Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:16]([N:24]1[CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH:27]2[N:26]([CH2:33][CH2:34][CH2:35][CH2:36]Br)[C:25]1=[O:38])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:16]([N:24]1[CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH:27]2[N:26]([CH2:33][CH2:34][CH2:35][CH2:36][N:4]2[CH2:5][CH2:6][N:1]([C:7]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[S:9][N:8]=3)[CH2:2][CH2:3]2)[C:25]1=[O:38])(=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: O=C(c1ccccc1)N1C(=O)N(CCCCBr)C2CCCCC21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)N1C(=O)N(CCCCN2CCN(c3nsc4ccccc34)CC2)C2CCCCC21
Temperature: 60 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
A suspension of 3-(1-piperazinyl)-1,2-benzisothiazole (0.44 g, 2.0 mmoles), 3-benzoyl-1-(4-bromobutyl)perhydrobenzimidazol-2-one (0.76 g, 2.0 mmoles) and potassium carbonate (0.33 g, 2.4 mmoles) in 4 ml of dimethylformamide was stirred at 60° C. for 2 hours. Insolubles were removed by filtration, and the solvent was evaporated under reduced pressure. The residue was dissolved in chloroform and washed with water, and the solvent was evaporated. The residue was purified by chromatography on a silica gel column to give 1.0 g of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:18][N+:19]([O-])=O)[CH2:9][P:10]([CH3:17])(=[O:16])[O:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:4][CH:3]=1.N.[H][H]>C(O)C.[Ni]>[NH2:19][CH2:18][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:9][P:10]([CH3:17])(=[O:16])[O:11][CH2:12][CH:13]([CH3:15])[CH3:14]
Reactant: [H][H]
Reactant: CC(C)COP(C)(=O)CC(C[N+](=O)[O-])c1ccc(Cl)cc1
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CC(C)COP(C)(=O)CC(CN)c1ccc(Cl)cc1

Procedure:
A solution of 6.8 g of isobutyl 2-(4-chlorophenyl)-3-nitro-propyl(methyl)phosphinate in 80 ml of ethanol is added to 64 g of an 8% solution of ammonia in ethanol. To this are added 8 ml of Raney Nickel slurry and the resulting mixture is hydrogenated at 1 bar until hydrogen treated under reduced pressure to give isobutyl 3-amino-2-(4-chlorophenyl)-propyl(methyl)phosphinate as a viscous oil, 31P N.M.R. spectrum: δ=±54.0 and +53.4 ppm (CDCl3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C1(N)CCCCC1>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([OH:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccc(F)cc2)cc1
Solvent: O
Solvent: NC1CCCCC1
Product: O=C(O)CCC(O)c1ccc(-c2ccc(F)cc2)cc1
Yield: 54 %

Procedure:
Prepared analogous to Example 25 from 4-(4'-fluoro-4-biphenylyl)-4-oxo-butyric acid. Melting point of the cyclohexylamine salt: 175°-177° C. (from water). Yield 54% of theory.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1.Cl[CH2:22][C:23]1[S:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1>C(COC)OC>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:20][CH2:19][N:18]([CH2:22][C:23]3[S:24][C:25]4[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=4[N:27]=3)[CH2:17][CH2:16]2)=[CH:13][CH:14]=1
Reactant: ClCc1nc2ccccc2s1
Reactant: Oc1ccc(N2CCNCC2)cc1
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: Oc1ccc(N2CCN(Cc3nc4ccccc4s3)CC2)cc1
Reaction time: 5 h
Yield: 81.1 %

