Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6](/[C:10](=[N:16]/[O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[N:28]=[C:29]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[O:30][C:31]=3[CH3:32])=[CH:21][CH:20]=2)/[C:11]([O:13]CC)=[O:12])[CH:7]=[CH:8][CH:9]=1.CO.Cl>O1CCCC1>[Br:3][C:4]1[CH:5]=[C:6](/[C:10](=[N:16]/[O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][C:27]3[N:28]=[C:29]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[O:30][C:31]=3[CH3:32])=[CH:23][CH:24]=2)/[C:11]([OH:13])=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1cccc(Br)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\C(=O)O)c2cccc(Br)c2)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 90.7 %

Procedure:
A 1N aqueous saturated solution of sodium hydroxide (5 ml) was added to a solution of ethyl Z-2-(3-bromophenyl)-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]acetate (430 mg) in tetrahydrofuran (10 ml)-methanol (5 ml) and stirred at 40° C. for 2 hours. 1N hydrochloric acid (5.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain Z-2-(3-bromophenyl)-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]acetic acid (370 mg, yield 91%) as colorless crystals. m.p. 181-182° C. (decomposition)
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:5]([CH3:15])=[C:6]([N+:12]([O-])=O)[C:7]([CH3:11])=[CH:8][C:9]=1[CH3:10])#[N:2].[Cl-].[NH4+]>CO.[Zn]>[C:1]([CH2:3][C:4]1[C:5]([CH3:15])=[C:6]([C:7]([CH3:11])=[CH:8][C:9]=1[CH3:10])[NH2:12])#[N:2]
Reactant: Cc1cc(C)c([N+](=O)[O-])c(C)c1CC#N
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: Cc1cc(C)c(CC#N)c(C)c1N
Yield: 69 %

Procedure:
To a solution of 3-cyanomethyl-1-nitro-2,4,6-trimethylbenzene (5.8 g in methanol (150 mL) were sequentially added ammonium chloride (6 g in 50 mL of water), zinc powder (6 g). The exothermic reaction was vigorously stirred until it was back to RT (2 h). To work up the crude mixture was filtered off and the cake was washed with methanol. The methanolic solutions were concentrated and the residue partitioned between ethyl acetate and 1 N NaOH. The organic layer was dried over MgSO4 and concentrated to give 3-cyanomethyl-2,4,6-trimethylaniline as a light brown solid (3.4 g, 69%).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]2[C:11]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17](C(O)=O)[CH:18]=4)[N:13]=3)=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:4][CH:3]=1.C([O:29][C:30](=[O:77])[C:31]1[CH:36]=[CH:35][C:34]([NH:37]C2CCCCC2)=[C:33]([NH:44][C:45](C2C=C3C(=CC=2)N=C(C2C(C4C=CC(Cl)=CC=4)=CC=C(C(N4CCCC4)=O)C=2)C=C3)=O)[CH:32]=1)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2[C:11]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:45]5[NH:37][C:34]6[CH:35]=[CH:36][C:31]([C:30]([OH:29])=[O:77])=[CH:32][C:33]=6[N:44]=5)[CH:18]=4)[N:13]=3)=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:25][CH:26]=1
Reactant: O=C(O)c1ccc2nc(-c3ccccc3-c3ccc(Cl)cc3)ccc2c1
Reactant: CCOC(=O)c1ccc(NC2CCCCC2)c(NC(=O)c2ccc3nc(-c4cc(C(=O)N5CCCC5)ccc4-c4ccc(Cl)cc4)ccc3c2)c1
Product: O=C(O)c1ccc2[nH]c(-c3ccc4nc(-c5ccccc5-c5ccc(Cl)cc5)ccc4c3)nc2c1

Procedure:
The title compound was synthesized from Compound 353b in two steps as described for Compound 25 and 27 Q=ethyl, respectively.
Reaction SMILES: [C:1]1([CH:7]([CH3:22])[CH2:8][NH:9][C:10](=O)[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:22][CH:7]1[C:1]2[C:6](=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:9][CH2:8]1
Reactant: CC(CNC(=O)c1ccc(C(F)(F)F)cc1)c1ccccc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC1CN=C(c2ccc(C(F)(F)F)cc2)c2ccccc21
Temperature: 110 °C

