Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[S:2]1[C:6]([NH2:7])=[CH:5][C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]1=2.[C:12]([C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1)#[N:13]>N1C=CC=CC=1.C(Cl)Cl>[S:2]1[C:6]([NH:7][S:20]([C:17]2[CH:16]=[CH:15][C:14]([C:12]#[N:13])=[CH:19][CH:18]=2)(=[O:22])=[O:21])=[CH:5][C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]1=2
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cc2ccccc2s1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1ccc(S(=O)(=O)Nc2cc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 77.6 %

Procedure:
To a stirred solution of compound 1-C (0.927 g, 5.0 mmol) in pyridine (10 mL) and methylene chloride (5 mL), cooled on an ice bath, was added 4-cyanobenzene-1-sulfonyl chloride (1.01 g, 5.0 mmol) portion-wise over 3 min. The reaction was allowed to warm slowly to ambient temperature and allowed to stir for 72 h. The reaction mixture was concentrated under reduced pressure, the crude residue was partitioned between EtOAc (100 mL) and 1N HCl (25 mL), the layers separated, the organic phase washed with brine (25 mL), dried over MgSO4, filtered and evaporated in vacuo. The crude residue was purified by flash column chromatography (SiO2) eluting with an EtOAc-heptane gradient to afford 1.22 g of compound 389-A as a tan-brown powder. 1H-NMR (DMSO-d6): δ 6.91 (s, 1H), 7.33-7.21 (m, 2H), 7.69-7.64 (m, 1H), 7.82-7.76 (m, 1H), 7.99-7.93 (m, 2H), 8.11-8.05 (m, 2H), 11.49 (br s, 1H); MS: m/z 313.1 (M-H)−.
Reaction SMILES: NCCCCN.Br[CH2:8][C:9]1[CH:28]=[CH:27][C:12]2[N:13]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[C:14](=[O:17])[CH2:15][O:16][C:11]=2[CH:10]=1.C[Si](Cl)(C)C.[C:34]([O:44][CH2:45][CH3:46])(=[O:43])[CH:35]=[CH:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[Cl-].[NH4+].[OH-].[NH4+]>O1CCCC1.[Cu]I>[O:17]=[C:14]1[N:13]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:12]2[CH:27]=[CH:28][C:9]([CH2:8][CH:36]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH2:35][C:34]([O:44][CH2:45][CH3:46])=[O:43])=[CH:10][C:11]=2[O:16][CH2:15]1
Reactant: CCOC(=O)C=Cc1ccccc1
Reactant: COc1ccc(CN2C(=O)COc3cc(CBr)ccc32)cc1
Agent: [Cu]I
Agent: C[Si](C)(C)Cl
Agent: NCCCCN
Solvent: C1CCOC1
Product: CCOC(=O)CC(Cc1ccc2c(c1)OCC(=O)N2Cc1ccc(OC)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of CuI in dry tetrahydrofuran under argon are added 1.1 equivalents of tetramethylene diamine and the reaction mixture stirred at room temperature for 15 minutes. The solution is cooled to −78° C. and the Grignard reagent prepared from 7-bromomethyl-4-p-methoxybenzyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine is added and the reaction mixture stirred for 15 minutes. Then, 2 equivalents of trimethylsilyl chloride and a solution of ethyl cinnamate in tetrahydrofuran are added and the reaction mixture is stirred while the temperature is allowed to rise to −30° C. After 18 hours the reaction is poured into a solution of ammonium chloride and ammonium hydroxide and extracted with dichloromethane. The extracts are washed with water, dried over sodium sulfate, evaporated and the product isolated by flash chromatography.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][Br:7].[C:8]1([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[Br:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OCCCCCc1ccccc1
Reactant: BrCCCCCBr
Product: BrCCCCCOCCCCCc1ccccc1

Procedure:
(3.2 g), b.p. 185°-195°/0.3 torr, from 1,5-dibromopentane (8.5 g) and benzenepentanol (2 g).
Reaction SMILES: C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1.Cl[C:24]1[C:25]2[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:26]=2[S:27][C:28]=1[C:29]([NH2:31])=[O:30].C(N)(=[S:40])C>CN(C=O)C.C(OCC)(=O)C>[SH:40][C:24]1[C:25]2[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:26]=2[S:27][C:28]=1[C:29]([NH2:31])=[O:30]
Reactant: CC(N)=S
Reactant: COc1ccc2sc(C(N)=O)c(Cl)c2c1
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc2sc(C(N)=O)c(S)c2c1
Temperature: 80 °C
Yield: 71 %

