Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14](Cl)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[C:23]([Cl:37])[C:24]=1[N:25]1[CH2:30][CH2:29][CH:28]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH2:27][CH2:26]1)[NH2:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:21][C:20]3[CH:19]=[C:18]([Cl:17])[C:24]([N:25]4[CH2:26][CH2:27][CH:28]([N:31]5[CH2:32][CH2:33][O:34][CH2:35][CH2:36]5)[CH2:29][CH2:30]4)=[C:23]([Cl:37])[CH:22]=3)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(Cl)cc1
Reactant: Nc1cc(Cl)c(N2CCC(N3CCOCC3)CC2)c(Cl)c1
Product: Cc1c(C(=O)Nc2cc(Cl)c(N3CCC(N4CCOCC4)CC3)c(Cl)c2)cnn1-c1ccc(Cl)cc1
Yield: 60.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 150 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (0.77 g) and 3,5-dichloro-4-(4-morpholinopiperidin-1-yl)aniline (1.0 g), the title compound (1.0 g) was obtained, melting point: 246–248° C.
Reaction SMILES: C1(S([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:31]#[N:32])=[C:18]([CH2:19][CH:20]4[CH2:25][CH2:24][N:23]([CH2:26][C:27]([F:30])([F:29])[F:28])[CH2:22][CH2:21]4)[C:13]=3[C:12]3[CH:33]=[CH:34][CH:35]=[N:36][C:11]2=3)(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[F:30][C:27]([F:28])([F:29])[CH2:26][N:23]1[CH2:22][CH2:21][CH:20]([CH2:19][C:18]2[C:13]3[C:12]4[CH:33]=[CH:34][CH:35]=[N:36][C:11]=4[NH:10][C:14]=3[CH:15]=[N:16][C:17]=2[C:31]#[N:32])[CH2:25][CH2:24]1
Reactant: N#Cc1ncc2c(c1CC1CCN(CC(F)(F)F)CC1)c1cccnc1n2S(=O)(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: N#Cc1ncc2[nH]c3ncccc3c2c1CC1CCN(CC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.3 %

Procedure:
9-Benzenesulfonyl-5-[1-(2,2,2-trifluoroethyl)-piperidin-4-ylmethyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (0.16 g, 0.3 mmol) was dissolved in tetrabutylammonium fluoride (1M in THF, 5 mL, 5 mmol) and stirred at ambient temperature for 24 h. The solution was filtered through 2 g NH2 cartridge, eluting with 1:1 methanol/dichloromethane. The filtrate was concentrated in vacuo and the residue diluted with water (10 mL) and the resultant precipitate collected by filtration. Purification of the solid by flash chromatography (silica, 5 g column, SPE Si-II, 0-6% methanol in DCM) afforded the title compound as a white solid (90 mg, 80%). 1H NMR (DMSO-D6, 400 MHz): 12.88 (s, 1H), 8.91 (s, 1H), 8.72-8.64 (m, 2H), 7.46 (dd, J=8.0, 4.8 Hz, 1H), 3.09 (q, J=10.3 Hz, 2H), 2.92-2.83 (m, 2H), 2.25-2.15 (m, 2H), 1.85-1.72 (m, 1H), 1.66-1.58 (m, 2H), 1.57-1.43 (m, 2H). LCMS (Method H): RT=9.20 min, M+H+=374.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH2:26][CH2:27][Cl:28]>CC(=O)CC.C(OCC)(=O)C>[Cl:28][CH2:27][CH2:26][CH2:25][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: ClCCCBr
Reactant: COC(=O)c1ccc(-c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: COC(=O)c1ccc(-c2ccc(OCCCCl)cc2)cc1
Temperature: 25 °C
Yield: 91.6 %

Procedure:
The product from Example 10A (4.50 g, 19.7 mmol), K2CO3 (4.0 g, 29.6 mmol) and 3-bromochloropropane (3.88 g, 24.6 mmol) in 2-butanone (100 mL) were heated at reflux for 24 hours. The mixture was allowed to cool to ambient temperature and then diluted with ethyl acetate (200 mL). The mixture was washed with water (2×100 mL) and brine (100 mL) and the remaining organic layer was dried over MgSO4 and filtered. The filtrate was evaporated under reduced pressure to provide the title compound as an off-white solid (5.5 g, 92% yield).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)[C:10]2[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=3)[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: Cc1sc2nc(Cl)nc(NCc3cccc([N+](=O)[O-])c3)c2c1C
Product: Cc1sc2nc(-n3ccnc3)nc(NCc3cccc([N+](=O)[O-])c3)c2c1C

