Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH3:8])[CH2:3][C:4]1([OH:7])[CH2:6][CH2:5]1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[CH3:29][N:30]1[C:34]([CH:35]=O)=[C:33]([N+:37]([O-:39])=[O:38])[CH:32]=[N:31]1.C(=O)([O-])[O-].[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:29][N:30]1[C:34]([CH:35]2[O:7][C:4]3([CH2:6][CH2:5]3)[CH2:3][CH:2]([CH3:8])[O:1]2)=[C:33]([N+:37]([O-:39])=[O:38])[CH:32]=[N:31]1
Reactant: Cn1ncc([N+](=O)[O-])c1C=O
Reactant: CC(O)CC1(O)CC1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC1CC2(CC2)OC(c2c([N+](=O)[O-])cnn2C)O1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-(2-hydroxypropyl)cyclopropanol (2.0 g, 17.2 mmol) in DCM (35 mL) at 0° C. was added 2,6-lutidine (5 mL, 42.9 mmol) followed by trimethylsilyl trifluoromethanesulfonate (6 mL, 32.9 mmol). The reaction mixture was warmed to room temperature and stirred for 18 hr. Additional amounts of 2,6-lutidine (5 mL, 42.9 mmol) and trimethylsilyl trifluoromethanesulfonate (6 mL, 32.9 mmol) were added at 0° C. The mixture was stirred for 1 hr and quenched with saturated aqueous NaHCO3 (30 mL). The mixture was extracted with DCM (50 mL) and the organic layer was washed with aqueous 0.1 M HCl (2×15 mL) and passed through a phase separation cartridge. To this solution was added 2-methyl-4-nitro-pyrazole-3-carbaldehyde (1.40 g, 9.03 mmol) and the resulting solution was cooled to −78° C. and trimethylsilyl trifluoromethanesulfonate (4.11 mL, 22.6 mmol) added. The mixture was warmed to 0° C., stirred for 3 hr, cooled to −78° C. and additional trimethylsilyl trifluoromethanesulfonate (4.11 mL, 22.6 mmol) added. The mixture was warmed to 0° C. and stirred for 1 hr and solid sodium carbonate (2.5 g) added. The reaction mixture was stirred for 10 min before saturated aqueous NaHCO3 (100 mL) was added. The organic layer was washed with water (100 mL) and brine (100 mL), separated, dried over Na2SO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave 1-methyl-5-(5-methyl-6,8-dioxaspiro[2.5]octan-7-yl)-4-nitro-pyrazole as a colourless solid (1.0 g, 44% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 6.59 (s, 1H), 4.29-4.02 (m, 4H), 2.33-2.23 (m, 1H), 1.33 (d, J=6.2 Hz, 3H), 1.17-1.12 (m, 1H), 1.02-0.89 (m, 2H), 0.70-0.52 (m, 2H).
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[CH3:31][S:32]([C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1)(=[O:34])=[O:33].N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)(Cl)Cl>[O:30]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:39]3[CH:38]=[CH:37][CH:36]=[C:35]([S:32]([CH3:31])(=[O:34])=[O:33])[CH:40]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCS(=O)(=O)CC2)n3-c2cccc(S(C)(=O)=O)c2)CC1
Yield: 16 %

Procedure:
The title compound was synthesized in analogy to example 66, from [2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 1), 3-methylsulfonylphenylboronic acid, copper(II) acetate, pyridine and using chloroforme instead of dichloromethane as solvent, to give the desired product as a colorless solid (16%).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH:19]1([C:22](Cl)=[O:23])[CH2:21][CH2:20]1.C([O-])(O)=O.[Na+]>C1COCC1>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:10][C:22]([CH:19]2[CH2:21][CH2:20]2)=[O:23])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)C1CC1
Reactant: NC(=O)C(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NC(=O)C(c1ccccc1)c1ccccc1)C1CC1
Yield: 20.2 %

