Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[OH-:12].[Na+].Br[CH2:15][CH:16]=[CH:17][CH2:18]Br>O>[CH2:15]([O:12][C:8]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH3:7])[CH:16]=[CH:17][CH2:18][O:9][C:8]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH3:7]
Reactant: [OH-]
Reactant: COc1cc(C=O)ccc1O
Reactant: BrCC=CCBr
Agent: [Na+]
Solvent: O
Product: COc1cc(C=O)ccc1OCC=CCOc1ccc(C=O)cc1OC

Procedure:
Vanillin (30.4 g, 0.20 m) is dissolved in water (150 mL), containing sodium hydroxide (8.5 g). 1,4-Dibromo-2-butene (21.4 g, 0.1 m) is added and the reaction mixture heated at reflux for 6 hours. After the reaction mixture is cooled, the product is collected by filtration, washed with water, dried in air, and finally recrystallized from toluene (200 mL). The yield is 18.8 g (52.8% of the theoretical yield) of 4,4'-[2-butene-1,4-diylbis(oxy)]bis[3-methoxybenzaldehyde] as indicated by mass spectroscopy analysis. A mixture of 4,4'-[2-butene-1,4-diylbis(oxy)]bis[3-methoxybenzaldehyde] (3.56 g, 0.01 m), ethyl cyanoacetate (2.26 g, 0.02 m), ethanol (90 mL), and piperidine (10 drops) is heated at reflux for 4 hours. The reaction mixture is cooled and the product is collected by filtration, washed with ethanol, and dried in air (yield--4.3 g). Mass spectrum analysis supports the following structure: ##STR30## In methylene chloride, the product has an absorption maximum at 316 nm.
Reaction SMILES: [C:1]([NH:4][C:5](=[O:8])[CH2:6][SH:7])(=[O:3])[CH3:2].[C:9]([CH2:13][CH2:14][C:15](Cl)=[O:16])([O:11][CH3:12])=[O:10].C(N(CC)CC)C>ClCCl>[C:1]([NH:4][C:5](=[O:8])[CH2:6][S:7][C:15](=[O:16])[CH2:14][CH2:13][C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2]
Reactant: COC(=O)CCC(=O)Cl
Reactant: CC(=O)NC(=O)CS
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCC(=O)SCC(=O)NC(C)=O
Reaction time: 1 h

