Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11]O)[CH:2]=1.S(Cl)([Cl:15])=O>C1(C)C=CC=CC=1>[ClH:15].[Cl:15][CH2:11][C:3]1[CH:2]=[N:1][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: OCc1cnc2ccccc2c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cl
Product: ClCc1cnc2ccccc2c1
Reaction time: 4 h
Yield: 60 %

Procedure:
To a solution of 2.53 g (15.9 mmol) of 3-quinolinemethanol in 25 mL of toluene was added dropwise at room temperature 5 mL of thionyl chloride. The reaction mixture was stirred at that temperature for 4 hours, then dried in vacuo to give a solid which was suspended in 20 mL of toluene and treated with 4 mL of thionyl chloride at room temperature overnight. The reaction mixture was concentrated under reduced pressure to give 2.05 g (60%) of a solid. The product, having the structural formula ##STR86## was not further purified. NMR (DMSO-d6) δ 9.36 (1H, d), 9.1 (1H, bs), 8.6-7.8 (4H, m), 5.2 (2H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4](O)=[O:5].C(N(CC)CC)C.C(Cl)(=O)OC(C)(C)C(Cl)(Cl)Cl.[BH4-].[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: Cc1cc(Cl)c(C(=O)O)cc1[N+](=O)[O-]
Agent: CC(C)(OC(=O)Cl)C(Cl)(Cl)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Cl)c(CO)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-chloro-4-methyl-5-nitrobenzoic acid (CAS; 101580-96-5, 15 g, 69.6 mmol) and triethylamine (11.1 mL, 80 mmol) in THF (200 mL) was added 1,1,1-trichloro-2-methylpropan-2-yl carbonochloridate (19.2 g, 80 mmol) at 0° C., and then the mixture was stirred at 0° C. for 1 hr. The resulting white solid was filtered off through Celite®. The solid was washed by THF (20 mL). To the filtrate was added NaBH4 (3.2 g, 83 mmol) at 0° C., followed by H2O (50 mL). The mixture was stirred at 0° C. for 0.5 h, and then stirred at room temperature for 1.25 h. The reaction was quenched by half satd. KHSO4. The layers were separated and the aqueous layer was extracted with CH2Cl2. The organic layers were combined, washed with H2O and brine, dried over Na2SO4, and then filtered through a silica pad. The SiO2 cake was washed with EtOAc. The residue was concentrated and then triturated with heptane. The resulting solid was collected by filtration to give the title compound. 1H NMR (400 MHz, ACETONITRILE-d3) δ 8.11 (s, 1H), 7.47 (s, 1H), 4.68 (s, 2H), 2.53 (s, 3H).
Reaction SMILES: [CH2:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[N+:13]([CH2:16][CH3:17])([O-:15])=[O:14].C(N)CCC>C(O)C>[CH2:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[C:16]([N+:13]([O-:15])=[O:14])[CH3:17])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C=O)cc1
Reactant: CC[N+](=O)[O-]
Solvent: CCCCN
Solvent: CCO
Product: CCCCc1ccc(C=C(C)[N+](=O)[O-])cc1

Procedure:
A stirred solution of 4-butylbenzaldehyde (13.5 g), nitroethane (9.0 ml) and butylamine (1.6 ml) in ethanol (20 ml) was heated under reflux for 6 hours and evaporated. The residue was distilled under vacuum to give 1-(4-butylphenyl)-2-nitropropene (bp 124°-125° C./0.15 mm).
Reaction SMILES: [CH2:1]1[NH:3][CH2:2]1.[CH2:4]1[O:12][CH:5]1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[K+]>O>[C:6]1([CH:5]([OH:12])[CH2:4][N:3]2[CH2:2][CH2:1]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C1CN1
Reactant: c1ccc(C2CO2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: OC(CN1CC1)c1ccccc1

