Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1[CH:11]=[CH:10][C:9]2[NH:8][CH2:7][CH:6]3[CH2:12][CH:13]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[CH2:14][C:4]=1[C:5]=23)#N.[CH3:22][Mg]Br.[NH4+].[Cl-].C([O:29][CH2:30][CH3:31])C>C1C=CC=CC=1>[C:30]([C:31]1[CH:11]=[CH:10][C:9]2[NH:8][CH2:7][C@@H:6]3[CH2:12][C@H:13]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[CH2:14][C:4]=1[C:5]=23)(=[O:29])[CH3:22]
Reactant: CCOCC
Reactant: CCCN(CCC)C1Cc2c(C#N)ccc3c2C(CN3)C1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccccc1
Product: CCCN(CCC)[C@@H]1Cc2c(C(C)=O)ccc3c2[C@H](CN3)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 0.5 g (1.8 mmol) of 6-cyano-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole prepared as in Example 2 in 75 mL of benzene was treated with 5 mL of 2.0M methylmagnesium bromide in diethyl ether. The reaction mixture was refluxed for 2 days. The reaction mixture was cooled and excess Grignard reagent was decomposed with addition of saturated aqueous NH4Cl solution. The benzene layer was separated and washed once with saturated aqueous NaCl solution. The organic solution was evaporated to an oil. The oil was dissolved in 25 mL of 5N HCl and the solution was stirred at room temperature for 30 minutes. The acidic solution was made alkaline with the addition of excess concentrated aqueous NH4OH solution. The basic mixture was extracted twice with CH2Cl2. The combined organic solution was washed once with saturated aqueous NaCl solution and dried over MgSO4. The CH2Cl2 solution was evaporated to yield 0.5 g of an oil. Chromatography of this oil over silica gel with ethyl acetate as eluent gave 0.4 g (75%) of product as an oil, which upon standing solidified, m.p. 76°-77° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[ClH:44]>CN(C)C=O>[ClH:44].[O:20]1[CH2:21][CH2:22][N:17]([C:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:16])[CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(C1CCNCC1)N1CCOCC1

Procedure:
A mixture comprising N-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (700 mg), morpholine (319 μL), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (702 mg), 1-hydroxybenzotriazole (495 mg) and N,N-dimethylformamide (9 ml) was stirred at room temperature for 16 hours to undergo reaction, and the resulting compound was acid-treated with hydrochloric acid to obtain 4-(morpholinocarbonyl)piperidine.hydrochloride.
Reaction SMILES: [F:1][C:2]12[CH2:14][CH2:13][CH2:12][CH:11]1[C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:4][C:3]2=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:25])=CC=1>C1COCC1>[F:1][C:2]12[CH2:14][CH2:13][CH2:12][CH:11]1[C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:4][C:3]2=[S:25]
Reactant: O=C1Nc2ccccc2C2CCCC12F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: FC12CCCC1c1ccccc1NC2=S
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 150 mg (0.73 mmol) of 3a-fluoro-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one in 50 ml of THF is mixed with 607 mg (1.5 mmol) of Lawesson's reagent. After 1 hour of stirring at room temperature, the batch is refluxed for 2 hours. Then, the reaction mixture is concentrated by evaporation and the residue is purified by column chromatography on silica gel (eluant: hexane-ethyl acetate): 150 mg of product.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[C:9]1([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C@H:23](/[CH:29]=[CH:30]\[CH3:31])[CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.IC>C1COCC1>[CH3:1][C@@H:24]([C@H:23]([C:20]1[CH:19]=[CH:18][C:17]([O:16][CH2:15][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:22][CH:21]=1)/[CH:29]=[CH:30]\[CH3:31])[C:25]([O:27][CH3:28])=[O:26]
Reactant: CC(C)[N-]C(C)C
Reactant: C/C=C\[C@H](CC(=O)OC)c1ccc(OCc2ccccc2)cc1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: C/C=C\[C@@H](c1ccc(OCc2ccccc2)cc1)[C@H](C)C(=O)OC