Procedure:
A solution of 1.05 g of triethylamine in 20 ml of absolute dimethoxyethane was added dropwise within 15 minutes with stirring to a mixture of 1.78 g (10 mmol) of 1-(4-hydroxyphenyl)piperazine, 2.48 g (13.5 mmol) of 2-chloromethylbenzothiazole and 80 ml of absolute 1,2-dimethoxyethane under reflux. The mixture was stirred for a further 5 hours under reflux, the solvent was evaporated in vacuo, the residue was taken up in CH2Cl2 /H2O, the phases were separated, and the aqueous phase was extracted three times with CH2Cl2. The combined CH2Cl2 extracts were dried, filtered and evaporated. The crystalline residue (3.2 g) was recrystallized from methanol. 2.64 g (81.2% of theory) of pure 1-(4-hydroxyphenyl)-4-(benzothiazol-2-ylmethyl)piperazine, melting point 175°-76° C., were obtained.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:25]([O:29][C:30](=[O:38])[NH:31][CH2:32][C:33]1([F:37])[CH2:36][NH:35][CH2:34]1)([CH3:28])([CH3:27])[CH3:26].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:25]([O:29][C:30](=[O:38])[NH:31][CH2:32][C:33]1([F:37])[CH2:34][N:35]([C:20](=[O:21])/[CH:19]=[CH:18]\[N:15]2[CH:16]=[N:17][C:13]([C:5]3[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:23])([F:24])[F:1])[CH:4]=3)=[N:14]2)[CH2:36]1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)NCC1(F)CNC1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC1(F)CN(C(=O)/C=C\n2cnc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C1
Temperature: -60 °C
Reaction time: 0.75 h
Yield: 49.8 %

Procedure:
(Z)-3-(3-(3,5-Bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.20 g, 0.56 mmol) was dissolved in DCM (10 mL). The reaction mixture was cooled to −60° C., at which temperature tert-butyl(3-fluoroazetidin-3-yl)methylcarbamate (0.127 g, 0.62 mmol), was added, followed by T3P (50% in EtOAc) (0.434 g, 0.67 mmol). DIPEA (0.144 g, 1.11 mmol) was then introduced slowly. The clear reaction mixture was stirred at −60° C. for a further 45 min. The reaction mixture was concentrated under reduced pressure to obtain crude product, which was purified by column chromatography (0-15% ethyl actetate-hexane) to afford 150 mg of (Z)-tert-butyl(1-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)-3-fluoroazetidin-3-yl)methylcarbamate (Yield 50%). 1H NMR (400 MHz, CDCl3, ppm) δ=9.7 (s, 1H); 8.63 (s, 2H); 7.94 (s, 1H); 7.24-7.21 (d, J=10.8 Hz, 1H); 5.67-5.64 (d, J=10.8, 1H); 4.41-4.16 (m, 4H); 3.76-3.54 (m, 3H).
Reaction SMILES: N1C=NC=N1.P(Cl)(Cl)(Cl)=O.[CH2:11]([N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])C.[CH3:18][C:19]1[N:27]2C(C(=O)[NH:24][CH:25]=[N:26]2)=[C:21]([C:29]2[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=2)[N:20]=1.Cl.N1CCC1>C(OCC)(=O)C.CO.C(#N)C>[N:13]1([C:14]2[C:15]3=[C:21]([C:29]4[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=4)[N:20]=[C:19]([CH3:18])[N:27]3[N:26]=[CH:25][N:24]=2)[CH2:11][CH2:17][CH2:16]1
Reactant: Cc1nc(-c2cnn(C)c2)c2c(=O)[nH]cnn12
Reactant: CCN(CC)CC
Agent: C1CNC1
Agent: Cl
Agent: c1nc[nH]n1
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CO
Product: Cc1nc(-c2cnn(C)c2)c2c(N3CCC3)ncnn12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Finely ground 1H-1,2,4-triazole (278 g, 4.02 mol) was mixed with acetonitrile (700 mL), cooled to 0° C., and treated drop-wise with phosphorus oxychloride (62.4 mL, 669 mmol) while maintaining the internal temperature below 15° C. The suspension was stirred for 10 minutes, then slowly treated drop-wise with triethylamine (607 mL, 4.35 mol) under vigorous stirring, while keeping the internal temperature below 48° C. The reaction was stirred for 15 minutes as it cooled to 41° C., and was then treated portion-wise with 7-methyl-5-(1-methyl-1H-pyrazol-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one (77.1 g, 335 mmol). At the completion of the addition, the reaction was warmed to 73° C. for 1 hour, then cooled to room temperature, at which point thin layer chromatography (Eluant: 10% methanol in ethyl acetate) indicated complete conversion to the triazole-substituted intermediate. The reaction slurry was treated successively with triethylamine (279 mL, 2.00 mol) and azetidine hydrochloride (94.0 g, 1.00 mol); over 10 minutes, the internal temperature rose from 18° C. to 38° C. The mixture was stirred for 1 hour, cooled to 15-20° C. and filtered. The filter cake was washed with acetonitrile (600 mL), and the filtrate was concentrated in vacuo. The resulting paste was diluted with water (650 mL) followed by aqueous sodium hydroxide solution (10 N, 450 mL). This slurry was extracted with dichloromethane (3×350 mL), and the combined organic layers were dried over sodium sulfate and filtered. This filtrate was passed through a plug of silica gel (230-400 mesh, 150 g), eluting with dichloromethane (1 L) followed by 10% methanol in ethyl acetate (1 L). The combined eluants containing product were concentrated in vacuo, and the residue was washed with tert-butyl methyl ether (350 mL), collected by filtration, and washed with diethyl ether. This solid was dissolved in water (200 mL) and diluted once more with aqueous sodium hydroxide solution (5 N, 250 mL). The mixture was extracted with dichloromethane (3×250 mL), and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The solid was washed with tert-butyl methyl ether (350 mL) and collected by filtration to afford C2 as a pale tan solid. Yield: 82.15 g, 305 mmol, 91%. 1H NMR (500 MHz, CDCl3) δ 2.23-2.30 (m, 2H), 2.65 (s, 3H), 3.96 (s, 3H), 3.98-4.07 (m, 4H), 7.61 (br s, 1H), 7.61 (br s, 1H), 7.85 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH2:16][CH2:15]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.O>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:6]([C:7]([N:17]2[C:18]3[C:14](=[CH:13][C:12]([F:11])=[CH:20][CH:19]=3)[CH2:15][CH2:16]2)=[O:9])[CH:5]=[N:4][CH:3]=1
Reactant: Fc1ccc2c(c1)CCN2
Reactant: O=C(O)c1cncc(Br)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1cncc(Br)c1)N1CCc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.44 g (2.2 mmol) 5-bromonicotinic acid, 0.30 g (2.2 mmol) 5-fluoroindoline, 0.75 g (2.3 mmol) TBTU and 0.60 mL (4.3 mmol) TEA were combined in 3.0 mL DMF and stirred overnight at RT. Then the reaction mixture was added to water, the precipitate formed was suction filtered and dried.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:16]([NH:18][C@H:19]([C@@H:27]([OH:33])[CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:17])[CH2:10][C:11]1[N:15]=[CH:14][NH:13][CH:12]=1)=O)(C)(C)C>FC(F)(F)C(O)=O.C(OCC)(=O)C>[NH2:8][C@H:9]([C:16]([NH:18][C@H:19]([C@@H:27]([OH:33])[CH2:28][CH2:29][CH:30]([CH3:31])[CH3:32])[CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:17])[CH2:10][C:11]1[N:15]=[CH:14][NH:13][CH:12]=1
Reactant: CC(C)CC[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CC[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@@H](N)Cc1c[nH]cn1
Yield: 91.5 %

