Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=O.[CH3:3][C:4](=[CH:6][CH2:7][CH2:8]/[C:9](=[CH:11]/[CH2:12][OH:13])/[CH3:10])[CH3:5]>CO>[CH3:3][C:4](=[CH:6][CH2:7][CH2:8][C@@H:9]([CH2:11][CH2:12][OH:13])[CH3:10])[CH3:5]
Reactant: CC(C)=CCC/C(C)=C/CO
Agent: O=O
Solvent: CO
Product: CC(C)=CCC[C@H](C)CCO
Reaction time: 6 h
Yield: 97.5 %

Procedure:
A 500 ml autoclave was charged in a glove box (O2 content <1 ppm) with 24.0 g (155.6 mmol) of geraniol [(E)-3,7-dimethyl-2,6-octadien-1-ol], 1200 ml of methanol and 2.9 mg of Ru[(R)-MeOBIPHEP](CF3COO)2 as the catalyst. The hydrogenation was effected at 20° C. and 60 bar. The conversion after 6 hours amounted to 99.9%. The hydrogenation solution was evaporated at 45° C./17 mbar and the crude product was distilled at 60°-65° C./0.03 mbar. There were obtained 23.7 g of (S)-citronellol [(S)-3,7-dimethyl-6-octen-1-ol] as a colourless oil; e.e. 98.9%.
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([O:6][CH:7]([CH3:16])[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:4][CH:3]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[CH3:14][CH:13]([S:10]([NH:9][CH2:8][CH:7]([O:6][C:5]1[CH:17]=[CH:18][C:2]([C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([C:20]([F:31])([F:30])[F:19])[CH:26]=2)=[CH:3][CH:4]=1)[CH3:16])(=[O:12])=[O:11])[CH3:15]
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(Br)cc1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2cccc(C(F)(F)F)c2)cc1
Yield: 15.4 %

Procedure:
The title compound (44 mg, 15%, white foam) was prepared from [2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine (240 mg, 0.714 mmol, prepared in example 1), 3-trifluoromethylbenzeneboronic acid (162 mg, 0.853 mmol), dichlorobis(triphenylphosphine)palladium(II) (20 mg, 0.028 mmol), 2 M sodium carbonate (255 mg in 1.2 mL water), and 1,2-dimethoxyethane (4.75 mL) in a manner analogous to the procedure described in Example 8. The crude material was purified utilizing a Chromatotron® with a 2000 μm rotor in a 1:1 hexane:ethyl acetate solvent system, yielding 192 mg of a co-eluting mixture of unreacted starting material and title compound. This mixture was further purified by reverse phase chromatography on a Vydac C-18 column on a gradient of 5 to 70% of 0.1% trifluoroacetic acid/acetonitrile in water over 45 minutes at 200 mL/min elution rate.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[C:6]=1[C:14]([C:16]1[S:20][CH:19]=[N:18][CH:17]=1)=[O:15].[CH3:22][Mg+].[Br-]>C1COCC1>[CH3:21][N:2]([CH3:1])[CH2:3][CH2:4][C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[C:6]=1[C:14]([C:16]1[S:20][CH:19]=[N:18][CH:17]=1)([OH:15])[CH3:22]
Reactant: CN(C)CCc1sc2ccccc2c1C(=O)c1cncs1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CN(C)CCc1sc2ccccc2c1C(C)(O)c1cncs1
Temperature: -78 °C
Reaction time: 1 h
Yield: 8.2 %

Procedure:
To a cooled (−78° C.) solution of [2-(2-dimethylamino-ethyl)-benzo[b]thiophen-3-yl]-thiazol-5-yl-methanone (35 mg, 0.11 mmol) in anhydrous THF (2 mL), MeMgBr (0.4 mL, 0.55 mmol, 3M in ether) was added. The mixture was stirred for 1 hour at −78° C., an additional batch of MeMgBr (10 mL, 14 mmol) was added and the temperature was allowed to slowly increase to room temperature. The reaction was quenched with diluted NH4OH until pH ˜8, extracted with EtOAc and concentrated. The residue was purified by mass triggered preparative HPLC to give 3 mg of 1-[2-(2-dimethylamino-ethyl)-benzo[b]thiophen-3-yl]-1-thiazol-5-yl-ethanol (Compound 17-1) as a TFA salt.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.[NH2:12][CH:13]([CH2:21][CH3:22])[C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15]>>[CH2:17]([O:16][C:14](=[O:15])[CH:13]([NH:12][C:9](=[O:11])[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[OH:1])[CH2:21][CH3:22])[CH:18]([CH3:19])[CH3:20]
Reactant: O=C(O)Cc1ccccc1O
Reactant: CCC(N)C(=O)OCC(C)C
Product: CCC(NC(=O)Cc1ccccc1O)C(=O)OCC(C)C

