Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH:10]1[CH:15]=[CH:14][C:13]([O-:16])=[CH:12][CH:11]=1.[Na+]>>[O:16]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[C:13]1[CH:14]=[CH:15][CH:10]=[CH:11][CH:12]=1
Reactant: [O-]c1ccccc1
Reactant: CCCCCCCCCl
Agent: [Na+]
Product: CCCCCCCCOc1ccccc1
Temperature: 140 °C
Yield: 96 %

Procedure:
Into a 100 ml reactor equipped with a reflux condenser and a magnetic stirrer, 17 g 1-chlorooctane, 1.16 g anhydrous sodium phenate and 0.31 g of the product prepared according to Example 1, were introduced. The mixture was heated to 140° C. for 3 hours, 30 minutes. 1-Phenoxyoctane was obtained in a yield of 96%. The mixture was filtered after cooling and the precipitate washed with water and methanol.
Reaction SMILES: [F:1][C:2]1[C:14]([F:15])=[C:13]([F:16])[CH:12]=[CH:11][C:3]=1[NH:4][CH:5]([CH3:10])[C:6]([O:8]C)=[O:7].P([O-])([O-])([O-])=O.Cl>C(Cl)Cl>[F:1][C:2]1[C:14]([F:15])=[C:13]([F:16])[CH:12]=[CH:11][C:3]=1[NH:4][C@@H:5]([CH3:10])[C:6]([OH:8])=[O:7]
Reactant: COC(=O)C(C)Nc1ccc(F)c(F)c1F
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Product: C[C@H](Nc1ccc(F)c(F)c1F)C(=O)O
Temperature: 30 °C

Procedure:
Methyl 2-(2,3,4-trifluoroanilino)propionate (2.0 g) was suspended in a 0.1 M phosphate buffer solution (pH 6.5; 400 ml). After adding Protease N (manufactured by Amano Seiyaku, originating in a bacterium belonging to the genus Bacillus; 0.4 g), the mixture was gently stirred. The mixture was further stirred for 14 hours while maintaining at 30° C. After adding methylene chloride, the liquid reaction mixture was filtered through celite to eliminate denatured protein and then separated. The organic layer was washed with a 5% aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. Next, the solvent was evaporated under reduced pressure to thereby give methyl (2R)-2-(2,3,4-trifluoroanilino)propionate (0.94 g). The optical purity of this product was 98% ee. On the other hand, the all aqueous layers obtained by the separation were combined and adjusted to pH 2 with 10% hydrochloric acid followed by extraction with IPE. The organic layer was dried over anhydrous magnesium sulfate and evaporated. Thus, the title compound was obtained as a crude product (0.96 g). The optical purity of this product was 96% ee. Further, the crude product was recrystallized from a solvent mixture of isopropyl ether with hexane. Thus, the title compound of 100% ee was obtained. The 1H-NMR and IR spectral data of this product was identical with those of the compound obtained in Example 28.
Reaction SMILES: C([O-])(=O)C.[Na+].[Cl:6][CH:7]([CH3:10])[CH2:8][OH:9].[CH2:11]=[C:12]1[O:16][C:14](=[O:15])[CH2:13]1>>[C:14]([O:9][CH2:8][CH:7]([Cl:6])[CH3:10])(=[O:15])[CH2:13][C:12]([CH3:11])=[O:16]
Reactant: C=C1CC(=O)O1
Reactant: CC(Cl)CO
Agent: CC(=O)[O-]
Agent: [Na+]
Product: CC(=O)CC(=O)OCC(C)Cl
Yield: 69.2 %

Procedure:
0.7 g of sodium acetate was added to 7.5 g of 2-chloropropanol, to which 7.4 g of diketene was added dropwise with stirring while the reaction temperature was maintained at 40°-50° C. The reaction mixture was stirred at room temperature for an additional 2 hours and then worked up in the manner described in Referential Example 4. The resulting crude product was purified by distillation to obtain 9.8 g of 2-chloropropyl acetoacetate.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[C:19](Cl)(=[O:22])[CH2:20][CH3:21]>C1COCC1>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:19](=[O:22])[CH2:20][CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Reactant: CCC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 93.9 %

