Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:16])[C:5](/[CH:8]=[N:9]/[S:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])=[N:6][CH:7]=1.[CH3:17][Mg]Cl.O>C(Cl)Cl.[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[C:4]([F:16])[C:5]([C@H:8]([NH:9][S:10]([C:12]([CH3:13])([CH3:15])[CH3:14])=[O:11])[CH3:17])=[N:6][CH:7]=1
Reactant: CC(C)(C)S(=O)/N=C/c1ncc(Br)cc1F
Reactant: C[Mg]Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C[C@@H](NS(=O)C(C)(C)C)c1ncc(Br)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of N-[(1E)-(5-bromo-3-fluoropyridin-2-yl)methylidene]-2-methyl-propane-2-sulfinamide (18.63 g, 60.65 mmol) in CH2Cl2 (375 mL) was cooled to −50° C. under N2. Methylmagnesium chloride (3M in THF, 30.32 mL, 90.97 mmol) was added dropwise, the reaction was stirred for 1 h. Additional methylmagnesium chloride (5.0 mL, 15.0 mmol) was added after 30 minutes to drive the reaction to completion. Water (200 mL) and brine (200 mL) were added, and the reaction allowed to warm to room temperature. The aqueous layer was extracted 4× with CH2Cl2, and the combined organics were dried over Na2SO4, filtered and concentrated under vacuum. The residue was subjected to silica gel chromatography eluted with 10–40% ethyl acetate in hexanes to provide N-[(1R)-1-(5-bromo-3-fluoropyridin-2-yl)ethyl]-2-methylpropane-2-sulfinamide that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 325.0 for M+H+(81Br).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[N:12]1[C:21]2[C:16](=[CH:17][C:18]([F:24])=[C:19]([F:23])[C:20]=2[F:22])[C:15](=[O:25])[C:14]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:13]1.C(O)(=O)C.ClC(Cl)C>CO.[Pd]>[NH2:9][C:5]1[CH:4]=[C:3]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([F:24])=[C:19]([F:23])[C:20]=3[F:22])[C:15](=[O:25])[C:14]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:13]2)[C:2]([F:1])=[CH:7][C:6]=1[F:8]
Reactant: CCOC(=O)c1cn(-c2cc([N+](=O)[O-])c(F)cc2F)c2c(F)c(F)c(F)cc2c1=O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1cn(-c2cc(N)c(F)cc2F)c2c(F)c(F)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.7 %

Procedure:
Ethyl 1-(2,4-difluoro-5-nitrophenyl)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (2.2 g) was dissolved in 20 ml of methanol, 50 ml of acetic acid, and 10 ml of dichloroethane, to which was added 200 mg of 10% palladium on carbon. Under a hydrogen atmosphere, the solution was stirred overnight at room temperature. The catalyst was removed by a membrane filter and the filtrate was concentrated in vacua. Ethanol was added to the residue whereupon the solid was collected by filtration and washed with diethyl ether to give 1.12 g of the title compound.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12].S(=O)(=O)(O)[OH:22].N([O-])=O.[Na+].F[B-](F)(F)F.[Na+]>O>[OH:22][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12]
Reactant: O=S(=O)(O)O
Reactant: Nc1ccccc1Sc1cc([N+](=O)[O-])ccc1C(=O)O
Agent: F[B-](F)(F)F
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc([N+](=O)[O-])cc1Sc1ccccc1O
Reaction time: 0.33 h

Procedure:
Suspend 10.15 g (35 mmoles) of the amino acid of Step A in 75 ml of water and add 4 ml concentrated sulfuric acid (7.36 g, 75 mmoles, 150 meq). Cool the mixture in an ice-bath and add 3.657 g (53 mmoles) of sodium nitrite in portions at 0°-5° C. Stir the suspension in the cold for 20 minutes. Add 10 g (91 mmoles) of sodium fluoroborate and stir for an additional 20 minutes. Separate the precipitated crude diazonium fluoroborate, suspend the precipitate in 250 ml of 50% sulfuric acid and heat in an oil bath at 90°-100° C. for 45 minutes. Cool the mixture and separate the precipitate. (Yield: 7.76 g).
Reaction SMILES: [O-]CC.[Na+].[CH3:5][C:6]([CH:8]1[CH2:10][CH2:9]1)=[O:7].[CH:11]1([C:14](OC)=[O:15])[CH2:13][CH2:12]1>CS(C)=O>[CH:11]1([C:14](=[O:15])[CH2:5][C:6]([CH:8]2[CH2:10][CH2:9]2)=[O:7])[CH2:13][CH2:12]1
Reactant: CC(=O)C1CC1
Reactant: COC(=O)C1CC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(CC(=O)C1CC1)C1CC1
Temperature: 60 °C