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of lithium diisopropylamide (0.2 mL, 2 mmol in heptane/THF/ethylbenzene) in THF (1.0 mL) was slowly added (S,Z)-methyl 3-(4-(benzyloxy)phenyl)hex-4-enoate 41.1 (0.50 g, 2 mmol) in THF (5.0 mL) at −78° C. The resulting mixture was stirred at −78° C. for 1 hour and then iodomethane (0.1 mL, 2 mmol) was added. The reaction mixture was stirred at the same temperature for 20 minutes, and then stirred at room temperature for 16 hours. The solvent was removed in vacuo. The residue was purified by silica gel, eluent with hexane/EtOAc 95/5 to 10/90 to give the title compound as a major product 41.2 in a ratio of 95:5. 1H NMR (400 MHz, CDCl3) δ ppm 1.08 (d, J=7.04 Hz, 3H) 1.46-1.61 (m, 1H) 2.64 (m, 1H) 3.34 (s, 3H) 4.90 (s, 2H) 5.35-5.53 (m, 2H) 6.76-6.84 (m, 2H) 6.97-7.07 (m, 2H) 7.15-7.34 (m, 5H). MS ESI (pos.) m/e: 325.1 (M+H)+. It is possible that the stereochemistry at the carbon atom adjacent to the carbonyl is opposite that shown which would carry through to the final product of this Example. However, it is believed that the structure of 41.2 is as shown above.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]([C:11]1[NH:12][CH:13]=[CH:14][N:15]=1)[CH3:10].N1C=CC=CC=1.[O:22]=[C:23](Cl)[O:24][C:25](Cl)(Cl)Cl.[CH2:30]([O:34][C:35]1[CH:40]=[CH:39][C:38](CO)=[CH:37][CH:36]=1)[CH2:31][CH2:32][CH3:33]>C(#N)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]([C:11]1[N:15]([C:23]([O:24][CH2:25][C:38]2[CH:39]=[CH:40][C:35]([O:34][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:36][CH:37]=2)=[O:22])[CH:14]=[CH:13][N:12]=1)[CH3:10]
Reactant: Cc1cccc([C@H](C)c2ncc[nH]2)c1C
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CCCCOc1ccc(CO)cc1
Solvent: CC#N
Solvent: c1ccncc1
Product: CCCCOc1ccc(COC(=O)n2ccnc2[C@@H](C)c2cccc(C)c2C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of the compound of Example 58 (200 mg, 1.0 mmol) and pyridine (177 μl, 2.2 mmol) in anhydrous acetonitrile (3 ml), at 0° C. and under nitrogen, was added diphosgene (132 μl, 1.1 mmol). The mixture was allowed to warm to room temperature and stirred for 10 min, before addition to (4-butoxyphenyl)methanol (198 mg, 1.1 mmol) via syringe. The reaction mixture was stirred at room temperature for 30 min and filtered.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[Cl:23][C:24]1[CH:25]=[C:26]([N:34]=[C:35]=[O:36])[C:27]([O:32][CH3:33])=[CH:28][C:29]=1[O:30][CH3:31]>C1(C)C=CC=CC=1>[Cl:23][C:24]1[CH:25]=[C:26]([NH:34][C:35]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:21][CH:20]=2)=[O:36])[C:27]([O:32][CH3:33])=[CH:28][C:29]=1[O:30][CH3:31]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: COc1cc(OC)c(N=C=O)cc1Cl
Solvent: Cc1ccccc1
Product: COc1cc(OC)c(NC(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)cc1Cl
Yield: 100.1 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (54 mg) was dissolved in toluene (5 ml) with heat, 3-chloro-4,6-dimethoxyphenyl isocyanate (76 mg) was added, and the admixture was refluxed with heat for 18 minutes. The reaction solution was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 93 mg of the title compound (yield: 100%)
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].[CH2:9](Br)[CH:10]=[CH2:11].[Cl-].[NH4+]>C1COCC1.O>[CH3:7][CH:6]([CH3:8])[CH2:5][CH2:4][CH2:3][CH2:11][CH:10]=[CH2:9]
Reactant: CC(C)CCCBr
Reactant: C=CCBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCCCCC(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
