Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[N:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:10].[O:17]1[C:21]([C:22]2[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[CH:20][N:19]=[CH:18]1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:28]([C:25]2[CH:26]=[CH:27][C:22]([C:21]3[O:17][CH:18]=[N:19][CH:20]=3)=[CH:23][CH:24]=2)(=[O:29])=[O:30])=[C:3]([C:9]([C:11]2[N:12]=[CH:13][CH:14]=[CH:15][N:16]=2)=[O:10])[CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2cnco2)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ncccn1
Product: O=C(c1ncccn1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(-c2cnco2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 116 mg of (2-Amino-5-chloro-phenyl)-pyrimidin-2-yl-methanone and 122 mg of 4-oxazol-5-yl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 7.43 (s, 1H), 7.45 (m, 1H), 7.50 (m, 1H), 7.55 (m, 1H), 7.64 (m, 2H), 7.66 (d, 1H, J=8.8 Hz), 7.86 (m, 2H), 7.97 (s, 1H), 8.86 (d, 2H), 10.63 (s, 1H). MS: m/z 441.9 (M++1).
Reaction SMILES: CS(O[C@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]2[S:13][C:14]3[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:15]=3[N:16]=2)[CH2:7]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].C(#N)C.[NH:31]1[CH2:34][CH2:33][CH2:32]1>C(OCC)C>[N:31]1([C@@H:6]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]3[S:13][C:14]4[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH2:7]2)[CH2:34][CH2:33][CH2:32]1
Reactant: C1CNC1
Reactant: CS(=O)(=O)O[C@H]1CCCN(c2nc3ccc(Br)cc3s2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Product: Brc1ccc2nc(N3CCC[C@@H](N4CCC4)C3)sc2c1
Temperature: 80 °C
Reaction time: 72 h

Procedure:
One equivalent of (S)-1-(6-bromobenzo[d]thiazol-2-yl)piperidin-3-yl methanesulfonate (Reference Example 10, 0.078 g, 0.2 mmol) and two equivalents of potassium carbonate (55.3 mg, 0.40 mmol) were weighed into a 2.5 mL Biotage microwave vial equipped with a magnetic stirbar. Acetonitrile (1 mL) was added, then 6 equivalents of azetidine (68.5 mg, 1.2 mmol) was weighed into the reaction mixture. The vial was sealed with a septum cap and the reaction mixture was stirred at 80° C. for 72 hours. The reaction mixture was transferred to a 100 mL round bottom flask (methanol rinse). Volatiles were removed under reduced pressure and the residue was partitioned between ethyl acetate and saturated aqueous sodium carbonate. The organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to give an oil. The oil was purified by column chromatography on an Analogix IntelliFlash-280 (Analogix SF10-4 g, 100% dichloromethane to 98:2 dichloromethane/2 M NH3 in methanol). Fractions containing product were combined and concentrated under reduced pressure to give an oil that was dissolved in diethyl ether and dried (MgSO4). The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to give a semi-solid that was triturated with diethyl ether/hexane to give (R)-2-(3-(azetidin-1-yl)piperidin-1-yl)-6-bromobenzo[d]thiazole as a solid. 1H NMR (300 MHz, CD3OD) δ ppm 1.23-1.38 (m, 1H), 1.53-1.69 (m, 1H), 1.80-1.96 (m, 2H), 2.11 (pentet, J=7 Hz, 2H), 2.32-2.43 (m, 1H), 2.93-3.02 (m, 1H), 3.22-3.38 (m, 5H), 3.79 (dt, J=4, 13 Hz, 1H), 3.96 (dd, J=4, 13 Hz, 1H), 7.33 (d, J=9 Hz, 1H), 7.39 (dd, J=2, 9 Hz, 1H), 7.79 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 352 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([N:24]2[CH2:28][CH2:27][C@@H:26]([OH:29])[CH2:25]2)=[N:4][CH:5]=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[N:35][CH:36]=1>>[F:30][C:31]1[CH:32]=[C:33]([C:2]2[C:3]([N:24]3[CH2:28][CH2:27][C@@H:26]([OH:29])[CH2:25]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])[CH:23]=2)[CH:34]=[N:35][CH:36]=1
Reactant: OB(O)c1cncc(F)c1
Reactant: O=C(Nc1ccc(C(F)(F)C(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Product: O=C(Nc1ccc(C(F)(F)C(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cncc(F)c2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 151 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(perfluoroethyl)phenyl)nicotinamide (Stage 208.1) and (5-fluoropyridin-3-yl)boronic acid to afford a beige solid. UPLC-MS (Condition 3) tR=1.10 min, m/z=497.4 [M+H]+, m/z=495.3 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.69-1.79 (m, 1H) 1.85 (m, J=9.05 Hz, 1H) 2.88 (d, J=11.25 Hz, 1H) 3.18-3.29 (m, 2H) 3.35-3.46 (m, 1H) 4.16-4.26 (m, 1H) 4.87 (d, J=3.42 Hz, 1H) 7.67 (d, J=8.80 Hz, 2H) 7.84 (dt, J=9.66, 2.26 Hz, 1H) 8.00 (d, J=8.80 Hz, 2H) 8.09 (d, J=2.20 Hz, 1H) 8.49-8.53 (m, 1H) 8.60 (d, J=2.93 Hz, 1H) 8.80 (d, J=2.20 Hz, 1H) 10.33 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=3)[CH2:25][CH2:24]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[F:42][C:39]([F:40])([F:41])[C:31]1[CH:30]=[C:29]([N:26]2[CH2:25][CH2:24][N:23]([S:20]([C:17]3[CH:16]=[CH:15][C:14]([NH:13][C:2]4[C:11]5[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=5)[N:5]=[CH:4][CH:3]=4)=[CH:19][CH:18]=3)(=[O:21])=[O:22])[CH2:28][CH2:27]2)[CH:34]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:32]=1
Reactant: Nc1ccc(S(=O)(=O)N2CCN(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)cc1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Product: O=S(=O)(c1ccc(Nc2ccnc3cc(Cl)ccc23)cc1)N1CCN(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1

