Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:23]([C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([C:37]([CH3:40])([CH3:39])[CH3:38])[C:35]=1[OH:36])[C:30](Cl)=[O:31])([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl>[C:37]([C:34]1[CH:33]=[C:29]([CH:28]=[C:27]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:35]=1[OH:36])[C:30]([O:9][N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:31])([CH3:40])([CH3:39])[CH3:38]
Reactant: ON(Cc1ccccc1)Cc1ccccc1
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(C(=O)ON(Cc2ccccc2)Cc2ccccc2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 27.9 g of dibenzylhydroxylamine and 10.3 g of pyridine in 100 ml of methylene chloride is added a solution of 39.0 g of 3,5-di-tert-butyl-4-hydroxybenzoyl chloride in 100 ml of methylene chloride. After stirring the mixture at room temperature for 24 hours, the reaction mixture is washed with 10% aqueous hydrochloric acid, water, brine and dried. Evaporation followed by crystallization of the residue from heptane affords the title compound as a white solid: mp 90°-92° C.
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1.[N+:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16])([O-:9])=[O:8]>>[CH:2]1([O:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N+:7]([O-:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: BrC1CCCC1
Product: O=[N+]([O-])c1ccccc1OC1CCCC1

Procedure:
In a similar manner as in Example 1, bromocyclopentane was reacted with o-nitrophenol to yield 2-cyclopentoxynitrobenzene; which was reduced to the corresponding aniline; then reacted with N-methylol-5-methylpyrrolidone to form the corresponding N-5-methyl-N-methylenepyrrolidonyl derivative; which was acylated with chloroacetyl chloride to form the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[CH3:32][C:33]1[CH:34]=[C:35]([S:39](Cl)(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=1>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:39]([C:35]4[CH:36]=[CH:37][CH:38]=[C:33]([CH3:32])[CH:34]=4)(=[O:41])=[O:40])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4cccc(C)c4)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 3-methyl-benzenesulfonyl chloride. Purity (ELSD, based on MW=575.7)=93%.
Reaction SMILES: [CH:1]1[CH:2]=[N:3][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]3[C:27](=[O:28])[CH2:26][C:21]4([CH2:25][CH2:24][CH2:23][CH2:22]4)[CH2:20][C:18]3=[O:19])[CH2:9][CH2:8]2)=[N:5][CH:6]=1.C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:36])C=CC=CC=1.C(Cl)Cl.CO.[NH4+].[OH-]>C1COCC1.C1(C)C=CC=CC=1>[CH:1]1[CH:6]=[N:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]3[C:27](=[O:28])[CH:26]([OH:36])[C:21]4([CH2:22][CH2:23][CH2:24][CH2:25]4)[CH2:20][C:18]3=[O:19])[CH2:9][CH2:8]2)=[N:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: O=C1CC2(CCCC2)CC(=O)N1CCCCN1CCN(c2ncccn2)CC1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: O=C1CC2(CCCC2)C(O)C(=O)N1CCCCN1CCN(c2ncccn2)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Buspirone (19.3 g, 50 mmole) was dissolved in dry THF (400 mL) and the resulting solution was cooled to −78° C. A solution of KN(SiMe3)2 in toluene (100 mL, 1 M) was added slowly. After the reaction mixture was stirred at −78° C. for 1 h, a solution of 2-(phenylsulfonyl)-3-phenyloxaziridine (Davis reagent, prepared according to literature method: F. A. Davis, et al., Org. Synth., 1988, 66, 203) (17.0 g, 65 mmole) in dry THF (150 mL, precooled to −78° C.) was added quickly via a cannular. After stirred for 30 mins at −78° C., the reaction was quenched with 1 N HCl solution (500 mL). It was extracted with EtOAc (3×500 mL). The aqueous layer was separated, neutralized with saturated sodium bicarbonate solution , and extracted with EtOAc (3×500 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a white solid residue which was subjected to column chromatography using CH2Cl2/MeOH/NH4OH (200:10:1) as the eluent to give pure 6-hydroxy-buspirone (I, 7.2 g) and a mixture of buspirone and 6-hydroxy-buspirone (I). The mixture was purified by above column chromatography to afford another 3.3 g of pure 6-hydroxy-buspirone (I).
Reaction SMILES: CN(C=[C:5]([C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22])[C:6](=[O:10])[CH2:7][CH2:8][CH3:9])C>O1CCOCC1>[N+:21]([C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][C:11]=1[CH2:5][C:6](=[O:10])[CH2:7][CH2:8][CH3:9])[C:15]([O:17][CH3:18])=[O:16])([O-:23])=[O:22]
Reactant: CCCC(=O)C(=CN(C)C)c1ccc(C(=O)OC)cc1[N+](=O)[O-]
Solvent: C1COCCO1
Product: CCCC(=O)Cc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Yield: 89.2 %

