Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[CH2:5]([NH:7][C:8]1N=C(NCC)N=[C:10](Cl)[N:9]=1)[CH3:6].[OH-].[Na+].Cl>O1CCOCC1.O>[CH2:5]([NH:7][C:8]1[N:9]=[CH:10][N:4]=[C:2]([SH:3])[N:1]=1)[CH3:6]
Reactant: NC(N)=S
Reactant: CCNc1nc(Cl)nc(NCC)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCNc1ncnc(S)n1
Reaction time: 2 h

Procedure:
A mixture of 1.5 g of thiourea and 4 g of 2,4-bis(ethylamino)-6-chloro-1,3,5-triazine in a mixture of 20 ml of dioxane and 20 ml of water is refluxed with stirring for 2 hours in 100 ml flask. After cooling, the mixture is mixed with 1.6 g of 50% sodium hydroxide and stirred for 10 minutes. The resulting mixture is neutralized with hydrochloric acid and extracted with ethyl acetate. The extract is concentrated under reduced pressure to give 4 g of 2,4-bis(ethylamino-6-mercapto-1,3,5-triazine. The product can be used for preparation of the objective compound without isolation.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][N:7]=[C:8]([C:11]3[O:12][C:13]([CH3:16])=[N:14][N:15]=3)[CH:9]=2)[O:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O>>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:2]1[C:10]2[C:5](=[CH:6][N:7]=[C:8]([C:11]3[O:12][C:13]([CH3:16])=[N:14][N:15]=3)[CH:9]=2)[O:4][CH:3]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: Cc1nnc(-c2cc3c(Br)coc3cn2)o1
Product: Cc1nnc(-c2cc3c(-c4ccccc4Cl)coc3cn2)o1
Yield: 21 %

Procedure:
In the same manner as in Example 132 and using 3-bromo-5-(5-methyl-1,3,4-oxadiazol-2-yl)furo[2,3-c]pyridine instead of 2-(3-bromo-1-benzofuran-5-yl)-5-methyl-1,3,4-oxadiazole and using (2-chlorophenyl)boronic acid instead of (4-fluorophenyl)boronic acid, the title compound (yield 21%) was obtained as colorless crystals.
Reaction SMILES: P([O-])(OC1C=CC=CC=1)OC1C=CC=CC=1.[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)O>N1C=CC=CC=1>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1Cl
Reactant: c1c[nH]cn1
Agent: [O-]P(Oc1ccccc1)Oc1ccccc1
Solvent: c1ccncc1
Product: Clc1ccccc1C(c1ccccc1)(c1ccccc1)n1ccnc1
Yield: 78.2 %

Procedure:
A mixture of pyridine (15 ml), diphenyl phosphite (2.34 g), imidazole (0.68 g) and o-chlorophenyldiphenylmethanol (2.36 g) obtained in Example 1 (B) was refluxed for 3 hours. The reaction mixture was treated in the same manner as in Example 1 (C) to give 2.16 g of 1-(o-chlorophenyldiphenylmethyl)imidazole. Yield, 78.3%. M.P., 142°-143° C.
Reaction SMILES: [C:1]1([C:7]([NH:20][CH:21]2[CH:24]([S:25][CH2:26][C:27]#[C:28][CH3:29])[NH:23][C:22]2=[O:30])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:31]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])(=[O:34])[CH:32]=[O:33].O>C1C=CC=CC=1>[OH:33][CH:32]([N:23]1[CH:24]([S:25][CH2:26][C:27]#[C:28][CH3:29])[CH:21]([NH:20][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:22]1=[O:30])[C:31]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]
Reactant: CC#CCSC1NC(=O)C1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)C=O
Solvent: O
Solvent: c1ccccc1
Product: CC#CCSC1C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N1C(O)C(=O)OC(C)(C)C
Yield: 72.2 %

Procedure:
3-(Triphenylmethylamino)-4-(but-2-ynylthio)azetidin-2-one (1.03g) and t-butyl glyoxalate (3.3g) were refluxed in dry benzene (50ml) with provision for the removal of water. After one hour the benzene solution was washed 5 times with water, dried and evaporated. Chromatography of the residue on silica -H gave 1-(1-hydroxy-1-t-butoxycarbonylmethyl)-3-(triphenylmethylamino)-4-(but-2-ynylthio)azetidin-2-one as an amorphous white solid (0.978 g) νmax (CHCl3) 3400, 1765, 1730 cm-1.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:16][C:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH:14]=2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.Br[C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH:3]1[CH2:16][C:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH:14]=2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1)[C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=1
Reactant: CNC1CCC2(C)C(=CCC3C2CCC24CN(C)C(C)C2CCC34)C1
Reactant: N#Cc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC1C2CCC3C4CC=C5CC(N(C)c6ccc(C#N)cc6)CCC5(C)C4CCC32CN1C
Temperature: 100 °C
Yield: 46.6 %

Procedure:
Compound 7B (20 mg, 0.058 mmol), 4-bromobenzonitrile (16 mg, 0.088 mmol), tris(dibenzylideneacetone)dipallidium (2.1 mg, 0.0023 mmol), racemic-2,2′- bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) (2.2 mg, 0.0035 mmol), cesium carbonate (29 mg, 0.088 mmol) and toluene (1 mL) were mixed and heated at 100° C. overnight. The reaction mixture was cooled, quenched with water, and extracted with dichloromethane 3×. Combined organic layer was dried over sodium sulfate, filtered and concentrated to give the crude product, which was then purified on silica gel column which was eluted with 0.3% ammonium hydroxide and 3% methanol in dichloromethane to give the desired product (12 mg, 46% yield).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9](O)=[O:10].S(Cl)(Cl)=O.C1C=CC=CC=1.C[N:25](C)C=O>>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]([NH2:25])=[O:10]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cnccc1C(F)(F)F
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: NC(=O)c1cnccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution comprising 3 g of 4-trifluoromethyl-3-pyridine carboxylic acid, 6.7 ml of thionyl chloride and 20 ml of benzene, was refluxed under heating for 1.5 hours in the presence of a catalytic amount of dimethylformamide. Excess thionyl chloride and benzene were distilled off. Then, the residue was dissolved in 5 ml of ethyl acetate. This solution was gradually dropwise added to 20 ml of ammonia under cooling with ice. After completion Of the dropwise addition, the mixture was stirred at room temperature for 30 minutes. Then, water and ethyl acetate were distilled off under reduced pressure. The residue was extracted with heated ethyl acetate to obtain 2.1 g of 4-trifluoromethyl-3-pyridine carboxamide (melting point: 162.7° C.) as the desired product.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH:23]1([CH:26]([C:28]2[S:29][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([NH:39][C:40]4[N:45]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:43]=[CH:42][N:41]=4)[CH:34]=3)=[CH:31][N:32]=2)[OH:27])[CH2:25][CH2:24]1>ClCCl.C(OCC)(=O)C>[CH:23]1([C:26]([C:28]2[S:29][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([NH:39][C:40]4[N:45]=[C:44]([C:46]([F:47])([F:48])[F:49])[CH:43]=[CH:42][N:41]=4)[CH:34]=3)=[CH:31][N:32]=2)=[O:27])[CH2:25][CH2:24]1
Reactant: OC(c1ncc(-c2cccc(Nc3nccc(C(F)(F)F)n3)c2)s1)C1CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(c1ncc(-c2cccc(Nc3nccc(C(F)(F)F)n3)c2)s1)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.7 %

Procedure:
Dess-Martin periodinane (110 mg, 0.260 mmol) was added to a stirred, cooled (room temperature) mixture of cyclopropyl[5-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]methanol (Example 4A-5, 85 mg, 0.217 mmol) in dichloromethane (0.72 mL) and the mixture was stirred at room temperature for 30 min. The mixture was cooled, diluted with ethyl acetate, washed with aqueous sodium sulfite then brine, dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography to give cyclopropyl[5-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]methanone (43 mg, 0.110 mmol, 50.8%) as a colorless solid. APCI: [M+H]+ m/z 391.0. 1H NMR (400 MHz, CDCl3): δ 8.71 (d, J=4.90, 1H), 8.26 (s, 1H), 8.24 (s, 1H), 7.58-7.50 (m, 2H), 7.46 (t, J=7.87, 1H), 7.42-7.38 (m, 1H), 7.13 (d, J=4.91, 1H), 3.28-3.23 (m, 1H), 1.39-1.34 (m, 2H), 1.22-1.17 (m, 2H). rhSYK activity=+++
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH2:9]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C=O.C1N2CN3CN(C2)CN1C3.C1([OH:43])C=CC=CC=1>>[CH2:1]=[O:2].[C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH3:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:18]1[CH:23]=[CH:22][C:21]([OH:43])=[CH:20][CH:19]=1
Reactant: CCCCCCCCCc1ccccc1O
Reactant: Oc1ccccc1
Agent: C1N2CN3CN1CN(C2)C3
Agent: C=O
Agent: Oc1cccc(O)c1
Product: CCCCCCCCCc1ccc(O)cc1

