Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1]I.[CH2:3]([C:5]1[NH:6][C:7]([CH2:12][CH3:13])=[CH:8][C:9](=[O:11])[CH:10]=1)[CH3:4].[OH-].[Na+]>O>[CH2:3]([C:5]1[NH:6][C:7]([CH2:12][CH3:13])=[CH:8][C:9](=[O:11])[C:10]=1[I:1])[CH3:4]
Reactant: II
Reactant: CCc1cc(=O)cc(CC)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1cc(=O)c(I)c(CC)[nH]1
Reaction time: 1 h
Yield: 36.9 %

Procedure:
Iodine (720 mg) was added to a solution of compound F (430 mg) and sodium hydroxide (120 mg) in water (15 ml) and the mixture was stirred for 1 hour. The precipitated solid was collected by filtration and purified by flash chromatography, eluting with methanol/dichloromethane (1:19 v/v), to give 2,6-diethyl-3-iodo-4(1H)-pyridone (G) (290 mg), m.p. 225°-227° C.; NMR (d6 -DMSO): 1.15(t, 6H), 2.5(q, 2H), 2.8(q, 2H), 5.9(s, 1H), 11.4(br s, 1H).
Reaction SMILES: Cl.[C:2]([C:6]1[CH:17]=[CH:16][CH:15]=[CH:14][C:7]=1[O:8][CH:9]1[CH2:13][CH2:12][NH:11][CH2:10]1)([CH3:5])([CH3:4])[CH3:3].Cl.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25](Cl)=[O:26]>N1C=CC=CC=1>[C:2]([C:6]1[CH:17]=[CH:16][CH:15]=[CH:14][C:7]=1[O:8][CH:9]1[CH2:13][CH2:12][N:11]([C:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=2)=[O:26])[CH2:10]1)([CH3:5])([CH3:3])[CH3:4]
Reactant: O=C(Cl)c1ccccn1
Reactant: CC(C)(C)c1ccccc1OC1CCNC1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)c1ccccc1OC1CCN(C(=O)c2ccccn2)C1
Yield: 43.2 %

Procedure:
To a stirred solution of 3-(2-tert-butylphenoxy)pyrrolidine hydrochloride (0.26 g, 1.00 mmol) in pyridine (2.5 mL) was added picolinoyl chloride hydrochloride (0.20 g, 1.10 mmol) at room temperature. After 16 h the reaction mixture was concentrated under reduced pressure, the residue partitioned between ethyl acetate (50.0 mL) and water (50.0 mL) and separated. The organic layer was washed with saturated sodium chloride (50.0 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 80:20 to 50:50 heptane/ethyl acetate) provided (3-(2-tert-butylphenoxy)pyrrolidin-1-yl)(pyridin-2-yl)methanone (0.14 g, 43%) as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:10][O:11][C:12]([CH:14]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:13]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[CH:14][C:12]([O:11][CH3:10])=[O:13]
Reactant: O=Cc1cccc(Br)c1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)C=Cc1cccc(Br)c1
Yield: 82.1 %

Procedure:
To a mixture of 3-bromobenzaldehyde (10 g) and methoxy-carbonylmethylenetriphenylphosphine (20 g) was added toluene (150 ml), and the mixture was refluxed under nitrogen atmosphere for 2 hours. The solvent was evaporated, and the organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column (ethyl acetate/hexane) to give methyl 3-bromocinnamate (10.7 g) as colorless crystals. 1H-NMR(δ ppm, CDCl3): 3.82 (3H, s), 6.44 (1H, d, J=16.0 Hz),
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Br[C:20]1[CH:21]=[C:22]([CH:26]([CH:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[NH:27][S:28]([CH2:31][CH3:32])(=[O:30])=[O:29])[CH:23]=[N:24][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.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>[Cl:1][C:2]1[CH:9]=[C:8]([C:20]2[CH:21]=[C:22]([CH:26]([CH:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[NH:27][S:28]([CH2:31][CH3:32])(=[O:29])=[O:30])[CH:23]=[N:24][CH:25]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CCS(=O)(=O)NC(c1cncc(Br)c1)C1CCCC1
Reactant: CC1(C)OB(c2ccc(C#N)c(Cl)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)NC(c1cncc(-c2ccc(C#N)c(Cl)c2)c1)C1CCCC1
Temperature: 100 °C
Yield: 33.4 %

