Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1.[C:16](OC=C)(=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1.[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([O:15][C:16](=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: C=COC(=O)CCCCC
Agent: CCOC(=O)CC(O)c1cccc(Cl)c1
Product: CCCCCC(=O)OC(CC(=O)OCC)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 312 h

Procedure:
The mixture of 5.0 g of ethyl 3-(3-chlorophenyl)-3-hydroxypropionate, 1.6 g of vinyl caproate and 2.0 g of lipase PS was stirred at room temperature for 13 days. After the lipase was removed by filtration, the filtrate was eluted by column chromatography (eluting solution; 9/1 of toluene/ethyl acetate) to obtain 2.34 g (40%ee) of (-)-ethyl 3-(3-chlorophenyl)-3-hydroxypropionate and 2.75 g (>90%ee) of (+)-ethyl 3-(3-chlorophenyl)-3-caproyloxypropionate.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([NH:10][CH2:11][CH2:12][C:13](OCC)=O)=[O:9])=[CH:6][C:5]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[N:4][NH:3]1.O=[C:25]1[C:30](C(O)=O)=[CH:29]C(C2C=CN=CC=2)=N[NH:26]1.ON1C2C=CC=CC=2N=N1.NCC1C=NC=CC=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[O:1]=[C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:13]=[N:26][CH:25]=[CH:30][CH:29]=2)=[O:9])=[CH:6][C:5]([C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)=[N:4][NH:3]1
Reactant: O=C(O)c1cc(-c2ccncc2)n[nH]c1=O
Reactant: CCOC(=O)CCNC(=O)c1cc(-c2ccncc2)n[nH]c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NCc1cccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCc1cccnc1)c1cc(-c2ccncc2)n[nH]c1=O

Procedure:
Working as in example 13 for the preparation of ethyl 3-[(3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carbonyl)amino]propionate, but starting with 0.3 g of 3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carboxylic acid, 30 cm3 of N,N-dimethylformamide, 0.233 g of 1-hydroxybenzotriazole, 0.18 cm3 of 3-(aminomethyl)pyridine, 0.31 cm3 of N,N-diisopropylethylamine and 0.65 g of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, 0.046 g of 3-oxo-6-pyridin-4-yl-N-(pyridin-3-ylmethyl)-2,3-dihydropyridazine-4-carboxamide was obtained in the form of a yellow solid melting at 262° C.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].CCN(CC)CC.[CH:22]1[CH:27]=CC=C[CH:23]=1>[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>[CH3:14][O:13][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([C:23]#[C:22][CH3:27])[C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6]
Reactant: COc1cc(C(=O)O)cc(I)c1OC
Reactant: c1ccccc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC#Cc1cc(C(=O)O)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution of 3-iodo-4,5-dimethoxybenzoic acid (12.32 g, 40.0 mmol) in mixture of Et3N (80 mL) and benzene (80 mL) at room temperature was added CuI (760 mg, 4 mmol) followed by Pd(PPh3)4 (924 mg, 0.8 mmol, 0.02 eq.). After stirring for 2 days under propyne atmosphere (balloon) at room temperature, the solvent was removed, the residue was suspended in 1N HCl aqueous solution (300 mL) and then extracted with EtOAc (3×100 mL). The combined organic layer wash washed with brine (300 mL), dried over Na2SO4 and then concentrated in vacuo to give 3,4-dimethoxy-5-prop-1-ynylbenzoic acid (9.7 g). The product was used without further purification.
Reaction SMILES: C(OC(=O)C1C=CC(N[C:12](=[O:38])[CH:13]([N:20]2[C:24]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=CC=1)C.ClC1C=CC(C2N(C(C3CCCCC3)C(O)=O)C3C=C(F)C(F)=CC=3N=2)=CC=1.[CH3:68][O:69][C:70](=[O:80])[C:71]1[CH:76]=[C:75]([F:77])[C:74]([NH2:78])=[C:73]([F:79])[CH:72]=1>N1C=CC=CC=1>[CH3:68][O:69][C:70](=[O:80])[C:71]1[CH:72]=[C:73]([F:79])[C:74]([NH:78][C:12](=[O:38])[CH:13]([N:20]2[C:24]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=2)[CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[C:75]([F:77])[CH:76]=1
Reactant: CCOC(=O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Reactant: COC(=O)c1cc(F)c(N)c(F)c1
Agent: O=C(O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Solvent: c1ccncc1
Product: COC(=O)c1cc(F)c(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(F)c1

