Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:5]1[C:9](=[CH:10][C:11]#[C:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:8](=[O:20])[CH2:7][CH:6]1O)[CH2:2][CH2:3][CH3:4]>C(O)(=O)C.O1CCCC1.O>[CH2:1]([CH:5]1[C:9](=[CH:10][C:11]#[C:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:8](=[O:20])[CH:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1C(=CC#CCCCC(=O)OC)C(=O)CC1O
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CCCCC1C=CC(=O)C1=CC#CCCCC(=O)OC
Temperature: 50 °C
Reaction time: 18 h
Yield: 47 %

Procedure:
29 mg (0.1 mmole) of 4-butyl-5-(6-methoxycarbonyl-2-hexynylidene)-3-hydroxycyclopentanone was dissolved in a mixture of 1 ml of acetic acid, 0.5 ml of tetrahydrofuran and 0.5 ml of water and the solution was stirred at 50° C. for 18 hours in the same way as in Example 1. The reaction mixture was worked up and separated in the same way as in Example 7 to give 13 mg (0.047 mmole; 47% yield) of 4-butyl-5-(6-methoxycarbonyl-2-hexynylidene)-2-cyclopentenone. The resulting compound had the following spectral data.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:19]=[C:12]2[C:13]([Cl:18])=[CH:14][CH:15]=[C:16](Cl)[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].[C:23](O)(=[O:25])C>CO>[CH2:1]([S:8][C:9]1[N:19]=[C:12]2[C:13]([Cl:18])=[CH:14][CH:15]=[C:16]([O:25][CH3:23])[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc(Cl)n2nc(SCc3ccccc3)nc12
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(Cl)c2nc(SCc3ccccc3)nn12

Procedure:
2-Benzylthio-5,8-dichloro[1,2,4]triazolo[1,5-a]pyridine (6.0 g, 0.019 mol) and 25 percent sodium methoxide in methanol (26.5 mL, 6.3 g, 0.116 mol) were combined in methanol and the mixture was heated to reflux for 2 hours. The mixture was then cooled, acidified with acetic acid, and concentrated by evaporation under reduced pressure. The residue was dissolved in dichloromethane and the solution was washed with water and concentrated by evaporation under reduced pressure The residue was triturated with hexane and the resulting solids were collected by filtration and dried to obtain 5.76 g (99 percent of theory) of the title compound as a light tan powder melting at 90°-91° C.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:15]([OH:17])=[O:16])[CH2:13][OH:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[F:18][C:19]1[C:24](O)=[C:23]([F:26])[C:22]([F:27])=[C:21]([F:28])[C:20]=1[F:29].C1CCC(N=C=NC2CCCCC2)CC1.O>CN(C=O)C>[F:18][C:19]1[C:24]([O:16][C:15](=[O:17])[C@H:12]([CH2:13][OH:14])[NH:11][C:1]([O:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:2])=[C:23]([F:26])[C:22]([F:27])=[C:21]([F:28])[C:20]=1[F:29]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: O=C(N[C@@H](CO)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(N[C@@H](CO)C(=O)Oc1c(F)c(F)c(F)c(F)c1F)OCc1ccccc1
Temperature: -10 °C
Reaction time: 3 h
Yield: 76.8 %

