Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([OH:15])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:29][NH2:30].CCCCCCC>C1COCC1>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:29][NH2:30])=[O:15]
Reactant: NN
Reactant: Cc1onc(-c2ccccc2)c1C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1onc(-c2ccccc2)c1C(=O)NN
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84.6 %

Procedure:
To a solution of 5-methyl-3-phenyl-isoxazole-4-carboxylic acid (5.00 g, 24.6 mmol) in THF (50 mL) was added in one portion 1,1′-carbonyl-diimidazole (4.39 g, 27.1 mmol). After stirring for 15 min at ambient temperature the solution was warmed to 70° C. and stirred for 30 min at this temperature. After the solution was cooled to 0° C. hydrazine monohydrate (2.4 mL, 49.0 mmol) was added over a period of 2 min while the temperature raised to 15° C. The resulting suspension was stirred for 30 min at 0° C. After addition of 20 mL heptane the suspension was stirred for 15 min at 0° C. and filtered off. Washing with water and drying afforded the title compound (4.52 g, 85%) as a white solid. MS: m/e=218.2 [M+H]+.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:22]=[C:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:23]5[NH:27][C:26]([CH:28]6[CH:33]7[CH2:34][CH:30]([CH2:31][CH2:32]7)[N:29]6[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[N:25][CH:24]=5)=[CH:17][C:18]=4[CH2:19][CH2:20]3)=[CH:11][CH:10]=2)O1.Br[C:44]1[NH:48][C:47]([C@@H:49]2[CH2:53][CH2:52][CH2:51][N:50]2[C:54](=[O:64])[C@@H:55]([NH:59][C:60](=[O:63])[O:61][CH3:62])[CH:56]([CH3:58])[CH3:57])=[N:46][CH:45]=1.C([O-])(O)=O.[Na+]>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.COCCOC>[CH3:62][O:61][C:60]([NH:59][C@@H:55]([CH:56]([CH3:58])[CH3:57])[C:54]([N:50]1[CH2:51][CH2:52][CH2:53][C@H:49]1[C:47]1[NH:48][C:44]([C:9]2[CH:22]=[C:21]3[C:12]([C:13]4[CH:18]=[CH:17][C:16]([C:23]5[NH:27][C:26]([C@@H:28]6[C@@H:33]7[CH2:34][C@@H:30]([CH2:31][CH2:32]7)[N:29]6[C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])=[N:25][CH:24]=5)=[CH:15][C:14]=4[CH2:19][CH2:20]3)=[CH:11][CH:10]=2)=[CH:45][N:46]=1)=[O:64])=[O:63]
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1ncc(-c2ccc3c(c2)CCc2cc(B4OC(C)(C)C(C)(C)O4)ccc2-3)[nH]1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(Br)[nH]1)C(C)C
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: COCCOC
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c(c2)CCc2cc(-c4cnc([C@@H]5[C@H]6CC[C@H](C6)N5C(=O)OC(C)(C)C)[nH]4)ccc2-3)[nH]1)C(C)C
Temperature: 120 °C
Yield: 88.2 %

Procedure:
To 1R,3S,4S)-tert-butyl 3-(5-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (97 mg, 0.17 mmol), methyl (S)-1-((S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (67 mg, 0.18 mmol), Pd(PPh3)4 (10 mg, 0.009 mmol). DME (1.7 mL) was added and followed by 0.7 mL 1M NaHCO3 aqueous solution. The reaction was purged with Ar and heated to 120° C. at microwave synthesizer for 0.5 hour. The reaction was cooled to room temperature and concentrated down. EtOAc was added and washed with sat. NaHCO3 aqueous (2×) and sat. NaCl aqueous (1×). The organic layer was concentrated down after drying over sodium sulfate and subject to silica gel chromatography with an eluent of ethyl acetate and hexane at a gradient of 40-100% with an ISCO column (12 g silica gel). The fractions containing product were combined and the solvent was removed under reduced pressure to provide (1R,3S,4S)-tert-butyl 3-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-9,10-dihydrophenanthren-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (110 mg, 88%). MS (ESI) m/z 734 [M+H]+.
