Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:28])[C:11]([CH3:27])([N:13]2[C:18](=[O:19])[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:16]([CH3:26])[O:15][CH2:14]2)[CH3:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[H-].[Na+].[CH3:31]I.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]([CH3:31])[C:10](=[O:28])[C:11]([CH3:12])([N:13]2[C:18](=[O:19])[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:16]([CH3:26])[O:15][CH2:14]2)[CH3:27])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CI
Reactant: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)Nc2cc(Cl)cc(Cl)c2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)N(C)c2cc(Cl)cc(Cl)c2)CO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
A solution of N-(3,5-dichlorophenyl)-2-methyl-2-(6-methyl-5-phenyl-2,3-dihydro-4-oxo-4H-1,3-oxazin-3-yl)-propanamide (0.6 g) in 2 ml of DMF was cooled in an ice bath and 60% sodium hydride in oil (0.06 g) was added. The mixture was stirred at room temperature for 30 min. and subsequently methyl iodide (0.31 g) was added and the mixture was stirred at room temperature for 5 h. Then the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by chromatography on a silica gel column to get the captioned compound (0.51 g).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([O:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:20]=2)[NH:17][C:16]([C:28]2[S:29][CH:30]([CH2:33][C:34](O)=[O:35])[CH2:31][N:32]=2)=[CH:15]3)=[N:9][CH:10]=1)(=[O:4])=[O:3].[N:37]1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.N>O.CN(C)C=O>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([O:21][CH:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[CH:20]=2)[NH:17][C:16]([C:28]2[S:29][CH:30]([CH2:33][C:34]([NH2:37])=[O:35])[CH2:31][N:32]=2)=[CH:15]3)=[N:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: On1nnc2ccccc21
Reactant: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C4=NCC(CC(N)=O)S4)cc3c2)nc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
A mixture of {2-[5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetic acid (210 mg), 1H-1,2,3-benzotriazol-1-ol (80 mg), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (120 mg) and N,N-dimethylformamide (5 mL) was stirred at 50° C. for 30 min and cooled to 0° C. 10% Aqueous ammonia (1 mL) was added to the mixture, and the mixture was stirred at room temperature for 2.5 days. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and subjected to silica gel short column chromatography (eluted with ethyl acetate-methanol (95/5, volume ratio)) to give pale-yellow crystals. The crystals were recrystallized from acetone-hexane to give the title compound (130 mg, yield 62%) as pale-yellow prism crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][CH2:15][N:14]([C:17]2[N:22]=[C:21]([C:23]#[N:24])[CH:20]=[CH:19][N:18]=2)[CH2:13]1)(=[O:11])=[O:10].[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.CCN(C(C)C)C(C)C>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([N:29]2[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]2)[CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][CH2:15][N:14]([C:17]2[N:22]=[C:21]([C:23]#[N:24])[CH:20]=[CH:19][N:18]=2)[CH2:13]1)(=[O:11])=[O:10]
Reactant: CN1CCNCC1
Reactant: N#Cc1ccnc(N2CC[C@H](S(=O)(=O)c3ccc(F)cc3Cl)C2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN1CCN(c2ccc(S(=O)(=O)[C@H]3CCN(c4nccc(C#N)n4)C3)c(Cl)c2)CC1
Temperature: 60 °C
Reaction time: 20 h
Yield: 69.1 %

