Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][C:10]=1[NH2:11])=[O:5])[CH3:2].[BH3-]C#N.[Na+].CC(O)=O.[Cl:20][C:21]1[CH:31]=[CH:30][C:24]2[NH:25][C:26]([CH:28]=O)=[N:27][C:23]=2[CH:22]=1.[OH-].[Na+]>CO.C(OCC)(=O)C.CN(C=O)C.C(Cl)Cl>[Cl:20][C:21]1[CH:31]=[CH:30][C:24]2[NH:25][C:26]([CH2:28][NH:11][C:10]3[CH:9]=[CH:8][NH:7][C:6]=3[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[N:27][C:23]=2[CH:22]=1
Reactant: O=Cc1nc2cc(Cl)ccc2[nH]1
Reactant: CCOC(=O)c1[nH]ccc1N
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)c1[nH]ccc1NCc1nc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.4 %

Procedure:
A reaction mixture of 3-amino-1H-pyrrole-2-carboxylic acid ethyl ester (0.077 g, 0.5 mmol), NaCNBH3 (0.057 g, 0.9 mmol) and HOAc (0.030 g, 0.5 mmol) in methanol (4 mL) were stirred at r.t. for 5 minutes before 5-chloro-1H-benzimidazole-2-carbaldehyde (0.144 g, 0.8 mmol) was added, followed by addition of CH2Cl2 (1 mL) and DMF (0.4 mL). The resulting mixture was allowed to stir for 16 h at r.t. under nitrogen atmosphere. Additional 5-chloro-1H-benzimidazole-2-carbaldehyde (0.030 g) and NaCNBH3 (0.015 g) were added and the reaction mixture was stirred at 4 h. The reaction mixture was neutralized with 2M NaOH and diluted with ethyl acetate. Extracted with water and the organic layer was dried (Na2SO4) and concentrated. The crude product was purified by flash column chromatography (heptane/ethyl acetate gradient; 0 to 100% ethyl acetate), obtaining 0.074 g (46%) of the title product.
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.[CH3:29][C:30]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:31]=1[CH:32]=O>>[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][CH2:32][C:31]3[C:34]([CH3:38])=[CH:35][CH:36]=[CH:37][C:30]=3[CH3:29])[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: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: Cc1cccc(C)c1C=O
Product: Cc1cccc(C)c1CNc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 2,6-dimethyl benzaldehyde. MS (ESI) m/z 497.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:12]([O:14][C:15]([CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])[CH3:13]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:20]2[CH2:21][CH2:22][CH:17]([C:15]([O:14][CH2:12][CH3:13])=[O:16])[CH2:18][CH2:19]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Product: CCOC(=O)C1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-bromophenylsulphonyl chloride (7.68 g) in dichloromethane (100 ml) was added dropwise over a period of 30 minutes to a solution of 4-(ethoxycarbonyl)piperidine (4.71 g) in dichloromethane (50 ml) at 0° C. and under argon. The mixture was stirred overnight during which time it was allowed to warm to room temperature. The organic phase was washed with water, brine, dried and evaporated to give a solid. This solid was triturated in petroleum ether (bp 40-60° C.) to give 1-(4-bromophenylsulphonyl)-4-(ethoxycarbonyl)piperidine (l0.05 g), m.p. 137-133° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([NH:11][C:12](=[O:14])[CH3:13])=[C:4]([F:15])[CH:3]=1>C(OCC)(=O)C>[NH2:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([F:15])=[C:5]([NH:11][C:12](=[O:14])[CH3:13])[CH:6]=1
Reactant: CC(=O)Nc1cc([N+](=O)[O-])c(Cl)cc1F
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cc(N)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.9 %

