Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:33])[N:10]([C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][N:14]([C:25]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[O:26])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.Br[C:35]1[S:36][CH:37]=[N:38][N:39]=1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:33])[N:10]([C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][N:14]([C:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:35]4[S:36][CH:37]=[N:38][N:39]=4)[CH2:29][CH2:28]3)=[O:26])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: Brc1nncs1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CN(C(=O)C2CCNCC2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CN(C(=O)C2CCN(c3nncs3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Yield: 32 %

Procedure:
To a solution of rac-[(3R,4S)-4-(3,4-dichloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester (100 mg, 0.20 mmol) in N-methylpyrrolidinone (1 mL) was added 2-bromo-1,3,4-thiadiazole (50 mg, 0.30 mmol) and N,N-diisopropyl ethyl amine (69 μl, 0.40 mmol). The solution was irradiated in the microwave for 35 min at 150° C. The reaction mixture was diluted with ethyl acetate (15 mL) and washed with an aqueous solution of sodium carbonate (1 M, 15 mL). The organic layer was separated and washed with brine (15 mL) and the aqueous layers were extracted with ethyl acetate (20 mL). The combined organic layers were dried over sodium sulfate and concentrated. Purification by chromatography (SiO2, ethyl acetate:methanol=100:0 to 80:20) afforded the title compound (37 mg, 32%) as an off-white foam. MS m/e: 578.1 [M]+.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][S:10]([C:13]1[N+:14]([O-:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11].[H-].[Na+].[CH2:24](Br)[CH:25]=[CH2:26]>CN(C=O)C>[CH2:26]([N:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:20])([F:1])[F:21])[S:10]([C:13]1[N+:14]([O-:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11])[CH:25]=[CH2:24]
Reactant: C=CCBr
Reactant: O=S(=O)(Nc1ccccc1C(F)(F)F)c1cccc[n+]1[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN(c1ccccc1C(F)(F)F)S(=O)(=O)c1cccc[n+]1[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To N-(2-trifluoromethylphenyl)-2-pyridinesulfonamide 1-oxide (compound 129, Table A) (1.0 g, 3.0 mmol) in 10 ml of DMF is added NaH (0.30 g, 6.2 mmol) under N2, and the mixture is stirred at RT for 30 minutes. Allyl bromide (0.82 g, 0.59 ml, 6.8 mmol) is added dropwise, and the mixture is stirred at RT for 48 hours. It is then worked up and purified to give the title compound (compound 37, Table A). (DMF is dimethylformamide; RT is room temperature.)
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6].F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=1[CH3:25].O>CN(C=O)C>[CH3:3][N:4]([S:5]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)(=[O:6])=[O:7])[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=1[CH3:25]
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: CNS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N(C)c2ccc([N+](=O)[O-])cc2C)cc1
Yield: 34.3 %

Procedure:
To a suspension of sodium hydride (60%, 0.08 g (2.00 mmol)) in 2.0 ml of DMF, N-methyl-p-toluenesulfonamide (0.37 g (2.00 mmol)) was added at room temperature with stirring. To the resulting mixture, after 15 minutes' stirring at room temperature, 2-fluoro-5-nitrotoluene (0.31 g (2.00 mmol)) was added. The reaction mixture was stirred at room temperature for 2 hours, poured into water and extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution, successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. Diisopropyl ether was added to the residue and crystals separated was filtered and washed to give 0.22 g (36%) of the title compound as pale yellow crystals.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]2[CH2:14][CH2:13][NH:12][C:11](=[O:15])[CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].I[CH3:19].[Cl-].[NH4+]>CN(C=O)C>[F:1][C:2]1[C:7]([CH:8]2[CH2:14][CH2:13][N:12]([CH3:19])[C:11](=[O:15])[CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CI
Reactant: O=C1CCC(c2cccnc2F)CCN1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CN1CCC(c2cccnc2F)CCC1=O

