Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([C:12]1([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]1=[O:25])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].C(N(C(C)C)CC)(C)C.[F:39][C:40]1[CH:41]=[C:42]([CH:46]=[CH:47][C:48]=1[F:49])[C:43](Cl)=[O:44]>C(Cl)Cl>[F:39][C:40]1[CH:41]=[C:42]([CH:46]=[CH:47][C:48]=1[F:49])[C:43]([NH:1][CH2:2][CH2:3][CH:4]([C:12]1([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]1=[O:25])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])=[O:44]
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: CC(C)CC1(C(CCN)C(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)CC1(C(CCNC(=O)c2ccc(F)c(F)c2)C(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 16 h
Yield: 64.6 %

Procedure:
To a solution of tert-butyl α-(2-aminoethyl)-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate (549 mg, 1.36 mmol), CH2Cl2 (8.4 mL), and diisopropylethylamine (0.29 ml, 1.6 mmol) at 0° C. is added 3,4-difluorobenzoyl chloride (0.21 mL, 1.6 mmol). The solution is stirred at 0° C. for 1 hour and 16 hours at room temperature. Basic workup (CH2Cl2, NaHCO3, MgSO4) and purification by flash chromatography (1:1 hexane:EtOAc) gives 477 mg (64%) of the title compound as a white solid (mp 147°-148° C.):
Reaction SMILES: [CH2:1]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[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].C(N(CC)CC)C.[Cl:41][CH:42]([Cl:54])[C:43]1[CH:53]=[CH:52][C:46]([O:47][CH2:48][C:49](Cl)=[O:50])=[CH:45][CH:44]=1>C(Cl)Cl>[CH2:18]([N: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])[C:49](=[O:50])[CH2:48][O:47][C:46]1[CH:52]=[CH:53][C:43]([CH:42]([Cl:54])[Cl:41])=[CH:44][CH:45]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: O=C(Cl)COc1ccc(C(Cl)Cl)cc1
Reactant: CCCCCCCCCCCCCCCCNCCCCCCCCCCCCCCCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCC)C(=O)COc1ccc(C(Cl)Cl)cc1
Reaction time: 16 h
Yield: 92 %

Procedure:
Dihexadecylamine (8.88 g, 0.019 mole) was dissolved in a solution of methylene chloride (75 ml) and triethylamine (2.02 g, 0.020 mole). 4-Dichloromethylphenoxy acetyl chloride (3.97 g, 0.02 mole), dissolved in methylene chloride (25 ml), was then added dropwise over a period of 10 minutes, and the resulting clear solution was stirred for 16 hours. The reaction mixture was then washed with water (2×100 ml), saturated sodium bicarbonate solution (2×100 ml) and saturated sodium chloride solution (2×100 ml), dried over sodium sulfate, filtered, and concentrated under vacuum to the desired amide: oil, 10.83 g (92% yield).
Reaction SMILES: C(N(CC)CC)C.[N+:8]([C:11]1[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1)([O-:10])=[O:9].[C:21]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][NH2:34])([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>CC(C)=O.O>[C:24]([O:23][C:21](=[O:22])[NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][NH:34][S:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N+:8]([O-:10])=[O:9])[CH:12]=1)(=[O:19])=[O:18])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)NCCCCCN
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCCCCNS(=O)(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.2 ml (30.1 mmol) of triethylamine is added to a solution of 3.21 g (14.5 mmol) of 3-nitrobenzenesulfonyl chloride and 3.0 ml (14.4 mmol) of N-Boc-1,5-diaminopentane in 50 ml of acetone and 15 ml of water. The reaction mixture is stirred for one hour at room temperature. Then, the acetone is drawn off in a rotary evaporator. After water (20 ml) is added, it is extracted with ethyl acetate (2×). The combined organic phases are dried (Na2SO4), filtered and concentrated by evaporation. 5.00 g (12.9 mmol, corresponding to 90% of theory) of the product is obtained as a light yellow oil.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([CH3:13])[C:5]([C:7]1[CH:8]=[N:9][CH:10]=[N:11][CH:12]=1)=O.[CH2:14](I)[CH3:15].[OH2:17]>CN(C)C=O>[CH3:3][C:4]([CH3:13])([CH2:14][CH3:15])[C:5]([C:7]1[CH:8]=[N:9][CH:10]=[N:11][CH:12]=1)=[O:17]
Reactant: CC(C)C(=O)c1cncnc1
Reactant: O
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(C)(C)C(=O)c1cncnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of oil-free sodium hydride (2.4g, 0.1 moles) in dry dimethylformamide (60 mls) was added dropwise a solution of 2-methyl-1-(pyrimid-5-yl)-propan- 1-one in dry dimethylformamide (20 mls). The temperature rose to 35° C. and effervescence was observed. After the addition was complete, the mixture was stirred at room temperature for twenty minutes, and a solution of ethyl iodide (18.72 g, 0.12 moles) in dry dimethylformamide was added with external cooling provided by a water bath. The resulting mixture was stirred at room temperature for three hours, left to stand overnight and then poured into water and extracted twice with ether. The combined ether extracts were washed with water and dried over magnesium sulphate. After filtration, the solvent was removed in vacuo to give an oil. Distillation at reduced pressure (70°-82° C. at 0.3 mm of mercury) gave an oil (8.4 g) which was used without further purification. NMR analysis indicated that, in addition to the desired intermediate, the product contained 1-(O-ethyl)-1-(pyrimid-5-yl)-2-methylprop-1-ene. This latter by-product did not adversely affect the course of the second stage of the reaction.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[C:15](Br)[CH:14]=3)[O:10][N:9]=2)=[N:6][CH:7]=1.B1([C:27]2[CH:32]=[CH:31][CH:30]=[N:29][CH:28]=2)OCCCO1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>CCCCCC.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.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:14]=[C:15]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)[CH:16]=[C:17]([F:19])[CH:18]=3)[O:10][N:9]=2)=[N:6][CH:7]=1
Reactant: Fc1ccc(-c2noc(-c3cc(F)cc(Br)c3)n2)nc1
Reactant: c1cncc(B2OCCCO2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Fc1ccc(-c2noc(-c3cc(F)cc(-c4cccnc4)c3)n2)nc1
Yield: 47.7 %

