Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:20]3=[CH:19][CH:18]=[CH:17][C:16]=5[OH:23])=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]#[N:33]>CN(C=O)C>[C:1]1([CH:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:16]([O:23][CH2:31][C:32]#[N:33])=[CH:17][CH:18]=[CH:19][C:20]=53)=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1cccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCOc1cccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Temperature: 85 °C
Yield: 92.7 %

Procedure:
To a mixture of 1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-ol (1.05 g 3.49 rumol) in DMF (15 mL) is added potassium carbonate (2.4 g, 17.4 mmol) and bromoacetonitrile (1.2 mL, 17.4 mmol). The mixture is heated at 85° C. for 1.5 h. The mixture is cooled and partitioned between water and Et2O. The organic layer is washed twice with water (200 mL), dried over magnesium sulfate and concentrated. Column chromatography (60 g silica gel) using CH2Cl2 as eluent gave 1.1 g (92%) of 2-[(1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]acetonitrile.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]23[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]2)[C:11](=[O:17])[O:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:19][CH2:20]O>O>[C:1]1([CH2:7][CH2:8][C:9]2[CH2:16][CH2:15][CH:12]([C:11]([O:10][CH2:19][CH3:20])=[O:17])[CH2:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1OC2(CCc3ccccc3)CCC1CC2
Reactant: CCO
Agent: Cl
Solvent: O
Product: CCOC(=O)C1CC=C(CCc2ccccc2)CC1

Procedure:
Slowly add 2-phenylethyl bromide (2.6 g) to a slurry of Mg (0.37 g) in THF (50 mL) and heat at reflux for 4 h. Cool the solution to ambient temperature and add to a solution of ethyl 4-oxo-cyclo-hexanecarboxylate (2.4 g) in THF (50 mL). After 2 h, pour the reaction mixture into a half-saturated solution of NH4Cl and extract with EtOAc. Partially purify the product on a silica gel column, eluting with EtOAc. Dissolve the product in toluene (100 mL), treat with p-TsOH and heat at reflux overnight with azeotropic removal of water. Cool the reaction mixture, wash with saturated NaHCO3 solution and concentrate. Purify the crude product on a silica gel column, eluting with CH2Cl2 to obtain ethyl 4-(2-phenylethyl)-cyclohex-3-enecarboxylate (0.45 g) and 1-(2-phenyl-ethyl)-2-oxabicyclo[2.2.2]octan-3-one (0.71 g). Dissolve 1-(2-phenyl-ethyl)-2-oxabicyclo[2.2.2]octan-3-one in EtOH, treat with conc.HCl (catalytic) and heat at reflux overnight. Dilute the reaction mixture with water and extract with EtOAc. Concentrate the organic layer to obtain additional ethyl 4-(2-phenylethyl)-cyclohex-3-enecarboxylate (0.88 g).
Reaction SMILES: [NH2:1][C:2]1[C:22]([F:23])=[CH:21][C:20]([F:24])=[CH:19][C:3]=1[NH:4][C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[C:6]=1[C:14](OCC)=O.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C1(OC)C=CC=CC=1>[Ti](Cl)(Cl)(Cl)Cl>[F:24][C:20]1[CH:21]=[C:22]([F:23])[C:2]2[N:1]=[C:14]([N:29]3[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]3)[C:6]3[C:7]4[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=4[S:9][C:5]=3[NH:4][C:3]=2[CH:19]=1
Reactant: CCOC(=O)c1c(Nc2cc(F)cc(F)c2N)sc2ccccc12
Reactant: CN1CCNCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: COc1ccccc1
Product: CN1CCN(C2=Nc3c(F)cc(F)cc3Nc3sc4ccccc4c32)CC1

Procedure:
In the same manner as in Example 1 and using ethyl 2-(2-amino-3,5-difluoroanilino)benzo[b]thiophene-3-carboxylate, 1-methylpiperazine, anisole and titanium tetrachloride, 8,10-difluoro-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:15]([OH:17])=O)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH2:29]([O:37][C:38](=[O:41])[CH2:39][NH2:40])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>>[CH2:29]([O:37][C:38]([CH2:39][NH:40][C:15]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:17])=[O:41])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: O=C(O)c1ncccc1OCc1ccccc1
Reactant: CCCCCCCCOC(=O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCCCCCCOC(=O)CNC(=O)c1ncccc1OCc1ccccc1

