Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][CH:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)(=[O:28])=[O:27])[CH2:22][CH2:21]2)=[CH:5][CH:4]=1)=O.[CH3:38][NH2:39].[BH4-].[Na+]>CO.C(Cl)Cl>[CH3:38][NH:39][CH2:1][C:3]1[S:7][C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][CH:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)(=[O:27])=[O:28])[CH2:22][CH2:21]2)=[CH:5][CH:4]=1
Reactant: NC(=O)c1cc(-c2ccc(C=O)s2)cc2c(C3CCN(S(=O)(=O)CCCN4CCOCC4)CC3)c[nH]c12
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CCCN5CCOCC5)CC4)c3c2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.8 %

Procedure:
To a solution of 5-(5-formyl-2-thienyl)-3-(1-{[3-(4-morpholinyl)propyl]sulfonyl}-4-piperidinyl)-1H-indole-7-carboxamide (20 mg, 0.04 mmol) in MeOH/CH2Cl2 (1 mL/1 mL) was added methyl amine (0.11 mL, 0.24 mmol). The reaction mixture was stirred at room temperature for 2 hours before NaBH4 (10.5 mg, 0.24 mmol) was added. The reaction mixture was stirred at room temperature overnight and evaporated all the solvent. The residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to give the title compound (13.4 mg, 65%).
Reaction SMILES: P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].SC[C@H]([C@@H](CS)O)O.C(SCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)COP(O)(=O)OP(O)(=O)OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1OP(O)(O)=O)(=O)CCCCCCCCCCCCCCC.[CH3:82][C:83]1[CH2:88][CH2:87][CH2:86][C:85]([CH3:90])([CH3:89])[C:84]=1/[CH:91]=[CH:92]/[C:93](/[CH3:102])=[CH:94]/[CH:95]=[CH:96]/[C:97](/[CH3:101])=[CH:98]/[CH2:99][OH:100]>>[CH3:82][C:83]1[CH2:88][CH2:87][CH2:86][C:85]([CH3:89])([CH3:90])[C:84]=1/[CH:91]=[CH:92]/[C:93](/[CH3:102])=[CH:94]/[CH:95]=[CH:96]/[C:97](/[CH3:101])=[CH:98]/[CH:99]=[O:100]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/CO)C(C)(C)CCC1
Agent: CCCCCCCCCCCCCCCC(=O)SCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O
Agent: O=P([O-])([O-])[O-]
Agent: O[C@H](CS)[C@H](O)CS
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=O)C(C)(C)CCC1

Procedure:
A solution containing 0.1M sodium phosphate pH 7 buffer, 5 mM dithiothreitol, 2 mg/ml bovine serum albumin, 40 micromolar palmitoyl CoA, 40 micromolar dilauroyl phosphatidyl choline, 10 micromolar retinol and a test compound or solvent blank, was incubated for 1 hour at 37° C. with a microsomal fraction isolated from bovine retinal pigment epithelial cells. After incubation, the reaction was quenched by addition of an equal volume of ethanol, and the retinyl esters formed (retinyl palmitate from the ARAT catalyzed reaction, and retinyl laurate from the LRAT catalyzed reaction) were extracted with hexane. The hexane layer was removed, evaporated under nitrogen, and the residue analyzed by HPLC on a 3.9×300 mm C18 reversed phase column using a 80% methanol in tetrahydrofuran mobile phase and fluorescence detection (325 nm excitation, 480 nm emission) to quantitate the retinyl esters. The quantity of ester formed in the presence of the solvent blank was taken as 100%, and this was used to calculate the percent inhibition of ester formation for the compounds tested. As a control, an aliquot of microsomes was inactivated by boiling for 5 minutes, which resulted in at least 95% inhibition of ester formation.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)=[O:2].[CH2:11](O)[CH2:12][OH:13].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:2]1[CH2:11][CH2:12][O:13][CH:1]1[C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1
Reactant: OCCO
Reactant: N#Cc1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1ccc(C2OCCO2)cc1
Yield: 94.3 %

