Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:25]([O:27]C)=[O:26])[C:5]([CH3:24])=[C:6]([N:8]([CH2:22][CH3:23])[CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:7]=1.[Li+].[OH-].[OH-].[Na+].Cl>O1CCCC1.O>[C:18]([O:17][C:15]([N:12]1[CH2:11][CH2:10][CH:9]([N:8]([CH2:22][CH3:23])[C:6]2[C:5]([CH3:24])=[C:4]([CH:3]=[C:2]([Cl:1])[CH:7]=2)[C:25]([OH:27])=[O:26])[CH2:14][CH2:13]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CCN(c1cc(Cl)cc(C(=O)OC)c1C)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCN(c1cc(Cl)cc(C(=O)O)c1C)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.1 %

Procedure:
To a solution of tert-butyl 4-{[5-chloro-3-(methoxycarbonyl)-2-methylphenyl](ethyl)amino}piperidine-1-carboxylate (131 mg, 0.32 mmol) in tetrahydrofuran (2 ml) was added LiOH (8.4 mg, 0.35 mmol) in deionized water (2 ml). The reaction mixture was stirred in air at room temperature for 24 hours. 1M NaOH (3.19 ml) was added to the reaction mixture and this was stirred for a further 24 hours. The reaction mixture was then warmed to 40° C. for 25 h. The reaction mixture was acidified to pH 2-3 with 1M HCl and extracted with EtOAc (3×20 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to give 122 mg of the title compound as a thick orange oil. LC-MS 76%, m/z=397.5/399.4, 1H NMR (500 MHz, Chloroform-d) δ ppm 7.74 (1H, s), 7.20-7.35 (2H, m), 3.92-4.11 (2H, m), 2.97-3.13 (2H, m), 2.81-2.95 (1H, m), 2.62-2.79 (2H, m), 2.53 (3H, s), 1.75 (2H, br. s.), 1.48-1.61 (2H, m), 1.46 (9H, s), 0.89 (3H, t, J=6.86 Hz).
Reaction SMILES: [CH2:1]([S:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH:17]([C@@H:19]1[C@:36]2([CH3:37])[C@H:22]([C@H:23]3[C@H:33]([CH2:34][CH2:35]2)[C@:31]2([CH3:32])[C@H:26]([N:27]([CH3:39])[C:28](=[O:38])[CH2:29][CH2:30]2)[CH2:25][CH2:24]3)[CH2:21][CH2:20]1)[CH3:18])=[O:15])[CH3:2].I([O-])(=O)(=O)=[O:41].[Na+].I([O-])(=O)(=O)=O>CC(C)=O.O>[CH2:1]([S:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH:17]([C@@H:19]1[C@:36]2([CH3:37])[C@H:22]([C@H:23]3[C@H:33]([CH2:34][CH2:35]2)[C@:31]2([CH3:32])[C@H:26]([N:27]([CH3:39])[C:28](=[O:38])[CH2:29][CH2:30]2)[CH2:25][CH2:24]3)[CH2:21][CH2:20]1)[CH3:18])=[O:15])=[O:41])[CH3:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCSCCCCCCCCCCC(=O)OC(C)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4N(C)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCS(=O)CCCCCCCCCCC(=O)OC(C)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4N(C)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
To a stirred solution of 20-(11-(ethylthio)undecanoyloxy)-4-methyl-5α-4-azapregnan-3-one (0.056 g, 0.1 mM) in acetone (5 mL) at room temperature was added a solution of sodium periodate (0.033 mg, 0.154mM) in water (3 drops). After prolonged stirring with additional portions of the periodate added (0.046 g total) over 3 days, the solvents were removed in vacuo, and the residue extracted with methylene chloride. The methylene chloride was removed in vacuo, and the resulting residue was flash chromatographed on silica gel (30% acetone/methylene chloride eluant) to give the title compound as a glaze. MS M+ calculated for C34H59NO4S, mw=577.90; observed m/e 577.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:12])[N:4]([CH3:11])[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[NH2:8].[CH2:13]1[O:26][C:25]2[CH:24]=[CH:23][C:17]([CH:18]=[CH:19][C:20](O)=O)=[CH:16][C:15]=2[O:14]1>>[CH2:13]1[O:26][C:25]2[CH:24]=[CH:23][C:17](/[CH:18]=[CH:19]/[C:20]3[NH:1][C:2]4[C:3](=[O:12])[N:4]([CH3:11])[C:5](=[O:10])[N:6]([CH3:9])[C:7]=4[N:8]=3)=[CH:16][C:15]=2[O:14]1
Reactant: O=C(O)C=Cc1ccc2c(c1)OCO2
Reactant: Cn1c(N)c(N)c(=O)n(C)c1=O
Product: Cn1c(=O)c2[nH]c(/C=C/c3ccc4c(c3)OCO4)nc2n(C)c1=O
Yield: 12.5 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 5.0 g (29.4 mmol) of 5,6-diamino-1,3-dimethyluracil and 6.78 g (35.3 mmol) of 3,4-methylenedioxycinnamic acid. Then, the resultant crude crystals were recrystallized from dimethylformamide/water to give 1.20 g (yield 13%) of Compound 86 as a pale yellow powder.
Reaction SMILES: C(OC([NH:11][C:12]1([C:18]([OH:20])=O)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=O)C1C=CC=CC=1.Cl.[NH2:22][CH2:23][C:24]#[N:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH3:57][S:58]([OH:61])(=[O:60])=[O:59]>CN(C=O)C>[CH3:57][S:58]([OH:61])(=[O:60])=[O:59].[NH2:11][C:12]1([C:18]([NH:25][CH2:24][C:23]#[N:22])=[O:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: N#CCN
Reactant: O=C(NC1(C(=O)O)CCCCC1)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CCNC(=O)C1(N)CCCCC1
Reaction time: 4 h
Yield: 100 %

