Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH3:2].[F:3][C:4]([F:11])([F:10])[C:5]([F:9])=[C:6]([F:8])[F:7]>>[F:3][C:4]([F:11])([F:10])[CH:5]([F:9])[C:6]([F:8])([F:7])[CH2:1][CH3:2]
Reactant: CC
Reactant: FC(F)=C(F)C(F)(F)F
Product: CCC(F)(F)C(F)C(F)(F)F

Procedure:
When a reaction between ethane and hexafluoropropene was carried out in a 250 ml. Hastalloy-lined autoclave at a temperature of 280° C and under an initial total pressure of 150 atmospheres, a similar yield (76% based on hexafluoropropene consumed) of 1,1,1,2,3,3-hexafluoropentane was obtained.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.CN(C)C=O.[Tl+].[CH3:18][CH2:19][CH2:20][CH2:21][CH:22]1[C:27](=[O:28])[N:26]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:25]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:23]1=[O:24]>CCOCC>[C:35]1([N:25]2[C:23]([O:24][S:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=3)(=[O:9])=[O:8])=[C:22]([CH2:21][CH2:20][CH2:19][CH3:18])[C:27](=[O:28])[N:26]2[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCC1C(=O)N(c2ccccc2)N(c2ccccc2)C1=O
Agent: [Tl+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCCc1c(OS(=O)(=O)c2ccc(C)cc2)n(-c2ccccc2)n(-c2ccccc2)c1=O
Reaction time: 8 h
Yield: 33 %

Procedure:
Then, p-Toluenesulfonyl chloride (0.95 g, 5.0 mmole) was allowed to react with a dimethylformamide (20 ml) suspension of the Thallium (I) salt of phenylbutazone. Within a few minutes the solvent became pink and a yellow solid, instead of the white Thallium (I) salt of phenylbutazone, was observed suspended in the pink solution. The suspension was stirred overnight in a tightly sealed flask, then it was diluted with 100 ml of ether and filtered. The filtrate was concentrated in vacuo to remove the ether and the dimethylformamide was evaporated under a stream of nitrogen. The residue from the evaporation was suspended in dichloromethane and filtered. Analysis of the filtrate by TLC showed that it contained only one major component. The dichloromethane was evaporated in vacuo and the residue was crystallized from ether to give 0.76 g (mp 112°-121° C, 33% yield) of yellow crystals which contained only one component by TLC analysis. Recrystallization of the yellow crystals gave analytically pure crystals, mp 125°-127° C with spectral properties identical to the crystals, mp 112°-121° C.
Reaction SMILES: C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.C(O[CH:17]1[O:33][C@:32]([CH2:40]S(C)(=O)=O)([CH2:34][O:35][S:36]([CH3:39])(=[O:38])=[O:37])[C@@H:23]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@H:18]1[O:19][C:20](=[O:22])[CH3:21])(=O)C.[NH2:45][C:46]1[N:54]=[C:53]2[C:49]([NH:50][CH:51]=[N:52]2)=[C:48]([Cl:55])[N:47]=1.C[Si]([O:60][S:61]([C:64](F)(F)F)(=[O:63])=[O:62])(C)C.C(=O)(O)[O-]>ClCCCl.C(O)(=O)C>[C:20]([O:19][C@@H:18]1[C@H:23]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:32]([CH2:34][O:35][S:36]([CH3:39])(=[O:37])=[O:38])([CH2:40][O:63][S:61]([CH3:64])(=[O:62])=[O:60])[O:33][C@H:17]1[N:47]1[C:48]([Cl:55])=[C:49]2[C:53](=[N:52][CH:51]=[N:50]2)[N:54]=[C:46]1[NH2:45])(=[O:22])[CH3:21]
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC(=O)OC1O[C@@](COS(C)(=O)=O)(CS(C)(=O)=O)[C@@H](OCc2ccccc2)[C@H]1OC(C)=O
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: O=C([O-])O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(=O)O[C@H]1[C@H](n2c(N)nc3ncnc-3c2Cl)OC(COS(C)(=O)=O)(COS(C)(=O)=O)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
N,O-bis(trimethylsilyl)acetamide (29.6 g, 35 ml) was added to a stirred slurry of (3) (30 g, 58.8 mmol) and 2-amino-6-chloropurine (12 g, 70 mmol) in 1,2-dichloroethane (dried over sieves, 450 ml) and the mixture was refluxed for 40 min. to give a homogenous solution. The mixture was then removed from the heat and trimethylsilyltriflat (22 ml, 118 mmol) was added dropwise. The reaction mixture was refluxed for another 2 h. The reaction mixture was cooled to room temperature and a saturated aqueous solution of bicarbonate (400 ml) was added. The slurry was allowed to stir for 15 min, pH was adjusted to 7-8 using glacial acetic acid and the mixture was extracted with chloroform. The aqueous phase was extracted with AcOEt and chloroform and the organic phases were combined. The organic phase was washed with brine (2×250 ml) and bicarbonate (2×250 ml). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give compound (4) as a yellowish foam which expands during vacuum dessication
Reaction SMILES: [O-:1][Mn](=O)(=O)=O.[K+].C[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[F:18])=[O:9]>>[F:18][C:11]1[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:10]=1[C:8]([OH:9])=[O:1]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: COc1ccc(C(C)=O)c(F)c1
Agent: [K+]
Product: COc1ccc(C(=O)O)c(F)c1

