Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Li].[CH2:3]([O:7][C:8]1[C:13]([CH:14]=[O:15])=[CH:12][C:11]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[C:10]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[N:9]=1)[CH2:4][CH2:5][CH3:6]>C1COCC1>[CH2:3]([O:7][C:8]1[C:13]([CH:14]([CH3:1])[OH:15])=[CH:12][C:11]([C:16]2[CH:17]=[CH:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)=[C:10]([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[N:9]=1)[CH2:4][CH2:5][CH3:6]
Reactant: [Li]C
Reactant: CCCCOc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)cc1C=O
Solvent: C1CCOC1
Product: CCCCOc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)cc1C(C)O
Temperature: -75 °C
Reaction time: 0.5 h

Procedure:
Methyl lithium (0.67 ml, 1.5M in diethyl ether, 1.02 mMol) was added by syringe to a stirring solution of 2-butoxy-6-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]pyridine-3-carboxaldehyde [Example 30](0.38 g, 0.88 mMol) in 50 mL THF cooled to -75° C. The cold bath was removed and the reaction mixture was allowed to come to room temperature. Acetic acid (10%, 5 ml) was added. After stirring for 30 minutes, the layers were separated. The organic layer was washed with 50 ml water, dried over sodium sulfate, filtered and concentrated to an oil. The titled material was purified by silica gel chromatography and recrystallized from ethyl acetate-hexane. Anal. Calc'd. C24H26NO4SF; C, 64.99; H, 5.91; N, 3.16. Found: C, 64.96; H, 6.07; N, 3.07.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=1[N:14]1[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2>ClCCl>[CH:25]1[C:26]2[N:14]([C:8]3[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]=3[OH:6])[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]=2[CH:22]=[CH:23][CH:24]=1
Reactant: COc1ccc(C)cc1-n1c2ccccc2c2ccccc21
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccc(O)c(-n2c3ccccc3c3ccccc32)c1
Temperature: 25 °C
Yield: 95.8 %

Procedure:
A 1.0 M boron tribromide solution in dichloromethane (90 mL, 90 mmol, 1.9 equiv) was added dropwise at -78° C., over 30 minutes, to a solution of 9-(2-methoxy-5-methylphenyl)-9H-carbazole (13.5 g, 46.98 mmol, 1 equiv) in anhydrous dichloromethane (400 mL). The reaction was warmed to room temperature, when liquid chromatography—mass spectrometry (LCMS) indicated that the reaction was complete. The reaction was quenched with ice-water (200 mL). The layers were separated and the aqueous phase was extracted with dichloromethane (2×100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on an ANALOGIX 40-150 g column, eluting with a gradient of 0 to 20% ethyl acetate in heptanes to give 2-(9H-carbazol-9-yl)-4-methylphenol (12.3 g, 95% yield) as a yellow oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.Br[C:17]1[CH:21]=[CH:20][O:19][CH:18]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O>CN(C=O)C.O.[Cu]I>[O:19]1[CH:20]=[CH:21][C:17]([N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)=[CH:18]1
Reactant: Brc1ccoc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2-c2ccoc2)CCN(C)C1
Yield: 0.6 %

