Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1)[CH2:2][C:3]#[CH:4].[Li]CCCC.CCCCCC.[CH2:23]=[O:24]>C1COCC1>[O:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]1[O:5][CH2:1][CH2:2][C:3]#[C:4][CH2:23][OH:24]
Reactant: C#CCCOC1CCCCO1
Reactant: C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OCC#CCCOC1CCCCO1
Reaction time: 0.5 h
Yield: 62 %

Procedure:
A solution of compound 2 (11.0 g, 71.3 mmol) in THF (80 mL) was treated with a 1.6 M solution of n-BuLi in hexane (58 mL, 92.8 mmol) dropwise at 0° C. for 20 min. After 30 min, paraformaldehyde (6.4 g) was added to the reaction mixture at 0° C. After 5 h, the reaction mixture was quenched with aq NH4Cl at 0° C. and diluted with EtOAc (200 mL) and washed with aq NH4Cl and brine. The organic layer was dried over MgSO4 and concentrated. The residue was purified with 20% EtOAc in hexanes by silica get column chromatography to give 8.15 g of compound 3 (44.2 mmol, 62% yield): 1H NMR (CDCl3) δ 4.63 (t, J=3.4 Hz, 1H), 4.22 (t, J=2.1 Hz, 2H), 3.91˜3.76 (m, 2H), 3.59˜3.46 (m, 2H), 2.51 (tt, J=7.1, 2.2 Hz, 2H), 1.86˜1.46 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C@@H:4]([NH:17][C:18](=[O:20])[CH3:19])[C:5](=C=O)[C@H:6](OC)[NH:7]2.[OH-:21].[Li+].Cl.[CH3:24][OH:25]>O>[C:24]([C@H:6]1[CH2:5][C@H:4]([NH:17][C:18](=[O:20])[CH3:19])[C:3]2[C:8](=[CH:9][C:10]([Cl:12])=[CH:11][C:2]=2[Cl:1])[NH:7]1)([OH:25])=[O:21]
Reactant: [OH-]
Reactant: CO[C@@H]1Nc2cc(Cl)cc(Cl)c2[C@@H](NC(C)=O)C1=C=O
Reactant: CO
Agent: Cl
Agent: [Li+]
Solvent: O
Product: CC(=O)N[C@H]1C[C@H](C(=O)O)Nc2cc(Cl)cc(Cl)c21
Reaction time: 7 h

Procedure:
To a suspension of trans-5,7-dichloro-2-methoxy-carbonyl-4-acetylamino-1,2,3,4-tetrahydroquinoline (0.12 g, 0.379 mmol) in methanol (5 ml) was added aqueous lithium hydroxide (0.42 ml of a 1.0M solution, 0.42 mmol) and the resulting mixture was stirred at room temperaure for 7 hours. To this mixture was added additional aqueous lithium hydroxide (0.20 ml of a 1.0M solution, 0.20 mmol) and the mixture was stirred for a further 16 hours. The solution was evaporated to dryness in vacuo and the residue obtained was redissolved in water (50 ml). The solution was acidified to pH 1 with dilute hydrochloric acid and extracted with ethyl acetate (2×30 ml). The combined extracts were washed with brine (30 ml), dried (Na2SO4) and evaporated to give the pure title compound as colourless crystals (0.108 g, 223-225 pc); δ (360 MHz, methanol) 1.70 (1H, ddd, J=13.3, 12.8 and 4.0 Hz, CHACHBHCCHD), 1.95 (3H, s, COCH3), 2.41 (1H, dm, J=13.3 Hz, CHACHBHCCHD), 3.92 (1H, dd, J=12.8 and 3.0 Hz, CHACHBHCCHD), 5.17 (1H, m, CHACHBHCCHD), 6.66 (1H, d, J=2.0 Hz, 6-H or 8-H), 6.72 (1H, d, J=2.0 Hz, 6-H or 8-H); m/e 302 (M+), 198 (100%, m-NHCOCH3, CO2H, H); found: C, 47.65; H, 4.11; N, 9.07. C12H12Cl2N2O3 requires C, 47.55; H, 3.99; N, 9.24%.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([NH2:21])=[O:20])=[CH:17][C:18]=4[N:9]3[CH2:8][C:7]([C:22]([NH2:24])=[O:23])=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1>[Pd].CO>[CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([NH2:21])=[O:20])=[CH:17][C:18]=4[N:9]3[CH:8]=[C:7]([C:22]([NH2:24])=[O:23])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)C1=Cc2ccccc2-c2cc3ccc(C(N)=O)cc3n2C1
Agent: [Pd]
Solvent: CO
Product: NC(=O)C1=Cn2c(cc3ccc(C(N)=O)cc32)-c2ccccc2C1
Reaction time: 8 h

