Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.Cl[C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH3:24])[CH:19]=2)[N:14]=1.[CH3:25]C#N>>[CH3:24][O:23][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH:25]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1)[CH:22]=[CH:21]2
Reactant: CC#N
Reactant: CCOC(=O)C1CCNCC1
Reactant: COc1ccc2nc(Cl)ccc2c1
Product: CCOC(=O)C1CCC(c2ccc3cc(OC)ccc3n2)CC1

Procedure:
Ethyl piperidine-4-carboxylate (100 mg) was treated with 2-chloro-6-methoxyquinoline (Intermediate 1) (90 mg) in MeCN (0.8 mL) and TEA (100 mg) in a sealed tube at 180° C. for 6 h in a microwave reactor. After aqueous work-up with EtOAc and column purification, eluting with EtOAc/hexane, ethyl 4-(6-methoxyquinolin-2-yl)cyclohexanecarboxylate (90 mg) was afforded as a solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C@@H:15]1[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]1.[C:21]([O:25][C:26]([NH:28][C@H:29]([CH2:34][C:35]1[CH:44]=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=1)[CH2:30][C:31](O)=[O:32])=[O:27])([CH3:24])([CH3:23])[CH3:22].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C@@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:31](=[O:32])[CH2:30][C@H:29]([NH:28][C:26](=[O:27])[O:25][C:21]([CH3:22])([CH3:23])[CH3:24])[CH2:34][C:35]2[CH:44]=[CH:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=2)[CH2:16]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc2ccccc2c1
Reactant: COCCCn1c([C@@H]2CCCNC2)nc2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COCCCn1c([C@@H]2CCCN(C(=O)C[C@@H](Cc3ccc4ccccc4c3)NC(=O)OC(C)(C)C)C2)nc2ccccc21
Yield: 92.8 %

Procedure:
(R)-1-(3-methoxypropyl)-2-(piperidin-3-yl)-1H-benzo[d]imidazole (7D) (0.387 mmol, 0.120 g) was added to a 10 mL round-bottomed flask equipped for stirring under nitrogen. DMF (3 mL), (R)-3-(tert-butoxycarbonylamino)-4-(naphthalen-2-yl)butanoic acid (0.387 mmol, 0.127 g) and N-methylmorpholine (1.55 mmol, 0.170 mL) were then added and the solution was allowed to stir at rt for 5 min. HATU (0.426 mmol, 0.162 g) was added and the resultant solution was stirred at room temperature for 3 hr. The reaction solution was then directly purified by preparative LC/MS (25-95% CH3CN in H2O). The resultant fractions were collected and the solvent was removed in-vacuo affording tert-butyl (R)-4-((R)-3-(1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-1-(naphthalen-2-yl)-4-oxobutan-2-ylcarbamate (7E) as a clear oil (0.359 mmol, 0.210 g, 93% yield). ESI-MS: m/z 585.5 (M+Hr.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.O=[C:18]([C:24](OCC)=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(O)C>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([N:8]2[C:24](=[O:25])[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:1][C:2]3[CH:7]=[CH:6][CH:5]=[N:4][C:3]2=3)=[CH:10][CH:11]=1
Reactant: CCOC(=O)C(=O)C(=O)OCC
Reactant: COc1ccc(Nc2ncccc2N)cc1
Solvent: CCO
Product: CCOC(=O)c1nc2cccnc2n(-c2ccc(OC)cc2)c1=O
Temperature: 25 °C
Yield: 37.1 %

