Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[C:9]([C:11]([O:13]C)=[O:12])[CH:10]=1)=[O:4].[C:15]([OH:18])(=[O:17])C>[C].[Rh]>[C:5]([O:18][C:15]([N:7]1[CH2:6][C@@H:5]([C:3]([OH:2])=[O:4])[CH2:10][C@@H:9]([C:11]([OH:13])=[O:12])[CH2:8]1)=[O:17])([CH3:6])([CH3:10])[CH3:3]
Reactant: CC(=O)O
Reactant: COC(=O)c1cncc(C(=O)OC)c1
Agent: [Rh]
Product: CC(C)(C)OC(=O)N1C[C@H](C(=O)O)C[C@H](C(=O)O)C1
Temperature: 50 °C
Reaction time: 15 h

Procedure:
Dimethylpyridine-3,5-dicarboxylate (50 g) was dissolved in acetic acid (300 ml), 5% rhodium carbon (5 g) was added, and the mixture was stirred under pressurized hydrogen atmosphere (5 atm) at 50° C. for 15 hr. The reaction mixture was allowed to cool to room temperature, the rhodium catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethanol (300 ml) and, under ice-cooling, triethylamine (107 ml) and di-tert-butyl dicarbonate (67 g) were successively added. The reaction mixture was stirred at room temperature for 15 hr, and concentrated under reduced pressure. The residue was dissolved in water, and the mixture was adjusted to pH 3 with 6 M hydrochloric acid. The mixture was extracted with ethyl acetate. The ethyl acetate extract layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in methanol (250 ml), and 8 N aqueous sodium hydroxide solution (128 ml) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 24 hr, and methanol was evaporated under reduced pressure. The concentrated solution was diluted with saturated aqueous sodium hydrogen carbonate solution (100 ml) and washed twice with diethyl ether. The basic aqueous layer was acidified (pH 3) with 6 M hydrochloric acid. The precipitated powder was collected by filtration, washed with water, and air-dried. The obtained powder (55 g) was dissolved in methanol (200 ml) by heating and the mixture was concentrated under reduced pressure until the amount of methanol became half. Water (50 ml) was added, and the mixture was stood at room temperature overnight. The precipitated white powder was collected by filtration, washed with cold methanol/water=2/1 (200 ml) and air-dried to give the object compound (38 g) as a powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13]Cl)[CH:10]([CH2:15]Cl)[CH2:9][N:8]=[C:7]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)[C:6]=2[CH:22]=1.[OH-].[Na+].[CH3:25][NH2:26]>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH2:12][CH2:13][N:26]([CH3:25])[CH2:15][CH:10]3[CH2:9][N:8]=[C:7]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)[C:6]=2[CH:22]=1
Reactant: CN
Reactant: ClCCN1c2ccc(Cl)cc2C(c2ccco2)=NCC1CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN1CCN2c3ccc(Cl)cc3C(c3ccco3)=NCC2C1

Procedure:
3.4 g of 7-chloro-1-(β-chloroethyl)-2-chloromethyl-5-(2-furyl)-2,3-dihydro-1H-1,4-benzodiazepine in 100 ml of methanol are left to react with 0.8 g of sodium hydroxide in 1 ml of water and 2.5 g of methylamine at 95° C. in an autoclave for 5 hours. The reaction mixture is then worked up in the customary manner and the reaction product is purified by chromatography on aluminium oxide of activity level II, using methylene chloride/chloroform, and the fractions containing the product of medium polarity are separated off and the 1,2,3,4,4a,5-hexahydro-9-chloro-3-methyl-7-(2-furyl)-pyrazino[1,2-a]-[1,4]benzodiazepine obtained therefrom is dissolved in isopropanol and converted into its salt with alcoholic hydrochloric acid. This salt crystallises from isopropanol as the dihydrochloride hemihydrate with 0.1 mol of isopropanol. Melting point: >240° C., yield: 0.8 g.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:13])[C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[I-].[Na+].C(N(CC)CC)C.C(Br)[CH:24]=[CH:25][C:26]1[CH:31]=CC=C[CH:27]=1>CS(C)=O>[CH3:27][C:26]([CH3:31])=[CH:25][CH2:24][C:11]1[C:10](=[O:12])[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:3](=[O:13])[C:2]=1[OH:1]
