Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:23][C@H:22]([CH2:24][O:25][CH2:26][CH3:27])[C@@H:17]([O:18]C(=O)C)[C@H:12]1[O:13]C(=O)C.[I:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][NH2:33].Cl>>[I:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][NH:33][C:2]1[C:3]2[N:4]=[CH:5][N:6]([C:7]=2[N:8]=[CH:9][N:10]=1)[C@@H:11]1[O:23][C@H:22]([CH2:24][O:25][CH2:26][CH3:27])[C@@H:17]([OH:18])[C@H:12]1[OH:13]
Reactant: CCOC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NCc1cccc(I)c1
Agent: Cl
Product: CCOC[C@H]1O[C@@H](n2cnc3c(NCc4cccc(I)c4)ncnc32)[C@H](O)[C@@H]1O

Procedure:
Method B. The reaction was carried out with 6-chloro-9-(2,3-di-O-acetyl-5-O-ethyl-β-D-ribofuranosyl)-purine (62, 367 mg, 0.92 mmol) and 3-iodobenzylamine.HCl (1.38 mmol, 372 mg). The mixture was purified by column chromatography (eluens 5% MeOH in CH2Cl2). Yield 339 mg (0.66 mmol, 72%), mp 164–166° C.; Rf 0.40 (10% MeOH in CH2Cl2). The product was re-crystallized from CH3CN; 1H NMR (DMSO-d6) δ 8.45 (bs, 1H, NH), 8.37 (s, 1H, H-8), 8.21 (s, 1H, H-2), 7.71 (s, 1H, CCHCI), 7.57 (d, 1H, J=7.90 Hz, CCHCHCH), 7.34 (d, 1H, J=6.52 Hz, CCHCH), 7.09 (t, 1H, J==6.87 Hz, CCHCH), 5.91 (d, 1H, J=4.46 Hz, H-1′), 5.53 (d, 1H, J=5.49 Hz, OH-2′), 5.27 (d, 1H, J=4.80 Hz, OH-3′), 4.67–4.64 (m, 2H, NHCH2), 4.56 (q, 1H, J=4.81 Hz, H-2′), 4.17 (q, 1H, J=4.81 Hz, H-3′), 4.00 (q, 1H, J=4.12 Hz, H-4′), 3.60 (dq, 2H, J=9.61 Hz, J=3.43 Hz, H-5′), 3.47 (q, 2H, J=6.52 Hz, OCH2CH3), 1.12 (t, 3,3 J=6.52 Hz, CH3); MS m/z 512 (M+H)+; Anal. (C19H22IN5O4.0.3 CH3CN) C, H, N.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][NH:20][C:21]([NH:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]=[C:26]([CH3:34])[CH:25]=3)=[O:22])[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:35](I)[CH3:36]>CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:35][CH3:36])[CH:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][NH:20][C:21]([NH:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]=[C:26]([CH3:34])[CH:25]=3)=[O:22])[CH2:16][CH2:17]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: Cc1cc(NC(=O)NCCN2CCC(NS(=O)(=O)c3ccc(Br)cc3)CC2)c2ccccc2n1
Reactant: CCI
Solvent: CS(C)=O
Product: CCN(C1CCN(CCNC(=O)Nc2cc(C)nc3ccccc23)CC1)S(=O)(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-bromo-N-(1-{2-[3-(2-methyl-quinolin-4-yl)-ureido]-ethyl}-piperidin-4-yl)-benzenesulfonamide (Example 109., 27.3 mg, 0.05 mmol) in DMSO (1 mL) are added ethyliodide (7.8 mg, 0.05 mmol) and CsCO3 (40 mg, 12 mmol). The reaction mixture is stirred at room temperature for 3 h and then quenched with formic acid (0.25 mL). The reaction mixture is purified by preparative HPLC to provide the title compound.
Reaction SMILES: Cl.O1CCOCC1.[F:8][C:9]([F:47])([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:10][NH:11][C:12]1[C:13]([F:40])=[C:14]([CH2:19][C:20]([NH:22][CH2:23][C:24]2[C:25]([CH3:39])=[N:26][C:27]([NH:31]C(OC(C)(C)C)=O)=[CH:28][C:29]=2[CH3:30])=[O:21])[C:15]([Cl:18])=[CH:16][CH:17]=1>>[ClH:18].[NH2:31][C:27]1[N:26]=[C:25]([CH3:39])[C:24]([CH2:23][NH:22][C:20](=[O:21])[CH2:19][C:14]2[C:15]([Cl:18])=[CH:16][CH:17]=[C:12]([NH:11][CH2:10][C:9]([F:8])([F:47])[C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:13]=2[F:40])=[C:29]([CH3:30])[CH:28]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)Cc1c(Cl)ccc(NCC(F)(F)c2ccccc2)c1F
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(N)nc(C)c1CNC(=O)Cc1c(Cl)ccc(NCC(F)(F)c2ccccc2)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 153.4 %

