Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C@@H:17]([NH2:22])[CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[N:39]1([C:46](Cl)=[O:47])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>C1C=CC=CC=1.CN(C)C1C=CN=CC=1>[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[N:10]2[CH2:11][CH2:12][N:13]([CH2:16][C@@H:17]([NH:22][C:46]([N:39]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)=[O:47])[CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:14][CH2:15]2)=[CH:5][CH:4]=1
Reactant: O=C(Cl)N1CCCCCC1
Reactant: CC(C)C[C@H](N)CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@@H](CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1)NC(=O)N1CCCCCC1
Temperature: 25 °C
Yield: 19.8 %

Procedure:
To a solution of (S)-1-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazin-1-ylmethyl}-3-methyl-butylamine monohydrochloride (189 mg, 0.46 mmol) in benzene (2 mL) were added sequentially N,N-diisopropylethylamine (0.26 mL, 1.5 mmol), 4-dimethylaminopyridine (20 mg), and azepane-1-carbonyl chloride (0.13 mL, 0.78 mmol) under nitrogen atmosphere. The resulting reaction mixture was refluxed for 16 hours, then cooled to ambient temperature. The reaction mixture was filtered to remove the white solid formed during the reaction; the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc (25 mL) and washed successively with saturated aqueous NaHCO3 solution (25 mL), brine (2×25 mL), and dried over Na2SO4. The solution was concentrated in vacuo affording a slightly amber colored oil. The crude product was purified first by flash chromatography (50% EtOAc in hexanes), then by preparative plate (50% EtOAc in hexanes) affording 46.6 mg (20%) of the pure titled compound as a clear oil. APCI-MS m/z 513.3 (MH+).
Reaction SMILES: Cl.C(O[C:7]([N:9]1[CH2:30][CH2:29][CH2:28][C@H:10]1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][C@H:14]1[CH:18]([OH:27])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:12])=[O:8])(C)(C)C.Cl.[C:32]1([CH2:38][C@H:39]([N:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)C(O)=O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[OH:27][CH:18]([C@@H:14]1[CH2:15][CH2:16][CH2:17][N:13]1[C:11](=[O:12])[C@@H:10]1[CH2:28][CH2:29][CH2:30][N:9]1[C:7](=[O:8])[C@@H:39]([N:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1)[CH2:38][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)[C@H](Cc1ccccc1)N1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)COc1ccccc1
Agent: Cl
Product: O=C([C@H](Cc1ccccc1)N1CCCCC1)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)COc1ccccc1
Yield: 84.9 %

Procedure:
The residue obtained by treating, with 4N hydrochloric acid, (2S)-1-[N-(tert-butoxycarbonyl)-L-prolyl]-2-(1-hydroxy-2-phenoxyethyl)pyrrolidine (751 mg) prepared in Example 46-C) was subjected to condensation with (2S)-3-phenyl-2-(1-piperidinyl)propionic acid hydrochloride (500 mg) in the same manner as in Example 48-B) to give 818 mg of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N+:17]([O-])=O)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.CCOC(C)=O.[Pd]>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc2c(cnn2Cc2ccccc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc2c(cnn2Cc2ccccc2)c1
Reaction time: 1.2 h

Procedure:
To 906.4 mg (3.58 mmol) of 1-benzyl-5-nitro-1H-indazole (Step 1) in 20 mL of MeOH and 5 mL of EtOAc at RT was added a slurry of 150 mg of 10% Pd—C in 5 mL of MeOH. The resulting slurry was then stirred under a balloon of H2 for 1.2 h, filtered through Celite®, and rinsed with MeOH and EtOAc. Concentration of the filtrate gave (1-benzyl-1H-indazol-5-yl)amine as a pinkish solid: MS m/z=224 [M+H]+. Calc'd for C14H13N3: 223.11.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:13]([C:16]1[S:17][C:18](B(O)O)=[CH:19][CH:20]=1)([OH:15])=[O:14].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([C:18]3[S:17][C:16]([C:13]([OH:15])=[O:14])=[CH:20][CH:19]=3)[S:3][C:4]=2[CH:10]=1
Reactant: O=C(O)c1ccc(B(O)O)s1
Reactant: COc1ccc2nc(Br)sc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2nc(-c3ccc(C(=O)O)s3)sc2c1
Temperature: 120 °C
Reaction time: 2 h
Yield: 37.8 %