Procedure:
A solution of methyl 4-(1-dimethylaminomethylene-2-oxopentyl)-3-nitrobenzoate (172 mg) in dioxane (9 ml) was refluxed for 4 days. The resulting mixture was evaporated in vacuo, and the residue was purified by thin layer chromatography with a mixture of hexane and ethyl acetate (2:1) to give methyl 3-nitro-4-(2-oxopentyl)benzoate (127 mg).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.ON1C2C=CC=CC=2N=N1.[F:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[CH2:51][C:52](O)=[O:53].Cl.CN(C)CCCN=C=NCC>C(#N)C>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:52](=[O:53])[CH2:51][C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=3[F:44])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(O)Cc1ccccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(Cc1ccccc1F)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.17 h
Yield: 75.2 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.82 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotriazole (0.4 g, 2.6 mmol) and 2-fluorophenylacetic acid (0.4 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). The reaction mixture was stirred at room temperature overnight and was then concentrated in vacuo. The residue was dissolved in CH2Cl2 (80 mL), and the solution was washed with water (40 mL), 1NHCl (2×30 mL), water (40 mL) and brine (40 mL), and dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (eluent: EtOAc: CH2Cl2=4:6) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-(2-fluoro-phenyl)-acetamide (0.7 g, 79%) as a white solid: mp 172-174° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=2.87 min. (98%); 1H NMR (DMSO-d6) δ 2.04-2.09 (m, 1H), 2.51-2.63 (m, 2H), 2.84-2.94 (m, 1H), 3.61 (s, 2H), 4.75 (d, J=5.9 Hz, 2H), 5.12-5.18 (dd, J=5.3 and 12.7 Hz, 1H), 7.12-7.38 (m, 4H), 7.68-7.86 (m, 3H), 8.70 (t, J=6.0 Hz, 1H), 11.14 (s, 1H); 13C NMR (DMSO-d6) δ 21.95, 30.90, 35.20, 37.87, 48.83, 114.83 (115.12), 121.88, 122.95 (123.17), 124.14 (124.19), 127.10, 128.60 (128.71), 131.51, 131.85 (131.91), 133.11, 134.68, 139.15, 158.96 (162.20), 166.90, 167.44, 169.59, 169.78, 172.73; Anal. Calcd. for C22H18N3O5F: C, 62.41; H, 4.29; N, 9.92; F, 4.49. Found: C, 62.65; H, 4.25; N, 9.95; F, 4.62.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:30])[O:6][CH:7]1[CH:11]([OH:12])[CH:10]([CH2:13][OH:14])[O:9][CH:8]1[N:15]1[C:19]2[N:20]=[C:21]([N:24]=CN(C)C)[N:22]=[CH:23][C:18]=2[S:17][C:16]1=[O:29])([CH3:3])[CH3:2].CC(O)=O>CO>[CH:1]([O:4][C:5](=[O:30])[O:6][CH:7]1[CH:11]([OH:12])[CH:10]([CH2:13][OH:14])[O:9][CH:8]1[N:15]1[C:19]2[N:20]=[C:21]([NH2:24])[N:22]=[CH:23][C:18]=2[S:17][C:16]1=[O:29])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)OC1C(O)C(CO)OC1n1c(=O)sc2cnc(N=CN(C)C)nc21
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)OC(=O)OC1C(O)C(CO)OC1n1c(=O)sc2cnc(N)nc21
Temperature: 35 °C
Yield: 68.4 %

