Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[C:10]([C:18]4[CH:23]=[C:22]([I:24])[C:21]([OH:25])=[C:20]([I:26])[CH:19]=4)=[C:11]4[C:16](=[CH:17][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1)[CH:15]=[CH:14][CH:13]=[CH:12]4.Br[CH2:28][C:29]([O:31][CH3:32])=[O:30].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:32][O:31][C:29](=[O:30])[CH2:28][O:25][C:21]1[C:20]([I:26])=[CH:19][C:18]([C:10]2[C:8]3[C:9]4[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=4[S:6][C:7]=3[CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][CH:14]=[CH:15]3)=[CH:23][C:22]=1[I:24]
Reactant: COC(=O)CBr
Reactant: Oc1c(I)cc(-c2c3ccccc3cc3sc4ccccc4c23)cc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1c(I)cc(-c2c3ccccc3cc3sc4ccccc4c23)cc1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
4-(Benzo[b]naphtho[2,3-d]thiophen-11-yl)-2,6-diiodo-phenol (0.543 g, 0.94 mmol), methyl bromoacetate (0.181 mL, 1.88 mmol), potassium carbonate (0.141 g, 1.03 mmol) and N,N-dimethylformamide (5.4 mL) were combined and stirred at ambient temperature for 1 h. The reaction mixture was added to water and filtered. The solid was washed with water and dried in vacuo to provide the (4-benzo [b]naphtho[2,3-d]thiophen-11-yl-2,6-diiodo-phenoxy)-acetic acid methyl ester as a white solid (0.537 g, 88%): mp 203-205 ° C. Aqueous potassium hydroxide (0.5 N, 2.54 mL, 1.28 mmol) was added to a stirred solution of this methyl ester (0.55 g, 0.85 mmol) in THF (5.0 mL) at ambient temperature. After 1 h the solution was concentrated, diluted with water (75 mL) and acidified with 10% aqueous HCl. The solid was filtered and washed with water to provide the title compounds as a white solid (0.428 g, 80%): mp 250-252° C.: NMR (DMSO-d6); δ8.66 (s, 1 H), 8.07 (d, J=8 Hz, 1 H), 8.01 (d, J=8 Hz, 1 H), 7.93 (s, 2 H), 7.61 (ddd, J=8, 7, 1 Hz, 1 H), 7.54-7.48 (m, 2 H), 7.47 (ddd, J=8, 7, 1 Hz, 1 H), 7.27 (ddd, J=8, 7, 1 Hz, 1 H), 6.71 (d, J=8 Hz, 1 H), 4.69 (s, 2 H); MS (EI): 636 (100%, MI); Anal. Calc. for C24H14I2O3S: C, 45.31, H, 2.22, N, 0.00. Found: C, 44.95, H, 1.99, N, 0.23.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[C:4]([NH:6][C:7]1[C:8](Cl)=[N:9][C:10]([CH3:20])=[N:11][C:12]=1[NH:13][CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=O.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[C:4]1[N:13]([CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:12]2[C:7]([N:6]=1)=[C:8]([N:30]1[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]1)[N:9]=[C:10]([CH3:20])[N:11]=2
Reactant: Cc1nc(Cl)c(NC(=O)c2ccccc2Cl)c(NC2CCOCC2)n1
Reactant: CN1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1nc(N2CCN(C)CC2)c2nc(-c3ccccc3Cl)n(C3CCOCC3)c2n1
Temperature: 160 °C
Reaction time: 0.5 h
Yield: 88.9 %

