Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:11][CH:10]=2)[S:3]1.S(Cl)(Cl)=O.CN(C)C=O.[CH3:29][O:30][C:31]1[CH:32]=[CH:33][C:34]([N+:39]([O-:41])=[O:40])=[C:35]([NH:37][CH3:38])[CH:36]=1>C(#N)C.O>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([O:13][CH2:14][C:15]([N:37]([C:35]3[CH:36]=[C:31]([O:30][CH3:29])[CH:32]=[CH:33][C:34]=3[N+:39]([O-:41])=[O:40])[CH3:38])=[O:17])=[CH:18][CH:19]=2)[S:3]1
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CNc1cc(OC)ccc1[N+](=O)[O-]
Solvent: O
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])c(N(C)C(=O)COc2ccc(CC3SC(=O)NC3=O)cc2)c1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 103 %

Procedure:
To a suspended solution of 4-[(2,4-dioxothiazolidin-5-yl)methyl]phenoxyacetic acid (8.00 g) in acetonitrile (64 ml) were added thionyl chloride (3.38 g) and dimethylformamide (3.2 ml) at room temperature, and the resulting mixture was stirred successively at 25° C. for 30 minutes and at 40° C. for 30 minutes. Subsequently, to the reaction mixture were added successively N-(5-methoxy-2-nitrophenyl)-N-methylamine (3.84 g), N,N-dimethylaminopyridine (0.32 g) and acetonitrile (16 ml), and the resulting mixture was stirred at the same temperature for 1 hour. After cooling the reaction mixture to 0° C., water (32 ml) was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (80 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate twice (16 ml for each) and evaporated to dryness to afford the title compound (9.67 g, yield: 100%) as an orange-colored amorphous solid.
Reaction SMILES: [C:1]1(C)[C:2]([C:7](O)=[O:8])=C[CH:4]=[CH:5][CH:6]=1.[Li].[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[O:18][CH2:19][CH2:20]CCBr>C(O)C>[OH:8][CH2:7][CH2:2][CH2:1][CH2:6][C:5]1[CH:4]=[CH:17][CH:16]=[CH:15][C:14]=1[C:13]([O:18][CH2:19][CH3:20])=[O:12]
Reactant: Cc1ccccc1C(=O)O
Reactant: BrCCCCOC1CCCCO1
Agent: [Li]
Solvent: CCO
Product: CCOC(=O)c1ccccc1CCCCO

Procedure:
Compound XIV is prepared by the following series of reactions. (1) o-Toluic acid is converted to its dianion with lithium diisoprpylamide; (2) the dianion is treated with 4-(tetrahydropyranyloxy)butyl bromide and the crude alkylate is heated with ethanol and a catalytic amount of mineral acid to yield ethyl 2-(4-hydroxybutyl)-benzoate; (3) the hydroxy ester in ether is treated with phosphorus tribromide to yield reagent XIV.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[N:24]=[C:23](Cl)[C:22]([CH3:26])=[CH:21][N:20]=1>C(#N)C>[Cl:18][C:19]1[N:24]=[C:23]([N:4]2[CH:5]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:2]([CH3:1])=[N:3]2)[C:22]([CH3:26])=[CH:21][N:20]=1
Reactant: CCOC(=O)c1c[nH]nc1C
Reactant: Cc1cnc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cn(-c2nc(Cl)ncc2C)nc1C
Temperature: 80 °C
Yield: 60.5 %

Procedure:
To a solution of ethyl 3-methyl-1H-pyrazole-4-carboxylate (4.7 g, 30.6 mmol) in acetonitrile were added potassium carbonate (10.6 g, 75.0 mmol) and 2,4-dichloro-5-methylpyrimidine (5.0 g, 30.6 mmol) at room temperature. The resulting suspension was heated at 80° C. for 3 hours with monitoring a reaction with LC-MS or thin layer chromatography (TLC). Volatiles were partially removed and the residue was extracted with ethyl acetate. The collected organic layer was washed with brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. The resulting solid was recrystallized in a mixture of heptanes and ethyl acetate to afford the desired intermediate 5 as a pale yellow solid (5.2 g, 61%); MS (ESI) m/z 281 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[NH2:21][C:22]1[CH:23]=[C:24]([CH:30]=[CH:31][C:32]=1[F:33])[C:25]([O:27][CH2:28][CH3:29])=[O:26]>>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:20]=[CH:19][C:16]([CH2:17][NH:21][C:22]3[CH:23]=[C:24]([CH:30]=[CH:31][C:32]=3[F:33])[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C=Cc2ccc(C=O)cc2)cc1
Reactant: CCOC(=O)c1ccc(F)c(N)c1
Product: CCCCc1ccc(C#Cc2ccc(CNc3cc(C(=O)OCC)ccc3F)cc2)cc1

