Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH:19]=3)=[O:17])[CH:12]=[CH:11][C:10]=2[CH3:30])[CH:5]=[CH:4][N:3]=1.[OH:31][CH:32]1[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]1.CC(C)([O-])C.[K+]>>[CH3:30][C:10]1[CH:11]=[CH:12][C:13]([NH:15][C:16]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:19]=2)=[O:17])=[CH:14][C:9]=1[NH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([O:31][CH:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)[N:7]=1
Reactant: CN1CCC(O)CC1
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1Nc1ccnc(Cl)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1Nc1ccnc(OC2CCN(C)CC2)n1
Temperature: 140 °C
Yield: 71.4 %

Procedure:
A mixture of 2-chloro-4-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)anilino]pyrimidine (0.13 g), 4-hydroxy-N-methylpiperidine (0.087 g) and potassium tert-butoxide (1M in tert-butanol, 1.5 ml) was stirred and heated to 140° C. for 1 hour. The mixture was partitioned between water and methylene chloride and the organic phase was washed with brine, dried over sodium sulphate and evaporated. There was thus obtained the title compound as a solid (0.11 g); NMR Spectrum: (DMSOd6) 1.45 (m, 2H), 1.88 (m, 2H), 1.97 (m, 2H), 2.05 (s, 3H), 2.15 (s, 3H), 2.23 (m, 2H), 3.5 (m, 4H), 5.7 (m, 4H), 4.77 (m, 1H), 6.28 (d, 1H), 6.89 (m, 1H), 7.1 (m, 1H), 7.21 (m, 1H), 7.24 (s, 1H), 7.47 (m, 1H), 7.9 (m, 1H), 7.98 (d, 1H), 8.25 (m, 1H), 8.9 (s, 1H), 10.24 (s, 1H); Mass Spectrum: M+H+ 504.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][C:23](OC)=[O:24])=[N:20][CH:21]=3)=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(OC)C=CC=CC=1>C1(C)C=CC=CC=1>[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][C:23]([NH:34][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:24])=[N:20][CH:21]=3)=[CH:14][CH:15]=2)[CH2:5][CH2:6]1
Reactant: NCc1ccccc1
Reactant: COC(=O)Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1
Solvent: COc1ccccc1
Solvent: Cc1ccccc1
Product: O=C(Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.1 %

Procedure:
A 1 L single-necked round-bottomed flask was charged with 7 (61.4 g, 0.172 mol), benzyl amine (55.6 g, 0.519 mol, 3 eq), and anhydrous anisole (300 g) and then stirred at reflux until reaction was essentially complete (23 h, 165° C. oil bath temperature; internal temperature was 147° C.) aid then allowed to cool to near room temperature. A portion (1 mL) of the reaction mixture was diluted with toluene (1 mL) resulting in the complete crystallization of that portion. This seed was then added to the reaction mixture and allowed to stand until the whole reaction mixture had crystallized to a single block. Toluene (150 mL) was added and the mixture swirled to break up the solid. Heptane/toluene (1:1, 100 mL) was added and the solid mixture broken up further. Finally, heptane (50 mL, then 25 mL) was added and the mixture broken up even further, allowing to stand an additional 30 min before filtering the solid. Filtration of the solid, washing with 2:1 toluene/heptane (300 mL), 1:2 toluene/heptane (300 mL), and then heptane (2×300 mL), and then drying (air, then high vac) gave 60.16 g (yield of 81%) of title product as a white solid (≧98.9% AUC). Another 2.5 g of less pure (97.4%) material was obtained from the mother liquors.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:18]2[CH:23]=[CH:22][C:21]([O:24]CC3C=CC=CC=3)=[CH:20][CH:19]=2)=[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:6]([CH3:12])[C:7]=1[C:8]([F:11])([F:10])[F:9])#[N:2].[H][H]>[OH-].[OH-].[Pd+2].C(O)C.C1COCC1>[C:1]([C:3]1[C:4]([C:18]2[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=2)=[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:6]([CH3:12])[C:7]=1[C:8]([F:11])([F:9])[F:10])#[N:2]
Reactant: [H][H]
Reactant: CCOC(=O)c1c(-c2ccc(OCc3ccccc3)cc2)c(C#N)c(C(F)(F)F)n1C
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1c(-c2ccc(O)cc2)c(C#N)c(C(F)(F)F)n1C

