Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:10][NH:11][C:12]([C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([C:21]([NH:23][CH2:24][C:25]3[C:26]([NH:38][CH:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)=[C:27]4[CH:35]=[N:34][N:33]([CH2:36][CH3:37])[C:28]4=[N:29][C:30]=3[CH2:31][CH3:32])=[O:22])[CH:15]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH:45]([C:47]1[CH:48]=[C:49](B(O)O)[CH:50]=[CH:51][CH:52]=1)=[O:46].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C(Cl)Cl.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>[CH2:36]([N:33]1[C:28]2=[N:29][C:30]([CH2:31][CH3:32])=[C:25]([CH2:24][NH:23][C:21]([C:16]3[CH:17]=[C:18]([CH3:20])[CH:19]=[C:14]([C:12]([NH:11][CH2:10][C:4]4[CH:3]=[C:2]([C:51]5[CH:50]=[CH:49][CH:48]=[C:47]([CH:45]=[O:46])[CH:52]=5)[C:7]([O:8][CH3:9])=[CH:6][CH:5]=4)=[O:13])[CH:15]=3)=[O:22])[C:26]([NH:38][CH:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[C:27]2[CH:35]=[N:34]1)[CH3:37]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)NCc2ccc(OC)c(Br)c2)c1
Reactant: O=Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)NCc2ccc(OC)c(-c3cccc(C=O)c3)c2)c1
Yield: 64.4 %

Procedure:
N-{[3-Bromo-4-(methyloxy)phenyl]methyl}-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-5-methyl-1,3-benzenedicarboxamide (900 mg, 1.356 mmol), (3-formylphenyl)boronic acid (203 mg, 1.356 mmol), potassium carbonate (562 mg, 4.07 mmol), and Pd(Ph3P)4 (78 mg, 0.068 mmol) were divided into 3 portions and added to three 2-5 mL Biotage microwave vials in 1,4-dioxane (3 mL) and water (1 mL). The vials were capped and the mixtures were microwaved at normal power in the Emrys Optimizer at 100° C. for 15 min. The combined crude product was partitioned between EtOAc (75 mL) and water (20 mL). The phases were separated and the organic phase was washed with water (2×20 mL), brine (20 mL), dried over anhydrous Na2SO4, filtered and evaporated to give the crude residue. It was taken up in DCM and absorbed on Isolute® Sorbent and purified by CombiFlash using an 80 g silica column eluted with 0-10% MeOH/DCM. The product fractions were combined and concentrated to give N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-{[3′-formyl-6-(methyloxy)-3-biphenylyl]methyl}-5-methyl-1,3-benzenedicarboxamide (632 mg, 0.873 mmol, 64.3% yield) as a white solid. LC-MS m/z 689.8 (M+H)+, 0.95 min (ret time); mp 117-119° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10].[CH2:11](CN)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+].[C:28](#[N:30])C>CC(OC)(C)C>[CH2:11]([N:30]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10])[CH3:28])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: OCCCCCCCCCl
Reactant: CC#N
Reactant: NCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: COC(C)(C)C
Product: CN(CCCCCCCCO)Cc1ccccc1
Temperature: 80 °C
Reaction time: 25 h
Yield: 96 %

Procedure:
From 8-Chlorooctan-1-ol: A 2-L flask was charged with benzylmethylamine (270 g, 2.23 mol), sodium carbonate (157 g, 1.48 mol), sodium iodide (11.1 g, 0.074 mol), 8-chlorooctanol (122 g, 0.74 mol) and acetonitrile (1000 mL) and the resulting suspension was stirred at 80° C. for 20-30 h. The reaction mixture was then concentrated to a volume of about 500 mL and water (600 mL) and tert-butyl methyl ether (1000 mL) were added. The MTBE layer was then separated and washed with water (500 mL). The MTBE solution was concentrated by distillation under vacuum to provide an oil and the oil was then further concentrated by distillation under high vacuum to remove excess benzylmethylamine. N-methyl-2-pyrrolidone (300 mL) was then added to the remaining oil and this solution concentrated by distillation under high vacuum to provide an oil. The oil was dissolved in MTBE (1000 mL) and the resulting solution was washed with water (2×500 mL), brine (500 mL), dried with sodium sulfate (100 g), filtered and concentrated by distillation to afford the title compound as an oil (178 g, 96% yield, >95% purity).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:9])=[N:6][C:7]=1[CH3:8].ClC1C=C(C=CC=1)C(OO)=[O:15].OS([O-])=O.[Na+]>ClCCl>[ClH:1].[Cl:1][C:2]1[C:7]([CH3:8])=[N+:6]([O-:15])[C:5]([NH2:9])=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1nc(N)ccc1Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(Cl)ccc(N)[n+]1[O-]
