Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C.[H-].[Na+]>[CH2:16]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([I:1])=[CH:10][CH:9]=2)[C:5]([CH2:11][CH2:12][N:13]([CH3:14])[CH3:15])=[CH:6]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCc1ccccc1
Reactant: CN(C)CCc1c[nH]c2ccc(I)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCc1cn(Cc2ccccc2)c2ccc(I)cc12
Temperature: 4 °C
Reaction time: 0.25 h
Yield: 63.3 %

Procedure:
To a solution of [2-(5-iodo-1H-indol-3-yl)ethyl]-dimethyl-amine (Example 7) (35.0 g, 111.4 mmol) in DMF (250 mL), sodium hydride is added (2.81 g, 117 mmol) at RT in portions during 15 minutes. The mixture is then stirred for another 15 minutes, and then cooled to 4° C. A solution of benzyl chloride (14.1 g, 111.4 mmol) in DMF (50 mL) is added during 20 minutes, and the temperature is maintained during 4 to 8° C. The mixture is left stirring over night, and then most of the solvent is removed on the rotavapor. To the residue is added water (500 mL), and the product is extracted with TBME (2×250 mL). The organic layer is washed with brine (2×250 mL), and after removal of the solvent, 28.5 g of a brown oil is obtained. This is dissolved in ethyl acetate (500 mL) and the product is extracted with 4 N Hcl (550 mL). The product is liberated by adding 30% NaOH to the aqueous layer (300 mL), and re-extracted into ethyl acetate (500 mL). The organic layer is washed with brine (2×250 mL), and the solvent removed to leave 20.2 g of a brown oil which is crystallized from di-isopropyl ether and pentane to give the title product (17.3 g, 38%). Concentrating the aqueous layer of the first gives a precipitate (18.8 g) which is recrystallized from ethyl acetate (250 mL) to give 12.3 g of the N-benzyl ammonium chloride of the target
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:35]=[C:34]3[C:30]([C:31]([NH:44][C:45](=[O:49])[CH2:46][CH2:47][CH3:48])=[N:32][N:33]3COCC[Si](C)(C)C)=[CH:29][CH:28]=2)=[CH:23][CH:22]=1.C(OCC)(=O)C>O1CCCC1>[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:35]=[C:34]3[C:30]([C:31]([NH:44][C:45](=[O:49])[CH2:46][CH2:47][CH3:48])=[N:32][NH:33]3)=[CH:29][CH:28]=2)=[CH:25][CH:26]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccc(OC)cc3)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1n[nH]c2cc(-c3ccc(OC)cc3)ccc12
Temperature: 66 °C

Procedure:
13.6 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 1 g of N-[6-(4-methoxyphenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously, in 30 cm3 of tetrahydrofuran, and the reaction medium is then heated at about 66° C. for 19 hours. The heating is then stopped and 75 cm3 of ethyl acetate are added. This mixture is washed with 2×50 cm3 of saturated aqueous sodium hydrogen carbonate solution and then with 50 cm3 of saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 50° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with an ethyl acetate/cyclohexane mixture (60/40 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). The residue is taken up in 10 cm3 of diisopropyl ether, filtered and washed with 2×5 cm3 of diisopropyl ether and then with 2×5 cm3 of ethyl acetate; after drying (90 Pa; 50° C.), 500 mg of N-[6-(4-methoxyphenyl)-1H-indazol-3-yl]butanamide are obtained in the form of a white product melting at 210° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][N:12]3[N:14]=[C:15]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[CH:22][CH:21]=4)[C:16]([C:17]([NH2:19])=[O:18])=[C:11]3[NH:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl.Cl[CH2:35][CH2:36][N:37]([CH3:39])[CH3:38]>>[CH3:38][N:37]([CH3:39])[CH2:36][CH2:35][O:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][N:12]3[N:14]=[C:15]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)=[CH:22][CH:21]=4)[C:16]([C:17]([NH2:19])=[O:18])=[C:11]3[NH:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)CCCl
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCC(c1cccc(O)c1)C2
Agent: Cl
Product: CN(C)CCOc1cccc(C2CNc3c(C(N)=O)c(-c4ccc(Oc5ccccc5)cc4)nn3C2)c1