Procedure:
A 250-mL round-bottomed flask was charged with N-(2-phenylpropyl)-4-(trifluoromethyl)benzamide (5.19 g, 16.9 mmol), phosphorous pentoxide (4.8 g, 33.8 mmol) and toluene (75 mL). The reaction mixture was heated at 110° C. overnight and allowed to cool down to RT. Then it was poured over ice-water and neutralized with NaOH (10%). The organic phase was separated and the aqueous phase was extracted several times with EtOAc. The combined organics were washed with satd. NaHCO3, water, brine and dried over Na2SO4. The solvent was removed under vacuum and the product used without further purification.
Reaction SMILES: [CH2:1]([NH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].[Cs+].[CH3:16][O:17][CH2:18][C@H]1COC(=O)O1>CS(C)=O>[CH2:1]([N:8]1[CH2:13][C@H:12]([CH2:16][O:17][CH3:18])[O:11][C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC[C@H]1COC(=O)O1
Reactant: CCOC(=O)NCc1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: CS(C)=O
Product: COC[C@H]1CN(Cc2ccccc2)C(=O)O1
Temperature: 140 °C
Reaction time: 28 h
Yield: 83.5 %

Procedure:
Benzylurethane (15.0 g, 83.9 mmol) was dissolved in dimethyl sulfoxide (40 mL), and thereto were added cesium fluoride (1.16 g, 7.63 mmol) and (S)-4-methoxymethyl-1,3- dioxolan-2-one (10.0 g, 76.3 mmol, optical purity 98.4%ee), in order. The mixture was stirred for 28 hours at 140° C. under an atmosphere of argon. After filtering off the insoluble materials, the filtrate was condensed in vacuo, and the residue was purified by silica gel chromatography to give the subject (R)-3-benzyl-5-methoxymethyloxazolidin-2-one (14.1 g, yield 83.5%, optical purity 98.2%ee).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[C:16]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:15]=[CH:14][C:13]=1[OH:25].[C:26](Cl)(=[O:30])[C:27]([CH3:29])=[CH2:28]>N1C=CC=CC=1>[C:26]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[C:16]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:15]=[CH:14][C:13]=1[OH:25])(=[O:30])[C:27]([CH3:29])=[CH2:28]
Reactant: CCCCCCCc1ccc(O)c(CCCCCCCCCCO)c1
Reactant: C=C(C)C(=O)Cl
Solvent: c1ccncc1
Product: C=C(C)C(=O)OCCCCCCCCCCc1cc(CCCCCCC)ccc1O

Procedure:
2-(10-Hydroxydecyl)-4-heptylphenol (0.1 mol) prepared according to Example 3a is reacted with methacryloyl chloride (0.1 mol) in 300 ml of pyridine at 5° C. to give 2-(10-methacryloyloxydecyl)-4-heptylphenol.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:13][C:14]([NH2:21])([CH3:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17]>>[CH3:13][C:14]([NH:21][C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:20]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: CC(C)(C)CC(C)(C)N
Product: CCCCCCC/C=C/C(=O)NC(C)(C)CC(C)(C)C

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and 1,1,3,3-tetramethylbutylamine as starting materials to give the aimed compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:4].[F:18][C:19]([F:34])([F:33])[C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][C:11]([C:22]1[CH:23]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:25]=[C:20]([C:19]([F:18])([F:34])[F:33])[CH:21]=1)=[CH:10][CH:9]=2)=[O:4]
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(=O)c1c(O)c2cc(Br)ccc2sc1=O
Product: COC(=O)c1c(O)c2cc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)ccc2sc1=O

Procedure:
6-(3,5-Bis-trifluoromethyl-phenyl)-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester was prepared from 6-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (Example 27e) under conditions analogous to Example 7(a) using 3,5-Bis-trifluoromethyl-phenylboronic acid. 1H NMR (200 MHz, CDCl3): δ (ppm)=8.572 (s, 1H), 8.037 (s, 2H), 7.908 (s, 1H), 7.820 (d, 1H), 7.510 (d, 1H), 4.04 (s, 3H).
Reaction SMILES: S(=O)(=O)(O)O.[N:6]([O-:8])=O.[Na+].[C:10]([CH2:13][C:14](=[O:16])[CH3:15])(=[O:12])[CH3:11]>O>[CH3:15][C:14](=[O:16])[C:13](=[N:6][OH:8])[C:10](=[O:12])[CH3:11]
Reactant: O=N[O-]
Reactant: CC(=O)CC(C)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(=O)C(=NO)C(C)=O
Yield: 91 %

