Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[O:4][C:5]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:6]=1[C:7](OC)=[O:8].C[Al](C)C.C1(C)C=CC=CC=1.O>C(Cl)Cl>[F:15][C:12]1[CH:13]=[CH:14][C:5]2[O:4][C:3]3[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=3[NH:1][C:7](=[O:8])[C:6]=2[CH:11]=1
Reactant: COC(=O)c1cc(F)ccc1Oc1ccccc1N
Agent: C[Al](C)C
Solvent: O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C1Nc2ccccc2Oc2ccc(F)cc21
Temperature: 0 °C
Yield: 72.6 %

Procedure:
Title compound 19 (802 mg, 3.07 mmol) was dissolved in DCM (10 mL) and the mixture was cooled to 0° C. Trimethylaluminum 2M in toluene (1.8 mL, 3.69 mmol) was added dropwise and the reaction mixture was allowed to warm to room temperature. The mixture was then heated to 45° C. for 45 h. The mixture was cooled to room temperature for the slow addition of water. The solution was extracted with ethyl acetate then washed twice with HCl (10%), water and saturated solution of bicarbonate. The organic layer was then dried over sodium sulfate and concentrated in vacuo until the product precipitated. The solid was filtered and dried to afford title compound 20 (511 mg, 73%) as a white solid. LRMS (ESI): (calc) 229.05. (found) 230.1 (MS)+.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[CH3:7][O:8][C:9]1[CH:15]=[CH:14][C:12](N)=[CH:11][CH:10]=1.[ClH:16]>C(#N)C>[Cl:16][CH:2]([CH2:3][C:12]1[CH:14]=[CH:15][C:9]([O:8][CH3:7])=[CH:10][CH:11]=1)[C:1]([O:5][CH3:6])=[O:4]
Reactant: Cl
Reactant: COc1ccc(N)cc1
Reactant: C=CC(=O)OC
Solvent: CC#N
Product: COC(=O)C(Cl)Cc1ccc(OC)cc1
Yield: 57.3 %

Procedure:
Following the general procedure of Example I, 339 mmols of methyl acrylate were reacted with 25 mmols of crude 4-methoxyaniline in 30 mL of acetonitrile and in the presence of 38 mmols of concentrated HCl and 2.5 mmols of cuprous oxide. The process resulted in a 57.3% yield of methyl 2-chloro-3-(4-methoxyphenyl)propionate.
Reaction SMILES: [CH:1]([N:4]([CH:18]([CH3:20])[CH3:19])[CH2:5][CH2:6][N:7]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10](=O)[C:8]1=[O:9])([CH3:3])[CH3:2].[CH3:21][NH:22][C:23](=[O:26])[NH:24][NH2:25].C(O)C>C(O)(=O)C.O>[CH3:21][NH:22][C:23](=[O:26])[NH:24]/[N:25]=[C:10]1/[C:8](=[O:9])[N:7]([CH2:6][CH2:5][N:4]([CH:18]([CH3:20])[CH3:19])[CH:1]([CH3:3])[CH3:2])[C:17]2[C:12]/1=[CH:13][CH:14]=[CH:15][CH:16]=2
Reactant: CC(C)N(CCN1C(=O)C(=O)c2ccccc21)C(C)C
Reactant: CNC(=O)NN
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CNC(=O)N/N=C1/C(=O)N(CCN(C(C)C)C(C)C)c2ccccc21
Temperature: 60 °C
Yield: 49.9 %

