Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]=[N:9][C:10]2[C:15]([CH:16]([CH3:18])[CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:5]=[CH:4][CH:3]=1.[CH2:22]([O:26][C:27]1[C:28]([CH3:37])=[CH:29][C:30]([CH3:36])=[C:31](B(O)O)[CH:32]=1)[CH2:23][CH:24]=[CH2:25].[OH-].[K+]>[Br-].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[Pd+].C1COCC1>[CH2:22]([O:26][C:27]1[C:28]([CH3:37])=[CH:29][C:30]([CH3:36])=[C:31]([C:2]2[N:7]=[C:6]([CH:8]=[N:9][C:10]3[C:15]([CH:16]([CH3:18])[CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=3[CH:19]([CH3:21])[CH3:20])[CH:5]=[CH:4][CH:3]=2)[CH:32]=1)[CH2:23][CH:24]=[CH2:25]
Reactant: C=CCCOc1cc(B(O)O)c(C)cc1C
Reactant: CC(C)c1cccc(C(C)C)c1N=Cc1cccc(Br)n1
Agent: [Pd+]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Solvent: C1CCOC1
Product: C=CCCOc1cc(-c2cccc(C=Nc3c(C(C)C)cccc3C(C)C)n2)c(C)cc1C
Reaction time: 5 h

Procedure:
In the glovebox, N-((6-bromopyridin-2-yl)methylene)-2,6-diisopropylaniline (1.392 g, 4.03 mmol) is combined with 5-(but-3-enyloxy)-2,4-dimethylphenylboronic acid (1.000 g, 4.03 mmol) and KOH (0.678 g, 12.1 mmol) and dry THF (40 mL) is added. Palladium(I) tri-tert-butylphosphine bromide, dimer [PtBu3)PdBr]2 (0.062 g, 0.040 mmol) is added and the reaction mixture is stirred for five hours, removed from the glovebox, and ether (100 mL) is added. The solution is washed with water (50 mL) and then brine (50 mL), dried over magnesium sulfate, filtered, and solvents removed by evaporation. Yield=1.86 g of orange sticky oil. The product is used without further purification.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH:10]([NH:18][C:19]1[C:28]2[C:23](=[C:24]([C:37](=[O:39])[NH2:38])[CH:25]=[C:26]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:27]=2)[N:22]=[CH:21][N:20]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)C)(C)(C)C.C1COCC1.Cl>O1CCOCC1>[CH2:30]([O:29][C:26]1[CH:27]=[C:28]2[C:23](=[C:24]([C:37]([NH2:38])=[O:39])[CH:25]=1)[N:22]=[CH:21][N:20]=[C:19]2[NH:18][CH:10]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[CH2:9][NH:7][CH3:6])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CN(CC(Nc1ncnc2c(C(N)=O)cc(OCc3ccccc3)cc12)c1cccc(Cl)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CNCC(Nc1ncnc2c(C(N)=O)cc(OCc3ccccc3)cc12)c1cccc(Cl)c1
Reaction time: 8 h
Yield: 97 %

Procedure:
A scintillation vial equipped with a stir bar was charged with [2-(6-benzyloxy-8-carbamoyl-quinazolin-4-ylamino)-2-(3-chloro-phenyl)-ethyl]-methyl-carbamic acid tert-butyl ester (20 mg, 0.035 mmol) and THF, (3 mL). Then, 4 M HCl in dioxane, (3 mL) was added at RT and the mixture was stirred overnight. After 18 h, a white precipitate had formed and LCMS indicated consumption of SM. The mixture was diluted with Et2O (30 mL) and the precipitate was filtered through a filter paper and washed with Et2O, (30 mL). The solid was dried under vacuum. Amount obtained: 15 mg, 0.034 mmol, 97% yield. LCMS (ESI) 462 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:11]([O-])=O)[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.NN.C(Cl)(Cl)Cl>C(O)(C)C.[Pd]>[Br:1][C:2]1[CH:3]=[C:4]([NH2:11])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2
Reactant: O=[N+]([O-])c1cc(Br)c2[nH]ccc2c1
Agent: [Pd]
Agent: NN
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: Nc1cc(Br)c2[nH]ccc2c1
Yield: 71.4 %

