Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)[N:13]=1)=[O:7])(=O)C.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>CO>[Br:20][C:17]1[CH:16]=[CH:15][C:14]([C:12]2[N:13]=[C:9]([NH:8][C:6](=[O:7])[CH2:5][OH:4])[S:10][CH:11]=2)=[CH:19][CH:18]=1
Reactant: CC(=O)OCC(=O)Nc1nc(-c2ccc(Br)cc2)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: O=C(CO)Nc1nc(-c2ccc(Br)cc2)cs1
Reaction time: 2 h
Yield: 69 %

Procedure:
2-{[4-(4-Bromophenyl)-1,3-thiazol-2-yl]amino}-2-oxoethyl acetate (1.1 g, 3.1 mmol), prepared in the previous step, was suspended in 20 mL of methanol and K2CO3 (0.43 g, 3.1 mmol) was added. The mixture was stirred for 2 h, then diluted using methylene chloride. The mixture was washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. Flash chromatography (2% methanol/chloroform) provided N-[4-(4-bromophenyl)-1,3-thiazol-2-yl]-2-hydroxyacetamide (670 mg, 68%) as a white solid. mp 222-224° C. HRMS: calcd for C11H9BrN2O2S+H+, 312.96408; found (ESI, [M+H]+), 312.9651. Analytical HPLC: retention time 9.0 min, 210-370 nm the Xterra® RP18 column, 3.5μ, 150×4.6 mm 40° C. 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min, 1.2 mL/min 5 μL injection.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[N:12]=[C:11]([C:20]([OH:22])=O)[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[S:23]1[CH2:27][CH2:26][NH:25][CH2:24]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[N:12]=[C:11]([C:20]([N:25]3[CH2:26][CH2:27][S:23][CH2:24]3)=[O:22])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2cccnc2)n1
Reactant: C1CSCN1
Product: O=C(c1cc(-c2cc(F)cc(Cl)c2)n(-c2cccnc2)n1)N1CCSC1

Procedure:
150 mg (0.43 mmol) of the compound of Example 22A is reacted analogously to the synthesis of the compound of Example 3 with 41 mg (0.46 mmol) of thiazolidine. After the crude product is purified by means of preparative HPLC (mobile solvent: acetonitrile/water gradient), 122 mg (74% of theory) of the title compound is obtained.
Reaction SMILES: O=[C:2]([CH2:8][C:9](=O)[CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:12]([NH:15][NH2:16])([CH3:14])[CH3:13]>C(O)(=O)C>[CH:12]([N:15]1[C:9]([CH3:10])=[CH:8][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:16]1)([CH3:14])[CH3:13]
Reactant: CC(C)NN
Reactant: CCOC(=O)C(=O)CC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(C)n(C(C)C)n1
Reaction time: 2 h
Yield: 31 %

Procedure:
To ethyl 2,4-dioxopentanoate (20.1 g, 127 mmol) in acetic acid (100 mL) at 0° C. was added drop-wise isopropylhydrazine (9.42 g, 127 mmol). The cold bath was removed and the reaction mixture was stirred for 2 hours. The reaction mixture was then diluted with EtOAc/H2O (300 mL/100 mL). The organic layer was washed with saturated NaHCO3 aqueous solution (100 mL), H2O (50 mL) and brine (50 mL). The organic layer was dried (Na2SO4) and concentrated. The residue was purified by silica gel flash chromatography (1:2 EtOAc/hexane) to give the desired product (31%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[CH:5]=[N:6][C:7]=1[O:8][CH3:9].F[C:12]1[C:17]([C:18]2[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=3)[CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[N:19]=2)=[CH:16][CH:15]=[CH:14][N:13]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:12]2[C:17]([C:18]3[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:26][C:27]4[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=4)[CH2:35][C:36]4[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=4)[N:19]=3)=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3F)n2)cc1
Reactant: COc1ncc(N)cc1Cl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3cnc(OC)c(Cl)c3)n2)cc1

