Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:12][C:5]2[CH2:6][O:7][C:8]([CH3:11])([CH3:10])[CH2:9][C:4]=2[C:3]=1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[Br:20][C:21]1[CH:31]=[CH:30][CH:29]=[CH:28][C:22]=1[C:23]([N:25]=[C:26]=[S:27])=[O:24]>C1COCC1>[Br:20][C:21]1[CH:31]=[CH:30][CH:29]=[CH:28][C:22]=1[C:23]([NH:25][C:26](=[S:27])[NH:1][C:2]1[S:12][C:5]2[CH2:6][O:7][C:8]([CH3:11])([CH3:10])[CH2:9][C:4]=2[C:3]=1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:24]
Reactant: O=C(N=C=S)c1ccccc1Br
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CC(C)(C)OC2
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1c(NC(=S)NC(=O)c2ccccc2Br)sc2c1CC(C)(C)OC2
Temperature: 50 °C
Yield: 49 %

Procedure:
tert-Butyl 2-amino-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate (0.28 g, 1.00 mmol) and 2-bromobenzoyl isothiocyanate (0.24 g, 1.00 mmol) were dissolved in THF (5 mL) and heated at 50° C. for 22 hours. The solvent was removed and EtOH (10 mL) was added. The product was filtered and rinsed with EtOH (2×10 mL). tert-Butyl 2-(3-(2-bromobenzoyl)thioureido)-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate (0.26 g, 0.49 mmol, 49% yield) was isolated as a white solid. 1H NMR (400 MHz, CDCl3) δ 14.64 (s, 1H), 9.04 (s, 1H), 7.75 (apparent dd, J=7.6, 1.8 Hz, 1H), 7.67 (apparent dd, J=7.9, 1.1 Hz, 1H), 7.45 (apparent td, J=7.5, 1.3 Hz, 1H), 7.40 (apparent td, J=7.7, 1.9 Hz, 1H), 4.74 (apparent t, J=1.5 Hz, 2H), 2.77 (t, J=1.5 Hz, 2H), 1.63 (s, 9H), 1.31 (s, 6H).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[N:9]([CH3:28])[N:10]=[C:11]([O:13][CH2:14][C:15]2[N:16]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[N:17]=[N:18][C:19]=2[CH3:20])[CH:12]=1)=[O:7]>O.C1COCC1>[F:27][C:24]1[CH:23]=[CH:22][C:21]([N:16]2[C:15]([CH2:14][O:13][C:11]3[CH:12]=[C:8]([C:6]([OH:7])=[O:5])[N:9]([CH3:28])[N:10]=3)=[C:19]([CH3:20])[N:18]=[N:17]2)=[CH:26][CH:25]=1
Reactant: COC(=O)c1cc(OCc2c(C)nnn2-c2ccc(F)cc2)nn1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nnn(-c2ccc(F)cc2)c1COc1cc(C(=O)O)n(C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
A solution of lithium hydroxide monohydrate (146 mg, 3.48 mmol) in water (6 mL) was added dropwise to a suspension of 5-[3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (600 mg, 1.74 mmol) in THF (6 mL). The reaction mixture was then stirred at room temperature for 2 h and was then evaporated and the residue dissolved in water, acidified with HCl (1N), and the resulting precipitate filtered off to afford the title product (544 mg, 95%) as a white solid. MS: m/e=330.2 [M−H]−.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1.C([Li])CCC.C(O[B:24]1[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]1)(C)C>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[B:24]2[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]2)[CH2:2][CH2:3]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: c1cc2c(cc1OCC1CC1)OCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)OB(c2c(OCC3CC3)ccc3c2OCO3)OC1(C)C
Reaction time: 2 h

Procedure:
A stirred solution of 5-cyclopropylmethoxy-benzo[1,3]dioxole from example A8 (38.44 g; 200.0 mmol) in dry THF (500 mL) is cooled to −40° C. before n-butyl lithium (138.0 mL; 1.6 M solution in hexane; 220 mmol) is slowly added via syringe. After complete addition, stirring is continued at −40° C. for two hours. At −78° C. neat 2-iso-propoxy-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (40.95 g; 220.0 mmol) is added via syringe and stirring is continued at −78° C. for two hours.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][O:6][CH2:5][CH:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:3]1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:16][S:17]([O:1][CH:2]1[CH2:3][CH:4]([NH:8][C:9]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:15])[CH2:5][O:6][CH2:7]1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC1COCC(O)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1COCC(OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.7 %