Procedure:
2-Fluoro-4-methoxybenzoic acid was synthesized by KMnO4 oxidation of 2-fluoro-4-methoxyacetophenone (Clarke, H. T.; Taylor, E. R., Org. Synth. Coll. Vol II, 135-136).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:13])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Br[C:15]1[CH:32]=[CH:31][C:18]([C:19]([N:21]([CH:28]([CH3:30])[CH3:29])[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:20])=[CH:17][CH:16]=1.Cl>N1C(C)=CC(C)=CC=1C>[CH:22]1([N:21]([CH:28]([CH3:30])[CH3:29])[C:19](=[O:20])[C:18]2[CH:31]=[CH:32][C:15]([O:13][C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:16][CH:17]=2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CC(C)N(C(=O)c1ccc(Br)cc1)C1CCCCC1
Reactant: COc1cc(O)cc(OC)c1OC
Agent: Cl
Solvent: Cc1cc(C)nc(C)c1
Product: COc1cc(Oc2ccc(C(=O)N(C(C)C)C3CCCCC3)cc2)cc(OC)c1OC
Reaction time: 18 h

Procedure:
A slurry of cuprous oxide (300 mg, 2.1 mmol) in a solution of 3,4,5-trimethoxyphenol (736 mg, 4.0 mmol) and 4-bromo-N-isopropyl-N-cyclohexyl benzamide (1.290 g, 3.98 mmol) in 2,4,6-collidine (20 ml) was refluxed with stirring under a nitrogen atmosphere for 18 hr. The reaction was cooled, poured onto dilute aqueous HCl and extracted three times with ethyl acetate. The combined organic layers were washed twice with saturated aqueous NaCl solution, twice with 5% NaOH solution, twice with saturated NaCl solution and dried (Na2SO4). The drying agent was filtered and the filtrate concentrated in vacuo to give 1.29 g of crude product. This material was chromatographed on silica gel using mixtures of ethyl acetate and hexane as the eluents to give the title compound as a crystalline solid that could be recrystallized from ethyl acetate hexane, melting point 124.01° C. (DSC).
Reaction SMILES: [C:1]([N:18]1[CH2:25][C@H:24]([OH:26])[CH2:23][C@H:19]1[C:20](O)=[O:21])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].B.CSC.CO>C1COCC1>[C:1]([N:18]1[CH:19]([CH2:20][OH:21])[CH2:23][CH:24]([OH:26])[CH2:25]1)([O:3][CH2:4][CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]2[C:17]1=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:2]
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCC1c2ccccc2-c2ccccc21
Agent: B
Solvent: C1CCOC1
Solvent: CO
Solvent: CSC
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1CC(O)CC1CO
Temperature: 25 °C

