Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH2:26][C:27]1[C:28]([F:44])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:38]#[N:39])[C:30]([Cl:33])=[CH:31][CH:32]=1.[C:45]([C:48]1[NH:52][C:51]([C:53](O)=[O:54])=[C:50]([Cl:56])[CH:49]=1)(=[O:47])[CH3:46].CCN(C(C)C)C(C)C>CN(C=O)C>[C:45]([C:48]1[NH:52][C:51]([C:53]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([O:34][C:35]3[CH:36]=[C:37]([C:38]#[N:39])[CH:40]=[C:41]([Cl:43])[CH:42]=3)[C:28]=2[F:44])=[O:54])=[C:50]([Cl:56])[CH:49]=1)(=[O:47])[CH3:46]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: CC(=O)c1cc(Cl)c(C(=O)O)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)c1cc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)[nH]1
Reaction time: 8 h
Yield: 16.4 %

Procedure:
HATU (0.092 g, 0.241 mmol) was added to a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.050 g, 0.161 mmol), 5-acetyl-3-chloro-1H-pyrrole-2-carboxylic acid (0.030 g, 0.161 mmol) and DIPEA (0.042 mL, 0.241 mmol) in DMF (2 mL). The resulting solution was stirred overnight. The reaction mixture was partitioned between water and EtOAc. The organic layer was separated, dried over MgSO4 and evaporated to a residue. Purification was accomplished by reverse-phase HPLC (water/acetonitrile with 0.1% TFA) to afford the title compound (0.0127 g, 16%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 3.29 (s, 3H) 4.48 (d, J=5.36 Hz, 2H) 7.10 (s, 1H) 7.36-7.56 (m, 4H) 7.80 (s, 1H) 8.71 (t, J=5.22 Hz, 1H) 12.31 (br. s., 1H). LCMS: m/z 477.9 (M−1).
Reaction SMILES: [C:1]([O:5][C:6]([C@@:8]1([CH2:22][CH:23]=C)[CH2:12][C:11](=[O:13])[N:10]([C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:25]=[O+][O-]>CO>[C:1]([O:5][C:6]([C@@:8]1([CH2:22][CH:23]=[O:25])[CH2:12][C:11](=[O:13])[N:10]([C@@H:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC[C@]1(C(=O)OC(C)(C)C)CC(=O)N([C@H](C)c2ccccc2)C1
Reactant: O=[O+][O-]
Solvent: CO
Product: C[C@H](c1ccccc1)N1C[C@@](CC=O)(C(=O)OC(C)(C)C)CC1=O
Temperature: -40 °C
Reaction time: 1.5 h

Procedure:
A solution of (3S)-3-allyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (3.29 g, 10.0 mmol) in methanol (100 mL) was bubbled with ozone at −74° C. When the reaction solution turned blue, ozone bubbling was stopped and then the solution was bubbled with nitrogen at the same temperature. Sodium borohydride (568 mg) was added at the same temperature, and the mixture was stirred for 1.5 hours while heating to −40° C. The reaction solution was poured into a 10% citric acid solution (50 mL), and then the mixture was stirred sufficiently. The methanol component was evaporated, and then the aqueous layer was extracted with ethyl acetate (200 mL, 100 mL). The organic layer was washed with brine (50 mL×2), and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure into a slurry. Hexane was added to the resulting residue, and the slurry was stirred. The solid was collected by filtration and dried to give 1.70 g of the title compound as a white solid. The filtrate was concentrated, hexane was added to the resulting residue, and the slurry was stirred. The solid was collected by filtration to give 0.66 g of the title compound as a white solid. The same operation was repeated to give 0.35 g of the title compound as a white solid (total yield: 2.71 g, 82%).
Reaction SMILES: [CH2:1]([C:8]1[CH:20]=[CH:19][C:11]([O:12][CH2:13][C@H:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32]>CN(C=O)C>[CH3:34][O:33][C:31](=[O:32])[CH2:30][CH2:29][N:15]1[CH2:16][CH2:17][CH2:18][C@@H:14]1[CH2:13][O:12][C:11]1[CH:19]=[CH:20][C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)CCBr
Reactant: c1ccc(Cc2ccc(OC[C@H]3CCCN3)cc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CCN1CCC[C@@H]1COc1ccc(Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.3 %

