Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:3]=1[O:4][CH:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].[Br:21]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:19]=[C:18]([CH2:20][Br:21])[CH:17]=[CH:16][C:3]=1[O:4][CH:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)C(Oc1ccc(C)cc1Cl)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Oc1ccc(CBr)cc1Cl)c1ccccc1
Yield: 33.7 %

Procedure:
To a solution of 1.70 g (5.86 mmol) of the product from Step A dissolved in 20 mL of CCl4 was added 1.04 g (5.86 mmol) of N-bromosuccinimide and 50 mg (catalytic amount) of AIBN. The reaction mixture was stirred and heated at reflux for 7 hours, then an additional 0.20 g of NBS was added. The reaction was refluxed for 48 hours, then cooled and concentrated in vacuo. The residue was purified on a silica flash chromatography column eluted with 10% ethyl acetate/hexane to afford 0.730 g (34%) of the title compound.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[C:20]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:32])[CH2:28][C:29]([OH:31])=O)=[CH:22][CH:21]=1.CCN=C=NCCCN(C)C.Cl.Cl.[N:52]1([C:58]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=2[C:66]([F:69])([F:68])[F:67])=[O:59])[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1>CN(C=O)C.O>[C:20]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:21]=[CH:22][C:23]([NH:26][C:27](=[O:32])[CH2:28][C:29](=[O:31])[N:55]2[CH2:56][CH2:57][N:52]([C:58](=[O:59])[C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=3[C:66]([F:69])([F:67])[F:68])[CH2:53][CH2:54]2)=[CH:24][CH:25]=1
Reactant: O=C(O)CC(=O)Nc1ccc(-c2ccccc2)cc1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)Nc1ccc(-c2ccccc2)cc1
Temperature: 10 °C
Reaction time: 8 h
Yield: 28.8 %

Procedure:
HOBt (19 mg, 0.14 mmol) and DIPEA (0.017 mg, 0.14 mmol) were added to a stirred solution of N-biphenyl-4-yl-malonamic acid (40 mg, 0.14 mmol) in DMF (3 mL). The mixture was cooled to 10° C. and EDCI.HCl (40 mg, 0.2 mmol) followed by piperazin-1-yl-(2-trifluoromethyl-phenyl)-methanone hydrochloride (45 mg, 0.15 mmol) were added. The mixture was stirred at room temperature overnight, then diluted with water. The resulting precipitate was filtered and the residue was purified by column chromatography using silica gel 60-120 mesh and 90% ethyl acetate in hexane as eluant to afford 20 mg (30%) of N-biphenyl-4-yl-3-oxo-3-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-propionamide. LCMS: 496.18 (M+1)+, 97.3%. 1H NMR: (CDCl3): δ 9.6 (d, 1H), 7.76 (d, 1H), 7.6 (m, 7H), 7.44 (t, 2H), 7.35 (t, 2H), 4.0 (m, 2H), 3.7 (m, 4H), 3.5 (m, 4H), 3.25 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:12]=[CH:11][N:10]([CH3:13])[C:5]2=[C:6]([O:8][CH3:9])[N:7]=1.[I:14]N1C(=O)CCC1=O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:12]([I:14])=[CH:11][N:10]([CH3:13])[C:5]2=[C:6]([O:8][CH3:9])[N:7]=1
Reactant: COc1nc(Br)cc2ccn(C)c12
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: COc1nc(Br)cc2c(I)cn(C)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
The product from Example 91B (0.82 g, 3.40 mmol) and N-iodosuccinimide (0.918 g, 4.08 mmol) were combined in dimethylformamide (17.01 mL), stirred for two hours at ambient temperature, and quenched with 100 mL of 10% aqueous sodium thiosulfate. The mixture was stirred for 15 minutes and the resulting solid was collected by filtration, washed repeatedly with water and dried to constant mass to afford the title compound (1.17 g, 94%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[CH:9]\[CH2:10][O:11][C:12]2[CH:23]=[CH:22][C:15]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:14]([CH3:24])[CH:13]=2)=[CH:4][CH:3]=1.[CH2:35]([N:38]1[CH:42]=[CH:41][CH:40]=[N:39]1)[C:36]#[CH:37]>O1CCCC1.C(N(CC)CC)C.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.[Cu]I>[CH3:24][C:14]1[CH:13]=[C:12]([O:11][CH2:10]/[CH:9]=[C:8](\[C:5]2[CH:4]=[CH:3][C:2]([C:37]#[C:36][CH2:35][N:38]3[CH:42]=[CH:41][CH:40]=[N:39]3)=[CH:7][CH:6]=2)/[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)[CH:23]=[CH:22][C:15]=1[O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: C#CCn1cccn1
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2cccc(C(F)(F)F)c2)cc1C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCn3cccn3)cc2)c2cccc(C(F)(F)F)c2)cc1C
Temperature: 25 °C
Reaction time: 30 h