Under a protective gas, 20 g. (0.82 gram atom) of magnesium filings in 150 ml. of tetrahydrofuran is charged into a 1-liter three-necked flask. Within about 60 minutes, 120 g. (0.73 mole) of 1-bromo-4-methylpentane in 270 ml. of tetrahydrofuran is added dropwise to the reaction mixture so that a reaction temperature of 60° C. evolves. The agitation is continued for another 11/2 hours at 50° C. The thus-formed Grignard compound is separated from the unreacted magnesium by means of a glass pipette and transferred into a dropping funnel placed on top of a 2-liter three-necked flask. This flask is to be used for dissolving 84.0 g. (0.7 mole) of allyl bromide in 620 ml. of tetrahydrofuran and for combining this solution with 2.5 millimoles of Li2CuCl4 (as a 0.1-molar solution in THF). Within 60 minutes, the Grignard solution is to be dropped under stirring to this mixture, which latter has been cooled to -10° to -5° C. The reaction mixture is maintained at 0° C. for another 11/2 hours before Grignard compound is gently decomposed with saturated ammonium chloride solution (or about 50 ml. of water). The organic phase is separated, the residue is extracted repeatedly with ether, and the combined, olefin-containing phases are dried over sodium sulfate. After the solvents have been evaporated, 7-methyl-1-octene can be obtained in the pure form by fractionation over a Vigreux attachment or a column:
Reaction SMILES: C(O[C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2)(=O)C.S(=O)(=O)(O)O.[CH2:20]1[O:28][C:27]2[CH:26]=[CH:25][C:24]([Br:29])=[CH:23][C:22]=2[O:21]1.C(=O)(O)[O-].[Na+]>C1CCCCC1.CCCCCCC.O>[C:5]12([C:26]3[CH:25]=[C:24]([Br:29])[CH:23]=[C:22]4[O:21][CH2:20][O:28][C:27]=34)[CH2:6][CH:7]3[CH2:13][CH:11]([CH2:10][CH:9]([CH2:8]3)[CH2:14]1)[CH2:12]2
Reactant: Brc1ccc2c(c1)OCO2
Reactant: CC(=O)OC12CC3CC(CC(C3)C1)C2
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCCCCCC
Solvent: C1CCCCC1
Product: Brc1cc2c(c(C34CC5CC(CC(C5)C3)C4)c1)OCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.82 g (24.9 mmol) of acetoxyadamantane and 0.75 ml (139 mmol) of concentrated sulphuric acid are added to 5 g (24.9 mmol) of 3,4-methylenedioxybromobenzene in 35 ml of cyclohexane and 35 ml of heptane. The reaction medium is stirred at room temperature overnight. This medium is then hydrolyzed with 250 ml of water, neutralized with sodium bicarbonate, extracted with 200 ml of dichloromethane, dried over magnesium sulphate and evaporated, to give 2.89 g (34.8%) of the expected derivative which melts at 134° C.)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:8][N:7]([CH3:9])[CH2:6][CH2:5][C:4]=1[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[C:12]([O:19][CH:20]([CH3:22])[CH3:21])[CH:11]=1>C(O)(=O)C.[Zn]>[CH3:1][O:2][C:3]1[CH2:8][N:7]([CH3:9])[CH2:6][CH2:5][C:4]=1[C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([O:19][CH:20]([CH3:22])[CH3:21])[CH:11]=1
Reactant: COC1=C(c2ccc([N+](=O)[O-])c(OC(C)C)c2)CCN(C)C1
Agent: [Zn]
Solvent: CC(=O)O
Product: COC1=C(c2ccc(N)c(OC(C)C)c2)CCN(C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
747 mg of zinc are added to a solution of 500 mg of 5-methoxy-1-methyl-4-[4-nitro-3-(propan-2-yloxy)phenyl]-1,2,3,6-tetrahydropyridine in 8 ml of acetic acid. The reaction medium is stirred for 1 hour at ambient temperature and then filtered on Clarcel. The Clarcel is rinsed with 8 ml of acetic acid, then 10 ml of ethanol and then of ethyl acetate. The filtrate is evaporated under reduced pressure and then the residue is taken up in 10 ml of ethyl acetate, 5 ml of water and 10 ml of a saturated aqueous sodium bicarbonate solution. 20 ml of ethyl acetate are added and the two phases are separated. The aqueous phase is extracted with ethyl acetate (2×10 ml). The combined organic phases are washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under vacuum. The residue is purified on 25 g of silica, elution being carried out with dichloromethane/acetone (100/0 to 95/5), so as to obtain 140 mg of 4-(5-methoxy-1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(propan-2-yloxy)aniline in the form of a brown oil.
