Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]([NH:13][C:14]3[CH:22]=[C:21]([S:23](=[O:26])(=[O:25])[NH2:24])[CH:20]=[CH:19][C:15]=3[C:16](O)=[O:17])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1.C(O)(=O)C.C(OC(=O)C)(=O)C>C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]3[O:12][C:16](=[O:17])[C:15]4[CH:19]=[CH:20][C:21]([S:23]([NH2:24])(=[O:26])=[O:25])=[CH:22][C:14]=4[N:13]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: NS(=O)(=O)c1ccc(C(=O)O)c(NC(=O)Cc2ccc3c(c2)OCO3)c1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: NS(=O)(=O)c1ccc2c(=O)oc(Cc3ccc4c(c3)OCO4)nc2c1
Yield: 34.2 %

Procedure:
A mixture of 2-(2-benzo[1,3]dioxol-5-yl-acetylamino)-4-sulfamoyl-benzoic acid (0.10 g, 0.26 mmol), acetic acid (1.5 mL) and acetic anhydride (0.10 mL, 1.06 mmol) was stirred at reflux for 1 h. The reaction was diluted with ethyl acetate and washed with NaHCO3 satured solution, then with water and brine. The organic phase was dried over Na2SO4, filtered and evaporated to give the 2-benzo[1,3]dioxol-5-ylmethyl-4-oxo-4H-benzo[d][1,3]oxazine-7-sulfonic acid amide intermediate (0.032 g) as yellow oil. To a solution of 2-benzo[1,3]dioxol-5-ylmethyl-4-oxo-4H-benzo[d][1,3]oxazine-7-sulfonic acid amide (0.032 g, 0.09 mmol) in dry pyridine (1 mL) was added aminoguanidine hydrogencarbonate (0.013 g, 0.098 mmol) and the mixture was heated under microwave condition at 180° C. for 1.5 h. The solvent was then evaporated and the crude was taken up in methanol to give the title compound (0.013 g, 12% yield).
Reaction SMILES: Cl[CH2:2][C@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][N:10]=2)[CH2:4]1.[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C)C=O.O>[N:16]([CH2:2][C@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][N:10]=2)[CH2:4]1)=[N+:17]=[N-:18]
Reactant: O=C1O[C@H](CCl)CN1c1ccc(Cl)cn1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@@H]1CN(c2ccc(Cl)cn2)C(=O)O1
Yield: 92.2 %

Procedure:
A mixture of (5S)-5-(chloromethyl)-3-(5-chloropyridin-2-yl)-1,3-oxazolidin-2-one (2.44 g, INTERMEDIATE 6) and sodium azide (1.28 g) was heated to 100° C. in 80 ml of dimethylformamide for 15 h. The mixture was then diluted with 500 ml of water and extracted with 500 ml of ethyl acetate (3×). The combined organic layers were washed with water (250 ml) and brine (250 ml). They were then dried over sodium sulfate and concentrated in vacuo to provide 2.31 g (92%) of the title compound in >95% purity via LC/MS. Mass spectrum (ESI) 254.1 (M+1).
Reaction SMILES: [CH:1]1[C:6]([C:7]2[C:16](=[O:17])[C:15]3[CH:14]=[CH:13][C:12]([OH:18])=[CH:11][C:10]=3[O:9][CH:8]=2)=[CH:5][CH:4]=[C:3]([OH:19])[CH:2]=1.[C:20]([O-])([O-])=O.[K+].[K+].IC>CS(C)=O>[CH3:20][O:18][C:12]1[CH:11]=[C:10]2[C:15]([C:16](=[O:17])[C:7]([C:6]3[CH:5]=[CH:4][C:3]([OH:19])=[CH:2][CH:1]=3)=[CH:8][O:9]2)=[CH:14][CH:13]=1
Reactant: O=c1c(-c2ccc(O)cc2)coc2cc(O)ccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CS(C)=O
Product: COc1ccc2c(=O)c(-c3ccc(O)cc3)coc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.1 %

