Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.FC(F)(F)S(O[C:29]1[C:34]([N+:35]([O-:37])=[O:36])=[C:33]([NH:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:32]=[C:31]([CH3:43])[N:30]=1)(=O)=O>C1(C)C=CC=CC=1>[CH2:39]([NH:38][C:33]1[CH:32]=[C:31]([CH3:43])[N:30]=[C:29]([N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:34]=1[N+:35]([O-:37])=[O:36])[CH2:40][CH2:41][CH3:42]
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: CCCCNc1cc(C)nc(OS(=O)(=O)C(F)(F)F)c1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCNc1cc(C)nc(N(Cc2ccccc2)Cc2ccccc2)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 97.4 %

Procedure:
Dibenzylamine (1.04 g, 5.28 mmole), triethylamine (0.53 g, 5.28 mmole), 4-butylamino-6-methyl-3-nitro-2-pyridinyl trifluoromethanesulfonate (1.72 g, 5.28 mmole) and toluene (45 mL) were combined and heated at reflux for 18 hours. The reaction mixture was cooled to ambient temperature then filtered through a layer of silica gel. The silica gel was eluted with methylene chloride. The combined organic filtrates were evaporated to provide 2.08 g of an oily semisolid.
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH:9]([C:11]1[S:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1)[CH3:10].[CH3:20][S:21](Cl)(=[O:23])=[O:22].[Cl-].[Na+]>C(Cl)Cl>[CH3:20][S:21]([O:8][CH:9]([C:11]1[S:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1)[CH3:10])(=[O:23])=[O:22]
Reactant: CC(O)c1nc2ccccc2s1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(OS(C)(=O)=O)c1nc2ccccc2s1
Reaction time: 2 h
Yield: 94.3 %

Procedure:
0.33 ml of triethylamine were added to a solution of 384.4 mg of 2-(1-hydroxyethyl)-benzothiazole [prepared as described in step (b) above] in 4 ml of methylene chloride cooled in an ice-water bath, and then 0.18 ml of methanesulfonyl chloride were added thereto. The temperature of the resulting mixture was elevated to room temperature, and the mixture was then stirred for 2 hours. At the end of this time, a saturated aqueous sodium chloride solution was added to the reaction mixture and the resulting mixture was then extracted with methylene chloride. The resulting extract was washed with water and dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure to given 519.4 mg (yield 94.3%) of the title compound as an oil.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[CH2:20]([O:22][CH:23]([O:32][CH2:33][CH3:34])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH:30]=[O:31])[CH3:21].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[F:13][C:14]1[C:19]([CH:30]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]([O:22][CH2:20][CH3:21])[O:32][CH2:33][CH3:34])[OH:31])=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: CCOC(OCC)c1ccccc1C=O
Reactant: Fc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(OCC)c1ccccc1C(O)c1cccnc1F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2.5 ml of diisopropylamine in 20 ml of dry tetrahydrofuran at -78° C. was added 11 ml of a 1.6 M solution of butyllithium in hexanes. The solution was stirred for 20 min. then a solution of 1.15 g of 2-fluoropyridine in 3 ml of tetrahydrofuran was added. The solution was stirred at -78° C. for 30 min then a solution of 2-formylbenzaldehyde diethylacetal in 3 ml of tetrahydrofuran was added dropwise. This solution was stirred for 1 h then warmed to room temperature overnight. The reaction was poured into a 5% solution of sodium carbonate and extracted with two 300 ml portions of ether. The combined organic layers were washed with 300 ml of water then the same volume of brine and dried over sodium sulfate. Evaporation of the solvent afforded (2-fluoropyridin-3-yl)-2-(diethoxymethyl)-phenyl methanol as a viscous oil; 1H-NMR (200 MHz, CDCl3) d 5.60 (CHOEt).
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].[CH3:5][CH:6]([N:11]=[N:12][C:13](Br)([CH2:15][CH3:16])[CH3:14])[CH2:7][CH:8]([CH3:10])[CH3:9].O>CC(C)=O>[CH3:5][CH:6]([N:11]=[N:12][C:13]([N:3]=[C:2]=[O:1])([CH2:15][CH3:16])[CH3:14])[CH2:7][CH:8]([CH3:9])[CH3:10]
Reactant: CCC(C)(Br)N=NC(C)CC(C)C
Reactant: N#C[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCC(C)(N=C=O)N=NC(C)CC(C)C
Temperature: 25 °C

