Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:4][C:5]1[C:6]([N+:14]([O-:16])=[O:15])=[CH:7][C:8]2[O:12][CH2:11][CH2:10][C:9]=2[CH:13]=1)(=O)C>OS(O)(=O)=O>[NH2:4][C:5]1[C:6]([N+:14]([O-:16])=[O:15])=[CH:7][C:8]2[O:12][CH2:11][CH2:10][C:9]=2[CH:13]=1
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])OCC2
Agent: O=S(=O)(O)O
Product: Nc1cc2c(cc1[N+](=O)[O-])OCC2
Temperature: 0 °C
Yield: 70.5 %

Procedure:
The product obtained in Step 4 (7.0 g, 31.5 mmol) and 2 mol/L H2SO4 solution (200 mL) were heated to reflux for 6 h. Then the reaction mixture was cooled to 0° C., filtered, washed with water, concentrated under vacuum and dried to obtain a product (4.0 g, 70%).
Reaction SMILES: [CH3:1][C:2]1([N:14]2[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]2)[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[CH2:21]1[CH2:26][C@@H:25]([NH2:27])[C@H:24]([NH2:28])[CH2:23][CH2:22]1>>[NH2:27][C@@H:25]1[CH2:26][CH2:21][CH2:22][CH2:23][C@H:24]1[NH:28][CH:17]1[CH2:18][CH2:19][N:14]([C:2]2([CH3:1])[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)[CH2:15][CH2:16]1
Reactant: N[C@@H]1CCCC[C@H]1N
Reactant: CC(C)(C)OC(=O)N1CCC(C)(N2CCC(=O)CC2)C1
Product: CC(C)(C)OC(=O)N1CCC(C)(N2CCC(N[C@@H]3CCCC[C@H]3N)CC2)C1

Procedure:
Following the procedure used in step D of the example 7 and starting with tert-butyl 3-methyl-3-(4-oxo-1-piperidyl)pyrrolidine-1-carboxylate (300 mg, 1.06 mmol) and 1R,2R-diaminocyclohexane (244.2 mg, 2.12 mmol), the title compound was obtained (300 mg). MS (M+1): 381.30
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:14]=[C:15]3[CH2:21][C:20](=[O:22])[N:19](COCC[Si](C)(C)C)[C:16]3=[N:17][CH:18]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:38][CH2:39][CH2:40][CH2:41]I>CN(C=O)C>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C:13]2[CH:14]=[C:15]3[C:21]4([CH2:41][CH2:40][CH2:39][CH2:38]4)[C:20](=[O:22])[NH:19][C:16]3=[N:17][CH:18]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(-c2cnc3c(c2)CC(=O)N3COCC[Si](C)(C)C)cc(OC)c1OC
Reactant: ICCCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc(-c2cnc3c(c2)C2(CCCC2)C(=O)N3)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.8 %

Procedure:
To a solution of 5-(3,4,5-trimethoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-pyrrolo[2,3-b]pyridin-2(3H)-one (Compound BN, 43 mg, 0.10 mmol) in DMF (2 mL) was added cesium carbonate (0.17 g, 0.50 mmol) and 1,4-diiodobutane (13 μL, 0.10 mmol). The resulting solution was stirred for 4 hr at room temperature, after which it was partitioned between EtOAc and H2O. The organic layer was separated, dried over MgSO4, filtered, and concentrated in vacuo. The residue was dissolved in 6 N HCl (10 mL) and MeOH (5 mL), and the resulting mixture was stirred at room temperature overnight, after which it was partitioned between EtOAc and H2O. The organic layer was concentrated in vacuo, and the residue was dissolved in EtOH (2 mL). Potassium acetate (100 mg) was then added, and the reaction was stirred for 2 hr. The resulting solution was purified via preparatory HPLC to give the title compound (18 mg, 51%). 1H NMR (CDCl3, 300 MHz): δ 9.53 (s, 1H), 8.32 (d, J=2.1 Hz, 1H), 7.56 (s, 1H), 6.69 (s, 2H), 3.95 (s, 6H), 3.90 (s, 3H), 2.28 (m, 2H), 2.24 (m, 2H), 1.97 (m, 4H). HPLC retention time: 2.00 minutes; MS ESI (m/z): 355.4 (M+1)+, calc. 354.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[S:12]([O-:15])([O-:14])=[O:13].[Na+:16].[Na+]>CO.O>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][S:12]([O-:15])(=[O:14])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Na+:16]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=[N+]([O-])c1ccc(CS(=O)(=O)[O-])cc1
Temperature: 25 °C
Yield: 90 %