Procedure:
To a solution of 1.37 g of 1-(2-diisopropylaminoethyl)isatin and 0.49 g of 4-methylsemicarbazide in ml of a mixture of ethanol and water (2:1) was added 3 drops of acetic acid, and then the mixture was heated at 60° C. for 6 hours. The yellow precipitates were collected by filtration and recrystallized from aqueous ethanol to obtain 0.86 g of (E)-1-(2-diisopropylaminoethyl)isatin 3-(4-methylsemicarbazone) having a melting point of 175°-177° C.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[N:5][C:6]([C:9]2[CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:13][CH:14]=2)=[CH:7][N:8]=1)[NH2:2].[CH:19]([O-])([O-])OCC>CCCCCC>[F:16][C:15]([F:18])([F:17])[C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([C:6]2[CH:7]=[N:8][C:3]3[N:4]([CH:19]=[N:2][N:1]=3)[N:5]=2)[CH:10]=1
Reactant: CCOC([O-])[O-]
Reactant: NNc1ncc(-c2cccc(C(F)(F)F)c2)nn1
Solvent: CCCCCC
Product: FC(F)(F)c1cccc(-c2cnc3nncn3n2)c1

Procedure:
A mixture of one gram of 3-hydrazino-6-(α,α,α-trifluoro-m-tolyl)-1,2,4-triazine and 15 ml. of ethyl orthoformate is refluxed for 4 hours, cooled and poured into hexane. The solid is collected by filtration and washed with ethanol giving the desired product, m.p. 229°-232° C.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9]O.C1OC2C=CC(C[Cl:21])=CC=2O1>CCOCC>[CH3:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9][Cl:21]
Reactant: COc1ccccc1CO
Reactant: ClCc1ccc2c(c1)OCO2
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: COc1ccccc1CCl
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
16.8 ml of thionyl chloride are added dropwise, over the space of approximately 30 min, to 10 ml of 2-methoxybenzyl alcohol (Fluka, Buchs, Switzerland) and 53.76 g of diisopropylaminomethylpolystyrene (polyhunig base, see Ex. 44a)) in 200 ml of abs. ether. After the mixture has been stirred at 0° C. for a further 1.5 h, it is filtered with suction and the filtrate is concentrated on a RE and under HV. The residue is purified by chromatography on silica gel (eluent: hexane/ethyl acetate, 6:1). TLC Rf (hexane:ethyl acetate=4:1)=0.5. 1H-NMR (200 MHz, CDCl3): 7.42-7.24 (m, 2H); 7.0-6.84 (m, 2H); 4.68 (s, 2H); 3.9 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Br:11])[N:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13].S(=O)(=O)(O)O.O>C(O)(=O)C.CCOCC>[C:12]([NH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Br:11])[N:3]=1)(=[O:14])[CH3:13]
Reactant: Nc1nc(Br)ccc1[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Solvent: CCOCC
Product: CC(=O)Nc1nc(Br)ccc1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2-amino-6-bromo-3-nitropyridine (23.9 g) in acetic acid (48 ml) were added acetic anhydride (48 ml) and sulfuric acid (2.9 ml), and the mixture was heated at 65° C. for 40 min. The reaction mixture once became homogeneous and a product soon precipitated to give a suspension. The reaction mixture was allowed to cool and poured into cold water (480 ml), which was followed by stirring for 30 min. The precipitate was collected by filtration and washed with water to give a crude product. This was suspended in ether (60 ml) and collected by filtration to give 2-(acetamido)-6-bromo-3-nitropyridine as a pale-yellow powder (27.2 g).
Reaction SMILES: [CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[C:10]([O:18][CH3:19])=[C:9]([CH:20]=O)[C:8]1=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:23][CH2:24][CH2:25][SH:26].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[C:10]([O:18][CH3:19])=[C:9]([CH:20]2[NH:23][CH2:24][CH2:25][S:26]2)[C:8]1=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: NCCS
Reactant: CCCCCCn1c(=O)c(C=O)c(OC)c2cc(C)ccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CCCCCCn1c(=O)c(C2NCCS2)c(OC)c2cc(C)ccc21
Reaction time: 3 h

