Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([N:35]([CH2:48][CH2:49][CH:50]([CH3:52])[CH3:51])[S:36]([C:39]1[CH:44]=[CH:43][C:42]([N+:45]([O-])=O)=[CH:41][CH:40]=1)(=[O:38])=[O:37])[CH2:4][S:5][C:6]1[CH:11]=[CH:10][NH:9][C:8](=[O:12])[C:7]=1[NH:13][C:14](=[O:34])[C@H:15]([CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH:16][C:17]([O:19][CH3:20])=[O:18].[Cl-].[NH4+]>C(O)C.C1COCC1.O.[Fe]>[NH2:45][C:42]1[CH:41]=[CH:40][C:39]([S:36]([N:35]([CH2:48][CH2:49][CH:50]([CH3:52])[CH3:51])[C@H:3]([CH2:2][OH:1])[CH2:4][S:5][C:6]2[CH:11]=[CH:10][NH:9][C:8](=[O:12])[C:7]=2[NH:13][C:14](=[O:34])[C@H:15]([CH:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:16][C:17]([O:19][CH3:20])=[O:18])(=[O:38])=[O:37])=[CH:44][CH:43]=1
Reactant: COC(=O)N[C@H](C(=O)Nc1c(SC[C@@H](CO)N(CCC(C)C)S(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc[nH]c1=O)C(c1ccccc1)c1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)N[C@H](C(=O)Nc1c(SC[C@@H](CO)N(CCC(C)C)S(=O)(=O)c2ccc(N)cc2)cc[nH]c1=O)C(c1ccccc1)c1ccccc1
Temperature: 74 °C
Reaction time: 1.5 h
Yield: 45.6 %

Procedure:
A solution of N-(4-{[(2R)-3-hydroxy-2-{(3-methylbutyl)[(4-nitrophenyl)sulfonyl]amino}propyl]sulfanyl}-2-oxo-1,2-dihydropyridin-3-yl)-Nα-(methoxycarbonyl)-β-phenyl-L-phenylalaninamide (50, 61.3 mg, 0.082 mmol) in ethanol (3 ml), THF (1.5 ml) and water (0.8 mL) was treated with saturated solution of ammonium chloride (298 mg, 5.57 mmol) in water (0.8 mL) followed by addition of powdered iron (80 mg, 1.433 mmol). The mixture was degassed and stirred under N2 at external temperature of 74° C. for 90 min. Diluted with DCM, washed with saturated NaHCO3, dried over MgSO4, filtered and concentrated. Purification performed in a column of silicagel eluted with 5% to 35% MeOH in DCM to afford the title compound (27 mg, 45% yield) as pale yellow foam. MS: m/z=722.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:9][NH2:10])=[CH:6][C:7]=1[CH3:8].[CH:11](O)=O>>[CH3:8][C:7]1[C:2]([Cl:1])=[N:3][N:4]2[CH:11]=[N:10][N:9]=[C:5]2[CH:6]=1
Reactant: O=CO
Reactant: Cc1cc(NN)nnc1Cl
Product: Cc1cc2nncn2nc1Cl

Procedure:
13.4 Grams (0.0845 mole) of 3-chloro-4-methyl-6-hydrazinopyridazine are dissolved in 100 milliliters of aqueous 88 percent formic acid. The mixture is heated at the boiling temperature under reflux for 2 hours. The mixture is evaporated under reduced pressure and the 7-methyl-6-chloro-s-triazolo[4,3-b]pyridazine intermediate product is obtained as a residue. The residue is triturated with diethyl ether, and found to melt at a temperature of 157.5°-158° C.
Reaction SMILES: O/[CH:2]=[C:3]1\[C:4](=[O:13])[NH:5][C:6]2[C:11]\1=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2.O/C=C1\C(=O)NC2C\1=CC=CC=2.[C:26]1([C:32]2[NH:36][N:35]=[C:34]([NH2:37])[CH:33]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.NC1C=CNN=1.C1(NC2C=CNN=2)C=CC=CC=1>O1CCCC1>[F:12][C:8]1[CH:7]=[C:6]2[C:11]([C:3](=[CH:2][NH:37][C:34]3[CH:33]=[C:32]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[NH:36][N:35]=3)[C:4](=[O:13])[NH:5]2)=[CH:10][CH:9]=1
Reactant: O=C1Nc2cc(F)ccc2/C1=C/O
Reactant: Nc1cc(-c2ccccc2)[nH]n1
Agent: Nc1cc[nH]n1
Agent: O=C1Nc2ccccc2/C1=C/O
Agent: c1ccc(Nc2cc[nH]n2)cc1
Solvent: C1CCOC1
Product: O=C1Nc2cc(F)ccc2C1=CNc1cc(-c2ccccc2)[nH]n1

Procedure:
The named compound is prepared by substituting E & Z-3-[(hydroxy)-methylene]-6-fluoro-1,3-dihydro-indol-2-one for E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one and 5-phenyl-1H-pyrazol-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-6-fluoro-1,3-dihydro-indol-2-one (0.033 gms.) is reacted with 0.065 gms. 5.-phenyl-1H-pyrazol-3-ylamine by refluxing in tetrahydrofuran (0.88 mL) to afford the named compound in the amount of 0.0417 gms.
Reaction SMILES: OC(C)(C)C[C:4]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:9][C:8](=[O:10])[N:7](C(C2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)(C)C)[CH2:6][CH2:5]1.C(=O)([O-])[O-].[Na+].[Na+].O.I[C:45]1[CH:50]=[CH:49][N:48]([CH3:51])[C:47](=[O:52])[CH:46]=1>C1(C)C=CC=CC=1.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:51][N:48]1[CH:49]=[CH:50][CH:45]([CH:6]2[CH2:5][CH:4]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[O:9][C:8](=[O:10])[NH:7]2)[CH2:46][C:47]1=[O:52]
Reactant: CC(C)(O)CC1(c2ccccc2)CCN(C(C)(C)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C(=O)O1
Reactant: Cn1ccc(I)cc1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CN1C=CC(C2CC(c3ccccc3)OC(=O)N2)CC1=O
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 60.8 %

Procedure:
To a solution of 6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-yl)-1,3-oxazinan-2-one (30 mg, 60.9 μmol) in toluene (3 mL) was added a solution of sodium carbonate (64.5 mg, 609 μmol) in EtOH (2 mL)/water (1 mL), 4-iodo-1-methylpyridin-2(1H)-one (14.5 mg, 609 μmol) and Pd(PPh3)4 (7.5 mg, 6 μmol) successively under nitrogen. The mixture was stirred at 100° C. for 2.5 h. The reaction mixture was concentrated under vacuum. The residue was dissolved in water, extracted with EtOAc (5 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum. The crude product was purified by HPLC to afford 6-(2_hydroxy-2-methylpropyl)-3-(2-(4-(1-methyl-2-oxo-dihydropyridin-4-yl)-6-phenyl-1,3-oxazinan-2-one (10.6 mg, 37%). 1H NMR (CDCl3) δ 7.40-7.19 (m, 8H), 7.09-7.06 (m, 2H), 6.73 (s, 1H), 6.38-6.36 (d, 1H), 3.51 (s, 3H), 3.27-3.24 (m, 1H), 2.85-2.76 (m, 1H), 2.34-2.21 (m, 2H), 2.16 (s, 2H), 1.65-1.53 (d, 3H), 1.45 (s, 3H), 1.08 (s, 3H), 0.96 (s, 3H); LC-MS Method 2 tR=1.05 min, m/z=475.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([C@@H:12]1[CH2:17][C@@H:16]2[C@@H:14]([CH2:15]2)[NH:13]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:18]([C:21]1[C:29]2[C:24](=[CH:25][N:26]=[CH:27][CH:28]=2)[N:23]([CH2:30][C:31](O)=[O:32])[N:22]=1)(=[O:20])[CH3:19].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:2]([O:9][C:10]([C@@H:12]1[CH2:17][C@@H:16]2[C@@H:14]([CH2:15]2)[N:13]1[C:31](=[O:32])[CH2:30][N:23]1[C:24]2=[CH:25][N:26]=[CH:27][CH:28]=[C:29]2[C:21]([C:18](=[O:20])[CH3:19])=[N:22]1)=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)c1nn(CC(=O)O)c2cnccc12
Reactant: O=C(OCc1ccccc1)[C@@H]1C[C@H]2C[C@H]2N1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)c1nn(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)OCc2ccccc2)c2cnccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (1R,3S,5R)-2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid benzyl ester hydrochloride (2.98 g, 9.06 mmol), (3-acetyl-pyrazolo[3,4-c]pyridin-1-yl)-acetic acid (prepared as described in Part A, 3.2 g, 9.06 mmol) and HBTU (5.15 g, 13.59 mmol) in DMF (30.2 mL) was added DIPEA (4.75 mL, 27.2 mmol). The reaction mixture was stirred for 16 h at RT under a nitrogen atmosphere. DMF was evaporated. The residue was diluted in EtOAc and washed with aq. HCl 1N then with NaHCO3 (5% in water). The organic layer was dried (Phase separator) and concentrated. The residual oil was purified by flash column chromatography on silica gel (c-hexane/EtOAc 10:0 to 0:10) to give the title compound. TLC, Rf (EtOAc)=0.33; MS (UPLC-MS): 419 [M+H]+; tR (HPLC conditions d): 2.97 min.
Reaction SMILES: [F:1][CH:2]([F:61])[O:3][N:4]=[C:5]([C:36]1[N:37]=[C:38]([NH:41][C:42]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[S:39][CH:40]=1)[C:6]([NH:8][C@@H:9]1[C:34](=[O:35])[N:11]2[C:12]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:13]([CH2:16][Cl:17])[CH2:14][S:15][C@H:10]12)=[O:7].[CH3:62][N:63]1[CH:67]=[CH:66][CH:65]=[N:64]1.[I-].[Na+]>CC(C)=O>[Cl-:17].[F:1][CH:2]([F:61])[O:3][N:4]=[C:5]([C:36]1[N:37]=[C:38]([NH:41][C:42]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[S:39][CH:40]=1)[C:6]([NH:8][C@@H:9]1[C:34](=[O:35])[N:11]2[C:12]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:13]([CH2:16][N+:64]3[N:63]([CH3:62])[CH:67]=[CH:66][CH:65]=3)[CH2:14][S:15][C@H:10]12)=[O:7]
Reactant: O=C(N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)C(=NOC(F)F)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: Cn1cccn1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cn1ccc[n+]1CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)C(=NOC(F)F)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 19 h
Yield: 83.5 %

Procedure:
A mixture of benzhydryl 7β-[2-difluoromethoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-chloromethyl-3-cephem-4-carboxylate (syn isomer, 8.76 g), N-methylpyrazole (8.76 g), sodium iodide (1.5 g) and acetone (9 ml) was stirred at ambient temperature for 19 hours The reaction mixture was evaporated, and ethyl acetate (200 ml) and 5% aqueous solution of sodium thiosulfate were added to the residue. The organic layer was separated and tetrahydrofuran (100 ml) was added thereto. The solution was dried over magnesium sulfate and evaporated and the residue was dissolved in a mixture of tetrahydrofuran (200 ml) and water (65 ml). The solution was subjected to column chromatography on an ion-exchange resin "Amberlite IRA-400" (Cl⃝ form), and eluted with a mixture of tetrahydrofuran and water (15:1 V/V). The fractions containing the object compound were collected, combined and evaporated. The residue was triturated with diisopropyl ether to give benzhydryl 7β-[2-difluoromethoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-(2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate chloride (syn isomer, 8.0 g).
Reaction SMILES: C(OC([N:8]1[C@H:12]([CH2:13][F:14])[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][C:24]([CH2:27][N:28]([CH3:30])[CH3:29])=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)[O:10]C1(C)C)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][C@H:12]([CH2:13][F:14])[C@H:11]([C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:22]=[N:23][C:24]([CH2:27][N:28]([CH3:29])[CH3:30])=[CH:25][CH:26]=2)=[CH:19][CH:20]=1)[OH:10]
Reactant: CN(C)Cc1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]3CF)cc2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)Cc1ccc(-c2ccc([C@H](O)[C@H](N)CF)cc2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 109.9 %

Procedure:
To a stirred solution of (4S,5R)-5-[4-(6-Dimethylaminomethyl-pyridin-3-yl)-phenyl]-4-fluoromethyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (80 mg, 0.180 mmol) in CH2Cl2 (0.32 mL) is added trifluoroacetic acid (0.32 mL). Reaction mixture allowed to warm to room temperature and stirred for 2 hours. The volatiles are removed under reduced pressure to obtain crude material purified by column chromatography eluting in 40% methanol in CH2Cl2 to afford the title compound (60 mg). LC-MS (m/z): [M+H]=304.1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2([CH2:15]O)[CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:41]I>ClCCl>[Cl:1][C:2]1[C:3]([C:12]2([CH2:15][I:41])[CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: OCC1(c2ncc(C(F)(F)F)cc2Cl)CC1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)c1cnc(C2(CI)CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
500 mg of [1-[3-chloro-5-(trifluoromethyl)-2-pyridyl]cyclopropyl]methanol (step 2) was dissolved in 20 ml dichloromethane and the solution was cooled in an ice bath. Then 560 mg triphenylphosphine and 150 mg imidazole were added. When a clear solution had formed, 550 mg iodine was added in portions. The reaction was stirred at ambient temperature overnight. The mixture was diluted with dichloromethane, washed with a saturated solution of sodium thiosulfate and the organic phase was concentrated. The residue was triturated with 30 ml of hexane. The solid was removed by filtration and the filtrate was concentrated. The residue was purified on 20 g of silica gel, eluent hexane/ethyl acetate (20:1). Thus, 610 mg of 3-chloro-2-[1-(iodomethyl)cyclopropyl]-5-(trifluoromethyl)pyridine was obtained as a pale yellow oil. 1H-NMR (CDCl3): 8.76 ppm (s, 1H), 7.93 ppm (s, 1H), 3.61 ppm (s, 2H), 1.49 ppm (m, 2H), 1.17 ppm (m, 2H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:15]([CH3:16])=[CH:14][S:13][CH:12]=1)[OH:4].[NH2:19][C:20]1[N:25]=[C:24](Cl)[CH:23]=[C:22]([Cl:27])[N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C(OCC)(=O)C>[Cl:27][C:22]1[CH:23]=[C:24]([O:4][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:11]2[C:15]([CH3:16])=[CH:14][S:13][CH:12]=2)[C:2]([F:1])([F:17])[F:18])[N:25]=[C:20]([NH2:19])[N:21]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: Cc1cscc1-c1ccccc1C(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cscc1-c1ccccc1C(Oc1cc(Cl)nc(N)n1)C(F)(F)F
Temperature: 110 °C
Yield: 75.8 %

Procedure:
A mixture of 2,2,2-trifluoro-1-[2-(4-methyl-thiophen-3-yl)-phenyl]-ethanol (100 mg, 0.37 mmol), 2-amino-4,6-dichloro-pyrimidine (54 mg, 0.33 mmol), cesium carbonate (481 mg, 1.48 mmol) and 1,4-dioxane (1 ml) was heated at 110° C. overnight. The reaction mixture was cooled to room temperature; 10 ml of ethyl acetate was added. The mixture was then filtered through Celite, the filtrate was concentrated to give 100 mg of 4-chloro-6-{2,2,2-trifluoro-1-[2-(4-methyl-thiophen-3-yl)-phenyl]-ethoxy}-pyrimidin-2-ylamine, yield: 76%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[O:7][C:8]([CH3:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10].C(N(C(C)C)CC)(C)C.Cl[C:29]1[O:30][C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[N:33]=1.C(OCC)(=O)C>O1CCCC1>[O:30]1[C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[N:33]=[C:29]1[NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[O:7][C:8]([CH3:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: Clc1nc2ccccc2o1
Reactant: CCOC(=O)C(C)(C)Oc1cccc(CCN)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C)(C)Oc1cccc(CCNc2nc3ccccc3o2)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Ethyl 2-[3-(2-aminoethyl)phenoxy]-2-methylpropionate (1.1 g, 4.38 mmol) was dissolved in tetrahydrofuran (22 mL). Subsequently, diisopropylethylamine (1.14 mL, 6.57 mmol) and then 2-chlorobenzoxazole (611 mL, 5.26 mmol) were added thereto, and the mixture was stirred under argon atmosphere for 14 hours at room temperature. Ethyl acetate was added to the reaction mixture. Washing was performed sequentially with water and saturated brine, followed by drying over sodium sulfate. Thereafter, the reaction mixture was subjected to filtration, concentration under reduced pressure, and purification by silica gel column chromatography (n-hexane/ethyl acetate=10/1), whereby the target compound was obtained (900 mg, 2.44 mmol, 55.8%).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([NH:28]CCCNC(=O)CCNC(=O)CCNC(=O)CCCCCNC4C=CC([N+]([O-])=O)=CC=4[N+]([O-])=O)[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].Br[CH2:64][CH2:65][CH2:66][CH2:67][C:68]([O:70][CH2:71][CH3:72])=[O:69].C([O-])([O-])=O.[K+].[K+].CC(OC(O[C:87]([O:89][C:90]([CH3:93])([CH3:92])[CH3:91])=[O:88])=O)(C)C.CCN(C(C)C)C(C)C>CN(C=O)C>[C:90]([O:89][C:87]([N:28]([C@H:18]1[CH2:19][CH2:20][C@@:21]2([CH3:22])[C:16](=[CH:15][CH2:14][C@@H:13]3[C@@H:23]2[CH2:24][CH2:25][C@@:26]2([CH3:27])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C@H:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:2]([CH3:3])[CH3:1])[CH2:17]1)[CH2:64][CH2:65][CH2:66][CH2:67][C:68]([O:70][CH2:71][CH3:72])=[O:69])=[O:88])([CH3:91])([CH3:92])[CH3:93]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CCOC(=O)CCCCBr
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](NCCCNC(=O)CCNC(=O)CCNC(=O)CCCCCNc5ccc([N+](=O)[O-])cc5[N+](=O)[O-])CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCCN(C(=O)OC(C)(C)C)[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]32)C1
Temperature: 60 °C
Reaction time: 24 h
Yield: 67.9 %

