Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13]([N:15]3[CH:24]([CH3:25])[CH2:23][C:22]4[C:17](=[CH:18][C:19]([CH:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:20][CH:21]=4)[CH2:16]3)[N:12]=[C:11]([NH2:32])[N:10]=2)[CH2:5][CH2:4]1.C(N(CC)C(C)C)(C)C.[CH:42]1([CH2:47][C:48](Cl)=[O:49])[CH2:46][CH2:45][CH2:44][CH2:43]1>C(#N)C.CO>[CH:42]1([CH2:47][C:48]([N:29]2[CH2:28][CH2:27][CH:26]([C:19]3[CH:18]=[C:17]4[C:22]([CH2:23][CH:24]([CH3:25])[N:15]([C:13]5[CH:14]=[C:9]([N:6]6[CH2:7][CH2:8][N:3]([CH3:2])[CH2:4][CH2:5]6)[N:10]=[C:11]([NH2:32])[N:12]=5)[CH2:16]4)=[CH:21][CH:20]=3)[CH2:31][CH2:30]2)=[O:49])[CH2:46][CH2:45][CH2:44][CH2:43]1
Reactant: CC1Cc2ccc(C3CCNCC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: O=C(Cl)CC1CCCC1
Agent: Cl
Solvent: CC#N
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC1Cc2ccc(C3CCN(C(=O)CC4CCCC4)CC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(4-Methylpiperazin-1-yl)-6-(3-methyl-7-piperidin-4-yl-3,4-dihydroisoquinolin-2(1H)-yl)pyrimidin-2-amine HCl salt (21.1 mg) in acetonitrile (0.50 mL) was treated with N,N-diisopropylethylamine (0.070 mL, 0.40 mmol). To the solution was added cyclopentylacetyl chloride (10.0 mg). The mixture was stirred at r.t. for 2 h. The mixture was diluted with methanol, and purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=532.3.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][N:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C>[NH3:6].[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:13]2[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CN1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CN1CCC(Nc2ccc(Br)cc2)CC1
Product: N
Temperature: 25 °C
Reaction time: 22 h
Yield: 127.8 %

Procedure:
4-bromoaniline (1.0 g, 5.813 mmol) was dissolved in anhydrous dichloroethane (30 mL) in a dry argon purged flask fitted with a magnetic stir bar. 1-methylpiperidin-4-one (671 ul, 5.813 mmol), acetic acid (329 ul, 5.813 mmol) and sodium triacetoxyborohydride (1.848 g, 8.719 mmol) are added to the flask and mixture stirred at ambient temperature for 22 hours then heated to 55° C. for 4 hours. After cooling to room temperature, the mixture was transferred to a separatory funnel and 1M sodium hydroxide solution added to adjust pH to 10. The organic layer was collected and the aqueous layer further extracted with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulphate, filtered, concentrated and the crude purified via chromatography on silica gel (methanol:CH2Cl2, 5:95 then 2M NH3 in methanol:CH2Cl2, 1:9) to yield an off-white solid, 78 (1.0 g, 63.9%). 1H NMR (CDCl3) δ 1.40-1.58 (m, 2H), 1.98-2.22 (m, 4H), 2.31 (s, 3H), 2.73-2.89 (m, 2H), 3.15-3.32 (m, 1H), 3.45-3.58 (m, 1H), 6.47 (d, 2H, J=8.8 Hz), 7.23 (d, 2H, J=8.8 Hz); ESI-MS (m/z, %): 269/271 (MH+, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:21])[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[CH:18][NH:17][C:16](=[O:20])[N:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CC1C=CC(S(O[CH2:33][C:34]2[S:35][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:37][CH:38]=2)(=O)=O)=CC=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:21])[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[CH:18][N:17]([CH2:33][C:34]4[S:35][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:37][CH:38]=4)[C:16](=[O:20])[N:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCc2ccc(C(F)(F)F)s2)cc1
Reactant: O=c1nc(N2CCC(O)(c3ccc(F)cc3)CC2)nc[nH]1
Product: O=c1nc(N2CCC(O)(c3ccc(F)cc3)CC2)ncn1Cc1ccc(C(F)(F)F)s1
Yield: 12.9 %