Procedure:
The titled compound was prepared following the procedure A using 4-[(4-butylphenyl)ethenyl]benzaldehyde and ethyl 3-amino-4-fluorobenzoate as a pale yellow oil (61%). 1H NMR (CDCl3, 300 MHz) δ 7.49 (d, J=8.3 Hz, 2H), 7.42 (d, J=7.9 Hz, 2H), 7.35 (m, 4H), 7.14 (d, J=7.9 Hz, 2H), 7.00 (dd, J=11.0, 8.7 Hz, 1H), 4.41 (brs, 2H), 4.30 (q, J=7.2 Hz, 2H), 2.60 (t, J=7.7 Hz, 2H), 1.69-1.53 (m, 4H), 1.34 (t, J=7.2 Hz, 3H), 0.91 (t, J=7.4 Hz, 3H). HPLC, Rt: 5.87 min (Purity: 94.3%).
Reaction SMILES: [CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:21][CH3:22])=[C:11]4[O:12][C@H:13]5[C:14]([CH:16]=[CH:17][C@@H:18]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15].[C:23]1(C)C=CC(S(O)(=O)=O)=CC=1.CO.C1C=CC=CC=1>O>[CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:21][CH3:22])=[C:11]4[O:12][C@H:13]5[C:14]([O:15][CH3:23])=[CH:16][CH:17]=[C:18]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1ccc2c3c1O[C@H]1C(=O)C=C[C@H]4[C@@H](C2)N(C)CC[C@]314
Solvent: O
Solvent: CO
Solvent: c1ccccc1
Product: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Yield: 26.8 %

Procedure:
Seki (18 Chem. Pharm. Bull. 671-676, 1970) discloses a method for preparing Δ6,8-diene compounds, such as thebaine, from α,β-unsaturated ketones such as codeinone, which may be obtained from the natural alkaloid codeine. Codeinone was added to a mixture of p-toluenesulfonic acid (dehydrated prior to reaction), absolute methanol and dried benzene, the solution refluxed for 3 hours under azeotropic removal of water, and the reaction mixture purified by washing with diluted sodium hydroxide, to obtain thebaine. A reported maximum yield of 26.8% was reported when using 1.1-0.15 molar equivalents of p-toluenesulfonic acid to codeinone. Eppenberger et al. (51 Helv. Chim. Acta 381, 1968) report a four step method for converting dihydrocodeinone to thebaine which results in a similar yield of 27%. Schwartz et al. (97 J. Am. Chem. Soc. 1239, 1975) demonstrate the total synthesis of thebaine in which the key step is the oxidative coupling of a reticuline derivative to a salutaridine derivative. The overall yield of dl-thebaine, however, was only in the 1-2% range based on isovanillin. Reaction of salutaridinol with an organic or inorganic acid halide or acid anhydride, followed by treatment with a strong base, is taught as a method of thebaine production in U.S. Pat. No. 3,894,026 to Sohar et al. A yield as high as 50.3% was reported (See, Col. 4, Line 29). Barber et al. (18 J Med. Chem. 1074-1077, 1975) report synthesizing thebaine (as well as oripavine) from codeine and morphine. Barber et al. teach methylation of the potassium salt of codeine to give codeine methyl ether followed by oxidation with γ-MnO2 (See also, U.S. Pat. No. 4,045,440 to Rapoport et al., 1977). These authors clainm a 67% yield of oxycodone from codeine. European Patent Application No. EP 0 889 045 A1 likewise teaches a process for the production of thebaine from the more readily available morphinans codeine and morphine. Such method provides for converting the starting material to an alkali metal or quaternary ammonium cation and reacting the same with a compound of the formula RX wherein R is an alkyl or acyl group and X is a leaving group.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].Cl[C:11]1[C:12](=[O:25])[NH:13][C:14](=[O:24])[C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[F:23].Cl>CO>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:11]2[C:12](=[O:25])[NH:13][C:14](=[O:24])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[F:23])[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: Nc1cc(F)cc(F)c1
Reactant: O=C1NC(=O)C(c2cccc(F)c2F)=C1Cl
Agent: Cl
Solvent: CO
Product: O=C1NC(=O)C(c2cccc(F)c2F)=C1Nc1cc(F)cc(F)c1