Procedure:
Variant c): In parallel, 490 g (2.5 mol) of 50% strength sulfuric acid and 852 g (5 mol) of 40.5% strength strength aqueous sodium nitrite solution were metered into a mixture of 500 g (5 mol) of acetylacetone and 2 l of water, the pH being adjusted to 3.7-4.2 and the temperature to 15-18° C. Work-up as in variant a) gave 588 g of the title compound (91% yield).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[C:5]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6].N([O-])=[O:17].[Na+]>S(=O)(=O)(O)O>[Cl:15][C:14]1[CH:13]=[CH:12][C:4]([C:5]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6])=[CH:3][C:2]=1[OH:17]
Reactant: Nc1cc(C(=O)CCC(=O)O)ccc1Cl
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)CCC(=O)c1ccc(Cl)c(O)c1

Procedure:
3-(3-amino-4-chlorobenzoyl)propionic acid was diagotised in sulphuric acid solution with sodium nitrite and the diazonium salt solution was added dropwise to boiling aqueous sulphuric acid to give 3-(4-chloro-3-hydroxybenzoyl)propionic acid.
Reaction SMILES: [C:1]1([C:15]([O:17][CH3:18])=[O:16])[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[CH:4]=[C:3]([C:11](OC)=[O:12])[CH:2]=1.[BH4-].[Na+].CO>C1COCC1>[OH:12][CH2:11][C:3]1[CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[CH:6]=[C:1]([CH:2]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1cc(C(=O)OC)cc(C(=O)OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(CO)cc(C(=O)OC)c1
Yield: 61.2 %

Procedure:
Trimethyl 1,3,5-benzenetricarboxylate (5.02 g, 19.9 mmol) was dissolved in THF (15 mL). The air was evacuated from the reaction system, and then Ar was charged therein. To the solution were added NaBH4 (901 mg, 23.8 mmol), and then a mixed solution of THF:MeOH (12.5 mL:3.7 mL) slowly dropwise. The reaction mixture was refluxed for 30 minutes. TLC was used to confirm the progress of the reaction. Then, the reaction was quenched with HCl (1 N, 20 mL). The mixture was extracted with EtOAc. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to remove the solvent. The residue was purified by neutral silica gel column chromatography (hexane:EtOAc=4:1 to 3:1) to isolate dimethyl 5-hydroxymethylisophthalate (32) (2.73 g, 61%) as white crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[O:19]=[C:20]1[N:24]([CH2:25][CH2:26]OS(C)(=O)=O)[CH2:23][CH2:22][O:21]1>CN(C=O)C>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][N:10]2[CH2:26][CH2:25][N:24]2[CH2:23][CH2:22][O:21][C:20]2=[O:19])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2cn[nH]c2c1
Reactant: CS(=O)(=O)OCCN1CCOC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1OCCN1CCn1ncc2ccc([N+](=O)[O-])cc21
Temperature: 60 °C
Yield: 39 %