Procedure:
2-Bromo-6-methoxy-benzothiazole (1.22 g, 5.00 mmol), 2-carboxythiophene-5-boronic acid (860 mg, 5.00 mmol), sodium carbonate (2.65 g, 25.00 mmol) and tetrakis(triphenylphosphine)palladium (300 mg, 0.25 mmol) were dissolved in a mixture of 80 mL N,N-dimethylformamide and 80 mL water. The mixture was stirred at 120° C. under argon for 2 h. The reaction mixture was evaporated and the residue was partitioned between 100 mL of water and 100 mL of dichloromethane. A considerable amount of white solid precipitated between the layers and was filtered off and triturated with diethyl ether, affording the title compound (550 mg, 1.89 mmol, 38%) as a white powder.
Reaction SMILES: [CH2:1]([NH:3][C:4]([O:6][C@H:7]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]1)=[O:5])[CH3:2].Cl>O1CCOCC1>[CH2:1]([NH:3][C:4](=[O:5])[O:6][C@H:7]1[CH2:11][CH2:10][NH:9][CH2:8]1)[CH3:2]
Reactant: CCNC(=O)O[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: CCNC(=O)O[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73 %

Procedure:
Crude tert-butyl (5)-3-(ethylcarbamoyloxy)pyrrolidine-1-carboxylate from step 2 was treated with hydrogen chloride (461 μL of 4 M, 1.8 mmol) in dioxane. The reaction mixture was stirred for 1.5 h at room temperature. The solvent was removed under reduced pressure to obtain (S)-pyrrolidin-3-yl ethylcarbamate (88 mg, 73%). 1H NMR (400 MHz, DMSO-d6) δ 9.56-8.98 (m, 2H), 4.38 (s, 1H), 3.29-3.05 (m, 4H), 3.03-2.94 (m, 2H), 1.95-1.75 (m, 3H), 1.29 (dd, J=13.8, 6.6 Hz, 1H), 1.01 (t, J=7.2 Hz, 1H). LC/MS m/z 159.4 [M+H]+.
Reaction SMILES: [CH2:1]([NH:13][C:14](=[O:36])[C:15]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)[C:18]([O:31][CH2:32][CH2:33]O)=[C:17]([Br:35])[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(Br)(Br)(Br)[Br:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH2:1]([NH:13][C:14](=[O:36])[C:15]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=2)[C:18]([O:31][CH2:32][CH2:33][Br:38])=[C:17]([Br:35])[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCNC(=O)c1cc(Br)c(OCCO)c(-c2cccc(C(F)(F)F)c2)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCCCCCCCCCNC(=O)c1cc(Br)c(OCCBr)c(-c2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of N-dodecyl-3-bromo-5-(m-trifluoromethylphenyl)-4-(2-hydroxyethoxy)-benzamide (0.996 g, 1.74 mmol, 1 eq) in CH2Cl2 (9 mL) was added carbon tetrabromide (0.760 g, 2.29 mmol 1.3 eq) and triphenylphosphine (0.603 g, 2.29 mmol, 1.3 eq). The reaction was stirred at overnight at rt and concentrated in vacuo. The residue was purified by flash chromatography (15% EtOAc:hexane) to afford N-dodecyl-3-bromo-4-(2-bromo-ethoxy)-5-(m-trifluoromethylphenyl)-benzamide (0.951 g, 89%) as a colorless oil. . 1H NMR (CDCl3) δ 7.98 (d, 1H); 7.78-7.40 (m, 5H); 6.20 (bt, 1H); 4.52 (dd, 2H); 3.95 (dd, 2H); 3.42 (dd, 2H); 1.50 (m, 2H); 1.30 (m, 18H); 0.92 (t, 3H).
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]([CH3:14])[CH2:8][CH2:7]2)[CH3:3].C([O:17][CH:18]=[C:19]([C:25](OCC)=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21])C.[OH-].[Na+]>O>[CH3:3][N:2]([C:4]1[CH:13]=[C:12]2[C:11]3[N:10]([CH:25]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:18]2=[O:17])[CH:9]([CH3:14])[CH2:8][CH2:7][C:6]=3[CH:5]=1)[CH3:1]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CC1CCc2cc(N(C)C)ccc2N1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)c1cn2c3c(cc(N(C)C)cc3c1=O)CCC2C
Temperature: 120 °C

