Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5]/[CH:6]=[C:7](\[CH3:23])/[CH2:8][CH2:9][C:10]1[C:15]([CH3:16])=[C:14]([O:17]C)[C:13]([CH3:19])=[C:12]([CH3:20])[C:11]=1[O:21]C)(=[O:3])[CH3:2]>C(#N)C.O.C(Cl)(Cl)Cl>[C:1]([O:4][CH2:5]/[CH:6]=[C:7](\[CH3:23])/[CH2:8][CH2:9][C:10]1[C:11](=[O:21])[C:12]([CH3:20])=[C:13]([CH3:19])[C:14](=[O:17])[C:15]=1[CH3:16])(=[O:3])[CH3:2]
Reactant: COc1c(C)c(C)c(OC)c(CC/C(C)=C/COC(C)=O)c1C
Solvent: ClC(Cl)Cl
Solvent: CC#N
Solvent: O
Product: CC(=O)OC/C=C(\C)CCC1=C(C)C(=O)C(C)=C(C)C1=O
Reaction time: 0.33 h
Yield: 93.9 %

Procedure:
A solution of 3.83 g (12 mmol) of (E)-5-(2,5-dimethoxy-3,4,6-trimethylphenyl)-3-methyl-2-pentenyl acetate in acetonitrile (50 ml) was treated dropwise at 0° C. with a solution of ceric ammonium nitrate (16.4 g; 30 mmol) in water (50 ml). After completion of the addition the mixture was stirred for a further 20 minutes and diluted with water and chloroform. The organic phase was separated, washed with water, dried and concentrated to a yellow oil, yielding (E)-3-methyl-5-(2,4,5-trimethyl-3,6-dioxo-1,4-cyclohexadien-1-yl)-2-pentenyl acetate (3.27 g).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10]([CH3:14])([CH3:13])[N:9]1[C:15](=[O:35])[CH:16]([C:18]1[CH:22]=[CH:21][N:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)[CH:19]=1)[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>N1C=CC=CC=1>[C:36]([O:17][CH:16]([C:18]1[CH:22]=[CH:21][N:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:27][CH:28]=2)[CH:19]=1)[C:15]([N:9]1[C@@H:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12][O:11][C:10]1([CH3:14])[CH3:13])=[O:35])(=[O:38])[CH3:37]
Reactant: CC1(C)OC[C@H](Cc2ccccc2)N1C(=O)C(O)c1ccn(-c2ccc(-c3ccccc3)cc2)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC(C(=O)N1[C@@H](Cc2ccccc2)COC1(C)C)c1ccn(-c2ccc(-c3ccccc3)cc2)c1
Reaction time: 4.5 h
Yield: 96.2 %

Procedure:
To a solution of 1-(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2-[1-(biphenyl-4-yl)1H-pyrrol-3-yl]-2-hydroxy-ethanone (867 mg, 1.86 mmol) in dry pyridine (5 mL) was added acetic anhydride (0.42 mL, 4.5 mmol). After 4.5 hours at ambient temperature, the mixture was partitioned between 1N aqueous NaHSO4 (25 mL) and EtOAc (25 mL). The EtOAc layer was washed with 1N pH7 phosphate buffer (25 mL) two times, H2O (25 mL), and brine (25 mL), dried over Na2SO4, and evaporated to give 0.91 g (100%) of 2-acetoxy-1-(4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2-[1-(biphenyl-4-yl)-1H-pyrrol-3-yl]-ethanone as an amorphous solid that was used without further purification. An analytical sample was obtained upon flash column chromatography with 0-2% EtOAc/CH2Cl2 gradient eluent. 1H NMR: δ 7.65 (d, 2H, J=8.5 Hz), 7.62 (d, 2H, J=7.0 Hz), 7.48-7.24 (m, 1H), 7.10 (t, 1H, J=2.6 Hz), 6.46 (dd, 1H, J=1.7, 2.8 Hz), 6.25 (s, 1H), 3.98-3.93 (m, 1H), 3.81 (d, 1H, J=9.2 Hz), 3.64-3.60 (m, 1H), 3.42 (d, 1H, J=13.6 Hz), 2.96 (dd, 1H, J=11.6, 13.8 Hz), 2.22 (s 3H), 1.78 (s, 3H), 1.55 (s, 3H). Anal. Calculated for C32H32N2O4: C, 75.57; H, 6.34; N, 5.51. Found: C, 75.47; H, 6.37; N, 5.45.
Reaction SMILES: [OH:1][C:2]1[C:7](Br)=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O>[OH:1][C:2]1[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11]
Reactant: CC(=O)c1cc(C)cc(Br)c1O
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(=O)c1cc(C)cc(-c2ccccc2)c1O
Temperature: 75 °C
Yield: 71.8 %