Procedure:
4-Formyl-benzonitrile (3.00 g, 22.9 mmol), ethane-1,2-diol (6.38 mL, 115 mmol) and toluene-4-sulfonic acid monohydrate (197 mg, 1.15 mmol) were dissolved in toluene (60 mL), and the solution was stirred under reflux for 10 hours. An aqueous solution of saturated sodium bicarbonate was added to the reaction solution at 0° C., which was then extracted with ethyl acetate, the organic layer was washed with brine, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=10:1), and the title compound (3.78 g, 21.6 mmol, 94%) was obtained as a white solid.
Reaction SMILES: CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.C([O:19][C:20](=O)/[CH:21]=[C:22](/[C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33](/[C:36](/[CH3:48])=[CH:37]/[CH2:38][O:39][CH2:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])=[CH:32][CH:31]=2)=[CH:26][CH:25]=1)\[CH3:23])C.Cl>C1COCC1.C(O)C>[Si:41]([CH2:40][O:39][CH2:38]/[CH:37]=[C:36](/[C:33]1[CH:32]=[CH:31][C:30]([C:27]2[CH:28]=[CH:29][C:24](/[C:22](/[CH3:23])=[CH:21]/[CH2:20][OH:19])=[CH:25][CH:26]=2)=[CH:35][CH:34]=1)\[CH3:48])([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42]
Reactant: CCOC(=O)/C=C(\C)c1ccc(-c2ccc(/C(C)=C/COC[Si](C)(C)C(C)(C)C)cc2)cc1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCO
Product: C/C(=C\CO)c1ccc(-c2ccc(/C(C)=C/COC[Si](C)(C)C(C)(C)C)cc2)cc1
Reaction time: 0.5 h

Procedure:
A 1M solution of DIBAL-H in toluene (7.3 mL, 7.3 mmol) was, under a atmosphere of nitrogen, added dropwise at −70° C. over 20 min. to a stirred solution of (E)(E) 3-(4′-{3-[(tert-butyldimethylsilanyl)-methoxy]-1-methylpropenyl}-biphenyl-4-yl)-but-2-enoic acid ethyl ester (1.13 g, 2.43 mmol) in dry THF (25 mL). The mixture was stirred for 30 min. followed by 2 h at room temperature. Ethanol (1 mL) was carefully added, followed by 1N HCl (50 mL) and the resulting mixture extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine, dried (MgSO4), and evaporated to give 1.02 g (99%) of (E)(E) 3-(4′-{3-[(tert-butyldimethylsilanyl)-methoxy]-1-methylpropenyl}-biphenyl-4-yl)-but-2-en-1-ol.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[Na+].[Na+].[C:16]1(B(O)O)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1>CN(C)C=O.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:24]1([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])[C:25]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: O=Cc1ccccc1Br
Reactant: OB(O)c1cccc2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccccc1-c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
To a suspension of 2-bromobenzaldehyde (200 μL, 1.71 mmol), sodium carbonate (218 mg, 2.06 mmol), and 1-naphthaleneboronic acid (353 mg, 2.05 mmol) in 3.4 mL of N,N-dimethylformamide/water (2:1) was added palladium acetate (20 mg, 89 μmol) under nitrogen. After being stirred at room temperature overnight, the reaction mixture was filtered. The filtrate was diluted with diethyl ether, and the solution was washed with saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 80/20) to obtain the title compound as a white solid (346 mg, 87%).
Reaction SMILES: II.[CH2:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][N:12]1[CH2:17][C:16]([C:18]([O:20][CH3:21])=[O:19])=[CH:15][CH2:14][CH2:13]1.Cl>CCOCC.C(Cl)C1C=CC=CC=1.O>[CH2:3]([CH:15]1[CH2:14][CH2:13][N:12]([CH3:11])[CH2:17][CH:16]1[C:18]([O:20][CH3:21])=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)C1=CCCN(C)C1
Reactant: ClCc1ccccc1
Agent: Cl
Agent: II
Solvent: O
Solvent: CCOCC
Product: COC(=O)C1CN(C)CCC1Cc1ccccc1
Temperature: -15 °C