Procedure:
4-[4-(4-Fluorophenyl)-4-hydroxypiperidin-1-yl]-1,3,5-triazin-2(1H)-one (100 mg, 0.34 mmol) synthesized in Reference Synthesis Example 14 and [5-(trifluoromethyl)thiophen-2-yl]methyl 4-methylbenzenesulfonate (558 mg, 0.67 mmol) synthesized in Reference Synthesis Example 51 were used to obtain the title compound (20 mg, yield 13%) by synthesis in a similar manner to Reference Synthesis Example 8.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].[N:13]([O-])=O.[Na+]>CC(O)=O.O>[NH:1]1[C:2]2[C:11](=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=2)[CH:12]=[N:13]1
Reactant: O=N[O-]
Reactant: COC(=O)c1ccc(C)c(N)c1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccc2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of methyl 3-amino-4-methylbenzoate D-1 (5.0 g, 30 mmol) in AcOH (140 mL) at 0° C. was added a solution of sodium nitrite (2.1 g, 30 mmol) in H2O (3.5 mL). After addition, the mixture was stirred at rt for 24 h. Then half of the solvent was removed under reduced pressure and the resulting mixture was diluted with H2O, and extracted with EtOAc. The combined organics were washed H2O and brine, and concentrated to give the title compound. LCMS (ESI) calc'd for C9H9N2O2 [M+H]+: 177. found 177.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([I:29])=[C:7]([C:21]([NH:23][CH2:24][CH:25]([OH:28])[CH2:26][OH:27])=[O:22])[C:8]([I:20])=[C:9]([C:18]=1[I:19])[C:10]([NH:12][CH2:13][CH:14]([OH:17])[CH2:15][OH:16])=[O:11])(=[O:3])[CH3:2].B(O)(O)O.[OH-].[K+].[CH2:36](Br)[CH:37]=[CH2:38]>O.CO>[CH2:38]([N:4]([C:5]1[C:18]([I:19])=[C:9]([C:10]([NH:12][CH2:13][CH:14]([OH:17])[CH2:15][OH:16])=[O:11])[C:8]([I:20])=[C:7]([C:6]=1[I:29])[C:21]([NH:23][CH2:24][CH:25]([OH:28])[CH2:26][OH:27])=[O:22])[C:1](=[O:3])[CH3:2])[CH:37]=[CH2:36]
Reactant: C=CCBr
Reactant: CC(=O)Nc1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I
Agent: OB(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=CCN(C(C)=O)c1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I
Reaction time: 3 h

Procedure:
To a stirred solution of 5-acetamido-N1,N3-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (7.5 g, 10 mmol) and boric acid (1.24 g, 20 mmol) in water (10 ml) and methanol (7 ml) is added potassium hydroxide (10 M) drop wise until a stable pH 12.5 is established. Allylbromide (860 ul, 10 mmol) is added and potassium hydroxide (10 M) is continuously added to maintain pH 12.5. for 3 h and the mixture is then left stirring over night. The following day the mixture is reduced in vacuo to remove methanol, the resulting aqueous phase is diluted with 50 ml water and treated with acidic and basic ion exchanger. Resins are removed and rinsed and the combined aqueous volume is reduced to dryness in vacuo to yield 5-(N-allylacetamido)-N1,N3-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][OH:11].Cl[C:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=[O:14]>C1COCC1>[C:13](=[O:14])([O:15][C:16]1[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=1)[O:11][CH2:10][C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1
Reactant: OCc1cc2ccccc2o1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: O=C(OCc1cc2ccccc2o1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
A solution of benzofuran-2-ylmethanol 59 (300 mg, 2.03 mmol) in THF (5 mL) was cooled to 0° C. TEA (280 μL, 2.03 mmol) was added dropwise followed by the portionwise addition of p-nitrophenyl chloroformate (282 mg, 3.05 mmol). The resulting solution was stirred at room temperature for 2 h. Solvent was evaporated off in vacuo and the crude residue was purified by flash chromatography, eluting with hexane:EtOAc (3:1) to give 60 (350 mg, 54%) as a white solid. H1 NMR (500 MHz, CDCl3): δ=8.31 (2H, m, ArH), 7.62 (1H, d, J=7.70 Hz, ArH), 7.54 (1H, d, J=7.70 Hz, ArH), 7.43-7.27 (3H, m, ArH), 7.29 (1H, t, J=7.72 Hz, ArH), 6.93 (1H, s, ArH), 5.43 (2H, s, CH2). 13C NMR CDEPT 135, (500 MHz, CDCl3): δ=125.47, 125.37, 123.23, 121.80, 121.66, 111.60, 108.53, 62.95.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>C(O)C.[OH-].[Na+]>[CH2:12]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH2:5][C:4]1[CH:8]=[CH:9][CH:10]=[CH:2][CH:3]=1)[C:5]([OH:7])=[O:6])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClCc1ccccc1
Reactant: O=C(O)c1ccc(O)c(O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 138.6 %

