Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1B(O)O>O1CCOCC1.O>[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:2])=[O:19])=[CH:13][CH:14]=1
Reactant: OB(O)c1ccco1
Reactant: COC(=O)c1cccc(COc2ccc(I)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cccc(COc2ccc(-c3ccco3)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-(4-iodo-phenoxymethyl)-benzoic acid methyl ester (of intermediate 1; 74 mg, 0.2 mmol) in dioxane/water (10:1, 4.4 mL) was degassed for 20 min and then added to a reaction vial containing potassium carbonate (82 mg, 0.6 mmol) and furan-2-boronic acid (0.6 mmol; available from Aldrich Chemical Company, Inc., Milwaukee, Wis.). The solution was degassed for a further 2 min and then bis(tri-cyclohexylphosphine)palladium (available from Strem Chemicals, Inc., Newburyport, Mass.; 14 mg, 0.02 mmol) was added. The mixture was degassed for 30 seconds and then heated in a microwave oven at 170 degrees for 25 min. The reaction mixture was filtered through silica and the silica washed with dioxane (1 mL), dimethylacetamide (1 mL), and 20% methanol in dichloromethane (1 mL). The filtrate was placed in a vial and 2 M potassium hydroxide solution (0.4 mL) was added. The mixture was stirred at room temperature overnight, and then 1 M HCl was added until a solid formed (approxiamtely 2 mL). The vial was centrifuged and the solvent was removed. The product was dried overnight in the oven. Mass spectrum MH+=295.
Reaction SMILES: Cl.[CH2:2]([CH2:4][NH2:5])[OH:3].[Na].[CH2:7]([Cl:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(O)(C)C>C1(C)C=CC=CC=1>[ClH:14].[C:8]1([CH2:7][O:3][CH2:2][CH2:4][NH2:5])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClCc1ccccc1
Reactant: NCCO
Agent: Cl
Agent: [Na]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: NCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethanolamine hydrochloride (20 g, 0.21 mol) in toluene (100 mL) was treated with sodium metal (pellets washed with hexane) (10.14 g, 0.44 mL). The reaction was refluxed until the sodium metal was no longer present. The mixture was cooled and benzyl chloride (24.17 mL, 0.21 mol) was added, the reaction was stirred at room temperature overnight. The reaction mixture was filtered and the solid washed with toluene. The filtrate was cooled to 0° C. and HCl gas was bubbled in for 10 minutes. A white precipitate was obtained and filtered. The solid was recrystallized using 70 mL of isopropyl alcohol (10.4 g, 0.056 mol); MS-CI 188 (m+1).
Reaction SMILES: C([O-])(=O)C.[Na+].[CH2:6]([O:8][C:9](=[O:23])[CH2:10][C:11](=O)[CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH3:7].[NH2:24][CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=O>O.C(O)C>[CH2:6]([O:8][C:9]([C:10]1[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:25][NH:24][C:11]=1[CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:23])[CH3:7]
Reactant: NCC(=O)c1ccccc1
Reactant: CCOC(=O)CC(=O)CCNC(=O)OC(C)(C)C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(-c2ccccc2)c[nH]c1CCNC(=O)OC(C)(C)C
Reaction time: 0.08 h
Yield: 95.5 %

