Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1(C)[C@]2(CS(O)(=O)=O)C(C[CH:3]1CC2)=O.[F:16][C:17]1[CH:22]=[C:21]([CH2:23][OH:24])[C:20]([OH:25])=[C:19]([CH2:26][OH:27])[CH:18]=1.COC(OC)(C)C.C([O-])(O)=O.[Na+]>CC(C)=O.C(OCC)(=O)C>[F:16][C:17]1[CH:18]=[C:19]([CH2:26][OH:27])[C:20]2[O:25][C:2]([CH3:3])([CH3:1])[O:24][CH2:23][C:21]=2[CH:22]=1
Reactant: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Reactant: OCc1cc(F)cc(CO)c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: COC(C)(C)OC
Product: CC1(C)OCc2cc(F)cc(CO)c2O1
Temperature: 55 °C
Yield: 91 %

Procedure:
D(+)-10-Camphorsulfonic acid (5.1 g, 22 mmol), 4-fluoro-2,6-bis(hydroxymethyl)phenol (74.5 g, 432 mmol), and 2,2-dimethoxypropane (90 mL, 734 mmol) were dissolved in acetone. To the solution was added 45 g of 4 Å molecular sieves. The resulting suspension was heated to 55° C. for 1 h and then cooled to rt. The mixture was neutralized with aqueous NaHCO3 (sat) and diluted with ethyl acetate. Solids were removed by filtration. The solvent volume was reduced in vacuo. Ethyl acetate and aqueous NaHCO3 (sat) were added, and the layers were partitioned. The organic phase was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Crude (6-fluoro-2,2-dimethyl-4H-1,3-benzodioxin-8-yl)methanol was isolated as an orange oil (91.7 g, 432 mmol, 100%). (17.2 g, 86.6 mmol, 91% yield). 1H NMR (400 MHz, CDCl3): δ 7.01 (dd, 1H), 6.79 (dd, 1H), 5.20 (t, 1H), 4.77 (s, 2H), 4.40 (d, 2H), 1.42 (s, 6H); GCMS for C11H13FO3: 212 (M+)
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:33]=[C:32]([O:34][CH2:35][CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:30][C:7]=1[C:8]([C:10]1[CH:11]=[CH:12][C:13]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[C:14]([CH:24]=1)[C:15]([NH:17][CH2:18][C:19]([O:21]CC)=[O:20])=[O:16])=[O:9])[CH:2]([CH3:4])[CH3:3].[OH-].[Na+].O.Cl>C(O)C.C(OCC)(=O)C>[CH2:1]([O:5][C:6]1[CH:33]=[C:32]([O:34][CH2:35][CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:30][C:7]=1[C:8]([C:10]1[CH:11]=[CH:12][C:13]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[C:14]([CH:24]=1)[C:15]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:16])=[O:9])[CH:2]([CH3:4])[CH3:3]
Reactant: CCOC(=O)CNC(=O)c1cc(C(=O)c2ccc(OCC(C)C)cc2OCC(C)C)ccc1OCC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CC(C)COc1ccc(C(=O)c2ccc(OCC(C)C)c(C(=O)NCC(=O)O)c2)c(OCC(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.3 %

Procedure:
In 7 ml of ethanol is dissolved 0.64 g of ethyl 2-{[5-(2,4-diisobutoxybenzoyl)-2-isobutoxybenzoyl]amino}acetate, to which is added 0.73 ml of 5 mol/L solution of sodium hydroxide. The mixture thus obtained is stirred at ambient temperature for one hour. Water and ethyl acetate are added to the reaction mixture, pH is adjusted to 2 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; chloroform:ethanol=20:1) to obtain 0.25 g of 2-{[5-(2,4-diisobutoxybenzoyl)-2-isobutoxybenzoyl]amino}-acetic acid as a white solid product.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][CH:23]=[CH2:24])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].N1C=CC=N1.[OH:30]O.O>ClCCl.C[Re](=O)(=O)=O>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][CH:23]2[CH2:24][O:30]2)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5]
Reactant: OO
Reactant: C=CCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Agent: C[Re](=O)(=O)=O
Agent: c1cn[nH]c1
Solvent: ClCCl
Solvent: O
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CC2CO2)ccc1Cl

