Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=2)[N:7]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[N:6]=1)=O.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.C(=O)([O-])O.[Na+].O>O1CCCC1CO>[N:24]1[C:3]([C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=3)[N:7]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[N:6]=2)=[CH:2][N:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=12
Reactant: Nc1ccccn1
Reactant: CC(C)(C)OC(=O)n1nc(C(=O)CBr)c2cc([N+](=O)[O-])ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: OCC1CCCO1
Solvent: O
Product: CC(C)(C)OC(=O)n1nc(-c2cn3ccccc3n2)c2cc([N+](=O)[O-])ccc21
Yield: 43.7 %

Procedure:
A total of 0.88 g of tert-butyl 3-(2-bromoacetyl)-5-nitro-1H-1-indazolecarboxylate was dissolved in 10 ml of tetrahydrofuran-methanol (1:1), and 240 mg of 2-aminopyridine and 210 mg of sodium hydrogencarbonate were added, followed by heating under reflux for 1 hour. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The mixture was washed with water, dried over magnesium sulfate and the solvent was removed. The residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=1:7), to give 0.38 g of the title compound as a pale yellow powder.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[C@H:21]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:20][CH2:19]3)=[N:9][CH:10]=1)#[N:4].[CH2:31](I)[CH2:32][CH3:33]>CN(C=O)C>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([N:11]([CH2:31][CH2:32][CH3:33])[CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[C@H:21]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:20][CH2:19]3)=[N:9][CH:10]=1)#[N:4]
Reactant: CCCI
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCNc3ccc(C#N)cn3)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN(CCCOc1ccc2c(c1)CC[C@H]2CC(=O)OCC)c1ccc(C#N)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
Sodium hydride (0.08 g, 3.16 mmol) was added to a solution of ethyl ((1S)-5-{3-[(5-cyano-2-pyridinyl)amino]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (Example 264) (0.6 g, 1.58 mmol) in DMF (15 mL). The heterogeneous mixture was stirred at rt for 30 min. Propyl iodide (0.62 mL, 6.32 mmol) was added, and the mixture was stirred at rt for 18 h. The excess NaH was quenched by the addition of water (5 mL) and the aqueous phase extracted with Et2O. The combined Et2O extracts were washed with water and brine, then dried (MgSO4), filtered, and concentrated under reduced pressure. The product (0.63 g, 99%) was isolated after column chromatography (2:1 hexanes/EtOAc). 1H NMR (400 MHz, CD2Cl2) δ 8.35 (dd, 1H), 7.54 (dd, 1H), 7.06 (d, 1H), 6.78 (d, 1H), 6.69 (d, 1H), 6.52 (dd, 1H), 4.17 (q, 2H), 3.99 (t, 2H), 3.72 (t, 2H), 3.56-3.44 (m, 3H), 2.95-2.78 (m, 2H), 2.71 (dd, 1H), 2.46-2.35 (m, 2H), 2.12-2.05 (m, 2H), 1.72-1.58 (m, 3H), 1.28 (t, 3H), 0.96 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)[CH:5]=[CH:6][CH:7]=1.[C:16]1([CH:22]2[CH2:26][CH2:25][NH:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:24]2[CH2:25][CH2:26][CH:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23]2)=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(C2CCNC2)cc1
Reactant: O=C(O)c1cnoc1-c1cccc(F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cnoc1-c1cccc(F)c1)N1CCC(c2ccccc2)C1
Temperature: 25 °C