Procedure:
A stirred solution of anhydrous sodium acetate (2.66 g, 82 mmol) in 140 ml of water was added with the solution of 5-tert-butoxycarbonylamino-3-oxo-pentanoic acid ethyl ester (4.20 g, 16.2 mmol) in 20 ml of absolute ethanol at room temperature. Upon completion of the addition, the mixture was stirred for 5 minutes, added with 2-amino-1-phenyl-ethanone (2.5 g, 14.6 mmol) and heated to reflux for 3 hours. The resulting mixture was added with water (300 ml), extracted with ethyl acetate (100 ml×3). The organic extracts were washed with brine (50 ml×3), dried with anhydrous sodium sulfate, filtered and concentrated to give 2-(2-tert-butoxycarbonylamino-ethyl)-4-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester (5.0 g, 88.7%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:20]([CH3:21])[C:11]3=[N:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=[C:10]3[N:9]=2)=[C:4]([S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:32]1[N:37]=[CH:36][CH:35]=[CH:34][N:33]=1)CCC.C1(C)C=CC=CC=1>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>[CH2:25]([S:22]([C:4]1[CH:3]=[C:2]([C:32]2[N:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[CH:7]=[CH:6][C:5]=1[C:8]1[N:20]([CH3:21])[C:11]2=[N:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=[C:10]2[N:9]=1)(=[O:24])=[O:23])[CH3:26]
Reactant: CCS(=O)(=O)c1cc(Br)ccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCS(=O)(=O)c1cc(-c2ncccn2)ccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 25 °C
Yield: 100.2 %

Procedure:
A mixture of 2-(4-bromo-2-ethylsulfonylphenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (0.20 g), 2-tributylstannylpyrimidine (0.17 g), tetrakis(triphenylphosphine)palladium (27 mg) and toluene (5 ml) was heated at reflux under nitrogen atmosphere for 5.5 hours. After the mixture was cooled to room temperature, to the mixture, 2-tributylstannylpyrimidine (0.17 g) and tetrakis(triphenylphosphine)palladium (27 mg) were added, and stirred under reflux for further 8 hours. After the mixture was cooled to room temperature, water was poured thereinto, and extracted with ethyl acetate. The combined organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.20 g of 2-[2-ethylsulfonyl-4-(pyrimidine-2-yl)-phenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter, Present Compound 333).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH:22]=O)[C:8]([F:11])=[CH:9][CH:10]=1.[CH2:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@H:27]([NH2:34])[C@@H:26]1[OH:35]>>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][C:13]=2[CH2:22][NH:34][C@H:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:25][C@H:26]2[OH:35])[C:8]([F:11])=[CH:9][CH:10]=1
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Reactant: COC(=O)Cc1ccc(F)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Product: COC(=O)Cc1ccc(F)c(-c2ccc(C(F)(F)F)cc2CN[C@H]2c3ccccc3C[C@H]2O)c1

Procedure:
Prepared according to the procedure described in Example 25, Step 4, using the following starting materials: (6-fluoro-2′-formyl-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and (1S,2R)-(−)-cis-1-amino-2-indanol.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:20]([OH:22])=[O:21])=[C:11]([CH3:19])[C:12]([O:15][CH:16]([CH3:18])[CH3:17])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:24]>C(Cl)Cl.CO>[CH2:1]([O:8][C:9]1[C:10]([C:20]([O:22][CH3:24])=[O:21])=[C:11]([CH3:19])[C:12]([O:15][CH:16]([CH3:18])[CH3:17])=[N:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Cc1c(OC(C)C)ncc(OCc2ccccc2)c1C(=O)O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1c(OCc2ccccc2)cnc(OC(C)C)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.2 %

Procedure:
To a solution of 5-(benzyloxy)-3-methyl-2-(propan-2-yloxy)pyridine-4-carboxylic acid (131a, 1.4 g, 4.7 mmol) in dry CH2Cl2 (50 mL) and dry MeOH (5 mL) was added dropwise TMSCHN2 (2.6 mL, 5.1 mmol, 2M in hexane) at 0° C. under N2. The reaction mixture was stirred at room temperature for 2 hours then concentrated under vacuum. The residue was purified by column chromatography (petroleum ether/EtOAc, 10/1) to give methyl 5-(benzyloxy)-3-methyl-2-(propan-2-yloxy)pyridine-4-carboxylate (131b, 1.1 g, 75%) as a colorless oil.
Reaction SMILES: C([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7]([OH:9])=O)(=O)C.[F:14][C:15]([F:25])([F:24])[C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1>>[F:14][C:15]([F:24])([F:25])[C:16]1[CH:17]=[CH:18][C:19]([CH2:20][NH:21][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[OH:4])=[CH:22][CH:23]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: CC(=O)Oc1ccccc1C(=O)O
Product: O=C(NCc1ccc(C(F)(F)F)cc1)c1ccccc1O