Procedure:
A solution of tert-butyl 5-hydroxy-tetrahydro-2H-pyran-3-ylcarbamate (109 mg, 0.5 mmol) and N,N-dimethylpyridin-4-amine (80 mg, 0.65 mmol) in 10 mL of dichloromethane was cooled in an ice bath, methanesulfonyl chloride (0.05 mL, 0.6 mmol) was added drop-wise. The reaction mixture was stirred overnight at room temperature, then was washed with 50 mL of water, organic phase dried with sodium sulfate filtered and concentrated. The residue was purified by column chromatography (silica gel. 200-300 mesh, eluting with ethyl acetate/petroleum ether=1/1) to afford 5-(tert-butoxycarbonylamino)-tetrahydro-2H-pyran-3-yl methanesulfonate (100 mg, 67%) as white solid. LCMS: (M+H)+=318; 1H NMR (300 MHz, CDCl3): δ 4.89-4.83 (m, 1H), 3.99-3.62 (m, 5H), 3.06 (s, 3H), 2.26-2.20 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([CH2:21][CH:22]2[S:26][C:25](=[O:27])[NH:24][C:23]2=[O:28])[CH:18]=[C:17]([Cl:29])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:15][CH3:16])=[C:9]([S:11](Cl)(=[O:13])=[O:12])[CH:10]=1.[CH:30]1([NH2:33])[CH2:32][CH2:31]1.CN1CCOCC1>O1CCCC1>[CH:30]1([NH:33][S:11]([C:9]2[CH:10]=[C:5]([O:4][C:3]3[C:2]([Cl:1])=[CH:20][C:19]([CH2:21][CH:22]4[S:26][C:25](=[O:27])[NH:24][C:23]4=[O:28])=[CH:18][C:17]=3[Cl:29])[CH:6]=[CH:7][C:8]=2[O:15][CH3:16])(=[O:13])=[O:12])[CH2:32][CH2:31]1
Reactant: COc1ccc(Oc2c(Cl)cc(CC3SC(=O)NC3=O)cc2Cl)cc1S(=O)(=O)Cl
Reactant: NC1CC1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COc1ccc(Oc2c(Cl)cc(CC3SC(=O)NC3=O)cc2Cl)cc1S(=O)(=O)NC1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.7 %

Procedure:
To the title compound of Step E (38 mg, 0.08 mmol) in dry tetrahydrofuran (1 ml) at room temperature was added cyclopropylamine (8.0 mL, 0.12 mmol) and N-methylmorpholine (17 ml, 0.15 mmol). The reaction mixture was stirred at room temperature for two hours, quenched with 1N HCl (15 ml), and extracted with ethyl acetate (3×15 ml). The combined extracts were washed with 1N HCl (2×15 ml), brine (15 ml), dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative TLC (8% methanol in dichloromethane) to afford the title compound (16 mg, 41% yield). MS (APCI+) Calc: 516.0, Found: 516.9 (M+1).
Reaction SMILES: [O:1]=[C:2](N(OC)C)[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)=[O:8].[CH2:22]([Mg]Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl>O1CCCC1>[CH3:17][O:16][C:13]1[CH:12]=[CH:11][C:10]([NH:9][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][C:2](=[O:1])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:15][CH:14]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: COc1ccc(NC(=O)CCCCC(=O)N(C)OC)cc1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)CCCCC(=O)Cc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 24 h

Procedure:
6-Oxo-6-(N,O-dimethylhydroxylamino)-N-(4-methoxyphenyl) hexanamide (454 mg) was dissolved in tetrahydrofuran (13 mL) and cooled to -78° C. Benzylmagnesium chloride in tetrahydrofuran (2.0M, 1.6 mL) was added and reaction was warmed to 20° C. After 24 hours, additional benzylmagnesium chloride in tetrahydrofuran (2.0M, 0.4 mL) was added. After 24 hours, 1.0M aqueous hydrochloric acid (10 mL) was added and reaction extracted using dichloromethane (2×15 mL). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The resulting solid was chromatographed eluting with 30:70 ethyl acetate:hexanes to afford the title compound (Rf of 0.68 in 70:30 ethyl acetate:hexanes) as white crystals (200 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH:19]3[CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20]3)[CH2:15][CH:16]=1)[CH:6]=[CH:5]2.[H][H]>[Pt]=O.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH:19]3[CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20]3)[CH2:15][CH2:16]1)[CH:6]=[CH:5]2
Reactant: [H][H]
Reactant: Clc1ccc2c(ccn2C2=CCN(CCC3Cc4ccccc4C3)CC2)c1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: Clc1ccc2c(ccn2C2CCN(CCC3Cc4ccccc4C3)CC2)c1