Procedure:
A solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.4 g, 2 mmol), 3-bromofuran (0.35 mL, 4 mmol), K3PO4 (0.848 g, 4 mmol), CuI (38 mg, 0.2 mmol) and L-Proline (46 mg, 0.39 mmol) in dry DMF (6 mL) was stirred at 150° C. for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 5-furan-3-yl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (3 mg). 1H NMR (TFA salt, CD3OD) d (ppm): 7.90 (s, 1H), 7.70 (s, 1H), 7.30 (s, 1H), 7.21 (d, 1H), 7.05 (d, 1H), 6.68 (s, 1H), 4.70 (d, 1H), 4.40 (d, 1H), 3.82 (m, 1H), 3.58 (m, 1H), 3.20-3.0 (m, 5H), 2.42 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3](=O)[O:4][CH:5]([CH:9](O)[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)[C:6]=1[O:7][CH3:8].C(N(CC)CC)C.CS(Cl)(=O)=O>C(Cl)Cl.CCOC(C)=O.O>[Br:1][C:2]1[CH2:3][O:4]/[C:5](=[CH:9]\[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)/[C:6]=1[O:7][CH3:8]
Reactant: COC1=C(Br)C(=O)OC1C(O)c1cccc2ccccc12
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(Br)CO/C1=C\c1cccc2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A solution of 3-bromo-5-(hydroxynaphthalen-1-ylmethyl)-4-methoxy-5H-furan-2-one (5.3 g, 15.17 mmol) and triethylamine (9.22 g, 12.7 mL, 91.1 mmol) in anhydrous CH2Cl2 at 0° C. is treated dropwise with methane sulfonyl chloride (6.96 g, 4.7 mL, 60.7 mmol), stirred for 0.5 h at 0° C., allowed to warm to room temperature, treated sequentially with additional triethylamine (4.64 g, 6.4 mL, 45.9 mmol) and methane sulfonyl chloride (3.55 g, 2.4 mL, 31 mmol), stirred until the disappearance of starting material and diluted with EtOAc and water. The phases are separated and the organic phase is dried over Na2SO4 and concentrated in vacuo. The resultant residue is flash chromatographed (silica gel, 25% EtOAc in hexanes as eluent) to afford the title product as a yellow solid, 4.0 g (80% yield), mp 143-148° C., identified by NMR and mass spectral analyses.
Reaction SMILES: C(OC(N1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])C1)=O)(C)(C)C.[F:31][C:32]1[CH:33]=C(CCN)[CH:35]=[CH:36][CH:37]=1>>[F:31][C:32]1[CH:33]=[C:12]([CH2:11][CH2:10][NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])[CH:35]=[CH:36][CH:37]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Reactant: NCCc1cccc(F)c1
Product: O=C(NCCc1cccc(F)c1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using 2-(3-fluorophenyl)ethylamine instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 381 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.87 (1H, br. s.) 10.38 (1H, s) 8.22 (1H, t, J=5.66 Hz) 8.05 (1H, d, J=6.05 Hz) 7.82 (1H, d, J=5.47 Hz) 7.42 (1H, d, J=5.27 Hz) 7.37 (1H, d, J=3.51 Hz) 7.26 (1H, td, J=8.00, 6.44 Hz) 7.04 (2H, dd, J=8.00, 2.54 Hz) 6.98 (1H, td, J=8.88, 2.93 Hz) 6.77 (1H, d, J=6.05 Hz) 6.54 (1H, d, J=3.51 Hz) 3.42-3.51 (2H, m) 2.82 (2H, t, J=7.13 Hz)
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][C@H:17]1[NH:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1.C1CCN2C(=NCCC2)CC1>>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([N:22]2[CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][C@H:17]2[CH3:16])[C:11]=1[CH3:12]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1c(N2CCN(C(=O)OC(C)(C)C)C[C@H]2C)nc2cc(F)cc(F)c2c1Cl

Procedure:
Prepared according to Procedure G using 2,4-dichloro-5,7-difluoro-3-methylquinoline (1.00 g, 4.10 mmol) and (R)-tert-butyl 3-methylpiperazine-1-carboxylate and using DBU (1.0 eq) as a base to give (R)-tert-butyl 4-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)-3-methylpiperazine-1-carboxylate. Mass Spectrum (ESI) m/e=412.1 (M+1).
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:16][CH:15]2[CH:11]([CH2:12][NH:13][CH2:14]2)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.Cl[C:27]1[CH:32]=[CH:31][C:30]2=[N:33][N:34]=[C:35]([C:36]([F:39])([F:38])[F:37])[N:29]2[N:28]=1>C(O)C>[CH2:2]([N:9]1[CH2:10][CH:11]2[CH2:12][N:13]([C:27]3[CH:32]=[CH:31][C:30]4=[N:33][N:34]=[C:35]([C:36]([F:39])([F:37])[F:38])[N:29]4[N:28]=3)[CH2:14][CH:15]2[CH2:16]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: c1ccc(CN2CC3CNCC3C2)cc1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: FC(F)(F)c1nnc2ccc(N3CC4CN(Cc5ccccc5)CC4C3)nn12
Temperature: 70 °C
Yield: 83 %

