Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:5]([CH3:21])=[CH:4][N:3]=1.[CH3:22][N:23]1[CH:27]=[C:26]([NH2:28])[CH:25]=[N:24]1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:21][C:5]1[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][C:17]([O:19][CH3:20])=[O:18])=[N:7][C:2]([NH:28][C:26]2[CH:25]=[N:24][N:23]([CH3:22])[CH:27]=2)=[N:3][CH:4]=1
Reactant: COC(=O)Cc1ccccc1C#Cc1nc(Cl)ncc1C
Reactant: Cn1cc(N)cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)Cc1ccccc1C#Cc1nc(Nc2cnn(C)c2)ncc1C
Temperature: 120 °C

Procedure:
To a solution of methyl 2-(2-((2-chloro-5-methylpyrimidin-4-yl)ethynyl)phenyl)acetate (K7) (0.200 g, 0.665 mmol) in 1,4-dioxane (8 mL) was added 1-methyl-1H-pyrazol-4-amine (0.065 g, 0.665 mmol), Cs2CO3 (0.867 g, 2.66 mmol), Pd2(dba)3 (0.061 g, 0.067 mmol) and Xantphos (0.115 g, 0.200 mmol). The resulting mixture was degassed with nitrogen for 5 minutes before heating under microwave irradiation for 30 minutes at 120° C. The mixture was diluted with EtOAc (100 mL), washed with water (2×25 mL), brine (25 mL), dried (Na2SO4) and concentrated under reduced pressure. The resulting brown oil was purified by silica gel column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-100% EtOAc in hexanes) to give the title compound A115 as a yellow solid (0.128 g, 53%); 1H NMR (400 MHz, d6-DMSO) δ 9.47 (s, 1H), 8.39 (s, 1H), 7.89 (s, 1H), 7.67 (d, J=7.4 Hz, 1H) 7.51-7.44 (m, 3H), 7.43-7.37 (m, 1H), 3.98 (s, 2H), 3.81 (s, 3H), 3.61 (s, 3H), 2.25 (s, 3H). LCMS-A: rt 5.856 min; m/z 362 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl[S:17]([OH:20])(=[O:19])=[O:18]>>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:11]([S:17]([OH:20])(=[O:19])=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=S(=O)(O)Cl
Reactant: O=[N+]([O-])c1cccc(-c2ccccc2)c1
Product: O=[N+]([O-])c1cccc(-c2ccccc2S(=O)(=O)O)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3′-Nitrobiphenyl (10 g) was added slowly to chlorosulfonic acid (20 mL) at room temperature and stirring was continued for 2 hours. The mixture was carefully dripped into ice water and extracted with DCM. The solvent was evaporated to give the title compound as a white powder.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH2:11][CH3:12])[C:4]=1N)[CH3:2].N([O-])=O.[Na+].S(=O)(=O)(O)N.[ClH:22]>O>[CH2:1]([C:3]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH2:11][CH3:12])[C:4]=1[Cl:22])[CH3:2]
Reactant: Cl
Reactant: CCc1cc(C)cc(CC)c1N
Agent: NS(=O)(=O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCc1cc(C)cc(CC)c1Cl
Temperature: 65 °C
Reaction time: 0.08 h