Procedure:
In a 10 mL round-bottomed flask, (S)-2-(3-(2-chloro-4-fluorophenylsulfonyl)pyrrolidin-1-yl)pyrimidine-4-carbonitrile (example 73) (50 mg, 136 μmol, 1 eq) was combined with acetonitrile (4 mL) to give a light yellow solution. 1-Methylpiperazine (20.7 mg, 22.9 μl, 204 μmol, 1.5 eq) and DIEA (35.2 mg, 47.6 μl, 273 μmol, 2 eq) were added. The reaction mixture was heated to 60° C. and stirred for 20 h. After that, 1-methylpiperazine (0.7 eq) and of DIEA (1 eq) were added. The reaction mixture was stirred at 60° C. for 5 h. After that, additional 1-methylpiperazine (1 eq) and DIEA (1.2 eq) were added. The reaction mixture was stirred at 60° C. for 16 h. The crude reaction mixture was concentrated in vacuo. The reaction mixture was poured into aqueous 5% Na2CO3 solution and extracted with EtOAc (3×10 mL). The organic layers were combined and washed with saturated aqueous NaCl solution (1×). The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10 g, CH2Cl2/MeOH 98/2) to yield a light yellow foam (42 mg, 69%). MS: m/z=447.1409 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[F:14][C:15]1[CH:16]=[CH:17][C:18]([NH2:22])=[N:19][C:20]=1[CH3:21]>C(#N)C>[Cl:8][C:6]1[N:5]=[N:4][C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:2]([NH:22][C:18]2[CH:17]=[CH:16][C:15]([F:14])=[C:20]([CH3:21])[N:19]=2)[CH:7]=1
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Reactant: Cc1nc(N)ccc1F
Solvent: CC#N
Product: CCOC(=O)c1nnc(Cl)cc1Nc1ccc(F)c(C)n1
Temperature: 140 °C
Yield: 16.3 %

Procedure:
A pressure tube was charged with ethyl 4,6-dichloropyridazine-3-carboxylate (300 mg, 1.36 mmol), 5-fluoro-6-methylpyridin-2-amine (257 mg, 2.04 mmol), and acetonitrile (8 mL) and then heated at 140° C. for 3 d. After cooling to room temperature the reaction mixture was concentrated in vacuo and the residue purified by chromatography (silica, 50 μm, 80 g, Analogix, 0 to 10% acetone in dichloromethane, 25 min) to afford ethyl 6-chloro-4-(5-fluoro-6-methylpyridin-2-ylamino)pyridazine-3-carboxylate (69 mg, 16%) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.72 (br. s., 1H) 9.06 (s, 1H) 7.38 (s, 1H) 6.74-6.85 (m, 1H) 4.58 (q, J=7.07 Hz, 2H) 2.56 (d, J=3.03 Hz, 3H) 1.53 (t, J=7.07 Hz, 3H) 1.27 (s, 1H). LCMS (EI/CI) m/z: 311 [M+H].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:7](=[O:21])[CH2:6][CH2:5]2.I.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[C:28](SC)=[NH:29]>C(O)C.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[N:15]1([CH2:14][CH2:13][CH2:12][N:8]2[C:9]3[C:4](=[CH:3][C:2]([NH:1][C:28]([C:24]4[S:23][CH:27]=[CH:26][CH:25]=4)=[NH:29])=[CH:11][CH:10]=3)[CH2:5][CH2:6][C:7]2=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: CSC(=N)c1cccs1
Reactant: Nc1ccc2c(c1)CCC(=O)N2CCCN1CCCCC1
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: N=C(Nc1ccc2c(c1)CCC(=O)N2CCCN1CCCCC1)c1cccs1
Reaction time: 64 h

Procedure:
A solution of 6-amino-1-(3-(piperidin-1-yl)propyl)-3,4-dihydroquinolin-2(1H)-one (0.065 g, 0.226 mmol) in dry ethanol (5 mL) was treated with methyl thiophene-2-carbimidothioate hydroiodide (0.129 g, 0.452 mmol) at room temperature and the resulting mixture was stirred for 64 hours. The reaction was transferred to a separatory funnel and diluted with ethyl acetate (30 mL) and saturated sodium hydrogen carbonate (20 mL). The aqueous was partitioned twice more with ethyl acetate (2×20 mL). The combined organics were washed with brine and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2M ammonia in methanol:dichloromethane, 0-1:10-9). The product was dried under high vacuum. Yield: 46 mg of yellow solid (51%). 1H NMR (DMSO-d6) δ: 8.02 (d, J=3.9 Hz, 1H), 7.99 (d, J=3 Hz, 1H), 7.32 (d, J =4.8 Hz, 1H), 7.28 (d, J=6.3 Hz, 1H), 7.20 (s, 1H), 7.17 (s, 1H), 4.32 (br s, 2H), 3.98−3.93 (m, 2H), 3.45-3.40 (m, 4H), 3.16-3.10 (m, 4H), 2.95-2.90 (m, 4H), 2.61-2.56(m, 2H), 2.01-1.90 (m, 2H). MS (ESI): 397.2 (M+1). ESI-HRMS calculated for C22H29N4SO (MH+): 397.2056, Observed: 397.2073.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([CH2:22][CH3:23])=[C:18]([CH3:24])[NH:17][C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].S(OC)(O[CH3:30])(=O)=O>CN(C)C=O>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([CH2:22][CH3:23])=[C:18]([CH3:24])[N:17]([CH3:30])[C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:8])[CH3:9])=[O:5]
Reactant: COS(=O)(=O)OC
Reactant: CCc1c(C)[nH]c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c1=O
Solvent: CN(C)C=O
Product: CCc1c(C)n(C)c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c1=O

