Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[CH2:2][Si:3]([CH3:33])([CH3:32])[CH2:4][CH2:5][C:6]1[C:18]2[CH2:17][N:16]3[C:11](=[CH:12][C:13]4[C@:23]([CH2:25][CH3:26])([OH:24])[C:22](=[O:27])[O:21][CH2:20][C:14]=4[C:15]3=[O:19])[C:10]=2[N:9]=[C:8]2[CH:28]=[CH:29][CH:30]=[CH:31][C:7]=12.[SH:34][CH2:35][CH2:36][OH:37]>>[CH2:25]([C@:23]1([OH:24])[C:13]2[CH:12]=[C:11]3[N:16]([C:15](=[O:19])[C:14]=2[CH2:20][O:21][C:22]1=[O:27])[CH2:17][C:18]1[C:6]([CH2:5][CH2:4][Si:3]([CH2:2][S:34][CH2:35][CH2:36][OH:37])([CH3:32])[CH3:33])=[C:7]2[CH:31]=[CH:30][CH:29]=[CH:28][C:8]2=[N:9][C:10]3=1)[CH3:26]
Reactant: OCCS
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CI
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CSCCO

Procedure:
Prepared according to Procedure F using Compound 4 and 2-mercaptoethanol, the crude product was purified on a silica gel column using 3% ethanol in dichloromethane to obtain the pure product in 83% yields.
Reaction SMILES: [CH2:1]1[CH:6]2[C:7]3[N:8]([CH:16]=[CH:17][CH:18]=3)[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]2[CH2:4][CH2:3][NH:2]1.Cl.[O-:20][C:21]#[N:22].[Na+].O1CCCC1>O>[C:21]([N:2]1[CH2:3][CH2:4][N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH2:9][N:8]3[CH:16]=[CH:17][CH:18]=[C:7]3[CH:6]2[CH2:1]1)(=[O:20])[NH2:22]
Reactant: N#C[O-]
Reactant: c1ccc2c(c1)Cn1cccc1C1CNCCN21
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)N1CCN2c3ccccc3Cn3cccc3C2C1

Procedure:
To the mixture of 100 mg of 1,3,4,14b-tetrahydro-2H,10H-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]-benzodiazepine, 1 ml of N hydrochloric acid and 10 ml of water, the solution of 54.5 mg of sodium cyanate in 2 ml of water is added while stirring followed by 2 ml of tetrahydrofuran. After stirring overnight at room temperature, it is extracted with methylene chloride, the extract washed with saturated aqueous sodium carbonate, dried and evaporated, to yield the 2-carbamoyl-1,3,4,14b-tetrahydro-10H-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]-benzodiazepine melting at 175°-177°.
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1.[F:29][C:30]([F:43])([F:42])[C:31]1[CH:41]=[CH:40][C:34](/[CH:35]=[CH:36]/[C:37](O)=[O:38])=[CH:33][CH:32]=1>>[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:24][CH2:25][N:26]([C:37](=[O:38])/[CH:36]=[CH:35]/[C:34]4[CH:33]=[CH:32][C:31]([C:30]([F:42])([F:43])[F:29])=[CH:41][CH:40]=4)[CH2:27][CH2:28]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1
Reactant: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCNCC1
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1
Agent: Cl
Product: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCN(C(=O)/C=C/c2ccc(C(F)(F)F)cc2)CC1

Procedure:
The title compound was prepared from the product of Example 1, step J, and trans-4-(trifluoromethyl)-cinnamic acid, by the method of Example 1, step K, giving a solid that was mostly the more polar cyclohexyl diastereomer by LCMS. Mass spectrum (LCMS, ESI pos.) calcd. for C31H35F3N4O2: 553 (M+H). Found: 553
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[CH2:3][C:4](=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>CN(C=O)C>[CH3:15][N:16]([CH:18]=[C:5]([C:4](=[O:11])[CH2:3][CH:2]([CH3:1])[CH3:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:17]
Reactant: CCOC(=O)CC(=O)CC(C)C
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C(=CN(C)C)C(=O)CC(C)C
Yield: 100 %

