Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:7]=[C:8]([C:23]([OH:25])=[O:24])[CH:9]=[C:10]([S:19]([NH2:22])(=[O:21])=[O:20])[C:11]=1[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1.[CH2:26]([N:28]([CH2:31]C)[CH2:29]C)[CH3:27].[I-].[Na+].CN(C)C=[O:38]>>[NH2:22][S:19]([C:10]1[CH:9]=[C:8]([CH:7]=[C:6]([NH:5][CH2:4][CH2:3][CH2:2][CH3:1])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:23]([O:25][CH2:27][C:26]([N:28]([CH3:31])[CH3:29])=[O:38])=[O:24])(=[O:21])=[O:20]
Reactant: CN(C)C=O
Reactant: CCCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Reactant: CCN(CC)CC
Agent: [I-]
Agent: [Na+]
Product: CCCCNc1cc(C(=O)OCC(=O)N(C)C)cc(S(N)(=O)=O)c1Oc1ccccc1
Temperature: 50 °C
Yield: 60 %

Procedure:
Bumetanide (1.2 g, 3.29 mmol) was dissolved in dimethylformamide (DMF, 10 mL) and 2-chloro-N,N-dimethylamide (410 uL, 3.9 mmol) was added, followed by triethylamine (0.70 mL) and sodium iodide (545 mg, 3.6 mmol). The reaction was heated to 50° C. for 10 hours, at which time TLC and LC/MS indicated the reaction was complete. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate, water and brine, and dried over anhydrous magnesium sulfate. The ethyl acetate was removed under reduced pressure and the product was purified via flash chromatography to yield 685 mg (60%) of pure N,N-dimethylaminocarbonylmethyl 3-aminosulfonyl-5-butylamino-4-phenoxybenzoate.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]1([CH:19]([CH3:25])[CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:26](Cl)(=[O:28])[CH3:27].C([O-])(O)=O.[Na+]>O1CCCC1.O>[C:26]([CH:20]([CH:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:25])[C:21]([O:23][CH3:24])=[O:22])(=[O:28])[CH3:27]
Reactant: COC(=O)CC(C)c1ccccc1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C(C(C)=O)C(C)c1ccccc1
Reaction time: 0.17 h

Procedure:
n-Butyllithium (2.5 M hexanes 12.4 ml, 30.9 mmol) is added to N,N-diisopropylamine (4.4 ml, 31.4 mmol) in tetrahydrofuran (THF, 50 ml) at 0° C. After 10 minutes, the resultant solution is transferred via cannula to a cooled (−78° C.) solution of methyl 3-phenylbutyrate (5.0 g, 28.05 mmol) in THF (50 ml). After 40 minutes, the resultant solution is transferred via cannula to a solution of acetyl chloride (19.15 ml) in THF (50 ml). The resultant mixture is stirred at −78° C. for 1.5 hours, then warmed to 0° C. after which water is added and the mixture is then poured into saturated NaHCO3 and extracted with EtOAc. The combined organic phases are washed with brine, dried (MgSO4) and evaporated. Purification by flash chromatography (12:1 EtOAc-hexane elution) affords the title compound. δH 1.3 (d J 7 3H), 2.3 (s 3H), 3.4 (s 3H), 3.6 (m 1H), 3.8 (m 1H), 7.2-7.4 (m 5H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:44])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@H:10]1[C:14](=[O:15])[CH2:13][C@@H:12](O[Si](C(C)(C)C)(C)C)[C@@H:11]1/[CH:24]=[CH:25]/[C@@H:26]([O:36][Si](C(C)(C)C)(C)C)[CH2:27][CH2:28][C:29]1[S:30][C:31]([CH3:35])=[C:32]([Br:34])[CH:33]=1.CC(O)=O.O.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:1][O:2][C:3](=[O:44])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@H:10]1[C:14](=[O:15])[CH:13]=[CH:12][C@@H:11]1/[CH:24]=[CH:25]/[C@@H:26]([OH:36])[CH2:27][CH2:28][C:29]1[S:30][C:31]([CH3:35])=[C:32]([Br:34])[CH:33]=1
Reactant: COC(=O)CCC/C=C\C[C@H]1C(=O)C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1/C=C/[C@H](CCc1cc(Br)c(C)s1)O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)CCC/C=C\C[C@H]1C(=O)C=C[C@@H]1/C=C/[C@@H](O)CCc1cc(Br)c(C)s1
Temperature: 70 °C
Reaction time: 17 h
Yield: 50.7 %