Procedure:
using isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-5-ethyl-4-methyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate and dimethyl sulphate in dimethylformamide there is obtained isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-5-ethyl-3,4-dimethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, 1H--NMR (CDCl3, 400 MHz) 7.83 ppm (d, 1H), 7.33 ppm (d, 1H), 5.23 ppm (m, 1H), 3.48 ppm (s, 3H), 2.51 ppm (m, 2H), 2.34 ppm (s, 3H), 1.35 ppm (2xd, 6H), 1.09 ppm (t, 3H),
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3][OH:4].[H-].[Na+].Br[C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][N:10]=1>CN(C)C=O.O>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([O:4][CH2:3][CH:2]([F:5])[F:1])=[N:10][CH:11]=1
Reactant: Brc1ccc(Br)nc1
Reactant: OCC(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)COc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
2,2-Difluoroethanol (0.40 ml) was added dropwise to a suspension of sodium hydride (0.270 g) in dimethylformamide (5 ml) cooled in an ice-bath under argon. The mixture was stirred at room temperature for 40 minutes, then re-cooled in an ice-bath. A solution of 2,5-dibromopyridine (1 g) in dimethylformamide (5 ml) was added. The solution was then heated at 65° C. under argon for 18 h, allowed to cool and diluted with water (50 ml). The aqueous phase was extracted three times with ethyl acetate. The combined extracts were washed with water, brine, dried over magnesium sulphate, filtered and evaporated. The product was purified by column chromatography eluting with hexane to give a colourless oil (0.946 g).
Reaction SMILES: N1[CH:6]=[CH:5][N:4]=[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])N=1.[C:12]1(=O)[CH2:16][CH2:15][CH2:14][CH2:13]1.N1CCCC1>C1(C)C=CC=CC=1>[C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:13]2[CH2:14][CH2:15][CH2:16][C:12]=2[CH:6]=[CH:5][N:4]=1
Reactant: CCOC(=O)c1nccnn1
Reactant: O=C1CCCC1
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Product: CCOC(=O)c1nccc2c1CCC2
Yield: 23.1 %

Procedure:
Ethyl 1,2,4-triazine-3-carboxylate (7 g, 45.8 mmol), cyclopentanone (4.9 mL, 55.0 mmol), and pyrrolidine (4.6 mL, 55.0 mmol) in toluene (100 mL) were heated to reflux for 12 h. The mixture was purified by column on silica gel chromatography (PE/EtOAc=5:1) to give the title compound (2.02 g, 25%) as a brown oil. LCMS: 192 (M+1)+
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[C:5]([NH2:20])=[N:4][CH:3]=1.[N:21]([O-])=O.[Na+]>C(O)(=O)C.O>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:9][C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][CH:14]=[CH:13]4)[N:21]=[N:20][C:5]2=[N:4][CH:3]=1
Reactant: Nc1ncc(Br)nc1NCc1ccc2ncccc2c1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Brc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.5 %

