Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([F:11])[C:3]=1[CH2:4][OH:5].Cl[CH2:13][C:14]1[N:18]=[C:17]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[O:16][N:15]=1.[CH3:24][C@@H:25]1[CH2:30][NH:29][CH2:28][CH2:27][N:26]1[C:31](OCC1C=C(OCC=C)C=CC=1F)=[O:32]>>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH2:13][C:14]2[N:18]=[C:17]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)[O:16][N:15]=2)[CH:7]=[C:6]([F:11])[C:3]=1[CH2:4][O:5][C:31]([N:26]1[CH2:27][CH2:28][NH:29][CH2:30][C@H:25]1[CH3:24])=[O:32]
Reactant: ClCc1noc(-c2cccs2)n1
Reactant: C=CCOc1ccc(F)c(COC(=O)N2CCNC[C@H]2C)c1
Reactant: OCc1c(F)cc(O)cc1F
Product: C[C@@H]1CNCCN1C(=O)OCc1c(F)cc(OCc2noc(-c3cccs3)n2)cc1F

Procedure:
(R)-2-Methyl-piperazine-1-carboxylic acid 2,6-difluoro-4-(5-thiophen-2-yl-[1,2,4]oxadiazol-3-ylmethoxy)-benzyl ester was prepared from 2,6-difluoro-4-hydroxybenzyl alcohol, 3-chloromethyl-5-thiophen-2-yl-[1,2,4]oxadiazole and (R) 2-methylpiperazine resin according to the methods described for Example 126 to give the product as a yellow oil: δH(400 MHz; d6-DMSO) 1.10 (3H, d, J 7.0 Hz), 2.40 (1H, td, J 12.0, 3.5 Hz), 2.62 (2H, br d, J, 2.5 Hz), 2.75–2.82 (1H, br d, J 12 Hz), 2.88 (1H, td, J 12.5, 3.5 Hz), 3.55 (1H, br d, J 12 Hz), 3.96 (1H, br s), 5.02 (1H, d, J 12.5 Hz), 5.07 (1H, d, J 12.5 Hz), 5.42 (2H, s), 6.93–7.01 (2H, m), 7.36(1H, dd, J 5.0 and 4 Hz), 8.06 (1H, dd, J4, 1.0 Hz) and 8.12 (1H, dd, J 5.0, 1 Hz); HPLC (XTERRA, 50–80%, 235 nm) 99.8% (4.22 min).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH3:11].[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:11][C:3]1[C:4]([N+:8]([O-:10])=[O:9])=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: Cc1c(F)cccc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cccc(F)c1CBr
Temperature: 25 °C

Procedure:
To a stirred solution of 1-fluoro-2-methyl-3-nitrobenzene (1.0 g, 0.00645 mol) in carbon tetrachloride (50 mL) were added N-bromosuccinimide (1.25 g, 0.00709 mol) and benzoylperoxide (0.3 g, 0.00129 mol) at room temperature with constant stirring. Reaction mass was refluxed for 5 h. The reaction mixture was cooled to room temperature and filtered through CELITE bed and the bed was washed thoroughly with carbon tetrachloride. The filtrate was concentrated under vacuum to obtain the title compound. 1H NMR (400 MHz, DMSO) δ 7.93-7.91 (d, J=8 Hz, 1H), 7.723-7.653 (m, 2H), 4.77 (s, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][OH:6].[H-].[Na+].Cl[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[O:20][CH3:21]>CS(C)=O.O>[CH3:21][O:20][C:12]1[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:11]=1[O:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:7])[CH3:1]
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Reactant: CN(C)CCCO
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1OCCCN(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35.6 %

Procedure:
3-(Dimethylamino)propan-1-ol (1 g, 10.6 mmol) was dissolved in dimethylsulfoxide (20 ml) and sodium hydride (0.42 g, 10.5 mmol) was added. After stirring at room temperature for 15 min, 1-chloro-2-methoxy-4-nitrobenzene (1 g, 5.3 mmol) in dimethylsulfoxide (10 ml) was added and the reaction mixture stirred 4 h at room temperature. The reaction mixture was diluted with water, extracted with ethyl acetate, and the organic phase dried over magnesium sulphate and filtered. After evaporation of the solvent, the residue was purified by flash chromatography using SP1® Purification System (0% to 85%, ethyl acetate-methanol) to obtain 480 mg (34% yield) of the title compound as an oil.
Reaction SMILES: [P:1]([OH:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].P(=O)(O)(O)[OH:10]>>[CH2:3]([O:2][P:1](=[O:10])([OH:8])[O:5][CH2:6][CH3:7])[CH3:4]
Reactant: CCOP(O)OCC
Reactant: O=P(O)(O)O
Product: CCOP(=O)(O)OCC