Procedure:
A mixture of 5 (1.486 g, 2.03 mmol), HOAc (20 mL), H2O (10 mL) and THF (10 mL) was stirred at 70° C. for 17 h. The reaction was then poured into 750 mL saturated NaHCO3 solution and the resulting mixture was extracted with ethyl acetate (4×200 mL). The combined ethyl acetate solution was dried (Na2SO4), filtered and evaporated. Flash chromatography (50% ethyl acetate/hexanes) gave 6 (497 mg, 1.03 mmol, 51%).
Reaction SMILES: [C:1]([NH:4][C:5]([NH2:7])=[S:6])(=[NH:3])[NH2:2].[Cl:8][CH2:9][C:10]([CH2:12]Cl)=O>CC(C)=O>[ClH:8].[NH:4]([C:5]1[S:6][CH:12]=[C:10]([CH2:9][Cl:8])[N:7]=1)[C:1]([NH2:2])=[NH:3]
Reactant: O=C(CCl)CCl
Reactant: N=C(N)NC(N)=S
Solvent: CC(C)=O
Product: Cl
Product: N=C(N)Nc1nc(CCl)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of amidinothiourea (16.8 g.) in acetone (75 ml.) was treated with 1,3-dichloroacetone (18 g.) in acetone (60 ml.). There was a slight exotherm and the crystalline suspension gradually changed to a fine white solid. After stirring overnight at room temperature the solid was filtered off and washed with acetone. Crystallization from ethanol gave 2-guanidino-4-chloromethylthiazole hydrochloride, m.p. 191°-193° C.
Reaction SMILES: [N+:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6]2)#[C-:2].[N:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[NH2:19].[CH3:20][N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH:30]=O)=[CH:22]1>C(Cl)Cl.CO.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Sc+3]>[CH3:20][N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([C:30]2[N:19]=[C:14]3[CH:15]=[N:16][CH:17]=[CH:18][N:13]3[C:2]=2[NH:1][C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[CH2:7][CH2:6]3)=[CH:22]1
Reactant: [C-]#[N+]c1ccc2c(c1)CCC2=O
Reactant: Cn1cc(C=O)c2ccccc21
Reactant: Nc1cnccn1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: CO
Solvent: ClCCl
Product: Cn1cc(-c2nc3cnccn3c2Nc2ccc3c(c2)CCC3=O)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Isocyano-2,3-dihydroinden-1-one (6) (60.0 mg, 379 μmol) was combined with pyrazin-2-amine (12) (36.1 mg, 379 μmol), 1-methyl-1H-indole-3-carbaldehyde (15) (60.4 mg, 379 μmol) and Sc(OTf)3 (18.7 mg, 37.9 μmol) in DCM/MeOH and stirred at room temperature overnight. The solvent was evaporated and purified by silica using 2% MeOH/EtOAc to provide 5-(2-(1-methyl-1H-indol-3-yl)imidazo[1,2-a]pyrazin-3-ylamino)-2,3-dihydroinden-1-one (16). MS (APCI) m/z (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:27][CH2:28][C:29]#[CH:30])[C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([O:25][CH3:26])[CH:19]=2)=[O:10])=[CH:4][CH:3]=1.C[O-].[Na+].[CH2:34](Cl)[C:35]#[C:36][CH2:37][CH3:38].C(OCC)(=O)C>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:27][CH2:28][C:29]#[CH:30])[C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:34][C:35]#[C:36][CH2:37][CH3:38])=[C:20]([O:25][CH3:26])[CH:19]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: CCC#CCCl
Reactant: C#CCOC(C(=O)Nc1ccccc1-c1ccc(O)c(OC)c1)c1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: C#CCOC(C(=O)Nc1ccccc1-c1ccc(OCC#CCC)c(OC)c1)c1ccc(Cl)cc1

