Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[CH3:3][N:4]([CH3:13])[CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23]Br)=[CH:17][CH:16]=1.C(N(CC)CC)C>CN(C=O)C>[ClH:1].[ClH:1].[CH3:13][N:4]([CH3:3])[CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:23][CH2:22][O:21][C:18]2[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=2)[CH2:9][CH2:8]1
Reactant: CN(C)CCC1CCNCC1
Reactant: Fc1ccc(OCCBr)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)CCC1CCN(CCOc2ccc(F)cc2)CC1

Procedure:
In a similar manner to Example 16, a mixture of 4-(2-dimethylaminoethyl)piperidine dihydrochloride (5.5 g), 2-bromoethyl 4-fluorophenyl ether (5.26 g), triethylamine (13.4 ml) and DMF (50 ml) was heated on a steam bath for 16 hours to give 4-(2-dimethylaminoethyl)-1-[2-(4-fluorophenoxy)ethyl]piperidine dihydrochloride, m.p. 260°-262° C.
Reaction SMILES: [Br-].[N:2]1[CH:7]=[CH:6][CH:5]=[N:4][C:3]=1[N:8]1[CH2:17][CH2:16][N+:11]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:10][CH2:9]1.[NH:18]1[CH:22]=[CH:21][CH:20]=[N:19]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:4]1[CH:5]=[CH:6][CH:7]=[N:2][C:3]=1[N:8]1[CH2:9][CH2:10][N:11]([CH2:15][CH2:14][CH2:13][CH2:12][N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)[CH2:16][CH2:17]1
Reactant: c1cnc(N2CC[N+]3(CCCC3)CC2)nc1
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1cnc(N2CCN(CCCCn3cccn3)CC2)nc1
Temperature: 140 °C

Procedure:
A mixture of 730 g (3.59 moles) of 8-(2-pyrimidinyl)-8-aza-5-azoniaspiro[4,5]decane bromide, 275 g (4.05 moles) of pyrazole and 745 g (5.4 moles) of potassium carbonate in 3 1 of dimethylformamide is heated to 140° C. for 14 hours. The mixture is evaporated under vacuum, chloroform is added, the solution is washed with water, dried over sodium sulfate and evaporated under vacuum, and 650 g (94%) of 1-{4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl}-1H-pyrazole are obtained in liquid form.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][N:12]=[C:11]([CH2:14]O)[CH:10]=2)=[CH:5][CH:4]=1.S(Cl)([Cl:20])=O>C(Cl)(Cl)Cl>[Cl:20][CH2:14][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:17])([F:16])[F:1])=[CH:4][CH:5]=2)[NH:13][N:12]=1
Reactant: OCc1cc(-c2ccc(C(F)(F)F)cc2)[nH]n1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: FC(F)(F)c1ccc(-c2cc(CCl)n[nH]2)cc1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 97.1 %

Procedure:
To a solution of [5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-yl]-methanol (40 mg, 0.17 mmol) in chloroform (4 ml) was added thionyl chloride (0.34 ml, 4.7 mmol) at 0° C. under an argon atmosphere. The solution was stirred at 40° C. for 2 h and at 60° C. for 10 min. The mixture was poured onto ice water/aqueous NaHCO3 1/1, extracted two times with dichloromethane and the combinded extracts were dried over sodium sulfate. Evaporation of the solvent under reduced pressure gave 43 mg (0.165 mmol, 97%) of the title compound as white crystals.
Reaction SMILES: CCOCC.C([Zn:8][CH2:9][CH3:10])C.[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CCCCCC>[CH2:9]([Zn:8][O:17][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10]
Reactant: CC[Zn]CC
Reactant: Oc1ccccc1
Solvent: CCCCCC
Solvent: CCOCC
Product: CC[Zn]Oc1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
In the drybox, a 100-mL Schlenk flask was charged with Et2O (30 mL) and cooled to −78° C. Diethylzinc (9.0 mL of a 1.0 M hexane solution, 9.0 mmol) was added via syringe. A solution of phenol (0.847 g of phenol in 10 mL of Et2O) was added to the Schlenk flask, and the colorless reaction mixture was stirred at −78° C. for 1 h. The mixture was evaporated to give a white solid (1.593 g, 94%). 1H NMR (300 MHz, DMSO-d6): δ 7.1, 6.6 (m, 5H), 1.2 (t, 3H), 0.1 (m, 2H).
Reaction SMILES: [CH2:1]([NH2:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:11](Cl)(=[O:16])[CH2:12][CH2:13][CH2:14][CH3:15]>C(OCC)C>[CH2:1]([NH:10][C:11](=[O:16])[CH2:12][CH2:13][CH2:14][CH3:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCC(=O)Cl
Reactant: CCCCCCCCCN
Solvent: CCOCC
Product: CCCCCCCCCNC(=O)CCCC

