Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[N:15][C:14]=2F)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[NH:23]1[C:27]2=[N:28][CH:29]=[CH:30][C:31]([CH2:32][NH2:33])=[C:26]2[CH2:25][CH2:24]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[N:15][C:14]=2[NH:33][CH2:32][C:31]2[CH:30]=[CH:29][N:28]=[C:27]3[NH:23][CH2:24][CH2:25][C:26]=23)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(NC(=O)c2cccnc2F)cc1
Reactant: NCc1ccnc2c1CCN2
Agent: Cl
Product: CC(C)(C)c1ccc(NC(=O)c2cccnc2NCc2ccnc3c2CCN3)cc1

Procedure:
The titled compound was prepared from N-(4-tert-butyl-phenyl)-2-fluoro-nicotinamide and C-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-methylamine dihydrochloride by the method described in Step A of Example 1. MS (ES+): 402 (M+H). Calc'd. for C24H27N5O—401.51.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]([O:14][C:15]3[C:20]([CH3:21])=[CH:19][C:18](/[CH:22]=[CH:23]/[C:24]([N:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)=[O:25])=[CH:17][C:16]=3[CH3:32])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[CH3:35][C:36]1[CH:41]=[CH:40][C:39]([O:42][CH2:43]/[CH:44]=[CH:45]/[C:46]2[CH:51]=[CH:50][C:49]([CH2:52]Cl)=[CH:48][C:47]=2[CH3:54])=[CH:38][CH:37]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]([O:14][C:15]3[C:20]([CH3:21])=[CH:19][C:18](/[CH:22]=[CH:23]/[C:24]([N:26]4[CH2:31][CH2:30][N:29]([CH2:52][C:49]5[CH:50]=[CH:51][C:46](/[CH:45]=[CH:44]/[CH2:43][O:42][C:39]6[CH:38]=[CH:37][C:36]([CH3:35])=[CH:41][CH:40]=6)=[C:47]([CH3:54])[CH:48]=5)[CH2:28][CH2:27]4)=[O:25])=[CH:17][C:16]=3[CH3:32])=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(/C=C/C(=O)N2CCNCC2)cc(C)c1Oc1ccc(OCc2ccc(F)cc2)cn1
Reactant: Cc1ccc(OC/C=C/c2ccc(CCl)cc2C)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(OC/C=C/c2ccc(CN3CCN(C(=O)/C=C/c4cc(C)c(Oc5ccc(OCc6ccc(F)cc6)cn5)c(C)c4)CC3)cc2C)cc1
Temperature: 25 °C
Reaction time: 20.5 h
Yield: 73.1 %

Procedure:
To a solution of (E)-3-[4-({5-[(4-fluorobenzyl)oxy]pyridin-2-yl}oxy)-3,5-dimethylphenyl]-1-(piperazin-1-yl)prop-2-en-1-one (0.328 g) and (E)-3-[4-(chloromethyl)-2-methylphenyl]prop-2-en-1-yl 4-methylphenyl ether (0.204 g) in DMF (2 mL) was added DIPEA (0.13 mL) at room temperature under an Ar atmosphere. The mixture was stirred at room temperature for 20.5 hours, and then heated at 50° C. for 1 hour, and then cooled to room temperature, and evaporated under reduced pressure. To the residue was added saturated aqueous NaHCO3, and the mixture was extracted with AcOEt. The organic layer was washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt) to afford (2E)-3-[4-({5-[(4-fluorobenzyl)oxy]pyridin-2-yl}oxy)-3,5-dimethylphenyl]-1-(4-{3-methyl-4-[(1E)-3-(4-methylphenoxy)prop-1-en-1-yl]benzyl}piperazin-1-yl)prop-2-en-1-one (0.370 g) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][C:20](=[O:27])[N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:35]([O:37][CH2:38][CH2:39][NH2:40])[CH3:36]>>[CH2:35]([O:37][CH2:38][CH2:39][NH:40][C:29]([C:14]1[C:15](=[O:28])[N:16]([CH2:19][C:20](=[O:27])[N:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)[C:17]2[C:12]([C:13]=1[OH:34])=[N:11][CH:10]=[C:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH:18]=2)=[O:30])[CH3:36]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCCCC2)c1=O
Reactant: CCOCCN
Product: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCCCC2)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-oxo-2-(1-piperidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-ethoxyethylamine employing methods similar to those those described in Example 9 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as a white solid: 1H NMR (CDCl3) δ 14.4 (1H, br), 10.18 (1H, m), 8.55 (1H, s), 7.15 (2H, dd, J=8.4, 5.5 Hz), 7.02 (2H, t, J=8.4 Hz), 6.98 (1H, s), 4.94 (2H, s), 4.11 (2H, s), 3.61 (4H, m), 3.59-3.43 (6H, m), 1.68 (2H, m), 1.54 (4H, m), 1.21 (3H, t, J=7 Hz); HRMS calcd for C27H31FN4O5+H+: 511.2357. Found: 511.2366.
Reaction SMILES: [CH2:1]([OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].ClCCl.C(N(C(C)C)CC)(C)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>O>[CH3:30][S:31]([O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCCCCCCCCCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCOS(C)(=O)=O
Temperature: 0 °C
Yield: 97.4 %

