Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH2:6][CH2:7][CH2:8][S:9][C:10]1[O:11][CH:12]=[CH:13][N:14]=1)=S.[N:15]#[C:16][NH2:17].[Pb]>>[C:16]([NH:17][C:3]([NH:2][CH3:1])=[N:5][CH2:6][CH2:7][CH2:8][S:9][C:10]1[O:11][CH:12]=[CH:13][N:14]=1)#[N:15]
Reactant: N#CN
Reactant: CNC(=S)NCCCSc1ncco1
Agent: [Pb]
Product: CNC(=NCCCSc1ncco1)NC#N

Procedure:
Reaction of N-methyl-N'-[3-(2-oxazolyl)thiopropyl]thiourea with lead cyanamide by the procedure of Example 121 gives the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:20])[N:7]([CH2:16][C:17]([OH:19])=[O:18])[C:8](=[O:15])[C:9]3[C:14]=2[C:13]=1[CH:12]=[CH:11][CH:10]=3.[CH2:21]([SH:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[O:15]=[C:8]1[C:9]2[C:14]3[C:13](=[C:2]([S:31][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:3]=[CH:4][C:5]=3[C:6](=[O:20])[N:7]1[CH2:16][C:17]([OH:19])=[O:18])[CH:12]=[CH:11][CH:10]=2
Reactant: O=C(O)CN1C(=O)c2cccc3c(Cl)ccc(c23)C1=O
Reactant: CCCCCCCCCCS
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCSc1ccc2c3c(cccc13)C(=O)N(CC(=O)O)C2=O
Yield: 60.8 %

Procedure:
In a nitrogen atmosphere, a suspension of 6-chloro-1,3-dioxo-1H-benz[de]-isoquinoline-2(3H)-acetic acid (5.0 g, 17.3 mmoles, described in Example 2), 1-decanethiol (3.3 g, 3.9 ml, 19 mmoles) and anhydrous sodium carbonate (2.4 g, 17.3 mmoles) in dimethylformamide (150 ml) was stirred and heated at reflux for 15 minutes. After cooling the precipitate was collected by filtration and then dissolved in water. The solution was acidified with 2 N hydrochloric acid and extracted with ethyl acetate. The extract was dried (MgSO4) and evaporated to dryness the oily residue was triturated with hexane. The solid was recrystallized from benzene-hexane to give 4.50 g of the title product; mp 137°-140° C.; UV (MeOH) 257, 329, 343 and 382, ε=16,375, 2,849, 4,929 and 15,820, respectively; IR (CHCl3) δ2900, 1725 (inflection), 1698, 1662 cm-1 ; NMR (CDCl3) 0.85 (t, 3H, J=5), 1.25 (m, 16H), 3.1 (t, 2H, J=6.5), 4.92 (s, 2H), 8.45 (m, 3H), 9.75 (broad, 1H); Anal. Calc'd: C, 67.42%; H, 6.84%; N, 3.28%; Found: C, 67.17%; H, 6.84%; N, 3.21%.
Reaction SMILES: [ClH:1].Cl.Cl.[Cl:4][C:5]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]2[C:6]=1[CH:7]=[C:8]([C:16]1[C:17]([NH2:33])=[N:18][CH:19]=[C:20]([C:22]3[CH:23]=[N:24][N:25]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH:26]=3)[CH:21]=1)[N:9]=[CH:10]2.[Cl:34]C1C=C2C(=CC=1)C=NC(OS(C(F)(F)F)(=O)=O)=C2>>[ClH:4].[ClH:34].[ClH:1].[Cl:15][C:12]1[CH:11]=[C:6]2[C:5](=[CH:14][CH:13]=1)[CH:10]=[N:9][C:8]([C:16]1[C:17]([NH2:33])=[N:18][CH:19]=[C:20]([C:22]3[CH:23]=[N:24][N:25]([CH:27]4[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]4)[CH:26]=3)[CH:21]=1)=[CH:7]2
Reactant: O=S(=O)(Oc1cc2cc(Cl)ccc2cn1)C(F)(F)F
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1cc2c(Cl)ccc(Cl)c2cn1
Agent: Cl
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1cc2cc(Cl)ccc2cn1

