Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][N:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16](=S)[C:15]([C:24](OCC)=[O:25])=[N:14]3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.C(O)C.[F:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[NH:39][NH2:40].C(=O)([O-])[O-].[K+].[K+]>COCCOC.C(Cl)(Cl)Cl>[F:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N:39]1[C:24](=[O:25])[C:15]2=[N:14][N:13]([CH2:12][C:9]3[CH:10]=[CH:11][C:6]([N:1]4[CH:5]=[CH:4][CH:3]=[N:2]4)=[CH:7][CH:8]=3)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]2=[N:40]1
Reactant: NNc1ccccc1F
Reactant: CCOC(=O)c1nn(Cc2ccc(-n3cccn3)cc2)c2ccccc2c1=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: COCCOC
Product: O=c1c2nn(Cc3ccc(-n4cccn4)cc3)c3ccccc3c-2nn1-c1ccccc1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Ethyl 1-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-4-thioxo-1,4-dihydrocinnoline-3-carboxylate (160 mg, 0.410 mmol) was dissolved in 1,2-dimethoxyethane (2 mL) and absolute ethanol (1 mL). 2-Fluorophenylhydrazine (114 mg, 0.902 mmol, 2.2 equiv) and potassium carbonate (170 mg, 1.23 mmol, 3.0 equiv) were added. The mixture was stirred vigorously for 15 minutes at ambient temperature and then placed into an oil bath preheated to 98° C. for 7 hours. The mixture was cooled ambient temperature, diluted with chloroform and washed once with water. The aqueous layer was extracted once with chloroform and the combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 99:1; chloroform:methanol), providing the titled compound: 1H-NMR (400 MHz, CDCl3) δ 8.32 (1H, d, J=7.8 Hz), 7.90 (1H, s), 7.71-7.61 (4H, m), 7.60-7.52 (3H, m), 7.43-7.37 (3H, m), 7.31-7.26 (2H, m), 6.47 (1H, s), 5.88 (2H, s) ppm; high resolution mass spectrometry (ES+) m/z 437.1517 [(M+H)+; calculated for C25H18FN6O: 437.1521].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH:17]=O>C(O)C.O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][CH:17]([C:13]1[S:12][CH:16]=[CH:15][CH:14]=1)[CH2:9][C:8]2=[O:10]
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: O=Cc1cccs1
Solvent: O
Solvent: CCO
Product: O=C1CC(c2cccs2)Oc2ccc(Br)cc21
Yield: 55.6 %

Procedure:
A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (20 g, 0.093 mol), thiophene-2-carbaldehyde (10.46 g, 0.093 mol) and borax (35.4 g, 0.093 mol) in ethanol (120 mL) and H2O (200 mL) was refluxed for one day. The reaction mixture was cooled, diluted with an equal volume of H2O and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated to give 6-bromo-2-thiophen-2-yl-chroman-4-one (16 g, 50%). 1H-NMR (CDCl3): 3.01 (m, 1H), 3.10 (m, 1H), 5.75 (dd, 1H), 6.94 (d, 1H), 7.02 (t, 1H), 7.05 (d, 1H), 7.32 (d, 1H), 7.54 (dd, 1H), 8.00 (d, 1H).
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:9]=[CH:8][C:7]([C:10]2([OH:23])[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[CH:6][C:5]=1[O:24][CH3:25].C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C(N(CC)CC)C>[CH2:16]([N:13]1[CH2:12][CH2:11][C:10]([C:7]2[CH:8]=[CH:9][C:4]([CH:3]=[O:2])=[C:5]([O:24][CH3:25])[CH:6]=2)([OH:23])[CH2:15][CH2:14]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc(C2(O)CCN(Cc3ccccc3)CC2)ccc1C(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(C2(O)CCN(Cc3ccccc3)CC2)ccc1C=O
Yield: 39.2 %

