Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])[CH:2]=1.[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=1[Cl:31]>CN(C)C=O>[Cl:29][C:28]1[CH:27]=[C:26]([CH3:30])[CH:25]=[C:24]([Cl:31])[C:23]=1[O:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:9]1[CH2:10][CH2:11][N:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[C:8]1=[O:12]
Reactant: O=C1NCCN1c1cccnc1
Reactant: Cc1cc(Cl)c(OCCCCCCBr)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Cl)c(OCCCCCCN2CCN(c3cccnc3)C2=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(3-pyridyl)-2-imidazolidinone (0.10 g, 0.63 mmol) dissolved in 10 mL dimethylformamide cooled in an ice bath was added NaH (60% dispersion in mineral oil, 38.2 mg, 0.96 mmol). The mixture was stirred at room temperature for 30 minutes and then cooled in ice bath. 2-[(6-Bromohexyl)oxy]-1,3-dichloro-5-methylbenzene (0.22 g, 0.64 mmol) was added, and the mixture was stirred at room temperature for additional 4 hours. The reaction was quenched with MeOH, and the solvents were pumped off. 5 mL of a saturated aqueous NH4Cl solution and 10 mL of dichloromethane were successively added to the residue. The dichloromethane layer was separated and dried over MgSO4, filtered, evaporated, and purified by column chromatography (ethyl acetate:MeOH=10:1) to give the product (i.e., Compound 5) as a white solid (0.36 g, 90%).
Reaction SMILES: [CH2:1]([O:6][C:7]1[C:8](/[CH:21]=[CH:22]/[C:23]2[CH:33]=[CH:32][C:26]([C:27]([O:29]CC)=[O:28])=[CH:25][CH:24]=2)=[CH:9][C:10]2[C:11]([CH3:20])([CH3:19])[CH2:12][CH2:13][C:14]([CH3:18])([CH3:17])[C:15]=2[CH:16]=1)[C:2]#[C:3][CH2:4][CH3:5].[OH-].[Na+]>C(O)C.C1COCC1>[CH2:1]([O:6][C:7]1[C:8](/[CH:21]=[CH:22]/[C:23]2[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:32][CH:33]=2)=[CH:9][C:10]2[C:11]([CH3:19])([CH3:20])[CH2:12][CH2:13][C:14]([CH3:18])([CH3:17])[C:15]=2[CH:16]=1)[C:2]#[C:3][CH2:4][CH3:5]
Reactant: CCC#CCOc1cc2c(cc1/C=C/c1ccc(C(=O)OCC)cc1)C(C)(C)CCC2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCC#CCOc1cc2c(cc1/C=C/c1ccc(C(=O)O)cc1)C(C)(C)CCC2(C)C
Yield: 87.9 %

Procedure:
1.30 g of ethyl (E)-4-[2-(3-pent-2-ynyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-vinyl]-benzoate were placed in 10 ml of abs. ethanol/THF=1/1 and treated under argon with 4.9 ml of 3N NaOH. After 40 h. at room temperature the mixture was poured on to ice and extracted with ethyl acetate. The organic phase was washed with water and saturated NaCl soln., dried and evaporated. Crystallization from hexane/ethyl acetate yielded 1.07 g of (E)-4-[2-(3-pent-2-ynyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-vinyl]-benzoic acid as beige crystals of m.p. 144-145°.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[OH:7][C@@H:8]1[C:25]2[C:24]3[N:23]([CH3:26])[C:22]4[N:21]=[C:20]5[CH:27]=[CH:28][CH:29]=[CH:30][C:19]5=[CH:18][C:17]=4[C:16](=[O:31])[C:15]=3[C:14]([O:32][CH3:33])=[CH:13][C:12]=2[O:11][C:10]([CH3:35])([CH3:34])[C@@H:9]1[OH:36]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:1]([O:36][C@@H:9]1[C@H:8]([OH:7])[C:25]2[C:24]3[N:23]([CH3:26])[C:22]4[N:21]=[C:20]5[CH:27]=[CH:28][CH:29]=[CH:30][C:19]5=[CH:18][C:17]=4[C:16](=[O:31])[C:15]=3[C:14]([O:32][CH3:33])=[CH:13][C:12]=2[O:11][C:10]1([CH3:34])[CH3:35])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)Cl
Reactant: COc1cc2c(c3c1c(=O)c1cc4ccccc4nc1n3C)[C@@H](O)[C@@H](O)C(C)(C)O2
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCCC(=O)O[C@@H]1[C@H](O)c2c(cc(OC)c3c(=O)c4cc5ccccc5nc4n(C)c23)OC1(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Add 2 equivalents of butyryl chloride to a solution of 0.74 mmol of the compound of Example 3 in 7 ml of anhydrous pyridine in the presence of 4-dimethylaminopyridine. Stir at ambient temperature for 72 hours and then add 5 equivalents of butyryl chloride and stir again for 72 hours and then evaporate to dryness. Chromatography on silica gel allows the expected product to be isolated.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7](Cl)(=[O:9])=[O:8])[CH:2]=1.Cl.[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1>>[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH:18][S:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)(=[O:9])=[O:8])=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: NCc1ccc(Br)cc1
Agent: Cl
Product: O=S(=O)(NCc1ccc(Br)cc1)c1cccnc1
Yield: 83.7 %

