Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[C:4]([CH3:13])[CH:3]=1.C(Cl)(=O)C(Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]2[C:5]([CH2:8][CH2:9][C:10]2=[O:12])=[C:4]([CH3:13])[CH:3]=1
Reactant: Cc1cc(F)ccc1CCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc(F)cc2c1CCC2=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-(4-fluoro-2-methylphenyl)propanoic acid (12 g, 65.93 mmol) in CH2Cl2 (200 mL) was added oxalyl chloride (11.3 mL, 131.7 mmol) and stirred at RT for 16 h. The reaction mixture was concentrated in vacuo and re-dissolved in CH2Cl2 (150 mL) and added to a suspension of AlCl3 (11.4 g, 85.7 mmol) in CH2Cl2 (150 mL) at 0° C. The reaction mixture was heated at 50° C. for 3 h and allowed to stir at RT for 16 h. The reaction mixture poured into ice water (150 mL), extracted with CH2Cl2 (2×100 mL), the organic extract was washed with 1N NaOH solution (2×50 mL), brine solution (50 mL), dried over Na2SO4 and concentrated in vacuo. The crude material was purified by silica gel column chromatography, eluting with 10% EtOAc/petroleum ether 60-80 to afford 6-fluoro-4-methyl-2,3-dihydro-1H-inden-1-one as an off white solid (7 g, 70%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:10]2[O:17][CH2:16][C@H:15]3[C@@H:11]2[CH2:12][O:13][C@H:14]3[C:18]2[CH:19]=[CH:20][C:21]([OH:26])=[C:22]([O:24][CH3:25])[CH:23]=2)[CH:6]=[CH:7][C:8]=1[OH:9].[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH2:36][C@@H:37]2[C@H:41]([CH2:42][OH:43])[C@@H:40]([C:44]3[CH:45]=[CH:46][C:47]([OH:52])=[C:48]([O:50][CH3:51])[CH:49]=3)[O:39][CH2:38]2)[CH:32]=[CH:33][C:34]=1[OH:35]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@@H:10]2[O:17][CH2:16][C@@H:15]3[C@H:11]2[CH2:12][O:13][C@H:14]3[C:18]2[CH:19]=[CH:20][C:21]([OH:26])=[C:22]([O:24][CH3:25])[CH:23]=2)[CH:6]=[CH:7][C:8]=1[OH:9].[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH2:36][C@@H:37]2[C@H:41]([CH2:42][OH:43])[C@@H:40]([C:44]3[CH:45]=[CH:46][C:47]([OH:52])=[C:48]([O:50][CH3:51])[CH:49]=3)[O:39][CH2:38]2)[CH:32]=[CH:33][C:34]=1[OH:35]
Reactant: COc1cc([C@H]2OC[C@H]3[C@@H]2CO[C@H]3c2ccc(O)c(OC)c2)ccc1O
Agent: COc1cc(C[C@H]2CO[C@H](c3ccc(O)c(OC)c3)[C@H]2CO)ccc1O
Solvent: CO
Product: COc1cc([C@@H]2OC[C@@H]3[C@H]2CO[C@H]3c2ccc(O)c(OC)c2)ccc1O
Temperature: 30 °C
Reaction time: 3 h