Procedure:
To a stirred solution of 3.25 grams (.04 moles) of potassium cyanate in 75 ml of 70% aqueous acetone in a 125 ml erlenmeyer flask was added 9.4 grams (.0377 moles) of 2-(1,3-dimethylbutylazo)2-bromobutane (from Example III) over 5 minutes while holding the reaction temperature at 15°-20° C with a cold water bath. After the addition was complete the reaction was stirred an additional hour at room temperature, poured into 200 ml of water and the product extracted with 100 ml of pentane. The pentane solution was separated, washed with 50 ml portions of water and saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and the pentane evaporated under reduced pressure on a rotating evaporator. The product was a yellow liquid and weighed 6.4 grams (80.5% crude yield). The infrared spectrum was in agreement with the structure of 2-(1,3-dimethylbutylazo)-2-isocyanatobutane (strong broad isocyanate band at 2125-2225 cm-1).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[N+:5]([C:8]1[CH:15]=[C:12]([CH:13]=[O:14])[C:11]([OH:16])=[CH:10][CH:9]=1)([O-:7])=[O:6].CO[CH2:19][Cl:20]>>[Cl:20][CH2:19][C:10]1[CH:9]=[C:8]([N+:5]([O-:7])=[O:6])[CH:15]=[C:12]([CH:13]=[O:14])[C:11]=1[OH:16]
Reactant: COCCl
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Agent: [Al+3]
Agent: [Cl-]
Product: O=Cc1cc([N+](=O)[O-])cc(CCl)c1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
Aluminum chloride (80 g) was added to an ice bath-cooled mixture of 20.0 g of 5-nitrosalicylaldehyde and 200 ml of chloromethyl methyl ether, and the reaction was carried out at room temperature for 1 hour and then at 63° C. for 17 hours. The reaction mixture was cooled on an ice bath, and then 300 ml of ice water was added, and the resultant white precipitate was collected by filtration and recrystallized from hexane to give 18.6 g of 3-chloromethyl-5-nitrosalicylaldehyde (yield 72%).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Cl:10][C:11]1[N:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>>[Cl:10][C:11]1[N:16]=[CH:15][C:14]([S:17]([N:7]2[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]2)(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: CC(C)N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Product: CC(C)N1CCN(S(=O)(=O)c2ccc(Cl)nc2)CC1
Yield: 89 %

Procedure:
The title compound was prepared as described for Example 25 using N-isopropylpiperazine and 6-chloropyridine-3-sulfonyl chloride (described in: Naegeli, C. et al. Helv. Chim. Actal. 1938, 21, 1746-1750). Yield: 89%: 1H NMR (CDCl3, 400 MHz) δ 8.73 (d, J=3 Hz, 1 H), 7.96 (dd, J=8, 3 Hz, 1 H), 7.48 (d, J=8 Hz, 1 H), 3.12-3.01 (m, 4 H), 2.76-2.63 (m, 1 H), 2.63-2.54 (m, 4 H), 0.99 (d, J=7 Hz, 6 H); 13C NMR (CDCl3, 100 MHz) δ 156.1, 149.3, 138.2, 131.7, 125.0, 54.8, 48.0, 46.7, 18.7; MS (ES) m/z 304 (M++1).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][C:10]1([CH3:27])[CH2:19][C:18](=O)[C:17]2[C:12](=[CH:13][C:14]([O:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])=[CH:15][CH:16]=2)[O:11]1.Cl>C1COCC1>[CH3:9][C:10]1([CH3:27])[CH:19]=[C:18]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:17]2[C:12](=[CH:13][C:14]([O:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])=[CH:15][CH:16]=2)[O:11]1
Reactant: CN(C)CCOc1ccc2c(c1)OC(C)(C)CC2=O
Reactant: Br[Mg]c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc2c(c1)OC(C)(C)C=C2c1ccccc1

