Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]3[CH2:17][N:16]4[CH:12]([CH2:13][CH2:14][CH2:15]4)[CH2:11][C:7]=3[NH:8]2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:33]=[CH:32][C:22]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][NH:28][C:27](=[O:31])[CH:26]=2)=[C:21]([F:34])[CH:20]=1>>[ClH:18].[Cl:18][C:19]1[CH:33]=[CH:32][C:22]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][N:28]([C:2]3[CH:10]=[C:9]4[C:5]([C:6]5[CH2:17][N:16]6[CH:12]([CH2:13][CH2:14][CH2:15]6)[CH2:11][C:7]=5[NH:8]4)=[CH:4][CH:3]=3)[C:27](=[O:31])[CH:26]=2)=[C:21]([F:34])[CH:20]=1
Reactant: Brc1ccc2c3c([nH]c2c1)CC1CCCN1C3
Reactant: O=c1cc(OCc2ccc(Cl)cc2F)cc[nH]1
Product: Cl
Product: O=c1cc(OCc2ccc(Cl)cc2F)ccn1-c1ccc2c3c([nH]c2c1)CC1CCCN1C3
Yield: 40.8 %

Procedure:
8-Bromo-2,3,5,10,11,11a-hexahydro-1H-indolizino[7,6-b]indole (200 mg, 0.685 mmol) and 4-(4-chloro-2-fluorobenzyloxy)pyridin-2(1H)-one (173 mg, 0.685 mmol) were reacted following the procedure for Example 2 (step b) to provide the title compound (70 mg, 20%) as a brown solid: 1H NMR (300 MHz, DMSO-d6) δ 11.44 (s, 1H), 10.41 (s, 1H), 7.65-7.61 (t, J=8.2 Hz, 1H), 7.56-7.50 (m, 3H), 7.40-7.37 (dd, J=8.2, 1.9 Hz, 1H), 7.34-7.33 (d, J=1.7 Hz, 1H), 6.97-6.95 (dd, J=8.4, 1.8 Hz, 1H), 6.08-6.06 (dd, J=7.6, 2.7 Hz, 1H), 6.03-6.02 (d, J=2.7 Hz, 1H), 5.17 (s, 2H), 4.80-4.76 (dd, J=13.9, 2.2 Hz, 1H), 4.34-4.28 (m, 1H), 3.77-3.74 (m, 2H), 3.31-3.25 (m, 2H), 3.05-2.99 (m, 1H), 2.44-2.38 (m, 1H), 2.18-2.09 (m, 2H), 1.90-1.75 (m, 1H); ESI MS m/z 464 [M+H]+; HPLC (Method B) 97.3% (AUC), tR=13.9 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.[CH3:9][C:10]([CH3:13])([O-])[CH3:11].[K+].BrCC1CC1>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH2:9][CH:10]2[CH2:13][CH2:11]2)[CH:7]=1
Reactant: Oc1ccc(Br)cn1
Reactant: CC(C)(C)[O-]
Agent: BrCC1CC1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1ccc(Br)cn1CC1CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-bromopyridin-2-ol (1.0 g, 5.75 mmol) in DMF (10 mL) at RT, potassium tert-butoxide (0.68 g, 6.07 mmol) was added and the mixture was stirred for 30 min. To this mixture, (bromomethyl)cyclopropane (1.03 g, 8.62 mmol) was added, and the resulting mixture was stirred at 70° C. for 2 h. The mixture was allowed to cool to RT, diluted with EtOAc (50 mL) and quenched with water (20 mL). The organic layer was washed with water (2×20 mL) and brine (20 mL), dried over anhydrous MgSO4 and filtered. The filtrate was concentrated in vacuo to afford 5-bromo-1-(cyclopropylmethyl)pyridin-2(1H)-one.
Reaction SMILES: [H-].[Na+].[CH2:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[C:4]#[CH:5].[H][H].[CH2:16](Br)[CH:17]=[CH2:18]>CN(C)C=O>[CH2:3]([N:6]([CH2:18][C:17]#[CH:16])[C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH:4]=[CH2:5]
Reactant: [H][H]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCN(CC=C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (6.53 g, 163 mmol, 60% in mineral oil) was added in small portions over 1 min to a solution of tert-butyl prop-2-ynylcarbamate (19.5 g, 126 mmol) in N,N-dimethylformamide (300 mL) at room temperature. Formation of hydrogen bubbles was observed along with gentle warming of the resulting suspension. After 30 min at room temperature, the mixture was cooled to 0° C. Allyl bromide (13.05 mL, 151 mmol) was added dropwise. The mixture was stirred at 0° C. for 20 min and at ambient temperature for 2.5 h. The mixture was carefully quenched with water (400 mL), and extracted with ether (3×300 mL). The combined extracts were dried (MgSO4) and concentrated. Silica gel chromatography, eluting with 0-10% ethyl acetate in hexanes, gave tert-butyl allyl(prop-2-yn-1-yl)carbamate as light tan liquid (23.3 g, 95% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 5.67-5.89 (1 H, m), 5.08-5.28 (2 H, m), 3.71-4.21 (4 H, m), 2.18 (1 H, t, J=2.42 Hz), 1.47 (9 H, s).
Reaction SMILES: Cl[C:2]1[C:3]2CN(C([O-])=O)[CH2:17][C:16](=[O:23])[C:4]=2[CH:5]=[C:6]2[C:11]=1[NH:10][C:9]([C:12]([O-:14])=[O:13])=[CH:8][C:7]2=[O:15].OC([NH+]([C:30]([OH:33])([OH:32])O)C)(O)O.O[C:35]([NH+:38](C)C(O)(O)O)(O)O.[O-2].[Mg+2].[H][H]>[Pd].O>[O:23]=[C:16]1[C:4]2[C:3](=[CH:2][C:11]3[NH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8][C:7](=[O:15])[C:6]=3[CH:5]=2)[NH:38][C:35]([C:30]([OH:32])=[O:33])=[CH:17]1
Reactant: C[NH+](C(O)(O)O)C(O)(O)O
Reactant: O=C([O-])c1cc(=O)c2cc3c(c(Cl)c2[nH]1)CN(C(=O)[O-])CC3=O
Reactant: [H][H]
Agent: [Pd]
Agent: [Mg+2]
Agent: [O-2]
Solvent: O
Product: O=C(O)c1cc(=O)c2cc3c(=O)cc(C(=O)O)[nH]c3cc2[nH]1

