Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:20]([F:23])([F:22])[F:21])[CH:9]=[C:10]([C:11]3[CH:16]=[C:15]([F:17])[C:14]([F:18])=[C:13]([F:19])[CH:12]=3)[C:4]=2[N:3]=1.[Br:24][C:25]1[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[N:27][CH:28]=[CH:29][CH:30]=1>>[Br:24][C:25]1[C:26]([N:31]2[CH2:32][CH2:33][N:34]([C:2]3[NH:3][C:4]4[C:10]([C:11]5[CH:16]=[C:15]([F:17])[C:14]([F:18])=[C:13]([F:19])[CH:12]=5)=[CH:9][C:8]([C:20]([F:23])([F:22])[F:21])=[CH:7][C:5]=4[N:6]=3)[CH2:35][CH2:36]2)=[N:27][CH:28]=[CH:29][CH:30]=1
Reactant: Fc1cc(-c2cc(C(F)(F)F)cc3[nH]c(Cl)nc23)cc(F)c1F
Reactant: Brc1cccnc1N1CCNCC1
Product: Fc1cc(-c2cc(C(F)(F)F)cc3nc(N4CCN(c5ncccc5Br)CC4)[nH]c23)cc(F)c1F

Procedure:
2-Chloro-6-(trifluoromethyl)-4-(3,4,5-trifluorophenyl)-1H-benzoimidazole (140 mg, 0.4 mmol, Example 51b) reacted with 1-(3-bromo-pyridin-2-yl)-piperazine (120 mg, 0.5 mmol, Example 41a) under the conditions of Example 3c to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 556 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[C:32]([C:43]([F:46])([F:45])[F:44])[CH:31]=1>CC(N(C)C)=O>[CH:37]1([CH2:36][C:33]2[CH:34]=[CH:35][C:30]([CH2:29][O:1][C:2]3[CH:10]=[CH:9][C:8]4[N:7]5[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]5=[CH:5][C:4]=4[CH:3]=3)=[CH:31][C:32]=2[C:43]([F:44])([F:45])[F:46])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]1
Reactant: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(O)ccc12
Reactant: FC(F)(F)c1cc(CCl)ccc1CC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(OCc3ccc(CC4CCCCC4)c(C(F)(F)F)c3)ccc12
Temperature: 60 °C
Reaction time: 16 h
Yield: 62.3 %

Procedure:
To a solution of tert-butyl 2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (0.045 g, 0.157 mmol) in DMA (1 mL) was added Cs2CO3 (0.0.077 g, 0.235 mmol) followed by 4-(chloromethyl)-1-(cyclohexylmethyl)-2-(trifluoromethyl)benzene (0.050 g, 0.172 mmol). The reaction was stirred at 60° C. for 16 h. The mixture was filtered. The filtrate was concentrated under vacuum and purified by silica gel column chromatography to give the title compound as a white solid (0.053 g). LCMS m/z=542.5 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.90-1.03 (m, 2H), 1.09-1.19 (m, 3H), 1.44 (s, 9H), 1.53-1.69 (m, 6H), 2.14-2.26 (m, 1H), 2.51-2.58 (m, 1H), 2.59-2.67 (m, 3H), 2.71-2.81 (m, 1H), 3.53-3.63 (m, 1H), 3.91-3.99 (m, 1H), 4.05-4.14 (m, 1H), 5.12 (s, 2H), 5.99 (s, 1H), 6.77 (dd, J=8.72, 2.40 Hz, 1H), 7.07 (d, J=2.40 Hz, 1H), 7.19 (d, J=8.72 Hz, 1H), 7.44 (d, J=7.96 Hz, 1H), 7.65 (d, J=7.96 Hz, 1H), 7.73 (s, 1H).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[O:7]=[C:8]([N:20]1[CH2:25][CH2:24][N:23]([C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]([F:36])([F:35])[F:34])[CH2:22][CH2:21]1)[CH2:9][NH:10][C:11]([C:13]1[N:14]=[N:15][C:16](Cl)=[CH:17][CH:18]=1)=[O:12].[C:38]1(B(O)O)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C=O)C.O.Cl[Pd]Cl>[O:7]=[C:8]([N:20]1[CH2:25][CH2:24][N:23]([C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]([F:36])([F:35])[F:34])[CH2:22][CH2:21]1)[CH2:9][NH:10][C:11]([C:13]1[N:14]=[N:15][C:16]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:17][CH:18]=1)=[O:12]
Reactant: OB(O)c1ccccc1
Reactant: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(Cl)nn1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(-c2ccccc2)nn1
Temperature: 80 °C
Yield: 12 %

