Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[CH:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14](=[O:29])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:18][CH:17]=3)[CH:11]=2)[CH:6]=[N:5]1.[CH:30]1([NH2:35])[CH2:34][CH2:33][CH2:32][CH2:31]1.[BH3-]C#N.[Na+]>C1COCC1.C(OCC)(=O)C>[CH:30]1([NH:35][CH2:2][CH2:3][N:4]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14](=[O:29])[CH2:15][C:16]4[CH:17]=[CH:18][C:19]([O:22][C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=5)=[CH:20][CH:21]=4)[CH:11]=3)[CH:6]=[N:5]2)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: O=CCn1ncc2ccc(NC(=O)Cc3ccc(Oc4ccccc4)cc3)cc21
Reactant: NC1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Cc1ccc(Oc2ccccc2)cc1)Nc1ccc2cnn(CCNC3CCCC3)c2c1
Reaction time: 18 h

Procedure:
A mixture of N-[1-(2-oxoethyl)-1H-indazol-6-yl]-2-(4-phenoxyphenyl)acetamide (20 mg, 0.05 mmol) and cyclopentylamine (10 μL, 0.10 mmol) in THF (1 mL) was stirred at room temperature for 0.5 hours after which NaCNBH3 (0.104 mL, 0.010 mmol, 1 M in THF) was added and the mixture was stirred for an additional 18 hours. The mixture was diluted with ethyl acetate (2 mL), washed with H2O (1 mL), concentrated under reduced pressure and purified by reverse phase-HPLC to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.5 (m, 6 H), 1.9 (m, 2 H), 2.9 (m, 1 H), 3.4 (m, 2 H), 3.8 (m, 2 H), 4.6 (t, 2 H), 7.0 (m, 4 H), 7.1 (m, 2 H), 7.4 (m, 4 H), 7.7 (m, 1 H), 8.05 (s, 1 H), 8.3 (s, 1 H), 8.6 (m, 1 H), and 10.4 (s, 1 H); MS (ESI) 455.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:13])=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[C:14]([NH:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31]Cl)[CH2:25][CH2:24]1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>COC(O)C>[C:14]([NH:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31][O:1][C:2]2[CH:11]=[C:10]3[C:5]([C:6]([CH3:13])=[CH:7][C:8](=[O:12])[NH:9]3)=[CH:4][CH:3]=2)[CH2:25][CH2:24]1)(=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1cc(=O)[nH]c2cc(O)ccc12
Reactant: O=C(NC1CCN(CCCCl)CC1)c1ccccc1
Agent: COC(C)O
Product: Cc1cc(=O)[nH]c2cc(OCCCN3CCC(NC(=O)c4ccccc4)CC3)ccc12
Yield: 46 %

Procedure:
In a manner analogous to that described in Example 8, by the reaction of 7-hydroxy-4-methyl-2-oxo-1,2-dihydroquinoline with 3-(4-benzamido-piperidino)-propyl chloride in methoxyethanol, there is obtained, in a yield of 46% of theory, 7-[3-(4-benzamidopiperidino)-propoxy]-4-methyl-2-oxo-1,2-dihydroquinoline; m.p. 275°-276° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[F:15][C:16]1[CH:17]=[C:18]([Mg]Br)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]>C(OCC)C.O>[F:15][C:16]1[CH:17]=[C:18]([C:2]2([OH:1])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: COc1ccc([Mg]Br)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: O
Solvent: CCOCC
Product: COc1ccc(C2(O)CCN(C(=O)OC(C)(C)C)CC2)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.4 %