Procedure:
To a solution of 5 gm. of di(tris-hydroxymethyl) methylammonium 10-chloro-1,4,6,9-tetrahydro-4,6-dioxopyrido[4,3-g]quinoline-2,8-dicarboxylate in 100 ml. of water is added 2.0 g. of 5% palladium-on-charcoal catalyst and 5.0 g. of magnesium oxide. The resulting mixture is hydrogenated at an initial pressure of 3 atmospheres of hydrogen until 1 mole of hydrogen has been absorbed. The mixture is filtered and the filtrate acidified by the addition of dilute hydrochloric acid. The resulting precipitate is removed by filtration. The 1,4,6,9-tetrahydro-4,6-dioxopyrido[3,2-g]quinoline-2,8-dicarboxylic acid obtained is converted to di(tris-hydroxymethyl)methylammonium 1,4,6,9-tetrahydro-4,6-dioxopyrido[3,2-g]quinoline-2,8-dicarboxylate by adding two equivalents of (tris-hydroxymethyl)methylamine in aqueous solution. The crystalline product is recovered after addition of methanol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[OH:22])[C:13]([C:23]#[N:24])=[CH:12]2)=[C:7](OC)[C:6]=1[O:27][CH3:28])[CH3:2].[C:30](=[O:33])([O-])[O-].[K+].[K+].BrC[CH2:38][CH2:39][O:40][CH3:41].O>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:38][CH2:39][O:40][CH3:41])[C:13]([C:23]#[N:24])=[CH:12]2)=[CH:7][C:6]=1[O:27][CH2:28][O:33][CH3:30])[CH3:2]
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c(-c3ccccc3O)c2)c(OC)c1OC
Reactant: COCCCBr
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(-n2cc(C#N)c(-c3ccccc3OCCOC)c2)cc1OCOC
Temperature: 70 °C
Reaction time: 18 h
Yield: 87.1 %

