Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH3:38])[C:6]([C:9]([NH:11][C:12]2[N:17]=[C:16]([C@:18]3([CH3:36])[CH2:23][C@@H:22]([C:24]([F:27])([F:26])[F:25])[O:21][C:20]([NH:28]C(=O)OC(C)(C)C)=[N:19]3)[C:15]([F:37])=[CH:14][CH:13]=2)=[O:10])=[N:7][CH:8]=1)#[N:2].FC(F)(F)C(O)=O>C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[NH2:28][C:20]1[O:21][C@H:22]([C:24]([F:25])([F:27])[F:26])[CH2:23][C@:18]([C:16]2[N:17]=[C:12]([NH:11][C:9](=[O:10])[C:6]3[C:5]([CH3:38])=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=3)[CH:13]=[CH:14][C:15]=2[F:37])([CH3:36])[N:19]=1
Reactant: Cc1cc(C#N)cnc1C(=O)Nc1ccc(F)c([C@]2(C)C[C@@H](C(F)(F)F)OC(NC(=O)OC(C)(C)C)=N2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C#N)cnc1C(=O)Nc1ccc(F)c([C@]2(C)C[C@@H](C(F)(F)F)OC(N)=N2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl ((4S,6S)-4-(6-(5-cyano-3-methylpicolinamido)-3-fluoropyridin-2-yl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)carbamate (9a, 0.052 g, 0.097 mmol) in DCM (1.5 mL) was treated with trifluoroacetic acid (0.747 mL, 9.69 mmol) and stirred at room temperature for 30 min. The reaction mixture was diluted with aqueous saturated Na2CO3 and extracted with DCM. The organic extract was washed with brine and dried over Na2SO4. The solution was concentrated under reduced pressure and the title compound was obtained as a white solid (40 mg, 95% yield). MS m/z=437 [M+H]+. Calculated for C19H16F4N6O2: 436.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH2:8][C@@H:9](OS(C(F)(F)F)(=O)=O)[C@@:10]2([N:22]=[N+:23]=[N-:24])[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:5])[CH3:2].C1CCN2C(=NCCC2)CC1>C1COCC1>[CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH:8]=[CH:9][C@:10]2([N:22]=[N+:23]=[N-:24])[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1[C@@H]2C[C@@H](OS(=O)(=O)C(F)(F)F)[C@@](N=[N+]=[N-])(C(=O)OCc3ccccc3)[C@@H]21
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)[C@H]1[C@@H]2C=C[C@](N=[N+]=[N-])(C(=O)OCc3ccccc3)[C@@H]21
Temperature: -50 °C
Reaction time: 3 h

Procedure:
To a solution of (1S,2R,3R,5R,6S)-2-azido-3-trifluoromethanesulfonyloxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (XXV) (1.36 g, 2.85 mmol) in THF (5.7 mL) was added DBU (0.47 mL, 3.13 mmol) and the mixture was stirred at -50° C. for 3 h. After dilution with ethyl acetate, the solution was washed with 1 N HCl-sol., sat. NaHCO3 -sol. and brine, followed by drying over MgSO4. Removal of the solvent in vacuum left the crude (1S,2R,5R,6S)-2-azido-bicyclo[3.1.0]hex-3-ene-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (XXVI) (566 mg, 61%) as a brownish oil, sufficiently pure for further transformations. 1H-NMR (250 MHz, CDCl3) □1.27 (3H, t, J=7.1 Hz), 1.76 (1H, t, J=3.5 Hz), 2.59 (1H, dt, J=7, 3.5 Hz), 2.67 (1H, ddd, J=7, 3.5, 2 Hz), 4.14 (2H, q,J=7.1 Hz), 5.27 (2H, s), 5.53 (1H, d, J=5.5 Hz), 6.25 (1H, dd, J=5.5, 2Hz), 7.37 (5H, s); MS[ISP] 345 (M+NH4+); □D20 -7183.54° (c=1.08, CHCl3).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC(=O)[NH:14][CH:15]([C:26]([N:28]1[CH2:31][C:30]([O:39][CH2:40][CH2:41][CH2:42][CH3:43])([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH3:38])[CH2:29]1)=[O:27])[CH:16]([OH:25])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)(C)(C)C>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:14][CH:15]([CH:16]([OH:25])[C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1)[C:26]([N:28]1[CH2:31][C:30]([O:39][CH2:40][CH2:41][CH2:42][CH3:43])([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH3:38])[CH2:29]1)=[O:27]
Reactant: CCCCOC1(c2ccccc2C)CN(C(=O)C(NC(=O)OC(C)(C)C)C(O)c2ccc(OC)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCOC1(c2ccccc2C)CN(C(=O)C(N)C(O)c2ccc(OC)cc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10 ml of trifluoroacetic acid are added to a solution containing 1.4 g (2.8 mmol) of tert-butyl[1-(3-butoxy-3-o-tolylazetidine-1-carbonyl)-2-hydroxy-2-(4-methoxy-phenyl)ethyl]carbamate in 20 ml of dichloromethane. After stirring for 1 hour at ambient temperature, the reaction medium is concentrated. 1.5 g of 2-amino-1-(3-butoxy-3-o-tolylazetidin-1-yl)-3-hydroxy-3-(4-methoxy-phenyl)propan-1-one trifluoroacetate are obtained in the form of a beige powder with a quantitative yield.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH:7]=O)=[C:5]([CH3:9])[O:4][N:3]=1.[NH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[C:16]([NH2:18])=[O:17].C(O)(=O)C.C([BH3-])#N.[Na+]>>[CH3:1][C:2]1[C:6]([CH2:7][NH:10][C:11]2[N:15]=[CH:14][NH:13][C:12]=2[C:16]([NH2:18])=[O:17])=[C:5]([CH3:9])[O:4][N:3]=1
Reactant: Cc1noc(C)c1C=O
Reactant: NC(=O)c1nc[nH]c1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1noc(C)c1CNc1nc[nH]c1C(N)=O
Yield: 96.7 %

