Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]=[C:2]([NH:8][CH2:9][C:10]([O:12]CC)=[O:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].S=[C:16](NCC(O)=O)CCCCC.Cl.COC(=O)CNC.Cl.C(OC(=O)CN)C>>[CH3:16][N:8]([CH2:9][C:10]([OH:12])=[O:11])[C:2](=[S:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCC(=S)NCC(=O)O
Reactant: CCCCCC(=S)NCC(=O)OCC
Agent: CCOC(=O)CN
Agent: CNCC(=O)OC
Agent: Cl
Product: CCCCCC(=S)N(C)CC(=O)O

Procedure:
Following the procedure of Example 1 A (1), (2) and (3) except substituting sarcosine methyl ester hydrochloride of glycine ethyl ester hydrochloride, the title compound is obtained.
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH2:6]([O:13][C:14](Cl)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:17][C@H:18]([C@@H:39]1[CH2:43][C@@H:42]([CH:44]([CH3:46])[CH3:45])[C:41](=[O:47])[O:40]1)[CH2:19][N:20]1[C:25]([CH3:27])([CH3:26])[CH2:24][N:23]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH2:35][O:36][CH3:37])[C:22](=[O:38])[CH2:21]1.C(OCC)(=O)C>[Cl-].[Na+].O.O>[CH2:6]([O:13][C:14](=[O:15])[NH:17][C@H:18]([C@@H:39]1[CH2:43][C@@H:42]([CH:44]([CH3:45])[CH3:46])[C:41](=[O:47])[O:40]1)[CH2:19][N:20]1[CH2:21][C:22](=[O:38])[N:23]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH2:35][O:36][CH3:37])[CH2:24][C:25]1([CH3:27])[CH3:26])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COCOc1ccccc1N1CC(C)(C)N(C[C@H](N)[C@@H]2C[C@@H](C(C)C)C(=O)O2)CC1=O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COCOc1ccccc1N1CC(C)(C)N(C[C@H](NC(=O)OCc2ccccc2)[C@@H]2C[C@@H](C(C)C)C(=O)O2)CC1=O
Reaction time: 2 h
Yield: 96.1 %

Procedure:
206 mg of cesium carbonate (0.63 mmol) was added to a solution of 326 mg of N-{(S)-1-[(2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl]-2-[4-(2-methoxymethoxyphenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]ethyl}-2-nitrobenzenesulfonamide obtained in the above reaction (0.53 mmol) and 0.12 ml of thiophenol (content: 95%) (1.1 mmol) in N,N-dimethylformamide (5 ml) under a nitrogen atmosphere at room temperature, and the mixture was stirred at the same temperature for two hours. Brine was added to the reaction mixture, followed by extraction with methylene chloride. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol=20/1-10/1). 49 mg of sodium bicarbonate (0.57 mmol) and 78 μl of benzyloxycarbonyl chloride (0.53 mmol) were added to a solution of 209 mg of 4-{(S)-2-amino-2-[(2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl]ethyl}1-(2-methoxymethoxyphenyl)-5,5-dimethylpiperazin-2-one obtained above (0.48 mmol) in a mixed solvent of ethyl acetate (3 ml) and water (3 ml) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. Brine was added to the reaction mixture, followed by extraction with ethyl acetate. Then, the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol=20/1) to obtain 263 mg of {(S)-1-[(2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl]-2-[4-(2-methoxymethoxyphenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]ethyl}carbamic acid benzyl ester (yield: 87%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:24]([OH:26])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O[N:40]=[C:41]([O:43][CH:44]([CH3:46])[CH3:45])[NH2:42]>CN(C=O)C.O1CCOCC1>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:10][CH:11]([C:24]3[O:26][N:42]=[C:41]([O:43][CH:44]([CH3:46])[CH3:45])[N:40]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:18][CH2:19][CH:20]([OH:23])[CH2:21][CH2:22]3)=[O:16])[CH2:14]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CC(C)OC(N)=NO
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCC(O)CC3)C2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CCc1ccc(C2CC(c3nc(OC(C)C)no3)CN(C(=O)N3CCC(O)CC3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 80.0 mg (0.222 mmol) of the carboxylic acid from Example 21A in 0.89 ml of DMF and 1.78 ml of 1,4-dioxane were added, at 60° C., 108 mg (0.666 mmol) of 1,1′-carbonyldiimidazole, and the mixture was stirred for 3 h. Subsequently, the mixture was admixed with 52.4 mg (0.333 mmol; 75% purity) of isopropyl N′-hydroxyimidocarbamate [G. Zinner, G. Nebel, Arch. Pharm. 1970, 303, 385-390] and then stirred at RT for 2 h and then at 120° C. for 2 h. The reaction solution was concentrated under reduced pressure and purified directly by means of preparative HPLC. Yield: 22.6 mg (22% of theory)
Reaction SMILES: [CH:1](O)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C(C)=C>C(Cl)Cl>[C:2]1([CH2:1][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC(c1ccccc1)c1ccccc1
Agent: C=C(C)C(=O)O
Solvent: ClCCl
Product: c1ccc(Cc2ccccc2)cc1