Reactant: BrCC=Cc1ccccc1
Reactant: O=C1C=C(O)C(=O)c2ccccc21
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)=CCC1=C(O)C(=O)c2ccccc2C1=O
Temperature: 50 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
To a solution of 20 gram (0.11 moles) of 2-hydroxy-1,4-naphthoquinone in 200 ml of DMSO, 16.5 grams (0.11 moles) of sodium iodide, 15.3 ml (0.11 moles) of triethylamine and 23.8 grams (0.12 moles) of cinnamyl bromide were added. The mixture was vigorously stirred at 50° C. overnight, and then cooled by addition of 400 ml of ice water, and the resulting mixture was extracted with 300 ml of toluene twice. The combined organic phase was washed successively with 500 ml of water, and 400 ml of 2N sodium hydroxide twice, and 500 ml of water. The organic phase was dried with sodium sulfate and evaporated to dryness. The crude product 2-2 (R1=H, R4=H, R7=C6H5) residue was dissolved in 200 ml of anhydrous ethanol and refluxed for 3 hours. After evaporation, the residue was dissolved in 200 ml of toluene, and extracted with 200 ml of 2N sodium hydroxide twice. The combined extract was neutralized by addition of concentrated hydrochloric acid to pH 3-5, and extracted with 300 ml of dichloromethane. The dichloromethane solution was washed with equal volume of water, and dried with sodium sulfate, and then evaporated to yield crude lapachol analog 2-3 (R1=H, R4=H, R7=C6H5). To 2 grams of crude 2-3 (R1=H, R4=H, R7=C6H5), 20 ml of sulfuric acid was added, and the resulting mixture was placed at room temperature for 1 hour. The sulfuric acid mixture was poured into 200 ml of water and extracted with 200 ml of dichloromethane twice to give crude dunione analog 2-4 (R1=H, R4=H, R7=C6H5) which was then purified with silica gel chromatograph. Treatment of 2-4 (R1=H, R4=H, R7=C6H5) with N-bromosuccinimide and lead (IV) acetate was performed according to the procedure described in example 9 to give crude 2-5 (R1=H, R4=H, R7=C6H5). Without silica gel chromatograph, the crude 2-5 (R1=H, R4=H, R7=C6H5) was directly dissolved in 200 ml ethanol/concentrated HCl (1:1) and refluxed for 1 hour to give crude 2-6 (R1=H, R4=H, R7=C6H5) which was purified with silica gel chromatograph. Overall yield 10%. 2-methyl-3-phenyl-4H,9H-naphtho[2,3-b]furan-4,9-dione 2-6 (R1=H, R4=H, R7=C6H5) 1H NMR (in CDCl3) δ 2.51 (s, 3H), 7.42-7.50 (m, 5H), 7.71-7.74 (m, 2H), 8.10-8.13 (m, 1H), 8.21-8.23 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][CH2:7][CH2:8][N:9]3[C:13]2=[N:12][C:11]([C:16](/[N:18]=[CH:19]/[N:20](C)C)=O)=[CH:10]3)=[CH:4][CH:3]=1.Cl.[CH:24]([NH:27]N)([CH3:26])[CH3:25]>CC(O)=O>[Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][CH2:7][CH2:8][N:9]3[C:13]2=[N:12][C:11]([C:16]2[N:27]([CH:24]([CH3:26])[CH3:25])[N:20]=[CH:19][N:18]=2)=[CH:10]3)=[CH:4][CH:3]=1
Reactant: CC(C)NN
Reactant: CN(C)/C=N/C(=O)c1cn2c(n1)-c1cc(Br)ccc1OCC2
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(Br)ccc1OCC2
Temperature: 100 °C
Yield: 78.8 %

Procedure:
To a solution of 13-bromo-N-[(1E)-(dimethylamino)methylidene]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaene-4-carboxamide (2.2 g, 6.1 mmol) in AcOH (20 mL) was added isopropylhydrazine hydrochloride (0.73 g, 6.6 mmol). The mixture was heated at 100° C. for 1 h. Most of the solvent was removed and water (50 mL) was added. The solid was collected by filtration, washed with water, and dried in vacuo to afford the title compound (1.8 g, 74% yield) as a yellow solid. LCMS m/z [M+H]+ 376.1.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].ClCCl.N1C=CC=CC=1.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=1[S:30](Cl)(=[O:32])=[O:31]>C(OCC)(=O)C>[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=1[S:30]([NH:1][C:2]1[C:3]([F:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])(=[O:32])=[O:31]
