Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:41]([CH2:45][CH2:46][OH:47])[CH:42]=[CH:43][N:44]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:57])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:41]([CH2:45][CH2:46][OH:47])[CH:42]=[CH:43][N:44]=5)=[O:57])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nccn4CCO)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nccn4CCO)cc2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[[1-(2-hydroxyethyl)-1H-imidazol-2-yl]methyl]thio]phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.40 g) in dichloromethane (10 ml) was added a solution of 3-chloroperbenzoic acid (70%, 0.22 g) in dichloromethane (10 ml) at −78° C. The mixture was stirred for 1 hour at −78° C., an aqueous solution of sodium thiosulfate was added to the mixture, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with an aqueous solution of sodium bicarbonate and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (basic silica gel, ethanol:ethyl acetate 1:9), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[[1-(2-hydroxyethyl)-1H-imidazol-2-yl]methyl]sulfinyl]phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 434) (280.5 mg) as yellow amorphous.
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[CH2:4][CH2:5][N:6]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11](F)=[CH:10][CH:9]=1)[CH3:2].[NH:28]1[CH:32]=[CH:31][N:30]=[CH:29]1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O.CO.C(Cl)Cl>[CH2:1]([N:3]([CH2:26][CH3:27])[CH2:4][CH2:5][N:6]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([N:28]2[CH:32]=[CH:31][N:30]=[CH:29]2)=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCN(CC)CCN(C(=O)c1ccc(F)cc1)c1cccc2ccccc12
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CO
Product: CCN(CC)CCN(C(=O)c1ccc(-n2ccnc2)cc1)c1cccc2ccccc12
Temperature: 150 °C

Procedure:
A mixture of 6.0 g (16.5 mmol) N-[2-(diethylamino)ethyl]-4-fluoro-N-(1-naphthalenyl)benzamide, 1.68 g (24.7 mmol) of imidazole, 4.55 g (33 mmol) of anhydrous potassium carbonate and 6.0 mL of dimethylsulfoxide is heated to 150° C. for 18 hr. After this time, the reaction mixture is dissolved in 150 mL water, 100 mL methylene chloride and 40 mL of methanol. The organic is dried over sodium sulfate, filtered and the solvent distilled in vacuo. The residue is recrystallized from acetone to provide the title compound.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH2:22][C:23]1[N:24]=[CH:25][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:27]=1)=[O:19])C1C=CC=CC=1>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH2:22][C:23]1[N:24]=[CH:25][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:27]=1)=[O:19]
Reactant: CC(C)(C)OC(=O)n1cnc(CONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)n1cnc(CONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3O)c1
Reaction time: 13 h
Yield: 101.8 %

