Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[CH:7][N:8]=[C:9]([Sn](CCCC)(CCCC)CCCC)[CH:10]=[C:5]2[C:4]([CH3:24])=[N:3]1.Br[C:26]1[S:27][C:28]2[C:34]([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)=[C:33]([C@H:42]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])[C:43]([O:45][CH2:46][CH3:47])=[O:44])[C:32]([CH3:53])=[CH:31][C:29]=2[N:30]=1.[Cl-].[Li+].C([SnH](CCCC)CCCC)CCC>O1CCOCC1.ClCCl.[Cu]I.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.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>[C:49]([O:48][C@@H:42]([C:33]1[C:32]([CH3:53])=[CH:31][C:29]2[N:30]=[C:26]([C:9]3[CH:10]=[C:5]4[C:4]([CH3:24])=[N:3][N:2]([CH3:1])[C:6]4=[CH:7][N:8]=3)[S:27][C:28]=2[C:34]=1[C:35]1[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=1)[C:43]([O:45][CH2:46][CH3:47])=[O:44])([CH3:50])([CH3:51])[CH3:52]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2c(C)nn(C)c2cn1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cc4c(C)nn(C)c4cn3)sc2c1-c1ccc(Cl)cc1
Temperature: 120 °C

Procedure:
A mixture of 1,3-dimethyl-5-(tributylstannyl)-1H-pyrazolo[3,4-c]pyridine (31 mg, 0.071 mmol), (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (42 mg, 0.085 mmol), copper(I) iodide (14 mg, 0.071 mmol) and lithium chloride (15 mg, 0.355 mmol) in dioxane (0.5 mL) was sparged with nitrogen for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.0008 mmol) and trans-dichlorobis(triphenylphosphine)palladium (II) (5 mg, 0.007 mmol) were added and reaction mixture was heated at 120° C. for 5 hours. Reaction mixture was cooled to rt, diluted with dichloromethane, adsorbed onto silica gel and purified by CombiFlash (0 to 70% EtOAc/Hex) to give product contaminated with tributylstannane impurity. LCMS-ESI+: calc'd for C35H35ClN5O3S: 640.2 (M+H+); Found: 640.4 (M+H+).
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][NH:7][C:8](=[O:47])[C@:9]([CH3:46])([N:20]([CH3:45])[C:21](=[O:44])[C:22]1[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30]2[CH:35]=[CH:34][C:33]([CH2:36][N:37]3[CH2:43][CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[CH:32][CH:31]=2)=[CH:24][CH:23]=1)[C:10]([NH:12][O:13]C1CCCCO1)=[O:11].[OH-].[Na+].C(=O)([O-])O.[Na+].[Cl-].[Na+]>C(OCC)(=O)C.O.O1CCOCC1>[OH:13][NH:12][C:10](=[O:11])[C@@:9]([CH3:46])([N:20]([CH3:45])[C:21](=[O:44])[C:22]1[CH:23]=[CH:24][C:25]([C:28]#[C:29][C:30]2[CH:35]=[CH:34][C:33]([CH2:36][N:37]3[CH2:43][CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[CH:32][CH:31]=2)=[CH:26][CH:27]=1)[C:8]([NH:7][CH3:6])=[O:47]
Reactant: CNC(=O)[C@@](C)(C(=O)NOC1CCCCO1)N(C)C(=O)c1ccc(C#Cc2ccc(CN3CCCOCC3)cc2)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CNC(=O)[C@@](C)(C(=O)NO)N(C)C(=O)c1ccc(C#Cc2ccc(CN3CCCOCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 66.3 %

