Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:12]1(OB([O-])[O-])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>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.O.C(O)C>[C:12]1([C:8]2[CH:9]=[C:10]3[C:5]([CH2:4][CH2:3][CH2:2][C:1]3=[O:11])=[CH:6][CH:7]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: [O-]B([O-])Oc1ccccc1
Reactant: O=C1CCCc2ccccc21
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1CCCc2ccc(-c3ccccc3)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
A mixture of 7- (trifluoromethanesulfoxy) -1-tetralone (23.3 g), phenylborate (11.8 g), potassiumcarbonate (21.9 g), toluene (500 ml), ethanol (50 ml) and water (50 ml) was stirred for 30 minutes at room temperature under argon atmosphere, and to the mixture was added tetrakis(triphenylphosphine)palladium (3.66 g). The mixture was refluxed for 20 hours and then cooled to room temperature. The organic layer was separated, washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate/toluene/hexane=1/5/5) to give 7-phenyl-1-tetralone (15.1 g) as pale brown oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[C:9]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[C:23](=[N:27][OH:28])[CH2:22][CH2:21]4)[CH:8]=2)[CH2:3][CH2:2]1.[CH3:29][O:30][CH2:31][CH:32]=O.C([BH3-])#N.C[NH+](C)C.C(O)(=O)C>CO>[CH3:29][O:30][CH2:31][CH2:32][N:1]1[CH2:2][CH2:3][CH:4]([C:7]2[O:11][C:10]([C:12]3[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=3)=[C:9]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[C:23](=[N:27][OH:28])[CH2:22][CH2:21]4)[CH:8]=2)[CH2:5][CH2:6]1
Reactant: ON=C1CCc2cc(-c3cc(C4CCNCC4)oc3-c3ccncc3)ccc21
Reactant: COCC=O
Agent: C[NH+](C)C
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CO
Product: COCCN1CCC(c2cc(-c3ccc4c(c3)CCC4=NO)c(-c3ccncc3)o2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.7 %

Procedure:
A mixture of the product of Example 31 (0.149 g, 0.4 mmol), methoxy-acetaldehyde (0.037 g, 0.5 mmol) (E. M. Acton et al, J. Med. Chem., 1986, 29, 2074) and polymer bound trimethylammonium cyanoborohydride (200 mg, 0.8 mmol, 4 mmol/g) in methanol (5 ml) containing acetic acid (0.2 ml) was stirred at room temperature for 24 hours. The reaction mixture was then filtered and the resin washed with methanol. The filtrate was concentrated in vacuo and the residue purified by silica gel chromatography eluting with a 1:9:90 mixture of 0.880 ammonia solution:ethanol:chloroform to give the title compound (0.103 g, 60%); MS(ES+) m/e 432 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1B1OC(C)(C)C(C)(C)O1)[S:4]([CH3:7])(=[O:6])=[O:5])[CH3:2].Br[C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:31]=[CH:32][C:33]([NH2:36])=[N:34][CH:35]=2)=[C:26]([F:37])[CH:25]=1>>[NH2:36][C:33]1[N:34]=[CH:35][C:30]([C:27]2[CH:28]=[CH:29][C:24]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[N:3]([CH2:1][CH3:2])[S:4]([CH3:7])(=[O:5])=[O:6])=[CH:25][C:26]=2[F:37])=[N:31][CH:32]=1
Reactant: CCN(c1ccccc1B1OC(C)(C)C(C)(C)O1)S(C)(=O)=O
Reactant: Nc1cnc(-c2ccc(Br)cc2F)cn1
Product: CCN(c1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1)S(C)(=O)=O

