Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N+:10]([CH3:14])=[C:9]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[N:8]=[C:7]2SC.[I-].[F:24][C:25]1[CH:26]=[CH:27][C:28]2[S:32][C:31]([CH3:33])=[N+:30]([CH3:34])[C:29]=2[CH:35]=1.C(N(CC)CC)C>CN(C)C=O>[I-:1].[F:24][C:25]1[CH:26]=[CH:27][C:28]2[S:32][C:31]([CH:33]=[C:7]3[C:6]4[C:11](=[CH:12][CH:13]=[C:4]([O:3][CH3:2])[CH:5]=4)[N:10]([CH3:14])[C:9]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)=[N:8]3)=[N+:30]([CH3:34])[C:29]=2[CH:35]=1
Reactant: COc1ccc2c(c1)c(SC)nc(-c1ccccc1)[n+]2C
Reactant: Cc1sc2ccc(F)cc2[n+]1C
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C(=Cc1sc3ccc(F)cc3[n+]1C)N=C(c1ccccc1)N2C
Temperature: 80 °C
Reaction time: 1 h

Procedure:
600 mg (1.41 mmol) 6-Methoxy-1-methyl-4-methylsulfanyl-2-phenyl-quinazolin-1-ium iodide and 436 mg (1.41 mmol) 5-fluoro-2,3-dimethyl-benzothiazol-3-ium iodide were dissolved in 3.0 ml dimethylformamide and 571 mg (0.79 ml, 5.64 mmol) triethylamine were added. The solution was stirred for 1 h at 80° C., filtrated and the residue was washed with water and methanol.
Reaction SMILES: COC(=O)C[C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[NH:7][C:6]=1[Cl:16].C([Li])(CC)C.C1CCCCC1.CN(CN1C2C(=CC(OC)=CC=2)C=C1)C.C1(S(Cl)(=O)=O)C=CC=CC=1>C1COCC1>[Cl:16][C:6]1[NH:7][C:8]2[C:13]([CH:5]=1)=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2
Reactant: COC(=O)Cc1c(Cl)[nH]c2ccc(OC)cc12
Agent: COc1ccc2c(ccn2CN(C)C)c1
Agent: O=S(=O)(Cl)c1ccccc1
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: COc1ccc2[nH]c(Cl)cc2c1
Reaction time: 0.3 h
Yield: 29 %

Procedure:
2-Chloro-5-methoxy-1H-indole-3-acetic acid methyl ester. Cooling with a dry ice-ethanol bath, 20 mL (0.026 mol) of 1.3M sec-butyl lithium/cyclohexane was added to 5.1 g (0.025 mol) of 1-dimethylaminomethyl-5-methoxy-1H-indole in 100 mL of THF keeping the temperature below −50° C. The cooling bath was removed and the temperature allowed to reach 0° C. and the bath then replaced. At −60° C., 3.32 mL (0.026 mol) of benzenesulfonyl chloride in 10 mL of THF was added, stirred 0.3 hours, the bath removed, and the temperature allowed to reach 20° C. over 1 hour. To this mixture was added 100 mL of 1N HCl and 50 mL of EtOAc and the mixture stirred for 20 hours. After making basic with 5N NaOH, the EtOAc layer was separated, washed with water, dried (Na2SO4), and concentrated at reduced pressure. The residue was chromatographed on silica eluting with toluene to give 1.37 g (29% yield) of crude 2-chloro-5-methoxy-1H-indole. To this material (7.55 mmol) in 30 mL of THF was added 4.7 mL (7.55 mmol) of 1.6M n-butyl lithium/hexane keeping the temperature below 10° C. with an ethanol-ice bath. After 0.25 h, 7.55 mL (7.55 mmol) of 1M ZnCl2/ether was added, stirred 2 hours, concentrated at reduced pressure, and 40 mL of toluene added followed by 0.72 mL (7.55 mmol) of methyl 2-bromoacetate. The mixture was stirred for 16 hours, warmed at 76° C. for 4 h, cooled, and 50 mL of 1N HCl and 40 mL of EtOAc added. After 0.5 hour, the organic layer was separated, dried(Na2SO4), and concentrated at reduced pressure. The residue was chromatographed on silica and eluted with a solvent gradient (toluene→20% EtOAc/toluene) to give 0.79 g (41% yield) of 2-chloro-5-methoxy-1H-indole-3-acetic acid methyl ester, as an oil.
Reaction SMILES: Cl[S:2]([OH:5])(=O)=[O:3].[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2.P(Cl)(Cl)(Cl)(Cl)Cl.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:24]1([NH:23][S:2]([NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:16]=2[N:15]=[CH:14][CH:13]=[CH:12]3)(=[O:5])=[O:3])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=S(=O)(O)Cl
Reactant: Nc1ccccc1
Reactant: Nc1cccc2cccnc12
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(Nc1ccccc1)Nc1cccc2cccnc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 11.2 %

