Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.Cl.[CH2:8]([O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>ClCCl.Cl>[CH2:8]([O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:20][C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:5])=[CH:21][CH:22]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(OCc2ccccc2)cc1)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Cyclopropane carbonyl chloride (4.54 ml) was added dropwise over 5 min to a stirred solution of 4-benzyloxyaniline hydrochloride (11.8 g) and triethylamine (15.33 ml) in dichloromethane (60 ml). The reaction mixture was stirred at room temperature under nitrogen for 2 h. The solution was diluted with 2N hydrochloric acid (100 ml) and dichloromethane (200 ml). The organic layer was washed with 2N sodium carbonate (100 ml), water (100 ml), 10% brine (50 ml) and dried over anhydrous sodium sulphate. Concentration in vacuo gave a pale brown solid which was washed with diethyl ether (3×50 ml) to afford the title compound (12 g) as a white solid, m.p. 162°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:27][O:28][CH2:29][CH2:30]Cl>CN(C)C=O.ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH2:30][CH2:29][O:28][CH3:27])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1
Reactant: N#Cc1cc(O)cc(-c2nc(-c3ccccn3)no2)c1
Reactant: COCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COCCOc1cc(C#N)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 150 °C
Yield: 49.6 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (40 mg, 0.15 mmol), potassium carbonate (42 mg, 0.30 mmol) and 2-chloroethyl methyl ether (83 μL, 0.91 mmol) in N,N-dimethylformamide (1 mL) was heated in a sealed vial at 150° C. for 5 minutes. The reaction was cooled, diluted with dichloromethane, washed with water (3×) and saturated brine, filtered and concentrated. Silica gel chromatography using hexanes:ethyl acetate:dichloromethane 1:1:2 followed by trituration with diethyl ether afforded 24 mg (50%) of 3-(2-pyridyl)-5-(3-cyano-5-(2-methoxyethoxy)phenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3), δ (ppm): 8.87 (d, 1H), 8.23 (d, 1H), 8.17 (s, 1H), 8.04 (s, 1H), 7.91 (t, 1H), 7.49 (m, 1H), 7.45 (s, 1H), 4.27 (t, 2H), 3.81 (t, 2H), 3.48 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH:16]=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1([NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH2:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.CN(C=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][NH:24][C:19]2[C:18]([NH2:25])=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1N
Reactant: O=CCCC1CCN(Cc2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Nc1ccccc1NCCCC1CCN(Cc2ccccc2)CC1

Procedure:
The title compound was prepared from 300 mg 3-(1-benzyl-piperidin-4-yl)-propionaldehyde (from Step D), 300 mg of 1,2-phenylenediamine and 200 mg sodium triacetoxyborohydride in THF and DMF using a procedure analogous to that described in Example 1, Step J.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]([CH3:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11].[Br:17][CH:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19](Cl)=[O:20].C(=O)([O-])O.[Na+]>C(#N)C>[Br:17][CH:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19]([NH:8][C:9]([CH3:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:20]
Reactant: CCOC(=O)C(C)(C)N
Reactant: O=C(Cl)C(Br)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)C(C)(C)NC(=O)C(Br)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 41.4 %

Procedure:
Triethylamine (11 g) was added suspension of ethyl aminoisobutyrate (7.5 g) in acetonitrile (80 mL) cooled to 0° C., and to the mixture was slowly added dropwise a solution of α-bromophenylacetyl chloride (11 g) in acetonitrile (20 mL). After the addition was completed, the solution was warmed to room temperature, and stirred overnight. The reaction solution was poured into a sodium hydrogencarbonate aqueous solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then the resulting crude product was washed with diisopropyl ether to give 6.4 g of ethyl 2-(α-bromophenylacetylamino)isobutyrate.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH3:11].B1([C:18]2[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=2)OCCCO1.C([O-])([O-])=O.[Na+].[Na+]>CCO.C1(C)C=CC=CC=1.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>[CH3:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: c1cncc(B2OCCCO2)c1
Reactant: Cc1ccc([N+](=O)[O-])cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc([N+](=O)[O-])cc1-c1cccnc1
Yield: 103.1 %