Procedure:
The title compound was prepared in accordance with the general method described in Example 17(e) using 3,5-dimethylisoxazole-4-carbaldehyde (0.50 g, 4.0 mmol), 5-amino-imidazole-4-carboxamide (0.50 g, 4.0 mmol), acetic acid (0.23 mL, 4.0 mmol) and sodium cyanoborohydride (0.30 g, 4.8 mmol) with the exception that after stirring o.n., more sodium cyanoborohydride (0.04 g, 0.6 mmol) was added and the reaction mixture refluxed for 2 h. The reaction mixture was then concentrated in vacuo and the crude product was triturated with ethyl ether and the solid removed by filtration. The filtrate was concentrated to give the title compound (0.91 g, 97% yield). This material was used in the next step without further purification. MS (ESI) m/z 236 (M+1).
Reaction SMILES: [H-].[Na+].Cl.Cl[C:5]1[N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1.[OH:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][Si](C(C)(C)C)(C)C.O>CS(C)=O>[OH:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:5]1[N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCCO
Reactant: Clc1cccc2nccn12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: OCCCCOc1cccc2nccn12
Reaction time: 0.25 h

Procedure:
In a nitrogen stream, 8.0 g (200 mmol) of 60% oily sodium hydride was added to a solution of 18.90 g (100 mmol) of 5-chloroimidazo[1,2-a]pyridine hydrochloride in 200 ml of dimethyl sulfoxide at 0° C., followed by stirring for 15 minutes. To this mixture, 20.44 g (100 mmol) of 4-hydroxy-1-t-butyldimethylsiloxybutane was added, followed by stirring room temperature for 5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to yield 3.73 g (11.6%, orange oily substance) of the desired product.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.[OH:10][C:11]1[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][N:12]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(#N)C>[F:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][O:17][C:15]2[CH:14]=[CH:13][NH:12][C:11](=[O:10])[CH:16]=2)=[CH:4][CH:5]=1
Reactant: Oc1ccnc(O)c1
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=c1cc(OCc2ccc(F)cc2)cc[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1.40 g (7.41 mmol) 1-bromomethyl-4-fluoro-benzene in 20 mL acetonitrile is added 822 mg (7.40 mmol) 2,4-dihydroxy pyridine and 2.05 g (14.8 mmol) potassium carbonate. The reaction mixture is stirred overnight at RT. 5 mL of DMF is added and the reaction is stirred overnight. After filtration and evaporation of the solvent, is the residue purified by HPLC (Zorbax stable bond, C18; water (0.15% formic acid)/acetonitrile 95:5 to 5:95).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[C:9]([F:18])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:19][O-:20].[Na+].O>C1COCC1>[F:18][C:9]1[C:10]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[N:11][C:2]([O:20][CH3:19])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(F)c(OCC(F)(F)F)nc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(F)c(OCC(F)(F)F)nc1OC
Temperature: 60 °C
Reaction time: 2 h
Yield: 28.1 %

