Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:27])([O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[N:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][NH2:26])=[CH:21][CH:20]=3)=[N:15]2)=[CH:10][CH:9]=1)[C:3]([F:6])([F:5])[F:4].[N:28]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][C:32]=1[CH3:39])=[C:29]=[S:30]>O1CCCC1>[CH3:38][O:37][C:34]1[CH:35]=[CH:36][C:31]([NH:28][C:29]([NH:26][CH2:25][C:22]2[CH:23]=[CH:24][C:19]([C:16]3[N:17]=[CH:18][N:14]([C:11]4[CH:12]=[CH:13][C:8]([O:7][C:2]([F:1])([F:27])[C:3]([F:6])([F:5])[F:4])=[CH:9][CH:10]=4)[N:15]=3)=[CH:20][CH:21]=2)=[S:30])=[C:32]([CH3:39])[CH:33]=1
Reactant: COc1ccc(N=C=S)c(C)c1
Reactant: NCc1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1
Solvent: C1CCOC1
Product: COc1ccc(NC(=S)NCc2ccc(-c3ncn(-c4ccc(OC(F)(F)C(F)(F)F)cc4)n3)cc2)c(C)c1
Temperature: 50 °C
Reaction time: 24 h
Yield: 44.4 %

Procedure:
To a solution of (4-(1-(4-(perfluoroethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)methanamine (0.075 mg, 0.20 mmol) in dry tetrahydrofuran (1 mL) was added 1-isothiocyanato-4-methoxy-2-methylbenzene (0.052 mg, 0.29 mmol) and the resulting mixture was stirred at 50° C. for 24 hours. The mixture was concentrated under reduced pressure to give a brown residue, which was purified by flash column chromatography eluting with mixtures of hexanes and ethyl acetate to afford the title compound as a white solid (0.050 g, 46%).
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[CH2:6][C:7]([OH:9])=O.[CH2:10]([C@@H:17]1[NH:22][CH2:21][CH2:20][N:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]3[CH2:35][CH2:34][CH2:33]3)[CH:24]=2)[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([C@H:17]1[CH2:18][N:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]3[CH2:35][CH2:34][CH2:33]3)[CH:24]=2)[CH2:20][CH2:21][N:22]1[C:7](=[O:9])[CH2:6][C:5]1[N:4]=[N:3][NH:2][N:1]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)Cc1nn[nH]n1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Product: COc1ccc(N2CCN(C(=O)Cc3nn[nH]n3)[C@@H](Cc3ccccc3)C2)cc1OC1CCC1