Procedure:
1-Benzyloxycarbonylaminocyclohexanecarboxylic acid (5.0 gm, 21.0 mmol) was taken up in DMF (40 mL). The mixture was cooled in an ice bath and then sequentially treated with aminoacetonitrile hydrochloride (3.8 gm, 42 mmol), HATU (8.25 gm, 21 mmol) and triethylamine (8.0 mL, 63 mmol). The reaction was allowed to proceed for 4 hours and then the mixture was concentrated under vacuum. The residue was treated with saturated NaHCO3 solution (40 mL) and ethyl acetate (150 mL). The organic layer was separated, sequentially washed with water, 1 M hydrochloric acid (20 mL), water and brine and dried over anhydrous MgSO4 and concentrated under reduced pressure. The free base of the product was purified from the residue using a plug of silica with ethyl acetate as an eluant. The free base of the product was taken up in dichlormethane (20 ml) and methanesulfonic acid (3.0 eq) and the mixture stirred for approximately 12 hours. The mixture was concentrated and the residue was triturated with ether (100 ml) and dried under vacuum to provide 1-amino-N-cyanomethylcyclohexanecarboxamide methanesulfonic acid salt (5.5 gm, 100% yield). LC-MS: 182.2, M+H+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:6]1[C:22](=[O:27])[O:23][C:24](=[O:26])[CH2:25][C:5]2=1.Cl.[F:29][C:30]1([F:34])[CH2:33][NH:32][CH2:31]1>CCN(CC)CC>[F:29][C:30]1([F:34])[CH2:33][N:32]([C:24](=[O:26])[CH2:25][C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[N:7]([CH2:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[CH:14][CH:13]=3)[C:6]=2[C:22]([OH:23])=[O:27])[CH2:31]1
Reactant: O=C1Cc2c(n(Cc3cccc4ccccc34)c3ccc(F)cc23)C(=O)O1
Reactant: FC1(F)CNC1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(O)c1c(CC(=O)N2CC(F)(F)C2)c2cc(F)ccc2n1Cc1cccc2ccccc12

