Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.C(=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCCCCC.O1CCCC1>[OH:4][C:3]1[CH2:5][CH:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:7][C:1](=[O:6])[CH:2]=1
Reactant: COC(=O)CC(C)=O
Reactant: O=Cc1ccccc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1C=C(O)CC(c2ccccc2)O1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
The title compound was prepared as described in General Method 1 using 13.67 g methyl acetoacetate, 8.5 g of NaH 60% dispersion in oil, 73.6 mL of 1.6M n-butyl lithium in hexane, 10 g of benzaldehyde, and 300 mL of tetrahydrofuran. After addition of the aldehyde, the reaction was stirred 15 minutes at -78° C. then allowed to warm to room temperature overnight. A solid was filtered off after concentration (m.p. 145°-146° C.). 1H NMR (CDCl3) δ 2.8-3.05 (m, 2 H), 3.5 (d, 1 H), 3.7 (d, 1 H), 5.7 (dd, 1 H), 7.3-7.5 (m, 5 H).
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13](OC)=[O:14])(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:20][NH2:21]>CO>[N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([NH:20][NH2:21])=[O:14])(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Reactant: NN
Solvent: CO
Product: NNC(=O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Temperature: 65 °C
Yield: 46.3 %

Procedure:
Methyl 3-(piperidin-1-ylsulfonyl)benzoate (150 mg, 0.529 mmol) was added to the hydrazine (50.9 mg, 1.588 mmol) in methanol and refluxed for 8 h at 65° C. Following cooling, reaction was monitored by TLC. After completion of the reaction, solvent was removed by vacuum and then compound was purified by flash chromatography (3% methanol/DCM) to yield the 3-(piperidin-1-ylsulfonyl)benzohydrazide (70 mg, 0.245 mmol, 46.2% yield) as a white solid. 1H NMR (CD3OD, 400 MHz): δ 8.17 (t, 1H, J=1.2 Hz), 8.05 (dt, 1H, J=1.2 & 8.0 Hz), 7.90 (dt, 1H, J=1.2 & 8.0 Hz), 7.69 (t, 1H, J=7.6 Hz), 2.99 (m, 4H), 1.62 (m, 4H), 1.43 (m, 2H). Mass [M+H]+: 284.1
Reaction SMILES: [CH2:1]([C:8]1([C:20]2[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2=[N:17][CH:18]=[CH:19][N:9]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[CH3:32][C:33]([CH3:35])=[O:34]>C1COCC1>[CH2:1]([C:8]1([C:20]2[CH:25]=[CH:24][C:23]([C:33]([OH:34])([CH3:35])[CH3:32])=[CH:22][CH:21]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2=[N:17][CH:18]=[CH:19][N:9]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: Brc1ccc(C2(Cc3ccccc3)c3ccccc3-c3nccn32)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(C2(Cc3ccccc3)c3ccccc3-c3nccn32)cc1
Temperature: -78 °C

Procedure:
A suspension of 5-benzyl-5-(4-bromophenyl)-5H-imidazo[2,1-a]isoindole (100 mg) in THF (3 mL) was cooled to −78° C. and n-BuLi solution (0.234 mL, 1.6 M in hexane) was added slowly. After stirring for 10 minutes acetone (29 mg) was added to the resulting red solution. After 30 min of the addition of acetone, reaction was quenched with aqueous saturated NH4Cl. The reaction mixture was partitioned between saturated aqueous NH4Cl and EtOAc.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].C1COCC1.[OH-].[Na+].[CH:17]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)=[O:18]>O>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:17]([C:19]2[CH:27]=[CH:26][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=2)=[O:18])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: O=Cc1ccc(C(=O)Cl)cc1
Reactant: CC(C)N1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Temperature: 2.5 °C