Procedure:
In a 20 L autoclave, 1395 g (6 mole) of N-(4-chloro-2-fluoro-5-nitrophenyl)acetamide and 14 g of Ir-catalyst (5% on carbon, 1% w/w) were suspended in 14 L of ethyl acetate. The autoclave was purged two times with nitrogen at 500 kPa (5 atmospheres) pressure followed by purging with hydrogen at 500 kPa (5 atmospheres). 400 kPa (4 atmospheres) pressure of hydrogen was applied for the hydrogenation and the mixture was heated. At 40° C. hydrogen uptake was accompanied by an exotherm. The temperature was allowed to rise to 75-83° C. The hydrogen uptake was complete after 90 minutes. The reactor was stirred an additional 45 minutes at this temperature and cooled to room temperature. The catalyst was removed by filtration through Celite®. After removal of the solvent at reduced pressure, 1165.5 g of the title compound (95.9%) was obtained as a crystalline solid melting at 142-143° C. (purity: >99.5% by HPLC).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([CH3:10])=[N:6][O:7][C:8]=1[NH2:9].[S:11]1[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[C:13]([S:20](Cl)(=[O:22])=[O:21])=[CH:12]1>C1COCC1>[Cl:3][C:4]1[C:5]([CH3:10])=[N:6][O:7][C:8]=1[NH:9][S:20]([C:13]1[C:14]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[S:11][CH:12]=1)(=[O:22])=[O:21]
Reactant: O=S(=O)(Cl)c1csc2ncccc12
Reactant: Cc1noc(N)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(NS(=O)(=O)c2csc3ncccc23)c1Cl
Yield: 96.6 %

Procedure:
N-(4-chloro-3-methyl-5-isoxazolyl)thieno[2,3-b]pyridine-3-sulfonamide was prepared by the method of Example 1(C) using NaH (0.16 g, 6.8 mmoles), THF (10 ml), 4-chloro-3-methyl-5-aminoisoxazole (0.36 g, 2.7 mmoles) and thieno[2,3-b]pyridine-3-sulfonyl chloride (0.70 g, 3.0 mmoles) to provide 0.86 g (96%) of the title compound as a tan solid. Recrystallization of 56 mg from EtOAc/hexanes provided 43 mg of a light tan solid, m.p. 176-177° C.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([S:9][CH:10]([CH3:12])[CH3:11])([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].O1CCOCC1.[OH-].[Na+].Cl[C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23]>O>[CH:25]([O:24][C:22]([NH:1][C@@H:2]([C:6]([S:9][CH:10]([CH3:12])[CH3:11])([CH3:7])[CH3:8])[C:3]([OH:5])=[O:4])=[O:23])([CH3:27])[CH3:26]
Reactant: CC(C)SC(C)(C)[C@H](N)C(=O)O
Reactant: CC(C)OC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)OC(=O)N[C@H](C(=O)O)C(C)(C)SC(C)C
Reaction time: 6 h
Yield: 64 %

Procedure:
2-(R)-Amino-3-isopropylsulfanyl-3-methyl-butyric acid (17 mmol; crude material obtained from D-penicillamine and isopropyl iodide) was dissolved in 40 mL of water and 40 mL of dioxane and pH 9.5 was adjusted by adding aqueous NaOH. Isopropyl chloroformate (22 mL; 1 M solution in toluene) was slowly added at 5° C. while maintaining pH 9.5 by addition of the appropriate amount of aqueous NaOH. Stirring was continued for 6 h at room temperature. Aqueous NaOH was added (pH 11) and the dioxane removed in vacuo followed by extraction of the remaining aqueous solution with ethyl acetate. KHSO4 was added and the acidified aqueous solution extracted with ethyl acetate several times, Evaporation of the solvent in vacuo gave a yellow oil, which was purified by HPLC (RP-18; pH 2.3; H2O/CH3OH 3/7) to give 3.0 g (64%) of the title compound as a colorless oil. (−)-APCI-MS: 276 ([M−H]−).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:23]2[O:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:26][N:27]=2)[C:5]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1.[O:34]1[C:38]2([CH2:43][CH2:42][C:41](B3OC(C)(C)C(C)(C)O3)=[CH:40][CH2:39]2)[O:37][CH2:36][CH2:35]1.C(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)(C)C.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O.C(Cl)Cl.Cl[Pd]Cl>[C:11]([O:10][C:9]([N:8]([C:5]1[C:4]([C:23]2[O:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:26][N:27]=2)=[N:3][C:2]([C:41]2[CH2:42][CH2:43][C:38]3([O:37][CH2:36][CH2:35][O:34]3)[CH2:39][CH:40]=2)=[CH:7][N:6]=1)[C:16](=[O:17])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC1(C)OB(C2=CCC3(CC2)OCCO3)OC1(C)C
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)nc1-c1nnc(-c2ccccc2)o1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(C2=CCC3(CC2)OCCO3)nc1-c1nnc(-c2ccccc2)o1
Temperature: 25 °C
Yield: 64.9 %

