Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:13])=[N:4][C:5]([C:9]([Cl:12])([Cl:11])[Cl:10])=[N:6][C:7]=1[CH3:8].C(N(CC)CC)C.[CH3:21][N:22]([CH3:26])[C:23](Cl)=[O:24]>C(#N)C>[CH3:21][N:22]([CH3:26])[C:23](=[O:24])[O:13][C:3]1[C:2]([Cl:1])=[C:7]([CH3:8])[N:6]=[C:5]([C:9]([Cl:10])([Cl:11])[Cl:12])[N:4]=1
Reactant: CN(C)C(=O)Cl
Reactant: Cc1nc(C(Cl)(Cl)Cl)nc(O)c1Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1nc(C(Cl)(Cl)Cl)nc(OC(=O)N(C)C)c1Cl
Yield: 20 %

Procedure:
A mixture of 3.9 g (0.015 mole) 5-chloro-4-hydroxy-6-methyl-2-trichloromethylpyrimidine, 1.6 g (0.015 mole) triethylamine, 1.7 g (0.015 mole) dimethylcarbamoyl chloride, and 80 ml acetonitrile was refluxed 3 days. Rotary evaporation to concentrate the solution yielded a precipitate that was removed by filtration. Rotary evaportation of the filtrate gave a residue which was triturated with petroleum ether to give 1.0 g (20% yield; mp 87°-88° C.) of product. The structure was confirmed via infrared and elemental analysis.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])=[CH:16][CH:15]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].[NH2:31][C:32]1[CH:33]=[CH:34][C:35]([O:39][CH3:40])=[C:36]([OH:38])[CH:37]=1>C1COCC1>[OH:38][C:36]1[CH:37]=[C:32]([NH:31][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]5[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=5)=[O:22])=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:30])[CH:33]=[CH:34][C:35]=1[O:39][CH3:40]
Reactant: Cc1cc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)cc2)n(C)n1
Reactant: COc1ccc(N)cc1O
Solvent: C1CCOC1
Product: COc1ccc(NC=C2C(=O)Nc3cc(C(=O)c4ccc(NC(=O)c5cc(C)nn5C)cc4)ccc32)cc1O
Temperature: 65 °C
Reaction time: 24 h

Procedure:
A small screw cap test tube was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 25, 100 mg, 0.240 mmol) and THF (1.5 mL). To the resulting solution was added 5-amino-2-methoxyphenol (39 mg, 0.274 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. The solid precipitate that formed was filtered and washed with ˜1 mL of ice cold THF yielding 61% (34 mg, 0.065 mmol) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[O:19][C:20](=[O:22])[CH3:21])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([OH:15])=[O:14])[CH:8]=1)=[O:6].Cl[C:24]1C=CC=CC=1O>>[CH3:24][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[O:19][C:20](=[O:22])[CH3:21])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([OH:15])=[O:14])[CH:8]=1)=[O:6]
Reactant: CC(=O)Oc1ccc(C(=O)c2cccc(C(=O)O)c2)cc1Cl
Reactant: Oc1ccccc1Cl
Product: CC(=O)Oc1ccc(C(=O)c2cccc(C(=O)O)c2)cc1C

Procedure:
The 3-chloro-4-acetoxy-3'-carboxybenzophenone may be obtained by similar reactions using o-chlorophenol in place of o-cresol.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:21]([O:23]N1C(=O)CCC1=O)=O)[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:7])([CH3:4])[CH3:3].[NH:31](C(OC(C)(C)C)=O)[C@H:32]([C:37]([NH:39][C@H:40]([C:45]([NH:47][NH:48][C:49]([O:51][CH2:52][C:53]([Cl:56])([Cl:55])[Cl:54])=[O:50])=[O:46])[CH2:41][CH2:42][S:43][CH3:44])=[O:38])[C@H:33]([CH2:35][CH3:36])[CH3:34]>C1COCC1.C(OCC)(=O)C>[NH:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[C@H:9]([C:21]([NH:31][C@H:32]([C:37]([NH:39][C@H:40]([C:45]([NH:47][NH:48][C:49]([O:51][CH2:52][C:53]([Cl:54])([Cl:55])[Cl:56])=[O:50])=[O:46])[CH2:41][CH2:42][S:43][CH3:44])=[O:38])[C@H:33]([CH2:35][CH3:36])[CH3:34])=[O:23])[CH2:10][C:11](=[O:12])[O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCSC)C(=O)NNC(=O)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC[C@H](C)[C@H](NC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCSC)C(=O)NNC(=O)OCC(Cl)(Cl)Cl
Reaction time: 4 h

