Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[CH:3]([O:9]C)[CH2:4][C:5]([OH:8])([CH3:7])[CH3:6].CS(O)(=O)=[O:13].C[C:17]([O:22]/N=C(/C(NCC=O)=O)\C1N=C(N)SC=1)([C:19]([OH:21])=O)[CH3:18]>O>[CH3:7][C:5]([CH3:6])([OH:8])[CH2:4][C@@H:3]([OH:9])[C@H:19]([OH:21])[C:17](=[O:22])[CH2:18][OH:13]
Reactant: COC(CC(C)(C)O)OC
Reactant: CS(=O)(=O)O
Reactant: CC(C)(O/N=C(/C(=O)NCC=O)c1csc(N)n1)C(=O)O
Solvent: O
Product: CC(C)(O)C[C@@H](O)[C@H](O)C(=O)CO
Reaction time: 4 h

Procedure:
3-hydroxy-3-methylbutanal dimethyl acetal 640 mg, 4.3 mmol) was hydrolyzed in 19.9 mL of H2O with CH3SO2OH (100 μL). After 4 h the hydrolysis was complete as determined by GC (50° C., 1 min to 250° C. at 15° C./min, DB-U; tR of acetal 4.2 min, aldehyde 2.0 min). FDP-Na3 (573 mg, 1.04 mmol) was added to the solution, and the pH was adjusted to 6.5. FDP aldolase (400 units) and TPI (100 units) were added and allowed to react for 16 h. Following the same workup procedure as used in Example 1 to remove the phosphate group, the crude sugar was extracted by vigorously stirring the residue with methanol and filtering (3×50 mL). The methanol was removed under water aspirator vacuum, and the residue, 5-deoxy-6,6-dimethyl-D-threo-hexulose, having the following structure: ##STR10## was chromatographed (silica gel, water saturated ethyl acetate), yield 0.20 g (1.04 mmol, 50%): [α]25D -21.8° C. (c 0.40, H2O); 1H--NMR (200 MHz, D2O) δ 1.03, 1.20 (s, 6 H, CH3), 1.37 (dd, J=13 Hz, J=11.8 Hz, 1 H, axial H at C5), 1.83 (dd, J=13 Hz, J=4.7 Hz, 1 H, equatorial H at C5), 3.15, 3.42 (d, J=11.8 Hz, 2 H, CH2OD), 3.27 (d, J=9.8 Hz, 1 H, C3), 3.91 (ddd, J=9.8 Hz, J=11.8 Hz, J=4.7 Hz, 1 H, C4); 13C--NMR (50 MHz, D2O) δ 27.14 31.11 (CH3), 43.66 (C5), 64.21, 65.82, 72.06, 75.08 (Cl, 3, 4, 6), 98.92 (C2). Anal. Calcd for C8H16O5 : C, 50.04; H, 8.4. Found: C, 50.2; H, 8.4.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2Cl.[CH:13]1([CH2:19][O-:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[Na+]>C1(CO)CCCCC1.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[O:20][CH2:19][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: [O-]CC1CCCCC1
Reactant: Clc1ccnc2ccc(Br)cc12
Agent: OCC1CCCCC1
Agent: [Na+]
Solvent: O
Product: Brc1ccc2nccc(OCC3CCCCC3)c2c1
Temperature: 120 °C
Yield: 71.3 %

Procedure:
To a solution of 6-bromo-4-chloro-quinoline (0.550 g, 2.27 mmol) in cyclohexylmethanol (5 mL) was added a solution of sodium cyclohexylmethoxide (11.34 mmol, prepared from cyclohexylmethanol and sodium) at room temperature. Then, the reaction mixture was heated to 120° C. for 15 h in a sealed reaction flask. After cooling to room temperature, the reaction mixture was diluted with water and the solvent was removed under the vacuum. Then, the remaining aqueous solution was neutralized with 3.0N hydrochloric acid and the organic compound was extracted into ethyl acetate (3×50 mL). The combined extracts were washed with brine solution and dried over anhydrous magnesium sulfate. After filtration of the drying agent, the filtrate was removed under the vacuum and the residue was purified by using a Biotage silica gel column chromatography to afford 0.518 g (71% yield) of 6-bromo-4-cyclohexylmethoxy-quinoline as a light yellow oil: EI-HRMS m/e calcd for C16H18BrNO (M+) 320.2304, found 320.2314.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[CH2:16][CH:15]([OH:18])[CH2:14][CH2:13][C:12]=3[N:11]([C:19]([NH:21][C@@H:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:23]([NH:25][CH3:26])=[O:24])=[O:20])[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].FC1C=C(C2C3CC4(OCCO4)CCC=3N(C(N[C@@H](C(C)(C)C)C(NC)=O)=O)N=2)C=CC=1F.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[CH2:16][C:15](=[O:18])[CH2:14][CH2:13][C:12]=3[N:11]([C:19]([NH:21][C@@H:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:23]([NH:25][CH3:26])=[O:24])=[O:20])[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CNC(=O)[C@@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCC(O)C2)C(C)(C)C
