Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][N:6]3[C:12]4[CH:13]=[CH:14][CH:15]=[C:16]([F:19])[C:17]=4[CH:18]=[C:5]3[C:4]=2[N:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:28][C:29]3[CH:39]=[C:38]([N:40]([CH3:45])[S:41]([CH3:44])(=[O:43])=[O:42])[C:37](B4OC(C)(C)C(C)(C)O4)=[CH:36][C:30]=3[C:31]=2[C:32]([NH:34][CH3:35])=[O:33])=[CH:23][CH:22]=1>O1CCOCC1.O.[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[F:19][C:16]1[C:17]2[CH:18]=[C:5]3[C:4]4[N:3]=[C:2]([C:37]5[C:38]([N:40]([CH3:45])[S:41]([CH3:44])(=[O:43])=[O:42])=[CH:39][C:29]6[O:28][C:27]([C:24]7[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=7)=[C:31]([C:32]([NH:34][CH3:35])=[O:33])[C:30]=6[CH:36]=5)[CH:11]=[CH:10][C:9]=4[CH2:8][CH2:7][N:6]3[C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: Fc1cccc2c1cc1n2CCc2ccc(Cl)nc2-1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CC4)cc12
Temperature: 90 °C
Reaction time: 4 h
Yield: 81.6 %

Procedure:
To a degassed solution of 2-chloro-11-fluoro-5,6-dihydroindolo[1,2-h][1,7]naphthyridine (50 mg, 0.18 mmol) and 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (120 mg, 0.24 mmol) in 1,4-dioxane (8 mL) and water (200 μl) was added CS2CO3 (119 mg, 0.37 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium chloride (20 mg, 0.03 mmol) under N2 protection. The resulting mixture was heated to 90° C. and stirred for 4 hours. The reaction was cooled, filtered through a pad of the celite and washed with ethyl acetate. The combined filtrate was evaporated in vacuo. Preparative TLC (eluted with 30% EtOAc/DCM) provide 5-(11-fluoro-5,6-dihydroindolo[1,2-h][1,7]naphthyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (90 mg, yield: 80%) MS (M+H)+: 613.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:35]([NH2:37])=[O:36])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][NH:28][C:29](=[O:34])[CH2:30][CH2:31][CH2:32]C)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].CC1(C)C(C)(C)OB(C2C=C(CNC(=O)CCCC)C=CC=2)O1>>[CH:30]1([C:29]([NH:28][CH2:27][C:23]2[CH:22]=[C:21]([C:18]3[CH:19]=[C:20]4[C:15](=[C:16]([C:35]([NH2:37])=[O:36])[CH:17]=3)[NH:14][CH:13]=[C:12]4[CH:9]3[CH2:8][CH2:7][N:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH2:11][CH2:10]3)[CH:26]=[CH:25][CH:24]=2)=[O:34])[CH2:32][CH2:31]1
Reactant: CCCCC(=O)NCc1cccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)c1
Agent: CCCCC(=O)NCc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNC(=O)C5CC5)c4)cc23)CC1
Yield: 11 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(pentanoylamino)methyl]phenyl}-1H-indole-7-carboxamide substituting N-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}cyclopropanecarboxamide (43 mg, 0.144 mmol) for N-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}pentanamide. Compound was purified by Mass Directed Auto Prep HPLC to give 5.5 mg of the title compound (11%).
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([N:15]2[C:23]3[CH:22]=[CH:21][N:20]=[C:19]([O:24]C)[C:18]=3[C:17]([C:26]3[CH:31]=[CH:30][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:28][CH:27]=3)=[N:16]2)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.[I-].[Na+].Cl[Si](C)(C)C.C(=O)([O-])O.[Na+]>C(#N)C>[OH:8][CH:9]1[CH2:14][CH2:13][CH:12]([N:15]2[C:23]3[CH:22]=[CH:21][NH:20][C:19](=[O:24])[C:18]=3[C:17]([C:26]3[CH:31]=[CH:30][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:28][CH:27]=3)=[N:16]2)[CH2:11][CH2:10]1
Reactant: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)nn2C1CCC(O[Si](C)(C)C(C)(C)C)CC1
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CC#N
Product: NS(=O)(=O)c1ccc(-c2nn(C3CCC(O)CC3)c3cc[nH]c(=O)c23)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
To a solution of 4-(1-(4-((tert-butyl(dimethyl)silyl)oxy)cyclohexyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)benzenesulfonamide (42.8 mg) obtained in Step A of Example 119 in acetonitrile (3 mL) were added sodium iodide (31.0 mg) and chloro(trimethyl)silane (0.105 mL), and the mixture was stirred at 50° C. for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate to ethyl acetate/methanol) to give the title compound (24.6 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.P(=O)(O)(O)O.[C:15]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)(=[O:17])[CH3:16]>C(O)(=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:21]1[CH2:22][CH2:23][N:18]([C:15](=[O:17])[CH3:16])[CH2:19][CH:20]=1
Reactant: CC(=O)N1CCC(=O)CC1
Reactant: c1ccc2[nH]ccc2c1
Agent: O=P(O)(O)O
Solvent: CC(=O)O
Product: CC(=O)N1CC=C(c2cc3ccccc3[nH]2)CC1

