Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][Cl:4].C(=O)([O-])[O-].[K+].[K+].[C:11]([N:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[NH:16][C:15]1=[O:23])([CH3:13])=[CH2:12]>CN(C)C=O>[Cl:4][CH2:3][CH2:2][N:16]1[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:14]([C:11]([CH3:13])=[CH2:12])[C:15]1=[O:23]
Reactant: ClCCBr
Reactant: C=C(C)n1c(=O)[nH]c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)n1c(=O)n(CCCl)c2ccccc21
Reaction time: 48 h

Procedure:
200 mmol of 1-bromo-2-chloroethane and 55 mmol of potassium carbonate are added to 50 mmol of 1-isopropenyl-2(3H)-benzimidazolone in 150 ml of dimethylformamide. The whole mixture is kept stirring for 48 hours. It is then poured into ice-cold water and extracted with dichloromethane. The organic phases are washed with water, dried and evaporated. The residue is then taken up in ether. The ether phase is washed with 2N potassium hydroxide and then with water, dried and evaporated and leads to the expected product.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22].C(=O)([O-])[O-].[K+].[K+].CO.C(Cl)Cl>CN(C)C=O>[C:13]([C:10]1[CH:9]=[CH:8][C:7]([N:1]2[CH2:6][CH2:5][N:4]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH2:3][CH2:2]2)=[CH:12][CH:11]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Reactant: COC(=O)CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)CCCCN1CCN(c2ccc(C(C)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 65 h

Procedure:
4'-Piperazinoacetophenone (102 mg) is dissolved in 1 mL of N,N-dimethylformamide. After addition of methyl 5-bromovalerate (0.077 mL) and potassium carbonate (69 mg), the mixture is stirred at room temperature for 65 hours. TLC (10% MeOH/CH2Cl2) should show a single product spot without residual starting material. The reaction solution is evaporated under vacuum. The residue is taken up in methylene chloride, washed twice with water and dried over sodium sulfate. Evaporation of the solvent yields 137 mg of 4-(4-acetylphenyl)-1-piperazinevaleric acid, methyl ester as yellow crystals whose 1H-NMR (CDCl3) spectrum is consistent with the assigned structure.
Reaction SMILES: O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[C@:30]([O:44][Si](C)(C)C)([C@H:37]([N:39]1[CH:43]=[N:42][N:41]=[CH:40]1)[CH3:38])[CH2:31][N:32]1[CH:36]=[N:35][CH:34]=[N:33]1>O1CCCC1>[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[C@:30]([OH:44])([C@H:37]([N:39]1[CH:40]=[N:41][N:42]=[CH:43]1)[CH3:38])[CH2:31][N:32]1[CH:36]=[N:35][CH:34]=[N:33]1
Reactant: C[C@@H](n1cnnc1)[C@@](Cn1cncn1)(O[Si](C)(C)C)c1ccc(F)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](n1cnnc1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.3 %

Procedure:
Tetrabutylammonium fluoride trihydrate (663 mg) was added to a solution of (2R,3R)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-(4H-1,2,4-triazol-4-yl)-2-trimethylsilyloxybutane (750 mg) in tetrahydrofuran (50 ml). The mixture was stirred for 30 minutes at room temperature, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate/hexane=2:1→ethyl acetate→ethyl acetate/methanol=10:1) to give Compound 20 (620 mg) as a white powder.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].C1COCC1.[N:37]1([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([NH2:49])=[CH:45][CH:44]=2)[CH2:41][CH2:40][CH2:39][CH2:38]1>CCOC(C)=O.CCCCCC>[O:31]=[C:4]1[C:3](=[CH:2][NH:49][C:46]2[CH:45]=[CH:44][C:43]([CH2:42][N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)=[CH:48][CH:47]=2)[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5]1
Reactant: Nc1ccc(CN2CCCC2)cc1
Reactant: CCn1nc(C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCn1nc(C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2ccc(CN3CCCC3)cc2)c1
Temperature: 65 °C
Reaction time: 24 h
Yield: 25 %