Procedure:
To a stirred solution of methyl 2-chloro-5-fluoro-6-(2,2,2-trifluoroethoxy)nicotinate (1.1 g, 3.9 mmol, Step-1 of Amine-42) in THF (35 mL) is added sodium methanolate (0.32 g, 5.8 mmol) at 0° C. The mixture is stirred at 60° C. for 2 hours and cooled to room temperature. The mixture is poured into water and extracted with dichloromethane (10 mL×3). The combined organic layer is washed with water, brine, and dried over sodium sulfate. The organic solvent is removed under reduced pressure. The residue is purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (9:1) to give 310 mg (28% yield) of the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([C@H:12]4[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15][CH2:14][C@H:13]4[N:8]3[CH2:7][CH2:6][CH2:5]2)[CH:11]=1.[Cl:25][C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1B(O)O>>[Cl:25][C:26]1[CH:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=[CH:28][C:27]=1[C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([C@H:12]4[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15][CH2:14][C@H:13]4[N:8]3[CH2:7][CH2:6][CH2:5]2)[CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cc(Br)cc3c1N2CCC3
Reactant: OB(O)c1ccc(C(F)(F)F)cc1Cl
Product: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cc(-c3ccc(C(F)(F)F)cc3Cl)cc3c1N2CCC3

Procedure:
The title compound was prepared by the method of Example 109 from tert-butyl (±)cis-2-bromo-5,6,8,9,11,11a-hexahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate (63 mg, 0.16 mmol) and 2-chloro-4-(trifluoromethyl)phenylboronic acid (69 mg, 0.32 mmol), after chromatographic purification (35.9 mg, 46%) as a white amorphous solid. 1H NMR (CDCl3, 300 MHz) δ7.69 (s, 1H), 7.51 (bd, 1 H, J=8.0 Hz), 7.42 (d, 1H, J=8.1 Hz), 7.04 (s, 1H), 6.97 (s, 1H), 3.60-3.75 (m, 1H), 3.48-60 (m, 1H), 3.15-3.35 (m, 4H), 2.65-2.80 (m, 4H), 2.10-2.20 (m, 2H), 1.85-2.00 (m, 2H), 1.46 (s, 9H) ppm. MS (CI, NH3): 493 (base, M+H).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[O:17][CH:16]([CH2:18][NH2:19])[CH2:15][C:14]=2[CH:20]=1>>[CH2:6]([O:5][C:1](=[O:4])[CH2:2][CH2:3][NH:19][CH2:18][CH:16]1[CH2:15][C:14]2[CH:20]=[C:10]([O:9][CH3:8])[CH:11]=[CH:12][C:13]=2[O:17]1)[CH3:7]
Reactant: C=CC(=O)OCC
Reactant: COc1ccc2c(c1)CC(CN)O2
Product: CCOC(=O)CCNCC1Cc2cc(OC)ccc2O1
Reaction time: 60 h

Procedure:
4.4 ml (0.04 mol) of ethyl acrylate are added to 6.5 g (0.04 mol) of 5-methoxy-2,3-dihydrobenzofuran-2-ylmethylamine and the reaction mixture is left to stand for 60 hours at room temperature, yielding 3-[N-(5-methoxy-2,3-dihydrobenzofuran-2-yl)methylamino]-propionic acid ethyl ester in the form of a yellowish oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.N1CCCC1.[C:17]1(=O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>CO>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][C:17]1([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH2:9][C:8]2=[O:10]
Reactant: O=C1CCCCC1
Reactant: CC(=O)c1cc(Br)ccc1O
Solvent: CO
Solvent: C1CCNC1
Product: O=C1CC2(CCCCC2)Oc2ccc(Br)cc21
Yield: 108.9 %