Procedure:
A solution of the above ester (400 mg, 0.68 mmol) in a mixture of tetrahydrofuran (12 mL) and triethylamine (12 mL) was degassed and 1-propargylpyrazole (144 mg, 1.36 mmol) was added in argon atmosphere. The solution was cooled down; tetrakis(triphenylphosphine)palladium (62 mg, 0.054 mmol) and copper(I) iodide (20 mg, 0.108 mmol) were added and the resulting mixture was stirred at ambient temperature for 30 h. The mixture was evaporated in vacuo; the residue was dissolved in ethyl acetate (20 mL) and the formed solution was washed with water (2×15 mL) and brine (10 mL). The organic solution was dried with anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 7:3) yielding methyl (E)-[2-methyl-4-[3-[4-[3-(pyrazol-1-yl)propynyl]phenyl]-3-(3-trifluoromethyl phenyl)allyloxy]-phenoxy]acetate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5](C#N)=[N:6][CH:7]=1.[C:11](=[O:14])([O-])[O-:12].[Cs+].[Cs+].FC(F)(F)S(O[CH2:23][C:24]([F:27])([F:26])[F:25])(=O)=O>CN(C=O)C.O.CCOC(C)=O>[CH3:10][C:4]1[C:5]([C:11]([OH:12])=[O:14])=[N:6][CH:7]=[C:2]([O:1][CH2:23][C:24]([F:27])([F:26])[F:25])[CH:3]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: Cc1cc(O)cnc1C#N
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(OCC(F)(F)F)cnc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
To a solution of 5-hydroxy-3-methylpicolinonitrile (0.487 g, 3.63 mmol) in DMF (5 mL) were added cesium carbonate (1.538 g, 4.72 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.011 ml, 4.36 mmol) and the resulting suspension was stirred at rt overnight. The reaction was diluted with water and EtOAc. The organic layer was washed with 1M LiCl solution and brine before drying over magnesium sulfate and concentrating under reduced pressure. The material was taken up in EtOH (20 mL) and NaOH, 1.0M aq (10.89 ml, 10.89 mmol) was added. The reaction was heated to 80° C. and stirred for 6 hours. The reaction was heated to reflux and stirred overnight. The reaction was continued at reflux for a total of 4 days. The reaction was cooled to rt and diluted with ether and water. The organic layer was washed with additional water and the combined aqueous layers were acidified to pH=1 (pH paper) by the addition of 1M HCl. The aqueous layer was extracted with DCM (2×) and the combined organics were brined, dried over magnesium sulfate and concentrated under reduced pressure to afford 3-methyl-5-(2,2,2-trifluoroethoxy)picolinic acid (0.754 g, 3.21 mmol, 88% yield). LC/MS (ESI+) m/z=236 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]([CH3:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1)[CH3:2].P(Cl)(Cl)(Cl)=O.CN([CH:21]=[O:22])C.C([O-])(=O)C.[Na+]>C(OCC)(=O)C.CCCCCC>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:21]=[O:22])=[C:6]([CH:10]([CH3:11])[CH3:12])[CH:5]=1)[CH3:2]
Reactant: CCOc1cccc(C(C)C)c1
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O=P(Cl)(Cl)Cl
Product: CCOc1ccc(C=O)c(C(C)C)c1
Yield: 3.5 %