Procedure:
A solution of HCl in 1,4-dioxane (4.0 M, 0.5 mL, 2 mmol) was added to 2-{3-[(2,2-difluoro-2-phenylethyl)amino]-6-chloro-2-fluorophenyl}-N-({6-[(tert-butoxy) carbonylamino]-2,4-dimethyl(3-pyridyl)}methyl) acetamide (18.5 mg, 32 μmol), as prepared in the preceding step. After stirring at ambient temperature for 3 hours, solid precipitated. A solution of MeOH (0.1 mL) in DCM (1 mL) was added to dissolve the solid. After stirring for another 2 hours the reaction was concentrated to give a brown solid, that was washed with ether and DCM and dried in vacuo to produce the title compound (12.6 mg, 77% yield) as a pale brown solid. 1H-NMR (400 MHz, CD3OD) δ 8.40 (bs, 1H),7.53-7.51 (m, 2H), 7.47-7.40 (m, 3H), 6.93 (dd, J=8.8, 1.3 Hz, 1H), 6.68 (s, 1H), 6.64 (t, J=9.1 Hz, 1H), 4.31 (d, J=4.6 Hz, 2H), 3.81 (t, J=13.8 Hz, 21H), 3.67 (d, J=1.2 Hz, 2H), 2.54 (s, 3H), 2.42 (s, 3H). Mass spectrum (LCMS, ESI) calc'd for C24H25ClF3N4O (M+H): 477.2. Found: 477.5.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].[CH2:13](I)[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:13]([O:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7])[CH3:14]
Reactant: CCI
Reactant: COC(=O)c1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(C(=O)OC)c(O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.9 %

Procedure:
Methyl 4-hydroxysalicylate (10.0 g, 59.5 mmol) was dissolved in DMF. Ethyl iodide (9.74 g, 62.4 mmol) was added, followed by potassium carbonate (8.63 g, 62.4 mmol), and the reaction mixture was stirred under N2 at room temperature for 18 h. The reaction mixture was concentrated in vacuo to remove the majority of the DMF, and the residue taken up in EtOAc, and washed with water (2×), dried, and concentrated in vacuo to give an off-white solid. Recrystallization from hexane gave 6.41 g, (54.9%) of methyl 4-ethoxysalicylate as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[NH:4][C:3]=1[C:18]([O:20][CH3:21])=[O:19].Br[CH2:23][CH2:24][CH2:25][O:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[N:4]([CH2:23][CH2:24][CH2:25][O:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29][CH:28]=2)[C:3]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: BrCCCOc1cccc2ccccc12
Reactant: COC(=O)c1[nH]c2cccc(-c3ccccc3C)c2c1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1c(Br)c2c(-c3ccccc3C)cccc2n1CCCOc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 126B (1.14 g) and 1-(3-bromopropoxy)naphthalene (0.922 g) in N,N-dimethylformamide (20 ml) was added cesium carbonate (2.158 g). The reaction was stirred at room temperature overnight and diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography, eluting with 0-50% dichloromethane in hexane to provide the title product.
Reaction SMILES: C(OC(OCC)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)C.C([Li])CCC.[O:18]=[C:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1.Cl>C1COCC1.C(OCC)(=O)C>[OH:18][C:19]1([C:6]2[NH:5][CH:9]=[CH:8][N:7]=2)[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOC(OCC)n1ccnc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ncc[nH]2)CC1
Temperature: 40 °C
Reaction time: 2 h
Yield: 42.9 %