Procedure:
Diazabicycloundecene (DBU) (1.8 mL, 12.3 mmol) is added to a room temperature solution of 3-chloro-5-methoxybenzo[b]thiophene-2-carboxamide (1.0 g, 4.1 mmol) and thioacetamide (1.0 g, 13.1 mmol) in 10 mL of DMF. The mixture is warmed to 80° C. for 5.5 hours. The reaction mixture is allowed to cool and is diluted with ethyl acetate and washed with 1N HCl and water. The organic layer is extracted four times with 1N NaOH followed by water. The basic layers are combined and acidified with 6N HCl. The precipitate is filtered and washed with water. Recrystallization from ethyl acetate:hexane gives 3-mercapto-5-methoxybenzo[b]thiophene-2-carboxamide in 71% yield; mp=205° C. dec.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[C:5]([F:25])=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([CH:21]=[O:22])[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1>CO>[Cl:3][C:4]1[C:5]([F:25])=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([CH2:21][OH:22])[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CO
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.2 %

Procedure:
Sodium borohydride (0.046 g, 1.21 mmol) was added to a stirred suspension of 4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazoline-6-carbaldehyde (0.20 g, 0.604 mmol) in methanol (1 ml) at 0° C., over period of 5 minutes. The reaction mixture was allowed to stir at room temperature for 10 minutes and concentrated to dryness. The resulting grey solid was washed with water (2×1 ml) and dried to a constant weight under high vacuum at 40° C. to afford {4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methanol (0.2 g, 100%) as a grey solid; Mass Spectrum: (M+H)+ 334.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-:16].[K+]>C(O)(C)(C)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:14]([NH2:15])=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#CC1(c2cccc(Br)c2)CCCCC1
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: NC(=O)C1(c2cccc(Br)c2)CCCCC1
Temperature: 0 °C

Procedure:
With overhead stirrer, a mixture of crude product from step 1, above, (380 g, 1207 mmol), powdered KOH (720 g) and t-BuOH (2.5 L) was heated at reflux overnight. See Hall, J. H.; Gisler, M. A simple method for converting nitriles to amides. Hydrolysis with potassium hydroxide in tert-butyl alcohol. J. Org. Chem. 1976, 41, 3769-3770. If deemed complete by GC analysis, it was cooled with ice-water (cool slowly to avoid shock to the glass), quenched with ice-water (1500 mL). The quenched mixture was then extracted with MTBE (3.5 L+1.5 L). MTBE layers were concentrated to a yellow solid, 390 g.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:11](=O)[CH:10]=[CH:9][C:7](=O)[C:5]=2[CH:6]=1.C1(=O)OC(=O)C2=CC=CC=C12.S(=O)(=O)(O)O>>[CH:6]1[C:5]2[C:4](=[CH:11][CH:10]=[CH:9][CH:7]=2)[CH:3]=[CH:2][CH:1]=1
Reactant: O=C1C=CC(=O)c2ccccc21
Agent: O=C1OC(=O)c2ccccc21
Agent: O=S(=O)(O)O
Product: c1ccc2ccccc2c1

Procedure:
The foregoing and other objects of the present invention have been attained by separating naphthoquinone having a purity of higher than 95% and phthalic acid from an aqueous slurry prepared by contacting a reaction mixture gas containing naphthoquinone, phthalic anhydride and sulfuric acid formed by a catalytic vapor phase oxidation of naphthalene with an aqueous medium, by adjusting the pH of the aqueous slurry to 1.2 to 5 and extracting the aqueous slurry with a chain or cyclic saturated hydrocarbon at 60° to 110° C. under the condition of substantially dissolving phthalic acid in the aqueous phase thereby separating a naphthoquinone solution phase, an aqueous phthalic acid solution phase and a resinous material phase.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][CH:3]=1.[C:16]([C:19]1[S:23][C:22](B(O)O)=[CH:21][CH:20]=1)(=[O:18])[CH3:17].C(=O)([O-])O.[Na+].O>C(COC)OC.O>[CH3:15][C:13]1[CH:12]=[CH:11][N:10]=[C:9]([NH:8][C:6]2[N:7]=[C:2]([C:22]3[S:23][C:19]([C:16](=[O:18])[CH3:17])=[CH:20][CH:21]=3)[CH:3]=[CH:4][CH:5]=2)[CH:14]=1
Reactant: CC(=O)c1ccc(B(O)O)s1
Reactant: Cc1ccnc(Nc2cccc(Br)n2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(=O)c1ccc(-c2cccc(Nc3cc(C)ccn3)n2)s1
Temperature: 130 °C
Reaction time: 12 h
Yield: 36.3 %