Procedure:
A solution of 1.3 g (3.1 mmol) 2-(4-chloro-phenyl)-N-(4′-hydroxy-3′-methoxy-biphenyl-2-yl)-2-prop-2-ynyloxy-acetamide, 6.0 ml (6.0 mmol) of a 1 M solution of sodium methoxide in methanol and 0.5 g (4.7 mmol) 2-pentynyl chloride in 50 ml of methanol is heated to reflux for 3 hours. After cooling, the reaction mixture is poured into ethyl acetate. The organic layer is washed with brine, dried over sodium sulfate and evaporated. The remaining product is subjected to flash-chromatography (ethyl acetate/hexane 4:6) to yield 2-(4-chlorophenyl)-N-(3′-methoxy-4′-pent-2-ynyloxy-biphenyl-2-yl)-2-prop-2-ynyloxy-acetamide as yellow oil.
Reaction SMILES: [CH:1]([O-:3])=O.[NH4+:4].[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[C:13](=O)[CH3:14]>C(O)=O>[CH:1]([NH:4][CH:13]([C:7]1[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:6]=1[Cl:5])[CH3:14])=[O:3]
Reactant: [NH4+]
Reactant: CC(=O)c1ccc(Cl)cc1Cl
Reactant: O=C[O-]
Solvent: O=CO
Product: CC(NC=O)c1ccc(Cl)cc1Cl
Reaction time: 3 h

Procedure:
In the same manner as in Example 4 except that a mixture of formic acid, ammonium formate and 2',4'-dichloroacetophenone was heated with stirring at 160° C. for 6 hours in place of the concurrent addition of 2',4'-dichloroacetophenone and formic acid to ammonium formate for 3 hours and keeping the mass ater the addition stirred for 3 hours, the reaction and post treatment were carried out to obtain 178.6 g of crude N-formyl-1-(2,4-dichlorophenyl)ethylamine; the purity: 70.4%.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[C:9]([N+:14]([O-])=O)[CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[Cl-].[NH4+].[O:20]([C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](O)=[O:35])=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>[Fe].C(O)C.O>[CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[C:9]([NH:14][C:34](=[O:35])[CH2:33][C:30]3[CH:31]=[CH:32][C:27]([O:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:28][CH:29]=3)[CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: CN(C)CCn1ncc2c([N+](=O)[O-])cccc21
Reactant: O=C(O)Cc1ccc(Oc2ccccc2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CN(C)CCn1ncc2c(NC(=O)Cc3ccc(Oc4ccccc4)cc3)cccc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of dimethyl-[2-(4-nitro-indazol-1-yl)-ethyl]-amine (1.6 g, 6.8 mmol), iron powder (3.8 g, 68 mmol), and ammonium chloride (0.18 g, 3.4 mmol) in a 4:1 ethanol/H2O solution (20 mL) was heated to reflux for 3 hours, cooled to room temperature and concentrated under reduced pressure. The residue was taken up and stirred in triethylamine/ethyl acetate (1/4, 10 mL) for 15 minutes and then filtered through a plug of silica gel which was rinsed with triethylamine/ethyl acetate (1/4). The combined filtrate was concentrated under reduced pressure to provide a play yellow oil. This material was then processed with (4-phenoxy-phenyl)-acetic acid according to the procedure described in Example 5 to provide the title compound. 1H NMR (300 MHz, DMSO-d6) ppm 2.85 (s, 6H), 3.62 (t, J=6.24, 2H), 3.80 (s, 2H), 4.78 (t, J=6.24, 2H), 6.99–7.01 (m, 3H), 7.13 (m, 2H), 7.36–7.40 (m, 5H), 7.45 (m, 1H), 7.71 (m, 1H), 8.40 (s, 1H), 9.61 (s, 1H); MS (DCI/NH3) m/z 415 [M+H]+.
Reaction SMILES: [CH3:1][O:2][S:3]([O-:6])(=[O:5])=[O:4].[CH3:7][N+:8]1([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[H][H]>C(O)C.[Pd]>[CH3:1][O:2][S:3]([O-:6])(=[O:5])=[O:4].[NH2:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[O:16][CH2:15][CH2:14][N+:8]1([CH3:7])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1
Reactant: C[N+]1(CCOc2ccccc2[N+](=O)[O-])CCOCC1
Reactant: [H][H]
Agent: [Pd]
Agent: COS(=O)(=O)[O-]
Solvent: CCO
Product: C[N+]1(CCOc2ccccc2N)CCOCC1
Reaction time: 2 h

