Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:5]2[N:6]([CH2:10][C:11]([OH:13])=O)[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[C:54]1([C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)[CH:59]=[CH:58][C:57]([CH:60]([NH:68][CH3:69])[CH2:61][N:62]2[CH2:67][CH2:66][O:65][CH2:64][CH2:63]2)=[CH:56][CH:55]=1>C(Cl)Cl>[C:54]1([C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)[CH:55]=[CH:56][C:57]([CH:60]([N:68]([CH3:69])[C:11](=[O:13])[CH2:10][N:6]2[C:5]3[CH:14]=[C:15]([O:16][CH3:17])[C:2]([CH3:1])=[CH:3][C:4]=3[O:8][C:7]2=[O:9])[CH2:61][N:62]2[CH2:63][CH2:64][O:65][CH2:66][CH2:67]2)=[CH:58][CH:59]=1
Reactant: COc1cc2c(cc1C)oc(=O)n2CC(=O)O
Reactant: CNC(CN1CCOCC1)c1ccc(-c2ccccc2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(cc1C)oc(=O)n2CC(=O)N(C)C(CN1CCOCC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 24.8 %

Procedure:
[6-Methyl-5-(methyloxy)-2-oxo-1,3-benzoxazol-3(2H)-yl]acetic acid (59 mg, 0.25 mmol) and BOP reagent (133 mg, 0.30 mmol) were dissolved in CH2Cl2 (1 mL), and diisopropylethylamine (32 mg, 0.25 mmol) was added. The resulting mixture was stirred at room temperature for 5 min, then 1-(4-biphenylyl)-N-methyl-2-(4-morpholinyl)ethanamine (74 mg, 0.25 mmol) was added. Stirring was continued for 16 h and then the mixture was concentrated. The residue was dissolved in CH3OH, and purified by preparative HPLC (YMC CombiPrep ODS-A, 50×50 mm, 50 mL/min, A: acetonitrile B: water with NH4OH at pH=10, A: 20% to 70% during 12 min, UV detection at 214 nm) to give 32 mg (25%) of the title compound as a white solid. MS (ES) m/e 516 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[C:5]([CH:9]=[O:10])[NH:6][C:7]=1I)[CH3:2].FC1C=CC(B(O)O)=CC=1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1B(O)O>>[CH2:1]([C:3]1[C:4]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[C:5]([CH:9]=[O:10])[NH:6][C:7]=1[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[O:32][CH3:31])[CH3:2]
Reactant: COc1ccccc1B(O)O
Reactant: CCc1c(I)[nH]c(C=O)c1C(=O)OCc1ccccc1
Agent: OB(O)c1ccc(F)cc1
Product: CCc1c(-c2ccccc2OC)[nH]c(C=O)c1C(=O)OCc1ccccc1

Procedure:
Following the procedures described in Example 5, replacing methyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate with benzyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate and 4-fluorophenylboronic acid with 2-methoxyphenylboronic acid, the title compound was obtained. Proton NMR for the product was consistent with the title compound. HRMS (ES) exact mass calculated for C22H22NO4 (M+H): 364.1544. Found 364.1537
Reaction SMILES: [CH:1]([NH:5][C:6](=[O:10])[CH:7]([CH3:9])[CH3:8])([CH2:3][CH3:4])[CH3:2].CN(C)CCN(C)C.[H-].[K+].C(S([C:27]1[O:28][CH:29]=[C:30]([CH3:32])[N:31]=1)=O)CCC>S1(CCCC1)(=O)=O.O>[CH:1]([N:5]([C:27]1[O:28][CH:29]=[C:30]([CH3:32])[N:31]=1)[C:6](=[O:10])[CH:7]([CH3:9])[CH3:8])([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)NC(=O)C(C)C
Reactant: CCCCS(=O)c1nc(C)co1
Agent: CN(C)CCN(C)C
Agent: [H-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: CCC(C)N(C(=O)C(C)C)c1nc(C)co1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
N-s-Butyl-isobutyramide (2.30 g, 0.016 m) and tetramethylethylenediamine (1.87 g, 0.016 m) were stirred at 40° C. in sulpholane (20 ml) under nitrogen during the portionwise addition of a 50% potassium hydride/oil dispersion (1.29 g, 0.016 m). After the addition, the mixture was warmed to 70° C. and 2-n-butylsulphinyl-4-methyloxazole (3.0 g, 0.016 m) in sulpholane (20 ml) was added. The mixture was stirred at 70° C. for 6 hours and then hydrolysed with water. Removal of the solvent in vacuo and column chromatography on silica using diethyl ether gave the title compound, which was a colourless oil after distillation in vacuo, b.p. 82° C./0.8 mm.
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:8][N:9]=1)(=O)C.Cl>C(O)C>[NH2:4][C:5]1[S:6][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:8][N:9]=1
Reactant: CC(=O)Nc1ncc(Sc2ccc(O)cc2)s1
Agent: Cl
Solvent: CCO
Product: Nc1ncc(Sc2ccc(O)cc2)s1
Yield: 83.1 %