Procedure:
In the manner given in Example 1C, 4,7-dichloroquinoline is heated with 1-[(p-aminophenyl)sulfonyl]-4-[3,5-di(trifluoromethyl)phenyl]piperazine, to give 1-[3,5-di(trifluoromethyl)phenyl]-4-[[4-[[7-chloro-4-quinolinyl]amino]phenyl]sulfonyl]piperazine.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[N:5]=1)=[N+:2]=[N-:3].C(OC=[C:15]([C:21](=O)[C:22]([F:25])([F:24])[F:23])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C>C(#N)C>[Cl:10][C:6]1[N:5]=[C:4]([N:1]2[C:21]([C:22]([F:23])([F:25])[F:24])=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:3]=[N:2]2)[CH:9]=[CH:8][CH:7]=1
Reactant: [N-]=[N+]=Nc1cccc(Cl)n1
Reactant: CCOC=C(C(=O)OCC)C(=O)C(F)(F)F
Solvent: CC#N
Product: CCOC(=O)c1nnn(-c2cccc(Cl)n2)c1C(F)(F)F
Temperature: 70 °C
Reaction time: 16 h

Procedure:
To a solution of the title compound from Example 330 Step A (300 mg, 1.94 mmol) in acetonitrile (4 mL) was added ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutyrate (0.284 mL, 1.94 mmol) followed by TEA (0.271 mL, 1.94 mmol), and the mixture was heated at 70° C. After 16 h, the reaction mixture was concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 65% EtOAc in hexanes) provided the title compound as a yellow oil: LCMS m/z 320.85 [M+H]+; 1H NMR (500 MHz, CD3OD) δ 8.03 (t, J=7.9 Hz, 1H), 7.77 (d, J=7.7 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H), 4.55 (q, J=7.2 Hz, 2H), 1.49 (t, J=7.2 Hz, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]1[N:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][CH:8]=1.C(N(CC)C(C)C)(C)C.Cl[CH2:27][O:28][CH3:29]>C(Cl)(Cl)Cl>[CH3:27][O:28][CH2:29][N:3]1[CH:4]=[CH:5][S:1][C:2]1=[N:6][C:7]1[N:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][CH:8]=1
Reactant: COCCl
Reactant: COC(=O)c1cccc(Nc2nccs2)n1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COCn1ccsc1=Nc1cccc(C(=O)OC)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a mixture of 4.85 g (20.6 mmol) of methyl 6-(thiazol-2-ylamino)-pyridine-2-carboxylate, 7.20 ml (41.2 mmol) of N,N-diisopropylethylamine and 100 ml of chloroform was added 2.35 ml (30.9 mmol) of chloromethylmethyl ether followed by stirring at room temperature for 1 hour. The reaction mixture was washed with 100 ml of water for three times and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated to about 20 ml in total and the resulting solid was filtered. The resulting solid was washed with ether and dried in vacuo to give 6.38 g (20.6 mmol) of the title compound as a white solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.[SH:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.[OH-].[K+]>C(COC)OC>[F:8][C:4]1[N:3]=[C:2]([S:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Oc1ccc(S)cc1
Reactant: Fc1cccc(F)n1
Agent: [K+]
Agent: [OH-]
Solvent: COCCOC
Product: Oc1ccc(Sc2cccc(F)n2)cc1

