Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](#[N:3])[CH3:2].CCCCCC.C([Li])CCC.Cl[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[N:17]=1.O>O1CCCC1>[Cl:22][C:18]1[N:17]=[C:16]([CH2:2][C:1]#[N:3])[CH:21]=[CH:20][CH:19]=1
Reactant: Clc1cccc(Cl)n1
Reactant: CC#N
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: N#CCc1cccc(Cl)n1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of acetonitrile (2.77 mL) in tetrahydrofuran (80 mL) was added dropwise n-butyl lithium hexane solution (1.6 M, 29.6 mL) at −78° C., and the reaction mixture was stirred at −78° C. for 1 hr under argon atmosphere. A solution of 2,6-dichloropyridine (2.0 g) in tetrahydrofuran (10 mL) was added dropwise thereto at −78° C., and the reaction mixture was stirred at −78° C. for 2 hr under argon atmosphere, and allowed to be warmed to room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.91 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:26][CH3:27])=[C:17]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:18]=2)[N:13]=[N:12][C:11]=1[C:28]([NH2:30])=[O:29].C(N(C(C)C)C(C)C)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:26][CH3:27])=[C:17]([CH:20]3[CH2:25][CH2:24][N:23]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:22][CH2:21]3)[CH:18]=2)[N:13]=[N:12][C:11]=1[C:28]([NH2:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc2nnc(C(N)=O)c(Nc3ccc(C)cc3F)c2cc1C1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc2nnc(C(N)=O)c(Nc3ccc(C)cc3F)c2cc1C1CCN(S(C)(=O)=O)CC1
Reaction time: 1 h
Yield: 23.9 %

Procedure:
To a solution of 4-(2-fluoro-4-methylphenylamino)-7-methoxy-6-(piperidin-4-yl)cinnoline-3-carboxamide (Example 51, 0.1 g, 0.24 mmol) in CH2Cl2 (2.5 ml) and DMF (2.5 ml) was added N-ethyldiisopropylamine (0.127 ml, 0.73 mmol) and methanesulphonyl chloride (0.021 ml, 0.27 mmol). The reaction mixture was stirred at for 1 hour, diluted with CH2Cl2 and washed with water. The organic layer was concentrated under reduced pressure and the residue purified by reverse phase chromatography using 0.1% formic acid in water and methanol (50-70%) to give 28 mg (24%) off-white solid. 1H NMR: 11.56 (s, 1H), 8.78 (s, 1H), 7.94 (s, 1H), 7.61 (s, 1H), 7.29 (m, 1H), 7.21 (m, 1H), 7.11 (m, 2H), 4.01 (s, 3H), 3.51 (m, 2H), 2.91 (m, 1H), 2.84 (s, 3H), 2.74 (m, 2H), 2.35 (s, 3H), 1.63 (m, 2H), 0.97 (m, 2H); m/z 488.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][C:9]=2[C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:28]Br.C([O-])(=O)C.[K+]>C(O)(=O)C>[Br:28][C:23]1[C:24]2[C:19](=[CH:18][C:17]([C:9]3[O:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:8]=3[CH2:7][CH2:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:26][CH:25]=2)[CH:20]=[CH:21][C:22]=1[OH:27]
Reactant: BrBr
Reactant: Oc1ccc2cc(-c3oc4ccccc4c3CCC3CCCC3)ccc2c1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: Oc1ccc2cc(-c3oc4ccccc4c3CCC3CCCC3)ccc2c1Br
Yield: 74.4 %

Procedure:
Following the procedure described in Step 4 of Example 1, 6-[3-(2-cyclopentylethyl)-1-benzofuran-2-yl]-2-naphthol (0.671 g, 1.88 mmol) was brominated with bromine (0.11 mL, 2.2 mmol) and potassium acetate (1.91 g, 19.5 mmol) in glacial acetic acid (19 mL). Purification by flash chromatography using 100% hexane and 1-30% chloroform in hexane as eluants afforded 1-bromo-6-[3-(2-cyclopentylethyl)-1-benzofuran-2-yl]-2-naphthol as a light brown semi-solid (0.609 g). 1HNMR (300 MHz, DMSO-d6): δ10.75 (s, 1H), 8.25 (s, 1H), 8.15 (d, 1H, J=8.6 Hz), 7.95-8.0 (m, 2H), 7.7 (d, 1H, J=8.6 Hz), 7.6 (d, 1H, J=8.6 Hz), 7.25-7.4 (m, 3H), 3.0 (t, 2H, J=8.6 Hz), 1.65-1.95 (m, 5H), 1.4-1.65 (m, 4H), and 1.1-1.25 ppm (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11](Br)([CH3:14])[O:10][C:9]2=[O:16])=[CH:4][CH:3]=1.[I-:17].[K+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]([I:17])([CH3:14])[O:10][C:9]2=[O:16])=[CH:4][CH:3]=1
Reactant: CC1(Br)OC(=O)N(c2ccc(Cl)cc2)C1=O
Reactant: [I-]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: CC1(I)OC(=O)N(c2ccc(Cl)cc2)C1=O
Temperature: 25 °C
Reaction time: 168 h

