Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[C:9]([S:10](Cl)(=[O:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=12.O1CCCC1.[NH3:19].[OH-].[NH4+]>O>[N:1]1[O:2][N:3]=[C:4]2[C:9]([S:10]([NH2:19])(=[O:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: O=S(=O)(Cl)c1cccc2nonc12
Reactant: N
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cccc2nonc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 3.0 g of 2,1,3-benzoxadiazole-4-sulfonyl chloride and 200 mL of tetrahydrofuran at -30° C. was added 10 mL of ammonia under an inert atmosphere. The resulting suspension was stirred at ambient temperature for 3 hours. Concentrated ammonium hydroxide (20 mL) and water (20 mL) were added. The reaction was extracted with ethyl acetate and the organic extracts were combined, dried over magnesium sulfate, filtered, and stripped to give a crude solid. Recrystallization from chlorobutaneethanol afforded 1.82 g of the title compound as an orange-tan solid, m.p. 157°-159° C.
Reaction SMILES: O.[OH-].[Li+].[Cl:4][C:5]1[CH:10]=[CH:9][C:8](/[C:11](=[N:22]/[O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]3[N:34]=[C:35]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[O:36][C:37]=3[CH3:38])=[CH:27][CH:26]=2)/[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]C)=[O:19])=[CH:7][CH:6]=1.O.Cl>O1CCCC1.CO>[Cl:4][C:5]1[CH:6]=[CH:7][C:8](/[C:11](=[N:22]/[O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]3[N:34]=[C:35]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[O:36][C:37]=3[CH3:38])=[CH:27][CH:26]=2)/[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:9][CH:10]=1
Reactant: COC(=O)CCCCCC/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccc(Cl)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\CCCCCCC(=O)O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.7 %

Procedure:
Lithium hydroxide monohydrate (160 mg) was added to a solution of methyl E-8-(4-chlorophenyl)-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]octanoate (730 mg) in tetrahydrofuran (10 ml)-water (4 ml)-methanol (4 ml) and stirred at room temperature for 3 hours. 1N hydrochloric acid (3.9 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-8-(4-chlorophenyl)-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]octanoic acid (632 mg, yield 89%) as colorless crystals. m.p. 90-91° C.
Reaction SMILES: C([O:3][C:4](=O)[CH:5](Cl)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2([CH3:32])[CH2:24][CH2:23][C:22]3[C:17](=[C:18]([CH3:31])[C:19]([CH3:30])=[C:20]([O:26]C(=O)C)[C:21]=3[CH3:25])[O:16]2)=[CH:9][CH:8]=1)C.[NH2:35][C:36](N)=[S:37].S1(CCCC1)(=O)=[O:40].Cl.C(=O)(O)[O-].[Na+]>O.C(O)(=O)C>[OH:26][C:20]1[C:21]([CH3:25])=[C:22]2[C:17](=[C:18]([CH3:31])[C:19]=1[CH3:30])[O:16][C:15]([CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][CH:5]3[S:37][C:36](=[O:40])[NH:35][C:4]3=[O:3])=[CH:12][CH:11]=1)([CH3:32])[CH2:24][CH2:23]2
Reactant: O=S1(=O)CCCC1
Reactant: CCOC(=O)C(Cl)Cc1ccc(OCC2(C)CCc3c(C)c(OC(C)=O)c(C)c(C)c3O2)cc1
Reactant: NC(N)=S
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Temperature: 25 °C