Procedure:
Enzyme Assays. Pinoresinol and lariciresinol reductase activities were assayed by monitoring the formation of [3H]lariciresinol and [3H]secoisolariciresinol as set forth in Example 8, with the following modifications. Briefly, each assay for pinoresinol reductase activity consisted of (±)-pinoresinols (5 mM in MeOH, 20 μl) and the enzyme preparation (i.e., total protein extract from E. coli, 210 μl). The enzymatic reaction was initiated by addition of [4R-3H]NADPH (10 mM, 6.79 kBq/mmol in distilled H2O, 20 μl). After 3 hour incubation at 30° C. with shaking, the assay mixture was extracted with EtOAc (500 μl) containing (±)-lariciresinols (20 μg) and (±)-secoisolariciresinols (20 μg) as radiochemical carriers. After centrifugation (13,800×g, 5 min), the EtOAc solubles were removed and the extraction procedure was repeated. For each assay, the EtOAc solubles were combined with an aliquot (100 μl) removed for determination of its radioactivity using liquid scintillation counting. The remainder of the combined EtOAc solubles was evaporated to dryness in vacuo, reconstituted in MeOH/H2O (30:70, 100 μl) and subjected to reversed phase and chiral column HPLC.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][N:35]=[C:9]23)[CH2:4][CH2:3]1.[CH3:36][S:37]([CH3:39])=O.C(OC(=O)C)(=O)C>O>[CH3:36][S:37][CH2:39][O:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][N:35]=[C:9]23)[CH2:4][CH2:3]1
Reactant: CS(C)=O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ncnn12
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCSC)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of 4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (2.0 g), dimethyl sulfoxide (30 mL) and acetic anhydride (10 mL) was stirred at room temperature for 14 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.3 g, 59%).
Reaction SMILES: [C:1](Cl)(=[O:40])[O:2][CH:3]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32]/[CH:33]=[CH:34]\[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[CH3:42][N:43]([CH3:66])[CH2:44][CH2:45][CH2:46][NH:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55]/[CH:56]=[CH:57]\[CH2:58]/[CH:59]=[CH:60]\[CH2:61][CH2:62][CH2:63][CH2:64][CH3:65].C(N(CC)CC)C>ClCCl>[CH3:66][N:43]([CH3:42])[CH2:44][CH2:45][CH2:46][N:47]([CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55]/[CH:56]=[CH:57]\[CH2:58]/[CH:59]=[CH:60]\[CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[C:1](=[O:40])[O:2][CH:3]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32]/[CH:33]=[CH:34]\[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCC(CCCCCCCC/C=C\C/C=C\CCCCC)OC(=O)Cl
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCNCCCN(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC/C=C\C/C=C\CCCCCCCCC(CCCCCCCC/C=C\C/C=C\CCCCC)OC(=O)N(CCCCCCCC/C=C\C/C=C\CCCCC)CCCN(C)C
Yield: 55.2 %

Procedure:
To a solution of (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl carbonochloridate (590 mg, 1.0 mmol), N,N-dimethyl-N′-((9Z,12Z)-octadeca-9,12-dienyl)propane-1,3-diamine (350 mg, 1 mmol) and triethylamine (500 μL, 3.6 mmol) in dichloromethane (8 mL) was stirred overnight at room temperature. Upon completion, the solution was concentrated in vacuo to dryness and purified by column chromatography on silica gel to afford (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl 3-(dimethylamino)propyl((9Z,12Z)-octadeca-9,12-dienyl)carbamate as a colorless oil (500 mg, 55%). 1H NMR (CDCl3, 400 MHz) δ 5.42-5.28 (m, 12H), 4.79-4.70 (m, 1H), 3.32-3.12 (m, 4H), 2.78 (t, 6H, J=6.3 Hz), 2.38-2.20 (m, 8H), 2.09-2.02 (m, 12H), 1.82-1.63 (m, 2H), 1.57-1.43 (m, 6H), 1.41-1.23 (m, 52H), 0.89 (t, 9H, J=7.0 Hz).
Reaction SMILES: C[O-].[Na+].[CH3:4][S:5][C:6]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:7]=1[C:8]([O:10]C)=O.[CH3:20][C:21]([CH:23]1[CH2:25][CH2:24]1)=[O:22]>CN1CCCC1=O>[CH:23]1([C:21](=[O:22])[CH2:20][C:8]([C:7]2[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][C:6]=2[S:5][CH3:4])=[O:10])[CH2:25][CH2:24]1
Reactant: CC(=O)C1CC1
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1SC
Agent: C[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CSc1cc(C(F)(F)F)ccc1C(=O)CC(=O)C1CC1
Temperature: 30 °C
Yield: 94.7 %