Procedure:
A small screw cap test tube was charged with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 69, 100 mg, 0.2401 mmol) and THF (3.0 mL). To the resulting solution was added 4-Pyrrolidin-1-ylmethyl-phenylamine (42.3 mg, 0.24 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and diluted with EtOAc (˜5 mL) and Hexane (˜50 mL). The precipitate that formed was collected by filtration and washed with 0° C. iPrOH (˜5 mL) to afford the title compound in 25% yield (0.035 g, 0.0609 mmol).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][S:9](=[O:12])(=[O:11])[OH:10])=[CH:3][CH:2]=1.[OH-].[Na+].[CH2:15]1[S:17][CH2:16]1>O.[N+]([O-])([O-])=O.[Ag+]>[OH-:10].[SH:17][CH2:16][CH2:15][N+:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][S:9]([OH:10])(=[O:11])=[O:12])=[CH:3][CH:2]=1
Reactant: C1CS1
Reactant: O=S(=O)(O)NCc1ccncc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=S(=O)(O)NCc1cc[n+](CCS)cc1

Procedure:
A suspension of N-(4-pyridylmethyl)sulfamic acid (800 ml, 4.25 mmol) in water (5.0 ml) was adjusted to pH 7.0 with aqueous sodium hydroxide solution (2.5N). The resulting solution was treated with a solution of silver nitrate (723 ml, 4.25 mmol) in water (3.0 ml) to give a white suspension. Additional water (5.0 ml) was added to facilitate stirring and the mixture was treated with ethylene sulfide (0.280 ml, 4.67 mmol).
Reaction SMILES: [N:1]([CH:4]([CH3:19])[CH2:5][O:6][C:7]1[C:8]([CH3:18])=[C:9]2[N:14]([CH:15]=1)[N:13]=[CH:12][N:11]=[C:10]2SC)=[N+:2]=[N-:3].[F:20][C:21]1[C:26]([OH:27])=[CH:25][N:24]=[C:23]2[NH:28][CH:29]=[CH:30][C:22]=12>>[N:1]([CH:4]([CH3:19])[CH2:5][O:6][C:7]1[C:8]([CH3:18])=[C:9]2[N:14]([CH:15]=1)[N:13]=[CH:12][N:11]=[C:10]2[O:27][C:26]1[C:21]([F:20])=[C:22]2[CH:30]=[CH:29][NH:28][C:23]2=[N:24][CH:25]=1)=[N+:2]=[N-:3]
Reactant: Oc1cnc2[nH]ccc2c1F
Reactant: CSc1ncnn2cc(OCC(C)N=[N+]=[N-])c(C)c12
Product: Cc1c(OCC(C)N=[N+]=[N-])cn2ncnc(Oc3cnc4[nH]ccc4c3F)c12

Procedure:
Procedures given in Tetrahedron Lett, 1977, 1977, and JACS, 1999, 3637 were modified. Thus, a 10 mL flask was charged with 1-(5-methyl-4-methylsulfanylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)-propan-2-ol (249 mg, 0.98 mmol), and tetrahydrofuran (4.91 mL) and cooled to 0° C. Triphenylphosphine (516 mg, 1.96 mmoles), diethyl azodicarboxylate (310 μL, 1.96 mmol) and diphenylphosphoryl azide (424 μL, 1.96 mmol) were added in order. The mixture was stirred at 23° C. for 15 h and then concentrated in vacuo. The crude material was purified by flash chromatography eluting with a mixture of 20% ethyl acetate in hexane to give (156 mg, 57%) of 6-(2-azidopropoxy)-5-methyl-4-methylsulfanylpyrrolo[2,1-f][1,2,4]triazine as white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.19 (1H, s), 7.85 (1H, s), 4.16 (1H, dd, J=2.8, 9.6 Hz), 4.05-3.96 (m, 2H), 2.60 (3H, s), 2.37 (3H, s), 1.21 (3H, d, J=6.3 Hz). LCMS m/z 254 (M+H+). B. 6-(2-Azido-propoxy)-5-methyl-4-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine and 4-fluoro-1H-pyrrolo[2,3-b]pyridin-5-ol were reacted together according to the procedure described in Example 7 to afford 6-(2-azido-propoxy)-4-(4-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yloxy)-5-methyl-pyrrolo[2,1-f][1,2,4]triazine. The crude material was purified by preparative HPLC. 1H NMR (400 MHz, DMSO-d6) δ 12.18 (1H, s), 8.32 (1H, d, J=9.6 Hz), 8.02 (1H, s) 7.96 (1H, s), 6.60 (1H, d, J=3.6 Hz), 4.21 (1H, d, J=7.0 Hz), 4.09-4.02 (2H, m), 2.42 (3H, s), 1.23 (3H, d, J=6.3 Hz). LCMS m/z 382 (M+H+). C. A solution of 6-(2-azido-propoxy)-4-(4-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yloxy)-5-methyl-pyrrolo[2,1-f][1,2,4]triazine (20 mg, 0.05 mmol) in ethyl acetate (2.0 mL) was stirred in the presence of hydrogen (14 psi) and 10% Pd/C (10 mg) for 12 h. Excess hydrogen was removed and the mixture was filtered through Celite® and evaporated. The residue was purified by preparative HPLC to afford (10 mg, 54%) of the title compound. LCMS: m/z 357 (M+H+). Dihydrochloride salt: 1H NMR (400 MHz, DMSO-d6) δ 12.19 (1H, s), 8.31 (1H, d, J=8.9 Hz), 8.16 (2H, br. s), 8.05 (1H, m), s), 7.97 (1H, s), 7.60 (1H, s), 6.60 (1H, s), 4.19 (2H, m), 4.03 (2H, m), 3.65 (1H, m), 1.30 (3H, d, J=6.8 Hz).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[NH2:29][CH:30]([CH2:33][OH:34])[CH2:31][OH:32].O>CN(C=O)C>[OH:32][CH2:31][CH:30]([NH:29][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1)[CH2:33][OH:34]
Reactant: NC(CO)CO
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CC3)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CNC(CO)CO)cc2)CC3)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 35.1 %