Procedure:
To a stirred and cooled (0° C.) solution of 2,2-diphenylacetamide (500 mg, 2.36 mmol) in THF (20 ml) was added sodium hydride (95 mg, 2.36 mmol; 60%) and the mixture was stirred at RT for 0.5 h. Then cyclopropanecarboxylic acid chloride(247 mg, 2.36 mmol) dissolved in THF (5 ml) was added dropwise at RT and the solution was stirred at RT for 20 h. The reaction mixture was poured into sat. NaHCO3 solution (50 ml) and extracted with ethyl acetate (2×70 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by column chromatography (toluene/ethyl acetate 19:1) yielded the product which was recrystallized from ethyl acetate/hexane to give a white solid (133 mg, 20%), m.p. 178° C. and MS: m/e=279 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)/[CH:5]=[CH:6]/[C:7](Cl)=[O:8].[CH3:13][NH2:14]>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)/[CH:5]=[CH:6]/[C:7]([NH:14][CH3:13])=[O:8]
Reactant: CN
Reactant: O=C(Cl)/C=C/c1cccc(Br)c1
Solvent: c1ccccc1
Product: CNC(=O)/C=C/c1cccc(Br)c1

Procedure:
A solution of trans 3-bromocinnamoyl chloride (5 g) in dry benzene (100 ml) was added with stirring to an ethereal (200 ml) solution of methylamine (3 g). After the addition was complete, a slow stream of methylamine gas was bubbled through the reaction mixture at room temperature for one hour. Solvent and excess amine were removed under reduced pressure. The crude product was triturated with water, filtered, and recrystallized from ethanol-water to give trans 3-bromo-N-methylcinnamamide, m.p. 147°-147.5° C. NMR, IR, and elemental analysis were consistent with this structure.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](/[CH:18]=[CH:19]/[C:20](OCC)=[O:21])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](/[CH:18]=[CH:19]/[C:20]([N:36]3[CH2:35][CH2:34][N:33]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[O:26][CH3:25])[CH2:38][CH2:37]3)=[O:21])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: CCOC(=O)/C=C/c1c(-c2ccc(C)cc2)nc2ccc(C)cn12
Product: COc1ccccc1N1CCN(C(=O)/C=C/c2c(-c3ccc(C)cc3)nc3ccc(C)cn23)CC1

Procedure:
Prepared from (E)-ethyl 3-[6-methyl-2-(4-methylphenyl)-imidazo[1,2-a]pyridin-3-yl]-2-propenoate (Description 23) and 1-(2-methoxyphenyl)piperazine according to the method of Example 1. 1H NMR (360 MHz, CDCl3) δ 8.15 (1H, d, J 1.5 Hz), 8.01 (1H, d, J 15.5 Hz), 7.66 (2H, d, J 8.2 Hz), 7.59 (1H, d, J 9.1 Hz), 7.27 (2H, d, J 8.2 Hz), 7.15 (1H, dd, J 9.1, 1.5 Hz), 7.04 (1H, m), 6.92 (3H, m), 6.80 (1H, d, J 15.5 Hz), 3.91 (2H, br s), 3.89 (3H, s), 3.60 (2H, br s), 3.06 (4H, br s), and 2.40 (6H, s). m/z (ES+) 467 (M+1).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[N:7]1[CH:12]=[CH:11][CH:10]=[C:9](B(O)O)[CH:8]=1.Br[C:17]1[CH:26]=[CH:25][C:20]([CH:21]=[CH:22][CH:23]=[O:24])=[CH:19][CH:18]=1>CO.C1(C)C=CC=CC=1.ClCCl.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>[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:17]2[CH:26]=[CH:25][C:20](/[CH:21]=[CH:22]/[CH:23]=[O:24])=[CH:19][CH:18]=2)[CH:8]=1
Reactant: O=CC=Cc1ccc(Br)cc1
Reactant: OB(O)c1cccnc1
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: Cc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: O=C/C=C/c1ccc(-c2cccnc2)cc1

