Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH:7]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[C:6]=2[CH:5]=[N:4][CH:3]=1.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[F:17][C:18]([F:29])([F:28])[C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:11]3[CH2:10][CH2:9][CH2:8][CH:7]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[C:6]=3[CH:5]=[N:4][CH:3]=2)=[CH:21][CH:20]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCC(=O)NC1CCCc2c(Br)cncc21
Product: CCC(=O)NC1CCCc2c(-c3ccc(C(F)(F)F)cc3)cncc21
Yield: 86 %

Procedure:
In analogy to the procedure described for the preparation of example 1, (rac)-N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide (intermediate A-1) was reacted with 4-(trifluoromethyl)phenylboronic acid to give the title compound as light grey foam in 86% yield. MS: 349.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](Cl)(Cl)=[O:13]>[OH-].[Na+].C1(C)C=CC=CC=1>[F:11][C:8]1[CH:9]=[CH:10][C:2]2[NH:1][C:12](=[O:13])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1ccc(F)cc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=c1[nH]c2ccc(F)cc2c(=O)o1
Temperature: 0 °C

Procedure:
2-Amino-5-fluorobenzoic acid (1.91 g, 12.3 mmol) was dissolved in 1N sodium hydroxide solution (15 mL) and cooled to 0° C. under a nitrogen atmosphere. Phosgene (10 mL of a 20% solution in toluene) was added dropwise. After the addition was complete, the thick slurry was allowed to warm to room temperature. The precipitate was filtered off and rinsed with deionized water (2×50 mL). The precipitate was slurried in diethyl ether (50 mL), filtered, and dried under reduced pressure to yield 2.04 g of 6-fluoro-2H-3,1-benzoxazine-2,4(1H)-dione.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:24](O)=[O:25])[CH2:9]2)=[O:7])[CH2:3]1.O[N:28]=[C:29]([NH2:37])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([C:29]1[N:37]=[C:24]([CH:10]2[CH2:11][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:23])[F:22])=[CH:16][CH:15]=3)[CH2:13][N:8]([C:6]([N:4]3[CH2:5][CH:2]([OH:1])[CH2:3]3)=[O:7])[CH2:9]2)[O:25][N:28]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NC(Cc1ccccc1)=NO
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CC(O)C2)C1
Product: O=C(N1CC(O)C1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(Cc3ccccc3)no2)C1

Procedure:
100 mg (0.269 mmol) of 1-[(3-hydroxyazetidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 101A) and 44.4 mg (0.295 mmol) of N′-hydroxy-2-phenylethanimidamide were reacted according to the General Method 1. Yield: 40.0 mg (29% of theory).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:15])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][N:9]=2)[CH:7]=1.[B:16]1(B2OCC(C)(C)CO2)[O:21]CC(C)(C)C[O:17]1.C([O-])(=O)C.[K+]>O1CCOCC1.CS(C)=O.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[F:15][C:5]1[CH:4]=[CH:3][C:2]([B:16]([OH:21])[OH:17])=[CH:7][C:6]=1[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][N:9]=1
Reactant: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Reactant: Fc1ccc(-c2cc(Br)ccc2F)nc1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: CS(C)=O
Solvent: ClCCl
Product: OB(O)c1ccc(F)c(-c2ccc(F)cn2)c1
Temperature: 85 °C
Reaction time: 15 h