Procedure:
To a solution of 5-(2-fluoropyridin-3-yl)azepan-2-one (0.15 g, 0.72 mmol) in DMF (2.5 mL) under argon was added sodium hydride (0.021 g, 0.86 mmol). The mixture was stirred at room temperature for 15 min before iodomethane (0.054 mL, 0.86 mmol) was added via syringe. This mixture was stirred for 4 h at room temperature before saturated aqueous ammonium chloride was added. The mixture was extracted with ethyl acetate (2×) and the combined extracts were washed with water (3×), saturated aqueous sodium chloride (1×), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give 5-(2-fluoropyridin-3-yl)-1-methylazepan-2-one. [M+1]=223.1.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:28]=[CH:27][C:9]([O:10][CH2:11][CH2:12][N:13]2[C:21]3[CH:20]=[CH:19][N:18]=[C:17](Cl)[C:16]=3[CH:15]=[C:14]2[C:23]([O:25][CH3:26])=[O:24])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:29]([O:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)[CH3:30].[F-].[K+]>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:1]([O:5][C:6]1[CH:28]=[CH:27][C:9]([O:10][CH2:11][CH2:12][N:13]2[C:21]3[CH:20]=[CH:19][N:18]=[C:17]([C:36]4[CH:35]=[CH:34][CH:33]=[C:32]([O:31][CH2:29][CH3:30])[CH:37]=4)[C:16]=3[CH:15]=[C:14]2[C:23]([O:25][CH3:26])=[O:24])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1cccc(B(O)O)c1
Reactant: COC(=O)c1cc2c(Cl)nccc2n1CCOc1ccc(OC(C)(C)C)cc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOc1cccc(-c2nccc3c2cc(C(=O)OC)n3CCOc2ccc(OC(C)(C)C)cc2)c1
Temperature: 25 °C
Yield: 77.4 %

Procedure:
Methyl 1-[2-(4-tert-butoxyphenoxy)ethyl]-4-chloro-1H-pyrrolo[3,2-c]pyridine-2-carboxylate (1 g, 2.482 mmole), 3-ethoxyphenylboronic acid (0.618 g, 3.72 mmole), KF (0.433 g, 7.45 mmole), and bis(tri-t-butylphosphine)palladium(0) (0.127 g, 0.248 mmole) were combined in 1,4-dioxane (10 mL). The mixture was degassed (3× pump/N2) then heated to reflux. After 5 hr the mixture was cooled to RT, diluted with EtOAc, filtered through a pad of Celite washing with EtOAc, and concentrated. Flash column chromatography (Biotage-SNAP-50 g SiO2, 0-30% EtOAc/hexanes) gave the title compound (939 mg, 77%) as an off-white foam. 1H NMR (400 MHz, CDCl3): 8.52 (d, J=6.0 Hz, 1 H); 7.61 (d, J=0.9 Hz, 1 H); 7.52-7.47 (m, 2 H); 7.43 (d, J=7.2 Hz, 2
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:9]2=O)=[CH:5][CH:4]=1.[CH2:19]([N:26]1[C:30]([CH:31]=O)=[CH:29][N:28]=[CH:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CO.[OH-].[Na+]>O1CCCC1.O.[Ti](Cl)(Cl)(Cl)Cl.[Zn]>[CH2:19]([N:26]1[C:30]([CH:31]=[C:9]2[C:10]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=3)[CH2:7][CH:8]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:29][N:28]=[CH:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=Cc1cncn1Cc1ccccc1
Reactant: COc1ccc2c(c1)C(=O)C(c1ccccc1)C2
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(c1)C(=Cc1cncn1Cc1ccccc1)C(c1ccccc1)C2
Temperature: 50 °C