Procedure:
A mixture of 2-acetylamino-5-(4-hydroxyphenylthio)thiazole (1.5 g) in a mixture of ethanol (40 ml) and aqueous 6N hydrochloric acid (6 ml) was refluxed for 4.5 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water. The solution was adjusted to pH 10 using aqueous sodium hydroxide under ice cooling. The precipitates were collected by filtration and recrystallized from a mixture of ethanol and water (3:1) to give 2-amino-5-(4-hydroxyphenylthio)thiazole (1.05 g, yield: 84.0%). mp: 187°-188° C.
Reaction SMILES: Cl.[C:2]([NH:6][OH:7])([CH3:5])([CH3:4])[CH3:3].[C:8]([O:11]CC)(=[O:10])[CH3:9].C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C>O>[C:8]([O-:11])(=[O:10])[CH3:9].[C:2]([NH2+:6][OH:7])([CH3:5])([CH3:4])[CH3:3]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)[O-]
Product: CC(C)(C)[NH2+]O
Reaction time: 1 h
Yield: 98.8 %

Procedure:
N-tert-Butylhydroxylamine hydrochloride (56 g, 0.43 mol, 97%) was dissolved in water (226 g) and charged to a 1 L three-necked glass bottle under argon gas. Ethyl acetate (246 g) and potassium carbonate (79 g, 0.57 mol, 1.3 equiv.) were added and the mixture was stirred vigorously for 1 h at +20 ° C. Both phases were siphoned to a separating funnel. The water phase was separated off and extracted once more with ethyl acetate (100 ml). The organic phases were pooled and acetic acid (28.1 g, 0.47 mol, −1.09 equiv.) was added. The solvent was evaporated off. The resulting clear, yellow-green oil was treated with additional ethyl acetate (203 g) and concentrated again. The bottle was placed in the refrigerator and after 2 h the product had turned crystalline. The substance was easily crushed giving a slightly yellowish powder (63.4 g, 90%). This material could be recrystallised using either toluene or ethyl acetate as solvent. Differential scanning calorimetry showed an endothermic melting point at +67.7° C. Powder X-ray diffraction analysis showed a high degree of crystallinity.
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([N:13]2[CH:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]2=[O:29])[CH2:9][CH2:8]1)=O)C.[NH3:30].CO>>[C:4]([CH2:6][N:7]1[CH2:8][CH2:9][CH:10]([N:13]2[CH:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]2=[O:29])[CH2:11][CH2:12]1)(=[O:3])[NH2:30]
Reactant: N
Reactant: CCOC(=O)CN1CCC(N2C(=O)Nc3ccccc3C2c2ccccc2)CC1
Solvent: CO
Product: NC(=O)CN1CCC(N2C(=O)Nc3ccccc3C2c2ccccc2)CC1

Procedure:
A solution of 200 mg (0.508 mmol) of 3-(1-ethoxycarbonylmethylpiperidin-4-yl)-4-phenyl-3,4-dihydro -2(1H)-quinazolinone in ammonia/methanol (6.09M, 30 mL) was stirred in an autoclave for 6 hours at temperature of approximately 150° C. After being cooled, the reaction mixture was concentrated in vacuo, and the residue was purified by means of column chromatography (silica gel, 1:9 methanol:chloroform) to give 167 mg (0.45 mmol) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:23][CH2:24][C:25](O)=[O:26])([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH2:12][C:11]2=[O:28])[CH3:9])=[CH:4][CH:3]=1.CC[N:31]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.N>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:23][CH2:24][C:25]([NH2:31])=[O:26])([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH2:12][C:11]2=[O:28])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCC(=O)O)(c2ccc(F)cc2)CC1=O
Reactant: CCN=C=NCCCN(C)C
Agent: N
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCC(N)=O)(c2ccc(F)cc2)CC1=O
Reaction time: 8 h