Procedure:
A 1 mol/L sulfuric acid aqueous solution (16 mL) was added dropwise, under water cooling, to a 1,4-dioxane (6.0 mL) suspension of (2S)-N,2-dimethyl-2-[methyl(4-{[4-(1,4-oxazepan-4-ylmethyl)phenyl]ethynyl}benzoyl)amino]-N′-(tetrahydro-2H-pyran-2-yloxy)propanediamide (3.0 g) as obtained in Example 16-(2), and the mixture was stirred for 2 hours and 50 minutes at room temperature. Water and ethyl acetate were added, and the aqueous layer was isolated. The isolate was adjusted to pH 7 with 20% sodium hydroxide and a saturated aqueous solution of sodium hydrogen carbonate, and then ethyl acetate and sodium chloride were added, followed by isolating the organic layer. The extract was washed with brine, and dried over anhydrous sodium sulfate. Then, the desiccant was filtered out, and the solvent was distilled off under reduced pressure. The resulting residue was purified by OH type silica gel column chromatography (gradient elution with chloroform/acetone=100/0→60/40, followed by gradient elution with chloroform/methanol=98/2→90/10) to obtain (2S)-N-hydroxy-N′,2-dimethyl-2-[methyl(4-{[4-(1,4-oxazepan-4-ylmethyl)phenyl]ethynyl}benzoyl)amino]propanediamide (Compound 376, pale yellow solid) (1.7 g, 65%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[C:25](O)(=[O:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>ClCCl>[C:25]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:13][C:11]=3[N:12]=2)=[CH:6][CH:7]=1)(=[O:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCC(=O)O
Reactant: CCCCCCCCc1ccc2oc(-c3ccc(O)cc3)nc2c1
Solvent: ClCCl
Product: CCCCCCCCc1ccc2oc(-c3ccc(OC(=O)CCCCCC)cc3)nc2c1
Yield: 60.9 %

Procedure:
In a 30 ml round-bottom flask, 0.50 g (1.55 m mole) of 2-(4-hydroxyphenyl)-5-octylbenzooxazole, 0.22 g (1.69 m mole) of heptanoic acid and 10 ml of dichloromethane were placed, followed by adding 0.32 g (1.55 m mole) of N,N-dicyclohexylcarbodiimide and 0.04 g of 4-pyrrodinopyridine in order at room temperature under stirring, and stirring at room temperature for 85 minutes. The resultant N,N'-dicyclohexylurea was filtered off and the filtrate was dried under reduced pressure to precipitate a resultant. The resultant was purified by silica gel column chromatography (eluent: toluene) and recrystallized from acetone to obtain 0.41 g of 2-(4-heptanoyloxyphenyl)-5-octylbenzooxazole (Yield: 60.9%). ##STR81##
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4](Cl)[C:3]=1[C:13]1[C:22](=[O:23])[N:21]([CH3:24])[C:20]2[N:19]=[C:18]([NH:25][C:26]3[C:31]([N+:32]([O-])=O)=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:35])[N:17]=[CH:16][C:15]=2[N:14]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:32][C:31]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:35])[C:26]=1[NH:25][C:18]1[N:17]=[CH:16][C:15]2[N:14]=[C:13]([C:3]3[CH:4]=[C:5]([O:10][CH3:11])[CH:6]=[C:7]([O:8][CH3:9])[CH:2]=3)[C:22](=[O:23])[N:21]([CH3:24])[C:20]=2[N:19]=1
Reactant: COc1cc(OC)c(Cl)c(-c2nc3cnc(Nc4c(C)cccc4[N+](=O)[O-])nc3n(C)c2=O)c1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1cc(OC)cc(-c2nc3cnc(Nc4c(C)cccc4N)nc3n(C)c2=O)c1
Yield: 44 %

