Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[Cl:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[S:31](Cl)(=[O:33])=[O:32]>>[Cl:20][C:21]1[CH:26]=[C:25]([C:27]([F:29])([F:28])[F:30])[CH:24]=[CH:23][C:22]=1[S:31]([NH:19][C:4]1[CH:5]=[N:6][C:7]([O:8][C:9]2[N:10]=[CH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:2]([Cl:1])[CH:3]=1)(=[O:33])=[O:32]
Reactant: Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Cl
Product: O=S(=O)(Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1)c1ccc(C(F)(F)F)cc1Cl

Procedure:
The title compound was prepared by reacting 5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 2) and 2-chloro-4-(trifluoromethyl)benzene-1-sulfonyl chloride.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH2:12][CH:13]=[CH2:14])=[C:10]([OH:15])[CH:9]=[CH:8][C:3]=1[C:4](OC)=[O:5].[Cl-].[NH4+:17]>C(O)C>[OH:1][C:2]1[C:11]([CH2:12][CH:13]=[CH2:14])=[C:10]([OH:15])[CH:9]=[CH:8][C:3]=1[C:4]([NH2:17])=[O:5]
Reactant: C=CCc1c(O)ccc(C(=O)OC)c1O
Reactant: [NH4+]
Agent: [Cl-]
Solvent: CCO
Product: C=CCc1c(O)ccc(C(N)=O)c1O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Methyl 2,4-dihydroxy-3-(2-propenyl)benzoate (4.4 g) was added to a mixture of about 10 to 15 ml of saturated ammonium chloride solution and 2 to 3 ml of ethanol. The reaction mixture was stirred overnight at 50° C. The reaction mixture was extracted five times with ethyl acetate, and the organic layer was concentrated under vacuum. The product was crystallized and recrystallized from chloroform. Subsequent chromatography of the precipitated product on a 25 g silica gel column with 40% ethyl acetate/hexane as eluant gave the pure product.
Reaction SMILES: OO.S(=O)(=O)(O)O.[NH2:8][C:9]1[C:13]([NH2:14])=[N:12][O:11][N:10]=1.[N:15]([C:17]1[C:18]([NH2:22])=[N:19][O:20][N:21]=1)=[O:16]>>[NH2:22][C:18]1[C:17]([N+:15](=[N:14][C:13]2[C:9]([NH2:8])=[N:10][O:11][N:12]=2)[O-:16])=[N:21][O:20][N:19]=1
Reactant: Nc1nonc1N=O
Reactant: Nc1nonc1N
Agent: O=S(=O)(O)O
Agent: OO
Product: Nc1nonc1N=[N+]([O-])c1nonc1N
Temperature: 18 °C
Yield: 88 %

Procedure:
This procedure was modeled from the original Russian preparation. To 30% hydrogen peroxide (100.0 g, 0.88 mol) in a 500 ml jacketed flask maintained at 18° C. was added 98% sulfuric acid (55.0 g, 0.56 mol) over 10 minutes with stirring. Then, 3,4-diaminofurazan (10.0 g, 0.10 mole) was added. The suspension was stirred for 24 hours in which time the soluble green nitroso-aminofurazan was converted to the insoluble orange DAAF. The product was filtered on a glass frit, washed with water and air dried to yield 9.29 g (88%) of crude material. For recrystallization the crude compound was dissolved in the minimum amount of room temperature DMSO (approximately 22 ml) and then water (45 ml) was added over 5 minutes with stirring. The pure DAAF was filtered, washed with water and air-dried. This material had the same properties as previously reported by the Russians. 1H NMR (deuteriomethylsulfoxide) δ 6.65 (s, 2H), 6.93 (s, 2H); 13C NMR (deuteriomethylsulfoxide) δ 148.3, 151.2, 152.6, 153.9.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH:14]([CH3:16])[CH3:15])[C:11](Cl)=[O:12])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[CH:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[C:28]([CH:30]([OH:33])[C:31]#[N:32])[CH:27]=[CH:26][CH:25]=2)=[CH:19][CH:18]=1.C(N(CC)CC)C>C(Cl)Cl>[N:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH:14]([CH3:16])[CH3:15])[C:11]([O:33][CH:30]([C:31]#[N:32])[C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([O:23][C:20]3[CH:19]=[CH:18][CH:17]=[CH:22][CH:21]=3)[CH:29]=2)=[O:12])=[CH:6][CH:5]=1)=[N+:2]=[N-:3]
Reactant: N#CC(O)c1cccc(Oc2ccccc2)c1
Reactant: CC(C)C(C(=O)Cl)c1ccc(N=[N+]=[N-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1)c1ccc(N=[N+]=[N-])cc1