Procedure:
In DMF (3 ml) was dissolved N-[4-(chloromethyl)phenyl]-7-(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (150 mg), and to the mixture was added 2-amino-1,3-propanediol (106 mg). The mixture was stirred at room temperature for 72 hours, and to the mixture was added water(50 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropylether to give N-[4-[(1,3-dihydroxy-2-propyl)aminomethyl]phenyl]-7-(4-methyl-phenyl)-3,4-dihydronaphthalene-2-carboxamide (Compound 48) (60 mg) as colorless crystals.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:8]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:7]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[N:6]=1)(=O)=O.C([Li])CCC.[CH:38]1([OH:42])[CH2:41][CH2:40][CH2:39]1>>[CH:38]1([O:42][C:5]2[N:10]=[C:9]([O:11][C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[C:8]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)=[C:7]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=3[Cl:32])[N:6]=2)[CH2:41][CH2:40][CH2:39]1
Reactant: OC1CCC1
Reactant: CS(=O)(=O)c1nc(Oc2cccnc2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Agent: [Li]CCCC
Product: Clc1ccc(-c2c(Oc3cccnc3)nc(OC3CCC3)nc2-c2ccc(Cl)cc2Cl)cc1

Procedure:
2-Methylsulfonyl-4-(3-pyridyloxy)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine from Example 86 (30 mg, 0.06 mmol) with 2 equivalents each of n-butyl lithium and cyclobutyl alcohol by the procedure described in Reference Examples 6 and 7 to afford 2-(2-cyclobutyloxy-4-(3-pyridyloxy)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine: HPLC/MS: m/e=498 (M++1); Rt4.16 min. 1H-NMR 400 MHz (CDCl3): δ 1.70-1.85 (m, 2H), 2.16-2.28 (m, 4H), 4.93 (m, 1H), 7.14-7.38 (m, 7H), 7.40-7.42 (m, 1H), 7.55-7.58 (m, 1H), 8.52-8.54 (m, 2H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:16][CH2:15][N:14]([CH:17](C)[CH2:18][CH2:19]C(NC2C=CC=CC=2C(O)=O)=O)[CH2:13][CH2:12]1.[C:33]([O:36][C:37](=O)[CH3:38])(=[O:35])[CH3:34]>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH2:19][CH2:38][C:37]2[O:36][C:33](=[O:35])[C:34]3[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=3[N:1]=2)[CH2:15][CH2:16]1
Reactant: CC(CCC(=O)Nc1ccccc1C(=O)O)N1CCN(c2ccc3ccccc3n2)CC1
Reactant: CC(=O)OC(C)=O
Product: O=c1oc(CCCCN2CCN(c3ccc4ccccc4n3)CC2)nc2ccccc12
Temperature: 80 °C
Yield: 201.4 %

