Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:29]=[CH:28][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25]C)=[O:24])=[CH:18][C:17]=3[F:27])=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[OH-].[Na+].O>O1CCOCC1.C(OCC)(=O)C.Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][C:17]=3[F:27])=[CH:28][CH:29]=2)=[O:10])=[CH:30][CH:31]=1
Reactant: COC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(F)c1
Reaction time: 3 h
Yield: 48.7 %

Procedure:
Methyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-fluorophenyl)acetate (32 mg, 0.072 mmol) was diluted with dioxane (1 mL) followed by the addition of NaOH (0.072 ml, 0.36 mmol) and 200 μL of water. After stirring for 3 hours, the reaction was diluted with ethyl acetate and 2N HCl. The organic layer was dried over MgSO4, filtered and concentrated to yield 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-fluorophenyl)acetic acid (15 mg, 48% yield) as a white solid. 1H NMR (400 MHz, CD3Cl3, CD3OD) 7.70 (d, 2H), 7.25 (d, 2H), 7.19 (m, 3H), 7.10 (m, 2H), 6.95 (d, 2H), 3.65 (m, 4H), 2.90 (t, 2H).
Reaction SMILES: C(S)C.CN(C=O)C.[H-].[Na+].[C:11]([C:15]1[C:16]([CH3:38])([CH3:37])[CH2:17][O:18][C:19]=1[C:20]1[CH:34]=[C:33]([O:35]C)[C:23]2[N:24]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:26][C:22]=2[CH:21]=1)([CH3:14])([CH3:13])[CH3:12]>O>[C:11]([C:15]1[C:16]([CH3:38])([CH3:37])[CH2:17][O:18][C:19]=1[C:20]1[CH:34]=[C:33]([OH:35])[C:23]2[N:24]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:26][C:22]=2[CH:21]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: COc1cc(C2=C(C(C)(C)C)C(C)(C)CO2)cc2oc(-c3ccccc3)nc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCS
Product: CC(C)(C)C1=C(c2cc(O)c3nc(-c4ccccc4)oc3c2)OCC1(C)C
Temperature: 155 °C
Yield: 86.8 %