Procedure:
A suspension of 100g (463 mmol, 1.0 equiv.) of 4-nitrobenzyl bromide and 64.2 g (509 mmol, 1.1 equiv.) of sodium sulfite in 500 mL of methanol and 500 mL of water was heated to reflux. The progress of the reaction was monitored by TLC. When the bromide was consumed, the reaction mixture was allowed to cool to room temperature. The product precipitated and was collected by filtration. It was thoroughly dried for sixteen hours at 65° C. at 0.05 mm Hg to give 100 g (90%) of sodium 4-nitrobenzyl sulfonate.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH2:9])=[O:8])[C:3]([SH:6])([CH3:5])[CH3:4].[CH2:10]=O>O>[CH3:4][C:3]1([CH3:5])[S:6][CH2:10][NH:1][CH:2]1[C:7]([NH2:9])=[O:8]
Reactant: C=O
Reactant: CC(C)(S)[C@H](N)C(N)=O
Solvent: O
Product: CC1(C)SCNC1C(N)=O
Temperature: 50 °C
Yield: 94 %

Procedure:
Penicillaminamide (74.0 g, 0.50 mol) was dissolved in distilled water (800 ml) and added with 37% formalin (60.8 g, 0.75 mol). The mixture was heated with stirring at 50° C. under normal pressure, allowed to react for 2 hours and cooled. Subsequently, water was evaporated by using an evaporator. The residue was washed with acetone to obtain white crystals of 5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid amide (75.5 g, 0.47 mol). The yield to penicillaminamide was 94.4 mole %.
Reaction SMILES: CO[C:3]([C:5]1[S:9][C:8]([CH2:10][CH:11]([C:13]2[C:14]([CH2:19][CH2:20][CH2:21][CH3:22])=[N:15][O:16][C:17]=2[CH3:18])O)=[N:7][CH:6]=1)=[O:4].[CH2:23]([CH2:25][NH2:26])[OH:24]>>[OH:24][CH2:23][CH2:25][NH:26][C:3]([C:5]1[S:9][C:8](/[CH:10]=[CH:11]/[C:13]2[C:14]([CH2:19][CH2:20][CH2:21][CH3:22])=[N:15][O:16][C:17]=2[CH3:18])=[N:7][CH:6]=1)=[O:4]
Reactant: CCCCc1noc(C)c1C(O)Cc1ncc(C(=O)OC)s1
Reactant: NCCO
Product: CCCCc1noc(C)c1/C=C/c1ncc(C(=O)NCCO)s1
Yield: 35 %

Procedure:
As described for example 124b, 2-[2-(3-butyl-5-methyl-isoxazol-4-yl)-2-hydroxy-ethyl]-thiazole-5-carboxylic acid methyl ester (90 mg, 0.29 mmol) was converted, using ethanolamine instead of isopropylamine, to the title compound (35 mg, 35%) which was obtained as a light yellow solid after purification by chromatography (silica, 0 to 10% methanol in dichloromethane). MS: m/e=336.3 [M+H]+.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].[Cl:9][SiH2:10][Cl:11]>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[CH:1]([Si:10]([CH:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])([Cl:11])[Cl:9])=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: Cl[SiH2]Cl
Reactant: C=CCCCCC=C
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Product: CCCCCCC=C[Si](Cl)(Cl)C=CCCCCCC
Reaction time: 120 h
Yield: 90 %