Procedure:
In a similar fashion, 3-(5-fluoro-2-pyridyl)-5-(3-bromo-5-fluorophenyl)-1,2,4-oxadiazole (60 mg, 0.154 mmol), pyridine-3-boronic acid 1,3-propanediol cyclic ester (50.4 mg, 0.309 mmol), and Pd(PPh3)4 (17.8 mg, 0.015 mmol), in a solution of ethylene glycol dimethyl ether (2 mL) and 2M sodium carbonate (2 mL) was heated in a selaed vial at 100° C. for 1 hour. Standard work up and silica gel chromatography using a gradient of 50% to 70% ethyl acetate in hexane afforded 24.7 mg (48%) of 3-(5-fluoro-2-pyridyl)-5-(3-fluoro-5-(3-pyridyl)phenyl)-1,2,4-oxadiazole: 1H-NMR (CDCl3), δ (ppm): 8.92 (d, 1H), 8.71 (m, 2H), 8.31 (s, 1H), 8.30 (dd, 1H), 8.00 (m, 2H), 7.62 (td, 1H), 7.57 (td, 1H), 7.45 (dd, 0.1H).
Reaction SMILES: [C:1]([C:4]1[C:13]([N:14]2[CH2:18][CH2:17][C@H:16]([NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[CH2:15]2)=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[C:6]([Cl:25])[CH:5]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:32].[Na+].O1CCCC1>CO.C(#N)C>[NH2:32][CH:1]([C:4]1[C:13]([N:14]2[CH2:18][CH2:17][C@H:16]([NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[CH2:15]2)=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[C:6]([Cl:25])[CH:5]=1)[CH3:2]
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CC[C@H](NC(=O)C(C)C)C1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(C)C(=O)N[C@H]1CCN(c2c(C(C)N)cc(Cl)c3cccnc23)C1
Temperature: 65 °C

