Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:28][CH2:29][CH2:30][CH2:31][NH:32][CH2:33][CH2:34][CH2:35][CH2:36][NH:37][CH2:38][CH2:39][CH2:40][NH2:41]>COCCOC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([NH:41][CH2:40][CH2:39][CH2:38][NH:37][CH2:36][CH2:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30][CH2:29][NH2:28])=[O:12])=[CH:7][CH:8]=1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: NCCCNCCCCNCCCN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: COCCOC
Product: COc1ccc(CC(=O)NCCCNCCCCNCCCN)cc1
Reaction time: 48 h

Procedure:
According to the General Procedure using 4-methoxyphenylacetic acid (83 mg, 0.50 mMol), dicyclohexylcarbodiimide (56 mg, 0.27 mMol), and spermine (201 mg, 0.99 mMol) in DME (4 ml), activation during 2.5 h and coupling over 48 h. The product was eluted over silica gel with the lower layer of dichloromethane/methanol/0.880 ammonia solution (4:1:1). The desired amide was in fractions 16-25 and was homogeneous when monitored by tlc on silica (CH2Cl2 /MeOH/NH4OH lower layer, 4:1:1), Rf =0.07, (30 mg, 32%), lyophilisation gave 21 mg of a colourless, viscous oil whose spectroscopic data include: pmr (90 MHz, 2H2O) 1.4-1.8 (m, 8H, 4×CH2 --CH2), 2.4-2.9 (m, 10H, 5×CH2 --N), 3.3 (t, J=7, 2H, CON2H--CH2 --CH2), 3.5 (s, 2H, Ar--CH2 --CO), 3.83 (s, 3H, OCH3), 6.8-6.95 (m, 2H, 2×ArH 3,5), and 7.1-7.3 (m, 2H, 2×ArH 2,6)ppm.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH2:13]([N:20]1[CH2:25][CH2:24]/[C:23](=[N:26]\[N:27]([CH3:29])[CH3:28])/[CH:22]([CH3:30])[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CI>C1COCC1.ClCCl>[CH2:13]([N:20]1[CH2:25][CH:24]([CH3:1])[C:23](=[N:26][N:27]([CH3:29])[CH3:28])[CH:22]([CH3:30])[CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)NC(C)C
Reactant: CC1CN(Cc2ccccc2)CC/C1=N\N(C)C
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC1CN(Cc2ccccc2)CC(C)C1=NN(C)C
Temperature: -5 °C
Reaction time: 0.17 h
Yield: 98.3 %

Procedure:
Diisopropylamine (3.3 ml, 23.5 mmol) is dissolved in 20 ml of THF and cooled to −5° C. A 1.6M solution of n-butyllithium in THF (14.7 ml, 23.5 mmol) is added dropwise within 10 min. After additional 10 min at −5° C., a solution of 42 (4.8 g, 19.6 mmol) in 30 ml of THF is added within 20 min (the color of the reaction mixture changed to red). Now, the solution is cooled to −78 C. Methyliodide (1.33 ml, 21.5 mmol) is added dropwise within 15 min and the mixture is allowed to warm to room temperature over night. Dichloromethane is added and the solution is washed with water. Evaporation gave 5 g of a colorless oil, which is further purified by flash-chromatography (silicagel, ethyl acetate/hexanes 1:1)
Reaction SMILES: CCCCCC.C([Li])CCC.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH:27]1([C:30]2[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=2)[CH2:29][CH2:28]1.O>C1COCC1>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:34]([C:33]1[CH:36]=[CH:37][C:30]([CH:27]2[CH2:28][CH2:29]2)=[CH:31][CH:32]=1)[OH:35])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Brc1ccccc1OCc1ccccc1
Reactant: O=Cc1ccc(C2CC2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: OC(c1ccc(C2CC2)cc1)c1ccccc1OCc1ccccc1
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
In a nitrogen stream, an n-butyllithium hexane solution (2.6 M, 3.5 mL) was added dropwise to a solution of 1-benzyloxy-2-bromobenzene (2.2 g, 8.3 mmol) in THF (83 mL) at −78° C. and the mixture was stirred at the same temperature for 30 minutes. To this solution, a solution of 4-cyclopropylbenzaldehyde (1.1 g, 6.9 mmol) in THF (280 mL) was added dropwise at −78° C. The reaction mixture was stirred at the same temperature for one hour. Water was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:5)] to obtain the title compound (1.7 g, 75%).
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[CH:5]=[CH:6][N:7]=1.[O:16]([CH2:23][C:24]([NH2:26])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(Cl)Cl>[F:14][C:11]1[CH:12]=[CH:13][C:8]([N:4]2[CH:5]=[CH:6][N:7]=[C:2]([NH:26][C:24](=[O:25])[CH2:23][O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]2=[O:15])=[CH:9][CH:10]=1
Reactant: NC(=O)COc1ccccc1
Reactant: O=c1c(Cl)nccn1-c1ccc(F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(COc1ccccc1)Nc1nccn(-c2ccc(F)cc2)c1=O
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 35 %

