Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C@H:2]1[C@H:8]([OH:9])[CH2:7][CH2:6][N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4][CH2:3]1.[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([O-:19])=[O:18].CCN(CC)CC>C(Cl)Cl>[F:1][C@H:2]1[C@H:8]([O:9][S:26]([C:23]2[CH:22]=[CH:21][C:20]([N+:17]([O-:19])=[O:18])=[CH:25][CH:24]=2)(=[O:27])=[O:28])[CH2:7][CH2:6][N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4][CH2:3]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)[C@H](F)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@@H](F)[C@H](OS(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 83 %

Procedure:
trans-tert-butyl 4-fluoro-5-hydroxyazepane-1-carboxylate (12.36 g, 52.98 mmol) was dissolved in CH2Cl2 (110 mL). The solution was cooled to 0° C., 4-nitrobenzene-1-sulfonyl chloride (14.09 g, 63.58 mmol) was added and the mixture was stirred for 10 minutes. NEt3 (11.08 mL, 79.48 mmol) was added and the mixture was slowly warmed to ambient temperature over 1 hour and stirred for an additional 2 hours. The mixture was diluted with CH2Cl2 and washed with water followed by 1N KHSO4 (2×50 mL), then with saturated aqueous NaHCO3 (50 mL) and brine, and the combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified via column chromatography (10 to 70% MTBE/hexanes) to provide 18.4 g of the product (84%) as a single isomer and as a faint orange powder.
Reaction SMILES: [OH-].[Na+].O.[CH2:4]1[CH:9]2[C:10]3[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=3[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:8]2[CH2:7][CH2:6][N:5]1[CH2:23][CH2:24][O:25][CH2:26][C:27]([O:29]CC)=[O:28]>C(O)C>[CH2:4]1[CH:9]2[C:10]3[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=3[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:8]2[CH2:7][CH2:6][N:5]1[CH2:23][CH2:24][O:25][CH2:26][C:27]([OH:29])=[O:28]
Reactant: CCOC(=O)COCCN1CCN2c3ccccc3Cc3ccccc3C2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)COCCN1CCN2c3ccccc3Cc3ccccc3C2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7 ml of a 10% w/v aqueous solution of sodium hydroxide and 10 ml of water were added to a solution of 3.2 g of ethyl 2-(1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepin-2-yl)ethoxyacetate (prepared as described in Example 1) dissolved in 20 ml of ethanol. The mixture was then stirred at room temperature for 1 hour, after which it was concentrated to about one half of its original volume by distillation under reduced pressure. The pH of the concentrate was then adjusted to a value of 4.0 by the addition of 10% w/v aqueous hydrochloric acid, and the mixture was extracted with chloroform. Concentration of the extract by evaporation under reduced pressure yielded 2.96 g (a quantitative yield) of the title compound as a foamy substance, which was recrystallized from water to give colorless needles, melting at 135° C. (with decomposition).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([OH:10])=[C:5]([Cl:11])[CH:4]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>O>[Cl:9][C:7]1[CH:8]=[C:3]([CH:4]=[C:5]([Cl:11])[C:6]=1[OH:10])[NH:2][C:12](=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Agent: Cl
Solvent: O
Product: CC(=O)Nc1cc(Cl)c(O)c(Cl)c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Into a 500 ml round bottom flask (fitted with a magnetic stirrer), water (200 ml) was mixed with 4-amino-2,6-dichlorophenol hydrochloride (20 g) until the solid was completely dissolved. The resulting solution was warmed to 70° C., and to it was added acetic anhydride (11 g) and the resulting solution was stirred for 1 hour. Upon cooling, crystals of 3', 5'-dichloro-4'-hydroxyacetanilide formed (19.6 g, 95% yield).
Reaction SMILES: [CH3:1][NH:2][S:3](Cl)(=[O:5])=[O:4].[Cl:7][C:8]1[CH:17]=[CH:16][C:11]([O:12][CH2:13][CH2:14][OH:15])=[CH:10][CH:9]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:7][C:8]1[CH:17]=[CH:16][C:11]([O:12][CH2:13][CH2:14][O:15][S:3](=[O:5])(=[O:4])[NH:2][CH3:1])=[CH:10][CH:9]=1
Reactant: CNS(=O)(=O)Cl
Reactant: OCCOc1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CNS(=O)(=O)OCCOc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 33.5 %

