Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[SH:11].Cl[C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[CH:20][C:21](=[O:31])[C:22]=2[C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])[N:18]=1>C1COCC1>[F:29][C:28]1[CH:27]=[CH:26][CH:25]=[C:24]([F:30])[C:23]=1[C:22]1[C:21](=[O:31])[CH:20]=[CH:19][N:17]2[C:16]=1[CH:15]=[CH:14][C:13]([S:11][C:5]1[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:4]=1[F:3])=[N:18]2
Reactant: O=c1ccn2nc(Cl)ccc2c1-c1c(F)cccc1F
Reactant: Fc1ccc(S)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1ccn2nc(Sc3ccc(F)cc3F)ccc2c1-c1c(F)cccc1F
Reaction time: 0.17 h

Procedure:
To a solution of NaH (20 mg, 0.83 mmol) and 2,4-difluorobenzenethiol (74 mg, 0.51 mmol), in THF 2 mL was added 2-chloro-5-(2,6-difluorophenyl)-6H-pyrido[1,2-b]pyridazin-6-one (50 mg, 0.17 mmol) as a solution in THF (1 mL). The reaction was complete in 10 min and concentrated in vacuo. The crude residue was purified via silica gel chromatography (EtOAc/CH2Cl2/MeOH) to yield the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][Si](C=[N+]=[N-])(C)C>CO.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[C:10]([O:12][CH3:22])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCSc1ccccn1)C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](CCSc1ccccn1)NC(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
To 2(S)-tert-butoxycarbonylamino-4-(pyridin-2-ylsulfanyl)butyric acid (0.75 g, 2.40 mmol) in methanol (16 mL) and toluene (50 mL) was added a 2.0M solution of (trimethylsilyl)diazomethane (3.12 mmol) dropwise. After 3 h, the reaction mixture was concentrated to give methyl 2(S)-tert-butoxycarbonylamino-4-(pyridin-2-ylsulfanyl)butyrate as an oily residue which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[N:10]([N:14]=[C:15]([NH2:17])[N:16]=3)[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.Cl>CCO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][N:10]3[N:14]=[C:15]([NH2:17])[N:16]=[C:9]23)=[CH:4][CH:3]=1
Reactant: Nc1nc2c(-c3ccc(F)cc3)cccn2n1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1nc2n(n1)CCCC2c1ccc(F)cc1

Procedure:
8-(4-Fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (232 mg, 1.02 mmol) in EtOH (10 mL) and aqueous HCl solution (25%, 162 L, 1.12 mmol) was hydrogenated in the presence of palladium on charcoal (10%, 232 mg, 0.22 mmol) at 50 bar and 50° C. for 18 hours. The catalyst was filtered off, washed thoroughly with EtOH and the solvent was removed from the combined filtrates. Saturated aqueous NaHCO3 solution was added to the residue. The aqueous phase was extracted with CH2Cl2, the combined organic phases were dried over sodium sulfate, the solvent was evaporated and the residue purified by silica gel chromatography using dichloromethane/methanol (with 10% ammonia) as eluent. The title compound was obtained as a white solid (174 mg, 74%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:21]1CCO[CH2:23][CH2:22]1.ClC(OCC(C)C)=O.C(N)C>O1CCCC1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]([NH:21][CH2:22][CH3:23])=[O:12])=[CH:14][CH:15]=1
Reactant: CN1CCOCC1
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccc(Cl)cc1
Agent: CC(C)COC(=O)Cl
Agent: CCN
Solvent: C1CCOC1
Product: CCNC(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Temperature: -25 °C
Reaction time: 16 h
Yield: 43 %

Procedure:
To 1.1 g (3.85 mM) of [(tert-butoxycarbonyl)amino](4-chlorophenyl)acetic acid in 10 ml of tetrahydrofurane were added, under stirring at −25° C., 0.5 ml (4.6 mM) of 4-methyl morpholine and 0.52 ml (4.0 mM) of isobutyl chloroformate. After 10 mn were then added, at −25° C. under stirring, 1.9 ml (3.85 mM) of ethylamine 2M in tetrahydrofurane. The reaction mixture was stirred at −25° C. for 1 h, and at room temperature for 16 h. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give an oil, which was further purified by silica gel column chromatography, using dichloromethane/cyclohexane (75/25) as eluant, to give 520 mg of tert-butyl 1-(4-chlorophenyl)-2-(ethylamino)-2-oxoethylcarbamate as a white solid.
Reaction SMILES: [C:1]([Si:5]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[O:6][CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([OH:16])=[C:11]([Cl:17])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].N12CCN(CC1)CC2.[CH3:38][N:39]([CH3:43])[C:40](Cl)=[S:41]>CN(C)C=O.C(OCC)(=O)C>[C:1]([Si:5]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[O:6][CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([O:16][C:40](=[S:41])[N:39]([CH3:43])[CH3:38])=[C:11]([Cl:17])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](OCCc1cc(Cl)c(O)c(Cl)c1)(c1ccccc1)c1ccccc1
Reactant: CN(C)C(=S)Cl
Agent: C1CN2CCN1CC2
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)C(=S)Oc1c(Cl)cc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.5 %