Procedure:
To a solution of benzhydrol (184 mg, 1 mmol) in methylene chloride (1 mL) is added 0.2 g 90 weight percent HF/10 weight percent methacrylic acid polymer, 100,000 m. wt., and the solution stirred until complete by TLC. The liquid is decanted and the gel washed with 2×1 mL methylene chloride. The organic layers are combined and washed with 1 mL water, 1 mL NaHCO3, dried through MgSO4 and evaporated. Diphenylmethane is afforded.
Reaction SMILES: C(OC(=O)[N:10]([C:13]1[N:42]=[C:16]2[N:17]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=3)[C:18]([CH3:31])=[C:19]([C:29]#[N:30])[C@@H:20]([C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=3)[N:15]2[N:14]=1)[CH2:11][CH3:12])C1C=CC=CC=1>CO.[Pd]>[C:27]([C:24]1[CH:23]=[CH:22][C:21]([C@H:20]2[N:15]3[N:14]=[C:13]([NH:10][CH2:11][CH3:12])[N:42]=[C:16]3[N:17]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:40])([F:41])[F:39])[CH:33]=3)[C:18]([CH3:31])=[C:19]2[C:29]#[N:30])=[CH:26][CH:25]=1)#[N:28]
Reactant: CCN(C(=O)OCc1ccccc1)c1nc2n(n1)[C@H](c1ccc(C#N)cc1)C(C#N)=C(C)N2c1cccc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: CCNc1nc2n(n1)[C@H](c1ccc(C#N)cc1)C(C#N)=C(C)N2c1cccc(C(F)(F)F)c1

Procedure:
Under an atmosphere of argon protective gas, benzyl{(7R)-6-cyano-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}(ethyl)carbamate (17.0 mg, 29 μmol) was dissolved in degassed methanol (2 ml). After addition of palladium on activated carbon (10%; 2 mg), the mixture was hydrogenated under a hydrogen atmosphere (˜1 atm) at RT for 1 h. The reaction mixture was then filtered, the filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC (Kromasil C18 column, 50×20 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (10.9 mg, 83% of theory).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:10])[C:5](=[CH:8][CH:9]=1)[CH:6]=[O:7].C(=O)([O-])[O-].[K+].[K+].Br[CH:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20]>CC(=O)CC>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([CH3:1])=[CH:3][C:4]=1[O:10][CH:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20])=[O:7]
Reactant: COC(=O)C(C)Br
Reactant: Cc1ccc(C=O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)C(C)Oc1cc(C)ccc1C=O
Temperature: 70 °C