Procedure:
A solution of tert-butyl N-[5-bromo-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl]-N-tert-butoxycarbonyl-carbamate (250 mg, 0.48 mmol), 2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (128 mg, 0.48 mmol), 4-ditert-butylphosphanyl-N,N-dimethyl-aniline; dichloropalladium (3.5 mg, 0.005 mmol) and K2CO3 (133 mg, 0.96 mmol) in toluene (2 mL) and water (250.0 μL) was heated to 80° C. for 18 h. The reaction mixture was cooled to room temperature and diluted with DCM (30 ml) and water (30 ml). The layers were separated and the organic layer was washed with 1M NaOH solution, dried (Na2SO4), filtered and concentrated. The crude material was purified via silica gel column chromatography using 0-30% EtOAc/Hexanes to obtain tert-butyl N-tert-butoxycarbonyl-N-[5-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl]carbamate (180 mg, 65%) as a yellow solid. LC/MS m/z 478.26 [M+H-Boc]+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[CH:11](O[Na])=[O:12].[C]=O>CN(C=O)C.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH:7]1[C:8]2[C:4](=[CH:3][C:2]([CH:11]=[O:12])=[CH:10][CH:9]=2)[CH:5]=[N:6]1
Reactant: Ic1ccc2[nH]ncc2c1
Reactant: O=CO[Na]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [C]=O
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 58.7 %

Procedure:
A mixture of 5-iodoindazole (10 g, 41 mmol), HCOONa (5.57 g, 82 mmol) and PdCl2(PPh3)2 (1.44 g, 2.05 mmol) in DMF (60 mL) was put under vacuum and charged with carbon monoxide (CO). This process was repeated three times, after which the mixture was kept at 110° C. for 6 hr. After cooling to room temperature (rt), the reaction mixture was diluted with brine and extracted with EtOAc. The organic phases were combined, washed with brine, dried, and concentrated. The crude product was purified by column chromatography to afford 1H-indazole-5-carboxaldehyde (3.52 g, 59%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[Cl-].[NH4+].C(O)C.O>CCOCC.[Fe]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:19][CH:18]=2)=[N:10][CH:11]=1
Reactant: O=[N+]([O-])c1ccc(OCCc2ccc(Cl)cc2)nc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: Nc1ccc(OCCc2ccc(Cl)cc2)nc1
Reaction time: 2 h

Procedure:
A mixture of 2-(4-chlorophenethoxy)-5-nitropyridine (1 g), ammonium chloride (1.9 g), ethanol (40 ml) and water (20 ml) is heated to 70° and then iron powder (1 g), under nitrogen, is added in small portions over about 15 minutes. Heating is continued about 2 hours after the addition of iron is complete. The reaction is cooled and stripped. The residue is taken up in ether, washed with water, dried and solvent evaporated to give 5-amino-2-(4-chlorophenethoxy)pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[N:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=O)=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH:25]3[CH2:27][CH2:26]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:28]([CH2:30][NH2:31])[OH:29].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[N:20]=[CH:19][C:18]([CH2:21][C:22]([NH:31][CH2:30][CH2:28][OH:29])=[O:24])=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH:25]3[CH2:26][CH2:27]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NCCO
Reactant: O=C(O)Cc1ccc(Nc2cc(C3CC3)nc(-c3cccc(Cl)c3)n2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1ccc(Nc2cc(C3CC3)nc(-c3cccc(Cl)c3)n2)nc1)NCCO
Reaction time: 2 h
Yield: 32.9 %

