Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([N:5]1[CH2:23][CH2:22][C:9]2[C:10]3[C:11]([C:17]4[S:18][CH:19]=[CH:20][N:21]=4)=[CH:12][CH2:13][C:14]=3[CH:15]=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].[H][H]>C(O)C.[Pd]>[F:25][C:2]([F:1])([F:24])[C:3]([N:5]1[CH2:23][CH2:22][C:9]2[C:10]3[CH:11]([C:17]4[S:18][CH:19]=[CH:20][N:21]=4)[CH2:12][CH2:13][C:14]=3[CH:15]=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C(N1CCc2ccc3c(c2CC1)C(c1nccs1)=CC3)C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C(N1CCc2ccc3c(c2CC1)C(c1nccs1)CC3)C(F)(F)F
Temperature: 25 °C
Yield: 76.8 %

Procedure:
The product from step (c) (22 mg) was dissolved in ethanol (30 ml) placed in a Parr Hydrogenation bottle. To this solution was added 10% Pd—C (100 mg). The mixture was shaken at 50° C. over 50 psi of hydrogen for 16 hours. The reaction mixture was purged with Nitrogen, cooled to RT, and filtered thru a pad of celite. The solvent was evaporated in vacuo to give the crude product as a light yellow oil. Purification by flash silica-gel chromatography (gradient elution: 0-50% EtOAc in hexanes) gave the sub-title compound (17 mg) as a white film. MS: ESI (positive): 367 (M+H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[O:13][CH2:14][C:15]#[C:16][CH:17]([OH:27])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1.C(OCC)(=O)C>CCOCC>[O:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[O:13][CH2:14]/[CH:15]=[CH:16]/[CH:17]([OH:27])[CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1
Reactant: OC(C#CCOC1CCCCO1)COc1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: OC(/C=C/COC1CCCCO1)COc1ccc(F)cc1
Reaction time: 1.5 h

Procedure:
Lithium aluminum hydride (7.6 g., 0.2 mole) is dissolved in ether (225 ml.) and 1-(2-tetrahydropyranyloxy)- 4-hydroxy-5-(4-fluorophenoxy)-2-pentyne (35.2 g., 0.12 mole) is added dropwise with stirring during 1.5 hour. The resulting mixture is stirred at 25° for 21 hours and then heated at reflux for 4 hours. The mixture is cooled and treated dropwise with ethyl acetate to consume excess lithium aluminum hydride. It is then poured into 600 ml. of ice-cold 20% aqueous potassium hydroxide solution. The oily product is taken up in ether, washed with water and brine, and dried over magnesium sulfate. Removal of solvent under vacuum leaves the title compound as a yellow residual oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16]([OH:20])([C:18]#[CH:19])[CH3:17]>C(#N)C.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:6]([C:7]1[CH:12]=[CH:11][C:10]([C:19]#[C:18][C:16]([CH3:17])([OH:20])[CH3:15])=[CH:9][CH:8]=1)([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:14]
Reactant: C#CC(C)(C)O
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(O)C#Cc1ccc(C(=O)OC(C)(C)C)cc1
Yield: 71.1 %

Procedure:
257.1 g of 4-Bromobenzoic acid tert.-butyl ester, 168 g of 2-methyl-3-butyn-2-ol and 15.6 g of (Ph3P)2PdCl2 in 1.5 l of absolute acetonitrile and 480 ml of triethylamine are stirred together at reflux for 6 hours under nitrogen. The product is then concentrated by evaporation and worked up with toluene/H2O to yield 185 g of an oil which slowly crystallises.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9](I)[CH:8]=[C:7]([I:12])[C:6]=1[O:13][CH3:14])([CH3:4])([CH3:3])[CH3:2].[NH:15]1[CH2:19][CH2:18][CH2:17][C:16]1=[O:20].P([O-])([O-])([O-])=O.[K+].[K+].[K+].N[C@@H]1CCCC[C@H]1N>O1CCOCC1.[Cu]I>[C:1]([C:5]1[CH:10]=[C:9]([N:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])[CH:8]=[C:7]([I:12])[C:6]=1[O:13][CH3:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCCN1
Reactant: COc1c(I)cc(I)cc1C(C)(C)C
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: COc1c(I)cc(N2CCCC2=O)cc1C(C)(C)C
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
In a 5 mL microwave tube under N2 flush were added 1-tert-butyl-3,5-diiodo-2-methoxybenzene (208 mg, 0.5 mmol), 2-pyrrolidone (0.092 mL, 1.200 mmol), potassium phosphate (223 mg, 1.050 mmol), (+/−)-trans-1,2-diaminocyclohexane (0.012 mL, 0.100 mmol) and copper(I) iodide (2.381 mg, 0.013 mmol) in dioxane (2 mL). The tube was sealed, sparged with N2 for 10 minutes, heated by microwave irradiation at 110° C. for 1 hour, cooled and partitioned between ethyl acetate and water adjusting the pH to 1 with HCl. The aqueous layer was extracted with ethyl acetate. The organics were combined, washed with H2O, and brine. The organic was dried (Na2SO4), filtered, and stirred for 0.5 hours with 3-mercaptopropyl functionalized silica, filtered and concentrated. The crude product was purified on an Isco 12 g silica cartridge eluting with 4:1 hexane/ethyl acetate to give the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([OH:3])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[F:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C1COCC1.CN(C=O)C>[F:26][CH:27]1[CH2:32][CH2:31][N:30]([C:1]([C:4]2[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=2)=[O:3])[CH2:29][CH2:28]1
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: FC1CCNCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccc(C(=O)N2CCC(F)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.7 %

Procedure:
To a solution of 4-carboxybenzenesulfonamide (2 g; 9.9 mmol; 1 eq) in THF 30 mL) at 0° C. is added 1,1′-carbonyldiimidazole (1.9 g; 11.9 mmol; 1.2 eq) in one portion and the mixture is stirred for 3 h at room temperature. 4-Fluoropiperidine (3.1 g; 29.8 mmol; 3 eq) in THF (3 mL) and DMF (10 mL) is added dropwise and the mixture is stirred at room temperature for 2 h. The solvent is removed under reduced pressure and a saturated solution of NaHCO3 is added to the colourless oil which precipitates. The solid is filtered off, washed with water and dried under vacuum to afford 2.6 g (91%) of the title compound as a white solid. 1H NMR (DMSO-d6) δ 7.87 (d, J=8.3, 2H), 7.58 (d, J=8.3, 2H), 7.37 (br s, 2H), 4.92 (d, J=48.2, 1H), 3.67 (br s, 2H), 3.25 (br s, 2H), 1.87 (m, HPLC (max plot) 99%; Rt 1.77 min. LC/MS: (ES+) 287.0; (ES−) 285.0
Reaction SMILES: [I-].[CH3:2][N+:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9](=[O:30])[NH:10][CH2:11][CH2:12][O:13][C:14](=[O:29])[CH:15]([CH3:28])[C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:26][CH3:27])=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)[CH:4]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+]>>[CH3:2][N:3]1[CH:8]=[CH:7][CH2:6][C:5]([C:9](=[O:30])[NH:10][CH2:11][CH2:12][O:13][C:14](=[O:29])[CH:15]([CH3:28])[C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:26][CH3:27])=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)=[CH:4]1
Reactant: COc1ccc2c(C(C)C(=O)OCCNC(=O)c3ccc[n+](C)c3)cccc2c1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [I-]
Product: COc1ccc2c(C(C)C(=O)OCCNC(=O)C3=CN(C)C=CC3)cccc2c1
Reaction time: 1 h
Yield: 66 %

Procedure:
The quaternary salt prepared in Example 94 (780 mg, 1.5 mmol) was dissolved in degassed, deionized water (200 mL) and acetonitrile (10 mL). Sodium dithionite (780 mg, 4.5 mmol) and sodium bicarbonate (630 mg, 7.5 mmol) were combined and added to the solution at room temperature. The reaction was continued for 1 hour, while nitrogen gas was slowly bubbled through the solution. The partially precipitated product was extracted repeatedly with ether (8×30 mL). The extracts were combined, washed with water (25 mL) and dried over magnesium sulfate. The drying agent was filtered and the solvent was removed from the filtrate under reduced pressure. The oily residue was dissolved in methylene chloride (3×5 mL) and removed under reduced pressure. The resulting foam was rinsed with anhydrous ether (3 mL) and the solvent was removed under vacuum. The final product weighed 390 mg, giving a 66% yield. The hygroscopic solid foam was stored under nitrogen at -100° C. It had the structural formula: ##STR126## as confirmed by UV, NMR and elemental analyses.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]1[C:8]([2H])([2H])[C:7]([2H])([2H])[NH:6][C:5]1=[O:13].[CH2:14](OCCNCC1(N)CCCC1)[C:15]1C=CC=[CH:17][CH:16]=1>>[Cl:1][CH2:2][CH2:3][N:4]1[CH2:8][C:7]2([CH2:17][CH2:16][CH2:15][CH2:14]2)[NH:6][C:5]1=[O:13]
Reactant: NC1(CNCCOCc2ccccc2)CCCC1
Reactant: [2H]C1([2H])NC(=O)N(CCCl)C1([2H])[2H]
Product: O=C1NC2(CCCC2)CN1CCCl

Procedure:
This compound was prepared by a procedure analogous to the procedure described for the synthesis of 4c using 12b as starting material.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:7]=1[CH2:20]O.CS(Cl)(=O)=O.[CH2:36]([N:38](CC)CC)C>ClCCl>[C:26]([O:25][C:23](=[O:24])[NH:22][CH:4]1[C:3](=[O:2])[N:38]([CH3:36])[CH2:20][C:7]2[CH:8]=[C:9]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:10]=[CH:11][C:6]=2[CH2:5]1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CCN(CC)CC
Reactant: COC(=O)C(Cc1ccc(OCc2ccccc2)cc1CO)NC(=O)OC(C)(C)C
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CN1Cc2cc(OCc3ccccc3)ccc2CC(NC(=O)OC(C)(C)C)C1=O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(2-acetoxymethyl-4-benzyloxy-phenyl)-2-tert-butoxycarbonylamino-propionic acid methyl ester (1.85 g, 4.0 mmol) in methanol (40 mL) was added potassium carbonate (560 mg, 4.0 mmol) at room temperature and stirred for 1 h. The reaction mixture was diluted with dichloromethane (150 mL), washed with 1.0 M aqueous hydrogen chloride and dried (Na2SO4) to give the pure 3-(4-benzyloxy-2-hydroxymethyl-phenyl)-2-tert-butoxycarbonylamino-propionic acid methyl ester in almost quantitative yield. To the alcohol (800 mg, 1.93 mmol) in dichloromethane (50 mL) was added methanesulfonyl chloride (0.18 mL, 2.3 mmol) followed by triethylamine (0.38 mL, 2.70 mmol) at 0° C. and then brought to room temperature. After 1 h, the reaction mixture was washed with aqueous sodium hydrogencarbonate, dried (Na2SO4). The solvent was removed, dissolved the crude product in anhydrous THF (20 mL) followed by addition of 2.0 M solution of methylamine in THF (10 mL) in a sealed tube. The sealed tube was heated at 80° C. for a period of 12 h and then removed the solvent. The crude product was purified by flash chromatography using 30% ethyl acetate in hexane to give (8-benzyloxy-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-yl)-carbamic acid tert-butyl ester in 39% overall yield. 1H NMR (500 MHz, CDCl3): in δ 7.40-7.31 (m, 5H), 7.01-7.00 (m, 1H), 6.83-6.82 (m, 1H), 6.66 (s, 1H), 5.91-5.90 (m, 1H), 5.13-5.01 (m, 4H), 3.50-3.46 (m, 1H), 3.03 (s, 3H), 2.85-2.78 (m, 1H), 1.45 (s, 9H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[C:13]([N:17]=[C:18]=[S:19])([CH3:16])([CH3:15])[CH3:14]>CCOCC>[C:13]([NH:17][C:18]([N:10]1[CH2:9][CH2:8][N:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)[CH2:12][CH2:11]1)=[S:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)N=C=S
Reactant: c1cnc(N2CCNCC2)cn1
Solvent: CCOCC
Product: CC(C)(C)NC(=S)N1CCN(c2cnccn2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of 4.92 g. of 1-(2-pyrazinyl)piperazine in 50 ml. of anhydrous ether is added a solution of 3.45 g. of tert-butyl isothiocyanate in 50 ml. of anhydrous ether. The mixture is stirred for 30minutes and the resulting solid is collected and recrystallized from 50 ml.of ethanol, giving 5.85 g. of the desired product as white crystals, m.p. 153°-156° C.