Procedure:
Na2CO3 (183 mg, 1.73 mmol) was added to a stirred solution of 6-chloro-pyridazine-3-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide (263 mg, 0.57 mmol) in DMF (6 mL). PdCl2 (dppf) (80.4 mg, 0.11 mmol) and phenyl boronic acid (89.9 mg, 0.69 mmol) were then added and the reaction mixture was heated at 80° C. for 2 hrs. The reaction mixture was diluted with water and the product was extracted with ethyl acetate. The organic layer was washed with saturated brine solution, dried over sodium sulphate and concentrated to get the residue. The residue obtained was purified by preparative HPLC afford 34 mg (11% yield) of 6-Phenyl-pyridazine-3-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 93.2%. 1H NMR (DMSO-d6): δ 9.3 (t, 1H), 8.5 (d, 1H), 8.3 (t, 3H), 8.0-7.5 (m, 7H), 4.4 (d, 2H), 3.8 (d, 4H), 3.46 (bs, 2H), 3.2 (d, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[N:3]=1.[Br:9]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:9][C:7]1[C:2]([CH3:1])=[N:3][C:4]([NH2:8])=[N:5][CH:6]=1
Reactant: Cc1ccnc(N)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1nc(N)ncc1Br
Reaction time: 18 h
Yield: 87.4 %

Procedure:
To a solution of 4-methylpyrimidine-2-ylamine (8.0 g, 0.073 mol) in chloroform (320 mL) was added N-bromosuccinimide (13.7 g, 0.077 mol). The reaction mixture was stirred in the dark for 18 hrs. LC/MS indicated the reaction was completed. The mixture was diluted with DCM, then washed with 1N NaOH aq solution and brine, dried over MgSO4, filtered and concentrated to yield 5-bromo-4-methylpyrimidine-2-ylamin (12 g, Yield: 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22]([C:24]3[C:25]([CH3:31])=[N:26][CH:27]=[CH:28][C:29]=3[CH3:30])=[O:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)[CH2:12][O:13][CH3:14])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:32]([F:35])([F:34])[F:33].ClC1C=C(C=CC=1)C(OO)=[O:41].N1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22]([C:24]3[CH:25]([CH3:31])[N:26]([OH:41])[CH:27]=[CH:28][C:29]=3[CH3:30])=[O:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)[CH2:12][O:13][CH3:14])(=[O:9])=[O:10])=[CH:4][C:3]=1[C:32]([F:35])([F:33])[F:34]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1c(C)ccnc1C)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCN(c1cc(Cl)cnc1C(=O)C1=C(C)C=CN(O)C1C)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
To a solution of 4-Chloro-N-[5-chloro-2-(2,4-dimethyl-pyridine-3-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (100 mg, 0.182 mmol) in 3.5 mL of DCM was added meta-chloroperoxybenzoic acid (77%, 95 mg, 0.424 mmol). After thirty hours the crude mixture was added 1.0 ml of pyridine and the mixture was concentrated. The mixture was diluted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated. The crude was used at next step without any further purification. MS: (M+H)/z=564.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]([CH:18]=[O:19])=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.O1CCC[CH2:21]1.C[Mg]Br.C(OCC)C>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]([CH:18]([OH:19])[CH3:21])=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: O=Cc1cc2ncccc2nc1-c1cccc(F)c1
Agent: C[Mg]Br
Solvent: CCOCC
Product: CC(O)c1cc2ncccc2nc1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirring mixture of 2-(3-fluorophenyl)-1,5-naphthyridine-3-carbaldehyde (0.0293 g, 0.116 mmol) in tetrahydrofuran (2.00 mL, 0.116 mmol) was added methylmagnesium bromide 3M in diethyl ether (0.0581 mL, 0.174 mmol) dropwise at 0° C. and the mixture was allowed to warm to room temperature with stirring. After 2.5 h, the reaction was quenched with saturated aq. NH4Cl (20 mL) and extracted with EtOAc (30 mL×2). The combined organic layers were washed with brine (30 mL×3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 40 g of Redi-Sep™ column using 0 to 100% gradient of EtOAc in hexane over 14 min and then 100% isocratic of EtOAc for 10 min as eluent to give 1-(2-(3-fluorophenyl)-1,5-naphthyridin-3-yl)ethanol as a colorless syrup: LC-MS (ESI) m/z 268.9 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[F:7][C:8]1[CH:13]=[C:12](B(O)O)[CH:11]=[CH:10][N:9]=1.Cl[C:18]1[N:23]=[CH:22][N:21]=[C:20]([NH:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH:19]=1.O1CCOCC1.O>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:7][C:8]1[CH:13]=[C:12]([C:18]2[N:23]=[CH:22][N:21]=[C:20]([NH:24][CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:19]=2)[CH:11]=[CH:10][N:9]=1
Reactant: OB(O)c1ccnc(F)c1
Reactant: Clc1cc(NC2CCOCC2)ncn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Fc1cc(-c2cc(NC3CCOCC3)ncn2)ccn1
Temperature: 80 °C
Reaction time: 6 h
Yield: 68.5 %