Procedure:
100 parts by weight of diethyl hydrogen phosphite and 50 parts by weight of phosphoric acid are mixed and reacted. The reaction is exothermic and the temperature of the reactants are keep below their boiling point for 30 minutes to 1 hour thereby producing a diethyl hydrogen-phosphoric acid compound.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[N:18]([C:19]3[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=3)[C:17](=[O:26])[C@@H:16]2[CH2:27][CH2:28][C@@H:29]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[OH:30])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:38]([NH2:41])[C:39]#[CH:40].C(N(CC)CC)C>CN(C=O)C.[Cu]I>[NH2:41][CH2:38][C:39]#[C:40][C:22]1[CH:23]=[CH:24][C:19]([N:18]2[C@H:15]([C:12]3[CH:13]=[CH:14][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:10][CH:11]=3)[C@@H:16]([CH2:27][CH2:28][C@@H:29]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[OH:30])[C:17]2=[O:26])=[CH:20][CH:21]=1
Reactant: C#CCN
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@@H]2[C@@H](CC[C@H](O)c3ccc(F)cc3)C(=O)N2c2ccc(I)cc2)cc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc([C@@H]2[C@@H](CC[C@H](O)c3ccc(F)cc3)C(=O)N2c2ccc(C#CCN)cc2)cc1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
To a solution of 8 mg (0.013 mmol, 1 equiv.) (3R,4S)-4-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-(4-iodophenyl)azetidin-2-one (intermediate step A) in 0.5 mL DMF was added 2.2 mg (0.002 mmol, 0.15 equiv.) tetrakistriphenylphosphine palladium(0) and 0.8 mg (0.004 mmol, 0.3 equiv) copper(I) iodide. The solution was deoxygenated by a slow stream of anhydrous nitrogen delivered by a needle through a rubber septum. To the resulting solution was added by syringe 0.012 mL (0.177 mmol, 14 equiv.) propargyl amine and 0.012 mL (0.09 mmol, 7 equiv.) triethylamine. The resulting solution was stirred at room temperature for 1.25 hr at which time the solvent was removed under vacuum. The residue was purified by prep. Tlc eluting with CH2Cl2/MeOH (9/1) to afford the title compound. m/z (ES) 559.3 (MH+), 542.3 (MH−NH3+).
Reaction SMILES: [CH2:1]([O:3]CC)[CH3:2].[OH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([CH3:16])[CH:8]=1.C(OC(=O)C)(=O)C>O>[C:1]([O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([CH3:16])[CH:8]=1)(=[O:3])[CH3:2]
Reactant: CCOCC
Reactant: Cc1cc(O)ccc1C(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Oc1ccc(C(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 2.4 h

Procedure:
Into 40 ml of anhydrous ethyl ether, was dissolved 7.1 g of 4-hydroxy-2-methylbenzoic acid followed by 21.3 g of acetic anhydride. The solution was stirred for 2.4 hours at room temperature. The reaction mixture was freed from the solvent under reduced pressure. The residue was admixed with hot water, then allowed to cool, and extracted with ethyl ether. The organic layer was washed with 2% hydrochloric acid, dried over anhydrous magnesium sulfate, and freed from the solvent by distillation under reduced pressure. The residue was recrystallized from an ethyl ether-petroleum ether mixture to obtain 7.5 g of 4-acetyloxy-2-methylbenzoic acid.
Reaction SMILES: [C@@H:1]12[C:10](=[O:11])[O:9][C:7](=[O:8])[C@@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.C(OC(=O)C)(=[O:14])C.[O-]O.C1(C(C)C)C=CC=CC=1.[C:30]([O:39][O:40][C:41]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([CH3:43])[CH3:42])([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([CH3:32])[CH3:31]>>[C:30]([O:39][O:40][C:41]([C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)([CH3:43])[CH3:42])([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([CH3:31])[CH3:32].[C@@H:1]1([C:10]([OH:9])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([OH:14])=[O:8]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Agent: CC(C)(OOC(C)(C)c1ccccc1)c1ccccc1
Agent: [O-]O
Solvent: CC(C)c1ccccc1
Product: O=C(O)[C@H]1CCCC[C@H]1C(=O)O