Procedure:
To a stirred solution of phenylmagnesium bromide [from bromobenzene and magnesium in dry tetrahydrofuran] was added 2,2-dimethyl-7-(2-dimethylaminoethoxy)-chroman-4-one in dry THF and the resulting solution was boiled under reflux for 2 weeks. The cooled reaction mixture was decomposed with 2.5 N hydrochloric acid and the organic layer separated and dried (magnesium sulphate). Removal of the solvent gave a yellow oil which was chromatographed on silica in 3% ether--97% light petroleum (b.p. 60°-80°) gave the title compound as a colourless oil. Dissolution in dry ether and passage of dry hydrogen chloride through the solution gave the hydrochloride salt, m.p. 186.5°-187.5°. An analogous procedure yielded 7-(2-N-benzyl-N-methyl-aminoethoxy)-4-(4-fluorophenyl)-2, 2-dimethyl-2H-chromene as a colourless oil.
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([NH:18][C:19]2[N:24]=[C:23]([C:25](=[O:27])[CH3:26])[C:22]([CH3:28])=[C:21]([CH2:29][O:30][CH2:31][C:32]([F:35])([F:34])[F:33])[N:20]=2)[CH:9]=[CH:10][C:11]=1[N:12]1[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]1>C1COCC1>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([NH:18][C:19]2[N:24]=[C:23]([C:25]([OH:27])([CH3:1])[CH3:26])[C:22]([CH3:28])=[C:21]([CH2:29][O:30][CH2:31][C:32]([F:33])([F:34])[F:35])[N:20]=2)[CH:9]=[CH:10][C:11]=1[N:12]1[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]1
Reactant: C[Mg]Br
Reactant: COc1cc(Nc2nc(COCC(F)(F)F)c(C)c(C(C)=O)n2)ccc1-n1cnc(C)c1
Solvent: C1CCOC1
Product: COc1cc(Nc2nc(COCC(F)(F)F)c(C)c(C(C)(C)O)n2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methylmagnesium bromide (0.199 mL of 3M solution, 0.28 mmol) was added slowly to a solution of 1-(2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-5-methyl-6-((2,2,2-trifluoroethoxy)methyl)pyrimidin-4-yl)ethanone (25 mg, 0.06 mmol) in THF (3 mL). The mixture was stirred at RT for 1 h. The mixture was quenched with saturated solution of ammonium chloride in water (1.5 mL) and diluted with brine (10 mL). The mixture was extracted with EtOAc (2×20 mL). The organic phase was dried over sodium sulfate and concentrated in vacuum. The residue was purified by preparative HPLC to give title compound as a dry film, 13 mg (45%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([OH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:12]1[O:24][C@H:23]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]1[O:14][C:15](=[O:17])[CH3:16].[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38]Br)=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:1][C:2]1[N:10]=[C:9]([O:11][CH2:38][CH2:37][C:34]2[CH:35]=[CH:36][C:31]([Cl:30])=[CH:32][CH:33]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:12]1[O:24][C@H:23]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]1[O:14][C:15](=[O:17])[CH3:16]
Reactant: Clc1ccc(CCBr)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(O)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(OCCc4ccc(Cl)cc4)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 32 h
Yield: 64 %

Procedure:
To a mixture of 6-chloro-2-hydroxy-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine (Example 2, Step C) and 2-(4-chlorophenyl)ethyl bromide (300.1 g, 1.36 mol) in dimethylformamide (7,280 mL), cesium carbonate (665 g, 2.04 mol) was added. The reaction was allowed to stir under inert atmosphere for 32 hours. The reaction was concentrated under reduced pressure and partitioned between dichloromethane and water. The organic layer was dried over magnesium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by column chromatography eluting with ethyl acetate/heptanes to yield a yellow solid of 6-chloro-2-[2-(4-chlorophenyl)ethoxy]-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine Typical Yield: 64%
Reaction SMILES: [CH:1]([S:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8])([CH3:3])[CH3:2].BrBr.[O-:15]S([O-])=O.[Na+].[Na+]>ClCCl>[CH:1]([S:4]([C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8])=[O:15])([CH3:3])[CH3:2]
Reactant: CC(C)Sc1ccccc1C=O
Reactant: O=S([O-])[O-]
Agent: BrBr
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)S(=O)c1ccccc1C=O
Reaction time: 0.33 h