Procedure:
A solution of 1-hexyl-3-formyl-4-methoxy-6-methyl-2(1H)-quinolinone (Step (2) of Example 1, 1 g) and 2-aminoethanethiol (0.26 g) in methylene chloride (20 ml) containing p-toluenesulfonic acid (0.1 g) was stirred for 3 hrs. The mixture was washed with aqueous sodium bicarbonate, dried, evaporated and then crystallized from ether-hexane to give 1-Hexyl-3-(2-thiazolidinyl)-4-methoxy-6-methyl-2(1H)-quinolinone. That the expected product was obtained was confirmed by the spectral data: MS: m/e 360(M.+); NMR (CDCl3): δ3.17 (m, 2H, CH2S), 3.86 (m, 2H, CH2N), 6.0 (d, 1H, S--CH--N).
Reaction SMILES: CC(N[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:12]=[CH:13][C:14]3[N:15]([C:17]([CH3:20])=[N:18][N:19]=3)[N:16]=2)[CH:6]=1)C.[CH:21]([N:24](C(C)C)[CH2:25][CH3:26])([CH3:23])[CH3:22].C(Cl)(=[O:32])C.O>ClCCl>[CH3:22][CH:21]([NH:24][C:25](=[O:32])[CH2:26][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:12]=[CH:13][C:14]3[N:15]([C:17]([CH3:20])=[N:18][N:19]=3)[N:16]=2)[CH:6]=1)[CH3:23]
Reactant: Cc1nnc2ccc(-c3cccc(NC(C)C)c3)nn12
Reactant: CC(=O)Cl
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: Cc1nnc2ccc(-c3cccc(CC(=O)NC(C)C)c3)nn12
Reaction time: 12 h

Procedure:
To a solution of 2 g of N-(1-methylethyl)-3-(3-methyl-1,2,4-triazolo[4,3-b]pyridazin-6-yl)benzenamine and 1.43 ml diisopropylethylamine in 200 ml of dichloromethane was added 0.6 ml of acetylchloride. This solution was stirred for 12 hours, then poured onto 200 ml of water and extracted with 150 ml portions of dichloromethane. The combined extracts were dried, concentrated in vacuo and the solid chromatographed on 300 g of silica gel using dichloromethane-methanol (97:3). The fractions containing the desired product were combined, concentrated in vacuo and the solid recrystalized from dichloromethane-hexane to give 0.72 g of yellow crystals, mp 197°-200° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13]OS(C)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:25][N:26]1[CH:30]=[C:29]([C:31]2[CH:32]=[C:33]([C:37]3[N:42]=[CH:41][C:40]([C:43]4[CH:44]=[N:45][NH:46][CH:47]=4)=[CH:39][N:38]=3)[CH:34]=[CH:35][CH:36]=2)[CH:28]=[N:27]1>O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][N:45]2[CH:44]=[C:43]([C:40]3[CH:39]=[N:38][C:37]([C:33]4[CH:34]=[CH:35][CH:36]=[C:31]([C:29]5[CH:28]=[N:27][N:26]([CH3:25])[CH:30]=5)[CH:32]=4)=[N:42][CH:41]=3)[CH:47]=[N:46]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1cc(-c2cccc(-c3ncc(-c4cn[nH]c4)cn3)c2)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: Cn1cc(-c2cccc(-c3ncc(-c4cnn(CC5CCN(C(=O)OC(C)(C)C)C5)c4)cn3)c2)cn1
Yield: 57.6 %

Procedure:
A solution of 3-Methanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (prepared as described in WO2010100144; 200 mg; 0.64 mmol; 1.0 eq.), cesium carbonate (420 mg; 1.29 mmol; 2.0 eq.) and 2-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]-5-(1H-pyrazol-4-yl)pyrimidine (example 3, 195 mg; 0.64 mmol; 1.0 eq.) was heated at 100° C. O/N. The reaction mixture was then diluted with water and extracted with EtOAc (three times). Combined organic phases were washed with brine (three times), dried over magnesium sulfate, filtered and concentrated. Purification by autopreparative LC/MS afforded the title compound as a white foam (179 mg, 57%). MS (ESI+): 486.5.
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[OH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([CH3:23])[C:15](=[O:24])[C:14]=1[N+:25]([O-:27])=[O:26].CCN(CC)CC>C(#N)C.CN(C1C=CN=CC=1)C>[CH3:23][N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([O:12][S:1]([C:4]2[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=2)(=[O:3])=[O:2])=[C:14]([N+:25]([O-:27])=[O:26])[C:15]1=[O:24]
Reactant: Cn1c(=O)c([N+](=O)[O-])c(O)c2ccccc21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)Oc2c([N+](=O)[O-])c(=O)n(C)c3ccccc23)cc1
Temperature: 35 °C
Yield: 75.5 %

