Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:18]=[CH:17][C:7]2[N:8]=[C:9]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[S:10][C:6]=2[CH:5]=1.C(N(CC)CC)C.C1COCC1.[Cl:31][CH2:32][C:33](Cl)=[O:34]>C(OCC)(=O)C.O>[Cl:31][CH2:32][C:33]([N:14]1[CH2:15][CH2:16][N:11]([C:9]2[S:10][C:6]3[CH:5]=[C:4]([Cl:3])[CH:18]=[CH:17][C:7]=3[N:8]=2)[CH2:12][CH2:13]1)=[O:34]
Reactant: O=C(Cl)CCl
Reactant: Clc1ccc2nc(N3CCNCC3)sc2c1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(CCl)N1CCN(c2nc3ccc(Cl)cc3s2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of 4-(6-chlorobenzothiazole-2-yl)piperazine dihydrochloride (0.50 g; 1.53 mmol), triethylamine (0.32 ml; 2.25 mmol) and anhydrous THF (10 ml) was added dropwise chloroacetylchloride (0.18 ml; 2.25 mmol) under ice-cooling. The mixture was stirred at room temperature for 24 hours. Water and ethyl acetate were added to the reaction solution and extracted. The organic layer was washed with brine, dried over anhydrous sodium sulphate, and evaporated under reduced pressure. The precipitate was washed with hexane to give 2-chloro-1-[4-(6-chlorobenzothiazole-2-yl)piperazine-1-yl]ethane-1-on as blackish brown crystal (0.15 g; 30%).
Reaction SMILES: [F:1][C:2]1([F:36])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:18]=[C:19]([C:27]5[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=5)[C:30](O)=[O:31])[C:20]5[C:25]([CH:26]=4)=[CH:24][CH:23]=[CH:22][CH:21]=5)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.S(Cl)([Cl:39])=O.CN(C)C=O>ClCCl>[F:1][C:2]1([F:36])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:18]=[C:19]([C:27]5[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=5)[C:30]([Cl:39])=[O:31])[C:20]5[C:25]([CH:26]=4)=[CH:24][CH:23]=[CH:22][CH:21]=5)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)cc3ccccc23)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)cc3ccccc23)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 3-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid (1.26 g, 2.58 mmol) in dichloromethane (5 mL) was added thionyl chloride (922 mg, 564 μL, 7.75 mmol) and N,N-dimethyl formamide (20 μL). The reaction mixture was stirred at room temperature for 30 minutes before it was evaporated to dryness to yield 3-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoyl chloride as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH:5]([SH:7])[CH3:6])C.Br[CH2:10][C:11]1[CH:12]=[C:13]([CH:33]=[CH:34][CH:35]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([C:20]2[C:25]3[O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:24]=3[CH:23]=[CH:22][CH:21]=2)[CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)C>[CH3:1][O:3][C:4](=[O:8])[CH:5]([S:7][CH2:10][C:11]1[CH:12]=[C:13]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]([C:20]3[C:25]4[O:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[C:24]=4[CH:23]=[CH:22][CH:21]=3)[CH:19]=2)[CH:33]=[CH:34][CH:35]=1)[CH3:6]
Reactant: CCOC(=O)C(C)S
Reactant: BrCc1cccc(-c2cccc(-c3cccc4c3oc3ccccc34)c2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)C(C)SCc1cccc(-c2cccc(-c3cccc4c3oc3ccccc34)c2)c1

