Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:13]([OH:17])[CH2:14][CH2:15][CH3:16])=[C:9]([CH2:11][CH3:12])[N:10]=2)[CH:5]=[CH:6][N:7]=1>C(OCC)(=O)C.C(Cl)Cl.[O-2].[Mn+4].[O-2]>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([C:13](=[O:17])[CH2:14][CH2:15][CH3:16])=[C:9]([CH2:11][CH3:12])[N:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CCCC(O)c1c(CC)nc2c(Cl)nccn12
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCC(=O)c1c(CC)nc2c(Cl)nccn12
Temperature: 60 °C
Reaction time: 5 h

Procedure:
The resulting 1-(8-chloro-2-ethylimidazo[1,2-a]pyrazin-3-yl)-1-butanol was dissolved in ethyl acetate (4 mL) and methylene chloride (1 mL), then activated manganese (IV) oxide (3 g) was added thereto, and the mixture was heated under stirring at 60° C. for 5 hours. After being allowed to cool, the reaction mixture was filtered and washed with ethyl acetate, and then the filtrates were combined and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:3) to give the title compound (226 mg) as white crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=2)=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>O1CCCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][O:15][C:26]2[CH:25]=[CH:24][C:23]([C:20]3[CH:19]=[CH:18][C:17]([Cl:16])=[CH:22][CH:21]=3)=[CH:28][CH:27]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)C1
Reactant: Oc1ccc(-c2ccc(Cl)cc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCC(COc2ccc(-c3ccc(Cl)cc3)cc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66.5 %

Procedure:
1-(tert-Butoxycarbonyl)piperidin-3-ylmethanol (323 mg, 1.50 mmol) and 4′-chloro-4-hydroxybiphenyl (307 mg, 1.50 mmol) were suspended in tetrahydrofuran (15 mL). To this suspension, triphenylphosphine (608 mg, 2.25 mmol) was added and the mixture was stirred at room temperature for 10 min. A 40% diethylazodicarboxylate/toluene solution (1.36 mL, 3.00 mmol) was then added and the mixture was stirred at room temperature for 16 hours. Subsequently, water was added and the mixture was extracted with ethyl acetate. The extract washed with brine, followed by drying over magnesium sulfate and evaporation of the solvent. Purification of the resulting residue by silica gel column chromatography (hexane:ethyl acetate=50:1->10:1) gave 401 mg (67%) of the desired compound as a colorless powder.
Reaction SMILES: [CH3:1][O:2][CH:3](C)[C:4]([CH3:11])=[CH:5][CH2:6][CH2:7][C:8](=[O:10])[CH3:9].[CH:13]([Mg]Cl)=[CH2:14].O>O1CCCC1>[CH3:1][O:2][CH2:3][C:4]([CH3:11])=[CH:5][CH2:6][CH2:7][C:8]([CH3:9])([OH:10])[CH:13]=[CH2:14]
Reactant: C=C[Mg]Cl
Reactant: COC(C)C(C)=CCCC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: C=CC(C)(O)CCC=C(C)COC
Yield: 85 %

Procedure:
141 g (0.9 mole) of 7-methoxy-6-methyl-oct-5-en-2-one are added to 1 mole of a 1.5 normal solution of vinyl-magnesium chloride in tetrahydrofuran, at below 20° C, in the course of one hour. After a further 2 hours' reaction, hydrolysis is carried out with 100 ml of water, whilst cooling with ice. After a homogeneous salt suspension has formed, the salt and the tetrahydrofuran solution are separated by filtering or centrifuging. The tetrahydrofuran is distilled off under reduced pressure and the reaction product which remains is purified by fractional distillation. 164 g of 8-methoxy-3,7-dimethyl-octa-1,6-dien-3-ol (yield 85%) are obtained. Boiling point 73°-75° C/0.01 bar; nD25 = 1.4676.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[S:28][C:27]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([C:36]([CH3:41])([CH3:40])[C:37]([NH2:39])=[O:38])[CH2:32][CH2:31]4)=[CH:26][C:9]=3[N:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:42]([N:44]1[C:52](I)=[C:51]2[C:46]([CH:47]=[CH:48][CH:49]=[CH:50]2)=[N:45]1)[CH3:43]>>[CH2:42]([N:44]1[C:52]([C:11]2[N:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[C:8]3[S:28][C:27]([CH2:29][N:30]4[CH2:31][CH2:32][N:33]([C:36]([CH3:41])([CH3:40])[C:37]([NH2:39])=[O:38])[CH2:34][CH2:35]4)=[CH:26][C:9]=3[N:10]=2)=[C:51]2[C:46]([CH:47]=[CH:48][CH:49]=[CH:50]2)=[N:45]1)[CH3:43]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2sc(CN3CCN(C(C)(C)C(N)=O)CC3)cc2n1
Reactant: CCn1nc2ccccc2c1I
Product: CCn1nc2ccccc2c1-c1nc(N2CCOCC2)c2sc(CN3CCN(C(C)(C)C(N)=O)CC3)cc2n1