Procedure:
A solution of 2(S)-(N-t-butoxycarbonyl-L-histidyl)amino-1-cyclohexyl-3(S)-hydroxy-6-methylheptane (383 mg) in trifluoroacetic acid (10 ml) was stirred at 0° C. for 30 minutes. After concentration of the mixture in vacuo, the residue was dissolved in ethyl acetate (20 ml). The solution was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate, and concentrated in vacuo to give 2(S)-(L-histidyl)amino-1-cyclohexyl-3(S)-hydroxy-6-methylheptane (275 mg) as an amorphous powder.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.P(Br)(Br)[Br:16].[Cl-].[Na+]>N1C=CC=CC=1>[Br:16][CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OCCCOCC=Cc1ccccc1
Reactant: BrP(Br)Br
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Product: BrCCCOCC=Cc1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
192 g (1.2 mol) of the obtained 3-hydroxypropoxy methylstyrene and 55 ml of dehydrated and purified pyridine were charged into a 300 ml four-necked flask, and 108 g (0.4 mol) of phosphorus tribromide was dropwise added thereto while maintaining the mixture at -10° C. with dry ice ethanol. After completion of the dropwise addition, the mixture was stirred at room temperature for 15 hours. The reaction mixture was poured into 250 ml of an aqueous sodium chloride solution (20 wt %) and extracted with toluene. The organic layer was washed with water and a 8% sodium hydrogencarbonate aqueous solution and dried over magnesium sulfate. Then, toluene was distilled off under reduced pressure. The solution thereby obtained was subjected to vacuum distillation (b.p. 90° to 91° C./54 Pa) in the presence of DPPH to obtain 3-bromopropoxymethylstyrene as the desired product. The yield was 35%. The obtained solution was analyzed by 1H-NMR and IR spectrum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[S:11](Cl)(=[O:13])=[O:12].S([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+].S(Cl)(Cl)(=O)=O>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[S:11]([OH:13])=[O:12]
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(=O)(Cl)Cl
Product: COc1ccc(S(=O)O)c(OC)c1
Temperature: 0 °C

