Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([NH:22][CH2:23][CH2:24][CH2:25][OH:26])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[N:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>COCCOC.O>[OH:26][CH2:25][CH2:24][CH2:23][NH:22][C:3]1[C:2]([C:31]2[CH:32]=[N:27][CH:28]=[N:29][CH:30]=2)=[CH:21][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])=[CH:5][N:4]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(NCCCO)c(Br)c1
Reactant: OB(O)c1cncnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(NCCCO)c(-c2cncnc2)c1
Temperature: 25 °C

Procedure:
A mixture of 5-bromo-6-((3-hydroxypropyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 161.1, 72 mg, 0.15 mmol), pyrimidin-5-ylboronic acid (18.7 mg, 0.15 mmol) and Na2CO3 (48 mg, 0.450 mmol) in a mixture of DME (3.2 mL), EtOH (0.43 mL) and water (0.64 mL) was flushed with argon for 5 min. Pd(PPh3)2Cl2 was added (5.3 mg, 0.0075 mmol) and the mixture was subjected to MW irradiation at 125° C. for 20 min. The vial was cooled to RT and the RM was evaporated to dryness under reduced pressure to give a residue that was triturated with THF and filtered. The filtrate was evaporated to dryness under reduced pressure and the crude product was purified by preparative LC-MS. TFA was removed using a SPE PL-HCO3 (StratoSpheres™ VariPure IPE) cartridge to afford the title compound. UPLC-MS (Condition 8) tR=2.05 min, m/z=434.1 [M+H]+, m/z=432.1 [M−H]−.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17](Br)[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][O:21][CH2:22][C:23]#[CH:24].C(N(CC)CC)C>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:24]#[C:23][CH2:22][O:21][CH3:20])[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#CCOC
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(Br)cnc21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCC#Cc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1
Temperature: 85 °C
Reaction time: 12 h
Yield: 79.4 %

Procedure:
To a solution of 1-benzenesulfonyl-5-bromo-1H-pyrrolo[2,3-b]pyridine (prepared as in Example 7, 6.5 g, 19.3 mmol) in N,N-dimethylformamide (30 mL) was added 3-methoxy-propyne (5 mL, 57.9 mmol), tetrakis(triphenylphosphine)palladium(0) (2.2 g, 1.93 mmol), copper (I) iodide (735 mg, 3.85 mmol) and triethylamine (8.1 mL, 57.9 mmol) at room temperature. The mixture was then heated at 85° C. and stirred for 12 h. The resulting mixture was cooled to room temperature, extracted with ethyl acetate (2×250 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 20% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-5-(3-methoxy-prop-1-ynyl)-1H-pyrrolo[2,3-b]pyridine as a light yellow solid (5 g, 89.1%): LC/MS m/e calcd for C17H14N2O3S [M+H]+ 327.38, observed 327.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=O)[CH2:12][NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]([CH3:22])[CH3:21])[CH:15]=2)[CH:5]=1.B.C1COCC1>>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH2:11][CH2:12][NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]([CH3:21])[CH3:22])[CH:15]=2)[CH:5]=1
Reactant: COC(=O)c1cccc(NC(=O)CNc2cccc(C(C)C)c2)c1
Agent: B
Solvent: C1CCOC1
Product: COC(=O)c1cccc(NCCNc2cccc(C(C)C)c2)c1
Yield: 73 %

Procedure:
3-[2-(3-Isopropylphenylamino)acetylamino]benzoic acid methyl ester (3.26 g, 10.0 mmol) prepared above was treated with BH3.THF (1.0 M, 40.0 mL, 40.0 mmol) at room temperature for 24 h. The excess borane was destroyed by the addition of HCl (6 M, 10 mL). THF was removed in vacuum and the residue was diluted with water and basified. The organics were separated and the aqueous phase was extracted with dichloromethane. The organics were combined and washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The crude product obtained after the removal of the solvent in vacuum was chromatographed (silica gel, dichloromethane: ethyl acetate, 9.5:0.5) to furnish 3-[2-(3-isopropylphenylamino)ethylamino]benzoic acid methyl ester as a colorless oil (2.28 g, 73.1%). MS (ES+) m/z: 313.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:33]=[CH:32][C:11]([O:12][C:13]2[C:14]([C:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27]C(C)(C)C)=O)[CH2:21][CH:20]=3)=[N:15][CH:16]=[CH:17][N:18]=2)=[CH:10][CH:9]=1.[C:34](Cl)(=O)C>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]2[C:14]([C:19]3[CH2:24][CH2:23][N:22]([C:25](=[O:27])[CH3:34])[CH2:21][CH:20]=3)=[N:15][CH:16]=[CH:17][N:18]=2)=[CH:32][CH:33]=1
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC=C(c2nccnc2Oc2ccc(Nc3ccccn3)cc2)CC1
Product: CC(=O)N1CC=C(c2nccnc2Oc2ccc(Nc3ccccn3)cc2)CC1