Procedure:
2-(4-Azidophenyl)-3-methylbutanoyl chloride, prepared in Example 7, was dissolved in 10 ml of methylene chloride. A solution of 3.79 g of m-phenoxybenzaldehyde cyanohydrin in 10 ml of methylene chloride was added, with cooling by an ice bath, followed by 2.4 ml of triethylamine, causing an exothermic reaction and precipitating white solid. After an hour without cooling, the mixture was evaporated to a residue, which was extracted with diethyl ether, the extract filtered, and the filtrate washed with water and saturated sodium bicarbonate solution, dried (MgSO4), and evaporated to 7.4 g of residual oil, 2-(4-azidophenyl)-3-methylbutanoic acid, α-cyano-3-phenoxybenzyl ester. The infrared spectrum shows absorption peaks at 2130 cm-1 (azide) and 1760 cm-1 (ester carbonyl). Mass spectral analysis showed a molecular ion, m/e 426, corresponding to the product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:14]([N:18]=[N+:19]=[N-:20])[CH2:15][CH2:16][CH3:17]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[C:12](=[O:13])[N:18]([CH2:14][CH2:15][CH2:16][CH3:17])[N:19]=[N:20]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Reactant: CCCCN=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CCCCn1nnn(S(=O)(=O)c2ccc(Cl)cc2)c1=O

Procedure:
Equimolar mixtures of (p-chlorophenyl)-sulphonyl isocyanate and n-butylazide were dissolved at room temperature in toluene with a molar concentration of 0.6. 1-(p-chlorophenylsulphonyl)-4-n-butyl-2-tetrazolin-5-one was obtained, which was a white powder or a clear crystalline precipitate, according to whether the precipitation occurred fast or slow. The product had a melting range of 76.5°-77.5° C. The following results were obtained by elementary analysis:
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([C:12]([O:14][C@H:15]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=2)[CH2:16][C:17]2[C:22]([Cl:23])=[CH:21][N+:20]([O-:24])=[CH:19][C:18]=2[Cl:25])=[O:13])[CH2:9]1)=O)(C)(C)C.Cl.C(OCC)C.C(#N)C>C(OCC)(=O)C>[ClH:23].[Cl:25][C:18]1[CH:19]=[N+:20]([O-:24])[CH:21]=[C:22]([Cl:23])[C:17]=1[CH2:16][C@H:15]([O:14][C:12]([CH:10]1[CH2:11][NH:8][CH2:9]1)=[O:13])[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=1
Reactant: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)C2CN(C(=O)OC(C)(C)C)C2)cc1OC
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)C2CNC2)cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 200.5 %

Procedure:
To a stirred solution of (S)-4-(2-((1-(tert-butoxycarbonyl)azetidine-3-carbonyl)oxy)-2-(3,4-dimethoxyphenyl)ethyl)-3,5-dichloropyridine 1-oxide (105 mg, 0.2 mmol) in ethyl acetate (0.5 mL) was added a 2M solution of HCl in diethyl ether (1.5 mL, 3 mmol). The mixture was allowed to stir at room temperature for 4 hours and then acetonitrile (5 mL) was added. The mixture was allowed to stir at room temperature for 3 hours. The solid was removed by filtration, washed with diethyl ether and dried to afford the title compound as a yellow solid (93 mg, 95%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([O:7][C:8]2[N:13]=[N:12][CH:11]=[C:10]([OH:14])[CH:9]=2)=[CH:5][C:4]([C:15]([F:18])([F:17])[F:16])=[N:3]1.[H-].[Na+].C(OC1C=C(OC2N(C)N=C([C:37](F)([F:39])[F:38])C=2)N=NC=1)C>CN(C=O)C>[F:38][CH:37]([F:39])[O:14][C:10]1[CH:9]=[C:8]([O:7][C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:15]([F:18])([F:16])[F:17])[CH:5]=2)[N:13]=[N:12][CH:11]=1
Reactant: Cn1nc(C(F)(F)F)cc1Oc1cc(O)cnn1
Reactant: CCOc1cnnc(Oc2cc(C(F)(F)F)nn2C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1nc(C(F)(F)F)cc1Oc1cc(OC(F)F)cnn1
Temperature: 0 °C
Yield: 12 %