Procedure:
A suspension of (6-bromopyridin-2-yl)-(4-methylpyridin-2-yl)amine (1.00 g, 3.79 mmol), 5-acetylthiophene-2-boronic acid (644 mg, 3.79 mmol), tetrakis triphenylphosphine palladium (440 mg, 0.38 mmol), sodium hydrogen carbonate (480 mg, 5.68 mmol) in dimethoxyethane-water (12 ml) was heated and stirred in an Ar stream at 130° C. for 12 hours. Water was added to the reaction solution and extracted with ethyl acetate. After the organic layer was washed with a saturated brine and dried over anhydrous magnesium sulfate, the residue obtained by concentration in vacuo was washed with tetrahydrofuran-ethyl acetate (1:1), dried, and the title compound (426 mg, 36%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:19]([C:20]4[CH:25]=[CH:24][C:23]([N+]([O-])=O)=[CH:22][CH:21]=4)[CH2:18][CH2:17][C@@:14]4([C:15]=2[CH:16]=1)[C@H:9]3[CH2:10][CH2:11][CH2:12][CH2:13]4.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.CCCCCC.O(C(C)(C)C)[Na]>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:18][CH2:17][C@@:14]4([C:15]=2[CH:16]=1)[C@H:9]3[CH2:10][CH2:11][CH2:12][CH2:13]4
Reactant: COc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(c1ccc([N+](=O)[O-])cc1)CC3
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)O[Na]
Solvent: CCCCCC
Product: COc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(c1ccccc1)CC3

Procedure:
Similar to the preparation of the compound of Example 13, the title compound is made from the reaction of Pd(OAc)2 (1.34 mg, 0.006 mmol), 10% solution of P(t-Bu)3 in hexane (0.015 ml, 0.0048 mmol), and NaO-t-Bu (86.4 g, 0.9 mmol) in the presence of argon and then a solution of (+)-3-methoxy-morphinan (0.1645 g, 0.5 mmol) and bromobenzene (0.094 g, 0.6 mmol) in toluene (˜12 mL).
Reaction SMILES: [OH-].[NH4+:2].[CH:3]1[C:8]([CH:9]=O)=[CH:7][C:6]2[O:11][CH2:12][O:13][C:5]=2[CH:4]=1.OO.S([O-])([O-])=O.[Na+].[Na+]>C(O)(C)C.O.C(Cl)(Cl)Cl.CCCCCCCCCCCCCCCC>[C:9](#[N:2])[C:8]1[CH:3]=[CH:4][C:5]2[O:13][CH2:12][O:11][C:6]=2[CH:7]=1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: [NH4+]
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: N#Cc1ccc2c(c1)OCO2
Yield: 30.7 %

Procedure:
To a stirred mixture of 200 ml of isopropanol and 1.36 g of cupric chloride at 17-23° C. was added dropwise 58 g (0.487 mole) of 29.4% aqueous ammonium hydroxide over a period of 190 min. Parallel to the addition of ammonium hydroxide, a solution of 601 g of 99% piperonal (0.396 mole) and 1.0 g of hexadecane (internal standard) in 100 ml of isopropanol was added over a period of 147 min. Parallel to the additions of ammonium hydroxide and piperonal, 150 g (2.2 moles) of 50% aqueous hydrogen peroxide was added over a period of 590 min. After the additions were finished, the mixture was worked up by stirring for 1 hour with 10% aqueous sodium sulfite, and diluted with water and chloroform. The organic layer was separated, the water layer was extracted with chloroform. After evaporation of the solvent, the weight of the crude solid product was 36.4 g (crude yield about 60%). Recrystallization of the crude from boiling heptane gave 17.9 g of crystalline piperonylonitrile; yield 30.7% of the theory.
Reaction SMILES: [CH3:1][C:2]1([CH2:6][N:7]2[CH:11]=[C:10]([N+:12]([O-])=O)[N:9]=[CH:8]2)[CH2:5][O:4][CH2:3]1.[F:15][C:16]1[CH:17]=[C:18]([CH2:23][C:24]([NH:26][CH:27]([CH2:31][CH2:32][CH3:33])[C:28](O)=[O:29])=[O:25])[CH:19]=[C:20]([F:22])[CH:21]=1>>[CH3:1][C:2]1([CH2:6][N:7]2[CH:11]=[C:10]([NH:12][C:28](=[O:29])[C@@H:27]([NH:26][C:24](=[O:25])[CH2:23][C:18]3[CH:19]=[C:20]([F:22])[CH:21]=[C:16]([F:15])[CH:17]=3)[CH2:31][CH2:32][CH3:33])[N:9]=[CH:8]2)[CH2:5][O:4][CH2:3]1
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: CC1(Cn2cnc([N+](=O)[O-])c2)COC1
Product: CCC[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(CC2(C)COC2)cn1