Procedure:
2′-Hydroxy-3′-bromo-5′methylacetophenone 233 (0.46 g, 2 mmol) and phenylboronic acid (0.24 g, 1 eq.) are dissolved in DME (10 ml) and placed under a nitrogen atmosphere. Na2CO3 (0.50 g, 3 eq.) in water (10 ml) is added, followed by Pd(Ph3)4 (0.12 g, 0.05 eq.) and the reaction mixture heated to 75° C. for 12-18 h. Most of the DME is removed in vacuo and the reaction mixture is diluted with ether, washed with water, brine, and dried (MgSO4), and concentrated in vacuo to give an oil. Purification by flash chromatography (5/95 EtOAc/hexanes) afforded 2′-Hydroxy-3′-phenyl-5′methylacetophenone 234 as a yellow solid (0.32 g, 71% yield) (Example 519, Table IIIa).
Reaction SMILES: Cl.[C:2]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][NH2:13])=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[CH3:14][C:15]([CH3:22])([CH3:21])[C:16](=O)[CH2:17][C:18]#[N:19]>>[C:15]([C:16]1[CH:17]=[C:18]([NH2:19])[N:12]([C:9]2[CH:8]=[CH:7][C:6]([C:2]([CH3:5])([CH3:3])[CH3:4])=[CH:11][CH:10]=2)[N:13]=1)([CH3:22])([CH3:21])[CH3:14]
Reactant: CC(C)(C)c1ccc(NN)cc1
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Product: CC(C)(C)c1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Yield: 73.7 %

Procedure:
Using the procedure in Example 161A Step 3, 4-tert-butylphenyl-hydrazine monohydrochloride (1.00 g, 4.98 mmol) and 4,4-dimethyl-3-oxopentanenitrile (625 mg, 4.98 mmol) were reacted to give 3-tert-butyl-1-(4-tert-butylphenyl)-1H-pyrazol-5-amine (996 mg, 3.67 mmol, 51%). 1H NMR (300 MHz, DMSO-d6) δ 7.46 (br s, 4H), 5.35 (s, 1H), 5.15 (br s, 2H), 1.30 (s, 9H), 1.20 (s, 9H); LC-MS (ESI) m/z 272 (M+H)+.
Reaction SMILES: [CH2:1]([C@@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[NH:6][C:5]1=[O:24])[CH:2]=[CH2:3].[H-].[Na+].Br[CH2:28][CH:29]1[CH2:32][CH2:31][CH2:30]1>CN(C=O)C>[CH2:1]([CH:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([CH2:28][CH:29]2[CH2:32][CH2:31][CH2:30]2)[C:5]1=[O:24])[CH:2]=[CH2:3]
Reactant: C=CC[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)NC1=O
Reactant: BrCC1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCC1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CCC2)C1=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of (3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (Example 42, Step A) (70 mg, 0.19 mmol) in 430 μL of DMF was added sodium hydride (60% suspension in mineral oil, 20 mg, 0.51 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 15 min and after treatment with (bromomethyl)cyclobutane (66 μL, 0.58 mmol) the reaction mixture was heated to 70° C. for 15 h. The reaction mixture was cooled to room temperature, quenched with sat. aqueous NaHCO3 and extracted (2×EtOAc). The combined organic layers were washed with sat. aq. NaCl and NaHCO3-solutions, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by silica gel prep plate (25% EtOAc/hexanes) provided the title compound as a colorless solid.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:20]=[CH:19][C:7]2[CH2:8][CH2:9][N:10](C(=O)C(F)(F)F)[CH2:11][CH2:12][C:6]=2[C:5]=1[NH:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([O:31][CH3:32])=[O:30])=[C:25]([F:33])[CH:24]=1>O1CCOCC1.O>[Cl:3][C:4]1[CH:20]=[CH:19][C:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH2:12][C:6]=2[C:5]=1[NH:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([O:31][CH3:32])=[O:30])=[C:25]([F:33])[CH:24]=1
Reactant: COC(=O)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(CNc2c(Cl)ccc3c2CCNCC3)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Add 1M aqueous NaOH (2.8 mL, 2.8 mmol) to a solution of 7-chloro-6-(3-fluoro-4-methoxycarbonyl-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.31 g, 2.86 mmol) in 1,4-dioxane (13.3 mL) and water (2.6 mL) at 11° C. Allow mixture to warm to room temperature and stir for 1 h. Concentrate in vacuo and partition the residue between dichloromethane (250 mL) and saturated aqueous NaHCO3 (100 mL). Dry the organic phase over Na2SO4, filter and concentrate in vacuo to afford the desired intermediate that was used without further purification.
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH:16]=2)=[CH:7][CH:6]=1)=[O:4].[Li+].[OH-].[N+:26]([C:29]1[CH:30]=[C:31]([S:45]([NH2:48])(=[O:47])=[O:46])[CH:32]=[CH:33][C:34]=1[NH:35][CH2:36][CH2:37][S:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([O-:28])=[O:27].CCN=C=NCCCN(C)C>C1COCC1.CO.CN(C1C=CN=CC=1)C.ClC(Cl)C.C(OCC)(=O)C.O>[N+:26]([C:29]1[CH:30]=[C:31]([S:45]([NH:48][C:3]([C:5]2[CH:10]=[CH:9][C:8]([C:11]3[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH:16]=3)=[CH:7][CH:6]=2)=[O:4])(=[O:46])=[O:47])[CH:32]=[CH:33][C:34]=1[NH:35][CH2:36][CH2:37][S:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([O-:28])=[O:27]
Reactant: NS(=O)(=O)c1ccc(NCCSc2ccccc2)c([N+](=O)[O-])c1
Reactant: COC(=O)c1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(C(=O)NS(=O)(=O)c3ccc(NCCSc4ccccc4)c([N+](=O)[O-])c3)cc2)CC1
Reaction time: 16 h