Procedure:
Prepared by the method outlined for Example 189 using (2H-tetrazol-5-yl)-acetic acid and 3(S)-benzyl-1-(3-cyclobutoxy-4-methoxy-phenyl)-piperazine (Example 7, Compound 95) as starting materials. Product as an oil (30 mg, 68%). LC/MS (Method B) 2.57 min, [M+1]+ 463. Potency class A.
Reaction SMILES: C([Li])CCC.O1CCCC1.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CN(C)[C:28](=[O:39])[C:29]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:30]=1[O:37][CH3:38]>Cl>[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:28]([C:29]2[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:30]=2[O:37][CH3:38])=[O:39])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Brc1ccc(OCc2ccccc2)cc1
Reactant: COc1ccc(OC)c(C(=O)N(C)C)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(OC)c(C(=O)c2ccc(OCc3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Butyllithium (2.0M in hexanes, 6.6 ml, 13.2 mmol) was added dropwise under nitrogen, at -78° C. to a stirred tetrahydrofuran (20 ml) solution of 4-benzyloxy-bromobenzene (3.15 g, 11.97 mmol) to give a yellow coloured suspension, which was stirred for 10 minutes. A tetrahydrofuran (10 ml) solution of N,N-dimethyl 2,5-dimethoxybenzamide (2.09 g, 9.99 mmol) was then added slowly, and the resulting mixture warmed to room temperature over 20 h. The mixture was diluted with 50 ml of 1M hydrochloric acid and the product extracted into dichloromethane (4×50 ml). The combined extracts were washed with brine, dried over sodium sulfate and evaporated to a yellow coloured solid. This crude product was purified by column chromatography on silica gel 60, using 4:1 petrol/ethyl acetate as the eluent. This gave the product as a colourless solid, which was recrystallised from hot ethanol (25 ml) to give the product as colourless platelets which were vacuum dried.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:24][C:25]4[CH:26]=[C:27]([NH2:31])[CH:28]=[CH:29][CH:30]=4)[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:32]([N:39]=[C:40]=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl.CCOC(C)=O>[CH2:32]([NH:39][C:40]([NH:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([CH2:24][CH:19]2[CH2:20][CH2:21][CH2:22][CH:23]=[C:18]2[C:9]2[O:10][C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)[CH:26]=1)=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C=NCc1ccccc1
Reactant: Nc1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(NCc1ccccc1)Nc1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
To a solution of (±)-3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}phenylamine (110 mg, 0.27 mmol) in methylene chloride (3 ml) was added benzylisocyanate (0.17 ml, 1.36 mmol) at 5° C., and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with EtOAc, washed with 1N hydrochloric acid, water, saturated sodium hydrogencarbonate solution, water and brine, dried over magnesium sulfate, and evaporated in vacuo. The resulting solid was collected and washed with EtOAc-hexane to give (±)-1-benzyl-3-{3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}phenyl}urea (100.7 mg, 69%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.C(O)C.[C:27]1([C:33]([N:35]=[C:36]=[S:37])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[C:33]([NH:35][C:36]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:17][C:18]=1[F:23])=[S:37])(=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (76 mg, yield 80%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([F:21])[CH:10]=2)[CH3:8])[N:6]=1.[C:22]1([N:28]=[C:29]=[S:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC(C)=O.C(=O)([O-])O.[Na+]>[C:22]1([NH:28][C:29]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH:7]([C:9]3[CH:14]=[CH:13][C:12]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)=[C:11]([F:21])[CH:10]=3)[CH3:8])[N:6]=2)=[S:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: S=C=Nc1ccccc1
Reactant: CC(c1ccc(-c2ccccc2)c(F)c1)c1csc(N)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(c1ccc(-c2ccccc2)c(F)c1)c1csc(NC(=S)Nc2ccccc2)n1
Yield: 15.8 %

Procedure:
To 2-amino-4-(1-(2-fluoro-4-biphenylyl)ethyl) thiazole (0.50 g, 1.68 mmol) in acetone (10 ml) were added phenylisothiocyanate (0.25 g, 1.85 mmol) in acetone (5 ml) and sodium hydrogen carbonate (0.30 g). After the mixture was refluxed for 10 h, phenyisothiocyanate (0.50 g, 3.70 mmol) was added to the mixture, and then the mixture was refluxed for 2 h. The mixture was evaporated under reduced pressure to a residue, which was chromatographed and recrystallized to afford N-phenyl-N'-(4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazol-2-yl)thiourea (0.115 g, 16% yield) as crystalline material: mp 176.5°-177.0° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:11]=[C:10]([NH2:12])[N:9]=[C:8]2[NH:13][N:14]=[CH:15][C:7]=12.[CH2:16]([N:23]=[C:24]=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C=O)C.CN(C1C=CN=CC=1)C>[NH2:12][C:10]1[N:9]=[C:8]2[N:13]([C:24]([NH:23][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:25])[N:14]=[CH:15][C:7]2=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[N:11]=1
Reactant: Nc1nc(-c2ccco2)c2cn[nH]c2n1
Reactant: O=C=NCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(-c2ccco2)c2cnn(C(=O)NCc3ccccc3)c2n1
Yield: 23.9 %

Procedure:
A solution of 4-(2-furyl)-1H-pyrazolo[3,4-d]pyrimidine-6-amine (210 mg, 1 mmol) in DMF (2 mL) was treated with benzyl isocyanate (123 μL, 1 mmol) and a catalytic amount of DMAP, stirred at room temperature for 1 h, poured into water, extracted with EtOAc, dried (MgSO4), concentrated in vacuo and purified by preparative HPLC (MeOH/H2O gradient) to give the title compound (80 mg, 24%) as a pale yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:8].[N:15]([O-])=[O:16].[Na+]>C(O)(=O)C.O>[OH:16][N:15]=[C:9]([C:7](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: O=N[O-]
Reactant: CCOC(=O)CC(=O)c1ccccn1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(=NO)C(=O)c1ccccn1
Reaction time: 2 h
Yield: 61.5 %