Procedure:
A mixture of 6.0 g (0.0441 mole) of 4-methylsalicylaldehyde, 7.31 g (0.0529 mole) of potassium carbonate, and 8.62 g (0.0529 mole) of methyl 2-bromopropionate in 50 mL of 2-butanone was heated at 70° C. for approximately seventeen hours. The mixture was then filtered, and the filtrate was evaporated under reduced pressure, leaving a light yellow oil as a residue. This oil was placed on a silica gel column and eluted first with diethyl ether/petroleum ether (25/75) and then with diethyl ether. After the product-containing fractions were combined and the solvents evaporated under reduced pressure, 8.2 g of methyl 2-(2-formyl-5-methylphenoxy)propionate was recovered as a white solid, m.p. 65°-68° C. The NMR and IR spectra were consistent with the proposed structure.
Reaction SMILES: C([O:3][C:4]([NH:6][N:7]([CH:10]([CH3:12])[CH3:11])[C:8]#[N:9])=O)C.[CH3:13][SH:14]>O>[CH:10]([N:7]1[C:8]([S:14][CH3:13])=[N:9][C:4]([OH:3])=[N:6]1)([CH3:12])[CH3:11]
Reactant: CCOC(=O)NN(C#N)C(C)C
Reactant: CS
Solvent: O
Product: CSc1nc(O)nn1C(C)C
Temperature: 120 °C
Reaction time: 24 h
Yield: 52.7 %

Procedure:
1370 g of 2-isopropyl-2-cyanohydrazinecarboxylic acid ethyl ester is placed into an autoclave, and 423 g of methyl mercaptan is injected. The temperature is held for 24 hours at 40° C. The resulting crystal mass is afterwards transferred to a 2.5 liter sulphonating flask, and heated in an oil bath for 2 1/2 hours at 120° C. There is then added to the reaction mixture cooled to 90° C 1.2 liters of water, whereupon the the reaction product precipitates in crystalline form. Crude 1-isopropyl-5-methylthio-3-hydroxy-1,2,4-thiazole is filtered off, and recrystallised from one liter of acetonitrile. There is obtained 730 g (52% of theory) of pure 1-isopropyl-5-methylthio-3-hydroxy-1,2,4-triazole, m.p. 88°-93° C.
Reaction SMILES: [Li].[F:2][C:3]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7](Br)=[CH:8]2.I[C:16]1[CH:21]=[CH:20][C:19]([C@H:22]2[CH2:27][CH2:26][C@H:25]([CH2:28][CH2:29][CH3:30])[CH2:24][CH2:23]2)=[CH:18][CH:17]=1.Cl>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.C1COCC1>[F:2][C:3]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([C:16]1[CH:17]=[CH:18][C:19]([C@H:22]3[CH2:27][CH2:26][C@H:25]([CH2:28][CH2:29][CH3:30])[CH2:24][CH2:23]3)=[CH:20][CH:21]=1)=[CH:8]2
Reactant: Fc1ccc2cc(Br)ccc2c1F
Reactant: CCC[C@H]1CC[C@H](c2ccc(I)cc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Li]
Solvent: C1CCOC1
Product: CCC[C@H]1CC[C@H](c2ccc(-c3ccc4c(F)c(F)ccc4c3)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a THF solution of an organic lithium reagent prepared from 5,6-difluoro-2-bromonaphthalene were added dropwise 4-iodo-1-(trans-4-propylcyclohexyl)benzene and a THF solution of tetrakis(triphenylphosphine)palladium (0) in the catalytic amount. The reaction mixture was then stirred at room temperature for 3 hours. To the reaction mixture were then added water and toluene to terminate the reaction. To the reaction solution was then added diluted hydrochloric acid until the aqueous phase became weakly acidic. The reaction solution was then extracted with toluene. The material thus extracted and the organic phase were together washed with water and then with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain an oily matter. The oily matter was purified through silica gel column chromatography (hexane), and then recrystallized from ethanol to obtain 5,6-difluoro-2-[4-(trans-4-propylcyclohexyl)phenyl]naphthalene in the form of white crystal.
Reaction SMILES: [CH:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[O:9]=[CH:10][C:11]([Cl:14])([Cl:13])[Cl:12].[Cl-].[Al+3].[Cl-].[Cl-]>Cl>[CH:1]1([CH:10]([OH:9])[C:11]([Cl:14])([Cl:13])[Cl:12])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: O=CC(Cl)(Cl)Cl
Reactant: C1=CCCCCCC1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: OC(C1C=CCCCCC1)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
A solution of cyclooctene (28 g; 254 m. moles) and chloral (36 g; 244 m. moles) in light petroleum (b.p. 80°-100° C.; 200 ml) was stirred and cooled and aluminum chloride (4 g; 30 m. moles) was added. The reaction was allowed to proceed for a period of 1 hour and was then stirred at room temperature for a further 31/2 hours. Ice (150 g) and concentrated hydrochloric acid (50 ml) was added, the mixture extracted with light petroleum (b.p. 40°-60° C.; 2×400 ml) and the combined extracts washed with saturated aqueous sodium carbonate (2×100 ml) and water (100 ml). The dried (Na2SO4) extract was evaporated to give crude 1-(2-cycloocten-1-yl)-2,2,2-trichloroethanol (61.4 g) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:24]C(=O)OCC=C)[C:10](=[O:23])[N:11]([CH2:15][CH:16]([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.CC1(C)C(=O)NC(=O)NC1=O>C(Cl)Cl>[NH2:24][CH:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:10]([N:11]([CH2:15][CH:16]([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])[CH:12]([CH3:14])[CH3:13])=[O:23]
Reactant: C=CCOC(=O)NC(Cc1ccc(Cl)cc1)C(=O)N(CC(OCC)OCC)C(C)C
Agent: CC1(C)C(=O)NC(=O)NC1=O
Solvent: ClCCl
Product: CCOC(CN(C(=O)C(N)Cc1ccc(Cl)cc1)C(C)C)OCC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
10 mg of palladium tetrakistriphenylphosphine are added to a solution of 13.2 g of allyl {2-(4-chlorophenyl)-1-[(2,2-diethoxyethyl)isopropylcarbamoyl]ethyl}carbamate, 18.9 g of dimethylbarbituric acid in 140 ml of methylene chloride under a protective argon gas atmosphere, and the reaction mixture is stirred for 12 h at room temperature. The reaction solution is concentrated under reduced pressure and purified by flash chromatography on silica gel (eluent methylene chloride, 1% Et3N, 0-10% methanol). The desired product is obtained with MW=356.90 (calculated monoisotopic); measured value (M−C2H6O+H)+: 311.10
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:13])([CH3:12])[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(N(CC)CC)C.CS(C)=O>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:13])([CH3:12])[CH:10]=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(CO)NC(=O)OC(C)(C)C
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C=O)NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
To a solution 2-(tert-Butoxycarbonylamino)-2-methyl-1-propanol (5.7 g, 30.0 mmol) in triethylamine (42 mL) was added a mixture of sulfur trioxide pyridine complex (14.3 g, 90.0 mmol) in anhydrous DMSO (dimethylsulfoxide) (50 mL) at room temperature. The reaction was stirred for 1 hour under nitrogen and concentrated. The residue was dissolved in EtOAc (200 mL), washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, and concentrated to give crude 2-(tert-butoxycarbonylamino)-2-methyl propionaldehyde as yellow oil. Purification by distillation afforded 4.90 g (87%) of waxy, white solid: 1H NMR (CDCl3) δ 1.30 (s, 6H), 1.41 (s, 9H), 4.97 (br, 1 H), 9.40 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.[F-].[K+]>C1COCC1>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2ccc(Cl)cc2)cc1
Yield: 99.5 %

