Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=2)[O:4][N:3]=1.[OH-].[Li+]>O1CCOCC1.O.C(O)(C)C>[CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)[O:4][N:3]=1
Reactant: COC(=O)c1ccc(-c2nc(C)no2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: C1COCCO1
Solvent: O
Product: Cc1noc(-c2ccc(C(=O)O)cc2)n1
Temperature: 25 °C

Procedure:
Methyl 4-(3-methyl-1,2,4-oxadiazol-5-yl)benzoate (J. R. Young and R. J. DeVita, Tetrahedron Lett., 1998, 39, 3931) was dissolved in a mixture of dioxan (110 ml), water (70 ml) and isopropanol (30 ml), and lithium hydroxide (1.38 g) was added. The mixture was stirred at room temperature for ca 5 h and then the mixture was acidified to ca pH 4 by addition of Amberlyst 15 H+ resin. The resin was removed by filtration and the filtrate was concentrated in vacuo. The solid white precipitate which was obtained was collected by filtration, washed with water on the filter and dried in vacuo at 40° C. for 48 h to give the title compound (D18) (4.23 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1.[CH3:16][CH:17]([CH3:33])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1)=[O:19]>>[N:7]1([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:30]2[CH2:31][CH2:32][CH:27]([C:24]3[CH:25]=[CH:26][C:21]([NH:20][C:18](=[O:19])[CH:17]([CH3:16])[CH3:33])=[CH:22][CH:23]=3)[CH2:28][CH2:29]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1
Reactant: CC(C)C(=O)Nc1ccc(C2CCNCC2)cc1
Reactant: ClCCCCCn1ccc2ccccc21
Product: CC(C)C(=O)Nc1ccc(C2CCN(CCCCCn3ccc4ccccc43)CC2)cc1

