Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:25][O:26][CH2:27][CH3:28])[N:18]([CH2:19][CH2:20][CH2:21][C:22](=O)[CH3:23])[C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1.[C:29]([BH3-])#N.[Na+].[OH-].[Na+]>O.C(O)C.C(O)(=O)C>[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:25][O:26][CH2:27][CH3:28])[N:18]([CH2:19][CH2:20][CH2:21][CH:22]([NH:4][O:2][CH2:3][CH3:29])[CH3:23])[C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: CON
Reactant: [BH3-]C#N
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CCCC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCCC(C)NOCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.9 %

Procedure:
Methoxylamine hydrochloride (0.25 g, 3.0 mmol) in water (4 mL) was added to a solution of 5-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one (0.81 g, 2.5 mmol) in ethanol (25 mL) and stirred at ambient temperature for 3 hours. Addition of acetic acid (20 mL) and sodium cyanoborohydride (2.0 g, 32 mmol) to the reaction mixture followed. After 2.5 hours, the reaction mixture was cooled to 0° C. and the pH was adjusted to ˜8 with 25% sodium hydroxide solution. The mixture was concentrated under reduced pressure, diluted with dichloromethane (75 mL) and saturated aqueous sodium bicarbonate and the layers were separated. The combined organic layers were washed with water (25 mL), dried over potassium carbonate, filtered, and concentrated under reduced pressure to afford 0.64 g of N-[4-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1-methylbutyl]-O-ethylhydroxylamine.
Reaction SMILES: [CH3:1][NH2:2].O[CH:4]=[C:5]1[C:9]([CH3:11])([CH3:10])[O:8][C:7]([CH3:13])([CH3:12])[C:6]1=[O:14]>C(Cl)(Cl)Cl>[CH3:12][C:7]1([CH3:13])[C:6](=[O:14])[C:5](=[CH:4][NH:2][CH3:1])[C:9]([CH3:11])([CH3:10])[O:8]1
Reactant: CN
Reactant: CC1(C)OC(C)(C)C(=CO)C1=O
Solvent: ClC(Cl)Cl
Product: CNC=C1C(=O)C(C)(C)OC1(C)C
Yield: 74 %

Procedure:
Methylamine gas was bubbled through a solution of 4-hydroxymethylene-dihydro-2,2,5,5-tetramethyl-3(2H)furanone (5.0 g, 29 mmol) in 50 mL of chloroform for 30 min. The solvents were evaporated. The solid residue was recrystallized from hexanes to give 4.0 g (74%) of dihydro-2,2,5,5-tetramethyl-4-methylaminomethylene-3(2H)furanone as a light yellow solid: mp 80°-82° C.; Anal Calc'd for C10H17NO2 : C, 65.57; H, 9.29; N, 7.65. Found: C, 65.47; H, 9.30; N, 7.60.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:8][C:9]1[CH:22]=[CH:21][CH:20]=[CH:19][C:10]=1[CH2:11][O:12][C:13]([CH3:18])([CH2:16]O)[CH2:14][OH:15]>C1C=CC=CC=1>[F:8][C:9]1[CH:22]=[CH:21][CH:20]=[CH:19][C:10]=1[CH2:11][O:12][C:13]1([CH3:18])[CH2:14][O:15][C:1]2([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[O:7][CH2:16]1
Reactant: CC(CO)(CO)OCc1ccccc1F
Reactant: O=C1CCCCC1
Solvent: c1ccccc1
Product: CC1(OCc2ccccc2F)COC2(CCCCC2)OC1

Procedure:
Using the procedure of Example 51, cyclohexanone and 2-(2-fluorobenzyloxy)-2-methyl-1,3-propanediol were reacted, using benzene as solvent, to give 3-(2-fluorobenzyloxy)-3-methyl-1,5-dioxaspiro[5.5]undecane, b.p. 170°-174°/0.03 mm, nD25 1.5081. The ir and nmr spectra were consistent with the assigned structure.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[C:14](=[O:18])[CH2:15][CH2:16][CH2:17][C:12]=3[N:11]=[C:10]2[CH:19]([CH3:21])[CH3:20])=[CH:4][CH:3]=1.ClCCl.[BH4-].[Na+]>CO>[I:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13]3[CH:14]([OH:18])[CH2:15][CH2:16][CH2:17][C:12]=3[N:11]=[C:10]2[CH:19]([CH3:21])[CH3:20])=[CH:6][CH:7]=1
Reactant: CC(C)c1nc2c(n1Cc1ccc(I)cc1)C(=O)CCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)c1nc2c(n1Cc1ccc(I)cc1)C(O)CCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.7 %