Procedure:
Reaction and post-treatment were carried out in the same manner as in Reference Example 2-(d) except for using 3-pyridylsulfonyl chloride (300 mg, 1.69 mmol), and using 4-bromobenzylamine hydrochloride (342 mg, 1.54 mmol) in place of (6-phenylpyridazin-3-ylmethyl)amine hydrochloride to afford the title compound (422 mg) as a white solid. (Yield: 84%)
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:19][CH2:20][C:21]([CH3:24])([OH:23])[CH3:22]>>[OH:23][C:21]([CH3:24])([CH3:22])[CH2:20][NH:19][C:10]([C:7]1[CH:6]=[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][N:8]=1)=[O:12]
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Reactant: CC(C)(O)CN
Product: CC(C)(O)CNC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1

Procedure:
The title compound was synthesized in analogy to Example 24d, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 48c) and 1-amino-2-methylpropan-2-ol (CAN 2854-16-2) as starting materials and isolated (28 mg, 34%) as a yellow oil; MS (ESI, m/z): 333.5 (M+H+).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[S:8][C:9]=1[CH2:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14](F)[CH:13]=1)[CH2:2][CH2:3][CH3:4].[CH3:31][S-:32].[Na+].O>CN(C)C=O>[CH2:1]([C:5]1[N:6]=[C:7]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[S:8][C:9]=1[CH2:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([S:32][CH3:31])[CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(C#N)c(F)c1
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(C#N)c(SC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 657.5 %

