Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH:5][CH3:6].[C:7](=[O:10])([O-])[O-:8].[Na+].[Na+].C(=O)([O-])OC1C=CC([N+]([O-])=O)=CC=1[CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27].O>C(O)C>[CH3:27][Si:26]([CH3:29])([CH3:28])[CH2:25][CH2:24][O:8][C:7]([N:2]([CH3:1])[CH2:3][CH2:4][NH:5][CH3:6])=[O:10]
Reactant: C[Si](C)(C)CCc1cc([N+](=O)[O-])ccc1OC(=O)[O-]
Reactant: O=C([O-])[O-]
Reactant: CNCCNC
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CNCCN(C)C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 35 %

Procedure:
N-(2-trimethylsilylethoxycarbonyl)-N,N′-dimethylethylenediamine was prepared as follows: to a stirred solution of N,N′-dimethylethylenediamine (616 mg, 5.94 mmol) and aqueous sodium carbonate (2M, 25 mL) at room temperature was added a solution of 2-(trimethylsilyl)ethyl-4-nitrophenyl carbonate (1.31 g, 4.63 mmol) in ethanol (15 mL). The reaction was heated at reflux for 1 h and then stirred at room temperature for 20 hours. The suspension was partially reduced in vacuo and the resulting slurry was added to water (100 mL) and extracted with methylene chloride (3×50 mL). The combined organics were filtered, dried over sodium sulfate and reduced in vacuo. The crude residue was purified via MPLC (silica gel, gradient 5–30%, methanol in methylene chloride) to yield N-(2-trimethylsilylethoxycarbonyl)-N,N′-dimethylethylenediamine as a light yellow solid (380 mg, 1.64 mmol, 35% yield); 1H NMR (CDCl3, 300 MHz): δ 4.14 (m, 2H), 3.34 (m, 2H), 2.88 (s, 3H), 2.71 (m, 2H), 2.42 (s, 3H), 0.97 (m, 2H), 0.01 (s, 9H); ESI (+) MS: 233 (M+H+); TLC: Rf=0.06 (4:1, methylene chloride:methanol, Whatman MK6F, 60 angstrom).
Reaction SMILES: Cl.[F:2][C:3]1([F:9])[CH:8]=C[CH:6]=[N:5][CH2:4]1.Cl[C:11]1[CH:16]=[C:15]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[CH:14]=[C:13]([Cl:30])[N:12]=1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O.C(OCC)(=O)C>[Cl:30][C:13]1[CH:14]=[C:15]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[CH:16]=[C:11]([N:5]2[CH2:6][CH2:8][C:3]([F:2])([F:9])[CH2:4]2)[N:12]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(Cl)nc(Cl)c2)CC1
Reactant: FC1(F)C=CC=NC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2cc(Cl)nc(N3CCC(F)(F)C3)c2)CC1
Yield: 46.8 %

Procedure:
A solution of 3,3-difluoropyridine hydrochloride (533 mg, 3.72 mmol, 3.18 equiv), tert-butyl 4-(2,6-dichloropyridin-4-yl)piperidine-1-carboxylate (1.00 g, 1.17 mmol, 1 equiv), and N,N-diisopropylethylamine (1.23 mL, 7.03 mmol, 6.00 equiv) in N-methylpyrrolidinone (2.3 mL) was heated at 130° C. in the microwave (CEM) for 1.5 h. The reaction mixture was diluted with ethyl acetate (50 mL), and the resulting solution was washed with saturated aqueous ammonium chloride solution (2×20 mL). The aqueous washes were extracted with ethyl acetate (25 mL). The combined organic was washed with water (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (4:1 heptane/ethyl acetate) provided product as a clear oil (220 mg, 47% yield). 1H NMR (400 MHz, CDCl3): 6.51 (s, 1H), 6.03 (s, 1H), 4.25 (m, 2H), 3.83 (t, J=13.1 Hz, 2H), 3.67 (t, J=7.3 Hz, 2H), 2.77 (m, 2H), 2.42-2.58 (m, 3H), 1.78 (m, 2H), 1.53-1.62 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][CH3:11])[C:3]=1[C:4]#[N:5].[S:12](Cl)(=[O:15])(=[O:14])[NH2:13]>>[S:12]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][CH3:11])[C:3]=1[C:4]#[N:5])(=[O:15])(=[O:14])[NH2:13]
Reactant: NS(=O)(=O)Cl
Reactant: CSc1cccc(N)c1C#N
Product: CSc1cccc(NS(N)(=O)=O)c1C#N