Procedure:
Titanium(IV)chloride (13.2 ml, 22.8 g, 0.12 mol) was added dropwise to a stirred suspension of activated zinc powder (15.9 g, 0.24 mol) in dry tetrahydrofuran (240 ml) at −5° C. -(−10° C.) under a nitrogen atmosphere. After completion of the addition the resulting mixture was refluxed for 2 hours with stirring. A solution of 6-methoxy-2-phenylindan-1-one (7.54 g, 0.032 mol) and 3-benzyl-3H-imidazole-4-carbaldehyde (7.37 g, 0.040 mol) in dry tetrahydrofuran (110 ml) was added dropwise to a refluxing mixture. After the addition the mixture was refluxed for 5 hours. Then the mixture was cooled to 50° C. and 50 ml of methanol and 25 ml of water was added, respectively. The cooled reaction mixture was made alkaline (pH 8-9) with 50% sodium hydroxide solution in water. The slurry was filtered through Celite, and the filtrate was evaporated to dryness under reduced pressure. Ethyl acetate (100 ml) was added to the residue and the mixture was heated. The cooled mixture was filtered and the filtrate was washed with water. The organic phase was dried and evaporated to dryness. The crude product was used in the next step.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:34]=[CH:33][C:12]([C:13]([CH:15]([N:17]2[CH2:22][CH2:21][C:20]3([C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]([CH3:31])[C:23]3=[O:32])[CH2:19][CH2:18]2)[CH3:16])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].C(O)(C)C>O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:13]([OH:14])[CH:15]([N:17]2[CH2:18][CH2:19][C:20]3([C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]([CH3:31])[C:23]3=[O:32])[CH2:21][CH2:22]2)[CH3:16])=[CH:33][CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C(=O)c1ccc(OCc2ccccc2)cc1)N1CCC2(CC1)C(=O)N(C)c1ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CC(C(O)c1ccc(OCc2ccccc2)cc1)N1CCC2(CC1)C(=O)N(C)c1ccccc12

Procedure:
A mixture of 4.5 g of 1'-[1-(4-benzyloxybenzoyl)ethyl]-1-methyl-2-oxo-indoline-3-spiro-4'-piperidine, 5.6 g of sodium borohydride and 150 ml of isopropylalcohol was refluxed for 1 hour. The resulting mixture was poured into water and was extracted with ethylacetate. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude solid was recrystallized from ethanol to give 1'-[1-(4-benzyloxyphenyl)-1-hydroxypropane-2-yl]-1-methyl-2-oxo-indoline-3-spiro-4'-piperidine.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:17])[CH2:3][CH2:2]1.[C:18]([O-:21])(=[O:20])[CH3:19].[H][H].ClCCl.CO.N>CO.[Rh+]=O.O.[Pt](=O)=O>[NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:16][CH:15]3[CH:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)[NH:9][C:8]2=[O:17])[CH2:3][CH2:2]1.[C:18]([O-:21])(=[O:20])[CH3:19]
Reactant: [H][H]
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Agent: O=[Pt]=O
Agent: O=[Rh+]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: O=C1NC2CCCCC2CN1C1CCNCC1

Procedure:
A solution of 5.0 g (17.17 mmol) of 3,4-dihydro-3-(4-piperidinyl)-2(1H)-quinazolinone-acetate in 70 ml of methanol was hydrogenated at room temperature and in the presence of 1.0 g rhodium (III) oxide-platinum (IV) oxide hydrate catalyst (46.45% rhodium, 20.15% platinum) until the hydrogen uptake had ceased. The catalyst and solvent were removed, the residue was triturated with 10 ml of diisopropylether and a few drops of isopropanol and the resulting crystals were suction filtered. After drying in vacuo 4.4 g (86.2% of theory) of colourless crystals were obtained, Rf=0.3 (eluant: dichloromethane/methanol/conc. ammonia 7.5/2.5/0.5 v/v/v).
Reaction SMILES: [CH2:1]([O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C1C=CC([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:32][C:33]2[CH:38]=[CH:37][C:36]([CH2:39][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:35][CH:34]=2)=CC=1.[Br-].[Br-]>CO>[CH2:1]([O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[CH:39][C:36]2[CH:35]=[CH:34][C:33]([CH:32]=[CH:21][C:20]3[CH:23]=[CH:24][C:17]([O:16][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:18][CH:19]=3)=[CH:38][CH:37]=2)=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCCCCCCOc1ccc(C=O)cc1
Reactant: c1ccc([P+](Cc2ccc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)cc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: CO
Product: CCCCCCCCCCCCCCCOc1ccc(C=Cc2ccc(C=Cc3ccc(OCCCCCCCCCCCCCCC)cc3)cc2)cc1
Reaction time: 3 h
Yield: 92.9 %

