Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:31][CH3:32])[CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[Cl:18])=[CH:12][CH:11]=1)[CH3:3]>O1CCCC1>[ClH:18].[CH2:31]([N:4]([CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13](/[C:16](/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:17](\[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)/[Cl:18])=[CH:12][CH:11]=1)[CH3:32]
Reactant: CCN(CC)CCCCOc1ccc(C(=C(Cl)c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CCN(CC)CCCCOc1ccc(/C(=C(/Cl)c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Combine (E and Z)-1-[4-(4-diethylaminobutoxy)phenyl]-1,2-diphenyl-2-chloro-ethylene hydrochloride salt (0.45 mol) and tetrahydrofuran (2 L). Heat to reflux. After 1 hour, cool to ambient temperature to give a solid. Collect the solid by filtration, rinse with tetrahydrofuran, and dry. Combine the solid and tetrahydrofuran (420 mL) and heat to reflux. After 24 hours, filter the mixture while hot, rinse with tetrahydrofuran, and dry to give (E)-1-[4-(4-diethylaminobutoxy)phenyl]-1,2-diphenyl-2-chloro-ethylene hydrochloride salt: mp; 188°-190° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[C:10](Br)=[CH:9][C:8]([F:12])=[C:7]([N+:13]([O-])=O)[C:6]=1Br>C(O)C.[Pd]>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([F:12])=[C:7]([NH2:13])[CH:6]=1
Reactant: O=[N+]([O-])c1c(F)cc(Br)c(OCCCl)c1Br
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(OCCCl)ccc1F
Reaction time: 120 h
Yield: 90.2 %

Procedure:
A solution of 1-(2-chloroethoxy)-2,6-dibromo-4-fluoro-3-nitrobenzene (73.2 g, 0.19 mol) in ethanol (1.1 L) containing 7.3 g of 10% palladium on carbon was hydrogenated at 40 psi for 5 days. The catalyst was filtered and the solvent was removed. The residue was dissolved in diethyl ether (300 mL) and washed with saturated aqueous sodium carbonate (200 L). The organic layer separated and washed with water, dried over anhydrous magnesium sulfate, filtered, and the solvent removed to afford an oil which solidies to afford 32.5 g (90.0%) a dark solid: mp 42°-43° C.; MS EI m/e 189/191 (M+); 1H NMR (CDCl3) δ 3.40-3.60 (2H, bs, NH2), 3.77 (2H, d, J=6 Hz), 4.14 (2H, d, J=6 Hz), 6.19-6.23 (1H, m), 6.36 (1H, dd, J=7, 3 Hz), 6.88 (1H, dd, J=11, 9 Hz).
Reaction SMILES: [N:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([C:12]([F:15])([F:14])[F:13])[CH:5]=1)=[C:2]=[O:3].[NH2:16][C:17]1([C:20]([OH:22])=[O:21])[CH2:19][CH2:18]1.[OH-].[Na+]>CC(C)=O.C(OCC)C>[C:8]([C:7]1[CH:10]=[CH:11][C:4]([NH:1][C:2]([NH:16][C:17]2([C:20]([OH:22])=[O:21])[CH2:19][CH2:18]2)=[O:3])=[CH:5][C:6]=1[C:12]([F:13])([F:14])[F:15])#[N:9]
Reactant: N#Cc1ccc(N=C=O)cc1C(F)(F)F
Reactant: NC1(C(=O)O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCOCC
Product: N#Cc1ccc(NC(=O)NC2(C(=O)O)CC2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
A solution of 4-isocyanato-2-(trifluoromethyl)benzonitrile (4.56 g, 21.5 mmol) in acetone (12 ml) is added dropwise to 1-aminocyclopropane carboxylic acid (2.02 g, 20 mmol) dissolved in an aqueous solution of sodium hydroxide (12 ml, 0.8 g, 20 mmol). The reaction medium is stirred for 1 hour at ambient temperature then poured into an aqueous solution of sodium hydroxide (1N, 40 ml). The solution obtained is washed with ethyl acetate (30 ml) then acidified by the addition of an aqueous solution of sulphuric acid (2M, 30 ml) and extracted with ethyl acetate (2×50 ml). The organic phase thus obtained is washed with water then with a saturated aqueous solution of sodium chloride, dried over Na2SO4 and filtered. The solvent is evaporated off under reduced pressure. The residue obtained is taken up in ethyl ether in order to produce a white solid, after filtration, with a yield of 50% (3.16 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.O[CH:10]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH:25]=[CH:26][CH:27]=2)[CH2:18][CH2:17]1.Cl>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:10]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:23]=[C:24]([NH:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH:25]=[CH:26][CH:27]=3)[CH2:18][CH2:17]2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccccc3)CC2)c1
Reactant: Oc1ccc(Cl)cc1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(Oc3ccc(Cl)cc3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 4-chlorophenol and N-{3-[1-(6-hydroxy-6-phenylhexyl)-4-piperidinyl]phenyl}-2-methylpropanamide: 1H NMR (400 MHz, CDCl3), HCl salt δ 8.28 (s, 1H), 7.78–6.70 (m, 13H), 5.08–4.98 (m, 1H), 3.64–3.46 (m, br, 2H), 3.02–2.82 (br, 2H), 2.82–2.56 (m, br, 4H), 2.56–2.34 (m, br, 2H), 2.05–1.75 (m, br, 6H), 1.64–1.48 (m, br, 1H), 1.48–1.34 (br, 3H), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 533.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][N:10]1[CH:15](/[CH:16]=[CH:17]/[C:18](=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][CH2:13][CH2:12][C:11]1=[O:25].[H][H]>[Pd].CO>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[CH:15]([CH2:16][CH2:17][C:18](=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][CH2:13][CH2:12][C:11]1=[O:25]
Reactant: [H][H]
Reactant: CCCCCC(=O)/C=C/C1CCCC(=O)N1C/C=C\CCCC(=O)OC
Agent: [Pd]
Solvent: CO
Product: CCCCCC(=O)CCC1CCCC(=O)N1CCCCCCC(=O)OC
Reaction time: 19 h
Yield: 94 %

