Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:10][C:11](=[O:16])[CH:12]([CH3:15])[CH2:13][NH2:14])[CH3:9].[O:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1.C([O-])(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:8]([O:10][C:11](=[O:16])[CH:12]([CH3:15])[CH2:13][NH:14][CH:20]1[CH2:21][CH2:22][O:17][CH2:18][CH2:19]1)[CH3:9]
Reactant: O=C1CCOCC1
Reactant: CCOC(=O)C(C)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(C)CNC1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.6 %

Procedure:
To a solution of 4.904 g (0.020 mole) of (rac)-3-amino-2-methyl-propanoic acid ethyl ester trifluoroacetate in 100 mL of dichloromethane was added 2.0 g (0.02 mole) of tetrahydro-4H-pyran-4-one, 3.28 g (0.040 mole) of sodium acetate and 6.70 g (0.030 mole) of sodium triacetoxyborohydride. The mixture was stirred at room temperature for 16 hours and then 100 mL of saturated aqueous sodium bicarbonate solution (100 mL) was added. After stirring for another 30 minutes, the layers were separated. The aqueous layer was extracted twice with 100 mL of dichloromethane. The organic layers were washed with 100 mL of brine, combined, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was distilled under vacuum to give 2.05 g of (rac)-2-methyl-3-(tetrahydro-pyran-4-ylamino)-propanoic acid ethyl ester as colorless oil. b.p. 135° C., 8 mm Hg.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[I:7]I.[NH:9]([C:16]1[N:17]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:18]2[C:23]([C:24](=[O:26])[CH:25]=1)=[C:22]([CH3:27])[CH:21]=[C:20]([Cl:28])[N:19]=2)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[O-]S([O-])(=S)=O.[Na+].[Na+]>CN(C=O)C>[NH:9]([C:16]1[N:17]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:18]2[C:23]([C:24](=[O:26])[C:25]=1[I:7])=[C:22]([CH3:27])[CH:21]=[C:20]([Cl:28])[N:19]=2)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: II
Reactant: Cc1cc(Cl)nc2c1c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Cl)nc2c1c(=O)c(I)c(Nc1ccccc1)n2-c1ccccc1
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
K2CO3 (210 mg, 1.52 mmol) and I2 (390 mg, 1.52 mmol,) were added to a solution 2-anilino-7-chloro-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (500 mg, 1.38 mmol) in DMF (10 mL). The mixture was stirred for 30 min and then poured into an aqueous solution of saturated Na2S2O3 (10 mL). The aqueous solution was extracted with EtOAc. The combined organic extracts were dried over MgSO4, and concentrated in vacuo. Silica gel flash chromatography of the residue using 4:1 to 1:1 Hex:EtOAc afforded 2-anilino-7-chloro-3-iodo-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (380 mg, 56%): LCMS RT: 3.45 min, MH+: 488.2, Rf=0.5 (2:1 Hex:EtOAc).
Reaction SMILES: [F:1][C:2]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:3]=1[O:4][C:5]1[CH:10]=[C:9]([F:11])[C:8]([C:12]2[C:20]3[C:15](=[C:16]([O:21]C)[N:17]=[CH:18][CH:19]=3)[N:14]([CH3:23])[CH:13]=2)=[CH:7][C:6]=1[NH:24][S:25]([CH3:28])(=[O:27])=[O:26].Cl.O1CCOCC1>>[F:1][C:2]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:3]=1[O:4][C:5]1[CH:10]=[C:9]([F:11])[C:8]([C:12]2[C:20]3[CH:19]=[CH:18][NH:17][C:16](=[O:21])[C:15]=3[N:14]([CH3:23])[CH:13]=2)=[CH:7][C:6]=1[NH:24][S:25]([CH3:28])(=[O:27])=[O:26]
Reactant: COc1nccc2c(-c3cc(NS(C)(=O)=O)c(Oc4ccc(F)cc4F)cc3F)cn(C)c12
Agent: Cl
Solvent: C1COCCO1
Product: Cn1cc(-c2cc(NS(C)(=O)=O)c(Oc3ccc(F)cc3F)cc2F)c2cc[nH]c(=O)c21
Temperature: 70 °C
Yield: 34.4 %