Procedure:
A stirred solution of tert-butyl 4-oxopiperidine-1-carboxylate (4.5 g, 22.6 mmol) in diethyl ether (100 mL) at 0° C. was treated with a solution of (3-fluoro-4-methoxyphenyl)magnesium bromide (49.7 mL, 24.8 mmol, 0.5 M in tetrahydrofuran). The reaction mixture was allowed to warm to rt and was stirred at for 12 h. It was then diluted with 100 mL water and the layers were separated. The aqueous layer was extracted three times with 150 mL of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was purified by silica gel chromatography (120 g column) eluting with 30% ethyl acetate in petroleum ether to obtain 6.5 g of tert-butyl 4-(3-fluoro-4-methoxyphenyl)-4-hydroxypiperidine-1-carboxylate as a clear liquid; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.33-1.47 (m, 11H) 1.52-1.61 (m, 2H) 1.69-1.84 (m, 2H) 3.03-3.22 (m, 2H) 3.77-3.89 (m, 6H) 5.09 (s, 1H) 7.10 (s, 1H) 7.17-7.26 (m, 1H) 7.25-7.33 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH2:7]2)[C:4](=[O:10])[C:3]=1[C:11]([C:13]1[C:14]([CH2:23][OH:24])=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=1)=[O:12].[H-].[Na+].[CH2:27]([CH:29]1[O:31][CH2:30]1)Br.Cl>CN(C)C=O.C(OCC)(=O)C>[OH:10][C:4]1[CH:5]2[CH2:9][CH:8]([CH2:7][CH2:6]2)[C:2](=[O:1])[C:3]=1[C:11]([C:13]1[C:14]([CH2:23][O:24][CH2:27][CH:29]2[CH2:30][O:31]2)=[N:15][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:17][CH:18]=1)=[O:12]
Reactant: BrCC1CO1
Reactant: O=C(C1=C(O)C2CCC(C2)C1=O)c1ccc(C(F)(F)F)nc1CO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(C1=C(O)C2CCC(C2)C1=O)c1ccc(C(F)(F)F)nc1COCC1CO1
Reaction time: 18 h

Procedure:
1.5 g of 4-hydroxy-3-(2-hydroxymethyl-6-trifluoromethylpyridine-3-carbonyl)-bicyclo[3.2.1]oct-3-en-2-one are dissolved in 15 ml of dimethylformamide and, at room temperature, treated with 0.4 g of sodium hydride (80% suspension in oil, 0.013 mol), a little at a time. After 15 minutes at a temperature of 22° C., 3 ml (0.036 mol) of epibromohydrin are added dropwise, and the reaction mixture is stirred at this temperature for another 18 hours. Ethyl acetate is then added, and the mixture is acidified to pH 3 using 10% hydrochloric acid and extracted with ethyl acetate. The organic phase is dried over sodium sulfate and the crude product is purified chromatographically (mobile phase: toluene/ethyl alcohol/dioxane/triethylamine/water 100:40:20:20:5 parts by volume). This gives the title compound (triethylamine salt) in the form of a yellowish resin, which is released similarly to example H4. Trituration with hexane gives 600 mg of pure 4-hydroxy-3-2-oxiranylmethoxymethyl-6-trifluoromethylpyridin-3-carbonyl)bicyclo[3.2.1]oct-3-en-2-one of melting point 54-56° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:12]3[N:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[N:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(OCC)(=O)C.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:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:3]=[C:4]([C:8]3[N:12]4[N:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[N:16][C:11]4=[N:10][CH:9]=3)[CH:5]=[CH:6][CH:7]=2)=[CH:23][CH:22]=1
Reactant: FC(F)(F)c1cnn2c(-c3cccc(Br)c3)cnc2n1
Reactant: OB(O)c1ccncc1
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
Product: FC(F)(F)c1cnn2c(-c3cccc(-c4ccncc4)c3)cnc2n1
Temperature: 65 °C
Reaction time: 12 h
Yield: 44.9 %

