Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3](=O)[C:4](=[N:35][O:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[C:5]([NH:7][CH:8]1[C:33](=[O:34])[N:10]2[C:11]([C:17]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])=[C:12]([CH:15]=[CH2:16])[CH2:13][S:14][C@H:9]12)=[O:6].[NH2:43][C:44]([NH2:46])=[S:45].C([O-])(=O)C.[Na+]>O1CCCC1.O>[NH2:46][C:44]1[S:45][CH:2]=[C:3]([C:4](=[N:35][O:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[C:5]([NH:7][CH:8]2[C:33](=[O:34])[N:10]3[C:11]([C:17]([O:19][CH:20]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[O:18])=[C:12]([CH:15]=[CH2:16])[CH2:13][S:14][C@H:9]23)=[O:6])[N:43]=1
Reactant: NC(N)=S
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC)C(=O)CCl)[C@H]2SC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC)c3csc(N)n3)[C@H]2SC1
Temperature: 40 °C
Reaction time: 4 h
Yield: 96.6 %

Procedure:
To a solution of benzhydryl 7-(4-chloro-2-methoxycarbonylmethoxyimino-3-oxobutyramido)-3-vinyl-3-cephem-4-carboxylate (syn isomer) (2.0 g) in a mixture of tetrahydrofuran (10 ml) and water (10 ml) were added thiourea (0.5 g) and sodium acetate (1.34 g). The mixture was stirred at 40° C. for 4 hours. The resultant solution was extracted with ethyl acetate (100 ml), and the extract was washed with a saturated aqueous sodium chloride twice. After the resultant solution was dried over magnesium sulfate, the solvent was removed by distillation under reduced pressure to give benzhydryl 7-[2-(2-aminothiazol-4-yl)-2-methoxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (2.0 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([N:9](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[N:7][CH:8]=1.[P:24]([O:31]CC)([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27].Cl.C([O-])(O)=O.[Na+]>O1CCOCC1.C(Cl)Cl>[NH2:9][C:6]1[N:7]=[CH:8][C:3]([CH2:2][P:24](=[O:31])([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])=[CH:4][CH:5]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ccc(CBr)cn1
Reactant: CCOP(OCC)OCC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOP(=O)(Cc1ccc(N)nc1)OCC
Temperature: 110 °C
Reaction time: 4 h
Yield: 31 %

Procedure:
A mixture of di-tert-butyl [5-(bromomethyl)pyridin-2-yl]imidodicarbonate (Compound 309B, 1.162 g, 3 mmol) and triethyl phosphite (0.598 g, 3.6 mmol) in dioxane (2 mL) was stirred at 110° C. for 4 h. The cooled reaction mixture (room temperature) was treated with 4 N HCl in dioxane (5 mL) and DCM (10 mL) and allowed to stir at room temperature for 6 h. Sat. NaHCO3(aq, 15 mL) was added and the mixture was extracted with DCM (3×40 mL). The combined organic phases were dried over MgSO4, concentrated, and purified by silica gel chromatography (5% 7 N ammonia in MeOH in DCM) to afford 227 mg of the title compound (yield: 31%). 1H NMR (CDCl3, 400 MHz): δ=1.29 (t, J=6.8 Hz, 6 H), 2.98 (d, J=20.8 Hz, 2H), 4.02-4.09 (m, 4 H), 5.65 (s, br, 2 H), 6.58 (d, J=8.8 Hz, 1 H), 7.51 (dt, J=2.4, 8.8 Hz, 1H), 7.82 (t, J=2.4 Hz, 1 H). MS (ES+): m/z 245.09 [MH+]. HPLC: tR=0.70 min (UPLC TOF, polar—3 min).
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@@H:2]([C:6]([OH:8])=O)[CH:3]([CH3:5])[CH3:4].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH2:29]1[O:40][C:39]2[CH:38]=[CH:37][C:33]([CH2:34][CH2:35][NH2:36])=[CH:32][C:31]=2[O:30]1.C(N(CC)CC)C>ClCCCl>[C:12]([O:11][C:9](=[O:10])[NH:1][C@@H:2]([C:6](=[O:8])[NH:36][CH2:35][CH2:34][C:33]1[CH:37]=[CH:38][C:39]2[O:40][CH2:29][O:30][C:31]=2[CH:32]=1)[CH:3]([CH3:4])[CH3:5])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NCCc1ccc2c(c1)OCO2
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)NCCc1ccc2c(c1)OCO2
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
Boc-D-Val-OH (282 mg, 1.30 mmol) was dissolved in DCE (5 mL), followed by addition of CDI (253 mg, 1.56 mmol). The reaction solution was stirred for 30 mins to activate the acid. After this period, 3,4-Methylenedioxyphenethylamine HCl (263 mg, 1.30 mmol) and triethylamine (363 μL) were added to the reaction vessel and it was stirred at room temperature for 16 hours. Next, the reaction mixture was concentrated under vacuum. The crude material was dissolved in DCM (50 mL), transferred to a separatory funnel, washed with sat. NaHCO3 (aq) (50 mL), dried over Na2SO4 and concentrated down to yield 447.1 mg (94.6%) of crude product, [1-(2-benzo[1,3]dioxol-5-yl-ethylcarbamoyl)-2-methyl-propyl]-carbamic acid tert-butyl ester, which was taken on crude. [M+H]+ 365.00.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23]O)=[CH:21][CH:20]=1)([O-:18])=[O:17].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23][O:14][C:13](=[O:15])[C@H:9]([CH:10]([CH3:11])[CH3:12])[NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])=[CH:21][CH:20]=1)([O-:18])=[O:17]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 75.8 %

Procedure:
To a solution of N-(t-butoxycarbonyl)-L-valine (2.50 g, 11.5 mmol) in methylene chloride (125 ml) were added p-nitrobenzyl alcohol (3.52 g, 23.0 mmol), WSC (4.41 g, 23.0 mmol) and 4-dimethylaminopyridine (140 mg, 1.15 mmol) in an ice bath. The mixture was stirred at room temperature under an atmosphere of nitrogen for 4.5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (2:1) as the eluant to afford N-(t-butoxycarbonyl)-L-valine p-nitrobenzyl ester (3.07 g, yield 76%) as white crystals.
Reaction SMILES: [CH2:1]([NH:7][CH2:8][CH2:9][CH:10]1[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]1)[CH2:2][CH2:3][CH:4]=[CH:5][CH3:6].C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:32](=[O:37])[CH:33]([Cl:36])[CH2:34][CH3:35]>O>[CH2:1]([N:7]([CH2:8][CH2:9][CH:10]1[O:11][C:12]([CH3:17])([CH3:18])[C:13]([CH3:16])([CH3:15])[O:14]1)[C:32](=[O:37])[CH:33]([Cl:36])[CH2:34][CH3:35])[CH2:2][CH2:3][CH:4]=[CH:5][CH3:6]
Reactant: CCC(Cl)C(=O)Cl
Reactant: CC=CCCCNCCC1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CC=CCCCN(CCC1OC(C)(C)C(C)(C)O1)C(=O)C(Cl)CC

Procedure:
N-Hex-4-enyl-N-(4,4,5,5-tetramethyl-1,3-dioxolan-2-ylethyl)-amine (10 grams), benzene (100 ml), water (100 ml) and sodium carbonate (8 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is cooled to a temperature of 5° to 10° C. and α-chlorobutanoyl chloride (7 grams) is added dropwise with stirring. After the addition is completed stirring is continued until the reaction mixture reaches room temperature. After this time the organic phase is separated from the aqueous phase and is washed with water. The washed solution is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-hex-4-enyl-N-(4,4,5,5-tetramethyl-1,3-dioxolan-2-ylethyl)-α-chlorobutanamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][C@H:17]([CH2:21]OS(C)(=O)=O)[O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.O.[CH3:28][NH2:29]>>[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][C@H:17]([CH2:21][NH:29][CH3:28])[O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)OC[C@H]1CCc2ccc(S(=O)(=O)c3cccc(F)c3)cc2O1
Reactant: CN
Solvent: O
Product: CNC[C@H]1CCc2ccc(S(=O)(=O)c3cccc(F)c3)cc2O1
Temperature: 100 °C
Yield: 97 %