Procedure:
The concentrated product of Step A. above was added to 100 ml. of dichloromethane and cooled to -5° C. under nitrogen. There was then added 8.3 g. (0.055 mole) of 3-carbomethoxypropionyl chloride in 20 ml. of dichloromethane, over from 5 to 10 minutes. Next, there was added 5.57 g. (0.055 mole) of triethylamine in 20 ml. of dichloromethance and the reaction mixture was aged for 1 hour at -5° C., then permitted to come to room temperature over 2 hours. The reaction mixture was then concentrated under vacuum after having been made slightly acidic with acetic acid. Ice water was then added to the reaction mixture, and the water was extracted with dichloromethane dried over magnesium sulfate and concentrated to an oil of 15.4 g. The oil was changed to a silica gel column and eluted with 25% ethylacetate/hexane to obtain 2.3 g. of final product having an m.p. of 111°-113° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:3]1.C(O[C:26]1(O[Si](C)(C)C)[CH2:28][CH2:27]1)C.[B-]C#N.[Na+].C(O)(=O)C>CO.C(OCC)(=O)C>[CH:26]1([N:19]2[CH2:18][CH2:17][N:16]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH:4]3[CH2:3][C:2]([CH3:22])([CH3:1])[CH2:7][C:6]([CH3:8])([CH3:9])[CH2:5]3)[CH2:21][CH2:20]2)[CH2:28][CH2:27]1
Reactant: CC1(C)CC(c2ccccc2N2CCNCC2)CC(C)(C)C1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [B-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC1(C)CC(c2ccccc2N2CCN(C3CC3)CC2)CC(C)(C)C1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine (30 mg, 0.1 mmol) produced in Example (8b) in methanol (3 mL) were added [(1-ethoxycyclopropyl)oxy]trimethylsilane (105 mg, 0.6 mmol), sodium cyanotrihydroborate (28.3 mg, 0.45 mmol), acetic acid (60.1 mg, 1 mmol) and molecular sieves 3A (50 mg) in that order, followed by stirring for 5 hours and 30 minutes at an external temperature of 80° C. Ethyl acetate was added to the reaction mixture, which was filtered through Celite, and the filtrate was concentrated. Water was then added to the residue, extraction was performed with ethyl acetate, and the organic layer was washed with 2N aqueous solution of sodium hydroxide and brine. The organic layer was dried over magnesium sulfate, the desiccant was filtered off, and then the filtrate was concentrated. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 1-cyclopropyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine as a white solid. The obtained compound was dissolved in ethyl acetate, and a 4N solution of hydrogen chloride in ethyl acetate (0.040 mL, 0.160 mmol) was added. The solution was concentrated, and hexane was added to the obtained residue to produce a solid, which was then triturated by sonication. The supernatant hexane solution was removed and the resulting solid residue was dried under reduced pressure to give 37.7 mg of the title compound as a white solid.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].Cl[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18].[Cl-].[NH4+]>CN(C)C=O>[CH3:1][N:2]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:14])[F:15])=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18])[CH2:3][CH2:4][OH:5]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: CNCCO
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CN(CCO)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(Methylamino)ethanol (17.3 g, 231 mmol) was added dropwise to a solution of 4-chloro-3-nitrobenzotrifluoride (26.0 g, 115 mmol) in N,N-dimethylformamide (100 ml) at 0° C. After the reaction temperature was raised to room temperature, the reaction mixture was stirred at room temperature for 1 hour, poured into a saturated aqueous ammonium chloride solution, and then extracted twice with ethyl acetate. The organic layer was washed with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol=97/3) to obtain an oil of 4-[N-methyl-N-(2-hydroxyethyl)amino]-3-nitrobenzotrifluoride.
Reaction SMILES: O1CCOCC1.[F:7][C:8]([F:24])([F:23])[C:9]1[C:10]([S:15]([NH:18][C:19](=[O:22])OC)(=[O:17])=[O:16])=[N:11][CH:12]=[CH:13][CH:14]=1.[CH3:25][C:26]1[CH2:30][C:29]([CH3:37])([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[NH:28][N:27]=1>N1C=CC=CC=1>[F:23][C:8]([F:7])([F:24])[C:9]1[C:10]([S:15]([NH:18][C:19]([N:28]2[C:29]([CH3:37])([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:30][C:26]([CH3:25])=[N:27]2)=[O:22])(=[O:16])=[O:17])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC1=NNC(C)(c2ccccc2)C1
Reactant: COC(=O)NS(=O)(=O)c1ncccc1C(F)(F)F
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CC1=NN(C(=O)NS(=O)(=O)c2ncccc2C(F)(F)F)C(C)(c2ccccc2)C1
Reaction time: 1 h
Yield: 86 %

Procedure:
A dry dioxane (10 ml) solution containing methyl N-(3-trifluoromethylpyridine-2-sulfonyl)carbamate (0.43 g, 1.5 mmol), 3,5-dimethyl-5-phenyl-2-pyrazoline (0.52 g, 3.0 mmol) and pyridine (0.45 g) was refluxed under heating and stirring for one hour. After cooling the mixture, the solvent was distilled off under reduced pressure, and the residue was stirred together with ethyl ether. Precipitated crystals were collected by filtration and then thoroughly washed with ethyl ether, and the crystals were suspended in 20 ml of water. Then, the pH was adjusted to a level of from 1 to 2 with concentrated hydrochloric acid, and the suspension was stirred at room temperature for 5 minutes. Crystals were collected by filtration, thoroughly washed with water and then with ethyl ether and dried to obtain 0.55 g of desired 1-(3-trifluoromethylpyridine-2-sulfonylcarbamoyl)-3,5-dimethyl-5-phenyl-2-pyrazoline. Melting point: 152°-153° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([S:7]([C:10]2[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:3][CH2:2]1.Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([OH:34])([C:30]([F:33])([F:32])[F:31])[C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>C(#N)C>[NH2:14][C:13]1[CH:15]=[CH:16][C:10]([S:7]([CH:4]2[CH2:3][CH2:2][N:1]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]([OH:34])([C:26]([F:27])([F:28])[F:29])[C:30]([F:31])([F:32])[F:33])=[CH:23][CH:24]=3)[CH2:6][CH2:5]2)(=[O:9])=[O:8])=[CH:11][CH:12]=1
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Reactant: Nc1ccc(S(=O)(=O)C2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CS(C)=O
Product: Nc1ccc(S(=O)(=O)C2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80.7 %

