Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[CH:5]=1.N1C=CN=C1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].[Cl-].[NH4+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH:5]=1
Reactant: COC(=O)c1cccc(O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(O[Si](C)(C)C(C)(C)C)c1
Temperature: 0 °C
Yield: 63.1 %

Procedure:
1.53 g of 3-hydroxybenzoic acid methyl ester and 1.69 g of imidazole were placed in a 50 ml flask, and a gas in the reaction system was replaced with nitrogen. 5 ml of DMF was added into the flask and stirred at 0° C. The obtained solution was mixed with 1.57 g of t-butyldimethylsilyl chloride, heated up to room temperature, simultaneously stirred overnight, and then mixed with a saturated aqueous solution of ammonium chloride to stop the reaction. The reaction solution was extracted with diethyl ether, and the obtained organic layer was sequentially washed with water, a saturated aqueous solution of potassium hydrogen sulfate and a saturated aqueous solution of sodium chloride and then dried over magnesium sulfate. The solvent was distilled away under reduced pressure to obtain 1.69 g of the title compound. Yield: 98%.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].Br.C(OC([NH:16][C@H:17]([C:24]([N:26]1[CH2:36][CH2:35][CH2:34][C@H:27]1[C:28]([NH:30][CH2:31][CH2:32]O)=[O:29])=[O:25])[CH2:18][C:19]1[N:23]=[CH:22][NH:21][CH:20]=1)=O)C1C=CC=CC=1>CCOCC>[NH2:16][C@H:17]([C:24]([N:26]1[CH2:36][CH2:35][CH2:34][C@H:27]1[C:28]([NH:30][CH2:31][CH2:32][O:3][C:1](=[O:4])[CH3:2])=[O:29])=[O:25])[CH2:18][C:19]1[N:23]=[CH:22][NH:21][CH:20]=1
Reactant: CC(=O)O
Reactant: O=C(N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(=O)NCCO)OCc1ccccc1
Agent: Br
Solvent: CCOCC
Product: CC(=O)OCCNC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)Cc1c[nH]cn1
Temperature: 25 °C

Procedure:
To 37.5 ml of ice-cooled acetic acid solution of 25% hydrobromic acid was added 3.22 g of compound (54) and the reaction was maintained for 3 hours at room temperature. The reaction mixture was added to 375 ml of dry ether and the precipitates thus formed were quickly collected by filtration and dried overnight in a desiccator containing potassium hydroxide to provide 4.43 g of L-histidyl-N-(2-acetoxyethyl)-L-prolinamide.2-hydrobromide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13]C=[N:11][C:10]=2[C:14]([O:16][CH3:17])=[O:15])[CH:5]=[CH:6][C:7]=1[F:8].CCOCC>CO.Cl>[CH3:17][O:16][C:14](=[O:15])[CH:10]([NH2:11])[C:9]([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1)=[O:13]
Reactant: COC(=O)c1ncoc1-c1ccc(F)c(F)c1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C(N)C(=O)c1ccc(F)c(F)c1
Temperature: 50 °C
Yield: 104.4 %

Procedure:
To 5-(3,4-difluorophenyl)-4-methoxycarbonyloxazole (1.0 g, 4.18 mmol) in methanol (6 mL), 1N HCl (2 mL) was added and the mixture was heated at 50° C. for 2 hours. The reaction mixture was then concentrated to yield a syrup. Ether was added and the solution filtered to give 1.0 g (87%) of the product as a white solid: 1H-NMR (CDCl3) 3.74 (s, 3 H), 6.15 (s, 1H), 7.45-7.55 (m, 1H), 8.11-8.13 (m, 2H)
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)([O-:3])=[O:2].[Na+].[Cl-].C(O)(=[O:18])C>OO>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N+:9]2[O-:18])([O-:3])=[O:2]
Reactant: CC(=O)O
Reactant: O=[N+]([O-])c1cccc2ncccc12
Agent: OO
Agent: [Cl-]
Agent: [Na+]
Product: O=[N+]([O-])c1cccc2c1ccc[n+]2[O-]

Procedure:
A solution of 25.5 g (146 mmol) of 5-nitroquinoline in 544 ml of acetic acid and 272 ml of 30% aqueous H2O2 solution are heated for 100 minutes to 62-69° C. The reaction mixture is poured onto saturated NaCl solution and extracted with ethyl acetate. The combined extracts are concentrated by evaporation to about 50 ml with the addition of toluene. Column chromatography on silica gel with ethyl acetate-MeOH yields 12.3 g of the product as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16])=[O:5])[CH3:2].[CH:17]1([OH:24])[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]1>>[OH:23][CH:20]1[CH2:21][CH2:22][CH:17]([O:24][C:7]([C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]([NH:6][C:4](=[O:5])[O:3][CH2:1][CH3:2])=[O:11])=[O:16])[CH2:18][CH2:19]1
Reactant: OC1CCC(O)CC1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Product: CCOC(=O)NC(=O)c1ccccc1C(=O)OC1CCC(O)CC1

Procedure:
According to the same manner as described in Example 1 except for reacting N-ethoxycarbonylphthalimide with 1,4-cyclohexanediol under conditions shown in Table 19, ethyl N-{2-(4-hydroxycyclohexyloxycarbonyl)benzoyl)carbamate was obtained. Characteristics and identified structure of the resulting compound are shown in Table 10.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][N:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[NH2:26].Cl.C(OCC)C>CC(O)C>[ClH:1].[N+:18]([C:5]1[C:6]([NH:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])=[N:7][C:2]([NH:26][C:25]2[CH:27]=[C:28]([O:32][CH3:33])[C:29]([O:30][CH3:31])=[C:23]([O:22][CH3:21])[CH:24]=2)=[N:3][CH:4]=1)([O-:20])=[O:19]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: O=C(O)c1ccccc1Nc1nc(Cl)ncc1[N+](=O)[O-]
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)O
Product: COc1cc(Nc2ncc([N+](=O)[O-])c(Nc3ccccc3C(=O)O)n2)cc(OC)c1OC
Temperature: 90 °C
Yield: 62.3 %

Procedure:
To a mixture of 2-[(2-chloro-5-nitropyrimidin-4-yl)amino]benzoic acid (52 mg, 0.178 mmol) and 3,4,5-trimethoxyaniline (34 mg, 0.185 mmol) in 2-propanol (2 mL) was added 1N HCl in diethyl ether (50 uL, 0.05 mmol). The reaction mixture was heated at 90° C. for 30 hours. After the reaction was cooled to room temperature the mixture was filtered, and the solid was washed with 2-propanol, hexane, and ethyl acetate. The solid was then dried under vacuum to give 2-({5-nitro-2-[(3,4,5-trimethoxyphenyl)-amino]pyrimidin-4-yl}amino)benzoic acid hydrochloride (53 mg, 63%) as a dirty orange solid. 1H NMR (DMSO-d6/D2O): δ 9.14 (s, 1H), 8.47 (m, 1 H), 8.02 (d, 1 H), 7.46 (m, 1 H), 7.26 (t, 1 H), 6.95 (s, 2 H), 3.69 (s, 3 H), 3.63 (s, 6 H); MS m/z 441 (M+1).
Reaction SMILES: O.[NH2:2][NH2:3].[OH:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=O)[C:10]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[C:11]([CH3:15])[O:12]2)=[CH:7][CH:6]=1>C(O)C>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:10]2[C:9]([C:8]3[CH:7]=[CH:6][C:5]([OH:4])=[CH:14][C:13]=3[OH:12])=[N:2][NH:3][C:11]=2[CH3:15])=[CH:17][CH:18]=1
Reactant: NN
Reactant: COc1ccc(-c2c(C)oc3cc(O)ccc3c2=O)cc1
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2c(-c3ccc(O)cc3O)n[nH]c2C)cc1

Procedure:
Hydrazine hydrate (2 ml, ˜55%) was added to a suspension of 7-hydroxy-3-(4-methoxy-phenyl)-2-methyl-chromen-4-one (0.57 g, 2 mmol) in ethanol (15 ml) and the mixture heated under reflux for ˜5 hrs., to give a pale brown solution. The solution was allowed to cool and concentrated to a pale yellow solid, the solids were washed with water, to give the pyrazole as an off-white solid, dried in vacuo, (0.45 g). Sample was recrystallised from boiling toluene, to give the 4-[4-(4-methoxy-phenyl)-5-methyl-1H-pyrazol-3-yl]-benzene-1,3-diol as a pale brown crystalline solid, washed with hexane, dried in vacuo.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:28]=3[N:27]=[CH:26][CH:25]=[CH:24]4)[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:29][C:30]1[CH:34]=[CH:33][N:32]([CH2:35][C:36]([CH3:39])([OH:38])[CH3:37])[N:31]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:28]=3[N:27]=[CH:26][CH:25]=[CH:24]4)[CH:13]=[N:12]2)[C:8]([NH:29][C:30]2[CH:34]=[CH:33][N:32]([CH2:35][C:36]([OH:38])([CH3:37])[CH3:39])[N:31]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2cccc3cccnc23)cc1=O
Reactant: CC(C)(O)Cn1ccc(N)n1
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3cccc4cccnc34)cc2=O)n1
Yield: 25 %

Procedure:
Using the method described in Example 17, 3-cyclopentyl-2-[6-oxo-4-(quinolin-8-yloxy)-6H-pyridazin-1-yl]-propionic acid (Intermediate 55) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[6-oxo-4-(quinolin-8-yloxy)-6H-pyridazin-1-yl]-propionamide as an off-white solid (0.34 g, 25%); ES+-HRMS m/e calcd for C28H32N6O4 [M+H+] 517.2558 found 517.2558. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.04 (s, 3H), 1.06 (s, 3H), 1.10 (m, 1H), 1.27-1.76 (m, 8H), 1.91 (m, 1H), 2.23 (m, 1H), 3.89 (s, 2H), 4.67 (s, 1H), 5.44 (dd, J=4.5, J=10.9 Hz, 1H), 5.50 (d, J=2.9 Hz, 1H), 6.40 (d, J=2.2 Hz, 1H), 7.52 (d, J=2.2 Hz, 1H), 7.65 (dd, Jo=8.3, 4.2 Hz, 1H), 7.72 (t, Jo=7.9 Hz, 1H), 7.76 (dd, Jo=7.5 Hz, Jm=1.5 Hz, 1H), 8.03 (dd, Jo=8.1 Hz, Jm=1.5 Hz, 1H), 8.24 (d, J=2.9 Hz, 1H), 8.52 (dd, Jo=8.3 Hz, Jm=1.7 Hz, 1H), 8.92 (dd, Jo=4.2 Hz, Jm=1.7 Hz, 1H), 10.81 (s, 1H).
Reaction SMILES: [OH:1][CH:2]([CH3:12])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[H-].[Na+].Cl[CH2:16][C:17]([CH2:19]Cl)=[CH2:18].O>CN(C=O)C>[CH3:12][CH:2]1[CH2:3][N:4]([C:5]([O:6][C:7]([CH3:8])([CH3:10])[CH3:9])=[O:11])[CH2:19][C:17](=[CH2:16])[CH2:18][O:1]1
Reactant: C=C(CCl)CCl
Reactant: CC(O)CNC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C1COC(C)CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 33.9 %

Procedure:
To a mixture of tert-butyl N-(2-hydroxypropyl)carbamate (5.00 g, 28.54 mmol, 1.00 eq) in DMF (100.00 mL), was added NaH (2.51 g, 62.79 mmol, 2.20 eq) in one portion at 0° C. under N2. The mixture was stirred at 0° C. for 1 hr, then 3-chloro-2-(chloromethyl)prop-1-ene (3.57 g, 28.54 mmol, 1.00 eq) was added to the mixture, the mixture was stirred at 0° C. for 4 hr. TLC showed the reaction was completed. The mixture was poured into water (100 mL) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (100 mL*2). The combined organic phase was washed with saturated brine (100 mL*2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate=10/1) to afford tert-butyl 2-methyl-6-methylene-1,4-oxazepane-4-carboxylate (2.20 g, 9.68 mmol, 33.91% yield) as yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]2Cl.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:25]2)=[N:22][CH:23]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:25]2)=[N:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccc(N)cn2)C1
Reactant: CCC(=O)c1cnc2ccc(Br)cc2c1Cl
Product: CCC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(N2CCC[C@H](NC(=O)OC(C)(C)C)C2)nc1
Yield: 29.7 %

Procedure:
Following general procedure C, 1-(6-bromo-4-chloroquinolin-3-yl)propan-1-one (301 mg, 1.02 mmol) was reacted with (S)-tert-butyl 1-(5-aminopyridin-2-yl)piperidin-3-ylcarbamate (600 mg, 2.05 mmol) to obtain the desired product (168 mg, 30%) as an purple semi-solid.: ESI MS m/z 554 [C27H32BrN5O3+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]([NH:21][CH2:22][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=O)=[O:20])=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:6][N:7]=1.C([O-])(O)=O.[Na+]>OS(O)(=O)=O>[CH2:17]([S:14]([N:11]1[CH2:10][CH2:9][N:8]([C:5]2[N:4]=[C:3]([C:19]3[O:20][C:23]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:22][N:21]=3)[C:2]([NH2:1])=[N:7][CH:6]=2)[CH2:13][CH2:12]1)(=[O:15])=[O:16])[CH3:18]
Reactant: CCS(=O)(=O)N1CCN(c2cnc(N)c(C(=O)NCC(=O)c3ccccc3)n2)CC1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCS(=O)(=O)N1CCN(c2cnc(N)c(-c3ncc(-c4ccccc4)o3)n2)CC1
Yield: 5.9 %

Procedure:
3-amino-6-(4-ethylsulfonylpiperazin-1-yl)-N-phenacyl-pyrazine-2-carboxamide (80 mg, 0.1850 mmol) in H2SO4 (1.5 mL) was stirred at ambient temperature for 16 hours. The reaction was neutralised by addition of NaHCO3 solution and then extracted with EtOAc (3×), combined organics dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the title compound as an orange solid (4.5 mg, 6% Yield). 1H NMR (DMSO) d 1.25 (3H, t), 3.11 (2H, q), 3.35 masked signal, 3.54 (4H, m), 7.00 (2H, br s), 7.42 (1H, m), 7.53 (2H, m), 7.84 (2H, m), 7.99 (1H, s), 8.14 (1H, s) ppm; MS (ES+) 415.0
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH:14]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:13]=[C:12]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][C:24]=2[N+:29]([O-])=O)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CO>CC(O)=O.[Fe]>[NH2:29][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][C:23]=1[C:12]1[CH2:11][CH2:10][CH:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[CH:14]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:13]=1
Reactant: CC(C)(C)OC(=O)NC1C=C(c2ccncc2[N+](=O)[O-])CCC1O[Si](C)(C)C(C)(C)C
Agent: [Fe]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC1C=C(c2ccncc2N)CCC1O[Si](C)(C)C(C)(C)C
Reaction time: 20 h
Yield: 94 %

Procedure:
To a solution of (+/−)-tert-butyl 6-(tert-butyldimethylsilyloxy)-3-(3-nitropyridin-4-yl)cyclohex-2-enylcarbamate (1.0 equiv.) in AcOH (0.18 M) was added Fe (6.0 equiv.) and the reaction was stirred for 20 h. Worked up by diluting the reaction with methanol, filtered, and concentrated the filtrate. To the crude was added ethyl acetate and saturated NaHCO3, the organics were dried with sodium sulfate and concentrated to give (+/−)-tert-butyl 3-(3-aminopyridin-4-yl)-6-(tert-butyldimethylsilyloxy)cyclohex-2-enylcarbamate as a yellow oil in 94% yield. LCMS (m/z): 420.3 (MH+), LC Rt=3.88 min.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH3:9])=[C:4]([CH3:10])[N:3]=1.Cl.[F:12][C:13]1([F:20])[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15][CH2:14]1.C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:19][CH:16]2[CH2:17][CH2:18][C:13]([F:20])([F:12])[CH2:14][CH2:15]2)[C:5]([CH3:9])=[C:4]([CH3:10])[N:3]=1
Reactant: NC1CCC(F)(F)CC1
Reactant: Cc1nc(Cl)nc(Cl)c1C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(Cl)nc(NC2CCC(F)(F)CC2)c1C
Temperature: 50 °C
Yield: 68.2 %

Procedure:
To the solution of 2,4-dichloro-5,6-dimethylpyrimidine (0.585 g, 3.304 mmol) in N,N-dimethylformamide (10 mL), (4,4-difluorocyclohexyl)amine hydrochloride (0.652 g, 3.800 mmol) and triethylamine (1.338 g, 13.218 mmol) were added, and reaction mixture was heated at 50° C. overnight. Volatiles were removed under reduced pressure, and the residue was poured into water (300 mL). The product was extracted with ether (3×50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica eluting with a mixture of hexane/ethyl acetate (gradient 4:1-2:1) to provide 621 mg (68%) of the titled compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.18-1.24 (m, 1H), 1.60-1.72 (m, 2H), 1.80-2.10 (m, 8H) 2.21 (s, 3H), 4.00-4.10 (m, 1H), 6.73 (d, J=7.79 Hz, 1H); MS (ESI) m/z 318.6 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]2.[F:14][C:15]([F:25])([F:24])[C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])/[C:6](=[CH:19]/[C:18]1[CH:21]=[CH:22][CH:23]=[C:16]([C:15]([F:14])([F:24])[F:25])[CH:17]=1)/[CH2:5]2
Reactant: COc1cc2c(cc1Br)CCC2=O
Reactant: O=Cc1cccc(C(F)(F)F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1Br)C/C(=C\c1cccc(C(F)(F)F)c1)C2=O
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a solution of 11 (200 mg, 0.829 mmol) in toluene was added 3-(trifluoromethyl)benzaldehyde 99 (158.86 mg, 0.9128 mmol). PTSA (285.5 mg, 172.20 mmol) was added to the reaction mass, then stirred at 120° C. for 6 h, diluted with ethyl acetate and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude compound 152 which was purified through flash chromatography by using 100-200 mesh silica gel. The compound (E)-5-bromo-6-methoxy-2-(3-(trifluoromethyl)benzylidene)-2,3-dihydro-1H-inden-1-one 152 was eluted at 30% ethyl acetate in hexane to afford yellow coloured solid.
Reaction SMILES: [CH3:1][C:2]1[S:6][CH:5]=[N:4][C:3]=1[C:7]([NH:9][NH:10]C(OC(C)(C)C)=O)=[O:8].Cl>>[CH3:1][C:2]1[S:6][CH:5]=[N:4][C:3]=1[C:7]([NH:9][NH2:10])=[O:8]
Reactant: Cc1scnc1C(=O)NNC(=O)OC(C)(C)C
Agent: Cl
Product: Cc1scnc1C(=O)NN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1,1-dimethylethyl 2-[(5-methyl-1,3-thiazol-4-yl)carbonyl]hydrazinecarboxylate (544 mg, 2.114 mmol) in HCl (2643 μl, 10.57 mmol) (4M in 1,4-dioxane) was stirred at room temperature under an atmosphere of argon for 17 hours (overnight). After this time, the reaction mixture was concentrated under reduced pressure to give an off-white coloured solid of desired material in 162 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([O:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[N:11][CH:12]=[C:13]([CH:24]=2)[C:14]([NH:16][CH2:17][C:18](=O)[C:19]([F:22])([F:21])[F:20])=[O:15])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:32][O:33][NH2:34]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([O:25][CH2:26][C:27]([F:30])([F:28])[F:29])=[N:11][CH:12]=[C:13]([CH:24]=2)[C:14]([NH:16][CH2:17]/[C:18](=[N:34]/[O:33][CH3:32])/[C:19]([F:20])([F:21])[F:22])=[O:15])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(NCC(=O)C(F)(F)F)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)c(Cl)c2)c1
Reactant: CON
Agent: Cl
Solvent: CCO
Solvent: O
Product: CO/N=C(/CNC(=O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)c(Cl)c2)c1)C(F)(F)F
Reaction time: 18 h
Yield: 89.9 %

Procedure:
To a solution of 0.241 g 5-(3,4-dichloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-N-(3,3,3-trifluoro-2-oxo-propyl)-nicotinamide in ethanol was added 0.051 g O-methylhydroxylamine hydrochloride and the mixture was kept at ambient temperature for 18 h. The mixture was then heated to reflux for 4 h. The clear reaction mixture was diluted with ca 2 ml water and concentrated under aspirator vacuum whereby crystallisation occurred. The product was collected by filtration and washed with water and dried to constant weight under high vacuum to yield 0.23 g of the title compound as white crystals melting at 124-126° C. MS (EI): 502.1 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH2:16])=[N:6][CH:7]=1.[I:18]I>C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[NH2:16][C:11]1[CH:12]=[CH:13][C:14]([I:18])=[CH:15][C:10]=1[C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:17]
Reactant: II
Reactant: Nc1ccccc1C(=O)Nc1ccc(Cl)cn1
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: Nc1ccc(I)cc1C(=O)Nc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 32.1 %

Procedure:
To an ice cold stirring suspension of N-(5-chloropyridin-2-yl)-2-aminobenzamide (1.01 g, 4.09 mmol) in ethanol (80 mL) was added a mixture of iodine (1.04 g, 4.10 mmol) and silver sulfate (1.29 g, 4.09 mmol). The mixture was stirred at room temperature for 3 d and filtered. The filtrate was concentrated, partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by chromatography over silica gel, eluting with a step gradient of 5–10% ethyl acetate in dichloromethane. The chromatography product was slurried in isopropanol and filtered to give 0.49 g (32%) of an orange solid.
Reaction SMILES: [H][H].[C:3]([O:7][C:8]([NH:10][C@@H:11]([CH2:20]/[CH:21]=[CH:22]/[C:23]1[CH:28]=[CH:27][C:26]([C:29]2[S:30][C:31]([NH:37][C:38](=[O:40])[NH2:39])=[C:32]([C:34](=[O:36])[NH2:35])[CH:33]=2)=[CH:25][CH:24]=1)[C:12]([O:14][CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].CC(O)C.C1(C)C=CC=CC=1>[C:3]([O:7][C:8]([NH:10][C@H:11]([C:12]([O:14][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19]1)=[O:13])[CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[S:30][C:31]([NH:37][C:38](=[O:40])[NH2:39])=[C:32]([C:34](=[O:36])[NH2:35])[CH:33]=2)=[CH:27][CH:28]=1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N[C@@H](C/C=C/c1ccc(-c2cc(C(N)=O)c(NC(N)=O)s2)cc1)C(=O)OC1CCCC1
Reactant: [H][H]
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](CCCc1ccc(-c2cc(C(N)=O)c(NC(N)=O)s2)cc1)C(=O)OC1CCCC1
Reaction time: 0.08 h
Yield: 36 %

