Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1/[CH:10]=[CH:11]/[CH:12]=[C:13](\[O:17][CH3:18])/[C:14]([OH:16])=O.[CH2:19]([N:21]([CH2:26][CH3:27])[CH2:22][CH2:23][CH2:24][NH2:25])[CH3:20].O.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1/[CH:10]=[CH:11]/[CH:12]=[C:13](\[O:17][CH3:18])/[C:14]([NH:25][CH2:24][CH2:23][CH2:22][N:21]([CH2:26][CH3:27])[CH2:19][CH3:20])=[O:16]
Reactant: CCN(CC)CCCN
Reactant: CO/C(=C\C=C\c1cc2ccccc2o1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCCNC(=O)/C(=C/C=C/c1cc2ccccc2o1)OC
Yield: 18 %

Procedure:
A solution of (2Z,4E)-5-(benzofuran-2-yl)-2-methoxy-2,4-pentadienoic acid (122 mg, 0.5 mmol), 3-diethylaminopropylamine (65 mg, 0.5 mmol), 1-hydroxy-7-azabenzotriazole hydrate (65 mg, 0.5 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (95 mg, 0.5 mmol) in DMF (2 ml) was stirred at RT overnight. After the same work-up described in example 3 the residue was chromatographed on silicagel (preparative TLC, EtOAc/MeOH/aq.NH3 8/2/1). The fraction collected was dried to give pure title compound (32 mg, O90 mmol, yield 18.0%) as pale brown crystals, m.p.=79°.
Reaction SMILES: Br[C:2]1[C:7]2[S:8][C:9]([C:11]3[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])=[N:10][C:6]=2[C:5]([Br:19])=[CH:4][N:3]=1.[CH3:20][C:21]1[N:26]=[CH:25][N:24]=[C:23]([NH2:27])[CH:22]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:19][C:5]1[C:6]2[N:10]=[C:9]([C:11]3[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[S:8][C:7]=2[C:2]([NH:27][C:23]2[CH:22]=[C:21]([CH3:20])[N:26]=[CH:25][N:24]=2)=[N:3][CH:4]=1
Reactant: Cc1cc(N)ncn1
Reactant: Fc1cccc(Cl)c1-c1nc2c(Br)cnc(Br)c2s1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(Nc2ncc(Br)c3nc(-c4c(F)cccc4Cl)sc23)ncn1
Temperature: 75 °C
Yield: 78.2 %