Procedure:
A solution of tosyl chloride (30.0 g, 160 mmol) in 100 mL of acetonitrile was added to a stirred solution of the 4-hydroxy-1-methyl-3-nitro-1H-quinolin-2-one (32.0 g, 145.0 mmol), Et3N (17.65 g, 174.4 mmol), and DMAP (0.178 g, 1.45 mmol) in 300 mL of MeCN at 0° C. After the addition was complete, the reaction mixture was heated at 35° C. for 3 h. After the solvent was evaporated under reduced pressure, water (35 mL) and CH2Cl2 (50 mL) were added to the residue. The resulting precipitate was removed by filtration, and the filtrate was extracted with CH2Cl2 (3×200 mL). The combined extracts were dried, filtered through a plug of SiO2, and concentrated. The resulting residue was combined with the solid isolated earlier, and was triturated with ether to give 41.0 g (75%) of toluene-4-sulfonic acid 1-methyl-3-nitro-2-oxo-1,2-dihydro-quinolin-4-yl ester. 1H-NMR (CDCl3): δ 8.16 (dd, 1H, J=7.6, 1.2 Hz), 7.90 (m, 2H), 7.79 (m, 1H), 7.44 (m, 4H), 3.79 (s, 3H), 2.51 (s, 3H). MS: calculated for C17H14N2O6S+H 375.1; found: 375.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:15][CH3:16])[C:11]=1[CH:12]([CH3:14])C)[C:6](Cl)=[O:7].[NH:17]1[CH2:19][CH2:18]1.C([O:22]CC)C>>[C:12]([C:11]1[C:10]([O:15][CH3:16])=[CH:9][C:5]([C:6]2[O:7][CH2:19][CH2:18][N:17]=2)=[CH:4][C:3]=1[O:2][CH3:1])(=[O:22])[CH3:14]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1C(C)C
Reactant: CCOCC
Reactant: C1CN1
Product: COc1cc(C2=NCCO2)cc(OC)c1C(C)=O

Procedure:
3,5-Dimethoxy-4-isopropyl-benzoyl chloride. The compound prepared under G) is first reacted with aziridine according to the procedure described by D. Haidukewych et al., Tetrahedron Letters, 30, 3031-3034, 1972, obtaining 4-acetyl-3,5-dimethoxy-1-(2-oxazolinyl)-benzene, m.p. 135°-37°C (diethyl ether). This compound is reacted with magnesium methyl iodide and 2-[2,6-dimethoxy-4-(2-oxazolinyl)]phenyl-2-propanol is obtained (m.p. 113°-16°C, from diisopropylether), from which, by treatment with sulphuric acid 3,5-dimethoxy-4-isopropenyl-benzoic acid is prepared. M.p. 169°-73°C (from ethanol/water). Said compound is hydrogenated to 3,5-dimethoxy-4-isopropyl-benzoic acid(m.p. 180°-83°C, from diethylether/light petroleum): the corresponding chloride melts at 75°-78°C (from light petroleum upon cooling).
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH2:13]=O>>[C:6]([C:5]1[CH:9]=[C:10]2[C:2](=[CH:3][CH:4]=1)[C:1](=[O:12])[O:11][CH2:13]2)([OH:8])=[O:7]
Reactant: C=O
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Product: O=C(O)c1ccc2c(c1)COC2=O