Procedure:
To 10.0 g of 4-(1-benzyl-4-hydroxypiperidin-4-yl)-2-methoxybenzaldehyde dimethyl acetal were added 100 ml of toluene and 6.15 g of p-toluenesulfonic acid monohydrate and the resulting mixture was heated under reflux for 1 hour. To the reaction mixture were added water and triethylamine followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol) to thereby give 3.43 g of the title compound as a pale brown oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](Cl)=[O:23]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:22]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=3)=[O:23])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: O=C(Cl)c1ccccn1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Product: O=C(NC1CCCc2c1[nH]c1ccc(Br)cc21)c1ccccn1

Procedure:
N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)pyridine-2-carboxamide was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and picolinoyl chloride in a similar manner as described above to give an off-white solid (64% yield). 1H-NMR (CDCl3): δ 8.96 (s, 1H), 8.52 (m, 1H), 8.37 (d, 1H), 8.21 (m, 1H), 7.86 (m, 1H), 7.61 (m, 1H), 7.43 (m, 1H), 7.22 (dd, 1H), 7.17 (d, 1H), 5.31 (m, 1H), 2.72 (m, 2H), 2.31 (m, 1H), 1.98 (m, 3H); MS m/z 370 (M−1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:43])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]2[N:23]=[C:22]3[C:18]([N:19]=[CH:20][N:21]3[CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[C:17]([NH:29][CH:30]3[CH2:35][CH2:34][N:33](CC4C=CC=CC=4)[CH2:32][CH2:31]3)[N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+].C(Cl)Cl>CO.O.[Pd]>[C:1]([O:5][C:6](=[O:43])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]2[N:23]=[C:22]3[C:18]([N:19]=[CH:20][N:21]3[CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[C:17]([NH:29][CH:30]3[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]3)[N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2nc(NC3CCN(Cc4ccccc4)CC3)c3ncn(C4CCCC4)c3n2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2nc(NC3CCNCC3)c3ncn(C4CCCC4)c3n2)CC1

Procedure:
Add to a solution of {4-[6-(1-benzyl-piperidin-4-ylamino)-9-cyclopentyl-9H-purin-2-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (8a, 40.2 g, 68 mmol) in 400 mL of methanol, a suspension of Pd black (2 g) in a small amount of water. Then add a solution of ammonium formate (13.3 g, 215 mmol) in 100 mL of water, and heat at a gentle reflux overnight. TLC shows the presence of starting material (TLC, silica plates, 4:1 DCM:methanol; Rf: starting material 0.75, product 0.15). Add an additional 5 g of ammonium formate and reflux 24 hours. Remove the catalyst by filtration through Celite® and concentrate the filtrate. Dissolve the residue in DCM and extract with water. Remove the white precipitate by filtration through a pad of Celite®, wash the filtrate with brine, dry over sodium sulfate and filter. Concentrate the filtrate and purify the residue on silica gel (500 g) using DCM:methanol (4:1) to give 33.4 g of trans-{4-[9-cyclopentyl-6-(piperidin-4-ylamino)-9H-purin-2-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (9a) as a white solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:16]2[CH2:15][CH2:14][C@H:13]3[C@@H:9]([CH2:10][NH:11][CH2:12]3)[C:8]=2[CH:7]=[CH:6][C:5]=1[O:17][CH3:18].[C:19](OC(=O)C)(=[O:21])[CH3:20]>N1C=CC=CC=1>[C:19]([N:11]1[CH2:10][C@@H:9]2[C@H:13]([CH2:14][CH2:15][C:16]3[C:4]([O:3][CH3:2])=[C:5]([O:17][CH3:18])[CH:6]=[CH:7][C:8]=32)[CH2:12]1)(=[O:21])[CH3:20]
Reactant: COc1ccc2c(c1OC)CC[C@@H]1CNC[C@@H]21
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc2c(c1OC)CC[C@@H]1CN(C(C)=O)C[C@@H]21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 114.7 %