Procedure:
To a solution of 480 mg of Mg in 2 mL of dry ether was added a little bit of I2 and several drops of benzyl chloride (about 0.5 mL) of the solution of 2.3 mL (20 mmol) of benzyl chloride in 10 mL of ether. The mixture was gentle stirred, as soon as the reaction sets in, the reminder of benzyl chloride in ether was added at the rate that the reaction went vigorously by cooling the flask with water. Then the resulting solution was stirred at gentle reflux for fifteen minutes after all the benzyl chloride has been added. Another 5 mL of dry ether was added to the Grignard reagent solution and it was cooled to −15° C., the arecoline (1.5 g) in 20 mL of dry ether was added dropwise to it. The resulting mixture was stirred at −15° C. for another 0.5 hour. The mixture was cooled to about −40° C. and treated slowly with 10% HCl (22 mL). The aqueous layer was separated, extracted with ether (20 mL), and then basified with saturated sodium bicarbonate solution when cooled in an ice bath. The mixture was extracted with ether and the combined organic extracts were washed with brine, dried and concentrated under reduced pressure. Flash chromatography afforded a mixture of cis isomer 76 and trans isomer 77 (500 mg, 21%).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][C:11]#[C:12][CH3:13])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:20]1([OH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[NH4+]>CN(C)C=O>[CH2:10]([O:9][C:6]1[C:7]([F:8])=[C:2]([O:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=[CH:4][N:5]=1)[C:11]#[C:12][CH3:13]
Reactant: CC#CCOc1ncnc(Cl)c1F
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCOc1ncnc(Oc2ccccc2)c1F
Temperature: 80 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
To 2 ml of N,N-dimethylformamide were added 0.1 g of 4-chloro-6-(2-butynyloxy)-5-fluoropyrimidine, 0.1 g of potassium carbonate, and 0.06 g of phenol, followed by stirring at 80° C. for 2 hours. The reaction mixture was left for cooling to room temperature and poured into a saturated aqueous ammonium chloride solution, which was extracted three times with t-butyl methyl ether. The organic layers were combined, washed with brine, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.12 g of 4-(2-butynyloxy)-5-fluoro-6-phenoxypyrimidine (the present compound (179)).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:14])[C:9](=[O:13])[C:10]([CH3:12])([CH3:11])[C:5]2=[CH:4][CH:3]=1.[CH3:15][O-:16].[Na+].O>CN(C=O)C>[CH3:15][O:16][C:2]1[N:7]=[C:6]2[N:8]([CH3:14])[C:9](=[O:13])[C:10]([CH3:12])([CH3:11])[C:5]2=[CH:4][CH:3]=1
Reactant: CN1C(=O)C(C)(C)c2ccc(Cl)nc21
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(n1)N(C)C(=O)C2(C)C
Temperature: 145 °C

Procedure:
A mixture of 0.3 g (1.4 mmol) 6-chloro-1,3,3-trimethyl-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one, 0.6 ml (2.8 mmol) of sodium methoxide (4.6M in methanol), and 1.2 mg of Cul in 6 ml of DMF was heated to 145° C. for 18 hours. The reaction mixture was cooled to room temperature and added to 25 ml of water. The mixture was extracted with ethyl acetate. The ethyl acetate extract were was washed with 25 ml of saturated sodium bisulfite, dried (Na2SO4) and evaporated. The residue was triturated twice with hot hexane, and the hexane decanted. The residue 6-methoxy-1,3,3-trimethyl-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one (0.25 g) was used without further purification. TLC: Rf=0.7 (5:1 hexane/ethyl acetate). 1H NMR (CDCl3) δ 7.35 (d, 1H), 6.38 (d, 1H), 3.92 (s, 3H), 3.22 (s, 3H), 1.33 (s, 3H). Mass spectrum: m/e=207.3 (p+1).
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([NH:42][C:43](=[O:46])[CH2:44][CH3:45])[CH:37]=2)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].Cl.N1C=CC=CC=1>>[OH:1][C:2]([C:30]1[CH:31]=[CH:32][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([NH:42][C:43](=[O:46])[CH2:44][CH3:45])[CH:37]=2)=[CH:34][CH:35]=1)([C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CCC(=O)Nc1cccc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)c1
Agent: Cl
Solvent: c1ccncc1
Product: CCC(=O)Nc1cccc(-c2ccc(C(O)(c3c[nH]cn3)C(C)C)cc2)c1
Yield: 32 %