Procedure:
The mixture of 4,7-dibromo-2-(2-chloro-6-fluoro-phenyl)thiazolo[5,4-c]pyridine (0.227 mmol; 96 mg), 6-methylpyrimidin-4-amine (0.34 mmol, 37 mg), Pd2(dba)3 (0.011 mmol, 10 mg), XantPhos (0.0227 mmol; 14 mg) and Cs2CO3 (0.4544 mmol, 148 mg) in 1,4-dioxane (3 mL) was heated at 75° C. under nitrogen in an oil bath for 4.5 hours. The reaction mixture was then cooled to room temperature, filtered through celite, washed with EtOAc. The filtrate was concentrated and the resulting crude product was purified by silica gel chromatography (30-100% EtOAc/hexane) to give the title compound as an off-white solid (80 mg, 78% yield). 1H NMR (400 MHz, DMSO-d6) δ 10.76 (s, 1H), 8.64 (s, 1H), 8.59 (s, 1H), 7.77-7.68 (m, 1H), 7.62 (d, J=8.1 Hz, 1H), 7.56-7.48 (m, 2H), 2.39 (s, 3H). LCMS (Method B): RT=4.39 min, m/z 450.0 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[C@@H:14](/[CH:15]=[CH:16]/[CH2:17][C:18]([OH:24])([CH3:23])[CH2:19][CH2:20][CH2:21][CH3:22])[CH:13]([O:25][Si](C(C)(C)C)(C)C)[CH2:12][C:11]1=[O:33].C(#N)C.F>O>[CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[C@@H:14](/[CH:15]=[CH:16]/[CH2:17][C:18]([OH:24])([CH3:23])[CH2:19][CH2:20][CH2:21][CH3:22])[CH:13]([OH:25])[CH2:12][C:11]1=[O:33]
Reactant: CCCCC(C)(O)C/C=C/[C@H]1C(O[Si](C)(C)C(C)(C)C)CC(=O)[C@@H]1CCCCCCC(=O)OC
Agent: F
Solvent: O
Solvent: CC#N
Product: CCCCC(C)(O)C/C=C/[C@H]1C(O)CC(=O)[C@@H]1CCCCCCC(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
Into a Teflon container were placed (±)-methyl(16RS, 13E)-11-tert-butyldimethylsilyloxy-16-hydroxy-16-methyl-9-oxoprost-13-en-1-oate (1.89 g, 3.81 mmol) and acetonitrile (50 ml), whereby 46% hydrofluoric acid (4.5 ml) was added and stirred at room temperature for 2 h. The reaction mixture was added with water (120 ml) and extracted with methylene chloride (60 ml) two times. The combined organic layer was washed with a saturated aqueous sodium hydrogencarbonate, a saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated in vacuo to remove solvent. The residue was purified by silica gel column chromatography [ethyl acetate/hexane (2/1)] to give 1.44 g (99% yield) of Misoprostol;
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:12][S:13](O)(=[O:15])=[O:14]>>[Cl:12][S:13]([C:8]1[CH:9]=[C:10]([F:11])[C:2]([F:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])(=[O:15])=[O:14]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(O)c1cccc(F)c1F
Product: O=C(O)c1cc(S(=O)(=O)Cl)cc(F)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 2,3-difluoro-benzoic acid (3 g) was added to a solution of chlorosulfonic acid and the reaction mixture was stirred for 2 hours at room temperature. After such time, the reaction mixture was poured onto ice. The resulting solid precipitate was then filtered off and dried in vacuo to yield the title compound as a light grey solid (4.8 g, mp=109-114° C., MS (EI): 256.0 (M+) and was used directly in the next step without any further purification.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([Br:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[C:18](OCC)(=O)C>CO>[Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([Br:12])=[CH:7][C:3]=1[C:4]([O:6][CH3:18])=[O:5]
Reactant: CCOC(C)=O
Reactant: Cc1cc(Br)c(C(=O)O)cc1Br
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1cc(Br)c(C)cc1Br

Procedure:
To a solution of 2,5-dibromo-4-methylbenzoic acid 5.88 g, 20 mmol) in 50 mL of methanol was added 0.2 mL of concentrated sulfuric acid. The resulting solution was refluxed for 24 hours. Evaporation of the solvent gave a residue, which was redissolved into 100 mL of ethyl acetate. The organic layer was washed with saturated sodium biocarbonate solution, water and brine. The resulting organic layer was dried over sodium sulfate. Filtration off sodium sulfate and evaporation of the solvent gave methyl 2,5-dibromo-4-methylbenzoate as a white solid: 6.20 g (100%).
Reaction SMILES: Cl[CH2:2][C:3]([O:5][C@H:6]1[CH2:25][C@@:24]2([CH3:26])[C@@H:17]([CH2:18][CH2:19][C@@H:20]2[C:21](=[O:23])[CH3:22])[C@H:16]2[C@H:7]1[C@:8]1([CH3:31])[C@@H:13]([CH2:14][CH2:15]2)[CH2:12][C@H:11]([OH:27])[C@@H:10]([O:28][CH2:29][CH3:30])[CH2:9]1)=[O:4].[I-:32].[Na+]>CC(C)=O>[CH2:29]([O:28][C@H:10]1[CH2:9][C@@:8]2([CH3:31])[C@@H:13]([CH2:14][CH2:15][C@@H:16]3[C@@H:7]2[C@@H:6]([O:5][C:3](=[O:4])[CH2:2][I:32])[CH2:25][C@@:24]2([CH3:26])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[C:21](=[O:23])[CH3:22])[CH2:12][C@@H:11]1[OH:27])[CH3:30]
Reactant: [I-]
Reactant: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2[C@@H](OC(=O)CCl)C[C@]2(C)[C@@H](C(C)=O)CC[C@@H]32)C[C@@H]1O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2[C@@H](OC(=O)CI)C[C@]2(C)[C@@H](C(C)=O)CC[C@@H]32)C[C@@H]1O
Yield: 101.1 %