Procedure:
Sodium ethoxide (8 g, 117.64 mmol) was added to a solution of cyclopropyl methyl ketone (5 g, 59.4 mmol) and methyl cyclopropane carboxylate (12 ml, 118.9 mmol) in DMSO (30 mL). The resulting mixture was heated at 60° C. overnight and then cooled to 0° C. After quenching the reaction with 6N HCl, work-up (H2O/AcOEt) gave the title compound as a brown liquid which was used without any purification. 1H-NMR (δ ppm, CDCl3, 400 MHz): 16.05 (bs, 0.6H), 5.72 (s, 0.6H) 3.78 (s, 0.8H), 2.08-2.0 (m, 0.8H), 1.62-1.53 (m, 1.2H), 1.12-1.05 (m, 4H), 0.97-0.83 (m, 4H). MS (m/z): 153.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[C:5](Cl)=[N:6][CH:7]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])(O)=O.[Na+]>CCCCO.CCOC(C)=O>[Br:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[C:5]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:6][CH:7]=1
Reactant: Nc1ccccc1
Reactant: Cn1c(Cl)ncc(Br)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: Cn1c(Nc2ccccc2)ncc(Br)c1=O
Temperature: 60 °C
Reaction time: 16 h
Yield: 99.5 %

Procedure:
A mixture of 5-bromo-2-chloro-3-methylpyrimidin-4(3H)-one (0.510 g, 2.282 mmol), aniline (0.271 ml, 2.967 mmol) and NaHCO3 (0.767 g, 9.129 mmol) in n-BuOH (15 mL) was stirred at 60° C. for 16 hours. The reaction mixture was cooled to room temperature and then diluted with EtOAc. The EtOAc layer was washed with H2O and saturated aqueous NaCl. The aqueous phase was re-extracted with EtOAc (1×). The combined EtOAc layers were dried (Na2SO4), filtered and concentrated to yield the desired product (0.636 g, 99%) as a pale yellow solid that was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 8.95 (br s, 1H), 7.94 (s, 1H), 7.47 (m, 2H), 7.35 (m, 2H), 7.14 (m, 1H), 3.53 (s, 3H). LRMS (ESI pos) m/e 280, 281 (M+, Br pattern).
Reaction SMILES: [OH:1][C:2]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH:10]2[O:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[O:12][CH2:11]2)[CH2:4][CH2:3]1.C([Li])CCC.[C:31]([Cl:37])(=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33].[Cl-].[NH4+]>O1CCCC1.CCCCCC.C(OCC)C>[ClH:37].[C:31]([O:1][C:2]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][CH:10]2[O:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[O:12][CH2:11]2)[CH2:6][CH2:7]1)(=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33]
Reactant: OC1(c2ccccc2)CCN(CCC2COc3ccccc3O2)CC1
Reactant: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)(C)C(=O)OC1(c2ccccc2)CCN(CCC2COc3ccccc3O2)CC1
Product: Cl
Temperature: 25 °C