Procedure:
This compound was prepared in analogy to example 20, intermediate d, from [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid, 4-amino-3,5-difluoro-benzoic acid methyl ester and using pyridine as a base.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:10]=[C:4]2[N:3]=1.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O>>[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:8]2[N:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[N:3][C:4]3=[N:10][CH:9]=2)[CH:12]=1
Reactant: Cc1ccn2c(-c3cccc(OS(=O)(=O)C(F)(F)F)c3)cnc2n1
Reactant: OB(O)c1ccccc1F
Product: Cc1ccn2c(-c3cccc(-c4ccccc4F)c3)cnc2n1
Yield: 122.4 %

Procedure:
Trifluoromethanesulfonic acid 3-(7-methylimidazo[1,2-a]pyrimidin-3-yl)phenyl ester (0.1 g, 0.28 mmol) was coupled to 2-fluorobenzene-boronic acid (52 μl, 0.59 mmol) as described in Example 21 to give 3-(2′-fluorobiphenyl-3-yl)-7-methylimidazo[1,2-a]pyrimidine as a white solid (104 mg): δH (400 MHz, CDCl3) 2.67 (3H, s), 6.78 (1H, d, J 7), 7.17-7.28 (2H, m), 7.37 (1H, m), 7.46-7.54 (2H, m), 7.60 (2H, m), 7.71 (1H, s), 7.85 (1H, s), 8.56 (1H,: d, J 7); m/z (ES+) 304 (M++H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][CH2:9][CH3:10])[N:5]=[C:4]([CH2:17][CH2:18][CH3:19])[C:3]=1[C:20]([NH2:22])=[O:21].[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([S:30]([CH:33]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:34](OC)=O)(=[O:32])=[O:31])[CH2:26][CH2:25]1.CC(C)([O-])C.[K+].C(=O)([O-])O.[Na+]>ClCCl>[CH3:23][N:24]1[CH2:25][CH2:26][N:27]([S:30]([CH:33]([C:34]2[NH:22][C:20](=[O:21])[C:3]3[C:4]([CH2:17][CH2:18][CH3:19])=[N:5][N:6]([CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][CH2:9][CH3:10])[C:2]=3[N:1]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)(=[O:32])=[O:31])[CH2:28][CH2:29]1
Reactant: CCCCCCC(CCC)n1nc(CCC)c(C(N)=O)c1N
Reactant: COC(=O)C(c1ccccc1)S(=O)(=O)N1CCN(C)CC1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClCCl
Product: CCCCCCC(CCC)n1nc(CCC)c2c(=O)[nH]c(C(c3ccccc3)S(=O)(=O)N3CCN(C)CC3)nc21
Yield: 36.9 %

Procedure:
6 mg (0.019 mmol) of 5-amino-3-propyl-1-(4-decyl)-1H-pyrazole-4-carboxamide and 20 mg (0.064 mmol) of methyl 4-N-methylpiperazinosulphonylphenylacetate are refluxed for 6 hours in 0.3 ml of a 0.5M ethanolic potassium tert-butoxide solution. After dichloromethane and saturated aqueous sodium hydrogen carbonate have been added, the phases are separated. Purification by chromatography gives 4 mg (36%) of a solid, Rf=0.16 (dichloromethane/methanol=15:1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](OS(C(F)(F)F)(=O)=O)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:15]=3[O:14]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(OS(=O)(=O)C(F)(F)F)c3O2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4ccccc4)c3O2)cc1
Yield: 31.7 %

