Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][C:3]=1[S:16]([N:19]([C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=1[CH3:31])[CH2:20][CH:21]([CH3:23])[CH3:22])(=[O:18])=[O:17].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[OH-:62].[K+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:31][C:25]1[CH:26]=[C:27]([CH3:30])[CH:28]=[CH:29][C:24]=1[N:19]([CH2:20][CH:21]([CH3:23])[CH3:22])[S:16]([C:3]1[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:7][C:2]=1[OH:62])(=[O:18])=[O:17]
Reactant: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(OCC3CCOCC3)cc2Cl)c(C)c1
Reactant: [OH-]
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(OCC3CCOCC3)cc2O)c(C)c1
Temperature: 150 °C

Procedure:
2-chloro-N-(2,4-dimethylphenyl)-N-isobutyl-4-((tetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide (200 mg, 0.429 mmol), tris(dibenzylideneacetone)dipalladium(0) (3.93 mg, 4.29 μmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (1.822 mg, 4.29 μmol) and potassium hydroxide (72.2 mg, 1.287 mmol) were added to a microwave vial. The reactants where dissolved in 1,4-dioxane (1.2 mL) and water (1.2 mL). The reaction vessel was sealed and heated by microwaves (Biotage Initiator) to 150° C. for 2 hours. The reaction mixture was concentrated in vacuo, 2N NaOH was added and the reaction was diluted with ethyl acetate. The organic phase was separated and was washed with 2N HCl. The organic phase was separated, dried using a hydrophobic frit and evaporated in vacuo to give the crude product as a yellow oil. The crude was purified by mass directed autoprep (ammonium carbonate modifier). The relevant fractions were then concentrated under a stream of nitrogen to give the required product, 32 mg. LCMS [LCMS2] Rt 1.51 min, m/z (ES+) 448 (M+H).
Reaction SMILES: [C@H:1]1([OH:8])[CH2:6][CH2:5][C@H:4]([OH:7])[CH2:3][CH2:2]1.N1C=CN=C1.[C:14]([Si:18]([CH3:21])([CH3:20])Cl)([CH3:17])([CH3:16])[CH3:15]>CN(C)C=O>[C:14]([Si:18]([CH3:21])([CH3:20])[O:7][C@H:4]1[CH2:5][CH2:6][C@H:1]([OH:8])[CH2:2][CH2:3]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O[C@H]1CC[C@H](O)CC1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](O)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of trans-1,4-cyclohexanediol (3 g, 26 mmol) in anhydrous N,N-dimethylformamide (30 mL) at 0° C. was added imidazole (1.7 g, 26 mmol) and tert-butyldimethylchlorosilane (3.87 g, 26 mmol). The reaction mixture was then stirred at 0° C. for 1 h. The mixture was partitioned between ethyl acetate and water. Organic layer was separated, aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc:hexanes=1;2) to give trans-4-(tert-buyl-dimethyl-silanyloxy)-cyclohexanol as a white solid (3.9 g, 65%).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].ClC(Cl)(Cl)[C:11]([C:13]([F:16])([F:15])[F:14])=[O:12]>CS(C)=O>[F:14][C:13]([F:16])([F:15])[C:11]([NH:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])=[O:12]
Reactant: O=C(C(F)(F)F)C(Cl)(Cl)Cl
Reactant: CC(C)[C@H](N)C(=O)O
Solvent: CS(C)=O
Product: CC(C)[C@H](NC(=O)C(F)(F)F)C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 94 %

