Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.OO.[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.[O-][W]([O-])(=O)=O.[Na+].[Na+].P([O-])(O)(O)=O.[Na+].P([O-])([O-])(O)=O.[Na+].[Na+].C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:7]=[O:8])=[CH:9][CH:10]=1
Reactant: COc1ccc(CO)cc1
Agent: O=[W](=O)([O-])[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=P([O-])(O)O
Solvent: Cc1ccccc1C
Product: COc1ccc(C=O)cc1
Temperature: 94.5 °C
Yield: 86.9 %

Procedure:
In a glass-made reaction vessel equipped with a thermometer, a temperature controller, a dropping device and a stirring device were charged 79 ml of xylene, 138.16 g (1 mol) of 4-methoxybenzyl alcohol, 3.30 g (0.01 mol) of sodium tungstate.dihydrate (Na2WO4.2H2O) and 3.40 g (0.01 mol) of tetrabutyl ammonium hydrogen sulfate. Then, to the mixture were added 4.68 g (0.03 mol) of sodium dihydrogen phosphate and 7.16 g (0.02 mol) of disodium hydrogen phosphate, and a pH value of the reaction mixture was adjusted to pH 6.0. Next, an inner temperature of the reaction mixture was maintained from 94 to 95° C., and 94.33 g (1.56 mol) of 60% aqueous hydrogen peroxide was added dropwise to the mixture with 18 g (0.3 mol)/hr, while maintaining the pH of the reaction mixture to 5.5 to 6.5 by using 8 mol/L aqueous sodium hydroxide solution. After completion of the reaction, the resulting reaction mixture was cooled to room temperature, and the organic layer was separated as a solution. The resulting organic layer solution was washed with 1 mol/L sodium hydroxide solution, and the solvent, xylene was distilled off under reduced pressure. The resulting concentrate (crude anisaldehyde) was purified by distillation (109° C./1.3 kPa) to obtain 118.28 g of anisaldehyde as colorless liquid (obtained yield: 86.9%, based on anisalcohol).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:7](=O)[CH:8]([CH3:10])[CH3:9]>>[O:4]1[CH2:5][CH2:6][N:1]([CH:7]=[C:8]([CH3:10])[CH3:9])[CH2:2][CH2:3]1
Reactant: CC(C)C=O
Reactant: C1COCCN1
Product: CC(C)=CN1CCOCC1

Procedure:
Morpholine (21.78 g, 0.25 mol) and isobutyraldehyde (18.02 g, 0.25 mol) were heated to reflux as a neat mixture, in a 100 ml round bottom flask with a Dean Stark Trap attached. After the mixture was refluxed overnight, the reaction mixture was purified by vacuum distillation. The pure enamine product (15.01 g, 0.10 mol, 42%) had a 1H-NMR (CDCl3): 5.32 (s, 1H), 3.72 (t, 4H), 2.87 (t, 4H), 1.81 (s, 3H), 1.68 (s, 3H) It had LC-MS (ES+): 142 [MH]+ m/e.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=1)[CH3:2].Cl[C:25]1[C:30]([C:31]#[N:32])=[CH:29][CH:28]=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([C:25]2[C:30]([C:31]#[N:32])=[CH:29][CH:28]=[CH:27][N:26]=2)[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: N#Cc1cccnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)Cc1ccc(OC)c(-c2ncccc2C#N)c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