Procedure:
Palladium (II) acetate (36 mg, 0.16 mmol) was added to a suspension of 3-chloro-1-(4-fluoro-phenyl)-1H-pyrazin-2-one (0.71 g, 3.2 mmol), phenoxyacetamide (0.57 g, 3.8 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.138 g, 0.24 mmol) and Cs2CO3 (1.5 g, 4.45 mmol) in 1,4-dioxane (10 mL). The mixture was stirred at 80° C. for 15 minutes. Then DCM was added, the solid was filtered off and washed with more DCM. The filtrate was separated and the solvent evaporated in vacuo and the crude product was purified by flash column chromatography (silica; AcOEt in DCM 1/99 to 1/4). The desired fractions were collected and the solvents evaporated in vacuo to yield N-[4-(4-fluoro-phenyl)-3-oxo-3,4-dihydro-pyrazin-2-yl]-2-phenoxy-acetamide (0.38 g, 84% yield).
Reaction SMILES: [CH:1]1[C:18]2=[C:19]3[C:8]([C:9]4[C:20]5[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=5)[CH:12]=[CH:11][CH:10]=4)=[CH:7][CH:6]=[C:5]2[C:21]([O:23][C:24](=O)[C:3](=[C:4]23)[CH:2]=1)=[O:22].[CH2:26]([NH2:29])[CH:27]=[CH2:28]>CN1CCCC1=O>[CH2:26]([N:29]1[C:21](=[O:22])[C:5]2[C:4]3[C:19]4[C:8](=[CH:7][CH:6]=2)[C:9]2[C:20]5[C:13]([CH:12]=[CH:11][CH:10]=2)=[CH:14][CH:15]=[CH:16][C:17]=5[C:18]=4[CH:1]=[CH:2][C:3]=3[C:24]1=[O:23])[CH:27]=[CH2:28]
Reactant: C=CCN
Reactant: O=C1OC(=O)c2ccc3c4cccc5cccc(c6ccc1c2c63)c54
Solvent: CN1CCCC1=O
Product: C=CCN1C(=O)c2ccc3c4cccc5cccc(c6ccc(c2c36)C1=O)c54
Temperature: 85 °C

Procedure:
A mixture of 5 g (15.5 mmol) of perylene-3,4-dicarboxylic anhydride (prepared in accordance with Liebigs Ann. 1995, 1229–1244), 11.4 g (0.2 mol) of allylamine and 1200 ml of N-methylpyrrolidone was heated at 85° C. in a 2 1 autoclave for 7 h and then cooled to room temperature, the autoclave was let down, the solvent was reduced to about 25% of its original volume by concentration, and the precipitation of the crude product was completed by adding four times the amount of methanol. The precipitate formed was isolated by filtration, washed with methanol and dried at 60° C. under reduced pressure. Chromatographic separation on silica gel using 40:1 chloroform/methanol as eluent, followed by twofold recrystallization from chloroform, gave 4.83 g (86%) of the desired end product in the form of brownish red crystals which underwent decomposition at temperatures above 260° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([CH3:11])[C:5]([N+:8]([O-])=O)=[CH:6][CH:7]=1.C1CCCCC=1>[Pd].C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH3:11])[C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: Cc1c([N+](=O)[O-])ccc(Cl)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: Cc1c(N)ccc(Cl)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A mixture of 3-chloro-2,6-dinitrotoluene (18.0 g), cyclohexene (51 mL), and 10% palladium on charcoal (4.5 g) in ethanol (350 mL) was heated at reflux under an atmosphere of nitrogen for 1.5 hr. The reaction mixture was cooled to room temperature, filtered through celite, then evaporated under reduced pressure. The residue was dissolved in ethyl ether and filtered through a short silica column. Evaporation of the ether afforded 14.8 g as an orange solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:31][CH3:32])[CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([N+:19]([O-])=O)=[CH:13][C:14]=2[N+:16]([O-])=O)[C:9]([NH:22][CH2:23][CH2:24][CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[N:8]1)[CH3:2].CO.O.Cl>[Fe].C(Cl)(Cl)Cl>[CH2:31]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([NH2:19])=[CH:13][C:14]=2[NH2:16])[C:9]([NH:22][CH2:23][CH2:24][CH2:25][N:26]([CH2:27][CH3:28])[CH2:29][CH3:30])=[N:8]1)[CH3:32]
Reactant: CCN(CC)CCCNc1nn(CCCN(CC)CC)c2c([N+](=O)[O-])cc([N+](=O)[O-])cc12
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCN(CC)CCCNc1nn(CCCN(CC)CC)c2c(N)cc(N)cc12
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 23.7 %