Procedure:
6-Fluoro-9-naphthalen-1-ylmethyl-4,9-dihydro-pyrano[3,4-b]indole-1,3-dione (from Example 68.1.) was ring opened with 3,3-difluoro-azetidine hydrochloride and NEt3 at 22° C. to give the title compound as a white solid. MS: 450.9 ([M−H]−).
Reaction SMILES: Cl[C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][CH2:9][C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([Cl:21])=[CH:16][CH:17]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[NH:30]1[CH2:35][CH2:34][CH:33]([CH2:36][OH:37])[CH2:32][CH2:31]1>>[Cl:21][C:15]1[CH:14]=[C:13]2[C:18]([C:19](=[O:20])[C:10]([CH2:9][NH:8][C:6]([C:5]3[CH:28]=[CH:29][C:2]([N:30]4[CH2:35][CH2:34][CH:33]([CH2:36][OH:37])[CH2:32][CH2:31]4)=[N:3][CH:4]=3)=[O:7])=[CH:11][N:12]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:17][CH:16]=1
Reactant: OCC1CCNCC1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(Cl)nc1
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(N2CCC(CO)CC2)nc1

Procedure:
4-Hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate E and 4-piperidinemethanol. MS calcd. for C28H27ClN4O3 [(M+H)+] 503.2, obsd. 503.
Reaction SMILES: [NH2:1][C:2](=[N:26][OH:27])[CH2:3][C@H:4]1[C@H:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[O:9][CH2:8][CH2:7][N:6]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:5]1.[CH3:28][C:29](C)([O-])C.[K+].C(OCC)(=O)C.O>C1(C)C=CC=CC=1>[Cl:18][C:13]1[CH:12]=[C:11]([C@@H:10]2[O:9][CH2:8][CH2:7][N:6]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:5][C@H:4]2[CH2:3][C:2]2[N:1]=[C:28]([CH3:29])[O:27][N:26]=2)[CH:16]=[CH:15][C:14]=1[Cl:17]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CC(N)=NO)C1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1nc(C[C@@H]2CN(C(=O)OC(C)(C)C)CCO[C@H]2c2ccc(Cl)c(Cl)c2)no1
Temperature: 100 °C
Reaction time: 8 h
Yield: 44.6 %

Procedure:
To a solution of tert-butyl (6R,7R)-6-[2-amino-2-(hydroxyimino)ethyl]-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (388 mg, 0.93 mmol) in toluene (4 mL) were added potassium tert-butoxide (208 mg, 1.86 mmol) and ethyl acetate (1 mL, 0.93 mmol). The reaction mixture was stirred at 100° C. overnight. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (183.4 mg).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=1)([CH3:3])[CH3:2].[CH3:14][S:15]([OH:18])(=O)=[O:16].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[OH:10][C:7]1[CH:8]=[CH:9][C:14]([S:15]([C:5]2[C:6]([O:12][CH3:13])=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:4]=2[CH:1]([CH3:3])[CH3:2])(=[O:18])=[O:16])=[CH:5][CH:6]=1
Reactant: COc1ccc(C(C)C)cc1OC
Reactant: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: COc1ccc(C(C)C)c(S(=O)(=O)c2ccc(O)cc2)c1OC
Temperature: 50 °C
Reaction time: 5 h

Procedure:
A mixture of 2 g (0.011 mole) of 1-isopropyl 3,4-dimethoxy benzene, 3.4 g (0.011 mole) of sodium 4-benzyloxy benzenesulfonate, 45 ml of anhydrous methanesulfonic acid and 4.5 g of phosphoric anhydride is stirred at 50° C. for 5 hours. It is poured into an ice/water mixture, the product is filtered off and washed on the filter with water. The still moist solid is taken up in 20 ml of ethanol and 5 ml of a 30% sodium hydroxide solution. It is heated at 60° C. for about 2 h until dissolution is complete, the solution is diluted with water, filtered and acidified with acetic acid. The product is filtered off and washed on the filter with water. It is then purified by chromatography on a column of silica using a dichloroethane/ethyl acetate mixture 95/5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=O)[C:5]2=[CH:11][CH:12]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1.C(OC(=O)C)(=O)C>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6](=[O:8])[C:5]2=[CH:11][CH:12]=1
Reactant: O=C1OC(=O)c2cc(Cl)ccc21
Reactant: Nc1ccccc1
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: O=C1c2ccc(Cl)cc2C(=O)N1c1ccccc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 69.9 %

Procedure:
A solution of 4-chlorophthalic anhydride (9.12 g, 500 mmol), aniline (4.65 g, 50 mmol), pyridine (12.01 g, 152 mmol) and DMAc (40 mL) was heated at 70° C. for 1 hour under argon. Acetic anhydride (20.0 g, 196 mmol) was added and the solution was allowed to stir at 80° C. for a total of 4 hours. The reaction mixture was cooled to ca. 5° C. and the crystalline solid removed by filtration, washed with acetone and methanol and dried in vacuo to give 9.0 g (70%) product which was recrystallized from acetic anhydride, mp 187°-189° C., (liturature melting point) 189.5°-191° C. 1H NMR(CDCl3) δ7.90 (d, J=1.6 Hz, 1), 7.88 (d, J=8.0 Hz, 1), 7.73 (dd, J=8.0, 1.6 Hz, 1), 7.50 (m, 2), 7.41 (m,3). 13C NMR (CDCl3) {1H} δ166.2, 165.9 141.1, 134.4, 133.5, 131.5, 129.9, 129.1, 128.2, 126.4, 124.9, 124.1.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[NH:17][C:16]3=[O:24])[CH2:8][CH2:7]2)[N:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:4][N:3]1[CH2:31][C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=1)[C:35]([O:37][CH3:38])=[O:36].[N:42]12[CH2:49]C[CH:45]([CH2:46][CH2:47]1)[C@@H:44](O)[CH2:43]2>C1(C)C=CC=CC=1.CC(O)C.CC(O)C.CC(O)C.CC(O)C.[Ti]>[O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[NH:17][C:16]3=[O:24])[CH2:8][CH2:7]2)[N:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:4][N:3]1[CH2:31][C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=1)[C:35]([O:37][C@@H:38]1[CH:45]2[CH2:46][CH2:47][N:42]([CH2:43][CH2:44]2)[CH2:49]1)=[O:36]
Reactant: COC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCn4c(=O)[nH]c5ccccc54)CC3)C2=O)c1
Reactant: O[C@H]1CN2CCC1CC2
Agent: [Ti]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: O=C(O[C@H]1CN2CCC1CC2)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCn4c(=O)[nH]c5ccccc54)CC3)C2=O)c1
Yield: 34 %