Procedure:
To a solution of (R)-4-benzyl-oxazolidin-2-one (3.0 g, 16.9 mmol) in THF (100 mL) at −78° C. was added n-BuLi (2.5 M hexanes, 7.1 mL, 17.8 mmol) in rapid drops via syringe. The solution was stirred for 20 min at −78° C. Propionyl chloride (1.6 mL, 18.4 mmol) was added rapidly via syringe. The reaction solution was allowed to warm slowly to rt overnight then was quenched by the addition of satd. aq. NH4Cl. The mixture was concentrated, diluted with water, and extracted with DCM (3×). The combined organic layers were dried (Na2SO4) and concentrated to give the crude product, which was purified by flash chromatography (EtOAc/hexanes) to afford the title compound as a white solid (3.70 g, 94%). 1H NMR (500 MHz, CDCl3): 7.36-7.31 (m, 2H), 7.30-7.25 (m, 1H), 7.23-7.19 (m, 2H), 4.71-4.64 (m, 1H), 4.20 (dd, J=9.1, 7.5, 1H), 4.17 (dd, J=9.1, 3.1, 1H), 3.31 (dd, J=13.4, 3.3, 1H), 2.99 (dq, J=17.9, 7.4, 1H), 2.93 (dq, J=17.9, 7.3, 1H), 2.77 (dd, J=13.4, 9.6, 1H), 1.21 (t, J=7.3, 3H).
Reaction SMILES: [C:1]1([C:7]2([C:11]#[N:12])[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:1]1([C:7]2([CH2:11][NH2:12])[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CC1(c2ccccc2)CCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC1(c2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
To a solution of 1-phenylcyclobutanecarbonitrile (0.96 g, 6.09 mmol) in anhydrous tetrahydrofuran (40 mL) was added a 1 N solution of lithium aluminum hydride (LAH) in tetrahydrofuran (12 mL, 12 mmol). After stirring 2 h at ambient temperature, the excess LAH was slowly quenched with water (10 mL) and diluted with additional tetrahydrofuran (20 mL). This was then reacted with 0.25 N aqueous NaOH (5 mL) at ambient temperature for 20 h and filtered, the filtrate concentrated in vacuo, and the residue purified by flash coliumn chromatography (10% methanol in dichloromethane, saturated with ammonia gas) giving the title compound as a yellow oil (0.52 g, 53%). 1H NMR (300 MHz, CDCl3) δ 7.32 (m, 2H), 7.19 (m, 1H), 7.10 (m, 2H), 2.93 (s, 2H), 2.38-2.26 (m, 2H), 2.18-2.01 (m, 3H), 1.92-1.82 (m, 1H), 1.14 (bs, 2H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.Cl.O1CCOCC1.[CH2:21]([NH:28][C:29]1[C:34]([C:35]([NH2:37])=[O:36])=[CH:33][N:32]=[C:31](Cl)[N:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN1C(=O)CCC1>[CH2:21]([NH:28][C:29]1[C:34]([C:35]([NH2:37])=[O:36])=[CH:33][N:32]=[C:31]([NH:11][C:10]2[CH:12]=[CH:13][C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[CH:8][CH:9]=2)[N:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NC(=O)c1cnc(Cl)nc1NCc1ccccc1
Reactant: Nc1ccc(N2CCOCC2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: NC(=O)c1cnc(Nc2ccc(N3CCOCC3)cc2)nc1NCc1ccccc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 42.9 %