Procedure:
According to Scheme 1 Step 1: A solution of ethyl 5-methyl-3-oxohexanoate (11.6 mmol, 2.00 g) and of 1,1-dimethoxy-N,N-dimethylmethanamine (11.6 mmole, 1.54 mL) in DMF (10 mL) was microwaved for 30 minutes at 120° C. After evaporation of the solvent, 2.64 g (11.6 mmol) of ethyl 2-((dimethylamino)methylene)-5-methyl-3-oxohexanoate as an orange oil were obtained and used without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([O:10][CH2:11][C@@H:12]2[O:14][CH2:13]2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[H][H]>CC(O)C>[OH:3][CH:1]([C:4]1[CH:5]=[C:6]([O:10][CH2:11][C@@H:12]2[O:14][CH2:13]2)[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CC(=O)c1cccc(OC[C@H]2CO2)c1
Reactant: [H][H]
Solvent: CC(C)O
Product: CC(O)c1cccc(OC[C@H]2CO2)c1
Reaction time: 14 h
Yield: 98 %

Procedure:
Chiral hydrogenation of (R)-glycidyl 3-acetylphenyl ether was carried out (see formula (12) below). That is, a reaction was carried out in accordance with the procedures of Example 4 using the (S,SS)-ruthenium hydride complex (1.5 mg; 0.00125 mmol) synthesized in Example 2 and using (R)-glycidyl 3-acetylphenyl ether (481 mg; 2.5 mmol) as the substrate and 2-propanol (2.5 mL) as the solvent. However, the hydrogen pressure was set to 8 atmosphere, the reaction temperature was set to 25° C., and the reaction time was set to 14 hours. As a result, one of the stereoisomers of (R)-glycidyl 3-(1-hydroxyethyl)phenyl ether was obtained at a conversion rate of 99%, isolation yield of 98% (475 mg; 2.45 mmol), and enantiomeric excess of 99%. GC (column: Chirasil-DEX CB; column temperature: 135° C.; injection and detection temperature: 250° C.; helium pressure: 60 kPa; tR of (R)-glycidyl (R) or (S)-3-(1-hydroxyethyl)phenyl ether: 94.9 minutes (98.6%); tR of the stereoisomers: 109.6 minutes (0.5%); tR of (R)-glycidyl 3-acetylphenyl ether: 46.5 minutes (0.9%); [α]29D: +32.0° (c: 1.36; CHCl3); The absolute structure was not determined.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][C:13]=3[CH:26]=2)[CH:5]=[N:6][C:7]=1[NH2:8].[CH3:27][O:28][C:29]([NH:31][C:32](=NC(OC)=O)SC)=[O:30]>C(O)(=O)C>[CH3:27][O:28][C:29]([NH:31][C:32]1[NH:1][C:2]2[C:7]([N:8]=1)=[N:6][CH:5]=[C:4]([C:9]1[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:14][C:13]=3[CH:26]=1)[CH:3]=2)=[O:30]
Reactant: COC(=O)N=C(NC(=O)OC)SC
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(-c3cnc(N)c(N)c3)cc2C1
Solvent: CC(=O)O
Product: COC(=O)Nc1nc2ncc(-c3ccc4c(c3)CN(C(=O)OC(C)(C)C)CCO4)cc2[nH]1
Temperature: 65 °C
Yield: 84.5 %

Procedure:
To a solution of 1,1-dimethylethyl 7-(5,6-diaminopyridin-3-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (0.51 g, 1.4 mmol) in acetic acid (5 mL) was added 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (0.3 g, 1.4 mmol). The reaction mixture was heated 65° C. for 18 h and then concentrated. The resulting residue was suspended in water and basified with portion wise addition of solid sodium bicarbonate. After complete neutralization of the aqueous mixture the insoluble solid was collected by filtration and washed with water then 50% ethyl acetate in hexanes and the filter cake dried to give 1,1-dimethylethyl 7-(2-{[(methyloxy)carbonyl]amino}-1H-imidazo[4,5-b]pyridin-6-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (0.52 g, 83% yield), MS (EI) for C22H25N5O5: 440 (MH+).
Reaction SMILES: C[Si](OS(C(F)(F)F)(=O)=O)(C)C.[CH2:13]([O:15][P:16]([O-:20])[O:17][CH2:18][CH3:19])[CH3:14].[C:21]1(=[O:26])[CH2:25][CH2:24][CH:23]=[CH:22]1.Cl>ClCCl>[CH2:13]([O:15][P:16]([CH:23]1[CH2:24][CH2:25][C:21](=[O:26])[CH2:22]1)(=[O:20])[O:17][CH2:18][CH3:19])[CH3:14]
Reactant: CCOP([O-])OCC
Reactant: O=C1C=CCC1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Product: CCOP(=O)(OCC)C1CCC(=O)C1
Reaction time: 1 h

