Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4](S(O)(=O)=O)=[CH:3][CH:2]=1.[C:12]1([CH2:20][OH:21])(CO)CCC=CC1.[CH:22](OCC)([O:26]CC)[O:23][CH2:24]C>C(O)C>[CH2:20]([O:21][CH:11]1[C:1]2([CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]2)[CH2:24][O:23][CH2:22][O:26]1)[CH3:12]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCOC(OCC)OCC
Reactant: OCC1(CO)CC=CCC1
Solvent: CCO
Product: CCOC1OCOCC12CC=CCC2
Temperature: 40 °C

Procedure:
For the purpose of producing the compound, a small quantity of p-toluene sulfonic acid was added to 14.2 gm (0.1 mol) of 3-cyclohexene-1,1-dimethanol and 14.8 gm (0.1 mol) of triethyl orthoformate and the mixture was agitated for several hours at 40° C. The ethyl alcohol formed was subsequently distilled off and the residue was worked up in the manner already described. A colorless oil was obtained, boiling point 78° C. at 0.15 torr, nD20 = 1.4758, and had a fruity odor with leather, castoreum and jasmine nuances.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[C:8]([O:16][CH3:17])=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11].[CH3:18]O>>[CH3:18][O:11][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][CH:15]=[C:7]([Br:6])[C:8]=1[O:16][CH3:17]
Reactant: CO
Reactant: COc1c(Br)cccc1C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(Br)c1OC
Temperature: 25 °C

Procedure:
5.0 mL of sulfuric acid (H2SO4) was slowly added to a solution of 5.0 g of 3-bromo-2-methoxy-benzoic acid 4 in 100 mL of methanol (MeOH). The resulting solution was heated to reflux overnight. The solution was cooled to room temperature and quenched with sodium bicarbonate to pH 7. The aqueous layer was extracted several times with ethyl acetate. The combined organic extracts were washed with brine and dried over sodium sulphate. The resulting mixture was filtered. The solvents were evaporated under reduced pressure to afford 5.3 g of 3-bromo-2-methoxy-benzoic acid methyl ester 5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([CH2:13][CH2:14][NH:15]C(=O)OCC2C=CC=CC=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1.C1CCCCC=1>C(O)C.[OH-].[Pd+2].[OH-]>[NH2:15][CH2:14][CH2:13][S:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:12]
Reactant: COc1ccc(NS(=O)(=O)CCNC(=O)OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1=CCCCC1
Solvent: CCO
Product: COc1ccc(NS(=O)(=O)CCN)cc1
Yield: 61.5 %

Procedure:
A solution comprised of benzyl 2-(4-methoxyphenylsulfamoyl)ethylcarbamate (2.78 g, 7.63 mmol), prepared as in Reference 1, in ethanol (20 mL) and cyclohexene (20 mL) was treated with 20% palladium hydroxide (0.95 g). The mixture was heated at reflux for 2 hours, cooled, and concentrated to dryness. The solid was triturated with ether, filtered and dried to provide 2-amino-N-(4-methoxyphenyl)ethanesulfonamide (1.08 grams, 61% yield). 1H NMR (DMSO-d6): 2.86 (2H, t, J=6.4 Hz); 3.04 (2H, t, J=6.4 Hz); 3.72 (3H, s); 4.16 (2H, br. s); 6.87 (2H, d, J=9 Hz); 7.05 (2H, d, J=9 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[C:3]=1[CH3:14].C(N(CC)CC)C.[C:22]([O:25][CH2:26][C:27](Cl)=[O:28])(=[O:24])[CH3:23]>ClCCl.O>[C:22]([O:25][CH2:26][C:27]([NH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:11])([F:12])[F:13])[C:3]=1[CH3:14])=[O:28])(=[O:24])[CH3:23]
Reactant: Cc1c(N)ccc(C#N)c1C(F)(F)F
Reactant: CC(=O)OCC(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)Nc1ccc(C#N)c(C(F)(F)F)c1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-amino-3-methyl-2-(trifluoromethyl)benzonitrile (commercially available, for example from Sunshine Chemlab, Downington, Pa., USA, 500 mg, 2.50 mmol) and triethylamine (0.383 mL, 2.75 mmol) in dichloromethane (10 mL) was added 2-chloro-2-oxoethyl acetate (0.269 mL, 2.50 mmol) dropwise. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with DCM (100 ml) and water (50 ml) and aqueous was extracted with DCM (100 ml). The organics were combined, passed through a phase separator and concentrated to afford 710 mg of the title compound as a pale yellow powder.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][S:4](=[O:24])[C@@H:5]2[CH:12]([NH:13][C:14](=[O:22])[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:11](=[O:23])[N:6]2[C:7]=1[C:8]([OH:10])=[O:9].[CH3:25][Si:26]([CH3:32])([CH3:31])NC(=O)C.NS(O)(=O)=O.[Br:38]N1C(=O)CCC1=O>ClCCl>[CH3:25][Si:26]([CH:3]1[C:2]([CH2:1][Br:38])=[C:7]([C:8]([OH:10])=[O:9])[N:6]2[C:11](=[O:23])[CH:12]([NH:13][C:14](=[O:22])[CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C@H:5]2[S:4]1=[O:24])([CH3:32])[CH3:31]
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S(=O)C1
Reactant: CC(=O)N[Si](C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: NS(=O)(=O)O
Solvent: ClCCl
Product: C[Si](C)(C)C1C(CBr)=C(C(=O)O)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S1=O
Temperature: 0 °C
Yield: 49 %

