Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[F:25][C:26]([F:35])([F:36])[C:27]1[CH:34]=[CH:33][C:30]([CH2:31][N:15]2[C:14](=[O:17])[N:11]3[N:12]=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[C:9]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[C:10]3=[N:16]2)=[CH:29][CH:28]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1n(Cc2ccc(C(F)(F)F)cc2)nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Temperature: 90 °C
Yield: 27.7 %

Procedure:
A solution of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (300 mg, 0.84 mmol), prepared as described in Example 1, 4-(trifluoromethyl)benzyl bromide (200 mg, 0.84 mmol) and K2CO3 (290 mg, 2.1 mmol) in DMF (10 ml), was heated at 90° C. for 2 hours. After this time, the reaction mixture was cooled to RT and diluted with ethyl acetate. The resultant solution was then washed with water. The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by preparative HPLC to give the title compound, 2-(4-(trifluoromethyl)benzyl)-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (120 mg, 28%) as a yellow solid. MS M+H=515; 1H NMR (CDCl3) δ 8.19 (1H), 7.60 (2H), 7.50 (2H), 7.34 (4H), 7.28 (2H), 7.10 (2H), 5.27 (2H).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1CCN2C(=NCCC2)CC1.[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(#N)C>[CH2:32]([O:19][C:18](=[O:20])[C@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([I:17])=[CH:15][CH:16]=1)[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)cc1)C(=O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-Boc-4-iodophenylalanine was dissolved in acetonitrile and DBU (1 equivalent) was added followed by benzyl bromide (1 equivalent). The mixture was stirred for 2 h at room temperature. After removal of the solvent under reduced pressure, the residue was dissolved in EtOAc and the solution washed with 10% aqueous HCl and water. Drying (MgSO4) and concentration under reduced pressure gave a crude product that was purified by crystallization from hexane.
Reaction SMILES: [CH3:1][CH:2]([CH3:32])[CH2:3][CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([Si:11]2(C3C=CC=CC=3)[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[C:21]([F:23])[C:20]([OH:24])=[C:19]([F:25])[CH:18]=3)[CH2:13][CH2:12]2)[CH2:7][CH2:6]1.[F:33][C@@H:34]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:35]O>>[CH3:1][CH:2]([CH3:32])[CH2:3][CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([Si@H:11]2[CH2:12][CH2:13][C@H:14]([C:17]3[CH:18]=[C:19]([F:25])[C:20]([O:24][CH2:35][C@H:34]([F:33])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[C:21]([F:23])[CH:22]=3)[CH2:15][CH2:16]2)[CH2:7][CH2:6]1
Reactant: CCCCCCCC[C@H](F)CO
Reactant: CC(C)CC[C@H]1CC[C@H]([Si]2(c3ccccc3)CCC(c3cc(F)c(O)c(F)c3)CC2)CC1
Product: CCCCCCCC[C@@H](F)COc1c(F)cc([C@H]2CC[Si@H]([C@H]3CC[C@H](CCC(C)C)CC3)CC2)cc1F

Procedure:
The general procedure of Example 1 was repeated using 4-(4-(trans-4-(3-methylbutyl)cyclohexyl)-4-phenyl-4-silacyclohexyl)-2,6-difluorophenol and (S)-2-fluoro-1-decanol, thereby obtaining the intended compound.
Reaction SMILES: Cl.[N+:2]([C:5]1[C:6]([NH:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].[NH:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[C:27](O)=[O:28].N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>CN(C)C=O.O>[NH:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[C:27]([N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:6]2[C:5]([N+:2]([O-:4])=[O:3])=[CH:10][CH:9]=[CH:8][N:7]=2)[CH2:13][CH2:14]1)=[O:28]
Reactant: O=[N+]([O-])c1cccnc1NC1CCNCC1
Reactant: O=C(O)c1nc2ccccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: O=C(c1nc2ccccc2[nH]1)N1CCC(Nc2ncccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.3 %