Procedure:
A mixture of imidazole (25.6 g, 0.4 mol), triethyl orthoformate (236.8 g, 1.6 mol) and p-toluenesulfonic acid (2 g) was heated at 130° C. overnight with no condenser so ethanol can boil off. The excess orthoformate was removed by rotary evaporation and the residue was purified by vacuum distillation to give 1-(diethoxymethyl)-1H-imidazole (46.7 g). To a solution of the resulting protected imidazole (46.7 g) in anhydrous THF (350 mL) under N2 cooled at −40° C., was added n-butyllithium (2.5 M in hexane, 110 mL) at such a rate that the temperature did not rise above −35° C. After complete addition, a solution of tert-butyl 4-oxopiperidine-1-carboxylate (18.25 g, 91.5 mmol) in anhydrous THF (70 mL) under N2 was added dropwise over 10 minutes keeping the temperature below −40° C. The reaction was stirred at 40° C. for 2 hours then 350 mL of 0.1 N HCl added and stirred for 15 minutes, ethyl acetate (350 mL) added and stirred for 5 minutes. The organic layer was separated and aqueous extracted with ethyl acetate (350 mL). The combined organic layers were washed with saturated NaHCO3, brine, dried over MgSO4, filtered and evaporated. The residue was purified by column chromatography on silica eluting with 10% methanol in ethyl acetate with 0.5% ammonia hydroxide to give tert-butyl 4-hydroxy-4-(1H-imidazol-2-yl)piperidine-1-carboxylate (10.5 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][C:12]1[S:16][C:15]([CH:17]=O)=[CH:14][CH:13]=1.C(O)(=O)C.CN(B)C>O.C1(C)C=CC=CC=1>[Cl:11][C:12]1[S:16][C:15]([CH2:17][NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(Cl)s1
Reactant: Nc1ccc(C(=O)O)cc1
Agent: BN(C)C
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1ccc(NCc2ccc(Cl)s2)cc1
Temperature: 40 °C

Procedure:
A mixture containing 46.6 grams (0.34 moles) of p-aminobenzoic acid, 50 grams (0.34 moles) of 5-chloro-2-thiophenecarboxaldehyde and 400 ml. of toluene was heated to reflux for about three and a half hours. The water formed was collected in a Dean-Stark trap. The reaction mass was cooled at the end of this period and the Schiff base collected as a tan solid. To a mixture of the intermediate Schiff base and 1.2 liters of glacial acetic acid 21.2 grams (0.36 moles) of dimethylaminoborane was added. The reaction mass was warmed to 40° C. for about 30 minutes and poured in 2 liters of ice water. The white precipitate of 4-(((5-chloro-2-thienyl)methyl)amino)benzoic acid was washed in water, dried, and recrystallized from toluene. The melting point was 177°-178° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH2:23][CH3:24])[CH:15]=1)[CH2:10][C:11](=[O:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH2:23][CH3:24])[CH:15]=1)[CH2:10][CH:11]([OH:13])[CH3:12])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOc1cc(C(CC(C)=O)NC(=O)OC(C)(C)C)ccc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1cc(C(CC(C)O)NC(=O)OC(C)(C)C)ccc1OC
Temperature: -15 °C
Reaction time: 4 h

Procedure:
A mixture of (tert-butoxy)-N-[1-(3-ethoxy-4-methoxyphenyl)-3-oxobutyl]carboxamide (2.0 g, 5.92 mmol) and sodium borohydride (0.4 g, 12.0 mmol) in methanol (40 mL) and tetrahydrofuran (10 mL) was stirred at −10 to −20° C. for 4 hours. The mixture was quenched with water (10 mL) and then concentrated in vacuo to afford an oil. The oil was dissolved in ethyl acetate and washed with water, brine, dried, and concentrated in vacuo to afford an oil. The oil was purified by chromatography (silica gel, methylene chloride:ethyl acetate 8:2) to give the two diasteromers of (tert-butoxy)-N-[1-(3-ethoxy-4-methoxyphenyl)-3-hydroxybutyl)carboxamide:
Reaction SMILES: ClC1N=C(Cl)C([CH2:9][NH:10][C:11]2[CH:16]=[CH:15][C:14](OC)=[CH:13][CH:12]=2)=CN=1.C[O:20]C(C)(C)C>>[C:11]1([N:10]=[C:9]=[O:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1ccc(NCc2cnc(Cl)nc2Cl)cc1
Reactant: COC(C)(C)C
Product: O=C=Nc1ccccc1
Temperature: 55 °C

Procedure:
A 500-mL, three-necked flask equipped with a mechanical stirrer, thermometer, condenser, and nitrogen-inlet bubbler was charged with [(2,4-dichloropyrimidin-5-yl)methyl](4-methoxyphenyl)amine (59.6 g, 209.7 mmol) (from Example 1d supra) and tert-butyl methyl ether (300 mL) (Aldrich). After heating to 55° C. to give a clear solution, phenyl isocyanate (27.48 g, 230.7 mmol) (Aldrich) was added and the mixture was heated to reflux for 10 hours. TLC analysis indicated essentially complete reaction. After cooling to room temperature, the resulting solid was collected by filtration, washed with tert-butyl methyl ether (100 mL), and dried by suction to give N-[(2,4-dichloropyrimidin-5-yl)methyl]-N-(4-methoxyphenyl)(phenylamino) carboxamide as white crystals; 98.46% pure by HPLC analysis. (Yield 78.8 g, 91.3%).
Reaction SMILES: Cl.[C:2]1([C@@H:8]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:9][O:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][C:30]([CH3:32])=O>>[CH:30]([N:15]1[CH2:16][CH2:17][CH:12]([CH2:11][O:10][CH2:9][C@H:8]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:14]1)([CH3:32])[CH3:29]
Reactant: O=C(N[C@@H](COCC1CCNCC1)c1ccccc1)OCc1ccccc1
Reactant: CC(C)=O
Agent: Cl
Product: CC(C)N1CCC(COC[C@H](NC(=O)OCc2ccccc2)c2ccccc2)CC1

Procedure:
Using alkylation method A, benzyl N-[(R)-1-phenyl-2-(piperidin-4-ylmethoxy)ethyl]carbamate hydrochloride (3.7 g, 0.91 mmol) and acetone (2.3 g, 40 mmol) afforded, after purification (SiO2: 8:2:1 hexane:EtOAc:isopropylamine), 1.1 g (29%) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[C:15]([C:17]([NH:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[O:18])[CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:45])[C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=2[C:41]([F:44])([F:43])[F:42])=[CH:28][CH:27]=1>>[CH3:23][N:22]([CH3:24])[CH2:21][CH2:20][NH:19][C:17]([C:15]1[CH:14]=[CH:13][C:5]2[C:6](=[O:12])[NH:7][C:8]3[C:3]([C:4]=2[CH:16]=1)=[C:2]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:45])[C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=2[C:41]([F:44])([F:42])[F:43])=[CH:28][CH:27]=1)[CH:11]=[CH:10][N:9]=3)=[O:18]
Reactant: Nc1ccc(NC(=O)c2ccc(F)cc2C(F)(F)F)cc1
Reactant: CN(C)CCNC(=O)c1ccc2c(=O)[nH]c3nccc(Cl)c3c2c1
Product: CN(C)CCNC(=O)c1ccc2c(=O)[nH]c3nccc(Nc4ccc(NC(=O)c5ccc(F)cc5C(F)(F)F)cc4)c3c2c1
Yield: 48.1 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 267 using 296 (40 mg, 0.12 mmol), and N-(4-aminophenyl)-4-fluoro-2-(trifluoromethyl)benzamide (36 mg, 0.12 mmol) to provide 297 (35 mg, 50% yield) as a solid. LC-MS (M+H=607, obsd.=607).
Reaction SMILES: C([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])[C@H:7]([CH2:16][OH:17])[CH2:6]1)(=O)C.[OH-].[Na+]>CO>[CH2:13]([O:12][C:10]([N:8]1[CH2:9][C@@H:5]([SH:4])[CH2:6][C@H:7]1[CH2:16][OH:17])=[O:11])[CH:14]=[CH2:15]
Reactant: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1CO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=CCOC(=O)N1C[C@@H](S)C[C@H]1CO
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
A solution of (2S,4S)-4-acetylthio-N-allyloxycarbonyl-2-hydroxymethylpyrrolidine (1.17 g, 4.5 mmol) in methanol (25 ml) was treated with 2N sodium hydroxide solution (4.95 ml) under ice-cooling, followed by stirring for 30 minutes, and partitioned between 6N hydrochloric acid (1.65 ml) and ethyl acetate (100 ml). The organic layer was washed with saturated aqueous sodium chloride (30 ml×3), dried over anhydrous sodium sulfate, and evaporated to afford the title compound (875 mg, 90% yield) as an oil.
Reaction SMILES: C(OC([NH:11][CH2:12][C:13]1[S:14][C:15]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[N:17]=1)=O)C1C=CC=CC=1.Cl>O1CCCC1>[NH2:11][CH2:12][C:13]1[S:14][C:15]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[C:16]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)[N:17]=1
Reactant: COc1ccc(-c2nc(CNC(=O)OCc3ccccc3)sc2-c2cccnc2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(-c2nc(CN)sc2-c2cccnc2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 60.5 %

Procedure:
In 10 ml of tetrahydrofuran was dissolved 1.2 g of 2-(benzyloxycarbonylaminomethyl)-4-(4-methoxyphenyl)-5-(3-pyridyl)-1,3-thiazole obtained by Example 11. To the solution was added 10 ml of 5N-HCl, and the mixture was stirred for 2 hours at 80° C. Tetrahydrofuran was evaporated off under reduced pressure. The remaining aqueous layer was made alkaline with 2N-NaOH, which was subjected to extraction with ethyl acetate. The extract was washed with water and dried, then the solvent was evaporated off. The residue was purified by means of a silica-gel column chromatography [eluent: chloroform-methanol (9:1)] to give 0.5 g (yield 60%) of 2-(aminomethyl)-4-(4-methoxyphenyl)-5-(3-pyridyl)-1,3-thiazole.
Reaction SMILES: S([O-])([O-])(=O)=O.CS[C:8]([NH2:10])=[NH2+:9].CSC(N)=[NH2+].O.[CH2:17]([O:24][NH2:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[CH2:17]([O:24][NH:25][C:8]([NH2:10])=[NH:9])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NOCc1ccccc1
Reactant: CSC(N)=[NH2+]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Solvent: O
Product: N=C(N)NOCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 30.0 g. (0.12 moles) of S-methylthiouronium sulfate in 200 ml. of H2O there is added a solution of 24.6 g. (0.20 moles) of benzyloxyamine in 250 ml. of 95% ethanol. The mixture is stirred for 72 hours at room temperature. The clear solution is heated at reflux for two hours under a stream of nitrogen. The solvents are removed in vacuo and the residue is treated with 300 ml. of isopropanol. The solid is removed by filtration and dissolved in 300 ml. of water. The solution is made basic with 90 ml. of 10% aqueous sodium hydroxide. The precipitate is collected, washed with water and dried to give benzyloxyguanidine, m.p. 104°-5° C.
Reaction SMILES: C[O-].[Na+].[C:4]([O:10][CH3:11])(=[O:9])/[CH:5]=[CH:6]\[CH2:7][CH3:8].[C:12](OC)(=[O:17])/C=C/CC>CO>[CH3:12][O:17][CH:6]([CH2:7][CH3:8])[CH2:5][C:4]([O:10][CH3:11])=[O:9]
Reactant: CC/C=C\C(=O)OC
Reactant: CC/C=C/C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCC(CC(=O)OC)OC
Temperature: 65 °C
Reaction time: 4 h
Yield: 2998.3 %

Procedure:
A solution of 5.4 g of sodium methylate in 64 g of methanol was added to a mixture of 192 g of methyl cis trans-3-pentenoate, 4 g of methyl 2-cis-pentenoate and 28 g of methyl 2-trans-pentenoate, and the mixture was heated to 65° C. and stirred for four hours at this temperature. After the working up procedure described in Example 1, 153.6 g (53% of theory) of methyl 3-methoxyvalerate were obtained.
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1)([O:3]C)=[O:2].[OH-].[K+].C(O)C.Cl>O>[C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1)([OH:3])=[O:2]
Reactant: COC(=O)CCCCCCCCCCCCCCCNc1ccc(C#N)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(NCCCCCCCCCCCCCCCC(=O)O)cc1

Procedure:
A solution of 3 g. of 4-(15-carbomethoxypentadecylamino)benzonitrile and 0.5 g. of potassium hydroxide in 50 ml. of 95% ethanol is stirred at 50° C. for 10 hours, diluted with water and acidified with dilute hydrochloric acid. The precipitate is collected, dried and recrystallized from ether-hexane to yield 4-(15-carboxypentadecylamino)benzonitrile as a white solid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[N+](C1C=CC=CC=1)([O-])=O.[CH2:18]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][C:21]1=[O:29])[CH3:19]>>[CH2:18]([N:20]1[C:28]2[C:23](=[CH:24][C:25]([C:1](=[O:3])[CH3:2])=[CH:26][CH:27]=2)[CH2:22][C:21]1=[O:29])[CH3:19]
Reactant: CC(=O)Cl
Reactant: CCN1C(=O)Cc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: CCN1C(=O)Cc2cc(C(C)=O)ccc21
Temperature: 45 °C
Reaction time: 1 h
Yield: 57.3 %

Procedure:
To a mixture of 29.25 g. (0.373 mole) of acetyl chloride and 65.9 g. of aluminum chloride in 60 ml. of nitrobenzene was added gradually 20.0 (0.124 mole) of 1-ethyloxindole. The reaction warmed to about 45° C. with an evolution of gas. After stirring for one hour the reaction was heated to 100° C. for one hour and allowed to stir at room temperature over night. The reaction mixture was poured into 2 l. of ice with stirring. After 30 minutes the product was filtered, air dried and dissolved in 200 ml. of methylene chloride. The solution was dried over magnesium sulfate and concentrated to dryness. The residue was recrystallized from toluene, 14.44 g. (57.3% yield), m.p. 141°-145° C.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][NH:4][CH2:5][C@@H:6]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][CH2:8][CH2:9][CH3:10].C(=O)(O)[O-].[Na+].Cl[CH2:27][C:28](Cl)=[O:29].C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C>[C:15]([O:14][C:12]([N:11]1[CH2:27][C:28](=[O:29])[N:4]([CH2:3][C:2]([F:19])([F:20])[F:1])[CH2:5][C@@H:6]1[CH2:7][CH2:8][CH2:9][CH3:10])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: O=C(Cl)CCl
Reactant: CCCC[C@@H](CNCC(F)(F)F)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Product: CCCC[C@H]1CN(CC(F)(F)F)C(=O)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of the product from Step C (0.590 g, 1.98 mmol) in ethyl acetate (30 mL) was vigorously stirred at 0° C. with saturated sodium bicarbonate (30 mL). Chloroacetyl chloride (0.315 mL, 3.96 mmol) was added, and the reaction stirred at 0° C. for 1 h. The layers were separated, and the ethyl acetate phase was washed with saturated brine, and dried over magnesium sulfate. The crude product was dissolved in DMF (15 mL) and cooled to 0° C. under nitrogen. Cesium carbonate (1.67 g, 5.12 mmol) was added and the reaction stirred 1 h at 0° C., then at room temperature overnight. The reaction was quenched with amminium chloride, and partitioned between ethyl acetate and water. The organic phase was washed with water, saturated brine, and dried over magnesium sulfate. The title compound was obtained as a colorless oil.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[F:32][C:33]([F:37])([F:36])[CH2:34][SH:35]>O>[F:32][C:33]([F:37])([F:36])[CH2:34][S:35][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1
Reactant: FC(F)(F)CS
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)CSc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 25 °C
Reaction time: 1.2 h
Yield: 85.3 %

Procedure:
To a mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.50 g of potassium carbonate and 2 ml of DMF, 0.15 g of 2,2,2-trifluoroethanethiol was added. The reaction mixture was stirred at room temperature for 1.2 hours. Water was added to reaction mixture, which followed by extraction with ethyl acetate twice. The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.32 g of 2-[3-(2,2,2-trifluoroethylthio)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 46”).