Procedure:
To a solution of 5.1 g of daidzein (20.06 mmol) in 40 ml of DMSO was added 3.5 g of anhydrous K2CO3 (25.4 mmol) and 6 ml of iodomethane (96.4 mmol). The mixture was stirred at room temperature for 2 hours and then poured into ice water to precipitate product. Precipitates were extracted with ethyl acetate, dried by flash evaporation and purified on a Sephadex LH-20 column (chloroform:methanol/7:3). Final product was recrystallized from acetone to give 2.3 g of crystalline analog 2, a yield of 45.1% (w/w): mp 210-211° C.; 1H NMR (DMSO-d6) δ 3.89 (—OCH3), 6.81 (d, 2H, J=8.43 Hz, 3′, 5′-H), 7.05 (dd, 1H, J=8.89, 2.39 Hz, 6-H), 7.11 (d, 1H, J=2.07 Hz, 8-H), 7.39 (d, 2H, J=8.62 Hz, 2′, 6′-H), 8.01 (d, 1H, J=8.87 Hz; 5-H), 8.35 (s, 1H, 2-H), 9.54 (s, 1H, 4′-OH). Anal. (C16H12O4) for C, H. Cacld: 71.64, 4.51; found: 71.24, 4.47.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:26])[NH:18][C:19]2[CH:24]=[C:23](Cl)[N:22]=[CH:21][N:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O)[CH3:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:26])[NH:18][C:19]2[CH:24]=[C:23]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[O:29][CH2:27][CH3:28])[N:22]=[CH:21][N:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOc1ccccc1B(O)O
Reactant: O=C(Nc1cc(Cl)ncn1)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCOc1ccccc1-c1cc(NC(=O)C2CCN(C(=O)OCc3ccccc3)CC2)ncn1
Temperature: 110 °C
Yield: 50.3 %

Procedure:
To a stirred mixture of 4-(6-chloro-pyrimidin-4-ylcarbamoyl)-piperidine-1-carboxylic acid benzyl ester (VIII) (6.15 g, 16.4 mmol), 2-ethoxyphenylboronic acid (II) (3.00 g, 18.1 mmol) in saturated sodium carbonate solution (10 ml) and 1,4-dioxane (10 ml) was added palladium(II) acetate (0.81 g, 3.6 mmol) followed by triphenylphosphine (0.94 g, 3.6 mmol) at room temperature under an atmosphere of nitrogen. The resulting reaction mixture was heated to reflux at 110° C. for one hour and monitored by TLC. The reaction mixture was filtered through a celite bed and the filtrate was extracted with ethyl acetate (3×100 ml). The organic layers were separated, combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, elution with 50% ethyl acetate/n-hexanes) to afford 4-[6-(2-ethoxy-phenyl)-pyrimidin-4-ylcarbamoyl]-piperidine-1-carboxylic acid benzyl ester (IX) (3.8 g, 50%) as a pale yellow oil.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](OS(C(F)(F)F)(=O)=O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH3:31][NH2:32].C1COCC1>CN1C(=O)CCC1.O>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[N:20][C:21]([NH:32][CH3:31])=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CN
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(OS(=O)(=O)C(F)(F)F)cc1OCC2
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Solvent: O
Product: CNc1cc2c(cn1)-c1nc(-c3ncnn3C(C)C)cn1CCO2
Temperature: 85 °C
Reaction time: 4 h
Yield: 28 %

Procedure:
A solution of trifluoro-methanesulfonic acid 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yl ester (100 mg, 0.23 mmol) in NMP was treated with 2M methylamine in THF (1.8 mL, 0.9 mmol) and heated at 85° C. for 20 h then diluted with water and stirred for 4 h. The precipitate was collected by filtration and dried in vacuo to give 416 as a white solid (19.5 mg, 28%). LCMS: RT=2.26 min, [M+H]+=326. 1H NMR 400 MHz (DMSO-d6) δ: 9.02 (1H, s), 7.88 (1H, s), 7.80 (1H, s), 6.70 (1H, br, m), 5.95 (1H, s), 5.91-5.90 (1H, m), 4.47 (4H, q, J=6.12 Hz), 2.78 (3H, d, J=4.86 Hz), 1.47 (6H, d, J=6.60 Hz)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([CH2:14][O:15]CC2C=CC=CC=2)[CH2:12][O:11][C@@H:10]([O:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([CH2:14][OH:15])[CH2:12][O:11][C@@H:10]([O:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)(C)CO[C@H]1CN(C(=O)OC(C)(C)C)[C@@H](COCc2ccccc2)CO1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)CO[C@H]1CN(C(=O)OC(C)(C)C)[C@@H](CO)CO1