Procedure:
11β-Chloroacetoxy-2β-ethoxy-3α-hydroxy-5α-pregnan-20-one (420 mg) in acetone (42 ml) was treated with sodium iodide (550 mg) and the solution was refluxed for one hour, during which time a fine white precipitate formed. The filtered solution was evaporated to an oily solid which was partitioned between ether/ethyl acetate and water. The organic layer was washed with water, dried over sodium sulphate and evaporated to give title compound (510 mg) as a white form, [α]D +80° (c 0.32%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1.[F:17][C:18]([F:23])([F:22])[C@@H:19]1[CH2:21][O:20]1.C(=O)([O-])[O-]>C(#N)C>[F:17][C:18]([F:23])([F:22])[C@@H:19]([OH:20])[CH2:21][N:9]1[CH2:10][CH2:11][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:6]=2[CH2:7][CH2:8]1
Reactant: COc1cc2c(cc1[N+](=O)[O-])CCNCC2
Reactant: FC(F)(F)[C@@H]1CO1
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: COc1cc2c(cc1[N+](=O)[O-])CCN(C[C@H](O)C(F)(F)F)CC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.8 %

Procedure:
7-Methoxy-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (215 mg, 0.967 mmol) was placed into a sealable vial, suspended in Acetonitrile (10 mL) then (S)-2-Trifluoromethyl-oxirane (130 uL, 1.5 mmol) was added, followed by Macroporous carbonate resin (3.16 mmol/g loading; 0.810 g, 2.56 mmol). The reaction was stirred at room temperature for 24 h, filtered and concentrated in vacuo to afford (S)-1,1,1-Trifluoro-3-(7-methoxy-8-nitro-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-propan-2-ol as an orange oil (316 mg, 97%), which was used without further purification. 1H-NMR (CDCl3, 400 MHz) δ 7.67 (s, 1H), 6.83 (s, 1H), 4.05 (m, 1H), 3.95 (s, 3H), 2.6-3.0 (m, 10H); 19F-NMR (CDCl3, 376 MHz) δ−78.7 (s).
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14](Cl)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]([C:29]2[CH:30]=[C:31]([CH:33]=[CH:34][C:35]=2[CH3:36])[NH2:32])[N:20]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C(O)(C)C>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([NH:32][C:31]3[CH:33]=[CH:34][C:35]([CH3:36])=[C:29]([C:21]4[N:20]=[CH:19][C:28]5[C:23]([CH:22]=4)=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH:30]=3)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncnc2c1CCN(Cc1ccccc1)C2
Reactant: Cc1ccc(N)cc1-c1cc2ccccc2cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: Cc1ccc(Nc2ncnc3c2CCN(Cc2ccccc2)C3)cc1-c1cc2ccccc2cn1
Temperature: 25 °C