Procedure:
4-Isopropyl-piperazine (79.53 g, 0.620 mol), THF (444 g, 5.04 mol), water (36 g, 2 mol) and a 50% solution of sodium hydroxide (130.6 g, 1.63 mol) were charged to a reaction vessel and cooled to 0-5° C. 4-Formyl-benzoyl chloride in THF (110.08 g, 0.630 mol) was added to the 4-isopropyl-piperazine reaction mixture while maintaining the temperature below about 10° C. The resulting white suspension was stirred at room temperature until the reaction was deemed complete. Water was added to the reaction slurry and the resulting hazy solution was filtered over Celite to remove insolubles. The filtered reaction solution was settled and the water layer was removed. The product/THF layer was dried sequentially with magnesium sulfate and molecular sieves. The product solution (KF≦0.5%) was stored at 5° C. for use without further manipulations.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:18][CH:19]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:20]([O-:22])=[O:21])([CH2:6][N:7]1[C:11](=[O:12])[C:10]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]2[C:8]1=[O:17])=[O:5])[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][P:4]([CH2:18][CH:19]([CH2:23][CH:24]([CH3:25])[CH3:26])[C:20]([OH:22])=[O:21])([CH2:6][N:7]1[C:8](=[O:17])[C:9]2=[CH:16][CH:15]=[CH:14][CH:13]=[C:10]2[C:11]1=[O:12])=[O:5])[CH3:2]
Reactant: CCOP(=O)(CC(CC(C)C)C(=O)[O-])CN1C(=O)c2ccccc2C1=O
Agent: [Pd]
Solvent: CCO
Product: CCOP(=O)(CC(CC(C)C)C(=O)O)CN1C(=O)c2ccccc2C1=O

Procedure:
4.5 g of benzyl (R or S)-2-[[(ethoxy)(phthalimidomethyl)phosphinyl]methyl]-4-methylvalerate were dissolved in 120 ml of ethanol and the solution was hydrogenated over 1.6 g of 10% palladium-on-charcoal for 5.5 hours. After filtration and evaporation of the filtrate, there were obtained 3.0 g of (R or S)-2-[[(ethoxy)(phthalimidomethyl)phosphinyl]methyl]-4-methylvaleric acid in the form of A white foam.
Reaction SMILES: [CH:1]1([C:7]2[CH:21]=[CH:20][C:10]([O:11][CH2:12][C:13]3([CH3:19])[O:17][C:16](=[NH:18])[NH:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:22](OCC)(=[O:25])[C:23]#[CH:24].C(O)C>C(O)(C)(C)C>[CH:1]1([C:7]2[CH:21]=[CH:20][C:10]([O:11][CH2:12][C:13]3([CH3:19])[O:17][C:16]4=[N:18][C:22](=[O:25])[CH:23]=[CH:24][N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C#CC(=O)OCC
Reactant: CC1(COc2ccc(C3CCCCC3)cc2)CNC(=N)O1
Solvent: CC(C)(C)O
Solvent: CCO
Product: CC1(COc2ccc(C3CCCCC3)cc2)Cn2ccc(=O)nc2O1
Temperature: 80 °C

Procedure:
A suspension of 5-(4-cyclohexyl-phenoxymethyl)-5-methyl-oxazolidin-2-ylideneamine (1.11 g, 3.85 mmol) in 15 ml of t-butanol was heated to 80° C. All of the suspension dissolved. Ethyl propiolate (0.51 ml, 5.0 mmol) was added followed by 5 ml of ethanol. The reaction mixture was heated at reflux for 8 hrs. An off-white precipitate gradually came out of the solution. The reaction was cooled to room temperature and the solid isolated by filtration and washed with ether to provide the title compound as a white solid. Yield 0.75 g.
Reaction SMILES: [Br:1][C:2]1[O:3][C:4](Br)=[CH:5][CH:6]=1.C([Li])CCC.[Cl:13][C:14]1[N:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C(OCC)C.CCOC(C)=O>[Br:1][C:2]1[O:3][C:4]([C:16]2[CH:17]=[CH:18][N:19]=[C:14]([Cl:13])[N:15]=2)=[CH:5][CH:6]=1
Reactant: Brc1ccc(Br)o1
Reactant: Clc1ncccn1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Clc1nccc(-c2ccc(Br)o2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.2 %