Procedure:
A solution of 2-(isopropylthio)benzaldehyde (0.33 g, 1.83 mmol) in dichloromethane (10 ml) was admixed with aqueous KHCO3 solution (1.18 g in 10 ml of H2O). With vigorous stirring, a solution of bromine (0.310 g, 1.93 mmol) in dichloromethane (1.5 ml) was added dropwise. After continuing to stir for 20 min, a spatula-tip of Na2SO3 was added, and the organic phase was removed, washed with saturated NaCl solution, dried over MgSO4 and filtered, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (3:1 to 1:1 hexane:ethyl acetate). The product precipitated out as a yellowish oil. Yield 0.304 g (85%).
Reaction SMILES: [H-].[Na+].[C:3]12([OH:13])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.Cl[CH2:15][C:16]([OH:18])=[O:17]>C1COCC1>[C:3]12([O:13][CH2:15][C:16]([OH:18])=[O:17])[CH2:10][CH:9]3[CH2:8][CH:7]([CH2:6][CH:5]([CH2:11]3)[CH2:4]1)[CH2:12]2
Reactant: O=C(O)CCl
Reactant: OC12CC3CC(CC(C3)C1)C2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)COC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83 %

Procedure:
To a stirred, ice-cooled suspension of sodium hydride (60% dispersion in mineral oil, 39.4 g, 985 mmol) in THF (250 mL) was added dropwise a solution of 1-adamantanol (50.0 g, 328 mmol) in THF (250 mL) over a period of 30 minutes. The resultant suspension was allowed to warm to ambient temperature and stirred at this temperature for 10 minutes. The suspension was re-cooled in ice/water and a solution of chloroacetic acid (46.5 g, 492 mmol) in THF (250 mL) was added slowly over 30 minutes (CARE VERY EXOTHERMIC). The coolant was removed and the suspension was stirred at ambient temperature for 30 minutes and then heated at reflux for 18 hours. The suspension was allowed to cool and carefully quenched with water (750 mL). The mixture was washed with diethyl ether (2×500 mL) and the combined organic phases were discarded. The pH of the aqueous phase was adjusted to 1 with concentrated HCl. The resultant suspension was filtered and the filter-cake washed with water (500 mL). The solid residue was dissolved in chloroform (750 mL) and then washed with saturated brine (750 mL). The organic phase was then dried over magnesium sulfate and the filtrate was evaporated at reduced pressure to give the title compound as a white solid (57.25 g, 83%). 1H NMR (CDCl3) 10.0-9.00 (1H, br s), 4.09 (2H, br s), 2.20 (3H, br s), 1.78-1.77 (6H, m), 1.70-1.58 (6H, m).
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:8]([CH2:9][OH:10])[O:7][C@@H:6]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:5]1)=[N+]=[N-].[H][H]>C(O)C.[Pd]>[NH2:1][C@@H:4]1[C@@H:8]([CH2:9][OH:10])[O:7][C@@H:6]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:5]1
Reactant: [H][H]
Reactant: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: [Pd]
Solvent: CCO
Product: Cc1cn([C@H]2C[C@H](N)[C@@H](CO)O2)c(=O)[nH]c1=O
Yield: 87.8 %

Procedure:
A slurry of 2.17 g of 3'-azido-3'-deoxythymidine (Aldrich, Milwaukee, Wis.) and 0.91 g of 10% Pd/C in 25 ml of ethanol were vigorously stirred under 1 atm. of hydrogen for 4 hr. The mixture was filtered through celite, washed with methanol, and the filtrate was evap. Purification by chromatography on silica (2 to 40% methanol/DCM) gave 1.72 g of 3'-amino-3'-deoxythymidine as a light yellow solid: NMR (300 MHz,d6-DMSO) δ7.76 (s,1H), 6.07 (t,1H,J=6 Hz), 4.97 (m,1H), 3.5-3.7 (m,3H), 3.39 (q,1H,J=7 Hz), 3.33 (br,2H), 1.9-2.15 (m,2H), 1.77 (s,3H).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:28])[C@@H:10]([CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH:11]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>ClCCl>[CH2:1]([NH:8][C:9](=[O:28])[C@@H:10]([CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH2:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H](COCc1ccccc1)C(=O)NCc1ccccc1
Agent: Cl
Solvent: ClCCl
Product: N[C@H](COCc1ccccc1)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.2 %