Procedure:
1.1 g (5 mmol) of 3-benzyloxypyridine-2-carboxylic acid were condensed with glycine 1-octyl ester tosylate in analogy with Example 147. 1.3 g of the title compound were obtained, without column chromatography, as a pale brown oil, 1H NMR (DMSO): δ=5.24 (s, CH2 -benzyl).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([N:14]([CH3:19])[S:15]([CH3:18])(=[O:17])=[O:16])[CH:13]=1)[C:8](O)=[O:9])=[O:4].O1CCCC1.O1CCCC1.CO>O1CCCC1>[OH:9][CH2:8][C:7]1[CH:6]=[C:5]([CH:13]=[C:12]([N:14]([CH3:19])[S:15]([CH3:18])(=[O:17])=[O:16])[CH:11]=1)[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)c1cc(C(=O)O)cc(N(C)S(C)(=O)=O)c1
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(CO)cc(N(C)S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83 %

Procedure:
To a solution of 3-(methoxycarbonyl)-5-[methyl(methylsulfonyl)amino]benzoic acid obtained in Reference Example 62.07 g (7.2 mmol) in tetrahydrofuran (10 mL) was added 1.0 M BH3.tetrahydrofuran/tetrahydrofuran solution 9 mL dropwise under ice-cooling and the mixture was stirred at room temperature for 16 hours. To the reaction solution was added methanol (3 mL) under ice-cooling, and the solvent was evaporated. To the residue was added water and the mixture was extracted with ethyl acetate. After drying of the mixture on magnesium sulfate, the solvent was evaporated and the resulting solid was recrystallized from chloroform/hexane to give 1.64 g (6.0 mmol) of the title compound (yield: 83%).
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:42][NH:43][C@@H:44]([CH2:51][CH3:52])[CH2:45][N:46]1[CH2:49][CH:48]([OH:50])[CH2:47]1>C1COCC1>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([N:43]([C@@H:44]([CH2:51][CH3:52])[CH2:45][N:46]2[CH2:47][CH:48]([OH:50])[CH2:49]2)[CH3:42])=[O:17])=[CH:18][CH:19]=1
Reactant: CC[C@@H](CN1CC(O)C1)NC
Reactant: O=C(O)c1ccc(Br)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC[C@@H](CN1CC(O)C1)N(C)C(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56.4 %

Procedure:
DIPEA (0.52 mL, 3.0 mmol) was added to a stirred suspension of 4-bromobenzoic acid (462 mg, 3.0 mmol) and TBTU (963 mg, 3.0 mmol) in THF (15 mL) at rt. After 10 min was (S)-1-(2-(methylamino)butyl)azetidin-3-ol (Compound M12) (475 mg, 3.0 mmol) added, followed by addition of DIPEA (0.52 mL, 3.0 mmol). The reaction was stirred at rt for 4 h. The mixture was concentrated under reduced pressure and the residue dissolved in DCM (60 mL). The organic phase was washed with NaHCO3 (aq., 60 mL). The aqueous layer was extracted with DCM (15 mL). The combined organic layers were washed with NaHCO3 (8% aq., 60 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (577 mg, 56%). Mixture of rotamers: 1H NMR (500 MHz, DMSO-d6) δ 0.82, 1.43-1.54, 2.43, 2.54-2.62, 2.70-2.80, 3.39-3.51, 4.18, 4.88, 7.33, 7.63. Total number of protons: 20. There is one additional very broad proton signal between 4.2 and 3.1 ppm. HRMS (M+H)+: calculated 341.0865. found 341.0870.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N+:4]([O-:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C([Mg]Cl)(C)C.[I:15]I.CCOC(C)=O>C1COCC1>[I:15][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][N+:4]=1[O-:9]
Reactant: Cc1cc(C)c[n+]([O-])c1
Reactant: II
Agent: CC(C)[Mg]Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C)c(I)[n+]([O-])c1
Reaction time: 2 h
Yield: 36.4 %