Procedure:
A mixture of tert-butyl 4-{[({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}-1H-imidazole-1-carboxylate 123 (0.40 g, 0.85 mmol) and Pd/C (0.10 g) in methanol (15 mL) was hydrogenated at 1 atm at room temperature for 13 h. The mixture was filtered through Celite pad and concentrated to provide 124 (0.33 g, quantitative) as a white foam.
Reaction SMILES: C([O:4][CH2:5][C@@H:6]([N:23]([CH2:31][C@H:32]([O:41]C(=O)C)[CH2:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)(=O)C.[H-].[Na+].I[CH3:48]>O1CCCC1>[CH2:24]([N:23]([C@H:6]([CH2:5][OH:4])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]([CH3:48])[C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:13]=1)[CH2:31][C@H:32]([OH:41])[CH2:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CI
Reactant: CC(=O)OC[C@H](Cc1ccc(NC(=O)c2ccccc2)cc1)N(Cc1ccccc1)C[C@@H](COc1ccccc1)OC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C(=O)c1ccccc1)c1ccc(C[C@@H](CO)N(Cc2ccccc2)C[C@H](O)COc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice-cooled solution of N-[4-[(2S)-3-acetoxy-2-[N-[(2S)-2-acetoxy-3-phenoxypropyl]-N-benzylamino]propyl]-phenyl]benzamide (107 mg) in tetrahydrofuran (1.1 ml) was added sodium hydride (60% in oil, 17 mg), and the mixture was stirred at the same temperature for 30 minutes. To the mixture was added iodomethane (25 μl), and the mixture was stirred at room temperature for 1.5 hours before being partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated and the residue was dissolved in methanol (1.1 ml)-1,4-dioxane (1.1 ml), then treated with 1N sodium hydroxide (0.5 ml) at room temperature for 1.5 hours. The mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate) to give N-[4-[(2S)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]-amino]-3-hydroxypropyl]phenyl]-N-methylbenzamide (55 mg) as a white amorphous powder.
Reaction SMILES: Cl[C:2]1[N:7]2[C:8]([CH3:11])=[N:9][CH:10]=[C:6]2[CH:5]=[C:4]([Cl:12])[N:3]=1.[CH3:13][S-:14].[Na+]>>[Cl:12][C:4]1[N:3]=[C:2]([S:14][CH3:13])[N:7]2[C:8]([CH3:11])=[N:9][CH:10]=[C:6]2[CH:5]=1
Reactant: Cc1ncc2cc(Cl)nc(Cl)n12
Reactant: C[S-]
Agent: [Na+]
Product: CSc1nc(Cl)cc2cnc(C)n12

Procedure:
Using the method of Example 53, 5,7-dichloro-3-methylimidazo[1,5-c]pyrimidine (from Example 35) was reacted with sodium methanethiolate to provide yellow solid 7-chloro-3-methyl-5-methylthioimidazo[1,5-c]pyrimidine, m.p. 153°-155° C. Analysis: Calculated for C8H8ClN3S: %C, 45.0; %H, 3.8; %N, 19.7; Found: %C, 44.8; %H, 3.5; %N, 19.7.
Reaction SMILES: [BH4-].[Na+].[N:3]1([C:8]2[CH:17]=[CH:16][C:11]([C:12](OC)=[O:13])=[CH:10][N:9]=2)[CH:7]=[CH:6][N:5]=[CH:4]1>CO.O>[N:3]1([C:8]2[CH:17]=[CH:16][C:11]([CH2:12][OH:13])=[CH:10][N:9]=2)[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: COC(=O)c1ccc(-n2ccnc2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCc1ccc(-n2ccnc2)nc1
Reaction time: 15 h

Procedure:
NaBH4 (37.82 g) is added portionwise to a suspension of the imidazolyl ester of Step 2. above (9.98 g) in methanol at about 0.° C. The reaction mixture is heated to reflux for 71/2 hours, allowed to cool and stand 15 hours. Water (75 ml) is added, and the quenched reaction mixture evaporated, affording a solid residue which is suspended in water, extracted with chloroform dried over Na2SO4, filtered and evaporated, recrystallized (CHCl3), affording the desired product as a white solid. M.P.=128.5°-130° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:23]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24])[C:10]1[C:11]([CH3:22])=[CH:12][C:13]([C:16]([NH:18][CH2:19][CH2:20]O)=[O:17])=[N:14][CH:15]=1.C(Cl)[Cl:34]>S(Cl)(Cl)=O>[Cl:34][CH2:20][CH2:19][NH:18][C:16]([C:13]1[CH:12]=[C:11]([CH3:22])[C:10]([CH:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])[S:23]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])=[CH:15][N:14]=1)=[O:17]
Reactant: Cc1cc(C(=O)NCCO)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Reactant: ClCCl
Solvent: O=S(Cl)Cl
Product: Cc1cc(C(=O)NCCCl)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[(4-fluorophenyl)sulfonyl]methyl]-N-(2-hydroxyethyl)-4-methylpyridine-2-carboxamide (120 mg, 0.258 mmol) obtained in Example 17 in methylene chloride (5 ml), thionyl chloride (100 μl) was added, and the mixture was stirred for 4 hours at room temperature. Thionyl chloride (100 μl) was added to the reaction solution, and the mixture was stirred for 1.5 hours at room temperature. The reaction solution was concentrated under reduced pressure, subsequently saturated aqueous sodium hydrogencarbonate was added thereto, and the mixture was extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting concentration residue was subjected to silica gel column chromatography, and the fraction obtained from an elution with 35% ethyl acetate/hexane was concentrated under reduced pressure, to obtain the title compound (102 mg, 0.211 mmol, 82%) as a white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>N1C=CC=CC=1.C(Cl)Cl>[O:1]1[CH2:6][CH2:5][CH:4]([O:7][S:14]([C:11]2[CH:12]=[CH:13][C:8]([CH3:18])=[CH:9][CH:10]=2)(=[O:16])=[O:15])[CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC1CCOCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.3 %