Agent: CNC(=O)[C@@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCC1(C2)OCCO1)C(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: CNC(=O)[C@@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCC(=O)C2)C(C)(C)C
Yield: 91 %

Procedure:
Preparation of 3-(3,4-difluorophenyl)-N—((S)-3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)-5-hydroxy-4,5,6,7-tetrahydro-1H-indazole-1-carboxamide (67) A mixture of compound 63 (0.91 g) and p-toluenesulfonic acid (1.3 g) was heated in acetone and water at 50° C. until starting material was consumed. After evaporation of acetone, the residue was extracted between EtOAc and saturated sodium bicarbonate. The organic phase was dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography with 70% to 80% EtOAc/Hex to give (S)-3-(3,4-difluorophenyl)-N-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)-5-oxo-4,5,6,7-tetrahydro-1H-indazole-1-carboxamide (0.75 g, 91% yield), which was reduced with sodium borohydride (1.0 equiv.) in MeOH to give compound 67 as a mixture of two diastereomers after purification with a preparative LC-MS. LCMS (+ESI) m/z=421.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[C:10](Cl)(=[O:16])[CH2:11][CH2:12][C:13](Cl)=[O:14].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([C:10](=[O:16])[CH2:11][CH2:12][C:13]([C:6]2[CH:5]=[C:4]([CH3:8])[C:3]([OH:9])=[C:2]([CH3:1])[CH:7]=2)=[O:14])[CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9]
Reactant: O=C(Cl)CCC(=O)Cl
Reactant: Cc1cccc(C)c1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc(C(=O)CCC(=O)c2cc(C)c(O)c(C)c2)cc(C)c1O
Temperature: 0 °C
Reaction time: 15 h
Yield: 15.3 %

Procedure:
To 300 ml of methylene chloride was dissolved 10 g/82 mmol of 2,6-dimethylphenol and 6.2 g/40 mmol of succinic dichloride, and the solution was cooled to 0° C. in sodium chloride-ice bath. 49 g/368 mmol of anhydrous aluminum chloride was added dropwise to the mixture with thorough stirring while maintaining the temperature to not more than 5° C. After completing the addition, the mixture was stirred at 5° C. for one hour, and at room temperature for 15 hours. The reaction mixture was then added to 50 ml of ice containing conc. hydrochloric acid to decompose excessive anhydrous aluminum chloride, and the mixture was extracted twice with methylene chloride. The organic layer was washed with saturated sodium chloride solution, and dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystalized from toluene to obtain 2.0 g of 1,4-bis(3',5'-dimethyl-4'-hydroxyphenyl)butane-1,4-dione. MS: 326 (M+).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:11]=[C:10]([N:12]([CH3:14])[CH3:13])[N:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:23]#[N:24])=[CH:18][CH:17]=1.ClCCl.N>C(O)C>[ClH:1].[CH3:13][N:12]([C:10]1[N:9]=[CH:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([CH:22]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:23]#[N:24])=[CH:20][CH:21]=3)[C:3]=2[CH:11]=1)[CH3:14]
Reactant: CN(C)c1cc2c(Cl)ncnc2cn1
Reactant: N#CC(c1ccccc1)c1ccc(N)cc1
Agent: N
Solvent: ClCCl
Solvent: CCO
Product: CN(C)c1cc2c(Nc3ccc(C(C#N)c4ccccc4)cc3)ncnc2cn1
Product: Cl

Procedure:
Prepared according to Procedure A from 4-chloro-6-(N,N-dimethylamino)pyrido[3,4-d]pyrimidine and (4-aminophenyl)-phenylacetonitrile (commercially available from Salor); tlc (dichloromethane:ethanol:aq.ammonia, 100:8:1) Rf 0.43; m/z (M+1)+381.