Procedure:
Resorcinol and nonyl phenol are reacted with formaldehyde in the presence of a catalytic amount of hexamethylenetetramine at a total phenol:formaldehyde molar ratio of 1.7:1 to afford a novolak cocondensate resin (97 mole % resorcinol/3 mole % nonylphenol). The solid resin is washed to remove formaldehyde odor. The wet resin is dried under vacuum. The dry resin is dispersed in water with sodium caseinate at 40% N.V. to afford Emulsion A.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].[CH2:13]([N:15](CC)[CH2:16]C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CNC.O1CCCC1>C(#N)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([N:15]([CH3:16])[CH3:13])=[O:8]
Reactant: COc1ncc(Br)cc1C(=O)O
Reactant: CCN(CC)CC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CC#N
Product: COc1ncc(Br)cc1C(=O)N(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 5-bromo-2-methoxynicotinic acid (80 mg, 0.34 mmol), triethylamine (192 μl, 1.38 mmol) and 2-(1 H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate in acetonitrile (1 mL) was added dimethylamine, 2 M in tetrahydrofuran (172 μl, 0.34 mmol). The reaction mixture was stirred at ambient temperature under an atmosphere of nitrogen for 3 h. The mixture was partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated in vacuo to give a crude product which was purified by column chromatography using a gradient of ethyl acetate in heptane affording 54 mg (60%) of the title compound as a white solid: 1H NMR (400 MHz, DMSO-d6) ppm 8.36 (d, 1 H), 7.91 (d, 1 H), 3.88 (s, 3 H), 2.96 (s, 3 H), 2.78 (s, 3 H); MS (ESI) m/z 259, 261[M+H+].
Reaction SMILES: [Li]CCCC.[CH3:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[C:12]([O:16][C:17]([N:19]1CCC[C@@H]1C=O)=[O:18])([CH3:15])([CH3:14])[CH3:13]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:12]([O:16][C:17]([N:19]1[CH2:11][CH2:10][CH2:9][C@@H:8]1[CH:7]=[CH2:6])=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C=O
Reactant: CCCCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=C[C@H]1CCCN1C(=O)OC(C)(C)C
Temperature: -78 °C
Yield: 78.5 %

