Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]3[NH:20][C:19]4[CH2:18][CH:17]([CH3:21])[NH:16][C:15](=[O:22])[C:14]=4[CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C(O)(C(F)(F)F)=O>CS(C)=O>[CH3:21][CH:17]1[NH:16][C:15](=[O:22])[C:14]2[CH:13]=[C:12]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[N:3]=[C:2]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:11]=[CH:10]4)[NH:20][C:19]=2[CH2:18]1
Reactant: CC1Cc2[nH]c(-c3cccc4ccc(Cl)nc34)cc2C(=O)N1
Reactant: Nc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: CC1Cc2[nH]c(-c3cccc4ccc(Nc5ccccc5)nc34)cc2C(=O)N1
Reaction time: 3 h
Yield: 31.3 %

Procedure:
2-(2-Chloroquinolin-8-yl)-6-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 31; 0.050 g, 0.160 mmol) and aniline (0.073 ml, 0.802 mmol) were treated with LHMDS (1.0 M solution in THF; 1.203 ml, 1.203 mmol). The dark red reaction was stirred for 3 h, at which point it was concentrated then treated with DMSO and TFA (0.185 ml, 2.406 mmol). This material was purified by rpHPLC (Phenomenex Gemini 150×30 mm C18 column, 10-80% ACN/H2O with 0.1% TFA); product-containing fractions were treated with saturated aq. NaHCO3 and DCM. The organic layer was separated, and the aq. layer was extracted 3×DCM. The combined organic layers were then dried over Na2SO4, filtered, and concentrated in vacuo to give rac-6-methyl-2-(2-(phenylamino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.018 g, 0.050 mmol, 31% yield, Example 237) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.15 (1H, br. s), 9.52 (1H, s), 8.11 (1H, d, J=9.0 Hz), 7.93 (1H, dt, J=7.4, 0.9 Hz), 7.65 (2H, d, J=7.6 Hz), 7.58 (1H, dt, J=7.7, 1.0 Hz), 7.40 (2H, t, J=7.9 Hz), 7.28 (1H, t, J=7.7 Hz), 7.02-7.15 (2H, m), 6.82-6.97 (2H, m), 3.75 (1H, dt, J=11.3, 5.8 Hz), 2.65 (1H, dd, J=15.6, 5.3 Hz), 2.36-2.47 (1H, m), 1.23 (3H, d, J=6.3 Hz). m/z (ESI, +ve) 369.2 (M+H)+. A portion of this material was resolved by chiral SFC (Chiralcel IC-H (150×21 mm, 5 μm); additive in supercritical fluid CO2 was 40% EtOH with 40 mM NH3; 70 mL/min; column temperature 40° C.; outlet pressure 100 bar) to give separated enantiomers 6-methyl-2-(2-(phenylamino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 33, first eluting enantiomer) and 6-methyl-2-(2-(phenylamino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 34, second eluting enantiomer).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Mg]Br>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[C:3]([F:10])=[C:4]([CH:5]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[O:12][CH3:11])[OH:6])[CH:7]=[CH:8][CH:9]=1
Reactant: COc1ccccc1[Mg]Br
Reactant: O=Cc1cccc(Br)c1F
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccccc1C(O)c1cccc(Br)c1F
Temperature: -78 °C
Yield: 80 %

