Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[NH:22][C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[N:9]=[C:4]2[CH:3]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[CH:33][C:34]([N:37]3[CH2:41][CH2:40][CH2:39][C:38]3=[O:42])=[N:35][CH:36]=2)O1>>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([O:18][CH3:19])[CH:15]=1)[CH2:11][CH2:10][C:8]1[N:9]=[C:4]2[CH:3]=[C:2]([C:31]3[CH:32]=[CH:33][C:34]([N:37]4[CH2:41][CH2:40][CH2:39][C:38]4=[O:42])=[N:35][CH:36]=3)[NH:22][C:5]2=[N:6][CH:7]=1
Reactant: COc1cc(CCc2cnc3[nH]c(Br)cc3n2)cc(OC)c1
Reactant: CC1(C)OB(c2ccc(N3CCCC3=O)nc2)OC1(C)C
Product: COc1cc(CCc2cnc3[nH]c(-c4ccc(N5CCCC5=O)nc4)cc3n2)cc(OC)c1

Procedure:
The compound was prepared by using procedures analogous to those described for the synthesis of Example 53, Step 2 starting from 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5H-pyrrolo[2,3-b]pyrazine and 1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]pyrrolidin-2-one (from JPM2 Pharmaceuticals). LCMS calculated for C25H26N5O3 (M+H)+: m/z=444.2. Found 444.2.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]1[C:24]([OH:26])=[O:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([O-])([O-])=O.[K+].[K+].COS(OC)(=O)=O>CC(C)=O>[N:11]1([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[CH2:13][CH:12]1[C:24]([O:26][CH3:27])=[O:25]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(C(=O)O)C1
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Yield: 90 %

Procedure:
This step was carried out using the procedure described in Tetrahedron Letters 30 (39), 1989, 5193-5196. A 0.5 M solution of A1 in acetone was treated with K2CO3 (1.3 eq.) and Me2SO4 (1.2 eq.) and the mixture was refluxed 6 h. The reaction mixture was filtered and filtrate was concentrated under reduced pressure. The residue was dissolved in Et2O and washed with sat. aq. NaHCO3 solution, and brine, then dried and evaporated. The residue was purified by column chromatography on silica gel, eluting with 20-100% EtOAc/petroleum ether to give the title compound in 90% yield. 1H NMR (300 MHz, CDCl3, 300K) δ 7.35 (5H, m), 5.17 (2H, m), 4.77-4.50 (2H, m), 4.10-3.85 (1H, m), 3.74 (1.5H, s), 3.64 (1.5H, s), 3.30 (1H, m), 3.10 (1H, dd, J 13.6, 4.4), 2.86 (1H, m), 1.45 (9H, s). MS (ES+) C19H26N2O6 requires 378, found: 401 (M+Na)+.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]([C:30]3[CH:31]=[N:32][NH:33][CH:34]=3)[C:13]3[O:22][C:21]4[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][C:16]=4[C:14]=3[CH:15]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:35]>O1CCCC1>[ClH:35].[C:1]1([S:7]([C:10]2[CH:11]=[C:12]([C:30]3[CH:34]=[N:33][NH:32][CH:31]=3)[C:13]3[O:22][C:21]4[CH2:20][CH2:19][NH:18][CH2:17][C:16]=4[C:14]=3[CH:15]=2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3c(-c4cn[nH]c4)cc(S(=O)(=O)c4ccccc4)cc3c2C1
Agent: Cl
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)c1cc(-c2cn[nH]c2)c2oc3c(c2c1)CNCC3
Reaction time: 8 h

