Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[C:9]2[C:17]3[C:12](=[CH:13][C:14](/[CH:18]=[C:19]4/[C:20](=[O:28])[NH:21][C:22]5[C:27]/4=[CH:26][CH:25]=[CH:24][CH:23]=5)=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[CH:3][CH:2]=1.[CH3:29][O:30]C1C=C2C(=CC=1)NC(=O)C2>>[CH3:29][O:30][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:28])/[C:19]/2=[CH:18]/[C:14]1[CH:13]=[C:12]2[C:17]([C:9](/[CH:8]=[CH:7]/[C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[N:10][NH:11]2)=[CH:16][CH:15]=1
Reactant: O=C1Nc2ccccc2/C1=C\c1ccc2c(/C=C/c3ccncc3)n[nH]c2c1
Reactant: COc1ccc2c(c1)CC(=O)N2
Product: COc1ccc2c(c1)/C(=C\c1ccc3c(/C=C/c4ccncc4)n[nH]c3c1)C(=O)N2
Yield: 51 %

Procedure:
According to procedure for the synthesis of (E)-3-((3-((E)-2-(pyridin-4-yl)vinyl)-1H-indazol-6-yl)methylene)indolin-2-one, except substituting 5-methoxyoxindole (11 mg, 0.068 mmol) to give the title compound as an orange solid (13.6 mg, 51%). 1H NMR (400 MHz, d6-DMSO) δ 13.58 (br s, 1H), 10.45 (br s, 1H), 8.57 (d, J=6.0 Hz, 2H), 8.37 (d, J=8.5 Hz, 1H), 7.93 (s, 1H), 7.87 (d, J=16.6 Hz, 1H), 7.79 (s, 1H), 7.71 (d, J=6.0 Hz, 2H), 7.57 (d, J=2.3 Hz, 1H), 7.54 (d, J=6.3 Hz, 1H), 7.18 (d, J=10.0 Hz, 1H), 6.86 (dd, J=8.8, 2.5 Hz, 1H) 6.80 (d, J=8.3 Hz, 1H), 3.6 (s, 3H); MS ESI 395.2 [M+H]+, calcd for [C24H18N4O2+H]+ 395.14.
Reaction SMILES: [Br-].[C:2]1([S+: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)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27]([OH:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1>O>[S:27]([C:24]1[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=1)([O-:30])(=[O:29])=[O:28].[C:15]1([S+:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Br-]
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 25 °C

Procedure:
A solution of triphenylsulfonium bromide (6.87 g, 20.0 mmol) and p-toluenesulfonic acid (3.80 g, 20.0 mmol) in water (100 ml) was heated at a gentle reflux for 15 hours under nitrogen. After cooling to room temperature, the clear solution was extracted with dichloromethane (4×75 ml). The combined organic extracts were washed with water until neutral (4×75 ml) and dried (MgSO4 ). The solvent was removed under reduced pressure and the residue dried by heating at 80° C. in vacuo for 36 hours to give a crude onium salt as a off-white solid (6.35 g). Recrystallization from acetone-ethyl acetate gave triphenylsulfonium rosylate as a white crystalline solid (5.72 g, 66%).
Reaction SMILES: [C:1]1([CH:7]2[S:18][CH:10]3[S:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[N:9]3[C:8]2=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:20]1[CH2:27][CH2:26][CH2:25][C@H:21]1[C:22]([OH:24])=[O:23].C(N(CC)CC)C>C(Cl)Cl>[S:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:9]=[C:10]1[S:18][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]([N:20]1[CH2:27][CH2:26][CH2:25][C@H:21]1[C:22]([OH:24])=[O:23])=[O:19]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=C1C(c2ccccc2)SC2Sc3ccccc3N12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)[C@@H]1CCCN1C(=O)C(Sc1nc2ccccc2s1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
5.7 g (0.02 m) 2-phenylthiazolo[2,3-b]benzothiazol-3(2H)-one mesoionic didehydro derivative, 2.2 g (0.02 m)-L-(-)-proline and 2.0 g (0.02 m) triethylamine are suspended in methylene chloride and the mixture is stirred at room temperature overnight. The reaction mixture is extracted with a dilute hydrochloric acid solution and dried over anhydrous magnesium sulfate. After the solvent is removed, the residue is extracted with hot cyclohexane. The solid obtained from the cyclohexane solution is recrystallized from acetonitrile. In order to remove all traces of acetonitrile, the solid is ground, stirred in water for 3 days, collected and then dried in an oven at 90° C. There is thereby obtained 3.0 g (37% yield) of the title compound, which has a melting point of 174°-5° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.N[C:17]1[CH:18]=[C:19]([CH2:23][C:24]#[N:25])[CH:20]=[CH:21][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][C:11]([C:13]([C:17]3[CH:18]=[C:19]([CH2:23][C:24]#[N:25])[CH:20]=[CH:21][CH:22]=3)=[O:15])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#CCc1cccc(N)c1
Reactant: O=C(O)c1ccc(-c2cccc(Cl)c2)o1
Product: N#CCc1cccc(C(=O)c2ccc(-c3cccc(Cl)c3)o2)c1