Procedure:
Under an inert atmosphere, e.g., nitrogen, a reactor was charged with 1-hexadecanol 3 (3.78 kg), anhydrous dichloromethane (40 L) and diisopropylethylamine (2.21 kg). The reaction mixture was cooled to −5 to 5° C. and methanesulfonyl chloride (1.87 kg) was added at a controlled rate over 2 hours to ensure that the reaction temperature was kept below 5° C. After the addition was complete, the mixture was warmed to 20 to 30° C. and stirred for one to two hours. The reaction was monitored by GC-MS and was deemed complete when the conversion rate was ≧95%. The reaction was maintained at 20 to 30° C. while being diluted with water (15 L). The organic layer was separated, washed with water (0.50 kg), and concentrated to dryness to yield 4 as a light yellow solid (4.87 kg, 96%). Typical HPLC (AUC) purity was >95%. 1H-NMR was consistent with structure.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11](N1C2C(=CC=CC=2)CCC1)=[O:12].[F:28][C:29]1[C:35]([F:36])=[CH:34][C:32]([NH2:33])=[C:31]([O:37][CH3:38])[CH:30]=1>CCCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:6]([C:11]([NH:33][C:32]2[CH:34]=[C:35]([F:36])[C:29]([F:28])=[CH:30][C:31]=2[O:37][CH3:38])=[O:12])=[CH:7][N:8]=[CH:9][CH:10]=1
Reactant: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21
Reactant: COc1cc(F)c(F)cc1N
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COc1cc(F)c(F)cc1NC(=O)c1cnccc1Oc1cc(Cl)ccc1Cl

Procedure:
The title compound was prepared in analogy to Example 1, from 4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate) and 4,5-difluoro-2-methoxyaniline (commercially available; CAS RN 1017779-71-3) and using a gradient of n-heptane:ethyl acetate (100:0 to 40:60) for the chromatographic purification. White solid (80%). MS (ESI): m/z=425.027 [M+H]+.
Reaction SMILES: [H-].[Na+].[Cl-].[CH3:4][S+](C)(C)=O.[CH3:9][O:10][C:11]([C:13]1[S:14][C:15]([C:35]#[C:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:16][C:17]=1[N:18]([C:26]([CH:28]1[CH2:33][CH2:32][CH:31]([CH3:34])[CH2:30][CH2:29]1)=[O:27])[CH:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1)=[O:12].C(OCC)C>CS(C)=O.C1COCC1.[Cl-].[Na+].O>[CH3:9][O:10][C:11]([C:13]1[S:14][C:15]([C:35]#[C:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[CH:16][C:17]=1[N:18]([C:26]([CH:28]1[CH2:29][CH2:30][CH:31]([CH3:34])[CH2:32][CH2:33]1)=[O:27])[CH:19]1[CH2:20][CH2:21][C:22]2([O:25][CH2:4]2)[CH2:23][CH2:24]1)=[O:12]
Reactant: C[S+](C)(C)=O
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)C1CCC(C)CC1)C1CCC(=O)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)C1CCC(C)CC1)C1CCC2(CC1)CO2
Reaction time: 0.25 h
Yield: 36.8 %

