Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7]([C:14]([O:16][CH3:17])=[O:15])=[C:6]2[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=1.[H-].[Na+].[CH2:30](I)[CH3:31].O>CN(C)C=O>[CH2:30]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:11]([O:12][CH3:13])[CH:10]=2)[C:6]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)=[C:7]1[C:14]([O:16][CH3:17])=[O:15])[CH3:31]
Reactant: CCI
Reactant: COC(=O)c1[nH]c2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(C(=O)OC)c(-c2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a solution of methyl 5,6-dimethoxy-3-(3,4-dimethoxyphenyl)indole-2-carboxylate (7.5 g) in N,N-dimethylformamide (100 ml) was added oily sodium hydride (60%, 1.6 g) and the mixture was stirred for 30 minutes at room temperature. After dropwise addition of ethyl iodide (4.8 ml), the reaction mixture was further stirred for 2 hours at room temperature, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The precipitated crystals were collected by filtration and recrystallized from ethyl ether to give methyl 1-ethyl-5,6-dimethoxy-3-(3,4-dimethoxyphenyl)indole-2-carboxylate (6.38 g, 77%) as pale red prisms.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N+:15]=2[O-])[CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:22]1C=CC=CC=1.CS(OS(C)(=O)=O)(=O)=O.C(CN)O>CC#N.O>[C:1]([O:5][C:6](=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([NH2:22])[N:15]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc[n+]([O-])c1-c1cccc(C(=O)OC(C)(C)C)c1
Reactant: c1ccncc1
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: O
Solvent: CC#N
Solvent: NCCO
Product: Cc1ccc(N)nc1-c1cccc(C(=O)OC(C)(C)C)c1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
A solution of 2-(3-(tert-butoxycarbonyl)phenyl)-3-methylpyridine-1-oxide (1 eq) and pyridine (4 eq) in MeCN (8 vol) is heated to 70° C. A solution of methanesulfonic anhydride (1.5 eq) in MeCN (2 vol) is added over 50 min via addition funnel maintaining the temperature at less than 75° C. The mixture is stirred for an additional 0.5 hours after complete addition. The mixture is then allowed to cool to ambient. Ethanolamine (10 eq) is added via addition funnel. After stirring for 2 hours, water (6 vol) is added and the mixture is cooled to 10° C. After stirring for NLT 3 hours, the solid is collected by filtration and washed with water (3 vol), 2:1 MeCN/water (3 vol), and MeCN (2×1.5 vol). The solid is dried to constant weight (<1% difference) in a vacuum oven at 50° C. with a slight N2 bleed to afford tert-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate as a red-yellow solid (53% yield).
Reaction SMILES: Br[C:2]1[C:3]([CH3:17])=[C:4]([C:12]2[CH2:16][CH2:15][O:14][N:13]=2)[C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:7]=1.[CH3:18][N:19]1[C:23]([OH:24])=[CH:22][CH:21]=[N:20]1.[C:25](=O)([O-])[O-:26].[K+].[K+].C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[CH3:18][N:19]1[C:23]([OH:24])=[C:22]([C:25](=[O:26])[C:2]2[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:4]([C:12]3[CH2:16][CH2:15][O:14][N:13]=3)[C:3]=2[CH3:17])[CH:21]=[N:20]1
Reactant: Cn1nccc1O
Reactant: Cc1c(Br)ccc(S(C)(=O)=O)c1C1=NOCC1
Reactant: O=C([O-])[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1c(C(=O)c2cnn(C)c2O)ccc(S(C)(=O)=O)c1C1=NOCC1
Temperature: 130 °C
Yield: 11.1 %

