Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[OH:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[CH2:33](Br)[CH:34]=[CH2:35]>CC#N.C(Cl)Cl>[CH2:35]([O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:8]1[NH:9][C:10]2[C:15]([C:7]=1[CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[CH:14][CH:13]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[CH:11]=2)[CH:34]=[CH2:33]
Reactant: C=CCBr
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3O)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: C=CCOc1ccccc1-c1[nH]c2cc(C(=O)OC)ccc2c1C1CCCCC1
Temperature: 50 °C

Procedure:
Methyl 3-cyclohexyl-2-(2-hydroxyphenyl)-1H-indole-6-carboxylate (prepared as described in published International patent application WO 2006/046030) was suspended in MeCN/DCM (1:1, 0.1M) and K2CO3 (1 eq) was added. To the stirred mixture allyl bromide (1.1 eq) was added and the mixture was warmed to 50° C. After 4 h a further 0.5 eq of allyl bromide were added and heating was continued over night. The mixture was filtered and the filter cake was extracted with hot ethyl acetate. The combined filtrates were evaporated in vacuo. The residual material was dissolved in hot DCM and precipitated by addition of PE. The precipitate was collected and dried in vacuo. The product was obtained as a beige crystalline powder. (81%). (ES+) m/z 390 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][C:14]=3[O:17][C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=3[F:25])[CH:9]=2)[N:5]=[CH:4]1)[CH3:2].[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][C:34]([N:36]=[C:37]=[S:38])=[O:35]>C1COCC1>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][C:14]=3[O:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:37]([NH:36][C:34](=[O:35])[CH2:33][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[F:26])=[S:38])=[CH:20][C:19]=3[F:25])[CH:9]=2)[N:5]=[CH:4]1)[CH3:2]
Reactant: CCn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Reactant: O=C(Cc1ccccc1F)N=C=S
Solvent: C1CCOC1
Product: CCn1cnc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5F)cc4F)c3s2)c1
Reaction time: 1 h
Yield: 67.4 %

Procedure:
To a suspension of the 308 (385 mg, 0.99 mmol) in THF (10 mL) was added 2-(2-fluorophenyl)acetyl isothiocyanate (263 mg, 1.49 mmol) and the reaction mixture was stirred for 1 hr, transferred onto a flash chromatography column and eluted with EtOAc/MeOH 19:1, to afford title compound 310a (366.9 mg, 67% yield) as a creamy solid. 1HNMR: (DMSO-d6) δ (ppm): 12.42 (s, 1H), 11.87 (s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.02 (d, J=11.5 Hz, 1H), 7.95 (s, 1H), 7.78 (s, 1H), 7.67 (s, 1H), 7.52 (m, 2H), 7.42 (m, 2H), 7.25 (m, 2H), 7.06 (d, J=5.5 Hz, 1H), 4.04 (q, J=7.3 Hz, 2H), 3.92 (s, 2H), 7.4 (t, J=7.3 Hz, 3H). MS (m/z): 550.0 (M+1).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1.C(OC([N:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1)=O)(C)(C)C.O>C(OCC)C>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:24]2[CH2:25][CH2:26][NH:21][CH2:22][CH:23]=2)=[N:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Clc1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: Clc1ccc(C2=CCNCC2)nc1
Reaction time: 0.5 h

Procedure:
Butyllithium (15% in hexane; 7.6 ml) was added dropwise to a solution of 2-bromo-5-chloropyridine (2.0 g) in diethyl ether (50 ml) at −78° C. and, after one hour, a solution of N-tert-butoxycarbonyl-4-piperidinone (2.1 g) in diethyl ether (10 ml) was added dropwise. After 30 minutes, water was cautiously added, and the mixture was extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was treated with thionyl chloride (3 g) for 24 hours, and the concentrated reaction solution was purified by preparative HPLC. The product with the molecular weight of 194.67 (C10H11ClN2); MS (ESI): 195 (M+H+) was obtained in this way.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:12])[C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Cl.[C:13]([N:16]1[C:22]([CH2:24][CH3:25])([CH3:23])[C:20](=[O:21])[NH:19][C:17]1=[S:18])(=[O:15])[CH3:14]>>[C:13]([N:16]1[C:22]([CH2:24][CH3:25])([CH3:23])[C:20](=[O:21])[N:19]=[C:17]1[S:18][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N:3]([CH3:12])[CH3:2])(=[O:15])[CH3:14]
Reactant: CN(C)c1ccccc1CCl
Reactant: CCC1(C)C(=O)NC(=S)N1C(C)=O
Agent: Cl
Product: CCC1(C)C(=O)N=C(SCc2ccccc2N(C)C)N1C(C)=O

