Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:5][C:6]([O:8][CH3:9])=[O:7].Cl[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=2[C:24]#[N:25])=[N:20][CH:21]=1.Cl>O1CCCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:24]([C:23]1[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=1[C:19]1[N:20]=[CH:21][C:16]([CH2:15][CH:5]([C:4](=[O:3])[CH2:10][CH2:11][CH2:12][CH3:13])[C:6]([O:8][CH3:9])=[O:7])=[CH:17][CH:18]=1)#[N:25]
Reactant: CCCCC(=O)CC(=O)OC
Reactant: N#Cc1ccccc1-c1ccc(CCl)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: CCCCC(=O)C(Cc1ccc(-c2ccccc2C#N)nc1)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12.9 %

Procedure:
To a mixture of 60% sodium hydride in oil (3.27 g) and tetrahydrofuran (50 mL) was added dropwise a mixture of methyl 3-oxoheptanoate (16.18 g) in tetrahydrofuran (50 mL) at 0° C., and the mixture was stirred at room temperature for 30 min. Then, 2-[5-(chloromethyl)pyridin-2-yl]benzonitrile (4.45 g) and tetrabutylammonium iodide (2.27 g) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 1 M hydrochloric acid (70 mL), and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a yellow oil (0.88 g, 12%).
Reaction SMILES: [H-].[H-].C[CH2-].C[CH2-].[Na+].[Al+3].[CH:9]1([NH2:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C[O:17][C:18](=O)[CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34].C(O)(=O)C>C1(C)C=CC=CC=1>[CH:9]1([NH:15][C:18](=[O:17])[CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: COC(=O)CCCCN(CCOc1ccccc1OC)Cc1ccccc1
Reactant: NC1CCCCC1
Agent: [Al+3]
Agent: [CH2-]C
Agent: [H-]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COc1ccccc1OCCN(CCCCC(=O)NC1CCCCC1)Cc1ccccc1
Temperature: 110 °C
Reaction time: 18 h
Yield: 47 %

Procedure:
A solution of sodium diethyldihydroaluminate (4.44 ml, 8.9 mmole) in a concentration of 2 moles per liter in toluene, is added to a solution of cyclohexylamine (1.76 g, 2.03 ml, 18 mmole) in anhydrous toluene (60 ml). The reaction mixture is heated to 110° C. for 1 hour, then a solution of methyl-5-[benzyl{2-(2-methoxyphenoxy)ethyl}amino]pentanoate (6 g, 16 mmole) in toluene (25 ml) is added dropwise. The mixture is heated under reflux for 3 hours and left for 18 hours at 20° C., then neutralised with a 10% solution of acetic acid. The organic phase is extracted then washed successively with a saturated solution of sodium hydrogen carbonate then with water. After drying over magnesium sulfate and evaporation of the solvents under reduced pressure, the product is purified by flash chromatography over silica gel in a mixture of ethyl acetate/heptane (2/1). 3.3 g (47%) of the desired product are obtained in the form of an oil.
Reaction SMILES: [O:1]=[S:2]1(=[O:29])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:28])[N:14]([N:23]=[CH:24][CH:25]([CH3:27])[CH3:26])[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:29]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:28])[N:14]([NH:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1
Reactant: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc21
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)CNn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 228A (0.132 g, 0.32 mmol) in tetrahydrofuran (6 mL) and methanol (0.026 mL, 0.64 mmol) at 0° C. was treated with dropwise addition of a 2.0M solution of lithium borohydride in tetrahydrofuran (0.24 mL, 0.48 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1 M hydrochloric acid to a pH of approximately 2-4, diluted with water (12 mL), and the resulting precipitate was collected by filtration and dried. The crude product was triturated with 1:1 ethyl acetate:hexane (10 ml) and filtered to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.03 (d, J=6.62 Hz, 6 H) 1.86 (m, 1 H) 2.73 (m, 2 H) 5.94 (t, J=7.35 Hz, 1 H) 7.07 (t, J=7.35 Hz, 1 H) 7.27 (m, 2 H) 7.54 (m, 2 H) 7.60 (d, J=6.99 Hz, 1 H) 7.66 (d, J=6.99 Hz, 1 H) 8.08 (d, J=8.09 Hz, 1 H) 16.27 (s, 1 H). MS (ESI−) (M−H)− m/z 411.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:34])(=[N:29][C:30](=[O:33])[CH2:31]Cl)=[O:28])=[CH:23][CH:22]=2)=[O:20])=[O:10])=[N:6][CH:7]=1.[CH3:35][NH:36][CH3:37]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:22]=[CH:23][C:24]([S:27]([CH3:34])(=[N:29][C:30](=[O:33])[CH2:31][N:36]([CH3:37])[CH3:35])=[O:28])=[CH:25][CH:26]=2)=[O:20])=[O:10])=[N:6][CH:7]=1
Reactant: CNC
Reactant: CS(=O)(=NC(=O)CCl)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CC(=O)N=S(C)(=O)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Temperature: 27.5 °C
Reaction time: 12 h
Yield: 56.3 %