Procedure:
Treatment of (±)-(7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.5 g, 3.32 mmol) with phenylboronic acid (0.95 g, 4.97 mmol), tetrakis(triphenylphosphine)palladium(0) (0.38 g, 0.33 mmol), and potassium phosphate (1.41 g, 6.64 mmol) generally according to the procedure described for Intermediate 50 provided 0.40 g (32%) of (±)-(7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. Rf=0.48 (silica, ethyl acetate:hexanes 1:3); Anal. calcd. for C22H20O4S.0.2H2O: C, 68.8; H, 5.35. Found: C, 68.78; H, 5.08.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH2:6][CH2:7][CH3:8].[CH2:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29](O)=[CH:28][N:27]=2)=[CH:22][CH:21]=1)[CH2:12][CH3:13].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH2:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([O:9][C:1](=[O:10])[CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH2:6][CH2:7][CH3:8])=[CH:28][N:27]=2)=[CH:24][CH:25]=1)[CH2:12][CH3:13]
Reactant: CCCOCCCCCc1ccc(-c2ccc(O)cn2)cc1
Reactant: CCCC/C=C\CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCC/C=C\CC(=O)Oc1ccc(-c2ccc(CCCCCOCCC)cc2)nc1

Procedure:
0.5 g of (Z)-3-octenoic acid, 1.0 g of 2-[4-(5-[propyloxy]-1-pentyl)phenyl]-5-hydroxypyridine, 07 g of N,N'-dicyclohexyl-carbodiimide, 0.04 g of (dimethylaminio)pyridine and 50 ml of dichloromethane were reacted in an analogous manner to Example 1 to give 2-[4-(5-[propyloxy]-1-pentyl)phenyl]-5-([(Z)-3-octenoyl]oxy)pyridine.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[C:7]([O:23]C)[C:8]=1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].B(Br)(Br)Br>>[C:27]1([CH:26]=[CH:25][C:5]2[CH:4]=[C:3]([OH:2])[C:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[C:7]([OH:23])[CH:6]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CCCCCCCCCCCCCCc1c(OC)cc(C=Cc2ccccc2)cc1OC
Agent: BrB(Br)Br
Product: CCCCCCCCCCCCCCc1c(O)cc(C=Cc2ccccc2)cc1O

Procedure:
This material was synthesized from 1-(3,5-dimethoxy-4-n-tetradecanylphenyl)-2-phenylethene and BBr3 by the same method as described in Example 6. 1HNMR (CDCl3, ppm): δ0.95 (m, 6H), 1.30 (m, 22H), 2.65 (m, 2H), 4.80 (s, 2H), 6.60 (s, 2H), 7.00 (s, 2H), 7.26 (m, 1H), 7.36 (m, 2H), 7.52 (m, 2H).
Reaction SMILES: C[C:2]1(C)[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])O1.N1C=CC=CC=1.[F:17][C:18]([F:24])([F:23])[CH2:19]C(Cl)=O>CN(C1C=CN=CC=1)C.ClCCl.CO>[CH3:2][O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[CH2:19][C:18]([F:24])([F:23])[F:17]
Reactant: O=C(Cl)CC(F)(F)F
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CO
Solvent: c1ccncc1
Product: COC(=O)CC(=O)CC(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 46.2 %