Procedure:
10% Palladium on carbon (60 mg, 0.06 mmol) was added to a solution of 7H-indolo[2,1-a][2]benzazepine-6,10-dicarboxamide, 13-cyclohexyl-N10-[(dimethylamino)sulfonyl]-3-methoxy-N6-methyl-N6-[2-(4-morpholinyl)-2-oxoethyl]- (59 mg, 0.09 mmol) in MeOH (3 mL) and the reaction mixture was vacuum flushed with nitrogen (3×) and then with hydrogen (3×). The reaction mixture was stirred under a balloon of hydrogen overnight. The reaction mixture was once again vacuum flushed with nitrogen (3×) and then with hydrogen (3×) and stirred under a balloon of hydrogen overnight. The solution was filtered through a pad of celite and concentrated to yield 5H-indolo[2,1-a][2]benzazepine-6,10-dicarboxamide, 13-cyclohexyl-N10-[(dimethylamino)sulfonyl]-6,7-dihydro-3-methoxy-N6-methyl-N6-[2-(4-morpholinyl)-2-oxoethyl]- (31 mg, 0.05 mmol, 53%) as a yellow solid. Mixture of atrope diastereomers: 1HNMR (500 MHz, CDCl3) δ 10.85 (br s, 1H), 8.07 (s, 1H), 7.85 (d, J=8.5 Hz, 1H), 7.70 (d, J=8.5 Hz, 1H), 7.34 (d, J=8.2 Hz, 1H), 6.93 (d, J=8.2 Hz, 1H), 6.91 (s, 1H), 4.75-4.33 (m, 2H), 3.88 (s, 3H), 3.94-2.44 (m, 13H), 3.31 (s, 3H), 3.02 (s, 6H), 2.95-2.84 (m, 1H), 2.19-1.17 (m, 10H). LCMS: m/e 678 (M−H)−, ret time 2.77 min, column A, 4 minute gradient.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][C:15]([OH:17])=[O:16])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:22][CH2:23]O>>[CH2:22]([O:16][C:15](=[O:17])[CH2:14][C:9]1[C:10]([CH3:13])=[N:11][O:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[CH3:23]
Reactant: CCO
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CC(=O)O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)Cc1c(C)noc1-c1ccc(Br)cc1
Reaction time: 1 h

Procedure:
To [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-acetic acid (0.200 g, 0.68 mmol) in EtOH (3 mL) was added thionyl chloride (0.10 mL, 1.35 mmol), and the reaction was stirred for 1 hour. The mixture was quenched with saturated aqueous NH4Cl and diluted with EtOAc and H2O. After standard aqueous workup, the crude material was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:10].N1C=CC=CC=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(=O)([O-])O.[Na+]>ClCCl>[CH3:17][S:18]([O:10][CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1ccccc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1ccccc1Br
Reaction time: 72 h