Procedure:
In nitrogen atmosphere at 0° C., 0.25 mL of ethanethiol was added to 3 mL of DMF dissolving 104 mg (2.6 mmol) of 60% sodium hydride. Adding 505 mg (1.3 mmol) of 4-t-butyl-5-(4-methoxy-2-phenylbenzo[d]oxazol-6-yl)-3,3-dimethyl-2,3-dihydrofuran (Compound [62]), the mixture was refluxed for 1.0 hours at 155° C. The resulting mixture was poured in pure water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride, dried with magnesium sulfate anhydride, and concentrated. The concentrate was applied to a silica gel column and the elution was carried out with the mixture of hexane and ethyl acetate (hexane:ethyl acetate=5:1) to obtain 410 mg of 4-t-butyl-5-(4-hydroxy-2-phenylbenzo[d]oxazol-6-yl)-3,3-dimethyl-2,3-dihydrofuran (Compound [63]). Yield 82.8%.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=O.[O:15]([C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[BH4-].[Na+]>C1CCCCC1>[O:15]([C:22]1[CH:23]=[C:24]([NH:25][CH2:8][C:7]2[CH:10]=[CH:11][CH:12]=[C:5]([O:4][CH2:3][C:2]([F:14])([F:13])[F:1])[CH:6]=2)[CH:26]=[CH:27][CH:28]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Nc1cccc(Oc2ccccc2)c1
Reactant: O=Cc1cccc(OCC(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCCCC1
Product: FC(F)(F)COc1cccc(CNc2cccc(Oc3ccccc3)c2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
The 3-(2,2,2-trifluoroethoxy)benzaldehyde (0.360 g, 1.76 mmol) product from EX-659A and 3-phenoxyaniline (0.326 g, 1.76 mmol) were combined in 50 mL of cyclohexane with 3A molecular sieves (1 g) and stirred overnight at 80° C. The mixture was cooled, filtered, and evaporated, then dissolved in 50 mL of methanol and cooled to 0° C. Solid sodium borohydride (0.030 g, 0.79 mmol) was added in portions, and the mixture was stirred overnight. The reaction was quenched with 5% aq. NaHCO3 and extracted with ether (3×). The combined ether layers were washed with water and brine, dried over MgSO4, filtered, and evaporated to give 0.50 g (76%) of the desired N-(3-phenoxyphenyl)[[3-(2,2,2-trifluoroethoxy)phenyl]methyl]amine product as an amber oil, >95% pure by normal phase HPLC analysis. MS m/z=373 [M+].
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([NH:10][CH2:11][CH2:12][O:13][CH3:14])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.N1([C:20](N2C=NC=N2)=[O:21])C=NC=N1.[CH3:27][O:28][CH:29]([O:51][CH3:52])[C:30]1[C:39]([CH2:40][N:41]([CH2:46][CH2:47][N:48]([CH3:50])[CH3:49])[S:42]([CH3:45])(=[O:44])=[O:43])=[CH:38][C:37]2[CH2:36][CH2:35][CH2:34][NH:33][C:32]=2[N:31]=1>CN(C=O)C>[C:6]([C:5]1[C:8]([NH:10][CH2:11][CH2:12][O:13][CH3:14])=[CH:9][C:2]([NH:1][C:20]([N:33]2[C:32]3[C:37](=[CH:38][C:39]([CH2:40][N:41]([CH2:46][CH2:47][N:48]([CH3:50])[CH3:49])[S:42]([CH3:45])(=[O:44])=[O:43])=[C:30]([CH:29]([O:28][CH3:27])[O:51][CH3:52])[N:31]=3)[CH2:36][CH2:35][CH2:34]2)=[O:21])=[N:3][CH:4]=1)#[N:7]
Reactant: COCCNc1cc(N)ncc1C#N
Reactant: COC(OC)c1nc2c(cc1CN(CCN(C)C)S(C)(=O)=O)CCCN2
Reactant: O=C(n1cncn1)n1cncn1
Solvent: CN(C)C=O
Product: COCCNc1cc(NC(=O)N2CCCc3cc(CN(CCN(C)C)S(C)(=O)=O)c(C(OC)OC)nc32)ncc1C#N
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
A solution of 6-amino-4-((2-methoxyethyl)amino)nicotinonitrile (intermediate 75, 720 mg, 3.75 mmol) in anhydrous DMF (6 ml) was added dropwise to a mixture of di(1H-1,2,4-triazol-1-yl)methanone (660 mg, 3.62 mmol) and DMF (6 ml) cooled at 0° C. After stirring for 50 minutes at 0° C. the reaction mixture was allowed to warm to room temperature and a solution of N-((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-N-(2-(dimethylamino)ethyl)methanesulfonamide (intermediate 201, 697 mg, 1.803 mmol) in DMF (6 ml) was added. The reaction mixture was stirred for 14 h at room temperature, quenched by the addition of MeOH and concentrated. The residue was diluted with EtOAc and water, filtered to remove insoluble byproducts. Phases were separated and the aqueous layer was washed with EtOAc. The organic layers were combined, washed with water, dried using Na2SO4, filtered and evaporated. The crude product was purified using silica gel column chromatography eluting with a gradient of MeOH (0-5%) in DCM. Fractions containing the product were combined and evaporated to yield the title compound as an orange resin. (UPLC-MS 3) tR 0.81 min, ESI-MS 605.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][NH:6][C:7]1[C:16]2[C:11](=[C:12]([NH2:17])[CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([CH3:18])[CH:8]=1.[Br:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28]Br.O>CN(C)C=O>[BrH:23].[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][NH:6][C:7]1[C:16]2[C:11](=[C:12]([N:17]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([CH3:18])[CH:8]=1
Reactant: BrCCOCCBr
Reactant: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(N)c2n1
Solvent: O
Solvent: CN(C)C=O
Product: Br
Product: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(N3CCOCC3)c2n1
Yield: 17.1 %