Procedure:
2-Chloro-5-(2-propenyl)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (Example 5a) (9.4 g), pyrazole (0.45 g) and methyltrioxorhenium(VII) (0.40 g) were stirred together in dichloromethane (40 mL) under nitrogen, and hydrogen peroxide (27.5% wt. solution in water, 13 mL) was added dropwise. The reaction was then monitored by HPLC/MS and further portions of pyrazole, methyltrioxorhenium(VII) and hydrogen peroxide were added over a period of 2 days until the reaction mixture consisted of a 1:1 mixture of starting material and product. The mixture was then poured into water (500 mL), extracted into dichloromethane (3×300 mL), washed with 2M aqueous hydrochloric acid (300 mL), brine (300 mL), saturated aqueous sodium thiosulfate (300 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to give an oil. This was purified by column chromatography eluting with 2:1 isohexane/ethyl acetate to give the sub-titled compound (4.71 g).
Reaction SMILES: [OH:1][C:2]1([C:8]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[C:9]=2[CH2:17][CH3:18])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[O:19]1[CH2:21][C@H:20]1[CH2:22][O:23][C:24]1[C:32]2[CH:31]=[CH:30][O:29][C:28]=2[CH:27]=[CH:26][CH:25]=1>CO>[OH2:1].[O:29]1[CH:30]=[CH:31][C:32]2[C:24]([O:23][CH2:22][C@@H:20]([OH:19])[CH2:21][N:5]3[CH2:6][CH2:7][CH:2]([C:8]4[S:12][C:11]5[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=5[C:9]=4[CH2:17][CH3:18])[CH2:3][CH2:4]3)=[CH:25][CH:26]=[CH:27][C:28]1=2
Reactant: c1cc(OC[C@@H]2CO2)c2ccoc2c1
Reactant: CCc1c(C2(O)CCNCC2)sc2ccccc12
Solvent: CO
Product: CCc1c(C2CCN(C[C@H](O)COc3cccc4occc34)CC2)sc2ccccc12
Product: O
Yield: 39.6 %

Procedure:
A solution 4-hydroxy-4-(3-ethylbenzo[b]thiophen-2-yl)piperidine (0.067 g, 0.273 mmol) and (S)-(+)-4-(oxiranylmethoxy)benzo[b]-furan (0.052 g, 0.273 mmol) in methanol (3 mL) was heated at reflux for 18 hours, and then cooled and evaporated. The residue was purified using silica gel chromatography (dichloromethane/2% methanol in dichloromethane gradient elution) to give the final title compound as a yellow oil (0.049 g, 41%). FDMS m/e=436 (M++1). C26H29NO3S.0.75H2O
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]([OH:17])[C:9]2[C:8](=[O:18])[CH2:7][C:6]([CH3:20])([CH3:19])[CH2:5][C:4]=2[N:3]=1.[CH2:21]([Zn]CC)[CH3:22]>>[CH2:21]([C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]([OH:17])[C:9]2[C:8](=[O:18])[CH2:7][C:6]([CH3:20])([CH3:19])[CH2:5][C:4]=2[N:3]=1)[CH3:22]
Reactant: CCOC(=O)c1c(Cl)nc2c(c1O)C(=O)CC(C)(C)C2
Reactant: CC[Zn]CC
Product: CCOC(=O)c1c(CC)nc2c(c1O)C(=O)CC(C)(C)C2

Procedure:
Obtained by starting from ethyl 2-chloro-4-hydroxy-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydroquinoline-3-carboxylate. Diethylzinc (1 M in hexane) is used instead of isopropyl-zinc-bromide.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]=S)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[NH2:14][CH2:15][CH2:16][CH2:17][NH2:18].C(N(CC)CC)C>C(#N)C.[Hg]Cl>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]2[NH:18][CH2:17][CH2:16][CH2:15][NH:14]2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(N=C=S)cc1
Reactant: NCCCN
Agent: Cl[Hg]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCc1ccc(N=C2NCCCN2)cc1
Reaction time: 1 h