Procedure:
A mixture of N-Cbz-L-serine (Novabiochem) (100 g, 0.42 mol) and pentafluorophenol (Aldrich) (84.7 g, 0.46 mol) in anhydrous DMF (250 ml) are cooled with stirring under nitrogen to -10° C. To this solution, a solution of DCC (95.0 g, 0.46 mol) in anhydrous DMF (125 ml) is added over 30 min while keeping the reaction temperature at -10° C. The reaction mixture is stirred at -10 to -5° C. for an additional 30 min and then at room temperature for 3 hours. The reaction mixture is poured into water (3.76 L). After stirring for 15 min, the solid that precipitated out is filtered, washed over the filter with water (3×500 ml) and air dried at room temperature. The solid is then taken up in EtOAc (1 L) and the residual solid (mainly dicyclohexylurea) is filtered off and washed with more EtOAc (3×150 ml). The combined EtOAc solutions are evaporated to dryness under reduced pressure. The residual solid is dissolved in hot CH2Cl2 (3.2 L). The hot solution is gravity filtered and the solvent is boiled off until solid began to crystallize. The solid which crystallized is filtered and air dried to ambient temperature to give N-Cbz-L-serine pentafluorophenyl ester (130.8 g, 77% yield) as a white solid.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N+:17]([O-:19])=[O:18])=[CH:14][CH:15]=2)[C:10]([CH2:20]Br)=[N:9]1)=O)(C)(C)C.[C:22]1(=[O:32])[NH:26][C:25](=[O:27])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12.[K].CCOC(C)=O.CCCCCC>CN(C=O)C.C(Cl)Cl.C(O)(C(F)(F)F)=O>[N+:17]([C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[NH:8][N:9]=[C:10]2[CH2:20][N:26]1[C:22](=[O:32])[C:23]2[C:24](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:25]1=[O:27])([O-:19])=[O:18]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2cc([N+](=O)[O-])ccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCCCCC
Product: O=C1c2ccccc2C(=O)N1Cc1n[nH]c2ccc([N+](=O)[O-])cc12

Procedure:
3-Bromomethyl-5-nitro-indazole-1-carboxylic acid tert-butyl ester (0.63 g, 1.77 mmol) and potassium phthalimide (0.396 g, 1.2 eq) were stirred in DMF (1 mL) at 80° C. for two hours. TLC (20% EtOAc/hexane) showed starting material consumed and new products formed. After DMF was evaporated, a residue, 1.33 g, was obtained. The resulting residue was stirred in DCM and filtered. The filtration cake then washed with DCM followed by hexane. The evaporation of the filtrate gave 0.79 g of crude. Flash chromatograph (20-30% EtOAc/hexane) gave a mixture, two spots shown on TLC. During the sample preparation, solid precipitated and the solid was collected, 95 mg. MS showed de-Boc product, (M+H)+ at 323. An adequate amount of this mixture was treated with TFA in DCM for two hours. TLC showed one spot and MS gave (M+H)+ at 323. The remaining mixture was stirred in a mixture of TFA (6 mL) and DCM (10 mL) for two hours. Evaporation of TFA and DCM gave the desired product, 0.71 g, (quant. yield).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:22])[NH:6][CH:7]1[CH2:11][C:10](=[O:12])[O:9][CH:8]1[O:13][CH2:14][CH2:15]C1C=CC=CC=1)[CH:2]=[CH2:3].[CH:23](O)(C)C>>[CH2:1]([O:4][C:5](=[O:22])[NH:6][CH:7]1[CH2:11][C:10](=[O:12])[O:9][CH:8]1[O:13][CH:14]([CH3:15])[CH3:23])[CH:2]=[CH2:3]
Reactant: CC(C)O
Reactant: C=CCOC(=O)NC1CC(=O)OC1OCCc1ccccc1
Product: C=CCOC(=O)NC1CC(=O)OC1OC(C)C
Yield: 81 %

Procedure:
Prepared as described for compound 40 using isopropanol to afford 3.80 grams (81% yield) of the title compound as a colorless oil. 1H-NMR (500 MHz, CDCl3) δ 1.10-1.35 (m, 6H), 2.32-2.60 (m, 1H), 2.82 (dd, 0.5H), 3.02 (dd, 0.5H), 3.82-4.11 (m, 1H), 4.48-4.66 (m, 3H), 5.20-5.36 (m, 2H), 5.54 (dd, 1H), 5.82-6.05 (m, 1H). LC-MS (ES+): m/e=244.2 (M+H+).
Reaction SMILES: [C:1]([OH:5])(C)([CH3:3])[CH3:2].[Cl:6][C:7]1[C:12](CC#C)=[C:11](Cl)[N:10]=[C:9]([NH2:17])[N:8]=1.[OH-].[Na+]>O>[Cl:6][C:7]1[C:12]2[CH:2]=[C:1]([CH3:3])[O:5][C:11]=2[N:10]=[C:9]([NH2:17])[N:8]=1
Reactant: C#CCc1c(Cl)nc(N)nc1Cl
Reactant: CC(C)(C)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc2c(Cl)nc(N)nc2o1