Procedure:
A solution of 7-bromo-5-nitroindole (0.68 g, 2.8 mmol), hydrazine (1.0 mL, 31 mmol) and 10% Pd/C (50 mg) in 50 mL of isopropanol was stirred at reflux for 2 h. The reaction mixture was filtered and concentrated in vacuo, yielding oily residue which was subjected to column chromatography (CHCl3, neat) to produce 0.41 g (2.0 mmol, 70%) of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][CH:9]([C:11]2[N:16]=[N:15][C:14]([NH:17][C:18]3[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=3)=[N:13][CH:12]=2)[CH3:10])=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>ClCCCl>[F:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]2[N:16]3[C:11]([CH:12]=[N:13][C:14]([NH:17][C:18]4[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=4)=[N:15]3)=[C:9]([CH3:10])[N:8]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3ccc(F)cc3)nn2)cc(OC)c1OC
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: COc1cc(Nc2ncc3c(C)nc(-c4ccc(F)cc4)n3n2)cc(OC)c1OC
Yield: 15.8 %

Procedure:
In a similar manner as described for Example 1, 4-fluoro-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (Intermediate 13) (0.16 g, 0.37 mmol) in 1,2-dichloroethane (20 mL) and phosphorus oxychloride (0.28 mL, 3.0 mmol) gave 7-(4-fluorophenyl)-5-methyl-N-(3,4,5-trimethoxyphenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (0.024 g) as a yellow solid. 1H NMR (CDCl3): δ8.78 (s, 1H), 8.50-8.42 (m, 2H), 7.17-7.10 (m, 2H), 7.01 (s, 1H), 6.86 (s, 2H), 3.85 (s, 3H), 3.82 (s, 6H), 2.58 (s, 3H). MS m/z 410 (M+1).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[C:13]#[N:14])=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1>[Pd].C(OCC)(=O)C>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[C:13]#[N:14])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccccc1C1=CCC2(CC1)OCCO2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: N#Cc1ccccc1C1CCC2(CC1)OCCO2

Procedure:
To a suspension of 10% palladium on carbon (1.5 g) in ethyl acetate (200 mL) at room temperature under argon was added a solutioin of 2-(1,4-Dioxaspiro[4.5]dec-7-en-8-yl)benzonitrile (8.9 g, 36.7 mmol) in ethyl acetate (50 mL). Hydrogen gas was then bubbled into the reaction mixture until all the starting material was consumed. The reaction was filtered through celite to remove the catalyst and the solution concentrated to give the product as a colorless oil.
Reaction SMILES: [CH:1]1([O:7][C:8]2[N:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B.C1COCC1>C1COCC1>[NH2:15][CH2:14][C:11]1[CH:12]=[N:13][C:8]([O:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[CH:9][CH:10]=1
Reactant: N#Cc1ccc(OC2CCCCC2)nc1
Agent: B
Solvent: C1CCOC1
Product: NCc1ccc(OC2CCCCC2)nc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 60.2 %

Procedure:
Dissolve 6-cyclohexyloxy-pyridine-3-carbonitrile (1 g, 5 mmol) in anhydrous THF (7 mL) under nitrogen and cool the mixture at 0° C. Add borane-THF complex (15 mL, 15 mmol, 1M solution in THF) and stir the reaction mixture at room temperature overnight. Pour slowly the reaction mixture into an ice-cold 5N aqueous HCl (50 mL) and stir the resulting solution for 4 h. Concentrate in vacuo, take up the resulting solid with a minimum amount of methanol and filter through a SCX-2 column eluting with methanol followed by 3N ammonia in methanol to obtain the title compound as a yellow oil (621 mg, 62%). MS (ES+) m/z: 207 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:6]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[CH:5]=1)(=O)[CH3:2].Cl.[O:25]([NH2:27])[CH3:26].N1C=CC=CC=1>C(O)C>[F:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[NH:15][C:6]1[CH:5]=[C:4]([C:1](=[N:27][O:25][CH3:26])[CH3:2])[CH:14]=[CH:13][C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(=O)c1ccc(NS(C)(=O)=O)c(Nc2ccc(F)cc2F)c1
Reactant: CON
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CON=C(C)c1ccc(NS(C)(=O)=O)c(Nc2ccc(F)cc2F)c1
Temperature: 25 °C
Yield: 86 %