[4-Methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (0.672 g, 2.1 mmol), 2-chloro-3-pyridinecarbonitrile (0.274 g, 2.0 mmol), and potassium carbonate (0.966 g, 7.0 mmol) were combined in deoxygenated 2:1 DME:H2O (21 mL). Tetrakis(triphenylphosphine)palladium(0) (0.115, 0.1 mmol) was added, and the reaction was stirred at 70° C. for 1 hour. Once no starting material was seen by analytical LCMS and tlc, the mixture was worked-up and purified by silica gel chromatography to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[O:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][C:16]2[C:21]([O:22]C)=[CH:20][N:19]=[CH:18][C:17]=2[Cl:24])=[CH:10][CH:9]=[CH:8][N:7]=1.Cl.N1C=CC=CC=1.C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[O:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][C:16]2[C:21]([OH:22])=[CH:20][N:19]=[CH:18][C:17]=2[Cl:24])=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: COc1cncc(Cl)c1CCCOc1cccnc1Oc1cccc(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: Oc1cncc(Cl)c1CCCOc1cccnc1Oc1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
2-(3-Chlorophenoxy)-3-[3-(3-chloro-5-methoxypyridin-4-yl)propoxy]pyridine (8.5 g, 21 mmol) obtained in Example 72 and pyridine.hydrochloride (100 g, 0.86 mol) are mixed, and the mixture is stirred for melting at 150° C. for one hour. To the mixture is added ice-water (300 ml), and the mixture is neutralized with sodium hydrogen carbonate, and extracted with ethyl acetate (100 ml×3). The organic layer is washed with a saturated aqueous sodium hydrogen carbonate solution (50 ml×2) and a saturated brine (50 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by basic silica gel column chromatography (eluent: ethanol/ethyl acetate), and further recrystallized from diethyl ether/diisopropyl ether to give the title compound (5.6 g) as colorless crystals, m.p. 95-96° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11]([N:13]3[CH2:16][CH:15]([O:17][CH3:18])[CH2:14]3)=[O:12])[N:10]=2)[CH2:3]1.[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(N(CC)CC)C>C(Cl)Cl>[CH3:19][S:20]([O:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11]([N:13]3[CH2:16][CH:15]([O:17][CH3:18])[CH2:14]3)=[O:12])[N:10]=2)[CH2:3]1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: COC1CN(C(=O)c2csc(N3CC(O)C3)n2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1CN(C(=O)c2csc(N3CC(OS(C)(=O)=O)C3)n2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
To a solution of 3-hydroxy-1-[4-(3-methoxyazetidine-1-carbonyl)-1,3-thiazol-2-yl]azetidine (480 mg, 1.71 mmol) (obtained as described in Reference Example 31(3)) in methylene chloride (25 ml) were added methanesulfonyl chloride (397 μl, 5.13 mmol) and triethylamine (719 μl, 5.13 mmol) in an ice bath. After stirring the mixture in the ice bath for 10 minutes, the mixture was stirred at room temperature for 1 hour. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate:methanol (95:5) as the eluant to afford 3-methanesulfonyloxy-1-[4-(3-methoxyazetidine-1-carbonyl)-1,3-thiazol-2-yl]azetidine (568 mg, yield 96%) as a pale yellow solid.
Reaction SMILES: BrC1CCOCC1.[OH-].[Na+].[CH:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([C:17]([O:19]O)=[O:18])[CH:11]=1>O>[Cl:16][C:14]1[CH:13]=[C:12]([CH:11]=[CH:10][CH:15]=1)[C:17]([OH:19])=[O:18]
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: BrC1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cccc(Cl)c1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