Procedure:
By the reaction in the same manner as in Example 4-(iii) using N-{4′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl][1,1′-biphenyl]-3-yl}propanamide (1.46 g) and pyridine hydrochloride (440 mg), the title compound (280 mg) was obtained as a colorless amorphous powder.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].Cl[CH2:7][Si:8]([O:11][CH3:12])([CH3:10])[CH3:9]>[Br-].C([P+](CCCC)(CCCC)CCCC)CCC>[C:1]([O:4][CH2:7][Si:8]([O:11][CH3:12])([CH3:10])[CH3:9])(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: CO[Si](C)(C)CCl
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Product: CO[Si](C)(C)COC(C)=O
Temperature: 150 °C
Reaction time: 6 h
Yield: 99 %

Procedure:
A mixture of 61.1 kg of Hydroseal G 400 H and 50 kg (609.4 mol) of sodium acetate was dried by heating at 150° C./2 mbar for 1 h. After cooling down to 112° C., the vacuum was broken with nitrogen, 3.76 kg (11.1 mol) of tetrabutylphosphonium bromide were added and the temperature was adjusted to 120° C. Then, under agitation, 76.8 kg (554 mol) of (chloromethyl)methoxydimethylsilane were metered in over 1 h. The mixture was subsequently stirred at the same temperature for a further 6 h. The product was then distilled out through a column at 20 mbar (head), 50-56° C. (head) and 70-145° C. (pot), while a further 36.7 kg of Hydroseal G 400 H were metered in during the distillation to ensure stirrability. The product (acetoxymethyl)methoxydimethylsilane (89.0 kg, 548.5 mol, 99% of theory; purity 99.5% (GC area %)) was obtained as a colorless liquid. The solvent, sodium chloride, excess sodium acetate and the phase transfer catalyst in the form of the chloride, bromide and acetate salt of tetrabutylphosphonium remained in the residue.
Reaction SMILES: [OH:1][C@H:2]([CH2:6][CH3:7])[C:3]([NH2:5])=[O:4].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>O1CCCC1>[C:3]([C@H:2]([O:1][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:6][CH3:7])(=[O:4])[NH2:5]
Reactant: CC[C@@H](O)C(N)=O
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC[C@@H](OS(C)(=O)=O)C(N)=O
Temperature: 20 °C

Procedure:
To a mixture of (R)-2-hydroxybutyramide (4.2 g, 40.7 mmol) and triethylamine (6.2 ml, 44.8 mmol, 1.1 equiv.) in tetrahydrofuran (50 ml) is added drop wise at −40° C. methanesulfonic acid chloride (3.5 ml, 44.8 mmol, 1.1 equiv.). The mixture is allowed to warm to 20° C. and is filtered over magnesium sulfate (8 g). The cake is rinsed twice with tetrahydrofuran (2×20 ml) and combined filtrates are concentrated to dryness under reduced pressure to afford methanesulfonic acid (R)-1-carbamoyl-propyl ester (IIi) as a solid. (7.9 g, 106%, triethylamine hydrochloride salts are present).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si:5]([CH3:15])([CH3:14])[O:6][Si](C)(C)CCCN.O.O.O.O.O.[OH-].[CH3:22][N+:23]([CH3:26])([CH3:25])[CH3:24]>O1CCCC1>[NH2:1][CH2:2][CH2:3][CH2:4][Si:5]([CH3:15])([CH3:14])[O-:6].[CH3:22][N+:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: C[Si](C)(CCCN)O[Si](C)(C)CCCN
Agent: C[N+](C)(C)C
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)([O-])CCCN

Procedure:
A 250 ml three-neck round-bottom flask equipped with a magnetic stirrer, argon inlet, and condenser with drying tube was charged with 12.4 g (0.05 mol) of 1,3-bis(3-aminopropyl)tetramethyldisiloxane, 18.1 (88.12 mmol) of tetramethylammonium hydroxide pentahydrate, and 30 ml of tetrahydrofuran. The mixture was heated under reflux in an inert gas atmosphere for 5 hours.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([CH3:11])=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:12][CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1>C(O)C>[CH2:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:21][CH:13]1[NH:12][C:2]1[C:3]2[C:10]([CH3:11])=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: NC1Cc2ccccc2C1
Reactant: Cc1csc2ncnc(Cl)c12
Solvent: CCO
Product: Cc1csc2ncnc(NC3Cc4ccccc4C3)c12
Yield: 100 %