Procedure:
The solution of 3-((S)-1-((S)-1-(4-bromophenyl)ethyl)-4-(4-fluorophenyl)-2-oxopiperidin-4-yl)propanoic acid (28 mg, 0.063 mmol), EDCI (38 mg, 0.189 mmol), HOBt (26 mg, 0.189 mmol), and DIEA (82 mg, 0.63 mmol) in CH2Cl2 was filled with NH3 at 0° C. The mixture was stirred overnight, and washed with water. The organic phase was separated and concentrated to give the crude product, which was purified by preparative HPLC to afford 3-((S)-1-((S)-1-(4-bromophenyl)ethyl)-4-(4-fluorophenyl)-2-oxopiperidin-4-yl)propanamide (6 mg, 21%□. LC-MS Method 2, tR=1.869 min, m/z=447. 1H NMR (CDCl3): δ 1.46 (d, 3H), 1.77 (m, 1H), 1.92 (m, 1H), 1.96 (m, 1H), 2.08 (m, 1H), 2.14 (m, 3H), 2.24 (m, 1H), 2.51 (d, 1H), 3.02 (m, 1H), 3.12 (m, 1H), 5.32 (m, 1H), 5.71 (m, 1H), 5.94 (q, 1H), 6.76 (m, 2H), 6.99 (m, 2H), 7.16 (m, 2H), 7.24 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:31]=[CH:30][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[CH:24]=[C:25]([C:27](O)=[O:28])[S:26][C:19]=23)=[CH:15][CH:14]=1)=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:65][CH2:66][CH2:67][CH:68]([O:72][CH2:73][CH3:74])[O:69][CH2:70][CH3:71].Cl>C(#N)C.O>[CH2:70]([O:69][CH:68]([O:72][CH2:73][CH3:74])[CH2:67][CH2:66][NH:65][C:27]([C:25]1[S:26][C:19]2[C:20](=[N:21][CH:22]=[CH:23][C:18]=2[O:17][C:16]2[CH:15]=[CH:14][C:13]([NH:12][C:10]([NH:9][C:3]3[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=3[F:1])=[O:11])=[CH:31][CH:30]=2)[CH:24]=1)=[O:28])[CH3:71]
Reactant: CCOC(CCN)OCC
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)O)sc34)cc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(CCNC(=O)c1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)c2s1)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylic acid (600 mg, 1.37 mmol) in 10 ml of anhydrous acetonitrile were added HATU (608 mg, 1.6 mmol) and N,N-diisopropylethylamine (388 mg, 3.0 mmol). The mixture was stirred at room temperature for 30 minutes, followed by addition of 1-amino-3,3-diethoxypropane (294 mg, 2.0 mmol). The mixture was stirred for another 10 minutes and poured into 100 ml of water with vigorous stirring. 1M HCl was added until pH=5. The precipitates were filtered, washed with water and dried in vacuo to give N-(3,3-diethoxypropyl)-7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide as yellow solid. Yield: 680 mg, 88%.
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:23])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=1)=[O:7])(C)(C)C.Cl>ClCCl.O1CCOCC1>[OH:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[O:15][CH2:14][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[C:6]([OH:7])=[O:5])=[O:23]
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)COc1cccc(O)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(O)[C@H]1CCCN1C(=O)COc1cccc(O)c1
Reaction time: 72 h
Yield: 96.8 %

Procedure:
To a solution of 120 mg (0.37 mmol) (R)-1-[(3-hydroxy-phenoxy)-acetyl]-pyrrolidine-2-carboxylic acid tert-butyl ester in 1 ml dichloromethane were added 5 ml of a 4 N solution of hydrochloric acid in dioxane. After 3 d, the solvent was removed in vacuo and the residue suspended in 10 ml ether. The resulting suspension was stirred overnight. Filtration and drying gave 95 mg (97%) of the title compound as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:27]([O-:29])=[O:28])=[C:6]([CH2:8][CH:9]([CH:18]([C:23]([O:25][CH3:26])=[O:24])[C:19]([O:21][CH3:22])=[O:20])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:7]=1.[H-].[Na+].I[CH2:33][CH3:34]>CN(C)C=O.CCOCC>[CH2:33]([C:18]([CH:9]([C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=1)[CH2:8][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[N+:27]([O-:29])=[O:28])([C:23]([O:25][CH3:26])=[O:24])[C:19]([O:21][CH3:22])=[O:20])[CH3:34]
Reactant: COC(=O)C(C(=O)OC)C(Cc1cc(Cl)ccc1[N+](=O)[O-])c1ccc(OC)cc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCC(C(=O)OC)(C(=O)OC)C(Cc1cc(Cl)ccc1[N+](=O)[O-])c1ccc(OC)cc1
Yield: 108.2 %