Procedure:
1-(3-Methyl-oxetan-3-ylmethyl)-4-nitro-1H-imidazole was reduced and then coupled with 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid (U.S. Ser. No. 11/078,898 filed Mar. 11, 2005) to afford the title compound: MS 421.3 m/z (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:19](=[O:22])[CH2:20][CH3:21])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:23])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:41]=[C:40]3[C:35]([CH:36]=[CH:37][CH:38]=[N:39]3)=[CH:34][CH:33]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[C:19]([N:16]1[CH2:17][CH2:18][C@@H:14]([CH2:13][C:12]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([C:32]4[CH:41]=[C:40]5[C:35]([CH:36]=[CH:37][CH:38]=[N:39]5)=[CH:34][CH:33]=4)=[CH:3][CH:4]=3)[C:9](=[O:23])[NH:10][N:11]=2)[CH2:15]1)(=[O:22])[CH2:20][CH3:21]
Reactant: CCC(=O)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2)C1
Reactant: CC1(C)OB(c2ccc3cccnc3c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCC(=O)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4cccnc4c3)cc2)C1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
A solution of 4-(4-bromophenyl)-5-{[(3S)-1-propanoyl-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (0.171 mmol) in dioxane (2 mL) was treated with 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (0.176 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (15 mg), and 2M aq potassium carbonate (1 mL). The reaction mixture was purged with nitrogen, sealed, and stirred at 110° C. for 1 h. The reaction mixture was cooled to room temperature, diluted with water, neutralized with the dropwise addition of 6N aq HCl, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Reverse phase HPLC (10-70% acetonitrile/water+0.1% NH4OH) was utilized to purify the title compound (44 mg, 59%). MS(ES)+ m/e 427.8 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[C:22]([CH3:24])[C:21]([C:25]2[NH:33][C:28]3[CH2:29][NH:30][CH2:31][CH2:32][C:27]=3[N:26]=2)=[CH:20][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[O:34]1[CH2:37][C:36](=O)[CH2:35]1.[B-]C#N.[Na+].C(O)(=O)C>CO.C1COCC1.ClCCl>[CH3:1][C:2]1[CH:23]=[C:22]([CH3:24])[C:21]([C:25]2[NH:26][C:27]3[CH2:32][CH2:31][N:30]([CH:36]4[CH2:37][O:34][CH2:35]4)[CH2:29][C:28]=3[N:33]=2)=[CH:20][C:3]=1[C:4]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[CH:13]=[CH:14][C:15]([C:16]#[N:17])=[CH:18][CH:19]=2)[CH2:10][CH2:11]1)=[O:5]
Reactant: O=C1COC1
Reactant: Cc1cc(C)c(-c2nc3c([nH]2)CNCC3)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Agent: [B-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cc(C)c(-c2nc3c([nH]2)CCN(C2COC2)C3)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Reaction time: 16 h
Yield: 60 %

