Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[F:2][C:3]([F:22])([F:21])[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH:9]=1)=[O:5]>[Pt].CO>[ClH:1].[F:21][C:3]([F:2])([F:22])[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH:9]=1)=[O:5]
Reactant: O=C(NCc1ccc(F)c(-c2ccncc2)c1)C(F)(F)F
Agent: [Pt]
Agent: Cl
Solvent: CO
Product: O=C(NCc1ccc(F)c(C2CCNCC2)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
A Parr flask is charged with compound 13 (123 g, 0.37 mol) and MeOH (740 mL) at rt, then 5% Pt/C (36.9 g, 30 w/w %) is added. The reaction flask is placed in a Parr hydrogenation system and charged with H2 at 50-60 psi. The mixture is shaken for >48 h while charging H2 until the pressure reached a steady state (H2 was refilled to 50-60 psi every 2-3 hours during day time while 10-20 psi is observed without any further refill after overnight). When HPLC analysis shows completion of the reaction, the reaction mixture is filtered through a pad of Celite. The filtrate is distilled at 40-50° C. while adding n-BuOAc (1.25 L). After completion of distillation of MeOH, additional n-BuOAc (1 L) is added. The resultant suspension is allowed to cool to rt overnight. The suspension is cooled to 10° C., filtered, and dried in oven at 50° C. to give 112 g (89%) of compound 14 as white solid: mp=134° C. Anal. Calcd for C14H10F4N2O—HCl: C, 50.24; H, 3.31; N, 8.37. Found: C, 50.16; H, 3.08; N, 8.38. MS (ESI) m/z 305.4 (M+H). 1H NMR (300 MHz, D2O) δ 7.16-6.98 (m, 3 H), 4.34 (s, 2H), 3.42 (d, J=12.9 Hz, 2H), 3.14-2.99 (m, 3H), 1.98-1.81 (m, 4H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[C:6](=O)([O-])[O-].[K+].[K+].[I-].[Na+].Br[CH2:15][CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>C(#N)C>[C:21]([Si:18]([CH3:20])([CH3:19])[O:17][CH2:16][CH2:15][N:1]1[CH:5]=[C:4]([CH3:6])[N:3]=[N:2]1)([CH3:24])([CH3:23])[CH3:22]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: c1c[nH]nn1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Product: Cc1cn(CCO[Si](C)(C)C(C)(C)C)nn1
Temperature: 80 °C
Yield: 41.4 %

Procedure:
To a suspension of 1H-[1,2,3]triazole (2.0 g, 29 mmol), potassium carbonate (4.6 g, 33.4 mmol, 1.15 eq.) and sodium iodide (4.3 g, 29 mmol, 1.0 eq.) in acetonitrile (50 mL) was added a solution of (2-bromo-ethoxy)-tert-butyl-dimethyl-silane (7.80 g, 33 mmol) in acetonitrile (7 mL). The resulting mixture was heated to 80° C. for 5 hr under an atmosphere of nitrogen. The mixture was cooled and filtered. The filtrate was evaporated under reduced pressure and the resulting residue partitioned between heptane (200 mL) and water (100 mL). The organic phase was washed with saturated brine solution (30 mL) and dried over sodium sulphate. The resulting mixture was filtered and the filtrate evaporated under reduced pressure to give an oil. This oil was was purified by chromatography on silica gel (100 g) eluting with a gradient of ethyl acetate in heptane (0:100 to 50:50) to give the title compound as a colourless oil (2.9 g, 44%).
Reaction SMILES: [N+:1]([C:4]1[C:12]2[N:11]=[CH:10][N:9]([CH2:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.Cl[CH2:22][C:23]1C2C(=CC=CC=2)N=[CH:25][CH:24]=1>>[N+:1]([C:4]1[C:12]2[N:11]=[CH:10][N:9]([CH2:13][C:14]3[C:19]4[C:18](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:17]=[CH:16][CH:15]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: ClCc1ccnc2ccccc12
Reactant: O=[N+]([O-])c1cccc2c1ncn2Cc1ccncc1
Agent: Cl
Product: O=[N+]([O-])c1cccc2c1ncn2Cc1ccnc2ccccc12