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 110 g (666 mmol) of 5-chloro-6-methyl-pyridineamine (Kress, T. J.; Moore, L. L.; Costantino, S. M. J. Org. Chem. (1976) 41(1), pp 93–96) in 1 L of dichloromethane was added 164 g (666 mmol) of m-chloroperoxybenzoic acid. The mixture was stirred at room temperature overnight and 20 g more of m-chloroperoxybenzoic acid was added. The mixture was stirred 1 h and 50 mL of saturated aqueous NaHSO3 were added. The solvent was removed and the residue was taken up in 1 L of 1N HCl. The insoluble solids were filtered and washed with 3N HCl. Solvent was removed from the aqueous filtrate to give a solid which was recrystallized from ethanol affording 56.9 g of 5-chloro-6-methyl-2-pyridinamine 1-oxide, hydrochloride as a white solid, mp>250° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.C[Mg]I.Br[C:15]1[C:20](=[O:21])[NH:19][C:17](=[O:18])[C:16]=1Br>C1C=CC=CC=1.C(OCC)C>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:16]1[C:17](=[O:18])[NH:19][C:20](=[O:21])[C:15]=1[C:10]1[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:3][C:2]=1[CH3:1])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cc1cc2ccccc2[nH]1
Reactant: O=C1NC(=O)C(Br)=C1Br
Agent: C[Mg]I
Solvent: CCOCC
Solvent: c1ccccc1
Product: Cc1[nH]c2ccccc2c1C1=C(c2c(C)[nH]c3ccccc23)C(=O)NC1=O
Reaction time: 0.5 h
Yield: 39.4 %

Procedure:
A solution of 4.12 g of 2-methylindole in 75 ml of benzene was treated with 9.2 ml of a 3M solution of methylmagnesium iodide in diethyl ether and the resulting solution was stirred under nitrogen for 0.5 hour. 2.0 g of dibromomaleimide were added and the mixture was heated to reflux for 14 hours. The cooled mixture was evaporated, dissolved in 200 ml of dichloromethane and acidified with 100 ml of 2M hydrochloric acid. The organic layer was separated, washed with 100 ml of water, dried and evaporated. The residue was triturated with dichloromethane and the obtained solid was recrystallized from acetone/water to give 1.1 g of 3,4-bis(2-methyl-3-indolyl)-1H-pyrrole-2,5-dione, m.p. 311°-313° C.
Reaction SMILES: [F:1][C:2]1[C:7]([N:8]2[C:12](SC3C=CC=C(C)C=3)=[CH:11][C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33](OO)=O)[CH:28]=1.[S:37]([O-:41])([O-])(=[O:39])=S.[Na+].[Na+]>C(OCC)(=O)C>[F:1][C:2]1[C:7]([N:8]2[C:12]([S:37]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[CH:28]=3)(=[O:41])=[O:39])=[CH:11][C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=S([O-])([O-])=S
Reactant: CCOC(=O)c1cc(Sc2cccc(C)c2)n(-c2cccnc2F)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(S(=O)(=O)c2cccc(C)c2)n(-c2cccnc2F)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
To a solution of crude ethyl 1-(2-fluoropyridin-3-yl)-5-[(3-methylphenyl)sulfanyl]-1H-pyrazole-3-carboxylate (334 mg) in ethyl acetate (7.5 mL) was added 3-chloroperbenzoic acid (1.59 g). The mixture was stirred at room temperature for 3 hr, treated with saturated aqueous sodium thiosulfate solution, and extracted with ethyl acetate. The extract was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=9:1→2:1) to give the title compound as a colorless oil (yield 384 mg, 2 steps yield 62%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=1)[C:10]([CH3:29])([CH3:28])[CH2:9]2)=[O:5])C.O.[OH-].[Li+].O.Cl>CO.O1CCCC1>[CH3:28][C:10]1([CH3:29])[CH2:9][C:8]2[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)[NH:12][CH:11]1[C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(N3CCOCC3)cc1)N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(N2CCOCC2)cc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 30 %

Procedure:
A mixture of 3,3-dimethyl-2-(4-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.20 g, 0.51 mmol), lithium hydroxide hydrate (0.21 g, 5.1 mmol), water (1 mL) in methanol (2 mL) and tetrahydrofuran (10 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 3,3-dimethyl-2-(4-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (56 mg, 30%) as a white solid: LC/MS m/e calcd for C22H26N2O3 (M+H)+: 367.5, observed: 367.1.