Procedure:
To a solution of 3-bromo-2-fluorobenzaldehyde (1.0 g, 4.93 mmol) in THF (21.42 mL) cooled to −78° C. was added (2-methoxyphenyl)magnesium bromide in THF (5.91 mL, 5.91 mmol). The reaction mixture was maintained at −78° C. for at least 1 hr, and then allowed to warm to room temperature. The reaction mixture was cooled to 0° C. and additional (2-methoxyphenyl)magnesium bromide in THF (5.91 mL, 5.91 mmol) was added. The mixture was allowed to warm to room temperature overnight. The reaction was quenched with a saturated aqueous solution of NH4Cl. The reaction mixture was diluted with DCM. The layers were separated and the aqueous phase extracted twice with DCM. The organic extracts were combined, dried over Na2SO4, filtered, and concentrated to afford a yellow residue. The crude material was dissolved in a minimal amount of DCM and purified via silica gel chromatography using an ISCO machine (80 g column, 60 mL/min, 0-0% EtOAc in hexanes over 27 min, tr=19 min) gave the title compound (1.22 g, 3.92 mmol, 80% yield) as a pale yellow liquid. 1H NMR (400 MHz, CD3OD) δ 7.54-7.40 (m, 2H), 7.35-7.23 (m, 2H), 7.09-6.90 (m, 3H), 6.38 (s, 1H), 4.12 (q, J=7.0 Hz, 1H), 3.76 (s, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([Cl:11])=[C:9]([NH2:12])[N:8]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[F:20])[N:6]=1)=[O:4].[OH-].[Na+].Cl>CO>[NH2:12][C:9]1[N:8]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[F:20])[N:6]=[C:5]([C:3]([OH:4])=[O:2])[C:10]=1[Cl:11]
Reactant: COC(=O)c1nc(-c2ccc(Cl)cc2F)nc(N)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1nc(-c2ccc(Cl)cc2F)nc(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.7 %

Procedure:
6-Amino-5-chloro-2-(4-chloro-2-fluorophenyl)pyrimidine-4-carboxylic acid methyl ester (400 mg, 1.26 mmol) was dissolved in 10 mL methanol and 2 mL of 2N sodium hydroxide (4 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours and then acidified with a slight excess of 2N HCl. The resulting solution was concentrated and the precipitate that formed was filtered, washed with water, and dried yielding the title compound (170 mg, 44% yield): mp 194-196° C.: 1H NMR (DMSO-d6+few drops of D2O): δ 7.92 (m, 1H), 7.54 (dd, 1H), 7.42 (dd, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH:25]3[CH2:30][CH2:29][N:28](C(OCC)=O)[CH2:27][CH2:26]3)[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.Br>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[CH2:21][CH2:20]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)N1CCC(N2CCC(Nc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)CC1
Agent: Br
Product: Fc1ccc(Cn2c(NC3CCN(C4CCNCC4)CC3)nc3ccccc32)cc1
Yield: 50 %

Procedure:
A mixture of 21 parts of ethyl 4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino][1,4'-bipiperidine]-1'-carboxylate and 450 parts of hydrobromic acid solution 48% was stirred and refluxed for 16 hours. The reaction mixture was evaporated. From the residue the free base was liberated in the conventional manner with sodium hydroxide in water and extracted with dichloromethane. The extract was dried, filtered and evaporated, yielding 8 parts (50%) of N-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl][1,4'-bipiperidine]-4-amine as a residue (intermediate 71).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].[CH3:19][C:20]1[N:21]=[C:22]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[S:23][C:24]=1[C:25](O)([CH3:27])[CH3:26].C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:25]([CH3:27])([C:24]2[S:23][C:22]([C:29]3[CH:30]=[CH:31][C:32]([C:35]([F:37])([F:38])[F:36])=[CH:33][CH:34]=3)=[N:21][C:20]=2[CH3:19])[CH3:26])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(C)(C)O
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)C(Cc1ccc(OC(C)(C)c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C)OCC

Procedure:
In analogy to the procedure described in example 10 c], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 10 b]) was reacted with 2-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propan-2-ol [PCT Int. Appl. (2002), WO 02/062774 A1] in the presence of tributylphosphine and N,N,N′,N′-tetramethyl azodicarboxamide to yield [rac]-2-ethoxy-3-(2-methyl-4-{1-methyl-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-phenyl)-propionic acid ethyl ester as light yellow liquid.
Reaction SMILES: [C:1](Cl)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:11]([OH:14])[CH2:12][OH:13].N1C=CC=CC=1>>[C:1]([O:13][CH2:12][CH2:11][OH:14])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC(=O)Cl
Reactant: OCCO
Solvent: c1ccncc1
Product: CCCCCCCC(=O)OCCO
Reaction time: 2 h
Yield: 79.5 %