Procedure:
A solution of 3,5-difluoroaniline (161 mg, 0.00125 mol) and 3-chloro-4-(2,3-di-fluorophenyl)-1H-pyrrole-2,5-dione (122 mg, 0.0005 mol) in methanol (2 mL) was heated in a sealed tube at 65° C. for 8 days. The mixture was acidified with aqueous hydrochloric acid (1M) and extracted with ethyl acetate. The combined organic solutions were washed with water and brine, dried with magnesium sulphate, evaporated and the residue triturated with hexane-dichloromethane (95:5 v/v) to afford the title compound as a solid.
Reaction SMILES: C([O:5][C:6]([CH2:8][NH:9][C:10]([C:12]1[O:13][C:14]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:15]=2[N:16]=1)=[O:11])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:6]([CH2:8][NH:9][C:10]([C:12]1[O:13][C:14]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:15]=2[N:16]=1)=[O:11])([OH:7])=[O:5]
Reactant: CC(C)(C)OC(=O)CNC(=O)c1nc2cc(Cl)ccc2o1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CNC(=O)c1nc2cc(Cl)ccc2o1
Yield: 118 %

Procedure:
Compound from Example 2 (3 g) in 10 ml of trifluoroacetic acid was kept at room temperature overnight. The solvent was removed and ether was added to give 2.9 g of product; mp 222°-224° (dec.).
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[C:13]([NH:20][CH2:21][C:22]([OH:24])=O)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[C:25]1([CH:31]2[NH:36][CH2:35][CH2:34][N:33]3[CH:37]=[CH:38][CH:39]=[C:32]23)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[N-]1C=CN=C1.C(NCC(O)=O)(OC(C)(C)C)=O>ClCCCl>[O:24]=[C:22]([N:36]1[CH2:35][CH2:34][N:33]2[CH:37]=[CH:38][CH:39]=[C:32]2[CH:31]1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:21][NH:20][C:13](=[O:14])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19]
Reactant: c1ccc(C2NCCn3cccc32)cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: c1c[n-]cn1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCC(=O)N1CCn2cccc2C1c1ccccc1
Temperature: 25 °C
Reaction time: 1.67 h
Yield: 61.2 %

Procedure:
(1.1 g, 7.0 mmol) of CDI were added to a solution of Boc-glycine (1.2 g, 6.7 mmol) in DCE (20 ml), and stirring was carried out for 100 min at RT. (1.3 g, 6.7 mmol) of 1-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine (A2) were then added, and stirring was carried out for a further 2 h at RT. The mixture was then heated for 2 h at 50° C. (450 mg, 2 mmol) of Boc-glycine imidazolide were subsequently added, and the mixture was heated for 2 h under reflux. After cooling to RT, washing was carried out with, in succession, a 5% aq. sodium carbonate solution, a 5% aq. citric acid solution, water and brine. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. CC (DCE) with the residue yielded 1.4 g (4.1 mmol, 61%) of tert-butyl 2-oxo-2-(1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethylcarbamate.
Reaction SMILES: [CH:1](=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[C:25]1([CH2:31][CH2:32][CH2:33][OH:34])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3]>C1(C)C=CC=CC=1>[C:1]([O:34][CH2:33][CH2:32][CH2:31][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCCCc1ccccc1
Reactant: O=CC=Cc1ccccc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=[Si]=O
Agent: [Al+3]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(C=Cc1ccccc1)OCCCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 84 %

Procedure:
A homogeneous mixture containing cinnamaldehyde (7.5 mmol), DDQ (22.5 mmol), 3-phenylpropanol (10 mL) and toluene (10 mL) is taken in a round bottom flask and catalytic amount of Montmorillonite K10 15 (0.1 g) is added to it. The mixture is stirred for 20 hrs at room temperature. After completion of the reaction (observed by TLC and by GC analysis), the reaction mixture is filtered and washed with ethylacetate (5 ml×2). Concentrate the filtrate under reduced pressure and the crude product thus obtained is loaded on a neutral alumina column and eluted with diethyl ether. 3-Phenylpropyl cinnamate (from formula I where X1═H, X2═H, X3═H, X4═H, X5═H, R═C9H11) is isolated in 84% yield. 1H-NMR (CDCl3, 300 MHz) δ7.74 (1H, d), 7.43 (2H, m), 7.28 (5H, m), 7.19 (3H, m), 6.48 (2H, d), 4.22 (2H, t), 2.69 (2H, t), 1.98 (2H, t); 13C-NMR (CDCl3, 75.4 MHz) δ166.7, 144.7, 141.4, 134.6, 130.6, 129.2, 128.6, 127.4, 126.5, 118.4, 63.9, 32.3, 30.5.
Reaction SMILES: [CH:1]1([C:9]2[N:10]=[C:11](/[CH:14]=[CH:15]/[C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=O)[CH:17]=3)[S:12][CH:13]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)C.O.O.[Sn](Cl)Cl>[OH-].[Na+]>[CH:1]1([C:9]2[N:10]=[C:11](/[CH:14]=[CH:15]/[C:16]3[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=3)[S:12][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: O=[N+]([O-])c1cccc(/C=C/c2nc(C3CCCCCCC3)cs2)c1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1cccc(/C=C/c2nc(C3CCCCCCC3)cs2)c1
Yield: 98.6 %

