Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@@H:4]1[CH2:8][C@@H:7]([C:9]#[N:10])[CH2:6][N:5]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>C(O)C.[Pd]>[CH3:1][O:2][C:3](=[O:18])[C@@H:4]1[CH2:8][C@H:7]([CH2:9][NH2:10])[CH2:6][N:5]1[C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12]
Reactant: COC(=O)[C@@H]1C[C@@H](C#N)CN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: COC(=O)[C@@H]1C[C@H](CN)CN1C(=O)OC(C)(C)C

Procedure:
A solution (4R)-1-(tert-butyloxycarbonyl)-4-cyano-L-proline methyl ester (204 mg, 0.802 mmol) in 90% ethanol (12 mL) was hydrogenated in the presence of 10% palladium-on-charcoal (60 mg) at 450 psi for 24 hours. The catalyst was removed by filtration through Celite, the filter washed with ethanol, and the combined filtrate and washings evaporated. Purification was achieved by flash silica gel chromatography eluting with 95:5:0.5 chloroform-methanol-ammonia; yield 66 mg (32%).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[N:14][N:15]2[CH:20]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[C:21]([O:23][CH3:24])=[O:22])=[O:9])([CH3:6])([CH3:5])[CH3:4].FC(F)(F)S(O[CH2:38][C:39]([F:42])([F:41])[F:40])(=O)=O>C1COCC1>[C:3]([O:7][C:8]([NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[N:14][N:15]2[C:20]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)([CH2:38][C:39]([F:42])([F:41])[F:40])[C:21]([O:23][CH3:24])=[O:22])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)C(c1ccc(Cl)cc1)n1ncc2c(NC(=O)OC(C)(C)C)cccc21
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(CC(F)(F)F)(c1ccc(Cl)cc1)n1ncc2c(NC(=O)OC(C)(C)C)cccc21
Reaction time: 0.5 h

Procedure:
A bottle flask was charged with NaH (580 mg, 14.4 mmol, 60% in oil) and then a solution of methyl 2-(4-(tert-butoxycarbonylamino)-1H-indazol-1-yl)-2-(4-chlorophenyl)acetate (3 g, 7.22 mmol), as described in Example 18 Step C, and 2,2,2-trifluoroethyl trifluoromethanesulfonate (3.35 g, 14.4 mmol) in THF (40 mL) at 0° C. The mixture was stirred for 30 min, quenched with saturated NH4Cl solution (10 mL), extracted with ethyl acetate. The organic layers were washed with brine (15 mL), dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography (PE/EA=3:1) to afford the title compound as colorless oil. LC/MS m/z=498.1[M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:13]1(/[CH:19]=[C:20](\B2OC(C)(C)C(C)(C)O2)/[CH2:21][OH:22])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[F-].[Cs+]>C1COCC1.C1(P([Pd-4](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)C=CC=CC=1>[CH:13]1(/[CH:19]=[C:20](\[C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=2)/[CH2:21][OH:22])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CNS(=O)(=O)c1ccc(Br)cc1
Reactant: CC1(C)OB(/C(=C\C2CCCCC2)CO)OC1(C)C
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc(/C(=C\C2CCCCC2)CO)cc1
Yield: 82.4 %

Procedure:
Heat a suspension of 4-bromo-N-methyl-benzenesulfonamide (0.51 g, 2.0 mmol), (E)-3-cyclohexyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-prop-2-en-1-ol (0.81 g, 3.06 mmol), caesiumfluoride (0.93 g, 6.12 mmol) and tetrakis(triphenylphosphino)palladium(0) (230 mg, 0.2 mmol) in 12 mL THF to 60° C. for 4 h. Remove the solvent under vacuum and add ethyl acetate, wash the organic layer with water followed by saturated sodium chloride solution. Filter through a hydrophobic filter paper and remove the solvent under vacuum. Further purify the resulting residue by column chromatography, eluting with a gradient from 100:0 to 35:65 hexanes:ethyl acetate to afford the title compound (0.51 g) as a gray solid. MS (m/e): 310 (M+H).
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].[CH3:5][OH:6]>>[CH:1]([O:4][C:5]([CH2:3][C:1]1[O:4][C:1]([CH3:3])([CH3:2])[O:4][C:5](=[O:6])[CH:2]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)O
Reactant: CO
Product: CC(C)OC(=O)CC1=CC(=O)OC(C)(C)O1

