Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[N+:10]([C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16])([O-:12])=[O:11].[OH-].[Na+]>CC(C)=O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:16][C:15]2[CH:17]=[CH:18][CH:19]=[C:13]([N+:10]([O-:12])=[O:11])[CH:14]=2)[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cccc(Nc2nc(Cl)nc(Cl)n2)c1
Temperature: 2.5 °C

Procedure:
To cyanuric chloride (1.3307 g, 7.2 mmol) dissolved in acetone (15 mL) stirring at 0-5° C., was added a solution of 3-nitroaniline (1.0023 g, 7.2 mmol) in acetone (15 mL) followed by the addition of 2.5 N NaOH (2.9 mL, 7.2 mmol). The reaction mixture was allowed to stir at 0-5° C. for 1 hour under nitrogen. The reaction mixture was poured over crushed ice. The solid that formed was collected by vacuum filtration and the resulting solid was dried overnight under vacuum. The product was used with no further purification, (158a, 2.01 g, 98%), mp 173° C.; HPLC: Inertsil ODS-3V C18, 40:30:30 [KH2PO4 (0.01M, pH 3.2): CH3OH: CH3CN], 264 nm, Rt 21.5 min, 97.1% purity; MS (TOF MS ES+): m/z 370 (80.33), 291 (43.4), 286 (M+H, 100).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]([C:14]1[N:15]=[N:16][CH:17]=[CH:18][CH:19]=1)(=[O:13])[CH3:12].[C:20](OC)(=[O:25])[C:21]([O:23][CH3:24])=[O:22]>O1CCCC1>[CH3:24][O:23][C:21](=[O:22])[C:20](=[O:25])[CH2:12][C:11]([C:14]1[N:15]=[N:16][CH:17]=[CH:18][CH:19]=1)=[O:13]
Reactant: CC(=O)c1cccnn1
Reactant: COC(=O)C(=O)OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(=O)CC(=O)c1cccnn1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
In an argon atmosphere and while cooling at −78° C., 1.0M lithium bis(trimethylsilyl)amide in tetrahydrofuran (19 mL) was added dropwise to 3-acetylpyridazine (2.097 g) in tetrahydrofuran (50 mL), followed by stirring for 1 hour. To the reaction mixture, dimethyl oxalate (4.055 g) in tetrahydrofuran (35 mL) was added dropwise, and the resultant mixture was stirred at 0° C. for 2 hours. The reaction solvent was removed under reduced pressure. Water was added to the residue, and the mixture was washed with diethyl ether. The aqueous layer was slightly acidified with aqueous 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate anhydrate, followed by filtration. The solvent was removed under reduced pressure, to thereby give 4-(3-pyridazinyl)-2,4-dioxobutanoic acid methyl ester as a solid (2.63 g, 73%).
Reaction SMILES: [Br-].[CH3:2][N+:3]([CH3:21])=[C:4]1[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][O:5]1.Cl.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2([OH:36])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[OH2:5].[Br:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2([OH:36])[CH2:31][CH2:32][N:33]([CH2:6][CH2:7][C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:4]([N:3]([CH3:21])[CH3:2])=[O:5])[CH2:34][CH2:35]2)=[CH:26][CH:25]=1
Reactant: OC1(c2ccc(Br)cc2)CCNCC1
Reactant: C[N+](C)=C1OCCC1(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: CN(C)C(=O)C(CCN1CCC(O)(c2ccc(Br)cc2)CC1)(c1ccccc1)c1ccccc1