Procedure:
Sodium methoxide (0.54 g, 0.01M) was added to a mixture of methyl 2-methylthio-4-trifluoromethylbenzoate (1.25 g. 0.005M) and cyclopropyl methyl ketone (0.5 g, 0,006M) in anhydrous N-methylpyrrolidinone and heated at 30° C. for 3 hours. The cooled mixture was acidified, extracted (ether), washed (Water) and evaporated to give 1-cyclopropyl-3-(2-methylthio-4-trifluoromethylphenyl)propane-1,3-dione (1.43 g), m.p.68° C. in a yield of 94%. The purity of the product was greater than 95%.
Reaction SMILES: [C:1]([C:4]1[O:5][CH:6]=[CH:7][CH:8]=1)(=O)[CH3:2].[NH2:9][C:10]([NH2:12])=[S:11]>ClCCl.CO.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[NH2:12][C:10]1[S:11][CH:2]=[C:1]([C:4]2[O:5][CH:6]=[CH:7][CH:8]=2)[N:9]=1
Reactant: NC(N)=S
Reactant: CC(=O)c1ccco1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CO
Solvent: ClCCl
Product: Nc1nc(-c2ccco2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
2-Acetylfuran (5.1 g, 46.0 mmol) was dissolved in a mixed solvent of dichloromethane (50 mL) and methanol (50 mL), and tetra(n-butyl)ammonium bromide (22.3 g, 46.0 mmol) was added thereto, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, water was added to the resulting residue, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was dissolved in acetonitrile (60 mL), thiourea (3.5 g, 46.0 mmol) was added thereto, followed by stirring at room temperature for 30 minutes. The precipitated solid was collected by filtration, and the resulting solid was dissolved in a mixed solvent of a saturated aqueous solution of sodium hydrogencarbonate and ethyl acetate, and subjected to liquid-liquid separation. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=3:1) to afford 2-amino-4-(2-furyl)thiazole (1.53 g, 20%).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:16])[O:4][C:5]1[C:13]2[O:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[CH2:17]([O:19][C:20]([CH2:22][N:23]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[S:24]Cl)=[O:21])[CH3:18].N1C=CC=CC=1>C(Cl)Cl>[CH2:30]([O:29][C:27]([CH2:26][N:23]([CH2:22][C:20]([O:19][CH2:17][CH3:18])=[O:21])[S:24][N:2]([CH3:1])[C:3](=[O:16])[O:4][C:5]1[C:13]2[O:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:28])[CH3:31]
Reactant: CCOC(=O)CN(CC(=O)OCC)SCl
Reactant: CNC(=O)Oc1cccc2c1OC(C)(C)C2
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)CN(CC(=O)OCC)SN(C)C(=O)Oc1cccc2c1OC(C)(C)C2
Reaction time: 30 h

Procedure:
4.4 g (0.02 mole) of 2,3-dihydro-2,2-dimethylbenzofuran-7-yl N-methyl-carbamate, 5.1 g (0.02 mole) of bis(ethoxycarbonylmethyl)aminosulfenyl chloride obtained in Example 1 or 2, and 4.7 g (0.06 mole) of pyridine were dissolved in 35 ml of methylene chloride, and the resulting solution was stirred for 30 hours at 30° to 35° C. After completion of the reaction, the reaction solution was washed successively with water, diluted hydrochloric acid and water. The methylene chloride layer was dried over sodium sulfate and concentrated under reduced pressure to obtain an oily product. Yield: 7.5 g (85.2%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:13])=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[C:16]1([CH3:42])[C:17]([C:22]([O:24][C@@H:25]2[C@@H:29]([CH2:30][O:31][C:32]([C:34]3[C:35]([CH3:40])=[CH:36][CH:37]=[CH:38][CH:39]=3)=[O:33])[O:28][C@H:27](Cl)[CH2:26]2)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=1>CN(C)C=O>[C:16]1([CH3:42])[C:17]([C:22]([O:24][C@@H:25]2[C@@H:29]([CH2:30][O:31][C:32]([C:34]3[C:35]([CH3:40])=[CH:36][CH:37]=[CH:38][CH:39]=3)=[O:33])[O:28][C@@H:27]([O:1][C:2]3[CH:11]=[C:10]4[C:5]([C:6]([CH3:13])=[CH:7][C:8](=[O:12])[O:9]4)=[CH:4][CH:3]=3)[CH2:26]2)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1ccccc1C(=O)OC[C@H]1O[C@H](Cl)C[C@@H]1OC(=O)c1ccccc1C
Reactant: Cc1cc(=O)oc2cc(O)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccccc1C(=O)OC[C@H]1O[C@@H](Oc2ccc3c(C)cc(=O)oc3c2)C[C@@H]1OC(=O)c1ccccc1C