Procedure:
The product from Example 12A (0.066 g, 0.138 mmol) and 4 M hydrogen chloride in dioxane (10 mL, 40.0 mmol) were combined and heated at 70° C. for 24 hours, cooled and concentrated. The residue was purified by reverse phase HPLC (C18, CH3CN/water (0.1% TFA), 10-100%) to afford the title compound (0.022 g, 34%). 1H NMR (300 MHz, DMSO-d6) δ ppm 11.00 (d, J=5.09 Hz, 1H) 9.53 (s, 1H) 7.47-7.59 (m, 3H) 7.30-7.41 (m, 1H) 7.11-7.20 (m, 1H) 6.90-6.96 (m, 1H) 6.78 (d, J=10.85 Hz, 1H) 6.49 (d, J=7.12 Hz, 1H) 4.11 (s, 3H) 3.05 (s, 3H). MS (ESI+) m/z 464 (M+H)+.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.Cl[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[NH:13]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:19][O:18][C:14]1[N:13]=[N:12][C:17]([S:1][C:2]2[NH:3][C:4]3[C:9]([CH:10]=2)=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:16][CH:15]=1
Reactant: COC1=CC=CN(Cl)N1
Reactant: Sc1cc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(Sc2cc3ccccc3[nH]2)nn1
Yield: 31 %

Procedure:
To a solution of 2-mercaptoindole (6.7 mmol, 1.0 g) in acetone (20 mL) was added 2-chloro-6-methoxy-pyridazine (144 mmol, 1.52 g) and potassium carbonate (70 mmol, 0.98 g) and the reaction mixture was refluxed for 2 hours. Excess acetone was removed and the residue was partitioned between CHCl3 (20 mL) and H2O (20 mL). The CHCl3 layer was collected, dried, filtered and the filtrate was evaporated to a residue, which was purified by silica gel chromatography (eluent: hexanes:EtOAc::4:1) to obtain 3-methoxy-6-(indole-2-sulfenyl)-pyridazine (31%, 534 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=2[CH:17]=1.[CH3:18][NH:19][C:20]([C:22]1[S:23][CH:24]=[CH:25][C:26]=1[NH:27][C:28]1[C:33]([Cl:34])=[CH:32][N:31]=[C:30](Cl)[N:29]=1)=[O:21]>>[CH3:18][NH:19][C:20]([C:22]1[S:23][CH:24]=[CH:25][C:26]=1[NH:27][C:28]1[C:33]([Cl:34])=[CH:32][N:31]=[C:30]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=3[CH:17]=2)[N:29]=1)=[O:21]
Reactant: CNC(=O)c1sccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1C(=O)CCC(C)(C)c2ccc(N)cc21
Product: CCN1C(=O)CCC(C)(C)c2ccc(Nc3ncc(Cl)c(Nc4ccsc4C(=O)NC)n3)cc21

Procedure:
The title compound was prepared with a procedure analogous to that used to prepare example 381 by combining 8-Amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 3-(2,5-Dichloro-pyrimidin-4-ylamino)-thiophene-2-carboxylic acid methylamide to yield a light yellow solid (6.7%). LCMS: m/z=499.46 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.28 (m, 1H), 8.09 (d, 1H, J=1.8 Hz), 7.74 (m, 1H), 7.34 (m, 1H), 7.24 (m, 2H), 3.78 (m, 2H), 2.96 (s, 3H), 2.34 (m, 2H), 2.06 (m, 2H), 1.36 (m, 6H), 1.21 (m, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[N:5]=[C:4]([CH3:21])[N:3]=1.[CH:22]([C:25]1[N:29]=[C:28]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[O:27][N:26]=1)([CH3:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+].C(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH:22]([C:25]1[N:29]=[C:28]([CH:30]2[CH2:35][CH2:34][N:33]([C:2]3[C:7]([C:8]#[N:9])=[C:6]([O:10][C:11]4[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=4)[N:5]=[C:4]([CH3:21])[N:3]=3)[CH2:32][CH2:31]2)[O:27][N:26]=1)([CH3:24])[CH3:23]
Reactant: Cc1nc(Cl)c(C#N)c(Oc2ccc(S(C)(=O)=O)cc2)n1
Reactant: CC(C)c1noc(C2CCNCC2)n1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nc(Oc2ccc(S(C)(=O)=O)cc2)c(C#N)c(N2CCC(c3nc(C(C)C)no3)CC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.4 %