Procedure:
6.1 g (0.02 mole) of the 3-(4-chlorophenyl)-5-bromo-5-methyl-oxazolidine-2,4-dione, produced in a manner analogous to that described in Example 1, and 33.2 g (0.2 mole) of potassium iodide are placed, together with a spatula tip of benzyltriethylammonium chloride, in 50 ml of water, and the mixture is stirred at 50° for 7 days. It is then cooled to room temperature, and the solid product is filtered off with suction. After washing with water, the crude product is taken up in methylene chloride, and extracted once with water. The organic phase is then dried over sodium sulphate, filtered, and concentrated in a vacuum evaporator. The substance remaining behind is digested with a small amount of ether/petroleum ether, then filtered off with suction and dried. There is obtained a yield of 3.3 g of substance having a melting point of 132°-142°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.[OH:12]O>C(O)(=O)C>[CH3:1][C:2]1[CH:3]=[N+:4]([O-:12])[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: OO
Reactant: Cc1cnc2c(c1)CCCC2
Solvent: CC(=O)O
Product: Cc1cc2c([n+]([O-])c1)CCCC2
Temperature: 80 °C

Procedure:
3-Methyl-5,6,7,8-tetrahydroquinoline (50 g.) dissolved in glacial acetic acid (180 ml.) and the solution treated with 30% hydrogen peroxide (70 ml.) and heated at 80° C for 20 hours. The solvent was removed in vacuo and the residual oil diluted with water (25 ml.) and re-evaporated. The resulting oil was dissolved in chloroform (100 ml.), washed with aqueous sodium carbonate (2 × 25 ml.), saturated brine (2 × 25 ml.), dried (MgSO4) and the solvent removed in vacuo to give 3-Methyl-5,6,7,8-tetrahydroquinoline -1 -oxide (60 g.) as a pale yellow solid which was used without purification. The N-oxide (60 g.) was dissolved in acetic anhydride (120 ml.) and added to boiling acetic anhydride (120 ml.) and the mixture heated at reflux for 30 minutes. The solvent was removed in vacuo and the residual oil was treated with 10% hydrochloric acid (700 ml.) and the solution heated on a steam bath for 2 hours. The cooled reaction mixture was adjusted to pH 9.0 with sodium hydroxide and extracted with ether (3 × 100 ml.). The combined etheral extracts were washed with saturated brine, dried (MgSO4) and the solvent removed in vacuo. The resultant oil was distilled at 0.15 mmHg to give a colourless oil (22 g.) b.p. 70-78° C which crystallised from n-hexane to give 8-hydroxy-3 -methyl-5,6,7,8-tetrahydroquinoline as colourless needles m.p. 58° C. (Found: C,73.7; H,8.2;N,8.3. C10H13NO requires: C,73.6; H,8.0; N,8.6%).
Reaction SMILES: [C:1]([C:3]1[C:12](=[O:13])[C:11]2[C:6](=[C:7]([Cl:15])[CH:8]=[C:9]([Cl:14])[CH:10]=2)[O:5][CH:4]=1)#N.N([O-])=[O:17].[Na+].[OH2:20]>S(=O)(=O)(O)O>[Cl:14][C:9]1[CH:10]=[C:11]2[C:6](=[C:7]([Cl:15])[CH:8]=1)[O:20][CH:1]=[C:3]([C:4]([OH:17])=[O:5])[C:12]2=[O:13]
Reactant: O=N[O-]
Reactant: O
Reactant: N#Cc1coc2c(Cl)cc(Cl)cc2c1=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)c1coc2c(Cl)cc(Cl)cc2c1=O
Reaction time: 18 h