Procedure:
A mixture of N-[(3S)-1-(7-acetyl-5-chloroquinolin-8-yl)pyrrolidin-3-yl]-2-methylpropanamide (0.031 g, 0.086 mmol) and ammonium acetate (0.066 g, 0.86 mmol) in methanol (0.3 mL) and acetonitrile (0.3 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.21 mL, 0.21 mmol). The reaction was heated at 65° C. overnight and then cooled to room temperature. The mixture was quenched with sat. NaHCO3 solution, extracted with dichloromethane, dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C19H26ClN4O (M+H)+: m/z=361.2; Found: 361.2.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][S:11]([C:14]1[N:18]=[C:17]([NH2:19])[NH:16][N:15]=1)(=[O:13])=[O:12].[C:20](Cl)(=[O:25])[CH2:21][C:22](Cl)=[O:23]>C(#N)C>[OH:23][C:22]1[CH:21]=[C:20]([OH:25])[N:16]2[N:15]=[C:14]([S:11]([NH:10][C:3]3[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=3[Cl:1])(=[O:13])=[O:12])[N:18]=[C:17]2[N:19]=1
Reactant: Cc1ccc(Cl)c(NS(=O)(=O)c2n[nH]c(N)n2)c1Cl
Reactant: O=C(Cl)CC(=O)Cl
Solvent: CC#N
Product: Cc1ccc(Cl)c(NS(=O)(=O)c2nc3nc(O)cc(O)n3n2)c1Cl
Temperature: 25 °C
Reaction time: 14 h
Yield: 85 %

Procedure:
To a stirred solution of 2.52 grams (g) (0.0078 moles) of N-(3-(((2,6-dichloro-3-methylphenyl)amino)sulfonyl)-1H-1,2,4-triazol-5-yl)amine in 100 milliliters (mL) of dry acetonitrile under nitrogen was added 1.5 g (0.01 moles) of freshly distilled malonyl chloride. The mixture was stirred at ambient temperature overnight (14 hr) and a yellow precipitate formed. The solid product was collected by filtration and dried; mp 280°-282° C. (decomposes). The filtrate was found to contain additional product which was recovered by concentrating the filtrate to dryness. The combined yield of product was 2.58 g (85 percent yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1.Cl[C:21]1[N:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][NH:25]2.CCN(C(C)C)C(C)C>CC(O)C>[NH3:7].[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:12][C:21]3[N:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)[CH3:11])[N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1
Reactant: FC(F)(F)c1nc(Cl)c2nc[nH]c2n1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@H](Nc1nc(C(F)(F)F)nc2[nH]cnc12)c1nc2ccc(F)cc2n1-c1ccccn1
Product: N
Temperature: 80 °C
Reaction time: 16 h
Yield: 86.3 %

Procedure:
A mixture of (S)-1-(6-fluoro-1-pyridin-2-yl-1H-benzoimidazol-2-yl)ethylamine (0.055 g, 0.22 mmol), 6-chloro-2-trifluoromethyl-9H-purine (0.040 g, 0.18 mmol) and DIPEA (0.096 mL, 5.39 mol) in IPA (1 mL) was stirred at 80° C. in a sealed tube for 16 h. The resulting mixture was concentrated in vacuo and the residue purified by chromatography (SiO2, O-15% (2M ammonia in methanol) in DCM) then by preparative HPLC (Phenomenex Gemini 5 μm C18 on a 60 min gradient 20-98% 0.1% HCO2H in acetonitrile/water) to give 313 as a white solid (0.042 g, 23%). LCMS (method K): Rt 4.11 min, [M+H]+ 443. 1H NMR (DMSO-d6) δ: 13.20-12.70 (1H, bs), 8.59 (2H, m), 8.32 (1H, s), 7.97 (1H, m), 7.74-7.67 (2H, m), 7.43 (1H, s), 7.16-7.13 (2H, m), 5.86 (1H, m), 1.69 (3H, d, J=6.82 Hz)
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:30])=[N:12][CH:13]=[C:14]([C:16]2[CH:17]=[N:18][N:19]([CH:21]3[CH2:27][CH:26]4[N:28](C)[CH:23]([CH2:24][CH2:25]4)[CH2:22]3)[CH:20]=2)[CH:15]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:38]([O:40][CH2:41][CH3:42])=[O:39]>C1(C)C=CC=CC=1.O>[CH2:41]([O:40][C:38]([N:28]1[CH:26]2[CH2:25][CH2:24][CH:23]1[CH2:22][CH:21]([N:19]1[CH:20]=[C:16]([C:14]3[CH:13]=[N:12][C:11]([NH2:30])=[C:10]([C:2]4[S:1][C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=5[N:3]=4)[CH:15]=3)[CH:17]=[N:18]1)[CH2:27]2)=[O:39])[CH3:42]
Reactant: CCOC(=O)Cl
Reactant: CN1C2CCC1CC(n1cc(-c3cnc(N)c(-c4nc5ccccc5s4)c3)cn1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)N1C2CCC1CC(n1cc(-c3cnc(N)c(-c4nc5ccccc5s4)c3)cn1)C2
Temperature: 110 °C