Procedure:
To a mixture of 3-(2-hydroxy-ethyl)-oxazolidin-2-one (1.00 g, 7.63 mmol) and Hunigs base (2.92 mL, 16.8 mmol) in dichloromethane (19 mL) at 0° C. was added mesyl chloride (0.650 mL, 8.40 mmol) slowly via syringe. The mixture was stir cold for three hours, diluted with 10 mL of water and 25 mL of dichloromethane. The layers were separated and the organic layer was washed with aqueous NaHCO3 (3×30 mL) followed by water (1×15 mL). The organic layer was then dried (Na2SO4), filtered, and concentrate under reduced pressure to provide 650 mg of methanesulfonic acid 2-(2-oxo-oxazolidin-3-yl)-ethyl ester as a light brown oil. In a separate flask 6-nitroindazole (318 mg, 1.95 mmol) was treated with potassium carbonate (538 mg 3.9 mmol) in DMF (10 mL) for 30 minutes, afer which methanesulfonic acid 2-(2-oxo-oxazolidin-3-yl)-ethyl ester (490 mg 2.34 mmol) was added. The reaction mixture was heated to 60° C. for 6 hours, cooled to room temperature, filtered through a plug of silica gel and rinsed with triethylamine/ethyl acetate (1/4). The filtrate was concentrated under reduced pressure and purified by flash chromatography (silica gel, triethylamine/ethyl acetate 1/30) to provide the title compound (210 mg, 39% yield). 1H NMR (300 MHz, DMSO-d6) ppm 3.49 (m, 2H), 3.62 (t, J=5.76, 2H), 4.13 (m, 2H), 4.76 (t, J=5.76, 2H), 7.97–8.03 (m, 2H), 8.33 (m, 1H), 8.83 (m, 1H); MS (DCI/NH3) m/z 277 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:12].C(=O)([O-])[O-].[K+].[K+].[CH:19]1[CH:24]=[CH:23][C:22]([CH2:25]Br)=[CH:21][CH:20]=1>CC#N>[CH2:25]([O:11][C:8]1[CH:9]=[CH:10][C:2]([Br:1])=[C:3]2[C:7]=1[C:6](=[O:12])[CH2:5][CH2:4]2)[C:22]1[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1CCc2c(Br)ccc(O)c21
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1CCc2c(Br)ccc(OCc3ccccc3)c21
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Into a 250-mL round bottom flask, was placed 4-bromo-7-hydroxy-2,3-dihydro-1H-inden-1-one (1.5 g, 6.61 mmol, 1.00 equiv), CH3CN (30 mL) and potassium carbonate (1.83 g, 13.24 mmol, 2.00 equiv). BnBr (1.18 g, 6.90 mmol, 1.04 equiv) was added dropwise. The resulting solution was stirred for 2 h at 60° C. in an oil bath. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:4). The solids were removed by filtration. The resulting mixture was concentrated under reduced pressure. The residue was applied to a silica gel column, eluting with ethyl acetate/petroleum ether (1:4). This resulted in 2.1 g (95%) of 7-(benzyloxy)-4-bromo-2,3-dihydro-1H-inden-1-one as a yellow solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=1>C1COCC1>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:9][CH:10]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: C1CNCCN1
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(N2CCNCC2)nc1

Procedure:
Piperazine (1.2 g, 13.77 mM) was heated with 2-chloro-5-(trifluoromethyl)pyridine (0.5 g, 2.75 mmol) in THF (2 mL) for 2 hours. Subsequently the reaction mixture was poured onto crushed ice and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate and evaporated to furnish the required product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:14]=2[O:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([CH3:12])[CH3:11])=[C:6]([O:31][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:5]=1)([O-])=O.NN>C(O)C.[Pd]>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([C:10]([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][C:6]=2[O:31][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([CH3:12])[CH3:11])=[C:14]([O:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:15]=1
Reactant: CC(C)(c1ccc([N+](=O)[O-])cc1OC(=O)c1ccccc1)c1ccc([N+](=O)[O-])cc1OC(=O)c1ccccc1
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: CC(C)(c1ccc(N)cc1OC(=O)c1ccccc1)c1ccc(N)cc1OC(=O)c1ccccc1
Reaction time: 3 h
Yield: 95.6 %

Procedure:
148.4 g (0.25 mol) of the 2,2-bis (4-nitrobenzoyloxyphenyl) propane obtained in Reference Example 5 was dispersed in 500 ml of ethanol charged into a 1-liter four-neck flask equipped with a reflux condenser, thermometer, agitator and dropping funnel, and 2.5 g of 10% palladium supported activated charcoal was added, 66 g (1.05 mol) of hydrazine was added over a period of 30 minutes using the dropping funnel, with caution to rapid refluxing, and the refluxing was continued for 3 hours. After the reaction, the precipitate was removed and the filtrate was concentrated by an evaporator and recrystallized with ethanol. 111.5 g (yield: 86.7%) of 2,2-bis(4-aminobenzoyloxyphenyl)propane was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]=[CH:10][C:11]([NH:13][C@H:14]([C:24]([O:26]C)=[O:25])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)=[O:12].[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]=[CH:10][C:11]([NH:13][C@H:14]([C:24]([OH:26])=[O:25])[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)=[O:12]
Reactant: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C=Cc1cc(F)ccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C[C@H](NC(=O)C=Cc2cc(F)ccc2F)C(=O)O)cc1
Yield: 89 %