Procedure:
To a solution of 6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-methyl-2-(2-methyl-6-nitrophenylamino)pteridin-7(8H)-one (200 mg, 0.38 mmol) in ethanol (50 mL) and water (2 mL) was added iron powder (210 mg, 3.8 mmol) and ammonium chloride (450 mg, 8 mmol). The mixture was refluxed for 2 h. The solvents were evaporated, and the residue was diluted with brine and dichloromethane. The solid was filtered off, and the filtrate was extracted with dichloromethane (50 mL*6). The organic layers were combined, dried over sodium sulfate, filtered and concentrated to give the title compound (70 mg, 38%). MS (ES+) C22H20Cl2N6O3 requires: 486, 488. found: 487, 489 [M+H]+. 1H-NMR (500 MHz, CDCl3) δ ppm 8.83 (s, 1H), 7.09 (t, 1H, J=8.0 Hz), 6.74-6.71 (m, 2H), 6.65 (s, 1H), 3.94 (s, 6H), 3.85 (br. s., 2H), 3.63-3.59 (br, 3H), 2.25 (s, 3H).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](O)=[O:35])=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([O:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:33][C:34]([NH:1][N:2]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:18])=[O:35])=[CH:31][CH:32]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Product: O=C(Cc1ccc(OCc2ccccc2)cc1)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-[4-(benzyloxy)phenyl]acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.30 (dd, J=7.9, 1.2 Hz, 1H), 8.02 (d, J=1.2 Hz, 1H), 7.97-8.00 (m, 1H), 7.89-7.92 (m, 1H), 7.28-7.47 (m, 7H), 6.98-7.00 (m, 2H), 5.10 (s, 2H), 3.75-3.83 (m, 4H), 3.58-3.60 (m, 2H), 3.07-3.13 (m, 4H); MS (ESI−) M/Z 469 (M−H)−.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.[NH:16]1[CH2:20][CH2:19][C@@H:18]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[O:23])[CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[F:36][C:33]([F:34])([F:35])[C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=1)[C:26]([NH:25][CH2:24][C:22]([NH:21][C@@H:18]1[CH2:19][CH2:20][N:16]([CH:2]2[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]2)[CH2:17]1)=[O:23])=[O:37]
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCNC1
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCC(N2CC[C@@H](NC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)C2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
To a solution of the ketone of step A (0.4 g, 1.9 mmol) and the pyrrolidine intermediate obtained in step C, Example 114 (0.4 g, 1.3 mmol) in THF (15 mL) was added sodium triacetoxyborohydride (0.4 g, 1.9 mmol). The reaction was stirred at room temperature overnight and quenched by addition of aqueous NaHCO3. The resulting solution was extracted with EtOAc three times. The combined organic phase was washed with NaHCO3 and brine, dried over MgSO4 and concentrated. Flash chromatography eluting with a gradient of 0-20% MeOH/CH2Cl2 provided 300 mg of the title compound. MS calculated (M+H)+ 513, found 513.
Reaction SMILES: Br[C@@H:2]1[CH2:7][C@H:6]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:4]2([CH3:5])[C:3]1=[O:22])[C@:16]1([CH3:17])[C:11]([CH2:12][C@@H:13]([CH3:21])[CH2:14][CH2:15]1)=[CH:10][CH2:9]3.[OH-:23].[Na+].Cl>CN(C)C=O.O>[OH:23][C@@H:2]1[CH2:7][C@H:6]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:4]2([CH3:5])[C:3]1=[O:22])[C@:16]1([CH3:17])[C:11]([CH2:12][C@@H:13]([CH3:21])[CH2:14][CH2:15]1)=[CH:10][CH2:9]3
Reactant: C[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)[C@H](Br)C[C@@H]32)C1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)[C@H](O)C[C@@H]32)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.2 %

Procedure:
16α-Bromo-3β-methylandrost-5-en-17-one (1.00 g, 2.74 mmol) was dissolved in dimethylformamide (90 mL). Sodium hydroxide (165 mg, 4.1 mmol) in water (10 mL) was added and the solution stirred for 2 h. at room temperature. The solution was poured into 1% HCl (200 mL) and extracted with ethyl acetate (2×50 mL). The organic layer was washed with 5% sodium biocarbonate, water, then dried over magnesium sulfate and filtered. Evaporation gave a pale yellow solid which was chromatographed on flash silica gel and eluted with ether/hexane (10/90). Recrystallization from ether gave 0.54 g (65%) 16α-hydroxy-3β-methylandrost-5-en-17-one mp 166°-168° C.; NMR (DMSO-d6) δ5.30 (br s, 1H, H-3), 4.38 (t, 1H, 16β-H), 2.0-1.05 (m, complex), 0.98 (s, 3H, C-19 Me), 0.95 (d, J= 8 Hz, 3H, C-3 Me), 0.87 (s, 3H, C-18 Me); IR (KBr) 3440, 2900, 1735, 1445, 1365, 1010; MS 302 (M+,100), 287(24), 274(7), 259(7), 241(7), 230(72), 215(41), 159(31); Anal. Calcd for C20H30O2 : C, 79.42; H, 9.99. Found: C, 79.24; H, 10.04.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[C:10](=[N:12]O)[CH2:9][CH2:8]2.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH2:12])[CH2:9][CH2:8]2
Reactant: COc1cccc2c1C(=NO)CC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1cccc2c1C(N)CC2

