Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([CH:23]([O:52][SiH](C)C)[C:24]1[C:25]([CH:49]([CH3:51])[CH3:50])=[N:26][C:27]([CH:46]([CH3:48])[CH3:47])=[C:28]([CH2:37][O:38][C:39](=[O:45])[C:40]([CH3:44])([CH3:43])[CH2:41][CH3:42])[C:29]=1C1C=CC(F)=CC=1)(C)(C)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH:46]([C:27]1[C:28]([CH2:37][O:38][C:39](=[O:45])[C:40]([CH3:43])([CH3:44])[CH2:41][CH3:42])=[CH:29][C:24]([CH2:23][OH:52])=[C:25]([CH:49]([CH3:50])[CH3:51])[N:26]=1)([CH3:48])[CH3:47]
Reactant: CCC(C)(C)C(=O)OCc1c(C(C)C)nc(C(C)C)c(C(O[SiH](C)C)C(C)(C)C)c1-c1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(C)(C)C(=O)OCc1cc(CO)c(C(C)C)nc1C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.6 ml (2.6 mmol) of a 1molar tetrabutylammonium fluoride solution in tetrahydrofuran are added to 1.3 g (2.6 mmol) of the compound from Example 65 dissolved in 20 ml of absolute tetrahydrofuran and the mixture is stirred for 1 hour of room temperature. Saturated sodium hydrogen carbonate solution is added to the mixture and it is extracted several times using dichloromethane. The organic phase is dried over magnesium sulphate and concentrated in vacuo, and the residue is chromatographed on a column (silicia gel 70-230 mesh, using ethyl acetate/petroleum ether 1:9) as eluent).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]1[CH2:7][OH:8].C[Si](C)(C)N[Si](C)(C)C.C[Si](C)(C)Cl.Cl[C:24]1[N:29]=[C:28]([S:30][CH2:31][CH3:32])[C:27]([C:33]([NH:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[CH:38]=2)=[O:34])=[C:26]([CH3:44])[CH:25]=1.CCN(C(C)C)C(C)C.Cl.C([O-])(O)=O.[Na+]>C1COCC1.CN1C(=O)CCC1>[CH2:31]([S:30][C:28]1[C:27]([C:33]([NH:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[CH:38]=2)=[O:34])=[C:26]([CH3:44])[CH:25]=[C:24]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]2[CH2:7][OH:8])[N:29]=1)[CH3:32]
Reactant: OC[C@H]1COCCN1
Reactant: CCSc1nc(Cl)cc(C)c1C(=O)NCc1cccc(F)c1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: CCSc1nc(N2CCOC[C@@H]2CO)cc(C)c1C(=O)NCc1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.1 %

Procedure:
To a cooled (ice-bath) solution of 450 mg (1.32 mmol) (S)-morpholin-3-yl-methanol in THF (5 ml) were added at 0° C. 570 μl (2.78 mmol) 1,1,1,3,3,3 hexamethyldisilazane and 33 μl (0.26 mmol) trimethylchlorosilane. The mixture was then stirred at RT for 1 h. Then another 33 μl (0.26 mmol) trimethylchlorosilane was added and stirring was continued at RT for 1 h followed by concentration in vacuo. The residue, 450 mg (1.3 mmol) 6-chloro-2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-pyridine-3-carboxylic acid amide (synthesis is described in section b) of example 2) and 903 μl (5.3 mmol) DIPEA were suspended in NMP (1.5 ml). Then the reaction mixture was heated at 180° C. for 32 h and stirred at RT for 72 h. Subsequently a 1M hydrochlorid acid was added and the mixture was stirred at RT for 15 min. After neutralization with a sat. aq. NaHCO3 sol. EtOAc was added and the layers were separated. The organic layer was washed with water and brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by CC (cyclohexane/EtOAc 1:1) provided mg (0.17 mmol, 13%) 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-6-[(3S)-3-(hydroxymethyl)-morpholin-4-yl]-4-methyl-pyridine-3-carboxylic acid amide (example 263). [M+H]+420.2
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:21][C@@H:22]2[CH2:26][CH2:25][CH2:24][O:23]2)[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][C:17]([F:20])([F:19])[F:18])=[CH:5][C:6]=1[C:7](O)=[O:8].CN(C(O[N:35]1N=N[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.C1(N)CCCCC1>CN(C)C=O>[CH:36]1([NH:35][C:7]([C:6]2[CH:5]=[C:4]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[O:16][C:17]([F:18])([F:19])[F:20])[N:3]([CH2:21][C@@H:22]3[CH2:26][CH2:25][CH2:24][O:23]3)[C:2]=2[CH3:1])=[O:8])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1c(C(=O)O)cc(-c2ccccc2OC(F)(F)F)n1C[C@@H]1CCCO1
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: NC1CCCCC1
Solvent: CN(C)C=O
Product: Cc1c(C(=O)NC2CCCCC2)cc(-c2ccccc2OC(F)(F)F)n1C[C@@H]1CCCO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.5 %