Reaction SMILES: [C:1]([C:9]1[NH:10][CH:11]=[CH:12][CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]([O:22][CH2:23][CH3:24])(=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].[C:25]([O-:28])(=[O:27])[CH3:26].[Na+]>C(O)(=O)C.C(OCC)C.O.O.C([O-])(=O)C.[Mn+3].C([O-])(=O)C.C([O-])(=O)C>[C:1]([C:9]1[NH:10][C:11]([CH2:26][C:25]([O:28][CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:14]([O:22][CH2:23][CH3:24])=[O:21])=[O:27])=[CH:12][CH:13]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1ccc[nH]1
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Mn+3]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC(=O)C(OC(=O)Cc1ccc(C(=O)c2ccccc2)[nH]1)C(=O)OCC
Temperature: 70 °C
Yield: 51.6 %

Procedure:
A mixture of 2-benzoylpyrrole (855 mg, 5 mmol), diethyl malonate (800 mg, 5 mmol), manganese(III) acetate dihydrate (4560 mg, 15 mmol) and sodium acetate (820 mg, 10 mmol) in acetic acid (30 mL) was stirred at 70° C. under a nitrogen atmosphere. The reaction mixture was diluted with diethyl ether and filtered. The filtrate was washed with 10% aqueous sodium hydroxide and saturated aqueous sodium chloride, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with hexane/ethyl acetate (70:30) to provide 1.00 g (57%) of diethyl (5-benzoylpyrrol-2-yl)acetoxy-methanedicarboxylate.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([CH2:16][CH3:17])[N:13]=[C:12]([NH:18][C:19]2[S:20][C:21]([C:24]#[N:25])=[CH:22][N:23]=2)[CH:11]=1)(C(C)(C)C)(C)C.N1C=CC=CC=1.F>C1COCC1>[CH2:16]([C:14]1[N:13]=[C:12]([NH:18][C:19]2[S:20][C:21]([C:24]#[N:25])=[CH:22][N:23]=2)[CH:11]=[C:10]([CH2:9][OH:8])[CH:15]=1)[CH3:17]
Reactant: CCc1cc(CO[Si](C)(C)C(C)(C)C)cc(Nc2ncc(C#N)s2)n1
Agent: F
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCc1cc(CO)cc(Nc2ncc(C#N)s2)n1
Reaction time: 1.5 h

Procedure:
2-{[4-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-6-ethylpyridin-2-yl]amino}-1,3-thiazole-5-carbonitrile (12-2) (0.225 g, 0.60 mmol) was dissolved in 2 mL THF. Hydrogen fluoride-pyridine (Aldrich, HF ˜70%, pyridine ˜30%) (0.060 mL) was added. After 1.5 hours, additional hydrogen fluoride-pyridine (0.50 mL) was added. After 2.5 hours the reaction was concentrated to remove THF and the residue was diluted with 1M aqueous K2CO3. The resulting precipitate was filtered and washed with water to afford the desired compound 12-3 as a yellow solid. 1H NMR (DMSO-d6) δ 12.19 (s, 1H), 8.26 (s, 1H), 6.96 (s, 1H), 6.86 (s, 1H), 4.51 (bs, 2H), 2.79 (q, 2H, J=7.63 Hz), 1.32 (t, 3H, J=7.63 Hz). [M+H]+=261.0816.
Reaction SMILES: [OH:1][CH:2]1[CH2:9][CH2:8][C:5]2([O:7][CH2:6]2)[CH:4]([C:10]2([CH3:18])[CH:12]([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[O:11]2)[CH:3]1[O:19][CH3:20].O1CCC[CH2:22]1.[H-].[Na+].IC>C(OCC)C>[CH3:20][O:19][CH:3]1[CH:2]([O:1][CH3:22])[CH2:9][CH2:8][C:5]2([O:7][CH2:6]2)[CH:4]1[C:10]1([CH3:18])[CH:12]([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[O:11]1
Reactant: C1CCOC1
Reactant: COC1C(O)CCC2(CO2)C1C1(C)OC1CC=C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOCC
Product: COC1CCC2(CO2)C(C2(C)OC2CC=C(C)C)C1OC

Procedure:
To a solution of 6-hydroxy-5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl) oxiranyl]-1-oxaspiro[2,5]octane (14.1 mg) in freshly distilled tetrahydrofuran (0.5 ml) was added sodium hydride (60% oil dispersion, 2.0 mg) in one portion in an ice bath. The suspension was stirred for half an hour at the same temperature and thereto iodomethane (71 mg) was added. After stirring for 2 hours at ambient temperature, the mixture was diluted with diethyl ether and washed with water. The organic layer was dried and evaporated to give a crude oil which was purified by column chromatography on silica gel eluted by a mixture of diethyl ether and n-hexane (1:2) to yield 5,6-dimethoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]octane (14.2 mg) as an oil.