Procedure:
To a solution of 6-bromo-N2-(quinolin-6-ylmethyl)pyrazine-2,3-diamine (6.55 g, 19.84 mmol) in acetic acid (15 mL), was added a the solution of sodium nitrite (2.74 g, 39.7 mmol) in water (3 mL). After stirring at rt for 3 h, the solution was concentrated in vacuo. The residue was taken with NaHCO3(aq), extracted with DCM. The organic layer was washed with NH4Cl(aq), dried over Na2SO4, filtered, concentrated in vacuo and purified by silica gel chromatography with EA:Hexanes to provide 6-((6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinoline (3.35 g, 47%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.05 (s, 1H), 8.89 (d, 1H), 8.34 (d, 1H), 8.02 (d, 1H), 7.9 3 (s, 1H), 7.76 (dd, 1H), 7.53 (dd, 1H), 6.19 (s, 2H). LCMS (method B): [MH]+=343, tR=2.11 min.
Reaction SMILES: C(OC([NH:8][C:9](=[NH:40])[C:10]1[S:14][C:13]([S:15][CH3:16])=[C:12]([S:17]([C:20]2[CH:21]=[C:22]([C:26]3[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:27]=3[CH2:33][O:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])[CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH:11]=1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:9]([C:10]1[S:14][C:13]([S:15][CH3:16])=[C:12]([S:17]([C:20]2[CH:21]=[C:22]([C:26]3[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:27]=3[CH2:33][O:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])[CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH:11]=1)(=[NH:8])[NH2:40]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2COCCC(=O)O)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2COCCC(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.8 %

Procedure:
A mixture of 3-{3′-[5-(tert-butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-2-ylmethoxy}-propionic acid (5.1 mg, 8.4 μmol) in TFA/DCM (1:1, 1.5 mL) was stirred at ambient temperature for 1 h. The mixture was concentrated and flash chromatographed on silica gel, eluting with MeOH/DCM (5 to 12%) to give the title compound (3.0 mg, 69% yield) as a white solid.
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:7]=[C:8]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:9]2[C:10](=[O:13])[C:11]=1[Br:12])(=O)C.Cl.O1CCOCC1.[OH-].[NH4+]>O>[Br:12][C:11]1[C:10](=[O:13])[N:9]2[C:14]([CH3:18])=[CH:15][CH:16]=[CH:17][C:8]2=[N:7][C:6]=1[CH2:5][OH:4]
Reactant: CC(=O)OCc1nc2cccc(C)n2c(=O)c1Br
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc2nc(CO)c(Br)c(=O)n12
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A heterogeneous mixture of (3-bromo-6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)methyl acetate (4.2444 g, 13.64 mmol), concd. HCl (3.87 mL, 46.4 mmol), and 1,4-dioxane (39.0 mL) was heated with stirring at 70° C. After 3 h, the mixture was cooled to rt and the mixture was concd under reduced pressure. The residue was diluted with water (100 mL) and the pH adjusted to 10 with 28% ammonium hydroxide (10 mL). The precipitate was filtered, washed with water (200 mL), and dried under high vacuum to give 3-bromo-2-(hydroxymethyl)-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one as a tan solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.74 (1 H, dd, J=8.8, 6.8 Hz), 7.49 (1 H, dd, J=9.0, 0.8 Hz), 7.01-7.06 (1 H, m), 5.24 (1 H, t, J=6.1 Hz), 4.52 (2 H, d, J=6.3 Hz), 2.96 (3 H, s); Mass Spectrum (ESI) m/e=268.9 [M+1 (79Br)] and 271.0 [M+1 (81Br)].
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.C([Li])CCC.C([O:18][B:19](OCC)[O:20]CC)C.Cl>O1CCCC1.CCCCCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([B:19]([OH:20])[OH:18])=[CH:7][C:6]=2[CH:10]=1