Procedure:
To a solution of the product from step A (36 mg, 0.07 mmol) in tetrahydrofuran (2.5 mL) was added concentrated HCl (0.5 mL) at 0° C. The reaction mixture was slowly allowed to reach ambient temperature and stirred overnight. The precipitate was filtered, washed with tetrahydrofuran, and dried overnight in vacuo at 45° C. to give 8-(phenylsulfonyl)-6-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridine hydrochloride (18 mg, 58%, AUC HPLC>99%) as a white solid: mp <<MP data>>; 1H NMR (DMSO-d6, 400 MHz) δ 9.46 (br s, 2H), 8.42 (s, 2H), 8.19 (d, J=1.6 Hz, 1H), 8.16 (d, J=2.0 Hz, 1H), 8.08-8.01 (m, 2H), 7.71-7.57 (m, 3H), 4.41 (s, 2H), 3.64 (br s, 2H); 3.22-3.12 (m, 2H); APCI MS m/z 380 [M+H]+.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[CH:23]=[CH:22][CH:21]=[CH:20][C:12]=1[NH:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN([C:29](N2C=NC=C2)=[S:30])C=1>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[C:9](=[O:10])[C:11]2[C:12](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:13]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:29]1=[S:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CNc1ccccc1C(=O)NCc1ccccc1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cn1c(=S)n(Cc2ccccc2)c(=O)c2ccccc21
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
A mixture of ethyl 2-[2-(N-benzylcarbamoyl)anilino]acetate (1.5 g) and N,N'-thiocarbonyldiimidazole (2.85 g) was stirred at 120° C. for 30 minutes. After cooling, the reaction mixture was diluted with chloroform and chromatographed on silica gel. Elution with chloroform gave ethyl 2-(3-benzyl-1,2,3,4-tetrahydro-4-oxo-2-thioxoquinazolin-1-yl)acetate. A mixture of ethyl 2-(3-benzyl-1,2,3,4-tetrahydro-4-oxo-2-thioxoquinazolin-1-yl)acetate and 1N sodium hydroxide (2 ml) in methanol (10 ml) was stirred for 4 hours at room temperature. The reaction mixture was poured into dilute hydrochloric acid and extracted with chloroform. The extract was washed with brine and dried. Removal of the solvent gave 2-(3-benzyl-1,2,3,4-tetrahydro-4-oxo-2-thioxoquinazolin-1-yl)acetic acid (280 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][N:8]=[C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[OH-].[K+]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:22])[CH:7]([N:8]=[C:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C(Cc1ccccc1)N=C(c1ccccc1)c1ccccc1
Yield: 95 %

Procedure:
74 mg of tert-butyl(benzhydrylideneamino)acetate, 2.0 mg of an optically active quaternary ammonium salt compound (R,R)-(29), and 36 μl of benzylbromide were added to 2 ml of a toluene solvent at 0° C. 0.5 ml of 50% KOH aqueous solution was added dropwise to the resulting solution while stirring. The reaction solution was stirred for 8 hours at 0° C. and thereafter extracted by adding water and ether. The reaction product was purified by column chromatography (hexane:ether=15:1) to obtain targeted tert-butyl-2-(benzhydrylideneamino)-3-phenylpropionate (yield was 95%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]1[C:16]([N:18]([CH2:40][CH:41]([CH3:43])[CH3:42])[C@H:19]1[CH2:24][C@@H:23]([C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:26])[CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]1)=[O:17].C(OCC)(=O)C.[ClH:50]>>[ClH:50].[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]1[C:16]([N:18]([CH2:40][CH:41]([CH3:43])[CH3:42])[C@H:19]1[CH2:24][C@@H:23]([C:25]([N:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)=[O:26])[CH2:22][NH:21][CH2:20]1)=[O:17]
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)cc2ccccc21
Agent: Cl
Solvent: CCOC(C)=O
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@@H]2CNC[C@H](C(=O)N3CCOCC3)C2)cc2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
tert-Butyl (3S,5R)-3-[{[1-(4-methoxybutyl)-1H-indol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (83.4 mg) was dissolved in 4N hydrogen chloride-ethyl acetate (3 ml), and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was concentrated to give the object product (67 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:5].Cl[C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=1>C1(C)C=CC=CC=1>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([C:4]([C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=2[NH:1][C:18]2[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=2)=[O:5])=[CH:7][CH:8]=1
Reactant: Nc1ccccc1C(=O)c1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: Cc1ccccc1
Product: O=C(c1ccc(Cl)cc1)c1ccccc1Nc1ncccc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 2 h
Yield: 56.3 %