Reaction SMILES: Br[CH2:2][C:3]1[S:7][C:6]([Cl:8])=[N:5][CH:4]=1.CN(C)C=O.[CH3:14][N:15]1[C:20](=[N:21][N+:22]([O-:24])=[O:23])[NH:19][CH2:18][O:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.O>[Cl:8][C:6]1[S:7][C:3]([CH2:2][N:19]2[CH2:18][O:17][CH2:16][N:15]([CH3:14])[C:20]2=[N:21][N+:22]([O-:24])=[O:23])=[CH:4][N:5]=1
Reactant: CN1COCNC1=N[N+](=O)[O-]
Reactant: Clc1ncc(CBr)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CN1COCN(Cc2cnc(Cl)s2)C1=N[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 5 h

Procedure:
3.18 g of 5-bromomethyl-2-chloro-thiazole, 12 ml of dimethylformamide, 1.99 g of 3-methyl-4-nitroimino-perhydro-1,3,5-oxadiazine and 3.79 g of potassium carbonate are combined and the mixture is stirred for 5 hours at 50° C. The mixture is cooled to room temperature and 50 ml of water and 50 ml of dichloromethane are added. The organic phase is separated off and dried over magnesium sulfate; the solvent is evaporated off in vacuo. The residue is purified by column chromatography on silica gel using hexane/ethyl acetate (1:1), yielding the title compound (compound 2-2).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:27][CH2:26][CH:25]([CH3:28])[CH2:24][CH2:23]2)=[C:4]([C@H:10]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].[F:29][C:30]1[CH:55]=[CH:54][C:33]([CH2:34][CH2:35][O:36][C:37]2[CH:42]=[CH:41][C:40](B3OC(=O)CN(C)CC(=O)O3)=[CH:39][CH:38]=2)=[CH:32][CH:31]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:18]([O:17][C@@H:10]([C:4]1[C:5]([CH3:9])=[N:6][C:7]([CH3:8])=[C:2]([C:40]2[CH:39]=[CH:38][C:37]([O:36][CH2:35][CH2:34][C:33]3[CH:32]=[CH:31][C:30]([F:29])=[CH:55][CH:54]=3)=[CH:42][CH:41]=2)[C:3]=1[N:22]1[CH2:27][CH2:26][CH:25]([CH3:28])[CH2:24][CH2:23]1)[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CCC(C)CC2)c1Br
Reactant: CN1CC(=O)OB(c2ccc(OCCc3ccc(F)cc3)cc2)OC(=O)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CCC(C)CC2)c1-c1ccc(OCCc2ccc(F)cc2)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 71.5 %

Procedure:
Pd(Ph3P)4 (76 mg, 0.066 mmol) was added to an argon-degassed solution of (S)-isopropyl 2-(5-bromo-2,6-dimethyl-4-(4-methylpiperidin-1-yl)pyridin-3-yl)-2-(tert-butoxy)acetate (150 mg, 0.329 mmol), 2-(4-(4-fluorophenethoxy)phenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione (94 mg, 0.362 mmol), potassium phosphate tribasic (524 mg, 2.47 mmol) in dioxane (2 ml) and water (0.5 ml) stirred in a screw-capped pressure vessel for 16 h at 80° C. The reaction was allowed to cool, diluted with EtOAc, and the organic layer was washed with brine and dried (MgSO4). The crude product was charged (DCM) to a 40 g ISCO silica gel cartridge and gradient elution (0-20% EtOAc/hexanes) using an Isolera chromatography station gave (S)-isopropyl 2-(tert-butoxy)-2-(5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethyl-4-(4-methylpiperidin-1-yl)pyridin-3-yl)acetate 139 mg (72%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 7.44-7.38 (m, 2H), 7.20 (d, J=7.3 Hz, 1H), 7.15 (t, J=8.8 Hz, 2H), 7.03-6.94 (m, 3H), 5.97 (br. s, 1H), 4.96 (dt, J=12.3, 6.3 Hz, 1H), 4.23 (t, J=6.6 Hz, 2H), 3.36-3.29 (m, 4H), 3.07 (t, J=6.6 Hz, 2H), 2.43 (s, 3H), 2.04 (s, 3H), 1.75 (t, J=11.4 Hz, 1H), 1.52-1.47 (m, 1H), 1.37 (br. s, 1H), 1.19 (d, J=6.2 Hz, 3H), 1.15-1.13 (m, 12H), 1.08-1.02 (m, 2H), 0.84 (d, J=5.1 Hz, 3H). UPLC (M+H)=591.56.