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-5,6-dimethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-5,6-dimethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.C([O:15][C:16](=O)[CH2:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)C.N>O>[C:7]1([N:5]2[N:6]3[C:16](=[O:15])[CH:17]=[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:1]=[C:2]3[CH:3]=[CH:4]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Nc1ccn(-c2ccccc2)n1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: N
Solvent: O
Product: O=c1cc(-c2ccccc2)nc2ccn(-c3ccccc3)n12
Reaction time: 1.5 h

Procedure:
A mixture of 10 g. of 5-amino-2-phenylpyrazole (0.063 mol.),12.1 g. of benzoylacetic acid ethyl ester (0.063 mol.) and 50 g. of polyphosphoric acid is heated at 110°-120° with stirring for 90 minutes. After cooling, 200 ml. of water and then concentrated aqueous ammonia is added under external cooling to adjust the mixture to pH 9. The collected 1,5-diphenylpyrazolo[1,5-a]pyrimidin-7(1H)-one is washed with water and dried at 70°, yield: 17 g. (94%); m.p. 194°-200°. A sample, recrystallized from absolute ethanol, melts at 205°-207°.
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([OH:20])[C:5]=1[O:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].[CH2:30](Br)[CH:31]([CH3:33])[CH3:32]>C(#N)C>[F:23][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([O:20][CH2:30][CH:31]([CH3:33])[CH3:32])[C:5]=1[O:21][CH3:22]
Reactant: COc1c(OC(F)F)ccc(-c2ccc3c(c2)COC3=O)c1O
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1c(OC(F)F)ccc(-c2ccc3c(c2)COC3=O)c1OCC(C)C
Temperature: 80 °C
Yield: 31.7 %

Procedure:
To a stirring solution of 5-(4-(difluoromethoxy)-2-hydroxy-3-methoxyphenyl)isobenzofuran-1(3H)-one (80 mg, 0.25 mmol) in acetonitrile (10 mL) was added potassium carbonate (103 mg, 0.75 mmol) and isobutyl bromide (102 mg, 0.75 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-20% ethyl acetate in pet ether) to afford title compound as a solid (30 mg, 32%).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:17])[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]=[N:15][OH:16])=[N:5][O:6][CH3:7].C(=O)([O-])[O-].[K+].[K+].[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Cl.O>CN(C=O)C>[CH3:1][NH:2][C:3](=[O:17])[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]=[N:15][O:16][CH2:28][C:27]1[CH:30]=[CH:31][CH:32]=[C:25]([Cl:24])[CH:26]=1)=[N:5][O:6][CH3:7]
Reactant: CNC(=O)C(=NOC)c1ccccc1C=NO
Reactant: ClCc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)C(=NOC)c1ccccc1C=NOCc1cccc(Cl)c1
Temperature: 110 °C
Yield: 58.7 %

Procedure:
To a solution of 1 g (4.26 mmol) of N-methyl-2-{2-(hydroxyiminomethyl)phenyl}-2-methoxyiminoacetamide and 0.62 g (4.5 mmol) of potassium carbonate in 10 ml of DMF, was added 0.69 g (4.29 mmol) of 3-chlorobenzyl chloride and the mixture was stirred under heating at 110° C. for 3 hours. After cooling, the reaction mixture was poured into water, extracted with ethyl acetate, successively washed with water and a saturated sodium chloride solution and dried over anhydrous sodium sulfate. After concentration in vacuo, the residue was chromatographed over SiO2 to give 0.9 g of the title compound (yield: 58.8%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:9]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[N:10][C:11]([NH2:17])=[C:12]([N+:14]([O-])=O)[CH:13]=1>[Pd].C1COCC1.C(O)C>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:9]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[N:10][C:11]([NH2:17])=[C:12]([NH2:14])[CH:13]=1
Reactant: Nc1nc(-c2cccnc2)c(-c2ccncc2F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1cc(-c2ccncc2F)c(-c2cccnc2)nc1N
Reaction time: 3 h
Yield: 98.8 %