Procedure:
A mixture of 2-chloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile (205 mg, 0.77 mmol), N-((5-bromopyridin-3-yl)(cyclopentyl)methyl)ethane-sulfonamide (270 mg, 0.77 mmol), PdCl2(PPh3)2 (45 mg, 0.06 mmol) and Na2CO3 (2 M in water, 0.97 mL, 1.94 mmol) in DMF(4 mL) was heated at 100° C. for 2 h. The solvent was removed in vacuo. The residue was dissolved in DCM and filtered. The DCM layer was concentrated and purified by flash column (EtOAc/Heptane, v/v, 0-50%) to give the title compound (104 mg, 33%); ESI-MS m/z: 404 [M+1]+; 1HNMR (MeOD, 400 MHz) δ 8.80 (1H, d, J=2.0 Hz), 8.61 (1H, d, J=2.0 Hz), 8.15 (1H, t, J=2.0 Hz), 8.01 (1H, d, J=1.6 Hz), 7.94 (1H, d, J=8.0 Hz), 7.82 (1H, dd, J=8.0, 1.6 Hz), 4.29 (1H, d, J=10 Hz), 2.92-2.72 (2H, m), 2.34-2.27 (1H, m), 2.03-1.97 (1H, m), 1.77-1.53 (6H, m), 1.38-1.28 (1H, m), 1.15 (1H, t, J=7.2 Hz).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Cl:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1.[CH2:16]([Sn:20](Cl)([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19]>C1COCC1.O>[Cl:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[Sn:20]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Clc1ccncc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)c1cnccc1Cl
Temperature: 25 °C

Procedure:
To a solution of LDA (1.1 eq) in THF (0.05M) at −78° C. was added 4-chloropyridine (1 eq). After 1.5 h tributyltin chloride (1.5 eq) was added and the reaction mixture was warmed at rt over 3 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (hexane:EtOAc, 95:5) to afforded the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH:6]([CH2:7][CH2:8][CH:9]2[O:14]CCO[CH2:10]2)[CH2:5][CH2:4][N:3]1[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].CC1C=CC(S(O)(=O)=O)=CC=1.CC(C)=O>CCOC(C)=O>[O:1]=[C:2]1[CH:6]([CH2:7][CH2:8][C:9](=[O:14])[CH3:10])[CH2:5][CH2:4][N:3]1[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)CN1CCC(CCC2COCCO2)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CN1CCC(CCC(C)=O)C1=O

Procedure:
A solution of 2-4 (1.1 g, 3.9 mmol), p-TSA (5 mg) and acetone (50 mL) was heated at reflux for 1 hr. The cooled reaction mixture was diluted with EtOAc and then washed with sat. NaHCO3 and brine, dried (MgSO4), and concentration to afford 2-5 as a yellow oil.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]([F:21])([F:20])[C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17](=[O:19])[CH3:18])[CH:12]=[CH:13][CH:14]=1>C1COCC1>[F:7][C:8]([F:20])([F:21])[C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH:17]([OH:19])[CH3:18])[CH:12]=[CH:13][CH:14]=1
Reactant: CC(=O)C=Cc1cccc(C(F)(F)F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)CCc1cccc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 89.3 %

Procedure:
590 mg (15.4 mmol) of LiAlH4 were added in portions at 0° C. to a solution of 2.2 g (10.3 mmol) of 4-(3-(trifluoromethyl)phenyl)but-3-en-2-one in THF (20 ml), and stirring was then carried out for 1 h at RT. The mixture was then quenched at 0° C. with a sat. aq. Na2SO4 sol. and the reaction solution was filtered over kieselguhr. The filtrate was extracted with EA (3×60 ml) and the combined organic phases were washed with water, dried over Na2SO4, filtered and concentrated in vacuo. There were obtained as residue 2.0 g (9.2 mmol, 89%) of 4-(3-(trifluoromethyl)phenyl)-butan -2-ol, which was reacted further without additional purification.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C@@H:19]1[CH2:23]O)=[O:17])([CH3:14])([CH3:13])[CH3:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[NH:6]1[C:7]2[C:3](=[C:2]([O:1][CH2:23][C@H:19]3[CH2:20][CH2:21][CH2:22][N:18]3[C:16]([O:15][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:17])[CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:5]1
Reactant: Oc1cccc2[nH]ccc12
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A stirred solution of 4-hydroxyindole (1.33 g, 10.0 mmol), (R)-(+)-1-(t-butoxycarbonyl)-2-pyrrolidinemethanol (4.02 g, 20.0 mmol) and triphenylphosphine (5.3 g, 20.0 mmol) in THF is treated with diethyl azodicarboxylate (3.2 mL, 20 mmol), stirred for 3 h at room temperature and concentrated in vacuo. The resultant residue is treated with EtOAc and filtered through a pad of silica gel. The filtrate is concentrated to give a residue which is purified by chromatography (silica gel, EtOAc:hexanes, 15:80) to afford the title compound as a white solid, 1.08 g, mp 146-147° C.; identified by NMR and mass spectral analyses.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[C:20]([C:21]([OH:23])=O)=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([Br:30])[CH:17]=4)[C:12]3=[O:31])=[CH:9][C:4]=2[O:3][CH2:2]1.[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[C:20]([C:21]([N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[O:23])=[C:19]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([Br:30])[CH:17]=4)[C:12]3=[O:31])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
Product: O=C(c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2)N1CCCCC1

Procedure:
The present compound was synthesized by a method similar to that in Example 249 and using 2-(benzo[1,3]dioxol-5-ylmethyl)-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (200 mg) and piperidine. Colorless crystals (150 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[CH3:22].[C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])(=[O:26])[CH:24]=[CH2:25].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC>CC([O-])=O.CC([O-])=O.[Pd+2].O>[C:16]1(=[C:8]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[C:5]2[CH:6]=[CH:7][C:2](/[CH:25]=[CH:24]/[C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[C:3]([CH3:22])[CH:4]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Cc1cc(C(=C2CCCCC2)c2ccc(O)cc2)ccc1Br
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(C(=C2CCCCC2)c2ccc(O)cc2)ccc1/C=C/C(=O)OC(C)(C)C
Temperature: 140 °C
Yield: 51.3 %

Procedure:
A mixture of 67 (380 mg, 1.06 mmol), tert-butyl acrylate (0.369 mL, 2.55 mmol), Pd(OAc)2 (15.0 mg, 0.067 mmol), P(o-tolyl)3 (40.0 mg, 0.131 mmol), and Et3N (0.520 mL, 3.73 mmol) were heated under microwave irradiation at 140° C. for 30 min. Water (30 mL) was added and the mixture was extracted with Et2O (3×20 mL). The combined ethereal extracts were washed with water (30 mL), brine (30 mL), and dried over MgSO4. Concentration followed by flash chromatography (20:1 to 5:1 hexanes:EtOAc) afforded 220 mg (51%) of 68. 1H NMR (400 MHz, CDCl3): δ1.52 (s, 9H), 1.58 (m, 6H), 2.22 (m, 4H), 2.34 (s, 3H), 4.85 (s, 1H), 6.25 (d, J=16.0 Hz, 1H), 6.74 (d, J=8.4 Hz, 2H), 6.90-6.97 (m, 4H), 7.44 (d, J=8.1 Hz, 1H), 7.84 (d, J=16.0 Hz, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4]1.S=[C:10]1[CH2:14][S:13][C:12](=[O:15])[NH:11]1>C(O)C>[OH:8][CH2:7][C:3]1([CH2:2][NH:1][C:10]2[CH2:14][S:13][C:12](=[O:15])[N:11]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: NCC1(CO)CCC1
Reactant: O=C1NC(=S)CS1
Solvent: CCO
Product: O=C1N=C(NCC2(CO)CCC2)CS1
Yield: 42.7 %