Procedure:
A starting compound of the formula II may also be obtained by reacting an indole of the formula IV in a mixture of glacial acetic acid and phosphoric acid with the equivalent quantity of N-acetyl-4-piperidone, preferably at room temperature. The corresponding 4-indolyl-1-acetyl-1,2,5,6-tetrahydropyridine is thus obtained, which is then hydrogenated in conventional manner in the presence of palladium/coal at room temperature and atmospheric pressure to form the corresponding piperidine derivative; the latter is subsequently hydrolized in a mixture of a lower alkanol and aqueous 50% potassium hydroxide.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:20][C:21]([O:23][CH3:24])=[O:22]>CN(C=O)C>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[CH2:20][C:21]([O:23][CH3:24])=[O:22])([O-:3])=[O:2]
Reactant: COC(=O)CBr
Reactant: O=[N+]([O-])c1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1ccc2c([N+](=O)[O-])cccc21
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-nitro-1H-indole (500 mg, 3.08 mmol) in DMF (10 ml), K2CO3 (511 mg, 3.70 mmol) and methyl 2-bromoacetate (343 μl, 3.70 mmol) were added, and the mixture was stirred at 100° C. under MW irradiation for 30 minutes. The insoluble inorganic salts was filtered off, and the solvent was evaporated, recovering crude desired methyl 2-(4-nitro-1H-indol-1-yl)acetate which was used in the next step without further purification (810 mg). MS/ESI+ 235.1 [MH]+.
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7]([OH:10])[CH2:8][OH:9])([CH3:4])([CH3:3])[CH3:2].C(C1C=C(S(OO[CH:24]([CH2:26][CH3:27])[CH3:25])(=O)=O)C=CC=1C)C.[H-].[Na+]>>[C:1]([O:5][CH2:6][CH:7]([O:10][CH2:7][CH2:8][O:9][CH2:27][CH2:26][CH2:24][CH3:25])[CH2:8][O:9][CH2:2][CH2:1][O:5][CH2:25][CH2:24][CH2:26][CH3:27])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OCC(O)CO
Reactant: CCc1cc(S(=O)(=O)OOC(C)CC)ccc1C
Agent: [H-]
Agent: [Na+]
Product: CCCCOCCOCC(COC(C)(C)C)OCCOCCCC

Procedure:
Compound 25 was prepared using a method similar to that described for 23. The o reagents used were as follows, compound 17 (25.5 g, 0.172 mol.), compound 19 (91.5 g, 0.336 mol.), sodium hydride (60% by wt. in mineral oil (14.0 g, 0.350 mol.). The final product was a colorless liquid (30.0 g 60%) (bpt. 100°-120 0° C., 0.06 torr.): 1H-NMR (CDCl3), d (ppm) 3.8-3.4 (m, 17H), 1.55 (m, 4H, CH2), 1.2 (s, 9H, C(CH3)3), 0.9 (t, 6H, --CH3). Mass spectroscopy, m/e 349 MH+.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[CH:16][C:13]([C:14]#[N:15])=[C:12]([NH:19][C@H:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH3:21])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.FC1C=CC([C@H](N)C)=CC=1.CCN(C(C)C)C(C)C>CCCCO>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[CH:16][C:13]([C:14]#[N:15])=[C:12]([NH:19][C@@H:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH3:21])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1C#N)c1ccc(F)cc1
Agent: C[C@@H](N)c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1C#N)c1ccc(F)cc1
Temperature: 140 °C
Yield: 28.9 %