Procedure:
To a stirred suspension of 2-(6-((2-(3-chlorophenyl)-6-cyclopropylpyrimidin-4-yl)amino)pyridin-3-yl)acetic acid (0.185 g, 0.48 mmol) in dimethylformaminde (7 mL) at 0° C. was added ethanolamine (0.044 mL, 0.72 mmol, 1.5 eq.) followed by diisopropylethylamine (0.34 mL, 1.94 mmol, 4.0 eq.) and HATU (0.221 g, 0.58 mmol). After stirring for 2 h, the reaction mixture was diluted with water (100 mL) and the resulting white solid isolated by filtration. The solid was purified by chromatography on silica using dichloromethane/methanol (10:0 to 9:1) as eluent followed by preparative HPLC (water/acetonitrile with 0.05% TFA) to afford 2-(6-((2-(3-chlorophenyl)-6-cyclopropylpyrimidin-4-yl)amino)pyridin-3-yl)-N-(2-hydroxyethyl)acetamide (67 mg, 33%) as a white solid. M.p. 131-133° C. 1H NMR (DMSO-d6, 500 MHz) δ 10.10 (s, 1H), 8.31-8.29 (m, 1H), 8.27 (dt, J=7.0, 1.5 Hz, 1H), 8.19 (d, J=1.5 Hz, 1H), 8.08 (t, J=5.5 Hz, 1H), 7.74-7.69 (m, 1H), 7.67 (dd, J=8.5, 2.0 Hz, 1H), 7.60 (br s, 1H), 7.58-7.52 (m, 2H), 4.68 (t, J=5.5 Hz, 1H), 3.44-3.39 (m, 4H), 3.13 (q, J=6.0 Hz, 2H), 2.07 (septet, J=4.5 Hz, 1H), 1.14-1.09 (m, 2H), 1.06-1.00 (m, 2H); APCI MS m/z 424 [M+H]+.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[C:18]4[CH:34]=[CH:33][CH:32]=[CH:31][C:19]=4[S:20][C:21]=3[C:22]3[CH:27]=[CH:26][C:25]([CH2:28][C:29]#[N:30])=[CH:24][CH:23]=3)=O)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C1COCC1.ClCCl>[C:29]([CH2:28][C:25]1[CH:24]=[CH:23][C:22]([C:21]2[S:20][C:19]3[CH:31]=[CH:32][CH:33]=[CH:34][C:18]=3[C:17]=2[CH2:15][C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:14][CH:13]=2)=[CH:27][CH:26]=1)#[N:30]
Reactant: N#CCc1ccc(-c2sc3ccccc3c2C(=O)c2ccc(OCCN3CCCC3)cc2)cc1
Agent: CC[SiH](CC)CC
Agent: [Al+3]
Agent: [H-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: N#CCc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1
Reaction time: 0.17 h
Yield: 69.2 %

Procedure:
2-[4-(Cyanomethyl)phenyl]benzo[b]thiophen-3-yl 4-[2-(1-pyrrolidinyl)ethoxy]phenyl ketone (158 mg) in THF (5.0 mL) was treated with lithium aluminum hydride (13 mg) at 0° C. for 2 h, and then quenched with water (0.5 mL) and sodium hydroxide (5.0 M, 0.5 mL). Stirring was continued for 10 min. The reaction mixture was diluted with brine (50 mL) and extracted with dichloromethane (3×50 mL). The combined organic layers were dried with sodium sulfate and concentrated in vacuo to give a yellow foam-like material. This material was dissolved in dichloromethane (5 mL), treated with triethylsilane (0.3 mL) and trifluroacetic acid (0.2 mL) at 0° C. for 1.5 h, and concentrated under reduced pressure. The residue was extracted with dichloromethane (50 mL×3) from saturated aqueous sodium bicarbonate (50 mL). The combined organic layers were dried with sodium sulfate and concentrated. Chromatography with Et3N:EtOAc (0-5%) afforded the product (106 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][C@H:17]([NH:25][CH3:26])[CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[CH2:12][CH2:11]3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:33][C:34]1([C:40](Cl)=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>ClCCl.O>[NH:1]1[C:9]2[C:4](=[C:5]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][C@H:17]([N:25]([CH3:26])[C:40]([C:34]4([CH3:33])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)=[O:41])[CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[CH2:12][CH2:11]3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CN[C@H](Cc1ccccn1)CN1CCN(c2cccc3[nH]ccc23)CC1
Reactant: CC1(C(=O)Cl)CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CN(C(=O)C1(C)CCCCC1)[C@H](Cc1ccccn1)CN1CCN(c2cccc3[nH]ccc23)CC1
Temperature: 25 °C