Procedure:
To a 100 ml glass ampoule equipped with a magnetic stirring bar was added hexachloroplatinic acid (0.15 ml, 0.090M solution in isopropanol). After the solvent was removed under reduced pressure, 1,7-octadiene (14.39 g, 130.6 mmoles) and dichlorosilane (2.08 g, 20.82 mmoles) were condensed in vacuo into the ampoule. The ampoule was sealed off, placed in an oil bath, and heated gradually to the final reaction temperature of 60° C. at which it was kept for 120 hours. After opening the ampoule into a vacuum line and observing no condensibles, the excess 1,7-octadiene was distilled off to yield 6.02 g (90.0% yield) of bis(octenyl)dichlorosilane. Step (b)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[CH3:27])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:29][OH:30].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[CH3:27])[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:29]\[OH:30])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 151, step 3, 5-(3-(4-bromophenyl)-3-(4-chloro-2-methylphenyl)propanoyl)-1-methylpyridin-2(1H)-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound containing 10% of the corresponding Z isomer as a colorless foam, MS (ESI+): m/z=461.05 [M+H]+.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][C@H:21]([NH:27][C@H:28]([C:30]([N:32]2[C@H:39]([C:40]([O:42]CC3C=CC=CC=3)=[O:41])[CH2:38][C@H:37]3[C@@H:33]2[CH2:34][CH2:35][CH2:36]3)=[O:31])[CH3:29])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>C(O)C.[C].[Pd]>[NH:11]1[CH2:12][CH2:13][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][C@H:21]([NH:27][C@H:28]([C:30]([N:32]2[C@H:39]([C:40]([OH:42])=[O:41])[CH2:38][C@H:37]3[C@@H:33]2[CH2:34][CH2:35][CH2:36]3)=[O:31])[CH3:29])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:15][CH2:16]1
Reactant: CCOC(=O)[C@H](CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@@H](C)C(=O)N1[C@H](C(=O)OCc2ccccc2)C[C@@H]2CCC[C@@H]21
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@H](CCCCC1CCNCC1)N[C@@H](C)C(=O)N1[C@H](C(=O)O)C[C@@H]2CCC[C@@H]21
Reaction time: 4 h

Procedure:
In 50 ml of ethanol is dissolved 0.26 g of benzyl (S,S,S)-2-[N-[(S)-5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl)-L-alanyl]-2-azabicyclo[3,3,0]octane-3-carboxylate, and a catalytic reduction is carried out at ambient temperature and under atmospheric pressure using 0.2 g of 10% palladium-carbon (50% wet) as a catalyst. After the reaction is allowed to proceed for 4 hours, the catalyst is filtered off, and the filtrate is concentrated under reduced pressure to give (S,S,S)-2-[N-[(S)-5-(4-piperidyl)-1-ethoxycarbonylpentyl)-L-alanyl]-2-azabicyclo[3,3,0]octane-3-carboxylic acid as a colorless oil. This product is dissolved in 5 ml of 1N aqueous sodium hydroxide, and the solution is allowed to stand at room temperature for 1 hour, made weakly acidic with 1 ml of acetic acid and purified by XAD-2 column chromatoraphy (0.15M aqueous ammonia-5% acetonitrile). The effluent is concentrated under reduced pressure, and the concentrate is lyophilized to give 0.15 g of (S,S,S)-2 -[N-[(S)-5-(4-piperidyl)-1-carboxypentyl]-L-alanyl]-2-azabicyclo-[3,3,0]octane-3-carboxylic acid as a colorless powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.O.[C:12]1(=[O:17])[CH2:16][CH2:15][CH:14]=[CH:13]1>O1CCOCC1.[B-](F)(F)(F)F.C1C2C=CC1C=C2.C1C2C=CC1C=C2.[Rh].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:14]2[CH2:15][CH2:16][C:12](=[O:17])[CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=C1C=CCC1
Reactant: OB(O)c1ccc(Br)cc1
Agent: [Rh]
Agent: C1=CC2C=CC1C2
Agent: F[B-](F)(F)F
Solvent: C1COCCO1
Solvent: O
Product: O=C1CC[C@@H](c2ccc(Br)cc2)C1
Reaction time: 0.33 h
Yield: 25.5 %

Procedure:
A solution of 4-bromophenylboronic acid (20 g, 100 mmol) in 1,4-dioxane (120 mL) was purged with nitrogen for 10 min. (R)-BINAP (0.992 g, 1.593 mmol) and bis(norbornadiene)rhodium (I) tetrafluoroborate (0.559 g, 1.494 mmol) were added sequentially, and the suspension was sonicated for 5 min. The mixture was stirred for 20 min. Water (20 mL) was added, and the reaction mixture became homogeneous. After 10 minutes, cyclopent-2-enone (8.06 mL, 100 mmol) was added, and the reaction mixture was stirred at room temperature overnight. HPLC and LCMS analysis indicated that the reaction had proceeded, but there was more starting material than product. The reaction mixture was filtered through a pad of CELITE®, and the CELITE® was washed with ethyl acetate (100 mL). The filtrate was diluted with an additional ethyl acetate (150 mL), washed with water (2×), washed with brine, and dried over anhydrous sodium sulfate. The product mixture was purified by flash silica gel chromatography using a mixture of ethyl acetate and hexane to give (R)-3-(4-bromophenyl)cyclopentanone (6.09 g, 25.5 mmol) as a white solid. The product was 98% pure by HPLC with a retention time=2.11 min.—(Condition J). LC/MS M+1=241 1H NMR (400 MHz, chloroform-d) δ 7.57-7.39 (m, 2H), 7.22-7.06 (m, 2H), 3.39 (ddd, J=10.9, 6.8, 4.1 Hz, 1H), 2.67 (dd, J=18.2, 7.4 Hz, 1H), 2.57-2.38 (m, 2H), 2.38-2.21 (m, 2H), 1.99-1.85 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([CH:11]=[O:12])=[N:9][N:8]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[C:5]2=[N:6][CH:7]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:2]2[CH:3]=[C:4]3[C:10]([CH:11]=[O:12])=[N:9][N:8]([CH:13]4[CH2:18][CH2:17][CH2:16][CH2:15][O:14]4)[C:5]3=[N:6][CH:7]=2)[CH:28]=1
Reactant: OB(O)c1cccnc1
Reactant: O=Cc1nn(C2CCCCO2)c2ncc(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1nn(C2CCCCO2)c2ncc(-c3cccnc3)cc12
Temperature: 90 °C