Procedure:
5-(3-fluorophenyl)-isoxazole-4-carboxylic acid (47.8 mg, 0.231 mmol), 3-phenylpyrrolidine (40 mg, 0.271 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (92.6 mg, 0.288 mmol) and diisopropylethylamine (49.7 mg, 0.384 mmol) were mixed in dimethylformamide (1.5 mL) and stirred at room temperature over night. Solvent was evaporated in vacuo (0.5-1.0 mL) and the residue was taken up in dichloromethane (1 mL), filtered and purified by normal-phase chromatography (20-50% EtOAc:petroleum ether). The combined fractions were partitioned between H2O/acetic acid (pH 4) and ethyl acetate. The organic fractions were washed with H2O/brine and concentrated in vacuo to afford the title compound. HRMS (ESI, pos. ion) m/z calcd for C20H17FN2O2: 336.1274, found 336.1277.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH:6]1[C:10](=[O:11])[N:9]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2([CH2:24][CH2:23][N:22]([CH2:25][CH2:26][C:27](=O)[C:28]([O:30]CC)=[O:29])[CH2:21][CH2:20]2)[S:7]1)C.[OH-].[Na+].C(OCC)(=[O:39])C.Cl>C(O)C>[C:4]([CH2:5][CH:6]1[C:10](=[O:11])[N:9]([CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:8]2([CH2:24][CH2:23][N:22]([C:25](=[O:39])[CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH2:21][CH2:20]2)[S:7]1)([OH:3])=[O:34]
Reactant: CCOC(=O)CC1SC2(CCN(CCC(=O)C(=O)OCC)CC2)N(CCc2ccccc2)C1=O
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCC(=O)N1CCC2(CC1)SC(CC(=O)O)C(=O)N2CCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In 2.5 ml of ethanol was dissolved 0.51 g of ethyl 4-[2-(2-ethoxy-2-oxoethyl)-3-oxo-4-phenethyl-1-thia-4,8-diazaspiro[4.5]decan-8-yl]-oxobutanoate. After adding 2.5 ml of 1 mol/L aqueous solution of sodium hydroxide at 0-5° C., the resulting mixture was stirred at ambient temperature for 1.5 hours. The reaction mixture was poured into a mixture of ice water and ethyl acetate, pH was adjusted to 2.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer thus obtained was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Thus, 0.34 g of 4-[2-(carboxymethyl)-3-oxo-4-phenethyl-1-thia-4,8-diazaspiro[4.5]decan-8-yl]-4-oxobutanoic acid was obtained as a yellow oily product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)([CH:10]2[CH2:15][CH2:14][N:13](CC3C=CC=CC=3)[CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.C(Cl)Cl>C(O)C.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)([CH:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)[OH:9])=[CH:4][CH:3]=1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Yield: 91.8 %

Procedure:
A solution of 31.2 g (0.079 mole) of α,α-bis-(4-fluorophenyl)-1-(phenylmethyl)-4-piperidinemethanol in 400 ml of absolute ethanol was hydrogenated at 50 psi and 70° C. over 5% palladium on carbon over the weekend. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a gum as residue. Methylene chloride was added to the residue and the gum crystallized. The mixture was diluted with petroleum ether and the solid was collected by filtration, washed with petroleum ether, and dried to yield 22 g (92%) of white solid which was recrystallized from isopropyl ether-2-propanol, m.p. 159.5°-160.5° C.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14].O>C1COCC1>[CH3:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:14]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccccc1C(=O)Oc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
Phenol (2.00 g, 12.3 mmol) was dissolved in THF (40 mL), 55% sodium hydride (1.02 g, 23.4 mmol) was added thereto at 0° C., followed by stirring at 0° C. for 30 minutes. A solution (10 mL) of 2-methylbenzoyl chloride (4.16 mL) in THF was added dropwise to the reaction mixture, followed by stirring overnight at room temperature. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=9:1) to afford phenyl 2-methylbenzoate (2.88 g, 64%).
Reaction SMILES: [O:1]=[C:2]([CH3:25])[CH:3](C(OCC)=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19].C(O)(=O)C.Cl.O>C(Cl)Cl.[OH-].[Na+]>[O:1]=[C:2]([CH3:25])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19]
Reactant: CCOC(=O)C(CCCCCN1C(=O)c2ccccc2C1=O)C(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)CCCCCCN1C(=O)c2ccccc2C1=O

Procedure:
A mixture of 350 g of crude N-[7-oxo(6-carboethoxy)octyl]phthalimide and 1000 ml of acetic acid, concentrated hydrochloric acid, and water was refluxed for three hours. The reaction mixture was stripped, the residue dissolved in methylene chloride and basified with 2 N NaOH solution. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and stripped to an orange oil, 73% pure by gc (SE-30, 90-280°@16°/min). This material was used without further purification in Preparation 3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]2=[CH:7][CH:8]=[C:9]3[C:13]([N:12]([CH2:14][C@@H:15]([NH:17]C(=O)C(F)(F)F)[CH3:16])[CH:11]=[CH:10]3)=[C:5]2[CH:4]=1.[OH-:26].[K+].[OH-:28].[Na+].[OH2:30]>CO>[C:3]([OH:2])(=[O:30])/[CH:25]=[CH:24]/[C:6]([OH:28])=[O:26].[CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]2=[CH:7][CH:8]=[C:9]3[C:13]([N:12]([CH2:14][C@@H:15]([NH2:17])[CH3:16])[CH:11]=[CH:10]3)=[C:5]2[CH:4]=1
Reactant: COc1ccc2ccc3ccn(C[C@H](C)NC(=O)C(F)(F)F)c3c2c1
Reactant: O
Reactant: [OH-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2ccc3ccn(C[C@H](C)N)c3c2c1
Product: O=C(O)/C=C/C(=O)O
Yield: 73 %