Procedure:
A solution of 144 g. of 4-n-butylphenylisothiocyanate in 800 ml of acetonitrile is added dropwise in 30 minutes at room temperature to a solution of 95 ml of 1,3-diaminopropane in 450 ml of acetonitrile, while solution is stirred. After 1 hour, 260 ml of triethylamine are added. A solution of 212 g of mercurychloride in 560 ml of acetonitrile is then added while stirring said solution for 1 hour. The reaction mixture is stirred for another 24 hours and then filtered while warm. The solvent is distilled from the filtrate and the residue is mixed with up in methylene chloride and washed with dilute alkaline solution and water. After drying, the methylene chloride is distilled off, the crude 2-(4-n-butylphenyl)iminohexahydropyrimidine being obtained in a yield of 165 g. The product can be purified by a recrystallisation from a mixture of carbon tetrachloride and petroleum ether. A product is obtained with a melting point of 116°-119° C. The product may also be purified by dissolving it in approximately 20% hydrochloric acid, washing the aqueous phase with ether and then making it alkaline again. The thus purified 2-(4-n-butylphenyl)imino-hexahydropyrimidine can be isolated by taking up in ether, drying and distilling the solvent. The thus purified product also has a melting point of 116°-119° C.
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([F:19])[C:16]=2[F:18])[CH:11]=[CH:10][C:9]=1[OH:20].[F:21][C:22]([F:28])([F:27])[S:23](O)(=[O:25])=[O:24]>ClCCl.O>[F:21][C:22]([F:28])([F:27])[S:23]([O:20][C:9]1[CH:10]=[CH:11][C:12]2[C:17](=[C:16]([F:18])[C:15]([F:19])=[CH:14][CH:13]=2)[C:8]=1[F:7])(=[O:25])=[O:24]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: Oc1ccc2ccc(F)c(F)c2c1F
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(Oc1ccc2ccc(F)c(F)c2c1F)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Pyridine (10 ml) was added slowly and dropwise to a dichloromethane (60 ml) solution of 1,7,8-trifluoro-2-naphthol (10 g) and trifluoromethanesulfonic acid anhydrate (10.3 ml) at the temperature of the ice/water, and then the reaction solution was stirred for 30 minutes. Water and dichloromethane were added slowly in the reaction solution. The organic layer was removed, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with water, 10% hydrochloric acid, a saturated sodium hydroxide aqueous solution, water, and brine consecutively, and concentrated. The residue was purified by column chromatography (silica gel, hexane/ethyl acetate=19/1), and 1,7,8-trifluoronaphthalene-2-yl trifluoromethanesulfonate was obtained as light yellow crystals.
Reaction SMILES: [OH-].[K+].CCOCC.[CH3:8][N:9]([N:16]=O)C(N[N+]([O-])=O)=N.[CH2:18]([O:25][C:26]1[C:27]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[N:28][N:29]2[CH:34]([C:35](Cl)=[O:36])[CH2:33][N:32]([CH3:38])[C:31](=[O:39])[C:30]=12)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[CH2:18]([O:25][C:26]1[C:27]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[N:28][N:29]2[CH:34]([C:35](=[O:36])[CH:8]=[N+:9]=[N-:16])[CH2:33][N:32]([CH3:38])[C:31](=[O:39])[C:30]=12)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)CC2C(=O)Cl
Reactant: CN(N=O)C(=N)N[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)CC2C(=O)C=[N+]=[N-]
Reaction time: 0.25 h

Procedure:
To a stirring biphasic mixture of 40% aqueous KOH (20 mL) and Et2O (10 mL) at 0° C. was slowly added N-methyl-N-nitroso-N′-nitroguanidine (492 mg, 3.34 mmol). The mixture was stirred for 15 minutes, and the Et2O layer was transferred to a solution of ethyl 3-benzyloxy-7-chlorocarbonyl-5-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (262 mg, 0.669 mmol) in CH2Cl2 (10 mL). The reaction was stirred at room temperature for 30 minutes, and the solvent was removed in vacuo to afford the title product. ES MS (M+H)=398.
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[Br:11].[F:13][C:14]([Si](C)(C)C)([F:16])[F:15].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>C1(C)C=CC=CC=1.CO>[Br:11][C:5]1[CH:6]=[C:7]([Cl:10])[CH:8]=[CH:9][C:4]=1[C:3](=[O:12])[C:14]([F:16])([F:15])[F:13]
Reactant: COC(=O)c1ccc(Cl)cc1Br
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C(c1ccc(Cl)cc1Br)C(F)(F)F
Temperature: 25 °C
Reaction time: 10 h
Yield: 69.6 %