Procedure:
In a manner analogous to the procedure set forth in Scheme II, step A, hydrogenate ethyl 4-cyano-1-methyl-3-[4-(phenylmethoxy)phenyl]-5-(trifluoromethyl)pyrrole-2-carboxylate, (intermediate prepared in example A-237) using Pearlman's catalyst and 60 psi of hydrogen gas in 1:1 ethanol/THF for 11 hours. Filter the reaction through diatomaceous earth and concentrate in vacuo. Purify the residue via radial chromatography eluting with ethyl acetate and hexane to provide the title compound. MS (m/e): 337.0 (M−1) 1H NMR: 7.20 (d, 2H, J=8.3 Hz), 6.84 (d, 2H, J=8.8 Hz), 5.85 (s, 1H), 4.16 (q, 2H, J=7.0 Hz), 4.05 (s, 3H), 1.07 (t, 3H, J=7.0 Hz)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[C:10]([O:17][CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=2)=[CH:2]1.Cl.[CH3:27][O:28][C:29](=[O:34])[CH:30]([CH2:32][OH:33])[NH2:31].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.C(N(CC)CC)C>[OH:33][CH2:32][CH:30]([NH:31][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][C:8]([O:7][CH2:6][C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)=[CH:9][C:10]=1[O:17][CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:29]([O:28][CH3:27])=[O:34]
Reactant: COC(=O)C(N)CO
Reactant: C[Si](C)(C)CCOCOc1cc(OCc2ccsc2)ccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C(CO)NC(=O)c1ccc(OCc2ccsc2)cc1OCOCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.6 %

Procedure:
A mixture of 4-(3-thienylmethoxy)-2-(2-trimethylsilylethoxymethoxy)benzoic acid (6 g), (RS) serine methyl ester hydrochloride (2.7 g), 1-hydroxybenzotriazole (2.6 g), triethylamine (2.4 mL), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (3.6 g) and DMF (100 mL) is stirred at ambient temperature for 16 hours. The reaction is concentrated in vacuo and the residue partitioned between ethyl acetate (150 mL) and 1N HCl (100 mL). The organic phase is washed with water (2×100 mL) then dried over magnesium sulphate, filtered and concentrated in vacuo. The residue is purified by flash chromatography on silica eluting initially with a mixture of ethyl acetate and cyclohexane (3:7 v/v) then with a mixture of ethyl acetate and cyclohexane (1:1 v/v). Fractions homogeneous in the required product are combined and evaporated to give methyl (RS)-3-hydroxy-2-[4-(3-thienylmethoxy)-2-(2-trimethylsilylethoxymethoxy)benzoyl]aminopropionate (6.5 g) as a colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([C:8]2[C:9]([CH3:19])=[C:10]([CH2:14][CH2:15][CH2:16][CH2:17][OH:18])[CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1.CC(C)=[O:24]>>[F:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([C:8]2[C:9]([CH3:19])=[C:10]([CH2:14][CH2:15][CH2:16][C:17]([OH:24])=[O:18])[CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: Cc1c(CCCCO)cccc1C(=O)c1ccc(F)cc1
Product: Cc1c(CCCC(=O)O)cccc1C(=O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
14 ml of a sulfochromic mixture titrating 26.5 g of chromic anhydride per 100 ml were added over 25 minutes at 10° C to a solution of 3.47 g of 4-(3'-p-fluorobenzoyl-2'-methyl-phenyl)-butanol in 35 ml of acetone and after returning the mixture to room temperature, the mixture was stirred overnight. The mixture was poured into ice water and vacuum filtered, was washed with water until the wash water was neutral and the precipitate recovered was dried over phosphoric acid and crystallized from cycloxane to obtain 3.02 g of 4-(3'-p-fluorobenzoyl-2'-methyl-phenyl)-butyric acid in the form of colorless crystals melting at 94° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1I.[CH3:29][O:30][C:31]1[C:36]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[NH2:1][C:2]1[C:3]([C:34]2[CH:35]=[C:36]([NH:37][S:38]([CH3:41])(=[O:39])=[O:40])[C:31]([O:30][CH3:29])=[N:32][CH:33]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3I)n(-c3ccccc3)c(=O)c12
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ncc(-c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)cc1NS(C)(=O)=O
Yield: 8.9 %