Procedure:
342 mg (0.98 mmole) of 3-methyl-7-phenylacetamido-3-cephem-4-carboxylic acid-1-oxide were suspended in 25 ml of dichloromethane and the mixture was heated to refluxed 157 mg of N-trimethylsilylacetamide (1.20 mmoles) were added thereto and refluxing was continued for 3/4 hour. To the clear, colorless solution obtained, 50 mg of amidosulfonic acid (0.51 mmoles) were added and the mixture was diluted to 40 ml with dichloromethane. The ice-cooled solution was brominated in half an hour using 280 mg (1.57 mmoles) of N-bromosuccinimide as the brominating agent to obtain a yield of 49% of trimethylsilyl 3-bromomethyl-7-phenylacetamido-3-cephem-4-carboxylic acid-1-oxide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.C1(C)C=C(C)C=C(C)C=1S(O[NH2:22])(=O)=O.[CH:24](=O)[C:25]1[C:26](=[CH:28][CH:29]=[CH:30][CH:31]=1)[OH:27]>>[NH2:8][C:6]1[N:5]2[N:22]=[C:24]([C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[OH:27])[N:9]=[C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=1
Reactant: O=Cc1ccccc1O
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: Nc1cc(Br)cc(N)n1
Product: Nc1cc(Br)cc2nc(-c3ccccc3O)nn12

Procedure:
The title compound, MS m/e (%): 307 (M+2, 100), was prepared in accordance with the general method of example 63 from 4-bromo-pyridine-2,6-diamine, O-mesitylene-sulfonylhydroxylamine, and salicylaldehyde. The purification was performed with reversed phase HPLC eluting with an acetonitrile/water gradient.
Reaction SMILES: [Cl:1][S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[CH2:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCl>[C:6]([NH:5][S:2]([Cl:1])(=[O:4])=[O:3])([O:15][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:7]
Reactant: OCc1ccccc1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: ClCCl
Product: O=C(NS(=O)(=O)Cl)OCc1ccccc1

