Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH2:9][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:2]1.[C:12]([OH:21])(=[O:20])[CH:13]([CH:15]([C:17]([OH:19])=[O:18])[OH:16])[OH:14]>C(O)C>[C:17]([CH:15]([CH:13]([C:12]([O-:21])=[O:20])[OH:14])[OH:16])([O-:19])=[O:18].[NH:1]1[CH2:11][CH2:10][CH2:9][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:2]1
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: CCOC(=O)C1CCCNC1
Solvent: CCO
Product: O=C([O-])C(O)C(O)C(=O)[O-]
Temperature: 25 °C

Procedure:
(±)-Ethyl nipecotate (70.16 g, 71ml) and (+)-tartaric acid (67 g) were dissolved in hot 95% ethanol (350 ml). The resulting solution was allowed to slowly cool to room temperature and refrigerated overnight. The crystals were filtered, washed with cold ethanol, and recrystallized from 95% ethanol (550 ml), cooling as before to give the (+)-tartrate salt of (+)-ethyl nipecotate (42.9 g). M.p. 155-156° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:18][CH2:17]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[C:29]([OH:38])(=[O:37])[CH:30]([CH:32]([C:34]([OH:36])=[O:35])[OH:33])[OH:31]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:17][CH2:18][N:19]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:20][CH2:21]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[C:34]([CH:32]([CH:30]([C:29]([O-:38])=[O:37])[OH:31])[OH:33])([O-:36])=[O:35]
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CC(C)=O
Product: O=C([O-])C(O)C(O)C(=O)[O-]
Temperature: 25 °C

Procedure:
Donepezil (3.79 g, dissolved in 200 ml of ethyl acetate) is slowly added to a solution of tartaric acid in acetone (35 ml) with stirring at room temperature. The solid precipitated is filtered and dried at 55° C. under vacuum to give the title compound.
Reaction SMILES: C(OC(=O)[N:7]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:29][C@H:28]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])[O:27][C:26]3=[O:35])=[CH:21][C:20]=2[F:36])=[CH:15][CH:14]=1)[CH2:8][CH2:9][CH2:10][F:11])(C)(C)C.[ClH:38]>O1CCOCC1>[ClH:38].[F:36][C:20]1[CH:21]=[C:22]([N:25]2[CH2:29][C@H:28]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])[O:27][C:26]2=[O:35])[CH:23]=[CH:24][C:19]=1[C:16]1[CH:17]=[CH:18][C:13]([CH2:12][NH:7][CH2:8][CH2:9][CH2:10][F:11])=[CH:14][CH:15]=1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(CN(CCCF)C(=O)OC(C)(C)C)cc3)c(F)c2)C(=O)O1
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(CNCCCF)cc3)c(F)c2)C(=O)O1

Procedure:
BOC-protected amine 121 was subsequently treated with 4 N hydrogen chloride in 1,4-dioxane as in Example 1 to afford compound 11. The product obtained from this process was identical by NMR and LCMS to the material obtained in Example 1.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:8][CH2:7][CH:6]([NH:9][C@@H:10]([CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[CH2:5][CH2:4]1.[Si]([Cl:37])(C)(C)C>CC(CC)=O>[ClH:37].[ClH:37].[CH3:32][N:2]([CH3:1])[C:3]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:8][CH2:7][CH:6]([NH:9][C@@H:10]([CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)[C:11]([N:13]([CH3:14])[CH3:15])=[O:12])[CH2:5][CH2:4]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C(=O)[C@H](Cc1c[nH]c2ccccc12)NC1CCC(c2ccccc2)(N(C)C)CC1
Solvent: CCC(C)=O
Product: Cl
Reaction time: 1 h

Procedure:
(S)-2-(4-(dimethylamino)-4-phenylcyclohexylamino)-3-(1H-indol-3-yl)-N,N-dimethylpropanamide (240 mg, 0.55 mmol, non-polar diastereomer from step 3) was dissolved in ethyl methyl ketone (10 ml) and mixed with Me3SiCl (0.18 ml, 1.39 mmol). The white crystalline solid was aspirated after 1 h.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:8][CH2:7][C:6](=[CH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[O:11])[CH2:5][CH2:4]1.[Cl:27][Si](C)(C)C>CC(CC)=O>[ClH:27].[CH3:26][N:2]([CH3:1])[C:3]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:4][CH2:5][C:6](=[CH:9][C:10]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)=[O:11])[CH2:7][CH2:8]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(c2ccccc2)CCC(=CC(=O)Nc2ccc(F)cc2)CC1
Solvent: CCC(C)=O
Product: Cl