Procedure:
Palladium on carbon (10 wt. %, 5 mg) was added to a solution of (Z)-7-[2-oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-hept-5-enoic acid methyl ester (40 mg, 0.11 mmol) in MeOH (3.0 mL). A hydrogen atmosphere was established by evacuating and refilling with hydrogen (3×) and the reaction mixture was stirred under a balloon of hydrogen for 19 h. The reaction mixture was filtered through celite, washing with MeOH, and the filtrate was concentrated in vacuo to afford 38 mg (94%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:11](=N)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClC(Cl)C>[C:11](=[N:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1ccc(C#N)c(N)c1
Reactant: N=C(c1ccccc1)c1ccccc1
Solvent: CC(Cl)Cl
Product: Cc1ccc(C#N)c(N=C(c2ccccc2)c2ccccc2)c1
Yield: 78.1 %

Procedure:
To a solution of 2-amino-4-methyl benzonitrile (20 g, 151 mmol) in 1000 mL of dichloroethane is added benzophenone imine (30 g, 166 mmol). The solution is refluxed for 48 hours After this time, the solution is cooled to ambient temperatures. The solution is washed with sat. NaHCO3, water and sat. NaCl. The organic layer is dried over MgSO4, filtered and concentrated under vacuum. The product is further purified by recrystallization from t-butyl ether. The title compound (25.5 g, 118 mmol) is obtained as a yellow solid. 1H NMR (CDCl3, 300 MHz) δ7.88 (m, 2H), 7.42 (m, 3H), 7.32 (m, 7H), 6.79 (d, 1H), 6.58 (s, 1H), 2.23 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[N+:10]([O-])([OH:12])=[O:11].[OH-].[Na+]>S(=O)(=O)(O)O>[CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH:4][N+:10]([O-:12])=[O:11]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(N)c(C)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(N[N+](=O)[O-])c(C)c1
Temperature: 4 °C
Reaction time: 0.33 h
Yield: 95 %