Procedure:
To a stirred solution of ethyl picolinoylacetate (0.500 g, 2.6 mmol) in acetic acid (0.5 mL) was added a solution of sodium nitrite (0.238 g, 3.4 mmol) in water (0.5 mL), dropwise. The resulting solution was stirred at room temperature for 2 hours after which water (0.5 mL) was added and the reaction was stirred for a further 2 hours. The mixture was extracted with Et2O and the combined organic phase was washed with water, saturated sodium bicarbonate solution and brine, dried over MgSO4 and the solvent removed in vacuo to afford ethyl 2-(hydroxyimino)-3-oxo-3-(pyridin-2-yl)propanoate (0.353 g, 1.6 mmol, 61%) as a white solid. 1H NMR (DMSO) δ 1.17 (3H, t), 4.22 (2H, q), 7.74 (1H, m), 8.04-8.11 (2H, m), 8.74 (1H, m), 12.87 (1H, s). LCMS (2) Rt: 1.09 min; m/z (ES+) 223.
Reaction SMILES: [CH2:1]1[CH:6]([C:7]([OH:9])=[O:8])[CH2:5][CH2:4][CH:3]([OH:10])[CH2:2]1.[H-].[Na+].[Br:13][C:14]1[CH:15]=[CH:16][C:17](F)=[N:18][CH:19]=1>CC(N(C)C)=O>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([O:10][C@@H:3]2[CH2:4][CH2:5][C@H:6]([C:7]([OH:9])=[O:8])[CH2:1][CH2:2]2)=[N:18][CH:19]=1
Reactant: Fc1ccc(Br)cn1
Reactant: O=C(O)C1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=C(O)[C@H]1CC[C@@H](Oc2ccc(Br)cn2)CC1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
A solution of (1S,4S)-4-hydroxycyclohexanecarboxylic acid (2.14 g, 14.9 mmol) in DMA (10 mL) was added to a stirred suspension of NaH (1.32 g, 30.2 mmol) in DMA (15 mL) at 0° C. where it was stirred for 10 min. The suspension was taken off the cooling bath and 5-bromo-2-fluoropyridine (1.53 mL, 14.87 mmol, CAS 766-11-0) was added followed by DMA (10 mL). The reaction was heated at 100° C. for 2.5 h. The solvent was evaporated and DCM and 2M HCl were added, the phases separated and the aqueous phase was extracted with DCM (2×50 mL). The combined organics were dried over MgSO4, filtered and evaporated. The remaining crude was purified by flash chromatography using 5-75% EtOAc (1% HOAc) in heptane to afford the title compound (1.86 g, 42%) as solid.
Reaction SMILES: O=[C:2]1[CH:11]([C:12]([O:14]C)=O)[CH2:10][CH2:9][CH2:8][C:3]21[CH2:7][CH2:6][CH2:5][CH2:4]2.Cl.[NH2:17][C:18]([NH2:20])=[NH:19].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:20][C:18]1[N:19]=[C:12]([OH:14])[C:11]2[CH2:10][CH2:9][CH2:8][C:3]3([CH2:7][CH2:6][CH2:5][CH2:4]3)[C:2]=2[N:17]=1
Reactant: COC(=O)C1CCCC2(CCCC2)C1=O
Reactant: N=C(N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(O)c2c(n1)C1(CCCC1)CCC2