Procedure:
2-(4-Dimethylamino-4-phenylcyclohexylidene)-N-(4-fluoro-phenyl)acetamide (266 mg, 0.755 mmol) was dissolved in ethyl methyl ketone (5 ml), and chlorotrimethylsilane (0.139 ml, 1.1 mmol) was added. After 2.5 h the hydrochloride was isolated as a colourless solid in a yield of 52% (152 mg).
Reaction SMILES: O.C[Si]([Cl:6])(C)C.[CH3:7][N:8]([CH2:10][CH:11]1[CH:17]2[CH2:18][CH:14]([CH2:15][CH2:16]2)[CH:13]=[C:12]1[C:19]1[CH:20]=[C:21]([O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=1)[CH3:9]>CC(=O)CC>[ClH:6].[CH3:9][N:8]([CH2:10][CH:11]1[CH:17]2[CH2:18][CH:14]([CH2:15][CH2:16]2)[CH:13]=[C:12]1[C:19]1[CH:20]=[C:21]([O:25][C:26](=[O:31])[C:27]([CH3:29])([CH3:28])[CH3:30])[CH:22]=[CH:23][CH:24]=1)[CH3:7]
Reactant: C[Si](C)(C)Cl
Agent: CN(C)CC1C(c2cccc(OC(=O)C(C)(C)C)c2)=CC2CCC1C2
Solvent: CCC(C)=O
Solvent: O
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Add H2O (18 mg, 1 mmol) and TMSCl (75 mg, 0.69 mmol) to a solution of 2,2-dimethyl-propionic acid 3-(4-dimethylaminomethyl-bicyclo[3.2.1]oct-2-en-3-yl)-phenyl ester (197 mg, 0.58 mmol) in 2-butanone (70 mL). Stir the reaction mixture at ambient temperature for 2 hours. Evaporate the mixture under vacuum to afford 2,2-dimethyl-propionic acid 3-(4-dimethylaminomethyl-bicyclo[3.2.1]oct-2-en-3-yl)-phenyl ester hydrochloride as white solid (219 mg, Yield: 100%). 1H NMR (400 MHz, Methanol-d4) δ 7.38-7.42 (t, J=16.4, 1H), 7.13-7.15 (d, J1=7.2, J2=0.8, 1H), 6.96-6.98 (m, 2H), 6.21-6.23 (d, J=6.8, 1H), 3.68-3.71 (d, J=12.0, 1H), 3.16-3.23 (t, J=25.6, 1H), 2.99-3.00 (m, 1H), 2.88-2.92 (d, J=14.8, 6H), 2.65 (m, 1H), 2.60 (m, 1H), 1.95-1.98 (m, 1H), 1.82-1.86 (m, 5H), 1.37 (s, 9H).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2([CH2:17][CH2:16][N:15]([C:18](=[O:22])[CH2:19][CH2:20][CH3:21])[CH2:14][CH2:13]2)[NH:11][C@@H:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:9]1=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C[Si]([Cl:36])(C)C>CC(CC)=O>[ClH:36].[CH2:1]([N:8]1[C:12]2([CH2:17][CH2:16][N:15]([C:18](=[O:22])[CH2:19][CH2:20][CH3:21])[CH2:14][CH2:13]2)[NH:11][C@@H:10]([CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:9]1=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)Cl
Agent: CCCC(=O)N1CCC2(CC1)N[C@@H](Cc1ccccc1)C(=O)N2Cc1ccccc1
Solvent: O
Solvent: CCC(C)=O
Product: Cl
Reaction time: 8 h

Procedure:
1,3-(S)-dibenzyl-8-butyryl-1,4,8-triazaspiro[4,5]decan-2-one (272 mg, 10.7 mmol) was dissolved in ethyl methyl ketone (2.2 mL), and water (7 μL) and TMSCl (93 μL) were added and the mixture was stirred overnight. The solid matter was isolated by filtration, washed with ether, and dried in vacuo. The product 1,3-(S)-dibenzyl-8-butyryl-1,4,8-triazaspiro[4,5]decan-2-one hydrochloride was obtained in a yield of 281 mg (95%).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2([CH2:17][CH2:16][N:15]([C:18]([C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=3)=[O:19])[CH2:14][CH2:13]2)[NH:11][C@@H:10]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:9]1=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C[Si]([Cl:43])(C)C.CCOCC>CC(CC)=O>[ClH:43].[CH2:1]([N:8]1[C:12]2([CH2:17][CH2:16][N:15]([C:18]([C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=3)=[O:19])[CH2:14][CH2:13]2)[NH:11][C@@H:10]([CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:9]1=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)Cl
Agent: O=C(c1ccc2ccccc2c1)N1CCC2(CC1)N[C@@H](Cc1ccccc1)C(=O)N2Cc1ccccc1
Solvent: CCC(C)=O
Solvent: CCOCC
Solvent: O
Product: Cl
Reaction time: 8 h

