Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH:7]=[CH2:8])[CH:2]1[O:4][CH2:3]1.[CH3:9][SiH:10]1[O:17][SiH:16]([CH3:18])[O:15][SiH:14]([CH3:19])[O:13][SiH:12]([CH3:20])[O:11]1>COCCOCCOC.[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[O:4]1[CH2:3][CH:2]1[CH2:1][O:5][CH2:6][CH2:7][CH2:8][Si:16]1([CH3:18])[O:17][Si:10]([CH2:8][CH2:7][CH2:6][O:5][CH2:1][CH:2]2[O:4][CH2:3]2)([CH3:9])[O:11][Si:12]([CH2:8][CH2:7][CH2:6][O:5][CH2:1][CH:2]2[O:4][CH2:3]2)([CH3:20])[O:13][Si:14]([CH2:8][CH2:7][CH2:6][O:5][CH2:1][CH:2]2[O:4][CH2:3]2)([CH3:19])[O:15]1
Reactant: C=CCOCC1CO1
Reactant: C[SiH]1O[SiH](C)O[SiH](C)O[SiH](C)O1
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: COCCOCCOC
Product: C[Si]1(CCCOCC2CO2)O[Si](C)(CCCOCC2CO2)O[Si](C)(CCCOCC2CO2)O[Si](C)(CCCOCC2CO2)O1
Temperature: 100 °C

Procedure:
Allyl glycidyl ether (57.1 g, 0.5 moles) was added to a 250 mL 3-neck flask, equipped with a stirrer, dropping funnel, internal thermometer and condenser, and heated to 100° C. After the addition of 1 mL of a 1 weight percent solution of hexachloroplatinic acid in diethylene glycol dimethyl ether, 24.0 g (0.1 moles) of 2,4,6,8-tetramethylcyclotetrasiloxane were added very rapidly with vigorous stirring, the internal temperature rising to 195° C. After the addition of 2,4,6,8-tetramethylcyclotetrasiloxane, stirring was continued until the temperature of the reaction product had dropped to 130° C. Unreacted portions of the allyl glycidyl ether and 2,4,6,8-tetramethylcyclotetrasiloxane were removed by stirring the reaction mixture at 60°-70° C. at a vacuum of 0.1 hPa, produced by an oil pump. The slightly yellowish crude product (77.8%), nD20 : 1.4633, was subjected to a fractional vacuum distillation using a packed column. The compound (21) distilled at about 335° C. and 1 hPa as a clear, viscous liquid, the greater portion polymerizing. nD20 : 1,4668.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=O)[CH2:7][O:8]2)=[CH:4][CH:3]=1.O.NN>C(O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][CH2:7][O:8][C:9]=2[CH:10]=1
Reactant: O=C1COc2cc(O)ccc21
Agent: NN
Solvent: O
Solvent: CCO
Product: Oc1ccc2c(c1)OCC2
Reaction time: 1.5 h

Procedure:
6-hydroxycoumaran-3-one (15 g) was suspended in ethanol (75 ml) and hydrazine hydrate (10 ml, 90%) was added and the mixture heated at reflux for 1 hour. The solvent was evaporated and a solution of potassium hydroxide (15 g) in ethylene glycol (100 ml) was added to the residue. The resulting mixture was distilled with stirring until the internal temperature reached 185°-190° C. This temperature was maintained until no more nitrogen was evolved, approximately 1.5 hours. After cooling, the mixture was added to dilute hydrochloric acid containing sufficient acid to make the mixture acidic. This acidified mixture was then extracted with ether, dried and distilled (110°-120° C./0.75 mm) to give 6-hydroxy-2,3-dihydrobenzofuran.
Reaction SMILES: [NH2:1]OS(=O)(=O)O.C(=O)([O-])O.[Na+].[CH:12]1([CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]#[C:24][C:25]3[CH:42]=[CH:41][C:28]([O:29][CH2:30][C@@H:31]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH3:32])=[CH:27][CH:26]=3)=[N:21][CH:22]=2)[CH2:14][CH2:13]1>O.CO>[CH:12]1([CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]3[N:21]([N:1]=[C:24]([C:25]4[CH:42]=[CH:41][C:28]([O:29][CH2:30][C@@H:31]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:37])([CH3:38])[CH3:39])[CH3:32])=[CH:27][CH:26]=4)[CH:23]=3)[CH:22]=2)[CH2:14][CH2:13]1
Reactant: NOS(=O)(=O)O
Reactant: C[C@@H](COc1ccc(C#Cc2ccc(OCC3CC3)cn2)cc1)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C[C@@H](COc1ccc(-c2cc3ccc(OCC4CC4)cn3n2)cc1)NC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 15.3 %