Procedure:
The reaction described in Example 2 was repeated with 14.7 gm (95 millimoles) cis-1,2-cyclohexanedicarboxylic anhydride substituted for the acetic anhydride. After a total reaction time of 125 minutes (at 18°±1° C.), 9.9% of the cumene hydroperoxide remained unreacted. The reaction was quenched (sodium acetate) after a total time of 245 minutes and, after recovery in a manner similar to Example 2, afforded 35.9 gm crude product which contained about 70% dicumyl peroxide. (An approximate value for dicumyl peroxide was obtained in this case because the elution of cis-1,2-cyclohexanedicarboxylic acid on the gas-liquid chromatography column partially overlapped with the dicumyl peroxide).
Reaction SMILES: [N+:1]([O-:4])([O-:3])=[O:2].[Hf+4:5].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[Zr+4:22].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>>[Hf:5].[Zr:22].[N+:1]([O-:4])([O-:3])=[O:2].[Hf+4:5].[N+:1]([O-:4])([O-:3])=[O:2].[N+:1]([O-:4])([O-:3])=[O:2].[N+:1]([O-:4])([O-:3])=[O:2]
Reactant: [Zr+4]
Agent: [Hf+4]
Agent: O=[N+]([O-])[O-]
Product: [Hf]
Product: [Zr]

Procedure:
Although anhydrous hafnium nitrate and anhydrous zirconium nitrate are not currently commercially available, synthesis and purification techniques for these materials are known. Synthesis of zirconium nitrate was reported in 1962. Due to the similarities between hafnium and zirconium, hafnium nitrate may also be isolated through a similar synthesis process. Hafnium nitrate may be prepared by refluxing hafnium tetrachloride over dinitrogen pentoxide at 30° C., and then purified by sublimation at 100° C./0.1 mmHg for hafnium nitrate. Zirconium nitrate can be similarly purified at 95° C./0.1 mmHg.
Reaction SMILES: [CH2:1]=[C:2]([CH:4]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:12])[CH3:3].[CH3:13][O:14][N:15]=[CH:16][CH3:17].Cl[Sn](Cl)(Cl)Cl>ClCCCl>[CH3:13][O:14][N:15]1[CH:16]([CH3:17])[CH2:3][C:2]([CH3:1])=[CH:4][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:12]
Reactant: C=C(C)C1CCCCCCC1=O
Reactant: CC=NOC
Agent: CON1C(=O)CCCCCC/C=C(\C)CC1C
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCCl
Product: CON1C(=O)CCCCCCC=C(C)CC1C

Procedure:
Following the general procedure as described in Example 23, 2-(prop-1-en-2-yl)cyclooctanone (1.50 g, 9.02 mmol), acetaldehyde O-methyl oxime (0.99 g, 13.53 mmol), and SnCl4 (2.35 g, 9.02 mmol) in 1,2-dichloroethane (90 ml) were reacted to give the title product as a colorless liquid (1.91 g, 89% yield). E isomer>95%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8](O)[CH2:9][N:10]([CH2:14][CH2:15]O)[CH2:11][CH:12]=[CH2:13])=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH2:30]([NH2:33])[CH:31]=[CH2:32].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:9][N:10]([CH2:11][CH:12]=[CH2:13])[CH2:14][CH2:15][N:33]2[CH2:30][CH:31]=[CH2:32])=[CH:4][CH:3]=1
Reactant: C=CCN(CCO)C[C@H](O)c1ccc(Cl)cc1
Reactant: C=CCN
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCN1CCN(CC=C)[C@H](c2ccc(Cl)cc2)C1
Temperature: 5 °C
Reaction time: 12 h
Yield: 102.5 %