Procedure:
2-Benzyl-3,3a,4,5,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole hydrochloride (0.129 g, 0.54 mmol) and then diisopropylethylamine (0.070 g, 0.54 mmol) were added sequentially to a solution of 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[3,4-f]pyridazine (0.080 g, 0.36 mmol) in ethanol (2 mL). The reaction mixture was heated at 70° C. for 4 hours and then evaporated to leave an involatile residue. The residue was purified by preparative hplc using a Phenomenex Luna C18 100A column (10% silica, 21 mm diameter, 150 mm length) eluted with decreasingly polar mixtures of water (containing 0.1% trifluoroacetic acid) and acetonitrile as eluents to give a partially purified product that was further purified by ion exchange chromatography an SCX column eluted with 7M aqueous ammonia in methanol as eluents to give 6-(5-benzyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-2-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[3,4-f]pyridazine (0.116 g, 83%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[C:9]1([CH2:15][CH2:16][OH:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:17][CH2:16][CH2:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: OCCc1ccccc1
Reactant: Brc1cccc(Br)n1
Product: Brc1cccc(OCCc2ccccc2)n1

Procedure:
Prepared according to the procedure described in Example 139, Step 1, using 2,6-dibromo-pyridine and 2-phenyl-ethanol.
Reaction SMILES: C([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]2[C:14]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[N:15][C:16]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[N:17][C:6]1=2)(C)(C)C>FC(F)(F)C(O)=O>[N:18]1([C:16]2[N:15]=[C:14]([N:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)[C:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[NH:5][C:6]=3[N:17]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC(C)(C)n1c2ccccc2c2c(N3CCCC3)nc(N3CCCC3)nc21
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2c(c1)[nH]c1nc(N3CCCC3)nc(N3CCCC3)c12

Procedure:
A mixture of 9-t-butyl-2,4-di-1-pyrrolidinyl-9H-pyrimido[4,5-b]indole (XII, EXAMPLE 25, 4.0 g) and 100 mL of trifluoroacetic acid is heated at reflux for 2 hr. Approximately one-half of the trifluoroacetic acid is removed by distillation. The reaction mixture is then cooled to 0°, made basic with 25% aqueous sodium hydroxide and extracted with methylene chloride. The combined organic phases are washed with saline, dried over anhydrous sodium sulfate and concentrated. Chromatography (silica gel, 5% ethyl acetate/methylene chloride) gives the title compound, NMR (CDCl3) 7.89, 7.86, 7.26-7.09, 3.95, 3.67 and 2.01-1.95 δ.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Mg]Br.[Cl-].[NH4+].C1C[O:24][CH2:23]C1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][CH2:23][OH:24])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: C1CCOC1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reaction time: 16 h
Yield: 31 %