Procedure:
7-Hydroxy-4-methylcoumarin (226 mg, 1.28 mmol) and sodium hydride (64 mg of a 60% dispersion in mineral oil, 1.6 mmol) were stirred at room temperature for 30 minutes in dry dimethylformamide (4 ml). Then the chloride (423 mg, 1.09 mmol) from Example 16 was added and after 24 hours the mixture was processed as in Stage 1 of Example 17 and the product isolated by flash chromatography on silica gel (eluting with 2% acetone in dichloromethane) to afford an oil which crystallized from hot methanol as colourless crystals (305 mg, 53%). 1H nmr indicated them to be a 91:9 mixture of the title compound and its α-anomer.
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]([N:17]3[CH2:20][CH:19]([O:21][CH3:22])[CH2:18]3)=[O:16])[N:14]=2)[CH2:7]1)(=O)=O.[C:23]([O-:26])(=[S:25])[CH3:24].[K+]>CN(C)C=O>[C:23]([S:25][CH:6]1[CH2:7][N:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]([N:17]3[CH2:18][CH:19]([O:21][CH3:22])[CH2:20]3)=[O:16])[N:14]=2)[CH2:9]1)(=[O:26])[CH3:24]
Reactant: CC([O-])=S
Reactant: COC1CN(C(=O)c2csc(N3CC(OS(C)(=O)=O)C3)n2)C1
Agent: [K+]
Solvent: CN(C)C=O
Product: COC1CN(C(=O)c2csc(N3CC(SC(C)=O)C3)n2)C1
Temperature: 80 °C
Reaction time: 4.5 h
Yield: 67.5 %

Procedure:
To a solution of 3-methanesulfonyloxy-1-[4-(3-methoxyazetidine-1-carbonyl)-1,3-thiazol-2-yl]azetidine (560 mg, 1.61 mmol) (obtained as described in Reference Example 31(4)) in dimethylformamide (28 ml) was added potassium thioacetate (1.10 g, 9.67 mmol) at room temperature. The mixture was stirred in an oil bath (80° C.) for 4.5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate→ethyl acetate:methanol (97:3) as the eluant to afford 3-acetylthio-1-[4-(3-methoxy-azetidine-1-carbonyl)-1,3-thiazol-2-yl]azetidine (356 mg, yield 68%) as a pale brown solid.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:21]1[CH2:24][CH:23]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:22]1>CCCCO>[Br:1][C:2]1[C:3]([N:21]2[CH2:24][CH:23]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:22]2)=[C:4]2[C:10]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1cccnc1
Reactant: CC(C)(C)OC(=O)NC1CNC1
Solvent: CCCCO
Product: CC(C)(C)OC(=O)NC1CN(c2c(Br)cnc3[nH]cc(NC(=O)c4cccnc4)c23)C1
Yield: 36.9 %

Procedure:
N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (100 mg, 0.3 mmol, Example 1, Step I) in n-BuOH (3 mL) and tert-butyl azetidin-3-ylcarbamate (154 mg, 0.9 mmol) were heated to 110° C. in a sealed tube for 24 hours. After cooling down, the reaction was concentrated to dryness, and the residue purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 10-90% CH3CN/water gradient; 30 CV) to yield tert-butyl 1-(5-bromo-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)azetidin-3-ylcarbamate (54 mg, 37% yield) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C@@H:15]([CH3:23])[CH2:14]2)[C:9](=[O:12])[CH2:10][OH:11])=[CH:4][CH:3]=1.C(Cl)CCl.[C:28](O)(=[O:30])[CH3:29]>C(Cl)Cl>[C:28]([O:11][CH2:10][C:9]([N:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C@H:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][C@@H:15]([CH3:23])[CH2:14]1)=[O:12])(=[O:30])[CH3:29]
Reactant: CC(=O)O
Reactant: C[C@H]1C[C@@H](N(C(=O)CO)c2ccc(Cl)cc2)c2ccccc2N1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(=O)OCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)Nc2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 70.7 %