Procedure:
To a solution of 3,5-dimethylpyridine 1-oxide (92 g, 0.75 mol) in THF (1300 mL) was added dropwise i-PrMgCl (600 mL, 1.2 mol) at −72° C. After stirring for 2 hr at the same temperature, a solution of iodine (350 g, 1.38 mol) in THF (500 mL) was added dropwise. After stirring for 1 hr, TLC (petroleum ether:EtOAc=1:4) showed the starting material was consumed almost. After quenching with Na2S2O3(aq.) (400 mL), THF was removed in vacuo and the residue was diluted with EtOAc (1500 mL). The solution was washed with water (400 mL) and brine (400 mL) and dried over Na2SO4. The resulting material was concentrated in vacuo to give crude material which was purified by chromatography on silica gel with petroleum ether:EtOAc=1:4 to afford 2-iodo-3,5-dimethylpyridine 1-oxide (68 g, 36.3%) as white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][C:14](=[CH:21][C:22]2([CH3:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:15]3=[O:20])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][CH:14]([CH2:21][C:22]2([CH3:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)[C:15]3=[O:20])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C=C2Cc3c(cccc3-c3ccc(C(C)(C)C)cc3)C2=O)CCCCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1(CC2Cc3c(cccc3-c3ccc(C(C)(C)C)cc3)C2=O)CCCCC1
Yield: 97.3 %

Procedure:
28.62 g of crude 4-(4-tert-butyl-phenyl)-2-(1-methylcyclo-hexylmethylene)-indan-1-one (GC: ˜83% purity) are dissolved in 286 ml of ethyl acetate in a flask with gas inlet and stirrer. 2 g of palladium on activated carbon (10 wt-% palladium) are added. The system is evacuated and refilled with argon three times to remove oxygen and then evacuated and refilled with hydrogen three times. The stirrer is started and the reaction mixture is vigorously stirred to help the diffusion of hydrogen gas into the liquid reaction mixture. The hydrogen uptake is monitored and stirring is continued until the hydrogen uptake ceases. Filtering the crude reaction mixture over a paper filter and removing the solvent in a vacuum leaves crude 4-(4-tert-butyl-phenyl)-2-(1-methyl-cyclohexylmethyl)-indan-1-one (yield 27.99 g, GC: ˜84% purity). The obtained crude product was used without further purification for the subsequent reduction/elimination-sequence.
Reaction SMILES: [C:1]1([CH:7]([NH:9][C:10]([C:12]2[S:13][C:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([OH:32])[CH:25]=4)[N:18]=3)=[CH:15][CH:16]=2)=[O:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:33][N:34]([CH2:36][CH2:37]O)[CH3:35].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC([N+](C(OC(C)C)=O)=[N-])=O)(C)C>C1COCC1.CS(C)=O>[C:1]1([CH:7]([NH:9][C:10]([C:12]2[S:13][C:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH2:37][CH2:36][N:34]([CH3:35])[CH3:33])[CH:25]=4)[N:18]=3)=[CH:15][CH:16]=2)=[O:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(Nc2nccc(-c3ccc(C(=O)NC(C)c4ccccc4)s3)n2)cc1O
Reactant: CN(C)CCO
Agent: CC(C)OC(=O)[N+](=[N-])C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COc1ccc(Nc2nccc(-c3ccc(C(=O)NC(C)c4ccccc4)s3)n2)cc1OCCN(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 0.8 %

Procedure:
5-[2-(3-Hydroxy-4-methoxy-phenylamino)-pyrimidin-4-yl]-thiophene-2-carboxylic acid (1-phenyl-ethyl)-amide (35 mg, 78 μmol), dimethylaminoethanol (26 μL, 156 μmol), and triphenylphosphine (41 mg, 156 μmol) were dissolved in 0.14 mL THF and cooled to 0° C. Diisopropyldiazodicarboxylate (31 μL, 156 μmol) were added dropwise. The reaction mixture was slowly warmed to room temperature and stirred overnight. The crude product was diluted with DMSO and purified by mass triggered reverse phase HPLC to afford 0.3 mg of pure 5-{2-[3-(2-Dimethylamino-ethoxy)-4-methoxy-phenylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic acid (1-phenyl-ethyl)-amide (0.6 μmol, 1%). 1H NMR (500 MHz, DMSO-d6) δ 9.49 (s, 1H), 8.94 (d, J=8 Hz, 1H), 8.47 (d, J=5 Hz, 1H), 7.98 (d, J=4 Hz, 1H), 7.93 (d, J=4 Hz, 1H), 7.57 (m, 1H), 7.38 (m, 2H), 7.31 (m, 4H), 7.23 (m, 1H), 6.88 (d, J=8 Hz, 1H), 5.12 (quintet, J=7.5 Hz, 1H), 4.05 (t, J=6 Hz, 2H), 3.71 (s, 3H), 2.64 (t, J=6 Hz, 2H), 2.17 (s, 6H), 1.48 (d, J=6.5 Hz, 3H). MS: m/z 518 (M+H+).
Reaction SMILES: C([NH:6][NH:7][CH2:8][CH2:9][CH:10]1[NH:14]C(=O)N[C:11]1=[O:16])(OCC)=O.[OH2:17].O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>O>[NH2:14][CH:10]([CH2:9][CH2:8][NH:7][NH2:6])[C:11]([OH:16])=[O:17]
Reactant: O
Reactant: CCOC(=O)NNCCC1NC(=O)NC1=O
Agent: [Ba+2]
Agent: [OH-]
Product: NNCCC(N)C(=O)O

Procedure:
Mix 5-[(2-(carbethoxyhydrazino)-ethyl)]-hydantoin (2.3 g, 10 mmol), barium hydroxide octahydrate (18.15 g, 10 mmol) and water (55 mL). Reflux for 12 hours, remove the white solid by filtration, extract the filter cake with boiling water (25 ml) and finally wash with hot water (25 mL). Combine the filtrate and washings, treat with ammonium carbonate (5.7 g) and heat with stirring. Filter off the barium carbonate, wash the filter cake with hot water and evaporate the filtrate and washings in vacuo to give 2-amino-4-hydrazino-butanoic acid.
Reaction SMILES: [H-].[Na+].[O:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH:4]1[CH2:13][C:14]1[NH:15][CH:16]=[CH:17][N:18]=1.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CN(C)C=O>[CH2:19]([N:18]1[CH:17]=[CH:16][N:15]=[C:14]1[CH2:13][CH:4]1[O:3][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH2:5]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: c1ccc2c(c1)OCC(Cc1ncc[nH]1)O2
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(Cn2ccnc2CC2COc3ccccc3O2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (3.0 g of 50% dispersion in oil) was added to a solution of 2-(1,4-benzodioxan-2-ylmethyl)-imidazole (5.2 g) in dimethylformamide (50 ml) and the resulting mixture was stirred for 30 minutes. The solution was cooled in an ice bath and benzyl bromide (3 ml) was added. After warming to room temperature the mixture was poured into water (250 ml) and extracted with ethyl acetate (3×100 ml). The ethyl acetate extracts were combined, washed with water (3×100 ml), dried over sodium sulfate, and evaporated. The residue was dissolved in methanolic hydrochloric acid and ether was added until an oil came out of solution. The oil was crystallized from isopropanol-ether to give the title compound (2.10 g) as a white powder, m.p. 105°-107° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28]C)[CH:23]=2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:16]O)[CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1.B(Br)(Br)[Br:31].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.C(=O)=O>[Br:31][CH2:16][CH2:15][C:11]1[CH:10]=[C:9]([NH:8][C:5]2[N:4]=[C:3]([NH:18][CH2:19][CH2:20][CH2:21][C:22]3[CH:23]=[C:24]([OH:28])[CH:25]=[CH:26][CH:27]=3)[C:2]([Cl:1])=[CH:7][N:6]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: COc1cccc(CCCNc2nc(Nc3cccc(CCO)c3)ncc2Cl)c1
Reactant: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1cccc(CCCNc2nc(Nc3cccc(CCBr)c3)ncc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of 2-{3-[(5-chloro-4-{[3-(3-methoxyphenyl)propyl]amino}pyrimidin-2-yl)amino]phenyl}ethanol (0.35 g, 0.73 mmol) in methylene chloride (4.7 mL) was added slowly a solution of boron tribromide in methylene chloride (3.6 mL, 3.6 mmol, 1.0 M) at 0° C. The mixture was allowed to warm up to rt and stirred overnight. The resultant mixture was cooled in dry ice when Na2CO3 (saturated aqueous solution) was added. The mixture was filtered and the solid collected was triturated with EtOAc, followed by washing with EtOAc and water successively to give the desired product as an off-white powder (303 mg, 90%). LCMS for C21H23BrClN4O (M+H)+: m/z=461.0, 463.0. 1H NMR (400 MHz, CD3OD): δ 7.95 (s, 1H), 7.91 (s, 1H), 7.44 (d, J=7.2 Hz, 1H), 7.38 (m, 1H), 7.08 (m, 1H), 6.97 (s, 1H), 6.68 (d, J=2.8 Hz, 1H), 6.59 (m, 2H), 3.60 (m, 4H), 3.18 (m, 2H), 2.66 (t, J=7.6 Hz, 2H), 1.99 (t, J=7.6 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[NH:12][CH:11]=1.[F:20][C:21]1[CH:22]=[C:23]([CH:29]=O)[C:24](=[O:28])[N:25]([CH3:27])[CH:26]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[F:20][C:21]1[CH:22]=[C:23]([CH2:29][NH:8][C:6]2[CH:5]=[CH:4][C:3]([CH2:9][C:10]3[C:18]4[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=4)[NH:12][CH:11]=3)=[C:2]([F:1])[N:7]=2)[C:24](=[O:28])[N:25]([CH3:27])[CH:26]=1
Reactant: Cn1cc(F)cc(C=O)c1=O
Reactant: Cc1cnc2[nH]cc(Cc3ccc(N)nc3F)c2c1
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc2[nH]cc(Cc3ccc(NCc4cc(F)cn(C)c4=O)nc3F)c2c1
Temperature: 80 °C
Yield: 50.3 %