Procedure:
To a mixture of 80 ml t-butanol and 60 ml water was added 6.0 g of 4,6-dichloro-5-(2-propynyl)-2-pyrimidinamine followed by 30 ml of 2N sodium hydroxide. After heating to reflux (ca 70°) for 20 hours, the mixture was cooled and the solid product was collected by filtration. The yield of product was 1.8 g, m.p. 255°-257°. An NMR (60 MHz) spectrum in trifluoroacetic acid solution exhibited absorptions at 2.8 (doublet) and 6.6 (triplet) ppm in a 3 to 1 ratio indicating the title compound.
Reaction SMILES: [Br:1][CH:2]1[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]([NH:7][C:8](=[O:9])[CH:3]12)=[O:6].N1C=CC=CC=1.[Cl:20][C:21]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:22]=1[C:23](Cl)=[O:24]>C1C=CC=CC=1>[Cl:20][C:21]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:22]=1[C:23]([N:7]1[C:8](=[O:9])[CH:3]2[CH:2]([Br:1])[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]1=[O:6])=[O:24]
Reactant: O=C1NC(=O)C2C1CCC(Br)C2Br
Reactant: O=C(Cl)c1cc(Cl)ccc1Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: O=C(c1cc(Cl)ccc1Cl)N1C(=O)C2CCC(Br)C(Br)C2C1=O
Temperature: 25 °C

Procedure:
3,4-Dibromohexahydrophthalimide (0.10 mole), benzene (300 ml) and pyridine (0.11 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,5-Dichlorobenzoyl chloride (0.10 mole) is then added dropwise to the flask with stirring at room temperature. After the addition is completed the reaction mixture is heated at reflux with continued stirring for a period of about 1 hour. After this time the reaction mixture is filtered and the filtrate is washed with water. The washed filtrate is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(2,5-dichlorobenzoyl)-3,4-dibromohexahydrophthalimide.
Reaction SMILES: [CH:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[N:17][C:18]4[N:19]([N:30]=[CH:31][C:32]=4[C:33](O)=[O:34])[C:20]=3[NH:21][C:22]3[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=3[CH3:29])=[O:14])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:36]([S:38]([NH2:41])(=[O:40])=[O:39])[CH3:37]>>[CH:1]1([CH:7]2[CH2:8][CH2:9][N:10]([C:13]([C:15]3[CH:16]=[N:17][C:18]4[N:19]([N:30]=[CH:31][C:32]=4[C:33]([NH:41][S:38]([CH2:36][CH3:37])(=[O:40])=[O:39])=[O:34])[C:20]=3[NH:21][C:22]3[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=3[CH3:29])=[O:14])[CH2:11][CH2:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1ccc(C)c(Nc2c(C(=O)N3CCC(C4CCCCC4)CC3)cnc3c(C(=O)O)cnn23)c1
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cc(C)ccc3C)c(C(=O)N3CCC(C4CCCCC4)CC3)cnc12
Yield: 55.1 %