Procedure:
NaH (140 mg of a 60% oil dispersion, 3.50 mmol) was added in portions to a solution of trimethylsulfoxonium chloride (452 mg, 3.51 mmol) in DMSO (8.0 mL) at room temperature. After 15 min, a solution of 5-(3,3-dimethyl-but-1-ynyl)-3-[(4-methyl-cyclohexanecarbonyl)-(4-oxo-cyclohexyl)-amino]-thiophene-2-carboxylic acid methyl ester (1.34 g, 2.93 mmol) in THF (8.0 mL) was added dropwise. After 3 h, brine was added and the reaction extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated to give a viscous yellow oil. Trituration with ethyl ether and hexanes provided 5-(3,3-dimethyl-but-1-ynyl)-3-[(4-methyl-cyclohexanecarbonyl)-(1-oxa-spiro[2.5]oct-6-yl)-amino]-thiophene-2-carboxylic acid methyl ester (509 mg, 37%) as a colorless solid.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO>[C:1]1([N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:11][CH2:12][CH2:13][OH:16])[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccc2nc(-c3ccccc3)n(-c3ccccc3)c2c1
Solvent: CO
Product: OCCCOc1ccc2nc(-c3ccccc3)n(-c3ccccc3)c2c1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
0.5 g of 1,2-diphenyl-6-hydroxy-1H-benzimidazole was reacted according to general operating instructions 8 with 3-(bromopropoxy)-tert-butyldimethylsilane. After chromatography on silica gel, it was taken up in 2.5 ml of methanol, 0.4 ml of concentrated-hydrochloric acid was added, and it was allowed to stir for 2 hours at 20° C. It was poured onto saturated aqueous sodium bicarbonate solution, extracted three times with ethyl acetate, the combined extracts were washed with saturated aqueous sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:21]([N:24]=[C:25]=[O:26])([CH3:23])[CH3:22]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:25]([NH:24][CH:21]([CH3:23])[CH3:22])=[O:26])[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CCN(CCCCCN)C1
Reactant: CC(C)N=C=O
Solvent: ClCCl
Product: CC(C)NC(=O)NCCCCCN1CC[C@H](CNC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
5-((3R)-3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)pentylamine (2.0 g) was dissolved in methylene chloride (20 ml) and a solution of isopropyl isocyanate (0.69 ml) in methylene chloride was dropwise added under ice-cooling. The mixture was stirred at room temperature for 0.25 hr, and the reaction mixture was concentrated under reduced pressure to give (3R)-3-tert-butoxycarbonylaminomethyl-1-(5-(3-isopropylureido)pentyl)pyrrolidine.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:23]=[C:10]3[CH:11]=[C:12]([NH:15]C(=O)OC(C)(C)C)[CH:13]=[CH:14][N:9]3[N:8]=2)[CH2:3][CH2:2]1.[ClH:24]>>[ClH:24].[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[N:23]=[C:10]3[CH:11]=[C:12]([NH2:15])[CH:13]=[CH:14][N:9]3[N:8]=2)[CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)Nc1ccn2nc(N3CCOCC3)nc2c1
Agent: Cl
Product: Nc1ccn2nc(N3CCOCC3)nc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 108.5 %

Procedure:
A mixture of tert-butyl 2-morpholino-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamate (356 mg, 1.11 mmol) and hydrochloric acid (6N in ether, 10 ml, 60.0 mmol) is stirred for 2 hours at 25° C. The solvent is removed in vacuo affording 2-morpholino-[1,2,4]triazolo[1,5-a]pyridin-7-amine hydrochloride (308 mg, 108%) as a light yellow solid. mp.: >250° C. MS: m/z=220.3 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH:21]1[CH2:23][CH2:22]1)[CH:13](O)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.C1CCN2C(=NCCC2)CC1>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH:21]1[CH2:23][CH2:22]1)[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(O)[C@@H](NC(=O)OCc1ccccc1)C1CC1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C=C[C@@H](NC(=O)OCc1ccccc1)C1CC1
Temperature: -15 °C
Yield: 83.6 %