Procedure:
A mixture of 1.2 g of (S)-N-[2-(8-methoxy-1H-benz[g]indol-1-yl)-1-methyl-ethyl]-trifluoracetamide, 1.2 g of potassium hydroxide in 3 ml of water and 50 ml of methanol was boiled under reflux for 3 hours. The reaction mixture was subsequently poured into 100 ml of 1N sodium hydroxide solution, extracted twice with 100 ml of diethyl ether each time and once with 100 ml of ethyl acetate, the combined organic phases were washed once with 150 ml and dried over magnesium sulfate. After concentration in a vacuum, the residue was dissolved in 100 ml of anhydrous diethyl ether, filtered and treated while stirring with a solution of 398 mg of fumaric acid in 30 ml of methanol. The mixture was stirred at room temperature for 16 hours and the white crystals were subsequently filtered off. 780 mg (73%) of (S)-2-(8-methoxy-1H-benz[g]indol-1-yl)-1-methyl-ethylamine fumarate (1:0.5) with m.p. 208° were obtained.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:16])[C@@H:5]([NH:8]C(OC(C)(C)C)=O)[CH2:6][NH2:7].[NH2:17][C:18]1[CH:19]=[C:20]([S:24]([OH:27])(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1.C(Cl)Cl.[O:31]1CCC[CH2:32]1>>[NH2:8][C@H:5]([C:4]([O:3][CH3:2])=[O:16])[CH2:6][NH:7][C:32]([NH:17][C:18]1[CH:19]=[C:20]([S:24]([OH:27])(=[O:25])=[O:26])[CH:21]=[CH:22][CH:23]=1)=[O:31]
Reactant: COC(=O)[C@H](CN)NC(=O)OC(C)(C)C
Reactant: Nc1cccc(S(=O)(=O)O)c1
Reactant: C1CCOC1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@@H](N)CNC(=O)Nc1cccc(S(=O)(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 127 mg (0.5 mmol) of (2S)-3-amino-2-{[(tert-butoxy)carbonyl]amino}propanoic acid methylester hydrochloride, 87 mg (0.5 mmol) of 3-aminobenzenesulfonic acid and 97 mg (0.6 mmol) of N,N-carbonyl diimidazole, 1 ml of methylene chloride and 1 ml of tetrahydrofuran were added and stirred at room temperature overnight. After distilling the solvent away, purification was carried out using purification step A to obtain a crude purified substance of the title compound in protected form. To the obtained crude purified substance, 1 ml of methylene chloride and 1 ml of trifluoroacetic acid were added and stirred at room temperature for 5 hours. After distilling the solvent away, purification was carried out by purification step A to obtain the title compound.
Reaction SMILES: C(OC([N:11]1[CH2:14][C:13]([N+:18]([O-:20])=[O:19])([N+:15]([O-:17])=[O:16])[CH2:12]1)=O)C1C=CC=CC=1.C1(OC)C=CC=CC=1.[F:29][C:30]([F:36])([F:35])[S:31]([OH:34])(=[O:33])=[O:32].C(=O)=O>C(Cl)Cl.C(OCC)C>[F:29][C:30]([F:36])([F:35])[S:31]([O-:34])(=[O:33])=[O:32].[N+:15]([C:13]1([N+:18]([O-:20])=[O:19])[CH2:14][NH2+:11][CH2:12]1)([O-:17])=[O:16]
Reactant: O=C(OCc1ccccc1)N1CC([N+](=O)[O-])([N+](=O)[O-])C1
Reactant: O=S(=O)(O)C(F)(F)F
Agent: O=C=O
Solvent: ClCCl
Solvent: CCOCC
Solvent: COc1ccccc1
Product: O=S(=O)([O-])C(F)(F)F
Product: O=[N+]([O-])C1([N+](=O)[O-])C[NH2+]C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.3 %