Procedure:
N*4*-(3,4-Dichlorobenzyl)-2-methylquinoline-4,8-diamine (60.0 mg, 0.181 mmole) and bis(2-bromoethyl)ether (83.7 mg, 0.361 mmole) in dimethylformamide (1 mL), were stirred at 100° C. for 90 min in a microwave oven. Water was added and the mixture was extracted with dichloromethane. The organic phases were washed with saturated NaCl solution, dried and the solvent was removed. The residue thus obtained was purified using silica gel chromatography, eluting with dichloromethane:water 90:10. Precipitation in ethyl acetate gave a brownish solid (15 mg, 17%).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([C:7]1[CH:31]=[CH:30][C:10]([CH2:11][C:12]23[CH2:19][CH2:18][CH2:17][N:16]2[C:15](=[O:20])[N:14]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)[C:13]3=[O:29])=[CH:9][CH:8]=1)#[N:6]>CN(C=O)C>[NH:1]1[C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH2:11][C:12]34[CH2:19][CH2:18][CH2:17][N:16]3[C:15](=[O:20])[N:14]([C:21]3[CH:22]=[C:23]([Cl:28])[CH:24]=[C:25]([Cl:27])[CH:26]=3)[C:13]4=[O:29])=[CH:30][CH:31]=2)=[N:6][N:3]=[N:2]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(CC23CCCN2C(=O)N(c2cc(Cl)cc(Cl)c2)C3=O)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1N(c2cc(Cl)cc(Cl)c2)C(=O)C2(Cc3ccc(-c4nnn[nH]4)cc3)CCCN12
Temperature: 140 °C
Yield: 17.8 %

Procedure:
NaN3 (64.5 mg) was added to a solution of Example 21 (137 mg) in DMF (3 mL). The reaction mixture was sealed and heated at 140° C. for 72 hours. The reaction mixture was cooled to room temperature and the solvent removed under reduced pressure. The residue was purified by HPLC (18C-Waters 40×210 mm, 1% HOAc/CH3CN gradient) to provide the titled compound (27 mg). MS (m/z) 457 (MH+). mp. 194.8° C.
Reaction SMILES: C1([Li])C=CC=CC=1.[CH3:8][C:9]1[N:14]=[C:13]([CH3:15])[C:12]([CH3:16])=[N:11][C:10]=1[CH3:17].[CH:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CCOCC>[OH:25][CH:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:17][C:10]1[C:9]([CH3:8])=[N:14][C:13]([CH3:15])=[C:12]([CH3:16])[N:11]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1nc(C)c(C)nc1C
Agent: [Li]c1ccccc1
Solvent: CCOCC
Solvent: O
Product: Cc1nc(C)c(CC(O)c2ccccc2)nc1C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of phenyllithium in benzene-ether (90 milliliters, 0.095 mole) was diluted with 100 milliliters anhydrous ether and cooled to 0° C. A solution of 13.6 grams tetramethylpyrazine (0.1 mole) in 50 milliliters ether was added slowly to the phenyllithium solution. The reaction mixture was stirred at room temperature for 2 hours and heated under reflux for 1 hour. The mixture was allowed to cool to room temperature and a solution of 10 grams of freshly distilled benzaldehyde (0.1 mole) in 50 milliliters of ether was added dropwise. The mixture was stirred at room temperature for an additional 1.5 hours and cooled to 0° C. Water was added, and the organic phase was separated and washed three times with water. The recovered water extracts were washed with methylene chloride.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:7][CH:8]=2)[N:3]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>O1CCCC1>[Cl:1][C:2]1[N:11]=[C:10]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:9]2[C:4](=[CH:5][C:6]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ccc(N3CCOCC3)cc2n1
Reactant: C1CCNCC1
Solvent: C1CCOC1
Product: Clc1nc(N2CCCCC2)c2ccc(N3CCOCC3)cc2n1
Reaction time: 3 h
Yield: 79.9 %

Procedure:
1.59 g (5.0 mmol) of 2,4-dichloro-7-morpholin-4-ylquinazoline were suspended in 50 ml of tetrahydrofuran, a solution of 1.24 ml (12.50 mmol) of piperidine in 20 ml of tetrahydrofuran was added at room temperature, and the mixture was stirred for 3 h. Conventional work-up gave 1.33 g of 2-chloro-7-morpholin-4-yl-4-piperidin-1-ylquinazoline (No. 2).
Reaction SMILES: Cl.[CH2:2]([S:4][CH2:5][CH2:6][NH2:7])[CH3:3].C(N(CC)CC)C.Cl[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>C(Cl)(Cl)Cl>[C:20]([O:19][C:17](=[O:18])[CH2:16][NH:7][CH2:6][CH2:5][S:4][CH2:2][CH3:3])([CH3:23])([CH3:22])[CH3:21]
Reactant: CCSCCN
Reactant: CC(C)(C)OC(=O)CCl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCSCCNCC(=O)OC(C)(C)C
Yield: 34.2 %