Procedure:
A mixture of 7-(3-bromophenyl)-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine (21 mg, 0.06 mmol), 4-pyridylboronic acid (11 mg, 0.09 mmol) and 2 M Na2CO3 (0.09 ml) in 1,2-dimethoxyethane (1.5 ml) was degassed with a stream of nitrogen for 10 min. Tetrakis(triphenylphosphine)palladium(0) (4 mg, 0.003 mmol) was added and the mixture was stirred under nitrogen at 65° C. for 12 h. After allowing to cool to room temperature, the mixture was diluted with ethyl acetate and partitioned between water (20 ml) and ethyl acetate (30 ml). The organic extracts were dried (MgSO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 5% MeOH/CH2Cl2) and triturated with diethyl ether to give 9.2 mg (44%) of the title compound: 1H NMR (400 MHz, CDCl3) δ 7.58 (2H, m), 7.70 (1H, t, J 7.3 Hz), 7.74-7.77 (1H, m), 8.13 (1H, dt, J 7.3, 1.6 Hz), 8.39 (1H, t, J 1.6 Hz), 8.68 (1H, s), 8.72 (2H, m), 8.83 (1H, s); MS (ES+) m/z 342 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13](Br)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:26][S:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:29])=[O:28].C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[CH3:8][N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:33]2[CH:34]=[CH:35][C:30]([S:27]([CH3:26])(=[O:29])=[O:28])=[CH:31][CH:32]=2)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[C:6](=[O:25])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(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: COCCOC
Solvent: O
Product: CN(Cc1cc(-c2ccc(S(C)(=O)=O)cc2)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 14 h
Yield: 54.4 %

Procedure:
A mixture of tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (430 mg), 4-(methanesulfonyl)phenylboronic acid (300 mg), tetrakis(triphenylphosphine)palladium (115 mg), sodium carbonate (320 mg), 1,2-dimethoxyethane (10 mL) and water (10 mL) was stirred under a nitrogen atmosphere at 80° C. for 14 hr. The reaction mixture was allowed to cool to room temperature, filtered through celite, and the filtrate was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=2:1→1:2) to give the title compound as an oil (yield 275 mg, 64%).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[C:13]([N:23]1[CH2:28][CH2:27][NH:26][CH:25]([C:29]([OH:31])=[O:30])[CH2:24]1)([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>>[C:13]([N:23]1[CH2:28][CH2:27][N:26]([C:2]2[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=2[N+:10]([O-:12])=[O:11])[CH:25]([C:29]([OH:31])=[O:30])[CH2:24]1)([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1Cl
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)CCN1
Product: O=C(O)C1CN(C(=O)OCc2ccccc2)CCN1c1c([N+](=O)[O-])ccc(Cl)c1Cl
Yield: 43.6 %

Procedure:
By the same procedure described for Example 7 A, from 0.86 g of 2,3,4-trichloronitro-benzene and 1.0 g of 4-carbobenzyloxypiperazine-2-carboxylic acid, there was obtained 0.75 g of the desired product as a brown oil.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH3:4].[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[O:15][C:14](=[O:16])[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:12]([OH:23])[C:11]=2[CH:24]=1.O>CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[O:15][C:14](=[O:16])[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:12]([O:23][CH2:1][CH2:2][CH2:3][CH3:4])[C:11]=2[CH:24]=1
Reactant: CCCCBr
Reactant: O=c1oc2ccc(Br)cc2c(O)c1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOc1c(-c2ccccc2)c(=O)oc2ccc(Br)cc12
Reaction time: 48 h

Procedure:
Butyl bromide (0.05 ml) was added with stirring to a mixture of a solution of 6-bromo-4-hydroxy-3-phenyl-2H-1-benzopyran-2-one (80 mg) (Synthesis 1993, 99), in dry dimethylformamide (0.5 ml) and potassium carbonate (70 mg). The mixture was stirred for 48 hours and water (5 ml) was added. The mixture was extracted with diethyl ether and the extract washed with water, dried and evaporated under reduced pressure. The residue was washed with water and dried to give 6-bromo-4-butoxy-3-phenyl-2H-1-benzopyran-2-one, m.p. 87-9° C. (compound 29)
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1/[C:10](=[N:21]/[O:22][CH3:23])/[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][CH:14]=1.[C:24]([CH:26]([C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1)[CH2:27][C:28]([O:30]C)=[O:29])#[N:25]>>[C:24]([CH:26]([C:32]1[CH:37]=[CH:36][C:35]([O:20][CH2:19][C:16]2[CH:15]=[CH:14][C:13]([O:12][CH2:11]/[C:10](/[C:2]3[CH2:1][C:9]4[C:4]([CH:3]=3)=[CH:5][CH:6]=[CH:7][CH:8]=4)=[N:21]\[O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:34][CH:33]=1)[CH2:27][C:28]([OH:30])=[O:29])#[N:25]
Reactant: CO/N=C(\COc1ccc(CO)cc1)C1=Cc2ccccc2C1
Reactant: COC(=O)CC(C#N)c1ccc(O)cc1
Product: CO/N=C(\COc1ccc(COc2ccc(C(C#N)CC(=O)O)cc2)cc1)C1=Cc2ccccc2C1
Yield: 20.5 %

