Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]([CH:7]1[C:12](=[O:13])[CH2:11][CH2:10][CH2:9][C:8]1=O)(=O)[CH3:5]>CCO>[CH3:5][C:4]1[C:7]2[C:12](=[O:13])[CH2:11][CH2:10][CH2:9][C:8]=2[NH:3][N:2]=1
Reactant: NN
Reactant: CC(=O)C1C(=O)CCCC1=O
Solvent: O
Solvent: CCO
Product: Cc1n[nH]c2c1C(=O)CCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.2 %

Procedure:
According to Scheme 4 Step 3: Hydrazine monohydrate (7.59 mmol, 0.37 mL) was added to a solution of 2-acetylcyclohexane-1,3-dione (7.59 mmol, 1.17 g) in EtOH (19 mL) at 0° C. and the reaction mixture was stirred at room temperature for 2 hours. After evaporation, the crude residue was purified by flash chromatography over silica gel using DCM/AcOEt (70:30 to 50:50) as eluent to yield 3-methyl-6,7-dihydro-1H-indazol-4(5H)-one (1.76 mmol, 265 mg, 23%) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][NH:24][O:25][CH3:26].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O1CCCC1>[CH3:26][O:25][N:24]([CH3:23])[C:18]([C:17]1[CH:16]=[CH:15][C:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[CH:22][CH:21]=1)=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)CC1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CON(C)C(=O)c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)benzoic acid (0.7 g, 2.3 mmol), N,O-dimethylhydroxylamine (0.27 g, 2.8 mmol), 1-hydroxybenzotriazole (0.37 g, 2.7 mmol) and 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (1.1 g, 5.8 mmol) in tetrahydrofuran (15 mL) was stirred at ambient temperature for 48 hours. Additional N,O-dimethylhydroxylamine (0.14 g, 1 mmol) was added and the mixture stirred an additional 4 hours and concentrated. The residue was dissolved in ethyl acetate, washed with water and filtered through silica gel. The solution was concentrated and used without further purification.
Reaction SMILES: [OH-].[K+].[CH3:3][N:4]([CH2:6][CH2:7][C@@H:8]([O:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1)[C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)[CH3:5]>CS(C)=O>[CH3:3][N:4]([CH2:6][CH2:7][CH:8]([O:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1)[C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)[CH3:5]
Reactant: CN(C)CC[C@@H](Oc1cccc2ccccc12)c1cccs1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CN(C)CCC(Oc1cccc2ccccc12)c1cccs1
Temperature: 100 °C
Yield: 83.9 %

Procedure:
Ground KOH (1.2 g) is added to a solution of (R)-N,N-dimethyl-3-(naphthyloxy)-3-(2-thienyl)propylamine (3.1 g) in DMSO (10 ml), bubbled with a moderate stream of nitrogen, and the mixture is stirred and heated at 100° C. for 1 hour. After cooling down to lab temperature, the mixture is diluted with water (30 ml) and the racemic product is extracted with toluene. After evaporation, 2.6 g (84%) of (RS)-N,N-dimethyl-3-(naphthyloxy)-3-(2-thienyl)propylamine is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:13]([C:14]([OH:16])=O)[C:12]=1[C:20]([OH:22])=O)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:24][CH:25]1[CH2:31][CH2:30][C:29](=[O:32])[NH:28][C:26]1=[O:27]>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:13]2[C:12]=1[C:20](=[O:22])[N:24]([CH:25]1[CH2:31][CH2:30][C:29](=[O:32])[NH:28][C:26]1=[O:27])[C:14]2=[O:16])[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(Cc1cccc(C(=O)O)c1C(=O)O)C(=O)OC(C)(C)C
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: c1ccncc1
Product: CN(Cc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O)C(=O)OC(C)(C)C
Yield: 59.6 %