Procedure:
To a solution of 50 mg of 4-[4-butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-fluoro-benzonitrile (prepared according to the method described in example 1) in 10 ml of dimethylformamide was added 121 mg of sodium thiomethoxide. The resulting mixture was stirred at room temperature overnight, then poured into water, extracted with diisopropyl ether. The combined organic extracts were washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by crystallization from diisopropyl ether/heptane to give 350 mg of 4-[4-butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methylsulfanyl-benzonitrile, which was transformed into 3-{4-[4-butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methylsulfanyl-phenyl}-4H-[1,2,4]oxadiazol-5-one according to the method described in example 1.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:23]2[C:31]3[C:26](=[C:27]([N:32]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[S:33]([CH3:36])(=[O:35])=[O:34])[CH:28]=[CH:29][CH:30]=3)[CH:25]=[N:24]2)([CH2:21][CH3:22])/[CH:17]=[CH:18]/[C:19]#[N:20])=[CH:12][CH:11]=1>CS(C)=O>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([N:23]2[C:31]3[C:26](=[C:27]([N:32]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:42])[CH3:43])[S:33]([CH3:36])(=[O:34])=[O:35])[CH:28]=[CH:29][CH:30]=3)[CH:25]=[N:24]2)([CH:17]2[CH2:4][CH:18]2[C:19]#[N:20])[CH2:21][CH3:22])=[CH:14][CH:15]=1
Reactant: C[S+](C)(C)=O
Reactant: CCC(/C=C/C#N)(c1ccc(Cl)cc1)n1ncc2c(N(COCC[Si](C)(C)C)S(C)(=O)=O)cccc21
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCC(c1ccc(Cl)cc1)(C1CC1C#N)n1ncc2c(N(COCC[Si](C)(C)C)S(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of NaH (22 mg) in anhydrous DMSO (0.9 mL) was added trimethylsulfoxonium iodide (128 mg) at 0° C. and the mixture was stirred at rt for 3 h until the solution became clear. Then was added the solution of (E)-N-(1-(3-(4-chlorophenyl)-1-cyanopent-1-en-3-yl)-1H-indazol-4-yl)-N-((2-(trimethylsilyl)ethoxy)methyl)methanesulfonamide (42 mg) in anhydrous DMSO (0.1 mL) and the reaction mixture was stirred at 70° C. for 16 h. The solution was quenched with saturated NH4Cl solution, extracted with ethyl acetate (15 mL). The organic layer was washed with brine, dried over dry sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography (PE/EA=4/1) to afford the title compound as a white solid. LC/MS m/z=559.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21](O)=[O:22])[C:17]=3[O:19][CH3:20])[NH:12][N:11]=2)=[CH:4][CH:3]=1.Cl.[C:25]([O:29][C:30](=[O:33])[CH2:31][NH2:32])([CH3:28])([CH3:27])[CH3:26].C(N(C(C)C)CC)(C)C.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O>[C:25]([O:29][C:30](=[O:33])[CH:31]([C:21]([C:16]1[C:17]([O:19][CH3:20])=[C:18]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2/[CH:9]=[CH:8]/[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:22])[NH2:32])([CH3:28])([CH3:27])[CH3:26]
Reactant: COc1c(C(=O)O)ccc2[nH]nc(/C=C/c3ccc(F)cc3)c12
Reactant: CC(C)(C)OC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(C(=O)C(N)C(=O)OC(C)(C)C)ccc2[nH]nc(/C=C/c3ccc(F)cc3)c12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic acid obtained by Example 234 and 258 mg of glycine ter-butyl ester hydrochloride were dissolved in 20 mL of N,N-dimethylformamide, and 0.871 mL of diisopropylethylamine and 235 mg of 1-hydroxybenzotriazole were added, and stirred at room temperature for 10 minutes. After cooling to 0° C., 491 mg of WSC hydrochloride was added, and stirred overnight at room temperature. After adding ice water to stop the reaction, the solution was extracted with ethyl acetate. The organic phase was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, to afford 547 mg of the title compound as pale green crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12](C)[C:13](=O)OC(C)(C)C)[CH:5]=[CH:4][N:3]=1.[ClH:21].O1CCOCC1>CO>[ClH:21].[ClH:21].[CH3:13][NH:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: CN(CCCNc1ccnc(N)n1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CNCCCNc1ccnc(N)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 16.6 %

Procedure:
A stirred solution of tert-butyl 3-(2-aminopyrimidin-4-ylamino)propyl(methyl)carbamate (Example 7A, 40 mg, 0.1422 mmol) in methanol (0.5 mL) was treated with a 4M solution of HCl in dioxane (0.5 mL, 2.0000 mmol). After stirring at ambient temperature for 18 hours, volatiles were removed under reduced pressure to give a white solid that was crystallized methanol/ether. White crystals were collected by filtration to provide N4-(3-(methylamino)propyl)pyrimidine-2,4-diamine dihydrochloride (6.0 mg, 16.6% yield). 1H NMR (300 MHz, CD3OD) δ ppm 2.01 (pentet, J=7 Hz, 2H), 2.72 (s, 3H), 3.07 (t, J=7 Hz, 2H), 3.58 (t, J=7 Hz, 2H), 6.13 (d, J=7 Hz, 1H), 7.58 (d, J=7 Hz, 1H). MS (DCl—NH3) m/z=182 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:20](=[O:22])[CH3:21])=[CH:10][C:11]([CH:18]=[CH2:19])=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:5]=[CH:6][CH:7]=1.[H][H]>[Pd].CO>[CH2:18]([C:11]1[CH:10]=[C:9]([C:20](=[O:22])[CH3:21])[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[C:17]2[C:12]=1[CH:13]=[CH:14][CH:15]=[N:16]2)[CH3:19]
Reactant: C=Cc1cc(C(C)=O)c(-c2cccc(F)c2)c2ncccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCc1cc(C(C)=O)c(-c2cccc(F)c2)c2ncccc12
Yield: 20.8 %