Procedure:
Combine 2-chloro-N-(4-chloro-2-methyl-6-(tetrahydro-2H-pyran-4-ylamino)-pyrimidin-5-yl) benzamide (45.0 g, 118.0 mmol), 1-methylpiperazine (23.0 mL, 207.0 mmol), di-isopropylethylamine (23.0 mL, 131.9 mmol) and isopropyl alcohol (225 mL) in a 1 L Parr reactor. Seal the reactor, start stirring, and adjust the set-point for heat control to 160° C. After the internal temperature reaches 160° C., stir the mixture for 24 hours. Cool the reactor contents to 60° C., vent the vessel of pressure, and transfer the contents to a 2 L flask equipped with overhead stirring apparatus. Rinse out reactor flask with isopropyl alcohol (25.0 mL) and combine the rinse with main solution. Add cold, de-ionized water (780 mL) to the mixture over 30 minutes and stir the resulting precipitate for 30 minutes. Filter the mixture, wash the solids with de-ionized water (2×270 mL) and pull dry on the funnel Further dry the product overnight at 45° C. to afford the 8-(2-Chloro-phenyl)-2-methyl-6-(4-methyl-piperazin-1-yl)-9-(tetrahydro pyran-4-yl)-9H-purine as an off-white solid (44.8 g) MS (m/z): 427/429 (M+1).
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[CH:10]=[C:9]([CH2:11][OH:12])[CH:8]=[C:7]([CH3:13])[N:6]=1>CN(C=O)C>[CH3:1][O:2][C:5]1[CH:10]=[C:9]([CH2:11][OH:12])[CH:8]=[C:7]([CH3:13])[N:6]=1
Reactant: C[O-]
Reactant: Cc1cc(CO)cc(Cl)n1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(CO)cc(C)n1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
Sodium methoxide (11.3 mL, 28% solution in methanol) was added to a solution of (2-chloro-6-methylpyridin-4-yl)methanol (1.75 g) in DMF (18 mL), and the mixture was stirred at 80° C. for 12 hours. Subsequently, the reaction mixture was stirred at 120° C. for seven hours. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous ammonium chloride solution was added to the residue, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 10% to 70%) to give the title compound (1.1 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:13][CH2:14]S(C)(=O)=O)[CH2:9]1)=[O:7].[O:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[CH2:37][N:38]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[N:40]=[C:39]1[C:47]([CH:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1)=[O:48]>CC(C)=O.CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:52]2[CH2:53][CH2:54][CH:49]([C:47]([C:39]3[N:38]([CH2:37][C:33]4[O:32][CH:36]=[CH:35][CH:34]=4)[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=4[N:40]=3)=[O:48])[CH2:50][CH2:51]2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCS(C)(=O)=O)(c3ccccc3)C2)cc(OC)c1OC
Reactant: O=C(c1nc2ccccc2n1Cc1ccco1)C1CCNCC1
Solvent: CCCCCC
Solvent: CC(C)=O
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)c4nc5ccccc5n4Cc4ccco4)CC3)(c3ccccc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 6.6.2 using 1-(3,4,5-trimethoxy-benzoyl)-3-phenyl-3-(2-methanesulfonyl-ethyl)-pyrrolidine and 4-(1-(fur-2-ylmethyl)-1 H-benzoimidazole-2-carbonyl)-piperidine obtain, after chromatography on silica gel eluting with 80% acetone/hexane, the title compound: Mass Spectra (CI/NH3) M++H=677.
Reaction SMILES: [C:1](#[N:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:11]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>C1(C)C=CC=CC=1>[C:1]([CH2:2][CH:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:11]([O:19][CH2:20][CH3:21])=[O:18])#[N:10]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: N#CC=Cc1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C(=O)OCC)C(CC#N)c1ccccc1
Temperature: 30 °C
Reaction time: 48 h

Procedure:
[(S,S)-N-methanesulfonyl-1,2-diphenylethylenediamine]-(hexamethylbenzene)ruthenium (5.5 mg, 0.01 mmol, S/C=50), cinnamonitrile (65 μl, 0.5 mmol), diethyl malonate (76 μl, 0.5 mmol) and toluene (0.5 ml) were added into Schlenk (20 ml) under an argon atmosphere, and stirred at 30° C. for 48 hours. 1HNMR determination of the solution showed that the yield of the product was 46%. The reaction solution was purified by flash column chromatography (hexane/acetone=90/10, SiO2), and the optical purity was measured by HPLC (CHIRALPACK AS manufactured by Daicel Co., Ltd., hexane:2-propanol=90:10, flow rate 0.5 ml/min, detection by 210 nm), resulting to 56% ee.
Reaction SMILES: Br[C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][CH3:15])[C:6](=[O:16])[N:5]([CH2:17][CH2:18][CH2:19][CH3:20])[C:4]=2[N:3]=1.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.N1C(=O)C2NC=NC=2NC1=O>>[CH2:21]([NH:28][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][CH3:15])[C:6](=[O:16])[N:5]([CH2:17][CH2:18][CH2:19][CH3:20])[C:4]=2[N:3]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCc1ccccc1
Reactant: CCCCn1c(=O)c2[nH]c(Br)nc2n(CCCC)c1=O
Agent: O=c1[nH]c(=O)c2[nH]cnc2[nH]1
Product: CCCCn1c(=O)c2[nH]c(NCc3ccccc3)nc2n(CCCC)c1=O