Procedure:
To a solution of 10 g of 2-ethylthioethylamine hydrochloride and 15 g of triethylamine in 20 ml of chloroform was added with stirring 11 g of tert-butyl chloroacetate over a period of 30 minutes, while maintaining the temperature at 30°-70° C. The reaction mixture was held at 70° C for an addition 1 hour. At the end of this period, the chloroform was evaporated in vacuo, and the residue was taken up in 40 ml of 2N NaOH solution and 50 ml of benzene, transferred into a separatory funnel and well shaken. The benzene solution was separated, washed with water, dried over anhydrous sodium sulfate and filtered. After evaporation of benzene, the residue was distilled under reduced pressure to give 5.3 g (34 percent) of N-(2-ethylthioethyl)glycine tert-butyl ester, B.P. 106°-9° C/1.5 mm Hg.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5](=O)[CH2:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C:5]1[NH:13][C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[O:17])[CH3:2]
Reactant: CCOC(=O)C(=O)Cc1ncccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cc2ncccc2[nH]1
Reaction time: 12 h

Procedure:
To a suspension of 3-(3-nitropyridin-2-yl)-2-oxopropionic acid ethyl ester (Preparation 30, 1.00 g, 4.20 mmol) in ethanol (30 mL, absolute) was added palladium (10% on activated carbon, 447 mg, 0.42 mmol) and the reaction mixture placed under an atmosphere of hydrogen at a pressure of 20–30psi for 12 h with vigorous stirring. The reaction mixture was filtered through celite, washing with ethyl acetate and the filtrate concentrated in vacuo to ca. 20 mL. Water (150 mL) was added and the mixture cooled to between 0° C. and 5° C. The precipitate that formed was collected by filtration and dried to give the title compound as a beige solid. δH (CDCl3): 1.44 (3H, t), 4.45 (2H, q), 7.25 (1H, dd), 7.39 (1H, s), 7.75 (1H, dd), 8.57 (1H, dd), 8.98 (1H, s).
Reaction SMILES: F[C:2](F)(F)[C:3]1[CH:8]=CC=C[C:4]=1P([C:16]1[CH:21]=CC=CC=1)C1C=CC=CC=1.C[OH:25].[O:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>[Pd](Cl)Cl>[C:4]([O:26][CH3:27])(=[O:25])[CH:3]([CH3:8])[CH3:2].[C:30]([O:29][CH3:28])(=[O:25])[CH2:31][CH2:21][CH3:16]
Reactant: FC(F)(F)c1ccccc1P(c1ccccc1)c1ccccc1
Reactant: CO
Reactant: C1COCCO1
Agent: Cl[Pd]Cl
Product: CCCC(=O)OC
Product: COC(=O)C(C)C
Temperature: 120 °C
Reaction time: 3 h

Procedure:
The autoclave was charged with 0.3 gms of palladium chloride, 5 gms o-trifluoromethylphenyldiphenylphosphine, 10 mls of methanol and 50 ml of p-dioxane. After flushing with nitrogen, the autoclave was pressurized with carbon monoxide to 800 psig and heated to 120 degrees C. with stirring. 10 gms of liquid propylene was added and the reaction continued at 120° C. and 100 psig for 3 hours. The autoclave was then cooled and the reaction fluid analyzed by gas chromatography. A methyl isobutyrate:methyl n-butyrate ratio of 7.1:1 was obtained.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][CH:9]=[C:8]2[CH2:15][CH2:16][CH2:17][C@@H:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][S:26][C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)[CH2:20][C@@H:19]1[C:32]([O:34]C)=[O:33].[ClH:36]>CO.O.ClCCl.CO>[ClH:36].[ClH:36].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][CH:9]=[C:8]2[CH2:15][CH2:16][CH2:17][C@@H:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][S:26][C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)[CH2:20][C@@H:19]1[C:32]([OH:34])=[O:33]
Reactant: COC(=O)[C@H]1CN(CCSc2cccs2)CC[C@H]1CCCc1ccnc2ccc(OC)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2nccc(CCC[C@@H]3CCN(CCSc4cccs4)C[C@@H]3C(=O)O)c2c1
Temperature: 60 °C