Procedure:
To 6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine (137, 3.99 g, 15.59 mmol) and 5-fluoro-1-methyl-2-oxo-1,2-dihydro-pyridine-3-carbaldehyde (33, 2.66 g, 17.15 mmol) in 50 mL of acetonitrile, triethylsilane (9.96 mL, 62.4 mmol) and trifluoroacetic acid (4.80 mL, 62.4 mmol) were added. The reaction was stirred at 80° C. for several hours, then concentrated under vacuum and the residue was taken up in ethyl acetate and poured into aqueous potassium carbonate. The organic layer was separated, concentrated under vacuum, and the residue purified by silica gel column chromatography, eluting with 0-5% methanol in dichloromethane. Appropriate fractions were combined and concentrated under vacuum, and the residue triturated with methanol to provide the desired compound (P-2156, 3.1 g, 7.84 mmol, 50.3% yield).
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].CCCCCC.C(C1C=[CH:25][C:24]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:16]=2[CH:15]=1)=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>[CH:4]([C:3]1[CH:2]=[CH:25][C:24]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:16]=2[CH:15]=1)=[CH2:5]
Reactant: CCCCCCCCC1(CCCCCCCC)c2ccccc2-c2ccc(C=O)cc21
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: CCOCC
Product: C=Cc1ccc2c(c1)C(CCCCCCCC)(CCCCCCCC)c1ccccc1-2
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 49 %

Procedure:
To a solution of methyltriphenylphosphonium bromide (714 mg, 2 mmol) in ether at 0° C. was added dropwise 1.6 M n-BuLi solution in hexane (1.25 mL, 2.00 mmol). The solution was stirred at 0° C. for 40 min and then was warmed to room temperature. A solution of 2-formyl-9,9-dioctylfluorene (585 mg, 1.4 mmol) was then added and reaction mixture was stirred overnight. The reaction mixture was quenched with 20 mL of 1% HCl. The mixture was extracted with ether and the organic layer was washed with NaHCO3 solution, and brine solution, and dried over MgSO4. The solvent was removed in vacuo and the product was purified by column chromatography on silica gel using hexane as the elutant to afford the purified 2-vinyl-9,9-dioctylfluorene (0.2834 g, 49% yield). EI-MS: 416 (M+), 360,192 (100). 1H NMR (CDCl3) δ 7.66 (m, 2H), 7.42-7.32 (m, 5H), 6.83 (dd, 1H), 5.82 (d, 1H), 5.28 (d, 1H), 1.97 (m, 4H), 1.28-1.06 (m, 22H), 0.83 (t, 5H), 0.63 (t, 3H). 13C NMR (CDCl3) δ151.09, 151.00, 141.08, 140.8, 137.51, 136.47, 127.05, 126.77, 125.21, 122.88, 120.54, 119.69 (2C), 112.89, 54.97, 40.39, 31.84, 31.65, 30.09, 29.25, 23.75, 22.65, 14.10
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[OH:9].N1C=CC=CC=1.[CH2:16]([N:23]1[CH2:28][CH2:27][CH:26]([C:29](Cl)=[O:30])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[CH2:16]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]([NH:1][C:2]2[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=2[OH:9])=[O:30])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1cc(Br)ccc1O
Reactant: O=C(Cl)C1CCN(Cc2ccccc2)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1cc(Br)ccc1O)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.9 %