Procedure:
1,3-(S)-dibenzyl-8-(naphthalin-2-carbonyl)-1,4,8-triazaspiro[4,5]decan-2-one (400 mg, 0.8 mmol) was dissolved in ethyl methyl ketone (3.2 mL), water (8 μL), TMSCl (114 μL), and ether (20 mL) were added and the mixture was stirred overnight. The solid matter was isolated by filtration, washed with ether, and dried in vacuo. The product 1,3-(S)-dibenzyl-8-(naphthalin-2-carbonyl)-1,4,8-triazaspiro[4,5]decan-2-one hydrochloride was obtained in a yield of 407 mg (95%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])#[N:2].C(O)(C)C.[ClH:16].CCOCC>C1COCC1.[Pt](=O)=O>[ClH:16].[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: N#Cc1cccc(C(=O)O)c1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC(C)O
Product: NCc1cccc(C(=O)O)c1
Temperature: 25 °C
Yield: 82 %

Procedure:
3-cyanobenzoic acid (5.88 g, 40 mmol) was suspended in 50 mL THF and the mixture was warmed up with stirring. After all solid went into solution, 50 mL isopropanol was added and the solution was allowed to cool to room temperature. To it was added 4.2 mL precooled concentrated HCl followed by 300 mg platinum(IV) oxide. The mixture was hydrogenated at 55 psi overnight. Ether (50 mL) was added, and the precipitate was filtered, washed with ether and dissolved in methanol. The catalyst was filtered off and the solvent was removed under reduced pressure to give 6.2 g (82%) product. 1H-NMR (DMSO-d6): δ=4.08 (d, 2H); 7.53 (t, 1H); 7.80 (d, 1H); 7.94 (d, 1H); 8.10 (s, 1H); 8.65 (s, 3H).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]([O:11][C:12]([N:14]1[CH2:18][C:17](=O)[CH2:16][C@H:15]1[C:20]([OH:22])=[O:21])=[O:13])([CH3:10])([CH3:9])[CH3:8]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:7]([O:11][C:12]([N:14]1[CH2:18][C:17](=[CH2:1])[CH2:16][C@H:15]1[C:20]([OH:22])=[O:21])=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)O
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 46.7 %

Procedure:
To a mixture of methyltriphenylphosphonium bromide (236.4 g, 2.7 eq) in THF (1 L) was rapidly added potassium tert-butoxide (75.6 g, 2.75 eq) while maintaining the temperature around 0° C. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 2 hours, and re-cooled to 0° C. (S)-1-(tert-butoxycarbonyl)-4-oxopyrrolidine-2-carboxylic acid (56.2 g, 0.245 mol) was added portionwise to the reaction mixture while maintaining the temperature below 5° C. Then, the reaction was allowed to warm to room temperature and stirred at room temperature overnight before being re-cooled to 0° C. and quenched by addition of saturated NaHCO3 solution (500 mL) and water (200 mL). The mixture was evaporated. The aqueous layer was extracted with tert-butyl methyl ether (2×400 mL). The aqueous layer was filtered through a pad of celite and the filtrate was acidified with 6N HCl (200 mL) and extracted with ethyl acetate (2×1 L). The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated to dryness. The residue was dissolved in ethyl acetate (0.7 L), extracted with 0.5 N NaOH (0.7 and 0.3 L). The aqueous layer was acidified with 6N HCl (100 mL), extracted with ethyl acetate (1 L and 0.8 L). The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated to dryness. The residue was dissolved in 50% ethyl acetate in cyclohexane (150 mL), slowly evaporated to give a yellowish solid. It was filtered and dried to give the title compound (26 g). The filtrate was evaporated to give a yellowish solid, filtered and dried to provide the title compound (10 g). Total 36 g (65%) as a white solid. Also, the residue contained 18 g of the product as 80% purity. 1H NMR (500 MHz, CDCl3): 5.04-5.02 (m, 2H), 4.53 (dd, J=8.4, 3.2 Hz, 0.5H), 4.42 (d, J=9.3 Hz, 0.5H), 4.09-3.98 (m, 2H), 3.05-2.69 (m, 2H), 1.49 and 1.43 (2 s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]2([OH:21])[CH2:17][CH:16]([C:18](O)=[O:19])[CH2:15]2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.Cl.[CH:23]1([CH2:26][NH:27][CH3:28])[CH2:25][CH2:24]1.C(N(CC)CC)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[OH-].[Na+]>CCOC(C)=O>[CH:23]1([CH2:26][N:27]([CH3:28])[C:18]([CH:16]2[CH2:17][C:14]([C:4]3[CH:5]=[CH:6][C:7]([CH2:8][N:9]4[CH2:10][CH2:11][CH2:12][CH2:13]4)=[C:2]([Cl:1])[CH:3]=3)([OH:21])[CH2:15]2)=[O:19])[CH2:25][CH2:24]1
Reactant: CNCC1CC1
Reactant: O=C(O)C1CC(O)(c2ccc(CN3CCCC3)c(Cl)c2)C1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN(CC1CC1)C(=O)C1CC(O)(c2ccc(CN3CCCC3)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.9 %

Procedure:
To a solution of crude intermediate 17, 3-(3-chloro-4-((pyrrolidin-1-yl)methyl)phenyl)-3-hydroxycyclobutanecarboxylic acid (˜4.3 mL ˜0.65 mmol) was added cyclopropylmethyl-methyl-amine hydrochloride (61 mg, 0.51 mmol), triethylamine (0.18 ml, 1.29 mmol) and T3P (50% solution in EtOAc, 0.62 ml, 0.97 mmol). The resulting reaction mixture was stirred at RT for 1 hr and then 25 ml of 1N NaOH and 100 ml of EtOAc were added and the layers were separated. The aqueous layer was subjected to EtOAc extraction (2×60 ml) again and the combined organic layers were dried over MgSO4 and evaporated. The residue was purified by flash column chromatography using a 40 g ISCO™ column, eluting with 5% MeOH/CH2Cl2 containing 0.25% NH4OH. The product containing fractions were collected and concentrated under reduced pressure to give the title compound (71 mg, 29% yield). Rf=0.50 (15% MeOH/CH2Cl2+0.2% NH4OH); LRMS m/z Calcd for C21H29Cl N2 O2, 376.9, found, 377.2 (M+1) APCI; 400 MHz 1H NMR (CDCl3) 1:1 mixture of rotomers, diagnostic peaks, δ 3.75 (s, 2H), 3.02 & 3.01 (2 singlets, 3H total), 2.62-2.54 (m, 6H), 1.82-1.74 (m, 4H); 100 MHz 13C NMR (CDCl3) 1:1 mixture of rotomers, peak list δ 175.9, 175.7, 146.4, 146.3, 135.2, 134.0, 130.9, 130.8, 126.5, 126.4, 123.7, 73.7, 73.5, 56.7, 54.6, 54.3, 52.4, 41.3, 41.0, 35.5, 34.5, 29.0, 28.5, 23.7, 10.5, 9.5, 3.8, 3.6.
Reaction SMILES: CB1N2CCC[C@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.B.[CH3:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=1)=[O:25].CO>C(Cl)Cl>[N+:32]([C:28]1[CH:27]=[C:26]([C@H:24]([OH:25])[CH3:23])[CH:31]=[CH:30][CH:29]=1)([O-:34])=[O:33]
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Solvent: ClCCl
Solvent: CO
Product: C[C@@H](O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 96.7 %

Procedure:
To a solution of (S)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c]- [1,3,2]-oxazaborole-borane (6.06 mmol) in CH2Cl2 (6 mL) at −20° C. was added a solution of 3-nitroacetophenone (6.06 mmol) in CH2Cl2 (6 mL) in a dropwise fashion over 30 min. The resulting mixture was stirred 45 min. longer then poured into cold methanol (−20° C.), and this mixture allowed to stir overnight while warming to room temperature. The mixture was then concentrated in vacuo then more methanol (100 mL) added and concentrated, and then added another 100 mL methanol and concentrated. The resulting crude was purified on silica gel in 60:40 hexanes:ethyl acetate to yield 0.98 g of the title compound. 1H NMR (500 MHz, CDCl3): δ 8.22 (m, 1H); 8.08 (m, 1H); 7.69 (d, J=7.8 Hz, 1H); 7.50 (t, J=7.8 Hz, 1H); 5.00 (m, 1H); 2.62 (s, 1H); 1.53 (d, J=7.1 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][Si](C(C)(C)C)(C)C)[CH2:14][C@H:13]([O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]([O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@H](OC(=O)c2ccccc2)CN(C(=O)OCc2ccccc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O[C@H]1C[C@@H](O)CN(C(=O)OCc2ccccc2)C1)c1ccccc1
Temperature: 25 °C
Yield: 95.7 %