Procedure:
A suspension of 3″-fluoro-5′-nitro-3,2′:3′,4″-terpyridin-6′-amine (2.25 g, 7.23 mmol) and 10% palladium on carbon (0.4 g) in a mixture of THF/ethanol 40:60 (100 mL) was stirred under hydrogen atmosphere. After 3 h, the mixture was filtered through Celite® and the filter cake was washed with ethanol. The combined filtrate and washings were evaporated to give the title compound as a solid (2.01 g, 99%).
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5].C(O)=O.OS(C(F)(F)F)(=O)=O.[CH2:20]=[CH:21][CH2:22][CH3:23]>>[C:1]([O:8][CH2:20][CH2:21][CH2:22][CH3:23])(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5]
Reactant: C=CCC
Reactant: CC(=O)CCC(=O)O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=CO
Product: CCCCOC(=O)CCC(C)=O
Temperature: 100 °C

Procedure:
A 5 cc autoclave is charged with 2 cc of an aqueous solution containing 2 mmoles of levulinic acid and 0.5 mmoles of formic acid. 2 wt. % triflic acid is added as a catalyst. The reactor is pressurized to 0.69 MPa with 1-butene and heated to 100° C. for 0.5 hours while maintaining a constant pressure of 1-butene. After cooling, the organic phase is separated. A mixture of butyl formate and butyl levulinate is formed as product.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[S:11][C:10]([C:12](=O)[CH2:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1.[C:19]1([NH:25][NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>C(O)C>[NH:3]1[CH:4]=[CH:5][N:1]=[C:2]1[CH2:6][C:7]1[S:11][C:10]([C:12]2[CH2:13][CH2:14][C:15](=[O:17])[N:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:26]=2)=[CH:9][CH:8]=1
Reactant: O=C(O)CCC(=O)c1ccc(Cc2ncc[nH]2)s1
Reactant: NNc1ccccc1
Solvent: O
Solvent: CCO
Product: O=C1CCC(c2ccc(Cc3ncc[nH]3)s2)=NN1c1ccccc1
Reaction time: 10 h

Procedure:
A mixture of 2.64 g of 4-[5-(1-imidazolylmethyl)-thien-2-yl]-4-oxobutyric acid, 1.12 g phenylhydrazine, 40 ml water and 40 ml ethanol was stirred for 10 hours under reflux. After cooling the mixture was evaporated, the residue shaken with chloroform/dilute caustic soda solution, the chloroform phase washed with water, dried and evaporated. The residue was recrystallized from diisopropyl ether/ethyl acetate.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[N:14]([CH2:17]C)[CH:15]=[N:16][C:3]=12.[CH2:19]([O:21]C(C1C(Cl)=C2N=CN(C)C2=NC=1C)=O)[CH3:20]>>[CH3:17][N:14]1[C:4]2=[N:5][C:6]([CH3:13])=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2]([O:21][CH2:19][CH3:20])=[C:3]2[N:16]=[CH:15]1
Reactant: CCOC(=O)c1c(C)nc2c(ncn2C)c1Cl
Reactant: CCOC(=O)c1c(C)nc2c(ncn2CC)c1Cl
Product: CCOC(=O)c1c(C)nc2c(ncn2C)c1OCC
Yield: 78 %