Procedure:
To (R)-1-(4-chlorophenyl)-2-[(2-hydroxyethyl)(2-propenyl)amino]-1-ethanol (724 mg, 2.5 mmol) produced in Example 13, tetrahydrofuran (2.51 g) and triethylamine (868 mg, 3.5 equivalents) were added. The mixture was cooled to 5° C. Methanesulfonyl chloride (899 mg, 3.2 equivalents) was added dropwise thereto, and then allylamine (839 mg, 6.0 equivalents) was added dropwise thereto. The temperature of the mixture was raised to 25° C., and then the mixture was stirred for 12 hours. To the mixture, 10 wt % aqueous solution of sodium carbonate (4.15 g) was added. After the organic layer and aqueous layer were separated, the aqueous layer was extracted with toluene (5 mL). The organic layers were combined, and washed twice with distilled water (5 mL). The obtained organic layer was concentrated and dried under vacuum, to obtain 709 mg of the title compound as pale yellow oil (yield: 92%, chemical purity: 81.7 area %).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1.[C:34]1([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(N(CC)CC)C>C(#N)C.O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:43]2[CH2:44][CH2:45][N:40]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:41][CH2:42]2)=[O:8])=[CH:9][CH:10]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Nc1ccc(C(=O)N2CCN(c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred suspension of 4-aminobenzoic acid (5 g, 36.5 mmol) in acetonitrile (100 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (7.67 g, 40.2 mmol), hydroxybenzotriazole hydrate (0.49 g, 3.65 mmol), 1-phenylpiperazine (11.2 ml, 3.65 mmol) followed by triethylamine (12.8 ml, 91.3 mmol) and the reaction mixture was stirred at room temperature for 16 hours. The reaction was diluted with the addition of water and the resulting aqueous mixture extracted using dichloromethane (3×100 ml). The organics were combined, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by flash column chromatography (SiO2) eluting with ethylacetate/dichloromethane (1:1) to afford the title compound as an off white solid. HPLC retention time 7.1 min. Mass spectrum (ES+) m/z 282 (M+H).
Reaction SMILES: C1CO[C:3]2([CH2:7][CH2:6][CH:5]([CH2:8][CH:9]=[O:10])[CH:4]2[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH3:15])[O:2]1.O1CCOCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH:9]([CH2:8][CH:5]1[CH2:6][CH2:7][C:3](=[O:2])[CH:4]1[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH3:15])=[O:10]
Reactant: CC/C=C\CC1C(CC=O)CCC12OCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCO1
Product: CC/C=C\CC1C(=O)CCC1CC=O
Yield: 47.9 %

Procedure:
A mixture of 47.6 g of 1,1-ethylenedioxy-3-formylmethyl-2-(cis-2-n-pentenyl)-cyclopentane, 80 ml of dioxane, 64 ml of water and 0.38 g para-toluenesulphonic acid is refluxed for 3 hours. It is then cooled, 120 ml of water added and extracted three times with 100 ml of benzene. The benzene solutions are washed to neutrality and concentrated under reduced pressure. There is obtained a crude product which is carefully rectified to yield 18.6 g of pure 3-formylmethyl-2-(cis-2-n-pentenyl)-1-cyclopentanone exhibiting: b.p.0.5 = 96°C. It can be represented by the formula ##SPC24##
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:4]=[C:3]1[C:18]([NH:20][NH2:21])=O.CO[C:24](OC)(N(C)C)[CH3:25].C(O)(=O)C.[NH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(#N)C>[CH3:24][C:25]1[N:35]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:18]([C:3]2[C:2](=[O:1])[CH:7]=[CH:6][N:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=3)[N:4]=2)=[N:20][N:21]=1
Reactant: NNC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Reactant: COC(C)(OC)N(C)C
Reactant: Nc1ccccc1
Solvent: CC(=O)O
Solvent: CC#N
Product: Cc1nnc(-c2nn(-c3cccc(C(F)(F)F)c3)ccc2=O)n1-c1ccccc1
Temperature: 125 °C
Yield: 48 %

Procedure:
A solution of 4-oxo-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carbohydrazide (0.207 g, 0.69 mmol) and N,N-dimethylacetamide dimethylacetal (0.1 mL, 0.68 mmol) in acetonitrile (2 mL) was heated at 60° C. for 2.5 h. After that time, acetic acid (2 mL) and aniline (0.06 mL, 0.66 mmol) were added and the temperature was increased to 125° C. for an additional 2 hours. During this time, the acetonitrile was allowed to distill-off. The reaction was then concentrated to a dark residue and the crude product purified by column chromatography (silica gel, ethyl acetate to 4:1 ethyl acetate/methanol) to give a yellow solid that was recrystallized from ethyl acetate/hexanes to give 3-(5-methyl-4-phenyl-4H-1,2,4-triazol-3-yl)-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (0.126 g, 46%) as light yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12](B(O)O)=[CH:11][C:10]2[S:16][C:17]([Cl:19])=[CH:18][C:9]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:21]1[CH:22]=[C:23]([O:32][CH3:33])[C:24](=[CH:26]N(CC)CC)[N:25]=1.[O-:34]P([O-])([O-])=O.[K+].[K+].[K+].Cl>O.O1CCOCC1>[Cl:19][C:17]1[S:16][C:10]2[CH:11]=[C:12]([C:21]3[NH:25][C:24]([CH:26]=[O:34])=[C:23]([O:32][CH3:33])[CH:22]=3)[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:9]=2[CH:18]=1
Reactant: CCN(C=C1N=C(Br)C=C1OC)CC
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2sc(Cl)cc21
Reactant: O=P([O-])([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(-c2cc3sc(Cl)cc3n2C(=O)OC(C)(C)C)[nH]c1C=O
Temperature: 80 °C
Reaction time: 3 h
Yield: 4.7 %