Procedure:
Following General Procedure BI above and using 2-hydroxyphenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:30]=[CH:29][C:8]([O:9][C:10]2[C:11]([C:16]3[CH2:17][CH2:18][CH2:19][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:21]=3)=[N:12][CH:13]=[CH:14][N:15]=2)=[CH:7][CH:6]=1)=[O:4].C1COCC1>[Pd].CCO>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[C:11]([CH:16]3[CH2:17][CH2:18][CH2:19][N:20]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:21]3)=[N:12][CH:13]=[CH:14][N:15]=2)=[CH:29][CH:30]=1)=[O:4]
Reactant: COC(=O)c1ccc(Oc2nccnc2C2=CN(C(=O)OC(C)(C)C)CCC2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Oc2nccnc2C2CCCN(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a rb flask containing tert-butyl 5-(3-(4-(methoxycarbonyl)phenoxy)pyrazin-2-yl)-3,4-dihydropyridine-1(2H)-carboxylate (900 mg, 2.187 mmol) and palladium on carbon (233 mg, 0.219 mmol) (10 wt %) under N2 is added THF (5.5 mL) and EtOH (5.5 mL). The flask is purged with H2 (3×), then stirred under H2 at rt 3 h. The reaction was filtered through celite and the filter cake washed with EtOAc (2×10 mL). The combined filtrates were concentrated and the residue purified by ISCO (12 g SiO2, 0-50% EtOAc/Hexane) to give tert-butyl 3-(3-(4-(methoxycarbonyl)phenoxy)pyrazin-2-yl)piperidine-1-carboxylate as a brown solid.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:9]=[C:10]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[C:11]3[N:16]=[CH:15][S:14][C:12]=3[N:13]=2)[C:6]2[CH:23]=[CH:24][CH:25]=[CH:26][C:5]=2[N:4]=1)[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.ClCC[I:40]>C1COCC1>[CH2:1]([C:3]1[N:7]([C:8]2[N:9]=[C:10]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)[C:11]3[N:16]=[C:15]([I:40])[S:14][C:12]=3[N:13]=2)[C:6]2[CH:23]=[CH:24][CH:25]=[CH:26][C:5]=2[N:4]=1)[CH3:2]
Reactant: ClCCI
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2ncsc2n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(I)sc2n1
Temperature: -5 °C

Procedure:
A solution of 5 -(2-ethylbenzoimidazol-1-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine (1.92 g, 5.23 mmol) in THF (60 mL) was cooled to −40° C. before the drop wise addition of LiHMDS (6.3 mL, 6.28 mmol, 1 M solution in THF). The resulting mixture was warmed to −5° C. over 30 min then mixture was cooled back to −30° C. before the addition of a solution of 1-chloro-2-iodoethane (2.0 g, 10.47 mmol) in THF (6 mL) The resulting mixture was allowed to warm to 0° C. then quenched with NH4Cl and extracted with EtOAc. The combined organics were washed with brine then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, EtOAc:DCM, 50-80%) followed by recrystallisation from iPrOAc affording the title compound as a yellow solid (1.58 g, 62%)._LCMS (method A): RT 3.50 min [M+H]+ 493.0
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH2:15]([NH2:17])[CH3:16]>C(O)C>[CH2:15]([NH:17][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[CH3:16]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CCN
Solvent: CCO
Product: CCNc1c([N+](=O)[O-])cnc2ccccc12
Yield: 97 %