Procedure:
A stirred mixture of 3-[(t-butoxycarbonyl-methyl-amino)-methyl]-phthalic acid (2.3 g, 7.1 mmol) from above and α-aminoglutarimide hydrochloride (1.3 g, 7.8 mmol) in pyridine (40 mL) was refluxed for 5 hours. The mixture was cooled and concentrated in vacuo. The residue was dissolved in EtOAc (100 mL) and water (50 mL). The EtOAc solution was separated and washed with water (40 mL), IN citric acid (2×40 mL), water (2×40 mL), and brine (40 mL), and then dried (MgSO4). Solvent was removed in vacuo, and the residue was purified by flash chromatography (SiO2, CH2Cl2: EtOAc 8:2) to give [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-methyl-carbamic acid t-butyl ester (1.7 g, 60%): mp 138-140° C.; 1H NMR (DMSO-d6) δ 11.14 (s, 1H), 7.91-7.81 (m, 2H), 7.57 (b, 1H), 5.19-5.12 (dd, J=5.3 and 12.6 Hz, 1H), 4.85 (s, 2H), 2.97-2.83 (m, 1H), 2.89 (s, 3H), 2.63-2.50 (m, 2H), 2.07-2.03 (m, 1H), 1.44-1.29 (d, 9H); 13CNMR (DMSO-d6) δ 172.70, 169.74, 167.48, 166.87, 154.75, 138.31, 134.99, 132.31, 131.74, 127.42, 121.98, 79.13, 48.86, 47.32, 34.84, 30.90, 27.93, 21.94; Anal. Calcd. for C20H23N3O6: C, 59.84; H, 5.78; N, 10.47. Found: C, 59.51; H, 5.68; N, 10.31.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:17])[CH:12]([NH2:16])[CH2:13]CC)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl>>[NH2:16][CH:12]([CH3:13])[C:11]([NH:10][C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[O:9][N:8]=1)=[O:17]
Reactant: CCCC(N)C(=O)Nc1cc(C(C)(C)C)on1
Agent: Cl
Product: CC(N)C(=O)Nc1cc(C(C)(C)C)on1

Procedure:
Prepared by methods analogous to those used in the preparation of 2-amino-pentanoic acid (5-tert-butyl-isoxazol-3-yl)-amide starting with the corresponding N-t-BOC analogs and HCl(g) in an appropriate solvent.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-])=O.[K+].[Cl-].[Mg+2].[Cl-].C(N(CC)CC)C.[F:21][C:22]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:23]=1C(Cl)=O>C(#N)C>[CH2:8]([O:7][C:1](=[O:6])[CH:2]([C:23]1[CH:27]=[C:28]([F:32])[C:29]([F:31])=[CH:30][C:22]=1[F:21])[CH3:3])[CH3:9]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=C(Cl)c1cc(F)c(F)cc1F
Agent: [Cl-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)c1cc(F)c(F)cc1F
Yield: 94 %

Procedure:
To an oven-dried flask was added potassium ethyl malonate (3.66 g, 21.5 mmol) and freshly distilled acetonitrile (70 mL). The mixture was cooled to 10° C. to 15° C. and stirred under an atmosphere of nitrogen and to it added anhydrous magnesium chloride (2.44 g, 25.7 mmol) and triethylamine (2.05 g, 20.3 mmol). The mixture was then stirred at room temperature under nitrogen for 2.5 hours. The resultant white slurry was recooled to 0° C. and 2,4,5-trifluorobenzoyl chloride was added over a period of 15 minutes, followed by more triethylamine (0.23 g, 2.3 mmol). The mixture was then stirred at room temperature overnight under nitrogen. Acetonitrile was then removed in vacuo and toluene (30 mL) was added. The mixture was reconcentrated and more toluene (60 mL) then added. Hydrochloric acid (1.5 M, 40 mL) was cautiously added, ensuring that the temperature did not exceed 25° C., and the aqueous layer separated. The organic fraction was washed with 1.5 M HCl (2×25 mL) and water (2×25 mL), dried over MgSO4, and solvent removed in vacuo to afford 3-oxo-3-(2,4,5-trifluoro-phenyl-propionic acid ethyl ester as a pale orange solid (2.35 g, 9.55 mmol, 94%). Rf 0.55 (CH2C2), mp 57-59° C. FTIR, νmax/cm −1 3088, 2990, 1735, 1687, 1514, 1429, 1321, 1205, 1140, 1055, 897, 807. 1 H NMR (CDCl3, 250 MHz), δ/ppm [12.69 (s), 5.81 (s) and 3.92 (d, J=3.9 Hz)] (2 H, keto-enol tautomers); 7.74 (1 H, m, Ar H); 6.98 (1 H, m, Ar H); 4.24 and 4.17 (2 H, both q, 3J=7.1 Hz); 1.31 and 1.24 (3 H, both t, 3J=7.1 Hz). 13C{1 H}NMR (CDCl3, 63 MHz), δ/ppm 187.8 (C=O); 173.0 (—HC=C); 166.9 (CO2Et); 163.7, 159.8, 155.9, 151.8, 149.0, 145.3, 120.9 (quat. Ar C); 118.7, 106.6 (Ar C—H); 92.9 (HC=C); 61.4 and 60.6 (—OCH2); 49.4 (—OCCH2CO—); 14.0 (—CH3). 19FNMR (CDCl3, 235 MHz) δ/ppm −110.6 and −111.7 (m, Ar F); −123.5 and −129.0 (m, Ar F); −140.5 and −141.7 (m, Ar F). λmax/nm (δ/dm3mol−1cm−1) 295 (4781), 281 (3962), 240 (5191). HRMS (EI), M+/z C11H9F3O3 (M−) requires 246.0504; found 246.0514.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:27])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24]CC)=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].O>C(O)C>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:27])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCCCCC(=O)Nc1ccccc1NC(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)CCCCCC(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.6 %