Procedure:
To a solution of 4-chloro-6-(4-methanesulfonyl-phenoxy)-2-methyl-pyrimidine-5-carbonitrile (80.0 mg, 0.25 mmol) and 4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidine (107.1 mg, 0.50 mmol) in DMF (1 mL) was added potassium carbonate (68.3 mg, 0.50 mmol) and the resulting mixture was left stirring for 2 hours at room temperature. Worked up with ethyl acetate, sodium bicarbonate, dried with magnesium sulfate and evaporated. The crude product was crystallized with ethyl acetate/hexane over night and filtered off to afford Compound A164 as a yellow solid (30.6 mg). LCMS (ESI) for C23H26N6O4S: m/z 483.3 (M+H+, 100%), 1H NMR 400 MHz CDCl3 δ (ppm): 8.00 (d, 2H), 7.38 (d, 2H), 4.82 (m, 2H), 3.45 (m, 2H), 3.31 (m, 1H), 3.10 (s, 3H), 3.08 (m, 1H), 2.35 (s, 3H), 2.24(m, 2H), 2.03 (m, 2H), 1.34(d, 6H).
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[N:18]=[C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:20][C:21]=3[C:22]([F:25])([F:24])[F:23])=[O:16])=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH2:39]([N:42]=[C:43]=[O:44])[CH2:40][CH3:41]>C1COCC1>[CH2:39]([NH:42][C:43]([N:5]1[CH2:6][CH2:7][N:2]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[N:18]=[C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:20][C:21]=3[C:22]([F:23])([F:25])[F:24])=[O:16])=[CH:10][CH:9]=2)[CH2:3][CH2:4]1)=[O:44])[CH2:40][CH3:41]
Reactant: CCCN=C=O
Reactant: O=C(Nc1ccc(N2CCNCC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCNC(=O)N1CCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
To a solution of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperazin-1-yl-phenyl)-amide hydrochloride (100 mg, 0.204 mmol) and triethylamine (57 μL, 0.408 mmol) in 5 mL THF at 0° C. was added n-propylisocyanate (21.6 mg, 0.255 mmol). The ice bath was removed and the reaction mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered, and evaporated under reduced pressure. The residue was crystallized from ethyl acetate/hexane to yield 4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperazine-1-carboxylic acid propylamide (83 mg, 81%). ES-MS calcd for C25H26F3N5O3 (m/e) 501.51, obsd 502.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([OH:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18](F)[C:15]=1[C:16]#[N:17]>CN(C)C=O.O>[F:13][C:14]1[CH:21]=[CH:20][C:19]([O:10][C@@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH3:9])=[CH:18][C:15]=1[C:16]#[N:17]
Reactant: N#Cc1c(F)cccc1F
Reactant: C[C@@H](O)c1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](Oc1ccc(F)c(C#N)c1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.2 %

Procedure:
A solution of (R)-1-(3-chlorophenyl)ethanol (0.730 g, 4.66 mmol) in dimethylformamide (5 mL) was added to a 0° C. slurry of sodium hydride (0.207 g, 5.18 mmol) in dimethylformamide (5 mL) under nitrogen atmosphere. The reaction mixture was warmed to room temperature, stirred for 3 hour, and then cooled with an ice bath. The cold orange solution was added dropwise to a 0° C. solution of 2,6-difluorobenzonitrile (0.720 g, 5.18 mmol) in dimethylfomamide (5 mL). After the reaction was stirred at ambient temperature for around 18 hours, the reaction was diluted with water and extracted with EA. The organic layer was washed with water and brine, dried over MgSO4, and concentrated in vacuo to a yellow semi-solid. Flash chromatography purification (silica gel, 50% hexane in DCM) afforded the 2-fluoro-5-[(R)-1-(3-chlorophenyl)ethoxy]benzonitrile as a pale yellow oil (0.645 g, 50%).
Reaction SMILES: C(N(CC)CC)C.Br[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1.[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21]>C(OCC)(=O)C.[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:19][Si:20]([CH3:22])([CH3:21])[C:23]#[C:24][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1
Reactant: FC(F)(F)c1cccc(Br)c1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cccc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 102.2 %