Procedure:
In the present Example, 2.27 g of 2-dimethylaminobenzylchloride hydrochloride and 2.0 g of 1-N-acetyl-5-ethyl-5-methyl-2-thiohydantoin were reacted following the procedure of Example 33. The desired compound was obtained in the form of needle-like crystal. The yield of this compound was 1.37 g with a yield ratio of 41.1%, and the melting point was 83°-85° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([I:9])[CH:3]=1.[CH3:10][N:11]([CH3:16])[CH2:12][CH2:13][CH2:14]O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:14][CH2:13][CH2:12][N:11]([CH3:16])[CH3:10])=[C:4]([I:9])[CH:3]=1
Reactant: Oc1ccc(Cl)cc1I
Reactant: CN(C)CCCO
Product: CN(C)CCCOc1ccc(Cl)cc1I

Procedure:
The title compound was synthesized using 4-chloro-2-iodophenol and 3-(dimethylamino)propan-1-ol, in an analogous procedure to that outlined in the preparation of Compound 174. 1H NMR (400 MHz, CDCl3) δ ppm 1.99-2.15 (m, 2H) 2.38 (s, 6H) 2.67 (t, J=7.33 Hz, 2H) 4.07 (t, J=6.06 Hz, 2H) 6.73 (d, J=8.84 Hz, 1H) 7.25 (d, J=2.53 Hz, 1H) 7.74 (d, J=2.53 Hz, 1H). [M+H] calc'd for C11H16Cl1NO, 339.99; found, 340.2.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]3([CH2:15][CH2:14][CH2:13][CH2:12]3)[NH:5][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:24]2[CH:25]=[N:26][NH:27][CH:28]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[NH:26]1[CH:25]=[C:24]([C:2]2[S:10][C:9]3[C:8](=[O:11])[NH:7][C:6]4([CH2:15][CH2:14][CH2:13][CH2:12]4)[NH:5][C:4]=3[CH:3]=2)[CH:28]=[N:27]1
Reactant: O=C1NC2(CCCC2)Nc2cc(Br)sc21
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C1NC2(CCCC2)Nc2cc(-c3cn[nH]c3)sc21
Yield: 27.4 %

Procedure:
A mixture of 3-amino-5-bromothiophene-2-carboxamide (0.072 g, 0.33 mmol) and p-toluenesulfonic acid monohydrate (0.013 g, 0.066 mmol) in cyclopentanone (2 mL) and acetic acid (1 mL) was stirred at 70° C. for 2 h. Then, the reaction mixture was cooled, carefully poured into sat. NaHCO3 (50 mL), and extracted with 2:1 ethyl acetate/tetrahydrofuran (2×50 mL). The combined organic layers were washed with brine (50 mL), dried over magnesium sulfate, filtered, and concentrated to give crude 6′-bromo-1′H-spiro[cyclopentane-1,2′-thieno[3,2-d]pyrimidin]-4′(3′H)-one as a brown gum (0.174 g), which was used without further purification. A mixture of the crude 6′-bromo-1′H-spiro[cyclopentane-1,2′-thieno[3,2-d]pyrimidin]-4′(3′H)-one (0.172 g), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.349 g, 1.80 mmol), 2 M sodium carbonate (1.2 mL, 2.4 mmol) and 1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride dichloromethane adduct (0.073 g, 0.090 mmol) in 1,4-dioxane (3 mL) was microwave-irradiated at 140° C. for 1 h. Then, the reaction mixture was cooled, and concentrated with silica gel, and the residue was purified by flash chromatography (Combiflash, silica gel, ethyl acetate to 90:10 ethyl acetate/methanol), and purified again by flash chromatography (Combiflash, silica gel, dichloromethane to 90:10 dichloromethane/methanol) to give the title compound (0.045 g, 2 step yield 50%) as a yellow solid:
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:6]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[CH:5][CH:4]=1.[OH:23][C:24]1[CH:25]=[C:26]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C(#N)C>[CH3:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:7]1[N:8]=[C:3]([CH2:2][O:23][C:24]2[CH:25]=[C:26]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=2)[CH:4]=[CH:5][C:6]=1[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[F:22]
Reactant: CCOC(=O)CCc1cc(O)cc(OC)c1
Reactant: COc1ccc(F)c(-c2ccc(CCl)nc2CC(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1cc(OC)cc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1
Yield: 94.7 %

Procedure:
To a solution of 6-(chloromethyl)-2-(2,2-dimethylpropyl)-3-(2-fluoro-5-methoxyphenyl)pyridine (300 mg) in acetonitrile (10 mL) were added ethyl 3-(3-hydroxy-5-methoxyphenyl)propanoate (270 mg) and cesium carbonate (510 mg), and the mixture was heated under reflux for 15 hr. Ethyl acetate was added to the reaction mixture, and the insoluble material was filtered off. The solvent in the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (450 mg) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19][CH2:18][C:7]=3[N:8](C(OC(C)(C)C)=O)[C:9]=2[CH:10]=1.[CH2:29]([O:36][C:37]1[CH:42]=[CH:41][NH:40][C:39](=[O:43])[CH:38]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([O:36][C:37]1[CH:42]=[CH:41][N:40]([C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[CH2:19][CH2:18][C:7]=4[NH:8][C:9]=3[CH:10]=2)[C:39](=[O:43])[CH:38]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(c3ccc(Br)cc3n2C(=O)OC(C)(C)C)C1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Product: CC(C)(C)OC(=O)N1CCc2[nH]c3cc(-n4ccc(OCc5ccccc5)cc4=O)ccc3c2C1
Yield: 12.1 %

Procedure:
Prepared from di-tert-butyl 7-bromo-3,4-dihydro-1H-pyrido[4,3-b]indole-2,5-dicarboxylate (1.24 g, 2.72 mmol) and 4-benzyloxypyridone (547 mg, 2.72 mmol) according to the procedure of Example 1 (step c). Purification by flash column chromatography (silica gel, hexanes/ethyl acetate, 100:0 to 80:20 to 50:50 to 25:75 then 0:100) gave the title compound (155 mg, 10%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 9.40 (br s, 1H), 7.44-7.38 (m, 5H), 7.30 (d, J=7.5 Hz, 1H), 7.22 (d, J=8.2 Hz, 1H), 7.16 (s, 1H), 6.82 (dd, J=8.2, 1.4 Hz, 1H), 6.12-6.09 (m, 2H), 5.09 (s, 2H), 4.46 (br s, 2H), 3.70 (br m, 2H), 2.54 (br m, 2H), 1.50 (s, 9H).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:8][C:7]2[C:9]3[C:14]([C:15](=[O:18])[C:16](=[O:17])[C:6]=2[S:5][CH2:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:38]1[CH:43]=[CH:42][CH:41]=[C:40](O)[CH:39]=1.N(/C(OCC)=O)=N/C(OCC)=O>O1CCCC1>[N:38]1[CH:43]=[CH:42][CH:41]=[C:40]([O:1][CH2:2][CH:3]2[O:8][C:7]3[C:9]4[C:14]([C:15](=[O:18])[C:16](=[O:17])[C:6]=3[S:5][CH2:4]2)=[CH:13][CH:12]=[CH:11][CH:10]=4)[CH:39]=1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC(CO)O2
Reactant: Oc1cccnc1
Agent: CCOC(=O)/N=N\C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1C(=O)c2ccccc2C2=C1SCC(COc1cccnc1)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.3 %

Procedure:
To a solution of 2-(hydroxymethyl)-2,3-dihydronaphtho[1,2-b][1,4]oxathiine-5,6-dione (0.35 g, 1.34 mmol) in tetrahydrofuran (10.0 mL) was added triphenylphosphine (1.4 g, 5.34 mmol) and pyridin-3-ol (0.507 g, 5.34 mmol) followed by diethyl (Z)-diazene-1,2-dicarboxylate (0.53 mL, 3.34 mmol). The reaction mixture was stirred at room temperature for 8 hours. The reaction was quenched by addition of water (30 mL). The aqueous layer was extracted with dichloromethane (2×20 mL). The organic extracts were combined and extracted thrice with 1.0N HCl (10 mL). The HCl extracts were combined and its pH adjusted to 9 with a saturated sodium carbonate solution. The aqueous layer was extracted with dichloromethane (2×20 mL), extracts combined, dried with sodium sulfate and concentrated under reduced pressure. The crude mixture was purified by flash column chromatography (SiO2, 50% EtOAc in hexanes to 80% EtOAc in hexanes) to give the product as a purple solid (0.065 g, 14%). M.p.=153-155° C.; 400 MHz 1H NMR (CDCl3) δ: 8.43-8.35 (m, 1H), 8.33-8.24 (m, 1H), 8.05-7.94 (m, 1H), 7.72-7.56 (m, 2H), 7.56-7.4 (m, 2H), 7.33-7.2 (m, 1H), 4.98-4.86 (m, 1H), 4.54-4.34 (m, 2H), 3.34-3.16 (m, 2H); LCMS: 340 [M+H].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[N:15]=2)[C:12](OC)=[N:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28][O:29][C:30]1[CH:39]=[CH:38][C:33]([C:34]([NH:36][NH2:37])=O)=[CH:32][CH:31]=1>CO.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]2[C:34]([C:33]3[CH:38]=[CH:39][C:30]([O:29][CH3:28])=[CH:31][CH:32]=3)=[N:36][N:37]=[C:12]2[CH:13]1[C:14]1[O:18][N:17]=[C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[N:15]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC1=NCCN(C(=O)OC(C)(C)C)C1c1nc(-c2cccc(Cl)c2)no1
Reactant: COc1ccc(C(=O)NN)cc1
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nnc3n2CCN(C(=O)OC(C)(C)C)C3c2nc(-c3cccc(Cl)c3)no2)cc1
Yield: 20.3 %