Procedure:
Sodium carbonate (4.24 g, 40.0 mmol) was added to 2-fluoropyridin-4-ylboronic acid (2.26 g, 16.0 mmol) and 6-chloro-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine (2.85 g, 13.3 mmol) in 4:1 dioxane/water (100 mL), and the suspension was purged with argon. PdCl2(dppf)*DCM (0.545 g, 0.667 mmol) was added, and the mixture was heated at 80° C. under nitrogen. After agitating for 6 hours, the reaction mixture was cooled, diluted with water and extracted with ethyl acetate two times. The extract was washed with water, brine, dried and evaporated. Purified by chromatography on silica gel, eluted with 50-70% ethyl acetate/hexane to give 6-(2-fluoropyridin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine (2.50 g, 9.11 mmol, 68.3% yield) as a solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14](Cl)(=[O:19])[CH2:15][CH2:16][CH2:17][CH3:18].C(N(CC)CC)C>ClCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:19])[CH2:15][CH2:16][CH2:17][CH3:18])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCC(=O)Cl
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC(=O)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 79.9 %

Procedure:
A solution of 1-benzylpiperazine (352 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath, and pentanoyl chloride (301 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:1). The fractions containing 1-(4-benzylpiperazin-1-yl)pentan-1-one are collected and the solvent is removed in vacuo to give 416 mg of colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][C:14](=[O:18])[NH:15]3)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[N:19]1([CH2:25][CH2:26][O:27][C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[NH:33][C:32]([CH:37]=O)=[CH:31]3)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[C:16]3[C:12]([C:13](=[CH:37][C:32]4[NH:33][C:34]5[C:30]([CH:31]=4)=[CH:29][C:28]([O:27][CH2:26][CH2:25][N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:36][CH:35]=5)[C:14](=[O:18])[NH:15]3)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=Cc1cc2cc(OCCN3CCOCC3)ccc2[nH]1
Reactant: COc1cccc(-c2ccc3c(c2)NC(=O)C3)c1
Product: COc1cccc(-c2ccc3c(c2)NC(=O)C3=Cc2cc3cc(OCCN4CCOCC4)ccc3[nH]2)c1

Procedure:
6-(3-Methoxy-phenyl)-1,3-dihydro-indol-2-one was condensed with 5-(2-morpholin-4-yl-ethoxy)-1H-indole-2-carbaldehyde to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](I)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:19][C:20]1([F:26])[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]1>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N:22]3[CH2:23][CH2:24][CH2:25][C:20]([F:26])([F:19])[CH2:21]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(I)cc2C1
Reactant: FC1(F)CCCNC1
Agent: Cl
Product: CC(C)(C)OC(=O)N1Cc2ccc(N3CCCC(F)(F)C3)cc2C1

Procedure:
Prepared in analogy to Example A3(d) from 5-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A38(b)) and 3,3-difluoropiperidine hydrochloride. Pink solid. MS (m/e): 339.1 ([M+H]+, 100%).
Reaction SMILES: [Cl-].[NH4+].[N-:3]=[N+:4]=[N-:5].[Na+].[CH2:7]([O:9][C:10]1[CH:11]=[C:12]([C:19]2[S:20][CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#[N:31])[N:25]=3)[N:23]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH3:18])[CH3:8].Cl>CN(C)C=O>[CH2:7]([O:9][C:10]1[CH:11]=[C:12]([C:19]2[S:20][CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[NH:31][N:5]=[N:4][N:3]=4)[N:25]=3)[N:23]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH3:18])[CH3:8]
Reactant: CCOc1ccc(-c2nc(-c3cccc(C#N)n3)cs2)cc1OCC
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2nc(-c3cccc(-c4nnn[nH]4)n3)cs2)cc1OCC
Temperature: 120 °C
Reaction time: 9 h
Yield: 70.7 %