Procedure:
To a solution of 1-(benzyloxycarbonyl)-3,3-dinitroazetidine (8.0 g, 0.028 mole) in 80 ml of methylene chloride containing anisole (9.24 g, 0.08 mole) was added trifluoromethanesulfonic acid (10 g, 0.067 mole), slowly with vigorous stirring at room temperature. Carbon dioxide was evolved and the solution turned light red in color. Stirring was continued for about 30 minutes after the addition. Diethyl ether was added slowly to quench the reaction and precipitate the resultant product. The solids were filtered, washed with diethyl ether and air-dried to give 4.10 g (97% yield) of pure 3,3-dinitroazetidinium trifluoromethanesulfonate. The melting point of the product was 176° (dec.).
Reaction SMILES: [OH-].[Li+].[F:3][C:4]1([F:32])[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[C:14]([C:16]([NH:18][C:19]3[C:28]([CH3:29])=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][C:20]=3[CH3:30])=[O:17])[C:13]([CH3:31])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.O.CO>C1COCC1>[F:32][C:4]1([F:3])[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[C:14]([C:16]([NH:18][C:19]3[C:20]([CH3:30])=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][C:28]=3[CH3:29])=[O:17])[C:13]([CH3:31])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1
Reactant: COC(=O)c1cc(C)c(NC(=O)c2nc(N3CCC(F)(F)CC3)ccc2C)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(N2CCC(F)(F)CC2)nc1C(=O)Nc1c(C)cc(C(=O)O)cc1C
Reaction time: 3 h
Yield: 71.6 %

Procedure:
Lithium hydroxide (LiOH.H2O, 0.048 g, 0.00115 mol) is added to a stirred solution of methyl 4-[[6-(4,4-difluoro-1-piperidyl)-3-methyl-pyridine-2-carbonyl]amino]-3,5-dimethyl-benzoate (0.24 g, 0.575 mmol) in THF:H2O:MeOH (1.5 ml:0.7 ml:1.5 ml). After 3 hours at 50° C., the organic solvent is removed under reduced pressure and the residue is diluted with water, acidified to pH 6 with aqueous 1N HCl, and extracted with ethyl acetate (3×20 ml). The organic layers are combined and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure and the resulting precipitate is triturated with diethyl ether and filtered to afford the title compound as a white solid (0.166 g, 71%). Mass spectrum (m/z): 404.2 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]=[CH:6][C:7]1[S:8][C:9]([N+:18]([O-])=O)=[C:10]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=1)[CH3:2]>O1CCOCC1.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2]>[CH2:1]([O:3][C:4](=[O:21])[CH:5]=[CH:6][C:7]1[S:8][C:9]([NH2:18])=[C:10]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1cc(CC(=O)OCC)c([N+](=O)[O-])s1
Agent: [Fe+2]
Agent: O=S(=O)([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)C=Cc1cc(CC(=O)OCC)c(N)s1
Yield: 71.5 %

Procedure:
Ethyl-4-[(ethoxycarbonyl)methyl]-5-nitro-2-thiopheneacrylate (230 mg, 0.74 mmol) was dissolved in aqueous dioxan (6 ml, 5:1 dioxan/water) and treated with reduced iron powder (0.4 g, 7.2 mmol) and iron sulfate heptahydrate (50 mg, 0.18 mmol). The reaction mixture was refluxed for 1 hour then filtered through celite and washed through with diethyl ether. The combined organics were then washed with saturated sodium hydrogen carbonate, saturated sodium chloride, dried over magnesium sulfate and evaporated to dryness. The residue was chromatographed on silica gel using hexane/ethyl acetate (2:1) as eluent to give 150 mg 3-(5-amino-4-ethoxycarbonylmethyl-thiophen-2-yl)-acrylic acid ethyl ester. MS(ES): m/e 284 [M+H].
Reaction SMILES: [CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[C:12](Br)[CH:13]=[CH:14][CH:15]=2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[B:32](OCC)([O:36]CC)[O:33]CC>O1CCCC1>[CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@H:9]1[CH2:10][C:11]2[C:12]([B:32]([OH:36])[OH:33])=[CH:13][CH:14]=[CH:15][C:16]=2[CH2:17][CH2:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc2c1C[C@H](N(Cc1ccccc1)Cc1ccccc1)CC2
Reactant: CCOB(OCC)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cccc2c1C[C@H](N(Cc1ccccc1)Cc1ccccc1)CC2
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 67 %