Procedure:
In the method of the invention, the terephthalic acid is condensed with paraformaldehyde liberating water, which reacts with the SO2. When the reaction is complete, 5-carboxyphthalide may be isolated as follows: The reaction mixture is hydrolysed with water. The condensed product, 5-carboxyphthalide inclusive possible diphthalide impurities may then be filtered off, and the 5-carboxyphthalide may be dissolved in aqueous medium by adjusting pH to about 6.7 to 7.3, leaving possible diphthalide impurities in the solid phase. The diphthalide present may be filtered off whereupon 5-carboxyphthalide may be precipitated by acidification, filtered off, washed with water and dried.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([O-:10])=[O:9])[CH:3]=1.[K+].S(=O)(=O)(O)O.[CH3:17]O>>[CH3:17][O:9][C:8]([C:4]1[CH:3]=[C:2]([CH3:1])[N:7]=[CH:6][N:5]=1)=[O:10]
Reactant: Cc1cc(C(=O)[O-])ncn1
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COC(=O)c1cc(C)ncn1

Procedure:
1.77 g (16.37 mmol) of 4,6-dimethylpyrimidine was dissolved in 20 ml of water and stirred. 5.69 g (36.01 mmol) of potassium permanganate solution in 60 ml of water was added thereto and heated at temperature of 70° C. to 75° C. After the color of potassium permanganate disappeared, the mixture was filtered with celite and extracted with dichloromethane to collect the remaining starting material. The aqueous layer was removed under reduced pressure to obtain potassium 6-methylpyrimidine-4-carboxylate (Intermediate compound 57). 3.45 g of the intermediate compound 57 was mixed with 250 ml of methanol and 1.7 ml of conc. sulfuric acid, and the mixture was refluxed under heating for 6 hours. The solvent in the mixture was then removed under reduced pressure. The residue was diluted with ethyl acetate and water, and neutralized by sodium bicarbonate solution, and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrated product was purified by the column chromatography (ethylacetate:hexane=1:1) to obtain 6-methylpyrimidine-4-carboxylic acid methyl ester (Intermediate compound 58, 930 mg, Yield of the first and second steps: 37%). The intermediate compound 58 was then subjected to the fifth step in the reaction of Example 1 to obtain 6-methylpyrimine-4-carboxylic acid (Intermediate compound 59, Yield of the third step: 62%). Next, the intermediate compound 59 and (−)-thiodeacetyl colchicine were subjected to the sixth step in the reaction of Example 1 to obtain the title compound 21 (Yield of the fourth step: 37%).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][O:17][CH:18]=[O:19])[C:10]([OH:12])=O)[N:8]=1)=[O:2].[NH2:20][CH:21]1[C:39](=[O:40])[N:23]2[C:24]([C:36]([OH:38])=[O:37])=[C:25]([CH2:28][S:29][C:30]3[N:34]([CH3:35])[N:33]=[N:32][N:31]=3)[CH2:26][S:27][C@H:22]12.C[Si](CC(N)=O)(C)C.P(Cl)(Cl)(Cl)=O>C(OCC)(=O)C.CN(C)C=O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][O:17][CH:18]=[O:19])[C:10]([NH:20][CH:21]2[C:39](=[O:40])[N:23]3[C:24]([C:36]([OH:38])=[O:37])=[C:25]([CH2:28][S:29][C:30]4[N:34]([CH3:35])[N:33]=[N:32][N:31]=4)[CH2:26][S:27][C@H:22]23)=[O:12])[N:8]=1)=[O:2]
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: O=CNc1nc(C(=NOCCOC=O)C(=O)O)cs1
Agent: C[Si](C)(C)CC(N)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCOC=O)c3csc(NC=O)n3)[C@H]2SC1
Yield: 34.9 %