Procedure:
A mixture composed of 2.0 g of (E)-4-cyclooctyl-2-[2-(3-nitrophenyl)ethenyl]thiazole, 50 ml of ethyl alcohol and 4.6 g of tin(II) chloride dihydrate was heated to reflux for 1.2 hr. The cooled reaction mixture was then diluted with 200 ml of 1.5N sodium hydroxide and this mixture was extracted with ethyl ether. The combined extracts were washed with brine, dried (MgSO4) and condensed in vacuo and the residual materials were further purified by silica gel chromatography using ethyl acetate as the eluant to yield 1.8 g of (E)-3-[2-[4-(cyclooctyl)-2-thiazolyl]ethenyl]benzeneamine as an oil.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][CH:6]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][C:8](Cl)=[O:9].[CH:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:5][CH:6]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:9]
Reactant: CC(CC(=O)Cl)CC(C)(C)C
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: CC(CC(=O)c1ccccc1)CC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 143.3 grams of aluminum chloride and 400 mL of benzene was added 100 grams of 3,5,5-trimethylhexanoyl chloride over a 50 minute period at a rate such that the temperature did not exceed 35° C. When the addition was complete, the mixture was stirred at room temperature for three hours. The mixture was poured over 500 grams of ice and extracted with 400 mL of ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate, filtered and the solvent was removed in vacuo to give 3,5,5-trimethylhexanoylbenzene.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:16][C@@H:17]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:18]([OH:20])=O)[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[NH2:41][CH2:42][C:43]#[N:44].P(O)([O-])([O-])=O.[Na+].[Na+]>C1COCC1.C(OCC)(=O)C>[C:42]([CH2:43][NH:44][C:18](=[O:20])[C@@H:17]([NH:16][C@@H:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[CH2:21][CH:22]([CH3:23])[CH3:24])#[N:41]
Reactant: N#CCN
Reactant: CC(C)C[C@H](N[C@H](c1ccc(F)cc1)c1ccc(Br)cc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: O=P([O-])([O-])O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)C[C@H](N[C@H](c1ccc(F)cc1)c1ccc(Br)cc1)C(=O)NCC#N
Reaction time: 1.5 h

Procedure:
To a solution of (2S)-2-{(R)-[(4-bromophenyl)-(4-fluorophenyl)-methyl]-amino}-4-methylpentanoic acid (1.17 g, 2.86 mmol) in THF (20 mL) at −10° C. were added 4-methylmorpholine (0.315 mL, 2.86 mmol) and isobutyl chloroformate (0.371 mL, 2.86 mmol). The reaction mixture was stirred for 10 minutes, whereupon aminoacetonitrile hydrochloride (0.318 g, 3.43 mmol) was added, followed by 4-methylmorpholine (0.315 mL, 2.86 mmol). The solution was stirred for 90 minutes. Ethyl acetate (30 mL) and aqueous disodium phosphate (30 mL) were added. The organic phase was separated, washed with brine, dried over MgSO4, and evaporated to dryness. The product was purified on a short plug of silica gel (10-50% ethyl acetate/hexane gradient elution) to give (2S)-2-{(R)-[(4-bromophenyl)-(4-fluorophenyl)-methyl]-amino}-4-methylpentanoic acid cyanomethylamide.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([NH:15][C:16]3[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=3[F:23])=[C:13]([C:24]([OH:26])=O)[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2].Cl.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[CH:32][CH:31]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([NH:15][C:16]3[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=3[F:23])=[C:13]([C:24]([N:39]3[CH2:40][CH2:41][CH:36]([C:33]4[CH:32]=[CH:31][C:30]([O:29][CH3:28])=[CH:35][CH:34]=4)[CH2:37][CH2:38]3)=[O:26])[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3F)c(C(=O)O)cnc12
Reactant: COc1ccc(C2CCNCC2)cc1
Agent: Cl
Product: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3F)c(C(=O)N3CCC(c4ccc(OC)cc4)CC3)cnc12
Yield: 0.1 %