Procedure:
Following the procedures for 143, 2-[4-(4-morpholin-4-yl-2-(tributylstannanyl)thieno[3,2-d]pyrimidin-6-ylmethyl)piperazin-1-yl]isobutyramide and 2-ethyl-3-iodo-2H-indazole were reacted to give 190. LCMS m/z: 549.3 (MH+)
Reaction SMILES: [NH4+].[OH-:2].[CH3:3][C:4]1[CH:9]=[C:8]2[C:10]([CH:24]([CH3:26])[CH3:25])=[C:11]([OH:23])[C:12](/[C:14](=[CH:15]\NC3C=CC=CC=3)/[C:7]2=[C:6]([OH:27])[C:5]=1[C:28]1[C:33]([OH:34])=[C:32]2[C:35]([CH:44]=[O:45])=[C:36]([OH:43])[C:37]([OH:42])=[C:38]([CH:39]([CH3:41])[CH3:40])[C:31]2=[CH:30][C:29]=1[CH3:46])=[O:13]>CO>[CH3:3][C:4]1[C:5]([C:28]2[C:29]([CH3:46])=[CH:30][C:31]3[C:38]([CH:39]([CH3:41])[CH3:40])=[C:37]([OH:42])[C:36]([OH:43])=[C:35]([CH:44]=[O:45])[C:32]=3[C:33]=2[OH:34])=[C:6]([OH:27])[C:7]2=[C:14]([CH:15]=[O:2])[C:12]([OH:13])=[C:11]([OH:23])[C:10]([CH:24]([CH3:26])[CH3:25])=[C:8]2[CH:9]=1
Reactant: Cc1cc2c(c(O)c1-c1c(C)cc3c(C(C)C)c(O)c(O)c(C=O)c3c1O)/C(=C/Nc1ccccc1)C(=O)C(O)=C2C(C)C
Reactant: [OH-]
Agent: [NH4+]
Solvent: CO
Product: Cc1cc2c(C(C)C)c(O)c(O)c(C=O)c2c(O)c1-c1c(C)cc2c(C(C)C)c(O)c(O)c(C=O)c2c1O

Procedure:
The mass spectrometer was a Micromass Quattro Ultima LC/MS/MS detector by Waters, and contained a triple quadrupole mass spectrometer with negative electrospray ionization. Because the HPLC did not provide the correct ionization matrix for negative electrospray ionization of the dianilino-gossypol, 0.6% NH4OH in methanol was introduced past the HPLC column at a flow rate of 0.05 mL/minute. Post-column mixing of the NH4OH in MeOH with the HPLC eluant was achieved using a mixing T-connection. In MS/MS mode, the first quadrupole was used to select 667.3 as the mass to charge ratio that represented the negative ion of dianilino-gossypol. In the second quadrupole, the 667.3 mass to charge ratio was fragmented in a collision cell. The third quadrupole was used to select the fragment ion, monoanilino-gossypol, which had a mass to charge ratio of 574.2 as a result of the loss of an aniline. Detection of the second fragment ion provides improved specificity and increased signal to noise ratios.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[C:21]([CH3:23])[C:20]([OH:24])=[C:19]([CH2:25][CH3:26])[CH:18]=3)[N:13]=2)=[CH:9][C:8]=1[CH3:27])[CH2:4][CH3:5])[CH3:2].[CH:28]([OH:31])([CH3:30])[CH3:29]>[OH-].[Na+].C([C@@H]1OC1)Cl.CC(=O)OCC>[CH2:1]([N:3]([CH2:4][CH3:5])[CH2:6][C:7]1[S:11][C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[C:21]([CH3:23])[C:20]([O:24][CH2:29][C@@H:28]4[CH2:30][O:31]4)=[C:19]([CH2:25][CH3:26])[CH:18]=3)[N:13]=2)=[CH:9][C:8]=1[CH3:27])[CH3:2]
Reactant: CCc1cc(-c2noc(-c3cc(C)c(CN(CC)CC)s3)n2)cc(C)c1O
Reactant: CC(C)O
Agent: ClC[C@H]1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCc1cc(-c2noc(-c3cc(C)c(CN(CC)CC)s3)n2)cc(C)c1OC[C@@H]1CO1
Temperature: 25 °C
Reaction time: 41 h