Procedure:
2.2 l of 1,4-dioxane, 100 g (0.315 mol) of 3-(3-bromo-2-methyl-6-methylsulfonylphenyl)-4,5-dihydroisoxazole, 30.82 g (0.315 mol) of 1-methyl-5-hydroxypyrazole, 87 g (0.63 mol) of potassium carbonate, 63.5 g (0.63 mol) of triethylamine and 11.2 g (0.016 mol) of bis(triphenylphosphine)-palladium dichloride were added to a 3.5 l autoclave. The autoclave was then flushed twice with nitrogen, a carbon monoxide pressure of 10 kg/cm2 was applied and the mixture was heated with stirring to 130° C. The carbon monoxide pressure was increased to 20 kg/cm2 and the mixture was stirred at 130° C. for 24 h. The mixture was then concentrated under reduced pressure and the residue was taken up in water. The aqueous phase of pH 11 was extracted with dichloromethane. The organic phase is discarded. The aqueous phase is adjusted to pH 4 using 18% strength hydrochloric acid. The precipitate was filtered off, washed three times with water and dried at 40° C. under reduced pressure. This gives 85 g of product. The filtrate is extracted with dichloromethane. The organic phase is dried with sodium sulfate, and the solvent is then removed under reduced pressure, giving a further 12.7 g of product.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([OH:17])(=[O:16])[CH2:11][CH2:12][C:13]([CH3:15])=[O:14].N1CCCCC1.C1(C)C=CC=CC=1>O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:15][C:13]([CH2:12][CH2:11][C:10]([OH:17])=[O:16])=[O:14])=[CH:4][CH:3]=1
Reactant: CC(=O)CCC(=O)O
Reactant: O=Cc1ccc(Cl)cc1
Solvent: C1CCNCC1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)CCC(=O)C=Cc1ccc(Cl)cc1
Yield: 44 %

Procedure:
To a dry 250 ml flask equipped with a magnetic stirrer, Dean-Stark trap, and reflux condenser was charged 15 g of 4-chlorobenzaldehyde, 12.4 g levulenic acid, 5.7 ml of piperidine, and 100 ml of toluene. The reaction was refluxed for 3 hours, after which no water was observed to azeotrope from the solution. The reaction was cooled and stripped to yield a reddish-brown liquid which was triturated with hexane to yield 11.2 g of product as a yellow solid.
Reaction SMILES: N1[C:9]2[C:4](=[C:5](C3N=C(N4CCOCC4)C4SC(COC)=CC=4N=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=N1.[Cl:28][C:29]1[N:30]=[C:31]([N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)[C:32]2[S:37][C:36]([CH2:38][OH:39])=[CH:35][C:33]=2[N:34]=1.C(Br)C1C=CC=CC=1>CN(C=O)C.[H-].[Na+]>[Cl:28][C:29]1[N:30]=[C:31]([N:40]2[CH2:41][CH2:42][O:43][CH2:44][CH2:45]2)[C:32]2[S:37][C:36]([CH2:38][O:39][CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:35][C:33]=2[N:34]=1
Reactant: COCc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Reactant: OCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1nc(N2CCOCC2)c2sc(COCc3ccccc3)cc2n1

Procedure:
Following the procedures for compound 314, (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-methanol in DMF and sodium hydride was alkylated with benzyl bromide to give 2-chloro-6-benzyloxymethyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine. Suzuki coupling of 2-chloro-6-benzyloxymethyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine and 7 was carried out via General Procedure A. Purification using column chromatography gave 315. NMR: CDCl3: 3.88-3.94 (4 H, m, CH2), 4.09-4.14 (4 H, m, CH2), 4.69 (2 H, s, CH2), 4.86 (2 H, s, CH2), 7.31-7.46 (6 H, m, Ar), 7.53 (1 H, t, J 8.22, Ar), 7.56 (1 H, t, J 8.24, Ar), 8.30 (1 H, d, J 6.94, Ar), 9.03 (1 H, s, Ar) and 10.11 (1 H, s, NH). MS: (ESI+): MH+ 458.16
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH:10][C:11](=[S:13])[NH2:12])=[CH:5][CH:4]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15].CC1C=CC=CC=1C.O(C(C)C)C(C)C>O>[NH2:12][C:11](=[S:13])[NH:10][N:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[C:14](=[O:16])[CH3:15]
Reactant: COc1ccc(NNC(N)=S)cc1
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1C
Solvent: CC(C)OC(C)C
Solvent: O
Product: COc1ccc(N(NC(N)=S)C(C)=O)cc1
Temperature: 25 °C
Yield: 89 %