Procedure:
A mixture of 7.4 mmol of L-valine, 10 ml of dimethyl sulfoxide and 23 mmol of sym-trichlorotrifluoroacetone was stirred at room temperature for 24 hours in a flask protected from atmospheric moisture. A complete solution was obtained within the first hour. The progress of the reaction was followed by taking samples periodically and submitting them to gas-liquid chromatographic analysis. The reaction mixture was poured into 50 ml of ice water and the resultant mixture was extracted thrice with n-butanol and chromatographed on a column packed with silica gel. N-trifluoroacetylvaline, melting at 88°-89° C., was obtained in a yield of 94 percent.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5]([N+:9]([O-])=O)=[CH:6][C:7]=1[Cl:8].[OH-].[NH4+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5]([NH2:9])=[CH:6][C:7]=1[Cl:8]
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1O
Agent: O=S([O-])S(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Product: Nc1cc(Cl)c(Cl)cc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
106 g of 9A was suspended in 636 ml of water. 233 ml of ammonium hydroxide was added. 239.2 g of sodium dithionite was added over a period of about two hours at such a rate that the temperature of the reaction mixture was kept at about 50° C. The mixture was stirred at room temperature for two hours. The solid product was filtered, and extracted with methanol. Evaporation of the solvent from the extract gave 3,4-dichloro-6-aminophenol (9B).
Reaction SMILES: [C:1]1([CH:7]2[CH2:15][C:14]3[C:9](=[C:10]([Cl:19])[C:11]([Cl:18])=[C:12]([O:16]C)[CH:13]=3)[C:8]2=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.N1C=CC=CC=1.Cl>>[C:1]1([CH:7]2[CH2:15][C:14]3[C:9](=[C:10]([Cl:19])[C:11]([Cl:18])=[C:12]([OH:16])[CH:13]=3)[C:8]2=[O:20])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(c1ccccc1)C2
Agent: Cl
Solvent: c1ccncc1
Product: O=C1c2c(cc(O)c(Cl)c2Cl)CC1c1ccccc1
Yield: 75 %

Procedure:
A stirred mixture of 2-phenyl-5-methoxy-6,7-dichloro-1-indanone (5.18 g., 16.8 mmol) and pyridine hydrochloride (23.3 g., 202 mmol) is heated at 190° for a period of 2 hrs. and then poured into 300 ml. of cold 2 N hydrochloric acid. Insolubles are collected, dried and crystallized from ethanol to afford 3.7 g. (75% yield) of 2-phenyl-5-hydroxy-6,7-dichloro-1-indanone, m.p. 252°-253.5°.
Reaction SMILES: [C:1]1([CH3:9])[C:2]([CH:7]=O)=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH3:10][N:11]([CH3:13])[NH2:12]>C1(C)C=CC=CC=1>[CH3:10][N:11]([CH3:13])[N:12]=[CH:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:9]
Reactant: Cc1ccccc1C=O
Reactant: CN(C)N
Solvent: Cc1ccccc1
Product: Cc1ccccc1C=NN(C)C
Yield: 93.9 %

Procedure:
A stirred solution of o-tolualdehyde (25.0 g, 0.21 mol), and 1,1-dimethyl hydrazine (25.2 g, 0.42 mol) was refluxed in toluene (200 mL) for 24 h. The solution was concentrated in vacuo and the residual oil was vacuum distilled (51°-60° C., 0.2 mm Hg) to afford the tided product (31.98 g, 94%): IR (neat) 2950, 2850, 1580, 1550, 1455, 1025, 745 cm-1; 1H NMR (CDCl3, 400 MHz) δ 7.8-7.6 (m, 1H), 7.4-7.3 (m, 1H), 7.1-6.9 (m, 3H), 2.9 (s, 6H), 2.4 (s, 3H).
Reaction SMILES: C[Si](OS(C(F)(F)F)(=O)=O)(C)C.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][CH2:23][CH2:24][C:25]2(O)[CH2:30][CH2:29][C:28]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([N:31]([CH3:33])[CH3:32])[CH2:27][CH2:26]2)=[CH:14]1>ClCCl>[CH2:34]([C:28]1([N:31]([CH3:33])[CH3:32])[CH2:29][CH2:30][C:25]2([C:14]3[NH:13][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]=3[CH2:22][CH2:23][CH2:24]2)[CH2:26][CH2:27]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CN(C)C1(Cc2ccccc2)CCC(O)(CCCc2c[nH]c3ccccc23)CC1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)C1(Cc2ccccc2)CCC2(CCCc3c2[nH]c2ccccc32)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Trifluoromethane sulphonic acid trimethylsilyl ester (1.30 mL, 1.59 g, 7.16 mmol) was added to a solution of 1-(3-(1H-indol-3-yl)propyl)-4-benzyl-4-(dimethylamino)cyclohexanol (700 mg, 1.79 mmol) in anhydrous dichloromethane (30 mL) and stirred for 2 d at room temperature. The reaction mixture was then diluted with dichloromethane (10 mL), and firstly washed with 1 N sodium carbonate solution (2×10 mL), then with water and saturated sodium chloride solution (10 mL each), dried with sodium sulphate and concentrated to low volume in a vacuum. The residue was taken up in methanol (30 mL), stirred over the weekend at room temperature and decanted off from the separated precipitate (fraction 1). The solution was concentrated to low volume, the residue taken up in methanol (2×10 mL) and decanted off from the precipitated solid again in each case. The remaining solution was concentrated to low volume in a vacuum, as a result of which fraction 2 was obtained.
Reaction SMILES: B(Br)(Br)Br.ClCCl.[F:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[O:18]C)[CH:14]([CH2:20][CH2:21][NH:22][C:23](=[O:26])[CH2:24][CH3:25])[CH2:13][CH2:12]2>O>[F:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[OH:18])[CH:14]([CH2:20][CH2:21][NH:22][C:23](=[O:26])[CH2:24][CH3:25])[CH2:13][CH2:12]2
Reactant: CCC(=O)NCCC1CCc2cc(F)c(OC)cc21
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCC(=O)NCCC1CCc2cc(F)c(O)cc21
Reaction time: 2 h
Yield: 92.7 %