Procedure:
To a solution of [1-(aminomethyl)cyclobutyl]methanol (1.00 g) in ethanol (30 mL) was added 4-thioxo-1,3-thiazolidin-2-one (1.16 g), and the mixture was heated under reflux overnight. The reaction mixture was concentrated under reduced pressure, and the obtained powder was washed with ethyl acetate to give the title compound (795 mg).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][C:18]1[N:19]=[C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:21][C:22]=1[CH3:23])[CH2:11]O)[CH3:6].O1CCCC1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:3][CH2:11][C:10]1[CH:13]=[CH:14][C:15]([O:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[C:8]([O:7][CH2:5][CH3:6])[CH:9]=1
Reactant: CCOc1cc(CO)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOc1cc(CCl)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
Thionyl chloride (0.73 ml) was added slowly to a mixture of 3-ethoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl alcohol (3.05 g), tetrahydrofuran (25 ml) and toluene (50 ml) at room temperature, which was stirred at 80° C. for 30 minutes. After cooling, the reaction mixture was poured into an aqueous saturated sodium bicarbonate solution, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium bicarbonate solution, dried (MgSO4) and concentrated to obtain 4-(4-chloromethyl-2-ethoxyphenoxymethyl)-5-methyl-2-phenyloxazole (2.94 g, yield 91%) as colorless crystals. This was recrystallized from tetrahydrofuran-hexane. Melting point: 138–139° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:13]I>C(Cl)(Cl)Cl.ClCCl.C(=O)([O-])[O-].[Ag+2]>[Br:1][C:2]1[C:3](=[O:12])[N:4]([CH3:13])[CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: CI
Reactant: Oc1ncc(C(F)(F)F)cc1Br
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cn1cc(C(F)(F)F)cc(Br)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.6 %

Procedure:
To a solution of 3-bromo-2-hydroxy-5-(trifluoromethyl)pyridine (1.0097 g, 4.1724 mmol) in chloroform (20 mL) was added silver carbonate (1.1964 g, 4.3388 mmol) and methyl iodide (0.40 mL, 6.4 mmol). The reaction mixture was stirred at room temperature for two hours and then at 40° C. for 24 hours. Additional methyl iodide (0.40 mL, 6.4 mmol) was added and the reaction kept at 40° C. for an additional 15 hours. The reaction mixture was then diluted with dichloromethane, filtered through celite, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (0 to 80% ethyl acetate in heptanes) to yield 0.5297 g (50%) of 3-bromo-1-methyl-5-(trifluoromethyl)pyridin-2(1H)-one. 1H NMR (400 MHz, DMSO-d6) δ: 8.47 (d, J=0.9, 1H), 8.22 (d, J=2.5, 1H), 3.56 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.[CH:12]([N-:15]C(C)C)(C)C.[Li+].C(OP(C#N)(=O)OCC)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8]([C:7]([C:12]#[N:15])=[CH:6][CH2:5]2)=[CH:9][CH:10]=1
Reactant: O=C1CCc2cc(Br)ccc21
Reactant: CC(C)[N-]C(C)C
Agent: CCOP(=O)(C#N)OCC
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CC1=CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-bromo-2,3-dihydro-1H-inden-1-one (1 g, 4.74 mmol) in anhydrous THF (15 ml) at −10° C. was added 2M lithium diisopropylamide in THF (0.242 ml, 0.483 mmol) dropwise. The resulting mixture was stirred at −10° C. for 15 min before diethylcyanophosphonate (0.791 ml, 5.21 mmol) was added dropwise. Following the addition, the mixture was allowed to warm to room temperature, and was stirred at room temperature for 3 h. The mixture was cooled to −78° C. and borontrifluoride diethyl etherate (1.196 ml, 9.52 mmol) was added dropwise. Following the addition, the mixture was stirred at −78° C. for 1 h and was then allowed to warm to room temperature and was stirred at room temperature for 16 h. The mixture was concentrated in vacuo, and the residue was partitioned between EtOAc (50 mL) and H2O (2×50 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo, and the crude product was purified by column chromatography on silica gel using 9:1 EtOAc:hexanes as the eluent. The title compound was obtained as an tan solid (0.72 g, 69%).
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[C:22]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)#[N:23]>>[C:22]([C:24]1[CH:29]=[CH:28][C:27]([C:2]2[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)=[CH:26][CH:25]=1)#[N:23]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Cl)nc2c1
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(-c3ccc(C#N)cc3)nc2c1
Yield: 74.6 %