Procedure:
Compound 4a was synthesized in the same manner as compound 3c using 4-chloromethylquinoline hydrochloride instead of 4-chloromethylpyridine hydrochloride.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([C:10]1[NH:18][C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[CH:11]=1)([CH3:9])([CH3:8])[CH3:7].O.[OH-].[Na+].CN(C)[CH:24]=[O:25]>>[C:6]([C:10]1[NH:18][C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[C:11]=1[CH:24]=[O:25])([CH3:9])([CH3:7])[CH3:8]
Reactant: CN(C)C=O
Reactant: CC(C)(C)c1cc2cccnc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)c1[nH]c2ncccc2c1C=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 41 %

Procedure:
Phosphorous oxychloride (4.01 mL, 43 mmol) was added drop-wise to N,N-dimethylformamide (9.96 mL, 129 mmol) at 0° C. and the mixture was stirred for 20 min. A solution of 2-tert-butyl-1H-pyrrolo[2,3-b]pyridine (5.0 g, 28.7 mmol) dissolved in N,N-dimethylformamide (30 mL) was added and the resulting mixture was slowly warmed up to room temperature. The mixture was stirred at room temperature for 2 h then at 40° C. for 3 h, and cooled in an ice bath, and 0.5 mL water was added. The reaction mixture was slowly warmed to 40° C. and stirred for 20 h. The mixture was poured onto approximately 100 mL ice, neutralized with an aqueous sodium hydroxide (5%) and extracted with dichloromethane. The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo, and the residue was purified via silica gel column chromatography (0-30% ethyl acetate in heptane) to obtain 2-tert-butyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (2.4 g, 11.9 mmol, 41% yield) as an off white solid.
Reaction SMILES: [CH2:1]([N:8]([CH2:16][CH2:17][OH:18])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23](O)=[CH:22][CH:21]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:1]([N:8]([CH2:16][CH2:17][O:18][C:23]1[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=1)[C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N(CCO)Cc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CCOc1ccc(F)cc1)Cc1ccccc1
Reaction time: 3 h
Yield: 86.9 %

Procedure:
To a solution of 2-(N-benzyl-N-tert-butoxycarbonylamino)ethanol (6.85 g, 27.3 mmol), 4-fluorophenol (3.07 g, 27.3 mmol) and PPh3 (7.83 g, 30.0 mmol) in THF (100 mL) was added DIAD (6.00 mL, 30.0 mmol) at room temperature After being stirred for 3 hr, the reaction mixture was concentrated. Chromatography of the residue with hexane-EtOAc (8:1, v/v) as eluent gave 1-[2-(N-benzyl-N-tert-butoxycarbonylamino)ethoxy]-4-fluorobenzene (8.19 g, 64%) as a yellow oil. 1H-NMR (CDCl3)δ 1.42–1.50 (m, 9H), 3.41–3.67 (m, 21H), 3.92–4.11 (m, 2H), 4.51–4.63 (m, 21), 6.73–6.85 (m, 2H), 6.89–6.98 (m, 21H), 7.24 (m 5H); FAB-MS m/z 346 (M++1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5](=[O:14])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].[H][H]>C1(C)C=CC=CC=1.CO>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([OH:14])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Solvent: Cc1ccccc1
Solvent: CO
Product: CCOC(=O)C(O)CCc1ccccc1

Procedure:
The general procedure described in Example B1 is repeated, with the following modifications to the reaction conditions: ethyl-4-phenyl-2-oxobutyrate (substrate): 0.352 g (1.7 mmol); solvent: 10 ml of toluene/methanol (1:1); hydrogen: 50 bar, temperature: 50° C.; reaction time: 19 hours. The conversion is 100%, ee: 44% (R).
Reaction SMILES: [OH:1][CH:2]([C:7]#[N:8])[CH2:3][CH2:4][S:5][CH3:6].[CH3:9][C:10]([CH3:12])=O.C(OC(=O)C)(=[O:15])C.S(=O)(=O)(O)O>C(O)(=O)C>[CH3:9][C:10]1([CH3:12])[NH:8][C:7](=[O:15])[CH:2]([CH2:3][CH2:4][S:5][CH3:6])[O:1]1
Reactant: CC(C)=O
Reactant: CSCCC(O)C#N
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CSCCC1OC(C)(C)NC1=O
Temperature: 110 °C
Reaction time: 0.25 h
Yield: 29.6 %

