Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[N:8]([C:12]3[CH:13]=[C:14]([CH:23]=[CH:24][C:25]=3[N+:26]([O-:28])=[O:27])[C:15]([NH:17][CH2:18][CH2:19][O:20][CH2:21][CH3:22])=[O:16])[CH:9]=[CH:10][N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:31]I>CN(C)C(=O)C.O>[CH:1]1([C:7]2[N:8]([C:12]3[CH:13]=[C:14]([CH:23]=[CH:24][C:25]=3[N+:26]([O-:28])=[O:27])[C:15]([N:17]([CH2:18][CH2:19][O:20][CH2:21][CH3:22])[CH3:31])=[O:16])[CH:9]=[CH:10][N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOCCNC(=O)c1ccc([N+](=O)[O-])c(-n2ccnc2C2CCCCC2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOCCN(C)C(=O)c1ccc([N+](=O)[O-])c(-n2ccnc2C2CCCCC2)c1
Reaction time: 1.8 h

Procedure:
To the solution of 3-(2-cyclohexyl-1H-imidazol-1-yl)-N-(2-ethoxyethyl)-4-nitrobenzamide as synthesized in above Production Example 48, 3.86 g in N,N-dimethylacetamide 32 mL, sodium hydride (formed by washing 60% sodium hydride, oiliness 600 mg with hexane) was added under cooling with ice. Then methyl iodide 1.55 mL was added and the ice bath was removed. After 1.8 hours' stirring, sodium hydride (formed by washing 60% sodium hydride, oiliness 200 mg with hexane) was added, followed by 5 hours' stirring. The reaction liquid was poured in water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. Distilling the solvent off, 3.35 g of the title compound was obtained.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:51]=[CH:50][C:16]2[N:17]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]4[N:41](COCC[Si](C)(C)C)[N:40]=[CH:39][CH:38]=4)[CH:32]=3)[C:18]([CH2:20][C:21]3([C:26]([O:28]C)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:19][C:15]=2[CH:14]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[NH:41]1[C:37]([C:33]2[CH:32]=[C:31]([CH:36]=[CH:35][CH:34]=2)[CH2:30][N:17]2[C:16]3[CH:50]=[CH:51][C:13]([O:12][CH2:11][C:2]4[CH:3]=[CH:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[N:1]=4)=[CH:14][C:15]=3[N:19]=[C:18]2[CH2:20][C:21]2([C:26]([OH:28])=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:38][CH:39]=[N:40]1
Reactant: COC(=O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2cccc(-c3ccnn3COCC[Si](C)(C)C)c2)CCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2cccc(-c3ccn[nH]3)c2)CCCC1
Temperature: 70 °C

Procedure:
To a 20 mL vial was added methyl 1-((5-(quinolin-2-ylmethoxy)-1-(3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)benzyl)-1H-benzo[d]imidazol-2-yl)methyl)cyclopentanecarboxylate (51 mg, 0.08 mmol) and THF (2 mL) followed by treatment with TBAF (0.4 mL, 1 M). The reaction mixture was heated to 70° C. After 24 hours the mixture was cooled to RT and concentrated to dryness. The residue was purified using FCC to provide the title compound. MS (ESI): mass calcd. for C35H33N5O3, 571.68; m/z found 572.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1.Cl.[CH2:17]([O:19][NH:20][CH3:21])[CH3:18]>>[CH2:13]([NH:12][C:4]1[N:5]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:7]=[C:2]([N:20]([CH3:21])[O:19][CH2:17][CH3:18])[N:3]=1)[CH2:14][CH3:15]
Reactant: CCCNc1nc(Cl)nc(NCCC)n1
Reactant: CCONC
Agent: Cl
Product: CCCNc1nc(NCCC)nc(N(C)OCC)n1
Yield: 93 %

