Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24](S(C)(=O)=O)[N:23]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:2]([O:1][C:24]2[N:25]=[C:26]([O:28][CH3:29])[CH:27]=[C:22]([O:21][CH3:20])[N:23]=2)[C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: COC(=O)c1c(O)cccc1C=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1c(C=Cc2ccccc2)cccc1Oc1nc(OC)cc(OC)n1
Yield: 54.2 %

Procedure:
A mixture of 1.2 g (4.7 mmol) of methyl 2-hydroxy-6-styrylbenzoate, 1.02 g (4.7 mmol) of 4,6-dimethoxy-2-methylsulphonyl-pyrimidine, 0.8 g (5.7 mmol) of potassium carbonate and 50 ml of acetonitrile is heated under reflux for 15 hours and then concentrated. The residue is shaken with methylene chloride/water, and the organic phase is dried with sodium sulphate and filtered. The filtrate is concentrated and the residue is purified by column chromatography (silica gel; hexane/ethyl acetate, 10:1). 1.0 g (54% of theory) of methyl 2-styryl-6-(4,6-di-methoxy-pyrimidin-2-yl-oxy)-benzoate is obtained as an amorphous product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1)[CH3:2].F[C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=[O:18].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:15]2[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=2[CH:17]=[O:18])[CH:7]=1)[CH3:2]
Reactant: O=Cc1ccccc1F
Reactant: CCOC(=O)Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)Cc1cccc(Oc2ccccc2C=O)c1
Temperature: 120 °C
Yield: 67.6 %

Procedure:
(3-Hydroxy-phenyl)-acetic acid ethyl ester (1.0 g, 5.2 mmol), 2-fluorobenzaldehyde (0.66 g, 5.2 mmol), and potassium carbonate (1.44 g, 10.4 mmol) were combined in 1,4-dioxane (30 mL) and heated to 120° C. for 3 days. After work-up, the crude material was purified by silica gel chromatography (0-20% EtOAc in hexanes) to give the desired product (1 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)=[O:9])[CH2:4][CH2:3]1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+].C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:52].Cl.Cl>C(Cl)Cl.CCOCC.CO.C(O)(=O)C>[ClH:52].[ClH:52].[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:17]=[CH:16][C:13]([CH2:14][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:12][CH:11]=2)=[O:9])[CH2:4][CH2:3]1
Reactant: C1COCCN1
Reactant: CN1CCN(C(=O)c2ccc(C=O)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: CN1CCN(C(=O)c2ccc(CN3CCOCC3)cc2)CC1

Procedure:
To a solution of the product of Example 16 (60 mg) and morpholine (0.025 mL) in DCM (5 mL) was added acetic acid (0.015 mL) and sodium triacetoxyborohydride (83 mg). After 16 h the reaction was treated with 1 N NaOH (10 mL) and extracted with DCM (3×20 mL). Organic layers were dried (Na2SO4), concentrated under reduced pressure, and chromatographed on silica gel (4% 2 M methanolic ammonia/DCM) to give the free base product. This material was converted into the dihydrochloride using methanol and 2 M HCl in ether to form a white solid (35 mg).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[C:15]([CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])[N:14]([CH2:28][CH2:29][CH3:30])[C:13]=2[CH:31]=1.C(O)(=O)C.C[N:37]1[CH:41]=[CH:40][N:39]=[C:38]1[CH:42]=O.C([BH3-])#N.[Na+]>CO>[NH:3]1[CH:4]=[CH:5][N:1]=[C:2]1[CH2:6][N:7]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[C:15]([CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:22][CH2:23][CH3:24])[CH2:25][CH2:26][CH3:27])[N:14]([CH2:28][CH2:29][CH3:30])[C:13]=2[CH:31]=1)[CH2:42][C:38]1[NH:37][CH:41]=[CH:40][N:39]=1
Reactant: Cn1ccnc1C=O
Reactant: CCCN(CCC)CCCCc1nc2ccc(CNCc3ncc[nH]3)cc2n1CCC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)CCCCc1nc2ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)cc2n1CCC
Temperature: 0 °C
Reaction time: 48 h