Procedure:
A mixture of 17.5 parts of 2-(4-methoxyphenyl)hydrazinecarbothioamide, 10 parts of acetic acid anhydride and 90 parts of dimethylbenzene is stirred and refluxed for one hour. The reaction mixture is allowed to cool to room temperature and 2,2'-oxybispropane and water are added. The precipitated product is filtered off and dried, yielding 14.5 parts (89%) of acetic acid 2-(aminothioxomethyl)-1-(4-methoxyphenyl)hydrazide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:30]1[CH2:29][CH2:28][N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[F:20])[CH2:32][CH2:31]1)=[O:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2cc(Cl)ccc2nc1OC
Reactant: Fc1ccccc1N1CCNCC1
Product: COc1nc2ccc(Cl)cc2nc1NC(=O)N1CCN(c2ccccc2F)CC1
Yield: 80 %

Procedure:
Ethyl N-(6-chloro-2-methoxyquinoxalin-3-yl)carbamate and 1-(2-fluorophenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound (yield, 80%). 1H NMR (300 MHz, CDCl3): δ 3.12-3.21 (m, 4H), 3.77-3.84 (m, 3H), 4.11-4.15 (m, 4H), 6.95-7.10 (m, 4H), 7.20-7.45 (m, 3H), 7.65-7.82 (m, 1H).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[C:23]3[N:27]=[N:26][NH:25][N:24]=3)=[CH:15][CH:16]=2)[C:8]([CH2:28][OH:29])=[C:7]([Cl:30])[N:6]=1.[OH-].[Ca+2:32].[OH-].CCCCCCC>C(O)(C)C>[CH3:1][CH2:2][CH2:3][CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[C:23]3[N:27]=[N:26][NH:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]([CH2:28][OH:29])=[C:7]([Cl:30])[N:6]=1.[Ca:32]
Reactant: [Ca+2]
Agent: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nn[nH]n2)cc1
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCCCCCC
Product: [Ca]
Temperature: 25 °C

Procedure:
To 40.81 g losartan of Example 1 in 235 ml i-propanol, 3.92 g calcium hydroxide were added, and it was stirred at reflux temperature for 1 hour, and hot filtered. 410 ml n-heptane were added to the filtrate and cooled to room temperature. The solvent was decanted from a resinous residue, and 820 ml n-heptane were added. It was stirred until a white solid crystallized. It was filtered, washed with 110 ml n-heptane, and dried in vacuo at 50° C. to yield 39.2 g losartan calcium.
Reaction SMILES: [C:1]1([PH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)S(O[C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]=1[C:30]([O:32][CH3:33])=[O:31])(=O)=O.C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:8]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]=2[C:30]([O:32][CH3:33])=[O:31])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: c1ccc(Pc2ccccc2)cc1
Reactant: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)ccc2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1c(P(c2ccccc2)c2ccccc2)ccc2ccccc12

Procedure:
Diphenylphosphine (0.72 mL, 4.14 mmol, 1 eq) was added to a stirred solution of methyl 2-trifluoromethanesulfonyloxy-1-naphthoate (1.384 g, 4.14 mmol, 1 eq), triethylamine (0.64 mL, 4.59 mmol, 1.1 eq) and palladium acetate (0.005 g, 0.02 mmol, 0.005 eq) in degassed DMF (10 mL) instantly giving a red coloration. The solution was heated at reflux under nitrogen for 17 hours. The blood-red solution was allowed to cool and an aliquot taken for NMR analysis.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][N:8]([C:12]1[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9]CO.[CH2:23]([Cl:25])Cl>>[Cl:3][CH2:6][CH2:7][N:8]([C:12]1[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9][CH2:23][Cl:25]
Reactant: ClCCl
Reactant: CCOC(=O)c1ccccc1N(CCO)CCO
Reactant: O=S(Cl)Cl
Product: CCOC(=O)c1ccccc1N(CCCl)CCCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
Thionyl chloride (0.8 ml; 11.0 mmol) was added to a solution of 1.0 g (4.0 mmol) of ethyl 2-[N,N-bis(2-hydroxyethyl)amino]benzoate in 5 ml of methylene chloride, followed by stirring at room temperature for 1 hour. After the solvent was distilled out under reduced pressure, methylene chloride was added again in a small amount and was then distilled out under reduced pressure. This procedure was repeated twice. The resultant mixture was concentrated under reduced pressure, whereby 950 mg of a brown oil were obtained (yield: 83%).
Reaction SMILES: COC.O[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])[O:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:7][CH:6]=1>C(Cl)(Cl)Cl.CC(CC(C)C)=O.C(O)(=O)C>[CH:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])[O:14][C:15]=2[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:7][CH:6]=1
Reactant: O=C(O)CCc1nc(-c2ccc(O)cc2)c(-c2ccccc2)o1
Agent: COC
Solvent: CC(=O)O
Solvent: CC(=O)CC(C)C
Solvent: ClC(Cl)Cl
Product: O=C(O)CCc1nc(-c2ccccc2)c(-c2ccccc2)o1