Procedure:
Carbonic acid 2-[5-(dimethylamino-methyleneamino)-2-oxo-thiazolo [4,5-d]pyrimidin-3-yl]-4-hydroxy-5-hydroxymethyl-tetrahydro-furan-3-yl ester isopropyl ester (15) (460 mg, 1.04 mmol) was dissolved in MeOH (5.0 mL) and HOAc (1.0 mL) was added. The reaction was warmed to 35° C. for 48 h, concentrated to a solid residue in vacuo, then subjected to flash chromatography (40-100% EtOAc-hexanes). The solids were triturated with a minimum of Et2O to yield 275 mg (69%) of 16 as a white powder: 1H NMR (400 MHz, DMSO-d6) δ 8.38 (1H, s), 6.86 (2H, bs), 5.87 (1H, d, J=5.6 Hz), 5.68 (1H, dd, J1=4.5 Hz, J2=8.3 Hz), 5.46 (1H, d, J=7.0 Hz), 4.66 (1H, septet, J=6.2 Hz), 4.58 (1H, t, J=5.8 Hz), 4.33-4.37 (1H, m), 3.96-4.03 (1H, m), 3.62-3.72 (2H, m), 1.17 (3H, d, J=6.3 Hz), 1.12 (3H, d, J=6.2 Hz); [M]+ @ m/z 386.9.
Reaction SMILES: CC1(C)COB(B2OCC(C)(C)CO2)OC1.C([O-])(=O)C.[K+].Br[C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.Br[C:36]1[CH:37]=[C:38]2[C:42](=[CH:43][C:44]=1[Cl:45])[NH:41][N:40]=[C:39]2[C:46]([OH:48])=[O:47].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1(C)C=CC=CC=1.CCO.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].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>[Cl:45][C:44]1[CH:43]=[C:42]2[C:38]([C:39]([C:46]([OH:48])=[O:47])=[N:40][NH:41]2)=[CH:37][C:36]=1[C:23]1[CH:24]=[CH:25][C:26]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:27][CH:28]=1
Reactant: Brc1ccc(C2CCCCC2)cc1
Reactant: O=C(O)c1n[nH]c2cc(Cl)c(Br)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: C1COCCO1
Product: O=C(O)c1n[nH]c2cc(Cl)c(-c3ccc(C4CCCCC4)cc3)cc12
Temperature: 110 °C
Yield: 8.7 %

Procedure:
A mixture of 5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane (75.0 mg, 0.22 mmol), oven dried potassium acetate (94.1 mg, 0.95 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (19.0 mg, 0.023 mmol), and 1-bromo-4-cyclohexylbenzene (49.5 mg, 0.21 mmol) in 1,4-dioxane (2 mL) was degassed with N2 for 10 minutes, and subjected to microwave irradiation at 115° C. for one hour. The black reaction mixture was cooled, filtered through cotton, and concentrated in vacuo to give a dark solid. To the dark solid was added 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (55.6 mg, 0.20 mmol), 2N aqueous potassium carbonate solution (0.40 mL, 0.81 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (16.3 mg, 0.020 mmol). The reaction mixture was diluted with degassed toluene (1 mL) and EtOH (1 mL), and heated at 110° C. for 18 hours in a sealed reaction vessel. The cooled reaction mixture was concentrated in vacuo and partitioned between 2N citric acid (15 mL) and EtOAc (15 mL). The layers were separated, and the aqueous phase was extracted with EtOAc (15 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give a dark oil, which was purified by reverse phase HPLC (Column: Waters XBridge C18 19×100 mm, 5 μm; Mobile phase A: 0.03% NH4OH in water (v/v); Mobile phase B: 0.03% NH4OH in MeCN (v/v); 80.0% H2O/20.0% MeCN linear to 40% H2O/60% MeCN in 8.5 min, 40% H2O/60% MeCN linear to 0% H2O/100% MeCN in 0.5 min, HOLD at 0% H2O/100% MeCN to 10.0 min. Flow: 25 mL/min) to give the title compound (6.2 mg, 9% yield). MS (ES+) 355.1 (M+H)+. Retention time=3.65 minutes (Column: Waters Atlantis dC18 4.6×50 mm, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); Gradient: 95:5 A:B linear to 5:95 A:B in 4.0 min, hold at 5:95 A:B to 5.0 min. Flow: 2 mL/min).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]1[N:26]([CH2:27][CH2:28][CH2:29][C:30](O)=[O:31])[CH2:25][CH2:24][N:23]2[CH2:33][CH2:34][CH2:35][CH2:36][CH:22]12>>[CH2:1]([N:8]([C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=1)[C:30](=[O:31])[CH2:29][CH2:28][CH2:27][N:26]1[CH2:25][CH2:24][N:23]2[CH2:33][CH2:34][CH2:35][CH2:36][CH:22]2[CH2:21]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(NCc2ccccc2)cc(OC)c1OC
Reactant: O=C(O)CCCN1CCN2CCCCC2C1
Product: COc1cc(N(Cc2ccccc2)C(=O)CCCN2CCN3CCCCC3C2)cc(OC)c1OC