Procedure:
Heat together a mixture of one equivalent of 8-bromo-1,3-di-n-butyl-xanthine and three to four equivalents of benzylamine at 160°-180° C. until thin layer chromatography shows that no starting xanthine remains. Cool. Triturate with ethanol and water to yield 8-benzylamino-1,3-di-n-butyl-xanthine.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[C:5]([NH2:18])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Cl:19][C:20]1[C:25]([C:26](O)=[O:27])=[C:24]([F:29])[C:23]([CH2:30][NH:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:22][CH:21]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:19][C:20]1[C:25]([C:26]([NH:18][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[N:3]=[C:2]([CH3:1])[N:11]=[C:10]3[N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:27])=[C:24]([F:29])[C:23]([CH2:30][NH:31][C:32](=[O:37])[C:33]([CH3:35])([CH3:34])[CH3:36])=[CH:22][CH:21]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Reactant: Cc1nc(N2CCOCC2)c2cccc(N)c2n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(N2CCOCC2)c2cccc(NC(=O)c3c(Cl)ccc(CNC(=O)C(C)(C)C)c3F)c2n1
Yield: 25.1 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 2-methyl-4-morpholinoquinazolin-8-amine (Intermediate-51, 100 mg, 0.41 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 176 mg, 0.61 mmol), oxalyl chloride (115 mg, 0.92 mmol), DMF (1 drop) and DIPEA (159 mg, 1.23 mmol) in CH2Cl2 (5 mL) to afford 53 mg of the title product. 1H NMR (400 MHz, DMSO-d6): δ 10.36 (s, 1H), 8.69 (d, J=7.6 Hz, 1H), 8.14-8.11 (t, J=5.7 Hz, 1H), 7.76-7.74 (d, J=8.4 Hz, 1H), 7.50-7.46 (t, J=8.1 Hz, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.37-7.33 (t, J=8.0 Hz, 1H), 4.30 (d, J=5.7 Hz, 2H), 3.77 (d, J=4.7 Hz, 2H), 3.73 (d, J=4.6 Hz, 2H), 3.30 (s, 3H), 1.13 (s, 9H); MS (m/z): 514.29 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[O:12]1[CH:16]=[N:15][N:14]=[C:13]1[C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.C(N(CC)CC)C.O=O>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:23][C:20]2[CH:19]=[CH:18][C:17]([C:13]3[O:12][CH:16]=[N:15][N:14]=3)=[CH:22][CH:21]=2)=[CH:5][CH:4]=1
Reactant: Oc1ccc(-c2nnco2)cc1
Reactant: COc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Oc2ccc(-c3nnco3)cc2)cc1
Yield: 72.1 %

Procedure:
A mixture of 4-methoxybenzeneboronic acid (1.9 g, 12 mmol), 4-(1,3,4)oxadiazol-2-yl-phenol (1.0 g, 6.2 mmol), copper(II)acetate (1.1 g, 6.2 mmol), crushed 4-Angstrom molecular sieves (0.65 g), triethylamine (4.2 mL) and methylene chloride (22.7 mL) was stirred under 1 atm of oxygen gas for 48 hours. The mixture was filtered through a pad of Celite®, concentrated in vacuo and purified by radial chromatography (2:1 hexane-ethyl acetate), affording 1.2 g of 2-[4-(4-Methoxy-phenoxy)-phenyl]-[1,3,4]oxadiazole.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH:18]1([CH2:24][NH2:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.CO>CO>[CH:18]1([CH2:24][NH:25][CH:14]2[CH2:15][CH2:16][CH:11]([NH:10][C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][N:2]=[CH:3]4)[CH2:12][CH2:13]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C1CCC(Nc2ccc3[nH]ncc3c2)CC1
Reactant: NCC1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: c1cc2[nH]ncc2cc1NC1CCC(NCC2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 35.7 %