Procedure:
To a solution of 43.0 g. (1.0 mole) of ethyleneimine and 60.0 g. (0.5 mole) of styrene oxide is added 3 drops of water and 0.2 g. of potassium hydroxide. The mixture is heated at reflux for 11/2 hours. Distillation of the excess ethyleneimine from the crude product gives 55.6 g. (68%) of the crystalline product. Recrystallization gives pure dl-α-phenyl-1-aziridineethanol with melting point 74°-76° C.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1)=[O:2].S(Cl)([Cl:14])=O>C1C=CC=CC=1.CN(C)C=O>[CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:14])=[O:8])=[CH:5][CH:4]=1)=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=Cc1ccc(C(=O)O)cc1
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: O=Cc1ccc(C(=O)Cl)cc1
Temperature: 25 °C
Yield: 101.5 %

Procedure:
In a suspension of 1.00 g of 4-formyl benzoic acid in 15 ml of benzene, 0.87 g of thionyl chloride and 2 drops of N,N-dimethylformamide were added, and stirred under reflux with heat for 2 hours. After the completion of the reaction, the reaction mixture was left and cooled to room temperature, and the solvent was distilled off under reduced pressure to obtain 1.14 g of crude 4-formyl benzoic acid chloride as white crystal. In a solution of 0.66 g of 2,2,2-trifluoroethylamine and 0.81 g of triethylamine in 6 ml of chlororform, the solution of 1.14 g of the crude 4-formyl benzoic acid chloride in 6 ml of chloroform was added dropwise under cooling with ice and with stirring, after the completion of the addition dropwise, continued to stir at room temperature for further 18 hours. After the completion of the reaction, the reaction mixture was added in 30 ml of water, extracted with chloroform (20 ml×3). The organic phase was washed with water, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, the residual solid was washed with hexane to obtain 1.32 g of the aimed product as white crystal. Melting point 83.0 to 84.0° C.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([C:16]2[S:20][C:19](=[S:21])[NH:18][N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[H-].[Na+].IC.[CH3:26]COCC>O1CCCC1>[CH3:15][C:12]([C:9]1[CH:8]=[C:7]([C:16]2[S:20][C:19]([S:21][CH3:26])=[N:18][N:17]=2)[CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:13])[CH3:14]
Reactant: CCOCC
Reactant: CC(C)(C)c1cc(-c2n[nH]c(=S)s2)cc(C(C)(C)C)c1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CSc1nnc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
5-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2(3H)-thione (3.0 g, 0.0093 mole) in tetrahydrofuran (15 ml) is added dropwise to a stirred 0° C. suspension of sodium hydride (0.37 g of a 60% dispersion in mineral oil, 0.0093 mole) in tetrahydrofuran (15 ml) under nitrogen. After 30 minutes, a solution of iodomethane (1.5 g, 0.0102 mole) in tetrahydrofuran (5 ml) is added dropwise. After stirring one hour at 0° C., ether (20 ml) is added and the resulting mixture is washed with aqueous 2M HCl (10 ml), saturated aqueous NaCl, and dried over MgSO4. Filtration and concentration in vacuo, followed by recrystallization from ether/hexane gives 2.6 g of 2,6-bis(1,1-dimethylethyl)-4-[5-(methylthio)-1,3,4-thiadiazol-2-yl]phenol (3.1 g, theor., 83%), mp 122°-122.5° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:10][N:9]=[C:8]([C:11]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]3[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=3)=[CH:27][C:12]=2[O:13][C@@H:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH:7]=1)=[O:5])C.[OH-].[K+]>CO>[OH2:3].[C:4]([C:6]1[NH:10][N:9]=[C:8]([C:11]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]3[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=3)=[CH:27][C:12]=2[O:13][C@@H:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH:7]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1cc(-c2ccc(OCc3cccnc3)cc2O[C@H](CCC(=O)O)c2ccccc2C)n[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccccc1[C@@H](CCC(=O)O)Oc1cc(OCc2cccnc2)ccc1-c1cc(C(=O)O)[nH]n1
Product: O
Yield: 54.4 %

Procedure:
A solution of (R)-4-[2-(5-ethoxycarbonylpyrazol-3-yl)-5-(3-pyridylmethoxy)phenoxy]-4-(2-methylphenyl)butanoic acid (150 mg) in methanol (50 mL) containing 10% w/v potassium hydroxide (5 mL) is stirred at reflux for 1 hour. The reaction mixture is partitioned between 1 N acetic acid (50 mL) and ethyl acetate (50 mL). Some precipitation occurred in the organic phase which is washed with water (50 mL) and concentrated under reduced pressure. Trituration with hot ethyl acetate followed by cooling affords a solid which is filtered then washed with ethyl acetate to give (R)-4-[2-(5-carboxypyrazol-3yl)-5-(3-pyridylmethoxy)phenoxy]-4-(2-methylphenyl) butanoic acid hydrate (40 mg) as a white solid, m.p. 144-146° C. [Elemental analysis:- C,64.1, H, 5.02, N, 8.27%. Calculated for C27H25N3O6.H2O:- C,64.2, H, 5.35, N, 8.32%].
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[OH-:10].[Na+].Cl>C1COCC1>[Br:1][C:2]1[C:3](=[O:10])[NH:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1[nH]c(Cl)ncc1Br
Yield: 64 %

Procedure:
5-Bromo-2,4-dichloro-pyrimidine (5.0 g, 22 mmol) was stirred in THF (10 mL) with 1N NaOH (30 mL) at r.t. for 3 h. The solution was made slightly acidic with 1N HCl and was extracted with CHCl3. Organics were dried (MgSO4) and concentrated in vacuo. Precipitation from 20% CHCl3/hexanes and collection by filtration gave 2.92 g (64%) of 5-bromo-2-chloro-3H-pyrimidin-4-one as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 13.33 (br s, 1H), 8.35 (s, 1H). MS (ES) [m+H] calc'd for C4H2N2OBrCl, 209, 211, 213; found 209, 211, 213.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:14])[CH3:13])=[N:8][C:7]=1[CH3:15])(=[O:5])[CH3:4]>O1CCOCC1>[BrH:1].[Br:1][CH2:4][C:3]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:14])[CH3:13])=[N:8][C:7]=1[CH3:15])=[O:5]
Reactant: BrBr
Reactant: CC(=O)Nc1nc(C)c(C(C)=O)s1
Solvent: C1COCCO1
Product: Br
Product: CC(=O)Nc1nc(C)c(C(=O)CBr)s1
Temperature: 50 °C
Yield: 60 %

Procedure:
A solution of Br2 (3.35 ml, 65.6 mmol) in 75 ml dioxane is added dropwise to a solution of N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)acetamide (P6), obtained in Step I as described above, (10.40 g, 52.5 mmol) in 200 ml dioxane. The resulting mixture is heated at 50° C. for 19 hours. The solution turns from dark red to beige and remains a heterogeneous mixture. By analytical HPLC, only 2.8% of starting material is detected. The suspension is filtered, washed with a 1:2 EtOAc/hexanes mixture (50 ml) and air dried for 15 min, to give Intermediate 1 as a beige solid (11.2 g, 60%). It is used in bis-thiazol synthesis as HBr salt or as parent, after 5 min treatment with Amberlyst A21 in DCM/MeOH mixture.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[C:3]1=[O:18].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](O)=[O:28])=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:1][N:2]2[N:11]=[C:10]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:9]3[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=3[C:3]2=[O:18])=[O:28])=[CH:22][CH:21]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: Nn1nc(-c2ccccc2)c2c(c1=O)CCCC2
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(-c2ccccc2)c2c(c1=O)CCCC2

Procedure:
The product from Example 185A and 2-(4-chlorophenyl)acetic acid were treated using a method similar to that described in Example 17C to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.64 (s, 1H), 7.29-7.51 (m, 9H), 3.65 (s, 2H), 2.50-2.55 (m, 2H), 2.36-2.40 (m, 2H), 1.68-1.76 (m, 2H), 1.57-1.65 (m, 2H); MS (APCI+) M/Z 394 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][C:14]([CH3:17])=[N:15][N:16]=1)[C:8]([C@@H:18]([N:20]1C(=O)C3C(=CC=CC=3)C1=O)[CH3:19])=[CH:7]2.O.NN>C1COCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][C:14]([CH3:17])=[N:15][N:16]=1)[C:8]([C@@H:18]([NH2:20])[CH3:19])=[CH:7]2
Reactant: Cc1nnc(-c2nc3c(Cl)cccc3cc2[C@H](C)N2C(=O)c3ccccc3C2=O)s1
Agent: NN
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Cc1nnc(-c2nc3c(Cl)cccc3cc2[C@H](C)N)s1
Temperature: 90 °C