Procedure:
The desired product was prepared from 6-(3-hydroxyphenyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide and 2-chloro-N,N-dimethylethanamine hydrochloride using the procedure similar to step 7 for compound 9. 1H NMR (400 MHz, DMSO-d6) δ 7.52 (d, J=8.4 Hz, 2H), 7.46-7.38 (m, 2H), 7.29 (t, J=7.6 Hz, 1H), 7.18 (t, J=7.6 Hz, 1H), 7.10-7.05 (m, 4H), 6.98-6.96 (m, 2H), 6.90-6.88 (m, 1H), 6.81 (d, J=2.4 Hz, 1H), 4.25-4.20 (m, 1H), 4.16-4.11 (m, 3H), 3.50-3.47 (m, 1H), 3.43-3.38 (m, 2H), 2.96-2.84 (m, 2H) and 2.43 (s, 6H). MS (ESI) m/e [M+1]+ 497.9.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:13](C(OCC)=O)[C:12]2=[O:28])=[CH:2]1>CN(C)C=O>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[C:12](=[O:28])[CH:13]=[C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:15]2)=[CH:2]1
Reactant: CCOC(=O)C1=C(Nc2ccccc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Solvent: CN(C)C=O
Product: O=C1C=C(Nc2ccccc2)OC1=Cc1c[nH]c2ncccc12
Temperature: 25 °C
Yield: 25.4 %

Procedure:
A solution of the compound (0.050 g, 0.13 mmol) of Example 1 in N,N-dimethylformamide (1.0 mL) was refluxed for 6 h. Cooled to ambient temperature, the reaction mixture was purified by preparative HPLC to afford the titled compound as solid (0.010 g, y. 25%).
Reaction SMILES: F[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([OH:18])[CH:10]=[CH:11][C:12]=3[OH:17])[C:7](=[O:19])[C:6]=2[C:5](F)=[C:4]([F:21])[C:3]=1[F:22].[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][NH2:27]>C(Cl)Cl>[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][NH:27][C:5]1[C:6]2[C:7](=[O:19])[C:8]3[C:13](=[C:12]([OH:17])[CH:11]=[CH:10][C:9]=3[OH:18])[C:14](=[O:16])[C:15]=2[C:2]([NH:27][CH2:26][CH2:25][N:24]([CH3:28])[CH3:23])=[C:3]([F:22])[C:4]=1[F:21]
Reactant: CN(C)CCN
Reactant: O=C1c2c(O)ccc(O)c2C(=O)c2c(F)c(F)c(F)c(F)c21
Solvent: ClCCl
Product: CN(C)CCNc1c(F)c(F)c(NCCN(C)C)c2c1C(=O)c1c(O)ccc(O)c1C2=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 1,2,3,4-tetrafluoro-5,8-dihydroxyanthraquinone (1.0 g, 3.2 mmol) and N,N-dimethylethylenediamine (3 mL) in CH2Cl2 (30 mL) was stirred at room temperature for 12 hours. After evaporation of the solvents, the residue was purified by silica gel chromatography using isocratic solvent system of EtOAc/MeOH/Et3N (10:10:1) yielding 830 mgs of Compound 1 as dark blue product. Abs (max, PBS pH 7.4)=568 nm; Em=675 nm. The structure of Compound 1 is given below:
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:22])([F:21])[C:5]1[CH:6]=[C:7]([CH:15]2[O:19][C:18](=[O:20])[NH:17][CH2:16]2)[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1.Br[CH2:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=1[I:35]>C1COCC1>[F:22][C:4]([F:3])([F:21])[C:5]1[CH:6]=[C:7]([CH:15]2[O:19][C:18](=[O:20])[N:17]([CH2:24][C:25]3[CH:30]=[C:29]([C:31]([F:32])([F:34])[F:33])[CH:28]=[CH:27][C:26]=3[I:35])[CH2:16]2)[CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1
Reactant: O=C1NCC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)O1
Reactant: FC(F)(F)c1ccc(I)c(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1OC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CN1Cc1cc(C(F)(F)F)ccc1I
Reaction time: 0.33 h