Procedure:
A mixture of 1-[8-(3-fluorophenyl)-5-vinylquinolin-7-yl]ethanone (0.03 g, 0.1 mmol) and 5% palladium on carbon (3 mg) in methanol (1 mL) was treated with hydrogen under balloon pressure, at room temperature, for 3 hours. The mixture was filtered. The filtrate was concentrated and purified on silica gel (eluting with 0 to 10% Ethyl acetate in hexane) to give the desired product (6.1 mg, 20%). LCMS calculated for C19H17FNO (M+H)+: m/z=294.1; Found: 294.1.
Reaction SMILES: [N:1]1[C:9]([NH:10][C@H:11]([C:13]2[N:14]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:15](=[O:24])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3Cl)[CH3:12])=[C:8]2[C:4]([NH:5][CH:6]=[N:7]2)=[N:3][CH:2]=1.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>O1CCOCC1>[N:1]1[C:9]([NH:10][C@H:11]([C:13]2[N:14]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:15](=[O:24])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[N:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[CH3:12])=[C:8]2[C:4]([NH:5][CH:6]=[N:7]2)=[N:3][CH:2]=1
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Reactant: C1CCNC1
Solvent: C1COCCO1
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1cc2cccc(N3CCCC3)c2c(=O)n1-c1ccccc1
Temperature: 135 °C
Reaction time: 17 h

Procedure:
To a solution of (S)-3-(1-((9H-purin-6-yl)amino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one (3) (100 mg, 0.24 mmol) in 1,4-dioxane (3 mL) in a sealed tube, pyrrolidine (1.25 mL, excess amount) was added and the resulting mixture was stirred at 135° C. for 17 h. The mixture was allowed to cool to RT, partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by ISCO (silica gel cartridge, 0-10% MeOH-DCM) to afford the product, (S)-3-(1-((9H-purin-6-yl)amino)ethyl)-2-phenyl-8-(pyrrolidin-1-yl)isoquinolin-1(2H)-one (4) as an off-white solid. ESI-MS m/z: 452.2 [M+H]+.
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[OH:45][C:46]1[CH:54]=[CH:53][C:49]([C:50](O)=[O:51])=[CH:48][N:47]=1>CN(C=O)C>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:50]([C:49]3[CH:53]=[CH:54][C:46](=[O:45])[NH:47][CH:48]=3)=[O:51])[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CCNCC1)C1CC1
Reactant: O=C(O)c1ccc(O)nc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(c1ccc(=O)[nH]c1)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 83.1 %