Procedure:
(Aminooxy)(hydroxy)sulfane dioxide (679 mg) was dissolved in water (3 mL), and saturated aqueous sodium hydrogen carbonate solution was added dropwise thereto at 0° C. to neutralize the solution. To the obtained mixture was added a solution of tert-butyl [(1S)-2-(4-{[5-(cyclopropylmethoxy)pyridin-2-yl]ethynyl}phenoxy)-1-methylethyl]carbamate (845 mg) in methanol (5 mL) at room temperature, and the mixture was stirred at 60° C. overnight, and concentrated under reduced pressure. To the residue were added DMF (8 mL) and potassium carbonate (829 mg), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate and water, and the aqueous layer was separated from the organic layer. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a colorless solid (134 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:18][CH3:19])[C:12]=2[O:16][CH3:17])[C:7]1=O)=[O:4].Cl.OC1C(O)=CC=C2C=1CCC(NC)C2>CO.[Pd]>[CH3:1][O:2][C:3]([NH:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:18][CH3:19])[C:12]=2[O:16][CH3:17])[CH2:7]1)=[O:4]
Reactant: COC(=O)NC1CCc2c(ccc(OC)c2OC)C1=O
Agent: [Pd]
Agent: CNC1CCc2c(ccc(O)c2O)C1
Agent: Cl
Solvent: CO
Product: COC(=O)NC1CCc2c(ccc(OC)c2OC)C1
Temperature: 30 °C

Procedure:
50 g of 2-methoxycarbonylamino-5,6-dimethoxy-1-tetralone are dissolved in 500 ml of methanol in a 1000 ml flask, with stirring, 20 g of 5% Pd/C are added, then the whole is placed into an autoclave (Hastelloy) under hydrogen atmosphere at 80° C. and a pressure of 25 atm. for about 6 hours with stirring, after that the mixture is left to cool to about 30° C. in autoclave. The mixture is filtered through Celite and the filtrate is evaporated to dryness under vacuum. The resulting white solid is triturated in 400 ml of n-hexane at 60° C., then is left to cool to about 30° C. with stirring, filtered and dried under vacuum at 60 ° C., to obtain a whitish solid. Yield: 40.6 g, 85.5% (moles), 81.2% (weight); T.L.C. Methylene chloride 95-Methanol 5; Rf=0.76; M.p.=108.7°-111.4 ° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]([CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[CH:15]=[CH:14][N:13]=2)[CH:5]=1.[CH3:31][C@H:32]1[CH2:37][CH2:36][C@H:35](O)[CH2:34][CH2:33]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O.C1COCC1>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]([CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C@H:35]4[CH2:36][CH2:37][C@@H:32]([CH3:31])[CH2:33][CH2:34]4)=[CH:20][CH:19]=3)[CH:15]=[CH:14][N:13]=2)[CH:5]=1
Reactant: COC(=O)c1cccc(CN(c2nccc(-c3ccc(O)cc3)n2)C2CCCC2)c1
Reactant: C[C@H]1CC[C@H](O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cccc(CN(c2nccc(-c3ccc(O[C@H]4CC[C@@H](C)CC4)cc3)n2)C2CCCC2)c1
Temperature: 25 °C