Reaction SMILES: FC(F)(F)S(O[C@@H:7]([C:12]1[CH:13]=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=1)[C:8]([F:11])([F:10])[F:9])(=O)=O.[OH:21][C@@H:22]1[CH2:26][NH:25][CH2:24][C@H:23]1[NH:27][C:28](=[O:37])[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C([O-])([O-])=O.[K+].[K+].O>C1COCC1.C(OCC)(=O)C>[Cl:18][C:15]1[N:14]=[CH:13][C:12]([C@@H:7]([N:25]2[CH2:26][C@@H:22]([OH:21])[C@H:23]([NH:27][C:28](=[O:37])[O:29][CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:24]2)[C:8]([F:11])([F:10])[F:9])=[CH:17][CH:16]=1
Reactant: O=C(N[C@@H]1CNC[C@H]1O)OCc1ccccc1
Reactant: O=S(=O)(O[C@@H](c1ccc(Cl)nc1)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(N[C@@H]1CN([C@H](c2ccc(Cl)nc2)C(F)(F)F)C[C@H]1O)OCc1ccccc1
Yield: 59.1 %

Procedure:
A solution of (S)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl trifluoromethanesulfonate (2.50 g, 7.28 mmol), benzyl (3R,4R)-4-hydroxypyrrolidin-3-ylcarbamate (2.41 g, 10.2 mmol) and K2CO3 (1.51 g, 10.9 mmol) in THF (40 mL) was stirred at 56° C. for 12 hours. Water (20 mL) and ethyl acetate (40 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (20:1 ethyl acetate/MeOH) to give benzyl (3R,4R)-1-((R)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl)-4-hydroxypyrrolidin-3-ylcarbamate (1.85 g, 59.2%) as a solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:16]([OH:26])[CH2:17][C:18]3[C:23]([Cl:24])=[CH:22][N:21]=[CH:20][C:19]=3[Cl:25])[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:15])[F:14])[CH2:3][CH2:2]1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[CH:35]=[C:34]([C@H:39]([CH3:43])[C:40](O)=[O:41])[CH:33]=[CH:32]2.Cl.C(N=C=NCCCN(C)C)C.O>CN(C=O)C.CN(C)C1C=CN=CC=1>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:16]([O:26][C:40](=[O:41])[CH:39]([C:34]3[CH:33]=[CH:32][C:31]4[C:36](=[CH:37][CH:38]=[C:29]([O:28][CH3:27])[CH:30]=4)[CH:35]=3)[CH3:43])[CH2:17][C:18]3[C:19]([Cl:25])=[CH:20][N:21]=[CH:22][C:23]=3[Cl:24])[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:14])[F:15])[CH2:3][CH2:2]1
Reactant: OC(Cc1c(Cl)cncc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2cc(C(C)C(=O)OC(Cc3c(Cl)cncc3Cl)c3ccc(OC(F)F)c(OCC4CC4)c3)ccc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.9 %

Procedure:
Compound (3) (12.0 g) was dissolved in DMF (100 ml) then (S)-2-(6-methoxy-naphthalen-2-yl)-propionic acid (7.5 g), 4-dimethylaminopyridine (3.6 g), and 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (5.7 g) was added. After stirring at rt for 4 hours, water (1000 ml) is added, The mixture was extracted with EtOAc (500 ml×2), the combined organic layers are dried over sodium sulphate, and the solvent was removed by evaporation under reduced pressure to afford 17.0 g of an oil which is crystallized from EtOH thus obtaining 11.5 g of the title compound as mixture of diastereomers (11) and (13).