Reaction SMILES: CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:14][N+:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH2:22][C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=1[F:30].[C:31]([O:36][CH2:37][CH3:38])(=[O:35])[C:32]#[C:33][CH3:34].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:37]([O:36][C:31]([C:32]1[C:33]([CH3:34])=[N:14][N:15]2[C:16]([O:21][CH2:22][C:23]3[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=3[F:30])=[CH:17][CH:18]=[CH:19][C:20]=12)=[O:35])[CH3:38]
Reactant: CC#CC(=O)OCC
Reactant: N[n+]1ccccc1OCc1c(F)cccc1F
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)nn2c(OCc3c(F)cccc3F)cccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred solution of 540 mg (1.00 mmol, 81% pure) of 1-amino-2-[(2,6-difluorobenzyl)oxy]pyridinium-2,4,6-trimethylbenzenesulphonate from Example 128A in DMF (10 ml) at 0° C. was admixed with 0.35 ml (3.06 mmol) of ethyl 2-butynoate and 623 mg (4.51 mmol) of potassium carbonate. The reaction mixture was stirred at room temperature overnight and added dropwise to 20 ml of water while stirring. The resulting suspension was extracted with ethyl acetate (2×20 ml). The combined organic phases were dried with a phase separation cartridge and concentrated under reduced pressure. The residue was purified by flash chromatography using a prepacked silica gel cartridge (eluent:cyclohexane-ethyl acetate 10:1 to 1:1), which gave 200 mg (25% of theory, 43% pure) of the target compound.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:6][C:7](=[O:19])[NH:8][C:9]3[CH:16]=[C:15]([Cl:17])[C:14](I)=[CH:13][C:10]=3[C:11]=2[N:12]=1.[CH2:20]([N:23]([CH3:25])[CH3:24])[C:21]#[CH:22].O>C(N(CC)CC)C.CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu](I)I>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:6][C:7](=[O:19])[NH:8][C:9]3[CH:16]=[C:15]([Cl:17])[C:14]([C:22]#[C:21][CH2:20][N:23]([CH3:25])[CH3:24])=[CH:13][C:10]=3[C:11]=2[N:12]=1
Reactant: C#CCN(C)C
Reactant: Nc1ncc2c(n1)-c1cc(I)c(Cl)cc1NC(=O)C2
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CN(C)CC#Cc1cc2c(cc1Cl)NC(=O)Cc1cnc(N)nc1-2
Temperature: 75 °C
Reaction time: 8 h
Yield: 109.8 %

Procedure:
A solution of 2-amino-9-chloro-10-iodo-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one (1.66 g, 4.29 mmol) and propargyl(dimethylamine) (0.74 mL, 6.89 mmol) in triethylamine (7 mL) and DMF (7 mL) was degassed with argon. To this solution was added bis(triphenylphosphine)palladium(II)chloride (0.30 g, 0.43 mmol) and copper iodide (0.163 g, 0.86 mmol). The reaction mixture was allowed to stir at 75° C. overnight. After the reaction mixture was allowed to cool to rt, water was added. The precipitate that formed was filtered and dried to give 2-amino-9-chloro-10-[3-(dimethylamino)prop-1-yn-1-yl]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one (1.61 g, 98%) as a brown solid. LCMS (FA): m/z=342 (M+H).