Procedure:
Chlorosulfonic acid (260 mg, 2.2 mmol) in DCM was added to a solution of 8-aminoquinoline (300 mg, 2.08 mmol) and TEA (310 mg, 3.12 mmol) in dry DCM (10 ml) at 0° C. and the mixture was stirred for 30 min. The reaction was allowed to warm to room temperature and stirring was continued for 1 h. PCl5 (460 mg, 2.20 mmol) was added to the reaction and the mixture was heated under reflux for 1 h, then allowed to cool to room temperature. Aniline (770 mg, 8.3 mmol) and DIPEA (0.72 ml, 4.16 mmol) were added and the reaction stirred at room temperature for 2.5 h. The reaction was quenched with water and extracted with DCM. The organic phase was washed with water, brine, dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography with DCM as the eluent to give the title compound (70 mg, 11%).
Reaction SMILES: CS(C)=O.[CH3:5][C:6]1[CH:7]=[C:8]([OH:20])[C:9]([C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:10][C:11]=1[CH3:12].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C1C=CN=CC=1)C.O>[CH3:33][O:32][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][C:28]=1[O:34][CH3:35])[N:25]=[CH:24][CH:23]=[C:22]2[O:20][C:8]1[C:9]([C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:10][C:11]([CH3:12])=[C:6]([CH3:5])[CH:7]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cc1cc(O)c(-c2ncccc2C)nc1C
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2nccc(Oc3cc(C)c(C)nc3-c3ncccc3C)c2cc1OC
Temperature: 140 °C
Reaction time: 8 h
Yield: 51.6 %

Procedure:
Dimethyl sulfoxide (1.4 ml) was added to 5,6,3′-trimethyl-[2,2′]bipyridin-3-ol (30 mg), 4-chloro-6,7-dimethoxyquinoline (94 mg), cesium carbonate (137 mg), and 4-(N,N-dimethylamino)-pyridine (51 mg), and the mixture was stirred at 140° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using hexane-acetone to give the title compound (29 mg, yield 52%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.Cl[C:25]1[N:30]=[CH:29][C:28]([CH2:31][CH3:32])=[CH:27][N:26]=1.O>CN(C=O)C>[CH2:31]([C:28]1[CH:27]=[N:26][C:25]([N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]2)=[N:30][CH:29]=1)[CH3:32]
Reactant: CCc1cnc(Cl)nc1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cnc(N2CCC(NC(=O)OC(C)(C)C)CC2)nc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 40 %

Procedure:
To a solution of tert-butyl piperidin-4-ylcarbamate (5.0 g, 25 mmol) and DIEA (13.0 mL, 74.9 mmol) in DMF (50 mL) was added 2-chloro-5-ethylpyrimidine (4.3 g, 30 mmol). This mixture stirred at 100° C. for 18 hours in a sealed tube. The mixture was poured into water (500 mL) and extracted into EtOAc (3×100 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified over silica gel (100% EtOAc) to yield tert-butyl 1-(5-ethylpyrimidin-2-yl)piperidin-4-ylcarbamate (3.2 g, 10 mmol, 42%).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:11][C:10]2[C:5](=[C:6]([Cl:14])[C:7]([Cl:13])=[C:8]([OH:12])[CH:9]=2)[C:4]1=[O:15])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:23][C:24]#[N:25].[I-].[K+]>CC(C)=O>[O:15]=[C:4]1[C:5]2[C:10](=[CH:9][C:8]([O:12][CH2:23][C:24]#[N:25])=[C:7]([Cl:13])[C:6]=2[Cl:14])[CH2:11][CH:3]1[CH2:1][CH3:2]
Reactant: CCC1Cc2cc(O)c(Cl)c(Cl)c2C1=O
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC1Cc2cc(OCC#N)c(Cl)c(Cl)c2C1=O