Procedure:
4-Bromobenzaldehyde (95 mg, 0.51 mmol) reacted with 4-chlorophenylboronic acid (101 mg, 0.65 mmol) using 0.5/1.0 mol % of Pd(dba)2/Ph5FcP(t-Bu)2 and KF (87 mg, 1.55 mmol) in THF solvent at room temperature to give the title compound (110 mg, 99%) as a white solid: 1H-NMR (400 MHz, CDCl3): δ 10.07 (s, 1H, —CHO), 7.96 (d, 2H, J=7.04 Hz), 7.73 (d, 2H, J=7.04 Hz), 7.58 (d, 2H, J=7.16 Hz), 7.46 (d, 2H, J=7.27 Hz). 13C{1H}-NMR (100 MHz, CDCl3): δ 191.80, 145.84, 138.10, 135.35, 134.70, 130.34, 129.20, 128.58, 127.51. GC/MS(EI): m/z 216 (M+), 218, 152.
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9](O)=O.[C:14]([OH:33])(=[O:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]/[CH:22]=C\CCCCCCCC>>[C:14]([OH:33])(=[O:32])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]=[CH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:13])=[O:12]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: O=C(O)CCCCCCCC(=O)O
Product: O=C(O)CCCCCCCC=CCCCCCCCC(=O)O