Procedure:
0.5 cm3 of 5N aqueous sodium hydroxide was added to a stirred solution of 0.34 g of methyl (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(thien-2-ylthio)ethyl]piperidine-3-carboxylate in 3 cm3 of methanol and then the mixture was heated at a temperature in the region of 60° C. for 20 hours. After evaporating the solvents under reduced pressure (5 kPa) at a temperature in the region of 40° C., the residue obtained was taken up in 5 cm3 of water and then acidified by addition of 1 cm3 of 35% hydrochloric acid. The mixture was again evaporated under reduced pressure under the same conditions as above; the residue obtained was taken up in 5 cm3 of a dichloromethane/methanol (90/10 by volume) mixture. The insoluble material was filtered off and then the solvent was evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 0.35 g of (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(thien-2-ylthio)ethyl]piperidine-3-carboxylic acid dihydrochloride was obtained in the form of a solid with a beige color which melts with softening in the region of 150° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[O:18][C:17](=[O:19])[NH:16][N:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N+:20]([C:23]1[O:27][C:26]([CH:28]=O)=[CH:25][CH:24]=1)([O-:22])=[O:21]>CC(O)=O.CO>[N+:20]([C:23]1[O:27][C:26](/[CH:28]=[N:1]/[C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:9][CH2:10][CH:11]([C:14]4[O:18][C:17](=[O:19])[NH:16][N:15]=4)[CH2:12][CH2:13]3)=[CH:6][CH:7]=2)=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Reactant: Nc1ccc(N2CCC(c3n[nH]c(=O)o3)CC2)cc1
Solvent: CO
Solvent: CC(=O)O
Product: O=c1[nH]nc(C2CCN(c3ccc(/N=C/c4ccc([N+](=O)[O-])o4)cc3)CC2)o1
Yield: 80 %

Procedure:
5-[1-(4-Aminophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (7a, 0.26 g, 1 mmol) on reacting with 5-nitro2-furaldehyde in the presence of catalytic amount of CH3COOH (3 drops) in methanol at 0° C. for 10 h and the obtained solid is filtered, washed with water and recrystallized in ethanol to obtain product 5-[1-(4-[(E)-1-(5-nitro-2-furyl)methylidene]aminophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (9a, 306 mg, 80%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:15][C:16](=[O:20])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30]>>[CH3:1][O:2][C:3]1[C:4]([NH:15][C:16]([N:36]2[CH2:35][CH2:34][N:33]([C:25]3[CH:24]=[C:23]([O:22][CH3:21])[C:28]([O:29][CH3:30])=[C:27]([O:31][CH3:32])[CH:26]=3)[CH2:38][CH2:37]2)=[O:20])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2
Reactant: CCOC(=O)Nc1nc2ccc(OC)cc2nc1OC
Reactant: COc1cc(N2CCNCC2)cc(OC)c1OC
Product: COc1ccc2nc(NC(=O)N3CCN(c4cc(OC)c(OC)c(OC)c4)CC3)c(OC)nc2c1
Yield: 92 %

Procedure:
Ethyl N-(3,6-dimethoxyquinoxalin-2-yl)carbamate and 1-(3,4,5-trimethoxyphenyl)piperazine were reacted by the same way with the example 148 to obtain the titled compound (yield, 92%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[CH3:9][N:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:15]=[O:16]>ClCCl>[C:5]([C:13]1[CH:12]=[C:11]([CH:15]=[O:16])[N:10]([CH3:9])[CH:14]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: Cn1cccc1C=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cc(C=O)n(C)c1
Yield: 97.8 %