Procedure:
Capryloyl chloride (0.602 mol; 98 g) was dropwise added during 1.5 hour into a mixture of ethylene glycol (3 mol; 186 g) and pyridine (0.6 mol; 47.4 g). The mixture was further stirred for 2 hours at laboratory temperature, allowed to stand overnight, and threetimes extracted with benzene (100+50+25 ml). The benzene extract was shaken with a 10% aqueous solution of NaHCO3 (2×30 ml) and water and benzene was evaporated in a rotation evaporator. Distillation of the residue gave 4 raw fractions with purity 79.9 to 97.9% at the overall yield of 2-hydroxyethyl caprylate 79.5%. Further procedure was carried out according to example 1.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH2:4]O.S(Cl)([Cl:14])=O>C1C=CC=CC=1>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH2:4][Cl:14]
Reactant: O=S(Cl)Cl
Reactant: COc1cccc(F)c1CO
Solvent: c1ccccc1
Product: COc1cccc(F)c1CCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.57 g (3.64 mmol) of 2-fluoro-6-methoxybenzyl alcohol was dissolved in 10 ml of benzene, and the resultant solution was added with 0.56 g (4.73 mmol) of thionyl chloride under a room temperature. The obtained solution was stirred for 1 hour at a room temperature to complete a reaction. The reacted solution was then condensed under reduced pressure to obtain a crude product of 2-fluoro-6-methoxybenzyl chloride.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[NH2:14][CH2:15][CH2:16][OH:17]>C1COCC1>[NH2:1][C:4]1[CH:5]=[C:6]([S:10]([NH:14][CH2:15][CH2:16][OH:17])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1
Reactant: NCCO
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Solvent: C1CCOC1
Product: Nc1cccc(S(=O)(=O)NCCO)c1
Reaction time: 8 h
Yield: 50.8 %

Procedure:
3-Nitrobenzenesulfonyl chloride (2.22 g) dissolved in 20 mL of THF was added to a solution of 2-aminoethanol (2.0 g) and tryethylamine (2.0 g) in 20 mL of THF. The reaction mixture was kept at ambient temperature overnight. The solvent was removed and the residue was dissolved in water (20 mL) and then extracted with EtOAc (2×50 mL). The solvent of the organic layer was removed and the residue was dissolved in 50 mL of EtOH and a catalytic amount of Raney-Nickel was added, followed by the addition of hydrazine hydrate (2 mL). The reaction mixture was kept at ambient temperature under argon overnight, filtered through a celite cake. The solvent of the filtrate was removed yielding 1.1 g of 3-amino-N-(2-hydroxyethyl)benzenesulfonamide which was used in the next step without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[O-:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15].[C:21]1([I+]C2C=CC=CC=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(OCC)C>O.C([O-])(=O)C1C=CC=CC=1.[Cu+2].C([O-])(=O)C1C=CC=CC=1>[O-:16][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:15])=[O:13].[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S+:6]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: c1ccc([I+]c2ccccc2)cc1
Reactant: c1ccc(Sc2cccs2)cc1
Agent: [Cu+2]
Agent: O=C([O-])c1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCOCC
Solvent: O
Product: c1ccc([S+](c2ccccc2)c2cccs2)cc1
Reaction time: 24 h
Yield: 89.6 %

