Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16](OS(C)(=O)=O)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K].[NH:24]1[CH:28]=[N:27][C-:26]=[N:25]1.O>CN(C)C=O>[CH:1]([N:14]1[CH2:17][CH:16]([N:24]2[CH:28]=[N:27][CH:26]=[N:25]2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [c-]1nc[nH]n1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(C(c2ccccc2)N2CC(n3cncn3)C2)cc1
Yield: 68.9 %

Procedure:
A suspension of N-benzhydryl-3-[(methylsulfonyl)oxy]azetidine (0. 951 g, 3 mmol) and potassium-1,2,4-triazolide (0.69 g, 6.5 mmol) in 50 ml of dimethylformamide was heated at 85°-90° C. overnight. To this, water (200 ml) was added and extracted with ethyl acetate. The combined organic layers were washed with water, dried (Na2SO4) and evaporated to yield 0.9 g of the crude which upon purification over silica gel using ethyl acetate as solvent yielded 0.6 g of the desired product as a white solid. 1H NMR (CDCl3) δ: 8.22 (s, 1H), 7.97 (s, 1H), 7.57-7.12 (m, 5H), 5.13-4.9 (m, 1H), 4.53 (s, 1H), 3.8-3.4 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][CH:9]3[CH2:18][CH2:17][N:16]4[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]4)[CH:10]3[C:4]=2[CH:3]=1.N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[CH:36]=[C:37]([C:39]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=1)[CH3:38]>CN(C=O)C.[Cu]I>[F:45][C:42]1[CH:43]=[CH:44][C:39](/[C:37](/[CH3:38])=[CH:36]/[N:8]2[C:9]3[CH2:18][CH2:17][N:16]4[CH:11]([C:10]=3[C:4]3[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]2=3)[CH2:12][CH2:13][CH2:14][CH2:15]4)=[CH:40][CH:41]=1
Reactant: CC(=CBr)c1ccc(F)cc1
Reactant: Cc1ccc2c(c1)C1C(CCN3CCCCC13)N2
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(C)ccc31)C1CCCCN1CC2)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
11-Methyl-1,2,3,4,6,7,7a,8,12b,12c-decahydroindolo[3,2-a]quinolizine (100 mg, 0.41 mmol) was dissolved in DMF (5 mL). Copper (I) iodide (7.9 mg, 0.0416 mmol), L-proline (9.6 mg, 0.08 mmol) and K3PO4 (176 mg, 0.83 mmol) were added and the reaction mixture was stirred for 10 min at RT. 1-(1-Bromoprop-1-en-2-yl)-4-fluorobenzene (107 mg, 53 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated at 85° C. overnight (prolonged heating in some cases was required). The DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh) eluting with 0-5% MeOH-DCM. The product was further purified by reverse phase HPLC. Yield: 13 mg as TFA salt;
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[F:22][C:23]([F:32])([F:31])[C:24]1[CH:25]=[CH:26][C:27](O)=[N:28][CH:29]=1>COCCOC>[F:21][C:18]([F:19])([F:20])[CH2:17][N:4]([CH2:3][CH2:2][O:1][C:27]1[CH:26]=[CH:25][C:24]([C:23]([F:32])([F:31])[F:22])=[CH:29][N:28]=1)[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:15])([F:16])[F:14])[CH:6]=1
Reactant: Oc1ccc(C(F)(F)F)cn1
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Solvent: COCCOC
Product: N#Cc1ccc(N(CCOc2ccc(C(F)(F)F)cn2)CC(F)(F)F)cc1C(F)(F)F

Procedure:
Synthesized as described in Example 1C from 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and 5-trifluoromethyl-2-pyridinol, using dry DME as reaction solvent: MS (ESI) m/z 458 (M+1).
Reaction SMILES: NC1C2C(OC)=CC=CC=2S(=O)(=O)N=1.[OH-].[Na+].C[O:18][C:19]1[C:24]2[C:25](=[O:30])[NH:26][S:27](=[O:29])(=[O:28])[C:23]=2[CH:22]=[CH:21][CH:20]=1.[C-]#N.[K+].[K]>CS(C)=O>[OH:18][C:19]1[C:24]2[C:25](=[O:30])[NH:26][S:27](=[O:29])(=[O:28])[C:23]=2[CH:22]=[CH:21][CH:20]=1
Reactant: COc1cccc2c1C(=O)NS2(=O)=O
Agent: COc1cccc2c1C(N)=NS2(=O)=O
Agent: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Product: O=C1NS(=O)(=O)c2cccc(O)c21
Yield: 62 %