Procedure:
A mixture of Example 455B (1 g, 3.1 mmol) and LiOH (0.264 mg 6.2 mmol) in THF (15 mL), methanol (2.5 mL), and water (1.5 mL) was heated to 50° C. for 3 hours and concentrated. The concentrate was dissolved in DMF (10 mL) and treated with a mixture of Example 77B (1.059 g, 3mmol), EDCI (1.146 g, 6 mmol), and DMAP (1.830, 15 mmol) in dichloroethane (10 mL), stirred for 16 hours, diluted with ethyl acetate (250 mL0, washed sequentially with 1N HCl (50 mL, water (100 mL) and brine (100 mL), dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 5% methanol/dichloromethane to provide the desired product. MS (ESI(−)) m/e 637 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 8.78 (br t, 1H), 8.60 (d, 1H), 7.92 (dd, 1H), 7.85 (d, 2H), 7.55 (d, 2H), 7.40-7.15 (m, 6H), 6.35 (m, 1H), 4.21 (d, 2H), 3.65 (m, 2H), 3.52 (t, 2H), 3.25 (m, 4H), 1.45 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=[O:13])[NH:8]2.[CH3:14][O:15]C(Cl)Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([CH:14]=[O:15])=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=[O:13])[NH:8]2
Reactant: COc1cccc2c1CCC(=O)N2
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(C=O)c2c1CCC(=O)N2
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
5-Methoxy-3,4-dihydro-1H-quinolin-2-one (5.00 g, 26 mmol) was dissolved in dichloromethane (100 ml), and dichloromethyl methyl ether (7.65 ml, 85 mmol) was added at 0° C. Titanium tetrachloride (12.4 ml, 113 mmol) was added dropwise at a temperature not higher than 10° C. Stirring was carried out at room temperature for 2 hours, and the reaction mixture was poured into ice water and separated into layers. The aqueous layer was subjected to extraction with dichloromethane. The organic layers were combined and washed twice with water, washed with a saturated sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in dichloromethane, diethyl ether was added, and the produced insoluble matter was collected by filtration and dried to thereby obtain 5.32 g (yield: 92%) of 5-methoxy-2-oxo-1,2,3,4-tetrahydroquinoline-8-carboxaldehyde as a light brown powder.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@@H:17]([CH2:23][OH:24])[O:16][CH:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:10]1[O:25][C:26](=[O:28])[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=[O:31]>S(=O)(=O)(O)O.[O-2].[O-2].[O-2].[Cr+6]>[CH2:1]([O:8][C@H:9]1[C@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@@H:17]([C:23]([OH:31])=[O:24])[O:16][CH:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:10]1[O:25][C:26](=[O:28])[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: CC(=O)OC1O[C@H](CO)[C@@H](OC(C)=O)[C@H](OCc2ccccc2)[C@H]1OC(C)=O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Product: CC(=O)OC1O[C@H](C(=O)O)[C@@H](OC(C)=O)[C@H](OCc2ccccc2)[C@H]1OC(C)=O
Reaction time: 5 h
Yield: 54 %