Procedure:
Next, a mixture containing 35.8 g (0.15 moles) of 2,4-dimethoxy-benzenesulfonyl chloride and 56 g (0.45 moles) of sodium sulfite is shaken for 3 hours with 100 g of ice until complete solution is obtained. The solution is maintained alkaline by adding 5% sodium hydroxide (to prevent formation of sulfur dioxide) and kept cold by adding additional ice (higher temperatures may cause hydrolysis of the sulfonyl chloride). At the end of 3 hours unreacted 2,4-dimethoxybenzenesulfonyl chloride can be filtered off and the filtrate acidified with cold concentrated hydrochloric acid to yield a white crystalline precipitate of 2,4-dimethoxybenzenesulfinic acid, m.p. 89-91° C. (lit. 92° C.). The 2,4-demethoxybenzene-sulfinic acid is suspended in water and an equimolar quantity of sodium carbonate added in small portions to dissolve the sulfinic acid. The condensation of the sodium salt of the sulfinic acid with ortho-dinitrobenzene can be carried out by refluxing equimolar amounts of the two for 4 hours. Upon cooling the mixture is filtered and the solid residue recovered and crystallized using acetic acid to yield white shiny crystals of 2,4-dimethoxy-2′-nitrobiphenyl sulfone having a melting point of from about 157.5° C. to about 158.5° C.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH:13]=[C:12]([C:15]2[N:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[CH:25]=[N:26][N:27]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][N:31]=4)[C:28]=3[CH3:29])=[O:23])=[CH:17][C:16]=2[CH3:40])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCOCC1.C(O)C.[C].[Pd]>[C:1]([N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[N:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[CH:25]=[N:26][N:27]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:38])([F:39])[F:37])=[CH:32][N:31]=4)[C:28]=3[CH3:29])=[O:23])=[CH:17][C:16]=2[CH3:40])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1=CCN(C(=O)c2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1CCN(C(=O)c2ccccc2)CC1
Temperature: 40 °C
Reaction time: 7 h
Yield: 79.7 %

Procedure:
N-{6-[1-Benzoyl-1,2,3,6-tetrahydropyridin-4-yl]-5-methylpyridin-3-yl}-5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (110 mg) described in Example K40 was dissolved in 1,4-dioxane (5 ml) and ethanol (5 ml), 10% palladium-carbon (containing ca. 50% water; 90 mg) was added, and stirred at 40° C. under hydrogen atmosphere for seven hours. The reaction solution was filtered through Celite, washed with chloroform and ethanol and the solvent was evaporated in vacuo. The resulting residue was purified with silica gel chromatography (chloroform/methanol) to give the titled compound (88 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[S:10])SC.O.[NH2:12][NH2:13]>C(O)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[S:10])[NH:12][NH2:13]
Reactant: COCCCNC(=S)SC
Reactant: NN
Solvent: O
Solvent: CCO
Product: COCCCNC(=S)NN
Temperature: 70 °C
Reaction time: 4.5 h
Yield: 98.5 %

Procedure:
A solution of methyl N-(3-methoxypropyl)-dithiocarbamate (100.2 g) in ethanol (300 ml) was added dropwise at 3° C. over 30 minutes to a solution of hydrazine hydrate (28 g) in ethanol (200 ml). The mixture was stirred for 4.5 hours at 70° C. The reaction mixture was concentrated and to the residue were added water and diethyl ether. The diethyl ether extract was dried over magnesium sulfate and evaporated in vacuo to give pinkish oil of 4-(3-methoxypropyl)thiosemicarbazide (89.9 g).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].C#C.[OH:7][C:8]1[C:25]2[CH2:24][CH2:23][C:22](=[O:26])[CH2:21][C:20]=2[C:19]([OH:27])=[C:18]2[C:9]=1[C:10](=[O:29])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=1[C:17]2=[O:28].C(O)(=O)C(O)=O>O1CCCC1>[C:1]([C:22]1([OH:26])[CH2:21][C:20]2[C:19]([OH:27])=[C:18]3[C:9]([C:10](=[O:29])[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=4[C:17]3=[O:28])=[C:8]([OH:7])[C:25]=2[CH2:24][CH2:23]1)#[CH:2]
Reactant: CC[Mg]Br
Reactant: O=C1CCc2c(O)c3c(c(O)c2C1)C(=O)c1ccccc1C3=O
Agent: C#C
Agent: O=C(O)C(=O)O
Solvent: C1CCOC1
Product: C#CC1(O)CCc2c(O)c3c(c(O)c2C1)C(=O)c1ccccc1C3=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 498.5 %

Procedure:
Acetylene, purified by passing it first through a column of alumina, then through concentrated sulfuric acid, was bubbled rapidly through freshly distilled tetrahydrofuran (100 ml) under nitrogen for 30 minutes. Ethylmagnesium bromide (3 ml, 3.15 M in ether, 12.6 mmole) was added in portions. When the frothing subsides, portionwise addition of the ethylmagnesium bromide solution was continued until the total solution had been added. The passage of acetylene was stopped and 7,10-dihydro-6,11-dihydroxy-5,9,12(8H)-naphthacenedione (VII) (250 mg, 0.12 mmole) in dry tetrahydrofuran (240 ml) was added dropwise. An immediate blue color was noted. After addition was completed, the mixture was stirred at room temperature under dry nitrogen overnight. To the dark blue solution was added 5% aqueous oxalic acid solution until the blue color disappeared and the brown reaction mixture extracted with chloroform. The chloroform extracts were washed well with water, dried over anhydrous sodium sulfate and the solvent removed to give a dark residue. The residue was chromatographed on Florisil (100-200 mesh) elution with methylene chloride, then with 2% methanol/methylene chloride yielded 9-ethynyl-7,10-dihydro-6,9,11-trihydroxy-5,12(8H)-naphthacenedione (VIII) (200 mg, 91%) as a red orange solid. m.p. 230° C. with decomposition; IR 6.15, 6.30μ; MS 334 (M+) 317 (M-OH); NMR (CDCl3) 13.40 (s 2H OH's), 8.3 (m 1H aryl), 7.7 (m 1H aryl), 3.1 (m 4H benzylic), 2.5 (s 1H ethynyl), 2.16 (m 2H allylic); UV (CHCl3) 289, 460, 485, 518 nm; PFT (CDCl3) δ13.46 (s 2H OH), 8.34 (m 2H aryl), 7.81 (m 2H aryl), 2.06 (t 2H benzylic), 2.50 (s 1H ethynyl), 2.15 (t 2H allylic).
Reaction SMILES: C([SiH](CC)CC)C.C([O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]([CH:31]=[N:32][OH:33])=[C:23]2[CH3:34])=[CH:18][CH:17]=1)C1C=CC=CC=1.[Cl-].[NH4+].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl.O1CCCC1.CC([O-])=O.CC([O-])=O.[Pd+2].C(OCC)(=O)C.C(N(CC)CC)C>[OH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]([CH:31]=[N:32][OH:33])=[C:23]2[CH3:34])=[CH:18][CH:17]=1
Reactant: Cc1c(C=NO)c2ccccc2n1-c1ccc(OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(C=NO)c2ccccc2n1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83 %

