Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][C:4]([S:17]([N:20]2[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]2)(=[O:19])=[O:18])=[CH:5][C:6]=1[C:7]1[S:11][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[N:9][C:8]=1[CH3:16].C([Li])CCC>C1COCC1>[OH:26][CH:23]1[CH2:22][CH2:21][N:20]([S:17]([C:4]2[S:3][CH:2]=[C:6]([C:7]3[S:11][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[N:9][C:8]=3[CH3:16])[CH:5]=2)(=[O:19])=[O:18])[CH2:25][CH2:24]1
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)N3CCC(O)CC3)sc2Br)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(C)c(-c2csc(S(=O)(=O)N3CCC(O)CC3)c2)s1
Temperature: -70 °C
Yield: 32 %

Procedure:
To N-{5-[2-Bromo-5-(4-hydroxy-piperidine-1-sulfonyl)-thiophen-3-yl]-4-methyl-thiazol-2-yl}-acetamide obtained in Step I as described above (3500 mg; 6.27 mmol; 1 eq), is dissolved in anhydrous THF (150 ml). The reaction mixture is cooled down to −70° C. and put under nitrogen. n-Butyllithium (18.8 ml; 1.6 M; 37.6 mmol; 6 eq) is added dropwise. The reaction is stirred over weekend and is quenched with water. Solvents are evaporated and the resulting crude product is dissolved in EtOAc, washed with water (2 times), brine and dried over MgSO4. After evaporation of the solvents, the resulting product is suspended in ACN and filtered, affording Compound (39) as a beige solid (830 mg; 32%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[C:6]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:13][C:11]=3[N:12]=2)[CH:7]=1.[CH:29]1[C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]2[C:38]([O:40][C:41](=O)[C:31]=2[CH:30]=1)=[O:39]>>[CH2:24]([NH:23][C:5]1[CH:4]=[CH:3][C:2]([N:1]2[C:38](=[O:39])[C:32]3[C:31](=[CH:30][CH:29]=[C:34]([C:35]([OH:37])=[O:36])[CH:33]=3)[C:41]2=[O:40])=[CH:7][C:6]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][C:11]=2[N:12]=1)[CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCNc1ccc(N)cc1-c1nc2cc(-c3ccccc3)ccc2o1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: CCCCCNc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2cc(-c3ccccc3)ccc2o1

Procedure:
Prepared by the method of Example 1b), from 2-(5-amino-2-pentylaminophenyl)-5-phenylbenzoxazole (239 mg, 0.64 mmol) and 1,2,4-benzenetricarboxylic anhydride (123 mg, 0.64 mmol) the title compound was obtained (114 mg, 33%). 1H NMR (DMSO) δ 8.48(t, 1H), 8.43(dd, 1H), 8.30(s, 1H), 8.14(d, 1H), 8.07(m, 2H), 7.83(d, 1H), 7.74(m, 3H), 7.48(m, 3H), 7.39(t, 1H), 7.02(d, 1H), 3.50(m, 2H), 1.75(q, 2H), 1.43(m, 4H), 0.95(t, 3H). MS 546 m/z (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:6]2=[N:7][C:8](Cl)=[CH:9][CH:10]=[C:5]2[S:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C.CN(C=O)C>CCOCC>[NH2:1][C:2]1[C:6]2=[N:7][C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:9][CH:10]=[C:5]2[S:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1sc2ccc(Cl)nc2c1N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)c1sc2ccc(-c3ccccc3)nc2c1N
Temperature: 90 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
Methyl 3-amino-5chlorothieno[3,2-b]pyridine-2-carboxylate, prepared as described in Example 6A (0.243 g, 1.0 mmol), phenylboronic acid (0.134 g, 1.1 mmol) and triethylamine (0.20 mL) were added to 3 mL of DMF containing [1,1'-bis(diphenylphosphino)ferrocenelpalladium(II) chloride (1:1 complex with CH2Cl2) under N2. The mixture was stirred at 90° C. for 4 h. The reaction was then cooled and diluted with Et2O. The organic layer was washed with H2O, brine, dried (MgSO4), concentrated and chromatographed (2:1CH2Cl2 : hexane) to yield the title compound (140 mg, 50%): 1H NMR (300 MHz, CDCl3) δ 8.93 (s, 3H), 6.30 (bs, 2H), 7.41-7.55 (m, 3H), 7.84 (d, J=8 Hz, 1H), 8.07-8.13 (m, 3H); MS (DCI/NH3)) m/e 285 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]2[N:7]=[C:8]([C:10]3[CH:24]=[CH:23][C:13]([CH2:14]P(=O)(OCC)OCC)=[CH:12][CH:11]=3)[S:9][C:5]=2[CH:4]=1.C[O-].[Na+].[F:30][CH2:31][CH2:32][O:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=1>CO>[F:30][CH2:31][CH2:32][O:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=[CH:14][C:13]2[CH:12]=[CH:11][C:10]([C:8]3[S:9][C:5]4[CH:4]=[C:3]([O:2][CH3:1])[CH:26]=[CH:25][C:6]=4[N:7]=3)=[CH:24][CH:23]=2)=[CH:36][CH:35]=1
Reactant: CCOP(=O)(Cc1ccc(-c2nc3ccc(OC)cc3s2)cc1)OCC
Reactant: O=Cc1ccc(OCCF)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2nc(-c3ccc(C=Cc4ccc(OCCF)cc4)cc3)sc2c1
Yield: 77.4 %