Procedure:
To the stirred solution of 4.0 g of 2-[2-(4-hydroxy-4-phenylpiperidino)-ethyl]-1,4-benzodioxan in 50 ml of anhydrous tetrahydrofuran is added 9.5 ml of 1.6 N n-butyl lithium in hexane at 0°. After warming the mixture up to room temperature, the solution of 1.5 ml of pivaloyl chloride in 10 ml of tetrahydrofuran is added while stirring and the whole is refluxed for 24 hours. After cooling 10 ml of saturated aqueous ammonium chloride are added, followed by 200 ml of diethyl ether. The organic layer is separated, washed with water, dried evaporated and the residue dissolved in isopropanol. The solution is made acidic with 6N ethanolic hydrogen chloride and the precipitate collected, to yield the 2-[2-(4-pivaloyloxy-4-phenylpiperidino)-ethyl]-1,4-benzodioxan hydrochloride melting at 195°-200° with decomposition.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.CN.C(Cl)CCl.C1C=CC2N(O)N=[N:27][C:25]=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH:27][CH3:25])=[O:8]
Reactant: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: On1nnc2ccccc21
Agent: CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CNC(=O)c1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
To the mixture of 5-fluoro-2-nitrobenzoic acid (371 mg, 2.0 mmol), methylamine hydrogen chloride (162 mg, 1.2 eq), EDC (575 mg, 1.5 eq), HOBt (324 mg, 1.2 eq) in DMF (10 mL) was added DIEA (1.8 mL, 5.0 eq). The mixture was stirred at room temperature overnight. The crude was concentrated and dissolved in EtOAc. It was washed with saturated NaHCO3 solution. The solvent was removed and the crude was purified by silica gel chromatography (0%˜20% MeOH/DCM) to obtain the desired product 5-fluoro-N-methyl-2-nitrobenzamide (356 mg, isolated yield 90%).
Reaction SMILES: OS(O)(=O)=O.[O:6]=S(=O)=O.[Cl:10][C:11]([F:23])([C:19]([F:22])([F:21])[Cl:20])[C:12]([F:18])([F:17])[C:13](F)([F:15])I>>[Cl:10][C:11]([F:23])([C:19]([F:22])([F:21])[Cl:20])[C:12]([F:18])([F:17])[C:13]([F:15])=[O:6]
Reactant: O=S(=O)=O
Reactant: FC(F)(Cl)C(F)(Cl)C(F)(F)C(F)(F)I
Agent: O=S(=O)(O)O
Product: O=C(F)C(F)(F)C(F)(Cl)C(F)(F)Cl
Temperature: 110 °C

Procedure:
A 1 L three-necked flask, fitted with a stir bar and condenser, was charged with 3.0 g of HgO (yellow), 125 mL of 20% oleum, 25 mL of 65% oleum and 75.6 g of 3,4-dichloro-1-iodoperfluorobutane. After the reaction mixture was heated at 110° C. for 2 hours, the condenser was replaced by a distillation head with a 250 mL flask for receiver cooled with ice water. Volatiles were collected, washed with 98% sulfuric acid to remove sulfur trioxide and redistilled to give 40.3 g of 3,4-dichloroperfluorobutyryl fluoride, bp 72°-75° C., 99.8% GC purity.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[CH3:15][C:16]1[N:24]([C:25]([C:27]2[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=2)=[O:26])[C:23]2[CH:22]=[CH:21][C:20]([O:34][CH3:35])=[CH:19][C:18]=2[C:17]=1[CH2:36][C:37](O)=[O:38].CCN=C=NCCCN(C)C>CC#N.CCOC(C)=O>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C:25]([N:24]2[C:23]3[C:18](=[CH:19][C:20]([O:34][CH3:35])=[CH:21][CH:22]=3)[C:17]([CH2:36][C:37]([NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:38])=[C:16]2[CH3:15])=[O:26])=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)NCCOCCN
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1ccc2c(c1)c(CC(=O)NCCOCCNC(=O)OC(C)(C)C)c(C)n2C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.5 %

Procedure:
tert-Butyl 2-(2-aminoethoxy)ethylcarbamate (150 mg, 0.735 mmol) was then taken up in CH3CN (10 mL) along with indomethacin (263 mg, 0.735 mmol) and EDCI (155 mg, 0.81 mmol). The resulting reaction mixture was stirred at room temperature for 18 h. It was then diluted with EtOAc (20 mL), washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (9:1 CH2Cl2/MeOH) to afford 310 mg of tert-butyl 2-(2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetamido)ethoxy)ethylcarbamate (78%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[C:4](Cl)[N:3]=1.[NH2:11][C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[C:14]([NH:16][CH3:17])=[O:15].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[C:14]([NH:16][CH3:17])=[O:15])[C:5]([C:8]#[N:9])=[CH:6][N:7]=1
Reactant: N#Cc1cnc(Cl)nc1Cl
Reactant: CNC(=O)c1ccccc1N
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1C#N