Reaction SMILES: [C:1]1([CH2:11][C:12]#[N:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C[Si]([NH-])(C)C.C[Si]([NH-])(C)C.[Na+].[Na+].[CH2:26]([CH:28]1[O:30][CH2:29]1)Cl.C(OCC)(=O)C.CCCCCC>O1CCCC1>[OH:30][CH2:29][CH:28]1[CH2:26][C@@:11]1([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[C:12]#[N:13]
Reactant: ClCC1CO1
Reactant: N#CCc1cccc2ccccc12
Agent: C[Si](C)(C)[NH-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: N#C[C@]1(c2cccc3ccccc23)CC1CO
Temperature: -15 °C
Reaction time: 0.75 h
Yield: 69.7 %

Procedure:
1-Naphthylacetonitrile (30 g, 180 mmole) was dissolved in dry tetrahydrofuran (THF, 300 mL) under nitrogen atmosphere, cooled to −15° C. and sodium-bis (trimethylsilylamide) in 1M tetrahydrofuran (180 mL) was added drop wise at −15° C. The resulting brown mixture was stirred for 45 min at −10° C. to 0° C. Then cooled the reaction mass to −15° C. A solution of S-(+) epichlorohydrin (16.6 g, 180 mmol) in tetrahydrofuran (20 mL) was added drop wise at −15° C. and stirred for 30 minutes. Sodiumbis (trimethylsilylamide) in 1M THF (180 mL) is added drop wise at −15° C. and the mixture was stirred for 45 min. The temperature of the reaction mass was then gradually raised to room temperature and maintained at room temperature for 30 minutes. The reaction is monitored by TLC (ethyl acetate/hexane (1:1)). The reaction was quenched with water (80mL). The aqueous layer was extracted with ethyl acetate (2×75 mL).The combined organic layer was washed with brine solution (200 mL), dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to yield 55 g of crude oil, which was purified by column chromatography (silica gel, ethyl acetate/hexane (10:90) to yield 28 g (69%) of product. The 1H NMR shows mixture of diasteromers (2:1 cis/trans). 1H NMR δ((300 MHz,CDCl3, partial assignment): 1.57-1.62 (2H,m), 1.92-2.03 (1H,m), 3.10-3.25 (1H,br,s), 3.91-3.97 (1H,m) 4.22-4.27 (1H,m), 7.37-7.69 (4H,m), 7.82-7.92 (2H,m), 8.36-8.49 (1H,m).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[N:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C@H:17]3[O:21]C(C)(C)[N:19]([C:24](=[O:28])[CH:25]([F:27])[F:26])[C@@H:18]3[CH2:29][F:30])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl.C(=O)(O)[O-]>[CH2:1]([NH:3][CH2:4][C:5]1[N:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]([C@@H:17]([OH:21])[C@@H:18]([NH:19][C:24](=[O:28])[CH:25]([F:26])[F:27])[CH2:29][F:30])=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCNCc1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)cn1
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNCc1ccc(-c2ccc([C@@H](O)[C@H](CF)NC(=O)C(F)F)cc2)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 62.4 %

Procedure:
To a solution of 1-{(4S,5R)-5-[4-(6-Ethylaminomethyl-pyridin-3-yl)-phenyl]-4-fluoromethyl-2,2-dimethyl-oxazolidin-3-yl}-2,2-difluoro-ethanone (0.062 g, 0.147 mmol) in CH2Cl2 (5 mL) is added trifluroacetic acid (1.0 mL) at room temperature. The resulting reaction mixture is stirred at room temperature for 5 hours. Solvent is evaporated in vacuo to get the crude residue and diluted with aqueous bicarbonate solution and extracted with ethyl acetate. Organic layer is dried over sodium sulphate, concentrated and purified by combi-flash chromatography using 15% methanol in CH2Cl2 as an eluent. Obtained solid is washed with n-pentane and diethyl ether to afford the title compound (0.035 g) after drying in lypholizer. 1H NMR (400 MHz, DMSO-d6) δ: 1.16 (t, J=7.2 Hz, 3H), 2.83-2.88 (q, 2H), 4.14 (s, 2H), 4.30-4.33 (m, 1.5H), 4.41-4.45 (m, 0.5H), 4.55-4.56 (m, 0.5H), 4.65-4.68 (m, 0.5H), 4.89 (t, J=4.08 Hz, 1H), 5.93 (d, J=4.55 Hz, 1H), 6.20 (t, J=53.76 Hz, 1H), 7.47 (d, J=8.24 Hz, 2H), 7.54 (d, J=8.2 Hz, 1H), 7.72 (d, J=8.24 Hz, 2H), 8.12-8.15 (dd, J1=2.32 Hz, J2=8.16 Hz, 1H), 8.85 (d, J=8.8 Hz, 1H), 8.90 (d, J=2.12 Hz, 1H). LC-MS (m/z): [M+H]=382.1.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Li]CCCC.I[C:12]1[CH:17]=[CH:16][C:15]([C:18]2([OH:28])[CH2:27][CH2:26][C:21]3(OCC[O:22]3)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1>C1COCC1.[Cl-].[Zn+2].[Cl-]>[OH:28][C:18]1([C:15]2[CH:16]=[CH:17][C:12]([C:2]3[O:1][CH:5]=[CH:4][N:3]=3)=[CH:13][CH:14]=2)[CH2:19][CH2:20][C:21](=[O:22])[CH2:26][CH2:27]1