Procedure:
2.08 g (5.5 mmol) of the compound from Step 5.2 was dissolved in 80 mL of ethanol and hydrogenated in the presence of 0.25 g of Pd/C (10%) under 9 bar of hydrogen pressure. After 2 hours, the catalyst was filtered off and the filtrate was evaporated to dryness. This gave 1.9 g (99% of the theoretical) of a colorless oil which was subjected to further reaction without additional purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[O:10])=[CH:5][C:4]=1[OH:11].C(N(CC)C(C)C)(C)C.[CH3:21][O:22][CH2:23]Cl.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[O:10])=[CH:5][C:4]=1[O:11][CH2:21][O:22][CH3:23]
Reactant: COc1ccc(C=O)cc1O
Reactant: COCCl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1cc(C=O)ccc1OC
Temperature: 0 °C
Yield: 85 %

Procedure:
In 100 ml of dimethylformamide was dissolved 10 g of isovaniline, and 14 ml of N,N-diisopropylethylamine was added to the solution and the mixture was stirred. The liquid mixture was cooled to 0° C. and 7.2 ml of chloromethyl methyl ether was added to the mixture, and the temperature was elevated to room temperature and the mixture was stirred for 5 hours. After the reaction, a large quantity of water was added to the reaction mixture, and the mixture was extracted with diethyl ether, washed with water and dried. Removal of the solvent by distillation gave 11.0 g (yield=85%) of 4-methoxy-3-methoxymethoxybenzaldehyde in the form of a yellow oil.
Reaction SMILES: [Se](=O)=[O:2].[C:4]([C@H:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:15]2[CH:24]=[C:23]3[C:18]([CH:19]=[C:20]([CH3:25])[N:21]=[CH:22]3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)([CH3:7])([CH3:6])[CH3:5]>C1(OC2C=CC=CC=2)C=CC=CC=1>[C:4]([C@H:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:15]2[CH:24]=[C:23]3[C:18]([CH:19]=[C:20]([CH:25]=[O:2])[N:21]=[CH:22]3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)([CH3:7])([CH3:6])[CH3:5]
Reactant: O=[Se]=O
Reactant: Cc1cc2ccc(O[C@H]3CC[C@H](C(C)(C)C)CC3)cc2cn1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C=O)ncc3c2)CC1
Temperature: 200 °C

Procedure:
Selenium dioxide (2.25 g, 20.3 mmol) was added to a solution of 7-(trans-4-tert-Butyl-cyclohexyloxy)-3-methyl-isoquinoline (2.01 g, 6.76 mmol) in Diphenyl ether (50 mL, 300 mmol) and the mixture was heated at 200° C. in a sealed tube for 4 hours. The reaction was then cooled to room temperature. Silica gel was added and the flask was placed in a cold water bath to solidify the diphenylether solvent. This solid mixture containing the crude product was purified by flash chromatography to give the title compound in 1.04 g (49%) yield. ESI-MS (M+H+): 312.27
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[O:5][CH2:6][C:7]#[N:8].Cl.[NH2:14][OH:15].[OH-].[Na+]>C(O)C.O>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[O:5][CH2:6][C:7](=[N:14][OH:15])[NH2:8]
Reactant: Cc1c(Cl)cccc1OCC#N
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(Cl)cccc1OCC(N)=NO
Yield: 90.2 %