Procedure:
Prepared as described in the Alkene Formation section using diethyl 4-(6-methoxybenzothiazol-2-yl)benzylphosphonate (0.06 g, 0.153 mmol), sodium methoxide (0.5 M solution in MeOH, 0.46 ml, 0.23 mmol) and 4-(2-fluoroethoxy)-benzaldehyde (0.028 g, 0.168 mmol) in dry MeOH (5 ml) to give the title compound (0.048 g, 77%) as a pale yellow solid after work-up.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:41]1[N:42]=[C:43]([NH2:46])[S:44][CH:45]=1)[C:5]([NH:7][CH:8]1[C:39](=[O:40])[N:10]2[C:11]([C:23]([O:25]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:24])=[C:12]([CH:15]=[CH:16][C:17]3[N:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH2:13][S:14][C@H:9]12)=[O:6].FC(F)(F)C(O)=O.C(OC(C)C)(C)C>C(Cl)Cl.C1(OC)C=CC=CC=1>[CH3:1][O:2][N:3]=[C:4]([C:41]1[N:42]=[C:43]([NH2:46])[S:44][CH:45]=1)[C:5]([NH:7][CH:8]1[C:39](=[O:40])[N:10]2[C:11]([C:23]([OH:25])=[O:24])=[C:12]([CH:15]=[CH:16][C:17]3[N:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=Cc3cccnn3)CS[C@H]12)c1csc(N)n1
Solvent: CC(C)OC(C)C
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C=Cc3cccnn3)CS[C@H]12)c1csc(N)n1
Yield: 76.3 %

Procedure:
To a solution of benzhydryl 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[2-(3-pyridazinyl)vinyl]-3-cephem-4-carboxylate (syn isomer) (trans isomer) (0.65 g) in methylene chloride (6.5 ml) and anisole (1.5 ml) was added trifluoroacetic acid (3.0 ml) under ice-cooling with stirring. The reaction mixture was stirred at ambient temperature for 30 minutes. The resultant solution was added dropwise to diisopropyl ether (100 ml), and the precipitate was collected by filtration, dissolved in an aqueous solution of sodium bicarbonate. The aqueous layer (100 ml) was washed with ethyl acetate (50 ml) twice, concentrated to 30 ml under reduced pressure and adjusted to pH 3.0 with 10% hydrochloric acid. The precipitate was collected by filtration, washed with water and dried over phosphorus pentoxide under reduced pressure to give 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[2-(3-pyridazinyl)vinyl]-3-cephem-4-carboxylic acid (syn isomer) (trans isomer) (0.37 g).
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11]2[N:16]=[C:15]([C:17]#[N:18])[C:14]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[N:13][C:12]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:5]1)([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=1.O>CC(N(C)C)=O>[CH3:28][O:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][N:19]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[C:14]2[C:15]([C:17]#[N:18])=[N:16][C:11]([C:6]3[CH:7]=[CH:8][C:9](=[O:10])[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=3)=[C:12]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:13]=2)=[CH:26][CH:25]=1
Reactant: COc1ccc(CNc2nc(-c3ccccc3)c(-c3ccc(=O)n(C(C)C)n3)nc2C#N)cc1
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(-c3ccccc3)c(-c3ccc(=O)n(C(C)C)n3)nc2C#N)cc1
Temperature: 22.5 °C