Procedure:
A 5 ml NMP solution of 352 mg of 4-morpholinoaniline was mixed with 0.95 ml of 4 M hydrogen chloride/1,4-dioxane solution and 400 mg of 4-benzylamino-2-chloropyrimidine-5-carboxamide, followed by stirring at 90° C. for 3 hours. The reaction mixture was cooled down to room temperature, and then the precipitate was collected by filtration. The collected solid was mixed with saturated sodium bicarbonate aqueous solution and extracted with a mixed solution of THF-ethyl acetate. The organic layer was washed with saturated brine, and then the solvent was evaporated. The resulting residue was crystallized by adding methanol and then recrystallized (methanol-THF) to obtain 264 mg of 4-benzylamino-2-{[4-(morpholin-4-yl)phenyl]amino}pyrimidine-5-carboxamide as colorless crystals.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH:13]=O)[C:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:21][O:22][C:23]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:24]=1[CH2:25][NH2:26].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClC(Cl)C>[CH3:21][O:22][C:23]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:24]=1[CH2:25][NH:26][CH2:13][C:11]1[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:9][N:8]([C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=2)[CH:12]=1
Reactant: O=Cc1cn(-c2ccc(I)cc2)nc1-c1ccccc1
Reactant: COc1ccc(CN)c(OC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COc1ccc(CNCc2cn(-c3ccc(I)cc3)nc2-c2ccccc2)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.5 %

Procedure:
1.34 g (3.581 mmol) of the product from Example 2A and 538 μl (3.581 mmol) of 2,4-dimethoxybenzylamine are dissolved in 40 ml of dichloroethane, and the mixture is stirred at room temperature for one hour. 1.52 g (7.162 mmol) of sodium triacetoxyborohydride and 820 μl (14.33 mmol) of glacial acetic acid are then added. The reaction mixture is stirred at room temperature for 15 hours. A saturated sodium bicarbonate solution is then added, and the product is extracted with dichloromethane. The organic extract is washed with water and dried over anhydrous sodium sulphate. After filtration, the solvent is removed on a rotary evaporator. The crude product is dried under high vacuum and used without further purification in the next reaction. What is obtained are 1.89 g of the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]2[CH2:13][CH2:12][CH2:11]2)[N:4]=1.C[O:15][C:16]([CH:18]1[CH2:20][CH:19]1[C:21]1[CH:26]=[C:25]([F:27])[C:24]([OH:28])=[C:23]([F:29])[CH:22]=1)=[O:17]>>[CH:10]1([S:9][C:5]2[N:4]=[C:3]([CH2:2][O:28][C:24]3[C:23]([F:29])=[CH:22][C:21]([CH:19]4[CH2:20][CH:18]4[C:16]([OH:17])=[O:15])=[CH:26][C:25]=3[F:27])[CH:8]=[CH:7][CH:6]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: ClCc1cccc(SC2CCC2)n1
Reactant: COC(=O)C1CC1c1cc(F)c(O)c(F)c1
Product: O=C(O)C1CC1c1cc(F)c(OCc2cccc(SC3CCC3)n2)c(F)c1
Yield: 88 %

Procedure:
2-Chloromethyl-6-cyclobutylsulfanyl-pyridine (0.018 g, 0.08 mmol) obtained in Step C of Preparation Example 37 and 2-(3,5-difluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester (more polar) (0.020 g, 0.08 mmol) obtained in Step C of Preparation Example 60 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.030 g, 88%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:32][CH2:33][CH3:34])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[O:35]1[CH:39]=[CH:38][CH:37]=[C:36]1[C:40](Cl)=[O:41]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([C:40]([C:36]3[O:35][CH:39]=[CH:38][CH:37]=3)=[O:41])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[N:12]=2)=[C:7]([O:32][CH2:33][CH3:34])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(Cl)c1ccco1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)c1ccco1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was reacted with furan-2-carbonyl chloride (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C34H35N2O3Cl2 [(M+H)+] 589.2019, observed 589.2017.
Reaction SMILES: [C:1]1([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=S)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>C(Cl)Cl>[C:11]1([N:10]=[C:8]=[N:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: S=C(Nc1ccccc1)Nc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: C(=Nc1ccccc1)=Nc1ccccc1