Procedure:
To a stirred solution of 2,2-dimethyl-[1,3]dioxane-4,6-dione (200 mg, 1.41 mmol), pyridine (0.125 ml, 1.55 mmol) and DMAP (344 mg, 2.81 mmol) in dichloromethane (10 ml), was added 3,3,3-trifluoro-propionyl chloride (0.16 ml, 1.55 mmol) at 0° C. The resulting reaction mixture was stirred under nitrogen for 1 h at 0° C. and then allowed to warm to room temperature and stirred for 2 h. Volatiles were removed under reduced pressure, and the crude residue was diluted with diethyl ether and washed with 1 N HCl. The organic layer was dried and concentrated to get the intermediate, which was diluted with 10 ml of methanol and refluxed for 5 h. Volatiles were removed under reduced pressure to afford the crude 5,5,5-trifluoro-3-oxo-pentanoic acid methyl ester (120 mg, 46%) as brown liquid which was used in the following step without further purification. FIA-MS: 183 (M−H)−.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[O:17][C:18](Br)=[CH:19][CH:20]=2)=[O:15])[CH:8]=1)[CH3:2].[CH2:23]([O:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:22])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[O:17][C:18]([C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([O:30][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:32]=3)=[CH:19][CH:20]=2)=[O:15])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Reactant: OB(O)c1cccc(OCc2ccccc2)c1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2ccc(-c3cccc(OCc4ccccc4)c3)o2)c1
Temperature: 85 °C

Procedure:
The furyl bromide (99)(100 mg, 0.28 mmol) was coupled to 3-benzyloxy-phenylboronic acid (69 mg, 0.30 mmol) acid using Method E, except that the reaction was heated at 85° C. The crude product was purified by column chromatography eluting with 20% EtOAc in heptane to give the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>N1C=CC=CC=1>[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][P:7](=[O:14])([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13])(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: CCOP(=O)(CCCCCO)OCC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCOP(=O)(CCCCCOS(=O)(=O)c1ccc(C)cc1)OCC
Temperature: 0 °C

Procedure:
30 g (0.134 mol) of diethyl 5-hydroxypentylphosphonate (see Example 21) were dissolved in 200 ml of pyridine, and the solution was cooled to 0° C. and treated with stirring with 26.1 g (0.134 mol) of 4-toluenesulfonyl chloride. The reaction mixture was concentrated under reduced pressure, taken up in ethyl acetate, washed several times with 20% strength citric acid solution and water and dried over sodium sulfate. After evaporating the solvent, a pale yellow oil remained, which was employed without further purification.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18](/[C:21](/[CH3:25])=[CH:22]/[CH:23]=O)=[CH:17][CH:16]=1.[S:26]1[CH2:30][C:29](=[O:31])[NH:28][C:27]1=[O:32]>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH:21]([CH3:25])[CH2:22][CH2:23][CH:30]2[S:26][C:27](=[O:32])[NH:28][C:29]2=[O:31])=[CH:19][CH:20]=1
Reactant: O=C1CSC(=O)N1
Reactant: C/C(=C\C=O)c1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(C(C)CCC2SC(=O)NC2=O)cc1
Yield: 6 %

Procedure:
According to the same manner as that described in Example 13, (E)-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)-phenyl]-2-butenal was condensed with 2,4-thiazolidinedione, and then the resulting compound was subjected to catalytic hydrogenation to give 5-[3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]butyl]-2,4-thiazolidinedione (yield: 6%). This product was recrystallized from isopropyl ether. Pale yellow prisms, mp: 64-65° C.
Reaction SMILES: [CH2:1]([C:3]1([S:6]([NH:9][C:10]([C@@:12]2([NH:17][C:18]([C@@H:20]3[CH2:24][C@@H:23]([OH:25])[CH2:22][N:21]3[C:26](=[O:40])[C@@H:27]([NH:32][C:33]([O:35][C:36](C)([CH3:38])[CH3:37])=[O:34])[C:28]([CH3:31])([CH3:30])[CH3:29])=[O:19])[CH2:14][C@H:13]2[CH:15]=[CH2:16])=[O:11])(=[O:8])=[O:7])[CH2:5][CH2:4]1)[CH3:2].ClC(OC(C)C)=O.CCN(C(C)C)C(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH:36]([O:35][C:33](=[O:34])[NH:32][C@H:27]([C:26]([N:21]1[CH2:22][CH:23]([OH:25])[CH2:24][C@H:20]1[C:18](=[O:19])[NH:17][C@:12]1([C:10]([NH:9][S:6]([C:3]2([CH2:1][CH3:2])[CH2:4][CH2:5]2)(=[O:8])=[O:7])=[O:11])[CH2:14][C@H:13]1[CH:15]=[CH2:16])=[O:40])[C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:37])[CH3:38]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)C(=O)NS(=O)(=O)C1(CC)CC1
Agent: CC(C)OC(=O)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1CC(O)CN1C(=O)[C@@H](NC(=O)OC(C)C)C(C)(C)C)C(=O)NS(=O)(=O)C1(CC)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.5 %