Procedure:
(S)-2-(1-((6-Amino-5-iodopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.10 mol) was treated with N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methanesulfonamide (51 mg, 0.16 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (14 mg, 0.02 mol) and sodium carbonate (2M, 231 μl, 0.46 mol) according to the method described in Example 3 to give 8 mg (14% yield) of the title compound as a white solid. Purity 97%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Si:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH3:15])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:30][C:31]([SH:34])([Cl:33])[Cl:32]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([Si:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([CH3:15])[CH2:9][N:10]2[C:14]([S:34][C:31]([Cl:33])([Cl:32])[Cl:30])=[N:13][CH:12]=[N:11]2)=[CH:6][CH:7]=1
Reactant: C[Si](Cn1cncn1)(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: SC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[Si](Cn1ncnc1SC(Cl)(Cl)Cl)(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 2 h
Yield: 59.6 %

Procedure:
To a solution of 4.0 g (0.013 mol) of bis(4-fluorophenyl)methyl(1H-1,2,4-triazol-1-ylmethyl)silane and 2.0 mL (0.014 mol) of triethylamine in 50 mL of methylene chloride at 6° was added 1.4 mL (0.013 mol) of perchloromethylmercaptan over 2 minutes. The reaction temperature rose 6°. The dark solution was stirred at 25° for 2 hours, then diluted with methylene chloride, washed with water and brine, and evaporated to give 3.6 g of the title compound as an oil: ir (neat) 3100, 3020, 2960, 1590, 1500; nmr (CDCl3) δ 0.7 (3H, s), 4.4 (2H, s), 7.1 (4H, t), 7.5 (4H, dd), 8.1 (1H, s); mass spectrum: m/e 464.
Reaction SMILES: S(Cl)([Cl:3])=O.[I:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][CH:7]=1>C(Cl)Cl.CN(C=O)C>[I:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([Cl:3])=[O:11])=[CH:8][CH:7]=1
Reactant: O=C(O)c1ccc(I)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
Thionyl chloride (36.0 g, 302 mmol) was added to a suspension of 4-iodobenzoic acid (50.0 g, 202 mmol) in anhydrous DCM (300 ml) followed by a few drops of DMF and the reaction mixture was stirred overnight at r.t. Upon completion, reaction flask was concentrated under reduced pressure to yield 51.6 g (96.0% yield) of crude 4-iodobenzoyl chloride that was used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([O:20]C)=[CH:15][CH:16]=[C:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1.[OH2:24].OO>C(O)=O>[CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([CH2:15][CH2:16][C@:17]2([OH:24])[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:20]
Reactant: O
Reactant: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Agent: OO
Solvent: O=CO
Product: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.7 %