Procedure:
Rf 0.50 silica gel 60 F254 chloroform:methylisobutylketone:acetic acid 50:50:1 A mixed melting point run with an authentic sample of the methyl ether of 4-(4-hydroxyphenyl)-5-phenyl-2-oxazolepropanoic acid (obtained from the metabolite of oxaprozin as disclosed by Janssen et al., Drug Metabolism and Disposition, 6, 495 (1978)), gave m.p. 92°-108° C., clearly demonstrating the lack of identity with the known metabolite. This, coupled with the identity of the 4'-methoxybenzoin starting material characterized the methyl ether as 5-(4-methoxy)-4-phenyl-2-oxazolepropanoic acid.
Reaction SMILES: [Cl:1][CH2:2][CH:3]([OH:28])[CH2:4][NH:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:21])[C:10]=2[C:9]([NH:22][CH2:23][CH:24]([OH:27])[CH2:25]Cl)=[CH:8][CH:7]=1.[CH2:29]([NH2:32])[CH2:30][CH3:31].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CO>[ClH:1].[CH2:29]([NH:32][CH2:2][CH:3]([OH:28])[CH2:4][NH:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:21])[C:10]=2[C:9]([NH:22][CH2:23][CH:24]([OH:27])[CH2:25][NH:5][CH2:4][CH2:3][CH3:2])=[CH:8][CH:7]=1)[CH2:30][CH3:31]
Reactant: CCCN
Reactant: O=C1c2ccccc2C(=O)c2c(NCC(O)CCl)ccc(NCC(O)CCl)c21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Product: CCCNCC(O)CNc1ccc(NCC(O)CNCCC)c2c1C(=O)c1ccccc1C2=O
Product: Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1,4-bis-(3-chloro-2-hydroxylpropylamino)-9, 10-anthracenedione (1 g, 2.36 mmole), propylamine (1.39 g, 23.6 mmole), and potassium iodide (0.26 g, 160 mmole) in methanol (20 mL), which had been stirred for 4 hours at room temperature, was added potassium carbonate (0.5 g, 3.62 mmole), and the reaction was stirred at room temperature for an additional 16 hours. Solvent was removed and the blue product was dissolved in dichloromethane, and was washed three times with water. The organic layer was dried over magnesium sulfate and the solvent was removed under reduced pressure. The blue product was purified by column chromatography (silica gel, dichloromethane with an increasing methanol gradient) to yield the free base of the title compound, which was then treated with hydrochloride gas through a stirring solution in acetone until a color change was noted to yield the title compound 1,4-Bis-(3-Propylamino-2-Hydroxypropylamino)-9, 10 anthracenedione hydrochloride (580 mg, 48%); NMR (CDCl3) δ 0.94 (t, J=7.3 Hz, 6H, CH3), 1.57 (m, 4H, CH2), 2.64 (m, 4H, CH2), 2.75 (m, 4H, CH2), 3.33 (m, 6H, CH and CH2), 4.05 b, 2H, OH), 6.80 (s, 2H, Ar (2, 3)), 7.52 (m, 2H, Ar (6, 7)), 7.94 (m, 2H, Ar (5, 8)), 10.63 (b, 2H, NH);
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10].S(Cl)([Cl:14])=O>N1C=CC=CC=1.ClCCl>[Cl:14][CH:10]=[CH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: C=CCCCCCCCCO
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCC=CCl
Reaction time: 8.5 h
Yield: 95.3 %