Procedure:
A mixture comprising 69 grams (0.6 mole) of 2,6-difluoropyridine, 75.6 grams (0.6 mole) of 4-mercaptophenol and 49.5 grams (0.75 mole) of 85 percent potassium hydroxide was stirred in 300 milliliters of monoglyme for ~ 4 days at room temperature. At the end of this time, the reaction mixture was filtered to remove any solid by-products present. The filtrate was concentrated to remove most of the monoglyme and the residue mixed with 400 milliliters of 5 percent sodium hydroxide. The mixture was washed with methylene chloride and the aqueous solution acidified with concentrated hydrochloric acid. The solid 4-((6-fluoro-2-pyridyl)thio)phenol product precipitated out and was recovered by filtration, washed with water and dried. The product was recovered in a yield of 112 grams (87 percent of theoretical) and melted at 123°-124° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:29][C:30]1[S:34][C:33]([CH:35]=O)=[CH:32][CH:31]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:35][C:33]3[S:34][C:30]([Br:29])=[CH:31][CH:32]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(Br)s1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4ccc(Br)s4)c3)c(Cc3ccccc3)cnc12

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 5-bromo-thiophene-2-carbaldehyde. MS (ESI) m/z 553.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[CH:4][C:3]=1[CH3:9].C([Li])CCC.CN([CH:18]=[O:19])C>CCOCC.CCCCCC>[CH3:9][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH3:8])[C:2]=1[CH:18]=[O:19]
Reactant: Cc1cncc(C)c1Br
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1cncc(C)c1C=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 4-bromo-3,5-dimethylpyridine (0.70 g, 3.76 mmol) in ether (10 mL) was cooled to −78° C. and then 2.50 M n-butyllithium in hexane (1.50 mL) was added to the reaction flask dropwise. After stirring at −78° C. for 1 h, DMF (1.75 mL, 22.6 mmol) was added to the reaction flask slowly. The reaction solution was allowed to warm to room temperature overnight. The reaction was quenched with 10 mL saturated NH4Cl solution and diluted with ethyl acetate. The aqueous layer was extracted with ethyl acetate once. The combined organic solutions were dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (40% to 50% ethyl acetate/hexanes) to afford the desired product as a solid. (280 mg, 55%). 1H NMR (400 MHz, CDCl3): δ 10.62 (s, 1H), 8.43 (s, 2H), 2.57 (s, 6H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.O.[NH2:13][NH2:14]>>[NH:13]([C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1)[NH2:14]
Reactant: NN
Reactant: CC(C)(O)c1ccc(Cl)nc1
Solvent: O
Product: CC(C)(O)c1ccc(NN)nc1
Temperature: 110 °C

Procedure:
A mixture of 2-(6-chloropyridin-3-yl)propan-2-ol (975 mg, 5.68 mmol), and hydrazine hydrate (5512 μl, 114 mmol) was heated in a microwave on high absorbance for 10 hr at 110° C. The mixture was cooled to room temperature and the hydrazine was removed via rotary evaporation. The resulting yellow residue was used without further work-up.
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:34])[CH3:33])[CH:26]=3)[S:10][C:11]=2[C:12]2[N:16](COCC[Si](C)(C)C)[N:15]=[CH:14][N:13]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:34])[CH3:33])[CH:26]=3)[S:10][C:11]=2[C:12]2[NH:13][CH:14]=[N:15][N:16]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1cc(-c2nc(Cc3ccc(Cl)cc3)c(-c3ncnn3COCC[Si](C)(C)C)s2)ccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1cc(-c2nc(Cc3ccc(Cl)cc3)c(-c3nnc[nH]3)s2)ccn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.1 %