Procedure:
Under nitrogen atmosphere, 50.0 g (0.216 mole) of 2-amino-4'-chlorobenzophenone was added in four portions at 15 min intervals to a stirred melt (105°-110° C.) of 35.9 g (0.227 mole) of 2-chloro-3-nitropyridine. The reaction temperature was increased to 120° C. for 3 hr and then to 150° C. for 2 hr. The stirred mixture was cooled to 115° C. and 100 ml of hot toluene was added. The cooled mixture (room temperature) was filtered. The filtrate was washed with 75 ml of 5% sodium hydroxide solution, 50 ml of water and 30 ml of saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The residue was crystallized from ethyl acetate-isopropyl ether to give 43 g (56.4%) solid. Recrystallization from ethyl acetate-isopropyl ether gave 18.26 g* of bright-yellow solid, m.p. 138'-140° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:5]2[S:10][C:9]([C:11]3[N:12]=[CH:13][S:14][CH:15]=3)=[N:8][C:6]=2[N:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:28](#[N:30])[CH3:29]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:19]1[CH2:20][CH2:21][N:16]([C:4]2[C:5]3[S:10][C:9]([C:11]4[N:12]=[CH:13][S:14][CH:15]=4)=[N:8][C:6]=3[N:7]=[C:2]([C:29]3[CH:28]=[N:30][C:2]([NH2:7])=[N:3][CH:4]=3)[N:3]=2)[CH2:17][CH2:18]1
Reactant: Clc1nc(N2CCOCC2)c2sc(-c3cscn3)nc2n1
Reactant: CC#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Nc1ncc(-c2nc(N3CCOCC3)c3sc(-c4cscn4)nc3n2)cn1

Procedure:
5-Chloro-7-morpholino-2-(thiazol-4-yl)thiazolo[4,5-d]pyrimidine, 5-pyrimidine-2-amine boronic acid (1.2 eq), and trans-dichlorobis(triphenylphosphine)palladium(II) (0.1 eq) were slurried with equal parts 1M sodium carbonate (3 eq) and acetonitrile. The solution was microwaved at 130° C. for 15 minutes. Acetonitrile was added and the solution was filtered. The resulting organic layer was purified by reverse phase silica gel chromatography to give the product 138. MS data: (ESI+): MH+399.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[C:4]([O:14][C:15]([F:18])([F:17])[F:16])[CH:3]=1.[C:19]([C:21]1[N:25]([CH3:26])[C:24](B(O)O)=[CH:23][CH:22]=1)#[N:20].[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:19]([C:21]1[N:25]([CH3:26])[C:24]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[C:4]([O:14][C:15]([F:18])([F:17])[F:16])[CH:3]=2)=[CH:23][CH:22]=1)#[N:20]
Reactant: CN(C)S(=O)(=O)c1ccc(Br)cc1OC(F)(F)F
Reactant: Cn1c(C#N)ccc1B(O)O
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CN(C)S(=O)(=O)c1ccc(-c2ccc(C#N)n2C)cc1OC(F)(F)F
Reaction time: 16 h
Yield: 33.1 %

Procedure:
According to general procedure B, 4-Bromo-N,N-dimethyl-2-trifluoromethoxy-benzenesulfonamide (209 mg, 0.59 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (107 mg, 0.71 mmol), potassium fluoride (113 mg, 1.95 mmol), and tris(dibenzylideneacetone)dipalladium (0) (15 mg, 0.01 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.4 mL) was added. Tri-t-butylphosphine (89 μL, 0.02 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N,N-dimethyl-2-(trifluoromethoxy)benzenesulfonamide (73 mg, 32%) was provided after purification. MS (ESI) m/z 373. HPLC purity 99.1% at 210-370 nm, 9.7 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5](=[O:25])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14](=[O:24])[C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])=[CH:8][CH:7]=1)C.[OH-].[Na+].O>CO>[O:24]=[C:14]([C:15]1[C:16]([CH3:23])=[CH:17][C:18]([CH3:22])=[CH:19][C:20]=1[CH3:21])[CH2:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([C:5](=[O:25])[C:4]([OH:26])=[O:3])=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(=O)c1ccc(OCC(=O)c2c(C)cc(C)cc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(C)c(C(=O)COc2ccc(C(=O)C(=O)O)cc2)c(C)c1
Yield: 73.6 %