Procedure:
Prepared as in Example 1 from 2-amino-6-(methylthio)benzonitrile (Example 8b) and sulfamoyl chloride. 1H NMR (400 MHz, DMSO-d6) δ 2.56 (s, 3H), 7.18 (d, J=8.4 Hz, 1H), 7.26 (s, 2H), 7.33 (d, J=8.0 Hz, 1H), 7.59 (t, J=8.40 Hz, 1H), 9.51 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[C:17]3[C:13]([C:14]([C:20](=[O:25])[C:21]([O:23]C)=[O:22])=[CH:15][N:16]3[CH3:19])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[OH-].[Na+].O.Cl>CO>[CH3:19][N:16]1[C:17]2[C:13](=[CH:12][CH:11]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:26])[F:27])=[CH:9][CH:8]=3)[CH:18]=2)[C:14]([C:20](=[O:25])[C:21]([OH:23])=[O:22])=[CH:15]1
Reactant: COC(=O)C(=O)c1cn(C)c2cc(-c3ccc(OC(F)(F)F)cc3)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1cc(C(=O)C(=O)O)c2ccc(-c3ccc(OC(F)(F)F)cc3)cc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 59.4 %

Procedure:
The mixture of methyl 2-[6-(4-trifluoromethoxyphenyl)-1 -methyl-1H-indol-3-yl]-2-oxoacetate (0.120 g, 0.318 mmol), and sodium hydroxide (1N, 1 mL, 1.0 mmol) in methanol (10 mL), was stirred at room temperature for 2.5 hours. The mixture was poured into excess water and acidified with 1N hydrochloric acid. The mixture was extracted with ethyl acetate. The organic phase was washed with water, brine and dried over anhydrous magnesium sulfate. The organic phase was evaporated to dryness and dried under vacuum at 55° C. for 12 hours to yield the title compound as a yellow solid (0.0686 g, 59.1%), mp: 233-235° C. (dec). Mass spectrum (+APCI, [M+H]+) m/z 364; 1HNMR (400 MHz, DMSO-d6): δ 13.8-14.0 (br s, 1H), 8.55 (s, 1H), 8.25 (d, 1H, J=8.3 Hz), 7.95 (d, 1H, J=1.1 Hz), 7.85-7.95 (m, 2H), 7.65 (dd, 1H, J=8.2 and 1.6 Hz), 7.45 (dd, 2H, J=8.8 Hz and 0.88 Hz), and 4.0 ppm (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([C:20]([CH3:23])([CH3:22])[CH3:21])[S:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:4][CH:3]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1.[N:57]1([C:63](=[O:65])[CH3:64])[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[C:63]([N:57]1[CH2:62][CH2:61][N:60]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][N:9]([C:20]([CH3:23])([CH3:22])[CH3:21])[S:10]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:12])=[O:11])=[CH:4][CH:3]=2)[CH2:59][CH2:58]1)(=[O:65])[CH3:64]
Reactant: CC(=O)N1CCNCC1
Reactant: CC(C)(C)N(Cc1ccc(Br)cc1)S(=O)(=O)Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: CC(=O)N1CCN(c2ccc(CN(C(C)(C)C)S(=O)(=O)Cc3ccccc3)cc2)CC1
Temperature: 100 °C
Reaction time: 16 h
Yield: 67.6 %

Procedure:
In a vial, N-[(4-bromophenyl)methyl]-N-tert-butyl-1-phenylmethanesulfonamide (186 mg; 0.47 mmol), palladium(II) acetate (5 mg, 0.023 mmol), 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (22 mg, 0.047 mmol) sodium tert-butoxide (61 mg, 0.61 mmol) were weighed out and the vial was purged with nitrogen. 1,4-Dioxane (3 mL) and 1-piperazin-1-ylethanone (78 mg, 0.61 mmol) were then added and the reaction was stirred at 100° C. for 16 hours. The reaction was filtered through diatomaceous earth, concentrated and purified by preparative reverse phase HPLC to yield 141 mg of N-(4-(4-acetylpiperazin-1-yl)benzyl)-N-tert-butyl-1-phenylmethanesulfonamide. 1H NMR (400 MHz, DMSO) δ 7.47-7.33 (m, 5H), 7.27-7.16 (m, 2H), 6.96-6.83 (m, 2H), 4.41 (s, 2H), 4.16 (s, 2H), 3.62-3.49 (m, 4H), 3.19-3.09 (m, 2H), 3.09-2.95 (m, 2H), 2.03 (s, 3H), 1.33 (s, 9H); LCMS (m/z) ES+ 444.1 [M+1]+.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20]>C(OCC)(=O)C>[C:4]1(=[O:6])[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]12
Reactant: NCCCCCCC(=O)O
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Product: O=C(O)CCCCCCN1C(=O)c2ccccc2C1=O
Yield: 50.8 %

Procedure:
A mixture of phthalic anhydride (5.3 g.) and 7-aminoheptanoic acid (5.8 g.) was heated at 185°-190° C. for 40 minutes and then cooled. The cooled partially solidified product was dissolved in ethyl acetate and the solution washed several times with dilute HCl. The organic layer was dried (MgSO4), filtered and evaporated to dryness and the residue recrystallized from acetic acid to give 7-phthalimidoheptanoic acid (5 g.), m.p. 112°-115° C.
Reaction SMILES: C[O:2][C:3]1[C:8]([N:9]2[C:13](=[O:14])[C:12]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]3[C:10]2=[O:19])=[CH:7][CH:6]=[C:5]([O:20][CH3:21])[N:4]=1.[BrH:22].CCOCC>C(O)(=O)C>[BrH:22].[O:19]=[C:10]1[C:11]2[C:12](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[O:14])[N:9]1[C:8]1[C:3]([OH:2])=[N:4][C:5]([O:20][CH3:21])=[CH:6][CH:7]=1
Reactant: COc1ccc(N2C(=O)c3ccccc3C2=O)c(OC)n1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: COc1ccc(N2C(=O)c3ccccc3C2=O)c(O)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
1,3-Dioxo-2-(2-hydroxy-6-methoxypyridin-3-yl)-isoindoline hydrobromide (6) was prepared and isolated as follows. To a flask were added 2,6-dimethoxy-3-phthalimidopyridine (155 mg, 0.546 mmol) and hydrogen bromide solution in acetic acid (30%, 6 ml). The mixture was stirred at room temperature under N2 for 18 h. Dry ether was added slowly until the solution became cloudy. White crystals were precipitated, filtered and washed with ether and ethyl acetate to afford 6 (127 mg, 67%) as white powdery crystals: mp 250° C.; 1H NMR (DMSO-d6) δ 7.97-7.94 (m, 2H), 7.91-7.88 (m, 2H), 7.64 (d, J=8.2 Hz, 1H), 6.25 (d, J=8.2 Hz, 1H), 3.86 (s, 3H); 13C NMR (DMSO-d6) δ 167.5, 162.1, 159.1, 142.8, 135.4, 132.1, 123.7, 108.2, 96.4, 54.8; MS (CI/CH4) 270 [M]+.
Reaction SMILES: [C:1](OC)(=O)[CH:2]=[CH2:3].[CH3:7][N:8]([CH2:10][CH2:11][CH2:12][NH2:13])[CH3:9].[CH3:14][O-:15].[Na+]>>[CH3:7][N:8]([CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:15])[CH:12]([NH:13][CH2:1][CH:2]([N:8]([CH3:9])[CH3:7])[CH3:3])[CH3:11])[CH3:9]
Reactant: CN(C)CCCN
Reactant: C=CC(=O)OC
Reactant: C[O-]
Agent: [Na+]
Product: CC(NCC(C)N(C)C)C(=O)NCCCN(C)C