Procedure:
The title compound was prepared using methods analogous to those described in Step B of Example 369 by using N-ethyl-N-(2-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide and 5-(4-bromo-2-fluorophenyl)pyrazin-2-amine. MS (ESI): mass calcd. C19H19FN4O2S.C2HF3O2, 386.12; m/z found, 387.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.44 (d, J=1.2, 1H), 8.33 (d, J=1.2, 1H), 8.14-8.04 (m, 1H), 7.51-7.33 (m, 6H), 3.46 (s, 2H), 2.95 (s, 3H), 1.05 (t, J=7.2, 3H).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[CH2:29][CH2:28]1)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(S)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:25][CH2:26][N:27]1[CH2:28][CH2:29][S:30](=[O:34])(=[O:33])[CH2:31][CH2:32]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCCN(CCN1CCS(=O)(=O)CC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCCNCCN1CCS(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
N-(3-((tert-butyl(dimethyl)silyl)oxy)propyl)-N-(2-(1,1-dioxido-4-thiomorpholinyl)ethyl)-2-nitrobenzenesulfonamide (0.540 g, 1.01 mmol) and thiophenol (0.333 g, 3.02 mmol) were combined in dry acetonitrile (10 mL). Potassium carbonate (0.557 g, 4.03 mmol) was added and the mixture was stirred at rt for 18 h. The mixture was diluted with ethyl acetate and filtered to remove unwanted solids. The crude filtrate was concentrated in vacuo, redissolved in methanol, and loaded onto a strong cation exchange resin cartridge to capture the desired product. Undesired materials were eluted from the cartridge with methanol, and then the desired material was released from the resin by elution with 2M ammonia in methanol. Concentration in vacuo gave the title compound as a yellow oil (0.294 g, 83% yield). No further purification was performed and the mixture was carried forward to the next step. LCMS: m/z 351 (M+H+), 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.06 (s, 6H) 0.90 (s, 9H) 1.75 (quin, J=6.46 Hz, 2H) 2.69-2.72 (m, 2H) 2.72-2.80 (m, 4H) 3.00-3.11 (m, 8H) 3.70 (t, J=6.02 Hz, 2H).
Reaction SMILES: [CH2:1]([OH:12])[C@H:2]1[O:8][C:6](=[O:7])[C@H:5]([OH:9])[C@@H:4]([OH:10])[C@@H:3]1[OH:11].[NH2:13][CH2:14][CH2:15][CH2:16][Si:17]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20]>>[CH2:22]([O:21][Si:17]([O:24][CH2:25][CH3:26])([O:18][CH2:19][CH3:20])[CH2:16][CH2:15][CH2:14][NH:13][C:6]([C@@H:5]([C@H:4]([C@@H:3]([C@@H:2]([CH2:1][OH:12])[OH:8])[OH:11])[OH:10])[OH:9])=[O:7])[CH3:23]
Reactant: O=C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: CCO[Si](CCCN)(OCC)OCC
Product: CCO[Si](CCCNC(=O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO)(OCC)OCC

Procedure:
In this work, sol-gel precursors that are based on covalent linkage of D-gluconolactone or D-maltonolactone to aminopropyltriethoxysilane to form N-(3-triethoxysilylpropyl)gluconamide (GLTES-1) or N-(3-triethoxysilylpropyl)maltonamide. (MLTES-2) were prepared. Diglycerylsilane (DGS), GLTES, MLTES and allylgluconamide (allyGL) were prepared by methods described above. For DGS based sol-gel preparations, sols were prepared by sonicating DGS (400 mg, 1.34 mM) and water (1000 L) at 0iC for 45 min to hydrolyze the monomer. The resulting sol was mixed with equal portions of Tricine buffer (25 mM, pH 7.8) containing 5 mM MgSO4, 0.1 mg.mL−1 BSA, 0.5 mM DTT and 0.5 mM EDTA. The buffer also contained either 0.2 M allylGL or a range of concentrations of GLTES or MLTES, respectively, to obtain a sugar/DGS molar ratio of 0.05, 0.1, 0.15, 0.2 or 0.25. Immediately after vortexing the sol, a solution of Firefly luciferase from Photinus pyralis was added at a volume ratio of 30:1 sol:enzyme solution. The sol was very briefly and carefully mixed to obtain a homogeneous solution and was then loaded in portions of 62 L into a 96-well white microplate. The total quantity of protein per well was 200 ng (3 pM). TEOS-derived materials were prepared using a similar procedure, except that DGS was replaced by a TEOS-derived sol that was prepared by sonicating with a diluted hydrochloric acid, as described elsewhere.22 The concentration of the enzyme in all gels was the same. TEOS was also prepared by a procedure in which the hydrolyzed sol containing TEOS was combined with an equal volume of deionized water and rotoevaporated until the volume was reduced to half,70 with the aim of removing the ethanol liberated during the hydrolysis. The obtained sol was then mixed with the buffer solution and the enzyme as described above. Sodium silicate-based gels were prepared from 0.9 mL sodium silicate solution and 4 mL of water. This solution was agitated for 1 min with 2.0 g Dowex 50WX8-100 resin and vacuum filtered consecutively through a filter paper in a Buchner funnel and a 0.45 M membrane filter with the aid of a syringe.71 The resulting sol was then combined with the buffer and the enzymes in the same proportions as for previous sols. In all cases, the plates were covered with Parafilm™ and over each well a small orifice was opened with a syringe in order to allow slow drying of the gel. The gel was aged at 4iC for 5 days forming a glass disk that adhered to the bottom of the wells.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH3:15])[CH2:3][NH:4][C@H:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:6]([NH2:8])=[O:7].C(N(CC)CC)C.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>ClCCl.C(=O)(O)[O-].[Na+]>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([N:4]([CH:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([NH2:8])=[O:7])[CH2:3][C:2]([CH3:16])([CH3:15])[CH3:1])(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CC(C)(C)CN[C@@H](C(N)=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)CN(C(C(N)=O)c1ccccc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 50 °C
Yield: 3 %