Procedure:
To a solution of N-{4-[4-(4-chlorobenzyl)-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-5-yl)-1,3-thiazol-2-yl]pyridin-2-yl}acetamide (0.112 g, 0.207 mmol) in dichloromethane (2.0 mL) at room temperature was added trifluoroacetic acid (3.1 mL, 40 mmol). The mixture was then stirred at room temperature for 4 hours. The solvent was evaporated and the excess trifluoroacetic acid was removed by azeotroping with toluene. Column chromatography was performed to yield the title compound (0.0520 g, 61%). LCMS: (FA) ES+ , 411. 1H NMR (400 MHz, d6-DMSO) δ: 14.46 (s, 1H), 10.69 (s, 1H), 8.80-8.73 (m, 1H), 8.64-8.60 (m, 1H), 8.43-8.37 (m, 1H), 7.59-7.54 (m, 1H), 7.37-7.28 (m, 4H), 4.66 (s, 2H), 2.12 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]2=[N:12][C:13]3[C:26]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[N:20]([CH3:27])[C:19]4[C:14]=3[C:15]([CH:16]=[CH:17][CH:18]=4)=[C:8]2[CH:7]=1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]2=[N:12][C:13]3[C:26]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[N:20]([CH3:27])[C:19]4[C:14]=3[C:15]([CH:16]=[CH:17][CH:18]=4)=[C:8]2[CH:7]=1
Reactant: COC(=O)/C=C/c1ccc2nc3c4c(cccc4c2c1)N(C)c1ccccc1-3
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)CCc1ccc2nc3c4c(cccc4c2c1)N(C)c1ccccc1-3
Yield: 70 %

Procedure:
(Method N) (E)-3-(8-Methyl-8H-quino[4,3,2-kl]acridin-3-yl)-acrylic acid methyl ester, 40 (50 mg, 0.14 mmol) was suspended in ethyl acetate (150 mL) and shaken under pressure of hydrogen (40 psi) with 10% palladium on carbon (100 mg) for 2 days. The mixture was filtered through celite, the solvent evaporated under reduced pressure, the product adsorbed onto silica and purified by column chromatography (1:4 EtOAc:hexane) to give the title compound (36 mg, 0.098 mmol, 70%).
Reaction SMILES: Br[C:2](=[C:5]([NH:13][CH3:14])[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)[C:3]#[N:4].[F:15][C:16]([F:21])([F:20])[C:17](=O)[CH3:18]>C(O)(=O)C.O>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([C:5]2[N:13]([CH3:14])[C:17]([C:16]([F:21])([F:20])[F:15])=[CH:18][C:2]=2[C:3]#[N:4])=[CH:7][CH:8]=1
Reactant: CC(=O)C(F)(F)F
Reactant: CNC(=C(Br)C#N)c1ccc(Cl)cc1
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(C(F)(F)F)cc(C#N)c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A solution of α-bromo-p-chloro-β-(methylamino)cinnamonitrile, (E)- or (Z)- (5.43 g, 0.02 mol) and trifluoroacetone (3.36 g, 2.7 mL, 0.03 mol) in acetic acid is heated at 80° C. for 1-2 hours, heated at 100° C. overnight, diluted with water and extracted with ethyl acetate. The combined organic extracts are washed with water, dried over anhydrous Na2SO4 and concentrated in vacuo to obtain a gum. The gum is flash chromatographed using silica gel and a 15% ethyl acetate in heptane solution to give the title product as a yellow solid (1.7 g, mp 129°-131° C.) which is identified by 1H and 19FNMR spectral analyses.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[N:4][C:5]([O:8]C)=[CH:6][CH:7]=1.[I-].[Na+].C[Si](Cl)(C)C.CO>CC#N>[F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[N:4][C:3]=1[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1
Reactant: COc1ccc(F)c(NCc2cccc(F)c2)n1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: Oc1ccc(F)c(NCc2cccc(F)c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.5 %