Procedure:
The procedure is as for Example 2 using as substrate benzyl-(3,4,5-trimethoxyphenyl)-amine and the compound obtained in Step B of Example 2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][C:10](=[CH:14][O:15]C)[CH2:9]2)=[CH:4][CH:3]=1>C(O)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([CH:14]=[O:15])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: COC=C1CCCC(c2ccc(Cl)cc2)C1
Solvent: O
Solvent: O=CO
Product: O=CC1CCCC(c2ccc(Cl)cc2)C1
Temperature: 25 °C

Procedure:
Crude C5 (1.25 g from the preceding step, ≦4.8 mmol) was dissolved in aqueous formic acid (3 M, 2.0 mL) and the mixture was refluxed for 2 hours. The solution was cooled to room temperature, diluted with water and extracted twice with ethyl acetate; the combined organic layers were dried over sodium sulfate and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptanes) afforded the title compound as an oil, presumed by 1H NMR to be a roughly 4:1 mixture of the two stereoisomers. Yield: 338 mg, 1.52 mmol, 32% over two steps. GCMS m/z 222 (M+). 1H NMR (400 MHz, CDCl3) δ [9.65 (d, J=1.4 Hz) and 9.79 (br s), total 1H], 7.25-7.30 (m, 2H), 7.12-7.18 (m, 2H), 1.21-2.66 (m, 10H).
Reaction SMILES: [CH2:1]([N:5]1[C:11](=[O:12])[CH2:10][CH2:9][N:8]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[CH2:7][CH2:6]1)[CH2:2][CH:3]=C.O.I([O-])(=O)(=O)=[O:25].[Na+]>CC(O)(C)C>[O:12]=[C:11]1[N:5]([CH2:1][CH2:2][CH:3]=[O:25])[CH2:6][CH2:7][N:8]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[CH2:9][CH2:10]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCCN1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: O=CCCN1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Reaction time: 1 h
Yield: 636.3 %

Procedure:
To a solution of 4-but-3-enyl-1-(3-trifluoromethyl-phenyl)-[1,4]diazepan-5-one 0.09 g (0.03 mmol) in tBuOH:water (2 ml 1:1) was added potassium osmate dihydrate 0.001 g (0.001 mmol) and sodium periodate 0.13 g (0.1 mmol). The mixture was stirred for 1 h, then extracted with CH2Cl2, dried (Na2SO4) and concentrated. Purification by flash column chromatography (EtOAc:n-heptane 1:1→1:0) afforded the title compound 0.06 g (64%) as a brown gum. MS: 315.2 (MH+).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9](O)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>[Pd].C1(C)C=CC=CC=1>[C:1]([O:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: OCc1ccccc1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)c1ccccc1

Procedure:
The oxidation of toluene appears to follow an obvious path as inferred from the kinetics of the product yields (Table IV). The intermediate products are benzyl alcohol, benzaldehyde, benzoic acid; whereas, benzyl benzoate is the final product by esterification of benzyl alcohol and benzoic acid. In a separate test at the same reaction conditions, but without the Pd catalyst, benzyl alcohol and benzoic acid were esterified in toluene to produce benzyl benzoate. The following reaction scheme explains these results:
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[O:11][CH3:12])=O.[CH3:13][C:14](=[O:19])[CH2:15][C:16](=[O:18])[CH3:17].C(O)(=O)C.N1CCCCC1>ClCCl>[C:16]([C:15]([C:14](=[O:19])[CH3:13])=[CH:1][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[O:11][CH3:12])(=[O:18])[CH3:17]
Reactant: CC(=O)CC(C)=O
Reactant: COc1cc(C#N)ccc1C=O
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc(C#N)ccc1C=C(C(C)=O)C(C)=O