Procedure:
The compound (64.0 mg) obtained in Example 126-1 was dissolved in methanol (1.3 ml) and added with acetic acid (0.065 ml) and 1-methyl-2-imidazole carboxaldehyde (16.6 mg), followed by cooling to 0° C. Then, the solution was added with sodium cyanoborohydride (14.2 mg) and stirred at room temperature for 2 days. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was then dissolved in chloroform. After washing with a 1 mol/l sodium hydroxide aqueous solution, the solution was subjected to extraction with chloroform. The organic layer was washed with saturated saline solution and dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (30.0 mg) of the subject compound as a white solid.
Reaction SMILES: C(O[C:4](=[O:28])[CH2:5][N:6]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][CH2:15]C(OCC)=O)[CH:10]=[CH:11][CH:12]=1)C.O(C)[Na]>>[C:22]1([CH2:21][N:6]2[CH:7]([CH2:12][C:11]3[CH:10]=[CH:9][CH:13]=[CH:14][CH:15]=3)[CH2:8][C:4](=[O:28])[CH2:5]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)CCCc1cccc(N(CC(=O)OCC)Cc2ccccc2)c1
Agent: CO[Na]
Product: O=C1CC(Cc2ccccc2)N(Cc2ccccc2)C1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 14.7 %

Procedure:
Intermediate 21 (0.2 mol) was heated to 80° C. under N2 flow. NaOCH3 (44 g) was added. The mixture was stirred at 80° C. for 30 minutes. The solvent was evaporated and water (170 ml) and HCl (6N, 60 ml) were added. The mixture was stirred and refluxed for 1 hour, then cooled, alkalized and NaOH and extracted with CH2Cl2. The organic layer was separated, washed with water and a saturated NaCl solution, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3CN 100/0 and 96/4). The pure fractions were collected and the solvent was evaporated, yielding 7.8 g of (±)-1,5-bis(phenylmethyl)-3-pyrrolidinone (intermediate 22).
Reaction SMILES: [CH2:1]([CH:4]1[N:10]2[C:11](=[O:14])[O:12][N:13]=[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5]1)[CH:2]=C.I([O-])(=O)(=O)=[O:16].[Na+]>O1CCOCC1.O.CCCCO.O.[Os](=O)(=O)(=O)=O.[Os](=O)=O>[O:14]=[C:11]1[N:10]2[CH:4]([CH2:1][CH:2]=[O:16])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]2=[N:13][O:12]1
Reactant: C=CCC1CCCCc2noc(=O)n21
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: O=[Os]=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCCCO
Product: O=CCC1CCCCc2noc(=O)n21
Temperature: 25 °C
Reaction time: 24 h
Yield: 67 %

Procedure:
EX-8) To a solution of the product of Example 6 in dioxane (200 mL) and water (135 mL) was added sodium periodate (15.11 g, 0.071 mol) and osmium tetraoxide (12 drops of a 1 ppm solution of osmium dioxide in n-BuOH/H2O). The reaction was stirred at room temperature and monitor by thin layer chromatography for one day. Since the starting material had not completely reacted, additional osmium tetraoxide (12 drops of 1 ppm solution of osmium dioxide in n-BuOH/H2O) was added. A white precipitate was filtered off and the filtrate was removed under reduced pressure to the point where no dioxane remained. Additional water (75 mL) was then added to the aqueous layer and this aqueous mixture was washed with CH2Cl2 (3×75 mL). The organic layer was combined, dried over magnesium sulfate, and stripped of all solvent under reduced pressure to afford a yellow oil. Chromatographic (silica gel) purification of this material eluting with the 1:1, ethyl acetate:hexane afforded 4.0 g (67%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:13])[C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:14][NH2:15]>C(O)C>[CH3:14][NH:15][CH:3]([C:11]1[C:10](=[O:12])[C:9]2[C:4]([C:3](=[O:13])[C:2]=1[OH:1])=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:2][CH2:11][CH3:10]
Reactant: CN
Reactant: O=C1C=C(O)C(=O)c2ccccc21
Solvent: CCO
Product: CCCC(NC)C1=C(O)C(=O)c2ccccc2C1=O