Procedure:
5.2 g (24 mmol) of 3-amino-2-(4-methoxyphenyl)aminopyridine was dissolved in ethanol (150 mL), and 4.6 g (27 mmol) of diethyl ketomalonate was added thereto. The mixture was heated to reflux for 9 hours while stirring. After confirming the completion of the reaction, the reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure. The residue thus obtained was purified by column chromatography (developing solvent:ethyl acetate:hexane=1:2), to obtain 2.9 g (yield: 37%) of ethyl 4-(4-methoxyphenyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine-2-carboxylate as yellow crystals.
Reaction SMILES: [CH3:1][Mg+].[Br-].[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14](=[O:19])[C:13]([C:20](N(OC)C)=[O:21])=[N:12]1>C1COCC1>[C:20]([C:13]1[C:14](=[O:19])[C:15]([O:17][CH3:18])=[CH:16][N:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[F:4])[N:12]=1)(=[O:21])[CH3:1]
Reactant: C[Mg+]
Reactant: COc1cn(-c2ccccc2F)nc(C(=O)N(C)OC)c1=O
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cn(-c2ccccc2F)nc(C(C)=O)c1=O
Reaction time: 1 h
Yield: 85.1 %

Procedure:
MeMgBr (1 M solution in THF, 30 mL, 30 mmol) was added dropwise at −78° C. to a solution of 1-(2-fluorophenyl)-N,5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (3.20 g, 10.4 mmol) in THF (30 mL). After stirring for 1 h, the reaction mixture was quenched with 1 M HCl aqueous solution, saturated with NaCl, and extracted with AcOEt rive times. The combined extracts were dried over MgSO4, and concentrated under reduced pressure. The residue was recrystallized from AcOEt to give the title compound (2.32 g, 85% yield) as pale yellow crystals: mp 154-156° C.; NMR (300 MHz, CDCl3): δ ppm 2.69 (3H, s), 3.91 (3H, s), 7.27-7.38 (2H, m), 7.45-7.53 (1H, m), 7.65 (1H, dt, J=1.5, 7.9 Hz), 7.77 (1H, d, J=2.3 Hz). Anal. Calcd for C13H11FN2O3: C, 59.54; H, 4.23; N, 10.68. Found: C, 59.62; H, 4.22; N, 10.79.
Reaction SMILES: [BH4-].[Na+].C[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[CH3:13]O.O>C1COCC1.C(OCC)(=O)C>[C:12]1([CH3:13])[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:5]([OH:6])[CH3:4]
Reactant: CO
Reactant: CCC(=O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccccc1C(C)O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Sodium borohydride (564 mg) was added to a solution of 2-methylacetophenone (1 g) in a mixture of THF (8 mL) with methanol (32 mL), and the reaction solution was stirred at room temperature for 20 minutes. Water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 911 mg of the title compound. The physical properties of the compound are as follows.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:39])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([S:18][CH2:19][CH2:20][CH3:21])=[C:16]([C:22](=[O:38])[NH:23][CH:24]3[CH:31]4[CH2:32][CH:27]5[CH2:28][C:29]([S:34]([CH3:37])(=[O:36])=[O:35])([CH2:33][CH:25]3[CH2:26]5)[CH2:30]4)[CH:15]=[N:14]2)=[CH:9][CH:8]=1.O>CO>[CH3:37][S:34]([C:29]12[CH2:33][CH:25]3[CH2:26][CH:27]([CH2:32][CH:31]([CH:24]3[NH:23][C:22]([C:16]3[CH:15]=[N:14][N:13]([C:10]4[CH:9]=[CH:8][C:7]([C:6]([OH:39])=[O:5])=[CH:12][CH:11]=4)[C:17]=3[S:18][CH2:19][CH2:20][CH3:21])=[O:38])[CH2:30]1)[CH2:28]2)(=[O:35])=[O:36]
Reactant: CCCSc1c(C(=O)NC2C3CC4CC2CC(S(C)(=O)=O)(C4)C3)cnn1-c1ccc(C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCSc1c(C(=O)NC2C3CC4CC2CC(S(C)(=O)=O)(C4)C3)cnn1-c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.2 %