Procedure:
A solution of trans-2,3,3a,4,5,9b-hexahydro-6,7-dimethoxy-1H-benz[e]isoindole hydrochloride (0.50 g, 1.9 mmole) and dry pyridine (9.5 mL) was stirred under N2 at room temperature as acetic anhydride (0.26 mL, 2.8 mmole) was added dropwise. The reaction mixture was stirred at room temperature for 0.75 hr, then was evaporated (in-vacuo). 2-Methoxyethanol was added and evaporated. The residue was dissolved in CH2Cl2 and was washed with 1N HCl, 1N KOH, water, saturated aqueous NaCl, dried (MgSO4), filtered and evaporated to yield 0.60 g white solid; M+ 275.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([C:6]([S:22][C:23]3[C:24]([F:32])=[C:25]([CH:29]=[CH:30][CH:31]=3)C(O)=O)=[C:7]([CH:19]3[CH2:21][CH2:20]3)[N:8]2[C:12]2[CH:13]=[N:14][N:15]([CH2:17][CH3:18])[CH:16]=2)=[CH:4][CH:3]=1.S(Cl)(Cl)=[O:34].C[Si](C=[N+]=[N-])(C)C.[C:44]([OH:48])([CH3:47])(C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([C:6]([S:22][C:23]3[C:24]([F:32])=[C:25]([CH2:47][C:44]([OH:48])=[O:34])[CH:29]=[CH:30][CH:31]=3)=[C:7]([CH:19]3[CH2:21][CH2:20]3)[N:8]2[C:12]2[CH:13]=[N:14][N:15]([CH2:17][CH3:18])[CH:16]=2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CCn1cc(-n2c(C3CC3)c(Sc3cccc(C(=O)O)c3F)c3ccc(Cl)c(F)c32)cn1
Reactant: CC(C)(C)O
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CCn1cc(-n2c(C3CC3)c(Sc3cccc(CC(=O)O)c3F)c3ccc(Cl)c(F)c32)cn1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 3-((6-chloro-2-cyclopropyl-1-(1-ethyl-1H-pyrazol-4-yl)-7-fluoro-1H-indol-3-yl)thio)-2-fluorobenzoic acid compound 1-34 (Example 9; 30 mg, 0.058 mmol) in toluene (2.0 mL) under inert atmosphere was added thionyl chloride (0.22 mL, 3.0 mmol) and the mixture was heated at 85° C. for 2 h. The volatiles were removed under reduced pressure and the residue was resuspended in toluene (2.0 mL) and (trimethylsilyl)diazomethane solution (2.0 M in hexanes, 0.88 mL, 0.88 mmol). After evolution of gas, t-butylalcohol (2.0 mL) was added and the mixture was heated for 0.5 hr at 50° C. The residue was purified by silica gel chromatography (0-20% Hx/EtOAC). After evaporation of the fractions, the residue was dissolved in 4.0 M HCl in 1,4-dioxane (0.5 mL) and the solution was stirred at RT for 2 hr. The solvent was removed and the residue was purified by HPLC to give the target compound as a clear film. MS (ESI): m/z 488.0 (M+H+).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH2:11][OH:12])=[CH:5][CH:4]=1.N1C=CC=CC=1.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:23]>C(Cl)Cl>[F:14][C:2]([F:13])([F:1])[C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH2:11][O:12][C:22](=[O:23])[O:24][C:25]2[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=2)=[CH:5][CH:4]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: OCCSc1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(OCCSc1ccc(C(F)(F)F)cc1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.2 %