Procedure:
Prepared by Procedure AH and Scheme P using 1-(5-chloropentyl)-1H-indole and 2-methyl-N-[4-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 432.3 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].N1C=CC=CC=1.C[CH:12]([CH2:16][CH2:17][CH2:18][C:19](Cl)=O)[C:13](Cl)=[O:14].Cl.[O:23]1CCC[CH2:24]1>[Cl-].[Na+].O>[CH2:1]([NH:4][CH2:19][CH2:18][CH2:17][CH2:16][CH2:12][C:13]([O:23][CH3:24])=[O:14])[CH2:2][CH3:3]
Reactant: CC(CCCC(=O)Cl)C(=O)Cl
Reactant: CCCN
Reactant: C1CCOC1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: CCCNCCCCCC(=O)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Propylamine (0.65 g) is dissolved in tetrahydrofuran (5 ml) and thereto is added pyridine (0.89 ml), followed by an addition dropwise of methyl adipoyl chloride (1.96 g) under ice-cooling and the mixture is stirred at room temperature for 1 hour. To the reaction mixture is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is dissolved in tetrahydrofuran (30 ml) and thereto is added sodium borohydride (1.93 g) at room temperature and the mixture is heated to 65° C. and thereto is added dropwise acetic acid (2.92 ml) over 1 hour and the mixture is stirred at the same temperature for 9 hours. To reaction mixture is added an ice-cooled dilute hydrochloric acid, and the mixture is stirred for 30 minutes and extracted with ethyl acetate, and the organic layer is washed with a mixed solution of a saturated aqueous sodium bicarbonate solution and a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is dissolved in methanol (5 ml) and thereto is added a 4N-hydrochloric acid in dioxane (7.5 mL) and the mixture is stirred at room temperature overnight. To the reaction mixture is added a saturated aqueous sodium bicarbonate solution and a saturated brine, and the mixture is extracted six times with ethyl acetate and the collected organic layer is dried over magnesium sulfate, and concentrated under reduced pressure to give methyl 6-propylamino-hexanoate (914 mg). MS (m/z): 188 [M+H]+
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(C1NC=CN=1)(C1NC=CN=1)=O.[C:22]1([NH:28][C:29]2[N:34]=[C:33]([NH2:35])[N:32]=[C:31]([C:36]3[N:40]=C(C4SC=CN=4)O[N:37]=3)[N:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>N1C=CC=CC=1>[C:22]1([NH:28][C:29]2[N:34]=[C:33]([NH2:35])[N:32]=[C:31]([C:36]3[N:37]=[C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[O:9][N:40]=3)[N:30]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Nc1nc(Nc2ccccc2)nc(-c2noc(-c3nccs3)n2)n1
Reactant: O=C(O)c1ccccn1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: c1ccncc1
Product: Nc1nc(Nc2ccccc2)nc(-c2noc(-c3ccccn3)n2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
A mixture of picolinic acid (90 mg, 0.73 mmol) and carbonyl di-imidazole (0.12 g, 0.73 mmol) in pyridine (1 ml) was stirred for 2 h. N-Phenyl-6-(5-thiazol-2-yl-[1,2,4]oxadiazol-3-yl)-[1,3,5]triazine-2,4-diamine (prepared in an analogous manner to Intermediate 4, 100 mg, 0.41 mmol) was added and the resulting mixture was heated to 100 C and stirred for 24 h. In a separate vessel, a second mixture of picolinic acid (90 mg, 0.73 mmol) and carbonyl di-imidazole (0.12 g, 0.73 mmol) in pyridine (1 ml) was stirred for 90 minutes and added to the first mixture, which was stirred for a further 24 h at 100 C. The mixture was cooled to room temperature, concentrated under vacuum and suspended in aqueous sodium hydrogencarbonate solution. The solid was filtered off, washed with water, ethyl acetate and methanol and dried under vacuum to give the title compound (73 mg, 54%).
Reaction SMILES: Cl[C:2]1C=C(C=CC=1)C(OO)=O.[CH3:12][O:13][C:14]1[N:19]=[C:18](SC)[N:17]=[C:16]([O:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:15]=1.[S:28]([O-:32])([O-])(=[O:30])=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH3:12][O:13][C:14]1[N:19]=[C:18]([S:28]([CH3:2])(=[O:32])=[O:30])[N:17]=[C:16]([O:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:15]=1
Reactant: O=S([O-])([O-])=S
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)COc1cc(OC)nc(SC)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COC(=O)COc1cc(OC)nc(S(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.59 g of 3-chloroperoxybenzoic acid was added to a solution of 1.22 g of 6-methoxy-4-(methoxycarbonyl)methoxy-2-methylthiopyrimidine in 10 ml of chloroform at 0° C. The mixture was stirred at room temperature for 3 hours, then 30 ml of saturated aqueous sodium thiosulfate solution was added to the mixture. The mixture was poured into saturated aqueous sodium bicarbonate solution, extracted with chloroform, the organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated, then, the resulted residue was subjected to silica gel chromatography to obtain 1.32 g of 6-methoxy-4-(methoxycarbonyl)methoxy-2-methylsulfonylpyrimidine.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH2:26][CH2:27][CH3:28])[N:5]([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]=[C:19]3[S:23][C:22](=[O:24])[NH:21][C:20]3=[O:25])=[CH:14][CH:13]=2)[C:6](=[O:8])[CH:7]=1.[H][H]>O1CCOCC1.[Pd]>[CH3:1][C:2]1[N:3]=[C:4]([CH2:26][CH2:27][CH3:28])[N:5]([CH2:9][CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([CH2:18][CH:19]3[S:23][C:22](=[O:24])[NH:21][C:20]3=[O:25])=[CH:16][CH:17]=2)[C:6](=[O:8])[CH:7]=1
Reactant: [H][H]
Reactant: CCCc1nc(C)cc(=O)n1CCOc1ccc(C=C2SC(=O)NC2=O)cc1
Agent: [Pd]
Solvent: C1COCCO1
Product: CCCc1nc(C)cc(=O)n1CCOc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 92 %

Procedure:
A solution of 5-[4-[2-[4-methyl-2-propyl-6-oxo 1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl methylene]thiazolidine-2,4-dione (5.0 g, 12.46 mmol) obtained from example 1 in 1,4-dioxane (75 ml) was reduced with hydrogen in the presence of 10% palladium on charcoal (12.0 g) at 60 psi pressure for 40 h. The mixture was filtered through a bed of celite. The filtrate was evaporated to dryness under reduced pressure, purified by column chromatography (2: 1 EtOAc/petroleum ether as eluent) followed by crystallisation (CH2C12) to afford the title compound (4.6 g, 92%), mp 144-146° C.
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:9]2[CH:14]=[CH:13][C:12](Br)=[CH:11][CH:10]=2)=[O:8])[CH:2]=1.[C:22]1([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C>C1(C)C=CC=CC=1.[Pd].[Pd].CC(C)=O>[C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([N:28]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:11][CH:10]=2)=[O:8])[CH:2]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: O=C(c1ccc(Br)cc1)c1cccc(-c2ccccc2)c1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: O=C(c1ccc(N(c2ccccc2)c2ccccc2)cc1)c1cccc(-c2ccccc2)c1
Reaction time: 24 h
Yield: 80.8 %