Procedure:
To a stirred solution of 45.0 g (0.347 mole) of methylsulfamoyl chloride prepared above in 100 ml of methylene chloride was added in a thin stream a solution of 25.0 g (0.145 mole) of 2-(4-chlorophenoxy)ethanol (Lancaster Synthesis, Inc., Windham, N.H. 03087) in 30 ml (0.369 mole) of pyridine and 100 ml of methylene chloride and the reaction mixture was stirred at ambient temperature for 3 days. The solids were removed by filtration and the filtrate was evaporated under reduced pressure to yield a brown viscous residue. The residue was partitioned between water and ethyl ether (400 ml each). The organic layer was washed twice with 300 ml portions of water, dried over magnesium sulfate and the solvent evaporated under reduced pressure to yield a solid residue. The solid was triturated with 100 ml of isopropyl ether and the solid was recollected by filtration. The solid was recrystallized from isopropyl ether to give 12.9 g (34%) of title compound as a white solid, m.p. 101° -104° C.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][C@H:8]([C@@H:23]1[CH2:28][CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24]1)[C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=2)[C:12]([F:15])=[CH:13][CH:14]=1)(=[O:3])[CH3:2].C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:15][C:12]1[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=2)=[CH:10][C:9]([C@@H:8]([C@@H:23]2[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]2)[CH2:7][CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])=[CH:14][CH:13]=1
Reactant: CC(=O)NCCC[C@@H](c1ccc(F)c(-c2cccc(C)c2)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NCCC[C@@H](c1ccc(F)c(-c2cccc(C)c2)c1)[C@@H]1CCCNC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
(S)-tert-butyl 3-((R)-4-acetamido-1-(6-fluoro-3′-methylbiphenyl-3-yl)butyl)piperidine-1-carboxylate (40 mg, 0.083 mmol) was dissolved in a solution of 20% (V/V) TFA/CH2Cl2 (3 mL). The reaction mixture was stirred at rt for 1 h (monitored by HPLC) and a solution of satd aq NaHCO3 was added dropwise to adjust the pH to 7-8. The resulting mixture was extracted with CH2Cl2 (3×5 mL) and the combined extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo to afford N—((R)-4-(6-fluoro-3′-methylbiphenyl-3-yl)-4-((S)piperidin-3-yl)butyl)acetamide (30 mg, 94%). MS (E/Z): 383 (M+H+).
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][CH2:5][NH2:6].C(N(C(C)C)CC)(C)C.[CH:16]1[C:28]2[CH:27]([CH2:29][O:30][C:31](Cl)=[O:32])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1>ClCCl>[CH:16]1[C:28]2[CH:27]([CH2:29][O:30][C:31]([NH:6][CH2:5][CH2:4][CH2:3][Br:2])=[O:32])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: NCCCBr
Agent: Br
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCCBr)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
To a solution of 3-bromopropylamine hydrobromide (5.0 g) and diisopropylethylamine (5.90 g) in dichloromethane (80 ml) was added portionwise 9-fluorenylmethoxycarbonyl chloride (5.91 g) and the mixture was stirred at ambient temperature for 3 hours and stand overnight. The resulting mixture was diluted with dichloromethane (50 ml) and the organic layer was washed successively with 1N hydrochloric acid and brine. Drying, filtering and removal of solvents afforded a crude product. The crude product was triturated with diethyl ether-hexane (1:5) to give 3-(9-fluorenylmethoxycarbonylamino)propyl bromide (7.82 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:16]=[CH:15][N:14]=[C:13](Cl)[CH:12]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:12]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: Clc1ccn2c(-c3ccnc(Cl)c3)cnc2c1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Clc1ccn2c(-c3ccnc(-c4ccccc4)c3)cnc2c1