Procedure:
In dry dichloromethane (7 ml) at 0 C, chlorosulfonyl isocyanate (1.0 g, 7.06 mmol, 1 equiv) and benzyl alcohol (764 mg, 7.06 mmol, 1 equiv) were stirred for 30 min to form a 1M solution of Cbz-sulfamoyl chloride. In a separate flask, the starting material (100.0 mg, 0.22 mmol, 1 equiv) was dissolved in DCM (3.0 ml) with pyridine (88 mg, 1.1 mmol, 5 equiv) was treated with the Cbz-sulfamoyl chloride (0.55 ml, mmol, 2.5 equiv) and stirred for 5 min at room temperature. The mixture was split between ethyl acetate and water, and the organic layer was then washed with brine and dried over sodium sulfate. The residue obtained upon concentration was purified by flash silica gel chromatography (0.25% acetic acid/80→100% ethyl acetate/hexanes) to provide a white solid. This material was dissolved in 1:1 ethanol/ethyl acetate (4 ml) with 0.25% acetic acid, and was stirred under a hydrogen atmosphere with 25 mg of 10% Pd/C (wet Degussa type) for 1 hour at room temperature. The mixture was filtered and its concentrated residue purified by silica gel chromatography (0.25% acetic acid/80→100% ethyl acetate/hexanes) to give a clear white solid, Compound 44 (32 mg: 529.1 [M+H]=m/z).
Reaction SMILES: ON1C2C=CC=CC=2N=N1.[Br:11][C:12]1[CH:13]=[C:14]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([NH:29][C:30]([CH:32]=[CH:33][C:34](O)=[O:35])=[O:31])[CH:27]=3)[N:22]=[CH:21][N:20]=2)[CH:15]=[CH:16][CH:17]=1.CCN(C(C)C)C(C)C.[CH2:46]([O:48][C:49]([CH2:51][N:52]([CH2:54][CH2:55][CH2:56][NH2:57])[CH3:53])=[O:50])[CH3:47]>CN(C)C=O.O>[Br:11][C:12]1[CH:13]=[C:14]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([NH:29][C:30](=[O:31])[CH:32]=[CH:33][C:34]([NH:57][CH2:56][CH2:55][CH2:54][N:52]([CH2:51][C:49]([O:48][CH2:46][CH3:47])=[O:50])[CH3:53])=[O:35])[CH:27]=3)[N:22]=[CH:21][N:20]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)C=CC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reactant: CCOC(=O)CN(C)CCCN
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN(C)CCCNC(=O)C=CC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
106 mg of benzotriazol-1-yl-N-tetramethyl-uronium-tetrafluoroborate and 68 mg of 1-hydroxybenzotriazole are added to a solution of 200 mg of 4-[(3-bromophenyl)amino]-6-{[(2-carboxyvinyl)carbonyl]amino}-quinazoline in 2.5 ml of dimethyl-formamide. The solution is stirred for 20 minutes at ambient temperature, then 0.5 ml of Hünig's base and 148 mg of 3-{N-[(ethoxycarbonyl)methyl]-N-methylamino}propylamine, dissolved in 0.5 ml of dimethylformamide, are added. The reaction mixture is stirred for a further two hours at ambient temperature before being poured onto 50 ml of water for working king up. The aqueous phase is extracted with ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated by evaporation. The crude product is purified by chromatography on a silica gel column with methylene chloride/ethanol (20:1 to 9:1). Yield: 106 mg (39% of theory), Melting point: 278-279° C. Mass spectrum (ESI*): m/z=569, 571 [M+H]*
Reaction SMILES: [Br:1][C:2]1[C:11]2[O:10][CH2:9][CH2:8][NH:7][C:6]=2[CH:5]=[C:4]([Cl:12])[CH:3]=1.NC1C=C(Cl)C=C(Br)C=1[OH:22].ClCC(Cl)=O>>[Br:1][C:2]1[C:11]2[O:10][CH2:9][C:8](=[O:22])[NH:7][C:6]=2[CH:5]=[C:4]([Cl:12])[CH:3]=1
Reactant: Clc1cc(Br)c2c(c1)NCCO2
Reactant: Nc1cc(Cl)cc(Br)c1O
Agent: O=C(Cl)CCl
Product: O=C1COc2c(Br)cc(Cl)cc2N1