Procedure:
The reaction was carried out in the same manner as in Example 2 except that 10 mL of isopropyl alcohol was used as the alcohol in lieu of methanol. The reaction mixture was treated in the same manner as mentioned above and the organic layer obtained by phase separation was dried and concentrated to give 0.999 g of nearly pure 6-isopropoxycarbonylmethyl-2,2-dimethyl-4H-1,3-dioxin-4-one. The yield of 6-isopropoxycarbonylmethyl-2,2-dimethyl-4H-1,3-dioxin-4-one was 74 mol % based on the starting material 6-chloromethyl-2,2-dimethyl-4H-1,3-dioxin-4-one. The NMR spectrum data on this compound are shown below.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:9]([NH:10][C@H:11]3[C@@H:15]([CH2:16][F:17])[CH2:14][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:12]3)=[C:8]([C:25](=[O:27])[NH2:26])[CH:7]=[N:6][N:5]2[CH:28]=1.[CH2:29]([N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1)[CH3:30].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[C:25]([C:8]1[CH:7]=[N:6][N:5]2[CH:28]=[C:2]([C:34]3[CH:33]=[N:32][N:31]([CH2:29][CH3:30])[CH:35]=3)[N:3]=[C:4]2[C:9]=1[NH:10][C@H:11]1[C@@H:15]([CH2:16][F:17])[CH2:14][N:13]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:12]1)(=[O:27])[NH2:26]
Reactant: CC(C)(C)OC(=O)N1C[C@H](CF)[C@H](Nc2c(C(N)=O)cnn3cc(Br)nc23)C1
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCn1cc(-c2cn3ncc(C(N)=O)c(N[C@@H]4CN(C(=O)OC(C)(C)C)C[C@@H]4CF)c3n2)cn1
Temperature: 100 °C
Yield: 65.3 %

Procedure:
A solution of (3S,4S)-tert-butyl 3-((2-bromo-7-carbamoylimidazo[1,2-b]pyridazin-8-yl)amino)-4-(fluoromethyl)pyrrolidine-1-carboxylate (22.2 mg, 0.049 mmol), 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (21.56 mg, 0.097 mmol), PdCl2(dppf) CH2Cl2 Adduct (1:1) (3.99 mg, 4.85 μmol) in dioxane (0.5 ml) and 2M aq K3PO4 (0.073 ml, 0.146 mmol) in dioxane (0.5 ml) in a reaction vial was purged with N2 for 2 min. The reaction mixture was sealed and heated at 100° C. for 120 min. The reaction mixture was partitioned between EtOAc and water. The organic phase was washed with brine, filtered through CELITE®, dried (Na2SO4) and concentrated. The crude product was purified by flash column (ISCO 12 g-column, 20-80% EtOAc/hexane over 15 min) to afford (3S,4S)-tert-butyl 3-((7-carbamoyl-2-(1-ethyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-8-yl)amino)-4-(fluoromethyl)pyrrolidine-1-carboxylate (15 mg, 0.032 mmol, 65.4% yield) as a white solid. ESI-MS (Method A): m/z 473.4 ([M+H]+).
Reaction SMILES: [CH2:1]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)=[CH:15][CH:16]=2)[C:11]([CH:25]=[O:26])=[CH:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[K].OO.[O-:30][Mn](=O)(=O)=O.[K+]>CC(C)=O.O>[CH2:1]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)=[CH:15][CH:16]=2)[C:11]([C:25]([OH:30])=[O:26])=[CH:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCn1cc(C=O)c2cc(-c3cccc(C)c3)ccc21
Reactant: O=[Mn](=O)(=O)[O-]
Agent: OO
Agent: [K+]
Agent: [K]
Solvent: CC(C)=O
Solvent: O
Product: CCCCCCCCn1cc(C(=O)O)c2cc(-c3cccc(C)c3)ccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 62 %