Procedure:
To a solution of 77 mg of 2-methyl-1-[(S)-1-(tetrahydro-furan-2-yl)methyl]-5-(2-trifluoromethoxy-phenyl)-1H-pyrrole-3-carboxylic acid in 3 ml of dimethylformamide were added 74 mg of TBTU, 179 μl of N,N-diisopropylethylamine and 26 μl of cyclohexylamine and the reaction mixture was stirred at ambient temperature for 18 hours. After such time the reaction mixture was then concentrated in vacuo and purified by column chromatography (SiO2, heptane/ethyl acetate) to give 70 mg of the title compound as a colorless solid, MS (ISP) 451.5 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].[CH2:12](C(CC)(CC)C([O-])([O-])[O-])[CH3:13]>>[CH3:12][C:13]1[O:11][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=2[N:1]=1
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Product: Cc1nc2c([N+](=O)[O-])cccc2o1
Temperature: 100 °C
Yield: 95.1 %

Procedure:
To 2-amino-3-nitrophenol (6.17 g, 40.0 mmol) was added triethylorthoacetate (25.96 g, 160.0 mmol) and the mixture was heated at 100° C. for 12 h to give a dark red solution. Cooling to room temperature produced a crystalline mass which was filtered and washed with hexane to give compound 474A (6.78 g, 95%) as light maroon needles. HPLC: 98.1% at 1.86 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10–90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 179.08 [M+H]+.
Reaction SMILES: [OH:1][N:2]=[C:3]([Cl:14])[C@H:4]1[CH2:8][O:7][C:6]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[O:5]1.[CH3:15][S:16](Cl)(=[O:18])=[O:17].C(N(C(C)C)C(C)C)C>C1COCC1>[CH3:15][S:16]([O:1][N:2]=[C:3]([Cl:14])[C@H:4]1[CH2:8][O:7][C:6]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[O:5]1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: ON=C(Cl)[C@H]1COC2(CCCCC2)O1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)ON=C(Cl)[C@H]1COC2(CCCCC2)O1
Temperature: 3 °C
Reaction time: 1 h
Yield: 73.9 %

Procedure:
In a 4 neck 5 L flask was added (R)-N-hydroxy-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (158 g, 719 mmol) in 2.5 L of THF. The material was cooled to 3° C. and methanesulfonyl chloride (56.1 ml, 719 mmol) added in 10 mL portions over 10 minutes. Next, N-ethyl-N-isopropylpropan-2-amine (126 ml, 719 mmol) was added through an addition funnel over 12 minutes. The reaction was stirred in the ice bath for 30 minutes and then at ambient temperature for 1 hour. The reaction was filtered and the solids washed with MTBE (about 3 L). The filtrate was concentrated and the residue was purified under silica gel (3 kg silica, 7:1 to 3:1 Hexane/EtOAc) to afford an oil that slowly solidified under vacuum. The solids were ground using a mortar and pestle, washed with hexanes (about 1000 mL) and dried to afford (R)-N-(methylsulfonyloxy)-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (158 g, 531 mmol, 73.8% yield) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH:27]=[N:26][C:25]([NH2:31])=[CH:24]2.CCN(CC)CC>C1COCC1.CN(C=O)C>[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH:27]=[N:26][C:25]([NH:31][C:10](=[O:12])[CH2:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)=[CH:24]2
Reactant: COc1ccc2cnc(N)cc2c1
Reactant: COc1ccc(CC(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(CC(=O)Nc2cc3cc(OC)ccc3cn2)cc1
Temperature: 25 °C
Reaction time: 0.04 h
Yield: 27.3 %