Procedure:
In a similar fashion as outlined in Example 191a, 2,6-dichloro-5-cyanopyrimidine was reacted with 2-amino-N-methylbenzamide and N,N-diisopropylethylamine in isopropyl alcohol (no microwave—20° C., 10 minutes) to afford 2-(2-chloro-5-cyano-pyrimidin-4-ylamino)-N-methyl-benzamide as a yellow solid. Mp: 228-32° C. (dec); MS: 288.26 (M+H); 1H NMR (chloroform-d): δ 12.49 (s, 1H), δ 8.69 (d, J=8 Hz, 1H), δ 8.50 (s, 1H), δ 7.57 (m, 2H), δ 7.22 (t, J=8 Hz, 1H), δ 6.31 (br s, 1H), δ 3.08 (d, J=5 Hz, 3H).
Reaction SMILES: [NH2:1]/[C:2](/[CH3:8])=[CH:3]\[C:4]([O:6][CH3:7])=[O:5].[CH3:9][S:10]([OH:13])(=[O:12])=[O:11].[H][H]>[Pt].CO>[CH3:9][S:10]([OH:13])(=[O:12])=[O:11].[NH2:1][CH:2]([CH3:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)/C=C(/C)N
Reactant: [H][H]
Agent: [Pt]
Agent: CS(=O)(=O)O
Solvent: CO
Product: COC(=O)CC(C)N

Procedure:
5.0 g (43.4 mmol) of methyl 3-aminocrotonate, 70 ml of anhydrous methanol, 1.0 equivalent of methanesulfonic acid and 0.22 g of Pt/C catalyst (Heraeus K0129) were introduced into a 160 ml Parr autoclave. The hydrogenation was carried out for 2 hours at approximately 20° C. under 5-10 bar of hydrogen. The catalyst was then filtered off and the solvent was completely removed by distillation on a rotary evaporator. 6.2 g of pure methyl (RS)-3-aminobutyrate methanesulfonate were obtained as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][CH2:12][CH2:11][N:10]=2)=[CH:5][CH:4]=1.[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CO.O>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[N:10][C:11]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:12][N:13]=2)=[CH:16][CH:17]=1
Reactant: COc1ccc(C2=NCCN=C2c2ccc(OC)cc2)cc1
Reactant: O=Cc1ccccc1
Solvent: O
Solvent: CO
Product: COc1ccc(-c2ncc(Cc3ccccc3)nc2-c2ccc(OC)cc2)cc1

Procedure:
The same procedures as in Example 3 were repeated using 2,3-bis(p-methoxyphenyl)-5,6-dihydropyrazine and benzaldehyde. 2,3-Bis(p-methoxyphenyl)-5-benzylpyrazine was obtained as colorless prisms, m.p. 107°-109° C. (recrystallized from methanol-water). Physical properties of the product support a chemical structure of the below formula (X).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[S:12](Cl)([OH:15])(=O)=[O:13].[CH:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>N1C=CC=CC=1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:15])=[O:13])=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10]
Reactant: O=S(=O)(O)Cl
Reactant: Nc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: c1ccccc1
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cc(NS(=O)(=O)c2ccccc2)ccc1Cl
Temperature: 120 °C

Procedure:
172.5 g (1 mol) of 4-amino-1-chloro-2-nitro-benzene are dissolved in 400 ml pyridine with heating. 193 g (1.09 mol) of benzene sulfochloride are slowly added dropwise, followed by heating for 1 hour at 120° C. (bath temperature). Subsequently, the solution is cast onto ice, and the 1-chloro-2-nitro-4-benzene-sulfonamido-benzene is evacuated in a vacuum. The compound is recrystallized from ethanol/water.
Reaction SMILES: [H-].[Na+].O[CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]1[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O.[C:22]([O:25][CH2:26][CH3:27])(=[O:24])[CH3:23]>COCCOC>[CH2:14]([N:5]1[C:6](=[O:13])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:4]1[CH2:23][C:22]([O:25][CH2:26][CH3:27])=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1c2ccccc2C(O)N1Cc1ccccc1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)CC1c2ccccc2C(=O)N1Cc1ccccc1
Temperature: 20 °C