Procedure:
0.52 mmol trimethylsilyltriflate are added dropwise to 11.4 mmol diethylphosphite and 12.4 mmol N,O-bis-(trimethylsilyl)acetamid in 5 ml dichlormethane at 0° C. After 30 minutes of stirring 0.52 mmol 2-cyclopenten-1-one are added dropwise thereto at the same temperature and stirring is continued for 1 h. The enolsilane intermediate product is hydrolized by 3 ml 1 n HCl and 3 hours of stirring. The organic phase is separated, dried over magnesiumsulfate and concentrated. The raw product may be chromatographed on SiO2 and, after concentrating the desired fractions, results to 3-(phosphonic acid diethylester)-cyclopentan-1-one (a) with boiling point0.25 Torr=104° C. in a good yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([C:19](O)=[O:20])[CH2:15][CH2:14]2)(=[O:10])=[O:9])=[C:4]([O:22][C:23]([F:26])([F:25])[F:24])[CH:3]=1.C([N:29](CC)CC)C.ClC(OCC)=O.N>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]([NH2:29])=[O:20])[CH2:15][CH2:14]2)(=[O:10])=[O:9])=[C:4]([O:22][C:23]([F:26])([F:25])[F:24])[CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)[C@H]1CC[C@H](CNS(=O)(=O)c2ccc(Br)cc2OC(F)(F)F)CC1
Agent: CCOC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: NC(=O)[C@H]1CC[C@H](CNS(=O)(=O)c2ccc(Br)cc2OC(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of trans-4-[(4-bromo-2-trifluoromethoxy-benzenesulfonylamino)-methyl]-cyclohexanecarboxylic acid (7.14 g, 15.5 mmol) and triethylamine (2.35 mL, 16.9 mmol) in THF (25 mL) was cooled to 0° C. To the mixture was added ethyl chloroformate (1.62 mL, 17 mmol) in THF (5 mL) over 10 min. After stirring at 0° C. for 15 min, aqueous ammonia (27 mL) was added dropwise and the mixture was stirred at ambient temperature for 2 hr. The mixture was concentrated under reduced pressure and the concentrate was treated with water to give a solid. The solid was filtered and washed with water and hexanes to give trans-4-[(4-bromo-2-trifluoromethoxy-benzenesulfonylamino)-methyl]-cyclohexanecarboxylic acid amide as a white solid (4.2 g, 59%).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].CC1(C)C(C)(C)OB([C:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]=2)O1>>[CH3:7][N:6]1[C:2]([C:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]=2)=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Product: Cn1ncc([N+](=O)[O-])c1C1=CCN(C(=O)OC(C)(C)C)CC1
Yield: 80 %

Procedure:
Following Example 231, reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate gave tert-butyl 4-(1-methyl-4-nitro-1H-pyrazol-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate (310 mg, 80%). 1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 5.89 (s br, 1H), 4.14 (s br, 2H), 3.81 (s, 3H), 3.73-3.67 (m, 2H), 2.37 (s br, 2H), 1.27 (s) and 1.24 (s) (9H)
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]1(=[O:15])[O:14][C:12](=[O:13])[CH:11]=[CH:10]1.[OH-].[NH4+]>O>[CH:1]([C:10]1=[CH:11][C:12]([O:14][C:9]1=[O:15])=[O:13])=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1C=CC(=O)O1
Reactant: C=Cc1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: O=C1C=C(C=Cc2ccccc2)C(=O)O1