Procedure:
To an initial charge of 65 ml of 36% aqueous HCl are added, in portions, 16.33 g [0.1 mol] of 2,6-diethyl-4-methylaniline. The resulting thick suspension is stirred at 65° C. for 5 minutes. It is then cooled to −10° C., and a solution of 8 g [0.116 mol] of NaNO2 in 35 ml of water is added dropwise within approx. 1 h at such a rate that the temperature does not exceed −5° C. 80 mg of sulphamic acid are added. Then the suspension of the diazonium salt, cooled to −10° C., is metered within about 30 minutes into a solution, heated to 70° C., of 8.36 g [0.05 mol] of FeCl3 in 65 ml of 36% aqueous HCl. The reaction mixture is then stirred at 65-75° C. for another 1 hour, allowed to cool to room temperature and admixed with 200 ml of water, the phases are separated and the aqueous phase is extracted three times with 50 ml each time of methylene chloride. The combined organic phases are washed twice with 25 ml each time of water, dried and concentrated under reduced pressure. This gives 18.1 g of an oil which, according to GC, contains 89% 2,6-diethyl-4-methylchlorobenzene (88% of theory).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[CH2:13]([C@H:15]1[O:17][CH2:16]1)Cl>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.C(O)(C)(C)C>[CH2:13]([C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:4]([NH:5][C:1](=[O:11])[C:2]=12)=[O:6])[C@@H:15]1[O:17][CH2:16]1
Reactant: ClC[C@@H]1CO1
Reactant: O=C1NC(=O)c2ccccc21
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [K]
Solvent: CC(C)(C)O
Product: O=C1NC(=O)c2c(C[C@H]3CO3)cccc21
Temperature: 20 °C
Reaction time: 24 h
Yield: 72 %

Procedure:
Into a reaction vessel were put potassium phthalimide (5.00 g, 27.0 mmol), benzyltrimethylammonium chloride (0.50 g, 2.70 mmol) and tert-buyl alcohol (50 ml) and then thereto was added (S)-epichlorohydrin (6.53 g, 54.0 mmol). The mixture was stirred at 20° C. for 24 hours and the solvent was removed. To the residue was added ethyl acetate (30 ml), the mixture was washed with water (20 ml), and then ethyl acetate was removed to give crude (S)-glycidylphthalimide (3.95 g, yield: 72%, optical purity: 97% e.e.) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][C:29]=1[O:36][CH3:37]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][C:29]=4[O:36][CH3:37])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: COc1cc(C#N)ccc1OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C#N)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 68.2 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.0 g, 13.6 mmol), K2CO3 (2.8 g), 4-(3-bromopropoxy)-3-methoxybenzonitrile (4.0 g, 14.8 mmol) in acetonitrile (70 ml) was heated at reflux for 3 hours. At the end of the reaction, the solvent was removed on a rotary evaporator. The organic material was extracted into dichloromethane (250 ml) and the inorganics were filtered off. The dichloromethane solution was concentrated to a crude oil. The purification was done by flash chromatography over a silica gel column (SIO2, 55 g; eluted with dichloromethane, 600 ml; 1% methanol in dichloromethane, 600 ml). The material thus obtained was crystallized from a small amount of dichloromethane. Recrystallization from ethanol (25 ml) provided 3.8 g (68%) of 4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-propoxy]-3-methoxybenzonitrile as white crystals, m.p.=107°-108° C.
Reaction SMILES: Br[C:2]1[N:3]([CH3:17])[CH:4]=[C:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[N:6]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1>COCCOC.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>[CH3:17][N:3]1[CH:4]=[C:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[N:6]=[C:2]1[C:30]1[CH:29]=[N:28][N:27]([CH3:26])[CH:31]=1
Reactant: Cn1cc(C(=O)OCc2ccccc2)nc1Br
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: Cn1cc(-c2nc(C(=O)OCc3ccccc3)cn2C)cn1
Temperature: 90 °C

Procedure:
Into a flask containing a solution of benzyl 2-bromo-1-methyl-1H-imidazole-4-carboxylate (2 g, 6.77 mmol) in 1,2-dimethoxyethane (40 ml), potassium phosphate (2.3 g, 20.3 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.41 g, 6.77 mmol) were added at RT under argon atmosphere. The resulting mixture was degassed and purged with argon for 10 minutes. Then Pd(PPh3)4 (0.310 g, 0.2 mmol) was added to the reaction mixture and heated at 90° C. for 12 h. The reaction mixture was filtered through a celite bed and the filtrate was diluted with water and extracted with EtOAc. The organic layer was concentrated and purified by flash chromatography. Yield 1.1 g. 1H-NMR (400 MHz; CDCl3): δ 3.77 (s, 3H), 3.95 (s, 3H), 5.36 (s, 2H), 7.30-7.37 (m, 3H), 7.45 (d, 2H), 7.59 (s, 1H), 7.79 (s, 1H), 7.89 (s, 1H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[O:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[NH2:14].[CH3:20][CH:21]1[C:26](=[O:27])[CH2:25][CH2:24][CH2:23][C:22]1=O>>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][CH:2]1[O:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[NH:14][C:22]1[CH2:23][CH2:24][CH2:25][C:26](=[O:27])[C:21]=1[CH3:20]
Reactant: CC1C(=O)CCCC1=O
Reactant: COc1ccc(N)cc1OC1Cc2ccccc2C1
Product: COc1ccc(NC2=C(C)C(=O)CCC2)cc1OC1Cc2ccccc2C1
Yield: 94.2 %

