Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N+:2]=1[O-].C(Cl)(Cl)[Cl:13].P(Cl)(Cl)(Cl)=O>O>[Cl:13][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: ClC(Cl)Cl
Reactant: [O-][n+]1ccc2ccccc2c1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1nccc2ccccc12
Reaction time: 3 h
Yield: 44.9 %

Procedure:
69.3 g (448 mmol) of isoquinoline N-oxide (made by Tokyo Kasei) and 225 ml of chloroform were placed and dissolved in a 1 liter-three-necked flask, and under stirring and cooling with ice, 219.6 g (1432 mmol) of phosphorus oxychloride was gradually added dropwise thereto while the internal temperature was held at 15–20° C. Thereafter, the temperature was raised, and reflux under stirring was performed for 3 hours. The reaction product was cooled by standing to room temperature and poured into iced water. After extraction with ethyl acetate, the organic layer washed with water until neutrality, and the solvent was removed under a reduced pressure to provide a dry solid, which was then purified by silica gel column chromatography (eluent: chloroform/hexane=5/1) to obtain 35.5 g (yield: 44.9%) of 1-chloroisoquinoline white crystal.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:22][OH:23]>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][C:17](=[N:22][OH:23])[CH2:16][CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C1CCN(CCCCCOCc2ccccc2)CC1
Agent: Cl
Product: ON=C1CCN(CCCCCOCc2ccccc2)CC1

Procedure:
1-(5-Benzyloxypentyl)-4-piperidone oxime is prepared from 1-(5-benzyloxypentyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: Cl[C:2]([F:7])([F:6])C([O-])=O.[Na+].[Cl:9][C:10]1[CH:11]=[CH:12][N:13]=[C:14]2[C:19]=1[N:18]=[CH:17][C:16]([OH:20])=[CH:15]2.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>CO.ClCCl>[Cl:9][C:10]1[CH:11]=[CH:12][N:13]=[C:14]2[C:19]=1[N:18]=[CH:17][C:16]([O:20][CH:2]([F:6])[F:7])=[CH:15]2
Reactant: Oc1cnc2c(Cl)ccnc2c1
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: FC(F)Oc1cnc2c(Cl)ccnc2c1
Reaction time: 3 h
Yield: 55.8 %

Procedure:
A round bottom flask under nitrogen atmosphere was charged with sodium 2-chloro-2,2-difluoroacetate (0.49 g, 3.2 mmol), 8-chloro-1,5-naphthyridin-3-ol (0.25 g, 1.4 mmol), cesium carbonate (1.4 g, 4.2 mmol), and DMF (2.8 mL, 0.5M). This was then placed in a 100° C. preheated oil bath and stirred at this temperature for 3 hours. Reaction mixture diluted with 10% Methanol/Dichloromethane and filtered over celite. Filtrate concentrated and purified by ISCO silica gel chromatography (40 g) in 1% MeOH/DCM to afford pure 8-chloro-3-(difluoromethoxy)-1,5-naphthyridine (0.18 g, 56% yield) as white solid. MS [M+H]=231.2. Calc'd for C9H5ClF2N2O=230.60.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][CH:5]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[CH:11][CH:10]=1)/[CH:6]=C\C.[O:23]1CCOCC1.O.N1C(C)=CC=CC=1C>[Os](=O)(=O)(=O)=O.C(OCC)(=O)C.C(O)(C)(C)C>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH:5]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[CH:11][CH:10]=1)[CH:6]=[O:23]
Reactant: C/C=C\C(CC(=O)OC)c1ccc(OC2CCCCO2)cc1
Reactant: C1COCCO1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: Cc1cccc(C)n1
Solvent: CC(C)(C)O
Product: COC(=O)CC(C=O)c1ccc(OC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
To a solution of (Z)-3-[4-(tetrahydropyran-2-yloxy)-phenyl]-hex-4-enoic acid methyl ester (3.83 g) obtained in Step 2 in a mixed solvent of dioxane (60 mL)-water (15 mL) was added 2,6-lutidine (2.8 mL). Then, to this was added dropwise a tert-butanol solution of osmium tetroxide (5 mg/mL, 12 mL) over 5 minutes, followed by stirring the reaction mixture at room temperature for 3 minutes. Then, to the reaction mixture was added dropwise-aqueous-sodium periodate solution (10.3 g/25 mL) over 7 minutes, followed by stirring the reaction mixture at room temperature for 2 hours. After addition of ethyl acetate to the reaction mixture, the organic layer was separated. The organic layer was washed successively with 1N aqueous hydrochloric acid solution, water, saturated aqueous sodium bicarbonate solution, saturated aqueous sodium thiosulfate solution and saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:4 to 1:3) to give 4-oxo-3-[4-(tetrahydropyran-2-yloxy)-phenyl]-butyric acid methyl ester (2.59 g).
Reaction SMILES: [CH2:1]([S:8][C:9]1[S:19][C:12]2=[N:13][C:14](O)=[CH:15][C:16](=[O:17])[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:21].P(Cl)(Cl)(Cl)=O>>[CH2:1]([S:8][C:9]1[S:19][C:12]2=[N:13][C:14]([Cl:21])=[CH:15][C:16](=[O:17])[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(O)nc2sc(SCc3ccccc3)nn12
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: O=c1cc(Cl)nc2sc(SCc3ccccc3)nn12
Reaction time: 0.42 h
Yield: 25 %