Procedure:
To Intermediate 87 (6.65 g) in a 250 mL round-bottom flask under nitrogen in Methanol (20 mL) and Dichloromethane (DCM) (20 mL) was added sodium borohydride (1.276 g) in three portions (effervescence) and the mixture stirred at room temperature under nitrogen for 16 h. The solvent was removed under vacuum and the residue was partitioned between ethyl acetate and water. The aqueous layer extracted well with ethyl acetate. The combined organics were dried (hydrophobic frit), filtered and evaporated to give the title compound 6.6 g as a white solid. LC/MS MH+397, Rt 2.61 min (5 min run).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[OH:7][C:8]1([CH2:14][CH2:15][N:16]2[C:20](=[O:21])[CH2:19][S:18][CH:17]2[CH2:22][CH2:23][CH2:24][C:25]2[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>CO.O>[OH:7][C:8]1([CH2:14][CH2:15][N:16]2[C:20](=[O:21])[CH2:19][S:18](=[O:2])[CH:17]2[CH2:22][CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:29]([OH:31])=[O:30])=[CH:32][CH:33]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: O=C(O)c1ccc(CCCC2SCC(=O)N2CCC2(O)CCCCC2)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(CCCC2N(CCC3(O)CCCCC3)C(=O)CS2=O)cc1

Procedure:
Sodium metaperiodate (0.75 g., 3.5 mmoles) is added to a cold (0°-5° C.) solution of 4-{3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}benzoic acid (1.33 g., 3.4 mmoles) in methanol (20 ml.) and water (5 ml.). The resulting mixture is stirred without further cooling for 16 hours. The precipitated solid is then removed by filtration. The filtrate is diluted with water and extracted with chloroform. The organic extract is washed with brine, dried over sodium sulfate, and evaporated in vacuo to leave an oily residue which is chromatographed on silica gel (25 g.). Elution with 4% acetic acid in chloroform affords the title compound as a viscous, yellowish oil.
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.CCN(C(C)C)C(C)C.Cl.[CH3:27][N:28]([CH3:39])[C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[NH:35][CH2:34][CH2:33][CH2:32]2>CN1C(=O)CCC1.O>[CH3:27][N:28]([CH3:39])[C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]([C:2]1[C:3](=[O:16])[NH:4][C:5]3[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)[CH2:34][CH2:33][CH2:32]2
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Reactant: CN(C)c1ccc2c(c1)CCCN2
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2[nH]c(=O)c(N3CCCc4cc(N(C)C)ccc43)nc2c1
Temperature: 130 °C
Reaction time: 2 h
Yield: 39 %

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (420 mg, 1.76 mmol,) in NMP (3 mL) was added DIEA (343 mg, 2.65 mmol), N,N-dimethyl-1,2,3,4-tetrahydroquinolin-6-amine hydrochloride (400 mg, crude) and the reaction was stirred for 2 h at 130° C. in an oil bath. The resulting solution was diluted with water (100 mL), and the solids were collected by filtration to give methyl 3-[6-(dimethylamino)-1,2,3,4-tetrahydroquinolin-1-yl]-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a red solid (260 mg, 39%).
Reaction SMILES: [N:1]1([C:6]2[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.N1C=CC=CC=1.Cl[C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21]>CN(C)C(=O)C>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([NH:10][C:20](=[O:21])[O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[CH:11][CH:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1ccc(-n2cccn2)cc1
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: O=C(Nc1ccc(-n2cccn2)cc1)OCC(Cl)(Cl)Cl
Temperature: 0 °C
Yield: 95.2 %