Procedure:
To a stirring solution of S-[4-(N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]-4-chlorophenyl}carbamoyl)phenyl]-S-methyl-N-chloroacetyl sulfoximide (100 mg, 0.185 mmol, Example 6) in DMF (0.2 mL) was added 50% aqueous dimethylamine solution (164 mg, 0.162 mmol) followed by catalytic amount of KI. The reaction mixture was stirred at 25-30° C. for 12 hr and then diluted with water (5 mL). Filtration and drying afforded 50 mg of titled compound in 49% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:13](=[O:17])[CH2:12][CH2:11][CH2:10][C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2].[Br:18][CH:19]=[CH:20][CH2:21]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:18][CH:19]=[CH:20][CH2:21][N:8]1[C:9]2[CH2:10][CH2:11][CH2:12][C:13](=[O:17])[C:14]=2[C:15](=[O:16])[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7]1
Reactant: BrC=CCBr
Reactant: CCOC(=O)c1c[nH]c2c(c1=O)C(=O)CCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(CC=CBr)c2c(c1=O)C(=O)CCC2
Temperature: 25 °C
Reaction time: 7 h

Procedure:
Ethyl-4,5-dioxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (714 mg, 3.04 mmol) was suspended in degassed N,N-dimethylformamide (8 mL) and treated with 1,3-dibromo-1-propene (0.364 mL, 3.64 mmol, 1.2 equiv) and potassium carbonate (503 mg, 3.64 mmol, 1.2 equiv). After stirring for 7 hrs at ambient temperature, the mixture was poured into water and extracted three times with ethyl acetate. The combined ethyl acetate extracts were washed once with water and brine, dried with sodium sulfate, filtered and concentrated in vacuo to afforded ethyl 1-[3-bromoprop-2-en-1-yl]-4,5-dioxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate as a mixture of E- and Z-isomers. Additional compound was obtained by concentration of the aqueous extract in vacuo and extraction of the resulting residue with a mixture of 80% chloroform and 20% methanol (v/v).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]([CH3:17])([CH3:16])[C:14]#[N:15])[CH:5]=[C:6]([CH:8]2OCC[O:9]2)[CH:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:13]([CH3:17])([CH3:16])[C:14]#[N:15])[CH:5]=[C:6]([CH:8]=[O:9])[CH:7]=1
Reactant: CC(C)(C#N)c1cc(Br)cc(C2OCCO2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C#N)c1cc(Br)cc(C=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 123.1 %

Procedure:
To a solution of 2-(3-bromo-5-(1,3-dioxolan-2-yl)phenyl)-2-methylpropanenitrile (1.9836 g, 6.70 mmol) in acetone (25 mL) was added p-toluenesulfonic acid hydrate (0.26 g, 1.36 mmol) and the reaction mixture was stirred at room temperature overnight to give an orange-red solution. The solvent was evaporated in vacuo to give an orange-brown residue. The residue was partitioned between aqueous saturated NaHCO3 solution (25 mL) and ethyl acetate (50 mL), the organic layer was removed, washed with brine (1×25 mL), dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to give an orange viscous liquid (2.08 g). Purification of the crude product by silica-gel flash chromatography on silica gel column and elution with 5-40% ethyl acetate in n-hexane afforded the desired product as a pale yellow crystalline solid (0.89 g). LC-MS analysis of the solid shows the desired product's mass: m/z 252 (79BrM+H), m/z 254 (81BrM+H); Calcd for C11H10BrNO: 252.11
Reaction SMILES: I[C:2]1[CH:27]=[CH:26][C:5]([O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[C@H:16]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:15][CH2:14]3)=[CH:4][CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C(Cl)Cl.CC([O-])=O.[K+].Br[C:55]1[CH:60]=[CH:59][CH:58]=[C:57]([CH3:61])[N:56]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:61][C:57]1[N:56]=[C:55]([C:2]2[CH:27]=[CH:26][C:5]([O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[C@H:16]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:15][CH2:14]4)=[CH:4][CH:3]=2)[CH:60]=[CH:59][CH:58]=1
Reactant: Cc1cccc(Br)n1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(I)cc3)ccc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(-c4cccc(C)n4)cc3)ccc21
Temperature: 80 °C
Yield: 427.9 %

Procedure:
To a solution of ethyl {(1S)-5-[3-(4-iodophenoxy)propoxy]-2,3-dihydro-1H-inden-1-yl}acetate (70 mg, 0.15 mmol, Example 94) in DMF (1 mL), was added bis(pinacolato)diboron (41 mg, 0.16 mmol), PdCl2(dppf).CH2Cl2 (11 mg, 0.01 mmol), and KOAc (43 mg, 0.44 mmol). Argon was passed through the solution, and the reaction mixture was heated at 80° C. for 2 h, and then cooled to rt. More PdCl2(dppf).CH2Cl2 (5 mg, 0.005 mmol) was added, followed by the addition of 2-bromo-6-methylpyridine (50 mg, 0.29 mmol) and Na2CO3 (2 M aqueous solution, 0.37 mL). The reaction mixture was heated to 80° C. for 12 h, after which the reaction mixture was cooled to rt, diluted with HCl (1N aqueous solution) and extracted with EtOAc. The combined organic phases were dried, filtered, and concentrated under reduced pressure. Purification by a preparative thin layer chromatography (2:3 EtOAc/hexanes) gave 286 mg (40%) of the title compound. 1H NMR (400 MHz, CDCl3): δ 8.00 (d, 2H), 7.73-7.62 (m, 1H), 7.62-7.52 (m, 1H), 7.16-6.96 (m, 4H), 6.83 (s, 1H), 6.52 (d, 1H), 4.28-4.04 (m, 6H), 3.52-3.38 (m, 1H), 2.96-2.63 (m, 3H), 2.54 (s, 3H), 2.48-2.12 (m, 4H), 1.82-1.62 (m, 1H), 1.23 (t, 3H).
Reaction SMILES: [OH-].[NH4+:2].[CH3:3][N:4]([N:6]=[N:7][C:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[Se:10][C:9]=1[C:19]([O:21]CC)=O)[CH3:5].O>C1COCC1>[CH3:3][N:4]([N:6]=[N:7][C:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[Se:10][C:9]=1[C:19]([NH2:2])=[O:21])[CH3:5]
Reactant: [NH4+]
Reactant: CCOC(=O)c1[se]c(-c2ccccc2)cc1N=NN(C)C
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)N=Nc1cc(-c2ccccc2)[se]c1C(N)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To an ice cold (0-5° C.) solution of ammonium hydroxide (160 mL) was added a solution of ethyl 3-[(dimethylamino)diazenyl]-5-phenylselenophene-2-carboxylate (1.2 g) in THF (25 mL) for 5 min and a catalytic amount of PEG-400 was added and stirred at rt for 48 h. The solution was poured into ice cooled water and extracted with chloroform (3×100 mL). The combined organic layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using chloroform-methanol (94:6) as eluents to give the product as off-white solid, which was recrystallized from chloroform-hexane (270 mg, 31%), mp 222-224° C. IR (Neat) νmax 3346, 2927, 2850, 1645, 1594, 1221, 1113, 1019, 875, 850 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.25 (1H, s, —CONH2), 7.87 (1H, s, H-4), 7.57-7.60 (2H, m, Ar—H), 7.30-7.40 (3H, m, Ar—H), 6.18 (1H, br s, —CONH2), 3.58 (3H, s, —N—CH3), 3.19 (3H, s, —N—CH3); 13C NMR (100 MHz, DMSO-d6): δ 165.6, 152.1, 151.9, 136.1, 131.1, 128.9, 128.5, 126.2, 118.1, 43.7, 36.6; LC-MS (positive ion mode): m/z 343, 345 (M+Na)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH2:16][CH2:17][OH:18])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].CC(=O)OCC>C(Cl)Cl>[CH3:26][S:27]([O:18][CH2:17][CH2:16][CH2:15][NH:14][C:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][CH:7]=1)=[O:13])(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)c1ccc(NC(=O)NCCCO)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(NC(=O)NCCCOS(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 108.3 %