Procedure:
Thebaine (15.94 g) was added to a 250 ml flask. Water (18 ml) was added and the mixture was stirred at room temperature. Formic acid (42 ml) was added over 3 minutes and then the mixture was cooled in an ice bath. Hydrogen peroxide (30%, 6.7 g) was added and the mixture was stirred for 1 hour. The mixture was removed from the ice bath, allowed to warm to room temperature and then heated to 48° C. for 2 hours. The mixture was transferred to a hydrogenation bottle. A 5 wt % palladium on carbon catalyst (2 g) was added and hydrogen was passed through the mixture at approximately 20 psi for 15 hours. The catalyst was removed by passing the mixture through a pad of celite and rinsing the filtered solid with water/formic acid (3:1, 8 ml). The mixture was cooled in an ice bath and 25% sodium hydroxide (109 ml) was added dropwise over 50 minutes to increase the pH to 9–10. The mixture was stirred for 1 hour and 15 minutes and the solid product was filtered, rinsed with cold water and dried under vacuum pump for 3 hours. The product was oxycodone base (14.152 g, 87.7% yield) and contained 178 ppm of the α,β-unsaturated ketone impurity, 14-hydroxycodeinone.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:6][C:7]2[C:12]([N:13]=1)=[CH:11][C:10]([N+:14]([O-:16])=[O:15])=[C:9](F)[CH:8]=2)[CH3:2].[F:23][C:24]([F:35])([F:34])[C:25]([NH:27][CH2:28][C:29]1[N:30]=[CH:31][NH:32][CH:33]=1)=[O:26].C(N(CC)CC)C>C(#N)C>[CH2:1]([O:3][C:4]1[C:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:6][C:7]2[C:12]([N:13]=1)=[CH:11][C:10]([N+:14]([O-:16])=[O:15])=[C:9]([C:31]1[NH:32][CH:33]=[C:29]([CH2:28][NH:27][C:25](=[O:26])[C:24]([F:23])([F:34])[F:35])[N:30]=1)[CH:8]=2)[CH3:2]
Reactant: O=C(NCc1c[nH]cn1)C(F)(F)F
Reactant: CCOC(=O)c1nc2cc(F)c([N+](=O)[O-])cc2nc1OCC
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1nc2cc(-c3nc(CNC(=O)C(F)(F)F)c[nH]3)c([N+](=O)[O-])cc2nc1OCC
Temperature: 130 °C
Reaction time: 15 h
Yield: 37.1 %

Procedure:
To a solution of ethyl 3-ethoxy-7-fluoro-6-nitroquinoxaline-2-carboxylate (308 mg, 999 μmol) and 4-(trifluoroacetamidomethyl)imidazole (1.72 g, 8.91 mmol) in acetonitrile (10 ml) was added triethylamine (3.00 ml, 21.5 mmol), and the mixture was stirred for 15 hours at 130° C. in sealed tube. The reaction mixture was concentrated under reduced pressure and the residue obtained was purified by means of silica gel column chromatography [methylene chloride] to obtain 179 mg of the title compound as light brown powder. Yield 37%.
Reaction SMILES: [N:1]1([C:11]([N:13]2[CH2:18][CH2:17][CH:16]([C:19](O)=[O:20])[CH2:15][CH2:14]2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[Cl:63][C:64]1[CH:69]=[CH:68][CH:67]=[C:66]([Cl:70])[C:65]=1[C:71](=[N:73]O)[NH2:72]>O.CN(C)C=O>[Cl:63][C:64]1[CH:69]=[CH:68][CH:67]=[C:66]([Cl:70])[C:65]=1[C:71]1[N:73]=[C:19]([CH:16]2[CH2:17][CH2:18][N:13]([C:11]([N:1]3[C:2]4[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:8][CH2:9][CH2:10]3)=[O:12])[CH2:14][CH2:15]2)[O:20][N:72]=1
Reactant: O=C(O)C1CCN(C(=O)N2CCCc3ccccc32)CC1
Reactant: NC(=NO)c1c(Cl)cccc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N1CCC(c2nc(-c3c(Cl)cccc3Cl)no2)CC1)N1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.8 %

Procedure:
0.3 g of 1-(3,4-dihydroquinolin-1(2H)-ylcarbonyl)piperidine-4-carboxylic acid, 11 ml of dimethylformamide, 0.67 g of O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate, 0.028 g of 1-hydroxybenzotriazole, 0.91 ml of diisopropylethylamine and then 0.32 g of 2,6-dichloro-N′-hydroxybenzenecarboximidamide are introduced into a 100 ml round-bottomed flask. The reaction medium is stirred at ambient temperature for 1 h 30 and then heated at 95° C. for 20 hours. Water is added and the mixture is extracted with ethyl acetate. The organic phase is washed three times with water and dried over sodium sulfate and the solvent is evaporated under reduced pressure. The residue is chromatographed on silica gel with a heptane/ethyl acetate gradient from 0/1 to 1/1. 0.18 g of 1-({4-[3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl}carbonyl)-1,2,3,4-tetrahydroquinoline is obtained.
Reaction SMILES: [CH3:1][C:2]([O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][CH2:17][CH3:18])[C:11]([CH3:19])=[C:10]2[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)([CH3:5])[CH2:3][OH:4].[OH-].[Na+].[Mn]([O-])(=O)(=O)=[O:29].[K+]>O1CCOCC1.O>[CH3:1][C:2]([O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][CH2:17][CH3:18])[C:11]([CH3:19])=[C:10]2[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)([CH3:5])[C:3]([OH:29])=[O:4]
Reactant: CCCn1c(C)c(-c2ccncc2)c2cc(OC(C)(C)CO)ccc21
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCn1c(C)c(-c2ccncc2)c2cc(OC(C)(C)C(=O)O)ccc21
Reaction time: 12 h