Procedure:
[2-(5-Chloro-2-nitrophenyl)-1-(4-methoxyphenyl)ethyl]propanedioic acid, dimethyl ester (15.29 g, 36.25 mmole) was dissolved in dry dimethylformamide (100 ml) under argon. Prewashed (ether, 3 times), 50% sodium hydride (1.04 g, 43.3 mmole) was added with stirring. (The mixture turned from yellow to a dark red color). Stirring was continued for 20 minutes before iodoethane (14.5 ml, 28.3 g, 181 mmole, 5 eq) was added dropwise, and the reaction mixture was allowed to stir for an additional 2 hours. The solution was diluted with ether and washed with water. The organic layer was dried (magnesium sulfate), concentrated, and vacuum-dried overnight to yield 17.65 g of crude product as a light yellow oil. This material was triturated with methanol leaving 12.73 g of white solid, melting point 95.5°-97.0° C. Additional product was present in the mother liquor.
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=1)=O.CSC.B.CO>C1COCC1>[CH3:1][NH:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=1
Reactant: COC(=O)Cc1ccc(NC=O)cc1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Solvent: CO
Product: CNc1ccc(CC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirred solution of methyl (4-formylaminophenyl)acetate (4.31 g) in THF (20.0 mL) at 0° C. was slowly added borane dimethylsulfide (8.61 mL, 90.8 mmol). The reaction mixture was stirred at room temperature overnight and then cooled to 0° C. MeOH (15 mL) was added cautiously and the resulting mixture was stirred for 3 h. The mixture was then concentrated under reduced pressure to give the title compound (4.0 g, 73% yield, 2 steps) as a clear oil.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:29])=[CH:7][C:5]=2[N:6]=1.[CH3:30][N:31]1[C:35]2[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][C:34]=2[N:33]=[CH:32]1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:25]([O:24][C@@H:18]([C:9]1[C:8]([CH3:29])=[CH:7][C:5]2[N:6]=[C:2]([C:37]3[CH:38]=[CH:39][C:34]4[N:33]=[CH:32][N:31]([CH3:30])[C:35]=4[CH:36]=3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:28])([CH3:27])[CH3:26]
Reactant: Cn1cnc2ccc(B(O)O)cc21
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4ncn(C)c4c3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A microwave vial was charged with (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (75 mg, 0.15 mmol), 1-methyl-1H-benzo[d]imidazol-6-ylboronic acid (34 mg, 0.19 mmol), then Pd(PPh3)4 (34 mg, 0.03 mmol). The vial was flushed with argon, diluted with dioxane (1.5 mL) and to this was added 2M aqueous K2CO3 (0.25 mL, 0.50 mmol). The vial was sealed, heated to 100° C. for 2 hours, and then allowed to cool to room temperature. The mixture was diluted with EtOAc, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (0-10% MeOH/CH2Cl2 gradient) to afford the desired product. LCMS-ESI+: calc'd for C30H31ClN3O3S: 548.2 (M+H+); Found: 548.3 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH3:17].[CH3:18][S:19]([N:22]([CH3:46])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[N:37]2[C:32]([CH:33]=[N:34][C:35](OS(C(F)(F)F)(=O)=O)=[N:36]2)=[CH:31][CH:30]=1)(=[O:21])=[O:20].C(N(CC)C(C)C)(C)C.COCC(O)C>>[OH:13][CH:10]1[CH2:11][CH2:12][N:7]([CH2:6][C:5]2[CH:14]=[CH:15][C:2]([NH:1][C:35]3[N:34]=[CH:33][C:32]4=[CH:31][CH:30]=[C:29]([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[N:22]([CH3:46])[S:19]([CH3:18])(=[O:21])=[O:20])[N:37]4[N:36]=3)=[C:3]([O:16][CH3:17])[CH:4]=2)[CH2:8][CH2:9]1
Reactant: CN(c1ccccc1-c1ccc2cnc(OS(=O)(=O)C(F)(F)F)nn12)S(C)(=O)=O
Reactant: COc1cc(CN2CCC(O)CC2)ccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: COc1cc(CN2CCC(O)CC2)ccc1Nc1ncc2ccc(-c3ccccc3N(C)S(C)(=O)=O)n2n1
Temperature: 120 °C