Procedure:
To a reaction vessel containing 7-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (518 mg, 2 mmol), 3-(isoquinolin-3-yl)-4-methylaniline (470 mg, 2 mmol), pTSA (144 mg, 0.6 mmol) is added isopropanol (7 ml). The vessel is purged with nitrogen, sealed. The reaction vessel is placed in a microwave reactor and irradiated for 30 minutes at 130° C. The reaction mixture is cooled to room temperature and diluted with ethyl acetate. It is washed with saturated aqueous NaHCO3, water and brine, dried over anhydrous MgSO4 and concentrated. The residue is subjected to silica gel flash chromatography (2% methanol in dichloromethane) to afford 7-Benzyl-N-(3-(isoquinolin-3-yl)-4-methylphenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine as a brown solid. LC-MS m/z: 458.2 (M+1).
Reaction SMILES: [F:1][CH:2]([F:32])[C:3]1[N:8]=[CH:7][C:6]([S:9]([CH:12]([C:23]2[C:28]([F:29])=[CH:27][CH:26]=[C:25]([F:30])[C:24]=2[F:31])[C:13]2[C:14]([CH3:22])=[CH:15][C:16]([C:19]([NH2:21])=[O:20])=[N:17][CH:18]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C=O.[OH-].[Na+].[C:37](OCC)(=[O:39])C>COCCOC>[F:32][CH:2]([F:1])[C:3]1[N:8]=[CH:7][C:6]([S:9]([CH:12]([C:23]2[C:28]([F:29])=[CH:27][CH:26]=[C:25]([F:30])[C:24]=2[F:31])[C:13]2[C:14]([CH3:22])=[CH:15][C:16]([C:19]([NH:21][CH2:37][OH:39])=[O:20])=[N:17][CH:18]=2)(=[O:10])=[O:11])=[CH:5][CH:4]=1
Reactant: Cc1cc(C(N)=O)ncc1C(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccc(C(F)F)nc1
Reactant: CCOC(C)=O
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: Cc1cc(C(=O)NCO)ncc1C(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccc(C(F)F)nc1
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of 5-[[[6-(difluoromethyl)pyridin-3-yl]sulfonyl](2,3,6-trifluorophenyl) methyl]-4-methylpyridine-2-carboxamide (90.0 mg, 0.191 mmol) in ethylene glycol dimethyl ether (2 ml), an aqueous solution of formaldehyde (37%, 43.0 μl, 0.573 mmol) and 1 N aqueous sodium hydroxide (9.5 μl) were added at room temperature, and the mixture was stirred for 1 hour. Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated aqueous ammonium chloride. Subsequently, 1 N hydrochloric acid (5 ml) was added to the organic layer, and the mixture was stirred for 1 hour. After the organic layer was separated, the organic layer was washed with saturated aqueous sodium hydrogencarbonate and then with saturated brine, dried over anhydrous sodium sulfate, and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was subjected to flash silica gel chromatography, and the fraction obtained from an elution with hexane:ethyl acetate=2:3 was concentrated under reduced pressure. The resulting residue was washed with a mixed solvent of 2-propanol and hexane, and then was collected by filtration, to obtain the title compound (77.0 mg, 0.154 mmol, 80%) as a white solid.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][C@H:7]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=1[CH3:29].[C:30](OCC)(=[O:32])C.CCCCCC>C(Cl)(Cl)Cl>[CH:17]([C:14]1[CH:13]=[CH:12][C:11]([C@@H:7]2[C:6]3[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[C:3]([CH3:29])=[C:2]([O:32][CH3:30])[C:10]=3[O:9][CH2:8]2)=[CH:16][CH:15]=1)([CH3:18])[CH3:19]
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)CC(C)(C)C)[C@@H](c1ccc(C(C)C)cc1)CO2
Reactant: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: COc1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1OC[C@@H]2c1ccc(C(C)C)cc1
Yield: 98 %

Procedure:
Using (−)-N-((3R)-7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 51, the title compound was synthesized in the same manner as in Example 36. Yield: 98%. Melting point: 150-151° C. (ethyl acetate-hexane). [α]D20=+55.9° (c=0.50, chloroform).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]([F:30])([F:29])[C:7]([F:28])([F:27])[C:8]([F:26])([F:25])[C:9]([F:24])([F:23])[C:10]([F:22])([F:21])[C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])(=[O:5])=[O:4].[CH2:31]([CH:33]1[O:35][CH2:34]1)Cl.C[O-].[Na+].[OH-].[Na+]>CO.O>[CH3:1][N:2]([CH2:31][CH:33]1[O:35][CH2:34]1)[S:3]([C:6]([F:30])([F:29])[C:7]([F:27])([F:28])[C:8]([F:25])([F:26])[C:9]([F:23])([F:24])[C:10]([F:21])([F:22])[C:11]([F:19])([F:20])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: ClCC1CO1
Agent: C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(CC1CO1)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 80 °C
Reaction time: 8 h