Procedure:
4-(Piperidin-4-ylsulfonyl)aniline (1.748 mmol, 420 mg), 2-(4-(bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (1.748 mmol, 589 mg) and potassium carbonate (3.50 mmol, 483 mg) were combined in acetonitrile (5 mL). Dimethylsulfoxide (0.5 mL) was added and the reaction stirred at room temperature for 1.5 hours. The reaction mixture was filtered and filtrate was concentrated under vacuum. The residue was purified by SCX chromatography to give the title compound (700 mg).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH:8]=[CH:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:20])C=1.C(OCC)C.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O1CCCC1>[O:20]1[CH:8]2[CH:7]1[CH2:6][C:5]1[CH:4]=[CH:3][CH:2]=[C:1]([OH:11])[C:10]=1[CH2:9]2
Reactant: Oc1cccc2c1CC=CC2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Oc1cccc2c1CC1OC1C2

Procedure:
Alternatively, the 2,3-trans-1,2,3,4-tetrahydro-5-[2-hydroxy-3-(alkylamino)propoxy]-2,3-naphthalenediol of formula II can be prepared from a 5,8-dihydro-1-naphthol of formula IX by mixing a cooled solution (temperature less than about 30° C.) of 5,8-dihydro-1-naphthol in ethyl acetate with m-chloroperbenzoic acid and mixing the resulting slurry with a mixture of ethyl ether and aqueous sodium bicarbonate, to form a 5,6,7,8-tetrahydro-6,7-epoxy-1-naphthol having the formula ##STR17## A 5,6,7,8-tetrahydro-6,7-epoxy-1-naphthol of formula XVI in tetrahydrofuran can be reacted with aqueous perchloric acid at a temperature within the range of from about 0° to about 60° C., to form a trans-5,6,7,8-tetrahydro-1,6,7-naphthalenetriol or formula XI which can be converted to the corresponding 2,3-trans-1,2,3,4-tetrahydro-5-[2,3-(epoxy)propoxy]-2,3-naphthanediol of formula XII, which in turn can be converted to the corresponding 2,3-trans-1,2,3,4-tetrahydro-5-[2-hydroxy-3-(alkylamino)propoxy]-2,3-naphthalenediol of formula II using the procedures described above.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24](O)=[O:25])=[CH:15][C:13]=2[N:14]=1.S(Cl)(Cl)=O.[F:31][CH:32]([F:41])[C:33]1[CH:34]=[CH:35][C:36]([F:40])=[C:37]([CH:39]=1)[NH2:38].CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:22])([CH3:23])[O:21][C:17]=3[C:16]([C:24]([NH:38][C:37]3[CH:39]=[C:33]([CH:32]([F:31])[F:41])[CH:34]=[CH:35][C:36]=3[F:40])=[O:25])=[CH:15][C:13]=2[N:14]=1
Reactant: Nc1cc(C(F)F)ccc1F
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)Cc2c(c(C(=O)Nc3cc(C(F)F)ccc3F)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Yield: 5.8 %