Procedure:
A solution of 4-[2-oxo-2-(2,4,6-trimethylphenyl]ethoxy]-alpha-oxobenzeneacetic acid ethyl ester (0.357 g) in hot methanol (5 mL) was treated with 1N sodium hydroxide (2 mL). Water (20 mL) was added, then after the methanol was removed in vacuo, the solution was acidified with 1N hydrochloric acid (2.5 mL) and extracted with dichloromethane methane (1×40 mL, 1×7 mL). The combined organic layers were washed with brine, then dried (MgSO4) and evaporated. The resulting residue was crystallized from diethyl ether-hexane to furnish 0.242 g of 4-[2-oxo-2-(2,4,6-trimethyl-phenyl]ethoxy]-alpha-oxobenzeneacetic acid, mp 144°-145° C.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].S(=O)(=O)(O)O.O.OO.[CH2:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>[Cu].C(#N)C>[CH:21]1([O:1][N:2]2[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]2([CH3:12])[CH3:11])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Reactant: C1CCCCC1
Agent: [Cu]
Agent: O=S(=O)(O)O
Agent: OO
Solvent: CC#N
Solvent: O
Product: CC1(C)CC(O)CC(C)(C)N1OC1CCCCC1
Yield: 70 %

Procedure:
Copper powder (0.060 g, 0.944 mmol) is added to a mixture of 5.00 g (29.0 mmol) of 1-oxyl-2,2,6,6-tetramethylpiperidin-4-ol, 44 ml of acetonitrile, and 30 ml of cyclohexane that has been heated to 40 degrees. A portion of a solution of 0.457 g of concentrated sulfuric acid in 3 mol of water is carefully added to the reaction mixture after the mixture is brought to reflux. To the refluxing reaction mixture is added dropwise over 2.5 hours a solution of 7.32 g (108 mmol) of 50% aqueous hydrogen peroxide. The remainder of the sulfuric acid solution is carefully added in portions to the reaction mixture during the first 15 minutes of the peroxide addition. After work up and purification according to the procedure of Example 54, the yield of the title compound is 5.22 g (70% yield), GC assay 94%.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH:7][CH2:8][CH2:9][OH:10].[C:11](Cl)(=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][N:7]([CH2:8][CH2:9][OH:10])[C:11](=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: OCCNCCNCCO
Product: CCCCCCCCCCCC(=O)N(CCO)CCNCCO

Procedure:
5.3 g of N,N'-Bis(2-hydroxyethyl)ethylenediamine and 3.0 g of dodecanoyl chloride were reacted together following the procedure under Example 3. This provided 3.3 g of pure product, m.p. 94° C.
Reaction SMILES: [C:1](Cl)(=[O:11])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.[Cl:13][C:14]1[C:15]([OH:21])=[CH:16][C:17](=[O:20])[NH:18][CH:19]=1>N1C=CC=CC=1>[Cl:13][C:14]1[C:15]([O:21][C:1](=[O:11])[C:2]2[CH:10]=[CH:9][C:8]3[O:7][CH2:6][O:5][C:4]=3[CH:3]=2)=[CH:16][C:17](=[O:20])[NH:18][CH:19]=1
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Reactant: O=c1cc(O)c(Cl)c[nH]1
Solvent: c1ccncc1
Product: O=C(Oc1cc(=O)[nH]cc1Cl)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 5 %