Procedure:
2M aq. Na2CO3 (1 mL) and a solution of 3-pyridinylboronic acid (148 mg, 1.20 mmol) in methanol (1 mL) were added to a solution of 4-bromocinnamaldehyde (211 mg, 1.00 mmol, prepared as described in Tetrahedron 1998, 54, 10761) and tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.030 mmol) in toluene (2 mL) and the mixture was heated to reflux for 36 h. The cooled reaction mixture was diluted with dichloromethane, washed with sat. aq. NaHCO3 and brine, dried (MgSO4), and concentrated. Purification by chromatography (SiO2, 1:1 hexane/ethyl acetate) yielded the title compound. MS 210 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][N:9]2[C:14]3=[N:15][C:16]([Sn](C)(C)C)=[CH:17][N:18]=[C:13]3[NH:12][CH2:11][C:10]2=[O:23])[CH2:3][CH2:2]1.Br[C:25]1[N:30]=[C:29]2[N:31]([CH2:36][CH2:37][CH:38]3[CH2:43][CH2:42]OCC3)C(=O)CNC2=NC=1.C[Sn](C)C.C[Sn](C)C>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.O1CCOCC1>[NH:31]1[C:29]2=[N:30][CH:25]=[C:42]([C:16]3[N:15]=[C:14]4[N:9]([CH2:8][CH2:7][CH:4]5[CH2:5][CH2:6][O:1][CH2:2][CH2:3]5)[C:10](=[O:23])[CH2:11][NH:12][C:13]4=[N:18][CH:17]=3)[CH:43]=[C:38]2[CH:37]=[CH:36]1
Reactant: C[Sn](C)(C)c1cnc2c(n1)N(CCC1CCOCC1)C(=O)CN2
Reactant: O=C1CNc2ncc(Br)nc2N1CCC1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Sn](C)C
Solvent: C1COCCO1
Product: O=C1CNc2ncc(-c3cnc4[nH]ccc4c3)nc2N1CCC1CCOCC1
Temperature: 110 °C
Yield: 54.6 %

Procedure:
1-(2-(Tetrahydro-2H-pyran-4-yl)ethyl)-7-(trimethylstannyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one. 7-Bromo-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (0.4 g, 1.29 mmol), hexamethylditin (0.57 g, 1.75 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.2 g, 0.176 mmol) were placed in a sealed tube with 1,4-dioxane (5 mL). The flask was evacuated, flushed with nitrogen, sealed and heated at 110° C. for 1 h. The reaction mixture was cooled to room temperature and filtered through Celite, washing with ethyl acetate. The filtrate was concentrated and sonicated with a small volume of solvent mixture (50% hexane in ethyl acetate) and isolated by filtration to yield the title compound (0.34 g, 0.8 mmol, 54.6% yield). MS (ESI) m/z 427 [M+2]−.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([OH:11])[CH:5]=1.C[O-].[Na+].Br[CH2:17][CH2:18]Br>CO>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]2[O:10][CH2:17][CH2:18][O:11][C:6]=2[CH:5]=1
Reactant: BrCCBr
Reactant: COC(=O)c1ccc(O)c(O)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc2c(c1)OCCO2

Procedure:
A solution of 4.20 g. of 3,4-dihydroxybenzoic acid methyl ester in 10.0 ml. of methanol is combined with 7.0 g. of sodium methoxide and then 15.0 g. of 1,2-dibromoethane is added. The resulting mixture is refluxed under nitrogen for 24 hours, then cooled, filtered, evaporated in vacuo and the resulting oil dissolved in 50 ml. of chloroform. The resulting solution after again filtering is chromatographed over 100 ml. of silica gel eluting with chloroform to obtain 3,4-ethylenedioxybenzoic acid methyl ester, m.p. 43°-45°C.
Reaction SMILES: [CH:1]1([C@@H:4]([OH:11])[C@H:5]([OH:10])[C:6]([O:8][CH3:9])=[O:7])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>C(Cl)Cl>[CH:1]1([C@@H:4]([OH:11])[C@H:5]([O:10][S:25]([C:22]2[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=2)(=[O:27])=[O:26])[C:6]([O:8][CH3:9])=[O:7])[CH2:2][CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@@H](O)[C@H](O)C1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H](OS(=O)(=O)c1ccc(C)cc1)[C@H](O)C1CC1
Reaction time: 72 h
Yield: 79 %