Procedure:
The procedure for the preparation of 3-(5,8-dichloroisoquinolin-3-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine trihydrochloride was followed, except using trifluoromethanesulfonic acid 6-chloroisoquinolin-3-yl ester in place of trifluoromethanesulfonic acid 5,8-dichloroisoquinolin-3-yl ester. This afforded the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=2.14-2.31 (m, 4H), 3.04-3.16 (m, 2H), 3.33-3.41 (m, 2H), 4.47-4.62 (m, 3H), 7.83 (dd, J=8.8, 2.0 Hz, 1H), 8.15 (s, 1H), 8.21 (d, J=1.8 Hz, 1H), 8.34 (d, J=8.8 Hz, 1H), 8.50 (d, J=2.0 Hz, 1H), 8.54 (s, 1H), 8.73 (s, 1H), 8.84 (d, J=2.0 Hz, 1H), 9.22 (br. s., 1H), 9.34 (br. s., 1H), 9.52 (s, 1H), MS(ES+): m/z=404.90/406.78 [MH+]. HPLC: tR=1.80 min (ZQ2, polar—5 min).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][C:8]([OH:10])=O)(=[O:4])[CH:2]=[CH2:3].S(Cl)([Cl:13])=O>C(Cl)Cl>[C:1]([O:5][CH2:6][CH2:7][C:8]([Cl:13])=[O:10])(=[O:4])[CH:2]=[CH2:3]
Reactant: O=S(Cl)Cl
Reactant: C=CC(=O)OCCC(=O)O
Solvent: ClCCl
Product: C=CC(=O)OCCC(=O)Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-Carboxyethyl acrylate (1 eq.) is dissolved in CH2Cl2 and the solution is cooled in an ice bath. Thionyl chloride (1 eq.) is added dropwise and the mixture is allowed to warm to room temperature and stir for 4 hours. The solvent is removed under reduced pressure and the desired product is isolated by vacuum distillation.
Reaction SMILES: CO[C:3]([S:5][S:6][CH2:7][C:8]([NH:10][CH:11]([CH2:15][C:16]([OH:18])=[O:17])[C:12]([OH:14])=[O:13])=[O:9])=O.S[CH:20]([OH:22])C>CO>[OH:22][CH2:20][CH2:3][S:5][S:6][CH2:7][C:8]([NH:10][CH:11]([CH2:15][C:16]([OH:18])=[O:17])[C:12]([OH:14])=[O:13])=[O:9]
Reactant: COC(=O)SSCC(=O)NC(CC(=O)O)C(=O)O
Reactant: CC(O)S
Solvent: CO
Product: O=C(O)CC(NC(=O)CSSCCO)C(=O)O
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 74.6 %

Procedure:
A round bottomed flask was charged with 399.6 mg (1 eq., 1.495 mmole) (methoxycarbonyldithio)ethylamidosuccinic acid dissolved in 5 ml methanol, cooled to 0° C., purged with argon, and then treated dropwise with a solution of 110.9 mg (0.95 eq., 995.9 μl, 1.42 mmole) mercaptoethanol in 4 ml methanol over a 30 min period. The stirred solution was allowed to warm to room temperature over 1 hour and then stirred at this temperature for an additional 3.5 hours, after which, the solvent was evaporated on the rotary evaporator (bath temp. 30° C.). The residue was subjected to vacuum transfer for 0.5 hours to ensure that all mercaptoethanol was removed. The resultant white solid was then titurated with 3 ml ether and then the solid was pumped on the high vacuum for 10 min. (bath temp. 40° C.) to yield approximately 0.3 g of (2-hydroxyethyldithio)ethylamidosuccinic acid as a pure white solid. 1H NMR (d6DMSO/TMS) δ: 2.31 (2H, t, J=6.02 Hz, CH2), 2.41 (2H, t, J=6.39 Hz, CH2), 2.77 (4H, q, J=6.86 Hz, 2×CH2), 3.35 (2H, t, J=6.75 Hz, CH2), 3.60 (2H, t, J=6.46 Hz, CH2), 8.06 (1H, t, NH). 13C NMR (d6DMSO/TMS) δ: 30.53 (CH2), 31.62 (CH2), 38.46 (CH2), 39.68 (CH2), 42.11 (CH2), 61.27 (CH2), 174.76 (Q), 176.63 (Q).
Reaction SMILES: [CH2:1]([C@H:8]([CH2:25][C@@H:26]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)C(O)=O)[C:9]([NH:11][C@H](C(O)=O)COCC1C=CC=CC=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:37][C:38]1([CH3:67])[O:42][CH:41]([CH2:43][O:44][C:45]([C@H](CC2C=CC=CC=2)C[C@@H](CC2C=CC=CC=2)C(O)=O)=[O:46])[CH2:40][O:39]1.[C:68]([O:71]CC)(=[O:70])[CH3:69]>>[CH3:37][C:38]1([CH3:67])[O:42][CH:41]([CH2:43][O:44][C:45]([C@H:26]([CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:25][C@@H:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]([NH:11][C@H:69]([C:68]([OH:71])=[O:70])[CH2:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])=[O:46])[CH2:40][O:39]1
Reactant: O=C(O)[C@H](Cc1ccccc1)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](COCc1ccccc1)C(=O)O
Reactant: CC1(C)OCC(COC(=O)[C@H](Cc2ccccc2)C[C@@H](Cc2ccccc2)C(=O)O)O1
Reactant: CCOC(C)=O
Product: CC1(C)OCC(COC(=O)[C@H](Cc2ccccc2)C[C@@H](Cc2ccccc2)C(=O)N[C@@H](CCc2ccccc2)C(=O)O)O1
Reaction time: 8 h