Procedure:
A solution of 2(S)-[1 (R)-(1-ethyl-cyclopropanesulfonylaminocarbonyl)-2(S)-vinyl-cyclopropylcarbamoyl]-N-[N-Boc-amino-(S)-t-butyl-acetyl]-4(R)-hydroxy-pyrrolidine (585 mg, 1.0 mmol) in TFA (2 ml) and CH2Cl2 (2 ml) was stirred at room temperature for 1 h and concentrated in vacuo. The residue was dissolved in CH2Cl2 (5 ml) and isopropyl chloroformate (1.0M in toluene, 1.0 ml, 1.0 mmol), DIPEA (0.5 ml) were added. The resulting mixture was stirred at room temperature overnight and the solvent was removed in vacuo. The crude product was purified by flash column chromatograph (Biotage Flash 40M) eluted with EtOAc to provide the title compound (180 mg, 32%). MS 571 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH:9][C:10]([C:12]2[CH:17]=[C:16]([Cl:18])[N:15]=[N:14][C:13]=2[S:19][CH2:20][CH3:21])=O)=[CH:7][C:6]([C:22]([F:25])([F:24])[F:23])=[CH:5][N:4]=1.P(Cl)(Cl)(Cl)=O.C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>O.C1(C)C=CC=CC=1>[Cl:18][C:16]1[N:15]=[N:14][C:13]([S:19][CH2:20][CH3:21])=[C:12]([C:10]2[N:2]([CH3:1])[C:3]3=[N:4][CH:5]=[C:6]([C:22]([F:25])([F:24])[F:23])[CH:7]=[C:8]3[N:9]=2)[CH:17]=1
Reactant: CCSc1nnc(Cl)cc1C(=O)Nc1cc(C(F)(F)F)cnc1NC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCSc1nnc(Cl)cc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 100 °C
Reaction time: 4 h
Yield: 62.2 %

Procedure:
A mixture of 900 mg of 6-chloro-3-ethylsulfanylpyridazine-4-carboxylic acid (2-methylamino-5-trifluoromethylpyridin-3-yl)-amide, 3.5 ml of phosphorus oxychloride, 592 mg of N,N-diisopropylethylamine and 15 ml of toluene was heated and stirred at 100° C. for 4 hours. Water was poured to the cooled reaction mixture, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was neutralized with a saturated aqueous sodium bicarbonate solution, extracted with t-butyl methyl ether. The organic layer was washed with water, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 534 mg of 2-(6-chloro-3-ethylsulfanylpyridazin-4-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter, referred to as Compound of Present Invention 16).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC([N:15]1[CH2:20][CH2:19][C:18]([CH2:27][N:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:35])[CH2:30][C:29]2=[O:44])([NH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17][CH2:16]1)=O)(C)(C)C>C1(C)C=CC=CC=1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:25]([O:24][C:22]([NH:21][C:18]1([CH2:27][N:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][CH2:37][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[O:35])[CH2:30][C:29]2=[O:44])[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]1)=[O:23])[CH3:26]
Reactant: CCOC(=O)NC1(CN2CCN(C(=O)OCc3ccccc3)CC2=O)CCN(C(=O)OC(C)(C)C)CC1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)NC1(CN2CCN(C(=O)OCc3ccccc3)CC2=O)CCNCC1
Yield: 60 %