Procedure:
6-(N,N-Dimethylamino)-2-methyltetrahydroquinoline (25 g., 0.132 mole) is mixed with diethyl ethoxymethylenemalonate (28.4 g., 0.132 mole), and the mixture is heated at 120° C. for 3 hours. Polyphosphoric acid (200 g.) is added, and the solution is heated gradually to 120° C. with occasional stirring. The solution is maintained at 120° to 130° C. for one hour then poured into 500 ml. of water, with stirring. The solution is neutralized with 40 percent sodium hydroxide solution. The yellow product is separated by filtration and recrystallized from ethanol giving ethyl 6,7-dihydro-9-(N,N-dimethylamino)-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylate, m.p. 219°-222° C.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24]Br)[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2].[C:27]([O-:46])(=[O:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44].[Na+]>CC(C)=O.O>[CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24][O:46][C:27](=[O:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2]
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CBr
Reactant: CCCCCCCCCCCCCCCCCC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCC(=O)OCC(=O)O[C@H]1[C@@H](CC)C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21C
Yield: 57.1 %

Procedure:
To 150 ml of acetone-water (2:1) are added 1.3 g of 16β-ethyl-17β-bromoacetoxy-4-estren-3-one and 1.0 g of sodium stearate and the mixture is refluxed for 4 hours and allowed to stand at room temperature (15°-25° C.) overnight. The solvent is then distilled off under reduced pressure and the residue is extracted with 150 ml of ethyl acetate. The organic layer is separated, washed with water and saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure and the residue is dissolved in 100 ml of ethanol. To the solution is added 0.3 g of activated carbon and the insoluble material is filtered off. The solvent is distilled off to give a colorless viscous oil, which is allowed to stand at room temperature (15°-25° C.) to give 1.1 g of the above-identified compound as a solid.
Reaction SMILES: S(=O)(=O)(O)O.[N:6]1([C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14](O)=[O:15])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.B>O1CCCC1.CO>[N:6]1([C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[CH2:14][OH:15])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1
Reactant: O=C(O)c1ccccc1N1CCNCC1
Agent: B
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: C1CCOC1
Product: OCc1ccccc1N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-piperazin-1-yl-benzoic acid sulfuric acid salt (˜10 mmol) was suspended in 50 mL of tetrahydrofuran. Then 100 mL of 1.0 M borane in tetrahydrofuran (100 mmol) was added and the reaction was stirred at room temperature overnight with a bubbler attached to release pressure in the flask. The reaction mixture was diluted with 50 mL of methanol. The reduced product (470 mg) crystallized out of the mixture during evaporation.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH3:8][N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>O1CCOCC1>[CH3:8][N:9]1[CH2:14][CH2:13][N:12]([C:1](=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5])[CH2:11][CH2:10]1
Reactant: CN1CCNCC1
Reactant: O=C1CCC(=O)O1
Solvent: C1COCCO1
Product: CN1CCN(C(=O)CCC(=O)O)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1.17 g of succinic anhydride and then 1.19 cm3 of N-methylpiperazine are added to 20 cm3 of dioxane. After stirring for 18 hours at room temperature, the precipitate obtained is filtered, rinsed with a minimum of dioxane and then, successively, with twice 10 cm3 of acetone and 10 cm3 of diethyl ether. After drying under reduced pressure (2.7 kPa) at 20° C., 1.09 g of 4-(4-methylpiperazin-1-yl)-4-oxobutyric acid are obtained in the form of a white solid melting at 114° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)=[CH:6][C:5]([C:19]([N:21]=[S:22]([CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])([CH2:24][CH2:25][CH2:26][CH2:27][C:28](=[O:31])[O:29][CH3:30])=[O:23])=[O:20])=[CH:4][N:3]=1.[CH3:40][O:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([NH2:48])[CH:43]=1>CN(C1C=CN=CC=1)C.ClCCCl.CCOC(C)=O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:19]([N:21]=[S:22]([CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])([CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:29][CH3:30])=[O:31])=[O:23])=[O:20])=[CH:6][C:7]=1[C:8]#[C:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:12]([C:13]([NH:48][C:44]2[CH:45]=[CH:46][CH:47]=[C:42]([O:41][CH3:40])[CH:43]=2)=[O:15])[CH:11]=1
Reactant: COC(=O)CCCCS(=O)(CCCCC(=O)OC)=NC(=O)c1cnc(N)c(C#Cc2cccc(C(=O)O)c2)c1
Reactant: COc1cccc(N)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: COC(=O)CCCCS(=O)(CCCCC(=O)OC)=NC(=O)c1cnc(N)c(C#Cc2cccc(C(=O)Nc3cccc(OC)c3)c2)c1
Temperature: 60 °C