Procedure:
7-Chloro-3-(2-chloro-pyridin-4-yl)-imidazo[1,2-a]pyridine (1 eq, 1.136 mmol, 300 mg) and phenyl boronic acid (1 eq, 1.136 mmol, 138 mg) are dissolved in DME (3 ml) and water (1 ml) and Na2CO3 (2 eq, 2.27 mmol, 282 mg) is added. PdCl2(PPh3)2 (0.1 eq, 0.114 mmol, 79.7 mg) is added and the reaction mixture is heated using microwave radiation at 120° C. for 10 min. At the completion of this time the solvent is removed in vacuo and the reaction mixture is purified by flash column chromatography eluting with 8:2 DCM/MeOH to yield 7-chloro-3-(2-phenyl-pyridin-4-yl)-imidazo[1,2-a]pyridine as a yellow solid; [M+H]+=306
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.[K+].C(N(CC)CC)C.[Cl-].[Mg+2].[Cl-].[Br:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)C(Cl)=O>C(#N)C>[CH2:8]([O:7][C:1](=[O:6])[CH2:2][C:3]([C:29]1[CH:28]=[CH:24][CH:23]=[C:22]([Br:21])[CH:30]=1)=[O:5])[CH3:9]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=C(Cl)c1cccc(Br)c1
Agent: [Cl-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)CC(=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
To potassium ethyl malonate (3.25 g, 19.13 mmol) in acetonitrile (50 mL) was sequentially added triethyl amine (4.1 mL, 29.16 mmol) and magnesium chloride (2.16 g, 22.78 mmol) at room temperature. After stirring the reaction mixture at room temperature for 2 hours, 3-bromobenzoyl chloride (2.0 g, 9.11 mmol) was added and the mixture was heated at 60° C. for 18 hours, concentrated under reduced pressure and partitioned between ethyl acetate (100 mL) and 1N HCl (25 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated under reduced pressure to yield the title compound (2.45 g, 99 %). 1H NMR (CDCl3): δ 8.1 (s, 1H), 7.85 (d, 1H), 7.7 (d, 1H), 7.35 (t, 1H), 4.3 (m, 2H), 3.4 (s, 1H), 1.3 (m, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:10]2[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH:35]1([CH2:38][S:39](Cl)(=[O:41])=[O:40])[CH2:37][CH2:36]1>ClCCl>[CH2:13]([CH:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([CH2:2][NH:1][S:39]([CH2:38][CH:35]3[CH2:37][CH2:36]3)(=[O:41])=[O:40])[CH:12]=2)[CH2:7][CH2:8][CH:9]1[NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=S(=O)(Cl)CC1CC1
Reactant: CC(C)(C)OC(=O)NC1CCc2ccc(CN)cc2C1Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCc2ccc(CNS(=O)(=O)CC3CC3)cc2C1Cc1ccccc1
Reaction time: 8 h
Yield: 75.7 %

Procedure:
tert-Butyl 7-(aminomethyl)-1-benzyl-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate (0.600 g, 1.637 mmol) was suspended in dichloromethane (5 mL) and triethylamine (0.228 mL, 1.637 mmol) and cooled to 0° C. Cyclopropylmethanesulfonyl chloride (0.253 g, 1.637 mmol) was added. The solid immediately dissolved. The mixture was stirred overnight and then diluted with dichloromethane and washed with brine (3×50 mL). The organic extract was collected dried on MgSO4 and evaporated under reduced pressure. The residue was purified by flash-chromatography on silica gel (100% dichloromethane 5 minutes then gradient to 1% MeOH in dichloromethane). Product was isolated as white powder (601.9 mg, 1.24 mmol, 76%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)#[N:2].[OH-].[Na+].[I:14]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[I:14])#[N:2]
Reactant: N#Cc1ccc2[nH]ccc2c1
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: N#Cc1ccc2[nH]cc(I)c2c1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 74.9 %

Procedure:
5-Cyanoindole (0.500 g, 3.52 mmol) was dissolved in DMF (25 mL), and sodium hydroxide (0.493 g, 8.79 mmol) and iodine (0.902 g, 3.55 mmol) were added thereto, then the mixture was stirred at room temperature for 25 minutes. A saturated aqueous sodium thiosulfate solution was added to the mixture, and the precipitated solid was filtered off to give 5-cyano-3-iodoindole (0.707 g, 75%).
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:10][S:11]([CH2:14][CH2:15][CH3:16])(=[O:13])=[O:12].[N:17]1[CH:22]=[CH:21][N:20]=[C:19]2[NH:23][CH:24]=[CH:25][C:18]=12.[OH-].[K+].O>CO>[F:1][C:2]1[C:7]([CH:8]([OH:9])[C:25]2[C:18]3[C:19](=[N:20][CH:21]=[CH:22][N:17]=3)[NH:23][CH:24]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:10][S:11]([CH2:14][CH2:15][CH3:16])(=[O:13])=[O:12]
Reactant: c1cnc2[nH]ccc2n1
Reactant: CCCS(=O)(=O)Nc1cccc(C=O)c1F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCS(=O)(=O)Nc1cccc(C(O)c2c[nH]c3nccnc23)c1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 48.4 %