Procedure:
A mixture of 2-bromo-4-nitrotoluene (3 g, 13.0 mmol) and pyridine-3-boronic acid-1,3-propanediol cyclic ester (2.72 g, 16.7 mmol) in EtOH (30 ml) and toluene (30 ml) together with 2N Na2CO3 solution (13.9 ml) was degassed with a stream of N2 for 10 min. Tetrakis(triphenylphosphine)palladium(0) (0.3 g, 0.26 mmol) was added and the reaction heated at reflux for 4 h. The mixture was concentrated under reduced pressure to remove the organic solvents and water (100 ml) was added. The organics were extracted with EtOAc (200 ml) and then washed with brine (75 ml), dried (MgSO4), and concentrated under reduced pressure while dry loading onto silica. The resulting crude residue was purified by column chromatography on silica, using 60% diethyl ether in hexane as the eluent, to yield 3-(2-methyl-5-nitrophenyl)pyridine (2.87 g, 99%): δH (360 MHz, CDCl3) 2.38 (3H, s), 7.36-7.50 (2H, m), 7.67 (1H, dt, J 7.9 and 1.9), 8.10 (1H, d, J 2.4), 8.61 (1H, d, J 1.8), 8.67 (1H, dd, J 4.8 and 1.5).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[S:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1.[C:16](O)(=[O:20])[C:17]([CH3:19])=[CH2:18].C(=O)(O)O.ClC(OCC)=O>>[C:16]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[S:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1)(=[O:20])[C:17]([CH3:19])=[CH2:18]
Reactant: C=C(C)C(=O)O
Reactant: NCCCCCc1nc2ccccc2s1
Agent: CCOC(=O)Cl
Agent: O=C(O)O
Product: C=C(C)C(=O)NCCCCCc1nc2ccccc2s1

Procedure:
2-(5-Aminopentyl)benzothiazole (synthesized from 2-aminobenzenethiol and ε-caprolactam) was reacted with a mixed acid anhydride of methacrylic acid and carbonic acid prepared through reaction of methacrylic acid and ethyl chloroformate under basic conditions to obtain 2-(5-methacryloylaminopentyl)benzothiazole. Copolymerization with acrylic acid afforded a Polymer [BP-3] which is used in the present invention. The weight average molecular weight measured by GPC was 11.0×104 (polystyrene standard)
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([OH:18])=[CH:4][C:3]=1[O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.O1CCOCC1.[F-:36].[K+]>O>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([OH:18])=[CH:4][C:3]=1[O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([F:36])(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: [F-]
Reactant: Nc1c(Oc2ccc(S(=O)(=O)Cl)cc2)cc(O)c2c1C(=O)c1ccccc1C2=O
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1c(Oc2ccc(S(=O)(=O)F)cc2)cc(O)c2c1C(=O)c1ccccc1C2=O
Temperature: 25 °C

Procedure:
To a mixture of 1-amino-4-hydroxy-2-(4-chlorosulphonylphenoxy)anthraquinone (2 parts) and 1,4-dioxane (25 parts), stirring at ambient temperature, was added a solution of potassium fluoride (0.6 parts) in water (5 parts). The mixture was heated to 60° C. and stirred at this temperature for 20 minutes. After cooling to 0°-5° C., the product was isolated by filtration, washed with water and dried at 50° C. to yield: 1-amino-4-hydroxy-2-(4-fluorosulphonylphenoxy)anthraquinone (1.6 parts). λmax=515.0 nm (CH2Cl2).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.C([O-])([O-])=O.[Na+].[Na+].[C:16](=O)([O:25]N1C(=O)CCC1=O)[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O.CC#N>[CH2:18]([O:17][C:16]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1)=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: O=C(O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 22.4 %

