Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:24]=[CH:23][C:11]([C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[CH3:25][SiH:26]([CH3:32])[O:27][Si:28]([CH3:31])([CH3:30])[CH3:29]>C1(C)C=CC=CC=1.C1([Pt](Cl)(Cl)C2C=CC=C2)C=CC=C1>[CH3:25][Si:26]([CH3:32])([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][O:7][C:8]1[CH:24]=[CH:23][C:11]([C:12]([O:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]#[N:22])=[CH:19][CH:20]=2)=[O:13])=[CH:10][CH:9]=1)[O:27][Si:28]([CH3:31])([CH3:30])[CH3:29]
Reactant: C=CCCCCOc1ccc(C(=O)Oc2ccc(C#N)cc2)cc1
Reactant: C[SiH](C)O[Si](C)(C)C
Agent: Cl[Pt](Cl)(C1C=CC=C1)C1C=CC=C1
Solvent: Cc1ccccc1
Product: C[Si](C)(C)O[Si](C)(C)CCCCCCOc1ccc(C(=O)Oc2ccc(C#N)cc2)cc1

Procedure:
0.94 g (0.024 mmol of Pt) of 0.5% strength dicyclopentadienylplatinum dichloride solution (dichloromethane) was added to a solution of 13.8 g (42.9 mmol) of 4-cyanophenyl 4-(5-hexenyloxy)benzoate and 6.48 g (43.7 mmol) of pentamethyldisiloxane in 50.0 g of toluene, and the mixture was refluxed for 3 hours. After complete hydrosilylation of the olefin, a further 0.94 g (0.024 mmol of Pt) of 0.5% strength dicyclopentadienylplatinum dichloride solution (dichloromethane) were added, and the mixture was refluxed for a further 2 hours. The reaction mixture was flushed with nitrogen, and the toluene was removed by vacuum distillation on a rotary evaporator. The crude product was purified by chromatography on silica gel. The 4-cyanophenyl 4-(6-pentamethyldisiloxanylhexyloxy)benzoate obtained was additionally recrystallized from petroleum ether (100° C.-140° C.) and exhibited the following phase behavior: c 54-55 (sA 53-55) i.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([OH:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2].Br[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(O)ccc2[nH]1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2cc(OCC(=O)OC(C)(C)C)ccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.6 %

Procedure:
A mixture of 5-hydroxy-1H-indole-2-carboxylic acid ethyl ester (2 g, 10 mmol), tert-butyl bromoacetate (2.35 g, 12 mmol) and cesium carbonate (10.5 g, 30 mmol) in dimethylformamide (10 mL) was stirred at room temperature for 16 hours. The reaction was diluted with ethyl acetate (150 mL), washed with water (5×50 mL) and brine, dried and concentrated. The residue was recrystallized from ethyl acetate and hexane to give 2 g (63%) 5-tert-butoxycarbonylmethoxy-1H-indole-2-carboxylic acid ethyl ester.
Reaction SMILES: N[C:2]1[S:3][C:4]2[C:9]([OH:10])=[N:8][C:7]([C:11]([F:14])([F:13])[F:12])=[N:6][C:5]=2[N:15]=1.N([O-])=O.[Na+].[ClH:20]>>[Cl:20][C:2]1[S:3][C:4]2[C:9]([OH:10])=[N:8][C:7]([C:11]([F:14])([F:13])[F:12])=[N:6][C:5]=2[N:15]=1
Reactant: Nc1nc2nc(C(F)(F)F)nc(O)c2s1
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Product: Oc1nc(C(F)(F)F)nc2nc(Cl)sc12
Temperature: 25 °C