Procedure:
Ethyl-2-mercaptopropionate (31 mg, 0.29 mmol) was added to a stirred suspension of 4-(3′-bromomethyl-biphen-3-yl)-dibenzofuran (100 mg, 0.24 mmol) and cesium carbonate (198 mg, 0.6 mmol) in 5 ml DMF. diluted with diethyl ether (30 mL) and washed with water (2×) and brine (3×). The ethereal solution was dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification of the product by flash column chromatography, using 30% ethyl acetate in hexane as eluent, afforded the title compound; methyl-2-(3′-dibenzofuran-4-yl-biphen-3-ylmethylsulfanyl)-propionate, as a colorless oil (105 mg, 94).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]=2)=[CH:11][C:10]=1[Cl:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[C:1]([O:5][C:6]([N:8]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:17][CH2:16]2)=[CH:11][C:10]=1[Cl:28])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(Cl)c2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of the product of Example 60B (4.39 g, 10.7 mmol) and 10% palladium on carbon in methanol (100 mL) was stirred under hydrogen at ambient temperature for 4 hours. The mixture was filtered through diatomaceous earth and concentrated. The crude title compound was used in the next step without further purification.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[C:37](=[O:38])[N:11]2[C:12]([C:34]([OH:36])=[O:35])=[C:13]([CH2:16][O:17][C:18](=[O:33])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25](=[O:32])[NH:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:14][S:15][C@H:10]12)=O)(C)(C)C>FC(F)(F)C(O)=O>[NH2:8][C@@H:9]1[C:37](=[O:38])[N:11]2[C:12]([C:34]([OH:36])=[O:35])=[C:13]([CH2:16][O:17][C:18](=[O:33])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25](=[O:32])[NH:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:14][S:15][C@H:10]12
Reactant: CCOC(=O)NC(=O)c1ccccc1C(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H]2SC1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)NC(=O)c1ccccc1C(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reaction time: 0.33 h
Yield: 86.7 %

Procedure:
7β-(t-Butoxycarbonyl)amino-3-[2-(N-carboethoxycarbamoyl)benzoyloxy]methyl-3-cephem-4-carboxylic acid (275 mg) is dissolved in trifluoroacetic acid (2 ml) under ice-cooling and the mixture is stirred for 20 minutes. The solution is concentrated and to the residue, ether (20 ml) is added. The resultant precipitate is triturated, collected by filtration, washed with ether and dried over phosphorus pentoxide. The procedure provides 7β-amino-3-[2-(N-carboethoxycarbamoyl)benzoyloxy]methyl-3-cephem-4-carboxylic acid (195 mg). In NMR spectrum, this product is good agreement with the product obtained in Example 20.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([O:12]CC3C=CC(OC)=CC=3)[C:7]=2[C:22]2[CH:23]=[C:24]([C@@H:33]3[CH2:38][CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34]3)[C:25]3[CH2:30][O:29][C:28](=[O:31])[NH:27][C:26]=3[N:32]=2)[CH2:3][CH2:2]1.[ClH:46]>O1CCOCC1>[ClH:46].[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[C:7]=2[C:22]2[CH:23]=[C:24]([C@@H:33]3[CH2:38][CH2:37][CH2:36][NH:35][CH2:34]3)[C:25]3[CH2:30][O:29][C:28](=[O:31])[NH:27][C:26]=3[N:32]=2)[CH2:2][CH2:3]1
Reactant: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc([C@@H]3CCCN(C(=O)OC(C)(C)C)C3)c3c(n2)NC(=O)OC3)cc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C1Nc2nc(-c3c(O)cccc3OCC3CC3)cc([C@@H]3CCCNC3)c2CO1
Reaction time: 3 h
Yield: 71 %

Procedure:
To a solution of tert-butyl (3S)-(−)-3-(7-{2-(cyclopropylmethoxy)-6-[(4-methoxy-benzyl)oxy]phenyl}-2-oxo-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl)-1-piperidinecarboxylate (1.0 g, 1.624 mmol) in dioxane (15 mL) was added 4N HCl in dioxane (30 mL) at room temperature. The stirring was continued for 3 hrs. After the solvent was removed by evaporation, the resulting solid was triturated with acetonitril, collected by filtration, and washed with acetonitrile. The solid was recrystallized from methanol to give (−)-7-[2-(cyclopropylmethoxy)-6-hydroxy-phenyl]-5-[(3S)-3-piperidinyl]-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one hydrochloride as a white solid (0.502 g, yield; 71%). The absolute configuration for the chiral atom was determined with (S) by the X-ray analysis.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:16][CH2:17][CH:18]=[CH2:19]>CN(C=O)C.C(OCC)(=O)C>[O:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([O:1][CH2:19][CH2:18][CH:17]=[CH2:16])[CH:11]=2)[CH:6]=[CH:7][C:8]1=[O:12]
Reactant: O=c1ccc2ccc(O)cc2o1
Reactant: C=CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCCOc1ccc2ccc(=O)oc2c1
Temperature: 60 °C
Yield: 63.7 %