Procedure:
To a solution of (2R)-N,N-dibenzyl-8-bromo-1,2,3,4-tetrahydronaphthalen-2-amine (1000 mg, 2.46 mmol) in dry tetrahydrofuran (10 mL) under an atmosphere of nitrogen, n-butyllithium (1.6M, 2.3 mL, 3.69 mmol) was added over 5 min at −70° C. The reaction mixture was stirred at 0° C. for 10 min before triethyl borate (0.50 mL, 2.95 mmol) was added. The reaction mixture was stirred for additional 5 min at 0° C. and then allowed to reach ambient temperature and stirred for another 2 h. The reaction mixture was quenched with saturated ammonium chloride (aq) and a white precipitate was filtered off. The filtrate was extracted with ethyl acetate, the organic layer was dried over magnesium sulfate and concentrated in vacuo to yield 612 mg (67%) of the title compound as a solid: 1H NMR (400 MHz, CDCl3) δ ppm 8.31 (d, 1 H), 7.39-7.45 (m, 4 H), 7.28-7.37 (m, 2 H), 7.02-7.26 (m, 6 H), 3.65-3.92 (m, 4 H), 3.34-3.45 (m, 1 H), 2.70-3.19 (m, 4 H), 2.16 (br. s., 1 H), 1.66-1.79 (m, 1 H); MS (ESI) m/z 371, 372[M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]=[O:14])[CH:7]=[CH:6]2.[CH2:15]([Mg]Br)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[NH4+].[Cl-]>CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([OH:14])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc(C=O)ccc2c1
Reactant: CCCCCC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCCCCCC(O)c1ccc2cc(OC)ccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
To a 3-neck flask equipped with an overhead stirrer, dropping funnel and thermometer was added 6-methoxy-2-naphthaldehyde (70.760 g, 380 mmol) and Et2O (1400 mL). The stirred suspension under N2 was cooled in an ice bath followed by the slow addition of hexylmagnesium bromide (228 mL of a 2 M solution in Et2O) over 1 h. Temperature was kept below 12° C. After the addition, the reaction was stirred for 3 h at room temperature then cooled in an ice bath and slowly quenched w/saturated aq. NH4Cl (250 mL). After quenching, the ice bath was removed and the mixture was stirred for a half-hour then diluted with H2O (750 mL) to dissolve all solids. The layers were separated and the aqueous layer extracted with Et2O (3×200 mL). The combined organics were washed with water (3×200 mL), and brine (2×200 mL), dried over Na2SO4, filtered, rotovap'd and dried in vacuo to give the desired product as an off-white solid (101.1 g, 371.2 mmol, 98%) with mp 71-74° C. 15 g of crude alcohol was recrystallized from hexane to give the desired product as a white solid (11.7 g) with mp 71-73° C.; 1H NMR (DMSO-d6) δ 0.82 (t, J=6.7 Hz, 3H), 1.15-1.38 (m, 8H), 1.58-1.71 (m, 2H) 3.85 (s, 3H), 4.58-4.64 (m, 1H), 5.14 (d, J−4.3 Hz, 1H), 7.12 (dd, J=2.6, 9.0 Hz, 1H), 7.26 (d, 2.4 Hz, 1H), 7.42 (dd, J=1.5, 8.4 Hz, 1H), 7.70 (s, 1H), 7.74 (d, J=8.6 Hz, 1H), 7.77 (d, J=8.9 Hz, 1H), IR (solid) 3280, 2920, 2860, 1610, 1270, 1170, 1040, and 860 cm−1; mass spectrum [ESI], m/z 255 (MH−H2O)+; Anal. Calcd. for C18H24O2: C, 79.37; H, 8.88; N, 0.00, Found: C, 79.27; H, 8.94; N, −0.03.
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)=[C:12]([OH:22])[CH:11]=1)([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].N1C=CC=CC=1.[C:29](OC(=O)C)(=[O:31])[CH3:30].Cl.[C:37](OCC)(=[O:39])[CH3:38]>>[C:29]([N:18]1[CH2:19][CH2:20][CH2:21][CH:16]([C:13]2[CH:14]=[CH:15][C:10]([C:2]([CH3:1])([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:11][C:12]=2[O:22][C:37](=[O:39])[CH3:38])[CH2:17]1)(=[O:31])[CH3:30]
Reactant: CCCCCCC(C)(C)c1ccc(C2CCCNC2)c(O)c1
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCC(C)(C)c1ccc(C2CCCN(C(C)=O)C2)c(OC(C)=O)c1