Procedure:
2 mole nonylamine are reacted with 1 mole valeroyl chloride in diethyl ether, the suspension is filtered off with suction, the filtrate is evaporated and N-nonyl-valeric acid amide is thus obtained quantitatively; m.p. 29°-31° C. Reduction with 1.65 mole lithium aluminium hydride in diethyl ether gives a colourless oil in a yield of 78% of theory; b.p. 142°-146° C./16 mm.Hg. The addition of this N-nonyl-N-pentylamine to methyl acrylate (oil; yield 96% of theory) and subsequent saponification with 1N aqeuous sodium hydroxide solution gives a yield of 64% of theory of pasty 3-(N-nonyl-N-pentylamino)-propionic acid which is reacted analogously to Example 3 to give the diphosphonic acid; yield 87% of theory; m.p. 168°-176° C.; Mrel =0.14.
Reaction SMILES: COC1C=C(OC)[CH:47]=[CH:46][C:4]=1[CH2:5][NH:6][CH:7]1[C:16]2[CH2:15][S:14][N:13]=[C:12]([N:17](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[C:11]3=[N:32][N:33]([CH2:35][C:36]4[C:41]([CH3:42])=[C:40]([O:43][CH3:44])[C:39]([CH3:45])=[CH:38][N:37]=4)[N:34]=[C:9]([C:10]=23)[CH2:8]1.C(N(CC)CC)C.ClCCCC(Cl)=[O:64].[OH-].[Na+]>ClCCl>[NH2:17][C:12]1[C:11]2[C:10]3[C:9](=[N:34][N:33]([CH2:35][C:36]4[C:41]([CH3:42])=[C:40]([O:43][CH3:44])[C:39]([CH3:45])=[CH:38][N:37]=4)[N:32]=2)[CH2:8][CH:7]([N:6]2[CH2:47][CH2:46][CH2:4][C:5]2=[O:64])[C:16]=3[CH2:15][S:14][N:13]=1
Reactant: COc1ccc(CNC2CC3=NN(Cc4ncc(C)c(OC)c4C)N=C4C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSCC2=C34)c(OC)c1
Reactant: O=C(Cl)CCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(C)cnc(CN2N=C3CC(N4CCCC4=O)C4=C3C(=N2)C(N)=NSC4)c1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 46 %

Procedure:
A mixture composed of di-tert-butyl {8-[(2,4-dimethoxybenzyl)amino]-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-2,7,8,9-tetrahydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-4-yl}imidodicarbonate of Example 42 (47 mg), triethylamine (36 μl), dichloromethane (1 ml) and 4-chlorobutyryl chloride (14 μl) was stirred at room temperature for 12 hours. A 0.1 N sodium hydroxide solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in dehydrated dichloromethane (1.5 ml). 1,3-Dimethoxybenzene (16 μl) and trifluoroacetic acid (1.5 ml) was added and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and a 0.1 N sodium hydroxide solution was added to the resulting residue, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure. Dimethylformamide (1 ml) and potassium tert-butoxide (15 mg) were added to the resulting residue, and the mixture was stirred at room temperature for two hours. The reaction mixture was separated with water and chloroform. Then, the organic layer was dried over sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel thin-layer chromatography (chloroform-methanol) to obtain the title compound (13 mg, 46%) as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.Cl.[I-].[K+].[I:13]([O-])(=O)=O.[K+]>CO.O>[CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[C:7]=1[I:13]
Reactant: Cc1cc(C)cc(O)c1
Reactant: [O-][I+2]([O-])[O-]
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1cc(O)cc(C)c1I
Temperature: 25 °C
Reaction time: 20 h