Procedure:
In a 30 ml four-necked flask, 7.87 g (23.7 mM) of the p-pentadecanoxybenzaldehyde synthesized above and 8.65 g (11.0 mM) of p-xylylenebis(triphenylphosphonium bromide) were suspended in 100 ml of methanol, and 6.87 g (35.6 mM) of 28 wt % methylate was added thereto dropwise at room temperature (25° C.). The mixture was aged at a refluxing temperature of 65° C. for 3 hours. Methanol was removed by evaporation, and 200 ml of water was added to the residue, followed by stirring. The precipitate thus formed was collected by filtration, washed with water and acetone, and dried to give 7.49 g of a 1,4-bis(4′-pentadecanoxystyryl)benzene isomeric mixture (compound (1a)). The 1H-NMR data for identification were as follows.
Reaction SMILES: [F:1][C:2]1[C:8]([OH:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[OH:4].C[O:12][C:13](=O)[CH2:14][C:15]([C:17]([F:20])([F:19])[F:18])=O>>[F:10][C:7]1[CH:6]=[C:5]2[C:3](=[C:2]([F:1])[C:8]=1[OH:9])[O:4][C:13](=[O:12])[CH:14]=[C:15]2[C:17]([F:20])([F:19])[F:18]
Reactant: Oc1ccc(F)c(O)c1F
Reactant: COC(=O)CC(=O)C(F)(F)F
Product: O=c1cc(C(F)(F)F)c2cc(F)c(O)c(F)c2o1
Temperature: 0 °C
Yield: 29.1 %

Procedure:
A solution of Compound 4 (0.46 g, 3.1 mmol) and methyl-4,4,4-trifluoroacetoacetate (0.55 g, 3.2 mmol) in 7 mL CH3 SO3H is stirred at 20° C. for 48 hours. The reaction mixture is poured into 70 mL ice water, and the resulting precipitate is collected by filtration, washed with water, dried in vacuo at 60° C. for 16 hours to yield 240 mg (30%) of Compound 20 as an off-white powder. 1 H-NMR (DMSO-d6) δ 7.33 (d, 1 H), 6.99 (s, 1H). 19F-NMR (DMSO-d6) Φ 59.38 (s, 3F), 129.93 (t, J=9.9 Hz, 1H), 147.78 (d, J=9.3 Hz, 1F).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C[O:8][C:9](=O)[CH:10]([C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1)[CH2:11][CH:12]1[CH2:16][CH2:15][CH:14]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH2:13]1.C[O-].[Mg+2].C[O-].CO>>[CH3:33][S:30]([C:27]1[CH:26]=[CH:25][C:24]([CH:10]([CH2:11][CH:12]2[CH2:16][CH2:15][CH:14]([O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[CH2:13]2)[C:9]([NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)=[O:8])=[CH:29][CH:28]=1)(=[O:32])=[O:31]
Reactant: COC(=O)C(CC1CCC(OC2CCCCO2)C1)c1ccc(S(C)(=O)=O)cc1
Reactant: Nc1nccs1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(CC2CCC(OC3CCCCO3)C2)C(=O)Nc2nccs2)cc1
Temperature: 25 °C
Yield: 40 %