Procedure:
To a solution of Example 1 (0.2 g, 0.66 mmol) in DMF (5 mL) was added triethylamine (0.16 mL, 1.14 mmol) and methyl 3-bromopropionate (0.07 mL, 0.64 mmol). The resulting slurry was stirred at ambient temperature overnight. The solvent was removed under reduced pressure and the crude residue was extracted into ethyl acetate. The organic portion was washed with water, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel flash chromatography using hexane/EtOAc (gradient system) to give the title compound (0.03 g, 13%); 1H NMR (400 MHz, CDCl3); δ 1.68-1.80 (m, 3H), 1.93-2.04 (m, 1H), 2.29 (q, J=8.4 Hz, 1H), 2.53 (t, J=7.2 Hz, 2H), 2.70 (m, 1H), 2.87 (m, 1H), 3.13 (m, 1H), 3.24 (m, 1H), 3.66 (s, 3H), 3.75 (m, 1H), 3.92 (s, 2H), 3.93 (m, 1H), 6.82 (d, J=8.8 Hz, 2H), 7.08 (d, J=8.4 Hz, 2H), 7.16-7.20 (m, 3H), 7.27 (m, 2H); MS (m/z) 354.2 (M+1); LC (100.0%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([OH:13])=O)=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH3:27][NH:28][O:29][CH3:30]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([N:28]([O:29][CH3:30])[CH3:27])=[O:13])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(O)c1n[nH]c2ncc(Br)cc12
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1n[nH]c2ncc(Br)cc12
Temperature: 65 °C
Yield: 91 %

Procedure:
To a solution of 5-bromo-1H-pyrazole[3,4-b]pyridine-3-carboxylic acid (VIII) (0.242 g, 1 mmol) in dry DMF (5 mL) was added CDI (0.178 g, 1.1 mmol) and heated for 3 h at 65° C. under nitrogen. The solution was cooled to room temperature and N,O-dimethyl hydroxylamine hydrochloride (0.107 g, 1.1 mmol) was added to the solution. The solution was again heated for 3 h at 65° C. under nitrogen. The solution was cooled and the solvent was evaporated under reduced pressure. The residue was dissolved in DCM, washed successively with a 10% HCl solution, a saturated NaHCO3 solution and brine. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to produce 5-bromo-N-methoxy-N-methyl-1H-pyrazolo[3,4-b]pyridine-3-carboxamide (IX) as a white solid (260 mg, 0.91 mmol, 92% yield). 1H NMR (CDCl3) δ ppm 3.55 (s, 3H), 3.78 (s, 3H), 8.59 (d, J=3.01 Hz, 1H), 8.67 (d, J=3.01 Hz, 1H); ESIMS found for C9H9BrN4O2 m/z 285.4 (M+H).
Reaction SMILES: C(OC([NH:11][C:12]1([C:25](=[O:27])[NH2:26])[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)=O)C1C=CC=CC=1.C(O)(=O)C>CO.[Pd]>[NH2:11][C:12]1([C:25](=[O:27])[NH2:26])[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)(C(N)=O)CC1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(N)(C(N)=O)CC1
Yield: 90 %

Procedure:
1B (1.0 equivalent) and a catalytic amount of acetic acid in MeOH (0.05M) was passed through H-cube hydrogenator equipped with Pd/C cartridge at 50° C. The methanol in the reaction mixture was then removed under reduced pressure, and the product was washed with cold ether twice to afford the tert-butyl 4-amino-4-carbamoylpiperidine-1-carboxylate (1C, 90%).
Reaction SMILES: [O-]CC.[Na+].[Br-].[CH3:6][N:7]([CH3:37])[C:8]1[C:9]([N+:34]([O-:36])=[O:35])=[C:10]([CH:31]=[CH:32][CH:33]=1)[CH2:11][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:38]1([C:44]2[N:45]=[CH:46][N:47]([CH2:49][CH2:50][CH:51]=O)[CH:48]=2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[C:38]1([C:44]2[N:45]=[CH:46][N:47]([CH2:49][CH2:50]/[CH:51]=[CH:11]\[C:10]3[C:9]([N+:34]([O-:36])=[O:35])=[C:8]([CH:33]=[CH:32][CH:31]=3)[N:7]([CH3:6])[CH3:37])[CH:48]=2)[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: CN(C)c1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1[N+](=O)[O-]
Reactant: O=CCCn1cnc(-c2ccccc2)c1
Agent: CC[O-]
Agent: [Br-]
Agent: [Na+]
Product: CN(C)c1cccc(/C=C\CCn2cnc(-c3ccccc3)c2)c1[N+](=O)[O-]
Yield: 48.7 %