Procedure:
To a solution of N-benzyl-O-benzyl-N2-Boc-D-serinamide (1 g) and dichloromethane (5 mL), aq. HCl (35%) (5 mL) was added. The solution was stirred for 2 hours at room temperature for completion of reaction. The solution was concentrated under vacuum to remove dichloromethane and subsequently water was added. The aqueous layer was basified to pH 8-10 with 5% sodium hydroxide. The aqueous layer was extracted with ethyl acetate and the combined organic layer was washed with brine solution. Organic layer was concentrated under vacuum to obtain an oily residue 0.46 g of N-benzyl-O-benzyl-D-serinamide.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([C:10](=O)[C:11]#[C:12][CH3:13])=[CH:6][C:5]=12.Cl.[NH2:16][OH:17].C(N(CC)CC)C>CN(C=O)C>[CH3:13][C:12]1[O:17][N:16]=[C:10]([C:7]2[CH:8]=[CH:9][N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=2)[CH:11]=1
Reactant: CC#CC(=O)c1ccn2ccnc2c1
Reactant: NO
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(-c2ccn3ccnc3c2)no1
Temperature: 80 °C
Yield: 25.4 %

Procedure:
To a solution of 1-Imidazo[1,2-a]pyridin-7-yl-but-2-yn-1-one (168 mg, 0.91 mmol) and hydroxylamine hydrochloride (94 mg, 1.37 mmol) in DMF (10 ml) was added triethylamine (0.21 ml, 1.83 mmol). The reaction mixture was heated at 80° C. for 18 h, then partitioned between EtOAc and H2O. The organic fraction was separated, dried (MgSO4), filtered and the solvent removed in vacuo. The crude residue was purified by silica column chromatography (0-50% MeOH in Et2O) to afford the product (46 mg). MS: [M+H]+=200.
Reaction SMILES: [OH:1][CH:2]([C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[CH:3]([NH:18][C:19]([C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[CH2:31][CH2:30][CH2:29][CH:28]=[CH:27][C:26]=12)=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:46][CH2:47][CH2:48][CH3:49]>CN(C)C=O.O>[CH2:46]([O:38][C:35]1[CH:36]=[CH:37][C:32]([CH:2]([OH:1])[CH:3]([NH:18][C:19]([C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[CH2:31][CH2:30][CH2:29][CH:28]=[CH:27][C:26]=23)=[O:20])[CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:16])([F:17])[CH:13]([F:15])[F:14])[CH:6]=2)=[CH:33][CH:34]=1)[CH2:47][CH2:48][CH3:49]
Reactant: CCCCI
Reactant: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(O)cc1)c1cccc2c1C=CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOc1ccc(C(O)C(Cc2cccc(OC(F)(F)C(F)F)c2)NC(=O)c2cccc3c2C=CCCC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-{(1RS,2SR)-2-hydroxy-2-(4-hydroxyphenyl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide (400 mg, 0.755 mmol) in N,N-dimethylformamide (15 ml) were added potassium carbonate (313 mg, 2.27 mmol) and 1-iodobutane (417 mg, 2.27 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave the objective substance (298 mg, 67%).
Reaction SMILES: [C:1]1([NH:11][NH2:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:13](OCC)(=O)[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1>C(O)(C)C>[N:17]1[CH:18]=[CH:19][C:14]([C:13]2[NH:12][N:11]=[C:1]3[C:10]4[C:5]([CH:4]=[CH:3][C:2]=23)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1ccncc1
Reactant: NNc1cccc2ccccc12
Solvent: CC(C)O
Product: c1ccc2c(c1)ccc1c(-c3ccncc3)[nH]nc12