Procedure:
In a solution that consists of 2,4-dimethylaniline (12.4 ml, 100 mmol) in 80 ml of concentrated sulfuric acid, it is mixed at 0° C. with 5.0 ml of fuming nitric acid and stirred for 20 minutes at 4° C., and then for 30 minutes at room temperature. The reaction mixture is poured into 600 ml of ice water, and set at a pH of 10 with 5N sodium hydroxide solution. The precipitate is suctioned off, washed with water and dried. 15.72 g (95% of theory) of 2,4-dimethylnitrophenylamine is obtained as a mixture of regioisomers.
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[Cl:16][C:17]1[CH:22]=[N:21][CH:20]=[C:19]([Cl:23])[N:18]=1.[CH:24](OCC)=[O:25]>C1COCC1>[Cl:16][C:17]1[C:22]([CH:24]=[O:25])=[N:21][CH:20]=[C:19]([Cl:23])[N:18]=1
Reactant: CCOC=O
Reactant: Clc1cncc(Cl)n1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ncc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81 %

Procedure:
To THF (200 mL) at −30° C. under N2 is added n-butyllithium (2.5 M in hexane, 8 mL, 20 mmol), followed by 2,2,6,6-tetramethylpiperidine (3.5 mL, 20.5 mmol). The mixture is warmed to room temperature and stirred at this temperature for 10 minutes. After the mixture is cooled to −78° C., 2,6-dichloropyrazine (2.5 g, 16.75 mmol) in THF (25 mL) is added and the mixture is stirred at this temperature for 1 hour. To the mixture is added ethyl formate (2 mL, 24.4 mmol) and the mixture is stirred at this temperature for an additional 2 hours. The reaction is quenched with saturated NH4Cl (25 mL), warmed to room temperature, and diluted with ethyl acetate (200 mL). The organic layer is separated and dried, and solvent removed. Column chromatography on silica gel (15% ethyl acetate in hexane) gives 2.4 g of 3,5-dichloro-pyrazine-2-carbaldehyde as an oil.
Reaction SMILES: C([O:4][CH2:5][C@@H:6]1[CH2:15][C:14]2[C:9](=[CH:10][C:11]([O:18][CH3:19])=[C:12]([O:16][CH3:17])[CH:13]=2)[C:8]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([N:26]3[N:35]=[C:34]([C:36]4[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=4)[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:27]3=[O:42])[CH:21]=2)=[N:7]1)(=O)C.[OH-].[Li+]>CO.O1CCCC1>[OH:4][CH2:5][C@@H:6]1[CH2:15][C:14]2[C:9](=[CH:10][C:11]([O:18][CH3:19])=[C:12]([O:16][CH3:17])[CH:13]=2)[C:8]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([N:26]3[N:35]=[C:34]([C:36]4[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=4)[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:27]3=[O:42])[CH:21]=2)=[N:7]1
Reactant: COc1cc2c(cc1OC)C(c1ccnc(-n3nc(-c4cccnc4)c4ccccc4c3=O)c1)=N[C@H](COC(C)=O)C2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc2c(cc1OC)C(c1ccnc(-n3nc(-c4cccnc4)c4ccccc4c3=O)c1)=N[C@H](CO)C2
Reaction time: 0.25 h
Yield: 62.2 %

Procedure:
(3S)-4-(3-Acetoxymethyl-3,4-dihydro-6,7-dimethoxyisoquinolin-1-yl)-2-[4-(3-pyridyl)phthalazin-1(2H)-on-2-yl]pyridine (400 mg) is suspended in a mixture of methanol (20 ml) and tetrahydrofuran (10 ml), and thereto is added dropwise a 1 M aqueous lithium hydroxide solution (1.43 ml) under ice-cooling. The mixture is stirred for 15 minutes under ice-cooling, and the mixture is reacted at room temperature for three hours. The reaction mixture is concentrated, and the water is added to the residue. The mixture is extracted with methylene chloride, and the extract is washed, dried and concentrated. The reside is purified by silica gel column chromatography (solvent; chloroform:methanol=10:1) to give (3S)-4-(3,4-dihydro-3-hydroxymethyl-6,7-dimethoxyisoquinolin-1-yl)-2-[4-(3-pyridyl)phthalazin-1(2H)-on-2-yl]pyridine (230 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Cl.C([O-])([O-])=O.[K+].[K+]>>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:25][C:24]1[CH:27]=[CH:28][CH:29]=[C:22]([O:21][CH3:20])[CH:23]=1)[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: COc1cccc(CCl)c1
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cccc(CN2C(=O)C(C)(C)c3cc(N)c([N+](=O)[O-])cc32)c1