Procedure:
A mixture of 31.7 g of the thus obtained 2-benzylthio-7-hydroxy-5H-1,3,4-thiadiazolo[3,2-a]-pyrimidin-5-one, 24.0 g of phosphorus pentachloride and 117 g of phosphorus oxychloride was heated to 70°-80° C. and stirred for 25 minutes. After cooling, the reaction mixture was concentrated under reduced pressure and chloroform and water were added to the residue. The organic layer was washed with an aqueous sodium hydrogen carbonate solution and water, and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was separated by silica gel column chromatography using an ethyl acetate/hexane mixture as an eluent, and thus 8.5 g of 2-benzylthio-7-chloro-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. m.p. 138°-140° C. Yield 25%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:40]=[CH:41][CH:42]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[C:22]([N:26]5[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]5)[CH:23]=[CH:24][CH:25]=4)[CH:18]=3)[NH:13][CH:12]=2)[C:8]([CH3:39])=[N:7]1.Cl>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:40]=[CH:41][CH:42]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([N:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)[CH:21]=4)[CH:18]=3)[NH:13][CH:12]=2)[C:8]([CH3:39])=[N:7]1
Reactant: Cc1nn(Cc2cccc(F)c2)cc1-c1c[nH]c2ncc(-c3cccc(N4CCN(C(=O)OC(C)(C)C)CC4)c3)cc12
Agent: Cl
Solvent: CO
Product: Cc1nn(Cc2cccc(F)c2)cc1-c1c[nH]c2ncc(-c3cccc(N4CCNCC4)c3)cc12
Yield: 29.4 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(3-(3-(1-(3-fluorobenzyl)-3-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (83 mg, 0.146 mmol) was deprotected in methanol (5 ml), HCl in dioaxane (5 ml). This afforded 20 mg (27.1% yield) of the titled compound. 1H NMR (CD3OD, 400 MHz): δ 8.852-8.818 (m, 1H), 8.726-8.723 (d, 1H), 8.272 (s, 1H), 7.951 (s, 1H), 7.832-7.798 (d, 1H), 7.499-7.459 (t, 1H), 7.407-7.317 (m, 3H), 7.160-7.129 (m, 2H), 7.070-7.048 (m, 2H), 5.404 (s, 2H), 3.549-3.523 (m, 4H), 3.418-3.393 (m, 4H), 2.392 (s, 3H). MS: m/z=467.2 (M+1); HPLC: 94.845% in method A.
Reaction SMILES: [C:1]([CH:6]1[C:11](=[O:12])[CH:10]([C:13]([O:15][CH3:16])=[O:14])[CH:9]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH2:8][C:7]1=[O:24])(=O)[CH2:2][CH2:3][CH3:4].[Cl-].[CH2:26]([O:28][NH3+:29])[CH3:27]>C(O)C.C([O-])(=O)C.[Na+]>[CH2:26]([O:28][NH:29][C:1](=[C:6]1[C:11](=[O:12])[CH:10]([C:13]([O:15][CH3:16])=[O:14])[CH:9]([CH2:17][CH:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[CH2:8][C:7]1=[O:24])[CH2:2][CH2:3][CH3:4])[CH3:27]
Reactant: CCCC(=O)C1C(=O)CC(CC2CCOCC2)C(C(=O)OC)C1=O
Reactant: CCO[NH3+]
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: CCCC(NOCC)=C1C(=O)CC(CC2CCOCC2)C(C(=O)OC)C1=O
Temperature: 20 °C
Reaction time: 20 h