Procedure:
2.5 gm (11.8 mmols) of 3-amino-4-methoxy-1,2-benzoisothiazole-1,1-dioxide were reacted with sodium hydroxide analogous to Example 5, and by subsequent acidification the reaction product was converted into 4-methoxy-1,2-benzoisothiazol-3(2H)-one-1,1-dioxide. The obtained compound, together with 650 mg (10 mmols) of potassium cyanide in dimethyl-sulfoxide, was heated at 180° C. for 3 hours. After addition of petroleum ether the potassium salt of the product was precipitated, and the precipitate was dissolved in water. After acidifying with aqueous hydrochloric acid, filtering and recrystallizing, 1.46 gm (62% of theory) of 4-hydroxy-1,2-benzoisothiazol-3(2H)-one-1,1-dioxide were obtained.
Reaction SMILES: C[O-].[Na+].Cl.[C:5]([NH2:8])(=[NH:7])[CH3:6].CO[CH:11]=[C:12]([CH:15]([O:18][CH3:19])[O:16][CH3:17])[C:13]#[N:14]>CO>[CH3:6][C:5]1[N:8]=[C:13]([NH2:14])[C:12]([CH:15]([O:18][CH3:19])[O:16][CH3:17])=[CH:11][N:7]=1
Reactant: COC=C(C#N)C(OC)OC
Reactant: CC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(OC)c1cnc(C)nc1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
In a 50 ml four-necked flask equipped with a calciumchloride tube, a thermometer and a reflux condenser, there were placed 11.6 g (60 mmoles) of a 28 wt. % solution of sodium methylate in methanol and 10 ml of methanol. Thereto was added with stirring 5.67 g of acetamidine hydrochloride (60 mmoles) and the mixture was stirred at room temperature for 30 minutes. Then, 7.85 g (50 mmoles) of 2-methoxymethylene-3,3-dimethoxypropanenitrile was added thereto and the mixture was heated and refluxed for 5 hours. After completion of the reaction, the reaction mixture was cooled and then the insoluble sodium chloride was removed by filtration. After concentration of the solvent, methanol, 50 ml of water was added thereto and the mixture was extracted four times with 20 ml of methylene chloride. After the extract was dried over sodium sulfate, the sodium sulfate was removed by filtration and the filtrate was concentrated to dryness to obtain a white crude crystal. The thus obtained product was recrystallized from a mixed solvent of 50 ml of hexane and 25 ml of toluene to obtain 8.05 g (yield: 88%) of 2-methyl-4-amino-5-dimethoxymethylpyrimidine melting at 102°-104° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH:10]([Mg]Cl)([CH3:12])[CH3:11].[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(C)[Mg]Cl
Reactant: O=Cc1ccc(Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)C(O)c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 4-brombenzaldehyde (27 mmol, 5.0 g) in THF (20 mL) was added at −78° C. a solution of isopropylmagnesium chloride (41 mmol, 20.2 mL, 2M in ether). The mixture was stirred at −78° C. for 1 h and warmed to 0° C. for 1 h. NH4Cl was added an the mixture was extracted with EtOAc. The organic extract was washed with brine, dried and concentrated to an oil. Chromatography (5-15% EtOAc/hexane) gave the desired alcohol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20](=O)([O-])O.[K+].CN(C)C=O.CI>O>[CH3:20][O:18][C:17](=[O:19])[C@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.4 %

Procedure:
To a mixture of N-tert-butoxycarbonylphenylalanine (13.3 g, 50.0 mmol), potassium hydrogencarbonate (10.0 g, 100 mmol) and N,N-dimethylformamide (80 mL) was added methyl iodide (5 mL, 80 mmol). The resulting mixture was stirred at room temperature for 5 h, and water (200 mL) was added. The mixture was extracted with ethyl acetate-benzene (1:1), and the organic layer was washed successively with water, 5% aqueous sodium sulfite solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was separated and purified by silica gel column chromatography (hexane-ethyl acetate, 90:10) to give 13.6 g (96%) of N-tert-butoxycarbonylphenylalanine methyl ester as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N+:15]=3[O-])[C:7]=2[CH:21]=1)#[N:2].P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([CH:8]2[C:7]3[CH:21]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=3[O:11][C:10]([CH3:13])([CH3:12])[CH2:9]2)[CH:19]=1
Reactant: CC1(C)CC(c2cccc[n+]2[O-])c2cc(C#N)ccc2O1
Reactant: O=P(Cl)(Cl)Cl
Product: CC1(C)CC(c2cc(Cl)ccn2)c2cc(C#N)ccc2O1
Temperature: 80 °C

Procedure:
1 g of 2-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)pyridine N-oxide was dissolved in 15 ml of phosphorus oxychloride, heated at 80° C. for 2 hours and allowed to cool to room temperature overnight. The phosphorus oxychloride was removed in vacuo and the residue was taken up in sodium bicarbonate solution and ethyl acetate. The aqueous phase was extracted several times with ethyl acetate and the combined ethyl acetate solutions were dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel. Elution with ethyl acetate/petroleum ether (1:4) gave 271 mg of 4-(6-chloro-2-pyridyl)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile and elution with ethyl acetate/petroleum ether (1:2) gave 170 mg of 4-(4-chloro-2-pyridyl)-3,4-dihydro-2,2-dimethyl-2H-1 -benzopyran-6carbonitrile.
Reaction SMILES: [H-].[Na+].[OH:3][C@H:4]1[C@H:9]([CH:10]([CH3:12])[CH3:11])[CH2:8][CH2:7][N:6]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5]1.I[CH2:21][CH3:22].O>CN(C=O)C>[CH2:21]([O:3][C@H:4]1[C@H:9]([CH:10]([CH3:11])[CH3:12])[CH2:8][CH2:7][N:6]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH2:5]1)[CH3:22]
Reactant: CC(C)[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1O
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1C(C)C
Reaction time: 0.42 h

Procedure:
Add sodium hydride (69 mg, 1.73 mmol) to a solution of trans-tert-butyl 3-hydroxy-4-isopropyl-piperidine-1-carboxylate (300 mg, 1.23 mmol) in anhydrous DMF (2.5 mL) at ambient temperature. Stir the mixture for 25 minutes and then add iodoethane (112 μL, 1.48 mmol). Stir the mixture overnight. Add additional iodoethane (59.3 μL, 0.74 μmol) and stir the mixture for 3 h, then add water. Extract the aqueous layer with EtOAc, combine the organic layers. Sequentially wash the combined organic layers with water then brine; dry over anhydrous sodium sulphate; filter; collect the filtrate; and then remove the solvent under vacuum. Purify the compound by silica gel chromatography eluting with hexane:ethyl acetate (0%, 2%, 4% and 6% ethyl acetate) to obtain the title compound as a waxy solid (260 mg, 78%). MS (m/z): 216 (M-tBu+1)
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:9][CH:10]([C:16](=O)[CH3:17])[C:11](OCC)=[O:12]>>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:3]=1[N:4]=[C:16]([CH3:17])[C:10]([CH3:9])=[C:11]2[OH:12]
Reactant: Nc1ccccc1Cl
Reactant: CCOC(=O)C(C)C(C)=O
Product: Cc1nc2c(Cl)cccc2c(O)c1C

Procedure:
Prepared according to R using 2-chloroaniline (1.28 mL, 10 mmol) and ethyl 2-methyl-3-oxobutanoate (2.89 g, 20 mmol) in PPA (4 g, 40 mmol). The resulting precipitate was collected by filtration, washed with water, and dried to give 8-chloro-2,3-dimethylquinolin-4-ol as an off white solid. Mass Spectrum (ESI) m/e=208 (M+1).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH:13]=[O:14].[CH2:15]([N:17]([CH2:21][CH3:22])[C:18](Cl)=[O:19])[CH3:16]>C1COCC1>[CH2:15]([N:17]([CH2:21][CH3:22])[C:18]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([Br:3])=[CH:12][CH:11]=2)[C:7]([CH:13]=[O:14])=[CH:8]1)=[O:19])[CH3:16]
Reactant: O=Cc1c[nH]c2ccc(Br)cc12
Reactant: CCN(CC)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CC)C(=O)n1cc(C=O)c2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 79.6 %