Procedure:
A suspension of 7-hydroxycoumarin (3 g, 19.6 mmol) in DMF (20 ml) is treated with NaH (60% suspension in oil, 1.03 g, 25.9 mmol), then with 4-bromo-1-butene (2.65 g, 19.6 mmol). It is heated to 60° C. for 24 hours, then it is diluted with ethyl acetate (400 ml), and it is washed with water (3×300 mL) then with 1 M NaOH (3×200 ml). The residue is chromatographed with the mixture (ethyl acetate-hexane) to obtain 4-(7-coumarinyloxy)-1-butene (2.7 g, 67%).
Reaction SMILES: [CH2:1]([NH:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([S:13]CC2C=CC(OC)=CC=2)=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:2].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH2:1]([NH:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([SH:13])=[CH:9][CH:8]=1)(=[O:5])=[O:6])[CH3:2]
Reactant: CCNS(=O)(=O)c1ccc(SCc2ccc(OC)cc2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCNS(=O)(=O)c1ccc(S)cc1
Temperature: 80 °C

Procedure:
To N-ethyl-4-(4-methoxy-benzylsulfanyl)-benzenesulfonamide 5.95 g was added trifluoroacetic acid 60 ml containing triethyl silane 3 ml and the mixture heated at 80° C. for 2 h. The reaction mixture was cooled and evaporated in vacuo. The residue was taken up in ethyl acetate and evaporated in vacuo ×2. The residue was then taken up in ethyl acetate and extracted with 2M sodium hydroxide 3×30 ml and the combined aqueous solution washed with ethyl acetate (×1). The aqueous solution was then acidified with conc. hydrochloric acid and extracted with dichloromethane ×3 and the organic solution washed with water, dried MgSO4 and evaporated in vacuo to give N-ethyl-4-mercapto-benzenesulfonamide, as a pale yellow oil, 3.05 g 79%. 1H NMR 7.72 (2H, d), 7.34 (2H, d), 4.65 (1H, bs), 3.70 (1H, s), 2.99 (2H, q), 1.11 (3H, t).
Reaction SMILES: [C:1]1([CH3:23])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([N:10]2[C@H:14]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[CH2:21][C@H:13]3[O:12][C:11]2=[O:22])=[O:9])[CH:2]=1.C[Si](C)(C)N[Si](C)(C)C.[Na].[Cl:34][C:35]1[CH:36]=[C:37]([C:42]2[N:46]([C:47]3[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=3)[N:45]=[C:44]([CH2:55]I)[CH:43]=2)[CH:38]=[CH:39][C:40]=1[Cl:41]>C1COCC1>[Cl:34][C:35]1[CH:36]=[C:37]([C:42]2[N:46]([C:47]3[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=3)[N:45]=[C:44]([CH2:55][C@@H:7]([C:3]3[CH:2]=[C:1]([CH3:23])[CH:6]=[CH:5][CH:4]=3)[C:8]([N:10]3[C@H:14]4[C:15]5[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=5[CH2:21][C@H:13]4[O:12][C:11]3=[O:22])=[O:9])[CH:43]=2)[CH:38]=[CH:39][C:40]=1[Cl:41]
Reactant: Cc1cccc(CC(=O)N2C(=O)O[C@@H]3Cc4ccccc4[C@@H]32)c1
Reactant: COc1ccc(-n2nc(CI)cc2-c2ccc(Cl)c(Cl)c2)cc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(C[C@H](C(=O)N3C(=O)O[C@@H]4Cc5ccccc5[C@@H]43)c3cccc(C)c3)cc2-c2ccc(Cl)c(Cl)c2)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 83.1 %