Procedure:
3.50 g (20.1 mmol) of 2-hydroxy-1,4-naphthoquinone (lawson) was added to 50 ml of ethanol, and 1.60 g (20.6 mmol) of an aqueous monomethylamine solution (40% by weight) was further added thereto to obtain uniform solution of the amine salt. Then, 1.90 g (26.4 mmol) of butylaldehyde was added thereto, and the mixture was reacted at 25° C. for 1.5 hours. In about 20 minutes, crystals started to precipitate. After completion of the reaction, precipitated crystals were collected by filtration and washed with methanol to obtain 4.43 g (17.1 mmol) of crude crystals of the desired product. The yield was 85.1 mol%.
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[N:5][CH:4]=[N:3]1.[F:11][C:12]1[CH:40]=[CH:39][C:15]([CH2:16][C@H:17]2[CH2:21][NH:20][C@H:19]([C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=4)=[CH:27][CH:26]=3)=[O:23])[CH2:18]2)=[CH:14][CH:13]=1>>[N:2]1([CH2:7][C:8]([N:20]2[CH2:21][C@H:17]([CH2:16][C:15]3[CH:39]=[CH:40][C:12]([F:11])=[CH:13][CH:14]=3)[CH2:18][C@H:19]2[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=3)=[CH:27][CH:26]=2)=[O:23])=[O:10])[CH:6]=[N:5][CH:4]=[N:3]1
Reactant: O=C(O)Cn1cncn1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(F)cc2)CN1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(F)cc2)CN1C(=O)Cn1cncn1
Yield: 33 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,4-triazol-1-yl)acetic acid hydrochloride and (2S,4R)-4-(4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 141, (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-(4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (39 mg, 33%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.00 (s, 1H), 8.43 (s, 1H), 7.95 (s, 1H), 7.57 (d, 2H), 7.35-7.08 (m, 7H), 7.05-6.90 (m, 4H), 5.23 (q, 2H), 4.56-4.47 (m, 1H), 3.87-3.74 (m, 1H), 3.39-3.29 (m, 1H), 2.79-2.62 (m, 3H), 2.04-1.89 (m, 2H). MS (EI) for C28H25F2N5O3. found 517.9 (MH+).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][C@H:8]1[CH2:32][CH:33]([NH:38][C:39]([O:41][CH2:42][CH:43]=[CH2:44])=[O:40])[C:34](OC)=[O:35])=[O:6])[CH:2]=[CH2:3].[Cl-].[Li+].[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.C(O)C>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:9][C@H:8]1[CH2:32][CH:33]([NH:38][C:39]([O:41][CH2:42][CH:43]=[CH2:44])=[O:40])[CH2:34][OH:35])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)NC(C[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCC=C)C(=O)OC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCO
Product: C=CCOC(=O)NC(CO)C[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCC=C
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
To a solution of (2R,4S)-N-allyloxycarbonyl-2-(2-allyloxycarbonylamino-2-methoxycarbonylethyl)-4-(triphenylmethylthio)pyrrolidine prepared in REFERENCE EXAMPLE 2-2 (810 mg, 1.32 mmol) in tetrahydrofuran (5 ml) was added lithium chloride (100 mg, 2.58 mmol), sodium borohydride (110 mg, 2.59 mmol) and ethanol (5 ml) under a nitrogen atmosphere, and the mixture was stirred overnight at room temperature. The reaction mixture was acidified with 10% aqueous citric acid under ice-cooling, and then the organic solvent was removed in vacuo. The residual aqueous solution was extracted with methylene chloride (1×40 ml, 2×20 ml), and the combined organic layer was washed successively with water and saturated aqueous sodium chloride. After drying over anhydrous sodium sulfate, the solvent was removed in vacuo, and the residue was subjected to silica gel column chromatography (heptane-ethyl acetate) to give (2R,4S)-N-allyloxycarbonyl-2-(2-allyloxycarbonylamino-3-hydroxypropyl)-4-(triphenylmethylthio)pyrrolidine (440 mg, yield: 57%).
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH:12]([CH3:14])[CH3:13])=[C:7]([O:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[CH:6]=1)C.O.[OH-].[Na+].Cl>O1CCOCC1>[Cl:25][C:19]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=1[CH2:17][CH2:16][O:15][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[O:11][CH:12]([CH3:14])[CH3:13])[C:4]([OH:26])=[O:3]
Reactant: CCOC(=O)c1ccc(OC(C)C)c(OCCc2ccc(Cl)cc2Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)Oc1ccc(C(=O)O)cc1OCCc1ccc(Cl)cc1Cl
Temperature: 60 °C
Reaction time: 16 h