Procedure:
An ethanolic solution of 90 mg of sodium ethoxide was dropped into an ethanolic solution containing 650 mg of 3-dimethylamino-2-nitrobenzyltriphenylphosphonium bromide and 320 mg of 3-(4-phenyl-1H-imidazol-1-yl)propionaldehyde. The obtained solution was heated under reflux for 2 hours to conduct a reaction. After the completion of the reaction, the mixture was distilled to remove the solvent. The residue was extracted with 2N NaOH and the obtained aqueous layer was made acidic again with 1N HCl and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of common salt, dried over magnesium sulfate and distilled to remove the solvent. The obtained oily substance which is a mixture of cis- and trans-isomers was purified by silica gel chromatography to give 220 mg of 3-[4-(4-phenyl-1H-imidazol-1-yl)-1-cis-butenyl]-2-nitro-N,N-dimethylaniline. 430 mg of zinc was added to a solution of this product in acetic acid to give 2-dimethylamino-6-[4-(4-phenyl-1H-imidazol-1-yl)-1-Cis-butenyl]aniline as an oily substance. This oily substance was dissolved in chloroform, followed by the dropwise addition of 50 mg of butyl isocyanate. The obtained mixture was heated under reflux for 2 hours to conduct a reaction. After the completion of the reaction, the obtained reaction mixture was concentrated to precipitate a crystal. This crystal was recrystallized from an ethyl acetate/hexane mixture to give 190 mg of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[NH:19])[NH2:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:25][S:26](Cl)(=[O:28])=[O:27].Cl>CC(C)=O.O.CC(C)=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[NH:18])[NH:19][S:26]([CH3:25])(=[O:28])=[O:27])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N=C(N)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CS(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reaction time: 2 h

Procedure:
To 10 mmol of (S)-N2-(benzyloxycarbonyl)-arginine suspended in a mixture of acetone/water 80/20 there is added, at 0° C., a sufficient amount of 4N sodium hydroxide solution to bring the pH of the reaction mixture to between 11 and 11.5. After stirring for 2 hours, there is then added a solution of methanesulphonyl chloride in acetone and then, after stirring for a further 3 hours, the mixture is neutralised using 1N hydrochloric acid solution; the acetone is then evaporated off, and the residue obtained is extracted with ether and then washed, dried, filtered and evaporated. The pale yellow oil thereby obtained is purified by chromatography over silica (eluant: dichloromethane/methanol 7/3) to yield the expected product in the form of a whitish meringue.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[CH:17]([O:19]C)Cl.O>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[C:6]([CH:17]=[O:19])=[CH:5][CH:4]=1
Reactant: COC(Cl)Cl
Reactant: COc1cccc2c1oc1ccccc12
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C=O)c2c1oc1ccccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 108.4 %

Procedure:
4-methoxy-dibenzofuran (3.07 g, 15.5 mmoles) is dissolved in DCM (50 mL) under nitrogen atmosphere. The solution is cooled to 0° C. and dichloromethyl-methyl ether (1.68 mL, 18.6 mmoles) and subsequently TiCl4 (1N solution in DCM, 18.6 mL, 18.6 mmoles) are added dropwise. The solution is stirred at 0° C. and the reaction is completed after 1 hour. The reaction mixture is poured into cold water and extracted with DCM. The combined organic layers are washed again with water and brine, dried over sodium sulphate and evaporated to dryness to give 3.54 g of crude compound. The reaction is repeated on additional 2.04 g of starting material to yield additional 2.51 g of crude compound. The two crude mixtures are combined and purified together by flash chromatography on SiO2 (eluent: gradient AcOEt/hexane from 10/90 to 20/80) to give 3.8 g of the desired compound.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15](Br)[CH:16]=1.[OH-].[Na+]>CN(C=O)C.O>[Br:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:16]=1
Reactant: Oc1ccccc1
Reactant: Brc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1cncc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.7 %