Procedure:
To a THF (2 mL) solution of 3-({cyclopentyl-[4-(4-hydroxy-phenyl)-pyrimidin-2-yl]-amino}-methyl)-benzoic acid methyl ester (44 mg, 0.11 mmol) was added trans-4-methyl-cyclohexanol (12.5 mg, 0.11 mmol) and triphenylphosphine (27 mg, 0.11 mmol). After the mixture was cooled 5 min. in an ice bath, diisopropyl azodicarboxylate (DIAD, 21.5 μL, 0.11 mmol) was added. The solution was stirred at room temperature until complete. Water was added, and the mixture was extracted with ethyl acetate (3×2 mL). The ethyl acetate layer was dried over Na2SO4 and concentrated. Purification was carried out by silica gel chromatography eluting with hexanes/ethyl acetate 9:1 then 4:1 to give 16 mg (30%) of 3-[(cyclopentyl-{4-[4-(cis-4-methyl-cyclohexyloxy)-phenyl]-pyrimidin-2-yl}-amino)-methyl]-benzoic acid methyl ester. LCMS m/z: 501 (M+1)+.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][CH2:5][N:6]1[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:17]=2[CH3:18])[C:9](=[O:19])[NH:8][C:7]1=[O:20]>C1COCC1>[CH3:18][C:17]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[C:10]1[C:9](=[O:19])[NH:8][C:7](=[O:20])[N:6]([CH2:5][CH2:4][CH:3]=[O:2])[CH:11]=1
Reactant: COC(CCn1cc(-c2cnccc2C)c(=O)[nH]c1=O)OC
Solvent: C1CCOC1
Product: Cc1ccncc1-c1cn(CCC=O)c(=O)[nH]c1=O
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
1-(3,3-Dimethoxy-propyl)-5-(4-methyl-pyridin-3-yl)-1H-pyrimidine-2,4-dione (Pre112, 100 mg, 0.32 mmol) was dissolved in THF (5 ml) and 1N HClaq (327 μl) was added. The solution was then stirred at 40° C. for 1.5 hours. TEA (45 μl) was added and the solvent was carefully removed in vacuum at room temperature. Residue was freeze dried to give the title compound that was used in the next step without further purification (quantitative yield).
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH:3]=[CH:2]1.[CH:7]([Si:10]([CH:15]([CH3:17])[CH3:16])([CH:12]([CH3:14])[CH3:13])Cl)([CH3:9])[CH3:8].N1C=CN=C1>CN(C=O)C.C(OC(=O)C)C>[CH:1]1([O:6][Si:10]([CH:15]([CH3:17])[CH3:16])([CH:12]([CH3:14])[CH3:13])[CH:7]([CH3:9])[CH3:8])[CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: OC1C=CCC1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)[Si](OC1C=CCC1)(C(C)C)C(C)C

Procedure:
A solution of 2-cyclopentenol (K. Alder, F. H. Flock, Chem. Ber. 1956, 89, 1732.) (2.31 g, 27.5 mmol), (triisopropyl)chlorsilane (5.30 g, 5.9 mL, 27.5 mmol), imidazole (2.06 g, 30.2 mmol) in DMF (50 mL) was stirred at room temperature for 3h and for an additional hour at 50° C. Then the solution was diluted with ethylacetate, washed 4 times with water and dried over sodium sulfate. Evaporation of the solvent yielded in 6.32 g (96%) of the silylether 513/13 as a colourless liquid. No major impurities were visible in the 1H-NMR-spectrum.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12](=[O:14])[CH3:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Br:15]CC(C1C=C(C(F)(F)F)C=C(Cl)C=1)=O>>[Br:15][CH2:13][C:12]([C:4]1[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=[C:2]([Br:1])[CH:3]=1)=[O:14]
Reactant: CC(=O)c1cc(Br)cc(C(F)(F)F)c1
Reactant: O=C(CBr)c1cc(Cl)cc(C(F)(F)F)c1
Product: O=C(CBr)c1cc(Br)cc(C(F)(F)F)c1
Yield: 99 %

Procedure:
The title compound was prepared from 1-(3-bromo-5-(trifluoromethyl)phenyl)ethanone (Reference Example 41) by a procedure similar to the one described for 2-bromo-1-(3-chloro-5-(trifluoromethyl)phenyl)ethanone (Reference Example 34) to provide 2-bromo-1-(3-bromo-5-(trifluoromethyl)phenyl)ethanone (23.17 g, >99%) as a yellow oil.
Reaction SMILES: O[CH:2]1[O:26][C:10]2=[CH:11][C:12]([O:14][CH:15]([CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:16])=[CH:13][C:8]3=[C:9]2[CH:4]([CH2:5][C:6]([CH3:28])([CH3:27])[O:7]3)[CH2:3]1.C(O)C.[CH3:32][O:33][NH2:34]>N1C=CC=CC=1>[CH3:32][O:33][NH:34][CH:2]1[O:26][C:10]2=[CH:11][C:12]([O:14][CH:15]([CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:16])=[CH:13][C:8]3=[C:9]2[CH:4]([CH2:5][C:6]([CH3:27])([CH3:28])[O:7]3)[CH2:3]1
Reactant: CON
Reactant: CC(CCCc1ccccc1)Oc1cc2c3c(c1)OC(C)(C)CC3CC(O)O2
Solvent: CCO
Solvent: c1ccncc1
Product: CONC1CC2CC(C)(C)Oc3cc(OC(C)CCCc4ccccc4)cc(c32)O1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 102.6 %