Procedure:
4-chloro-5-methylthieno[2,3-d]pyrimidine (92 mg, 0.50 mmol) (see J. Pharm. Soc. JAPAN, 109, 464 (1989)) and 2-aminoindan (330 mg, 2.5 mmol) in dry ethanol (1 ml) were heated to reflux under an argon atmosphere for 40 minutes. The solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel chromatography (hexane:ethyl acetate=5:1) to obtain the title compound (140 mg, 0.50 mmol) having the following physical properties:
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.[C:19]1([C:25]2[CH:29]=[C:28]([CH2:30][N:31]3[CH2:36][CH2:35][CH:34]([CH2:37][OH:38])[CH2:33][CH2:32]3)[O:27][N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl>[CH3:18][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O:38][CH2:37][CH:34]2[CH2:33][CH2:32][N:31]([CH2:30][C:28]3[O:27][N:26]=[C:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:29]=3)[CH2:36][CH2:35]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: OCC1CCN(Cc2cc(-c3ccccc3)no2)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2CCN(Cc3cc(-c4ccccc4)no3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.3 %

Procedure:
Triethylamine (12.1 mL) and p-toluene sulfonylchloride (6.61 g) were added sequentially to a room temperature mixture of the compound prepared in Example 64 (7.86 g) in dichloromethane (100 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and washed sequentially with a saturated aqueous sodium bicarbonate solution and brine. The combined organics were dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel to obtain the title compound (1.52 g) having the following physical data.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10]([NH:13][CH2:14][CH:15]=[CH2:16])[CH:11]=[CH2:12].C(=O)([O-])[O-].[Na+].[Na+]>[Cl-].C([N+](CCCCCC)(CCCCCC)CCCCCC)CCCCC.C1(C=CC(O)=CC=1)O.CN(C)P(N(C)C)(N(C)C)=O>[CH2:10]([N:13]([C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH2:14][CH:15]=[CH2:16])[CH:11]=[CH2:12]
Reactant: C=CCNCC=C
Reactant: O=Cc1ccc(F)cc1
Agent: CCCCCC[N+](CCCCCC)(CCCCCC)CCCCCC
Agent: O=C([O-])[O-]
Agent: Oc1ccc(O)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=CCN(CC=C)c1ccc(C=O)cc1
Yield: 49.7 %

Procedure:
A mixture of 4-fluorobenzaldehyde (16.4 ml, 0.15 mol), diallylamine (20.8 ml, 0.17 mol), sodium carbonate (18.0 g, 0.17 mol), hexamethylphosphoramide (HMPA) (115 ml), hydroquinone (180 mg) and tetrahexyl ammonium chloride (200 mg) was heated under a nitrogen atmosphere for 100 hours. The reaction mixture was cooled and poured into distilled water (1 L). Extraction with toluene (4×300 ml) followed by washing of the combined extracts with distilled water (3×250 ml), drying over anhydrous magnesium sulfate, filtration and concentration in vacuo yielded 32 g as a viscous yellow oil. Fractional distillation at 0.8 mm Hg gave 15 g (50%) of 4-(N,N'-diallylamino)benzaldehyde as a pale yellow oil.
Reaction SMILES: [N+]([C:4]1[CH:5]=C(S([O-])(=O)=O)C=[CH:8][CH:9]=1)([O-])=O.[Na+].OS(O)(=O)=O.O=S(=O)=O.[F:24][C:25]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:26]=1[NH2:27].C(=O)/C=C/C.[OH-].[Na+]>O>[F:32][C:31]1[C:25]([F:24])=[C:26]2[C:28]([CH:5]=[CH:4][C:9]([CH3:8])=[N:27]2)=[CH:29][CH:30]=1
Reactant: Nc1cccc(F)c1F
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: C/C=C/C=O
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Solvent: O
Product: Cc1ccc2ccc(F)c(F)c2n1
Temperature: 105 °C
Reaction time: 1 h