Procedure:
To propane-1-sulfonic acid (2-fluoro-3-formyl-phenyl)-amide (18, 50 mg, 0.42 mmol) in 0.8 mL of methanol, 5H-pyrrolo[2,3-b]pyrazine (3, 103 mg, 0.42 mmol) and potassium hydroxide (71 mg, 1.3 mmol) were added under an atmosphere of nitrogen. The reaction was stirred at room temperature for 48 hours, then poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with 60% ethyl acetate in dichloromethane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as a solid (19, 74 mg, 49%). MS (ESI) [M−H+]−=363.5.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](Br)=[CH:4][C:3]=1[CH3:10].[O:11]1[CH2:16][CH:15]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH2:13][CH2:12]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:14]2[CH2:15][CH2:16][O:11][CH2:12][CH:13]=2)=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(Br)cc(C)c1Br
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc(C2=CCOCC2)cc(C)c1Br
Temperature: 60 °C
Reaction time: 12 h

Procedure:
In a microwave vial 2,5-dibromo-1,3-dimethylbenzene (800 mg), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (640 mg) and K3PO4 (1.3 g) are suspended in toluene (12 mL) and water (1.2 mL) and purged for 10 minutes with argon. [1,1′-Bis(diphenylphosphino)-ferrocene]-dichloropalladium-(II) (100 mg) is added, the vial is sealed and the mixture is stirred at 60° C. for 12 hours. After cooling to room temperature the mixture is diluted with diethylether and washed with saturated aqueous NH4Cl solution. The organic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 99:1→60:40) to give the title compound. Yield: 404 mg.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:7][CH:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[S:19][C:18]4[CH:20]=[C:21]([OH:24])[CH:22]=[CH:23][C:17]=4[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH2:5][C:4]([CH3:26])([CH3:25])[NH:3]1.[H-].[Na+].[CH2:30](Br)[CH:31]=[CH2:32].O>CN(C)C=O>[CH2:32]([O:24][C:21]1[CH:22]=[CH:23][C:17]2[CH:16]=[C:15]([C:13]3[CH:12]=[CH:11][N:10]=[C:9]([NH:8][CH:6]4[CH2:7][C:2]([CH3:27])([CH3:1])[NH:3][C:4]([CH3:26])([CH3:25])[CH2:5]4)[N:14]=3)[S:19][C:18]=2[CH:20]=1)[CH:31]=[CH2:30]
Reactant: CC1(C)CC(Nc2nccc(-c3cc4ccc(O)cc4s3)n2)CC(C)(C)N1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1ccc2cc(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)sc2c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Compound of Example 153 (191 mg, 0.5 mmol) was suspended in 2 ml dimethylformamide. 24 mg (0.5 mmol) sodium hydride was added in small portions at room temperature. After 15 minutes 72 mg (0.6 mmol) allylbromide was added and the mixture was stirred at 100° C. for 2 hours. Then the cooled solution was poured on 200 ml water and extracted with EtOAc. The crude was purified by chromatography on silicagel (DCM/MeOH/ammonia:9/1/0.1). Yield: 110 mg (52%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([Cl:9])[C:7]=1Cl.[F-].[Li+].[NH3:16]>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[NH2:16]
Reactant: N
Reactant: FC(F)(F)c1cc(Cl)c(Cl)c(Cl)c1
Agent: [F-]
Agent: [Li+]
Solvent: CN1CCCC1=O
Product: Nc1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: -95 °C
Reaction time: 4 h
Yield: 72.2 %

Procedure:
3,4,5-Trichloro-trifluoromethylbenzene (0.681 g, 2.73 mmol), lithium fluoride (7.1 mg, 0.273 mmol) and N-methylpyrrolidone (1.8 ml) are mixed in an autoclave. The autoclave is cooled to −95° C. and then ammonia (1.3 g, 76.4 mmol) is added. The autoclave is then heated at 250° C. and with stirring for 4 h and is subsequently allowed to return to room temperature. The reaction product is extracted by washing with water and with dichloromethane and then the organic phase is evaporated, after having been dried. 0.453 g (1.97 mmol) of 2,6-dichloro-4-trifluoromethylaniline is obtained with a degree of conversion of the 3,4,5-trichloro-trifluoromethylbenzene of 97%, a ratio equal to 83/17 for the selectivity for 2,6-dlchloro-para-trifluoromethylaniline with respect to 2,6-dichloro-meta-trifluoromethylaniline and an 87% yield of 2,6-dichloro-para-trifluoromethylaniline.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.[CH3:19][C:20](=O)[CH2:21][C:22](=[O:24])[CH3:23]>C(O)(=O)C.S(=O)(=O)(O)O>[CH3:19][C:20]1[N:1]=[C:2]2[S:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[C:3]2=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:21]=1[C:22](=[O:24])[CH3:23]
Reactant: Nc1sc2ccccc2c1C(=O)c1ccccc1
Reactant: CC(=O)CC(C)=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(=O)c1c(C)nc2sc3ccccc3c2c1-c1ccccc1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 50.9 %