Procedure:
Under argon atmosphere, a solution of 4.22 g of methyl (2S,3R)-3-cyclopropyl-2,3-dihydroxypropionate in 140 ml of methylene chloride is cooled to -3° C. Then, 4.00 g of triethylamine and 5.17 g of p-toluenesulfonyl chloride are added to the mixture successively. The mixture is stirred for 3 days. Then, the solvent is removed in vacuo. The residue is poured into a mixture of ethyl acetate and water. The organic layer is washed with brine and dried. The solvent is removed in vacuo. The residue is purified by silica gel column chromatography (solvent; hexane:ethyl acetate=1:3) to give 6.54 g of methyl (2S,3R)-3-cyclopropyl-3-hydroxy-2-(p-toluenesulfonyloxy)propionate
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([S:26][C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1)([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)[C:14]#[N:15].Cl.[CH3:35][O:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][C:46]=1[O:47][CH3:48])[CH2:43][NH:42][CH2:41][CH2:40]2>>[CH3:25][O:24][C:18]1[CH:17]=[C:16]([C:13]([S:26][C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:42]2[CH2:41][CH2:40][C:39]3[C:44](=[CH:45][C:46]([O:47][CH3:48])=[C:37]([O:36][CH3:35])[CH:38]=3)[CH2:43]2)[C:14]#[N:15])[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: COc1ccc(C(C#N)(CCCCCCCCCCCBr)Sc2ccc(C)cc2)cc1OC
Agent: Cl
Product: COc1ccc(C(C#N)(CCCCCCCCCCCN2CCc3cc(OC)c(OC)cc3C2)Sc2ccc(C)cc2)cc1OC
Yield: 57.9 %

Procedure:
The procedure of Example 3 is repeated using 3.14 g of α-(11-bromoundecyl)-3,4-dimethoxy-α-[(4-methylphenyl)thio]benzeneacetonitrile and 2.03 g of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride. This affords 2.2 g of the desired product as a light yellow oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[C:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl.[CH2:19]([O:21][C:22](=[O:25])[CH2:23][NH2:24])[CH3:20].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[CH2:19]([O:21][C:22](=[O:25])[CH2:23][NH:24][CH2:2][CH2:3][CH:4]=[C:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:20]
Reactant: BrCCC=C(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: CCOC(=O)CNCCC=C(c1ccccc1)c1ccccc1
Reaction time: 7 h
Yield: 57.8 %

Procedure:
A mixture of 5.95 g (20.7 mmol) 4-bromo-1,1-diphenyl-1-butene (prepared as described in F. A. Ali et al., J. Med. Chem. 28: 653-660, 1985), 4.71 g (33.7 mmol) glycine ethyl ester hydrochloride (Aldrich, Milwaukee, Wis.), 11.62 g (84 mmol) potassium carbonate and 1.06 g (6.38 mmol) potassium iodide in 50 ml acetonitrile was refluxed with stirring under argon for seven hours. The reaction mixture was filtered, the solvent evaporated and the residue chromatographed on silica gel column with 20% ethyl acetate in hexanes to give 3.70 g (yield 58%) of N-[(4,4-diphenyl)but-3-enyl]glycine ethyl ester (compound A26) as an oil. NMR spectra of the product showed: 1H NMR (CDCl3, 300 MHz) 7.60-7.00 (m, 10 H), 6.09 (t, 1 H), 4.16 (q, 2 H), 3.35 (s, 2 H), 2.71 (t, 2 H), 2.32 (dt, 2 H), 1.25 (t, 3 H), 13C NMR (CDCl3, 75 MHz) 172.29, 143.25, 142.37, 139.82, 129.72, 128.13, 128.04, 127.97, 127.13, 126.92, 126.88, 126.68, 60.56, 50.73, 49.32, 30.33, 14.14.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:25])[CH2:6][CH2:7][C@H:8]([NH:15][C:16]([C:18]1[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=1)=[O:17])[CH2:9][O:10][CH2:11][O:12][CH2:13][CH3:14])[CH:2]=[CH2:3].[Cu](C#N)[C:27]#[N:28]>CN(C=O)C.C(OCC)(=O)C.O>[CH2:1]([O:4][C:5](=[O:25])[CH2:6][CH2:7][C@H:8]([NH:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:27]#[N:28])=[CH:20][CH:19]=1)=[O:17])[CH2:9][O:10][CH2:11][O:12][CH2:13][CH3:14])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)CC[C@@H](COCOCC)NC(=O)c1ccc(I)cc1
Reactant: N#C[Cu]C#N
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)CC[C@@H](COCOCC)NC(=O)c1ccc(C#N)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 71.7 %