Procedure:
4-(1H-5-Indazolylamino)-1-cyclohexanone (intermediate 3) (57 mg) and cyclohexanemethylamine (57 mg) were dissolved in methanol (1 ml), and sodium triacetoxyborohydride (105 mg) was added by portions to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. Hydrochloric acid-methanol was then added thereto, and the reaction mixture was stirred and was then concentrated. The residue was purified by HPLC [0.5% aqueous trifluoroacetic acid solution/acetonitrile]. A saturated aqueous sodium hydrogencarbonate solution (2 ml) was then added to fractions containing respective compounds, followed by extraction with chloroform-propanol (3/1). The organic layers were dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure to give an anti-form compound (29 mg) and a syn-form compound (35 mg).
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8]O)(=[O:5])[C:2]([CH3:4])=[CH2:3].C(N(CC)CC)C.C(Cl)[Cl:18]>>[Cl:18][C:1]([OH:6])=[O:5].[C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: ClCCl
Reactant: C=C(C)C(=O)OCCO
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCC
Product: O=C(O)Cl
Temperature: -15 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A solution of 50 cm3 of phosgene (0.7 mol) in 100 cm3 of methylene chloride was prepared in a one liter four-necked round-bottomed flask provided with a dry ice cooler, a thermometer, a mechanical stirrer and a dropping funnel. A mixture comprising 65 g (0.5 mol) of 2-hydroxyethyl methacrylate and 51 g (0.5 mol) of triethylamine in 100 cm3 of methylene chloride was added to this solution, cooled to -15° C. After one hour of stirring at 0° C., the excess phosgene was removed by bubbling nitrogen. The reaction mixture was then washed in the cold with acidified water, and then with pure water. After drying the organic phase over sodium sulphate and evaporating the solvent under reduced pressure at 30° C., ethyl methacrylate chloroformate was obtained in a yield of 96%.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH2:16][CH2:17][CH:18]2[C:23]([OH:25])=[O:24])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:26](O)[CH3:27]>>[C:6]([C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH2:16][CH2:17][CH:18]2[C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:13])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCO
Reactant: O=C(c1ccccc1)c1cccc2c1CCC2C(=O)O
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1CCc2c(C(=O)c3ccccc3)cccc21

Procedure:
To 250 ml. of ethanol is added 20 ml. of concentrated sulfuric acid, followed by the addition of 13.3 g. of 4-benzoylindan-1-carboxylic acid. The mixture is refluxed for 5.5 hours. After cooling, the ethanol is distilled off under reduced pressure and water is added to the residue, followed by extraction with ether. The ethereal layer is washed with a 5 % aqueous solution of sodium hydroxide and a saturated aqueous solution of sodium chloride and, then, dried. The solvent is distilled off under reduced pressure and the residue is purified by column chromatography on silica gel (eluted with chloroform). The described procedure gives ethyl 4-benzoylindan-1-carboxylate as an oily product.
Reaction SMILES: [OH:1]/[N:2]=[C:3](\Cl)/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[C:12](=[CH:18][CH2:19][CH2:20][CH3:21])[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(N(CC)CC)C>C(Cl)Cl.CCCCCC>[C:4]1([C:3]2[C:18]([CH2:19][CH2:20][CH3:21])=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[O:1][N:2]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O/N=C(\Cl)c1ccccc1
Reactant: CCCC=C(Br)C(=O)OCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCCCCC
Product: CCCc1c(-c2ccccc2)noc1C(=O)OCC
Reaction time: 24 h
Yield: 2.6 %

Procedure:
To a solution of (Z)-N-hydroxybenzimidoyl chloride (770 mg, 4.95 mmol) and ethyl 2-bromohex-2-enoate (1.09 g, 4.95 mmol) in DCM (15 mL) was added triethylamine (2.07 mL, 14.85 mmol) over 5 minutes. After ˜50% of the addition was complete, a precipitate formed. Stirring was continued for 24 hr at rt. The reaction mixture was partitioned between Et2O (100 ml) and water (100 ml). The organic layer was washed with brine (100 ml), dried (MgSO4) and concentrated to afford a yellow oil. This oil was chromatographed on a 5×15 cm silica gel column, eluting with a 0-8% EtOAc/Hex gradient. The product containing fractions were concentrated to afford 343 mg of a waxy, white solid. This material was triturated with heptane. The solid contained no product. The mother liquor was concentrated to afford a partially purified semisolid residue. The portion of the residue that dissolved in ˜3 ml of hexane was chromatographed on a 12 gm Isco silica gel cartridge, eluting with a 0-1% EtOAc/Hex gradient. Fractions containing the product were concentrated to afford ethyl 3-phenyl-4-propylisoxazole-5-carboxylate (34 mg, 0.131 mmol, 2.65% yield) as a colorless oil. HPLC retention time=1.91 minutes (PHENOMENEX® Luna 4.6×30 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.1% TFA over a 2 minute gradient. MS: (M+H)=260.23. 1H NMR (500 MHz, chloroform-d) δ ppm 0.90 (t, J=7.4 Hz, 3H), 1.45 (t, J=7.2 Hz, 3H), 1.53 (m, 2H), 2.80 (m, 2H), 4.46 (q, J=7.2 Hz, 2H), 7.45 (m, 1H), 7.50 (m, 2H), 7.59 (m, 2H).
Reaction SMILES: [CH:1]([O:14][C:15]1[C:24]2[N:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:18]([C:25]([OH:27])=O)=[C:17]2[CH2:28][N:29]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[C:30](=[O:31])[C:16]=12)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[N:43]1[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=1[CH2:41][NH:40][C:25]([C:18]1[C:19]2[CH:20]=[CH:21][CH:22]=[N:23][C:24]=2[C:15]([O:14][CH:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[C:16]2[C:30](=[O:31])[N:29]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[CH2:28][C:17]=12)=[O:27]
Reactant: NCc1ccccn1
Reactant: O=C(O)c1c2c(c(OC(c3ccccc3)c3ccccc3)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1ccccn1)c1c2c(c(OC(c3ccccc3)c3ccccc3)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2
Temperature: 25 °C
Reaction time: 15 h
Yield: 57 %

Procedure:
Carboxylic acid 213 (0.010 g, 0.0193 mmol) was dissolved in 0.3 mL of dimethylformamide. To this was added 2-aminomethylpyridine (0.004 g, 0.0386 mmol), triethylamine (0.008 mL, 0.058 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.074 g, 0.0386 mmol), 1-Hydroxybenzotriazole hydrate (0.0039 g, 0.029 mmol) and stirred at room temperature. After 15 hours, starting material was consumed. Dilute with dichloromethane, washed with 1M HCl solution, saturated brine solution, dried (Na2SO4), concentrated to give crude product. Chromatographed (0 to 8% methanol/dichloromethane) to give 9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylic acid (pyridin-2-ylmethyl)-amide 231 (0.007 g, 0.011 mmol, 59%.) 1H NMR (CDCl3) 8.94 (s, 1H), 8.45 (d, 2H), 8.05 (s, 1H), 7.70 (d, 4H), 7.57-7.17 (m, 12H), 7.05 (d, 2H), 4.78 (s, 1H), 4.69 (d, J=5 Hz, 1H), 4.38 (s, 1H). MS: 609 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]2[CH2:18][O:17]C(C)(C)[O:15][CH2:14]2)=[C:4](Cl)[N:3]=1.[CH3:22][CH:23]([CH3:25])[O-:24].[Na+].Cl.O>C(O)(C)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]([CH2:14][OH:15])[CH2:18][OH:17])=[C:4]([O:24][CH:23]([CH3:25])[CH3:22])[N:3]=1
Reactant: CC(C)[O-]
Reactant: CC1(C)OCC(CCn2cnc3c(Cl)nc(N)nc32)CO1
Agent: Cl
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CC(C)Oc1nc(N)nc2c1ncn2CCC(CO)CO
Reaction time: 0.42 h

Procedure:
A solution of 2-amino-6-chloro-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]purine (0.25 g, 0.8 mmol) in isopropanol (2.5 ml) containing sodium isopropoxide (0.5M) was stirred at 60° for 25 minutes. After cooling, hydrochloric acid (5M, 0.3 ml) and water (0.7 ml) were added and the solution was stirred for 15 minutes at room temperature. The solution was neutralised by addition of aqueous.sodium bicarbonate and the solvent was removed. The residue was extracted with chloroform-ethanol (2:1) and the solution purified by column chromatography on silica gel eluting with chloroform-methanol (7:1) to afford 2-amino-9-(4-hydroxy-3-hydroxymethylbut-1-yl)-6-isopropoxypurine which was crystallised from chloroform-carbon tetrachloride (0.18 g, 76%), m.p. 111.5-113.5° C., δH [(CD3)2SO] 1.34 (6H, d, J 6.3 Hz, C(CH3)2), 1.45 (1H, m, 3′-H), 1.74 (2H, q, J 7.2 Hz, 2′-H), 3.3-3.5 (4H, AB part of ABX, 2×4′-H), 4.06 (2H, t, J 7.3 Hz, 1′-H), 4.40 (2H, br, 2×OH), 5.49 (1H, septet, J 6.3 Hz, CH(CH3)2), 6.27 (2H, s, 2-NH2), and 7.83 (1H, s, 8-H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[CH2:5][CH2:6][CH2:7][NH2:8])[CH3:2].[CH2:16]([O:18][C:19]1[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=1[O:21][CH2:22][CH2:23]Cl)[CH3:17].[I-].[Na+].[C:31](=[O:34])([OH:33])[O-].[Na+]>O.CN(C)C=O>[C:4]([OH:3])(=[O:18])[C:31]([OH:33])=[O:34].[CH2:1]([O:3][CH:4]([C:9]1[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=1)[CH2:5][CH2:6][CH2:7][NH:8][CH2:23][CH2:22][O:21][C:20]1[CH:25]=[CH:26][CH:27]=[CH:28][C:19]=1[O:18][CH2:16][CH3:17])[CH3:2]
Reactant: CCOc1ccccc1OCCCl
Reactant: CCOC(CCCN)c1ccc(F)cc1
Reactant: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccccc1OCCNCCCC(OCC)c1ccc(F)cc1
Product: O=C(O)C(=O)O
Temperature: 110 °C
Reaction time: 20 h

Procedure:
A mixture of 2 g of N-[4-ethoxy-4-(4-fluorophenyl)butyl]amine, 2 g of 2-(2-ethoxyphenoxy)ethyl chloride, 0.1 g of sodium iodide, 1 g of sodium bicarbonate and 20 ml of N,N-dimethylformamide was stirred at about 110° C for 20 hours. After cooling, the reaction mixture was poured into 200 ml of water and extracted with benzene. The benzene layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was treated with ethanolic oxalic acid and recrystallized from ethanol to give N-[4-ethoxy-4-(4-fluorophenyl)butyl]-2-(2-ethoxyphenoxy)ethylamine oxalate, M.P. 157° - 160° C.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[Br:15][C:16]1[CH:29]=[CH:28][C:27]2[O:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([Br:30])[CH:24]=3)[CH:19]([CH2:31]O)[C:18]=2[CH:17]=1>C1(C)C=CC=CC=1>[Br:15][C:16]1[CH:17]=[CH:18][C:27]2[O:26][C:25]3[CH:24]=[C:23]([Br:30])[CH:22]=[CH:21][C:20]=3[CH:19]=[CH:31][C:28]=2[CH:29]=1
Reactant: OCC1c2ccc(Br)cc2Oc2ccc(Br)cc21
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Cc1ccccc1
Product: Brc1ccc2c(c1)C=Cc1ccc(Br)cc1O2
Temperature: 25 °C
Yield: 79.4 %

Procedure:
Phosphorus pentoxide (5.04 g, 35.5 mmol) was added portion-wisely to a stirred solution of (2,6-dibromo-9H-xanthen-9-yl)methanol (10-1) (1.01 g, 2.73 mmol) in toluene (100 mL) and the suspension was heated under reflux for 20 min. The mixture was allowed to cool to rt and toluene was removed by decantation. The residual solid was washed with toluene (2×100 mL) by further decantation. The combined organics were cooled in an ice bath and brine (400 mL) was added slowly. The layers were separated and the organic washed with water (300 mL), brine (300 mL), dried over MgSO4 and evaporated to dryness, to give a yellow oily solid. The product was purified by column chromatography (SiO2, 0-10% EtOAc/isohexanes) to give 2,7-dibromodibenzo[b,f]oxepine (10-2) (763 mg, 79% yield) as a clear oil. 1H NMR (CDCl3) δ 7.41-7.36 (1H, m), 7.33-7.31 (1H, m), 7.29-7.24 (2H, m), 7.04-6.99 (2H, m), 6.68-6.57 (2H, m) ppm.