Procedure:
1,3-Diphenylthiourea (22.8 g), triphenylphosphine (10.1 g) triethylamine (10.1 g) and carbon tetrachloride (21.6 g) were refluxed for 4 hours in methylene chloride (300 ml). The solvent was removed under vacuum. The residue was shaken with hexane (300 ml); the hexane solution was evaporated and the residue was distilled to afford the title compound as an oil bp 115°-120°/0.3 mm. Similarly, by using this procedure, but employing other 1,3-disubstituted thioureas instead of 1,3-diphenylthiourea, other carbodiimides can be made.
Reaction SMILES: [C:1]1([CH:11]=[C:12]2[CH2:17][C:16](=[O:18])[O:15][C:13]2=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:19]([NH2:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl>[C:1]1([CH:11]=[C:12]([CH2:17][C:16](=[O:18])[NH:27][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13]([OH:15])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CC(=Cc2cccc3ccccc23)C(=O)O1
Reactant: NCCc1ccccc1
Solvent: ClCCl
Product: O=C(CC(=Cc1cccc2ccccc12)C(=O)O)NCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.2 %

Procedure:
In 60 ml of dichloromethane were dissolved 3.00 g of the succinic anhydride and 1.52 g of phenethylamine, and the mixture was stirred for 2 hours at room temperature. The precipitated crystals were collected by filtration to obtain 4.02 g of 2-(1-naphthylmethylene)-3-(phenethylcarbamoyl)propionic acid as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[CH:32][CH:33]=[C:29]4[N:28]=[C:27]([C:34]4[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([OH:41])[CH:35]=4)[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:54][O:55][CH2:56][C:57]1[O:58][CH:59]=[C:60]([OH:64])[C:61](=[O:63])[CH:62]=1>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:54]/[O:55][CH2:56][C:57]2[O:58][CH:59]=[C:60]([OH:64])[C:61](=[O:63])[CH:62]=2)/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[CH:32][CH:33]=[C:29]4[N:28]=[C:27]([C:34]4[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([OH:41])[CH:35]=4)[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: NOCc1cc(=O)c(O)co1
Reactant: Nc1nc(C(=O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CSc4cc(-c5ccc(O)c(O)c5)nc5ccnn45)CS[C@H]23)cs1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: Nc1nc(/C(=N/OCc2cc(=O)c(O)co2)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CSc4cc(-c5ccc(O)c(O)c5)nc5ccnn45)CS[C@H]23)cs1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.2 %

Procedure:
(6R,7R)-7-(2-Amino-4-thiazoleglyoxylamido)-3-[[[5-(3,4-dihydroxyphenyl)pyrazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (59 mg) (0.095 mmol) and 41 mg (0.121 mmol) of 2-[(aminooxy)methyl]-5-hydroxy-4H-pyran-4-one p-toluenesulphonate (1:1) are dissolved in 2 ml of absolute dimethylaeetamide. After stirring at room temperature for 24 hours the solvent is removed and the residue is treated with 4 ml of water. The precipitated product is filtered off and washed with water. After drying in a high vacuum at room temperature there are obtained 67 mg of (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[(5-hydroxy-4-oxo-4 H-pyran-2-yl)methoxy]imino]acetamido]-3-[[[5-(3,4-dihydroxyphenyl)pyrazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:10])=[CH:5][C:6]=1[C:7](=[O:9])C.[O-:11]Cl.[Na+].[OH-].[Na+]>>[Cl:1][C:2]1[S:3][C:4]([Cl:10])=[CH:5][C:6]=1[C:7]([OH:11])=[O:9]
Reactant: [O-]Cl
Reactant: CC(=O)c1cc(Cl)sc1Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc(Cl)sc1Cl
Temperature: 55 °C
Reaction time: 6 h