Procedure:
In a stirred flask, under nitrogen, was placed (0.045 mole) 2-hydroxy-5,5-dimethyl-8-(5-phenyl-2-pentyloxy)-3,3a,4,5-tetrahydro-2H-pyrano[4,3,2-de]benzopyran, 250 ml ethanol and 250 ml pyridine. The solution was cooled to 0° C. and 3.94 g (0.047 mole) methoxyamine was added. The resulting mixture was stirred at 0° C. for 2.5 hours, the solvent evaporated in vacuo, the residue taken up in 500 ml ethyl ether and washed twice with water. The aqueous phase was backwashed with ether and the combined ether layers washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo to obtain 19 g of residual oil. The structure of the product was verified by 1H-NMR. Mass spectrum (m/e): 411 (M+), 380 (M-OCH3), 364 (M-NH2OCH3).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([O:11]C1C3C(=CC(OCC4CCNCC4)=CC=3)N=CN=1)=[CH:6][CH:5]=2.C(OC([N:37]1[CH2:42][CH2:41][CH:40]([CH2:43][CH2:44][O:45][C:46]2[CH:55]=[C:54]3[C:49]([C:50](OC4C=C5C(=CC=4)NC(C)=C5)=[N:51][CH:52]=[N:53]3)=[CH:48][C:47]=2[O:67][CH3:68])[CH2:39][CH2:38]1)=O)(C)(C)C>>[CH3:68][O:67][C:47]1[CH:48]=[C:49]2[C:54](=[CH:55][C:46]=1[O:45][CH2:44][CH2:43][CH:40]1[CH2:39][CH2:38][NH:37][CH2:42][CH2:41]1)[N:53]=[C:52]([O:11][C:7]1[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=1)[NH:3][C:2]([CH3:1])=[CH:10]3)[N:51]=[CH:50]2
Reactant: Cc1cc2cc(Oc3ncnc4cc(OCC5CCNCC5)ccc34)ccc2[nH]1
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCC1CCN(C(=O)OC(C)(C)C)CC1
Product: COc1cc2cnc(Oc3ccc4[nH]c(C)cc4c3)nc2cc1OCCC1CCNCC1
Yield: 87 %

Procedure:
Using an analogous procedure to that described for the synthesis of 4-(2-methylindol-5-yloxy)-7-(piperidin-4-ylmethoxy)quinazoline, (prepared as described in Example 122), 7-(2-(1-tert-butoxycarbonylpiperidin-4-yl)ethoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (400 mg, 0.75 mmol), (prepared as described in Example 126), was used to give 6-methoxy (2-methylindol-5yloxy)-7-(2-(piperidin-4-yl)ethoxy)quinazoline (284 mg, 87%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]([CH2:34][CH:35]([CH3:37])[CH3:36])[C@H:13]1[CH2:18][C@@H:17]([C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[CH2:16][N:15]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:14]1)=[O:11].[CH2:38](O)[CH2:39][CH2:40][OH:41].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.C1COCC1.C(=O)(O)[O-].[Na+]>[OH:41][CH2:40][CH2:39][CH2:38][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]([CH2:34][CH:35]([CH3:37])[CH3:36])[C@H:13]1[CH2:18][C@@H:17]([C:19]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[O:20])[CH2:16][N:15]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH2:14]1)=[O:11]
Reactant: OCCCO
Reactant: CC(C)CN(C(=O)c1nc2ccccc2[nH]1)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)CN(C(=O)c1nc2ccccc2n1CCCO)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Reaction time: 15 h