Procedure:
A solution of Example 1B (4.5 g, 21.4 mmol), guanidine hydrochloride (6.13 g, 64.2 mmol), and K2CO3 (9.46 g, 68.5 mmol) in DMF (30 mL) was heated at 105-110° C. for 3 hours. The mixture was then filtered through a layer of diatomaceous earth, and the filter pad was washed with a small amount of DMF. Approximately two volumes of water were then added, and the pH of the resulting mixture was adjusted to pH 6-7 with HOAc. The precipitate was collected, washed with H2O, and dried under vacuum to provide the title product. 1H NMR (300 MHz, DMSO-d6) δ 10.50-10.61 (m, 1 H), 5.98-6.08 (m, 2 H), 2.20 (t, 2 H), 1.95-2.04 (m, 2 H), 1.68-1.76 (m, 2 H), 1.61-1.68 (m, 2 H), 1.48-1.58 (m, 4 H), 1.34-1.45 (m, 2 H). MS (DCI+) m/z 220 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[CH2:16][CH2:15][NH:14][CH2:13][C:12]=3[C:11](=[O:18])[C:10]3[CH:19]=[CH:20][CH:21]=[N:22][C:9]2=3)[CH:5]=[CH:6][CH:7]=1>[Pd].C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[C:12](=[CH:13][N:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[C:10]3[CH:19]=[CH:20][CH:21]=[N:22][C:9]2=3)[CH:5]=[CH:6][CH:7]=1
Reactant: O=c1c2c(n(-c3cccc(Cl)c3)c3ncccc13)CCNC2
Agent: [Pd]
Solvent: Cc1ccccc1C
Product: O=c1c2cnccc2n(-c2cccc(Cl)c2)c2ncccc12
Reaction time: 15 h

Procedure:
Oxidize 10-(3-chlorophenyl)-6,7,8,9-tetrahydropyrido[2,3-b][1,6]naphthyridin-5(10H)-one (1.6 mmol) in a refluxing solution of xylene (15 ml), using air as the oxidant and 5% Pd on C (15 mg) as the catalyst. Follow the procedure of Tetrahedron Letters 26, 1259-1260 (1985); pass air through the hot solution for 15 hours. Evaporate the xylene and elute the residue from silica gel with chloroform to provide 10-(3-chlorophenyl)pyrido[2,3-b][1,6]naphthyridin-5(10H)-one, m.p. 222°-224° C. after crystallization from CH3Cl/pet. ether.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH2:12][N+:13]([O-])=[CH:14][CH:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[CH:23]=1.CC(C)([O-])C.[K+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][CH:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[CH:23]=1
Reactant: [O-][N+]1=CC2CN=C(c3ccccc3F)c3cc(Cl)ccc3N2C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Product: Fc1ccccc1C1=NCc2cncn2-c2ccc(Cl)cc21

Procedure:
A solution of 50 mg of 8-chloro-6-(2-fluorophenyl)-3a,4-dihydro-1H-imidazo[1,5-a][1,4]benzodiazepine 2-oxide in 3 ml of methanol contianing 25 mg of potassium t-butoxide was heated to reflux for 10 min. The mixture was evaporated partially and the residue was partitioned between methylene chloride and sodium bicarbonate solution. The organic phase was dried and evaporated. Crystallization of the residue from ether yielded product with mp 148°-151° C.
Reaction SMILES: [CH2:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20]OS(C)(=O)=O)=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:2][CH2:3][CH3:4].[N-:26]=[N+:27]=[N-:28].[Na+]>>[N:26]([CH2:20][CH2:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][CH:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:13][CH:14]=1)=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCC(Cc1ccc(OCCOS(C)(=O)=O)cc1)C(=O)OCC
Agent: [Na+]
Product: CCCCC(Cc1ccc(OCCN=[N+]=[N-])cc1)C(=O)OCC
Yield: 114.5 %

Procedure:
In a similar manner to that described in Reference example 3(h), a reaction was carried out using ethyl 2-butyl-3-[4-(2-methanesulfonyloxyethoxy)phenyl]propionate (1.65 g), which is the product of Reference example 6(f), and sodium azide (0.95 g) and the reaction mixture was treated to afford the desired compound (1.62 g) as a syrup.
Reaction SMILES: C([O:4][CH2:5][CH:6]([CH2:20][O:21]C(=O)C)[CH2:7][CH2:8][N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][C:12]([NH2:19])=[N:13][C:14]=2Cl)(=O)C.C([O-])=O.[NH4+]>CO.[Pd]>[NH2:19][C:12]1[N:11]=[C:10]2[C:15]([N:16]=[CH:17][N:9]2[CH2:8][CH2:7][CH:6]([CH2:20][OH:21])[CH2:5][OH:4])=[CH:14][N:13]=1
Reactant: CC(=O)OCC(CCn1cnc2c(Cl)nc(N)nc21)COC(C)=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Nc1ncc2ncn(CCC(CO)CO)c2n1
Reaction time: 20 h