Procedure:
A mixture of 12.1 parts of dimethyl (tetrahydro-3,3-diphenyl-2-furylidene) ammonium bromide, 8.8 parts of 4-(p-bromophenyl)-4-piperidinol hydrochloride, 10.6 parts of sodium carbonate, 0.5 parts of potassium iodide and 200 parts of 4-methyl-2-pentanone is stirred and refluxed for 14 hours with water separator. The reaction mixture is cooled and water (200 parts) is added. The organic layer is separated, washed with diluted sodium hydroxide solution, dried, filtered, and while stirring the filtrate, the product is crystallized. It is filtered off and recrystallized from 80 parts of 4-methyl-2-pentanone (activated charcoal), yielding 4-(p-bromophenyl)-4-hydroxy-N,N-dimethyl-α,α-diphenylpiperidine-1-butyramide hydrate; m.p. 123.7° C.
Reaction SMILES: C[Al](C)C.CO[C:7](=[O:25])[CH2:8][C:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:13][CH:14]=1.[Br:26][C:27]1[C:28]([NH2:33])=[N:29][CH:30]=[CH:31][CH:32]=1>ClC(Cl)C>[Br:26][C:27]1[C:28]([NH:33][C:7](=[O:25])[CH2:8][C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:16])[CH2:13][CH:14]=2)=[N:29][CH:30]=[CH:31][CH:32]=1
Reactant: COC(=O)CC1=CCN(C(=O)OCc2ccccc2)CC1
Reactant: Nc1ncccc1Br
Agent: C[Al](C)C
Solvent: CC(Cl)Cl
Product: O=C(CC1=CCN(C(=O)OCc2ccccc2)CC1)Nc1ncccc1Br
Temperature: 55 °C
Reaction time: 18 h
Yield: 52.8 %

Procedure:
Trimethylaluminum (0.91 g, 12.61 mmol) was added to a solution of benzyl 4-(2-methoxy-2-oxoethyl)-3,6-dihydropyridine-1(2H)-carboxylate (2.43 g, 8.41 mmol) and 3-bromopyridin-2-amine (1.60 g, 9.25 mmol) in dichloroethane (45 mL) at 0° C. The reaction mixture was slowly warmed to 55° C. After 18 h, the reaction mixture was quenched with saturated aqueous sodium bicarbonate and extracted with dichloromethane (4×). The combined organic extracts were washed with Rochelle's salts (1N in water), saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (50% hexanes/ethyl acetate→100% ethyl acetate) gave the title compound (1.91 g). MS 430.0 (M).
Reaction SMILES: C([O:8][C@H:9]([C:35]([F:38])([F:37])[F:36])[C@@H:10]([NH:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([Cl:33])[C:26]=1[CH3:34])[C:11]1[O:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)=[N:14][N:15]=1)C1C=CC=CC=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:33][C:27]1[C:26]([CH3:34])=[C:25]([NH:24][C@@H:10]([C:11]2[O:12][C:13]([C:16]3[CH:17]=[CH:18][C:19]([C:22]#[N:23])=[CH:20][CH:21]=3)=[N:14][N:15]=2)[C@H:9]([OH:8])[C:35]([F:36])([F:37])[F:38])[CH:32]=[CH:31][C:28]=1[C:29]#[N:30]
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(C#N)cc3)o2)[C@H](OCc2ccccc2)C(F)(F)F)ccc(C#N)c1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(C#N)cc3)o2)[C@H](O)C(F)(F)F)ccc(C#N)c1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 52.1 %