Procedure:
7-Methoxy-indan-1-one oxime (5 g, 28 mmol) was suspended in 250 mL methanol. Palladium on charcoal (10%, 0.3 g) was added and the reaction was hydrogenated with a hydrogen ballon for 5 days. Palladium on charcoal was filtered off and the filtrate was evaporated. The title compound was obtained as a yellow liquid (1.89, 41%) and used without any further purification for the next step.
Reaction SMILES: O.NN.[CH3:4][S:5][C:6]1[CH:7]=[CH:8][C:9]2[N:15]3[C:16]([CH2:19][O:20][N:21]4C(=O)C5=CC=CC=C5C4=O)=[N:17][N:18]=[C:14]3[CH2:13][N:12]=[C:11]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:10]=2[CH:38]=1>C(O)C>[NH2:21][O:20][CH2:19][C:16]1[N:15]2[C:9]3[CH:8]=[CH:7][C:6]([S:5][CH3:4])=[CH:38][C:10]=3[C:11]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[N:12][CH2:13][C:14]2=[N:18][N:17]=1
Reactant: CSc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CON3C(=O)c4ccccc4C3=O)n1-2
Agent: NN
Solvent: CCO
Solvent: O
Product: CSc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CON)n1-2

Procedure:
In the manner given in Example 2, a solution of hydrazine hydrate in ethanol is reacted at 65° C. with 8-methylthio-6-phenyl-1-[(phthalimidooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine to give 1-[(aminooxy)methyl]-8-methylthio-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7].[Br:11]Br>ClCCl>[Br:11][C:8]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH:6]=[O:7]
Reactant: BrBr
Reactant: COc1cccc(C=O)c1
Solvent: ClCCl
Product: COc1ccc(Br)c(C=O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 105.2 %

Procedure:
A stirred solution of 3-methoxybenzaldehyde (27.23 g) in dichloromethane (150 mL) at 0° C. is treated with a solution of bromine (32 g) in dry dichloromethane (50 mL) over 30 minutes. The reaction mixture is stirred at room temperature for 4 hours, combined with a previous preparation carried out on the same scale, and washed with saturated sodium metabisulphite solution (400 mL), with water (400 mL), brine (400 mL) and dried over magnesium sulphate. Evaporation and recrystallisation of the residue from petroleum ether (b.p. 40-60° C.) gives 2-bromo-5-methoxybenzaldehyde (45.25 g) as a white solid, m.p. 73-74° C.
Reaction SMILES: [NH2:1][CH:2]1[C:19](=[O:20])[N:4]2[C:5]([C:16]([OH:18])=[O:17])=[C:6]([CH2:9][S:10][C:11]3[S:12][CH:13]=[N:14][N:15]=3)[CH2:7][S:8][C@H:3]12.[CH:21]([NH:23][C:24]1[S:25][CH:26]=[C:27]([C:29](=[N:33][O:34][CH2:35][CH2:36][Cl:37])[C:30](O)=[O:31])[N:28]=1)=[O:22]>>[CH:21]([NH:23][C:24]1[S:25][CH:26]=[C:27]([C:29](=[N:33][O:34][CH2:35][CH2:36][Cl:37])[C:30]([NH:1][CH:2]2[C:19](=[O:20])[N:4]3[C:5]([C:16]([OH:18])=[O:17])=[C:6]([CH2:9][S:10][C:11]4[S:12][CH:13]=[N:14][N:15]=4)[CH2:7][S:8][C@H:3]23)=[O:31])[N:28]=1)=[O:22]
Reactant: O=CNc1nc(C(=NOCCCl)C(=O)O)cs1
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12
Product: O=CNc1nc(C(=NOCCCl)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nncs4)CS[C@H]23)cs1
Yield: 73.3 %