Procedure:
280 mg of ammonium chloride and 380 mg of sodium azide were added to a solution of 1.5 g of 2-(3,4-diethoxyphenyl)-4-(6-cyano-2-pyridyl)thiazole dissolved in 30 ml of dimethylformamide. The mixture was stirred at 120° C. for 9 hours. To the reaction mixture was added diluted hydrochloric acid to make the mixture acidic, followed by extraction three times with 150 ml of ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation. The residue was recrystallized from ethanol-ethyl acetate to obtain 1.19 g of 2-(3,4-diethoxyphenyl)-4-[6-(1,2,3,4-tetrazol-5-yl)-2-pyridyl]thiazole.
Reaction SMILES: O.[OH-].[Na+].[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:24]2[NH:25][C:26]3[C:31]([CH:32]=2)=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:9]=[C:10]([O:22][CH3:23])[C:11]=1[O:12]S(C1C=CC=CC=1)(=O)=O.Cl>CO>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:24]2[NH:25][C:26]3[C:31]([CH:32]=2)=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:9]=[C:10]([O:22][CH3:23])[C:11]=1[OH:12]
Reactant: COc1cc(-c2cc3ccccc3[nH]2)cc(OC)c1OS(=O)(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(-c2cc3ccccc3[nH]2)cc(OC)c1O
Reaction time: 1 h
Yield: 80 %

Procedure:
Into a reactor were introduced 10 ml of water containing 4.8g of solid sodium hydroxide, 30 ml of methanol and 75.6g (0.02 mol) of 2-(3',5'-dimethoxy-4'-benzenesulphonyloxy-phenyl)-indole. The reaction medium was heated to 50°-55° C., was stirred for 1 hour and was poured into an aqueous solution of hydrochloric acid. The indole derivative was extracted with ether and the ethereal phase was washed with water to neutrality, dried, treated with charcoal and, finally concentrated under reduced pressure to give 2-(3',5'-dimethoxy-4'-hydroxy-phenyl)-indole which was recrystallized from a mixture of ethanol-acetone 60/40.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][C:8]=2[C:9]#[N:10])=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20].[H-].[Na+].Cl[C:26]1[CH:27]=[C:28]2[N:35]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][CH2:33][N:29]2[C:30](=[O:32])[N:31]=1>>[C:39]([O:38][C:36]([N:35]1[C:28]2[N:29]([C:30](=[O:32])[N:31]=[C:26]([O:16][CH2:15][C:12]3[CH:13]=[CH:14][C:7]([O:6][C:5]4[CH:17]=[CH:18][C:2]([Cl:1])=[C:3]([C:19]([F:20])([F:21])[F:22])[CH:4]=4)=[C:8]([C:9]#[N:10])[CH:11]=3)[CH:27]=2)[CH2:33][CH2:34]1)=[O:37])([CH3:42])([CH3:40])[CH3:41]
Reactant: N#Cc1cc(CO)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)c(C#N)c1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 2-(4-chloro-3-(trifluoromethyl)phenoxy)-5-(hydroxymethyl)benzonitrile NaH and tert-butyl 7-chloro-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:21]=[CH:20][C:12]([CH2:13][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:11][CH:10]=2)O1.Br[C:24]1[N:29]2[N:30]=[C:31]([NH2:33])[N:32]=[C:28]2[CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(COC)OC.O>C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:17]1[CH2:16][CH2:15][N:14]([CH2:13][C:12]2[CH:11]=[CH:10][C:9]([C:24]3[N:29]4[N:30]=[C:31]([NH2:33])[N:32]=[C:28]4[CH:27]=[CH:26][CH:25]=3)=[CH:21][CH:20]=2)[CH2:19][CH2:18]1
Reactant: Nc1nc2cccc(Br)n2n1
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1nc2cccc(-c3ccc(CN4CCOCC4)cc3)n2n1
Yield: 64.6 %