Procedure:
To a cooled (−78° C.) solution of 2,5-dibromofurane (3.06 g, 8.88 mmol) in anhydrous diethyl ether (50 ml) was added n-Butyllithium (3.9 ml of 2.5M solution in Hexanes, 9.77 mmol). The mixture was stirred at this temperature for 90 minutes before the addition of 2-chloropyrimidine. The mixture was stirred for a further 30 minutes before being warmed to room temperature and stirred for further 2 hours. DDQ (2 g, 8.88 mmol) was them added to the solution which was stirred for 30 minutes before being concentrated in vacuo to give a thick brown syrup. The syrup was dissolved in EtOAc and washed with saturated sodium carbonated solution. The organic extract was removed, dried (MgSO4), filtered and concentrated in vacuo to give a crude residue which was purified by flash chromatography (SiO2) (100% hexane going to 7:2—hexane:EtOAc) to give the title compound (3.06 g, 40.20%) in pure form. m/z (LC-MSW, ESP):346 [M+H]+, R/T=4.41 mins
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:18])[C:6]=1[C:7]1[CH:8]=[C:9]([C:15]([OH:17])=O)[S:10][C:11]=1[CH2:12][CH2:13][CH3:14].[NH2:19][C@@H:20]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]([F:43])([F:42])[F:41])[CH2:21][N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:18])[C:6]=1[C:7]1[CH:8]=[C:9]([C:15]([NH:19][C@@H:20]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:40]([F:43])([F:41])[F:42])[CH2:21][N:22]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]2=[O:32])=[O:17])[S:10][C:11]=1[CH2:12][CH2:13][CH3:14]
Reactant: CCCc1sc(C(=O)O)cc1-c1c(Br)cnn1C
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1sc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Br)cnn1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.2 %

Procedure:
To a solution of 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylic acid (171 mg, 0.52 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (200 mg, 0.52 mmol) [prepared according to Preparation 6] and diisopropylethylamine (0.45 ml, 2.60 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (267 mg, 0.57 mmol) in one portion. The solution stirred at 25° C. for 12 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-propyl-2-thiophenecarboxamide (251 mg, 0.37 mmol, 72% yield) as a yellow oil: LCMS (ES) m/e 659,661 (M, M+2)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:23][CH:24]([CH3:27])[C:25]#[N:26])([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[O:12][C:11]2=[O:28])[CH3:9])=[CH:4][CH:3]=1.CI.[Li+].[CH3:32][Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:23][C:24]([CH3:32])([CH3:27])[C:25]#[N:26])([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[O:12][C:11]2=[O:28])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(C#N)C[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccc(F)cc2)OC1=O
Reaction time: 8 h
Yield: 74 %

Procedure:
To a solution of 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)-2-methylpropanenitrile (0.332 g, 0.746 mmol) and MeI (1.40 g, 13 equiv) in THF (12 mL) at −78° C. was added 2.4 mL (2.4 mmol, 3.2 equiv) of a 1.0 M LiHMDS solution in THF. The resulting mixture was stirred overnight, with the temperature slowly rising to ambient. The reaction mixture was quenched with brine (1 mL), diluted with CH2Cl2, and dried over Na2SO4. After the solvents were evaporated, the residue was purified by reversed-phase HPLC (SunFire™ Prep O18 OBD™ 5 μm 19×50 mm column, 10%→90% CH3CN/H2O, 0.1% CF3COOH over 8 min and then 90% CH3CN/H2O, 0.1% CF3COOH over 2 min, flow rate 20 mL/min) to afford 0.255 g (74%) of 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile. LC-MS Method 1 tR=1.89 min, m/z 459, 461 (MH+); 1H NMR (400 MHz, CD3OD) δ7.31-7.27 (m, 2H), 7.22-7.18 (m, 2H), 7.04-6.99 (m, 2H), 6.83 (d, J=8.2 Hz, 2H), 5.41 (q, J=7.0 Hz, 1H), 3.02-2.97 (m, 1H), 2.42-2.36 (m, 1H), 2.29-2.08 (m, 4H), 1.42 (d, J=7.0 Hz, 3H), 1.30 (s, 3H), 1.22 (s, 3H); 19F NMR (376 MHz, CD3OD) δ −116.50 (m).
Reaction SMILES: [N:1]([C:4]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:5]=1[C:6]([OH:8])=O)=[N+:2]=[N-:3].[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>S(Cl)(Cl)=O.ClCCl>[N:1]([C:4]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:5]=1[C:6]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([Cl:15])=[CH:17][CH:18]=1)=[O:8])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1cc(F)c(F)cc1C(=O)O
Reactant: Nc1ccc(Cl)cc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: [N-]=[N+]=Nc1cc(F)c(F)cc1C(=O)Nc1ccc(Cl)cc1
Reaction time: 1.5 h
Yield: 46 %