Procedure:
A mixture consisting of 12.0 g of the 1-(3-diethylaminopropyl)-3-(3-diethylaminopropylamino)-5,7-dinitroindazole, 18 g of iron powder, 60 ml of methyl alcohol, 30 ml of water and 3 ml of hydrochloric acid was stirred for 1.5 hours at 70° C. After cooling, the mixture was filtered, and the pH of the filtrate was adjusted to 11 with an aqueous potassium carbonate solution. The filtrate was extracted three times with 50 ml of ethyl acetate, and the ethyl acetate layer was washed with water. The layer was dried over anhydrous sodium sulfate, and ethyl acetate was removed under reduced pressure. The residue thus obtained was subjected to an alumina-column chromatography (alumina: 200 g) using chloroform as the developing solvent to give 2.46 g of 1-(3-diethylaminopropyl)-3-(3-diethylaminopropylamino)-5,7-diaminoindazole having the following analytical values in a yield of 23%.
Reaction SMILES: [N+]([O-])([O-])=O.[Nd+3:5].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[CH3:14][O:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19].C(N(CC)CC)C>C(O)C>[Nd:5].[CH3:14][O:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19]
Reactant: [Nd+3]
Agent: COc1ccccc1C(=O)O
Agent: O=[N+]([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: [Nd]
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
The compound was synthesized by the same method as that for Synthesis Example 1-2 above, that is, after forming a triethylamine salt of 2-methoxybenzoic acid in anhydrous ethanol, an ethanol solution of neodymium nitrate was added while stirring. Specifically, a reactor similar to that of 1-1 was used to stir a slurry solution obtained by adding 100 ml of an anhydrous ethanol to 45.65 g (0.3 mol) of 2-methoxybenzoic acid, while dripping 30.4 g (0.3 mol) of triethylamine while maintaining at 20-30° C. by cooling in an ice water bath. After dripping about one-third of the triethylamine, the slurry disappeared and became transparent. After dripping, the solution was heated for 30 minutes at 40° C. to prepare a transparent synthesis solution of 2-methoxybenzoic acid-triethylamine salts. Next, while stirring this synthesis solution and holding at 25° C., a solution obtained by dissolving 43.8 g of neodymium nitrate into 120 ml of ethanol was dripped in. Upon completion of dripping, the solution was heated to 40° C., began to cloud after 40 minutes, and the clouding increased with time. After another 20 minutes, it became an extremely thick slurry solution, so 100 ml of ethanol were further added, and the solution was stirred for another hour at 40° C., then cooled to end the reaction. Next, crystals obtained by filtering this slurry solution were added to 200 ml of methanol, stirred and washed, then refiltered, and 200 ml of methanol were once again added to the crystals, stirred and washed, then filtered. The resulting crystals were dried under reduced pressure at 50° C., to obtain 50.83 g of a neodymium salt of 2-methoxybenzoic acid (yield 85%).
Reaction SMILES: CN(C)C=CC1[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[CH:6]=1.O=[O+][O-].OO.[C:18]([OH:21])(=[O:20])[CH3:19]>>[CH3:11][C:7]1[CH:6]=[C:19]([CH:10]=[CH:9][N:8]=1)[C:18]([OH:21])=[O:20]
Reactant: CC(=O)O
Reactant: Cc1cc(C=CN(C)C)ccn1
Agent: O=[O+][O-]
Agent: OO
Product: Cc1cc(C(=O)O)ccn1
Temperature: 17.5 °C
Reaction time: 0.5 h