Procedure:
Biphenyl-3-yl(4-bromophenyl)methanone (5.0 g, 14.83 mmol) and diphenylamine (3.8 g, 22.2 mmol) were dissolved in toluene (150 mL) under a nitrogen atmosphere, and then tris(benzylidine acetone dipalladium) (0.3 g, 0.3 mmol) was added thereto under nitrogen. Also, P(t-Bu)3 (0.3 g, 1.5 mmol) was added to the reaction mixture solution, followed by addition of NaOBut (4.3 g, 44.5 mmol). The reaction mixture solution was refluxed and stirred for 24 hours. After the reaction was over, the reaction mixture solution was filtered through a thin silica pad at a high temperature to thereby remove palladium. The filtrate was concentrated, and was passed through a silica gel column by using hexane-dichloromethane 7:3 as an eluant. After the solvent was removed, the residue material was dried in vacuum to thereby obtain a white solid (5.1 g, yield: 81%).
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]2[NH:15][C:14]3[CH:16]=[C:17]([N:32]([CH2:35][CH3:36])[CH2:33][CH3:34])[C:18]([C:20](=[O:31])[NH:21][C:22]4[CH:30]=[C:29]5[C:25]([CH:26]=[N:27][NH:28]5)=[CH:24][CH:23]=4)=[CH:19][C:13]=3[N:12]=2)[CH:5]=1.[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.C1COCC1>[CH2:35]([N:32]([CH2:33][CH3:34])[C:17]1[C:18]([C:20](=[O:31])[NH:21][C:22]2[CH:30]=[C:29]3[C:25]([CH:26]=[N:27][NH:28]3)=[CH:24][CH:23]=2)=[CH:19][C:13]2[N:12]=[C:11]([NH:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:37])=[O:2])[NH:15][C:14]=2[CH:16]=1)[CH3:36]
Reactant: CCN(CC)c1cc2[nH]c(Nc3cccc(C(=O)OC)c3)nc2cc1C(=O)Nc1ccc2cn[nH]c2c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCN(CC)c1cc2[nH]c(Nc3cccc(C(=O)O)c3)nc2cc1C(=O)Nc1ccc2cn[nH]c2c1
Temperature: 25 °C

Procedure:
To a solution of 3-[6-diethylamino-5-(1H-indazol-6-ylcarbamoyl)-1H-benzimidazol-2-ylamino]-benzoic acid methyl ester (0.2 mmol; see Example 115) in methanol (2 mL) and THF (2 mL) was added 1M aqueous LiOH solution (2 mL). The resulting solution was then stirred at RT until the reaction was complete. The pH of the reaction mixture was adjusted with 5% aqueous citric acid solution to bring its pH to 4-5. The solid obtained was filtered, washed with ice-cold water, and dried under vacuum to afford 3-[6-diethylamino-5-(1H-indazol-6-ylcarbamoyl)-1H-benzimidazol-2-ylamino]-benzoic acid as a white solid. MS: m/z 484 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[CH2:9][CH2:10][NH:11][CH3:12])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[N:31][NH:32][CH:33]=2)O1>>[Cl:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[O:13][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([C:29]2[CH:30]=[N:31][NH:32][CH:33]=2)=[CH:3][CH:4]=1)[CH2:9][CH2:10][NH:11][CH3:12]
Reactant: CNCCC(Oc1cccc(Cl)c1)c1ccc(Br)cc1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: CNCCC(Oc1cccc(Cl)c1)c1ccc(-c2cn[nH]c2)cc1