Reaction SMILES: F[C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[C:22]1[S:26][CH:25]=[N:24][CH:23]=1.[NH:27]1[CH2:31][C@H:30]([OH:32])[C@@H:29]([OH:33])[CH2:28]1>CS(C)=O>[OH:33][C@@H:29]1[C@@H:30]([OH:32])[CH2:31][N:27]([C:2]2[CH:21]=[CH:20][C:5]([C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=3)=[O:7])=[CH:4][C:3]=2[C:22]2[S:26][CH:25]=[N:24][CH:23]=2)[CH2:28]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(F)c(-c2cncs2)c1
Reactant: O[C@H]1CNC[C@@H]1O
Solvent: CS(C)=O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2C[C@H](O)[C@@H](O)C2)c(-c2cncs2)c1

Procedure:
A solution of 4-fluoro-3-(thiazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 1.1, 60 mg, 0.13 mmol), (3S,4S)-pyrrolidine-3,4-diol (28.2 mg. 0.273 mmol) and TEA (76 μL, 0.546 mmol) in DMSO (103 μL) was stirred at 105° C. for 90 h. The solvent was evaporated off under reduced pressure and the crude product was purified by preparative SFC (Column Diol, from 22% to 27% in 10 min) to afford the title compound as a yellow powder. UPLC-MS (Condition 1) tR=2.18 min, m/z=466.0 [M+H]+, m/z=464.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.86 (d, J=10.51 Hz, 2H) 3.36 (dd, J=10.51, 3.67 Hz, 2H) 3.90 (br. s, 2H) 5.05 (br. s, 2H) 6.93 (d, J=8.80 Hz, 1H) 7.33 (d, J=8.56 Hz, 2H) 7.78-7.98 (m, 5H) 9.16 (s, 1H) 10.12 (s, 1H).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[CH:7]=1)=[O:5].[CH2:26]([C:28]1[CH:33]=[CH:32][C:31](I)=[CH:30][N:29]=1)[CH3:27].C([Mg]Cl)(C)C>C1COCC1>[Cl:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:15](=[O:16])[C:6]([C:4]([C:31]2[CH:30]=[N:29][C:28]([CH2:26][CH3:27])=[CH:33][CH:32]=2)=[O:5])=[CH:7]1
Reactant: CCc1ccc(I)cn1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Cl)c2)c2ccccc2c1=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCc1ccc(C(=O)c2cn(Cc3cccc(Cl)c3)c3ccccc3c2=O)cn1

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60, from 300 mg (0.84 mmol) of 1-(3-chloro-benzyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 2 mL THF and 433 mg (1.86 mmol) of 2-ethyl-5-iodo-pyridine in 2 mL THF with 0.97 mL 2M isopropylmagnesium chloride. Yield: 127 mg of a white powder. LC-MSD, m/z for C24H19ClN2O2 [M+H]+=403.1, 405.1; HPLC retention time: 1.8 min.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33]/[CH:34]=[C:35](\[C:39]2[CH:44]=[CH:43][C:42]([S:45]([CH3:48])(=[O:47])=[O:46])=[CH:41][CH:40]=2)/[C:36]([OH:38])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[CH2:49]([O:51][C:52]([C:54]1[S:58][C:57]([NH2:59])=[N:56][CH:55]=1)=[O:53])[CH3:50]>C(Cl)Cl>[CH2:49]([O:51][C:52]([C:54]1[S:58][C:57]([NH:59][C:36](=[O:38])/[C:35](/[C:39]2[CH:44]=[CH:43][C:42]([S:45]([CH3:48])(=[O:47])=[O:46])=[CH:41][CH:40]=2)=[CH:34]/[CH2:33][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32]2)=[N:56][CH:55]=1)=[O:53])[CH3:50]
Reactant: CCOC(=O)c1cnc(N)s1
Reactant: CS(=O)(=O)c1ccc(/C(=C\CC2CCCC2)C(=O)O)cc1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)c1cnc(NC(=O)/C(=C/CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
A solution of triphenylphosphine (787 mg, 3 mmol) in methylene chloride (40 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (534 mg, 3 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with (E)-4-cyclopentyl-2-(4-methanesulfonyl-phenyl)-but-2-enoic acid (prepared in Example 21, 462 mg, 1.5 mmol). The clear solution was stirred for 10 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 1 h. The reaction mixture was then treated with 2-aminothiazole-5-carboxylic acid ethyl ester (774 mg, 4.5 mmol), and the resulting suspension was stirred at 25° C. over the weekend. The reaction mixture was concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (70 mL) and a 1N aqueous hydrochloric acid solution (70 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×50 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 3/1 to 1/1 hexanes/ethyl acetate) afforded (E)-2-[4-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-but-2-enoylamino]-thiazole-5-carboxylic acid ethyl ester (250 mg, 36%) as an amorphous white solid: ET-HRMS m/e calcd for C22H26N2O5S2 (M+) 462.1283, found 462.1282.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:21][C:22]([C:24]2[N:25]([CH3:48])[C:26]3[C:31]([CH:32]=2)=[CH:30][CH:29]=[CH:28][C:27]=3[CH2:33][N:34]2[CH2:39][CH2:38][N:37]([C:40]([CH:42]3[CH2:46][CH2:45][CH2:44][N:43]3[CH3:47])=[O:41])[CH2:36][CH2:35]2)=[O:23])[C:8]([O:19][CH3:20])=[C:9]([NH:11]C(=O)OC(C)(C)C)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[ClH:49]>ClCCl.C(O)(C)C>[ClH:49].[ClH:49].[ClH:49].[NH2:11][C:9]1[C:8]([O:19][CH3:20])=[C:7]([NH:21][C:22]([C:24]2[N:25]([CH3:48])[C:26]3[C:31]([CH:32]=2)=[CH:30][CH:29]=[CH:28][C:27]=3[CH2:33][N:34]2[CH2:35][CH2:36][N:37]([C:40]([C@@H:42]3[CH2:46][CH2:45][CH2:44][N:43]3[CH3:47])=[O:41])[CH2:38][CH2:39]2)=[O:23])[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:10]=1
Reactant: COc1c(NC(=O)OC(C)(C)C)cc(C(C)(C)C)cc1NC(=O)c1cc2cccc(CN3CCN(C(=O)C4CCCN4C)CC3)c2n1C
Agent: Cl
Solvent: CC(C)O
Solvent: ClCCl
Product: COc1c(N)cc(C(C)(C)C)cc1NC(=O)c1cc2cccc(CN3CCN(C(=O)[C@@H]4CCCN4C)CC3)c2n1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.59 g tert-butyl [5-tert-butyl-2-methoxy-3-({1-methyl-7-[4-(1-methyl-pyrrolidine-2-carbonyl)-piperazin-1-ylmethyl]-1H-indole-2-carbonyl}-amino)-phenyl]-carbamate are dissolved in 15 ml dichloromethane, combined with 10 ml of a 5 M solution of hydrogen chloride in isopropanol and stirred for 3 hours at ambient temperature. Then the solvents are eliminated in vacuo. The product thus obtained is further reacted directly.