Procedure:
2-(4-Trifluoromethyl-phenylsulfanyl)ethanol (15.00 g, 67.50 mmol) prepared in the above Step (1) was dissolved in anhydrous DCM (100 ml), pyridine (7.59 ml, 93.81 mmol) and 4-nitrophenyl chloroformate (13.61 g, 67.50 mmol) were added thereto at 0° C. in order, and the mixture was stirred for 2 hours at room temperature. The reaction was stopped by adding distilled water, and the reaction mixture was extracted with DCM. The organic layer thus extracted was washed with aqueous NH4Cl solution, dried over anhydrous MgSO4, and then concentrated. The concentrate was purified by silica gel column chromatography (DCM/n-hexane=5/1, v/v) to give carbonic acid 4-nitro-phenyl ester 2-(4-trifluoromethyl-phenylsulfanyl)-ethyl ester (22.54 g, 86.21%) of a pale yellow oil.
Reaction SMILES: [N+:1]([CH:4]([N+:10]([O-:12])=[O:11])[CH2:5][O:6][CH2:7][CH:8]=[CH2:9])([O-:3])=[O:2].[OH-].[Na+].Cl([F:19])(=O)(=O)=O.C(=O)=O>O.CO>[N+:1]([C:4]([N+:10]([O-:12])=[O:11])([F:19])[CH2:5][O:6][CH2:7][CH:8]=[CH2:9])([O-:3])=[O:2]
Reactant: C=CCOCC([N+](=O)[O-])[N+](=O)[O-]
Agent: O=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=CCOCC(F)([N+](=O)[O-])[N+](=O)[O-]
Yield: 53 %

Procedure:
The pure allyl 2,2-dinitroethyl ether, prepared according to the procedure set forth in Example 1, was added (4.11 grams; 0.0234 mole) slowly to a well stirred solution of sodium hydroxide (0.935 grams; 0.0234 mole), water (15 mls) and methanol (34 mls). The slightly exothermic reaction yielded an immediate orange color. The final pH was approximately 8. Perchloryl fluoride was then metered into the system to which was added a dry ice reflux condenser to prevent excess perchloryl fluoride from sweeping out of the reaction flask. When the perchloryl fluoride began to reflux vigorously, it was shut off and under slight nitrogen flow reflux was maintained for about 4 hours. The reaction temperature was maintained between 20°-25° C. with a water bath. The reaction mixture changed from deep orange to pale orange in color. Water (50 mls) was added and a yellow oil dropped out of solution. The mixture was then extracted with three 60 ml portions of methylene chloride. The methylene chloride extracts were washed with three 30 ml portions of 3 percent sodium hydroxide and finally with water. After drying with magnesium sulfate, excess methylene chloride was removed under vacuum and the residual liquid was distilled through a small Vigreux column. The distillation yielded 2.4 grams (53% yield) of allyl 2,2-dinitro-2-fluoroethyl ether, b. p. 42° C./1.1 mm, nD25 1.4240, d25 1.28. The calculated elemental analysis for C5H7N2O5 was C, 30.93; H, 3.64; N, 14.43. The found analysis was C, 30.85; H, 3.45; N, 14.43. The infrared spectrum for the compound, in Nujol, exhibited maximum peaks at 6.2, 7.6 and 9.0 microns.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:22]2[CH2:26][C@H:25]([CH2:27][NH:28][C:29](=[O:31])[CH3:30])[O:24][C:23]2=[O:32])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:11][N:10](C(OCC2C=CC=CC=2)=O)[CH2:9]1>C(OCC)(=O)C.C(O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([N:22]2[CH2:26][C@H:25]([CH2:27][NH:28][C:29](=[O:31])[CH3:30])[O:24][C:23]2=[O:32])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:11][NH:10][CH2:9]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CN(C(=O)OCc4ccccc4)C3)c(F)c2)C(=O)O1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CNC3)c(F)c2)C(=O)O1