Procedure:
The title compound was prepared by following the same procedure as described for Example-108 using 2-[(2-chloro-6-fluorophenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-15, 0.150 g, 0.400 mmol), thionyl chloride (2.0 mL), 5-(difluoromethyl)-2-fluoroaniline (Intermediate-46, 0.097 g, 0.600 mmol), THF (5.0 mL) and DIPEA (2 mL). The obtained crude product was purified by column chromatography on basic alumina eluting with 0.7-1.0% MeOH:DCM to afford 0.012 g of the desired product. 1HNMR (DMSO-d6): δ 1.56 (s, 6H), 3.13 (s, 2H), 7.07 (t, J=55.5 Hz, 1H), 7.33-7.52 (m, 6H), 8.76 (d, J=6.9 Hz, 1H), 10.24 (s, 1H), 11.20 (s, 2H); MS [M+H]+: 519.20.
Reaction SMILES: [C:1]1([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[CH2:24][CH2:23]1>CN(C)C=O.O.C(OCC)(=O)C>[F:34][C:31]1[CH:30]=[CH:29][C:28]([N:25]2[CH2:24][CH2:23][N:22]([CH2:21][CH2:20][CH2:19][N:11]([C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)[S:12]([CH3:15])(=[O:14])=[O:13])[CH2:27][CH2:26]2)=[CH:33][CH:32]=1
Reactant: Fc1ccc(N2CCN(CCCCl)CC2)cc1
Reactant: CS(=O)(=O)Nc1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CS(=O)(=O)N(CCCN1CCN(c2ccc(F)cc2)CC1)c1cccc2ccccc12
Temperature: 110 °C
Reaction time: 0.25 h
Yield: 39.1 %

Procedure:
A solution of N-(1-naphthyl)methanesulphonamide (6.6 g) in dry N,N-dimethylformamide (20 cc) is added dropwise to a suspension of sodium hydride (0.9 g, 80% suspension in oil) in N,N-dimethylformamide (50 cc). After stirring for 15 minutes, a solution of 1-(3-chloropropyl)-4-(4-fluorophenyl)piperazine (7.2 g) in N,N-dimethylformamide (20 cc) is added. The reaction mixture is heated to 110° C. for 2 hours and 30 minutes and is then cooled and poured in a mixture of water (300 cc) and ethyl acetate (500 cc). The organic phase is washed with water, is diluted with dichloromethane (50 cc), is dried over magnesium sulphate and is concentrated to dryness under reduced pressure (2.7 kPa) down to 50 cc. The crystals are filtered off and washed with ethyl acetate (3×50 cc) and then with isopropyl ether (2×30 cc) and are dried. After recrystallization, from ethyl acetate (300 cc), N[3-(4-(4-fluorophenyl)- 1-piperazinyl)propyl]-N-(1-naphthyl)methanesulphonamide (4.84 g) is obtained, melting at 170° C.
Reaction SMILES: C(O[CH:4]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])[CH3:5])C.[CH:14]([O:16][CH2:17][CH3:18])=[CH2:15]>>[C:7]1([C:8](=[CH:9][CH:10]=[CH:11][CH:12]=1)[OH:13])[OH:6].[CH2:14]([O:16][CH2:17][CH2:18][O:13][CH2:8][CH2:7][O:6][CH2:4][CH3:5])[CH3:15]
Reactant: C=COCC
Reactant: CCOC(C)Oc1ccccc1O
Product: CCOCCOCCOCC
Product: Oc1ccccc1O