Procedure:
Ethyl (2-benzyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate is prepared as described in Example 2, starting with 3.2 9 of 60% sodium hydride in 200 cm3 of 1,2-dimethoxyethane, 16.4 cm3 of triethyl phosphonoacetate and 9.5 g of 3-hydroxy-2benzyl-2,3-dihydroisoindol-1-one. The mixture is refluxed for 18 hours and is then cooled to a temperature in the region of 20° C. The reaction mixture is treated with 100 cm3 of water and then with 100 cm3 of ethyl acetate. After separation of the phases by settling, the aqueous phase is extracted twice with 100 cm3 of ethyl acetate. The organic extracts are combined, washed with 50 cm3 of brine, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is purified by chromatography under argon pressure (60 kPa) on a column of silica gel (particle size 15-40 μm), eluting with successive mixtures of cyclohexane/ethyl acetate (75/25 and then 67/33 by volume). The fractions comprising the expected product are combined and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 8.7 g of ethyl (2-benzyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate are thus obtained in the form of a viscous yellow oil. (Rf=0.35, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (75/25 by volume)).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:14]=1.C([N-]C(C)C)(C)C.[Li+].CON(C)[C:30](=[O:32])[CH3:31]>O1CCCC1>[CH3:17][CH:16]([CH3:18])[CH2:15][N:3]1[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:14]=[C:2]1[CH2:1][C:30](=[O:32])[CH3:31]
Reactant: Cc1nc2cnc3ccccc3c2n1CC(C)C
Reactant: CON(C)C(C)=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)Cc1nc2cnc3ccccc3c2n1CC(C)C
Temperature: -78 °C

Procedure:
2-Methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (1 g, 4.2 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) then cooled to −78° C. A portion of lithium diisopropyl amide (2.8 mL, 4.2 mmol) was added dropwise to the cooled solution. At 10 minutes post addition, N-methoxy-N-methylacetamide (0.45 g, 4.4 mmol), prepared according to the method of T. A. Oster and T. M. Harris, Tetrahedron Letters, 24, 1851 (1983) was added. After 15 minutes the reaction was quenched with water and the resulting precipitate was collected and dried to provide the desired product as a solid. The structure was confirmed by nuclear magnetic resonance spectroscopy.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([OH:10])=O.C(N(CC)CC)C.ClC(OCCCC)=O.[CH3:26][C:27]1([CH3:33])[NH:31][C:30](=[O:32])[CH2:29][NH:28]1>CN(C)C=O>[CH3:26][C:27]1([CH3:33])[NH:31][C:30](=[O:32])[CH2:29][N:28]1[C:8](=[O:10])[CH2:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1]
Reactant: O=C(O)CN1CCCC1=O
Reactant: CC1(C)NCC(=O)N1
Agent: CCCCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(C)NC(=O)CN1C(=O)CN1CCCC1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
An ice cold solution of 2-oxo-1-pyrrolidineacetic acid (2.2 g) and triethylamine (2.15 ml) in dimethylformamide (10 ml) was treated dropwise while stirring with butyl chloroformate (1.95 ml). After stirring at 0° C. for 30 minutes, 2,2-dimethyl-4-imidazolidinone (1.75 g) was added at once, and stirring was continued at room temperature overnight. After evaporation under reduced pressure the residue was chromatographed on a silica gel column, eluting with dichloromethane/methanol 1:1. The selected fractions were collected and evaporated to give an oil which was washed twice with ethyl acetate. The residue was crystallized from ethyl acetate, to give the title compound as a white powder, m.p. 214°-217° C. (decomp.).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=2)=[CH:8][N:7]=[CH:6]1.[H][H]>CO.[Pd]>[CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]1[C:9]([C:10]2[CH:11]=[C:12]([NH2:16])[CH:13]=[CH:14][CH:15]=2)=[CH:8][N:7]=[CH:6]1
Reactant: [H][H]
Reactant: CN(C)CCn1cncc1-c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CN(C)CCn1cncc1-c1cccc(N)c1