Procedure:
A mixture of 4.32 g of 2-[4-(4-quinolin-2-ylpiperazin-1-yl)-pentanoylamino]benzoic acid as synthesized in above Step 7-15-A and 3.06 g of acetic anhydride was stirred at 80° C. for an hour, and the solvent was distilled off under reduced pressure to provide 4.17 g (100%) of 2-[4-(4-quinolin-2-ylpiperazin-1-yl)butyl]-3,1-benzoxazin-4-one.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:16]=[C:15]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])[C:14]([C:23]3[CH:24]=[CH:25][C:26]4[O:39][CH2:38][N:29]5[C:30]6[CH:31]=[CH:32][CH:33]=[C:34]([F:37])[C:35]=6[CH:36]=[C:28]5[C:27]=4[N:40]=3)=[CH:13][C:7]=2[C:8]=1[C:9]([NH:11][CH3:12])=[O:10])(=O)[CH3:2].Cl.[CH3:42][O:43][NH2:44]>C(O)C.N1C=CC=CC=1>[F:37][C:34]1[C:35]2[CH:36]=[C:28]3[C:27]4[N:40]=[C:23]([C:14]5[C:15]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:19])=[O:20])=[CH:16][C:6]6[O:5][C:4](/[C:1](=[N:44]/[O:43][CH3:42])/[CH3:2])=[C:8]([C:9]([NH:11][CH3:12])=[O:10])[C:7]=6[CH:13]=5)[CH:24]=[CH:25][C:26]=4[O:39][CH2:38][N:29]3[C:30]=2[CH:31]=[CH:32][CH:33]=1
Reactant: CNC(=O)c1c(C(C)=O)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CNC(=O)c1c(/C(C)=N/OC)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Temperature: 70 °C
Reaction time: 2 h
Yield: 38.4 %

Procedure:
To a solution compound 2-acetyl-5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (50 mg, 0.088 mmol) in ethanol (1.5 mL) was added O-methylhydroxylamine hydrochloride (25 mg, 0.26 mmol) and 2 drops pyridine. The resulting mixture was stirred at 70° C. for 2 hours. The solvent was removed under reduced pressure and the residue was purified by prep-HPLC to give the product of (E)-5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(1-(methoxyimino)ethyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (20 mg, yield: 40%). 1H-NMR (CDCl3, 400 MHz) δ 9.56 (s, 1H), 8.65 (s, 1H), 7.67 (s, 1H), 7.48 (dd, J=10 Hz, 2H), 7.18˜7.23 (m, 2H), 7.10 (d, J=8.0 Hz, 1H), 6.84 (t, J=8.0 Hz, 1H), 5.99 (s, 2H), 4.12 (s, 3H), 3.41 (s, 3H), 2.99 (d, J=4.8 Hz, 3H), 2.66 (s, 3H), 2.41 (s, 3H). MS (M+H)+: 592.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH3:11])=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)([O-:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[N:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[CH2:51][CH2:52]O>O1CCCC1>[CH3:11][C:5]1[CH:6]=[C:7]([O:10][CH2:52][CH2:51][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][N:45]=2)[CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: OCCc1ccccn1
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(OCCc2ccccn2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-nitro-m-cresol (3.0 g, 0.020 mmol) and triphenylphosphine (7.7 g, 0.029 mmol) in tetrahydrofuran (50 mL) cooled with ice bath, diisopropyl azodicarboxylate (5.8 mL, 0.030 mmol) was added dropwise. The mixture was stirred at ambient temperature for 30 min. The reaction mixture was cooled with ice bath, and a solution of 2-pyridineethanol (2.6 mL, 0.024 mmol) in tetrahydrofuran (5.0 mL) was added dropwise to the reaction mixture then the mixture was stirred at ambient temperature for further 16 h. The solvent was removed under reduced pressure, then the residue was purified by chromatography on silica gel(hexane/ethyl acetate) to afford 2-methyl-4-[2-(2-pyridinyl)ethoxy]-1-nitrobenzene as solid (2.0 g, y. 40%).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH2:20])[O:16][C:15]3=[O:21])=[CH:10][C:9]=2[F:22])[CH2:4][CH2:3]1.C(OP([CH:31]([C:33]#[N:34])[CH3:32])(=O)OCC)C>>[C:33]([C:31](=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH2:20])[O:16][C:15]3=[O:21])=[CH:10][C:9]=2[F:22])[CH2:4][CH2:3]1)[CH3:32])#[N:34]
Reactant: CCOP(=O)(OCC)C(C)C#N
Reactant: NC[C@H]1CN(c2ccc(N3CCC(=O)CC3)c(F)c2)C(=O)O1
Product: CC(C#N)=C1CCN(c2ccc(N3C[C@H](CN)OC3=O)cc2F)CC1
Yield: 74 %