Procedure:
In a 100 mL three-neck flask, 13.1 g of 96% strength 1-hydroxy-3-(methylthio)propanecarbonitrile (11) (0.1 mol) and 7.0 g of acetone (0.12 mol) were dissolved in 30 mL of glacial acetic acid at 10° C. Then, 5 mL of acetic anhydride (0.05 mol) were slowly added dropwise. Subsequently, a mixture of 10 mL of conc. sulfuric acid and 10 mL of glacial acetic acid was added slowly at 0° C. During this it must be ensured that the entire reaction solution does not become warmer than 0° C. This produced a viscous, yellowish, scarcely stirrable suspension. After addition was complete, the mixture was stirred for 1 h at 110° C. and subsequently 15 min at RT. The reaction solution was poured onto ice (approximately 150 g) and thereafter extracted three times with 100 mL of diethyl ether each time. The ether phase was washed once with saturated sodium hydrogencarbonate solution and subsequently with saturated sodium chloride solution and dried over sodium sulfate. The Na2SO4 was filtered off and the ether was taken off in vacuum. This produced 4.5 g of an orange-brown oil which was recrystallized from n-hexane. After filtration and removal of final solvent residues in high vacuum, 2.8 g (14.8 mmol, M=189.28 g/mol, yield=15%) of 2,2-dimethyl-5-(2-(methylthio)ethyl)-4-oxazolidinone (10) were isolated as a slightly yellowish solid. The NMR data agreed with those of Example 10.
Reaction SMILES: [I:1]([O-])(=O)=O.[K+].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][CH:9]=1.[I-:27].[K+]>C(O)(=O)C>[I:27][C:23]1[CH:24]=[CH:25][C:26]2[N:14]([C:11]3[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[CH:13][CH:12]=3)[C:15]3[C:20]([C:21]=2[CH:22]=1)=[CH:19][C:18]([I:1])=[CH:17][CH:16]=3
Reactant: [I-]
Reactant: COc1ccc(-n2c3ccccc3c3ccccc32)cc1
Reactant: [O-][I+2]([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: COc1ccc(-n2c3ccc(I)cc3c3cc(I)ccc32)cc1

Procedure:
Potassium iodate (16.05 g, 75 mmol, obtained from Aldrich) was added in one portion to a stirred mixture of 9-(4-methoxyphenyl)carbazole (9.54 g, 34 mmol), potassium iodide (10.96 g, 66 mmol), and acetic acid (100 ml) at 80° C. The reaction mixture was stirred and heated for 1 hour. After the reaction was completed, the acetic acid was removed by distillation. The residue was dissolved in ethyl acetate and washed several times with an aqueous solution of sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated, and dried. The yield of 3,6-diiodo-9-(4-methoxyphenyl)carbazole was 16.07 g (87.6%). The 1H-NMR spectrum (100 MHz) of the product in CDCl3 was characterized by the following chemical shifts (δ, ppm): 4.04 (s, 3H, OCH3), 7.24-7.63 (m, 6H, Ar), 8.35-8.40 (m, 4H, Ar). The mass spectrum of the product was characterized by the following ions (in m/z): 525 (M+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N:7]1[C:14]([Cl:15])=[N:13][C:11](Cl)=[N:10][C:8]=1[Cl:9]>C(Cl)(Cl)Cl.O>[Cl:9][C:8]1[N:7]=[C:14]([Cl:15])[N:13]=[C:11]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[N:10]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: C1COCCN1
Solvent: O
Solvent: ClC(Cl)Cl
Product: Clc1nc(Cl)nc(N2CCOCC2)n1
Temperature: -5 °C
Reaction time: 1 h
Yield: 39.4 %

Procedure:
Morpholine (9.5 mL, 108 mmol)) was added to a solution of cyanuric chloride (20 g, 108 mmol) in chloroform (10 mL) and stirred at −5° C. for 1 hour. Reaction mixture was diluted with water, extracted with dichloromethane. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Crude product was purified by silica gel (100-200 mesh) column chromatography using 5% ethyl acetate in pet-ether as an eluent to give 4-(4,6-dichloro-1,3,5-triazin-2-yl)morpholine (10 g, 39% yield).
Reaction SMILES: [CH:1]1([S:4][C:5]([F:18])([F:17])[C:6]2([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=3[F:16])[CH2:8][O:7]2)[CH2:3][CH2:2]1.[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH:1]1([S:4][C:5]([F:18])([F:17])[C:6]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])([OH:7])[CH2:8][N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)[CH2:3][CH2:2]1
Reactant: Fc1ccc(C2(C(F)(F)SC3CC3)CO2)c(F)c1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: OC(Cn1cncn1)(c1ccc(F)cc1F)C(F)(F)SC1CC1
Temperature: 55 °C
Reaction time: 1.5 h
Yield: 39.8 %