Procedure:
8-Bromo-6-chloro-2,3-dihydro-benzo[1,4]oxazine used in this Example was prepared by first reacting 2-amino-6-bromo-4-chloro-phenol with chloroacetyl chloride to provide 8-bromo-6-chloro-4H-benzo[1,4]oxazin-3-one using the procedure reported by Combs et al.; J. Med. Chem.; 33; 380-386 1990. This benzoxazinone was then reduced to 8-bromo-6-chloro-2,3-dihydro-benzo[1,4]oxazine using borane in THF according to the procedure described in Tetrahedron; 53(26); 8853-8870 1997.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B1OC(C)(C)C(C)(C)O1>COCCOC.O.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>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[NH2:14]
Reactant: Brc1ccccn1
Reactant: CC1(C)OB(c2ccccc2N)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Nc1ccccc1-c1ccccn1
Temperature: 100 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
Under air, to 2-bromopyridine (4.54 g, 28.7 mmol, 1.00 equiv) in DME—H2O (1:1, 100 mL) at 23 ° C. was added K2CO3 (5.96 g, 43.1 mmol, 1.50 equiv), 2-aminophenylboronic acid pinacol ester (6.30 g, 28.7 mmol, 1.00 equiv), and tetrakis(triphenylphosphine)palladium (1.66 g, 1.44 mmol, 5.00 mol%). The reaction mixture was stirred at 100 ° C. for 3.0 h. After cooling to 23 ° C., the phases were separated and the aqueous phase was extracted with EtOAc (3×50 mL). The combined organic phases were washed with brine (100 mL) and dried (Na2SO4). The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica gel eluting with hexanes/EtOAc 4:1 (v/v) to afford 4.20 g of the title compound as a red-brown oil (86%). Rf=0.38 (hexanes/EtOAc 3:1 (v/v)). NMR Spectroscopy: 1H NMR (500 MHz, CDCl3, 23 ° C., δ): 8.61-8.60 (m, 1H), 7.78-7.75 (m, 1H), 7.65 (d, J=7.9 Hz, 1H), 7.51 (dd, J=7.6 Hz, 1.4 Hz, 1H), 7.19-7.16 (m, 2H), 6.80-6.76 (m, 2H), 5.72 (br s, 2H). 13C NMR (125 MHz, CDCl3, 23 ° C., δ): 159.5, 147.9, 146.6, 136.9, 129.9, 129.4, 122.2, 122.2, 121.0, 117.6, 117.2.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:13]2[NH:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][C:17]([O:26][CH3:27])=[CH:18][C:19]=3[O:24][CH3:25])[N:14]=2)[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>C1COCC1>[CH3:25][O:24][C:19]1[CH:18]=[C:17]([O:26][CH3:27])[CH:16]=[C:15]2[C:20]=1[C:21](=[O:23])[NH:22][C:13]([C:7]1[CH:6]=[C:5]([O:4][CH2:3][CH2:2][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=1)=[N:14]2
Reactant: COc1cc(OCCBr)cc(-c2nc3cc(OC)cc(OC)c3c(=O)[nH]2)c1
Reactant: C1CCNC1
Solvent: C1CCOC1
Product: COc1cc(OCCN2CCCC2)cc(-c2nc3cc(OC)cc(OC)c3c(=O)[nH]2)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 2-[3-(2-bromo-ethoxy)-5-methoxy-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (7.10 g, 16.0 mmol) in THF (20 mL) was added pyrrolidine (11.38 g, 160.0 mmol) and the reaction mixture was stirred at room temperature for 15 hours. THF was removed under reduced pressure, the residue was purified by column chromatography (silica gel 230-400 mesh; eluting with 5% 2.0 M ammonia in methanol solution in dichloromethane) to give the title compound as a white solid. Yield: 3.2 g (47%). MP 159-160° C. 1H NMR (400 MHz, CDCl3): δ 10.66 (s, 1H), 7.25 (m, 2H), 6.84 (d, J=2.0 Hz, 1H), 6.67 (t, J=2.4 Hz, 1H), 6.45 (d, J=2.0 Hz, 1H), 4.21 (t, J=6.0 Hz, 2H), 3.95 (s, 3H), 3.93 (s, 3H), 3.89 (s, 3H), 2.93 (t, J=6.0 Hz, 2H), 2.64 (m, 4H), 1.80 (m, 4H). MS (ES+) m/z: 426.20 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[NH2:21][CH2:22][C:23]1[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=1)[O:26][CH2:27][CH2:28][CH2:29][N:30]([CH3:32])[CH3:31]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:21][CH2:22][C:23]2[CH:35]=[CH:34][CH:33]=[C:25]([O:26][CH2:27][CH2:28][CH2:29][N:30]([CH3:31])[CH3:32])[CH:24]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: CN(C)CCCOc1cccc(CN)c1
Product: CN(C)CCCOc1cccc(CNC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)c1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and 3-[3-(aminomethyl)phenoxy]-N,N-dimethyl-propan-1-amine (25.0 mg, 0.12 mmol). The title compound was obtained as a solid (35.4 mg, 65% yield). MS m/z: 541.06, 543.05 [M+H]+.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][C:3]=1[CH3:13].O.[ClH:15]>CN(C)C=O.Cl[Ni]Cl>[Cl:15][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][C:3]=1[CH3:13]
Reactant: Cc1cc(C(C)(C)C)cc(C)c1Br
Reactant: Cl
Agent: Cl[Ni]Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C(C)(C)C)cc(C)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 500 mL round bottom flask 4.50 g of 2-bromo-5-tert-butyl-1,3-dimethylbenzene (18.6 mmol) and 9.50 g of NiCl2.6 H2O (40.0 mmol) were added. Then 30 mL of N,N-dimethylformamide was added to the flask, giving a blue-green solution. The flask was fitted with a condenser and was left to reflux with stirring. After 0.5 hours the solution was dark blue. After refluxing for 5 days the mixture was cooled to rt and then diluted with 25 mL of 2 M HCl. The aqueous phase was extracted with 40 mL of ethyl acetate. The volatiles were removed from the extract by evaporation to give a white solid. (91% conversion to the title product) All of the solids were dissolved in 25 mL of N,N-dimethylformamide and the solution was placed in a 125 mL round bottom flask. Then 5.1 g of NiCl2·6 H2O (21.5 mmol) was added to the flask. The flask was fitted with a condenser and was left to reflux with stirring. After 0.5 hours the solution was dark blue. After refluxing for 5 days the mixture was cooled to rt and then diluted with 25 mL of 2 M HCl. The aqueous phase was extracted with 40 mL of ethyl acetate. The volatiles were removed from the extract by evaporation to give a white solid. C12H17Cl, fw=196.72. Yield 3.51 g, 95.6%. Mp: 39° C. (melt). 1H NMR (300 MHz, CDCl3): δ 7.01 (s, 2H), 2.30 (s, 6H), 1.22 (s, 9H). Rf=0.69 (cyclohexane/silica).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[O:6][C:7]3[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=3[CH2:9][N:10]([C:11]([NH:13][NH2:14])=[O:12])[C:4]=2[CH:3]=1.[N:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][C:30](OC)=[O:31])=[CH:23][CH:22]=1.[Cl-].C[Al+]C.CO>C1(C)C=CC=CC=1>[O:31]=[C:30]([NH:14][NH:13][C:11]([N:10]1[CH2:9][C:8]2[CH:15]=[CH:16][CH:17]=[CH:18][C:7]=2[O:6][C:5]2[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][C:4]1=2)=[O:12])[CH2:29][CH2:28][CH2:27][C:24]1[CH:23]=[CH:22][N:21]=[CH:26][CH:25]=1
Reactant: NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: COC(=O)CCCc1ccncc1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C(CCCc1ccncc1)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Temperature: 25 °C
Yield: 82.4 %