Reactant: CCOB(OCC)OCC
Reactant: Fc1ccc2occc2c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1cc2cc(F)ccc2o1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
In a nitrogen atmosphere, to a solution of 2.0 g of 5-fluorobenzofuran in 150 ml tetrahydrofuran was added 18.5 ml of a 1.59 M solution of n-butyllithium in n-hexane at −78° C., and the mixture was stirred at the same temperature for 10 minutes and at 0° C. for further 10 minutes. At −78° C., 3.7 ml of triethoxyborane was added, and the mixture was stirred for 2 hours while elevating to 0° C. 30 ml of 1 N hydrochloric acid was added, stirred at room temperature for 1 hour, and then the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:3 to 1:1), to give 525 mg of the title compound as colorless crystals.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][CH:13]=O)=[CH:9][CH:10]=2)[CH:5]=[CH:4][O:3]1.[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][CH2:13][N:18]3[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19]3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][O:3]1
Reactant: O=CCc1ccc2c(=O)occc2c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCN(CCc2ccc3c(=O)occc3c2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(1-oxo-1H-isochromen-6-yl) acetaldehyde (240 mg, 1.275 mmol) and tert-butyl piperazine-1-carboxylate (238 mg, 1.275 mmol) were dissolved in dichloroethane (10 mL) and added sodium triacetoxyborohydride (811 mg, 3.83 mmol) then stirred at RT for 16 hrs. LC-MS showed product peak. The reaction was washed with NaHCO3, brine, dried over Na2SO4 and evaporated to dryness. The residue was chromatographed through a 80 g. ISCO Redi-Sep column and eluted with 0-100% ethyl acetate/hexane to yield tert-butyl 4-[2-(1-oxo-1H-isochromen-6-yl)ethyl]piperazine-1-carboxylate. 1H-NMR (500 MHz, CDCl3) δ ppm 8.25 (d, J=8 Hz, 1H), 7.42 (d, J=9.4 Hz, 2H), 6.49 (d, J=5.7 Hz, 1H), 3.49 (s, 4H), 2.96 (t, J=7.6 Hz, 2H), 2.69 (t, J=7.3 Hz, 2H), 2.51 (s, 4H), 1.50 (s, 9H).
Reaction SMILES: C([O:8][C:9]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[S:11][CH:10]=1)C1C=CC=CC=1.ClC(Cl)(Cl)Cl.I[Si](C)(C)C>O>[OH:8][C:9]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[S:11][CH:10]=1
Reactant: FC(F)(F)c1cc(OCc2ccccc2)cs1
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: Oc1csc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
A mixture of 1G (7.75 g) and tetrachloromethane (50 ml) was treated with iodotrimethylsilane (12.30 ml) and heated to 60 ° C. for 12 hours. The reaction mixture was stirred at room temperature for 12 hours. Water (50 ml) was added and the resulting reaction mixture was extracted with dichloromethane three times. The combined organic phases were washed with water and dried. The crude reaction mixture was eluted through hexane (100 g/silica gel) to remove benzyliodide and then with diethyl ether. The ether phases were concentrated and distilled in vacuo to give the product (3.33 g, 74% having point of 65-66 ° C. at 4 mm.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][C:13](=O)[CH2:14][CH2:15][C:16](=O)[CH3:17]>>[N+:9]([C:3]1[CH:4]=[C:5]([N:6]2[C:16]([CH3:17])=[CH:15][CH:14]=[C:13]2[CH3:12])[CH:7]=[CH:8][C:2]=1[F:1])([O-:11])=[O:10]
Reactant: CC(=O)CCC(C)=O
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Product: Cc1ccc(C)n1-c1ccc(F)c([N+](=O)[O-])c1
Yield: 98 %

Procedure:
Prepared analogously from 4-fluoro- 3-nitroaniline and 2,5-hexanedione. Yield: 98%. Mp 99-101° C.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][CH:5]([CH2:9][CH2:10][CH3:11])[C:6](O)=[O:7].S(Cl)([Cl:18])=O>>[Br:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][CH:5]([CH2:9][CH2:10][CH3:11])[C:6]([Cl:18])=[O:7]
Reactant: CCCC(Oc1ccccc1Br)C(=O)O
Reactant: O=S(Cl)Cl
Product: CCCC(Oc1ccccc1Br)C(=O)Cl
Temperature: 80 °C
Yield: 76 %

Procedure:
23.8 g (87 mmol) of 2-(2-bromophenoxy)pentanoic acid and 90 ml of thionyl chloride are placed in a 250 ml round-bottomed flask equipped with a reflux condenser. The mixture is heated at 80° C. for 4 hours. The thionyl chloride is evaporated and the residue purified by distillation under reduced pressure (0.1 millibar). 19.3 g of 2-(2-bromophenoxy)pentanoic acid chloride are obtained (76% yield); B.p.=114° C. (0.1 mb, 10 Pa).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:31]([CH3:39])([CH3:38])[O:32][SiH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[C:4]([C:8]2[CH:9]=[C:10]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][N:18]=3)[C:11](=[O:15])[N:12](C)[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[Br:40][C:41]1[CH:46]=[CH:45][C:44]([S:47](Cl)(=[O:49])=[O:48])=[C:43]([CH2:51][CH2:52]Br)[CH:42]=1.CCN(C(C)C)C(C)C>ClC(Cl)C>[Br:40][C:41]1[CH:46]=[CH:45][C:44]2[S:47](=[O:49])(=[O:48])[N:1]([C:2]3[C:3]([C:31]([CH3:39])([CH3:38])[O:32][SiH2:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[C:4]([C:8]4[CH:9]=[C:10]([NH:16][C:17]5[CH:22]=[CH:21][C:20]([C:23]([N:25]6[CH2:26][CH2:27][O:28][CH2:29][CH2:30]6)=[O:24])=[CH:19][N:18]=5)[C:11](=[O:15])[NH:12][CH:13]=4)[CH:5]=[CH:6][CH:7]=3)[CH2:52][CH2:51][C:43]=2[CH:42]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1CCBr
Reactant: Cn1cc(-c2cccc(N)c2C(C)(C)O[SiH2]C(C)(C)C)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Solvent: CC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[SiH2]OC(C)(C)c1c(-c2c[nH]c(=O)c(Nc3ccc(C(=O)N4CCOCC4)cn3)c2)cccc1N1CCc2cc(Br)ccc2S1(=O)=O
Yield: 53.4 %

Procedure:
The mixture of 5-[3-Amino-2-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-1-methyl-3-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-1H-pyridin-2-one (0.2 g, 0.36 mmol), 4-bromo-2-(2-bromo-ethyl)-benzenesulfonyl chloride (0.4 g, 1.08 mmol) and DIPEA (1 mL) in dichloroethane (10 mL) was microwaved at 120° C. for 30 min, then added 4-bromo-2-(2-bromo-ethyl)-benzenesulfonyl chloride (0.4 g, 1.08 mmol) and DIPEA (1 mL) and microwaved at 120° C. for 30 min. After repeating this process three times, the mixture was concentrated to afford a dark residue. Purification by silica gel chromatography (methylene chloride/acetone) afforded 0.15 g of 5-[3-(6-Bromo-1,1-dioxo-3,4-dihydro-1H-1lambda*6*-benzo[e][1,2]thiazin-2-yl)-2-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-3-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-1H-pyridin-2-one as a pale solid MS (ESI) 796.2 (M+H)+.
Reaction SMILES: CO.[CH2:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:4].[C:11]([O:15]OC(C)(C)C)(C)(C)C>>[C:5]1([CH:3]([CH3:4])[O:15][CH3:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCc1ccccc1
Reactant: CC(C)(C)OOC(C)(C)C
Solvent: CO
Product: COC(C)c1ccccc1
Temperature: 90 °C
Yield: 35 %

Procedure:
Into a pressure vessel methanol (84 μL, 1 mmol, 1 eq) was added and diluted with ethylbenzene (1.225 mL, 10 mmol, 10 eq). To this stirring solution was added 1 mol % of a stock solution of {[Cl2NN]Cu}2(benzene) from the catalyst stock solution described in Example 4 (200 μL=0.01 mmol). After adding of tert-butyl peroxide (220 μL, 1.2 mmol), the pressure vessel was sealed and heated to 90° C. for 24 hr. The catalyst was separated by exposing the mixture to air and filtering through Celite®. After removing ethylbenzene under vacuum, the residue was analyzed by GC/MS and 1H NMR to determine the yield and consumption of starting materials. 1H NMR Yield: 35%.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH2:13])=[O:11])=[CH:9][C:4]=2[NH:3][CH:2]=1.[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[CH2:22][CH2:23][C:24](O)=O>>[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[CH2:22][CH2:23][C:24]1[O:11][C:10]([C:8]2[CH:7]=[CH:6][C:5]3[NH:1][CH:2]=[N:3][C:4]=3[CH:9]=2)=[N:12][N:13]=1
Reactant: NNC(=O)c1ccc2nc[nH]c2c1
Reactant: O=C(O)CCc1ccc(F)cc1F
Product: Fc1ccc(CCc2nnc(-c3ccc4[nH]cnc4c3)o2)c(F)c1

Procedure:
The compound was synthesized starting from benzimidazol-5-carbohydrazide (176 mg, 1 mmol) and 3-(2,4-difluorophenyl)propionic acid (186 mg, 1 mmol) as described in method 2;