Procedure:
Lithium hydroxide monohydrate (27.5 mg, 0.65 mmol) was added to a suspension of 4-[4-(5-Methanesulfonyl-adamantan-2-ylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]-benzoic acid methyl ester (Intermediate #105) (116 mg, 0.22 mmol) in methanol (4 mL)/water (2 mL) at ambient temperature. The resulting suspension was stirred at ambient temperature for 18 hours. The bulk of the organic solvent was removed in vacuo and the resulting solution was diluted with water (10 mL) and washed with ether (10 mL). The aqueous layer was acidified to ˜pH4 with 2M HCl then extracted with EtOAc (3×25 ml). The EtOAc layers were combined, washed sequentially with water (5 mL) and saturated to brine (10 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford 4-[4-(5-Methanesulfonyl-adamantan-2-ylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]-benzoic acid (113 mg, 100%) as a white solid.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][C:6]2[CH:16]=[CH:15][C:9]3[CH2:10][CH2:11][CH:12]([CH3:14])[O:13][C:8]=3[CH:7]=2)[CH2:2]1.[NH2:17][CH:18]([CH3:20])[CH3:19]>>[CH3:14][CH:12]1[CH2:11][CH2:10][C:9]2[CH:15]=[CH:16][C:6]([O:5][CH2:4][CH:3]([OH:1])[CH2:2][NH:17][CH:18]([CH3:20])[CH3:19])=[CH:7][C:8]=2[O:13]1
Reactant: CC1CCc2ccc(OCC3CO3)cc2O1
Reactant: CC(C)N
Product: CC(C)NCC(O)COc1ccc2c(c1)OC(C)CC2

Procedure:
Following the process of example 9 (a) and reacting 1,2-epoxy-3-(2-methyl-3,4-dihydro-2H-1-benzopyrane-7-yloxy)-propane with 2-aminopropane, 1-(2-methyl-3,4-dihydro-2H-1-benzopyrane-7-yloxy)-3-(1-methylethylamino)-2-propanol was obtained as a base (m.p. 79°-81° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:12])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[N:13]([O-])=O.[Na+].O.O.Cl[Sn]Cl.[CH3:22][C:23]([CH3:30])([CH3:29])[C:24](=O)[CH2:25][C:26]#[N:27]>Cl.O.CCO>[NH2:27][C:26]1[N:1]([C:2]2[CH:11]=[C:10]3[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]3)=[CH:4][CH:3]=2)[N:13]=[C:24]([C:23]([CH3:30])([CH3:29])[CH3:22])[CH:25]=1
Reactant: O=N[O-]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: Nc1ccc2c(O)ncnc2c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(-c2ccc3c(=O)[nH]cnc3c2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 48.1 %

Procedure:
To a stirred suspension of 7-aminoquinazolin-4-ol (2.00 g, 12.4 mmol) in conc. HCl (20.0 ml) at 0° C. was added dropwise NaNO2 (0.98 g, 14.3 mmol, 1.15 eq) as a solution in H2O (15.0 ml). The resulting mixture was stirred at 0° C. for 1 h, and then treated with a solution of SnCl2.2H2O (12.0 g, 53.4 mmol, 4.30 eq) in conc. HCl (15.0 ml). The reaction was stirred at 0° C. for 1 h and then at RT for 2 h. The reaction was diluted with EtOH (130 ml) and 4,4-dimethyl-3-oxopentanenitrile (2.02 g, 16.1 mmol, 1.30 eq) added, heated at reflux overnight, then cooled to RT and concentrated. The residue was diluted with EtOAc (100 mL), placed in an ice/H2O bath and the stirred solution made basic (pH 8) with solid NaOH. The mixture was filtered through Celite®, washed with H2O (50 mL) and then EtOAc (100 mL). The organic phase washed with brine, dried (Na2SO4) and concentrated to yield a tan solid, which was dried then stirred in ether (100 mL) and allowed to stand. The solid was collected by filtration and dried to yield 7-(5-amino-3-t-butyl-1H-pyrazol-1-yl)quinazolin-4(3H)-one (1.69 g, 48% yield). 1H NMR (300 MHz, DMSO-d6): 8.17-8.11 (m, 2H), 7.90-7.83 (m, 2H), 5.47 (m, 3H), 1.23 (s, 9H). MS (ESI) m/e (M+H+) 284.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[CH3:9][Si:10]([C:13]#[CH:14])([CH3:12])[CH3:11]>C(NC(C)C)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[CH3:9][Si:10]([CH3:12])([CH3:11])[C:13]1[CH:3]=[CH:4][C:5]([CH3:8])=[C:6]([C:7]#[CH:2])[CH:14]=1
Reactant: Cc1ccc(Br)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CC(C)NC(C)C
Product: C#Cc1cc([Si](C)(C)C)ccc1C
Temperature: 80 °C
Yield: 96.3 %