Procedure:
A solution of 2-chloro-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro nicotinonitrile (Method 1, 0.3 g, 1.0 mmol) and (R)-1-(4-fluorophenyl)ethanamine (0.3 g, 2.1 mmol) was added to n-BuOH (2 ml) and DIEA (0.18 g, 1.4 mmol) in a sealed tube. The reaction was heated to 140° C. for 48 hours, then cooled to room temperature and concentrated. The resulting residue was purified by column chromatography (DCM-MeOH=80:1) to give the title compound (0.11 g, 26%). 1H NMR (400 MHz, CDCl3) δ 8.44 (br s, 1H), 7.37-7.33 (m, 2H), 7.27 (d, J=9.6 Hz, 1H), 7.07-7.03 (m, 2H), 6.11 (s, 1H), 5.24-5.20 (m, 2H), 1.87-1.83 (m, 1H), 1.60 (d, J=6.2 Hz, 3H), 1.01-0.98 (m, 2H), 0.79-0.65 (m, 2H). MS: Calcd.: 380. Found: [M+H]+ 381.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][CH:12]=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[C:19]([C:13](=[CH:12][NH:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[O:4][CH3:3])[C:14]([O:16][CH2:17][CH3:18])=[O:15])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)C=CNc1ccccc1OC
Reactant: O=C(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CNc1ccccc1OC)C(=O)c1ccccc1
Temperature: 5 °C
Yield: 46.8 %

Procedure:
50% Sodium hydride (2.4 g, 0.05 mol) was washed with petroleum ether, suspended in dry toluene (50 ml) and stirred at 5° C. Ethyl 3-(2-methoxyphenylamino)acrylate (8.7 g, 0.05 mol) in dry toluene (25 ml) was added and the mixture was stirred for 2.5 hours. Benzoyl chloride (6.8 g, 0.05 mol) in dry toluene (25 ml) was added dropwise and the mixture was heated under reflux for 2 hours. The mixture was cooled, washed with dilute hydrochloric acid, water and brine, then dried and evaporated. The residue was chromatographed (silica gel, dichloromethane) to afford ethyl 2-benzoyl-3-(2-methoxyphenylamino)acrylate (7.62 g, 46.8%) as a yellow oil.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([CH:11]([F:13])[F:12])[N:7]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=3[CH3:22])[C:6]=2[CH:5]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:3]=1.C[O:30][B:31](OC)[O:32]C>>[Cl:21][C:17]1[C:16]([CH3:22])=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH2:14][N:7]1[C:6]2[CH:5]=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:3]=[C:2]([B:31]([OH:32])[OH:30])[C:10]=2[N:9]=[C:8]1[CH:11]([F:13])[F:12]
Reactant: Cc1c(Cl)cccc1Cn1c(C(F)F)nc2c(Br)cc(N3CCOCC3)cc21
Reactant: COB(OC)OC
Product: Cc1c(Cl)cccc1Cn1c(C(F)F)nc2c(B(O)O)cc(N3CCOCC3)cc21

Procedure:
The titled compound was prepared from 4-(4-bromo-1-(3-chloro-2-methylbenzyl)-2-(difluoromethyl)-1H-benzo[d]imidazol-6-yl)morpholine (430 mg, 0.913 mmol) using Method A with trimethylborate to give the product (55 mg, 0.126 mmol, 13.82% yield) as a light brown solid. LC/MS: MS (ES+) m/e 436.2 [M+H]+; 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.44-7.58 (m, 1H), 7.27-7.38 (m, 1H), 7.15 (d, J=2.27 Hz, 1H), 7.00 (t, J=7.96 Hz, 1H), 6.26 (d, J=7.58 Hz, 1H), 5.75 (s, 2H), 3.81-3.94 (m, 4H), 2.50 (s, 3H)
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C[Al](C)C.[Br:19][C:20]1[C:32]([CH3:33])=[CH:31][C:23]([O:24][C@H:25]2[CH2:29][CH2:28][O:27][C:26]2=[O:30])=[C:22]([F:34])[CH:21]=1>C(Cl)Cl>[Br:19][C:20]1[C:32]([CH3:33])=[CH:31][C:23]([O:24][C@@H:25]([CH2:29][CH2:28][OH:27])[C:26]([NH:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)=[O:30])=[C:22]([F:34])[CH:21]=1
Reactant: Cc1cc(O[C@H]2CCOC2=O)c(F)cc1Br
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: C[Al](C)C
Solvent: ClCCl
Product: Cc1cc(O[C@@H](CCO)C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c(F)cc1Br
Reaction time: 0.25 h
Yield: 65 %