Procedure:
N-(4-Chlorophenyl)-2-hydroxy-N-[(2S,4R)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]acetamide (300 mg, 0.91 mmol, 1 equ.) was dissolved in methylene chloride (3 mL). To this solution was added EDC (464 mg, 2.7 mmol, 3 equ.) and acetic acid (164 mg, 2.7 mmol, 3 equ.) and the reaction mixture was stirred at room temperature for 20 h. Reaction mixture was concentrated and the residue dissolved in ethyl acetate and washed with water, brine, and then dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (methylene chloride/methanol: 99/1 to 98/2 gradient) to afford 2-{(4-chlorophenyl)[(2S,4R)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]amino}-2-oxoethyl acetate (240 mg, 84%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]2[C:7]([CH:10]=[O:11])=[CH:8][O:9][C:5]=2[CH:4]=1.[OH:14][CH2:15][CH2:16]O.O>C1C=CC=CC=1>[O:11]1[CH2:16][CH2:15][O:14][CH:10]1[C:7]1[C:6]2[CH:12]=[CH:13][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[O:9][CH:8]=1
Reactant: COc1ccc2c(C=O)coc2c1
Reactant: OCCO
Solvent: O
Solvent: c1ccccc1
Product: COc1ccc2c(C3OCCO3)coc2c1
Yield: 94.7 %

Procedure:
A mixture of 6-methoxybenzofuran-3-carbaldehyde (0.600 g, 3.41 mmol), HOCH2CH2OH (3.17 g, 51 mmol) and p-toluenesulfonic acids (0.001 g) in benzene (20 mL) was refluxed for 8 h using a Dean-Stark water trap. The mixture was concentrated under reduced pressure and then diluted with EtOAc. The organic solution was washed with water, dried over anhydrous MgSO4, and concentrated to give 3-(1,3-dioxolan-2-yl)-6-methoxybenzofuran (0.711 g, 95%)
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:17])[C:4]=2[CH:3]=1.C1([Li])C=CC=CC=1>O1CCCC1>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]([OH:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]([OH:17])[C:4]=2[CH:3]=1
Reactant: O=C1c2ccccc2C(=O)c2cc(Br)ccc21
Agent: [Li]c1ccccc1
Solvent: C1CCOC1
Product: OC1c2ccccc2C(O)c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
In a 300 mL three-neck flask was put 4.90 g (17.0 mmol) of 2-bromo-9,10-anthraquinone, and the atmosphere in the flask was replaced with nitrogen. To the flask was added 100 mL of tetrahydrofuran (THF), and 17.8 mL (37.3 mmol) of phenyllithium was dropped into this solution. After the completion of the dropping, this solution was stirred at room temperature for 15 hours. Then, this solution was washed with water, and the aqueous layer was extracted with ethyl acetate. The extract solution and the organic layer were combined and dried with magnesium sulfate. Then, this mixture was gravity filtered. The obtained filtrate was concentrated to give 2-bromo-9,10-dihydroanthracene-9,10-diol, which was the object of the synthesis.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([O:10][C@@H:11]([C:16]([O:29][CH3:30])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([O:14]C)=[O:13])[N:4]=1.[OH-].[Na+]>CO.O>[OH:1][CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([O:10][C@@H:11]([C:16]([O:29][CH3:30])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:12]([OH:14])=[O:13])[N:4]=1
Reactant: COC(=O)[C@@H](Oc1nc(C)cc(CO)n1)C(OC)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(c1ccccc1)(c1ccccc1)[C@H](Oc1nc(C)cc(CO)n1)C(=O)O
Temperature: 25 °C
Yield: 77.6 %