Procedure:
The ester product was obtained via a Suzuki coupling reaction using the method previously shown in Example 13, Step 6, with methyl 3-chloro-2-phenylquinoxaline-6-carboxylate (100 mg, 0.33 mmol, 1.00 equiv) and 4-cyanophenylboronic acid (74 mg, 0.50 mmol, 1.50 equiv) as reactants. Purification via silica gel column (ethyl acetate/petroleum ether (1:20 to 1:10)) afforded 90 mg (73%) of methyl 3-(4-cyanophenyl)-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [C:1]1([CH:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][C:17]([CH3:22])=[CH:18][C:19](Cl)=[O:20]>>[CH3:16][C:17]([CH3:22])=[CH:18][C:19]([N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8]1)=[O:20]
Reactant: c1ccc(C2CNc3ccccc32)cc1
Reactant: CC(C)=CC(=O)Cl
Product: CC(C)=CC(=O)N1CC(c2ccccc2)c2ccccc21
Yield: 57.8 %

Procedure:
The procedure of Example 16 was repeated using 1.95 g of 3-phenylindoline and 1.5 g of 3,3-dimethylacryloyl chloride. In this way 1.6 g of the desired N-(3,3-dimethylacryloyl)-3-phenylindoline having a melting point of 97°-8° C. was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:22]=1)[C:7]([NH:9][CH2:10][CH2:11][C:12]1[S:13][C:14]([CH3:21])=[C:15]([S:17](=[O:20])(=[O:19])[NH2:18])[CH:16]=1)=[O:8].[O:25]([C:27]#[N:28])[K]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:22]=1)[C:7]([NH:9][CH2:10][CH2:11][C:12]1[S:13][C:14]([CH3:21])=[C:15]([S:17]([NH:18][C:27]([NH2:28])=[O:25])(=[O:19])=[O:20])[CH:16]=1)=[O:8]
Reactant: COc1ccc(Cl)cc1C(=O)NCCc1cc(S(N)(=O)=O)c(C)s1
Reactant: N#CO[K]
Product: COc1ccc(Cl)cc1C(=O)NCCc1cc(S(=O)(=O)NC(N)=O)c(C)s1

Procedure:
Analogously to Example 2 from 2-[2-(5-chloro-2-methoxybenzoylamino)ethyl]-4-sulfamoyl-5-methylthiophene and KOCN.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[C@H:11]12[N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@H:15]([CH2:16][CH2:17]1)[CH2:14][NH:13][CH2:12]2.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1>C(Cl)Cl>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([N:13]2[CH2:14][C@@H:15]3[N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@@H:11]([CH2:17][CH2:16]3)[CH2:12]2)=[O:36])=[CH:30][CH:29]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@H]1CNC2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(NC(=O)N2C[C@H]3CC[C@@H](C2)N3C(=O)OC(C)(C)C)cc1
Reaction time: 20 h
Yield: 102.4 %

Procedure:
DIPEA (0.53 mL, 3.0 mmol) was added to a suspension of tert-butyl (1S,5R)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate hydrochloride (0.50 g, 2.00 mmol) in DCM (20 mL). To the mixture was added 4-methoxyphenyl isocyanate (0.26 mL, 2.0 mmol) dropwise, and the reaction mixture was stirred for 20 h. The reaction mixture was washed with brine (2×20 mL), then passed through a phase separator and evaporated. The crude material was purified by flash chromatography on silica, with a gradient of 25% increasing to 75% EtOAc/isohexane over 20 column volumes. The title compound (0.74 g, >99%) was obtained as a white solid. LCMS (ES+) 362.8 (M+H)+, RT 2.02 minutes (method 3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]([OH:18])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1)[CH3:24].ClCCl.CO.N>>[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH2:25][C:26]1[CH:27]=[CH:28][C:29]([NH:32][C:16](=[O:18])[C:15]#[C:14][C:11]2[CH:10]=[CH:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[CH:13][CH:12]=2)=[CH:30][CH:31]=1)[CH3:24]
Reactant: O=C(O)C#Cc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: COCCN(C)Cc1ccc(N)cc1
Agent: N
Solvent: ClCCl
Solvent: CO
Product: COCCN(C)Cc1ccc(NC(=O)C#Cc2ccc(-c3ccc(Cl)cc3)cc2)cc1