Procedure:
The preceding 30 g of oil in solution in 250 ml of THF are treated with 6.4 ml (50 mM) of NEM and 18.9 (45 mM) of Boc-Asp(OBzl)O Su. The apparent pH is adjusted between 6 and 7 by successive additions of NEM. After 4 hours, the product is isolated by evaporation of the THF, take-up in 400 ml of ethyl acetate followed by the same washings as the preceding homologue (3). The residue after drying and evaporation (36.5 g) is purified by chromatography over a column of silica with dichloromethane as solvent containing from 0 to 1.5% of methanol. 25 g (66%) of product presenting an NMR spectrum in accordance with the expected structure are thus obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12](Cl)=[C:11](Cl)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl.S([O-])([O-])(=O)=S.[Na+].[Na+].[IH:27]>>[CH2:1]([N:8]1[C:13](=[O:14])[CH:12]=[C:11]([I:27])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c(Cl)c(Cl)cnn1Cc1ccccc1
Reactant: I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: O=c1cc(I)cnn1Cc1ccccc1
Temperature: 115 °C

Procedure:
2-Benzyl-4,5-dichloropyridazin-3(2H)-one (32.3 g, 127 mmol) was dissolved in hydriodic acid (223 mL) and the mixture was refluxed at 115° C. overnight. The mixture was poured into dichloromethane and 30% sodium thiosulphate (250 mL), and extracted with dichloromethane (3×250 mL). The combined organics were washed with 30% sodium thiosulphate several times (total 1 L), dried (sodium sulfate), and concentrated. Dichloromethane was added to the residue and the precipitate was collected by filtration to afford the title compound. 1H NMR (500 MHz, CD3SOCD3) δ 8.17 (s, 1H); 7.61 (s, 1H); 7.23-7.33 (m, 5H); 5.17 (s, 2H). LRMS (APCI) calc'd for (C11H10IN2O) [M+H]+, 313.0. found 313.0.
Reaction SMILES: [Cl:1][C:2](Cl)([P:10]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])=[O:11])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].S([O-])([O-])=O.[Na+].[Na+]>C(O)C.O>[Cl:1][CH:2]([P:10]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])=[O:11])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: CCOP(=O)(OCC)C(Cl)(Cl)C(=O)OC(C)(C)C
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOP(=O)(OCC)C(Cl)C(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 100 %

Procedure:
The title compound of Step B (18.4 g, 0.0572 mol) was dissolved in ethanol (140 mL) and cooled to 0° C. A solution of sodium sulfite (14.4 g, 0.1144 mol) in H2O (63 mL) was added with stirring such that the internal temperature remained below 14° C. The cooling bath was removed and the mixture was stirred at room temperature for 30 min. The reaction mixture was extracted five times with chloroform, and the combined organic phase was dried (MgSO4), filtered and concentrated to afford 16.4 g of the title compound of Step C as a clear oil. 1H NMR (300 MHz, CDCl3): δ 4.43 (d,1H, J=15.9 Hz), 4.30-4.24 (m,4H), 1.52 (s,9H), 1.38 (t,6H, J=6.9 Hz).
Reaction SMILES: C(OC(=O)[N:7]([C:27]1[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=1)[C:8]1[N:12]([CH3:13])[C:11]2[CH:14]=[CH:15][C:16]([N:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([Cl:26])[N:21]=3)[CH3:19])=[CH:17][C:10]=2[N:9]=1)(C)(C)C.[NH2:38][C:39]1[CH:40]=[CH:41][C:42]([CH3:49])=[C:43]([S:45]([NH2:48])(=[O:47])=[O:46])[CH:44]=1>>[ClH:26].[C:33]([C:30]1[CH:31]=[CH:32][C:27]([NH:7][C:8]2[N:12]([CH3:13])[C:11]3[CH:14]=[CH:15][C:16]([N:18]([CH3:19])[C:20]4[CH:25]=[CH:24][N:23]=[C:22]([NH:38][C:39]5[CH:40]=[CH:41][C:42]([CH3:49])=[C:43]([S:45]([NH2:48])(=[O:46])=[O:47])[CH:44]=5)[N:21]=4)=[CH:17][C:10]=3[N:9]=2)=[CH:28][CH:29]=1)([CH3:36])([CH3:34])[CH3:35]
Reactant: Cc1ccc(N)cc1S(N)(=O)=O
Reactant: CN(c1ccc2c(c1)nc(N(C(=O)OC(C)(C)C)c1ccc(C(C)(C)C)cc1)n2C)c1ccnc(Cl)n1
Product: Cc1ccc(Nc2nccc(N(C)c3ccc4c(c3)nc(Nc3ccc(C(C)(C)C)cc3)n4C)n2)cc1S(N)(=O)=O
Product: Cl
Yield: 54.4 %