Procedure:
To 2-(5-bromo-2-fluorophenyl)-5-fluoropyridine (0.94 g, 3.48 mmol) and bis(neopentyl glycolato)diboron (0.943 g) in 1,4-dioxane (12 ml) and dimethylsulfoxide (1.5 ml) was added potassium acetate (0.725 g) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (100 mg). The mixture was degassed with nitrogen and then stirred at 85° C. for 15 h. On cooling to ambient temperature, 1 N aqueous sodium hydroxide (32 ml) was added and the mixture stirred for 20 min. Diethyl ether was added and the aqueous phase separated and washed with diethyl ether. The organic extracts were washed with water and the combined aqueous phases filtered then acidified to pH 5 by addition of 2 N aqueous hydrochloric acid (18 ml). The resulting white solid was collected by filtration, washed with water and dried in vacuo to afford 4-fluoro-3-(5-fluoropyridin-2-yl)phenylboronic acid: 1H NMR (400 MHz, DMSO-d6) 868.73 (1H, dd, J 2 and 1), 8.33 (1H, dd, J 9 and 2), 8.17 (2H, s), 7.87 (3H, m), 7.31 (1H, dd, J 12 and 8).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:19]=[N:18][CH:17]=[CH:16][C:11]=1[C:12]([NH:14][NH2:15])=[O:13].[CH2:20](S)[SH:21].[OH-].[K+]>CO>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:19]=[N:18][CH:17]=[CH:16][C:11]=1[C:12]1[O:13][C:20](=[S:21])[NH:15][N:14]=1
Reactant: SCS
Reactant: NNC(=O)c1ccncc1Nc1ccc(I)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Fc1cc(I)ccc1Nc1cnccc1-c1n[nH]c(=S)o1
Temperature: 60 °C
Reaction time: 7 h

Procedure:
To a solution of 3-(2-Fluoro-4-iodo-phenylamino)-isonicotinic acid hydrazide (744 mg, 2.ommol) in methanol (15 mL) were added dithiomethane (0.22 mL, 4.66 mmol), followed by potassium hydroxide (2.51 mL, 2.13 mmol). The reaction mixture was stirred at 60° C. for 7 h. The solvent was evaporated and the residue was dissolved in ethyl acetate (50 mL), washed with Brine (15 mL×3), dried over anhydrous MgSO4, filtered, removed off solvent. Residue was subjected to silica gel column (EtOAc:Hexane=1:1) collected product 210 mg. LC-MS (Method A) [5.71 min; 415(M+1)]
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([C:9]2[CH:10]=[CH:11][C:12](=[O:16])[N:13]([CH3:15])[CH:14]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>C1COCC1.CO>[OH:3][CH:1]([C:4]1[S:8][C:7]([C:9]2[CH:10]=[CH:11][C:12](=[O:16])[N:13]([CH3:15])[CH:14]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(=O)c1ccc(-c2ccc(=O)n(C)c2)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(O)c1ccc(-c2ccc(=O)n(C)c2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.4 %

Procedure:
To a solution of 5-(5-acetylthiophen-2-yl)-1-methylpyridin-2(1H)-one (0.65 g, 2.78 mmol) in THF (8 mL) and MeOH (8 mL) was added NaBH4 (0.26 g, 6.97 mmol) under nitrogen. The mixture was stirred at rt for 10 min, quenched with ammonium chloride solution (15 mL) and extracted with ethyl acetate (2×100 mL). The organic extracts were washed with brine solution (2×50 mL), dried over sodium sulphate and evaporated to obtain the crude compound. Purification by flash chromatography (100-200μ; 100% ethyl acetate) afforded 5-(5-(1-hydroxyethyl)thiophen-2-yl)-1-methylpyridin-2(1H)-one (0.5 g, 76% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.00 (s, 1H), 7.69 (d, 1H), 7.07 (d, 1H), 6.83 (d, 1H), 6.43 (d, 1H), 5.51 (bs, 1H), 4.88 (q, 1H), 3.45 (s, 3H), 1.38 (d, 3H); LC-MS m/z calcd for [M+H]+ 236.07 found 236.3.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[C:12](Br)[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1.C([O-])(=O)C.[K+].[NH2:21][C:22]1[C:23]([C:29]([O:31][CH3:32])=[O:30])=[N:24][C:25](Br)=[CH:26][N:27]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1.O.C(OCC)(=O)C>[NH2:21][C:22]1[N:27]=[CH:26][C:25]([C:12]2[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:4]([C:3]([O:2][CH3:1])=[O:15])[CH:13]=2)=[N:24][C:23]=1[C:29]([O:31][CH3:32])=[O:30]
Reactant: COC(=O)c1nc(Br)cnc1N
Reactant: COC(=O)c1cc(Br)cc(C(=O)OC)c1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(C(=O)OC)cc(-c2cnc(N)c(C(=O)OC)n2)c1
Temperature: 80 °C
Yield: 9.5 %