Procedure:
To a solution of (2R)-1-[4-(1H-indol-4-yl)piperazin-1-yl]-N-methyl-3-pyridin-2-ylpropan-2-amine (349 mg.; 1 mmol, from Example 20) in dichloromethane (10 mL) at 0° C. is added a solution of potassium carbonate (690 mg.; 5 mmol) in water (1.6 mL), followed by a solution of 1-methyl-1-cyclohexanecarbonyl chloride (160 mg.; 1 mmol) in dichloromethane (1.6 mL). The reaction mixture is stirred while allowing to warm to ambient temperature over 1 hour, diluted with dichloromethane (20 mL), and the layers allowed to separate. The organic layer is dried over MgSO4, filtered, and the solvent removed in vacuo. The crude residue is purified by flash chromatography on silica gel (10% methanol/ethyl acetate) to yield the free base of the title compound. The fumarate salt is prepared by treatment with an equimolar amount of fumaric acid in ethanol.
Reaction SMILES: C(S[C:4](=[N:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:5])C.[C:13]([NH:21][NH2:22])(=O)[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=1>C(O)CCC>[CH3:5][C:4]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:21][N:22]=1
Reactant: NNC(=O)c1cccnc1
Reactant: CCSC(C)=Nc1ccccc1
Solvent: CCCCO
Product: Cc1nnc(-c2cccnc2)n1-c1ccccc1
Yield: 42 %

Procedure:
First, into a 100-mL three-neck flask were placed 3.64 g of N-[1-(ethylsulfanyl)ethylidene]aniline, 20 mL of 1-butanol, and 2.78 g of nicotinic acid hydrazide, and the mixture was stirred at 130° C. for 22 hours. After the stirring, this reaction solution was concentrated under reduced pressure to give an oily substance. This oily substance was washed with ethyl acetate, and subjected to suction filtration to give a solid. This solid was purified by alumina column chromatography using ethyl acetate as a developing solvent. The obtained fraction was concentrated to give a solid. This solid was washed with a mixed solvent of ethyl acetate and hexane, so that 3-methyl-4-phenyl-5-(3-pyridyl)-4H-1,2,4-triazole (abbreviation: HMpytz) was obtained (a white solid, 42% yield). The synthesis scheme of Step 1 is illustrated in the following (a-1).
Reaction SMILES: CO[C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[N:6][CH:5]=1.[NH2:29][CH:30]([CH2:33][OH:34])[CH2:31][OH:32]>>[OH:32][CH2:31][CH:30]([CH2:33][OH:34])[NH:29][C:3]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]3[C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:16][CH2:17]2)=[O:11])=[N:6][CH:5]=1)=[O:28]
Reactant: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)nc1
Reactant: NC(CO)CO
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NC(CO)CO)cn2)CC1
Yield: 78 %

Procedure:
By the same procedure as described in the example 2, synthesis was carried out starting with 6-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid methyl ester and using 2-amino-1,3-propandiol. Then, the product was recrystallized with ethyl acetate and hexane to give a desired compound.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH2:18])[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl[C:21]1[N:26]=[CH:25][N:24]=[C:23]([NH2:27])[CH:22]=1>O1CCOCC1>[C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:18][C:21]2[CH:22]=[C:23]([NH2:27])[N:24]=[CH:25][N:26]=2)[CH3:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](N)c1nc2ccccc2n1-c1ccccc1
Reactant: Nc1cc(Cl)ncn1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H](Nc1cc(N)ncn1)c1nc2ccccc2n1-c1ccccc1
Yield: 66.5 %