Procedure:
8 g of the product of step (a) are dissolved in 30 ml of conc. sulphuric acid and the solution is allowed to stand for 18 hours at room temperature. After addition of 90 m of conc. and 200 ml of 80% sulphuric acid, 5.5 g of sodium nitrite in 10 ml of water are introduced under the liquid surface at 5°-10°. The mixture is stirred at 10° for 15 minutes and at 70° for 30 minutes and then poured into 1 l of water. The resulting precipitate is separated, washed 3 times with water and twice with ethanol, to obtain the heading compound, m.p. 196°, which can be crystallised from acetic acid.
Reaction SMILES: Cl[CH2:2][CH:3]1[O:7][C:6](=[O:8])[NH:5][CH2:4]1.[CH3:9][NH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]3[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=3)[CH:19]=2)[N:14]=[C:13]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[N:12]=1.CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC>CN1C(=O)CCC1.CO>[CH3:9][NH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]3[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=3)[O:27][CH2:2][CH:3]3[O:7][C:6](=[O:8])[NH:5][CH2:4]3)[CH:19]=2)[N:14]=[C:13]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[N:12]=1
Reactant: O=C1NCC(CCl)O1
Reactant: CNc1nc(-c2cccnc2)nc2ccc(-c3cccc(O)c3)cc12
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CO
Solvent: CN1CCCC1=O
Product: CNc1nc(-c2cccnc2)nc2ccc(-c3cccc(OCC4CNC(=O)O4)c3)cc12
Temperature: 90 °C

Procedure:
To 5-(chloromethyl)oxazolidin-2-one (45 μmol) was added the solution of 3-(4-(methylamino)-2-(pyridin-3-yl)quinazolin-6-yl)phenol (30 μmol) in NMP (200 μL). PS-BEMP (90 μmol) was added to the vials by resin dispenser. After the reaction mixture was heated at 90° C. for 12 h, the residue was diluted with methanol and purified by PREP-HPLC Condition D. The target fraction was lyophilized to afford the titled compound whose structure was finally confirmed by LCMS using LCMS Method E.
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[H-].[Na+].[CH2:12]([O:14][C:15](=[O:20])[CH2:16][CH2:17][CH2:18]Br)[CH3:13].CCOCC>CN(C)C=O>[CH2:12]([O:14][C:15](=[O:20])[CH2:16][CH2:17][CH2:18][O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH:1]=[O:9])[CH3:13]
Reactant: O=Cc1ccccc1O
Reactant: CCOC(=O)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)CCCOc1ccccc1C=O
Reaction time: 0.25 h
Yield: 47.5 %

Procedure:
A solution of 12.2 g of salicylaldehyde in 20 ml of dimethylformamide is instilled into a suspension of 4.36 g of sodium hydride (55% dispersion in mineral oil) in 80 ml of dimethylformamide by stirring and ice cooling within 15 minutes. After 3 hours, a solution of 21.5 g of 4-bromobutyric acid ethyl ester in 16 ml of dimethylformamide is instilled by ice cooling within 15 minutes, and the mixture is stirred for 72 hours at room temperature. The batch is poured on ice/water, shaken with ether, the organic phase is washed briefly with 1 n sodium hydroxide solution, dried with sodium sulfate and concentrated by evaporation. The crude product is distilled at 130°-140° C./0.1 mbar in a bulb tube and 11.2 g of 4-(2-formylphenoxy)-butyric acid ethyl ester is thus obtained as a colorless oil.
Reaction SMILES: OC=[C:3]([C:13]1[O:17][N:16]=[C:15]([CH3:18])[CH:14]=1)[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=CN=1)=[O:5].[N:19]1C=CC=C[C:20]=1NC(=O)CC1ON=C(C)C=1.[H-].[Na+].C(OCC)=O>C1COCC1.[OH-].[Na+]>[N:19]1[CH:10]=[CH:11][CH:12]=[C:7]([NH:6][C:4](=[O:5])[CH2:3][C:13]2[O:17][N:16]=[C:15]([CH3:18])[CH:14]=2)[CH:20]=1
Reactant: Cc1cc(C(=CO)C(=O)Nc2ccccn2)on1
Reactant: Cc1cc(CC(=O)Nc2ccccn2)on1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC=O
Solvent: C1CCOC1
Product: Cc1cc(CC(=O)Nc2cccnc2)on1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
General method for the synthesis of α-hydroxymethylene-3-methyl-N-pyridyl-5-isoxazoleacetamide: A solution of N-pyridyl-3-methyl-5-isoxazoleacetamide (1.1 g, 5 mmol) in THF (20 mL) was slowly added to a suspension of NaH (60% in oil; 0.5 g, 12.5 mmol) in 10 mL of THF. The reaction mixture was stirred at rt for 30 mins. and then ethyl formate (2 mL, 25 mmol) was added. After stirring at rt overnight, the reaction was conc. in vacuo and the residue was dissolved in 100 mL of a 1N aqueous NaOH solution and extracted with 25 mL of EtOAc. The aqueous layer was separated and brought to pH 5-6 with the addition of an aqueous 6N HCl solution. The resulting light yellow precipitate was collected and washed with cold water, affording the desired product.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([O:9][C:10]([C:12]1[C:21](=[O:22])[C:20]2[C:15](=[C:16](F)[CH:17]=[C:18]([I:23])[CH:19]=2)[N:14]([N:25]([CH2:27][CH:28]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH3:26])[CH:13]=1)=[O:11])[CH3:8]>CS(C)=O.O.C(O)(=O)C>[I:23][C:18]1[CH:17]=[C:16]2[C:15]3=[C:20]([C:21](=[O:22])[C:12]([C:10]([O:9][CH2:7][CH3:8])=[O:11])=[CH:13][N:14]3[N:25]([CH3:26])[CH2:27][C:28]2([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:19]=1
Reactant: CCOC(=O)c1cn(N(C)CC(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2c(F)cc(I)cc2c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1cn2c3c(cc(I)cc3c1=O)C(C(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)CN2C
Temperature: 85 °C
Yield: 75 %

Procedure:
Cesium carbonate (0.367 g) is added to a solution of di(tert-butyl) 2-(((3-(ethoxycarbonyl)-8-fluoro-6-iodo-4-oxoquinolin-1(4H)-yl)(methyl)amino)methyl)malonate (Preparation 37, 0.517 g) in dimethylsulfoxide (5 mL) and the mixture is heated at 85° C. in an oil bath under a nitrogen atmosphere for 2 h. The mixture is cooled in an ice bath, diluted with 65 mL of water containing 2.5 mL of acetic acid, stirred, and the resultant yellow precipitate collected and dried in a vacuum oven to provide the title compound in 75% yield as a golden oil. Physical characteristics: 1H NMR (CDCl3) δ8.79, 8.54, 8.29, 4.40, 4.16, 2.78, 1.51, 1.41; MS (ESI+) m/z 599 (M+H)+; TLC (silica gel GF): Rf=0.59 acetone/CH2Cl2 (1/4).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([CH:27]=1)[CH2:7][C@@H:8]([CH2:12][NH:13][CH2:14][C:15]1[C:20]([O:21][CH3:22])=[CH:19][C:18]([O:23][CH3:24])=[CH:17][C:16]=1[O:25][CH3:26])[C:9]([OH:11])=O.Cl.C([O:33][C:34](=[O:37])[CH2:35][NH2:36])C.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(#N)C.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([CH:27]=1)[CH2:7][C@@H:8]([CH2:12][NH:13][CH2:14][C:15]1[C:16]([O:25][CH3:26])=[CH:17][C:18]([O:23][CH3:24])=[CH:19][C:20]=1[O:21][CH3:22])[C:9]([NH:36][CH2:35][C:34]([OH:37])=[O:33])=[O:11]
Reactant: CCOC(=O)CN
Reactant: COc1cc(OC)c(CNC[C@H](Cc2cc(Cl)ccc2OC)C(=O)O)c(OC)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1cc(OC)c(CNC[C@H](Cc2cc(Cl)ccc2OC)C(=O)NCC(=O)O)c(OC)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of (2S)-2-(5-chloro-2-methoxybenzyl)-3-[(2,4,6-trimethoxybenzyl)amino]propionic acid (1g) in acetonitrile (10 ml), glycine ethyl ester hydrochloride (345 mg), 1-hydroxy benzotriazole (478 mg), and triethylamine (0.35 ml) were added at room temperature, and the mixture was stirred at room temperature for 40 minutes. At room temperature, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (678 mg) was added to the reaction solution, and the mixture was stirred for 3 hours. The reaction solution was concentrated in vacuo, and ethyl acetate was added to the obtained residue. Then the mixture was washed with saturated aqueous sodium bicarbonate and saturated brine, an the organic layer was concentrated. To the obtained residue, isopropyl alcohol (5 ml) and 5N aqueous sodium hydroxide solution were added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was adjusted with 5N hydrochloric acid to pH 5, then the precipitated crystals were obtained by filtration and dried to obtain the title compound (978 mg) as a colorless crystal. The various types of spectral data match with those of Example 326.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=2)[N:5]=[C:4]2[N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:16]=[CH:17][C:3]=12.Cl.[CH:25]12[O:32][CH:29]([CH2:30][CH2:31]1)[CH2:28][NH:27][CH2:26]2.C(N(CC)CC)C>C(O)C>[CH:29]12[O:32][CH:25]([CH2:31][CH2:30]1)[CH2:26][N:27]([C:2]1[N:7]=[C:6]([C:8]3[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=3)[N:5]=[C:4]3[N:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:16]=[CH:17][C:3]=13)[CH2:28]2
Reactant: C1CC2CNCC1O2
Reactant: Oc1cccc(-c2nc(Br)c3cnn(-c4ccccc4)c3n2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Oc1cccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(-c4ccccc4)c3n2)c1
Temperature: 180 °C

Procedure:
A Smith process vial was charged with a suspension of 3-(4-bromo-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenol (0.15 g, 0.41 mmol) and 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (approximately 1 mmol) in ethanol (5 mL). The suspension was treated with triethylamine (500 μL, 3.8 mmol) and was then heated in the microwave reactor for 10 minutes at 180° C. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by reverse-phase high performance liquid chromatography using a Phenomenex Prodigy 21 mm×250 mm column, running a gradient elution of 15% acetonitrile/88% of 0.1% aqueous trifluoroacetic acid to 100% acetonitrile to provide 3-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenol. MS (ES+): 400.1 (M+H)+
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8](=[O:23])[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:6][CH:7]=1.[CH2:24]([S:31][Sn](C)(C)C)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[C:36]1(C)C=CC=CC=1>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.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>[CH2:24]([S:31][C:2]1[CH:3]=[C:4]([C:8](=[O:23])[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:36])=[O:13])[CH:5]=[CH:6][CH:7]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)CCC(C(=O)c1cccc(I)c1)c1ccccc1C
Reactant: Cc1ccccc1
Reactant: C[Sn](C)(C)SCc1ccccc1
Agent: Cl[Pd]Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)CCC(C(=O)c1cccc(SCc2ccccc2)c1)c1ccccc1C

Procedure:
A mixture of methyl (RS)-5-(3-iodophenyl)-4-(2-methylphenyl)-5-oxopentanoate (1.7 g), bis(triphenylphosphine)palladium (II) chloride (0.1 g), tetrakis(triphenylphosphine)palladium (0) (0.13 g) and benzylthiotrimethylstannane (1.17 g) in toluene (37 mL) is heated at reflux for 24 hours. The reaction mixture is washed twice with 10% aqueous potassium fluoride (20 mL), with water (20 mL), dried over magnesium sulphate and evaporated. The residue (2.87 g) is purified by flash chromatography on silica eluting with a mixture of pentane and ethyl acetate (98:2 v/v). Fractions homogeneous in the required product are combined and evaporated to give ethyl (RS)-5-(3-benzylthiophenyl)-4-(2-methylphenyl)-5-oxopentanoate as an orange oil (0.57 g).
Reaction SMILES: [C:1]([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:32]=2[N:33]=[CH:34][N:35]=1)[C@@H:15]1[O:31][C@H:28]([CH2:29][OH:30])[C@@H:26]([OH:27])[C@H:16]1[O:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]1[O:24][CH3:25])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC([C:44](Cl)([C:51]2[CH:56]=[CH:55][C:54](OC)=[CH:53][CH:52]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=CC=1.[C:60](=[O:63])(O)[O-].[Na+]>N1C=CC=CC=1>[C:1]([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:32]=2[N:33]=[CH:34][N:35]=1)[C@@H:15]1[O:31][C@H:28]([CH2:29][O:30][C:44]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([O:17][CH3:16])[C:19]=2[O:63][CH3:60])[C@@H:26]([OH:27])[C@H:16]1[O:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]1[O:24][CH3:25])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: O=C([O-])O
Reactant: CO[C@@H]1CCCC[C@H]1O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(NC(=O)c3ccccc3)ncnc21
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1cccc(C(OC[C@H]2O[C@@H](n3cnc4c(NC(=O)c5ccccc5)ncnc43)[C@H](O[C@@H]3CCCC[C@H]3OC)[C@@H]2O)(c2ccccc2)c2ccccc2)c1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of N6-benzoyl-2′-O-(trans-2-methoxycyclohexyl)adenosine (0.285 mol) in pyridine (100 mL) is evaporated under reduced pressure to an oil. The residue is redissolved in dry pyridine (300 mL) and 4,4′-dimethoxytriphenylmethyl chloride (DMT-Cl, 10.9 g, 95%, 0.31 mol) added. The mixture is stirred at 25° C. for 16 h and then poured onto a solution of sodium bicarbonate (20 g) in ice water (500 mL). The product is extracted with ethyl acetate (2×150 mL). The organic layer is washed with brine (50 mL), dried over sodium sulfate (powdered) and evaporated under reduced pressure (below 40° C.). The residue is chromato-graphed on silica gel (400 g, ethyl acetate-hexane 1:1. Selected fractions were combined, concentrated under reduced pressure and dried at 25° C./0.2 mmHg to give the title compound.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:8]=[C:7](C(Cl)(Cl)Cl)[O:6][N:5]=1)[CH3:3].[NH:13]1[CH2:18][CH2:17][CH:16]([C@H:19]([OH:21])[CH3:20])[CH2:15][CH2:14]1.[OH-].[Na+]>CO>[CH3:1][CH:2]([C:4]1[N:8]=[C:7]([N:13]2[CH2:18][CH2:17][CH:16]([C@H:19]([OH:21])[CH3:20])[CH2:15][CH2:14]2)[O:6][N:5]=1)[CH3:3]
Reactant: C[C@@H](O)C1CCNCC1
Reactant: CC(C)c1noc(C(Cl)(Cl)Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)c1noc(N2CCC([C@@H](C)O)CC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.3 %

Procedure:
A solution of 3-(1-methylethyl)-5-(trichloromethyl)-1,2,4-oxadiazole (25.8 g, 112 mmol) and (1R)-1-(4-piperidinyl)ethanol (13.4 g, 104 mmol) in MeOH (15 mL) was stirred at ambient temperature under a stream of nitrogen for 7 days. The reaction was diluted with MeOH (40 mL), cooled in an ice bath and 1N NaOH (25 mL) was added. The mixture was allowed to warm to ambient temperature and stir for 1 h. The reaction was partitioned in EtOAc (300 mL)/1N NaOH (75 mL) and the layers were separated. The aqueous layer was saturated with NaCl and extracted with EtOAc (200 mL). The combined EtOAc layers were dried over MgSO4, concentrated and placed under high vacuum for 18 h to afford (1R)-1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethanol (16.75 g, 68%) as an orange oil. 1H NMR (400 MHz, CDCl3): δ 4.14 (m, 2H), 3.57 (quint, 1H, J=6.3 Hz), 2.98 (m, 2H), 2.83 (septet, 1H, J=7.0 Hz), 1.90 (m, 1H), 1.86 (br, 1H), 1.67 (m, 1H), 1.45 (m, 1H), 1.33 (m, 2H), 1.23 (d, 6H, J=7.0 Hz), 1.16 (d, 3H, J=6.3 Hz); LRMS (ESI), m/z 240 (M+H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])[CH:2]=C.[O:14]=[O+][O-]>C(Cl)Cl>[O:14]=[CH:2][CH2:1][O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9]
Reactant: C=CCOc1cccc(C(=O)O)c1
Reactant: O=[O+][O-]
Solvent: ClCCl
Product: O=CCOc1cccc(C(=O)O)c1
Yield: 93 %

Procedure:
A solution of 300 mg (1.68 mmol) of 3-(2-propenyloxy)benzoic acid in 5 mL of methylene chloride is cooled to -78° C. Ozone is introduced by bubbling the gas into the solution through a glass tube until a blue color persists. The solution is then purged with a stream of argon and 1 mL of methyl sulfide is added. The solution is diluted with 20 mL of ether and washed with water. The organic layer is separated and allowed to stand over magnesium sulfate then concentrated in vacuo to give 283 mg (93%) of 3-(2-oxoethoxy)benzoic acid as a colorless oil. The product is utilized in the next reaction without further purification: m.p. 120°-130°; the 1H NMR (300 MHz, CDCl3) is consistent with the desired product; IR (KBr) 3400, 3000, 1680, 1590 cm-1 ; MS (CI low res) m/e 181 (M+H), 163, 139, 119.