Procedure:
Stir (2R,5S)-5-benzyloxymethyl-2-(2,2-dimethylpropoxy)-morpholine-4-carboxylic acid tert-butyl ester (7.05 g, 17.92 mmol) and 20% palladium hydroxide on carbon in methanol (150 mL) under 1 atmosphere of hydrogen gas at room temperature for 12 hours. Filter and concentrate to give the desired compound as a thick oil which is used directly in the next step without further purification (5.10 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[N:11]=1.C1C(C(C[Br:28])=O)=CC=C(O)C=1.N1C=CC=CC=1C(N)=S>>[BrH:28].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[N:11]=1
Reactant: O=C(CBr)c1ccc(O)cc1
Agent: NC(=S)c1ccccn1
Agent: Oc1ccc(-c2csc(-c3ccccn3)n2)cc1
Product: Br

Procedure:
4-(2-Pyridin-2-yl-thiazol-4-yl)phenol hydrobromidewas preparedfrom α-bromo-4-hydroxyacetophenone and thiopicolinamide as described in Preparation 48; m.p. 261-262° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:4]([CH:5]=O)[C:3]=1[OH:11].[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13].N.[ClH:18]>C(O)C.CCOCC.C(O)=O>[ClH:18].[C:12]([NH:16][CH2:5][C:4]1[CH:7]=[C:8]([Br:10])[CH:9]=[C:2]([Br:1])[C:3]=1[OH:11])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)N
Reactant: O=Cc1cc(Br)cc(Br)c1O
Agent: Cl
Agent: N
Solvent: O=CO
Solvent: CCO
Solvent: CCOCC
Product: CC(C)(C)NCc1cc(Br)cc(Br)c1O

Procedure:
7 gm of 3,5-dibromo-salicylaldehyde, 17.5 gm of tert. butylamine and 7.7 gm of formic acid were heated for 6 hours at 70°-80° C. Subsequently, the reaction mixture was admixed with aqueous 2 N ammonia, vigorously shaken, and the precipitate formed thereby was sucked off. The residue was dissolved in ethanol, acidified with ethanolic hydrochloric acid and admixed with ether in order to crystallize the product out. N-tert.butyl-3,5-dibromo-2-hydroxy-benzylamine hydrochloride, m.p. 216°-220° C (decomp.), was obtained after recrystallization from absolute ethanol/ether.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]4[CH:27]=3)=[CH:14][CH:13]=2)=O)[CH2:6][CH2:5][CH2:4]C[CH2:2]1>C1(C)C=CC=CC=1>[N:1]1([CH2:7][CH2:8][CH2:9][NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[N:19]=[C:20]4[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]4[CH:27]=3)=[CH:16][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:2]1
Reactant: Cc1cccn2cc(-c3ccc(NC(=O)CCN4CCCCC4)cc3)nc12
Solvent: Cc1ccccc1
Product: Cc1cccn2cc(-c3ccc(NCCCN4CCCC4)cc3)nc12
Temperature: 25 °C
Yield: 53.3 %

