Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]2[C:13]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[C:12](=N)[NH:11][C:10]2=[O:19])=[CH:4][C:3]=1[CH3:20].O.C(=O)([O-])[OH:23].[Na+]>C(O)(=O)C>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]2[C:13]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[C:12](=[O:23])[NH:11][C:10]2=[O:19])=[CH:4][C:3]=1[CH3:20]
Reactant: Cc1cc(N2C(=O)NC(=N)C23CCCC3)cc(C)c1Br
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(N2C(=O)NC(=O)C23CCCC3)cc(C)c1Br
Temperature: 65 °C
Reaction time: 17 h

Procedure:
A mixture of 1-(4-bromo-3,5-dimethylphenyl)-4-imino-1,3-diazaspiro[4.4]nonan-2-one (the crude product obtained in the previous reaction) in acetic acid (1.0 mL) and water (0.25 mL) was stirred for 1.5 hours at 65° C. under nitrogen atmosphere. After further addition of acetic acid (1.0 mL) and water (0.25 mL), the mixture was stirred for 17 hours at 65° C. under nitrogen atmosphere. The reaction mixture was cooled, followed by dilution with water and adjustment of its pH to 8 using a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to afford 1-(4-bromo-3,5-dimethylphenyl)-1,3-diazaspiro[4.4]nonane-2,4-dione (121 mg).
Reaction SMILES: [C:1]([O:5][C:6]1[C:11](/[CH:12]=[CH:13]\OC)=[N:10][CH:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[F:17][C:18]1[CH:31]=[CH:30][CH:29]=[CH:28][C:19]=1[O:20][CH2:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6]1[C:11]([CH2:12][CH2:13][N:25]2[CH2:24][CH2:23][CH:22]([CH2:21][O:20][C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=3[F:17])[CH2:27][CH2:26]2)=[N:10][CH:9]=[CH:8][N:7]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CO/C=C\c1nccnc1OC(C)(C)C
Reactant: Fc1ccccc1OCC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)Oc1nccnc1CCN1CCC(COc2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.1 %

Procedure:
After adding 139 mg of (Z)-2-tert-butoxy-3-(2-methoxyvinyl)pyrazine and 196 mg of 4-(2-fluorophenoxymethyl)piperidine hydrochloride in 5 ml of dichloromethane, 213 mg of sodium triacetoxyborohydride was added and the mixture was stirred overnight at room temperature. Aqueous sodium carbonate solution was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine in that order and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (26 mg, 10% yield).
Reaction SMILES: Cl[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1.C1C2CC3(N)CC(C2)CC1C3.Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+3].C([O-])(=O)C.C([O-])(=O)C.C(Cl)Cl.O.O1CCOCC1>[F:10][C:8]1[CH:7]=[CH:6][C:3]2[C:2]([CH:9]=1)=[C:13]1[C:12]([CH:17]=[CH:16][CH:15]=[CH:14]1)=[N:11][C:4]=2[NH2:5]
Reactant: CC1(C)OB(c2ccccc2N)OC1(C)C
Reactant: N#Cc1ccc(F)cc1Cl
Agent: [Pd+3]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: Nc1nc2ccccc2c2cc(F)ccc12
Yield: 3082.6 %

Procedure:
To a solution of 2-chloro-4-fluorobenzonitrile (1.0 g, 6.42 mmol), 2-aminophenylboronic acid pinacol ester (1.6 g, 7.1 mmol), palladium(III) acetate (0.07 g, 0.32 mmol), amantadine hydrochloride (0.24 g, 1.3 mmol) and cesium carbonate (4.6 g, 14.1 mmol) were added to dioxane previously deaerated with nitrogen and heated to reflux for 17 hours. After cooling, both distilled water and methylene chloride (50 mL) were added to the reaction mixture. The solvent layer was separated and concentrated to give a crude oil that was purified by column chromatography by first using 1:1 ethyl acetate and hexanes ratio followed by 4:1 ethyl acetate/hexanes as the eluants. The pure product was collected to give 9-fluoro-6-phenanthridinamine (42 g, 32% Yield) whose NMR spectrum is consistent with the proposed structure.
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16]([NH2:21])[CH:15]=[CH:14]2)=[O:10])C1C=CC=CC=1.CC(O)C.[OH-].[K+:27]>O>[K+:27].[NH2:21][C:16]1[CH:15]=[CH:14][C:13]2[C:18](=[CH:19][CH:20]=[C:11]([C:9]([O-:10])=[O:8])[CH:12]=2)[N:17]=1
Reactant: Nc1ccc2cc(C(=O)OCc3ccccc3)ccc2n1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: Nc1ccc2cc(C(=O)[O-])ccc2n1
Reaction time: 12 h
Yield: 95 %

Procedure:
A mixture of 2-amino-quinoline-6-carboxylic acid benzyl ester (15.63 g, 0.0562 moles), 2-propanol (235 mL), water (15.6 mL) and potassium hydroxide (6.3 g, 0.112 moles) was heated to reflux, 80° C. to 85° C., for 2 to 4 hours. The reaction mixture was then cooled to 20° C. to 25° C., vacuum concentrated (volume of 160 mL) and granulated at 20° C. to 25° C. for 8 to 16 hours. The product was isolated by filtration (12.08 g, 0.0534 moles, 95% yield).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][CH:5](C(OCC)=O)[C:6]([O:8]CC)=[O:7].Cl>C(O)(=O)C>[F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)C(Cc1ccccc1F)C(=O)OCC
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)CCc1ccccc1F

Procedure:
49 g (0.183 mol) of diethyl 2-(2-fluorobenzyl)malonate were mixed with 183 ml of 37% HCl and 9.4 ml of glacial acetic acid. The mixture was heated atreflux for 27 hours, then cooled; the solid precipitated was filtered, taken up with water, basified with sat. NaHCO3, washed with diethyl ether, then reacidified with 20% HCl, extracted with diethyl ether and washed with brine. After drying and evaporation, the oily residue was taken up with petroleum ether: upon freezing a white solid precipitated (21.5 g; 70%).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1.CCCCC.C([Li])(C)(C)C.[CH3:21][O:22][C:23]([C:25]1[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=1)=[O:24].[Cl-].[NH4+]>C(OCC)C>[CH3:21][O:22][C:23]([C:25]1[CH:32]=[CH:31][C:28]([CH:29]([C:10]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[O:4][CH2:3][O:2][CH3:1])[OH:30])=[CH:27][CH:26]=1)=[O:24]
Reactant: COCOc1cccnc1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCC
Product: COCOc1cnccc1C(O)c1ccc(C(=O)OC)cc1
Temperature: -70 °C
Reaction time: 1 h
Yield: 9.4 %

Procedure:
Next, to a mixture of 3-(methoxymethoxy)pyridine (10.0 g, 71.9 mmol) and diethyl ether (1000 ml), a 1.47 mol/L t-butyllithium n-pentane solution (62 ml, 86.2 mmol) was added dropwise at −70° C. over 25 minutes. After stirring at −70° C. for 1 hour, a solution of 4-methoxycarbonylbenzaldehyde (14.0 g, 90.5 mmol) in diethyl ether (80 mL) was added over 30 minutes and stirred at −70° C. for 1.5 hours. After warming to room temperature, the reaction mixture was poured into saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:80) to give (4-methoxycarbonylphenyl)-[3-(methoxymethoxy)pyridin-4-yl]-methanol (2.06 g, 9.4%) as a yellow powder.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]([CH2:18][C:19]([N:21]([N:23]1[CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24]1)[CH3:22])=[O:20])[C:7]1[C:15]([CH3:16])=[CH:14][C:13]2[C:9](=[CH:10][N:11]([CH3:17])[N:12]=2)[CH:8]=1)C.[OH-:33].[Na+].Cl>CO.O1CCCC1>[CH2:31]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][N:23]1[N:21]([CH3:22])[C:19](=[O:20])[CH2:18][N:6]([C:7]1[CH:8]=[C:9]2[C:10](=[CH:14][C:15]=1[CH3:16])[N:11]([CH3:17])[N:12]=[CH:13]2)[CH2:5][C:4]([OH:3])=[O:33]
Reactant: CCOC(=O)CN(CC(=O)N(C)N1Cc2ccccc2C1)c1cc2cn(C)nc2cc1C
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc2c(cnn2C)cc1N(CC(=O)O)CC(=O)N(C)N1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 88 %