Procedure:
2-(2-Formamidothiazol-4-yl)-2-(2-formyloxyethoxyimino)acetic acid (syn isomer, 3.4 g.), 7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (4.3 g.), trimethylsilylacetamide (12.6 g.), dry N,N-dimethylformamide (1.0 g.), phosphoryl chloride (2.0 g.), ethyl acetate (139 ml.) PG,71 were treated in a similar manner to that of Example 11-(1) to give 7-[2-(2-formamidothiazol-4-yl)-2-(2-formyloxyethoxyimino)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 2.47 g.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][CH:10]([O:12][CH2:13][CH3:14])[CH3:11].[Mg].BrCC.CON(C)[C:22]([C:24]1[CH:28]=[C:27]([CH3:29])[O:26][N:25]=1)=[O:23]>O.C1COCC1>[CH3:29][C:27]1[O:26][N:25]=[C:24]([C:22]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][O:9][CH:10]([O:12][CH2:13][CH3:14])[CH3:11])=[O:23])[CH:28]=1
Reactant: CCOC(C)OCc1ccccc1Br
Reactant: CON(C)C(=O)c1cc(C)on1
Agent: [Mg]
Solvent: CCBr
Solvent: C1CCOC1
Solvent: O
Product: CCOC(C)OCc1ccccc1C(=O)c1cc(C)on1
Temperature: 52.5 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
A mixture of 1-bromo-2-(1-ethoxyethyl)oxymethylbenzene (12.96 g, 0.05 mol) and THF (45 ml) was added to a mixture of magnesium (1.82 g, 0.075 mol) and bromoethane (0.2 ml) and THF (5 ml) at 45 to 550° C. under an atmosphere of nitrogen gas, and the resulting mixture was stirred at 50 to 55° C. for 1 hour to prepare a Grignard reagent. The Grignard reagent was added dropwise to a mixture of N-methoxy-5, N-dimethyl-3-isoxazolcarboxamide (5.62 g, 0.033 mol) and THF (40 ml) cooled to −50° C. The mixture was stirred at −60° C. to room temperature for 1 hour, water (200 ml) was added, and the mixture was extracted with ether (200 ml). The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(1-ethoxyethyl)oxymethylphenyl 5-methylisoxazol-3-yl ketone (8.61 g, yield: 90.2%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:17])=[C:4]([CH:14]=[CH:15][CH:16]=1)[NH:5][C:6]1[C:7]([CH2:11][C:12]#N)=[CH:8][S:9][CH:10]=1.S(=O)(=O)(O)[OH:19].[OH2:23]>>[Cl:1][C:2]1[C:3]([CH3:17])=[C:4]([CH:14]=[CH:15][CH:16]=1)[NH:5][C:6]1[C:7]([CH2:11][C:12]([OH:19])=[O:23])=[CH:8][S:9][CH:10]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1c(Cl)cccc1Nc1cscc1CC#N
Reactant: O
Product: Cc1c(Cl)cccc1Nc1cscc1CC(=O)O
Reaction time: 1 h

Procedure:
26.3 g (0.1 mole) of 4-(3-chloro-2-methylanilino)-3-thiophenacetonitrile are introduced into 135 ml of concentrated sulfuric acid; the resulting mixture is stirred at 20° for 1 hour; 49 ml of water are then added dropwise and the obtained mixture is heated to 100° for 3 hours. It is poured onto ice, and the precipitate, which has formed, is filtered off. Recrystallization from diisopropyl ether gives 4-(3-chloro-2-methylanilino)-3-thiophenacetic acid. m. 126° to 128°.
Reaction SMILES: Cl.[CH2:2]1[C@H:6]2[CH2:7][CH:8]([CH2:10][OH:11])[CH2:9][C@H:5]2[CH2:4][NH:3]1.C(=O)([O-])[O-].[K+].[K+].F[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=1[C:29]([F:32])([F:31])[F:30].O>CN(C=O)C>[F:26][C:25]([F:27])([F:28])[C:22]1[CH:21]=[C:20]([C:29]([F:30])([F:31])[F:32])[CH:19]=[CH:24][C:23]=1[N:3]1[CH2:4][C@@H:5]2[CH2:9][CH:8]([CH:10]=[O:11])[CH2:7][C@@H:6]2[CH2:2]1
Reactant: Fc1ccc(C(F)(F)F)cc1C(F)(F)F
Reactant: OCC1C[C@H]2CNC[C@H]2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=CC1C[C@@H]2CN(c3ccc(C(F)(F)F)cc3C(F)(F)F)C[C@@H]2C1
Temperature: 80 °C
Reaction time: 3 h
Yield: 12.6 %