Procedure:
A mixture of 3-nitro-N-(piperidin-4-yl)pyridin-2-amine hydrochloride (intermediate 58, 580 mg, 2.3 mmol), 1H-benzo[d]imidazole-2-carboxylic acid (365 mg, 2.3 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (365 mg, 2.7 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (516 mg, 2.7 mmol) and N-methylmorpholine (455 mg, 4.6 mmol) in dry dimethylformamide (15 mL) was stirred at room temperature overnight. The mixture was diluted with water (60 mL), and extracted with ethyl acetate (2×50 mL). The organic layer was washed with brine, dried over sodium sulfate and concentrated to give the crude compound which was purified by silica chromatography to afford (1H-benzo[d]imidazol-2-yl)(4-((3-nitro-pyridin-2-yl)amino)piperidin-1-yl)methanone (600 mg, 1.64 mmol, 72.8% yield).
Reaction SMILES: I[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[NH:16][C:15](=[O:22])/[C:14]/2=[CH:23]\[NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([OH:33])[CH:27]=1>CN(C)C=O>[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[NH:16][C:15](=[O:22])/[C:14]/2=[CH:23]\[NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:2][CH3:3])=[C:28]([OH:33])[CH:27]=1
Reactant: CCI
Reactant: O=C1NC(=O)c2ccc(Br)cc2/C1=C/NCc1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(CN/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)cc1O
Temperature: 25 °C
Yield: 24 %

Procedure:
To a solution of 1-iodoethane (43.3 μl, 0.28 mmol) in anhydrous N,N-dimethylformamide (2 ML) is added potassium carbonate (207 mg, 1.5 mmol). The mixture stirred at room temperature and (4Z)-6-bromo-4-{[(3,4-dihydroxybenzyl)amino]methylene} isoquinoline-1,3(2H,4H)-dione (100 mg, 0.26 mmol) is added. After the mixture is stirred at 65° C. for 30 min, the resulting mixture is concentrated and the residue is then partitioned between water (50 ml) and ethyl acetate (50 ml). The organic layer is then dried and purified by high performance liquid chromatography to give 26 mg of a white solid. MS (ESI) m/z 416.7 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.C(Cl)(=O)C([Cl:14])=O.CN(C=O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:14])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
A carboxylic acid, e.g., 6-Chloronicotinic acid (3.151 g, 20 mmol) was dissolved in dry DCM. The mixture was cooled down to 0° C. Oxalyl chloride (2.58 mL, 30 mmol) followed by DMF (77 μL) were added. The mixture was stirred at 0° C. for 1 h 30, then at RT overnight. The solvents were evaporated. The crude product was dissolved in toluene and the solvents were evaporated again to give the corresponding acid chloride (XVIII*), e.g., 6-chloronicotinoyl chloride (2.886 g, 82% yield). It was dissolved in benzene (50 mL) and AlCl3 (5.248 g, 39.4 mmol) was added. The mixture was stirred overnight at 80° C. After cooling down to RT, water was added. The two phases were separated and the aqueous layer was extracted with two portions of ethyl acetate. Combined organic layers were washed with brine and dried over MgSO4, filtrated and concentrated to give the desired product (XIX*), e.g., (6-chloropyridin-3-yl)(phenyl)methanone as a yellowish oil (3.884 g, 67% yield). It was used in the next step without further purification.
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:18])=[CH:13][CH:14]=[N:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[N:32]=[CH:31][CH:30]=[C:29]2[OH:36])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[N+:37]([O-:40])([OH:39])=[O:38]>>[CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:18])=[C:13]([N+:37]([O-:39])=[O:38])[CH:14]=[N:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:19]([C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[N:32]=[CH:31][C:30]([N+:37]([O-:40])=[O:38])=[C:29]2[OH:36])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Oc1ccnc2cc(Cc3ccccc3)ccc12
Reactant: Oc1ccnc2ccc(Cc3ccccc3)cc12
Reactant: O=[N+]([O-])O
Product: O=[N+]([O-])c1cnc2cc(Cc3ccccc3)ccc2c1O
Product: O=[N+]([O-])c1cnc2ccc(Cc3ccccc3)cc2c1O