Procedure:
In the same manner as in Example 21, step 5 and using 3-ethoxycarbonyl-7-(2-fluoro-5-methylphenylamino)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.5 g, 1.40 mmol) obtained in Example 90, step 2 and 4-(4-methoxyphenyl)piperidine hydrochloride (0.38 mg, 1.67 mmol), the title compound (0.58 mg, 78%) was obtained.
Reaction SMILES: [BH4-].[O:2]([CH:9]([CH3:13])[C:10](O)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O1CCCC1>[O:2]([CH:9]([CH3:13])[CH2:10][OH:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(Oc1ccccc1)C(=O)O
Agent: [BH4-]
Solvent: C1CCOC1
Product: CC(CO)Oc1ccccc1
Reaction time: 23 h

Procedure:
To 200 ml of one molar borohydride in tetrahydrofuran chilled in an ice bath under nitrogen is added dropwise with stirring 24.9 g of 2-phenoxypropionic acid in 100 ml of dry tetrahydrofuran over 25 minutes. The mixture is allowed to stand at room temperature for 23 hours and is poured onto ice. After standing, the mixture is extracted with dichloromethane and the extracts dried (magnesium sulfate) and concentrated under vacuum to give the product as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[NH:11][C:12]1[C:13]2[CH:20]=[CH:19][N:18]([CH3:21])[C:14]=2[N:15]=[CH:16][CH:17]=1>C(O)C.C1COCC1.[Pt](=O)=O>[F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[NH:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]2[N:18]([CH3:21])[CH:19]=[CH:20][C:13]=12
Reactant: Cn1ccc2c(Nc3ccc([N+](=O)[O-])cc3F)ccnc21
Agent: O=[Pt]=O
Solvent: CCO
Solvent: C1CCOC1
Product: Cn1ccc2c(Nc3ccc(N)cc3F)ccnc21
Reaction time: 8 h

Procedure:
195 mg (0.68 mmol) of N-(2-fluoro-4-nitrophenyl)-1-methyl-1H-pyrrolo[2,3-b]pyridine-4-amine are dissolved in 10 ml of a mixture of ethanol/THF. (1:1). 15 mg (0.07 mmol) of platinum(IV) oxide are added, and the mixture is stirred under a hydrogen atmosphere at atmospheric pressure overnight. The suspension is then filtered through Celite, the Celite is washed with a little ethanol and the solvent is removed under reduced pressure.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][NH:13][S:14]([C:17]2[C:18]3[CH:19]=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])(=O)=O)=CC=1.[CH2:28]1[O:38][C:37]2[CH:36]=[CH:35][C:32]([CH2:33][NH2:34])=[CH:31][C:30]=2[O:29]1>O1CCCC1>[CH2:28]1[O:38][C:37]2[CH:36]=[CH:35][C:32]([CH2:33][NH:34][CH2:11][CH2:12][NH:13][S:14]([C:17]3[C:18]4[CH:19]=[CH:20][N:21]=[CH:22][C:23]=4[CH:24]=[CH:25][CH:26]=3)(=[O:15])=[O:16])=[CH:31][C:30]=2[O:29]1
Reactant: Cc1ccc(S(=O)(=O)OCCNS(=O)(=O)c2cccc3cnccc23)cc1
Reactant: NCc1ccc2c(c1)OCO2
Solvent: C1CCOC1
Product: O=S(=O)(NCCNCc1ccc2c(c1)OCO2)c1cccc2cnccc12
Yield: 48 %