Procedure:
To a solution of 4-[4-(2-hydroxyphenyl)-3-cyanopyrrole-1-yl]-2-methoxy-methoxy benzoic acid ethyl ester (0.12 g) and potassium carbonate (0.10 g) in N,N-dimethylformamide (1 mL) was added 1-bromo-3-methoxy-propane (0.092 g), and this mixture was stirred at 70° C. for 18 hours. This reaction mixture was poured into water, and this mixture was extracted with ethyl acetate. This organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (0.12 g).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[CH2:15][C:16]([N:18]([CH3:20])[CH3:19])=[O:17].C(N(CC)CC)C>C(Cl)(Cl)Cl.ClCCl>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:15][C:16](=[O:17])[N:18]([CH3:20])[CH3:19])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CN(C)C(=O)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN(C)C(=O)CN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C

Procedure:
A mixture of 1-BOC-piperazine (387 mg), 2-chloro-N,N-dimethylacetamide (0.43 mL) and triethylamine (0.58 mL) in chloroform was stirred at room temperature. After stirring overnight the reaction mixture was diluted with dichloromethane, washed with brine, dried (MgSO4) and the solvent removed in vacuo to yield 4-dimethylcarbamoylmethyl-piperazine-1-carboxylic acid tert-butyl ester (558 mg). Treatment of this compound with HCl in dichloromethane/methanol yielded N,N-dimethyl-2-piperazin-1-yl-acetamide, which was isolated as the hydrochloride salt.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[S:15][CH:16]=[CH:17][N:18]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:26][O:27][CH3:28].C[N:30](C=O)C>O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]([CH2:26][O:27][CH3:28])[C:14]2[S:15][CH:16]=[CH:17][N:18]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)#[N:30]
Reactant: CC(=O)c1ccc(S(=O)(=O)Nc2nccs2)cc1
Reactant: COCCl
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COCN(c1nccs1)S(=O)(=O)c1ccc(C#N)cc1
Reaction time: 4 h

Procedure:
To a suspension of 4-acetyl-N-thiazol-2-yl-benzenesulfonamide (10 mmol) and potassium carbonate (15 mmol) in DMF (30 mL) was added chloro-methoxy-methane (10 mmol) and the mixture was stirred for 4 h. The reaction mixture was diluted with water (30 mL) and the resulting mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by column chromatography to give 4-cyano-N-methoxymethyl-N-thiazol-2-yl-benzenesulfonamide (5.2 mmol) as a white solid.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[CH3:39][N:40]([CH3:61])[C:41]1[CH:42]=[C:43]([NH:56][S:57]([CH3:60])(=[O:59])=[O:58])[CH:44]=[C:45](B2OC(C)(C)C(C)(C)O2)[CH:46]=1.C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O>[CH3:39][N:40]([CH3:61])[C:41]1[CH:42]=[C:43]([NH:56][S:57]([CH3:60])(=[O:59])=[O:58])[CH:44]=[C:45]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)[CH:46]=1
Reactant: CN(C)c1cc(NS(C)(=O)=O)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(NS(C)(=O)=O)cc(N(C)C)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 72.3 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.17 mmol) was treated with N-(3-(dimethylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (145 mg, 0.43 mmol), bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (42 mg, 0.05 mmol) and sodium carbonate (45 mg, 0.42 mmol) in DME (1.6 ml) and water (0.4 ml). The reaction mixture was submitted to vacuum-argon cycles and stirred at 70° C. for 1.5 h. The reaction mixture was cooled down to room temperature and poured into ice-water, basified with potassium carbonate and extracted with ethyl acetate (×3). The organic phase was successively washed with water and brine, dried over magnesium sulphate, filtered and the solvent evaporated under reduced pressure. The residue was purified by normal phase using SP1® Purification System (0% to 10%, hexane-ethyl acetate) to obtain 89.5 mg (73% yield) of the title compound. Purity: 100%.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]([NH2:7])=[NH:6])=[NH:3].C(=O)=O.[Br:11][C:12]1[CH:17]=[C:16]([Br:18])[CH:15]=[C:14]([Br:19])[C:13]=1[NH:20][CH2:21][C:22](OCC)=O>CO>[NH2:6][C:5]1[N:4]=[C:2]([NH2:1])[N:3]=[C:22]([CH2:21][NH:20][C:13]2[C:14]([Br:19])=[CH:15][C:16]([Br:18])=[CH:17][C:12]=2[Br:11])[N:7]=1
Reactant: N=C(N)NC(=N)N
Reactant: CCOC(=O)CNc1c(Br)cc(Br)cc1Br
Agent: O=C=O
Solvent: CO
Product: Nc1nc(N)nc(CNc2c(Br)cc(Br)cc2Br)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57 %