Procedure:
Under an argon atmosphere, 33 g (0.193 mol) of 4-bromotoluene, 2.7 g (3.85 mmol) of bis(triphenylphosphine)palladium(II) dichloride and 0.735 mg (3.85 mmol) of copper Iodide were put into a 1 L 3-necked flask equipped with a stirrer, thermometer and reflux condenser, and dissolved in 500 ml of diisopropylamine. 37.9 g (0.385 mol) of trimethylsilyl acetylene was slowly dropped into the resluting solution at room temperature. The reaction mixture was slowly heated to 80° C. and refluxed for 12 hours. After the reaction was completed, the reaction mixture was cooled down to room temperature. The precipitated salt was filtered off, and then the solvent was removed under a reduced pressure. The residue was dissolved in methylene chloride. The organic solution was washed with water several times and then dried with anhydrous magnesium sulfate. The solvent was removed to obtain liquid, which was purified by silica gel column chromatography using hexane as an eluent, to give 35 g (99.3% yield) of pale brown viscous liquid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][O-:16].[Na+]>>[CH3:15][O:16][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: C[O-]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Agent: [Na+]
Product: COc1ccc(C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
Reaction of 4-chloro-3-nitrobenzotrifluoride with sodium methoxide to give 4-methoxy-3-nitro-benzotrifluoride
Reaction SMILES: Cl[C:2]1[C:15]2[C:6](=[N:7][C:8]3[C:9]4[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[C:10]=4[CH2:11][CH2:12][C:13]=3[CH:14]=2)[CH:5]=[CH:4][CH:3]=1.[CH2:22](B(O)O)[CH:23]([CH3:25])[CH3:24]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>[CH2:22]([C:2]1[C:15]2[C:6](=[N:7][C:8]3[C:9]4[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[C:10]=4[CH2:11][CH2:12][C:13]=3[CH:14]=2)[CH:5]=[CH:4][CH:3]=1)[CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)CB(O)O
Reactant: Cc1cc(C)c2c(c1)-c1nc3cccc(Cl)c3cc1CC2
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1cc(C)c2c(c1)-c1nc3cccc(CC(C)C)c3cc1CC2
Temperature: 25 °C
Yield: 92.4 %

Procedure:
8-chloro-2,4-dimethyl-5,6-dihydrobenzo[c]acridine (15.0 g, 51.1 mmol), isobutylboronic acid (7.8 g, 77 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (1.6 g, 4.08 mmol) potassium phosphate monohydrate (41.2 g, 179 mmol) were mixed in 300 mL of toluene. The system was degassed for 20 minutes. Pd2(dba)3 (0.93 g, 1.02 mmol) was then added and the system was refluxed overnight. After cooling to room temperature, the reaction mixture was filtered through a Celite® plug and eluted with 30% ethyl acetate in toluene. ˜19.5 crude liquid was obtained. The crude product was recrystallized from 5% acetone in hexane to obtain ˜14.9 g pure product (99.6%) which was confirmed by GC-MS.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:14]([C:17]1[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[CH:20]=[C:19]([CH:26]([CH3:28])[CH3:27])[C:18]=1[S:29](Cl)(=[O:31])=[O:30])([CH3:16])[CH3:15].[Cl-].[Al+3].[Cl-].[Cl-]>>[CH:14]([C:17]1[CH:22]=[C:21]([CH:23]([CH3:24])[CH3:25])[CH:20]=[C:19]([CH:26]([CH3:28])[CH3:27])[C:18]=1[S:29]([C:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1)(=[O:31])=[O:30])([CH3:15])[CH3:16]
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Agent: [Al+3]
Agent: [Cl-]
Product: CC(C)c1cc(C(C)C)c(S(=O)(=O)c2cccc3c2Cc2ccccc2-3)c(C(C)C)c1

