Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Cl:20])[C:5]2[O:9][CH:8]([CH2:10][N:11]([CH2:15][CH2:16][CH2:17][CH3:18])[C:12](Cl)=[O:13])[CH2:7][C:6]=2[CH:19]=1.[NH:21]1[CH:25]=[N:24][C-:23]=[N:22]1.[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([Cl:20])[C:5]2[O:9][CH:8]([CH2:10][N:11]([CH2:15][CH2:16][CH2:17][CH3:18])[C:12]([N:21]3[CH:25]=[N:24][CH:23]=[N:22]3)=[O:13])[CH2:7][C:6]=2[CH:19]=1
Reactant: CCCCN(CC1Cc2cc(Cl)cc(Cl)c2O1)C(=O)Cl
Reactant: [c-]1nc[nH]n1
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCN(CC1Cc2cc(Cl)cc(Cl)c2O1)C(=O)n1cncn1
Temperature: 65 °C
Reaction time: 6 h
Yield: 88.7 %

Procedure:
13.5 g (0.04 mole) of N-(5,7-dichloro-2,3-dihydrobenzofuran-2-ylmethyl)-N-butylcarbamyl chloride were added dropwise to a suspension of 5.5 g (0.06 mole) of sodium 1,2,4-triazolide in 120 ml of dry tetrahydrofuran at 20° C. The mixture was stirred for 6 hours at 65° C., after which it was cooled to 20° C., and the precipitate was filtered off under suction. The filtrate was evaporated down, the residue was suspended in 30 ml of diethyl ether, and the product was filtered off under suction. 13.1 g of 1-(N-(5,7-dichloro-2,3-dihydrobenzofuran-2-ylmethyl)-N-butylcarbamyl)-1,2,4-triazole were obtained as colorless crystals of melting point 122°-124° C. (compound NO. 2).
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][N:5]([CH:17]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:18]1[CH2:23][CH2:22][CH2:21][CH2:20][NH:19]1)[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[OH-].[Na+]>CO>[C:27]([O:26][C:24]([CH:17]([C@@H:18]1[CH2:23][CH2:22][CH2:21][CH2:20][NH:19]1)[N:5]([CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)[CH2:4][C:3]([OH:31])=[O:2])=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: COC(=O)CN(Cc1cccc2ccccc12)C(C(=O)OC(C)(C)C)[C@@H]1CCCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)C([C@@H]1CCCCN1)N(CC(=O)O)Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
N-(t-Butoxycarbonylpiperidin-2(S)-ylmethyl)-N-(1-naphthylmethyl)glycine methyl ester (3.71 g, 8.7 mmol) was dissolved in MeOH (130 ml) in an ice-H2O bath, and 1N NaOH (43.5 ml, 43.5 mmol) was added. The mixture was stirred at ambient temperature for 5 h and concentrated. The resulting residue was dissolved in H2O (50 ml) and neutralized with 1N HCl (43.5 ml). The aqueous layer was washed with EtOAc (3×75 ml). The organic layers were combined, dried (MgSO4), filtered, and concentrated to give the title compound as a white foam.
Reaction SMILES: C([Li])CCC.[C:6]([O:10][C:11]([N:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19](Br)[CH:20]=2)[C:15]([CH3:24])([CH3:23])[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].CON(C)[C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(OCC)C>[C:6]([O:10][C:11]([N:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:28](=[O:35])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:20]=2)[C:15]([CH3:24])([CH3:23])[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CON(C)C(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2ncc(Br)cc21
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CC(C)(C)c2ncc(C(=O)c3ccccc3)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
n-Butyl lithium (5.0 mL of a 2.5 M solution in hexanes, 12 mmol) was added dropwise to a solution of 6-bromo-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-b]pyridine-1-carboxylic acid tert-butyl ester (3.27 g, 10.0 mmol) in diethyl ether (20 mL) at −78° C. The resulting orange slurry was stirred 30 minutes at this temperature, then a solution of N-methoxy-N-methyl-benzamide (2.3 mL, 15.0 mmol) in diethyl ether (10 mL) was added dropwise. The reaction was allowed to warm to room temperature and stirred 1 h further, then quenched with saturated aqueous ammonium chloride and the two layers were separated. The aqueous fraction was further extracted with EtOAc (2×20 mL). The combined organic fractions were dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography (0-30% EtOAc/petrol) to give the title compound (2.4 g, 67%) as a yellow solid. MS: [M+H]+=353.