Procedure:
A solution of crude 17 in the minimum amount of dichloromethane was stirred at room temperature with aqueous 80% acetic acid (100 mL) until TLC demonstrated the disappearance of 17. Water was then added with stirring; the solid was removed and the filtrate was concentrated. The crude 3-O-benzyl-1,2,4-tri-O-acetyl-D-glucopyranose (18) was thus obtained; 1H NMR data: 60:40 mixture of anomers 6.32 (d, 1 H, alpha-H), 5.64 (d, 1 H, beta-H). A solution of the crude residue 18 in acetone was cooled to -5° C. and a solution of chromium trioxide in 3.5M sulfuric acid was added dropwise with stirring. The mixture was allowed to attain room temperature, and, after 5 hours at room temperature, was poured into ice-cold water and extracted with chloroform. The extract was washed with water and concentrated, and a solution of the crude methyl ester of 3-O-benzyl-1,2,4-tri-O-acetyl-D-glucopyranosuronic acid (19) in ether was esterified with ethereal diazomethane. The product was eluted from a column of silica gel with chloroform-ethyl acetate (20:10) to give 19 (54%). 1H NMR date: mixture of anomers alpha:beta=60:40; 7.23-7.36 (m, 5 H, arom.), 6.38 (d, 1 H, alpha-H), 5.69 (d, 1 H, beta-H), 3.72 (s, 3 H, alpha-COOMe), 3.71 (s, 3 H, beta-COOMe), 1.96-2.16 (9 H, Ac).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:19])[C:5]2[CH:11]=[C:10](Br)[C:9](=[O:13])[N:8]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[N:30][N:31](C(OC(C)(C)C)=O)[CH:32]=2)O1.C(=O)([O-])[O-].[K+].[K+]>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.CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([CH3:19])[C:5]2[CH:11]=[C:10]([C:28]3[CH:29]=[N:30][NH:31][CH:32]=3)[C:9](=[O:13])[N:8]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1nc(N)nc2c1cc(Br)c(=O)n2C1CCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(N)nc2c1cc(-c1cn[nH]c1)c(=O)n2C1CCCC1
Temperature: 120 °C
Yield: 65 %

Procedure:
To a solution of 2-amino-6-bromo-8-cyclopentyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (100 mg, 0.31 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxy late (110 mg, 1.2 equiv), dichlorobis(triphenylphosphine)palladium(II) (6.5 mg, 009 mmol), DMF (2 mL) in a 10 mL microwave vial was added potassium carbonate (3 M, 0.8 mL). The solution was degassed with N2 for 10 min before being capped and heated in the microwave reactor for 10 min at 120° C. Once complete, the reaction was diluted with 1 N NaOH (10 mL) and EtOAc (50 mL). The EtOAc layer was washed with 3N HCl, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was submitted for chromatography purification. the title compound was obtained in (62.5 mg, 65% yield).
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.[N:20]1([C:26]2[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:18][O:17][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][O:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH:27]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:19]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Reactant: Oc1cccc(N2CCOCC2)c1
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCOc2cccc(N3CCOCC3)c2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step 2) and 3-morpholin-4-yl-phenol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a yellow oil.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[C:16]3[C:12]([C:13]([C:20](=[O:26])[C:21]([O:23]CC)=[O:22])=[CH:14][N:15]3[CH2:18][CH3:19])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[OH-].[Na+].FC(F)(F)C1C=CC(C2C=C3C(C(C(=O)C([O-])=O)=CN3CC)=CC=2)=CC=1>CO>[CH2:18]([N:15]1[C:16]2[C:12](=[CH:11][CH:10]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:27])([F:1])[F:28])=[CH:8][CH:7]=3)[CH:17]=2)[C:13]([C:20](=[O:26])[C:21]([OH:23])=[O:22])=[CH:14]1)[CH3:19]
Reactant: CCOC(=O)C(=O)c1cn(CC)c2cc(-c3ccc(C(F)(F)F)cc3)ccc12
Agent: CCn1cc(C(=O)C(=O)[O-])c2ccc(-c3ccc(C(F)(F)F)cc3)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCn1cc(C(=O)C(=O)O)c2ccc(-c3ccc(C(F)(F)F)cc3)cc21