Procedure:
To a suspension of sodium hydride (0.93 g, 37 mmol) in anhydrous THF (75 mL) was added dropwise a solution of 5-bromo-1H-indole-3-carbaldehyde (7.5 g, 34 mmol) in anhydrous THF (60 ml) at 0° C. After stirring at 0° C. for 15 min, N,N-diethylcarbamyl chloride (5.0 g, 37 mmol) was added dropwise into the reaction mixture. The mixture was warmed to room temperature and stirred overnight. The reaction was then quenched with water and extracted with ethyl acetate. The organics were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was crystallized from ether/hexane to give the title compound (8.75 g, 80%) as a white solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:11]([OH:12])=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1.[CH2:19]([O:26][CH2:27][C:28](Cl)=[O:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>N1C=CC=CC=1>[C:16]([NH:15][CH2:14][CH2:13][CH:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([NH:2][C:28](=[O:29])[CH2:27][O:26][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:11]=2[OH:12])[CH2:7][CH2:8]1)(=[O:18])[CH3:17]
Reactant: O=C(Cl)COCc1ccccc1
Reactant: CC(=O)NCCC1CCc2ccc(N)c(O)c21
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)NCCC1CCc2ccc(NC(=O)COCc3ccccc3)c(O)c21
Reaction time: 0.25 h
Yield: 80.3 %

Procedure:
N-[2-(6-Amino-7-hydroxy-2,3-dihydro-1H-inden-1-yl)ethyl]acetamide hydrochloride (251 mg, 0.928 mmol) was dissolved in pyridine (10 mL), (benzyloxy)acetyl chloride (160 μL, 1.01 mmol) was added under ice-cooling, and the mixture was stirred for 15 min. Water was added to the reaction solution, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=80/20→100/0) to give the title compound (285 mg, yield 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:14](=[O:15])[CH:13]=[CH:12][C:11]([C:16]([OH:18])=O)=[CH:10]1.[NH2:19][C:20]1[CH:21]=[C:22]([NH:27][C:28]([NH:30][C:31]2[N:35]([C:36]3[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=3)[N:34]=[C:33]([C:43]([CH3:46])([CH3:45])[CH3:44])[CH:32]=2)=[O:29])[CH:23]=[CH:24][C:25]=1[CH3:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[C:43]([C:33]1[CH:32]=[C:31]([NH:30][C:28]([NH:27][C:22]2[CH:23]=[CH:24][C:25]([CH3:26])=[C:20]([NH:19][C:16]([C:11]3[CH:12]=[CH:13][C:14](=[O:15])[N:9]([C:3]4[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[CH:10]=3)=[O:18])[CH:21]=2)=[O:29])[N:35]([C:36]2[CH:37]=[CH:38][C:39]([CH3:42])=[CH:40][CH:41]=2)[N:34]=1)([CH3:46])([CH3:45])[CH3:44]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(C)c(N)c2)cc1
Reactant: O=C(O)c1ccc(=O)n(-c2c(Cl)cccc2Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(C)c(NC(=O)c3ccc(=O)n(-c4c(Cl)cccc4Cl)c3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.9 %