Procedure:
The compound (631 mg, 1.45 mmol) of step C was dissolved in a methanol (5 ml)-tetrahydrofuran (2 ml) mixed solvent, 1N sodium hydroxide (5 ml) was added at room temperature, and the mixture was stirred at room temperature for 70 min. To the reaction mixture was added 1N hydrochloric acid (5 ml), and the solution was concentrated under reduced pressure. The precipitated solid was filtered, washed with water, and dried under reduced pressure to give the title compound (517 mg, yield 88%) as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([C:13]2[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=2)[N:3]=1.[CH3:20][C:21]([S-:24])([CH3:23])[CH3:22].[Na+].C(O)CO.O>CN1CCCC1=O.[Cu]I>[C:21]([S:24][C:16]1[CH:17]=[CH:18][C:13]([N:4]2[NH:3][C:2](=[O:1])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]2=[O:12])=[CH:14][CH:15]=1)([CH3:23])([CH3:22])[CH3:20]
Reactant: CC(C)(C)[S-]
Reactant: O=c1c2ccccc2c(O)nn1-c1ccc(I)cc1
Agent: [Cu]I
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: OCCO
Solvent: O
Product: CC(C)(C)Sc1ccc(-n2[nH]c(=O)c3ccccc3c2=O)cc1
Temperature: 150 °C
Reaction time: 96 h

Procedure:
4-Hydroxy-2-(4-iodo-phenyl)-2H-phthalazin-1-one (see Method Q) (0.30 g, 0.8 mmol), sodium 2-methyl-propane-2-thiolate (0.094 g, 0.8 mmol), CuI (0.011 g, 0.06 mmol) and ethylene glycol (0.10 g, 1.6 mmol) were dissolved in N-methyl-pyrrolidinone (NMP) (0.5 ml) under argon and heated to 150° C. Stirring at this temperature was continued for 4 d before the mixture was allowed to warm to RT. H2O (50 ml) was added and the precipitated solid was collected by filtration. The title compound was obtained after purification of the raw product by chromatography over silica gel with DCM (0.21 g, 78%). 1H-NMR: (400 MHz, D6-DMSO) 12.35 (1H, s), 8.73 (1H, d), 8.33-8.41 (3H, m), 8.14 (2H, d), 8.01 (2H, d), 1.70 (9H, s); MS (ESI+)=327.14 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:32]=[CH:31][C:7]([CH2:8][C:9]2[C:17]3[O:16][C:15]([CH3:19])([CH3:18])[C:14](=[O:20])[C:13]=3[C:12]([CH3:21])=[C:11]([NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:10]=2[CH3:30])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>C1COCC1.CCCCCC>[OH:20][CH:14]1[C:13]2[C:12]([CH3:21])=[C:11]([NH:22][C:23](=[O:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:10]([CH3:30])=[C:9]([CH2:8][C:7]3[CH:31]=[CH:32][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=3)[C:17]=2[O:16][C:15]1([CH3:19])[CH3:18]
Reactant: Cc1c(Cc2ccc(C(C)C)cc2)c2c(c(C)c1NC(=O)CC(C)(C)C)C(=O)C(C)(C)O2
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1c(Cc2ccc(C(C)C)cc2)c2c(c(C)c1NC(=O)CC(C)(C)C)C(O)C(C)(C)O2
Yield: 81 %

Procedure:
Using N-(7-(4-isopropylbenzyl)-2,2,4,6-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Reference Example 330, the title compound was synthesized in the same manner as in Example 234. Yield: 81%. Melting point: 244-245° C. (THF-hexane).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:25][C:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[CH2:11][C:10](=[O:26])[CH2:9]2)=[CH:4][CH:3]=1.[Cl-].[Cl-].[Cl-].[Ce+3].[BH4-].[Na+].[Cl-].[NH4+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:25][C:12]3([CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:16][CH2:17]3)[CH2:11][C@@H:10]([OH:26])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)CC(c1ccc(F)cc1)O2
Agent: [BH4-]
Agent: [Ce+3]
Agent: [Cl-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)C[C@@H](O)C[C@H](c1ccc(F)cc1)O2
Reaction time: 0.08 h
Yield: 32 %