Procedure:
A mixture of 70 g of ethyl-3-[4-(6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)phenyl]-2-chloropropionate, 13.12 g of thiourea and 80.2 ml of sulpholane was reacted for 80 min., under a nitrogen stream at 115°-120° C. Subsequently, a 656.2 ml Acetic acid, 218.7 ml conc. hydrochloric acid and 109.4 ml water was added to this and the resulting mixture was further heated for 12 hrs at 85°-90° C. The reaction mixture was cooled to room temperature and 196.8 g of sodium bicarbonate was added and once the evolution of carbondioxide had ceased, the solvent was distilled off applying high vacuum. A 10:1 by volume mixture of benzene and ethyl acetate was added to the residue and the crude product was washed with a mixture of equal volumes of a saturated aq. sodium bicarbonate solution & water. The organic layer was dried over anhydrous sodium sulphate and the solvent was distilled off. The resulting crude product was quickly eluted from a silica gel column with 50% ethylacetate-hexane to furnish 40 g of the required 5-{4-(6-hydroxy-2, 5, 7, 8-tetramethylchroman-2-yl-methoxy) benzyl) thiazolidine-2,4-dione (Troglitazone) with a HPLC purity of ~67-70%. The elution of column was continued further to yield 5-[4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl-methoxy)benzyl]2-iminothiazolidine-4-one with HPLC purity of ~70%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[C:6]([CH3:11])=[N:7][NH:8][C:9]=1[CH3:10].[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1)([O-:15])=[O:14].C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[C:9]([CH3:10])=[N:8][N:7]([CH2:20][C:19]2[CH:22]=[CH:23][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][CH:18]=2)[C:6]=1[CH3:11]
Reactant: COC(=O)Cc1c(C)n[nH]c1C
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)Cc1c(C)nn(Cc2ccc([N+](=O)[O-])cc2)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 119.5 %

Procedure:
To a solution of (3,5-dimethyl-1H-pyrazol-4-yl)acetic acid methyl ester (3.90 g, 23 mmol) and 4-nitrobenzyl bromide (4.60 g, 20.7 mmol) in acetonitrile is added K2CO3 (2.76 g, 19.9 mmol) and the mixture is stirred for one hour at room temperature. The reaction mixture is poured into water and extracted twice with ethyl acetate. The organic phase is dried over MgSO4 and evaporated under reduced pressure. To yield 7.50 g of [3,5-Dimethyl-1-(4-nitro-benzyl)-1H-pyrazol-4-yl]-acetic acid methyl ester (ESI mass spectrum: [M+H]+=304). b) To a solution of [3,5-dimethyl-1-(4-nitrobenzyl)-1H-pyrazol-4-yl]acetic acid methyl ester (3.90 g, 10.3 mmol) in methanol (10 mL) is added 10% palladium on charcoal (500 mg) and the mixture is hydrogenated. The catalyst is filtered off and the filtrate is concentrated under reduced pressure. The mixture is purified via preparative reversed phase HPLC (gradient of methanol in water+0.1% NH3) to yield 1.18 g of the title compound (ESI mass spectrum: [M+H]+=274; Retention time HPLC: 2.13 min (method A))
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=2[CH2:24][CH2:25][CH3:26])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[CH3:29][C:30]1[C:35](B(O)O)=[CH:34][CH:33]=[CH:32][N:31]=1>>[CH3:12][CH:11]([N:8]1[C:9]2[CH:10]=[C:2]([C:35]3[C:30]([CH3:29])=[N:31][CH:32]=[CH:33][CH:34]=3)[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=3[CH2:24][CH2:25][CH3:26])=[O:15])[C:5]=2[CH:6]=[N:7]1)[CH3:13]
Reactant: Cc1ncccc1B(O)O
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1cnn2C(C)C
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2cccnc2C)cc2c1cnn2C(C)C

Procedure:
The title compound was prepared in a similar manner as described for example 8 from 6-bromo-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (100 mg, 0.225 mmol) and (2-methyl-3-pyridinyl)boronic acid (46 mg, 0.337 mmol). The product was collected as a white solid (68 mg, 66%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.44 (br. s., 1H) 8.57 (br. s., 1H) 8.50 (dd, J=4.93, 1.64 Hz, 1H) 8.43 (s, 1H) 7.90 (s, 1H) 7.73 (dd, J=7.71, 1.64 Hz, 1H) 7.59 (d, J=1.26 Hz, 1H) 7.34 (dd, J=7.33, 4.80 Hz, 1H) 5.90 (s, 1H) 5.10 (quin, J=6.57 Hz, 1H) 4.40 (s, 1H) 4.38 (s, 1H) 2.46 (s, 3H) 2.12 (s, 3H) 1.50-1.58 (m, 2H) 1.50 (s, 3H) 1.48 (s, 3H) 0.88 (t, J=7.33 Hz, 3H). LC-MS (ES) m/z=458.3 [M+H]+
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1)[CH3:2].[Li][CH2:11]CCC.CI.O>C1COCC1>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][CH3:11])=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(N)nc1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CI
Product: CCc1ccc(NC)nc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 9.5 %