Procedure:
(2-thienyl)phenylsulfide (2.0 g, 0.0104 mole), diphenyliodonium triflate (5.8 g, 0.0135 mole) and copper benzoate (0.08 g, 0.003 mole) are heated without solvent for 3 hours at 120-145° C. under nitrogen atmosphere. After cooling down, 75 ml ethyl ether was added and the mixture vigorously stirred overnight to achieve solidification. Filtration and washing with ethyl ether yielded a brown solid, which was dissolved in hot water, the solution filtered and the water removed in vacuo. The resulting white solid was stirred in 50 ml ether for 24 hours, the mixture filtered and the residue washed with ethyl ether, yielding 3.9 g (90%) of the title compound, (2-thienyl)diphenylsulfonium triflate. The structure was confirmed by 1H/13C NMR.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[CH2:11]([O:13][P:14]([CH2:19][CH2:20][CH2:21][NH:22][OH:23])(=[O:18])[O:15][CH2:16][CH3:17])[CH3:12].[OH-].[Na+]>C(Cl)(Cl)Cl.CO.O>[CH2:16]([O:15][P:14]([CH2:19][CH2:20][CH2:21][N:22]([OH:23])[CH:1]=[O:3])(=[O:18])[O:13][CH2:11][CH3:12])[CH3:17]
Reactant: CCOP(=O)(CCCNO)OCC
Reactant: O=CO
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CCOP(=O)(CCCN(O)C=O)OCC

Procedure:
1.38 (0.030 mol) formic acid were added drop by drop at room temperature to 2.04 g (0.020 mol) acetic anhydride and stirred at the same temperature. This solution was added with cooling with ice to 2.8 g (0.013 mol) 3-(N-hydroxyamino)-propylphosphonic acid diethylester dissolved in chloroform. The reaction mixture is stirred for 30 minutes at 0-5° C. and for a further 1.5 hours at room temperature. After concentration under reduced pressure until an oily residue is obtained, this oily residue is taken up in 15 ml methanol and 5 ml water, adjusted to pH=8 with 2 n NaOH and stirred for a further 1.5 hours at room temperature. Methanol is removed under reduced pressure and the resultant aqueous solution is adjusted to pH=5 with concentrated HCl. The yellow solution is extracted with chloroform (1×30 ml, 2×10 ml in each case) and the CHCl3 phases are dried over MgSO4. After concentration of the solution in the entire diaphragm pump vacuum 3 g of a yellow oil are obtained. After removal of volatile constituents in the entire diaphragm pump vacuum, chromatography on 60 g SiO2 with chloroform shows: methanol in the ratio 25:1 2.65 g product as yellow oil (DE-A-27 33 658).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[Cl:11])=[O:3].[CH2:12]([O:14][C:15](=O)[O:16]CC)[CH3:13].[H-].[Na+]>>[CH2:12]([O:14][C:15](=[O:16])[CH2:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[Cl:11])=[O:3])[CH3:13]
Reactant: CC(=O)c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(=O)c1ccc(Cl)cc1Cl

Procedure:
Synthesis of Intermediate 1a was done by standard procedure starting from 2,4-dichloroacetophenone, diethylcarbonate (25 eq) and NaH (2 eq) at 80° C. for 60 minutes.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[S:11]1([C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:15](=[O:16])[NH:14]1)(=[O:13])=[O:12].[Na]>O1CCCC1>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:14]1[C:15](=[O:16])[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:11]1(=[O:13])=[O:12])=[O:5]
Reactant: O=C1NS(=O)(=O)c2ccccc21
Reactant: O=C(Cl)c1ccccc1F
Agent: [Na]
Solvent: C1CCOC1
Product: O=C(c1ccccc1F)N1C(=O)c2ccccc2S1(=O)=O

Procedure:
A mixture of 2-fluorobenzoyl chloride, from example 4A, above, and 18.5 g (0.09 mole) of sodium saccharin is refluxed in 100 ml of tetrahydrofuran (THF) overnight. The reaction mixture is filtered hot, and the filtrate is concentrated to a partial solid/oil. The product is triturated with ether and air dried to yield 10.3 g of 2-(2-fluorobenzoyl)saccharin, m.p. 148°-151° C.
Reaction SMILES: [CH2:1]([N:5]([CH3:26])[C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[NH:13][C:14](=[O:25])[NH:15][C:16]1[S:17][CH:18]=[C:19]([CH2:21][C:22]([OH:24])=O)[N:20]=1)[CH:2]([CH3:4])[CH3:3].[CH3:27][NH2:28]>>[CH2:1]([N:5]([CH3:26])[C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[NH:13][C:14](=[O:25])[NH:15][C:16]1[S:17][CH:18]=[C:19]([CH2:21][C:22]([NH:28][CH3:27])=[O:24])[N:20]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: CN
Reactant: Cc1ccc(NC(=O)Nc2nc(CC(=O)O)cs2)c(N(C)CC(C)C)c1
Product: CNC(=O)Cc1csc(NC(=O)Nc2ccc(C)cc2N(C)CC(C)C)n1
Yield: 65 %