Procedure:
Add copper (I) iodide (48.2 mg, 0.25 mmol), bis(triphenylphosphine)palladium (II) dichloride (155.8 m g, 0.22 mmol) and triethylamine (2.51 mL, 17.8 mmol), to a solution of 1-bromo-3-trifluoromethylbenzene (0.62 mL, 4.44 mmol) and trimethylsilylacetylene (0.81 mL, 5.78 mmol), in ethyl acetate (4 mL). Stir at 50° C. for 18h. Cool the reaction mixture to room temperature, concentrate and purify the residue by silica gel chromatography, eluting with hexanes, to give the title compound (1.1 g, 100%).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][NH:11][CH3:12].[Cl:13][C:14]1[C:15]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=2)=[N:16][C:17]([Cl:20])=[CH:18][CH:19]=1>N1C=CC=CC=1>[Cl:13][C:14]1[C:15]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:31])[N:11]([O:10][CH3:9])[CH3:12])=[CH:25][CH:24]=2)=[N:16][C:17]([Cl:20])=[CH:18][CH:19]=1
Reactant: O=C=Nc1ccc(OCc2nc(Cl)ccc2Cl)cc1
Reactant: CNOC
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CON(C)C(=O)Nc1ccc(OCc2nc(Cl)ccc2Cl)cc1
Temperature: 60 °C

Procedure:
Triethylamine (4.55 grams; 0.045 mole) was added to a solution of O,N-dimethylhydroxylamine hydrochloride (4.1 grams; 0.042 mole) in 40 ml. of dry pyridine. 3,6-dichloro-2-((4-isocyanatophenoxy)methyl)pyridine (12.4 grams; 0.042 mole) was added thereto and the resulting mixture heated for 20 minutes at about 60° C. The reaction mixture was then mixed with ice and the resulting precipitate recovered by filtration and recrystallized from a benzenehexane (90:10) mixture. As a result of such operations, the desired N'-(4-((3,6-dichloro-2-pyridinyl)methoxy)phenyl)-N-methoxy-N-methyl urea compound was recovered as a crystalline solid having a melting point of 152°-153.5° C.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([C:19]1[C:20]([Cl:30])=[N:21][N:22]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH:23]=1)[C:12](=[O:18])[CH:13]([CH3:17])[CH2:14][S:15][CH3:16])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.[Cl-].[Na+].O>[Cl:30][C:20]1[C:19]([N:11]([CH2:10][CH2:9][OH:8])[C:12](=[O:18])[CH:13]([CH3:17])[CH2:14][S:15][CH3:16])=[CH:23][N:22]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[N:21]=1
Reactant: CSCC(C)C(=O)N(CCO[Si](C)(C)C(C)(C)C)c1cn(-c2cccnc2)nc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CSCC(C)C(=O)N(CCO)c1cn(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.5 %

Procedure:
To a solution of N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-2-methyl-3-(methylthio)propanamide (0.180 g, 0.384 mmol) in tetrahydrofuran (1.54 ml) was added tetrabutylammonium fluoride (0.201 g, 0.767 mmol) and the reaction was stirred at room temperature for 2 hours. Brine was added and the mixture was extracted with ethyl acetate. The combined organic phases were concentrated and chromatographed (0-100% water/acetonitrile) to give N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-(2-hydroxyethyl)-2-methyl-3-(methylthio)propanamide as a white oil (0.081 g, 0.217 mmol, 56.5%): IR (thin film) 3423, 1654 cm−1; 1H NMR (400 MHz, CDCl3) δ 9.00 (d, J=2.5 Hz, 1H), 8.62 (dd, J=4.7, 1.2 Hz, 1H), 8.25 (s, 1H), 8.07 (ddd, J=8.3, 2.4, 1.3 Hz, 1H), 7.47 (dd, J=8.3, 4.7 Hz, 1H), 4.47-3.70 (m, 3H), 3.65-3.09 (m, 2H), 2.91-2.68 (m, 2H), 2.48 (dd, J=12.4, 5.0 Hz, 1H), 2.01 (s, 3H), 1.18 (d, J=6.5 Hz, 3H); ESIMS m/z 356 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]([F:29])[CH:20]=1)[CH2:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14](=[O:17])[NH:13][CH:12]=1.IC.[C:32](=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]([F:29])[CH:20]=1)[CH2:9][C:10]([C:11]1[CH:16]=[CH:15][C:14](=[O:17])[N:13]([CH3:32])[CH:12]=1)=[O:18]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc(C(CC(=O)c2ccc(=O)[nH]c2)c2ccccc2Cl)cc1F
Agent: [K+]
Solvent: CI
Product: COC(=O)c1ccc(C(CC(=O)c2ccc(=O)n(C)c2)c2ccccc2Cl)cc1F