Procedure:
N-Cyclopropyl-N-piperidin-4-yl-3-trifluoromethyl-benzenesulfonamide (0.174 g, 0.50 mmol), HOBt (0.068 g, 0.50 mmol), EDCI (0.115 g, 0.60 mmol) and 6-hydroxynicotinoic acid (0.078 g, 0.55 mmol) were dissolved in 5 ml of dry DMF. The mixture allowed to stir at room temperature for 10 hours. The reaction mixture was concentrated and dried under reduced pressure. Then residue was dissolved in EtOAc (30 ml) and the mixture was washed with saturated NaHCO3 (15 ml) and brine (15 ml). The organic layer was dried over MgSO4 and concentrated to dryness. The crude product was purified through a column of silica gel with a gradient of 5% to 10% MeOH in CHCl3 to afford the title compound 6 (colorless solid, 195 mg, 83%). LC: 100%. MS: m/z=469.
Reaction SMILES: [N:1]1[S:2][N:3]=[C:4]2[C:9]([CH2:10][NH:11][C@@H:12]([CH3:20])[CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:21]1[C:33]2[CH:32]([CH2:34][O:35][C:36]([NH:38][C@@H:39]([CH2:43][C:44]3[CH:49]=[CH:48][C:47]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:46][CH:45]=3)[C:40](O)=[O:41])=[O:37])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]=2[CH:24]=[CH:23][CH:22]=1>>[N:1]1[S:2][N:3]=[C:4]2[C:9]([CH2:10][N:11]([C@@H:12]([CH3:20])[CH:13]([O:14][CH2:15][CH3:16])[O:17][CH2:18][CH3:19])[C:40](=[O:41])[C@@H:39]([NH:38][C:36](=[O:37])[O:35][CH2:34][CH:32]3[C:33]4[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=4[C:26]4[C:31]3=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:43][C:44]3[CH:49]=[CH:48][C:47]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:46][CH:45]=3)=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CCOC(OCC)[C@H](C)NCc1cccc2nsnc12
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2nsnc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Yield: 67.6 %

Procedure:
According to the procedure described in the synthesis method of Compound III-1, (S)—N-(benzo[c][1,2,5]thiadiazol-4-ylmethyl)-1,1-diethoxypropan-2-amine (Compound IX-4) 1.41 g (4.78 mmol) was coupled with (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-tert-butoxyphenyl)propanoic acid 2.4 g (5.23 mmol) and purified on Buch silica gel column chromatography (n-hexane:ethyl acetate=7:3) to obtain the title compound 2.38 g (68%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:11]1[N:15]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:14]([N:24]2[CH2:29][CH2:28][N:27]([S:30]([CH2:33][CH3:34])(=[O:32])=[O:31])[CH2:26][CH2:25]2)=[N:13][C:12]=1[C:35]1[CH:36]=[C:37]([O:42][CH3:43])[C:38]([NH2:41])=[N:39][CH:40]=1>COCCOC.C([O-])([O-])=O.[Na+].[Na+].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>[CH2:33]([S:30]([N:27]1[CH2:28][CH2:29][N:24]([C:14]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:11]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[C:12]([C:35]3[CH:36]=[C:37]([O:42][CH3:43])[C:38]([NH2:41])=[N:39][CH:40]=3)[N:13]=2)[CH2:25][CH2:26]1)(=[O:32])=[O:31])[CH3:34]
Reactant: OB(O)c1ccncc1
Reactant: CCS(=O)(=O)N1CCN(c2nc(-c3cnc(N)c(OC)c3)c(Br)n2COCC[Si](C)(C)C)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: [Na+]
Solvent: COCCOC
Product: CCS(=O)(=O)N1CCN(c2nc(-c3cnc(N)c(OC)c3)c(-c3ccncc3)n2COCC[Si](C)(C)C)CC1

Procedure:
A mixture of pyridin-4-ylboronic acid (17.0 mg, 0.14 mmol) and 5-(5-bromo-2-(4-(ethylsulfonyl)piperazin-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-3-methoxypyridin-2-amine (26.5 mg, 0.05 mmol) in DME (1.5 mL) and 2.0 M aqueous Na2CO3 (0.5 mL) was sparged with Ar for 2 min. Tetrakis(triphenylphosphine)palladium(0) (10.6 mg, 9.2 μmol) was added. The mixture was sparged with Ar for an additional 2 min and was irradiated in a sealed tube in a microwave reactor at 115° C. for 15 min. The reaction mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with sat aqueous NaHCO3 (30 mL), brine (30 mL), dried over Na2SO4, filtered and concentrated in vacuo. The material purified by preparative TLC (SiO2, 0.25 mm, 95:5 DCM-MeOH) to afford 5-(2-(4-(ethylsulfonyl)piperazin-1-yl)-5-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-3-methoxypyridin-2-amine was isolated as colorless solid: LCMS (m/z): 574.3 (MH+), tR=0.68 min.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5](=[O:9])[C:6]([CH3:8])=[CH2:7].ClC(Cl)C.[Cl:14][C:15]([Cl:20])([Cl:19])[C:16](Cl)=[O:17]>C(N(CC)CC)C>[Cl:14][C:15]([Cl:20])([Cl:19])[C:16]([O:1][CH2:2][CH2:3][O:4][C:5](=[O:9])[C:6]([CH3:8])=[CH2:7])=[O:17]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: C=C(C)C(=O)OCCO
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: C=C(C)C(=O)OCCOC(=O)C(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 6 h