Procedure:
[3-(4-Bromo-phenyl)-3-(3-chloro-phenoxy)-propyl]-methyl-amine was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1 to give the title compound. LC/MS: (PS-B3) Rt 2.80 [M+H]+ 342.26. 1H NMR (Me-d3-OD) δ 2.19-2.30 (1H, m), 2.30-2.45 (1H, m), 2.72 (3H, s), 3.10-3.28 (2H, m), 5.40-5.47 (1H, m), 6.80-6.88 (1H, d), 6.88-6.94 (1H, d), 6.96 (1H, s), 7.15-7.20 (1H, t), 7.38-7.45 (2H, d), 7.57-7.65 (2H, d), 7.98 (2H, s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]1[CH2:8][C@H:7]([OH:9])[CH2:6][N:5]1C(OC(C)(C)C)=O.[Cl:18][C:19]1[CH:20]=[C:21](O)[CH:22]=[CH:23][C:24]=1[Cl:25]>>[Cl:18][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][C:24]=1[Cl:25])[O:9][C@@H:7]1[CH2:6][NH:5][C@H:4]([C:3]([O:2][CH3:1])=[O:17])[CH2:8]1
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Product: COC(=O)[C@@H]1C[C@H](Oc2ccc(Cl)c(Cl)c2)CN1

Procedure:
The compound was prepared by analogy with Example 217(ii) from N-Boc-cis-4-hydroxy-L-proline methylester and 3,4-dichlorophenol.
Reaction SMILES: [N:1]1([CH:7]2[CH2:30][N:29]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])[C:10]3=[N:11][C:12]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=4)[N:14]=[C:9]3[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCO>[N:1]1([CH:7]2[CH2:30][N:29]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])[C:10]3=[N:11][C:12]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[C:13]([C:15]4[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=4)[N:14]=[C:9]3[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CCCCCCN1CC(N2CCCCC2)Cc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(CCCCCCC(=O)O)CC(N2CCCCC2)C3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ethyl 7-(7-(piperidin-1-yl)-2,3-di-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoate (step 8) (39 mg, 0.070 mmol) in EtOH (1 ml) was treated with 2M NaOH (0.105 mL, 0.211 mmol) and stirred at room temperature overnight. The resulting mixture was added to water (30 ml) and the pH was adjusted to pH4 by addition of 10% aqueous citric acid solution. The aqueous portion was extracted with DCM (×3) and the combined extracts were passed through a phase separating column. The solvent was removed under reduced pressure to afford the titled compound;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:19]([OH:21])=O)=[C:11]([CH2:13][CH:14]([O:17][CH3:18])[O:15][CH3:16])[N:12]=2)=[CH:4][CH:3]=1.[C:22]([O:26][C:27]([N:29]1[CH2:32][CH:31]([O:33][C:34]2[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][C:35]=2[O:41][CH3:42])[CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>C1COCC1.O>[C:22]([O:26][C:27]([N:29]1[CH2:30][CH:31]([O:33][C:34]2[CH:39]=[CH:38][C:37]([NH:40][C:19]([C:10]3[S:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[N:12][C:11]=3[CH2:13][CH:14]([O:15][CH3:16])[O:17][CH3:18])=[O:21])=[CH:36][C:35]=2[O:41][CH3:42])[CH2:32]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: COC(Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)O)OC
Reactant: COc1cc(N)ccc1OC1CN(C(=O)OC(C)(C)C)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc(NC(=O)c2sc(-c3ccc(Cl)cc3)nc2CC(OC)OC)ccc1OC1CN(C(=O)OC(C)(C)C)C1
Temperature: 10 °C
Yield: 90.2 %

Procedure:
Dissolve 2-(4-chloro-phenyl)-4-(2,2-dimethoxy-ethyl)-thiazole-5-carboxylic acid (147 g, 448 mmol), 3-(4-amino-2-methoxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (120 g, 402 mmol), and 1-hydroxybenzotriazole hydrate (75 g, 490 mmol) in THF (1.2 L) and cool to about 10° C. under a nitrogen atmosphere Treat the above solution with diisopropylethylamine (117 mL, 673 mmol) dropwise over 2 min while keeping the temperature between 10-15° C. Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (93 g, 489 mmol) to the solution and stir at room temperature for 19 h. Cool the solution to 0° C. and dilute with water (1.2 L). Collect the precipitate by filtration and triturate with water (5×700 mL). Dry the tan solid for 3 days at 50° C. under vacuum to obtain 219 g (90%) of the title compound. 1H NMR (300 MHz, CDCl3) δ: 10.03 (s, 1H), 7.90 (m, 2H), 7.66 (d, 1H, J=2.4), 7.42 (m, 2H), 6.88 (dd, 1H, J=2.4, 8.6), 6.57 (d, 1H, J=8.6), 4.86 (m, 1H), 4.84 (t, 1H, J=5.7), 4.26 (dd, 2H, J=6.7, 10.6), 4.08 (dd, 2H, J=4.3, 10.6), 3.90 (s, 3H), 3.53 (s, 6H), 3.37 (d, 2H, J=5.5), 1.43 (s, 9H).
Reaction SMILES: [NH:1]([CH:8]([CH3:23])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:14][C:13]=1[Cl:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]=O>C(O)C>[CH3:23][CH:8]1[N:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:24][N:11]([C:12]2[CH:17]=[CH:16][C:15]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:14][C:13]=2[Cl:22])[C:9]1=[O:10]
Reactant: CC(Nc1ccccc1)C(=O)Nc1ccc(S(N)(=O)=O)cc1Cl
Reactant: C=O
Solvent: CCO
Product: CC1C(=O)N(c2ccc(S(N)(=O)=O)cc2Cl)CN1c1ccccc1