Procedure:
In analogy to example 161, step 1, methyl 4-(1-(2-chlorophenyl)-3-oxo-3-(6-oxo-1,6-dihydropyridin-3-yl)propyl)-2-fluorobenzoate was reacted with iodomethane in the presence of potassium carbonate to give the title compound as an off-white foam, MS (ESI+): m/z=428.2 [M+H]+.
Reaction SMILES: OS(O)(=O)=O.[Cl:6][C:7]1[S:8][C:9]([C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])=[C:10]([CH2:12][OH:13])[N:11]=1.C([OH:23])(C)C>CC(C)=O.O.[Na+].[Cl-]>[Cl:6][C:7]1[S:8][C:9]([C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])=[C:10]([C:12]([OH:23])=[O:13])[N:11]=1
Reactant: CC(C)O
Reactant: CC(C)OC(=O)c1sc(Cl)nc1CO
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)OC(=O)c1sc(Cl)nc1C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 3 mL H2SO4 and 12 mL water were cooled in an ice water bath, and 2.3 g (23 mmol) CrO3 was added portionwise. The solution was added dropwise to a cooled (ice water bath) solution of 2.74 g (11.6 mmol) of isopropyl 2-chloro-4-(hydroxymethyl)-1,3-thiazole-5-carboxylate (Intermediate 13) in acetone (50 mL) The resulting mixture was stirred 4 hours with warming to room temperature. Isopropanol (2 mL) was added and stirring was continued for 15 min. The solution was diluted with water, saturated with NaCl and extracted 3 times with EtOAc. The EtOAc was washed with brine, dried (MgSO4) and concentrated to give 2.86 g of an oil. NMR: 1.3 (d, 6H), 5.1 (m, 1H), 14.1 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:27]=[O:28])=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[BH4-].[Na+].Cl>C(O)C>[CH3:1][C:2]1[NH:3][C:4]([CH2:27][OH:28])=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1=C(C)NC(C=O)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(CO)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Yield: 88.6 %

Procedure:
To a solution of diethyl 2-methyl-4-(2-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (2.0881 g) in ethanol (20 ml) was gradually added sodium borohydride (0.1892 g) under stirring and the resultant mixture was further stirred at room temperature for an hour. The solution was acidified with dilute hydrochloric acid and stirred at room temperature for 30 minutes. After the resultant solution was filtered, the filtrate was concentrated under reduced pressure and extracted with ethyl acetate. The extract was washed with water and dried and then the solvent was removed to give orange oil (1.8596 g) of diethyl 2-methyl-4-(2-nitrophenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate. After the crude, product was dissolved in ethanol, the solution was filtered. The filtrate was concentrated under reduced pressure and the oily residue was allowed to stand for 3 days. Thus obtained crystals were recrystallized from ether to give pure product, m.p. 112° to 113° C.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[CH:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[C:20]([F:28])[CH:19]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:32]O.Cl>CO.O.C(Cl)Cl>[F:28][C:20]1[CH:19]=[C:18]([CH:10]2[CH2:9][CH:8]([C:6]3[O:7][NH:32][C:4](=[O:3])[CH:5]=3)[CH2:13][CH2:12][N:11]2[C:14]([O:16][CH3:17])=[O:15])[CH:23]=[CH:22][C:21]=1[C:24]([F:27])([F:26])[F:25]
Reactant: CCOC(=O)CC(=O)C1CCN(C(=O)OC)C(c2ccc(C(F)(F)F)c(F)c2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: COC(=O)N1CCC(c2cc(=O)[nH]o2)CC1c1ccc(C(F)(F)F)c(F)c1
Temperature: -40 °C
Reaction time: 0.25 h
Yield: 33.1 %