Procedure:
3,5-dimethyl-4-iodophenol was prepared as follows: To a solution of 59.1 g (484 mmol) of 3,5-dimethylphenol in 1 l of methanol was added 395 ml of 36% hydrochloric acid, with occasional cooling to maintain the temperature at 20°-30° C. To the resulting solution was then added a solution of 54.3 g (327 mmol) potassium iodide and 33.5 g (157 mmol) potassium iodate in 500 ml water over a 5 minute period. The solution became red and cloudy and a tan precipitate formed. After stirring at room temperature for 20 hours, the reaction mixture was cooled in ice and the precipitate collected and washed with ice cold 2/1 (v:v) water/methanol. The resulting tan solid was recrystallized several times from hot methanol and water to yield 36.4 g (15% yield) of white needles, mp 131°-132° C., which were identified as 3,5-dimethyl-4-iodophenol. 1H NMR analysis indicated the following: (δ, CDCls) 8.03 (br s, lH), 6.52 (s, 2H) and 2.35 (s, 6H). Mass spectrum analysis indicated the following: (m/e) 248 (m+, 100%), 121, 91 and 77.
Reaction SMILES: Cl.[CH:2]1([CH2:5][N:6]([C@H:15]2[CH2:20][CH2:19][C@H:18]([OH:21])[CH2:17][CH2:16]2)[C:7]([C@H:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)=[O:8])[CH2:4][CH2:3]1.[Cl:22][C:23]1[C:24]([CH3:33])=[C:25]([S:29](Cl)(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1.C(N(CC)CC)C>C(#N)C>[Cl:22][C:23]1[C:24]([CH3:33])=[C:25]([S:29]([N:11]2[CH2:12][CH2:13][CH2:14][C@H:9]([C:7]([N:6]([CH2:5][CH:2]3[CH2:3][CH2:4]3)[C@H:15]3[CH2:16][CH2:17][C@H:18]([OH:21])[CH2:19][CH2:20]3)=[O:8])[CH2:10]2)(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1
Reactant: O=C([C@H]1CCCNC1)N(CC1CC1)[C@H]1CC[C@H](O)CC1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1c(Cl)cccc1S(=O)(=O)N1CCC[C@H](C(=O)N(CC2CC2)[C@H]2CC[C@H](O)CC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (3S)—N-(cyclopropylmethyl)-N-(trans-4-hydroxycyclohexyl)piperidine-3-carboxamide hydrochloride (10 mg, 0.03 mmol), 3-chloro-2-methylbenzenesulfonyl chloride (7.1 mg, 0.03 mmol), triethylamine (11 μL, 0.08 mmol) in acetonitrile (0.2 mL) was stirred at r.t. for 1 hour, then purified with flash column. 5.1 mg (yield: 34%) final product was obtained. LCMS: m/z 468.9 (M+H)+.
Reaction SMILES: [C:1]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]#[C:16][CH2:17][OH:18])=[CH:12][CH:13]=2)[C:8](=[O:19])[C:7]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[O:21])=[CH:6]1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C1COCC1.CO.[Pt]=O>[C:1]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([CH2:15][CH2:16][CH2:17][OH:18])=[CH:12][CH:13]=2)[C:8](=[O:19])[C:7]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[O:21])=[CH:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)n1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)ccc21
Agent: O=[Pt]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)n1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCCO)ccc21
Yield: 96.1 %