Procedure:
According to the same procedure as in Example 1(3), using 3-(2-indanyloxy)-4-methoxyaniline produced in Example 9(2) instead of 3-cyclopentyloxy-4-methoxyaniline, and using 2-methyl-1,3-cyclohexanedione instead of the 1,3-cyclopentanedione, the title compound (yield 94.2%) was obtained as a light brown solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:12]=[C:11]2[C:6]([N:7]=[C:8]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[C:9]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[C:10]2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[N:5]1.[OH:33][CH2:34][C:35](O)=[O:36]>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:10]2[C:11]3[C:6](=[N:5][N:4]([CH2:3][CH2:2][NH:1][C:34](=[O:33])[CH2:35][OH:36])[CH:12]=3)[N:7]=[C:8]([C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[C:9]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[CH:14][CH:15]=1
Reactant: NCCn1cc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc2n1
Reactant: O=C(O)CO
Product: O=C(CO)NCCn1cc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc2n1

Procedure:
Following a similar procedure to that described in example 48, but starting from 2-(2-aminoethyl)-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine (obtained in example 90) and hydroxyacetic acid, the title compound was obtained.
Reaction SMILES: [OH:1][C:2]([CH2:5][CH2:6][CH2:7][C@H:8]([C@@H:10]1[C@:28]2([CH3:29])[C@H:13]([C@H:14]3[C@H:25]([CH2:26][CH2:27]2)[C@:23]2([CH3:24])[C:17]([CH2:18][C@H:19]([CH2:21][CH2:22]2)[OH:20])=[CH:16][CH2:15]3)[CH2:12][CH2:11]1)[CH3:9])([CH3:4])[CH3:3]>O1CCOCC1>[OH:1][C:2]([CH2:5][CH2:6][CH2:7][C@H:8]([C@@H:10]1[C@:28]2([CH3:29])[C@H:13]([C@H:14]3[C@H:25]([CH2:26][CH2:27]2)[C@:23]2([CH3:24])[C:17](=[CH:18][C:19](=[O:20])[CH:21]=[CH:22]2)[CH:16]=[CH:15]3)[CH2:12][CH2:11]1)[CH3:9])([CH3:3])[CH3:4]
Reactant: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: C1COCCO1
Product: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C

Procedure:
25-Hydroxycholesterol (3.4 gms) and dichlorodicyanoquinone (6.5 gms) dissolved in purified dioxan (100 mls) were heated at reflux for 20 hrs. The mixture was filtered and the solvent evaporated. Chromatography of the residue on alumina and elution with ethyl acetate and benzene afforded the trienone. Recrystallization from methanol gave the title compound, melting point 183°-184°. νmax. 3600, 1650 and 1600 cm-1.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C-:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH2:10][N:11]([CH3:13])[CH3:12])[CH3:3].[CH-:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1.[Fe+2:19].C([Li])CCC.[CH2:25]=[O:26]>C(OCC)C>[OH:26][CH2:25][C-:9]1[CH:8]=[CH:7][C:6]([CH2:10][N:11]([CH3:13])[CH3:12])=[C:5]1[CH2:4][N:2]([CH3:1])[CH3:3].[CH-:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1.[Fe+2:19]
Reactant: CN(C)Cc1ccc[c-]1CN(C)C
Reactant: C=O
Agent: [Fe+2]
Agent: [Li]CCCC
Agent: c1cc[cH-]c1
Solvent: CCOCC
Product: CN(C)Cc1cc[c-](CO)c1CN(C)C
Reaction time: 3 h
Yield: 91 %