Procedure:
A solution of 5-ethylpyridin-2-amine (330 mg, 2.70 mmol) in THF (10 mL) was cooled to −78° C. and n-BuLi (1.2 mL, 3.0 mmol) was added. The reaction stirred at −78° C. for 30 min, and then MeI (423 mg, 2.97 mmol) was added. The reaction was stirred for 2 h while warming to r.t. Water (10 mL) was added, and the solution was extracted with EtOAc (20 mL). The organic layer was dried (Na2SO4) and concentrated. The residue was purified by silica gel chromatography (PE:EtOAc=5:1) to give 35 mg (9%) of the title compound as a yellow oil. [M+H] Calc'd for C8H12N2, 137. Found, 137.
Reaction SMILES: Br[C:2]1[C:3]([F:21])=[C:4]([F:20])[C:5]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH3:22][Si:23]([C:26]#[CH:27])([CH3:25])[CH3:24].N(C(C)C)C(C)C>C1COCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:20][C:4]1[C:5]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[C:6]([CH:11]=[C:2]([C:27]#[C:26][Si:23]([CH3:25])([CH3:24])[CH3:22])[C:3]=1[F:21])[C:7]([O:9][CH3:10])=[O:8]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1cc(Br)c(F)c(F)c1Nc1ccccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)c1cc(C#C[Si](C)(C)C)c(F)c(F)c1Nc1ccccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.8 %

Procedure:
A mixture of methyl 5-bromo-3,4-difluoro-2-(2-fluorophenylamino)benzoate (2.70 g, 7.50 mmol), trimethylsilylacetylene (1.23 ml, 8.63 mmol), CuI (143 mg, 0.75 mmol), dichlorobis(triphenylphosphine)palladium (526 mg, 0.75 mmol) and i-Pr2NH (2.12 ml, 15.0 mmol) in THF (40 ml) was stirred at room temperature for 16 h. The reaction was concentrated and diluted with EtOAc (100 ml). The organic solution was washed with saturated aqueous NH4Cl (50 ml), dried over Na2SO4 and concentrated. Silica gel chromatography (EtOAc:Hexanes=5:95) yielded 2.40 g (85%) of methyl 3,4-difluoro-2-(2-fluorophenylamino)-5-((trimethylsilyl)ethynyl)benzoate as a tan solid.
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:16]#[N:17].[Na+].[Cl-].[NH4+:20].[OH-].[NH4+]>CO>[NH2:20][CH:10]([C:9]1[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=1[O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:16]#[N:17]
Reactant: O=Cc1ccccc1Oc1ccccc1
Reactant: [NH4+]
Reactant: [C-]#N
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#CC(N)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.2 %

Procedure:
A solution of 2-phenoxybenzaldehyde (1.0 g, 5.04 mmol) in methanol (10 mL) was added to a solution of sodium cyanide (0.297 g, 6.05 mmol) and ammonium chloride (0.494 g, 9.23 mmol) in ammonium hydroxide (10 mL, 85 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 4 hours. The reaction mixture was concentrated by rotary evaporation. The residue was taken up in water and extracted with dichloromethane (2×). The combined organics were washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, 50% ethyl acetate in hexanes) to provide the title compound (1.065 g, 94% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:11]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:12]2)[CH2:10][CH2:9][C:8](=[O:19])[CH:7]=3)=[CH:4][C:3]=1[F:20].N#N.N1C=CC=CC=1.[C:29](Cl)(=[O:31])[CH3:30]>C(Cl)Cl>[C:29]([NH:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:11]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:12]2)[CH2:10][CH2:9][C:8](=[O:19])[CH:7]=3)=[CH:4][C:3]=1[F:20])(=[O:31])[CH3:30]
Reactant: CC(=O)Cl
Reactant: CCCCC12CCC(=O)C=C1c1cc(F)c(N)cc1C2
Agent: N#N
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCC12CCC(=O)C=C1c1cc(F)c(NC(C)=O)cc1C2
Reaction time: 4.5 h
Yield: 85.1 %