Procedure:
2-(2-{3-[2-(Isobutyl-methyl-amino)-4-methyl-phenyl]-ureido}-thiazol-4-yl)-N-methyl-acetamide (63 mg, 65%) was prepared from (2-{3-[2-(isobutyl-methyl-amino)-4-methyl-phenyl]-ureido}-thiazol-4-yl)-acetic acid (95 mg, 0.25 mmol) and methylamine following the general procedure K.
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([NH:24][C:25]1[CH:26]=[N:27][N:28]([CH2:44][C:45]([F:48])([F:47])[F:46])[C:29]=1[N:30]1[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[C@H:32]([CH3:43])[CH2:31]1)=[O:23])=O)(C)(C)C.N>Cl.CO.CO>[NH2:8][C:9]1[S:13][C:12]([C:14]2[C:15]([F:21])=[CH:16][CH:17]=[CH:18][C:19]=2[F:20])=[N:11][C:10]=1[C:22]([NH:24][C:25]1[CH:26]=[N:27][N:28]([CH2:44][C:45]([F:47])([F:48])[F:46])[C:29]=1[N:30]1[CH2:35][CH2:34][NH:33][C@H:32]([CH3:43])[CH2:31]1)=[O:23]
Reactant: C[C@@H]1CN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3NC(=O)OC(C)(C)C)cnn2CC(F)(F)F)CCN1C(=O)OC(C)(C)C
Agent: Cl
Agent: N
Solvent: CO
Product: C[C@@H]1CN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3N)cnn2CC(F)(F)F)CCN1
Temperature: 25 °C
Reaction time: 20 h
Yield: 53.2 %

Procedure:
A mixture of tert-butyl (R)-4-(4-(5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxamido)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)-2-methylpiperazine-1-carboxylate (82 mg, 0.12 mmol) in HCl/MeOH (10 mL) was stirred at ambient temperature for 20 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with MeOH (30 mL), neutralized with 28% ammonia solution, concentrated, and purified by preparative HPLC to afford 233 as a white solid (32 mg, 56%). 1H-NMR (500 MHz, CD3OD) δ (ppm): 7.69 (s, 1H), 7.51-7.45 (m, 1H), 7.17-7.12 (m, 2H), 4.84-4.78 (m, 2H), 3.22-3.17 (m, 1H), 3.05-2.86 (m, 6H), 1.08 (d, J=6 Hz, 3H); MS (ESI) m/z: 502 [M+H+].
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:10]([OH:12])=O)[N:8]=1)=[O:2].P(Cl)(Cl)(Cl)=O.Cl.[NH2:26][CH:27]1[C:48](=[O:49])[N:29]2[C:30]([C:35]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=3)=[O:36])=[C:31]([Cl:34])[CH2:32][S:33][C@H:28]12.C[Si](CC(N)=O)(C)C>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][C:16]([F:19])([F:18])[F:17])[C:10]([NH:26][CH:27]2[C:48](=[O:49])[N:29]3[C:30]([C:35]([O:37][CH2:38][C:39]4[CH:40]=[CH:41][C:42]([N+:45]([O-:47])=[O:46])=[CH:43][CH:44]=4)=[O:36])=[C:31]([Cl:34])[CH2:32][S:33][C@H:28]23)=[O:12])[N:8]=1)=[O:2]
Reactant: O=CNc1nc(C(=NOCC(F)(F)F)C(=O)O)cs1
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12
Agent: C[Si](C)(C)CC(N)=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=CNc1nc(C(=NOCC(F)(F)F)C(=O)NC2C(=O)N3C(C(=O)OCc4ccc([N+](=O)[O-])cc4)=C(Cl)CS[C@H]23)cs1
Yield: 96.7 %