Procedure:
A mixture of 4-(tert-butoxycarbonyl)-2-chloro-4H-thieno[3,2-b]pyrrol-5-ylboronic acid (200 mg, 0.66 mmol), N-((5-bromo-3-methoxy-2H-pyrrol-2-ylidene)methyl)-N-ethylethanamine (160 mg, 0.61 mmol, provided by Chemzon Scientific Inc, Montreal, Canada), Pd(dppf)2Cl2CH2Cl2 (18 mg) and K3PO4 (260 mg) in a 20 mL sealed-tube flask was vented 4 times with nitrogen. 1,4-Dioxane (3 mL and water (0.4 mL) were introduced by syringes and the mixture was vented twice with nitrogen. The reaction mixture was heated at 80° C. for 1 h and TLC showed no starting materials were left. After being cooled to r.t., the reaction mixture was treated with 3 mL of 1N HCl, and stirred for 3 h. The mixture was then extracted with 20 mL of EtOAc, and the extract was dried over Na2SO4, filtered through a pad of silica gel. The filtrate was concentrated under vacuum and the residue was purified by Combiflash on a silica gel column eluted with a gradient of up to 60% EtOAc/hexanes to give 11 mg of the title compound as a solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].C1C=CC2C(=CC=CC=2O)C=1.[Cl:23]Cl.[CH2:25]([N:27](CC)[CH2:28][CH3:29])[CH3:26].N1CCCC1>C1(C)C=CC=CC=1>[Cl:23][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([N:27]2[CH2:28][CH2:29][CH2:26][CH2:25]2)=[CH:3][C:2]=1[OH:11]
Reactant: CCN(CC)CC
Reactant: Oc1ccc2ccccc2c1
Reactant: ClCl
Agent: Oc1cccc2ccccc12
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Product: Oc1cc(N2CCCC2)c2ccccc2c1Cl
Yield: 104.4 %

Procedure:
2-Naphthol (14.43 g; 0.100 mol) was dissolved in toluene (200 ml) by warming. The pale brown solution was cooled and vigorously stirred until the naphthol began to precipitate and chlorine (15.22 g;0.21 mol) was then passed through the solution at approximately 2.5-3.0 g/min followed immediately by nitrogen gas. The resulting amber solution was treated firstly with triethylamine (12.12 g;0.12 mol) in one portion and then with a solution of pyrrolidine (7.10;0.10 mol), in toluene (100 ml), dropwise over 1.5 hours keeping the temperature at 15°-20° C. The resulting brown mixture was filtered to remove triethylamine hydrochloride as a white amorphous solid. The toluene filtrate was washed with water, dried and evaporated to give 1-chloro-4-pyrrolidino-2-naphthol as a brown viscous oil (25.87 g). Purification by chromatography over silica (eluent: toluene) gave the product as a red-brown oil (3.825 g;15%). ##STR27## (b) 4-Pyrrolidino-2-naphthol
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([NH2:16])=[NH:15])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:19][O:20][CH:21]([C:26](OC)=[O:27])[C:22](OC)=[O:23].C(O)C.C[O-].[Na+]>C(O)(=O)C>[OH:23][C:22]1[C:21]([O:20][CH3:19])=[C:26]([OH:27])[N:16]=[C:14]([C:13]2[CH:12]=[CH:11][C:10]([O:9][CH2:2][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[CH:18][CH:17]=2)[N:15]=1
Reactant: COC(=O)C(OC)C(=O)OC
Reactant: N=C(N)c1ccc(OCc2ccccc2)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1c(O)nc(-c2ccc(OCc3ccccc3)cc2)nc1O
Temperature: 80 °C
Yield: 61.2 %