Procedure:
To a solution of the compound (3.00 g) obtained in Step 6 in 6N hydrochloric acid (45 ml) was added sodium nitrite (8.76 g) in several portions with stirring at room temperature, and the mixture was further stirred at room temperature for 30 min. The precipitated crystals were collected by filtration, washed with water and dried to give the title compound (1.46 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[CH3:11])([O-])=O.O>CO.[Fe]>[NH2:1][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[CH3:11]
Reactant: Cc1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CO
Solvent: O
Product: Cc1ccc(Cl)cc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
To a solution of 2-nitro-4-chlorotoluene (86 g, 0.5 mol) in MeOH (250 mL) was added Fe powder (92 g, 3.65 mol) by portions over 45 min while refluxing gently. The mixture was stirred for 3 h at room temperature, poured into water (1.5 L) and extracted with AcOEt. The organic layers were dried over MgSO4 and concentrated in vacuo to give 63 g of the title compound.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([CH3:34])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[Cl:37][C:38]1[CH:46]=[CH:45][C:41]([CH2:42][CH2:43][NH2:44])=[CH:40][CH:39]=1>>[Cl:37][C:38]1[CH:46]=[CH:45][C:41]([CH2:42][CH2:43][NH:44][C:3]([C:5]2[N:14]3[C:8]([CH2:9][N:10]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[CH3:33])=[C:23]([CH3:34])[CH:22]=4)=[O:20])[C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[CH2:13]3)=[CH:7][CH:6]=2)=[O:4])=[CH:40][CH:39]=1
Reactant: NCCc1ccc(Cl)cc1
Reactant: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Product: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCCc4ccc(Cl)cc4)n3Cc3ccccc32)cc1C

Procedure:
The title compound was synthesized in the manner of Example 13 from 2,2,2-trichloro-1-{10-[(2,2′-dimethyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 6 and 4-chlorophenethylamine, m.p. 169-171° C. MS [(+)ESI, m/z]: 574 [M+H]+ Anal. Calcd for C36H32CIN3O2: C, 75.31; H, 5.62; N, 7.32. Found: C, 75.32; H, 5.48; N, 7.23.
Reaction SMILES: BrCC[O:4][C:5]1[C:14]([O:15][C:16]([C:18]2C=CC=CC=2)=O)=[CH:13][C:12]([N+:24]([O-:26])=[O:25])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[K+].[K+]>CO>[N+:24]([C:12]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]2[O:4][CH2:18][CH2:16][O:15][C:14]=2[CH:13]=1)([O-:26])=[O:25]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc(OC(=O)c2ccccc2)c1OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1cc([N+](=O)[O-])cc2c1OCCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.1 %

Procedure:
To a solution of methyl 2-[(2-bromoethyl)oxy]-5-nitro-3-[(phenylcarbonyl)oxy]benzoate (30 g, 70.7 mmol) in methanol (200 mL) was added potassium carbonate (9.8 g, 70.7 mmol). The reaction mixture was allowed to stir at room temperature for 30 min., at which time it was concentrated in vacuo. The residue was taken up in N,N-dimethylformamide (150 mL) and the resulting suspension was heated to 65° C. and stirred for 12 h. The reaction mixture was then cooled to room temperature and concentrated. The residue was dissolved in water (300 mL) and extracted with ethyl acetate (2×300 mL). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was triturated with 10% diethyl ether/hexanes to give 5.6 g (33%) of methyl 7-nitro-2,3-dihydro-1,4-benzodioxine-5-carboxylate as an off-white powder: 1H NMR (400 MHz, CDCl3): 8.34 (d, J=2.8 Hz, 1H), 7.90 (d, J=2.8 Hz, 1H), 4.48-4.46 (m, 2H), 4.37-4.35 (m, 2H), 3.93 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[OH-].[K+].Cl[O-].[Na+]>>[F:21][C:18]([F:19])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:4]3=[N+:1]([O-:3])[O:2][N:6]=[C:5]3[CH:7]=2)=[CH:13][CH:14]=1
Reactant: Nc1cc(Oc2ccc(C(F)(F)F)cc2)ccc1[N+](=O)[O-]
Agent: [K+]
Agent: [Na+]
Agent: [O-]Cl
Product: [O-][n+]1onc2cc(Oc3ccc(C(F)(F)F)cc3)ccc21

