Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+].[C:4](=[O:7])([O-])[OH:5].[Na+].[CH:9]1([C:12]2[S:50][C:15]3[N:16]([CH2:34][C:35]4[CH:40]=[CH:39][C:38]([C:41]5[C:42]([C:47]#[N:48])=[CH:43][CH:44]=[CH:45][CH:46]=5)=[CH:37][C:36]=4[F:49])[C:17](=[O:33])[N:18]([CH2:21][C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=4[O:31][CH3:32])=[O:23])[C:19](=[O:20])[C:14]=3[CH:13]=2)[CH2:11][CH2:10]1.[N:51]12CCCN=C1CCCCC2>C(Cl)(Cl)Cl.C(Cl)Cl.CS(C)=O>[CH:9]1([C:12]2[S:50][C:15]3[N:16]([CH2:34][C:35]4[CH:40]=[CH:39][C:38]([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=5[C:47]5[NH:51][C:4](=[O:7])[O:5][N:48]=5)=[CH:37][C:36]=4[F:49])[C:17](=[O:33])[N:18]([CH2:21][C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=4[O:31][CH3:32])=[O:23])[C:19](=[O:20])[C:14]=3[CH:13]=2)[CH2:11][CH2:10]1
Reactant: COc1cc(F)ccc1C(=O)Cn1c(=O)c2cc(C3CC3)sc2n(Cc2ccc(-c3ccccc3C#N)cc2F)c1=O
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [NH3+]O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1cc(F)ccc1C(=O)Cn1c(=O)c2cc(C3CC3)sc2n(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2F)c1=O
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
A mixture of hydroxylammonium chloride (0.36 g), sodium hydrogencarbonate (0.65 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[6-cyclopropyl-3-[2-(4-fluoro-2-methoxyphenyl)-2-oxoethyl]-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile (0.3 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue obtained by silica gel column chromatography was dissolved in methylene chloride (15 mL), N,N′-carbonyldiimidazole (0.1 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.085 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. To the obtained residue were added 25% sulfuric acid (5 mL) and 1-butanol (10 ml), and the mixture was stirred at 100° C. for 1 hr, and extracted with chloroform and water. The chloroform layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.14 g, 42%).
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:6]=1[C:7]([OH:9])=[O:8])([OH:3])=O.[C:15](OC(=O)C)(=O)C.N1C=CC=CC=1.[OH-].[Na+].Cl>O1CCCC1>[F:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:5]([CH2:4][C:1](=[O:3])[CH3:15])[C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=C(O)Cc1cccc(F)c1C(=O)O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)Cc1cccc(F)c1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 111.3 %

Procedure:
2-Carboxymethyl-6-fluoro-benzoic acid (11.16 g, 56.32 mmol) in acetic anhydride (65 mL, 690 mmol) was heated at 110° C. for 60 minutes. Pyridine (20 mL, 250 mmol) was added. Gas evolution was observed. The reaction mixture was refluxed overnight and rotovaped. The residue was dissolved in tetrahydrofuran (100 mL) and 4 M aq. NaOH (100 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was acidified with conc. HCl (aq). The two phases were separated and the aqueous phase was extracted with ethyl acetate (2×300 mL). The combined organic phases were washed with brine, dried over MgSO4 and rotavaped. 20 mL toluene was added and the mixture was rotovaped to give crude 2-Fluoro-6-(2-oxo-propyl)-benzoic acid (12.3 g, yield 55.7%, purity ca. 50%). The purity was estimated by 1H NMR and the crude product was used in the next step without further purification.
Reaction SMILES: [H-].[Na+].[CH2:3]([P:14](=[O:23])([O:19][CH:20]([CH3:22])[CH3:21])[O:15][CH:16]([CH3:18])[CH3:17])[P:4](=[O:13])([O:9][CH:10]([CH3:12])[CH3:11])[O:5][CH:6]([CH3:8])[CH3:7].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].O>O1CCCC1>[CH:20]([O:19][P:14]([O:15][CH:16]([CH3:18])[CH3:17])([CH:3]([P:4]([O:9][CH:10]([CH3:11])[CH3:12])([O:5][CH:6]([CH3:8])[CH3:7])=[O:13])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:23])([CH3:22])[CH3:21]
Reactant: CCOC(=O)CBr
Reactant: CC(C)OP(=O)(CP(=O)(OC(C)C)OC(C)C)OC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CC(P(=O)(OC(C)C)OC(C)C)P(=O)(OC(C)C)OC(C)C
Reaction time: 0.17 h
Yield: 27 %