Procedure:
Compound 101 was synthesized from (4-{[(2Z)-2-(1H-inden-2-yl)-2-(methoxyimino)ethyl]oxy}phenyl)methanol (0.079 g, 0.4 mmol) and methyl 3-cyano-3-(4-hydroxyphenyl)propanoate (0.11 g, 0.4 mmol) by following the procedure described in scheme 5 (0.008 g, yield: 20.5%); Purity: 97.17%.
Reaction SMILES: C([Li:5])CCC.[CH2:6]([C:10]1[CH:19]=[CH:18][C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[N:11]=1)[CH2:7][CH2:8][CH3:9]>>[CH2:6]([C:10]1[CH:19]=[CH:18][C:17]2[CH2:16][CH2:15][CH2:14][CH:13]([Li:5])[C:12]=2[N:11]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCc1ccc2c(n1)CCCC2
Reactant: [Li]CCCC
Product: [Li]C1CCCc2ccc(CCCC)nc21

Procedure:
By the method described in Example 7 using n-butyl lithium solution (9% w/v, 13.5 g, 0.03 mol) and 2-n-butyl-5,6,7,8-tetrahydroquinoline (6 g., 0.03 mol) the title compound is prepared and converted in situ to methyl 2-n-butyl-5,6,7,8-tetrahydroquinoline-8-carboxylate and then to the corresponding 8-thioamide by the procedure described in U.S. Ser. No. 460,265.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][N:18]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[C:35]=2[Cl:44])[CH2:19][CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:9]=1)(C)(C)C.C(Cl)[Cl:47].FC(F)(F)C(O)=O>CCOCC.Cl>[ClH:44].[ClH:47].[Cl:44][C:35]1[C:36]([C:40]([F:41])([F:42])[F:43])=[CH:37][CH:38]=[CH:39][C:34]=1[CH2:33][N:18]([CH2:19][CH:20]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:17][CH2:16][CH2:15][O:14][C:10]1[CH:9]=[C:8]([NH2:7])[CH:13]=[CH:12][CH:11]=1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)Nc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Agent: Cl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: Nc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1

Procedure:
(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-carbamic acid tert-butyl ester, (0.51 g, 0.8 mmol) was stirred overnight at room temperature in a mixture methylene chloride (5 mL) and trifluoroacetic acid (0.5 mL). The solvents were removed in vacuo to yield the crude amine as an oil. The oil was diluted with ether, and 1 N HCl in Et2O was added to precipitate the HCl salt of the product. The title compound was isolated as a cream yellow powder, 0.53 g (100%). MS (ESI) 539 (M+H+).
Reaction SMILES: [CH3:1][C@@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[F:21][C:22]([F:37])([F:36])[C:23]1[CH:24]=[C:25]([N:33]=[C:34]=[O:35])[CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1.Cl>CN(C)C1C=CN=CC=1.ClCCl>[F:21][C:22]([F:36])([F:37])[C:23]1[CH:24]=[C:25]([NH:33][C:34]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:35])[CH:26]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:28]=1
Reactant: CC1(C)C2CC[C@]1(C)C(=O)CC2=O
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C2CC[C@]1(C)C(=O)C(C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C2=O
Temperature: 30 °C
Reaction time: 8 h
Yield: 41.3 %