Procedure:
1.63 g Dimethyl-[2-(2-methyl-pyridin-4-yl)-vinyl]-amine (10 mmol) were dissolved in 19 ml acetic acid containing 1 ml H2O. To the red solution maintained and stirred at ca. 15-20° C. was passed O3 (˜85 mmol/hour) for 1 hour. The reaction was mildly exothermic, changing in appearance from an orange (10 min) to a yellow solution (15 min) then from a yellow (20 min) to a white suspension (30 min). Excess ozone was purged with argon until a peroxide test was essentially negative. 1.02 ml 30% aqueous H2O2 (10 mmol) was added in one portion, and the resulting yellow suspension was stirred at 50° C. for 2 hours during which time a white suspension was formed. With the aid of toluene, the aqueous acetic acid solvent was removed under reduced pressure (45° C./100-50 mbar). The white residue was briefly digested in 25 ml tert. butyl methyl ether (TBME) at 40° C. then at ambient temperature for 30 min. The product was filtered, washed with TBME and dried for 2 hours at 45° C./25 mbar: 1.17 g (85%) biege crystals (GLC 98 area %, as trimethylsilylester).
Reaction SMILES: C([O:8][CH2:9][CH2:10][N:11]1[C:15]([CH3:16])=[C:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][CH:19]=2)[C:13]([O:26][C@@H:27]2[O:35][C@H:34]([CH2:36][OH:37])[C@@H:32]([OH:33])[C@H:30]([OH:31])[C@H:28]2[OH:29])=[N:12]1)C1C=CC=CC=1>C(O)C.[C].[Pd]>[CH2:24]([C:21]1[CH:20]=[CH:19][C:18]([CH2:17][C:14]2[C:13]([O:26][C@@H:27]3[O:35][C@H:34]([CH2:36][OH:37])[C@@H:32]([OH:33])[C@H:30]([OH:31])[C@H:28]3[OH:29])=[N:12][N:11]([CH2:10][CH2:9][OH:8])[C:15]=2[CH3:16])=[CH:23][CH:22]=1)[CH3:25]
Reactant: CCc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)nn(CCOCc3ccccc3)c2C)cc1
Agent: [Pd]
Solvent: CCO
Product: CCc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)nn(CCO)c2C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 111.2 %

Procedure:
To a solution of 1-(2-benzyloxyethyl)-4-[(4-ethylphenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-methyl-1H-pyrazole (0.012 g) in ethanol (2 mL) was added a catalytic amount of 10% palladium-carbon powder, and the mixture was stirred at room temperature under a hydrogen atmosphere for 30 minutes. Insoluble materials were removed by filtration, and the solvent was removed under reduced pressure to give 4-[(4-ethylphenyl)methyl]-3-(β-D-glucopyranosyloxy)-1-(2-hydroxyethyl)-5-methyl-1H-pyrazole (0.011 g).
Reaction SMILES: [N+:1]([C:4]1[C:5](CC(OC(C)(C)C)=O)=[N:6][C:7]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:9]=1)([O-])=O.[C:25](O)(=[O:27])[CH3:26]>[Fe]>[C:11]1([S:10][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][N:6]=2)[NH:1][C:25](=[O:27])[CH2:26]3)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)Cc1nc(Sc2ccccc2)ccc1[N+](=O)[O-]
Reactant: CC(=O)O
Agent: [Fe]
Product: O=C1Cc2cc(Sc3ccccc3)ncc2N1
Temperature: 25 °C
Yield: 77 %

Procedure:
A solution of t-butyl (3-nitro-6-phenylthio-2-pyridyl)acetate (1.04 g, 3.0 mmol) in glacial acetic acid containing iron powder (600 mg, 10.7 mmol) was heated at reflux for 5 hours. After cooling to room temperature, the mixture was poured into ice/water and extracted with chloroform. The combined chloroform extracts were washed with brine, dried (MgSO4) and concentrated to leave 5-phenylthio-6-azaoxindole as a light yellow solid (560 mg, 77%); m.p. 186°-189° C.
Reaction SMILES: Cl.[O:2]=[C:3]1[C@@H:8]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][CH2:6][CH2:5][N:4]1[CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.Cl[C:27]1[N:32]=[CH:31][C:30]([CH2:33][CH3:34])=[CH:29][N:28]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:33]([C:30]1[CH:29]=[N:28][C:27]([N:23]2[CH2:24][CH2:25][CH:20]([N:4]3[CH2:5][CH2:6][CH2:7][C@H:8]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:3]3=[O:2])[CH2:21][CH2:22]2)=[N:32][CH:31]=1)[CH3:34]
Reactant: CCc1cnc(Cl)nc1
Reactant: O=C(N[C@H]1CCCN(C2CCNCC2)C1=O)OCc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cnc(N2CCC(N3CCC[C@H](NC(=O)OCc4ccccc4)C3=O)CC2)nc1
Temperature: 100 °C
Yield: 58.2 %