Procedure:
The method of Andreani, A.; Granaiola, M.; Leoni, A.; Locatelli, A.; Morigi, R.; Rambaldi, M.; Roda, A.; Guardigli, M.; Traniello, S.; Spisani, S. N-Benzyl-2-chloroindole-3-carboxylic acids as potential anti-inflammatory agents. Synthesis and screening for effects on human neutrophil functions and on COX1/COX2 activity. Eur J Med. Chem. 2004, 39, 785-91, was followed. Compound 9 (0.573 mmol, 1 equiv) was dissolved in 10 mL of acetone and treated with a solution of potassium permanaganate (KMnO4, 1.5 mmol) in water (5 mL). The reaction mixture was stirred at room temperature for 5 h, treated with 10% H2O2 until the pink color of KMnO4 was not observed and then filtered. The solvent was removed under reduced pressure and the resulting residue was filtered again (if necessary), acidified with 2M HCl and extracted with Et2O. The organic solvent was removed in vacuo and the residue was purified by column chromatography with hexane/EtOAc as eluting solvents. Yield: 62%; 1H NMR (300 MHz, CDCl3): δ 8.84 (s, 1 H), 7.92 (s, 1 H), 7.54-7.48 (m, 2 H), 7.41-7.29 (m, 3 H), 7.14 (d, J=6.6 Hz, 1 H), 4.12 (t, J=6.6 Hz, 2 H), 2.44 (s, 3 H), 1.87 (t, J=6.6 Hz, 3 H), 1.37-1.25 (m, 10 H), 0.86 (t, J=6.6 Hz, 3 H); 13C NMR (75 MHz, CDCl3): δ 170.3, 142.3, 141.9, 138.4, 138.2, 136.1, 136.0, 135.8, 128.5, 128.3, 127.4, 124.6, 120.3, 110.3, 106.3, 47.2, 31.7, 31.1, 29.8, 29.1, 22.6, 21.5, 21.5, 14.0.
Reaction SMILES: [CH3:1][O:2]/[CH:3]=[C:4](\[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][O:16][C:17]1[CH:22]=[C:21]([CH3:23])[C:20]([C:24](=O)/[CH:25]=[CH:26]/[N:27]([CH3:29])C)=[CH:19][C:18]=1[CH3:31])/[C:5]([O:7][CH3:8])=[O:6].C[NH:33]O>CO>[CH3:1][O:2]/[CH:3]=[C:4](\[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][O:16][C:17]1[CH:22]=[C:21]([CH3:23])[C:20]([C:24]2[CH:25]=[CH:26][N:27]([CH3:29])[N:33]=2)=[CH:19][C:18]=1[CH3:31])/[C:5]([O:7][CH3:8])=[O:6]
Reactant: CNO
Reactant: CO/C=C(/C(=O)OC)c1ccccc1COc1cc(C)c(C(=O)/C=C/N(C)C)cc1C
Solvent: CO
Product: CO/C=C(/C(=O)OC)c1ccccc1COc1cc(C)c(-c2ccn(C)n2)cc1C
Yield: 73.8 %

Procedure:
(E)-methyl 3-methoxy-2-(2-((4-((E)-3-(dimethylamino)acryloyl)-2,5-dimethylphenoxy)-methyl)phenyl)acrylate (0.11 g, 0.25 mmol) obtained in Step 1 was reacted with 17 mg (1.5 eq) of methylhydroxyamine in 10 mL of methanol at room temperature for 3 hours with stirring, and then the reaction solvent was removed at a reduced pressure. The residue was stirred in water (20 mL), and the aqueous layer was extracted twice with 30 mL of dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated in a vacuum. Purification by chromatography afforded (E)-methyl 3-methoxy-2-(2-((2,5-dimethyl-4-(1-methyl-1H-pyrazol-3-yl)phenoxy)methyl)phenyl)acrylate as a white solid (75 mg, yield: 74%).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:18]1([CH3:25])[C:23]([OH:24])=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N1C=CN=C1)CCC.CCCCCCCCCCCCCC>[Cu]Cl.C(OCC)C.O.C1(C)C=CC=CC=1>[C:18]1([CH3:25])[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=1[O:24][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc2ccccc12
Reactant: Cc1ccccc1O
Agent: Cl[Cu]
Agent: CCCCCCCCCCCCCC
Agent: CCCCn1ccnc1
Solvent: O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cc1ccccc1Oc1cccc2ccccc12
Temperature: 120 °C
Yield: 89 %