Procedure:
(R)-2-(2,2-Dimethyl-propylamino)-2-phenyl-acetamide (700 mg, 3.2 mmol) was dissolved in dichloromethane (15 mL) and chilled in an ice bath. The solution was treated with triethylamine (553 uL, 4.0 mmol) followed by 4-chlorobenzenesulfonyl chloride (671 mg, 3.2 mmol). After heating at 50° C. for 18 h, the mixture was cooled, diluted with aqueous sodium bicarbonate and extracted with dichloromethane. The combined organic extracts were dried (Na2SO4) and concentrated to an oil. Purification on a silica gel flash column (40% EtOAc in hexanes, eluent) afforded the title compound in 3% yield. 13CNMR (100 MHz, CDCl3) 28.6, 33.2, 62.7, 70.0, 128.8, 129.0, 121.1, 129.2, 130.7, 133.6, 138.7, 139.0, 172.7. MS 395.1 m/z (M+1).
Reaction SMILES: FC1C=CC(C2NC(C(OC)=O)CC2)=CC=1.C(C1C=CC(S(Cl)(=O)=O)=CC=1)C.[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH:36]2[N:40]([S:41]([C:44]3[CH:49]=[CH:48][C:47]([CH2:50][CH3:51])=[CH:46][CH:45]=3)(=[O:43])=[O:42])[CH:39]([C:52](OC)=[O:53])[CH2:38][CH2:37]2)=[CH:32][CH:31]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH2:50]([C:47]1[CH:46]=[CH:45][C:44]([S:41]([N:40]2[CH:36]([C:33]3[CH:32]=[CH:31][C:30]([F:29])=[CH:35][CH:34]=3)[CH2:37][CH2:38][CH:39]2[CH2:52][OH:53])(=[O:43])=[O:42])=[CH:49][CH:48]=1)[CH3:51]
Reactant: CCc1ccc(S(=O)(=O)N2C(C(=O)OC)CCC2c2ccc(F)cc2)cc1
Agent: CCc1ccc(S(=O)(=O)Cl)cc1
Agent: COC(=O)C1CCC(c2ccc(F)cc2)N1
Agent: [Al+3]
Product: CCc1ccc(S(=O)(=O)N2C(CO)CCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, pale yellow oil, MS: m/e=363 (M+) was prepared in accordance with the general methods of example 1d and 84a from methyl (2RS,5SR)-5-(4-fluoro-phenyl)-pyrrolidine-2-carboxylate and 4-ethyl-benzenesulfonyl chloride and subsequent reduction of methyl (2RS,5SR)-5-(4-fluoro-phenyl)-1-(4-ethyl-benzenesulfonyl)-pyrrolidine-2-carboxylate with lithium aluminum hydride according to the general method of example 2.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][C:14](=[O:16])[CH3:15])[CH2:5][CH2:4][CH:3]=[CH:2]1.ClCCl.C([O:24]C)(C)(C)C>>[CH:2]12[O:24][CH:3]1[CH2:4][CH2:5][CH:1]2[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14](=[O:16])[CH3:15]
Reactant: CC(=O)Nc1ccccc1OC1C=CCC1
Reactant: COC(C)(C)C
Solvent: ClCCl
Product: CC(=O)Nc1ccccc1OC1CCC2OC12
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
To an ice bath cooled solution of N-[2-(2-cyclopenten-1-yloxy)phenyl]acetamide (149 mg, 686 μmol, 1.0 equiv.) in dichloromethane (4 ml) m-chloroperbenzoic acid (85 proc.; 146 μmol, 1.1 equiv.) was added. After stirring overnight with slowly warming up to an ambient temperature the reaction mixture was diluted by tertbutyl(methyl)ether, washed successively by a sat. sodium bisulfate solution, 5 proc. sodium hydroxide and brine and dried over sodium sulfate. Evaporation of the solvent and flash chromatography on silica gel (ethyl acetate/heptane, 2:3 continued to ethyl acetate) yielded 93 mg (58%) of the subtitle compound as a mixture of the trans, (minor) and the cis (major) diastereoisomeric epoxides as a pale yellow oil. The cis/trans ratio was determined as 2:1 by 1H-NMR.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[C:13]([C:29]([F:32])([F:31])[F:30])=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25]C(=O)[NH:23]2)[N:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C(O)C.[OH-].[Li+].O>>[NH2:23][C@@:22]([C:17]1[N:16]=[CH:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][C@H:8]3[CH2:7][CH2:6][C@H:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][CH2:9]3)[C:13]=2[C:29]([F:32])([F:30])[F:31])[N:18]=1)([CH3:28])[CH2:26][OH:25]
Reactant: CC(C)(C)C1CCC(Oc2ccc3nc([C@]4(C)COC(=O)N4)ncc3c2C(F)(F)F)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3nc([C@@](C)(N)CO)ncc3c2C(F)(F)F)CC1
Temperature: 80 °C