Procedure:
Sodium hydride (1.35 g of 80% in mineral oil, 45.0 mmol) was added to a stirred solution of phenol (4.26 g, 45.3 mmol) in DMF (30 mL) at 0° C., under nitrogen. The mixture was stirred at room temperature for 3 h, treated with 3,5-dibromopyridine (4.0 g, 16.9 mmol) and heated at 100° C. for 48 h. The reaction mixture was cooled to room temperature, poured into a mixture of water (100 mL) and 5M sodium hydroxide (10 mL), and extracted with ether (3×60 mL). The combined ether extracts were dried (Na2SO4), filtered, and rotary evaporated to a pale yellow semi-solid (4.9 g). This was chromatographed on a silica gel (200 g) column with hexane/ethyl acetate/chloroform (8:1:1, v/v) as eluant to give 2.86 g (68% yield) of a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]=[CH2:11])=[N:7][C:6]=2[CH:12]=1.[C:13]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)#[N:14].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.O1CCCC1>CCCCCC>[CH:10]([C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([C:18]3[CH:19]=[CH:20][C:15]([C:13]#[N:14])=[CH:16][CH:17]=3)=[CH:12][C:6]=2[N:7]=1)=[CH2:11]
Reactant: C=Cc1nc2cc(Br)ccc2o1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=Cc1nc2cc(-c3ccc(C#N)cc3)ccc2o1
Temperature: 23 °C
Reaction time: 24 h
Yield: 78 %

Procedure:
A mixture of 224 mg (1 mmol) of 5-bromo-2-vinyl-benzooxazole, 191 mg (1.3 mmol) of 4-cyanophenylboronic acid, 55 mg (0.03 mmol) of tris-(dibenzylidineacetone)dipalladium (0) (CAS #52409-22-0), 0.2 mL (0.06 mmol) of a 10% solution of tri-tert-butylphosphine in hexane, and 1.5 mL of tetrahydrofuran was stirred at 23° C. for 24 hours. It was then heated at 65° C. for 0.5 hour, then cooled. The mixture was suction filtered to remove particulates, then partitioned between 80 mL of water and a mixture of 30 mL of ethyl acetate and 10 mL of hexane. The organic phase was collected, dried over Na2SO4, and purified by flash chromatography on silica gel (eluting with 1:1 hexane: dichloromethane) to give 4-(2-vinyl-benzooxazol-5-yl)-benzonitrile (192 mg, 78%) as a white solid: mp 143-144° C.; 1H NMR (300 MHz, CDCl3) δ 7.90 (d, J=1.8 Hz, 1 H), 7.76 (d, J=8.4 Hz, 2 H), 7.70 (d, J=8.4 Hz, 2 H), 7.62 (d, J=7.5 Hz, 1 H), 7.55 (dd, J=7.5, 1.8 Hz, 1 H), 6.79 (dd, J=17.4, 10.5 Hz, 1 H), 6.52 (d, J=17.4 Hz, 1 H), 5.91 (d, J=10.5 Hz, 1 H); Mass spectrum: [M+H]+ 247.1.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[S:13][C:12]([S:14](Cl)(=[O:16])=[O:15])=[CH:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1.[N:18]1[CH:23]=CC=C[CH:19]=1.CNC.C1COCC1>C(Cl)Cl>[CH3:19][N:18]([CH3:23])[S:14]([C:12]1[S:13][C:9]([C:7]2[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=2)=[CH:10][CH:11]=1)(=[O:16])=[O:15]
Reactant: CSc1nccc(-c2ccc(S(=O)(=O)Cl)s2)n1
Reactant: c1ccncc1
Agent: CNC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CSc1nccc(-c2ccc(S(=O)(=O)N(C)C)s2)n1
Reaction time: 8 h
Yield: 74.9 %