Procedure:
The method described in Part D of Example 10 was used to treat 7-benzylquinolin-4-ol or 6-benzylquinolin-4-ol with nitric acid to provide 7-benzyl-3-nitroquinolin-4-ol or 6-benzyl-3-nitroquinolin-4-ol, respectively, as solids.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]([C:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:19][CH:20]=2)[N:15]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[C:14]=1[CH3:37])=[N:11][OH:12].CC([O-])=O.[Na+].CC(OC(C)=O)=O>CN(C=O)C.C(Cl)Cl>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]2[C:10]([C:13]3[C:21]4[C:16](=[CH:17][C:18]([O:22][C:23]([F:26])([F:24])[F:25])=[CH:19][CH:20]=4)[N:15]([S:27]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)(=[O:28])=[O:29])[C:14]=3[CH3:37])=[N:11][O:12][C:2]=2[CH:7]=1
Reactant: COc1ccc(C(=NO)c2c(C)n(S(=O)(=O)c3ccc(C)cc3)c3cc(OC(F)(F)F)ccc23)c(O)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2c(-c3c(C)n(S(=O)(=O)c4ccc(C)cc4)c4cc(OC(F)(F)F)ccc34)noc2c1
Temperature: 110 °C

Procedure:
To a solution of 9 (3.8 g, 7.1 mmol) and NaOAc (3 eq, 1.8 g) in DMF (120 mL) was added Ac2O (3 eq, 2 mL). The reaction was heated to 110° C. for 4 hours at which time no starting material was detected by LC analysis. The reaction was cooled and diluted with DCM. The solution was washed with NH4Cl, brine and NaHCO3, then dried over Na2SO4 and concentrated. The residue was purified via flash chromatography eluding with 20% EtOAc/hexanes. Product was isolated as white foam.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2)=[O:2].[H-].[Na+].[N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1/[CH:24]=[CH:25]/[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Cl.O>CN(C)C=O.C1COCC1>[N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1/[CH:24]=[CH:25]/[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[CH:4][C:3]=2[CH:1]=[O:2])[CH:8]=[CH:9]1
Reactant: ClCc1cccc(/C=C/c2ccc3ccccc3n2)c1
Reactant: O=Cc1cccc2cc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cccc2ccn(Cc3cccc(/C=C/c4ccc5ccccc5n4)c3)c12
Reaction time: 0.5 h