Procedure:
To a stirred solution of 2-((S)-1-(8-chloro-2-(5-methyl-1,3,4-thiadiazol-2-yl)-quinolin-3-yl)ethyl)isoindoline-1,3-dione (30 mg, 69 μmol) in THF (1.0 mL) and ethanol (3.0 mL) was added hydrazine monohydrate (69 μl, 1380 μmol). The reaction was heated to 90° C. for 40 minutes and then cooled to room temperature evaporated in vacuo. The resulting residue was diluted with ethyl acetate (60 mL) and water (40 mL) and the aqueous layer was extracted with ethyl acetate (30 mL). The combined organic layers were washed with brine and then dried (MgSO4), filtered and evaporated in vacuo to give (1S)-1-(8-chloro-2-(5-methyl-1,3,4-thiadiazol-2-yl)quinolin-3-yl)ethanamine. 1H NMR (500 MHz, choroform-d) δ ppm 8.62 (1H, s), 7.79-7.84 (2H, m), 7.49-7.52 (1H, m), 5.61 (1H, d, J=6.4 Hz), 2.86 (3H, s), 1.57 (3H, d, J=6.6 Hz). Mass Spectrum (ESI) m/e=305.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[C:12]([CH:14]=[CH:15][NH:16][C:17]([O:19][CH3:20])=[O:18])[CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]1[O:9][CH2:8]1.C([NH2:24])(C)C.[CH:25](O)([CH3:27])[CH3:26]>>[CH3:1][O:2][C:3]1[CH:13]=[C:12]([CH:14]=[CH:15][NH:16][C:17]([O:19][CH3:20])=[O:18])[CH:11]=[CH:10][C:4]=1[O:5][CH:6]([NH2:24])[CH:7]([OH:9])[CH2:8][CH:25]([CH3:27])[CH3:26]
Reactant: COC(=O)NC=Cc1ccc(OCC2CO2)c(OC)c1
Reactant: CC(C)N
Reactant: CC(C)O
Product: COC(=O)NC=Cc1ccc(OC(N)C(O)CC(C)C)c(OC)c1

Procedure:
4.2 g (0.015 mol) of 1-[2-methoxy-4-(2-methoxycarbonylaminovinyl)-phenoxy]-2,3-epoxy-propane are heated with a solution of 1.3 ml (0.016 mol) of isopropylamine in 100 ml of isopropanol to 80° C. under reflux for 3 hours. The mixture is then evaporated in vacuo and the resulting crude base is crystallised from acetone-ether. 1-[2-Methoxy-4-(2-methoxycarbonylaminovinyl)-phenoxy]-2-hydroxy-3-isopropyl-aminopropane, of melting point 109°-111° C. is obtained.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.I[CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1>O1CCCC1.CCOCC>[F:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:12][CH2:13][CH:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:18][CH2:19]2)=[CH:6][CH:5]=1
Reactant: Fc1ccc(S)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CCI)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(CCSc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 95.2 %

Procedure:
To a slurry of sodium hydride (47 mg, 60% in mineral oil, 1.2 mmol) in tetrahydrofuran at 0° C. was added 4-fluorothiophenol (0.1 mL, 0.94 mmol). The reaction mixture was warmed to rt. for 20 min, followed by addition of 4-(2-iodoeth-1-yl)-1-tert-butoxycarbonylpiperidine (265 mg, 0.78 mmol, from Step C). The reaction was then heated to reflux for 10 min, cooled and diluted with ether. The organic layer was washed with 1 N NaOH, dried over magnesium sulfate and concentrated to provide 252 mg (95%) of the title compound. ESI-MS: 340.0 (M+H); HPLC A: 4.07 min.
Reaction SMILES: C1(C)C=CC=CC=1.[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([NH:16][S:17]([C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:19])=[O:18])[CH2:12][CH2:11]1)#[N:9].[C:24]1([C:30]2[CH:35]=[CH:34][C:33](N)=[C:32]([NH2:37])[CH:31]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>C(OCC)(=O)C>[C:20]([S:17]([NH:16][CH:13]1[CH2:12][CH2:11][N:10]([C:8]2[NH:37][C:32]3[CH:31]=[C:30]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:35]=[CH:34][C:33]=3[N:9]=2)[CH2:15][CH2:14]1)(=[O:19])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: Nc1ccc(-c2ccccc2)cc1N
Reactant: CC(C)(C)S(=O)(=O)NC1CCN(C#N)CC1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)S(=O)(=O)NC1CCN(c2nc3ccc(-c4ccccc4)cc3[nH]2)CC1
Temperature: 130 °C
Reaction time: 16 h
Yield: 32.4 %