Procedure:
Trifluoroacetic acid (78 ml) was added to a solution of benzyl 4-[[1-(tert-butoxycarbonyl)-4-[(ethoxycarbonyl)amino]-4-piperidinyl]methyl]-3-oxo-1-piperazinecarboxylate (26 g) obtained in Reference Example 7 in toluene (78 ml) at room temperature while stirring, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate/diethyl ether=5/1) to obtain the title compound (16 g, 60%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:34][OH:35])[C:8]([NH:10][CH:11]2[C:32](=[O:33])[N:13]3[C:14]([C:19]([O:21]CC4C=CC([N+]([O-])=O)=CC=4)=[O:20])=[C:15]([Cl:18])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.CO.O>[C].[Pd].O1CCCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:34][OH:35])[C:8]([NH:10][CH:11]2[C:32](=[O:33])[N:13]3[C:14]([C:19]([OH:21])=[O:20])=[C:15]([Cl:18])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: Nc1nc(C(=NO)C(=O)NC2C(=O)N3C(C(=O)OCc4ccc([N+](=O)[O-])cc4)=C(Cl)CS[C@H]23)cs1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Nc1nc(C(=NO)C(=O)NC2C(=O)N3C(C(=O)O)=C(Cl)CS[C@H]23)cs1
Yield: 34.2 %

Procedure:
4-Nitrobenzyl 7-[2-(2-aminothiazol-4yl)-2-hydroxyiminoacetamido]-3-chloro-3-cephem-4-carboxylate (syn isomer, 5.0 g.), 10% palladium carbon (3.0 g.), methanol (100 ml.), water (10 ml.) and tetrahydrofuran (150 ml.) were treated in a similar manner to that of Example 37-(2), to give 7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer, 1.28 g.).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([NH:6]C(=O)C)=[C:4]([F:12])[CH:3]=1.Cl>>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([NH2:6])=[C:4]([F:12])[CH:3]=1
Reactant: CC(=O)Nc1ccc(Cl)cc1F
Agent: Cl
Product: Nc1ccc(Cl)cc1F

Procedure:
4'-Chloro-2'-fluoroacetanilide is refluxed in a mixture of a lower alcohol (50%) (e.g. ethanol) and concentrated hydrochloric acid (50%) for several hours (e.g. 5 or more) at 70°-90° C. and atmospheric pressure. The solvent mixture is removed at a reduced pressure of 100 to 300 mm.Hg and 20°-50° C. to leave a residue of the hydrochloride salt of 4-chloro-2-fluoroaniline.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])=[CH:10][CH:9]=2)=[O:5])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(OCC(=O)OC(C)(C)C)ccc2[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc2cc(OCC(=O)O)ccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.3 %

Procedure:
A mixture of 5-tert-butoxycarbonylmethoxy-1H-indole-2-carboxylic acid ethyl ester (2 g, 6 mmol) and trifluoroacetic acid (8 mL) in dichloromethane (8 mL) was stirred at room temperature for 2 hours. The reaction was concentrated to give 1.6 g (97%) of 5-carboxymethoxy-1H-indole-2-carboxylic acid ethyl ester as a light brown solid.
Reaction SMILES: [OH:1][CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH2:20][C:21]([OH:28])([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])[CH:14]=1)[CH2:3][CH2:4][NH:5][C:6](=O)OC(C)(C)C.B.C1COCC1>>[OH:1][CH:2]([C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)[CH2:19][CH2:20][C:21]([OH:28])([CH2:22][CH2:23][CH3:24])[CH2:25][CH2:26][CH3:27])[CH2:3][CH2:4][NH:5][CH3:6]
Reactant: CCCC(O)(CCC)CCc1cccc(C(O)CCNC(=O)OC(C)(C)C)c1
Agent: B
Solvent: C1CCOC1
Product: CCCC(O)(CCC)CCc1cccc(C(O)CCNC)c1

Procedure:
Reduction of tert-butyl 3-hydroxy-3-(3-(3-hydroxy-3-propylhexyl)phenyl)propylcarbamate using BH3-THF gives Example 167.