Procedure:
A stirred suspension of sodium hydride (60% in oil, 167 mg, 4.18 mmol) in THF (5 mL) was treated at 0° C. with 5-[3,5-bis(trifluoromethyl)phenyl]-1,3-oxazolidin-2-one (500 mg, 1.67 mmol) dissolved in THF (1 mL), under an atmosphere of N2. The reaction was stirred for 20 min and a solution of 2-(bromomethyl)-1-iodo-4-(trifluoromethyl)benzene (610 mg, 1.67 mmol) in THF (1 mL) was added dropwise. The reaction was stirred at room temperature for 18 h. The reaction was quenched with H2O (1 mL) and partitioned between EtOAc (80 mL) and H2O (25 mL). The aqueous phase was re-extracted with EtOAc (2×20 mL) and the combined organic extracts were washed with brine (30 mL), dried (MgSO4) and concentrated in vacuo to give the crude product. This was purified by flash silica-gel chromatography (0-30% EtOAc in hexanes gradient) to afford 5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]1,3-oxazolidin-2-one. Rf=0.55 (515% EtOAc/hexanes). LCMS 584 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 8.05 (d, J=8.2 Hz, 1H), 7.95 (br s, 1H), 7.85 (br s, 2H), 7.51 (br s, 1H), 7.32 (m, 1H), 5.72 (t, J=8.0 Hz, 1H), 4.74 (d, J=15.5 Hz, 1H), 4.64 (d, J=15.3 Hz), 4.14 (t, J=7.1 Hz, 1H), 3.47 (dd, J=7.1, 1.6 Hz).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1>CN(C)C=O>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:23])[NH:1][C:2]2[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)=[CH:17][CH:16]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1csc(NC(=O)Nc2ccc(Cl)cc2)n1

Procedure:
Following a procedure similar to that described in Preparation 1, the desired compound was prepared from 10 g of ethyl 2-aminothiazol-4-ylglyoxylate, 8.6 g of p-chlorophenyl isocyanate and 100 ml of dimethylformamide. The resulting product was a yellow powder having the following physical properties.
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][CH2:10][C:11]1[S:12][C:13]([Cl:16])=[CH:14][CH:15]=1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CC1(C)CCCC(C)(C)N1.Cl.C1C[O:36][CH2:35]C1>CN(C=O)C>[Si:5]([O:8][CH2:9][CH2:10][C:11]1[S:12][C:13]([Cl:16])=[C:14]([CH:35]=[O:36])[CH:15]=1)([C:1]([CH3:4])([CH3:2])[CH3:3])([CH3:6])[CH3:7]
Reactant: C1CCOC1
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccc(Cl)s1
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: [Li]CCCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCc1cc(C=O)c(Cl)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl(2-(5-chlorothiophen-2-yl)ethoxy)dimethylsilane [Aromatic Intermediate 17, step a] (0.8 g) was added dropwise over 5 min to a stirred solution of butyllithium (2.5M in hexanes, 1.73 mL) and 2,2,6,6-tetramethylpiperidine (0.73 mL) in THF (25 mL) at −78° C. The resulting mixture was stirred for 2 h then DMF (0.67 mL) was added. The mixture was stirred for a further 1 h and allowed to warm to RT. The reaction mixture was cautiously poured into aqueous HCl (0.5M, 200 mL) and extracted with ethyl acetate (3×100 mL). The combined organic phases were washed with water (2×100 mL) and brine (100 mL), then dried over sodium sulphate, filtered and evaporated. The resulting oil was purified by silica gel chromatography eluting with isohexane to 5% ether in isohexane gradient. The fractions containing product were combined and evaporated to give the subtitled compound as a clear oil. Yield 0.80 g.
Reaction SMILES: [C:1]([C:5]1[CH:26]=[CH:25][C:8]([O:9][CH:10]([C:16]2[CH:21]=[CH:20][C:19]3[O:22][CH2:23][O:24][C:18]=3[CH:17]=2)[C:11]([O:13]CC)=[O:12])=[C:7]([CH2:27][CH2:28][CH3:29])[CH:6]=1)([O:3][CH3:4])=[O:2]>CO>[C:1]([C:5]1[CH:26]=[CH:25][C:8]([O:9][CH:10]([C:16]2[CH:21]=[CH:20][C:19]3[O:22][CH2:23][O:24][C:18]=3[CH:17]=2)[C:11]([OH:13])=[O:12])=[C:7]([CH2:27][CH2:28][CH3:29])[CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: CCCc1cc(C(=O)OC)ccc1OC(C(=O)OCC)c1ccc2c(c1)OCO2
Solvent: CO
Product: CCCc1cc(C(=O)OC)ccc1OC(C(=O)O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
A 1 L 3 necked 24/40 round bottom flask equipped with a mechanical stirrer, a dropping funnel, and a nitrogen inlet was charged with a solution of 76.3 g 0.185 mol) of the semi-purified product of Step A dissolved in 500 mL of methanol. The flask was purged with nitrogen, the stirrer was started, and 37 mL of a 5.0 N aqueous solution of sodium hydroxide was added over a 30 minute period via an addition funnel. The reaction mixture was stirred at room temperature for an additional 30 minutes at which point TLC analysis (CH2Cl2 --MeOH--NH4OH90:10:1) indicated that the starting material had been consumed. The reaction mixture was adjusted to pH=4 with 6 N HCl, and the bulk of the organic solvent was removed in vacuo. The precipitated organic product and the aqueous layer were next partitioned between CH2Cl2 (1 L) and water (1 L) which produced a copious emulsion. The reaction mixture was then aged overnight in a refridgerator which resulted in crystallization of the organic product. The crystalline solid was separated from the two phase mixture by filtration and washed with CH2Cl2. The solid was slurried again in diethylether, filtered, washed with hexane, and then dried in a vacuum to afford 65 g (94%) of the title compound as a white crystalline solid. 1H-NMR (400 MHz, CD3OD, ppm): δ0.93 (t, J=7.20 Hz, 3H), 1.62-1.75 (m, 2H), 2.63-2.70 (m, 1H), 2.77-2.81 (m, 1H), 3.84 (s, 3H), 5.54 (s, 1H), 5.94 (s, 2H), 6.81 (d, J=7.60 Hz, 1H), 6.89 (d, J=9.20 Hz, 1H), 7.08 (d, J=1.60 Hz, 1H), 7.11 (br s, 1H), 7.78-7.81 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:8]=1)[NH2:5].[CH3:18][O:19][CH2:20][CH2:21][S:22](Cl)(=[O:24])=[O:23]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:5][S:22]([CH2:21][CH2:20][O:19][CH3:18])(=[O:24])=[O:23])[CH:6]=[C:7]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:8]=1
Reactant: COCCS(=O)(=O)Cl
Reactant: CC1(C)OB(c2cc(N)cc(F)c2)OC1(C)C
Solvent: c1ccncc1
Product: COCCS(=O)(=O)Nc1cc(F)cc(B2OC(C)(C)C(C)(C)O2)c1
Temperature: 45 °C
Reaction time: 3 h
Yield: 17 %

Procedure:
3-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (250 mg, 1.05 mmol) was treated with 2-methoxyethanesulfonyl chloride (326 mg, 2.06 mmol) and 1 ml pyridine as a solvent according to the method described in Preparation 15b but stirring at 45° C. during 3 h. The residue was purified using SP1® Purification System (0% to 100% hexane-ethyl acetate) to obtain 80 mg (17% yield, 81% purity) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[C@@H:16]([CH3:17])[C:15](=[O:18])[C:12]3([CH2:14][CH2:13]3)[C:11]2=[O:19])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:20][Mg]Br.O1CCCC1>O1CCCC1.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[C@@H:16]([CH3:17])[C@:15]([OH:18])([CH3:20])[C:12]3([CH2:14][CH2:13]3)[C:11]2=[O:19])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C[C@H]1C(=O)C2(CC2)C(=O)N1c1ccc(C#N)c(Cl)c1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1N(c2ccc(C#N)c(Cl)c2)C(=O)C2(CC2)[C@]1(C)O
Reaction time: 1 h

Procedure:
To a solution of 2-chloro-4-[(6S)-6-methyl-4,7-dioxo-5-azaspiro[2.4]hept-5-yl]benzonitrile (35 mg) in tetrahydrofuran (6.0 mL) was added dropwise 1 mol/L-methylmagnesium bromide/tetrahydrofuran solution (1.3 mL) under ice-cooling, and the mixture was stirred at the same temperature for 1 hr. Brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
Reaction SMILES: Cl.O=[C:3]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:4]1[CH2:5][C@H:6]1[CH2:10][O:9][CH2:8][N:7]1[C:11](=[O:22])[CH2:12][N:13](C)[C:14](OC(C)(C)C)=O.C(O)(C(F)(F)F)=[O:28]>CCOCC>[CH3:14][NH:13][CH2:12][C:11]([N:7]1[C@@H:6]([CH2:5][C:4]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:3]=2)[CH2:10][O:9][C:8]1=[O:28])=[O:22]
Reactant: CN(CC(=O)N1COC[C@@H]1CC1C=CC=CC1=O)C(=O)OC(C)(C)C
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Solvent: CCOCC
Product: CNCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
HCl gas was bubbled into a solution of N-{2-[(4S)-2-oxo4-benzyl(1,3-oxazolidin-3-yl)]-2-oxoethyl}(tert-butoxy)-N-methylcarboxamide (7.2 g, 21 mmol) in Et2O (150 mL) over 30 min. The resulting white slurry was stirred for 2 h, allowed to warm to room temperature, and stirred for 2 h. A solution of HCl (1M in Et2O, 20 mL, 20 mmol, 3.6 equiv) was added and the reaction mixture was stirred overnight, then treated with TFA (10 mL), and stirred for 2 h. HCl gas was again bubbled into the mixture over 15 min, and the reaction was stirred for 3 h. The resulting mixture was concentrated under reduced pressure and the residue was triturated (100 mL of 50% EtOAc/hexanes). The resulting precipitate was filtered and washed with hexanes to give (4S)-3-[2-(methylamino)acetyl]-4-benzyl-1,3-oxazolidin-2-one (5.69 g, 96%) as a white solid: 1H NMR (CDCl3) δ 2.62 (br s, 3H), 2.91-3.04 (m, 2H), 4.22-4.44 (m, 4H), 4.65-4.73 (m, 1H), 7.22-7.34 (m, 5H), 9.26 (br s, 2H); HPLC ES-MS m/z (rel abundance) 249 (MH+, 100%).
Reaction SMILES: [F:1][CH:2]([F:18])[N:3]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][C:12]([SH:15])=[CH:11][C:10]=2[F:16])[N:5]=[C:4]1[CH3:17].Cl[CH2:20][C:21]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:22]=1[O:23][CH:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:18][CH:2]([F:1])[N:3]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15][CH2:20][C:21]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:22]=3[O:23][CH:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26])=[CH:11][C:10]=2[F:16])[N:5]=[C:4]1[CH3:17]
Reactant: Cc1nn(-c2ccc(S)cc2F)c(=O)n1C(F)F
Reactant: COC(=O)C(C)Oc1cc(Cl)ccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1cc(Cl)ccc1CSc1ccc(-n2nc(C)n(C(F)F)c2=O)c(F)c1
Yield: 22 %

Procedure:
By the method of Example 1, Step I, 1.35 g (0.0049 mole) of 4-(4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-on-1-yl)-3-fluorothiophenol and 3.0 g (0.011 mole) of methyl 2-(2-chloromethyl-5-chlorophenoxy)propionate (Example 2, Step E) were reacted in the presence of 1.02 g (0.0074 mole) of anhydrous potassium carbonate in 75 mL of N,N-dimethylformamide, yielding 0.54 g of methyl 2-[2-[4-(4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-on-1-yl)-3-fluorophenylthiomethyl]-5-chlorophenoxy]propionate as a yellow syrup. The NMR spectrum was consistent with the proposed structure. NMR: 1.65 (d, 3H, JHH =8.0 Hz); 2.44 (s, 3H); 3.78 (s, 3H); 4.20 (dd, 2H, JHH =13.0 Hz); 4.78 (q, 1H, JHH =8.0 Hz); 6.70-7.38 (m, 7H) .
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[Br-].[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][Zn+])=[CH:13][CH:12]=1>>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH2:15][C:14]2[CH:17]=[CH:18][C:11]([F:10])=[CH:12][CH:13]=2)[N:3]=1
Reactant: Brc1cccc(Br)n1
Reactant: Fc1ccc(C[Zn+])cc1
Agent: [Br-]
Product: Fc1ccc(Cc2cccc(Br)n2)cc1