Procedure:
To a solution of tert-butyl 10-(4-fluorophenyl)-8-oxo-11-oxa-3-azaspiro[5.5]undecane-3-carboxylate (2.00 g, 5.50 mmol) in MeOH (50 mL) was added cerium trichloride (1.49 g, 6.05 mmol). The mixture was stirred for 5 minutes prior to the addition of sodium borohydride (250 mg, 6.60 mmol). The reaction mixture was allowed to stir at room temperature for 1 hour. Saturated ammonium chloride (50 mL) was added to quench the reaction. It was stirred for 5 minutes, and extracted with ethyl acetate (3×75 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (20-40% ethyl acetate/hexane) to provide tert-butyl cis-(4-fluorophenyl)-8-hydroxy-11-oxa-3-azaspiro[5.5]undecane-3-carboxylate (749 mg) and tert-butyl trans-10-(4-fluorophenyl)-8-hydroxy-11-oxa-3-azaspiro[5.5]undecane-3-carboxylate (644 mg). Cis-isomer: 1H NMR (400 MHz, CDCl3) δ 7.39-7.33 (m, 2H), 7.03 (ddd, J=8.8, 5.8, 2.5 Hz, 2H), 4.94 (d, J=11.5 Hz, 1H), 4.37 (dd, J=6.1, 3.0 Hz, 1H), 3.76 (d, J=13.9 Hz, 2H), 3.27 (ddd, J=13.2, 10.2, 4.9 Hz, 1H), 3.10-2.98 (m, 1H), 2.69 (d, J=15.7 Hz, 1H), 1.96-1.89 (m, 1H), 1.71 (ddd, J=11.9, 11.0, 2.9 Hz, 2H), 1.64-1.55 (m, 4H), 1.55-1.48 (m, 1H), 1.44 (s, 9H). ESI-MS m/z calc. 365.20, found 366.3 (M+1)+; Retention time: 1.54 minutes (3 minute run). trans-isomer: 1H NMR (400 MHz, CDCl3) δ 7.38-7.31 (m, 2H), 7.03 (ddd, J=10.7, 5.9, 2.5 Hz, 2H), 4.58-4.50 (m, 1H), 4.13 (ddd, J=11.3, 6.8, 4.6 Hz, 1H), 3.82-3.72 (m, 2H), 3.26 (ddd, J=13.3, 10.4, 4.6 Hz, 1H), 3.07-2.96 (m, 1H), 2.23 (ddd, J=10.3, 4.4, 2.2 Hz, 1H), 2.12 (d, J=14.7 Hz, 1H), 1.96 (ddd, J=12.5, 4.6, 1.8 Hz, 1H), 1.70-1.58 (m, 2H), 1.55 (s, 1H), 1.49-1.43 (m, 9H), 1.43-1.27 (m, 2H). ESI-MS m/z calc. 365.20, found 366.5 (M+1)+. Retention time: 1.63 minutes (3 minute run).
Reaction SMILES: [NH:1]([C:8]1[C:17]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:16]([N+:24]([O-])=O)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCCC1.[Pd]>[NH2:24][C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:17]=1[N:18]1[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1
Reactant: O=[N+]([O-])c1c(N2CCOCC2)c(Nc2ccccc2)nc2ccccc12
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1c(N2CCOCC2)c(Nc2ccccc2)nc2ccccc12

Procedure:
The 2-anilino-3-morpholino-4-nitroquinoline (2.9 g, 0.0083 mol) was dissolved in tetrahydrofuran (10 ml) and subjected to reduction in the presence of 10g palladium-on-carbon (0.3 g). After completion of the reaction, the palladium-on-carbon catalyst was filtered off and the mother liquor was concentrated. Following purification by chromatography on an alumina column using chloroform as a developing solvent, recrystallization from methanol was conducted to obtain 4-amino-2-anilino-3-morpholinoquinoline in an amount of 1.89 g (yield, 69%).
Reaction SMILES: [CH2:1]([N:5]([S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[C@H:6]([C:16]([OH:18])=[O:17])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:15])[CH2:13]I)[CH:2]([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.[NH2:38][CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>>[CH3:28][C:25]1[CH:26]=[CH:27][C:22]([S:19]([N:5]([C@H:6]([C:16]([OH:18])=[O:17])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([CH2:13][NH:38][CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)=[O:15])[CH2:1][CH:2]([CH3:4])[CH3:3])(=[O:21])=[O:20])=[CH:23][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)CI)C(=O)O)cc1
Reactant: NCCN1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)CNCCN2CCOCC2)C(=O)O)cc1