Procedure:
Ethyl 4-(S)-benzyloxycarbonylamino-4-cyclopropyl-3-hydroxybutanoate (1.488 g, 4.630 mmol) was dissolved in dry dichloromethane (50 ml) and stirred at -15° C. while adding triethylamine (1,291 μl, 9.260 mmol), and then methanesulfonyl chloride (449 μl, 5.80 mmol) was added dropwise thereto and the mixture was stirred at the same temperature for 1 hour. 1,8-Diazabicyclo[5.4.0]-7-undecene (1,486 μl, 1.955 mmol) was added dropwise to the reaction solution, and the mixture was gradually warmed up to room temperature and then stirred for 15 hours. The reaction solution was washed with 10% citric acid aqueous solution (50 ml), and the organic layer was separated and then the aqueous layer was extracted with chloroform (30 ml). The organic layers were combined, washed with water (50 ml) and saturated sodium chloride aqueous solution (50 ml) in that order, and then dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under a reduced pressure, and the thus obtained residue was applied to a flash silica gel chromatography and eluted with n-hexane:ethyl acetate=4:1, thereby obtaining 1.174 g (87.2%) of the title compound as a light yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH:15]2[C:24]3[N:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH2:18][CH2:17][CH2:16]2)[CH2:11][CH2:12][CH2:13][NH2:14])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.C[Si]([N:29]=[C:30]=[O:31])(C)C>CC(O)C>[CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH:15]2[C:24]3[N:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH2:18][CH2:17][CH2:16]2)[CH2:11][CH2:12][CH2:13][NH:14][C:30]([NH2:29])=[O:31])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: Cc1cnc(CN(CCCN)C2CCCc3cccnc32)c(C)c1
Solvent: CC(C)O
Product: Cc1cnc(CN(CCCNC(N)=O)C2CCCc3cccnc32)c(C)c1
Yield: 72.9 %

Procedure:
To a solution of N1-(3,5-Dimethyl-pyridin-2-ylmethyl)-N1-(5,6,7,8-tetrahydro-quinolin-8-yl)-propane-1,3-diamine (101 mg, 0.31 mmol) in 2-propanol (4 mL) was added trimethylsilyl-isocyanate (65 μL, 0.48 mmol). The resultant solution was stirred at room temperature overnight then concentrated. Purification of the crude material by radial chromatography on silica gel (1 mm plate, 20:1:1 CH2Cl2-MeOH—NH4OH) provided 83 mg (73%) of the free base of the title compound as a white foam. Conversion of the white foam to the HBr salt gave COMPOUND 363 as a white solid. 1H NMR (D2O) δ 1.40-1.50 (m, 2H), 1.71-1.84 (m, 1H), 1.99-2.23 (m, 2H), 2.34-2.40 (m, 2H), 2.41 (s, 3H), 2.44 (s, 3H), 2.63-2.73 (m, 1H), 2.88 (t, 2H, J=6.3 Hz), 2.95-2.98 (m, 2H), 4.12 (d, 1H, J=17.4 Hz), 4.33 (d, 1H, J=17.4 Hz), 4.45 (dd, 1H, J=5.7, 10.5 Hz), 7.83 (dd, 1H, J=7.8, 5.4 Hz), 8.18 (s, 1H), 8.32 (d, 1H, J=7.8 Hz), 8.42 (s, 1H), 8.57 (d, 1H, J=5.4 Hz); 13C NMR (D2O) δ 17.06, 17.52, 20.46, 20.62, 27.83, 28.80, 37.85, 49.55, 51.95, 61.05, 125.86, 136.65, 137.41, 137.78, 139.38, 140.73, 148.09, 148.74, 149.24, 151.20; ES-MS m/z 368 (M+H). Anal. Calcd. For C21H29N5O.3.0HBr.2.9H2O: C, 38.07; H, 5.75; N, 10.57; Br, 36.18. Found: C, 38.05; H, 5.86; N, 10.68; Br, 36.20.
Reaction SMILES: [CH2:1]([CH:5]1[C:10](=O)[CH:9]([CH3:12])[CH2:8][N:7]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6]1)[C:2]([CH3:4])=O.[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1>>[CH2:13]([N:7]1[CH2:8][CH:9]([CH3:12])[C:10]2[N:26]([CH2:25][C:24]3[CH:27]=[CH:28][C:21]([Cl:20])=[CH:22][CH:23]=3)[C:2]([CH3:4])=[CH:1][C:5]=2[CH2:6]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)CC1CN(Cc2ccccc2)CC(C)C1=O
Reactant: NCc1ccc(Cl)cc1
Product: Cc1cc2c(n1Cc1ccc(Cl)cc1)C(C)CN(Cc1ccccc1)C2