Procedure:
To a solution of Ethyl 7-((2-((tert-butoxycarbonyl)amino)phenyl)amino)-7-oxoheptanoate (14 g, 37 mmol) in ethanol (80 mL) was added KOH (6.2 g, 111 mmol) and water (80 mL). The mixture was stirred at room temperature for 4 hours and concentrated under reduced pressure. The pH value of the solution was adjusted to 4 by concentrated HCl. The resulting mixture was extracted by EtOAc (200 mL×3). The organic layers were combined and dried over Na2SO4, then concentrated to give the desired compound (12 g, yield 92.5%).
Reaction SMILES: Cl.[CH2:2]([C:9]1[NH:10][NH:11][C:12]2[CH:18]=[CH:17][N:16]=[CH:15][C:13]=2[N:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:19]([Cl:29])(=[O:28])[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[ClH:29].[CH2:2]([C:9]1[NH:10][N:11]([C:19](=[O:28])[CH:20]=[CH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:12]2[CH:18]=[CH:17][N:16]=[CH:15][C:13]=2[N:14]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc(CC2=Nc3cnccc3NN2)cc1
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: Cl
Product: O=C(C=Cc1ccccc1)N1NC(Cc2ccccc2)=Nc2cnccc21
Yield: 78 %

Procedure:
3-Benzyl-1,2-dihydropyrido[3,4-e]-as-triazine hydrochloride is reacted with cinnamoyl chloride as described in Example 1 to obtain 3-benzyl-1-cinnamoyl-1,2-dihydropyrido[3,4-e]-as-triazine hydrochloride with a yield of 78%; m.p.: 228° C.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:21]2[C:12](=[N:13][C:14]3[C:19]([N:20]=2)=[C:18]2[CH:22]=[CH:23][C:24]([O:26]C)=[CH:25][C:17]2=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=1)=[O:7].[S-]CC.[Na+].Cl>CN(C)C=O>[CH3:1][N:2]([CH3:28])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:21]2[C:12](=[N:13][C:14]3[C:19]([N:20]=2)=[C:18]2[CH:22]=[CH:23][C:24]([OH:26])=[CH:25][C:17]2=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=1)=[O:7]
Reactant: COc1ccc2c(ccc3nc4cccc(C(=O)NCCN(C)C)c4nc32)c1
Agent: CC[S-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCNC(=O)c1cccc2nc3ccc4cc(O)ccc4c3nc12
Yield: 86.8 %

Procedure:
To a solution of 3-methoxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide (170 mg) in dry N,N-dimethylformamide (3 mL) was added sodium thioethoxide (380 mg). The reaction mixture was then heated to reflux under argon for 3 hours. The reaction mixture was cooled, acidified (dilute HCl) and volatiles removed in vacuo. The residue was purified using column chromatography (20% methanol in dichloromethane) to yield the title compound as a red solid (142 mg).
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14](C=O)=[CH:13][C:12]=2[N+:19]([O-:21])=[O:20])[CH2:4][CH2:3]1.[CH:22]([O:27][CH3:28])([O:25][CH3:26])OC.Cl.C(=O)([O-])[O-].[K+].[K+]>ClCCl.CO>[CH3:28][O:27][CH:22]([O:25][CH3:26])[C:14]1[CH:17]=[CH:18][C:11]([O:10][CH2:9][CH2:8][N:5]2[CH2:4][CH2:3][O:2][CH2:7][CH2:6]2)=[C:12]([N+:19]([O-:21])=[O:20])[CH:13]=1
Reactant: COC(OC)OC
Reactant: O=Cc1ccc(OCCN2CCOCC2)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: COC(OC)c1ccc(OCCN2CCOCC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.4 %