Procedure:
A mixture of 2-ethyl-5-hydroxy-6,7-dichloroindanone (24.5 g., 0.1 mole), anhydrous potassium carbonate (13.8 g., 0.10 mole), chloroacetonitrile (7.55 g., 0.10 mole) and potassium iodide (1.66 g.) in acetone (0.5 1.) is refluxed for 18 hours. The product which precipitates upon addition of water to the reaction mixture (20 g., 71%) melts at 139°-141° C. after recrystallization from butyl chloride.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:18]([NH2:21])(=[O:20])[CH3:19]>>[C:18]([NH:21][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])(=[O:20])[CH3:19]
Reactant: CC(N)=O
Reactant: COC(=O)c1cc(Br)cc(N2CCCC2=O)c1
Product: COC(=O)c1cc(NC(C)=O)cc(N2CCCC2=O)c1

Procedure:
D12 was prepared as for E1, from methyl 3-bromo-5-(2-oxopyrrolidin-1-yl)benzoate and acetamide.
Reaction SMILES: [Cl-].[NH4+].CO.[N+:5]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)([O-])=O>O.C1COCC1.[Zn]>[N:14]1([C:11]2[CH:10]=[CH:9][C:8]([NH2:5])=[CH:13][CH:12]=2)[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77.1 %

Procedure:
Ammonium chloride (1.2 g, 23.0 mmol) in water (4.5 mL) then MeOH (9 mL) were added to a stirred solution of 4-(4-nitro-phenyl)-morpholine (480 mg, 2.3 mmol) in THF (9 mL). Zinc powder (1.2 g, 18.4 mmol) was then added portion wise and the resulting mixture was stirred at room temperature for 15 minutes. The reaction mixture was filtered over celite and the filtrate was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated to afford 316 mg (77%) of 4-morpholin-4-yl-phenylamine. 1H NMR: (DMSO-d6): δ 6.7 (m, 2H), 6.5 (m, 2H), 4.6 (s, 2H), 3.7 (t, 4H), 2.8 (t, 4H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([Br:19])[C:3]=1[S:20][CH3:21].S(OOS([O-])(=O)=O)(O)(=O)=[O:23].[K+].O.S(=O)(O)[O-].[Na+]>CO>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:15])[F:16])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([Br:19])[C:3]=1[S:20]([CH3:21])=[O:23]
Reactant: O=S(=O)([O-])OOS(=O)(=O)O
Reactant: CSc1c(Br)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CS(=O)c1c(Br)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 43.4 %

Procedure:
A solution of 5-amino-3-bromo-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-methylthiopyrazole (2.0 g) [preparation described in Example 15] in methanol (45 ml) at -25° C. was treated with a rapidly added solution of potassium hydrogen persulphate (1.66 g), followed immediately by the addition of water (22 ml). The mixture was stirred for 30 minutes at 0° C., and potassium hydrogen persulphate (0.4 g) added. After 21/2 hours stirring at room temperature, the mixture was poured onto water (300 ml) and saturated sodium bisulphite solution (35 ml) added. This was extracted with dichloromethane (2×150 ml) and the extract washed with water (2×50 ml), dried over anhydrous magnesium sulphate, and evaporated in vacuo. The crude product was purified by chromatography eluting with dichloromethane/ethyl acetate (4:1) to give 5-amino-3-bromo-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-methylsulphinylpyrazole (0.9 g) as a white solid, m.p. 135°-136° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]2[O:12][CH2:11][O:10][C:9]=12)[CH:5]=[O:6].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]2[O:12][CH2:11][O:10][C:9]=12)[CH:5]=[O:6]
Reactant: COc1ccccc1B(O)O
Reactant: O=Cc1cc(Br)c2c(c1)OCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccccc1-c1cc(C=O)cc2c1OCO2
Temperature: 25 °C
Yield: 32.4 %