Procedure:
To a stirred solution of dichloromethane (20 mL), Pd(OAc)2 (50 mg, 0.2 mmol), and triethylsilane (2 mL) was added triethylamine (1 mL), and the mixture was stirred at room temperature for 15 min. To the mixture was added 1-(4-benzyloxyphenyl)-2-methyl-1H-indole-3-carbaldehyde oxime (0.36 g, 1 mmol) in dichloromethane (10 mL), and stirred for 90 min. Ethyl acetate (25 mL) and ammonium chloride (25 mL of 10% solution) were added and the product extracted into ethyl acetate (2×25 mL). The combined organic layers were washed with water (3×25 mL) and brine (25 mL) and dried over MgSO4. After removing the solvent, a liquid was obtained, which was dissolved in anhydrous tetrahydrofuran (10 mL). To this mixture was added tetrabutyl ammonium fluoride (3 mL). After stirring for 30 min, the mixture was extracted with ethyl acetate and water. The organic layer was washed with water and brine and dried over MgSO4. After evaporation of the solvent afforded the crude solid which was purified by silica gel chromatography (25% ethyl acetate-hexanes) to give a pale yellow solid (83%): mp 171-173° C.; 1H NMR (DMSO-d6): δ 2.29 (3H, s), 6.95 (4H, d, J=7.7 Hz), 7.09-7.13 (2H, m), 7.22 (2H, d, J=8.7 Hz), 7.98-8.01 (1 H, m), 8.40 (1H, s), 9.89 (1H, s), 10.63 (1H, s); MS m/z (M+H)+ 267. Anal. for C16H14N2O2: Calc'd: C, 72.17; H, 5.30; N, 10.52. Found: C, 71.78; H, 5.23; N, 10.37.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C:11]1[C:20]([CH3:21])=[C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:30])[CH:17]=2)[CH:12]=1)=O.O.[OH-].[Na+]>O1CCCC1>[CH2:23]([O:22][C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:30])[CH:17]=2)[CH:12]=[C:11]([CH2:9][OH:8])[C:20]=1[CH3:21])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)c1cc2ccc(F)cc2c(OCc2ccccc2)c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CO)cc2ccc(F)cc2c1OCc1ccccc1
Temperature: -4 °C
Yield: 100.4 %

Procedure:
A round-bottom flask was charged with lithium aluminum hydride (3.5 g, 88 mmol), and the flask was placed in an brine/ice bath. Tetrahydrofuran (100 mL) was added slowly. The resulting solution was maintained at −4° C. with stirring. A solution of 4-benzyloxy-6-fluoro-3-methyl-naphthalene-2-carboxylic acid methyl ester (14.27 g, 44.00 mmol) in tetrahydrofuran (30 mL) was slowly added to the cold lithium aluminum hydride suspension drop-wise via an addition funnel. The rate of drop-wise addition was monitored so that the reaction temperature did not exceed 6° C. After the drop-wise addition was complete, the reaction was warmed to room temperature. The reaction mixture was stirred at room temperature for 1 hour. After this time, the reaction mixture was cooled to 4° C. in an ice bath. Water (3.5 mL) was added slowly, keeping the reaction temperature below 4° C. A 15% aqueous NaOH solution (3.5 mL) was next added, followed by an additional portion of water (10.5 mL). The precipitated solids were filtered, and then rinsed with ethyl acetate. The combined filtrates were concentrated to obtain 13.09 g (quantitative yield) of (4-benzyloxy-6-fluoro-3-methyl-naphthalen-2-yl)-methanol as a white solid. This product was used in the next step without additional purification. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.00 (dd, J=8.9, 5.9 Hz, 1 H), 7.77 (s, 1 H), 7.54-7.63 (m, 3 H), 7.31-7.51 (m, 4 H), 5.26-5.35 (m, 1 H), 4.94 (s, 2 H), 4.64 (d, J=5.1 Hz, 2 H), 2.34 (s, 3 H).
Reaction SMILES: [CH2:1]([N:8]1[CH:12](O)[C:11]([CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(C)C>[CH2:1]([N:8]1[CH2:12][CH:11]([CH2:14][C:15]([F:17])([F:18])[F:16])[CH2:10][C:9]1=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C=C(CC(F)(F)F)C(O)N1Cc1ccccc1
Solvent: CC(C)O
Product: O=C1CC(CC(F)(F)F)CN1Cc1ccccc1
Reaction time: 24 h

Procedure:
The crude solution of 1-benzyl-5-hydroxy-4-(2,2,2-trifluoroethyl)-1,5-dihydro-2H-pyrrol-2-one x101 in isopropyl alcohol (40 ml) is added to a suspension of Pd(C) (10%) (0.53 g) in isopropylalcohol (40 ml) and the resulting solution is degassed 3 times with nitrogen. The reaction mixture is stirred under hydrogen (balloon) for 1 day. The Pd(C) is removed by filtration through celite, and the filtrates are concentrated under reduced pressure. Purification by chromatography on silicagel (petroleum ether/ethyl acetate 10/50) affords 1.67 g of 1-benzyl-4-(2,2,2-trifluoroethyl)pyrrolidin-2-one x102.