Procedure:
3-fluoro-N-(3-fluorobenzyl)-6-methoxypyridin-2-amine (0.100 g, 0.400 mmol) was dissolved in anhydrous CH3CN (1.6 mL). This mixture was treated with sodium iodide (0.301 g, 2.01 mmol) followed by trimethylsilylchloride (0.257 mL, 0.218 g, 2.01 mmol). The resulting reaction mixture was then heated at reflux for 2 hr. The reaction mixture was then treated with MeOH (1 ml), and the resulting mixture was stirred at ambient temperature for 2 hr, and then concentrated in vacuo. The resulting residue was dissolved in EtOAc (25 ml) and partitioned with H2O (25 ml). The H2O layer was extracted with EtOAc (2×25 ml). The organic layers were combined and washed with brine (1×25 ml). The organic layer was dried (Na2SO4), filtered, and the solvent removed in vacuo. The resulting residue was subjected to silica gel column chromatography. Elution using 10 EtOAc/90 hexanes to 60 EtOAc/40 hexanes gave 0.060 g (64%) of 5-fluoro-6-(3-fluorobenzylamino)pyridine-2-ol. LCMS (m/z): 237.2 (MH+), retention time=0.74 min.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:10]=1)[C:5]([OH:7])=[O:6].[CH3:15][S-:16].[Na+].CCOC(C)=O.Cl>C1COCC1>[CH3:15][S:16][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1cc(Cl)nc(C(F)(F)F)c1
Reactant: C[S-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CSc1cc(C(=O)O)cc(C(F)(F)F)n1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
To a suspension of 2-chloro-6-(trifluoromethyl)isonicotinic acid (0.1 g, 443 μmol, prepared according to F. Cottet, M. Schlosser, Eur. J. Org. Chem. 2004, 18, 3793-3798) in THF (5 mL) was added sodium thiomethoxide (155 mg, 2.22 mmol, CAS RN 50615-16-2) and the reaction mixture was heated to 70° C. (oil bath temperature) for 15 hours. After cooling down to room temperature, EtOAc (5 mL) and 1M aqueous HCl (2 mL) were added and the reaction mixture was stirred at room temperature for 30 min. The layers were separated and the aqueous layer was extracted with EtOAc. The organic layers were washed with brine, dried over MgSO4, filtered and evaporated to give the desired compound as an off-white solid (0.105 g; 99%) which was used in the next step without further purification. MS (ESI): m/z=236.01 [M−H]−.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:8]([S:12]([NH:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)(=[O:14])=[O:13])=[CH:7][C:6]([C:21]3[C:22]([CH3:27])=[N:23][O:24][C:25]=3[CH3:26])=[CH:5][C:4]=2[N:3]=1.[CH:28]1([CH2:31][NH2:32])[CH2:30][CH2:29]1>CN(C=O)C>[CH:16]1([NH:15][S:12]([C:8]2[C:9]3[CH:10]=[CH:11][C:2]([NH:32][CH2:31][CH:28]4[CH2:30][CH2:29]4)=[N:3][C:4]=3[CH:5]=[C:6]([C:21]3[C:22]([CH3:27])=[N:23][O:24][C:25]=3[CH3:26])[CH:7]=2)(=[O:14])=[O:13])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Cc1noc(C)c1-c1cc(S(=O)(=O)NC2CCCC2)c2ccc(Cl)nc2c1
Reactant: NCC1CC1
Solvent: CN(C)C=O
Product: Cc1noc(C)c1-c1cc(S(=O)(=O)NC2CCCC2)c2ccc(NCC3CC3)nc2c1
Temperature: 110 °C