Procedure:
9.8 g of 2-(2-bromophenyl)ethanol and 4.7 cm3 of pyridine are dissolved under an inert atmosphere in 200 cm3 of dichloromethane at a temperature close to 20° C. The reaction mixture is cooled to a temperature close to 0° C. and 4.55 cm3 of methanesulfonyl chloride are introduced dropwise. The stirring is continued for 72 h, during which time the medium is allowed to gradually climb back up to a temperature close to 20° C. 100 cm3 of a saturated aqueous solution of sodium hydrogen carbonate are added to the reaction mixture. Stirring is continued for 10 min. The aqueous phase is extracted with dichloromethane. The organic phases are combined, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered then concentrated using a rotary evaporator under reduced pressure (5 kPa). The 18 g of brown oil obtained are purified by flash chromatography over silica (column: 200 g; particle size: 15-40 μm; eluent: 100% dichloromethane to 90% dichloromethane/10% ethyl acetate gradient). After concentrating the fractions under reduced pressure, 12.9 g of 2-(2-bromophenyl)ethyl methanesulfonate are obtained in the form of a colorless oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8](/[C:10](=[N:21]/[O:22][CH3:23])/[CH2:11][O:12][C:13]3[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][CH:14]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.[C:24]([CH:26]([C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1)[CH2:27][C:28]([O:30]C)=[O:29])#[N:25]>>[C:24]([CH:26]([C:32]1[CH:37]=[CH:36][C:35]([O:20][CH2:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH2:11]/[C:10](/[C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][CH2:3][C:4]=4[CH:9]=3)=[N:21]\[O:22][CH3:23])=[CH:14][CH:15]=2)=[CH:34][CH:33]=1)[CH2:27][C:28]([OH:30])=[O:29])#[N:25]
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1ccc2c(c1)CCO2
Reactant: COC(=O)CC(C#N)c1ccc(O)cc1
Product: CO/N=C(\COc1ccc(COc2ccc(C(C#N)CC(=O)O)cc2)cc1)c1ccc2c(c1)CCO2
Yield: 56.2 %

Procedure:
Compound 102 was synthesized from ((4-{[(2Z)-2-(2,3-dihydro-1-benzofuran-5-yl)-2-(methoxyimino)ethyl]oxy}phenyl)methanol (0.330 g, 1.0 mmol) and methyl 3-cyano-3-(4-hydroxyphenyl)propanoate (0.216 g, 1.0 mmol) by following the procedure described in scheme 5 (0.008 g, yield: 56.2%); Purity: 94.55%.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10][CH2:9]2)[C:6]=1[CH3:7].C1COCC1.C([Mg]Cl)(C)C.CO[B:27]1[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]1>>[CH3:7][C:6]1[N:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10][CH2:9]2)[N:4]=[CH:3][C:2]=1[B:27]1[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]1
Reactant: Cc1c(I)cnn1[C@H]1CC[C@H](O)CC1
Reactant: COB1OC(C)(C)C(C)(C)O1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cc1c(B2OC(C)(C)C(C)(C)O2)cnn1[C@H]1CC[C@H](O)CC1
Reaction time: 0.5 h

Procedure:
To a solution of trans-4-(4-iodo-5-methyl-1H-pyrazol-1-yl)cyclohexanol (150.0 mg, 0.4900 mmol) in THF (9 mL, 100 mmol) was added 2 M isopropylmagnesium chloride in THF (0.73 mL, 1.5 mmol) at rt, and the mixture was stirred for 30 min. 2-Methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.32 mL, 2.0 mmol) was added, and the mixture stirred at rt for 2 h. The reaction was quenched with sat. NH4Cl, and the organic solvent was removed in vacuo. The material was extracted with DCM and water, and the organic layer was concentrated in vacuo to afford the title compound as a clear oil.
Reaction SMILES: C([NH:8][CH:9]([CH3:39])[CH:10](C(OCC1C=CC=CC=1)=O)[C:11]1[CH:16]=[CH:15][C:14]([O:17]CC2C=CC=CC=2)=[C:13]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:12]=1)C1C=CC=CC=1.[H][H]>CO.[PdH2]>[C:25]([C:13]1[CH:12]=[C:11]([CH2:10][CH:9]([NH2:8])[CH3:39])[CH:16]=[CH:15][C:14]=1[OH:17])([CH3:28])([CH3:26])[CH3:27]
Reactant: [H][H]
Reactant: CC(NCc1ccccc1)C(C(=O)OCc1ccccc1)c1ccc(OCc2ccccc2)c(C(C)(C)C)c1
Agent: [PdH2]
Solvent: CO
Product: CC(N)Cc1ccc(O)c(C(C)(C)C)c1