Procedure:
A 3.80 g quantity of piperonyloyl chloride was added to a suspension of 2.00 g of 5-chloro-4-hydroxy-2-pyridone in 60 ml of pyridine, and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was filtered and the filtrate was concentrated. The concentrate was washed successively with ethyl acetate, water and chloroform and then purified by silica gel column chromatography using as an eluent 2% methanol-chloroform, thereby producing 200 mg of the title compound in a yield of 5%.
Reaction SMILES: N#N.C([SiH2][O:8][C:9](C)(C)[C:10]1[O:11][C:12]([C:15](=[O:17])[CH3:16])=[CH:13][N:14]=1)(C)(C)C.[CH2:20](O)[CH2:21][OH:22].COC(OC)OC>C([O-])(O)=O.[Na+]>[CH3:16][C:15]1([C:12]2[O:11][C:10]([CH2:9][OH:8])=[N:14][CH:13]=2)[O:17][CH2:20][CH2:21][O:22]1
Reactant: OCCO
Reactant: CC(=O)c1cnc(C(C)(C)O[SiH2]C(C)(C)C)o1
Agent: N#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COC(OC)OC
Product: CC1(c2cnc(CO)o2)OCCO1
Temperature: 95 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and a condenser under inert atmosphere (N2), a solution of 1-[2-(tert-butyl-dimethyl-silanyloxymethyl)-oxazol-5-yl]-ethanone (105 mg, 0.41 mmol) in ethylene glycol (0.46 mL, 8.22 mmol) was treated with trimethylorthoformate (0.09 mL, 0.82 mmol) followed by LiBF4 (8 mg, 0.08 mmol). The reaction mixture was heated at 95° C. until reaction completion. Sat. aq. NaHCO3 (10 mL) was added and the mixture was extracted with EA (2×10 mL). The combined org. extracts were washed with brine (20 mL), dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (4:1 EA-Hept) gave the title compound as a yellow oil. TLC: rf (4:1 EA-Hept)=0.25. LC-MS-conditions 02: tR=0.56 min; [M+H]+=186.55.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH2:10]([O:12][C:13](=[O:22])[CH:14](Br)[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH3:11]>>[CH2:10]([O:12][C:13](=[O:22])[CH:14]([N:7]1[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]1)[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH3:11]
Reactant: CC(=O)N1CCNCC1
Reactant: CCOC(=O)C(Br)c1cccnc1
Product: CCOC(=O)C(c1cccnc1)N1CCN(C(C)=O)CC1
Yield: 60 %

Procedure:
N-acetyl-piperazine (3.7 g; 28.8 mmol; 2.8 equiv) was combined with bromo-pyridin-3-yl-acetic acid ethyl ester (approx. 2.5 g; 10 mmol). Purification on a 3×16 cm silica column using a 30% then 40% ethyl acetate/hexanes (v/v) mobile phase followed by a 2% methanol/dichloromethane (v/v) mobile phase resulted in 1.84 g light yellow oil (approx. 60% yield). MS(ES) calc'd: [M+H]+=292.2 m/z; [M+Na]+=314.2 m/z.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH3:11])=[CH:6][CH:5]=1)=[O:3].[H-].[Na+].[C:14](OCC)(=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16].Cl>CN(C)C=O>[CH3:11][S:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH2:1][C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:5][CH:6]=1
Reactant: CSc1ccc(C(C)=O)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)CC(=O)c1ccc(SC)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-(methylthio)acetophenone 1 g) and sodium hydride (60%; 288 mg) in N,N-dimethylformamide (7 ml) was stirred at ambient temperature for 30 minutes. The mixture was cooled to 0° C., and diethyl oxalate (0.98 ml) was added dropwise to the mixture. The resulting mixture was stirred at ambient temperature for 3 hours, poured into ice-water and acidified with dilute hydrochloric acid. The precipitates were filtered, washed with water, and dried under reduced pressure to give a pale brown powder of ethyl 4-[4-(methylthio)phenyl]-2,4-dioxobutanoate (1.6 g).
Reaction SMILES: [C:1]([O:14][CH2:15][CH:16]=[CH2:17])(=[O:13])[CH2:2][CH2:3][C:4]([O:6][CH2:7][CH2:8][CH2:9][C:10](Cl)=[O:11])=[O:5].[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C@@:26]([OH:55])([CH2:49][N:50]1[CH:54]=[N:53][CH:52]=[N:51]1)[C@H:27]([S:29][C@@H:30]1[CH2:35][O:34][C@@H:33](/[CH:36]=[CH:37]/[CH:38]=[CH:39]/[C:40]2[CH:47]=[CH:46][C:43]([C:44]#[N:45])=[CH:42][C:41]=2[F:48])[O:32][CH2:31]1)[CH3:28].[H-].[Na+]>>[C:1]([O:14][CH2:15][CH:16]=[CH2:17])(=[O:13])[CH2:2][CH2:3][C:4]([O:6][CH2:7][CH2:8][CH2:9][C:10]([O:55][C@:26]([C:20]1[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:19]=1[F:18])([CH2:49][N:50]1[CH:54]=[N:53][CH:52]=[N:51]1)[C@H:27]([S:29][C@@H:30]1[CH2:31][O:32][C@@H:33](/[CH:36]=[CH:37]/[CH:38]=[CH:39]/[C:40]2[CH:47]=[CH:46][C:43]([C:44]#[N:45])=[CH:42][C:41]=2[F:48])[O:34][CH2:35]1)[CH3:28])=[O:11])=[O:5]
Reactant: C=CCOC(=O)CCC(=O)OCCCC(=O)Cl
Reactant: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Product: C=CCOC(=O)CCC(=O)OCCCC(=O)O[C@@](Cn1cncn1)(c1ccc(F)cc1F)[C@@H](C)S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1
Yield: 40 %