Procedure:
A flask containing a suspension of methyltriphenylphosphonium bromide (24.04 g, 67.3. mmol) and THF (375 mL) is stirred under nitrogen at −78° C. To this was added a 2.5 M solution of nBuLi in hexane (26.92 mL, 67.3 mmol) over 1 h. A solution of 2-(R)-Formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (6.70 g, 33.65 mmol) in THF (30 mL) is added over 10 minutes and the reaction is warmed to RT. The reaction is quenched with H20 (180 mL) and the mixture concentrated. The residue is extracted with EtOAc (3×150 mL) and the combined extracts are dried over MgSO4 and concentrated. Purification by flash chromatography 20% EtOAc/Hexanes yields the title compound as a yellow oil (5.2 g, 26.4 mmol). 1H NMR (CDCl3, 300 MHz) 5.81-5.63(m, 1H), 5.03(d, 2H), 4.40-4.15(m, 1H), 3.45-3.25(m, 2H), 2.05-1.90(m, 1H), 1.89-1.75(m, 2H), 1.74-1.61(m, 1H), 1.43(s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C@H:8]2[CH2:13][CH2:12][C@H:11]([CH:14]=[CH2:15])[CH2:10][CH2:9]2)[CH:5]=[C:4]([F:16])[CH:3]=1.CCCCCC.C([Li])CCC.[C:28](=[O:30])=[O:29]>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([C@H:8]2[CH2:9][CH2:10][C@H:11]([CH:14]=[CH2:15])[CH2:12][CH2:13]2)[CH:5]=[C:4]([F:16])[C:3]=1[C:28]([OH:30])=[O:29]
Reactant: O=C=O
Reactant: C=C[C@H]1CC[C@H](c2cc(F)cc(F)c2)CC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=C[C@H]1CC[C@H](c2cc(F)c(C(=O)O)c(F)c2)CC1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
25 g of 1,3-difluoro-5-(trans-4-vinylcyclohexyl) benzene was dissolved in 100 ml of tetrahydrofuran, and then cooled to a temperature of −70° C. To the solution was then added dropwise 88 ml of a 1.53 mol/l n-hexane solution of n-butyllithium at a rate such that the liquid temperature was kept at −60° C. After 30 minutes of stirring, carbon dioxide was then introduced into the system at a rate such that the liquid temperature was kept at −60° C. When heat generation was terminated, the temperature of the reaction solution was returned to room temperature. To the reaction solution was then added 50 ml of a 10% hydrochloric acid. The reaction solution was then extracted with 250 ml of ethyl acetate. The resulting organic phase was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvents were then distilled off to obtain 28.9 g of 2,6-difluoro-4-(trans-4-vinylcyclohexyl)benzoic acid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][C:9]([Br:13])=[C:10]([C:11]#[N:12])[C:3]=12.C(O[CH:18]1[O:26][C@H:25]([CH2:27][O:28][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:24]([CH3:37])[C@H:19]1[O:20][C:21](=[O:23])[CH3:22])(=O)C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>C(#N)C.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]2[C:10]([C:11]#[N:12])=[C:9]([Br:13])[N:8]([C@@H:18]3[O:26][C@H:25]([CH2:27][O:28][C:29](=[O:36])[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C@@H:24]([CH3:37])[C@H:19]3[O:20][C:21](=[O:23])[CH3:22])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: N#Cc1c(Br)nc2[nH]cnc(N)c1-2
Reactant: CC(=O)OC1O[C@H](COC(=O)c2ccccc2)[C@@H](C)[C@H]1OC(C)=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)O[C@@H]1[C@H](C)[C@@H](COC(=O)c2ccccc2)O[C@H]1n1c(Br)c(C#N)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
BSA (0.29 mL, 2.0 mmol) was added into a stirred suspension of 4-amino-6-bromo-5-cyano-1H-pyrrolo[2,3-d]pyrimidine (0.24 g, 1 mmol; prepared according to Nucleic Acid Chemistry, Part IV, Townsend, L. B. and Tipson, R. S.; Ed.; Wiley-Interscience: New York, 1991, pp. 16–17 and Synthetic Commun. 1998, 28, 3835) in dry acetonitrile (10 mL) at room temperature under argon. After 15 min, 1,2-di-O-acetyl-5-O-benzoyl-3-deoxy-3-methyl-D-ribofuranose (J. Med. Chem. (1976), 19, 1265) (0.36 g, 1.0 mmol) was added along with TMSOTf (0.54 g, 3 mmol). The mixture was stirred at room temperature for 5 min and then at 80° C. for 0.5 h. The solution was cooled, diluted with ethyl acetate (50 mL) and poured into ice-cold saturated aqueous NaHCO3 (15 mL). The layers were separated. The organic layer was washed with brine (15 mL), dried (Na2SO4) and then evaporated. The residue was purified on silica gel column using a solvent system of hexanes/EtOAc: 3/1. Appropriate fractions were collected and evaporated to provide the title compound as colorless foam (0.21 g).
Reaction SMILES: [F:1][C:2]1([F:27])[C:4]2([C:11]3[N:16]=[C:15]4[N:17]([CH3:26])[C:18](=[O:25])[N:19]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:14]4=[CH:13][CH:12]=3)[CH2:5][CH:6]3[CH:10]([CH:3]12)[CH2:9][NH:8][CH2:7]3.[O:28]1[CH:32]=[CH:31][C:30]([C:33](O)=[O:34])=[N:29]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[F:27][C:2]1([F:1])[C:4]2([C:11]3[N:16]=[C:15]4[N:17]([CH3:26])[C:18](=[O:25])[N:19]([CH2:20][C:21]([CH3:24])([CH3:22])[CH3:23])[C:14]4=[CH:13][CH:12]=3)[CH2:5][CH:6]3[CH:10]([CH:3]12)[CH2:9][N:8]([C:33]([C:30]1[CH:31]=[CH:32][O:28][N:29]=1)=[O:34])[CH2:7]3
Reactant: O=C(O)c1ccon1
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(C34CC5CNCC5C3C4(F)F)nc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(C34CC5CN(C(=O)c6ccon6)CC5C3C4(F)F)nc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5-(4,4-Difluorooctahydro-4aH-cyclopropa[3,4]cyclopenta[1,2-c]pyrrol-4a-yl)-1-(2,2-dimethylpropyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (30-3, 50 mg, 0.14 mmol, 1.0 equiv), isoxazole-3-carboxylic acid (2-6, 22.5 mg, 0.20 mmol, 1.5 equiv), DIPEA (0.070 mL, 0.40 mmol, 3.0 equiv) and HATU (76 mg, 0.20 mmol, 1.5 equiv) were added to anhydrous acetonitrile (1 mL). After stirring for 10 min at room temperature, LCMS showed consumption of starting material. Purification by reverse-phase HPLC (20-100% CH3CN:0.1% TFA in H2O) provided 30-4 as a white solid. MS m/z (M+H): calculated=472.2155; observed=472.2153.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:14])[CH:12]=2)[NH:7][CH:6]=1.[N-:15]=[N+:16]=[N-:17].[Na+].O>CN(C)C=O>[N:15]([CH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:14])[CH:12]=2)[NH:7][CH:6]=1)=[N+:16]=[N-:17]
Reactant: Fc1ccc2[nH]cc(CCCBr)c2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCCc1c[nH]c2ccc(F)cc12
Yield: 91 %