Procedure:
To a refluxing solution of methyl 3-((4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.33 g, 0.59 mmol) and (R)-3-quinuclidinol (0.3 g, 2.4 mmol) in toluene (5 mL), was added titanium(IV)-i-propoxide (0.173 mL, 0.59 mmol, d=0.97). After refluxing for 18 h, the reaction mixture was concentrated in vacuo and isolated by reverse phase HPLC to obtain the title compound (0.13 g, 34%); 1H NMR (DMSO-d6): δ 1.31-1.34 (m, 1H), 1.51-1.55 (m, 4H), 1.78-1.88 (m, 3H), 1.98-2.01 (m, 1H), 2.33 (t, 2H, J=7.2 Hz), 2.52-2.72 (m, 11H), 3.15-3.21 (m, 1H), 3.85 (t, 2H, J=6.8 Hz), 4.59-4.62 (m, 4H), 4.90-4.92 (m, 1H), 6.76 (t, 1H, J=7.2 Hz), 6.84 (d, 2H, J=8.4 Hz), 6.96 (d, 3H, J=2.4 Hz), 7.17-7.24 (m, 3H), 7.52-7.59 (m, 2H), 7.87-7.92 (m, 2H), 10.80 (br, 1H); MS for C38H44N6O4 m/z 649.11 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([NH2:12])[CH3:11])=[CH:6][CH:5]=1.C([O:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][N:35]2[C:43]3[C:38](=[CH:39][C:40]([C:44](O)=[O:45])=[CH:41][CH:42]=3)[C:37]([CH3:47])=[C:36]2[CH3:48])=[CH:30][CH:29]=1)=[O:21])(C)(C)C>>[CH3:48][C:36]1[N:35]([CH2:34][C:31]2[CH:32]=[CH:33][C:28]([C:23]3[C:22]([C:20]([OH:21])=[O:19])=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:29][CH:30]=2)[C:43]2[C:38]([C:37]=1[CH3:47])=[CH:39][C:40]([C:44](=[O:45])[NH:12][C@H:10]([C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:13])([F:14])[F:1])=[CH:9][CH:8]=1)[CH3:11])=[CH:41][CH:42]=2
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: C[C@H](N)c1ccc(OC(F)(F)F)cc1
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3ccc(OC(F)(F)F)cc3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(4-(trifluoromethoxy)phenyl)ethanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 587 [M+H]+.
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]1[C@H:14]([OH:15])[C@H:13]([OH:16])[C@@H:12]2[O:17][C@@H:11]2[C@@H:10]1[C:18]1[C:19](C(OC)=O)=[C:20]([O:27]CC2C=CC=CC=2)[C:21]2[O:25][CH2:24][O:23][C:22]=2[CH:26]=1)=[O:7])(C)(C)C.C([O-])(=[O:46])C1C=CC=CC=1.[Na+]>O>[CH:26]1[C:18]2[C@H:10]3[C@@H:11]([OH:46])[C@H:12]([OH:17])[C@@H:13]([OH:16])[C@@H:14]([OH:15])[C@@H:9]3[NH:8][C:6](=[O:7])[C:19]=2[C:20]([OH:27])=[C:21]2[O:25][CH2:24][O:23][C:22]=12
Reactant: COC(=O)c1c([C@@H]2[C@@H](NC(=O)OC(C)(C)C)[C@H](O)[C@H](O)[C@@H]3O[C@@H]32)cc2c(c1OCc1ccccc1)OCO2
Reactant: O=C([O-])c1ccccc1
Agent: [Na+]
Solvent: O
Product: O=C1N[C@H]2[C@H](O)[C@H](O)[C@@H](O)[C@H](O)[C@@H]2c2cc3c(c(O)c21)OCO3
Temperature: 100 °C
Reaction time: 144 h
Yield: 1550.6 %

Procedure:
A suspension of epoxide 16 (109 mg, 0.21 mmol) and sodium benzoate (1 mg) in water (8 ml) was stirred at 100° C. for 6 days. The mixture was then concentrated and subjected to chromatography (CHCl3 /CH3OH, 4:1) to afford 35 mg (51%) of pancratistatin. 1H NMR (400 MHz, DMSO-d6) ε 13.06 (s, 1H), 7.51 (s, 1H), 6.48 (s, 1H), 6.05 (d, J=1.0 Hz, 1H), 6.02 (d, J=1.0 Hz, 1H), 5.35 (bs, 1H), 5.04 (bs, 2H), 4.84 (bs, 1H), 4.27 (bs, 1H), 3.95 (bs, 1H), 3.84 (bs, 1H), 3.74 (m, 2H), 2.96 (d, J=11.5 Hz, 1H).
Reaction SMILES: [I:1]I.[OH-].[K+].[CH:5]1([C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][CH:18]=[CH:17]4)[CH:11]=[N:10][CH:9]=2)[CH2:7][CH2:6]1.OS([O-])=O.[Na+]>CN(C=O)C>[CH:5]1([C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][CH:18]=[C:17]4[I:1])[CH:11]=[N:10][CH:9]=2)[CH2:7][CH2:6]1
Reactant: II
Reactant: c1cc2cc(-c3cncc(C4CC4)n3)ccc2[nH]1
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Ic1c[nH]c2ccc(-c3cncc(C4CC4)n3)cc12
Yield: 24.5 %