Procedure:
6-[[1-Methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]oxy]-4-pyridazinol (Compound No. 12, 1.0 g, 0.0038 mole) and NaH (1.15 g of 80% NaH in oil, 0.0384 mole) were heated to 80° C. in DMF (20 mL) while CF2ClH was continuously bubbled through the solution for 6.5 h. The mixture was cooled to 0° C. and quenched by dropwise addition of water under an N2 sweep. After H2 ceased to evolve the mixture was poured into water/ethyl acetate and made acidic with excess ammonium chloride and then extracted 3×100 mL with ethyl acetate. The organic layers were extracted with brine, dried (MgSO4), filtered through silica gel with ethyl acetate, and evaporated in vacuo. Two compounds were present as evidenced by TLC. The mixture was separated by reverse phase chroma-tography to give 5-(difluoromethoxy)-3-[[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]oxy]pyridazine (0.144 g, 12% yield) as a yellow solid (mp= 86 -88° C.) and 5-ethoxy-3-[[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]oxy]pyridazine (0.058 g, 5% yield as a yellow solid.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH3:18])[N:3]=1.[Br:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22](Br)[N:21]=1>C([Mg]Br)(C)C.[Zn+2].[Br-].[Br-]>[Br:19][C:20]1[N:21]=[C:22]([C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[CH:5]=[C:4]([CH3:18])[N:3]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(I)n1
Reactant: Brc1cccc(Br)n1
Agent: CC(C)[Mg]Br
Agent: [Br-]
Agent: [Zn+2]
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(Br)n2)n1

Procedure:
The title compound was prepared from 2-iodo-6-methyl-4-(4-trifluoromethyl-phenyl)-pyridine (example A.31) (1.09 g, 3.0 mmol), i-PrMgBr/ZnBr2 and commercially available 2,6-dibromopyridine (2.13 g, 9 mmol) according to the general procedure IVc protocol b. Obtained as a light yellow solid (0.826 g, 70%). MS (ISP) 393.0 [(M+H)+] and 394.8 [(M+2+H)+].
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:30][CH2:31][CH3:32])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH:27]([F:29])[F:28])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[F:13])[CH2:4]1.[CH3:33][C:34]([CH3:36])=O>>[Cl:14][C:11]1[C:12]([F:13])=[C:7]([CH:5]2[CH2:6][N:3]([CH:34]([CH3:36])[CH3:33])[CH2:4]2)[C:8]([O:30][CH2:31][CH3:32])=[C:9]([CH:15]([N:17]2[C:21]3=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]3[C:19]([CH:27]([F:29])[F:28])=[N:18]2)[CH3:16])[CH:10]=1
Reactant: CC(C)=O
Reactant: CCOc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(Cl)c(F)c1C1CNC1
Agent: Cl
Product: CCOc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(Cl)c(F)c1C1CN(C(C)C)C1

Procedure:
This compound was prepared using procedures analogous to those for Example 1 step 8, with 1-[1-(3-azetidin-3-yl-5-chloro-2-ethoxy-4-fluorophenyl)ethyl]-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride and acetone as starting materials. The product was isolated as a racemic mixture. LCMS calculated for C22H27ClF3N6O (M+H)+: m/z=483.2; Found: 483.2
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:14][CH2:15][OH:16].C(N(CC)C(C)C)(C)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(OCC)(=O)C>ClCCl>[CH3:26][S:27]([O:16][CH2:15][CH2:14][C:3]1[N:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[S:6][C:2]=1[CH3:1])(=[O:29])=[O:28]
Reactant: Cc1ccc(-c2nc(CCO)c(C)s2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2nc(CCOS(C)(=O)=O)c(C)s2)cc1
Reaction time: 4 h
Yield: 104.9 %

Procedure:
To a yellow solution of 2-(5-methyl-2-p-tolylthiazol-4-yl)ethanol (200 mg, 857 μmol) in dichloromethane (3 mL) was added N,N-diisopropylethylamine (166 mg, 225 μL, 1.29 mmol) at RT. Methanesulfonyl chloride (113 mg, 76.8 μL, 986 μmol) was added at 0-5° C. and stirring was continued for 4 h at 0° C. The reaction mixture was poured into ethyl acetate (25 mL) and extracted with KHSO4 (10% aqueous solution, 15 mL). The organic phase was washed with water (2×15 mL) and brine (1×20 mL). The aqueous layers were back-extracted with ethyl acetate (1×25 mL) and the combined organic layer was dried over MgSO4 and concentrated in vacuo to give 280 mg (99%) of yellow oil which was used without further purification for the next step.
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[H-].[Na+].Cl[CH2:23][C:24]1[CH:43]=[CH:42][C:27]([O:28][CH2:29][C:30]2[N:31]=[C:32]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[O:33][C:34]=2[CH3:35])=[CH:26][CH:25]=1.Cl>CN(C)C=O>[CH3:1][N:2]([C:3]1[S:4][C:5]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1)[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:28][CH2:29][C:30]2[N:31]=[C:32]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[O:33][C:34]=2[CH3:35])=[CH:42][CH:43]=1
Reactant: CNc1nc(-c2ccccc2)c(CCC(=O)OC)s1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCc1sc(N(C)Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1-c1ccccc1
Temperature: 0 °C
Yield: 72.4 %

Procedure:
To a solution of methyl 3-[2-(N-methylamino)-4-phenyl-5-thiazolyl]propionate (400 mg) in N,N-dimethylformamide (10 ml) was added sodium hydride (60% in oil, 70 mg) at 0° C. and the mixture was stirred at said temperature for 10 min. 4-(4-Chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (500 mg) was added and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into ice water, neutralized with 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[2-[N-methyl-N-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]amino]-4-phenyl-5-thiazolyl]propionate (580 mg, yield 72%) was obtained as a colorless oil from fraction eluted with ethyl acetate-hexane (1:9, volume ratio).
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].[N+:9]([C:12]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:13]=1[CH:14]=O)([O-])=O.CO.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>[NH4+].[Cl-].CCO.[Fe]>[Cl:20][C:17]1[CH:18]=[CH:19][C:12]([NH2:9])=[C:13]([C:14]2[N:4]3[CH:5]=[CH:6][CH:7]=[N:8][C:3]3=[N:1][N:2]=2)[CH:16]=1
Reactant: NNc1ncccn1
Reactant: O=Cc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1ccc(Cl)cc1-c1nnc2ncccn12
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A 5 mL scintillation vial was charged with 2-hydrazinopyrimidine (61 mg, 0.55 mmol), 2-nitro-5-chlorobenzaldehyde (112 mg, 0.60 mmol) and MeOH (500 μL) and heated to 60° C. for 30 minutes. The MeOH was then removed in vacuo and the resultant solid was washed with Et2O. The crude solid (30 mg) was then suspended in CH2Cl2 (1 mL) and iodobenzene diacetate (39 mg, 0.12 mmol) was added. The reaction was stirred at room temperature for 30 minutes after which the solvent was removed in vacuo. The resultant residue was then dissolved in a 10% solution of saturated NH4Cl(aq) in EtOH and iron (19 mg, 0.33 mmol) was then added and the reaction was stirred at 80° C. for 4 h. The solvent was then removed in vacuo and the product was purified by silica gel chromatography to afford 4-chloro-2-[1,2,4]triazolo[4,3-a]pyrimidin-3-yl-phenylamine as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](/[C:12](=[N:14]/[OH:15])/[NH2:13])=[N:9][C:8]([C@@H:16]([NH:18][C:19]1[N:27]=[CH:26][N:25]=[C:24]3[C:20]=1[N:21]=[CH:22][N:23]3[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[CH3:17])=[CH:7]2.[C:37](OC(=O)C)(=O)[CH3:38]>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([C:12]1[N:13]=[C:37]([CH3:38])[O:15][N:14]=1)=[N:9][C:8]([C@@H:16]([NH:18][C:19]1[N:27]=[CH:26][N:25]=[C:24]3[C:20]=1[N:21]=[CH:22][N:23]3[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)[CH3:17])=[CH:7]2
Reactant: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(/C(N)=N/O)n4)ncnc32)cc1
Reactant: CC(=O)OC(C)=O
Product: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(-c5noc(C)n5)n4)ncnc32)cc1
Temperature: 25 °C