Procedure:
An amount of 3.38 g (10 m mole) of 2-methyl-2-[2-methyl-1-propyl-3-(4-pyridyl)-1H-indole-5-yloxy]propanol in 50 ml of dioxane was successively mixed with 300 mg of sodium hydroxide in 5 ml of water and then with 3.4 g of potassium permanganate dissolved in 30 ml of water. After stirring for 12 hours, the reaction mixture was filtered, evaporated, and neutralized with dilute sulfuric acid. After extraction with chloroform, the organic phase was dried over sodium sulfate and evaporated. The evaporation residue was recrystallized from ethanol.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11].Br[CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[C@H:22]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:21][CH2:20]2.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[C@H:22]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:21][CH2:20]3)=[C:3]([O:10][CH3:11])[CH:4]=1)#[N:7]
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCBr)ccc21
Reactant: COc1cc(C#N)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(C#N)cc3OC)ccc21
Temperature: 40 °C
Reaction time: 16 h
Yield: 68 %

Procedure:
To a mixture of 4-hydroxy-3-methoxybenzonitrile (2.6 g, 17.6 mmol), ethyl [(1S)-5-(3-bromopropoxy)-2,3-dihydro-1H-inden-1-yl]acetate (Example 45) (6 g, 17.6 mmol), and Cs2CO3 (6.9 g, 21.1 mmol) in DMF (30 mL) was added water (15 drops). The reaction mixture was stirred at 40° C. for 16 h and concentrated under reduced pressure. The residue was diluted with water and extracted with EtOAc (2×). The combined organic phases were dried over MgSO4, filtered, and concentrated under reduced pressure. Recrystallization from MeOH (5 mL) gave 4.9 g (68%) of the title compound as an off-white solid. LC-MS: RT=3.59 min; (M+H)+ 410.0.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][C@H:5]([CH2:10][NH2:11])[CH2:6][C:7]([OH:9])=[O:8])[CH3:3].C(N(CC)CC)C.C[Si](C)(C)Cl.C(=O)([O-])OC1C=CC([N+]([O-])=O)=CC=1[CH:35]([O:37][C:38](=[O:42])[CH:39]([CH3:41])[CH3:40])[CH3:36].C(O)(=O)CC(CC(O)=O)([C:49]([OH:51])=[O:50])O>ClCCl>[C:38]([O:37][CH:35]([O:51][C:49]([NH:11][CH2:10][CH:5]([CH2:4][CH:2]([CH3:1])[CH3:3])[CH2:6][C:7]([OH:9])=[O:8])=[O:50])[CH3:36])(=[O:42])[CH:39]([CH3:40])[CH3:41]
Reactant: CC(C)C[C@H](CN)CC(=O)O
Reactant: CC(C)C(=O)OC(C)c1cc([N+](=O)[O-])ccc1OC(=O)[O-]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CC(CNC(=O)OC(C)OC(=O)C(C)C)CC(=O)O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 48 %