Procedure:
Into an 8-dram vial, [1-(4-Amino-3-methoxy-benzyl)-piperidin-4-ol (0.102 g, 0.430 mmol), Trifluoro-methanesulfonic acid 7-[2-(methanesulfonyl-methyl-amino)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester (88.0 mg, 0.195 mmol), N,N-Diisopropylethylamine (0.0749 mL, 0.430 mmol), and 1-Methoxy-2-propanol (0.70 mL, 7.2 mmol) were added. The reaction mixture was heated at 120° C. for 6 hours. The solvent was removed under vacuum. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN. The collected fractions were lyophilized to give N-(2-{2-[4-(4-Hydroxy-piperidin-1-ylmethyl)-2-methoxy-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-phenyl)-N-methyl-methanesulfonamide a yellow solid (92 mg, 72%). LCMS (E/I+) 537.11 (M+H). NMR 1H (DMSO-d6)-9.16 (bs, 1H), 9.00 (s, 1H), 8.07-8.12 (m, 1H), 7.95-8.01 (m, 1H), 7.86 (s, 1H), 7.64-7.70 (m, 1H), 7.52-7.58 (m, 1H), 7.19 (d, 1H, J=9.96 Hz), 7.03 (d, 1H, J=4.60 Hz), 7.01 (d, 1H, J=4.60 Hz), 6.90-7.00 (m, 1H), 4.24 (dd, 2H, J=4.64, 16.65 Hz), 2.80-4.00 (m, 15H), 1.40-2.00 (m, 4H).
Reaction SMILES: [CH2:1]([S:8]([NH:11][C@@H:12]([C:30]([NH:32][CH2:33][C:34](O)=[O:35])=[O:31])[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[NH:29])[NH:18][S:19]([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20])(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:37][C@H:38]([C:56]([OH:58])=[O:57])[CH2:39][CH2:40][CH2:41][NH:42][C:43](=[NH:55])[NH:44][S:45]([C:48]1[CH:54]=[CH:53][C:51]([CH3:52])=[CH:50][CH:49]=1)(=[O:47])=[O:46].[S:59]1[CH:63]=[CH:62][N:61]=[CH:60]1>>[CH2:1]([S:8]([NH:11][C@@H:12]([C:30]([NH:32][CH2:33][C:34]([NH:37][C@H:38]([C:56]([OH:58])=[O:57])[CH2:39][CH2:40][CH2:41][NH:42][C:43](=[NH:55])[NH:44][S:45]([C:48]1[CH:54]=[CH:53][C:51]([CH3:52])=[CH:50][CH:49]=1)(=[O:47])=[O:46])=[O:35])=[O:31])[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[NH:29])[NH:18][S:19]([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:20])=[O:21])(=[O:9])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[S:59]1[CH:63]=[CH:62][N:61]=[CH:60]1
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](NS(=O)(=O)Cc2ccccc2)C(=O)NCC(=O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](N)C(=O)O)cc1
Agent: c1cscn1
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)CNC(=O)[C@@H](CCCNC(=N)NS(=O)(=O)c2ccc(C)cc2)NS(=O)(=O)Cc2ccccc2)C(=O)O)cc1
Yield: 63 %

Procedure:
A 100 mg portion of the compound of Example 11 was coupled with 0.19 mmol of H—Arg(Tos)—thiazole (prepared following the procedure of Example 5) following the procedure as described in Example 6. RP—HPLC purification gave the title compound (110 mg, 63% yield). FAB—MS (M+H)+917.8
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8]([CH3:10])=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[O:14][C:15]([CH2:18][O:19][CH3:20])=[CH:16][CH:17]=2)[N:3]=1.SC[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:13]2[O:14][C:15]([CH2:18][O:19][CH3:20])=[CH:16][CH:17]=2)[C:5]([C:11]#[N:12])=[C:6]([S:8][CH2:10][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[N:7]=1
Reactant: SCCc1ccccn1
Reactant: COCc1ccc(-c2nc(N)nc(S(C)=O)c2C#N)o1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: COCc1ccc(-c2nc(N)nc(SCCc3ccccn3)c2C#N)o1