Procedure:
The title compound was prepared in an analogous manner to that described in Example 164 using 5-chloro-6-methoxypyridin-3-amine and 4-(2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine, and isolated as a brown oil (100%). 1H NMR (400 MHz, d6-DMSO) δ 11.71 (s, 1H); 8.78 (dd, J=7.8, 2.2 Hz, 1H); 8.33 (dd, J=4.7, 2.0 Hz, 1H); 8.26 (d, J=2.5 Hz, 1H); 8.19 (d, J=2.3 Hz, 1H); 7.17-7.29 (m, 4H); 6.82-6.96 (m, 5H); 4.81 (d, J=6.5 Hz, 4H); 3.91 (s, 3H); 3.74 (s, 3H); 3.70 (s, 3H); 2.55-2.58 (m, 3H). m/z (ESI, +ve ion) 584.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]3[CH:19]=[C:18]([Sn](CCCC)(CCCC)CCCC)[N:17]=[CH:16]3)[N:9]=2)=[CH:4][CH:3]=1.[C:33]([NH:37][S:38]([C:41]1[S:45][C:44](Cl)=[N:43][CH:42]=1)(=[O:40])=[O:39])([CH3:36])([CH3:35])[CH3:34].[F-].[K+].O>C1(C)C=CC=CC=1>[C:33]([NH:37][S:38]([C:41]1[S:45][C:44]([C:18]2[N:17]=[CH:16][N:15]([C:10]3[N:9]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH:13]=[C:12]([CH3:14])[N:11]=3)[CH:19]=2)=[N:43][CH:42]=1)(=[O:39])=[O:40])([CH3:36])([CH3:34])[CH3:35]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(C)cc(-c3ccc(Cl)cc3)n2)cn1
Reactant: CC(C)(C)NS(=O)(=O)c1cnc(Cl)s1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(-c3ncc(S(=O)(=O)NC(C)(C)C)s3)c2)n1
Yield: 25.6 %

Procedure:
A stirred mixture of 4-(4-chloro-phenyl)-6-methyl-2-(4-tributylstannanyl-imidazol-1-yl)-pyrimidine (Example G.3) (0.45 g, 0.80 mmol), 2-chloro-thiazole-5-sulfonic acid tert-butylamide (Example H.1) (0.225 g, 0.88 mmol), tetrakis(triphenyl-phosphine)palladium (0.056 g, 0.048 mmol) in toluene (10 mL) was heated under reflux conditions for 15 h. The mixture was poured into saturated potassiumfluoride solution (10 mL), water (40 mL) was added and the water layer was extracted with ethyl acetate (2×60 mL). The combined organic layers were washed with brine (60 mL), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (heptane/ethyl acetate) and crystallization (THF/hexane) to yield N-tert-butyl-2-{1-[4-(4-chloro-phenyl)-6-methyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiazole-5-sulfonamide (0.1 g) as a light brown solid.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:3]=1.[CH2:21]1[CH2:25]O[CH2:23][CH2:22]1>>[F:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](=[O:7])[CH2:23][CH2:22][C:21]2[CH:25]=[CH:4][CH:3]=[CH:2][CH:13]=2)=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:3]=1
Reactant: C1CCOC1
Reactant: CON(C)C(=O)c1ccc(F)cc1Nc1ccccc1
Product: O=C(CCc1ccccc1)c1ccc(F)cc1Nc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 0° C. solution of 4-fluoro-N-methoxy-N-methyl-2-phenylamino-benzamide (10 g) in THF (80 mL) was slowly added phenethyl-MgBr (91.2 mL, 1 M in THF), and the mixture stirred at 0° C. for 30 min, followed by 1 h at RT. The reaction mixture was then quenched with NH4Cl (sat'd aq), extracted with EtOAc, and chromatographed (0-40% EtOAc/DCM) to provide 1-(4-fluoro-2-phenylamino-phenyl)-3-phenyl-propan-1-one (11.34 g) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:23])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:23][C:32]([NH:31][C:28]2[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=2)=[O:33])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Cn1ncc(Br)c1-c1cc(N)ccc1OCc1ccc(Cl)cc1
Solvent: ClCCl
Product: Cn1ncc(Br)c1-c1cc(NC(=O)Nc2ccc(F)cc2)ccc1OCc1ccc(Cl)cc1
Yield: 50 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(4-chloro-benzyloxy)-phenylamine (0.032 g, 0.08 mmol) was treated with 4-fluorophenyl isocyanate (0.014 g, 11.1 μL, 0.10 mmol, 1.2 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.2 to afford Compound 64 (0.023 g, 0.04 mmol, 54%) as a white solid. LCMS m/z (%)=545 (M+H79Br35Cl, 65), 547 (M+H81Br35Cl, 100), 549 (M+H81Br37Cl, 25). 1H NMR (400 MHz, acetone-d6) δ: 8.13 (s, 2H), 7.66 (dd, J=2.7, 9.0 Hz, 1H), 7.51-7.56 (m, 3H), 7.50 (s, 1H), 7.46 (d, J=2.7 Hz, 1H), 7.37 (d, J=8.7 Hz, 2H), 7.33 (d, J=8.7 Hz, 2H), 7.21 (d, J=9.0 Hz, 1H), 7.05-7.75 (m, 2H), 5.14 (AB quartet, J=12.3, 24.8 Hz, 2H), 3.69 (s, 3H).
Reaction SMILES: I.[NH2:2][NH:3][C:4]([NH:23][CH3:24])=[N:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:11]=1.[C:25](O)(=O)[CH2:26][OH:27]>C1C=CC=CC=1>[CH3:24][N:23]1[C:4]([NH:5][CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][N:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)[CH:11]=2)=[N:3][N:2]=[C:25]1[CH2:26][OH:27]
Reactant: CNC(=NCCCOc1cccc(CN2CCCCC2)c1)NN
Reactant: O=C(O)CO
Agent: I
Solvent: c1ccccc1
Product: Cn1c(CO)nnc1NCCCOc1cccc(CN2CCCCC2)c1
Yield: 0.7 %