Procedure:
2-Chloro-N-(4,6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV) was reacted with O-ethyl-N-methyl-hydroxylamine hydrochloride as described in Example 13, to yield XCVI in 93% yield. ESI-MS (m/z) 269 [M+H]+.
Reaction SMILES: Cl.[CH3:2][S:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:10][CH:11]=2)[N:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:5]=1.C(N(CC)CC)C.[C:32](O)(=[O:39])[C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.C(OCC)(=O)C>[CH3:2][S:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([N:13]3[CH2:14][CH2:15][N:16]([C:32]([C:33]4[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=4)=[O:39])[CH2:17][CH2:18]3)=[CH:10][CH:11]=2)[N:6]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:5]=1
Reactant: O=C(O)c1ccncc1
Reactant: CSc1nn(-c2ccccc2)c2cc(N3CCNCC3)ccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1nn(-c2ccccc2)c2cc(N3CCN(C(=O)c4ccncc4)CC3)ccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3-(methylthio)-1-phenyl-6-(piperazin-1-yl)-1H-indazole hydrochloride (200 mg, 0.55 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL), triethylamine (140.3 mg, 1.39 mmol, 2.51 equiv), isonicotinic acid (82 mg, 0.67 mmol, 1.20 equiv), and the resulting solution was stirred for 10 min at room temperature. HATU (631 mg, 1.66 mmol, 3.00 equiv) was added and resulting solution was stirred for an additional 2 h at room temperature. The resulting solution was diluted with ethyl acetate (20 mL). The resulting mixture was washed with brine (2×15 mL). The resulting mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate:petroleum ether:THF (1:1:1) to yield (4-(3-(methylthio)-1-phenyl-1H-indazol-6-yl)piperazin-1-yl)(pyridin-4-yl)methanone as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11](C)([C:17](OCC)=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[Cl-].[Na+].CS(C)=O>O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CCOC(=O)C(C)(C(=O)OCC)c1ccc([N+](=O)[O-])c(F)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C(C)c1ccc([N+](=O)[O-])c(F)c1

Procedure:
A mixture of 100 millimoles of diethyl 2-(3-fluoro-4-nitrophenyl)-2-methylmalonate, 110 millimoles of sodium chloride and 50 milliliters of dimethyl sulfoxide is heated under nitrogen at about 130° to 180° C. for about 6 hours. On cooling the mixture is diluted with 100 milliliters of water and 100 milliliters of ethyl acetate. The layers are separated and the organic layer is washed two times with 25 milliliters of water. After drying over disodium sulfate the organic layer is concentrated in vacuo to give the desired ethyl 2-(3-fluoro-4-nitrophenyl)propionate.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][N:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[N:7]([CH3:16])[C:6]=2[CH:17]=1.[OH:18][CH2:19][C:20]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:25])[CH2:21][CH:22]([CH3:24])[CH3:23]>CCOCC>[C:29]([O:28][C:27](=[O:33])[NH:26][C:20]([CH3:25])([CH2:21][CH:22]([CH3:23])[CH3:24])[CH2:19][O:18][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][N:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[N:7]([CH3:16])[C:6]=2[CH:17]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: Cn1c(=O)c2cnccc2c2ccc(Cl)cc21
Reactant: CC(C)CC(C)(CO)NC(=O)OC(C)(C)C
Solvent: CCOCC
Product: CC(C)CC(C)(COc1ccc2c3ccncc3c(=O)n(C)c2c1)NC(=O)OC(C)(C)C
Yield: 28 %

Procedure:
Synthesis of 8-chloro-6-methylbenzo[c][2,7]naphthyridin-5(6H)-one was described in example 2, Part C. 8-chloro-6-methylbenzo[c][2,7]naphthyridin-5(6H)-one (0.15 g, 0.613 mmol) and tert-butyl (1-hydroxy-2,4-dimethylpentan-2-yl)carbamate (0.284 g, 1.226 mmol) were subjected to ether synthesis as described in Example 16, Part H, to afford product, tert-butyl(2,4-dimethyl-1-((6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)pentan-2-yl)carbamate (0.3 g, 28% yield) as pale yellow solid. LC/MS (ESI) m/e 440.2 [(M+H)+, calcd for C25H34N3O4, 440.2]; LC/MS retention time (method C): tR=2.67 min.
Reaction SMILES: [C:1]1([CH:7]2[C:11](=[O:12])[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)=[C:9]([NH2:23])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN.O1C=CC[CH2:27]1.O>CO>[C:1]1([CH:7]2[C:11](=[O:12])[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=3)=[C:9]([NH:23][CH3:27])[O:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1=COCC1
Reactant: NC1=C(c2cccc(C(F)(F)F)c2)C(=O)C(c2ccccc2)O1
Agent: CN
Solvent: O
Solvent: CO
Product: CNC1=C(c2cccc(C(F)(F)F)c2)C(=O)C(c2ccccc2)O1