Procedure:
For example, fluorene can be reacted with 2,4,6-triisopropylbenzenesulfonyl chloride in the presence of aluminum chloride to yield 2 (2,4,6-tri-isopropylphenylsulfonyl)fluorene, which can be refluxed with sodium dichromate dihydrate in glacial acetic acid to yield 2 (2,4,6-triisopropylphenyl sulfonyl)fluorenone, which in turn can be refluxed with malononitrile in methanol in the presence of piperidine to yield 2 (2,4,6-triisopropylphenylsulfonyl)-9-(dicyanomethylene)fluorene.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[CH:8]=[CH:7]2.[CH3:13][O-:14].[Na+].[H-].[Na+].[H][H]>CN(C=O)C.CO>[NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:14][CH3:13])[CH:8]=[CH:7]2
Reactant: Nc1cccc2ccc(Cl)nc12
Reactant: [H][H]
Reactant: C[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccc2cccc(N)c2n1

Procedure:
Thus, the 8-amino-2-chloroquinoline VI was allowed to react with a solution of sodium methylate in DMF (prepared under nitrogen by adding sodium hydride to a solution of methanol in DMF accompanied by the liberation of hydrogen). This procedure afforded 8-amino-2-methoxyquinoline VII. The introduction of the 8-(4-amino-1-methylbutyl) side chain was accomplished in the same manner as for the COMPARATIVE COMPOUND (U.S. Pat. No. 4,431,801). Thus intermediate VII was treated with 4-iodo-1-phthalimidopentane to give the target precursor 8-(4-phthalimido-1-methylbutylamino)quinoline VIII. The phthalimido group was removed with hydrazine to give the title compound free base IX. The free base was treated with succinic acid in a suitable solvent system to give the 2-methoxy target compound X as the succinic acid salt.
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]([C:38]1[N:39]=[C:40]([NH:43][C:44]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[S:41][CH:42]=1)[C:7]([NH:9][CH:10]1[C:36](=[O:37])[N:12]2[C:13]([C:20]([O:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])=[C:14]([CH2:18][I:19])[CH2:15][S:16](=[O:17])[C@H:11]12)=[O:8])[CH:2]=[CH2:3].O.Br.[OH:65][C:66]1[CH:67]=[C:68]2[C:73](=[CH:74][C:75]=1[OH:76])[CH:72]=[N:71][CH:70]=[CH:69]2>>[I-:19].[CH2:1]([O:4][N:5]=[C:6]([C:38]1[N:39]=[C:40]([NH:43][C:44]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[S:41][CH:42]=1)[C:7]([NH:9][CH:10]1[C:36](=[O:37])[N:12]2[C:13]([C:20]([O:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])=[C:14]([CH2:18][C:72]3[C:73]4[C:68](=[CH:67][C:66]([OH:65])=[C:75]([OH:76])[CH:74]=4)[CH:69]=[CH:70][NH+:71]=3)[CH2:15][S:16](=[O:17])[C@H:11]12)=[O:8])[CH:2]=[CH2:3]
Reactant: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS(=O)[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: Oc1cc2ccncc2cc1O
Agent: Br
Solvent: O
Product: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(Cc3[nH+]ccc4cc(O)c(O)cc34)CS(=O)[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Product: [I-]
Yield: 88.1 %