Procedure:
To a solution of (4-methoxyphenyl)acetic acid (166.2 mg, 0.86 mmol) in 5 ml of anhydrous THF were added oxalyl chloride (126.9 mg, 4.3 mmol) and 100 ul of DMF. A vigorous effervescence occurred. Within 1-4 minutes the effervescence stopped and the mixture was stirred for 30 minutes at room temperature. Then the 6-methoxyisoquinolin-3-amine (150.0 mg, 0.86 mmol) and Et3N (0.86 mmol) were added. The reaction was stirred at the ambient temperature over 16 hours. The reaction was monitored by LC/MS that showed no more start material left. The reaction crude was purified by a silica gel column to give product 75.7 mg (yield 27.3%). 1H NMR (400 MHz, DMSO-d6) ppm 3.68 (s, 2H), 3.72 (s, 3H), 3.89 (s, 3H), 6.89 (d, J=8.81 Hz, 2H), 7.14 (dd, J=8.94, 2.39 Hz, 1H), 7.26 (d, J=2.27 Hz, 1H), 7.30 (d, J=8.81 Hz, 2H), 7.95 (d, J=9.06 Hz, 1H), 8.32 (s, 1H), 8.98 (s, 1H), 10.73 (s, 1H). HRMS: m/z 323.13882 [M+H]+), calc. 323.13902. MS m/z, (APCI); 323.2 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:12][CH:13]=[CH2:14])[CH:6]=[C:7]2O[CH2:10][O:9][C:8]=12.COC1C=C(CC=C)C(OC)=C2OCOC=12.CC(C)=CCC/C(/C)=C/COC1C2C=COC=2C=C2C=1C=CC(O2)=O.COC1C=CC(C2OC3C(OC)=C(OC)C(OC)=C(OC)C=3C(=O)C=2)=CC=1.CC1CCC([C@@](O)(CCC=C(C)C)C)CC=1>>[CH3:10][O:9][C:8]1[CH:7]=[CH:6][C:5]([CH2:12][CH:13]=[CH2:14])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: C=CCc1cc(OC)c2c(c1)OCO2
Agent: C=CCc1cc(OC)c2c(c1OC)OCO2
Agent: CC(C)=CCC/C(C)=C/COc1c2ccoc2cc2oc(=O)ccc12
Agent: CC(C)=CCC[C@](C)(O)C1CC=C(C)CC1
Product: C=CCc1ccc(OC)c(OC)c1

Procedure:
Chemicals were purchased from Sigma-Aldrich Chemical Company (St. Louis, Mo.) unless noted. Plant oils were manufactured by Aura Cacia (Weaverville, Calif.). Juvocimene was synthesized as described (Mestres, R. and E. Munoz, 1996, Synthetic Comm., 26:1309-1319). Myristicin, apiole, bergamotin, tangeretin, bisabolol, and cucurbitacin were obtained from Indofine Chemical Company (Somerville, N.J.). Methyleugenol was provided by the Batelle Chemical Company (Columbus, Ohio). Man-made insecticides were purchased from Chem Service (West Chester, Pa.). The precocene-like suicide substrate 3,4-dimethoxyisopentenylphenol was prepared as described Bowers, W. S., et al., 1976, Science, 217:647-648) except that a 3,4-dimethoxylated reactant was used.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH:9]=O)=[N:5][CH:6]=[CH:7][N:8]=1.Cl.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19](=[O:27])[CH2:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.ClCCCl>[CH3:1][O:2][C:3]1[C:4]([CH2:9][N:24]2[CH2:25][CH2:26][CH:21]([CH2:20][C:19]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[F:12])=[O:27])[CH2:22][CH2:23]2)=[N:5][CH:6]=[CH:7][N:8]=1
Reactant: O=C(CC1CCNCC1)c1ccccc1F
Reactant: COc1nccnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: COc1nccnc1CN1CCC(CC(=O)c2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.9 %