Procedure:
To a stirred solution of 32 mg (0.13 mmol) (2-amino-benzo[b]thiophen-3-yl)-phenyl-methanone in 2 ml acetic acid was added 0.09 ml (0.13 mmol) of pentane-2,4-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Flash chromatography (heptane/ethyl acetate 6:1) afforded 21 mg (52%) (2-methyl-4-phenyl-benzo[4,5]thieno[2,3-b]pyridin-3-yl)-ethanone as a light yellow solid. ES-MS m/e (%): 318 (M+H+, 100).
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]([C:14]1[N:31]([CH2:32][C@H:33]2[CH2:38][CH2:37][C@H:36]([CH3:39])[CH2:35][CH2:34]2)[C:17]2[C:18]([C:24]3[CH:25]=[N:26][CH:27]=[C:28]([Cl:30])[CH:29]=3)=[N:19][C:20]([C:22]#[N:23])=[CH:21][C:16]=2[N:15]=1)[O:11][CH2:12][CH3:13])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OCC)(=O)C>[Cl:30][C:28]1[CH:29]=[C:24]([C:18]2[C:17]3[N:31]([CH2:32][C@H:33]4[CH2:34][CH2:35][C@H:36]([CH3:39])[CH2:37][CH2:38]4)[C:14]([CH:10]([O:11][CH2:12][CH3:13])[CH2:9][OH:8])=[N:15][C:16]=3[CH:21]=[C:20]([C:22]#[N:23])[N:19]=2)[CH:25]=[N:26][CH:27]=1
Reactant: CCOC(CO[Si](C)(C)C(C)(C)C)c1nc2cc(C#N)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(CO)c1nc2cc(C#N)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
2-(2-((tert-butyldimethylsilyl)oxy)-1-ethoxyethyl)-4-(5-chloropyridin-3-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile was dissolved in THF (3.9 mL) and cooled to 0° C. before adding TBAF (1M in THF, 1.5 mL). After stirring at 0° C. for 25 minutes, the reaction mixture was diluted with ethyl acetate and washed with water followed by brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (DCM/0-10% MeOH) to afford 4-(5-chloropyridin-3-yl)-2-(1-ethoxy-2-hydroxyethyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ESI calc'd. for C24H28ClN5O2 [M+H]+ 454. found 454.
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: CC(=O)OC(C)=O
Reactant: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(/C(N)=N/O)n4)ncnc32)cc1
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: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]1[N:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:13]=1[C:19]([F:22])([F:21])[F:20])=[N:7]2.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=1>CCOC(C)=O>[NH2:18][C:15]1[CH:14]=[C:13]([C:19]([F:22])([F:21])[F:20])[C:12]([C:6]2[N:7]=[C:8]3[C:3]([C:2]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:32])([F:31])[F:33])=[CH:26][N:25]=4)=[CH:11][CH:10]=[N:9]3)=[CH:4][CH:5]=2)=[N:17][CH:16]=1
Reactant: Nc1cnc(-c2ccc3c(Cl)ccnc3n2)c(C(F)(F)F)c1
Reactant: Nc1ccc(C(F)(F)F)cn1
Solvent: CCOC(C)=O
Product: Nc1cnc(-c2ccc3c(Nc4ccc(C(F)(F)F)cn4)ccnc3n2)c(C(F)(F)F)c1

Procedure:
Heat a mixture of 6-(5-chloro-1,8-naphthyridin-2-yl)-5-(trifluoromethyl)pyridin-3-amine (64.8 mg, 0.2 mmol) and 2-amino-5-trifluoromethylpyridine (64 mg, 0.4 mmol) at 180° C. for 2.0 hours. Cool the mixture, dilute with EtOAc/1.0 N aq. NaOH (5.0 mL each), and separate the organic layer. Extract the aqueous layer with EtOAc (3×5 mL) and dry combined organic layers with MgSO4. Filter the dried extract and concentrate under vacuum to afford crude product. Purify the crude product by HPLC to afford title compound as a yellow solid. 1H NMR (400 MHZ, DMSO-D6) δ 10.15 (s, 1H), 8.96 (d, 1H, J=2.2 Hz), 8.89 (m, 1H), 8.67 (s, 1H), 8.41 (m, 1H), 8.29(s, 1H), 8.25 (d, 1H, J=0.7 Hz), 8.07 (dd, 1H), 7.94 (d, 1H, J=2.2 Hz), 7.41 (d, 1H, J=0.6 Hz), 6.17 (s, 2H). MS=451.36 (M+H). The IC50 determined as described in Example 6 is less than 1 micromolar.