Procedure:
A mixture of 303 mg of 1-(tert-butyl)-N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide from Preparation No. 11 and 15 mg of platinum oxide in 10 mL of 1: 1 THF-methanol is stirred under 1 atm of hydrogen gas for 3 h, then filtered through diatomaceous earth and concentrated under reduced pressure. The mixture was purified by flash chromatography on silica using 2-3% methanol in dichloromethane to afford 294 mg of the title compound.
Reaction SMILES: C([O:4][C@H:5]([CH3:25])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH3:21])[C:16]([CH2:22]O)=[N:15][C:14]=2[N:13]([CH3:24])[C:11]1=[O:12])(=O)C.S(Cl)([Cl:28])=O>>[OH:4][C@H:5]([CH3:25])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH3:21])[C:16]([CH2:22][Cl:28])=[N:15][C:14]=2[N:13]([CH3:24])[C:11]1=[O:12]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(nc(CO)n2C)n(C)c1=O
Reactant: O=S(Cl)Cl
Product: C[C@@H](O)CCCCn1c(=O)c2c(nc(CCl)n2C)n(C)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To thionyl chloride (30 ml) stirred at 0-5° C. was added (R)-1-(5-acetoxyhexyl)-8-hydroxymethyl-3,7-dimethylxanthine (6.3 g, 17.9 mmol). After stirring overnight at room temperature, unreacted thionyl chloride and volatile byproducts were evaporated under reduced pressure. To the residual oil was added methanol (300 ml) followed by hydrogen chloride in ether (1.0 M, 20 ml). After stirring for 12 hours, volatile materials were evaporated under reduced pressure to provide (R)-1-(5-hydroxyhexyl)-8-chloromethyl-3,7-dimethylxanthine (5.6 g, 96% yield) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[CH2:7][C:8]([CH3:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].[N:12]([O-])=[O:13].[Na+]>C(O)(=O)C.O>[C:1]([O:5][C:6](=[O:11])/[C:7](=[N:12]\[OH:13])/[C:8](=[O:9])[CH3:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=N[O-]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)/C(=N/O)C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
592.1 g of acetoacetic acid tert.butyl ester are dissolved in 560 ml of glacial acetic acid. To this solution is added dropwise at 5°-10° C. during 21/2 hours a solution of 290.6 g of sodium nitrite in 655 ml of water. The resulting yellow suspension is stirred for 30 minutes at 20° C., treated with 940 ml of water and stirred for a further 2 hours. The mixture is treated with 900 ml of water and 900 g of ice and extracted in the stirring vessel three times with 1 l of ethyl acetate each time. The combined ethyl acetate extracts are washed three times with 1 l of water each time, then treated with 5 l of water and the pH-value is adjusted to 6.8 with sodium hydrogen carbonate. After separating the aqueous phase, the organic phase is washed once with water. Thereafter, the ethyl acetate solution is dried over sodium sulphate and evaporated in vacuo at 40 ° C. There is obtained (Z)-2-hydroxyimino-3-oxo-butyric acid tert-butyl ester as a yellow oil which is dried for a further 9 hours in a high vacuum at 40° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][N:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]([OH:13])=[O:12]>C(OC(=O)C)(=O)C>[CH3:5][N:6]1[CH:10]=[C:9]([N+:1]([O-:4])=[O:2])[CH:8]=[C:7]1[C:11]([OH:13])=[O:12]
Reactant: Cn1cccc1C(=O)O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: Cn1cc([N+](=O)[O-])cc1C(=O)O
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Acetic anhydride (20 mL) was treated with nitric acid (4.0 mL, 70%) and the mixture heated to 50° C. for 15 min then cooled to room temperature, and slowly added to a suspension of 1-methyl-2-pyrrolecarboxylic acid (4 g, 15.98 mmol) in of Ac2O (12 mL) cooled to −25° C. The mixture was stirred at −15° C. for 0.5 hr, then the temperature was allowed to rise to ambient, and stirring was continued for 20 min. The mixture was again cooled to −25° C. and the precipitate collected in a funnel cooled with dry ice, the solid was washed with a small quantity of cold Ac2O (−25° C.). The crystalline solid was taken up in water containing NaOH (1 g). Acidification with the HCl precipitated the pure compound. NMR as previously reported.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:22])[CH2:16][CH2:17][C:18]([O:20]C)=[O:19])=[CH:11][CH:10]=1.[OH-].[Na+].Cl>ClCCl>[O:22]=[C:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5])=[CH:10][CH:11]=1)[CH2:16][CH2:17][C:18]([OH:20])=[O:19]
Reactant: CCCCC(=O)Cl
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCCCC(=O)Nc1ccc(C(=O)CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.9 %