Procedure:
A mixture of 4'-acetyl-2'-(2,4-difluorophenylamino)methanesulfonanilide (1.5 g), methoxylamine hydrochloride (0.4 g) and pyridine (0.43 ml) in ethanol (15 ml) was refluxed for 3 hours. The mixture was cooled to room temperature. Precipitates were filtered, washed with water, and recrystallized from ethanol to give colorless needles of 2'-(2,4-difluorophenylamino)-4'-[1-(methoxyimino)ethyl]methanesulfonanilide (1.4 g).
Reaction SMILES: [N:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]([CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:8]2=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[O:26]=O>>[OH:26][C:9]1([CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]1=[O:23]
Reactant: O=O
Reactant: O=C1C(Cc2ccncc2)c2ccccc2N1N1CCCCC1
Agent: [H-]
Agent: [Na+]
Product: O=C1N(N2CCCCC2)c2ccccc2C1(O)Cc1ccncc1
Yield: 25 %

Procedure:
1,3-dihydro-1-(1-piperidinyl)-3-(4-pyridinyl methyl)-2H-indol-2-one could be reacted with sodium hydride and oxygen as reported in Example 22. After column chromatography, the product was recrystallized from hexane-chloroform to give the product as a brown solid, m.p. 156°-158° C. in 25% yield. High Res. Mass Spec. Calcd. for C19H21N3O2 : 324.1712 (M+H). Found: 324.1709.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:31]=[CH:30][C:23]([C:24]([NH:26][CH2:27][CH2:28][OH:29])=[O:25])=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=O)=[C:4]([CH3:32])[CH:3]=1.Cl.[NH2:34][OH:35].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:31]=[CH:30][C:23]([C:24]([NH:26][CH2:27][CH2:28][OH:29])=[O:25])=[CH:22][CH:21]=2)[CH2:9]/[C:10](=[N:34]\[OH:35])/[C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[C:4]([CH3:32])[CH:3]=1
Reactant: NO
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NCCO)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NCCO)cc1

Procedure:
In analogy to example 151, step 3, 4-(1-(4-chloro-2-methylphenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)-N-(2-hydroxyethyl)benzamide was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound containing less than 10% of the corresponding Z isomer as an off-white solid, MS (ESI+): m/z=468.2 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:18]=[N:19][CH:20]=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([N:38]5[CH2:43][CH2:42][N:41]([CH:44]6[CH2:47][O:46][CH2:45]6)[CH2:40][C@@H:39]5[CH3:48])=[CH:34][N:33]=4)[C:28](=[O:49])[N:27]([CH3:50])[CH:26]=3)[C:22]=1[CH:23]=[O:24])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:18]=[N:19][CH:20]=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([N:38]5[CH2:43][CH2:42][N:41]([CH:44]6[CH2:47][O:46][CH2:45]6)[CH2:40][C@@H:39]5[CH3:48])=[CH:34][N:33]=4)[C:28](=[O:49])[N:27]([CH3:50])[CH:26]=3)[C:22]=1[CH2:23][OH:24])[N:9]=[CH:8]2)([CH3:3])([CH3:2])[CH3:4]
Reactant: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3cncc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3C=O)cn(C)c2=O)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3cncc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)cn(C)c2=O)nc1
Reaction time: 0.5 h
Yield: 18.7 %

Procedure:
To a suspension of 109b (95 mg, 0.106 mmol) at 0° C. in methanol (5 mL) was added sodium borohydride (24 mg, 0.636 mmol) and the mixture was stirred for 30 minutes. Then the reaction mixture was quenched with water (1.0 mL) and concentrated. The residue was purified by reverse-phase prep-HPLC to afford 109 (13.5 mg, 18.7%). LCMS: [M+H]+ 681. 1H NMR (500 MHz, CDCl3) δ 8.76 (s, 1H), 8.65 (d, J=2.0, 1H), 8.61 (s, 1H), 8.32 (d, J=2.5, 1H), 7.96 (d, J=3.0, 1H), 7.82 (s, 1H), 7.56-7.58 (m, 2H), 7.40 (d, J=2.0, 1H), 7.28-7.31 (m, 1H), 6.81 (d, J=9.0, 1H), 4.61-4.70 (m, 4H), 4.43 (s, 2H), 3.95 (s, 1H), 3.72 (s, 3H), 3.45-3.53 (m, 2H), 3.07 (t, J=5.25, 2H), 2.43-2.56 (m, 3H), 2.18-2.22 (m, 1H), 1.43 (s, 9H), 0.99 (d, J=6.5, 3H)
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:29]([C:31]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:32]=1[CH:33]=[CH:34][NH:35]2)=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:29][C:31]3[CH:39]=[CH:38][CH:37]=[C:36]4[C:32]=3[CH:33]=[CH:34][NH:35]4)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1cccc2[nH]ccc12
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4cccc5[nH]ccc45)c3)c(Cc3ccccc3)cnc12