Procedure:
To a solution of 2.3 g (5.0 mmol) (3S,5R)-3-benzoyloxy-5-(tert-butyl-dimethyl-silanyloxy)-piperidine-1-carboxylic acid benzyl ester in 20 ml dry THF were added 5.5 ml (5.5 mmol) of a 1M solution of tetrabutyl ammoniumfluoride in THF at 0° C. After completed addition, the mixture was allowed to warm to room temperature over 30 min. Addition of water was followed by extraction with three portions of tert-butyl methyl ether. The combined organic extracts were dried over sodium sulfate. Kugelrohr distillation gave 1.7 g (95%) of the title compound as a light yellow oil.
Reaction SMILES: COC1C=CC([C:9]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[C:17](OC)[C:11]=3[CH:10]=2)=CC=1.COC1C=C(C=C(OC)C=1OC)C(Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-].O>C(Cl)Cl.CCOC(C)=O>[S:13]1[CH:9]=[CH:10][C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]1=2
Reactant: COc1ccc(-c2cc3c(OC)cccc3s2)cc1
Agent: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: c1ccc2sccc2c1
Reaction time: 18 h
Yield: 6.8 %

Procedure:
To a well stirred solution of 2-(4′-methoxyphenyl)-4-methoxybenzo[b]thiophene (0.200 g, 0.74 mmol) and 3,4,5-trimethoxybenzoyl chloride (0.1 84 g, 0.74 mmol) in CH2Cl2 (7 mL) was added AlCl3 (0.200 g, 1.48 mmol) portion-wise over a 15 minute period. After 18 h, water was added, and the product was isolated initially with CH2Cl2 and subsequently by extraction with EtOAc. The organic layers were separately washed sequentially with NaHCO3 and brine and then dried over MgSO4. Purification by flash chromatography (silica gel, 70:30 hexane/EtOAc) afforded benzo[b]thiophene (0.023 g, 0.05 mmol, 7%) as a white solid. Recrystallization (Ethanol/hexane/CH2Cl2)yielded a highly pure crystalline sample. 1H-NMR (CDCl3, 360 MHz) δ7.80 (d, J=8.4 Hz, 1H, ArH), 7.73 (d, J=8.8 Hz, 2H, ArH), 7.66 (s, 1H, ArH), 7.02 (s, 2H, ArH), 6.96 (d, J=8.8 Hz, 2H, ArH), 6.70 (d, J=8.3 Hz, 1H, arH), 4.08 (s, 3H, —OCH3), 3.95 (s, 3H, —OCH3), 3.91 (s, 6H, —OCH3), 3.87 (S, 3H, —OCH3), HRMS (EI) M+ calcd for C26H24O6S 464.1294, found 464.1310. Anal. Calcd for C26H24O6S: C, 67.23; H, 5.21; S, 6.90. Found C, 67.19; H, 5.26; S, 6.87. Compound 13A shows an inhibition of tubulin polymerization >40 μM. Biological activity of compound 13A is shown in Table 19.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]23[CH:17]4[CH2:18][CH:14]([CH2:15][CH2:16]4)[CH:13]2[CH2:12][N:11](C)[CH2:10]3)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1(C)C=CC=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]23[CH:17]4[CH2:18][CH:14]([CH2:15][CH2:16]4)[CH:13]2[CH2:12][N:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:10]3)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN1CC2C3CCC(C3)C2(c2ccc(Cl)c(Cl)c2)C1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC2C3CCC(C3)C2(c2ccc(Cl)c(Cl)c2)C1