Procedure:
A solution of 4-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-2,6-dichloro-phenol (70) (289 mg, 0.78 mmol) in N,N-dimethylformamide (4 mL) at 25° C. was treated with 1,4-diazabicyclo[2.2.2]octane (172 μL, 1.56 mol) and dimethylthiocarbamoyl chloride (154 mg, 1.25 mmol). The reaction was stirred at 25° C. for 18 h. At this time, the reaction was diluted with ethyl acetate and was then washed with a 1N aqueous hydrochloric acid solution, water, and a saturated aqueous sodium chloride solution, dried with magnesium sulfate, filtered and concentrated under vacuum. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 95:5 petroleum ether/ethyl acetate) afforded dimethyl-thiocarbamic acid O-{4-[2-(tert-butyl-diphenyl-silanyloxy)ethyl]-2,6-dichloro-phenyl}ester (71) (376 mg, 90%) as a white solid; EI(+)-HRMS m/e calcd for C27H31Cl2N2O2SSi (M+H)+ 532.1295, found 532.1292. Exact Mass=531.1222; Molecular weight=532.61
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[N:18]1([C:23]2[CH:24]=[C:25]([CH2:29]O)[CH:26]=[CH:27][CH:28]=2)[CH:22]=[CH:21][CH:20]=[CH:19]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][CH:4]([C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([N:18]3[CH:22]=[CH:21][CH:20]=[CH:19]3)[CH:24]=2)=[CH:15][CH:16]=1)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)CC(OCC)c1ccc(O)cc1
Reactant: OCc1cccc(-n2cccc2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(OCC)c1ccc(OCc2cccc(-n3cccc3)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
Ethyl 3-ethoxy-3-(4-hydroxyphenyl)propionate (100 mg, 0.420 mmol) produced in Example 1 (1C) and 3-(1H-pyrrol-1-yl)phenylmethanol (104 mg, 0.600 mmol) were dissolved in tetrahydrofuran (2 mL), and triphenylphosphine (165 mg, 0.629 mmol) and a diethyl azodicarboxylate toluene solution (2.2 M, 290 μL, 0.638 mmol) were added thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at room temperature for 2 hours. The solvent in the reaction solution was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 90:10 (v/v)), whereby the objective title compound was obtained as a light yellow oily substance (107 mg, yield: 65%).
Reaction SMILES: [Cl:1][C:2]1([Cl:20])[CH:8]2[CH:4]([CH:5]([CH2:9][CH2:10][CH2:11][CH2:12][CH:13](OCC)[CH2:14][CH3:15])[CH2:6][CH2:7]2)[C:3]1=[O:19].C(C1CCC=C1)CCCCCC.ClC(Cl)(Cl)C(Cl)=O.P(Cl)(Cl)(Cl)=O>CCOCC.[Zn].[Cu]>[Cl:1][C:2]1([Cl:20])[CH:8]2[CH:4]([CH:5]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:6][CH2:7]2)[C:3]1=[O:19]
Reactant: CCOC(CC)CCCCC1CCC2C1C(=O)C2(Cl)Cl
Agent: [Cu]
Agent: CCCCCCCC1C=CCC1
Agent: O=C(Cl)C(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Product: CCCCCCCC1CCC2C1C(=O)C2(Cl)Cl