Procedure:
A solution of 7-amino-9a-butyl-6-fluoro-1,2,9,9a-tetrahydro-3H-fluoren-3-one (1.12 g, 4.1 mmol) in anhydrous CH2Cl2 (13.7 mL) was purged with N2, cooled in an ice bath, and treated with pyridine (0.33 mL, 4.1 mmol) followed by acetyl chloride (0.65 mL, 9 mmol). After stirring at 0–5° C. for 4.5 hours, the reaction mixture was partitioned between water and EtOAc. The organic portion was washed with brine, dried over MgSO4, filtered, and concentrated under vacuum to provide 7-(acetylamino)-9a-butyl-6-fluoro-1,2,9,9a-tetrahydro-3H-fluoren-3-one (1.1 g) as an orange foam. This material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH3:13])[C:6]([CH2:14][N:15]1C(=O)C3C(=CC=CC=3)C1=O)=[C:5]2[O:26][CH3:27].O.NN.C(=O)([O-])O.[Na+]>C(O)C.O1CCCC1>[ClH:1].[NH2:15][CH2:14][C:6]1[N:7]([CH3:13])[C:8](=[O:12])[C:9]2[C:4]([C:5]=1[O:26][CH3:27])=[CH:3][C:2]([Cl:1])=[CH:11][CH:10]=2
Reactant: COc1c(CN2C(=O)c3ccccc3C2=O)n(C)c(=O)c2ccc(Cl)cc12
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: COc1c(CN)n(C)c(=O)c2ccc(Cl)cc12
Product: Cl
Yield: 55.3 %

Procedure:
To a solution of 2-{(6-chloro-4-methoxy-2-methyl-1oxo-1,2-dihydro-3-isoquinolinyl)methyl}-1H-isoindole-1,3(2H)-dione (0.38 g, 1 mmol) in ethanol (10 ml) and tetrahydrofuran (10 ml) was added hydrazine monohydrate (0.14 ml, 3 mmol). The obtained mixture was refluxed under heating for 2 h. The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the residue was added a solution of 4N hydrogen chloride in ethyl acetate (2 ml), and the precipitated crystals were recrystallized from methanol-diethyl ether to give 3-(aminomethyl)-6-chloro-4-methoxy-2-methyl-1(2H)-isoquinolinone hydrochloride (0.08 g, 28.6%) as crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1>C(Cl)(Cl)Cl.[O-2].[Mn+4].[O-2]>[Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1
Reactant: CSc1ncc(CO)c(Cl)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CSc1ncc(C=O)c(Cl)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 72 %

Procedure:
(4-Chloro-2-(methylthio)pyrimidin-5-yl)methanol (105 mmol) was dissolved in CHCl3 (500 mL) to give a yellow suspension. Manganese(IV) oxide (546 mmol) was added in 0.5 g portions over 15 min. The mixture was stirred at room temperature for 6 h. Further Manganese(IV) oxide (210 mmol) was added. The mixture was stirred at room temperature for 18 h. Again, manganese(IV) oxide (210 mmol) was added. The mixture was stirred at room temperature for 20 h, then at 40° C. for 4 h, and then overnight at room temperature. The mixture was then stirred at 40° C. for 6 h, allowed to cool to room temperature, filtered though Celite, washed with 400 mL CHCl3 and concentrated under reduced pressure to give 4-chloro-2-(methylthio)pyrimidine-5-carbaldehyde as a solid (72%).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([C:15]2[CH:16]([CH3:22])[NH:17][C:18](=[O:21])[NH:19][N:20]=2)[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8]CC)=O.[NH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>C(O)C>[Cl:1][C:2]1[CH:14]=[C:13]([C:15]2[CH:16]([CH3:22])[NH:17][C:18](=[O:21])[NH:19][N:20]=2)[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([NH:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:8]
Reactant: CCOC(=O)COc1ccc(C2=NNC(=O)NC2C)cc1Cl
Reactant: NCCN1CCNCC1
Solvent: CCO
Product: CC1NC(=O)NN=C1c1ccc(OCC(=O)NCCN2CCNCC2)c(Cl)c1
Yield: 68.5 %