Procedure:
To a stirred solution of 1,2-bis-(dimethylaminomethyl) ferrocene (Example 1, 0.70 g, 2.32 mmol) in diethyl ether (15 cm3) under argon is added 1.2 equivalents n-butyl lithium (Aldrich, 1.75 mL, 1.6M in diethyl ether) and the mixture stirred for three hours to yield a red solution. The reaction mixture is cooled in a dry ice/acetone bath, calcined paraformaldehyde added in 2:1 excess, and the resultant mixture stirred at room temperature overnight. The mixture is quenched with water and extracted with diethyl ether. The ethereal extracts are dried over MgSO4, filtered over celite and the solvent removed in vacuo, to yield the title compound (0.7 g, 2.12 mmol, 91%) as an orange oil, which partially crystallized on cooling.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([Cl:13])[C:9]=1[O:10][CH2:11][CH3:12])[NH2:6])[CH3:2].CCN(C1C=CC=CC=1)CC.Cl[C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27]>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:4]=[C:5]([NH:6][C:26](=[O:27])[O:28][CH:29]([CH3:31])[CH3:30])[CH:7]=[C:8]([Cl:13])[C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CC(C)OC(=O)Cl
Reactant: CCOc1c(Cl)cc(N)cc1CC
Solvent: CCN(CC)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOc1c(Cl)cc(NC(=O)OC(C)C)cc1CC
Temperature: 0 °C
Reaction time: 12 h
Yield: 88.3 %

Procedure:
3-Ethyl-4-ethoxy-5-chloroaniline (1.9 g) and diethylaniline (1.5 g) were dissolved in toluene (20 ml). To the resultant solution was dropwise added isopropyl chloroformate (1.2 g) in 5 minutes under ice-cooling. After being allowed to stand at room temperature for 12 hours, the reaction mixture was poured into ice-water and extracted with toluene. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using toluene as the eluent to give isopropyl N-(3-ethyl-4-ethoxy-5-chlorophenyl)carbamate (Compound No. 53) (2.4 g) in a yield of 89%. M.P., 79°-80.5° C.
Reaction SMILES: [C:1]1([C@H:7]([NH:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)[CH2:12][OH:13])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[CH2:29][C:30](Cl)=[O:31].[OH-].[K+]>ClCCl>[Br:20][C:17]1[CH:16]=[CH:15][C:14]([C@@H:11]2[CH2:12][O:13][CH2:29][C:30](=[O:31])[N:9]([C@@H:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH3:8])[CH2:10]2)=[CH:19][CH:18]=1
Reactant: O=C(Cl)CCl
Reactant: C[C@@H](NCC(CO)c1ccc(Br)cc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](c1ccccc1)N1C[C@H](c2ccc(Br)cc2)COCC1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of diastereopure 3-((R)-1-phenylethylamino)-2-(4-bromophenyl)propan-1-ol (2.40 g, 7.18 mmol) in dichloromethane (22.0 ml) was added triethylamine (0.799 g, 7.90 mmol) and chloroacetyl chloride (0.892 g, 7.90 mmol) at 0° C. The mixture was stirred at 0° C. for one hour. The reaction mixture was partitioned between 0.5N—HCl and dichloromethane, and the organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. To the residue dissolved into 2-propanol (48 ml) was added potassium hydroxide (805 mg, 14.4 mmol) at 0° C. The mixture was stirred at 0° C. for 3 hours and partitioned between saturated ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluant: hexane/ethyl acetate=7/3) to afford (S)-6-(4-bromophenyl)-4-((R)-1-phenylethyl)-1,4-oxazepan-3-one as white solid (2.42 g, 90 W. An analytical sample for X-ray was obtained by crystallization from dichloromethane-hexane and the absolute configuration of 6-position was found to be the (S)-configuration.
Reaction SMILES: [Br:1][CH2:2][CH:3]([OH:27])[CH2:4][O:5][C:6]1[C:14]([Br:15])=[C:13]2[C:9]([CH:10]=[N:11][N:12]2[CH2:16][CH:17]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH3:18])=[CH:8][CH:7]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:39]([O:41][CH2:42][CH3:43])=[CH2:40]>ClCCl>[Br:15][C:14]1[C:6]([O:5][CH2:4][CH:3]([O:27][CH:39]([O:41][CH2:42][CH3:43])[CH3:40])[CH2:2][Br:1])=[CH:7][CH:8]=[C:9]2[C:13]=1[N:12]([CH2:16][CH:17]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:21])[CH3:22])[CH3:18])[N:11]=[CH:10]2
Reactant: CC(Cn1ncc2ccc(OCC(O)CBr)c(Br)c21)O[Si](C)(C)C(C)(C)C
Reactant: C=COCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CCOC(C)OC(CBr)COc1ccc2cnn(CC(C)O[Si](C)(C)C(C)(C)C)c2c1Br
Yield: 77.1 %