Procedure:
The next procedure followed is that of the preceding Example for the preparation of 7,7-dichloro-4-(5-ethoxyheptyl)bicyclo [3.2.0] heptan-6-one, substituting 3-heptylcyclopentene (49 g, 0.30 moles) diluted in ether (490 ml), trichloroacetyl chloride (97 g, 0.53 moles) and phosphorous oxychloride (81 g, 0.53 moles) both diluted with ether (150 ml), zinc/copper couple (30 g, 0.59 moles) were used. The crude product is submitted to short path distillation and subsequently fractionally distilled under reduced pressure, leaving a clear, colorless oil of 7,7-dichloro-4-heptylbicyclo[3.2.0]heptan-6-one (20.6 g, 0.075 moles), BP 115° C./0.22 mm.
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[N+:10]([C:13]1[CH:26]=[CH:25][C:16]([C:17]([O:19][CH2:20][C@:21]2([CH3:24])[CH2:23][O:22]2)=[O:18])=[CH:15][CH:14]=1)([O-:12])=[O:11].C(N(CC)CC)C>C(OCC)(=O)C>[Cl:1][C:2]1[N:3]([CH2:24][C@@:21]([OH:22])([CH3:23])[CH2:20][O:19][C:17](=[O:18])[C:16]2[CH:15]=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:26][CH:25]=2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Reactant: C[C@@]1(COC(=O)c2ccc([N+](=O)[O-])cc2)CO1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[C@@](O)(COC(=O)c1ccc([N+](=O)[O-])cc1)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 62.5 °C
Reaction time: 10 h
Yield: 87.2 %

Procedure:
2-Chloro-4-nitro-1H-imidazole (3 g, 20.34 mmol) and (S)-2-methyloxiran-2-ylmethyl 4-nitrobenzoate (5.31 g, 22.37 mmol) were dissolved in ethyl acetate (10 ml). Triethylamine (0.57 ml, 4.07 mmol) was added to the solution, and the resulting mixture was stirred at 60-65° C. for 10 hours. The reaction mixture was concentrated under reduced pressure. Ethyl acetate (3 ml) and toluene (30 ml) were added to the residue, and the resulting precipitates were filtered off to afford (S)-2-chloro-4-nitro-1-[2-hydroxy-3-(4-nitrobenzoyloxy)-2-methylpropyl]imidazole (6.82 g, yield 87%) as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:20][CH3:21])=[CH:9][C:10]=2[O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[N:5]=[CH:4][N:3]=1.[Cl:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][CH:27]=[C:28]2[NH2:33].Cl>C(O)(C)C>[ClH:1].[ClH:22].[Cl:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][CH:27]=[C:28]2[NH:33][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:20][CH3:21])=[CH:9][C:10]=2[O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[N:5]=[CH:4][N:3]=1
Reactant: Nc1cccc2c(Cl)cccc12
Reactant: COc1cc(OC2CCN(C)CC2)c2c(Cl)ncnc2c1
Agent: Cl
Solvent: CC(C)O
Product: COc1cc(OC2CCN(C)CC2)c2c(Nc3cccc4c(Cl)cccc34)ncnc2c1
Temperature: 25 °C
Yield: 159.7 %

Procedure:
A mixture of 4-chloro-7-methoxy-5-(N-methylpiperidin-4-yloxy)quinazoline (0.08 g), 5-chloro-1-naphthylamine (0.055 g), 6.2M hydrogen chloride in isopropanol (0.044 ml) and isopropanol (3 ml) was stirred and heated to reflux for 2 hours. The mixture was cooled to ambient temperature and the precipitate was isolated, washed with diethyl ether and dried under vacuum. There was thus obtained the title compound (0.129 g), a portion of which was treated with a saturated methanolic ammonia solution. The mixture was filtered and the filtrate was evaporated to give the free base; NMR Spectrum: (CDCl3) 1.9–2.1 (m, 4H), 2.22 (s, 3H), 2.25–2.4 (m, 2H), 2.6–2.7 (m, 2H), 3.94 (s, 3H), 4.7 (br s, 1H), 6.6 (s, 1H), 6.9 (s, 1H), 7.4 (m, 1H), 7.62 (d, 1H), 7.7 (m, 1H), 8.0 (m, 2H), 8.25 (d, 1H), 8.46 (s, 1H), 9.9 (br s, 1H); Mass Spectrum: M+H+ 449 and 451.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]([NH:16][CH2:17][CH2:18][CH2:19]C)=[O:15])(=[O:12])=[O:11])=[CH:6][CH:5]=1.CC1C=CN(C(Cl)=O)N=1>>[NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]([NH:16][CH2:17][CH2:18][CH3:19])=[O:15])(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: CCCCNC(=O)NS(=O)(=O)c1ccc(CCN)cc1
Agent: Cc1ccn(C(=O)Cl)n1
Product: CCCNC(=O)NS(=O)(=O)c1ccc(CCN)cc1