Procedure:
To the toluene solution (1 mL) containing 1-cyano-4-(tert-butylsulfonylamino)piperidine (22 mg) were added 4-phenyl-1,2-phenylenediamine (20 mg) and ytterbium triflate (20 mg), and the mixture was stirred in a sealed tube at 130° C. for 16 hrs. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The organic layer was washed with aqueous saturated sodium hydrogencarbonate solution and aqueous saturated sodium chloride solutions successively, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated and purified on a collective thin-layer chromatograph (chloroform:methanol=15:1) to give the title compound (12 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]([CH2:20][C:21](O)=[O:22])[S:10]([C:13]2[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1.[CH2:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=1)[CH3:25]>>[CH2:24]([N:26]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=1)[C:21](=[O:22])[CH2:20][N:9]([C:6]1[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[S:10]([C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11])[CH3:25]
Reactant: CCNCc1cccc(C)n1
Reactant: COc1ccc(N(CC(=O)O)S(=O)(=O)c2ccccc2C)cn1
Product: CCN(Cc1cccc(C)n1)C(=O)CN(c1ccc(OC)nc1)S(=O)(=O)c1ccccc1C

Procedure:
prepared by reaction of [(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-acetic acid with ethyl-(6-methyl-pyridin-2-ylmethyl)-amine
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[C:5](=[O:19])[NH:6][C:7](=[O:18])[N:8]([CH:17]=1)[C@@H:9]1[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([OH:12])[CH2:10]1.[C:20]1([CH2:30]Br)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>>[F:3][C:4]1[C:5](=[O:19])[NH:6][C:7](=[O:18])[N:8]([CH:17]=1)[C@@H:9]1[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([O:12][CH2:30][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)[CH2:10]1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1F
Reactant: BrCc1cccc2ccccc12
Agent: [K+]
Agent: [OH-]
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](OCc3cccc4ccccc34)[C@@H](CO)O2)cc1F
Yield: 17.8 %

Procedure:
The general procedures of Examples 4 and 5 were followed using 1.3 g of potassium hydroxide, 1.00 g of 2'-deoxy-5-fluorouridine and 2.7 g of 1-naphthylmethyl bromide, thereby producing 0.28 g of the title compound in a yield of 18%.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@:12]2([CH3:20])[OH:13])=[C:4]([O:21][CH3:22])[N:3]=1.C1C(=O)N([Br:30])C(=O)C1>CO>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([Br:30])[N:8]2[C@H:11]2[C@:12]([CH3:20])([OH:13])[C@H:14]([OH:15])[C@@H:16]([CH2:18][OH:19])[O:17]2)=[C:4]([O:21][CH3:22])[N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1nc(N)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@]1(C)O
Solvent: CO
Product: COc1nc(N)nc2c1nc(Br)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@@]1(C)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.7 %