Procedure:
278 μL (2 mmol) 1-bromonaphthaline, 20 mg (0.2 mmol) copper(I) chloride, 550 mg (4 mmol) potassium carbonate, 260 mg (2.4 mmol) o-cresol, 130 μL 1-butylimidazole, 2 mL toluene and 200 μL internal standard (tetradecane) were added to an Ace pressure tube under argon and heated to 120° C. for 16 h. After cooling, water and diethyl ether were added, the organic phase was washed with 10% K2CO3 solution, water and brine and dried over Na2SO4. GC analysis of the organic phase showed a yield of 89%. After evaporation of the solvents, the dark brown oil was submitted to column chromatography over silica gel, eluent light petroleum. 0.38 g of colourless oil was recovered (81% isolated yield). The substance was identified by gc/ms and nmr spectroscopy.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5](Br)[N:6]2[CH2:16][C:17]1[CH:31]=[CH:30][C:20]([CH2:21][P:22](=[O:29])([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])=[CH:19][CH:18]=1.[CH3:33][O-:34].[Na+]>CO>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:34][CH3:33])[N:6]2[CH2:16][C:17]1[CH:31]=[CH:30][C:20]([CH2:21][P:22](=[O:29])([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])=[CH:19][CH:18]=1
Reactant: CCOP(=O)(Cc1ccc(Cn2c(Br)nc3c(N)nc(OCCOC)nc32)cc1)OCC
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCOP(=O)(Cc1ccc(Cn2c(OC)nc3c(N)nc(OCCOC)nc32)cc1)OCC
Temperature: 70 °C
Reaction time: 18 h

Procedure:
To a solution of diethyl 4-((6-amino-8-bromo-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)benzylphosphonate in methanol (0.10 M) was added sodium methoxide (20 equiv.). The reaction mixture was then allowed to stir at 70° C. for 18 h. At this point the reaction mixture was allowed to cool to room temperature and then quenched by the addition of ammonium chloride. The mixture was then diluted with DCM, transferred to a separatory funnel and washed with DCM three times. The combined organic layers were then dried over anhydrous Na2SO4 and the volatiles were removed in vacuo. The resulting solid compound (38%) was carried onto the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[N:13]=[C:14]([NH:17][CH:18]([CH3:20])[CH3:19])[O:15][CH:16]=1)[CH:8]=[C:7]2[OH:21].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:37][O:38][C:39]([C:41]1([NH:46][C:47]([CH:49]2[CH2:53][CH:52](OS(C3C=CC(Br)=CC=3)(=O)=O)[CH2:51][N:50]2[C:65](=O)[CH:66]([NH:71][C:72]([O:74][C:75]([CH3:78])([CH3:77])[CH3:76])=[O:73])[C:67]([CH3:70])([CH3:69])[CH3:68])=[O:48])[CH2:43][CH:42]1[CH:44]=[CH2:45])=[O:40].C(=O)(O)[O-].[Na+]>CN1C(=O)CCC1.CCOC(C)=O.[Cl-].[Li+].CO>[CH3:37][O:38][C:39]([C:41]1([NH:46][C:47]([CH:49]2[CH2:53][CH:52]([O:21][C:7]3[C:6]4[C:11](=[C:2]([Cl:1])[C:3]([O:22][CH2:23][CH2:24][N:25]5[CH2:26][CH2:27][O:28][CH2:29][CH2:30]5)=[CH:4][CH:5]=4)[N:10]=[C:9]([C:12]4[N:13]=[C:14]([NH:17][CH:18]([CH3:19])[CH3:20])[O:15][CH:16]=4)[CH:8]=3)[CH2:51][N:50]2[CH2:65][CH:66]([NH:71][C:72]([O:74][C:75]([CH3:78])([CH3:77])[CH3:76])=[O:73])[C:67]([CH3:69])([CH3:70])[CH3:68])=[O:48])[CH2:43][CH:42]1[CH:44]=[CH2:45])=[O:40]
Reactant: C=CC1CC1(NC(=O)C1CC(OS(=O)(=O)c2ccc(Br)cc2)CN1C(=O)C(NC(=O)OC(C)(C)C)C(C)(C)C)C(=O)OC
Reactant: CC(C)Nc1nc(-c2cc(O)c3ccc(OCCN4CCOCC4)c(Cl)c3n2)co1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN1CCCC1=O
Solvent: CO
Solvent: CCOC(C)=O
Product: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3coc(NC(C)C)n3)nc3c(Cl)c(OCCN4CCOCC4)ccc23)CN1CC(NC(=O)OC(C)(C)C)C(C)(C)C)C(=O)OC
Temperature: 65 °C
Yield: 136.5 %