Procedure:
0.75 g (1.89 mmol) of 3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-isopropoxy-benzoic acid ethyl ester was dissolved in 15 ml of dioxan. 5 ml of water and 2N aqueous NaOH was added to the solution to give a pH of 13. The reaction solution was heated at 60° C. for 4 h and stirred at room temperature for 16 h. The reaction solution was cooled to 0° C. and concentrated hydrochloric acid was added to give a pH of 1–2, whereupon the product precipitated from solution. The suspension was stirred for 30 min, then the product was filtered off and dried under reduced pressure.
Reaction SMILES: C(OCC)C.O=[C:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1.[C-:20]#[N:21].[Na+].C(=O)([O-])O.[Na+]>O>[C:20]([C:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH:8]=1)#[N:21]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(C#N)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.7 %

Procedure:
Diethyl ether (15 ml) and 8 ml of water were added to 790 mg of tert-butyl 4-oxopiperidine-1-carboxylate, 216 mg of sodium cyanide and 672 mg of sodium hydrogen carbonate and the solution was stirred at room temperature for 1.5 hours. The resulting product was extracted with ether, washed with water and a saturated saline solution and dried over sodium sulfate. After the solvent was evaporated in vacuo, 10 ml of chloroform, 0.84 ml of triethylamine and 0.34 ml of methanesulfonyl chloride were added to the resulting residue followed by stirring at room temperature for 20 minutes. The reaction was stopped by water, the product was extracted with chloroform and the organic layer was washed with a saturated sodium hydrogen carbonate and a saturated saline solution and dried over sodium sulfate. The solvent was evaporated in vacuo, 10 ml of pyridine was added to the resulting residue and the mixture was stirred for one night under heating to reflux. After cooling to room temperature, the solvent was evaporated in vacuo followed by adding ethyl acetate and water. The organic layer washed with a saturated saline solution and dried over sodium sulfate and the solvent was evaporated in vacuo. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=6/1) to give 650 mg of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]2[CH2:23][C:22]3[C:17](=[C:18]([O:30]C)[C:19]([O:28][CH3:29])=[C:20]([O:26][CH3:27])[C:21]=3[O:24]C)[CH2:16]2)=[CH:4][CH:3]=1.N1C(C(O)=O)=CC=CC=1C(O)=O.C1COCC1.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]2[CH2:16][C:17]3[C:18](=[O:30])[C:19]([O:28][CH3:29])=[C:20]([O:26][CH3:27])[C:21](=[O:24])[C:22]=3[CH2:23]2)=[CH:32][CH:33]=1
Reactant: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCOc1ccc(Cl)cc1)C2
Agent: O=C(O)c1cccc(C(=O)O)n1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Solvent: O
Solvent: C1CCOC1
Product: COC1=C(OC)C(=O)C2=C(CC(CCCCCCCCOc3ccc(Cl)cc3)C2)C1=O
Reaction time: 0.25 h
Yield: 50.5 %