Procedure:
To a suspension of 3,4-dihydroxybenzoic acid (25.4 g, 0.17 mle) in ethanol (250 ml), 5N NaOH aq. (270 ml) and benzyl chloride (102 g, 0.81 mole) were added. The resulting mixture was reacted with stirring for 6 hours under reflux. The reaction mixture was cooled to room temperature, allowed to stand at same temperature overnight and acidified with conc. hydrochloric acid (40 ml). The precipitate was filtered, washed with hot ethanol and dried under reduced pressure to give 38.2 g of 3,4-dibenzyloxybenzoic acid as pale yellow crystals having a m.p. of 184°-186° C.
Reaction SMILES: CS[C:3]1[NH:12][C:11](=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:14][O:15][CH2:16][CH2:17][O:18][C:19]1[CH:20]=[N:21][NH:22][CH:23]=1.O.Cl>CN(C)C=O>[CH3:14][O:15][CH2:16][CH2:17][O:18][C:19]1[CH:20]=[N:21][N:22]([C:3]2[NH:12][C:11](=[O:13])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=2)[CH:23]=1
Reactant: COCCOc1cn[nH]c1
Reactant: CSc1nc2ccccc2c(=O)[nH]1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1cnn(-c2nc3ccccc3c(=O)[nH]2)c1
Yield: 58.5 %

Procedure:
96 g (0.5 mole) of 2-methylthio-4(3H)-quinazolinone are stirred in 250 ml of dimethylformamide with 142 g (1 mole) of 4-(β-methoxy-ethoxy)pyrazole at the reflux temperature for 40 hours. After cooling, 2.5 litres of water are added and a pH value of 3 is established with hydrochloric acid. The crude product which separates out (97.3 g of melting point 119°-24°) is recrystallized from isopropanol. 83.8 g of 2-(4-β-methoxyethoxy-1H-pyrazol-1-yl)-4(3H)-quinazolinone of melting point 125° to 127° C. are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[Cl:9].[H-].[Na+].Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:27][CH3:28])=[C:20]([C:23]([O:25][CH3:26])=[O:24])[CH:21]=2)[N:16]=[CH:15][CH:14]=1.C(OCC)(=O)C>CS(C)=O.O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:13]2[C:22]3[C:17](=[CH:18][C:19]([O:27][CH3:28])=[C:20]([C:23]([O:25][CH3:26])=[O:24])[CH:21]=3)[N:16]=[CH:15][CH:14]=2)=[CH:4][C:3]=1[Cl:9]
Reactant: COC(=O)c1cc2c(Cl)ccnc2cc1OC
Reactant: Nc1ccc(O)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1cc2c(Oc3ccc(N)c(Cl)c3)ccnc2cc1OC
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 58.6 %

Procedure:
After dissolving 4-amino-3-chlorophenol (3.17 g, 22.05 mmol) in dimethylsulfoxide (50 ml), sodium hydride (882 mg, 22.05 mmol) was gradually added at room temperature and the mixture was stirred for 30 minutes. The 4-chloro-7-methoxy-6-methoxycarbonylquinoline (3.70 g, 14.7 mmol) described in WO0050405 was added, and the mixture was heated at 100° C. for 3 hours. After standing to cool to room temperature, the reaction solution was distributed between ethyl acetate and water, and the organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off, silica gel column chromatography (eluent—ethyl acetate) was performed, the fraction containing the target substance was concentrated, suspended in ethyl acetate and diluted with hexane, and the crystals were filtered out and blow-dried to obtain the title compound (3.092 g, 8.62 mmol, 57.4%) as light brown crystals.
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[NH2:7][OH:8].[OH:9][CH:10]1[CH2:14][CH2:13][C:12](=O)[C:11]1([CH3:17])[CH3:16].Cl>C(O)C.O>[OH:9][CH:10]1[CH2:14][CH2:13][C:12](=[N:7][OH:8])[C:11]1([CH3:17])[CH3:16]
Reactant: NO
Reactant: CC1(C)C(=O)CCC1O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC1(C)C(=NO)CCC1O
Temperature: 25 °C
Yield: 92.1 %