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (1 g) is alkylated using 3-methoxybenzyl chloride (0.6 g; 3.85 mmol) and K2CO3 (1.5 g; 10.9 mmol) at RT for 20 h. After filtration and evaporation of the solvent the crude material is de-acetylated under reflux conditions in 2-propanol (10 ml) and hydrochloric acid (6 N; 30 ml). Pure 5-amino-1-(3-methoxy-benzyl)-3,3-dimethyl-6-nitro-1,3-dihydro-indol-2-one (1.06 g) precipitates by pouring the reaction mixture into ice-water.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([NH2:12])=[N:7][CH:6]=[CH:5]2.[C:13]([N:20]1[CH2:27][CH2:26][CH2:25][C@H:21]1[C:22](O)=[O:23])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:16]([O:15][C:13]([N:20]1[CH2:27][CH2:26][CH2:25][CH:21]1[C:22](=[O:23])[NH:12][C:8]1[C:9]2[C:4](=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)[CH:5]=[CH:6][N:7]=1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: Nc1nccc2cc(Br)ccc12
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)Nc1nccc2cc(Br)ccc12
Reaction time: 6 h
Yield: 115.4 %

Procedure:
To a mixture of 6-Bromo-isoquinolin-1-ylamine (0.80 g), Boc-L-proline (0.803 g), and 4-methylmorpholine (0.83 mL) in DMF (10 mL) was added HATU (1.39 g). Reaction mixture was stirred for 6 hours. Additional Boc-L-proline (0.803 g), 4-methylmorpholine (0.83 mL) and HATU (1.39 g) were added and reaction stirred overnight at ambient temperature and then concentrated. The residue was dissolved in ethyl acetate and washed with 10:1 H2O/saturated sodium bicarbonate solution, 5% lithium chloride solution, brine and dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 20 to 70% ethyl acetate/hexanes) to give 2-(6-Bromo-isoquinolin-1-yl carbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (1.74 g): LCMS-ESI+: calc'd for C19H23BrN3O3: 421.31 (M+H+). Found: 419.8, 421.8 (M+H+).
Reaction SMILES: [SH:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]3[C:12](=[CH:13][C:4]=2[N:3]=1)[C:11]([CH3:15])([CH3:14])[C:10](=[O:16])[C:9]3([CH3:18])[CH3:17].Cl.Cl[CH2:21][C:22]1[CH:27]=[C:26]([O:28][CH2:29][CH3:30])[C:25]([CH3:31])=[CH:24][N:23]=1.[OH-].[Na+]>O>[CH2:29]([O:28][C:26]1[C:25]([CH3:31])=[CH:24][N:23]=[C:22]([CH2:21][S:1][C:2]2[NH:3][C:4]3[CH:13]=[C:12]4[C:8](=[CH:7][C:5]=3[N:6]=2)[C:9]([CH3:18])([CH3:17])[C:10](=[O:16])[C:11]4([CH3:14])[CH3:15])[CH:27]=1)[CH3:30]
Reactant: CCOc1cc(CCl)ncc1C
Reactant: CC1(C)C(=O)C(C)(C)c2cc3[nH]c(S)nc3cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOc1cc(CSc2nc3cc4c(cc3[nH]2)C(C)(C)C(=O)C4(C)C)ncc1C