Procedure:
The reaction mixture of 3-{[2-amino-5-({[bis(5-methoxy-5-oxopentyl)(oxido)-sulfanylidene]amino}carbonyl)pyridin-3-yl]ethynyl}benzoic acid (56 mg, 0.1 mmol, 1.0 equiv.), m-anisidine (13.4 μL, 0.12 mmol, 1.2 equiv.), DMAP (2.5 mg, 0.02 mmol, 0.2 equiv.) and EDC (29 mg, 0.15 mmol, 1.5 equiv.) in DCE (1 mL) in a sealed vial was stirred and heated at 60° C. for 3 hours. The resulting brown solution was diluted with EtOAc, washed with sat. aq. NaHCO3, aq. NH4Cl, and brine, and finally dried with anhydrous Na2SO4. The solution was decanted, concentrated, and the oily residue was subject to a gradient column chromatography (from EtOAc-Hex 1:4 to 6:1) to yield Dimethyl 5,5′-[N-({6-amino-5-[(3-{[(3-methoxyphenyl)amino]carbonyl}phenyl)ethynyl]pyridin-3-yl}carbonyl)sulfonimidoyl]dipentanoate
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][CH:13]([C:15]([OH:17])=O)[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH:18]1[CH2:21][CH:20]([C:22]#[N:23])[CH2:19]1>>[Cl:1][C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][CH:13]([C:15]([N:18]4[CH2:21][CH:20]([C:22]#[N:23])[CH2:19]4)=[O:17])[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: N#CC1CNC1
Reactant: O=C(O)C1CCc2c(sc3ncnc(Cl)c23)C1
Product: N#CC1CN(C(=O)C2CCc3c(sc4ncnc(Cl)c34)C2)C1

Procedure:
150 mg (558 μmol) (RS)-4-chloro-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylic acid (prepared according to intermediate example 31b) were transformed in analogy to example 3 using azetidine-3-carbonitrile to give after working up and purification 72 mg (39%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])(=[O:19])=[O:18])=[CH:13][N:12]=1>C(OCC)(=O)C>[OH:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])(=[O:18])=[O:19])=[CH:13][N:12]=1
Reactant: O=S(=O)(c1ccc(/C=C/c2ccc(F)cc2O)nc1)c1ccccc1F
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc(CCc2ccc(F)cc2O)nc1)c1ccccc1F
Reaction time: 8 h
Yield: 14.2 %