Procedure:
A solution of 5-(2-methylsulfanyl-pyrimidin-4-yl)-thiophene-2-sulfonyl chloride (200 mg, 0.652 mmol) in 6 mL DCM was treated with pyridine (0.078 mL, 0.97 mmol) and 2 M dimethylamine/THF (0.485 mL, 0.97 mmol). The solution was stirred overnight. Additional 2 M dimethylamine/THF (0.400 mL, 0.8 mmol) was added and the reaction was stirred overnight. The mixture contained <5% starting material by LCMS. The mixture was washed 2× 1 N HCl, 1× brine and dried over Na2SO4. 5-(2-Methylsulfanyl-pyrimidin-4-yl)-thiophene-2-sulfonic acid dimethylamide (154 mg, 74.9%) was obtained as an off-white solid, >95% pure by LCMS. This material was taken to the next step. MS: m/z 316 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=[O:5].[Br:18][CH2:19][C:20](Cl)=[O:21]>C(OCC)C>[Br:18][CH2:19][C:20]([NH:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=[O:5])=[O:21]
Reactant: O=C(Cl)CBr
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Solvent: CCOCC
Product: O=C(CBr)Nc1ccc(Cl)cc1C(=O)c1ccccc1Cl

Procedure:
To an iced solution of 266 g (1 mol) of 2-amino-2', 5-dichlorobenzophenone in 3 liters of ethyl ether there are added, drop by drop, 90 cc (1.1 mol) of bromacetyl chloride dissolved in 500 cc of ethyl ether. The batch is allowed to come to room temperature, whereupon it is evaporated to dryness and the crystalline residue extracted with petroleum ether and filtered. In this manner, 371 g of crystals are recovered.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:31][O:32][CH2:33][C:34]([OH:36])=[O:35])[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O-:28])=[O:27])=[C:15]([CH2:18][N+:19]4([CH3:25])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.C(=O)(O)[O-].[Na+].C([O:45][C:46]1[CH:47]=[C:48]([CH:52]=[CH:53][C:54]=1[O:55]C(=O)C)[C:49](Cl)=[O:50])(=O)C>CC(C)=O.O>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:31][O:32][CH2:33][C:34]([OH:36])=[O:35])[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O-:28])=[O:27])=[C:15]([CH2:18][N+:19]4([CH3:25])[CH2:20][CH2:21][N:22]([C:49](=[O:50])[C:48]5[CH:52]=[CH:53][C:54]([OH:55])=[C:46]([OH:45])[CH:47]=5)[CH2:23][CH2:24]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1OC(C)=O
Reactant: C[N+]1(CC2=C(C(=O)[O-])N3C(=O)[C@@H](NC(=O)C(=NOCC(=O)O)c4nsc(N)n4)[C@H]3SC2)CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: C[N+]1(CC2=C(C(=O)[O-])N3C(=O)[C@@H](NC(=O)C(=NOCC(=O)O)c4nsc(N)n4)[C@H]3SC2)CCN(C(=O)c2ccc(O)c(O)c2)CC1
Yield: 39.2 %

Procedure:
The solution of 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-carboxymethoxyiminoacetamido]-3-(1-methyl-1-piperazinio)methyl-3-cephem-4-carboxylate (syn isomer) (540 mg) in acetone (5 ml) and water (5 ml) was adjusted to pH 7.0 with a saturated aqueous solution of sodium bicarbonate. To the mixture was added 3,4-diacetoxybenzoyl chloride (308 mg) at pH 6.5-7.0. The mixture was stirred for an hour and evaporated in vacuo to remove acetone. The residue was adjusted to pH 8.5 with a saturated aqueous solution of sodium bicarbonate and then stirred for 2 hours at room temperature. The mixture was adjusted to pH 3.5 with 3N hydrochloric acid and then filtered. The filtrate was subjected to column chromatography on Diaion HP-20 using 5% aqueous isopropyl alcohol as an eluent. The eluate was evaporated in vacuo to remove isopropyl alcohol and then lyophilized to give 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-carboxymethoxyiminoacetamido]-3-[1-methyl- 4-(3,4 -dihydroxybenzoyl)-1-piperazinio]methyl-3-cephem-4-carboxylate (syn isomer) (265 mg).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH3:8][O:9][CH:10]([O:13][CH3:14])[CH2:11][NH2:12].[OH-].[Na+].C(O)(=O)CCC(O)=O>C(Cl)Cl>[CH3:8][O:9][CH:10]([O:13][CH3:14])[CH2:11][NH:12][C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7]
Reactant: O=C1CCC(=O)O1
Reactant: COC(CN)OC
Agent: O=C(O)CCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COC(CNC(=O)CCC(=O)O)OC
Reaction time: 0.5 h