Procedure:
A suspension of 2.35 g (4.50 mmol) of N-benzyl-2-(4-benzyloxy-3-tert-butylphenyl)-1-methyl-N-(benzyloxycarbonyl)ethylamine and 0.50 g of a 20% palladium hydride on carbon catalyst in methanol (30 ml) was stirred overnight in a hydrogen atmosphere. After filtering off the catalyst, the solvent was distilled off under reduced pressure to give 2-(3-tert-butyl-4-hydroxyphenyl)-1-methylethylamine in the amount of 0.90 g (96%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([O:20][CH2:21][CH3:22])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1)C1C=CC=CC=1.[C:23](OCC)(=O)[CH3:24]>[Pd]>[CH2:23]([O:19][C:17](=[O:18])[C@@H:16]([O:20][CH2:21][CH3:22])[CH2:15][C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=1)[CH3:24]
Reactant: CCO[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Reactant: CCOC(C)=O
Agent: [Pd]
Product: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Yield: 76 %

Procedure:
3-(4-Benzyloxyphenyl)-2-(S)-ethoxypropanoic acid (7.13 g; 21.7 mmole) was hydrogenated at atmospheric pressure for 2 hours in ethyl acetate (70 ml) using Pd/C as catalyst. Purification by chromatography on silica gel using toluene:ethyl acetate as eluant gave 3.83 g (yield in 3 step 76%) of (S)-2-ethoxy-3-(4-hydroxyphenyl)propanoic acid ethyl ester.
Reaction SMILES: [C:1]1([CH2:7][S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14]3)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28](=[O:39])[CH2:29][C:30]2[C:31]([CH3:38])=[C:32]([CH:36]=O)[NH:33][C:34]=2[CH3:35])[CH2:24][CH2:23]1.N1CCCCC1>C(O)C>[OH:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28](=[O:39])[CH2:29][C:30]2[C:31]([CH3:38])=[C:32](/[CH:36]=[C:14]3\[C:15](=[O:20])[NH:16][C:17]4[C:13]\3=[CH:12][C:11]([S:8]([CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:10])=[O:9])=[CH:19][CH:18]=4)[NH:33][C:34]=2[CH3:35])[CH2:24][CH2:23]1
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3ccccc3)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1CC(=O)N1CCC(O)CC1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4ccccc4)cc32)c(C)c1CC(=O)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5-phenylmethanesulfonyl-1,3-dihydro-indol-2-one (100 mg, 0.35 mmol), 4-[2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (180 mg, 0.68 mmol) and piperidine (0.5 eq.) in ethanol (2 mL) was stirred at rt for 48 hours. The reaction was concentrated and triturated with methanol to give the titled compound as an orangish-red solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH:4]=[CH:5][N:6]=1.[S:14]([Cl:18])(=[O:17])(=[O:16])[NH2:15]>C(#N)C>[ClH:18].[CH3:1][C:2]1[N:3]([C:7]2[CH:8]=[C:9]([O:13][S:14](=[O:17])(=[O:16])[NH2:15])[CH:10]=[CH:11][CH:12]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1nccn1-c1cccc(O)c1
Reactant: NS(=O)(=O)Cl
Solvent: CC#N
Product: Cc1nccn1-c1cccc(OS(N)(=O)=O)c1
Product: Cl
Yield: 27.6 %