Procedure:
Treating in an analogous way N-[4-(2-aminoethyl)-benzenesulphonyl]-N'-n-butylurea of the melting point at 193°-195° C. with 3-methylpyrazole-1-carboxylic acid chloride, N-{4-[2-(3-methylpyrazole-1-carbonamide)-ethyl]-benzenesulphonyl}-N'-n-butylurea of the melting point at 145°-147° C. is obtained whereas from N-[4-(2-aminoethyl)-benzenesulphonyl]-N'-n-propylurea of the melting point at 194°-196° C., N-{4-[2-(3-methylpyrazole-1-carbonamide)-ethyl]-benzenesulphonyl}-N'-n-propylurea of the melting point at 146°-148° C. is obtained.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][O:2]1.[N+:11]([O-])([O-:13])=[O:12].[K+]>OS(O)(=O)=O>[N+:11]([C:7]1[CH:8]=[C:9]2[C:4]([CH2:3][O:2][C:1]2=[O:10])=[CH:5][CH:6]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])[O-]
Reactant: O=C1OCc2ccccc21
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C1OCc2ccc([N+](=O)[O-])cc21
Temperature: 20 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
To a stirred solution of 3H-Isobenzofuran-1-one (30.0 g, 0.220 mol) in H2SO4 (38 mL) was added KNO3 (28.0 g, 0.290 mol) in H2SO4 (60 mL) at 0° C. After the addition, the mixture was stirred at 20° C. for 1 h. The reaction mixture was poured into ice and the resulting precipitate was filtered off and recrystallized from ethanol to give 6-nitroisobenzofuran-1(3H)-one (32.0 g, 80%). 1H NMR (300 MHz, CDCl3) □ 8.76 (d, J=2.1, 1H), 8.57 (dd, J=8.4, 2.1, 1H), 7.72 (d, J=8.4, 1H), 5.45 (s, 2H).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[C:9](=[O:10])[C:8]2[CH:11]=[CH:12][CH:13]=[C:14]([C:15](Cl)=[O:16])[C:7]=2[O:6][C:5]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl.[OH-].[Na+]>CN(C)C=O.O>[OH:16][CH2:15][C:14]1[C:7]2[O:6][C:5]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[C:4]([CH3:3])[C:9](=[O:10])[C:8]=2[CH:11]=[CH:12][CH:13]=1
Reactant: Cc1c(-c2ccccc2)oc2c(C(=O)Cl)cccc2c1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(-c2ccccc2)oc2c(CO)cccc2c1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 56.1 %

Procedure:
467 ml of a 1.48N solution of sodium borohydride in anhydrous dimethyl formamide was added over a period of 30 minutes, under stirring at ambient temperature, to a solution of 100 g of 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carbonyl chloride (prepared as described in Da Re, supra) in 1 liter of anhydrous dimethylformamide. The reaction mixture was stirred for 2.5 hours at ambient temperature. 88 ml of 2N aqueous hydrochloric acid solution was added while maintaining the temperature at 0°-5° C. 102 ml of 12.7N aqueous sodium hydroxide solution was then added. The mixture was poured into 6 liters of water, stirred for 3 hours, and filtered on a Buchner funnel. The filter cake was washed with 4N sodium hydroxide solution and then with water. The resultant white solid was crystallized from methanol to give 50 g of the title compound, m.p. 145°-147° C.
Reaction SMILES: C(O)(=O)CCCCCCC/C=C\C[C@@H](CCCCCC)O.[C:22]([O:42][CH3:43])(=[O:41])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32][C@@H](CCCCCC)O>>[C:22]([O:42][CH3:43])(=[O:41])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=[CH2:32]
Reactant: CCCCCC[C@@H](O)C/C=C\CCCCCCCC(=O)OC
Agent: CCCCCC[C@@H](O)C/C=C\CCCCCCCC(=O)O
Product: C=CCCCCCCCCC(=O)OC
Yield: 100 %

