Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=O)=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)[N:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[NH2:28][NH2:29].[CH:30]([OH:34])(CC)[CH3:31]>>[F:19][C:18]([F:21])([F:20])[O:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:6]2[N:5]=[CH:4][N:3]=[C:2]3[N:28]([CH2:31][CH2:30][OH:34])[N:29]=[CH:8][C:7]=23)=[CH:12][CH:13]=1.[F:19][C:18]([F:21])([F:20])[O:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:6]2[C:7]3[C:2](=[N:28][N:29]([CH2:31][CH2:30][OH:34])[CH:8]=3)[N:3]=[CH:4][N:5]=2)=[CH:12][CH:13]=1
Reactant: CCC(C)O
Reactant: NN
Reactant: O=Cc1c(Cl)ncnc1Nc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: OCCn1cc2c(Nc3ccc(OC(F)(F)F)cc3)ncnc2n1
Product: OCCn1ncc2c(Nc3ccc(OC(F)(F)F)cc3)ncnc21
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To solution of 4-chloro-6-(4-trifluoromethoxy-phenylamino)-pyrimidine-5-carbaldehyde (50 g, 0.15 mmol) in sec-BuOH was added Na2CO3 (30 mg, 0.26 mmol) and hydrazine (20 mg, 0.18 mmol). The reaction was stirred at 60° C. temperature for 8 hours. The reaction mixture was partitioned in 100 ml water and 100 ml ethyl acetate, extracted with ethyl acetate three times. The organic phase was combined and washed with brine, dried over Na2SO4. The crude product was purified by silica gel flash chromatography by using hexane:ethyl acetate as eluent resulting 2-(4-(4-(trifluoromethoxy)phenylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethanol and 2-(4-(4-(trifluoromethoxy)phenylamino)-2H-pyrazolo[3,4-d]pyrimidin-2-yl)ethanol in the ratio of 4:1 as yellow solids.
Reaction SMILES: O[CH2:2][C:3]1[CH:30]=[CH:29][C:6]2[N:7]([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:8]([CH2:10][N:11]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[N:13]([CH:20]([CH3:22])[CH3:21])[C:12]3=[O:23])=[N:9][C:5]=2[CH:4]=1.CCN(S(F)(F)[F:37])CC>C(Cl)Cl>[F:37][CH2:2][C:3]1[CH:30]=[CH:29][C:6]2[N:7]([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:8]([CH2:10][N:11]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[N:13]([CH:20]([CH3:22])[CH3:21])[C:12]3=[O:23])=[N:9][C:5]=2[CH:4]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2cc(CO)ccc21
Solvent: ClCCl
Product: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2cc(CF)ccc21
Yield: 78.3 %

Procedure:
To a solution of 1-[5-hydroxymethyl-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-3-isopropyl-1,3-dihydro-benzoimidazol-2-one (41 mg, 0.10 mmol) in DCM (1 mL) was added DAST (32 mg, 0.20 mmol) at 0° C. The final solution was stirred at ambient temperature for 12 h then washed with sat. NaHCO3 and brine. The organic layer was dried over MgSO4 and evaporated. The residue was purified by slash chromatography (hexanes:EtOAc 2:1 to 1:1) to give 32 mg (78%) of 1-[5-fluoromethyl-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-3-isopropyl-1,3-dihydro-benzoimidazol-2-one as a white solid.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[Cl:14][C:15]1[N:20]=[C:19](Cl)[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][N:16]=1>ClCCl>[Cl:14][C:15]1[N:20]=[C:19]([NH:4][CH:1]2[CH2:3][CH2:2]2)[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][N:16]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: NC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc(Cl)nc1NC1CC1
Yield: 47 %