Reactant: COC(=O)c1cccc(N)c1F
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1cccc(NS(=O)(=O)c2c(F)cccc2F)c1F
Temperature: 15 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
Methyl 3-amino-2-fluorobenzoate (50 g, 1 eq) was charged to reactor followed by dichloromethane (250 mL, 5 vol). The contents were stirred and cooled to ˜15° C. and pyridine (26.2 mL, 1.1 eq) was added. After addition of the pyridine, the reactor contents were adjusted to ˜15° C. and the addition of 2,6-difluorobenzenesulfonyl chloride (39.7 mL, 1.0 eq) was started via addition funnel. The temperature during addition was kept <25° C. After complete addition, the reactor contents were warmed to 20-25° C. and held overnight. Ethyl acetate (150 mL) was added and dichloromethane was removed by distillation. Once distillation was complete, the reaction mixture was then diluted once more with ethyl acetate (5 vol) and concentrated. The reaction mixture was diluted with ethyl acetate (10 vol) and water (4 vol) and the contents heated to 50-55° C. with stirring until all solids dissolve. The layers were settled and separated. The organic layer was diluted with water (4 vol) and the contents heated to 50-55° for 20-30 min. The layers were settled and then separated and the ethyl acetate layer was evaporated under reduced pressure to ˜3 volumes. Ethyl Acetate (5 vol.) was added and again evaporated under reduced pressure to ˜3 volumes. Cyclohexane (9 vol) was then added to the reactor and the contents were heated to reflux for 30 min then cooled to 0° C. The solids were filtered and rinsed with cyclohexane (2×100 mL). The solids were air dried overnight to obtain methyl 3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorobenzoate (94.1 g, 91%).
Reaction SMILES: C([O:8][C:9]1[C:10]2[C:19]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])=[C:18]1[C:13]([C:14]3[CH:28]=[CH:27][CH:26]=[CH:25][C:15]=3[CH:16]=[CH:17]1)=[N:12][CH:11]=2)C1C=CC=CC=1.FC(F)(F)S(O[CH2:35][CH3:36])(=O)=O.Cl.[S:40](=[O:44])(=[O:43])([OH:42])[OH:41]>CO.C(O)(=O)C.C1(C)C=CC=CC=1>[S:40]([O-:44])([OH:43])(=[O:42])=[O:41].[CH2:35]([N+:12]1[CH:11]=[C:10]2[C:19]([CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:9]2[OH:8])=[C:18]2[C:13]=1[C:14]1[CH:28]=[CH:27][CH:26]=[CH:25][C:15]=1[CH:16]=[CH:17]2)[CH3:36]
Reactant: CCOS(=O)(=O)C(F)(F)F
Reactant: O=S(=O)(O)O
Reactant: COc1ccc2c(cnc3c4ccccc4ccc23)c1OCc1ccccc1
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC[n+]1cc2c(O)c(OC)ccc2c2ccc3ccccc3c21
Product: O=S(=O)([O-])O
Temperature: 100 °C
Yield: 79.7 %

Procedure:
183 mg (0.5 mmol) of 7-benzyloxy-8-methoxybenzo[c]phenanthridine (compound D-7) were admixed with 0.13 ml (1.0 mmol) of ethyl trifluoromethanesulfonate and 0.9 ml of dry toluene, and the resulting mixture was heated to 100° C. for 5 hours. After that, the mixture was admixed with 4 ml of acetic acid and 1 ml of concentrated hydrochloric acid, and heated to 100° C. for 1 hour. Thereafter, the reaction mixture was gradually added to ice water. The reaction mixture thus diluted was neutralized by portionwise adding thereto sodium hydrogen carbonate, and then extracted with chloroform. The chloroform extract layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resultant residue was refined by a silica gel chromatography, wherein use was made, as eluant, of a chloroform-methanol mixture (9:1). The main fractions were collected and concentrated to obtain a dark violet solid material, which was compound E-7 having a structure represented by the general formula E. Next, compound E-7 was dissolved in a small amount of methanol, and the solution thus obtained was acidified by portionwise adding thereto a dilute aqueous solution of sulfuric acid in an amount of from 1.0 to 2.0 mol per 1 mol of the compound, so that the color of the solution of the compound was changed into yellow or orange. The aqueous solution of the compound was then concentrated under reduced pressure. Acetone was added portionwise to the concentrated solution under shaking to form a precipitate, which was separated by filtration, and dried, so that the aimed compound A-7, wherein X- =HSO4-, was obtained as yellow powder in an amount of 160 mg (yield: 79.7%).
Reaction SMILES: [C:1]([NH:11][C:12]([CH3:16])([CH3:15])[CH2:13][OH:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[C:17](Cl)(=[O:19])[CH3:18].C(N(CC)CC)C>ClCCl>[C:17]([O:14][CH2:13][C:12]([NH:11][C:1]([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2])([CH3:16])[CH3:15])(=[O:19])[CH3:18]
Reactant: CC(C)(CO)NC(=O)OCc1ccccc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCC(C)(C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a dichloromethane solution containing 2.52 g (0.011 mol) 2-carbobenzoxyamino-2-methyl-1-propanol and 1.17 g (0.015 mol) acetyl chloride was added dropwise with stirring 1.11 g (0.011 mol) triethylamine. The reaction was stirred at ambient temperature overnight and the dichloromethane was removed under reduced pressure. The triethylamine hydrochloride residue was triturated in anhydrous ether. Following filtration, the ether was removed under reduced pressure to afford 2.38 g (0.009 mol), 82%, crude 2-carbobenzoxyamino-2-methyl-1-propyl acetate as a pale yellow liquid, pmr (CDCl3) δ 7.2 (s, 5H), 5.4 (bs, 1H), 5.0 (s, 2H), 2.0 (s, 3H) and 1.2 (s, 6H) ppm.
Reaction SMILES: [Na].CO.Cl.[NH2:5][C:6]([NH2:8])=[NH:7].Cl.[Cl:10][C:11]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[N:15]([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[C:24]([CH3:32])[CH:23]=2)[CH:14]=1)=[O:12]>O1CCCC1.ClCCl>[ClH:10].[CH3:32][C:24]1[CH:23]=[C:22]([N:15]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:21]3[C:13]([C:11]([NH:7][C:6]([NH2:8])=[NH:5])=[O:12])=[CH:14]2)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=1
Reactant: Cc1cc(-n2cc(C(=O)Cl)c3cccnc32)c2ccccc2n1
Reactant: N=C(N)N
Agent: Cl
Agent: [Na]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(-n2cc(C(=O)NC(=N)N)c3cccnc32)c2ccccc2n1
Temperature: 20 °C
Reaction time: 2 h
Yield: 13.1 %

Procedure:
0.43 g (19 mmol) of sodium was added portionwise, at a temperature in the region of 20° C. under an argon atmosphere, to 30 cm3 of methanol and then, after the sodium has been completely consumed, 1.9 g (20 mmol) of guanidine hydrochloride were added. The reaction mixture was stirred at a temperature in the region of 20° C. for 2 h, then it was concentrated to dryness under reduced pressure (2.7 kPa) and the residue was 2 times in succession taken up in 10 cm3 of dichloromethane (stabilized over amylene) and the supernatant separated. The residue was subsequently concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained was taken up in 40 cm3 of a 1:1 mixture of dichloromethane (stabilized over amylene) and tetrahydrofuran under an argon atmosphere at a temperature in the region of 20° C. and 1.1 g (3.4 mmol) of 3-chlorocarbonyl-1-(2-methylquinolin-4-yl)-1H-pyrrolo[2,3-b]pyridine hydrochloride, in suspension in 20 cm3 of a 1:1 mixture of dichloromethane (stabilized over amylene) and tetrahydrofuran, were added with stirring. After stirring at a temperature