Procedure:
Boron tribromide (7.9 g, 31.5 mmols) was gradually and dropwise added to a dichloromethane (100 ml) solution of N-[2-(5-fluoro-6-methoxyindan-1-yl)ethyl]propionamide (4.18 g, 15.8 mmols) while cooling with ice. After having been stirred for 2 hours while still cooling with ice, the reaction mixture was poured into water containing ice and then stirred at room temperature for 3 hours, and the organic substance was extracted with ethyl acetate. The extract was washed with a saturated saline solution and water and then dried with anhydrous magnesium sulfate, and the solvent was removed through distillation under reduced pressure. The resulting residue was purified through silica-gel column chromatography (ethyl acetate/hexane=9/1) to obtain 3.68 g (yield: 93%) of the target compound.
Reaction SMILES: [Br:1][C:2]1[C:3]2[O:19][CH:18]([CH2:20][OH:21])[CH2:17][C:4]=2[C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]=2[CH:16]=1.O.S(=O)(=O)(O)[OH:24]>CC(C)=O.[O-2].[Cr+6].[O-2].[O-2]>[Br:1][C:2]1[C:3]2[O:19][CH:18]([C:20]([OH:24])=[O:21])[CH2:17][C:4]=2[C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:6]=2[CH:16]=1
Reactant: O=S(=O)(O)O
Reactant: OCC1Cc2c(c(Br)cc3c(-c4ccccc4)noc23)O1
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)C1Cc2c(c(Br)cc3c(-c4ccccc4)noc23)O1
Temperature: 25 °C
Reaction time: 6 h
Yield: 54.9 %

Procedure:
A portion (0.7 g) of the 5-bromo-7,8-dihydro-3-phenylfuro[2,3-g]-1,2-benzisoxazole-7-methanol prepared in Example 4 was dissolved in 50 ml of acetone. To the stirred solution, a mixture of chromium (VI) oxide (1 g), water (3 ml) and concentrated sulfuric acid (1.4 g) was added dropwise over time, and the solution was stirred for 6 hours at room temperature. The insolubles were filtered off by suction. After distilling off the acetone, water was added to the residue and the mixture was subjected to extraction with ether. The ether layer was washed with water and dried. After distilling off the solvent, the residue was recrystallized with acetone-water, yielding 0.4 g of 5-bromo-7,8-dihydro-3-phenylfuro[2,3-g]-1,2-benzisoxazole-7-carboxylic acid. m.p. 241.5°-243.5° C. (with decomposition).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[C:14](I)=[CH:13][N:12]=[C:11]([NH2:16])[N:10]=2)[CH2:4][CH2:3]1.[Cl:18][C:19]1[C:20]([O:28][CH3:29])=[N:21][CH:22]=[CH:23][C:24]=1B(O)O.N#N.C(=O)([O-])[O-].[Na+].[Na+].C([O-])(O)=O.[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[Cl:18][C:19]1[C:20]([O:28][CH3:29])=[N:21][CH:22]=[CH:23][C:24]=1[C:14]1[C:9]([NH:8][CH:5]2[CH2:6][CH2:7][C:2]([CH3:17])([CH3:1])[CH2:3][CH2:4]2)=[N:10][C:11]([NH2:16])=[N:12][CH:13]=1
Reactant: CC1(C)CCC(Nc2nc(N)ncc2I)CC1
Reactant: COc1nccc(B(O)O)c1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N#N
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: COc1nccc(-c2cnc(N)nc2NC2CCC(C)(C)CC2)c1Cl
Temperature: 80 °C
Yield: 81.7 %