Procedure:
To a solution of 0.5 g of (L)-homophenylalanine 1,2:5,6-di-O-isopropylidene-D-glucofuranos-3-yl ester, 0.51 g of 4-[(2,2-dimethyl-1,3-dioxolan-4-yl)-methoxycarbonyl]-(S,S)-2,4-dibenzylbutyric acid is added 0.23 g of 1-(3-dimethylminopropyl)-3-ethylcarbodiimide hydrochloride. The solution is stirred overnight. The solution is diluted with ethyl acetate, washed in sequence with 1N hydrochloric acid, water, saturated sodium bicarbonate, water, dried (Na2SO4), filtered and concentrated. The residue is flash chromatographed on silica gel eluting with ethyl acetate-methylene chloride (1:4) giving N-{4-[(2,2-dimethyl-1,3-dioxolan-4-yl)-methoxycarbonyl]-(S,S)-2,4-dibenzylbutyryl}-(L)-homophenylalanine 1,2:5,6-di-O-isopropylidene-D-glucofuranos-3-yl ester melting at 48°-50°.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]([O:12]C)=O)[CH2:4][CH2:3]1.[CH2:14]([NH2:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C(Cl)(Cl)Cl.CO>[CH2:14]([NH:26][C:10](=[O:12])[CH2:9][CH2:8][N:5]1[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: COC(=O)CCN1CCN(C)CC1
Reactant: CCCCCCCCCCCCN
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCNC(=O)CCN1CCN(C)CC1
Temperature: 185 °C

Procedure:
Methyl 3-(4-methylpiperazin-1-yl)propanoate 40.0 g (0.21 moles) and dodecylamine 39.7 g (0.21 moles) are charged into a 3-neck 250-mL round bottom flask equipped with a Dean-Stark trap, thermocouple, and reflux condenser. The mixture is agitated using a magnetic stirring bar and heated to 185° C. for five hours. The volume of methanol that is distilled from the reaction is used to monitor the progress of the reaction. Evidence of the chemical transformation is observed by thin layer chromatography (TLC) analysis using a 4:1 CHCl3/MeOH as mobile phase. The final product is a light yellow solid at ambient temperature. 1H-NMR (300 MHz, CDCl3): δ 2.98 (m, 2H), 2.07 (m, 1511), 1.27 (m, 2H), 1.0 (m, 18H), 0.65 (t, 6.7 Hz, 3H). 13C-NMR (75 MHz, CDCl3): δ 171.70, 54.60, 54.39, 54.34, 53.45, 51.86, 45.39, 38.45, 31.60, 31.38, 29.14, 29.11, 28.93, 28.85, 28.83, 26.65, 22.15, 13.61.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C@@H:13]2[OH:21])=[N:5][C:6]([CH2:9]C)=[CH:7][N:8]=1)C.ClC1C(C)=NC=C(C)N=1>>[CH3:1][C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C@@H:13]2[OH:21])=[N:5][C:6]([CH3:9])=[CH:7][N:8]=1
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Agent: Cc1cnc(C)c(Cl)n1
Product: Cc1cnc(C)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 3-chloro-2,5-dimethylpyrazine and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ) 7.68, 7.32–7.28, 5.59, 4.80, 3.27, 3.09, 2.92, 2.38; HRMS (FAB) calcd for C15H17N3O+H 256.1450, found 256.1460.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[CH:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1.C(OCC)(=[O:22])C>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[CH:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N+:14]=3[O-:22])[C:6]=2[CH:19]=1
Reactant: CC1(C)C=C(c2ccccn2)c2cc(Br)ccc2O1
Reactant: CCOC(C)=O
Product: CC1(C)C=C(c2cccc[n+]2[O-])c2cc(Br)ccc2O1

Procedure:
In an analogous manner to that described in the first paragraph of Example 6, from 6-bromo-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran there was obtained 2-(6-bromo-2,2-dimethyl-2H-1-benzopyran-4-yl)pyridine N-oxide of melting point 146°-148° C. (from ethyl acetate).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][NH:6][C:7](=[O:27])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:19][C:20]2[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=2)[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].[F:35][C:36]([F:48])([F:47])[O:37][C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1>>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][NH:6][C:7](=[O:27])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:19][C:20]2[CH:25]=[CH:24][C:23]([C:41]3[CH:40]=[CH:39][C:38]([O:37][C:36]([F:35])([F:47])[F:48])=[CH:43][CH:42]=3)=[CH:22][CH:21]=2)[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:10][CH:9]=1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CC(C)C)Sc2ccc(Br)cc2)cc1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)CCNC(=O)c1ccc(C(CC(C)C)Sc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)cc1
Yield: 71.8 %

Procedure:
3-{4-[1-(4-bromo-phenylsulfanyl)-3-methyl-butyl]-benzoylamino}-propionic acid methyl ester (350 mg, 0.75 mmol), potassium carbonate (311 mg, 2.25 mmol), 4-trifluoromethoxylphenyl boronic acid (311 mg, 1.5 mmol) and tetrakis-(triphenylphosphine)palladium (87 mg, 0.075 mmol) are place in a flask. After the reaction is purged with N2 for several times, THF/H2O (20 ml/5 ml) is added. The resulting solution is refluxed overnight, loaded on silica gel, eluted with hexane and ethyl acetate to give 3-{4-[3-Methyl-1-(4′-trifluoromethoxy-biphenyl-4-ylsulfanyl)-butyl]-benzoylamino}-propionic acid methyl ester (294 mg) as a yellow solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH:12]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(N(CC)CC)C.O>CN(C)C=O>[CH:12]1([NH:18][C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: NC1CCCCC1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=[N+]([O-])c1cc(F)ccc1NC1CCCCC1
Temperature: 25 °C
Yield: 82.6 %

Procedure:
A solution of 5.0 g (31 mmol) 2,5-difluoronitrobenzene, 3,8 ml (31 mmol) cyclohexylamine and 4.4 ml (31 mmol) triethylamine in 50 ml dimethylformamide was stirred at 80° C. for 2 h. After cooling to 25° C. 100 ml water was added. The precipitate was filtered off and washed with water to give 6.1 g (82%) N-cyclohexyl-4-fluoro-2-nitroaniline. M.p. 93.0° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3]O.[OH2:5].C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:17]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18]1>>[Br:1][CH:2]([O:5][CH:22]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1)[CH3:3]
Reactant: O
Reactant: OCCBr
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(Br)OC1CCCCO1

Procedure:
To 2-bromoethanol (125 g, 1.0 equiv), cooled in an ice bath, was added p-toluenesulfonic acid monohydrate (catalytic amount). Dihydropyran (93 g, 1.1 equiv) was added dropwise, with stirring, under an argon atmosphere. When the addition was complete, the reaction was stirred for 1 hour at room temperature. The residue was purified by short path distillation, giving approximately 125 g of product.
Reaction SMILES: [C:1]12([C:11]3[CH:30]=[CH:29][C:14]([O:15][CH2:16][C:17]4[NH:18][C:19]5[CH:25]=[C:24]([C:26](O)=[O:27])[CH:23]=[CH:22][C:20]=5[N:21]=4)=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Cl-].[NH4+].C(Cl)CCl.C1C=CC2N(O)N=[N:43]C=2C=1.CCN(C(C)C)C(C)C>CN(CC1C=C(CN(C)C)C(O)=C(CN(C)C)C=1)C>[C:1]12([C:11]3[CH:30]=[CH:29][C:14]([O:15][CH2:16][C:17]4[NH:18][C:19]5[CH:25]=[C:24]([C:26]([NH2:43])=[O:27])[CH:23]=[CH:22][C:20]=5[N:21]=4)=[CH:13][CH:12]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: O=C(O)c1ccc2nc(COc3ccc(C45CC6CC(CC(C6)C4)C5)cc3)[nH]c2c1
Reactant: On1nnc2ccccc21
Agent: CN(C)Cc1cc(CN(C)C)c(O)c(CN(C)C)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccc2nc(COc3ccc(C45CC6CC(CC(C6)C4)C5)cc3)[nH]c2c1
Temperature: 25 °C
Yield: 38 %

Procedure:
To solution of 2-(4-adamantan-1-yl-phenoxymethyl)-3H-benzoimidazole-5-carboxylic acid (44-0.8 mg, 0.11 mmol), ammonium chloride (11.8 mg, 0.22 mmol), EDC (32.6 mg, 0.17 mmol) and HOBt (23.0 mg, 0.17 mmol) in DMF 3.0 mL was added DIPEA (0.03 ml 0.17 mmol). After stirring at room temperature, the mixture was partitioned between ethyl acetate and 10% HCl. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2:MeOH=6:1) to give 2-(4-adamantan-1-yl phenoxymethyl)-3H benzoimidazole-5-carboxylic acid amide as a white solid (16.8 mg, 37.5% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([CH3:17])[CH:5]([F:16])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.ClC1C=C(C=CC=1)C(OO)=[O:24].S(C1C(C)=CC(O)=C(C(C)(C)C)C=1)C1C(C)=CC(O)=C(C(C)(C)C)C=1>ClCCCl>[CH3:1][O:2][C:3]([C:4]1([CH:5]([F:16])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:17][O:24]1)=[O:18]
Reactant: COC(=O)C(C)C(F)CCCCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cc1cc(O)c(C(C)(C)C)cc1Sc1cc(C(C)(C)C)c(O)cc1C
Solvent: ClCCCl
Product: COC(=O)C1(C(F)CCCCc2ccccc2)CO1
Reaction time: 8 h

Procedure:
A solution of 500 mg (2.0 mmol) of β-fluoro-α-methylbenzene-heptanoic acid methyl ester in 50 ml of 1,2-dichloroethane is treated with 1.38 g (8 mmol) of m-chloroperoxybenzoic acid and 20 mg of 4,4'-thiobis(6-t-butyl-m-cresol). The mixture is heated to reflux and maintained under nitrogen for 10.5 hours. An additional 1.38 g (8 mmol) of m-chloroperoxybenzoic acid and 20 mg of 4,4'-thiobis(6-t-butyl-m-cresol) is added and reflux is continued for 8 hours.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:38]=[CH:37][C:18]([CH2:19][C:20]2[S:21][C:22]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[C:23]([CH2:25][CH2:26][C:27]([O:29]C)=[O:28])[N:24]=2)=[CH:17][CH:16]=1.O.[OH-].[Li+].O1CCCC1.Cl>CO.O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:38]=[CH:37][C:18]([CH2:19][C:20]2[S:21][C:22]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[C:23]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])[N:24]=2)=[CH:17][CH:16]=1
Reactant: COC(=O)CCc1nc(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)sc1-c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cc2nc(CCC(=O)O)c(-c3ccccc3)s2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.6 %

Procedure:
A mixture of methyl 3-[2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-5-phenyl-4-thiazolyl]propionate (487 mg), lithium hydroxide hydrate (117 mg), tetrahydrofuran (6 ml), water (4 ml) and methanol (4 ml) was stirred at room temperature for 1.5 hrs. 1N Hydrochloric acid (2.8 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give 3-[2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-5-phenyl-4-thiazolyl]propionic acid (434 mg, yield 92%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 119–120° C.
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[C:12]2[N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[N:9]([CH2:22][CH2:23][O:24][CH3:25])[C:8]=2[C:7]([O:26][CH3:27])=[CH:6][C:5]=1[CH:28]=[O:29]>C(O)C>[Br:3][C:4]1[C:12]2[N:11]=[C:10]([C:13]3[CH:14]=[CH:15][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:17][CH:18]=3)[N:9]([CH2:22][CH2:23][O:24][CH3:25])[C:8]=2[C:7]([O:26][CH3:27])=[CH:6][C:5]=1[CH2:28][OH:29]
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(C=O)cc(OC)c21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(CO)cc(OC)c21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 102.2 %