Procedure:
Following the procedure of Example 4, N-methylcarbonyl 2-nitro-5-fluoroaniline (3.1 g, 15.4 mmol), 4-trifluoromethylphenol (2.5 g, 15.4 mmol) and potassium carbonate (4.3 g, 31.0 mmol) are reacted together to give N-methylcarbonyl 2-nitro-5-(4-trifluoromethylphenoxy)aniline, 4.0 g of which is then reacted with 20% hydrochloric acid (~50 ml) to give 2-nitro-5-(4-trifluoromethylphenoxy)aniline. 2-Nitro-5-(4-trifluoromethylphenoxy)aniline (2.0 g, 6.7 mmol) is reacted with potassium hydroxide (0.4 g, 7.0 mmol) and sodium hypochlorite (19 ml of 5.2% solution, 1.0 g, 13.4 mmol) to yield 5-(4-trifluormethylphenoxy)benzo-2,1,3-oxadiazole N-oxide, m.p. 40°-42°.
Reaction SMILES: Cl[Sn]Cl.Cl.[CH3:5][C:6]1[C:14]2[S:13][CH:12]=[N:11][C:10]=2[CH:9]=[CH:8][C:7]=1[N+:15]([O-])=O.[OH-].[Na+]>>[CH3:5][C:6]1[C:14]2[S:13][CH:12]=[N:11][C:10]=2[CH:9]=[CH:8][C:7]=1[NH2:15]
Reactant: Cc1c([N+](=O)[O-])ccc2ncsc12
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Product: Cc1c(N)ccc2ncsc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 113.1 %

Procedure:
To a solution of SnCl2 (3.0 g, 3.8 mmol) and 10 mL of con.HCl was added 7-methyl-6-nitrobenzothiazole (0.68 g, 3.5 mmol) in a portion and the resulting reaction mixture was stirred for 1 h at 25° C. The reaction mixture was basified with aqueous NaOH and extracted with EtOAc and CHCl3. Combined organic layers were dried over Na2SO4 and concentrated in vacuo, yielding an oil (0.65 g, >95%) which was identified as the desired amine and subjected to a following reaction without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[CH:4][C:3]=1[NH:10][C:11](=[O:16])[CH:12]=[C:13]([CH3:15])[CH3:14].[Cl-].[Al+3].[Cl-].[Cl-]>ClC1C=CC=C(Cl)C=1>[CH3:14][C:13]1([CH3:15])[C:4]2[C:3](=[CH:2][CH:7]=[CH:6][C:5]=2[OH:8])[NH:10][C:11](=[O:16])[CH2:12]1
Reactant: COc1ccc(Br)c(NC(=O)C=C(C)C)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1cccc(Cl)c1
Product: CC1(C)CC(=O)Nc2cccc(O)c21
Temperature: 120 °C
Reaction time: 0.67 h
Yield: 42.5 %

Procedure:
N-(2-Brom-5-methoxyphenyl)-3,3-dimethylacrylamide (530 mg, 1.87 mmol) was dissolved in m-dichlorobenzene (10 ml). To the resultant solution, aluminum chloride (1.24 g, 9.33 mmol) was added, and the mixture was stirred at 120° C. for 40 minutes. The reaction mixture was poured into ice-water, followed by extracting with chloroform-methanol (10:1), and drying. Subsequently, the residue was subjected to silica gel column chromatography (developer=chloroform-methanol =30:1). From the first eluate, 152 mg of 4,4-dimethyl-5-hydroxy-3,4-dihydrocarbostyril (152 mg, 42.5%) was obtained as pale yellow needles. From the second eluate, 4,4-dimethyl-7-hydroxy-3,4-dihydrocarbostyril (63 mg, 17.6%) was obtained as pale yellow needles.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13](=O)[CH2:14][CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O)[CH:7]=[CH:6]2.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[N:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:14]=1)[CH:7]=[CH:6]2
Reactant: COc1ccc2cc(C(=O)CCC(=O)c3ccccc3)ccc2c1
Reactant: Nc1ccccc1
Product: COc1ccc2cc(-c3ccc(-c4ccccc4)n3-c3ccccc3)ccc2c1
Yield: 76.9 %