Procedure:
N-Amino-N'-methyl-N"-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]guanidine hydroiodide (2.24 g) and glycolic acid (1.52 g) were heated together for 3 h in dry benzene (25 ml) at reflux. The benzene was decanted from the residual oil, which was partitioned between ethyl acetate and aqueous 1N sodium hydroxide solution. The organic phase was chromatographed on silica using methanol to give a white solid. This solid was washed with boiling ethyl acetate to leave the title compound as a white solid (0.013 g) m.p. 151°-2°.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:16]([O:18]C)=[O:17])[C:6]2[C:7]([CH3:15])=[CH:8][N:9]([CH:12]([CH3:14])[CH3:13])[C:10]=2[CH:11]=1)#[N:2].CO.[OH-].[Na+]>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([C:16]([OH:18])=[O:17])[C:6]2[C:7]([CH3:15])=[CH:8][N:9]([CH:12]([CH3:14])[CH3:13])[C:10]=2[CH:11]=1)#[N:2]
Reactant: COC(=O)c1cc(C#N)cc2c1c(C)cn2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cn(C(C)C)c2cc(C#N)cc(C(=O)O)c12
Temperature: 25 °C
Reaction time: 20 h
Yield: 64.2 %

Procedure:
To a 50 ml round bottom was added methyl 6-cyano-3-methyl-1-(1-methylethyl)-1H-indole-4-carboxylate (230 mg, 0.897 mmol), followed by methanol (1 mL) and THF (1 mL). To the solution was added 3 M NaOH (0.449 mL, 2.69 mmol). The reaction stirred at rt for 20 h. The reaction was evaporated and treated with acidic water to pH 5. A brown solid crashed out and was collected by filtration. The solid was an impurity. The pH of the liquid was adjusted to 3 and the liquid was evaporated leaving a residue. Trituration of the residue with water, followed by filtration yielded 6-cyano-3-methyl-1-(1-methylethyl)-1H-indole-4-carboxylic acid (155 mg, 0.576 mmol, 64.2% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-δ6) δ ppm 13.16 (br. s., 1 H) 8.33 (s, 1 H) 7.78 (s, 1 H) 7.66 (s, 1 H) 4.81-4.98 (m, 1 H) 2.33 (s, 4 H) 1.45 (d, J=6.57 Hz, 6 H). MS(ES) [M+H]+ 243.3.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C@@:11]([NH:33][C:34](=[O:46])[C:35]2[CH:40]=[CH:39][C:38]([F:41])=[C:37]([C:42]([F:45])([F:44])[F:43])[CH:36]=2)([C:19]2[CH:24]=[C:23]([O:25][C:26]([F:31])([F:30])[CH:27]([F:29])[F:28])[CH:22]=[C:21]([F:32])[CH:20]=2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=[CH:8][C:9]=1[F:10].N1C=CC=CC=1.[C:53](OC(=O)C)(=[O:55])[CH3:54].Cl>C(Cl)Cl>[C:53]([NH:2][CH2:3][C:4]1[CH:5]=[C:6]([C@@:11]([NH:33][C:34](=[O:46])[C:35]2[CH:40]=[CH:39][C:38]([F:41])=[C:37]([C:42]([F:45])([F:44])[F:43])[CH:36]=2)([C:19]2[CH:24]=[C:23]([O:25][C:26]([F:31])([F:30])[CH:27]([F:28])[F:29])[CH:22]=[C:21]([F:32])[CH:20]=2)[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:7]=[CH:8][C:9]=1[F:10])(=[O:55])[CH3:54]
Reactant: NCc1cc([C@@](Cc2ccccc2)(NC(=O)c2ccc(F)c(C(F)(F)F)c2)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NCc1cc([C@@](Cc2ccccc2)(NC(=O)c2ccc(F)c(C(F)(F)F)c2)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
To a solution of (R)—N-(1-(3-(aminomethyl)-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamide hydrochloride (Example 269, 30 mg, 0.04 mmol) in DCM (2 mL) at rt was added pyridine (7.8 μL, 0.1 mmol) followed by acetic anhydride (4.6 μL, 0.05 mmol). The reaction mixture was stirred at rt for 1 h, then poured into 1N HCl and the aqueous layer was extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. The resulting residue was purified by ISCO column chromatography (4 g, 0-50% EtOAc/hexane) to yield (R)—N-(1-(3-(acetamidomethyl)-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamide (Example 270) as a white foam (21 mg, 100%). 1H NMR (400 MHz, CDCl3) δ ppm 7.98 (dd, J=6.57, 2.02 Hz, 1H), 7.86 (dt, J=8.53, 2.18 Hz, 1H), 7.25 (m, 2H), 7.13 (m, 3H), 6.99 (m, 5H), 6.81 (s, 1H), 6.69 (m, 2H), 5.87 (m, 2H), 4.38 (m, 2H), 4.04 (d, J=13.14 Hz, 1H), 3.75 (d, J=13.14 Hz, 1H), 1.92 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:12]1([C@@H:18](O)[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[O:1]=[C:2]1[CH:3]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:9]=[CH:10][N:11]1[C@@H:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:19]
Reactant: COC(=O)c1ccnc(O)c1
Reactant: C[C@H](O)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)c1ccn([C@H](C)c2ccccc2)c(=O)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.4 %

Procedure:
To a solution of methyl 2-hydroxyisonicotinate (459 mg, 3 mmol) and (S)-1-phenylethanol (366 mg, 3 mmol) in tetrahydrofuran (30 mL) was added dropwise a solution of tributylphosphine (909 mg, 4.5 mmol) in tetrahydrofuran (10 mL). The reaction solution was stirred at 0° C. for 0.5 hours. To the above solution was added 1,1′-(Azodicarbonyl)-dipiperidine (1134 mg, 4.5 mmol). The reaction mixture was stirred at 0° C. for 0.5 hours. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=1:1) to give (R)-methyl 2-oxo-1-(1-phenylethyl)-1,2-dihydropyridine-4-carboxylate as a white solid (451 mg, 58%).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([CH3:11])[CH3:10].[Mg].CN(C)[CH:15]=[O:16]>C(OCC)C>[CH:9]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[CH:15]=[O:16])([CH3:11])[CH3:10]
Reactant: Cc1cccc(C(C)C)c1Br
Reactant: CN(C)C=O
Agent: [Mg]
Solvent: CCOCC
Product: Cc1cccc(C(C)C)c1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
To a solution of 1-bromo-2-isopropyl-6-methylbenzene (6.9 g, 32.4 mmol) in diethyl ether (50 ml) was added magnesium turnings (0.9 g, 37 mmol) and the mixture was refluxed in nitrogen atmosphere until the reaction was started and was then stirred overnight at room temperature. Dimethylformamide (4 ml) was added dropwise during 10 min. and the mixture was stirred for 30 min. Saturated ammmoniumchloride solution (30 ml) was added and the mixture was stirred for 1 h. The organic layer was separated, filtrated and evaporated under reduced pressure. Purification by column chromatography on silica gel using hexane:methylene chloride (3:2) as eluent gave 1.75 g (33%) of the title compound .
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.Cl[C:10]1[C:15]([C:16](=[O:25])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:14][CH:13]=[CH:12][N:11]=1.O>C1(C)C=CC=CC=1>[CH3:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([C:16]([C:15]2[C:10]([N:5]3[CH2:6][CH2:7][CH2:8][C:4]3=[O:3])=[N:11][CH:12]=[CH:13][CH:14]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: O=C1CCCN1
Reactant: COc1ccc(C(=O)c2cccnc2Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)c2cccnc2N2CCCC2=O)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a suspension of 1.3 g of 60% sodium hydride in 20 ml of toluene is added 5.1 g of 2-oxopyrrolidine, followed by addition of 7.4 g of 2-chloro-3-(4-methoxybenzoyl)pyridine. The mixture is stirred at 50° C. for 1 hour. After the reaction mixture is poured into water, the toluene layer is washed with water and the solvent thereof is distilled off. The residue is recrystallized from a mixed solvent of isopropyl ether and ethyl acetate to give 3-(4-methoxybenzoyl)-2-(2-oxopyrrolidin-1-yl)pyridine, m.p. 76°-77° C.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][C@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:14]([OH:16])=[O:15])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>C(O)(C)C>[CH2:1]([C@H:8]([CH2:12][C@@H:13]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:14]([OH:16])=[O:15])[C:9]([OH:11])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)O
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: O=C(O)[C@H](Cc1ccccc1)C[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 0.33 h

Procedure:
The chiral (S,S)-2,4-dibenzylglutaric acid is prepared as follows: To 5.0 g of (R*,R*)-2,4-dibenzylglutaric acid in 20 ml of isopropanol is added 0.81 g of triethylamine and the mixture is stirred for 20 minutes. To this mixture is added 0.97 g of d(+)-alpha-methylbenzylamine in 20 ml of isopropanol and the solution is stirred overnight. The solid is collected and recrystallized twice from isopropanol to yield (S,S)-2,4-dibenzylglutaric acid as the d(+)-alpha-methylbenzylamine salt melting at 201°-203°; [alpha]D =-20.4° (c=1 in methanol). To a warm solution of the above salt in 70 ml of water and 30 ml of ethanol is added 1 ml of concentrated hydrochloric acid. After standing 24 hours the solid is collected, washed with water and dried to yield (S,S)-2,4-dibenzylglutaric acid melting at 150°-152°; [alpha]D =+8.9° (c=2.0 in methanol).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:33]1[C:37](=[O:38])[C:36]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:35]2[C:34]1=[O:43].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[CH2:2][O:1][N:33]1[C:34](=[O:43])[C:35]2=[CH:42][CH:41]=[CH:40][CH:39]=[C:36]2[C:37]1=[O:38]
Reactant: OCc1ccc2ccccc2n1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OCc1ccc2ccccc2n1
Reaction time: 8 h
Yield: 75.8 %

Procedure:
2-(hydroxymethyl)quinoline (1.20 g, 7.55 mmol), triphenyl phosphine (1.00 g, 6.29 mmol, 1.05 equiv) and N-hydroxyphthalimide (1.08 g, 6.63 mmol, 1.05 equiv) were dissolved in 25 mL of dry THF. Diethylazodicarboxylate (1.09 mL, 6.93 mmol, 1.10 equiv) was then added dropwise and the reaction was stirred overnight. The reaction mixture filtered to give a white solid. The filtrate was concentrated and a second crop of material was obtained by triturating with Et2O. This was combined with the original solid and recrystallization from EtOH gave the desired product (1.53 g) as a fluffy white solid. MS(CI) m/e 305 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[CH3:11][C:12]1[CH:21]=[C:20]([CH3:22])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[CH:23]1[CH2:28][C:27](=[O:29])[C:26]([C:30](=[N:34][O:35][CH2:36][CH3:37])[CH2:31][CH2:32][CH3:33])=[C:25]([OH:38])[CH2:24]1>CC(C)=O>[C:1]([O:29][C:27]1[CH2:28][CH:23]([C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]([CH3:22])=[CH:21][C:12]=2[CH3:11])[CH2:24][C:25](=[O:38])[C:26]=1[C:30](=[N:34][O:35][CH2:36][CH3:37])[CH2:31][CH2:32][CH3:33])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCC(=NOCC)C1=C(O)CC(c2c(C)cc(C)c3ccccc23)CC1=O
Agent: [Na]
Solvent: CC(C)=O
Product: CCCC(=NOCC)C1=C(OC(=O)c2ccccc2)CC(c2c(C)cc(C)c3ccccc23)CC1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A slight excess of benzoyl chloride was added to a suspension of the sodium salt of 5-(2,4-dimethylnaphth-1-yl)-2-[1-(ethoxyimino)butyl]-3-hydroxycyclohex-2-en-1-one (0.34 g) in acetone (20 ml) and the mixture was stirred at room temperature for 12 hr. The mixture was filtered, the filtrate was evaporated and the residue was purified by column chromatography overe silica with dichloromethane elution to give 3-benzoyloxy-5-(2,4-dimethylnaphth-1-yl)-2-[1-(ethoxyimino)butyl]cyclohex-2-en-1-one as a pale yellow oil. The product was characterized by proton nuclear magnetic resonance spectroscopy and the spectroscopic data is recorded in Table 4, Example 10.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([C:26](O)=[O:27])[N:16]([CH3:25])[C:17]=2[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[CH:9][CH:8]=1>>[N:1]1([C:26]([C:15]2[N:16]([CH3:25])[C:17]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:13]([C:10]3[CH:9]=[CH:8][C:7]([CH3:6])=[CH:12][CH:11]=3)[N:14]=2)=[O:27])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: Cc1ccc(-c2nc(C(=O)O)n(C)c2-c2ccc(C)cc2)cc1
Product: Cc1ccc(-c2nc(C(=O)N3CCCC3)n(C)c2-c2ccc(C)cc2)cc1