Procedure:
A solution of 7-formyl indole (Example 10a (iv) (2 g, 13.8 mmole) in dry dimethyl formamide (40 ml) was cooled in an ice bath and stirred as sodium hydride (60% dispersion in mineral oil) (0.66 g, 16.5 mmole) was added in portions over 10 minutes. The mixture was stirred for a further 30 minutes, then a solution of 3-[2-(E)-quinolin-2-yl ethenyl]benzyl chloride (Example 1b) (4.24 g, 15.2 mmole) in dry THF (12 ml) was added over 2 minutes. The reaction mixture was stirred at room temperature for 3 days, then poured into water, extracted into ethyl acetate, dried and evaporated. The residue was chromatographed on silica, eluting with ethyl acetate-hexane (1:3) to give the product.
Reaction SMILES: [N:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[CH3:14])=[C:2]=[O:3].[NH2:15][C:16]([CH3:20])([CH3:19])[CH2:17][OH:18]>C1COCC1>[CH3:19][C:16]([NH:15][C:2](=[O:3])[NH:1][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[CH3:14])([CH3:20])[CH2:17][OH:18]
Reactant: COC(=O)c1ccc(N=C=O)c(C)c1
Reactant: CC(C)(N)CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC(=O)NC(C)(C)CO)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5.70 g (29.8 mmol) methyl 4-isocyanato-3-methyl-benzoate are dissolved in 100 ml THF and a solution of 2.86 ml (30.0 mmol) 2-amino-2-methyl-propan-1-ol in 25 ml THF is added dropwise. The mixture is stirred for 2 hours at ambient temperature and then evaporated down i. vac. The residue is further reacted without any more purification.
Reaction SMILES: [NH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)[NH2:2].Br[CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([CH3:22])=[N:20][CH:21]=1>C(N(CC)CC)C>[CH3:22][C:19]1[N:20]=[CH:21][C:16]([CH2:15][CH2:14][N:1]([C:3]2[CH:4]=[CH:5][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:11][CH:12]=2)[NH2:2])=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc(NN)cc1
Reactant: Cc1ccc(CCBr)cn1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(N(N)CCc2ccc(C)nc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
Methyl 4-hydrazinylbenzoate (1 g, 0.005 moles) and 5-(2-bromoethyl)-2-methylpyridine (1 g, 0.005 moles) was taken up in 2.1 mL of triethylamine and stirred at RT for 1 hr. The reaction was then heated at 100 degrees C., overnight. LCMS analysis of the reaction mixtures shows the formation of product. Reaction mixture was concentrated, water (20 mL) was added to the reaction mixture and the mixture extracted with ethyl acetate. The crude product was dissolved in ethyl acetate and purified by column chromatography using neutral alumina, using 100% ethyl acetate as the eluent. After chromatography 400 mg of Methyl 4-(1-(2-(6-methylpyridin-3-yl)ethyl)hydrazinyl)benzoate was obtained, 28.5% yield.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][NH2:13]>>[F:8][C:5]1[CH:6]=[CH:7][C:2]([NH:13][CH3:12])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: CN
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Product: CNc1ccc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7.3 g of 1,4-difluoro-2-nitrobenzene are slowly added to 30 ml of a 40% aqueous methylamine solution whilst cooling with ice and the reaction mixture is stirred for 1 hour at ambient temperature. The precipitated product is suction filtered and recrystallised from water and ethanol. 6.3 g product are obtained as a solid. M.p=74-76° C.
Reaction SMILES: Br[CH:2]([C:7]1[C:11]([C:12]2[CH:13]=[CH:14][C:15]3[O:20][CH2:19][CH2:18][CH2:17][C:16]=3[CH:21]=2)=[C:10]([CH3:22])[S:9][C:8]=1[CH3:23])[C:3]([O:5][CH3:6])=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:30][C:31]([SH:34])([CH3:33])[CH3:32]>CN(C)C=O>[C:31]([S:34][CH:2]([C:7]1[C:11]([C:12]2[CH:13]=[CH:14][C:15]3[O:20][CH2:19][CH2:18][CH2:17][C:16]=3[CH:21]=2)=[C:10]([CH3:22])[S:9][C:8]=1[CH3:23])[C:3]([O:5][CH3:6])=[O:4])([CH3:33])([CH3:32])[CH3:30]
Reactant: COC(=O)C(Br)c1c(C)sc(C)c1-c1ccc2c(c1)CCCO2
Reactant: CC(C)(C)S
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)C(SC(C)(C)C)c1c(C)sc(C)c1-c1ccc2c(c1)CCCO2
Temperature: 25 °C
Reaction time: 5 h
Yield: 55.6 %