Procedure:
To a solution of 133 g (1.31 mol) of tetrahydropyran-4-ol in pyridine (1.5 L) are added 373 g (1.95 mol) of p-toluenesulfonylchloride portionwise at 10° C. After complete addition the reaction is allowed to warm to room temperature and stirred for 18 h. The reaction is poured onto a stirred mixture of aqueous HCl/ice. The resulting precipitate is isolated by filtration and dissolved in DCM (1 L). The organic layer is washed with 1M aqueous HCl solution (1 L), followed by saturated aqueous NaHCO3 solution (1 L) and is then dried over Na2SO4. Filtration and concentration of the filtrate under reduced pressure gives 300 g of toluene-4-sulfonic acid tetrahydropyran-4-yl ester as an orange oil. Yield: 90%, ES-MS: m/z: 257 [M+H], 279 [M+Na]
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][N:18]=1>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][N:18]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc([N+](=O)[O-])cn2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
A solution of (S)-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (500 mg, 2.67 mmol) in anhydrous tetrahydrofuran (10 mL) was added to sodium hydride (60% in mineral oil, 215 mg, 5.34 mmol) gradually, and the resulting mixture was stirred at room temperature for 1 h. 2-Chloro-5-nitropyridine (425 mg, 2.68 mmol) was added, and the reaction mixture was stirred at room temperature for 3 h, then quenched with water, extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated to afford (S)-3-(5-nitro-pyridin-2-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester as a brown oil (800 mg, 98% yield). The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1)=O.[N:13]1[NH:14][C:15](=[O:19])[CH:16]=CC=1>>[O:19]=[C:15]1[NH:14][N:13]=[C:2]([C:4]2[CH:5]=[C:6]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:8][CH:9]=2)[CH:1]=[CH:16]1
Reactant: O=c1cccn[nH]1
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1
Product: O=c1ccc(-c2cccc([N+](=O)[O-])c2)n[nH]1

Procedure:
18 g of 3-nitroacetophenone are converted into the pyridazinone in accordance GWP 1.
Reaction SMILES: [CH2:1]([Li])CCC.[F:6][C:7]([F:19])([F:18])[CH2:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][N:11]=1.O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[F:6][C:7]([F:19])([F:18])[CH2:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[CH2:1])=[CH:12][N:11]=1
Reactant: O=Cc1ccc(OCC(F)(F)F)nc1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1ccc(OCC(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.5 %