Procedure:
A solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxaldehyde (14.9 g, 69.8 mmol) in THF at −78° C. was treated with methylmagnesium bromide (25.6 mL, 3.0 M in THF, 76.8 mmol). After 16 h, the mixture was treated with additional methylmagnesium bromide (15.0 mL, 3.0 M in THF). After 1 h, the mixture was treated with saturated aqueous ammonium chloride and partitioned between EtOAc and water. The aqueous phase was washed with EtOAc, the organic extracts were combined and washed with brine, dried (MgSO4), and concentrated. The residue was purified by column chromatography (SiO2: 30 to 40% EtOAc:hexanes) affording 5.0 g (31%) of the title compound.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11].[H-].[Na+].Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].O>O1CCCC1.CN(C1C=CN=CC=1)C.CCCCCC.C(OCC)(=O)C>[O:11]=[C:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]
Reactant: O=C1CCc2ccccc2N1
Reactant: O=C(Cl)OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1CCc2ccccc2N1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
A reactor was charged with 1.5 g (10 mmol) of 3,4-dihydroquinolin-2(1H)-one and 77 mL of tetrahydrofuran as a solvent. After cooling the mixture to 0° C., 0.8 g (20 mmol) of sodium hydride was added dropwise to the mixture. The mixture was stirred for 30 minutes, and held at 0° C., followed by the addition of 5.12 g (30 mmol) of benzyl chloroformate (acyl chloride (RCl)) and 0.24 g (2 mmol) of N,N-dimethyl-4-aminopyridine (DMAP). After adjusting the temperature of the reaction system to room temperature (about 20° C.), the mixture was reacted for 12 hours with stirring. After cooling the mixture including the reaction product to 0° C., water was added dropwise to the mixture, followed by extraction with ethyl acetate. After the addition of excess anhydrous magnesium sulfate to the resulting organic layer, the solvent was evaporated under reduced pressure to obtain a concentrate including a crude product. The concentrate was subjected to silica gel flash column chromatography (eluant: hexane/ethyl acetate=1/1) to obtain benzyl 2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (yellow oily product) represented by the following formula (ai2) having a Cbz group (PhCH2OCO—) as a protecting group (yield: 76%). The analysis data for the resulting compound (ai2) is shown below.
Reaction SMILES: S1C2C=CC=CC=2N=C1S[S:11][CH:12]1[N:15](/[C:16](=[C:20](/[O:22][CH3:23])\[CH3:21])/[C:17](Cl)=[O:18])[C:14](=[O:24])[CH:13]1[NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.S1C2C=CC=CC=2N=C1SSC1N(/C(=C(\OC)/C)/C(Cl)=O)C(=O)C1NC(=O)COC1C=CC=CC=1.C(N(CC)CC)C.[C:78]([OH:82])([CH3:81])([CH3:80])[CH3:79]>C(Cl)Cl>[C:78]([O:82][C:17]([CH:16]1[N:15]2[C:14](=[O:24])[C@@H:13]([NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@H:12]2[S:11][CH:21]=[C:20]1[O:22][CH3:23])=[O:18])([CH3:81])([CH3:80])[CH3:79]
Reactant: CC(C)(C)O
Reactant: CO/C(C)=C(\C(=O)Cl)N1C(=O)C(NC(=O)COc2ccccc2)C1SSc1nc2ccccc2s1
Agent: CO/C(C)=C(/C(=O)Cl)N1C(=O)C(NC(=O)COc2ccccc2)C1SSc1nc2ccccc2s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=CS[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OC(C)(C)C
Reaction time: 0.25 h

Procedure:
A solution of 266 mg (0.5 mM) of a crude mixture consisting of 2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl ]-3-methoxy-crotonic acid chloride and 2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-isocrotonic acid chloride in 5 ml of dry methylene chloride is added dropwise over the course of 15 minutes at 0° C., whilst stirring, to a solution of 0.10 ml of triethylamine in 0.5 ml of dry tert.-butanol and 3 ml of methylene chloride. After a further 15 minutes stirring, the reaction mixture is diluted with methylene chloride, washed with water, with dilute hydrochloric acid and again with water, dried over sodium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed on 10 g of acid-washed silica gel, using toluene/ethyl acetate (4:1) as the running agent. 7β-Phenoxyacetamido-3-methoxy-ceph-2-em-4-carboxylic acid tert.butyl ester is obtained. IR spectrum (in CH2CL2): characteristic bands at 5.60, 5.77, 5.90 and 8.29 μ.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[N:21]=[CH:20][C:19]3[C:14](=[C:15]([F:26])[CH:16]=[C:17]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:18]=3)[C:13]2=[O:27])=[CH:10][CH:9]=[CH:8][C:7]=1[C:28]1[CH:29]=[C:30](Br)[C:31]2[N:32]([N:34]=[CH:35][N:36]=2)[CH:33]=1)(=[O:3])[CH3:2].[NH2:38][C:39]1[N:44]=[CH:43][C:42]([C:45]([N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)=[O:46])=[CH:41][CH:40]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:22]([C:17]1[CH:18]=[C:19]2[C:14](=[C:15]([F:26])[CH:16]=1)[C:13](=[O:27])[N:12]([C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([C:28]3[CH:29]=[C:30]([NH:38][C:39]4[CH:40]=[CH:41][C:42]([C:45]([N:47]5[CH2:52][CH2:51][O:50][CH2:49][CH2:48]5)=[O:46])=[CH:43][N:44]=4)[C:31]4[N:32]([N:34]=[CH:35][N:36]=4)[CH:33]=3)[C:6]=1[CH2:5][O:4][C:1](=[O:3])[CH3:2])[N:21]=[CH:20]2)([CH3:24])([CH3:23])[CH3:25]
Reactant: Nc1ccc(C(=O)N2CCOCC2)cn1
Reactant: CC(=O)OCc1c(-c2cc(Br)c3ncnn3c2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C(=O)N4CCOCC4)cn3)c3ncnn3c2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Temperature: 100 °C
Yield: 94.4 %