Procedure:
The compound was prepared by following the procedure of Example-1 and by using (S)-{3-[4-(4-oxo-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-amine and diethyl-(1-cyanoethyl)-phosphonate in 74% yield.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13](COCC[Si](C)(C)C)[C:12]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[C:33]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:24][CH2:23]3)=[N:11][C:10]=2[C:38](O)=[O:39])=[CH:5][CH:4]=1.[NH2:43][CH2:44][CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][N:46]1C(OC(C)(C)C)=O.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH:46]1[CH2:47][CH2:48][CH2:49][CH2:50][CH:45]1[CH2:44][NH:43][C:38]([C:10]1[N:11]=[C:12]([N:22]2[CH2:23][CH2:24][N:25]([C:28]3[C:33]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:31]=[CH:30][N:29]=3)[CH2:26][CH2:27]2)[NH:13][C:9]=1[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:42])[F:41])=[CH:8][CH:7]=1)=[O:39]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CN
Reactant: C[Si](C)(C)CCOCn1c(N2CCN(c3ncccc3C(F)(F)F)CC2)nc(C(=O)O)c1-c1ccc(C(F)(F)F)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCC1CCCCN1)c1nc(N2CCN(c3ncccc3C(F)(F)F)CC2)[nH]c1-c1ccc(C(F)(F)F)cc1

Procedure:
A mixture of 5-(4-(trifluoromethyl)phenyl)-2-(4-(3-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylic acid (300. mg, 0.487 mmol, Example 16(e)), tert-butyl 2-(aminomethyl)piperidine-1-carboxylate (209 mg, 0.974 mmol, Astatech), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (323 mg, 0.731 mmol, Aldrich), and DIEA (0.25 mL, 0.98 mmol, Aldrich) in DCM (3 mL) reacted under the condition of Example 16(f) to give the title compound as a light purple solid. MS (ESI, positive ion) m/z: 812 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:7])[CH2:6][CH2:5][CH2:4][NH:3]1.[CH:8]1([C:11]2[N:16]=[C:15]([C:17]([NH:19][C:20]3[CH:28]=[N:27][CH:26]=[CH:25][C:21]=3[C:22](O)=[O:23])=[O:18])[C:14]([NH:29][C:30]3[CH:31]=[N:32][CH:33]=[N:34][CH:35]=3)=[CH:13][CH:12]=2)[CH2:10][CH2:9]1>>[CH3:1][C:2]1([CH3:7])[CH2:6][CH2:5][CH2:4][N:3]1[C:22]([C:21]1[CH:25]=[CH:26][N:27]=[CH:28][C:20]=1[NH:19][C:17]([C:15]1[C:14]([NH:29][C:30]2[CH:31]=[N:32][CH:33]=[N:34][CH:35]=2)=[CH:13][CH:12]=[C:11]([CH:8]2[CH2:10][CH2:9]2)[N:16]=1)=[O:18])=[O:23]
Reactant: CC1(C)CCCN1
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Product: CC1(C)CCCN1C(=O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Yield: 23 %

Procedure:
According to the general method described in step 3 of example 53, reaction of 2,2-dimethylpyrrolidine with 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-isonicotinic acid provided the title compound (23%) as sticky yellow solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[Cl:9][CH:10]=[CH:11][CH2:12]Cl.[C:14]1([C@H:24]([NH2:26])[CH3:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1>C(O)(C)C>[Cl:9][CH:10]=[CH:11][CH2:12][NH:26][C@@H:24]([C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)[CH3:25]
Reactant: C[C@@H](N)c1cccc2ccccc12
Reactant: ClC=CCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Product: C[C@@H](NCC=CCl)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.7 %