Procedure:
6-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-5-methoxy-3,6-dihydro-2H-pyrazine-1-carboxylic acid tert-butyl ester (284.6 mg, 0.70 mmol) and 4-methoxy-benzoic acid hydrazide (116.2 mg, 0.70 mmol) under argon in methanol (10 mL) were heated at reflux for 3 days. After cooling, the reaction mixture was diluted with ethyl acetate and then washed with water (3 times) and brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel using 40-85% ethyl acetate in hexanes afforded the titled compound (72.5 mg, 20%). 1H NMR (CDCl3) δ (ppm): 8.07 (m, 1H), 7.96 (m, 1H), 7.64 (m, 2H), 7.47 (m, 2H), 7.05 (m, 2H), 6.04 (m, 1H), 4.11 (m, 2H), 3.89 (s, 3H), 3.86 (m, 2H), 3.55 (m, 1H), 3.31 (m, 1H), 1.28 (bs, 9H).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[N:14]=[C:13]([NH2:15])[C:12]([O:16][CH3:17])=[CH:11][CH:10]=2)[CH2:3]1.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[C:21]([Cl:29])[CH:20]=1>N1C=CC=CC=1.ClCCl>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:15][C:13]2[C:12]([O:16][CH3:17])=[CH:11][CH:10]=[C:9]([N:4]3[CH2:3][C@H:2]([CH3:1])[NH:7][C@H:6]([CH3:8])[CH2:5]3)[N:14]=2)(=[O:26])=[O:27])=[C:21]([Cl:29])[CH:20]=1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)nc1N
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)nc1NS(=O)(=O)c1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
6-[cis-3,5-dimethyl-1-piperazinyl]-3-(methyloxy)-2-pyridinamine (D7, Method C) (473 mg, 2 mmol) was dissolved in pyridine (5 ml) and dichloromethane (5 ml). 4-Bromo-2-chlorobenzene sulfonyl chloride (870 mg, 3 mmol) was added and the solution stirred at room temperature for 5 hours. The mixture was concentrated in vacuo and azeotroped with methanol. The residue was loaded on to an SCX cartridge (Varian, 10 g) in methanol, washed with methanol and the basic products eluted with 2M ammonia/methanol. The product containing fractions were concentrated in vacuo and purified by flash chromatography (Biotage SP4, 40+S, 0-20% 2M ammonia/methanol in dichloromethane to afford the title product (D11), 478 mg, MS (ES+) m/e 489/491/493 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1=[C:3]([CH3:9])[C:4]([O:6][C:7]1=[O:8])=O.N1C=CC=CC=1.[NH2:16][CH2:17][CH2:18][CH2:19][Si:20]([O:27][CH2:28][CH3:29])([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23]>C1CCCCC1>[CH3:9][C:3]1[C:4](=[O:6])[N:16]([CH2:17][CH2:18][CH2:19][Si:20]([O:27][CH2:28][CH3:29])([O:21][CH2:22][CH3:23])[O:24][CH2:25][CH3:26])[C:7](=[O:8])[C:2]=1[CH3:1]
Reactant: CC1=C(C)C(=O)OC1=O
Reactant: CCO[Si](CCCN)(OCC)OCC
Solvent: c1ccncc1
Solvent: C1CCCCC1
Product: CCO[Si](CCCN1C(=O)C(C)=C(C)C1=O)(OCC)OCC
Temperature: 25 °C
Yield: 42.9 %