Procedure:
(S,Z)-8-chloro-N′-hydroxy-3-(1-((9-(4-methoxybenzyl)-9H-purin-6-yl)amino)ethyl)isoquinoline-1-carboximidamide 30 (502 mg, 1 mmol, 1.0 eq) was dissolved in acetic anhydride (10 mL) and the resulting mixture was stirred at reflux overnight. The mixture was cooled to RT and concentrated in vacuo to remove acetic anhydride. The resulting suspension was diluted with water (50 mL) and neutralized with concentrated ammonium hydroxide to adjust the pH value to 7-8. The mixture was extracted with DCM (3×100 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (1-10% MeOH-DCM) to afford the product ((S)—N-(1-(8-chloro-1-(5-methyl-1,2,4-oxadiazol-3-yl)isoquinolin-3-yl)ethyl)-9-(4-methoxybenzyl)-9H-purin-6-amine 31.
Reaction SMILES: [NH:1]([C:15]([O:17][CH2:18][CH:19]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[C@H:2]([C:12]([OH:14])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C1(C)C=CC(S(O)(=O)=[O:39])=CC=1.O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[NH:1]([C:15]([O:17][CH2:18][CH:19]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[C@H:2]([C:12]([OH:14])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[O:17]1[CH2:18][C:19](=[O:39])[NH:1][CH2:15]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(N[C@@H](COCc1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1COCN1

Procedure:
A suspension of FMOC-Ser(O-Bzl) (4.16 g), paraformaldahyde (2.0 g), and p-toluenesulfonic acid (0.2 g) in toluene (400 ml) was heated under reflux with azeotropic water removal for 45 min. The solution was cooled, diluted with ethyl acetate (250 ml) and washed three times with 5% aqueous NaHCO3, dried (Na2SO4), and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with (8:2) hexane:ethyl acetate to give FMOC-Ser(O-Bzl)-oxazolidin-4-one as a crystalline product, m.p. 108°-109° C. Fab Mass spec. m/e 430(M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:3]=1.[Br:18][CH2:19][CH2:20]O.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:20][CH2:19][Br:18])=[C:4]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:3]=1
Reactant: Oc1ccc(Br)cc1-c1cc2ccccc2[nH]1
Reactant: OCCBr
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: BrCCOc1ccc(Br)cc1-c1cc2ccccc2[nH]1
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To a mixture of 4-bromo-2-(1H-indol-2-yl)phenol (1.44 g, 5 mmol) and 2-bromoethanol (1.12 g, 9 mmol) in 20 mL of THF was added DBAD (2.07 g, 9 mmol) followed by triphenylphosphine (2.36 g, 9 mmol) in portions at room temperature with stirring. After 1 hour, the reaction was concentrated to near dryness, and purified using flash column chromatography (hexane/EtOAc 30:1) to provide the crude product of 2-(5-bromo-2-(2-bromoethoxy)phenyl)-1H-indole (1.98 g, 100%). MS (M+H)+: 394/396/398.
Reaction SMILES: [CH3:1][C:2]([CH3:25])([CH3:24])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:14]=3[C:15]#[N:16])=[CH:10][CH:11]=2)[N:6]([CH3:22])[C:5]1=[O:23].C(=O)([O-])[O-].[K+].[K+].Cl[C:33]1[CH:38]=[CH:37][N:36]=[C:35]([C:39]#[N:40])[CH:34]=1>CS(C)=O>[C:15]([C:14]1[CH:17]=[CH:18][C:19]([O:21][C:33]2[CH:38]=[CH:37][N:36]=[C:35]([C:39]#[N:40])[CH:34]=2)=[CH:20][C:13]=1[C:9]1[N:8]=[C:7]2[N:6]([CH3:22])[C:5](=[O:23])[N:4]([CH2:3][C:2]([CH3:25])([CH3:24])[CH3:1])[C:12]2=[CH:11][CH:10]=1)#[N:16]
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(-c3cc(O)ccc3C#N)nc21
Reactant: N#Cc1cc(Cl)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(-c3cc(Oc4ccnc(C#N)c4)ccc3C#N)nc21