Procedure:
To a solution of (3aR,6aS)-octahydrocyclopenta[c]pyrrol-5-ylmethanol hydrochloride (862 mg) and potassium carbonate (1.68 g) in DMF (10 mL) was added 1-fluoro-2,4-bis(trifluoromethyl)benzene (1.24 g). The reaction mixture was stirred at 80° C. for 3 hr, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane). To a solution of the obtained oil (1.71 g) and triethylamine (2.03 mL) in DMSO (10 mL) and ethyl acetate (10 mL) was added sulfur trioxide pyridine complex (2.32 g) under cooling to 0° C. The reaction mixture was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (215 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:54][N:55]2[CH:59]=[N:58][CH:57]=[N:56]2)[O:13][CH:12]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][C:31]([N:34]5[C:38](=[O:39])[N:37]([CH:40]([CH3:53])[CH:41]([NH:43][CH:44]([C:47]6[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=6)[C:45]#[N:46])[CH3:42])[N:36]=[CH:35]5)=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH2:11][O:10]1.[H][H]>CO.N.[Ni]>[NH2:46][CH2:45][CH:44]([NH:43][CH:41]([CH3:42])[CH:40]([N:37]1[C:38](=[O:39])[N:34]([C:31]2[CH:32]=[CH:33][C:28]([N:25]3[CH2:24][CH2:23][N:22]([C:19]4[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH:12]5[CH2:11][O:10][C:9]([C:3]6[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=6[F:1])([CH2:54][N:55]6[CH:59]=[N:58][CH:57]=[N:56]6)[O:13]5)=[CH:21][CH:20]=4)[CH2:27][CH2:26]3)=[CH:29][CH:30]=2)[CH:35]=[N:36]1)[CH3:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: [H][H]
Reactant: CC(NC(C#N)c1ccccc1)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(OCC5COC(Cn6cncn6)(c6ccc(F)cc6F)O5)cc4)CC3)cc2)c1=O
Agent: [Ni]
Agent: N
Solvent: CO
Product: CC(NC(CN)c1ccccc1)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(OCC5COC(Cn6cncn6)(c6ccc(F)cc6F)O5)cc4)CC3)cc2)c1=O
Yield: 15.4 %

Procedure:
A mixture of compound 122 (0.003 mol) in CH3OH NH3 (200 ml) was hydrogenated overnight with Raney Nickel (1 g) as a catalyst. After uptake of hydrogen (2 equivalents), the catalyst was filtered off and the filtrate was evaporated. The residue was triturated in DIPE and 2-propanol, filtered off and dried. The residue was purified by HPLC (eluent: (ammonium acetate 0.5% in H2O/CH3CN 90/10)/CH3CN 90/10 to 0/100; column: HYPERPREP C18 BDS 8 μm). Two pure fractions were collected and their solvents were evaporated. The residue was triturated in DIPE, filtered off and dried, yielding 0.45 g [2S-[2α,4α[(S*,R*)(A)]]]-2-[2-[(2-amino-1-phenylethyl)amino]-1-methylpropyl]-4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihyro-3H-1,2,4-triazol-3-one (18.7%) (compound 174) and 0.37 g [2S-[2α,4α[(S*,R*)(B)]]]-2-[2[(2-amino-1-phenylethyl)amino]-1-methylpropyl]-4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]-phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (15.4%) (compound 178).