Procedure:
A solution of 4-(2-morpholinoethoxy)-3-nitrobenzaldehyde hydrochloride obtained in Step 1 (2.97 g, 9.38 mmol) in dichloromethane (10.0 mL) was added with trimethyl orthoformate (15.0 mL, 13.7 mmol) and a 10% solution of hydrogen chloride in methanol (5.00 mL), followed by stirring at room temperature for 4 hours. The reaction mixture was added with potassium carbonate (10.0 g, 72.4 mmol), then stirred at room temperature for 5 hours, and the solvent was evaporated under reduced pressure. The residue was added with water (50 mL) and was extracted with ethyl acetate (50 mL×3). After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to obtain 4-dimethoxymethyl-1-(2-morpholinoethoxy)-2-nitrobenzene (2.98 g, 97%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[CH2:15][N:14]([C:21](=[N:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[CH:26][C:25]=1[C:34]#[N:35])[CH3:22])[CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(N(C)C)=O.[OH-].[Na+]>[Cl-].[Zn+2].[Cl-].O>[NH2:35][C:34]1[C:25]2[C:24](=[CH:29][C:28]([O:30][CH3:31])=[C:27]([O:32][CH3:33])[CH:26]=2)[N:23]=[C:21]([N:14]2[CH2:13][CH2:12][C:11]3[C:16](=[CH:17][C:18]([O:19][CH3:20])=[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:10]=3)[CH2:15]2)[CH:22]=1
Reactant: COc1cc(C#N)c(N=C(C)N2CCc3cc(OCc4ccccc4)c(OC)cc3C2)cc1OC
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc2nc(N3CCc4cc(OCc5ccccc5)c(OC)cc4C3)cc(N)c2cc1OC
Yield: 65 %

Procedure:
N-(1-[6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinol-2-yl]ethylidene)-2-cyano-4,5-dimethoxyaniline (10.92 g), anhydrous zinc chloride (3.16 g) and dimethylacetamide (25 ml) were mixed at 20° and then stirred at reflux for two hours. The reaction mixture was allowed to cool to about 40° and then 2N sodium hydroxide (16 ml) was added. The mixture was cooled to 25°and stirred for fifteen minutes. 2N Sodium hydroxide (10 ml) and water (50 ml) were added and the reaction mixture was then extracted with methylene chloride (3×100 ml). The combined organic extracts were washed (H2O), dried (MgSO4) and evaporated in vacuo. The residue was chromatographed on silica (Merck "ART.9385") under medium pressure eluting with methylene chloride containing gradually increasing amounts (1-20%) of methanol. The combined product-containing fractions were evaporated and the residue was recrystallised from ethanol and washed (Et2O) to give 4-amino-2-(6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinol-2-yl)-6,7-dimethoxyquinoline (7.1 g) as a pale yellow powder, m.p. 181°-2°.
Reaction SMILES: [C:1]1([NH:7][NH:8][C:9]([NH2:11])=[S:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(O)C>[CH2:16]([O:15][C:13]([N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[NH:8][C:9]([NH2:11])=[S:10])=[O:14])[CH3:17]
Reactant: NC(=S)NNc1ccccc1
Reactant: CCOC(=O)Cl
Solvent: CCO
Product: CCOC(=O)N(NC(N)=S)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1-phenylthiosemicarbazide (25 g), ethanol (180 ml) and ethyl chloroformate (17 ml) was heated under reflux with stirring for 30 minutes. The mixture was cooled to room temperature and the solid was filtered, washed with ethanol and then with ether to give 28.9 g of the desired product.
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[F:12][C:13]([F:22])([F:21])[C:14]1[CH:15]=[CH:16][C:17](Cl)=[N:18][CH:19]=1.[CH3:23][O:24][N:25]=[C:26]([C:35]1[N:39]=[C:38]([CH3:40])[O:37][N:36]=1)[C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[OH:34]>CCOCC>[CH3:23][O:24][N:25]=[C:26]([C:35]1[N:39]=[C:38]([CH3:40])[O:37][N:36]=1)[C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[O:34][C:17]1[CH:16]=[CH:15][C:14]([C:13]([F:22])([F:21])[F:12])=[CH:19][N:18]=1
Reactant: CON=C(c1noc(C)n1)c1cc(Cl)ccc1O
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CON=C(c1noc(C)n1)c1cc(Cl)ccc1Oc1ccc(C(F)(F)F)cn1
Temperature: 110 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
N,N-Dimethylformamide (1 ml), potassium carbonate (0.10 g, 0.74 mmol) and 5-trifluoromethyl-2-chloropyridine (0.10 g, 0.56 mmol) were added to 5-chloro-2-hydroxyphenyl 5-methyl-1,2,4-oxadiazol-3-yl ketone O-methyloxime (0.10 g, 0.37 mmol), and the mixture was stirred at 110° C. for 2 hours. After completion of the reaction, ether (100 ml) was added, and the mixture was washed with saturated brine (80 ml) twice. The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 5-chloro-2-(5-trifluoromethyl-2-pyridyloxy)phenyl 5-methyl-1,2,4-oxadiazol-3-yl ketone O-methyloxime (0.14 g, 91.7%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]=[C:12]=[S:13])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH2:14]([NH2:17])[CH2:15][NH2:16].O>CCOCC>[NH2:16][CH2:15][CH2:14][NH:17][C:12]([NH:11][C:5]1[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[S:13]
Reactant: COc1cc(N=C=S)cc(OC)c1
Reactant: NCCN
Solvent: O
Solvent: CCOCC
Product: COc1cc(NC(=S)NCCN)cc(OC)c1
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
A slurry of 9.75 g (0.05 mole) of 3,5-dimethoxyphenyl isothiocyanate in 27 ml of ether was added dropwise to a stirred solution of 3.0 g (0.05 mole) of ethylenediamine at room temperature. A five-degree rise in temperature was noted at the start of the one hour addition period. A solid appeared during the addition, and stirring was continued for 2.5 hours. The batch was allowed to stand overnight, and 100 ml of H2O was added. The solid was removed by filtration and the filtrate acidified with 4.5 ml of concentrated HCl and evaporated to dryness on the steam bath. The residue was sonicated with 100 ml of water and warmed to 50° C. for 10 minutes. This was filtered and basified to pH 10 with 10% NaOH. This gave 2.6 g of 14, m.p. 125°-126° C. Analysis satisfactory for C11H17N3O2S.
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][N:6]=1.O.[NH2:14][NH2:15]>CC(O)C>[C:7]1([C:4]2[S:3][C:2]([NH:14][NH2:15])=[N:6][N:5]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Clc1nnc(-c2ccccc2)s1
Reactant: NN
Solvent: CC(C)O
Solvent: O
Product: NNc1nnc(-c2ccccc2)s1