Procedure:
In the same manner as in Example 1, step 6 and using 6-(4-cyclohexylpiperidine-1-carbonyl)-7-(2,5-dimethylphenylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (75 mg, 0.16 mmol) obtained in step 2 and ethanesulfonamide (84 mg, 0.80 mmol), the title compound (50 mg, 55%) was obtained.
Reaction SMILES: [N+](C1C=C(C2[NH:14][C:13]3[CH:15]=[CH:16][C:17]([C:19](N)=[O:20])=[CH:18][C:12]=3N=2)C=CC=1)([O-])=O.NC1C=CC(C=O)=CC=1.N1C=CC=CC=1.[Cl:37][C:38]1[CH:39]=[C:40]([S:45](Cl)(=[O:47])=[O:46])[CH:41]=[CH:42][C:43]=1[Cl:44]>C(Cl)Cl>[Cl:37][C:38]1[CH:39]=[C:40]([S:45]([NH:14][C:13]2[CH:12]=[CH:18][C:17]([CH:19]=[O:20])=[CH:16][CH:15]=2)(=[O:46])=[O:47])[CH:41]=[CH:42][C:43]=1[Cl:44]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: NC(=O)c1ccc2[nH]c(-c3cccc([N+](=O)[O-])c3)nc2c1
Agent: Nc1ccc(C=O)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=Cc1ccc(NS(=O)(=O)c2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
2-(3-Nitro-phenyl)-1H-benzoimidazole-5-carboxylic acid amide. To a flask containing crude 4-amino-benzaldehyde (100 mg, 0.82 mmol), pyridine (0.15 mL, 1.87 mmol) and CH2Cl2 (4 mL), was added 3,4-dichlorobenzenesulfonyl chloride (184 mg, 0.75 mmol). The mixture was stirred for 16 h at room temperature, and was then cooled and concentrated. The crude product was purified by silica gel flash chromatography (eluted with 5% methanol/CH2Cl2) to provide 179 mg (72%) of 3,4-dichloro-N-(4-formyl-phenyl)-benzenesulfonamide.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:7]=1)=[O:5])C.[Li+].[OH-].CO>O>[Cl:18][C:14]1[CH:13]=[C:12]([N:8]2[C:9](=[O:11])[NH:10][C:6]([C:4]([OH:5])=[O:3])=[N:7]2)[CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1nn(-c2cccc(Cl)c2)c(=O)[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1nn(-c2cccc(Cl)c2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
A mixture of 1-(3-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylic acid ethyl ester (200.0 mg, 747 mmol), LiOH (71.6 mg, 1.5 mmol) in water (2 mL), and MeOH (10.0 mL, 247 mmol) was stirred at room temperature overnight then concentrated. The residue was acidified with 1N HCl to pH 3-4, forming a precipitate, which was filtered, washed with water (2×5 mL), and dried in vacuo to yield the title compound (100.6 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=[C:9]2[S:16][CH2:17][C:18]2[C:23]([F:24])=[CH:22][CH:21]=[C:20]([F:25])[C:19]=2[F:26])=[CH:4][CH:3]=1.C([O-])(O)=[O:28].[Na+].OOS([O-])=O.[K+].O>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=[C:9]2[S:16]([CH2:17][C:18]2[C:23]([F:24])=[CH:22][CH:21]=[C:20]([F:25])[C:19]=2[F:26])=[O:28])=[CH:4][CH:3]=1
Reactant: O=C([O-])O
Reactant: O=C(O)c1cnc(SCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Agent: O=S([O-])OO
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)c1cnc(S(=O)Cc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1-(4-fluorophenyl)-2-((2,3,6-trifluorobenzyl)thio)-1H-imidazole-5-carboxylic acid (11) (261 mg, 0.68 mmol) in acetone (7 mL) was added 0.2 M NaHCO3 (7 mL) and Oxone (1.05 g, 1.71 mmol) and stirred at room temperature for 2 h. Water was added and the mixture was extracted with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated in vacuo to obtain 1-(4-fluorophenyl)-2-((2,3,6-trifluorobenzyl)sulfinyl)-1H-imidazole-5-carboxylic acid (20) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([Cl:12])=[CH:9][CH:10]=[O:11])=[CH:4][CH:3]=1.[CH3:13][Mg]Br.[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([Cl:12])=[CH:9][CH:10]([OH:11])[CH3:13])=[CH:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: O=CC=C(Cl)c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)C=C(Cl)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
To a cooled (-78° C.) solution of 3-(4-chlorophenyl)-3-chloroacrolein (2.0 g, 10.4 mmol, obtained according to Hauptmann et al, Tetrahedron Lett. 1968, 1317) in dry THF (30 mL) was added dropwise a 3M solution of methylmagnesium bromide in THF (3.47 mL, 10.4 mmol). After the addition was complete, the reaction mixture was stirred at -78° C. for 0.5 h. Next, saturated aqueous NH4Cl solution was added and the mixture was concentrated. The resulting aqueous residue was extracted with CHCl3, dried, filtered, concentrated and purified by flash chromatography to give 4-(4-chlorophenyl)-4-chloro-3-buten-2-ol (1.54 g, 71%) as a colourless oil: 1H NMR (300 MHz, CDCl3) δ (TMS) 7.51 (dt, Jt =2.6, Jd =8.6, 2H, arom), 7.33 (dt, Jt =2.6, Jd =8.6, 2H, arom), 6.18 (d, J=7.5, 1H, =CH), 4.93 (quint, J=6.4, 1H, CHOH), 1.39 (d, J=6.4, 3H, CHCH3).
Reaction SMILES: Cl.C[O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].C(N(CC)CC)C.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[BH4-].[Na+].[OH-].[Na+].Cl>O.CO>[CH2:17]([NH:6][C@H:5]([C:4]([OH:3])=[O:9])[CH2:7][OH:8])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(O)[C@H](CO)NCc1ccccc1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
To a reaction vessel was added solid serine methyl ester hydrochloride (1 eq). Methanol (2.85 vol) was added and agitation was started. Triethylamine (1 eq) was added over 10 min while maintaining the temperature at 14˜18° C. Stirring was continued until all solids dissolved. The mixture was cooled to 10° C. and benzaldehyde (1 eq) was added over 15 min while maintaining the temperature between 11˜15° C. The reaction was held for 30 min at 8˜12° C. Solid sodium borohydride (4 eq) was added over 2 hr while maintaining the temperature at 10˜20° C. The reaction was held for 30 min at 14˜16° C. In a separate flask, methanol (1.15 vol) and water (1.72 vol) were added. Sodium hydroxide, 50 wt/wt % in water (3 eq) was added and the resulting solution was cooled to 15° C. The Schiff's base was transferred to this mixture over 1 hr maintaining the internal temperature between 16˜22° C. Water was added (1.72 vol), followed by concentrated HCl, 12.2 M in water (2.67 eq) while maintaining the temperature at 15˜25° C. to adjust the pH to 9.5. The mixture was filtered and the filter-cake was washed with two portions of water (0.58 vol). The combined aqueous portions were washed two times with ethyl acetate (5.75 vol). The mixture was cooled from 25° C. to 15° C., and concentrated HCl was added, 12.2 M in water (0.89 eq), until the pH of the mixture reached 6.5, while maintaining the temperature between 17–22° C. The mixture was held for 15˜25 hr at 5° C. and then the solids were collected on a filter funnel. The filter-cake was washed with two portions of water (1.43 vol) and two portions of heptane (1.43 vol). The wet solid was transferred to a drying tray, and dried at 45° C. for 21 h to afford the product.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[C:8]1([CH3:16])[C:9]([CH:14]=O)=[CH:10][CH:11]=[CH:12][CH:13]=1.Cl>C(O)C>[CH3:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH:16]=[C:3]1[C:4](=[O:7])[C:5](=[CH:16][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])[CH2:6][S:1][CH2:2]1
Reactant: O=C1CCSCC1
Reactant: Cc1ccccc1C=O
Agent: Cl
Solvent: CCO
Product: Cc1ccccc1C=C1CSCC(=Cc2ccccc2C)C1=O
Yield: 87.8 %