Procedure:
To a solution of 4-(1H-pyrazol-1-yl)aniline (1.00 g, 6.28 mmol) and pyridine (1.52 ml, 18.8 mmol) in N,N-dimethylacetamide (20 ml) was added 2,2,2-trichloroethyl chloroformate (1.30 ml, 9.42 mmol) under ice-cooling, and the mixture was stirred under ice-cooling for 2 hours. The reaction mixture was poured into ice-water, and 2.00 g (95.2%) of the desired product was collected by filtration as a solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH:10]1[CH2:18][CH2:17][CH2:16][CH:12]([C:13]([NH2:15])=[O:14])[CH2:11]1.[NH2:19][C:20]1[CH:28]=[C:27]2[C:23]([CH:24]=[N:25][NH:26]2)=[CH:22][CH:21]=1.C(O)CCC>CC#N>[NH:26]1[C:27]2[C:23](=[CH:22][CH:21]=[C:20]([NH:19][C:2]3[N:7]=[C:6]([N:10]4[CH2:18][CH2:17][CH2:16][CH:12]([C:13]([NH2:15])=[O:14])[CH2:11]4)[C:5]([F:9])=[CH:4][N:3]=3)[CH:28]=2)[CH:24]=[N:25]1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: NC(=O)C1CCCNC1
Solvent: CC#N
Solvent: CCCCO
Product: NC(=O)C1CCCN(c2nc(Nc3ccc4cn[nH]c4c3)ncc2F)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 23.6 %

Procedure:
A mixture of 2,4-dichloro-5-fluoropyrimidine (167 mg, 1.00 mmol), nipecotamide (128 mg, 1.00 mmol) and DEA (0.350 mL, 2.01 mmol) in CH3CN (4 mL) was stirred at room temperature for 20 h. It was concentrated in vacuo. The residue was dissolved in nBuOH (4 mL). 2 mL of the nBuOH solution was taken, to which 6-aminoindazole (100 mg, 0.75 mmol) was added. The solution was stirred at 116° C. for 6 h. nBuOH was removed in vacuo. The residue was purified by HPLC to give the titled compound (63 mg). MS 356.3 (M+H); UV 206.8, 249.8, 276.8, 291.8 nm.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH:4]([CH:5]([OH:13])[C:6]([Cl:12])([Cl:11])[C:7]([F:10])([F:9])[F:8])[CH:3]1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[CH3:20][S:21](Cl)(=[O:23])=[O:22].C(N(CC)CC)C.CCCCCC>C(OCC)C>[CH3:1][C:2]1([CH3:19])[CH:4]([CH:5]([O:13][S:21]([CH3:20])(=[O:23])=[O:22])[C:6]([Cl:11])([Cl:12])[C:7]([F:8])([F:9])[F:10])[CH:3]1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C1C(C(O)C(Cl)(Cl)C(F)(F)F)C1(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CCOC(=O)C1C(C(OS(C)(=O)=O)C(Cl)(Cl)C(F)(F)F)C1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.3 %

Procedure:
To a solution of 135 mg (0.794 mmol) of ethyl 2,2-dimethyl-3-(1-hydroxy-2,2-dichloro-3,3,3-trifluoropropyl)cyclopropanecarboxylate obtained in Example 2, in 2 ml of diethyl ether, 0.073 ml (0.94 mmol) of methanesulfonyl chloride and 0.133 ml (0.95 mmol) of triethylamine, were added, and the mixture was stirred at room temperature for 2 hours. After an addition of 5 ml of hexane to the mixture, the precipitated inorganic salt was filtered off, and the filtrate was concentrated under reduced pressure. The product was purified by thin layer chromatography (silica gel, dichloromethane/hexane=1/1) to obtain 157 mg of ethyl 2,2-dimethyl-3-(1-methanesulfonyloxy-2,2-dichloro-3,3,3trifluoropropyl)cyclopropanecarboxylate as a colorless oily substance.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].CCN(C(C)C)C(C)C.Cl[C:22]([O:24][CH3:25])=[O:23]>C1COCC1>[F:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH:4][C:22](=[O:23])[O:24][CH3:25]
Reactant: COC(=O)Cl
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Nc1cc([N+](=O)[O-])ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
A solution of 2-fluoro-5-nitroaniline (500 mg, 3.20 mmol) in THF (20 mL) was treated with DIEA (0.84 mL, 4.8 mmol) followed by methyl chloroformate (0.25 mL, 3.20 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. The crude product was dissolved in a small amount of DCM and purified by flash chromatography (SiO2, 20% ethyl acetate/hexanes to 50% ethyl acetate/hexanes, 40 g column, 30 min. gradient) to afford Intermediate 59A (450 mg, 65.6%). HPLC: Rt=2.868 min. (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min. gradient, monitored at 220 nm). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.94 (1H, s), 8.72 (1H, dd, J=6.80, 2.77 Hz), 7.87-8.09 (1H, m), 7.52 (1H, t), 3.72 (3H, s).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][N:21]4[C:30](Br)=[CH:31][N:32]=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:35]1(B(O)O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[O:44]1CCOC[CH2:45]1>C(Cl)Cl.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][N:21]4[C:30]([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=5[O:44][CH3:45])=[CH:31][N:32]=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ncc(Br)n4cc3-c3ccccc3)cc2)CCC1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: [CH]1[CH][CH][C](P(c2ccccc2)c2ccccc2)[CH]1
Solvent: ClCCl
Product: COc1ccccc1-c1cnc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cn12
Temperature: 100 °C