Procedure:
I2 (1.62 g, 6.38 mmol) followed by powdered KOH (0.671 g, 11.95 mmol) was added to a solution of 5-(6-cyclopropylpyrazin-2-yl)-1H-indole (750 mg, 3.19 mmol) in 7 mL of DMF at RT overnight. The mixture was added to 30 mL of 10% NaHSO3 (aq.). The mixture was extracted with EtOAc (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude was purified by silica gel chromatography, eluting with a gradient of 0-30% EtOAc in hexanes, to provide 5-(6-cyclopropylpyrazin-2-yl)-3-iodo-1H-indole (280 mg, 0.78 mmol, 24% yield) as an orange solid. MS (ESI, pos. ion) m/z: 362.0 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[CH2:18]([NH2:36])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].[OH-].[Na+]>C(Cl)(Cl)Cl>[CH2:2]([CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]/[CH:27]=[CH:26]\[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][NH2:36])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCC/C=C\CCCCCCCCN
Reactant: CCCCCCCCCCCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCCCCCCC/C=C\CCCCCCCCN
Temperature: 120 °C
Yield: 83.3 %

Procedure:
1-bromohexadecane (15.27 g, 50 mmol) was rapidly added to oleylamine (26.75 g, 100 mmol) at 100° C. The reaction mixture was heated at 120° C. for 30 minutes and than cooled to room temperature. Chloroform(200 ml) was added followed by 1 N NaOH (50 ml). The mixture was then extracted with H2O (200 ml), the organic layer dried (Na2SO4) and concentrated to a syrup. Silica gel column chromatography using 5-20% gradient methanol in dichloromethane afforded 20.5 g of palmityloleylamine as a syrup (yield, 83%). The identity of the product was confirmed using NMR spectroscopy. 1H NMR (CDCl3) d 5.34 (m, 2H, CH═CH), 2.58 (m, 4H), 2.00 (m, 4H), 1.47 (m, 4H), 1.25 (m, 48H), 0.86 (m, 6H). FAB-MS: 493 [M+H]+. (Other reagents could include oleyl-bromide and hexadecane amine)
Reaction SMILES: Cl.[C:2]1([CH3:25])[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2([C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)[CH:16]3[CH:12]([CH2:13][NH:14][CH2:15]3)[C:11](=[O:17])[CH2:10][CH2:9]2)[CH:3]=1.C(N(CC)CC)C.[C:33]1([CH2:39][C:40](Cl)=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>ClCCl>[C:2]1([CH3:25])[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2([C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)[CH:16]3[CH:12]([CH2:13][N:14]([C:40](=[O:41])[CH2:39][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:15]3)[C:11](=[O:17])[CH2:10][CH2:9]2)[CH:3]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Cc1cccc(C2(c3cccc(C)c3)CCC(=O)C3CNCC32)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(C2(c3cccc(C)c3)CCC(=O)C3CN(C(=O)Cc4ccccc4)CC32)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 20.2 %