Procedure:
To a solution of the product from Step E (3.78 g, 7.2 mmol) and p-toluenesulfonic acid (0.14 g) in dichloromethane (50 mL) at 0° C. was added ethyl vinyl ether (2.75 mL, 28.8 mmol). After 30 min the reaction was quenched with a saturated solution of sodium bicarbonate (50 mL) and the mixture was extracted with dichloromethane (3×80 mL). Evaporation and purification by chromatography (silica, 1% to 8% EtOAc/hexane) gave a viscous oil (3.30 g, 77%): LC/MS (+APCI) m/z 593, 595, 597 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:12][C:13]1[S:17][C:16]([Sn](CCCC)(CCCC)CCCC)=[N:15][CH:14]=1>CN(C=O)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>[CH3:12][C:13]1[S:17][C:16]([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[N:15][CH:14]=1
Reactant: COC(=O)c1ccnc(Br)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncc(C)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccnc(-c2ncc(C)s2)c1
Temperature: 90 °C

Procedure:
A mixture of commercially available methyl 2-bromoisonicotinate (2.750 g; 12.70 mmol), 5-methyl-2-(tributylstannyl)thiazole (4.942 g; 12.70 mmol), copper iodide CuI (242 mg; 1.27 mmol), and Pd(PPh3)4 (1.471 g; 1.27 mmol) in anh. DMF (55 ml) was heated to 90° C., under nitrogen, for 18 h. After cooling to rt, the reaction mixture was filtered over a pad of celite, and the separated solids were washed with AcOEt. The organic layer was washed with water and brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (heptane/AcOEt=7/3) afforded methyl 2-(5-methylthiazol-2-yl)isonicotinate as an orange solid. LC-MS (conditions A): tR=0.74 min.; [M+H]+: 235.10 g/mol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH:13][CH3:14])=[CH:6][C:5]=1F.[CH3:17][O-:18].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH:13][CH3:14])=[CH:6][C:5]=1[O:18][CH3:17]
Reactant: CNc1cc(F)c(C(=O)OC)cc1[N+](=O)[O-]
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNc1cc(OC)c(C(=O)OC)cc1[N+](=O)[O-]
Yield: 57 %

Procedure:
2-Methoxy-4-methylamino-5-nitro-benzoic acid methyl ester (120 mg) was prepared by following General Procedure A starting from 2-Fluoro-4-methylamino-5-nitro-benzoic acid methyl ester (200 mg) and sodium methoxide (190 mg) in DMF.
Reaction SMILES: [NH2:1][CH:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][S:10][C:11]3[N:15]([CH3:16])[N:14]=[N:13][N:12]=3)[CH2:7][S:8][C@H:3]12.[Br:22][CH2:23][C:24](Br)=[O:25].P([O-])([O-])([O-])=O.P([O-])([O-])(O)=O.[K+].[K+]>CN(C)C=O.C(N(CC)CC)C.C(Cl)Cl.C(OCC)(=O)C>[Br:22][CH2:23][C:24]([NH:1][CH:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][S:10][C:11]3[N:15]([CH3:16])[N:14]=[N:13][N:12]=3)[CH2:7][S:8][C@H:3]12)=[O:25]
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: O=C(Br)CBr
Agent: O=P([O-])([O-])O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)CBr)[C@H]2SC1
Temperature: 25 °C