Procedure:
A mixture containing 5-bromoisophthalic acid dimethyl ester (0.20 g, 0.73 mmol), bispinacolatodiboron (0.21 g, 0.80 mmol), 1,1′-bis(diphenylphosphine)ferrocene palladium dichloride (0.029 g, 0.035 mmol), and potassium acetate (0.26 g, 2.3 mmol) in dioxane (5 mL) was heated at 80° C. for 1 h. The reaction mixture was cooled to room temperature and methyl 3-amino-6-bromo-pyrazine-2-carboxylate (0.17 mg, 0.70 mmol), 1,1′-bis(diphenylphosphine)ferrocene palladium dichloride (0.035 g, 0.042 mmol), sodium bicarbonate (320 mg, 3.8 mmol), and water (1 mL) were added. The mixture was heated at 80° C. for 12 h, after which time, the mixture was diluted with water and ethyl acetate. The layers were separated and the organic layer was extracted with 1 N hydrochloric acid (2×) and dried over sodium sulfate. Filtration, concentration, and silica gel chromatography gave the product as a yellow solid (23 mg, 12% yield). 1H NMR (400 MHz, d6-DMSO): δ 9.04 (s, 1H), 8.74 (d, 2H), 8.44 (t, 1H), 7.62 (s, 2H), 3.32 (s, 3H), 2.49 (s, 3H), 2.48 (s, 3H). MS (EI) for C16H15N3O6: 346 (MH+).
Reaction SMILES: [NH:1]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@H:2]([C:8]([O:10][CH3:11])=[O:9])[CH2:3]SSCC.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.O.C(OCC)C>[C:15]([O:14][C:12]([NH:1][C:2](=[CH2:3])[C:8]([O:10][CH3:11])=[O:9])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCSSC[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: C=C(NC(=O)OC(C)(C)C)C(=O)OC
Reaction time: 0.17 h
Yield: 78.3 %

Procedure:
N-(tert-Butoxycarbonyl)-ethylthio-L-cysteine methyl ester 15 (106 mg, 0.40 mmol) was added to a 50 mL round bottom flask and dissolved in DMF (5 mL). Potassium carbonate (278 mg, 2.01 mmol) was added by pipette as a solution in water (1.0 mL). MSH 1 (172 mg 0.80 mmol) was added as a solid in one portion (open air, room temperature). TLC analysis (ethyl acetate:petrol; 1:4) after 1 min of reaction revealed a strongly UV active product (Rf 0.6) and a trace of starting material (Rf 0.5). A second dose of MSH 1 (172 mg 0.80 mmol) was added after 5 min of reaction time and TLC analysis revealed only the UV active product. After 10 min of total reaction time, the reaction mixture was diluted with diethyl ether (100 mL) and water (50 mL). The organic layer was separated and the aqueous layer was extracted with diethyl ether (2×50 mL). The combined organics were dried (MgSO4), filtered, and the solvent removed by rotary evaporation. Column chromatography (3% ethyl acetate in petrol) provided methyl 2-[(tert-butoxycarbonyl)amino]acrylate 3 (63 mg, 79%); this material was spectroscopically identical to that obtained from N-(tert-butoxycarbonyl)-L-cysteine methyl ester 2.
Reaction SMILES: [F:1][CH:2]([F:21])[CH2:3][O:4][C:5]1[CH:15]=[C:14]([NH:16][CH3:17])[C:13]([N+:18]([O-])=O)=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[O-]S([O-])(=O)=O.[Na+].[Na+]>[Ni].C1COCC1>[NH2:18][C:13]1[C:14]([NH:16][CH3:17])=[CH:15][C:5]([O:4][CH2:3][CH:2]([F:21])[F:1])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(NC)cc1OCC(F)F
Agent: [Ni]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(N)c(NC)cc1OCC(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl 2-(2,2-difluoroethoxy)-4-(methylamino)-5-nitrobenzoate (2.0 g; 6.57 mmol), RaNi (1.0 g) and THF (100 mL) is stirred under H2-atmosphere (8 atm) overnight at rt. Na2SO4 is added and the mixture is stirred another 30 min under H2-atmosphere. The mixture is filtered through celite and concentrated and the sub-title compound is used in the next step without further purification.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]=[C:11]=[O:12].[OH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>ClCCl>[Cl:1][CH2:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[NH:10][C:11](=[O:12])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: Cc1cccc(N=C=O)c1CCl
Reactant: OCc1ccccn1
Solvent: ClCCl
Product: Cc1cccc(NC(=O)OCc2ccccn2)c1CCl