in the region of 20° C. for 65 h, the reaction mixture was concentrated to dryness under reduced pressure (2.7 kPa). The residue was taken up in 30 cm3 of ethanol and the mixture was heated at reflux for 5 minutes and then reconcentrated to dryness under reduced pressure (2.7 kPa). The residue was taken up in 50 cm3 of water and extracted successively with 50 cm3 and then 25 cm3 of ethyl acetate. The organic extracts were combined, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa). The residue was purified by flash chromatography on a column of silica gel (0.06–0.20 mm), elution being carried out with a dichloromethane/methanol (95/5 by volume) mixture. The fractions comprising the expected product were combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue was triturated in 10 cm3 of diisopropyl ether, filtered off, washed twice with 5 cm3 of diisopropyl ether and dried under reduced pressure (2.7 kPa) at a temperature in the region of 50° C. 0.17 g of N-[1-(2-methylquinolin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine hydrochloride was thus obtained in the form of a yellow crystalline solid melting at 178° C. (Analysis C19H16N6O.HCl % calculated C, 59.92; H, 4.50; N, 22.07; O, 4.20%. found C, 60.40; H, 4.50; N, 21.47).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:28])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[C:10](=[O:21])[C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:8]2)=[O:4].[NH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH:16]1([CH2:15][N:11]2[C:12]3[C:7](=[C:6]([OH:28])[C:5]([C:3]([NH:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:4])=[N:14][CH:13]=3)[CH:8]=[C:9]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:10]2=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: NCCCC(=O)O
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2CC2CCCC2)c1O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCCNC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2CC2CCCC2)c1O
Temperature: 25 °C
Yield: 40.8 %

Procedure:
A mixture of 1-cyclopentylmethyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (45 mg, 0.12 mmol), 4-aminobutyric acid (736 mg, 7.1 mmol) and NaOMe solution (10.7 mL, 5.4 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added until pH was about 2-3. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (5-40% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3, and the resulting precipitate was isolated by filtration to give 22 mg of the title compound as a yellow solid. MS: (+) m/z 450.36 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][OH:5].[C:7]1([CH3:17])[CH:12]=CC(S(O)(=O)=O)=[CH:9][CH:8]=1>>[CH2:4]([O:5][CH2:9][CH:8]=[C:7]([CH3:17])[CH3:12])[CH:3]=[C:2]([CH3:6])[CH3:1]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)=CCO
Product: CC(C)=CCOCC=C(C)C
Yield: 50 %

Procedure:
To 30 g of 3-methyl-2-buten-1-ol [prenol] was added 0.74g of p-toluenesulfonic acid, and the mixture was stirred under reflux (at 130°-140° C.) for 3 hours. The reaction solution separated into two layers. The lower layer comprised water and the upper layer was subjected to gas chromatographic analysis revealing that about 4% of the starting prenol remained and that diprenyl ether was formed in a yield of about 50% based on the starting prenol together with unknown products. After distillation under reduced pressure was isolated diprenyl ether having the following properties.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)([O-:22])=[O:21]>[OH-].[K+].C(O)C>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[C:14](=[CH:27][C:26]2[CH:29]=[CH:30][C:23]([N+:20]([O-:22])=[O:21])=[CH:24][CH:25]=2)[CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C(=Cc2ccc([N+](=O)[O-])cc2)CCc2cc(OCCn3ccnc3)ccc21