Procedure:
N-methyl-N-glycidyl-perfluorooctanesulfonamide ("epoxide A") was prepared by placing 450 grams N-methyl-perfluorooctanesulfonamide ("amide A") in a two-liter three-necked round-bottom flask and heating to 80° C., 101 grams epichlorohydrin was then added followed by 91 grams methanol. The temperature was reduced to 65° C. before 30 grams 25 wt % sodium methoxide in methanol solution was slowly added keeping the temperature below 70° C. 60 grams 50 wt % aqueous sodium hydroxide solution was slowly added keeping the temperature below 70° C. After addition the reaction was stirred at 65° C. overnight. Water-aspirator vacuum was applied to the flask and excess methanol and epichlorohydrin were removed. 450 grams water was then added to the flask with stirring at 65° to wash the product. The water was decanted after allowing the product to settle. This washing step was repeated a second time. Vacuum was applied to 20 mm Hg and the temperature of the flask was raised to 90° C. to remove volatile materials.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)=[N:9][CH:10]=1.[CH2:23]([O:25][C:26]1[C:30]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:29][NH:28][N:27]=1)[CH3:24].O>CN(C)C=O>[CH2:23]([O:25][C:26]1[C:30]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:29][N:28]([CH2:4][C:5]2[CH:10]=[N:9][C:8]([O:11][CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)=[CH:7][CH:6]=2)[N:27]=1)[CH3:24]
Reactant: CCOC(=O)CCc1c[nH]nc1OCC
Reactant: ClCc1ccc(OCc2ccc3ccccc3n2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3ccc4ccccc4n3)nc2)nc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
Sodium hydride (60%, oily, 70.0 mg) was added to a solution of 2-(5-chloromethyl-2-pyridyloxymethyl)quinoline (498 mg), ethyl 3-(3-ethoxy-1H-pyrazol-4-yl)propionate (371 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[3-ethoxy-1-[6-(2-quinolylmethoxy)-3-pyridylmethyl]-1H-pyrazol-4-yl]propionate (733 mg, yield: 91%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[CH2:22]([C:24]1([CH2:27][CH3:28])[CH2:26][O:25]1)[CH3:23]>>[CH2:22]([C:24]([OH:25])([CH2:27][CH3:28])[CH2:26][O:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1)[CH3:23]
Reactant: CCC1(CC)CO1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc(O)c1
Product: CCC(O)(CC)COc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1

Procedure:
Reaction of 2-(3-(3-hydroxyphenyl)propyl)isoindoline-1,3-dione with 2,2-diethyloxirane following method described in Example 18 gave 2-(3-(3-(2-ethyl-2-hydroxybutoxy)phenyl)propyl)isoindoline-1,3-dione. 1H NMR (400 MHz, CDCl3) δ 7.75-7.88 (m, 4H), 7.06 (t, J=6.8 Hz, 1H), 6.72-6.76 (m, 2H), 6.61 (d, J=8.4 Hz, 1H), 3.74 (s, 2H), 3.69 (t, J=6.4 Hz, 2H), 2.63 (t, J=7.2 Hz, 2H), 1.95-2.05 (m, 2H), 1.61-1.66 (m, 4H), 0.91 (t, J=7.6 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:4].[H][H]>CO.[C].[Pd]>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1cc(OC)cc(OC)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1c(-c2ccccc2)c2ccccc2c(=O)n1Cc1cc(OC)cc(OC)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.4 %

Procedure:
To a solution of 6-bromo-2-(3,5-dimethoxybenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (153 mg) in methanol (5 ml) was added palladium carbon (10%, 15 mg), and hydrogen gas was filled. The mixture was stirred at room temperature for 15 hrs. and filtered through celite. The solvent was evaporated under reduced pressure, and the obtained residue was recrystallized from methanol to give the title compound (113 mg, 88%).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]2[C:10](Br)=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:7]=2[CH:6]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:15][O:14][C:13]1[C:7]2[CH:6]=[C:5]([C:3]([OH:2])=[O:4])[S:9][C:8]=2[C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:11][CH:12]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1cc2c(OC)ccc(Br)c2s1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ccc(-c2ccccc2)c2sc(C(=O)O)cc12
Temperature: 100 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
A suspension of 7-bromo-4-methoxy-benzo[b]thiophene-2-carboxylic acid methyl ester (5 g, 16.6 mmol) with bis(triphenylphosphine)palladium (II) chloride (350 mg, 0.496 mmol, 0.03 eq.) and K2CO3 (4.88 g, 49.8 mmol, 3 eq.) under argon in dioxane (40 ml) at 20° C. was stirred for 60 minutes. Phenylboronic acid (2.16 g, 17.4 mmol, 1.05 eq.) and 2N Na2CO3 (80 ml) was then added and the mixture heated to 100° C. overnight. After cooling, filtration and acidification to pH 1 with aq. HCl the product precipitated and was filtered off and dried under vacuum at 50° C. to afford the title compound (3.16 g, 67% yield) as a light brown solid. MS m/z=282.9 (M−H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:20]=[CH:19][C:11]([O:12]C2CCCCO2)=[CH:10][CH:9]=1.[O:21]1[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C1(C=CC(O)=CC=1)O>C(Cl)Cl>[C:8]1([CH:20]=[CH:19][C:11]([OH:12])=[CH:10][CH:9]=1)[OH:7].[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C1=COCCC1
Reactant: c1cc(OC2CCCCO2)ccc1OC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Oc1ccc(O)cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C1CCOCC1
Reaction time: 12 h