Procedure:
A mixture of methanesulfonic acid (R)-7-(3-fluoro-benzenesulfonyl)-chroman-2-ylmethyl ester (1.145 g, 2.86 mmol) and methylamine hydrate (10.mL) was heated in a sealed tube at 100° C. for 24 hours. The mixture was cooled and extracted with methylene chloride. The combined organic layers were washed with water and brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (methylene chloride:MeOH 4:1) to give 0.932 g (97%) of [(R)-7-(3-fluoro-benzenesulfonyl)-chroman-2-ylmethyl]-methyl-amine. MP=259.0-261.0° C.; MS (M+H)=336.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[C@@H:7]([NH:24][C:25](=[O:36])[C:26]1[CH:31]=[CH:30][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[CH:19][C:18]([C:21]([OH:23])=O)=[CH:17][N:16]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.[C:42]([NH:50][NH2:51])(=[O:49])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]>C(Cl)Cl.CN(C1C=CN=CC=1)C.C([O-])(O)=O.[Na+]>[C:32]([C:29]1[CH:28]=[CH:27][C:26]([C:25]([NH:24][C@@H:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:20]=[CH:19][C:18]([C:21]([NH:51][NH:50][C:42](=[O:49])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:23])=[CH:17][N:16]=3)=[CH:11][CH:10]=2)[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:37])=[O:36])=[CH:31][CH:30]=1)([CH3:34])([CH3:33])[CH3:35]
Reactant: CCCCCCC(=O)NN
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(-c2ncc(C(=O)O)cn2)cc1)NC(=O)c1ccc(C(C)(C)C)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CCCCCCC(=O)NNC(=O)c1cnc(-c2ccc(C[C@H](NC(=O)c3ccc(C(C)(C)C)cc3)C(=O)OC(C)(C)C)cc2)nc1
Reaction time: 18 h
Yield: 60.3 %

Procedure:
Prepared using General Procedure 7. Into a stirring solution of (S)-2-(4-(3-(tert-butoxy)-2-(4-(tert-butyl)benzamido)-3-oxopropyl)phenyl)pyrimidine-5-carboxylic acid (50 mg, 0.10 mmol) in DCM (2 mL) were added EDC (34 mg, 0.20 mmol), DMAP (3 mg, 0.02 mmol) and heptanehydrazide (16 mg, 0.11 mmol). After 18 h, the reaction mixture was diluted with NaHCO3 and extracted with DCM (2×). The organic layers were combined, dried (Na2SO4), concentrated and purified by chromatography (EA/Hexane) to provide 38 mg (61%) of tert-butyl (S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(2-heptanoylhydrazine-1-carbonyl)pyrimidin-2-yl)phenyl)propanoate. LCMS-ESI (m/z) calculated for C36H47BN5O5: 629.8; no m/z observed, tR=3.84 min (Method 1). 1H NMR (400 MHz, CDCl3) δ 9.17 (s, 2H), 8.42 (d, J=8.2 Hz, 2H), 7.69 (d, J=8.4 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H), 7.34 (d, J=8.2 Hz, 2H), 6.70 (d, J=7.3 Hz, 1H), 5.01 (dd, J=12.6, 5.8 Hz, 1H), 3.41-3.20 (m, 2H), 2.35 (t, J=7.5 Hz, 2H), 1.81-1.61 (m, 2H), 1.59 (d, J=14.0 Hz, 2H), 1.45 (s, 4H), 1.42-1.22 (m, 18H), 0.88 (t, J=6.8 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][OH:10].[Br:11][CH2:12][C:13](Br)=[O:14].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Br:11][CH2:12][C:13]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][OH:10])=[O:14]
Reactant: Nc1ccc(Cl)cc1CO
Reactant: O=C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CBr)Nc1ccc(Cl)cc1CO
Reaction time: 0.08 h
Yield: 96 %

Procedure:
To a solution of (2-amino-5-chlorophenyl)methanol (4.30 g, 27.3 mmol) in dichloromethane (220 ml) was added 2-bromoacetyl bromide (6.06 g, 2.61 ml, 30.0 mmol) at 0-5° C. Stirring for 5 minutes was followed by dropwise addition of aqueous 2 M sodium carbonate solution (130 ml) during approximately 10 minutes. The cooling bath was removed, and stirring was continued for 2 h. The solvent was removed in vacuo. The aqueous residue was extracted with three 100-ml portions of ethyl acetate. The combined organic layers were washed with one 50-ml portion of brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (7.30 g, 96%) as light grey solid, which was used in the next step without purification. MS m/e: 276 ([M+H]+).
Reaction SMILES: C[O:2][C:3](=[O:43])[C@@H:4]([NH:32][C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])[CH2:5][NH:6][C:7]([CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH:16]=2)[CH2:11][CH2:10]1)=[O:8].[OH-].[Na+].FC(F)(F)C(O)=O>CO>[CH2:25]([NH:24][C:22]([NH:21][C:17]1[CH:16]=[C:15]([N:12]2[CH2:11][CH2:10][CH:9]([C:7]([NH:6][CH2:5][C@H:4]([NH:32][C:33]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:34])[C:3]([OH:43])=[O:2])=[O:8])[CH2:14][CH2:13]2)[CH:20]=[CH:19][CH:18]=1)=[O:23])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)[C@H](CNC(=O)C1CCN(c2cccc(NC(=O)NCc3ccccc3)c2)CC1)NC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1ccccc1)Nc1cccc(N2CCC(C(=O)NC[C@H](NC(=O)OCc3ccccc3)C(=O)O)CC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the compound of Example 29 in methanol (10 ml) is added 2M aqueous sodium hydroxide solution (10 ml), and the mixture is stirred at 25° C. overnight. The reaction solution is neutralized with trifluoroacetic acid, purified by CHP-20 (eluent: gradient, 35% to 100% methanol/0.05% aqueous trifluoroacetic acid solution) to give the title compound.
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].FC(F)(F)C(O)=O.[CH3:28][N:29]([CH3:36])[C:30](=[O:35])[C@@H:31]([NH:33][CH3:34])[CH3:32]>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([N:33]([CH3:34])[C@@H:31]([CH3:32])[C:30]([N:29]([CH3:36])[CH3:28])=[O:35])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: CN[C@@H](C)C(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C1(N(C)[C@@H](C)C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 1.64 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and the compound obtained in Step 71-2 (5.86 mmol, crude form) as starting materials, respectively 0.90 g (Isomer A, colorless amorphous) and 1.41 g (Isomer B, colorless amorphous) of two species of diastereoisomers of the title compound were obtained by a similar method to Step 4-2.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[C:13]([CH3:20])[C:14]([F:19])=[C:15](F)[CH:16]=3)[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1.[CH3:27][NH2:28]>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[C:13]([CH3:20])[C:14]([F:19])=[C:15]([NH:28][CH3:27])[CH:16]=3)[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1
Reactant: CN
Reactant: Cc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2-c1cc(N)c(F)cc1F
Solvent: c1ccncc1
Product: CNc1cc2c(c(C)c1F)c(=O)c(C(=O)O)cn2-c1cc(N)c(F)cc1F
Temperature: 60 °C
Reaction time: 8 h

Procedure:
1-(5-Amino-2,4-difluorophenyl)-6,7-difluoro-5-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (200 mg) and a 40% aqueous solution (210 mg) of methylamine were added to pyridine (1 ml), and the mixture was heated and stirred overnight at 60° C. After the reaction mixture was allowed to cool, the solvent was distilled off under reduced pressure. Ethanol was added to the residue to collect solids. The solids were washed successively with ethanol and diethyl ether to obtain the title compound (115 mg) as a colorless powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:17])[C@@H:9]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]([O:22][C:23]([NH:25]O)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:1]([O:5][C:6]([N:8]([CH3:17])[C@@H:9]([CH2:13][CH:14]([CH3:15])[CH3:16])[C:10]([O:12][NH:25][C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:24])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NO
Product: CC(C)C[C@@H](C(=O)ONC(=O)OC(C)(C)C)N(C)C(=O)OC(C)(C)C

Procedure:
[(tert-Butoxy)carbonyl]amino (2S)-2-{[(tert-butoxy)carbonyl](methyl)amino}-4-methylpentanoate is prepared from (2S)-2-{[(tert-butoxy)carbonyl](methyl)amino}-4-methylpentanoic acid and N-tert-butoxycarbonyl hydroxylamine according to Scheme 6. The compound exists as rotomers and is reported as such. (1.8 g, 58%), 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.49-8.06 (1H, m), 4.75-5.10 (1H, m), 2.86 (3 H, d, 7.8 Hz), 1.66-1.88 (2H, m), 1.54-1.64 (1H, m), 1.50 (9H, s), 1.47 (9H, d, 3.7 Hz), 0.96 (6H, dd, 10.7, 6.6 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:8].[C:9]1([S:15](Cl)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1C=CC=CC=1>[C:9]1([S:15]([O:8][N:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]2=[O:1])(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: [O-][n+]1ccccc1O
Solvent: c1ccncc1
Product: O=c1ccccn1OS(=O)(=O)c1ccccc1
Yield: 77 %

Procedure:
2-Hydroxypyridine-1-oxide (1.0 g, 9.1 mmol) was reacted with benzenesulfonyl chloride (1.27 mL, 10.0 mmol) in 75 mL of pyridine to afford PZBG-1a in 77% yield (1.75 g, 7.0 mmol). 1H NMR (500 MHz, CDCl3) δ=8.02 (d, J=8.0 Hz, 2H), 7.75 (t, J=8.0 Hz, 1H), 7.59 (m, 3H), 7.28 (dt, J1=6.9 Hz, J2=2.3 Hz, 1H), 6.52 (d, J=9.8 Hz, 1H), 6.15 (t, J=7.5 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ=157.0, 139.7, 137.1, 136.0, 133.8, 130.0, 129.5, 123.4, 105.4. ESI-MS(+): m/z 252.01 [M+H]+, 273.95 [M+Na]+. Anal. calcd for C11H9NO4S: C, 52.58; H, 3.61; N, 5.57. Found: C, 52.21; H, 3.99; N, 5.44.
Reaction SMILES: C([O:5][C:6]([CH2:8][N:9]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:10]1=[O:22])=[O:7])(C)(C)C.[OH-].[K+]>C(O)C.O>[C:18]([O:17][C:15]([CH2:14][N:11]1[CH2:12][CH2:13][N:9]([CH2:8][C:6]([OH:7])=[O:5])[C:10]1=[O:22])=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)CN1CCN(CC(=O)OC(C)(C)C)C1=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)CN1CCN(CC(=O)O)C1=O
Temperature: 70 °C
Reaction time: 5 h
Yield: 32 %

Procedure:
To a solution of tert-butyl 2-(3-{[(tert-butyl)oxycarbonyl]methyl}-2-oxoimidazolidinyl)acetate (1.14 g) in ethanol (10 ml) and water (10 ml) was added potassium hydroxide (0.22 g) and then the reaction mixture stirred at 70° C. for 5 hours. After the ethanol was removed under reduced pressure, to the residue was added saturated aqueous sodium hydrogen carbonate solution. The aqueous phase was washed with ethyl acetate, acidified with 10% hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The precipitate was recrystallized with ethyl acetate and filtered off to give 2-(3-{[(tert-butyl)oxycarbonyl]methyl}-2-oxoimidazolidinyl)acetic acid (0.30 g) as a colorless solid.
Reaction SMILES: [C:1]([C:9]1[CH:24]=[CH:23][C:12]([CH2:13][O:14][C:15]2[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:25]1[CH2:31][C:29](=[O:30])[NH:28][C:26]1=[S:27]>>[C:2]1([C:1]([C:9]2[CH:24]=[CH:23][C:12]([CH2:13][O:14][C:15]3[CH:22]=[CH:21][C:18]([CH:19]=[C:31]4[S:25][C:26](=[S:27])[NH:28][C:29]4=[O:30])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)=[O:8])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CSC(=S)N1
Reactant: O=Cc1ccc(OCc2ccc(C(=O)c3ccccc3)cc2)cc1
Product: O=C1NC(=S)SC1=Cc1ccc(OCc2ccc(C(=O)c3ccccc3)cc2)cc1