Procedure:
The same procedures as in Example 64 were carried out from the compound obtained in Example 48 (2.8 g), 1 mol/L of an aqueous sodium hydroxide solution (11 mL), and methanol (110 mL), to give the captioned compound (2.4 g, 89%) as crystals.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH2:23]([C:27]1[S:28][CH:29]=[C:30]([C:32]([N:34]2[CH2:39][C:38]3([CH2:44][CH2:43][N:42]([CH2:45][C:46]4[CH:51]=[CH:50][CH:49]=[C:48]([CH2:52][CH2:53][OH:54])[C:47]=4[F:55])[CH2:41][CH2:40]3)[O:37][CH2:36][CH2:35]2)=[O:33])[N:31]=1)[CH2:24][CH2:25][CH3:26].FC(F)(F)C(O)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[CH2:23]([C:27]1[S:28][CH:29]=[C:30]([C:32]([N:34]2[CH2:39][C:38]3([CH2:40][CH2:41][N:42]([CH2:45][C:46]4[C:47]([F:55])=[C:48]([CH2:52][CH:53]=[O:54])[CH:49]=[CH:50][CH:51]=4)[CH2:43][CH2:44]3)[O:37][CH2:36][CH2:35]2)=[O:33])[N:31]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4F)CC3)C2)cs1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CC=O)c4F)CC3)C2)cs1
Reaction time: 1 h

Procedure:
Dess-Martin periodinane (0.278 g) was added to a stirred solution of (2-butylthiazol-4-yl)(9-(2-fluoro-3-(2-hydroxyethyl)benzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone (example 78, step i) (0.240 g) and trifluoroacetic acid (0.058 mL) in DCM (5 mL). After 1 h, ethyl acetate (30 mL) was added followed by a mixture of saturated sodium thiosulphate solution (5 mL) and saturated sodium bicarbonate solution (5 mL). The reaction mixture was shaken well and separated. The ethyl acetate solution was washed with saturated sodium bicarbonate solution, water and brine. Acetic acid (0.08 mL) was added, the solution was dried over sodium sulphate, filtered and evaporated in vacuo (bath temperature ˜30° C.) to give the subtitled compound as a gum. Yield 0.24 g. Used directly.
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])(=[O:5])[CH3:4].Br[CH2:16][C:17]1[O:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1.[Cl-].[NH4+]>CN(C)C=O>[O:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=[C:17]1[CH2:16][O:13][C:10]1[CH:11]=[CH:12][C:7]([NH:6][C:3](=[O:5])[CH3:4])=[C:8]([CH3:14])[CH:9]=1
Reactant: CC(=O)Nc1ccc(O)cc1C
Reactant: BrCc1nc2ccccc2o1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(OCc2nc3ccccc3o2)cc1C
Reaction time: 0.08 h
Yield: 60.9 %

Procedure:
53.2 mg of sodium hydride (as a 60% w/w dispersion in mineral oil) were added to a solution of 200.0 mg of 4-acetamido-3-methylphenol in 10 ml of dimethylformamide cooled in an ice-water bath. The resulting mixture was stirred at the same temperature for 5 minutes, and then 307.9 mg of 2-bromomethylbenzoxazole [prepared as described in Example 28(a) above] were added. The temperature of the resulting mixture was elevated to room temperature and the mixture was stirred for 30 minutes. At the end of this time, the temperature of the reaction mixture was elevated to 50° C. and the mixture was stirred for a further 1.5 hours. At the end of this time, a saturated aqueous ammonium chloride solution was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The resulting extract was washed consecutively with water and a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure to give a crude crystalline solid which was purified by column chromatography through silica gel using a 3:1 by volume mixture of ethyl acetate and hexane as the eluent, to give 218.5 mg (yield 61%) of the title compound as a solid having a melting point of 160° C.
Reaction SMILES: [C:1]1(=[O:14])[C:13]2[C:5]([C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:4][CH:3]=[CH:2]1.[C:15](OC(=O)C)(=[O:17])[CH3:16].[Cl-].[Al+3].[Cl-].[Cl-].C(C1C=CC2C3C(=CC=CC=3)CC=2C=1)(=O)C.[Cr](O)(O)(=O)=O>C(O)(=O)C>[C:15]([C:2]1[C:1](=[O:14])[C:13]2[C:5](=[CH:4][CH:3]=1)[C:6]1[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:12]=2)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1C=CC=C2C1=Cc1ccccc12
Agent: O=[Cr](=O)(O)O
Agent: CC(=O)c1ccc2c(c1)Cc1ccccc1-2
Agent: [Al+3]
Solvent: CC(=O)O
Product: CC(=O)C1=CC=C2C(=Cc3ccccc32)C1=O