Procedure:
2-[(E)-2-(2-Hydroxy-4-fluorophenyl)vinyl]-5-[(2-fluorophenyl)sulfonyl]pyridine (Example 9, 55 mg, 0.15 mmol) was dissolved in ethyl acetate (3 mL) and degassed. Palladium (10% wt. on activated carbon, 15 mg) was added and the reaction stirred under a balloon of hydrogen overnight, then under a fresh balloon for 3 days. The catalyst was removed by filtration and the solvent removed in vacuo. The residue was purified by flash column chromatography on silica eluting with 2:1 isohexane:ethyl acetate to give the title compound (8 mg, 14%). δH (400 MHz, CDCl3): 9.67 (1H, s), 9.08 (1H, s), 8.25-8.22 (1H, m), 8.11-8.07 (1H, m), 7.63-7.58 (1H, m), 7.37-7.32 (2H, m), 7.15-7.09 (1H, m), 7.05-7.00 (1H, m), 6.58-6.50 (2H, m), 3.32 (2H, t, J=5.8 Hz), 3.07 (2H, t, J=6.0 Hz); m/z (ES+) 376 [MH+].
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([OH:15])=O)=[CH:4][N:3]=1.[CH:16]12[CH2:22][CH:19]([NH:20][CH2:21]1)[CH2:18][O:17]2>>[CH:16]12[CH2:22][CH:19]([NH:20][CH2:21]1)[CH:18]([C:13]([C:5]1[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][C:7]=3[CH3:12])[C:2]([Cl:1])=[N:3][CH:4]=1)=[O:15])[O:17]2
Reactant: C1OC2CNC1C2
Reactant: Cc1cccc2c(Cl)ncc(C(=O)O)c12
Product: Cc1cccc2c(Cl)ncc(C(=O)C3OC4CNC3C4)c12

Procedure:
The title compound was prepared by using 1-chloro-5-methylisoquinolin-4-carboxylic acid (Intermediate-10) and 2-oxa-5-azabicyclo[2.2.1]heptane by following the similar procedure as described for intermediate-11a.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([NH:36]N)=[CH:28][CH:27]=1>>[N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([N:36]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)=[CH:28][CH:27]=1
Reactant: NNc1ccnc2ccccc12
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Product: O=c1ccn(-c2cccc(OC(F)(F)F)c2)nc1-c1ccnn1-c1ccnc2ccccc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and quinolin-4-yl-hydrazine according to the method described for example 91. MS: M=450.2 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([NH2:6])=[O:5].[CH:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=2)[CH2:17][CH2:16]1)([CH3:14])[CH3:13].CC1C=CC(S(O)(=O)=O)=CC=1.OS([O-])=O.[Na+]>CC(N(C)C)=O.C(Cl)Cl>[Cl:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:6][C:25]([C:24]1[CH:23]=[CH:22][C:21]([N:18]3[CH2:17][CH2:16][N:15]([CH:12]([CH3:14])[CH3:13])[CH2:20][CH2:19]3)=[CH:28][CH:27]=1)=[N:1]2
Reactant: CC(C)N1CCN(c2ccc(C=O)cc2)CC1
Reactant: NC(=O)c1c(N)cccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CC(C)N1CCN(c2ccc(-c3nc4cccc(Cl)c4c(=O)[nH]3)cc2)CC1
Temperature: 140 °C

