Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N:13]([CH2:18][CH3:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].[C:20]([Mg]Br)#[CH:21]>>[C:1]([C:5]1[CH:6]=[C:7]([CH:8]([OH:9])[C:20]#[CH:21])[CH:10]=[CH:11][C:12]=1[N:13]([CH2:18][CH3:19])[CH2:14][CH:15]([CH3:16])[CH3:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#C[Mg]Br
Reactant: CCN(CC(C)C)c1ccc(C=O)cc1C(C)(C)C
Product: C#CC(O)c1ccc(N(CC)CC(C)C)c(C(C)(C)C)c1

Procedure:
In a manner analogous to example 1 e, the process is carried out by a reaction of 800 mg (3 mmol) of 3-tert-butyl-4-(ethylisobutylamino)benzaldehyde with 8 ml (4 mmol) of a 0.5M solution of ethynylmagnesium bromide. 700 mg of 1-[3-tert-butyl-4-(ethylisobutyl-amino)phenyl]prop-2-yn-1-ol are obtained in the form of a colourless oil (yield=81%).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:15]=[C:14]([CH2:16][CH2:17][OH:18])[CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:19](Cl)([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>N1C=CC=CC=1>[C:1]1([C:7]2[NH:8][C:9]3[CH:15]=[C:14]([CH2:16][CH2:17][O:18][S:19]([C:22]4[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=4)(=[O:21])=[O:20])[CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCc1ccc2nc(-c3ccccc3)[nH]c2c1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCc2ccc3nc(-c4ccccc4)[nH]c3c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Benzimidazole 190 (50 mg) was dissolved in pyridine (5 mL) and tosyl chloride (40 mg) was added as a solid. The reaction was allowed to stir for 16 h under nitrogen at room temperature before being quenched by addition of a saturated, aqueous solution of NH4Cl. This mixture was extracted with EtOAc which was in turn washed with dilute acid to ensure complete removal of pyridine. The organic layer was separated, dried over Na2SO4, and solvent removed under reduced pressure to give 191 which was used directly without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([N:8]2C3=NC=CC=C3C(C3C=CC=CC=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=C[CH:24]=1>>[CH3:24][O:1][C:2]1[CH:3]=[C:4]([NH:8][NH2:9])[CH:5]=[CH:6][CH:7]=1
Reactant: c1ccncc1
Reactant: Oc1cccc(-n2nc(-c3ccccc3)c3cccnc32)c1
Product: COc1cccc(NN)c1

Procedure:
Therein, among the starting compounds, for example, 1-(3-hydroxyphenyl)-3-phenyl-1H-pyrazolo[3,4-b]pyridine can be obtained by heating under reflux 2-chloro-3-benzoylpyridine and 3-methoxyphenylhydrazine in pyridine to obtain the corresponding hydrazone, and subjecting to ring-closure reaction the obtained hydrazone by heating under reflux in isopentyl alcohol with the use of potassium carbonate as a deacidifying agent to obtain 1-(3-methoxyphenyl)-3-phenyl-1H-pyrazolo[3,4-b]pyridine, followed by the elimination of the methoxy group thereof with the use of a butylmercaptanaluminium chloride system.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[N:6][NH:7][CH:8]=1.Br[CH2:10][CH2:11][F:12]>CN(C=O)C>[Br:3][C:4]1[CH:5]=[N:6][N:7]([CH2:10][CH2:11][F:12])[CH:8]=1
Reactant: FCCBr
Reactant: Brc1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FCCn1cc(Br)cn1
Reaction time: 0.25 h