Procedure:
20 g of 7-amino-3-(1-methyl-tetrazol-5-ylthio)methylceph-3-em-4-carboxylic acid are dissolved in 460 ml of dimethylformamide and 15.7 ml of triethylamine. This solution is added dropwise over the course of 25 minutes, whilst stirring vigorously, to a solution, precooled to -20° C., of 14.1 g of bromoacetyl bromide in 115 ml of methylene chloride. During the addition the temperature is kept low, and then the batch is allowed to warm to room temperature and is finally stirred for a further hour at room temperature. Thereafter, the reaction mixture is filtered through a "Celite" layer and is concentrated to a syrupy consistency in a high vacuum, using a solid carbon dioxide/acetone condenser. The residue obtained is taken up in 160 ml of 10% strength phosphate buffer of pH 6.7, and 500 ml of ethyl acetate. A pH of 6.0 is established by stirring and adding a total of 37 ml of 20% strength dipotassium hydrogen phosphate solution. After separating the phases, the aqueous phase is again re-extracted with 500 ml of ethyl acetate. The organic phases are discarded. The aqueous phase is now covered with 1.5 liters of ethyl acetate and is brought to pH 2.8 with strong acid. After the phase separation, the aqueous phase is re-extracted with 1.2 and 1.0 liter of ethyl acetate. The organic phases are successively washed with twice 100 ml of saturated sodium chloride solution, dried by means of sodium sulphate and evaporated to dryness in vacuo. The light-coloured resin is dissolved in 60 ml of acetone. An impurity is precipitated by adding 70 ml of absolute ether, and the decanted liquid is treated with 600 ml of ether and 700 ml of pentane whilst stirring vigorously. 7-Bromoacetylamino-3-(1-methyl-tetrazol-5-ylthio)methyl-ceph-3-em-4-carboxylic acid is obtained as an almost colourless precipitate which can directly be used further.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)[CH2:14][C:15]([NH:17]/[N:18]=[CH:19]/[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N+:26]([O-])=O)=[O:16])(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH3:2]>C(Cl)Cl.[Pd]>[NH2:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1/[CH:19]=[N:18]/[NH:17][C:15](=[O:16])[CH2:14][N:13]([C:29]1[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=1)[S:10]([C:7]1[CH:6]=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[CH:9][CH:8]=1)(=[O:12])=[O:11]
Reactant: CCOc1ccc(S(=O)(=O)N(CC(=O)N/N=C/c2ccccc2[N+](=O)[O-])c2ccc(C)cc2)cc1
Agent: [Pd]
Solvent: ClCCl
Product: CCOc1ccc(S(=O)(=O)N(CC(=O)N/N=C/c2ccccc2N)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
4-ethoxy-N-(4-methylphenyl)-N-{2-[(2E)-2-(2-nitrobenzylidene)hydrazino]-2-oxoethyl}benzenesulfonamide (99 mg, 0.2 mmol) was dissolved in methylene chloride. Palladium 5% on charcoal was added (10 mol %). The mixture was stirred under H2 at athmospheric pressure at room temperature overnight. It was filtered on Celite and solvents were evaporated. The expected product, e.g. N-{2-[(2E)-2-(2-aminobenzylidene)hydrazino]-2-oxoethyl}-4-ethoxy-N-(4-methylphenyl)benzenesulfonamide (71.2 mg, 76%), was obtained as a light yellow solid, in 90.9% purity by HPLC (MaxPlot detection between 230 and 400 nm).