Procedure:
By replacing 7-chloro-3-ethyl-5-methyl-3H-imidazo-[4,5-b]pyridine-6-carboxylic acid, ethyl ester in Example 1 e with 7-chloro-3,5-dimethyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid ethyl ester, 3,5-dimethyl-7-ethoxy-3H-imidazo[4,5-b]pyridine -6-carboxylic acid, ethyl ester is obtained. Yield 78%, m.p. 85°-87° (ether).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[NH2:11][CH2:12][CH2:13][N:14]1[C:18]([CH3:19])=[CH:17][CH:16]=[C:15]1[CH3:20].C(OCC)C>O1CCCC1>[CH3:20][C:15]1[N:14]([CH2:13][CH2:12][NH:11][C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:10])[C:18]([CH3:19])=[CH:17][CH:16]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: Cc1ccc(C)n1CCN
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc(C)n1CCNC(=O)Nc1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
7.7 g (0.05 mol) of 4-chlorophenyl isocyanate, dissolved in 10 ml of tetrahydrofura, are added dropwise, over the coruse of 30 minutes, to 6.9 g (0.05 mol) of 1-(2-aminoethyl)-2,5-dimethylpyrrole, dissolved in 10 ml of tetrahydrofuran, a 20° C. The mixture is then left to stir at 20° C. for 60 minutes. After addition of diethyl ether to the reaction mixture the product crystallizes out, and is filtered off with suction and recrystallized from isopropanol. Yield: 8.4 g (58% of theory), Melting point: 175°-177° C. Elemental analysis: C15H18ClN3 0 (291.83) calculated: C 61.7 H 6.2 CL 12.2 N 14.4 0 5.5 found: C 61.0 H 6.5 Cl 12.5 N 14.6 0 5.8
Reaction SMILES: [CH2:1]([O:6][C:7]([NH:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:8])[CH2:2][CH2:3][CH:4]=[CH2:5].[CH2:18](O)CCCC=C>>[CH2:1]([O:6][C:7]([NH:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:8])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:18]
Reactant: C=CCCCCO
Reactant: C=CCCCOC(=O)N[C@@H](CCCC)C(=O)O
Product: C=CCCCCOC(=O)N[C@@H](CCCC)C(=O)O

Procedure:
N-[(Hex-5-en-1-yloxy)carbonyl]-L-norleucine was prepared according to the procedure for N-[(pent-4-en-1-yloxy)carbonyl]-L-norleucine by using 5-hexenol instead of 4-pentenol. LRMS (ESI) m/z 258 [(M+H)+; calcd for C13H24NO4: 258].
Reaction SMILES: [CH3:1][C:2](=[CH2:16])[CH2:3][N:4]([CH2:10][CH:11](OC)[O:12]C)[C:5]([O:7][CH2:8][CH3:9])=[O:6]>CC(C)=O.O>[CH3:16][C:2](=[CH2:1])[CH2:3][N:4]([CH2:10][CH:11]=[O:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: C=C(C)CN(CC(OC)OC)C(=O)OCC
Solvent: CC(C)=O
Solvent: O
Product: C=C(C)CN(CC=O)C(=O)OCC

Procedure:
11.5 g (50 mmol) of N-(2-methylprop-2-enyl)-N-(2,2-dimethoxyethyl)-urethane and 1.25 g (5 mmol) of pyridinium p-toluenesulphate in 100 ml of acetone and 10 ml of water are heated under reflux for two days. The mixture is concentrated and the residue is distilled.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[P:11]([O-:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14].[CH2:19]([O:26][C:27]([NH:29][CH2:30][CH2:31][CH:32]=[O:33])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[CH2:19]([O:26][C:27]([NH:29][CH2:30][CH2:31][CH:32]([P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[OH:33])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=CCCNC(=O)OCc1ccccc1
Reactant: CCOP([O-])OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(O)CCNC(=O)OCc1ccccc1
Reaction time: 0.17 h
Yield: 27.7 %

Procedure:
To a solution of potassium bis(trimethylsilyl)amide (1.13 g, 5.66 mmol) in tetrahydrofuran (10 mL) at 0° C. was added diethyl phosphite (0.73 g, 5.66 mmol). After 10 min, 3-(benzyloxycarbonylamino)propanal (0.78 g, 3.77 mmol) was added as a solution in tetrahydrofuran (5 mL). After 30 min, the reaction was quenched by the addition of 2N hydrochloric acid (25 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with sat'd sodium chloride (50 mL), dried over magnesium sulfate and concentrated in vacuo. Silica gel chromatography eluting with hexane/acetone (1:1) gave a colorless oil (0.36 g): ESI-MS 346.1 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:12][C:13](=[O:24])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([O:22]C)=[O:21])[CH:15]=1.[OH-].[Na+].Cl>CO.O1CCOCC1>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:12][C:13](=[O:24])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([OH:22])=[O:21])[CH:15]=1
Reactant: COC(=O)c1cccc(C(=O)Nc2cccc3cc(Br)cnc23)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: O=C(O)c1cccc(C(=O)Nc2cccc3cc(Br)cnc23)c1
Yield: 115.7 %