Procedure:
A solution of 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine (1.9 g, 6.3 mmol), 5-bromo-[1,2,4]triazolo[1,5-a]pyridine-2-amine (1 g, 5 mmol), 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride (250 mg, 0.63 mmol), and cesium carbonate (4.1 g, 12.6 mmol) in 10:1 dimethoxyethane/water (11 mL) was heated at 140° C. under microwave radiation for 1 h. The reaction mixture was diluted with ethyl acetate (200 mL), and the resulting suspension was filtered through celite. The filtrate was concentrated, and the resulting residue was purified by flash column chromatography (petroleum ether→ethyl acetate) to provide product (1 g, 69% yield). LCMS (ESI) m/z: 310.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:21](=[O:25])[NH:22][C:23](=[O:24])[C:19]=2[C:18]2[C:17]3[CH:16]=[C:15]([O:26]C)[CH:14]=[CH:13][C:12]=3[N:11]([CH2:28][CH2:29][C:30]([N:32]3[CH2:37][C@H:36]([CH3:38])[NH:35][C@H:34]([CH3:39])[CH2:33]3)=[O:31])[C:10]=2[CH:9]=1.B(Br)(Br)Br>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:21](=[O:25])[NH:22][C:23](=[O:24])[C:19]=2[C:18]2[C:17]3[CH:16]=[C:15]([OH:26])[CH:14]=[CH:13][C:12]=3[N:11]([CH2:28][CH2:29][C:30]([N:32]3[CH2:33][C@H:34]([CH3:39])[NH:35][C@H:36]([CH3:38])[CH2:37]3)=[O:31])[C:10]=2[CH:9]=1
Reactant: COc1ccc2c(c1)c1c3c(c(-c4ccccc4Cl)cc1n2CCC(=O)N1C[C@@H](C)N[C@@H](C)C1)C(=O)NC3=O
Agent: BrB(Br)Br
Product: C[C@@H]1CN(C(=O)CCn2c3ccc(O)cc3c3c4c(c(-c5ccccc5Cl)cc32)C(=O)NC4=O)C[C@H](C)N1
Reaction time: 48 h
Yield: 38 %

Procedure:
Demethylation of (126) prepared as described in example 239 (with BBr3 using the procedure described in example 80 except that the reaction time was 48 h gave (127) as a yellow powder (38%), mp 220–224° C. (dec). 1H NMR δ [(CD3)2SO] 11.07 (br s, 1H) 9.36 (br s, 1H), 8.72 (br, 1H), 8.34 br, 1H), 7.72 (s, 0.5H), 7.71 (s, 0.5H), 7.60–7.54 (m, 2H), 7.52–7.43 (m, 3H), 7.13 (dd, J=8.8, 2.4 Hz, 1H), 4.68 (m, 3H), 4.15, 4.12 (2s, 2H), 2.94 (m, 1H), 2.72 (m, 1H), 2.19 (m, 1H), 2.00 (m, 1H), 1.84 (m, 1H), 0.86, 0.84 (2d, J=5.8 Hz, 3H), 0.64 (2d, J=6.1 Hz, 3H). Found: C, 63.38; H, 5.38; N, 9.96. C29H17ClN4O4.H2O requires C, 63.44; H, 5.32; N, 10.20.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:25]=[C:26]([N+:28]([O-:30])=[O:29])[CH:27]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([N:17]([CH2:19][CH:20](OC)OC)[CH3:18])=[O:16])=[CH:10][CH:9]=1)([O-:3])=[O:2].Cl>O>[CH3:18][N:17]1[CH2:19][CH2:20][N:14]([C:11]2[CH:12]=[CH:13][C:8]([O:7][C:6]3[CH:25]=[C:26]([N+:28]([O-:30])=[O:29])[CH:27]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)=[CH:9][CH:10]=2)[C:15]1=[O:16]
Reactant: COC(CN(C)C(=O)Nc1ccc(Oc2cc([N+](=O)[O-])cc([N+](=O)[O-])c2)cc1)OC
Agent: Cl
Solvent: O
Product: CN1CCN(c2ccc(Oc3cc([N+](=O)[O-])cc([N+](=O)[O-])c3)cc2)C1=O