Procedure:
To a 50 mL single-necked round bottom flask were placed compound 326 (0.80 g, 2.3 mmol), 3-chloro-2-methoxypyridin-4-ylboronic acid (1.3 g, 6.9 mmol), and trans-dichlorobis(triphenyl-phosphine)palladium (ii) (0.16 g, 0.23 mmol). The flask was subjected to 3 cycles of evacuation and back-filling with N2. 1,4-Dioxane (12 mL) was added followed with sodium carbonate (2 N aqueous solution) (5.8 mL, 12 mmol). The resulting mixture was heated in an oil bath at 80° C. for 18 h. Upon workup, the mixture was poured into ice and saturated NaHCO3 aqueous solution and extracted with ethyl acetate (3×). The combined organics were dried over Na2SO4 and concentrated in vacuo. The residue was subjected to combi-flash column chromatography (methanol/DCM) to give compound 332 (0.68 g, 81% yield) as a light yellow solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.09 (1 H, d, J=5.1 Hz), 7.48 (1 H, s), 6.92 (1 H, d, J=5.1 Hz), 6.13 (2 H, s), 5.79 (1 H, d, J=8.3 Hz), 3.91-4.02 (4 H, m), 1.26-1.63 (6 H, m), 1.13-1.25 (2 H, m), 0.88 (6 H, d, J=9.8 Hz). LCMS-ESI (POS), M/Z, M+1: Found 362.0.
Reaction SMILES: [C:1]([CH:6]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:3][CH2:4][CH3:5])=[O:2].[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH:31]=O>ClCCl>[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH:31]=[CH:6][C:1]([O:3][CH2:4][CH3:5])=[O:2]
Reactant: COc1ccc(C=O)cc1OC
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C=Cc1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Carbethoxymethylene triphenylphosphorane (150 g, 0.3 mol) was added to a solution of 3,4-dimethoxybenzaldehyde (50 g, 0.3 mol) in dry dichloromethane (150 ml), and the mixture was stirred at room temperature overnight. The solution was concentrated to about 50 ml, and the precipitate was filtered off and washed with hexane-dichloromethane (4:1, v/v). The combined filtrates were evaporated to a residue, which was purified by silica gel chromatography using hexane-ethyl acetate (9:1, v/v) as the eluant. The title compound was isolated as a crystalline mass (65 g, 91%), m.p. 52°-53° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12]O)=[CH:4][N:3]=1.C(Br)(Br)(Br)[Br:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCOCC1>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][Br:15])=[CH:4][N:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: Nc1ncc2ncn(CCO)c2n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: Nc1ncc2ncn(CCBr)c2n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
17.92 g (0.1 mole) of 2-amino-9-(2-hydroxyethyl)purine was completely dissolved in 200 ml of 1,4-dioxane. The solution was added with 49.75 g (0.15 mole) of carbon tetrabromide and cooled below 5° C. To the cooled material, 39.34 g (0.15 mole) of triphenylphosphine was added, followed by stirring for 5 hours at room temperature. After completion of the reaction, 300 ml of water was added to the reaction product, which was then extracted four times with 500 ml portions of a mixed solution of chloroform and methanol (4:1). The organic layer was collected, and dried with anhydrous magnesium sulfate, followed by filtration and washing. The resulting filtrate was concentrated under reduced pressure, and crystallized from chloroform, 15.74 g (65%) of white 2-amino-9-(2-bromoethyl)purine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[C:10](\[CH3:14])/[C:11](O)=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].Cl.[CH3:16][NH:17][O:18][CH3:19].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[C:10](\[CH3:14])/[C:11]([N:17]([O:18][CH3:19])[CH3:16])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C/C(=C\c1ccc(F)c(Cl)c1)C(=O)O
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)C(=O)/C(C)=C/c1ccc(F)c(Cl)c1
Yield: 47.9 %