Procedure:
To a solution of 5.0 g of 3a-(3,4-dichlorophenyl)octahydro-2-methyl-4,7-methano-1H-isoindole in 200 ml of toluene was added, dropwise over a 30 minute period, at room temperature, 30 ml of a solution of freshly distilled ethyl chloroformate in toluene. The reaction mixture was heated under reflux for 16 hours, then was concentrated in vacuo to give a colorless, viscous liquid. This liquid was dissolved in dichloromethane and chromatographed by preparative liquid chromatography on a silica gel column, eluting with 10% ethyl acetate/hexane and gave 1.9 g of 3a-(3,4-dichlorophenyl)octahydro-4,7-methano-2H-isoindole-2-carboxylic acid, ethyl ester as a slightly yellow, viscous liquid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([OH:14])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].Cl[O-].[Na+].S(=O)(=O)(O)O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:15])[C:5](=[O:14])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)C(O)CCc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: CCOC(=O)C(=O)CCc1ccccc1
Yield: 91.9 %

Procedure:
According to the same procedure as described in Example 2, using 20.8 g (100 mmol) of 2-hydroxy-4-phenylbutyric acid ethyl ester, methylene chloride (50 ml), 72.6 g (purity 12.3%, 120 mmol) of sodium hypochlorite, 43 mg (0.2 mmol) of 4-acetoxy-2,2,6,6-tetramethylpiperidinyl-1-oxy, and 10 ml (10 mmol) of 1N sulfuric acid, was obtained 18.95 g of 2-keto-4-phenylbutyric acid ethyl ester. The yield was 92%.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:18][CH2:19][CH2:20][CH2:21]I.CCCCCCC>C(#N)C>[Cl:18][CH2:19][CH2:20][CH2:21][N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1][CH2:2][C:3]1=[O:11]
Reactant: ClCCCI
Reactant: O=C1COc2ccccc2N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCCC
Solvent: CC#N
Product: O=C1COc2ccccc2N1CCCCl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2H-1,4 benzoxazine-3(4H)one (1.0 g, 6.70 mmol) and Cs2CO3 (3.28 g, 10.1 mmol) were dissolved in dry acetonitrile (20 mL) under nitrogen atmosphere and stirred at rt for 30 min. 3-chloro-1-iodopropane (1.58 g, 7.38 mmol) dissolved in acetonitrile (4 mL) was added via a syringe. The reaction mixture was stirred at rt for 18 hours and concentrated in vacuo. Water (150 mL) was added and the reaction mixture was extracted with ethyl acetate (3×150 mL). The combined organic phases were dried (MgSO4) and concentrated in vacuo to give 1.65 g of crude. The crude product was subjected to CC[eluent:Heptane:EtOAC(4:1)] to give the pure title compound as a colorless oil. Yield 1.36 g, 89.2%. Rf=0.24 [Heptane:EtOAC(4:1)], 1H NMR (CDCl3): δ 2.16 (m, 2H), 3.62 (t, 2H), 4.10 (t, 2H), 4.59 (s, 2H), 7.00 (m, 2H), 7.05 (m, 2H), 13C NMR (CDCl3): δ 30.16, 39.04, 42.45, 67.72, 114.80, 117.38, 123.07, 124.14, 128.49, 145.47, 164.58.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=3)=[CH:16][CH:15]=2)=[CH:8][C:7]=1[CH3:32].[K+].[Br-]>>[C:28]([C:25]1[CH:26]=[CH:27][C:22]([CH2:21][O:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:13][S:12][C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:33])=[O:2])=[C:7]([CH3:32])[CH:8]=3)=[CH:15][CH:16]=2)=[CH:23][CH:24]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: COC(=O)COc1ccc(SCc2ccc(OCc3ccc(C(C)(C)C)cc3)cc2)cc1C
Agent: [Br-]
Agent: [K+]
Product: Cc1cc(SCc2ccc(OCc3ccc(C(C)(C)C)cc3)cc2)ccc1OCC(=O)O

Procedure:
The title compound was prepared in the manner analogous to Example 1 using 34C. mp 135-137° C.; IR (KBr) cm−1: 2961, 2908, 1751, 1495, 1233, 1194; 400 MHz 1H NMR (DMSO-d6): δ 13.00 (br(s), 1H), 7.27-7.38 (m, 4H), 7.02-7.17 (m, 4H), 6.82-6.88 (m, 2H), 6.69 (d, 1H, J=8.5 Hz), 4.96 (s, 2H), 4.61 (s, 2H), 3.99 (s, 2H), 2.08 (s, 3H), 1.22 (s, 9H); MS m/z 451 (M+1). Anal. Calc'd for C27H30O4S: C, 71.97; H, 6.71. found: C, 71.66; H, 6.52.