Procedure:
Tetrahydro-4H-thiopyran-4-one (9.3 g, 0.08 mole) and o-tolualdehyde (25 g, 0.20 mole) are dissolved in 60 ml of ethanol and treated with concentrated hydrochloric acid (6 ml). After heating at reflux temperature for 4 hours, the mixture is cooled and product is collected by filtration. The combined filtrate and washings (ethanol) are concentrated to the original volume and additional concentrated hydrochloric acid (4 ml) is added and the mixture is refluxed for 4 hours. This procedure is repeated 3 times. The combined crude material (23 g) is recrystallized from chloroform/ethanol/H2O to give 22.5 g (88%) of product, m.p. 123°-125°.
Reaction SMILES: [C:1]([CH:4]1[C:9](=[O:10])[CH2:8][CH:7]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[CH2:6][C:5]1=O)(=O)[CH3:2].[NH2:17][C:18]1[N:27]=C(C)C2C(=O)CC(C3C=CC(F)=CC=3)CC=2[N:19]=1>>[NH2:27][C:18]1[N:19]=[C:1]([CH3:2])[C:4]2[C:9](=[O:10])[CH2:8][CH:7]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[CH2:6][C:5]=2[N:17]=1
Reactant: Cc1nc(N)nc2c1C(=O)CC(c1ccc(F)cc1)C2
Reactant: CC(=O)C1C(=O)CC(c2ccco2)CC1=O
Product: Cc1nc(N)nc2c1C(=O)CC(c1ccco1)C2