Procedure:
The method of (a) is employed, except that 300 parts by weight of ethyl vinyl ether is used instead of 150 parts by weight. 248 parts by weight of a colorless oil is obtained having a boiling point of 97° to 102° C. at 0.3 mm.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:16][C@H:17]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:18]([NH2:20])=[O:19])=[N:7][C:8]=1[NH:9][C:10]1[S:14][N:13]=[C:12]([CH3:15])[CH:11]=1)#[N:2].[OH-].[Na+].OO.CC(O)=[O:31]>CCO.CS(C)=O>[NH2:20][C:18](=[O:19])[C@H:17]([NH:16][C:6]1[N:7]=[C:8]([NH:9][C:10]2[S:14][N:13]=[C:12]([CH3:15])[CH:11]=2)[C:3]([C:1]([NH2:2])=[O:31])=[N:4][CH:5]=1)[CH2:21][CH:22]([CH3:24])[CH3:23]
Reactant: CC(=O)O
Reactant: Cc1cc(Nc2nc(N[C@H](CC(C)C)C(N)=O)cnc2C#N)sn1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: Cc1cc(Nc2nc(N[C@H](CC(C)C)C(N)=O)cnc2C(N)=O)sn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The compound (R)-2-(5-cyano-6-(3-methylisothiazol-5-ylamino)pyrazin-2-ylamino)-4-methylpentanamide (17 mg, 0.049 mmol) was dissolved in EtOH (1 mL) and DMSO (0.5 mL), aq. 1N NaOH (0.50 mL) and aq. H2O2 (30%, 0.50 mL) were added. The mixture was stirred at room temperature for 60 min. HOAc (0.1 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (7 mg). MS 364.3 (M+H); UV 210.2, 275.0, 323.7 nm; t 0.458 min.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:4]([CH3:9])=[N:5][O:6][C:7]=1[CH3:8].[C:10]1([P:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[Cl-:1].[CH3:9][C:4]1[C:3]([CH2:2][P+:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[C:7]([CH3:8])[O:6][N:5]=1
Reactant: Cc1noc(C)c1CCl
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1noc(C)c1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Cl-]

Procedure:
A solution of 59.6 g. (0.402 mole) of 4-chloromethyl-3,5-dimethylisoxazole, prepared as described above, and 116 g. (0.44 mole) of triphenylphosphine in 1 liter of tolune was heated at reflux under nitrogen for 6 hours. The resulting suspension was cooled and filtered. The filtrate was heated at reflux for an additional 20 hours. The precipitate was again removed by filtration and the combined solids were washed well with ether and benzene. The solvent was removed from the filtrate and the residue was taken up in 150 ml. of fresh toluene and refluxed for an additional 18 hours. Filtration as before gave another small quantity of solid. The combined solids were crystallized from ethanol-ether to give the desired phsophonium salt as a cream-white solid, m.p. 313°-316°.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:6]1[S:10][C:9]([C:11]([OH:13])=[O:12])=[CH:8][CH:7]=1)([CH3:5])[CH3:4].[C:14]([O-])([O-])=O.[K+].[K+].IC.O>CN(C=O)C>[CH3:14][O:12][C:11]([C:9]1[S:10][C:6]([C:3]([CH3:4])([CH3:5])[CH2:2][OH:1])=[CH:7][CH:8]=1)=[O:13]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(CO)c1ccc(C(=O)O)s1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)c1ccc(C(C)(C)CO)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
A solution of 5-(2-hydroxy-1,1-dimethyl-ethyl)-thiophene-2-carboxylic acid (0.495 g, 2.47 mmol) in DMF (12.0 mL) is treated with K2CO3 (0.515 g, 3.73 mmol), iodomethane (0.23 mL, 3.69 mmol), and stirred at rt overnight. The mixture is poured into H2O (25 mL) and extracted with EtOAc (3×25 mL). The combined extracts are washed with H2O, brine, dried over MgSO4, filtered, and concentrated. The residue is loaded onto silica gel and eluted with hexanes using a gradient of 0% to 75% EtOAc to give 5-(2-hydroxy-1,1-dimethyl-ethyl)-thiophene-2-carboxylic acid methyl ester (0.439 g, 83%). MS (ES): 215.1 [M+H]+.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.O1CCCC1.[NH:16]1[CH2:21][CH2:20][CH2:19][NH:18][C:17]1=[O:22].C(Cl)(Cl)Cl>C(N(CC)CC)C>[C:4]1([S:7]([N:16]2[CH2:21][CH2:20][CH2:19][NH:18][C:17]2=[O:22])(=[O:9])=[O:8])[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: O=C1NCCCN1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C1NCCCN1S(=O)(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
20.4 parts by weight of benzenesulfochloride in 20 parts by volume of tetrahydrofurane were added dropwise at 10°-15°C over the course of 15 minutes to a stirred mixture of 10 parts by weight of 1,3-diaza-cyclohexane-2-one, 80 parts by volume of tetrahydrofurane and 80 parts by volume of chloroform, followed by 10.1 parts by weight of triethylamine at the same temperature. The mixture was stirred at 10°-15°C for 30 minutes and then overnight at 50°C. Subsequently the mixture was evaporated to dryness; the residue was stirred with 100 parts by volume of water, filtered, stirred with water once more, filtered and washed with ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[Li]CCCC.[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[C:23]#[N:24]>>[C:10]([C:9]1[N:24]=[C:23]([C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=2[F:20])[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:7]=2)[N:8]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: N#Cc1ccccc1F
Reactant: CC(C)(C)C(=O)Nc1ccc(Cl)cc1
Agent: [Li]CCCC
Product: CC(C)(C)c1nc(-c2ccccc2F)c2cc(Cl)ccc2n1
Yield: 57 %