Procedure:
A slurry of 8.7 g (0.05 mole) of 3-(2-methyl-1H-imidazol-1-yl)phenol in 150 ml of acetonitrile was treated with a solution of 0.05 mole of sulfamoyl chloride in 20 ml of acetonitrile. The mixture dissolved and slowly deposited off-white crystals over the period of 24 hr. The precipitate was collected and triturated with hot absolute ethanol. The slurry was cooled and the precipitate was collected and dried to give 4.0 g (32%) of an off-white powder, mp 197°-200° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4](CCO)[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([N+:12]([O-])=O)[CH:6]=1.OCCNC1C=CC(O)=C([N+]([O-])=O)C=1.C1OC1.C.NC1C=CC(O)=C([N+]([O-])=O)C=1>COCCOC.O>[OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([NH2:12])[CH:6]=1
Reactant: O=[N+]([O-])c1cc(N(CCO)CCO)ccc1O
Agent: Nc1ccc(O)c([N+](=O)[O-])c1
Agent: O=[N+]([O-])c1cc(NCCO)ccc1O
Solvent: O
Solvent: COCCOC
Solvent: C1CO1
Product: Nc1cc(NCCO)ccc1O
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
Preparation of 4-[bis(2-hydroxyethyl)-amino]-2-nitrophenol by ethoxylation (B5.c): 397 g (2 mol) 4-(2-hydroxyethylamino)-2-nitrophenol is added to a mixture of 1.6 liters of water and 1.1 liters of 1,2-dimethoxyethane. The system is closed with a bubble counter and heated with stirring to 60° C. Ethylene oxide is conducted into this solution so that no ethylene oxide escapes through the bubble counter. After 5 hours the temperature is increased to 85° C., 9.2 g activated charcoal and 4.6 g Celite are added, and stirring is continued for 15 minutes. Then the mixture is filtered with suction. The residue is washed with 100 ml of 1,2-dimethoxyethane/water (1:1 v/v). 500 ml of 1,2-dimethoxyethane is distilled off the solution. The product which precipitates is filtered off with suction and dried. (This product is obtained starting from 4-amino-2-nitrophenol according to this procedure.)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=1.Cl.[OH-].[Na+]>O.C(O)C>[O:17]1[CH2:18][CH2:19][N:14]([C:4]2[N:5]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:7]=[C:2]([NH:28][C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([O:21][CH3:20])[CH:23]=3)[CH:3]=2)[CH2:15][CH2:16]1
Reactant: COc1cccc(N)c1
Reactant: Clc1cc(N2CCOCC2)nc(-c2ccccc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cccc(Nc2cc(N3CCOCC3)nc(-c3ccccc3)n2)c1
Yield: 9.1 %

Procedure:
A mixture of 4-(6-chloro-2-phenyl-4-pyrimidyl)morpholine (50 mg, 0.181 mmol), m-anisidine (20 μl, 0.181 mmol) and aqueous 2N HCl (150 μl) in water:ethanol (1:1, 10 ml) was refluxed for 5 days. The mixture was cooled to room temperature and basified with aqueous 2N NaOH to pH 10-12. The mixture was extracted with ethyl acetate (50 ml), which was washed with water (2×25 ml), aqueous saturated NaCl, and dried over anhydrous sodium sulfate. The ethyl acetate solution was concentrated in vacuo and isolated as a yellow solid (6 mg, 9%). 1H NMR (CDCl3): 8.40-8.37 (m, 2H), 7.46-7.43 (m, 3H), 7.31-7.25 (m, 2H), 7.00 (t, J=2.3 Hz, 1H), 6.91 (dd, J=1.7, 8.0 Hz, 1H), 6.70-6.67 (m, 2H), 3.83 (s, 3H), 3.81-3.63 (m, 8H).
Reaction SMILES: [O:1]=[C:2]1[CH:6]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:5][CH2:4][NH:3]1.[H-].[Na+].[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26](F)=[C:25]([N+:30]([O-:32])=[O:31])[CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C=O)C>[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([N:3]2[CH2:4][CH2:5][CH:6]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2]2=[O:1])=[C:25]([N+:30]([O-:32])=[O:31])[CH:24]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1F
Reactant: CCOC(=O)CC1CCNC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC1CCN(c2ccc(OCc3ccccc3)cc2[N+](=O)[O-])C1=O
Temperature: 0 °C
Yield: 26.5 %

