Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:3]1[O:5][CH2:4]1)Cl.[CH3:6][C:7]1([CH3:18])[CH2:16][CH2:15][CH2:14][C:13]2[CH:12]=[C:11]([OH:17])[CH:10]=[CH:9][C:8]1=2.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:6][C:7]1([CH3:18])[CH2:16][CH2:15][CH2:14][C:13]2[CH:12]=[C:11]([O:17][CH2:1][C@@H:3]3[CH2:4][O:5]3)[CH:10]=[CH:9][C:8]1=2
Reactant: ClC[C@H]1CO1
Reactant: CC1(C)CCCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(C)CCCc2cc(OC[C@@H]3CO3)ccc21
Temperature: 45 °C
Reaction time: 168 h
Yield: 66.6 %

Procedure:
To a mixture of (R)-epichlorohydrin (2.2 g, 23.8 mmol) and 5,5-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ol (2.1 g, 11.9 mmol) in acetone (30 ml) was added potassium carbonate (1.65 g, 11.9 mmol). The mixture was stirred at 45° C. for 7 days. The reaction mixture was then concentrated. The residue was partitioned between ethyl acetate and water and extracted twice with ethyl acetate. The organic extracts were combined and washed with water, brine, dried over sodium sulfate and concentrated under vacuum. The resulting residue was purified by flash chromatography (silica, methylene chloride/heptane) to give 1.84 g (67%) of (S)-2-(5,5-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yloxymethyl)-oxirane.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:7]([O:11][CH3:12])(=[O:10])[CH:8]=[CH2:9].C(O)(=O)C>[Pd].C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Pd+2]>[C:7]([O:11][CH3:12])(=[O:10])[CH:8]=[CH:9][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccccc1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)/C=C(/C)[O-]
Solvent: CC(=O)O
Product: COC(=O)C=Cc1ccccc1
Temperature: 120 °C
Reaction time: 6 h
Yield: 10 %

Procedure:
In contradistinction to the above experiment, another experiment was run utilizing a solid catalyst. To a 300 cc. stirred, stainless steel autoclave was added 0.5 mole of benzene, 0.10 mole of methyl acrylate, 0.50 mole of glacial acetic acid, 0.002 mole of cupric acetate monohydrate and 0.002 mole of palladium black powder. The latter comprised a solid catalyst and was used in place of the palladium (II) acetylacetonate which was the soluble catalyst in the above experiment. The autoclave was sealed and pressured to 1500 pounds per square inch gauge with air. Thereafter the autoclave was stirred, heated to a temperature of 120°C. and maintained thereat for a period of 6 hours. During this reaction period, the bulk of the palladium powder remained in solid form and did not dissolve in the reaction medium. As in the above example, liquid samples were again periodicially withrawn during the reaction time and analyzed by means of gas chromatography. After 6 hours of reaction, it was noted that there had been only a 10% conversion of the methyl acrylate and only a 10% yield of methyl cinnamate, the desired product, based on the methyl acrylate charged.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C(O)CO.I[C:12]1[CH:13]=[C:14]([CH3:19])[CH:15]=[C:16]([CH3:18])[CH:17]=1.[C:20]1([SH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCCCCCCCCCCC>[Cu-]=O.C(OCC)(=O)C.CC(O)C>[CH3:18][C:16]1[CH:17]=[C:12]([S:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:13]=[C:14]([CH3:19])[CH:15]=1
Reactant: Cc1cc(C)cc(I)c1
Reactant: Sc1ccccc1
Agent: O=[Cu-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: OCCO
Product: Cc1cc(C)cc(Sc2ccccc2)c1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
Copper(I) oxide (7.2 mg, 0.05 mmol) and potassium carbonate (276 mg, 2.0 mmol) were added to a screw-capped test tube with a Teflon-lined septum. The tube was evacuated and backfilled with argon (3 cycles). 2-Propanol (1.0 mL, bench top grade solvent without degassing and pre-drying), ethylene glycol (111 μL, 2.0 mmol, bench top grade solvent) and 5-iodo-m-xylene (144 μL, 1.0 mmol) and thiophenol (103 μL, 1.0 mmol) were added by syringes at room temperature. The tube was heated to 80° C. and stirred for 20 hours. The reaction mixture was then allowed to reach room temperature. Ethyl acetate (approx. 5 mL) and dodecane (227 μL, GC standard) were added. The aliquot was analyzed by GC to give 93% conversion of ArI and 93% GC yield of phenyl 3,5-dimethylphenyl sulfide.
Reaction SMILES: [O:1]1[CH2:5][CH:4]([OH:6])[CH:3]2[O:7][CH2:8][CH:9]([OH:10])[CH:2]12.[H-].[Na+].Br[CH2:14][CH2:15][O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[CH2:17]([O:16][CH2:15][CH2:14][O:6][CH:4]1[CH:3]2[O:7][CH2:8][CH:9]([OH:10])[CH:2]2[O:1][CH2:5]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCCOCc1ccccc1
Reactant: OC1COC2C(O)COC12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OC1COC2C(OCCOCc3ccccc3)COC12
Reaction time: 0.25 h
Yield: 27.1 %