Procedure:
To a solution of 4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenol (1.49 g, 3.87 mmol) in isopropanol (70 mL) and 3 N aq. NaOH (19 mL), (R)-epichlorohydrine is added. The mixture is stirred at rt for 41 h. The mixture is diluted with EA and washed with 1 M aq. NaOH. The washing is extracted back with EA. The organic extracts are combined, dried over MgSO4, filtered and concentrated. The crude product is purified by prep. HPLC (XBridge C18, 50×50 mm, 10 μm, eluting with a gradient of acetonitrile in water containing 0.5% of concentrated aq. ammonia) to give diethyl-{5-[3-((S)-3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-3-methyl-thiophen-2-ylmethyl}-amine (990 mg) as a pale yellow resin; LC-MS: tR=0.65 min; [M+1]+=442.09. b) A solution of diethyl-{5-[3-((S)-3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-3-methyl-thiophen-2-ylmethyl}-amine (450 mg, 1.02 mmol) in 7 N NH3 in methanol is stirred in a sealed vessel at 65° C. for 16 h. The solvent is evaporated and the crude product is purified by prep. HPLC. The product containing fractions are filtered over Amberlyst A21. The filtrate is concentrated and dried to give the title compound (381 mg) as a yellow resin; LC-MS: tR=0.44 min; [M+1]+=459.10; 1H NMR (D6-DMSO): δ1.03 (t, J=7.0 Hz, 6H), 1.23 (t, J=7.5 Hz, 3H), 2.22 (s, 3H), 2.35 (s, 3H), 2.58 (q, J=7.0 Hz, 4H), 2.73 (q, J=7.5 Hz, 2H), 2.88 (dd, J=12.8, 9.0 Hz, 1H), 3.10 (dd, J=12.5, 3.0 Hz, 1H), 3.73 (s, 2H), 3.81 (d, J=5.3 Hz, 2H), 4.04-4.12 (m, 1H), 7.75 (s, 2H), 7.80 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[N:13]=[CH:12][N:11]=[C:10]([NH:14][CH3:15])[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[F:16][C:17]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:18]=1[C:19]([OH:21])=[O:20].C([O-])([O-])=O.[Cs+].[Cs+].CS(C)=O>O>[F:16][C:17]1[CH:25]=[CH:24][C:23]([O:26][C:2]2[C:7]([C:8]3[N:9]=[C:10]([NH:14][CH3:15])[N:11]=[CH:12][N:13]=3)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:22][C:18]=1[C:19]([OH:21])=[O:20]
Reactant: CNc1ncnc(-c2cccnc2Cl)n1
Reactant: O=C(O)c1cc(O)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CNc1ncnc(-c2cccnc2Oc2ccc(F)c(C(=O)O)c2)n1
Temperature: 130 °C

Procedure:
To [4-(2-chloro-pyridin-3-yl)-[1,3,5]triazin-2-yl]-methyl-amine (6.90 g, 31.1 mmol), 2-fluoro-5-hydroxybenzoic acid (4.9 g, 31.1 mmol) and Cs2CO3 (20.3 g, 62.2 mmol) was added DMSO (25 mL). The mixture was heated overnight at 130° C. in a sealed tube. The cooled mixture was diluted with water and extracted with EtOAc. The aqueous layer was acidified (pH˜4) with TFA and the resulting solid was filtered, washed with water and dried to yield 2-fluoro-5-[3-(4-methylamino-[1,3,5]triazin-2-yl)-pyridin-2-yloxy]-benzoic acid. MS m/z=342 [M+1]+. Calc'd for C16H12FN5O3: 341.30.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH:11]([OH:14])[CH2:12][OH:13].N1C=CC=CC=1.[CH3:21][NH:22][S:23](Cl)(=[O:25])=[O:24].O>C(Cl)Cl>[OH:14][CH:11]([CH2:10][O:9][C:8]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:2][CH3:1])[CH2:12][O:13][S:23](=[O:25])(=[O:24])[NH:22][CH3:21]
Reactant: CNS(=O)(=O)Cl
Reactant: COc1ccccc1OCC(O)CO
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CNS(=O)(=O)OCC(O)COc1ccccc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.7 %