Procedure:
During a resynthesis of Example 279 (Step 1) an incomplete hydrogenation resulted in a small fraction of tert-butyl 4-(3-(4-(pyridin-2-ylamino)phenoxy)pyrazin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (Example 278) to be carried forward through Example 279 (Step 2), which was subsequently treated in similar fashion using acetyl chloride. The impurity was separated from the major product by SFC using MeOH (1% diethyl amine) to give 1-(4-(3-(4-(pyridin-2-ylamino)phenoxy)pyrazin-2-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone as a white solid. MS (ESI, pos. ion) m/z: 388.1 (M+1). IC50 (uM) 0.00234.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]#[N:20])=[CH:16][CH:17]=3)[CH2:12][O:11]2)=[CH:6][CH:5]=1.[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25]Cl.CN(C)CCN(C)C>C1COCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.COC(C)(C)C.CN(C)C=O>[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25][C:10]1([C:7]2[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=2)[C:18]2[C:13](=[CH:14][C:15]([C:19]#[N:20])=[CH:16][CH:17]=2)[CH2:12][O:11]1
Reactant: N#Cc1ccc2c(c1)COC2c1ccc(F)cc1
Reactant: CN(C)CCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CN(C)CCN(C)C
Agent: [Br-]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(C)CCCC1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Reaction time: 0.17 h
Yield: 77.2 %

Procedure:
60% Sodium hydride (0.58 g) was dispersed in THF (12 ml), and to this suspension was added dropwise a solution of 1-(4′-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (3.0 g) in THF (6 ml) at 40-50° C. under a nitrogen atmosphere. Thereto was added tetra n-butylammonium bromide (0.12 g), and a solution of 3-(dimethylamino)propyl chloride (2.0 g) in t-butyl methyl ether (12 ml) was added dropwise, which was followed by stirring for 10 min. Further, N,N,N′,N′-tetramethylethylenediamine (0.73 g) and N,N-dimethylformamide (14.2 g, 15 ml) were added and the mixture was stirred at 61-64° C. for 7 hr. The reaction mixture was treated in the same manner as in Example 22 to give 1-(3-(dimethylamino)propyl)-1-(4′-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (citalopram base) as a viscous oil (3.14 g, yield 77.2%). Hydrobromide thereof showed the same HPLC retention time and melting point as obtained in Example 22.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[N:20]([C:21]([CH3:24])([CH3:23])[CH3:22])[N:19]=[CH:18][CH:17]=2)[N:12]=[C:11]([CH2:25][C:26]2([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)[CH:10]=1)C1C=CC=CC=1>O1CCCC1.CO.[OH-].[OH-].[Pd+2]>[C:21]([N:20]1[C:16]([NH:15][C:13]2[N:12]=[C:11]([CH2:25][C:26]3([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:28][CH2:27]3)[CH:10]=[C:9]([OH:8])[CH:14]=2)=[CH:17][CH:18]=[N:19]1)([CH3:22])([CH3:23])[CH3:24]
Reactant: CCOC(=O)C1(Cc2cc(OCc3ccccc3)cc(Nc3ccnn3C(C)(C)C)n2)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)C1(Cc2cc(O)cc(Nc3ccnn3C(C)(C)C)n2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1 g of 1-tert-butyl 4-ethyl 4-((4-(benzyloxy)-6-((1-tert-butyl-1H-pyrazol-5-yl)amino)pyridin-2-yl)methyl)piperidine-1,4-dicarboxylate in 10 ml of tetrahydrofuran and 10 ml of methanol was added 300 mg of 20% palladium hydroxide on carbon, followed by stirring the reaction mixture at room temperature for 2 hours under hydrogen atmosphere. Palladium catalyst was filtered off using Celite, washed with methanol, and the filtrate was concentrated in vacuo to give the title compound as a pale brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][CH2:11][CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.Br[CH:26]([CH2:30]Br)[C:27]([NH2:29])=[O:28]>>[Br:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:11][CH2:12][N:13]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)[CH:26]([C:27]([NH2:29])=[O:28])[CH2:30]2)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(Br)cc(NCCNCc2ccc(OC)c(OC)c2)c1
Reactant: NC(=O)C(Br)CBr
Product: COc1cc(Br)cc(N2CCN(Cc3ccc(OC)c(OC)c3)C(C(N)=O)C2)c1