Reactant: c1cocn1
Reactant: OC1(c2ccc(I)cc2)CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Product: O=C1CCC(O)(c2ccc(-c3ncco3)cc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of oxazole (240 mg, 3.5 mmol) in THF (5 mL) at −78° C. was added n-BuLi (1.6 M, 2.6 mL). After the mixture was stirred for 1 hour, a solution of zinc chloride in THF (0.5 M, 8.2 mL) was added in and the resulting mixture was allowed to warm to 0° C. over 1 hour. To the mixture was added 8-(4-iodo-phenyl)-1,4-dioxa-spiro[4.5]decan-8-ol (1.35 g, 3.5 mmol) and the resulting mixtue was degassed with N2 for 3 times. To a suspension of PdCl2(PPh3)2 (122 mg, 5%) in THF (2 mL) was added nBuLi (1.6 M, 0.26 mL) and the mixture was added into the above mixture. The resulting mixture was heated to reflux under N2 for 4 hours. The resulting mixture was diluted with ethyl acetate (50 mL). The organic layer was filtered through Celite and the filtrate was washed with saline solution (2×10 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was dissolved in THF (2.5 mL) and was treated with 5% HCl (22.5 mL) at rt for 24 h. The mixture was neutralized with 1 N NaOH to pH 7, concentrated on rotvap, and then extracted with EtOAc (2×50 mL). The organic extracts were combined, washed with saline solution (2×50 mL), dried over sodium sulfate, concentrated in vacuo. The resulting residue was chromatographed on silica gel, eluting with hexane/ethyl acetate (100/0 to 100/0), to provide the desired compound (0.56 g, 62% for the two steps). LCMS: 258.2 (M+H+, 100%). 1H NMR: (CDCl3) δ 8.06 (d, 2H), 7.73 (s, 1H), 7.63 (d, 2H), 2.99-2.91 (m, 2H), 2.42-2.30 (m 4H), 2.22-2.05 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][N:13]=[C:12]2O.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:12]1[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH:10]=2)[N:15]=[CH:14][N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccccc1-c1ccc2ncnc(O)c2c1
Product: COc1ccccc1-c1ccc2ncnc(Cl)c2c1
Temperature: 25 °C

Procedure:
Preparation D6, Step 3. A suspension of 6-(2-methoxyphenyl)quinazolin-4-ol (250 mg, 0.99 mmol) in POCl3 (10 mL) was heated at reflux for 1 h, during which time a clear solution was observed. The mixture was cooled to room temperature, concentrated in-vacuo, then concentrated from methylene chloride (3×100 mL) to remove any remaining POCl3. The residue was partitioned between ethyl acetate (25 mL) and saturated NaHCO3 (30 mL), and the mixture was stirred until gas evolution ceased (10 min). The layers were separated, the organic phase was washed with saturated NaHCO3, water, and brine, dried over sodium sulfate, and concentrated in-vacuo. The residue was purified over silica gel, eluting with 1:3 ethyl acetate/heptane, to yield 217 mg of 4-chloro-6-(2-methoxyphenyl)quinazoline as a white solid. 1H NMR (500 MHz, CDCl3) δ ppm 9.03 (s, 1H), 8.36 (s, 1H), 8.19 (d, J=7.15 Hz, 1H), 8.10 (d, J=8.80 Hz, 1H), 7.42 (m, 2H), 7.10 (t, J=7.42 Hz, 1H), 7.04 (d, J=8.25 Hz, 1H), 3.86 (m, 3H).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][S:13][C:14]1[C:22]2[C:17](=[CH:18][C:19]([C:23]([N:25]3[CH2:29][CH2:28][C@@H:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:26]3)=[O:24])=[CH:20][CH:21]=2)[N:16]([C:38]2[N:43]=[CH:42][C:41]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[CH:40][N:39]=2)[CH:15]=1>C1COCC1.C(OCC)(=O)C>[CH3:12][S:13]([C:14]1[C:22]2[C:17](=[CH:18][C:19]([C:23]([N:25]3[CH2:29][CH2:28][C@@H:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:34])[CH3:35])[CH2:26]3)=[O:24])=[CH:20][CH:21]=2)[N:16]([C:38]2[N:39]=[CH:40][C:41]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[CH:42][N:43]=2)[CH:15]=1)=[O:6]
Reactant: CSc1cn(-c2ncc(-c3ccccc3)cn2)c2cc(C(=O)N3CC[C@@H](NC(=O)OC(C)(C)C)C3)ccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CS(=O)c1cn(-c2ncc(-c3ccccc3)cn2)c2cc(C(=O)N3CC[C@@H](NC(=O)OC(C)(C)C)C3)ccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