Procedure:
21 g (130 mmol) of 4-formyl-3-methoxybenzonitrile, 14.7 ml (143 mmol) of 2,4-pentanedione, 11.2 ml (195 mmol) of acetic acid and 2.6 ml (26 mmol) of piperidine in 400 ml of dry dichloromethane are stirred under reflux with a water trap for 24 h. After cooling, the reaction solution is washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated. The residue is recrystallized from diethyl ether. 23.2 g (92% of theory) of the title compound are obtained as a pale brown solid.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:28](=[O:29])[N:7]2[CH:8]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=3)[C:9]3[NH:10][C:11]4[C:16]([C:17]=3[CH2:18][C:6]2([CH3:30])[C:5]1=[O:31])=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=4.[CH:32]1([NH2:35])[CH2:34][CH2:33]1>>[CH:32]1([NH:35][CH2:2][CH2:3][N:4]2[C:28](=[O:29])[N:7]3[CH:8]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=4)[C:9]4[NH:10][C:11]5[C:16]([C:17]=4[CH2:18][C:6]3([CH3:30])[C:5]2=[O:31])=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=5)[CH2:34][CH2:33]1
Reactant: NC1CC1
Reactant: COc1ccc2[nH]c3c(c2c1)CC1(C)C(=O)N(CCBr)C(=O)N1C3c1cccc(O)c1
Product: COc1ccc2[nH]c3c(c2c1)CC1(C)C(=O)N(CCNC2CC2)C(=O)N1C3c1cccc(O)c1

Procedure:
The title compound is prepared similarly as described for example 30 using (3aSR,10RS)-2-(2-Bromoethyl)-10-(3-hydroxy-phenyl)-6-methoxy-3a-methyl-3a,4,9,10-tetrahydro-2,9,10a-triaza-cyclopenta[b]-fluorene-1,3-dione (example 24) and cyclopropyl amine as starting materials. MS: m/z (MH+)=461.2
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C:16]2([C:29]([NH:31][OH:32])=[O:30])[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].Cl>O1CCOCC1>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C:16]2([C:29]([NH:31][OH:32])=[O:30])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)(=[O:13])=[O:14])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)NC2(C(=O)NO)CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CC#CCOc1ccc(S(=O)(=O)NC2(C(=O)NO)CCNCC2)cc1

Procedure:
To a solution of tert-butyl 4-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-4-[(hydroxyamino)carbonyl]-1-piperidinecarboxylate (0.114 g) from Example 287, in dioxane (1 mL) was added 4N hydrochloric acid in dioxane (2 mL). After 4 hours the reaction mixture was concentrated in vacuo. Trituration with dichloromethane and diethyl ether gave 4-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-4-piperidinecarboxamide as an off-white powder. Electrospray Mass Spec 368.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:15][CH2:16][CH3:17])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([O:25][C:26]1[CH:35]=[CH:34][C:29]([C:30](=O)[CH2:31]Br)=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])O.[Na+]>>[CH2:16]([C:15]1[C:30]([C:29]2[CH:34]=[CH:35][C:26]([O:25][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:27][CH:28]=2)=[CH:31][N:11]2[C:10]=1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[CH:14][CH:13]=[CH:12]2)[CH3:17]
Reactant: CCCc1ncccc1OCc1ccccc1
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: CCc1c(-c2ccc(OCc3ccccc3)cc2)cn2cccc(OCc3ccccc3)c12
Yield: 66 %

Procedure:
3-Benzyloxy-2-propylpyridine was reacted with 4-benzyloxyphenacylbromide and with sodium hydrogen carbonate by the general synthetic principles outlined in example 1, step 2, to afford 1-ethyl-8-benzyloxy-2-(4-benzyloxyphenyl)indolizine as yellow crystals in 66% yield. M.p. 104-105° C. MS(SP): m/z 433 (M+). 1H--NMR (DMSO-d6, 200 MHz) δ: 1.10 (t, 3 H); 2.86 (q, 2 H); 5.12 (s, 2 H); 5.19 (s, 2 H); 6.13 (d, 1 H); 6.38 (t, 1 H); 7.06 (d, 2 H); 7.28-7.54 (m, 13 H); 7.77 (d, 1 H).
Reaction SMILES: C([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][N:7]=1)C.[OH-].[Na+]>C(O)C>[CH3:12][C:10]1[CH:9]=[CH:8][N:7]=[C:6]([CH2:5][C:4]([OH:13])=[O:3])[CH:11]=1
Reactant: CCOC(=O)Cc1cc(C)ccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccnc(CC(=O)O)c1
Yield: 118.6 %