Procedure:
In a similar manner as described in step 1 of Example 8, the title compound was prepared from 1-(6-methoxy-2-naphthyl)-4-phenylbutane-1,4-dione (1.50 g, 4.71 mmol), prepared in step 3 of Example 1, and aniline (3.07 g, 33.0 mmol). Purification on silica gel (500 g, 200–300 mesh) using 0% to 50% methylene chloride in hexane as the eluent gave 2-(6-methoxy-2-naphthyl)-1,5-diphenyl-1H-pyrrole as an off-white solid (1.36 g, 77%), mp 199–200° C. Elemental Analysis for C27H21NO.0.11 CH2Cl2 Calc'd: C, 84.62; H, 5.56; N, 3.64. Found: C, 84.55; H, 5.67; N, 3.61.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[CH3:12][CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14]1>C(O)CCC>[CH3:12][C:13]1[N:14]([C:4]2[N:3]=[C:2]([Cl:1])[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][NH:8]3)[C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: CC1Cc2ccccc2N1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: CCCCO
Product: Cc1cc2ccccc2n1-c1nc(Cl)nc2[nH]cnc12
Temperature: 130 °C
Yield: 61.3 %

Procedure:
The same procedure as in stage 1 of Example 1 is carried out, mixing 189 mg of 2,6-dichloropurine, 5 ml of butanol and 0.16 g of 2-methylindoline. The mixture is heated at 130° C. for approximately 1 hour and allowed to return to ambient temperature. Partial drying is carried out, followed by washing with isopropanol. The product is dried and 174 mg of expected product are thus obtained.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.[OH:9][C:10]1[CH:11]=[C:12]2[C:17](=O)[O:16][C:14](=[O:15])[C:13]2=[CH:19][CH:20]=1.O.Cl>N1C=CC=CC=1>[OH:9][C:10]1[CH:11]=[C:12]2[C:17](=[O:16])[N:7]([C:6]3[CH:5]=[CH:4][C:3]([OH:8])=[CH:2][CH:1]=3)[C:14](=[O:15])[C:13]2=[CH:19][CH:20]=1
Reactant: O=C1OC(=O)c2cc(O)ccc21
Reactant: Nc1ccc(O)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C1c2ccc(O)cc2C(=O)N1c1ccc(O)cc1

Procedure:
In a stirred dry flask under N2, to a solution of 54.5 g p-aminophenol (0.5 mole) in 500 ml dry pyridine was added over 10 min at room temperature 82.0 g powdered 4-hydroxyphthalic anhydride (0.31 mole) and the mixture refluxed 5 hr. This black solution was cooled, poured into 1500 ml water, acidified with HCl, filtered, washed, and dried. M.P. 302°-304° C. Recrystallization was unnecessary. Yield 104 g, 82%.
Reaction SMILES: C[C:2]1C=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:20]=[O:21])[C:14]=2[CH:13]=[CH:12]1)(=[O:10])=[O:9].[N:22]1C=CC=C(S(N2C3C(=C(C=C)C=CC=3)C=C2)(=O)=O)C=1.N1C(C)=CC=CC=1C.I([O-])(=O)(=O)=O.[Na+]>O=[Os](=O)(=O)=O>[N:22]1[CH:6]=[CH:5][CH:4]=[C:3]([S:8]([N:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH:20]=[O:21])[C:14]=3[CH:13]=[CH:12]2)(=[O:10])=[O:9])[CH:2]=1
Reactant: Cc1ccccc1S(=O)(=O)n1ccc2c(C=O)cccc21
Reactant: C=Cc1cccc2c1ccn2S(=O)(=O)c1cccnc1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: Cc1cccc(C)n1
Product: O=Cc1cccc2c1ccn2S(=O)(=O)c1cccnc1