Procedure:
7-Amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (1.8 g.) and 2-(2-formamidothiazol-4-yl)-2-(2-chloroethoxyimino)acetic acid (syn isomer, 1.4 g.) were treated in a similar manner to that of Example 24-(1) to give 7-[2-(2-formamidothiazol-4-yl)-2-(2-chloroethoxyimino)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 2.18 g.).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[NH:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=1.Br[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.[OH-].[K+].C1OCCOCCOCCOCCOCCOC1>O.CS(C)=O>[N:21]1[CH:22]=[CH:23][C:18]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[N:9]=2)=[CH:19][CH:20]=1
Reactant: Brc1ccncc1
Reactant: OCCCCCSc1nc2ccccc2[nH]1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: c1ccc2[nH]c(SCCCCCOc3ccncc3)nc2c1
Temperature: 150 °C
Yield: 31.9 %

Procedure:
0.47 g of the compound obtained in Example 13a, 0.30 g of 4-bromo-pyridine, 0.80 g of KOH and 0.20 g of 18-crown-6-ether were added to 20 ml of dimethyl sulfoxide and heated to 150° C. for 8 hours. The reaction mixture was cooled, then added with water and extracted with ethyl acetate. The extract was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate) to obtain 0.19 g of the title compound (yield: 30%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:15][C:16](=[O:33])[C@@H:17]([NH:25]C(=O)OC(C)(C)C)[CH2:18][S:19][S:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCl>[NH2:25][C@@H:17]([CH2:18][S:19][S:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:16]([NH:15][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:33]
Reactant: CC(C)(C)OC(=O)N[C@@H](CSSC(C)(C)C)C(=O)NCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)SSC[C@H](N)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.2 %

Procedure:
Trifluoroacetic acid (3 ml) was added to a solution of (R)-tert-butyl (1-(benzylamino)-3-(tert-butyldisulfanyl)-1-oxopropan-2-yl)carbamate (Compound tk92) (1.049 g, 2.63 mmol) in dichloromethane (9 ml), and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and then extracted with ethyl acetate/saturated sodium bicarbonate, and the organic layer was washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford (R)-2-amino-N-benzyl-3-(tert-butyldisulfanyl)propanamide (Compound tk93) (810 mg, 100%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[N:27]=[C:26]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)[O:25][N:24]=3)=[C:17]([Cl:36])[CH:16]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:36][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[O:21][CH2:22][C:23]1[N:27]=[C:26]([C:28]2[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)[O:25][N:24]=1)[CH2:14][C@H:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: COc1ccc(-c2nc(COc3ccc(C[C@@H]4CN(C(=O)OC(C)(C)C)CCO4)cc3Cl)no2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(-c2nc(COc3ccc(C[C@@H]4CNCCO4)cc3Cl)no2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
The solution of 0.30 g (0.6 mmol) (R)-2-{3-chloro-4-[5-(4-methoxy-phenyl)-[1,2,4]oxadiazol-3-ylmethoxy]-benzyl}-morpholine-4-carboxylic acid tert-butyl ester in 3 mL dichloromethane was cooled to 0° C. and treated with 1.5 mL (19.6 mmol) trifluoroacetic acid. The cooling bath was removed and the solution stirred at room temperature for 1 h. The volatile components were evaporated and the residue dissolved in dichloromethane and extracted with 1N aqueous sodium hydroxide solution. The organic layer was washed with brine, dried over magnesium sulfate, evaporated and dried under high vacuum to give 0.23 g (95%) of the product as colorless oil.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([N:14](C)[C:15](=O)OC(C)(C)C)[CH2:11][CH:12]=[CH2:13])(C(C)(C)C)(C)C.[ClH:23]>CO>[CH3:15][NH:14][C@@H:10]([CH2:11][CH:12]=[CH2:13])[CH2:9][OH:8].[ClH:23]
Reactant: C=CC[C@@H](CO[Si](C)(C)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: C=CC[C@@H](CO)NC
Reaction time: 2 h