Procedure:
n-Butyllithium (5.14 mL, 13.4 mmol) is added to a suspension of methyltriphenylphosphonium bromide (4.41 g, 12.34 mmol) in tetrahydrofuran (51 mL) at −78° C. under nitrogen atmosphere. The reaction mixture is warmed to room temperature to yield deep red ylide solution. To ylide solution, cooling in ice, is introduced 6-(2,2,2-trifluoroethoxy)nicotinaldehyde (2.11 g, 10.3 mmol, Step-1) in tetrahydrofuran (10 mL) and stirred at room temperature for 3 hours. The reaction mixture is poured into water, extracted with ethyl acetate and dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (10:1) to give 1.56 g (75% yield) of the title compound as colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:36])[C:11]([C:32]([O:34]C)=[O:33])=[CH:12][N:13]([CH2:26][CH:27]([O:30][CH3:31])[O:28][CH3:29])[C:14]=1[C:15](=[O:25])[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[OH-].[Li+]>O1CCCC1>[CH2:1]([O:8][C:9]1[C:10](=[O:36])[C:11]([C:32]([OH:34])=[O:33])=[CH:12][N:13]([CH2:26][CH:27]([O:28][CH3:29])[O:30][CH3:31])[C:14]=1[C:15](=[O:25])[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cn(CC(OC)OC)c(C(=O)NCc2cccc(Cl)c2)c(OCc2ccccc2)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(Cn1cc(C(=O)O)c(=O)c(OCc2ccccc2)c1C(=O)NCc1cccc(Cl)c1)OC
Temperature: 70 °C
Reaction time: 1 h
Yield: 61.7 %

Procedure:
To a solution of methyl 5-benzyloxy-6-(3-chlorobenzylcarbamoyl)-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-3-carboxylate (2.0 g) in tetrahydrofuran (20 ml)-methanol (10 ml) was added 4N aqueous lithium hydroxide solution (1.5 ml) and the mixture was stirred at 70° C. for 1 hr. The precipitated solid was removed by thin layer of celite and washed with methanol. The solvent was evaporated and 1N aqueous hydrochloric acid (6.5 ml) and water (50 ml) were added. The mixture was extracted twice with ethyl acetate (75 ml each). The ethyl acetate layer was dried, concentrated and crystallized from ethyl acetate-diisopropyl ether to give 5-benzyloxy-6-(3-chlorobenzylcarbamoyl)-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (1.2 g).
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[N:8][C:7]=1[NH:13]C(=O)C(C)(C)C)[CH2:4][CH3:5])[CH3:2]>Cl>[CH2:1]([CH:3]([C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[N:8][C:7]=1[NH2:13])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)c1cc(C)nnc1NC(=O)C(C)(C)C
Agent: Cl
Product: CCC(CC)c1cc(C)nnc1N
Temperature: 95 °C
Yield: 82.2 %

Procedure:
Dissolve 12.0 g (45 mmol) of N-[4-(1-ethyl-propyl)-6-methyl-pyridazin-3-yl]-2,2-dimethyl-propionamide in 60 ml of concentrated hydrochloric acid. Heat to 95° C. in a sealed flask for 2 h. Work up by pouring over ice and extracting with ethyl acetate three times. Discard the organic and adjust pH of aqueous to basic using 2N sodium hydroxide. Extract basic solution with ethyl acetate five times. Dry over magnesium sulfate, filter, and evaporate to obtain 6.68 g (37 mmol, 81.0%) of the title compound as brownish oil. 1H-NMR (DMSO-d6): δ 6.95 (s, 1H); 5.89 (s, br, 2H); 2.52-2.56 (m, 1H); 2.34 (s, 3H); 1.44-1.58 (m, 4H); 0.72 (t, J=7.04 Hz, 6H) ppm. MS/ES+=180 (100%, M+1).
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH2:3][CH2:2]1.Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CCOCC>[O:7]=[C:1]1[CH2:2][CH2:3][C:4](=[O:6])[N:5]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CCCCCCBr
Reactant: O=C1CCC(=O)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)CCCCCCN1C(=O)CCC1=O
Yield: 68.3 %