m-Chloroperoxybenzoic acid (77%, 0.20 g, 0.92 mmol) in THF (5 mL) was added to an ice-cooled solution of 223c) (0.54 g, 1.02 mmol) in THF (100 mL) and the resulting mixture was stirred at room temperature for 4 h. The reaction mixture was then diluted with ethyl acetate (50 mL) and successively washed with saturated sodium hydrogen carbonate solution (2×50 mL) and brine (1×50 mL). The organic phase was dried over sodium sulfate and evaporated. The residue was purified by flash column chromatography [silica gel; dichloromethane with 2% methanol]. White solid. Yield: 0.28 g (51% of theory)
Reaction SMILES: [CH2:1]([C:8]1[N:12]([CH3:13])[C:11](=[O:14])[O:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=[O:17])C>[O-2].[Cr+6].[O-2].[O-2]>[C:1]([C:8]1[N:12]([CH3:13])[C:11](=[O:14])[O:10][N:9]=1)(=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c(Cc2ccccc2)noc1=O
Reactant: CC(=O)O
Agent: [Cr+6]
Agent: [O-2]
Product: Cn1c(C(=O)c2ccccc2)noc1=O
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of 3-benzyl-4-methyl-1,2,4-oxadiazol-5(4H)-one (3.87 g, 20.34 mmol, 1 eq.) in acetic acid (120 ml) was added chromium(VI) oxide (6.10 g, 61.04 mmol, 3 eq.) and stirring was allowed overnight. The reaction was quenched by addition of water and extracted with Et2O (3×50 ml). The organics were combined, washed with aq. sat. NaHCO3, dried over MgSO4 and concentrated to give 3-benzoyl-4-methyl-1,2,4-oxadiazol-5(4H)-one (3.85 g, 88% yield) as a white solid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].OS(O)(=O)=O.O=S(=O)=O.[N+]([O:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)([O-])=O>>[N+:1]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:18]=1[OH:17])([O-:4])=[O:2]
Reactant: O=[N+]([O-])Oc1ccncc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: O=[N+]([O-])c1cnccc1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A nitric acid solution (HNO3>90%, 13.3 ml) is slowly added to a solution of oleum (H2SO4 containing 20% SO3, d=1.9, 10.5 ml) cooled to 0° C. 4-Pyridol nitrate (10 g, 63 mmol) is added at 0° C. to the mixture which is then heated at 90° C. for 1 h 30 min. The reaction mixture is poured over 50 g of ice. The suspension is stirred for 30 min at 0° C. and is then filtered. The solid is washed with a few ml of water and then air-dried.
Reaction SMILES: F[P-](F)(F)(F)(F)F.CN(C)C(F)=[N+](C)C.[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH:28]([CH3:30])[CH3:29])[C:25]([OH:27])=O)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(C(C)C)CC)(C)C.[NH:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH2:42][C@H:41]1[C:49]([O:51][CH2:52][CH3:53])=[O:50]>C(Cl)Cl.CCOC(C)=O>[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH:28]([CH3:30])[CH3:29])[C:25]([N:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH2:42][C@H:41]1[C:49]([O:51][CH2:52][CH3:53])=[O:50])=[O:27])=[O:22])([CH3:17])([CH3:18])[CH3:19]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCOC(=O)[C@@H]1Cc2ccccc2N1
Agent: CN(C)C(F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1Cc2ccccc2N1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Yield: 56.9 %

Procedure:
N,N,N′,N′-tetramethylfluoroformamidinium hexafluorophosphate (1.1 g, 4.18 mmol, Eq: 1.6) was added to a solution of (S)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid (738 mg, 3.4 mmol, Eq: 1.3) and diisopropylethylamine (1.4 mL, 7.84 mmol, Eq: 3) in DCM (10 mL) and the resulting solution was stirred at rt for 1 h. (S)-Ethyl indoline-2-carboxylate (0.5 g, 2.61 mmol, Eq: 1.00) was added and the reaction mixture was stirred at rt over the weekend. The reaction mixture was diluted with EtOAc (50 mL) and washed with 0.1 M aqueous HCl (50 mL), 0.1 M aqueous NaOH (50 mL) and brine (25 mL). The crude material was purified by flash chromatography (silica gel, 24 g, 0% to 20% EtOAc in hexanes) to give (S)-ethyl 1-((S)-2-(tert-butoxycarbonylamino)-3-methylbutanoyl)indoline-2-carboxylate (0.58 g), m/z=391 (M+H).