Procedure:
To an ice-cooled solution of (1S)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.36 g, 2.0 mmole), triethylamine (0.20 g, 2.0 mmole) and 4-(dimethylamino)pyridine (0.24 g, 2.0 mmole) in dry dichloromethane (25 mL) was added a solution of 3,5-bis-(trifluoromethyl)phenyl isocyanate (0.51 g, 2.0 mmole) in dry dichloromethane (5 mL). The resulting mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature, and then was heated at 30° C. for 7 hours. The reaction mixture was treated with 2N aqueous HCl and the layers separated. The acidic aqueous layer was extracted with two additional portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give a yellow oil, which was purified by chromatography on silica gel (10% ethyl acetate/hexane) to yield a yellow oil, which was crystallized from 95% ethanol to yield the title compound as a beige solid (0.36 g, 42% yield), mp=68–72° C.; MS (−) ESI m/z=434 (M−H)−; [α]D25=−21.0° (c=1, EtOH).
Reaction SMILES: [CH2:1]([C:3]#[CH:4])[CH3:2].C([Li])CCC.[CH3:10][O:11][C:12]([CH:14]1[CH2:18][C:17](=[O:19])[CH2:16][N:15]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:13]>C1COCC1>[CH3:10][O:11][C:12]([CH:14]1[CH2:18][C:17]([CH2:2][CH2:1][CH2:3][CH3:4])([OH:19])[CH2:16][N:15]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:13]
Reactant: COC(=O)C1CC(=O)CN1C(=O)OC(C)(C)C
Reactant: C#CCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCC1(O)CC(C(=O)OC)N(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To ethyl acetylene (140 mg, 2.6 mmol) in THF (5 mL) at −78° C., n-butyllithium (1.1 mL, 2.6 mmol) was added with stirring at −78° C. for 1 hour. Then 4-oxo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (prepared as described in the example 56) (570 mg, 2.3 mmol) in THF (5 mL) was added at −78° C. with stirring for 2 h, the reaction mixture was then allowed to warm to −40° C. over 1 hour. The reaction mixture was extracted with EtOAc (20 mL), washed with saturated NH4Cl (5 mL) and dried over sodium sulfate. Purification of the crude product was carried out by silica gel chromatography using 50% EtOAc in hexane to obtain the 4-butyl4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (520 mg, 73%). To the DAST (556 mg, 3.4 mmol) in DCM (5 mL) at −78° C., was added a solution of the above ester (520 mg, 1.7 mmol) in DCM (5 mL) at −78° C. and stirred for 1 hour. The reaction mixture was extracted with DCM (50 mL) and washed with NaHCO3 (30 mL, 10%). The product obtained after removal of solvent was purified by silica gel chromatography using 5% EtOAc in hexanes to obtain 4-butyl-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (276 mg, 52%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[CH:7][C:8]#[N:9])=[CH:4][CH:3]=1.C(O)C.[NH:15]([C:17]1[S:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1)[NH2:16].OCC[N+](C)(C)C>CO>[NH2:9][C:8]1[CH2:7][CH:6]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:11][CH:10]=2)[N:15]([C:17]2[S:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[N:21]=2)[N:16]=1
Reactant: N#CC=Cc1ccc(Cl)cc1
Reactant: NNc1nc2ccccc2s1
Agent: C[N+](C)(C)CCO
Solvent: CCO
Solvent: CO
Product: NC1=NN(c2nc3ccccc3s2)C(c2ccc(Cl)cc2)C1

Procedure:
A mixture of 3.28 g. of p-chlorocinnamonitrile, 50 ml. of absolute ethanol, 3.1 g. of 2-hydrazinobenzothiazole and 1.0 g. of 50% w/v choline in methanol is refluxed on a steam bath for 16 hours. The reaction mixture is cooled and the precipitate is collected by filtration. The solid is washed with ethanol to yield 3.2 g. of crude product. This material is recrystallized from acetone to give 1.65 g. of the product of the Example as yellow crystals, m.p. 273°-275° C.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)=[N:15][N:16]4[C:21]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH2:27])=[CH:20][CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[P:43](Cl)([O:48][CH2:49][CH3:50])([O:45][CH2:46][CH3:47])=[O:44]>ClCCl>[CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:28]4[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=4)=[N:15][N:16]4[C:21]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][P:43]([O:48][CH2:49][CH3:50])([O:45][CH2:46][CH3:47])=[O:44])=[CH:20][CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOP(=O)(Cl)OCC
Reactant: COc1ccc(-c2nn3c(NCCCCN)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOP(=O)(NCCCCNc1cccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(OC)cc3)nn12)OCC
Yield: 81 %