Reaction SMILES: CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].[CH3:15][N:16]1[CH2:33][C:31]2=[C:32]3[C:27](=[C:28]([O:34][CH3:35])[CH:29]=[CH:30]2)[O:26][C@@H:25]2[C@:19]3([CH:20]=[CH:21][C:22]([CH2:24]2)=[O:23])[CH2:18][CH2:17]1.CO>C1COCC1.C(Cl)(Cl)Cl>[CH3:15][N:16]1[CH2:33][C:31]2=[C:32]3[C:27](=[C:28]([O:34][CH3:35])[CH:29]=[CH:30]2)[O:26][C@@H:25]2[C@:19]3([CH:20]=[CH:21][C@H:22]([OH:23])[CH2:24]2)[CH2:18][CH2:17]1
Reactant: COc1ccc2c3c1O[C@H]1CC(=O)C=C[C@@]31CCN(C)C2
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c3c1O[C@H]1C[C@@H](O)C=C[C@@]31CCN(C)C2
Temperature: -78 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
2 mmole (1 N in tetrahydrofuran {THF}) of L-Selectride® (lithium tri-sec-butylborohydride, Aldrich)is charged into 8 ml THF and cooled to -78° C. 1 mmole of (-)-narwedine in 50 ml THF is added dropwise over a period of 30 minutes. After addition, the solution is stirred at -78° C. for 2 hours and then warmed to 0° C. 0.4 ml of methanol is added and the solution is warmed to 25° C. and stirred for 15 minutes. Solvent is then evaporated under vacuum to dryness to obtain a syrup. The syrup is dissolved in 0.5 ml CHCl3 and the solution is loaded into a SiO2 200-400 mesh, 6A, column. The column is eluted with a solvent mixture of CH2Cl2 /CH3OH 6:1 to obtain 286 mg of pure (-)-galanthamine (a yield of 99.5%). HPLC of the resultant mixture indicates there is no epigalanthamine or lycoramine present. {m.p. 128°-129° C.; [α]D25 =-93.4}. Natural (-)-galanthamine has a melting point of 126°-127° C. ([α]D25 =-91.0)
Reaction SMILES: C[Si](C)(C)[O:3][C:4](=[CH2:18])[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].[O:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36](=[O:61])[C:37]#[C:38][CH2:39][C:40]2([CH2:46][CH2:47][C:48]3[CH:53]=[CH:52][C:51]([O:54][CH:55]4[CH2:60][CH2:59][CH2:58][CH2:57][O:56]4)=[CH:50][CH:49]=3)[S:45][CH2:44][CH2:43][CH2:42][S:41]2)=[CH:30][CH:29]=1.O.C(OCC)(=O)C>C1COCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[O:56]1[CH2:57][CH2:58][CH2:59][CH2:60][CH:55]1[O:54][C:51]1[CH:52]=[CH:53][C:48]([CH2:47][CH2:46][C:40]2([CH2:39][CH:38]([CH2:18][C:4](=[O:3])[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])[CH2:37][C:36](=[O:61])[CH2:35][CH2:34][C:31]3[CH:32]=[CH:33][C:28]([O:27][CH:22]4[CH2:23][CH2:24][CH2:25][CH2:26][O:21]4)=[CH:29][CH:30]=3)[S:41][CH2:42][CH2:43][CH2:44][S:45]2)=[CH:49][CH:50]=1
Reactant: C=C(CCCCCCCCCCCCC)O[Si](C)(C)C
Reactant: O=C(C#CCC1(CCc2ccc(OC3CCCCO3)cc2)SCCCS1)CCc1ccc(OC2CCCCO2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCC(=O)CC(CC(=O)CCc1ccc(OC2CCCCO2)cc1)CC1(CCc2ccc(OC3CCCCO3)cc2)SCCCS1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Trimethyl-(1-methylene-tetradecyloxy)-silane (176 mg, 0.6 mmol) and the enone 21 (176 mg, 0.3 mmol) are dissolved in 2 mL of anhydrous THF and the solution is cooled down to −78° C. Two drops of tetrabutylammonium fluoride (1 M in THF) are injected. The mixture is stirred for 1 h at this temperature, then the solution is left to return to ambient temperature under stirring. After the addition of water and extraction with ethyl acetate, the product is dried and the solvent is evaporated off. The residue is purified by flash chromatography in order to produce compound 22.