Procedure:
The title compound was prepared from 2-acetyl-5-furan-2-yl-cyclohexane-1,3-dione (321 mg, 1.46 mmol), from stage 1, following the procedure describing the synthesis of 2-amino-7-(4-fluoro-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one (example 3/a stage 2/3).
Reaction SMILES: CO[C:3](=[O:15])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:13]Br.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N1C=CC=CC=1>C(O)C>[N+:10]([C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[C:3](=[O:15])[N:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:13]2)([O-:12])=[O:11]
Reactant: Nc1ccccc1
Reactant: COC(=O)c1c(CBr)cccc1[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: CCO
Product: O=C1c2c(cccc2[N+](=O)[O-])CN1c1ccccc1
Temperature: 25 °C
Yield: 62 %

Procedure:
A solution of 2-bromomethyl-6-nitro-benzoic acid methyl ester (0.40 g, 1.46 mmol) and aniline (0.23 g, 2.44 mmol) in ethanol (20 ml) was added with pyridine (0.15 g, 1.95 mmol), and the mixture was refluxed by heating for 30 hours. The reaction solution was cooled to room temperature, and then poured into ice water, and the deposited crystals were collected by filtration, washed with ethanol and water, and dried. The resulting crystals were recrystallized (acetone) to obtain 7-nitro-2-phenyl-2,3-dihydro-isoindol-1-one as pale yellow crystals (0.23 g, yield: 62.9%).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[CH:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:24])=[O:23])=[CH:18][CH:17]=2)[C:4]2[C:9]([C:10]=1[CH2:11][C:12]([OH:14])=[O:13])=[CH:8][CH:7]=[CH:6][CH:5]=2.[F:25]C(Cl)(Cl)Cl.FOC(F)(F)F>>[F:25][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[C:3](=[CH:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([CH3:24])=[O:23])=[CH:18][CH:17]=1)[C:2]([CH3:1])=[C:10]2[CH2:11][C:12]([OH:14])=[O:13]
Reactant: CC1=C(CC(=O)O)c2ccccc2C1=Cc1ccc(S(C)=O)cc1
Reactant: FC(Cl)(Cl)Cl
Agent: FOC(F)(F)F
Product: CC1=C(CC(=O)O)c2cc(F)ccc2C1=Cc1ccc(S(C)=O)cc1
Temperature: -15 °C
Reaction time: 1.33 h