Procedure:
A solution of 2-amino-6-chlorobenzamide (0.314 g, 1.85 mmol) and 4-(4-isopropylpiperazin-1-yl)benzaldehyde (0.430 g, 1.85 mmol) in DMA (25 mL) were treated with p-TsOH (0.035 g, 0.185 mmol) and NaHSO3 (0.212 g, 2.04 mmol), and the mixture was heated at 140° C. for 18 hours. Then, the mixture was cooled, diluted with CH2Cl2 (200 mL), and washed with saturated NaHCO3 (100 mL). The organic phase was dried over anhydrous MgSO4, filtered, concentrated, and purified by silica gel chromatography, eluting with 1:1 CH2Cl2/92:7:1 CHCl3/MeOH/concentrated NH4OH to 100% 92:7:1 CHCl3/MeOH/concentrated NH4OH to 100% 6:3:1 CHCl3/MeOH/concentrated NH4OH. The resulting solids were rechromatographed with 9:1 CH2Cl2/MeOH to afford the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 12.24 (br s, 1H), 8.11 (d, J=8.8 Hz, 2H), 7.66-7.71 (m, 1H), 7.59 (d, J=7.9 Hz, 1H), 7.42 (d, J=7.4 Hz, 1H), 7.03 (d, J=8.6 Hz, 2H), 3.28-3.34 (m, 4H), 2.64-2.73 (m, 1H), 2.55-2.59 (m, 4H), 1.01 (d, J=6.4 Hz, 6H). ESI MS m/z 383 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][C:2]1=[O:7].C(=O)(OC(C)(C)C)[O:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=O.N1C=CN=C1.C(OCC)(=O)C>C1COCC1.CN(C1C=CN=CC=1)C>[O:7]=[C:2]1[CH2:3][O:4][CH2:5][CH2:6][N:1]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:9]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: O=C1COCCN1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCOCC1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Morpholin-3-one (35 g, 346.2 mmol) was slurried in dry THF (350 ml). Tert-butoxycarbonyl tert-butyl carbonate (105.8 g, 111.4 mmol) was added, followed by DMAP (4.2 g, 34.6 mmol). The mixture began to degass rapidly over 30 minutes. The resulting orange solution was stirred at ambient temperature for 24 hrs. The mixture was then cooled in an ice bath and imidazole (23.57 g, 346.2 mmol) was added. After stirring for 30 minutes ethyl acetate (500 ml) was added. The organic phase was separated and washed with 1% (v/v) HCl (500 ml), then sat NaHCO3 (500 ml), then brine (200 ml), dried (MgSO4), filtered and concentrated. The crude was purified through a plug of silica gel, eluting with ethyl acetate. The filtrate was evaporated to give an oil. 40/60 pet ether (200 ml) was added slowly with stirring to generate a white solid. The mixture was aged for 30 minutes, cooled briefly in an ice bath and filtered, washing with 40/60 pet ether. Tert-butyl 3-oxomorpholine-4-carboxylate was obtained as a white solid which was dried under vacuum (52.7 g, 76%); 1H-NMR (CDCl3) 1.47 (9H, s), 3.68 (2H, m), 3.82 (2H, m), 4.15 (2H, s); MS ES(+) 145.8 (M+-tBu).
Reaction SMILES: [CH2:1]([SH:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([NH:25][CH:26]([CH2:31][CH:32]3[O:34][CH2:33]3)[C:27]([O:29]C)=[O:28])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1>>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:17]=[CH:18][C:19]([S:22]([NH:25][CH:26]([CH2:31][CH:32]([OH:34])[CH2:33][S:7][CH2:1][C:2]3[O:6][CH:5]=[CH:4][CH:3]=3)[C:27]([OH:29])=[O:28])(=[O:23])=[O:24])=[CH:20][CH:21]=2)=[CH:14][CH:15]=1
Reactant: SCc1ccco1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CSCc3ccco3)C(=O)O)cc2)cc1

Procedure:
Example 52 is prepared from furfuryl mercaptan and 1d using the procedure described for compound 20.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:3]=1.[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[OH:31]>ClCCl.CCCCCC>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:4]2[CH:3]=[C:2]([O:31][C:25]3[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:24]=3[F:23])[N:7]=[N:6][C:5]=2[C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)=[CH:17][CH:18]=1
Reactant: CSc1ccc(-c2nnc(Cl)cc2-c2ccc(Cl)cc2)cc1
Reactant: Oc1ccc(F)cc1F
Solvent: CCCCCC
Solvent: ClCCl
Product: CSc1ccc(-c2nnc(Oc3ccc(F)cc3F)cc2-c2ccc(Cl)cc2)cc1

Procedure:
In a similar manner as in Example 2, 6-chloro-4-(4-chlorophenyl)-3-[4-(methylthio)phenyl]pyridazine (230.0 mg, 0.662 mmol) and 2,4-difluorophenol were reacted as starting materials at 150° C. for 20 hours and post-treatment was then conducted, whereby the title compound was obtained as colorless plates (dichloromethane-hexane, 216.2 mg, 74.0%). Melting point: 163.2-164.0° C.