Procedure:
To a solution of piperidine-4-carboxylic acid (10.0 g, 77.4 mmol) and Na2CO3 (8.21 g, 77.4 mmol) in water (100 mL) was added a solution of benzyl 2,5-dioxopyrrolidin-1-yl carbonate (19.3 g, 77.4 mmol) in MeCN (100 mL). The reaction was stirred at ambient temperature for about 16 h and then concentrated under reduced pressure. The resulting aqueous solution was quenched with aqueous NH4Cl and was then extracted with EtOAc (2×100 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 1-(benzyloxycarbonyl)piperidine-4-carboxylic acid as a white solid (4.56 g, 22%): LC/MS (Table 2, Method a) Rt=1.93 min; MS m/z: 262 (M−H)−.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[CH:10]1.[Li]C(C)(C)C.CN([CH:26]=[O:27])C.C([O-])(O)=O.[Na+]>C1COCC1.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[CH:26]=[O:27]
Reactant: CN(C)C=O
Reactant: c1ccc(CCn2cnc3ccccc32)nc1
Agent: O=C([O-])O
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1nc2ccccc2n1CCc1ccccn1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
Under an atmosphere of Ar, 1-(2-pyridin-2-yl-ethyl)-1H-benzimidazole (0.46 g, 2.1 mmol) (Ichikawa, M. et al. Chem. Pharm. Bull. 1981, 29, 3042-7) was dissolved in anhydrous THF (10 mL), cooled to −40° C., and treated with tert-BuLi (1.5 mL, 1.7M, 2.5 mmol) for 30 minutes. DMF (0.80 mL, 10.3 mmol) was then added and the solution slowly warmed to room temperature. After 1 hour, water (10 mL) and saturated aqueous NaHCO3 solution (10 mL) were added and the medium was extracted with EtOAc (3×25 mL). The combined organic phases were then dried (MgSO4), filtered, and concentrated under reduced pressure. The crude product was then purified by column chromatography with silica gel (50:1:0.1 MeOH:NH4OH:CH2Cl2) to afford 1-(2-pyridin-2-yl-ethyl)-1H-benzimidazole-2-carbaldehyde as a brown liquid that was used immediately in the next reaction (147 mg, 28%).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=O)[N:5]=[C:6]([C:8]#[N:9])[N:7]=1.P(Cl)(Cl)([Cl:13])=O.C(=O)([O-])[O-].[Na+].[Na+]>>[NH2:1][C:2]1[N:3]=[C:4]([Cl:13])[N:5]=[C:6]([C:8]#[N:9])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1nc(N)[nH]c(=O)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: N#Cc1nc(N)nc(Cl)n1
Temperature: 25 °C

Procedure:
To 2-amino-4-cyano-6-oxo-1,3,5-triazine (J. Am. Chem. Soc., 1961, 83, 1261-2, 2.30 g, 16.8 mmol) was added phosphoryl trichloride (50 mL, 547 mmol) and the mixture heated at 90 C for 2 h. The reaction mixture was cooled to room temperature before pouring onto ice-water (250 mL) and basifying to pH 8 with solid sodium carbonate. The mixture was then extracted into DCM (3×250 mL) and the combined organics were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the desired compound, which was used crude without further purification (343 mg, 13%). Method C HPLC-MS: 2 MH+ requires m/z=311. Found: m/z=311, Rt=0.74 min (100%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:12][CH:13]([O:19][CH:20]([CH3:22])[CH3:21])[C:14]([O:16]CC)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[Cl:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1>>[Cl:23][C:24]1[CH:25]=[C:26]([CH:27]=[CH:28][CH:29]=1)[NH:30][C:31]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:12][CH:13]([O:19][CH:20]([CH3:21])[CH3:22])[C:14]([OH:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])=[O:32]
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CCO)c1)OC(C)C
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1CCOC(=O)Nc1cccc(Cl)c1

Procedure:
Using ethyl 3-[3-(2-hydroxyethyl)-4-methoxyphenyl]-2-isopropoxypropanoate and 3-chlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: [C:1]([C:9]1([CH2:16][CH2:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[O:19])[CH2:14]CCC[C:10]1=[O:15])(=O)[C:2]1C=CC=C[CH:3]=1.[OH:30]O>C(O)(C)(C)C.S(=O)(=O)(O)O>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][O:20][C:18]([CH2:17][CH2:16][C:9]2([C:10]([OH:30])=[O:15])[CH2:14][CH2:3][CH2:2][CH2:1]2)=[O:19])=[CH:23][CH:24]=1
Reactant: OO
Reactant: COc1ccc(COC(=O)CCC2(C(=O)c3ccccc3)CCCCC2=O)cc1
Agent: O=S(=O)(O)O
Solvent: CC(C)(C)O
Product: COc1ccc(COC(=O)CCC2(C(=O)O)CCCC2)cc1
Reaction time: 48 h
Yield: 44.5 %