Procedure:
To a solution of 8-chloro-2-(2-isopropylaminooxazol-4-yl)-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-ol (341 mg, 0.63 mmol) and cesium carbonate (1.23 g, 3.78 mmol) in NMP was added 1-{[4-(4-bromobenzenesulfonyloxy)-1-(2-tert-butoxycarbonylamino-3,3-dimethylbutyryl)-pyrrolidine-2-carbonyl]-amino}-2-vinyl-cyclopropanecarboxylic acid methyl ester (432 mg, 0.63 mmol) and the reaction was heated to 65° C. After 2 h an additional 0.5 eq of 1-{[4-(4-bromo-benzenesulfonyloxy)-1-(2-tert-butoxycarbonylamino-3,3-dimethyl-butyryl)-pyrrolidine-2-carbonyl]-amino}-2-vinyl-cyclopropanecarboxylic acid methyl ester was added and stirred an additional hour. The reaction was diluted with EtOAc and 5% lithium chloride with stirring. The reaction was transferred to a separatory funnel and saturated sodium bicarbonate and MeOH (2 ml) was added. The layers were separated and the aqueous extracted again with EtOAc. The combined organic layers were then washed with 5% lithium chloride, dried over magnesium sulfated and concentrated to give 747 mg (99% yield) of 1-({1-(2-tert-butoxycarbonylamino-3,3-dimethylbutyl)-4-[8-chloro-2-(2-isopropylaminooxazol-4-yl)-7-(2-morpholin-4-yl-ethoxy)quinolin-4-yloxy]-pyrrolidine-2-carbonyl}-amino)-2-vinyl-cyclopropanecarboxylic acid methyl ester as a yellow oil. LCMS found 882.11 [M+H]+.
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:12][C:13]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[C:14]=1[C:15](O)=[O:16]>>[CH3:12][C:13]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[C:14]=1[C:15]([NH:11][C@@H:7]1[CH2:8][CH2:9][CH2:10][C@@H:6]1[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:16]
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Reactant: Cc1cc(C)c(C(=O)O)c(C)c1
Product: Cc1cc(C)c(C(=O)N[C@@H]2CCC[C@@H]2N2CCCC2)c(C)c1

Procedure:
The title compound, white solid, MS: m/e=301.2 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 2,4,6-trimethylbenzoic acid.
Reaction SMILES: O1CCCC1.[CH3:6][N:7]([CH3:29])[C:8]([C@@H:10]1[CH2:14][C@H:13]([SH:15])[CH2:12][N:11]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:17])=[O:9].C([N-]C1CCCCC1)(C)C.Br[Mg+].C(N(CC)C(C1C=CC=CC=1S([C:55]1[C@H:56]([CH3:83])[C@@H:57]2[C@@H:74]([C@H:75]([O:77][Si:78]([CH3:81])([CH3:80])[CH3:79])[CH3:76])[C:73](=[O:82])[N:58]2[C:59]=1[C:60]([O:62][CH2:63][C:64]1[CH:69]=[CH:68][C:67]([N+:70]([O-:72])=[O:71])=[CH:66][CH:65]=1)=[O:61])=O)=O)C>C(OCC)(=O)C>[CH3:6][N:7]([CH3:29])[C:8]([C@H:10]1[N:11]([C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=2)=[O:17])[CH2:12][C@@H:13]([S:15][C:55]2[C@H:56]([CH3:83])[C@@H:57]3[C@@H:74]([C@H:75]([O:77][Si:78]([CH3:81])([CH3:80])[CH3:79])[CH3:76])[C:73](=[O:82])[N:58]3[C:59]=2[C:60]([O:62][CH2:63][C:64]2[CH:65]=[CH:66][C:67]([N+:70]([O-:72])=[O:71])=[CH:68][CH:69]=2)=[O:61])[CH2:14]1)=[O:9]
Reactant: CN(C)C(=O)[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CCN(CC)C(=O)c1ccccc1S(=O)C1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O[Si](C)(C)C)[C@H]2[C@H]1C
Agent: CC(C)[N-]C1CCCCC1
Agent: [Mg+]Br
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@@H](O[Si](C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N(C)C)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 78.4 %