Procedure:
A mixture of 3-bromo-8-[3-(methoxycarbonyl)benzoylamino]quinoline (356 mg) and 1N sodium hydroxide aqueous solution (1.1 ml) in methanol (5 ml) and dioxane (5 ml) was gently refluxed for 2 hours. After cooling, the mixture was neutralized with 1N hydrochloric acid. The solvent was removed in vacuo, and the residue was washed with hot 95% ethanol and collected by filtration to give 3-bromo-8-(3-carboxybenzoylamino)quinoline (397 mg) as pale tan solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.C(O)(=O)C.[NH2:13][C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([Cl:21])=[CH:16][C:15]=1[N:22]1[CH:26]=[CH:25][CH:24]=[CH:23]1>C(O)C>[Cl:20][C:18]1[CH:19]=[C:14]2[C:15](=[CH:16][C:17]=1[Cl:21])[N:22]1[CH:23]=[CH:24][CH:25]=[C:26]1[C:5]1([CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)[NH:13]2
Reactant: Nc1cc(Cl)c(Cl)cc1-n1cccc1
Reactant: CN1CCC(=O)CC1
Solvent: CCO
Solvent: CC(=O)O
Product: CN1CCC2(CC1)Nc1cc(Cl)c(Cl)cc1-n1cccc12

Procedure:
3.39 g (0.03 mole) of 1-methyl-4-piperidone and 5 ml. of glacial acetic acid are added to a solution of 6.81 g (0.03 mole) of 1-(2-amino-4,5-dichlorophenyl)pyrrole in 100 ml. of absolute ethanol. The solution is refluxed for 50 hours and concentrated, and the residue is dissolved in water. The solution is filtered and basified. A solid precipitates and is filtered, dried, and recrystallized from ethanol to give 7,8-dichloro-4,5-dihydro-1'-methylspiro[pyrrolo(1,2-a)quinoxaline-4,4'-piperidine], m.p. 214°-215° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15](COCCOC)[C:14]3[CH:22]=[C:23]([Cl:34])[C:24]([S:26][C:27]4[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=4)=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2].CCO.Cl>O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:15][C:14]3[CH:22]=[C:23]([Cl:34])[C:24]([S:26][C:27]4[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=4)=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Sc4cccc(C)c4)c(Cl)cc3n2COCCOC)c1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)c1cnn(-c2nc3cc(Sc4cccc(C)c4)c(Cl)cc3[nH]2)c1
Temperature: 23 °C
Reaction time: 3 h
Yield: 91.4 %

Procedure:
To a mixture of 1-[6-chloro-1-(2-methoxy-ethoxymethyl)-5-m-tolylsulfanyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.190 g, 0.379 mmol) and EtOH (1 mL) was added 4M HCl in dioxane (1 mL). The mixture was stirred for 3 h at 23° C. The reaction mixture was concentrated and Et2O (10 mL) was added. The solids were filtered and washed with Et2O to yield the titled compound (0.143 g, 91%). MS (ESI/CI): mass calcd. for C20H17ClN4O2S, 412.1; m/z found, 413.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 8.95 (s, 1H), 8.35 (s, 1H), 7.77 (s, 1H), 7.41 (s, 1H), 7.29 (t, J=7.7 Hz, 1H), 7.19-7.14 (m, 2H), 7.12-7.06 (m, 1H), 4.30 (q, J=7.1 Hz, 2H), 2.29 (s, 3H), 1.31 (t, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]1[C:19](=[O:37])[CH2:20][NH:21][C:22](=[O:36])[NH:23][C:24]1[CH:34]=[C:28]([C:29]([O:31]CC)=[O:30])[C:27]([OH:35])=[CH:26][CH:25]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>CO.O>[C:1]([O:5][C:6]([CH:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:9]1[C:19](=[O:37])[CH2:20][NH:21][C:22](=[O:36])[NH:23][C:24]1[CH:34]=[C:28]([C:29]([OH:31])=[O:30])[C:27]([OH:35])=[CH:26][CH:25]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc(NC(=O)NCC(=O)N2C(C(=O)OC(C)(C)C)CCC2c2ccccc2)ccc1O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)C1CCC(c2ccccc2)N1C(=O)CNC(=O)Nc1ccc(O)c(C(=O)O)c1
Yield: 51.8 %