Procedure:
After adding 150 mg of 3-methoxypyrazine-2-carboxaldehyde and 340 mg of 1-(2-fluorophenyl)-2-(piperidin-4-yl)ethanone hydrochloride to 5 ml of 1,2-dichloroethane, 350 mg of sodium triacetoxyborohydride was added and the mixture was stirred for 4 hours at room temperature. Aqueous sodium carbonate solution was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine in that order and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (268 mg, 71% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[N:8][C:7]([C:15]([NH:17][C:18]1[NH:22][C:21]3[CH:23]=[C:24]([O:30][CH2:31][CH3:32])[CH:25]=[C:26]([C:27]([OH:29])=O)[C:20]=3[N:19]=1)=[O:16])=[CH:6]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.S(O)(O)(=O)=O.[NH2:71][C:72]1[NH:73][CH:74]=[CH:75][N:76]=1>CN(C=O)C.[Cl-].[Na+].O>[CH2:31]([O:30][C:24]1[CH:25]=[C:26]([C:27](=[O:29])[NH:71][C:72]2[NH:73][CH:74]=[CH:75][N:76]=2)[C:20]2[NH:19][C:18]([NH:17][C:15]([C:7]3[N:8]=[CH:9][C:10]4[C:5]([CH:6]=3)=[CH:4][C:3]([O:2][CH3:1])=[C:12]([O:13][CH3:14])[CH:11]=4)=[O:16])=[N:22][C:21]=2[CH:23]=1)[CH3:32]
Reactant: Nc1ncc[nH]1
Reactant: CCOc1cc(C(=O)O)c2nc(NC(=O)c3cc4cc(OC)c(OC)cc4cn3)[nH]c2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(C(=O)Nc2ncc[nH]2)c2[nH]c(NC(=O)c3cc4cc(OC)c(OC)cc4cn3)nc2c1
Yield: 47.9 %

Procedure:
100 mg (0.25 mmol) of 2-[(6,7-dimethoxy-isoquinoline-3-carbonyl)-amino]-6-ethoxy-1H-benzoimidazole-4-carboxylic acid and 200 mg (0.53 mmol) of HBTU were dissolved in 1.0 mL of DMF and 0.5 mL of DIEA and treated with 200 mg (1.5 mmol) of 2-aminoimidazole sulfate as described in general procedure A. Upon completion, the reaction was diluted with brine. The resulting solid was filtered, washed with water and EtOAc, and dried under vacuum to produce 60 mg (47%) of 6,7-dimethoxy-isoquinoline-3-carboxylic acid [5-ethoxy-7-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide. LCMS: 502 (M+1)+.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][CH:9]2[CH2:12][N:11]([CH2:13][CH2:14][C:15](O)=[O:16])[CH2:10]2)=[CH:6][CH:5]=1.S(Cl)([Cl:24])=O>>[F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][CH:9]2[CH2:12][N:11]([CH2:13][CH2:14][C:15]([Cl:24])=[O:16])[CH2:10]2)=[CH:6][CH:5]=1
Reactant: O=C(O)CCN1CC(Oc2ccc(OC(F)(F)F)cc2)C1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)CCN1CC(Oc2ccc(OC(F)(F)F)cc2)C1
Yield: 100 %

Procedure:
3-(3-(4-(trifluoromethoxy)phenoxy)azetidin-1-yl)propionic acid (400 mg, 1.31 mmol) was dissolved in thionyl chloride, raised the temperature to reflux for 3 h, spun dry, residuals were washed by an appropriate amount of ethyl ether, generated 423 mg target product, yield was 100%, directly put to the next reaction step.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][N:10]2[N:13]=[C:14]([CH3:38])[C:15]([C:16]3[S:17][C:18]([C:27]4[N:31]=[CH:30][N:29]([CH:32]5[CH2:37][CH2:36][CH2:35][CH2:34][O:33]5)[N:28]=4)=[C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:20]=3)=[C:9]2[CH:8]=1)(=O)=O.[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH3:38][C:14]1[C:15]([C:16]2[S:17][C:18]([C:27]3[N:31]=[CH:30][N:29]([CH:32]4[CH2:37][CH2:36][CH2:35][CH2:34][O:33]4)[N:28]=3)=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:20]=2)=[C:9]2[CH:8]=[C:7]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)[CH:12]=[CH:11][N:10]2[N:13]=1
Reactant: Cc1nn2ccc(OS(=O)(=O)C(F)(F)F)cc2c1-c1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Reactant: C1COCCN1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1nn2ccc(N3CCOCC3)cc2c1-c1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Temperature: 25 °C
Yield: 56.9 %