Procedure:
Cyclopropylamine (1.8 ml) and N,N-diisopropylethylamine (6.6 ml) were dissolved into 75 ml dichloromethane. The mixture was added dropwise to a solution of 2,4-dichloro-5-nitropyrimidine (5.0 g) in dichloromethane (15 ml) at 0° C. After the completion of the dropwise addition, the mixture was kept at the same temperature to react for 40 min. Purification was conducted by a column chromatography to obtain a bright-yellow solid (2.6 g) in a yield of 47%. 1H NMR (400 MHz, CDCl3): δ 8.84 (s, 1H), 7.35 (s, 1H), 3.84 (m, 1H), 1.36 (m, 4H) ppm.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:23]=[CH:22][C:6]([O:7][C:8]2[CH:21]=[CH:20][C:11]([O:12][CH2:13][C@@H:14]3[CH2:19][CH2:18][CH2:17][CH2:16][NH:15]3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.Br[CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29].C(N(CC)CC)C>ClCCl.O>[CH3:31][O:30][C:28](=[O:29])[CH2:27][CH2:26][CH2:25][N:15]1[CH2:16][CH2:17][CH2:18][CH2:19][C@H:14]1[CH2:13][O:12][C:11]1[CH:20]=[CH:21][C:8]([O:7][C:6]2[CH:22]=[CH:23][C:3]([Cl:2])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)CCCBr
Reactant: Clc1ccc(Oc2ccc(OC[C@@H]3CCCCN3)cc2)cc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCCN1CCCC[C@H]1COc1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 33.8 %

Procedure:
A solution of (S)-2-[4-(4-chloro-phenoxy)-phenoxymethyl]-piperidine hydrochloride (218 mg, 0.615 mmol), methyl 4-bromobutyrate (139 mg, 0.769 mmol), and triethylamine (124 mg, 1.23 mmol) in dichloromethane (2.5 mL) was heated for 18 h at 30° C. The mixture was diluted with 5 mls of water and extracted with dichloromethane (8 mL). The aqueous layer was re-extracted with ethyl acetate (8 mL). The combined organic layers were dried over anhy. Na2SO4 and the solvent was removed in vacuo to obtain the crude mixture, which was purified by silica gel flash chromatography to obtain the title product (87 mg, 34%): 1H NMR (400 MHz, CDCl3) δ 1.52-1.86 (m, 6H), 2.11-2.12 (m, 1H), 2.21-2.2 (m, 1H), 2.27-2.33 (m, 3H), 2.49-2.56 (m, 1H), 2.66-2.70 (m, 1H), 2.74-2.81 (m, 1H), 2.86-2.91 (m, 1H) 3.64 (s, 3H), 3.91-3.94 (dd, 1H J1=4.4 Hz, J2=10 Hz), 4.0-4.03 (dd, 1H J1=4.4 Hz, J2=10 Hz) 6.86-6.89 (m, 4H), 6.94-6.96 (m, 2H), 7.23-7.25 (m, 2H); MS
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)C=C.[C:23]1(OC2C=CC=CC=2)[CH:28]=CC=C[CH:24]=1>CCOCC>[CH2:28]([C:10]1[CH:9]=[C:8]([N:11]2[CH2:12][CH2:13][N:14]([C:17]3[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=3)[CH2:15][CH2:16]2)[CH:7]=[CH:6][C:5]=1[OH:4])[CH:23]=[CH2:24]
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: C=CCOc1ccc(N2CCN(c3ccncc3)CC2)cc1
Solvent: CCOCC
Product: C=CCc1cc(N2CCN(c3ccncc3)CC2)ccc1O
Temperature: 25 °C
Yield: 17.6 %

Procedure:
The product from step (i) (5 g) was heated under argon in gently refluxing diphenyl ether (15 g) for 2 1/2 hours. The mixture was cooled to room temperature and ether (70 ml) was added. The solid material was filtered and purified by flash chromatography on silica gel, eluting with methanol/dichloromethane (1/4 v/v) to give 2-allyl-4-[4-(4-pyridyl)piperazin-1-yl]phenol (0.88 g) as a solid, m.p. 180°-182° C.; NMR (d6 -DMSO) δ 8.88(1H,s), 8.19(2H,dd), 6.87(2H,dd), 6.7(3H,m), 5.88-6.03(1H,m), 5.0(2H,m), 3.44(4H,t), 3.28(2H,d), 3.05(4H, t); m/e 296 (M+H)+.
Reaction SMILES: CO[C@H]1OC(CO)[C@H](O)[C@@H](O)[C@@H]1O.[C:14]([NH:17][C@@H:18]1[C@@H:25]([OH:26])[C@H:24]([OH:27])[C@@H:23]([CH2:28][OH:29])[O:22][C@H:19]1[O:20][CH3:21])(=[O:16])[CH3:15].[C:30]([Si:34]([CH3:37])([CH3:36])Cl)([CH3:33])([CH3:32])[CH3:31]>CN(C=O)C.N1C=CN=C1>[C:14]([NH:17][C@@H:18]1[C@@H:25]([OH:26])[C@H:24]([OH:27])[C@@H:23]([CH2:28][O:29][Si:34]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:37])[CH3:36])[O:22][C@H:19]1[O:20][CH3:21])(=[O:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1NC(C)=O
Agent: CO[C@H]1OC(CO)[C@H](O)[C@@H](O)[C@@H]1O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CO[C@@H]1O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O)[C@H](O)[C@H]1NC(C)=O

Procedure:
This compound was prepared from the corresponding methyl glucoside, Methyl 2-acetamido-2-deoxy-β-D-glucopyranoside (Carbohydrates, Ed. Collins, P. M., Chapman and Hall, New York, 1987, p. 414) by treatment with t-butyldimethychlorosilane in DMF and imidazole. 1H NMR δ0.00 (2×s, 6H), 0.80 (2×s, 9H), 1.98 (s, br, 3H), 3.20-3.32 (m, 1H), 3.32-3.50 (s superimposed on m 5H), 3.59 (dd, J=12, 8, 1H), 3.76, 3.84 (ABX, JAB=18, 2H), 4.28 (d, J=8, 1H), 6.42 (d br J=4, 3H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][OH:5].[CH2:6]([O:8][C:9](=[O:13])/[CH:10]=[CH:11]/[CH3:12])[CH3:7].[H-].[Na+]>>[CH2:6]([O:8][C:9](=[O:13])[CH2:10][CH:11]([CH3:12])[O:5][CH2:4][CH2:3][CH2:2][Cl:1])[CH3:7]
Reactant: OCCCCl
Reactant: C/C=C/C(=O)OCC
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(C)OCCCCl

Procedure:
The 3-chloropropanol was added to the crotonic acid ethyl ester in the presence of sodium hydride to obtain the 7-chloro-3-methyl-4-oxaheptanoic acid ethyl ester (boiling point1 : 74° - 82°C.). Then the 7-iodo-3-methyl-4-oxaheptanoic acid ethyl ester (boiling point0.05 : 62° - 65°C) was obtained in acetone with sodium iodide according to Finkelstein.
Reaction SMILES: O[C:2]1[C:7]([CH:8]=[CH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[C:6](O)[C:5](O)=[C:4](O)[C:3]=1O.P(O)(O)([O-])=[O:23].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[Na+]>O>[CH:4]1[CH:5]=[CH:6][C:7](/[CH:8]=[C:9]2/[C:10]([C:12]3[C:17]([O:23]/2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:11])=[CH:2][CH:3]=1
Reactant: O=P([O-])(O)O
Reactant: O=C(C=Cc1c(O)c(O)c(O)c(O)c1O)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: O
Product: O=C1/C(=C/c2ccccc2)Oc2ccccc21

Procedure:
In addition, the reaction was carried out under the same conditions using pentahydroxychalcone (PHC) instead of THC as a substrate, and using 0.116 M sodium citrate phosphate buffer (pH 5.4) as a buffer. Similarly, water was used instead of tyrosinase as a control.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N:26]=[C:27]=[O:28])(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH:16]2[CH2:17][CH2:18][N:19]([C:27](=[O:28])[NH2:26])[CH2:20][CH2:21]2)[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCN(CC2CCNCC2)CC1
Reactant: C[Si](C)(C)N=C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(CC2CCN(C(N)=O)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
To a solution of 4-(t-butoxycarbonylamino)-1-(4-piperidinylmethyl)piperidine (590 mg) in methylene chloride (30 ml) is added trimethylsilyl isocyanate (220 mg) under ice-cooling, and the mixture is stirred at room temperature for 8 hours. The reaction mixture is washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (eluent; chloroform:methanol=10:1) to give 4-(t-butoxycarbonylamino)-1-(1-carbamoyl-4-piperidinylmethyl)piperidine (540 mg).
Reaction SMILES: [O-2].[O-2].[O-2].[O-2].[O-2].[V+5:6].[V+5].[C:8]([OH:13])(=[O:12])[C:9]([OH:11])=[O:10]>O>[C:8]([O-:13])(=[O:12])[C:9]([O-:11])=[O:10].[V+5:6].[C:8]([O-:13])(=[O:12])[C:9]([O-:11])=[O:10].[C:8]([O-:13])(=[O:12])[C:9]([O-:11])=[O:10].[C:8]([O-:13])(=[O:12])[C:9]([O-:11])=[O:10].[C:8]([O-:13])(=[O:12])[C:9]([O-:11])=[O:10].[V+5:6]
Reactant: O=C(O)C(=O)O
Agent: [V+5]
Agent: [O-2]
Solvent: O
Product: O=C([O-])C(=O)[O-]
Temperature: 1300 °C