Procedure:
(R)-4-[6-(4-tert-Butyl-cyclohexyloxy)-5-trifluoromethyl-quinazolin-2-yl]-4-methyl-oxazolidin-2-one (180.0 mg, 0.0003987 mol) was dissolved in ethanol (7 mL, 0.1 mol), followed by 4 M lithium hydroxide in water (3 mL, 0.01 mol). The reaction mixture was then heated at 80° C. for 2 hours. All solvent was removed. The solid was extracted with DCM, and organic layers were dried over Na2SO4. Removal of solvent gave a pure product (152 mg, 90%). 1H NMR (MeOD) δ: 9.73 (s, 1H), 8.24 (d, J=9.3 Hz, 1H), 8.05 (d, J=9.5 Hz, 1H), 4.50-4.68 (m, 1H), 4.11 (d, J=11.0 Hz, 1H), 3.84 (d, J=11.0 Hz, 1H), 2.22 (d, J=10.8 Hz, 2H), 1.92 (d, J=13.1 Hz, 2H), 1.61 (s, 3H), 1.43-1.58 (m, 2H), 1.18-1.35 (m, 2H), 1.04-1.18 (m, 1H), 0.91 (s, 9H). MS (M+1): 426.30.
Reaction SMILES: CC(OC([NH:8][C@@H:9]([CH2:14][C:15]#[C:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])=[CH:19][N:18]=1)[C:10]([O:12][CH3:13])=[O:11])=O)(C)C.CO.C(Cl)(C)=O>C(OCC)(=O)C>[NH2:8][C@@H:9]([CH2:14][C:15]#[C:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])=[CH:19][N:18]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)[C@H](CC#Cc1ccc(OCc2ccccc2F)cn1)NC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(=O)Cl
Product: COC(=O)[C@@H](N)CC#Cc1ccc(OCc2ccccc2F)cn1
Reaction time: 4 h
Yield: 91.4 %