Procedure:
To a stirred solution of tert-butyl 4-aminopiperidine-1-carboxylate (2.4 g, 12 mmol) in CH2Cl2 (30 mL) was added trimethylaluminum (6.0 mL, 12 mmol) dropwise. The resulting mixture was stirred for 15 minutes, then (S)-3-(4-bromo-2-fluoro-5-methylphenoxy)dihydrofuran-2(3H)-one (2.9 g, 10 mmol) in CH2Cl2 (30 mL) was added slowly and stirred at ambient temperature for 1 hour. The reaction was slowly quenched with 5% tartaric acid, neutralized with aqueous NaHCO3 and filtered through celite. The filtrate was extracted with CH2Cl2, dried over Na2SO4, filtered and concentrated. The residue was purified over silica gel (100% EtOAc) to afford (S)-tert-butyl 4-(2-(4-bromo-2-fluoro-5-methylphenoxy)-4-hydroxybutanamido)piperidine-1-carboxylate (3.2 g, 6.5 mmol, 65% yield).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[N:5][C:6]1[N:7]2[N:12]=[C:13]([CH3:15])[CH:14]=1.[NH2:16][C:17]1[CH:22]=[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)[CH:20]=[CH:19][C:18]=1[S:35][C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=1>C(O)C>[CH3:15][C:13]1[CH:14]=[C:6]2[N:5]=[CH:4][C:3]3[C:8](=[N:9][CH:10]=[N:11][C:2]=3[NH:16][C:17]3[CH:22]=[C:21]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:32])([F:33])[F:34])[CH:26]=4)[CH:20]=[CH:19][C:18]=3[S:35][C:36]3[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=3)[N:7]2[N:12]=1
Reactant: Nc1cc(OCc2cccc(C(F)(F)F)c2)ccc1Sc1ccc(O)cc1
Reactant: Cc1cc2ncc3c(Cl)ncnc3n2n1
Solvent: CCO
Product: Cc1cc2ncc3c(Nc4cc(OCc5cccc(C(F)(F)F)c5)ccc4Sc4ccc(O)cc4)ncnc3n2n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 53.5 %

Procedure:
The product from Example 4a (88 mg, 0.40 mmol) was reacted with 4-[2-Amino-4-(3-trifluoromethyl-benzyloxy)-phenylsulfanyl]-phenol (151 mg, 0.40 mmol) in 5 mL of ethanol at 70° C. with stirring for 6 hours. After cooling to room temperature the product was isolated by suction filtration and was triturated with diethyl ether to give the title compound as a pale yellow solid (123 mg, 50%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 10.45 (s, 1H) 9.65 (s, 1H) 9.34 (s, 1H) 8.57 (s, 1H) 7.62-7.85 (m, 4H) 7.09-7.21 (m, 4H) 7.02 (dd, J=3.02 Hz, J=8.74 Hz, 1H) 6.74 (s, 1H) 6.65 (dd, J=2.19 Hz, J=8.74 Hz, 2H) 5.23 (s, 2H) 2.48 (s, 3H); (ESI+) m/z 575 (M+H−Cl)+; (ESI−) m/z 573 (m−H−Cl)−.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[K+].Br[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16]Br)[CH:11]=1>CC(C)=O>[N:1]1([CH2:9][C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[CH2:16][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: BrCc1cccc(CBr)c1
Reactant: c1c[nH]cn1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: c1cc(Cn2ccnc2)cc(Cn2ccnc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
To a 500 mL round bottom flask equipped with a stirbar was added 11.6 g imidazole (170 mmol) and 9.55 g (170 mmol) finely pulverized potassium hydroxide. These were stirred in 200 mL acetone until the solution became yellow translucent. 15.0 g (56.8 mmol) α,α′-dibromo-m-xylene was then added, and the solution was stirred at room temperature overnight. The cloudy solution was filtered, and the white solids rinsed with acetone. The resulting filtrate was dried on silica and partitioned on a silica gel column using 30/70 acetonitrile/methanol as eluent. The product fractions were evaporated of solvent and the resulting oil recrystallized from ethyl acetate/hexanes to give 8.65 g 1-[3-(1H-imidazole-1yl-methyl)benzyl]-1H-imidazole as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][CH:16]3[CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17]3)[CH2:8][CH2:7][CH2:6][C:5]2=1.[ClH:25]>CO>[ClH:25].[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C@@H:9]([NH:15][CH:16]3[CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17]3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: Brc1ccc2[nH]c3c(c2c1)CCCC3NC1Cc2ccccc2C1
Agent: Cl
Solvent: CO
Product: Brc1ccc2[nH]c3c(c2c1)CCC[C@@H]3NC1Cc2ccccc2C1