Procedure:
A solution of the 2-Chloro-5-phenyl-[1,3,4]thiadiazole (2 mmol) and hydrazine hydrate (6 mmol, 3 eq) in iPrOH (10 mL) was heated at reflux overnight. The solvent was evaporated, water was added, and the product was isolated by filtration (110 mg, 57%).
Reaction SMILES: C([O:5][C:6]([C:8]1[N:12]([CH2:13][CH2:14][CH2:15][CH3:16])[C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:10][N:9]=1)=O)CCC.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:13]([N:12]1[C:11]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[N:10][N:9]=[C:8]1[CH2:6][OH:5])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCOC(=O)c1nnc(-c2ccccc2)n1CCCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCn1c(CO)nnc1-c1ccccc1

Procedure:
4-Butyl-5-phenyl-4H-[1,2,4]triazole-3-carboxylic acid butyl ester (169) (1.38 g, 5 mmol) is taken up in 50 ml anhydrous THF. LAH is added (3 eq.). The reaction is refluxed for 12 hours and then quenched carefully with water. Purification by column with 2.5% MeOH/DCM gives the desired product (170). 1HNMR(CDCl3): δ=7.40-7.60(5H, m, phenyl-H), 4.88(2H, s, —CH2OH), 4.26(1H, br, —OH), 4.10 (2H, t, J=7.8 Hz, —CH2—), 1.58-1.70 (2H, m, —CH2—), 1.08-130(2H, m, —CH2—), 0.82 (3H, t, J=7.5HZ, —CH3)
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20](O)=[O:21])=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[CH2:25]([CH2:27][NH2:28])[OH:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[OH:26][CH2:25][CH2:27][NH:28][C:20]([C:18]1[CH:17]=[CH:16][C:13]2[N:14]([CH3:15])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:19]=1)=[O:21]
Reactant: NCCO
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCCO)ccc21
Yield: 8.9 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethyl)-amide (9 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (90 mg), ethanolamine (17 mg), HBTU (114 mg), and DIEA (66 uL). LC/MS: m/z 402.9. 1H NMR (DMSO-d6, 400 MHz): δ 12.35 (bs, 1H), 8.36 (s, 1H), 8.06 (s, 1H), 7.91 (s, 1H), 7.74 (s, 1H), 7.63 (s, 1H), 7.45 (d, 1H), 7.37 (dd, 1H), 4.72 (t, 1H), 3.63 (bs, 3H), 3.52 (q, 2H), 3.34 (q, 2H).
Reaction SMILES: C([O:4][C@@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[CH2:8][O:7][C@H:6]1[N:19]1[C:23]2[CH:24]=[C:25]([Cl:29])[C:26]([Cl:28])=[CH:27][C:22]=2[N:21]=[C:20]1[Cl:30])(=O)C.C(=O)([O-])[O-].[Na+].[Na+].C(O)(=O)C>C(O)C.O>[C@@H:6]1([N:19]2[C:23]3[CH:24]=[C:25]([Cl:29])[C:26]([Cl:28])=[CH:27][C:22]=3[N:21]=[C:20]2[Cl:30])[O:7][CH2:8][C@H:9]([OH:15])[C@@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](OC(C)=O)CO[C@H]1n1c(Cl)nc2cc(Cl)c(Cl)cc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: O[C@@H]1[C@H](O)[C@@H](O)CO[C@H]1n1c(Cl)nc2cc(Cl)c(Cl)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 100 ml round bottom flask was charged with 1-(2,3,4-Tri-O-acetyl-α-L-lyxopyranosyl)-2,5,6-trichlorobenzimidazole (303 mg, 0.65 mmol) and this was dissolved in 50 ml of an