Procedure:
In this example, a mixture containing 0.5 g of 2-phenyl-3-oxo-4-(3-trifluoromethylphenyl)-5-amino-2,3-dihydrofuran ("dihydrofuran starting material") and 25 ml of aqueous 40 wt. % methylamine in 10 ml of methanol was refluxed for 18 hours. The mixture was analyzed by thin-layer chromatography for the dihydrofuran starting material. Another 10 ml of aqueous 40 wt. % methylamine was added and the mixture refluxed for about four hours. The mixture was cooled, poured into 100 ml of water and extracted several times with ethyl ether. The organic extracts were dried over magnesium sulfate, concentrated in vacuo and chromatographed using 3% tetrahydrofuran/chloroform as eluent to yield 0.36 g of the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH2:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[C:3](OCC)=[O:4].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][CH:2]([CH2:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[CH2:3][OH:4]
Reactant: CCOC(=O)C(C)Cc1cccnc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(CO)Cc1cccnc1
Yield: 101.8 %

Procedure:
According to Step 2 of Reference Example 8-63, tetrahydrofuran (10 mL) and a solution prepared by dissolving, in tetrahydrofuran (5 mL), ethyl 2-methyl-3-(pyridin-3-yl)propanoate (200 mg, 1.0 mmol) obtained in Step 2 of Reference Example 8-65 were added to lithium aluminum hydride (75 mg, 2.0 mmol), and the mixture was stirred with cooling in an ice bath for 1 hour. Thus, 2-methyl-3-(pyridin-3-yl)propan-1-ol (Compound EM) (154 mg, yield: 99%) was obtained.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[N:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1.CN(C1C=CC=CN=1)C>C(O)C>[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=3)[N:3]=2)=[CH:17][CH:16]=1
Reactant: COc1ccc2nc(Cl)ccc2c1
Reactant: Nc1ccc(S)cc1
Agent: CN(C)c1ccccn1
Solvent: CCO
Product: COc1ccc2nc(Sc3ccc(N)cc3)ccc2c1

Procedure:
2-Chloro-6-methoxyquinoline (52.0 mmoles, 10.0 g), 4-aminothiophenol (52.0 mmoles, 6.5 g) and dimethylaminopyridine (52.0 mmoles, 6.3 g) were stirred for 16 hr in 250 ml ethanol. The reaction was condensed and purified by HPLC over silica gel eluted with 25-30% ethyl acetate/hexane to yield 2-(4-aminophenylthio)-6-methoxyquinoline. 8.5 g, 58% product. Mass spec (FD) 282. Calculated for C16H14N2OS: C, 68.06; H, 5.00, N, 9.92. Found: C, 68.04; H, 4.97; N, 10.02.
Reaction SMILES: Cl[C:2]1(Cl)[C:8](=[O:9])[CH:7]2[CH:3]1[CH2:4][CH:5]=[C:6]2[C:10]([O:12][CH:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].C(O)(=O)C>O1CCCC1.C(Cl)Cl.[Zn]>[C:14]1([CH:13]([O:12][C:10]([C:6]2[CH:7]3[CH:3]([CH2:4][CH:5]=2)[CH2:2][C:8]3=[O:9])=[O:11])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C1=CCC2C1C(=O)C2(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=CCC2CC(=O)C12
Temperature: 25 °C
Reaction time: 6 h
Yield: 85.4 %