Procedure:
To a stirred suspension of pregabalin (2) (150 mg, 0.94 mmol) in anhydrous dichloromethane (10 mL) at 0° C. was added triethylamine (0.26 mL, 1.88 mmol) and trimethylchlorosilane (0.24 mL, 1.88 mmol). After stirring for 15 min at 0° C., a solution of α-isobutanoyloxyethyl-p-nitrophenyl carbonate (111) (267 mg, 0.94 mmol) in dichloromethane (3 mL) was added. The resulting mixture was stirred at room temperature for 1.5 h. The reaction mixture was acidified with citric acid and extracted with dichloromethane. The combined organic extracts were washed with brine and dried over Na2SO4. After filtration and evaporation, the crude product was purified by silica gel chromatography, eluting first with dichloromethane to remove nitrophenol, then with 30% ethyl acetate in dichloromethane to afford 130 mg (48%) of the title compound as a mixture of two diastereomers. 1H-NMR (CDCl3, 400 MHz): δ 0.90 (m, 6H), 1.70 (m, 8H), 1.46 (d, J=5.6 Hz, 3H), 1.66 (1H, m), 2.15 (m, 1H), 2.33 (m, 2H), 2.53 (m, 1H), 3.12 (m, 1H), 3.29 (m, 1H), 5.08 (t, J=6.0 Hz, 1H), 6.79 (m, 1H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:11][CH3:12])[CH2:3]1.Cl[C:14]1[C:15]2[C:22]([CH3:23])=[CH:21][S:20][C:16]=2[N:17]=[CH:18][N:19]=1.C(N(CC)CC)C>C(O)C>[CH3:12][O:11][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH2:10][CH:2]([NH:1][C:14]1[C:15]3[C:22]([CH3:23])=[CH:21][S:20][C:16]=3[N:17]=[CH:18][N:19]=1)[CH2:3]2
Reactant: Cc1csc2ncnc(Cl)c12
Reactant: COc1cccc2c1CC(N)C2
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1cccc2c1CC(Nc1ncnc3scc(C)c13)C2
Yield: 94.1 %

Procedure:
Using 2-amino-4-methoxyindan (27 mg, 0.17 mmol) synthesized in the above b) in Preparation Example 5, 4-chloro-5-methylthieno[2,3-d]pyrimidine (31 mg, 0.17 mmol), triethylamine (71 μl, 0.51 mmol), and ethanol (1.5 ml), a similar procedure to b) in Example 19 was carried out. The product obtained was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to obtain the title compound (50 mg, 0.16 mmol) having the following physical properties:
Reaction SMILES: C(C1C=CC(N)=CC=1)(C)(C)C.N[C:13]1[CH:14]=[C:15]([CH:27]=[CH:28][C:29]=1OC)[C:16]([NH:18]C1C=CC(F)=C(F)C=1)=[O:17]>>[C:16]([NH2:18])(=[O:17])[C:15]1[CH:27]=[CH:28][CH:29]=[CH:13][CH:14]=1
Reactant: COc1ccc(C(=O)Nc2ccc(F)c(F)c2)cc1N
Agent: CC(C)(C)c1ccc(N)cc1
Product: NC(=O)c1ccccc1
Yield: 11.5 %

Procedure:
The title compound was synthesized as in Example 1 using 4-t-butyl aniline (1.3 mL, 8.1 mmol), CSI (0.85 mL, 9.8 mmol), and 3-amino-N-(3,4-difluoro-phenyl)-4-methoxy-benzamide (1.9 g, 6.8 mmol) to give 0.095 g of benzamide, N-(3,4-difluorophenyl)-3-[[[[[[4-(1,1-dimethylethyl)phenyl]amino]carbonyl]amino]sulfonyl]amino]-4-methoxy-. Microanalysis: C25H26F2N4O5S.0.46 H2O; calculated: C=55.52; H=5.02; N=10.36. found: C=55.46; H=4.94; N=10.40. MS: M++1=533 Da. Mp 199-202° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]([C:15]#[N:16])[C:9]2=[O:17])=[CH:4][CH:3]=1.O1CCCC1.[Br:23]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>C(#N)C.C(OCC)(=O)C>[Br:23][C:12]1[CH:11]=[C:10]([C:15]#[N:16])[C:9](=[O:17])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:13]=1[CH3:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C#N)c(=O)n1-c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1c(Br)cc(C#N)c(=O)n1-c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of 1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (1 g, 4.05 mmol) in acetonitrile (10 mL)/tetrahydrofuran (5 mL) was added N-bromosuccinimide (792 mg, 4.46 mmol), and the mixture was stirred at 60° C. overnight. After cooling to room temperature, saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure. The obtained residue was washed with diethyl ether and collected by filtration to give the title compound (1.07 g, 86%) as a slightly yellow solid.