Procedure:
2-Methyl-1-(p-methylsulfinylbenzylidene)inden-3-acetic acid (2.25 g.) dissolved in 80 ml. of fluorotrichloromethane was ultraviolet irradiated and stirred at -15° C. for 80 min.; meanwhile 1.2 g. of fluoroxytrifluoromethane was passed in. The residue obtained after evaporation of the solvent was subjected to chromatography on a silica gel column, to give 5-fluoro-2-methyl-1-(p-methylsulfinylbenzylidene)inden-3-acetic acid, m.p. 188°-189° C.
Reaction SMILES: C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[N+:47]([C:50]1[CH:55]=[CH:54][C:53](I)=[CH:52][CH:51]=1)([O-:49])=[O:48].Cl.[CH2:58]([O:65][C:66]1[CH:72]=[CH:71][C:69]([NH2:70])=[CH:68][CH:67]=1)[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC([O-])=O.CC([O-])=O.[Pd+2].O.C1(C)C=CC=CC=1>[CH2:58]([O:65][C:66]1[CH:67]=[CH:68][C:69]([NH:70][C:53]2[CH:54]=[CH:55][C:50]([N+:47]([O-:49])=[O:48])=[CH:51][CH:52]=2)=[CH:71][CH:72]=1)[C:59]1[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: O=[N+]([O-])c1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: O=[N+]([O-])c1ccc(Nc2ccc(OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 31.2 %

Procedure:
To a oven dried flask was charged with Pd(OAc)2 (81 mg, 0.36 mmol) and (S)-(−)-BINAP (336 mg, 0.54 mmol), followed by toluene (10 mL). The mixture was stirred under Ar at room temperature for 5 min. To this mixture was added 4-nitroiodobenzene (3.0 g, 12 mmol), 4-benzyloxyaniline hydrochloride (3.39 g, 14.4 mmol), Cs2CO3 (9.8 g, 30 mmol) and toluene (40 mL). The resulting mixture was heated under Ar at 100° C. for 16 hrs, and then cooled to room temperature and poured into H2O (100 mL). The layers were separated. The aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (2×20 mL), dried (MgSO4) and filtered. The filtrate was concentrated. The residue was purified via column chromatography (silica gel, 5-40% EtOAc/hexane) to give the desired product as an orange solid (1.2 g, 31%). 1H NMR (CDCl3, 400 MHz) δ: 8.09 (d, J=9.2 Hz, 2H), 7.30-7.49 (m, 5H), 7.15 (d, J=9.2 Hz, 2H), 7.01 (d, J=9.2 Hz, 2H), 6.77 (d, J=8.8 Hz, 2H), 6.10 (br s, 1H), 5.09 (s, 2H). MS: m/z=321 (M+H+)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[CH2:15][CH:14]([CH2:16][N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[O:13][C:5]2=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[C:28](Cl)=[O:29]>N1C=CC=CC=1>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[C:28]([N:20]1[CH2:21][CH2:22][N:17]([CH2:16][CH:14]2[O:13][C:5]3=[C:6]4[C:11](=[C:2]([CH3:1])[CH:3]=[C:4]3[CH2:15]2)[NH:10][C:9](=[O:12])[CH2:8][CH2:7]4)[CH2:18][CH2:19]1)=[O:29]
Reactant: Cc1cc2c(c3c1NC(=O)CC3)OC(CN1CCNCC1)C2
Reactant: COc1ccc(C(=O)Cl)cc1OC
Solvent: c1ccncc1
Product: COc1ccc(C(=O)N2CCN(CC3Cc4cc(C)c5c(c4O3)CCC(=O)N5)CC2)cc1OC
Reaction time: 1 h
Yield: 95 %

Procedure:
To a solution of 5-methyl-2-(1-piperazinomethyl)-2,3,6,7,8,9-hexahydrofuro-[2,3-f]quinoline-7-one (1.474 g) in pyridine (40 ml), a solution of 3,4-dimethoxybenzoyl chloride (1.003 g) in pyridine (20 ml) was added dropwise while cooling on ice. Subsequently, stirring was continued at room temperature for 1 hour. The solvent was distilled off under reduced pressure. The residue was combined with water, and extracted with chloroform. The extract was washed with sodium bicarbonate water and water in this order, and dried and concentrated. The residue was crystallized from chloroform--n-hexane to obtain 2.163 g of a free base of the title compound as colorless prisms (mp. 190°-191° C.).