Procedure:
To 4 moles of methyl acrylate were added 8.8 moles of dimethylaminopropylamine and the mixture was subjected to an addition reaction in the same manner as in Comparative Example 2. Then sodium methoxide was added thereto to conduct the amidation reaction. After completion of the reaction, the low-boiling-point substances were removed by distillation to give a crude N-dimethylaminopropyl-beta-dimethylaminopropylaminopropionamide. This contained about 13% of high-boiling-point impurities.
Reaction SMILES: CO.[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12](=O)[CH3:13])[N:7]=1)(=O)[CH3:4].[CH3:15][C:16]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:17]=1[NH2:18]>C(O)=O>[CH3:15][C:16]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:17]=1[N:18]=[C:3]([C:6]1[N:7]=[C:8]([C:12](=[N:18][C:17]2[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:16]=2[CH3:15])[CH3:13])[CH:9]=[CH:10][CH:11]=1)[CH3:4]
Reactant: CC(=O)c1cccc(C(C)=O)n1
Reactant: Cc1ccc(N)c(C)c1
Solvent: O=CO
Solvent: CO
Product: CC(=Nc1ccc(C)cc1C)c1cccc(C(C)=Nc2ccc(C)cc2C)n1
Reaction time: 1 h
Yield: 43.3 %

Procedure:
100 ml of methanol, 1.63 g of 2,6-diacetylpyridine (molecular weight 163.18; 10 mmols), and 4.84 g of 2,4-dimethylaniline (molecular weight 121.18; 40 mmols) were put into a 300 ml flask, and thoroughly stirred to prepare a homogeneous mixture. 0.6 ml of formic acid was added to this, and further the mixture was stirred for 12 hours to make the compounds reacted completely. The reaction mixture was left at −78° C. for 1 hour, and the resulting pale yellow crystal was taken out through filtration, washed with methanol, and dried under reduced pressure. Its 1H-NMR spectrum was assigned as the intended product, 2,6-diacetylpyridine-bis(2,4-dimethylphenylimine) (molecular weight 369.52; 1.60 g, 4.33 mmols, yield 43%).
Reaction SMILES: ICCCCCI.[C:8]12([S:18][C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:30]C[CH2:28][CH2:27][CH2:26]4)=[CH:21][CH:20]=3)[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2>>[C:8]12([S:18][C:19]3[CH:20]=[CH:21][C:22]([N:25]4[CH2:26][CH2:27][CH2:28][CH2:30]4)=[CH:23][CH:24]=3)[CH2:17][CH:12]3[CH2:11][CH:10]([CH2:16][CH:14]([CH2:13]3)[CH2:15]1)[CH2:9]2
Reactant: c1cc(N2CCCCC2)ccc1SC12CC3CC(CC(C3)C1)C2
Agent: ICCCCCI
Product: c1cc(N2CCCC2)ccc1SC12CC3CC(CC(C3)C1)C2

Procedure:
In a similar manner, using 1,5-diiodopentane, 1-(p-1-adamantylthiophenyl)piperidine can be prepared.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:17]=[C:18]([CH2:23]O)[CH:19]=[CH:20][C:21]=1[CH3:22]>>[F:15][C:16]1[CH:17]=[C:18]([CH2:23][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)[CH:19]=[CH:20][C:21]=1[CH3:22]
Reactant: Cc1ccc(CO)cc1F
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: Cc1ccc(COc2ccnn2-c2cc(C#N)ccn2)cc1F