Procedure:
To a solution of 2-benzoyl-2-[2-(4-methoxybenzyloxycarbonyl)-ethyl]cyclohexanone (see Preparation 9) (2.16 g, 5.47 mmol) in tert-butanol (4.3 ml) was added, dropwise, a 30% aqueous solution of hydrogen peroxide (0.74 ml, 6.56 mmol) and concentrated sulphuric acid (98% w/w, one drop) at room temperature. The mixture was stirred for 48 hours, partitioned between toluene (25 ml) and 5% aqueous sodium sulphite solution and the layers separated. The toluene layer was washed with dilute aqueous ammonia solution (25 ml of 0.880 ammonia in 200 ml of distilled water, 4×25 ml). The combined aqueous extracts were washed with toluene (25 ml), acidified to pH 2-3 with 5.ON aqueous hydrochloric acid solution and extracted with toluene (3×25 ml). The combined toluene extracts were dried over magnesium sulphate, filtered and concentrated under reduced pressure to give the title compound as an oil, (0.746 g, 44.6%). RF. 0.16 silica, hexane/ethyl acetate 2:1). 1H-NMR (300 MHz, CDCl3) =1.45-1.59 (m, 2H), 1.65-1.78 (m, 4H), 1.98-2.06 (m, 2H), 2.12-2.22 (m, 2H), 2.34-2.46 (m, 2H), 3.84 (s, 3H), 5.06 (s, 2H), 6.91 (d, 2H), 7.31 (d, 2H) ppm. Analysis %: Found: C, 67.05; H, 7.18; C17 H2205 requires C, 66.65; H, 7.24.
Reaction SMILES: [Cl-].[OH:2][NH3+:3].C(=O)([O-])O.[Na+].[CH3:9][O:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([CH2:24][C:25]3[N:30]=[C:29]([C:31]#[N:32])[CH:28]=[CH:27][CH:26]=3)=[C:16]([C:20]3([CH3:23])[CH2:22][CH2:21]3)[NH:17]2)=[CH:13][CH:12]=1>CS(C)=O.O>[CH3:9][O:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([CH2:24][C:25]3[N:30]=[C:29]([C:31](=[N:3][OH:2])[NH2:32])[CH:28]=[CH:27][CH:26]=3)=[C:16]([C:20]3([CH3:23])[CH2:22][CH2:21]3)[NH:17]2)=[CH:13][CH:12]=1
Reactant: [NH3+]O
Reactant: COc1ccc2c(Cc3cccc(C#N)n3)c(C3(C)CC3)[nH]c2c1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc2c(Cc3cccc(C(N)=NO)n3)c(C3(C)CC3)[nH]c2c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 106.3 %

Procedure:
To a solution of hydroxylammonium chloride (117 mg) in dimethylsulfoxide (1.7 mL) was added sodium hydrogen carbonate (170 mg), and the mixture was stirred at 50° C. for 1 hour. Then, a solution of 6-[6-methoxy-2-(1-methylcyclopropyl)-1H-indol-3-ylmethyl]pyridine-2-carbonitrile (53.6 mg) in dimethylsulfoxide (1.7 mL) was added dropwise thereto, followed by stirring at 80° C. for 2.5 hours. The reaction mixture was left to be cooled and diluted with water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the title compound (62.9 mg). 1H-NMR (CDCl3) δ ppm: 0.68-0.76 (2H, m), 0.84-0.92 (2H, m), 1.34 (3H, s), 3.82 (3H, s), 4.35 (2H, s), 5.68 (2H, br s), 6.69 (1H, dd, J=2.3, 8.8 Hz), 6.82 (1H, d, J=2.3 Hz), 6.98-7.05 (1H, m), 7.23 (1H, d, J=8.8 Hz), 7.50 (1H, t, J=7.8 Hz), 7.66-7.73 (1H, m), 7.82 (1H, br s). ESI-MS (m/z): 351 (M+H)+
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:15](=[O:16])[N:5]2[C:6]([C:12]([OH:14])=[O:13])=[C:7]([CH:10]=[O:11])[CH2:8][S:9][C@H:4]12.N1C=CC=CC=1>CO>[NH2:2][C@@H:3]1[C:15](=[O:16])[N:5]2[C@@H:4]1[S:9][CH2:8][C:7]([CH:10]=[O:11])=[C:6]2[C:12]([OH:14])=[O:13]
Reactant: NC1C(=O)N2C(C(=O)O)=C(C=O)CS[C@H]12
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: N[C@@H]1C(=O)N2C(C(=O)O)=C(C=O)CS[C@H]12