Procedure:
A mixture of 5-Chloro-1-[1-[2-(indan-2-yl)ethyl]-1,2,3,6-tetrahydropyridin-4yl]-1H-indol. 28a. (1.9 g), acetic acid (50 ml), and platinum oxide (0.1 g) was shaken for 3 h under 3 atm. hydrogen pressure. The mixture was filtered and evaporated in vacuo. The residue was dissolved in ethyl acetate and the organic phase was shaken with dilute ammonium hydroxide and then worked up in a conventional manner. Further purification was done on silica gel eluted with ethyl acetate-heptane (1:1) to give 2.0 g of crude product. The crude product was crystallized (ethyl acetate), and the title compound was collected by filtration (1.1 g, 58%).
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4]1.[Cl:9][C:10]1[N:11]=[C:12](Cl)[C:13]2[C:18]([C:19]3[CH:28]=[CH:27][C:22]4[N:23]=[C:24]([CH3:26])[O:25][C:21]=4[CH:20]=3)=[CH:17][N:16]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:14]=2[N:15]=1>C1COCC1>[Cl:9][C:10]1[N:11]=[C:12]([O:8][CH:5]2[CH2:6][CH2:7][O:3][CH2:4]2)[C:13]2[C:18]([C:19]3[CH:28]=[CH:27][C:22]4[N:23]=[C:24]([CH3:26])[O:25][C:21]=4[CH:20]=3)=[CH:17][N:16]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:34])([CH3:36])[CH3:35])[C:14]=2[N:15]=1
Reactant: OC1CCOC1
Reactant: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Cl)nc(Cl)c34)cc2o1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Cl)nc(OC5CCOC5)c34)cc2o1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 83 %

Procedure:
To a suspension of sodium hydride (1.2 equiv, 60% by weight in mineral oil) in THF (0.3 M) under nitrogen atmosphere was added tetrahydrofuran-3-ol (1.5 equiv) in THF (0.6 M) at 0° C. The resulting reaction mixture was stirred at 0° C. for 20 min. A solution of 6-(2,4-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylbenzo[d]oxazole (1 equiv) in THF (0.6 M) was added and the resulting reaction mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (0.6 M) and the organic solvents were removed under reduced pressure. The resulting residue was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure and the crude product was purified by silica gel chromatography (15% ethyl acetate in petroleum ether) to afford the title compound (83% yield). MS (ESI) m/z 501.1 [M+H]+.
Reaction SMILES: [C:1]([NH:18][C@H:19]1[CH2:23][CH2:22][C@@H:21]([C:24](O)=[O:25])[CH2:20]1)([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].[O:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[C:36]1[CH:41]=[CH:40][C:39]([NH:42][CH3:43])=[CH:38][CH:37]=1.N1C(C)=CC(C)=CC=1C>C(Cl)Cl>[CH:16]1[C:17]2[CH:5]([CH2:4][O:3][C:1](=[O:2])[NH:18][CH:19]3[CH2:23][CH2:22][CH:21]([C:24](=[O:25])[N:42]([C:39]4[CH:40]=[CH:41][C:36]([C:28]5[O:27][C:31]6[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=6[N:29]=5)=[CH:37][CH:38]=4)[CH3:43])[CH2:20]3)[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: O=C(N[C@H]1CC[C@@H](C(=O)O)C1)OCC1c2ccccc2-c2ccccc21
Reactant: CNc1ccc(-c2nc3ccccc3o2)cc1
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClCCl
Product: CN(C(=O)C1CCC(NC(=O)OCC2c3ccccc3-c3ccccc32)C1)c1ccc(-c2nc3ccccc3o2)cc1
Reaction time: 2 h