Procedure:
A flask was charged with (S)-benzyl 2-oxo-1,4′-bipiperidin-3-ylcarbamate hydrochloride (4.1 g, 11 mmol), 2-chloro-5-ethylpyrimidine (1.7 g, 12 mmol), DIEA (3.9 mL, 22 mmol), and DMF (30 mL). The reaction was heated to 100° C. overnight. The reaction was cooled to ambient temperature, concentrated and purified over silica gel (25-75% EtOAc in hexanes) to afford (S)-benzyl 1′-(5-ethylpyrimidin-2-yl)-2-oxo-1,4′-bipiperidin-3-ylcarbamate (2.8 g, 57% yield).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:15]=[CH:14][C:7]([CH:8]=[C:9]([C:12]#[N:13])[C:10]#[N:11])=[CH:6][CH:5]=1.[CH:18]([Mg]Br)([CH3:20])[CH3:19]>O1CCCC1.[Cu]I>[F:1][C:2]([F:16])([F:17])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH:8]([CH:9]([C:12]#[N:13])[C:10]#[N:11])[CH:18]([CH3:20])[CH3:19])=[CH:14][CH:15]=1
Reactant: CC(C)[Mg]Br
Reactant: N#CC(C#N)=Cc1ccc(OC(F)(F)F)cc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: CC(C)C(c1ccc(OC(F)(F)F)cc1)C(C#N)C#N
Yield: 55 %

Procedure:
Using 1.19 g of (4-(trifluoromethoxy)benzylidene)malononitrile, 20 ml of tetrahydrofuran, a catalytic amount of copper (I) iodide, and a solution of isopropyl magnesium bromide in tetrahydrofuran (prepared from 0.39 g of magnesium, 10 ml of tetrahydrofuran, and 2.36 g of isopropyl bromide), and according to the process described in Reference Production Example 2, there was obtained 0.77 g of (1-(4-(trifluoromethoxy)phenyl)-2-methylpropyl)malononitrile (the intermediate (8)).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:25][C:26]([OH:30])([C:28]#[CH:29])[CH3:27].C(NC(C)C)(C)C>C1COCC1.[Cu]I.[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>[CH2:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:29]#[C:28][C:26]([OH:30])([CH3:27])[CH3:25])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCCCCCCCCOc1ccc(-c2ccc(C#CC(C)(C)O)cc2)cc1

Procedure:
A stirred mixture of compound 68 (15.00 g, 0.039 mol), 2-methylbut-3-yn-2-ol (7.15 g, 0.085 mol), copper(I) iodide (0.34 g, 1.80 mmol), tetrakis (triphenylphosphine) palladium(0) (2.89 g, 2.50 mmol) and diisopropylamine (150 ml) was heated under reflux in a dry nitrogen atmosphere for 24 h. The resultant mass was dissolved in THF and filtered over hyflo filter aid to remove inorganic materials. Volatile materials were removed in vacuo and the brown solid was recrystallised from ethanol to give a white, fluffy solid.
Reaction SMILES: N1CCCCC1.[CH2:7]([O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][C:16]=1[O:23][CH3:24])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([CH2:28][C:29]([NH:31][C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34]([OH:36])=[O:35])=[O:30])(O)=O.CC(O)=O>C1(C)C=CC=CC=1>[CH2:7]([O:14][C:15]1[CH:22]=[CH:21][C:18](/[CH:19]=[CH:28]/[C:29]([NH:31][C:32]2[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=2[C:34]([OH:36])=[O:35])=[O:30])=[CH:17][C:16]=1[O:23][CH3:24])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1cc(/C=C/C(=O)Nc2ccccc2C(=O)O)ccc1OCc1ccccc1