Procedure:
To a solution of methyl (2S)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-5-(5-{[(2-fluorophenyl)methyl]oxy}-2-pyridinyl)-4-pentynoate (D83, 0.439, 1.0 mmol), prepared by an analogous procedure to that described hereinabove, in ethyl acetate (4.5 ml) and methanol (0.5 ml) at 0° C. was added dropwise AcCl (0.5 ml, 7.0 mmol) and the mixture was stirred from 0° C. to r.t. for four hours. The solvent was removed under vacuum. The residue was diluted with a saturated solution of sodium bicarbonate and extracted with dichloromethane. The organic layer was dried, filtered and evaporated affording the title compound as yellow oil (0.30 g, 91%). Rt (HPLC): 3.60 min; MS: (ES/+) m/z: 329 [MH]+ C18H17FN2O3 requires 328; 1H NMR (400 MHz, CDCl3) δ (ppm): 8.30-8.36 (m1H); 7.45-7.51 (m, 1H); 7.31-7.40 (m, 2H); 7.16-7.24 (m, 2H); 7.07-7.16 (m, 1H); 5.19 (s, 2H); 3.75-3.81 (m, 1H); 3.79 (s, 3H); 2.80-2.99 (m, 2H).
Reaction SMILES: [CH2:1]([C:8]1([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18](=[O:31])[C@H:19]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)[NH2:20].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:16][O:17][C:18](=[O:31])[C@H:19]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)[NH:20][C:13]([C:8]1([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10][CH2:11][CH2:12]1)=[O:15]
Reactant: COC(=O)[C@@H](N)Cc1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)C1(Cc2ccccc2)CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)C1(Cc2ccccc2)CCCC1
Yield: 71.6 %

Procedure:
A solution of 1-benzylcyclopentane carboxylic acid (0.135 g, 0.66 mmol), 4-nitro-L-phenylalanine methyl ester (0.187 g, 0.72 mmol), and HBTU (0.272 g, 0.72 mmol) in 2 mL of DMF was treated with diisopropylethylamine (0.35 mL, 2 mmol). The mixture was stirred over night, concentrated, diluted with ethyl acetate, washed with water, 1 N HCl, water, saturated NaHCO3 and dried (MgSO4). The residue obtained after evaporation was purified by chromatography over 30 g of silica gel, eluting with 40% ethyl acetate:hexane to give 4-nitro-N-[[1-(phenylmethyl)cyclopentyl]carbonyl]-L-phenylalanine methyl ester (194 mg, 71%). as a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[CH:19]=[C:18]([CH2:20]Cl)[O:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH:30]([CH:32]1[CH2:36][CH2:35][CH2:34][NH:33]1)[OH:31]>>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[CH:19]=[C:18]([CH2:20][N:33]4[CH2:34][CH2:35][CH2:36][C@@H:32]4[C@H:30]([C:26]4[O:25][CH:29]=[CH:28][CH:27]=4)[OH:31])[O:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: OC(c1ccco1)C1CCCN1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)oc21
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCC[C@@H]3[C@@H](O)c3ccco3)oc21

Procedure:
Analogous to the procedures described in Example 59, N-(4-chlorobenzyl)-2-(chloromethyl)-7-methyl-4-oxo-4,7-dihydrofuro[2,3-b]pyridine-5-carboxamide (Example 2) is treated with 2-furyl(pyrrolidin-2-yl)methanol (Preparation 73) to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH:8]2[OH:13])=[CH:4][CH:3]=1.[CH3:16][O:17][C@@:18]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:22]([F:25])([F:24])[F:23])[C:19](Cl)=[O:20]>>[CH2:1]([N:10]1[CH2:11][CH2:12][C@H:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:15][CH:14]=2)[C@H:8]([O:13][C:19](=[O:20])[C@:18]([O:17][CH3:16])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:22]([F:25])([F:24])[F:23])[CH2:9]1)[C:2]1[CH:15]=[CH:14][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(CC2CCNCC2O)cc1
Reactant: CO[C@@](C(=O)Cl)(c1ccccc1)C(F)(F)F
Product: CO[C@@](C(=O)O[C@@H]1CN(Cc2ccccc2)CC[C@@H]1Cc1ccc(C)cc1)(c1ccccc1)C(F)(F)F
Yield: 33 %

