Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11](O)=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:21][CH3:22])=[C:5]([CH3:23])[O:4][N:3]=1.O=P(Cl)(Cl)[Cl:26]>>[Cl:26][C:11]1[C:10]2[C:15](=[CH:16][C:7]([C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:23])=[C:8]([O:21][CH3:22])[CH:9]=2)[N:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18]
Reactant: COc1cc2c(O)c([N+](=O)[O-])cnc2cc1-c1c(C)noc1C
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc2c(Cl)c([N+](=O)[O-])cnc2cc1-c1c(C)noc1C
Yield: 94 %

Procedure:
A suspension of 7-(3,5-dimethyl-4-isoxazolyl)-6-(methoxy)-3-nitro-4-quinolinol (for a preparation see Intermediate 17, 5 g, 16 mmol) in POCl3 (20 ml) was refluxed overnight. After cooling, the mixture was evaporated to dryness. The resulting residue was poured over saturated aqueous Sodium hydrogen carbonate and extracted with DCM. The organic layer was washed with water, dried over Na2SO4. The solvent was evaporated under reduce pressure to give the title compound as a light brown powder (5 g, 94%). 1H NMR (300 MHz, DMSO-d6, ppm) δ: 9.27 (s, 1H), 8.15 (s, 1H), 7.73 (s, 1H), 4.05 (s, 3H), 2.36 (s, 3H), 2.16 (s, 3H).
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:18]2[C@H:21]([S:22][CH2:23][C:24]=1[CH2:25][Cl:26])[C@H:20]([NH:27][C:28](=[O:67])/[C:29](=[N:44]\[O:45][C@@H:46]([CH2:59][C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[C:47]([O:49][CH2:50][C:51]1[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=1)=[O:48])/[C:30]1[N:31]=[C:32]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[S:33][C:34]=1[Cl:35])[C:19]2=[O:68])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:77])C=1.[O-]S([O-])(=S)=O.[Na+].[Na+]>ClCCl>[CH:1]([O:14][C:15]([C:17]1[N:18]2[C@H:21]([S@:22](=[O:77])[CH2:23][C:24]=1[CH2:25][Cl:26])[C@H:20]([NH:27][C:28](=[O:67])/[C:29](=[N:44]\[O:45][C@@H:46]([CH2:59][C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[C:47]([O:49][CH2:50][C:51]1[CH:52]=[CH:53][C:54]([O:57][CH3:58])=[CH:55][CH:56]=1)=[O:48])/[C:30]1[N:31]=[C:32]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[S:33][C:34]=1[Cl:35])[C:19]2=[O:68])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(COC(=O)[C@H](CC(=O)OC(C)(C)C)O/N=C(\C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CCl)CS[C@H]23)c2nc(NC(=O)OC(C)(C)C)sc2Cl)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(COC(=O)[C@H](CC(=O)OC(C)(C)C)O/N=C(\C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CCl)C[S@@](=O)[C@H]23)c2nc(NC(=O)OC(C)(C)C)sc2Cl)cc1
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
To a solution of (S)-4-tert-butyl 1-(4-methoxybenzyl) 2-(((Z)-(2-(((6R,7R)-2-((benzhydryl oxy)carbonyl)-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-7-yl)amino)-1-(2-((tert-butoxycarbonyl)amino)-5-chlorothiazol-4-yl)-2-oxoethylidene)amino)oxy)succinate (27.5 g, 27.2 mmol) in Dichloromethane (DCM) (IL) at −40° C. was added dropwise a solution of m-CPBA (6.40 g, 28.6 mmol) in Dichloromethane (DCM) (200 mL) over 10 min. The mixture was stirred at the same temperature over 30 min. LCMS indicated completion of the reaction. The mixture was treated with 15% aq. Na2S2O3 (200 mL). The organic solution was separated and washed with 5% NaHCO3 (400 mL), brine (400 mL), dried (Na2SO4), filtered, and concentrated (temperature of the water bath should not be too high—apx. 25° C.). The residue was purified by CombiFlash automated silica gel chromatography (220 g column), eluting with EtOAc/Hexanes (0-60%) to afford (S)-4-tert-butyl 1-(4-methoxybenzyl) 2-(((Z)-(2-(((5R,6R,7R)-2-((benzhydryloxy)carbonyl)-3-(chloromethyl)-5-oxido-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-7-yl)amino)-1-(2-((tert-butoxycarbonyl)amino)-5-chlorothiazol-4-yl)-2-oxoethylidene)amino)oxy)succinate (27.5 g, 25.4 mmol, 94% yield) as a light yellow foaming solid. LCMS: (M+H)+: 1026.3
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12](O)=[O:13])=[CH:7][CH:6]=2.C(OC(Cl)=O)C.[BH4-].[Na+]>C1COCC1.O>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][OH:13])=[CH:7][CH:6]=2
Reactant: O=C(O)c1ccc2ncc(Br)cc2c1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc2ncc(Br)cc2c1
Reaction time: 0.5 h
Yield: 17.6 %

Procedure:
To a mixture of 3-bromoquinoline-6-carboxylic acid (1.32 g, 5.24 mmol) and TEA (876 uL, 6.29 mmol) in THF (30 mL) was added EtOCOCl (599 uL, 6.29 mmol) at 0° C. and stirred for 30 min. Then, a solution of NaBH4 (793 mg, 21.0 mmol) in H2O (6 mL) was added at the same temperature. The resulting reaction mixture was stirred at 0° C. for 30 min before being warmed to it and stirred overnight. THF was removed. The residue was diluted with H2O, acidified with 4 N HCl, then neutralized with NaHCO3, extracted with EtOAc, and purified by a SiO2 column (0-50% EtOAc/Hexanes, Rf=0.35 in 50% EtOAc) to afford the titled compound as a colorless oil (220 mg).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1/[CH:27]=[CH:28]/[C:29](O)=[O:30]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:21]3[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:20]=3[Cl:19])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)/C=C/c1ccc(F)cc1Cl
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)/C=C/c3ccc(F)cc3Cl)n2)o1

Procedure:
Following general procedure A followed by L, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and (E)-3-(2-chloro-4-fluoro-phenyl)-acrylic acid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([SH:11])=[CH:7][CH:6]=1)[CH3:2].[H-].[Na+].CS(O[CH2:20][CH2:21][N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([CH3:31])=[C:23]1[C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)(=O)=O>CN(C)C=O>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:20][CH2:21][N:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]([CH3:31])=[C:23]2[C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)=[CH:7][CH:6]=1)=[O:12])[CH3:2]
Reactant: Cc1c(-c2cccnc2)n(CCOS(C)(=O)=O)c2ccccc12
Reactant: CCOC(=O)c1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(SCCn2c(-c3cccnc3)c(C)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 5.9 g of p-mercaptobenzoic acid ethyl ester (prepared according to the procedure found in J. Chem. Soc., 1963, 1947-1954) in 30 ml of dimethylformamide is added dropwise to a slurry of 1.55 g of 50% sodium hydride (dispersion in mineral oil in 30 ml of dimethylformamide. This mixture is stirred at room temperature for 0.5 hour under nitrogen atmosphere. This solution is added dropwise to a solution of 9.78 g of 1-(2-methylsulfonyloxyethyl)-2-(3-pyridyl)-3-methylindole in 60 ml of dimethylformamide at -10°. This mixture is stirred at room temperature overnight and poured into 1 liter of ice-water. This is extracted several times with ether (ca 1 liter total). The ether extract is washed with water (3×200 ml), dried over MgSO4 and evaporated in vacuo yielding 1-[2-(4-ethoxycarbonylphenylthio)ethyl]-2-(3-pyridyl)-3-methylindole as an oil; NMR (CDCl3) confirms the structure.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C@@H:7]2[CH2:10][C@H:9]([C:11](OCC)=[O:12])[CH2:8]2)=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.CO.Cl>C(Cl)Cl>[F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C@@H:7]2[CH2:10][C@H:9]([CH:11]=[O:12])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@H]1C[C@@H](Oc2ccc(F)cc2)C1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Solvent: CO
Product: O=C[C@H]1C[C@@H](Oc2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.4 %