Procedure:
A mixture of 2-chloro-N-cyclopentyl-7-(3,5-dimethylisoxazol-4-yl)quinoline-5-sulfonamide (23 mg, 0.057 mmol), cyclopropylmethyl amine (0.2 mL) and DMF (0.5 mL) was heated at 110° C. for 1 hour. The reaction mixture was purified by preparative HPLC to give the desired product, N-cyclopentyl-2-((cyclopropylmethyl)amino)-7-(3,5-dimethylisoxazol-4-yl)quinoline-5-sulfonamide.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[CH:21]([OH:28])[C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:29][C@@H:30](O)[C@@H:31]([OH:33])[CH3:32]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][S:10]([C:7]2[CH:6]=[CH:5][C:4]([C:1]3([CH3:2])[O:33][C@H:31]([CH3:32])[C@H:30]([CH3:29])[O:3]3)=[CH:9][CH:8]=2)(=[O:11])=[O:12])=[C:15]([C:21]([C:22]2[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=2)=[O:28])[CH:16]=1
Reactant: C[C@H](O)[C@@H](C)O
Reactant: CC(=O)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(O)c2ccncc2)cc1
Product: C[C@@H]1OC(C)(c2ccc(S(=O)(=O)Nc3ccc(Cl)cc3C(=O)c3ccncc3)cc2)O[C@@H]1C

Procedure:
The title compound was prepared using 4-Acetyl-N-[4-chloro-2-(hydroxy-pyridin-4-yl-methyl)-phenyl]-benzenesulfonamide and (2R,3S)-Butane-2,3-diol following the procedure described in the preceding two examples. MS: m/z 487 M++1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH:12]1([NH:17][CH2:18][C:19]([F:27])([CH2:25][CH3:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([N:17]([CH2:18][C:19]([F:27])([CH2:25][CH3:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16]2)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: CCOC(=O)C(F)(CC)CNC1CCCC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(F)(CC)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2,4-dichloro-5-nitropyrimidine (1.4 g, 7.2 mmol) in anhydrous acetone (50 ml) at 0° C., was added dropwise a solution of ethyl 2-((cyclopentylamino)methyl)-2-fluorobutanoate (1.38 g, 6 mmol) in acetone (10 mL) over 10 min. After which, potassium carbonate (2.5 g, 18 mmol) was added and the whole was stirred at rt for 18 h. After evaporation in vacuo, the residue was partitioned between ethyl acetate (200 ml) and water (200 ml). The organic layer was washed with NaHCO3, brine and water, dried over Na2SO4 and concentrated in vacuo to give a red residue which was used directly for next step (2.6 g). [M+H] calc'd for C16H22ClFN4O4, 389. found 389.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[C:29]2[N:28]=[C:26]([NH2:27])[NH:25][C:23](=O)[C:22]=2[N:21]=[CH:20]1)(=[O:3])[CH3:2].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:55])=O>[Cl-].C([N+](CC)(CC)CC)C.C(#N)C>[NH2:27][C:26]1[N:28]=[C:29]2[C:22]([N:21]=[CH:20][N:19]2[C@@H:6]2[O:7][C@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@H:5]2[O:4][C:1](=[O:3])[CH3:2])=[C:23]([Cl:55])[N:25]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=P(Cl)(Cl)Cl
Agent: CC[N+](CC)(CC)CC
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Cl-]
Solvent: CN(C)c1ccccc1
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 47.5 °C
Reaction time: 0.25 h

Procedure:
An 8-liter, 3-neck, round bottom flask equipped with a mechanical stirrer, a condenser, a thermometer, and an argon inlet is charged with dry acetonitrile (2.2 liters) and 2′,3′,5′-tri-O-acetyl-guanosine (550 g, 1.344 moles). Tetraethylammonium chloride (423 g, 2.55 moles), previously dried for 18 hours over P2O5 at 110° C./high vacuum is added to afford a clear, green solution. After heating to 45-50° C., N,N-dimethylaniline (179 g, 1.48 moles) is added, followed by phosphorus oxychloride (825 g, 5.38 moles) over 15 minutes, during which the temperature rose to 75±3° C. The mixture was kept at 75±3° C. for 15 minutes, flash evaporated (TBath<40° C.), and the dark red residue taken up in dichloromethane (4 liters). With vigorous stirring, the mixture is washed with ice water (2.5 L), the organic phase is collected, and the aqueous phase extracted with additional dichloromethane (2×1 L). The combined organic phases are washed with cold water (2×2 liters), saturated aqueous NaHCO3 (2×2 L), dried (Na2SO4), filtered, and concentrated to approximately 1.5 liters. Absolute ethanol (1.5 L) is added and the mixture concentrated to approximately 2 liters. Upon cooling to room temperature, the product crystallizes as a colorless solid (321 g, 56%) after drying in vacuo at 40° C. for 17 hours.