Procedure:
6-(1-Isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-3-[(4-methoxybenzyl)amino]-5-phenyl-2-pyrazinecarbonitrile (14.61 g) was added to a suspension of NaH (60% in oil suspension) (1.36 g) in DMA (36.5 ml) and the mixture was stirred at 20-25° C. for an hour. After addition of 1-(chloromethyl)-4-methoxybenzene (4.82 ml), the mixture was stirred at the same temperature for 20 hours. To the reaction mixture was added water (183 ml) and a precipitate was collected by filtration. The precipitate was purified by column chromatography on silica gel (EtOAc only) to give a solid. The solid was crystallized from a mixture of n-hexane and CHCl3 to give 3-[bis(4-methoxybenzyl)amino]-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-5-phenyl-2-pyrazinecarbonitrile (16.58 g).
Reaction SMILES: B([O-])([O-])O[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH3:15])=[CH:5][CH:4]=1.Br[C:19]1[CH:20]=[CH:21][C:22]2[N:28]([CH2:29][CH2:30][CH3:31])[CH2:27][CH2:26][C:25]([C:32]([NH:34][C:35]3[CH:40]=[CH:39][C:38]([CH2:41][N:42]([CH3:49])[CH:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)=[CH:37][CH:36]=3)=[O:33])=[CH:24][C:23]=2[CH:50]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.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>[CH3:49][N:42]([CH2:41][C:38]1[CH:37]=[CH:36][C:35]([NH:34][C:32]([C:25]2[CH2:26][CH2:27][N:28]([CH2:29][CH2:30][CH3:31])[C:22]3[CH:21]=[CH:20][C:19]([C:3]4[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH3:15])=[CH:5][CH:4]=4)=[CH:50][C:23]=3[CH:24]=2)=[O:33])=[CH:40][CH:39]=1)[CH:43]1[CH2:44][CH2:45][O:46][CH2:47][CH2:48]1
Reactant: CCCN1CCC(C(=O)Nc2ccc(CN(C)C3CCOCC3)cc2)=Cc2cc(Br)ccc21
Reactant: CCCOCCOc1ccc(OB([O-])[O-])cc1
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: CCOC(C)=O
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3CCC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.3 %

Procedure:
In a mixture of water:ethanol toluene (1:1:10, v/v, 18.0 ml) were dissolved 4-(2-propoxyethoxy)phenyl borate (260 mg) and 7-bromo-1-propyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (396 mg). To the solution was added potassium carbonate (256 mg), and the mixture was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (36 mg), and the mixture was heated to reflux under argon atmosphere for 10 hours. The mixture was diluted with ethyl acetate, and washed with water and saturated brine, and the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (25 g, ethyl acetate→ethyl acetate ethanol=10:1) and recrystallized from ethyl acetate-IPE to give N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-7-[4-(2-propoxyethoxy)phenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 26) (252 mg, 53%) as yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[CH:10]=[C:9]([NH:11][C:12](=[O:14])[CH3:13])[C:8]([CH3:15])=[CH:7][N:6]=1.C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].[N:33](OCCC(C)C)=O.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1.C(O)(=O)C>[F:1][C:2]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]2[CH:15]=[N:33][N:11]([C:12](=[O:14])[CH3:13])[C:9]=2[CH:10]=1
Reactant: CC(=O)Nc1cc(Oc2ccc(F)cc2F)ncc1C
Reactant: CC(C)CCON=O
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CC(=O)n1ncc2cnc(Oc3ccc(F)cc3F)cc21
Reaction time: 18 h
Yield: 11 %