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (3-fluoro-4-methylphenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 2.28 (3H, s), 5.19 (2H, s), 5.72 (1H, d, J=2.0 Hz), 7.18-7.20 (1H, m), 7.07-7.11 (2H, m), 7.41 (1H, dd, J=1.2, 4.8 Hz), 7.56 (1H, d, J=1.6 Hz), 8.03 (1H, s), 8.71 (1H, d, J=4.8 Hz). [M+H] Calc'd for C17H13FN4O, 309. Found, 309.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:13][CH:14]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[C:15]3[N:16]=[C:17]([CH3:20])[NH:18][CH:19]=3)=[O:12])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[C:28]([O-:31])([O-])=O.[Cs+].[Cs+].FC(F)(F)S(O[CH2:40][C:41]([F:44])([F:43])[F:42])(=O)=O>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([CH2:10][C:11]([NH:13][C:14]([C:1]3[CH:4]=[CH:5][C:28]([OH:31])=[CH:3][CH:2]=3)([C:15]3[N:16]=[C:17]([CH3:20])[NH:18][CH:19]=3)[C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:40][C:41]([F:44])([F:43])[F:42])=[CH:23][CH:22]=3)=[O:12])=[CH:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: O=C([O-])[O-]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: Cc1nc(C(NC(=O)Cc2ccc(C3CC3)cc2)c2ccc(O)cc2)c[nH]1
Agent: [Cs+]
Product: Cc1nc(C(NC(=O)Cc2ccc(C3CC3)cc2)(c2ccc(O)cc2)c2ccc(OCC(F)(F)F)cc2)c[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.7 %

Procedure:
To a 5 ml round bottom flask containing solution of 2-(4-cyclopropylphenyl)-N-[(4-hydroxyphenyl)(2-methyl-1H-imidazol-4-yl)methyl]acetamide (10.00 mg, 0.0280 mmol) in 0.3 ml of CH2Cl at RT was added Cs2CO3 (18.03 mg, 0.0550 mmol). To the mixture was added dropwise 2,2,2-trifluoroethyl trifluoromethanesulfonate (6.420 mg, 0.0280 mmol). The resulting solution was stirred at RT for 16 hours. Filtered and the filtrate was purified by preparative HPLC (10-90% CH3CN/H2O over 30 min, 0.05% added TFA, C18 column) to afford 5.60 mg (46%) of the title compound. 1H NMR (CDCl3, 400 MHz) δ 8.448 (d, J=7.32 Hz, 1H), 7.152 (d, J=8.60 Hz, 2H), 7.071 (d, J=8.06 Hz, 2H), 6.936 (d, J=8.05 Hz, 2H), 6.874 (d, J=8.61 Hz, 2H), 6.592 (s, 1H), 6.109 (d, J=7.88 Hz, 1H), 4.308 (q, J=8.06 Hz, 2H), 3.544 (s, 2H), 2.395 (s, 3H), 1.798 (m, 1H), 0.918 (m, 2H), 0.590 (m, 2H). ES-MS [M+1]+: 444.2.
Reaction SMILES: [F:1]C1C=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(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>>[F:1][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: Nc1ccc(F)cc1[N+](=O)[O-]
Reactant: FC(F)(F)c1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1
Product: Fc1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1

Procedure:
The titled compound was prepared from 4-fluoro-2-nitroaniline according to the preparation of (E)-1-(2-pyridyl)-2-styryl-5-trifluoromethyl-1H-benzimidazole (Example 57). MW: 315.35; mp: 134.0-135.0° C.; 1H-NMR (CDCl3) δ: 8.78 (1H, ddd, J=4.8, 1.8, 1.1 Hz), 8.04-7.96 (1H, m), 8.00 (1H, d, J=15.8 Hz), 7.54-7.45 (5H, m), 7.42-7.30 (4H, m), 7.10 (1H, d, J=16.1 Hz), 7.01 (1H, td, J=9.2, 2.6 Hz).
Reaction SMILES: [CH2:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl.Cl[CH2:22][CH2:23][N:24]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[CH2:32]([N:24]([CH2:23][CH2:22][CH:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: ClCCN(Cc1ccccc1)Cc1ccccc1
Reactant: N#CCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CC(CCN(Cc1ccccc1)Cc1ccccc1)c1ccccc1
Temperature: 50 °C
Yield: 90.7 %

Procedure:
Benzyl cyanide (0.97 mL, 8.4 mmole) was reacted with lithium bis(trimethylsilyl)amide (LHMDSA) (8.4 mL, 8.4 mmole) in 5 mL of THF at -78° C. for 1 hour. After an additional aliquot of LHMDSA (4.2 mL, 4.2 mmole) was added, N-(2-chloroethyl)dibenzylamine hydrochloride (1.0 g, 3.4 mmole) was then added. The reaction was allowed to stand at room temperature and was then warmed to 50° C. for 3.5 hours. The mixture was poured into ice/water, and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure to afford alpha-(N,N-dibenzylaminoethyl) benzyl cyanide (1.05 g), isolated in 94% yield (MS: (M+H)+ =341).
Reaction SMILES: C(=O)=O.C(O)(C)C.[CH2:8]([C:11]1[S:12][C:13]2[CH:29]=[CH:28][CH:27]=[CH:26][C:14]=2[C:15]=1[C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=1)=O)[CH:9]=[CH2:10].B(Br)(Br)Br.O>C(Cl)Cl>[C:16]1([C:18]2[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=2)[C:15]2[C:14]3[CH:26]=[CH:27][CH:28]=[CH:29][C:13]=3[S:12][C:11]=2[CH:8]=[CH:9][CH:10]=1
Reactant: C=CCc1sc2ccccc2c1C(=O)c1ccc(OC)cc1
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: CC(C)O
Solvent: O
Solvent: ClCCl
Product: Oc1ccc(-c2cccc3sc4ccccc4c23)cc1
Yield: 57.4 %

Procedure:
To a mechanically stirred, cold (-74° C. dry ice-isopropanol bath) solution of (2-allyl-benzothiophen-3-yl)-(4-methoxy-phenyl)-methanone (11.27 g, 36.5 mmol) in anhydrous methylene chloride (112 mL) was added a 1 M solution of boron tribromide in methylene chloride (146 mL, 146 mmol, 4 eq) dropwise over a period of 1.25 hours under a dry nitrogen atmosphere. The reaction mixture was stirred in the warming bath overnight and at ambient temperature for 6 days. The reaction mixture was diluted with methylene chloride (total volume 500 mL) and added cautiously to water (1 L) with cooling in an ice bath. The layers were separated and the aqueous phase was extracted with ether (500 mL). The organic phases were combined, washed with a dilute aqueous solution of sodium bisulfite (2×1 L), and combined with silica gel. The solvents were removed and the adsorbate was flash chromatographed (82/18 petroleum ether/ethyl acetate) and chased with benzene and petroleum ether to provide the title compound as a white solid (5.79 g, 57%): mp 117-119° C.; NMR (CDCl3): δ 7.84 (dd, J=8, 1 Hz, 1H), 7.82 (dm, J=8 Hz, 1H), 7.45 (dd, J=8, 8, 1 Hz, 1H), 7.37-7.31 (multiplet with overlapping doublet at 7.33, J=8 Hz, 3H), 7.25 (s, 1H), 7.24 (dd, J=7, 1 Hz, 1H), 7.22 (dm, J=7 Hz, 1H), 7.10 (ddd, J=8, 7, 1 Hz, 1H), 7.01-6.98 (multiplet with overlapping doublet at 6.98, J=8 Hz, 2H); MS (EI): [M+] 276 (100%); Anal. Calc. for C18H12OS: C, 78.23, H, 4.38, N, 0.00. Found: C, 77.83, H, 4.22, N, 0.05.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH2:40]([N:47]1[CH2:51][CH2:50][N:49]([C@@H:52]([C:56]([CH3:59])([CH3:58])[CH3:57])[C:53](O)=[O:54])[C:48]1=[O:60])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH2:40]([N:47]1[CH2:51][CH2:50][N:49]([C@@H:52]([C:56]([CH3:58])([CH3:57])[CH3:59])[C:53]([NH:1][C@@H:2]([CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C@@H:3]([OH:32])[CH2:4][C@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[CH:9][CH:8]=2)=[O:54])[C:48]1=[O:60])[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: CC(C)(C)[C@@H](C(=O)O)N1CCN(Cc2ccccc2)C1=O
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccccc2)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.5 %