Procedure:
To a suspension of hexahydrofuro[3,2-b]furan-3,6-diol (7.50 g, 51.37 mmol) in anhydrous DMF (100 mL) was added sodium hydride (60% mineral oil suspension, 2.90 g, 72.39 mmol) at 0° C. in portions under the nitrogen atmosphere. Then the mixture was moved to room temperature and stirred for 15 min. To the mixture was added 2-bromoethoxymethylbenzene (12.26 g, 56.97 mmol), and then the mixture was stirred at 115° C. overnight. The mixture was quenched with water (100 mL), and extracted with DCM (300 mL×3). The combined organic phases were washed with brine (200 mLx3), then dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica chromatography (EtOAc/PE (v/v)=1/2) to give the title compound as brown liquid (3.90 g, 27%).
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N[C:21]1[CH:22]=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C>[N:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:30]=[C:21]([C:1]([NH2:8])=[O:2])[CH:22]=1.[C:1]([NH:8][C@@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: Nc1cnc2ccccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Solvent: CCOC(C)=O
Product: NC(=O)c1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of N-Boc-D-phenylalanine (1.25 g, 4.7 mmol) in ethyl acetate (40 mL) was treated sequentially with 3-aminoquinoline (1.4 g, 9.4 mmol) and dicyclohexylcarbo-diimide (1.02 g, 4.9 mmol). The reaction mixture was stirred at room temperature for 16 hr, filtered and the filtrate washed with 1M hydrochloric acid (2×25 mL), saturated sodium bicarbonate (1×25 mL), and brine (1×25 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to dryness to afford titled compound (950 mg) as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[C:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O.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]>[C:15]([O:14][C:12]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][CH:6]=[CH:5]3)[CH2:21][CH2:20]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: Brc1ccc2ncccc2c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3ncccc3c2)CC1
Temperature: 150 °C

Procedure:
A mixture of the 6-bromoquinoline (328 mg, 1.6 mmol, TCI America), 1-BOC-piperazine (340 mg, 1.8 mmol, Aldrich), tris(dibenzylideneacetone)dipalladium(0) (75 mg, 0.1 mmol, Strem), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (91 mg, 0.15 mmol, Strem) and sodium-tert-butoxide (252 mg, 2.7 mmol, Aldrich) in toluene (4 mL) was heated at 150° C. in a microwave synthesizer for 13 min. The reaction mixture was cooled to room temperature, diluted with EtOAc (5 mL) and filtered through a Celite® pad. The filtrate was concentrated in vacuo and the residue was dissolved in MeOH (4 mL) and purified by preparative HPLC (gradient 0.1% trifluoroacetic acid in acetonitrile) to give the title compound as pale-yellow oil. MS (ESI, pos. ion) m/z: 314 (M+1).
Reaction SMILES: CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.Cl[C:36]1[CH:37]=[CH:38][N:39]2[C:44]=1[C:43]([O:45][C:46]1[CH:51]=[CH:50][C:49]([NH2:52])=[CH:48][C:47]=1[F:53])=[N:42][CH:41]=[N:40]2.[C:54]([NH:57][C:58]1[CH:59]=[C:60](B(O)O)[CH:61]=[CH:62][CH:63]=1)(=[O:56])[CH3:55].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:52][C:49]1[CH:50]=[CH:51][C:46]([O:45][C:43]2[C:44]3=[C:36]([C:62]4[CH:63]=[C:58]([NH:57][C:54](=[O:56])[CH3:55])[CH:59]=[CH:60][CH:61]=4)[CH:37]=[CH:38][N:39]3[N:40]=[CH:41][N:42]=2)=[C:47]([F:53])[CH:48]=1
Reactant: Nc1ccc(Oc2ncnn3ccc(Cl)c23)c(F)c1
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Product: CC(=O)Nc1cccc(-c2ccn3ncnc(Oc4ccc(N)cc4F)c23)c1
Temperature: 80 °C
Reaction time: 9 h
Yield: 26.5 %