Reaction SMILES: [CH:1](/[CH:4]1[O:8][C@H:7]([C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])[C@@H:6]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[O:5]1)=[CH:2]\[CH3:3].[CH2:21]([Zn]CC)C.ICI>>[CH3:3][C@H:2]1[CH2:21][C@@H:1]1[CH:4]1[O:5][C@H:6]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[C@@H:7]([C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])[O:8]1
Reactant: C/C=C/C1O[C@H](C(=O)OC(C)C)[C@@H](C(=O)OC(C)C)O1
Reactant: CC[Zn]CC
Solvent: ICI
Product: CC(C)OC(=O)[C@H]1OC([C@H]2C[C@@H]2C)O[C@@H]1C(=O)OC(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a −20° C. solution of intermediate diisopropyl (4S,5S)-2-[(1E)-prop-1-enyl]-1,3-dioxolane-4,5-dicarboxylate (4.10 g, 14.32 mmol) in 60 mL hexanes was added 1M diethylzinc in hexanes (42.96 mL, 42.96 mmol). Diiodomethane (6.92 mL, 85.92 mmol) was added dropwise with vigorous stirring. After 1 h at −20° C., the reaction was refrigerated at −5° C. After 17 h at −5° C., the reaction was stirred at 0° C. for an additional 5 h and then quenched with cold saturated ammonium chloride solution (100 mL) and extracted with Et2O (100 mL×3). The combined organics were washed w/aqueous sodium thiosulfate (100 mL) and brine (100 mL), filtered, dried over Na2SO4, filtered again and concentrated in vacuo. Purification by normal phase chromatography (10->30% EtOAc/hexanes) yielded 3.85 g (89%) of diisopropyl (4S,5S)-2-[(1S,2S)-2-methylcyclopropyl]-1,3-dioxolane-4,5-dicarboxylate as a yellow oil. 1H NMR (CDCl3, 400 MHz) 5.12 (m, 2H); 4.78 (d, J=6.41 Hz, 1H); 4.66 (d, J=4.21 Hz, 1H); 4.57 (d, J=4.22 Hz, 1H); 1.30 (m, 12H); 1.09 (d, J=5.68 Hz, 3H); 0.94 (m, 2H); 0.67 (m, 1H); 0.39 (m, 1H); LC/MS [M+H]+=301.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[CH2:4][CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)[CH3:2].[CH3:19][S:20]([NH:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([Cl:30])=[O:29])=[CH:26][CH:25]=1)(=[O:22])=[O:21]>>[ClH:30].[CH2:17]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)[C:28](=[O:29])[C:27]1[CH:31]=[CH:32][C:24]([NH:23][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:25][CH:26]=1)[CH3:18]
Reactant: CCN(CC)CCNc1cccc2ccccc12
Reactant: CS(=O)(=O)Nc1ccc(C(=O)Cl)cc1
Product: CCN(CC)CCN(C(=O)c1ccc(NS(C)(=O)=O)cc1)c1cccc2ccccc12
Product: Cl

Procedure:
In a manner similar to Example I react N,N-diethyl-N'-(1-naphthalenyl)-1,2-ethanediamine with 4-[(methylsulfonyl)amino]benzoyl chloride to obtain the title compound.