Procedure:
To a solution of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (60 g, 280 mmol) and pyrrolidine (37.8 g, 532 mmol) in methanol (1200 mL) was added cyclohexanone (55 g, 560 mmol), and the mixture was reflux overnight. The solvent was removed in vacuo, and then added H2O and HCl to make the mixture to PH=1, extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated to give 6-bromospiro[chroman-2,1′-cyclohexan]-4-one (90 g, 100%). 1H NMR (CDCl3): 1.49 (d, 4H), 1.64 (d, 4H), 1.83 (s, 1H), 1.98 (d, 2H), 2.11 (t, 1H), 2.31 (s, 1H), 2.68 (s, 1H), 6.87 (d, 1H), 7.50 (d, 1H), 7.92 (s, 1H).
Reaction SMILES: C(OC([N:8]([CH:19]([C:24]1[CH:25]=[N:26][C:27]([N:30]2[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[N:31]2)=[CH:28][CH:29]=1)[CH2:20][CH:21]([CH3:23])[CH3:22])[C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][N:10]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:22][CH:21]([CH3:23])[CH2:20][CH:19]([NH:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][N:10]=1)[C:24]1[CH:25]=[N:26][C:27]([N:30]2[CH:34]=[C:33]([C:35]([F:36])([F:38])[F:37])[CH:32]=[N:31]2)=[CH:28][CH:29]=1
Reactant: COC(=O)c1ccc(N(C(=O)OC(C)(C)C)C(CC(C)C)c2ccc(-n3cc(C(F)(F)F)cn3)nc2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(CC(C)C)c2ccc(-n3cc(C(F)(F)F)cn3)nc2)nc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 39.3 %

Procedure:
To a 0° C. solution of (+\−)-methyl 6-(tert-butoxycarbonyl(3-methyl-1-(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)butyl)amino)nicotinate (110 mg, 4.7 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (10 mL). The solution was stirred at 20° C. for 2 h. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (20 mL) and washed with water (20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give (+\−)-methyl 6-(3-methyl-1-(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)butylamino)nicotinate (800 mg) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 11.11 (d, J=4.0 Hz, 1H), 8.76 (s, 1H), 8.45 (d, J=1.6 Hz, 1H), 8.36 (d, J=1.6 Hz, 1H), 8.17 (d, J=9.2 Hz, 1H), 7.96 (d, J=8.4 Hz, 1H), 7.86-7.82 (m, 2H), 6.59 (d, J=9.6 Hz, 1H), 4.54-4.49 (m, 1H), 3.83 (s, 3H), 2.06-1.97 (m, 1H), 1.72-1.58 (m, 2H), 0.96 (d, J=6.4 Hz, 3H), 0.89 (d, J=6.4 Hz, 3H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([CH3:21])[CH:14]=2)(=[O:12])=[O:11])[C:3]=1[C:4]#[N:5].[NH3:22]>C(O)C.C1COCC1>[NH2:22][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([CH3:21])[CH:14]=2)(=[O:12])=[O:11])[C:3]=1[C:4]#[N:5]
Reactant: N
Reactant: COc1cc(C)cc(S(=O)(=O)c2cccc(F)c2C#N)c1
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(C)cc(S(=O)(=O)c2cccc(N)c2C#N)c1
Temperature: 130 °C
Yield: 34 %

Procedure:
A solution of 0.3 g (0.00098 mol) of 2-fluoro-6-[(3-methyl-5-methoxyphenyl)sulfonyl]benzonitrile (Example 25) in 10 mL of absolute ethanol and ca. 2 mL of THF was saturated with ammonia. The resultant solution was sealed in a glass-lined Parr bomb and heated to 130° C. for 4 h. The solvent was removed in vacuo. 20 mL of 1 NaOH was added. This aqueous solution was extracted with 3×50 mL of EtOAc. The EtOAc solution was dried over MgSO4. After solvent removal, the crude product was recrystallized from absolute ethanol to give 0.1 g (34%) of 2-amino-6-[(3-methyl-5-methoxyphenyl)sulfonyl]benzonitrile: mp 166°-168° C.; NMR (Me2SO-d6, 200 MHz δ 2.4 (s, 3H), 3.87 (s, 3H), 6.7 (br s, 2H), 7.13 (apparent d, 1H), 7.2 (unresolved s, 1H), 7.3-7.5 (m, 2H), 7.57 (apparent t, 1H). Anal. Calc. for C15H14N2O3S: C, 59.59; H, 4.67;N, 9.27; S, 10.6. Found: C, 59.67;H, 4.71;N, 9.25; S, 10.51.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]([CH2:14][N:15]2[CH:20]=[CH:19][N:18](C(OCC3C=CC=CC=3)=O)[CH2:17][C:16]2=[O:31])([C:10]([O:12][CH3:13])=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]>[Pd].CO>[C:1]([N:4]1[CH2:5][CH2:6][C:7]([CH2:14][N:15]2[CH2:20][CH2:19][NH:18][CH2:17][C:16]2=[O:31])([C:10]([O:12][CH3:13])=[O:11])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: COC(=O)C1(CN2C=CN(C(=O)OCc3ccccc3)CC2=O)CCN(C(C)=O)CC1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1(CN2CCNCC2=O)CCN(C(C)=O)CC1
Yield: 84.3 %