Procedure:
The 4-(4-benzoylbenzyloxy)benzaldehyde was coupled with rhodanine to yield the title compound by admixing the 4-(4-benzoylbenzyloxy)benzaldehyde (2.09 g, 6.3 mmol) with rhodanine (1.0 g, 7.5 mmol), sodium acetate (1.8 g, 22 mmol) and acetic acid (75 ml) in a 250 ml flask. The reaction mixture was heated to reflux and refluxed overnight.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[NH:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]1=O>COCCOC>[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:15])([F:16])[F:14])[CH:6]=1
Reactant: O=c1cccc[nH]1
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Solvent: COCCOC
Product: N#Cc1ccc(N(CCOc2ccccn2)CC(F)(F)F)cc1C(F)(F)F

Procedure:
Synthesized as described in Example 1C from 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and 2-pyridone, using dry DME as reaction solvent: MS (APCI) m/z 390 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].Br[C:12]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:13]=1[C:14]([OH:16])=[O:15].CCOC(C)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[Br:21][C:18]1[CH:19]=[CH:20][C:12]([O:10][C:3]2[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=2[F:1])=[C:13]([CH:17]=1)[C:14]([OH:16])=[O:15]
Reactant: COc1ccc(O)c(F)c1
Reactant: O=C(O)c1cc(Br)ccc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(Oc2ccc(Br)cc2C(=O)O)c(F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A three-neck RBF equipped with a reflux condenser and overhead stirrer was charged with 2-fluoro-4-methoxyphenol (14.24 g, 100 mmol), 2,5-dibromobenzoic acid (25.5 g, 91 mmol), EtOAc (0.446 mL, 4.55 mmol), copper (I) triflate toluene complex (2:1) (0.484 g, 2.27 mmol) and toluene (300 mL). Cesium carbonate (59.4 g, 182 mmol) was carefully added portion-wise. The mixture was stirred for 10 minutes at RT then heated at 95° C. for 3 hours. The toluene was cooled to RT then extracted twice with 300 ml of water. The combined water extracts were acidified with 6 N HCl at which time a precipitate formed. The mixture was extracted with EtOAc (3×500 mL) and the combined organic fractions were dried over sodium sulfate and concentrated in vacuo. The resulting solid was triturated with minimal 1:1 Hexanes:EtOAc and filtered. The collected solid was dried in vacuo to afford 5-bromo-2-(2-fluoro-4-methoxyphenoxy)benzoic acid as a grey solid. The mother liquors were set aside for later recrystallizatio. MS m/z=341.0 [M+H].
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.CC1C=CC(S(O[CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][N:35]=[N+:36]=[N-:37])(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[N:35]([CH2:34][CH2:33][O:32][CH2:31][CH2:30][O:29][CH2:28][CH2:27][O:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[CH:6][CH:7]=1)=[N+:36]=[N-:37]
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCCN=[N+]=[N-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1ccc(OCCOCCOCCN=[N+]=[N-])cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 112.5 %

Procedure:
A suspension of tert-butyl 4-hydroxyphenylcarbamate (1.24 g, 5.93 mmol), 2-(2-(2-azidoethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (1.50 g, 4.56 mmol) and K2CO3 (2.45 g, 17.79 mmol) in acetonitrile was stirred at 80° C. overnight. The reaction mixture was filtered and washed with acetonitrile. After the solvent was evaporated, the reaction mixture was diluted with DCM. The DCM solution was washed with sat. K2CO3 aqueous solution and brine. The organic phase was dried, and concentrated in vacuo to afford tert-butyl 4-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)phenylcarbamate (1.88 g, 100%). 1H NMR (400 MHz, CDCl3) δ 7.26 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 6.35 (s, 1H), 4.10 (t, J=4.8 Hz, 2H), 3.85 (t, J=4.8 Hz, 2H), 3.76-3.62 (m, 6H), 3.39 (t, J=5.2 Hz, 2H), 1.52 (s, 9H); MS (ESI), 389 (M+Na)+.