Procedure:
NaBH4 (65 mg, 1.72 mmol) is added to a solution of 370 mg (0.858 mmol) 4-bromo-2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carbaldehyde in 5 ml absolute ethanol at 0° C. The reaction mixture is stirred at 0° C. for 20 min. Then the reaction mixture is poured on water and extracted (3×) with dichloromethane/isopropanol (3:1). The combined organic layers are washed with water (2×) and brine, dried over MgSO4, filtered and concentrated in vacuo to afford 380 mg of the title compound as a pure crystalline solid.
Reaction SMILES: Cl.ClCC1C=CC(N2C=CN=C2)=CC=1.[CH3:15][O:16][CH:17]1[C:22](=O)[CH2:21][CH2:20][N:19]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:18]1.[CH3:29][CH:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[NH2:31].S1C=CC=C1.[H][H]>C(O)C.[Pd].CO>[CH3:15][O:16][C@H:17]1[C@@H:22]([NH:31][CH:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH3:29])[CH2:21][CH2:20][N:19]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:18]1
Reactant: [H][H]
Reactant: CC(N)c1ccccc1
Reactant: CCOC(=O)N1CCC(=O)C(OC)C1
Agent: [Pd]
Agent: Cl
Agent: ClCc1ccc(-n2ccnc2)cc1
Solvent: c1ccsc1
Solvent: CO
Solvent: CCO
Product: CCOC(=O)N1CC[C@H](NC(C)c2ccccc2)[C@H](OC)C1
Yield: 51 %

Procedure:
A solution of 20 parts of ethyl 3-methoxy-4-oxo-1-piperidinecarboxylate, 12 parts of (-)-α-methylbenzenemethanamine, 2 parts of a solution of thiophene in ethanol 4% and 200 parts of methanol was hydrogenated at normal pressure and at room temperature with 4 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated in vacuo. The residue was purified by HPLC using a mixture of hexane, trichloromethane and methanol (50:49.5:0.5 by volume) as eluent. The pure A-fractions were collected and the eluent was evaporated, yielding 15.62 parts (51%) of (-)-ethyl cis-3-methoxy-4-[(1-phenylethyl)-amino]-1-piperidinecarboxylate as a residue (intermediate 103).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6](Cl)[N:5]=1.[CH2:14]([OH:16])[CH3:15]>>[NH2:3][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([O:16][CH2:14][CH3:15])[N:5]=1
Reactant: CCO
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Product: CCOc1ccc([N+](=O)[O-])c(N)n1
Reaction time: 0.17 h

Procedure:
2.4 g of 60% sodium hydride was slowly added to 100 ml of ethanol and stirred as it was at room temperature for 10 minutes. 10 g of 2-amino-6-chloro-3-nitropyridine was added thereto and reacted at room temperature for 30 minutes. After concentration, water was added thereto, and it was extracted with ethyl acetate. It was washed with water and brine sucsessively, and dried over anhydrous sodium sulfate. After concentration, 9.7 g of the title compound was obtained.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([CH3:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:17]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]([CH3:28])[CH3:27])[C:21]=1[N:29]=[C:30]=[O:31])([CH3:19])[CH3:18].C([N-]C(C)C)(C)C.[Li+]>>[CH3:19][CH:17]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]([CH3:27])[CH3:28])[C:21]=1[NH:29][C:30](=[O:31])[CH2:10][C:8](=[O:9])[CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:18]
Reactant: CC(=O)C(c1ccccc1)c1ccccc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CC(=O)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, mp 153°-155° C., was prepared from 1,1-diphenylacetone (5.0 g, 0.023 mol), 2,6-diisopropylphenyl isocyanate (4.6 g, 0.023 mol) and lithium diisopropylamide (0.023 mol) using the procedure described in Example 1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[CH:7][NH:6][C:5]2=[O:14].[C:15](OC(=O)C)(=[O:17])[CH3:16]>N1C=CC=CC=1>[C:15]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[CH:7][NH:6][C:5]2=[O:14])(=[O:17])[CH3:16]
Reactant: COc1cc2nc[nH]c(=O)c2cc1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1cc2nc[nH]c(=O)c2cc1OC(C)=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 53 %

Procedure:
To a suspension of 6-hydroxy-7-methoxyquinazolin-4(3H)-one (0.57 g) and pyridine (4 mL) was added acetic anhydride (10 mL) at room temperature. The reaction mixture was stirred at 100° C. for 3 hours, and then poured into ice-water. The resulting mixture was filtered to give the title compound (0.40 g, 53.00%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, d6-DMSO) δ: 2.30 (s, 3H), 3.92 (s, 3H), 7.28 (s, 1H), 7.75 (s, 1H), 8.08 (s, 1H).