Procedure:
To a solution of 2-[(cyclopropylthio)(difluoro)-methyl]-2-(2,4-difluorophenyl)oxirane (5.0 g, 0.017 mol) in DMSO (70 ml), 1,2,4-triazole (3.48 g, 0.05 mol) and potassium carbonate (6.95 g, 0.05 mol) were added, followed by stirring at 55° C. for 1.5 hours. After the completion of the reaction, water was added to the reaction mixture. The resulting mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated saline and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue so obtained was crystallized from isopropyl ether-ethyl acetate, whereby 1-(cyclopropylthio)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol (2.35 g, yield: 32%) was obtained as colorless crystals.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:33])([CH3:32])[C@@H:11]([O:22]CC1C=CC(OC)=CC=1)[C:12]([O:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:13])(=[O:7])=[O:6].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>ClCCl.O>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:33])([CH3:32])[C@@H:11]([OH:22])[C:12]([O:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:13])(=[O:6])=[O:7]
Reactant: COc1ccc(CO[C@@H](C(=O)OCc2cccnc2)C(C)(C)COS(=O)(=O)CCCCl)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: ClCCl
Product: CC(C)(COS(=O)(=O)CCCCl)[C@@H](O)C(=O)OCc1cccnc1
Yield: 8.8 %

Procedure:
Following the general procedure for the oxidative cleavage of (4-methoxy)benzyl ethers of Description 19, 3-pyridylmethyl (2R)-4-[(3-chloropropyl)sulfonyloxy]-2-[(4-methoxyphenyl)methoxy]-3,3-dimethylbutanoate (37a) (0.30 g, 0.60 mmol) dissolved in a mixture of dichloromethane (DCM) and water (10:1) (5 mL) was treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (190 mg, 0.84 mmol). After work-up, the crude material was purified by silica gel column chromatography using ethyl acetate (EtOAc) to provide 20 mg (9% yield) of the title compound (37b) as a white solid. 1H NMR (400 MHz, CDCl3): δ=0.96 (s, 3H), 1.08 (s, 3H), 2.29-2.36 (m, 2H), 3.28-3.32 (m, 2H), 3.67-3.70 (m, 2H), 3.98 (d, J=9.2 Hz, 1H), 4.08 (s, 1H), 4.15 (d, J=9.2 Hz, 1H), 5.20 (s, 2H), 7.32-7.35 (m, 1H), 7.72-7.75 (m, 1H), 8.60-8.65 (m, 2H) ppm. MS (ESI) m/z: 379.99 (M+H)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([OH:30])([C:26]([F:29])([F:28])[F:27])[C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38](=O)[O:39]C2C=CC=CC=2)=[CH:33][CH:32]=1>O1CCOCC1>[F:25][C:22]([F:23])([F:24])[C:21]([C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:11]2[CH2:12][CH2:13][CH:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:38]([NH:37][C:34]4[CH:35]=[CH:36][N:31]=[CH:32][CH:33]=4)=[O:39])=[CH:3][CH:4]=3)[CH2:9][CH2:10]2)=[CH:16][CH:17]=1)([OH:30])[C:26]([F:29])([F:27])[F:28]
Reactant: O=C(Nc1ccncc1)Oc1ccccc1
Reactant: Nc1ccc(C2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Solvent: C1COCCO1
Product: O=C(Nc1ccncc1)Nc1ccc(C2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Temperature: 100 °C

Procedure:
Reaction 2: A mixture of 2-(4-((4-(4-aminophenyl)piperidin-1-yl)methyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.925 mmol, 400 mg) and phenyl pyridin-4-ylcarbamate (1.388 mmol, 297 mg) in dioxane was heated in a reactivial at 100° C. (heating block temperature) for 48 hours.
Reaction SMILES: CO.[N+](C1C=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])([O-])=O.[C:13]([O:21]CC)([O:18][CH2:19][CH3:20])(OCC)[CH3:14].C(O)C>C(OCC)(=O)C>[O:12]1[CH:7]=[CH:8][CH:9]=[C:10]1[CH2:14][C:13]([O:18][CH2:19][CH3:20])=[O:21]
Reactant: CCOC(C)(OCC)OCC
Reactant: O=[N+]([O-])c1ccccc1O
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)Cc1ccco1
Yield: 377.8 %