Procedure:
2-Aminothiazole (259 mg, 2.58 mmol) and 2-(4-methanesulfonyl-phenyl)-3-[3-(tetrahydropyran-2-yloxy)-cyclopentyl]-propionic acid methyl ester (1.06 g, 2.58 mmol) were treated with a solution of magnesium methoxide in methanol (7.4 wt. % , 14.76 mL, 10.32 mmol). The reaction mixture was then concentrated in vacuo to approximately one-half the volume of methanol. The resulting reaction mixture was heated under reflux for 24 h. The reaction mixture was allowed to cool to 25° C. and then filtered through a pad of celite. The pad of celite was washed well with ethyl acetate until the washings indicated the absence of product by thin layer chromatography. The filtrate was then washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/2 hexanes/ethyl acetate) afforded 2-(4-methanesulfonyl-phenyl)-3-[3-(tetrahydropyran-2-yloxy)-cyclopentyl]-N-thiazol-2-yl-propionamide (494 mg, 40%) as a yellow foam: mp 68-70° C. (foam to gel); FAB-HRMS m/e calcd for C23H30N2O5S2 (M+H)+ 479.1674. found 479.1666.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:6]2.C(=O)([O-])[O-].[K+].[K+].S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:26][C@H:27]1[O:29][CH2:28]1)(=O)=O.O>CN(C=O)C>[CH2:26]([O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:6]2)[C@H:27]1[O:29][CH2:28]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Reactant: CCOC(=O)c1cc2c(O)cccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(OC[C@@H]3CO3)cccc2[nH]1
Reaction time: 24 h
Yield: 178.6 %

Procedure:
To a solution of ethyl 4-hydroxy-1H-indole-2-carboxylate (1.3 g) in DMF (50 ml) were added potassium carbonate and (S)-glycidyl nosylate (1.0 g) and the mixture was stirred one day. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to give ethyl (S)-4-glycidyloxy-1H-indole-2-carboxylate (1.8 g) as a brown oil. This was dissolved in methanol (50 ml) and the solution was refluxed under heating with 4-(naphthalen-2-yl)piperidine (1.5 g) for 3 hr. The solvent was evaporated under reduced pressure to give ethyl (S)-4-(2-hydroxy-3-(4-(naphthalen-2-yl)piperidino)propyloxy)-1H-indole-2-carboxylate (1.4 g) as pale-brown crystals (melting point 115–117° C.). By the reactions in the same manner as in Starting Material Synthesis Example 22, the title compound (1.1 g) was obtained as white crystals, melting point 171–173° C.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[N:14]=[C:13]([NH2:15])[N:12]=[C:11]([NH2:16])[CH:10]=1)C.[OH-].[Na+].Cl>O>[NH2:15][C:13]1[N:12]=[C:11]([NH2:16])[CH:10]=[C:9]([CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:17])=[O:3])[N:14]=1
Reactant: CCOC(=O)CCCCc1cc(N)nc(N)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1cc(CCCCC(=O)O)nc(N)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The ethyl ester 2-2 (190 mg, 0.8 mmol) in TBF (10 mL) and water (10 mL) was treated with 1 N NaOH (1.6 mL, 1.6 mmol). After stirring at room temperature for 16 hours, the solution was neutralized with 1N HCl and then the solvents removed in vacuo. The residue, 2-3, was used as such in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:4]=1[NH2:5].N1C=CC=CC=1.[C:19](Cl)([O:21][CH2:22][CH:23]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20]>C1COCC1>[C:19]([C:4]1([CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][CH:3]1[O:2][CH3:1])[NH2:5])([O:21][CH2:22][CH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:30]2[C:35]1=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:20]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: COc1cc([N+](=O)[O-])ccc1N
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC1C=C([N+](=O)[O-])C=CC1(N)C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A solution of 2-methoxy-4-nitroaniline (3.0 g) and pyridine (1.6 ml) in THF (30 ml) was cooled to 0° C. FmocCl (5.07 g) was added in portions and after complete addition the ice-bath was removed and the mixture was stirred for 5 h. The THF was removed in vacuo and the residue dissolved in CH2Cl2 (175 ml). Methanol (ca 100 ml) was added and the CH2Cl2 was partly removed in vacuo until a precipitate formed. The mixture was allowed to stand for 1 h, after which time the crystals were collected by filtration and dried in vacuo to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([Cl:13])[C:8]=1F)=O.NC(N)=[S:24].N1C=CC=CC=1.CCN(CC)CC>C(O)(C)C>[Cl:13][C:9]1[C:8]2[S:24][C:4]([C:3]3[C:15]([N+:19]([O-:21])=[O:20])=[CH:16][CH:17]=[CH:18][C:2]=3[Cl:1])=[N:6][C:7]=2[CH:12]=[CH:11][N:10]=1
Reactant: NC(N)=S
Reactant: O=C(Nc1ccnc(Cl)c1F)c1c(Cl)cccc1[N+](=O)[O-]
Solvent: CC(C)O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccc(Cl)c1-c1nc2ccnc(Cl)c2s1
Temperature: 25 °C
Yield: 97.2 %