Procedure:
A solution of 2-chloromethyl-1-isocyanato-3-methylbenzene (2.5 g) and 2-hydroxymethylpyridine (1.5 g) in dichloromethane (25 ml) is stirred at RT for 16 h. By concentration on a rotary evaporator (bath temperature 22° C.) and subsequent chromatography on silica gel (eluent: dichloromethane/methanol 13:1), a solution of the title compound is obtained which is concentrated (not crystallization, but decomposition) on a rotary evaporator. (bath temperature 22° C.). The crude product of the title compound obtained is immediately reacted further.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>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].O1CCOCC1.O>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH:20]=[C:21]([C:2]2[S:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: Brc1nc2ccccc2s1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2nc3ccccc3s2)CC1
Temperature: 90 °C

Procedure:
A mixture of 2-bromo-benzothiazole (0.38 g, 1.1 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.5 g, 1.62 mmol), potassium carbonate (0.67 g, 4.85 mmol), Pd(dppf)Cl2 (0.132 g, 0.16 mmol) and 4/1/dioxane/water (10 ml) was degassed for 15 minutes. Then it was heated at 90° C. for overnight. Cooled to room temperature and diluted with EtOAc (200 mL). The organic layer was washed with water (100 ml), dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel to give the desired product 21BB (0.4 g, 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:16]([C:18]2([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH2:20][CH2:19]2)=[O:17])[C@H:13]([C:27]([NH:29][C:30]2([C:33]#[N:34])[CH2:32][CH2:31]2)=[O:28])[CH2:12]1)(=[O:10])=[O:9].[CH3:35][S:36](Cl)(=[O:38])=[O:37].C(N(C(C)C)C(C)C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:16]([C:18]2([N:21]3[CH2:22][CH2:23][N:24]([S:36]([CH3:35])(=[O:38])=[O:37])[CH2:25][CH2:26]3)[CH2:19][CH2:20]2)=[O:17])[C@H:13]([C:27]([NH:29][C:30]2([C:33]#[N:34])[CH2:31][CH2:32]2)=[O:28])[CH2:12]1)(=[O:10])=[O:9]
Reactant: CS(=O)(=O)Cl
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2C(=O)C2(N3CCNCC3)CC2)CC1
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1CCN(C2(C(=O)N3C[C@H](S(=O)(=O)c4ccccc4Cl)C[C@H]3C(=O)NC3(C#N)CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 95.4 %

Procedure:
To a solution of (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(piperazin-1-yl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide (35.4 mg, 70 μmol) in methylenehloride (0.7 mL) was added under stirring ethyldiisopropyl amine (18.3 μL, 105 μmol) and methanesulfonyl chloride (6.00 μL, 77.0 μmol). The reaction was stirred at room temperature for 5 hours and additional ethyldiisopropyl amine (18.3 μL, 105 μmol) and methanesulfonyl chloride (6.00 μL, 77.0 μmol) was added. The reaction was stirred at room temperature over night. The reaction was purified by column chromatography on silica gel using ethyl acetate as solvent to yield the title compound as a yellow solid (39 mg, 95%). MS ISP (m/e): 584.1/586.1 (100/44) [(M+H)]+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([S:13][CH2:14][C:15](Cl)=[O:16])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)Cl>[C:15]1(=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][S:13][CH2:14]1
Reactant: O=C(Cl)CSCCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1CSCCc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of aluminum chloride (12.21 g, 92 mmol) in CH2Cl2 (200 mL) was treated dropwise with a solution of Example 107B (9.83 g, 45.8 mmol) in CH2Cl2 (100 mL) over 35 minutes, stirred at ambient temperature for 30 minutes, poured into a flask containing ice water (˜400 mL) and transferred to a separatory funnel using ˜50 mL CH2Cl2. The layers were separated and the aqueous was extracted with CH2Cl2 (100 mL). The combined CH2Cl2 layers were dried (MgSO4), filtered, concentrated and purified by chromatography on silica gel eluting with 20:1, 10:1 and 5:1 hexane:EtOAc to provide the title compound. 1H NMR (CDCl3) δ 2.99 (t, J=6.4 Hz, 2H), 3.19 (t, J=6.4 Hz, 2H), 3.55 (s, 2H), 7.21-7.26 (m, 1H), 7.40 (dt, J=7.6, 1.4 Hz, 1H), 7.50 (dt, J=7.5, 1.4 Hz, 1H), 7.93 (dd, J=7.8, 1.4 Hz, 1H); MS (M+H)+ m/z 179 (20%), (M+NH4)+ m/z 196 (100%).
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[CH2:4][CH2:5][NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:22][CH3:23])[CH:17]=3)[S:12][C:11]=2[C:10]([CH:24]=O)=[CH:9][CH:8]=1)[CH3:2].[CH:28]([NH2:30])=[O:29].[OH-].[Na+]>>[CH2:1]([N:3]([CH2:26][CH3:27])[CH2:4][CH2:5][NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:22][CH3:23])[CH:17]=3)[S:12][C:11]=2[C:10]([CH2:24][NH:30][CH:28]=[O:29])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCN(CC)CCNc1ccc(C=O)c2sc3ccc(OC)cc3c(=O)c12
Reactant: NC=O
Agent: [Na+]
Agent: [OH-]
Product: CCN(CC)CCNc1ccc(CNC=O)c2sc3ccc(OC)cc3c(=O)c12
Temperature: 170 °C