Procedure:
Following the procedure described in Step 4 of Example 2, using ethyl 2-[6-(4-trifluoromethylphenyl)-1-ethyl-1H-indol-3-yl]-2-oxoacetate (0.0987 g, 0.253 mmol), and 1N sodium hydroxide (0.76 mL, 0.76 mmol) in methanol (5 mL), 2-[6-(4-trifluoromethylphenyl)-1-ethyl-1H-indol-3-yl]-2-oxoacetate acid (0.0714 g, 78%) was prepared as a yellow solid, mp 247-248° C. Mass spectrum (+APCI, [M+H]+) m/z 362; 1HNMR (400 MHz, DMSO-d6): δ 13.7-14.1 (br s, 1H), 8.55 (s, 1H), 8.3 (d, 1H, J=8.3 Hz), 8.05 (d, 1H, J=0.98 Hz), 8.0 (d, 2H, J=8.1 Hz), 7.8 (d, 2H, J=8.5 Hz), 7.7 (dd, 1H, J=8.5 Hz and 1.6 Hz), 4.45 (q, 2H, J=7.2 Hz), and 1.45 ppm (t, 3H, J=7.2 Hz).
Reaction SMILES: CC1C=CC(S(OCC(O)[CH2:14][C:15]2[CH:24]=[C:23]([Cl:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]=2[O:26][CH2:27][C:28]2C=CC=CC=2)(=O)=O)=CC=1.Cl.CC1C=CC(S(OCC(O)CC2C=C(Cl)C3C(=CC=CC=3)C=2O)(=O)=O)=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.CC1C=CC(S(OCC2OC3C4C(C(Cl)=CC=3C2)=CC=CC=4)(=O)=O)=CC=1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[N-:133]=[N+:134]=[N-:135].[Na+]>[Pd].C(O)(C)C>[Cl:25][C:23]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]2[O:26][CH:27]([CH2:28][N:133]=[N+:134]=[N-:135])[CH2:14][C:15]=2[CH:24]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCC(O)Cc2cc(Cl)c3ccccc3c2OCc2ccccc2)cc1
Agent: [Pd]
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: Cc1ccc(S(=O)(=O)OCC(O)Cc2cc(Cl)c3ccccc3c2O)cc1
Solvent: CC(C)O
Product: [N-]=[N+]=NCC1Cc2cc(Cl)c3ccccc3c2O1