Procedure:
250 mg (0.71 mmol) (−)-(1S,3R)—N-Fmoc-1-Aminocyclopentane-3-carboxylic acid and 0.14 mL (1.07 mmol) 1-chloro-N,N,2-trimethylpropenyldiamine are dissolved in 5 mL DCM and stirred for 2 hours. The resulting product is added to a mixture of 159.6 mg (0.71 mmol) (4-Benzooxazol-2-yl-phenyl)-methyl-amine and 0.14 mL (1.07 mmol) 2,4,6-collidine in 5 mL DCM. The reaction mixture is stirred overnight at RT. The mixture is concentrated under reduced pressure. The residue is taken up in water and extracted with DCM. The organic layer is dried, filtered off and concentrated under reduced pressure. The product is purified by RP-HPLC (water+5-95% acetonitrile (with addition of 0.1% TFA)). The solvent is evaporated.
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]2=[C:6]3[N:17]=[C:16]([C:18]4[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:25])[NH:15][C:7]3=[C:8]3[C:13]([C:12](=[O:14])[NH:11][CH:10]=[CH:9]3)=[C:4]2[CH:3]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)C.C1(C)C=CC=CC=1>[Cl:25][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([F:24])[C:18]=1[C:16]1[NH:15][C:7]2=[C:8]3[C:13](=[C:4]4[CH:3]=[C:2]([C:32]5[CH:31]=[N:30][C:29]([Cl:28])=[CH:34][CH:33]=5)[CH:27]=[CH:26][C:5]4=[C:6]2[N:17]=1)[C:12](=[O:14])[NH:11][CH:10]=[CH:9]3
Reactant: CC1(C)OB(c2ccc(Cl)nc2)OC1(C)C
Reactant: O=c1[nH]ccc2c3[nH]c(-c4c(F)cccc4Cl)nc3c3ccc(Br)cc3c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=c1[nH]ccc2c3[nH]c(-c4c(F)cccc4Cl)nc3c3ccc(-c4ccc(Cl)nc4)cc3c12
Temperature: 80 °C

Procedure:
9-Bromo-2-(2-chloro-6-fluorophenyl)-3,6-dihydro-7H-benzo[h]imidazo[4,5-f]isoquinolin-7-one (500 mg, 1.130 mmol) was dissolved in ethanol (15 ml) and toluene (15.00 ml). (Dichlorobis)palladiumtriphenylphosphine (79 mg, 0.113 mmol), 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (298 mg, 1.242 mmol) and Na2CO3 (2 M, 1.135 mL) were added and argon was bubbled through the solution for several minutes. The solution was heated at 80° C. for 2 hours. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate and water. The organic layer was separated, dried over magnesium sulftate, filtered and concentrated. The crude residue was purified via a chiral AD column which afforded the title compound. 1H NMR (500 MHz, CD3OD, δH) 10.68 (s, 1 H), 8.56 (d, 1 H, J=1.8 Hz), 8.30 (dd, 1 H, J=8.4, 3.0 Hz), 8.04 (dd, 1 H) J=9.0, 1.8 Hz), 7.68-7.64 (m, 1 H), 7.63-7.60 (m, 2 H), 7.54 (d, 1 H, J=8.4 Hz), 7.38 (td, 1 H, J =9, 1.2 Hz): [M+1]+ 475.
Reaction SMILES: [C:1]12([CH2:11][CH2:12][NH:13][CH2:14][CH2:15][CH3:16])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[N:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=O)=[CH:19][CH:18]=1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[C:1]12([CH2:11][CH2:12][N:13]([CH2:14][CH2:15][CH3:16])[C:27](=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23][C:20]3[CH:19]=[CH:18][N:17]=[CH:22][CH:21]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: CCCNCCC12CC3CC(CC(C3)C1)C2
Reactant: O=C(O)CCCCc1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCCN(CCC12CC3CC(CC(C3)C1)C2)C(=O)CCCCc1ccncc1
Temperature: 25 °C
Yield: 32.3 %