Procedure:
A solution of (S)-N-[[3-[3-fluoro-4-[1-(carbobenzyloxy)-3-azetidinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (Example 81, Step 9, 1.44 g, 3.26 mmol) in ethyl acetate (25 mL) and absolute ethanol (50 mL) was added to 10% Pd/C (1.0 g) and hydrogenated at 30 psi for 7 hr. Filtration and evaporation gave the title compound as a white glassy solid. FAB-HRMS: theory 308.1410 (M+1); meas. 308.1408.
Reaction SMILES: I[C:2]1[CH:10]2[CH:5]([N:6]=[CH:7][N:8]=[C:9]2[NH:11][CH3:12])[N:4]([CH:13]([CH3:15])[CH3:14])[CH:3]=1.COC(O)C(O)OC.O[C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[CH:13]([N:4]1[CH:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:11][CH3:12])[CH:10]2[C:2]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:3]1)([CH3:15])[CH3:14]
Reactant: CNC1=NC=NC2C1C(I)=CN2C(C)C
Reactant: OB(O)c1cccc(O)c1
Agent: COC(O)C(O)OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CNC1=NC=NC2C1C(c1ccccc1)=CN2C(C)C
Reaction time: 48 h
Yield: 74.4 %

Procedure:
7,7a-Dihydro-5-iodo-7-isopropyl-N-methyl-4aH-pyrrolo[2,3-d]pyrimidin-4-amine (0.15 g, 0.475 mmol) from above was placed in a 50 ml round bottom flask, whereupon 12 ml dimethoxy ethyleneglycol was added. 3-Hydroxyphenylboronic acid (0.262 g, 1.9 mmol pre-dissolved in 3.3 ml ethanol) was added at once, and was followed by 1.9 ml saturated aqueous sodium carbonate. Pd0(PPh3)4 (55 mg, 47 umol) was added to the reaction, the vessel was purged with argon, and set to stir at 80 C for 48 h. The reaction was subsequently cooled, and filtered through a bed of celite. The filtrate was evaporated in vacuo, and the residual material was adhered to silica gel using ethyl acetate as solvent. Silica gel chromatography (ethyl acetate:hexanes) and evaporation in vacuo of the requisite fractions yielded the desired product (94.8 mg, 70.7% yield). 1H NMR (399.6 MHz, d6-DMSO) δ 1.76 (6H, d, J=6.8 Hz), 5.03 (3H, d, J=4.8 Hz), 5.34 (1H, sp, J=6.4 Hz), 5.53 (1H, q, J=4.8 Hz), 6.73 (1H, m), 6.85 (1H, m), 7.25 (1H, app t, J=7.6 Hz), 7.37 (1H, s), 7.59 (1H, s).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]Br.[N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1>>[Br-:1].[Br-:1].[CH2:2]([N+:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N+:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: BrCCCCCCCCCBr
Reactant: c1ccc2ncccc2c1
Product: [Br-]
Product: c1ccc2c(c1)ccc[n+]2CCCCCCCCC[n+]1cccc2ccccc21
Temperature: 65 °C
Yield: 92 %

Procedure:
1,9-Dibromononane (mmol) was added to a solution (30 mL) of dry quinoline, and the solution heated for 24 hours at 65° C. The resulting precipitate was filtered, and the product washed five times with dry diethyl ether. The resulting purple solid was isolated in a 92% yield. 1H NMR (300 MHz, DMSO-D6) δ 9.68 (1H, d, C2-H), 9.34 (1H, d, C3-H), 8.67 (1H, d, C8-H), 8.55 (1H, d, C4-H), 8.27 (2H, m, C5&C7-H), 8.07 (1H, d, C6-H), 5.09 (2H, t, C′1-CH2), 1.95 (2H, m, C′2-CH2), 1.19-1.45 (5H, m, C′3-5-CH2).
Reaction SMILES: [CH:1](=[CH:8][C:9]([CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd]>[C:13]1([CH2:12][CH2:11][C:9](=[O:10])[CH2:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:13]1([CH2:12][CH2:11][CH:9]([OH:10])[CH2:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Product: O=C(CCc1ccccc1)CCc1ccccc1
Product: OC(CCc1ccccc1)CCc1ccccc1
Yield: 28 %