Reaction SMILES: [CH:1](NC(C)C)(C)C.[CH3:8][S:9][C:10]1[N:15]=[C:14](C)[CH:13]=[CH:12][N:11]=1.CON(C)[C:20](=[O:31])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1>C1COCC1>[CH3:8][S:9][C:10]1[N:11]=[CH:12][C:13]([CH2:1][C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)=[O:31])=[CH:14][N:15]=1
Reactant: CC(C)NC(C)C
Reactant: CON(C)C(=O)c1cccc(C(F)(F)F)c1
Reactant: CSc1nccc(C)n1
Solvent: C1CCOC1
Product: CSc1ncc(CC(=O)c2cccc(C(F)(F)F)c2)cn1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 74.2 %

Procedure:
To a solution of diisopropylamine (7.9 mL, 0.056 mole) in THF (100 mL) at −78° C. and under argon was added 2.5M n-butylithium (22.5 mL, 0.056 mole) followed, after 5 minutes, by a solution of 2-methylthio-4-methylpyrimidine (5.27 g, 0.376 mole) in THF (20 mL). Upon stirring for 15 min. at -78° C., a solution of N-methoxy-N-methyl-3-trifluoromethylbenzamide (9.63 g, 0.041 mole) in THF (90 mL) was added. The reaction was allowed to warm to 0° C. and then quenched into water (400 mL) and ethyl acetate (400 mL). The layers were separated and the aqueous layer washed with ethyl acetate (200 mL). The ethyl acetate extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to a solid (11.9 g). Trituration from 10% ether/hexane (100 mL) gave 9.5 g (78%) of the title compound.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:27]1[CH:32]=[C:31]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([N:40]3[CH2:45][CH2:44][N:43]([CH:46]4[CH2:49][O:48][CH2:47]4)[CH2:42][C:41]3([CH3:51])[CH3:50])=[CH:36][N:35]=2)[C:30](=[O:52])[N:29]([CH3:53])[CH:28]=1)(=O)C.[OH-].[Li+].C(O)(C)C.C1COCC1>O>[CH3:50][C:41]1([CH3:51])[CH2:42][N:43]([CH:46]2[CH2:49][O:48][CH2:47]2)[CH2:44][CH2:45][N:40]1[C:37]1[CH:38]=[CH:39][C:34]([NH:33][C:31]2[C:30](=[O:52])[N:29]([CH3:53])[CH:28]=[C:27]([C:7]3[C:6]([CH2:5][OH:4])=[C:11]([N:12]4[CH2:24][CH2:23][N:15]5[C:16]6[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=6[CH:22]=[C:14]5[C:13]4=[O:25])[CH:10]=[C:9]([F:26])[CH:8]=3)[CH:32]=2)=[N:35][CH:36]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C5COC5)CC4(C)C)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)O
Product: Cn1cc(-c2cc(F)cc(N3CCn4c(cc5c4CCCC5)C3=O)c2CO)cc(Nc2ccc(N3CCN(C4COC4)CC3(C)C)cn2)c1=O
Temperature: 30 °C
Reaction time: 1 h
Yield: 57.3 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and was charged with 125f (85 mg, 1 eq., 0.11 mmol), lithium hydroxide (14 mg, 5 eq., 0.55 mmol), i-propanol (3 mL), THF (3 mL) and water (2 mL). The mixture was stirred at 30° C. for 1 h. It was then filtered and the residue was concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 125 (43 mg, 57%). MS: [M+H]+ 682.4. 1H NMR (500 MHz, DMSO) δ 8.62 (d, J=2.0 Hz, 1H), 8.55 (s, 1H), 7.94 (d, J=2.5 Hz, 1H), 7.41-7.39 (m, 2H), 7.33-7.31 (m, 1H), 7.23-7.17 (m, 2H), 6.52 (s, 1H), 4.86 (brs, 1H), 4.54 (t, J=6.5 Hz, 2H), 4.42 (t, J=6.0 Hz, 2H), 4.30 (s, 2H), 4.17-4.11 (m, 3H), 3.89-3.86 (m, 1H), 3.58 (m, 3H), 3.39-3.36 (m, 1H), 3.08-2.98 (m, 2H), 2.63-2.56 (m, 2H), 2.46 (t, J=6.0 Hz, 2H), 2.33-2.12 (m, 4H), 1.80-1.67 (m, 4H), 0.96 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[C:11]([C:22]#[N:23])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.CC(O)=[O:26].Cl>CO.C(O[Pd]OC(=O)C)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[C:13]3[C:12](=[C:11]([C:22]([NH2:23])=[O:26])[CH:10]=2)[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[N:18][C:17]3=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2ccc(Nc3cccnc3)c(C#N)c2)c1
Reactant: CC(=O)O
Agent: CC(=O)O[Pd]OC(C)=O