Procedure:
A solution of 2-(2-formamidothiazol-4-yl)-2-(2,2,2-trifluoroethoxyimino)acetic acid (syn isomer, 0.9 g.), N,N-dimethylformamide (0.24 g.) and phosphoryl chloride (0.5 g.) in ethyl acetate (10 ml.) and a solution of 4-nitrobenzyl 7-amino-3-chloro-3-cephem-4-carboxylate hydrochloride (1.23 g.) and trimethylsilylacetamide (2.8 g.) in ethyl acetate (20 ml.) were treated in a similar manner to that of Example 21-(1) to give 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-(2,2,2-trifluoroethoxyimino)acetamido]-3-chloro-3-cephem-4-carboxylate (syn isomer, 1.9 g.).
Reaction SMILES: [CH2:1]([N:4]([CH2:8][CH:9]=[CH2:10])[C:5](Cl)=[O:6])[CH:2]=[CH2:3].[CH2:11]([S:13][C:14]1[N:18]=[CH:17][NH:16][N:15]=1)[CH3:12].C(N(CC)CC)C>O1CCCC1>[CH2:1]([N:4]([CH2:8][CH:9]=[CH2:10])[C:5]([N:16]1[CH:17]=[N:18][C:14]([S:13][CH2:11][CH3:12])=[N:15]1)=[O:6])[CH:2]=[CH2:3]
Reactant: CCSc1nc[nH]n1
Reactant: C=CCN(CC=C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCN(CC=C)C(=O)n1cnc(SCC)n1

Procedure:
Diallylcarbamoyl chloride (8 g.) was added to a solution of 7.1 g. 3-ethylthio-1,2,4-triazole and 8 ml. dry triethylamine in 50 ml. dry tetrahydrofuran and the mixture refluxed for 4 hours under anhydrous conditions. The cooled reaction mixture was diluted with 100 ml. toluene and washed, firstly with 1N aqueous sodium hydroxide and then with water. The resulting solution was dried over anhydrous sodium sulphate and distilled under reduced pressure to remove the solvent and give 1-diallylcarbamoyl-3-ethylthio-1,2,4-triazole, b.p. 120° - 122° C./0.1 mm. (97.1% 1-isomer by GLC assay).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1(=[O:18])[O:17][CH2:16][CH2:15][CH2:14]1.[CH2:19]([O:26][CH2:27][C:28](OCC)=[O:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>O1CCCC1.C(OCC)(=O)C.CCCCCC>[CH2:19]([O:26][CH2:27][C:28]([CH:14]1[CH2:15][CH2:16][O:17][C:13]1=[O:18])=[O:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1CCCO1
Reactant: CCOC(=O)COCc1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(COCc1ccccc1)C1CCOC1=O
Reaction time: 0.25 h
Yield: 73.1 %

Procedure:
A solution of 10.6 ml of diisopropylamine in 75 ml of tetrahydrofuran was chilled to -70° C., and 46 ml of a 1.6N hexane solution of n-butyllithium were added dropwise to the solution. After completion of the addition, the mixture was stirred for 15 minutes, and a solution of 54.8 g of γ-butyrolactone in 50 ml of tetrahydrofuran was added dropwise over 55 minutes, and the mixture was stirred for 50 minutes. Further, a solution of 14.75 g of ethyl benzyloxyacetate in 50 ml of tetrahydrofuran was added, and the resultant mixture was stirred for 2.5 hours at -60 to -50° C. 5N hydrochloric acid was then added so as not to exceed 20° C. to adjust the pH of the mixture to 1-2. Ethyl acetate was added to the reaction system, and the resultant mixture was washed with a saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The thus-obtained crude product was subjected to column chromatography on silica gel (elution solvent: hexane:ethyl acetate=3:1→2:1→1:1) to obtain 13.01 g (yield: 87.2%) of the intended product as a colorless oil.