Procedure:
Freshly prepared biguanide (6.1 g, 0.06 mole) in methanol (700 ml) was placed in a flask equipped with a stirrer and a soda lime trap to exclude CO2. IV (25.0 g, 0.06 mole) was added all at once through a powder funnel. After the solution was stirred for 10 min at room temperature, a white precipitate began to form. After being stirred for 7.5 h, the mixture was allowed to stand overnight. The crystals were filtered and washed with fresh methanol. They were then slurried with water (250 ml), filtered again, and washed with methanol. A crude yield of 21.9 g (81%) was obtained. It was recrystallized by dissolving 21.8 g in 80 ml of hot DMF (125° C.) and then adding 9 ml of water dropwise. When the solution cooled, white crystals separated. A second crop of crystals was obtained from the filtrate. The total recovery was 15.5 g, a yield of 57% based on the theoretical yield of 27.2 g. An analytical sample with mp of 250°-51° C. was obtained by recrystallizing again from hot DMF and finally washing with cold methanol. Anal. calcd. for C10H9Br3N6 : C, 26.52; H, 2.00; Br, 52.93; N, 18.55. Found: C, 26.52; H, 2.02; Br, 52.71; N, 18.59.
Reaction SMILES: [CH:1]1([C:4]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[CH3:19])([C:6]2[S:7][CH:8]=[CH:9][C:10]=2[CH3:11])O)[CH2:3][CH2:2]1.[Br:20][Si](C)(C)C.O>ClCCl>[Br:20][CH2:3][CH2:2][CH:1]=[C:4]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=1[CH3:19])[C:6]1[S:7][CH:8]=[CH:9][C:10]=1[CH3:11]
Reactant: C[Si](C)(C)Br
Reactant: Cc1ccc(C(O)(c2sccc2C)C2CC2)c(C)c1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(C(=CCCBr)c2sccc2C)c(C)c1
Temperature: 10 °C

Procedure:
A solution of cyclopropyl(2,4-dimethylphenyl)(3-methyl-2-thienyl)methanol (7.0 g, 0.026 mole; obtained by the method described in Example 7) in dichloromethane (125 ml) was cooled to 10° C. and bromotrimethylsilane (4.0 g, 0.026 mole) in dichloromethane (50 ml) was added dropwise keeping the temperature at about 10° C. When addition was complete, water was added (250 ml) and the phases were separated. The aqueous phase was extracted with dichloromethane (25 ml). The combined organic phases was washed with a saturated sodium bicarbonate solution, brine and dried over sodium sulphate. The solvent was removed in vacuo leaving 1-bromo-4-(2,4-dimethylphenyl)-4-(3-methyl-2-thienyl)but-3-ene (8.7 g) as an oil. This bromide was converted by the method described in Example 7 into the title acid hydrochloride, M.p.=200°-201° C. (i-Propanol).
Reaction SMILES: C([C:6]1[O:7][C:8]2[CH:16]=[C:15](O)[CH:14]=[CH:13][C:9]=2[C:10](=[O:12])[CH:11]=1)(OCC)=O.CC1C=CC2C(=CC=CC=2)N=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CC(C)=O>[O:12]=[C:10]1[C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[O:7][CH:6]=[CH:11]1
Reactant: CCOC(=O)c1cc(=O)c2ccc(O)cc2o1
Agent: Cc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: O=c1ccoc2ccccc12

Procedure:
A mixture of 1.5g (6.41 mmoles) of 2-carboethoxy-7- hydroxy-4-oxo-4H-1-benzopyran, 1.82g (6.41 mmoles) of 2-3-chloromethylphenoxy)methylquinoline and 0.886 g of potassium carbonate in 12 ml of dimethylformamide and 96 ml of acetone is refluxed for 2 days, cooled, concentrated in vacuo and the residue taken up in water and is extracted into ethyl acetate. The solution is concentrated and the crude product is recrystallized from ethyl acetate to give 0.585g of 2-carboethoxy-7-(3-quinolin-2-ylmethoxy)benzyloxy)-4-oxo-4H-1-benzopyran as a pale yellow solid having an m.p. of 123°-24° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:14][OH:15])[CH:7]=[C:8]([O:11][CH2:12][CH3:13])[C:9]=1[F:10])[CH3:2]>ClCCCl.O=[Mn]=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:7]=[C:8]([O:11][CH2:12][CH3:13])[C:9]=1[F:10])[CH:14]=[O:15])[CH3:2]
Reactant: CCOc1cc(CO)cc(OCC)c1F
Agent: O=[Mn]=O
Solvent: ClCCCl
Product: CCOc1cc(C=O)cc(OCC)c1F
Temperature: 50 °C
Reaction time: 21 h