Procedure:
To 4.06 g of the thus obtained N-(2-paratoluenesulfonyloxyethyl)-5-isoquinolinesulfonamide was added 40 ml of tetrahydrofuran containing 4.53 g of 3,4-methylenedioxybenzylamine. The resultant mixture was heated in a sealed vessel at 100° C. for 17 hours and then, the solvent was removed by distillation under reduced pressure to obtain a residue. The thus obtained residue was subjected to purification by means of a column for chromatography packed with 200 g of silica gel (Wacogel C-200, manufactured by Wako Pure Chemical Industries, Ltd., Japan) using, as an eluent, a mixture of methanol and chloroform (0.5% methanol) to obtain 1.84 g of N-[2-(3,4-methylenedioxybenzylamino)ethyl]-5-isoquinolinesulfonamide (3) (yield: 48%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([C:9]([F:12])([F:11])[F:10])[C:5]([F:13])=[C:4]([F:14])[C:3]=1[N:15]1[C:19]([NH:20][C:21]([CH3:23])=[O:22])=[CH:18][CH:17]=[N:16]1.C(OC(=O)C)(=O)C.[N+:31]([O-])([OH:33])=[O:32]>C(O)(=O)C>[F:1][C:2]1[C:7]([F:8])=[C:6]([C:9]([F:12])([F:10])[F:11])[C:5]([F:13])=[C:4]([F:14])[C:3]=1[N:15]1[C:19]([NH:20][C:21]([CH3:23])=[O:22])=[C:18]([N+:31]([O-:33])=[O:32])[CH:17]=[N:16]1
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccnn1-c1c(F)c(F)c(C(F)(F)F)c(F)c1F
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1c([N+](=O)[O-])cnn1-c1c(F)c(F)c(C(F)(F)F)c(F)c1F
Temperature: 25 °C
Yield: 63.4 %

Procedure:
A stirred solution of 7.86 grams (0.0230 mole) of 1-(2,3,5,6-tetrafluoro-4-trifluoromethylphenyl)-5-methylcarbonylaminopyrazole in 20 mL of glacial acetic acid was cooled in an ice-water bath. Acetic anhydride (2.9 mL, 0.031 mole) was added dropwise, and the mixture was stirred briefly. Concentrated nitric acid (1.05 mL, 0.0245 mole) was added dropwise, and the reaction mixture was allowed to warm to room temperature and was stirred for four hours. The mixture was poured into 60 mL of ice-water and stirred, forming a granular yellow solid. This solid was collected by filtration and washed with water. The solid was purified by recrystallization from ethanol and water to yield 5.63 grams of 1-(2,3,5,6-tetrafluoro-4-trifluoromethylphenyl) -5-methylcarbonylamino-4-nitropyrazole, m.p. 136.5-138.5° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][CH2:2][Mg+].[Br-].CON(C)[C:8]([C:10]1[CH:14]=[CH:13][S:12][CH:11]=1)=[O:9].CCOC(C)=O>C1COCC1>[S:12]1[CH:13]=[CH:14][C:10]([C:8](=[O:9])[CH2:2][CH3:1])=[CH:11]1
Reactant: CON(C)C(=O)c1ccsc1
Reactant: CC[Mg+]
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(=O)c1ccsc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
EtMgBr (3 M, 1.2 eq, 18.6 mL) was added to a solution of N-methoxy-N-methylthiophene-3-carboxamide (8 g, 1.0 eq) in dry THF. Once the addition was complete, the mixture was stirred at rt overnight. The reaction mixture was washed with saturated NH4Cl (aq), dried, concentrated, and purified by column chromatography with petroleum ether:EtOAc=5:1 to give the desired product as a yellow oil (3.4 g, 52% yield). 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.31 (d, J=8.4 Hz, 1H), 2.92 (q, J=7.6 Hz, 2H), 1.21 (t, J=7.6 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[CH2:3].[C:5]([O:9][CH:10]([CH3:12])[CH3:11])(=[O:8])[CH:6]=[O:7]>C(=O)([O-])O.[Na+]>[OH:7][C@H:6]([CH2:3][C:2]([CH3:4])=[CH2:1])[C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8]
Reactant: C=C(C)C
Reactant: CC(C)OC(=O)C=O
Agent: O=C([O-])O
Agent: [Na+]
Product: C=C(C)C[C@@H](O)C(=O)OC(C)C
Temperature: -70 °C
Yield: 75.5 %

Procedure:
A solution of an (R)-binaphthol-dichlorotitanium complex which had been prepared in the same manner as in Example 1 was cooled to -70° C., into which was bubbled 0.56 g (10 mmoles) of 2-methyl-l-propene, followed by adding thereto 116 mg (1 mmole) of isopropyl glyoxylate. Subsequently, the mixture was reacted at -30° C. for 15 hours. Then, 10 ml of an aqueous sodium hydrogen carbonate solution was added to terminate the reaction. The reaction mixture was filtered through Celite and extracted with two 20 ml portions of diethyl ether and two 20 ml portions of ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. Thereafter, the solvents were distilled off, and the residue was purified by means of silica gel column chromatography to obtain 0.13 g of isopropyl (R)-2-hydroxy-4-methyl-4-pentenoate. The yield was 78%.