4-Bromotetrahydropyran (Frontier Scientific #B10197, 25.8 g, 156 mmol) was added to the solution of sodium hydroxide (16.0 g, 400 mmol) in 40 mL water. The biphase mixture was stirred in 90° C. with a condenser for 1 day. The mixture was cooled to RT and transferred to a small separatory funnel. The organic phase was carefully separated. It was a mixture of alkene J79 (major) and leftover 4-bromotetrahydropyran. This mixture was dissolved in 100 mL chloroform. To it was added MCPBA (77%, 26.8 g, 120 mmol) in small portions. The mixture was vigorously stirred at RT for overnight. The thick suspension was chilled in ice bath and filtered through celite. The solid cake was washed with ice-chilled chloroform 500 mL×3. All the filtrate and wash solutions were transferred into a big separatory funnel. It was washed with saturated NaHCO3 solution twice. The organic phase was then dried over anhydrous Na2SO3 (30 g). The mixture was filtered and the filtrate was concentrated on a rotary instrument in ice-bath bath (<5° C.) to remove chloroform. A light liquid (J80) with some remaining meta-chlorobenzoic acid solid was obtained. This mixture was dissolved in 100 mL isopropanol. To it was added (S)-(−)-α-methylbenzylamine (15.2 mL, 120 mmol). A gel-like mixture was got initially. The mixture was slowly heated to 70° C. and stirred. A clean solution was then got. The clear solution was stirred for 2 days at 70° C. It was then concentrated in vacuo. The residue was taken into 500 mL EtAOc and washed with saturated Na2CO3 solution three times. The organic phase was dried, concentrated and subjected to flash column (0-40% EtOAc in DCM) to isolate desired product J81 (3.52 g) as a cream-colored solid. UV: 259 nm. M+H found for C13H19NO2: 222.2. NMR (DMSO-d6): 7.32-7.25 (4H, m), 7.18 (1H, t), 4.89 (1H, d), 3.86 (1H, m), 3.63 (1H, m), 3.45-3.37 (2H, m, partially obscured by water), 3.19 (1H, m), 2.66 (1H, m), 2.22 (1H, m), 1.92 (1H, m), 1.74 (1H, d), 1.35 (1H, m), 1.22 (3H, d, J=6.4 Hz) ppm.
Reaction SMILES: [C:1]1(/[CH:7]=[C:8]2/[C:9](=[O:13])[O:10][CH2:11][CH2:12]/2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=C(C=CC=1)C(OO)=[O:19].CC(N=NC(C#N)(C)C)(C#N)C>>[C:1]1([CH:7]2[C:8]3([CH2:12][CH2:11][O:10][C:9]3=[O:13])[O:19]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C1OCC/C1=C\c1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: O=C1OCCC12OC2c1ccccc1
Yield: 60 %

Procedure:
To a solution of 3-[1-phenyl-meth-(E)-ylidene]-dihydro-furan-2-one (21a) (4.0 g, 22.9 mmol) and 3-chloroperoxybenzoic acid (6.18 g, 27.6 mmol) in 1,2-dichloroetheane (70 mL) was added catalytic amount of AIBN (50 mg) at 80° C. and refluxed in the dark for 6 h. The resulting solution was cooled and filtered, the solvent was removed under reduced pressure, and the residue dissolved in dichloromethane. The organic phase was washed consecutively with saturated aqueous solutions of NaHCO3 (20 mL), KI (20 mL), Na2S2O3 (20 mL), and NaHCO3 (20 mL) then dried over anhydrous MgSO4 and evaporated under reduced pressure. Product was purified by silica gel flash chromatography using ethyl acetate:petroleum ether (1:4) gave 2.62 g in 60% yield of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].C[O-].[Na+].[CH3:15][O:16][C:17](=[O:25])/[CH:18]=[C:19](/[O:22][CH2:23]C)\[CH2:20]Cl>CN(C=O)C>[CH3:15][O:16][C:17](=[O:25])/[CH:18]=[C:19](/[O:22][CH3:23])\[CH2:20][CH:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:4]([O:3][CH2:1][CH3:2])=[O:11]
Reactant: CCO/C(=C/C(=O)OC)CCl
Reactant: CCOC(=O)CC(=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C/C(=C\C(=O)OC)OC)C(=O)OCC
Temperature: 20 °C
Reaction time: 2 h

Procedure:
83.9 g (0.5 mol) of malonic acid diethyl ester was placed in 250 ml of N,N'-dimethylformamide. 27.8 g (0.5 mol) of sodium methylate was added at 20° C., 10 minutes later 48 g (0.25 mol) of 4-chloro-3-ethoxy-2E-butenoic acid methyl ester was added within 5 minutes. It was stirred for 2 hours at 20° C. Then 10.8 g (0.2 mol) of sodium methylate was added once more. After stirring for 15 hours at 20° C., the solvent was distilled off. After working up according to Example (a), 63.75 g (79 percent) of the title compound, with a purity of 98 percent (GC), was obtained. Data for the compound was:
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:27])[CH:25]=[CH2:26])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:27])[CH:25]=[CH2:26])=[CH:19][CH:18]=2)(=[O:15])=[O:16])[CH2:10][CH2:9]1
Reactant: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCC(NC(=O)OC(C)(C)C)CC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCC(N)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.3 %

Procedure:
To a solution of [1-(4-Acryloylamino-benzenesulfonyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (0.57 g, 1.4 mmol) in DCM (10 ml) was added trifluoroacetic acid (10 ml) in one portion. The resulting mixture was then stirred at room temperature under a nitrogen atmosphere for 3 hours. After this time the reaction was concentrated under vacuum to afford the title compound (0.40 g, 93% yield) as an orange solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]4[O:26][C:27](=S)[N:28]=[C:22]4[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>O1CCOCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:28][C:27]([N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)=[O:26])[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNC1
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccn4oc(=S)nc4c3)C(C)(C)C2=O)cc1
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(NC(=O)N4CCCC4)c3)C(C)(C)C2=O)cc1

Procedure:
This compound may be prepared as obtained in stage c) of Example 9, but starting with 200 mg of 3-(4-tert-butylphenyl)-5,5-dimethyl-1-[(2-thioxo-2H-[1,2,4]oxadiazolo[2,3-a]pyridin-7-yl)methyl]imidazolidine-2,4-dione obtained in stage b) of Example 9, 4 mL of dioxane and 40.2 mg of pyrrolidine. After chromatography on a column of silica, eluting with a mixture of heptane/ethyl acetate (gradient from 100/0 to 0/100 by volume), 64.3 mg of N-(4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl]methyl}pyridin-2-yl)pyrrolidine-1-carboxamide are obtained in the form of a beige-coloured powder, the characteristics of which are as follows:
Reaction SMILES: [NH2:1][N:2]1[CH2:6][CH2:5][O:4][C:3]1=[O:7].[F:8][C:9]1[C:18]([CH2:19][C:20]2[N:24]3[N:25]=[C:26]([C:29](=O)[CH3:30])[CH:27]=[CH:28][C:23]3=[N:22][N:21]=2)=[C:17]([F:32])[CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[N:14]2>>[F:8][C:9]1[C:18]([CH2:19][C:20]2[N:24]3[N:25]=[C:26](/[C:29](=[N:1]/[N:2]4[CH2:6][CH2:5][O:4][C:3]4=[O:7])/[CH3:30])[CH:27]=[CH:28][C:23]3=[N:22][N:21]=2)=[C:17]([F:32])[CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[N:14]2
Reactant: NN1CCOC1=O
Reactant: CC(=O)c1ccc2nnc(Cc3c(F)cc4ncccc4c3F)n2n1
Product: C/C(=N\N1CCOC1=O)c1ccc2nnc(Cc3c(F)cc4ncccc4c3F)n2n1
Yield: 86 %

Procedure:
The title compound was prepared from 3-aminooxazolidin-2-one and 1-(3-((5,7-difluoroquinolin-6-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone in 86% yield as white solid using the same procedure as described in the synthesis of example 40. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.00 (d, 1H), 8.50 (d, 1H), 8.33 (d, 1H); 7.87 (d, 1H), 7.75 (d, 1H), 7.63 (dd, 1H), 4.81 (s, 2H), 4.49 (t, 2H), 4.05 (t, 2H), 2.33 (s, 3H). LCMS (method A): [MH]+=424, tR=4.54 min.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[N:16]1[CH:20]([C:21]2[S:22][C:23]([C:26]3[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=3)=[CH:24][CH:25]=2)[CH2:19][C:18]([C:32]([F:38])([F:37])[C:33]([F:36])([F:35])[F:34])=[N:17]1.C(N(CC)CC)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>ClCCl>[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[N:16]1[CH:20]([C:21]2[S:22][C:23]([C:26]3[CH2:27][CH2:28][N:29]([S:47]([CH3:46])(=[O:49])=[O:48])[CH2:30][CH:31]=3)=[CH:24][CH:25]=2)[CH2:19][C:18]([C:32]([F:37])([F:38])[C:33]([F:35])([F:36])[F:34])=[N:17]1
Reactant: CS(=O)(=O)Cl
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2ccc(C3=CCNCC3)s2)c(F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CC=C(c2ccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)s2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 18.5 %

Procedure:
1-(2,4-Difluoro-phenyl)-5-[5-(1,2,3,6-tetrahydropyridin-4-yl)-thiophen-2-yl]-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole trifluoroacetate (27.0 mg, 0.05 mmol) prepared in Step 1, triethylamine (32.5 uL, 0.23 mmol) and methanesulfonyl chloride (8.0 mg, 0.07 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 18 hours, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 5.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14]S(C2C=CC=CC=2)(=O)=O)=[C:6]([CH:13]=1)/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].Br.Br[CH2:26][C:27]([C:29]1[N:30]([CH3:34])[CH:31]=[CH:32][N:33]=1)=[O:28]>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:13]=2)[NH:14][C:26]=1[C:27]([C:29]1[N:30]([CH3:34])[CH:31]=[CH:32][N:33]=1)=[O:28]
Reactant: Cn1ccnc1C(=O)CBr
Reactant: COC(=O)/C=C/c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Agent: Br
Product: COC(=O)Cc1c(C(=O)c2nccn2C)[nH]c2ccc(Cl)cc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (Example 36, step 3) and 2-bromoacetyl-1-methylimidazole hydrobromide (Preparation is described in Example 241).
Reaction SMILES: [C:1]1([C:7](=[O:17])[CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[N+:27]([O-:29])=[O:28])=[CH:21][CH:20]=1>C(OCC)C>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C@H:25]([CH:8]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:17])[CH2:26][N+:27]([O-:29])=[O:28])=[CH:23][CH:24]=1
Reactant: O=[N+]([O-])/C=C/c1ccc(Cl)cc1
Reactant: O=C(CC(=O)c1ccccc1)c1ccccc1
Solvent: CCOCC
Product: O=C(c1ccccc1)C(C(=O)c1ccccc1)[C@H](C[N+](=O)[O-])c1ccc(Cl)cc1
Temperature: 23 °C

Procedure:
To a solution of 1,3-diphenyl-1,3-propanedione (1a) (0.3 mmol, 3 eq) and 1-chloro-4-((E)-2-nitrovinyl)benzene (2g) (0.1 mmol, 1 eq) in diethyl ether (0.3 mL) was added catalyst VI (Q-NH2) (0.015 mmol, 0.15 eq). The resulting mixture was stirred at room temperature (23° C.). After the reaction was complete (monitored by TLC), the product 3g was isolated and purified by centrifuge/washing with diethyl ether (0.3 mL). All the catalyst VI (0.15 equiv) and 2 equivalents of the excess the dione 1a were retained in the filtrate. The combined ethereal filtrate was evaporated to 0.3 mL before the dione 1a (1 eq) and 2g (1 eq) were added again to the solution for the next round of the Michael reaction. This was to ensure that the reaction condition for each cycle was almost the same as the previous one. The excellent yields (96% in average) and enantioselectivities (98-94% ee) were achieved in seven cycles.