Procedure:
The title compound was prepared from Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-Nε-iodoacetyl-L-lysine (150 mg, 0.29 mmol, example 105, step B) by following the indications of general procedure H using DIEA (0.12 mL, 0.69 mmol) and 4-(2-aminoethyl)morpholine (0.11 mL, 0.84 mmol). The crude material was purified by preparative HPLC. The product was isolated as a solid (51 mg, 34% yield).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1[NH:12][C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25].[CH2:29]([O:31][CH2:32]Cl)[CH3:30]>CS(C)=O>[CH2:29]([O:31][CH2:32][N:12]1[C:8]([CH3:7])=[C:9]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:11]1[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:30]
Reactant: CCOC(=O)c1[nH]c(C)c(C(=O)OCC)c1-c1ccccc1
Reactant: CCOCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOCn1c(C)c(C(=O)OCC)c(-c2ccccc2)c1C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.9 %

Procedure:
Potassium tert-butoxide (557 mg, 4.97 mmol) was added to a stirred solution of diethyl 5-methyl-3-phenyl-1H-pyrrole-2,4-dicarboxylate (600 mg, 1.99 mmol) in dimethylsulfoxide (15 mL) at 10° C. and stirred at ambient temperature for 1 h. Upon cooling to 10° C., chloromethyl ethyl ether (377 mg, 3.99 mmol) was added and stirred at ambient temperature for 12 h. The mixture was poured onto ice-water and extracted with diethyl ether (5×10 mL). The combined organic layers were washed with water, brine, dried over anhydrous sodium sulphate and filtered. The filtrate was concentrated in vacuo and subjected to column chromatography over silica gel (100-200 mesh) using 8% ethyl acetate in petroleum ether as eluent to afford diethyl 1-(ethoxymethyl)-5-methyl-3-phenyl-pyrrole-2,4-dicarboxylate (400 mg, 56%) as a liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:4]=1[CH2:5][N:6]1[C:11]([C:12]2[CH:20]=[CH:19][C:18]3[N:17]4[CH2:21][CH2:22][CH:23]([OH:24])[C:16]4=[CH:15][C:14]=3[CH:13]=2)=[C:10]([CH2:25][CH3:26])[CH:9]=[C:8]([C:27]([O:29][CH3:30])=[O:28])[C:7]1=[O:31]>C(Cl)Cl.O=[Mn]=O>[CH3:1][O:2][C:3]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:4]=1[CH2:5][N:6]1[C:11]([C:12]2[CH:20]=[CH:19][C:18]3[N:17]4[CH2:21][CH2:22][C:23](=[O:24])[C:16]4=[CH:15][C:14]=3[CH:13]=2)=[C:10]([CH2:25][CH3:26])[CH:9]=[C:8]([C:27]([O:29][CH3:30])=[O:28])[C:7]1=[O:31]
Reactant: CCc1cc(C(=O)OC)c(=O)n(Cc2ccc(OC)cc2OC)c1-c1ccc2c(c1)cc1n2CCC1O
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCc1cc(C(=O)OC)c(=O)n(Cc2ccc(OC)cc2OC)c1-c1ccc2c(c1)cc1n2CCC1=O
Yield: 84.5 %

Procedure:
To a solution of methyl 1-(2,4-dimethoxybenzyl)-5-ethyl-6-(1-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-7-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate (1.3 g, 2.6 mmol) in CH2Cl2 (20 mL) was added MnO2 in two batches over 2 hrs (2.3 g, 26 mmol). The reaction mixture was then filtered through celite and concentrated to afford the title compound as an orange solid (1.1 g, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[OH:30][C:31]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:34]2[CH2:35][CH2:36][C:31]([OH:30])([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH2:32][CH2:33]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CN3CCC(O)(c4ccccc4)CC3)ccc21