Procedure:
A mixture of compound 4-3 (52 mg 0.1 mmol), 2-methoxy]phenyl boronic acid (30 mg, 0.15 mmol), aq.Na2 CO3 (2M, 0.25 mmol, 0.12 mL) and Pd(DPPF)Cl2 (10 mg) in dioxane (3 mL) was heated at 100° C. in microwave system under N2 atmosphere for 30 min. After cooling, the mixture was diluted with 15 mL of DCM, the combined organic phase was washed with 0.1N HCl aq and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep.TLC to give 36 mg of 4-7.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:26]=[CH:25][CH:24]=[CH:23][C:12]=2[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[O:8]C.C(Cl)Cl.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>O>[F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:26]=[CH:25][CH:24]=[CH:23][C:12]=2[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc(Nc2ncccc2C(=O)Nc2ccc(F)cc2)cc1F
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1ccc(F)cc1)c1cccnc1Nc1ccc(O)c(F)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.4 %

Procedure:
A 250 mL round-bottomed flask was charged with 2-(3-fluoro-4-methoxyphenylamino)-N-(4-fluorophenyl)nicotinamide (8.00 g, 22.5 mmol) and DCM (75 mL). The reaction mixture was cooled to 0° C. and BBr3 (10.9 ml, 115 mmol) was added dropwise over 5 minutes. The reaction mixture was stirred for 2 hours, then slowly quenched by pipetting the reaction into a flask (500 mL) containing saturated NaHCO3 (20 mL), water (150 mL). This solution was extracted with EtOAc. The organic layer was dried and concentrated to provide the product 6.25 g (73%). LRMS M−1 (339.9) observed.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][C:29]1[NH:33][CH:32]=[N:31][C:30]=1[C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1>>[CH3:28][C:29]1[NH:33][CH:32]=[N:31][C:30]=1[C:34]1[CH:40]=[CH:39][C:37]([NH:38]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:36][CH:35]=1
Reactant: Cc1[nH]cnc1-c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(-c2nc[nH]c2C)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(5-methyl-imidazol-4-yl)-aniline Rf value: 0.5 (silica gel, methylene chloride/methanol/ammonia=10:1:0.01) C27H22N4O3
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:24](=[O:25])[N:5]2[C:6]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[O:13])=[C:7]([CH2:10][Cl:11])[CH2:8][S:9][C@H:4]12.[CH:26](=O)[C:27]1[C:28](=[CH:30][CH:31]=[CH:32][CH:33]=1)[OH:29].C(N(CC)CC)C>CO>[OH:29][C:28]1[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=1[CH:26]=[N:2][C@@H:3]1[C:24](=[O:25])[N:5]2[C:6]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[O:13])=[C:7]([CH2:10][Cl:11])[CH2:8][S:9][C@H:4]12
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3[C@H](N)C(=O)N23)cc1
Reactant: O=Cc1ccccc1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3[C@H](N=Cc4ccccc4O)C(=O)N23)cc1
Reaction time: 5 h
Yield: 90.1 %