Procedure:
A solution of 16 grams (0.10 mole) of 1-naphthyl hydrazine, 15.1 grams (0.10 moles) of ethyl isonicotinate and 300 ml. of isopropanol are stirred and refluxed for 48 hours. The solvent is removed in vacuo and the resultant 2-(1-naphthyl)-isonicotinic acid hydrazide is added to 125 ml. of phosphorous oxychloride and stirred and refluxed for about 15 hours. The reaction mixture is then concentrated in vacuo and the resultant simi-solid dissolved in about 250 ml. methylene dichloride. The methylene dichloride layer is washed with 100 ml of cold 2N potassium hydroxide, 100 ml. of water, dried with magnesium sulfate, filtered and concentrated in vacuo. Crystallization from ethanol/ether yields 3-(4-pyridyl)-2H-naphtho[1,2-c]pyrazole, m.p. 271°-273°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C=O.[C:22](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH3:22])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CC(=O)O
Reactant: COC(=O)c1cc(Br)cc(NC2CCOCC2)c1C
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)c1cc(Br)cc(N(C)C2CCOCC2)c1C
Reaction time: 18 h
Yield: 58.1 %

Procedure:
To a stirred solution of methyl 5-bromo-2-methyl-3-[(oxan-4-yl)amino]benzoate (1.20 g, 3.66 mmol) in DCE (10 ml) under a nitrogen atmosphere was added paraformaldehyde (659 mg, 21.9 mmol) followed by acetic acid (1.26 ml, 21.9 mmol) and the reaction was left to stir for 5 min before the addition of sodium triacetoxyborohydride (4.65 g, 21.9 mmol). The reaction was stirred for 16 h at room temperature after which time additional paraformaldehyde (325 mg, 10.8 mmol) and sodium triacetoxyborohydride (2.40 g, 11.3 mmol) was added and the reaction was stirred for a further 18 h whereupon distilled water (30 ml) was added and solid NaHCO3 was added until the aqueous phase was pH7 and the phases were separated, the aqueous phase was washed with EtOAc (3×50 ml), the combined organics were then washed with brine (50 ml), dried using Na2SO4, filtered and evaporated. The crude residue was purified using FCC over silica eluting with 0-10% EtOAc in heptane to afford the title compound as a colourless oil (728 mg, 52%). LC-MS 87%, m/z=341.9/343.9, 1H NMR (500 MHz, Chloroform-d) δ 7.60 (d, J=2.0 Hz, 1H), 7.25 (d, J=1.9 Hz, 1H), 3.92 (d, J=11.1 Hz, 2H), 3.82 (s, 3H), 3.27 (td, J=11.5, 2.0 Hz, 2H), 2.94-2.79 (m, 1H), 2.57 (s, 3H), 2.36 (s, 3H), 1.74-1.52 (m, 4H).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][C:17]([S:20][C:21]2[CH:26]=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:24]([OH:31])=[C:23]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:22]=2)([CH3:19])[CH3:18])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].Cl[CH2:37][CH2:38][CH2:39][C:40]([O:42][CH3:43])=[O:41].[F-].[K+]>CN(C=O)C>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([S:16][C:17]([S:20][C:21]2[CH:22]=[C:23]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:24]([O:31][CH2:37][CH2:38][CH2:39][C:40]([O:42][CH3:43])=[O:41])=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:26]=2)([CH3:18])[CH3:19])[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]=1[OH:11])([CH3:1])[CH3:3]
Reactant: COC(=O)CCCCl
Reactant: CC(C)(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCCOc1c(C(C)(C)C)cc(SC(C)(C)Sc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 20.5 h
Yield: 16.4 %

Procedure:
Probucol (5, 9.69 mmol) and methyl 4-chlorobutyrate (3.1 g. 1.4 eq) were stirred in DMF (15 mL) and potassium fluoride on alumina (7 g, 5 eq) was added. The mixture was stirred at room temperature under nitrogen for 20.5 hours. It was filtered, diluted with ethyl acetate (100 mL), washed with water and brine, dried over sodium sulfate, and evaporated. Chromatography (MPLC, 10% to 80% of dichloromethane in hexanes) gave 0.98 g of methyl 4-[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenoxy]butyrate.