Procedure:
Sodium acetate (3.58 g, 43.7 mmol) and hydroxylamine hydrochloride (2.85 g, 41.0 mmol) were added to a solution of 3-hydroxy-2,2-dimethylcyclopentanone (3.50 g, 27.3 mmol, from Step 1) in ethanol (50 mL) and water (10 mL). The resultant mixture was heated to 80° C. for 15 h, cooled to room temperature and acidified to pH 2-3 with 1 N hydrochloric acid. After removal of ethanol in vacuo, the aqueous residue was extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with brine (30 mL), dried (MgSO4), filtered and concentrated, to give 3-hydroxy-2,2-dimethylcyclopentanone oxime (3.60 g, 92% yield). 1H NMR (400 MHz, methanol-d4) δ ppm 3.76 (1 H, t, J=6.16 Hz), 2.51-2.80 (1 H, m), 2.32-2.53 (1 H, m), 1.91-2.16 (1 H, m), 1.58-1.81 (1 H, m), 0.92-1.13 (6 H, m).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[CH2:9]([Mg]Cl)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl[C:20]([O:22][CH3:23])=[O:21].Cl>C1COCC1>[O:2]=[C:3]1[CH:8]=[CH:7][N:6]([C:20]([O:22][CH3:23])=[O:21])[CH:5]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:4]1
Reactant: COC(=O)Cl
Reactant: Cl[Mg]CCc1ccccc1
Reactant: COc1ccncc1
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)N1C=CC(=O)CC1CCc1ccccc1
Temperature: -15 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
4-Methoxypyridine (9.30 mL, 91.64 mmol) was dissolved in THF (150 mL) under nitrogen atmosphere and cooled to −15° C. Phenethylmagnesium chloride (93 mL, 93.47 mmol, 1 M in THF) was added dropwise and a suspension was formed. After stirring at −20° C. for 30 minutes methyl chloroformate (9.23 mL, 119.13 mmol) was added over 1 minute. Stirring was continued at −10° C. for 1 h and then HCl (10%) was added. The mixture was stirred for 20 minutes and then concentrated. The aqueous phase was extracted with ether (×2) and the organic phase was dried (MgSO4) and evaporated to yield methyl 4-oxo-2-phenethyl-3,4-dihydropyridine-1(2H)-carboxylate (21.7 g, 82%) as an oil. 1H NMR (600 MHz, cdcl3) δ 1.98 (m, 2H), 2.54 (m, 2H), 2.69 (m, 1H), 2.81 (m, 1H), 3.83 (s, 3H), 4.62 (m, 1H), 5.33 (m, 1H), 7.12-7.38 (m, 5H), 7.72 (m, 1H); MS m/z 260 (M+H)+.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]([C:10]1[CH:11]=[C:12]([CH:37]=[CH:38][C:39]=1[OH:40])[O:13][CH2:14][CH2:15][NH:16][CH2:17][CH:18]([OH:36])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[NH:28][CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[N:31]=2)=[CH:23][CH:22]=1)(=[O:9])[NH2:8].CI>CN(C)C=O>[C:7]([C:10]1[CH:11]=[C:12]([CH:37]=[CH:38][C:39]=1[OH:40])[O:13][CH2:14][CH2:15][NH:16][CH2:17][CH:18]([OH:36])[CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[N:28]([CH3:1])[CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[N:31]=2)=[CH:25][CH:26]=1)(=[O:9])[NH2:8].[C:7]([C:10]1[CH:11]=[C:12]([CH:37]=[CH:38][C:39]=1[OH:40])[O:13][CH2:14][CH2:15][NH:16][CH2:17][CH:18]([OH:36])[CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[N:31]([CH3:1])[C:30]([C:32]([F:35])([F:34])[F:33])=[CH:29][N:28]=2)=[CH:25][CH:26]=1)(=[O:9])[NH2:8]
Reactant: NC(=O)c1cc(OCCNCC(O)COc2ccc(-c3nc(C(F)(F)F)c[nH]3)cc2)ccc1O
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c(C(F)(F)F)cnc1-c1ccc(OCC(O)CNCCOc2ccc(O)c(C(N)=O)c2)cc1
Product: Cn1cc(C(F)(F)F)nc1-c1ccc(OCC(O)CNCCOc2ccc(O)c(C(N)=O)c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.48 g of potassium tert.-butoxide is added while stirring in an ice bath to a solution of 1 g of the 1-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-[4-[4-(trifluoromethyl)-1H-imidazol-2-yl]-phenoxy]-2-propanol obtained according to Example 3 in 20 ml of dimethylformamide. After 10 minutes, a solution of 0.3 g of methyl iodide in 1 ml of dimethylformamide is added dropwise over a period of 20 minutes. The mixture is then stirred for 2 hours at room temperature, the solvent is removed in a rotary evaporator and the residue is chromatographed on silica gel with a solvent mixture of chloroform/methanol/ammonia (700:50:1), yielding the two isomeric compounds 1-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-[4-[1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl]-phenoxy]-2-propanol having a melting point of 195°-197° and 1-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-[4-[1-methyl-5-(trifluoromethyl)-1H-imidazol-2-yl]-phenoxy]-2-propanol having a melting point of 157°-159°.
Reaction SMILES: Br.[Cl:2][C:3]1[CH:4]=[C:5]([C:9]2[O:13][N:12]=[C:11]([CH:14]([S:16][C:17]3[N:18]([CH2:30][CH3:31])[C:19]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]([O:28]C)[CH:23]=4)=[N:20][N:21]=3)[CH3:15])[N:10]=2)[CH:6]=[CH:7][CH:8]=1.C([O-])(O)=O.[Na+]>CC(O)=O>[Cl:2][C:3]1[CH:4]=[C:5]([C:9]2[O:13][N:12]=[C:11]([CH:14]([S:16][C:17]3[N:18]([CH2:30][CH3:31])[C:19]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]([OH:28])[CH:23]=4)=[N:20][N:21]=3)[CH3:15])[N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCn1c(SC(C)c2noc(-c3cccc(Cl)c3)n2)nnc1-c1ccnc(OC)c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCn1c(SC(C)c2noc(-c3cccc(Cl)c3)n2)nnc1-c1ccnc(O)c1
Temperature: 80 °C
Yield: 99.1 %