Procedure:
To a stirred suspension of 1.40 g of 4-chloro-3-nitroquinoline in 30 ml of dry ethanol is introduced excess amount of gaseous ethylamine at room temperature for 3 hours. Treatment of the reaction mixture as in Example 98 yielded 1.41 g (97%) of 4-ethylamino-3-nitroquinoline. Recrystallization from the ethyl acetate-n-hexane affords yellow crystals melting at 151°-152° C.
Reaction SMILES: O1CCCC1.[NH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[NH:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[C:21]#[N:22].[C:26](Cl)(=[O:30])[C:27](Cl)=[O:28]>CO>[C:21]([C:20]1[CH:19]=[C:18]([N:17]2[C:8]3[CH:9]=[CH:10][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=4[C:7]=3[NH:6][C:27](=[O:28])[C:26]2=[O:30])[CH:25]=[CH:24][CH:23]=1)#[N:22]
Reactant: N#Cc1cccc(Nc2ccc3ccccc3c2N)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1cccc(-n2c(=O)c(=O)[nH]c3c4ccccc4ccc32)c1
Temperature: 25 °C
Yield: 9.5 %

Procedure:
To an anhydrous tetrahydrofuran (18 mL) solution of 3-(1-amino-2-naphthylamino)benzonitrile (200 mg, 0.771 mmol) was added an anhydrous tetrahydrofuran (2 mL) solution of oxalyl chloride (66 μL, 0.771 mmol) under cooling in an ice-bath. The mixture was stirred under cooling in an ice-bath for 30 minutes and at room temperature for one hour. After addition of methanol (1 mL), the solvent was removed by evaporation under reduced pressure. The mixture was suspended by chloroform, and washed with a saturated aqueous sodium hydrogen carbonate solution. The precipitated solid was collected by filtration, and washed with water. The obtained solid was purified by silica gel chromatography (chloroform/methanol=9/1) to obtain the titled compound as a white powder (23 mg, yield 10%).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:15]=[C:8]2[N:9]=[C:10]([CH3:14])[CH:11]=[C:12]([SH:13])[N:7]2[N:6]=1)=O.O.[NH2:17][NH2:18]>CO>[NH:17]([C:3]([C:5]1[N:15]=[C:8]2[N:9]=[C:10]([CH3:14])[CH:11]=[C:12]([SH:13])[N:7]2[N:6]=1)=[O:2])[NH2:18]
Reactant: NN
Reactant: COC(=O)c1nc2nc(C)cc(S)n2n1
Solvent: CO
Solvent: O
Product: Cc1cc(S)n2nc(C(=O)NN)nc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 2-methoxycarbonyl-7-mercapto5-methyl-s-triazolo[1,5-a]pyrimidine (10 g) in 200 ml of methanol was dropwise added hydrazine hydrate (110 ml). The mixture was stirred at room temperature for two hours, the insoluble matters were filtered off, and the solvent was removed by distillation from the filtrate. Water (100 ml) was added to the residue and the pH was adjusted to 4.0 with 1N hydrochloric acid. The formed crystals were collected by filtration and washed with 100 ml of water, then with 100 ml of methanol, affording 7.2 g of the objective compound as yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][C@:11]([CH:17]([CH3:19])[CH3:18])([C:14]([OH:16])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20]1([C:26]2([OH:32])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]1[CH2:13][CH2:12][C@@:11]([C:14]([N:29]2[CH2:30][CH2:31][C:26]([OH:32])([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:27][CH2:28]2)=[O:16])([CH:17]([CH3:19])[CH3:18])[CH2:10]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)[C@]1(C(=O)O)CC[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: OC1(c2ccccc2)CCNCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@]1(C(=O)N2CCC(O)(c3ccccc3)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1S,3R)-3-[(tert-butoxycarbonyl)amino]-1-isopropylcyclopentane-carboxylic acid (200 mg, 0.7 mmol), 4-phenylpiperidin-4-ol (140 mg, 0.81 mmol), and triethylamine (0.15 g, 1.5 mmol) in methylene chloride (4 mL) was added (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (0.42 g, 0.81 mmol). After being stirred overnight at room temperature, the reaction was quenched by addition of a saturated NaHCO3 solution. The resulting solution was extracted with methylene chloride three times. The combined extracts were dried (MgSO4), filtered, and concentrated. The crude was carried on to the next step without purification. MS calculated for C25H38N2O4: (M+H) 431; found 431.2.
Reaction SMILES: C(=[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][CH:6]1[CH2:11][NH2:12])C(C)C.[CH3:13][C:14]([O-])([CH3:16])[CH3:15].[K+]>C1(C)C=CC=CC=1>[N:7]1[CH:8]=[CH:9][CH:10]=[CH:5][C:6]=1[CH:11]=[N:12][CH2:13][CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)C=C1C=CC=NC1CN
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)CN=Cc1ccccn1
Yield: 1583.3 %

Procedure:
The procedure is carried out as described in Example 1 (b) but with the use of 138 g (0.85 mol) of isobutylidene-2-aminomethylpyridine, 150 ml of toluene and 4 g (0.036 mol) of potassium tert-butylate. After a reaction time of 30 minutes at 40° C. and subsequent distillation, there is obtained 92 g (0.57 mol) of 2-pyridylmethylidene-isobutylamine; yield 67% of theory; b.p. 95° C./2.0×103Pa.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][C:15]2[N:20]=[CH:19][N:18]=[C:17]([NH:21][C:22](=O)[O:23]C(C)=C)[CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C[N:29]1CCOCC1.N.CO>C1COCC1>[N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][C:15]2[N:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]([NH2:29])=[O:23])[CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CN1CCOCC1
Reactant: C=C(C)OC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])c3ccccc23)ncn1
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])c3ccccc23)ncn1
Temperature: 55 °C
Reaction time: 5 h
Yield: 614.9 %

Procedure:
To a solution of prop-1-en-2-yl 6-(4-nitronaphthalen-1-yloxy)pyrimidin-4-ylcarbamate (109 mg, 0.298 mmol) and 4-methylmorpholine (3.3 μL, 0.030 mmol) in dry THF (27 mL) was added a solution of NH3 in MeOH (0.6 mL, 1M, 0.6 mmol) and the reaction mixture heated to 55° C. Further aliquots of the methanolic NH3 solution were added after 1 hr (0.6 ml, 0.6 mmol) and after 5 hr (1.0 mL, 1 mmol) and after a further 16 hr the reaction mixture was evaporated in vacuo. The residue was taken up into THF (3.0 mL) and NMM (3.3 μL, 0.030 mmol) and NH3 in MeOH (0.6 mL, 1M, 0.6 mmol) were added and the reaction mixture was heated to 55° C. Further aliquots of the methanolic NH3 solution (1M, 1.0 mL, 1.0 mmol) were added after 2 hr and after 3 hr. After 3.5 hr additional aliquots of NMM (3.3 μL, 0.030 mmol) and methanolic NH3 (1M, 1.0 mL, 1.0 mmol) were added and the reaction mixture was maintained at 55° C. for 15 hr. The reaction mixture was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, 4 g, EtOAc in isohexane, 0-100%, gradient elution) to afford the title compound as a yellow solid (60 mg, 61%); Rt 1.87 min (Method 2); m/z 326 (M+H)+ (ES+).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)=[C:4]([CH2:25][CH3:26])[CH:3]=1.C([Li])CCC.C([O:34]B(OCC)OCC)C.Cl>O1CCCC1>[CH2:25]([C:4]1[CH:3]=[C:2]([OH:34])[CH:7]=[C:6]([CH3:8])[C:5]=1[O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)[CH3:26]
Reactant: CCc1cc(Br)cc(C)c1OCCCOc1ccc(OC(F)(F)F)cc1
Reactant: CCOB(OCC)OCC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cc(O)cc(C)c1OCCCOc1ccc(OC(F)(F)F)cc1
Temperature: -70 °C
Reaction time: 2 h
Yield: 60.9 %

Procedure:
Then, 6.6 g of 4-bromo-2-ethyl-6-methyl-1-[3-(4-trifluoromethoxyphenoxy)propyloxy]benzene was dissolved in 200 ml of tetrahydrofuran, and the solution was stirred at -70° C., to which 9.6 ml of n-butyl lithium solution (in hexane, 1.58 mol/liter) was added dropwise, followed by further stirring at -70° C. for 2 hours. To this reaction mixture was added dropwise a solution of 2.2 g of triethoxy borane dissolved in 60 ml of tetrahydrofuran. Then, the reaction mixture was stirred for 1 hour, while warming to room temperature, and 13 ml of 10% aqueous hydrochloric acid solution was added in small portions, followed by stirring at room temperature for 20 minutes. The tetrahydrofuran layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated, to which 50 ml of toluene was added, and the mixture was heated at 70° C. under stirring, to which 6 ml of 30% aqueous hydrogen peroxide solution was added dropwise. The mixture was heated under reflux for 1 hour, and washed once with water, twice with 10% aqueous ammonium ferrous sulfate solution, and once with water. The toluene layer was dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 3.4 g of 3-ethyl-4-[3-(4-trifluoromethoxyphenoxy)propyloxy]-5-methylphenol (61% yield), nD25.4 1.4955.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[CH:29]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)([CH3:31])[CH3:30]>>[CH:29]([N:32]1[CH2:37][CH2:36][N:35]([CH2:2][C:3]2[N:4]([CH3:28])[C:5]3[C:10]([N:11]=2)=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:8]=[C:7]([N:18]2[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[N:20]=[C:19]2[CH3:27])[N:6]=3)[CH2:34][CH2:33]1)([CH3:31])[CH3:30]
Reactant: CC(C)N1CCNCC1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(C)C)CC3)n(C)c2n1

Procedure:
Following General Procedure E for Displacement of alkyl bromide with amines, 4-(8-(bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine and 1-isopropylpiperazine were reacted to give 441. LCMS m/z: 490.3 (MH+)
Reaction SMILES: O[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[CH:6][N:5]=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[CH:6][N:5]=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc(-c2cncnc2O)cc1
Product: Cc1ccc(-c2cncnc2Cl)cc1
Yield: 71 %

Procedure:
A mixture of 4-hydroxy-5-(p-tolyl)pyrimidine (9 g, 48 mmol) and phosphorous oxychloride (44 ml) was heated under reflux for 2 hours. After the reaction mixture was concentrated to dryness, the residue was poured into iced water to precipitate crystals which were extraced with methylene chloride. The extract was washed with water, dried and concentrated to dryness. The residue was purified by column chromatography on silica gel to afford colorless powders (7 g, 71%), m.p. 67°-70° C.
Reaction SMILES: OC([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C@H:16]3CC[C@H](CCCCC)C[CH2:17]3)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)C.S([O-])(O)(=O)=O.[K+].[C:33]1([CH3:39])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CCOCC>[CH2:39]([C@H:33]1[CH2:38][CH2:37][C@H:36]([CH:17]=[CH:16][C:13]2[CH:12]=[CH:11][C:10]([C:7]3[CH:8]=[CH:9][CH:4]=[CH:5][CH:6]=3)=[CH:15][CH:14]=2)[CH2:35][CH2:34]1)[CH2:9][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc(C(C)O)cc3)cc2)CC1
Reactant: Cc1ccccc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCOCC
Product: CCCCC[C@H]1CC[C@H](C=Cc2ccc(-c3ccccc3)cc2)CC1

Procedure:
First, 9.39 g of 4-(1-hydroxyethyl)-4′-(trans-4-pentylcyclohexyl)biphenyl, 0.52 g of potassium hydrogensulfate, and 50 ml of toluene were put in a 300 ml flask provided with a water content quantitative tube, and subjected to azeotropic dehydration under reflux for four hours. After the reaction, ether was added to the reaction solution, which was then washed with a saturated brine, and dried with sodium sulfate. The solvent was then distilled off. The residue was recrystallized from hexane to obtain 1.88 g (Y: 21.1%) of 4-(trans-4-pentylcyclohexyl)vinylbiphenyl. The purity of the resultant compound was 100.0% as measured by GC, 99.9% as measured by HPLC, and 1 spot as measured by TLC. The phase transfer temperature of the resultant compound was as follows.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].[C:14](OC(=O)C)(=[O:16])[CH3:15].C([O-])(O)=O.[Na+]>ClCCl>[C:14]([NH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: CNc1ccc(C(=O)OC)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CNc1ccc(C(=O)OC)cc1NC(C)=O
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
A solution of Example 75A (1.80 g, 10.0 mmol) in dichloromethane (100 mL) was treated sequentially with acetic anhydride (3.06 g, 30.0 mmol) and 10% NaHCO3 (100 mL) and stirred for 30 minutes. The organic layer was separated, washed with brine (30 mL), dried (MgSO4), filtered, concentrated until solid precipitated, treated with diethyl ether, and filtered to provide 1.66 g of desired product.
Reaction SMILES: [C:1]1(=[O:8])O[C:5](=[O:6])[CH2:4][C:2]1=[CH2:3].[CH2:9]([NH2:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>N1C=CC=CC=1>[CH2:3]=[C:2]1[CH2:4][C:5](=[O:6])[N:17]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:1]1=[O:8]
Reactant: CCCCCCCCN
Reactant: C=C1CC(=O)OC1=O
Solvent: c1ccncc1
Product: C=C1CC(=O)N(CCCCCCCC)C1=O
Temperature: 90 °C

Procedure:
A solution of itaconic anhydride (0.1 M) in pyridine (20 ml)was treated with octylamine (0.1 M). The reaction mixture was heated to 90° C. for six hours. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]1[CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13][C:12]=2[CH2:11]1.[CH:21](O)=O>C(=O)(O)[O-].[Na+]>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]([CH:10]2[CH2:19][CH2:18][C:17]3[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13][C:12]=3[CH2:11]2)=[C:2]([NH:1][CH3:21])[CH:7]=1
Reactant: COc1ccc(C2CCc3cc(O)ccc3C2)c(N)c1
Reactant: O=CO
Agent: O=C([O-])O
Agent: [Na+]
Product: CNc1cc(OC)ccc1C1CCc2cc(O)ccc2C1

Procedure:
A mixture of 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (800 mg) and formic acid (8 ml) was refluxed overnight. The reaction mixture was diluted with a saturated aqueous solution of sodium bicarbonate, extracted with ethyl acetate, then washed with brine, dried over anhydrous magnesium sulfate, then the solvent was evaporated in vacuo. Synthesized from the resulting residue according to an analogous synthetic method to Example 337 described below, the title compound (730 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][C@H:14]2[C@@H:18]3[O:19][C:20]([CH3:23])([CH3:22])[O:21][C@@H:17]3[C@@H:16]([O:24][CH2:25][C:26]([OH:28])=[O:27])[CH2:15]2)=[N:4][C:5]([S:9][CH2:10][CH2:11][CH3:12])=[N:6][C:7]=1[Cl:8].C(O[N:35]=O)CC(C)C>C(#N)C>[Cl:8][C:7]1[C:2]2[N:1]=[N:35][N:13]([C@H:14]3[C@@H:18]4[O:19][C:20]([CH3:22])([CH3:23])[O:21][C@@H:17]4[C@@H:16]([O:24][CH2:25][C:26]([OH:28])=[O:27])[CH2:15]3)[C:3]=2[N:4]=[C:5]([S:9][CH2:10][CH2:11][CH3:12])[N:6]=1
Reactant: CCCSc1nc(Cl)c(N)c(N[C@@H]2C[C@H](OCC(=O)O)[C@H]3OC(C)(C)O[C@H]32)n1
Reactant: CC(C)CCON=O
Solvent: CC#N
Product: CCCSc1nc(Cl)c2nnn([C@@H]3C[C@H](OCC(=O)O)[C@H]4OC(C)(C)O[C@H]43)c2n1
Temperature: 60 °C
Reaction time: 4 h
Yield: 92.6 %

Procedure:
To a solution of compound 8a (10 g) in acetonitrile (100 mL) was added isoamylnitrite (4.0 g) at 10-30° C. The reaction mixture was stirred at 50-70° C. for 3-5 h. The reaction was monitored by TLC. After completion, the reaction was quenched with 10% aqueous NaHSO3 (10 ml) and concentrated under reduced pressure. The obtained residue was extracted with ethyl acetate (10 vol). The extract was washed with water and then concentrated at reduced pressure to provide the product (9.5 g, 92.68%).