Procedure:
To an appropriately sized reaction vessel equipped with a thermowell, Dean Stark trap connected to condenser with a nitrogen inlet, addition funnel, and mechanical stirrer. was charged 2.2 L of cyclohexane followed by dimethylmaleic anhydride (DMMA, 107.8 g, 0.85 mol) and pyridine (3.5 mL, 0.042 mol) with stirring. A slight endotherm was observed (20 to 14° C.) as the dimethylmaleic anhydride dissolved in the cyclohexane. The mixture was warmed to 25° C. and a turbid solution was observed. The addition funnel was charged with 3-aminopropyltriethoxysilane (189.2 g, 200 mL, 0.85 mol) which was added slowly over 15 minutes. An additional 300 mL cyclohexane was added to rinse in the 3-aminopropyltriethoxysilane and the addition funnel was replaced by a stopper. The mixture immediately exothermed to 24° C. and a white turbid solution was observed. The mixture was heated carefully (to avoid excessive foaming) over 30 minutes to reflux. A clear solution was observed at 40° C. and again turned to a white turbid solution at 70° C. The reaction mixture was refluxed for 1 h at 70° C. and aliquot was analyzed and indicated that the reaction was completed (88% product with 11% DMMA and no 3-aminopropyltriethoxysilane). The reaction mixture was cooled to room temperature and the cyclohexane layer decanted to a 5 L flask leaving the white polymeric residue (120 g). The cyclohexane layer was concentrated on the rotary evaporator at 60° C. bath temperature. The residue was transferred to a 500 mL RBF and dried under high vacuum for 2 h at 7° C. bath temperature to give 132 g of crude product as a viscous oil (crude purity 96.5% with 3.2% DMMA). The crude product was further purified via Kugelrohr distillation at 150-170° C. oven temperature under vacuum 0.15-0.2 torr to give 64.4 g (23% yield) of product with 99.7% purity by gas chromatography (GC) as a clear liquid. 1H NMR and mass were consistent with the desired structure. Pot residue was 60.6 g and total polymeric residue was 180.1 g (64%). Data: GC analysis performed on a DB-5MS Column, 25 meters, 0.32 mm ID, 0.52 μm film, heat from 75° C. to 200° C. @15° C./min, then 200° C. to 300° C. hold for 2 min @300° C., Injector temperature: 200° C., Detector temperature: 350° C., Retention time: 9.250 minutes.
Reaction SMILES: [O:1]=[S:2]1(=[O:27])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:15](=[C:16]([N+:18]([O-])=O)[CH:17]=2)[NH:14][C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:12]3)[CH2:4][CH2:3]1.[O:28]1[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]1>>[O:28]1[CH2:33][CH2:32][CH:31]([NH:18][C:16]2[CH:17]=[C:9]([CH2:8][N:5]3[CH2:6][CH2:7][S:2](=[O:27])(=[O:1])[CH2:3][CH2:4]3)[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:12]3)[CH2:30][CH2:29]1
Reactant: O=[N+]([O-])c1cc(CN2CCS(=O)(=O)CC2)cc2cc(-c3ccccc3)[nH]c12
Reactant: O=C1CCOCC1
Product: O=S1(=O)CCN(Cc2cc(NC3CCOCC3)c3[nH]c(-c4ccccc4)cc3c2)CC1

Procedure:
5-(1,1-Dioxo-thiomorpholin-4-yl)methyl-2-phenyl-7-nitro-1H-indole prepared in Step B and tetrahydropyran-4-one were reacted according to the same procedure as Example 1 to give the title compound.
Reaction SMILES: C[N:2](C)[CH:3]=[N:4][C:5]([C:7]1[N:16]=[C:15]2[N:9]([CH2:10][CH2:11][O:12][C:13]3[CH:20]=[C:19]([Cl:21])[N:18]=[CH:17][C:14]=32)[CH:8]=1)=O.Cl.[CH:24]1([NH:30]N)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[Cl:21][C:19]1[N:18]=[CH:17][C:14]2[C:15]3[N:9]([CH2:10][CH2:11][O:12][C:13]=2[CH:20]=1)[CH:8]=[C:7]([C:5]1[N:30]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[N:2]=[CH:3][N:4]=1)[N:16]=3
Reactant: NNC1CCCCC1
Reactant: CN(C)C=NC(=O)c1cn2c(n1)-c1cnc(Cl)cc1OCC2
Agent: Cl
Product: Clc1cc2c(cn1)-c1nc(-c3ncnn3C3CCCCC3)cn1CCO2