Procedure:
This compound was obtained as a white solid starting from acetylsalicyclic acid and 4-trifluoromethylbenzylamine using the same procedure described in example 5.
Reaction SMILES: [CH2:1]([NH2:8])C1C=CC=CC=1.Cl.CN.[C:12]([C:15]1[S:19][C:18]([N:20]2[CH2:24][CH2:23][N:22]([CH2:25][C:26]3[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=3)[C:29]([OH:31])=O)[C:21]2=[O:35])=[N:17][C:16]=1[CH3:36])(=[O:14])[CH3:13]>>[C:12]([C:15]1[S:19][C:18]([N:20]2[CH2:24][CH2:23][N:22]([CH2:25][C:26]3[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=3)[C:29]([NH:8][CH3:1])=[O:31])[C:21]2=[O:35])=[N:17][C:16]=1[CH3:36])(=[O:14])[CH3:13]
Reactant: CC(=O)c1sc(N2CCN(Cc3cccc(C(=O)O)c3)C2=O)nc1C
Reactant: NCc1ccccc1
Agent: CN
Agent: Cl
Product: CNC(=O)c1cccc(CN2CCN(c3nc(C)c(C(C)=O)s3)C2=O)c1
Yield: 85 %

Procedure:
Following the procedure as describe in Example 8, making variations as required to replace benzylamine with methylamine monohydrochloride to react with 3-((3-(5-acetyl-4-methylthiazol-2-yl)-2-oxoimidazolidin-1-yl)methyl)benzoic acid, the title compound was obtained as a white powder in 85% yield: 1H NMR (300 MHz, CDCl3) δ 7.73-7.62 (m, 2H), 7.42-7.34 (m, 2H), 6.32 (br s, 1H), 4.51 (s, 2H), 4.13-4.04 (m, 2H), 3.49-3.41 (m, 2H), 2.97 (d, J=4.8 Hz, 3H), 2.60 (s, 3H), 2.45 (s, 3H): MS (ES+) m/z 373.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([OH:13])=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=[N:9]1.[C:19](N1C=CN=C1)(N1C=CN=C1)=[S:20]>O1CCCC1>[O:13]=[C:12]1[N:8]2[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH:1][C:19](=[S:20])[N:9]2[CH:10]=[C:11]1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)c1cnn(-c2ccccc2N)c1O
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cn2c(=S)[nH]c3ccccc3n2c1=O
Yield: 84.8 %