Procedure:
From 2-amino-4-methanesulfinyl-6-(5-methoxymethyl-furan-2-yl)-pyrimidine-5-carbonitrile, 2-mercaptoethylpyridine and DBU in DME. ES-MS m/e (%): 368 (M+H+, 100).
Reaction SMILES: [Br-].[Cl:2][CH2:3][CH2:4][N+:5]([CH3:14])([CH3:13])[CH2:6][CH2:7][CH2:8][C:9]([O:11]C)=[O:10]>O>[Cl-:2].[C:9]([CH2:8][CH2:7][CH2:6][N+:5]([CH2:4][CH2:3][Cl:2])([CH3:14])[CH3:13])([OH:11])=[O:10]
Reactant: COC(=O)CCC[N+](C)(C)CCCl
Agent: [Br-]
Solvent: O
Product: C[N+](C)(CCCl)CCCC(=O)O
Product: [Cl-]
Temperature: 70 °C
Reaction time: 15 h
Yield: 159.6 %

Procedure:
N-(2-Chloroethyl)-4-methoxy-N,N-dimethyl-4-oxobutan-1-aminium bromide (5) (7.477 g, 25.9 mmol) was dissolved in water (10 ml) and passed through Amberlite® IRA-410 (Cl) ion exchange resin column (100 ml) slowly (ca. 0.5 ml/min) eluting with water (control with 2% AgNO3 solution). The eluate was evaporated; the residue (˜6 g) was dissolved in 1N HCl (50 ml) and stirred for 15 h at 70° C. The reaction mixture was evaporated and dried to give 4.755 g (79%) of 3-carboxy-N-(2-chloroethyl)-N,N-dimethylpropan-1-aminium chloride as a yellowish solid. The purity of the obtained compound can be increased by crystallization from acetonitrile. Thus, 2 g of the obtained material was crystallized from acetonitrile (120 ml) to afford 1.32 g of white crystalline 6 with m.p. 130° C.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[C:30]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][CH:42]=O)=[CH:36][CH:35]=1)([OH:32])=[O:31].C(OCC)C>C1(C)C=CC=CC=1.O1CCCC1>[CH3:2][O:3][CH:4]=[CH:42][CH2:41][CH2:40][C:37]1[CH:36]=[CH:35][C:34]([CH2:33][C:30]([OH:32])=[O:31])=[CH:39][CH:38]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CCCc1ccc(CC(=O)O)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COC=CCCc1ccc(CC(=O)O)cc1
Reaction time: 0.17 h
Yield: 78.1 %

Procedure:
To 3.77 g (11 mmol) of methoxymethyltriphenyl phosphonium chloride in 10 ml of toluene at 0° C. under nitrogen was added 11 ml (11 mmol) of 1M potassium t-butoxide in tetrahydrofuran over 20 minutes. The resulting solution was stirred for 10 minutes, then 1.92 g (10 mmol) of 3-(4-carboxymethylphenyl)-propanal in 10 ml of toluene was added over 15 minutes. After stirring the mixture for 20 minutes 40 ml of ethyl ether were added. The resulting precipitate was filtered with diatomaceous earth, collected, washed with 20 ml of water, 20 ml of saturated sodium chloride and dried with a 9:1 sodium sulfate:saturated sodium chloride mixture. Vacuum concentration of the filtered solution and trituration of the residue with hexane gave 1.72 g of 1-methoxy-4-(4-carboxymethyl phenyl)-1-butene. Chromatography of the above product (silica gel, 8:2 hexane:ethyl acetate) gave 1.0 g of a mixture of geometric isomers (Z/E-6:4) of the above product in a combined yield of 45 percent. b.p. 140° C. @0.07 torr. 1H NMR (CDCl3) δ2.23 (dq, J=1.0, 8.1 Hz), 2.40 (dq, J=1.3, 8.0 Hz) total 2H, 2.70 (t, J=8.1 Hz), 2.71 (t, J=8.0 Hz), total 2H, 3.48 (s), 3.55 (s), total 3H, 3.89 (s), 3.90 (s), total 3H, 4.32 (q, J=6.2 Hz), 4.71 (dr, J=7.3, 12.6 Hz), total 1H, 5.87 (dr, J=1.3, 6.2 Hz), 6.28 (dt, J=1.0, 12.6 Hz) , total 1H, 7.23 (d, J=8.2 Hz), 7.27 (d, J=8.2 Hz), total 1H, 7.94 (d, J=8.2 Hz), 7.95 (d, J=8.2 Hz), total 2H; 13C NMR (CDCl3) δ8 25.2, 29.3, 36.0, 37.4, 51.9, 56.0, 59.5, 101.8, 101.9, 105.5, 127.9, 28.0, 128.5, 128.6, 129.6, 129.7, 146.9, 147.5, 147.9, 48.0, 167.1, 167.2; IR (CHCl3) 3025, 2954, 1716, 1656, 1610, 1437, 1284, 1112 cm-1 ; MS(FD) m/z 220 (M+).