Procedure:
4.0 g of ethyl α-[2-chloro-4-(2,3,4,5-tetrahydro-5-methyl-3-oxo-1,2,4-triazin-6-yl)phenoxy]acetate (prepared as described in Example 5) and 1.59 g of N-(2-aminoethyl)piperazine were added to 50 ml of ethanol, and the mixture was heated under reflux for 60 hours. The mixture was then cooled, after which the crystals which precipitated were collected by filtration and then recrystallized from ethanol to give 3.44 g of the title compound as pale yellow prisms melting at 208°-210° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[F:11].[C:12]([O:16][C:17]([N:19]1[CH2:22][C:21]2([CH2:26][CH2:25][NH:24][CH2:23]2)[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][C:17]([N:19]1[CH2:22][C:21]2([CH2:26][CH2:25][N:24]([C:2]3[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=3[F:11])[CH2:23]2)[CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CC2(CCNC2)C1
Product: CC(C)(C)OC(=O)N1CC2(CCN(c3ccc(N)cc3F)C2)C1

Procedure:
According to methods E and F, 1,2-Difluoro-4-nitro-benzene was reacted with 2,6-Diaza-spiro[3.4]octane-2-carboxylic acid tert-butyl ester and hydrogenated. The product with the molecular weight of 321, 40 (C17H24FN3O2) was obtained in this way; MS (ESI): 322 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[S:10][C:11]3[C:17]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=3[N:13]=2)=[O:7])=[CH:4][N:3]=1.[H-].[Na+].[CH3:30][OH:31]>O1CCOCC1.CN(C=O)C>[CH3:30][O:31][C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[S:10][C:11]3[C:17]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=3[N:13]=2)=[O:7])=[CH:4][N:3]=1
Reactant: CO
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(Cl)nc3)nc12
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cn1

Procedure:
From 6-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide with sodium hydride and methanol in dioxane and DMF. ES-MS m/e (%): 423 (M+Na+, 15), 401 (M+H+, 100).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:22]([NH:24][CH2:25][CH:26]1[CH2:30][CH2:29][NH:28][CH2:27]1)[CH3:23].C(N(CC)CC)C>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11]([N:28]4[CH2:29][CH2:30][CH:26]([CH2:25][NH:24][CH2:22][CH3:23])[CH2:27]4)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: CCNCC1CCNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCNCC1CCN(c2c(F)c(C)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
A mixture of 0.80 g (2.70 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 0.41 g (3.20 mmol) of N-ethyl-3-pyrrolidinemethanamine, 0.82 g (8.10 mmol) of triethylamine, and 25 mL of acetonitrile was refluxed for 4 hours, then stirred at room temperature overnight. The precipitate was collected by filtration, washed with acetonitrile and ether, and dried to give 0.90 g of the title compound, mp 198°-199° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH2:25][CH3:26])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]3=[C:15]([CH3:23])[N:16]=[C:17]([CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:10]3[N:9]=2)[CH:7]=1.[CH2:27]([O:31][C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1)[CH2:28][CH2:29][CH3:30].N1C=CC=CC=1>O1CCCC1>[CH2:27]([O:31][C:32]1[CH:37]=[CH:36][C:35]([S:38]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([O:24][CH2:25][CH3:26])=[C:6]([C:8]3[NH:13][C:12](=[O:14])[C:11]4=[C:15]([CH3:23])[N:16]=[C:17]([CH:18]5[CH2:22][CH2:21][CH2:20][CH2:19]5)[N:10]4[N:9]=3)[CH:7]=2)(=[O:40])=[O:39])=[CH:34][CH:33]=1)[CH2:28][CH2:29][CH3:30]
Reactant: CCOc1ccc(N)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1
Reactant: CCCCOc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCCOc1ccc(S(=O)(=O)Nc2ccc(OCC)c(-c3nn4c(C5CCCC5)nc(C)c4c(=O)[nH]3)c2)cc1