Procedure:
A solution of 2-azido-4,5-difluoro-benzoic acid (26.2 g, 132 mmol; Grieder A.; Thomas, A. W., Synthesis (2003), (11), 1707-1711) in thionyl chloride (216 ml) was stirred under reflux conditions for 1.5 h. The solvent was removed under reduced pressure to give the corresponding crude acid chloride which was suspended in dichloromethane (200 ml). 4-Chloroaniline (16.8 g, 132 mmol) was added and the mixture was stirred at ambient temperature for 14 h. Under ice cooling saturated NaHCO3 solution was added until pH 8 was reached. The mixture was extracted two times with dichloromethane, the combined extracts were washed with ice water/brine 1/1 and dried over Na2SO4. The solvent was removed under reduced pressure to give a brown solid which was crystallized from dichloromethane/n-heptane to give the title compound (18.5 g, 60 mmol; 46%) as yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:28])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10](=[O:21])[C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:8]2)=[O:4].[Br:29]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:28])=[C:7]2[C:12](=[C:13]([Br:29])[N:14]=1)[N:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10](=[O:21])[C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:8]2)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2-c2ccccc2)c1O
Solvent: ClCCl
Product: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3)c(=O)n2-c2ccccc2)c1O
Yield: 68.3 %

Procedure:
A mixture of 5-hydroxy-2-oxo-1,3-diphenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (138 mg, 0.37 mmol) and N-bromosuccinimide (73 mg, 0.41 mmol) in CH2Cl2 (1.5 mL) was refluxed for 3.5 h. Solvent was evaporated in vacuo, and the residue was purified twice by silica gel chromatography (0-100% EtOAc/hexanes+1% AcOH, then 30-100% CH2Cl2/hexanes) to give 114 mg of the title compound as a pale yellow solid. MS: (+) m/z 451.25, 453.01 (M+1, 79/81Br).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:34])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[N:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][C:30]([OH:32])=[CH:31][C:18]3=4)[CH2:10][CH:9]2[CH3:33])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:38][C:39]([O:41][CH3:42])=[O:40]>CN(C)C=O>[CH3:42][O:41][C:39](=[O:40])[CH2:38][O:32][C:30]1[CH:29]=[CH:28][C:19]2[O:20][CH2:21][C:22]3[N:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:17](=[CH:16][CH2:15][CH2:14][N:11]3[CH2:12][CH2:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)([OH:34])[CH:9]([CH3:33])[CH2:10]3)[C:18]=2[CH:31]=1
Reactant: CC1CN(CCC=C2c3cc(O)ccc3OCc3ncccc32)CCC1(O)c1ccc(Cl)cc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc2c(c1)C(=CCCN1CCC(O)(c3ccc(Cl)cc3)C(C)C1)c1cccnc1CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.5 %

Procedure:
A solution of 5-{3-[4-(4-Chloro-phenyl)-4-hydroxy-3-methyl-piperidin-1-yl]-propylidene}-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-ol (0.14 g, 0.28 mmol) in dimethylformamide (3 mL) was treated with sodium hydride (60% in mineral oil, 0.016 g, 0.4 mmol) and methyl bromoacetate (0.038 mL, 0.4 mmol). The mixture was allowed to stir at rt for 2 hr, then quenched with aqueous brine, and extracted with ethyl acetate (3×10 mL). The combined organics were washed several time with water, dried over sodium sulfate, and evaporated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate→487:10:3 ethyl acetate/methanol/triethylamine) to yield 0.07 g (50%) of the title compound, ESI-MS m/z: 549 [M+1].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[C:3]([NH2:8])[CH:2]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=[C:18]2[NH:26][CH:27]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][N:34]=[C:35]=[S:36])[CH2:28]2)=[CH:12][CH:11]=1>O1CCCC1>[NH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][C:3]=1[NH:8][C:35]([NH:34][CH2:33][CH2:32][N:29]1[CH2:30][CH2:31][CH:27]([NH:26][C:18]2[N:17]([CH2:16][C:13]3[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=2)[CH2:28]1)=[S:36]
Reactant: Fc1ccc(Cn2c(NC3CCN(CCN=C=S)C3)nc3ccccc32)cc1
Reactant: Nc1ccncc1N
Solvent: C1CCOC1
Product: Nc1ccncc1NC(=S)NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)C1
Yield: 51 %