Agent: Cl
Solvent: CO
Product: COc1cccc(-c2cc(C(N)=O)c3[nH]c4cccnc4c3c2)c1
Temperature: 160 °C
Reaction time: 0.33 h

Procedure:
To a 5 mL microwave vial 3′-methoxy-4-(pyridine-3-ylamino)biphenyl-3-carbonitrile (100.0 mg, 0.33 mmol), diacetoxypalladium (149.0 mg, 0.66 mmol) and AcOH (2 mL) were added. The vessel was sealed, and the reaction stirred at 160° C. 1 h. The reaction mixture was filtered and purified by preparative HPLC (100×30 mm Luna C18 column, flow rate 42 ml permin, gradient elution starting with A:B=80:20 and ending with A:B=0:100 [A=10% MeOH, 90% water, 0.1% TFA; B=90% MeOH, 10% water, 0.1% TFA] over 20 min). The HPLC fractions that contained the product were applied onto a cartridge of PHENOMENEX® Strata-X-C 33 um cation mixed-mode polymer. This was washed with methanol and the product was eluted with a 2N solution of ammonia in methanol. The solvents were removed and the product was converted to the HCl salt by adding a (1 eq) solution of 1N HCl in methanol. The solvents were removed to afford 12.00 mg of 8-(3-methoxyphenyl)-5H-pyrido[3,2-b]indole-6-carboxamide, carboxamide, HCl. MS (ESI) m/z 318.2 (M+H). 1H NMR (MeOD) d ppm 8.77-8.85 (3H, m), 8.62 (1H, d, J=1.83 Hz), 8.06 (1H, dd, J=8.24, 5.80 Hz), 7.48 (1H, t, J=7.93 Hz), 7.39-7.44 (2H, m), 7.04 (1H, dd, J=8.09, 1.68 Hz), 3.93 (3H, s).
Reaction SMILES: I[Si](C)(C)C.C(OC([NH:16][C:17]1([CH2:29][N:30]2[CH2:35][CH2:34][N:33]([S:36]([C:39]3[CH:48]=[CH:47][C:46]4[C:41](=[CH:42][CH:43]=[C:44]([Cl:49])[CH:45]=4)[CH:40]=3)(=[O:38])=[O:37])[CH2:32][C:31]2=[O:50])[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[CH2:19][CH2:18]1)=O)C1C=CC=CC=1.CO.[ClH:53]>ClCCl.C(OCC)(=O)C>[ClH:49].[ClH:53].[NH2:16][C:17]1([CH2:29][N:30]2[CH2:35][CH2:34][N:33]([S:36]([C:39]3[CH:48]=[CH:47][C:46]4[C:41](=[CH:42][CH:43]=[C:44]([Cl:49])[CH:45]=4)[CH:40]=3)(=[O:37])=[O:38])[CH2:32][C:31]2=[O:50])[CH2:22][CH2:21][N:20]([C:23]2[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1
Reactant: O=C(NC1(CN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)CCN(c2ccncc2)CC1)OCc1ccccc1
Agent: C[Si](C)(C)I
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: NC1(CN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Iodotrimethylsilane (2.51 ml) was added to a solution of 1-[4-benzyloxycarbonylamino-1-(4-pyridyl)-4-piperidylmethyl]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone (4.58 g) in dichloromethane (50 ml), and the mixture was stirred at room temperature for 4 hours. Methanol (10 ml) and 4N hydrochloric acid solution in ethyl acetate (8 ml) were added thereto. Methanol was added to obtain a solution, followed by concentration under reduced pressure. Dilute hydrochloric acid was added to the residue, and the mixture was washed with ether. The aqueous layer was made basic with 6N sodium hydroxide, followed by extraction with ethyl acetate. The organic layer was washed successively with an aqueous sodium bicarbonate solution and an aqueous saturated sodium chloride solution, dried, and concentrated. Dilute hydrochloric solution was added to the residue, which was purified by CHP20 column chromatography (water:acetonitrile:1N hydrochloric acid=100:0:1→80:20:1) to obtain the colorless amorphous title compound (3.66 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[NH:4][CH:5]([C:9]([N:11]1[CH:15]([C:16]2[NH:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=3)[N:20]=2)[CH2:14][N:13]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:35][O:36][C:37](=[O:70])[NH:38][CH:39]([C:43]([N:45]1[CH2:49][CH2:48][CH2:47][CH:46]1[C:50]1[NH:51][CH:52]=[C:53]([C:55]2[CH:60]=[CH:59][C:58](B3OC(C)(C)C(C)(C)O3)=[CH:57][CH:56]=2)[N:54]=1)=[O:44])[CH:40]([CH3:42])[CH3:41].C(=O)([O-])[O-].