Procedure:
To a solution of 50 g of 6,6-dichloro-7-oxobicyclo[3.2.0]hept-2-en-2-carboxylic acid, diphenylmethyl ester, from Example 4, in 75 mL of tetrahydrofuran, was added 500 mL of acetic acid and 100 g of zinc dust. This mixture was stirred mechanically for 6 hr at room temperature and then diluted with 1 L of methylene chloride and filtered. The filtrate was evaporated to a residue which was partitioned between methylene chloride and water. The organic layer was washed with brine, dried over sodium sulfate, and evaporated to give a colorless solid which, when triturated with 150 mL of ether-petroleum ether (1:1), afforded 35.1 g (85.5%) of crystalline 7-oxobicyclo[3.2.0]hept-2-ene-2-carboxylic acid diphenylmethyl ester: IR (Nujol mull): 1625, 1715, 1785 cm-1 ; NMR (220 MHz; CDCl3): δ 2.57 (1H, m), 2.89 (3H, m), 3.27 (1H, m), 4.48 (1H, m), 6.80 (1H, s), 6.86 (1H, m) and 7.1-7.4 (10H, m).
Reaction SMILES: [Mg].[CH2:2]([O:9][C:10]1[CH:11]=[C:12](Br)[CH:13]=[CH:14][CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br-].II.[O:20]=[C:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1>C1COCC1>[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([C:21]2([OH:20])[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[CH2:25][CH2:26]2)[CH:13]=[CH:14][CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Brc1cccc(OCc2ccccc2)c1
Agent: II
Agent: [Br-]
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cccc(OCc3ccccc3)c2)CC1
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
A suspension of magnesium metal (0.144 g, 6.0 mmol) in THF (10 mL) was rapidly stirred for 30 minutes under nitrogen then a solution of 3-benzyloxybromobenzene (1.58 g, 6.00 mmol) in THF (10 mL) added slowly via dropping funnel. Once approximately 1 mL of the bromide solution had been added a crystal of iodine was added to the reaction and the mixture gently heated until Grignard formation began. The remaining bromide solution was then added at a rate to maintain a reaction temperature range of 50-60° C. Once addition was complete the reaction was heated to gentle reflux for 1 hour then cooled in an ice bath. A solution of tert-Butyl 4-oxopiperidine-1-carboxylate (1.00 g, 5.02 mmol) in THF (10 mL) was the added to the reaction over a period of 30 minutes then the mixture was allowed to warm to room temperature with stirring over a 2 hour period. After this time the reaction was quenched by the addition of 25% ammonium chloride solution (50 mL) and the layers separated. The aqueous was extracted with ethyl acetate (2×10 mL) and the combined organics were washed with water (20 mL) and brine (20 mL) then dried over magnesium sulfate. Subsequent filtration, concentration and purification of the residue by column chromatography (SiO2, 0-25% ethyl acetate/heptanes) afforded a 61% yield of tert-butyl 4-(3-benzyloxyphenyl)-4-hydroxypiperidine-1-carboxylate as a viscous clear oil that became a white solid on standing.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[C:14]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[CH2:20]2)([OH:16])=[O:15].N1CCCCC1>C(O)C>[C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=[C:20]2[C:19]3[C:23](=[CH:24][CH:25]=[C:17]([C:14]([OH:16])=[O:15])[CH:18]=3)[NH:22][C:21]2=[O:26])[NH:9][CH:10]=1)([OH:3])=[O:2]
Reactant: O=C1Cc2cc(C(=O)O)ccc2N1
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(CCC(=O)O)c[nH]c1C=C1C(=O)Nc2ccc(C(=O)O)cc21
Yield: 30 %

Procedure:
4-(2-Carboxyethyl)-2-formyl-3-methylpyrrole (90.6 mg), 88.6 mg 5-carboxy-2-oxindole, and 75 μL piperidine in 2 mL of ethanol were heated at 95° C. for 5 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven. The crude product was purified by chromatography on a silica gel column using ethyl acetate-hexane-acetic acid as the eluant to give 51 mg(30%) of the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:26][CH2:25][C:24]1[CH:27]=[CH:28][C:21]([O:20][CH3:19])=[CH:22][CH:23]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: COc1ccc(CN)cc1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Product: CCOC(=O)c1cnc2c(OC)cccc2c1NCc1ccc(OC)cc1