Procedure:
Polymers of hydrolyzed styrene-maleic anhydride and starch were prepared according to the following process: Three or six parts of starch and one part SMA 3000 (styrene-maleic anhydride copolymer sold by Arco Chemical Company, having a ratio of styrene or maleic anhydride of 3:1, a molecular weight of 1900 and an acid number of 275) were added to and heated in water for 45 minutes at a temperature of 160° F. with stirring. Then 0.88 parts of 28% ammonium hydroxide (per part of SMA) was added with mixing for an additional 20 minutes and the final pH was adjusted to 9.5 with additional ammonium hydroxide resulting in binders having about a 25% solids content. Four polymers prepared by this process are shown in Table I.
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[F:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:2]2[CH:16]=[CH:15][C:5]3[C:6](=[O:14])[NH:7][C:8]4[C:13]([C:4]=3[CH:3]=2)=[CH:12][CH:11]=[CH:10][N:9]=4)=[CH:20][CH:19]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=c1[nH]c2ncccc2c2cc(Cl)ccc12
Product: O=c1[nH]c2ncccc2c2cc(Nc3ccc(F)cc3)ccc12
Yield: 25.3 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 231 using 6 (50 mg, 0.22 mmol) and 4-fluoroaniline (0.03 mL, 0.33 mmol) to provide 235 (17 mg, 23% yield) as a green/brown solid. LC-MS (M+H=306, obsd.=306).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=O)[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([I:17])[CH:13]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2].P(Cl)(Cl)([Cl:20])=O>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:20])=[CH:13][C:12]([I:17])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c[nH]c2ccc(I)cc2c1=O
Product: CCOC(=O)c1cnc2ccc(I)cc2c1Cl
Yield: 98 %

Procedure:
A mixture of 6-iodo-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester (56 g, 0.16 mol) in phosphorus oxychloride (180 mL) was refluxed under N2 for 14 h. After cooling, the solvent was removed by rotary evaporator and then by the oil pump. Sat. sodium bicarbonate (200 mL) was slowly added. The solid was collected by filtration, washed with sat. sodium bicarbonate, water and dried to obtain 4-chloro-6-iodo-quinoline-3-carboxylic acid ethyl ester (58 g, 98%) as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH2:8][S:9]([O-])(=[O:11])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Na+].P(Cl)(Cl)(Cl)(Cl)[Cl:17]>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH2:8][S:9]([Cl:17])(=[O:11])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CS(=O)(=O)[O-])cc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(CS(=O)(=O)Cl)cc1
Yield: 100 %

Procedure:
To a suspension of 28.3 g (118 mmol, 1.0 equiv.) of finely ground sodium 4-nitrobenzyl sulfonate in 250 mL of toluene was added 24.6 g (118 mmol, 1.0 equiv) of finely ground phosphorous pentachloride as the solid in portions. After addition the mixture was heated to reflux for one hour. The mixture was cooled, and volatile material was removed in vacuo. The residue was dissolved in 500 mL chloroform and 250 mL of water. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated to give 27.8 g (100%) of 4-nitrobenzyl sulfonyl chloride, pure by 1H NMR.
Reaction SMILES: C([Si](CC)(CC)[C:4]#[C:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][O:14][CH3:15])=[CH:8][C:7]=1[CH3:16])C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[C:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][O:14][CH3:15])=[CH:8][C:7]=1[CH3:16])#[CH:4]
Reactant: CC[Si](C#Cc1ccc(OCOC)cc1C)(CC)CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: C#Cc1ccc(OCOC)cc1C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of triethyl((4-(methoxymethoxy)-2-methylphenyl)ethynyl)silane (1.0 equiv.) at 0° C. was slowly added tetrabutylammonium fluoride (1M solution in THF, 0.20 equiv.). At this point, the ice-bath was removed and the reaction mixture was allowed to stir at room temperature for 45 minutes. The reaction mixture was then passed through a pad of silica (packed with hexane) and eluted with 20% EtOAc in Hexanes to remove insoluble salts. The crude product was then purified by Combiflash using 0-10% EtOAc in Hexanes to give 1-ethynyl-4-(methoxymethoxy)-2-methylbenzene (8) as a slightly brown liquid.
Reaction SMILES: C([BH3-])#N.[Na+].[CH3:5][O:6][N:7]=[C:8]([CH2:10][CH2:11][CH2:12][N:13]1[C:25]2[C:24]3[CH:23]=[CH:22][C:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:20][C:19]=3[N:18]=[C:17]([NH2:32])[C:16]=2[N:15]=[C:14]1[CH2:33][CH2:34][CH3:35])[CH3:9]>C(O)C.C(O)(=O)C>[NH2:32][C:17]1[C:16]2[N:15]=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]([CH2:12][CH2:11][CH2:10][CH:8]([NH:7][O:6][CH3:5])[CH3:9])[C:25]=2[C:24]2[CH:23]=[CH:22][C:21]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[CH:20][C:19]=2[N:18]=1
Reactant: CCCc1nc2c(N)nc3cc(-c4ccccc4)ccc3c2n1CCCC(C)=NOC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCCc1nc2c(N)nc3cc(-c4ccccc4)ccc3c2n1CCCC(C)NOC
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
Sodium cyanoborohydride (2.26 g, 36.1 mmol) was added to a solution of 5-(4-amino-7-phenyl-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one O-methyloxime (3.0 g, 7.22 mmol) in ethanol (50 mL) and acetic acid (3 mL) and stirred at ambient temperature overnight. Another portion of sodium cyanoborohydride was added (1.0 g) and the reaction was stirred for an additional 4 hours. The reaction mixture was concentrated under reduced pressure and the residue was diluted in water and neutralized to pH ˜8 with 10% sodium hydroxide solution. The product was extracted into dichloromethane, washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, and concentrated under reduced pressure to provide 2.73 g of N-[4-(4-amino-7-phenyl-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-1-methylbutyl]-O-methylhydroxylamine.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.[CH3:13][CH:14]([CH3:30])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:19]=1)=[O:16]>>[CH3:13][CH:14]([CH3:30])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]2[CH2:29][CH2:28][N:27]([CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)[CH2:26][CH2:25]2)[CH:19]=1)=[O:16]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=Cc1ccc2ccccc2n1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4ccccc4n3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 2-quinolinecarbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 388.1 (M+H)+.
Reaction SMILES: [CH2:1]([CH:3]1[CH:8]([CH3:9])[C:7](=[O:10])[C:6]2[CH:11]=[C:12]([CH:15]([CH3:20])[C:16]([O:18]C)=[O:17])[CH:13]=[CH:14][C:5]=2[O:4]1)[CH3:2].C(=O)(O)[O-].[Na+].O>C(O)C>[CH2:1]([CH:3]1[CH:8]([CH3:9])[C:7](=[O:10])[C:6]2[CH:11]=[C:12]([CH:15]([CH3:20])[C:16]([OH:18])=[O:17])[CH:13]=[CH:14][C:5]=2[O:4]1)[CH3:2]
Reactant: CCC1Oc2ccc(C(C)C(=O)OC)cc2C(=O)C1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCC1Oc2ccc(C(C)C(=O)O)cc2C(=O)C1C