[K+].[K+].COCCOC>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.O>[CH3:1][O:2][C:3](=[O:34])[NH:4][CH:5]([C:9]([N:11]1[CH:15]([C:16]2[NH:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:58]4[CH:59]=[CH:60][C:55]([C:53]5[NH:54][C:50]([CH:46]6[CH2:47][CH2:48][CH2:49][N:45]6[C:43](=[O:44])[CH:39]([NH:38][C:37]([O:36][CH3:35])=[O:70])[CH:40]([CH3:42])[CH3:41])=[N:51][CH:52]=5)=[CH:56][CH:57]=4)=[CH:23][CH:22]=3)=[CH:18][N:17]=2)[CH2:14][N:13]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)N1CN(c2ccccc2)CC1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CN(c6ccccc6)CN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C
Temperature: 120 °C
Yield: 8.7 %

Procedure:
{1-[4-(4-Bromo-phenyl)-1′-phenyl-1′,2′,4′,5′-tetrahydro-1H-[2,4′]biimidazolyl-3′-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (40 mg, 0.076 mmol) was combined with [2-Methyl-1-(2-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (37.6 mg, 0.076 mmol) under an argon atmosphere. Potassium carbonate (20.9 mg, 0.152 mmol) and Pd(PPh3)4 (8.7 mg, 0.0076 mmol) were added, followed by DME (1.8 mL) and water (0.3 mL). The mixture was heated under microwave conditions for 20 minutes at 120° C. All volatiles were removed in vacuo and the crude material was dissolved in DMF and purified via RP-HPLC (eluent: water/MeCN w 0.1% TFA) to yield the product {1-[5-(4′-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1′-phenyl-1′,2′,4′,5′-tetrahydro-1H-[2,4′]biimidazolyl-3′-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (5.4 mg): LCMS-ESI+: calc'd for C45H53N9O6: 815.9 (M+). Found: 816.5 (M+H+); 1H-NMR: 300 MHz, (MeOH-d4) δ: 7.89-7.86 (m, 10H), 7.35 (m, 2H), 7.18 (m, 1H), 6.94 (m, 2H), 5.67 (m, 1H), 5.37 (m, 1H), 5.25 (m, 1H), 5.12 (m, 1H), 4.31-4.08 (m, 3H), 4.01-3.79 (m, 3H), 3.67 (s, 3H), 3.66 (s, 3H), 2.58 (m, 1H), 2.29-1.99 (m, 5H), 0.99-0.89 (m, 12H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7](=[S:15])[C:6]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22].[H][H].Cl.[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29][Cl:30]>CN(C)C=O.O>[ClH:30].[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29][S:15][C:7]1[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[C:5]([O:4][CH3:3])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1
Reactant: [H][H]
Reactant: CN(C)CCCl
Reactant: COc1c(-c2ccccc2C)c(=S)[nH]c2ccccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(-c2ccccc2C)c(SCCN(C)C)nc2ccccc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Sodium hydride (0.25 g. of a 50% w/w dispersion in mineral oil) was added to a solution of 4-methoxy-3-o-tolylquinolin-2-thione (0.7 g.) in dimethylformamide (10 ml.) at ambient temperature. When all the hydrogen had evolved, 2-dimethylaminoethyl chloride hydrochloride (0.36 g.) was added and the mixture was stirred at ambient temperature for 20 hr. The reaction mixture was then poured into water (100 ml.) and extracted with ethyl acetate (2×25 ml.). The ethyl acetate extract was washed with water (2×10 ml.) and then dried (MgSO4). The ethyl acetate was evaporated, the residue was dissolved in diethyl ether (50 ml.), and ethereal hydrogen chloride was added until precipitation was complete. The mixture was filtered and the solid residue was crystallised from ethanoldiethyl ether to give 2-(2-dimethylaminoethylthio)-4-methoxy-3-o-tolylquinoline hydrochloride, m.p. 196°-8°.