Procedure:
Sodium hydride (24.22 mg, 0.606 mmol, 60% suspension in mineral oil) was added to a solution of 4-bromo-1H-pyrazole (89 mg, 0.606 mmol) in DMF (3028 μl) at RT. After 15 min, 1-bromo-2-fluoroethane (100 mg, 0.787 mmol) was added to the mixture. After 30 min, the mixture was diluted with DMF and purified by HPLC, followed by neutralization (K2CO3), to afford the title compound as a colorless oil.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][C:6](Cl)=[O:7].[NH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([NH:16]C(=O)OCC2C=CC=CC=2)[CH2:12][CH2:11]1.C(N(CC)CC)C>O1CCCC1>[NH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([N:16]2[CH2:2][CH2:3][O:4][CH2:5][C:6]2=[O:7])[CH2:12][CH2:11]1
Reactant: NC1CCC(NC(=O)OCc2ccccc2)CC1
Reactant: O=C(Cl)COCCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NC1CCC(N2CCOCC2=O)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
13-9.1 6.32 g (40.3 mmol) of (2-chloroethoxy)acetyl chloride are added to the solution of 10 g (40.3 mmol) of benzyl (4-aminocyclohexyl)carbamate and 6.2 ml of triethylamine (TEA) in 300 ml of tetrahydrofuran, and the mixture is subsequently stirred at room temperature for 20 hours. The reaction mixture is then evaporated under reduced pressure, the residue is taken up in 20 ml of water, and the aqueous solution is extracted three times with 20 ml of ethyl acetate each time. After the combined organic phases have been dried over sodium sulfate and the solvent has been stripped off, the residue is taken up in 20 ml of acetonitrile, and 2.3 g of caesium carbonate are added to the resultant solution. The reaction mixture is then left to stir at room temperature for 48 hours and then evaporated under reduced pressure, the residue is taken up in 20 ml of water, and the aqueous solution is extracted four times with 20 ml of ethyl acetate each time. After the combined organic phases have been dried over sodium sulfate and the solvent has been stripped off, the residue is taken up in 50 ml of tetrahydrofuran, 0.3 g of 5% palladium/carbon is added to the resultant solution, and the mixture is hydrogenated until the take-up of hydrogen ceases. The catalyst is subsequently filtered off, and the filtrate is evaporated to dryness under reduced pressure, giving 1.5 g of 4-(4-aminocyclohexyl)morpholin-3-one as a colourless oil; ESI 199. 13-9.2 Analogously to Example 7.3, reaction of cis-N′-BOC-4-hydroxy-D-proline and 4-chlorophenyl isocyanate gives the compound (2R,4R)-1-(4-chlorophenylcarbamoyl)-4-hydroxypyrrolidine-2-carboxylic acid; ESI 285; m.p. 132°. 13-9.3 Analogously to Example 7.1, reaction of the amine 13-9.1 and the acid 13-9.2 gives the compound 1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)cyclohexan-1-yl]}-(2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxamide, ESI 465; m.p. 245°.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[O:14][CH3:15].[CH2:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][NH:17]1>ClCCl.CO>[CH3:15][O:14][C:6]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][N:17]1[CH2:18][CH2:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16]1
Reactant: c1ccc2c(c1)CCNC2
Reactant: COc1cc([N+](=O)[O-])ccc1OCCBr
Solvent: CO
Solvent: ClCCl
Product: COc1cc([N+](=O)[O-])ccc1OCCN1CCc2ccccc2C1

Procedure:
Prepared analogously to Example 1.1.c. from 1 g (3.622 mmol) of 1-(2-bromoethoxy)-2-methoxy-4-nitrobenzene and 1.36 mL (10.87 mmol) of 1,2,3,4-tetrahydroisoquinoline. Yield: 1.4 g (77% of theory); C18H20N2O4 (M=328.36); calc.: molecular ion peak (M+H)+: 329; found: molecular ion peak (M+H)+: 329; Rf value: 0.7 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2([F:19])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>N1C=CC=CC=1>[F:21][C:2]([F:20])([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2([F:19])[CH2:18][CH2:17][N:16]([S:30]([C:27]3[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[CH:29][CH:28]=3)(=[O:32])=[O:31])[CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)C1(F)CCNCC1
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)N2CCC(F)(C(=O)Nc3ccc(OC(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 48.6 %