Procedure:
Using a procedure analogous to Example 3, 3-acetonyl-1-benzyl-5-methyl-4-piperidone may be reacted with p-chlorobenzylamine to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:20]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:13][C:12]=3[C:11]([C:21]#[N:22])=[C:10]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].C1C[O:34]CC1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:20]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13](=[O:34])[C:12]=3[C:11]([C:21]#[N:22])=[C:10]([N:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)[CH:9]=2)=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: N#Cc1c(N2CCCCC2)cc(-c2ccc(F)cc2)c2c1Cc1ccccc1-2
Agent: [H-]
Agent: [Na+]
Product: N#Cc1c(N2CCCCC2)cc(-c2ccc(F)cc2)c2c1C(=O)c1ccccc1-2
Temperature: 2.5 °C

Procedure:
A solution of 4-(4-fluorophenyl)-2-(piperidin-1-yl)-9H-fluorene-1-carbonitrile (368 mg) in THF was added sodium hydride (38 mg) and was stirred at 0-5° C. for less than five minutes. After completion, the reaction solvent was evaporated under vacuum and the crude solid obtained was quenched with ice water and subsequently neutralized by dilute HCl. The precipitate thus obtained was filtered and purified on a silica gel column using ethyl acetate-hexane as eluent. Red solid; mp 152-154° C.; ESIMS 383 (M++1); IR (KBr) 1708 cm−1 (CO), 2221 (CN); HRMS calcd. for C25H19 FN2O 382.1481 found 382.1471.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10](=[O:15])[CH2:9]2)=[CH:4][C:3]=1Br.[C:17]1(B(O)O)[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>C1(C)C=CC=CC=1.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2].O1CCOCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10](=[O:15])[CH2:9]2)=[CH:4][C:3]=1[C:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1
Reactant: Nc1ccc(C2CC(=O)NC(=O)C2)cc1Br
Reactant: OB(O)C1=CCCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: Nc1ccc(C2CC(=O)NC(=O)C2)cc1C1=CCCCC1
Temperature: 90 °C

Procedure:
A solution of 69.0 mg (0.244 mmol) of 4-(4-amino-3-bromo-phenyl)-piperidine-2,6-dione (as prepared in the previous step) in toluene (10 mL) and dioxane (10 mL) was treated with 30.7 mg (0.244 mmol) of cyclohex-1-enylboronic acid, 104 mg (0.487 mmol) of K3PO4, and 34.2 mg (0.0975 mmol) of 2-(dicyclohexylphosphino)biphenyl. The mixture was degassed via sonication, placed under Ar, treated with 5.50 mg (0.0244 mmol) of Pd(OAc)2, and heated to 90° C. for 5 h. The mixture was diluted with EtOAc (30 mL) and washed with water (2×20 mL). The organic layer was dried (MgSO4) and concentrated in vacuo to afford 73.5 mg (106%, some solvent trapped) of the title compound as a tan solid: Mass spectrum (ESI, m/z): Calcd. for C17H20N2O2, 285.2 (M+H). found 285.2.
Reaction SMILES: [CH:1]1([C:6]([CH2:8][N:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:12][C@@H:11]([NH:26][C:27]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[CH:31]=3)=[O:28])[C:10]2=[O:37])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+]>C(O)C>[CH:1]1([C@H:6]([OH:7])[CH2:8][N:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:12][C@@H:11]([NH:26][C:27]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[CH:31]=3)=[O:28])[C:10]2=[O:37])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cccc(NC(=O)N[C@@H]2N=C(c3ccccc3)c3ccccc3N(CC(=O)C3CCCC3)C2=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cccc(NC(=O)N[C@@H]2N=C(c3ccccc3)c3ccccc3N(C[C@@H](O)C3CCCC3)C2=O)c1