Procedure:
To a solution of 3-benzothiazol-2-yl-5-[1-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazol-4-yl]-pyridin-2-ylamine (50.8 mg, 0.122 mmol; 1 eq) and K2CO3 (1.2 mg, 0.0087 mmol, 7 mol %) in toluene (3 mL), ethyl chloroformate (67.0 mg, 0.617 mmol, 5 eq) in toluene (1 mL) was added. The solution was heated to reflux for a total of 10 h (temp=110° C.). The residue was dissolved in water. The aqueous mixture was extracted with CH2Cl2 (3×) and the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude was purified by column chromatography on silica gel [0.5″×10″ column, eluting with CH2Cl2:EtOAc 1:0→2:1→1:1→1:2→0:1]. Fractions containing product were combined and concentrated in vacuo to give the title compound. MS (ES+): m/z=475.13 (100) [MH+]. HPLC: tR=3.41 min (ZQ2, polar—5 min).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([C@@H:13]2[CH2:16][CH2:15][NH:14]2)=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[O:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CN(C=O)C>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([C@@H:13]2[CH2:16][CH2:15][N:14]2[CH:21]2[CH2:22][CH2:23][O:18][CH2:19][CH2:20]2)=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2CCN2)on1
Reactant: O=C1CCOCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2CCN2C2CCOCC2)on1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a solution of (S)-Azetidine-2-carboxylic acid (3-tert-butyl-isoxazol-5-yl)-amide; hydrochloride (78.6 mg; 0.303 mol) in DMF (1 mL) is added tetrahydro-4H-pyran-4-one (0.056 mL; 0.606 mmol) and acetic acid (0.069 mL; 1.212 mmol). The reaction is stirred at room temperature for 50 minutes before adding sodium cyanoborohydride (57 mg; 0.909 mmol). The reaction mixture is left stifling at room temperature for 18 hours. After this time, the reaction mixture is quenched with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate twice. The organics are combined and washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography on silica gel using methanol/methylene chloride provides the title compound, m/z 308 [M+H+].
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][C:12]([F:14])=[CH:13][C:8]=2[CH2:7][O:6][C:5]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:4]1=2.[N:20]1([CH2:26][CH2:27][N:28]2[C:32]3[CH:33]=[CH:34][C:35](B4OC(C)(C)C(C)(C)O4)=[CH:36][C:31]=3[NH:30][C:29]2=[O:46])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C([O-])([O-])=O.[Na+].[Na+]>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.O1CCOCC1>[F:19][C:16]1[CH:17]=[CH:18][C:4]2[C:3](=[CH:2][C:35]3[CH:34]=[CH:33][C:32]4[N:28]([CH2:27][CH2:26][N:20]5[CH2:21][CH2:22][O:23][CH2:24][CH2:25]5)[C:29](=[O:46])[NH:30][C:31]=4[CH:36]=3)[C:9]3[CH:10]=[CH:11][C:12]([F:14])=[CH:13][C:8]=3[CH2:7][O:6][C:5]=2[CH:15]=1
Reactant: Fc1ccc2c(c1)COc1cc(F)ccc1C2=CBr
Reactant: CC1(C)OB(c2ccc3c(c2)[nH]c(=O)n3CCN2CCOCC2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=c1[nH]c2cc(C=C3c4ccc(F)cc4COc4cc(F)ccc43)ccc2n1CCN1CCOCC1
Yield: 76.6 %