Procedure:
A mixture of N-[2-(2,4-difluorophenoxy)-5-methylpyridin-4-yl]acetamide (2.3 g), acetic anhydride (2.6 g), acetic acid (2.7 mL) and potassium acetate (1.7 g) in 40 mL of benzene was brought to reflux. A solution of isoamyl nitrite (1.5 mL) in 10 mL of benzene was added to the refluxing solution over a period of two hours and refluxing was continued for an additional 18 hours. The reaction mixture was cooled and stirred with 50 mL of a 5% aqueous sodium carbonate solution for 3 hours. The organic layer was separated, dried, concentrated and purified via chromatography (silica gel, 8% ethyl acetate/hexane) to give 0.27 g of 1-[6-(2,4-difluorophenoxy)pyrazolo[4,3-c]pyridine-1-yl]ethanone (11% yield). Mass Spec. M+H=290.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=O.[NH2:13][C:14]1[CH:29]=[CH:28][CH:27]=[CH:26][C:15]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=1)=[O:17]>CCO>[Br:25][C:22]1[CH:23]=[CH:24][C:19]([N:18]2[C:16](=[O:17])[C:15]3[C:14](=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:13]=[C:5]2[C:4]2[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:2]([CH3:1])[CH:3]=2)=[CH:20][CH:21]=1
Reactant: Nc1ccccc1C(=O)Nc1ccc(Br)cc1
Reactant: Cc1cc(C=O)ccc1[N+](=O)[O-]
Solvent: CCO
Product: Cc1cc(-c2nc3ccccc3c(=O)n2-c2ccc(Br)cc2)ccc1[N+](=O)[O-]
Yield: 61.7 %

Procedure:
3-methyl-4-nitrobenzaldehyde (0.85 g, 5.20 mmol) and anhydrous CuCl2 (2.1 g, 15.5 mmol) were added to a solution of 2-amino-N-(4-bromophenyl)benzamide (1.5 g, 5.20 mmol) in anhydrous EtOH (60 mL). After heating at reflux temperature for 3.5 hours, the mixture was concentrated in vacuo. The residue was dissolved in EtOAc, washed with H2O, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 15% to 60% EtOAc in heptane, afforded 3-(4-bromophenyl)-2-(3-methyl-4-nitrophenyl)quinazolin-4(3H)-one (1.4 g, 62%).
Reaction SMILES: [BH4-].[Na+].Cl[CH:4]([CH3:27])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:26])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)=[CH:9][CH:8]=1)=[O:6].[OH-].[Na+]>CO>[CH3:25][O:24][C:18]1[CH:17]=[C:16]([CH2:15][C:14]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([CH:5]3[CH:4]([CH3:27])[O:6]3)=[CH:8][CH:9]=2)=[O:26])[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)C(C)Cl)cc2)cc1OC
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(CC(=O)Nc2ccc(C3OC3C)cc2)cc1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
Sodium tetrahydroborate (0.0502 mol) was added portionwise at 0° C. to a mixture of (±)—N-[4-(2-chloro-1-oxopropyl)phenyl]-3,4-dimethoxybenzeneacetamide (0.0502 mol) in methanol (280 ml). The mixture was stirred at 0° C. for 1 hour, then poured out into a mixture of NaOH (280 ml) and ice, stirred for 1 hour and extracted with CH2Cl2. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 15.48 g (94%) of (±)-3,4-dimethoxy-N-[4-(3-methyl-2-oxiranyl)phenyl]benzeneacetamide (interm. 11).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[O:18][NH2:19]>ClCCl>[OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:19][O:18][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][O:12]2)=[O:9])=[CH:10][CH:11]=1
Reactant: O=C(O)c1ccc(CO)cc1
Reactant: NOC1CCCCO1
Solvent: ClCCl
Product: O=C(NOC1CCCCO1)c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
A mixture of 4-(Hydroxymethyl)benzoic acid (0.75 g, 5 mmol), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.59 g, 5 mmol), and 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (1.15 g, 6 mmol) in dichloromethane (50 mL) was stirred at room temperature for 2 h (monitored by TLC). The mixture was extracted with water and dried over magnesium sulfate. The residue was purified by chromatography (MeOH:DCM=1:50) to give the title compound (0.88 g, 70%). NMR (400 MHz in DMSO, Bruker AVANCE-400): δ 1.52 (m, 3H, OTHP), 1.72 (m, 3H, OTHP), 3.51 (m, 1H, OTHP), 4.04 (m, 1H, OTHP), 4.53 (s, 2H, CH2), 4.98 (s, 1H, OTHP), 5.28 (s, 1H, NH), 7.38 (d, 2H, J=10.0 Hz, Ar—H), 7.72 (d, 2H, J=5.0 Hz, Ar—H), 11.55 (s, 1H, OH).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][C@@H:19]([C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[C:29]([O:34][CH3:35])[CH:30]=2)[CH:25]=1)[C:20]([O:22][CH3:23])=[O:21]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][C@@H:19]([C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[C:29]([O:34][CH3:35])[CH:30]=3)[CH:25]=2)[C:20]([O:22][CH3:23])=[O:21])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COC(=O)[C@@H](N)c1ccc2cc(OC)ccc2c1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: COC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)c1ccc2cc(OC)ccc2c1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl (S)-2-amino-2-(6-methoxy-2-naphthyl)acetate (from Example D3 above), the title compound was prepared as a solid (mp=177-178° C.). The product was purified by tituration using hexanes/EtOAc.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([CH:11]([CH2:15][CH3:16])[C:12](O)=[O:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CN(C=O)C>C(Cl)Cl>[C:5]1([CH:11]([CH2:15][CH3:16])[C:12]([Cl:3])=[O:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCC(C(=O)O)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCC(C(=O)Cl)c1ccccc1
Reaction time: 8 h
Yield: 67.9 %

Procedure:
Thionyl chloride (0.12 mol) in 60 mL of CH2Cl2 was added to a stirred solution of 2-phenylbutyric acid (16.4 g, 0.10 mol). A catalytic amount of DMF was added and the reaction was allowed to continue overnight at room temperature. The volatiles were removed under vacuum and the residual liquid was vacuum distilled to yield 12.4 g (68%) of 2-phenylbutyryl chloride. IR (neat) 1798 cm-1 (C=O).
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[C:7]([N+:14]([O-:16])=[O:15])=[CH:6][C:3]=1[CH:4]=O.[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](O)=[O:28])=[CH:22][CH:21]=1)([O-:19])=[O:18].C(N(CC)CC)C.P(Cl)(Cl)(OC1C=CC=CC=1)=O>ClCCCl.C(Cl)Cl>[CH3:13][O:12][C:8]1[C:9]([O:10][CH3:11])=[C:2]2[C:3]([CH:4]=[C:26]([C:23]3[CH:22]=[CH:21][C:20]([N+:17]([O-:19])=[O:18])=[CH:25][CH:24]=3)[C:27](=[O:28])[O:1]2)=[CH:6][C:7]=1[N+:14]([O-:16])=[O:15]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: COc1c([N+](=O)[O-])cc(C=O)c(O)c1OC
Agent: O=P(Cl)(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1c([N+](=O)[O-])cc2cc(-c3ccc([N+](=O)[O-])cc3)c(=O)oc2c1OC