Procedure:
To a solution of 4-((1R,2S)-2-(benzyloxy)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)-3,3,3-trifluoropropylamino)-2-chloro-3-methylbenzonitrile (170 mg, 0.32 mmol) in DCM (15 mL) was added BBr3 (380 mg, 1.52 mmol) in 0.7 mL DCM at 0° C. The reaction mixture was stirred at 0° C. for 2 h until the starting material completely disappeared. The reaction was quenched with saturated aq. NaHCO3 solution, extracted with EtOAc. The EtOAc extracts were washed with water, brine and dried over Na2SO4. After the solvent was removed, the residue was purified by flash chromatography to provide the title compound 2-chloro-4-((1R,2S)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)-3,3,3-trifluoro-2-hydroxypropylamino)-3-methylbenzonitrile (74.6 mg, 53%) as a white solid. 1H NMR (400 MHz, Acetone-d6, δ in ppm) 8.23 (d, J=8.6 Hz, 2H), 8.01 (d, J=8.6 Hz, 2H), 7.55 (d, J=8.6 Hz, 1H), 7.06 (d, J=8.6 Hz, 1H), 6.73 (b, 1H), 5.77 (d, J=9.4 Hz, 1H), 5.72 (dd, J=2.4, 9.0 Hz, 1H), 5.21 (m, 1H), 2.40 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]#[C:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:8][C:9]=1[N:10]1[C@H:15]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:14][O:13][C@H:12]([CH2:22][CH:23]=C)[C:11]1=[O:25])=[O:4].C[N+]1([O-])CC[O:36]CC1.O.I([O-])(=O)(=O)=O.[Na+]>CC(C)=O.[Os](=O)(=O)(=O)=O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]#[C:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[CH:8][C:9]=1[N:10]1[C@H:15]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:14][O:13][C@H:12]([CH2:22][CH:23]=[O:36])[C:11]1=[O:25])=[O:4]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CC[C@H]1OC[C@@H](C2CCCCC2)N(c2cc(C#CC(C)(C)C)sc2C(=O)OC)C1=O
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N1C(=O)[C@@H](CC=O)OC[C@H]1C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.4 %

Procedure:
To a solution of 3-((2R,5R)-2-allyl-5-cyclohexyl-3-oxo-morpholin-4-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (3.15 g, 7.10 mmol, 1.0 equiv) in acetone (40 mL) at 0° C. was added N-methylmorpholine oxide (2.51 g, 21.30 mmol, 3.0 equiv), water (14 mL) and osmium tetroxide (3.60 g, 2.5% wt in THF, 0.36 mmol, 0.05 equiv). The mixture was stirred at room temperature for 60 minutes. Acetone was removed under vacuum and the residue was partitioned between EtOAc (80 mL) and brine (15 mL). The phases were separated and the organic layer was dried (over Na2SO4) and concentrated. To the residue was added THF (40 mL) and water (14 mL). At 0° C., sodium periodate (2.28 g, 10.65 mmol, 1.5 equiv) was added to the mixture and the mixture was stirred at room temperature for 30 minutes. After cooled at 0° C., another portion of sodium periodate (0.76 g, 3.55 mmol, 0.5 equiv) was added. The mixture was stirred at room temperature for another 30 minutes. Volatile solvent was removed under vacuum and the residue was partitioned between EtOAc (100 mL) and brine (10 mL). The organic layer was separated, dried (over Na2SO4) and concentrated. The residue was purified by silica gel column chromatography (EtOAc/Heptane, 25% to 50%) to give product (2.1 g, 66%). MS: 446.3 [M−H+].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:11][CH2:10][C:9](OS(C(F)(F)F)(=O)=O)=[CH:8][CH2:7]1)=[O:5])[CH3:2].[Cl:25][C:26]1[CH:31]=[CH:30][C:29](OB(O)O)=[CH:28][CH:27]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(C#C)(C)(C)C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.C(COC)OC.C(O)C>[CH2:1]([O:3][C:4]([C:6]1([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:11][CH2:10][C:9]([C:29]2[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=2)=[CH:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: OB(O)Oc1ccc(Cl)cc1
Reactant: CCOC(=O)C1(C(=O)OCC)CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: C#CC(C)(C)C
Solvent: COCCOC
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C1(C(=O)OCC)CC=C(c2ccc(Cl)cc2)CC1
Temperature: 80 °C
Reaction time: 16 h
Yield: 76.4 %