Procedure:
A solution containing the product from Example 1H (0.040 g, 0.075 mmol) in THF (0.6 mL) was treated with the product from Example 70A (0.027 g, 0.092 mmol), DEPBT (0.034 g, 0.114 mmol), and N,N-diisopropylethylamine (0.066 mL, 0.379 mmol), stirred at 25° C. for 16 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane, followed by elution with 0-5% methanol in ethyl acetate to give the title compound (0.045 g, 73% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.80 (s, 9 H), 0.87 (s, 9 H), 1.38 (t, J=11.58 Hz, 1 H), 1.54 (m, 1 H), 2.41 (m, 1 H), 2.64 (m, 3 H), 2.87 (m, 3 H), 3.19 (m, 1 H), 3.53 (m, 4 H), 3.84 (d, J=9.56 Hz, 1 H), 3.95 (m, 1 H), 4.04 (s, 1 H), 4.18 (m, 1 H), 4.29 (m, 2 H), 4.45 (d, J=7.35 Hz, 1 H), 6.88 (d, J=9.56 Hz, 1 H), 7.05 (m, 5 H), 7.30 (m, 8 H), 7.53 (d, J=9.56 Hz, 1 H), 7.90 (m, 5 H), 8.65 (d, J=4.41 Hz, 1 H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32]Cl)(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1.[NH2:34][C@@H:35]([CH2:38][CH3:39])[CH2:36][OH:37]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32][NH:34][C@H:35]([CH2:36][OH:37])[CH2:38][CH3:39])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1
Reactant: CC[C@H](N)CO
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Product: CC[C@@H](CO)NCCCS(=O)(=O)N1CCC(Nc2ncc(C(=O)c3c(OC)ccc(F)c3F)c(N)n2)CC1

Procedure:
The compound was prepared from [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (Example 226) and (S)-2-amino-1-butanol (Aldrich) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C24H35N6O5SF2 [(M+H)+] 557.2352, observed 557.2356.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([F:15])[CH:3]=1.[CH3:16][Zn]C.CO>O1CCOCC1.C(OCC)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Br[Pd]Br>[F:15][C:4]1[CH:3]=[C:2]([CH3:16])[C:7]([F:8])=[CH:6][C:5]=1[CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)C(C)c1cc(F)c(Br)cc1F
Reactant: C[Zn]C
Agent: Br[Pd]Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)C(C)c1cc(F)c(C)cc1F
Temperature: 25 °C
Yield: 144 %

Procedure:
To a solution of trans-dibromobis(triphenylphosphine)-palladium(II) [trans-Pd(PPh3)2Br2] (0.048 g, 5.6 mol %) in 1,4-dioxane (30 mL), a solution of compound (30a) (3.0 g, 10.7 mmol) in dry 1,4-dioxane (4 mL) was added under argon gas flow. To this mixture, dimethyl zinc (2M-solution in toluene, 11.0 mL, 22.0 mmol) was slowly added dropwise and the reaction mixture was heated to reflux for 4 hours. After cooling the reaction mixture to room temperature, methanol (4.0 mL) was added to the reaction mixture and the obtained mixture was diluted with diethyl ether. The organic layer was washed with a 1M aqueous solution (34 mL) of hydrochloric acid and dried (over magnesium sulfate). The solvent was distilled off, and the obtained residue was subjected to silica gel column chromatography and elution with an n-hexane/ethyl acetate (4:1) solution to give 3.3 g (83%) of compound (31a) as colorless liquid matter.