Procedure:
Granulated alumina (8 - 16 mesh) is heated at 1300° C. for 4 hours. Ferric oxalate and vanadium pentoxide are suspended in 5 parts of water, heated to 80° C., and oxalic acid is added slowly to obtain a blue-colored vanadium oxalate solution. Sodium carbonate is added and the alumina is also placed in the solution. The mixture is dried over a water bath with agitation. While air is pumped in, it is indurated in a furnace at 400° C. for 16 hours to obtain the catalyst ready for use after cooling.
Reaction SMILES: [CH2:1]([NH:3][N:4]=[CH:5][C:6](=[O:8])[CH3:7])[CH3:2].[C:9]([C:13]1[CH:18]=[CH:17][C:16]([C:19](=O)[CH:20]=[O:21])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>C(O)(=O)C>[C:9]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:3]([CH2:1][CH3:2])[N:4]=[C:5]([C:6](=[O:8])[CH3:7])[C:20]=2[OH:21])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CCNN=CC(C)=O
Reactant: CC(C)(C)c1ccc(C(=O)C=O)cc1
Solvent: CC(=O)O
Product: CCn1nc(C(C)=O)c(O)c1-c1ccc(C(C)(C)C)cc1
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 15.6 %

Procedure:
2-Oxopropanal ethylhydrazone (4.736 mmol, 540.6 mg) synthesized in Reference Synthetic Example 2 and (4-tert-butylphenyl)(oxo)acetaldehyde (4.736 mmol, 901.0 mg) synthesized in Reference Synthetic Example 4 were dissolved in acetic acid (20 mL) and stirred at 100° C. for about 3.5 hours. Then, the solvent was evaporated, and the residue was dried by means of a vacuum pump and purified by silica gel thin layer chromatography (n-hexane/AcOEt=1/2, 3/1 and 4/1) to give the desired product as an orange liquid (212 mg, yield 160).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([OH:16])([C:14]#[CH:15])[C:10]([F:13])([F:12])[F:11].[C:17](N1C=CN=C1)(N1C=CN=C1)=[O:18]>C1COCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:17](=[O:18])[O:16][C:9]([C:14]#[CH:15])([C:10]([F:13])([F:11])[F:12])[C:3]=2[CH:4]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C#CC(O)(c1cc(Cl)ccc1N)C(F)(F)F
Solvent: C1CCOC1
Product: C#CC1(C(F)(F)F)OC(=O)Nc2ccc(Cl)cc21

Procedure:
A THF solution of 2-(2-amino-5-chlorophenyl)-1,1,1-trifluoro-3-butyn-2-ol (5.0 g, 20.0 mmol in 225 mL THF) was treated. with 1,1'-carbonyldiimidazole (13.0 g, 80.0 mmol) and heated in an oil bath at 60° C. for 17 h. The THF was removed in vacuo, the residue dissolved in ethyl acetate then washed with 10% citric acid, sodium bicarbonate, water and brine before drying over sodium sulfate. Following filtration and evaporation in vacuo the crude product was isolated (3.6 g) and recrystallized from ethyl acetate: hexane. The product (±) 6-chloro-4-ethynyl-4-(1,1,1-trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one was isolated as a white crystalline solid (3.22 g, 58.4% yield): mp 226°-227° C. 1H-NMR (CDCl3 +trace DMSO): δ3.16 (s, 1H), 6.98 (d, J=3.3 Hz, 1H), 7.35 (m, 1H), 7.51 (s, 1H), 10.66 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([O:11][CH3:12])[CH:5]=1.CCN(CC)CC.[Cl:21][C:22]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:23]=1[C:24](Cl)=[O:25]>ClCCl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:24](=[O:25])[C:23]2[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:22]=2[Cl:21])=[C:6]([O:11][CH3:12])[CH:5]=1
Reactant: O=C(Cl)c1cc(F)ccc1Cl
Reactant: COC(=O)c1ccc(N)c(OC)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(NC(=O)c2cc(F)ccc2Cl)c(OC)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A dry, 3-L, 3-necked, round-bottomed flask equipped with a thermometer and addition funnel was charged a solution of 33 (96 g, 0.53 mol, 1.0 equiv.) and Et3N (88 ml, 0.64 mol, 1.2 equiv.) in dichloromethane (1.2 L). The solution was cooled to 0° C. by an ice bath and 2-chloro-5-fluoro-benzoyl chloride (110 g, 0.57 mol, 1.05 equiv.) was added drop-wise over 40 min at 0° C. After the addition, the reaction mixture was stirred at 0° C. for further 1.5 h. The organic layer was washed with brine three times, dried over MgSO4, filtered, and evaporated to yield 4-(2-chloro-5-fluoro-benzoylamino)-3-methoxy-benzoic acid methyl ester 34 as a white solid. 1H NMR (400 MHz, CDCl3) δ: 8.84 (s, 1H), 8.61 (d, 1H), 7.75 (dd, 1H), 7.60 (d, 1H), 7.55 (dd, 1H), 7.45 (dd, 1H), 7.20-7.13 (m, 1H), 3.97 (s, 3H), 3.93 (s, 3H). MS (ES) m/z 338.0 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2.[C:13](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O.[Cl-].[Na+].O>[CH3:13][N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[CH2:6][C:7]1=[O:12]
Reactant: COc1ccc2c(c1)CC(=O)N2
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc2c(c1)CC(=O)N2C
Temperature: 25 °C
Reaction time: 10 h
Yield: 62.8 %