Procedure:
Potassium carbonate (161.2 g) and potassium iodide (5 g) were added to the mixture of 1,3-dichloropropene (97.3 g) and (R)-1-(1-naphthyl)ethylamine (100 g) in isopropyl alcohol (500 mL) at room temperature. The reaction mixture was refluxed at 80° C. to 85° C. for about 4 hours. After the completion of the reaction, mixture was cooled to room temperature and filtered through hyflo bed. Hyflo bed was washed with isopropyl alcohol (500 mL). The filtrate was combined and treated with hydrochloric acid (6 Normal; 100 mL) at room temperature. The solution was allowed to stir for about one hour at room temperature to give solid. The solid was filtered and was washed twice with isopropyl alcohol (2×100 mL). Methanol (750 mL) was added to the wet solid and stirred for 10-15 minutes at room temperature. The pH of solution was adjusted to 11 to 12 using a solution of sodium hydroxide in water (20%). The solution was diluted with de-ionized water (750 mL) and extracted with dichloromethane (500 mL). Layers were separated and the organic layer was washed twice with de-ionized water (2×500 mL). The organic layer was completely concentrated under vacuum at 40° C. to 45° C. to give 3-chloro-N-[(1R)-1-(naphthalen-1-yl)ethyl]prop-2-en-1-amine as oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([NH:31]C(=O)OC(C)(C)C)[C:11]([N:13]1[CH2:30][CH2:29][CH2:28][C:15]2([C:19](=[O:20])[N:18]([CH3:21])[CH2:17][CH:16]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:14]1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:31][C@H:10]([CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:11]([N:13]1[CH2:30][CH2:29][CH2:28][C:15]2([C:19](=[O:20])[N:18]([CH3:21])[CH2:17][CH:16]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:14]1)=[O:12]
Reactant: CN1CC(c2ccccc2)C2(CCCN(C(=O)[C@@H](COCc3ccccc3)NC(=O)OC(C)(C)C)C2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CC(c2ccccc2)C2(CCCN(C(=O)[C@H](N)COCc3ccccc3)C2)C1=O

Procedure:
A mixture comprising tert-butyl (2R)-3-(benzyloxy)-1-(2-methyl-1-oxo-4-phenyl-2,7-diazaspiro[4.5]decan-7-yl)-1-oxopropan-2-ylcarbamate (500 mg, 0.959 mmol) and TFA (2.215 ml, 28.8 mmol) in DCM (5 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo. The crude was then diluted with DCM (10 mL) and washed with a saturated solution of sodium bicarbonate (10 mL). The aqueous phase was further extracted with DCM (3×10 mL). The combined organic portions were dried (MgSO4), and concentrated under reduced pressure to afford the title compound. No purification was performed on the title compound.
Reaction SMILES: [C:1]1([C:7]2([C:12](O)=[O:13])C[CH2:10][CH2:9][CH2:8]2)C=CC=[CH:3][CH:2]=1.[F:15][C:16]([F:34])([F:33])[C:17]1[CH:18]=[C:19]([CH:30]=[CH:31][CH:32]=1)[CH2:20][N:21]1[CH2:25][C@H:24]2[C@@H:26]([NH2:29])[CH2:27][CH2:28][C@H:23]2[CH2:22]1.C(N1C[C@H]2C(N)CC[C@H]2C1)C1C=CC=CC=1>>[CH2:1]([CH:7]([CH2:8][CH2:9][CH3:10])[C:12]([NH:29][C@@H:26]1[C@H:24]2[C@H:23]([CH2:22][N:21]([CH2:20][C:19]3[CH:30]=[CH:31][CH:32]=[C:17]([C:16]([F:33])([F:15])[F:34])[CH:18]=3)[CH2:25]2)[CH2:28][CH2:27]1)=[O:13])[CH2:2][CH3:3]
Reactant: N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21
Reactant: O=C(O)C1(c2ccccc2)CCCC1
Agent: NC1CC[C@H]2CN(Cc3ccccc3)C[C@@H]12
Product: CCCC(CCC)C(=O)N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21

Procedure:
The title compound was prepared by substituting 2-propylpentanoic acid for 1-phenylcyclopentanecarboxylic acid and (3aS*,4S*,6aR*)-2-(3-(trifluoromethyl)benzyl)octahydrocyclopenta[c]pyrrol-4-amine from Example 122 Step E for (3aS*,6aR*)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described for Example 1: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.94 (d, J=6.9, 1H), 7.72 (s, 1H), 7.62 (d, J=7.7, 1H), 7.56 (d, J=7.7, 1H), 7.47 (t, J=7.7, 1H), 4.48 (dt, J=7.3, 14.6, 1H), 3.52 (d, J=13.0, 1H), 3.48 (d, J=13.0, 1H), 2.84 (ddd, J=3.0, 7.7, 16.7, 1H), 2.74 (dd, J=3.1, 9.5, 1H), 2.52-2.45 (m, 1H), 2.38-2.34 (m, 2H), 2.27 (dd, J=7.6, 9.5, 1H), 2.22 (td, J=4.6, 9.5, 1H), 1.90 (dt, J=7.3, 11.5, 1H), 1.84-1.75 (m, 2H), 1.73-1.61 (m, 2H), 1.48-1.27 (m, 6H), 1.20-1.08 (m, 1H), 0.88 (t, J=7.0, 3H), 0.83 (t, J=7.1, 3H); MS (ESI+) m/z 411 (M+H)+.