Procedure:
1-Benzylpiperidine-4-carboxylic acid (29 g, 0.13 mol) dissolved in DCM (300 ml), cooled to 0° C. and added oxalyl chloride (17.3 ml, 0.2 mol). Catalytic amount of DMF was added to this mixture and stirred at rt for 2 h. After 2 h, DCM removed on rotavapour and co-distilled the residue two times with DCM to obtain 1-benzylpiperidine-4-carbonyl chloride quantitatively. 2-Amino-4-bromophenol (23 g, 0.12 mol) dissolved in DCM and added pyridine (11.5 g, 0.15 mol) under nitrogen atmosphere. This mixture stirred at rt for 30 mins and added 1-benzylpiperidine-4-carbonyl chloride (29 g, 0.12 mol) in DCM (100 ml). After continuing stirring at rt for 2 h, DCM was removed on the rotavapour to obtain the titled compound (47.6 g), which was used in the next step without further purification.
Reaction SMILES: [CH:1]([C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)=O.[CH2:16]([NH2:20])[CH2:17][CH2:18][CH3:19].C1C=CC=CC=1>O>[CH2:16]([N:20]=[C:1]=[C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH2:4]1)[CH2:17][CH2:18][CH3:19]
Reactant: CCOC(=O)COc1ccc(C=O)cc1
Reactant: CCCCN
Solvent: c1ccccc1
Solvent: O
Product: CCCCN=C=C1C=CC(OCC(=O)OCC)=CC1
Reaction time: 1 h
Yield: 82.5 %

Procedure:
Ethyl (4-formylphenoxy)acetate (104.1 g, 0.5 mole), butylamine (36.6 g, 0.5 mole) and benzene (400 ml) were united and refluxed in a flask equipped with a Dean-Stark water separator. After one hour, water ceased to separate. The heating was terminated after 6 hours and the mixture distilled. There was obtained 108.6 g of product boiling at 178°-181° C. at 0.5 mm Hg pressure.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH2:10]1.[C:19]([N:27]=[C:28]=S)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C>[C:19](/[N:27]=[C:28]1/[N:8]([C@@H:9]2[CH2:10][CH2:11][C@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:13][CH2:14]2)[C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[NH:1]/1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)[C@H]1CC[C@@H](Nc2ccncc2N)CC1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC#N
Product: COC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccccc3)[nH]c3cnccc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.9 %

Procedure:
To a solution of cis-methyl 4-(3-aminopyridin-4-ylamino)cyclohexanecarboxylate (70 mg, 0.281 mmol) in ACN (5.6 mL) under nitrogen was added benzoyl isothiocyanate (0.045 mL, 0.337 mmol). The reaction mixture was stirred for 30 minutes at RT. To the mixture was added polymer-supported-carbodiimide (936 mg, 1.123 mmol; Loading: 1.2 mmol/g;), and the resulting mixture was stirred at 70° C. for 16 hours. The reaction mixture was cooled to RT and filtered, and the resin was washed with 1% MeOH/DCM. The filtrate was concentrated and purified by silica gel chromatography (1-4% MeOH/DCM) to afford cis-methyl 4-((E)-2-(benzoylimino)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarboxylate as an off-white solid (18 mg, 17% yield). MS m/z=379.2 [M+H]. Calc'd for C21H22N4O3: 378.2.