Reaction SMILES: [C:1]([C:6]1[N:10]2[C:11]([NH2:15])=[CH:12][CH:13]=[CH:14][C:9]2=[N:8][CH:7]=1)(OCC)=[O:2].C[O-].[Na+].CO.Cl>C(#N)C>[NH:15]1[C:11]2[N:10]3[C:9](=[N:8][CH:7]=[C:6]3[C:1]1=[O:2])[CH:14]=[CH:13][CH:12]=2
Reactant: CCOC(=O)c1cnc2cccc(N)n12
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: O=c1[nH]c2cccc3ncc1n32
Yield: 180 %

Procedure:
To a solution prepared by dissolving 1.44 g (7.0 mM) of 3-carbethoxy-5-aminoimidazo[1,2-a]pyridine in 10 ml of acetonitrile followed by addition of 3.2 ml (14.0 mM) of 25% sodium methoxide-methanol and the mixture was refluxed for 1 hour. After completion of the reaction, 1.15 ml (14.0 mM) of 12N-hydrochloric acid was added to the reaction mixture under ice-cooling and the solvent was thoroughly distilled off under reduced pressure to provide 2.01 g (yield 100%) of a crude product as tan-colored solid.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Br>>[CH3:16][C:13]1([CH3:17])[N:12]([CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[C:19]([F:18])([F:28])[F:29])[N:11]([CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)[C:14]1=[O:15]
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1ccccc1C(F)(F)F

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2-(trifluoromethyl)benzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])[N:4]([C@@H:23]2[CH2:31][CH2:30][CH2:29][C:28]3[N:27]([S:32]([C:35]4[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=4)(=[O:34])=[O:33])[N:26]=[CH:25][C:24]2=3)[N:3]=1.CC1(C)C(C)(C)OB([C:50]2[CH:68]=[CH:67][C:53]([C:54]([NH:56][C:57]3[CH:62]=[C:61]([C:63]([F:66])([F:65])[F:64])[CH:60]=[CH:59][N:58]=3)=[O:55])=[CH:52][CH:51]=2)O1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:22][O:21][C:14]1[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=1[CH2:12][NH:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@@H:23]3[CH2:31][CH2:30][CH2:29][C:28]4[N:27]([S:32]([C:35]5[CH:36]=[CH:37][C:38]([CH3:39])=[CH:40][CH:41]=5)(=[O:33])=[O:34])[N:26]=[CH:25][C:24]3=4)[N:3]=[C:2]([C:50]3[CH:68]=[CH:67][C:53]([C:54]([NH:56][C:57]4[CH:62]=[C:61]([C:63]([F:64])([F:65])[F:66])[CH:60]=[CH:59][N:58]=4)=[O:55])=[CH:52][CH:51]=3)[C:10]=12
Reactant: COc1ccc(CNc2ncnc3c2c(Br)nn3[C@@H]2CCCc3c2cnn3S(=O)(=O)c2ccc(C)cc2)c(OC)c1
Reactant: CC1(C)OB(c2ccc(C(=O)Nc3cc(C(F)(F)F)ccn3)cc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CNc2ncnc3c2c(-c2ccc(C(=O)Nc4cc(C(F)(F)F)ccn4)cc2)nn3[C@@H]2CCCc3c2cnn3S(=O)(=O)c2ccc(C)cc2)c(OC)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
The mixture of (R)-3-bromo-N-(2,4-dimethoxybenzyl)-1-(1-tosyl-4,5,6,7-tetrahydro-1H-indazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (80 mg, 0.125 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (59 mg, 0.150 mmol), Pd(PPh3)2Cl2 (9.2 mg, 0.0125 mmol) and K2CO3 (43 mg, 0.313 mmol) in dioxane/H2O (3 mL/0.3 mL) was stirred for 2 h at 90° C. under nitrogen atmosphere. Then the mixture was added water and extracted with DCM. The combined organic layer was washed with water, brine and dried over anhydrous Na2SO4. Concentrated in vacuo and the residue was purified with silica gel chromatography with PE/EA=1/1 to give (R)-4-(4-((2,4-dimethoxybenzyl)amino)-1-(1-tosyl-4,5,6,7-tetrahydro-1H-indazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (90 mg, yield 87.2%) as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][C:12]([C:15]#[N:16])([CH3:14])[CH3:13])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:41][C:42]1[CH:43]=[C:44]([N:49]([CH3:65])[C:50]2[N:55]=[C:54]3[S:56][C:57]([NH:59][C:60]([CH:62]4[CH2:64][CH2:63]4)=[O:61])=[N:58][C:53]3=[CH:52][CH:51]=2)[CH:45]=[CH:46][C:47]=1[F:48]>N1C=CC=CC=1>[Cl:1][C:2]1[C:10]([O:11][C:12]([C:15]#[N:16])([CH3:14])[CH3:13])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:41][C:42]1[CH:43]=[C:44]([N:49]([C:50]2[N:55]=[C:54]3[S:56][C:57]([NH:59][C:60]([CH:62]4[CH2:63][CH2:64]4)=[O:61])=[N:58][C:53]3=[CH:52][CH:51]=2)[CH3:65])[CH:45]=[CH:46][C:47]=1[F:48])=[O:6]
Reactant: CC(C)(C#N)Oc1cccc(C(=O)O)c1Cl
Reactant: CN(c1ccc(F)c(N)c1)c1ccc2nc(NC(=O)C3CC3)sc2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Product: CN(c1ccc(F)c(NC(=O)c2cccc(OC(C)(C)C#N)c2Cl)c1)c1ccc2nc(NC(=O)C3CC3)sc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
To a solution of 2-chloro-3-(1-cyano-1-methylethoxy)benzoic acid (4.8 g, 20 mmol) produced in Example C70(iii) in pyridine (100 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (7.6 g, 20 mmol), and the mixture was stirred at room temperature for 2 hr. To the obtained solution was added N-{5-[(3-amino-4-fluorophenyl)(methyl)amino][1,3]thiazolo[5,4-b]pyridin-2-yl}cyclopropanecarboxamide (3.57 g, 9.99 mmol), and the mixture was stirred at 90° C. for 3 hr. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (350 mL), and washed with water (350 mL). The aqueous layer was extracted with ethyl acetate (150 mL). The combined organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (250 mL×2) and saturated brine (250 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=60/40→20/80), the obtained solution was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate to give the title compound (5.02 g, 87%) as a colorless powder.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[C:13]1[C:21]2[C:16](=[N:17][C:18]([NH2:22])=[N:19][CH:20]=2)[N:15]([CH3:23])[N:14]=1.B(Br)(Br)Br>C(Cl)Cl>[NH2:22][C:18]1[N:17]=[C:16]2[N:15]([CH3:23])[N:14]=[C:13]([C:4]3[CH:5]=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:7]=[CH:8][C:3]=3[OH:2])[C:21]2=[CH:20][N:19]=1
Reactant: COc1ccc(C(F)(F)F)cc1-c1nn(C)c2nc(N)ncc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cn1nc(-c2cc(C(F)(F)F)ccc2O)c2cnc(N)nc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(2-Methoxy-5-trifluoromethyl-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (Example 88) (0.08 g, 0.25 mmol) in DCM (5 ml) is added drop wise boron tribromide (1M solution in DCM, 0.99 ml, 0.99 mmol), under an inert atmosphere of argon at 0-5° C. (ice-bath). The reaction mixture is warmed to room temperature, stirred for 2 hours and then quenched with water (10 ml). The resulting solid is collected by filtration and dried under vacuum to afford the title compound.
Reaction SMILES: [H-].[Na+].C(C(C(OC1C=CC=CO1)=O)C(OC1C=CC=CO1)=O)C.[CH2:24]([CH:26]([C:30]([OH:32])=O)C(O)=O)[CH3:25].O1C=CCCC1.S(=O)(=O)(O)O.C(C(C([O-])=O)C([O-])=O)C.C(OC1C=CC=CO1)(=O)CC(OC1C=CC=CO1)=O.[Na].[CH3:73][C:74]1[CH:79]=[CH:78][C:77]([C:80]2[CH:84]=[C:83](C(Cl)=O)[O:82][N:81]=2)=[CH:76][CH:75]=1>C1C=CC=CC=1.O.C(O)(=O)C.O1CCCC1>[CH3:73][C:74]1[CH:75]=[CH:76][C:77]([C:80]2[CH:84]=[C:83]([C:30](=[O:32])[CH2:26][CH2:24][CH3:25])[O:82][N:81]=2)=[CH:78][CH:79]=1
Reactant: CCC(C(=O)O)C(=O)O
Reactant: Cc1ccc(-c2cc(C(=O)Cl)on2)cc1
Agent: C1=COCCC1
Agent: CCC(C(=O)OC1C=CC=CO1)C(=O)OC1C=CC=CO1
Agent: CCC(C(=O)[O-])C(=O)[O-]
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CCCC(=O)c1cc(-c2ccc(C)cc2)no1

Procedure:
In 50 ml of benzene, 2.6 g (57.5 mmol) of 60% sodium hydride were added to dipyranyl ethylmalonate which had been prepared from 5.7 g (43.2 mmol) of ethylmalonic acid, 9.0 g (107.1 mmol) of 3,4-dihydropyran and 1 droplet of concentrated sulfuric acid. At 40°-50° C., the ethylmalonate was converted to sodium dipyranyl malonate, to which a tetrahydrofuran solution of 3-(4-methylphenyl)isoxazole-5-carboxylic acid chloride synthesized above in the procedure (3) was added dropwise at room temperature. They were reacted for 3 hours. The reaction mixture was added with 10 ml of acetic acid and then heated under reflux for 6 hours. The mixture thus obtained was added into water and then extracted with benzene. The benzene extract was washed successively with an aqueous solution of sodium hydrogencarbonate and water. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off. Hexane was added to the residue, and 3-(4-methylphenyl)-5-butyrylisoxazole precipitated as crystals was collected by filtration. Analytical results of the crystals obtained: Yield: 6.3 g (76.5%). Melting point: 86°-87° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][C:8]([O:11][C:12]3[CH:13]=[CH:14][C:15]([CH3:28])=[C:16]([NH:18][C:19]([C:21]4[N:25]([CH3:26])[N:24]=[C:23]([CH3:27])[CH:22]=4)=[O:20])[CH:17]=3)=[N:7][N:6]2[CH:29]=1.C(N(CC)CC)C.[CH:37]1([S:40](Cl)(=[O:42])=[O:41])[CH2:39][CH2:38]1.O>CN1CCCC1=O>[CH:37]1([S:40]([NH:2][C:3]2[N:4]=[C:5]3[CH:10]=[CH:9][C:8]([O:11][C:12]4[CH:13]=[CH:14][C:15]([CH3:28])=[C:16]([NH:18][C:19]([C:21]5[N:25]([CH3:26])[N:24]=[C:23]([CH3:27])[CH:22]=5)=[O:20])[CH:17]=4)=[N:7][N:6]3[CH:29]=2)(=[O:42])=[O:41])[CH2:39][CH2:38]1
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)cn4n3)ccc2C)n(C)n1
Reactant: O=S(=O)(Cl)C1CC1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NS(=O)(=O)C5CC5)cn4n3)ccc2C)n(C)n1
Temperature: 70 °C
Reaction time: 16 h
Yield: 15.8 %

Procedure:
To a solution of N-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide.hydrochloride (400 mg, 0.97 mmol) in 1-methyl-2-pyrrolidone (4.0 mL) were added triethylamine (404 μL, 2.90 mmol) and cyclopropanesulfonyl chloride (204 mg, 1.45 mmol), and the mixture was stirred at 70° C. for 16 hr. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran, washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate alone) and recrystallized from hexane/ethyl acetate to give the title compound (74 mg, 16%) as a white powder.
Reaction SMILES: N1(CC2N3C=C(C)C=CC3=NC=2C2C=CC(C)=CC=2)C=CN=C1.Cl.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([C:32]([CH2:41]Cl)=[C:33]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:34]=2)[CH:31]=1.[NH:43]1[CH:47]=[N:46][C:45]([C:48]([O:50][CH3:51])=[O:49])=[N:44]1>>[CH3:51][O:50][C:48]([C:45]1[N:46]=[CH:47][N:43]([CH2:41][C:32]2[N:30]3[CH:31]=[C:26]([Cl:25])[CH:27]=[CH:28][C:29]3=[N:34][C:33]=2[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:44]=1)=[O:49]
Reactant: ClCc1c(-c2ccccc2)nc2ccc(Cl)cn12
Reactant: COC(=O)c1nc[nH]n1
Agent: Cc1ccc(-c2nc3ccc(C)cn3c2Cn2ccnc2)cc1
Agent: Cl
Product: COC(=O)c1ncn(Cc2c(-c3ccccc3)nc3ccc(Cl)cn23)n1

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 1 from 6-chloro-3-(chloromethyl)-2-phenylimidazo[1,2-a]pyridine hydrochloride and methyl 1H-1,2,4-triazole-3-carboxylate. The two isomers were separated by silica gel chromatography (eluted with 20% acetone/hexane to flush out the less polar isomer (44) and then flashed with 50% acetone to get the second compound off the column (45). Compound 44: m/e+ 368 for C18H15ClN5O2 [M+H]−; 1H-NMR (400 MHz, CDCl3) δ 8.35 (d, J=1.1 Hz, 1H), 7.98 (s, 1H), 7.76 (dd, J=1.4, 8.0 Hz, 2H), 7.61 (d, J=9.5 Hz, 1H), 7.42 (m, 3H), 7.24 (m, 1H), 6.17 (s, 2H), 3.97 (s, 3H) ppm; Compound 45: m/e+ 368 for C18H15ClN5O2 [M+H]+; 1H-NMR (400 MHz, CDCl3) δ 8.18 (d, J=1.1 Hz, 1H), 7.99 (s, 1H), 7.63 (m, 3H), 7.44 (m, 3H), 7.25 (m, 1H), 5.82 (s, 2H), 3.97 (s, 3H) ppm.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[O:11][CH3:12].[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:12][O:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[CH2:1][Br:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc([N+](=O)[O-])c1C
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cccc([N+](=O)[O-])c1CBr
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3.0 g (18 mmol) of 2-methyl-3-nitroanisole was dissolved in 500 ml of carbon tetrachloride. The resultant solution was added with 6.4 g (36 mmol) of N-bromosuccinimide, and the mixture was subjected to irradiation of light emitted from an infrared lamp of 375 W (manufactured by Toshiba) for 3 hours at the reflux temperature. The mixture was then cooled to a room temperature. Succinimide precipitated in the mixture was separated by filtration, and the obtained filtrate was condensed under reduced pressure to obtain a crude product of 2-methoxy-6-nitrobenzyl bromide.
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([CH2:8][OH:9])[CH2:6][C:5](=[O:10])[CH2:4]1)[CH3:2].N1C=CN=C1.[C:16]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])([CH3:18])[CH3:17].CCCCCCC>CN(C=O)C>[Si:20]([O:9][CH2:8][C@@H:7]1[C@H:3]([CH2:1][CH3:2])[CH2:4][C:5](=[O:10])[CH2:6]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:22])[CH3:21]
Reactant: CC[C@@H]1CC(=O)C[C@@H]1CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCCCCCC
Solvent: CN(C)C=O
Product: CC[C@@H]1CC(=O)C[C@@H]1CO[Si](C)(C)C(C)(C)C
Reaction time: 4 h
Yield: 74.6 %

Procedure:
To a solution of (3R,4S)-3-ethyl-4-(hydroxymethyl)cyclopentanone (2.60 g, 18.3 mmol) in DMF (30 mL) was added imidazole (1.87 g, 27.4 mmol) followed by tert-butylchlorodimethylsilane (3.03 g, 20.1 mmol). After about 4 h, heptane (50 mL) was added. The heptane layer was removed and washed with brine. The brine layer was combined with the DMF layer and extracted with EtOAc/heptane (1:1, 30 mL). The heptane and EtOAc layers were combined, concd in vacuo and purified by chromatography on silica gel eluting with EtOAc/heptane (0-30%) to provide (3S,4R)-3-((tert-butyldimethylsilyloxy)methyl)-4-ethylcyclopentanone (3.5 g, 75%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 3.77 (dd, J=10.5, 4.3 Hz, 1H), 3.64 (dd, J=10.5, 4.0 Hz, 1H), 2.40-2.20 (m, 5H), 2.18-2.02 (m, 1H), 1.65-1.55 (m, 1H), 1.52-1.37 (m, 1H), 0.97 (t, J=7.4 Hz, 3H), 0.87 (s, 9H), 0.43 (s, 3H), 0.03 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([CH3:12])=[C:6]([C:13]2[O:17][N:16]=[C:15]([CH3:18])[N:14]=2)[C:3]=1[CH:4]=O.[SH:19][CH2:20][C@H:21]([NH:28][C:29](=[O:31])[CH3:30])[C:22]1[O:26][N:25]=[C:24]([CH3:27])[N:23]=1>>[OH:1][C:2]1[C:3]([CH2:4][S:19][CH2:20][C@H:21]([NH:28][C:29](=[O:31])[CH3:30])[C:22]2[O:26][N:25]=[C:24]([CH3:27])[N:23]=2)=[C:6]([C:13]2[O:17][N:16]=[C:15]([CH3:18])[N:14]=2)[C:7]([CH3:12])=[C:8]([O:10][CH3:11])[CH:9]=1
Reactant: COc1cc(O)c(C=O)c(-c2nc(C)no2)c1C
Reactant: CC(=O)N[C@@H](CS)c1nc(C)no1
Product: COc1cc(O)c(CSC[C@H](NC(C)=O)c2nc(C)no2)c(-c2nc(C)no2)c1C

Procedure:
2-Hydroxy-4-methoxy-5-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)-benzaldehyde and (R)-N-[2-mercapto-1-(3-methyl-1,2,4-oxadiazol-5-yl)-ethyl]-acetamide were subjected in an analogous manner to the procedure described in Example 1(g) to yield (R)-N-[2-[6-hydroxy-4-methoxy-3-methyl-2-(3-methyl-1,2,4-oxadiazol-5-yl)benzylsulfanyl]-1-(3-methyl-1,2,4-oxadiazol-5-yl)-ethyl]-acetamide as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](C(O)=O)[CH:5]=[C:6]2[C:10]=1[N:9]([C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[N:8]=[C:7]2[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=1.C([N:42](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(O)C1C=CC=CC=1>C1(C)C=CC=CC=1.O>[F:1][C:2]1[CH:3]=[C:4]([NH2:42])[CH:5]=[C:6]2[C:10]=1[N:9]([C:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[N:8]=[C:7]2[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cc(F)c2c(c1)c(-c1cccc(F)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: OCc1ccccc1
Solvent: Cc1ccccc1
Product: Nc1cc(F)c2c(c1)c(-c1cccc(F)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1.0 g of 7-fluoro-3-(3-fluorophenyl)-1-trityl-1H-indazole-5-carboxylic acid in 20 ml toluene at room temperature were added 0.40 ml of triethylamine and 0.46 ml of diphenylphosphoryl azide, the mixture was stirred at the same temperature for 2 hours and at 120° C. for 1.5 hours. To the reaction mixture was added 1.0 ml of benzyl alcohol, followed by stirring at 120° C. for 1.5 hours. After cooling to room temperature, water was added to the reaction mixture was and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and the solvent was evaporated. To a solution of the resulting crude product in a solvent mixture of 20 ml of methanol and 10 ml of tetrahydrofuran was added 1.0 g of 10% palladium-carbon at room temperature, and the mixture was subjected to catalytic hydrogenation at the same temperature and at normal atmospheric pressure. After stirring for 4 hours, the reaction mixture was filtrated through Celite, the filtrate was evaporated, and the residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=1:5), to give 540 mg of the title compound.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH:3]=[CH2:4].[O:6]1[CH:11]=[CH:10][CH2:9][CH2:8][CH2:7]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl>[CH2:1]([O:5][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][O:6]1)[CH2:2][CH:3]=[CH2:4]
Reactant: C1=COCCC1
Reactant: C=CCCO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C=CCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
In a 1000 ml rb flask were placed 3-buten-1-ol (7.21 g, 100.00 mmol), 3,4-dihydro-2H-pyran (12.62 g, 150.00 mmol) and pyridinium p-toluenesulfonate (2.51 g, 10.00 mmol) in 350 ml of anhydrous dichloromethane. The reaction mixture was stirred at room temperature for 4 h. Then the reaction mixture was concentrated and the residue was purified by column with Hexane/Ethyl acetate=100/5 to provide 13.90 g of the desired product as an oil (89.0%). 1H-NMR (DMSO-d6) δ 5.851-5.742 (m, 1H), 5.103-5.011 (d, 1H), 4.997-4.985 (d, 1H), 4.555-4.537 (t, 1H), 3.745-3.611 (m, 2H), 3.433-3.347 (m, 2H), 2.290-2.236 (m, 2H), 1.698-1.675 (m, 2H), 1.611-1.566 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[C:7](Cl)=[O:8].[NH2:14][C:15]1[CH:37]=[CH:36][C:18]([C:19]([N:21]2[CH2:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[CH2:24][C:23]3[CH:32]=[CH:33][CH:34]=[CH:35][C:22]2=3)=[O:20])=[CH:17][CH:16]=1>>[CH:32]1[C:23]2[CH2:24][C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[CH2:27][N:21]([C:19]([C:18]3[CH:17]=[CH:16][C:15]([NH:14][C:7]([C:6]4[S:5][C:4]5[CH:10]=[CH:11][CH:12]=[CH:13][C:3]=5[C:2]=4[Cl:1])=[O:8])=[CH:37][CH:36]=3)=[O:20])[C:22]=2[CH:35]=[CH:34][CH:33]=1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1)c1sc2ccccc2c1Cl

Procedure:
As described for Example 9, 3-chlorobenzo[b]-thiophene-2-carbonyl chloride is reacted with 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine to give the product. Recrystallization from dichloromethane-hexane gives crystals, m.p. 252°-254° C.