Procedure:
In a 100 ml flask, 2-(8-bromo-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)benzyl acetate (250 mg, 443 μmol, Eq: 1.00), (6-aminopyridin-3-yl)(morpholino)methanone (110 mg, 532 μmol, Eq: 1.2) and cesium carbonate (722 mg, 2.21 mmol, Eq: 5.0) were combined with dioxane (31.3 ml) to give an orange suspension. 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (38.4 mg, 66.4 μmol, Eq: 0.15) and tris(dibenzylideneacetone)dipalladium(0) (20.3 mg, 22.1 μmol, Eq: 0.05) were added. The solution was degassed with Ar for 10 min. The reaction was heated at 100° C. for 18 h. The reaction mixture was diluted with 200 ml DCM. MgSO4 was added and the mixture was stirred. The solid was removed by filtration and washed several times with DCM. The combined filtrate and washes were concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 5% to 10% MeOH in DCM gradient). The resulting residue was triturated with Et2O. The solid was filtered, and then washed with Et2O. The solid was dried overnight at 50° C. to give acetic acid 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-{8-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-[1,2,4]triazolo[1,5-a]pyridin-6-yl}-benzyl ester (289 mg, 95%). LC/MS-ESI observed [M+H]+ 691.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:13]=[C:14]([CH:19]2[C@@H:24]([CH2:25][CH2:26][OH:27])[O:23][CH2:22][CH2:21][N:20]2[C:28](=[O:41])[C:29]2[CH:34]=[C:33]([O:35][CH3:36])[C:32]([O:37][CH3:38])=[C:31]([O:39][CH3:40])[CH:30]=2)[CH:15]=[CH:16][C:17]=1[Cl:18].C(N(CC)CC)C>C(Cl)Cl.O>[Cl:11][C:12]1[CH:13]=[C:14]([CH:19]2[C@@H:24]([CH2:25][CH:26]=[O:27])[O:23][CH2:22][CH2:21][N:20]2[C:28](=[O:41])[C:29]2[CH:34]=[C:33]([O:35][CH3:36])[C:32]([O:37][CH3:38])=[C:31]([O:39][CH3:40])[CH:30]=2)[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: COc1cc(C(=O)N2CCO[C@H](CCO)C2c2ccc(Cl)c(Cl)c2)cc(OC)c1OC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(C(=O)N2CCO[C@H](CC=O)C2c2ccc(Cl)c(Cl)c2)cc(OC)c1OC
Reaction time: 0.5 h
Yield: 92.8 %