Reaction SMILES: CS(C)=O.Cl[C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14]#[C:15][CH3:16])[N:9]=[CH:8][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH:23]([NH2:26])([CH3:25])[CH3:24]>COC(C)(C)C>[CH2:13]([O:12][C:10]1[CH:11]=[C:6]([NH:26][CH:23]([CH3:25])[CH3:24])[N:7]=[CH:8][N:9]=1)[C:14]#[C:15][CH3:16]
Reactant: CC#CCOc1cc(Cl)ncn1
Reactant: CC(C)N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CS(C)=O
Product: CC#CCOc1cc(NC(C)C)ncn1
Temperature: 70 °C
Reaction time: 6 h
Yield: 82.6 %

Procedure:
To 4 ml of dimethylsulfoxide were added 365 mg of 4-chloro-6-(2-butynyloxy)pyrimidine, 332 mg of potassium carbonate, and 591 mg of isopropylamine, followed by stirring at 70° C. for 6 hours. The reaction mixture was then left for cooling to room temperature, diluted with tert-butyl methyl ether, and washed twice with an aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel thin layer chromatography to give 339 mg of 4-(2-butynyloxy)-6-(isopropylamino)pyrimidine (the present compound (106)).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[NH:11][C:10]([Cl:15])=[N:9][C:8]=2[N:7]=[C:6]1[N:16]1[CH2:21][CH2:20][CH2:19][CH:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:17]1)[C:2]#[C:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[C:36]([C:38]1[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=1[CH2:40]Br)#[N:37]>CN(C)C=O>[CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:40][C:39]3[CH:42]=[CH:43][CH:44]=[CH:45][C:38]=3[C:36]#[N:37])[C:10]([Cl:15])=[N:9][C:8]=2[N:7]=[C:6]1[N:16]1[CH2:21][CH2:20][CH2:19][CH:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:17]1)[C:2]#[C:3][CH3:4]
Reactant: N#Cc1ccccc1CBr
Reactant: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2nc(Cl)[nH]c(=O)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2nc(Cl)n(Cc3ccccc3C#N)c(=O)c21
Temperature: 25 °C
Reaction time: 5 h
Yield: 35.1 %

Procedure:
A mixture consisting of 100 mg of t-butyl [1-[7-(2-butynyl)-2-chloro-6-oxo-6,7-dihydro-1H-purin-8-yl]piperidin-3-yl]carbamate, 66 mg of anhydrous potassium carbonate, 70 mg of 2-cyanobenzyl bromide and 1 ml of N,N-dimethylformamide was stirred at room temperature for five hours. The reaction solution was partitioned between ethyl acetate and water, and the organic layer was washed with water and then with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated. The residue was purified by silica gel column chromatography using 50% ethyl acetate/hexane to give 44.7 mg of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[C@@H:5]([O:27][CH2:28][CH3:29])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)[CH3:2].I[CH3:32].[H-].[Na+]>O1CCCC1>[CH2:1]([O:3][C:4](=[O:30])[C@@H:5]([O:27][CH2:28][CH3:29])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]([S:23]([CH3:26])(=[O:25])=[O:24])[CH3:32])=[CH:18][CH:17]=2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: CI
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCc2ccc(NS(C)(=O)=O)cc2)cc1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](Cc1ccc(OCCc2ccc(N(C)S(C)(=O)=O)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.9 %

Procedure:
(S)-2-Ethoxy-3-[4-{2-(4-[methylsulfonylamino]phenyl)ethoxy}phenyl]propanoic acid ethyl ester (0.17 g; 0.39 mmole) was dissolved in tetrahydrofuran (10 ml). Iodomethane (0.277 g; 1.95 mmole) and sodium hydride (0.019 g; 0.79 mmole) were added and the reaction mixture was stirred at room temperature for 3 hours and then evaporated. The residue was redissolved and extracted with diethyl ether and water. The organic phase was washed once more with water, dried with sodium sulfate and evaporated. Chromatography with ethyl acetate:petroleum ether (1:1) gave 0.098 g (55.8% yield) of (S)-2-ethoxy-3-[4-{2-(4-[methylsulfonyl(methyl)amino]phenyl)ethoxy}phenyl]propanoic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]12[CH2:27][CH:5]([C:6]3([CH3:26])[C:10]1([CH3:11])[C:9]1[CH:12]=[C:13]([CH:16]([OH:25])[C:17]4[CH:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][CH:18]=4)[CH:14]=[CH:15][C:8]=1[O:7]3)[CH2:4][CH2:3]2.