Procedure:
To a heterogeneous solution of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbaldehyde (III) (328 mg, 1.05 mmol) and K3PO4 (334 mg, 1.57 mmol) in DMF (10 mL) and water (2 mL) was added pyridin-3-ylboronic acid (143 mg, 1.16 mmol). The solution was purged with argon by using argon/vacuum cycle (3×). Pd(PPh3)4 (36 mg, 0.03 mmol) was added to the solution and again purged with argon. The solution was heated at 90° C. for 4 h under argon. The DMF was removed under vacuum. The residue was partitioned between EtOAc and water. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined EtOAc was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified through a silica gel column (10:90 EtOAc:hexane→50:50 EtOAc:hexane) to produce 5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbaldehyde (CXXXI) as an off-white waxy solid (283 mg, 0.92 mmol, 91% yield). 1H NMR (DMSO-d6) δ ppm 1.57-1.68 (m, 3H), 1.75-1.89 (m, 1H), 2.01-2.13 (m, 2H), 2.49-2.56 (m, 1H), 3.78 (dt, J=11 Hz, J=4 Hz, 1H), 3.94-4.03 (m, 1H), 6.25 (dd, J=10 Hz, J=2 Hz, 1H), 7.58-7.64 (m, 1H), 8.25 (td, J=8 Hz, J=2 Hz, 1H), 8.66 (dd, J=5 Hz, J=2 Hz, 1H), 8.77 (d, J=2 Hz, 1H), 9.02 (d, J=2 Hz, 1H), 9.09 (d, J=2 Hz, 1H), 10.21 (s, 1H); ESIMS found for C17H16N4O2 m/z 309.4 (M+H).
Reaction SMILES: C([O:3][C:4]([CH2:6][O:7][CH:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([C:19](=[O:37])[C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:36])[C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[Cl:35])=[CH:22][CH:21]=2)[CH2:11][CH2:10][CH2:9]1)=[O:5])C.[OH-].[Na+]>C(O)C>[C:4]([CH2:6][O:7][CH:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([C:19](=[O:37])[C:20]2[CH:21]=[CH:22][C:23]([NH:26][C:27](=[O:36])[C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[Cl:35])=[CH:24][CH:25]=2)[CH2:11][CH2:10][CH2:9]1)([OH:5])=[O:3]
Reactant: CCOC(=O)COC1CCCN(C(=O)c2ccc(NC(=O)c3ccc(Cl)cc3Cl)cc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COC1CCCN(C(=O)c2ccc(NC(=O)c3ccc(Cl)cc3Cl)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
5-Ethoxycarbonylmethoxy-1-[4-(2,4-dichlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.94 g) is dissolved in ethanol (100 ml) and thereto is added 5N aqueous sodium hydroxide solution (0.50 ml). The mixture is stirred at room temperature for 2 hours. The reaction solution is concentrated under reduced pressure and to the resulting residue is added diluted hydrochloric acid and then extracted with dichloromethane. The extract is dried over magnesium sulfate and the solvent is distilled off. The resulting residue is washed with n-hexane and collected by filtration to give 5-carboxymethoxy-1-[4-(2,4-dichlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.79 g) as colorless amorphous.
Reaction SMILES: [CH2:1]1[C:4](=[O:5])[N:3]2[C@@H:6]([C:12]([OH:14])=[O:13])/[C:7](/[O:11][C@H:2]12)=[CH:8]/[CH2:9][OH:10].C(=O)([O-])[O-].[K+:19].[K+]>>[CH2:1]1[C:4](=[O:5])[N:3]2[C@@H:6]([C:12]([O-:14])=[O:13])/[C:7](/[O:11][C@H:2]12)=[CH:8]/[CH2:9][OH:10].[K+:19]
Reactant: O=C(O)[C@H]1/C(=C/CO)O[C@@H]2CC(=O)N21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C([O-])[C@H]1/C(=C/CO)O[C@@H]2CC(=O)N21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 91.9 %