Procedure:
A mixture of 85 g of 4-benzyloxybenzamidine hydrochloride, 78.6 g of dimethyl methoxymalonate, 1700 ml of ethanol, and 187 g of sodium methylate (28% methanol solution) was heated at 80° C. for 4 hours with stirring. After cooling, 1000 ml of acetic acid was slowly added to the reaction mixture, whereupon a yellow crystal precipitated. The precipitated crystals were collected by filtration, washed twice with water until the washing became neutral, and dried at 80° C. for 3 hours in high vacuo to obtain 64.2 g (percent yield: 60.7% ) of 4,6-dihydroxy-5-methoxy-2-(4-benzyloxyphenyl)pyrimidine.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[N+:21]([O-:23])=[O:22])[CH2:10][CH2:9]1)=O)(C)(C)C.F[C:25](F)(F)[C:26](O)=O.Cl[CH2:32][Cl:33]>>[Cl:33][C:32]1[CH:18]=[CH:19][C:14](/[CH:25]=[CH:26]/[CH2:6][N:8]2[CH2:9][CH2:10][N:11]([C:14]3[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=3[N+:21]([O-:23])=[O:22])[CH2:12][CH2:13]2)=[CH:15][CH:16]=1
Reactant: O=C(O)C(F)(F)F
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(F)ccc2[N+](=O)[O-])CC1
Product: O=[N+]([O-])c1ccc(F)cc1N1CCN(C/C=C/c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of 4-(5-fluoro-2-nitrophenyl)-piperazine-1-carboxylic acid tert-butyl ester (10 g, prepared from 2,4-difluoronitrobenzene as described in Example 1, Step A) in dichloromethane (80 ml) was treated with trifluoroacetic acid (23 ml) for 24 hours at room temperature. The reaction mixture was concentrated in vacuo. The residue was dissolved in acetonitrile (100 ml), diisopropylethylamine (27 ml) and 4-chloro-cinnamyl chloride (6.8 g) were added. The solution was stirred for 17 hours at room temperature, the solvent was removed in vacuo and the residue was subjected to silica gel chromatography (cyclohexane:ethyl acetate 1:1) to afford 1-[(E)-3-(4-chloro-phenyl)-allyl]-4-(5-fluoro-2-nitro-phenyl)-piperazine (10.5 g); 1H NMR (400 MHz, CDCl3) 2.7 (t, J=8 Hz, 4H), 3.1 (t, J=8 Hz, 4H), 3.2 (d, J=9 Hz, 2H), 6.2 (dt, J=18, 9 Hz, 1H), 6.5 (d, J=18 Hz, 1H), 6.6 (dt, J=1.0, 7.0 Hz, 1H), 6.7 (dd, J=1.0, 10 Hz, 1H), 7.2-7.3 (m, 4H), 7.8 (d, J=7.0, 10.0 Hz, 1H); MS (ES+) 151/153, 376/378 (M+H+).
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1.Br[CH2:14][CH2:15][OH:16].O>CS(C)=O>[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][N:10]2[CH2:14][CH2:15][OH:16])=[CH:6][CH:5]=1
Reactant: OCCBr
Reactant: Brc1ccc2cc[nH]c2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: OCCn1ccc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.2 %

Procedure:
KOH (571 mg, 10.2 mmol) was stirred in 5 mL of anhydrous DMSO at room temperature. 6-Bromoindole (500 mg, 2.55 mmol) was added as solid. After 30 min, 2-bromoethanol (181 μL, 2.55 mmol) was added to the green solution, which was then stirred at room temperature overnight. Water was then added and the reaction mixture was extracted with ethyl acetate (2×25 mL). The organic layer was then washed with water and brine, dried over Na2SO4, evaporated in vacuo. MPLC purification of the crude product provided the titled compound as a light brown oil (344 mg, 56% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[Cl:13])[CH:10]=O)=[CH:5][CH:4]=1.Cl.[NH2:23][OH:24]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[Cl:13])[CH:10]=[N:23][OH:24])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(Cl)=C(C=O)c2ccc(OC)cc2)cc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(C(Cl)=C(C=NO)c2ccc(OC)cc2)cc1

Procedure:
30.2 g of 2,3-bis(4-methoxyphenyl)-3-chloro-acrylaldehyde (0.1 mol) were dissolved in 250 ml of pyridine and heated for half an hour on the steam bath together with 30 g of hydroxylamine hydrochloride. Then the solution was evaporated; the remaining solid substance was taken up with ethanol. The whole was boiled, suction-filtered and dried. The 2,3-bis(4-methoxyphenyl)-3-chloro-acrylaldoxime had a melting point of from 207° to 208° C (decomposition). The following compounds were prepared according to the same process: