Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH2:15]([N:18]1[C:26](=[O:27])[C:25]2[C:20](=[N:21][C:22](SC)=[N:23][CH:24]=2)[N:19]1[C:30]1[CH:35]=[C:34]([N:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]2=[O:42])[CH:33]=[C:32]([F:43])[CH:31]=1)[CH:16]=[CH2:17]>>[CH2:15]([N:18]1[C:26](=[O:27])[C:25]2[C:20](=[N:21][C:22]([NH:12][C:11]3[CH:13]=[CH:14][C:8]([N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)=[CH:9][CH:10]=3)=[N:23][CH:24]=2)[N:19]1[C:30]1[CH:35]=[C:34]([N:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]2=[O:42])[CH:33]=[C:32]([F:43])[CH:31]=1)[CH:16]=[CH2:17]
Reactant: C=CCn1c(=O)c2cnc(SC)nc2n1-c1cc(F)cc(-n2ccccc2=O)c1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Product: C=CCn1c(=O)c2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc2n1-c1cc(F)cc(-n2ccccc2=O)c1

Procedure:
The entitled compound was obtained as a yellow solid (68.4 mg) in the same manner as in Production Example 12-2, for which, however, 4-(4-methylpiperazin-1-yl)aniline was used in place of [5-amino-2-(4-methylpiperazin-1-yl)phenyl]methanol used in Production Example 12-2, and 2-allyl-1-[3-fluoro-5-(2-oxopyridin-1(2H)-yl)phenyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one was used in place of 2-allyl-6-(methylthio)-1-pyridin-2-yl-3H-pyrazolo[3,4-d]pyrimidin-3-one.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH:26]([C:33]([O:35]C)=[O:34])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:21]([CH2:37][CH2:38][CH3:39])[CH:20]=2)[C:7](=[O:17])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[N:9]=1)[CH2:2][CH2:3][CH3:4]>C(Cl)Cl.CO>[CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH:26]([C:33]([OH:35])=[O:34])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:21]([CH2:37][CH2:38][CH3:39])[CH:20]=2)[C:7](=[O:17])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(-c2ccccc2Cl)c(=O)n1Cc1ccc(OC(C(=O)OC)c2ccccc2)c(CCC)c1
Solvent: CO
Solvent: ClCCl
Product: CCCCc1nn(-c2ccccc2Cl)c(=O)n1Cc1ccc(OC(C(=O)O)c2ccccc2)c(CCC)c1
Yield: 50 %

Procedure:
This compound was prepared from the product of Step A by the same procedure as for Example 7, Step E. After chromatographic purification, a 50% yield of the title compound was obtained, homogeneous on TLC (9:1 CH2Cl2 /MeOH).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:12]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[S:3][C:4]([C:8]([Cl:12])=[O:10])=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(C)c(C(=O)O)s1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1nc(C)c(C(=O)Cl)s1

Procedure:
9.30 g of 2,4-dimethylthiazole-5-carboxylic acid was suspended in 90 ml of toluene, and 15.0 g of phosphorus pentachloride was added. The mixture was refluxed for 1 hour. Under reduced pressure, the resulting phosphorus oxychloride and the toluene were evaporated to give 2,4-dimethylthiazole-5-carboxylic acid chloride which was used in the following reaction without purification.
Reaction SMILES: CC1[C@@H]([O:20][C:21]([C@H:23]([OH:40])[C@@H:24]([NH:31]C(C2C=CC=CC=2)=O)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])C[C@]2(O)C(C)(C)C=1[C@@H](OC(C)=O)C([C@@]1(C)[C@H]([C@@H]2OC(C2C=CC=CC=2)=O)[C@]2(OC(C)=O)CO[C@@H]2C[C@@H]1O)=O.C(N[C@@H](C1C=CC=CC=1)[C@H](C(O)=O)O)(=O)C1C=CC=CC=1.[ClH:84]>>[C:25]1([C@@H:24]([C@H:23]([C:21]([OH:22])=[O:20])[OH:40])[NH2:31])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[ClH:84]
Reactant: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Agent: Cl
Agent: O=C(N[C@@H](c1ccccc1)[C@@H](O)C(=O)O)c1ccccc1
Product: N[C@@H](c1ccccc1)[C@@H](O)C(=O)O