Procedure:
To DMF (10 mL) was added 3β-amino-5-cholestene (2, 386 mg, 1.0 mmol),1 ethyl 5-bromovalerate (174 μL, 1.1 mmol) and K2CO3 (276 mg, 2.0 mmol). The solution was heated to 60° C. and stirred for 24 h. The reaction was cooled to 23° C. and DMF was removed in vacuo. To the resulting solid residue was added CH2Cl2 (10 mL), insoluble salts were removed by filtration, and solids were washed with additional CH2Cl2 (5 mL). To this solution containing the crude secondary amine product was added (Boc)2O (327 mg, 1.5 mmol) and DIEA (0.5 mL, 3.0 mmol). The reaction was stirred for 3 h at 23° C. and concentrated in vacuo. Flash column chromatography (hexanes/ethyl acetate, 10:1) afforded 3 (417 mg, 68%) as a white solid, mp 78-79° C.; 1H NMR (400 MHz, CDCl3) δ 5.30 (d, 1H), 4.10 (q, J=7.1 Hz, 2H), 3.73 (br s, 1H), 3.09 (br s, 2H), 2.30 (t, J=7.1 Hz, 2H), 2.01-0.83 (m, 56H), 0.66 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 173.6, 155.5, 141.3, 121.4, 79.3, 60.4, 56.9, 56.3 (×2), 50.3, 42.6 (×2), 39.9, 39.7, 38.6, 37.1, 36.8, 36.3, 35.9, 34.2, 32.0 (×2), 28.7 (Boc Me3), 28.4, 28.1 (×2), 26.9, 24.4, 24.0, 23.0, 22.7, 22.6, 21.2, 19.6, 18.9, 14.4, 12.0; IR (film) ν max 2935, 2867, 1737, 1692, 1466, 1409, 1365, 1247, 1173 cm−1; CI m/z 614.5146 (MH+, C39H68NO4 requires 614.5148).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][NH:10][CH3:11])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:12][O:13][C:14]([C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([OH:21])=O)=[O:15].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]([CH3:11])[C:19]([C:18]2[CH:17]=[C:16]([CH:24]=[CH:23][CH:22]=2)[C:14]([O:13][CH3:12])=[O:15])=[O:21])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)c1cccc(C(=O)O)c1
Reactant: CNCc1ccc(F)c(Br)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(C(=O)N(C)Cc2ccc(F)c(Br)c2)c1
Temperature: 25 °C
Reaction time: 65 h
Yield: 67.6 %

Procedure:
To a solution of [(3-bromo-4-fluorophenyl)methyl]methylamine (0.355 g, 1.63 mmol) in THF (16 mL) was added 3-[(methyloxy)carbonyl]benzoic acid (0.294 g, 1.63 mmol), HBTU (0.929 g, 2.45 mmol), Et3N (0.458 mL, 3.26 mmol) and stirred at room temperature for 65 h, and then quenched with H2O. The organic layer was loaded onto silica gel cartridge and purified by CombiFlash chromatograph to afford the title compound 0.419 g (68%). LC-MS m/z 380 (M+H)+.
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:33]=[CH:32][C:10]([O:11][C:12]3[CH:13]=[C:14]([C:24]4[NH:28][C:27]([C:29](O)=[O:30])=[CH:26][CH:25]=4)[CH:15]=[C:16]([O:18][C@@H:19]([CH3:23])[CH2:20][O:21][CH3:22])[CH:17]=3)=[C:9]([F:34])[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[C:35]([NH:38][NH2:39])(=[O:37])[CH3:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl>[C:35]([NH:38][NH:39][C:29]([C:27]1[NH:28][C:24]([C:14]2[CH:15]=[C:16]([O:18][C@@H:19]([CH3:23])[CH2:20][O:21][CH3:22])[CH:17]=[C:12]([O:11][C:10]3[CH:32]=[CH:33][C:7]([C:5]([N:1]4[CH2:2][CH2:3][CH2:4]4)=[O:6])=[CH:8][C:9]=3[F:34])[CH:13]=2)=[CH:25][CH:26]=1)=[O:30])(=[O:37])[CH3:36]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2F)cc(-c2ccc(C(=O)O)[nH]2)c1
Reactant: CC(=O)NN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2F)cc(-c2ccc(C(=O)NNC(C)=O)[nH]2)c1
Reaction time: 1 h
Yield: 61.4 %

Procedure:
5-{3-[4-(Azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrole-2-carboxylic acid (126 mg, 0.27 mmol) synthesized in Example (66g) and acetohydrazide (40 mg, 0.54 mmol) were dissolved in dichloromethane (5 mL), and HATU (153 mg, 0.40 mmol) and N,N-diisopropylethylamine (70 μL, 0.40 mmol) were added at room temperature, followed by stirring under nitrogen atmosphere for 1 hour. The reaction solution was diluted with dichloromethane (60 mL), washed with 1N hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/dichloromethane=5%) to afford the desired product (87 mg, yield 62%) as a white solid.
Reaction SMILES: [Na+].[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][C:12]([NH:14][CH:15]3[C:22](=[O:23])[N:21]4[CH:16]3[S:17][CH2:18][C:19]([CH2:27][S:28][C:29]3[N:33]([CH3:34])[N:32]=[N:31][N:30]=3)=[C:20]4[C:24]([O-:26])=[O:25])=[O:13])=[CH:10][C:5]=2[CH2:4][CH2:3]1.ClCO[C:38](=[O:51])[C@H:39]([CH:48]([CH3:50])[CH3:49])[NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42].[CH3:52]N(C)C=O>C(OCC)(=O)C>[C:44]([O:43][C:41]([NH:40][CH:39]([CH:48]([CH3:49])[CH3:50])[C:38]([CH2:52][O:25][C:24]([C:20]1[N:21]2[CH:16]([S:17][CH2:18][C:19]=1[CH2:27][S:28][C:29]1[N:33]([CH3:34])[N:32]=[N:31][N:30]=1)[CH:15]([NH:14][C:12](=[O:13])[CH2:11][C:9]1[CH:8]=[CH:7][C:6]3[O:2][CH2:3][CH2:4][C:5]=3[CH:10]=1)[C:22]2=[O:23])=[O:26])=[O:51])=[O:42])([CH3:45])([CH3:46])[CH3:47]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCCl
Reactant: CN(C)C=O
Reactant: Cn1nnnc1SCC1=C(C(=O)[O-])N2C(=O)C(NC(=O)Cc3ccc4c(c3)CCO4)C2SC1
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)C(NC(=O)OC(C)(C)C)C(=O)COC(=O)C1=C(CSc2nnnn2C)CSC2C(NC(=O)Cc3ccc4c(c3)CCO4)C(=O)N12
Reaction time: 72 h

Procedure:
A suspension of 50 mmole of 7-[[(2,3-dihydro-5-benzofuranyl)acetyl]amino]-3-[[(1-methyltetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt and 50 mmole of N-tert-butoxycarbonyl-L-valine chloromethyl ester, prepared by the procedure described in W. German Offen. No. 2,236,620, are mixed in 100 ml of dimethylformamide and stirred for about 72 hours. The mixture is diluted with ethyl acetate, washed with water, with aqueous sodium bicarbonate, and with water a second time. The organic layer is dried over magnesium sulfate, filtered and evaporated to give 7-[[(2,3-dihydro-5-benzofuranyl)acetyl]amino]-3-[[(1-methyltetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid N-tert-butoxycarbonyl-2-amino-3-methylbutyrylmethyl ester from which the amine protecting group is removed by standard procedures to give the title compound.