Reaction SMILES: [CH:1]([N:4]([CH3:30])[C:5]1[C:6]([C:19]2[CH:20]=[N:21][C:22]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:23][CH:24]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2].[OH-].[Na+].O>CO>[CH:1]([N:4]([CH3:30])[C:5]1[C:6]([C:19]2[CH:20]=[N:21][C:22]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:23][CH:24]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2nc(-c3ccc(N4CCCC4)nc3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc(N2CCCC2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.1 %

Procedure:
To a solution of methyl 3-(isopropyl(methyl)amino)-2-(6-(pyrrolidin-1-yl)pyridin-3-yl)quinoxaline-6-carboxylate (130.0 mg, 0.32 mmol) in methanol (20 mL) was added sodium hydroxide (64.3 mg, 1.61 mmol) and water (1 mL) with stirring overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (20 mL) and adjusted to pH 7 with hydrochloric acid (1N). The solids were collected to afford 3-(isopropyl(methyl)amino)-2-(6-(pyrrolidin-1-yl)pyridin-3-yl)quinoxaline-6-carboxylic acid as a light yellow solid (60.3 mg, 48%).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[F:14][C:15]1[CH:16]=[C:17]([CH2:25][CH2:26][NH2:27])[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].[BH4-].[Na+].Cl>CO>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:27][CH2:26][CH2:25][C:17]2[CH:18]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:20]=[C:15]([F:14])[CH:16]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCc1cc(F)cc(C(F)(F)F)c1
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: CO
Product: CC(C)(C)c1ccc(CNCCc2cc(F)cc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
3.1 ml of 4-tert-butylbenzaldehyde (18.47 mmol), 3 g of 2-(3-fluoro-5-trifluoromethyl -phenyl)-ethylamine hydrochloride (12.3 mmol) and 1.7 g of potassium carbonate (12.3 mmol) were suspended in 36 ml methanol at rt, and after stirring for 30 min at rt, were refluxed for 2 h. After cooling down to rt, 700 mg (18.47 mmol) of sodium borohydride were added and after stirring for 5 min at rt, the reaction mixture was refluxed for 2.5 h. After cooling down to rt, the reaction mixture was treated with 2.4 ml 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by column chromatography (90 g silica gel; EtOAc/heptane 1:2) to give 4.35 g light yellow oil (90%). MS (ISP) 354.3 (M+H)+.
Reaction SMILES: [N:1]#[C:2][NH2:3].[Na].[C:5]([C:7]1[CH:12]=[CH:11][C:10]([N:13]=[C:14]=[S:15])=[CH:9][CH:8]=1)#[N:6]>C(O)C>[C:2]([NH:3][C:14]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]#[N:6])=[CH:8][CH:9]=1)=[S:15])#[N:1]
Reactant: N#CN
Reactant: N#Cc1ccc(N=C=S)cc1
Agent: [Na]
Solvent: CCO
Product: N#CNC(=S)Nc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
The suspension of monosodium cyanamide (4.3 g, 67.2 mmol) in absolute ethanol (170 mL) was slowly treated with 4-cyanophenylisothiocyanate (10.75 g, 67.2 mmol). The reaction was allowed to stir at room temperature for 1 hour and then heated at 75° C. for 4 hours. The reaction was cooled to room temperature and the colorless solid was filtered and washed with ethanol to give the title A compound (10.0 g), m.p. >250° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4](=[CH2:11])[CH2:5][CH2:6][C:7](OC)=[O:8].[CH3:13][O:14][C:15]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([CH:4]1[CH2:5][CH2:6][C:7](=[O:8])[N:18]([CH2:17][C:16]2[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:15]=2[O:14][CH3:13])[CH2:11]1)=[O:12]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: C=C(CCC(=O)OC)C(=O)OC
Solvent: Cc1ccccc1
Product: COC(=O)C1CCC(=O)N(Cc2ccc(OC)cc2OC)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 2-methylenepentanedioic acid dimethyl ester (19.2 g) in toluene (195 ml) was added 2,4-dimethoxybenzylamine (16.6 ml), and the mixture was stirred for 3 days at reflux. This reaction solution was cooled to room temperature, and then washed with a 1M aqueous solution of hydrochloric acid, water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product of the titled compound (26.8 g).