Procedure:
A 100 ml heavy wall round bottom flask was charged with the crude intermediate 4-trifluoromethanesulfonyloxy-cyclohex-3-ene-1,1-dicarboxylic acid diethyl ester (4.0 g, 80% purity, 8.55 mmol, 1.0 equiv) from last step, PdCl2(dppf)-CH2Cl2 adduct (0.628 g, 0.769 mmol, 0.09 equiv), 4-chloro-phenylboric acid (2.67 g, 17.1 mmol, 2.0 equiv), tripotassium phosphate (4.54 g, 21.37 mmol, 2.5 equiv), ethanol (8 ml), dimethoxyethane (32.0 ml) and t-butyl acetylene (7.9 g, 97 mmol, 2.0 equiv). The flask was sealed, flushed with nitrogen for three times and stirred at 80° C. for 16 hours. After cooled at room temperature, the reaction mixture was filtered and washed with ethyl acetate (20 ml). The filtrate was concentrated under vacuum and the residue was purified by chromatography (heptanes/ethyl acetate 2/1) to give 4-(4-chloro-phenyl)-cyclohex-3-ene-1,1-dicarboxylic acid diethyl ester (2.2 g, 76%) as colorless oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.27 (t, J=8.00 Hz, 6H) 2.29 (t, J=6.38 Hz, 2H) 2.46 (td, J=6.25, 2.02 Hz, 2H) 2.65-2.85 (m, 2H) 4.21 (q, J=8.00 Hz, 4H) 6.07 (m, 1H) 7.26 (s, 4H).
Reaction SMILES: [C:1](#[N:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:7](Cl)([CH3:10])([CH3:9])[CH3:8].[Na]>CCCCCC.O1CCCC1.O.CO.ClC1C=CC=CC=1>[C:2]([C:1](=[NH:6])[C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)Cl
Reactant: CC(C)(C)C#N
Agent: [Na]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)C(=N)C(C)(C)C
Reaction time: 1 h

Procedure:
This was prepared by the method of J. Chem. Soc., Perkin I, 2087 (1976); ibid, 1797 (1974). Pivalonitrile (33.2 g.) and t-butyl chloride (44.4 g.) were added under nitrogen to a well stirred suspension of sodium sand (18.4 g.) in a mixture of hexane (80 ml.), tetrahydrofuran (20 ml.) and methanol (1 ml.) over one hour at 15-20° C. The mixture was stirred three hours, a solution of chlorobenzene (2 g) in tetrahydrofuran (5 ml.) added dropwise over 10 minutes and stirring continued for one hour. Methanol (20 ml.) was added with caution over 0.5 hr. followed by water until phases separated. The aqueous phase was extracted with ether and the combined organic phases dried and evaporated in vacuo. The residue was distilled to afford di-t-butylketone imine, b.p. 62°-63° C./19 mm.
Reaction SMILES: [H-].[Na+].[CH2:3]([C@@:6]1([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[O:11][C:10](=[O:12])[N:9]([C@H:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24](=[O:27])[NH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH3:14])[CH2:8][CH2:7]1)[CH:4]=[CH2:5].[CH3:35]I>C1COCC1>[CH2:3]([C@@:6]1([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[O:11][C:10](=[O:12])[N:9]([C@H:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][C:24](=[O:27])[N:23]([CH3:35])[CH:22]=3)=[CH:19][CH:20]=2)[CH3:14])[CH2:8][CH2:7]1)[CH:4]=[CH2:5]
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(=O)[nH]c3)cc2)C(=O)O1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(=O)n(C)c3)cc2)C(=O)O1
Reaction time: 1 h
Yield: 69 %