Yield: 67.7 %

Procedure:
According to the method of Example 4, 6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.19 g, 0.74 mmol) was reacted with 4-nitrobenzaldehyde (0.112 g, 0.74 mmol) in 1.5 mL of 4% KOH in ethanol for 3 hours at room temperature to afford 0.195 g (68%) of the title compound as a fine tan powder, mp 184-185° C.: CI-MS m/e 389 (M+), 390 (M++1);
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH:5]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)[CH2:6][N+:7]([O-:9])=[O:8].[C:18]([O:22][CH3:23])(=[O:21])[CH:19]=[CH2:20].Cl>C(O)(C)(C)C.C(OCC)C>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH:5]([C:10]1[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=1)[CH:6]([N+:7]([O-:9])=[O:8])[CH2:20][CH2:19][C:18]([O:22][CH3:23])=[O:21]
Reactant: C=CC(=O)OC
Reactant: COC(=O)CC(C[N+](=O)[O-])c1ccc(C)cc1
Agent: Cl
Solvent: CC(C)(C)O
Solvent: CCOCC
Product: COC(=O)CCC(C(CC(=O)OC)c1ccc(C)cc1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 94 h

Procedure:
A solution of 356 g of 4-nitro-3-(4-methylphenyl)-butanoic acid methyl ester, 138 g of methyl acrylate and 25 ml of Triton B in 500 ml of t-butanol is allowed to stir at room temperature for 94 hours. Excess aqueous hydrochloric acid (1 N) is added and the solution is diluted with diethyl ether. The organic layer is separated, dried over anhydrous magnesium sulfate and evaporated to give 4-nitro-3-(4-methylphenyl)heptanedioic acid dimethyl ester.
Reaction SMILES: [CH3:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:14][CH:13]=2)[C:10](=[O:28])[C:9]2[C:4](=[CH:5][CH:6]=[C:7](Br)[CH:8]=2)[N:3]=1.[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC>[CH3:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:14][CH:13]=2)[C:10](=[O:28])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:8]=2)[N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1nc2ccc(Br)cc2c(=O)n1-c1ccc(OCCCN2CCCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1nc2ccc(-c3ccccc3)cc2c(=O)n1-c1ccc(OCCCN2CCCCC2)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
2-methyl-6-bromo-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone synthesized in Example 34 (100 mg, 0.25 mmol) and phenylboronic acid (40 mg, 0.32 mmol) were dissolved in dimethoxyethane (1 mL), and the atmosphere in the system was replaced by nitrogen. 2M sodium carbonate aqueous solution (0.3 mL) and palladium tetrakis(triphenylphosphine) complex (10 mg, 0.012 mmol) were added, and stirred at 80° C. for 3 hours. Ethyl acetate and distilled water were added to the reaction mixture to perform an ethyl acetate extraction. The organic phase was washed with saturated brine and dried with anhydrous sodium sulfate. The product was purified by silica gel column chromatography (chloroform/methanol=20/1), and the target substance (61 mg, 61%) was obtained as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH:5]2[C:12]([O:14][CH3:15])=[O:13].[C:16]1([N:22]=[C:23]=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[C:16]1([NH:22][C:23]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)[CH:5]([C:12]([O:14][CH3:15])=[O:13])[C:6]2=[O:11])=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)C1C(=O)Nc2ccc(Cl)cc21
Reactant: O=C=Nc1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)C1C(=O)N(C(=O)Nc2ccccc2)c2ccc(Cl)cc21

Procedure:
To 6.0 g. (0.027 mole) of methyl 5-chlorooxindole-3-carboxylate in 200 ml. of toluene was added 5.25 ml. (0.048 mole) of phenylisocyanate and the resulting reaction mixture heated to reflux overnight. The reaction mixture was cooled and diluted with petroleum ether to give, after filtration and drying, 2.0 g. of the desired product.