Procedure:
In 50 ml of methanol was dissolved 4.05 g(10 mmol) of 4-methoxybenzyl 7 β-amino-3-chloromethyl-ceph-3-em-4-carboxylate hydrochloride, and 1.28 ml(12 mmol) of salicylaldehyde and 1.39 ml(10 mmol) of triethylamine were added thereto. The reaction mixture was stirred for 5 hours. The resulting precipitate was filtered, washed with 50 ml of methanol and dried to give 4.26 g of the desired compound(90%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[S:20](Cl)(=[O:22])=[O:21]>CN(C1C=CN=CC=1)C>[Cl:19][C:18]1[C:13]([CH3:12])=[C:14]([S:20]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)(=[O:22])=[O:21])[CH:15]=[CH:16][CH:17]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: Nc1cccc2cccnc12
Agent: CN(C)c1ccncc1
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1cccc2cccnc12
Yield: 64.4 %

Procedure:
In a similar fashion using route 14 general procedure 27, 8-aminoquinoline (100 mg, 0.7 mmol), 2-methyl-3-chlorobenzenesulfonyl chloride (180 mg, 0.8 mmol) and DMAP (cat.) gave the title compound (150 mg, 65%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH3:7][C:8]1[CH:14](/[CH:15]=[CH:16]/[CH:17]([OH:19])[CH3:18])[C:13]([CH3:21])([CH3:20])[CH2:12][C:10](=[O:11])[CH:9]=1.N1C=CC=CC=1>ClCCl>[CH2:5]([O:4][C:2](=[O:11])[OH:3])[CH3:6].[OH:19][CH:17]([CH3:18])[CH:16]=[CH:15][CH:14]1[C:13]([CH3:20])([CH3:21])[CH2:12][C:10](=[O:11])[CH:9]=[C:8]1[CH3:7]
Reactant: CC1=CC(=O)CC(C)(C)C1/C=C/C(C)O
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1=CC(=O)CC(C)(C)C1C=CC(C)O
Product: CCOC(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of ethyl chloroformate (5.42 g, 0.05 mol) in dichloromethane (10 mL) was added dropwise over a 30 minute period to a cold (10° C.) solution of 3-oxo-α-ionol (5.20 g, 0.025 mol, which may be prepared as described by A. J. Aasen, B. Kimland and C. R. Enzell in Acta Chem. Scand., 1973, 27, 2107-2114) and pyridine (3.96 g, 0.05 mol) in dichloromethane (80 mL). The mixture was stirred at 25° C. for 18 hours. Dichloromethane (100 mL) was then added and the mixture washed with 5% phosphoric acid solution (3×100 mL), saturated sodium bicarbonate solution until neutral and dried (sodium sulfate). Evaporation of solvent an chromatography of the residue followed by kugelrohr distillation (50° C. both temp. 0.5 mm) provided 4-(3-hydroxy-1-butenyl)-3,5,5,-trimethyl-2-cyclohexen-1-one ethyl carbonate (2.15 g, GLC purity; 87%) 1H-NMR (CDCl3) δ0.97 (3H,s), 1.05 (3H, s), 1.31 (3H, t, J=7Hz), 1.41 (3H, d, J=7Hz), 1.92 (3H,s) 2.1-2.3 (2H,dd), 2.4-2.7 (1H,m), 4.25 (2H,q, J=7Hz), 5.0-5.4 (1H,m), 5.5-5.8 (2H,m), 5.95 (1H,s); IR (film) vmax 2960, 1750, 1670, 1630, 1470, 1450, 1370, 1260 cm-1 ; MS m/e 280, 224, 190, 175, 134, 108. ##STR7##
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:22]([CH:24]1[C:32]2[CH:31]=[C:30]([C:33]([F:36])([F:35])[F:34])[N:29]=[CH:28][C:27]=2[C:26](=O)[O:25]1)[CH3:23].Cl>C1COCC1>[CH2:22]([CH:24]1[C:32]2[CH:31]=[C:30]([C:33]([F:36])([F:35])[F:34])[N:29]=[CH:28][C:27]=2[C:26](=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][C:6]2=[O:11])[O:25]1)[CH3:23]
Reactant: CCC1OC(=O)c2cnc(C(F)(F)F)cc21
Reactant: O=C1Cc2cc(F)ccc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC1OC(=C2C(=O)Nc3ccc(F)cc32)c2cnc(C(F)(F)F)cc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 18.7 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (99 mg, 0.66 mmol.) in THF (2 mL) is cooled to 0° C. under an Argon atmosphere and treated with a solution of lithium bis(trimethylsilyl)amide (1.3 mL of a 1 M solution in THF, 1.3 mmol) dropwise. The resulting solution is stirred at 0° C. for 10 min and warmed to room temperature. A solution of 1-ethyl-6-trifluoromethyl-1H-furo[3,4-c]pyridin-3-one, (100 mg, 0.44 mmol) in THF (2 mL) is added dropwise to the reaction mixture. The resulting solution is stirred for 4 h. The reaction mixture is poured into aqueous 10% HCl solution (50 mL). The resulting mixture is heated to 90° C. for 45 min and then stirred at room temperature for 36 h. The precipitate which formed is collected by filtration and dried. The solid obtained is purified by chromatography (silica gel, 40% EtOAc/hexane). The product containing fractions are concentrated to give the title compound as a yellow solid (30 mg, 19%).
Reaction SMILES: C1(C(C2[C:14]([CH2:15][O:16][CH2:17][C:18]3[C:23](C4C(=CC=C(O)C=4)O)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=[CH:11][CH:10]=2)=CC(=CC=1)O)O.Br[CH:33]([CH3:38])[C:34]([O:36][CH3:37])=[O:35].C(=O)([O-])[O-:40].[K+].[K+]>C(C(C)=O)C>[CH2:17]([O:16][C:15]1[CH:10]=[CH:11][C:12]([O:40][CH:33]([CH3:38])[C:34]([O:36][CH3:37])=[O:35])=[CH:13][CH:14]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(O)c(-c2ccccc2COCc2ccccc2-c2cc(O)ccc2O)c1
Reactant: COC(=O)C(C)Br
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)C(C)Oc1ccc(OCc2ccccc2)cc1
Reaction time: 24 h
Yield: 197.8 %