Procedure:
A mixture of 3-bromo-4,5-methylenedioxybenzaldehyde (2.51 g, 10.97 mmol), 2-methoxyphenylboronic acid (2.00 g, 13.16 mmol) and potassium carbonate (3.41 g, 24.68 mmol) in 1,2-dimethoxyethane (70 mL) and water (3.5 mL) was degassed with argon for 30 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.63 g, 0.548 mmol) was added and the mixture heated at reflux under argon overnight. The solution was cooled to room temperature, diluted with ethyl acetate (100 mL) and washed successively with water (50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified on silica gel (eluent: hexane:ether, 9:1) to give 0.910 g of 3-(2-methoxyphenyl)-4,5-methylenedioxybenzaldehyde (32%) as a white solid. 1H NMR (300 MHz; CDCl3): δ 3.84 (s, 3H); 6.07 (s, 2H); 7.00–7.10 (m, 2H); 7.31 (brs, 1H); 7.30–7.45 (m, 2H); 7.53 (brs, 1H); 9.83 (s, 1H).
Reaction SMILES: [O:1]([C@@H:9]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:10]#[CH:11])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].C([Li])CCC.[Cl-].C([Al+]CC)C.C(N([CH2:34][C:35]1[C:36](=[O:48])[CH2:37][C@@H:38]([O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH:39]=1)CC)C>C1(C)C=CC=CC=1.CCCCCC>[CH2:34]=[C:35]1[C@@H:39]([C:11]#[C:10][C@@H:9]([O:1][Si:2]([C:5]([CH3:7])([CH3:8])[CH3:6])([CH3:4])[CH3:3])[CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)[C@H:38]([O:40][Si:41]([C:44]([CH3:46])([CH3:45])[CH3:47])([CH3:42])[CH3:43])[CH2:37][C:36]1=[O:48]
Reactant: C#C[C@@H](O[Si](C)(C)C(C)(C)C)C1CCCCC1
Reactant: CCN(CC)CC1=C[C@H](O[Si](C)(C)C(C)(C)C)CC1=O
Agent: CC[Al+]CC
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: C=C1C(=O)C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1C#C[C@@H](O[Si](C)(C)C(C)(C)C)C1CCCCC1
Reaction time: 0.5 h

Procedure:
(3S)-3-(tert-Butyldimethylsiloxy)-3-cyclohexylprop-1-yne (6.58 g) was dissolved in toluene (80 ml), and n-butyl lithium (3.0 M, hexane solution, 8.0 ml) was added at 0° C., followed by stirring at the same temperature for 30 minutes. To the solution was added diethylaluminum chloride (0.95 M, hexane solution 29.0 ml) at 0° C., followed by stirring until the solution reached room temperature for 30 minutes. To the solution was added (4R)-2-(N,N-diethylamino)methyl-4-(tert-butyldimethylsiloxy)-cyclopent-2-en-1-one (0.25 M, toluene solution, 80.0 ml) at room temperature, followed by stirring for 15 minutes. The reaction solution, while stirring, was added to a mixture of hexane (190 ml), a saturated aqueous ammonium chloride solution (190 ml) and an aqueous hydrochloric acid solution (3 M, 56 ml), and the organic layer was separated and washed with a saturated aqueous sodium bicarbonate solution (50 ml). The resulting organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified by silica gel column chromatography (developing solvent; hexane:ether=10:1) to give (3R,4R)-2-methylene-3-[(3S)-3-(tert-butyldimethylsiloxy)-3-cyclohexylprop-1-ynyl]-4-(tert-butyldimethylsiloxy)cyclopentan-1-one (7.92 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:20])=[C:11]([CH2:13][CH2:14][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[N:12]=2)=[CH:4][CH:3]=1.[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)(=[O:24])=[O:23]>>[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][C:10]([CH3:20])=[C:11]([CH2:13][CH2:14][N:15]4[CH2:19][CH2:18][CH2:17][CH2:16]4)[N:12]=3)=[CH:4][CH:3]=2)=[CH:27][CH:26]=1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCCC1
Product: Cc1oc(-c2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2)nc1CCN1CCCC1