Procedure:
The experimental for Intermediate 16 was followed using 1-(pyridine-3-ylsulfonyl)-4-vinyl-1H-indole (208 mg, 0.73 mmol; Intermediate 25), OsO4 (9 mg, 0.04 mmol), 2,6-lutidine (170 μL, 1.46 mmol) and sodium periodate (0.625 g, 2.92 mmol). After flash purification by flash chromatography, some material was insoluble in DCM/MeOH and filtered off. The title compound (123 mg, 59%, still some dioxane according to HNMR) was obtained as a black gum. MS (ESI+) for C14H10N2O3S m/z 287 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:14]=[C:15]([C:19]([S:22][C:23]2[CH:28]=[CH:27][C:26]([S:29]([N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)(=[O:31])=[O:30])=[CH:25][CH:24]=2)=[CH:20][N:21]=1)[C:16](O)=[O:17])(=[O:11])=[O:10].Cl.[CH3:39][NH:40][O:41][CH3:42].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:14]=[C:15]([C:19]([S:22][C:23]2[CH:28]=[CH:27][C:26]([S:29]([N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)(=[O:30])=[O:31])=[CH:25][CH:24]=2)=[CH:20][N:21]=1)[C:16]([N:40]([O:41][CH3:42])[CH3:39])=[O:17])(=[O:11])=[O:10]
Reactant: O=C(O)c1cc(NS(=O)(=O)c2ccc(Cl)cc2Cl)ncc1Sc1ccc(S(=O)(=O)N2CCCCC2)cc1
Reactant: CNOC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1cc(NS(=O)(=O)c2ccc(Cl)cc2Cl)ncc1Sc1ccc(S(=O)(=O)N2CCCCC2)cc1
Yield: 81.7 %

Procedure:
A solution of 2-(2,4-dichloro-benzenesulfonylamino)-5-[4-(piperidine-1-sulfonyl) -phenylsulfanyl]-isonicotinic acid (173 mg, 0.29 mmol), N,O-dimethylhydroxylamine hydrochloride (84 mg, 0.86 mmol), TBTU (276 mg, 0.86 mmol) and DIPEA (0.18 ml, 1 mmol) in DMF (10 ml) was stirred at room temperature overnight under nitrogen. The reaction was diluted with ethyl acetate (25 ml), washed with brine (3×25 ml), dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash column chromatography using methanol 1/9 chloroform as eluent to afford 2-(2,4-dichloro -benzenesulfonylamino)-N-methoxy-N-methyl-5-[4-(piperidine-1-sulfonyl)-phenylsulfanyl]-isonicotinamide as a yellow oil (153 mg, 82%). 1H NMR (CDCl3): 8.40 (1H, s, Ar); 8.07 (1H, d, Ar); 7.53 (2H, d, Ar); 7.46 (1H, s, py); 7.34 (1H, d, Ar); 7.22 (3H, m, py and Ar); 3.34 (3H, s, CH3O); 3.24 (3H, s, CH3N); 2.88 (4H, m, 2×CH2N pip); 1.55 (4H, m, 2×CH2 pip); 1.33 (2H, m, CH2 pip).
Reaction SMILES: [OH:1][CH:2]([CH2:35][OH:36])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([S:33][CH3:34])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)[C:8]([OH:10])=O.[NH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[OH:1][CH:2]([CH2:35][OH:36])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([S:33][CH3:34])=[CH:29][CH:28]=2)(=[O:25])=[O:26])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)[C:8]([NH:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:10]
Reactant: Nc1ccccc1
Reactant: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(SC)cc3)cc(C(=O)O)cc2OCC(O)CO)c1
Product: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(SC)cc3)cc(C(=O)Nc3ccccc3)cc2OCC(O)CO)c1