Procedure:
The benzodiazepine of Example 17 (335 mg, 0.677 mmol) was treated with sodium borohydride in ethanol as described in Examples 12 and 13. The residue was chromatographed to afford the two title compounds (eluant EtOAc/Hexane 35:65 v/v).
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([C:10]([O:12]CC)=[O:11])[C:5]([CH3:15])=[C:4]([CH3:16])[C:3]=1[C:17](=[O:35])[CH:18]=CC1C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=1.[Br:36][C:37]1[CH:38]=[C:39]([CH:42]=[C:43]([Br:46])[C:44]=1[OH:45])[CH:40]=O>>[OH:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([C:10]([OH:12])=[O:11])[C:5]([CH3:15])=[C:4]([CH3:16])[C:3]=1[C:17](=[O:35])[CH:18]=[CH:40][C:39]1[CH:38]=[C:37]([Br:36])[C:44]([OH:45])=[C:43]([Br:46])[CH:42]=1
Reactant: O=Cc1cc(Br)c(O)c(Br)c1
Reactant: CCOC(=O)c1c(C)c(C)c(C(=O)C=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(O)c1OC
Product: COc1c(O)c(C(=O)C=Cc2cc(Br)c(O)c(Br)c2)c(C)c(C)c1C(=O)O

Procedure:
This compound was synthesized from 2′-hydroxy-4′-(ethoxycarbonyldimethylmethyloxy)acetophenone (starting material 1) and 3,5-dibromo-4-hydroxybenzaldehyde according to general method 2 described earlier.
Reaction SMILES: [OH-].[Li+].[C:3]([O:7][C:8]([NH:10][C:11]1([CH3:20])[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]([O:18]C)=[O:17])=[O:9])([CH3:6])([CH3:5])[CH3:4]>C1COCC1.O>[C:3]([O:7][C:8]([NH:10][C:11]1([CH3:20])[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]([OH:18])=[O:17])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)C1CCCC1(C)NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC1(C)CCCC1C(=O)O
Temperature: 50 °C
Reaction time: 18 h

Procedure:
Lithium hydroxide (23.50 g, 981 mmol) was added to a solution of methyl 2-{ [(tert-butoxy)carbonyl]amino}-2-methylcyclopentane-1-carboxylate (50.51 g, 196 mmol) in THF (300 ml) and water (150 ml). The reaction was heated at 50° C. for 18 hours and then to 60° C. for 18 hours. The reaction was concentrated in vacuo and then acidified to pH 7 with concentrated HCl and then to pH 3 with 2 M HCl (aq). The organics were extracted with ethyl acetate (3×300 ml) and the combined organics were washed with brine (50 ml), dried over magnesium sulfate and concentrated in vacuo to afford the title compound which was used without further purification.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]2[CH:10]=1.Cl>CN(C=O)C.[C-]#N.[Zn+2].[C-]#N.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>[N:3]1[CH:2]=[CH:10][N:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=12
Reactant: Brc1cn2ccccc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [C-]#N
Solvent: CN(C)C=O
Product: c1ccn2ccnc2c1
Temperature: 130 °C

Procedure:
To a solution of bromo-imidazo[1,2-a]pyridine derivatives (1.0 equiv.) in DMF, Zinc cyanide (1.1 equiv.) and Pd(PPh3)4 (5%) were added under inert atmosphere. The resulting mixture was heated through microwave irradiation for 10 min at 130° C. (Power max tolerated was 70 W). The yellow cloudy reaction mixture was hydrolyzed with HCl 1N solution then extracted with Et2O. Aqueous layer was cooled by an ice bath, and NaOH solid was added until a pH was greater than 10. The resulting aqueous basic layer was extracted with EtOAC. Organic layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure.