Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:28]=[CH:27][CH:26]=[CH:25][C:10]=1[CH2:11][C:12]1[C:13](=[O:24])[NH:14][NH:15][C:16]=1[C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][C:30]([O:32][CH2:33][C@H:34]1[O:39][C@H:38](Br)[C@H:37]([O:41][C:42]([CH3:44])=[O:43])[C@@H:36]([O:45][C:46]([CH3:48])=[O:47])[C@@H:35]1[O:49][C:50]([CH3:52])=[O:51])=[O:31].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([O:8][C:9]1[CH:28]=[CH:27][CH:26]=[CH:25][C:10]=1[CH2:11][C:12]1[C:13]([O:24][C@@H:38]2[O:39][C@H:34]([CH2:33][O:32][C:30](=[O:31])[CH3:29])[C@@H:35]([O:49][C:50](=[O:51])[CH3:52])[C@H:36]([O:45][C:46](=[O:47])[CH3:48])[C@H:37]2[O:41][C:42](=[O:43])[CH3:44])=[N:14][NH:15][C:16]=1[C:17]([F:22])([F:23])[C:18]([F:19])([F:20])[F:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH][nH]c(C(F)(F)C(F)(F)F)c1Cc1ccccc1OCc1ccccc1
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(F)(F)C(F)(F)F)c2Cc2ccccc2OCc2ccccc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-(2-benzyloxybenzyl)-5-pentafluoroethyl-1,2-dihydropyrazol-3-one (55 mg) and acetobromo-α-D-glucose (63 mg) in acetonitrile (2 mL) was added potassium carbonate (23 mg), and the mixture was stirred at room temperature for 3 days. The reaction mixture was purified by column chromatography on aminopropyl silica gel (eluent: ethyl acetate/hexane=1/1-ethyl acetate) to give 4-(2-benzyloxybenzyl)-5-pentafluoroethyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole. To a solution of 4-(2-benzyloxybenzyl)-5-pentafluoroethyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole in tetrahydrofuran (1 mL) and methanol (0.5 mL) was added sodium methoxide (28% methanol solution, 50 μL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1-5/1) to give the title compound (33 mg).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[C:21]([Cl:31])(=[O:30])[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[ClH:31].[C:21]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(=[O:30])[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: NCCCSc1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C=Cc1ccccc1)NCCCSc1ccncc1
Yield: 79.2 %

Procedure:
To a solution of 1.00 g (4.15 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.78 ml (19.9 mmol) of triethylamine in 40 ml of methylene chloride was added 830 mg (4.98 mmol) of cinnamoyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: methanol/ethyl acetate=1:10) to obtain the powder which was washed with ether and dried to obtain 1.10 g of the desired compound (free base) (88.8%, colorless powder), mp: 116.0°-11.7.0° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:27](=[O:28])[N:26]([CH3:29])[C:12]2[N:13]([CH3:25])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20](=O)[CH2:21][C:22]#[N:23])=[CH:16][CH:15]=3.C([O-])(=O)C.[Na+].Cl.[OH:36][NH-:37]>C(Cl)Cl.CO>[NH2:23][C:22]1[O:36][N:37]=[C:20]([C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH3:25])[C:12]2[N:26]([CH3:29])[C:27](=[O:28])[C:9]([C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])=[CH:10][C:11]3=2)[CH:21]=1
Reactant: [NH-]O
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(C(=O)CC#N)ccc3n(C)c21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4cc(N)on4)ccc3n(C)c21
Temperature: 50 °C
Reaction time: 24 h

Procedure:
A solution containing 300 mg (0.707 mmol) of compound 3-[3-(2,4-dichlorophenyl)-1,9-dimethyl-2-oxo-2,9-dihydro-1H-pyrido[2,3-b]indol-6-yl]-3-oxopropionitrile from Example 20A, 238 mg (2.9 mmol) of sodium acetate and 152 mg (2.2 mmol) of hydroxylamide hydrochloride in 4 ml of CH2Cl2 and 4 ml of MeOH is stirred at 50° C. for 24 h and then at ambient temperature for 18 h. The reaction medium is concentrated by adsorbing it onto silica, and purification is carried out on a silica column, elution being carried out with EtOAc/20% cyclohexane and then 100% EtOAc.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[CH2:12][CH2:13][OH:14].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:22][S:23]([O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[CH2:12][CH2:13][O:14][S:23]([CH3:22])(=[O:25])=[O:24])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ccc(CO)c(CCO)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1cc([N+](=O)[O-])ccc1COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
A solution of 2-[2-(hydroxymethyl)-5-nitrophenyl]ethanol (2.95 g, 14.96 mmol, J. Org. Chem., 1998, 63, 4116-4119) and triethylamine (6.26 mL, 44.9 mmol) in dry CH2Cl2 (60 mL) at 0° C. under N2 is treated with methanesulfonyl chloride (2.89 mL, 37.4 mmol) dropwise and stirred at 0° C. for 30 mins. The mixture is then diluted with CH2Cl2 (40 mL), washed with 1M aqueous HCl (20 mL), saturated aqueous NaHCO3 (20 mL) and brine (20 mL), dried over Na2SO4 and concentrated under reduced pressure to give the crude product which is chromatographed on a Flash 40M silica gel (90 g, 32-63 μm) cartridge, eluting with a gradient of EtOAc/heptane (30/70-70/30). Pooling and concentration of those fractions with an Rf=0.18 by TLC (EtOAc/hexane, 50/50) provides 4.58 g (87%) of the title compound as a white solid, mp 88-89° C.
Reaction SMILES: I[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:11]>[Cu]>[CH3:11][C:3]1[C:2]([C:2]2[C:3]([CH3:11])=[CH:4][CH:5]=[CH:6][C:7]=2[N+:8]([O-:10])=[O:9])=[C:7]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:5][CH:4]=1
Reactant: Cc1cccc([N+](=O)[O-])c1I
Agent: [Cu]
Product: Cc1cccc([N+](=O)[O-])c1-c1c(C)cccc1[N+](=O)[O-]
Yield: 73 %

Procedure:
In an eggplant flask having a ground-in stopper and equipped with a condenser were charged 2-iodo-3-nitrotoluene (6) as obtained in Preparation Example 3 and an equivalent weight of a copper powder, and the contents were stirred in an oil bath at 200° C. for 10 hours. The mixture was extracted with benzene by means of a Soxhlet extractor. The solvent was removed from the extract by distillation under reduced pressure, and the resulting crude crystal was recrystallized from 99% ethanol to obtain 6,6'-dimethyl-2,2'-dinitro-1,1'-biphenyl (7) as a black needle-like crystal having a melting point of 107.4° to 108.3° C. and a 73% yield.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=2)[CH:17]=[CH:16][C:15]=1[S:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:39])[CH3:38])=[CH:32][CH:31]=1>C(O)C>[Br:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][O:20][C:18]2[CH:17]=[CH:16][C:15]([S:29][C:30]3[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:39])[CH3:38])=[CH:32][CH:31]=3)=[C:14]([NH:13][C:2]3[C:3]4[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=4)[N:9]=[CH:10][CH:11]=3)[CH:19]=2)=[CH:23][CH:24]=1
Reactant: CC(=O)Nc1ccc(Sc2ccc(OCc3ccc(Br)cc3)cc2N)cc1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Solvent: CCO
Product: CC(=O)Nc1ccc(Sc2ccc(OCc3ccc(Br)cc3)cc2Nc2ccnc3nc(C)ccc23)cc1

Procedure:
The product from Example 1d (18 mg, 0.085 mmol) was reacted in ethanol (1 mL) with the product from Example 158a (37 mg, 0.085 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (26 mg, 42%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (t, J=7.35 Hz, 3H) 1.67-1.92 (m, 2H) 2.02 (s, 3H) 2.99 (t, J=7.54 Hz, 2H) 5.14 (s, 2H) 6.30 (d, J=6.99 Hz, 1H) 7.14 (d, J=8.46 Hz, 2H) 7.16-7.26 (m, 2H) 7.31-7.49 (m, 5H) 7.53-7.66 (m, 2H) 7.80 (d, J=8.46 Hz, 1H) 8.37 (d, J=6.99 Hz, 1H) 8.97 (d, J=8.82 Hz, 1H) 9.97 (s, 1H) 11.00 (s, 1H) 14.37 (s, 1H); MS (ESI+) m/z 615 (M+H)+.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][CH3:10])(=[O:3])[CH3:2].CO.[BH4-].[Na+]>[OH-].[Na+]>[CH2:8]([O:7][CH2:6][CH2:5][CH2:4][CH:1]([OH:3])[CH3:2])[CH2:9][CH3:10]
Reactant: CCCOCCCC(C)=O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCOCCCC(C)O
Yield: 40 %

Procedure:
To 34.8 g of the 3-acetyl-1-propyloxy-propane obtained in (1) was added 50 ml of methanol, and a solution of 44.4 g of NaBH4 in 8% sodium hydroxide was dropwise added at room temperature. After the reaction, the methanol was distilled off, 200 ml of water was added, and the mixture was extracted with ether. An organic layer was washed with water and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was filtered off, then, the ether was distilled off, and the remainder was distilled under vacuum for isolation and purification (104° C./20 mmHg; yield 40%).
Reaction SMILES: [C:1]([C:20]1[NH:24][N:23]=[C:22]([S:25][CH2:26]Cl)[N:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:28].[Na+]>CC(C)=O.O>[C:1]([C:20]1[NH:24][N:23]=[C:22]([S:25][CH2:26][I:28])[N:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: ClCSc1n[nH]c(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: ICSc1n[nH]c(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a suspension of trityl-3-chloromethylthio-1,2,4-triazole (11.75 g: 30.0 mMol.) in acetone (150 ml) is added sodium iodide (9.00 g: 60.0 mMol.), and the mixture is stirred at 50° C. for 3 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The extract is washed with brine, dried over sodium sulfate, and concentrated to give trityl-3-iodomethylthio-1,2,4-triazole as yellow crystals [NMR δ(CDCl3) ppm: 4.70(s, 2H), 7.1 to 7.2(m, 6H), 7.3 to 7.4(m, 9H), 7.96(s, 1H): 13 g]. To a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetylamino]-3-argentiothio-3-cephem-4-carboxylic acid diphenylmethyl ester 1-oxide (16.8 g: 15 mMol.) in hexamethylphosphoramide (90 ml) is added trityl-3-iodomethylthio-1,2,4-triazole (13 g), and the mixture is stirred at room temperature for 3 hours. The reaction mixture is diluted with ethyl acetate, mixed with saturated brine, and filtered through Celite. The organic layer is taken, washed with brine, dried over sodium sulfate, and concentrated. The residue is purified by silica gel chromatography (toluene: ethyl acetate=5:1-3:1) to give 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetylamino]-3-(trityl-1,2,4-triazol-3-ylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester 1-oxide (11.29 g) as pale brown foam. Yield: 59%.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([CH3:38])=[C:14]([CH:18]2[C:30]3[C:29]4[C:24](=[CH:25][C:26]([Br:31])=[CH:27][CH:28]=4)[NH:23][C:22]=3[CH:21]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[NH:20][CH:19]2[CH3:37])[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([CH3:38])=[C:14]([C:18]2[C:30]3[C:29]4[C:24](=[CH:25][C:26]([Br:31])=[CH:27][CH:28]=4)[NH:23][C:22]=3[C:21]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[N:20][C:19]=2[CH3:37])[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1NC(C)C(c2cccc(NC(=O)OCc3ccccc3)c2C)c2c1[nH]c1cc(Br)ccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1nc(C)c(-c2cccc(NC(=O)OCc3ccccc3)c2C)c2c1[nH]c1cc(Br)ccc12
Yield: 32 %

Procedure:
A solution of ethyl 4-(3-(((benzyloxy)carbonyl)amino)-2-methylphenyl)-7-bromo-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-carboxylate (4.68 g, 8.12 mmol) and 10% palladium on carbon (2.59 g, 2.44 mmol) in xylene (130 mL) was heated at 120° C. overnight. The reaction mixture was diluted with ethyl acetate and filtered through a pad of CELITE®. The CELITE® pad was washed well with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography using a mixture of ethyl acetate in hexane (20%-35%-50%) to give ethyl 4-(3-(((benzyloxy)carbonyl)amino)-2-methylphenyl)-7-bromo-3-methyl-9H-pyrido[3,4-b]indole-1-carboxylate (1.49 g, 2.60 mmol, 32% yield) as a burgundy solid. LC/MS M+1=572.2 and 574.2.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)=[O:41])([CH3:38])([CH3:37])[CH3:36]>C(Cl)Cl>[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][N:45]([C:20](=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:44][CH2:43]1)=[O:41])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)NCCCCCCCCCCCC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCCCCCCCCCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
A mixture of 12-tert-butoxycarbonylaminododecanoic acid (3) (320 mg, 1.01 mmol) and 1,1′-carbonyldiimidazole (181 mg, 1.12 mmol) in anhydrous CH2Cl2 (10 mL) was stirred at room temperature for 2 hours. Then N-tert-butoxycarbonylpiperazine (227.0 mg, 1.22 mmol) was added in one portion and the reaction mixture was stirred at room temperature for 66 hours. After this time, the solvent was removed by rotary evaporation and the resulting residue was purified with Biotage silica gel column chromatography, eluting with 5% to 36% ethyl acetate/hexanes, to afford the desired amide 10 (462.0 mg, 94%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 1.25 (m, 14H), 1.42 (s, 9H), 1.47 (s, 9H), 1.62 (m, 2H), 2.30 (t, 2H), 3.10 (m, 2H), 3.42 (m, 6H), 3.60 (m, 2H), 4.49 (br, 1H). m/z (ESI) 484 [C26H49N3O5+H]+.
Reaction SMILES: [Br:1][CH2:2][C:3](=O)[C:4]([F:7])([F:6])[F:5].Cl.[NH2:10][OH:11]>C(Cl)(Cl)Cl.O>[Br:1][CH2:2][C:3](=[N:10][OH:11])[C:4]([F:7])([F:6])[F:5]
Reactant: O=C(CBr)C(F)(F)F
Reactant: NO
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: ON=C(CBr)C(F)(F)F
Reaction time: 24 h
Yield: 54.6 %

Procedure:
To a solution of 10.5 mL (102.3 mmol) of 1-bromo-3,3,3-trifluoropropan-2-one in 100 mL of chloroform (passed through a pad of basic Al2O3) was added a solution of 10.4 g (149.7 mmol) of hydroxylamine hydrochloride in 20 mL of water and the mixture was warmed at reflux. After 24 hours, the mixture was cooled and the organic phase was separated. The aqueous layer was extracted with three 30 mL portions of methylene chloride. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford 11.5 g (55.7%) of 3-bromo-1,1,1-trifluoropropan-2-one oxime as a mixture (3:2) of geometric isomers.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:35]=[CH:36][CH:37]=1)[CH2:6][N:7]([C@@H:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1)[C:8]([C:10]1[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[C:13]([C:19]([OH:21])=[O:20])=[CH:12][C:11]=1[C:22]([OH:24])=[O:23])=[O:9])=O.[O:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH:39]1[O:44][NH2:45]>>[C@@H:25]1([N:7]([CH2:6][C:5]2[CH:35]=[CH:36][CH:37]=[C:3]([CH:1]=[N:45][O:44][CH:39]3[CH2:40][CH2:41][CH2:42][CH2:43][O:38]3)[CH:4]=2)[C:8]([C:10]2[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[C:13]([C:19]([OH:21])=[O:20])=[CH:12][C:11]=2[C:22]([OH:24])=[O:23])=[O:9])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1
Reactant: NOC1CCCCO1
Reactant: O=Cc1cccc(CN(C(=O)c2cc(C(=O)O)c(C(=O)O)cc2C(=O)O)[C@H]2CCCc3ccccc32)c1
Product: O=C(O)c1cc(C(=O)O)c(C(=O)N(Cc2cccc(C=NOC3CCCCO3)c2)[C@H]2CCCc3ccccc32)cc1C(=O)O

Procedure:
The product from Example 76E and O-tetrahydro-2H-pyran-2-ylhydroxylamine were processed as described in Example 76F to provide the title compound.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5].[Na].[NH:12]1[CH:16]=[N:15][CH:14]=[N:13]1>CN(C)C=O.C(Cl)Cl>[F:10][C:7]1[CH:8]=[CH:9][C:2]([N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: c1nc[nH]n1
Reactant: N#Cc1cc(F)ccc1F
Agent: [Na]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1cc(F)ccc1-n1cncn1
Temperature: 80 °C
Yield: 49 %

Procedure:
A suspension of 2,5-diflurobenzonitrile (4.5 g, 32.35 mmol) and 1,2,4-triazole sodium salt (3.6 g, 40 mmol) in dimethylformamide (40 mL) was heated at 80° C. for 15 h. The reaction mixture was then cooled, diluted with CH2Cl2 (200 mL), washed with water (3×30 mL) and brine (30 mL), then dried (Na2SO4), filtered and concentrated to give a white solid which was purified by flash column chromatography (SiO2) using 1:1 to 3:1 ethyl acetate/Hexanes to afford the title compound (2.98 g, 49% yield) as a white powder. 1H NMR (500 MHz, CDCl3) δ: 8.70 (1H, s), 8.18 (1H, s), 7.76 (1H, dd, J=9.0, 4.8 Hz), 7.55 (1H, dd, J=7.3, 2.8 Hz), 7.51–7.47 (1H, m). LCMS (M+H) calcd for C9H6FN4: 189.17; found: 189.10.
Reaction SMILES: C[C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=1.I[CH2:27]CC>C1COCC1.C(#N)C>[CH3:27][C:6]1[N:5]([CH2:7][CH2:20][CH3:25])[CH:4]=[N:3][CH:2]=1
Reactant: Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCCI
Solvent: C1CCOC1
Solvent: CC#N
Product: CCCn1cncc1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 24.8 %

Procedure:
To a solution of 4-methyl-1-triphenylmethylimidazole (20.0 g) in THF (300 ml) and acetonitrile (300 ml) was added 1-iodopropane (26.2 g) and the mixture was stirred overnight under nitrogen atmosphere at 80° C. The solvent was distilled off under reduced pressure and the residue was dissolved in acetic acid (200 ml), and the mixture was stirred for 3 hours under nitrogen atmosphere at 60° C. The mixture was allowed to be at room temperature, water was added to the mixture, and the insolubles were filtered off. Potassium carbonate was added to the filtrate to make it basic and the mixture was extracted with chloroform three times, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained oil was distilled off under reduced pressure (1.5 mmHg, 72° C. to 73° C.), to give 5-methyl-1-propylimidazole (1.9 g) as colorless oil.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]2([C:24]3[CH:29]=[C:28]([CH3:30])[C:27]([O:31][Si](C(C)(C)C)(C)C)=[C:26]([CH3:39])[CH:25]=3)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])=[CH:9][C:8]=1[CH3:40])(C)(C)C.[C:43]1(B(O)O)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[OH:31][C:27]1[C:28]([CH3:30])=[CH:29][C:24]([C:14]2([C:10]3[CH:9]=[C:8]([CH3:40])[C:7]([OH:6])=[C:12]([CH3:13])[CH:11]=3)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:15]2=[O:23])=[CH:25][C:26]=1[CH3:39]
Reactant: Cc1cc(C2(c3cc(C)c(O[Si](C)(C)C(C)(C)C)c(C)c3)C(=O)Nc3ccccc32)cc(C)c1O[Si](C)(C)C(C)(C)C
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C2(c3cc(C)c(O)c(C)c3)C(=O)N(c3ccccc3)c3ccccc32)cc(C)c1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 38.6 %

Procedure:
Combine 3,3-Bis-[4-(tert-butyl-dimethyl-silanyloxy)-3,5-dimethyl-phenyl]-1,3-dihydro-indol-2-one (0.816 g, 1.36 mmol), phenylboronic acid (0.330 g, 2.71 mmol), copper (II) acetate (0.25 g, 1.36 mmol), triethylamine (0.38 mL, 2.71 mmol), 4 angstrom molecular sieves, and dichloromethane (20 mL). Stir at room temperature for 72 h under ambient atmosphere. Filter the reaction through Celite. Elute through a column of silica gel with 70% dichloromethane in hexanes and concentrate. Dissolve the resulting compound in (0.446 g, 0.655 mmol), Add a solution of tetrabutylammonium fluoride (1.0 M) in THF (1.64 mL). Stir for 1 h. Add 1N aqueous HCl (10 mL), water (40 mL), and ethyl acetate (50 mL). Separate the layers, and concentrate the organic layer in vacuo. Chromatograph on silica gel eluting with ethyl acetate to give 0.236 g (39%) of the title compound: mass spectrum (FAB): m/z=450(M+1); 1H NMR(DMSO-d6): δ8.24 (s, 2H), 7.58-7.54 (m, 2H), 7.48-7.41 (m, 3H), 7.32 (dd, 1H), 7.22 (td, 1H), 7.10 (td, 1H), 6.77 (d, 1H), 6.74 (s, 4H), 2.07 (s, 12H).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][CH:13]=1>C(N(CC)CC)C.[Cu]I>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1Br
Reactant: C#Cc1ccc(OC)cc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COc1ccc(C#Cc2ccccc2C=O)cc1
Temperature: 50 °C
Yield: 88.9 %

Procedure:
To a solution of 2-bromobenzaldehyde (1.85 g, 10 mmol) and 4-methoxyphenyl acetylene (1.58 g, 12 mmol) in 40 mL of triethylamine were added dichlorobis(triphenylphosphine) palladium(II) (140 mg, 2 mol %) and copper(I) iodide (20 mg, 1 mol %). The reaction mixture was heated at 50° C. under nitrogen for 3 h. The reaction mixture was cooled to room temperature and the ammonium salt was removed by filtration. The filtrate was concentrated under reduced pressure. Purification of the crude compound by column chromatography (SilicaGel 230-400 mesh; 10% ethyl acetate in hexanes as eluent) afforded of 2-(4-methoxy phenylethynyl)benzaldehyde (2.1 g, 89%).
Reaction SMILES: [C:1]([N:4]([CH3:21])[N:5]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19]O)=[CH:15][CH:14]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2].CC(C)(O)[C:24]#[N:25].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C1COCC1>[C:1]([N:4]([CH3:21])[N:5]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:24]#[N:25])=[CH:15][CH:14]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(C)(O)C#N
Reactant: CC(=O)N(C)N(C(=O)OC(C)(C)C)c1ccc(CO)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CC(=O)N(C)N(C(=O)OC(C)(C)C)c1ccc(CC#N)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.5 %

Procedure:
tert-Butyl 2-acetyl-1-[4-(hydroxymethyl)phenyl]-2-methylhydrazinecarboxylate (1.27 g), acetone cyanohydrin (550 mg) and 1,1′-(azodicarbonyl)dipiperidine (1.63 g) were dissolved in THF (60 ml), and tributylphosphine (1.31 g) was added at 0° C. The obtained mixture was stirred at room temperature for 18 hr, and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed with water and then saturated brine. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1 (volume ratio)→1:1 (volume ratio)), and further recrystallized from ethyl acetate-hexane to give the title compound (910 mg) as colorless crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][CH:8]=O)=[CH:3][CH:2]=1.[Cl:10][C:11]1[N:19]=[C:18]2[C:14]([N:15]=[CH:16][N:17]2[CH3:20])=C(Cl)[N:12]=1>>[Cl:10][C:11]1[N:19]=[C:18]2[C:14]([N:15]=[CH:16][N:17]2[CH3:20])=[C:8]([NH:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[N:12]=1
Reactant: O=CNc1ccncc1
Reactant: Cn1cnc2c(Cl)nc(Cl)nc21
Product: Cn1cnc2c(Nc3ccncc3)nc(Cl)nc21

Procedure:
Was prepared according to Example 3 from N-pyridin-4-yl-formamide and 2,6-dichloro-9-methyl-9H-purine.