Procedure:
10.0 parts by weight of 2-butyryl-4-methoxycarbonyl-5-[tetrahydropyran-4-ylmethyl]-cyclohexane-1,3-dione were dissolved in 150 parts by volume of ethanol, and 2.93 parts by weight of ethoxyammonium chloride and 2.71 parts by weight of anhydrous sodium acetate were added. The mixture was stirred at 20° C. for 20 hours, poured into ice-water and extracted with methylene chloride. The organic phase was concentrated to give 10.5 parts by weight of 2-(1-ethoxyaminobutylidene)-4-methoxycarbonyl-5-[tetrahydropyran-4-ylmethyl]-cyclohexane-1,3-dione (compound No. 1) as a viscous oil having the following structure: ##STR7##
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=O)[CH2:14][CH2:15][O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][Mg]Br.[NH4+].[Cl-].Cl>C1COCC1>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([CH3:20])=[CH:14][CH2:15][O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCOc2cc(OCc3ccccc3)ccc21
Reactant: C[Mg]Br
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1=CCOc2cc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7-(benzyloxy)-2,3-dihydro-4H-chromen-4-one was dissolved in THF, a solution (0.97 M, 5 mL) of methylmagnesium bromide in THF was added dropwise thereto at 0° C., followed by stirring at room temperature for 1 hour, and a solution (0.97 M, 5 mL) of methylmagnesium bromide in THF was added dropwise thereto, followed by stirring at room temperature for 2 hours. To the reaction liquid was added a saturated aqueous NH4Cl solution and subsequently 2 M hydrochloric acid (20 mL), followed by stirring at room temperature for 2 hours and then extracting with EtOAc three times. The organic layer was combined, washed with water and brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=95:5 to 90:10) to obtain 7-(benzyloxy)-4-methyl 2H-chromene (445 mg) as a colorless transparent liquid.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([OH:15])[C@H:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:12]2[CH2:24][O:25][C@@H:10]1[O:11]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CI.[CH2:30](O)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH3:30])[C@H:13]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@H:12]2[CH2:24][O:25][C@@H:10]1[O:11]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCO
Reactant: O[C@@H]1[C@@H](OCc2ccccc2)[C@@H]2OC[C@@H](O2)[C@H]1OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CI
Solvent: C1CCOC1
Product: CO[C@@H]1[C@@H](OCc2ccccc2)[C@@H]2OC[C@@H](O2)[C@H]1OCc1ccccc1
Yield: 109 %