Procedure:
Another preferred embodiment of the invention is the preparation of azelaic acid by biooxidation of oleic acid to form 9-octadecenedioic acid followed by oxidation of the 9-octadecenedioic acid to azelaic acid. While any grade of oleic acid can be used as the substrate, a typical technical grade oleic acid consists of the following carboxylic acids: 0.42% C12 ; 2.7% C14 ; 0.86% C14:1 ; 6.3% C16 ; 4.6% C16:1 ; 0.93% C17 ; 2.8 C18 ; 71.8% C18:1 ; 8.3% C18:2 ; 0.58% C18:3. The oleic acid can also be a high grade oleic acid obtained from a fatty oil of a Helianthus annuus (sunflower seed oil) species described, for example, in U.S. Pat. No. 4,627,192, the entire contents of which are incorporated herein by reference. Such oils are very rich in oleic acid and contain at least 80% by weight of oleic.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[S:19](Cl)(=[O:21])=[O:20]>N1C=CC=CC=1>[CH3:1][C:2]1[N:7]=[C:6]([NH:8][S:19]([C:10]2[CH:11]=[CH:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]=2)(=[O:21])=[O:20])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(N)n1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Solvent: c1ccncc1
Product: Cc1cccc(NS(=O)(=O)c2ccc3ccccc3c2)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 79 %

Procedure:
6-Methyl-pyridin-2-ylamine (1 g) and 2-naphthalenesulfonyl chloride (2.3 g) were dissolved in pyridine (5 mL) and the resulting mixture was allowed to stir at RT for 12 hours. After concentration in vacuo the residue was taken up in EtOAc, the solution washed with 1 N aqueous HCl, saturated brine then dried over sodium sulphate and concentrated in vacuo. The residue was purified by flash chromatography (heptane/EtOAc 5:1) to give the desired product naphthalene-2-sulfonic acid (6-methyl-pyridin-2-yl)-amide as a white foam (2.18 g). MS (ESI−): 297.2 ([M−H]−).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.[H-].[Na+].[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1>C(#N)C.CCOC(C)=O>[NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([CH2:20][C:19]2[CH:22]=[CH:23][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)[N:3]=1
Reactant: CCOC(=O)c1c[nH]nc1N
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1cn(Cc2ccc(OC)cc2)nc1N
Reaction time: 0.25 h

Procedure:
To a solution of 3-amino4-carbethoxypyrazole (15 g, 96.7 mmol) in acetonitrile (750 mL) was add NaH (60% oil dispersion, 4 g, 100 mmol) at rt. After 15 min., 4-methoxybenzyl chloride (15.7 g, 100 mmol) was added with stirring. The reaction was allowed to run for 24 h. The reaction mixture was then diluted with EtOAc and washed with H2O, brine and dried (Na2SO4). Removal of the solvent gave the crude product which was further purified by flash column (silica gel, EtOAc/hexane, 1:1) to give ethyl 5-amino-2-p-methoxybenzyl-4-pyrazolecarboxylate (4.2 g, LC: 3.10′ MH+: 276) along with Ethyl 5-amino-1-p-methoxybenzyl-4-pyrazolecarboxylate (4.5 g) (LC: 3.07′ [Gradient 1] MH+: 276) and mixture of the two (10.2 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10]Br.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.Cl>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: C1COCCN1
Reactant: COC(=O)c1ccccc1CBr
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1CN1CCOCC1
Yield: 38.3 %