Procedure:
A mixture of 1.00 g (4.27 mmol) of dibenzylidene acetone and 0.15 g of 10% palladium on carbon in 150 ml of methyl cellusolve was shaken under 4 atm. of hydrogen for 2 h. The solution was filtered and concentrated in vacuo. Flash chromatography using 10-20% ethyl acetate in hexane gave 0.60 g (59%) of 1,5-diphenyl-3-pentanone (Rf 0.43, 20% ethyl acetate in hexane) as a colorless Oil and 0.29 g (28%) of 1,5-diphenyl-3-pentanol (Rf 0.36) as a white solid, m.p. 43°-5° C. 1,5-Diphenyl-3-pentanone: 1H NMR (CDCl3) δ 2.71 (t, J=7 Hz, 4H), 2.89 (t, J=7 Hz, 4H), 7.1-7.3 (m, 10H). Mass spectrum (M+NH4)+ 256.
Reaction SMILES: Cl.Cl.[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[N:17]([CH2:18][CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[C:16]([CH2:25][O:26][CH2:27][CH3:28])=[N:15][C:9]=3[C:10]([NH2:14])=[N:11][C:12]=2[CH:13]=1.C(N(CC)CC)C.[C:36](Cl)(=O)[CH:37]([CH3:39])[CH3:38].[C:42](OCC)(=[O:44])C>C(Cl)(Cl)Cl>[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[N:17]([CH2:18][CH:19]4[CH2:24][CH2:23][N:22]([C:42]([CH2:36][CH:37]([CH3:39])[CH3:38])=[O:44])[CH2:21][CH2:20]4)[C:16]([CH2:25][O:26][CH2:27][CH3:28])=[N:15][C:9]=3[C:10]([NH2:14])=[N:11][C:12]=2[CH:13]=1
Reactant: CC(C)C(=O)Cl
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CC1CCNCC1
Reactant: CCOC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CC1CCN(C(=O)CC(C)C)CC1
Reaction time: 1 h

Procedure:
A solution of 7-bromo-2-ethoxymethyl-1-(piperidin-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine dihydrochloride (4.0 g, 8.1 mmol) and triethylamine (5.67 mL, 40.7 mmol) in chloroform (300 mL) was treated with isobutyryl chloride (0.85 mL, 8.1 mmol) according to the method described in Part A of Examples 583-611. The reaction was complete after one hour. Following trituration with ethyl acetate, the solid was recrystallized from ethyl acetate and then triturated with hot acetonitrile and isolated by filtration to provide 3.63 g of 7-bromo-2-ethoxymethyl-1-{[1-(2-methylpropylcarbonyl)piperidin-4-yl]methyl}-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 199-200° C.
Reaction SMILES: C[Si]([Br:5])(C)C.Cl[C:7]1[C:12]2[S:13][C:14]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:23])=[N:15][C:11]=2[C:10]([F:24])=[CH:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)CC>[Br:5][C:7]1[C:12]2[S:13][C:14]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:23])=[N:15][C:11]=2[C:10]([F:24])=[CH:9][N:8]=1
Reactant: Fc1cccc(Cl)c1-c1nc2c(F)cnc(Cl)c2s1
Reactant: C[Si](C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC#N
Product: Fc1cccc(Cl)c1-c1nc2c(F)cnc(Br)c2s1
Temperature: 85 °C
Yield: 33.6 %