Procedure:
To a 2-dram vial was added pentanoyl chloride (0.040 mL, 0.00033 mol), 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.051 g, 0.00025 mol) (Example 1, Step (c)), dichloromethane (3 mL), and a 3.6 mmol amine per gram of 4-morpholinomethyl polystyrene resin (0.10 g, 0.00036 mol amine), the vial was tightly capped, and the mixture was shaken at room temperature for approximately 5 hours. To the mixture was added an excess of [Bis(2-aminoethyl)amino-ethyl]amino-methyl polystyrene resin, the vial was tightly capped, and the mixture was shaken at room temperature overnight. The mixture was gravity filtered into a clean 2-dram vial, and the solvent evaporated under a stream of nitrogen. The residue was dissolved in THF (3 mL), 1.0 M NaOH (0.5 mL, 0.0005 mol) was added, and the mixture was shaken overnight. Additional 1.0 M NaOH (0.25 mL, 0.00025 mol) was added, and the mixture was shaken overnight. To the mixture was added 1.0 M HCl (1.0 mL, 0.001 mol), and the two-phase mixture was shaken for 1 hour. The bottom layer was withdrawn by pipet, and the remaining organics were evaporated under a stream of nitrogen. The residue was dried in vacuo to give 0.054 g of 4-oxo-4-(4-pentanoylamino-phenyl)-butyric acid as a pink solid; mp 153-155° C.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:14]([CH2:16][C:17](=[O:19])[OH:18])[OH:15])[CH2:10][CH:11]([CH3:13])[CH3:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O>[CH2:26]([O:19][C:17](=[O:18])[CH2:16][C@H:14]([OH:15])[C@H:9]([CH2:10][CH:11]([CH3:13])[CH3:12])[NH:8][C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CC(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CC(=O)OCc1ccccc1

Procedure:
Boc-Statine, 8.83 g., was dissolved in dry dimethylformamide and treated at 25° C. for 4.5 hours with 4.43 g. potassium carbonate and 3.81 ml. benzyl bromide. The mixture was concentrated in vacuo, 500 ml. ethyl acetate was added and the suspension was washed with saturated aqueous lithium chloride (2×50 ml.), water (5×50 ml.), dried magnesium sulfate, filtered and concentrated to give 11.8 g. of a yellow syrup which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:16][C:17]([CH3:26])([O:19][CH2:20][CH2:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH3:18])[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[C:6]([NH2:14])[C:5]=2[N:15]=1.[H][H].[OH-].[Na+]>FC(F)(F)C(O)=O.O.[Pt](=O)=O>[CH3:1][C:2]1[N:3]([CH2:16][C:17]([CH3:26])([O:19][CH2:20][CH2:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH3:18])[C:4]2[C:13]3[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=3[N:7]=[C:6]([NH2:14])[C:5]=2[N:15]=1
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CC(C)(C)OCCS(C)(=O)=O
Reactant: [H][H]
Agent: O=[Pt]=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2c(N)nc3c(c2n1CC(C)(C)OCCS(C)(=O)=O)CCCC3
Yield: 64 %

Procedure:
A mixture of 2-methyl-1-{2-methyl-2-[2-(methylsulfonyl)ethoxy]propyl}-1H-imidazo[4,5-c]quinolin-4-amine (prepared as described in Example 21, 1.70 g, 4.52 mmol) and platinum(IV) oxide (1.0 g) in trifluoroacetic acid (23 mL) was hydrogenated on a Parr apparatus at 50 psi (3.5×105 Pa) hydrogen pressure for 20 hours. The mixture was filtered through CELITE filter agent, which was washed afterwards with dichloromethane. The filtrate was concentrated under reduced pressure to afford an oil that was suspended in water (50 mL) and adjusted to pH 12 with 50% aqueous sodium hydroxide. A white solid formed that was isolated by filtration, washed with water, and recrystallized from ethanol. The crystals were isolated and dried under vacuum at 65° C. to afford 1.10 g of 2-methyl-1-{2-methyl-2-[2-(methylsulfonyl)ethoxy]propyl}-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine as white crystals, mp 226-229° C.
Reaction SMILES: [CH3:1][CH2:2][CH2:3]I.C([O:7][C:8]1[C:9](/C(/CC)=C(/F)\C=C\C(\C)=C\C(OCC)=O)=[CH:10][C:11]2[C:12]([CH3:21])([CH3:20])[CH2:13][CH2:14][C:15]([CH3:19])([CH3:18])[C:16]=2[CH:17]=1)C.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH2:3]([O:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12]([CH3:21])([CH3:20])[CH2:13][CH2:14][C:15]([CH3:19])([CH3:18])[C:16]=2[CH:17]=1)[CH2:2][CH3:1]
Reactant: CCCI
Reactant: CCOC(=O)/C=C(C)/C=C/C(F)=C(/CC)c1cc2c(cc1OCC)C(C)(C)CCC2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCCOc1ccc2c(c1)C(C)(C)CCC2(C)C