Procedure:
HBr (1 ml) and HOAc (1 ml) were added to 4-(5-{1-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-ethyl-4H-[1,2,4]triazol-3-yl)-2-methoxy-pyridine (9 mg, 0.02 mmol) and the reaction was stirred at 80° C. on. Saturated NaHCO3 (aq) was added to the reaction and the mixture was extracted three times with dichloromethane. The combined organic phases were dried and concentrated to give the title compound (8.5 mg, 99 %). 1H NMR (CDCl3), δ (ppm): 1.37 (t, 3 H), 1.96 (d, 3 H), 4.10 (q, 2 H), 5.23 (q, 1 H), 6.80 (m, 2 H), 7.49 (t, 2 H), 7.59 (m, 1 H), 7.99 (d, 1 H), 8.11 (s, 1 H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[Br:11]Br>C(O)(=O)C.O>[Br:11][C:6]1[CH:5]=[C:4]([CH2:3][CH2:2][OH:1])[CH:9]=[CH:8][C:7]=1[OH:10]
Reactant: OCCc1ccc(O)cc1
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: OCCc1ccc(O)c(Br)c1
Reaction time: 0.25 h

Procedure:
To a solution of 4-(2-hydroxyethyl)phenol 9.50 g in acetic acid 60 ml is dropped bromine 3.54 ml over a period of 10 minutes on a water bath, and the mixture is stirred for 15 minutes. The reaction mixture is diluted with water and extracted with ethyl acetate. The ethyl acetate layer is washed, dried and concentrated in vacuo. The residue is dissolved in methanol 120 ml and thereto is added potassium carbonate 25 g. The mixture is stirred at room temperature for 5 hours. and then diluted with water and with ethyl acetate. The solution is acidified with concentrated sulfuric acid. The organic layer is extracted with ethyl acetate, washed, dried and concentrated in vacuo. The residue is crystallized from chloroform to give 2-bromo-4-(2-hydroxyethyl)phenol as a slightly brown crystalline powder 9.37 g. mp 83-85° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.C.[ClH:10]>CO>[Cl:10][C:7]1[C:2]([OH:1])=[CH:3][CH:4]=[C:5]([CH3:8])[N:6]=1
Reactant: Cc1ccc(O)cn1
Reactant: Cl
Solvent: CO
Product: Cc1ccc(O)c(Cl)n1
Reaction time: 8 h
Yield: 67.3 %