Procedure:
A mixture of succinimide (1, 3.2 g, 31.6 mmol) and ethyl 7-bromoheptanoate (5 g, 21 mmol) in dimethylformamide (30 mL) containing potassium carbonate (3.5 g, 25 mmol) was heated at about 55° to 60° C. for twenty hours. The mixture was then diluted with ether and washed twice with water, once with saturated aqueous sodium chloride, and dried over magnesium sulfate. Removal of the solvent under reduced pressure gave the crude product which was purified by high performance liquid chromatography (HPLC) to give 3.66 g of 7-(2-oxo-5-oxopyrrolidin-1-yl)heptanoic acid, ethyl ester, 2. IR (neat): 1775, 1735, 1700 cm-1 ; PMR (CDCl3): δ 4.10 (q, J=7, 2H), 3.46 (t, J=7, 2H), 2.67 (s, 4H), 2.26 (t, J=7, 2H), 1.77-1.11 (m, 8H), and 1.23 (t, J=7, 3H).
Reaction SMILES: [Na].[C:2]1([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][C:12](=[O:17])[C:11]=3[CH:10]=[N:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:18](OCC)=[O:19].C(O)C>C1(C)C=CC=CC=1.O>[O:17]=[C:12]1[CH:13]([CH:18]=[O:19])[CH2:14][CH2:15][C:16]2[N:8]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[N:9]=[CH:10][C:11]1=2
Reactant: O=C1CCCc2c1cnn2-c1ccccc1
Reactant: CCOC=O
Agent: [Na]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: O=CC1CCc2c(cnn2-c2ccccc2)C1=O
Reaction time: 0.5 h
Yield: 3.7 %

Procedure:
To a stirred suspension of sodium (0.75 g, 33 mmol) in toluene (200 mL) was added 1-phenyl-6,7-dihydro-1H-indazol-4(5H)-one (2.6 g, 123 mmol). The reaction mixture was stirred for 30 minutes and a solution of ethyl formate (2.22 mL, 276 mmol) in toluene (10 mL) was added over 10 minutes followed by absolute ethanol (1 mL). The reaction was stirred at room temperature for 40 hours. The reaction mixture was cautiously poured into ice-cooled water (100 mL). The organic layer was separated. The aqueous layer was extracted with diethylether (100 mL) and acidified with 6N HCl to a pH between 5 and 6. The aqueous layer was then extracted with dichloromethane (3×75 mL). The combined organic layer was dried using sodium sulfate and concentrated under reduced pressure to give a residue which on trituration with hexane gave the desired product (1.1 g, 32%) as a solid. 1H NMR (CDCl3, 400 MHz): δ 10.75 (s, 1H), 8.00 (s, 1H), 7.61-7.54 (m, 5H), 7.48-7.45 (m, 1H), 3.00-2.96 (m, 2H), 2.76-2.70 (m, 2H); LCMS [M+H]: 241.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:16]([OH:18])=O)[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.Cl.[NH2:20][CH2:21][C:22]1[C:23](=[O:30])[NH:24][C:25]([CH3:29])=[CH:26][C:27]=1[CH3:28].Cl.CN(C)CCCN=C=NCC.O.N1C2C(=NC=CC=2)N(O)N=1.CN1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]([C:16]([NH:20][CH2:21][C:22]2[C:23](=[O:30])[NH:24][C:25]([CH3:29])=[CH:26][C:27]=2[CH3:28])=[O:18])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15]3)[C:9]=2[CH:10]=1
Reactant: O=C(O)c1cc(Br)cc2c1cnn2C1CCCC1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN1CCOCC1
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-bromo-1-cyclopentyl-1H-indazole-4-carboxylic acid (1.44 g, 4.61 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone hydrochloride (1.138 g, 6.03 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (1.335 g, 6.96 mmol), and 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol hydrate (1.073 g, 6.96 mmol) were suspended in DMSO (8.00 mL), followed by N-methylmorpholine (2.82 g, 27.8 mmol). The reaction mixture was stirred at room temperature overnight to afford a slurry. The slurry was diluted with DMSO (10 mL) and added dropwise to a ice-chilled aqueous solution of 1N Na2CO3 (50 ml) and water (200 mL), and stirred rapidly for 30 min. The precipitate was collected by vacuum filtration and washed with water. The cake was dried in the vacuum oven at 60° C. overnight (16 h). The title compound was obtained as a pale yellow-white solid (2.05 g, 98% yield). 1H NMR (400 MHz, DMSO-δ6) δ 11.50 (br. s., 1H), 8.64 (br. s., 1H), 8.37 (s, 1H), 8.20 (s, 1H), 7.70 (d, J=1.52 Hz, 1H), 5.89 (s, 1H), 5.22 (quin, J=7.01 Hz, 1H), 4.34 (d, J=4.55 Hz, 2H), 2.20 (s, 3H), 2.13 (s, 3H), 2.06-2.11 (m, 2H), 1.91-2.03 (m, 2H), 1.80-1.91 (m, 2H), 1.61-1.75 (m, 2H). LC-MS(ES) [M+H]+ 443.0.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:16]1(=O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C(Cl)Cl>[CH:16]1([N:13]2[CH2:14][CH2:15][N:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[CH2:11][CH2:12]2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C1CCCCC1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(N2CCN(C3CCCCC3)CC2)cc1
Yield: 68.8 %