Procedure:
To 26.0 g of 9-decene-1-ol was added 10 drops of pyridine, and the mixture was placed into an eggplant flask. To the mixture was added dropwise 24.0 g of thionyl chloride, during cooling with ice. After dropping thionyl chloride, reaction was carried out for 8.5 hours at 70° C. After conclusion of the reaction, the reaction solution was diluted with dichloromethane, and then washed with an aqueous potassium carbonate. The washed solution was dried on magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain 27.7 g of 1-chloro-1-decene. (Yield: 95%)
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47](O)=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][CH:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].O.ON1C2C=CC=CC=2N=N1.[C:61]1([N:67]2[CH2:72][CH2:71][NH:70][CH2:69][CH2:68]2)[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1.[ClH:73]>C1COCC1.CO>[ClH:73].[OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([N:70]1[CH2:71][CH2:72][N:67]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[CH2:68][CH2:69]1)=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][CH:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CO[C@@H]1[C@@H](O)[C@@H](OC)C(NC2=CC(=O)c3c(cc4c(c3O)C(=O)[C@]3(OC)[C@H](O)Cc5cc(C)c(C(=O)O)c(O)c5[C@]3(O)C4=O)C2=O)O[C@H]1C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CO[C@@H]1[C@@H](O)[C@@H](OC)C(NC2=CC(=O)c3c(cc4c(c3O)C(=O)[C@]3(OC)[C@H](O)Cc5cc(C)c(C(=O)N6CCN(c7ccccc7)CC6)c(O)c5[C@]3(O)C4=O)C2=O)O[C@H]1C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylic acid (60 mg, 0.09 mmol) in THF (2 mL) was added polystyrene-carbodiimide (156 mg, 0.18 mmol), 1-hydroxybenzotriazole hydrate (24 mg, 0.18 mmol) and 1-phenylpiperazine (21 mg, 0.13 mmol). The reaction mixture was stirred at room temperature under nitrogen for 5 h. The reaction was filtered through a micro filter and concentrated. The crude material was purified by preparative TLC (silica gel, 90:10 dichloromethane/methanol) to afford a dark red solid. The solid was dissolved in methanol (1 mL) and treated with HCl (1.25 M solution in methanol, 0.5 mL) at 0° C. The solution was concentrated and triturated with diethyl ether to afford (6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-2-(4-phenylpiperazine-1-carbonyl)-6,6a-dihydrobenzo[a]tetracene-7,9,12,14(5H,14aH)-tetraone hydrochloride as a mixture of diastereomers (9.0 mg, 25%) and as a red solid: 1H NMR (500 MHz, CD3OD) δ 8.10 (s, 1H), 7.60-7.20 (m, 5H), 6.70 (s, 1H), 6.20-6.10 (m, 0.3H), 6.04-5.95 (m, 0.7H), 5.49 (s, 1H), 4.96-4.85 (m, 1H), 4.18-4.08 (m, 1H), 4.05-3.89 (m, 1H), 3.78-3.62 (m, 7H), 3.54 (s, 3H), 3.61-3.52 (m, 2H), 3.51-3.41 (m, 7H), 3.27-3.16 (m, 1H), 3.09-2.90 (m, 1H), 3.16 (s, 3H), 1.30-1.20 (m, 3H); MS (ESI−) m/z 826 (M−H); HPLC 94.2% (AUC), tR 11.89 min.
Reaction SMILES: [CH2:1]([NH:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[C:12]#[N:13])[CH2:2][CH2:3][CH2:4][CH3:5].[C:14]([NH:17][NH2:18])(=O)[CH3:15].C(=O)([O-])[O-].[K+].[K+]>C(O)CCC.O>[CH3:15][C:14]1[N:13]=[C:12]([C:11]2[NH:10][CH:9]=[N:8][C:7]=2[NH:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[NH:18][N:17]=1
Reactant: CCCCCNc1nc[nH]c1C#N
Reactant: CC(=O)NN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCO
Product: CCCCCNc1nc[nH]c1-c1nc(C)n[nH]1
Temperature: 165 °C
Reaction time: 14 h
Yield: 9.6 %