Procedure:
Methyl 2-[2,3-dihydro-2-ethyl-3-methyl-4-oxo-4H-1-benzopyran-6-yl]propionate (6 g) was dissolved in ethanol (200 ml) and heated to reflux with dilute aqueous sodium bicarbonate solution (50 ml) for eight hours. The reaction mixture was poured into water, acidified and extracted with ether. The combined etheral extracts were washed with water and dried (MgSO4) and concentrated in vacuo affording a mixture of the desired product and starting material which were separated by chromatography on silica gel using dichloromethane/ether mixtures as eluant. The title compound was recrystallised from petroleum ether (bp 40°-60° C.) as a white solid: 1.4 g, mp 114°-115° C.
Reaction SMILES: [Na].[CH2:2]([OH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[C:11]1[N:12]([C:21]2[N:22]=[C:23]([NH2:29])[NH:24][C:25](=[O:28])[C:26]=2[N:27]=1)[C@@H:13]1[O:20][C@H:17]([CH2:18][OH:19])[C@@H:15]([OH:16])[CH2:14]1.C(O)(=O)C>CS(C)=O>[CH2:2]([O:9][C:11]1[N:12]([C:21]2[N:22]=[C:23]([NH2:29])[NH:24][C:25](=[O:28])[C:26]=2[N:27]=1)[C@@H:13]1[O:20][C@H:17]([CH2:18][OH:19])[C@@H:15]([OH:16])[CH2:14]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Nc1nc2c(nc(Br)n2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Reactant: OCc1ccccc1
Agent: [Na]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: Nc1nc2c(nc(OCc3ccccc3)n2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Temperature: 65 °C