Procedure:
To a stirred solution of (3aS,8aR)-3-(2-m-tolyl-acetyl)-3,3a,8,8a-tetrahydro-indeno[1,2-d]oxazol-2-one (product of Step F., 12 g, 0.039 mol) in THF (100 mL) was added 1.0 M sodium 1,1,1,3,3,3-hexamethyldisilazane (NaHMDS) (41 mL, 0.041 mol) in THF at −78° C. The mixture was stirred for 45 min at −78° C. then treated with 5-(3,4-dichloro-phenyl)-3-iodomethyl-1-(4-methoxy-phenyl)-1l-H-pyrazole (product of Step E., 18.4 g, 0.0405 mol) in THF (100 mL). The reaction mixture was allowed to warm to rt overnight and then was quenched with H2O (100 mL) and concentrated to half the volume. The aqueous layer was washed with EtOAc (3×75 mL). The extracted organic layer was washed with saturated NaCl, dried over Na2SO4, filtered and concentrated to an oil. The crude oil was purified by flash column chromatography (silica gel, 7:3 hexane/EtOAc) to obtain 20.7 g of the title compound (83%) as white foam. HPLC: Rt=11.38 (Method E). MS (ES+): mass calculated for C36H29Cl2N3O4, 638.55; m/z found 660.3 [M+Na]+. 1H NMR (400 MHz, CDCl3): 7.52 (d, J=7.6 Hz, 1H), 7.11-7.35 (m, 8H), 6.93-6.99 (m, 3H), 6.74-6.82 (m, 3H), 6.20 (s, 1H), 5.89 (d, J=6.8 Hz, 1H), 5.58 (q, J=6.1, 4.5 Hz, 1H), 5.11-5.15 (m, 1H), 3.8 (s, 3H), 3.72 (dd, J=10.6, 4.1 Hz, 1H), 3.33 (br, s, 2H), 3.07 (dd, J=9.8, 4.8 Hz, 1H), 2.37 (s, 3H).
Reaction SMILES: [ClH:1].CN(C)CCCN=C=NCC.[NH2:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][N:18]=[C:17]2[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=1.N1C=CC=CC=1.Cl.[CH2:42]1C[O:45][CH2:44][CH2:43]1.CN(C=O)C>>[ClH:1].[F:32][C:31]([F:33])([F:34])[C:27]1[CH:26]=[C:25]([NH:24][C:17]2[C:16]3[C:21](=[CH:22][CH:23]=[C:14]([NH:13][C:44](=[O:45])[CH:43]=[CH2:42])[CH:15]=3)[N:20]=[CH:19][N:18]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: Nc1ccc2ncnc(Nc3cccc(C(F)(F)F)c3)c2c1
Reactant: C1CCOC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: C=CC(=O)Nc1ccc2ncnc(Nc3cccc(C(F)(F)F)c3)c2c1
Temperature: 0 °C
Yield: 45 %

Procedure:
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (212 mg, 1.1 mmol) was added to a solution of 6-amino-4[(3-(trifluoromethyl)phenyl)amino]quinazoline (153 mg, 0.5 mmol) acrylic acid (73 mg, 1.0 mmol) and pyridine (206 mg, 2.5 nmmol) in THF/DMF (4:1, 2.5 mL), stirred under nitrogen at 0° C. After 15 minutes the reaction mixture was stirred at 25° C. for 1 hour, and then recooled to 0° C. Dilute hydrochloric acid (0.5 M, 10 mL) was added, and after 15 minutes the precipitate was collected by Buchner filtration. The residue was rinsed with water (5 mL) and ether (2×5 mL) and dried in a vacuum oven at 75° C. overnight to give N-[4-[(3-(trifluoromethyl) phenyl)amino]quinazolin-6-yl]acrylamide hydrochloride (87 mg, 45%) as a light greenish solid, mp 195-199° C.
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH:8]1[CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Cl.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](Cl)=[O:24]>N1C=CC=CC=1>[C:1]([C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH:8]1[CH2:9][N:10]([C:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=2)=[O:24])[CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1OC1CNC1
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)c1ccccc1OC1CN(C(=O)c2ccccn2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.1 %

Procedure:
To an ice-cold stirred solution of 3-(2-tert-butylphenoxy)azetidine (2.00 g, 9.74 mmol) in pyridine (20.0 ml) was added picolinoyl chloride hydrochloride (2.08 g, 11.7 mmol). After stirring for 16 h at room temperature, the reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and 10% aqueous Na2CO3 and separated. The organic layer was washed with saturated sodium chloride, dried (Na2SO4), filtered by a pad of silica gel and concentrated under reduced pressure. The residue was purified with flash column chromatography (silica gel, 90:10 to 50:50 heptane/ethyl acetate) to provide a yellow solid. The solid was recrystallized from heptane/ethyl acetate to provide (3-(2-tert-butylphenoxy)azetidin-1-yl)(pyridin-2-yl)methanone (0.94 g, 31%) as a off-white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([O:11][N:12]=[C:13]([C:36]2[N:37]=[C:38]([NH:41]C=O)[S:39][CH:40]=2)[C:14]([NH:16][C@@H:17]2[C:34](=[O:35])[N:19]3[C:20]([C:31]([O-:33])=[O:32])=[C:21]([CH2:24][N+:25]4[N:26]([CH3:30])[CH:27]=[CH:28][CH:29]=4)[CH2:22][S:23][C@H:18]23)=[O:15])[CH2:10][CH2:9]1.Cl.C(OCC)C>CO>[NH2:41][C:38]1[S:39][CH:40]=[C:36]([C:13](=[N:12][O:11][CH:8]2[CH2:9][CH2:10]2)[C:14]([NH:16][C@@H:17]2[C:34](=[O:35])[N:19]3[C:20]([C:31]([O-:33])=[O:32])=[C:21]([CH2:24][N+:25]4[N:26]([CH3:30])[CH:27]=[CH:28][CH:29]=4)[CH2:22][S:23][C@H:18]23)=[O:15])[N:37]=1
Reactant: Cn1ccc[n+]1CC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)C(=NOC3CC3)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: Cn1ccc[n+]1CC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)C(=NOC3CC3)c3csc(N)n3)[C@H]2SC1
Reaction time: 2 h
Yield: 30.5 %

Procedure:
To a solution of trifluoroacetic acid salt of 7β-[2-cyclopropyloxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate (syn isomer, 2.35 g) in methanol (12 ml) was added conc. hydrochloric acid (0.8 ml) at ambient temperature, and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was added to diethyl ether (300 ml), and the precipitates were collected by filtration. The precipitates were dissolved in water (20 ml) and the solution was adjusted to pH 5 with saturated aqueous solution of sodium bicarbonate. The solution was subjected to column chromatography on macroporous non-ionic adsorption resin "Diaion HP-20" (Trademark, manufactured by Mitsubishi Chemical Industries) and eluted with 15% aqueous solution of isopropyl alcohol. The fractions containing the object compound were collected and evaporated in vacuo to remove isopropyl alcohol. The solution was lyophilized to give 7β-[2-(2-aminothiazol-4-yl)-2-(cyclopropyloxyimino)acetamido]-3-(2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate (syn isomer, 0.68 g).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.[Cl:15][C:16]1[S:17][CH:18]=[C:19]([C:21](O)=[O:22])[N:20]=1>>[C:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][C@H:3]([CH2:2][NH:1][C:21]([C:19]2[N:20]=[C:16]([Cl:15])[S:17][CH:18]=2)=[O:22])[CH2:4]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(O)c1csc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN)C1
Product: CC(C)(C)OC(=O)N1CC[C@H](CNC(=O)c2csc(Cl)n2)C1

Procedure:
61.1 Using general procedure E, (R)-3-aminomethyl-1-N-tert-butoxycarbonyl-pyrrolidine was coupled with 2-chloro-thiazole-4-carboxylic acid (prepared according to R. Walsh et al. Chimica Therapeutica, 1973, 8, 199) to give (R)-3-{[(2-chloro-thiazole-4-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester. White solid. MS 343.9 ([M−H]−)
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][CH3:12])[C:3]=1[C:4]([NH2:6])=[O:5].N1C=CC=CC=1.[C:19]([O:22][CH2:23][C:24](Cl)=[O:25])(=[O:21])[CH3:20]>C(Cl)Cl>[C:19]([O:22][CH2:23][C:24]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][CH3:12])[C:3]=1[C:4]([NH2:6])=[O:5])=[O:25])(=[O:21])[CH3:20]
Reactant: CNc1cccc(N)c1C(N)=O
Reactant: CC(=O)OCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CNc1cccc(NC(=O)COC(C)=O)c1C(N)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-6-(methylamino)benzamide (3.6 g) in methylene chloride (100 ml) is added pyridine (4.8 ml), and thereto is added dropwise acetoxyacetyl chloride (3.2 ml) which is cooled in an ice bath. The mixture is stirred at room temperature for 1 hour, and thereafter, the solvent is distilled off under reduced pressure. The resulting crude crystals are washed with water and ether and then are recrystallized from ethanol to give the title compound (4.2 g) having the following physical properties.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[OH-].[K+].N1[C:31]2[C:22](=[CH:23][CH:24]=[C:25]3[C:30]=2N=CC=C3)C=CC=1.IC1C=CC=CC=1>Cl[Cu].C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:22]2[CH:31]=[CH:30][CH:25]=[CH:24][CH:23]=2)[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(Nc2ccc(C)cc2)cc1
Reactant: c1cnc2c(c1)ccc1cccnc12
Agent: Cl[Cu]
Agent: [K+]
Agent: [OH-]
Solvent: Ic1ccccc1
Solvent: Cc1ccccc1
Product: Cc1ccc(N(c2ccccc2)c2ccc(C)cc2)cc1
Temperature: 120 °C
Reaction time: 12 h