Procedure:
A solution of 60.8 g (0.4 mole) of the carbinol obtained according to letter (a) above, 11.1 g (0.08 mole) of o-nitro-phenol and 194.4 g (1.2 mole) of triethyl ortho-acetate were slowly heated during 8-10 h to 145°-150° under nitrogen atmosphere while stirring. Meanwhile, ethanol and ethyl acetate formed in the course of the reaction were gradually distilled off whereas the excess of triethyl ortho-acetate was recovered by vacuum distillation. The thus obtained residue was dissolved in petrol ether (b.p. 30°-50°) and the resulting solution was washed with 5% aqueous NaOH, dried over Na2SO4 and finally evaporated. 46.6 g (yield 52.5%) of the title ethyl furyl-acetate were obtained by fractional distillation. Purity ca. 35%; b.p. 65°-70°/0.2 Torr.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH:7]2[C:13]3=[CH:14][CH:15]=[CH:16][N:12]3[CH2:11][C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=3[O:8]2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].CS(O[CH2:32][CH2:33][C:34]1[CH:39]=[C:38]([O:40][CH3:41])[C:37]([O:42][CH3:43])=[C:36]([O:44][CH3:45])[CH:35]=1)(=O)=O>CN(C)C=O>[CH3:45][O:44][C:36]1[CH:35]=[C:34]([CH2:33][CH2:32][N:1]2[CH2:2][CH2:3][CH:4]([CH:7]3[C:13]4=[CH:14][CH:15]=[CH:16][N:12]4[CH2:11][C:10]4[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=4[O:8]3)[CH2:5][CH2:6]2)[CH:39]=[C:38]([O:40][CH3:41])[C:37]=1[O:42][CH3:43]
Reactant: c1ccc2c(c1)Cn1cccc1C(C1CCNCC1)O2
Reactant: COc1cc(CCOS(C)(=O)=O)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(CCN2CCC(C3Oc4ccccc4Cn4cccc43)CC2)cc(OC)c1OC
Temperature: 70 °C

Procedure:
A mixture of 11-(piperidin-4-yl)-5H,11H-pyrrolo[2,1-c][1,4]benzoxazepine (5.8 g, 0.022 mole), K2CO3 (11.0 g) and 2-(3,4,5-trimethoxyphenyl)ethyl methanesulfonate (7.53 g, 0.026 mole) in 120 ml dimethylformamide was heated at 70° C. for 4.5 hours.
Reaction SMILES: [N:1]1([C:7]([C:9]2[C:10]3[CH2:27][S:26](=[O:29])(=[O:28])[C:25]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:11]=3[N:12]([CH:14]3[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]3)[N:13]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[O:39]1[CH:43]=[CH:42][C:41]([C:44](Cl)=[O:45])=[CH:40]1>C(Cl)Cl>[O:39]1[CH:43]=[CH:42][C:41]([C:44]([N:16]2[CH2:17][CH2:18][CH2:19][CH:14]([N:12]3[C:11]4[C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=5[S:26](=[O:29])(=[O:28])[CH2:27][C:10]=4[C:9]([C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:8])=[N:13]3)[CH2:15]2)=[O:45])=[CH:40]1
Reactant: O=C(c1nn(C2CCCNC2)c2c1CS(=O)(=O)c1ccccc1-2)N1CCOCC1
Reactant: O=C(Cl)c1ccoc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1ccoc1)N1CCCC(n2nc(C(=O)N3CCOCC3)c3c2-c2ccccc2S(=O)(=O)C3)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
To a solution of Enantiomer B of 3-(morpholin-4-ylcarbonyl)-1-[piperidin-3-yl]-1,4-dihydrothiochromeno[4,3-c]pyrazole 5,5-dioxide (30 mg; 0.07 mmol; 1 eq.) in DCM (0.45 mL) is added N,N-diisopropylethylamine (25 μl; 0.14 mmol; 2 eq.) followed by 3-furoyl chloride (14 mg; 0.11 mmol; 1.5 eq.) and the reaction mixture is stirred at rt overnight. The solvent is concentrated and the residue is purified by flash chromatography (eluent MeOH/EtOAc 0 to 10%) to afford 20 mg (54%) of the title compound as a white foam. 1H NMR (DMSO-d6): δ 8.04 (d, J=7.7 Hz, 2H), 7.86 (s, 1H), 7.75 (d, J=7.8 Hz, 2H), 6.67 (s, 1H), 4.85 (s, 1H), 4.79 (s, 2H), 3.91 (s, 2H), 3.64 (d, J=9.7 Hz, 5H), 2.26 (s, 2H), 1.95-1.61 (m, 2H). HPLC (max plot) 99.4%; Rt 3.02 min. MS (ESI+): 511.30.
Reaction SMILES: [C:1]([N:8]1[CH2:11][C:10](=[O:12])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:13][Mg]Cl>C1COCC1>[C:4]([O:3][C:1]([N:8]1[CH2:11][C:10]([OH:12])([CH3:13])[CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: C[Mg]Cl
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Solvent: C1CCOC1
Product: CC1(O)CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
In a dry round-bottomed flask, 1-Boc-3-azetidinone (0.70 g, 4.1 mmol) was dissolved in THF (20 mL). The solution was cooled to 0° C. and methylmagnesium chloride (3.0 M solution in THF, 2.0 mL, 6.0 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was quenched with 10 mL saturated NH4Cl, diluted with 5 mL water and extracted with 100 mL EtOAc (2×). The combined organic layers were washed with 10 mL water and 10 mL brine then combined, dried over sodium sulfate, filtered and concentrated to afford 757 mg (99%) of 3-hydroxy-3-methyl-azetidine-1-carboxylic acid tert-butyl ester as an off-white solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:10][C:11]([F:23])([F:22])[O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1>>[F:10][C:11]([F:22])([F:23])[O:12][C:13]1[CH:18]=[C:17]([C:2]2[N:3]=[CH:4][CH:5]=[CH:6][C:7]=2[C:8]#[N:9])[CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Reactant: N#Cc1cccnc1Cl
Product: N#Cc1cccnc1-c1cccc(OC(F)(F)F)c1
Yield: 91 %

