Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:5][CH:4]=1.Cl.O1[CH:22]=[CH:21][C:20](=[O:23])[CH:19]=[CH:18]1>O>[O:23]=[C:20]1[CH:21]=[CH:22][N:2]([C:3]2[CH:4]=[CH:5][C:6]([C:9]3[N:10]=[CH:11][C:12](=[O:15])[NH:13][CH:14]=3)=[CH:7][CH:8]=2)[CH:18]=[CH:19]1
Reactant: O=c1ccocc1
Reactant: Nc1ccc(-c2c[nH]c(=O)cn2)cc1
Agent: Cl
Solvent: O
Product: O=c1ccn(-c2ccc(-c3c[nH]c(=O)cn3)cc2)cc1

Procedure:
A stirred mixture of 5-(4-aminophenyl)-2(1H)pyrazinone hydrochloride (1.5 g, from hydrolysis of the corresponding acetamido derivative with hydrochloric acid) 4H-pyran-4-one (0.71 g) and water (15 ml) was heated under reflux for 21/2 hours under a nitrogen atmosphere. The resultant solution was neutralised to give a solid, 1.79 g, m.p. 345° C. (dec). Recrystallisation from aqueous ethanol gave the title compound. 0.93 g. m.p. 354-357° C. (dec).
Reaction SMILES: [SH:1][CH:2]([CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[CH:16]=1)[CH:3]([P:8](=[O:11])([OH:10])[OH:9])[P:4](=[O:7])([OH:6])[OH:5]>O=[Pt]=O.O>[SH:1][CH:2]([CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=1)[CH:3]([P:4](=[O:5])([OH:6])[OH:7])[P:8](=[O:9])([OH:10])[OH:11]
Reactant: O=[N+]([O-])c1cccc(CCCC(S)C(P(=O)(O)O)P(=O)(O)O)c1
Agent: O=[Pt]=O
Solvent: O
Product: Nc1cccc(CCCC(S)C(P(=O)(O)O)P(=O)(O)O)c1

Procedure:
[2-Mercapto-5-(3-nitrophenyl)pentylidene]bis[phosphonic acid] (0.25 mmol), distilled water (75 ml) and PtO2 (0.20 mg) are placed in a 500 ml Parr hydrogenation bottle. The mixture is hydrogenated at room temperature (40 psi) for 6 hours. The solution is filtered through celite and concentrated under reduced pressure. The resultant solid is triturated in acetone and then further dried overnight in a vacuum desiccator.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:21][C:22]([OH:24])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1)[CH3:2].[CH3:25][S:26]([NH2:29])(=[O:28])=[O:27].Cl.CN=C=NCCCN(C)C.CN(C1C=CC=CN=1)C>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH2:21][C:22]([NH:29][S:26]([CH3:25])(=[O:28])=[O:27])=[O:24])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1)[CH3:2]
Reactant: CCc1cc(CC(=O)O)ccc1OCc1ccc2ccccc2n1
Reactant: CS(N)(=O)=O
Agent: CN(C)c1ccccn1
Agent: CN=C=NCCCN(C)C
Agent: Cl
Product: CCc1cc(CC(=O)NS(C)(=O)=O)ccc1OCc1ccc2ccccc2n1

Procedure:
Analogously to the procedure of Example XVI, the title compound is prepared from 1.7 g (5.3 mmol) of the compound from Example XXXV, 0.6 g (6 mmol) of methanesulphonamide, 1.2 g (6 mmol) of N-methyl-N'-dimethylaminopropylcarbodiimide hydrochloride and 0.8 g (6 mmol) of dimethylaminopyridine.
Reaction SMILES: C(=[N:8][N:9]1[CH2:14][CH2:13][N:12]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-:26])=[O:25])(=[O:17])=[O:16])[CH2:11][CH2:10]1)C1C=CC=CC=1.Cl.C(=O)C1C=CC=CC=1>>[N+:24]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[S:15]([N:12]1[CH2:11][CH2:10][N:9]([NH2:8])[CH2:14][CH2:13]1)(=[O:17])=[O:16])([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N1CCN(N=Cc2ccccc2)CC1
Agent: Cl
Solvent: O=Cc1ccccc1
Product: NN1CCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CC1
Reaction time: 6 h
Yield: 95.9 %

Procedure:
To the compound (6.61 g, 17.67 mmol) obtained in step B was added 1N hydrochloric acid, and generated benzaldehyde was evaporated by azeotropic distillation in a flask mounted with Dean-Stark water removing apparatus (Dean-Stark trap) for 6 hr. The reaction mixture was cooled, washed with diethyl ether, and the aqueous layer was alkalified with potassium carbonate. The layer was extracted twice with ethyl acetate (150 ml), and the organic layer was combined. The mixture was washed with saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solvent was concentrated under reduced pressure to give the title compound (4.85 g, yield 96%) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:23]O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:9]([O:11][CH3:23])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)C(c1ccccc1)c1ccc(Br)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C(c1ccccc1)c1ccc(Br)cc1
Temperature: 60 °C
Reaction time: 14 h

Procedure:
To a solution of compound 2-(4-Bromophenyl)-2-phenylacetic acid, 14-c, (5.6 g, 19.3 mmol) in methanol (200 mL) was added concentrated sulfuric acid (6 mL) and the reaction mixture was stirred at 60° C. for 14 h. The resulting solution was concentrated and ice-water was added. The aqueous layer was extracted by EA. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to yield title compound, 14-d, (5.5 g, 93%). 1H NMR (300 MHz, CDCl3) δ3.73 (s, 3H), 4.96 (s, 1H), 7.16 (d, J=8.4 Hz, 2H), 7.25-7.30 (m, 5H), 7.42 (d, J=8.4 Hz, 2H). LC-MS: (M+H)+ 304, 306.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[N:15]=[C:14]([S:16][CH3:17])[CH:13]=[C:12]([Sn](CCCC)(CCCC)CCCC)[N:11]=1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:8][C:7]1[C:2]([C:12]2[CH:13]=[C:14]([S:16][CH3:17])[N:15]=[C:10]([CH3:9])[N:11]=2)=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(SC)nc(C)n1
Reactant: Clc1nccnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CSc1cc(-c2nccnc2Cl)nc(C)n1
Temperature: 110 °C
Reaction time: 48 h
Yield: 20.8 %

Procedure:
A mixture of 2,3-dichloropyrazine (0.034 mL, 0.228 mmol, Aldrich, St. Louis, Mo.), 2-methyl-4-(methylthio)-6-(tributylstannyl)pyrimidine (98 mg, 0.228 mmol) and tetrakis(triphenylphosphine)palladium (26.4 mg, 0.023 mmol, Strem Chemicals, Inc., Newburyport, Mass.) in toluene (2 mL) was stirred at 110° C. for 48 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography eluting with 20% EtOAc/CH2Cl2 to give 4-(3-chloropyrazin-2-yl)-2-methyl-6-(methylthio)pyrimidine (12 mg, 21% yield). 1H NMR (300 MHz, CDCl3) δ 8.63 (d, J=2.05 Hz, 1H); 8.47 (d, J=2.19 Hz, 1H); 7.44 (s, 1H); 2.77 (s, 3H); 2.56 (s, 3H). m/z (ESI, +ve ion) 253 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9](=[O:21])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[C:12]([NH2:20])[CH:11]=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:31]=[N:32][S:33][CH:34]=2)=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9](=[O:21])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[C:12]([NH:20][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[N:31]=[N:32][S:33][CH:34]=3)=[CH:26][CH:25]=2)[CH:11]=1
Reactant: CC(=O)Nc1ccc(C(=O)NCc2ccccn2)cc1N
Reactant: BrCc1ccc(-c2csnn2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(=O)Nc1ccc(C(=O)NCc2ccccn2)cc1NCc1ccc(-c2csnn2)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 64.3 %

Procedure:
A solution of 0.800 g of N-(2-pyridylmethyl)-4-acetylamino-3-aminobenzamide in 10 ml of methanol were added 1.08 g of 4-(4-bromomethylphenyl)-1,2,3-thiadiazole and 0.710 g of sodium hydrogencarbonate, and the mixture was stirred at 70° C. for 1 hour. The reaction solution was concentrated, and was purified through silica-gel column chromatography (eluent: a mixture of ethyl acetate and methanol at a ratio of 9:1) to give 0.830 g of N-(2-pyridylmethyl)-4-acetylamino-3-[4-(1,2,3-thiadiazol-4-yl)benzylamino]benzamide
Reaction SMILES: O[C:2]1[C:3]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:4]=2[N:5]=[CH:6][N:7]=1.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:2]1[C:3]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1c(C)n(Cc2ccccc2)c2ncnc(O)c12
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1c(C)n(Cc2ccccc2)c2ncnc(Cl)c12
Temperature: 25 °C

Procedure:
2.5 g of 4-hydroxy-5,6-dimethyl-7-benzyl-pyrrolo[2,3-d]pyrimidine are boiled at reflux with 20 ml of POCl3 for 2.5 hours. The brown solution is cooled to RT and poured onto ice-water. The brownish precipitate is filtered off with suction and dissolved in ethyl acetate. The ethyl acetate phase is washed with water, dried and concentrated in a rotary evaporator until white crystals form. 4-Chloro-5,6-dimethyl-7-benzyl-pyrrolo[2,3-d]-pyrimidine is obtained in the form of white crystals having a melting point of 115-116° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH3:9][O:10][C:11](=[O:37])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)[C:20](=[O:29])[C:21]#[C:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:13]=1>>[CH3:9][O:10][C:11](=[O:37])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]2[C:30]3[C:31](=[C:32]([F:36])[CH:33]=[CH:34][CH:35]=3)/[C:21](=[C:22](\[C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)/[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)/[C:20]2=[O:29])[CH:13]=1
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2cccc(F)c2)c1
Reactant: Clc1ccc(I)cc1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(\c3ccccc3)c3ccc(Cl)cc3)c3c(F)cccc32)c1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 1-chloro-4-iodo-benzene (commercially available) and 3-{[(3-fluoro-phenyl)-(3-phenyl-propynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (300 Hz, CDCl3): δppm 4.97 (s, 2H), 6.39-6.51 (m, 2H), 7.25-7.45 (m, 11H), 7.53 (d, 1H), 7.99 (d, 1H), 8.00 (s, 1H).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[N:9]([CH3:29])[CH:10]=[C:11]([C:27]#[N:28])[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH:25]=[O:26])=[CH:15][CH:14]=1)=[O:7])[CH3:4].O>CO>[CH2:3]([O:5][C:6]([C:8]1[N:9]([CH3:29])[CH:10]=[C:11]([C:27]#[N:28])[C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:25][OH:26])=[CH:17][CH:18]=1)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1c(-c2ccc(-c3ccccc3C=O)cc2)c(C#N)cn1C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)c1c(-c2ccc(-c3ccccc3CO)cc2)c(C#N)cn1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Add sodium borohydride (0.79 g, 2.1 mmol) to 4-cyano-3-(2′-formyl-biphenyl-4-yl)-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (0.50 g, 1.40 mmol, prepared in example E-23) in methanol at 0° C. with stirring. After 1 hour, allow the reaction mixture to warm to ambient temperature. After 2 hours, pour the reaction mixture into water and extract with ethyl acetate. Combine the organic extracts, wash with water and brine, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Purify the residue by flash chromatography eluting with ethyl acetate:hexane to provide the title compound. Mass spectrum: EI+=360.2
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]1=[O:12])[CH3:2].[Cl:13][CH2:14][CH2:15][C@@H:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:13][CH2:14][CH2:15][C@@H:16]([N:5]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:3]([CH2:1][CH3:2])[C:4]1=[O:12])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O[C@@H](CCCl)c1ccccc1
Reactant: CCn1c(=O)[nH]c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCn1c(=O)n([C@H](CCCl)c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.6 %

Procedure:
To a mixture of 1-ethyl-1,3-dihydro-benzimidazol-2-one (1 g, 6.2 mmol), (S)-(−)-3-chloro-1-phenyl-1-propanol (1.16 g, 6.8 mmol), and triphenylphosphine (1.78 g, 6.8 mmol) in anhydrous THF (25 mL) was added DIAD (1.38 g, 6.8 mmol) under nitrogen at room temperature. The mixture was stirred under nitrogen at room temperature for 18 hrs and solvent removed in vacuo. The residue was purified by a silica gel column (33% ethyl acetate in hexane) to afford 1-[(1R)-3-chloro-1-phenylpropyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one as an oil (0.5g, 26%). MS (ESI) m/z 315.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CC1(C)O[C@H]2[C@@H]3OC(C)(C)O[C@]3(C(O)=O)O[C@H]2C[O:11]1.O.OO.NC(N)=O>ClCCl>[C:3]1([CH:2]2[CH2:1][O:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC1(C)OC[C@@H]2O[C@@]3(C(=O)O)OC(C)(C)O[C@H]3[C@@H]2O1
Reactant: C=Cc1ccccc1
Agent: NC(N)=O
Agent: OO
Solvent: ClCCl
Solvent: O
Product: c1ccc(C2CO2)cc1
Temperature: 25 °C
Yield: 70 %

Procedure:
Styrene (1 g, 9.6 mmol) was taken with 100 mg Immobilized lipase and 2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid monohydrate (0.3 g, 1.03 mmol) in dry dichloromethane (15 mL) and stirred at 25° C. and added urea hydrogen peroxide (3 g, 32 mmol) portion-wise at a pH 5 for 20 hours. The reaction was monitored occasionally on TLC. The mixture was filtered and washed the residue with dichloromethane and the filtrate was reduced its volume under reduced pressure using vacuum flash evaporator. The product was purified by preparative TLC with 40% CH2Cl2/hexane. Yield: 70%; oil (Found: C, 79.91; H, 6.65. C8H8O requires C, 79.97; H, 6.71%); Rf (40% CH2Cl2/hexane) 0.55. The enantiomeric excess was determined by HPLC analysis using a Chiralcel OD column [iPrOH:hexane=0.2:99.8, flow rate 0.2 cm3 min−1], [α]D22+21.6 (c 0.7, PhH) 48% ee; {lit., [α]D22+44.8 (c 1.00, PhH), R}; νmax (neat/cm−1) 1496, 1476, 1452, 1390; δH (300 MHz; CDCl3) 2.80 (1H, dd, J 2.6 and 5.5, HCOCHH), 3.13 (1H, dd, J 4.1 and 5.5, HCOCHH), 3.85 (1H, dd, J 2.6 and 4.0, PhCHOCH2), 7.26-7.36 (5H, m, 5×CH, arom.); δC (300 MHz; CDCl3) 51.7 (CH2), 52.8 (CH), 125.9, 126.3, 128.6, 128.9 and 138.0 (6×C-Ph). MS m/z (rel. intensity %): 122 (M+2, 15), 121 (M+1, 43), 120 (M+, 20), 105(100), 91(68), 77 (88).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[C:13]([F:23])=[C:14]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]=[CH:17][CH:16]=[CH:15]4)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:29]([O:31][CH2:32][CH3:33])=[CH2:30])CCC>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:32]([O:31][C:29]([C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[C:13]([F:23])=[C:14]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]=[CH:17][CH:16]=[CH:15]4)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1)=[CH2:30])[CH3:33]
Reactant: Fc1cc2ncccc2c(F)c1Cn1nnc2ncc(Br)nc21
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=C(OCC)c1cnc2nnn(Cc3c(F)cc4ncccc4c3F)c2n1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 54.3 %

Procedure:
To a degassed solution of 6-((6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)-5,7-difluoroquinoline (10 mg, 0.03 mmol) in DMF (1 mL) was added Pd(Ph3P)4 (3.1 mg, 2.65 μmol). After stirring for 20 min, tributyl(1-ethoxyvinyl)stannane (14.4 mg, 0.04 mmol) was added. The reaction was heated at 100° C. until the LC-MS showed its completetion. The reaction mixture was filtered through celite and washed with ether. The filtration was washed with water, dried over Na2SO4, and concentrated. The crude product was purified by column chromatography with hexane:EtOAc to give 6-((6-(1-ethoxyvinyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)-5,7-difluoroquinoline (6.0 mg, 61%). 1H-NMR (400 MHz, CDCl3) δ ppm 9.16 (s, 1H), 8.98 (d, 1H), 8.43 (d, 1H), 7.65 (d, 1H), 7.48 (m, 1H), 6.17 (s, 2H), 5.60 (s, 1H), 4.57 (s, 1H), 4.04 (q, 2H), 1.49 (t, 3H). LCMS (method B): [MH]+=369.0, tR=2.45 min.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.O=[C:24]1[NH:29][CH2:28][CH2:27][N:26]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH2:25]1>O1CCCC1>[S:10]=[C:24]1[NH:29][CH2:28][CH2:27][N:26]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH2:25]1
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCNC(=S)C1

Procedure:
Lawesson's reagent (10.1 g, 20 mmol) was added to a solution of benzyl 3-oxo-1-piperazinecarboxylate (10 g, 43 mmol) in tetrahydrofuran (110 mL), and the reaction heated under reflux for 4 hours. The cooled mixture was concentrated under reduced pressure and the residue partitioned between 1N sodium hydroxide solution (150 mL) and ethyl acetate (250 mL), and the layers separated. The organic extract was washed with 1N sodium hydroxide solution (2×100 mL), then brine (100 mL), and the combined aqueous solutions extracted with ethyl acetate (200 mL). The combined organic solutions were dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane:methanol (98:2) as eluant to afford the title compound as a tan-coloured solid, 6.7 g.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][O:21][Si](C(C)(C)C)(C)C)[C:13](=[O:29])[N:12]([CH3:30])[C:11]=2[N:10]=[C:9]1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(O)C.O.C(OCC)C>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][OH:21])[C:13](=[O:29])[N:12]([CH3:30])[C:11]=2[N:10]=[C:9]1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2c1nc(-c1ccc(Cl)c(Cl)c1)n2Cc1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: Cn1c(=O)n(CCCO)c(=O)c2c1nc(-c1ccc(Cl)c(Cl)c1)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
Step 2 7-Benzyl-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-8-(3,4-dichlorophenyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.49 g, 0.854 mmol) was dissolved in ethanol (15 mL) and 6 N HCl (2.0 mL) was added. The clear solution was stirred at room temperature for 1 h. The reaction was diluted with water (100 mL) and extracted with DCM (3×75 ml). The combined extracts were dried with magnesium sulfate, filtered and the solvent was removed under reduced pressure to give a white solid. The solid was slurried in diethyl ether (5 mL) and filtered to give 7-benzyl-8-(3,4-dichlorophenyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.28 g, 71% yield) as a white solid. LCMS retention time=3.567 min and 96% purity, LCMS MH+=459. 1H NMR (CDCl3) δ 7.71 (s, 1H), 7.53 (d, 1H, J=8 Hz), 7.38-7.41 (d, 1H, J=4 Hz), 7.26-7.29 (m, 3H), 7.04 (d, 2H), 5.64 (s, 2H), 4.20 (t, 2H, J=8 Hz), 3.65 (s, 3H), 3.47-3.54 (m, 2H), 3.30 (t, 2H, J=8 Hz).
Reaction SMILES: O1CCOCCOCCOCCOCCOCC1.CC(C)([O-])C.[K+].[N+:25]([C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32]([C:37]([NH:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:38])=[CH:31]2)([O-:27])=[O:26].Br[CH2:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49]>ClCCl.C1COCC1>[NH:39]([C:37]([C:32]1[N:33]([CH2:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[C:34]2[C:30]([CH:31]=1)=[CH:29][C:28]([N+:25]([O-:27])=[O:26])=[CH:36][CH:35]=2)=[O:38])[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: O=C(Nc1ccccc1)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: CC(C)(C)OC(=O)CBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cn1c(C(=O)Nc2ccccc2)cc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Under argon, 328 mg (1.24 mmol) of 1,4,7,10,13,16-hexaoxacyclooctadecane (18-crown-6) are initially charged in 61 ml of dichloromethane, and 15 ml (14.93 mmol) of a 1-molar potassium tert-butoxide solution in THF and 3.50 g (12.44 mmol) of 5-nitro-N-phenyl-1H-indole-2-carboxamide from Example XLVIII are added. The mixture is stirred at RT for 15 minutes and then cooled to. 0° C. A solution of 3.64 g (18.67 mmol) of tert-butyl bromoacetate in 100 ml of THF is slowly added dropwise. The ice-bath is removed and the mixture is stirred at RT overnight. For work-up, the mixture is diluted with water and the THF is removed under reduced pressure using a rotary evaporator. The aqueous residue is extracted with ethyl acetate and the organic phase is washed with sat. sodium chloride solution, dried with sodium sulphate, filtered and dried under reduced pressure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([C:13]1[NH:17][C:16]([CH3:18])=[C:15]([CH3:19])[CH:14]=1)=[O:12].[CH:20]1([CH2:23]Br)[CH2:22][CH2:21]1>>[CH:20]1([CH2:23][N:17]2[C:13]([C:11](=[O:12])[CH2:10][CH2:9][C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[CH:14][C:15]([CH3:19])=[C:16]2[CH3:18])[CH2:22][CH2:21]1
Reactant: Cc1cc(C(=O)CCc2ccc(F)cc2F)[nH]c1C
Reactant: BrCC1CC1
Product: Cc1cc(C(=O)CCc2ccc(F)cc2F)n(CC2CC2)c1C

Procedure:
The title compound was prepared as a yellow solid in 85.16 yield in a similar procedure to that described in Referential Example 97 by using 5-[3-(2,4-difluorophenyl)propionyl]-2,3-dimethylpyrrole and cyclopropylmethyl bromide.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:12][C:13]1[C:14]([S:22][CH3:23])=[N:15][C:16]([CH3:21])=[CH:17][C:18]=1[S:19][CH3:20])=[O:11].[CH3:24][O:25][C:26]([C:28]1[C:36]2[O:35][C:34]([SH:37])=[N:33][C:32]=2[CH:31]=[CH:30][CH:29]=1)=[O:27].C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+]>O.CN(C=O)C>[CH3:24][O:25][C:26]([C:28]1[C:36]2[O:35][C:34]([S:37][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:12][C:13]3[C:14]([S:22][CH3:23])=[N:15][C:16]([CH3:21])=[CH:17][C:18]=3[S:19][CH3:20])=[O:11])=[N:33][C:32]=2[CH:31]=[CH:30][CH:29]=1)=[O:27]
Reactant: COC(=O)c1cccc2nc(S)oc12
Reactant: CSc1cc(C)nc(SC)c1NC(=O)CCCCCCCCBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2nc(SCCCCCCCCC(=O)Nc3c(SC)cc(C)nc3SC)oc12
Temperature: 80 °C
Reaction time: 4 h
Yield: 69.7 %

Procedure:
To a DMF (4 ml) solution of 9-bromo-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]nonanamide (90 mg, 0.22 mmol) and 7-methoxycarbonyl-2-mercaptobenzoxazole (45 mg, 0.22 mmol) were added 18-crown-6 (6 mg, 0.02 mmol) and potassium carbonate (36 mg, 0.26 mmol), and the mixture was stirred at 80° C. for 4 hours. The reaction mixture was diluted with water, and then extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was recrystallized from a mixture of ethyl acetate and hexane to obtain 84 mg (yield 72%) of the desired compound as a colorless powdery crystal.
Reaction SMILES: [C:1]1([CH:7]2[N:12]([CH2:13][C:14]#[N:15])[C:11]3[CH:16]=[CH:17][CH:18]=[CH:19][C:10]=3[S:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20](Cl)(=[O:24])[CH:21]([CH3:23])[CH3:22]>>[CH3:22][CH:21]([CH3:23])[C:20]([NH:15][CH2:14][CH2:13][N:12]1[C:11]2[CH:16]=[CH:17][CH:18]=[CH:19][C:10]=2[S:9][CH2:8][CH:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:24]
Reactant: CC(C)C(=O)Cl
Reactant: N#CCN1c2ccccc2SCC1c1ccccc1
Product: CC(C)C(=O)NCCN1c2ccccc2SCC1c1ccccc1

Procedure:
The procedure is as in Example 15, starting from the compound obtained in Step A and with the replacement of benzoyl chloride with isobutyryl chloride.