Procedure:
A stirred suspension of 2-chloro-N-(2-chloro-3-fluoropyridin-4-yl)-6-nitrobenzamide (3.90 g, 11.2 mmol), thiourea (3.40 g, 44.8 mmol) and pyridine (3.1 mL, 38.1 mmol) in isopropanol (35 mL) under a nitrogen atmosphere, was heated under reflux for 4 hours. After this time, Et3N (9.4 mL, 67.2 mmol) was added and the reaction mixture was heated under reflux for 16 hours. After cooling to room temperature, the volatiles were removed under reduced pressure. The crude residue was triturated with ethyl acetate and the solid was removed by filtration. The resultant filtrate was washed with 10% citric acid, brine, dried over MgSO4 and evaporated under reduced pressure to afford the title compound as a pale orange solid (3.55 g, 97%). 1H NMR (400 MHz, CDCl3): δ 8.51 (d, J=5.5 Hz, 1H), 8.13 (dd, J=1.2, 8.4 Hz, 1H), 7.91 (d, J=5.7 Hz, 1H), 7.87 (dd, J=1.2, 8.3 Hz, 1H), 7.72 (t, J=8.1 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:7]=[CH:6][NH:5][N:4]=1.[H-].[Na+].Cl[C:13]1[CH:22]=[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[C:20]2[C:15](=[C:16]([Cl:35])[C:17]([O:33][CH3:34])=[CH:18][CH:19]=2)[N:14]=1.CCOC(C)=O>CN(C=O)C>[Cl:35][C:16]1[C:17]([O:33][CH3:34])=[CH:18][CH:19]=[C:20]2[C:15]=1[N:14]=[C:13]([N:5]1[CH:6]=[CH:7][C:3]([C:2]([F:9])([F:8])[F:1])=[N:4]1)[CH:22]=[C:21]2[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1
Reactant: COc1ccc(COc2cc(Cl)nc3c(Cl)c(OC)ccc23)cc1
Reactant: FC(F)(F)c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(COc2cc(-n3ccc(C(F)(F)F)n3)nc3c(Cl)c(OC)ccc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To a stirred solution of compound 233a (821 mg, 1.1 eq.) in anhydrous DMF (20 mL) at 0° C. was added NaH (241 mg, 1.1 eq.) portionwise. After the reaction mixture was stirred for 1 hr at room temperature, compound 221d (2 g, 1 eq.) was added and the mixture was stirred at 90° C. for 16 hrs. After the reaction mixture was cooled to room temperature, EtOAc was added. The organic phase was washed with HCl (2.5 N), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by chromatography on silica gel (petroleum ether/DCM, 50/50) to give compound 234a as a white solid in 51% yield. MS (ESI, EI+): m/z=461.9 (MH−).
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][C:9](=[O:11])[CH2:8][C:7](=[O:12])[CH2:6]2)[CH2:4][CH2:3][CH2:2]1>C(O)C(C)C>[CH2:4]([O:12][C:7]1[CH2:6][C:5]2([CH2:1][CH2:2][CH2:3][CH2:4]2)[CH2:10][C:9](=[O:11])[CH:8]=1)[CH:5]([CH3:6])[CH3:1]
Reactant: O=C1CC(=O)CC2(CCCC2)C1
Solvent: CC(C)CO
Product: CC(C)COC1=CC(=O)CC2(CCCC2)C1
Yield: 56 %

Procedure:
By following a procedure analogous to that described in Organic Syntheses, Collective Volume 5, p 539, using 81.2 g of spiro[4.5]decane-7,9-dione instead of dihydroresorcinol and isobutyl alcohol instead of ethyl alcohol, a corresponding isobutyl enol ether was prepared. It was purified by silica gel chromatography, obtaining 9-isobutyloxyspiro[4.5]dec-8-en-7-one in a yield of 56%.