Procedure:
To a mixture of 2-[8-(4-chlorophenoxy)octyl]-4,5,6,7-tetramethoxyindan (676 mg), 2,6-pyridinedicarboxylic acid (712 mg), THF (14 ml), and water (7 ml) was dropwise added a solution of CAN (3.11 g) in water (7 ml) with cooling with ice. After the reaction mixture was stirred for 15 min, water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography (hexane to hexane:ethyl acetate=10:1) and then with recrystallization from hexane-diethyl ether to yield the entitled compound (320 mg) as crystals.
Reaction SMILES: [CH3:1][C@:2]12[C:9]3[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][C:8]=3[N:7]([CH3:15])[C@H:6]1[N:5]([CH3:16])[CH2:4][CH2:3]2.C([Li])CCC.[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>C(COC)OC>[CH3:1][C@:2]12[C:9]3[CH:10]=[C:11]([O:14][C:29]([NH:28][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[O:30])[CH:12]=[CH:13][C:8]=3[N:7]([CH3:15])[C@H:6]1[N:5]([CH3:16])[CH2:4][CH2:3]2
Reactant: CN1CC[C@@]2(C)c3cc(O)ccc3N(C)[C@@H]12
Reactant: O=C=Nc1ccccc1
Agent: [Li]CCCC
Solvent: O
Solvent: COCCOC
Product: CN1CC[C@@]2(C)c3cc(OC(=O)Nc4ccccc4)ccc3N(C)[C@@H]12
Reaction time: 0.17 h
Yield: 96456.5 %

Procedure:
Eseroline base (50 g, 0.229 mol) was dissolved in 400 mL anhydrous dimethoxyethane under an argon atmosphere. Catalytic amounts of 2.5 M n-butyl lithium in hexanes (6.4 mL, 16 mmol) were added within 1 minute and the solution stirred for 10 minutes. Phenyl isocyanate (27.269 g, 0.2286 mmol) was added over 32 minutes keeping the temperature between 20 and 23° C. The reaction solution was stirred at r.t. for 2 hours 20 minutes, then transferred to an addition funnel. The reaction solution was added over 49 minutes to mixture of DI water (630 mL) and dimethoxyethane (42 mL) under vigorous stirring. The obtained slurry was stirred for 30 minutes, then filtered via a Buchner funnel (Whatman #3 filterpaper). The solid residue was washed four times with DI water (100 mL each) and once with heptane (100 mL), then dried at 45° C. and >29 inches of vacuum for 9 hours. Phenserine base (74.4 g) was obtained as reddish solid in 96.2% yield and 95.1% purity.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][N:6]([C:12]([O:14][C@H:15]1[CH2:19][N:18](C(OC(C)(C)C)=O)[C@H:17]([C:27]([O:29][CH3:30])=[O:28])[CH2:16]1)=[O:13])[CH2:7]2)=[CH2:2].[ClH:31]>C(OCC)(=O)C>[ClH:31].[CH:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][N:6]([C:12]([O:14][C@@H:15]1[CH2:16][C@@H:17]([C:27]([O:29][CH3:30])=[O:28])[NH:18][CH2:19]1)=[O:13])[CH2:7]2)=[CH2:2]
Reactant: C=Cc1cccc2c1CN(C(=O)O[C@@H]1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1)C2
Agent: Cl
Solvent: CCOC(C)=O
Product: C=Cc1cccc2c1CN(C(=O)O[C@H]1CN[C@H](C(=O)OC)C1)C2
Temperature: 25 °C
Yield: 95 %

Procedure:
A solution of 1-tert-Butyl 2-methyl (2S,4R)-4-{[(4-vinyl-1,3-dihydro-2H-isoindol-2-yl)carbonyl]oxy}pyrrolidine-1,2-dicarboxylate (13.9 g, 33.4 mmol) in ethyl acetate (700 mL) was cooled in an ice bath the saturated with hydrogen chloride gas. The reaction flask was sealed and allowed to warm to room temperature. After 3.5 h the solvent was removed by evaporation to give the title compound as a gray solid, 11.2 g, 95% yield). 1H NMR (500 MHz, ppm, CD3OD) δ 7.47-7.45 (m, 1H), 7.32-7.31 (m, 1H), 7.26-7.21 (m, 1H), 6.79-6.73 (m, 1H), 5.79-5.73 (m, 1H), 5.46 (s, 1H), 5.41-5.38 (m, 1H), 4.80-4.72 (m, 4H), 3.91 (s, 3H), 3.74-3.63 (m, 2H), 2.77-2.71 (m, 1H), 2.51-2.46 (m, 1H). LRMS (ESI) m/z 317 [(M+H)+; calcd for C17H21N2O4: 317].
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4]Br.C(O)C.[S:9]([O-:12])([O-:11])=[O:10].[Na+:13].[Na+]>O>[Cl:1][CH2:2][CH2:3][CH2:4][S:9]([O-:12])(=[O:11])=[O:10].[Na+:13]
Reactant: ClCCCBr
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=S(=O)([O-])CCCCl
Reaction time: 2 h