Procedure:
N,N-Dimethylformamide (8.4 ml) was added to a mixture of 2-(1-adamantyl)-N-propylethylamine (Intermediate No. 1-6) (0.37 g, 1.7 mmol) and 5-(4-pyridyl)valeric acid (Intermediate No. 5-1) (0.30 g, 1.7 mmol), and the whole was stirred at room temperature. N-Methylmorpholine (0.27 ml, 2.5 mmol) and then 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.38 g, 2.0 mmol) were added thereto, and the whole was stirred overnight. The reaction mixture was concentrated under reduced pressure, ethyl acetate (20 ml) was added to the residue, and the whole was washed with a saturated aqueous sodium hydrogencarbonate solution (20 ml) and saturated brine (5 ml) successively. The organic layer was dried over sodium sulfate, and ethyl acetate was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography to give 0.21 g (33%) of the titled compound as a colorless oily matter.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[F:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1>CCOC(C)=O>[F:10][C:11]1[CH:16]=[C:15]([C:2]2[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: COc1ccnc(Br)c1
Reactant: OB(O)c1cccc(F)c1
Solvent: CCOC(C)=O
Product: COc1ccnc(-c2cccc(F)c2)c1
Temperature: 85 °C
Reaction time: 8 h
Yield: 144 %

Procedure:
A 100-mL recovery flask containing 2-bromo-4-methoxypyridine (1.446 g, 7.69 mmol, purchased from Combi-Blocks, Inc.), 3-fluorophenylboronic acid (2.152 g, 15.38 mmol, purchased from Oakwood Products, Inc.), and 1,1′-bis(diphenylphosphino)ferrocene palladium(11)dichloride dichloromethane adduct (0.314 g, 0.385 mmol) was flushed with N2 and subsequently charged with dioxane (29 mL) and 1.9 M Na2CO3 in H2O (10 mL). The black-red mixture was stirred at 85° C. overnight. The next morning, after cooling to rt, the dark red mixture was diluted with H2O and extracted thrice with EtOAc. The organic extracts were combined, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to a black oil. Column chromatography (50 g Snap Ultra column, 10-100% EtOAc/hept) afforded 2-(3-fluorophenyl)-4-methoxypyridine (2.25 g, >99% yield) as a viscous yellow oil. m/z (ESI) 204.2 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:29]([NH:30][C:31](=[O:41])[C:32](=[N:39][OH:40])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:28](=[O:42])[N:10]2[C:11]=1[C:12]([O:14][CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])(=[O:3])[CH3:2].N1C=CC=CC=1.[N+:49]([C:52]1[CH:60]=[CH:59][C:55]([C:56](Cl)=[O:57])=[CH:54][CH:53]=1)([O-:51])=[O:50]>C(OC(=O)C)C>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:29]([NH:30][C:31](=[O:41])[C:32](=[N:39][O:40][C:56](=[O:57])[C:55]3[CH:54]=[CH:53][C:52]([N+:49]([O-:51])=[O:50])=[CH:60][CH:59]=3)[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:28](=[O:42])[N:10]2[C:11]=1[C:12]([O:14][CH:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:13])(=[O:3])[CH3:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)C(=NO)c3ccccc3)[C@H]2SC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)C(=NOC(=O)c3ccc([N+](=O)[O-])cc3)c3ccccc3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.1 %

Procedure:
To a solution of diphenylmethyl 3-acetoxymethyl-7β-(2-hydroxyimino-2-phenylacetamido)ceph-3-em-4-carboxylate (syn-isomer) (1.5 g.) and pyridine (0.5 ml.) in ethylacetate (100 ml.) was added 4-nitrobenzoyl chloride (0.42 g) and the resulting solution was stirred at room temperature for one hour. Further portions (0.042 g 0.015 g and 0.20 g.) of the acid chloride were added, and the reaction stirred for a total of 4 hours at room temperature. Then the solution was washed with 2 N-hydrochloric acid and brine, dried, concentrated to ca. 5 ml. and added dropwise with stirring to petroleum spirit (b.p. 40°-60°). This gave a solid which was filtered and dried, yielding the title ester (1.1 g; 58%), λmax. (EtOH) 263 nm (ε 29,000), νmax. (CHBr3) 3400 (NH), 1780 (β-lactam), 1395 and 1525 (NO2), 1687 and 1515 cm.- 1 (CONH), τ (CDCl3) values include 1.70 and 2.71 (two doublets, J 8 Hz; ##STR33## 2.1-2.85 (multiplet; aromatic protons), 8.03 (singlet; OCOCH3)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7](/[CH:10]=[C:11]3/[C:12](=[O:20])[NH:13][C:14]4[C:19]/3=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:8]=2)[CH:3]=[N:2]1.[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23](C2C3C(=CC(C=O)=CC=3)NN=2)[CH:22]=1>>[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23]([C:3]2[C:4]3[C:9](=[CH:8][C:7]([CH:10]=[C:11]4[C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[NH:13][C:12]4=[O:20])=[CH:6][CH:5]=3)[NH:1][N:2]=2)[CH:22]=1
Reactant: O=C1Nc2ccccc2/C1=C\c1ccc2cn[nH]c2c1
Reactant: O=Cc1ccc2c(-c3cnc4ccccc4c3)n[nH]c2c1
Product: O=C1Nc2ccccc2C1=Cc1ccc2c(-c3cnc4ccccc4c3)n[nH]c2c1