Procedure:
In a manner similar to Preparation 1, react N-(3-bromo-5-methoxyphenyl)-N'-[(3,4-dimethoxyphenyl)methyl]-1,2-ethanediamine with 2,3-dibromopropanamide to obtain the title compound.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH2:25])=[CH:7][CH:6]=1)(=O)C.[CH:26](=O)[CH2:27][CH2:28][CH3:29].C([BH3-])#N.[Na+].Cl>CN(C)C=O.O>[NH2:4][C:5]1[CH:6]=[CH:7][C:8]([S:11][C:12]2[C:20]([S:21](=[O:23])(=[O:24])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:9][CH:10]=1
Reactant: CC(=O)Nc1ccc(Sc2c(N)cc(C(=O)O)cc2S(N)(=O)=O)cc1
Reactant: CCCC=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Sc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the solution of 1.52 g of 4-(4-acetamidophenylmercapto)-3-amino-5-sulfamoylbenzoic acid in 600 ml of dimethylformamide, 40 g of butyraldehyde and 1.60 g of molecular sieves [Na12 (AlSiO4)12. 27 H2O], 36 g of sodium cyanoborohydride are added while stirring under nitrogen and keeping the temperature between about 20° and 30° for 1 hour. After stirring the mixture for 68 hours at room temperature, 6 lt of water are added, followed by 110 ml of concentrated hydrochloric acid and stirring is continued for 1 hour. The precipitate formed is filtered off, washed with water, dissolved in 1.2 lt of 2N aqueous sodium hydroxide and the solution refluxed for 2 hours under nitrogen. After cooling to room temperature it is filtered and the filtrate combined with 250 ml of glacial acetic acid. The precipitate formed is collected, 333 g thereof are dissolved in 2.8 lt of hot, 80% aqueous acetonitrile, the solution filtered, the filter washed with 500 ml more of said acetonitrile and the filtrate diluted with 3.3 lt of hot water. The precipitate formed at 14° is filtered off, taken up in 2.15 lt of hot, 90% aqueous ethanol and the solution diluted with 2.5 lt of hot water. The solids separated after cooling are collected and washed with water, to yield the 4-(4-aminophenylmercapto)-3-n-butylamino-5-sulfamoylbenzoic acid melting at 232°-234°, it is identical with that obtained according to Example 3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][O:15][CH2:16][C:17]3[CH:18]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[N:23]=[CH:22]4)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:31]([BH3-])#N.[Na+].C=O.C(O)(=O)C>C(#N)C.C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][O:15][CH2:16][C:17]3[CH:18]=[C:19]([C:27]([F:28])([F:29])[F:30])[CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[N:23]=[CH:22]4)[CH2:13][CH2:12][N:11]([CH3:31])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: Cn1ncc2cc(C(F)(F)F)cc(COCC3(c4ccc(F)cc4)CCNCC3)c21
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CN1CCC(COCc2cc(C(F)(F)F)cc3cnn(C)c23)(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 7-(((4-(4-fluorophenyl)piperidin-4-yl)methoxy)methyl)-1-methyl-5-(trifluoromethyl)-1H-indazole (35 mg, 0.083 mmol) and sodium cyanoborohydride (10.4 mg, 0.166 mmol) in acetonitrile (1 mL) at room temperature was added formalin (50 μL). To this was added 1 drop of acetic acid. After 5 min, a second drop of acetic acid was added and the reaction stirred at room temperature for 15 min. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was washed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated to give 15 mg (42%). 1H-NMR (CDCl3, 500 MHz) δ 8.01 (s, 1H), 7.95 (s, 1H), 7.29 (s, 1H), 7.14 (m, 2H), 6.87 (m, 2H), 4.68 (s, 2H), 3.98 (s, 3H), 3.44 (s, 2H), 2.50 (m, 2H), 2.00-2.25 (m, 7H), 1.91 (m, 2H); 13C-NMR (CDCl3, 126 MHz) δ 162.2, 160.2, 139.4, 133.9, 128.62, 128.56, 124.8, 124.6 (q, J=272 Hz), 124.5 (q, J=2.9 Hz), 122.6 (q, J=33 Hz), 121.1, 119.7 (q, J=4.8 Hz), 115.0, 114.9, 78.7, 70.5, 51.8, 46.2, 40.2, 38.3, 32.6. Mass spec.: 436.15 (MH)+. Accurate mass spec.: m/z 436.2008 [MH]+, Δ=0.9 ppm.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([F:13])[CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:14][N:15](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[C:7]([F:13])[CH:8]=1)[N:5]=[CH:4][CH:3]=[C:2]2[C:14]#[N:15]
Reactant: CN(C)C=O
Reactant: Fc1cc(F)c2nccc(Cl)c2c1
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccnc2c(F)cc(F)cc12
Reaction time: 12 h