Procedure:
By proceeding in a fashion similar to that described in Example 9, but starting from 4.7 g of ethyl (2RS,5SR)-5-{3-[2-(2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}salicylate in solution in 80 cm3 of methanol and 1.04 g of potassium hydroxide dissolved in 40 cm3 of water and after treatment, 2.3 g of (2RS,5SR)-5-{3-[2-(2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}salicylic acid, melting at 190° C., are obtained.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[C:8]([Br:11])[N:7]([CH2:12][C:13]#[C:14][CH3:15])[C:6]=2[C:5](=[O:16])[NH:4][C:3]1=[O:17].Br[CH2:19][C:20]1[S:21][C:22]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:23]=2[N:24]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:29][C:26]1[CH:27]=[CH:28][C:22]2[S:21][C:20]([CH2:19][N:4]3[C:5](=[O:16])[C:6]4[N:7]([CH2:12][C:13]#[C:14][CH3:15])[C:8]([Br:11])=[N:9][C:10]=4[N:2]([CH3:1])[C:3]3=[O:17])=[N:24][C:23]=2[CH:25]=1
Reactant: CC#CCn1c(Br)nc2c1c(=O)[nH]c(=O)n2C
Reactant: Fc1ccc2sc(CBr)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCn1c(Br)nc2c1c(=O)n(Cc1nc3cc(F)ccc3s1)c(=O)n2C
Yield: 98 %

Procedure:
By utilizing the well known method, 3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine 1a (156 mg, 0.53 mmol) was dissolved in N,N-dimethylformamide (3 ml). 2-bromomethyl-5-fluoro-1,3-benzothiazole (140 mg, 0.57 mmol), potassium carbonate (118 mg, 0.79 mmol) were added to give a reaction mixture. The obtained reaction mixture was reacted overnight at room temperature and TLC was used to monitor the reaction progress. After the reaction was completed, the obtained reaction mixture was poured into water, suction filtered, and the obtained solid was washed with water, dried to give 1-[(5-fluoro-1,3-benzothiazol-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine 1b (240 mg, off-white solid), yield: 99%.
Reaction SMILES: FC1C=C(Cl)C(OC2CCCC2)=CC=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].COC1C=C(CC[NH2:38])C=CC=1OC.C(N(CC)CC)C>C1C=CC=CC=1>[C:16]([NH2:38])(=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH2:15])=[O:20]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Reactant: COc1ccc(CCN)cc1OC
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: NC(=O)C1=C(C(N)=O)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 250.8 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.75 mmol), 2-(3,4-dimethoxyphenyl)ethylamine (0.600 g, 3.31 mmol), triethylamine (0.310 g, 3.06 mmol) and benzene (20. ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-{2-3,4-dimethoxyphenyl)ethyl)-3,4,5,6-tetrahydrophthalamide as white crystals (1.16 g, 77.5% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:5][N:6]1[C:15](=[S:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]([O:20]CC)=[O:19])[C:7]1=[S:23].[OH-].[Na+].O1CCCC1.Cl>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:5][N:6]1[C:15](=[S:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]([OH:20])=[O:19])[C:7]1=[S:23]
Reactant: CCOC(=O)Cn1c(=S)n(Cc2ccc(Cl)c(Cl)c2)c(=S)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)Cn1c(=S)n(Cc2ccc(Cl)c(Cl)c2)c(=S)c2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 45.2 %

Procedure:
A mixture of ethyl 2-[3-(3,4-dichlorobenzyl)-1,2,3,4-tetrahydro-2,4-dithioxoquinazolin-1-yl]acetate (85 mg), 1N aqueous sodium hydroxide (0.5 ml) and tetrahydrofuran (1 ml) was stirred at room temperature for 20 hours. The reaction mixture was poured into a mixture of ethyl acetate and 0.5N hydrochloric acid. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate. The solvent was removed and the residue was crystallized from chloroform to give 2-[3-(3,4-dichlorobenzyl)-1,2,3,4-tetrahydro-2,4-dithioxoquinazolin-1-yl]acetic acid (36 mg).