Procedure:
To a suspension of NaH (330 mg, 8.24 mmol) in THF (20 mL) was added a solution of (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (891 mg, 0.174 mmol) in THF (30 mL) at 0° C., and the resulting mixture was stirred for 1 h. CH3I (2 ml) was added and the mixture was stirred overnight. The reaction was quenched by aqueous NH4Cl solution. The organic phase was separated, and concentrated to give the crude product, which was purified by preparative TLC to give (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (634 mg, 69%). 1H NMR (CDCl3): δ=1.52 (d, 3H), 2.16-2.35 (m, 3H), 2.52-2.64 (m, 2H), 2.94 (m, 1H), 3.61 (s, 3H), 5.00-5.11 (m, 2H), 5.66-5.74 (m, 2H), 6.64 (d, 1H), 6.90 (d, 2H), 7.02 (t, 2H), 7.11-7.14 (d, 2H), 7.25-7.28 (m, 2H), 7.41 (m, 1H), 7.53 (m, 1H).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C@H:13]3[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][CH2:14]3)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24](O)=[CH:23][N:22]=1>>[Cl:20][C:21]1[N:22]=[CH:23][C:24]([O:19][C@@H:16]2[CH2:17][CH2:18][C@H:13]([C:11]([N:8]3[CH2:9][CH2:10][N:5]([CH:1]4[CH2:4][CH2:3][CH2:2]4)[CH2:6][CH2:7]3)=[O:12])[CH2:14][CH2:15]2)=[CH:25][CH:26]=1
Reactant: O=C([C@H]1CC[C@H](O)CC1)N1CCN(C2CCC2)CC1
Reactant: Oc1ccc(Cl)nc1
Product: O=C([C@H]1CC[C@@H](Oc2ccc(Cl)nc2)CC1)N1CCN(C2CCC2)CC1

Procedure:
According to the procedure described for example 1, the title compound had been synthesized from trans-(4-cyclobutyl-piperazin-1-yl)-(4-hydroxy-cyclohexyl)-methanone and 2-chloro-5-hydroxypyridine. MS (m/e): 378.3 (MH+).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:8]([OH:16])[N:7]=[C:6]([SH:17])[N:5]=1.[F:18][C:19]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Br.O>CN(C=O)C>[F:18][C:19]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][S:17][C:6]1[N:7]=[C:8]([OH:16])[C:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([OH:3])[N:5]=1
Reactant: CCOC(=O)Cc1c(O)nc(S)nc1O
Reactant: Fc1cccc(CBr)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1c(O)nc(SCc2cccc(F)c2F)nc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 60% sodium hydride in oil (1.37 g) in dry DMF (10 ml) was added a solution of the product from example 1, step (a) (7.9 g) in dry DMF (30 ml). After the addition the mixture was stirred at room temperature for 1 hour. To the solution was added 2,3-difluorobenzylbromide (4.45 ml) and the mixture allowed to stir overnight. The mixture was poured into water (200 ml) and the product collected by filtration to give the subtitle compound (8.1 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:30][C:12]2=[CH:13][C:14]3[C:15](=[O:29])[N:16]([CH:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)[C:17](=[O:21])[C:18]=3[C:19]([CH3:20])=[C:11]2[N:10]=1.[F:31][C:32]1[CH:33]=[CH:34][C:35]([CH3:42])=[C:36]([CH2:38][CH:39]([NH2:41])[CH3:40])[CH:37]=1>C(O)CCC>[F:31][C:32]1[CH:33]=[CH:34][C:35]([CH3:42])=[C:36]([CH2:38][CH:39]([NH:41][C:2]2[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=2[C:9]2[NH:30][C:12]3=[CH:13][C:14]4[C:15](=[O:29])[N:16]([CH:22]5[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]5)[C:17](=[O:21])[C:18]=4[C:19]([CH3:20])=[C:11]3[N:10]=2)[CH3:40])[CH:37]=1
Reactant: Cc1ccc(F)cc1CC(C)N
Reactant: Cc1c2c(cc3[nH]c(-c4c(Cl)cc[nH]c4=O)nc13)C(=O)N(C1CCN(C)CC1)C2=O
Solvent: CCCCO
Product: Cc1ccc(F)cc1CC(C)Nc1cc[nH]c(=O)c1-c1nc2c(C)c3c(cc2[nH]1)C(=O)N(C1CCN(C)CC1)C3=O
Yield: 100.1 %