Procedure:
To a solution of 2.0 g of 3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-piperidine in 20 ml. of pyridine at 10° C. is added 20 ml. of acetic anhydride and the mixture stirred under nitrogen for 18 hours. It is then poured onto ice/water and acidified with dilute hydrochloric acid. The product is isolated by extraction with ethyl acetate (2×100 ml). The combined extracts are washed with brine, dried (MgSO4) and evaporated to give the produce as an oil.
Reaction SMILES: C(=O)C(C)C.[CH2:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]([N:18]3[CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19]3)=[O:17])=[CH:12][CH:13]=2)[CH2:8][NH:7]1.N1C[CH:31]=[C:30]([C:33]2C=CC(NC(N3CC4C(=CC=CC=4)C3)=O)=CC=2)[CH2:29][CH2:28]1>>[CH3:31][CH:30]([CH3:33])[CH2:29][CH2:28][N:7]1[CH2:8][C:9]2[C:14](=[CH:13][CH:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19]3)=[O:17])[CH:10]=2)[CH2:6]1
Reactant: O=C(Nc1ccc(C2=CCNCC2)cc1)N1Cc2ccccc2C1
Reactant: O=C(Nc1ccc2c(c1)CNC2)N1Cc2ccccc2C1
Agent: CC(C)C=O
Product: CC(C)CCN1Cc2ccc(NC(=O)N3Cc4ccccc4C3)cc2C1

Procedure:
The title compound was prepared as described in Example 429, substituting 3-methylbutanal for isobutyraldehyde and N-(isoindolin-5-yl)isoindoline-2-carboxamide for N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)isoindoline-2-carboxamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.28 (s, 1H), 7.47 (s, 1H), 7.29-7.37 (m, 5H), 7.09 (d, J=8.1 Hz, 1H), 4.75 (s, 4H), 3.77-3.79 (m, 2H), 3.74-3.76 (m, 2H), 2.64 (t, J=7.5 Hz, 2H), 1.60-1.71 (m, 1H), 1.37-1.43 (m, 2H), 0.91 (d, J=6.6 Hz, 6H); MS (ESI(+)) m/e 350 (M+H)+.
Reaction SMILES: [C:1]([OH:7])([C:3](F)(F)F)=[O:2].[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([I:15])[C:10]=1[C:16]1[C:20]([C:21]([OH:23])=O)=[C:19]([CH3:24])[O:18][N:17]=1.CC[N:27]([CH2:30][CH3:31])CC>ClCCl>[CH3:24][C:19]1[O:18][N:17]=[C:16]([C:10]2[C:9]([F:8])=[CH:14][CH:13]=[CH:12][C:11]=2[I:15])[C:20]=1[C:21]([NH:27][C@H:30]1[CH2:31][CH2:24][CH2:19][C@@H:20]([CH2:3][C:1]([O:7][CH2:16][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:9]=2)=[O:2])[CH2:21]1)=[O:23]
Reactant: O=C(O)C(F)(F)F
Reactant: CCN(CC)CC
Reactant: Cc1onc(-c2c(F)cccc2I)c1C(=O)O
Solvent: ClCCl
Product: Cc1onc(-c2c(F)cccc2I)c1C(=O)N[C@H]1CCC[C@@H](CC(=O)OCc2ccccc2)C1
Yield: 86 %

Procedure:
In a fashion similar to that described for preparation 99, a compound from preparation 45 (5.1 g, 14.7 mmol), dichloromethane (30 mL), TFA (30 mL), dichloromethane (150 mL), 3-(2-fluoro-6-iodo-phenyl)-5-methylisoxazole-4-carboxylic acid (6.39 g, 17.49 mmol), and Et3N (6.03 mL, 43.4 mmol) gave the title compound (7.15 g, 86%) after column chromatography (silica gel, hexanes/EtOAc gradient). Mass Spectrum (ES+) (m/z) 577.0 [M+1].