Procedure:
2-Bromo-4-chloro-benzoic acid methyl ester (12.4 g, 50 mmol) in toluene (200 ml) was cooled to −70° C., and trifluoromethyl trimethyl silane (13 ml, 70 mmol) was added. Tetrabutylamonium fluoride (1M, 2.5 ml) was added dropwise, and the mixture was allowed to warm to room temperature over 4 h, after which it was stirred for 10 h at room temperature. The reaction mixture was concentrated to give the crude [1-(2-bromo-4-chloro-phenyl)-2,2,2-trifluoro-1-methoxy-ethoxy]-rimethyl-silane. The crude intermediate was dissolved in methanol (100 ml) and 6N HCl (100 ml) was added. The mixture was kept at 45-50° C. for 12 h. Methanol was removed, and the crude was extracted with dichloromethane (200 ml). The combined DCM layer was washed with water (50 ml), NaHCO3 (50 ml), brine (50 ml), and dried over sodium sulfate. Removal of solvent gave a crude product, which was purified by ISCO column chromatography, using 1-2% ethyl acetate in hexane as solvent, to afford 1-(2-bromo-4-chloro-phenyl)-2,2,2-trifluoro-ethanone (10 g, 70%). 1H-NMR (300 MHz, CDCl3): δ (ppm) 7.50 (d,1H), 7.65(d,1H), 7.80(s,1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[N:6]2[C:7](=[O:10])CC[C@@H]2C[O:3]1.[Li+].[CH3:13]C([N-]C(C)C)C.C1COCC1.CC[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].IC.[NH4+].[Cl-]>C1COCC1>[CH3:1][C:2]1([CH3:11])[N:6]2[C:7](=[O:10])[C:30]([CH3:31])([CH3:13])[CH2:29][C@@H:28]2[CH2:27][O:3]1
Reactant: CC1(C)OC[C@H]2CCC(=O)N21
Reactant: CCCCCCC
Reactant: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1(C)C[C@@H]2COC(C)(C)N2C1=O
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of (R)-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one (D34) (1.3 g, 8.37 mmol) in dry THF (120 ml) cooled to −78° C., LDA 2M sol in THF/heptane (6.28 ml, 12.6 mmol) was added. The red solution was stirred at this temperature for 40 min before adding iodomethane (0.78 ml, 12.6 mmol). The reaction mixture was warmed to RT (40 min) then cooled to −78° C. prior addition of LDA 2M sol in THF/heptane (6.28 ml, 12.6 mmol). The mixture was stirred at −78° C. for 1 h before adding iodomethane (0.78 ml, 12.6 mmol) then the mixture was slowly warmed to RT and stirred overnight. The resulting solution was treated with NH4Cl sat sol (10 ml) and extracted with Et2O (3×10 ml). The organic phases were collected and washed with NaCl sat. sol, dried over Na2SO4 and evaporated in vacuo to afford the title compound (D35) (1.2 g).
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH:19]=O)=[CH:11]2)[O:6][CH2:5][CH2:4][O:3]1.[C:21]([CH:26]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:23][CH2:24][CH3:25])=[O:22]>C1(C)C=CC=CC=1>[CH2:24]([O:23][C:21](=[O:22])[CH:26]=[CH:19][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:10]([CH2:9][CH2:8][CH2:7][C:2]2([CH3:1])[O:3][CH2:4][CH2:5][O:6]2)[CH:11]=1)[CH3:25]
Reactant: CC1(CCCn2cc(C=O)c3ccccc32)OCCO1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=Cc1cn(CCCC2(C)OCCO2)c2ccccc12

Procedure:
A mixture of 27.3 g of 1-[3-(2-methyl-2-dioxolanyl)propyl]-3-indolecarboxaldehyde (0.1 mole) and 40 g. (0.11 mole) of carbethoxymethylene triphenylphosphorane in 400 ml. of toluene is heated at reflux overnight. The resulting cold solution is filtered through a Silica gel column to remove the inorganic material to give 1-[3-(2-methyl-2-dioxolanyl)propyl]-3-indoleacrylic acid ethyl ester, m.p. 61°-62° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[Br:19]Br>C(O)(=O)C>[Br:19][C:10]1[C:5]2[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:3][C:2]([Br:1])=[N:7][C:6]=2[N:8]([CH:11]([CH3:13])[CH3:12])[N:9]=1
Reactant: BrBr
Reactant: CCOC(=O)c1cc(Br)nc2c1cnn2C(C)C
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(Br)nc2c1c(Br)nn2C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.7 %