Procedure:
A flask was charged with palladium acetate (4.5 mg, 0.02 mmol), X-Phos ligand (24 mg, 0.05 mmol, Strem), 4-(5-chloropyrrolo[2,1-f][1,2,4]triazin-4-yloxy)-3-fluorobenzenamine (56 mg, 0.20 mmol), 3-acetamidobenzene boronic acid (72 mg, 0.40 mmol, Lancaster), and potassium phosphate (127 mg, 0.60 mmol) in that order. The flask was flushed with nitrogen and then t-BuOH was added (0.40 mL). The mixture was heated at 80° C. for 8 h. Additional shots of palladium acetate (4.5 mg, 0.02 mmol), X-Phos ligand (24 mg, 0.05 mmol), and 3-acetamidobenzene boronic acid (72 mg, 0.40 mmol) were added and the reaction was stirred an additional 9 h at 80° C. After cooling to rt, the reaction was filtered using MeOH to remove the potassium phosphate and then concentrated in vacuo. The crude product was purified by reverse phase prep HPLC and the appropriate fractions were concentrated in vacuo to remove MeOH. The resulting aqueous layer was made basic with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (20 mg, 26%) as a white solid. 1H NMR (CD3OD) δ 7.84–7.94 (m, 2H), 7.44–7.41 (m, 1H), 7.34–7.19 (m, 3H), 6.92 (t, 1H, J=8.8 Hz), 6.87 (d, 1H, J=2.8 Hz), 6.50 (dd, 1H, J=12.4, 2.4 Hz), 6.46–6.43 (m, 1H), 2.04 (s, 3H); MS(ESI+) m/z 378.3 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([CH3:9])[C:5]([O:7][CH3:8])=[O:6].C(Cl)(Cl)Cl.Cl[C:15]1[O:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1>>[CH3:8][O:7][C:5](=[O:6])[CH:4]([CH3:9])[CH2:3][NH:2][C:15]1[O:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1
Reactant: COC(=O)C(C)CN
Reactant: Clc1nc2ccccc2o1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)C(C)CNc1nc2ccccc2o1
Temperature: 40 °C
Reaction time: 12 h
Yield: 70.4 %

Procedure:
To the suspension of 0.55 g (4 mmol) methy 3-amino-2-methylpropionate hydrogen chloride salt and 4 ml chloroform 0.52 g (5.2 mmol) triethylamine and 0.3 g (2 mmol) 2-chloro-1,3-benzoxazole are added and the mixture is stirred at 40° C. for 4 hours and at room temperature for 12 hours. The chloroform solution is washed with water, citric acid solution and water, dried over sodium sulfate and evaporated in vacuum. The residue is treated with hexane, the crystals are filtered off and washed. 0.33 g title compound is obtained as white crystals. Mp: 89-90° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14].[CH3:25]I>CCOCC>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH3:25]
Reactant: COC(=O)c1cc(Br)cc(C)c1NS(=O)(=O)c1ccc(OC)cc1
Reactant: CI
Solvent: CCOCC
Product: COC(=O)c1cc(Br)cc(C)c1N(C)S(=O)(=O)c1ccc(OC)cc1
Yield: 79.2 %