Procedure:
2.47 g 1-(2-aminophenyl)-5-hydroxy-1H-pyrazole-4-carboxylic acid, ethyl ester and 1.78 g 1,1'-thiocarbonyl-bis-[1H-imidazole] are dissolved in 50 ml tetrahydrofuran and heated for 8 hours. The residue, after distilling off the solvent, is recrystallized from dimethylformamide to yield 2.45 g of 5,6-dihydro-1-oxo-5-thioxo-1H-pyrazolo[1,2-a][1,2,4]benzotriazine-2-carboxylic acid, ethyl ester having a melting point of 277°-282° C.; yellow needles.
Reaction SMILES: [CH3:1][C:2]([CH3:20])=[CH:3][CH2:4][C@H:5]1[O:7][C@@:6]1([C@@H:9]1[C@:14]2([O:16][CH2:15]2)[CH2:13][CH2:12][C@@H:11]([OH:17])[C@H:10]1[O:18][CH3:19])[CH3:8].[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>>[O:7]1[CH:5]([CH2:4][CH:3]=[C:2]([CH3:20])[CH3:1])[C:6]1([CH:9]1[CH:10]([O:18][CH3:19])[CH:11]([OH:17])[CH2:12][CH2:13][C:14]1([CH2:15][N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)[OH:16])[CH3:8]
Reactant: C1CCNC1
Reactant: CO[C@@H]1[C@H](O)CC[C@]2(CO2)[C@H]1[C@@]1(C)O[C@@H]1CC=C(C)C
Product: COC1C(O)CCC(O)(CN2CCCC2)C1C1(C)OC1CC=C(C)C
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Fumagillol (500 mg) was dissolved in pyrrolidine (1 ml), and the solution was stirred at 50° C. overnight. Excess volume of pyrrolidine was distilled off under reduced pressure to leave 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-(pyrrolidin-1-yl)methyl-1,4-cyclohexanediol as a crude product. This crude product was dissolved in chloroform (5 ml), to which was added m-chloroperbenzoic acid (458 mg), and the mixture was stirred for 30 minutes. The solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (carrier 25 g, developing solvent: chloroform - methanol - ammoniacal water=15:1:0.1) to obtain 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-(pyrrolidin-1-yl)methyl-1,4-cyclohexanediol N-oxide (554 mg: yield 84%) as colorless powder.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:13][CH2:14][OH:15])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[F:12].[OH-].[K+].[CH:18]1[CH:23]=[CH:22][C:21]([CH2:24]Br)=[CH:20][CH:19]=1>CCO>[OH:1][CH2:2][CH2:3][N:4]([CH2:13][CH2:14][OH:15])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:24][C:21]2[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=2)=[CH:7][C:6]=1[F:12]
Reactant: OCCN(CCO)c1ccc(O)cc1F
Reactant: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: OCCN(CCO)c1ccc(OCc2ccccc2)cc1F
Yield: 81.3 %

Procedure:
To a solution of N,N-bis-(2-hydroxyethyl)-2-fluoro-4-hydroxyaniline (2 g) and KOH (0.64 g, 10.0 mmole) in EtOH (13 mL) was added BnBr (1.1 mL, 9.1 mmole) and the reaction mixture stirred at reflux for 3 h. The reaction mixture was cooled, evaporated to in dryness and purified by silica gel chromatography (0-7% MeOH/DCM) to provide N,N-bis-(2-hydroxyethyl)-2-fluoro-4-benzyloxyaniline (2.26 g) as a yellow syrup.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([CH2:48][CH2:49][CH3:50])[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:27]=[N:26][N:25]=3)=[CH:14][CH:13]=2)[C:7]=1[C:8]([OH:10])=[O:9])[CH3:2].[C:51]([O:54][CH2:55]Cl)(=[O:53])[CH3:52].C(N(CC)CC)C>C1COCC1>[CH2:1]([C:3]1[N:4]=[C:5]([CH2:48][CH2:49][CH3:50])[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[NH:28][N:27]=[N:26][N:25]=3)=[CH:14][CH:13]=2)[C:7]=1[C:8]([O:10][CH2:55][O:54][C:51](=[O:53])[CH3:52])=[O:9])[CH3:2]
Reactant: CCCc1nc(CC)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(=O)OCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCc1nc(CC)c(C(=O)OCOC(C)=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 8 h
Yield: 45.2 %