Procedure:
50.04 g (0.5 mol) of freshly distilled succinic anhydride are dispersed in 100 ml of methylene chloride. 52.75 g (0.5 mol) of aminoacetaldehyde dimethyl acetal are added, and the mixture is boiled under reflux. After 30 minutes, the homogeneous solution is evaporated in vacuo and freed from solvent at 60° C. under a high vacuum, giving a viscous oil which, according to titration with sodium hydroxide solution, has a purity of 99.4%. NMR data: 2.63 ppm (m) 4 methylene protons of succinic acid, 3.42 ppm (s) 6 methoxy protons, 4.42 ppm (t) 1 acetal proton, 3.6 ppm (d) 2 methylene protons, 6.60 ppm (t) 1 amide proton, 9.79 ppm 1 acid proton
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[C:5]([Br:11])=[CH:4][CH:3]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:13]>C(OCC)(=O)C.CO>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:13])=[O:9])[C:5]([Br:11])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Nc1ccc(Br)c(C(=O)O)n1
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(N)ccc1Br
Reaction time: 72 h

Procedure:
To a solution of 6-amino-3-bromopicolinic acid (30 g) in ethyl acetate (300 mL) and methanol (300 mL) was added TMS-diazomethane (70 mL, 2M in hexanes) and the reaction mixture was stirred for 3 days. The mixture was concentrated, taken up in ether (500 mL) and washed with aqueous Na2CO3 solution (twice), then washed with brine, dried over sodium sulfate, filtered and concentrated to provide the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:9]CCCN)[CH:5]=[CH:6][C:7]=1Cl.FC(F)(F)C1C=C(C=C(C(F)(F)F)C=1)C=O.[C:30]([NH:33][C:34]1([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[CH2:39][CH2:38][N:37]([CH:40]([CH2:53][C:54]2[CH:59]=[C:58]([C:60]([F:63])([F:62])[F:61])[CH:57]=[C:56]([C:64]([F:67])([F:66])[F:65])[CH:55]=2)[CH2:41][CH:42]([C:45]2[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=2)[CH2:43][NH2:44])[CH2:36][CH2:35]1)(=[O:32])[CH3:31].C(=O)C1C=CC=CC=1>>[C:30]([NH:33][C:34]1([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[CH2:35][CH2:36][N:37]([CH:40]([CH2:53][C:54]2[CH:55]=[C:56]([C:64]([F:65])([F:66])[F:67])[CH:57]=[C:58]([C:60]([F:62])([F:61])[F:63])[CH:59]=2)[CH2:41][CH:42]([C:45]2[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=2)[CH2:43][NH:44][CH2:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=2)[CH2:38][CH2:39]1)(=[O:32])[CH3:31]
Reactant: CC(=O)NC1(c2ccccc2)CCN(C(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC(CN)c2ccc(Cl)c(Cl)c2)CC1
Reactant: NCCCCc1ccc(Cl)c(Cl)c1
Agent: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: O=Cc1ccccc1
Product: CC(=O)NC1(c2ccccc2)CCN(C(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC(CNCc2ccccc2)c2ccc(Cl)c(Cl)c2)CC1

Procedure:
Using a procedure similar to that described in Example 1, except replacing the (3,4-dichlorophenyl)butylamine and the 3,5-bis-(trifluoromethyl)benzaldehyde used therein with 4-(4-acetamido-4-phenylpiperidino)-2-(3,4-dichlorophenyl)-N-[3,5-bis(trifluoromethyl)benzyl]butylamine and benzaldehyde, respectively, the title compound was prepared; mp 65-67° C.; NMR: 7.85 (s,1), 7.75 (s,1), 7.65 (s,1), 7.45 (s,1), 7.40-6.95 (broad m,10), 3.85 (d,1, J=15.9), 3.65 (d,1 J=13.6), 3.56 (d,1, J=15.9), 3.42 (d,1, J=13.6), 3.05 (m,1), 2.75-2.40 (m,4), 2.35-2.18 (m, 2), 2.18-1.95 (m,4), 1.85 (s,3); MS: m/z=750(M+1,100%). Analysis for C39H39Cl2F6N3O: Calculated: C, 61.10; H, 5.13; N, 5.48; Found: C, 61.12; H, 5.34; N, 5.65.