Procedure:
A solution of 2-[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]-4-hydroxybenzonitrile (16-2, 100 mg, 0.30 mmol) in DMSO (4 ml) was charged with Potassium carbonate (82 mg, 0.59 mmol, 2.0 equiv) and 4-Chloro-pyridine-2-carbonitrile (82 mg, 0.59 mmol, 2.0 equiv). The reaction was irradiated at 160° C. for 20 min. The dark mixture was purified via reverse-phase HPLC (Acetonitrile/Water gradient with 0.1% TFA present) to afford the title compound, 4-{4-cyano-3-[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]phenoxy}pyridine-2-carbonitrile (3), as a pure yellow-tan solid-oil. 1H NMR (500 MHz, CDCl3) δ 8.64 (d, 1H, J=5.6 Hz), 7.91 (d, 1H, J=8.3 Hz), 7.62 (bs, 1H), 7.54 (d, 1H, J=8.1 Hz), 7.36-7.33 (m, 2H), 7.21-7.15 (m, 2H), 3.71 (s, 2H), 3.58 (s, 3H), 1.06 (s, 9H). LRMS m/z: Calc'd for C25H22N6O2 (M+H) 439.0. found 439.1.
Reaction SMILES: Br[C:2]1[C:3](=[O:20])[C:4]([CH2:18][CH3:19])([CH3:17])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>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>[CH2:18]([C:4]1([CH3:17])[C:3](=[O:20])[C:2]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:6]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[O:5]1)[CH3:19]
Reactant: OB(O)c1ccccc1
Reactant: CCC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(Br)C1=O
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: Cc1ccccc1
Product: CCC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(c2ccccc2)C1=O
Yield: 30.2 %

Procedure:
To a stirred solution of 4-bromo-2-ethyl-2-methy-5-{4-(methysulfonyl)-phenyl}-3(2H)-furanone (200 mg) in 15 ml of toluene, were added 40 mg of tetrakis(triphenylphosphine)palladium(0), 5 ml of 2 M aqueous sodium carbonate solution, and 100 mg of benzeneboronic acid. The reaction solution was stirred at reflux for 12 hours. Then the reaction solvent was evaporated under reduced pressure. The resulting residue was extracted with water and dichloromethane (30 ml×3). The organic layer was concentrated in vacuo. The resulting crude product mixture was purified by column chromatography (hexane/ethylacetate=2:1) to give 60 mg of 2-ethyl-2-methyl-5-{4-(methylsulfonyl)phenyl}-4-phenyl-3(2H)-furanone as a solid. mp: 115-117° C. NMR: δ0.96 (t, J=7.5 Hz, 3H), 1.55 (s, 3H), 1.97 (q, J=7.5 Hz, 2H), 3.07 (s, 3H), 7.37 (m, 5H), 7.85 (d, J=8.7 Hz, 2H), 7.93 (d, J=8.7 Hz, 2H). IR (cm−1): 2928, 1697, 1620, 1403, 1318, 1149, 959, 769, 552.