Procedure:
To a suspension of 9-(4-acetoxy-3-acetoxymethylbut-1-yl)-2-amino-6-chloropurine (4.86 g 13.7 mmol) in methanol (140 ml) containing ammonium formate (400 mM) was added 10% palladium-on-charcoal (0.4 g) and the mixture was heated under reflux for 40 minutes. After cooling the solution was filtered and the solvent removed. The residue was taken up in water and extracted with chloroform (100ml and 50ml). The organic layers were combined, dried (magnesium sulphate) and the solvent removed. The residue was dissolved in methanol saturated with ammonia at 0° C. (150 ml) and the solution was stirred for 20 hours. The solvent was removed and the residue suspended in chloroform (20 ml) and filtered. The solid was recrystallised from isopropanol-water and a second recrystallisation was carried out from the mother liquors from ethanol (total 2.71 g, 83%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)=[N:5][N:4]=[N:3]1.[Cl-].[OH:16][NH3+:17]>N1C=CC=CC=1>[CH3:1][N:2]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:17][OH:16])=[N:5][N:4]=[N:3]1
Reactant: [NH3+]O
Reactant: Cn1nnnc1C(=O)c1ccccc1
Agent: [Cl-]
Solvent: c1ccncc1
Product: Cn1nnnc1C(=NO)c1ccccc1
Temperature: 45 °C
Reaction time: 24 h
Yield: 99.9 %

Procedure:
(1-methyltetrazol-5-yl)phenylmethanone (11.1 g, 59.1 mmol) and hydroxylammonium chloride (10.3 g, 148 mmol) were added to 100 ml of pyridine, followed by stirring at 45° C. for 24 hours. After the completion of the reaction, the reaction solution was concentrated under reduced pressure and water and ethyl acetate were added to the resulting residue, and then the reaction product was extracted. The organic layer was washed in turn with dilute hydrochloric acid, water and an aqueous sodium hydrogencarbonate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off from the organic layer to obtain (1-methyltetrazol-5-yl)phenylmethanoneoxime (12.0 g, yield: 100%) represented by the formua:
Reaction SMILES: [F:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C=O)C>[CH2:17]([O:10][C:3]1[C:2]([F:1])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[O:6])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1cccc(F)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cccc(F)c1OCc1ccccc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
9.0 g (64 mmol) of 3-fluoro-2-hydroxybenzaldehyde are dissolved in 200 ml of DMF, 10.7 g (77.1 mmol) of potassium carbonate and 8.4 ml (12 g, 71 mmol) of benzyl bromide are added and the mixture stirred at 80° C. for 24 h. The mixture is poured into 600 ml of water, extracted several times with ethyl acetate, and the organic phase is dried over sodium sulfate, concentrated in vacuo and dried under high vacuum. The crude product is purified by silica gel chromatography (cyclohexane:ethyl acetate 2:1).
Reaction SMILES: S1C=CC=C1S([NH:9]C1C=CC=CC=1N)(=O)=O.[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]=[C:25]=[O:26]>>[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][C:25](=[O:26])[NH2:9]
Reactant: Nc1ccccc1NS(=O)(=O)c1cccs1
Reactant: O=C=Nc1ccccc1Br
Product: NC(=O)Nc1ccccc1Br
Yield: 134.9 %

Procedure:
The urea was synthesized from 2-(2-thiophene sulfonyl amino) aniline(1 mmol) and 2-bromo phenyl isocyanate(1 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the desired compound(0.29 g, 64%). EI-MS m/z 450(M-H)-
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][CH3:23])[N:17]=2)=[CH:12][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH3:2].[CH:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[N:34]=[C:35]=[O:36]>>[CH2:1]([O:3][C@@H:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N:22]([CH3:23])[C:35]([NH:34][C:25]3[CH:26]=[CH:27][C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:24]=3)=[O:36])[N:17]=2)=[CH:12][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH3:2]
Reactant: O=C=Nc1ccc2ccccc2c1
Reactant: CCO[C@@H](Cc1ccc(-c2cccc(NC)n2)cc1)C(=O)OC
Product: CCO[C@@H](Cc1ccc(-c2cccc(N(C)C(=O)Nc3ccc4ccccc4c3)n2)cc1)C(=O)OC
Yield: 62 %