Procedure:
To a solution of the compound prepared in Example 3 (2.00 g) in DMF (40 ml), copper cyanide (520 mg) was added. The mixture was vigorously stirred for 3 hours at 50° C. The reaction mixture was cooled, and diluted with ethyl acetate and water. The solution was filtered, the filtrate was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated to give the title compound (1.12 g) having the following physical data.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1[CH:16]=[CH:15][C:11]2[NH:12][N:13]=[N:14][C:10]=2[CH:9]=1.Cl[C:18]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][C:26]=2[N+:28]([O-:30])=[O:29])[C:20](=[O:21])[O:19]1>CN(C)C=O>[C:31]1([C:18]2([N:12]3[C:11]4[CH:15]=[CH:16][C:8]([CH3:7])=[CH:9][C:10]=4[N:14]=[N:13]3)[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][C:26]=3[N+:28]([O-:30])=[O:29])[C:20](=[O:21])[O:19]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C1OC(Cl)(c2ccccc2)c2c1cccc2[N+](=O)[O-]
Reactant: Cc1ccc2[nH]nnc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)nnn2C1(c2ccccc2)OC(=O)c2cccc([N+](=O)[O-])c21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To 37 ml of thionyl chloride was added 40 g of 2-benzoyl-3-nitrobenzoic acid. The mixture was heated and stirred for 4 hours on an oil bath kept at a temperature of 50° to 60° C. Excess thionyl chloride was distilled away under reduced pressure, and 40.2 g of 3-chloro-3-phenyl-4-nitrophthalide was obtained as a brown oily substance. Separately, 9.0 g (0.08 mol.) of potassium tert-butoxide and 9.3 g (0.07 mol.) of 5-methylbenzotriazole were added to 300 ml of dried dimethylformamide, and stirred for 20 minutes at room temperature. The resulting mixture was cooled to 5° C. and thereto, was added dropwise gradually the previously prepared solution containing 20 g (0.07 mol.) of 3-chloro-3-phenyl-4-nitrophthalide in 100 ml of dried dimethylformamide as the mixture was kept at 5° C. After the dropwise addition, the cooling bath was removed, and the stirring was further continued for 5 hours at room temperature. Thereto, 300 ml of a saturated aqueous solution of ammonium chloride was added subsequently. The reaction mixture was extracted with ethyl acetate repeatedly, and the extract was washed with water. The rsulting organic layer was dried over anhydrous sodium sulfate, and the sodium sulfate was filtered off with suction. The filtrate was concentrated to obtain 27.5 g of oily substance. This oily substance was separated and purified by flash column chromatography (silica gel: 1 Kg, eluate: hexane-ethyl acetate (2:1 by volume) mixture) to obtain the intended compound, 3-phenyl-3-(5-methyl-1-benzotriazolyl)-4-nitrophthalide, in the form of white crystals. Yield 6.9 g, Melting Point 240° to 248° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:17]2[C:22](=[O:23])[NH:21][CH2:20][CH:19]=[N:18]2)[CH:5]=[C:6]([Cl:16])[C:7]=1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1.[OH:24]O.O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:17]2[C:22](=[O:23])[NH:21][C:20](=[O:24])[CH:19]=[N:18]2)[CH:5]=[C:6]([Cl:16])[C:7]=1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1
Reactant: OO
Reactant: O=C1NCC=NN1c1cc(Cl)c(Cc2ccc(Cl)cc2)c(Cl)c1
Solvent: O
Solvent: CC(=O)O
Product: O=c1cnn(-c2cc(Cl)c(Cc3ccc(Cl)cc3)c(Cl)c2)c(=O)[nH]1
Reaction time: 3 h
Yield: 85 %