Procedure:
Following procedures essentially as described in Example 219, mix 11-bromomethylene-3,8-difluoro-6,11-dihydro-dibenzo[b,e]oxepine (E-isomer, 40 mg, 0.12 mmol), 1-(2-morpholin-4-yl-ethyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-benzoimidazol-2-one (44 mg, 0.12 mmol), Na2CO3 (2M in water, 155 μL, 0.310 mmol), dioxane (1 mL), and Pd(PPh3)4 (7 mg, 0.006 mmol). Purify on silica gel (12 g), eluting with 2% to 5% (2M NH3/MeOH)/CH2Cl2 to afford 45 mg (78%) of the title compound as a white foam. HPLC (ISO80-10) t=1.86 min, 99%; MS [ES] 488 (M−H), 490 (M+H); 1H-NMR (DMSO-d6) δ 10.70 (s, 1H), 7.59 (dd, 1H, J=8.5, 7.1 Hz), 7.51 (dd, 1H, J=8.8, 2.6 Hz), 7.08 (td, 1H, J12.5, 4.3 Hz), 7.01 (m, 2H), 6.96 (d, 1H, J=7.9 Hz), 6.80 (td, 1H, J=12.0, 4.2 Hz), 6.73 (d, 1H, J=7.9 Hz), 6.62 (dd, 1H, J=10.3, 2.4 Hz), 6.58 (s, 1H), 5.72-4.85 (br d, 2H), 3.81 (t, 2H, J=6.4 Hz), 3.47 (t, 4H, J=4.4 Hz), 2.48 (m, 2H), 2.38 (s, 4H).
Reaction SMILES: COC1C=CC(CCC2C=CC(OC)=CC=2)=C(C=1)OC1C=CC(O)=CC=1.Cl.ClCCN1CCCCC1.C[O:38][C:39]1[CH:40]=[CH:41][C:42]([CH2:61][CH2:62][C:63]2[CH:68]=[CH:67][C:66]([O:69]C)=[CH:65][CH:64]=2)=[C:43]([CH:60]=1)[O:44][C:45]1[CH:59]=[CH:58][C:48]([O:49][CH2:50][CH2:51][N:52]2[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]2)=[CH:47][CH:46]=1.Cl.N1C=CC=CC=1>O1CCCC1>[OH:69][C:66]1[CH:67]=[CH:68][C:63]([CH2:62][CH2:61][C:42]2[CH:41]=[CH:40][C:39]([OH:38])=[CH:60][C:43]=2[O:44][C:45]2[CH:59]=[CH:58][C:48]([O:49][CH2:50][CH2:51][N:52]3[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57]3)=[CH:47][CH:46]=2)=[CH:64][CH:65]=1
Reactant: COc1ccc(CCc2ccc(OC)cc2Oc2ccc(OCCN3CCCCC3)cc2)cc1
Agent: COc1ccc(CCc2ccc(OC)cc2Oc2ccc(O)cc2)cc1
Agent: Cl
Agent: ClCCN1CCCCC1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Oc1ccc(CCc2ccc(O)cc2Oc2ccc(OCCN3CCCCC3)cc2)cc1
Temperature: 170 °C
Reaction time: 0.17 h
Yield: 34.4 %

Procedure:
Synthesized from 4-{5-methoxy-2-[2-(4-methoxyphenyl)ethyl]phenoxy}phenol and 1-(2-chloroethyl)piperidine hydrochloride according to an analogous synthetic method to Preparation Example 40,to 1-{2-{4-{5-methoxy-2-[2-(4-methoxyphenyl)ethyl]phenoxy}phenoxy}ethyl}piperidine (344 mg) was added pyridine hydrochloride (1.2 g), and the solution was stirred for 3 hours and 10 minutes at 170° C. To the reaction solution were added tetrahydrofuran and an aqueous solution of 1N sodium hydroxide, the solution was extracted with ethyl acetate, then washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (ethyl acetate-methanol system) to provide the title compound (111 mg).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16]([CH3:20])=[C:15]([O:21][CH2:22][C:23]#[N:24])[CH:14]=[CH:13]2.[C:25](Cl)(=[O:30])[CH2:26][CH2:27][CH2:28][CH3:29].[Sn](Cl)(Cl)(Cl)Cl>C(Cl)Cl>[CH3:20][C:16]1[C:17]2[C:12](=[CH:11][C:10]([C:2]3[O:1][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[C:3]=3[C:25](=[O:30])[CH2:26][CH2:27][CH2:28][CH3:29])=[CH:19][CH:18]=2)[CH:13]=[CH:14][C:15]=1[O:21][CH2:22][C:23]#[N:24]
Reactant: CCCCC(=O)Cl
Reactant: Cc1c(OCC#N)ccc2cc(-c3cc4ccccc4o3)ccc12
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCCCC(=O)c1c(-c2ccc3c(C)c(OCC#N)ccc3c2)oc2ccccc12
Yield: 31.4 %