Procedure:
2.64 g of the hydrochloride of 6-amino-1,4,5a,6-tetrahydro-3-hydroxy-1,7-dioxo-3H,7H-aceto[2,1-b]furo[3,4-d][1,3]thiazine (hydroxylactone of the hydrochloride of 7-amino-3-formyl-3-cephem-4-carboxylic acid) are dissolved in 50 ml of methanol. A solution of 0.78 g of pyridine in 10 ml of methanol is added dropwise to this solution whilst stirring and cooling with ice. The precipitated product is filtered off under nitrogen whilst excluding moisture, washed with a little methanol and dried over a drying agent in vacuo at room temperature. (6R-trans)-7-amino-3-formyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid is thus obtained in the form of a light brown powder. IR (KBr): 1799 cm-1 (β-lactam), 1672 cm-1 (CHO), 1606 and 1542 cm-1 (carboxylate) UV spectrum: λmax in H2O=302 nm.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:25][C:26]1[CH:46]=[CH:45][C:29]2[NH:30][C:31]([C@@H:33]3[CH2:37][CH2:36][CH2:35][N:34]3[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[N:32][C:28]=2[CH:27]=1.O>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]([CH2:25][C:26]2[CH:46]=[CH:45][C:29]3[NH:30][C:31]([C@@H:33]4[CH2:37][CH2:36][CH2:35][N:34]4[C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])=[N:32][C:28]=3[CH:27]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:16][CH:17]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CNc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2cc(CBr)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2cc(CN(Cc3ccc([N+](=O)[O-])cc3)c3ccccc3)ccc2[nH]1
Reaction time: 2.5 h
Yield: 28.6 %

Procedure:
The product from Example 20A (0.530 g, 2.32 mmol) and K2CO3 (0.802 g, 5.81 mmol) were combined in dry DMF (20 mL) at room temperature, and nitrogen was bubbled through the solution for 10 min. The product from Example 7C (1.0 g, 2.63 mmol) was added in three equal portions in 20 min. intervals, and the reaction was stirred a total of 2.5 h. The mixture was poured into water, extracted into EtOAc, washed with brine. The organic was dried (MgSO4), filtered and evaporated. The product was purified by chromatography on silica gel, eluting with c 0-4% MeOH in CH2Cl2, and a second column eluting with 0-5% EtOAc in CH2Cl2 to give the title compound (0.350 g, 28.6% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:32]2[CH:33]=[N:34][N:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=23)=[N:4][C:5]([NH:8][C:9]2[C:14]([O:15][CH3:16])=[CH:13][C:12]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][C:24]([N:26]([CH3:28])[CH3:27])=[O:25])[CH2:19][CH2:18]3)=[C:11]([N+:29]([O-])=O)[CH:10]=2)=[N:6][CH:7]=1.[NH4+].[Cl-]>C(O)C.O.[Fe]>[NH2:29][C:11]1[CH:10]=[C:9]([NH:8][C:5]2[N:4]=[C:3]([C:32]3[CH:33]=[N:34][N:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=34)[C:2]([Cl:1])=[CH:7][N:6]=2)[C:14]([O:15][CH3:16])=[CH:13][C:12]=1[N:17]1[CH2:18][CH2:19][N:20]([CH2:23][C:24]([N:26]([CH3:27])[CH3:28])=[O:25])[CH2:21][CH2:22]1
Reactant: COc1cc(N2CCN(CC(=O)N(C)C)CC2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1cc(N2CCN(CC(=O)N(C)C)CC2)c(N)cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Temperature: 25 °C
Yield: 86.5 %