Procedure:
(1S)-6-Bromo-N-(2,3-dihydro-1H-inden-2-yl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine hydrochloride salt was prepared by separation of racemic 6-bromo-N-(2,3-dihydro-1H-inden-2-yl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine by preparative SFC (Diacel AD-H, Chiral Technologies, 30% methanol, 3000 psi, 40° C., 2 mL/min, retention time: 8.6 min.) The oil obtained was converted to the HCl salt to give a white solid. 1H-NMR (DMSO-d6): δ 11.4 (s, 1H), 9.61 (s, 1H), 9.42 (s, 1H), 7.69 (s, 1H), 7.36 (d, 1H), 7.35-7.19 (m, 5H), 4.68 (t, 1H), 4.32 (m, 1H), 3.47 (dd, 1H), 3.32 (m, 3H), 2.74 (m, 1H), 2.65 (m, 1H), 2.18 (m, 2H), 2.01 (m, 1H), 1.87 (m, 1H); MS m/z 379, 381 (ES-1).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[I:12][C:13]1[CH:18]=[CH:17][C:16](O)=[C:15]([O:20][CH3:21])[CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([CH2:10][O:11][C:16]3[CH:17]=[CH:18][C:13]([I:12])=[CH:14][C:15]=3[O:20][CH3:21])=[CH:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: OCc1ccc(C2CC2)cc1
Reactant: COc1cc(I)ccc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(I)ccc1OCc1ccc(C2CC2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 46.5 %

Procedure:
To a solution of (4-cyclopropylphenyl)methanol (4.5 g) prepared in (2) and 4-iodo-2-methoxyphenol (7.5 g) in THF (40 mL) were added triphenylphosphine (8.7 g) and diisopropyl azodicarboxylate (6.5 mL) at 0° C. The reaction mixture was stirred at RT for 22 hr. The solvent was removed under reduced pressure. The residue was purified by silica-gel chromatography (Developing solvent: hexane/ethyl acetate=9/1) to give the title compound (5.3 g, 46%).
Reaction SMILES: Br[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.CCC([O-])(C)C.[Na+].[NH2:16][C@@H:17]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1.O>C1(C)C=CC=CC=1.Cl[Pd-](P(C1CC2CC1CC2)C1CC2CC1CC2)[C-]1C=CC=C1N(C)C.[CH-]1C=CC=C1.[Fe+2].CCCCCCC>[Cl:8][C:7]1[C:2]([NH:16][C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Reactant: Clc1cccnc1Br
Agent: CN(C)c1ccc[c-]1[Pd-](Cl)P(C1CC2CCC1C2)C1CC2CCC1C2
Agent: [Fe+2]
Agent: CCC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCCCCCC
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ncccc2Cl)C1
Temperature: 80 °C
Reaction time: 3 h
Yield: 72.9 %

Procedure:
A mixture of 2-bromo-3-chloropyridine (203.8 g, 1.06 moles), sodium tert-amylate (147 g, 1.27 moles), tert-butyl (3R)-3-aminopiperidine-1-carboxylate (249.5 g, 1.25 moles) in toluene (2 L) was heated to 80° C. To this solution was added chloro(di-2-norbornylphosphino)(2-dimethylaminoferrocen-1-yl) palladium (II) (6.1 g, 10.06 mmol) followed by heating to 105° C. and holding for 3 h. The reaction mixture was cooled to room temperature, 1 L of water was added, then the biphasic mixture was filtered through Celite®. After layer separation, the organic phase was washed with 1 L of water followed by treatment with 60 g of Darco® G-60 at 50° C. The mixture was filtered through Celite®, and concentrated to a final total volume 450 mL, resulting in the precipitation of solids. To the slurry of solids was added 1 L of heptane. The solids were collected via filtration and then dried to afford the title compound as a dull orange solid (240.9 g, 73% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17]C)=[O:16])[CH:13]=2)[C:8](=[O:19])[N:7]([CH2:20][CH3:21])[C:6]1=[O:22].[OH-].[Na+].Cl>CO>[C:15]([C:12]1[CH:13]=[C:14]2[C:9]([C:8](=[O:19])[N:7]([CH2:20][CH3:21])[C:6](=[O:22])[N:5]2[CH2:4][C:3]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:2]=2[Cl:1])=[CH:10][CH:11]=1)([OH:17])=[O:16]
Reactant: CCn1c(=O)c2ccc(C(=O)OC)cc2n(Cc2ccc(Cl)cc2Cl)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCn1c(=O)c2ccc(C(=O)O)cc2n(Cc2ccc(Cl)cc2Cl)c1=O
Yield: 99.6 %