Procedure:
To a solution of N-Fmoc-trans-4-hydroxy-L-proline (13.4 g, 38.1 mmol) in 250 ml THF was added borane-methyl sulfide (78 mmol, 5.78 g, 7.22 ml) dropwise at room temperature. After the evolution of H2 had ceased, the solution was heated to reflux with mechanical stirring. After 1 hour a white precipitate had formed. Methanol was carefully added, and the resulting solution refluxed for a further 15 minutes. The solution was cooled to room temperature, the solvents evaporated under reduced pressure, and the residual gum coevaporated with 2×100 ml methanol. The resulting crystalline product weighed 12.0 g (35.3 mmol, 93%). 1H NMR: (CDCl3, 200 MHz) δ 7.85-7.25 (8H, m, ArH), 4.50-4.10 (5H, m, ArCHCH2, H3, H5), 3.80-3.40 (4H, m, 2 H2, 2 H6), 2.15-1.95 (1H, m, H2a), 1.80-1.60 (1H, m, H2b).
Reaction SMILES: Br[CH:2](Br)[C:3]1[NH:4][C:5]2[C:10]([CH:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:9]([O:24][CH:25]([CH3:27])[CH3:26])[N:8]=[CH:7][CH:6]=2.C([OH:31])C>O.[N+]([O-])([O-])=O.[Ag+]>[CH:2]([C:3]1[NH:4][C:5]2[C:10]([CH:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:9]([O:24][CH:25]([CH3:27])[CH3:26])[N:8]=[CH:7][CH:6]=2)=[O:31]
Reactant: CCO
Reactant: CCOC(=O)C1=C(C(Br)Br)Nc2ccnc(OC(C)C)c2C1c1ccccc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: CCOC(=O)C1=C(C=O)Nc2ccnc(OC(C)C)c2C1c1ccccc1

Procedure:
A solution of 3.1 g (6.1 mMole) ethyl (±)-2-dibromomethyl-1,4-dihydro-5-isopropoxy-4-phenyl-1,6-naphthyridine-3-carboxylate (Example 4) in 70 ml ethanol is heated to 60° C. and, at this temperature, a solution of 2.1 g (12.4 mMole) silver nitrate in 5 ml water/3 ml ethanol is added dropwise thereto. The reaction mixture is heated under reflux for ten minutes, cooled and the precipitate filtered off, whereafter the filtrate is evaporated. After dilution with dichloromethane, it is washed with water and the organic phase is dried over anhydrous magnesium sulphate and subsequently evaporated in a vacuum. The residue is chromatographed on silica gel with toluene/ethyl acetate (9:1 v/v). The fraction with the Rf of 0.3 is isolated and recrystallized from n-hexane/cyclohexane. There is obtained ethyl (±)-2-formyl-1,4-dihydro-5-isopropoxy-4-phenyl-1,6-naphthyridine-3-carboxylate in the form of yellow crystals; mp 132°-135° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N:13](C(OC(C)(C)C)=O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][CH:9]1[C:30](O)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)=[CH:37][CH:36]=1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][C@H:9]1[C:30]([N:44]1[CH2:45][CH2:46][N:41]([C:38]2[CH:37]=[CH:36][C:35]([O:34][CH3:33])=[CH:40][CH:39]=2)[CH2:42][CH2:43]1)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1F)C1CC(C(=O)O)N(Cc2ccccc2)C1
Reactant: COc1ccc(N2CCNCC2)cc1
Product: COc1ccc(N2CCN(C(=O)[C@@H]3C[C@H](NCc4ccc(F)cc4F)CN3Cc3ccccc3)CC2)cc1
Yield: 2.4 %

Procedure:
As described for Example 1f, 1-benzyl-4-[tert-butoxycarbonyl-(2,4-difluoro-benzyl)-amino]-pyrrolidine-2-carboxylic acid (60.0 mg, 0.134 mmol) was converted, using 1-(4-methoxy-phenyl)-piperazine instead of 2-piperazin-1-yl-benzonitrile, to the title compound (1.7 mg, 2.4%) as light yellow oil. MS m/e=521.4 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([O:8][C:9](=[O:10])[C:2]1=2)=[O:7].[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Mg]Br>C1COCC1>[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:6]([C:3]1[CH:4]=[CH:5][S:1][C:2]=1[C:9]([OH:8])=[O:10])=[O:7]
Reactant: O=C1OC(=O)c2sccc21
Reactant: Cc1ccccc1[Mg]Br
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)c1ccsc1C(=O)O