Procedure:
A mixture of 4-chloro-6,8-difluoroquinoline (APOLLO) (1000 mg, 5.01 mmol), zinc cyanide (1180 mg, 10.0 mmol) and palladium (0) tetrakis(triphenylphosphine)(579 mg, 0.501 mmol) in dry DMF (15 ml) was treated at room temperature with stirring for 12 hours. Then, the reaction was quenched with saturated aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was separated and the crude product was purified by column chromatography on silica gel (ca. 250 g) with hexane-ethyl acetate (3:1) to give the title compound (787 mg, yellow solid). 1H NMR (270 MHz, CDCl3) 5 ppm 7.37-7.50 (1H, m), 7.65-7.75 (1H, m), 7.83-7.90 (1H, m), 9.05-9.10 (1H, m).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.[Cu](C#N)[C:10]#[N:11].C(OCC)(=O)C>CN(C=O)C>[C:10]([C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1)#[N:11]
Reactant: N#C[Cu]C#N
Reactant: O=Cc1cc(Br)cs1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1csc(C=O)c1
Yield: 64.1 %

Procedure:
4-Bromo-2-thiophenecarboaldehyde (5.00 g) was dissolved in DMF (40 ml), and copper cyanide (3.52 g) was added thereto. After heating under reflux for 3 hours, the mixture was cooled as it was to room temperature and ethyl acetate was added thereto. The mixture was washed with an aqueous ammonia, water, 0.1N aqueous hydrochloric acid and further brine, dried over anhydrous magnesium sulfate and then evaporated. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate system), and then recrystallized from ethyl acetate-hexane, to give the title compound as pale yellowish white crystals (2.30 g, 71%).
Reaction SMILES: [K].[CH3:2][CH:3]([CH3:5])[O-:4].[K+].Br[C:8]1[CH:9]=[N:10][CH:11]=[C:12]([Br:14])[CH:13]=1>CC(O)C.[Cu]>[Br:14][C:12]1[CH:13]=[C:8]([O:4][CH:3]([CH3:5])[CH3:2])[CH:9]=[N:10][CH:11]=1
Reactant: Brc1cncc(Br)c1
Reactant: CC(C)[O-]
Agent: [Cu]
Agent: [K+]
Agent: [K]
Solvent: CC(C)O
Product: CC(C)Oc1cncc(Br)c1
Temperature: 25 °C
Yield: 71.2 %

Procedure:
Potassium metal (6.59 g, 168.84 mmol) was dissolved in dry 2-propanol (60.0 mL) under nitrogen. The resulting potassium isopropoxide was heated with 3,5-dibromopyridine (20.00 g, 84.42 mmol) and copper powder (1 g, 5% by weight of 3,5-dibromopyridine) at 140° C. (oil bath temperature) in a sealed glass tube for 14 h. The reaction mixture was cooled to ambient temperature and extracted with diethyl ether (4×200 mL). The combined ether extracts were dried over sodium sulfate, filtered, and concentrated by rotary evaporation. The crude product obtained was purified by column chromatography over aluminum oxide, eluting with ethyl acetate-hexane (1:9, v/v). Selected fractions were combined and concentrated by rotary evaporation, producing a pale-yellow oil (12.99 g, 71.2%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)[O:16]1.C(OO)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>CCCCCCC.O.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([OH:16])[CH:5]=[N:4][C:3]=1[O:8][CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: Clc1cccnc1OC1CCOCC1
Agent: CC(=O)OO
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCCCCCC
Product: Oc1cnc(OC2CCOCC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 32.1 %