Procedure:
A mixture of the product of Step C (122 mg) and borane-methylsulfide complex (0.5 mL of a 2M solution in toluene) in toluene (3.5 mL) was stirred and heated at reflux for 18 hours. The mixture was cooled to ambient temperature and evaporated. The residue was treated with 1M HCl (10 mL) and heated to reflux. The aqueous mixture was cooled to ambient temperature and treated with solid sodium hydroxide until the pH of the mixture was 8. The aqueous mixture was extracted three times with dichloromethane (10 mL each). The combined organic layers were dried over sodium sulfate, decanted and evaporated. The residue was purified via silica gel chromatography (methanol/dichloromethane) to yield the title compound (60 mg). 1H-NMR (CD3OD) δ 8.16 (d, J=7.0 Hz, 1H), 7.90 (s, 1H), 7.72 (m, 2H), 7.00 (m, 1H), 6.71 (m, 3H), 3.16 (t, J=7.0 Hz, 2H), 2.59 (m, 9H), 1.86 (m, 2H), 1.65 (m, 4H), 1.50 (m, 2H)
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([C@H:12]1[O:16][C:15](=[O:17])[C@H:14]([CH3:18])[CH2:13]1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].O>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C@@H:10]([O:11][S:27]([CH3:26])(=[O:29])=[O:28])[C@@H:12]1[CH2:13][C@@H:14]([CH3:18])[C:15](=[O:17])[O:16]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H]1C[C@@H]([C@H](O)COCc2ccccc2)OC1=O
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1C[C@@H]([C@@H](COCc2ccccc2)OS(C)(=O)=O)OC1=O
Reaction time: 3 h
Yield: 96.6 %

Procedure:
A solution of 7.80 g of (3R,5S)-5-[(R)-2-benzyloxy-1-hydroxyethyl]-3-methyldihydrofuran-2-one obtained in Example (76c) (31.2 mmol) in methylene chloride (200 ml) was cooled in an ice bath. Then, 9.45 g of triethylamine (93.6 mmol) and 5.36 g of methanesulfonyl chloride (47.0 mmol) were added thereto, and the mixture was stirred at the same temperature for three hours. 500 ml of water was added to the reaction mixture, followed by extraction with methylene chloride. Then, the organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:n-hexane/ethyl acetate=4/1-1/1) to obtain 9.90 g of the title compound (yield: 97%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[NH2:22][C@@H:23]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([NH:22][C@@H:23]([CH2:29][CH:30]([CH3:31])[CH3:32])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CCOC(=O)[C@@H](N)CC(C)C
Agent: Cl
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinic acid (Example 69 b) and (S)-ethyl 2-amino-4-methylpentanoate hydrochloride (CAN 2743-40-0) as starting materials. MS (EI): m/e=426.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:10])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.CN(C=O)C.Cl[CH2:17][C:18](=[O:24])[CH2:19][C:20]([O:22][CH3:23])=[O:21].C([O-])([O-])=O.[K+].[K+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([S:10][CH2:17][C:18](=[O:24])[CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(S)cc(Cl)c1
Reactant: COC(=O)CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CC(=O)CSc1cc(Cl)cc(OC)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 3-chloro-5-methoxybenzenethiol (2.1 g) and DMF (dry) (30 mL) were added methyl 4-chloroacetoacetate (1.407 mL) and K2CO3 (1.994 g) at 0° C., and the mixture was stirred at room temperature for 5 h. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (1.440 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:33])[C:10]([NH:12][NH:13][C:14](=[O:32])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:17]([CH3:29])[C:16]=2[CH2:30][CH3:31])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1>O1CCCC1.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C@@H:9]([OH:33])[C:10]([NH:12][NH:13][C:14](=[O:32])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[C:17]([CH3:29])[C:16]=2[CH2:30][CH3:31])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCc1c(C(=O)NNC(=O)C(=O)c2cc(F)cc(F)c2)ccc(OCc2ccccc2)c1C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCc1c(C(=O)NNC(=O)[C@H](O)c2cc(F)cc(F)c2)ccc(OCc2ccccc2)c1C
Reaction time: 6 h
Yield: 20.8 %