Procedure:
The title compound was prepared following the procedure of example 5 using (4-tert-Butyl-phenyl)-{5-[(2-chloro-pyrimidin-4-yl)-methyl-amino]-1-methyl-1H-benzoimidazol-2-yl}-carbamic acid tert-butyl ester (104 mg, 0.20 mmol) and 5-amino-2-methyl-benzenesulfonamide (37 mg, 0.20 mmol) to give the desired product as a white solid (66 mg, 48%). 1H NMR (300 MHz, d6-DMSO+NaHCO3) δ 9.35 (s, 1H), 8.96 (s, 1H), 8.62 (s, 1H), 7.71-7.78 (m, 4H), 7.32-7.38 (M, 3H), 7.27 (s, 1H), 7.17-7.23 (M, 3H), 6.96 (d, J=8.4 Hz, 1H), 5.63 (d, J=6.0 Hz, 1H), 3.74 (s, 3H), 3.48 (s, 3H), 2.50 (s, 3H), 1.28 (s, 9H). MS (ESI) m/z=571 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])O.[Na+].Br[CH:15]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:16](Cl)=[O:17]>C(OCC)(=O)C.O.C1(C)C=CC=CC=1>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([CH:15]2[C:16](=[O:17])[NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[O:8]2)=[CH:20][CH:21]=1
Reactant: O=C(Cl)C(Br)c1ccc(Cl)cc1
Reactant: Nc1ccccc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1Nc2ccccc2OC1c1ccc(Cl)cc1
Yield: 76.9 %