Procedure:
2 ml of a tetrahydrofuran solution containing 68 mg (0.19 mmol) of (2S,4S)-2-dimethylcarbamoyl-1-(4-nitrobenzyloxycarbonyl)-4-mercaptopyrrolidine were cooled in an ice bath, and then 0.19 ml (0.19 mmol) of a 1M tetrahydrofuran solution of bromomagnesium N-isopropyl-N-cyclohexylamide were added dropwise over a period of 2 minutes. The mixture was stirred for a further 10 minutes at this temperature, and then 1 ml of a tetrahydrofuran solution containing 100 mg of 4-nitrobenzyl (1R,5S,6S)-2-(2-diethylcarbamoylphenylsulfinyl)-1-methyl-6-[1(R)-trimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate (prepared as described in Example 38) was added. The mixture was stirred for a further 15 minutes at this temperature, after which ice water was added. The reaction solution was then diluted with ethyl acetate, washed with an aqueous solution of ammonium chloride then with a saturated aqueous solution of sodium chloride. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 10 g of silica gel, eluted with ethyl acetate, to give 94 mg (yield 78%) of the title compound as a foam-like solid.
Reaction SMILES: [F:1][C:2]1([C:6]2[C:7]([O:15][C@@H:16]([CH3:21])[C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12](O)=[O:13])=[N:10][CH:11]=2)[CH2:5][O:4][CH2:3]1.[NH2:22][C:23]1([CH2:29][C:30]([NH2:32])=[O:31])[CH2:26][S:25](=[O:28])(=[O:27])[CH2:24]1>>[NH2:32][C:30](=[O:31])[CH2:29][C:23]1([NH:22][C:12]([C:9]2[CH:8]=[C:7]([O:15][C@@H:16]([CH3:21])[C:17]([F:20])([F:18])[F:19])[C:6]([C:2]3([F:1])[CH2:3][O:4][CH2:5]3)=[CH:11][N:10]=2)=[O:13])[CH2:24][S:25](=[O:27])(=[O:28])[CH2:26]1
Reactant: NC(=O)CC1(N)CS(=O)(=O)C1
Reactant: C[C@H](Oc1cc(C(=O)O)ncc1C1(F)COC1)C(F)(F)F
Product: C[C@H](Oc1cc(C(=O)NC2(CC(N)=O)CS(=O)(=O)C2)ncc1C1(F)COC1)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-(3-fluorooxetan-3-yl)-4-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine-2-carboxylic acid (example 142b) and 2-(3-amino-1,1-dioxo-thietan-3-yl)acetamide (example 160d) as starting materials and isolated (9.3 mg, 12%); MS (ESI, m/z): 470.3 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]([NH:10][C:11](=O)[CH3:12])[CH3:9])[CH:3]=1.P(Cl)(Cl)(Cl)=O.C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:11]([CH3:12])=[N:10][C:8]([CH3:9])=[C:4]2[CH:3]=1
Reactant: CC(=O)NC(C)c1cc(Br)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc(C)n2ccc(Br)cc12