Procedure:
A solution of 1,6-anhydro-2,4-di-O-benzyl-β-D-glucopyranose (Chem Ber 70 (1937) 1848-1856) (1.5 g, 4.4 mmol) and a trace of tetrabutylammonium iodide in tetrahydrofuran (10 ml) was stirred with sodium hydride (60% dispersion in oil, 200 mg, 5 mmol). Methyl iodide (0.7 g, 5 mmol) was added. The reaction was complete almost immediately (t.l.c evidence). Ethanol was added to the reaction mixture to destroy excess sodium hydride. The mixture was diluted with chloroform and washed with water and brine. The organic phase was dried and evaporated and the residue was chromatographed on silica gel (hexane/ethyl acetate, 2:1) to give the title compound (1.7 g, 109%), as a colourless syrup that yellowed on standing [α]D -33.5°. 13C Nmr peaks were recorded at 100.5 (C-1), 76.6 (C-2), 79.0 (C-3), 76.1 (C-4), 74.3 (C-5), 65.3 (C-6), 71.9 and 71.2 (PhCH2O), 58.0 (OCH3), and 138.0, 137.9, 128.4, 127.9 and 127.8 (aromatic).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]2[CH:16]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[O:15][B:14]([OH:24])[C:13]=2[CH:12]=[C:11]([O:25]C2CCCCO2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CCN(CC)CC>C1COCC1>[CH2:1]([O:8][C:9]1[C:17]2[CH:16]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[O:15][B:14]([OH:24])[C:13]=2[CH:12]=[C:11]([OH:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(OC3CCCCO3)cc(OCc3ccccc3)c21
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CC1OB(O)c2cc(O)cc(OCc3ccccc3)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
To a mixture of ethyl 2-(4-(benzyloxy)-1-hydroxy-6-(tetrahydro-2H-pyran-2-yloxy)-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (1.48 g, 3.1 mmol) in THF (10 mL) was slowly added conc. HCl (1.48 mL) at 0° C. The reaction mixture was stirred at room temperature for 1 h and neutralized by addition of Et3N. The resulting mixture was extracted with EtOAc (3×25 mL), dried over anhydrous Na2SO4 and concentrated to give the title compound as a white powder (1.01 g, Yield: 95%).
Reaction SMILES: [CH:1]1([CH:4]([C:13]([N:15]2[CH2:20][CH2:19][C:18]3[N:21]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:23][C:17]=3[CH2:16]2)=[O:14])[CH2:5][C:6]([O:8][C:9](C)(C)C)=[O:7])[CH2:3][CH2:2]1>Cl>[CH:1]1([CH:4]([C:13]([N:15]2[CH2:20][CH2:19][C:18]3[N:21]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:23][C:17]=3[CH2:16]2)=[O:14])[CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)CC(C(=O)N1CCc2nc(-c3ccccc3)oc2C1)C1CC1
Agent: Cl
Product: COC(=O)CC(C(=O)N1CCc2nc(-c3ccccc3)oc2C1)C1CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
1.4 g (3.6 mmol) tert-butyl 3-cyclopropyl-4-(2-phenyl-6,7-dihydro-4H-oxazolo[5,4-c]pyridin-5-yl)-4-oxobutanoate are mixed with 150 ml of 1.25 M HCl and stirred for 8 h at 60° C. The mixture is evaporated down and the residue is taken up in dichloromethane. It is filtered to remove the precipitate and the filtrate is evaporated down. This yields 650 mg of colourless resin which is dissolved in 10 ml MeOH and combined with 1 ml 2M trimethylsilyl-diazomethane solution in hexane while being cooled to −5° C. The yellow solution is left overnight with stirring while the ice bath is heated. The solvent is eliminated and the residue is reacted in the following step without any further purification.
Reaction SMILES: [CH2:1]([C:8]1([C:15]#[C:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].C1([Se]Cl)C=CC=CC=1.OO>C1COCC1.C(OCC)C>[CH2:1]([C:8]1([C:15]#[C:16][Si:17]([CH3:19])([CH3:18])[CH3:20])[CH2:13][CH2:12][C:11](=[O:14])[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C#CC1(Cc2ccccc2)CCC(=O)CC1
Agent: CC(C)[N-]C(C)C
Agent: Cl[Se]c1ccccc1
Agent: OO
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#CC1(Cc2ccccc2)C=CC(=O)CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 38.6 %