Reaction SMILES: Br[C:2]1[NH:22][C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[N:9]=[C:4]2[CH:3]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[C:33]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[CH:34]=[N:35][CH:36]=2)O1>>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([O:18][CH3:19])[CH:15]=1)[CH2:11][CH2:10][C:8]1[N:9]=[C:4]2[CH:3]=[C:2]([C:31]3[CH:32]=[C:33]([N:37]4[CH2:38][CH2:39][O:40][CH2:41][CH2:42]4)[CH:34]=[N:35][CH:36]=3)[NH:22][C:5]2=[N:6][CH:7]=1
Reactant: CC1(C)OB(c2cncc(N3CCOCC3)c2)OC1(C)C
Reactant: COc1cc(CCc2cnc3[nH]c(Br)cc3n2)cc(OC)c1
Product: COc1cc(CCc2cnc3[nH]c(-c4cncc(N5CCOCC5)c4)cc3n2)cc(OC)c1

Procedure:
The compound was prepared by using procedures analogous to those described for the synthesis of Example 53, Step 2 starting from 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5H-pyrrolo[2,3-b]pyrazine and 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl]morpholine (from Small Molecules). LCMS calculated for C25H28N5O3 (M+H)+: m/z=446.2. Found 446.1.
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:26])[CH:11]=[C:12]([CH:16](OS(C)(=O)=O)[C:17]([F:20])([F:19])[F:18])[N:13]([CH3:15])[CH:14]=1)C1C=CC=CC=1.C(O)C>CO.[Pd]>[OH:8][C:9]1[C:10](=[O:26])[CH:11]=[C:12]([CH2:16][C:17]([F:18])([F:19])[F:20])[N:13]([CH3:15])[CH:14]=1
Reactant: Cn1cc(OCc2ccccc2)c(=O)cc1C(OS(C)(=O)=O)C(F)(F)F
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: Cn1cc(O)c(=O)cc1CC(F)(F)F
Reaction time: 1.5 h
Yield: 77 %

Procedure:
In a 500-mL reaction vessel was placed methanesulfonic acid 1-(5-benzyloxy-1-methyl-4-oxo-1,4-dihydro-pyridin-2-yl)-2,2,2-trifluoro-ethyl ester (1.80 g, 4.60 mmol), and ethanol (120 mL). The mixture was sonicated to give a clear solution. To the solution was added 1.80 g of Pd/C (10 wt. %, dry basis, on activated carbon, wet, Degussa type E101 NE/W). Hydrogenation was carried out under a hydrogen atmosphere set at a pressure of 50 psi. The reaction was completed within 90 min. The reaction mixture was diluted with methanol (120 mL), and the resulting mixture was sonicated for 10 min. The reaction mixture was then filtered through a short hydrochloric acid pre-treated CELITE™ bed. The filtrate was collected, and concentrated in vacuo to a volume of about 100 mL. To the resulting solution was added morpholine polymer-bound beads (1% cross-linked w/DVB, 200-400 mesh, 2.5-4.0 mmol N/g, 5.2 g), and the mixture was vortexed for 3 h. The morpholine beads were removed by filtration. Upon partial concentration in vacuo, a solid separated and the first crop of the title compound was obtained as the free base (0.74 g, 77% yield, HPLC Method 1 (Example 24); RT=8.2 min, HPLC purity (peak percent area): 98.7% at λ=280 nm). 1H NMR (CD3OD) δ ppm: 7.55 (s, 1H), 6.52 (s, 1H), 3.77 (q, J=10 Hz, 2H), 3.78 (s, 3H); MS-ESI (m/z): 208.2 ([M+1]+, 100%), 188.2, 139.2.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:4][CH:5]=[C:6]([CH2:11][CH2:12][CH2:13][CH3:14])[C:7]=1[N+:8]([O-:10])=[O:9].[OH:15]O>C(O)(=O)C>[CH3:1][S:2]([C:3]1[NH:4][CH:5]=[C:6]([CH2:11][CH2:12][CH2:13][CH3:14])[C:7]=1[N+:8]([O-:10])=[O:9])=[O:15]