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.CCCCCC.C(Cl)Cl>C(Cl)Cl>[CH3:1][C:2]12[CH2:27][CH:5]([C:6]3([CH3:26])[C:10]1([CH3:11])[C:9]1[CH:12]=[C:13]([C:16]([C:17]4[CH:18]=[CH:19][C:20]([CH:23]=[O:24])=[CH:21][CH:22]=4)=[O:25])[CH:14]=[CH:15][C:8]=1[O:7]3)[CH2:4][CH2:3]2
Reactant: CC12CCC(C1)C1(C)Oc3ccc(C(O)c4ccc(CO)cc4)cc3C21C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCCCCC
Product: CC12CCC(C1)C1(C)Oc3ccc(C(=O)c4ccc(C=O)cc4)cc3C21C
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.3 %

Procedure:
3.1 g (8.5 mmol) of the diol obtained in Example 10, in solution in 60 ml of CH2Cl2, were treated with 5.5 g of pyridinium chlorochromate. The reaction mixture was maintained under stirring at room temperature for 3 hours. The reaction mixture was then filtered through Celite. The organic phase was washed with a saturated ammonium chloride solution, rinsed with water, dried and evaporated to yield, after chromatography on silica in a CH2Cl2 /hexane (9/1) eluent mixture, 2 g (66%) of the expected compound, melting at 138°-142° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[N:6][CH:7]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=1B1OC(C)(C)C(C)(C)O1>>[F:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:18]2[CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:17]=2[F:16])[CH:3]=1
Reactant: CC1(C)OB(c2cc([N+](=O)[O-])ccc2F)OC1(C)C
Reactant: O=S(=O)(Oc1cncc(F)c1)C(F)(F)F
Product: O=[N+]([O-])c1ccc(F)c(-c2cncc(F)c2)c1

Procedure:
Trifluoromethanesulfonic acid 5-fluoropyridin-3-yl ester was coupled with 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane as described in Example 1 to give 3-fluoro-5-(2-fluoro-5-nitrophenyl)pyridine as a white solid: δH (360 MHz, CDCl3) 7.39 (1H, t, J 9), 7.65 (1H, m), 8.31-8.36 (1H, m), 8.42 (1H, dd, J 7 and 3), 8.58 (1H, d, J 3), 8.67 (1H, d, J 1).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH:17]([OH:28])[C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)=C(C(O)=O)[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].[CH3:29]N(C)C=O.CI.C[CH2:37][O:38][C:39]([CH3:41])=[O:40]>[Ag-]=O>[C:1]([C:3]1[C:4]([CH:17]([O:28][CH3:29])[C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)=[C:41]([C:39]([O:38][CH3:37])=[O:40])[S:6][C:7]=1[N:8]1[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)#[N:2]
Reactant: N#Cc1c(N2CCOCC2)sc(C(=O)O)c1C(O)c1ccc2ccccc2c1
Reactant: CN(C)C=O
Reactant: CCOC(C)=O
Agent: O=[Ag-]
Solvent: CI
Product: COC(=O)c1sc(N2CCOCC2)c(C#N)c1C(OC)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 26 h

Procedure:
To a round bottom flask was added silver(I) oxide (56.15 g, 0.2423 mol), 4-cyano-3-[hydroxy(2-naphthyl)methyl]-5-(morpholin-4-yl)thiophene-2-carboxylic acid (15.17 g, 0.02423 mol), and N,N-dimethylformamide (66.2 mL), followed by methyl iodide (53.7 mL, 0.863 mol). Added another 10 mL DMF, sonicated to suspend/mix all solid. The reaction mixture was stirred at room temperature for 26 hours, then was diluted with EtOAc, filtered through a pad of Celite, concentrated filtrate in vacuo, azeotroped w/toluene (10×10 mL), DCM (20 mL), dried on high vacuum pump. The rude material was used directly in the next step. LC/MS (AA) ES+ 423, ES+Na+ 445; 1H NMR (400 MHz, DMSO) δ 7.97 (s, 1H), 7.91-7.86 (m, 3H), 7.53-7.48 (m, 3H), 6.62 (s, 1H), 3.85 (s, 3H), 3.72-3.69 (m, 4H), 3.52-3.50 (m, 4H), 3.43 (s, 3H).