Procedure:
2,3-Thiophenedicarboxylic anhydride was allowed to react with 2-methylphenyl magnesium bromide in THF, and the reaction mixture was processed to give 3-(2-methylbenzoyl)-2-thiophenecarboxylic acid as colorless crystals.
Reaction SMILES: Cl[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:19]1[CH2:26][NH:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[C:13]1([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]([CH:11]=[O:12])=[C:2]2[N:19]2[CH2:26][NH:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C1CNCNCCN1
Reactant: O=Cc1c(Cl)n(-c2ccccc2)c2ccccc12
Product: O=Cc1c(N2CCNCCNC2)n(-c2ccccc2)c2ccccc12
Yield: 37 %

Procedure:
2-Chloro-1-phenyl-1H-indole-3-carboxaldehyde is reacted with [1,4,7]triazocane as described in Example 1 to afford 1-phenyl-2-[1,4,7]triazocan-1-yl-1H-indole-3-carboxaldehyde (37% yield) as a yellow solid. LC/MS: 321 (M+H—H2O); RT 2.96 min; NMR (CDCl3): 7.37 (1H, d), 7.18-7.30 (3H, m), 7.13 (1H, t), 6.97 (2H, d), 6.90 (1H, t), 6.79 (1H, t), 2.76-3.10 (12H, m).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>CN(C)C=O>[CH2:23]([O:15][C:12]1[CH:11]=[CH:10][C:9]([C:1]([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:2])[CH3:3])=[CH:14][CH:13]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)cc1
Reactant: CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(C(C)(C)CC(C)(C)C)cc1
Temperature: 50 °C
Yield: 80.8 %

Procedure:
To 700 ml of N,N-dimethylformamide were added 206 g of 4-t-octylphenol and 207 g of anhydrous potassium carbonate and the mixture was stirred at 50° C. To the mixture was added dropwise 251 g of 1-bromooctane and thereafter the mixture was stirred for 7 hours at 65° to 80° C. Then, after removing insoluble matter by filtration, water was added to the filtrate thus obtained and the product was extracted with ethyl acetate. The organic solvent layer was collected, washed with a saturated aqueous sodium chloride solution, dried on anhydrous magnesium sulfate, and concentrated under reduced pressure. The oily material thus obtained was distilled under reduced pressure (169°-172° C./0.05-0.06 mmHg) to provide 257 g (81% in yield) of 1-octyloxy-4-t-octylbenzene (Compound A).
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[C:34](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.CCOCC>[CH3:34][O:20][C:19](=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:6][SiH2:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH:9]=1
Reactant: CC(C)(C)[SiH2]OC(c1ccccc1)(c1ccccc1)c1cccc(CCCCCC(=O)O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)CCCCCc1cccc(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)c1
Reaction time: 6 h
Yield: 70.8 %