Procedure:
Carboxylic acid (65) (127 mg, 0.57 mmol) was coupled to aniline (80) (75 mg, 0.57 mmol) using Method C. The crude residue was purified by column chromatography eluting with 17% EtOAc in heptane to give the title compound.
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[CH:20][C:21]([NH2:24])=[N:22][CH:23]=2)[CH2:14][CH2:13]1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:8][C:6]1[CH:7]=[C:2]([NH:24][C:21]2[CH:20]=[CH:19][C:18]([N:15]3[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]3)=[CH:23][N:22]=2)[C:3](=[O:10])[N:4]([CH3:9])[N:5]=1
Reactant: CN1CCN(c2ccc(N)nc2)CC1
Reactant: Cn1nc(Cl)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CN1CCN(c2ccc(Nc3cc(Cl)nn(C)c3=O)nc2)CC1
Yield: 53.5 %

Procedure:
Following Example 119b, 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (1.5 g, 6.7 mmol), 5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamine (1.3 g, 6.7 mmol), cesium carbonate (4.8 g, 39.4 mmol), and Xantphos (330 mg, 8.5 mol %), dioxane (50 ml) and tris(dibenzylideneacetone)dipalladium(0) (307 mg, 5 mol %) were reacted. Purified via column chromatography: ISCO 40 g silica, 50-100% ethyl acetate/hexanes then 0-10% methanol to give 307a (1.2 g, 53%) as a light tan solid.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[CH2:19][CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:33][C:34]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:35]=1[CH2:36]Br.CCCCCC.C(OCC)(=O)C>C1COCC1>[C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:36][C:35]2[CH:38]=[CH:39][C:40]([F:42])=[CH:41][C:34]=2[F:33])[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CCC(=O)O1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1C[C@@H](Cc2ccc(F)cc2F)C(=O)O1
Temperature: -60 °C

Procedure:
In analogy with Example 1h), 5.0 g (16.37 mmol) of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]dihydrofuran-2-(3H)-one [Example 2b)] dissolved in 100 ml of THF are deprotonated, at -75° C., with 32.7 ml of a 1 M solution of lithium bis(trimethylsilyl)amide in THF, and alkylated with 2.51 ml (19.6 mmol) of 2,4-difluorobenzyl bromide (Aldrich; Milwaukee/USA) at -75° C. initially (heating to a maximum of -60° C. over a period of 2 h). Column chromatography (SiO2, hexane/ethyl acetate, 2:1) affords the title compound: TLC Rf (D)=0.5; tRet (II)=17.2 min.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][NH:13][C:12](=[N:15][CH2:16][CH:17](O)[CH2:18][C:19]([F:22])([F:21])[F:20])[C@@H:11]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:10]1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(=O)(O)[O-].[Na+].O>C(#N)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][N:13]2[C:17]([CH2:18][C:19]([F:22])([F:21])[F:20])=[CH:16][N:15]=[C:12]2[C@@H:11]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](c2cccc(F)c2F)CNC1=NCC(O)CC(F)(F)F
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)cnc21
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 62.4 %