Procedure:
A mixture of 2.8 parts of 3,4-pyridinediamine, 10.7 parts of 1-[(4-fluorophenyl)methyl]-N-[1-(2-isothiocyanatoethyl)-3-pyrrolidinyl]-1H-benzimidazol-2-amine and 90 parts of tetrahydrofuran was stirred and refluxed for 7 hours. The precipitated product was filtered off while hot, washed with a small amount of tetrahydrofuran and dried, yielding 6.5 parts (51%) of N-(4-amino-3-pyridinyl)-N'-[2-[3-[[1-[(4-fluorophenyl) methyl]-1H-benzimidazol-2-yl]amino]-1-pyrrolidinyl]ethyl]thiourea; mp. 225° C. (compound 177).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)=[CH:17][C:9]1=2.[NH2:32][CH2:33][CH:34]1[CH2:38][CH2:37][CH2:36][O:35]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:29])([F:31])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:32][CH2:33][CH:34]3[CH2:38][CH2:37][CH2:36][O:35]3)=[O:23])=[CH:17][C:9]1=2
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: NCC1CCCO1
Product: O=C(NCC1CCCO1)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 2-(aminomethyl)tetrahydrofuran as in General Procedure 10 to give the title compound. LCMS: m/z=530.97 (M+H+); retention time=0.81 minutes.
Reaction SMILES: [N:1]#[C:2]Br.[CH2:4]([C:6]1[C:15]([CH3:16])=[C:14]([OH:17])[CH:13]=[CH:12][C:7]=1[C:8]([NH:10][NH2:11])=[O:9])[CH3:5].C(=O)([O-])O.[Na+].CN(C=O)C>O>[NH2:1][C:2]1[O:9][C:8]([C:7]2[CH:12]=[CH:13][C:14]([OH:17])=[C:15]([CH3:16])[C:6]=2[CH2:4][CH3:5])=[N:10][N:11]=1
Reactant: N#CBr
Reactant: CCc1c(C(=O)NN)ccc(O)c1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1c(-c2nnc(N)o2)ccc(O)c1C
Yield: 11.8 %

Procedure:
196 mg of cyanogen bromide are added dropwise to a solution of 300 mg of 2-ethyl-4-hydroxy-3-methylbenzohydrazide in 50 ml of water, 130 mg of sodium hydrogencarbonate and 4 ml of DMF. A gas forms and a precipitate deposits. The latter is filtered off with suction and purified by column chromatography on silica gel, giving 40 mg of 4-(5-amino-1,3,4-oxadiazol-2-yl)-3-ethyl-2-methylphenol as colourless powder; MS-FAB (M+H+)=220; Rf (polar method): 1.43 min;
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1[Cl:3].CN(C)C=O.[Br:15][C:16]1[C:17]([O:27][CH3:28])=[C:18]([CH:24](O)[CH3:25])[CH:19]=[C:20]([Cl:23])[C:21]=1[CH3:22]>C(Cl)Cl>[Br:15][C:16]1[C:21]([CH3:22])=[C:20]([Cl:23])[CH:19]=[C:18]([CH:24]([Cl:3])[CH3:25])[C:17]=1[O:27][CH3:28]
Reactant: COc1c(C(C)O)cc(Cl)c(C)c1Br
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1c(C(C)Cl)cc(Cl)c(C)c1Br
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.1 %