Procedure:
To a solution of 2-aminophenol (13.5 g) in ethyl acetate (150 ml) is added a solution of sodium hydrogen carbonate (15 g) in water (300 ml), and to the mixture is added dropwise a solution of α -bromo-4-chlorophenylacetyl chloride (32.2 g) in toluene with vigorous stirring under ice cooling. After the mixture is stirred at room temperature for one hour, the solvent in the organic layer is distilled off and the residue is dissolved in acetone. To the solution is added potassium carbonate (20 g), and the mixture is stirred at room temperature overnight. The solvent is distilled off and to the residue is added water. The mixture is extracted with ethyl acetate. The ethyl acetate layer is washed, dried and distilled to remove the solvent, and the residue is recrystallized from ethyl acetate-n-hexane to give 2-(4-chlorophenyl)-3-oxo 3,4-dihyro-2H-1,4-benzoxazine (24.0 g) as crystals. M.p. 180.5°-181.5° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C=O)C.[Cl:17][C:18]1[CH:19]=[C:20]([C:24]2[C:29]([NH2:30])=[C:28]([CH3:31])[N:27]=[C:26]([S:32][CH3:33])[N:25]=2)[CH:21]=[CH:22][CH:23]=1.N1C=CC=CC=1>S(Cl)(Cl)=O>[Cl:17][C:18]1[CH:19]=[C:20]([C:24]2[C:29]([NH:30][C:9](=[O:11])[CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:28]([CH3:31])[N:27]=[C:26]([S:32][CH3:33])[N:25]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: O=C(O)CCc1ccccc1
Reactant: CSc1nc(C)c(N)c(-c2cccc(Cl)c2)n1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CSc1nc(C)c(NC(=O)CCc2ccccc2)c(-c2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
51.4 mg (0.342 mmol) of 3-phenylpropionic acid was dissolved in 1 ml of thionyl chloride. A catalytic amount of DMF was added and stirred at room temperature for 3 hours. After the solvent was evaporated under reduced pressure, 45.4 mg (0.171 mmol) of 4-(3-chlorophenyl)-6-methyl-2-(methylthio)-5-pyrimidinamine and 1 ml of pyridine were added and stirred at 50° C. overnight. After the solvent was evaporated under reduced pressure, the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=10/1 to 1/1) to obtain the title compound.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([F:7])=[C:4]([F:6])[F:5].[S:10](=[O:13])(=[O:12])=[O:11]>>[F:1][C:2]([F:9])([F:8])[C:3]1([F:7])[C:4]([F:6])([F:5])[O:13][S:10]1(=[O:12])=[O:11]
Reactant: O=S(=O)=O
Reactant: FC(F)=C(F)C(F)(F)F
Product: O=S1(=O)OC(F)(F)C1(F)C(F)(F)F
Reaction time: 96 h

Procedure:
A mixture of commercial liquid sulfur trioxide (10 ml) and hexafluoropropene (45 g, 0.30 mol) was sealed in a Carius tube at liquid nitrogen temperature, mixed well at 25° C., allowed to stand for 4 days at 25° C., and finally heated in a steam bath for 6 hours. From two such tubes, there was obtained by distillation, 3-(trifluoromethyl)-3,4,4-trifluoro-1-oxa-2-thiacyclobutane 2,2-dioxide (2-hydroxy-1-trifluoromethyl-1,2,2-trifluoroethane sulfonic acid sultone, D. C. England, M. A. Dietrich and R. V. Lindsey, Jr., J. Amer. Chem. Soc., 82, 6181 (1960)) (25 g, 22%) bp 44° C., and pentafluoro-2-propenyl fluorosulfate (hereinafter referred to as perfluoroallyl fluorosulfate) (73 g, 63%), bp 58°-60° C.
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]([C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]([NH:18][C:19]2[C:23]3[CH:24]=[C:25]([C:28]([N:30]([CH3:32])[CH3:31])=[O:29])[CH:26]=[CH:27][C:22]=3[O:21][C:20]=2[C:33]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][N:37]=2)=[O:34])=[O:17])[CH2:12][CH2:11]1)[CH3:9])=[O:7])(=O)C.[OH-].[Na+].Cl>O1CCCC1.CO.C(Cl)(Cl)Cl>[CH3:31][N:30]([CH3:32])[C:28]([C:25]1[CH:26]=[CH:27][C:22]2[O:21][C:20]([C:33]([NH:35][C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][N:37]=3)=[O:34])=[C:19]([NH:18][C:16]([C@H:13]3[CH2:14][CH2:15][C@H:10]([N:8]([C:6](=[O:7])[CH2:5][OH:4])[CH3:9])[CH2:11][CH2:12]3)=[O:17])[C:23]=2[CH:24]=1)=[O:29]
Reactant: CC(=O)OCC(=O)N(C)[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccc(C(=O)N(C)C)cc23)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CN(C)C(=O)c1ccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](N(C)C(=O)CO)CC3)c2c1
Reaction time: 4 h