Procedure:
Ethyl 2-(2-oxopyrrolidin-3-yl)acetate (1.77 g, 10.34 mmol) was dissolved in DMF (20 mL) and cooled to 0° C. Sodium hydride (60% in mineral oil, 0.414 g, 10.34 mmol) was added. After stirring for several min, the reaction was allowed to warm to room temperature and stirred for 10 min. 4-(Benzyloxy)-1-fluoro-2-nitrobenzene (2.56 g, 10.34 mmol) was added and the mixture was stirred at room temperature for 21 h. The reaction was poured into water and acidified to pH 5 with 1.0 M HCL. The aqueous mixture was extracted three times with EtOAc and the combined extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to provide the title compound (1.09 g). LCMS m/z=399.4 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.27 (t, J=7.2 Hz, 3H), 1.97-2.01 (m, 1H), 2.46-2.59 (m, 2H), 2.95 (dd, J=12.9, 3.8 Hz, 1H), 2.96-3.06 (m, 1H), 3.69-3.76 (m, 1H), 3.79-3.88 (m, 1H), 4.17 (q, J=7.1 Hz, 2H), 5.13 (s, 2H), 6.90 (d, J=2.5 Hz, 1H), 6.94 (dd, J=9.0, 2.7 Hz, 1H), 7.37-7.42 (m, 5H), 8.04 (d, J=9.1 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[C:12]2=[C:13]3[C:5]([CH:6]=[CH:7][CH:8]=[C:9]3[CH2:10][C:11]2=[O:14])=[CH:4][CH:3]=1.[C:15](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:15][O:1][C:2]1[C:12]2=[C:13]3[C:5]([CH:6]=[CH:7][CH:8]=[C:9]3[CH2:10][C:11]2=[O:14])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1Cc2cccc3ccc(O)c1c23
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc2cccc3c2c1C(=O)C3
Temperature: 25 °C
Reaction time: 5 h
Yield: 75.7 %

Procedure:
A known compound, 8-hydroxyacenaphthen-1-one (7.0 g) (J. Chem. Soc., 1954, p. 4299), was dissolved in N,N-dimethylformamide (70 ml), potassium carbonate (7.9 g) and methyl iodide (6.8 g) were added, and the mixture was stirred at room temperature for 5 hr. After completion of the reaction, the mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give 8-methoxyacenaphthen-1-one (5.7 g). The obtained methoxy form was dissolved in methanol (25 ml), sodium borohydride (220 mg) was added, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was gradually added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 8-methoxy-1-acenaphthenol (5.6 g). The title compound (2.28 g) was obtained according to the method of Example 125 and using the obtained alcohol form.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[CH:20]([C:26]([CH3:28])=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CO.C(OCC)(=O)C>[CH3:28][C:26]1[N:1]=[C:2]2[C:7]([O:8][CH2:9][C:10]3([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:12][CH2:11]3)=[CH:6][CH:5]=[CH:4][N:3]2[C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: Nc1ncccc1OCC1(c2ccccc2)CC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)c1c(C)nc2c(OCC3(c4ccccc4)CC3)cccn12
Yield: 8.6 %