Procedure:
A solution of 3-(3-bromopropyl)-5-flouro-1H-indole (0.95 g, 3 mmol) and sodium azide (0.59 g, 9 mmol) in anhydrous dimethyl formamide is stirred at 60° C. for 18 h, poured into water and extracted with methylene chloride. The extracts are combined, washed with water, dried over Na2SO4 and concentrated in vacuo. The resultant residue is purified by flash chromatography (silica gel, EtOAc/hexane: 3/7) to afford the title product as a clear oil, 0.98 g (91% yield), identified by NMR and mass spectral analyses.
Reaction SMILES: [H-].[Na+].[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>C1COCC1>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH:4]([C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6])[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH3:28]
Reactant: CCOC(=O)CCCCCBr
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CCCCCC(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.7 %

Procedure:
To a suspension of sodium hydride (0.11 g, 2.78 mmol) in THF (5 mL) at 0° C. was added a solution of di-tert-butyl malonate (0.53 mL, 0.5 g, 2.31 mmol) in THF (1.5 mL). The mixture was warmed to room temperature and stirred for 10 min. To the mixture was slowly added a solution of ethyl 6-bromohexanoate (0.42 mL, 0.52 g, 2.31 mmol) in THF (0.5 mL) and the mixture was stirred at 70° C. for 10 hours. After dilution of the mixture with ethyl acetate (10 mL), the solution was washed with water (20 mL) and brine (20 mL), dried over MgSO4 and evaporated. The residue was purified by chromatography on silica gel (80:20 petroleum ether 60-80° C.:ethyl acetate) to give the 2-tert-butoxycarbonyloctanedioate 1-tert-butyl ester 8-ethyl ester (14a) as a clear oil (0.61 g, 74%); Rf=0.33 (5:1 petroleum ether 60-80° C.:ethyl acetate); 1H NMR (300 MHz, CDCl3): δ 4.11 (2H, q, J=7.2 Hz, OCH2CH3), 3.37 (1H, t, J=5.7 Hz, COCH), 2.27 (2H, t, J=7.1 Hz, CH2CO), 1.87 (2H, br m, CHCH2CH2CH2CH2), 1.46 (2H, t, J=7.6 Hz, CHCH2), 1.37 (4H, br m, CHCH2CH2CH2), 1.22 (3H, t, J=7.2 Hz, OCH2CH3), 1.43 (18H, s, C(CH3)3); 13C NMR (75 MHz, CDCl3): δ 173.93 (CO), 173.93 (CO), 171.15 (CO), 61.14 (OCH2CH3), 51.66 (COCH), 33.89 (CH2CO), 29.44 (CH(CH3)3), 28.91 (CHCH2CH2CH2), 28.27 (CHCH2CH2), 26.83 (CHCH2CH2CH2CH2), 24.46 (CHCH2), 14.17 (OCH2CH3).
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][C:9](=O)[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][C:14]1[C:18]([C:19]#[N:20])=[C:17]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:23][CH2:22]2)[NH:16][N:15]=1.C(O)(=O)C>ClCCl>[CH3:10][C:9]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:15]2[N:16]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:23][CH2:22]3)[C:18]([C:19]#[N:20])=[C:14]2[N:13]=1
Reactant: N#Cc1c(N)n[nH]c1N1CCN(Cc2ccccc2)CC1
Reactant: CC(=O)CC(=O)c1ccccc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1cc(-c2ccccc2)n2nc(N3CCN(Cc4ccccc4)CC3)c(C#N)c2n1
Yield: 74.8 %

Procedure:
A mixture of 2.9 g (0.018 moles) of 1-phenyl-1,3-butanedione, 5.0 g (0.018 moles) of 3-amino-5-(4-phenylmethyl-1-piperazinyl)-4-pyrazolecarbonitrile (prepared as described in Example 1) and 25 ml of glacial acetic acid was refluxed for 4 hours. The reaction mixture was evaporated in vacuo and gave a thick oil. The oil was dissolved in dichloromethane and partitioned with saturated sodium bicarbonate. The organic layer was separated, dried over anhydrous sodium sulfate and passed through magnesium silicate. The solution was evaporated in vacuo and gave a yellow solid which was recrystallized from isopropanol and cyclohexane and gave 5.5 g of the desired product as a light yellow solid, mp 160°-164° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[CH:16]=[C:15]([CH2:17][OH:18])[CH:14]=[C:13]([NH:19][C:20]3[CH:25]=[N:24][CH:23]=[CH:22][N:21]=3)[N:12]=2)[CH3:9])=[CH:4][CH:3]=1.[C:26](Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[CH:16]=[C:15]([CH2:17][O:18][CH3:26])[CH:14]=[C:13]([NH:19][C:20]3[CH:25]=[N:24][CH:23]=[CH:22][N:21]=3)[N:12]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: C[C@H](Nc1cc(CO)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COCc1cc(Nc2cnccn2)nc(N[C@@H](C)c2ccc(F)cc2)c1
Reaction time: 0.5 h
Yield: 33.6 %

Procedure:
20 mg of (S)-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}methanol (Example 140) was dissolved in methylene chloride, and 59 mg of carbon tetrabromide and 47 mg of triphenylphosphine were added under ice-cooling, and the mixture was stirred for 30 minutes. Subsequently, 90 μl of 9.8M sodium methoxide/methanol solution was added thereto, and the mixture was stirred overnight. The reaction solution was diluted with ethyl acetate and was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled of f under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 7 mg of the objective compound as yellow powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6]([OH:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:18]([F:23])([F:22])C([O-])=O.[Na+]>CN(C=O)C.O>[Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6]([O:8][CH:18]([F:23])[F:22])[CH:7]=1
Reactant: N#Cc1ncc(O)cc1Cl
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ncc(OC(F)F)cc1Cl
Temperature: 100 °C

Procedure:
To a solution of 3-chloro-5-hydroxy-pyridine-2-carbonitrile (314 mg, 2.03 mmol) in DMF (10 ml) was added K2CO3 (841 mg, 6.09 mmol) and sodium chlorodifluoroacetate (1.29 g, 8.11 mmol) and the reaction mixture was heated at 100° C. for 10 min. The reaction mixture was diluted with H2O and extracted with TBME. Combined extracts were washed with brine, dried over MgSO4, filtered and concentrated. The title compound was obtained as a yellow oil after chromatography on silica gel (hexane-EtOAc 20:1 to 1:1) to provide the title compound as a light yellow oil: TLC (hexane-EtOAc 2:1): Rf=0.54;