Procedure:
A mixture of 4-(1-(2,4-dimethyl-5-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 2.9, 62 mg), oxetan-3-one (18 μl), sodium cyanotrihydroborate (18 mg), and acetic acid (80 μl) in MeOH/THF (1:1 v/v) was stirred for 16 hours. The reaction was then diluted with dichloromethane, washed with saturated sodium bicarbonate solution followed by brine. The organic layer was dried (MgSO4) and concentrated. The residue was purified by preparative TLC at 8% MeOH in DCM to give 42 mg white solid (60%). m/z (ES+) 496 (M+H)+. 1H NMR (400 MHz, Chloroform-d) δ 7.63 (d, 2H), 7.32 (d, 2H), 7.27 and 7.20 (2 singlet, amide rotamers, 1H), 7.02 (s, 1H), 4.96 (s, 1H), 4.74 (m, 4H), 3.88-3.77 (m, 1H), 3.63 (d, 1H), 3.49 (d, 2H), 3.08 (t, 1H), 2.97-2.62 (m, 6H), 2.45 (d, 3H), 2.31 and 2.22 (2 singlets, amide rotamers, 3H), 2.11-1.40 (m, 4H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[CH3:14][C:15]([C:17]1[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=1)=[O:16].[OH-].[Na+]>CO>[CH2:1]([O:5][C:6]1[CH:13]=[CH:12][C:9](/[CH:10]=[CH:14]/[C:15]([C:17]2[CH:18]=[C:19]([O:27][CH3:28])[C:20]([O:25][CH3:26])=[C:21]([O:23][CH3:24])[CH:22]=2)=[O:16])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Reactant: CCCCOc1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCOc1ccc(/C=C/C(=O)c2cc(OC)c(OC)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.2 %

Procedure:
To a stirred solution of 4-butoxybenzaldehyde (1.64 ml, 9.5 mmol) and 3,4,5-trimethoxyacetophenone (2.0 g, 9.5 mmol) in methanol (30 ml) was added 50% w/v of aqueous sodium hydroxide (7.6 ml, 0.095 mol). The reaction was stirred for 24 h at room temperature. A precipitate was isolated by filtration, washed with pet:ether and subsequently recrystallised from ethanol to give 3.0 g (85%) of a pale yellow powder. 1H-NMR (CDCl3) δ 7.8 (d, 1H), 7.6 (d, 2H), 7.4 (d, 1H), 7.25 (d, 2H), 7.0 (d, 2H), 4.05 (t, 2H), 4.0 (s×2, 9H), 1.8 (m, 2H), 1.5 (m, 2H), 1.0 (t, 3H). Mass Spectrum m/e (M+1) 370.
Reaction SMILES: CS(O)(=O)=O.[C:6]([NH:10][CH:11]1[CH2:15][C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]=[CH:12]1)([CH3:9])([CH3:8])[CH3:7].[OH-].[Na+]>C(OCC)(=O)C>[C:6]([NH:10][CH:11]1[CH2:12][CH2:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:15]1)([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)NC1C=CC(c2ccccc2)(c2ccccc2)C1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)(C)NC1CCC(c2ccccc2)(c2ccccc2)C1
Yield: 100 %