Procedure:
To a solution of 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, hydrazide (1) (1.5 g, 5 mmol), prepared as described above in Example 1, and methyl 4-(4-pyridyl)butanoate (48) (2.4 g, 13 mmol), prepared as described above in Example 48, in toluene (250 mL) was added dimethylaluminumchloride (20.0 mmol). The resulting yellow solution was refluxed under a N2 atmosphere for 16 hours. The reaction mixture was allowed to cool to room temperature, followed by the addition of methanol (7 mL). The reaction mixture was extracted with sodium hydroxide (1M, 2×200 mL), and the aqueous extracts were combined and extracted with ethyl acetate (3×200 mL). The organic solutions were combined, dried (Na2SO4) and evaporated to yield 1.8 g of crude product as a thick oil.
Reaction SMILES: Cl([O-])=[O:2].[Na+].[Cl:5][C:6]1[N:7]=[C:8]([NH:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[S:9][C:10]=1[CH:11]=[O:12]>O.C(#N)C.CC(O)(C)C.CC(=CC)C>[C:14]([NH:13][C:8]1[S:9][C:10]([C:11]([OH:2])=[O:12])=[C:6]([Cl:5])[N:7]=1)(=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=Cc1sc(NC(=O)c2ccccc2)nc1Cl
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: CC#N
Product: O=C(Nc1nc(Cl)c(C(=O)O)s1)c1ccccc1
Reaction time: 1 h
Yield: 17 %