Procedure:
To a mixed solution of tert-butyl (3S,5R)-3-[(1H-benzimidazol-2-ylcarbonyl)(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (103 mg), propane-1,3-diol (152 mg) and triphenylphosphine (105 mg) in toluene (5 ml) and THF (5 ml) was added diisopropyl azodicarboxylate (202 μl) at room temperature, and the mixture was stirred at the same temperature for 15 hr. The reaction mixture was diluted with aqueous sodium bicarbonate, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give tert-butyl (3S,5R)-3-[{[1-(3-hydroxypropyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate. The obtained tert-butyl (3S,5R)-3-[{[1-(3-hydroxypropyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate was dissolved in 10-20% hydrogen chloride-methanol (3 ml), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated to give the object product (22 mg).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][CH:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5]1.[Br:15][C:16]1[CH:17]=[CH:18][C:19](F)=[N:20][CH:21]=1>CN(C=O)C.C([O-])(O)=O.[Na+]>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([O:3][CH:4]2[CH2:5][CH2:6][CH:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:8][CH2:9]2)=[N:20][CH:21]=1
Reactant: Fc1ccc(Br)cn1
Reactant: CCOC(=O)C1CCC(O)CC1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCC(Oc2ccc(Br)cn2)CC1
Temperature: 80 °C

Procedure:
NaH (0.250 g, 6.25 mmol) was added to a mixture of ethyl 4-hydroxycyclohexanoate (0.916 ml, 5.68 mmol), and 5-bromo-2-fluoropyridine (0.585 mL, 5.68 mmol) in DMF (15 mL) at room temperature under an Argon atmosphere. The reaction mixture was heated to 80° C. for 2.5 hours. Upon cooling, the reaction mixture was diluted with saturated NaHCO3 (50 mL), and extracted with ethyl acetate (50 mL) and diethyl ether (50 mL). The organic layer was washed with water, brine, dried over sodium sulfate, filtered, concentrated in vacuo and purified by silica gel chromatography (hexanes/ethyl Acetate) to afford ethyl 4-[(5-bromopyridin-2-yl)oxy]cyclohexanecarboxylate. MS ESI calc'd. for C14H19BrNO3 [M+H]+ 328 and 330. found 328 and 330.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4](Cl)[N:3]=1.[NH2:15][C:16]1[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=1.CCN(C(C)C)C(C)C>C(O)CCC.C(OCC)(=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:15][C:16]2[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=2)[N:3]=1
Reactant: CC(C)n1cnc2c(Cl)nc(Cl)nc21
Reactant: Cn1cc(N)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: CC(C)n1cnc2c(Nc3cnn(C)c3)nc(Cl)nc21
Temperature: 100 °C
Yield: 98 %

Procedure:
2,6-Dichloro-9-isopropyl-9H-purine (1.16 g, 5 mmol), as prepared in step 1 of Example 1, was mixed with 4-amino-1-methylpyrazole (1.02 g, 10 mmol) and DIPEA (1.74 mL, 10 mmol) in nBuOH (33 mL) and was stirred and heated at 100° C. (block temperature) for 1 hr. The reaction was cooled, and the volatiles were removed under vacuum to give a dark residue. Ethyl acetate (120 mL) was added and the mixture was washed with sat. aq. NaHCO3 (3×30 mL), dried over Na2SO4 and evaporated to give a dark residue. This residue was dissolved in ethyl acetate, passed through a thin pad of silica gel, and eluted with 90% ethyl acetate-10% ammonia (7 N in methanol). The eluent was evaporated to afford the title compound as a dark solid (1.43 g, 98% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.41 (br. s., 1 H) 8.38 (s, 1 H) 8.00 (s, 1 H) 7.68 (s, 1 H) 4.71 (quin, J=6.72 Hz, 1 H) 3.84 (s, 3 H) 1.52 (d, J=6.72 Hz, 6 H). m/z (APCI+) for C12H14ClN7 292.1 with Cl isotope pattern (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:14][CH:13]=2)[CH2:9][OH:10])OCC[O:3]1.Cl>O1CCOCC1>[OH:10][CH2:9][CH:8]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:14][CH:13]=1)[CH2:7][C:2](=[O:3])[CH3:1]
Reactant: CCCCCCCCCCCCCCOc1ccc(CC(CO)CC2(C)OCCO2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCCCCCCCCCCCCCOc1ccc(CC(CO)CC(C)=O)cc1
Reaction time: 3 h
Yield: 97 %