Procedure:
In a similar manner to Step 1 of Example 56, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.0 mg, 0.0487 mmol) was dissolved in dichloromethane (0.5 mL). The solution was treated with 4-hydroxy-4-phenylpiperidine (35 mg, 0.20 mmol) and sodium triacetoxyborohydride (32 mg, 0.15 mmol) to obtain 4-chloro-7-[1-(tert-butoxycarbonyl)-5-(4-hydroxy-4-phenylpiperidinomethyl)indol-2-yl]isoindolinone.
Reaction SMILES: [O:1]=[C:2]1[CH2:26][C:10]2([CH:15]=[CH:14][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:12][CH2:11]2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32].I[CH3:36]>O1CCCC1>[CH3:36][CH:26]1[C:10]2([CH:11]=[CH:12][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:17])[CH2:14][CH2:15]2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:2]1=[O:1]
Reactant: C[Si](C)(C)CCOCN1C(=O)CC2(C=CN(C(=O)OCc3ccccc3)CC2)c2cccnc21
Reactant: CI
Solvent: C1CCOC1
Product: CC1C(=O)N(COCC[Si](C)(C)C)c2ncccc2C12C=CN(C(=O)OCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Lithium hexamethyldisilylazide (1.0 M in THF; 0.135 mL, 0.135 mmol) was added to solution of benzyl 2-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-2,2′,3,3′-tetrahydro-1H,1′H-spiro[1,8-naphthyridine-4,4′-pyridine]-1′-carboxylate (50.0 mg, 0.104 mmol) in tetrahydrofuran (1 mL) at −78° C. After 40 min, iodomethane (8.0 μL, 0.135 mmol) was added and the reaction mixture was slowly warmed to ambient temperature. After 1 h, the mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (3×). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated to give the title compound. MS 494.3 (M+1).
Reaction SMILES: FC1C=C(C=CC=1)[O:5][CH:6](OC1C=CC=C(F)C=1)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[N:8]=1.C(O)(=O)C>O>[F:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[O:13][C:9]1[N:8]=[C:7]([CH:6]=[O:5])[CH:12]=[CH:11][CH:10]=1
Reactant: Fc1cccc(Oc2cccc(C(Oc3cccc(F)c3)Oc3cccc(F)c3)n2)c1
Solvent: O
Solvent: CC(=O)O
Product: O=Cc1cccc(Oc2cccc(F)c2)n1
Temperature: 150 °C
Reaction time: 8 h

Procedure:
A solution of 2.5 g (0.0059 m) of 2-[bis-(3-fluorophenoxy)methyl]-6-(3-fluorophenoxy)pyridine and 20 ml of 80 percent acetic acid was heated, with stirring, at 150° C. overnight. The reaction mixture was cooled, diluted with water and extracted with methylene chloride. The extract was washed with water and concentrated under reduced pressure. The desired 6-(3-fluorophenoxy)picolinaldehyde which melted at 42°-43° C.
Reaction SMILES: C[O:2][C:3](=[O:23])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14](=[O:22])[N:15]([CH3:21])[C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[CH:9][CH:8]=1)[NH2:5].[Br:24][C:25]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:26]=1[C:27](O)=[O:28]>>[Br:24][C:25]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:26]=1[C:27]([NH:5][C@H:4]([C:3]([OH:2])=[O:23])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14](=[O:22])[N:15]([CH3:21])[C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[CH:9][CH:8]=1)=[O:28]
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2cn(C)c(=O)n(C)c2=O)cc1
Product: COc1ccc(Br)c(C(=O)N[C@@H](Cc2ccc(-c3cn(C)c(=O)n(C)c3=O)cc2)C(=O)O)c1

Procedure:
N-[(2-bromo-5-methoxyphenyl)carbonyl]-4-[1,3-dimethyl-2,4-dioxo-5-pyrimidinyl]-L-phenylalanine was prepared from 4-[1,3-dimethyl-2,4-dioxo-5-pyrimidinyl]-L-phenylalanine methyl ester and 2-bromo-5-methoxybenzoic acid using the general procedures described in example 2. EI-HRMS m/e calcd for C23H22N3O6Br (M+H) 516.0770, found 516.0780.