Procedure:
2-Amino-6-methoxy-9-(2-C-methyl-β-D-ribofuranosyl)purine (1.5 g, 4.82 mmol) was suspended in MeOH (50 mL) and 1 mol eq. of NBS (1.03 g, 4.82 mmol) was added. The mixture was stirred at room temperature for 4 h. After that time, solution was concentrated and the resulting solid was purified by silica gel chromatography using 1-4% (gradient) of MeOH in chloroform to yield 1.65 g (88% yield) of the desired product.
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[C:10]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]3[C:35]([CH3:37])([CH3:36])[CH2:34][C:33]4[C:28](=[C:29]([C:39](O)=[O:40])[CH:30]=[C:31]([Cl:38])[CH:32]=4)[NH:27]3)[CH:21]=2)=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11].C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[C:10]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]3[C:35]([CH3:37])([CH3:36])[CH2:34][C:33]4[C:28](=[C:29]([C:39]([NH:9][S:6]([CH:3]5[CH2:5][CH2:4]5)(=[O:8])=[O:7])=[O:40])[CH:30]=[C:31]([Cl:38])[CH:32]=4)[NH:27]3)[CH:21]=2)=[CH:16][CH:15]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: NS(=O)(=O)C1CC1
Reactant: CC(C)(C)c1ccc(-c2cccc(C3Nc4c(cc(Cl)cc4C(=O)O)CC3(C)C)c2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(-c2cccc(C3Nc4c(cc(Cl)cc4C(=O)NS(=O)(=O)C4CC4)CC3(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.6 %

Procedure:
To a suspension of 60% sodium hydride (128 mg, 3.2 mmol) in N,N-dimethylformamide (1.5 mL) was added cyclopropanesulfonamide (400 mg, 3.3 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 2-(4′-tert-butyl-biphenyl-3-yl)-6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (150 mg, 0.33 mmol)) and 1,1′-carbonyldiimidazole (136 mg, 0.84 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of cyclopropanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid [2-(4′-tert-butyl-biphenyl-3-yl)-6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carbonyl]-amide (72 mg, 40%) as a white solid: LC/MS m/e calcd for C31H35ClN2O3S (M+H)+: 552.11, observed: 551.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[CH:2]=1.[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[C:24]1[N:25]=[C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[S:27][CH:28]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[C:24]1[N:25]=[C:26]([N:29]2[CH2:30][CH2:31][N:32]([C:8]([NH:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[O:15])[CH2:33][CH2:34]2)[S:27][CH:28]=1
Reactant: O=C(Nc1cccnc1)OCC(Cl)(Cl)Cl
Reactant: Clc1ccc(-c2csc(N3CCNCC3)n2)c(Cl)c1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(Nc1cccnc1)N1CCN(c2nc(-c3ccc(Cl)cc3Cl)cs2)CC1
Temperature: 70 °C
Reaction time: 72 h
Yield: 45.6 %

Procedure:
A mixture of 2,2,2-trichloroethyl pyridin-3-ylcarbamate (189 mg, 0.700 mmol), 1-[4-(2,4-dichlorophenyl)-1,3-thiazol-2-yl]piperazine (200 mg, 0.636 mmol) and diisopropylethylamine (0.222 ml, 1.27 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 3 days. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate), and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 126 mg (45.5%) of the desired product as a solid.
Reaction SMILES: [C:1]1([CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:3]=1[OH:4])[OH:2].[H-].[Na+].B(OCC)(OCC)OCC.B([O-])([O-])O[CH2:24][CH:25]=[CH2:26]>CN(C)C=O>[CH2:26]([O:2][C:1]1[CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:3]=1[OH:4])[CH:25]=[CH2:24]
Reactant: C=CCOB([O-])[O-]
Reactant: Oc1cccc(O)c1O
Agent: CCOB(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1cccc(O)c1O
Reaction time: 3 h

Procedure:
A mixture of 3.8 g of pyrogallol, 76 ml of anhydrous dimethylformamide and 2.72 g of sodium hydride in suspension at 53% in oil was stirred for 3 hours under an inert gas atmosphere and then 5.27 ml of triethyl borate were added, followed by stirring for 30 minutes. Then, 2.6 ml of allyl borate in solution in 26 ml of dimethylformamide were added over 45 minutes and the mixture was stirred for 16 hours and poured into water-ice-N hydroohloric acid mixture. Extraction took place with ethyl acetate and the crude product was chromatographed on silica, eluting with a cyclohexane-ethyl acetate mixture (7-3) to obtain 3.8 g of the expected product in the form of white crystals (Yield: 76.3%).