Procedure:
To a stirred solution of ethyl 6-bromo-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (2 g, 6.43 mmol) in acetic acid (6 mL) was added bromine (5.14 g, 32.15 mmol) at 0° C. Resulting reaction mass was stirred at room temperature for 3 h. Reaction was monitored by TLC. On completion, reaction was quenched with ice, NaHCO3 solution was added to it. Extraction was carried out using ethyl acetate; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4. Solvent was removed under reduced pressure and residue was purified by silica gel column chromatography to obtain the desired intermediate (1.2 g, 48%).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=O.[CH3:12]OC(OC)N(C)C.[NH:20]([C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([OH:27])=[O:26])[NH2:21]>O>[CH:12]1[C:1]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[CH2:4][CH2:3][C:2]=2[N:20]([C:22]2[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=2)[C:25]([OH:27])=[O:26])[N:21]=1
Reactant: COC(OC)N(C)C
Reactant: O=C1CCc2ccccc2C1
Reactant: NNc1cccc(C(=O)O)c1
Solvent: O
Product: O=C(O)c1cccc(-n2ncc3c2CCc2ccccc2-3)c1
Yield: 62.9 %

Procedure:
A mixture of 2-tetralone (2.00 mL, 14.7 mmol) and dimethylformamide dimethyl acetal (2.10 mL, 15.0 mmol) is heated to reflux for 14 h. The mixture is cooled and evaporated, and approximately half of the residue is dissolved in acetic acid (10 mL) and treated with 3-hydrazinobenzoic acid (750 mL, 4.93 mmol). The solution is heated to reflux for 12 h, then cooled and poured into water (100 mL). The resulting precipitate is collected by filtration, washed with water, and evaporated under high vacuum to afford the title compound (900 mg, 3.10 mmol, 63%) as a tan solid, m.p. 273-275° C. 1H NMR (300 MHz, DMSO-d6): δ 13.30 (1H, br), 8.15 (1H, s), 8.10 (1H, t, J=1.9 Hz), 7.95 (1H, dt, J=7.6, 1.3 Hz), 7.82 (1H, ddd, J=8.0, 2.2, 1.0 Hz), 7.66 (1H, t, J=7.9 Hz), 7.53 (1H, dd, J=7.6, 1.2 Hz), 7.26-7.22 (2H, m), 7.10 (1H, dt, J=7.3, 1.2 Hz), 3.05-3.02 (2H, m), 3.00-2.87 (2H, m). MS (ES+): m/e 292 (21), 291 (100). MS (ES−): m/e 290 (20), 289 (100).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[O:12][CH3:13].[C-:14]#[N:15].[Na+]>CCO>[CH3:13][O:12][C:4]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=1[CH2:2][C:14]#[N:15]
Reactant: [C-]#N
Reactant: COc1ccc([N+](=O)[O-])cc1CBr
Agent: [Na+]
Solvent: CCO
Product: COc1ccc([N+](=O)[O-])cc1CC#N

Procedure:
2-Bromomethyl-1-methoxy-4-nitro-benzene (25 g) was dissolved in warm EtOH (45 mL) and stirred while slowly adding a solution of NaCN (6.0 g in 12 mL water) at 70° C. After the addition was complete, the reaction was stirred at 70° C. for 90 min. The inorganic solid, which separated on cooling, was collected and washed well with CH3CN. The CH3CN filtrate was filtered again giving further inorganic solid, and again washed with CH3CN. The final CH3CN filtrate was evaporated giving a red-brown solid. This solid was triturated with CH2Cl2 until the washings were colorless. Evaporation of the CH2Cl2 filtrate gave (2-methoxy-5-nitrophenyl)-acetonitrile as a red-brown solid, which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][C:6]([C:7]#[N:8])=[C:5]([NH2:13])[CH:4]=1.C(O)C.Cl.[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31](=N)OCC)[CH2:27][CH2:26]1)=[O:24].C([N:38](CC)CC)C>>[CH3:12][O:11][C:10]1[CH:9]=[C:6]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[N:13]=[C:31]([N:28]1[CH2:29][CH2:30][N:25]([C:23]([C:19]3[O:18][CH:22]=[CH:21][CH:20]=3)=[O:24])[CH2:26][CH2:27]1)[N:8]=[C:7]2[NH2:38]
Reactant: COc1cc(N)c(C#N)cc1OC
Reactant: CCOC(=N)N1CCN(C(=O)c2ccco2)CC1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CCO
Product: COc1cc2nc(N3CCN(C(=O)c4ccco4)CC3)nc(N)c2cc1OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of 1.78 g. (0.01 mole) of 4,5-dimethoxy-2-aminobenzonitrile in 50 ml. of anhydrous ethanol is added 10 ml. of triethylamine, followed by 2.88 g. (0.01 mole) of ethyl 4-(2-furoyl)piperazin-1-ylformimidate hydrochloride. The reaction mixture is stirred at ambient temperature for 5 hours, and then it is heated under reflux for 12 hours. At this point, all the solvents are removed by evaporation in vacuo, and the residue is triturated under water. The solid is filtered off and dried, yielding crude 6,7-dimethoxy-4-amino-2-[4-(2-furoyl)piperazin-1-yl]quinazoline.
Reaction SMILES: C([O:3][C:4](=[O:31])[C:5]([CH3:30])([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][NH:19][C:18](=[O:21])[N:17]2[CH3:22])=[CH:9][CH:8]=1)C.[H-].[Na+].F[C:35](F)(F)[C:36]1[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=1CBr.[OH-].[Na+].CN([CH:51]=[O:52])C>C(O)C>[CH3:51][O:52][C:40]1[CH:37]=[C:36]([CH:43]=[CH:42][CH:41]=1)[CH2:35][N:19]1[CH2:20][CH:16]([CH2:15][CH2:14][O:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][C:5]([CH3:30])([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:4]([OH:3])=[O:31])=[CH:8][CH:9]=2)[N:17]([CH3:22])[C:18]1=[O:21]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CNC(=O)N2C)cc1)Oc1ccccc1
Reactant: CN(C)C=O
Reactant: FC(F)(F)c1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cccc(CN2CC(CCOc3ccc(CC(C)(Oc4ccccc4)C(=O)O)cc3)N(C)C2=O)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 68 %