Procedure:
The inclusion complex (100 g) of clavulanic acid with heptakis-(2,3,6-tri-O-acetyl)-β-CD, which was prepared in the same way as in Example 4, was suspended in a 3% aqueous potassium carbonate solution (200 ml), in which methyl-β-CD (53.6 g, 40.9 mmol) was dissolved. The suspension was stirred for 5 min at ambient temperature, the solid particles were filtered off and the filtrate was frozen in liquid nitrogen and then freeze-dried. There was obtained a yellowish microcrystalline inclusion complex (56.7 g, 91.9%) of potassium clavulanate with methyl-β-CD. The complex contained 14.9% of potassium clavulanate as it was determined by the HPLC method.
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1>O.CC(C)=O>[CH3:9][O:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][C:5]2[C:4]([NH:15][C:14]3[CH:16]=[CH:17][C:11]([O:10][CH3:9])=[CH:12][CH:13]=3)=[N:3][C:2](=[O:1])[C:7](=[O:8])[CH:6]=2)=[CH:13][CH:12]=1
Reactant: Oc1cccnc1O
Reactant: COc1ccc(N)cc1
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(NC2=CC(=O)C(=O)N=C2Nc2ccc(OC)cc2)cc1
Reaction time: 2 h
Yield: 32 %

Procedure:
2,3-dihydroxypyridine (0.0027 mol), p-methoxyaniline (0.0054 mol); and NaIO3 (0.0009 mol) were dissolved in 160 ml of water/acetone (80:1, v/v) solvent. The reaction mixture was stirred for 2 hours, and maintained still overnight. It was then filtered, and recrystallized with chloroform. The final product was 5,6-di(p-methoxyphenylamino)-2,3-pyridindione in a red powder. The yield was 32%-50%.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]2[O:8][C:9]([CH2:15][C:16]([F:19])([F:18])[F:17])([C:11]([F:14])([F:13])[F:12])[O:10][C:6]=2[CH:5]=1)([O-])=O>O1CCCC1.[H][H]>[NH2:1][C:4]1[CH:21]=[CH:20][C:7]2[O:8][C:9]([CH2:15][C:16]([F:19])([F:18])[F:17])([C:11]([F:12])([F:13])[F:14])[O:10][C:6]=2[CH:5]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc2c(c1)OC(CC(F)(F)F)(C(F)(F)F)O2
Solvent: C1CCOC1
Product: Nc1ccc2c(c1)OC(CC(F)(F)F)(C(F)(F)F)O2

Procedure:
57.4 g of the product of Example 15a were dissolved in 400 ml of tetrahydrofuran and hydrogenated with hydrogen for 5 hours at 30° C. at 50 bar in the presence of 4 g of catalyst (palladium on charcoal, 10% strength by weight). The mixture was then subjected to filtration, the solvent was removed and the residue was distilled under a high vacuum. This gave 37 g of product (=63% of theory) having a boiling point of 83° C. at 0.07 mbar. 19F-NMR: -59.0 and -84.6 ppm. 1H-NMR: 2.98 ppm.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C:7]2([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:12][C:11]([OH:13])=[N:10][C:8]2=[O:9])=[CH:5][CH:6]=1.C=O.[C:22]([O-])([O-])=[O:23].[K+].[K+]>O>[C:14]1([C:7]2([C:4]3[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=3)[NH:12][C:11](=[O:13])[N:10]([CH2:22][OH:23])[C:8]2=[O:9])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1N=C(O)NC1(c1ccccc1)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: [K+]
Solvent: O
Product: O=C1NC(c2ccccc2)(c2ccccc2)C(=O)N1CO
Reaction time: 24 h
Yield: 91 %