Procedure:
A mixture of Example 9B (11.9 g, 55.45 mmol), N,O-dimethylhydroxylamine hydrochloride (5.7 g, 58 mmol), 1-hydroxybenzotriazole hydrate (7.88 g, 53.8 mmol), 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (11 g, 57.58 mmol) and diisopropylethyl amine (47.4 g, 63.9 mL, 370 mol) was stirred in DMF (400 mL) at ambient temperature overnight. The solution was diluted with water and extracted with ethyl acetate. The combined organic extract was washed with saturated sodium bicarbonate solution, 1N HCl, water, brine, dried over Na2SO4, filtered, and evaporated in vacuo. The resulting material was chromatographed (SiO2, 20% ethyl acetate/hexanes to 50% ethyl acetate/hexanes) to leave the title compound (6.85 g, 48% yield). 1H NMR (300 MHz, CDCl3) δ ppm 7.39 (dd, J=7.12, 2.37 Hz, 1H), 7.10-7.21 (m, 2H), 6.71 (s, 1H), 3.69 (s, 3H), 3.28 (s, 3H), 2.10 (s, 3H). MS (DCI+) 258 (M+H).
Reaction SMILES: [CH3:1][CH:2]([CH:7]([CH3:9])[CH3:8])[C:3](=[CH2:6])[CH:4]=[O:5].[CH2:10]=[CH:11][C:12](=[CH2:14])[CH3:13]>>[CH3:1][CH:2]([C:3]1([CH:4]=[O:5])[CH2:10][CH2:11][C:12]([CH3:14])=[CH:13][CH2:6]1)[CH:7]([CH3:9])[CH3:8]
Reactant: C=C(C=O)C(C)C(C)C
Reactant: C=CC(=C)C
Product: CC1=CCC(C=O)(C(C)C(C)C)CC1
Temperature: 160 °C
Reaction time: 12 h
Yield: 49 %

Procedure:
3,4-Dimethyl-2-methylene-pentanal (550 g, obtained as detailed above) and 393 g of isoprene were charged to a Parr Bomb, heated to 160° C., and aged for 12 hours. The rushed over material provided ˜32% recovery of 1-(1,2-dimethyl-propyl)-4-methyl-cyclohex-3-enecarbaldehyde (415 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]=[O:12])=[C:8]([CH3:13])[C:7]=2[CH:14]=1.[CH2:15]([Mg]Br)[CH:16]([CH3:18])[CH3:17].[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([OH:12])[CH2:15][CH:16]([CH3:18])[CH3:17])=[C:8]([CH3:13])[C:7]=2[CH:14]=1
Reactant: COc1ccc2oc(C=O)c(C)c2c1
Reactant: CC(C)C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc2oc(C(O)CC(C)C)c(C)c2c1
Reaction time: 1 h
Yield: 62 %

Procedure:
To a solution (4.0 mL) of 5-methoxy-3-methyl-1-benzofuran-2-carbaldehyde (1.91 g) synthesized in Example A27(2) in tetrahydrofuran was added a solution (15.0 mL) of 1.0M isobutylmagnesium bromide in tetrahydrofuran at 0° C., and the mixture was stirred for 1 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, tetrahydrofuran was evaporated in an evaporator, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate/hexane) to give the title object compound (1.53 g, 62%) as a yellow oil.
Reaction SMILES: [CH3:1][Mg]Cl.[O:4]=[C:5]([CH3:32])[CH2:6][CH:7]([C:20]1[CH:21]=[C:22]([Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[O:23][CH:24]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>O1CCCC1>[OH:4][C:5]([CH3:1])([CH3:32])[CH2:6][CH:7]([C:20]1[CH:21]=[C:22]([Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:26])[CH3:27])[O:23][CH:24]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCCC(CC(C)=O)c1coc([Si](C)(C)C(C)(C)C)c1
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(CC(C)(C)O)c1coc([Si](C)(C)C(C)(C)C)c1