Procedure:
2.0 g (yield: 86%) of benzhydryl 7-[2-allyloxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-(6,7-dihydroxyisoquinolinio)methyl-3-cephem-4-carboxylate 1-oxide iodide (syn-isomer) was prepared from 2.0 g (2.0 mmol) of benzhydryl 7-[2-allyloxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-iodomethyl-3-cephem-4-carboxylate 1-oxide (syn-isomer) and 600 mg (2.3 mmol) of 6,7-dihydroxyisoquinoline hydrobromide monohydrate in the same manner as in Example 1(D).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][N:10]([CH3:23])[C:11]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=2)[C:16]([O:18][CH3:19])=[O:17])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:24][C:25]([O:28][C:29]([N:31]1[CH2:36][CH2:35][N:34]([CH2:37][C:38]2[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][CH:43]=2)[CH2:33][C@@H:32]1[CH3:47])=[O:30])([CH3:27])[CH3:26].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[F:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:9][N:10]([CH3:23])[C:11]([C:13]2[CH:22]=[CH:21][CH:20]=[C:15]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=2)=[O:12])=[CH:3][C:2]=1[C:40]1[CH:41]=[CH:42][CH:43]=[C:38]([CH2:37][N:34]2[CH2:35][CH2:36][N:31]([C:29]([O:28][C:25]([CH3:27])([CH3:26])[CH3:24])=[O:30])[C@@H:32]([CH3:47])[CH2:33]2)[CH:39]=1
Reactant: COC(=O)c1cccc(C(=O)N(C)Cc2ccc(F)c(Br)c2)c1
Reactant: C[C@H]1CN(Cc2cccc(B(O)O)c2)CCN1C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cccc(C(=O)N(C)Cc2ccc(F)c(-c3cccc(CN4CCN(C(=O)OC(C)(C)C)[C@@H](C)C4)c3)c2)c1
Temperature: 130 °C
Yield: 69.3 %

Procedure:
To a solution of methyl 3-{[[(3-bromo-4-fluorophenyl)methyl](methyl)amino]carbonyl}benzoate (0.20 g, 0.526 mmol) in p-dioxane/H2O (4.5/1.5 mL) was added {3-[((3S)-4-{[(1,1-dimethylethyl)oxy]carbonyl}-3-methyl-1-piperazinyl)methyl]-phenyl}boronic acid (0.264 g, 0.789 mmol), Pd(PPh3)4 (0.030 g, 0.026 mmol), and K2CO3 (0.29 mL, 2.1 mmol). The mixture was heated with z microwave at 130° C. for 15 min. The mixture was then filtered, and the filtrate concentrated and purified by CombiFlash chromatograph to afford the title compound 0.215 g (69%). LC-MS m/z 590 (M+H)+.
Reaction SMILES: [N+:1]([CH:3](S(C1C=CC(C)=CC=1)(=O)=O)[C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)#[C-:2].[O:22]=[CH:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].N1CCNCC1>O1CCCC1>[C:8]([C:7]1[CH:6]=[CH:5][C:4]([C:3]2[N:1]=[CH:2][O:22][C:23]=2[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:11][CH:10]=1)#[N:9]
Reactant: CCOC(=O)C=O
Reactant: [C-]#[N+]C(c1ccc(C#N)cc1)S(=O)(=O)c1ccc(C)cc1
Agent: C1CNCCN1
Solvent: C1CCOC1
Product: CCOC(=O)c1ocnc1-c1ccc(C#N)cc1
Yield: 49 %