Procedure:
A solution of 26.5 g (0.13 mole) of glycerol guaiacolate in 100 ml of methylene chloride and 10.8 ml (0.13 mole) of pyridine was added in a thin stream to a stirred solution of 17.1 g (0.13 mole) of N-methylsulfamoyl chloride (Preparation 22) in 70 ml of methylene chloride, and the reaction mixture was stirred at ambient temperature for 2 hr. The reaction mixture was treated with 150 ml of water, the layers were separated, and the organic layer was washed successively with a 200 ml portion of 2N hydrochloric acid solution, four 200 ml portions of water, dried (magnesium sulfate), and the solvent was evaporated under reduced pressure to yield a viscous oil. The oil was purified by preparative high pressure liquid chromatography. Fractions containing the desired product were combined and the solvents evaporated under reduced pressure to give 13.9 g (37%) of the title compound as a yellow gum.
Reaction SMILES: [CH:1]1([N:4]2[C:9](=[O:10])[C:8]3[C:11]([OH:18])=[C:12]([CH3:17])[C:13](=[O:16])[N:14]([CH3:15])[C:7]=3[N:6]([C:19]3[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=3[F:26])[C:5]2=[O:27])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl.CN(C)C.[S:40](Cl)([C:43]1[CH:49]=[CH:48][C:46]([CH3:47])=[CH:45][CH:44]=1)(=[O:42])=[O:41]>C(#N)C.CO>[CH:1]1([N:4]2[C:9](=[O:10])[C:8]3[C:11]([O:18][S:40]([C:43]4[CH:49]=[CH:48][C:46]([CH3:47])=[CH:45][CH:44]=4)(=[O:42])=[O:41])=[C:12]([CH3:17])[C:13](=[O:16])[N:14]([CH3:15])[C:7]=3[N:6]([C:19]3[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=3[F:26])[C:5]2=[O:27])[CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1c(O)c2c(=O)n(C3CC3)c(=O)n(-c3ccc(I)cc3F)c2n(C)c1=O
Agent: CN(C)C
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1ccc(S(=O)(=O)Oc2c(C)c(=O)n(C)c3c2c(=O)n(C2CC2)c(=O)n3-c2ccc(I)cc2F)cc1
Yield: 91 %

Procedure:
Under a nitrogen atmosphere, to 3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-5-hydroxy-6,8-dimethyl-1H,8H-pyrido[2,3-d]pyrimidine-2,4,7-trione 55 (23.9 g) was added acetonitrile (167 ml), and the mixture was stirred under ice-cooling. Triethylamine (11.0 ml) and trimethylamine hydrochloride (2.37 g) were added, and a solution of p-toluenesulfonyl chloride 11 (12.3 g) in acetonitrile (72.0 ml) was added dropwise. The mixture was stirred under ice-cooling for 1 hr, and stirred at room temperature for 3 hrs. Methanol (239 ml) was added, and the mixture was stirred at room temperature for 1 hr. The crystals were collected by filtration and dried to give p-toluenesulfonic acid 3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-yl ester 77 (28.7 g, yield 91%) as colorless crystals.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:9]=[C:8]([Cl:10])[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:6]=1)=[O:4].[OH-].[K+:20]>CCO.CCOCC>[K+:20].[Cl:10][C:8]1[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:17])([CH3:18])[CH3:16])[N:6]=[C:5]([C:3]([O-:4])=[O:2])[N:9]=1
Reactant: COC(=O)c1nc(Cl)n(COCC[Si](C)(C)C)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: C[Si](C)(C)CCOCn1nc(C(=O)[O-])nc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91 %