Procedure:
A mixture of the 1-(2,5-dichloro-thiophen-3-yl)-ethanone (10 g, 51.26 mmol) and 9.5% NaOCl (150 mL, 230 mmol, 4.5 eq., commercial bleach) was treated with 5N NaOH (1 mL, 5 mmol, 0.1 eq.). The mixture was stirred vigorously and heated to 55° C. The internal temperature was monitored closely and heat was removed to control the exotherm. After 6 h at 61° C., starting material was completely consumed. The mixture was cooled to 0° C. and carefully quenched with 20% aq. NaHSO3 solution (20 mL). At 0° C., 6M HCl (12 mL) was added to adjust the pH to 1.5. The mixture was extracted with EtOAc (300 mL and 3×50 mL). The combined organic layers were washed with brine (200 mL), dried (Na2SO4), and concentrated to a white solid (8.8 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([C:12](=[O:37])[N:13]([CH3:36])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:28])[CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH2:60][C:61]1[C:69]2[N:68]=[C:67]([CH2:70][N:71]3[CH2:76][CH2:75][N:74]([CH3:77])[CH2:73][CH2:72]3)[NH:66][C:65]=2[CH:64]=[CH:63][CH:62]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([CH:9]=[CH:8][C:4]=1[C:5](=[O:6])[NH:60][C:61]1[C:69]2[N:68]=[C:67]([CH2:70][N:71]3[CH2:72][CH2:73][N:74]([CH3:77])[CH2:75][CH2:76]3)[NH:66][C:65]=2[CH:64]=[CH:63][CH:62]=1)[C:12]([N:13]([CH3:36])[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]1[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]1)=[O:28])=[O:37]
Reactant: CN1CCN(Cc2nc3c(N)cccc3[nH]2)CC1
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1C(=O)Nc1cccc2[nH]c(CN3CCN(C)CC3)nc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 36 %

Procedure:
To a solution of 2-methoxy-4-[N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]-carbamoyl]benzoic acid (200 mg) in N,N-dimethylformamide (3 ml) at 0° C. were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (97 mg), N-hydroxybenzotriazole (79 mg) and 4-amino-2-[(4-methylpiperazin-1-yl)methyl]-1H-benzimidazole (105 mg) and the mixture was stirred at ambient temperature for 15 hours. The reaction mixture was poured into saturated sodium bicarbonate aqueous solution and extracted with chloroform. The organic layer was washed with saturated sodium bicarbonate aqueous solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) to give 3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]-4-[2-[(4-methylpiperazin-1-yl)methyl]-1H-benzimidazol-4-yl]carbamoylbenzamide (104 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([NH:24][C:25]4[CH:29]=[CH:28][O:27][N:26]=4)(=[O:23])=[O:22])=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:30])[C:5]([O:9][CH3:10])=[N:6][C:7]=1Cl.[CH:31]1(B(O)O)[CH2:33][CH2:32]1>CCOC(C)=O.CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([NH:24][C:25]4[CH:29]=[CH:28][O:27][N:26]=4)(=[O:22])=[O:23])=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:30])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH:31]1[CH2:33][CH2:32]1
Reactant: OB(O)C1CC1
Reactant: COc1nc(Cl)c(Cl)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1nc(C2CC2)c(Cl)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Temperature: 50 °C
Reaction time: 12 h
Yield: 42.1 %