Procedure:
0.37 g of 4-ethyl-2-propyl-1-[[2'-(N-triphenylmethyl(tetrazol-5-yl))biphenyl-4-yl]methyl]imidazole-5-carboxylic acid was dissolved in 5 mL THF and 0.5 g chloromethyl acetate and 0.5 mL triethylamine were added. The resulting solution was stirred overnight. The solvent was evaporated and the residue dissolved in methanol with 0.25 mL acetic acid and stirred 8 hours with 10 g silica gel. The mixture was evaporated and the residue on the gel was flash chromatographed with MeOH/CH2Cl2 (1:9) to provide 0.124 g of the title compound.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][CH:18]=2)([OH:14])[CH2:10][CH2:9]1)C1C=CC=CC=1>[Pd].CO>[CH3:26][O:25][C:23]([C:20]1[CH:19]=[CH:18][C:17]([O:16][CH2:15][C:11]2([OH:14])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:22][CH:21]=1)=[O:24]
Reactant: COC(=O)c1ccc(OCC2(O)CCN(Cc3ccccc3)CC2)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(OCC2(O)CCNCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
10% palladium on carbon (2.5 g) was added to a methanol solution (200 mL) of the compound (25 g) obtained in Step 5 and the mixture was stirred at room temperature overnight under hydrogen atmosphere. The catalyst was removed by filtration with Celite™ and the filtrate was condensed under reduced pressure to obtain the titled compound (18.7 g) as crystals.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]([CH3:12])[CH3:11])=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:15][C:16]([CH:18]1[CH2:20][CH:19]1[CH2:21][C:22]1[CH:27]=[C:26]([F:28])[C:25]([OH:29])=[C:24]([F:30])[CH:23]=1)=[O:17])C>>[F:28][C:26]1[CH:27]=[C:22]([CH:23]=[C:24]([F:30])[C:25]=1[O:29][CH2:2][C:3]1[C:4]([S:9][CH:10]([CH3:12])[CH3:11])=[N:5][CH:6]=[CH:7][CH:8]=1)[CH2:21][CH:19]1[CH2:20][CH:18]1[C:16]([OH:17])=[O:15]
Reactant: CCOC(=O)C1CC1Cc1cc(F)c(O)c(F)c1
Reactant: CC(C)Sc1ncccc1CCl
Product: CC(C)Sc1ncccc1COc1c(F)cc(CC2CC2C(=O)O)cc1F
Yield: 79.1 %

Procedure:
3-Chloromethyl-2-isopropylsulfanyl-pyridine (0.019 g, 0.09 mmol) obtained in Step C of Preparation Example 1 and 2-(3,5-difluoro-4-hydroxy-benzyl]-cyclopropane carboxylic acid ethyl ester (0.023 g, 0.09 mmol) obtained in Step D of Preparation Example 49 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.028 g, 75%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH:7]=[CH:6][C:5]=1[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])([O-])=O.[H][H]>CCOC(C)=O.[Pd]>[NH2:1][C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH:7]=[CH:6][C:5]=1[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
Compound 3 was suspended in AcOEt and placed under nitrogen atmosphere; then 10% palladium on carbon (catalytic amount) was added. The reaction mixture was placed under vacuum for a few min then opened up under a balloon of hydrogen and stirred at ambient temperature for 18 h. The reaction mixture was filtered through Celite® and concentrated to give compound 4 (0.393 g, 95% yield).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([C:19]4([CH2:23][C:24]#[N:25])[CH2:22][NH:21][CH2:20]4)[CH:18]=3)[N:11]3[CH:26]=[CH:27][N:28]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1.C(#N)C.C(N(CC)CC)C.[CH:39](=O)[CH2:40][CH3:41].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([C:19]4([CH2:23][C:24]#[N:25])[CH2:22][N:21]([CH2:39][CH2:40][CH3:41])[CH2:20]4)[CH:18]=3)[N:11]3[CH:26]=[CH:27][N:28]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1
Reactant: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CNC4)c3)n2)cn1
Reactant: CCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCN1CC(CC#N)(n2cc(-c3nc(-c4cnn(C)c4)cc4nccn34)cn2)C1
Reaction time: 0.5 h
Yield: 50.5 %