Procedure:
To a cold (0° C.) solution of N-[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]butane-1,4-diamine (21 mg, 0.04 mmol) in dichloromethane (3 mL) was added triethylamine (0.1 mL), and diethyl chlorophosphate (0.1 mL of a stock solution prepared from 0.1 mL of diethyl chlorophosphate in 3 mL of dichloromethane). The resultant solution was stirred for 3 hours at 0° C. and then quenched by the addition of saturated aqueous sodium bicarbonate. The organic layer was washed with brine. The aqueous layer was extracted with dichloromethane and the combined organics were dried over sodium sulfate. Filtration and concentration followed by flash chromatography (5% methanol in dichloromethane) provided diethyl 4-{[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butylamidophosphate (22 mg, 81%) as a yellow solid. 1H NMR (CDCl3): δ 7.98 (d, 1 H), 7.76 (d, 1 H), 7.55 (d, 2 H), 7.28 (m, 1 H), 6.96 (d, 2 H), 6.31 (d, 1 H), 6.06 (m, 1 H), 5.97 (d, 1 H), 5.11 (d, 1 H), 4.34 (m, 1 H), 4.09–3.98 (m, 4 H), 3.86 (s, 3 H), 3.37 (m, 2 H), 2.95 (m, 2 H), 2.64 (m, 1 H), 2.11–1.48 (m, 12 H), 1.31–1.27 (m, 6 H); MS m/z 608 (M+1).
Reaction SMILES: [OH:1][CH2:2]/[C:3](/[CH2:13][CH2:14]/[CH:15]=[C:16](\[CH3:23])/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[CH:4]/[CH2:5][CH2:6]/[C:7](/[CH3:12])=[CH:8]\[C:9]([OH:11])=O.Cl.[CH2:25]([NH2:27])[CH3:26].C(N(CC)CC)C>CN(C)C=O>[CH2:25]([NH:27][C:9](=[O:11])/[CH:8]=[C:7](/[CH3:12])\[CH2:6][CH2:5]/[CH:4]=[C:3](/[CH2:2][OH:1])\[CH2:13][CH2:14]/[CH:15]=[C:16](\[CH3:23])/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])[CH3:26]
Reactant: CCN
Reactant: CC(C)=CCC/C(C)=C/CC/C(=C\CC/C(C)=C\C(=O)O)CO
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCNC(=O)/C=C(/C)CC/C=C(/CO)CC/C=C(\C)CCC=C(C)C

Procedure:
Following the same manner as in Example 9, the reaction and after-treatment were conducted by using 1.1 g of (E,Z,E), (E,E,E), (Z,Z,E) and (Z,E,E)-7-hydroxymethyl-3,11,15-trimethyl-2,6,10,14-hexadecatetraenoic acid, 350 mg of ethylamine hydrochloride, 0.80 ml of diphenylphosphoric acid azide and 1.0 ml of triethylamine in 6.0 ml of N,N-dimethylformamide to afford 780 mg of the end product.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])[N:3]=1.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>>[Cl:8][C:6]1[CH:7]=[C:2]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[N:3]=[C:4]([NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])[N:5]=1
Reactant: C1CCNC1
Reactant: CC(C)(C)Nc1nc(Cl)cc(Cl)n1
Product: CC(C)(C)Nc1nc(Cl)cc(N2CCCC2)n1
Yield: 93 %

Procedure:
4,6-Dichloro-2-(1,1-dimethylethylamino)pyrimidine is reacted with pyrrolidine as described in Example 28 to give the title compound in a yield of 93%, m p.: 153°-157° C.