Procedure:
To a solution of (3,5-diethoxy-4-fluoro-phenyl)-methanol (2.30 g, 10.7 mmol, 1.0 equiv) in 1,2-dichloroethane (50 mL) was added activated MnO2 (2.89 g, 33.3 mmol, 3.1 equiv). The reaction mixture was stirred for 21 h at 50° C. and then filtered through Hyflo Super Cel providing after evaporation of the solvent under reduced pressure 1.90 g (83%) of the title compound. 1H NMR (400 MHz, CDCl3): δ 1.38 (t, J=7.0 Hz, 6H), 4.09 (q, J=7.0 Hz, 4H), 7.04 (d, J=7.2 Hz, 2H), 9.75 (s, 1H). MS (EI): 212.1 [M]+.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:19])[CH2:9][NH:10][C:11]2[C:12](=[O:18])[N:13]([CH3:17])[N:14]=[CH:15][CH:16]=2)[CH2:4][CH2:3]1.[N+:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1O)([O-:22])=[O:21]>>[CH3:17][N:13]1[C:12](=[O:18])[C:11]([NH:10][CH2:9][C:8]([N:5]2[CH2:4][CH2:3][CH:2]([O:1][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[N+:20]([O-:22])=[O:21])[CH2:7][CH2:6]2)=[O:19])=[CH:16][CH:15]=[N:14]1
Reactant: Cn1nccc(NCC(=O)N2CCC(O)CC2)c1=O
Reactant: O=[N+]([O-])c1ccccc1O
Product: Cn1nccc(NCC(=O)N2CCC(Oc3ccccc3[N+](=O)[O-])CC2)c1=O
Yield: 24 %

Procedure:
Compound 15 is prepared from intermediate 5b and from 2-nitro-phenol following synthesis method 3 (yield: 24%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]=[C:10]1[NH:14][CH2:13][CH2:12][N:11]1[OH:15].[Cl:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N+:19]=1[O-:24].CC(C)=O.[ClH:29]>O1CCOCC1>[ClH:16].[ClH:29].[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]=[C:10]1[NH:14][CH2:13][CH2:12][N:11]1[O:15][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N+:19]=1[O-:24]
Reactant: [O-][n+]1ccccc1CCl
Reactant: ON1CCNC1=Nc1c(F)cccc1F
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)=O
Product: [O-][n+]1ccccc1CON1CCNC1=Nc1c(F)cccc1F

Procedure:
From 2-[(2,6-difluorophenyl)imino]-1-hydroxy-imidazolidine and 2-chloromethyl-pyridine N-oxide there is obtained, in analogy to the details in Example 1,2-([{2-[(2,6-difluorophenyl)imino]-1-imidazolidinyl}oxy]methyl)-pyridine 1-oxide dihydrochloride of melting point 188°-189° (acetone/hydrogen chloride in dioxane).
Reaction SMILES: [OH:1][CH:2]([CH2:7][NH:8][S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19])(=[O:11])=[O:10])[C:3]([O:5][CH3:6])=[O:4].[C:21](=O)([O-])[O-].[Cs+].[Cs+].CI.CN(C)C=O>O>[OH:1][CH:2]([CH2:7][N:8]([CH3:21])[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19])(=[O:10])=[O:11])[C:3]([O:5][CH3:6])=[O:4]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)C(O)CNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)C(O)CN(C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
A mixture of methyl 2-hydroxy-3-{[(2-nitrophenyl)sulfonyl]amino}propanoate (1.1 g), cesium carbonate (1.4 g), methyl iodide (0.3 mL) and N,N-dimethylformamide (10 mL) was stirred overnight at room temperature. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (1.1 g, 100%) as an oil.
Reaction SMILES: [CH3:1][S:2]([CH3:5])(=[O:4])=[O:3].C[Li].[F:8][C:9]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:10]=1[C:11](Cl)=[O:12].Cl>O1CCCC1>[F:8][C:9]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:10]=1[C:11](=[O:12])[CH2:1][S:2]([CH3:5])(=[O:4])=[O:3]
Reactant: CS(C)(=O)=O
Reactant: COc1ccc(C(=O)Cl)c(F)c1
Agent: Cl
Agent: [Li]C
Solvent: C1CCOC1
Product: COc1ccc(C(=O)CS(C)(=O)=O)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 46 %