Procedure:
Following the procedure described in Step 2 of Example 1, 2-{[6-(1-benzofuran-2-yl)-1-methyl-2-naphthyl]oxy}acetonitrile (1.15 g, 3.67 mmol) was acylated with valeryl chloride (0.52 mL, 4.4 mmol), in presence of tin (IV) chloride (0.52 mL, 4.4 mmol) in methylene chloride (15 mL). 2-{[1-methyl-6-(3-pentanoyl-1-benzofuran-2-yl)-2-naphthyl]oxy}acetonitrile was prepared. Purification by flash chromatography (Biotage apparatus) using 10-20% chloroform in hexane and 100% hexane and 0.5-5% ethyl acetate in hexane as eluants yielded the title compound as a yellow gum (0.458 g). 1HNMR (300 MHz, DMSO-d6): δ8.45 (s, 1H), 8.2 (d, 1H, J=7.7 Hz), 8.05 (t, 2H, J=8.8 Hz), 7.95 (d, 1H, J=7.7 Hz), 7.75 (d, 1H, J=7.7 Hz), 8.65 (d, 1H, J=7.7 Hz), 7.4-7.5 (m, 2H), 5.35 (s, 2H), 2.75 (t, 2H, J=8.1 Hz), 2.55 (s, 3H), 1.5-1.6 (m, 2H), 1.1-1.25 (m, 2H), and 0.7 ppm (t, 3H, J=8.8 Hz).
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Br)=[O:4].[N:7]([CH2:10][CH2:11][OH:12])=[N+:8]=[N-:9].Br.O>C(Cl)Cl.C(N(CC)CC)C>[Br:1][CH:2]([CH3:6])[C:3]([O:12][CH2:11][CH2:10][N:7]=[N+:8]=[N-:9])=[O:4]
Reactant: CC(Br)C(=O)Br
Reactant: [N-]=[N+]=NCCO
Agent: Br
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Br)C(=O)OCCN=[N+]=[N-]

Procedure:
The synthesis was carried out in methylene chloride at 0° C. A solution of 2-bromopropionyl bromide in methylene chloride was added dropwise to a mixture of 2-azidoethanol in methylene chloride, triethylamine was added to neutralize the formed hydrobromic acid. After stirring at room temperature over-night water was added and the organic layer was extracted three times with water, the organic phase was then dried and the solvent evaporated. The product was a mixture of byproducts and had to be separated via silica gel column producing pure 2-azidoethyl 2-bromopropionate. Characterization was made with 1H-NMR and FT-IR.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][N:5]=1.[H][H]>C(O)C.Cl.[Pt]=O>[ClH:1].[NH2:10][CH:7]1[CH2:6][NH:5][C:4](=[NH:3])[CH2:9][CH2:8]1
Reactant: [H][H]
Reactant: Nc1ccc(N)nc1
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Product: N=C1CCC(N)CN1

Procedure:
2,5-diaminopyridine dihydrochloride (1.2 g) and platinum oxide (500 mg) in ethanol (20 mL) and conc HCl (2 mL) were shaken on a Parr hydrogenation apparatus at 55 psi of hydrogen overnight. Product was obtained as a dark solid which was purified by C-18-reverse phase chromatography, eluting with H2O/CH3CN. Fractions containing the product were lyophilized, redissolved in 1N HCl and lyophilized to give the product as a yellow solid. The analysis of the product was found to be consistent with the proposed structure. MH+=114; 1H NMR (D2O): δ3.8-3.6 (m, 2H); 3.4-3.25 (m, 1H); 2.75-2.65 (m, 2H); 2.25-2.15 (m, 1H); 2.15-1.85 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10](Cl)=[O:11].C(N(CC)CC)C.[OH:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([O:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1)=[O:11]
Reactant: O=C(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: Oc1cccnc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(Oc1cccnc1)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 70.7 %

Procedure:
To a stirred solution of 5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitrobenzoyl chloride (3.79 g, 0.01 mole) and triethyl amine (1.01 g, 0.01 mole) in toluene (50 ml) was added 3-hydroxypyridine (0.95 g, 0.01 mole). The temperature exothermed to 33° C. and there was an immediate precipitate. The reaction was then refluxed for 24 hours, cooled to room temperature and the triethylamine hydrochloride precipitate collected by filtration. The toluene solution was washed with dilute sodium hydroxide solution and then with saturated sodium chloride solution. After drying and evaporation of the solvent there was obtained 3.1 g of brown oil which solidified. This was triturated with hexane and the solid filtered and dried to give a tan product, m.p. 65°-68° C.