Procedure:
A suspension 2-methyl-3-{4-phenyl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}pyrazolo[1,5-a]pyridin-5-yl trifluoromethanesulfonate (150 mg, 0.25 mmol) obtained in Example 82-B(i), morpholine (501 mg, 5.73 mmol), tris(dibenzylideneacetone)dipalladium (0) (45 mg, 0.049 mmol), (R)-BINAP (50 mg, 0.080 mmol) and cesium carbonate (720 mg, 2.21 mmol) in toluene (30 mL) was stirred at 110° C. for 1 h. The reaction mixture was allowed to cool to room temperature, and then water (150 mL) was added. The mixture was extracted with EtOAc (150 mL×2). The combined organic layers were dried over anhydrous magnesium sulfate and insoluble materials were removed by filtration. The filtrate was concentrated and the residue was purified by silica gel column chromatography (EtOAc/hexane=10/90→100/0) to give the title compound (75 mg, 56%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[C:4]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.[CH3:18][CH:19]([CH3:42])[CH:20]([NH:25][C:26]([C:28]1[S:29][CH:30]=[C:31]([C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-])=O)=[CH:35][CH:34]=2)[N:32]=1)=[O:27])[C:21]([O:23][CH3:24])=[O:22]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[NH:39][C:36]2[CH:37]=[CH:38][C:33]([C:31]3[N:32]=[C:28]([C:26]([NH:25][CH:20]([CH:19]([CH3:42])[CH3:18])[C:21]([O:23][CH3:24])=[O:22])=[O:27])[S:29][CH:30]=3)=[CH:34][CH:35]=2)=[C:4]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:3]=1
Reactant: O=C=Nc1ccc(Cl)cc1Oc1ccccc1
Reactant: COC(=O)C(NC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)cs1)C(C)C
Product: COC(=O)C(NC(=O)c1nc(-c2ccc(NC(=O)Nc3ccc(Cl)cc3Oc3ccccc3)cc2)cs1)C(C)C
Yield: 61 %