Procedure:
Methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-fluoro-4-(trifluoromethyl)phenyl)piperidine-1-carboxylate (2.19 g, 5.22 mmol) was dissolved in MeOH (20 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.219 g, 5.48 mmol) dissolved in water (2.000 mL) was added and the mixture was stirred at −40° C. for 15 min. Hydroxylamine (50% by weight in water, 0.336 mL, 5.48 mmol) was added. The resulting solution was stirred at −40° C. for 1 h. The mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (27.0 mL, 161.89 mmol) and the mixture was stirred at 80° C. for 20 min. Water and DCM were added and the phases separated. The aqueous phase was extracted with DCM and the combined organic layers were filtered through a phase separator and evaporated. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 15-55% Acetonitrile in H2O/MeCN/FA 95/5/0.2 buffer over 25 minutes with a flow of 100 mL/min. Methyl 2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.670 g, 33.0%) was yielded as a colorless solid. 1H NMR (400 MHz, cdcl3) δ 1.82-1.93 (m, 1H), 2.12-2.44 (m, 3H), 3.04-3.16 (m, 1H), 3.35-3.46 (m, 1H), 3.69 (s, 3H), 4.11-4.21 (m, 1H), 5.09-5.18 (m, 1H), 5.56 (s, 1H), 6.97-7.09 (m, 2H), 7.52 (t, 1H). MS m/z 387 (M−H)−
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[NH:10][CH:11]([C:13]1[N:14]=[C:15]2[CH:20]=[N:19][CH:18]=[CH:17][N:16]2[CH:21]=1)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N([I:30])C(=O)C1>C(#N)C.O>[CH2:1]([O:8][C:9](=[O:22])[NH:10][CH:11]([C:13]1[N:14]=[C:15]2[CH:20]=[N:19][CH:18]=[CH:17][N:16]2[C:21]=1[I:30])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CC(NC(=O)OCc1ccccc1)c1cn2ccncc2n1
Solvent: CC#N
Solvent: O
Product: CC(NC(=O)OCc1ccccc1)c1nc2cnccn2c1I
Reaction time: 8 h

Procedure:
To a solution of (1-imidazo[1,2-a]pyrazin-2-yl-ethyl)-carbamic acid benzyl ester (1.7 g, 5.74 mmol) in acetonitrile (10 mL) was added n-iodosuccinimide (1.3 g, 5.74 mmol) at rt and stirred overnight. After completion of the reaction, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed with satd. sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography using silica gel (100-200 mesh) and 0-4% MeOH in DCM to provide [1-(3-iodo-imidazo[1,2-a]pyrazin-2-yl)-ethyl]-carbamic acid benzyl ester: LC-MS (ESI) m/z 422.9 [M+H]+.
Reaction SMILES: C(O[C:4]([C:6]1[C:11]([NH:12][C:13]2[CH:14]=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=2)=[CH:10][CH:9]=[C:8]([CH3:20])[N:7]=1)=[O:5])C.[NH2:21][C:22]1[S:23][CH:24]=[C:25]([CH3:27])[N:26]=1>>[CH3:27][C:25]1[N:26]=[C:22]([NH:21][C:4]([C:6]2[C:11]([NH:12][C:13]3[CH:14]=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=3)=[CH:10][CH:9]=[C:8]([CH3:20])[N:7]=2)=[O:5])[S:23][CH:24]=1
Reactant: Cc1csc(N)n1
Reactant: CCOC(=O)c1nc(C)ccc1Nc1cncc(C)c1
Product: Cc1cncc(Nc2ccc(C)nc2C(=O)Nc2nc(C)cs2)c1

Procedure:
The title compound, was prepared from 6-Methyl-3-(5-methyl-pyridin-3-ylamino)-pyridine-2-carboxylic acid ethyl ester and 2-Amino-4-methylthiazole in accordance with the general method of Example 78, step 2 to yield the final compound as a yellow solid, MS (ISP): m/e=340.3 (M+H+).