Procedure:
2-Anilino-N-(2-chloro-4-sulfamoylphenyl)-propionamide (3.5 g) was dissolved in ethanol (100 ml) and reacted with paraformaldehyde (0,7 g) as before to yield 1.8 g, m.p. 202°C
Reaction SMILES: [N:1]([C:4]1[S:5][C:6]([CH3:19])=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]=1[C:9]([O:11]C)=O)=[C:2]=[S:3].[CH3:20][C:21]1[N:25]([CH2:26][CH2:27][CH2:28][NH2:29])[CH:24]=[N:23][CH:22]=1>>[CH3:19][C:6]1[S:5][C:4]2[NH:1][C:2](=[S:3])[N:29]([CH2:28][CH2:27][CH2:26][N:25]3[C:21]([CH3:20])=[CH:22][N:23]=[CH:24]3)[C:9](=[O:11])[C:8]=2[C:7]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1c(N=C=S)sc(C)c1-c1ccccc1
Reactant: Cc1cncn1CCCN
Product: Cc1sc2[nH]c(=S)n(CCCn3cncc3C)c(=O)c2c1-c1ccccc1

Procedure:
The compound was synthesized starting from methyl 2-isothiocyanato-5-methyl-4-phenylthiophene-3-carboxylate (0.10 g, 0.35 mmol) and 3-(5-methyl-1H-imidazol-1-yl)propan-1-amine (5) (0.048 g, 0.35 mmol) as described above.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N+:13]=1[O-])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1CCCCC=1>CCO.[Pd]>[C:1]([NH:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)NCCNc1cccc[n+]1[O-]
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CC(C)(C)OC(=O)NCCNc1ccccn1
Reaction time: 16 h
Yield: 200 %

Procedure:
10% Pd/C (106.4 mg, 0.10 mmole) was added to a solution of 2-[[2-(Boc-amino)ethyl]amino]pyridine-N-oxide (126.7 mg, 0.5 mmole) and cyclohexene (0.25 mL, 0.25 mmole) in absolute EtOH (5 mL), and the mixture was heated to reflux. After 16 hr, the reaction was filtered through celite® and the filtrate was concentrated. The residue was combined with the residue obtained from a separate preparation (0.5 mmole scale), and the combined materials were purified by silica gel chromatography (5% MeOH/CHCl3). The title compound (148.4 mg, 63% based on 1 mmole of 2-[[2-(Boc-amino)ethyl]amino]pyridine-N-oxide) was obtained as a yellow oil: TLC (5% MeOH/CHCl3) Rf 0.43; 1H NMR (400, CDCl3) δ 8.05-8.12 (m, 1H), 7.37-7.46 (m, 1H), 6.53-6.61 (m, 1H), 6.41 (d, J=8.3 Hz, 1H), 5.12 (br s, 1H), 4.86 (br s, 1H), 3.26-3.51 (m, 4H), 1.44 (s, 9H); MS (ES) m/e 238 (M+H)+.
Reaction SMILES: O.[NH2:2][NH2:3].C[O:5][C:6](=O)[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1>CO>[NH:2]([C:6]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)=[O:5])[NH2:3]
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: NN
Solvent: CO
Solvent: O
Product: NNC(=O)c1ccc(C(=O)O)cc1
Reaction time: 1 h
Yield: 90.09 %