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (250 mg, 0.94 mmol) was treated with 4-methoxybenzylamine following general procedure B to afford 8-methoxy-4-(4-methoxy-benzylamino)-quinoline-3-carboxylic acid ethyl ester (290 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid using general procedure D and then transformed into the corresponding ethylamide (190 mg) following general procedure E. The above ethylamide (0.41 mmol) was subjected to reaction with methyl chloroformate according to general procedure F to furnish 3-ethyl-7-methoxy-1-(4-methoxy-benzyl)-1H-pyrimido[5,4-c]quinoline-2,4-dione (110 mg). LCMS: m/z 422 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[CH:18][CH2:19][CH3:20])[C:15]([OH:17])=O)[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CS(Cl)(=O)=O.[NH2:26][C@@H:27]1[C:56](=[O:57])[N:29]2[C:30]([C:40]([O:42][CH:43]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:41])=[C:31]([CH2:34][O:35][C:36](=[O:39])[NH:37][CH3:38])[CH2:32][S:33][C@H:28]12.CN1CCOCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.C(N(CC)CC)C>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[CH:18][CH2:19][CH3:20])[C:15]([NH:26][C@@H:27]2[C:56](=[O:57])[N:29]3[C:30]([C:40]([O:42][CH:43]([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)=[O:41])=[C:31]([CH2:34][O:35][C:36](=[O:39])[NH:37][CH3:38])[CH2:32][S:33][C@H:28]23)=[O:17])[N:13]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CCC=C(C(=O)O)c1csc(NC(=O)OC(C)(C)C)n1
Agent: CS(=O)(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COC(=O)NC)CS[C@H]12)c1csc(NC(=O)OC(C)(C)C)n1
Temperature: -65 °C
Reaction time: 3 h
Yield: 85.3 %

Procedure:
To a solution of 2-(2-tert-butoxycarbonylaminothiazol-4-yl)-2-pentenoic acid (1.49 g) in dichloromethane (60 ml) are added triethylamine (0.83 ml) and methanesulfonyl chloride (0.4 ml) at -65° C., and the mixture is stirred for 3 hours at -65° C. To the mixture is added diphenylmethyl 7β-amino-3-methylcarbamoyloxymethyl-3-cephem-4-carboxylate (2.26 g) and N-methylmorpholine (0.55 ml) in dichloromethane (60 ml). After 2 hours, the reaction mixture is neutralized with 10% citric acid, washed with water, dried, and concentrated to give diphenylmethyl 7β-[2-(2-tert-butoxycarbonylaminothiazol-4-yl)-2-pentenoylamino]-3-methylcarbamoyloxymethyl-3-cephem-4-carboxylate (3.12 g). Yield: 85%.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:13][CH:12]=2)[C:8]2[CH:25]=[CH:26][CH:27]=[CH:28][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[N-:29]=[N+:30]=[N-:31].[Na+].[Cl-].[NH4+].O>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:31][N:30]=[N:29][N:24]=3)=[CH:13][CH:12]=2)[C:8]2[CH:25]=[CH:26][CH:27]=[CH:28][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccccc2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCc1nc2ccccc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 40.8 %