Procedure:
302 mg of N′-[2-(3,5-difluorophenyl)-2-oxoacetyl]-4-benzyloxy-2-ethyl-3-methylbenzohydrazide (B3) are dissolved in 25 ml of tetrahydrofuran. This solution is added dropwise over the course of 5 min to a solution of 49 μl of borane/dimethyl sulfide complex and 55 μl of (R)-methyloxazaborolidine [(R)-Me-CBS, 1-1.5 M in toluene) in 17 ml of tetrahydrofuran at a temperature of (−)78° C. The cooling bath is subsequently removed, and the solution is stirred for 6 h, during which the reaction solution warms to room temperature: 100 ml of water are then added, and the mixture is extracted three times with 150 ml of ethyl acetate each time. The combined organic phases are washed with 40 ml of each of water, 0.1 M HCl and sat. NaCl solution, dried over NaSO4, filtered off with suction and evaporated to dryness. The residue is purified by means of preparative HPLC (solvent gradient: water/1-50% by vol. of acetonitrile), giving 63 mg of the title compound as colourless, amorphous solid. MS: 932 (2M+Na+); TLC: Rf=0.56 (cyclohexane/methyl tert-butyl ether 1:4, parts by volume).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[CH2:15][CH2:14][CH2:13][C:12]3=[O:16])[CH2:7][CH2:6]2)[O:4]CC1.Cl>C(#N)C>[O:4]=[C:5]1[CH2:6][CH2:7][CH:8]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH2:9][CH2:10]1
Reactant: O=C1CCCN1C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: CC#N
Product: O=C1CCC(N2CCCC2=O)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.1 %

Procedure:
1-(1,4-dioxaspiro[4.5]decan-8-yl)pyrrolidin-2-one (143 mg, 0.64 mmol) from above step B, was dissolved in acetonitrile, treated with 6N HCl, and stirred at room temperature for 18 h. reaction mixture was concentrated in vacuo, treated with saturated NaHCO3 to pH 6. The solvents were removed under vacuum and the residue treated with saturated NaCl (2 mL) and extracted with 4:1 EtOAc/iPrOH (x4). The organic fractions were combined, filtered and evaporated to give 115 mg of 1-(4-oxocyclohexyl)pyrrolidin-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([F:27])[CH:21]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[C:4]([CH3:28])[CH:3]=1.[CH3:29][O:30][C:31]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)=[O:32].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:29][O:30][C:31](=[O:32])[C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([O:26][C:23]2[CH:24]=[CH:25][C:20]([CH:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=3[CH3:28])[CH2:9][C:10]([C:12]3[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=3)=[O:11])=[CH:21][C:22]=2[F:27])[CH:38]=1
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(O)c(F)c1
Reactant: COC(=O)c1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cccc(Oc2ccc(C(CC(=O)c3ccc(=O)n(C)c3)c3ccc(Cl)cc3C)cc2F)c1

Procedure:
In analogy to example 222, step 1, 5-[3-(4-chloro-2-methyl-phenyl)-3-(3-fluoro-4-hydroxy-phenyl)-propionyl]-1-methyl-1H-pyridin-2-one (example 324, step 1) was reacted with 3-methoxycarbonylphenylboronic acid in dichloromethane in the presence of copper(II) acetate, pyridine and air to give the title compound as a colourless solid, MS (ESI+): m/z=534.1 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]1[C:23](=[O:24])[N:4]2[C:5]([C:10]([O:12]CC3C=CC([N+]([O-])=O)=CC=3)=[O:11])=[C:6]([Cl:9])[CH2:7][S:8][C@H:3]12.[I-].[Li+].Cl>O1CCCC1>[NH2:1][C@@H:2]1[C:23](=[O:24])[N:4]2[C:5]([C:10]([OH:12])=[O:11])=[C:6]([Cl:9])[CH2:7][S:8][C@H:3]12
Reactant: N[C@@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12
Agent: Cl
Agent: [I-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N[C@@H]1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12
Yield: 25.1 %

Procedure:
To a slurry of 3.7 g (10 mmol) of p-nitrobenzyl 7β-amino-3-chloro-3-cephem-4-carboxylate and 61 ml of tetrahydrofuran, was added 8.03 g (60 mmol) of lithium iodide. The resulting reaction mixture was then heated to reflux and allowed to react for about 21/2 hours. The solution was cooled to complete the precipitation of lithium 7β-amino-3-chloro-3-cephem-4-carboxylate. This precipitate was isolated by filtration, slurried in 25 ml of tetrahydrofuran and then acidified to a pH of 3.7 with 1N hydrochloric acid resulting in the formation of a light solid. This solid was isolated by filtration and washed with a 25:3 tetrahydrofuran/water solution to provide 0.59 g of the desired titled product.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]([O:13][C@@H:14]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@@H:15]1Br)(=[O:12])[CH3:11]>C(Cl)Cl.[N-]1C=CN=C1.[Ag+].[Cl-].[Zn+2].[Cl-]>[C:10]([O:13][C@@H:14]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:15]1[O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5])(=[O:12])[CH3:11]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)SC[C@H]1OC(C)=O
Reactant: N#Cc1ccccc1O
Agent: [Ag+]
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccccc1C#N
Yield: 20 %