Procedure:
1-(2,4-Dichlorobenzyl)-3-ethyl-7-(methoxycarbonyl)-2,4(1H,3H) -quinazolinedione (2.36 g) in a mixture of a 5% aqueous sodium hydroxide solution (10 g) and methanol (30 g) was heated under reflux for 1 hr. After cooling, concentrated hydrochloric acid (3.9 g) was added to the reaction mixture and the precipitate was collected by filtration. The precipitate was washed with water (100 g) and toluene (20 ml) and dried to give the objective compound (2.27 g) as white crystals.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[NH:14][CH3:15])[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[CH3:16][NH:17][CH2:18][C:19]([O:21][CH3:22])=[O:20]>>[CH3:22][O:21][C:19](=[O:20])[CH2:18][N:17]([CH3:16])[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[NH:14][CH3:15])[C:8]([OH:10])=[O:9])(=[O:4])=[O:3]
Reactant: CNc1ccc(C(=O)O)cc1S(=O)(=O)Cl
Reactant: CNCC(=O)OC
Product: CNc1ccc(C(=O)O)cc1S(=O)(=O)N(C)CC(=O)OC

Procedure:
3-(Chlorosulfonyl)-4-(methylamino)benzoic acid 1.2 was reacted with methyl 2-(methylamino)acetate Ad following the procedure described in Example 1A.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([NH:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)=[N:4][C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[S:23]1[CH:27]=[CH:26][C:25]([C:28](Cl)=[O:29])=[CH:24]1>N1C=CC=CC=1>[CH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[CH:17][C:8]=1[NH:7][C:5]1[S:6][C:2]([NH:1][C:28]([C:25]2[CH:26]=[CH:27][S:23][CH:24]=2)=[O:29])=[C:3]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:4]=1
Reactant: CCOC(=O)c1nc(Nc2ccc3ccccc3c2)sc1N
Reactant: O=C(Cl)c1ccsc1
Solvent: c1ccncc1
Product: CCOC(=O)c1nc(Nc2ccc3ccccc3c2)sc1NC(=O)c1ccsc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.6 %

Procedure:
To a solution of ethyl 5-amino-2-(naphthalen-2-ylamino)thiazole-4-carboxylate (100 mg, 0.32 mmol) in pyridine (3 mL) was added 3-thiophene carbonyl chloride (61 mg, 0.42 mmol) at 0° C. The mixture was allowed to warm to rt and stirred overnight. The reaction was quenched with ice-water, and the mixture was extracted with EtOAc. The organic layer was washed with water, and dried over Na2SO4. The solvent was evaporated, and the resulting solids were collected and washed with EtOAc to give 55 mg (40% yield) of the titled compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:22]([O-])=O)=[C:6]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)(=[O:10])=[O:9])[CH:7]=1.Cl[Sn]Cl>Cl.CCO>[NH2:22][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][C:6]=1[S:8]([NH:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[CH:19][CH:18]=[CH:17]2)(=[O:10])=[O:9]
Reactant: Cc1ccc([N+](=O)[O-])c(S(=O)(=O)Nc2cccc3cccnc23)c1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Cc1ccc(N)c(S(=O)(=O)Nc2cccc3cccnc23)c1
Yield: 50.1 %

Procedure:
In a similar fashion using route 1 general procedure 4, 5-methyl-2-nitro-N-quinolin-8-yl-benzenesulfonamide (Intermediate 266) (350 mg, 1.02 mmol), SnCl2 (773 mg, 4.08 mmol), 6N HCl (5 drops) and EtOH (5 ml), at 80° C. for 2 h gave the title compound (160 mg, 50%) after purification by column chromatography with n-hexane/EtOAc (98:2) as the eluent.