Procedure:
Trans-3-[4-(N-acetoxyacetyl-N-methylamino)cyclohexylcarbonylamino]-5-dimethylaminocarbonyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (91 mg) obtained in Example 398 is dissolved in tetrahydrofuran/methanol (2:3, 5 ml), and thereto is added at room temperature 2N aqueous sodium hydroxide solution (300 μl), and the mixture is stirred for 4 hours. The reaction solution is acidified with diluted hydrochloric acid, and the mixture is diluted with chloroform. The mixture is dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The resulting residue is purified by recycle HPLC to give the title compound (44 mg).
Reaction SMILES: [CH:1]([CH:3]=[CH2:4])=O.[CH3:5][CH:6](N1CCOCC1)[CH:7]=[CH:8][CH3:9].[CH3:16][NH2:17]>[Pd]>[CH3:16][NH:17][C:4]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:3]=1[CH3:1]
Reactant: CN
Reactant: CC=CC(C)N1CCOCC1
Reactant: C=CC=O
Agent: [Pd]
Product: CNc1c(C)cccc1C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
14.0 g (0.25 mol) of acrolein is added dropwise at 25° to 30° C. to 23.3 g (0.15 mol) of N-(3-penten-2-yl)-morpholine. The mixture obtained is stirred for 15 hours at 25° C. and subsequently, for further 15 hours at 50° C. Then the mixture is transferred into an autoclave and after addition of 400 ml of a 40% by weight aqueous solution of methylamine and 10.0 g of palladium coal (5%), the whole is heated under a nitrogen pressure of 50 bar for 5 hours at 280° to 290° C. Subsequently the catalyst is separated off by filtration and washed with ether. The filtrate is several times extracted with ether, the combined extracts are dried over magnesium sulphate and the ether is distilled off. Then water is added to the residue and the whole is acidified by addition of hydrochloric acid. The acid solution obtained is extracted with ether and the extract is discarded. Now sodium bicarbonate is added to the acid solution until the mixture shows alkaline reaction and the whole is again extracted with ether. The extract is dried over sodium sulphate and the ether is distilled off. N-methyl-2,6-dimethylaniline is obtained by distillation of the residue at 0.1 Torr.
Reaction SMILES: CS(Cl)(=O)=O.[Cl:6][C:7]1[CH:30]=[CH:29][C:10]([CH2:11][NH:12][C:13]([C:15]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[C:21](CO)[CH:22]=3)[N:17]([CH3:28])[CH:16]=2)=[O:14])=[CH:9][CH:8]=1.N1C(C)=CC(C)=C[C:32]=1C.[CH3:40][NH:41][CH2:42][CH2:43][OH:44]>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][NH:12][C:13]([C:15]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([CH2:40][N:41]([CH2:42][CH2:43][OH:44])[CH3:32])[CH:22]=3)[N:17]([CH3:28])[CH:16]=2)=[O:14])=[CH:29][CH:30]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CO)ccc21
Reactant: Cc1cc(C)nc(C)c1
Reactant: CNCCO
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Product: CN(CCO)Cc1ccc2c(c1)c(=O)c(C(=O)NCc1ccc(Cl)cc1)cn2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
Methanesulfonyl chloride (0.065 mL) is added to a cold (0° C.) solution of N-(4-chlorobenzyl)-6-(hydroxymethyl)-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide (0.27 g) from Preparation No. 10, DMAP (0.017 g), and 2,4,6-collidine (0.12 mL) in anhydrous DMF (14 mL). The mixture is stirred at room temperature overnight and 2-(methylamino)ethanol (0.61 mL) is added. The reaction mixture is stirred at room temperature for 2 h, poured into water, and extracted with CH2Cl2 (3×). The organic layers are combined, dried (Na2SO4), filtered, and concentrated in vacuo. The residue is dissolved in CH2Cl2/MeOH and adsorbed onto silica. Purification by chromatography (eluent CH2Cl2 (1 L), 1.5% MeOH/CH2Cl2 (1 L), 2.5% MeOH/CH2Cl2 (1 L), 3.5% MeOH/CH2Cl2 (1 L), 5% MeOH/CH2Cl2 (1 L), 6% MeOH/CH2Cl2 (1 L)) affords the product as a clear residue. The residue is crystallized by addition of CH2Cl2/hexanes followed by removal of the solvents in vacuo to give 0.21 g (69%) of the title compound as a white solid.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:32])[C:6]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22][C:23]3[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)=[CH:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.CN(C=O)C.[CH:38]1[CH:39]=[CH:40][C:41]2[N:46](O)N=[N:44][C:42]=2[CH:43]=1.C1(N)C=CC=CC=1N>O>[NH2:44][C:42]1[CH:43]=[CH:38][CH:39]=[CH:40][C:41]=1[NH:46][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][C:23]([CH2:22][NH:21][C:18]2[CH:17]=[CH:16][C:15]([C:6]([C:5]([NH:4][CH:1]3[CH2:3][CH2:2]3)=[O:32])=[CH:7][C:8]3[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=3)=[CH:20][CH:19]=2)=[CH:24][CH:25]=1
Reactant: O=C(NC1CC1)C(=Cc1ccc(F)cc1)c1ccc(NCc2ccc(C(=O)O)cc2)cc1
Reactant: On1nnc2ccccc21
Agent: Nc1ccccc1N
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccccc1NC(=O)c1ccc(CNc2ccc(C(=Cc3ccc(F)cc3)C(=O)NC3CC3)cc2)cc1
Reaction time: 4 h
Yield: 7.7 %