Procedure:
To a suspension of aluminium chloride (22.9 g, 172 mmol) in anhydrous dichloromethane (100 ml) and acetylchloride (4.5 g, 57.3 mmol)was added a solution of 1-methyl pyrrole-2-carboxaldehyde (5 g, 46 mmol) in anhydrous. dichloromethane (20 ml). The mixture was refluxed for 90 min, poured into ice and stirred until melted. The layers were separated and aqueous layer was extracted with dichloromethane (2×100 ml). The organic phase and extracts were combined, dried over sodium sulfate. The solvent was removed in vacuo to give the title compound (6.8 g, 94%), 1H NMR (d6-DMSO) d 9.6 (s, 1H), 7.9 (s, 1H), 7.4 (s, 1H), 3.9 (s, 3H),2.4 (s,3H)
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[S:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27]Cl>>[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][N:8]1[C:9]([S:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19]
Reactant: Cc1cc(C)cc(Sc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: ClCc1ccccn1
Product: Cc1cc(C)cc(Sc2c(C(C)C)c(=O)[nH]c(=O)n2Cc2ccccn2)c1
Yield: 29.4 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 2-picolyl chloride were reacted by the same way with the example 1 to obtain the titled compound (112 mg, yield: 29.4%).
Reaction SMILES: [C:1]([CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[CH:7]=1)#[N:2].[Cl:13][C:14]([Cl:29])([Cl:28])[C:15]([NH:17][C:18]1[CH:19]=[C:20]([O:24][C:25](Cl)=[O:26])[CH:21]=[CH:22][CH:23]=1)=[O:16]>C(#N)C>[Cl:13][C:14]([Cl:28])([Cl:29])[C:15]([NH:17][C:18]1[CH:19]=[C:20]([O:24][C:25](=[O:26])[N:5]([CH2:4][CH2:3][C:1]#[N:2])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[CH:7]=2)[CH:21]=[CH:22][CH:23]=1)=[O:16]
Reactant: Cc1cccc(NCCC#N)c1
Reactant: O=C(Cl)Oc1cccc(NC(=O)C(Cl)(Cl)Cl)c1
Solvent: CC#N
Product: Cc1cccc(N(CCC#N)C(=O)Oc2cccc(NC(=O)C(Cl)(Cl)Cl)c2)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Into a solution of 16.0 g N-(2-cyanoethyl)-3-methylaniline in 100 ml acetonitrile, 31.7 g chloroformic acid-3-(trichloromethylcarbonylamino)-phenyl ester taken up in 100 ml acetonitrile is added dropwise. The reaction mixture is heated to boiling for another 10 minutes, cooled, stirred in 500 ml ice water, the precipitate filtered and recrystallized from isopropanol.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[S:10])[NH2:9])=[CH:4][C:3]=1[O:11][CH3:12].Cl[CH2:14][C:15](N(C)C)=O.[CH:20]([OH:23])([CH3:22])[CH3:21]>>[CH:20]([O:23][C:14]1[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([O:11][CH3:12])[CH:4]=2)[S:10][CH:15]=1)([CH3:22])[CH3:21]
Reactant: CN(C)C(=O)CCl
Reactant: CC(C)O
Reactant: COc1cc(C(N)=S)ccc1O
Product: COc1cc(-c2nc(OC(C)C)cs2)ccc1O
Yield: 46 %

Procedure:
4-Hydroxy-3-methoxybenzenecarbothioamide (3.0 g, 16.37 mmol) (Example 35) and 2-chloro-N,N-dimethylacetamide were dissolved in isopropanol, and the mixture was heated at reflux for 12 h. The solvent was removed under reduced pressure. The residue was washed with water and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and the solvent was removed in vacuo. Purification via silica gel flash chromatography (ethyl acetate/hexane (v/v)=1:4) yielded a solid (1.99 g, 46%). 1H NMR (400 MHz, CDCl3) δ 1.42 (d, 6H), 3.91 (s, 3H), 4.64 (septet, 1H), 5.95 (s, 1H), 6.0 (br, 1H), 6.91 (d, 1H), 7.36 (d, 1H), 7.53 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH:4]=[CH:5][C:6]12[CH2:13][CH2:12][C:9]([C:14]3[NH:22][C:21]4[C:20](=[O:23])[NH:19][C:18](=[O:24])[N:17]([CH2:25][CH2:26][CH3:27])[C:16]=4[N:15]=3)([CH2:10][CH2:11]1)[CH2:8][CH2:7]2>C1COCC1.[Pd]>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C:6]12[CH2:11][CH2:10][C:9]([C:14]3[NH:22][C:21]4[C:20](=[O:23])[NH:19][C:18](=[O:24])[N:17]([CH2:25][CH2:26][CH3:27])[C:16]=4[N:15]=3)([CH2:8][CH2:7]1)[CH2:12][CH2:13]2
Reactant: CCCn1c(=O)[nH]c(=O)c2[nH]c(C34CCC(C=CC(=O)OC)(CC3)CC4)nc21
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCn1c(=O)[nH]c(=O)c2[nH]c(C34CCC(CCC(=O)OC)(CC3)CC4)nc21
Reaction time: 6 h
Yield: 92.8 %

Procedure:
3-[4-(2,6-Dioxo-3-propyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-acrylic acid methyl ester (300 mg) was dissolved in 20 mL of THF. 10% Pd on C (25 mg) was added and the resulting reaction mixture was hydrogenated under 50 psi of H2 at rt for 6 h. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to afford 280 mg of the desired product.