Procedure:
A mixture of methyl 2-bromo-2-[4-(3,4-dihydro-2H-1-benzopyran-6-yl)-2,5-dimethylthiophen-3-yl]acetate (32a) (50 mg, 0.126 mmol), cesium carbonate (82 mg, 0.253 mmol) and 2-methyl-2-propanethiol (23 mg, 0.253 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 5 hours. The reaction mixture was quenched with water (6 mL) and extracted with ethyl acetate (4×5 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC (cyclohexane/ethyl acetate 80/20) to provide the desired thio-ether (32b) (28 mg, 0.07 mmol, 55%) as a clear yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:23]=[C:22]([CH3:24])[O:21][N:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[N:28]1([CH2:34][C:35]2[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(OCC)C>[Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:23]=[C:22]([CH3:24])[O:21][N:20]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:39]([C:38]3[CH:37]=[CH:36][C:35]([CH2:34][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:42][CH:41]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=Cc1ccc(CN2CCOCC2)cc1
Reactant: Cc1cc(CN2CCN(c3c(Cl)cnc(N)c3[N+](=O)[O-])CC2)no1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: Cc1cc(CN2CCN(c3c(Cl)cnc4[nH]c(-c5ccc(CN6CCOCC6)cc5)nc34)CC2)no1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
To a mixture of 5-chloro-4-[4-(5-methyl-isoxazol-3-ylmethyl)-piperazin-1-yl]-3-nitro-pyridin-2-ylamine (0.031 g, 0.09 mmol) and EtOH (3.0 ml) was added 4-morpholin-4-ylmethyl-benzaldehyde (0.025 g, 0.12 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.36 ml, 0.36 mmol). The reaction mixture was stirred at 80° C. for 20 h, then allowed to cool to room temperature and concentrated in vacuo. The resulting residue was absorbed on silica, and the free-running powder was placed on a 10 g isolute silica column. Elution with a gradient of methanol (0 to 7%) in ethyl acetate/dichloromethane (v:v; 1:1) afforded a yellow solid. The title compound was obtained as a yellow solid after trituration with diethyl ether (0.018 g, 39%); 1H-NMR (500 MHz, DMSO-d6) 2.38 (br s, 4H) and 3.58 (t, J=4.8 Hz, 4H) (morpholine N(CH2)2 and morpholine O(CH2)2), 2.40 (s, 3H, isoxazole 5-CH3), 2.63 (br s, 4H, piperazine N(CH2)2), 3.53 (s, 2H) and 3.60 (s, 2H) (C6H4CH2N and NCH2 isoxazole), 3.70 (br s, 4H, piperazine N(CH2)2), 6.25 (s, 1H, isoxazole 4-H), 7.47 (d, J=8.2 Hz, 2H) and 8.13 (d, J=8.2 Hz, 2H) (3,5-C6H4— and 2,6-C6H4—), 8.11 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.48 (br s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:25]>>[Br-:1].[C:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N+:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])=[CH:8][CH:9]=1
Reactant: Cc1ccccn1
Reactant: BrCCCCCc1ccc(-c2ccccc2)cc1
Product: Cc1cccc[n+]1CCCCCc1ccc(-c2ccccc2)cc1
Product: [Br-]
Temperature: 65 °C
Yield: 84 %

Procedure:
A mixture of 4-(5-bromopentyl)-1,1′-biphenyl (358 mg, 1.18 mmol) and 2-picoline (1 mL) was heated at 60-70° C. for 12 hrs. The resulting mixture was washed with diethyl ether and then dissolved in water (15 mL). The aqueous solution was extracted with diethyl ether (30 mL×3). Water was removed by lyophilization to afford 393 mg of the title compound. Yield: 84%. 1H NMR (300 MHz, CDCl3) δ 1.53 (m, 2H), 1.71 (m, 2H), 1.95 (m, 2H), 2.65 (t, J=7.5 Hz, 2H), 2.92 (s, 3H), 4.83 (t, J=8.1 Hz, 2H), 7.20-7.60 (m, 9H), 7.89-8.02 (m, 2H), 8.38 (d, J=7.5 Hz, 1H), 9.53 (d, J=6.0 Hz, 1H) ppm; 13C NMR (75 MHz, CDCl3) δ 20.9, 25.9, 30.6, 30.8, 35.2, 58.3, 126.3, 126.8, 126.9, 127.0, 128.7, 128.8, 130.3, 138.5, 140.7, 140.9, 145.2, 146.3, 154.1 ppm.
Reaction SMILES: [I-].[CH3:2][S+](C)C.[H-].[Na+].[C:8]([O:12][C:13](=[O:21])[NH:14][C@H:15]([CH3:20])[CH:16]=[CH:17][C:18]#[N:19])([CH3:11])([CH3:10])[CH3:9]>CS(C)=O.O.C(OCC)(=O)C>[C:8]([O:12][C:13](=[O:21])[NH:14][C@@H:15]([CH:16]1[CH2:2][CH:17]1[C:18]#[N:19])[CH3:20])([CH3:11])([CH3:9])[CH3:10]
Reactant: C[S+](C)C
Reactant: C[C@H](C=CC#N)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: C[C@@H](NC(=O)OC(C)(C)C)C1CC1C#N
Temperature: 25 °C
Reaction time: 48 h