Procedure:
Phenytoin (5 g, 0.02 mol) was suspended in 180 ml of water; 20 ml of formaldehyde (37% solution) and 0.25 g K2CO3 were added and the mixture was stirred at 25°-30° C. for 24 hours. The white solid which formed was removed by filtration and washed repeatedly with a 3% solution of formaldehyde, then air dried for 3 to 4 hours and over P2O5 in a vacuum dessicator. Yield 91-93%, m.p. 185°-189° C. Anal. calc. for C16H14N2O3 : C, 68.07; H, 5.00; N, 9.93. Found: C, 67.97; H, 5.05; N, 9.93. The product has the formula: ##STR1532##
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[CH3:10].Cl.[O:12]([NH2:14])[CH3:13]>>[CH3:13][O:12][N:14]=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([F:1])=[C:3]([CH3:10])[CH:4]=1
Reactant: Cc1cc(C=O)ccc1F
Reactant: CON
Agent: Cl
Product: CON=Cc1ccc(F)c(C)c1

Procedure:
Reaction of 4-fluoro-3-methyl-benzaldehyde with methoxylamine hydrochloride as described in the preparation of compound 1-A gave the title oxime ether as a clear oil after chromatography on silica gel (elution hexane-ethyl acetate 8:2) (100% yield). 1HNMR indicated a 9:1 mixture of E- and Z-isomers. 1HNMR 400 MHz (CDCl3) δ (ppm): (E-isomer) 2.29 (3H, broad s, CH3), 3.96 (3H, s, OCH3), 7.0 (1H, m, aromatic), 7.34 (1H, m, aromatic), 7.4 (1H, m, aromatic), 8.0 (1H, s, CH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11][CH3:12])[CH:10]=1)[NH:7][C:6](=O)[C:5]2=O.[BH4-].[Li+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11][CH3:12])[CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: CCc1cc(Br)cc2c1NC(=O)C2=O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1cc(Br)cc2cc[nH]c12
Temperature: 90 °C
Reaction time: 5 h

Procedure:
To a solution of 5-bromo-7-ethyl-1H-indole-2,3-dione (36.g, 144 mmol) in tetrahydrofuran (120 mL) at room temperature was dropped a 2.0 M solution of lithium borohydride in tetrahydrofuran. The reaction mixture was stirred at 90° C. (oil bath) for 5 hours. After cooling down to room temperature, it was quenched with 5% hydrochloric acid solution until the excess lithium borohydride was destroyed. To the mixture was added saturated sodium bicarbonate solution (300 mL) and extracted with ethyl acetate. Extracts were dried over magnesium sulfate and concentrated under reduced pressure to give the crude product of 5-bromo-7-ethyl-1H-indole, which went to next reaction without further purification.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([O:17][CH3:18])[C:6]([NH:9][CH2:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[N:7][CH:8]=1)#[N:2].[CH2:19]([O:26][C:27](ON1C(=O)CCC1=O)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([O:26][C:27]([N:14]1[CH2:15][CH2:16][CH:11]([CH2:10][NH:9][C:6]2[C:5]([O:17][CH3:18])=[N:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=2)[CH2:12][CH2:13]1)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: COc1nc(C#N)cnc1NCC1CCNCC1
Product: COc1nc(C#N)cnc1NCC1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
The above compound was prepared in a similar manner as described in EXAMPLE 130 from 4-[(5-cyano-3-methoxy-pyrazin-2-ylamino)-methyl]-piperidine using N-(benzyloxycarbonyloxy)succinimide (Sigma-Aldrich). M.S.(M+1): 382.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:25])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9](Br)=[CH:8]2)=[O:4].[C:26]1([Sn](CCCC)(CCCC)CCCC)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CCOC(C)=O>CN(C=O)C.[Cl-].[Na+].O.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>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:25])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[CH:8]2)=[O:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Reactant: COC(=O)c1ncc2c(cc(Br)c(=O)n2CCc2ccccc2)c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2CCc2ccccc2)c1O
Temperature: 120 °C
Yield: 92 %

Procedure:
A mixture of 3-bromo-5-hydroxy-2-oxo-1-phenethyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (166 mg, 0.41 mmol), PhSnBu3 (0.16 mL, 0.49 mmol), and PdCl2(PPh3)2 (58 mg, 0.082 mmol) in DMF (4 mL) was heated at 120° C. under nitrogen atmosphere for 2 h. After the mixture was cooled to r.t., brine (10 mL) and EtOAc (50 mL) were added. The aqueous layer was extracted with additional EtOAc and the organic layers were combined, washed with water, and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was chromatographed (0-40% EtOAc/hexanes+2% AcOH) to give 151 mg of the title compound as a light yellow solid. MS: (+) m/z 401.30 (M+1).