Procedure:
6.1 g of 5,7-dihydro-2-mercapto-5,5,7,7-tetramethylindeno[5,6-d]imidazol-6(1H)-one were suspended in 100 ml of alcohol and treated while cooling with ice with 5.2 g of 2-chloromethyl-4-ethoxy-5-methylpyridine hydrochloride. Thereafter, a solution of 1.9 g of sodium hydroxide in 50 ml of water was added dropwise thereto, the mixture was left to boil at reflux overnight and subsequently evaporated to dryness in vacuo. The residue was dissolved in 300 ml of methylene chloride. The solution was washed firstly with 200 ml of 1.5N sodium hydroxide solution and then with 3×200 ml of water, dried over sodium sulfate and evaporated in vacuo. The product was purified on 120 g of silica gel with ethyl acetate/methylene chloride (1:1) as the elution agent. Crystallization from methylene chloride/petroleum ether gave 2-[[(4-ethoxy-5-methyl-2pyridyl)methyl]thio]-5,7-dihydro-5,5,7,7-tetramethylindeno [5,6-d]imidazol-6(1H)- one of melting point 187°-189° .
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([N:5]([CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]=1)=[O:4].[H][H]>C(O)C.[Pd]>[CH3:1][N:2]([CH3:20])[C:3]([N:5]([CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][N:7]=1)=[O:4]
Reactant: [H][H]
Reactant: CN(C)CCN(C(=O)N(C)C)c1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CCO
Product: CN(C)CCN(C(=O)N(C)C)c1ccc(N)cn1

Procedure:
N,N-Dimethyl-N'-(2-dimethylaminoethyl)-N'-(5-nitro-2-pyridyl)urea (9.68 g., 0.034 mole) is dissolved in absolute ethanol (50 ml.) containing 10% palladium-on-carbon and is hydrogenated at an initial 42 psi of hydrogen at ambient temperature for two hours. The reaction mixture is flushed with nitrogen and then is filtered under nitrogen. The filtrate is concentrated in vacuo on a steam bath to give a nearly colorless oil (8.05 g.) which partially solidifies on standing. Crystallization from acetonitrile yields 5.19 g. of the title compound, m.p. 118°-119° C.
Reaction SMILES: [N+:1]([CH2:4][C:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1
Reactant: O=[N+]([O-])CC1=Cc2ccccc2CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: NCC1CCc2ccccc2C1

Procedure:
2-Nitromethyl-3,4-dihydronaphthalene (XXXV) (25 g) and 20% Pd/C (1.0 g) were combined in MeOH (200 ml) and shaken in a Parr hydrogenator at 3 atmospheres hydrogen pressure for 24 hours, by which time the theoretical amount of hydrogen (4 equivalents) had been absorbed. Removal of the catalyst and solvent left an oil (24 g) which was converted to its HCl salt by solution in MeOH and addition of concentrated HCl. The product, compound XXXI.HCl, was recrystallized from 2-propanol, yielding a white solid, m.p. 230° (dec.). Its elemental analysis and NMR spectrum were consistent with the structure indicated.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([N:19]4[CH2:22][CH:21]([N:23]5[CH2:28][CH2:27][N:26]([C:29]([C:31]6[S:32][CH:33]=[CH:34][N:35]=6)=[O:30])[CH2:25][CH2:24]5)[CH2:20]4)=[O:18])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.C1C(=O)N([Cl:43])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Cl:43][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([C:17]([N:19]3[CH2:20][CH:21]([N:23]4[CH2:28][CH2:27][N:26]([C:29]([C:31]5[S:32][CH:33]=[CH:34][N:35]=5)=[O:30])[CH2:25][CH2:24]4)[CH2:22]3)=[O:18])[CH:12]=2)[N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:9]=1
Reactant: O=C(c1ccc2c(ccn2-c2ccc(F)cc2)c1)N1CC(N2CCN(C(=O)c3nccs3)CC2)C1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1ccc2c(c1)c(Cl)cn2-c1ccc(F)cc1)N1CC(N2CCN(C(=O)c3nccs3)CC2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of Cpd 487 (0.2 mmol, 100 mg) in CCl4 (4 mL) and CH2Cl2 (4 mL) was added NCS (0.25 mmol, 33 mg). The reaction mixture was stirred at room temperature for 4 h. It was then diluted with CH2Cl2 and washed with 1N aqueous NaOH and H2O, dried over Na2SO4, and concentrated. Purification by flash column chromatography (silica gel, 3% MeOH/CH2Cl2) gave 51 mg of Cpd 1365. MS m/z (M+H+) 524.
Reaction SMILES: [CH2:1]([C:3]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([CH3:16])[CH3:15])[CH:9]=2)[C:5](=[O:17])[C:4]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)[CH3:2].B.[Na].Cl>C(O)C>[CH2:1]([CH:3]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([CH3:16])[CH3:15])[CH:9]=2)[C:5](=[O:17])[CH:4]1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)[CH3:2]
Reactant: CCC1=C(c2cccc(Cl)c2)C(=O)N(c2cccc(C(C)C)c2)C1
Agent: B
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCC1CN(c2cccc(C(C)C)c2)C(=O)C1c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.0 g (14.7 mmol) of 4-ethyl-3-(3-chlorophenyl)-1-(3-isopropylphenyl)-3-pyrroline-2-one synthesized in Example 4 were dissolved in 50 ml of ethanol, and 0.56 g (14.7 mmol) of sodium boron hydride were added thereto little by little at room temperature under stirring. Reaction was further allowed to proceed at the same temperature for 1 hour, and the reaction mixture was then poured into 1 N hydrochloric acid, followed by extraction with ethyl acetate. The resultant organic layer was washed with water, an aqueous saturated sodium bicarbonate solution and water in this order, and then dried over magnesium sulfate. Next, the solvent was distilled off under reduced pressure. The resultant residue was analyzed by high-speed liquid chromatography (column: YMC-A302 (ODS), mobile phase: MeCN/H2O=9/1 (v/v), UV: 254 nm), and as a result, it was apparent that the residue was a mixture of the starting material/the end product=3/1 and a large amount of the raw material remained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([CH:10]=[O:11])[C:7]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6](Br)[CH:5]=1.[F:22][C:23]1[CH:24]=[CH:25][C:26]([O:32][CH3:33])=[C:27](B(O)O)[CH:28]=1>>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]([C:25]2[CH:24]=[C:23]([F:22])[CH:28]=[CH:27][C:26]=2[O:32][CH3:33])[C:7]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]([CH:10]=[O:11])[CH:9]=1)=[O:21]
Reactant: COc1ccc(F)cc1B(O)O
Reactant: COC(=O)c1cc(Br)c(OCc2ccccc2)c(C=O)c1
Product: COC(=O)c1cc(C=O)c(OCc2ccccc2)c(-c2cc(F)ccc2OC)c1
Yield: 58 %