Procedure:
N-[4-(3,5-Dinitrophenoxy)phenyl]-N'-(2,2-dimethoxyethyl)-N'-methylurea (0.02 mole), water (30 ml) and concentrated hydrochloric acid (3 ml) are charged into a glass reaction vessel fitted with a mechanical stirrer, thermometer and condenser. The mixture is refluxed for a period of about 30 minutes and then cooled and extracted with ethyl acetate. The extract is washed with dilute aqueous sodium bicarbonate, with two portions of water and is then dried. The ethyl acetate is removed by mild warming under reduced pressure to yield the desired product 1-methyl-3-[4-(3,5-dinitrophenoxy)phenyl]-imidazolin-2-one.
Reaction SMILES: [O:1]=[C:2]1[CH:5]([N:6]=[N+:7]=[N-:8])[CH:4]([CH2:9][CH2:10][C:11](=[O:14])[CH2:12][OH:13])[N:3]1[CH:15]([P:32]([O:37][CH2:38][CH3:39])([O:34][CH2:35][CH3:36])=[O:33])[C:16]([O:18][CH:19]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].C(Cl)Cl.[CH3:43][S:44](Cl)(=[O:46])=[O:45].O=C1C(N=[N+]=[N-])C(CCC(=O)COS(C)(=O)=O)N1C(P(OCC)(OCC)=O)C([O-])=O>C(N(CC)CC)C>[O:1]=[C:2]1[CH:5]([N:6]=[N+:7]=[N-:8])[CH:4]([CH2:9][CH2:10][C:11](=[O:14])[CH2:12][O:13][S:44]([CH3:43])(=[O:46])=[O:45])[N:3]1[CH:15]([P:32]([O:34][CH2:35][CH3:36])([O:37][CH2:38][CH3:39])=[O:33])[C:16]([O:18][CH:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:17]
Reactant: CCOP(=O)(OCC)C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(N=[N+]=[N-])C1CCC(=O)CO
Reactant: CS(=O)(=O)Cl
Agent: CCOP(=O)(OCC)C(C(=O)[O-])N1C(=O)C(N=[N+]=[N-])C1CCC(=O)COS(C)(=O)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(N=[N+]=[N-])C1CCC(=O)COS(C)(=O)=O
Reaction time: 0.03 h

Procedure:
Benzhydryl (2-oxo3-azido-4-[3-keto-4-hydroxybutyl]-N-azetidinyl)diethylphosphonoacetate, 251 mg., is treated at 0° under N2 in 22 ml. CH2Cl2 with 0.056 ml. methanesulfonyl chloride for 5 min., and then .100 ml. triethylamine is added. After 2 min. more at 0° and 30 min. at 25°, the solvent is evaporated and the product chromatographed by PLC, eluting with 10:3 CHCl3 -acetone, affording 197 mg. pure benzyhydryl (2-oxo-3-azido-4-[3-keto-4-methanesulfonyloxybutyl]-N-azetidinyl)diethylphosphonoacetate. NMR (δ, CDCl3): 1.24 m, POCH2CH3 ; 2.0-2.5 m, CH2CH2 ; 3.14 s, CH3SO2 ; 3.8-4.4 m, POCH2CH3 ; 4.71 s, COCH2OSO2Me; 5.09 d, J=22, CHP; 6.93 s, CHφ2 ; 7.36 s, Ar. IR (μ, film): 4.73, azido; 5.64, β-lactam; 5.72, ester.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([CH:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@H:21]3[S:20][CH2:19][C:18]2=[O:36])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+](=[CH:39][CH2:40][CH2:41][CH3:42])=[N-]>CO.C(OCC)C>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@H:21]3[S:20][CH2:19][C:18]=2[O:36][CH2:39][CH2:40][CH2:41][CH3:42])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCC=[N+]=[N-]
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(=O)CS[C@H]12
Solvent: CCOCC
Solvent: CO
Product: CCCCOC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution, cooled to 0° C., of 2.0 g of 7β-phenylacetylamino-cepham-3-one-4ξ-carboxylic acid diphenylmethyl ester in 75 ml of methanol is treated with excess diazo-n-butane in diethyl ether. The mixture is stirred for 15 minutes at 0° C. and is then evaporated under reduced pressure. The oily residue is purified by means of preparative thin layer chromatography (silica gel plates, 6×100 cm; system: toluene/ethyl acetate, 3:1). The layer which is visible under ultraviolet light (λ=254 mμ) is removed and in each case eluted with acetone. This zone (Rf~0.33) yields 3-n-butoxy-7β-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester which after crystallisation from a mixture of methylene chloride and diethyl ether is in the form of colourless flakes which melt at 168°-170° C., [α]D20 =+55°±1° (c=0.38 in chloroform); ultraviolet absorption spectrum (in 95% strength aqueous ethanol): λmax =264 mμ (ε=7,300); infrared absorption spectrum (in methylene chloride): characteristic bands at 2.98μ, 5.62μ, 5.81μ, 5.92μ, 6.25μ and 6.62μ.