Procedure:
In analogy to Example 121, by coupling 3-(2,3-dihydroxy-propoxy)-4-(3-methoxy-phenoxy)-5-(4-methylsulphanyl-benzenesulphonylamino)-benzoic acid with aniline there was obtained 3-(2,3-dihydroxy-propoxy)-4-(3-methoxy-phenoxy)-5-(4-methylsulphanyl-benzenesulphonylamino)-N-phenyl-benzamide as a foam.
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([CH2:6][NH:7][C:8]2[C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]([S:17]([NH2:20])(=[O:19])=[O:18])=[C:10]([Cl:21])[CH:9]=2)[O:4][CH:5]=1.[OH-].[CH2:23]([N+:39]([CH3:42])([CH3:41])[CH3:40])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>O>[NH2:20][S:17]([C:11]1[C:10]([Cl:21])=[CH:9][C:8]([NH:7][CH2:6][C:3]2[O:4][CH:5]=[CH:1][CH:2]=2)=[C:13]([CH:12]=1)[C:14]([O-:16])=[O:15])(=[O:18])=[O:19].[CH2:23]([N+:39]([CH3:42])([CH3:40])[CH3:41])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: NS(=O)(=O)c1cc(C(=O)O)c(NCc2ccco2)cc1Cl
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [OH-]
Solvent: O
Product: NS(=O)(=O)c1cc(C(=O)[O-])c(NCc2ccco2)cc1Cl

Procedure:
In similar manner to Example 10, furosemide can be reacted with cetyltrimethylammonium hydroxide in water to yield cetyltrimethylammonium 5-aminosulfonyl-4-chloro-2-[(2-furanylmethyl)amino]benzoate.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:27])=[C:11]([N:14]4[CH2:17][CH:16]([N:18](CC)[C:19](=O)[C:20](F)(F)F)[CH2:15]4)[CH:12]=3)[C:7](=[O:28])[C:6]3[C:29](=[O:32])[NH:30][S:31][C:5]2=3)[CH2:3][CH2:2]1.[OH-].[Na+]>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:27])=[C:11]([N:14]4[CH2:15][CH:16]([NH:18][CH2:19][CH3:20])[CH2:17]4)[CH:12]=3)[C:7](=[O:28])[C:6]3[C:29](=[O:32])[NH:30][S:31][C:5]2=3)[CH2:3][CH2:2]1
Reactant: CCN(C(=O)C(F)(F)F)C1CN(c2cc3c(cc2F)c(=O)c2c(=O)[nH]sc2n3C2CC2)C1
Agent: [Na+]
Agent: [OH-]
Product: CCNC1CN(c2cc3c(cc2F)c(=O)c2c(=O)[nH]sc2n3C2CC2)C1

Procedure:
By a procedure completely analogous to that described in Example 2, 9-cyclopropyl-6-fluoro-7-{3-[N-(ethyl)trifluoroacetamido]-1-azetidinyl}-2,3,4,9-tetrahydroisothiazolo[5,4-b]quinoline-3,4-dione, melting point 256°-259° C., is obtained, which product is hydrolyzed by heating it with 10% sodium hydroxide for 2 hours; 9-cyclopropyl-6-fluoro-7-(3-ethylamino-1-azetidinyl)-2,3,4,9-tetrahydroisothiazolo[5,4-b]quinoline-3,4-dione, melting point 231°-236° C., is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](C#N)=[O:7])=[CH:4][CH:3]=1.[CH3:12][N:13]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]1[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(O)(=O)C(O)=O>CCOCC.C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([C:17]2[N:13]([CH3:12])[C:14]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:15][C:16]=2[CH3:18])=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1cc(C)cn1C
Reactant: N#CC(=O)c1ccc(Cl)cc1
Agent: O=C(O)C(=O)O
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(Cl)cc2)n1C
Yield: 32.5 %