Procedure:
To a solution of ethyl cis-3-(4-fluorophenoxy)cyclobutanecarboxylate (5.07 g, 21.3 mmol) in dry methylene chloride (100 ml) cooled to -78° C. was added dropwise diisobutylaluminum hydride (23.7 ml, 22.0 mmol, 0.93M in hexane) under an argon atmosphere. After completion of addition, the mixture was stirred at the same temperature for 0.5 h. Methanol (5 ml) was carefully added to the reaction mixture at -78° C. and the whole allowed to warm to room temperature over 1 h. 2N aqueous hydrochloric acid (200 ml) was added, the whole extracted with ethyl acetate (300 ml) and the combined extracts washed with brine (200 ml). The organic layer was dried (MgSO4) and concentrated in vacuo. Chromatographic purification of the residue {SiO2, 300 g; hexane/ethyl acetate (4:1)} provided 3.20 g (78%) of title compound as a colorless oil: 1H NMR δ9.73 (d, J=2.6 Hz, 1H), 7.03-6.91 (m, 2H), 6.80-6.70 (m, 2H), 4.72-4.59 (m, 1H), 2.97-2.83 (m, 1H), 2.75-2.61 (m, 2H), 2.48-2.33 (m, 2H).
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Br[C:16]1[CH:17]=[N:18][CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1>>[CH3:23][O:22][C:20]1[CH:21]=[C:16]([N:5]2[CH2:6][C@@H:1]3[CH2:7][C@H:4]2[CH2:3][N:2]3[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:17]=[N:18][CH:19]=1
Reactant: COc1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Product: COc1cncc(N2C[C@@H]3C[C@H]2CN3C(=O)OC(C)(C)C)c1

Procedure:
tert-Butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate, prepared as described in (J. Med. Chem., (1988) 31, 1598-1611), and the product from Example 43A were coupled according to the procedure described in Example 1A to provide the title compound. MS (DCI/NH3) m/z 306 (M+H)+.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=3)[CH2:4][CH2:3]1.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(O)(=O)C>C(O)(C)C>[C:22]1([C:9]2[C:8]([N:5]3[CH2:6][CH2:7][CH:2]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:3][CH2:4]3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=3)[N:10]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC(=O)CC3)nc2c1
Solvent: CC(=O)O
Solvent: CC(C)O
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC(Nc4ccccc4)CC3)nc2c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of methyl 3-(4-oxopiperidin-1-yl)-2-phenylquinoxaline-6-carboxylate (329.7 mg, 0.91 mmol, 1.00 equiv) in isopropanol (12 mL). Then aniline (255.2 mg, 2.74 mmol, 3.00 equiv) and acetic acid (221.8 mg, 3.70 mmol, 4.00 equiv) was added dropwise with stiffing. The resulting solution was stirred for 1 h at 60° C. in an oil bath. To the above NaHB(OAc)3 (968.1 mg, 4.57 mmol, 4.57 equiv) was added at 0° C. The resulting solution was stirred for an additional 3 h at room temperature. The reaction was then quenched by the addition of water. The resulting aqueous solution was extracted with 6×20 mL of dichloromethane. The organic layers were combined and dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with DCM/MeOH (30:1). This resulted in 297.4 mg (74%) of methyl 2-phenyl-3-(4-(phenylamino)piperidin-1-yl)quinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[F:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:13][C:10]1[CH:11]=[CH:12][C:7]([F:6])=[CH:8][CH:9]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: Oc1ccc(F)cc1
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)Oc1ccc(F)cc1

Procedure:
For example: Acryloyl chloride and 4-fluorophenol react in dichloromethane in the presence of triethylamine to give 4-fluorophenyl acrylate 10 (R=4-fluorophenyl). Compound 10 is then added to a solution of 9 in ethanol and diethylamine to give 11 (R=4-fluorophenyl) after usual workup.
Reaction SMILES: [OH:1][C@H:2]1[C@H:6]([CH3:7])[CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:3]1.[N+:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)([O-:20])=[O:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:7][C@H:6]1[C@@H:2]([O:1][C:25]([C:24]2[CH:23]=[CH:22][C:21]([N+:18]([O-:20])=[O:19])=[CH:29][CH:28]=2)=[O:26])[CH2:3][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:5]1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1OC(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 8 h
Yield: 79.6 %

Procedure:
To a solution of enantiopure phenylmethyl (trans)-3-hydroxy-4-methyl-1-pyrrolidinecarboxylate (E1) (1 g, 4.25 mmol) in THF (21 mL) was added 4-nitrobenzoic acid (1.42 g, 8.5 mmol), triphenylphosphine (2.23 g, 8.5 mmol) and DIAD (1.7 mL, 8.5 mmol). The resulting solution was stirred overnight. Removal of the solvent under reduced pressure yielded the crude product which was purified by RP-HPLC yielding phenylmethyl (cis)-3-methyl-4-{[(4-nitrophenyl)carbonyl]oxy}-1-pyrrolidinecarboxylate (1.30 g, 79%). LCMS: (M+H)+: 385.0 (single unknown enantiomer).
Reaction SMILES: [H-].[Na+].[S:3]1([C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:7](=[O:8])[NH:6]1)(=[O:5])=[O:4].[C:15]([O:19][C:20](=[O:34])[C@H:21]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22][CH2:23][CH2:24]I)([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C.C1OCCOCCOCCOCCOCCOC1>[C:15]([O:19][C:20](=[O:34])[C@H:21]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22][CH2:23][CH2:24][N:6]1[C:7](=[O:8])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=2[S:3]1(=[O:4])=[O:5])([CH3:16])([CH3:17])[CH3:18]
Reactant: O=C1NS(=O)(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@H](CCCI)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](CCCN1C(=O)c2ccccc2S1(=O)=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.6 %

Procedure:
Sodium hydride (0.311 g, 7.78 mmol) was added to a solution of saccharin (1.73 g, 9.44 mmol) and 18-crown-6 (0.025 g) in 10 mL of DMF. After stirring at RT for 30 min, (2R)-(t-butyloxycarbonylamino)-5-iodopentanoic acid t-butyl ester (2.78 g, 6.96 mmol) in 10 mL of DMF was added, and the solution was stirred at RT for 30 min, then at 60° C. for 6 h. The solvent was removed under reduced pressure, and the residue was partitioned between ethyl acetate and 0.05M aqueous HCl. The organic phase was washed with water and brine, dried over MgSO4 and concentrated. The crude material was purified by silica gel chromatography (hexane/ethyl acetate=4/1˜3/1) to give the title compound (1.98 g, 63% yield): NMR (400 MHz, CDCl3) 1.44 (s, 9H), 1.46 (s, 9H), 1.68-1.96 (m, 4H), 3.81 (t, 2H, J=7.0 Hz), 4.19-4.29 (m, 1H), 5.09 (br d, 1H, J=7.9 Hz), 7.82-7.93 (m, 3H), 8.06 (d, 1H, J=7.3 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:27][CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:13](=O)[CH2:14][CH2:15][C:16]([C:18]2[S:19][C:20]([CH:23]([OH:25])[CH3:24])=[CH:21][N:22]=2)=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C([O-])(=O)C.[NH4+:38].[OH-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([C:13]2[NH:38][C:16]([C:18]3[S:19][C:20]([CH:23]([OH:25])[CH3:24])=[CH:21][N:22]=3)=[CH:15][CH:14]=2)[CH2:27][CH:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: [NH4+]
Reactant: CC(O)c1cnc(C(=O)CCC(=O)C(CC2CCOCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)s1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(O)c1cnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)[nH]2)s1
Temperature: 90 °C
Reaction time: 3 h
Yield: 29.9 %

Procedure:
A mixture of 5-[3-chloro-4-(methylsulfonyl)phenyl]-1-[5-(1-hydroxyethyl)-1,3-thiazol-2-yl]-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (0.66 g), ammonium acetate (0.50 g) and acetic acid (5 mL) was stirred at 90° C. for 3 hr. The reaction mixture was neutralized with 8M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The ethyl acetate layer was concentrated, 2M aqueous sodium hydroxide solution (1.5 mL), tetrahydrofuran (4 mL) and methanol (4 mL) were added to the residue, and the mixture was stirred with heating under reflux for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to basic silica gel column chromatography, and the title compound (0.19 g, yield 34%) was obtained as a yellow amorphous solid from a fraction eluted with ethyl acetate. MS: 495 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][NH:14][C:15]([C@@H:17]2[CH2:23][CH2:22][C@@H:21]3[CH2:24][N:18]2[C:19](=[O:30])[N:20]3[O:25][S:26]([O-:29])(=[O:28])=[O:27])=[O:16])[CH2:9]1)=O)(C)(C)C.C([N+](CCCC)(CCCC)CCCC)CCC.FC(F)(F)C(O)=O>C(Cl)Cl>[O:30]=[C:19]1[N:18]2[CH2:24][C@@H:21]([CH2:22][CH2:23][C@H:17]2[C:15]([NH:14][O:13][C@@H:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)=[O:16])[N:20]1[O:25][S:26]([OH:29])(=[O:28])=[O:27]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OS(=O)(=O)[O-])C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NO[C@@H]1CCNC1)[C@@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)O
Reaction time: 1 h

Procedure:
To a solution of N,N,N-tributylbutan-1-aminium ({[(2S,5R)-2-({[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]oxy}carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl]oxy}sulfonyl)oxidanide 6 (0.245 g, 0.35 mmol) in DCM (14 mL) was added trifluoroacetic acid (0.70 mL, 9.08 mmol) dropwise at 0° C. The reaction mixture was stirred for 1 h, then evaporated. Ether was added to the residue and the resulting white precipitate was collected by centrifugation. The solid was triturated with acetonitrile (2×) and the white solid was collected by centrifugation. The white solid was purified by HPLC on a prep-X Bridge-19×250 mm column and freeze-dried to give (2S,5R)-7-oxo-N-[(3R)-pyrrolidin-3-yloxy]-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide Compound 1 (Table 1) (0.03 g, 25%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].[N+:10]([O-])([OH:12])=[O:11]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[OH:9]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(O)c(F)c1
Solvent: ClCCl
Product: Cc1cc(F)c(O)c([N+](=O)[O-])c1
Yield: 59 %

Procedure:
To 2-fluoro-4-methylphenol (500 mg, 3.96 mmol) in dichloromethane (5 mL) at room temperature was added dropwise nitric acid 70% (0.4 mL, 4.44 mmol) [exotherm observed]. After 15 min more washed with water, dried, evaporated to give 2-fluoro-4-methyl-6-nitrophenol (400 mg, 2.337 mmol, 59.0% yield) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][NH2:25]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:25][NH:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[F:17])[N:3]=1
Reactant: NNc1ccccc1F
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: Fc1ccccc1NNc1nc(Cl)nc2c1ncn2C1CCCC1

Procedure:
2-Chloro-6-[2-fluorophenylhydrazino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 2-fluorophenylhydrazine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:64])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6C(=O)C(NC(OC(C)(C)C)=O)C6C=CC=CC=6)=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:65][O:66][C:67]([NH:69][CH:70]([C:74]1[CH:79]=[CH:78][CH:77]=[C:76]([O:80][CH3:81])[CH:75]=1)[C:71]([OH:73])=O)=[O:68]>>[CH3:1][O:2][C:3](=[O:64])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:71](=[O:73])[CH:70]([NH:69][C:67]([O:66][CH3:65])=[O:68])[C:74]6[CH:79]=[CH:78][CH:77]=[C:76]([O:80][CH3:81])[CH:75]=6)=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)O)c1cccc(OC)c1
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC(C)(C)C)c6ccccc6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1)c1cccc(OC)c1
Yield: 5 %

Procedure:
This compound was prepared using the procedure used to prepare [1-(2-{5-[6-(4-{2-[1-(2-tert-Butoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester using Methoxycarbonylamino-(3-methoxy-phenyl)-acetic acid (0.049 g, 0.206 mmol) to provide {1-[2-(5-{6-[4-(2-{1-[2-Methoxycarbonylamino-2-(3-methoxy-phenyl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (0.006 g, 5%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:15][CH:14]=[CH:13][C:10]=1C=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:29])C=1>ClCCl>[CH2:1]([O:8][C:9]1[C:16]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:15][CH:14]=[CH:13][C:10]=1[OH:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)c1cccc(C=O)c1OCc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)c1cccc(O)c1OCc1ccccc1
Reaction time: 8 h
Yield: 83.7 %

Procedure:
A solution of 2-(benzyloxy)-3-tert-butylbenzaldehyde (20 g, 74.53 mmol) in dichloromethane (400 mL) was treated with m-chloroperbenzoic acid (70%, 20 g) in 3 portions at room temperature. Stirring was continued overnight. The reaction mixture was diluted with dichloromethane (to 1 L) and washed with saturated sodium bicarbonate (2×400 mL) and water (500 mL). The organic layer was dried over sodium sulfate and filtered. The solvent was removed in a rotary evaporator. The residue was taken in methanol (375 mL), potassium hydroxide (7.5 g) was added and this mixture was stirred at room temperature overnight. The solvent was removed in a rotary evaporator. The residue was taken in water (250 mL) and made acidic with 6N hydrochloric acid. The aqueous phase was extracted with ethyl acetate (800 mL). The organic extract was washed with water (300 mL), dried over sodium sulfate and the solvent was removed in a rotary evaporator. The crude product was purified by chromatography on silica (350 g) with 5% ethyl acetate in heptane (4 L) to afford pure 7 (16 g, 84%).
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([CH2:12]OS(C3C=CC(C)=CC=3)(=O)=O)[O:7][C:6]=2[CH:5]=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[NH2:28][CH2:29][CH2:30][OH:31]>C(#N)C>[F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([CH2:12][NH:28][CH2:29][CH2:30][OH:31])[O:7][C:6]=2[CH:5]=[C:4]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3c(F)cc(S(C)(=O)=O)cc3O2)cc1
Reactant: NCCO
Solvent: CC#N
Product: CS(=O)(=O)c1cc(F)c2c(c1)OC(CNCCO)CO2

Procedure:
Preparation according to Example 42 using [5-fluoro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl-4-methylbenzenesulfonate (0.005 g, 0.012 mmol), 2-aminoethanol (0.5 ml), ACN (2.5 ml). 1H-NMR (400 MHz, MeOD): δ 7.36 (2H, m), δ 4.54 (1H, dd, J 12, 2.4), δ 4.44 (1H, m), δ 4.18 (1H, dd, J 12, 7.2), δ 3.71 (2H, t, J 5.6), δ 3.13 (3H, s), δ 2.98 (2H, m), 2.81 (2H, m) ppm (J-values are in Hz and shifts relative to solvent-peak at 3.31 ppm).