Procedure:
4-Fluoro-piperidine-4-carboxylic acid (4-trifluoromethoxy-phenyl)-amide (0.1 g) and 4-methoxybenzenesulfonyl chloride (0.067 g) were dissolved in pyridine (10 ml) at RT and under an argon atmosphere and stirred for 24 h at RT. The solvent was evaporated off, the residue was absorbed on silica gel and purified by flash chromatography (AcOEt/heptane, gradient from 0 to 25%) to give the desired 4-fluoro-1-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid (4-trifluoromethoxy-phenyl)-amide (0.075 g) as a white solid. MS (ESI): 475.1 (MH+).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.[C:7]([O:10][CH2:11][CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)(=[O:9])[CH3:8]>ClCCl>[C:7]([O:10][CH2:11][CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:8]2[C:7](=[O:9])[O:10][C:1](=[O:5])[C:2]=2[C:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:13]([CH3:12])[CH:14]=2)=[CH:14]1)(=[O:9])[CH3:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)OCCn1ccc2ccccc21
Solvent: ClCCl
Product: CC(=O)OCCn1cc(C2=C(c3cn(C)c4ccccc34)C(=O)OC2=O)c2ccccc21
Reaction time: 2 h

Procedure:
2.57 ml of oxalyl chloride were added to a solution of 5.7 g of 1-(2-acetoxyethyl)indole in 70 ml of dichloromethane at 0° C. The resulting solution was stirred for 2 hours and the solvent was then evaporated. To the residue, dissolved in 210 ml of dichloromethane, were added 7.7 ml of triethylamine and 5.29 g of 1-methylindole-3-acetic acid under a nitrogen atmosphere. After stirring for 18 hours the solvent was evaporated and the residue was purified on silica gel with ethyl acetate/petroleum ether (1:2). Crystallization from ethyl acetate/hexane gave 1.87 g of 3-[1-(2-acetoxyethyl)-3-indolyl]-4-(1-methyl-3-indolyl)furan-2,5-dione, m.p. 198°-199° C.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl.Cl[CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:4][CH:3]=1
Reactant: ClCCN1CCCC1
Reactant: Oc1ccc(I)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Ic1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A reaction mixture of 44 g (0.2 mol) 4-iodophenol, 34 g (0.2 mol) 1-(2-chloro-ethyl)-pyrrolidine-hydrochloride, 110.56 g (0.8 mol) K2CO3 and 800 mL DMF is stirred for 48 h at RT. The reaction mixture is filtered and the filtrate is evaporated down. The residue is taken up in water and extracted with EtOAc. The organic phase is extracted with saturated NaCl solution and dried over Na2SO4. The purification is carried out by column chromatography on silica gel (EtOAc/MeOH/NH3 85:15:1.5).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:16]1[CH2:21][CH2:20][S:19][CH2:18][CH2:17]1>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:16]2[CH2:21][CH2:20][S:19][CH2:18][CH2:17]2)=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: C1CSCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Brc1ccc(CN2CCSCC2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 1-bromo-4-(bromomethyl)benzene (760 mg) in dry THF (10 ml) containing potassium carbonate (386 mg) was treated dropwise with thiomorpholine (0.36 ml, 369 mg). The resulting mixture was stirred at room temperature under nitrogen for 20 h before filtering and concentrating in vacuo to give impure title compound which was purified by FCC eluting with dichloromethane to give the title compound as a crystalline white solid (634 mg). m.p. 74°-75° C.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=3[O:20][CH3:21])[C:14]([OH:16])=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.O[C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1.C1COCC1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.O>[C:1]12([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=3[O:20][CH3:21])[C:14]([O:16][C:23]3[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)=[O:15])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: NS(=O)(=O)c1ccc(O)cc1
Reactant: COc1ccc(C(=O)O)cc1C12CC3CC(CC(C3)C1)C2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=O)Oc2ccc(S(N)(=O)=O)cc2)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 45.3 %