Reaction SMILES: [CH2:1]([C@@H:8](/[CH:24]=[CH:25]/[CH2:26][C:27]([N:29]1[C@@H:33]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:32][O:31][C:30]1=[O:41])=[O:28])[C:9]([N:11]1[C@@H:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:14][O:13][C:12]1=[O:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:42][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI.[NH4+].[Cl-]>C1COCC1>[CH2:1]([C@@H:8](/[CH:24]=[CH:25]/[C@H:26]([CH3:42])[C:27]([N:29]1[C@@H:33]([CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:32][O:31][C:30]1=[O:41])=[O:28])[C:9]([N:11]1[C@@H:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:14][O:13][C:12]1=[O:23])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(C/C=C/[C@H](Cc1ccccc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: C[C@@H](/C=C/[C@H](Cc1ccccc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
To a solution of (S,E)-2-benzyl-1,6-bis((S)-4-benzyl-2-oxooxazolidin-3-yl)hex-3-ene-1,6-dione (250 mg, 0.450 mmol) in THF (50 mL) at −78° C., a solution of NaHMDS (1 M in THF, 0.54 mL, 0.54 mmol) in diluted in THF (2.5 mL) was added dropwise. The reaction mixture was stirred for 1 hr at −78° C. and then methyl iodide (0.078 g, 0.55 mmol) was added in two portions. The reaction mixture was warmed to rt and allowed to stir overnight. Saturated aqueous NH4Cl (3 mL) was added to the reaction mixture and crude product was extracted with ethyl acetate (5 mL). The organic layer was separated, dried (Na2SO4) and concentrated to afford crude product, which was purified using silica gel chromatography to afford (2S,5S,E)-2-benzyl-1,6-bis((S)-4-benzyl-2-oxooxazolidin-3-yl)-5-methylhex-3-ene-1,6-dione (137 mg, 0.243 mmol, 54% yield). Anal. Calcd. for C34H34N2O6 m/z 566.2. found 565.2 (M−): 1H NMR (400 MHz, CDCl3) δ ppm 7.36-7.30 (m, 5H), 7.29-7.26 (m, 5H), 7.25-7.18 (m, 3H), 7.08-7.05 (m, 2H), 5.75-5.62 (m, 2H), 4.72-4.57 (m, 3H), 4.36-4.29 (m, 1H), 4.23-4.12 (m, 4H), 3.28-3.21 (m, 2H), 3.10 (m, 1H), 2.84 (m, 1H), 2.76 (m, 1H), 2.61 (m, 1H), 1.24 (d, J=6.8 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH3:13])(=[O:12])=[O:11].C(N(CC)CC)C.[C:21](Cl)(=[O:25])[C:22]([CH3:24])=[CH2:23]>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][C:21](=[O:25])[C:22]([CH3:24])=[CH2:23])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH3:13])(=[O:12])=[O:11]
Reactant: C=C(C)C(=O)Cl
Reactant: Cc1cc(O)ccc1NS(C)(=O)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)Oc1ccc(NS(C)(=O)=O)c(C)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 61.3 %

Procedure:
To a mixture of 24.00 g (0.089 mol) of N-(2-methyl-4-hydroxyphenyl)methanesulfonamide, 9.00 g (0.089 mol) of triethylamine, and 150 ml of methylene chloride cooled to approximately 0° C. was added a solution of 9.32 g (0.089 mol) of methacryloyl chloride in 150 ml of methylene chloride and 50 ml of methylene chloride wash over approximately 20 minutes. The reaction mixture was then stirred for another 4 hours at reduced temperature, after which it was washed with 2 percent hydrochloric acid and twice with water. The organic phase was dried over magnesium sulfate, treated with decolorizing carbon, filtered and concentrated to an oil, which crystallized on cooling. The solid was recrystallized from 1:1 dichloroethane:hexane to give 14.7 g (61.3 percent of theory) of N-(2-methyl-4-methacryloyloxyphenyl)methanesulfonamide, m.p.