Procedure:
Hydrazine hydrate was added to a solution of terephthalic acid monomethyl ester (1 g, 5.5 mmol) in MeOH (10 mL) and stirring was continued for 1 hr. The reaction mixture was concentrated to afford 900 mg (90.09% Yield) of 4-hydrazinocarbonyl-benzoic acid. p-Toluene sulfonic acid (48 mg, 0.277 mmol) was added to a solution of 4-hydrazinocarbonyl-benzoic acid (500 mg, 2.77 mmol) in triethylorthoformate (7.5 mL, 44.0 mmol) and stirring was continued with heating at 100° C. for 3 hrs. The reaction mixture was diluted with water, the solid was collected to afford 200 mg (37.9% Yield) of 4-[1,3,4]oxadiazol-2-yl-benzoic acid.
Reaction SMILES: [CH2:1]1[O:13][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21]>C(O)C>[CH2:20]([NH:21][CH2:1][CH:2]([OH:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:14][CH2:1][CH:2]([OH:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCC1CO1
Reactant: NCCCCCCN
Solvent: CCO
Product: CCCCCCCCCCC(O)CNCCCCCCNCC(O)CCCCCCCCCC

Procedure:
In a manner similar to that of Example 1, condensation of 1-dodecene oxide (50 g.) and hexamethylenediamine (15.8 g.) and recrystallization of the resulting product from ethanol gave N,N'-(1,6-hexylene)-bis[2-hydroxydodecylamine] (I: R = CH3 (CH2)9, R' = H, X = (CH2)6, Z = H) (35 g., m.p. 123.6°-128.0° C.).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([NH:14][C:15]3[N:20]=[C:19]([CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH2:29][C:30]([O:32]C)=[O:31])[C:18]([C:34]([F:37])([F:36])[F:35])=[CH:17][N:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:4][CH2:3]1.O[Li].O.O.CO>C1COCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([NH:14][C:15]3[N:20]=[C:19]([CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH2:29][C:30]([OH:32])=[O:31])[C:18]([C:34]([F:36])([F:35])[F:37])=[CH:17][N:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: COC(=O)Cc1ccccc1CCc1nc(Nc2cccc(N3CCN(C)CC3)c2)ncc1C(F)(F)F
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CN1CCN(c2cccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(=O)O)n3)c2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl 2-(2-(2-(2-((3-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetate (I67) (150 mg, 292 μmol) was dissolved in a THF (10 mL), then LiOH.H2O (36.7 mg, 876 μmol) was added. Water (2 mL) then MeOH (1 mL) was added. The resulting mixture was stirred at room temperature for 16 hours then the volatiles were removed by evaporation under reduced pressure. The residue was dissolved in MeOH (3 mL) then acidified with concentrated HCl to pH 2-3. The volatiles were evaporated under reduced pressure to give an orange residue. The residue was chromatographed on silica gel (0-20% MeOH/DCM) to give the title compound (I68) (120 mg, 82%) as a yellow crystalline solid; 1H NMR (400 MHz, d6-DMSO) δ 11.04 (bs, 1H), 10.12 (s, 1H), 8.68 (s, 1H), 7.44 (m, 1H), 7.35 (m, 1H), 7.24-7.18 (m, 5H), 6.72 (m, 1H), 3.77-3.74 (m, partially obscured by residual water signal), 3.44 (m, 3H), 3.17-3.03 (m, 8H), 2.78 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[C:9]1[CH:10]=[CH:11][C:12]([O:29][CH2:30][CH3:31])=[C:13]([C:15]2[NH:16][C:17](=[O:28])[C:18]3[N:23]([CH3:24])[N:22]=[C:21]([CH2:25][CH2:26][CH3:27])[C:19]=3[N:20]=2)[CH:14]=1>>[CH2:30]([O:29][C:12]1[CH:11]=[CH:10][C:9]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:14][C:13]=1[C:15]1[NH:16][C:17](=[O:28])[C:18]2[N:23]([CH3:24])[N:22]=[C:21]([CH2:25][CH2:26][CH3:27])[C:19]=2[N:20]=1)[CH3:31]
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(Br)ccc3OCC)nc12
Reactant: Brc1ccccn1
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(-c4ccccn4)ccc3OCC)nc12

Procedure:
The title compound was prepared from 2-bromopyridine and 5-(5-bromo-2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, following the procedure described in Example 32, and was obtained as an off-white solid (33%), m.p. 216°-218° C. Found: C,67.71; H,5.81; N,17.63. C22H23N5O2 requires C,67.85; H,5.95; N,17.98%.