Procedure:
A suspension of (3aRS,7aRS)-7,7-bis-(3-tolyl)-4-perhydroisoindolone hydrochloride (1.5 g) in dichloromethane (30 cc) cooled to +4° C. is treated with triethylamine (1.15 cc) and then with phenylacetyl chloride (0.63 g). The reaction mixture is stirred for 5 hours at 25° C. and then washed with water (3×100 cc). The organic phase is dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized twice from acetonitrile to give (3aRS,7aRS)-7,7-bis-(3-tolyl)-2-(phenylacetyl)-4-perhydroisoindolone (0.36 g). m.p.=207° C.
Reaction SMILES: C(OC[N:5]1[C:10](C)=[C:9](C(O)=O)[C@@H:8]([C:15]2C=CC=[C:17]([N+:21]([O-])=O)[CH:16]=2)[C:7]([C:24](OC)=O)=[C:6]1C)C.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[N:5]12[CH2:6][CH2:7][CH2:24][N:21]=[C:17]1[CH2:16][CH2:15][CH2:8][CH2:9][CH2:10]2
Reactant: CCOCN1C(C)=C(C(=O)O)[C@@H](c2cccc([N+](=O)[O-])c2)C(C(=O)OC)=C1C
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: C1CCC2=NCCCN2CC1
Temperature: 40 °C

Procedure:
2.925 g (0.0075 mol) of (R)-N-(ethoxymethyl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid and 1.34 g (0.0082 mol) of carbonyldiimidazole are dissolved in 50 ml of dimethylformamide. The mixture is heated at 40° C. for one hour. 2.13 g (0.0075 mol) of the product obtained in Preparation XX and 1.12 ml (0.0075 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene are then added to the reaction medium. The mixture is heated to 100° C. After 2 hours, the mixture is left to cool and then poured into 100 ml of water. The medium is extracted 3 times with 30 ml of ethyl acetate. The organic phases obtained are washed twice with 10 ml of water, dried over magnesium sulfate and filtered and the solvent is evaporated off. The crude product obtained is purified by flash chromatography, elution being carried out with a toluene/isopropanol mixture (97:3 v/v). This gives 4.8 g (yield: 98%) of an oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]([CH2:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[O:5][N:4]=1.Br[CH2:27][C:28]([O:30][CH3:31])=[O:29].CN1CCOCC1>C1COCC1.CCOC(C)=O>[CH:20]1([CH2:19][CH2:18][CH2:17][C@@H:8]([C:6]2[O:5][N:4]=[C:3]([CH2:2][NH:1][CH2:27][C:28]([O:30][CH3:31])=[O:29])[N:7]=2)[CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CN)no1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: COC(=O)CNCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 70.4 %

Procedure:
A solution of tert-butyl(3R)-3-[3-(aminomethyl)-1,2,4-oxadiazol-5-yl]-6-cyclohexylhexanoate (preparation 18) (200 mg, 0.57 mmol) in THF (2 ml) was treated with methyl bromoacetate (55 μl, 0.57 mmol) and NMM (63 μl, 0.57 mmol) and stirred at room temperature, under a nitrogen atmosphere for 3 days. The reaction mixture was diluted with EtOAc and washed with H2O followed by brine, dried over anhydrous MgSO4 and filtered. The solvent was removed under reduced pressure. The crude material was purified on a silica column eluting with a solvent gradient of EtOAc:pentane (5:95) gradually changing to (50:50) to afford the title compound as a colourless oil (170 mg, 70%).
Reaction SMILES: C(O[C:6]([N:8](C)[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18])=O)(C)(C)C.Cl>O1CCOCC1>[CH3:6][NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: COc1ccc(N(C)C(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Agent: Cl
Solvent: C1COCCO1
Product: CNc1ccc(OC)cc1[N+](=O)[O-]
Yield: 90.6 %

Procedure:
A procedure similar to that described in Preparation 8 was repeated, except that 2.0 g of N-t-butoxycarbonyl-N-methyl-4-methoxy-2-nitroaniline (prepared as described in Preparation 23) and 30 ml of a 4N solution of hydrogen chloride in 1,4-dioxane were used, to give 1.17 g of the title compound having an Rf value=0.62 (on thin layer chromatography on silica gel; developing solvent: a 1:5 by volume mixture of ethyl acetate and hexane).