Procedure:
Under a nitrogen atmosphere and with stirring, a sample of 30 (50 mg, 0.176 mmol) was suspended in dry THF (1.4 mL) and the solution was cooled to −78° C. in a dry ice/isopropanol bath. To the stirred mixture was added lithium diisopropylamide (LDA, 2 M in THF/n-heptane/ethylbenzene, 132 μL, 0.26 mmol) dropwise. The isopropanol bath was then removed and the mixture was allowed to reach room temperature over 20 minutes. The mixture was again cooled to −78° C. and to it was added dropwise a solution of phenylselenenyl chloride (66.5 mg, 0.347 mmol, 2 eq) in dry THF (0.42 mL). The isopropanol bath was removed and the reaction was stirred at room temperature for 2 hours. During this time a yellow precipitate appeared, indicating the formation of solid lithium chloride. The reaction was then quenched with brine (5 mL) and the aqueous layer was extracted with dichloromethane/ethyl ether (1:2, 3×4 mL). The organic layers were combined, washed with brine (1×4 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to give a dark yellow-brown residue. This residue was dissolved in ethyl ether (2.82 mL) and hydrogen peroxide (30% aqueous, 3×42.3 μL) was added in 3 successive portions, allowing the mixture to stir 5 minutes between each addition. After the third portion was added, the color of the mixture changed from brown to pale yellow and translucent. The reaction mixture was then washed with water (1×4 mL), saturated aqueous sodium bicarbonate solution (2×4 mL), and brine (1×4 mL). The organic layers were combined and dried over magnesium sulfate, filtered, and concentrated in vacuo to give the crude product as a yellow oil (43.1 mg). The crude was purified by flash column chromatography [hexanes-ethyl acetate (5:1)] to give 31 (19.2 mg, 0.068 mmol, 39%) as a clear oil: 1H NMR (CDCl3) δ 7.34-7.24 (5H, m), 6.74 (1H, dd, J=1.5, 10 Hz), 5.94 (1H, dd, J=0.6, 10 Hz), 2.98 (1H, d, J=13 Hz), 2.89 (1H, d, J=13 Hz), 2.46 (2H, dt, J=5, 17 Hz), 2.08 (2H, td, J=1.5, 6 Hz), 0.16 (9H, s); 13C NMR (CDCl3) δ 209.1, 199.1, 152.1, 135.9, 130.9, 128.2, 128.1, 127.3, 109.0, 106.1, 89.4, 46.4, 38.5, 35.0, 34.5, 0.11; MS (ESI+) m/z 283.1 [M+H]+, HRMS (ESI+) calcd for C18H22OSi+H 283.1518. found 283.1508.
Reaction SMILES: [C:1]([NH:4][C:5](=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]>CO>[C:1]([NH:4][C@@H:5]([C:6]([OH:8])=[O:7])[CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC(=Cc1ccccc1)C(=O)O
Solvent: CO
Product: CC(=O)N[C@H](Cc1ccccc1)C(=O)O
Reaction time: 2 h
Yield: 102.8 %

Procedure:
A solution of α-acetamido-cinnamic acid (0.5 g, 2.44 mmol) and the catalyst (1) (16 mg, 0.024 mmol, 1.0 mol %) in degassed methanol (10 ml) was placed in a 50 ml Parr pressure reactor purged with nitrogen. The vessel was then purged with hydrogen (×3) and charged to 4.34 MPa (630 psi) of hydrogen. After stirring for 2 h, the solution was evaporated to give (R)-N-acetylphenylalanine (0.52 g, quantitative yield, 84.4% ee).
Reaction SMILES: [F:1][C:2]1([F:59])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18]CC4C=CC(OC)=CC=4)[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]4[N:41]=[CH:40][C:39]([CH:42](O)[CH:43]([CH3:45])[CH3:44])=[CH:38][N:37]=4)[CH2:32][CH2:31]3)[C:9]=2[CH:47]([F:58])[C:48]2[CH:53]=[CH:52][C:51]([C:54]([F:57])([F:56])[F:55])=[CH:50][CH:49]=2)[CH2:4][CH2:3]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[F:59][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([C:8]2[C:17]3[CH:16]([OH:18])[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]4[N:41]=[CH:40][C:39]([CH2:42][CH:43]([CH3:44])[CH3:45])=[CH:38][N:37]=4)[CH2:32][CH2:31]3)[C:9]=2[CH:47]([F:58])[C:48]2[CH:49]=[CH:50][C:51]([C:54]([F:55])([F:57])[F:56])=[CH:52][CH:53]=2)[CH2:6][CH2:7]1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(C(O)C(C)C)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3C(F)c3ccc(C(F)(F)F)cc3)C(O)CC(C)(C)C4)CC2)nc1
Temperature: 25 °C
Reaction time: 41 h
Yield: 27.3 %