Procedure:
Prepared analogously to Example 3.8. from (4′-chlorobiphenyl-4-yl)propynoic acid and 4-{[(2-methoxyethyl)methylamino]methyl}phenylamine. Yield: 150 mg (35% of theory); melting point: 130° C.-133° C.; C26H25ClN2O2 (M=432.94); calc.: molecular ion peak (M+H)+: 433/435 (Cl); found: molecular ion peak (M+H)+: 433/435 (Cl); Rf value: 0.50 (silica gel, dichloromethane/methanol/ammonia (90:10:1)).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][S:5][C:4]([NH:7][C@H:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][O:10][C:11](=[O:13])[CH3:12])=[N:3]1.[NH:20]1[C:24]2=[N:25][CH:26]=[CH:27][CH:28]=[C:23]2[C:22]([CH:29]=O)=[CH:21]1.C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[O:1]=[C:2]1[C:6](=[CH:29][C:22]2[C:23]3[C:24](=[N:25][CH:26]=[CH:27][CH:28]=3)[NH:20][CH:21]=2)[S:5][C:4]([NH:7][C@H:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][O:10][C:11](=[O:13])[CH3:12])=[N:3]1
Reactant: CC(=O)OC[C@H](NC1=NC(=O)CS1)c1ccccc1
Reactant: O=Cc1c[nH]c2ncccc12
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CC(=O)OC[C@H](NC1=NC(=O)C(=Cc2c[nH]c3ncccc23)S1)c1ccccc1
Temperature: 150 °C
Yield: 145.3 %

Procedure:
To a suspension of acetic acid 2-[4-oxo-4,5-dihydro-thiazol-2-ylamino]-2-(R)-phenyl-ethyl ester (400 mg, 1.43 mmol) and 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (77.3 mg, 0.53 mmol) in toluene (5 mL) in a microwave tube was added benzoic acid (17.64 mg, 0.144 mmol) and piperidine (14.5 uL, 0.144 mmol) at room temperature. The microwave tube was sealed and heated to 150° C. in a closed microwave for 1 h. Then, the mixture was cooled to room temperature and diluted with toluene. The solids were collected by filtration and washed with toluene and dichloromethane. After drying in air, 313 mg (53.6% yield) of acetic acid 2-[4-oxo-5-(1H-pyrrolo[2,3,b]pyridine-3-ylmethylene)-4,5-dihydro-thiazol-2-ylamino]-2-(R)-phenyl-ethyl ester was isolated as a white solid: mp 243.7-246.8° C.; HRES(+) m/e calcd for C21H18N4O3S (M+H)+ 407.1173. found 407.1172.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](O)=[O:12])=[CH:6][CH:5]=1.C1C[N:19]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH2:19])=[O:12])=[CH:6][CH:5]=1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: O=C(O)Cc1ccc(OC(F)(F)F)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: NC(=O)Cc1ccc(OC(F)(F)F)cc1
Yield: 57.3 %

Procedure:
4-(Trifluoromethoxy)phenylacetic acid (2 g, 9.085 mmol) was dissolved in DMF (20 ml, dry) and PyBOP (4.728 g, 9.085 mmol) was added. The mixture was stirred in an ice-bath and ammonia gas was bubbled in for 5 mins. The ice-bath was removed and the mixture was stirred at rt overnight and then evaporated in vacuum. Water (50 ml) was added into the residue and it was extracted with EtOAc (20 ml×3). The extracts were combined, washed with saturated aqueous NaHCO3 (15 ml), water (20 ml×3), brine (15 ml), dried (MgSO4) and evaporated. The residue was purified by column chromatography (ISOLUTE SI, 20 g/70 ml), eluting with DCM, then MeOH/DCM (1:99), to give the title compound (1.14 g, 57%) as a white solid. Mass Spectrum: M−H+ 218. 1H NMR (400 MHz, CD3OD): δ 3.53 (s, 2H), 7.20 (d, 2H), 7.38 (d, 2H). 13C NMR (100 MHz, CD3OD): 42.5, 121.9 (q, J=253 Hz), 122.1, 131.8, 136.3, 149.4, 176.2.