Procedure:
To a suspension of 4-((4-(3-(cyclopropylamino)-1-(4-fluorophenyl)-3-oxoprop-1-en-2-yl)phenylamino)methyl)benzoic acid (0.215 g, 0.5 mmol) in DMF (3 mL) EDCl (0.23 g, 1.1 mmol), HOBt (0.08 g, 0.55 mmol), o-phenylene diamine (0.086 g, 0.7 mmol), were added followed by TEA (0.2 mL, 1.5 mmol). The reaction mixture was stirred for 4 hours after which the mixture was added to cold water (100 mL) and kept at 0° C. for 1 hour. The pale yellow solid formed was filtered and washed with ethyl acetate (15 mL) dried under vacuum to afford the title compound (0.020 g, 8% yield). 1H NMR (DMSO-d6) δ (ppm): 0.46-0.47 (2H, m, —CH2), 0.60-0.62 (2H, m, —CH2), 2.70-2.71 (1H, m, —CH), 4.36-4.37 (2H, d, —CH2), 4.88 (2H, s, —NH2), 6.55-6.61 (4H, m, Ar—H and —NH), 6.76-6.82 (3H, m, Ar—H), 6.93-6.94 (1H, t, Ar—H), 6.98-7.04 (3H, m, Ar—H), 7.06-7.17 (3H, m, Ar—H), 7.48-7.50 (3H, m, Ar—H and ═CH), 7.93-7.95 (2H, d, Ar—H and —NH), 9.61 (1H, s, —NH), MS m/z: 521.1 (M++1).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C@H:11]([C:13]3[C:14]([F:24])=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[CH3:25][C@H:26]1[NH:31][CH2:30][CH2:29][NH:28][C:27]1=[O:32]>>[F:24][C:14]1[C:13]([C@@H:11]([C:8]2[N:6]3[N:7]=[C:2]([N:31]4[CH2:30][CH2:29][NH:28][C:27](=[O:32])[C@H:26]4[CH3:25])[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH3:12])=[C:22]([F:23])[CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[N:19]2
Reactant: C[C@H]1NCCNC1=O
Reactant: C[C@@H](c1c(F)cc2ncccc2c1F)c1cnc2ccc(Cl)nn12
Product: C[C@@H](c1c(F)cc2ncccc2c1F)c1cnc2ccc(N3CCNC(=O)[C@H]3C)nn12