Procedure:
If the procedure described in Preparation LXXXIII is followed starting from 2 g (16.8.10-3 mol) of 2-hydroxybenzonitrile, 4.4 g (25.1.10-3 mol) of silver imidazolate, 6.5 g (18.3.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide and 4.6 g (33.6.10-3 mol) of zinc chloride in 80 ml of methylene chloride, 1.32 g (yield: 20%) of the expected product are obtained after purification by chromatography on silica gel using a toluene/ethyl acetate mixture (6/1 v/v) as the eluent, and precipitation in ether.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:8][C:9]([CH3:19])([CH3:18])[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11].FC(F)(F)C(O)=O.C([SiH](CC)CC)C.C(=O)(O)[O-].[Na+]>CCOCC>[OH:8][C:9]([CH3:19])([CH3:18])[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11].[CH2:10]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[OH:7])[CH:9]([CH3:19])[CH3:18]
Reactant: Oc1ccccc1
Agent: CC(C)(O)C(=O)c1ccccc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cc1ccccc1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 55 %

Procedure:
2-Hydroxy-isobutyrophenone was prepared from phenol following the procedure described in Canadian Journal of Chemistry, 31, 1956, 851. To a solution of 2-hydroxy-isobutyrophenone (2g, 12.2 mmol) in trifluroacetic acid (14 g, 122 mmol) was slowly added triethylsilane (26.8 mmol). The solution was stirred at room temperature for 6 hours. Saturated sodium bicarbonate solution was added to the reaction mixture, followed by ether. The layers were separated, and the aqueous layer was extracted with ether. The organic layers were combined, dried over magnesium sulfate, and concentrated. The crude material was distilled under vacuum (about 9.3×10−4 MPa, 75° C.). The distillate was washed with potassium hydroxide solution, followed by addition of hydrogen chloride solution, and extraction with ether. The ether layers were combined, dried over magnesium sulfate, and concentrated to give 1.0 g (55%) of 2-isobutylphenol. 1H NMR (300 Mhz, δ, CDCl3): 7.0 (m, 2H), 6.8 (t, 1H), 6.7 (d, 1H), 4.6 (br. s, 1H), 2.4 (d, 2H), 1.9 (s, 1H), 0.9 (d, 6H).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([O:17]CC)=O)[CH2:10][CH2:9]2)=[CH:5][CH:4]=1.[NH2:24][NH2:25]>C(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([NH:24][NH2:25])=[O:17])[CH2:10][CH2:9]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CN1CCN(Cc2ccc(C(F)(F)F)cc2)CC1
Reactant: NN
Solvent: CCO
Product: NNC(=O)CN1CCN(Cc2ccc(C(F)(F)F)cc2)CC1

Procedure:
Synthesized according to General Procedure C: 6{15} (4.76 g, 14.4 mmol, 1 equiv.), anhydrous hydrazine (1.4 mL, 43.2 mmol, 3 equiv.), ethanol (28.9 mL). Purification by silica gel column chromatography (4:1 EtOAc:MeOH) afforded 1{15} (3.70 g, 81%) as a white solid. 1H-NMR (500 MHz, CDCl3): δ 8.13 (br s, 1H), 7.55 (d, 2H, J=8.0 Hz), 7.41 (d, 2H, J=8.0 Hz), 3.84 (br s, 2H), 3.53 (s, 2H), 3.07 (s, 2H), 2.53 (br s, 4H), 2.45 (br s, 4H). 13C-NMR (125 MHz, CDCl3): δ 170.3, 142.2, 129.3 (q, JC-F=32.0 Hz), 129.0, 125.1 (q, JC-F=3.8 Hz), 19624.1 (q, JC-F=270.5 Hz) 129.1, 62.2, 60.5, 53.6, 53.0. 19F-NMR (470 MHz, CDCl3): δ-62.8.