Procedure:
To a solution of 1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid (35 mg) and 1-(3-amino-4-methylphenyl)-3-[3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]urea (70 mg) in DMF (1 mL) were added HATU (71 mg) and iPr2NEt (96 mg) successively under a nitrogen atmosphere, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with EtOAc (5 mL) and the resulted mixture was successively washed with 1M HCl (5 mL×2), saturated aqueous NaHCO3 (5 mL×2) and brine, dried over MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with 5% MeOH in CH2Cl2. The isolated material was triturated with CH2Cl2, and the precipitates were collected by filtration to give N-[5-[({[3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]amino]carbonyl)amino]-2-methylphenyl}-1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide (34 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15]Br.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl-].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[N:9][N:8]([CH2:15][C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[F:12])[C:5]2=[N:6][CH:7]=1
Reactant: Fc1ccccc1CBr
Reactant: Fc1cnc2[nH]nc(I)c2c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Fc1cnc2c(c1)c(I)nn2Cc1ccccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
141 g (462.11 mmol) of the compound from Example 5A were introduced into DMF (2538 ml), and 96.09 g (508.32 mmol) of 2-fluorobenzyl bromide and 165.62 g (508.32 mmol) of caesium carbonate were then added. The mixture was stirred at RT for two hours. The reaction mixture was then poured into saturated aqueous sodium chloride solution (13 670 ml) and extracted twice with ethyl acetate (5858 ml). The collected organic phases were washed with saturated aqueous sodium chloride solution (3905 ml), dried, filtered and concentrated. The residue was chromatographed on silica gel (mobile phase: petroleum ether/ethyl acetate 97:3) and the product fractions were concentrated. The resulting solid was dissolved in dichloromethane and washed once with saturated aqueous sodium thiosulphate solution (500 ml) and then with saturated aqueous sodium chloride solution (500 ml). The product was concentrated to dryness and the residue was suspended in diethyl ether, isolated by filtration with suction and dried under high vacuum. This gave 106.6 g (62% of theory) of the desired compound.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][NH2:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:9][C:10]1[N:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>>[Cl:9][C:10]1[N:15]=[CH:14][C:13]([S:16]([NH:8][CH2:7][CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: NCCN1CCCC1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Product: O=S(=O)(NCCN1CCCC1)c1ccc(Cl)nc1

Procedure:
The title compound was prepared as described for Example 3 using 2-pyrrolidin-1-yl-ethylamine and 6-chloropyridine-3-sulfonyl chloride (described in: Naegeli, C. et al. Helv. Chim. Actal. 1938, 21, 746-1750). Purification on a silica gel column using ethyl acetate/triethylamine, (9:1), as the eluent gave the title compound. Yield: 58%: 1H NMR (CDCl3, 400 MHz) δ 8.79 (d, J=2Hz, 1 H), 8.05 (dd, J=8, 3Hz, 1 H), 7.42 (d, J=9 Hz, 1 H), 3.00 (app. t, J=6 Hz, 2 H), 2.50 (app. t, J=6 Hz, 2 H), 2.33 (m, 4 H), 1.67 (m, 4 H); 13C NMR (CDCl3, 100 MHz) δ 155.7, 148.8, 137.8, 136.1, 125.0, 54.1, 53.9, 41.6, 23.9; MS (TSP) m/z 290 (M++1).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14](=[O:19])C(F)(F)F)=[C:4]1[CH3:20])[CH3:2].[OH-:21].[K+].Cl>C(O)C.O>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]([OH:19])=[O:21])=[C:4]1[CH3:20])[CH3:2]
Reactant: CCn1c(C)c(C(=O)C(F)(F)F)c2ccc(OC)cc21
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCn1c(C)c(C(=O)O)c2ccc(OC)cc21
Temperature: 25 °C
Yield: 73.9 %

Procedure:
To a solution of 1-(1-ethyl-6-methoxy-2-methyl-1H-indol-3-yl)-2,2,2-trifluoro-ethanone 71b (580 mg, 2.03 mmole) in 10 ml ethanol was added a solution of KOH (1.1 g, 20 mmole) in 10 ml water. The mixture was heated to reflux for 1 hour and cooled to room temperature. Concentrated HCl was added to adjust pH to 1. The mixture was extracted with EtOAc and the combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was further purified by column chromatography (eluting with 1-2% MeOH in CH2Cl2) to give 350 mg product as brown solid (74% yield). 1H NMR (400 MHz, CDCl3) δ8.07 (1H, d, J=8.7 Hz), 6.90 (1H, dd, J=2.2, 8.7 Hz), 6.80 (1H, d, J=2.2 Hz), 4.14 (2H, q, J=7.2 Hz), 3.88 (3H, s), 2.77 (3H, s), 1.37 (3H, t, J=7.2 Hz).
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[CH:16]=2)[C:13](=[O:27])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[F:28])[N:6]=1)[CH2:3][CH3:4].Cl[C:30]1[C:31]2[CH:38]=[CH:37][NH:36][C:32]=2[N:33]=[CH:34][N:35]=1.C(N(C(C)C)CC)(C)C>CC(O)(C)C>[N:33]1[C:32]2[NH:36][CH:37]=[CH:38][C:31]=2[C:30]([NH:1][C@H:2]([C:5]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]([F:26])([F:24])[F:25])[CH:16]=3)[C:13](=[O:27])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[F:28])[N:6]=2)[CH2:3][CH3:4])=[N:35][CH:34]=1
Reactant: CC[C@H](N)c1nc2cccc(F)c2c(=O)n1-c1cccc(OCC(F)(F)F)c1
Reactant: Clc1ncnc2[nH]ccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: CC[C@H](Nc1ncnc2[nH]ccc12)c1nc2cccc(F)c2c(=O)n1-c1cccc(OCC(F)(F)F)c1
Temperature: 120 °C
Reaction time: 14 h
Yield: 17.4 %

Procedure:
Under nitrogen, to (S)-2-(1-aminopropyl)-5-fluoro-3-(3-(2,2,2-trifluoroethoxy)phenyl)quinazolin-4(3H)-one (22 mg, 0.056 mmol, 1.0 equiv) in t-BuOH (0.11 mL) at 23° C. was added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (10 mg, 0.067 mmol, 1.2 equiv) and diisopropylethylamine (19 μL, 0.11 mmol, 2.0 equiv). After stirring for 14 hr at 120° C. in a sealed tube, the reaction mixture was concentrated in vacuo and the residue was purified by preparative TLC eluting with CH2Cl2/MeOH to afford 5.0 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-])=O>[Pd]>[F:9][C:8]([F:10])([F:11])[C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([NH2:12])[CH:4]=1
Reactant: Nc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Product: Nc1ccc(C(F)(F)F)cc1N

Procedure:
A solution of 6.18 g (30 m mol) of 4-amino-3-nitrobenzotrifluoride in 150 ml of ehtanol was hydrogenated at atmospheric pressure over 1.5 g of 5% Pd/C with Ishii's Catalytic Hydrogenation Apparatus with Magnetic Stirrer Model CHA-M. The catalyst was filtered off. The filterate was evaporated and the residue was crystallized from petroleum ether to give 4.5 g (85.17%) as white crystals.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[ClH:10].Cl.[CH2:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[C:22]([C:30]3[CH:35]=[CH:34][C:33]([S:36]([CH2:39][CH2:40][CH2:41]O)(=[O:38])=[O:37])=[CH:32][CH:31]=3)[N:21]=2)[CH2:16][CH2:15]1)[CH3:13].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.C(Cl)(Cl)Cl>[ClH:10].[ClH:10].[CH2:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[C:22]([C:30]3[CH:35]=[CH:34][C:33]([S:36]([CH2:39][CH2:40][CH2:41][F:7])(=[O:38])=[O:37])=[CH:32][CH:31]=3)[N:21]=2)[CH2:16][CH2:15]1)[CH3:13]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCN1CCN(c2nc(-c3ccc(S(=O)(=O)CCCO)cc3)cc3ccccc23)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCN1CCN(c2nc(-c3ccc(S(=O)(=O)CCCF)cc3)cc3ccccc23)CC1
Temperature: -78 °C

Procedure:
Diethylaminosulfur trifluoride (DAST, 0.14 ml) was added to anhydrous methylene chloride (3 ml), and the resulting mixture was stirred at −78° C. in nitrogen atmosphere, to which was then added a solution of 1-(4-ethylpiperazin-1-yl)-3-[4-(3-hydroxypropyl)sulfonylphenyl]isoquinoline (0.31 g) obtained in Example 352 in methylene chloride (5 ml), and the mixture was further stirred for 6 hr. DAST (0.09 ml) was further added thereto, and the resulting mixture was further stirred overnight. The bulk temperature was raised to room temperature. The reaction solution was diluted with chloroform, followed by the addition of a 10% aqueous solution of sodium carbonate. The organic layer was separated, and then it was washed with brine and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give 0.23 g of the free compound of the title compound as a pale brown viscous oil.