Procedure:
Under a nitrogen atmosphere, 60% sodium hydride (0.132 g) was suspended in dry tetrahydrofuran (4 ml), and tetraisopropyl methylenebisphosphonate (1.1 g) was added dropwise thereto at room temperature. After stirring for 10 minutes, ethyl bromoacetate (0.354 ml) was added dropwise thereto and the resulting mixture was stirred at the same temperature for 1 hour. Water was added thereto, followed by extraction (twice) with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (methanol:methylene chloride=2:98) to obtain ethyl 3,3-bis(diisopropoxyphosphinoyl)propionate (0.37 g, yield 27%).
Reaction SMILES: C(O)C.Br[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([S:17][CH2:18][C:19]([F:22])([F:21])[F:20])[C:14]([Cl:23])=[CH:13][C:12]=1[F:24].[S-:25][C:26]#[N:27].[K+].CCCCCC>C(OCC)(=O)C>[S:25]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([S:17][CH2:18][C:19]([F:22])([F:21])[F:20])[C:14]([Cl:23])=[CH:13][C:12]=1[F:24])[C:26]#[N:27]
Reactant: Fc1cc(Cl)c(SCC(F)(F)F)cc1OCCCCCBr
Reactant: N#C[S-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCO
Product: N#CSCCCCCOc1cc(SCC(F)(F)F)c(Cl)cc1F
Temperature: 25 °C
Yield: 97.6 %

Procedure:
To 60 ml of ethanol were added 4.2 g (10.3 mmol) of 5-bromopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether and 5.0 g (51.5 mmol) of potassium thiocyanate. The mixture was refluxed for 4 hours under heating. The mixture was allowed to cool to room temperature, and the solvent was distilled off under reduced pressure. Then extraction was conducted by adding water and ethyl acetate. The organic phase obtained was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: a mixed solvent of n-hexane:ethyl acetate=10:1), to obtain 3.9 g (yield: 98%) of an intended product.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([N:5]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][O:13][C:7]=2[CH2:6]1)=[O:4].[CH3:16][NH:17][CH3:18].[CH2:19]=O>C(O)(=O)C>[CH3:16][N:17]([CH2:19][C:12]1[O:13][C:7]2[CH2:6][N:5]([C:3](=[O:4])[C:2]([F:1])([F:14])[F:15])[CH2:10][CH2:9][C:8]=2[CH:11]=1)[CH3:18]
Reactant: O=C(N1CCc2ccoc2C1)C(F)(F)F
Reactant: C=O
Reactant: CNC
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(o1)CN(C(=O)C(F)(F)F)CC2
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
To a solution of 0.722 g (3.294 mmol) of 6-trifluoroacetyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridine in 50 ml of acetic acid, 0.36 g (4.0 mmol) of 50% aqueous dimethylamine and 0.32 g (4.0 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 1.5 hours. After the solvent was distilled off under reduced pressure, the residue was diluted with water, gently poured into ice-cooled aqueous sodium hydrogen carbonate, and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=4/1) to yield the desired product.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:4]=[C:5]2[C:10]=1[CH:9]=[CH:8][C:7]([C:11]1[CH:12]=[C:13]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:14]3[C:19]=1[C:18]([NH2:20])=[N:17][CH:16]=[N:15]3)=[CH:6]2.ClC[C:36]([N:38]([CH3:40])[CH3:39])=[O:37]>>[NH2:20][C:18]1[C:19]2=[C:11]([C:7]3[CH:8]=[CH:9][C:10]4[C:5]([CH:6]=3)=[N:4][N:3]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:2]=4[NH2:1])[CH:12]=[C:13]([CH:21]3[CH2:26][CH2:25][N:24]([C:36]([N:38]([CH3:40])[CH3:39])=[O:37])[CH2:23][CH2:22]3)[N:14]2[N:15]=[CH:16][N:17]=1
Reactant: CN(C)C(=O)CCl
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4c(N)n(Cc5ccccc5)nc4c3)c12
Product: CN(C)C(=O)N1CCC(c2cc(-c3ccc4c(N)n(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Yield: 46 %