Procedure:
To a solution of crude tert-butyl {(3S,5S)-5-(2,3-difluorophenyl)-2-[(4,4,4-trifluoro-2-hydroxybutyl)imino]piperidin-3-yl}carbamate (99.0 mg, 0.219 mmol) in acetonitrile (2.19 mL) was added pyridinium dichromate (247 mg, 0.657 mmol), and the mixture was stirred 2.5 h at 60° C. Pyridinium dichromate (392 mg, 1.04 mmol) was added and the resulting mixture stirred 72 h at 60° C. Pyridinium dichromate (300 mg, 0.797 mmol) was added and the resulting mixture stirred 4 h at 60° C. The mixture was cooled to ambient temperature and saturated aqueous sodium bicarbonate was added. Water was added, and the mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by reverse phase chromatography (C-18, 95% water/acetonitrile→15% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (59 mg). MS 432.2 (M+1).
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:34])[N:18]([C:25]1([CH3:33])[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[CH2:35]([N:37]=[C:38]=[O:39])[CH3:36]>C(#N)C>[CH2:35]([NH:37][C:38]([NH:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:34])[N:18]([C:25]1([CH3:33])[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24])=[O:39])[CH3:36]
Reactant: CC1(N2C(=O)c3cccc(CN)c3C2=O)CCC(=O)NC1=O
Reactant: CCN=C=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCNC(=O)NCc1cccc2c1C(=O)N(C1(C)CCC(=O)NC1=O)C2=O
Reaction time: 0.5 h
Yield: 53.7 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.2 g, 2.2 mmol) was added to a stirred suspension of 4-aminomethyl-2-(3-methyl-2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.3 g, 1.0 mmol) in acetonitrile (40 mL). After stirring for 30 minutes, ethyl isocyanate (0.09 g, 1.3 mmol) was added, and the mixture was stirred at room temperature for 24 hours. The mixture was concentrated and the residue was dissolved in methylene chloride (60 mL). The methylene chloride solution was washed with water (2×30 mL) and brine (30 mL), and dried (MgSO4). Solvent was removed and purified by chromatography (silica gel) to give 1-ethyl-3-[2-(3-methyl-2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-urea (0.2 g, 55%) as a white solid: mp 220-222° C.; 1H NMR (DMSO-d6) δ 0.99 (t, J=7.1 Hz, 3H, CH3), 1.90 (s, 3H, CH3), 2.03-2.09 (m, 1H), 2.50-2.74 (m, 3H), 2.97-3.07 (m, 2H), 4.59 (d, J=5.8 Hz, 2H), 6.09 (t, J=5.0 Hz, 1H), 6.41 (t, J=5.6 Hz, 1H), 7.65-7.82 (e, 3H, Ar), 11.01 (s, 1H, NH); 13C NMR (DMSO-d6) δ 15.59, 21.01, 28.58, 29.11, 34.16, 38.65, 58.69, 121.25, 126.64, 131.37, 133.26, 134.46, 140.79, 157.92, 167.78, 168.41, 172.14, 172.22; Anal. calcd. for C18H20N4O5+0.08H2O: C, 57.83; H, 5.44; N, 14.99. Found: C, 57.26; H, 5.21; N, 14.79.
Reaction SMILES: [C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH:13]=O)=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:20]([O:30][CH3:31])[CH:19]=1>>[C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH2:13][NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[C:20]([O:30][CH3:31])[CH:19]=3)=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1
Reactant: COc1cc(N)ccc1-c1ccccc1
Product: COc1cc(NCc2cncn2Cc2ccc(C#N)cc2)ccc1-c1ccccc1

Procedure:
The titled compound was prepared from the product of Step 5 and 1-amino-3-methoxy-4-phenylbenzene using the procedure described in Step 3 of Example 1.
Reaction SMILES: C([NH:8][C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])(OC(C)(C)C)=O.C1(N=C=NC2CCCCC2)CCCCC1.[C:31](=[N:34]O)([NH2:33])[CH3:32]>ClCCl.N1C=CC=CC=1>[NH2:8][C@H:9]([C:13]1[O:15][N:34]=[C:31]([CH3:32])[N:33]=1)[CH:10]([CH3:11])[CH3:12]
Reactant: CC(N)=NO
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1noc([C@@H](N)C(C)C)n1

Procedure:
A solution of BOC-L-valine (4.34 g, 20.0 mmol) in dichloromethane (20 mL) was cooled to 0° C. and treated dropwise with a solution of dicyclohexylcarbodiimide (2.06 g, 10.0 mmol) in dichloromethane (5 mL). After 1 hour the white solid which had formed was removed by filtration and the filtrate concentrated under reduced pressure. The residue was dissolved in pyridine (15 mL) and treated with acetamidoxime (488 mg, 6.6 mmol) in pyridine (5 mL) and the mixture heated at reflux for 1 hour. The pyridine was evaporated under reduced pressure and the residue partitioned between ethyl acetate and water. The organic phase was washed several times with water, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel using 10% ethyl acetate in hexanes to elute the product (0.62 g, 25%) as a white solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:27]=[CH:26][C:8]([CH2:9][C@H:10]2[CH2:15][C@@H:14]([C:16]3[O:20][NH:19][C:18](=[O:21])[CH:17]=3)[CH2:13][CH2:12][N:11]2C(OC)=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br>>[CH3:1][S:2]([C:5]1[CH:27]=[CH:26][C:8]([CH2:9][C@H:10]2[CH2:15][C@@H:14]([C:16]3[O:20][NH:19][C:18](=[O:21])[CH:17]=3)[CH2:13][CH2:12][NH:11]2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccc(S(C)(=O)=O)cc1
Agent: Br
Product: CS(=O)(=O)c1ccc(C[C@H]2C[C@@H](c3cc(=O)[nH]o3)CCN2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
(2R,4S)-Methyl 2-(4-(methylsulfonyl)benzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (231 mg, 0.59 mmol) was dissolved in HBr (33% in acetic acid, 5 mL, 28.55 mmol) and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2R,4S)-2-(4-(methylsulfonyl)benzyl)piperidin-4-yl)isoxazol-3(2H)-one (171 mg, 87%). 1H NMR (600 MHz, dmso) δ 1.06-1.15 (m, 1H), 1.30-1.39 (m, 1H), 1.76 (d, 2H), 2.43-2.56 (omitted signals), 2.62-2.81 (m, 4H), 2.95-3.00 (m, 1H), 3.16 (s, 3H), 5.68 (s, 1H), 7.46 (d, 2H), 7.80 (d, 2H). HRMS Calcd for [C16H20N2O4S+H]+: 337.1222. Found: 337.1198
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:13][O:14][C:15](=[O:18])[CH2:16][NH2:17].C(N(CC)CC)C.O>CS(C)=O>[CH3:13][O:14][C:15](=[O:18])[CH2:16][NH:17][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1F
Reactant: COC(=O)CN
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)CNc1cc([N+](=O)[O-])ccc1C#N
Yield: 97.8 %

Procedure:
A solution of 2-fluoro-4-nitro-benzonitrile (16.6 g, 0.1 mol), glycine methyl ester (16 g, 0.125 mol, 1.25 eq.) and triethylamine (20 g, 0.2 mol) in DMSO (250 mL) was stirred at 70° C. for 12 hours. Water (2 L) was added and the solid precipitate was collected by filtration. Washed with ether and dried to give (2-cyano-5-nitro-phenylamino)-acetic acid methyl ester (23 g, 97.8 mmol, 98%): 1H NMR (300 MHz, CDCl3) δ 7.61 (dd, 2H), 7.40 (d, 1H), 4.10 (d, 2H), 3.87 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][C:33](Cl)=[O:34].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][C:33]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:23][CH:24]=1)=[O:34]
Reactant: O=C(Cl)Cc1ccccc1Cl
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1Cl)Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 38.5 %

Procedure:
A mixture of 0.471 g (1.5 mmol) of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine, 0.340 g (1.8 mmol) of 2-chlorophenylacetyl chloride, 0.20 g of triethylamine and 9 mg of 4-(dimethylamino)pyridine in 10 ml of dichloromethane is stirred at room temperature for 48 hours. An additional 0.27 g of 2-chlorophenylacetyl chloride is added and the mixture stirred at room temperature for 2,5 hr. The mixture is washed with 1N HCl, H2O, 1M NaHCO3, brine and dried (Na2SO4). The solvent is removed and the solid recrystallized from dichloromethane to give 0.27 g of crystals, m.p. 191°-194° C. Anal. Calc'd for C29H23ClN2 O2 : C,74.6; H,5.0; N,6.0; Cl,7.6. Found: C,74.4; H,4.9; N,5.9; Cl,7.8.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH2:11]Br)=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[N:7]=1)=[O:5])[CH3:2].[CH:27]([NH2:30])([CH3:29])[CH3:28].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH2:11][NH:30][CH:27]([CH3:29])[CH3:28])=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1CBr
Reactant: CC(C)N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1CNC(C)C
Temperature: 25 °C
Reaction time: 17 h
Yield: 21 %

Procedure:
A mixture of 4-bromomethyl-1-(2-chloro-phenyl)-5-(4-chloro-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester I-4b (200 mg, 0.44 mmol), isopropyl amine (26 mg, 0.44 mmol), K2CO3 (182 mg, 1.32 mmol) in CH3CN (5 ml) was stirred for 17 hours at room temperature. The reaction mixture was filtered to remove insoluble material and concentrated under vacuum. The residue was diluted with EtOAc and the organic solution was washed with H2O and sat'd aq. NaCl, dried, and concentrated in vacua. The crude residue was purified on SiO2-gel chromatography using a solvent gradient of 20% EtOAc/hexanes to 75% EtOAc/hexanes to give the product (I-4c) as an amorphous solid (40 mg, 21%): +APCI MS (M+1) 432.2.
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6][O:7][C:8]1[C:9]([CH2:31][CH2:32][CH3:33])=[C:10]([CH:18]=[CH:19][C:20]=1[C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH3:29])[O:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[N:17]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.CCCCCC>[CH3:6][O:7][C:8]1[C:9]([CH2:31][CH2:32][CH3:33])=[C:10]([CH:18]=[CH:19][C:20]=1[C:21]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH3:29])=[CH2:1])[O:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[N:17]
Reactant: CCCc1c(OCCCCC#N)ccc(C(=O)c2ccccc2OC)c1OC
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=C(c1ccccc1OC)c1ccc(OCCCCC#N)c(CCC)c1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 0.56 g of methyltriphenylphosphonium bromide in 10 ml of dry tetrahydrofuran were added 0.88 ml of a 1.6 molar n-butyllithium solution in hexane. After stirring for 3 hours under a nitrogen atmosphere, 0.5 g of 5-[3-methoxy-4-(2-methoxybenzoyl)-2-propylphenoxy]pentanenitrile were added in 5 ml of tetrahydrofuran. The reaction was stirred for 40 hours at 25° C. and then at 65° C. for 24 hours. After cooling to room temperature, the reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was purified by preparative thin layer chromatography using a solvent system of 10% ethyl acetate in hexane. The appropriate band was isolated, extracted with ethyl acetate, dried over sodium sulfate, and evaporated in vacuo providing 50 mg of the desired title product as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[CH3:10][NH:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][N:11]([CH3:12])[CH3:10])=[CH:6][CH:7]=1
Reactant: CNC
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CN(C)Cc1ccc(Cl)nc1

Procedure:
2-Chloro-5-(chloromethyl)pyridine (500 mg) was dissolved in ethanol (7.0 ml). dimethylamine (0.83 ml, 33% in ethanol) and potassium carbonate (641 mg) were added and the resulting mixture was refluxed for 1.5 hours. After evaboration of ethanol, water was added and the aqueous mixture was extracted with ethyl acetate. 1H NMR (400 MHz, d6-DMSO) δ: 8.31 (d, 1H, J 2.3 Hz), 7.77 (dd, 1H, J 8.2, 2.3 Hz), 7.47 (d, 1H, J 8.2 Hz), 3.41 (s, 2H), 2.14 (s, 6H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([F:30])([F:29])[F:28]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH:14]2[CH2:15][CH2:16][N:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])[CH2:18][CH2:19]2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)C2CCNCC2)cc1
Reactant: FC(F)(F)c1ccccc1Br
Product: CC(C)(C)c1ccc(S(=O)(=O)C2CCN(c3ccccc3C(F)(F)F)CC2)cc1
Yield: 17 %

Procedure:
Using the procedure from Example 7A, 4-[(4-tert-butylphenyl)sulfonyl]piperidine (100 mg, 0.36 mmol) was reacted with 2-bromobenzotrifluoride (59 μl, 0.43 mmol) to afford the title compound (26 mg), a white solid, in 17% yield.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH:22]=O)=[CH:14][CH:13]=2)[CH2:4][CH2:3]1.[CH3:24][C:25]1[CH:26]=[C:27]([NH2:32])[C:28]([NH2:31])=[CH:29][CH:30]=1>>[CH3:24][C:25]1[CH:30]=[CH:29][C:28]2[NH:31][C:22]([C:15]3[C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:12]([O:11][CH2:10][CH2:9][CH2:8][N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:13][CH:14]=3)=[N:32][C:27]=2[CH:26]=1
Reactant: CN1CCN(CCCOc2ccc(C=O)c3ccccc23)CC1
Reactant: Cc1ccc(N)c(N)c1
Product: Cc1ccc2[nH]c(-c3ccc(OCCCN4CCN(C)CC4)c4ccccc34)nc2c1

Procedure:
This compound was prepared by the method described in Example 1, using 4-[3-(4-methyl-piperazin-1-yl)-propoxy]-naphthalene-1-carbaldehyde (63 mg, 0.20 mmol, 1.0 equiv), 4-methyl-benzene-1,2-diamine (24 mg, 0.20 mmol, 1.0 equiv), and Na2S2O5 (49 mg, 0.26 mmol, 1.3 equiv) in General Procedure 3. The desired product was isolated from the reaction mixture using Method 1 and was subsequently re-purified by Method 2 to afford 54.6 mg (66%) of the title compound. MS (electrospray): mass calculated for C26H30N4O, 414.24; m/z found, 415.62 [M+H]+. 1H NMR (400 MHz, CD3OD): 8.48 (d, J=8.0 Hz, 1H), 8.10 (d, J=8.4 Hz, 1H), 8.0 (d, J=8.2 Hz, 1H), 7.78-7.65 (m, 4H), 7.50 (d, J=8.4 Hz, 1H), 7.21 (d, J=8.2 Hz, 1H), 4.43 (t, J=6.0 Hz, 2H), 3.40 (br s, 4H), 3.30-3.00 (m, 6H), 2.88 (s, 3H), 2.59 (s, 3H), 2.36-2.30 (m, 2H).
Reaction SMILES: [CH2:1]1[CH:8]([NH2:9])[C:6](=[O:7])[NH:5][C:3](=[O:4])[CH2:2]1.Cl.Br[CH2:12][C:13]1[C:22]([F:23])=[C:21]([F:24])[C:20]([F:25])=[C:19]([F:26])[C:14]=1[C:15](OC)=[O:16].C(N(CC)CC)C>CN(C)C=O>[O:16]=[C:15]1[C:14]2[C:13](=[C:22]([F:23])[C:21]([F:24])=[C:20]([F:25])[C:19]=2[F:26])[CH2:12][N:9]1[CH:8]1[CH2:1][CH2:2][C:3](=[O:4])[NH:5][C:6]1=[O:7]
Reactant: COC(=O)c1c(F)c(F)c(F)c(F)c1CBr
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CCC(N2Cc3c(F)c(F)c(F)c(F)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 16.25 g of 2,6-dioxopiperidin-3-ammonium chloride, and 30.1 g of methyl 2-bromomethyl-3,4,5,6-tetrafluorobenzoate, and 12.5 g of triethylamine in 100 mL of dimethylformamide is stirred at room temperature for 15 hours. The mixture is then concentrated in vacuo and the residue mixed with methylene chloride and water. The aqueous layer is separated and back-extracted with methylene chloride. The combined methylene chloride solutions are dried over magnesium sulfate and concentrated in vacuo to give 1-oxo-2-(2,6-dioxopiperidin-3-yl)-4,5,6,7-tetrafluoroisoindoline.