis-(triphenylphosphine)-palladium(II)-chloride were added. The mixture was stirred for 16 hrs at 80° C. and then cooled to 0° C. in an ice bath. The precipitate was filtered off, washed with ice-cold toluene and petrolether and dried in vacuum. This yields 4-chloro-2-(6-methylpyridin-2-yl)-[1,8]naphthyridine as gray felt-like needles; HPLC-MS: 2.25 min, [M+H] 256.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11]([OH:13])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].NC1C=CC(C=CC(O)=O)=CC=1.P(Cl)(OCC)(OCC)=O.[CH3:37][N:38]([CH3:49])[CH2:39][CH2:40][NH:41][C@H:42]1[CH2:47][CH2:46][C@H:45]([CH3:48])[CH2:44][CH2:43]1>CN(C)C1C=CN=CC=1.C(Cl)Cl.C(N(CC)CC)C>[CH3:37][N:38]([CH3:49])[CH2:39][CH2:40][N:41]([C@H:42]1[CH2:43][CH2:44][C@H:45]([CH3:48])[CH2:46][CH2:47]1)[C:11](=[O:13])[CH:10]=[CH:9][C:8]1[CH:7]=[CH:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:15][CH:14]=1
Reactant: CN(C)CCN[C@H]1CC[C@H](C)CC1
Reactant: CC(=O)Nc1ccc(C=CC(=O)O)cc1
Agent: CCOP(=O)(Cl)OCC
Agent: CN(C)c1ccncc1
Agent: Nc1ccc(C=CC(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc(C=CC(=O)N(CCN(C)C)[C@H]2CC[C@H](C)CC2)cc1

Procedure:
Using 2.0 g of 4-acetylaminocinnamic acid derived from 4-aminocinnamic acid by the acetylation thereof, 1.9 ml of diethyl chlorophosphate, 3.5 ml of triethylamine, 60 ml of methylene chloride, 2.3 ml of N-(2-dimethylaminoethyl)-trans-4-methylcyclohexylamine (Example 78), and 0.04 g of 4-dimethylaminopyridine, a reaction similar to that conducted in Example 81 was carried out. As a result, 2.08 g of N-(2-dimethylaminoethyl)-N-(trans-4-methylcyclohexyl)-4-acetylaminocinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [CH:1]1[C:13]2[C:12](=[O:14])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[N-:20]=[N+]=[N-].[Na+]>>[CH:4]1[C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12](=[O:14])[NH:20][C:13]=2[CH:1]=[CH:2][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1c2ccccc2-c2ccccc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=c1[nH]c2ccccc2c2ccccc12

Procedure:
In Scheme I, a 9-fluorenone (A) is treated with sulfuric acid and aqueous sodium azide in a ring-expansion, or Schmidt, reaction to produce 6(5H)-phenanthridinone (B). Nitration of (B) produces 2-nitro-6(5H)-phenanthridinone (C) as a major product, which is then reduced by Fe, NH4Cl and DMF, or catalytic dehydrogenation, to produce 2-amino-6(5H)-phenanthridinone (D). In general, a compound falling within Formula II is prepared by modifying the parent molecule 6(5H)-Phenanthridinone. See, e.g., U.S. Pat. Nos. 3,291,801 and 3,932,643; Taylor et al., J. Am. Chem. Soc. 78:5104-5108 (1956). The 2-nitro (Compound C)-and 2-amino (Compound D)-6(5H)-phenanthridinones are synthesized by a slight modification of procedures described in Andrievskii, et al., Chem. Heterocycl. Compds (English Transl.) 21:8, 924-931 (1985), and Migachev, et al. Chem. Heterocycl. Compds (English Transl.) 17:3, 394-397 (1981)
Reaction SMILES: C[O:2][C:3](=[O:42])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28]CC3C=CC=CC=3)[C:25](Br)=[CH:24][C:23]=2[CH2:37][CH3:38])[C:12]=1[CH2:39][CH2:40][CH3:41].[O:43]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44]1.C(=O)([O-])[O-].[Na+:55].[Na+]>O1CCCC1.O.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>[OH2:2].[Na+:55].[CH2:37]([C:23]1[CH:24]=[C:25]([CH:45]2[CH2:46][CH2:47][O:43][CH2:44]2)[C:26]([OH:28])=[CH:27][C:22]=1[O:21][CH2:20][CH2:19][CH2:18][O:17][C:13]1[C:12]([CH2:39][CH2:40][CH3:41])=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([O-:42])=[O:2])[CH3:38].[CH2:37]([C:23]1[CH:24]=[C:25]([CH:45]2[CH2:46][CH2:47][O:43][CH2:44]2)[C:26]([OH:28])=[CH:27][C:22]=1[O:21][CH2:20][CH2:19][CH2:18][O:17][C:13]1[C:12]([CH2:39][CH2:40][CH3:41])=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([O-:42])=[O:2])[CH3:38].[Na+:55]
Reactant: OB(O)c1ccoc1
Reactant: CCCc1c(OCCCOc2cc(OCc3ccccc3)c(Br)cc2CC)cccc1Oc1ccccc1C(=O)OC
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: CCCc1c(OCCCOc2cc(O)c(C3CCOC3)cc2CC)cccc1Oc1ccccc1C(=O)[O-]
Temperature: 100 °C
Yield: 65 %