Procedure:
To a solution of 4-(4-{[5-chloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-[1,2,4]triazole-3-carboxylic acid methyl ester (as prepared in the previous step, 227 mg, 0.780 mmol) in EtOH (2 mL), 2 N KOH (0.4 mL, 0.8 mmol) was added. The resulting solution was stirred at RT for 20 min and concentrated in vacuo. The residue obtained was suspended in ether (10 mL) and sonicated for 5 min. The ether was then removed and the resulting residue was dried in vacuo for 4 h to obtain 4-(4-{[5-chloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-[1,2,4]triazole-3-carboxylic acid potassium salt (223 mg, 91%) which was directly used in the next step without any further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[NH:4][C:5]([CH3:23])=[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[N:8]=1.C(N(CC)CC)C.[C:31]1([S:37](Cl)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>ClCCl>[CH3:23][C:5]1[NH:4][CH:3]([O:2][CH3:1])[N:8]([S:37]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:39])=[O:38])[CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[C:6]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)C1=C(C)NC(OC)=NC1c1cccc([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=C(C)NC(OC)N(S(=O)(=O)c2ccccc2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
A solution of 1, 4-dihydro-2-methoxy-6-methyl-4-(3-nitrophenyl) -5-pyrimidinecarboxylic acid, ethyl ester (3.19 g, 10.0 mmole; see Example 5A) and distilled triethylamine (4.18 ml, 30.0 mmol) in distilled dichloromethane (20 ml) in an ice bath under argon was treated dropwise via syringe with benzenesulfonyl chloride (1.53 ml, 12.0 mmol). The reaction was then stirred at room temperature overnight; and then over the weekend. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with saturated sodium chloride and flash chromatographed to give the title compound as a light brown oil (2.94 g).
Reaction SMILES: [C:1]1([C:13](Cl)=[O:14])[CH:6]=[C:5]([C:7](Cl)=[O:8])[CH:4]=[C:3](C(Cl)=O)[CH:2]=1.C1(N)C=CC=C(N)C=1.NC1C=CC=CC=1.O.CN1[C:37](=[O:38])CCC1>>[C:13](=[C:1]1[CH2:2][CH:3]=[CH:4][C:5](=[C:7]=[O:8])[C:6]1=[C:37]=[O:38])=[O:14]
Reactant: O=C(Cl)c1cc(C(=O)Cl)cc(C(=O)Cl)c1
Reactant: CN1CCCC1=O
Agent: Nc1cccc(N)c1
Solvent: Nc1ccccc1
Solvent: O
Product: O=C=C1C=CCC(=C=O)C1=C=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a nitrogen atmosphere, a 50 mL four-neck flask was charged with 3 g (11.3 mmol) of 1,3,5-benzenetricarbonyl trichloride (Tokyo Chemical Industry) and 13.3 g of NMP (Junsei Chemical Co., Ltd.), following which a solution of 0.92 g (8.48 mmol) of 1,3-phenylenediamine (DuPont K.K.) and 0.79 g (8.48 mmol) of aniline (Junsei Chemical Co., Ltd.) in 13.3 g of NMP (Junsei Chemical Co., Ltd.) was added dropwise over a period of 30 minutes at an internal temperature of 12° C. and polymerization was carried out. Following the completion of dropwise addition, the flask contents were stirred for 30 minutes at room temperature, pure water (3 g) was added dropwise, followed by another 30 minutes of stirring, after which the reaction mixture was added to 450 g of pure water, thereby effecting re-precipitation. The resulting precipitate was collected by filtration, then again dissolved in a mixed solvent of 24 g of THF (Kanto Chemical Co., Ltd.) and 1.8 g of pure water, after which the solution was added to 450 g of pure water, thereby effecting re-precipitation. The resulting precipitate was collected by filtration and dried at 150° C. for 2 hours in a vacuum desiccator, thereby giving 3.3 g of the target tricarbonylbenzene-based hyperbranched polymer (abbreviated below as “TmPDA-An”). FIG. 2 shows the 1H-NMR spectrum obtained for TmPDA-An.
Reaction SMILES: CCCC[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH3:12]CCCCC.[C:18]([OH:21])(=O)[CH3:19]>>[CH3:12][C:10](=[CH:9][CH2:8][CH2:7][C:6](=[CH:19][CH:18]=[O:21])[CH3:5])[CH3:11]
Reactant: CCCCCCCCCCC
Reactant: CC(=O)O
Reactant: CCCCCC
Product: CC(C)=CCCC(C)=CC=O