Procedure:
Using essentially the same procedure as Example 9, Step B, but using pyrrolidine (0.022 mL), 4,5-di-(4-methylphenyl)-1-methylimidazole-2-carboxylic acid (25 mg, 0.08 mmol) from Example 9, Step A was converted to the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH3:23])([CH3:22])[CH2:5][CH2:6][CH2:7][CH:8]([CH3:21])[CH2:9][CH:10](O)[CH2:11][C:12]([CH:14]1[CH2:19][O:18][C:16](=[O:17])[CH2:15]1)=[O:13].[CH3:24]O>>[CH3:24][O:13][C:12](=[C:14]1[CH2:19][O:18][C:16](=[O:17])[CH2:15]1)/[CH:11]=[CH:10]/[CH2:9][CH:8]([CH3:21])[CH2:7][CH2:6][CH2:5][C:4]([O:3][CH3:2])([CH3:23])[CH3:22]
Reactant: COC(C)(C)CCCC(C)CC(O)CC(=O)C1COC(=O)C1
Reactant: CO
Agent: Cl
Product: COC(/C=C/CC(C)CCCC(C)(C)OC)=C1COC(=O)C1
Reaction time: 8 h
Yield: 52.1 %

Procedure:
1 ml of methanol saturated with hydrochloric acid is added to a solution of 1.05 g (0.0033 moles) of 3-(9-methoxy-3-hydroxy-5,9-dimethyl-decanoyl)-4-butyrolactone in 10 ml of dry methanol, and the mixture is allowed to stand at room temperature overnight. The solvent is distilled off in vacuo, the residue is dissolved in ether, the etheral solution is washed with distilled water, dried, the solvent is distilled off, and the residue is purified by column chromatography (adsorbent: Kieselgel 60, solvent: a 10:0.1 mixture of benzene and methanol). 0.54 g (52.1%) of the aimed compound are obtained; Rf =0.8 (developed with a 10:0.2 mixture of benzene and methanol).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])=[CH:7][C:6]=1[NH2:21])=O.C(O)(=O)C.[CH:26](N)=[NH:27]>COCCO.[OH-].[Na+]>[F:18][C:17]([F:20])([F:19])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:8]1[CH:7]=[C:6]2[C:5]([C:3](=[O:2])[NH:27][CH:26]=[N:21]2)=[CH:10][CH:9]=1
Reactant: N=CN
Reactant: COC(=O)c1ccc(-c2ccccc2C(F)(F)F)cc1N
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Solvent: CC(=O)O
Product: O=c1[nH]cnc2cc(-c3ccccc3C(F)(F)F)ccc12

Procedure:
Heat a solution of 3-amino-2′-trifluoromethyl-biphenyl-4-carboxylic-acid methyl ester (5.0 g, 0.0169 mol) and formamidine acetate (2.8 g, 0.0203 mol) in 2-methoxyethanol at reflux for 8 hours. Cool the mixture and concentrate under reduced pressure to give a dark oil. Dissolve the residue in 10% NaOH and wash the aqueous with ether (3×). Bring the aqueous layer to pH 4 using 12N HCl to produce a milky solution. Extract the solution with EtOAc, wash the EtOAc with brine, dry (Na2SO4) and concentrate under reduced pressure to give 7-(2-Trifluoromethyl-phenyl)-3H-quinazolin-4-one as a beige solid.