Procedure:
A mixture of 60 g of hydroquinone monobenzyl ether, 50 g of methyl 2-bromopropionate, 42 g of anhydrous potassium carbonate and 500 ml of methyl ethyl ketone, is heated with stirring for 24 hours to reflux temperature. After it has cooled, the reaction mixture is filtered and washed with methyl ethyl ketone. The filtrate is then concentrated in vacuo. The residual oil soon becomes crystalline. Recrystallisation from cyclohexane/petroleum ether yields 82 g of methyl 4-(benzyloxy)-α-phenoxypropionate with a melting point of 67°-68° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([F:23])=[CH:20][CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[NH:24]1[CH2:29][CH:28]=[C:27]([C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[NH:32][CH:31]=2)[CH2:26][CH2:25]1.C(=O)(O)[O-].[Na+]>CN(C)C=O.O1CCCC1>[F:23][C:19]1[C:17]2[O:18][CH:13]([CH2:12][N:24]3[CH2:25][CH:26]=[C:27]([C:30]4[C:38]5[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=5)[NH:32][CH:31]=4)[CH2:28][CH2:29]3)[CH2:14][O:15][C:16]=2[CH:22]=[CH:21][CH:20]=1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3cccc(F)c3O2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Fc1cccc2c1OC(CN1CC=C(c3c[nH]c4ccccc34)CC1)CO2

Procedure:
[(2R)-8-Fluoro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl 4-methylbenzenesulfonate (1.2 g, 3.5 mmole) was dissolved in a mixture of dimethylformamide/tetrahydrofuran (1:1 v/v, 30 mL) and 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.60 g, 3.0 mmole) added, followed by the addition of sodium bicarbonate (0.60 g, 7.1 mmole) and the mixture refluxed under nitrogen for 18 hours. The solvent was evaporated in vacuum, and the residue partitioned between 400 mL each of methylene chloride and water. The organic phase was dried over magnesium sulfate and filtered. The filtrate was evaporated and the residue chromatographed on silica gel using 4% methanol in chloroform as eluant. The product fractions were combined and concentrated in vacuum to give 0.20 g (16%) of the (S)-enantiomer of the title compound as a yellow solid, m.p. 174–177° C.