Procedure:
5-Hydroxy-2-methylpyridine (1-014-01) (27.01 g) was dissolved in conc. hydrochloric acid (200 mL) and to the reaction mixture was bubbled chlorine gas at 68 to 74° C. After the reaction mixture was stood overnight, the volatile was removed by bubbling nitrogen gas. The reaction mixture was evaporated under reduced pressure to give the crystal residue. The crystal residue was dissolved in methanol, and treated with active charcoal. After recrystallization, the desired 2-chloro-3-hyroxy-6-methylpyridine (1-014-02) (23.96 g, 67.3%) was obtained.
Reaction SMILES: [C-]#[N:2].[Na+].[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1.[C:12]1(=O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(OCC)(=O)C>C(O)(=O)C>[CH3:11][C:8]1[CH:9]=[CH:10][C:5]([NH:4][C:14]2([C:13]#[N:2])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:12]2)=[CH:6][CH:7]=1
Reactant: [C-]#N
Reactant: O=C1CCCCCC1
Reactant: Cc1ccc(N)cc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1ccc(NC2(C#N)CCCCC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 96 %

Procedure:
Sodium cyanide (0.147 g, 3 mmol) was added to a mixture of p-toluidine (0.214 g, 2 mmol) and cycloheptanone (0.337 g, 3 mmol) in acetic acid 90% (3 ml). The reaction mixture was stirred at room temperature for 12 h and then 20 ml of ethyl acetate was added. The organic layer was washed with water (3×10 ml), dried over magnesium sulfate and concentrated under vacuum to dryness to yield 1-(4-methylphenyl)aminocyclohexanenitrile, 10a (0.438 g, 1.92 mmol, 96%) as a brown solid.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[C@@H:13]([OH:21])[C@H:12]2[OH:22])=[C:4]([NH:23][CH2:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:3]=1.[CH3:38][O:39][C:40]([CH:42]1[CH2:47][CH2:46][CH:45]([CH2:48][C:49]#[CH:50])[CH2:44][CH2:43]1)=[O:41].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C.CN(C=O)C>[CH3:38][O:39][C:40]([CH:42]1[CH2:47][CH2:46][CH:45]([CH2:48][C:49]#[C:50][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[C@@H:11]3[CH2:15][C@H:14]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[C@@H:13]([OH:21])[C@H:12]3[OH:22])=[C:4]([NH:23][CH2:24][CH:25]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:3]=2)[CH2:44][CH2:43]1)=[O:41]
Reactant: C#CCC1CCC(C(=O)OC)CC1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C#CCC4CCC(C(=O)OC)CC4)nc32)[C@H](O)[C@@H]1O
Temperature: 120 °C

Procedure:
The title compound is prepared by combining N-{(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide (intermediate J), 4-prop-2-ynyl-cyclohexanecarboxylic acid methyl ester (prepared as described by Rieger J. M., Brown M. L., Sullivan G. W., Linden J. and Macdonald T. L.′; J. Med. Chem.(2001), 44, 531-539), copper (I) iodide, triphenylphosphine and dichlorobis(triphenylphosphine)palladium(II) in a 2:1 mixture of triethylamine/DMF, and heating by microwave irradiation for 3600 seconds at 120° C. Purification by column chromatography affords the title compound.
Reaction SMILES: C[C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:5]([NH2:6])=[C:4]([N+:12]([O-])=O)[CH:3]=1.[CH2:15](O)C>O>[CH3:15][NH:6][C:5]1[C:7]([N+:9]([O-:11])=[O:10])=[CH:8][CH:2]=[CH:3][C:4]=1[NH2:12]
Reactant: Cc1cc([N+](=O)[O-])c(N)c([N+](=O)[O-])c1
Reactant: CCO
Solvent: O
Product: CNc1c(N)cccc1[N+](=O)[O-]
Temperature: 28 °C
Yield: 85 %

Procedure:
The procedure of Gillespie et al., J. Org. Chem. 25:942 (1960) was adopted as follows. A dark black solution of 4-methyl-2,6-dinitroaniline (0.100 g, 0.561 mmol, Aldrich, used as received) in 6.66% aq. (NH4)2S (3.3 mL, prepared from 20% aq.(NH4)2S solution supplied by Aldrich) and ethanol (3.5 mL) was refluxed for 45 min. It was then cooled to 28° C. and the solvents were removed as much as possible under vacuum (inside the hood to avoid the stench of ammonium sulfide). The slurry so obtained was diluted with water (10 mL) and the -resulting red solid was filtered and dried under vacuum to obtain 0.072 g (85%) solid as a red powder, which was used as such for the next reaction. 1H NMR (acetone-dip: 2.205 (s, 3H), 6.342 for s, 2H), 6.622 (s, 1H), 7.571 (s, 1H).