Procedure:
Two hundred mL of dimethyl sulfoxide (DMSO) are added to a freshly prepared solution of sodium benzoylate (made from benzyl alcohol (75 mL) and sodium (2.14 g)) under an atmosphere of argon. 8-Bromodeoxyguanosine (10 g, 29 mmol) in DMSO (80 mL) is added to the resulting mixture and the reaction is heated to 65° C. for 24 hours. After cooling to room temperature, the reaction mixture is neutralized with glacial acetic acid and the DMSO is removed by vacuum distillation at 65° C. The remaining solution is poured into ether with stirring. The oily residue that remains after decanting off the ether is added to acetone and the resulting white precipitate is removed by filtration. After stirring with water, the slurry is filtered and the collected white solid recrystallized from methanol to give 8-(benzyloxy)-2'-deoxyguanosine.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Li]CCCC.[Br:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)=[O:23])[CH:20]=2)[N:15]=[C:14]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH:13]=1>O1CCCC1>[Br:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)([C:2]3[S:1][CH:5]=[CH:4][N:3]=3)[OH:23])[CH:20]=2)[N:15]=[C:14]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH:13]=1
Reactant: c1cscn1
Reactant: CC(C)(C)Oc1cc(Br)c2cc(C(=O)c3ccc(Cl)cc3)ccc2n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)Oc1cc(Br)c2cc(C(O)(c3ccc(Cl)cc3)c3nccs3)ccc2n1
Temperature: -78 °C
Reaction time: 0.83 h

Procedure:
Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of thiazole (255 mg, 3.00 mmol, 2.00 equip) in tetrahydrofuran (15 mL). To the resulting mixture was then added n-BuLi (1 mL, 1.70 equip, 2.5 M) dropwise with stirring at −78° C. The resulting solution was stirred for 50 min at −78° C. To the resulting mixture was added a solution of (4-bromo-2-tert-butoxyquinolin-6-yl) (4-chlorophenyl) methanone (630 mg, 1.50 mmol, 1.00 equip) in tetrahydrofuran (5 mL) dropwise with stirring at −78° C. The resulting solution was allowed to react, with stirring, for an additional 40 min at −78° C. The resulting solution was stirred for 30 min at 0° C. The reaction was then quenched by the addition of water. The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers combined. The resulting mixture was washed with water (2×50 mL) and brine (1×50 mL). The resulting mixture was dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with ethyl acetate:petroleum ether (1:4) to yield (4-bromo-2-tert-butoxyquinolin-6-yl)(4-chlorophenyl)(thiazol-2-yl)methanol as a white solid. (ES, m/z): [M+H]+ 505
Reaction SMILES: [CH2:1]([N:8]([CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([O:45]C)=[C:41]([C:47]([O:49]C)=[O:48])[CH:40]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24]C)=[C:20]([C:26]([O:28]C)=[O:27])[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BrH:51]>>[BrH:51].[BrH:51].[CH2:1]([N:8]([CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[C:41]([C:47]([OH:49])=[O:48])[CH:40]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([C:26]([OH:28])=[O:27])[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(CCN(CCCCCCN(CCc2ccc(OC)c(C(=O)OC)c2)Cc2ccccc2)Cc2ccccc2)ccc1OC
Agent: Br
Product: O=C(O)c1cc(CCN(CCCCCCN(CCc2ccc(O)c(C(=O)O)c2)Cc2ccccc2)Cc2ccccc2)ccc1O

Procedure:
A mixture of 1.56 g. (0.0023 m.) of N,N'-dibenzyl-N,N'-bis[2-(3-carbomethoxy-4-methoxyphenyl)-ethyl]-hexamethylenediamine and 40 ml. of 48% aqueous hydrobromic acid is refluxed for four hours. The cooled reaction mixture is filtered to give N,N'-dibenzyl-N,N'-bis[2-(3-carboxy-4-hydroxyphenyl)-ethyl]-hexamethylenediamine dihydrobromide. The latter is hydrogenated with palladium-on-carbon as described in Example 1 to yield N,N'-[2-(3-carboxy-4-hydroxyphenyl)-ethyl]-hexamethylenediamine dihydrobromide. The free base obtained from this dihydrobromide (0.8 g., 0.0018 m.) is added to an ice cold solution of 40 ml. of 1M borane in tetrahydrofuran (0.04 m.) while stirring under nitrogen. The temperature is maintained at 0° C. for 20 hours, the solution is then refluxed for one hour and concentrated in vacuo. Several portions of methanol are added, the solution is concentrated and the residue is dissolved in ethanol and filtered. Sulfuric acid is added to pH 2.0 to give N,N'-bis[2-(4-hydroxy-3-hydroxmethylphenyl)-ethyl]-hexamethylenediamine sulfate.