Procedure:
A solution of 1-(1-acetyl-4-methoxycarbonylpiperidin-4-ylmethyl)-4-benzyloxycarbonyl-2-oxo-1,2,3,4-tetrahydropyrazine (2.4 g) and 10% palladium on carbon (500 mg) in methanol (100 ml) was stirred at room temperature for 15 hours, under hydrogen atmosphere, and the catalyst was filtered off. The reaction solution was concentrated to give colorless oil of the title compound (1.40 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5](=O)[NH:4][CH2:3]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22].O>C1C=CC=CC=1>[CH3:1][N:2]1[CH2:7][C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5](=[S:22])[NH:4][CH2:3]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CN1CNC(=O)C(c2ccccc2)(c2ccccn2)C1
Solvent: c1ccccc1
Solvent: O
Product: CN1CNC(=S)C(c2ccccc2)(c2ccccn2)C1

Procedure:
To a solution of 1,2,3,6-tetrahydro-1-methyl-5-phenyl-5-(2-pyridyl)-4(5H)-pyrimidinone in benzene is added 0.16 equivalent of phosphorus pentasulfide. The reaction mixture is heated gently for 30 minutes then water is added and the layers are separated. The aqueous layer is extracted again with benzene and the organic layers are combined, washed with water, dried (MgSO4) and concentrated in vacuo to give 1,2,3,6-tetrahydro-1-methyl-5-phenyl-5-(2-pyridyl)-4(5H)-pyrimidinethione.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][C@@H:7]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)[C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[NH2:1][CH2:4][CH2:5][O:6][C@@H:7]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)[C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCN=[N+]=[N-])c2cccc(Cl)c2)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCN)c2cccc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
(R)-tert-butyl 3-((R)-(2-azidoethoxy)(3-chlorophenyl)methyl)piperidine-1-carboxylate (13.3 g, 33.8 mmol) was dissolved in THF/H2O (20:1, 180 mL/9 mL), triphenylphosphine (36.0 g, 135 mmol) was added in portions. The reaction mixture was stirred overnight at rt. The solvent was removed under reduced pressure to the residue, which was purified on silica gel chromatography to afford (R)-tert-butyl 3-((R)-(2-aminoethoxy)(3-chlorophenyl)methyl)piperidine-1-carboxylate (10.4 g, purity: HPLC=75%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([CH2:11][C:12]#[N:13])=[C:9]([CH3:14])[NH:8][C:5]2=[N:6][CH:7]=1.[CH2:15](Br)[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17]>CC#N>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([CH2:11][C:12]#[N:13])=[C:9]([CH3:14])[N:8]=[C:5]2[N:6]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])[CH:7]=1
Reactant: Cc1[nH]c2ncc(Cl)cc2c1CC#N
Reactant: O=C(CBr)c1ccccc1
Solvent: CC#N
Product: Cc1nc2n(CC(=O)c3ccccc3)cc(Cl)cc-2c1CC#N