Procedure:
In 2 ml of acetic acid were dissolved 0.2 g of 2-[3,5-dichloro-4-(4-chlorobenzyl)phenyl]-4,5-dihydro-1,2,4-triazine-3(2H)-one and 0.2 ml of hydrogenperoxide (30%). The reaction was allowed to proceed for 3 hours at temperatures ranging from 100 to 110° C. To the reaction mixture was added 20 ml of water to cause precipitation of the titled compound as crystalline product. The product was collected by filtration. The yield was 85%. m.p.175-176° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:20]2[O:21][CH2:22][C:23]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)=[CH:27][CH:26]=3)[CH:24]=[C:19]2[C:18]=1[C:48]([O:50][CH3:51])=[O:49].N1C=CC=CC=1>C(Cl)Cl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:17]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:20]2[O:21][CH2:22][C:23]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)=[CH:27][CH:26]=3)[CH:24]=[C:19]2[C:18]=1[C:48]([O:50][CH3:51])=[O:49])(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)C1=C(O)c2ccccc2C2OCC(c3ccccc3)(c3ccc(N4CCCC4)cc3)C=C12
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)c2ccccc2C2OCC(c3ccccc3)(c3ccc(N4CCCC4)cc3)C=C12
Yield: 58.4 %

Procedure:
Trifluoromethanesulfonic anhydride (5.32 g, 18.9 mmol) was added dropwise to a solution of 6-hydroxy-5-methoxycarbonyl-3-phenyl-3-(4-pyrrolidinophenyl)-2H-naphtho-[1,2-b]pyran (4.8 g, 10 mmol) and pyridine (1.7 g, 21.6 mmol) in DCM (100 mL) at 0° C. under N2 with stirring. After 1 h the resulting solution was washed with HCl (100 mL, 2 M), water (100 mL), dried (MgSO4) and the solvent removed under reduced pressure. The residue was filtered through a short plug of silica using DCM as eluent. The solvent was removed under reduced pressure to give the title compound (3.57 g, 58%) as a blue powder.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3]([Cl:5])=[O:4].[CH3:16]C(CCCCCCCCCC)C(O)=O>>[CH3:1][C:2]([CH3:16])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3]([Cl:5])=[O:4]
Reactant: CCCCCCCCCCC(C)C(=O)O
Reactant: CCCCCCCCCCC(C)C(=O)Cl
Product: CCCCCCCCCCC(C)(C)C(=O)Cl

Procedure:
In a similar manner to that described in Example 25 except for the use of 2-methyldodecanoyl chloride [synthesized by chlorinating 2-methyldodecanoic acid which was synthesized by the process described in Organic Synthesis, 4, 616, by the method as described in B. D. Roth, et al., Journal of Medicinal Chemistry, 35, 1609-1617 (1992)] instead of 2,2-dimethyldodecanoyl chloride, 82.5 mg of the desired compound was obtained as a white powder.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH:16]([CH3:18])[O:15][CH:14]([CH3:19])[CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:20].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](Cl)=[O:30])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([NH:1][N:2]2[N:11]=[C:10]([N:12]3[CH2:13][CH:14]([CH3:19])[O:15][CH:16]([CH3:18])[CH2:17]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:20])=[O:30])=[CH:24][CH:23]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: CC1CN(c2nn(N)c(=O)c3ccccc23)CC(C)O1
Product: CC1CN(c2nn(NC(=O)Cc3ccc(Cl)cc3)c(=O)c3ccccc23)CC(C)O1

Procedure:
The product from Example 60A and 2-(4-chlorophenyl)acetyl chloride were processed using a method similar to that described in Example 4C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.48-11.49 (bs, 1H), 8.29 (ddd, J=7.9, 1.4, 0.6 Hz, 1H), 8.01 (ddd, J=8.1, 1.5, 0.7 Hz, 1H), 7.98 (ddd, J=8.2, 6.9, 1.3 Hz, 1H), 7.89 (ddd, J=7.9, 6.9, 1.5 Hz, 1H), 7.40-7.41 (m, 4H), 3.81-3.94 (m, 2H), 3.67 (s, 2H), 3.29-3.36 (m, 2H), 2.43 (dd, J=12.3, 10.3 Hz, 2H), 1.12 (d, J=6.2 Hz, 6H); MS (APCI+) M/Z 427 (M+H)+.