Procedure:
DMSO was added to trimethylsulfonium iodide (1.79 g, 8.15 mmol) and sodium hydride (60% in mineral oil, 326 mg, 8.15 mmol) at 0° C. Then a 3:1 E:Z mixture of ((R)-3-cyano-1-methyl-allyl)-carbamic acid tert-butyl ester (0.4 g, 2.04 mmol) in DMSO was added. The reaction mixture was left to warm up to room temperature overnight. The reaction was stirred at room temperature for 2 days then diluted with water and ethyl acetate. The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 80 g, 20% to 50% EtOAc in hexanes) to provide [(R)-1-(2-cyanocyclopropyl)-ethyl]-carbamic acid tert-butyl ester as two discreet diastereomers (arbitrarily assigned). Diastereomer A (250 mg, 58%) as a colorless oil; MS: (M+H)+=211. Diastereomer B (130 mg, 30%) as a white powder; M+Na)+=233.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=O.Cl[C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][N:14]=1.ClC1C=C(Cl)C=CC=1C1[C:34]([C:35]2[NH:36][CH:37]=[CH:38][N:39]=2)=[CH:33][N:32]=[C:31]([NH:40][CH2:41][CH2:42][NH:43]C2C=CC([N+]([O-])=O)=CN=2)[N:30]=1>>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]1[C:34]([C:35]2[NH:36][CH:37]=[CH:38][N:39]=2)=[CH:33][N:32]=[C:31]([NH:40][CH2:41][CH2:42][NH:43][C:13]2[N:14]=[CH:15][C:16]([C:19]#[N:20])=[CH:17][CH:18]=2)[N:30]=1
Reactant: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Reactant: N#Cc1ccc(Cl)nc1
Product: N#Cc1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(F)cc3Cl)n2)nc1

Procedure:
6-[(2-{[4-(2-chloro-4-fluorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]amino}ethyl)amino]pyridine-3-carbonitrile was prepared from 2-chloro-4-fluorobenzoyl chloride and 2-chloro-5-(cyano)pyridine using the general method for [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:15][C:16]([F:23])([C:19]([F:22])([F:21])[F:20])[CH2:17][OH:18]>>[CH3:14][S:11]([C:8]1[CH:9]=[CH:10][C:2]([O:18][CH2:17][C:16]([F:23])([F:15])[C:19]([F:22])([F:21])[F:20])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])(=[O:13])=[O:12]
Reactant: OCC(F)(F)C(F)(F)F
Reactant: CS(=O)(=O)c1ccc(F)c(C(=O)O)c1
Product: CS(=O)(=O)c1ccc(OCC(F)(F)C(F)(F)F)c(C(=O)O)c1

Procedure:
Prepared in analogy to Example A14(c) from 2-fluoro-5-methanesulfonyl-benzoic acid (Example A14(b)) and 2,2,3,3,3-pentafluoro-1-propanol. MS (m/e): 346.9 ([M−H]−, 100%)
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]2[C:10]([C:11]=1[CH2:12][C:13]([NH2:15])=[O:14])=[C:9]([OH:16])[CH:8]=[CH:7][CH:6]=2)[CH3:2].[H-].[Na+].Br[CH2:27][C:28]([O:30][CH3:31])=[O:29]>CN(C=O)C.O>[CH3:31][O:30][C:28](=[O:29])[CH2:27][O:16][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[C:11]([CH2:12][C:13]([NH2:15])=[O:14])=[C:3]([CH2:1][CH3:2])[N:4]2[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)CBr
Reactant: CCc1c(CC(N)=O)c2c(O)cccc2n1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1c(CC(N)=O)c2c(OCC(=O)OC)cccc2n1Cc1ccccc1
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
2-Ethyl-4-hydroxy-1-(phenylmethyl)-1H-indole-3-acetamide (135 mg, 0.44 mmol) was added to 17.6 mg (0.44 mmol) of NaH/mineral oil (washed with hexanes) in 5 mL of DMF, stirred 0.5 hour, 0.04 mL (0.44 mmol) of methyl 2-bromoacetate added and stirring maintained for 5 hours. The mixture was diluted with water, extracted with ethyl acetate. Some material was insoluble and was filtered. The ethyl acetate was washed with brine, dried (MgSO4) and concentrated. The residue was combined with the filtered material to give 119 mg (71% yield) of 2-[[3-(2-amino-2-oxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetic acid methyl ester.