equimolar mixture of ethanol and water. To the stirred solution was added anhydrous sodium carbonate (212 mg, 2.0 mmol) and the reaction mixture allowed to stir at room temperature for 3 hours. The solution was neutralized with acetic acid and the solvent evaporated in vacuo. the resultant solid was dissolved in ethyl acetate and this was washed successively with water, sat. NaHCO3 solution, and sat. NaCl solution (1×50 ml each). The organic layer was dried over sodium sulfate and the solvent evaporated in vacuo to yield, upon vacuum drying, 205 mg (89.1%) of the title compound as a white foam. mp 184-184.5° C. 1H NMR (DMSO-d6, 360 at MHz) δ7.980 (s,1H), 7.922 (s, 1H), 5.644 (d,1H, J=9.26 Hz), 5.489 (d, 1H, J=3.24 Hz), 5.401 (d, 1H, J=3.76 Hz), 5.266 (d, 1H, J=6.52 Hz), 4.245 (m, 1H), 3.924 (d, 1H, J=2.81 Hz), 3.905 (dd, 2H, J=11.64 Hz, J=72.50 Hz). Anal. Calcd. for C, 40.76; H, 3.14; N, 7.92. Found: C, 40.78; H, 3.28; N, 7.75.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]3[C:12]4[N:20]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:19]([CH3:25])=[N:18][C:13]=4[CH:14]=[N:15][C:16]=3[CH:17]=2)=[CH:2]1.ClC1C=C(C=CC=1)C(OO)=O.[OH-].[NH4+:38].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl>[O:1]1[CH:5]=[CH:4][C:3]([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]3[C:12]4[N:20]([CH2:21][CH:22]([CH3:23])[CH3:24])[C:19]([CH3:25])=[N:18][C:13]=4[C:14]([NH2:38])=[N:15][C:16]=3[CH:17]=2)=[CH:2]1
Reactant: Cc1nc2cnc3cc(OCc4ccoc4)ccc3c2n1CC(C)C
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClCCl
Product: Cc1nc2c(N)nc3cc(OCc4ccoc4)ccc3c2n1CC(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
7-(Furan-3-ylmethoxy)-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (500 mg) was dissolved in 30 mL of dichloromethane and 3-chloroperoxybenzoic acid (60% pure, 403 mg) was added. The reaction was stirred for 30 minutes at ambient temperature and then 30 mL of aqueous ammonium hydroxide was added. After 10 minutes, p-toluenesulfonyl chloride (268 mg, 1.40 mmol) was added and the reaction was stirred for an additional 15 minutes. The layers were separated and the aqueous fraction was washed with two portions of dichloromethane (20 mL). The organic fractions were combined and washed three times with 20 mL portions of aqueous sodium carbonate. The combined sodium carbonate fractions were extracted with four portions of chloroform (20 mL). All of the organic fractions were combined, dried over magnesium sulfate, and concentrated to yield an orange foam. The crude product was purified using flash column chromatography on silica gel, eluting with a gradient of methanol in chloroform. The clean fractions were combined, concentrated, and the resulting solid was recrystallized from acetonitrile to give 102 mg of 7-(furan-3-ylmethoxy)-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine as a white powder, mp 181.0-183.0.