Procedure:
A method of producing the bisulphite compound of 2-fluorenonyl-glyoxal, viz, the active principle of said medicinal preparation, consists in that fluorene is acylated by dichloroacetyl chloride in the presence of aluminum chloride and phosphoryl chloride in an organic solvent, the resultant 2-ω-dichloroacetylfluorene is oxidized by the salts of chromic acid in an acetic-acid medium at 50°-90° C into 2-ω-dichloroacetylfluorenone which is made to interact with morpholine at 50°-98° C to form 2-ω-dimorpholinoacetylflourenone, or otherwise, fluorenone is acylated by acetic anhydride in an organic solvent in the presence of aluminum chloride, the resultant 2-acetylfluorene is oxidized by chromic acid or by the salts thereof in an acetic acid medium at 50°-90° C to obtain 2-acetylfluorenone which is brominated in an organic solvent at 60°-110° C, the resultant 2-ω-dibromoacetylfluorenone is reacted with morpholine at 50°-98° C to form 2-ω-dimorpholinoacetylfluorenone the latter is hydrolyzed by dilute mineral acids at 20°-100° C into 2-fluorenonyl-glyoxal hydrate which is then made to react with sodium bisulphite in an aqueous-alcohol medium at 60°-80° C to isolate the final product.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=[O:8])[CH3:7])(=[NH:3])[CH3:2].C(=O)(O)[O-].[Na+].Br[CH2:15][C:16]([C:18]1[CH:19]=[N:20][N:21]([CH3:30])[C:22]=1[C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)=O>C(#N)C.ClCCl>[CH3:2][C:1]1[N:4]([NH:5][C:6](=[O:8])[CH3:7])[CH:15]=[C:16]([C:18]2[CH:19]=[N:20][N:21]([CH3:30])[C:22]=2[C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)[N:3]=1
Reactant: Cc1ccc(-c2c(C(=O)CBr)cnn2C)cc1
Reactant: CC(=N)NNC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: CC(=O)Nn1cc(-c2cnn(C)c2-c2ccc(C)cc2)nc1C
Temperature: 80 °C

Procedure:
N′-Ethanimidoylacetohydrazide (147 mg, 1.28 mmol) and sodium bicarbonate (99%, 181 mg, 2.13 mmol) were added to a solution of 2-bromo-1-[1-methyl-5-(4-methylphenyl)-1H-pyrazol-4-yl]ethanone (250 mg, 0.853 mmol) in acetonitrile (9 mL), and the mixture was heated at 80° C. for 3 hours. The reaction was allowed to cool to room temperature, and was then diluted with dichloromethane and filtered through Celite. The filtrate was concentrated in vacuo, and the residue was purified by silica gel chromatography (Eluant: 10% methanol in dichloromethane) to provide the product as a yellow oil. Yield: 236 mg, 0.763 mmol, 89%. LCMS m/z 310.5 (M+1). 1H NMR (400 MHz, CDCl3), presumed to be a mixture of rotamers: δ 2.10 and 1.77 (2 s, 3H), 2.25 and 2.36 (2 s, 3H), 2.44 and 2.46 (2 s, 3H), 3.69 and 3.72 (2 s, 3H), 6.21 (s, 1H), 7.22-7.33 (4H, m, assumed; partially obscured by solvent peak), 7.96 (br s, 1H).