Procedure:
3-Chloro-2-(tetrahydro-2H-pyran-4-yloxy)pyridine (Preparation 25, 1.40 g, 6.55 mmol) and bis(pinacolato)diboron (6.65 g, 13.11 mmol) were dissolved in heptane (30 mL) and degassed five times with nitrogen. Di-tert-butyldipyridyl (0.017 mg, 0.066 mmol) was added, followed by (1,5-cyclooctadiene)(methoxy)lridium(I) dimer (0.022 mg, 0.033 mmol). The mixture was again degassed five times with nitrogen and stirred at room temperature for 18 hours. The reaction was quenched by slow addition of methanol (50 mL) and concentrated in vacuo to afford a red/orange oil, which was purified by silica gel chromatography eluting with 66% EtOAc in heptane to afford an impure product. The obtained crude product was dissolved in and a 1:1 mixture of acetic acid:water (30 mL) was added and cooled to 5° C. (ice bath). Peracetic acid was slowly added over 2 minutes. The reaction was stirred at 5° C. for 30 minutes, then a 1 M aqueous solution of sodium thiosulfate was added. The reaction was allowed to slowly warm to room temperature over 30 minutes, diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organics were then dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a yellow oil, which was purified by silica gel chromatography eluting with EtOAc to afford an off-white solid. The solid was triturated in heptane to afford the title compound as a white solid (0.483 g, 43%):
Reaction SMILES: CC1C=CC(N)=C([N+]([O-])=O)C=1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[C:22]2[CH:23]=[CH:24][C:25]([C:27](F)(F)F)=[CH:26][C:21]=2[N:20]=[C:19]1/[CH:31]=[CH:32]/[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH3:27][C:25]1[CH:24]=[CH:23][C:22]2[N:18]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=3)[C:19](/[CH:31]=[CH:32]/[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[N:20][C:21]=2[CH:26]=1
Reactant: FC(F)(F)c1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1
Agent: Cc1ccc(N)c([N+](=O)[O-])c1
Product: Cc1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1

Procedure:
The titled compound was prepared from 4-methyl-2-nitroaniline according to the preparation of (E)-1-(2-pyridyl)-2-styryl-5-trifluoromethyl-1H-benzimidazole (Example 57). MW: 311.39; mp: 144.8-146.0° C.; 1H-NMR (CDCl3) δ: 8.77-8.72 (1H, m), 7.99-7.91 (1H, m), 7.98 (1H, d, J=16.1 Hz), 7.61 (1H, s), 7.53-7.26 (8H, m), 7.15 (1H, d, J=16.1 Hz), 7.10-7.05 (1H, m), 2.50 (3H, s).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:20])=[C:4]2[NH:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=3)=[N:8][C:5]2=[N:6][CH:7]=1.Cl>CO.[Fe]>[Br:1][C:2]1[C:3]([CH3:20])=[C:4]2[NH:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1c(Br)cnc2nc(-c3ccc([N+](=O)[O-])cc3)[nH]c12
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: Cc1c(Br)cnc2nc(-c3ccc(N)cc3)[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
6-Bromo-7-methyl-2-(4-nitrophenyl)-1H-imidazo[4,5-b]pyridine (Example 259) (0.11 g, 0.34 mmol) was dissolved in methanol (15 ml) and iron powder (0.097 g, 1.70 mmol) was added. Conc. HCl (1.8 ml) was added dropwise over 15 min. and the reaction mixture was stirred at room temperature for 2 h. Methanol was partly removed by evaporation, after which water and ammonia were added. The aqueous phase was extracted with CHCl3, dried (Na2SO4), filtered and evaporated to yield the product (81.2 mg, 78%).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:21](N1C=CN=C1)([N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)=[O:22].O>O1CCCC1>[N:23]1([C:21]([N:20]=[C:16]([N:7]2[CH2:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8]2)[O:17][CH2:18][CH3:19])=[O:22])[CH:27]=[CH:26][N:25]=[CH:24]1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=NC(=O)n1ccnc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
2.0 g of ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6carboximidate and 1.83 g of 1,1'-carbonyldiimidazole are stirred at room temperature for 5 hours in 20 ml of tetrahydrofuran. The reaction mixture is poured into water and extracted twice with ethyl acetate. The extracts are washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated. The residue is chromatographed on silica gel with n-hexane/acetone (1:4) as the eluent, and there is obtained ethyl N-(1-imidazolylcarbonyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6 carboximidate, m,p. 134°-137° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[C:37]([NH:41][C:42](=[O:50])[CH2:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)([CH3:40])([CH3:39])[CH3:38]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:47]3[CH2:46][CH2:45][N:44]([CH2:43][C:42]([NH:41][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:50])[CH2:49][CH2:48]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([C:32]#[N:33])([CH3:30])[CH3:31])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CC(C)(C)NC(=O)CN1CCNCC1
Product: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)NC(C)(C)C)CC1

Procedure:
2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl}-piperazin-1-yl)-N-tert-butyl-acetamide was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (example 12j) and N-tert-butyl-2-piperazin-1-yl-acetamide (example 16g) in an analogous manner as described in example 25. LR-MS: 703.3 [(M+H)+]