Procedure:
A mixture of methylmagnesium chloride (a 3 M solution in tetrahydrofuran; 0.68 ml, 2.04 mmol) and 4-[1-(2-oxopropyl)tridecyl]-2-tert-butyldimethylsilylfuran (Compound 31, 429 mg, 1.02 mmol) in tetrahydrofuran (3 ml) was stirred at 0° at room temperature for 6 hours. The mixture was quenched with saturated ammonium chloride and extracted with ether. Evaporation of the dried (magnesium sulfate) extracts gave an oil, which was chromatographed on a silica column using 5% ethyl acetate/hexane to give the title alcohol.
Reaction SMILES: ClCCl.[Si:4]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2(O)[C:27]3[C:22](=[CH:23][C:24]([O:28][CH2:29][O:30][CH3:31])=[CH:25][CH:26]=3)[S:21][CH2:20][C:19]2([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH2:40][O:41][CH3:42])=[CH:35][CH:34]=2)[CH3:32])=[CH:14][CH:13]=1)([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:6])[CH3:5].C([BH3-])#N.[Na+].CC(C)=O>[I-].[Zn+2].[I-].O>[Si:4]([O:11][C:12]1[CH:13]=[CH:14][C:15]([CH:18]2[C:27]3[C:22](=[CH:23][C:24]([O:28][CH2:29][O:30][CH3:31])=[CH:25][CH:26]=3)[S:21][CH2:20][C:19]2([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH2:40][O:41][CH3:42])=[CH:35][CH:34]=2)[CH3:32])=[CH:16][CH:17]=1)([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:5])[CH3:6]
Reactant: COCOc1ccc(C2(C)CSc3cc(OCOC)ccc3C2(O)c2ccc(O[Si](C)(C)C(C)(C)C)cc2)cc1
Agent: [BH3-]C#N
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: ClCCl
Product: COCOc1ccc(C2(C)CSc3cc(OCOC)ccc3C2c2ccc(O[Si](C)(C)C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.8 %

Procedure:
To dichloromethane solution (30 ml) of 4-(4-t-butyldimethylsilyloxyphenyl)-4-hydroxy-7-methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-3-methylthiochroman (1.134 g, 1.95 mmol) were added zinc iodide (1.367 g, 4.9 mmol) and sodium cyanoborohydride (797 mg, 12.7 mmol), and the resulting mixture was stirred for 2 hours at room temperature. After adding acetone (5 ml) and water, the reaction solution was extracted with dichloromethane and the organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the organic solvent. The crude product thus obtained was purified with silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain 783 mg (yield: 71%) of the title compound.
Reaction SMILES: [Cl-].[C:2]([C:4]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C@H:8]1[CH2:12][CH2:11][CH2:10][NH2+:9]1)#[N:3].[CH:20]([N:23]=[C:24]=[O:25])([CH3:22])[CH3:21]>>[C:2]([C:4]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:24]([NH:23][CH:20]([CH3:22])[CH3:21])=[O:25])#[N:3]
Reactant: N#Cc1c(OC[C@H]2CCC[NH2+]2)cccc1[N+](=O)[O-]
Reactant: CC(C)N=C=O
Agent: [Cl-]
Product: CC(C)NC(=O)N1CCC[C@@H]1COc1cccc([N+](=O)[O-])c1C#N
Yield: 100 %

Procedure:
Prepared as in Example 165b from (R)-2-((2-cyano-3-nitrophenoxy)methyl)pyrrolidinium chloride (Example 165c) and isopropyl isocyanate in 100% yield as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 1.07 (d, J=6.5 Hz, 6H), 1.91 (m, 3H), 2.13 (m, 1H), 3.17 (m, 1H), 3.79 (m, 1H), 4.19 (m, 2H), 4.32 (d, J=8.8 Hz, 1H), 5.91 (d, J=8.1 Hz, 1H), 7.89 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[C:11](=O)[CH2:12][CH:13]([CH3:19])[CH2:14][C:15](OC)=[O:16].C([O-])(=O)C.[NH4+].[BH3-]C#[N:28].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:28][C:15](=[O:16])[CH2:14][CH:13]([CH3:19])[CH2:12]1
Reactant: [BH3-]C#N
Reactant: COC(=O)CC(C)CC(=O)c1c(OC)cccc1OC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Product: COc1cccc(OC)c1C1CC(C)CC(=O)N1
Temperature: 80 °C

Procedure:
A sealed tube containing a mixture of methyl 5-(2,6-dimethoxyphenyl)-3-methyl-5-oxopentanoate (200 mg; 0.71 mmol), ammonium acetate (549 mg; 7.13 mmol), and NaBH3CN (47 mg; 0.71 mmol) in anh. MeOH (3 ml) was heated to 80° C. for 48 h. After cooling to rt, 2 M aq. HCl (6 ml) was added, and the volatiles were removed under reduced pressure. The resulting aq. layer was extracted with DCM (3×20 ml), and the mixed organic layers were dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=25/1) afforded 6-(2,6-dimethoxyphenyl)-4-methylpiperidin-2-one as a colorless oil. LC-MS (conditions D): tR=0.89 min.; [M+H]+: 250.35 g/mol.