Procedure:
According to the procedure for the synthesis of (E)-3-((1H-indazol-6-yl)methylene)-indolin-2-one, except substituting 3-(quinolin-3-yl)-1H-indazole-6-carbaldehyde (8 mg, 0.03 mol), the title compound was obtained as a yellow solid (4.3 mg, 38%). A mixture of (E)- and (Z)-isomers (94:6 by NMR) was obtained. 1H NMR (400 MHz, d6-DMSO) δ 13.75 (br s, 1H), 10.66 (br. s, 1H), 9.61 (d, J=2.0 Hz, 1H), 9.04 (d, J=2.3 Hz, 1H), 8.47 (d, J=8.8 Hz, 1H), 8.22 (d, J=7.8 Hz, 1H), 8.08 (d, J=8.0 Hz, 1H), 8.01 (s, 1H), 7.83 (s, 1H), 7.80 (td, J=6.8, 1.3 Hz, 1H), 7.68 (t, J=7.8, 1H), 7.64 (d, J=7.8 Hz, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.25 (t, J=7.8 Hz, 1H), 6.90 (d, J=8.3 Hz, 1H), 6.86 (t, J=7.8 Hz, 1H); MS ESI 389.1 [M+H]+, calcd for [C25H16N4O+H]+ 389.13.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.Cl[CH2:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13]>>[Br:1][C:2]1[CH:3]=[C:4]([S:8][CH2:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCl)C(F)(F)F
Reactant: Sc1cccc(Br)c1
Product: O=C(CSc1cccc(Br)c1)C(F)(F)F

Procedure:
Prepared according to the procedure described in Example 6, Step 1, using the following starting materials: 3-bromothiophenol and 3-chloro-1,1,1-trifluoropropane-2-one.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1.[CH2:13]([S:15]([C:18]1[CH:23]=[CH:22][C:21](F)=[C:20]([Cl:25])[CH:19]=1)(=[O:17])=[O:16])[CH3:14]>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([O:8][C:21]2[CH:22]=[CH:23][C:18]([S:15]([CH2:13][CH3:14])(=[O:17])=[O:16])=[CH:19][C:20]=2[Cl:25])[CH:7]=1
Reactant: CCS(=O)(=O)c1ccc(F)c(Cl)c1
Reactant: O=C(O)Cc1cc(O)cc(Br)c1
Product: CCS(=O)(=O)c1ccc(Oc2cc(Br)cc(CC(=O)O)c2)c(Cl)c1

Procedure:
The title compound was prepared as described in example 2 step (iii) but instead using the product from step (v) and the product from example 3 step (i).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH2:10][C@H:9]2[NH2:15])=[O:5].C(N(CC)CC)C.[Cl:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>ClCCl.C([O-])(O)=O.[Na+]>[CH3:2][O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH2:10][C@H:9]2[NH:15][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=1[Cl:23])=[O:5]
Reactant: COC(=O)c1ccc2c(c1)[C@H](N)CC2
Reactant: O=C(Cl)c1ccccc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(c1)[C@H](NC(=O)c1ccccc1Cl)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
Method 1 (3R)-3-Amino-2,3-dihydro-1H-indene-5-carboxylic acid methyl ester hydrochloride (A-01) (8.784 mmol, 1 eq) was dissolved in dichloromethane, and triethylamine (3 eq) and 2-chlorobenzoic acid chloride (1.2 eq) were added at 0° C. under a protecting gas atmosphere. The reaction mixture was stirred for 1 h at RT. Then the reaction mixture was diluted with sat. NaHCO3 solution and the aqueous phase was extracted with dichloromethane (3×50 ml). The organic phase was dried over sodium sulfate and concentrated to yield (3R)-3-[(2-chloro-benzoyl)amino]-2,3-dihydro-1H-indene-5-carboxylic acid methyl ester (B-01). Yield: 98%