Procedure:
Treatment of (±)-3-[1-(benzyloxy)-4-chloro-2-naphthyl]-2-hydroxypropyl 4-methylbenzenesulfonate (4.6 g, 9.26 mmol) with palladium on carbon (5 wt. %, 0.50 g) and hydrogen chloride in isopropanol (4.0 M, 4.0 mL) generally according to the procedure described for Intermediate 4 provided (±)-3-(4-chloro-1-hydroxy-2-naphthyl)-2-hydroxypropyl 4-methylbenzenesulfonate. Treatment of the phenyl with triphenylphosphine (3.5 g, 13.3 mmol) followed by diisopropylazodicarboxylate (2.69 g, 13.3 mmol) generally according to the procedure described for Intermediate 5 afforded (±)-(5-chloro-2,3-dihydronaphtho[1,2-b]furan-2-yl)methyl 4-methylbenzenesulfonate as a colorless oil. Treatment of the tosylate with sodium azide (1.1 g, 16.4 mmol) generally according to the procedure described for Intermediate 24 gave (±)-(5-chloro-2,3-dihydronaphtho[1,2-b]furan-2-yl)methyl azide as a pale brown oil. Treatment of the azide with sulfided platinum on carbon (5 wt. %, 0.15 g) generally according to the procedure described for Example 2 provided 1.07 g (43%) of (±)-1-(5-chloro-2,3-dihydronaphtho[1,2-b]furan-2-yl)methanamine as a white solid, hydrochloride salt. mp 269-271° C.; Anal. calcd. for C13H12ClNOHCl.0.8H2O: C, 54.87; H, 5.17; N, 4.92. Found: C, 54.68; H, 4.78; N, 4.79.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:29]/[O:30]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)/[C:8]([NH:10][CH:11]2[C:27](=[O:28])[N:13]3[C:14]([C:24]([O-:26])=[S:25])=[C:15]([CH2:18][CH:19]4[CH2:23][O:22][CH2:21][O:20]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:51]([O:57][CH2:58]I)(=[O:56])[C:52]([CH3:55])([CH3:54])[CH3:53]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:29]/[OH:30])/[C:8]([NH:10][CH:11]2[C:27](=[O:28])[N:13]3[C:14]([C:24]([O:26][CH2:58][O:57][C:51](=[O:56])[C:52]([CH3:55])([CH3:54])[CH3:53])=[S:25])=[C:15]([CH2:18][CH:19]4[CH2:23][O:22][CH2:21][O:20]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)NC2C(=O)N3C(C([O-])=S)=C(CC4COCO4)CS[C@H]23)cs1
Reactant: CC(C)(C)C(=O)OCI
Agent: [Na+]
Product: CC(C)(C)C(=O)OCOC(=S)C1=C(CC2COCO2)CS[C@@H]2C(NC(=O)/C(=N\O)c3csc(N)n3)C(=O)N12
Yield: 76.1 %

Procedure:
Sodium 7-[(Z)-2-(2-aminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-(1,3-dioxolan-4-yl)methylthio-3-cephem-4-carboxylate (71 mg) as prepared in Example 35(b) was reacted with iodomethyl pivalate (68 mg) similarly to Example 28 for the esterification reaction. The resulting reaction solution was post-treated and the produced compound was recovered and purified similarly to Example 28 to give the titled compound (43 mg; 51%).
Reaction SMILES: [CH2:1]([CH:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]([OH:18])=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[NH2:19][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][N:24]=[CH:25]2>>[CH:25]1[C:26]2[C:21](=[C:20]([NH:19][C:16]([CH:12]3[CH2:13][CH2:14][CH2:15][CH:11]3[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:18])[CH:29]=[CH:28][CH:27]=2)[CH:22]=[CH:23][N:24]=1
Reactant: Nc1cccc2cnccc12
Reactant: CCCCCCCCCCC1CCCC1C(=O)O
Product: CCCCCCCCCCC1CCCC1C(=O)Nc1cccc2cnccc12

Procedure:
2-(Decyl) cyclopentane carboxylic acid, prepared according to the procedure of Hoefle, et. al. (U.S. Pat. No. 4,715,175), was coupled with 5-aminoisoquinoline according to the procedure outlined in Example 47 to give the title compound.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)=[N:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:36])C=1>C(Cl)Cl>[Cl:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)=[N+:5]([O-:36])[CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(Cc2ncc(CCl)c3cc(OC)c(OC)cc23)cc1OC
Solvent: ClCCl
Product: COc1ccc(Cc2c3cc(OC)c(OC)cc3c(CCl)c[n+]2[O-])cc1OC
Temperature: 0 °C
Yield: 70.2 %

Procedure:
To an ice-cooled solution of 5.2 g 4-chloromethyl-6,7-dimethoxy-1-[(3,4-dimethoxyphenyl)methyl]isoquinoline in 150 ml methylene chloride, was added under stirring and nitrogen a solution of 3.04 g m-chloroperbenzoic acid in 100 ml methylene chloride over 2 hours, so that the temperature did not exceed 3°-5°. The solution was stirred over night at room temperature and the red solution applied to a column, packed with 100 g silica gel 60 Merck, 230-400 mesh ASTM. From elution with ether and ethyl acetate the unreacted base 4-chloromethyl-6,7-dimethoxy-1-[(3,4-dimethoxyphenyl)methyl]isoquinoline was separated. Elution with ethyl acetate/ethanol (4:1) afforded 3.8 g of a brownish foam. The 4-(chloromethyl)-1-(3,4-dimethoxybenzyl)-6,7-dimetoxyisoquinoline 2-oxide crystallized from methylene chloride/ethyl acetate: 3.5 g yellow crystals, mp 167°-168°.