Procedure:
The title compound was prepared from (3SR,4SR)-4-(4-methyl-benzyl)-piperidin-3-ol and (S)-(+)-alpha-methoxy-alpha-trifluoromethylphenylacetyl chloride in 33% yield as a yellow oil.
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[CH:7]([NH:10][NH2:11])([CH3:9])[CH3:8].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[CH:12](=[N:11][NH:10][CH:7]([CH3:9])[CH3:8])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)NN
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)NN=Cc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a round-bottom flask containing anhydrous sodium acetate (8.2 g, 0.1 mol) in 125 ml 50% ethanol was added isopropylhydrazine HCl salt (11.1 g, 0.1 mole) and benzaldehyde (10.6 g, 0.1 mole). The mixture was stirred at rt for 20 h. The reaction was extracted with ether (3×250 ml). The organic layers were combined and washed with aqueous sodium bicarbonate solution and brine and dried over sodium sulfate. Filtration, concentration, and co-evaporation with toluene (3×) provided the title compound as an oil. MS m/z 163.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH3:12])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].C([O-])(O)=[O:14].[Na+]>CC(O)=O.OO>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:9]=[C:10]([CH3:12])[N+:11]=1[O-:14]
Reactant: O=C([O-])O
Reactant: COC(=O)c1cc(C)nc(Cl)c1
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1cc(C)[n+]([O-])c(Cl)c1
Reaction time: 3 h
Yield: 63 %

Procedure:
A solution of 6.05 g (32.6 mmol) of methyl 2-chloro-6-methylisonicotinate (Aldrich) in 30 mL of AcOH and 30 mL of H2O2 (30 wt. % in H2O) was stirred at 135° C. for 45 min. and 9 mL of H2O2 (30 wt. % in water) was added. Heating was continued for 3 h, and saturated NaHCO3 solution was added to pH=8. The aqueous layer was extracted with EtOAc (4×), and the combined extracts were washed with 100 mL of brine, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (80% EtOAc/hexanes) provided 4.1 g of the 2-chloro-4-(methoxycarbonyl)-6-methylpyridine 1-oxide as an off-white solid in 63% yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[C:6]([CH:13]([O:16][CH3:17])[O:14][CH3:15])[CH:5]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([CH:13]([O:14][CH3:15])[O:16][CH3:17])[CH:5]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(C(OC)OC)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(N)c(C(OC)OC)c1
Reaction time: 0.25 h

Procedure:
100 mg 10% Pd/C and 1 g Mg2SO4 were suspended in 20 mL methanol and were hydrogenated in a Parr apparatus at 30 psi for 15 minutes. The apparatus was opened, and 1.22 g (4.78 mmol) of Compound 5 dissolved in 40 mL methanol was added, followed by 2 mL TEA. The mixture was hydrogenated at 30 psi for 30 minutes, the catalyst was removed by means of filtration and the solution was evaporated to dryness. The solid material was dried over P2O5/H3PO4 overnight to give Compound 6.
Reaction SMILES: C1C(=O)N(Br)C(=[O:4])C1.[CH2:9]([O:11][C:12]([C:14]1([CH2:20][CH:21]2[CH2:23][CH2:22]2)SCCCS1)=[O:13])[CH3:10].CCCCCC.C(Cl)Cl>C(#N)C.O>[CH2:9]([O:11][C:12](=[O:13])[C:14](=[O:4])[CH2:20][CH:21]1[CH2:23][CH2:22]1)[CH3:10]
Reactant: CCOC(=O)C1(CC2CC2)SCCCS1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CC#N
Solvent: CCCCCC
Product: CCOC(=O)C(=O)CC1CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 61.2 %

Procedure:
To a 0° C. suspension of NBS (439 mmol, 79 g) in a mixture of acetonitrile (400 mL) and water (100 mL) is added a solution of 2-cyclopropylmethyl-[1,3]dithiane-2-carboxylic acid ethyl ester (73.2 mmol, 18.05 g) in acetonitrile (50 mL) over 15 minutes. The reaction is warmed and stirred at room temperature. After 45 minutes, 500 mL of 1:1 hexane/DCM is added. The layers are separated. The organic layer is washed with saturated Na2SO3 (2×225 mL) and brine (2×225 mL), dried with Na2SO4, filtered, and concentrated under reduced pressure to a residue. The residue is diluted in CCl4 and filtered. The filtrate is concentrated to give the title compound (7 g, 61%). LC-ES/MS: 157.0 (M+1).