Procedure:
Following the general procedure described above for the synthesis of 11-(4-nitrophenyl)-4-(pentan-3-yl)piperazine, treatment of 1-(4-nitrophenyl)piperazine (5.00 g, 24.1 mmol, 1.0 equiv.) with cyclohexanone (7.10 g, 72.4 mmol, 2.0 eq) in DCM (100 mL) at rt for 72 h provided the title compound as a yellow solid (4.80 g, 68% recovery, 89% purity as determined by LC/MS analysis @ UV 254 nm detection). In this case, an additional portion (25 mL) is added to the reaction mixture after 1 h. Upon addition of hexane (25 mL) to the crude residue, obtained from evaporation of the DCM extract, and stirring for 24 h the product precipitated from solution and was collected by filtration, washed with hexanes (2×25 mL), and dried under vacuum. The crude product is used in the next step without further purification. LCMS purity: 89% by UV 254 nm detection. LCMS-ESI (m/z): calcd for C16H23N3O2, 289; [M+H]+ found, 290.
Reaction SMILES: C([NH:5][CH2:6][CH2:7][N:8]1[C:16]([CH2:17][C:18]2[C:27]([I:28])=[CH:26][C:21]3[O:22][CH2:23][CH2:24][O:25][C:20]=3[CH:19]=2)=[N:15][C:14]2[C:9]1=[N:10][C:11]([F:30])=[N:12][C:13]=2[NH2:29])(C)(C)C.[C:31](N)([CH3:34])([CH3:33])[CH3:32]>CN(C=O)C>[F:30][C:11]1[N:10]=[C:9]2[C:14]([N:15]=[C:16]([CH2:17][C:18]3[C:27]([I:28])=[CH:26][C:21]4[O:22][CH2:23][CH2:24][O:25][C:20]=4[CH:19]=3)[N:8]2[CH2:7][CH2:6][NH:5][CH2:32][CH:31]([CH3:34])[CH3:33])=[C:13]([NH2:29])[N:12]=1
Reactant: CC(C)(C)NCCn1c(Cc2cc3c(cc2I)OCCO3)nc2c(N)nc(F)nc21
Reactant: CC(C)(C)N
Solvent: CN(C)C=O
Product: CC(C)CNCCn1c(Cc2cc3c(cc2I)OCCO3)nc2c(N)nc(F)nc21

Procedure:
9-(2-(tert-butylamino)ethyl)-2-fluoro-8-((7-iodo-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-9H-purin-6-amine [DZ4-84]. S10-6 (8 mg, 0.0149 mmol) and tert-butylamine (109 mg, 157 μl) in DMF (0.5 mL) was stirred overnight at rt. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH2Cl2:EtOAc:MeOH—NH3 (7N), 7:2:1:0.5) to give 6 mg (77%) of DZ4-84. 1H NMR (500 MHz, CDCl3) δ 7.36 (s, 1H), 6.55 (s, 1H), 5.86 (br s, 2H), 4.29 (s, 2H), 4.17-4.23 (m, 4H), 4.04 (t, J=6.4 Hz, 2H), 2.85 (t, J=6.4 Hz, 2H), 0.99 (s, 9H); MS (ESI) m/z 527.1 [M+H]+.