Procedure:
Hydrogen gas was bubbled through a suspension of Wilkinson's catalyst (767 mg, 0.829 mmol) in IPA (10 ml) and toluene (5 ml). After 5 minutes, a solution of cyclopentyl(2S,4E)-2-[(tert-butoxycarbonyl)amino]-5-{4-[4-carbamoyl-5-(carbamoylamino)-2-thienyl]phenyl}pent-4-enoate (300 mg, 0.553 mmol) in IPA (10 ml) was added. The mixture was kept under an atmosphere of hydrogen and placed in a preheated oil bath at 80° C. After 4 hrs the reaction was judged to be complete by LC-MS. The mixture was filtered whilst still hot and the filtrate evaporated in vacuo. The residue was subjected to column chromatography eluting with 4% MeOH in DCM. Yield=120 mg, 0.198 mmol, 36% yield. LCMS purity 90%: m/z 543 [M−H]+.
Reaction SMILES: [NH2:1][O:2][CH2:3][S:4]([C:7]1[CH:8]=[C:9]([OH:14])[C:10](=[CH:12][CH:13]=1)[OH:11])(=[O:6])=[O:5].[NH2:15][C:16]1[S:17][CH:18]=[C:19]([C:21](=O)[C:22]([NH:24][C@@H:25]2[C:32](=[O:33])[N:31]3[C@@H:26]2[S:27][CH2:28][C:29]([CH2:37][S:38][C:39]2[N:44]4[N:45]=[C:46]([C:48]([O:50][CH3:51])=[O:49])[N:47]=[C:43]4[N:42]=[C:41]([CH3:52])[CH:40]=2)=[C:30]3[C:34]([OH:36])=[O:35])=[O:23])[N:20]=1.[OH-].[Na+:55].O.CO>O.CO>[Na+:55].[NH2:15][C:16]1[S:17][CH:18]=[C:19](/[C:21](=[N:1]/[O:2][CH2:3][S:4]([C:7]2[CH:13]=[CH:12][C:10]([OH:11])=[C:9]([OH:14])[CH:8]=2)(=[O:5])=[O:6])/[C:22]([NH:24][C@@H:25]2[C:32](=[O:33])[N:31]3[C@@H:26]2[S:27][CH2:28][C:29]([CH2:37][S:38][C:39]2[N:44]4[N:45]=[C:46]([C:48]([O:50][CH3:51])=[O:49])[N:47]=[C:43]4[N:42]=[C:41]([CH3:52])[CH:40]=2)=[C:30]3[C:34]([O-:36])=[O:35])=[O:23])[N:20]=1
Reactant: COC(=O)c1nc2nc(C)cc(SCC3=C(C(=O)O)N4C(=O)[C@@H](NC(=O)C(=O)c5csc(N)n5)[C@H]4SC3)n2n1
Reactant: NOCS(=O)(=O)c1ccc(O)c(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)c1nc2nc(C)cc(SCC3=C(C(=O)[O-])N4C(=O)[C@@H](NC(=O)/C(=N\OCS(=O)(=O)c5ccc(O)c(O)c5)c5csc(N)n5)[C@H]4SC3)n2n1

Procedure:
122 mg of 4-[[(aminooxy)methyl]sulphonyl]pyrocatechol were reacted with 236 mg of (6R,7R)-7-(2-amino-4-thiazoleglyoxylamido)-3-[[[2-(methoxycarbonyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid according to the procedure described in Example 7. The crude product obtained was suspended in 10 ml of water and brought into solution by the slow addition of 0.1N sodium hydroxide solution, with care being taken that the pH of the solution did not exceed 7. By chromatography on MCI gel CHP 2OP using water as the elution agent as well as water/methanol mixtures with increasing amounts of methanol and lyophilization of the concentrated product fractions, there was obtained (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[[(3,4-dihydroxyphenyl)sulphonyl]methoxy]imino]acetamido]-3-[[(2-(methoxycarbonyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl] thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid monosodium salt as a white powder.