Procedure:
In the same manner as described in Example 9, 27.0 g (65 mmol) of the product of Example 10 and 4.87 ml (78 mmol) of methyl iodide provided 22.06 g (86%) of the desired product as a white solid after trituration with ether. Electrospray Mass Spec 430 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:11][CH2:12][CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:3]=1[CH2:18]O.[CH:20]1([N:23]2[C:31]3[CH:30]=[CH:29][N:28]=[CH:27][C:26]=3[NH:25][C:24]2=[O:32])[CH2:22][CH2:21]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Br:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:11][CH2:12][CH2:13][S:14]([CH3:17])(=[O:15])=[O:16])[C:3]=1[CH2:18][N:25]1[C:26]2[CH:27]=[N:28][CH:29]=[CH:30][C:31]=2[N:23]([CH:20]2[CH2:21][CH2:22]2)[C:24]1=[O:32]
Reactant: CS(=O)(=O)CCCn1c(CO)c(Br)c2cnccc21
Reactant: O=c1[nH]c2cnccc2n1C1CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CS(=O)(=O)CCCn1c(Cn2c(=O)n(C3CC3)c3ccncc32)c(Br)c2cnccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (3-bromo-1-(3-(methylsulfonyl)propyl)-1H-pyrrolo[3,2-c]pyridin-2-yl)methanol 12 (200 mg, 0.576 mmol), 1-cyclopropyl-1H-imidazo[4,5-c]pyridin-2(3H)-one (101 mg, 0.576 mmol) and triphenylphosphine (151 mg, 0.576 mmol) in dry THF (4 ml) was placed under N2 atmosphere. Then diisopropylazodicarboxylate (DIAD) (113 μl, 0.576 mmol) was added at room temperature. The reaction mixture was stirred at room temperature overnight. The formed solid was filtered off and washed with diethyl ether to give 83 mg of the desired product P17 as a white powder (0.165 mmol, 27.0%). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.89-0.98 (m, 2H) 1.03-1.12 (m, 2H) 1.74-1.88 (m, 2H) 2.92 (s, 3H) 3.00 (tt, J=6.84, 3.45 Hz, 1H) 3.07 (t, J=7.30 Hz, 2H) 4.39 (t, J=7.65 Hz, 2H) 5.35 (s, 2H) 7.28 (d, J=5.27 Hz, 1H) 7.62 (d, J=5.77 Hz, 1H) 8.23 (s, 1H) 8.24 (d, J=5.27 Hz, 1H) 8.36 (d, J=6.02 Hz, 1H) 8.75 (s, 1H); m/z=504 (M+H)+, Br pattern.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH2:24][CH2:25][CH3:26])=[N:5][C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:10][C:9]([O:19][CH2:20][C:21]([NH2:23])=[O:22])=[CH:8][CH:7]=2)#[N:2].N.CO>[Co].O1CCCC1>[NH2:2][CH2:1][C:3]1[C:4]([CH2:24][CH2:25][CH3:26])=[N:5][C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:10][C:9]([O:19][CH2:20][C:21]([NH2:23])=[O:22])=[CH:8][CH:7]=2
Reactant: CCCc1nc2ccc(OCC(N)=O)cc2c(-c2ccccc2)c1C#N
Agent: [Co]
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: CCCc1nc2ccc(OCC(N)=O)cc2c(-c2ccccc2)c1CN
Yield: 61.2 %