Procedure:
Following the procedures of Example 378, 8-Chloro-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulene-2-carboxylic acid 1-dimethylamino-methylideneamide was reacted with cyclohexylhydrazine hydrochloride to give 8-Chloro-2-(2-cyclohexyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulene (MS (ESI+) 371.2/373.2) which was reacted with L-prolineamide to give 409. MS (ESI+) 449.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([CH2:23][C:24]#[C:25][CH3:26])[C:21]3[C:20](=[O:27])[NH:19][C:18](=[O:28])[N:17]([CH2:29][O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:44][CH2:45][O:46][CH2:47][CH3:48]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([CH2:23][C:24]#[C:25][CH3:26])[C:21]3[C:20](=[O:27])[N:19]([CH2:44][CH2:45][O:46][CH2:47][CH3:48])[C:18](=[O:28])[N:17]([CH2:29][O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)[nH]c(=O)n2COC(=O)C(C)(C)C
Reactant: CCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)n(CCOCC)c(=O)n2COC(=O)C(C)(C)C
Temperature: 60 °C
Reaction time: 5 h

Procedure:
4-[7-(2-Butynyl)-3-(2,2-dimethylpropionyloxymethyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (40 mg) and potassium carbonate (17 mg) were dissolved in N,N-dimethylformamide (1.5 ml), and 2-bromoethylethyl ether (14 μl) was added to the solution. The mixture was stirred at 60° C. for 5 hours, diluted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. After removing the solvent by distillation, the residue was purified by silica gel column chromatography to give 4-[7-(2-butynyl)-3-(2,2-dimethylpropionyloxymethyl)-1-(2-ethoxyethyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester from the elution fraction of hexane-ethyl acetate (1:1). The obtained 4-[7-(2-butynyl)-3-(2,2-dimethylpropionyloxymethyl)-1-(2-ethoxyethyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester was dissolved in a solvent mixture of tetrahydrofuran (1.0 ml) and methanol (0.5 ml), sodium hydride (5 mg) was added to the solution, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was neutralized with 2 N hydrochloric acid, and extracted with ethyl acetate. Then, the organic layer was dried over anhydrous magnesium sulfate and the solvent was removed by distillation. The obtained residue was dissolved in N,N-dimethylformamide (1 ml), and potassium carbonate (10 mg) and methyl bromoacetate (10 μl) were added to the solution. The mixture was stirred at room temperature for 2 hours, diluted with ethyl acetate, and washed with water. After the organic layer was concentrated by distillation, the residue was dissolved in trifluoroacetic acid (0.5 ml), and the solution was stirred at room temperature for 30 minutes. After removing the solvent by distillation, a half of the residue was purified by HPLC with a reversed phase column using water-acetonitrile-trifluoroacetic acid system as elution solvent to give 6.2 mg of the title compound.
Reaction SMILES: C1C=CC2N=C[NH:9][C:7](=[O:8])C=2C=1.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([CH3:22])=O)=[C:15]([CH3:23])[CH:14]=1>>[CH3:22][C:20]1[NH:9][C:7](=[O:8])[C:17]2[C:16](=[C:15]([CH3:23])[CH:14]=[C:13]([CH3:12])[CH:18]=2)[N:19]=1
Reactant: O=c1[nH]cnc2ccccc12
Reactant: CC(=O)Nc1ccc(C)cc1C
Product: Cc1cc(C)c2nc(C)[nH]c(=O)c2c1

Procedure:
The quinazolinone used as starting material was obtained using the first part of the process described in Example 1 concerning the preparation of starting materials except that 2,4-dimethylacetanilide was used in place of 3,4-dimethylacetanilide. Only one isomer, 3,4-dihydro-2,6,8-trimethylquinazolin-4-one, was obtained. Sodium hydride (2.39 g) was added to a stirred suspension of the product thus obtained (9.3 g) in dimethylformamide (100 ml) and the mixture was stirred at laboratory temperature for 1 hour. A solution of chloromethyl pivalate (8.23 ml) in dimethylformamide (20 ml) was added and the mixture was stirred at laboratory temperature for 18 hours, then poured onto a mixture of ice water (350 ml). The precipitate was filtered off, dried and purified by chromatography on a silica gel column using methylene chloride as eluent. There was thus obtained 3,4-dihydro-2,6,8-trimethyl-3-pivaloyloxymethylquinazolin-4-one (8.7 g).