Procedure:
To a solution of 6-[3-(tert-butyl-diphenyl-silanyloxymethyl)-phenyl]-hexanoic acid (3.3 g, 7.2 mmol) in DMF (15 mL) is added potassium carbonate (1.09 g, 7.9 mmol) and iodomethane (500 μL, 7.9 mmol). The mixture is stirred for 6 hrs then diluted with ether. The organic layer is washed with water, brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (eluting with 10% ether/hexanes) to give 2.42 g of title compound. 1H NMR (300 MHz, CDCl3) δ 7.70 (m, 4H), 7.38 (m, 6H), 7.20 (m, 2H), 7.12 (s, 1H), 7.06 (d, 1H), 4.76 (s, 2H), 3.65 (s, 3H), 2.59 (t, 2H), 2.30 (t, 2H), 1.64 (m, 4H), 1.37 (m, 2H), 1.10 (s, 9H).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1.O.[NH2:31][NH2:32]>CN(C=O)C>[CH3:28][O:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][C:19]2[C:3]3[C:4](=[O:18])[N:5]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:6]4[N:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]=3[NH:32][N:31]=2)=[CH:26][CH:25]=1
Reactant: COc1ccc(CC(=O)c2c(O)c3cccnc3n(-c3ccccc3)c2=O)cc1
Reactant: NN
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)cc1
Yield: 88.5 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-2-(4-methoxyphenyl)ethyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (50 mg, 0.13 mmol, prepared in Synthetic Example 15) in DMF (1 ml) was added hydrazine monohydrate (80%, 1 ml, 24.96 mmol, 192 eq.), and the mixture was treated in the same manner as in Example 16 to give 3-(4-methoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (44 mg, 89%).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[NH:11][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:9]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:8]=1)=[O:6].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(=O)C>[O:6]=[C:5]1[C:7]2[C:12](=[N:11][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:9]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:8]=2)[O:13][CH:3]=[CH:4]1
Reactant: CCOC(=O)c1cc(C(=O)C=CN(C)C)c(=O)[nH]c1C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2c(=O)ccoc2nc1C(=O)OCC

Procedure:
Diethyl 5-[3-(dimethylamino)acryloyl]-1,6-dihydro-6-oxo-2,3-pyridinedicarboxylate (6 g, 0.0178 mol), and p-toluenesulfonic acid (4.5 g, 0.021 mol) in acetic acid (60 mL) are heated at reflux for three hours. The mixture is then evaporated to dryness, neutralized with a saturated NaHCO3 solution and extracted with methylene chloride. The organic solution is dried over Na2SO4, and concentrated to a thick oil, which solidifies after trituration with hexane-ether (4 g, 77%). The product is recrystallized from isopropanol to give a melting point 71°-72° C.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[F:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([C:18]2O[C:20](/[CH:23]=[CH:24]/[C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32]4)=[C:27]([O:37][CH3:38])[CH:26]=3)=[N:21][N:22]=2)[C:14](=[O:17])[CH:15]=[CH2:16])=[CH:9][CH:8]=1>C(O)(=O)C>[F:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:14](=[O:17])[CH2:15][CH2:16][N:5]3[C:20](/[CH:23]=[CH:24]/[C:25]4[CH:30]=[CH:29][C:28]([N:31]5[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32]5)=[C:27]([O:37][CH3:38])[CH:26]=4)=[N:21][N:22]=[C:18]23)=[CH:9][CH:8]=1
Reactant: C=CC(=O)N(c1ccc(F)cc1)c1nnc(/C=C/c2ccc(-n3cnc(C)c3)c(OC)c2)o1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: COc1cc(/C=C/c2nnc3n2CCC(=O)N3c2ccc(F)cc2)ccc1-n1cnc(C)c1
Temperature: 150 °C
Reaction time: 6 h
Yield: 4.6 %