Reactant: OO
Reactant: CCCCc1c[nH]c(SC)c1[N+](=O)[O-]
Solvent: CC(=O)O
Product: CCCCc1c[nH]c(S(C)=O)c1[N+](=O)[O-]
Yield: 40.2 %

Procedure:
2-Methylthio-3-nitro-4-n-butylpyrrole (3.7g) was suspended in glacial acetic acid (50 ml) and 30% hydrogen peroxide (1.62g) was added. The mixture was heated to 80° for 7 hours, and it was then evaporated to a brown oil. The crude product was purified by column chromatography using silica gel, eluted with benzene and chloroform, to give an oil which crystallized on standing. This was recrystallised from 2-propanol to give 2-methylsulphinyl-3-nitro-4-butyl-pyrrole (1.6g), m.p. 133-4°.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=1)[C:22]([O:24][CH3:25])=[O:23].I[CH2:30][CH2:31][CH2:32][C:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[NH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O>[NH:35]1[C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:33]([CH2:32][CH2:31][CH2:30][N:9]2[CH2:10][CH2:11][C:6]3([N:5]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:4][N:3]([CH2:18][C:19]4[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=4)[C:22]([O:24][CH3:25])=[O:23])[C:2]3=[O:1])[CH2:7][CH2:8]2)=[CH:34]1
Reactant: ICCCc1c[nH]c2ccccc12
Reactant: COC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCc4c[nH]c5ccccc45)CC3)C2=O)c1
Temperature: 65 °C
Yield: 23.4 %

Procedure:
A mixture of methyl 3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (871 mg, 2.11 mmol, 1.05 equiv), 3-(3-iodopropyl)-1H-indole (574 mg, 2.01 mmol, 1 equiv), and potassium carbonate (833 mg, 6.03 mmol, 3 equiv) in N—N-dimethylformamide was heated at 65° C. for 16 h. The reaction was cooled to ambient temperature and worked up using ethyl acetate and water. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified using preparatory thin layer chromatography in 7% methanol in dichloromethane to afford the title compound as cream crystals (252 mg, 46%); 1H NMR (400 MHz, DMSO-d6): δ 1.62 (d, 2H, J=12 Hz), 1.84 (bs, 2H); 2.41 (bs, 2H); 2.57 (bs, 2H); 2.67 (bs, 2H); 2.71-2.75 (m, 4H); 3.85 (s, 3H); 4.59 (s, 2H); 4.63 (s, 2H); 6.77 (d, 1H, J=7.6 Hz); 6.85 (d, 2H, J=8 Hz); 6.96 (t, 1H, J=6.8 and 7.6 Hz); 7.03-7.07 (m, 1H); 7.13 (bs, 1H); 7.22 (t, 2H, J=8 Hz); 7.33 (d, 1H, J=8 Hz); 7.52-7.59 (m, 3H); 7.89-7.91 (m, 2H); 10.75 (s, 1H); MS for C33H36N4O3 m/z 537.06 (M+H)+.