Procedure:
A mixture of 2-{3-[3-(5-benzyloxy-4-bromo-2-ethylphenoxy)propoxy]-2-propylphenoxy}-benzoic acid methyl ester (3.00 g, 4.73 mmol), furan-3-boronic acid (1.06 g, 9.47 mmol), tetrakis(triphenylphosphine)palladium(0) (0.54 g, 0.47 mmol), and 2 M aqueous sodium carbonate solution (20 mL) in tetrahydrofuran (40 mL) was heated at 100° C. for 48 h. The mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was separated, washed once with water, once with saturated sodium chloride solution, dried (sodium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, 10% ethyl acetate/90% hexane) of the residue provided 1.9 g (65%) of the title compound as a yellow oil. 1H NMR (CDCl3) δ 7.88 (dd, J=8, 2 Hz, 1H), 7.87 (s, 1H), 7.40 (m, 7H), 7.26 (s 1H), 7.05 (m, 2H), 6.80 (d, J=9 Hz, 1H), 6.76 (d, J=2 Hz, 1H), 6.67 (d, J=9 Hz, 1H), 6.60 (s, 1H), 6.43 (d, J=9 Hz, 1H), 5.11 (s, 2H), 4.18 (m, 4H), 3.83 (s, 3H), 2.66 (t, J=8 Hz, 2H), 2.62 (q, J=7 Hz, 2H), 2.30 (quintet, J=6 Hz, 2H), 1.57 (hextet, J=8 Hz, 2H), 1.20 (t, J=7 Hz, 3H), 0.92 (t, J=7 Hz, 3H); MS ES+ m/z=621 (p+1); IR (CHCl3, cm−1) 3000, 1727, 1603, 1461.
Reaction SMILES: FC1C=CC([C:8]2[CH:13]=[C:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](C)=[C:19](C4C=CC(F)=CC=4)[CH:18]=3)(=[O:16])=[O:15])[CH:11]=[CH:10][C:9]=2[CH3:31])=CC=1.[O:32]1[C:36]2([CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[O:35][CH2:34][CH2:33]1.C(=O)([O-])[O-].[K+].[K+].O>CN1C(=O)N(C)CCC1>[C:9]1([CH3:31])[CH:10]=[CH:11][C:12]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([N:39]3[CH2:40][CH2:41][C:36]4([O:35][CH2:34][CH2:33][O:32]4)[CH2:37][CH2:38]3)=[CH:19][CH:18]=2)(=[O:15])=[O:16])=[CH:13][CH:8]=1
Reactant: C1CC2(CCN1)OCCO2
Reactant: Cc1ccc(S(=O)(=O)c2ccc(C)c(-c3ccc(F)cc3)c2)cc1-c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCN(C)C1=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)c2ccc(N3CCC4(CC3)OCCO4)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.4 %

Procedure:
To a solution of 4-fluorophenyl-4-tolylsulfone (1.25 g, 5 mmol) in N,N′-dimethylpropyleneurea (5 ml) was added 1,4-dioxa-8-aza-spiro[4.5]decane (0.88 g, 6 mmol), and potassium carbonate (0.83 g, 6 mmol). The mixture was stirred at room temperature for 4 h and then heated at 70° C. for 18 h. An additional 0.22 g of 1,4-dioxa-8-aza-spiro[4.5]decane was added, and the reaction was continued for 1 day. The mixture was cooled to room temperature, and treated with water. The resulting suspension was filtered, and the precipitate washed with water and methanol, and dried in vacuo to give 1.80 g of a white solid; m.p. 164-165° C.; MS (ES) m/z 373.9 (MH+); HRMS (EI) Calcd. for C20H23NO4S (M+): 373.1348, Found: 373.1342.