Procedure:
The following were charged into the aqueous phase: undecane, N-oxide, hexane (same quantities as above) and a supplementary amount of acetic acid (0.6 g). The mixture was then heated for 1 hour and the procedure was thereafter as before. Nine conversions were performed in this manner on the same catalytic lower layer. The yields of citral are given in the following table:
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][C@@H:9]1[CH2:12][C@H:11]([C:13]([OH:15])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCCCC1.ClC(OCC(C)C)=O.Cl.[CH3:32][NH:33][O:34][CH3:35]>ClCCl>[C:1]([O:5][C:6](=[O:7])[CH2:8][C@H:9]1[CH2:10][C@@H:11]([C:13](=[O:15])[N:33]([O:34][CH3:35])[CH3:32])[CH2:12]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](C(=O)O)C1
Reactant: CNOC
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCCCC1
Solvent: ClCCl
Product: CON(C)C(=O)[C@H]1C[C@@H](CC(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 99.5 %

Procedure:
To an ice cold solution of 1.74 g of cis-3-tert-butoxycarbonylmethyl-cyclobutanecarboxylic acid, 3 mL of N-methyl-piperidine, and 50 mL of dichloromethane was added 1.7 mL of isobutyl chloroformate drop-wise over 5 min. After an additional 5 min, 1.6 g of N-methyl-N-methoxy-amine hydrochloride was added and the mixture allowed to warm with stirring overnight. The resulting mixture was diluted with 100 mL of dichloromethane, washed with 100 mL of water, 100 mL of 0.1 N HCl, 50 mL of saturated sodium carbonate and dried over magnesium sulfate. The solution was diluted with 50 mL of toluene and concentrated under reduced pressure. Drying under vacuum overnight gave 2.08 g of product as a colorless thick oil: MS (m+1)=258.3; 1H NMR (400 MHz, CDCl3) 3.62 (s, 3H), 3.16 (s, 3H), 2.35 (d, 2H), 2.0 (dd, 1H), 1.4 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[C:10]#[C:11][CH3:12].N1C=CC=CC=1.Cl.[CH3:21][O:22][NH2:23].S([O-])([O-])(=O)=O.[Na+].[Na+]>CO.O>[CH3:21][O:22]/[N:23]=[C:9](/[C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])\[C:10]#[C:11][CH3:12]
Reactant: CC#CC(=O)c1ccc(F)cc1F
Reactant: CON
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: CO
Product: CC#C/C(=N\OC)c1ccc(F)cc1F
Reaction time: 0.03 h

Procedure:
1-(2,4-Difluorophenyl)but-2-yn-1-one (3.95 g, 21.93 mmol, prepared as described in WO 2000008002, Intermediate #39) was dissolved in MeOH (60 mL) then pyridine (6 mL) and O-methylhydroxylamine hydrochloride (3.66 g, 43.9 mmol) were added. The mixture was stirred for about 2 min until a solution was obtained then sodium sulfate (6.23 g, 43.9 mmol) was added. The mixture was stirred overnight at ambient temperature then the mixture was diluted with water (150 mL) and extracted with ethyl acetate (3×50 mL). The combined organic solutions were extracted with brine (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure to an oil. The material was purified by flash chromatography silica gel with heptane/ethyl acetate (85:15) as an eluent to give the title compound: (2.29 g, 50%): LC/MS (Table 1, Method g) Rt=2.58 min; MS m/z: 210.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([OH:16])=O)[N:9]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:27](C(C)C)CC)(C)C.[CH2:33](N)[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@:10]([C:14](=[O:16])[NH2:27])([CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:9]1[C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: NCCc1ccccc1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)N1C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC[C@@](CCc2ccccc2)(C(N)=O)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of (S)-tetrahydro-pyridazine-1,2,3-tricarboxylic acid 1,2-di-tert-butyl ester (83 mg, 2.5 mmol) in DMF (10 mL) at room temperature, is added diisopropylethylamine (1.4 mL) slowly. After stirring at room temperature for 20 minutes, to the reaction mixture, is added phenethylamine (445 mg, 3.67 mmol), and followed by a solution of HOBT (545 mg, 4.04 mmol) and HBTU (1.53 g, 4.04 mmol) in DMF (10 mL). After stirring for 1.5 hours at room temperature, the reaction solution is diluted with ether (100 mL), and washed with water (2×50 mL). The combined organic solution is concentrated. The crude product is diluted with CH2Cl2 and dried over Na2SO4, and purified by chromatography (CH2Cl2/MeOH:97/3) to give (S)-3-phenethyl carbamoyl-tetrahydro-pyridazine-1,2-dicarboxylic acid di-tert-butyl ester as pale gum (920 mg, 83.6% in two steps). (NMR and MS data confirmed, U-3133-57-26).