Procedure:
To a solution of (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)pent-4-en-2-yl(methyl)carbamate (3.4 g, 10.3 mmol) in methanol (10 mL) was added HCl (4.0 M in 1,4-dioxane, 25 mL, 0.10 mol). The resulting solution was stirred for 2 h. The solvent was removed, and the remaining residue was dried under vacuum to give (S)-2-(methylamino)pent-4-en-1-ol as a HCl salt, which was used without further purification. LRMS (M+H+) m/z 116.2.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][C:5]2[CH:8]=[CH:9][C:10]([O:12][CH2:13][CH2:14][CH2:15][CH:16]=O)=[N:11][C:4]=2[NH:3]1.[Cl:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CCOCC>ClC(Cl)C>[Cl:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[N:26]1[CH2:31][CH2:30][N:29]([CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:10]2[CH:9]=[CH:8][C:5]3[O:6][CH2:7][C:2](=[O:1])[NH:3][C:4]=3[N:11]=2)[CH2:28][CH2:27]1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Reactant: O=CCCCOc1ccc2c(n1)NC(=O)CO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(Cl)Cl
Product: O=C1COc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)nc2N1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 62.3 %

Procedure:
To a solution of 4-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yloxy)-butyraldehyde (0.325 g, 1.37 mmol) in dichloroethane (6 mL) was added a solution of 1-(2,3-dichloro-phenyl)-piperazine (0.318 g, 1.37 mmol) in dichloroethane (3 mL) via cannula. The mixture was stirred for 20 minutes at room temperature and NaBH(OAc)3 (0.377 g, 1.78 mmol) was added. The reaction was stirred for 2.5 h and quenched with saturated NaHCO3 and water. The mixture was extracted with EtOAc and the organic layer was washed with saturated NaHCO3, water and brine, dried over Na2SO4 and concentrated. Purification by chromatography on silica gel (0–5% MeOH/CH2Cl2) gave a foam. Et2O was added and product crashed out. The precipitate was filtered and dried to give the title compound as a white solid (0.386 g, 0.854 mmol, 63%). MS: APCI: M+1: 451.1 (Exact Mass: 450.12).
Reaction SMILES: C(Cl)(=O)OC(C)C.[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]([NH:15][C:16]1([C:22]([NH:24][C@H:25]([C:29](O)=[O:30])[CH:26]([CH3:28])[CH3:27])=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:14].C(N(CC)CC)C.[BH4-].[Na+]>O1CCCC1.O.C(OCC)(=O)C>[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]([NH:15][C:16]1([C:22]([NH:24][C@H:25]([CH2:29][OH:30])[CH:26]([CH3:28])[CH3:27])=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:14]
Reactant: CC(C)[C@H](NC(=O)C1(NC(=O)c2ccco2)CCCCC1)C(=O)O
Agent: CC(C)OC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)[C@@H](CO)NC(=O)C1(NC(=O)c2ccco2)CCCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 15.8 %

Procedure:
Under an argon atmosphere, 72 mg (0.59 mmol) of isopropyl chlorocarbonate was added to a solution of 200 mg (0.59 mmol) of N-[[1-[(2-furanylcarbonyl)amino]cyclohexyl]carbonyl]-L-valine and 60 mg (0.59 mmol) of triethylamine in 2 ml of tetrahydrofuran under ice-cooling. After the mixture was stirred at 0° C. for 2 hours, the reaction solution was filtered and poured to a solution of 45 mg (1.2 mmol) of sodium borohydride in 1 ml of water, and the mixture was stirred overnight. Ethyl acetate was added to the reaction solution, and the mixture was successively washed with a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, followed by drying with sodium sulfate. After the solvent was distilled off under reduced pressure, the obtained crystal was washed with ether to obtain 30 mg (16%) of the title compound.