Procedure:
N-(1-(4-bromopyridin-2-yl)ethyl)acetamide (2.28 g, 9.38 mmol) was suspended in anhydrous benzene (20 mL), then phosphorus oxychloride (2.2 mL, 23.6 mmol) was added and the reaction heated to reflux for 3 hours. The crude reaction was then added portion-wise to 1M potassium carbonate solution (60 mL) and stirred until gas evolution ceased. The pH was then adjusted to pH 10 with potassium carbonate. The aqueous layer was extracted with DCM (50 mL×2), the organic were combined, dried over Na2SO4, and concentrated to afford the product, which was used without further purification. LCMS-ESI+: calc'd for C9H10BrN2: 225.1 (M+H+); Found: 225.05 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[N:15][N:14]([CH:17]([CH3:21])[C:18]([OH:20])=[O:19])[C:13]=2[CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[C:28]([O-])([O-])=O.[K+].[K+]>CO.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[N:15][N:14]([CH:17]([CH3:21])[C:18]([O:20][CH3:28])=[O:19])[C:13]=2[CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C(=O)O)n1nnc2ccc(OCc3ccccc3)cc21
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C(C)n1nnc2ccc(OCc3ccccc3)cc21

Procedure:
A mixture of 6-(benzyloxy)-α-methyl-1H-benzotriazole-1-acetic acid (36.6 g, 0.123 mole) and concentrated sulfuric acid (2.7 ml) in methanol is stirred at reflux temperature for 6 hours, cooled in an ice bath and treated with K2CO3 (25 g). The resulting mixture is stirred vigorously until a thick slurry results, diluted with methylene chloride and filtered. The filtrate is concentrated in vacuo to give a solid residue. Recrystallization of the residue from methanol affords the title product as a white solid, 27 g, mp 88°-91.5° C., identified by NMR and elemental analyses. Another 4.2 g (81.7% total yield) of the title product is obtained from the mother liquor.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C@@H:23]([CH3:35])[CH2:24][CH2:25][CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[C@@H:10]([CH3:22])[CH2:11][O:12]CC1C=CC(OC)=CC=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(Cl)Cl.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>O>[Si:1]([O:8][C@H:9]([C@@H:23]([CH3:35])[CH2:24][CH2:25][CH2:26][O:27][Si:28]([C:31]([CH3:32])([CH3:34])[CH3:33])([CH3:29])[CH3:30])[C@@H:10]([CH3:22])[CH2:11][OH:12])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: COc1ccc(COC[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)CCCO[Si](C)(C)C(C)(C)C)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: O
Product: C[C@@H](CO)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)CCCO[Si](C)(C)C(C)(C)C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
The PMB alcohol 62 (6.11 mmol) was added to CH2Cl2 (19 ML) then H2O (1 mL) and DDQ (1.80 g, 7.93 μmol) were added. After 1 h of stirring, the reaction was quenched by adding saturated aqueous NaHCO3 (100 mL). The organic phase was washed with saturated aqueous NaHCO3 (3×100 mL) and brine, dried over MgSO4 filtered and concentrated. Purification by flash column chromatography (EtOAc/hexane 1:9) furnished 63 (2.23 g, 90%) as a colorless oil: IR (CHCl3) 3403, 2928, 2856, 1472, 1463, 1388, 1256, 1100, 836, 773 cm−1; 1H NMR (300 MHz, CDCl3) ε3.59-3.50 (m, 4H), 3.46 (dd, J=5.5, 3.7 Hz, 1H), 1.83-1.75 (m, 1H), 1.62-1.52 (m, 2H), 1.49-1.35 (m, 2H), 1.18-1.05 (m, 1H), 0.91 (d, J=7.0 Hz, 3H), 0.87-0.84 (m, 21H), 0.05 (s, 3H), 0.03 (s, 3H), 0.00 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 80.4, 65.8, 63.3, 38.1, 37.8, 31.1, 29.6, 26.0, 25.9, 18.2, 15.9, 14.9, 4.0, −4.2, −5.4; LRMS (ESI) 427.3 [M+Na]+, 256.8, 212.1; HRMS (ESI) calcd for C21H48O3Si2Na 427.3040 [M+Na]+, found 427.3050; [α]20D−14.0 (c 0.6, CHCl3).