Procedure:
Piperidine (0.20 mL, 2.1 mmol) was added to a suspension of 4-benzyloxy-3-methoxybenzaldehyde (0.50 g, 2.1 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.42 g, 1.9 mmol) in toluene (5 mL) and treated according to Procedure 2, acidifying with 20% AcOH. The crude product was recrystallised from EtOH providing (E)-2-[[3-(4-benzyloxy-3-methoxyphenyl)-1-oxo-2-propenyl]amino]benzoic (0.48 g, 63%) as a yellow crystalline solid; mp 197-199° C.; δH (400 MHz, DMSO-d6) 3.84 (s, 3H, OCH3), 5.13 (s, 2H, OCH2), 6.79 (d, J=15.6 Hz, 1H, CH═CHCO), 7.07 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.16 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.22 (d, J5′,6′=8.0 Hz, 1H, H6′), 7.31-7.46 (m, 6H, H2′, Ph), 7.55 (d, J=15.6 Hz, 1H, CH═CHCO), 7.61 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 8.00 (d, J3,4=8.0 Hz, 1H, H3), 8.62 (d, J5,6=8.0 Hz, 1H, H6), 11.28 (s, 1H, NH), 13.60 (br s, 1H, CO2H); do (100 MHz, DMSO-d6) 55.7, 69.8, 110.7, 113.1, 116.6, 120.0, 120.3, 122.5, 122.7, 127.5, 127.8, 127.9, 128.4, 131.1, 134.0, 136.8, 141.1, 141.6, 149.3, 149.6, 164.2, 169.5; HRMS (ESI) calculated for C24H21NO5 [M−H]− 402.1336. found 402.1342; vmax 697, 1133, 1233, 1516, 1599, 1673, 1697, 3035 cm−1.
Reaction SMILES: [C:1]([C:14]1[C:18]([CH3:19])=[C:17]([CH2:20][C:21]([O:23]CC)=[O:22])[N:16]([CH2:26][C:27]2[CH:28]=[C:29]([CH:37]=[CH:38][CH:39]=2)/[CH:30]=[CH:31]/[C:32]([O:34]CC)=[O:33])[C:15]=1[CH3:40])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[OH-].[K+]>C(O)C>[C:21]([CH2:20][C:17]1[N:16]([CH2:26][C:27]2[CH:28]=[C:29]([CH:37]=[CH:38][CH:39]=2)/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33])[C:15]([CH3:40])=[C:14]([C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:18]=1[CH3:19])([OH:23])=[O:22]
Reactant: CCCCCCCCCCCC(=O)c1c(C)c(CC(=O)OCC)n(Cc2cccc(/C=C/C(=O)OCC)c2)c1C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCC(=O)c1c(C)c(CC(=O)O)n(Cc2cccc(/C=C/C(=O)O)c2)c1C
Reaction time: 1 h

Procedure:
A mixture of 55 mg (0.1 mmol) of ethyl (E)-3-({3-dodecanoyl-5-[(ethoxycarbonyl)methyl]-2,4-dimethyl-pyrrol-1-yl}methyl)cinnamate, 12 ml of ethanol and 4 ml of 10% strength aqueous KOH solution is boiled for 1 h. Cooling is followed by dilution with water, acidification with dilute HCl and extraction with ether. The organic phase is washed with dilute HCl, dried over Na2SO4 and concentrated. The product is recrystallized from methanol/H2O.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[C:5]1([OH:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.F>>[OH:11][C:5]1[CH:10]=[CH:9][C:8]([C:2]([NH2:3])=[S:1])=[CH:7][CH:6]=1
Reactant: N#C[S-]
Reactant: Oc1ccccc1
Agent: F
Agent: [K+]
Product: NC(=S)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 85 %

Procedure:
At a temperature and in the manner as described in Example 1, 69 g of potassium thiocyanate (0.7 mol) and 52 g of phenol (0.55 mol) are stirred with 0.5 l of 98% hydrofluoric acid, and subsequently, the mixture is stirred for 3 days at room temperature. 0.3 l of hydrofluoric acid are then distilled off at normal pressure and a bath temperature of up to 60° C, the remainder is cooled and the residue is stirred with ice and water. The crude product precipitated is suction-filtered and may be purified by dissolving in dilute soda solution at room temperature, clarifying the solution and subsequent precipitation of the product with mineral acid or by recrystallization from water. The 4-hydroxy-thiobenzamide so obtained has a melting point of 192° - 193° C. The yield is 85% of the theoretical yield, relative to the phenol used.