Procedure:
1-Chloro-3-bromopropane (104.0 g), ethanol (250 ml), and water (90 ml) were stirred under reflux, and a solution of sodium sulphite (25.0 g) in distilled water (90 ml) was added to the stirred refluxing reaction mixture over a period of two hours. After the addition, refluxing was continued for a further 2 hours after which the excess alcohol and 1-chloro-3-bromopropane were removed by distillation. The remaining aqueous solution was evaporated to dryness on a steam bath and the product was recrystallised from alcohol to yield sodium 3-chloro-propane-sulphonate as a white crystalline solid.
Reaction SMILES: C(O[C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])=[O:18])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.B(Br)(Br)Br.C[OH:31].O>C(Cl)Cl>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:17](=[O:18])[CH:16]=[CH:15][C:11]1[CH:12]=[CH:13][CH:14]=[CH:9][C:10]=1[OH:31]
Reactant: O=C(C=Cc1cccc(OCc2ccccc2)c1)c1ccccc1Cl
Reactant: CO
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=C(C=Cc1ccccc1O)c1ccccc1Cl

Procedure:
To a solution of 740 mg (2.12 mmol) of 1-4 in 15 mL of CH2Cl2 at −78° C. was added dropwise 2.75 mL (2.75 mmol) of a 1M solution of BBr3 in CH2Cl2. After stirring for 30 min at that temperature, 1 mL of MeOH was added, and the mixture was dumped into water, extracted twice with 50 mL of CH2Cl2, washed again with water, and dried over Na2SO4. After concentration, the residue was purified by column chromatography on silica gel with a gradient of 2 to 70% EtOAc in hexanes over 30 min to provide 1-5 as a beige solid. Data for 1-5: 1HNMR (500 MHz, CDCl3) δ 7.5-7.3 (m, 5H), 7.25 (m, 1H), 7.2-7.0 (m, 3H), 6.9 (m, 1H), 5.1 (bs, 1H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[CH:14][NH:15]3)[CH:6]=1.C([OH:23])C.C(O)(=O)C.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CC(O)(C)C.[Zn].O>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][C:14](=[O:23])[NH:15]3)[CH:6]=1
Reactant: CCO
Reactant: COC(=O)Cc1cccc(-c2cccc3[nH]ccc23)c1
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Product: COC(=O)Cc1cccc(-c2cccc3c2CC(=O)N3)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the suspension of [3-(1H-indol-4-yl)phenyl]-acetic acid methyl ester (3.72 g, 14 mmol) in t-BuOH: ethanol: acetic acid (93 mL: 56 mL: 67.2 mL) was added pyridinium tribromide (14.14 g, 44 mmol) portionwise. The mixture was stirred at room temperature for 3 hours, and then to the mixture was added acetic acid (60 mL). Water (2 mL) and zinc dust (14 g, excess) was added to the reaction mixture portionwise. After stirring at rt for one hour, any unreacted zinc was filtered off and most of the solvent was removed under reduced pressure. The residue was diluted with diluted with water (380 mL), extracted with ethyl acetate, washed with 0.5 N HCl (2×), 10% Na2CO3, (2×), brine (2×), water (1×), dried over Na2SO4, concentrated and triturated with ether to give [3-(2-oxo-2,3-dihydro-1H-indol-4-yl)phenyl]-acetic acid methyl ester.