Procedure:
In a 2 mL flask, 2-(3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile hydrochloride (Example 62; 15 mg, 0.035 mmol) was suspended in acetonitrile (350 μL, 0.035 mmol). To this was added triethylamine (19 μL, 0.14 mmol), followed by propionaldehyde (25 μL, 0.35 mmol). After stirring for 30 minutes, NaBH(OAc)3 (37 mg, 0.17 mmol) was added. After the reaction was complete, it was quenched with saturated bicarbonate solution and extracted with EtOAc. The organic layer was washed with brine, dried with MgSO4, filtered and concentrated in vacuo. The residue was purified by reverse phase HPLC using a 0-100% acetonitrile/water gradient to afford 2-(3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo-[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)-1-propylazetidin-3-yl)acetonitrile (7.1 mg, 51% yield) as a white solid. MS (apci) m/z=402.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:18])[C:5]2[C:6]([CH:17]=1)=[C:7]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[O:8][N:9]=2.[Br:19]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:18][C:4]1[C:5]2[C:6](=[C:7]([C:10]3[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=3)[O:8][N:9]=2)[CH:17]=[C:2]([Cl:1])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Cl)cc2c(-c3ccc(Cl)cc3)onc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(-c2onc3c(CBr)cc(Cl)cc23)cc1
Yield: 81.5 %

Procedure:
A mixture of 12.2 g (0.044 mole) of 5-chloro-3-(4-chlorophenyl)-7-methyl-2,1-benzisoxazole, 8.0 g (0.045 mole) of N-bromosuccinimide, 0.1 g of dibenzoylperoxide and 500 ml of carbon tetrachloride was heated at reflux under white light illumination for 2 hr. The hot mixture was filtered and the filtrate was washed once with sodium bicarbonate solution, dried (sodium sulfate) and concentrated to give a solid as residue. The solid was recrystallized from acetonitrile to give 12.8 g (81%) of crude product. A portion of the solid was chromatographed on silica gel. The purified product was recrystallized from acetonitrile to yield an analytical sample of pale yellow solid, m.p. 145°-147° C.
Reaction SMILES: [CH:1]1([N:12]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:13]([O:15]C(C2C=CC([N+]([O-])=O)=CC=2)C)=O)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].C(=O)([O-])[O-].[K+].[K+].[CH3:45][NH:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64]>CN(C)C=O>[CH:1]1([N:12]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:13]([N:46]([CH3:45])[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64])=[O:15])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: CCCCCCCCCCCCCCCCCCNC
Reactant: CCCCCCCCCCCCN(C(=O)OC(C)c1ccc([N+](=O)[O-])cc1)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCN(C)C(=O)N(CCCCCCCCCCCC)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 50 °C

Procedure:
3.1 g of the compound of Example 47 are dissolved in 50 ml of dimethylformamide and treated with 5.0 g of potassium carbonate. 1.8 g of N-methyloctadecylamine are added and the mixture is heated to 50° C. After the reaction has ended, the mixture is cooled to room temperature and filtered, the filtrate is evaporated in vacuo and the residue is purified by column chromatography (eluent toluene/isopropanol 10:1).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][CH2:8][C:9]1[CH:27]=[CH:26][C:12]([CH2:13][N:14]([CH3:25])[CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:11][CH:10]=1.[CH3:28][N:29]1[CH:33]=[CH:32][N:31]=[C:30]1[CH:34]=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]([CH3:25])[CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:26][CH:27]=1)[CH2:34][C:30]1[N:29]([CH3:28])[CH:33]=[CH:32][N:31]=1
Reactant: CN(CCCCN1CCCCC1)Cc1ccc(CNCc2ncc[nH]2)cc1
Reactant: Cn1ccnc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN(CCCCN1CCCCC1)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Temperature: 25 °C
Reaction time: 144 h
Yield: 112 %

Procedure:
The compound (116.3 mg) obtained in Example 44-6 was dissolved in methanol (5.81 ml) and added with 1-methyl-2-imidazole carboxaldehyde (52.0 mg) and sodium cyanoborohydride (39.6 mg). The solution was adjusted to pH 4 with acetic acid and stirred at room temperature for 6 days. The reaction solution was concentrated under reduced pressure. The residue was dissolved in chloroform, washed with a 1 mol/l sodium hydroxide aqueous solution and a saturated saline solution, and dried with anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining a hydrochloride (163.4 mg) of the subject compound as a white solid.