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 4-formylindole to the procedure of step 1, Example 66. MS (ES) m/z 506.2.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[C:9](I)=[N:10][C:11]([CH3:14])=[CH:12][CH:13]=1)(=[O:3])[CH3:2].[O:28]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29]1>>[C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[C:9]([C:30]2[CH:31]=[CH:32][O:28][CH:29]=2)=[N:10][C:11]([CH3:14])=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: OB(O)c1ccoc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(C)nc1I
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(C)nc1-c1ccoc1

Procedure:
By carrying out the operation analogously to example 1, starting from 2-iodo-6-methyl-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside obtained according to preparation V, and 3-furanboronic acid, the desired product is obtained in the form of a white solid (yield=42%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[N:13][CH:14]=2)O1.Br[C:21]1[N:26]=[C:25]2[S:27][C:28]([NH:30][C:31](=[O:43])[C:32]3[CH:37]=[CH:36][C:35]([C:38]([CH3:42])([CH3:41])[CH2:39][OH:40])=[CH:34][CH:33]=3)=[N:29][C:24]2=[CH:23][CH:22]=1>>[C:16]([NH:15][C:12]1[N:13]=[CH:14][C:9]([C:21]2[N:26]=[C:25]3[S:27][C:28]([NH:30][C:31](=[O:43])[C:32]4[CH:37]=[CH:36][C:35]([C:38]([CH3:41])([CH3:42])[CH2:39][OH:40])=[CH:34][CH:33]=4)=[N:29][C:24]3=[CH:23][CH:22]=2)=[CH:10][CH:11]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)(CO)c1ccc(C(=O)Nc2nc3ccc(Br)nc3s2)cc1
Product: CC(=O)Nc1ccc(-c2ccc3nc(NC(=O)c4ccc(C(C)(C)CO)cc4)sc3n2)cn1
Yield: 14 %

Procedure:
The titled compound (yield=14%, white solid) was prepared using a procedure analogous to that described in connection with 10 (Example 10) except N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)acetamide and 2F (Example 2) were used as starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.27 (s, 6H) 2.14 (s, 3H) 3.49 (d, J=5.31 Hz, 2H) 4.78 (t, J=5.31 Hz, 1H) 7.58 (d, J=8.59 Hz, 2H) 8.06-8.18 (m, 3H) 8.18-8.26 (m, 2H) 8.52 (dd, J=8.84, 2.53 Hz, 1H) 9.09 (d, J=1.77 Hz, 1H) 10.73 (s, 1H) 13.00 (s, 1H); ESI-MS: m/z 462.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:41]=[CH:40][C:5]2[N:6]([CH3:39])[C:7](=[O:38])[CH:8]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17]CC4C=CC(OC)=CC=4)=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:41]=[CH:40][C:5]2[N:6]([CH3:39])[C:7](=[O:38])[CH:8]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=3)[C:4]=2[CH:3]=1
Reactant: COc1ccc(COc2ccc(C3=NC(Cc4ccc(C(F)(F)F)cc4)C(=O)N(C)c4ccc(Cl)cc43)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CN1C(=O)C(Cc2ccc(C(F)(F)F)cc2)N=C(c2ccc(O)cc2)c2cc(Cl)ccc21
Reaction time: 3 h