Procedure:
Trimethylsilyl bromide (0.4 mL, 3 mmol) was added to a solution of 4-chloro-2-(2-chloro-6-fluorophenyl)-7-fluorothiazolo[5,4-c]pyridine (0.317 g, 10 mmol) in propionitrile (10 mL) at room temperature under an argon atmosphere. The reaction mixture was heated at 85° C. in a sealed vial for three days then it was poured in an ice-cooled saturated solution of potassium carbonate. The resultant mixture was extracted with DCM (×2). The combined organic washings were dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as an off-white solid (0.365 g, quantitative). 1H NMR (400 MHz, CDCl3): δ 8.39 (d, J=1.9 Hz, 1H), 7.51 (td, J=8.3, 5.8 Hz, 1H), 7.41 (dt, J=8.2, 1.1 Hz, 1H), 7.25-7.16 (m, 1H).
Reaction SMILES: [NH2:1][C@H:2]1[C:7]2[CH:8]=[C:9]([NH2:13])[C:10]([NH2:12])=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[C@@H:3]1[OH:16].[CH:17]([CH:19]=O)=O.Cl>C(O)C>[NH2:1][C@H:2]1[C:7]2[CH:8]=[C:9]3[C:10]([N:12]=[CH:17][CH:19]=[N:13]3)=[CH:11][C:6]=2[O:5][C:4]([CH3:14])([CH3:15])[C@@H:3]1[OH:16]
Reactant: CC1(C)Oc2cc(N)c(N)cc2[C@H](N)[C@H]1O
Reactant: O=CC=O
Agent: Cl
Solvent: CCO
Product: CC1(C)Oc2cc3nccnc3cc2[C@H](N)[C@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
To a solution of (3R*,4S*)-4,6,7-triamino-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-3-ol (280 mg, 1.25 mmol) in ethanol (5.6 mL), 40% aqueous glyoxal solution (226 mg, 1.56 mmol) was added, and the resulting mixture was stirred at room temperature for 1 hour. Upon the completion of the reaction, 1 mol/L hydrochloric acid was added thereto, the resulting solution was washed with ethyl acetate, the resulting aqueous phase was adjusted to pH 14 with 1 mol/L aqueous sodium hydroxide solution. Then, the resulting solution was extracted with ethyl acetate, washed with saturated sodium chloride solution, and dried over magnesium sulfate and concentrated. The resulting mixture was purified by silica gel column (ethyl acetate/methanol=10/1) to obtain the aimed product (yield: 35%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][CH:5]([C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)Cl.[NH2:16][NH:17][C:18]([NH2:20])=S.[C:21]([OH:26])(=[O:25])[C:22]([OH:24])=[O:23].[CH2:27](O)[CH2:28][CH2:29]C>>[C:21]([OH:26])(=[O:25])[C:22]([OH:24])=[O:23].[CH2:1]([O:2][C:3](=[O:15])[CH2:4][C:5]1[C:18]([NH2:20])=[N:17][NH:16][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCO
Reactant: NNC(N)=S
Reactant: COC(=O)CC(Cl)C(=O)c1ccccc1
Agent: O=C(O)C(=O)O
Product: CCCCOC(=O)Cc1c(N)n[nH]c1-c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 10.0 g (0.044 mole) of methyl-3-benzoyl-3-chloropropionate and 4.0 g (0.044 mole) of thiosemicarbazide in 50 ml of 1-butanol was refluxed under a nitrogen atmosphere for 32 hours. After cooling to room temperature, the precipitated sulfur was removed by filtration. The filtrate was evaporated under reduced pressure and the residue partitioned between methylene chloride and aqueous 7% sodium bicarbonate. The layers were separated and the organic layer was extracted with water, dried over magnesium sulfate and evaporated under reduced pressure. The residue was dissolved in toluene and chromatographed on an 85 g column of silica gel (47 mm×20 cm) packed in toluene. The column was washed with toluene, methylene chloride, 10% and 50% ethyl acetate-methylene chloride and ethyl acetate, respectively. The fractions containing relatively pure products were combined and evaporated under reduced pressure. The residual oil (4.7 g) was dissolved in isopropanol and treated with 1.5 g (0.017 mole) of anhydrous oxalic acid. The mixture was refluxed until solution was complete, filtered, and the filtrate was treated with isopropyl ether to the cloud point. The oxalate salt of the butyl ester was collected by filtration: 4.8 g (30%), mp 169°-172° C.