Procedure:
A mixture of cyanuric chloride (1.7 g, 9.2 mmol) and N,N-dimethylformamide (710 μL, 9.2 mmol) was stirred at room temperature for 10 minutes and then a solution of 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanol (from Example 16, Step 1) (1.72 g, 6.15 mmol) in methylene chloride (34 mL) was added and the reaction was stirred at room temperature overnight. The mixture was diluted with methylene chloride, washed with sat. NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography, eluting with 0 to 10% EtOAc in hexanes, to give the desired product (1.01 g, 60%).
Reaction SMILES: [Cl:1][C:2]([Cl:28])([Cl:27])[CH2:3][O:4][C:5](=[O:26])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](Cl)=[O:21])=[CH:16][C:15]=2[N+:23]([O-:25])=[O:24])=[CH:9][CH:8]=1.[Cl:29][C:30]1[CH:35]=[C:34]([CH3:36])[C:33]([NH2:37])=[C:32]([CH3:38])[CH:31]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]([Cl:28])([Cl:27])[CH2:3][O:4][C:5](=[O:26])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:21])[NH:37][C:33]3[C:34]([CH3:36])=[CH:35][C:30]([Cl:29])=[CH:31][C:32]=3[CH3:38])=[CH:16][C:15]=2[N+:23]([O-:25])=[O:24])=[CH:9][CH:8]=1
Reactant: O=C(Nc1ccc(Sc2ccc(C(=O)Cl)cc2[N+](=O)[O-])cc1)OCC(Cl)(Cl)Cl
Reactant: Cc1cc(Cl)cc(C)c1N
Solvent: Cc1ccccc1
Product: Cc1cc(Cl)cc(C)c1NC(=O)c1ccc(Sc2ccc(NC(=O)OCC(Cl)(Cl)Cl)cc2)c([N+](=O)[O-])c1

Procedure:
The product of Example 162b (300 mg, 0.6197 mmol) and 4-Chloro-2,6-dimethyl-phenylamine (119 mg, 0.6197 mmol) were combined in toluene (10 mL) and reacted as in Example 162c to give the title compound that was used without further manipulation.
Reaction SMILES: [F:1][CH:2]([F:38])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([O:20][CH:21]3[CH2:26][CH2:25][N:24]([S:27]([CH:30]=[CH2:31])(=[O:29])=[O:28])[CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:32]=[CH:33][CH:34]=[C:35]([O:36][CH3:37])[C:5]=2[N:4]=1.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>>[F:38][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([O:20][CH:21]3[CH2:22][CH2:23][N:24]([S:27]([CH2:30][CH2:31][N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)(=[O:29])=[O:28])[CH2:25][CH2:26]3)[N:9]=2)[C:6]2[CH:32]=[CH:33][CH:34]=[C:35]([O:36][CH3:37])[C:5]=2[N:4]=1
Reactant: C=CS(=O)(=O)N1CCC(Oc2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OC)cccc43)n2)CC1
Reactant: C1COCCN1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(OC2CCN(S(=O)(=O)CCN3CCOCC3)CC2)nc(N2CCOCC2)n1
Yield: 81 %

Procedure:
Reaction of 2-(difluoromethyl)-4-methoxy-1-(4-(4-morpholinyl)-6-{[1-(vinylsulfonyl)-4-piperidinyl]oxy}-1,3,5-triazin-2-yl)-1H-benzimidazole (Example 50) with morpholine as in Example 11 gave 2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[(1-{[2-(4-morpholinyl)ethyl]sulfonyl}-4-piperidinyl)oxy]-1,3,5-triazin-2-yl}-1H-benzimidazole in 81% yield. Hydrochloride: mp (MeOH) 255-259° C.; 1H NMR (DMSO-d6) δ10.87 (br s, 1H), 7.96 (d, J=8.3 Hz, 1H), 7.72 (t, JHF=52.8 Hz, 1H), 7.45 (t, J=8.3 Hz, 1H), 6.99 (d, J=7.8 Hz, 1H), 5.30-5.25 (m, 1H), 4.06-3.95 (m, 2H), 3.98 (s, 3H), 3.86-3.84 (m, 4H), 3.74-3.71 (m, 8H), 3.53-3.49 (m, 6H), 3.37-3.27 (m, 2H), 3.15 (m, 2H), 2.16-2.15 (m, 2H), 2.19-1.87 (m, 2H); Anal. Calcd. for C27H37ClF2N8O6S.0.1H2O: C, 47.9; H, 5.5; N, 16.6; Cl, 5.2. Found: C, 47.9; H, 5.6; N, 16.6; Cl, 5.5%.