Procedure:
4,4′-dimethyldiphenylamine (0.99 g, 5.0 mmol), KOH (2.52 g, 45.0 mmol), CuCl (99 mg, 1.0 mmol) and 1,10-phenanthroline (180 mg, 1.0 mmol) were charged in a two-necked bottle. The bottle was deoxygenated and purged with nitrogen, and added dried toluene (12 mL) and iodobenzene (0.67 ml, 6.0 mmol). The reaction was heated to 120° C., and stirred for 12 hours. The resulting was filtered to remove metal and then concentrated under reduced pressure and the residue was purified by column chromatography (hexanes/CH2Cl2=1/1) to afford G (916 g, 67%) as white solid.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([Br:18])=[C:13]2[N:12]=[CH:11][C:10]=1[C:19]([OH:21])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([Br:18])=[C:13]2[N:12]=[CH:11][C:10]=1[C:19]([N:33]1[CH2:34][CH2:35][CH:30]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[F:23])[CH2:31][CH2:32]1)=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccccc1C1CCNCC1
Reactant: O=C(O)c1cnc2c(Br)cnn2c1NCc1ccccc1
Agent: Cl
Product: O=C(c1cnc2c(Br)cnn2c1NCc1ccccc1)N1CCC(c2ccccc2F)CC1
Yield: 136.1 %

Procedure:
In the same manner as in Example 21, step 5 and using 7-benzylamino-3-bromopyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.174 g, 0.506 mmol) obtained in Example 22, step 3 and 4-(2-fluorophenyl)piperidine hydrochloride (0.120 g, 0.556 mmol), the title compound (0.35 g, 90%) was obtained.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([C:18](O)=[O:19])=[CH:16][N:17]=3)[CH:14]=2)=[CH:5][CH:4]=1.O[NH:24][C:25]([C:27]1[S:28][C:29]([S:32](=[O:35])(=[O:34])[NH2:33])=[CH:30][CH:31]=1)=[NH:26]>>[F:21][C:2]([F:1])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([C:18]4[O:19][N:26]=[C:25]([C:27]5[S:28][C:29]([S:32]([NH2:33])(=[O:35])=[O:34])=[CH:30][CH:31]=5)[N:24]=4)=[CH:16][N:17]=3)[CH:14]=2)=[CH:5][CH:4]=1
Reactant: O=C(O)c1cnc2ccc(-c3ccc(C(F)(F)F)cc3)cn12
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)s1
Product: NS(=O)(=O)c1ccc(-c2noc(-c3cnc4ccc(-c5ccc(C(F)(F)F)cc5)cn34)n2)s1

Procedure:
The title compound was prepared from 6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine-3-carboxylic acid (example C.35) (153 mg, 0.5 mmol) and N-hydroxy-5-sulfamoyl-thiophene-2-carboxamidine (example B.2) (166 mg, 0.75 mmol) according to general procedure II. Obtained after trituration with water and further purification by crystallization (heptane/diethyl ether) as an off-white solid (179 mg, 83%). MS (ISP) 492.2 [(M+H)+]; mp 280° C.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[N+:17]([O-])=O)=[CH:6][N:5]=1>CO.[Pd]>[CH3:20][N:2]([CH2:3][C:4]1[N:5]=[CH:6][C:7]([O:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[NH2:17])=[CH:8][CH:9]=1)[CH3:1]
Reactant: CN(C)Cc1ccc(Oc2ccncc2[N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CO
Product: CN(C)Cc1ccc(Oc2ccncc2N)cn1

Procedure:
N,N-dimethyl-1-(5-((3-nitropyridin-4-yl)oxy)pyridin-2-yl)methanamine (150 mg, 0.5469 mmol), Pd/C (10%) (58.20 mg, 0.5469 mmol) in MeOH (15 mL) was stirred overnight at RT under hydrogen (balloon). The catalyst was filtered off and the filtrate was concentrated in vacuo to yield the title product as a clear oil. MS (ES+) 245.2.