Procedure:
To a solution of 70 mg (0.085 mmol) of 4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-{1-[5-(1-hydroxy-2-methylpropyl)pyrimidin-2-yl]piperidin-4-yl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 19, in 5 ml of dichloromethane, 2 ml of triethyl silane and 1 ml of trifluoroacetic acid were added, and the reaction solution was stirred at room temperature for 41 hours. After completion of the reaction, the reaction solution was poured into saturated sodium hydrogencarbonate aqueous solution and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=95/5-85/15 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure. n-Hexane was added to the obtained residue and the precipitate was obtained by filtration to provide 16 mg of the title compound as a white solid (yield: 27%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16]>C(O)(=O)C.C([O-])(O)=O.[Na+]>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6]([OH:11])[CH:5]=[C:14]2[C:15]([OH:17])=[O:16]
Reactant: O=C(O)CC(=O)O
Reactant: O=C1Nc2ccc(F)cc2C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)c1cc(O)nc2ccc(F)cc12
Yield: 54 %

Procedure:
A stirred suspension of 5-fluoroisatin, also known as 5-fluoro-2,3-indoledione, available from Sigma-Aldrich (10.00 g, 61 mmol) and malonic acid (18.91 g, 182 mmol) in acetic acid (400 ml) was refluxed for 16 h. Acetic acid was removed under reduced pressure, the residue was suspended in water (400 ml), filtered and washed with water (300 ml) to give a brown solid. The solid was stirred in NaHCO3 saturated aqueous solution (800 ml) and the insoluble material was filtered off. The filtrate was acidified to pH 1-2 with concentrated HCl and the resulting precipitate was filtered, washed with water (300 ml) and dried. The resulting pale yellow solid (10 g, Yield 54%) was used directly for synthesis of preparation 4 without further purification. The mixture was analysed by 1H NMR and LCMS: 1H NMR (500 MHz; d6-DMSO) δ 2.08 (s, 1.5 H), 7.01 (s, 1H), 7.35-7.37 (m, 0.5 H)*, 7.48-7.49 (m, 2H), 7.64-7.68 (m, 0.9H)*, 8.01-8.04 (m, 1H), 12.29 (brs, 1H), 13.38 (brs, 0.7H)* ppm.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[C:12]1=[O:27])C.[OH-].[Na+]>>[Cl:26][C:22]1[CH:21]=[C:20]([N:13]2[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:28])=[O:3])[C:12]2=[O:27])[CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)CCCCCCn1c(=O)n(-c2cccc(Cl)c2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCCCn1c(=O)n(-c2cccc(Cl)c2)c2ccccc21

Procedure:
The product is produces as described in example 22 from 9 g. of 7-[3-(3-chlorophenyl)-2-oxo-benzimidazolin-1-yl]-enanthic acid ethyl ester and 1.76 g. of NaOH.
Reaction SMILES: Br[C:2](Br)=[CH:3][C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].O1CCCC1.C([Li])(CC)C>CCOCC>[C:3]([C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])#[CH:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C=C(Br)Br
Agent: [Li]C(C)CC
Solvent: CCOCC
Solvent: C1CCOC1
Product: C#C[C@H]1CCCN1C(=O)OC(C)(C)C

Procedure:
In according with Scheme I, N-α-BOC-D-proline 2a is reacted in an ether solvent such as tetrahydrofuran at a temperature ranging from -2° C. to the reflux temperature of the solvent with 10M boran-methyl sulfide complex to produce (R)-2-(hydroxymethyl)-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester 3a. Compound 3a in a chlorinated hydrocarbon solvent such as methylene chloride is treated with an oxidizing agent such as pyridinium chlorochromate, 4 Å molecular sieves and glacial acetic acid to give (R)-2-formyl-1-pyrrolidinecarboxylic acid 1,1-dimethylethyl ester 4a. Compound 4a in methylene chloride is treated with a methylene chloride solution of triphenylphosphine and carbon tetrabromide to produce (R)-2-(2,2-dibromoethenyl)-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester 5a. The dibromo compound 5a in an ether solvent such as tetrahydrofuran is reacted at -78° C. with an alkyl lithium reagent such as sec-butyllithium to give (R)-2-ethynyl-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester 6a.