Procedure:
The title compound was prepared in analogy to Example 18, using enantiomerically pure 6-[(S)-1-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-ethyl]-5,7-difluoro-quinoline (Intermediate B, 50 mg, 0.145 mmol) and (R)-3-methyl-piperazin-2-one (33.1 mg, 0.29 mmol) instead of the racemates and flash chromatography for the purification. 2:1 mixture of title compound with compound of Example 60 (tR 3.59 min (conditions 5), tR 8.66 and 10.19 min (conditions 3, 90% n-hexane and 10% isopropanol), MH+=423.1, 1H-NMR in DMSO-d6: 8.91 (m, 1H); 8.42 (d, 1H); 7.90 (s, 1H); 7.80 (d, 1H); 7.69-7.50 (m, 3H); 7.05 (d, 1H); 4.93 (m, 1H); 4.50 and 4.28 (q, 1H); 3.87 (m, 1H); 3.43-2.89 (m, 3H); 1.84 (m, 3H); 1.30 and 0.93 (d, 3H)).
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[C:26]([C:28]1[C:29]([CH3:34])=[N:30][CH:31]=[CH:32][CH:33]=1)=[O:27]>>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][S:14]([C:11]2[CH:12]=[CH:13][C:8]([C:2]3([CH3:1])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]3)=[CH:9][CH:10]=2)(=[O:16])=[O:15])=[C:20]([C:26]([C:28]2[C:29]([CH3:34])=[N:30][CH:31]=[CH:32][CH:33]=2)=[O:27])[CH:21]=1
Reactant: CC1(c2ccc(S(=O)(=O)Cl)cc2)CCOCC1
Reactant: Cc1ncccc1C(=O)c1cc(Cl)ccc1N
Product: Cc1ncccc1C(=O)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(C2(C)CCOCC2)cc1

Procedure:
The title compound was prepared by the reacting 4-(4-methyl-tetrahydro-pyran-4-yl)-benzenesulfonyl chloride with (2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-3-yl)-methanone according to the general procedure described for the preparation of (N-aryl-benzenesulfonamides. MS: m/z 486 (M++1).
Reaction SMILES: [C@@H:1]1([N:10]2[C:20]3[N:19]=[C:17]([NH2:18])[NH:16][C:14](=[O:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[C:21](Cl)(=[O:33])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>CN(C1C=CN=CC=1)C.CN(C)C=O>[C:21]([C@@:1]1([N:10]2[C:20]3[N:19]=[C:17]([NH2:18])[NH:16][C:14](=[O:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3])(=[O:33])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CCCCCCCCCCCC(=O)[C@@]1(n2cnc3c(=O)[nH]c(N)nc32)O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a 100 mL flask was added guanosine (2.0 g, 7.06 mmol) and N,N-dimethyl-4-aminopyridine (0.017 g, 0.14 mmol). N,N-dimethylformamide (25 mL) was added via cannula with stirring, the flask was purged with argon gas and pyridine (14 mL) was added via cannula. The slurry was allowed to cool 10 min. in an ice/NaCl bath and lauroyl chloride (2.12 mL, 9.2 mmol) was added dropwise. The mixture was allowed to stir while it slowly warmed to 25° C. After 18 h, the mixture was poured into 300 mL of ice-cold 0.1 M sodium bicarbonate solution giving a white solid which was isolated by suction filtration, washed with 3×100 mL hot water, air dried, and recrystallized from hot methanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([CH2:13]Br)[CH:7]=[CH:6]2.[CH2:15]([NH2:18])[CH2:16][NH2:17].[C:19](=[O:22])([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([CH2:13][N:17]([CH2:13][C:8]1[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:22][CH3:19])[CH:4]=3)[N:9]=1)[CH2:16][CH2:15][N:18]([CH2:13][C:8]1[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=1)[CH2:13][C:8]1[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=1)[CH:7]=[CH:6]2
Reactant: COc1ccc2nc(CBr)ccc2c1
Reactant: NCCN
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc2nc(CN(CCN(Cc3ccc4cc(OC)ccc4n3)Cc3ccc4cc(OC)ccc4n3)Cc3ccc4cc(OC)ccc4n3)ccc2c1
Yield: 33.3 %

Procedure:
A mixture of 6-methoxy-2-bromomethylquinoline (0.076 g, 0.302 mmol), ethylenediamine (5 μL, 0.0755 mmol), potassium carbonate (0.125 g, 0.904 mmol) and acetonitrile (6 mL) was refluxed by heating for 14 hours. The solvent was evaporated under reduced pressure, and then the residue was separated by phase separation using chloroform and water. The organic layer was dried, and then the solvent was evaporated. The residue was washed with ethanol to obtain the objective compound as white powder (yield: 18.7 mg, 33%).