Procedure:
A mixture of 2-(4-chloro-2-oxo-1,2-dihydropyridin-3-yl)-4-methyl-6-(1-methylpiperidin-4-yl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione (1.00 g, 2.35 mmol), 1-(5-fluoro-2-methylphenyl)propan-2-amine (0.47 g, 2.82 mmol), Hunig,s base (1.52 g, 0.011 mol), and 20 mL of anhydrous 1-butanol was heated at reflux for 14-15 h under an argon atmosphere. Product was purified by a silica gel column using methylene chloride and methanol (9:1 v/v) as eluent to afford 1.31 g (99%) of the designed compound as yellowish solid. 1H NMR (300 MHz, DMSO-d6) δ 13.37 (s, 1H, NH), 11.25 (d, J=6.3 Hz, 1H, NH), 11.02 (d, J=8.1 Hz, 1H, NH), 7.98 (s, 1H, ArH), 7.32 (t, J=7.2 Hz, 1H, ArH), 7.16-7.07 (m, 2H, ArH), 6.92-6.86 (m, 1H, ArH), 6.17 (d, J=7.5 Hz, 1H, ArH), 4.34-4.19 (m, 2H, 2×CH), 3.51-3.47 (m, 2H, CH2), 3.18-3.11 (m, 2H, CH2), 2.97 (d, J=6.3 Hz, 2H, CH2), 2.83 (s, 3H, CH3), 2.76 (s, 3H, CH3), 2.69-2.61 (m, 2H, CH2), 2.27 (s, 3H, CH3), 1.95-1.91 (m, 2H, CH2), 1.34 (d, J=6.3 Hz, 3H, CH3); Mass (ESI, positive) m/z 557.2 [M+H]+.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:40])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[NH:24][N:23]=4)[N:20]=3)[N:15]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].[H-].[Na+].Br.[CH3:44][N:45]([CH2:47][CH2:48]Br)[CH3:46]>CN(C=O)C>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:40])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[N:24]([CH2:48][CH2:47][N:45]([CH3:46])[CH3:44])[N:23]=4)[N:20]=3)[N:15]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2]
Reactant: CN(C)CCBr
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(Cl)ccc34)nc12)C(=O)N1CC(C#N)C1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCN(C)C)c4cc(Cl)ccc34)nc12)C(=O)N1CC(C#N)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 43.3 %

Procedure:
In a 10 mL pear-shaped flask, 2-(6-chloro-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (280 mg, 0.48 mmol) was combined with DMF (8 ml) at 0° C. to give a yellow solution. Sodium hydride (60% in mineral oil, 70 mg, 1.74 mmol) was added and the reaction was stirred at 0° C. for 10 min. Dimethylaminoethyl bromide hydrobromide (169 mg, 0.73 mmol) was added and the reaction was stirred at 0° C. for 30 min then allowed to warm up to room temperature and stirred for 2 h. The reaction was quenched with 5 ml of brine and 10 ml of water then extracted with EtOAc (2×). The combined organics were washed with water and brine then dried and purified by SiO2 chromatography (0% to 10% MeOH/CH2Cl2 to isolate 135 mg (43%) of 2-[6-chloro-1-(2-dimethylamino-ethyl)-1H-indazol-3-yl]-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a foaming solid. MS: (M+H)+=651.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH:18]([CH3:20])[CH3:19])=[N:4][C:5]([O:11][CH2:12][C:13]([O:15]CC)=O)=[N:6][C:7]=1[CH:8]([CH3:10])[CH3:9].[CH:21]1([CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([NH:31][CH3:32])[CH2:27][CH2:26]2)[CH2:23][CH2:22]1>>[NH2:1][C:2]1[C:7]([CH:8]([CH3:9])[CH3:10])=[N:6][C:5]([O:11][CH2:12][C:13]([N:31]([CH:28]2[CH2:27][CH2:26][N:25]([CH2:24][CH:21]3[CH2:23][CH2:22]3)[CH2:30][CH2:29]2)[CH3:32])=[O:15])=[N:4][C:3]=1[CH:18]([CH3:19])[CH3:20]
Reactant: CNC1CCN(CC2CC2)CC1
Reactant: CCOC(=O)COc1nc(C(C)C)c(N)c(C(C)C)n1
Product: CC(C)c1nc(OCC(=O)N(C)C2CCN(CC3CC3)CC2)nc(C(C)C)c1N

Procedure:
As in Example 11, a carboxylic acid derivative was synthesized from Compound 13. Then, the title compound was synthesized from the obtained carboxylic acid derivative and 1-(cyclopropylmethyl)-N-methylpiperidine-4-amine in the same manner as in Example 49.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8].Cl[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][N:15]=1.Cl>CN(C)C=O>[C:18]([C:17]1[CH:20]=[CH:21][C:14]([S:3][C:4]2[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=2)[C:7]([OH:9])=[O:8])=[N:15][CH:16]=1)#[N:19]
Reactant: O=C(O)c1cccc(S)c1
Reactant: N#Cc1ccc(Cl)nc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Sc2cccc(C(=O)O)c2)nc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 67.6 %

Procedure:
Add sodium hydride (60% dispersion in mineral oil, 635 mg, 15.88 mmol) to a solution of 3-mercapto-benzoic acid (1.11 g, 7.22 mmol) in dimethylformamide (50 mL) chilled to 0° C. and stir. After 10 minutes add 6-chloro-nicotinonitrile (1.00 g, 7.22 mmol). Warm gradually to ambient temperature. After 18 hours, add 1N aqueous hydrochloric acid (200 mL). Filter resulting precipitate, washing with water and hexanes to yield the title compound as a tan solid (1.25 g, 68%): 1H NMR (DMSO-d6) δ 7.22 (d, 1H), 7.67 (t, 1H), 7.88 (dt, 1H), 8.07-8.12 (m, 3H), 8.82 (dd, 1H), 13.30 (bs, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][N:8]=2)[CH2:3][CH2:2]1.[CH2:16](Br)[CH:17]=[CH2:18].C(=O)(O)[O-].[Br-].[I-].[K+].[ClH:27]>CN(C)C=O.CCOCC>[ClH:27].[CH2:18]([N:1]1[CH2:2][CH2:3][CH:4]([C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][N:8]=2)[CH2:5][CH2:6]1)[CH:17]=[CH2:16]
Reactant: c1ccc2c(C3CCNCC3)noc2c1
Reactant: C=CCBr
Agent: Cl
Agent: O=C([O-])O
Agent: [Br-]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=CCN1CCC(c2noc3ccccc23)CC1
Reaction time: 20 h

Procedure:
A suspension of 4.0 g of 3-(4-piperidyl)-1,2-benzisoxazole, 2.6 g of allyl bromide, 5.0 g of bromide bicarbonate, and 3.0 g of potassium iodide in 90 ml of dimethylformamide was stirred at 80° for 20 hrs. The reaction was cooled, filtered and poured into 1 l of water. The mixture was extracted with ether (three times) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give an oil. The oil was dissolved in a small amount of ether into which hydrochloric acid was bubbled. The precipitate was recrystallized from ethanol-ether (three times) to give 2.4 g of product, mp, 174°-176°.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH: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:6](=[O:8])[N:7]=1.[OH:20][CH2:21][C@@H:22]([NH2:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C>>[OH:20][CH2:21][C@@H:22]([NH:30][C:3]1[S:4]/[C:5](=[CH: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:6](=[O:8])[N:7]=1)[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Reactant: N[C@H](CO)Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(N[C@H](CO)Cc2ccccc2)S/C1=C\c1ccc2ncccc2c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, (S)-1-hydroxymethyl-2-phenyl-ethylamine and DIEA to give 2-((S)-1-hydroxymethyl-2-phenyl-ethylamino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 390 (MH+).