Procedure:
To a solution of 4.15 g (44.07 mmol) of dimethylsulfone in 140 ml of anhydrous tetrahydrofuran are added dropwise at −10° C. under argon 24 ml of methyllithium solution (1.6M in diethyl ether, 38.2 mmol). The reaction mixture is stirred for 15 min at room temperature, the reaction mixture is then cooled to −60° C. A solution of 5.54 g (29.38 mmol) of 2-fluoro-4-methoxybenzoyl chloride dissolved in 60 ml of tetrahydrofuran is then added dropwise to the reaction mixture. This mixture is stirred for 4 h at between −60° C. and 0° C., then a 1M hydrochloric acid solution is added. The product is extracted several times with ethyl acetate. The organic phases are combined, dried over magnesium sulfate and concentrated. The residue is triturated in minimum methanol and the solid is filtered to yield 3.33 g (46%) of 1-(2-fluoro-4-methoxyphenyl)-2-(methylsulfonyl)ethanone in the form of a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1O)=[CH:13][CH:12]=[CH:11][C:10]=2[C:17]([F:20])([F:19])[F:18])=[O:5])[CH3:2].C1(C)C=CC=CC=1.O=P(Cl)(Cl)[Cl:30].C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:30])=[CH:13][CH:12]=[CH:11][C:10]=2[C:17]([F:20])([F:19])[F:18])=[O:5])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc2c(C(F)(F)F)cccc2c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc2c(C(F)(F)F)cccc2c1Cl
Temperature: 0 °C

Procedure:
4-Hydroxy-8-(trifluoromethyl)-3-quinolinecarboxylic acid ethyl ester (compound of formula (V)), 11.27 g, 39.55 mmol) was taken into toluene (125 mL), then POCl3 (7.4 mL, 79.08 mmol) was added and the mixture was refluxed for 1.5 hours. The reaction was carefully poured into ice-water with vigorous stirring, then added carefully added saturated NaHCO3 until the solution was neutral. Dilute with ethyl acetate and separate the layers. The organic layer was dried over MgSO4, filtered and concentrated. The resulting material was passed through a short silica gel plug using 10% ethyl acetate in hexane. Concentration and drying under high vacuum yielded 9.93 g of the title compound as a white solid.
Reaction SMILES: [O:1]=[S:2]1(=[O:21])[C:6]2[CH:7]=[CH:8][C:9]3[O:14][CH2:13][CH2:12][O:11][C:10]=3[C:5]=2[C:4](=[O:15])[N:3]1[CH2:16][CH2:17][CH2:18][CH2:19]O.C(Br)(Br)(Br)[Br:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[O:1]=[S:2]1(=[O:21])[C:6]2[CH:7]=[CH:8][C:9]3[O:14][CH2:13][CH2:12][O:11][C:10]=3[C:5]=2[C:4](=[O:15])[N:3]1[CH2:16][CH2:17][CH2:18][CH2:19][Br:23]
Reactant: BrC(Br)(Br)Br
Reactant: O=C1c2c(ccc3c2OCCO3)S(=O)(=O)N1CCCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C1c2c(ccc3c2OCCO3)S(=O)(=O)N1CCCCBr

Procedure:
To a solution of 1,1-dioxido-2-(4-hydroxybutyl)-4,5-ethylenedioxy-1,2-benzisothiazol-3(2H)-one (313 mg, 1 mmol) and carbon tetrabromide (432 mg, 1.3 mmol) in methylene chloride (2 mL) cooled in an ice bath under a nitrogen atomosphere was added dropwise a solution of triphenylphosphine (341 mg, 1.3 mmol) in methylene chloride (3.5 mL). The reaction was allowed to stir with gradual warming to room temp. over a four hour period and then the solvent was evaporated and the residue chromatographed on a column of silica gel by elution with chloroform to give crystalline 1,1-dioxido-2-(4-bromobutyl)-4,5-ethylenedioxy-1,2-benzisothiazol-3(2H)-one from diethyl ether/hexane, melting point 135-136° C.