Procedure:
A mixture of 2-butyl-1-[(2'-cyanobiphenyl-4-yl)methyl]benzimidazole (1.8 g), sodium azide (0.98 g) and ammonium chloride (0.80 g) was stirred in DMF (6 ml) at 110° C. for 5 days, while supplementing sodium azide (1.6 g), ammonium chloride (1.3 g) and DMF (5 ml) to the reaction system. To the reaction mixture were added water and ethyl acetate, and precipitating crystals were collected by filtration. The organic layer of the filtrate was washed with water, dried and concentrated under reduced pressure to give crude crystals. These crystals were combined with the crystals obtained previously, this was followed by recrystallization from ethyl acetate - methanol to afford colorless prisms (0.82 g, 41%), m.p. 235-236° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][N:7]([C:9](=[O:22])[C@H:10]([NH:17][C:18](=[O:21])[O:19][CH3:20])[C:11]2[CH:16]=CC=C[CH:12]=2)[C@H:6]([C:23]2[NH:27][C:26]3[C:28]4[C:33]([CH:34]=[CH:35][C:25]=3[N:24]=2)=[CH:32][C:31]([C:36]2[CH:37]=[C:38]3[C:63](=[CH:64][CH:65]=2)[C:42]2[NH:43][C:44]([C@@H:46]5[CH2:51][C@@H:50]6[C@@H:48]([CH2:49]6)[N:47]5[C:52](=[O:62])[C@@H:53]([NH:57][C:58]([O:60][CH3:61])=[O:59])[CH:54]([CH3:56])[CH3:55])=[N:45][C:41]=2[CH:40]=[CH:39]3)=[CH:30][CH:29]=4)[CH2:5]1.CO[CH2:68][C@@H:69]1CN(C(=O)[C@@H](NC(=O)OC)C(C)C)[C@H](C2NC3C4C(C=CC=3N=2)=CC(B2OC(C)(C)C(C)(C)O2)=CC=4)[CH2:70]1.CC1(C)C(C)(C)OB(C2C=C3C(=CC=2)C2NC([C@@H]4C[C@@H]5[C@@H](C5)N4C(OC(C)(C)C)=O)=NC=2C=C3)O1>>[CH3:61][O:60][C:58]([NH:57][C@H:53]([C:54]1[CH:55]=[CH:70][CH:69]=[CH:68][CH:56]=1)[C:52]([N:47]1[C@H:46]([C:44]2[NH:43][C:42]3[C:63]4[C:38](=[CH:37][C:36]([C:31]5[CH:32]=[C:33]6[C:28](=[CH:29][CH:30]=5)[C:26]5[NH:27][C:23]([C@@H:6]7[CH2:5][C@H:4]([CH2:3][O:2][CH3:1])[CH2:8][N:7]7[C:9](=[O:22])[C@@H:10]([NH:17][C:18](=[O:21])[O:19][CH3:20])[CH:11]([CH3:16])[CH3:12])=[N:24][C:25]=5[CH:35]=[CH:34]6)=[CH:65][CH:64]=4)[CH:39]=[CH:40][C:41]=3[N:45]=2)[CH2:51][C@@H:50]2[C@H:48]1[CH2:49]2)=[O:62])=[O:59]
Reactant: COC[C@H]1C[C@@H](c2nc3ccc4cc(-c5ccc6c(ccc7nc([C@@H]8C[C@H]9C[C@H]9N8C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c76)c5)ccc4c3[nH]2)N(C(=O)[C@H](NC(=O)OC)c2ccccc2)C1
Reactant: COC[C@H]1C[C@@H](c2nc3ccc4cc(B5OC(C)(C)C(C)(C)O5)ccc4c3[nH]2)N(C(=O)[C@@H](NC(=O)OC)C(C)C)C1
Agent: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1nc2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2[nH]1
Product: COC[C@H]1C[C@@H](c2nc3ccc4cc(-c5ccc6c(ccc7nc([C@@H]8C[C@H]9C[C@H]9N8C(=O)[C@H](NC(=O)OC)c8ccccc8)[nH]c76)c5)ccc4c3[nH]2)N(C(=O)[C@@H](NC(=O)OC)C(C)C)C1
Yield: 27 %

Procedure:
This compound was made using the same procedure as was used to make methyl (R)-2-((2S,4S)-4-(methoxymethyl)-2-(2′-((1R,3S,5R)-2-((S)-3-methyl-2-methoxycarbonylaminobutanoyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate, using methyl (S)-1-((2S,4S)-4-(methoxymethyl)-2-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate and (1R,3S,5R)-tert-butyl 3-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate in the Suzuki-Miyaura cross coupling to give methyl (S)-1-((2S,4S)-2-(2′-((1R,3S,5R)-2-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H,1′H-7,7′-binaphtho[2,1-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (0.048 g, 27%). MS (ESI) m/z 877.71 [M+H]. 1H NMR (400 MHz, cd3od) δ 8.68-8.50 (m, 2H), 8.42-8.23 (m, 2H), 8.14-7.90 (m, 2H), 7.86-7.67 (m, 3H), 7.62-7.51 (m, J=6.2 Hz, 2H), 7.49-7.39 (m, J=15.3, 7.6 Hz, 2H), 6.86-6.01 (m, 5H), 5.83-5.67 (m, 1H), 5.59 (s, 1H), 5.49-5.33 (m, 2H), 4.64-4.18 (m, 3H), 4.13-3.92 (m, 2H), 3.87-3.76 (m, J=7.2 Hz, 2H), 3.68 (s, 2H), 2.89-2.22 (m, 7H), 2.19-2.00 (m, 3H), 1.77-1.48 (m, 2H), 1.11-0.85 (m, 7H), 0.80-0.68 (m, J=4.5 Hz, 2H).