Procedure:
A solution of 2-methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionic acid ethyl ester (0.109 g, 0.255 mmol) in DMF (7 mL) is treated with NaH (60% oil suspension, 0.021 g, 0.525 mmol) and stirred at room temperature under N2 for 20 minutes. The reaction is treated with 2-trifluoromethyl benzyl bromide (0.092 g, 0.385 mmol) and then warmed to room temperature and stirred for 3 hours. The reaction is quenched with acid and worked up extractively with Et2O and water. The organic layer is dried and the solvent removed to afford crude product that is dissolved in ethanol (20 mL) is treated with aqueous 5 N NaOH (1.5 mL) and heated to reflux 1 hour. The reaction mixture is cooled, the solvent removed. The resultant residue is acidified with aqueous 1 N HCl (20 mL) and extracted with CH2Cl2. The organic layer is dried and the solvent removed in vacuo to afford crude acid that is purified by preparative HPLC to give 0.096 g (68%) of 2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(2-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy-propionic acid 1H NMR. HRMS (ES+) m/z exact mass calc'd for C30H32N2O5F3 (M+1) 557.2263. Found m/z 557.2274.
Reaction SMILES: [C:1]([CH:5]1[O:11][CH:10]2[C:7]([C:27](=[O:35])[CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:8](=[O:26])[N:9]2[C:12](=[C:23]([CH3:25])[CH3:24])[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[NH:6]1)([O:3]C)=[O:2].O.[OH-].[Na+].Cl>CC(C)=O.C(OCC)(=O)C>[C:1]([CH:5]1[O:11][CH:10]2[C:7]([C:27](=[O:35])[CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)([C:8](=[O:26])[N:9]2[C:12](=[C:23]([CH3:24])[CH3:25])[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[NH:6]1)([OH:3])=[O:2]
Reactant: COC(=O)C1NC2(C(=O)Cc3ccccc3)C(=O)N(C(C(=O)OCc3ccccc3)=C(C)C)C2O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)=C(C(=O)OCc1ccccc1)N1C(=O)C2(C(=O)Cc3ccccc3)NC(C(=O)O)OC12
Temperature: 0 °C
Reaction time: 1 h
Yield: 110.2 %

Procedure:
To a solution of 39 g of benzyl α-(3ξ-carbomethoxy-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate in 628 ml of acetone is added 228 ml of water and then dropwise added 90.8 ml of 1.0 N aqueous solution of sodium hydroxide. The mixture is stirred for 1 hour under ice-cooling, diluted with 630 ml of ice water, covered with ethyl acetate, adjusted to pH 2 with 20% hydrochloric acid and extracted with ethyl acetate. The extract is washed with water, dried on sodium sulfate and concentrated under reduced pressure to yield 41.7 g of benzyl α-(3ξ-carboxy-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate as crude product.