Procedure:
A mixture of 2-[(3-cyano-4-phenyl-2-propylquinolin-6-yl)oxy]acetamide (1.0 g, 2.9 mmol), Raney-cobalt (5 ml), 25% aqueous ammonia (5 ml), methanol (5 ml) and tetrahydrofuran (5 ml) was reacted under a hydrogen atmosphere at 0.5 MPa, 70° C. for 6 hrs. The reaction mixture was filtered, and water was added to the filtrate. The mixture was extracted with ethyl acetate and the extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.62 g, yield 62%) as white crystals.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[C:10]([C:12]1[CH:32]=[CH:31][C:15]2[N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[N:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[CH:20]=3)[CH:17]=[N:18][C:14]=2[CH:13]=1)#N.C(Cl)Cl.[NH4+].[Cl-].[OH2:38]>C1(C)C=CC=CC=1>[CH:10]([C:12]1[CH:32]=[CH:31][C:15]2[N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[N:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[CH:20]=3)[CH:17]=[N:18][C:14]=2[CH:13]=1)=[O:38]
Reactant: O
Reactant: N#Cc1ccc2c(c1)ncn2-c1cccc(-c2ncccn2)c1
Agent: CC(C)C[AlH]CC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=Cc1ccc2c(c1)ncn2-c1cccc(-c2ncccn2)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
A solution of DIBAL-H in toluene (2.5 ml, 1.0 M) was added to a mixture of (67) (367 mg, 1.2 mmol) and CH2Cl2 (60 ml) at -78° C. The reaction mixture was stirred for 1 hr at -78° C. and for 1 hr at room temperature. A saturated NH4Cl solution was added to the reaction mixture and stirring was continued for 0.5 hr. The mixture was poured into water and extracted with CH2Cl2. The organic extract was dried over MgSO4, and the solvent was evaporated under reduced pressure to give (68) (142 mg, 38%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][CH:3]=1.[CH2:11]([OH:14])[C:12]#[CH:13]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1CCCC1>[OH:14][CH2:11][C:12]#[C:13][C:2]1[CH:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(I)cc1
Reactant: C#CCO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNC1
Product: OCC#Cc1ccc(B(O)O)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 0.1 %

Procedure:
Pyrrolidine (100 mL) was added to a mixture of 4-iodophenylboronic acid (19.83 g, 80.01 mol) and Pd(Ph3P)4 (0.93 g, 0.80 mmol) and the mixture was stirred for 5 min to give a solution. The solution was cooled to 0° C. and propargyl alcohol (9.4 mL, 161.5 mol) was added. The resulting solution was stirred for 1 h at 0° C. and 18 h at room temperature and then concentrated in vacuo. The residue was diluted with 2 N NaOH (200 ml), washed with dichloromethane (2×100 mL), cooled to 0° C., and acidified with 10% HCl. The precipitated solids were isolated by filtration, washed with water and dried in vacuo to provided 12.76 g (91%) of the title compound as a tan solid. MS 175 (M−H)−.
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.[Br:11]Br.N>C(Cl)(Cl)Cl>[Br:11][C:6]1[NH:7][C:8]2[C:4](=[N:3][CH:2]=[N:1][C:9]=2[NH2:10])[N:5]=1
Reactant: BrBr
Reactant: Nc1ncnc2nc[nH]c12
Agent: N
Solvent: ClC(Cl)Cl
Product: Nc1ncnc2nc(Br)[nH]c12
Temperature: 25 °C
Reaction time: 72 h
Yield: 60.1 %

Procedure:
Adenine (47 g, 0.35 mole) was suspended in 200 ml of CHCl3 before adding bromine (180 ml, 3.5 mole) in one portion. The suspension was left stirring at room temperature for 72 hours in a closed system that was vented by a 20 G needle. The reaction was worked up by adding shaved ice into the suspension before slowly neutralizing with aqueous ammonia to pH 8-9, followed by precipitation of the desired product with acetic acid. The crude product was dried under reduced pressure for 2 days to give 8-Bromoadenine as a light brown powder (45 g, 60% yield). 1H NMR (DMSO-d6) δ 8.12 (s, 1H), 7.22 (s, 2H). Rf(75% EtOAc/Hex)=0.4.
Reaction SMILES: [Br:1]Br.[OH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C:12](=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[Br:1][C:7]1[C:8]([O:10][CH3:11])=[CH:9][C:4]([OH:3])=[C:5]([C:12](=[O:21])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH:6]=1
Reactant: BrBr
Reactant: COc1ccc(C(=O)Cc2ccc(O)cc2)c(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc(O)c(C(=O)Cc2ccc(O)cc2)cc1Br
Reaction time: 8 h
Yield: 18.8 %

Procedure:
A solution of bromine (3.6 mL, 75.6 mmol) in acetic acid (50 mL) was added dropwise to a stirring solution of 1-(2-hydroxy-4-methoxy-phenyl)-2-(4-hydroxy-phenyl)-ethanone (20 g, 77.4 mmol) in acetic acid (500 mL), and the reaction mixture was allowed to stir for 8 h. The acetic acid was then removed under reduced pressure, and the resulting solid was recrystallized from methanol/water to provide 8.9 g of crude product. Further purification using reverse-phase preparatory HPLC (30–100% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 18 min, then at 100% acetonitrile for 15 min) provided fractions that were subsequently neutralized with sodium bicarbonate and extracted using ethyl acetate. The organic fractions were combined, dried over magnesium sulfate and filtered, and the solvent was removed under reduced pressure to afford the title compound (4.8 g, 18%). MS (ESI) m/z 337.3 (M+1)+, 339.3 (M+1+2)+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.Br[CH:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C1C=CC=CC=1>[CH3:9][O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:11][CH:10]=1)=[O:7]
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: COC(=O)c1ccc(N)cc1
Solvent: c1ccccc1
Product: CCOC(=O)C(Nc1ccc(C(=O)OC)cc1)C(=O)OCC
Reaction time: 16 h
Yield: 85.6 %

Procedure:
A mixture of methyl 4-aminobenzoate (3.1 g, 20.5 mmol) and diethyl bromomalonate (2.45 g, 10.2 mmol) in a round bottom flask was placed in an oven at 115° C. for 16 h. The reaction mixture, which had turned into a solid cake, was suspended in 20 mL of benzene and filtered. The filtrate was diluted with 50 mL of benzene and the organic layer was washed with 2 N hydrochloric acid (3×10 mL), water (10 mL), dried (Na2SO4) and evaporated to give an oily material which solidified upon standing. The crude was recrystallized from ether/hexane to give 2.7 g (85%) of diethyl (4-methoxycarbonylphenyl)aminomalonate, mp 66-69° C. (ether/hexane).
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[C:10]2[C:5]([C:6](=[O:21])[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19]C)=[CH:8][O:9]2)=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:1][C:2]1[C:11]([OH:12])=[C:10]2[C:5]([C:6](=[O:21])[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[OH:19])=[CH:8][O:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccccc1-c1coc2c(O)c(O)ccc2c1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=c1c(-c2ccccc2O)coc2c(O)c(O)ccc12
Temperature: -80 °C
Reaction time: 12 h
Yield: 49.5 %

Procedure:
To a stirred solution of 7,8-dihydroxy-3-(2-methoxyphenyl)-4H-chromen-4-one (2 gm, 7.1 mmol) in dry CH2Cl2 (50 ml) at −80° C. was added BBr3 (1.4 ml in DCM, 14.2 mmol). The reaction mixture was then stirred for 1 hour at −80° C. and 12 hours at room temperature. The reaction was then quenched with ice-cooled water. The reaction mixture was then extracted with CH2Cl2 and the organic layer was separated, washed with brine, dried over Na2SO4, and evaporated. The residue was purified by silica gel column chromatography using hexane-chloroform as the eluent to give 7,8-dihydroxy-3-(2-hydroxy-phenyl)-chromen-4-one (0.95 gm, 50%) as white solid.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CN=C1.[CH2:14]([N:21]1[C:29]2[C:24](=[N:25][C:26]([Cl:30])=[CH:27][CH:28]=2)[CH:23]=[C:22]1[CH2:31][OH:32])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[CH2:14]([N:21]1[C:29]2[C:24](=[N:25][C:26]([Cl:30])=[CH:27][CH:28]=2)[CH:23]=[C:22]1[CH2:31][O:32][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cc2nc(Cl)ccc2n1Cc1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1cc2nc(Cl)ccc2n1Cc1ccccc1
Reaction time: 4 h
Yield: 92 %

Procedure:
tert-Butyldimethylsilyl chloride (0.12 g, 0.81 mmol) and 1H-imidazole (60. mg, 0.88 mmol) were added to a solution of (1-benzyl-5-chloro-1H-pyrrolo[3,2-b]pyridin-2-yl)methanol (0.20 g, 0.73 mmol, from Step 2) in DCM (10 mL) After stirring for 4 hours, additional tert-butyldimethylsilyl chloride (33 mg, 0.22 mmol) and 1H-imidazole (15 mg, 0.22 mmol) were added and the reaction was continued for one hour. The mixture was filtered and the filtrate was concentrated. The product was purified by flash chromatography, eluting with a gradient from 0-10% EtOAc in hexanes to afford a white solid (0.26 g, 92%).