Procedure:
Proceeding as in Reference 19, but substituting 4-benzyloxy-3-bromo-5-formyl-benzoic acid methyl ester (1.0 g, 2.71 mmol) and 5-fluoro-2-methoxyphenyl boronic acid (0.691 g, 4.16 mmol), gave 6-benzyloxy-5′-fluoro-5-formyl-2′-methoxybiphenyl-3-carboxylic acid methyl ester (0.620 g).
Reaction SMILES: C([O:5][C:6](=[O:33])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:18])[C:15]=2[F:17])[C:10]([S:19][C:20]2[C:21]([F:31])=[C:22]([CH:28]=[CH:29][CH:30]=2)[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:9]1[CH3:32])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:18][C:14]1[C:15]([F:17])=[C:16]2[C:11]([C:10]([S:19][C:20]3[CH:30]=[CH:29][CH:28]=[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:21]=3[F:31])=[C:9]([CH3:32])[N:8]2[CH2:7][C:6]([OH:33])=[O:5])=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1cccc(Sc2c(C)n(CC(=O)OC(C)(C)C)c3c(F)c(Cl)ccc23)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cccc(Sc2c(C)n(CC(=O)O)c3c(F)c(Cl)ccc23)c1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 84.7 %

Procedure:
To a stirred solution of compound 5 (200 mg, 0.40 mmol) in CH2Cl2 (10 mL) under inert atmosphere was added TFA (0.8 mL) at 0° C.; warmed to RT and stirred for 12 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed under reduced pressure. The residue was diluted with water (20 mL) and extracted with CH2Cl2 (2×30 mL). The combined organic extracts were washed with water (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. The crude was triturated with n-pentane (2×5 mL) to afford compound 6 (149 mg, 81%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.59-7.55 (m, 1H), 7.19-7.06 (m, 3H), 6.79-6.75 (m, 1H), 4.93 (s, 2H), 4.32 (q, 2H), 2.40 (s, 3H), 1.31 (t, J=7.2 Hz, 3H); LC-MS: 98.7%; 440.3 (M++1); (column: X Select CSH C-18, 50×3.0 mm, 3.5 μm); RT 2.90 min. 5 mM NH4OAc: ACN; 0.8 mL/min).