Procedure:
A solution of 1.65 g (0.01 mole) of p-chlorobenzoylcyanide, 1.81 g (0.01 mole) of ethyl 1,4-dimethylpyrrole-2-acetate and 0.08 g of anhydrous oxalic acid in 4 ml of ether was stored in the dark under nitrogen for four days. The solution was diluted with CH2Cl2. The organic solution was washed with 10 percent NaOH solution, dried (MgSO4), and the solvent evaporated in vacuo. The residue was recrystallized from 1,1,1-trichloroethane to give 1.04 g of ethyl 5-(4-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate, mp 105°-108° C., undepressed by admixture with authentic material.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([O:20]CC)=[O:19])=[CH:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([OH:20])=[O:19])=[CH:12]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc2cc(NC(=O)OC(C)(C)C)ccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc2[nH]c(C(=O)O)cc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.4 %

Procedure:
A solution of compound 30 (2.61 g, 8.6 mmol) in methanol (200 mL) was treated with 3N sodium hydroxide solution (50 mL) , and the reaction mixture was stirred for 18 h at room temperature. Solvent was removed. Water (100 mL) was added. The solution was neutralized with 20% hydrochloric acid and the precipitate was filtered to give compound 31 (2.03 g, 86%) as a yellow solid. m.p.192°-193° C. 1H NMR (DMSO-d6, ppm) 12.83 (brs, 1 H, COOH), 11.69 (s, 1 H, NH), 9.13 (s, 1 H, CONH), 7.79-7.04 (m, 4 H, Ar--H), 1.48 (s, 9 H, C(CH3)3). Anal. (C14H16N2O4 0.5H2 O), C, H, N.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:24][C:25]1[O:26][C:27]([CH3:33])=[C:28]([C:30](Cl)=[O:31])[N:29]=1.C(OCC)(=O)C.O1CCCC1.C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:30]([C:28]5[N:29]=[C:25]([CH3:24])[O:26][C:27]=5[CH3:33])=[O:31])[CH:23]=[CH:22][CH:21]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Cc1nc(C(=O)Cl)c(C)o1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Cc1nc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)c(C)o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
To a solution of N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (202 mg, 0.652 mmol) in N,N-dimethylacetamide (4.0 mL) was added a solution of 2,5-dimethyl-1,3-oxazole-4-carbonyl chloride (135 mg, 0.847 mmol) in N,N-dimethylacetamide (1.0 mL), and the mixture was stirred at 0° C. for 1 hr. Ethyl acetate/tetrahydrofuran and saturated aqueous sodium hydrogencarbonate solution were added to the mixture, and the aqueous layer was extracted three times with ethyl acetate/tetrahydrofuran. Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80→490/10), and precipitated from ethyl acetate/hexane to give the title compound (213 mg, 76%) as a white powder. melting point 224° C.
Reaction SMILES: [Na].CC(C)=O.Cl.[C:7]([NH2:16])(=[NH:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1>C1C=CC=CC=1>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:15][C:7](=[NH:16])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:26])=[CH:20][CH:19]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CCCCCCCC(=N)N
Agent: Cl
Agent: [Na]
Solvent: CC(C)=O
Solvent: c1ccccc1
Product: CCCCCCCC(=N)NC(=O)Nc1ccc(Cl)cc1

Procedure:
Following a procedure similar to that described in Example 1 but using 2.2 g. sodium in 200 ml. dry acetone, 17.8 g. octanamidine hydrochloride, and 15.3 g. 4-chlorophenyl isocyanate in 100 ml. benzene, there was obtained after recrystallization from acetonitrile 19.7 g. of the hydrochloride of 1-(4-chlorophenyl)-3-(octanimidoyl)urea; m.p. 156°-165°C.