Procedure:
A 20-mL vial was charged with 1-(5,6-dichloro-2-methoxypyridin-3-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (200 mg, 0.428 mmol), cyclopropyl boronic acid (66.2 μl, 0.856 mmol), and (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (62.6 mg, 0.086 mmol) then purged with nitrogen. The reaction vessel was then sequentially charged with dioxane (3.2 mL) and an aqueous solution of sodium carbonate (1.1 mL, 1.9 M) via syringe. The vial was sealed with a PTFE line cap and the resultant red reaction mixture was heated to 50° C. After 12 h, the reaction mixture was allowed to cool to ambient temperature and an aqueous solution of 1.0 N HCL (5 mL) was added and the mixture diluted with EtOAc (5 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to furnish a brown oil, which was dissolved in DMSO (2 mL) filtered through a 0.2 micron filter and purified by reverse-phase HPLC (Waters XBridge Prep Shield RP18 10 μm OBD 19×100 mm) gradient, 20 to 75% MeCN in water (containing 0.1% trifluoroacetic acid as an additive), flow rate 40 mL/min to afford 1-(5-chloro-6-cyclopropyl-2-methoxy-3-pyridinyl)-N-3-isoxazolyl-2-oxo-1,2-dihydro-6-quinolinesulfonamide (85 mg, 0.180 mmol, 42.0% yield) as a white amorphous solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.23 (d, J=1.76 Hz, 1 H) 8.13 (d, J=1.97 Hz, 1 H) 7.74-7.80 (m, 2 H) 7.46 (s, 1 H) 6.82 (d, J=9.64 Hz, 1 H) 6.75 (d, J=9.02 Hz, 1 H) 6.56 (d, J=1.66 Hz, 1 H) 3.76 (s, 3 H) 2.41-2.61 (m, 1 H) 1.14-1.23 (m, 2 H) 1.09 (dd, J=8.09, 3.21 Hz, 2 H). m/z (ESI) 473.0 (M+H)+.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:21])[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[N+:18]([O-])=O)=[O:8])[CH2:2][CH2:3][CH3:4].CO>[Pd].CC(C)=O>[NH2:18][C:11]1[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:10]=1[NH:9][C:7](=[O:8])[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:21]
Reactant: CCCCNC(=O)C(=O)Nc1ccc(OC)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(C)=O
Solvent: CO
Product: CCCCNC(=O)C(=O)Nc1ccc(OC)cc1N
Reaction time: 3 h
Yield: 90.3 %

Procedure:
A mixture of 27.0 g (91 mmol) of N-Butyl-N′-(4-methoxy-2-nitro-phenyl)oxalamide, 1200 ml of methanol and 7.3 g of 5% Pd/C catalyst is hydrogenated from 3 h. To the reaction mixture is added 600 ml of acetone. The catalyst is filtered off, washed with acetone, the filtrate is concentrated and the residue si crystallized with diethyl ether to yield 21.8 g (90.1%) of the titled compound. Mp.: 180-181° C. (diethyl ether).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:22])[CH2:19][CH2:20][NH2:21])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.CCN=C=NCCCN(C)C.[C:35]1([CH3:53])[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[N:41]1[CH:45]=[C:44]([C:46](O)=[O:47])[C:43]([C:49]([F:52])([F:51])[F:50])=[N:42]1.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)C(C)C)C>ClCCl.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C@H:5]1[CH2:6][CH2:7][C@H:8]([C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:18](=[O:22])[CH2:19][CH2:20][NH:21][C:46]([C:44]3[C:43]([C:49]([F:52])([F:51])[F:50])=[N:42][N:41]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=4[CH3:53])[CH:45]=3)=[O:47])=[CH:15][CH:16]=2)[CH2:9][CH2:10]1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCN)cc2)CC1
Reactant: Cc1ccccc1-n1cc(C(=O)O)c(C(F)(F)F)n1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3cn(-c4ccccc4C)nc3C(F)(F)F)cc2)CC1
Reaction time: 24 h

Procedure:
A mixture of trans-{4-[4-(3-aminopropionylamino)phenyl]cyclohexyl}acetic acid methyl ester (50 mg, 0.16 mmol), EDCI (75.26 mg, 0.39 mmol), 1-o-tolyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (51 mg, 0.19 mmol), HOBt (31.8 mg, 0.24 mmol) and ethyldiisopropylamine (71.2 mg, 0.6 mmol) dissolved in dichloromethane solvent (10 mL) was stirred for 24 hours. The reaction mixture was diluted with aqueous NaHCO3 and extracted with dichloromethane. The extract was washed with brine and dried with anhydrous sodium sulfate and concentrated under vacuum. The residue was purified with silica gel column chromatography to obtain the desired compound (82 mg, 91%) as a white solid.