Procedure:
A mixture of about 12.0 g of 2-methyl-β-[[4-(tetradecyloxy)phenyl]methyl]-1,3-dioxolane-2-propanol, about 50 ml of about 1N hydrochloric acid and about 300 ml of dioxane was stirred for about 3 hours. The dioxane was then removed, the residue diluted with water and extracted with ether. The ether extract was washed with saturated aqueous sodium bicarbonate, dried and the solvent removed, giving an oil, which crystallized on standing, giving about 10.5 g of the desired title compound.
Reaction SMILES: N#N.[Br:3][C:4]1[CH:5]=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1.[CH2:13](O)[CH2:14][OH:15].COC(OC)OC.C([O-])([O-])=O.[Na+].[Na+]>>[Br:3][C:4]1[CH:5]=[C:6]([C:10]2([CH3:11])[O:15][CH2:14][CH2:13][O:12]2)[CH:7]=[CH:8][CH:9]=1
Reactant: OCCO
Reactant: CC(=O)c1cccc(Br)c1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COC(OC)OC
Product: CC1(c2cccc(Br)c2)OCCO1
Temperature: 95 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-(3-bromo-phenyl)-ethanone (1360 mg, 6.83 mmol) in ethylene glycol (8.00 mL, 143.46 mmol) was treated with trimethylorthoformate (1.50 mL, 13.68 mmol) followed by LiBF4 (131 mg, 1.37 mmol). The reaction mixture was heated at 95° C. for 15 h. Sat. aq. Na2CO3 was added and the mixture was extracted twice with ether and the combined organic extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (20:1 hept-EA) gave the title compound as a pale yellow oil: TLC:rf (10:1 hept-EA)=0.34. LC-MS-conditions 02: tR=1.01 min.
Reaction SMILES: [C:1]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[H-].[Na+].F[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27]>CN(C)C=O.O>[CH3:13][C:12]([O:11][C:1](=[O:10])[CH:2]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27])[C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4])([CH3:15])[CH3:14]
Reactant: Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 29.1 %

Procedure:
A stirred solution of di-tert-butyl malonate (1.5 mL, 6.70 mmol) in N,N-dimethylformamide (15 mL) at 0° C. under argon was treated portionwise over 10 minutes with sodium hydride (276 mg of 60% oil dispersion, 6.90 mmol) and stirred at 0° C. for 15 minutes before allowing to warm to room temperature over 1 hour. A white precipitate was produced. The stirred mixture was cooled to 0° C. and treated with a solution of 4-fluoro-3-nitrotoluene (1.0 g, 6.45 mmol) in N,N-dimethylformamide (2 mL) and a deep purple colour was immediately formed. This mixture was stirred at room temperature for 28 hours then heated at 70° C. for 6 hours. The mixture was cooled, then diluted with water (100 mL) and extracted with Et2O (2×50 mL). The combined extract was washed with water (70 mL), dried (Na2SO4) and concentrated under vacuum. The residue was purified by chromatography on silica gel (40 g) eluting with toluene to afford the title compound as a yellow oil (660 mg, 29%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]([SH:11])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[S:8].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Na].Cl>C(=O)([O-])O.[Na+]>[NH2:1][C:2]1[C:3]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:4]([S:11][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[S:8]
Reactant: BrCc1ccccc1
Reactant: Nc1cc(C(O)=S)cc(S)c1-c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Nc1cc(C(O)=S)cc(SCc2ccccc2)c1-c1ccccc1
Reaction time: 20 h

Procedure:
5-Amino-3-mercapto-4-phenylthiobenzoic acid (1.6 g) is dissolved in 1 N sodium hydrogen carbonate (50 ml), and after addition of benzyl bromide (0.7 ml), the reaction mixture is stirred for 20 hours. The resulting suspension of the sodium salt of the reaction product is adjusted to pH 2 by addition of 4 N hydrochloric acid. The precipitated 5-amino-3-benzylthio-4-phenylthiobenzoic acid is collected by filtration and recrystallized from aqueous ethanol to yield the compound with a melting point of 170.5°-172° C.