Procedure:
Acetic acid (1 mL) and ammonium acetate (0.11 g) were added to N-(4-fluorophenyl)-N-{5-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-[1,3,4]oxadiazol-2-yl}acrylamide (22 mg), and the reaction solution was stirred at 150° C. for six hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to the resulting residue, followed by extraction with chloroform. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system, then ethyl acetate-methanol system) to obtain 1 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:46])[O:5][C:6]1[CH:7]=[C:8]([CH:20]=[C:21]([C:23]2[NH:24][C:25]([C:28]3[O:29][C@@H:30]([CH3:45])[C@@H:31]([CH2:33][O:34][Si](C(C)C)(C(C)C)C(C)C)[N:32]=3)=[CH:26][CH:27]=2)[CH:22]=1)[O:9][C:10]1[CH:11]=[CH:12][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[N:14][CH:15]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH3:1][O:2][CH2:3][C@H:4]([CH3:46])[O:5][C:6]1[CH:22]=[C:21]([C:23]2[NH:24][C:25]([C:28]3[O:29][C@@H:30]([CH3:45])[C@@H:31]([CH2:33][OH:34])[N:32]=3)=[CH:26][CH:27]=2)[CH:20]=[C:8]([O:9][C:10]2[CH:15]=[N:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=2)[CH:7]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C3=N[C@H](CO[Si](C(C)C)(C(C)C)C(C)C)[C@H](C)O3)[nH]2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C3=N[C@H](CO)[C@H](C)O3)[nH]2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{5-[(4R,5S)-5-methyl-4-{[(triisopropylsilyl)oxy]methyl}-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-2-(methylsulfonyl)pyridine (901 mg, 1.34 mmol) synthesized in Example (91c) was dissolved in tetrahydrofuran (15 mL), and tetrabutylammonium fluoride (1 mol/L tetrahydrofuran solution, 1.54 mL, 1.54 mmol) was added at 0° C., followed by stirring at room temperature for 1 hour under nitrogen atmosphere. Water (20 mL) was added, and extraction was carried out with ethyl acetate (40 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=80%-100%) to afford the desired compound (578 mg, yield 84%) as a white solid.
Reaction SMILES: [Si]([O:18][C:19]1[CH:59]=[CH:58][C:22]([O:23][CH2:24][C@@H:25]([OH:57])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:56]=[CH:55][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([C:43]4[NH:44][C:45]5[C:50]([CH:51]=4)=[CH:49][CH:48]=[CH:47][C:46]=5[N+:52]([O-:54])=[O:53])=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[OH:57][C@H:25]([CH2:24][O:23][C:22]1[CH:21]=[CH:20][C:19]([OH:18])=[CH:59][CH:58]=1)[CH2:26][NH:27][CH2:28][CH2:29][C:30]1[CH:31]=[CH:32][C:33]([NH:34][CH:35]2[CH2:36][CH2:37][N:38]([C:41]([C:43]3[NH:44][C:45]4[C:50]([CH:51]=3)=[CH:49][CH:48]=[CH:47][C:46]=4[N+:52]([O-:54])=[O:53])=[O:42])[CH2:39][CH2:40]2)=[CH:55][CH:56]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H](O)CNCCc2ccc(NC3CCN(C(=O)c4cc5cccc([N+](=O)[O-])c5[nH]4)CC3)cc2)cc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(c1cc2cccc([N+](=O)[O-])c2[nH]1)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 70.1 %

Procedure:
{4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxypropyl]amino}ethyl)anilino]-1-piperidinyl}(7-nitro-1H-indol-2-yl)methanone (0.117 g, 0.144 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol) to give the title compound (0.058, 0.101 mmol).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7]([C@H:9]1[CH2:13][C@H:12](Br)[CH2:11][N:10]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:8]>CN(C)C=O.O>[CH3:5][O:6][C:7]([C@H:9]1[CH2:13][C@@H:12]([N:1]=[N+:2]=[N-:3])[CH2:11][N:10]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:8]
Reactant: COC(=O)[C@H]1C[C@H](Br)CN1C(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H]1C[C@@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Temperature: 72.5 °C
Yield: 100 %

Procedure:
Add sodium azide (157 g, 2.39 mol) to (2R,4S)-4-bromo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (370 g, 1.20 mol) in N,N-dimethylformamide (2.5 L) and heat at 70-75° C. for 16 h under nitrogen. Cool to room temperature, dilute with water (5 L), and extract with ethyl acetate (3 L). Wash with brine (2 L). Extract the brine layer with ethyl acetate (3 L), combine the organic layers, dry over sodium sulfate, filter and concentrate to obtain an oil (324.5 g). Dissolve the material in ether (2 L), wash with water (2×2 L), dry over sodium sulfate, filter, and concentrate to obtain 261.2 g of a dark yellow oil. Back-extract the aqueous layer with ether (2×2 L), dry over sodium sulfate, filter, and concentrate to obtain an additional 7.3 g of product. Overall yield 268.5 g (83%). [α]D20+39.5 (c=1.0 in methanol). 1H NMR (400 MHz, CDCl3) δ 1.40-1.41 (s, 9H), 2.09-2.13 (m, 1H), 2.40-2.44 (m, 1H), 3.37-3.45 (m, 1H), 3.61-3.65 (m, 1H), 3.67-3.69 (s, 3H), 4.09-4.15 (m, 1H), 4.25-4.38 (m, 1H).