Procedure:
150 mg (0.424 mmol) of the compound from example 42A are reacted with 186 mg (0.747 mmol) of 4-(n-butoxy)-benzenesulfonyl chloride and 0.34 g (4.30 mmol) of pyridine in 6 ml of tetrahydrofuran.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[C:12](Cl)(=[O:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].O>CN(C)C=O>[C:12]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6])(=[O:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: Cc1ccc(C(=O)O)cc1N
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCC(=O)Nc1cc(C(=O)O)ccc1C
Yield: 73.8 %

Procedure:
A solution of 3-amino-4-methylbenzoic acid (15.1 g) and n-decanoyl chloride (19.4 g) in dry dimethylformamide (150 ml) was heated on a steam bath for 90 minutes. The solution was poured into water and the solid was collected, and recrystallised from ethanol (600 ml) to give 3-(n-decanamido)-4-methylbenzoic acid (22.5 g), in the form of a white powder, m.p. 246°-250° C.
Reaction SMILES: [Br:1]C[C:3]1[CH:39]=[CH:38][CH:37]=[CH:36][C:4]=1[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:15](=[O:24])[CH:14]2[CH2:25][CH2:26][CH:27]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[OH:28])=[CH:9][CH:8]=1.[CH2:40]1[N:45]2[CH2:46][CH2:47][N:42]([CH2:43][CH2:44]2)[CH2:41]1.[C:48]1(C)C=CC=CC=1>>[Br-:1].[F:23][C:20]1[CH:19]=[CH:18][C:17]([N:16]2[C:15](=[O:24])[CH:14]([CH2:25][CH2:26][CH:27]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[OH:28])[CH:13]2[C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4]3[CH:36]=[CH:37][C:38]([CH2:48][N+:42]45[CH2:47][CH2:46][N:45]([CH2:44][CH2:43]4)[CH2:40][CH2:41]5)=[CH:39][CH:3]=3)=[CH:12][CH:11]=2)=[CH:22][CH:21]=1
Reactant: C1CN2CCN1CC2
Reactant: Cc1ccccc1
Reactant: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(OCc3ccccc3CBr)cc2)N1c1ccc(F)cc1
Product: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(OCc3ccc(C[N+]45CCN(CC4)CC5)cc3)cc2)N1c1ccc(F)cc1
Product: [Br-]

Procedure:
Compound (15) and DABCO were dissolved in toluene and reacted analogously to Example IV, giving the product (16) as a colorless solid of molecular weight 704.66 (C38H40BrF2N3O3); MS (ESI): 624.30 (MH+).
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:12]1([C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:16](=[O:17])[NH:15]1)(=[O:14])=[O:13].O>ClCCl.CC(C)=O>[NH2:9][C:10]([NH2:15])=[S:11].[C:1]([N:15]1[C:16](=[O:17])[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[S:12]1(=[O:13])=[O:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NS(=O)(=O)c2ccccc21
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: O
Product: NC(N)=S
Product: O=C(c1ccccc1)N1C(=O)c2ccccc2S1(=O)=O
Yield: 37 %

Procedure:
To a 250 mL 3-neck RBF equipped with a condenser, magnetic stirrer, thermo-probe, nitrogen purge and pressure-equilibrated addition funnel was added benzoyl isothiocyanate (25.0 g, 0.150 mol) and saccharin (28.1 g, 0.150 mol) followed by dichloromethane (100 mL). The mixture was cooled in an ice-water bath at a temperature below 5° C., at which point water (28.1 g, 0.150 mol) and acetone as the solvent and dichloromethane (100 mL) were added slowly over a period of time of about 30 minutes. The ice-water bath was removed and the reaction mixture was stirred under a nitrogen purge overnight. The reaction mixture was then concentrated in vacuo at a temperature of 40° C. to provide a solid that was dried to constant weight in vacuo at a temperature of 50° C. and a pressure of <1 mTorr in a 37% yield.