Procedure:
Another functionalization substance may be 2-[2-(undec-10-enyl)-4-(tetrahydro-2H-pyran-2-yloxy) phenoxy]tetrahydro-H-pyran. This molecule, whose structure is shown in FIG. 13, may be synthesized from 2-[4-(tetrahydro-2H-pyran-2-yloxy) phenoxy]tetrahydro-2H-pyran using any prior art process. The intermediate may be synthesized by first adding dihydropyran (0.83 mL, 9.1 mmol) and pyridinium p-toluenesulfonate (0.11 g, 0.45 mmol) to a solution of hydroquinone (0.25 g, 2.3 mmol) in CH2Cl2 (3 mL). This reaction mixture is then stirred for about 12 hours and diluted with 10 mL of CH2Cl2. The mixture is subsequently washed by 3×5 mL of NaHCO3 and 1×5 mL brine, dried over MgSO4, and concentrated to a white solid. Silica gel chromatography (4:1 hexane/ethyl acetate) provides the di-tetrahydropyran hydroquinone as a white solid (0.48 mg, 75%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([OH:22])=[O:21].Cl>CN(C=O)C.O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:19][C:20]([OH:22])=[O:21])=[C:4]([Cl:11])[N:3]=1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: O=C(O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(Cl)c2ncn(CC(=O)O)c2n1
Reaction time: 20 h

Procedure:
To a suspension of 2-amino-6-chloropurine (5.02 g; 29.6 mmol) and potassium carbonate (12.91 g; 93.5 mmol) in DMF (50 ml) was added bromoacetic acid (4.70 g; 22.8 mmol). The mixture was stirred vigorously for 20 h. under nitrogen. Water (150 ml) was added and the solution was filtered through Celite to give a clear yellow solution. The solution was acidified to a pH of 3 with 4 N hydrochloric acid. The precipitate was filtered and dried, in vacuo, over sicapent. Yield (3.02 g; 44.8%). 1H-NMR(DMSO-d6): d=4.88 ppm (s, 2H); 6.95 (s, 2H); 8.10 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH:11]1([CH2:14][N:15]2[C:23]3[N:22]=[C:21]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([NH:31][CH3:32])=[CH:27][CH:26]=4)[NH:20][C:19]=3[C:18](=[O:33])[N:17]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[F:41])[C:16]2=[O:42])[CH2:13][CH2:12]1>>[CH:11]1([CH2:14][N:15]2[C:23]3[N:22]=[C:21]([CH2:24][C:25]4[CH:26]=[CH:27][C:28]([N:31]([CH3:32])[C:7](=[O:9])[C:6]5[CH:10]=[C:2]([CH3:1])[CH:3]=[N:4][CH:5]=5)=[CH:29][CH:30]=4)[NH:20][C:19]=3[C:18](=[O:33])[N:17]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[F:41])[C:16]2=[O:42])[CH2:13][CH2:12]1
Reactant: Cc1cncc(C(=O)O)c1
Reactant: CNc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Product: Cc1cncc(C(=O)N(C)c2ccc(Cc3nc4c([nH]3)c(=O)n(Cc3ccccc3F)c(=O)n4CC3CC3)cc2)c1

Procedure:
This compound was prepared by a method similar to that described in example 79 except that 5-methylnicotinic acid (Lancaster) was used in place of N-acetyl-6-amino-2-pyridine carboxylic acid and 2 equivalents of 3-cyclopropylmethyl-8-[4-(methylamino)-benzyl]-1-(2-fluorobenzyl)-3,7-dihydropurine-2,6-dione were used. The product was purified by chromatography using silica gel eluted with 96:4 chloroform/methanol. MS, m/z(M+)=553.2365.