Procedure:
Prepared in 91% yield from 2-chloro-3-cyanopyridine and 3-trifluoromethoxyphenylboronic acid according to the procedure described for Example 153A. MS (ESI−) m/z 264.9 (M+H)+; 1H NMR (CDCl3) δ 7.37-7.45 (m, 2H), 7.57 (dd, J=8.0, 8.0 Hz, 1H), 7.82 (br s, 1H), 7.91 (d, J=7.8 Hz, 1H), 8.11 (dd, J=7.8, 1.7 Hz, 1H), 8.90 (dd, J=4.7, 1.7 Hz, 1H).
Reaction SMILES: [NH2:1][CH:2]1[C:22](=[O:23])[N:4]2[C:5]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=3)=[O:10])=[CH:6][CH2:7][S:8][C@H:3]12.C[Si](CC(N)=O)(C)C.[F:32][C:33]([F:57])([F:56])[C:34]([NH:36][C:37]1[S:38][CH:39]=[C:40]([C:42](=NOCC2C=CC(C)=CC=2)[C:43](O)=[O:44])[N:41]=1)=[O:35].P(Cl)(Cl)(Cl)=O>O1CCCC1.CN(C)C=O>[F:57][C:33]([F:32])([F:56])[C:34]([NH:36][C:37]1[S:38][CH:39]=[C:40]([CH2:42][C:43]([NH:1][CH:2]2[C:22](=[O:23])[N:4]3[C:5]([C:9]([O:11][CH2:12][C:13]4[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=4)=[O:10])=[CH:6][CH2:7][S:8][C@H:3]23)=[O:44])[N:41]=1)=[O:35]
Reactant: Cc1ccc(CON=C(C(=O)O)c2csc(NC(=O)C(F)(F)F)n2)cc1
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12
Agent: C[Si](C)(C)CC(N)=O
Solvent: C1CCOC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cc1csc(NC(=O)C(F)(F)F)n1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12
Yield: 129.4 %

Procedure:
A solution of 4-nitrobenzyl 7-amino-3-cephem-4-carboxylate (2.01 g.), trimethylsilylacetamide (5.51 g.) and tetrahydrofuran (40 ml.) and a solution of 2-[2-(2,2,2-trifluoroacetamido)thiazol-4-yl]-2-(4-methylbenzyloxyimino)acetic acid (syn isomer, 2.32 g.), phosphoryl chloride (1.20 g.) and N,N-dimethylformamide (570 mg.) in tetrahydrofuran (12 ml.) were treated in a similar manner to that of Example 1-(1) to give 4-nitrobenzyl 7-[2-[2-(2,2,2-trifluoroacetamido)thiazol-4-yl]-acetamido]-3-cephem-4-carboxylate (syn isomer, 4.43 g.).