Procedure:
A solution of 4-(isocyano(tosyl)methyl)benzonitrile (1 g, 3.37 mmol, 1.00 equiv), ethyl 2-oxoacetate (1 g, 4.90 mmol, 1.45 equiv) and piperazine (500 mg, 5.80 mmol, 1.72 equiv) in tetrahydrofuran (20 mL) was stirred at room temperature overnight. The resulting mixture was concentrated under vacuum and the residue was purified on a silica gel column eluted with 0-30% of ethyl acetate in petroleum ether to afford 0.4 g (49%) of ethyl 4-(4-cyanophenyl)oxazole-5-carboxylate as a yellow solid. 1H-NMR (300 MHz, CDCl3): δ 8.27-8.24 (m, 2H), 8.07 (s, 1H), 7.76-7.73 (m, 2H), 4.47-4.36 (m, 2H), 1.43-1.33 (m, 3H) ppm.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:9](=[O:10])[C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[NH:6][S:5]1(=[O:16])=[O:15])[CH3:3].C[C:18](C)([O-:20])C.[K+].Cl[C:24](OC)=[S:25]>C(#N)C>[CH3:3][CH:2]([N:4]1[C:9](=[O:10])[C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[N:6]([C:18](=[O:20])[S:25][CH3:24])[S:5]1(=[O:16])=[O:15])[CH3:1]
Reactant: CC(C)N1C(=O)c2ccccc2NS1(=O)=O
Reactant: COC(=S)Cl
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC#N
Product: CSC(=O)N1c2ccccc2C(=O)N(C(C)C)S1(=O)=O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To 200 ml of acetonitrile was added 24 g (0.1 mole) of 3-(1-methylethyl)-1H-2,1,3-benzothiadiazin-4(3H)-one-2,2-dioxide and 11.8 g of potassium t-butoxide. The mixture was heated to reflux, cooled to 50° C. and 12.6 g (0.114 mole) of methyl chlorothioformate in 100 ml of acetonitrile was added over a 0.5 hour period. The temperature was maintained at 50°-52 C. Stirring was continued at 50° C. overnight. The mixture was cooled, filtered, and the solvent removed from the filtrate in vacuo. The residual solid was washed with 3-50 ml-portions of methanol to afford 21.7 g of analytically pure S-methyl 3,4-dihydro-3-(1-methylethyl)-4-oxo-1H-2,1,3-benzothiadiazine-1-carbothioate-2,2-dioxide, m.p. 125°-127° C.
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]1=[O:11].[SH:13][CH:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][OH:17].C(N(C(C)C)CC)(C)C>C(#N)C>[CH2:18]([CH:14]1[CH2:15][CH2:16][O:17][C:4]2[C:5]3[C:10]([C:1](=[O:12])[C:2](=[O:11])[C:3]=2[S:13]1)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:19][CH3:20]
Reactant: CCCC(S)CCO
Reactant: O=C1C=Cc2ccccc2C1=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCCC1CCOC2=C(S1)C(=O)C(=O)c1ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 6.2 %

Procedure:
To a solution of naphthalene-1,2-dione (1.5 g, 9.5 mmol) in acetonitrile (50 mL) was added 3-mercaptohexan-1-ol (1.6 g, 11.9 mmol) followed by the addition of diisopropylethylamine (1.65 mL, 9.5 mmol). The mixture was stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure and the residue dissolved in ethyl acetate (50 mL). The organic layer was washed with water (30 mL), dried with sodium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in acetonitrile (35 mL) and reacted with p-toluenesulfonic acid (1.9 g). The reaction mixture was stirred at room temperature for 40 min and solvent removed under reduced pressure. Crude product was purified by flash column (5% EtOAc in hexane to 15% EtOAc in hexanes) to give product as purple solid (0.170 g). M.p.=74-75° C. (decomposition); 400 MHz 1H NMR (DMSO-d6) δ: 7.88 (d, J=7.2 Hz, 1H), 7.73 (m, 2H), 7.56 (m, 1H), 5.08 (m, 1H), 4.67 (m, 1H), 3.58 (m, 1H), 1.40-1.82 (m, 6H), 0.89 (brt, 3H); LCMS: 289 [M+H].