Procedure:
Hydroxyethylmethacrylate (13.0 g) was placed in a 250 ml, three-necked, round-bottomed flask, fitted with a stirrer, air condenser and two dropping funnels, as well as a thermometer. The apparatus was placed in an ice/salt freezing bath. Dichloroethane (100 ml) was added, followed by the simultaneous dropwise addition of triethylamine (10.1 g) and trichloroacetyl chloride (18.2 g). During the addition the temperature was not allowed to rise above 2° C. After the addition was complete, the mixture was stirred for a further 6 hours, during this time the temperature rose gradually to room temperature. The mixture stood overnight, and the precipitated salt was filtered off, and the residue was washed thoroughly with dichloroethane. The washings and the filtrate were combined and the solvent was removed on a rotary evaporator. The residue still contained some solid. It was dissolved in ether, the ether solution was washed with water (3 times). The solution was then dried (MgSO4), filtered, and the solvent was removed under vacuum. The residue was distilled under high vacuum, collecting the fraction, boiling between 84°-90° C./0.1 mm (16 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C@@H:17]([NH:26][C:27](=[O:40])[CH2:28][C:29]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])([CH3:31])[CH3:30])[C:16]2=[O:41])=[CH:10][CH:9]=1.[CH3:42][N:43]=[C:44]=[O:45].N12CCCN=C1CCCCC2>C(Cl)Cl>[CH3:42][NH:43][C:44]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11]([CH2:14][N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C@@H:17]([NH:26][C:27](=[O:40])[CH2:28][C:29]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])([CH3:31])[CH3:30])[C:16]2=[O:41])=[CH:12][CH:13]=1)=[O:45]
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3O)cc2)C1=O)NC(=O)OC(C)(C)C
Reactant: CN=C=O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CNC(=O)Oc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)CC(C)(C)NC(=O)OC(C)(C)C)CCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 100 mg (approx. 0.2 mmol) of the crude intermediate obtained in Step G in 5 mL of methylene chloride was treated with 1.0 mL of methyl isocyanate (17 mmol) and 0.1 mL of 1,8-diazabicyclo[5.4.0]undec-7-ene under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 10 minutes and then evaporated under vacuum to give 146 mg ofo crude product. 1H NMR (400 MHz, CDCl3): 1.32 (s, 3H), 1.33 (s, 3H), 1.39 (s, 9H), 2.12 (m, 1H), 2.33 (m, 1H), 2.52 (dd, 1H), 2.57 (m, 2H), 2.59 (s, 3H), 4.38 (dd, 1H), 4.8 (d, 1H), 5.26 (d, 1H), 7.10 (d, 1H), 7.36 (m, 11H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[CH:14]([NH2:17])([CH3:16])[CH3:15].CCN(CC)CC>CO>[CH:14]([NH:17][S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])([CH3:16])[CH3:15]
Reactant: CC(C)N
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To the solution of 2-nitrobenzene-1-sulfonyl chloride (1.11 g, 5.0 mmol) in MeOH (30 mL) was added isopropylamine (0.85 mL, 2.0 eq) and Et3N (1.4 mL, 2.0 eq). The mixture was stirred overnight at room temperature. The solvent was removed and the crude was purified by silica gel chromatography to obtain the desired product N-isopropyl-2-nitrobenzenesulfonamide (0.774 g, isolated yield 63%).