Procedure:
A solution of sodium chlorite (2.20 g, 19.40 mmol) and NaH2PO4 (2.32 g, 19.10 mmol) in water (10 mL) was added to a mixture of N-(4-chloro-5-formylthiazol-2-yl)benzamide (0.52 g, 1.95 mmol) in acetonitrile (20 mL), t-BuOH (20 mL) and 2-methyl-2-butene (4 mL) at 0° C. The mixture was stirred for 1 h, then extracted with chloroform, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the crude product in 17% yield (0.097 g), which was used for next step without purification; MS (ES+) m/z 283.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[O:5][CH:6]([CH2:10][CH3:11])[C:7]([OH:9])=[O:8].[Si:16]([O:23][C@H:24]1[CH2:33][C@H:32](O)[C@H:31]2[C:26]([CH:27]=[CH:28][C@H:29]([CH3:52])[C@@H:30]2[CH2:35][CH2:36][C@H:37]2[O:42][C:41](=[O:43])[CH2:40][C@H:39]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[CH2:38]2)=[CH:25]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>>[Si:16]([O:23][C@H:24]1[CH2:33][C@H:32]([O:8][C:7](=[O:9])[CH:6]([O:5][C:4]2[CH:12]=[CH:13][CH:14]=[CH:15][C:3]=2[O:2][CH3:1])[CH2:10][CH3:11])[C@H:31]2[C:26]([CH:27]=[CH:28][C@H:29]([CH3:52])[C@@H:30]2[CH2:35][CH2:36][C@H:37]2[O:42][C:41](=[O:43])[CH2:40][C@H:39]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:46])[CH3:47])[CH2:38]2)=[CH:25]1)([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:18])[CH3:17]
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reactant: CCC(Oc1ccccc1OC)C(=O)O
Product: CCC(Oc1ccccc1OC)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 96.4 %

Procedure:
A procedure similar to that described in Example 1, above, was followed, but using 0.42 g of (2RS)-2-(2-methoxyphenoxy)butyric acid and 1.0 g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 1.30 g of the title compound as a colorless foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[O:5][CH2:6][C:7]([OH:9])=O.[CH3:14][NH:15][C@@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[N:22]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[ClH:1].[CH3:14][N:15]([C@@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[N:22]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[C:7](=[O:9])[CH2:6][O:5][C:4]1[CH:10]=[CH:11][C:12]([Cl:13])=[C:2]([Cl:1])[CH:3]=1
Reactant: CN[C@@H]1CCCC[C@H]1N1CCCCCC1
Reactant: O=C(O)COc1ccc(Cl)c(Cl)c1
Product: CN(C(=O)COc1ccc(Cl)c(Cl)c1)[C@@H]1CCCC[C@H]1N1CCCCCC1
Product: Cl

Procedure:
The title compound was prepared according to the method described in Example 2, using 3,4-dichlorophenoxyacetic acid (2.15 g, 10 mmol) and (±)-trans-N-methyl-N-[2-(1-hexahydroazepinyl)cyclohexyl]amine prepared in Example 10 (2 g, 10 mmol). The crude product, which precipitated without the addition of any diethyl ether, was recrystallised from hot methanol (150 mL). Yield 3.58 g (80%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:13]2[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]2[CH3:19])[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH:8]=[CH:7]2.[N+:20]([O-])([OH:22])=[O:21].C(=O)([O-])[O-].[Na+].[Na+]>S(=O)(=O)(O)O>[CH3:1][C:2]1[CH:3]=[C:4]([N:13]2[C:17]([N+:20]([O-:22])=[O:21])=[C:16]([CH3:18])[N:15]=[C:14]2[CH3:19])[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH:8]=[CH:7]2
Reactant: O=[N+]([O-])O
Reactant: Cc1cn(-c2cc(C)c3[nH]c(=O)ccc3c2)c(C)n1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1nc(C)n(-c2cc(C)c3[nH]c(=O)ccc3c2)c1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
To a stirred solution of 8-methyl-6-(2,4-dimethylimidazol-1-yl)-2-(1H)-quinolone (0.5 g) in concentrated sulphuric acid (4 cm3) at 0° was added concentrated nitric acid (1 cm3). The mixture was stirred for 1 hour, poured carefully onto ice (100 g), and the solution basified to pH8 with solid sodium carbonate. The resulting suspension was extracted with dichloromethane (3×100 cm3) and the combined organic phases were dried (MgSO4), filtered, and evaporated to yield a foam which was triturated with ethyl acetate/ether or afford 8-methyl-6-(2,4-dimethyl-5-nitro-imidazol-1-yl)-2-(1H)-m.p. 244°-247°, (0.52 g).