Procedure:
5-methoxy oxindole (450 mg, 2.76 mmol) and potassium carbonate (585 mg, 4.23 mmol) were combined in 45 ml of acetone under an inert atmosphere. To this white, heterogenous mixture was added 0.33 ml of methyl iodide (5.30 mmol) via syringe. The reaction mixture was stirred at room temperature for 10 hours and then at 75° C. for 3 hours. Additional potassium carbonate and methyl iodide were added (290 mg and 0.11 ml, respectively), and the reaction mixture was stirred at 75° C. for 6 more hours. The reaction mixture was then poured into 300 ml of saturated brine solution and extracted with 3×200 ml ether. The combined organic layers were dried over MgSO4, filtered, and stripped to a yellow oil. This was purified via flash chromatography (3:1 ethyl ether/hexane) to provide the title compound (307 mg, 63% yield) as white crystals: m.p. 93°-94° C. M/z calculated for C10H11NO2 : 177.0790, Found: 177.08066.
Reaction SMILES: [O-]CC.[Na+].[Br:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.[N:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N+:15]=[N-:16].O>C(O)C.C1(C)C=CC=CC=1>[N:14](/[C:17](=[CH:10]\[C:9]1[CH:12]=[CH:13][C:6]([Br:5])=[CH:7][CH:8]=1)/[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N+:15]=[N-:16]
Reactant: O=Cc1ccc(Br)cc1
Reactant: CCOC(=O)CN=[N+]=[N-]
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)/C(=C/c1ccc(Br)cc1)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 39 %