Procedure:
This example illustrates the synthesis of the C20 diacid starting from ricinoleic acid. During the first stage, methyl ricinoleate is subjected to a pyrolysis at a temperature of 550° C. to form methyl 10-undecenoate, which is converted to the acid form by hydrolysis. In the second homometathesis stage, use is made of the ruthenium complex (3) catalyst described in the publication by Stefan Randl et al., Synlett (2001), 10, 430, which is very stable and does not decompose when it is exposed to air or to water. The homometathesis reaction is carried out in CH2Cl2, at a 0.15M 10-undecenoic acid concentration, at a temperature of 30° C. and for 2 hours with a catalyst concentration of 0.5 mol %. The yields are determined by chromatographic analysis. The yield of diacid HOOC—(CH2)8—CH═CH—(CH2)8—COOH is 67 mol %. This product can be hydrogenated according to a conventional process with a yield of 100%.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:10][N:9]=2)[CH2:3]1.C(N(CC)CC)C.[S:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[C:36](Cl)=[O:37]>ClCCl.C(OCC)(=O)C>[CH3:1][CH:2]1[CH2:3][N:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:10][N:9]=2)[CH2:5][CH2:6][N:7]1[C:36]([C:32]1[S:31][CH:35]=[CH:34][CH:33]=1)=[O:37]
Reactant: O=C(Cl)c1cccs1
Reactant: CC1CN(c2nnc(-c3ccccc3)c3ccccc23)CCN1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1CN(c2nnc(-c3ccccc3)c3ccccc23)CCN1C(=O)c1cccs1
Reaction time: 2 h

Procedure:
To a solution of 1-(3-methylpiperazin-1-yl)-4-phenylphthalazine BSL-2 (200 mg, 0.58 mmol) in 10 mL dichloromethane was added triethylamine (0.23 mL, 1.6 mmol, 3 eq) and thiophene-2-carbonyl chloride (0.095 mL, 0.88 mmol, 1.5 eq). After 2 h, the reaction was diluted with ethyl acetate and washed with sat. NaHCO3, water, and brine. The organic layer was dried over MgSO4, filtered, and concentrated. Purification by column chromatography afforded (2-methyl-4-(4-phenylphthalazin-1-yl)piperazin-1-yl)(thiophen-2-yl)methanone, 1. MS (M+H)+=415.1.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].O1CCCC1.B>C1COCC1>[OH:5][CH2:4][C:3]1[CH:7]=[CH:8][C:9]([S:11]([CH3:14])(=[O:12])=[O:13])=[CH:10][C:2]=1[OH:1]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(O)c1
Agent: B
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(CO)c(O)c1
Temperature: 0 °C
Reaction time: 17 h
Yield: 98.3 %

Procedure:
2-hydroxy-4-(methylsulfonyl)benzoic acid (3.59 g, 16.6 mmol) was dissolved in dry THF (100 ml) under a blanket of nitrogen. The solution was cooled down to 0° C. and 1.0 M borane tetrahydrofuran complex (61.4 ml, 61.4 mmol) was slowly added. After completed addition the reaction mixture was brought to ambient temperature and stirred for 17 h. Then it was cooled once more to 0° C. and carefully quenched with water, acidified with aqueous HCl (5%) and finally extracted several times with EtOAc. The combined organic phases were dried (Na2SO4), filtered and evaporated to dryness. Since 50% of the starting material remained the reaction was done once more with THF (250 ml) and 1.0 M borane tetrahydrofurane (50 ml, 50 mmol). Same workup as before but prior to extraction the pH was adjusted to 7. The organic phase was dried (Na2SO4), filtered and evaporated under reduced pressure to give a white powder (3.3 g). 1H-NMR (400 MHz, MeOH): δ 7.6 (1H, d, J 8 Hz), δ 7.39 (1H, d, J 8 Hz), δ 7.28 (1H, s), δ 4.69 (2H, s), δ 3.06 (3H, s).
Reaction SMILES: C([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([OH:24])[CH3:23])[C:13](=[O:25])[N:12]([CH3:26])[C:11]=2[N:10]=[C:9]1[CH3:27])C1C=CC=CC=1>C(O)(=O)C.C(OCC)(=O)C.[Pd]>[OH:24][C@H:22]([CH3:23])[CH2:21][CH2:20][CH2:19][CH2:18][N:14]1[C:15](=[O:17])[C:16]2[NH:8][C:9]([CH3:27])=[N:10][C:11]=2[N:12]([CH3:26])[C:13]1=[O:25]
Reactant: Cc1nc2c(c(=O)n(CCCC[C@@H](C)O)c(=O)n2C)n1Cc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1nc2c([nH]1)c(=O)n(CCCC[C@@H](C)O)c(=O)n2C