Procedure:
(4-Methyl-pyridin-2-yl)-acetic acid ethyl ester (1.0 g)—prepared according to Chem. Parm. Bull 32 (12), 1984, 4866-4872—was dissolved in ethanol (30 ml) and treated with a 1M ethanolic NaOH solution (5.83 ml). The mixture was refluxed for 4 hours, cooled and evaporated in vacuo. The residue was dissolved in water (50 ml) and the pH was adjusted to 3.0 with 1M HCl. The solvent was evaporated and the residue was suspended in ethanol (150 ml) and filtered. The clear filtrate was evaporated to dryness and the residue was dried in vacuo to give a light yellow solid (1.0 g). NMR (DMSO-d6): 8.65 (d, 1H); 7.72 (s, 1H), 7.68 (d, 1H), 4.04 (s, 2H), 2.49 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([CH3:13])([CH3:12])[CH2:7][CH2:6][C:5]([CH3:15])([CH3:14])[C:4]=2[CH:3]=1.[N+:16]([O-])([OH:18])=[O:17].C(O)(=O)C>C(OC(=O)C)(=O)C>[CH3:1][C:2]1[C:11]([N+:16]([O-:18])=[O:17])=[CH:10][C:9]2[C:8]([CH3:13])([CH3:12])[CH2:7][CH2:6][C:5]([CH3:15])([CH3:14])[C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc2c(c1)C(C)(C)CCC2(C)C
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Cc1cc2c(cc1[N+](=O)[O-])C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
50 g (250 mmoles) of 2-methyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl naphthalene are dissolved in 200 ml of acetic anhydride. The solution is cooled to 0° C. and there is slowly added a solution of 10.5 ml (250 mmoles) of nitric acid, 20 ml of acetic acid and 20 ml of acetic anhydride, while maintaining the temperature between 0° and 5° C. The reaction mixture is then stirred for 1 hour at ambient temperature, poured into ice water and filtered. The resulting solid is washed with water. The solid is dissolved in methylene chloride, washed with water and then with a saturated solution of sodium bicarbonate, dried on MgSO4 and evaporated. 45.8 g (74%) of 2-methyl-3-nitro-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl naphthalene which melts at 143°-144° C. are obtained.
Reaction SMILES: [OH:1][C:2]([C@@H:4]1[CH:19]=[C:18]2[C@@H:8]([CH2:9][C:10]3[C:20]4[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=4)[NH:12][CH:11]=3)[N:6]([CH3:7])[CH2:5]1)=[O:3].C(O)(C(F)(F)F)=O.[Br:28]Br>O1CCOCC1.C(Cl)(Cl)Cl>[Br:28][C:11]1[NH:12][C:13]2[C:20]3[C:10]=1[CH2:9][C@@H:8]1[C:18](=[CH:19][C@@H:4]([C:2]([OH:1])=[O:3])[CH2:5][N:6]1[CH3:7])[C:17]=3[CH:16]=[CH:15][CH:14]=2
Reactant: BrBr
Reactant: CN1C[C@H](C(=O)O)C=C2c3cccc4[nH]cc(c34)C[C@H]21
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: CN1C[C@H](C(=O)O)C=C2c3cccc4[nH]c(Br)c(c34)C[C@H]21
Temperature: 5 °C

Procedure:
Lysergic acid (8.05 g, 30 mmol) is suspended in dioxane and is treated with dropwise addition of TFA (exothermic). Bromine (1.54 ml, 30 mmol, 1.0 eq.) in chloroform is added dropwise. The reaction is cooled to 5° C. and product crystallizes. (6aR,9R)-5-Bromo-7-methyl-4,6,6a,7,8,9-hexahydro-indolo[4,3-fg]quinoline-9-carboxylic acid is isolated by filtration and re-crystallised from diethylether. Rf=0.5, 10% MeOH:DCM, M+H+=346, 348, m.p.>245 (decomposition).