Procedure:
A solution of N-bromosuccinimide, dibromomethane (3.56 g, 20 mmol) and methyl-2-methylbenzoate (3.04 g, 20 mmol) in 30 mL CHCl3 was refluxed for 4 h. The solvent was evaporated and the residue was purified by column chromatography, with EtOAc:hexanes, 1:5, as eluant, yielding (3.496 g, 76%) of 2-bromomethyl-benzoic acid methyl ester. A solution of 2-bromomethyl-benzoic acid methyl ester (368 mg, 2 mmol) and morpholine (174 mg, 2.0 mmol) in 8 mL DMF with 1 mL HCl (2 N) was refluxed overnight. The solvent was evaporated in vacuo and the residue was purified by column chromatography with EtOAc:hexanes, 1:4, yielding (180 mg, 38%) 2-(morpholin-4-ylmethyl)-benzoic acid methyl ester. The title compound was prepared from 2-(morpholin-4-ylmethyl)-benzoic acid methyl ester, hydrazine and then 3-trifluoromethyl-benzaldehyde in two steps by procedures similar to Example 29. 1H NMR (CDCl3): 8.46 (s, 1H), 8.02 (m, 2H), 7.96 (d, J=7.8 Hz, 1H), 7.45 (d, J=7.8 Hz, 1H), 7.54 (d, J=7.8 Hz, 1H), 7.45 (m, 2H), 7.22 (m, 1H), 3.82 (t, J=4.8 Hz, 4H), 2.64 (t, J=4.8 Hz, 4H).
Reaction SMILES: [F:1][C:2]1[C:10]([OH:11])=[C:9]2[C:5]([CH:6]=[C:7]([C:12](O)=[O:13])[NH:8]2)=[CH:4][C:3]=1[O:15][C:16]1[CH:17]=[N:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=1.[NH4+].O[N:28]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[F:1][C:2]1[C:10]([OH:11])=[C:9]2[C:5]([CH:6]=[C:7]([C:12]([NH2:28])=[O:13])[NH:8]2)=[CH:4][C:3]=1[O:15][C:16]1[CH:17]=[N:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=1
Reactant: CS(=O)(=O)c1ccc(Oc2cc3cc(C(=O)O)[nH]c3c(O)c2F)cn1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Oc2cc3cc(C(N)=O)[nH]c3c(O)c2F)cn1
Temperature: 0 °C
Yield: 22.1 %

Procedure:
To an ice-cooled and stirred mixture of 6-fluoro-7-hydroxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylic acid (2.5 g) in N,N-dimethylformamide (30 mL) were added 1-hydroxybenzotriazole ammonium salt (1.25 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.57 g). After stirred at 4° C. to room temperature for 15 h, the reaction mixture was partitioned between ethyl acetate and aqueous citric acid solution. The organic layer was washed successively with aqueous sodium hydrogen carbonate and brine, dried (MgSO4), filtered, and concentrated to give a light brown solid, which was washed with tetrahydrofuran-ethyl acetate to give the title compound (0.55 g, 22%) as a light pink solid. MS 366 (MH+).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5](C(OC(C)(C)C)=O)[C@H:4]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:3]1.[ClH:24].CCOC(C)=O>CCOC(C)=O>[ClH:24].[OH:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)[C@@H]1C[C@@H](O)CN1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 10.0 g of the compound obtained in Step 157-1 in EtOAc (49 ml) was added a solution of 4 mol/L hydrochloric acid/EtOAc (39 ml). The solution was stirred at room temperature for one hour. The precipitated crystal was filtered, and the crystal was washed with EtOAc. The title compound in the amount of 6.70 g (colorless solid) was obtained.
Reaction SMILES: [Cl-:1].[Al+3].[Cl-:3].[Cl-:4].ClC(Cl)(Cl)[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[Cl:1][C:9]1[CH:10]=[C:11]([Cl:3])[C:12]([Cl:4])=[CH:13][C:8]=1[OH:7]
Reactant: ClC(Cl)(Cl)Oc1ccccc1
Reactant: [Cl-]
Agent: [Al+3]
Product: Oc1cc(Cl)c(Cl)cc1Cl
Yield: 24 %

Procedure:
Although aluminium chloride is a member of the class of Lewis acids, other Lewis acids have not been found effective or useful in the process of the invention. Ferric chloride did not effect significant demethylation. Only a 24% yield of 2,4,5-trichlorophenol was obtained when trichloroanisole was treated with a large excess of concentrated sulphuric acid for six hours at 75° C. in the absence of solvent. Other Lewis acids, viz. boron trichloride, boron trifluoride and pyridinium hydrochloride, are not economically attractive for this use. Thus aluminium trichloride is preferred as the demethylating agent.