Procedure:
0.88 ml (10.1 mmole) of oxalyl chloride was dissolved in 10 ml of methylene chloride, and 5 ml of a methylene chloride solution containing 0.79 ml (11.1 mmole) of dimethyl sulfoxide were added dropwise to the resulting solution at -78° C. under a nitrogen atmosphere. The mixture was then stirred for 30 minutes. 10 ml of a methylene chloride solution containing 950 mg (2.02 mmole) of 2-[(2 R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholin-2-yl]ethanol [prepared as described in step (d) above] were added dropwise to the resulting mixture, and the mixture as stirred for 4 hours. At the end of this time, a further 2.24 ml (16.2 mmole) of triethylamine was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then poured into water and extracted with methylene chloride. The organic extract was washed with water, and then with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography, using a gradient elution method, with mixtures of methylene chloride and acetone ranging from 23:2 to 21:4 by volume as the eluent, to give 878 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([C:7](=O)[C:8](OC)=[O:9])[C:3]([O:5][CH3:6])=[O:4].[CH:14]1([CH2:19][N:20]2[C:24]3=[N:25][CH:26]=[C:27]([F:29])[CH:28]=[C:23]3[C:22]([C:30](=[NH:33])[NH:31][NH2:32])=[N:21]2)[CH2:18][CH2:17][CH2:16][CH2:15]1>C(O)C>[CH:14]1([CH2:19][N:20]2[C:24]3=[N:25][CH:26]=[C:27]([F:29])[CH:28]=[C:23]3[C:22]([C:30]3[N:31]=[N:32][C:7]([C:2]([CH3:13])([CH3:1])[C:3]([O:5][CH3:6])=[O:4])=[C:8]([OH:9])[N:33]=3)=[N:21]2)[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: N=C(NN)c1nn(CC2CCCC2)c2ncc(F)cc12
Reactant: COC(=O)C(=O)C(C)(C)C(=O)OC
Solvent: CCO
Product: COC(=O)C(C)(C)c1nnc(-c2nn(CC3CCCC3)c3ncc(F)cc23)nc1O

Procedure:
841 mg (4.473 mmol) of dimethyl 2,2-dimethyl-3-oxobutanedioate were initially charged in 20 ml of ethanol, and the mixture was heated to reflux. Subsequently, 1.070 g (2.982 mmol) of 1-(cyclopentylmethyl)-5-fluoro-1H-pyrazolo[3,4-b]pyridine-3-carboximidohydrazide suspended in 26 ml of ethanol were added, and the mixture was boiled under reflux overnight. After cooling, the mixture was concentrated, taken up in acetonitrile and filtered. The filtrate was purified by preparative HPLC (mobile phase: acetonitrile/water, gradient 30:70→100:0). This gave 396 mg of the target compound (32% of theory).
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:12][C:13]([C:15]1[CH:20]=[C:19]([F:21])[C:18]([S:22][CH3:23])=[C:17]([F:24])[CH:16]=1)=O.C(N(C(C)C)CC)(C)C.N12CCCN=C1CCCCC2.Cl>C(#N)C>[F:24][C:17]1[CH:16]=[C:15]([C:13]2[CH2:12][O:9][C:8](=[O:10])[C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:20]=[C:19]([F:21])[C:18]=1[S:22][CH3:23]
Reactant: O=C(O)Cc1ccccc1
Reactant: CSc1c(F)cc(C(=O)CBr)cc1F
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CSc1c(F)cc(C2=C(c3ccccc3)C(=O)OC2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
To a mixture of phenylacetic acid (4.2 g, 0.030 mol) and crude 2-bromo-1-[3,5-difluoro-4-(methylthio)-phenyl]ethanone (8.6 g, 0.030 mol) in anhydrous acetonitrile (100 mL) was added diisopropylethylamine (3.9 g, 0.030 mol). The reaction mixture was stirred for one hour at room temperature and 1,8-diazabicyclo[5.4.0]undec-7-ene (5.0 g, 0.032 mol) was added. After 2 hours the mixture was poured into dilute HCl and extracted with dichloromethane (1×200 mL, 2×75 mL). The combined extracts were dried using magnesium sulfate, and concentrated. The residue was treated with anhydrous acetonitrile (100 mL) and DBU (10.0 g, 0.065 mol), stirring at room temperature for 3 hours. The mixture was poured into dilute HCl and extracted with dichloromethane (1×200 mL, 2×50 mL). The combined extracts were dried using magnesium sulfate, and concentrated. Purification by silica gel chromatography using 5% dichloromethane/10% ethyl acetate in hexanes afforded 4-[3,5-difluoro-4-(methylthio)-phenyl]-3-phenylfuran-2(5H)-one as an orange liquid (7.2 g, 76%). 1H NMR (CDCl3/400 MHz) 7.37-7.41 (m, 5H), 6.97 (m, 2H 5.09 (s, 2H), 2.48 (s, 3H). ESHRMS m/z 319.0601 (M+H+, Calcd 319.0604). Anal. Calcd for C17H12F2O2S: C, 64.14; H, 3.80; Found: C, 63.56; H, 3.54.