Procedure:
To a solution of the compound of Example 11 (0.8 g, 1.96 mmol) in methanol (10 mL) is added a solution of sodium hydroxide (0.392 g, 9.8 mmol) in water (5 mL) and the resultant mixture refluxed for 2 hr. The reaction is cooled to room temperature and the methanol is removed under reduced pressure on a rotary evaporator. The residual aqueous phase is washed with ether (2×10 mL), and then the pH of the aqueous phase is adjusted to 2-3 with 2N sulfuric acid and extracted with ethyl acetate (2×20 mL) to yield the title compound (0.6 g, 80%). MS m/z 395.1 (M+.+1); [α]D20=+141.09° (c=1, CH3OH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.[NH2:11][CH:12]([CH3:26])[CH2:13][C:14]1[C:22]2[C:17](=[C:18]([O:23][CH2:24][CH3:25])[CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1>>[CH2:24]([O:23][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:17]=1[NH:16][CH:15]=[C:14]2[CH2:13][CH:12]([NH:11][CH2:10][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[OH:9])[CH3:26])[CH3:25]
Reactant: Clc1cccc(C2CO2)c1
Reactant: CCOc1cccc2c(CC(C)N)c[nH]c12
Product: CCOc1cccc2c(CC(C)NCC(O)c3cccc(Cl)c3)c[nH]c12
Yield: 52.3 %

Procedure:
(3-Chlorophenyl)oxirane (0.92 g) and 3-(2-aminopropyl)-7-ethoxyindole (2.18 g) are treated in the same manner as in Example 1, Process (a) to give the desired compound (1.16 g) as an oily product.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH2:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>C(OCC)(=O)C>[CH2:8]([O:15][C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OCc1ccccc1
Reactant: O=C1CCC(=O)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(O)CCC(=O)OCc1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
A mixture of 5.0 g (0.05 mol) of succinic acid anhydride, 5.4 g (0.05 mol) of benzyl alcohol, 16.25 g (0.05 mol) of cesium carbonate, and 50 ml of N,N-dimethylforamide was stirred at 100° C. for 2 hours. The reaction mixture was cooled to room temperature, and then poured into 200 ml of ethyl acetate. The mixture was washed with saturated aqueous NaCl containing 0.35 N HCl (3×100 mL). The ethyl acetate phase, which contains the product, was collected and dried over anhydrous MgSO4. The MgSO4 was removed via filtration, and the ethyl acetate was removed under reduced pressure. The crude product was purified by crystallization in diethyl ether and hexane to provide 7.34 g of succinic acid monobenzyl ester, 70.47%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:37])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][N:9]2[C:28]([C:30]2[CH:35]=[CH:34][C:33](=[O:36])[NH:32][CH:31]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1.[C:38](=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.IC.CCOC(C)=O>[Cl:1][C:2]1[C:3]([F:37])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH2:10][N:9]2[C:28]([C:30]2[CH:35]=[CH:34][C:33](=[O:36])[N:32]([CH3:38])[CH:31]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)CC1CN(C(=O)c2ccc(=O)[nH]c2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: Cn1cc(C(=O)N2CC(CC(C)(C)C)C(C#N)(c3ccc(Cl)cc3F)C2c2cccc(Cl)c2F)ccc1=O
Reaction time: 3 h
Yield: 97 %

Procedure:
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-1-(6-oxo-1,6-dihydro-pyridine-3-carbonyl)-pyrrolidine-3-carbonitrile (15.1 mg, 0.0277 mmol, example 40), cesium carbonate (27 mg, 0.0829 mmol, Aldrich) in DMF (3 mL) and iodomethane was stirred at room temp. for 3 hrs before it was diluted with EtOAc, washed with water and brine, dried and concentrated. The residue was purified by flash column to give rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-1-(1-methyl-6-oxo-1,6-dihydro-pyridine-3-carbonyl)-pyrrolidine-3-carbonitrile (15.0 mg, 96%) as a white solid.