Procedure:
The crude allyl 4-chloro-4-oxobutyl succinate was treated with 4-[(1E,3E)-4-[trans-5-[[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-1,3-butadienyl]-3-fluorobenzonitrile (814 mg, 1.50 mmol) described in Reference example 1 and sodium hydride (55% dispersion in mineral oil; 70 mg, 1.6 mmol) according to a similar procedure to that described in Example 13-(2). The obtained crude title compound was purified by recycle preparative HPLC [LC-908; Japan Analytical Industry Co., Ltd.; GPC column JAIGEL-1H (20 mm i.d.×600 mm) and JAIGEL-2H (20 mm i.d.×600 mm) connected in series for use; solvent, chloroform] to afford the title compound (459 mg, 40% yield) as a colorless viscous material.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH3:12])[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:13]#[N:14].C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:22][C:23]1[N:27]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)[O:25][N:24]=1>CN(C=O)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH3:12])[N:7]([CH2:22][C:23]3[N:27]=[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=4)[O:25][N:24]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:13]#[N:14]
Reactant: CCc1nc2c(Cl)c(C#N)ccc2[nH]1
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCc1nc2c(Cl)c(C#N)ccc2n1Cc1noc(-c2cccc(C(F)(F)F)c2)n1
Temperature: 90 °C
Yield: 12.6 %

Procedure:
4-Chloro-2-ethyl-1H-benzimidazole-5-carbonitrile (0.014 g, 0.068 mmol), Cs2CO3 (0.033 g, 0.102 mmol), and 3-(chloromethyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole (0.027 g, 0.102 mmol) were combined in DMF (10 mL) and heated to 90° C. for 30 min. The cooled reaction mixture was partitioned between Et2O and water. The organic portion was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification (SiO2, EtOAc/hexanes) afforded the title compound (0.0037 g): MS (ESI) m/z 432 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]#[N:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C:21]([F:24])([F:23])[F:22])[C:17]([OH:19])=O)[C:10](=[O:25])[CH:9]=2)[CH:7]=1.[NH2:28][C:29]1[CH:39]=[CH:38][C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:31][CH:30]=1.CC(C)N=C=NC(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]#[N:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C:21]([F:24])([F:23])[F:22])[C:17]([NH:28][C:29]3[CH:30]=[CH:31][C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:38][CH:39]=3)=[O:19])[C:10](=[O:25])[CH:9]=2)[CH:7]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: COc1cn(C(CC(F)(F)F)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(NC(=O)C(CC(F)(F)F)n2cc(OC)c(-c3cc(Cl)ccc3C#N)cc2=O)cc1
Reaction time: 0.58 h

Procedure:
63.0 mg (157 μmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4,4,4-trifluorobutanoic acid (racemate), 26.0 mg (157 μmol) of ethyl 4-aminobenzoate, 22.3 mg (157 μmol) of Oxima and 24.0 μl (157 μmol) of DIC in 1.6 ml of dimethylformamide were reacted according to General Method 5B. The reaction product was purified by preparative HPLC [column: Chromatorex C18, 10 μm, 125×30 mm, mobile phase: acetonitrile/0.05% formic acid gradient (0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrile and a further 3 min 90% acetonitrile)]. Yield: 25.1 mg (28% of theory)