Procedure:
When the desired product is the side chain of taxol, N-benzoyl-(2R,3S)-3-phenylisoserine, R1 is phenyl, and R7 is preferably trimethylsilyl. In this synthesis the product of the reaction Scheme 1 is (3R,4S)-3-triisopropylsilyloxy-4-phenyl-2-azetidin-2-one (see Scheme 2), which is hydrolyzed, for example with hydrochloric acid, to yield the corresponding (2R,3S)-3-phenylisoserine as hydrochloric acid salt. The phenylisoserine is then benzoylated by procedures known in the art, for example, the Schotten-Baumann procedure, and purified, if necessary, by recrystallization or through a short silica gel column to give enantiomerically pure N-benzoyl-(2R,3S)-3-phenylisoserine (see Scheme 3).
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][CH:7]([CH2:11][N:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[C:21]([NH:23][C:24]3[N:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][N:25]=3)[CH:20]=[C:19]([CH3:34])[CH:18]=2)[CH:14]=[N:13]1)[C:8]([OH:10])=[O:9].[CH3:35]O>O>[OH:6][C@H:7]([CH2:11][N:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[C:21]([NH:23][C:24]3[N:29]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:27]=[CH:26][N:25]=3)[CH:20]=[C:19]([CH3:34])[CH:18]=2)[CH:14]=[N:13]1)[C:8]([O:10][CH3:35])=[O:9]
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnn(CC(O)C(=O)O)c2)c1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)[C@H](O)Cn1cc(-c2cc(C)cc(Nc3nccc(C(F)(F)F)n3)c2)cn1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Sulfuric acid (0.10 ml, 1.83 mmol) was added to an oven-dried vial containing 2-hydroxy-3-[4-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-pyrazol-1-yl]propanoic acid (1.78 g, 1.83 mmol) in MeOH (12.2 ml) and the solution was warmed to 70° C. and stirred for 1 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0 to 80% EtOAc/hexanes) to afford racemic methyl (2R)-2-hydroxy-3-[4-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-pyrazol-1-yl]propanoate. The racemic sample was purified by super critical fluid chiral chromatography (AD-H 2.1×25 cm, 5 μm, 45%/55% 2-propanol/CO2, 70 mL/min, 12 min. run time, 220 nM) to afford (R or S) 2-methyl-2-hydroxy-3-[4-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-pyrazol-1-yl]propanoate (early eluting enantiomer). MS ESI calcd. for C19H19F3N5O3 [M+H]+ 422. found 422.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:22][CH2:23][C@@H:24]3[O:26][CH2:25]3)=[CH:12][C:13]=2[O:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:8]=[CH:7][N:6]=1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.C(O)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:22][CH2:23][C@H:24]([OH:26])[CH2:25][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:12][C:13]=2[O:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:8]=[CH:7][N:6]=1
Reactant: COc1ccc(Cl)c(Nc2ncnc3cc(OC[C@H]4CO4)cc(OC4CCOCC4)c23)c1
Reactant: C1COCCN1
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: COc1ccc(Cl)c(Nc2ncnc3cc(OC[C@H](O)CN4CCOCC4)cc(OC4CCOCC4)c23)c1
Temperature: 45 °C

Procedure:
A mixture of 4-(2-chloro-5-methoxyanilino)-7-[(2R)-2,3-epoxypropoxy]-5-tetrahydropyran-4-yloxyquinazoline (0.08 g), morpholine (0.044 ml), ethanol (1 ml) and chloroform (1 ml) was stirred and heated to 45° C. for 16 hours. The mixture was cooled to ambient temperature and evaporated. The residue was triturated under pentane. The resultant solid was isolated, washed with diethyl ether and dried under vacuum to give the title compound (0.08 g); NMR Spectrum: (DMSOd6 and CF3CO2D) 1.9–2.05 (m, 2H), 2.15 (d, 2H), 3.1–3.45 (m, 5H), 3.45–3.6 (m, 3H), 3.7–3.9 (m, 2H), 3.8 (s, 3H), 3.9–4.1 (m, 2H), 4.22 (m, 1H), 4.45 (m, 1H), 5.15 (m, 1H), 6.95 (s, 1H), 7.02 (m, 1H), 7.15 (s, 1H), 7.5–7.6 (m, 2H), 8.9 (s, 1H); Mass Spectrum: M+H+ 545 and 547.
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]1[CH:17]=[C:18]([CH:35]=[CH:36][CH:37]=1)[CH2:19][NH:20][CH2:21][C@@:22]12[CH2:34][CH2:33][CH2:32][N:23]1[C@@H:24]([C:28]([Cl:31])([Cl:30])[Cl:29])[O:25][C:26]2=[O:27].C=O.C(O)(=O)C>ClCCCl>[F:15][C:16]1[CH:17]=[C:18]([CH:35]=[CH:36][CH:37]=1)[CH2:19][N:20]([CH2:21][C@@:22]12[CH2:34][CH2:33][CH2:32][N:23]1[C@@H:24]([C:28]([Cl:30])([Cl:31])[Cl:29])[O:25][C:26]2=[O:27])[CH3:1]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=C1O[C@H](C(Cl)(Cl)Cl)N2CCC[C@@]12CNCc1cccc(F)c1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN(Cc1cccc(F)c1)C[C@@]12CCCN1[C@@H](C(Cl)(Cl)Cl)OC2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium triacetoxyborohydride (889 mg, 4.19 mmol) was added to a mixture of (3R,7aR)-7a-[(3-fluoro-benzylamino)-methyl]-3-trichloromethyl-tetrahydro-pyrrolo[1,2-c]oxazol-1-one (Stage K.2, 400 mg, 1.048 mmol), formaldehyde (37% in H2O, 0.102 mL, 1.36 mmol) and acetic acid (0.150 mL, 2.62 mmol) in DCE (4 mL) under an argon atm. After 2 h stirring at rt the RM was partitioned between DCM and water. The combined organic layers were dried over Na2SO4 and evaporated to give the title compound as a pale brown oil which was used without further purification.
Reaction SMILES: [CH2:1]([C:3]([C:26]1[CH:31]=[CH:30][C:29]([B:32]2[O:36][C:35]([CH3:38])([CH3:37])[C:34]([CH3:40])([CH3:39])[O:33]2)=[C:28]([CH3:41])[CH:27]=1)([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2([O:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:8]([CH3:25])[CH:7]=1)[CH2:4][CH3:5])[CH3:2]>C(OCC)(=O)C.[C].[Pd]>[CH2:1]([C:3]([C:26]1[CH:31]=[CH:30][C:29]([B:32]2[O:33][C:34]([CH3:40])([CH3:39])[C:35]([CH3:37])([CH3:38])[O:36]2)=[C:28]([CH3:41])[CH:27]=1)([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]2([O:20][Si:21]([CH3:23])([CH3:24])[CH3:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:8]([CH3:25])[CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)(c1ccc(C#CC2(O[Si](C)(C)C)CCCCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCC(CC)(c1ccc(CCC2(O[Si](C)(C)C)CCCCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reaction time: 3 h
Yield: 86.6 %

Procedure:
10% palladium carbon (11.3 mg) was added to a solution of 2-(4-{1-ethyl-1-[3-methyl-4-(1-trimethylsilanyloxy-cyclohexylethynyl)-phenyl]-propyl}-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (Example 35-(4); 49.7 mg, 0.0867 mmol) in ethyl acetate (0.5 mL), and the mixture was stirred under hydrogen charging for three hours. The reaction mixture was filtered and concentrated to give the title compound (43.3 mg, 86%).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([CH3:9])[C:6]2[CH:10]=[CH:11][CH:12]=[C:13]([N:14]([CH3:16])[CH3:15])[C:5]=2[N:4]([CH2:17][C:18]([N:20]2[CH2:26][CH:25]3[CH2:27][CH2:28][CH:22]([CH2:23][CH2:24]3)[CH2:21]2)=[O:19])[C:3]1=[O:29].[C:30]1([CH3:39])[CH:35]=[CH:34][CH:33]=[C:32]([N:36]=[C:37]=[O:38])[CH:31]=1.[ClH:40]>O1CCCC1.C(OCC)(=O)C>[ClH:40].[CH:25]12[CH2:24][CH2:23][CH:22]([CH2:28][CH2:27]1)[CH2:21][N:20]([C:18]([CH2:17][N:4]1[C:5]3[C:13]([N:14]([CH3:16])[CH3:15])=[CH:12][CH:11]=[CH:10][C:6]=3[C:7]([CH3:9])=[N:8][CH:2]([NH:1][C:37]([NH:36][C:32]3[CH:33]=[CH:34][CH:35]=[C:30]([CH3:39])[CH:31]=3)=[O:38])[C:3]1=[O:29])=[O:19])[CH2:26]2
Reactant: CC1=NC(N)C(=O)N(CC(=O)N2CC3CCC(CC3)C2)c2c1cccc2N(C)C
Reactant: Cc1cccc(N=C=O)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1=NC(NC(=O)Nc2cccc(C)c2)C(=O)N(CC(=O)N2CC3CCC(CC3)C2)c2c1cccc2N(C)C
Temperature: 25 °C
Yield: 61.5 %

Procedure:
To a solution of (3RS)-3-amino-1-[(3-azabicyclo[3.2.2]non-3-yl)-carbonylmethyl]-5-methyl-9-(N,N-dimethylamino)-2,3-dihydro-1H-1,4-benzodiazepin-2-one (285 mg) in tetrahydrofuran (4 ml) was added dropwise 3-tolyl isocyanate (100 mg) under stirring at room temperature. The mixture was stirred at room temperature for 2 hours. Removal of the solvent in vacuo afforded a residue, which was triturated in diisopropyl ether and collected by filtration to give a white powder. To a solution of the powder in ethyl acetate was added 4N-hydrogen chloride in ethyl acetate (0.25 ml) under cooling. The mixture was evaporated in vacuo to dryness. The residue was washed with diisopropyl ether and collected by filtration to afford N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-5-methyl-9-(N,N-dimethylamino )-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-methylphenyl)urea hydrochloride (250 mg,61.5%) as a crystalline powder.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([CH3:12])[C:3]=1[CH3:13].[H-].[Na+].Br[CH2:17]/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=1.O>CN(C)C=O>[CH:26]([C:23]1[CH:22]=[CH:21][C:20](/[CH:19]=[CH:18]/[CH2:17][O:1][C:2]2[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([CH3:12])[C:3]=2[CH3:13])=[CH:25][CH:24]=1)([CH3:28])[CH3:27]
Reactant: Cc1cc(O)c(C)c(C)c1NC=O
Reactant: CC(C)c1ccc(/C=C/CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OC/C=C/c2ccc(C(C)C)cc2)c(C)c(C)c1NC=O
Reaction time: 0.17 h
Yield: 59.3 %

Procedure:
To a solution of N-(4-hydroxy-2,3,6-trimethylphenyl)formamide (5.20 g, 29.0 mmol) in N,N-dimethylformamide (30 ml) was added at 0° C. under a nitrogen atmosphere sodium hydride (a 60% dispersion in liquid paraffin, 1.39 g, 34.8 mmol) and the resulting mixture was stirred at the same temperature for 10 minutes. To the reaction solution was added 1-[(E)-3-bromo-1-propenyl]-4-isopropylbenzene (9.00 g, 37.7 mmol) and the resulting mixture was stirred at room temperature for 30 minutes. Water was added into the reaction solution and the product was extracted twice with ethyl acetate. The combined extracts were washed with water, dried on magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was crystallized from ethyl acetate-hexane to obtain 5.80 g (59% yield) of the title compound. Melting point: 165-167° C.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[NH:18][C:17]([C:21]2[CH:26]=[CH:25][C:24](I)=[CH:23][C:22]=2[F:28])=[N:16]1.[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]#[CH:37])[C:31]=1[F:38].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[NH:18][C:17]([C:21]2[CH:26]=[CH:25][C:24]([C:37]#[C:36][C:32]3[CH:33]=[CH:34][CH:35]=[C:30]([Cl:29])[C:31]=3[F:38])=[CH:23][C:22]=2[F:28])=[N:16]1
Reactant: C#Cc1cccc(Cl)c1F
Reactant: O=C(NCc1ccc(Cl)c(-n2nc(-c3ccc(I)cc3F)[nH]c2=O)c1)C1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: O=C(NCc1ccc(Cl)c(-n2nc(-c3ccc(C#Cc4cccc(Cl)c4F)cc3F)[nH]c2=O)c1)C1CC1
Yield: 57.3 %

Procedure:
The title compound was prepared according to the procedure described in Example-3 using N-(4-chloro-3-(3-(2-fluoro-4-iodophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)cyclopropanecarboxamide (Intermediate-48, 0.050 g, 0.097 mmol), 1-chloro-3-ethynyl-2-fluorobenzene (Intermediate-24, 0.022 g, 0.14 mmol), TBAF (0.061 g, 0.19 mmol), bis(triphenylphosphine)palladium(II) chloride (catalytic) and DMSO (1.0 mL) at 80° C. to afford 0.030 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 0.69 (m, 4H), 1.60 (m, 1H), 4.33 (d, J=5.7 Hz, 2H), 7.30-7.41 (m, 3H), 7.48-7.74 (m, 5H), 7.87-7.93 (m, 1H), 8.69 (m, 1H), 12.40-12.58 (br s, 1H); MS (m/z): 539.36 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([OH:8])[CH:7]=1.[H-].[Na+].[CH3:12][O:13][CH2:14]Cl>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([O:8][CH2:12][O:13][CH3:14])[CH:7]=1
Reactant: COCCl
Reactant: Oc1cc(Br)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1cc(Br)ccc1F
Reaction time: 0.17 h
Yield: 95.8 %

Procedure:
To a stirred solution of 5-bromo-2-fluorophenol (5 g, 26.2 mmol) in DMF (50 mL) at 0° C. was added sodium hydride (1.571 g, 39.3 mmol). After stirring for 10 min, chloromethyl methyl ether (2.386 mL, 31.4 mmol) was added dropwise to mixture and the mixture was then stirred for 1 hour at 0° C. The reaction was quenched with addition of saturated NH4Cl aq. and the mixture was poured into water (150 mL). The mixture was extracted with ethyl acetate (30 mL×2). The organic layers were combined, washed with brine (100 mL), dried over MgSO4, filtered and evaporated in vacuo. The crude residue was purified by chromatography on silica, eluting with a gradient of 0-10% ethyl acetate in cyclohexane to give the title compound (5.90 g). 1H NMR (CDCl3, 400 MHz) δ ppm: 3.55 (3H, s), 5.24 (2H, s), 6.95-7.02 (1H, m), 7.08-7.14 (1H, m), 7.36-7.40 (1H, m).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:21]=[CH:22][C:23]=1[N:24]1[CH2:28][C:27](=[O:29])[N:26](CC[Si](C)(C)C)[S:25]1(=[O:37])=[O:36])[CH2:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[C:15]#[N:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:21]=[CH:22][C:23]=1[N:24]1[CH2:28][C:27](=[O:29])[NH:26][S:25]1(=[O:37])=[O:36])[CH2:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[C:15]#[N:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(Cc3ccccc3C#N)cc2OCc2ccccc2)S1(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: N#Cc1ccccc1Cc1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 2-{3-benzyloxy-4-[1,1,4-trioxo-5-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-2-yl]-benzyl}-benzonitrile (57 mg, 0.107 mmol) in THF (10 mL) is added TBAF (0.16 mL, 1.5 equiv) and the mixture is stirred at 60° C. for 2 h. The mixture is partitioned between EtOAc and 1N HCl. The organic phase is washed with 1N HCl and brine then is dried over sodium sulfate. The solvent is removed under reduced pressure and the residue purified by column chromatography using a gradient of 0-40% EtOAc/hexane as eluent to give the title compound.
Reaction SMILES: [I-:1].C(OC([NH:9][CH:10]1[C:40](=[O:41])[N:12]2[C:13]([C:24](OC(C3C=CC=CC=3)C3C=CC=CC=3)=[O:25])=[C:14]([CH2:17][N+:18]3([CH3:23])[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:15][S:16][C@H:11]12)=O)(C)(C)C.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].C(OC(C)C)(C)C>ClCCl.C1(OC)C=CC=CC=1>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[NH2:9][CH:10]1[C:40](=[O:41])[N:12]2[C:13]([C:24]([I:1])=[O:25])=[C:14]([CH2:17][N+:18]3([CH3:23])[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:15][S:16][C@H:11]12
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C[N+]3(C)CCCC3)CS[C@H]12
Reactant: [I-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: C[N+]1(CC2=C(C(=O)I)N3C(=O)C(N)[C@H]3SC2)CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of benzhydryl 7-tert-butoxycarbonylamino-3-(1-methylpyrrolidinio)methyl-3-cephem-4-carboxylate iodide (4.42 g) in a mixture of dichloromethane (12 ml) and anisole (4.4 ml) was added trifluoroacetic acid (8.8 ml) under ice-cooling. After stirring for 30 minutes at room temperature, the reaction mixture was gradually poured into diisopropyl ether. The resultant precipitate was collected by filtration, washed with diisopropyl ether and dried over phosphorus pentoxide to give trifluoroacetic acid salt of 7-amino-3-(1-methyl-1-pyrrolidinio)methyl-3-cephem-4-carboxylic acid iodide (2.51 g).
Reaction SMILES: [CH2:1]([N:8]([CH2:42][CH:43]([O:47][CH2:48][CH3:49])[O:44][CH2:45][CH3:46])[C:9](=[O:41])[C@@H:10]([NH:23]C(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1CCCCC1>>[NH2:23][C@@H:10]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[CH:16][CH:17]=1)[C:9]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:42][CH:43]([O:47][CH2:48][CH3:49])[O:44][CH2:45][CH3:46])=[O:41]
Reactant: CCOC(CN(Cc1ccccc1)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21)OCC
Solvent: C1CCNCC1
Product: CCOC(CN(Cc1ccccc1)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1)OCC
Yield: 106.4 %

Procedure:
According to the procedure described in the synthesis method of Compound IV-1, (S)-(9H-fluoren-9-yl)methyl 1-(benzyl(2,2-diethoxyethyl)amino)-3-(4-tert-butoxyphenyl)-1-oxopropan-2-ylcarbamate (Compound III-13) (3.22 g, 4.8 mmol) was treated with piperidine and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=9:1, chloroform:methanol=100:0 and 8:2) to obtain the title compound (2.26 g, 106%).
Reaction SMILES: Cl.OC(C)(C)[CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:33])[C@@H:12]([N:17]2[CH2:21][C:20]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH2:30][CH3:31])=[CH:19][C:18]2=[O:32])[CH2:13][CH:14]([CH3:16])[CH3:15])=[N:6]1.CN1C=CC(N)=N1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH3:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:33])[C@@H:12]([N:17]2[CH2:21][C:20]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH2:30][CH3:31])=[CH:19][C:18]2=[O:32])[CH2:13][CH:14]([CH3:15])[CH3:16])=[N:6]1
Reactant: CCOc1ccccc1OC1=CC(=O)N([C@@H](CC(C)C)C(=O)Nc2ccn(CC(C)(C)O)n2)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: Cn1ccc(N)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1ccccc1OC1=CC(=O)N([C@@H](CC(C)C)C(=O)Nc2ccn(C)n2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of (S)-2-[4-(2-ethoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (prepared as in Example 81, 120 mg, 0.36 mmol) in N,N-dimethylformamide (4 mL) was treated with 1-methyl-1H-pyrazol-3-ylamine (42 mg, 0.43 mmol), benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (320 mg, 0.72 mmol) and N,N-diisopropylethylamine (100 mg, 0.80 mmol). The reaction mixture was stirred for 4 h at 25° C., under nitrogen. The reaction mixture was diluted with ethyl acetate, washed with saturated ammonium chloride, water, a saturated sodium chloride solution and dried over sodium sulfate. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g, 20% to 70% ethyl acetate/hexanes) to afford (S)-2-[4-(2-ethoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (1-methyl-1H-pyrazol-3-yl)-amide as a waxy material. This material was dissolved in diethyl ether (4 mL) and treated with hydrogen chloride in diethyl ether (1 M, 2 mL). Solvents were evaporated and the residue was triturated with diethyl ether. The resulting mixture was filtered to give (S)-2-[4-(2-ethoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (1-methyl-1H-pyrazol-3-yl)-amide hydrochloride (30 mg, 19%) as a brown solid: HR-ES-MS m/z calculated for C22H28N4O4 [M+Na]+ 435.2003, observed 435.2002; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.87 (d, J=6.6 Hz, 3H) 0.90 (d, J=6.6 Hz, 3H) 1.24 (t, J=6.9 Hz, 3H) 1.30-1.61 (m, 2H) 1.62-1.82 (m, 1H) 3.71 (s, 3H) 3.94-4.13 (m, 3H) 4.48 (d, J=18.1 Hz, 1H) 4.72 (s, 1H) 4.86 (dd, J=10.6, 4.5 Hz, 1H) 6.37 (d, J=1.2 Hz, 1H) 6.97 (t, J=7.4 Hz, 1H) 7.17 (d, J=8.2 Hz, 1H) 7.20-7.32 (m, 2H) 7.52 (s, 1H) 10.68 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:30]2[CH2:31][CH2:32][N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=3)[CH2:28][CH2:29]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: CCOC(=O)Nc1nc2cc(OC)ccc2nc1OC
Product: COc1ccc2nc(OC)c(NC(=O)N3CCN(c4ccccn4)CC3)nc2c1
Yield: 84 %

Procedure:
Ethyl N-(2,6-dimethoxyquinoxalin-3-yl)carbamate and 1-(2-pyridyl)piperazine were reacted by the same way with the example 64 to obtain the titled compound (yield, 84%).