Procedure:
A mixture of 1-[[2-(diethylamino)ethyl]amino]-7-methoxy-9-oxothioxanthen-4-carboxaldehyde (3.6 g, 0.0094 mol), formamide (48 mL) nd formic acid (6 mL) was heated to 170° C. under N2 for 8 hours. The mixture was poured into ice-water, basified with 35% NaOH and extracted with chloroform. The organic layer was separated, washed with water (2X), then brine and was dried over Na2SO4 and concentrated in vacuo to afford 3.88 g of N-[[1-[[2-(diethylamino)ethyl]amino]-7-methoxy-9-oxothioxanthen-4-yl]methyl]formamide.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][C:10]2[C:11]([F:19])=[C:12]([CH2:17][NH2:18])[CH:13]=[CH:14][C:15]=2[Cl:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Br-].[CH:21]1([Zn+])[CH2:23][CH2:22]1>C1COCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:16][C:15]1[CH:14]=[CH:13][C:12]([CH2:17][NH2:18])=[C:11]([F:19])[C:10]=1[O:9][C:4]1[CH:3]=[C:2]([CH:21]2[CH2:23][CH2:22]2)[CH:7]=[C:6]([Cl:8])[CH:5]=1
Reactant: NCc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2)c1F
Reactant: [Zn+]C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NCc1ccc(Cl)c(Oc2cc(Cl)cc(C3CC3)c2)c1F
Temperature: 60 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
To a solution of ({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)amine (0.460 g, 1.260 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.029 g, 0.025 mmol) in THF (10 ml) was added cyclopropylzinc bromide (0.5 M solution in THF) (6.30 ml, 3.15 mmol) and the reaction mixture was stirred at 60° C. for 1 hour. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give ({4-chloro-3-[(3-chloro-5-cyclopropylphenyl)oxy]-2-fluorophenyl}methyl)amine (0.281 g, 0.861 mmol, 68% yield). 1H NMR (400 MHz, METHANOL-d4) d ppm 7.20-7.44 (m, 3H), 6.76 (s, 1H), 6.54 (s, 1H), 3.86 (s, 2H), 1.74-2.05 (m, 1H), 0.83-1.08 (m, 2H), 0.40-0.76 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[OH-].[Na+].CO.[C:15](=O)=[O:16]>O>[CH3:15][O:16][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12
Reactant: Clc1ccnc2[nH]ccc12
Reactant: O=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccnc2[nH]ccc12
Temperature: 170 °C

Procedure:
To 4-chloro-1H-pyrrolo[2,3-b]pyridine [2,3 g, Reference Example 64] in a stainless steel pressure vessel was added sodium hydroxide (2 g), and methanol (40 mL). The pressure vessel was sealed and heated at 170° C. for 4 hours. After cooling, water (100 mL) was added and the mixture was neutralised by addition of excess solid carbon dioxide pellets (30 g). After concentration to a slurry and filtration, the residue was washed twice with water (5 mL) to afford 4-methoxy-1H-pyrrolo[2,3-b]pyridine as a solid. To a mixture of 4-methoxy-1H-pyrrolo[2,3-b]pyridine (5.85 g) in toluene (150 mL) and water (150 mL) was added potassium hydroxide pellets (2.5 g), 4-methylbenzene sulfonyl chloride (7.53 g) and tetra-n-butyl ammonium hydrogen sulfate (0.02 g). This mixture was stirred at room temperature for 20 hours then extracted four times with ethyl acetate (100 mL). The combined organic extracts were concentrated and then subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and heptane (35:65, v/v) to afford the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([OH:12])[N:8]=[CH:9]2)=[N:4][CH:3]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][N:8]([CH2:17][C:16]1[CH:19]=[CH:20][CH:21]=[C:14]([F:13])[CH:15]=1)[C:7](=[O:12])[CH:6]=2
Reactant: Oc1cc2ncc(Br)cc2cn1
Reactant: Fc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=c1cc2ncc(Br)cc2cn1Cc1cccc(F)c1

Procedure:
The alkylation of 7-bromo-3-hydroxy-5-azaisoquinoline (1.00 g, 4.40 mmol) using 3-fluorobenzyl bromide (1.27 g, 6.69 mmol) and cesium carbonate (2.18 g, 6.69 mmol) in dimethylformamide is carried out as previously described in Example 1, Step (1). Purification on a silica gel column eluted with hexanes/ethyl acetate 3:1, followed by trituration with hexanes/ethyl acetate 4:1 will afford the desired product. Step (2): 2-(3-fluorobenzyl)-7-(3-phenyl-prop-1-ynyl)-2H-5-azaisoquinolin-3-one
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9]=2[C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=O.ClC1C=C(C=CC=1)C(O)=O.C([O-])(=O)C.[Na+]>ClCCl.C(O)(=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:15]3[CH:16]=[CH:17][C:18]([S:21]([NH2:24])(=[O:22])=[O:23])=[CH:19][CH:20]=3)=[CH:10][C:11]([CH3:14])([CH3:13])[CH:12]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)CC(c2ccc(F)cc2)=C(c2ccc(S(N)(=O)=O)cc2)C1
Agent: CC(=O)[O-]
Agent: O=C(O)c1cccc(Cl)c1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC1(C)C=C(c2ccc(F)cc2)C(c2ccc(S(N)(=O)=O)cc2)=C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
A solution of 1.0 g (2.89 mmol) of 4-[2-(4-fluorophenyl) -4,4-dimethylcyclopenten-1-yl)benzenesulfonamide (from Step 2) in 20 mL of dichloromethane was treated with 800 mg (80% peroxyacid, 3.7 mmol ) of m-chloroperoxybenzoic acid (MCPBA). The reaction was stirred at ambient temperature for 3 hours, washed with aqueous saturated sodium bisulfite, dried (MgSO4), and concentrated in vacuo to give a mixture of desired expoxide intermediate and m-chlorobenzoic acid; this crude mixture in 15 mL of acetic acid and 2 mL of water was subsequently treated with 1.0 g (12.2 mmol) of sodium acetate and stirred at 80° C. for 15 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was partitioned between water and ethyl acetate; the organic phase was washed with aqueous saturated sodium bicarbonate, water, brine, dried (MgSO4), and reconcentrated in vacuo. Purification by silica gel chromatography gave 665 mg (67%) of 4-[4-(4-fluorophenyl)-1,1-dimethylcyclopenta-2,4-dien-3-yl]benzenesulfonamide as a colorless solid: mp 163.5°-164.5° C. (dec); NMR (CDCl3) d 1.33 (s, 6H), 4.83 (br s, 2H), 6.34 (d, J=2 Hz, 1H), 6.45 (d, J=2 Hz, 1H), 6.94 (t, J=9 Hz, 2H), 7.00-7.20 (m, 2H), 7.25 (d, J=8 Hz, 2H), 7.78 (d, J=8 Hz, 2H).