Procedure:
A solution of (S)-1-(1-phenyl-1H-benzo[d]imidazol-2-yl)ethanamine from Example 4 (321.6 mg, 1.36 mmol, 1.00 equiv) in dioxane (10 mL) and 6-chloropyrimidin-4-amine hydrochloride (456.3 mg, 2.71 mmol, 2.00 equiv, 98%) was stirred overnight at 130° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a C18 column with acetonitrile/water (0-40%) to afford 298.6 mg (60%) of 146 hydrochloride as yellow crystals. LC-MS (ES, m/z): 331 [M+H]+H-NMR: (400 MHz, CD3OD, ppm) δ: 8.15 (s, 1H), 7.87-7.58 (m, 8H), 7.38-7.36 (m, 1H), 5.88 (br s, 1H), 5.41-5.36 (q, 1H), 1.747-1.73 (d, 3H)
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]([CH2:12][N:13]([CH2:26][CH2:27][CH2:28][CH:29]=[CH2:30])[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-:25])=[O:24])(=[O:16])=[O:15])[C:9](O)=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH2:33]([O:35][C:36]([C:38]1([NH:43][C:44]([CH:46]2[CH2:50][CH:49]([O:51][C:52]3[C:61]4[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=4)[CH:55]=[CH:54][N:53]=3)[CH2:48][NH:47]2)=[O:45])[CH2:40][CH:39]1[CH:41]=[CH2:42])=[O:37])[CH3:34].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CCCCCC.C(OCC)(=O)C>[C:1]([O:5][C:6]([C@@H:8]([CH2:12][N:13]([CH2:26][CH2:27][CH2:28][CH:29]=[CH2:30])[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-:25])=[O:24])(=[O:16])=[O:15])[C:9]([N:47]1[C@H:46]([C:44]([NH:43][C@:38]2([C:36]([O:35][CH2:33][CH3:34])=[O:37])[CH2:40][C@H:39]2[CH:41]=[CH2:42])=[O:45])[CH2:50][C@@H:49]([O:51][C:52]2[C:61]3[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=3)[CH:55]=[CH:54][N:53]=2)[CH2:48]1)=[O:10])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2nccc3ccccc23)CN1)C(=O)OCC
Reactant: C=CCCCN(C[C@@H](C(=O)O)C(=O)OC(C)(C)C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C=CCCCN(C[C@H](C(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc2nccc3ccccc23)C[C@H]1C(=O)N[C@]1(C(=O)OCC)C[C@H]1C=C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 71.1 %

Procedure:
(S)-2-(tert-butoxycarbonyl)-3-(2-nitro-N-(pent-4-enyl)phenylsulfonamido)propanoic acid (1.10 g, 2.40 mmol) dissolved in 20 mL of DCM was treated sequentially with 1-{[4-(isoquinolin-1-yloxy)-pyrrolidine-2-carbonyl]-amino}-2-vinyl-cyclopropanecarboxylic acid ethyl ester, bis hydrochloride (1.27 g, 2.72 mmol), N-methyl morpholine (0.92 mL, 8.34 mmol), and HATU (PE biosystems)(1.28 g, 3.36 mmol). The reaction mixture was stirred at rt under N2 for 15 h, and then concentrated in vacuo. The residue was partitioned between ethyl acetate and pH 4 buffer (biphthalate). The organic phase was washed with sat. aq. NaHCO3, dried (MgSO4), and concentrated in vacuo to give 2.0 g of the crude product. Flash chromatography (30% hexane/ethyl acetate) gave 1.4 g (70%) of (1R,2S)-ethyl 1-((3R,5S)-1-((S)-2-(tert-butoxycarbonyl)-3-(2-nitro-N-(pent-4-enyl)phenylsulfonamido)propanoyl)-3-(isoquinolin-1-yloxy)pyrrolidine-5-carboxamido)-2-vinylcyclopropanecarboxylate as a purple solid. 1H NMR (CD3OD, 500 MHz) δ 1.23–1.31 (m, 9H), 1.46–1.52 (m, 4H), 1.59 (br s, 1H), 1.66 (br s, 1H), 1.74 (dd, J=7.93, 5.19 Hz, 1H), 2.00 (br s, 2H), 2.29 (q, J=8.95 Hz, 1H), 2.47 (m, 1H), 2.72 (m, 1H), 3.38–3.51 (m, 2H), 3.68 (m, 2H), 4.09–4.26 (m, 3H), 4.37 (d, J=11.29 Hz, 1H), 4.64 (m, 1H), 4.72 (m, 1H), 4.95 (d, J=10.99 Hz, 1H), 4.99 (dd, J=18.92, 1.53 Hz, 1H), 5.12 (d, J=10.68 Hz, 1H), 5.32 (d, J=17.40 Hz, 1H), 5.73–5.86 (m, 2H), 5.92 (s, 1H), 7.36 (m, 1H), 7.58 (m, 1H), 7.73 (m, 1H), 7.80–7.88 (m, 4H), 7.99 (m, 1H), 8.11 (m, 1H), 8.24 (d, J=8.24 Hz, 1H). LC-MS (Method D, retention time: 3.15 min), MS m/z 835 (M++1).