=95° to 97° C.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]([F:14])[C:5]=1[C:6]([NH2:8])=[NH:7].O=[C:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]1>>[ClH:1].[NH2:7][C:6]1[C:5]2[C:4](=[CH:12][C:11]([F:13])=[CH:10][C:9]=2[F:14])[NH:3][C:16]2([CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]2)[N:8]=1
Reactant: N=C(N)c1c(N)cc(F)cc1F
Reactant: CCOC(=O)N1CCC(=O)CC1
Agent: Cl
Product: CCOC(=O)N1CCC2(CC1)N=C(N)c1c(F)cc(F)cc1N2

Procedure:
This was prepared by the method of Example 173 using 2-anino-4,6-difluorobenzamidine dihydrochloride (Example H) and ethyl 4-oxopiperidine-1-carboxylate to give the title compound, m.p. 245°-246° C.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C@@H:5]1[C:25](=[O:26])[N:7]2[C:8]([C:22]([O-:24])=[O:23])=[C:9]([CH2:12][N+:13]3[N:14]([CH2:19][CH2:20][OH:21])[C:15]([NH2:18])=[CH:16][CH:17]=3)[CH2:10][S:11][C@H:6]12.C[Si](C)(C)NC(=O)C.Cl.[NH2:36][C:37]1[S:41][N:40]=[C:39](/[C:42](=[N:46]/[O:47][CH2:48][CH:49]=[CH2:50])/[C:43](Cl)=[O:44])[N:38]=1.C(OC(C)C)(C)C>O1CCCC1>[NH2:36][C:37]1[S:41][N:40]=[C:39]([C:42](=[N:46][O:47][CH2:48][CH:49]=[CH2:50])[C:43]([NH:4][C@@H:5]2[C:25](=[O:26])[N:7]3[C:8]([C:22]([O-:24])=[O:23])=[C:9]([CH2:12][N+:13]4[N:14]([CH2:19][CH2:20][OH:21])[C:15]([NH2:18])=[CH:16][CH:17]=4)[CH2:10][S:11][C@H:6]23)=[O:44])[N:38]=1
Reactant: C=CCO/N=C(\C(=O)Cl)c1nsc(N)n1
Reactant: Nc1cc[n+](CC2=C(C(=O)[O-])N3C(=O)[C@@H](N)[C@H]3SC2)n1CCO
Agent: CC(=O)N[Si](C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Product: C=CCON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccc(N)n3CCO)CS[C@H]12)c1nsc(N)n1
Reaction time: 1 h
Yield: 43.7 %

Procedure:
To a solution of 7β-amino-3-[3-amino-2-(2-hydroxyethyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate trihydrochloride (2 g) and N-(trimethylsilyl)acetamide (5.85 g) in tetrahydrofuran (40 ml) was added (Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-allyloxyiminoactyl chloride hydrochloride (1.26 g) under ice-cooling. After being stirred for 1 hour at the same temperature, the reaction mixture was poured into diisopropyl ether (200 ml). The resulting precipitate was collected by filtration, dissolved in water (100 ml) and adjusted to pH 2.0 with 5% sodium bicarbonate solution. This solution was subjected to column chromatography on macroporous non-ionic adsorption resin "Diaion HP-20" (Trademark : prepared by Mitsubishi Chemical Industries). The desired compound was eluted with 10% isopropyl alcohol and lyophilized to give 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-allyloxyiminoacetamido]-3-[3-amino-2-(2-hydroxyethyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate (syn isomer) (1.07 g).