Procedure:
The title compound was synthesized analogous to Example 23, using 4-chloro-1-isocyanato-2-phenoxybenzene and intermediate 3. Yield: 61%; 1H NMR (DMSO-d6, 300 MHz): δ 9.54 (s, 1H), 8.81 (d, 1H), 8.71 (s, 1H), 8.41 (s, 1H), 8.32 (s, 1H), 8.06 (d, 2H), 7.57 (d, 2H), 7.44 (d, 2H), 7.22 (t, 1H), 7.11 (d, 2H), 7.02 (d, 1H), 6.86 (d, 1H), 4.39 (t, 1H), 3.69 (s, 3H), 2.31 (m, 1H), 0.99 (d, 6H).
Reaction SMILES: [OH:1][C@H:2]([CH3:6])[C:3]([NH2:5])=O.F[B-](F)(F)F.C([O+](CC)CC)C.N[C:20]1[C:21]([NH:29][CH:30]2[CH2:35][CH2:34][CH:33]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:32][CH2:31]2)=[C:22]2[S:28][CH:27]=[CH:26][C:23]2=[N:24][CH:25]=1>O1CCCC1.C(O)C>[OH:1][C@@H:2]([C:3]1[N:29]([CH:30]2[CH2:31][CH2:32][CH:33]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:41])([CH3:40])[CH3:42])[CH2:34][CH2:35]2)[C:21]2=[C:22]3[S:28][CH:27]=[CH:26][C:23]3=[N:24][CH:25]=[C:20]2[N:5]=1)[CH3:6]
Reactant: C[C@@H](O)C(N)=O
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2c(N)cnc3ccsc23)CC1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: C1CCOC1
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1C1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (2R)-2-hydroxypropanamide (320 mg, 3.6 mmol) and triethyloxonium tetrafluoroborate (0.69 g, 3.6 mmol) in tetrahydrofuran (3 mL) was stirred at room temperature for 1 h and then concentrated. A mixture of tert-butyl {4-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}carbamate (191 mg, 0.527 mmol) and the above made reagent in ethanol (4.8 mL) was heated at reflux for 2 h. The mixture was concentrated and purified on silica gel column (eluting with 0-10% MeOH in methylene chloride) to give the desired product. LCMS calculated for C21H29N4O3S (M+H)+: m/z=417.2. Found: 417.0.
Reaction SMILES: N1(O[C:11]2[N:16]=[C:15]([NH:17][C@H:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=3)[CH3:19])[C:14]([C:27]([NH2:29])=[O:28])=[CH:13][N:12]=2)C2C=CC=CC=2N=N1.[CH3:30][O:31][C:32]1[C:37]([NH2:38])=[CH:36][CH:35]=[CH:34][N:33]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C@@H:18]([NH:17][C:15]2[C:14]([C:27]([NH2:29])=[O:28])=[CH:13][N:12]=[C:11]([NH:38][C:37]3[C:32]([O:31][CH3:30])=[N:33][CH:34]=[CH:35][CH:36]=3)[N:16]=2)[CH3:19])=[N:21][CH:22]=1
Reactant: C[C@H](Nc1nc(On2nnc3ccccc32)ncc1C(N)=O)c1ccc(F)cn1
Reactant: COc1ncccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCO1
Product: COc1ncccc1Nc1ncc(C(N)=O)c(N[C@@H](C)c2ccc(F)cn2)n1
Yield: 68.5 %

Procedure:
A solution of (S)-2-(1H-benzo[d][1,2,3]triazol-1-yloxy)-4-(1-(5-fluoropyridin-2-yl) ethyl amino)pyrimidine-5-carboxamide (Preparation 5c, 30 mg, 0.08 mmol), 2-methoxy pyridin-3-amine (14 mg, 0.11 mmol) and p-toluenesulfonic acid hydrate (15 mg, 0.08 mmol) in 1,4-dioxane (3 mL) was heated at 120° C. for 4 hours. The solvent was evaporated under reduced pressure and the resulting residue was purified by reverse phase chromatography (C-18 silica from Waters©, water/acetonitrile/methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%) to give the title compound (21 mg, 72%) as a solid.
Reaction SMILES: [N:1]1([S:5]([NH2:8])(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:50]1[CH:55]=[C:54]([O:56][CH:57]([F:59])[F:58])[N:53]=[C:52]([S:60][CH2:61][C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([F:68])[C:63]=2[F:69])[N:51]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[F:59][CH:57]([F:58])[O:56][C:54]1[N:53]=[C:52]([S:60][CH2:61][C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([F:68])[C:63]=2[F:69])[N:51]=[C:50]([NH:8][S:5]([N:1]2[CH2:4][CH2:3][CH2:2]2)(=[O:7])=[O:6])[CH:55]=1
Reactant: NS(=O)(=O)N1CCC1
Reactant: Fc1cccc(CSc2nc(Cl)cc(OC(F)F)n2)c1F
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=S(=O)(Nc1cc(OC(F)F)nc(SCc2cccc(F)c2F)n1)N1CCC1

Procedure:
The title compound was prepared according to the procedure outlined in example 1 step (iv) using a mixture of azetidine-1-sulphonamide (prepared according to patent WO 2004/011443, 0.11 g), tris(dibenzylideneacetone)dipalladium (0) (0.10 g), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (60 mg), cesium carbonate (0.26 g), 4-chloro-6-(difluoromethoxy)-2-[[(2,3-difluorophenyl)methyl]thio]-pyrimidine (product of step (0.18 g) and anhydrous dioxane (5 mL). Purification was by column chromatography on silica gel using EtOAc/isohexane (3:7) as eluent and the relevant fractions were evaporated. The resulting oil was triturated with diethyl ether/iso-hexane to give the title compound as a white solid. Yield: 70 mg