Procedure:
Prepared according to the procedure described in Example 53, Step 2, using 2,6-dibromo-pyridine and 4-fluoro-benzylzinc bromide.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=1)=[O:6]>[Pd].C(OCC)(=O)C>[NH2:14][C:10]1[CH:9]=[C:8]([NH:7][C:5](=[O:6])[CH2:4][CH2:3][N:2]([CH3:17])[CH3:1])[CH:13]=[CH:12][CH:11]=1
Reactant: CN(C)CCC(=O)Nc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CN(C)CCC(=O)Nc1cccc(N)c1

Procedure:
10% Palladium on charcoal (1.0 g) was suspended in a solution of 3-(dimethylamino)-N-(3-nitrophenyl)propanamide (4.7 g, 20 mmol) in ethyl acetate. The mixture was hydrogenated at 35 psi overnight. The reaction mixture was filtered through a pad of Celite. The filter cake was washed successively with ethyl acetate and methanol. The combined filtrate and washings were evaporated in vacuo to dryness to give N-(3-aminophenyl)-3-(dimethylamino)propanamide as brown gum, 3.9 g (94%). 1H NMR (DMSO-d6) δ: 2.16 (6H, s, CH3), 2.36 (2H, t, J=6.8 Hz, CH2), 3.40 (2H, t, J=6.8 Hz, CH2), 5.20 (2H, brs, NH2), 6.66 (1H, d, J=7.8 Hz, Ar—H), 6.91 (1H, d, J=7.7 Hz, Ar—H), 7.04 (1H, s, Ar—H), 7.15 (1H, t, J=7.4 Hz, Ar—H), 9.05-9.08 (1H, brs, NH).
Reaction SMILES: [I:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[C:8]([O:10]C)=[O:9].[OH-].[Na+].CO.Cl>C1COCC1>[I:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[C:8]([OH:10])=[O:9]
Reactant: COC(=O)c1scc(C)c1I
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1csc(C(=O)O)c1I
Reaction time: 4 h
Yield: 100.1 %

Procedure:
To a solution of methyl 3-iodo-4-methylthiophene-2-carboxylate [Oakwood Product Inc.] (10 g, 35.4 mmol) in THF (200 mL) was added a solution of 2N NaOH (19.50 mL, 39.0 mmol). MeOH was added to the reaction mixture until a homogeneous solution was obtained. After about 4 h, concentrated HCl was added until a pH of about 1 was obtained. The reaction mixture was partially concentrated under reduced pressure and the resulting solid was collected by filtration and dried under reduced pressure to provide the title compound as a brown solid (9.50 g, 100%): LC/MS (Table 1, Method a) Rt=2.55 min; m/z: 267 (M−H)−.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])(C)(C)C.C(O[C:26](=[O:42])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][N:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=2)[CH:31]=1)=O)(C)(C)C>>[N:33]1[CH:34]=[CH:35][C:30]([C:28]2[CH2:27][C:26](=[O:42])[NH:19][C:9]3[CH:10]=[C:11]([C:15]([F:16])([F:17])[F:18])[C:12]([CH3:14])=[CH:13][C:8]=3[N:7]=2)=[CH:31][C:32]=1[C:36]1[CH:37]=[CH:38][N:39]=[CH:40][CH:41]=1
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnc(-c2ccncc2)c1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1ccnc(-c3ccncc3)c1)=N2

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (116 mg, 0.4 mmol) and 3-[2,4′]bipyridinyl-4-yl-3-oxo-propionic acid tert-butyl ester (Example K58) (119 mg, 0.4 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (86 mg).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([C:38]([F:41])([F:40])[F:39])=[C:34]([CH:37]=1)[CH:35]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:35][C:34]3[CH:37]=[C:30]([Cl:29])[CH:31]=[CH:32][C:33]=3[C:38]([F:40])([F:39])[F:41])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1cc(Cl)ccc1C(F)(F)F
Product: FC(F)(F)c1ccc(Cl)cc1CNc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 5-chloro-2-trifluoromethyl-benzaldehyde according to the procedure of Example 66. MS (ESI) m/z 571.