Procedure:
Into a solution of sodium ethoxide (a 20% solution in ethanol, 22.2 g) in toluene (100 ml) was added at 0° C. over a period of more than 10 minutes a solution of 4-bromobenzaldehyde (10 g) and ethyl azidoacetate (7.0 g) in toluene (50 ml). After being stirred at room temperature for 2 hours, the reaction mixture was mixed with water and was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the residue was subjected to separation and purification using column chromatography (ethyl acetate/hexane 1:19) to obtain ethyl (Z)-2-azido-3-(4-bromophenyl)acrylate (6.24 g) as a yellow oily substance.
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:17](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+].O1[CH2:41][CH2:40][CH2:39]C1>>[CH2:17]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:2][CH2:3]1)[CH:40]([CH3:39])[CH3:41]
Reactant: CC(=O)O
Reactant: C1CCOC1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Product: CC(C)CN1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Benzyl 1-piperazinecarboxylate (1.1 g, 5.00 mmol) and isobutylaldehyde (0.91 mL, 10.0 mmol) were dissolved in 30 mL of tetrahydrofuran, and acetic acid (0.57 mL, 10.0 mmol) and sodium triacetoxyborohydride (2.11 g, 10.0 mmol) were added thereto, and the reaction mixture was stirred at room temperature for two hours. The reaction mixture was mixed with a 1N aqueous solution of sodium hydroxide, extracted with ethyl acetate twice, and the combined organic layers were washed with brine once. The mixture was dried over anhydrous sodium sulfate and evaporated. The resulting residue was purified by silica gel column chromatography (Fuji Silysia, NH Silica gel; ethyl acetate:hexane=50:50) to give benzyl 4-isobutylpiperazin-1-carboxylate (1.05 g) as a colorless oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=O)=[CH:2]1.[CH3:12][NH2:13].[BH4-].[Na+]>CO>[CH3:12][NH:13][CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of indole-3-carboxaldehyde (5.4 g, 34.1 mmole) in MeOH (30 mL) was added a solution of 2.0 M CH3NH2 in MeOH (51.3 mL, 102.6 mmole). The reaction was stirred at RT overnight, then was concentrated to a light yellow oil. This oil was dissolved in EtOH (40 mL), and NaBH4 (1.3 g, 34.1 mmole) was added. After 16 hrs the reaction was concentrated to a slurry and dissolved in 10% Na2CO3 (100 mL). The aqueous solution was extracted with EtOAc (2×200 mL) and the combined organic fractions were dried over Na2SO4 and concentrated. Drying in high vacuum left the title compound (5.2 g, 94%) as a faintly yellow oil: MS (ES) m/e 161 (M+H)+.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Br)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2].CC1(C)C(C)(C)OB([C:46]2[CH:52]=[CH:51][C:49]([NH2:50])=[CH:48][CH:47]=2)O1>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:46]3[CH:52]=[CH:51][C:49]([NH2:50])=[CH:48][CH:47]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(Br)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(-c4ccc(N)cc4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene obtained in Example 128-(4) and 4-(4,4,5,5-tetramethyl-1,3-dioxaborolan-2-yl)aniline were treated in a manner similar to Example 168-(1) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(4-aminophenyl)-2-thienylmethyl)-4-chlorobenzene as pale yellow powder. APCI-Mass m/Z 630/632 (M+H).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][C:8]2([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12](=[O:19])[O:11]2)[CH2:7][CH2:6]1)=[O:4].[C:20]1([CH:26]([NH2:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.O>CN(C=O)C>[C:27]1([CH:26]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:33][CH2:2][C:3]([N:5]2[CH2:10][CH2:9][C:8]3([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[C:12](=[O:19])[O:11]3)[CH2:7][CH2:6]2)=[O:4])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C1OC2(CCN(C(=O)CCl)CC2)c2ccccc21
Reactant: NC(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1OC2(CCN(C(=O)CNC(c3ccccc3)c3ccccc3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 60 h

Procedure:
1′-(Chloroacetyl)-3H-spiro[2-benzofuran-1,4′-piperidine]-3-one (50 mg, 0.179 mmol)) and diphenylmethylamine (33 mg, 0.179 mmol) were dissolved in dry DMF (0.8 mL). Then triethylamine (0.074 mL, 0.536 mmol) was added and the reaction mixture was shaken at 25° C. for 2.5 days. Water (0.1 mL) was added and the whole mixture was directly purified by preparative HPLC on YMC-AQ column with a gradient of MeCN in water from 0-90% in 15 min. MS: m/z=427 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1.[CH3:17][N:18]1CCCC1=O.Cl>O>[O:16]=[C:13]1[C:14]2[CH:15]=[C:2]([C:17]#[N:18])[CH:3]=[CH:4][C:5]=2[O:6][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1=2
Reactant: CN1CCCC1=O
Reactant: O=c1c2c(oc3ccc(Br)cc13)CCCC2
Agent: Cl
Solvent: O
Product: N#Cc1ccc2oc3c(c(=O)c2c1)CCCC3
Temperature: 190 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
A mixture of 252.6 g of 7-bromo-1,2,3,4-tetrahydro-9-xanthone obtained in Example 1, 89.1 g of cuprous cyanide and 900 ml of N-methyl-2-pyrrolidone was heated with stirring for 2 hours at 190° C. and then allowed to cool to 80° C. To the reaction mixture was added a mixture of 300 g of ferric chloride, 450 ml of water and 80 ml of concentrated hydrochloric acid, and the resulting solution was agitated for 30 minutes. After allowing the reaction mixture to stand overnight, the deposited crystals were collected by filtration and washed thoroughly with water. Subsequently, the crystals were dried and recrystallized from acetonitrile to obtain 169.6 g (yield: 83.6%) of 5,6,7,8-tetrahydro-9-oxo-xanthene-2-carbonitrile as brownish prism-like crystals having a melting point of 198° to 200° C.