Procedure:
Starting with 2-(4-Bromo-phenyl)-5-methyl-4-(2-pyrrolidin-1-yl-ethyl)-oxazole (See Example 8) and 4-methylsulfonylphenylboronic acid, follow a procedure significantly analogous to that found in Example 22 to give the titled compound. MS (m/e): 411.2 (M+1)
Reaction SMILES: [C:1]([C:3]1[C:8]([F:9])=[C:7]([F:10])[C:6]([OH:11])=[C:5]([F:12])[C:4]=1[F:13])#[N:2].[C:14](=[O:17])([O-])[O-].[Ca+2].Cl.[CH:20]1C=CC=C[CH:21]=1>>[C:14]([O:11][C:6]1[C:5]([F:12])=[C:4]([F:13])[C:3]([C:1]#[N:2])=[C:8]([F:9])[C:7]=1[F:10])(=[O:17])[CH:20]=[CH2:21]
Reactant: c1ccccc1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1c(F)c(F)c(O)c(F)c1F
Agent: Cl
Agent: [Ca+2]
Product: C=CC(=O)Oc1c(F)c(F)c(C#N)c(F)c1F
Yield: 57.1 %

Procedure:
In 30 ml of benzene, 3.82 g (0.020 mol) of 4-cyano-2,3,5,6-tetrafluorophenol and 2.26 g (0.025 mol) of calcium carbonate added thereto as a hydrogen chloride trapping agent were stirred under reflux for 40 hours. The resultant reaction mixture was cooled off and filtered to separate calcium carbonate. The filtrate was dried with magnesium sulfate and then evaporated to dryness with a rotary evaporator. Consequently, there was obtained 2.8 g of 4-cyano-2,3, 5,6-tetrafluorophenyl acrylate (yield 57.1%, purity 95.8%). The analyses obtained of the novel substance for the determination of its chemical structure were the same as those of Example 5.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O.[NH2:18][C:19]1[CH:31]=[C:30](/[CH:32]=[CH:33]/[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)Cl.CN(C)C=O>[CH3:7][C:8]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([NH:18][C:19]1[CH:31]=[C:30](/[CH:32]=[CH:33]/[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:12]
Reactant: COc1cccc(/C=C/c2ccc(C(=O)OC(C)(C)C)c(N)c2)c1
Reactant: Cc1cccc(C(=O)O)c1C
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cccc(/C=C/c2ccc(C(=O)OC(C)(C)C)c(NC(=O)c3cccc(C)c3C)c2)c1
Reaction time: 1 h

Procedure:
1.7 mL of methylene chloride, 1.0 μL of N,N-dimethylformamide and 0.025 mL of oxalyl chloride were added to 41 mg of 2,3-dimethylbenzoic acid at room temperature sequentially and stirred at the same temperature for 1 hour. The reaction mixture was added to a mixed solution of 52 mg of tert-butyl 2-amino-4-((E)-2-(3-methoxyphenyl)vinyl)benzoate, 2.8 mL of methylene chloride and 0.36 mL of triethylamine and stirred at room temperature for 1 hour. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane; ethyl acetate=4:1] to obtain tert-butyl 2-(2,3-dimethylbenzamido)-4-((E)-2-(3-methoxyphenyl)vinyl)benzoate.
Reaction SMILES: [OH-].[Na+].[NH2:3][CH:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[S:14].Cl[C:16]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][C:23]([N+]([O-])=O)=[CH:22][C:17]=1[C:18]([O:20]C)=[O:19]>C(O)C>[N+:26]([C:25]1[CH:24]=[C:23]2[C:22](=[C:17]([C:18]([OH:20])=[O:19])[CH:16]=1)[NH:3][C:4]1[CH:13]=[CH:12][C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]=1[S:14]2)([O-:28])=[O:27]
Reactant: NC1C=Cc2ccccc2C1=S
Reactant: COC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc([N+](=O)[O-])cc2c1Nc1ccc3ccccc3c1S2
Yield: 34.6 %