Procedure:
N-Propyl iodide (4.9 mL, 50 mmol) was added to a stirring suspension of 6-hydroxy-1,2,3,4-tetrahydronaphthalene (Intermediate 1, 2.07 g, 10 mmol), potassium carbonate (6.9 g, 50 mmol), in acetone (50 mL), and the mixture was stirred at reflux for 14 h. The solution was poured into a separatory funnel, water was added, and the products were extracted three times with hexane. The combined organic layers were washed with brine and dried over magnesium sulfate. The solvent was removed in vacuo to give the title compound as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:13][N:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[N:11]=[C:10]([N:3]([CH3:2])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CNc1ccccc1
Reactant: Clc1nc(Cl)c2ccccc2n1
Product: CN(c1ccccc1)c1nc(N(C)c2ccccc2)c2ccccc2n1

Procedure:
The title compound was prepared from 2,4-dichloroquinazoline (50 mg, 0.251 mmol) and N-methylaniline (40 μL, 0.401 mmol) by a procedure similar to example 1b and was isolated as white powder (33 mg, 66%). 1H NMR (CDCl3): 7.54 (dd, J=8.2 and 0.6 Hz, 1H), 7.45 (dd, J=8.4 and 1. Hz, 1H), 7.44-7.29 (m, 6H), 7.21-7.10 (m, 4H), 6.86 (dd, J=8.4 and 0.9 Hz, 1H), 6.67 (ddd, J=8.4, 7.2 and 1.1 Hz, 1H), 3.69 (s, 3H), 3.33 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:11][C:10]=2[C:21]2[CH:32]=[CH:31][C:24]([C:25]([NH:27][NH:28][CH:29]=O)=O)=[CH:23][CH:22]=2)=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:34]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:11][C:10]=2[C:21]2[CH:32]=[CH:31][C:24]([C:25]3[S:34][CH:29]=[N:28][N:27]=3)=[CH:23][CH:22]=2)=[CH:4][CH:3]=1
Reactant: Cn1c(-c2ccccn2)nc(-c2ccc(C(=O)NNC=O)cc2)c1Sc1ccc(Cl)cc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: C1COCCO1
Product: Cn1c(-c2ccccn2)nc(-c2ccc(-c3nncs3)cc2)c1Sc1ccc(Cl)cc1
Temperature: 55 °C

Procedure:
4-{5-[(4-Chlorophenyl)thio]-1-methyl-2-pyridin-2-yl-1H-imidazol-4-yl}-N′-formylbenzohydrazide (Example 49, 450 mg, 0.98 mmol) was treated with P2S5 (218 mg, 0.98 mmol) in 12 mL of dioxane. After the reaction mixture was heated at 55° C. overnight, the volatiles were removed in vacuo. The residue was diluted with EtOAc, washed with 1N NaOH, water, and brine. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was subjected to silica gel column chromatography eluting with 30-85% EtOAc in hexanes to afford the title compound. 1H NMR (500 MHz, (CDCl3): 9.13 (s, 1H), 8.67 (d, 1H), 8.43 (broad d, 1H), 8.38 (d, 2H), 8.06 (d, 2H), 7.89 (t, 1H), 7.39 (t, 1H), 7.25 (d, 2H), 7.04 (d, 2H), 4.16 (s, 3H). LCMS: m/z 462 (M+H)+.