Procedure:
In a manner similar to that of Example 7(i), starting with 0.4 g (0.8 mmol) of methyl 2(S)-ethoxy-3-[4-(6-methylaminopyrid-2-yl)phenyl]propanoate and 2-naphthyl isocyanate, 0.2 g (62%) of methyl 2(S)-ethoxy-3-{4-[6-(1-methyl-3-naphthalen-2-ylureido)pyrid-2-yl]phenyl}propionate is obtained.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[CH2:15]([O:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][NH2:27])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:27][CH2:26][C:25]1[CH:28]=[CH:29][CH:30]=[C:23]([O:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:24]=1)#[N:2]
Reactant: NCc1cccc(OCc2ccccc2)c1
Reactant: CC(C)OC(=NC#N)c1cccnc1
Solvent: CO
Product: N#CNC(=NCc1cccc(OCc2ccccc2)c1)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.30 g, 1.6 mmol) was dissolved in methanol (10 ml), and 3-benzyloxybenzylamine (0.41 g, 1.9 mmol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The concentrated residue was subjected to chromatography on a silica gel column (WAKO GEL C-200, 30 g). Elution with chloroform-methanol (100:1) was conducted, the eluted fractions were concentrated under reduced pressure, and the concentrated residue thus obtained was crystallized from methanol-diethyl ether to give the title compound (0.48 g, 1.4 mmol, yield: 88%) as colorless crystals.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[N:6]([CH3:16])[N:5]=1.FC(F)(F)C(O)=O>O>[F:15][C:12]1[CH:11]=[CH:10][C:9]([C:7]2[N:6]([CH3:16])[N:5]=[C:4]([CH:3]=[O:2])[CH:8]=2)=[CH:14][CH:13]=1
Reactant: COC(OC)c1cc(-c2ccc(F)cc2)n(C)n1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(C=O)cc1-c1ccc(F)cc1

Procedure:
The compound from Step 1 (9 g) was treated with trifluoroacetic acid (30 mL) and water (30 mL). The trifluoacetic acid was removed in vacuo and the reaction mixture partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was washed with saturated sodium bicarbonate (×2), brine and dried over MgSO4. The solvent was removed in vacuo to give a yellow oil which was crystallised from ethyl acetate/hexanes to give the title compound. 4.6 g 1H NMR (360, CDCl3) δ 9.97 (s, 1H), 7.38 (m, 2H), 7.20 (m, 2H), 6.80 (s, 1H), 3.95 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([S:8]([OH:11])(=[O:10])=[O:9])[CH2:4][C:5]([OH:7])=[O:6].[C:12]1(=[O:18])[O:17][C:15](=[O:16])[CH:14]=[CH:13]1>CC(N(C)C)=O>[C:5]([CH2:4][CH:3]([S:8]([OH:11])(=[O:9])=[O:10])[CH2:2][NH:1][C:12](=[O:18])/[CH:13]=[CH:14]\[C:15]([OH:17])=[O:16])([OH:7])=[O:6]
Reactant: NCC(CC(=O)O)S(=O)(=O)O
Reactant: O=C1C=CC(=O)O1
Solvent: CC(=O)N(C)C
Product: O=C(O)/C=C\C(=O)NCC(CC(=O)O)S(=O)(=O)O
Yield: 86.9 %

Procedure:
To the solution of 4-amino-3-sulfobutanoic acid (˜2.50 g, 13.66 mmol) in 100 ml of DMA was added maleic anhydride (1.48 g, 15.10 mmol) and the mixture was stirred over night, evaporated, purified on C-18 column (2×30 cm) eluted with 1% HAc in water and crystallized with MeOH/Acetone/toluene to afford 3.34 g (83%) of (Z)-4-(3-carboxy-2-sulfopropylamino)-4-oxobut-2-enoic acid. 1H NMR (CD3OD) 6.33 (d, 1H, J=12.6 Hz), 6.10 (d, 1H, J=12.6 Hz), 3.64 (dd, 1H, J=5.8, 14.0 Hz), 3.54 (m, 1H), 3.30 (m, 1H), 2.78 (dd, 1H, J=4.9, 16.8 Hz), 2.39 (m, 1H); 13C NMR 173.52, 168.68, 167.98, 135.59, 127.79, 57.31, 40.56, 34.52; ESI MS m/z−279.7 (M−H).