Procedure:
To the mixture of 4-(pentylamino)-1H-imidazole-5-carbonitrile (0.40 g, 2 mmol), acetic acid, hydrazide (0.33 g, 4.5 mmol) in 1-butanol (10 mL) was added potassium carbonate (0.10 g, 0.72 mmol). The mixture was sealed and stirred at 165° C. for 14 hours. The reaction mixture was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative LCMS (method A) to yield the desired product (45 mg, 10% yield). LCMS calculated for C11H19N6(M+H): 235.2; found: 235.1.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7](S(O)(=O)=O)=[CH:8][C:9]([OH:12])=[C:10]([NH2:11])[C:4]2=[CH:3][CH:2]=1.N1[CH:22]=[CH:21]C=CC=1.C(OC(=O)C)(=O)C.[S:30](=O)(=[O:33])([OH:32])[OH:31]>O>[CH3:21][C:22]1[O:12][C:9]2[CH:8]=[CH:7][C:5]3[C:4](=[CH:3][C:2]([S:30]([OH:33])(=[O:32])=[O:31])=[CH:1][CH:6]=3)[C:10]=2[N:11]=1
Reactant: O=S(=O)(O)O
Reactant: Nc1c(O)cc(S(=O)(=O)O)c2ccccc12
Reactant: c1ccncc1
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: Cc1nc2c(ccc3ccc(S(=O)(=O)O)cc32)o1

Procedure:
(1 mole) of 1-amino-2-naphthol-4-sulfonic acid and 80 ml of pyridine are mixed and this mixture is then dissolved by adding 30 ml water. The amber colored solution is then heated gently in a heating jacket and 360 ml of acetic anhydride are added in small fractions. During this addition, a large amount of heat is evolved, causing the mixture to reflux vigorously. After the addition of the acetic anhydride is complete, the mixture is heated under reflux for 2 hours. By removing the solvents under reduced pressure, a thick syrup is obtained which is dissolved in 500 ml water. The aqueous solution is then rendered strongly acid to universal indicator paper by adding concentrated sulfuric acid, with stirring. The product thereupon precipitated from the solution in the form of a white solid. The solid is collected by filtration, washed with water and dried. After two recrystallizations from ethyl alcohol, 35 g (67%) of a white solid, melting above 320° C. are obtained.
Reaction SMILES: [CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:31][CH2:32][CH:33]([OH:36])[CH2:34][OH:35])(=[O:30])=[O:29])=[CH:24][CH:23]=1>>[CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([S:28]([NH:31][CH2:32][CH:33]([OH:36])[CH2:34][OH:35])(=[O:30])=[O:29])=[CH:24][CH:23]=3)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1ccc(S(=O)(=O)NCC(O)CO)cc1
Reactant: O=C(O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Product: O=C(Nc1ccc(S(=O)(=O)NCC(O)CO)cc1)c1cc(N(CC2CC2)C2CCCCC2)ncn1

Procedure:
Following the general method as outlined in Example 1, starting from 6-[cyclohexyl(cyclopropylmethyl)amino]pyrimidine-4-carboxylic acid (Intermediate 13) and 4-amino-N-(2,3-dihydroxypropyl)benzenesulfonamide (Intermediate 15), the title compound was obtained as a brown solid after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [N:1]1[N:5]2[C:6]3[C:11]([C:12]([OH:14])=[CH:13][C:4]2=[N:3][N:2]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3.[N+:15]([O-])([OH:17])=[O:16]>C(O)(=O)C>[OH2:14].[N+:15]([C:13]1[C:4]2[N:5]([N:1]=[N:2][N:3]=2)[C:6]2[C:11]([C:12]=1[OH:14])=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:17])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: Oc1cc2nnnn2c2ccccc12
Solvent: CC(=O)O
Product: O
Product: O=[N+]([O-])c1c(O)c2ccccc2n2nnnc12
Temperature: 40 °C
Yield: 120.4 %

Procedure:
Tetrazolo[1,5-a]quinolin-5-ol (10 g, 54 mmole, Example 1) was suspended in acetic acid (200 mL) then warmed to 40° C. Nitric acid (4 mL of 16M, 59 mmole) was added to the reaction mixture. The reaction mixture was heated at 80° C. for 30 minutes then allowed to cool to ambient temperature. The resulting precipitate was isolated by filtration, rinsed with water then recrystallized from isopropanol/water to provide 8.1 g of 4-nitrotetrazolo[1,5-a]quinolin-5-ol hydrate as light yellow plates, m.p. 186.5-187° C. Analysis: Calculated for C9H5N5O3.H2O: % C, 43.38; % H, 2.83; % N, 28.10; Found: % C, 43.27; % H, 2.84; % N, 28.25.