Procedure:
To a suspension of (-)-N-t-butyl-4,4-diphenyl-2-cyclopentenylamine methanesulfonate (0.70 g) in ethyl acetate was added 2N sodium hydroxide aqueous solution (10 ml), and the organic layer was separated. The solution was washed with brine and hydrogenated over 10% palladium-on-carbon (0.06 g) to give (-)-N-t-butyl-3,3-diphenylcyclopentylamine (0.53 g). To a solution of (-)-N-t-butyl-3,3-diphenylcyclopentylamine (0.53 g) in chloroform was added a solution of methanesulfonic acid (174 mg) in methanol. The solvent was evaporated in vacuo and triturated with diethyl ether to give (-)-N-t-butyl-3,3-diphenylcyclopentylamine methanesulfonate (0.63 g).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C@@H:13]([OH:42])[C@@H:14]1[O:18][C@@H:17]([C@H:19]([OH:41])[CH2:20][CH2:21][CH2:22][CH2:23][C:24]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C@@H:31]([OH:40])[CH2:32][C:33]2[C:37](=[O:38])[O:36][C@@H:35]([CH3:39])[CH:34]=2)=[O:25])[CH2:16][CH2:15]1.[CH3:43][O:44][CH2:45]Cl>C(N(C(C)C)CC)(C)C>[CH3:43][O:44][CH2:45][O:40][CH:31]([CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][C:24](=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]([O:41][CH2:35][O:36][CH3:37])[CH:17]1[CH2:16][CH2:15][CH:14]([CH:13]([O:42][CH2:17][O:18][CH3:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[O:18]1)[CH2:32][C:33]1[C:37](=[O:38])[O:36][CH:35]([CH3:39])[CH:34]=1
Reactant: CCCCCCCCCCCC[C@@H](O)[C@H]1CC[C@H]([C@H](O)CCCCC(=O)CCCCC[C@@H](O)CC2=C[C@H](C)OC2=O)O1
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCCCC(OCOC)C1CCC(C(CCCCC(=O)CCCCCC(CC2=CC(C)OC2=O)OCOC)OCOC)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of annonacinone (595 mg, 1.0 mmol) in diisopropylethylamine (7 mL) is stirred at room temperature while chloromethyl methyl ether (360 mg, 4.5 mmol) is added. The mixture is stirred at room temperature for eight hours, concentrated in vacuo, and the residue is partitioned between water (50 mL) and ethyl acetate (50 mL). The aqueous phase is separated and extracted with ethyl acetate (2×50 mL) and the combined organic fractions are washed (1× water), dried (saturated aqueous NaCl, sodium sulfate), filtered, and concentrated. Chromatography (hexane-2:1 hexane:ethyl acetate gradient over silica gel 230-400 mesh) affords 3-{2,13-bis(methoxymethyloxy)-13-[tetrahydro-5-(1-methoxymethyloxytridecyl) furan-2-yl]tridecan-8-on-1-yl}-5-methyl-2-(5H)-furanone.
Reaction SMILES: [ClH:1].C([O:9][C:10]1[CH:33]=[CH:32][C:13]([O:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][C:20]([OH:31])([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)[CH2:19][CH2:18]2)=[CH:12][CH:11]=1)C1C=CC=CC=1.[H][H].CCOCC>CO.[OH-].[OH-].[Pd+2]>[ClH:1].[OH:9][C:10]1[CH:11]=[CH:12][C:13]([O:14][CH2:15][CH2:16][N:17]2[CH2:18][CH2:19][C:20]([OH:31])([CH2:23][C:24]3[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=3)[CH2:21][CH2:22]2)=[CH:32][CH:33]=1
Reactant: [H][H]
Reactant: Cc1ccc(CC2(O)CCN(CCOc3ccc(OCc4ccccc4)cc3)CC2)cc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Product: Cc1ccc(CC2(O)CCN(CCOc3ccc(O)cc3)CC2)cc1
Reaction time: 8 h
Yield: 99.9 %

Procedure:
1-[2-(4-Hydroxyphenoxy)ethyl]-1-hydroxy-4-(4-methylbenzyl)piperidine hydrochloride. To a solution of 1-[2-(4-benzyloxyphenoxy)ethyl]-4-hydroxy-4-(4-methylbenzyl)piperidine hydrochloride (0.25 g, 0.53 mmol) in 30 mL of methanol was added 62.5 mg of 20% Pd(OH)2. The resulting mixture was hydrogenated at 20 psi of hydrogen for 3 h. The catalyst was removed through a short column of celite (5 g) and washed with methanol (3×15 mL). Methanol was evaporated in vacuo to give a residue, to which 50 mL of ether was added. The resulting mixture was stirred overnight. A white solid was collected by filtration and dried in vacuo, giving 200 mg (100%) of the title product: mp 133-135° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:5])[CH3:2].[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C([O-])(O)=O.[Na+]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1.CCO>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:21]1[CH:22]=[CH:23][C:18]([C:17]([F:28])([F:27])[F:16])=[CH:19][CH:20]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)c1cc2cc(Br)ccc2[nH]1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1cc2cc(-c3ccc(C(F)(F)F)cc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 5-bromoindole-2-carboxylic acid ethyl ester (4.22 g, 16 mmol), 4-trifluoromethylphenylboronic acid (4.50 g, 24 mmol), K3PO4 (11.7 g, 55 mmol), Pd(OAc)2 (176 mg, 0.78 mmol), tri-o-tolylphosphine (478 mg, 1.6 mmol), EtOH (20 mL) and toluene (90 mL) was stirred under argon for 20 min at rt, heated at 100° C. for 2 h, cooled and poured into NaHCO3 (aq, sat). The mixture was extracted with EtOAc and the combined extracts were washed with H2O and brine, dried (Na2SO4), concentrated and purified by chromatography to give the sub-title compound. Yield 3.91 g (75%).