Procedure:
A solution of dimethyl-{2-[5-(3-nitrophenyl)imidazol-1-yl]ethyl}amine (140 mg, 0.54 mmol) and 10% Pd/C (80 mg) in methanol (8 mL) was hydrogenated under 1 atm hydrogen pressure for 5 h. The reaction mixture was filtered through a Celite pad. The filtrate was concentrated to dryness to afford the desired amine, which was used directly in the next step without purification. 1H-NMR (CD3OD, 400 MHz): δ=2.15 (s, 6H), 2.49 (t, J=6.8 Hz, 2H), 4.18 (t, J=7.2 Hz, 2H), 6.69-6.77 (m, 3H), 6.91 (d, J=1.2 Hz, 1H), 7.18 (dt, J=1.2, 7.6 Hz, 1H), 7.44 (d, J=0.8 Hz, 1H). MS (ES+): m/z 231.29 [MH+]. HPLC: tR=0.39 min (ZQ2000, polar—5 min).
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[S:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[N+:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1)([O-:25])=[O:24]>ClCCl.CN(C1C=CN=CC=1)C>[N+:23]([C:26]1[CH:27]=[CH:28][C:29]([C:30]([N:8]2[CH2:7][C:6]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]2=3)=[O:31])=[CH:33][CH:34]=1)([O-:25])=[O:24]
Reactant: c1ccc2c(c1)CNc1ccccc1S2
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2ccccc2Sc2ccccc21
Temperature: 0 °C
Reaction time: 16 h
Yield: 112.6 %

Procedure:
To a solution of 1.6 g of 10,11-dihydrodibenz[b,f][1,4]thiazepine in 30 ml of dichloromethane is added 0.1 g of 4-(N,N-dimethylamino)pyridine, 4 ml of triethylamine and 1.0 g of 4-nitrobenzoyl chloride and the mixture is stirred for 16 hours. The mixture is poured into ice-water and extracted with 3×150 ml of dichloromethane. The combined organic extract is washed with water, 2N HCl, 2N Na2CO3, water and dried (MgSO4). The solvent is removed in vacuo and the product (2.6 g) purified by chromatography on silica gel with hexane-ethyl acetate (4:1) as eluent to give 2.2 g of crystals, m.p. 147°-149° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]([N:8]1[CH:12]=[C:11]([NH:13][C:14](=[O:20])[CH:15]([NH2:19])[CH2:16][CH2:17][CH3:18])[N:10]=[CH:9]1)([CH3:7])[CH3:6].[OH:22][C@@H:23]([CH:27]([CH3:29])[CH3:28])[C:24](O)=[O:25]>>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]([N:8]1[CH:12]=[C:11]([NH:13][C:14](=[O:20])[CH:15]([NH:19][C:24](=[O:25])[CH:23]([OH:22])[CH:27]([CH3:29])[CH3:28])[CH2:16][CH2:17][CH3:18])[N:10]=[CH:9]1)([CH3:6])[CH3:7]
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CC(=O)OC)cn1
Reactant: CC(C)[C@H](O)C(=O)O
Product: CCCC(NC(=O)C(O)C(C)C)C(=O)Nc1cn(C(C)(C)CC(=O)OC)cn1

Procedure:
3-[4-(2-Amino-pentanoylamino)-imidazol-1-yl]-3-methyl-butyric acid methyl ester was coupled with (S)-2-hydroxy-3-methyl-butyric acid to provide the title compound: C13 NMR (100 MHz, CDCl3) 13.9, 16.0, 19.1, 19.4, 28.1, 32.2, 35.5, 47.1, 51.9, 52.7, 56.4, 105.1, 131.1, 137.6, 169.6, 170.0, 174.0.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:6]=1[S:12]([NH2:15])(=[O:14])=[O:13])=[O:4].S(Cl)(Cl)=O.N1C=CC=CC=1.[C:26](Cl)(Cl)=[O:27]>ClCCCl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:6]=1[S:12]([N:15]=[C:26]=[O:27])(=[O:14])=[O:13])=[O:4]
Reactant: COC(=O)c1ccc(I)cc1S(N)(=O)=O
Reactant: O=C(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCCl
Product: COC(=O)c1ccc(I)cc1S(=O)(=O)N=C=O

Procedure:
50 g of the sulfonamide obtained in Example 6 are suspended in 150 ml of 1,2-dichloroethane and the suspension is treated with 27.7 ml of thionyl chloride. The mixture is heated at the boil for 4 hours, cooled to 50°-55° C. and treated with 0.5 ml of pyridine, and phosgene is passed for 31/2 hours into the solution which has now been brought to the boil. The mixture is concentrated under reduced pressure with the exclusion of moisture. The crude sulfonyl isocyanate which remains (52.6 g) crystallises upon standing.