Procedure:
A solution of (R)-7-benzyl-1-(5-hydroxyhexyl)-3,8-dimethylxanthine (250 mg) in a mixture of acetic acid (10 ml) and ethyl acetate (10 ml) was hydrogenated in presence of palladium on carbon (50 mg) for 12 hours. The mixture was filtered through celite (5 g) and concentrated. The residue was dissolved in ethyl acetate (100 ml), washed with saturated sodium bicarbonate solution (50 ml), dried over magnesium sulfate and concentrated. The product was purified by flash chromatography (silica gel) eluting with 10% methanol/ethyl acetate. Yield=180 mg.
Reaction SMILES: [O:1]=[C:2]1[C:15]2[CH:14]=[CH:13][C:12]([C:16]([OH:18])=O)=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.S(Cl)([Cl:21])=O>>[O:1]=[C:2]1[C:15]2[CH:14]=[CH:13][C:12]([C:16]([Cl:21])=[O:18])=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: O=C(O)c1ccc2c(=O)c3ccccc3oc2c1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc2c(=O)c3ccccc3oc2c1

Procedure:
9-oxo-9H-xanthene-3-carboxylic acid (9 g, 37.4 mmol) was added to thionyl chloride (28 mL, 334 mmol). The mixture was refluxed for 5 h. At that time, the thionyl chloride was removed under vacuum and the remaining residue was diluted with toluene and concentrated to dryness to give 9-oxo-9H-xanthene-3-carbonyl chloride. A portion of 9-oxo-9H-xanthene-3-carbonyl chloride (0.25 g, 0.96 mmol) was dissolved in acetonitrile (7 mL). Diisopropylethylamine (335 μL, 1.9 mmol) was then added to the mixture with the subsequent addition of pyrrolidine (113 μL, 1.3 mmol). After stirring 2 h, the solvent was concentrated and the residue was purified by reverse phase preparative HPLC, using a gradient of acetonitrile (10%- 90%) in water with trifluoroacetic acid (0.1%) to afford the 3-(pyrrolidine-1-carbonyl)-xanthen-9-one. MS m/z (MH+) 294.1.
Reaction SMILES: Br[C:2]1[S:3][C:4]([S:7]([CH3:10])(=[O:9])=[O:8])=[CH:5][CH:6]=1.[F-].[Cs+].[CH:13]1([CH:18]=[C:19](B2OC(C)(C)C(C)(C)O2)[CH2:20][OH:21])[CH2:17][CH2:16][CH2:15][CH2:14]1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:13]1(/[CH:18]=[C:19](\[C:2]2[S:3][C:4]([S:7]([CH3:10])(=[O:9])=[O:8])=[CH:5][CH:6]=2)/[CH2:20][OH:21])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CS(=O)(=O)c1ccc(Br)s1
Reactant: CC1(C)OB(C(=CC2CCCC2)CO)OC1(C)C
Agent: [Pd]
Agent: [Cs+]
Agent: [F-]
Product: CS(=O)(=O)c1ccc(/C(=C\C2CCCC2)CO)s1
Yield: 56.1 %

Procedure:
According to method 17a was used 2-bromo-5-methanesulfonyl-thiophene (593 mg, 2.46 mmol), caesium fluoride ( 747 mg, 4.92 mmol), tetrakis-(triphenylphosphin)-palladium(0) (142 mg, 0.123 mmol) and 3-cyclopentyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-prop-2-en-1-ol (620 g, 2.46 mmol) to give 395 mg of purified compound. MS (m/e): 309.0 (M+Na).
Reaction SMILES: C([O:5][C:6](=[O:19])[CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)CCC.C(O)(C(F)(F)F)=O>ClCCl>[CH2:12]([O:11][CH2:10][CH2:9][O:8][CH2:7][C:6]([OH:19])=[O:5])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCCCOC(=O)COCCOCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)COCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
To a stirred solution of ester 9 (2.66 g, 10 mmol) in dichloromethane (91 ml) was added TFA (9 ml) reaction mixture was stirred at room temperature for 2 hrs and mixture was concentrated. Obtained residue was diluted in water and basified with a NaOH 1N solution. This aqueous layer was extracted with ether then acidified and extracted twice with EtOAc. Combined organic layers were dried over MgSO4, filtered and concentrated to give acid 10 (2 g, 95%) as an oil, used for next step without further purification.