Procedure:
5 ml of a 2 N aqueous solution of sodium hydroxide was added to a solution of 1.7 g (9.73 mmol) of 2-amino-1-naphthalenethione in ethanol (30 ml) and the obtained mixture was heated under reflux. To this mixture was added 2.54 g(9.76 mmol) of methyl 2-chloro-3,5-dinitrobenzoate and the obtained mixture was heated under reflux for 1 hour. To this mixture were added 10 ml of a 2 N aqueous solution of sodium hydroxide and 40 ml of ethanol and the obtained mixture was heated under reflux for additional 10 hours. Then it was brought back to room temperature and concentrated. After adding water, 1 N hydrochloric acid was slowly added thereto under stirring to thereby regulate the pH value to about 1. The precipitate was recovered by filtration and washed successively with ethanol and methanol to thereby give 1.14 g of the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=[O:8].C([O-])([O-])=O.[Na+].[Na+].[C:16](Cl)([O:18][CH2:19][CH:20]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17]>O.O1CCOCC1>[CH:31]1[C:32]2[CH:20]([CH2:19][O:18][C:16]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]3[C:7]([OH:9])=[O:8])=[O:17])[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]=2[CH:28]=[CH:29][CH:30]=1
Reactant: O=C(O)[C@@H]1CCCCN1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)[C@@H]1CCCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.8 %

Procedure:
To a stirred mixture of (S)-piperidine-2-carboxylic acid (1.0 g, 7.75 mmol) and Na2CO3 (1.65 g, 15.50 mmol) in water (10 mL) was added a solution of FMOC-Cl (3.0 g, 11.63 mmol) in 1,4-dioxane (10 mL) dropwise at 0° C. and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (50 mL) and washed with MTBE (25 mL). The aqueous layer was acidified with 1M aqueous HCl (10 mL) to pH 2 and extracted with EtOAc (3×50 mL). The combined organic extracts were washed with brine solution (50 mL), dried over anhydrous Na2SO4, filtered and concentrated to afford the title compound (1.41 g) as an off-white solid. The crude product was used in the next step without purification.
Reaction SMILES: [NH2:1][C:2]1O[C:4]2[C:9]([CH:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=3)[C:11]=1C#N)=[CH:8][C:7]1[CH:25]=[CH:26][CH:27]=[CH:28][C:6]=1[CH:5]=2.CI.C(=O)([O-])[O-].[K+].[K+].[CH3:37][N:38]([CH3:41])[CH:39]=[O:40]>>[CH3:37][N:38]([CH3:41])[C:39]1[O:40][C:4]2[C:9]([CH:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=3)[C:11]=1[C:2]#[N:1])=[CH:8][C:7]1[CH:25]=[CH:26][CH:27]=[CH:28][C:6]=1[CH:5]=2
Reactant: COc1cc(C2C(C#N)=C(N)Oc3cc4ccccc4cc32)cc(Br)c1OC
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: COc1cc(C2C(C#N)=C(N(C)C)Oc3cc4ccccc4cc32)cc(Br)c1OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
2-Amino-4-(3-bromo-4,5-dimethoxy-phenyl)-4H-benzo[g]chromene-3-carbonitrile (30) (24 mg) was taken in 1 ml dry DMF (dimethylformamide) and then charged with methyl iodide (30 μl) and potassium carbonate (30 mg) at room temperature. The reaction was completed after 20 h stirring at room temperature. The title compound was purified on HPLC (21 mm×250 mm, RP18, 5 mm) with a Methanol/water gradient (5% MeOH to MeOH in 25 min, flow 21 ml/min) to yield pale yellowish solids (18 mg).