Procedure:
29.2 g (160.7 mmol) of 3-chloro-2-methyl-phenoxyacetonitrile are added to a solution of 13.5 g (194.2 mmol) of hydroxylamine hydrochloride, 7.7 g (194.2 mmol) of sodium hydroxide in 265 ml of ethanol and 68 ml of water. The mixture is heated at reflux temperature until the reaction is complete (approximately 48 to 60 hours) and the entire batch is subsequently stirred into 250 ml of water. The solid which precipitates in this process is separated off, washed with a small amount of water and dried. 31.1 g (90.2% of theory) of 3-chloro-2-methylphenoxyacetamide oxime are obtained.
Reaction SMILES: [C:1]([C:4]1[CH:23]=[CH:22][C:7]([CH2:8][S:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[NH:21][N:20]=[N:19][N:18]=3)=[CH:13][CH:12]=2)=[C:6]([CH2:24][CH2:25][CH3:26])[C:5]=1[OH:27])(=[O:3])[CH3:2].OO.C(O)(=[O:32])C>C(Cl)Cl>[C:1]([C:4]1[CH:23]=[CH:22][C:7]([CH2:8][S:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[NH:18][N:19]=[N:20][N:21]=3)=[CH:15][CH:16]=2)=[O:32])=[C:6]([CH2:24][CH2:25][CH3:26])[C:5]=1[OH:27])(=[O:3])[CH3:2]
Reactant: CCCc1c(CSCc2ccc(-c3nnn[nH]3)cc2)ccc(C(C)=O)c1O
Reactant: CC(=O)O
Agent: OO
Solvent: ClCCl
Product: CCCc1c(CS(=O)Cc2ccc(-c3nnn[nH]3)cc2)ccc(C(C)=O)c1O

Procedure:
A solution of 3.8 g. of 5-[4-(4-acetyl-3-hydroxy-2-propylbenzylthiomethyl)phenyl]-tetrazole in 1.5 ml. of 30% hydrogen peroxide, 100 ml. of acetic acid, and 50 ml. of methylene chloride was stirred for 24 hours at room temperature. The solution was evaporated in vacuo and the residue was dissolved in hot isopropyl alcohol. Water was added and the resulting precipitate was recovered by filtration. Recrystallization from isopropyl alcohol gave 0.8 g. of the title sulfoxide, m.p. 112°-116° C. NMR, IR.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:15]2[C:14]([CH3:16])=[C:13]([CH3:17])[N:12]=[C:11]([NH2:18])[C:10]=2[N:9]=[C:8]1[CH2:19][CH3:20].[C:21]([N:29]=[C:30]=[O:31])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[NH2:18][C:11]1[C:10]2[N:9]=[C:8]([CH2:19][CH3:20])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:30]([NH:29][C:21](=[O:28])[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:31])[C:15]=2[C:14]([CH3:16])=[C:13]([CH3:17])[N:12]=1
Reactant: O=C=NC(=O)c1ccccc1
Reactant: CCc1nc2c(N)nc(C)c(C)c2n1CCOCCN
Product: CCc1nc2c(N)nc(C)c(C)c2n1CCOCCNC(=O)NC(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 22 %