Procedure:
A mixture of 2-(4-{4-[(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]-5-methoxy-2-nitrophenyl}piperazin-1-yl)-N,N-dimethylacetamide (Intermediate 58, 0.234 g, 0.41 mmol), iron (0.139 g, 2.48 mmol) and NH4Cl (0.015 g, 0.29 mmol) in ethanol (10 mL) and water (3.33 mL) was heated at reflux for 4 h. The mixture was then allowed to cool to r.t., was filtered and the filtrate concentrated in vacuo. Purification by ion exchange chromatography, using an SCX column and eluting with 1M methanolic ammonia, gave a brown gum after concentration of appropriate fractions. Further purification by FCC, eluting with 0-5% CH3OH in CH2Cl2 gave the title compound (0.19 g, 86%) as a yellow foam; 1H NMR: (CDCl3) 2.72 (4H, s), 2.93-3.01 (7H, m), 3.13 (3H, s), 3.27 (2H, s), 3.65-3.83 (2H, m), 3.84 (3H, s), 6.71 (1H, s), 6.96 (1H, td), 7.38 (1H, ddd), 7.55 (1H, s), 7.92 (1H, s), 8.36 (1H, s), 8.57 (1H, dt), 8.61-8.68 (1H, m), 8.94 (1H, s); m/z: ES+ MH+ 536.53.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:31])=[C:6]([CH:30]=1)[O:7][C:8]1[N:9]=[C:10]([NH:21][C:22]2[CH:23]=[N:24][N:25]([CH2:27][CH2:28][OH:29])[CH:26]=2)[C:11]([C:18]([NH2:20])=[O:19])=[N:12][C:13]=1[C:14](O)([CH3:16])[CH3:15].C(N(C(C)C)CC)(C)C>CN1CCCC1=O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:31])=[C:6]([CH:30]=1)[O:7][C:8]1[N:9]=[C:10]([NH:21][C:22]2[CH:23]=[N:24][N:25]([CH2:27][CH2:28][OH:29])[CH:26]=2)[C:11]([C:18]([NH2:20])=[O:19])=[N:12][C:13]=1[C:14]([CH3:16])=[CH2:15]
Reactant: CC(C)(O)c1nc(C(N)=O)c(Nc2cnn(CCO)c2)nc1Oc1cc(N)ccc1F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C)c1nc(C(N)=O)c(Nc2cnn(CCO)c2)nc1Oc1cc(N)ccc1F
Yield: 82.7 %

Procedure:
A mixture of 5-(5-amino-2-fluorophenoxy)-3-{[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]amino}-6-(2-hydroxypropan-2-yl)pyrazine-2-carboxamide (515 mg), diisopropylethylamine (409 μL), and N-methylpyrrolidone (3 mL) was reacted in a microwave reaction device at 200° C. for 4 hours. The mixture was purified by silica gel column chromatography (eluent; chloroform:methanol=98:2-90:10) to obtain 5-(5-amino-2-fluorophenoxy)-3-{[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]amino}-6-(prop-1-en-2-yl)pyrazine-2-carboxamide (408 mg) as a yellow solid.
Reaction SMILES: [Na].CS(C)=O.[Cl:6][C:7]1[CH:8]=[C:9]([N:13]2[CH:17]=[N:16][C:15]([OH:18])=[N:14]2)[CH:10]=[CH:11][CH:12]=1.Br[CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CO>[Cl:6][C:7]1[CH:8]=[C:9]([N:13]2[CH:17]=[N:16][C:15]([O:18][CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH3:26])=[N:14]2)[CH:10]=[CH:11][CH:12]=1
Reactant: Oc1ncn(-c2cccc(Cl)c2)n1
Reactant: CCOC(=O)C(C)Br
Agent: [Na]
Solvent: CO
Solvent: CS(C)=O
Product: CCOC(=O)C(C)Oc1ncn(-c2cccc(Cl)c2)n1
Temperature: 0 °C
Reaction time: 4 h
Yield: 29.4 %

Procedure:
A 2.2 g portion of sodium was dissolved in 75 ml of methanol and the solution was added to 100 ml of dimethylsulfoxide. To that was added 19.2 g of 1-(3-chlorophenyl)-3-hydroxy-1,2,4-1H-triazole, and the mixture was stirred on the steam bath for 4 hours. To it was then added 17.7 g of ethyl 2-bromopropionate, and heating was continued for 2 hours more. The mixture was then cooled and poured over ice-water, and the solid was collected, dried and recrystallized from ethanol and then from toluene to obtain 8.5 g of the desired product, m.p. 70°-72°.