Procedure:
Into a round bottom flask, there are introduced 2.86 g (10 mmoles) of 3-(1-adamantyl)-4-methoxybenzoic acid, 1.73 g (10 mmoles) of 4-hydroxybenzenesulfonamide and 50 ml of THF. There are added, successively, 2.1 g (10 mmoles) of 1,3-dicyclohexylcarbodiimide and then 1.22 (10 mmoles) of 4-dimethylaminopyridine. The medium is stirred at ambient temperature for 4 hours. The reaction medium is poured into water and extracted with ethyl ether. The organic phase is decanted, washed with water, dried on magnesium sulfate and evaporated. The resulting solid is purified by chromatography on a silica column eluted by a 60:40 mixture of ethyl ether and hexane. After evaporation of the solvents, 2 g (46% yield) of 4-[3-(1-adamantyl)-4-methoxybenzoyloxy]benzenesulfonamide having a melting point of 223°-224° C. are recovered.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=1)=[O:5].[Br:18]Br>C(O)(=O)C>[Br:18][C:10]1[CH:11]=[CH:12][C:7]([NH:6][C:4](=[O:5])[C:3]2[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=2[CH3:1])=[CH:8][C:9]=1[CH3:13]
Reactant: Cc1cccc(NC(=O)c2ccccc2C)c1
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1cc(NC(=O)c2ccccc2C)ccc1Br
Temperature: 12.5 °C
Reaction time: 1 h

Procedure:
3-(2-methylbenzoylamino)toluene (80 g) is dissolved in acetic acid (500 mL), and thereto is added a solution of bromine (19.0 ml) in acetic acid (40 mL) with stirring under ice cooling over a period of about one hour. During which the mixture is cooled at an inner temperature of below 20° C. (mean inner temperature: 10-15° C.) since the temperature raises. The reaction mixture is continuously stirred overnight. The resulting suspension is added to ice-water, and the resulting crystals are taken by filtration, washed with water, and dried at 60° C. The resultant is recrystallized from methanol-water to give 2-bromo-5-(2-methylbenzoylamino)toluene (105.0 g), white needles (yield 97%, Mp 144.5-146.0° C.)
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[NH:9]1)=[O:7])(C)(C)C.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>ClCCl>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[Cl:19][C:15]1[C:14]([F:20])=[C:13]([CH:12]2[C:11]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[F:30])([C:21]#[N:22])[CH:10]([CH2:31][CH:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)C1NC(CC2CCOCC2)C(C#N)(c2ccc(Cl)cc2F)C1c1cccc(Cl)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CC1(c2ccc(Cl)cc2F)C(CC2CCOCC2)NC(C(=O)O)C1c1cccc(Cl)c1F
Yield: 80 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(tetrahydro-pyran-4-ylmethyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 101b (0.45 g, 0.81 mmol) was vented with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(tetrahydro-pyran-4-ylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (0.4 g, 80%).
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:13]=[N:12][C:11]([C:14]([NH2:16])=[O:15])=[CH:10][CH:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[CH2:21]([NH2:26])[CH2:22][CH:23]([CH3:25])[CH3:24].[BH4-].[Na+]>CO>[CH3:20][O:19][C:5]1[CH:4]=[C:3]([CH2:1][NH:26][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[N:13]=[N:12][C:11]([C:14]([NH2:16])=[O:15])=[CH:10][CH:9]=1
Reactant: CC(C)CCN
Reactant: COc1cc(C=O)ccc1Oc1ccc(C(N)=O)nn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(CNCCC(C)C)ccc1Oc1ccc(C(N)=O)nn1
Reaction time: 8 h
Yield: 44.4 %

Procedure:
Place 6-(4-formyl-2-methoxyphenoxy)pyridazine-3-carboxamide (Example 721, Part C) (0.200 g, 0.732 mmol), isoamylamine (0.0670 g, 0.769 mmol) and 3 Å molecular sieves in a vial. Add methanol (3.6 mL), cap and stir overnight. Add NaBH4 (ca. 3-5 eq in two portions) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 10% to 20% (2.0 M NH3 in methanol) in ethyl acetate. Concentrate the fractions containing the product. Take the solid up in ethyl acetate (50 mL) and wash with 1.0 N NaOH (2× 10 mL). Dry the organic layer over Na2SO4, filter and concentrate to give the title compound (0.112 g, 44%): TOF MS ES+ 345.2 (M+H)+, HRMS calcd for C18H25N4O3 345.1927 (M+H)+, found 345.1926, time 0.52 min; Anal. Calcd for C18H24N4O3: C, 62.77; H, 7.02; N, 16.27. Found: C, 62.29; H, 7.01; N, 15.50.
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[N:10]=[C:9]([CH2:12][CH3:13])[CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.[CH3:14][N:15]=[C:16]=[S:17]>>[CH2:12]([C:9]1[CH:8]=[CH:7][C:6]2[CH2:5][CH2:4][CH2:3][CH:2]([NH:1][C:16](=[S:17])[NH:15][CH3:14])[C:11]=2[N:10]=1)[CH3:13]
Reactant: CCc1ccc2c(n1)C(N)CCC2
Reactant: CN=C=S
Product: CCc1ccc2c(n1)C(NC(=S)NC)CCC2

Procedure:
The amino compound of Example 17 may be converted to the title compound by treatment with methylisothiocyanate according to the procedure of Example 4.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:10]=[CH:11][C:12]1[CH:13]=[CH:14][C:15]([S:18]([O:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:20])=[O:19])=[CH:16][CH:17]=1
Reactant: C=Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=Cc1ccc(S(=O)(=O)OCCc2ccccc2)cc1

Procedure:
2-Phenylethanol (3.1 g) was reacted with p-styrene sulfonyl chloride (5.3 g) and triethylamine (2.7 g) in 20 ml of dichloromethane for 3 hours to give the desired product as a light yellow viscous oil that was purified by passing through basic aluminum oxide.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([CH2:14][CH:15]2[CH2:19][CH2:18][N:17]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:16]2=[O:26])=[C:9]([Cl:27])[CH:8]=1)(=O)=O.[C:30]([CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)([OH:32])=[O:31]>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>[Cl:27][C:9]1[CH:8]=[C:7]([C:38]2[CH:39]=[CH:40][C:35]([CH2:34][CH2:33][C:30]([OH:32])=[O:31])=[CH:36][CH:37]=2)[CH:12]=[C:11]([Cl:13])[C:10]=1[CH2:14][CH:15]1[CH2:19][CH2:18][N:17]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:16]1=[O:26]
Reactant: O=C1C(Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)CCN1C1CCCCC1
Reactant: O=C(O)CCc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(O)CCc1ccc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)cc1
Temperature: 95 °C
Yield: 124.8 %

Procedure:
Charge a vial with 3,5-dichloro-4-((1-cyclohexyl-2-oxopyrrolidin-3-yl)methyl)phenyl trifluoromethanesulfonate (Example 240) (0.30 g, 0.63 mmol), 4-(2-carboxyethyl)benzene boronic acid (0.123 g, 0.634 mmol) and Pd(Ph3)4 (0.073 g, 0.063 mmol) in 1,4-dioxane (5 mL) and 2 M Na2CO3 (1 mL) and heat to 95° C. for 16 hours. Cool the reaction, extract with ethyl acetate and water, dry the organic layer (Na2SO4) and purify by HPLC (5 to 95% acetonitrile in water with 0.1% trifluroacetic acid buffer) to afford 373 mg (62%) of the title compound: LC-MS (ES +) m/z=exact mass calcd for C26H29Cl2NO3 473, found 474 and 476 (M+1 and M+3, 100%).
Reaction SMILES: [F-].[K+].[C:3]([O:7][C:8]([N:10]1[CH2:17][CH:16]2[CH:12]([CH2:13][C:14]3[C:20]([Br:21])=[C:19](I)[S:18][C:15]=32)[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[F:23][C:24]([Si](C)(C)C)([F:26])[F:25]>CN(C=O)C.CN1CCCC1=O.[Cu]I>[C:3]([O:7][C:8]([N:10]1[CH2:17][CH:16]2[CH:12]([CH2:13][C:14]3[C:20]([Br:21])=[C:19]([C:24]([F:26])([F:25])[F:23])[S:18][C:15]=32)[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC2Cc3c(sc(I)c3Br)C2C1
Agent: [Cu]I
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CC2Cc3c(sc(C(F)(F)F)c3Br)C2C1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Dipyridyl (31 mg, 0.20 mmol), CuI (34 mg, 0.18 mmol) and KF (10 mg, 0.18 mmol) were added to a solution of the product from step b) (78 mg, 0.17 mmol) in 1.6 mL of 1:1 DMF/1-methyl-2-pyrollidinone. The reaction mixture was stirred for 1 hour at 80° C. and then cooled to room temperature. Next, trifluoromethyl trimethylsilane (118 mg, 0.83 mmol) was added and the reaction mixture was heated to 80° C. for 12 hours. The reaction was cooled to room temperature and filtered through a silica plug eluting with CH2Cl2 (10 ml). The organic mixture was washed with brine (2×3 mL), dried with MgSO4, and was concentrated to a dark oil that was purified by preparative LC/MS to give the subtitle compound. MS calculated for C15H17BrF3NO2S +H: 412, observed: 413.
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21]C>B(Br)(Br)Br>[N:4]1[NH:3][N:2]=[N:1][C:5]=1[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21]
Reactant: COc1ccccc1-c1n[nH]c2ccc(-c3nn[nH]n3)cc12
Agent: BrB(Br)Br
Product: Oc1ccccc1-c1n[nH]c2ccc(-c3nn[nH]n3)cc12
Temperature: 25 °C
Reaction time: 96 h
Yield: 6.3 %

Procedure:
The compound of Example 161 (0.050 g, 0.17 mmol) was suspended in 1 mL of boron tribromide (1.0 M commercial solution in dichloromethane). The reaction mixture was stirred at room temperature in a closed system for 4 days to achieve completion. The product was then collected by filtration and washed with small portions of dichloromethane. Trituration in a few mL of tetrahydrofuran and filtration did not afford satisfactory purity. Final purification by preparative HPLC (30-80% acetonitrile in water, 20 mm) afforded 3 mg of pure product. (6% yield): 1H NMR (DMSO-d6) δ 13.6 (s, 1H), 10.3 (s, 1H), 8.7 (s, 1H), 8.1 (d, 1H), 7.8 (t, 2H), 7.3 (t, 1H), 7.08-7.00 (m, 2H); ES-MS (m/z) 279 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:11]3=[N:12][C:13](Cl)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:44]2[CH:45]=[C:46]([NH:50][C:51]([CH:53]3[CH2:58][CH2:57][O:56][CH2:55][CH2:54]3)=[O:52])[CH:47]=[CH:48][CH:49]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[NH2:1][C:2]1[C:7]([C:8]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:11]3=[N:12][C:13]([C:44]4[CH:49]=[CH:48][CH:47]=[C:46]([NH:50][C:51]([CH:53]5[CH2:54][CH2:55][O:56][CH2:57][CH2:58]5)=[O:52])[CH:45]=4)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(Cl)nc43)cc2)CCC1
Reactant: CC1(C)OB(c2cccc(NC(=O)C3CCOCC3)c2)OC1(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(-c5cccc(NC(=O)C6CCOCC6)c5)nc43)cc2)CCC1
Temperature: 80 °C
Yield: 50.6 %

Procedure:
To a suspension of tert-butyl (1-{4-[2-(2-aminopyridin-3-yl)-5-chloro-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}cyclobutyl)carbamate (50 mg) and N-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]tetrahydro-2H-pyran-4-carboxamide (67 mg) and potassium phosphate (65 mg) and PdCl2(dppf)CH2Cl2 (8 mg) in dioxane (2 mL) and H2O (0.2 mL) was degassed for 5 minutes and then heated to 80° C. for 18 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (2 times: 0-10% methanol in chloroform then 0-10% methanol in ethyl acetate) gave the product (34 mg, 51%).