Procedure:
A solution of 1-[2-(2-aminoethoxy)ethyl]-2-ethyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine (1.60 g, 5.77 mmol) was treated with benzoyl isocyanate (0.98 g, 6.6 mmol) using the method described in Example 105. The crude product was purified by column chromatography on silica gel (150 mL, cluting with 90:10 dichloromethane:methanol) and recrystallized from acetonitrile (75 mL/g). The crystals were subsequently recrystallized twice from 2-propanol (40-44 mL/g) and then stirred in water for 30 minutes and isolated by filtration. The solid was dried for three days under high vacuum to provide 0.54 g of N-{2-[2-(4-amino-2-ethyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)ethoxy]ethyl}-N′-benzoylurea as a white solid, mp 185-187° C. 1H NMR (300 MHz, CDCl3) δ 8.98 (br s, 1H), 8.87 (br t, 1H), 7.93-7.87 (m, 2H), 7.63-7.56 (m, 1H), 7.52-7.44 (m, 2H), 4.84 (s, 2H), 4.45 (t, J=5.8 Hz, 2H), 3.76 (t, J=5.8, 2H), 3.57-3.46 (m, 4H), 2.91 (q, J=7.5, 2H), 2.42 (s, 6H), 1.41 (t, J=7.5, 3H); MS (APCI) m/z 425 (M+H)+; Anal. Calcd for C22H28N6O3.0.25 H2O: C, 61.59; H, 6.70; N, 19.59. Found: C, 61.25; H, 6.90; N, 19.72.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[OH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=CC=1.O[CH2:23][CH2:24][C:25]1C=C(O)C=C[CH:30]=1.OCCC1C=CC=CC=1O.OCCC1C=CC(O)=CC=1>>[O:21]1[CH2:18][CH2:19][CH2:20][CH2:15][CH:14]1[O:13][CH2:23][CH2:24][CH2:25][CH2:30][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1
Reactant: OCc1ccc(O)cc1
Reactant: OCCCCc1ccc(O)cc1
Reactant: OCCc1cccc(O)c1
Agent: OCCc1ccc(O)cc1
Agent: OCCc1ccccc1O
Product: Oc1ccc(CCCCCCCCOC2CCCCO2)cc1

Procedure:
Similarly, proceding as in part (C) above but substituting 4-(3-hydroxypropyl)phenol, 4-(4-hydroxybutyl)phenol, 4-(hydroxymethyl)phenol, 3-(2-hydroxyethyl)phenol, and 2-(2-hydroxyethyl)phenol for 4-(2-hydroxyethyl)phenol, the following compounds are prepared:
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([CH:9]=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].CC(C)=[O:13].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C.O>CC(C)=O.C(Cl)Cl>[N+:1]([C:4]1[S:8][C:7]([C:9]([OH:13])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)=O
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: ClCCl
Solvent: O
Product: O=C(O)c1ccc([N+](=O)[O-])s1

Procedure:
To a solution of 5-nitro-2-thiophenecarboxaldehyde (1.00 g, 6.24 mmol) in acetone (50 ml) was added Jones reagent (8N in acetone, 8.12 ml, 65 mmol) at −20° C. After stirring for 1H, 30 ml of isopropanol was added to the mixture. H2O was added to the mixture and excited with CH2Cl2. The extract was washed with water, brine, dried (Na2SO4), and concentrated to give 967 mg (90%) of yellow amorphous.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]([OH:11])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)(Cl)=O.[CH3:16][C:17]1[N:21](CCO)[C:20]([N+:25]([O-:27])=[O:26])=[CH:19][N:18]=1>O>[CH3:16][C:17]1[NH:21][C:20]([N+:25]([O-:27])=[O:26])=[CH:19][N:18]=1.[N+:1]([C:4]1[O:8][C:7]([C:9]([O:11][CH2:16][CH3:17])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Cc1ncc([N+](=O)[O-])n1CCO
Reactant: O=C(O)c1ccc([N+](=O)[O-])o1
Solvent: O=S(Cl)Cl
Solvent: O
Product: CCOC(=O)c1ccc([N+](=O)[O-])o1
Product: Cc1ncc([N+](=O)[O-])[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 25.9 %

Procedure:
The reaction mixture of 5-Nitro-2-furoic acid (157 mg, 1.0 mmol) and thionyl chloride (2 ml) was refluxed for 2 h. The excessive thionyl chloride was evaporated under vacuum. The residue was dissolved in 4 ml of dichloromethane. To this solution, metronidazole (152 mg, 0.89 mmol) was added. After the mixture was stirred at room temperature for 20 h, water was added to this mixture. The organic layer of dichloromethane was separated, washed with 5% Na2CO3, H2O, and brine, and then dried over MgSO4. The solvent was removed, and the residue was recrystallized from C2H5OH—EtOAc to give 36 mg 2-methyl-5-nitro-1H-imidazole-1-ethyl 5-nitro-2-furoate. m.p.: 150-152° C.
Reaction SMILES: Cl.N([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)C=NN=1)N.[CH3:14][C:15](=[O:18])CC>CO.O>[CH2:15]([OH:18])[CH3:14].[CH3:4][CH2:13][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCC(C)=O
Reactant: NNc1nncc2ccccc12
Agent: Cl
Solvent: CO
Solvent: O
Product: CCCCCCC
Product: CCO
Yield: 78 %