Procedure:
A mixture of 5-chloro-3-cyanomethyl-2-methyl-pyrrolo[2,3-b]pyridine (147 mg, 0.7 mmol) and phenacylbromide (142 g, 7 mmol) in 12 ml CH3CN was refluxed for 22h. The reaction mixture was cooled and precipitated title compound was collected and washed with small portions of ice cold diethyl ether. Treatment of the filtrate with diethyl ether afforded a second and third lot of pure title compound. Total yield 257 mg (91%) calculated as the hydrobromide.
Reaction SMILES: [OH:1][C@@H:2]1[C:15]([CH3:17])([CH3:16])[O:14][C:13]2[C:4](=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([C:18]#[N:19])[CH:7]=[CH:6]3)[C@H:3]1[NH:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[OH-:29].[K+].[Cl-].[Na+]>C(O)(C)(C)C>[OH:1][C@@H:2]1[C:15]([CH3:17])([CH3:16])[O:14][C:13]2[C:4](=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([C:18]([NH2:19])=[O:29])[CH:7]=[CH:6]3)[C@H:3]1[NH:20][CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: [OH-]
Reactant: CC1(C)Oc2ccc3nc(C#N)ccc3c2[C@@H](NCCc2ccccc2)[C@@H]1O
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CC1(C)Oc2ccc3nc(C(N)=O)ccc3c2[C@@H](NCCc2ccccc2)[C@@H]1O
Temperature: 90 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
To a solution of (±)-trans-2-hydroxy-3,3-dimethyl-1-[(2-phenylethyl)amino]-2,3-dihydro-1H-pyrano[3,2-f]quinoline-8-carbonitrile (400 mg, 1.07 mmol) in t-butanol (40 mL), potassium hydroxide (800 mg, 14.3 mmol) was added at room temperature and the resulting mixture was stirred at 90° C. for 2 hour. Upon the completion of the reaction, sodium chloride aqueous solution was added to the reaction solution, and it was extracted with ethyl acetate and the resulting organic phase was dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by column chromatography (hexane/ethyl acetate=1/1) and recrystallized with hexane-ethyl acetate to obtain the aimed product (yield: 54%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]1[O:13][C:14](=[O:16])[CH3:15].[CH2:34]([O:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][CH:38]=1)[CH3:35]>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:41]([C:40]1[CH:44]=[CH:45][C:37]([O:36][CH2:34][CH3:35])=[CH:38][CH:39]=1)=[O:42])=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]1[O:13][C:14](=[O:16])[CH3:15]
Reactant: CCOc1ccc(C(=O)Cl)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(F)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CCOc1ccc(C(=O)c2cn([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)c3cccc(F)c23)cc1

Procedure:
4-Fluoro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-indole obtained in Example 2-(3) and 4-ethoxybenzoyl chloride were treated in a manner similar to Example 2-(4) to give 4-ethoxyphenyl 4-fluoro-1-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyl)indol-3-yl ketone as a colorless powder. APCI-Mass m/Z 614 (M+H). 1H-NMR (DMSO-d6) δ 1.38 (t, J=6.9 Hz, 3H), 1.68 (s, 3H), 1.97 (s, 3H), 1.98 (s, 3H), 2.04 (s, 3H), 4.11 (d, J=4.0 Hz, 2H), 4.16 (q, J=7.0 Hz, 2H), 4.28-4.31 (m, 1H), 5.30 (t, J=9.8 Hz, 1H), 5.54 (t, J=9.6 Hz, 1H), 5.76 (t, J=9.3 Hz, 1H), 6.34 (d, J=9.0 Hz, 1H), 7.01 (dd, J=10.6, 8.0 Hz, 1H), 7.07 (d, J=8.7 Hz, 2H), 7.36 (td, J=8.1, 4.9 Hz, 1H), 7.62 (d, J=8.3 Hz, 1H), 7.83 (d, J=8.8 Hz, 2H), 8.14 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:20]([O-:22])=[O:21])[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH:16]([CH3:18])[CH3:17])[CH:10]=1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].N1C=CN=C1.CCOCC>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:20]([O-:22])=[O:21])[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])=[C:11]([CH:16]([CH3:18])[CH3:17])[CH:10]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)c1cc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)ccc1O
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)c1cc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)ccc1O[Si](C)(C)C(C)(C)C

Procedure:
3,5-Dichloro-4-(3'-isopropyl-4'-hydroxyphenoxy)-nitrobenzene (10.2 g), 6.75 g. of t-butyldimethylsilyl chloride, 4.06 g of imidazole, and 2 mg of N ,N-dimethylaminopyridine in 10 ml dimethylformamide are stirred 18 hours at room temperature. The solution is poured into ether and extracted six times with water. The ether is dried, filtered and stripped to afford 3,5-dichloro-4-(3'-isopropyl-4'-t-butyldimethylsiloxyphenoxy)-nitrobenzene. NMR (CDCl3): δ0.2 (6H, s), 1.1 (9H,s), 1.2 (6H,d), 3.3 (1H,m), 6.5 (1H,d of d), 6.7 (1H,d), 8.3 (2H,s).