Procedure:
Using an analogous formylation procedure to that employed by Campaigne et al 3-ethoxycumene (5 g, 30.49 mmol) was added dropwise to a mixture of phosphorous oxychloride (2.84 mL, 30.5 mmol) and DMF (8.6 mL, 0.111 mol) at 0° C. and the resultant mixture was heated to 80-90° C. for 48 hrs before being poured onto crushed ice. The solution was taken to pH 7 with saturated sodium acetate, extracted with diethyl ether and upon drying and solvent removal a clear colourless oil was obtained. Column chromatography (silica, ethyl acetate/hexane, 1:9, Rf 0.44) gave the tide compound as a clear colourless oil (202.4 mg, 7.5% based on reacted material). 1H n.m.r. [400 MHZ, CDCl3] δ 10.11, s, 1H, CHO; 7.715, d, J 8.8 Hz, 1H, H6; 6.865, d, J 2.4 Hz, 1H, H3; 6.75, dd, J 8.55, 2.4 Hz, 1H, H5; 4.05, q, J 7 Hz, 2H, CH2; 3.95, septet, J 6.9 Hz, 1H, CH(CH3)2; 1.39, t, J 7 Hz, 3H, CH3; 1.225, d, J 7.1, 6H, CH(CH3)2. 13C n.m.r [100 MHZ, CDCl3] δ190.53, CHO; 163.42, C4; 153.87, C2; 134.77, C6; 126.37, C1, 112.42, C3; 110.87, C5; 63.48, OCH2CH3; 27.52, CH(CH3)2; 23.48, CH(CH3)2; 14.47, OCH2CH3. Mass spectrum (f.a.b.) calculated 192.115023, found 192.1151.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]2[CH2:23][O:24][C@H:11]([O:12]2)[C@@H:10]1[O:25]C1CCCCO1)C1C=CC=CC=1.Cl.[OH-:33].[Na+].[CH3:35][C:36]([CH3:38])=O>>[C:35]([O:12][C@@H:13]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@H:9]([O:8][CH2:1][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:10]2[CH2:11][O:24][C@@H:23]1[O:25]2)(=[O:33])[C:36]1[CH:38]=[CH:11][CH:10]=[CH:9][CH:14]=1
Reactant: [OH-]
Reactant: c1ccc(CO[C@@H]2[C@@H](OC3CCCCO3)[C@@H]3OC[C@@H](O3)[C@H]2OCc2ccccc2)cc1
Reactant: CC(C)=O
Agent: Cl
Agent: [Na+]
Product: O=C(O[C@H]1[C@@H]2OC[C@@H](O2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1)c1ccccc1

Procedure:
A solution of 51 g of 1,6-anhydro-3,4-di-O-benzyl-2-O-tetrahydropyranyl-β-D-glucopyranose in 400 ml of acetone is warmed with 20 ml 1 N hydrochloric acid to 50° for 20 minutes. After cooling, this solution is neutralised with 1 N sodium hydroxide solution and evaporated to dryness. The residue is taken up in ether, this solution is washed thoroughly with water and dried over magnesium sulphate and the solvent is evaporated. The product is benzoylated as described in Example 3 and the 1,6-anhydro-2-O-benzoyl-3,4-di-O-benzyl-β-D-glucopyranose which is thus obtained is purified by recrystallisation.
Reaction SMILES: CNC(=NS([CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=1)(=O)=O)C.[OH-].[Na+].[CH3:21][N:22](C=CC1C=CC([N+]([O-])=O)=CC=1)[C:23](=[NH:30])[C:24]1C=CC=CC=1>CC(C)=O>[CH3:21][N:22]([CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=1)[C:23](=[NH:30])[CH3:24]
Reactant: CNC(C)=NS(=O)(=O)C=Cc1ccc(Cl)c(Cl)c1
Reactant: CN(C=Cc1ccc([N+](=O)[O-])cc1)C(=N)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC(=N)N(C)C=Cc1ccc(Cl)c(Cl)c1

Procedure:
Treating N-methyl-N'-(3,4-dichlorostyrylsulfonyl)acetamidine with aqueous sodium hydroxide in acetone according to the procedure of Example 32 (c) provides N-methyl-N-(3,4-dichlorostyryl)acetamidine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[NH:11][C:12]([C:20]2[CH:29]=[CH:28][CH:27]=[C:26]3[C:21]=2[N:22]=[C:23]([NH:31][CH2:32][C:33]([F:36])([F:35])[F:34])[C:24]([CH3:30])=[N:25]3)=[CH:13][C:14]=1[C:15]([O:17]CC)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCOCC1.O.CCOCC>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[NH:11][C:12]([C:20]2[CH:29]=[CH:28][CH:27]=[C:26]3[C:21]=2[N:22]=[C:23]([NH:31][CH2:32][C:33]([F:34])([F:35])[F:36])[C:24]([CH3:30])=[N:25]3)=[CH:13][C:14]=1[C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc(-c2cccc3nc(C)c(NCC(F)(F)F)nc23)[nH]c1CNC(=O)OC(C)(C)C
Solvent: O
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cc1nc2cccc(-c3cc(C(=O)O)c(CNC(=O)OC(C)(C)C)[nH]3)c2nc1NCC(F)(F)F
Temperature: 110 °C
Yield: 85.3 %

Procedure:
A glass microwave reaction vessel was charged with ethyl 2-(((tert-butoxycarbonyl)amino)methyl)-5-(2-methyl-3-((2,2,2-trifluoroethyl)amino)quinoxalin-5-yl)-1H-pyrrole-3-carboxylate (301b) (380 mg, 0.75 mmol) and LiOH monohydrate (157 mg, 3.74 mmol) in dioxane (5 mL) and water (2.5 mL). The tube was sealed and the reaction mixture was stirred and heated at 110° C. for 3 h. After cooling to RT, the reaction mixture was diluted with Et2O and water and the layers were separated. The Et2O layer was discarded. The aq. layer was acidified with 2 M HCl (aq.) and extracted with EtOAc (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give 2-(((tert-butoxycarbonyl)amino)methyl)-5-(2-methyl-3-((2,2,2-trifluoroethyl)amino)quinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid (308 mg, 0.64 mmol) as an orange solid. m/z (ESI, +ve) 480.2 (M+H)+. The orange solid (308 mg) was dissolved in 4 mL of dioxane and treated with a 4 M solution of HCl in 1,4-dioxane (4.68 mL, 18.72 mmol) at RT. The reaction mixture was stirred at RT overnight and was then concentrated. The solid was suspended with 1/1 Et2O/hexanes and collected by filtration to give 2-(aminomethyl)-5-(2-methyl-3-((2,2,2-trifluoroethyl)amino)quinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (301c) (255 mg, 0.61 mmol, 82% yield) as a red solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.30 (br. s., 1H), 8.37 (t, J=5.77 Hz, 2H), 7.95 (dt, J=7.48, 0.76 Hz, 1H), 7.77 (t, J=6.16 Hz, 1H), 7.71 (dt, J=7.97, 0.81 Hz, 1H), 7.46 (t, J=7.82 Hz, 1H), 7.42 (dd, J=2.35, 0.39 Hz, 1H), 4.38-4.49 (m, 2H), 4.34 (q, J=5.35 Hz, 2H), 2.60 (s, 3H). 19F NMR (377 MHz, DMSO-d6) δ ppm −69.61 (s, 3F). m/z (ESI, +ve) 363.0 (M-NH2)′.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])=[C:19]([CH3:30])[CH:18]=3)=[O:16])[CH2:6][C:5]=12.C(N(CC)CC)C.[Cl:38][C:39]([Cl:44])([Cl:43])[C:40](Cl)=[O:41]>ClCCl>[Cl:38][C:39]([Cl:44])([Cl:43])[C:40]([C:3]1[N:4]2[C:5]([CH2:6][N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])=[C:19]([CH3:30])[CH:18]=3)=[O:16])[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10]2)=[CH:1][CH:2]=1)=[O:41]
Reactant: Cc1ccccc1-c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1C
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Temperature: 25 °C

Procedure:
To a solution of (10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-10-yl)-(2,2′-dimethyl-biphenyl-4-yl)-methanone of Step C (8.38 mmol) and triethylamine (16.76 mmol) in dichloromethane (30 mL) at −5° C. was added, rapidly dropwise, trichloroacetyl chloride (25 mmol). The mixture was allowed to stir and warm to room temperature overnight. The mixture was washed with 0.1N hydrochloric acid and dilute brine, then dried over anhydrous sodium sulfate, and evaporated to leave a light green oil. The compound was purified by filtration over a plug of Merck silica gel-60 eluting with dichloromethane and then treated with hot ethyl acetate/hexane (3/1) to yield a light yellow crystalline solid, m.p. 212-214° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:25])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29](=[O:49])[CH2:30][C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)[CH3:27]>>[CH2:26]([O:28][C:29](=[O:49])[CH2:30][C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:25])[CH2:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)=[CH:4][CH:3]=3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)[CH3:27]
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: COc1ccc(CC(C)Nc2c(C)noc2-c2ccc(Br)cc2)cc1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)Cc4ccc(OC)cc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amine and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:15](Cl)=[O:16]>>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:15]([O:16]/[C:15](/[C:14]1[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:12]([O:11][CH3:10])[CH:13]=1)=[CH:8]\[C:7]1[C:6]([Cl:9])=[CH:5][N:4]=[CH:3][C:2]=1[Cl:1])=[O:16]
Reactant: Cc1c(Cl)cncc1Cl
Reactant: COc1ccc(C(=O)Cl)cc1OC
Product: COc1ccc(C(=O)O/C(=C\c2c(Cl)cncc2Cl)c2ccc(OC)c(OC)c2)cc1OC

Procedure:
The compound was obtained starting from 3,5-dichloro-4-methyl-pyridine and 3,4-dimethoxy-benzoyl chloride, following the procedure of Example 31.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:17])=[C:6]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1.[Br:18][CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][N:21]=1>>[C:9]([NH:8][C:6]1[CH:7]=[C:2]([NH:1][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][C:20]([CH2:19][Br:18])=[N:21][CH:22]=2)[CH:3]=[CH:4][C:5]=1[Cl:17])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)c1ccc(CBr)nc1
Reactant: Nc1ccc(Cl)c(NC(=O)c2ccccc2)c1
Product: O=C(Nc1ccc(Cl)c(NC(=O)c2ccccc2)c1)c1ccc(CBr)nc1

Procedure:
N-(5-amino-2-chlorophenyl)benzamide (1.0 mmol) was used in general procedure 2 with 6-(bromomethyl)nicotinic acid (21.1 mmol) to give N-(3-benzamido-4-chlorophenyl)-6-(bromomethyl)-nicotinamide. MS (Q1) 444.0 (M)+
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:16]([CH2:21][C:22](=N)O)([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[CH2:19]([O:18][C:16]([CH2:21][C:22]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]=1)=[O:17])[CH3:20]
Reactant: Nc1ccccc1Nc1ccccc1
Reactant: CCOC(=O)CC(=N)O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)Cc1nc2ccccc2n1-c1ccccc1

Procedure:
N-phenyl-o-phenylenediamine (55.27g; 0.3 mole) and carboethoxyacetimidate hydrochloride [Ber., 28, 478 (1895)](58.70g; 0.3 mole) are refluxed in ethanol (200ml) for 4 hours. The separated ammonium chloride is filtered from the hot solution. The filtrate is evaporated to a syrup which is taken up in chloroform and washed twice with water. After drying (MgSO4), the chloroform is evaporated, ligroin is added, and crystallization slowly occurs. The solid is filtered and recrystallized from ligroine to give 50.3g (59.8%); m.p. 87°-89°; Lit. m.p. 89°-91° [J. Hetero. Chem., 3(3), 280 (1966)].
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:39][OH:40])[C:8]([NH:10][CH:11]2[C:37](=[O:38])[N:13]3[C:14]([C:21]([O:23]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:22])=[C:15](/[CH:18]=[CH:19]/[Cl:20])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.B(F)(F)F.CCOCC>C(O)(=O)C.C1(OC)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>[OH:40][N:39]=[C:7]([C:5]1[N:6]=[C:2]([NH2:1])[S:3][CH:4]=1)[C:8]([NH:10][CH:11]1[C:37](=[O:38])[N:13]2[C:14]([C:21]([OH:23])=[O:22])=[C:15](/[CH:18]=[CH:19]/[Cl:20])[CH2:16][S:17][C@H:12]12)=[O:9]
Reactant: Nc1nc(C(=NO)C(=O)NC2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(/C=C/Cl)CS[C@H]23)cs1
Agent: FB(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COc1ccccc1
Solvent: CC(=O)O
Solvent: CCOCC
Product: Nc1nc(C(=NO)C(=O)NC2C(=O)N3C(C(=O)O)=C(/C=C/Cl)CS[C@H]23)cs1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 147 %

Procedure:
To a solution of benzhydryl 7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(E)-2-chlorovinyl]-3-cephem-4-carboxylate (syn isomer) (2.5 g) in a mixture of acetic acid (2.5 ml) and anisole (9.6 ml) was dropwise added boron trifluoride etherate (2.5 ml) at 3° C. and the mixture was stirred for 30 minutes at the same temperature for 30 minutes. The reaction mixture was dissolved in 20% aqueous solution of potassium carbonate, washed with ethyl acetate, concentrated to remove the organic solvent under reduced pressure, cooled to 5° C. and adjusted to pH 2.3 with 10% hydrochloric acid. The resultant precipitates were collected by filtration, washed with water and dried in vacuo to give 7-[2-hydroxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[(E)-2-chlorovinyl]-3-cephem-4-carboxylic acid (syn isomer) (2.65 g)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=3)=[N:13][C:12]([C:25]([F:28])([F:27])[F:26])=[N:11]2)=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+].C(O)C>[Fe].O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14]([C:15]3[CH:16]=[CH:17][C:18]([S:21]([CH3:24])(=[O:22])=[O:23])=[CH:19][CH:20]=3)=[N:13][C:12]([C:25]([F:26])([F:27])[F:28])=[N:11]2)=[CH:8][CH:9]=1
Reactant: CS(=O)(=O)c1ccc(-c2nc(C(F)(F)F)nn2-c2ccc([N+](=O)[O-])cc2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1ccc(-c2nc(C(F)(F)F)nn2-c2ccc(N)cc2)cc1
Yield: 89.9 %

Procedure:
A mixture of 1-(4-nitro-phenyl)-5-(4-methylsulfonyl-phenyl)-3-trifluoromethyl-1H-1,2,4-triazole (1.2 g, 2.91 mmol), iron powder (0.8 g, 14.27 mmol), ammonium chloride (0.80 g, 1.45 mmol), ethanol (25 ml) and water (13 ml) was heated to reflux for 1 hour, then cooled and filtered. The filtrate was poured onto water, extracted with ethyl acetate and a dichloromethane/methanol solution. The organic extracts were washed with saturated brine, dried over Na2SO4 and evaporated to give a yellow powder (1 g, 91%), which was used for the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:22]=[CH:21][C:8]([CH2:9][N:10]([CH2:12][C:13]2[CH:18]=[C:17]([Br:19])[CH:16]=[C:15](Br)[CH:14]=2)[CH3:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:23]([Li])[CH2:24][CH2:25]C.CCCCCC.[Cl-].[NH4+].[O:36]1CCCC1>O.CC(C)=O>[Br:19][C:17]1[CH:16]=[C:15]([C:24]([OH:36])([CH3:25])[CH3:23])[CH:14]=[C:13]([CH2:12][N:10]([CH2:9][C:8]2[CH:21]=[CH:22][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:6][CH:7]=2)[CH3:11])[CH:18]=1
Reactant: CN(Cc1ccc(C(C)(C)C)cc1)Cc1cc(Br)cc(Br)c1
Reactant: C1CCOC1
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: O
Solvent: CC(C)=O
Product: CN(Cc1ccc(C(C)(C)C)cc1)Cc1cc(Br)cc(C(C)(C)O)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 77.7 %

Procedure:
Compound 139 (4.21 g; 9.90 mmol) was dissolved in tetrahydrofuran (40 ml). While the solution was stirred at −78° C. under nitrogen atmosphere, n-butyl lithium in n-hexane (1.63 M: 6.1 ml; 9.94 mmol) was added dropwise. After 10 minutes, acetone (1.5 ml) was added dropwise thereto, and the mixture was gradually brought to room temperature. Saturated aqueous ammonium chloride solution was added dropwise to the mixture, and water was added thereto, followed by extraction with diethyl ether (100 ml). The organic layer was washed with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1→2:1), to thereby yield 3.11 g of the target compound as pale yellow oily matter (yield: 77.7%).