Procedure:
A 10 parts 1-hydrazinophthalazine HCL (0.05 Molar) in 50% methanol-water are mixed with 1 part 2-butanone. After evaporation of solvents, 1-hydrazinophthalazine 2-butanone hydrazone is crystallized from ethanol-heptane (78% yield). [The Journal of Pharmacology and Experimental Therapeutics 205 (2): 418-425 (1978)].
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]([O:14][CH3:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:6][CH:5]=[CH:4][C:3]=1[C:16]1[N:17]=[C:18]([NH2:21])[S:19][CH:20]=1.Br[C:23]1[CH:28]=[C:27]([F:29])[C:26](/[CH:30]=[C:31](\[O:36][CH3:37])/[C:32]([O:34][CH3:35])=[O:33])=[C:25]([F:38])[CH:24]=1.C(N(CC)CC)C.O.CN([CH:50]=[O:51])C>>[F:29][C:27]1[CH:28]=[C:23]([C:50](=[O:51])[NH:21][C:18]2[S:19][CH:20]=[C:16]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([CH:8]([O:14][CH3:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:2]=3[F:1])[N:17]=2)[CH:24]=[C:25]([F:38])[C:26]=1/[CH:30]=[C:31](\[O:36][CH3:37])/[C:32]([O:34][CH3:35])=[O:33]
Reactant: CCCCCC(OC)c1cccc(-c2csc(N)n2)c1F
Reactant: COC(=O)/C(=C/c1c(F)cc(Br)cc1F)OC
Reactant: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCC(OC)c1cccc(-c2csc(NC(=O)c3cc(F)c(/C=C(\OC)C(=O)OC)c(F)c3)n2)c1F
Temperature: 85 °C
Reaction time: 16 h

Procedure:
4-[2-Fluoro-3-(1-methyloxyhexyl)phenyl]thiazol-2-ylamine (460 mg) and methyl (Z)-3-(4-bromo-2,6-difluorophenyl)-2-methyloxyacrylate (462 mg), and dichlorobistriphenylphosphinepalladium (150 mg) were dissolved in DMF (6 mL). Triethylamine (0.84 mL) was added into the mixture, and the reaction mixture was stirred under carbon monoxide atomosphere at 85° C. for 16 h. Water added into the reaction mixture, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, and brine, dried over magnesium sulfate, evaporated. The obtained residue was purified by Colum chromatography (hexane:ethyl acetate=4:1) to obtain the compound (24) 630 mg.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].C([O-])([O-])=O.[Na+].[Na+].[F:31][C:32]([F:43])([F:42])[C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1>COCCOC>[F:31][C:32]([F:43])([F:42])[C:33]1[CH:38]=[C:37]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:11])[CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CSc1ccccc1Br
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)CSc1ccccc1-c1cccc(C(F)(F)F)c1
Yield: 13.8 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-phenylsulfanyl)-acetyl]-N′-isopropyl-hydrazide (50 mg, 0.123 mmol) in DME (4 ml)/2M Na2CO3 (0.215 ml, 0.43 mmoles) was treated with 3-trifluoromethylphenylboronic acid (47 mg, 0.25 mmol) and Pd[PPh3]4 (14 mg, 0.012 mmol) for 12 hours at 90° C. The reaction mixture was partitioned between water and DCM. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was adsorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexane gradient. Further purification by RP HPLC afforded the product (8 mg, 14%). MS m/e 473.16 (M+H+)