Procedure:
(Z)-7-chloro-5-(4-(4-methoxybenzyloxy)phenyl)-1-methyl-3-(4-(trifluoromethyl)benzyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (50 mg, 0.086 mmol) was dissolved in 4 N HCl in dioxane (3 mL) and stirred for 3 h. The solution was then concentrated, and sonicated in 5 mL of diethyl ether. The product was collected by filtration as a bright yellow solid (24.2 mg, 61%). 1HNMR (300 MHz, DMSO-d6) δ 3.30 (s, 3H), 3.32-3.43 (m, 3H), 6.80 (d, 2H), 7.22 (d, 1H), 7.30-7.40 (m, 2H), 7.50-7.78 (m, 6H); ESI m/z measured 459.1078 [M+H+], calculated 459.1087. The following compounds were prepared based on the above procedures:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][C:8]1[N:9]=[CH:10][N:11]([C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=1)[C:3]([O:5][CH3:6])=[O:4].Cl[CH2:33][CH2:34][N:35]([CH2:46][CH2:47]Cl)[S:36]([C:39]1[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=1)(=[O:38])=[O:37]>C(N(C(C)C)CC)(C)C.C(#N)C>[CH3:45][C:42]1[CH:43]=[CH:44][C:39]([S:36]([N:35]2[CH2:34][CH2:33][N:1]([C@@H:2]([CH2:7][C:8]3[N:9]=[CH:10][N:11]([C:13]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:12]=3)[C:3]([O:5][CH3:6])=[O:4])[CH2:47][CH2:46]2)(=[O:38])=[O:37])=[CH:40][CH:41]=1
Reactant: Cc1ccc(S(=O)(=O)N(CCCl)CCCl)cc1
Reactant: COC(=O)[C@@H](N)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)N1CCN(S(=O)(=O)c2ccc(C)cc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 19 %

Procedure:
A suspension of methyl (2S)-2-amino-3-(1-trityl-1H-imidazol-4-yl)propanoate (1 g, 2.4 mmol) in diisopropylethylamine (5 ml), was stirred at room temperature for 20 minutes. N,N-Bis(2-chloroethyl)-4-methylbenzenesulfonamide (720 mg, 2.4 mmol) was added and the mixture was stirred at reflux for 3 hours. The mixture was allowed to cool and diluted with acetonitrile. The resultant solution was concentrated under reduced pressure and the residue was suspended in aqueous sodium carbonate solution and extracted with dichloromethane (3×20 ml). The combined organic extracts were washed with brine (3×20 ml), dried (Na2SO4), filtered, and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a solvent gradient of dichloromethane:methanol (99:1). The isolated material was dissolved in ether and the resultant solution concentrated under reduced pressure to afford the title compound as a colorless foam, 300 mg, 19% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:14])([CH3:13])[C:11](=N)[N:10]([C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:17]=3)[C:9]2=[S:28])=[CH:4][CH:3]=1.C[OH:30].O>Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:14])([CH3:13])[C:11](=[O:30])[N:10]([C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:17]=3)[C:9]2=[S:28])=[CH:4][CH:3]=1
Reactant: Cc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=N)C2(C)C)cc1
Reactant: CO
Agent: Cl
Solvent: O
Product: Cc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C2(C)C)cc1
Temperature: 25 °C
Yield: 98 %

Procedure:
A mixture of 5b (0.121 g, 0.3 mmol) in HCl aq., 2N (2 ml) and methanol (5 ml) was heated to reflux for 2 h. After being cooled to room temperature, the reaction mixture was poured into cold water (10 ml) and extracted with ethyl acetate (10 ml). The organic layer was dried over MgSO4, concentrated and chromatographed (dichloromethane) to yield 4-[3-(4-methylphenyl)-4,4 -dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-trifluoromethylbenzonitrile, 5c (0.118 g, 0.294 mmol, 98%) as a white powder.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:21](O)=[O:22])[C:7]3[C:12]([CH3:13])=[N:11][N:10]([CH:14]4[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]4)[C:8]=3[N:9]=2)[CH2:3][CH2:2]1.[NH2:24][CH2:25][C:26]1[C:27](=[O:34])[NH:28][C:29]([CH3:33])=[CH:30][C:31]=1[CH3:32].ON1C2N=CC=CC=2N=N1.C(Cl)CCl.CN1CCOCC1>CS(C)=O.O>[CH:1]1([C:4]2[CH:5]=[C:6]([C:21]([NH:24][CH2:25][C:26]3[C:27](=[O:34])[NH:28][C:29]([CH3:33])=[CH:30][C:31]=3[CH3:32])=[O:22])[C:7]3[C:12]([CH3:13])=[N:11][N:10]([CH:14]4[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]4)[C:8]=3[N:9]=2)[CH2:2][CH2:3]1
Reactant: Cc1nn(C2CCN(C)CC2)c2nc(C3CC3)cc(C(=O)O)c12
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: ClCCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(C3CC3)nc3c2c(C)nn3C2CCN(C)CC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 9.3 %

Procedure:
6-Cyclopropyl-3-methyl-1-(1-methyl-4-piperidinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (150 mg, 0.477 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (117 mg, 0.620 mmol), 1-hydroxy-7-azabenzotriazole (130 mg, 0.954 mmol), EDC (183 mg, 0.954 mmol) and N-methylmorpholine (0.210 mL, 1.909 mmol) were suspended in DMSO(10 mL) and stirred at room temperature for 16 h. Next was added 25 mL of water, stirred for 10 minutes, and then extracted with EtOAc (5×). The organic layers were concentrated in vacuo to afford 20 mg product. The aqueous phase was concentrated in vacuo and the crude residue purified by reverse phase HPLC (mobile phase: 10-60% ACN in H2O, 0.1% NH4OH) to afford additional product. The final product was collected as a solid, 0.100 g (47%). LCMS E-S (M+H)=449.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.97-1.05 (m, 4 H), 1.79 (d, J=9.60 Hz, 2 H), 2.11 (s, 3 H), 2.15 (d, J=8.34 Hz, 3 H), 2.21 (s, 3 H), 2.23-2.27 (m, 3 H), 2.35 (s, 3 H), 2.91 (d, J=8.08 Hz, 2 H), 4.33 (d, J=4.80 Hz, 2 H), 4.49-4.72 (m, 1 H), 5.86 (s, 1 H), 6.97 (s, 1 H), 6.92-7.07 (m, 1 H), 8.58 (t, J=4.93 Hz, 1 H), 11.50 (s, 1 H).
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[C:12]1([CH:18]([NH:21][C:22]([C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[NH:29][CH:28]=[CH:27]3)=[O:23])[CH2:19][CH3:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[K+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(Cl)Cl>[C:12]1([CH:18]([NH:21][C:22]([C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[N:29]([S:1]([C:4]2[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=2)(=[O:3])=[O:2])[CH:28]=[CH:27]3)=[O:23])[CH2:19][CH3:20])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCC(NC(=O)c1ccc2[nH]ccc2c1)c1ccccc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: ClCCl
Product: CCC(NC(=O)c1ccc2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1)c1ccccc1

Procedure:
Tosyl chloride (1.1 equiv), benzyltriethylammonium chloride (0.5 equiv) was added to a solution of N-(1-phenylpropyl)-1H-indole-5-carboxamide in CH2Cl2, KOH (1.3 equiv) at room temperature. After the reaction was completed, the solvent was evaporated and the residual was purified by silica gel column chromatography to get the product. LC-MS 433 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[C:11]([CH3:23])=[C:12]([C:14]([NH:16][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:15])[N:13]=1.C(N(CC)CC)C.[CH3:38][CH:39]([CH3:46])[CH2:40][CH2:41][S:42](Cl)(=[O:44])=[O:43].O>ClCCl>[CH3:38][CH:39]([CH3:46])[CH2:40][CH2:41][S:42]([O:30][C:27]1[CH:26]=[CH:25][C:24]([N:10]2[C:11]([CH3:23])=[C:12]([C:14]([NH:16][N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:15])[N:13]=[C:9]2[C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[CH:29][CH:28]=1)(=[O:44])=[O:43]
Reactant: CC(C)CCS(=O)(=O)Cl
Reactant: Cc1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(O)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(OS(=O)(=O)CCC(C)C)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 71 %

Procedure:
2-(2,4-Dichlorophenyl)-1-(4-hydroxyphenyl)-5-methyl-N-piperidin-1-yl-1H-imidazole-4-carboxamide, prepared as described in Ex. 2, Step 1 (50 mg, 0.11 mmol) was dissolved in dichloromethane (3.0 ml), cooled to 0° C. and triethylamine (20 μl, 0.13 mmol) was added to the mixture. The resulting mixture was cooled to −78° C. and 3-methylbutane-1-sulfonyl chloride (23 mg, 0.13 mmol) was carefully added. The reaction was stirred at −78° C. for 1.5 h. Water was added to the reaction, the product extracted with dichloromethane and dried. The solvent was removed under reduced pressure and separation by preparatory HPLC gave the title compound (46 mg, 71%) as a solid.