Procedure:
Sodium 3-nitrobenzenesulfonate (2.7 g, 12 mmol) was dissolved in H2O (3 mL), and oleum (4 mL) was added to the mixture. 2,3-Difluoroaniline was then added to the mixture. The mixture was heated to 105° C. and (E)-but-2-enal (2.34 g, 33.4 mmol) was added dropwise. The mixture was stirred at 120° C. for 1 h. Then the mixture was poured into ice (50 g), and solid NaOH was added until pH 12. The mixture was extracted with EtOAc (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography to afford 7,8-difluoro-2-methylquinoline (1.5 g) as a white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15].[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C=O)C>[N+:14]([C:6]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=1[N:4]([CH3:3])[S:23]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:25])=[O:24])([O-:16])=[O:15]
Reactant: CNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])S(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 77.9 %

Procedure:
To a suspension of sodium hydride (60%, 0.12 g (3.00 mmol)) in DMF (4.0 ml), N-methyl-2,4-dinitroaniline (0.39 g (1.98 mmol)) was added with stirring at room temperature. To the resulting mixture, after 15 minutes' stirring at room temperature, benzenesulfonyl chloride (0.38 ml (2.98 mmol)) was added dropwise. After two hours' stirring at room temperature, the reaction mixture was poured into water and extracted with diethyl ether. The extract was washed with water and saturated sodium chloride solution, successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel chromatography with ethyl acetate-hexane (1:2) as eluent, to give 0.52 g (78%) of the title compound as pale yellow crystals.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[K+].C(O)(=O)C.Cl[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13].[Cl-].[K+]>C(O)C.O>[C:1]([O:4][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: O=C(CCl)c1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)OCC(=O)c1ccccc1
Temperature: 25 °C
Yield: 79.3 %

Procedure:
78.5 g (0.80 mol) of potassium acetate, 5.0 g (0.08 mol) of acetic acid, and 123.7 g (0.80 mol) of 2-chloroacetophenone were heated under reflux in 500 mL of ethanol for 6 hours. After completion of heating, the reaction mixture was cooled to room temperature, deposited potassium chloride was filtered off, and the ethanol was distilled off in vacuo to obtain a pale brown oily material. This oily material was poured into one litter of water, and a precipitated solid was collected by filtration and recrystallized from methanol to obtain 113.1 g (yield: 79.3%) of 2-acetoxyacetophenone as a pale yellow solid.
Reaction SMILES: C[O:2][C:3]([C:5]12[CH2:12][CH2:11][C:8]([C:13]3[NH:21][C:20]4[C:19](=[O:22])[N:18]([CH2:23][CH2:24][CH3:25])[C:17](=[O:26])[NH:16][C:15]=4[N:14]=3)([CH2:9][CH2:10]1)[CH2:7][CH2:6]2)=O.[BH4-].[Li+]>C1COCC1.CO>[OH:2][CH2:3][C:5]12[CH2:10][CH2:9][C:8]([C:13]3[NH:21][C:20]4[C:19](=[O:22])[N:18]([CH2:23][CH2:24][CH3:25])[C:17](=[O:26])[NH:16][C:15]=4[N:14]=3)([CH2:11][CH2:12]1)[CH2:7][CH2:6]2
Reactant: CCCn1c(=O)[nH]c2nc(C34CCC(C(=O)OC)(CC3)CC4)[nH]c2c1=O
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCn1c(=O)[nH]c2nc(C34CCC(CO)(CC3)CC4)[nH]c2c1=O

Procedure:
To a solution of 4-(2,6-dioxo-1-propyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carboxylic acid methyl ester (2.4 g, 0.006 moles) in THF (35 ml), methanol (0.4 ml) was added. To this mixture, lithium borohydride (1.45 g, 0.066 mole) was added slowly and refluxed overnight. Reaction mixture was concentrated under reduced pressure and quenched with 1N HCl. Water was added to the residue and extracted with ethyl acetate. Organic layer was dried over anhydrous sodium sulphate and concentrated under vacuum.