Reaction SMILES: O[C:2]1([C:17]2[C:25]([CH2:26][OH:27])=[CH:24][C:20]3[O:21][CH2:22][O:23][C:19]=3[CH:18]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3]1=[O:16].C1(CCN2C3C(=CC=CC=3)C(C3C(O)=CC4OCOC=4C=3)(CO)C2=O)CC1>>[CH2:11]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]2([C:17]3=[CH:18][C:19]4[O:23][CH2:22][O:21][C:20]=4[CH:24]=[C:25]3[CH2:26][O:27]2)[C:3]1=[O:16])[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCN1C(=O)C(O)(c2cc3c(cc2CO)OCO3)c2ccccc21
Agent: O=C1N(CCC2CC2)c2ccccc2C1(CO)c1cc2c(cc1O)OCO2
Product: CCCCCN1C(=O)C2(OCc3cc4c(cc32)OCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 1, and making non-critical variations using 3-hydroxy-3-[6-(hydroxymethyl)-1,3-benzodioxol-5-yl]-1-pentyl-1,3-dihydro-2H-indol-2-one to replace 1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained (45%) as a colorless solid: mp 113-115° C.; 1H NMR (300 MHz, CDCl3) δ 7.24-7.33 (m, 1H), 7.12 (dd, 1H), 7.01 (t, 1H), 6.87 (d, 1H), 6.74 (s, 1H), 6.15 (s, 1H), 5.92 (dd, 2H), 5.48 (d, 1H), 5.27 (d, 1H), 3.76-3.56 (m, 2H), 1.71-1.64- (m, 2H), 1.37-1.27- (m, 4H), 0.89-0.84 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 175.9, 148.7, 148.1, 143.6, 133.7, 132.1, 130.3, 129.8, 125.3, 125.0, 123.1, 113.5, 109.1, 108.7, 101.9, 101.7, 88.7, 74.4, 40.0, 29.7, 29.0, 25.3, 13.3; MS (ES+) m/z 352.1 (M+1).
Reaction SMILES: N1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:7](Br)(=O)C.[CH3:11]/[C:12](/[O:18][Si](C)(C)C)=[N:13]\[Si](C)(C)C.C[Si](C)(C)NS(N[Si](C)(C)C)(=O)=O>O1CCOCC1>[C:2]1([CH2:11][C:12]([NH2:13])=[O:18])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccncc1
Reactant: CC(=O)Br
Reactant: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: C[Si](C)(C)NS(=O)(=O)N[Si](C)(C)C
Solvent: C1COCCO1
Product: NC(=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
0.36 ml (4.5 mmoles) of pyridine were added to a suspension of 0.525 g (1.50 mmoles) of benzylpenicillin sulphoxide in 10 ml of dioxane and the resulting solution was cooled to 0° C. followed by the addition of 0.05 ml (0.5 mmole) of acetyl bromide and the reaction mixture was stirred for 30 minutes at 0° C. 0.49 ml (1.9 mmoles) of N,O-bis(trimethylsilyl)acetamide and 0.38 g (1.6 mmoles) of N,N'-bis-trimethylsilyl sulphamide were added. The mixture was heated to reflux and after 4 hours at reflux, the amount of Δ3 -phenylacetamide desacetoxycephalosporanic acid formed, titrated by a microbiological analysis, was 95%.
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:6]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[CH:5][CH:4]=1.[OH:23][C:24]1[CH:25]=[CH:26][C:27]([O:37][CH3:38])=[C:28]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C(#N)C>[CH3:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:7]1[N:8]=[C:3]([CH2:2][O:23][C:24]2[CH:25]=[CH:26][C:27]([O:37][CH3:38])=[C:28]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:29]=2)[CH:4]=[CH:5][C:6]=1[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[F:22]
Reactant: CCOC(=O)CCc1cc(O)ccc1OC
Reactant: COc1ccc(F)c(-c2ccc(CCl)nc2CC(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1cc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)ccc1OC
Yield: 59.1 %

Procedure:
To a solution of 6-(chloromethyl)-2-(2,2-dimethylpropyl)-3-(2-fluoro-5-methoxyphenyl)pyridine (330 mg) in acetonitrile (8.0 mL) were added ethyl 3-(5-hydroxy-2-methoxyphenyl)propanoate (216 mg) and cesium carbonate (647 mg), and the mixture was heated under reflux for 15 hr. Ethyl acetate was added to the reaction mixture, and the insoluble material was filtered off. The solvent in the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (290 mg) as a white solid.