Procedure:
In a manner similar to the procedure described for Example 369 and using 5-(3-amino-2-benzyl-2H-indazol-6-yl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine and substituting dimethylcarbamyl chloride for 2-chloro-N,N-dimethylacetamide as starting materials, 40 mg (46%) of the desired product was isolated. 1H NMR (400 MHz, CD3OD) 8 ppm 7.82 (s, 1 H) 7.71 (d, 1 H) 7.23-7.37 (m, 6 H) 6.96 (d, 1 H) 6.57 (s, 1 H) 5.44 (s, 2 H) 3.79 (d, 2 H) 3.41 (dt, 1 H) 3.01 (d, 2 H) 2.86 (s, 6 H) 2.16 (d, 2 H) 1.77 (dt, 2 H). LC-MS [M+H]+=510.2, RT=2.21 min.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:26]=[CH:25][C:11]3/[C:12](=[CH:21]/[C:22](O)=[O:23])/[C:13]4[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=4[CH2:15][CH2:16][C:10]=3[CH:9]=2)[C:5]2[CH:27]=[C:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:29]=[C:30]([CH3:31])[C:4]=2[N:3]=1.[CH3:38][S:39]([NH2:42])(=[O:41])=[O:40].C1CCN2C(=NCCC2)CC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:26]=[CH:25][C:11]3/[C:12](=[CH:21]/[C:22]([NH:42][S:39]([CH3:38])(=[O:41])=[O:40])=[O:23])/[C:13]4[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=4[CH2:15][CH2:16][C:10]=3[CH:9]=2)[C:5]2[CH:27]=[C:28]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:29]=[C:30]([CH3:31])[C:4]=2[N:3]=1
Reactant: CS(N)(=O)=O
Reactant: Cc1cc(-c2ccccc2)cc2c1nc(C)n2Cc1ccc2c(c1)CCc1ccccc1/C2=C\C(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccccc2)cc2c1nc(C)n2Cc1ccc2c(c1)CCc1ccccc1/C2=C\C(=O)NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 55.2 %

Procedure:
(E)-[2-(2,4-Dimethyl-6-phenylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetic acid (50 mg, 0.10 mmol) obtained in Example 55 was dissolved in DMF (2 mL), and the mixture was cooled to 0° C. N,N′-carbonyldiimidazole (36 mg, 0.22 mmol) was added, and the mixture was stirred at room temperature for 2 hr. To this mixture were added methanesulfonamide (21 mg, 0.22 mmol) and DBU (21 mg, 0.22 mmol), and the mixture was stirred at 60° C. for 5 hr. 5% Aqueous citric acid solution was added to the mixture, and the precipitate was collected by filtration, and washed with water to give the title compound (compound 57) (31 mg, 55%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.[C:12](=O)([O-])[O-].[K+].[K+].CI.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([CH3:12])[C:6]=2[CH:11]=1
Reactant: O=c1[nH]c2cc(Br)ccc2o1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)oc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.8 %

Procedure:
Commercially available 5-bromobenzo[d]oxazol-2(3H)-one (1.00 g, 4.67 mmol) was dissolved in DMF (23 mL), and the mixture was stirred at room temperature for 30 minutes after adding potassium carbonate (3.87 g, 28.0 mmol) and methyl iodide (0.87 mL, 14.0 mmol). Water was added to the mixture, and the mixture was stirred. The precipitated solid was filtered off and dried to give 5-bromo-3-methylbenzo[d]oxazol-2(3H)-one (839 mg, 79%).
Reaction SMILES: C[O:2][C:3]1C=C(C=C[C:10]=1OCC1C=CC(OC)=CC=1)C=O.C[O-].[Na+].Cl.[NH:25]([CH:32]=[C:33]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=2)=[C:39]([O:53][CH3:54])[CH:38]=1)[C:34]#[N:35])[C:26]1C=CC=C[CH:27]=1>CS(C)=O.ClCCl.O>[CH3:54][O:53][C:39]1[CH:38]=[C:37]([CH:42]=[CH:41][C:40]=1[O:43][CH2:44][C:45]1[CH:46]=[CH:47][C:48]([O:51][CH3:52])=[CH:49][CH:50]=1)[CH2:36][C:33](=[CH:32][N:25]1[CH2:26][CH2:27][O:2][CH2:3][CH2:10]1)[C:34]#[N:35]
Reactant: COc1ccc(COc2ccc(CC(C#N)=CNc3ccccc3)cc2OC)cc1
Reactant: COc1ccc(COc2ccc(C=O)cc2OC)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(COc2ccc(CC(C#N)=CN3CCOCC3)cc2OC)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3-Methoxy-4-[(4-methoxybenzyl)oxy]benzaldehyde (20.0 g, 73.4 mmol) and 3-morpholinopropronitrile (Lancaster, 11.0 g, 77.1 mmol) were stirred in DMSO (15 mL) at 65 C until the mixture was homogeneous. The solution was cooled to 40 C and sodium methoxide (0.79 g, 14.7 mmol) was added. The mixture was stirred at 75 C for 15 minutes, then cooled to room temperature and diluted with dichloromethane (150 mL) and water (200 mL). 1N HCl (25 mL) was added and the two layers were seperated. The organics were combined and dried (magnesium sulfate), filtered and concentrated to a red oil (29.5 g, 73 mmol) that was used directly in the synthesis of 3-anilino-2-{3-methoxy-4-[(4-methoxybenzyl)oxy]benzyl}prop-2-enenitrile. 1H NMR (300 MHz, d6-DMSO): δ 7.38 (d, 2H), 7.03-6.95 (m,3H), 6.84 (t, J=13.5 Hz, 2H), 6.73 (d, J=8.2 Hz, 1H), 4.98 (s, 3H), 3.78 (s, 3H), 3.76 (s, 3H), 3.66-3.60 (m, 2H), 3.55-3.50 (m, 3H), 3.46-3.43 (m, 2H), 3.36 (s, 1H), 3.33-3.29 (m, 2H). MS (ES+, m/z)=395 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[CH:3]=1.[Cl:9][CH2:10][CH2:11][N:12]=[C:13]=[O:14]>C1(C)C=CC=CC=1>[Cl:9][CH2:10][CH2:11][NH:12][C:13]([NH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[CH:3]=1)=[O:14]
Reactant: Nc1ccnc(Cl)c1
Reactant: O=C=NCCCl
Solvent: Cc1ccccc1
Product: O=C(NCCCl)Nc1ccnc(Cl)c1
Yield: 60.4 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 1 above, 4-amino-2-chloro pyridine (3.0 g, 23.33 mmol) in toluene (30 mL) was reacted with 1-chloro-2-isocyanatoethane (3.69 g, 350 mmol) and purified by column chromatography on silica gel (1.5% methanol in DCM) to afford 3.3 g of the product (61% yield).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[N:17]3[C:12]([C:13]([NH2:18])=[N:14][CH:15]=[N:16]3)=[C:11]([C:19]3[CH:20]=[CH:21][C:22]4[C:26]([CH:27]=3)=[N:25][N:24]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:23]=4)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[C:35]1(=O)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH2:28]([N:24]1[CH:23]=[C:22]2[C:26]([CH:27]=[C:19]([C:11]3[CH:10]=[C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][NH:1][CH:35]5[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]5)[CH:4]=4)[N:17]4[C:12]=3[C:13]([NH2:18])=[N:14][CH:15]=[N:16]4)[CH:20]=[CH:21]2)=[N:25]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NCc1cccc(-c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)c1
Reactant: O=C1CCCCC1
Product: Nc1ncnn2c(-c3cccc(CNC4CCCCC4)c3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Yield: 11 %

Procedure:
Using a procedure similar to that of Example 111 with 7-(3-aminomethyl-phenyl)-5-(2-benzyl-2H-indazol-6-yl)-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine and cyclohexanone as starting materials, 40 mg (11%) of the desired product was isolated. 1H NMR (300 MHz, DMSO-d6) δ 8.80 (s, 1 H), 8.05 (d, 2 H), 8.0 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 7.25 (d, 1 H), 7.20 (s, 1 H), 5.70 (s, 2 H), 3.80 (m, 2 H), 3.60 (t, 1 H), 1.90 (m, 4 H), 1.70 (m, 2 H), 1.10 (m, 4 H); ES-MS m/z 528.18 [M+H]+, HPLC RT (min) 2.51.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH3:12][C:13]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:14]=1[CH2:15]Cl.O>CS(C)=O>[CH3:12][C:13]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:14]=1[CH2:15][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: Cc1cc(C)c(CCl)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(C)c(Cn2ccc3ccccc32)c(C)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 87.2 %

Procedure:
A solution of indole (1.185 g) in dry DMSO (3 ml) is dropped into a suspension of sodium hydride (60% suspension in mineral oil; 0.44 g) in dry DMSO (10 ml). After two hours, the resulting solution is added with a solution of 2,4,6-trimethylbenzyl chloride (1.9 g) in dry DMSO (2 ml) and the reaction mixture is heated at 60° C. for 6 h. After a night at room temperature, the reaction mixture is poured into water (250 ml) and extracted with ethyl acetate, then dried (Na2SO4) The drying agent is filtered off and the solvent is evaporated off under reduced pressure. The resulting residue is purified by column chromatography (silica gel; eluent n-hexane/AcOEt 9/1), to obtain 2.2 g of 1-(2,4,6-trimethylbenzyl)indole.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9](=[O:12])[CH2:10][CH3:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:13](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.C(OCC)(=O)C>O>[CH3:13][O:1][N:2]=[C:3]([C:9](=[O:12])[CH2:10][CH3:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C(=NO)C(=O)CC
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=NOC)C(=O)CC
Temperature: 25 °C
Yield: 127.1 %

Procedure:
A mixture of ethyl 2-hydroxyimino-2-propionylacetate (10.7 g.), potassium carbonate (9.8 g.), dimethyl sulfate (7.79 g.) and ethyl acetate (70 ml.) was stirred at room temperature for an hour. Water (50 ml.) was added to the reaction mixture and stirred for 20 minutes. The ethyl acetate layer was separated, washed with water (50 ml.) twice and with an aqueous solution of sodium chloride, dried over magnesium sulfate and then filtered. The filtrate was evaporated in vacuo to give ethyl 2-methoxyimino-2-propionylacetate (14.7 g.).
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([CH:21]=1)[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)=[O:8].[BrH:24].N([O-])=O.[Na+].[C:29]([O:33][CH3:34])(=[O:32])[CH:30]=[CH2:31]>CC(C)=O.CO>[Br:24][CH:30]([CH2:31][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([C:7](=[O:8])[NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH:21]=1)[C:29]([O:33][CH3:34])=[O:32]
Reactant: C=CC(=O)OC
Reactant: COc1ccc(N)cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)=O
Product: COC(=O)C(Br)Cc1ccc(OC)c(C(=O)NCc2ccc(C(F)(F)F)cc2)c1
Temperature: 30 °C
Reaction time: 0.17 h

Procedure:
To a solution of 17.3 g of 5-amino-2-methoxy-N-(4-trifluoromethylbenzyl)benzamide in 170 ml of acetone and 85 ml of methanol were added 43 ml of 47% solution of hydrobromic acid and 17 ml of aqueous solution of 4.15 g of sodium nitrite under cooling with ice-salt, and the mixture was stirred for 10 minutes. To the reaction mixture were added 26 ml of methyl acrylate, and, after heated to 30° C., 1.04 g of cupric oxide were added little by little, and the mixture was stirred further for 1 hour at 40 to 50° C. Solvent was distilled off under reduced pressure, and 25% aqueous ammonia was added to the residue, which was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in sequence and dried over anhydrous sodium sulfate. Solvent was distilled off under reduced pressure, and the residue obtained was crystallized from hexane-ethyl acetate, then the crystals were collected by filtration to obtain 10.3 g of methyl 2-bromo-3-[4-methoxy-3-[N-(4-trifluoromethylbenzyl)]carbamoylphenyl]-propionate as light brown crystals.
Reaction SMILES: [C:1]([N:3]=[S:4]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH2:14])=C[CH:8]=1)([CH3:6])=[O:5])#[N:2].C(N=S(C1C=CC(N2C(=O)C3C(=CC=CC=3)C2=O)=NC=1)(C)=O)#[N:16]>>[C:1]([N:3]=[S:4]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH2:14])=[N:16][CH:8]=1)([CH3:6])=[O:5])#[N:2]
Reactant: CS(=O)(=NC#N)c1ccc(CN)cc1
Reactant: CS(=O)(=NC#N)c1ccc(N2C(=O)c3ccccc3C2=O)nc1
Product: CS(=O)(=NC#N)c1ccc(CN)nc1

Procedure:
The title compound is prepared in analogy to preparation 6d, substituting 2-(4-(N-cyano-S-methylsulfonimidoyl)benzyl)isoindoline-1,3-dione with 2-(5-(N-cyano-S-methylsulfonimidoyl)pyridin-2-yl)-isoindole-1,3-dione (preparation 16d). ESI mass spectrum: [M+H]+=211; r.t. HPLC: 0.23 min (Z011_S03).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:16])[C:8]([CH2:14][CH3:15])=[C:9]([C:12]#[N:13])[C:10]=1I)=[O:5])[CH3:2].[Br:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>C(Cl)Cl.O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:16])[C:8]([CH2:14][CH3:15])=[C:9]([C:12]#[N:13])[C:10]=1[C:21]1[CH:22]=[CH:23][C:18]([Br:17])=[CH:19][CH:20]=1)=[O:5])[CH3:2]
Reactant: OB(O)c1ccc(Br)cc1
Reactant: CCOC(=O)c1c(I)c(C#N)c(CC)n1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(=O)c1c(-c2ccc(Br)cc2)c(C#N)c(CC)n1C
Temperature: 80 °C
Yield: 78.9 %

Procedure:
A mixture of 4-cyano-5-ethyl-3-iodo-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (2.0 g, 6.0 mmol, prepared in preparation 38), 4-bromophenyl boronic acid (1.32 g, 6.6 mmol), 10 mL of Na2CO3 (2M) and 20 mL of dioxane is degassed under reduced pressure (−29 inches) for 30 minutes till no bubbles. Recharge with nitrogen. Add PdCl2 (PPh)4 (0.24 mmol). Well seal the flask and heat the mixture at 80° C. overnight. After cooling, water and methylene chloride are added to the reaction mixture. It is then extracted with methylene chloride. The organic layers are combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by flash chromatography to provide the title compound (1.71 g, 78%). MS(ES, m/e) 361.1(M+1), 380.1(M+18). Rf=0.35 (50% ether in hexanes).
Reaction SMILES: C([O:4][CH:5]([CH:9]([O:32]C(=O)C)[C:10]([NH:12][CH2:13][C:14]1[CH:27]=[CH:26][C:25]2[O:24][C:23]3[C:18]4=[C:19]([C:28](=[O:31])[NH:29][N:30]=[C:17]4[C:16]=2[CH:15]=1)[CH:20]=[CH:21][CH:22]=3)=[O:11])[C:6]([OH:8])=[O:7])(=O)C.[OH-].[Na+]>O.O1CCOCC1>[OH:4][CH:5]([CH:9]([OH:32])[C:10]([NH:12][CH2:13][C:14]1[CH:27]=[CH:26][C:25]2[O:24][C:23]3[C:18]4=[C:19]([C:28](=[O:31])[NH:29][N:30]=[C:17]4[C:16]=2[CH:15]=1)[CH:20]=[CH:21][CH:22]=3)=[O:11])[C:6]([OH:8])=[O:7]
Reactant: CC(=O)OC(C(=O)O)C(OC(C)=O)C(=O)NCc1ccc2c(c1)-c1n[nH]c(=O)c3cccc(c13)O2
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)C(O)C(O)C(=O)NCc1ccc2c(c1)-c1n[nH]c(=O)c3cccc(c13)O2
Temperature: 40 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
Compound 51 was dissolved in a solution of NaOH (2.5 equivalent) in H2O/Dioxane. The reaction mixture was stirred overnight at 40° C., then was acidified to pH=3. Aqueous layer was extracted with ethyl acetate. Organic layer was dried with MgSO4. Solvent was removed in vacuo to afford a white solid 52 in 25% yield. MS: (ES+): 398; Mp: 181-185° C.; 1H-NMR (DMSO-d6, 400 MHz): 12.54 (s, 1H), 8.32 (t, J=6.2 Hz, 1H), 7.93 (d, J=2.0 Hz, 1H), 7.90-7.80 (m, 2H), 7.62 (dd, J=7.5 and 2.0 Hz, 1H), 7.40 (dd, J=8.5 and 2.0 Hz, 1H), 7.25 (d, J=8.5 Hz, 1H), 4.30-4.19 (m, 4H); Anal. Calcd for C19H15N3O7.(3H2O): C, 50.56; H, 4.69; N, 9.31. Found: C, 50.59; H, 4.07; N, 9.28.