Procedure:
The preparation of 4-phenylquinazolines from amidobenzenes or benzonitriles, as shown in the reaction when p-chloropivalamidobenzene was dilithiated with n-BuLi followed by the addition of o-fluorobenzonitrile to give 57% of 2-t-butyl-6-chloro-4-o-fluorophenylquinazoline [26], and the treatment of o-aminobenzonitrile with phenylmagnesium halide from which the resulting intermediate 2-H2NC6H4C(Ph)=N− then cyclized with carbonyl compounds (e.g., acid chlorides, anhydrides, formates) to give 4-phenyl-quinazolines [27]. Alternatively, the reaction between benzanilides and benzonitriles in the presence of PCl5 and AlCl3 in PhNO2 at 120-150° C. also afforded 2,4-diphenylquinazoline [28];
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:11][N:10]=[C:9]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:24]([O-])([OH:26])=[O:25].C(=O)(O)[O-].[Na+]>C(O)(=O)C>[N+:24]([C:5]1[CH:4]=[CH:3][C:2]([CH2:1][N:8]2[C:12]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:11][N:10]=[C:9]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:7][CH:6]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)Cc1cnc(-c2ccccc2)n1Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)Cc1cnc(-c2ccccc2)n1Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 20 ml of glacial acetic acid was dissolved 1.2 g of methyl 1-benzyl-2-phenylimidazole-5-acetate, and 20 ml of fuming nitric acid (specific gravity of 1.52) was added to the solution, followed by stirring at room temperature for 2 hours. The reaction solution was poured into 1 l of ice water, neutralized with sodium bicarbonate, and extracted with three 100 ml portions of ethyl acetate. The ethyl acetate layers were combined and evaporated to dryness under reduced pressure, followed by chromatographing on a column of 50 g of silica gel to thereby elute with benzene-ethyl acetate (1:1). The fractions of the objective compound were collected and evaporated to dryness under reduced pressure, yielding 1.25 g of methyl 1-(4-nitrobenzyl)-2-phenylimidazole-5-acetate as colorless crystals. Recrystallization of a part of the compound from benzene-hexane afforded the crystals, m.p. 113°-116° C.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[O:25][CH2:26][CH2:27][S:28][CH3:29])(=[O:5])[CH2:2][CH2:3][CH3:4].[OH2:30].Cl[O-].[Na+]>C(Cl)Cl>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[O:25][CH2:26][CH2:27][S:28]([CH3:29])=[O:30])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(OCCSC)cccc2c1Nc1c(C)cccc1Cl
Reactant: O
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: CCCC(=O)c1cnc2c(OCCS(C)=O)cccc2c1Nc1c(C)cccc1Cl
Reaction time: 3 h
Yield: 27 %

Procedure:
3-butyryl-4-(2-methyl,6-chlorophenylamino )-8-(2-methylthioethoxy)quinoline (0.35 g, 0.82 mmol) was dissolved in methylene chloride (4 ml). Water (2 ml) and sodium hypochlorite (5% in water) (1.7 ml) were added and the mixture was stirred for 3 h. The organic layer was dried over sodium sulfate and evaporated. The residue crystallized from ethyl acetate and 0.10 g (27%) of the title compound was obtained.