Procedure:
A stirred mixture of 2-amino-3-[(1-phenylcyclopropyl)methoxy]pyridine (2.82 g, 11.7 mmol, see example 23), ethyl 2-chloroacetoacetate (6.5 mL, 47 mmol) and molecular sieves (15.1 g, type 4 Å, beads, 8–12 mesh) in anhydrous methanol (55 mL) was refluxed for 39 h under argon. The molecular sieves were filtered off and the filtrate was concentrated in vacuo to give an oil which was dissolved in ethyl acetate (200 mL) and then washed successively with a 1:1 (v/v) mixture of saturated aq sodium bicarbonate and water (2×25 mL), and water (20 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo to yield the crude product. Purification by dry column (600 mL funnel with 450 mL of silica gel 10–40μ, Sigma cat. S-6628) eluted with a mixture of ethyl acetate-hexanes (1:3 v/v, containing 0.5% v/v isopropylarnine) afforded 0.352 g (8.6% yield) of ethyl 2-methyl-8-[(1-phenylcyclopropyl)methoxy]imidazo[1,2-α]pyridine-3-carboxylate (Rf=0.30 in ethyl acetate-hexanes, 1:3 v/v, containing 0.5% v/v isopropylamine). A stirred solution of ethyl 2-methyl-8-[(1-phenylcyclopropyl)methoxy]imidazo[1,2-α]pyridine-3-carboxylate (0.190 g, 0.542 mmol) in a mixture of dichloromethane (3.5 mL) and anhydrous diethyl ether (3 mL) was treated with ethereal hydrogen chloride to form the hydrochloride salt. Concentration of the solution in vacuo gave a residue which was triturated in anhydrous diethyl ether to afford the title compound as an off-white solid (0.168 g, 80% yield). 1H-NMR (300 MHz, CDCl3) δ 16.91 (br s, 1H, +NH), 9.05 (d, 1H, Ar), 7.65 (d, 2H, Ar), 7.18 (m, 4H, Ar), 6.92 (d, 1H, Ar), 4.45 (q, 2H, CH3CH2), 4.32 (s, 2H, CH2O), 3.03 (s, 3H, CH3), 1.42 (t, 3H, CH3CH2), 1.15 (m, 4H, CH2CH2); 13C-NMR (75 MHz, CDCl3, APT) δ 159.49 (+), 145.10 (+), 143.90 (+), 142.24 (+), 133.68 (+), 130.21 (−), 128.26 (−), 126.78 (−), 120.27 (−), 118.13 (−), 113.77 (+), 112.02 (−), 78.61 (+), 62.09 (+), 25.48 (+), 14.14 (−), 12.56 (−), 11.51 (+); LRMS-FAB m/z: MH+ 351 (100%); Anal. calcd for C21H22N2O3.HCl: C, 65.20; H, 5.99; N, 7.24%. found: C, 64.87; H, 5.96; N, 7.20%.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([NH:17][C:18]([O:20][CH2:21][CH:22]2[C:34]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:28]3[C:23]2=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:19])[C:14](O)=[O:15])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[C:50]1([C:56]2[N:57]=[C:58]([CH:61]3[CH2:70][C:69]4[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=4)[CH2:63][NH:62]3)[NH:59][CH:60]=2)[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>ClCCl>[CH:24]1[C:23]2[CH:22]([CH2:21][O:20][C:18](=[O:19])[NH:17][CH:13]([CH2:12][C:9]3[CH:8]=[CH:7][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:11][CH:10]=3)[C:14](=[O:15])[N:62]3[CH:61]([C:58]4[NH:59][CH:60]=[C:56]([C:50]5[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=5)[N:57]=4)[CH2:70][C:69]4[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=4)[CH2:63]3)[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]=2[CH:27]=[CH:26][CH:25]=1
Reactant: c1ccc(-c2c[nH]c(C3Cc4ccccc4CN3)n2)cc1
Reactant: CC(C)(C)Oc1ccc(CC(NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)Oc1ccc(CC(NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)N2Cc3ccccc3CC2c2nc(-c3ccccc3)c[nH]2)cc1
Temperature: 0 °C
Yield: 88.2 %

Procedure:
3-(4-tert-Butoxy-phenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-propionic acid (1.93 g, 4.2 mmol) was dissolved in dichloromethane (100 mL), cooled to 0° C., then N-methyl-morpholine (0.42 g, 4.2 mmol) was added neat followed by isobutyl chloroformate (0.52 mL, 4 mmol). After 1.25 hour 3-(4-phenyl-1H-imidazol-2-yl)-1,2,3,4-tetrahydro-isoquinoline (1.10 g, 4 mmol) was added neat and the reaction was allowed to warm to room temperature. After 16 hours the reaction was extracted with water, then saturated NaHCO3, dried over Na2SO4, filtered, and concentrated under reduced pressure to give 2.53 g (88%) of brown foam desired product {1-(4-tert-butoxy-benzyl)-2-oxo-2-[3-(4-phenyl-1H-imidazol-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-carbamic acid 9H-fluoren-9-ylmethyl ester, which was used without further purification.