Procedure:
A solution of 2-hydroxy-3,4-dimethoxy-5-nitro-benzaldehyde obtained from Preparation Example (1a) (0.46 g), 4-nitrophenyl acetic acid (0.39 g) and triethylamine (0.84 ml) in 1,2-dichloroethane (30 ml) was treated with phenyl dichlorophosphate (0.44 ml) at 0° C. The mixture was refluxed for 5 hours and cooled. The cool reaction mixture was diluted with methylene chloride, washed successively with 2.5 M NaOH, 2 M HCl and water, dried and evaporated. The product was finally triturated with pethroleum ether and filtered. Yield: 0.52 g, melting point 219-223° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].[CH2:14](Br)[C:15]#[CH:16]>CC(C)=O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:16][C:15]#[CH:14])[CH2:4][CH2:3]1
Reactant: C#CCBr
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCN1CCN(C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 1-methylpiperazine (37.7 ml, 337 mmol) and K2CO3 (46.6 g, 337 mmol) in acetone (380 ml) was added propargyl bromide (25 ml, 225 mmol, 80% in toluene) in acetone (70 ml) dropwise at 0° C. under N2. The internal temperature of the reaction was kept <10° C. The reaction was stirred at room temperature for 3 hours. The reaction was filtered, and the salts were washed with small portions of acetone (×2). The filtrates were combined evaporated to concentration (gently). To the residue was added water and the product was extracted with DCM (×3). The combined organic layers were washed with brine and dried over MgSO4. The product was filtered and evaporated to dryness to yield 1-methyl-4-prop-2-ynyl-piperazine as a yellow oil.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]([C:16](/[N:18]=[C:19](/[NH:28][CH2:29][C:30]3[CH:35]=[C:34]([Cl:36])[C:33]([NH:37][C:38](=[O:54])[CH2:39][N:40]([CH2:48][CH2:49][CH2:50][CH2:51]C=C)[C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[C:32]([Cl:55])[CH:31]=3)\[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:17])=[C:14]([CH3:56])[O:13][N:12]=2)=[CH:7][CH:6]=1)[CH:2]=[CH2:3]>ClCCCl.Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1>[C:24]([O:23][C:21]([NH:20][C:19]1[NH:28][CH2:29][C:30]2[CH:31]=[C:32]([Cl:55])[C:33](=[C:34]([Cl:36])[CH:35]=2)[NH:37][C:38](=[O:54])[CH2:39][N:40]([C:41]([O:42][C:43]([CH3:45])([CH3:46])[CH3:44])=[O:47])[CH2:48][CH2:49][CH2:50][CH2:51][CH:3]=[CH:2][CH2:1][O:4][C:5]2[CH:10]=[CH:9][C:8](=[CH:7][CH:6]=2)[C:11]2[C:15](=[C:14]([CH3:56])[O:13][N:12]=2)[C:16](=[O:17])[N:18]=1)=[O:22])([CH3:26])([CH3:25])[CH3:27]
Reactant: C=CCCCCN(CC(=O)Nc1c(Cl)cc(CN/C(=N/C(=O)c2c(-c3ccc(OCC=C)cc3)noc2C)NC(=O)OC(C)(C)C)cc1Cl)C(=O)OC(C)(C)C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Agent: Cc1onc2c1C(=O)N=C(NC(=O)OC(C)(C)C)NCc1cc(Cl)c(c(Cl)c1)NC(=O)CN(C(=O)OC(C)(C)C)CCCC/C=C/COc1ccc-2cc1
Solvent: ClCCCl
Product: Cc1onc2c1C(=O)N=C(NC(=O)OC(C)(C)C)NCc1cc(Cl)c(c(Cl)c1)NC(=O)CN(C(=O)OC(C)(C)C)CCCCC=CCOc1ccc-2cc1
Temperature: 45 °C
Reaction time: 2 h

Procedure:
The intermediate (85 mg, 0.104 mmol) from Step 7(B) was dissolved in 27 mL of 1,2-dichloroethane, followed by the addition of Grubbs Catalyst 2nd Generation (6 mg, 0.007 mmol) with 1 mL of 1,2-dichloroethane. The resulting reaction mixture was stirred at 45° C. for 2 hrs. Solvent was evaporated in vacuo to give a crude product, which was purified by flash chromatography (8% EtOAc/DCM) to give two compounds, 8 mg of cis-8C (Rf 0.37) and 45 mg of trans-8C (Rf 0.26).
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3].[CH2:8]([SH:10])[CH3:9].C(N(CC)CC)C>C(OCC)C>[C:2](=[O:3])([S:10][CH2:8][CH3:9])[O:4][CH:5]([Cl:7])[CH3:6]
Reactant: CCS
Reactant: CC(Cl)OC(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCSC(=O)OC(C)Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.9 %

Procedure:
A solution of 1-chloroethyl chloroformate (71.5 g, 0.5 mol) in diethyl ether (600 mL) was cooled to 0-4° C. in an ice-water bath and a solution of ethanethiol (37 mL, 0.5 mol) and triethylamine (69.3 mL, 0.5 mol) in diethyl ether (200 mL) was added dropwise over 1 h. The reaction mixture was removed from the ice bath and stirred at ambient temperature for 4 h. Triethylamine hydrochloride was removed by filtration, the filtrate concentrated under reduced pressure and the residue purified by vacuum distillation (67-68° C. at 240 mTorr) to afford the title compound (2) as a colorless liquid (75 g, 89%). 1H NMR (CDCl3, 400 MHz): δ 1.35 (t, 3H), 1.8 (d, 3H), 2.9 (dq, 2H), 6.6 (q, 1H).
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)=[CH:11][C:10]=1[Cl:28])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:28][C:10]1[CH:11]=[C:12]([N:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]2)[CH:13]=[CH:14][C:9]=1[NH2:8]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(Cl)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(N2CCNCC2)cc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of the product of EXAMPLE 42B (320 mg, 0.63 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (1 mL) dropwise and the mixture was stirred at ambient temperature for 4 hours. The solvent was removed and the crude title compound was used in the next step without further purification. MS: 212 (M+H+).