Procedure:
A solution of 1-(4-tert-butylphenyl)-3-(3-hydroxypropyl)urea (563 mg, 2.25 mmol) in methylene chloride (14 mL) was cooled at 0° C. and treated dropwise with triethylamine (0.376 mL, 2.70 mmol) followed by methanesulfonyl chloride (0.191 mL, 2.47 mmol) and the mixture was stirred at 0° C. until complete by TLC. After 30 minutes, the reaction was complete by TLC (100% EA). The reaction mixture was diluted with 15 mL CH2Cl2 and the organic phase was washed with 15 mL portions of 1N HCl, sat NaHCO3 and H2O and dried over MgSO4. The solution was filtered and concentrated to a viscous oil that was placed under high vacuum to yield the title compound (800 mg) as a colorless viscous oil that was stored in the freezer: MS (ESI+) for C15H24N2O4S m/z 329.1 (M+H)+; HPLC purity 93% (ret. time, 3.95 min).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH:8]1([N:13]2[C:17]3[N:18]=[C:19]([NH2:22])[N:20]=[CH:21][C:16]=3[C:15]3[CH:23]=[CH:24][N:25]=[CH:26][C:14]2=3)[CH2:12][CH2:11][CH2:10][CH2:9]1.Cl[C:28]1[N:33]=[N:32][C:31]([N:34]2[CH2:39][CH2:38][N:37]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:36][CH2:35]2)=[CH:30][CH:29]=1>>[CH:8]1([N:13]2[C:17]3[N:18]=[C:19]([NH:22][C:28]4[N:33]=[N:32][C:31]([N:34]5[CH2:39][CH2:38][N:37]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:36][CH2:35]5)=[CH:30][CH:29]=4)[N:20]=[CH:21][C:16]=3[C:15]3[CH:23]=[CH:24][N:25]=[CH:26][C:14]2=3)[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CCOC(=O)CN1CCN(c2ccc(Cl)nn2)CC1
Reactant: Nc1ncc2c3ccncc3n(C3CCCC3)c2n1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CN1CCN(c2ccc(Nc3ncc4c5ccncc5n(C5CCCC5)c4n3)nn2)CC1

Procedure:
Compound 344 was prepared as a light yellow solid (TFA salt) from compound 4 and compound 345 using chemistry similar to that described in example 200. 1H NMR (500 MHz, CD3OD) δ ppm 9.65 (1 H, s), 9.33 (1 H, s), 8.63-8.68 (2 H, m), 8.15 (1 H, d, J=9.8 Hz), 7.94 (1 H, d, J=9.8 Hz), 5.46 (1 H, qt), 4.33 (2 H, q, J=7.1 Hz), 4.11 (2 H, s), 3.98 (4 H, br. s.), 3.46 (4 H, t, J=5.1 Hz), 2.45-2.59 (2 H, m), 2.13-2.31 (4H, m), 1.84-1.96 (2 H, m), 1.34 (3 H, t, J=7.2 Hz). LCMS-ESI (POS), M/Z, M+1: Found 502.3.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:11]3=[N:12][C:13](Cl)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:36][N:37]([CH3:61])[C:38]([CH:40]1[CH2:45][CH2:44][N:43]([C:46]2[CH:51]=[CH:50][CH:49]=[C:48](B3OC(C)(C)C(C)(C)O3)[CH:47]=2)[CH2:42][CH2:41]1)=[O:39].CC(N)CC1C=CC=CC=1.OP(O)(O)=O.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O>[NH2:1][C:2]1[C:7]([C:8]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:11]3=[N:12][C:13]([C:48]4[CH:49]=[CH:50][CH:51]=[C:46]([N:43]5[CH2:44][CH2:45][CH:40]([C:38](=[O:39])[N:37]([CH3:36])[CH3:61])[CH2:41][CH2:42]5)[CH:47]=4)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CN(C)C(=O)C1CCN(c2cccc(B3OC(C)(C)C(C)(C)O3)c2)CC1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(Cl)nc43)cc2)CCC1
Agent: CC(N)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=P(O)(O)O
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)C1CCN(c2cccc(-c3ccc4nc(-c5cccnc5N)n(-c5ccc(C6(NC(=O)OC(C)(C)C)CCC6)cc5)c4n3)c2)CC1
Temperature: 160 °C

Procedure:
To a solution of tert-butyl (1-{4-[2-(2-aminopyridin-3-yl)-5-chloro-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}cyclobutyl)carbamate (400 mg, 0.81 mmol) in DMF (8.1 mL)/water (0.45 mL), were added N,N-dimethyl-1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine-4-carboxamide. (584 mg, 1.6 mmol), AMPHOS (58 mg, 0.08 mmol) and Na2CO3 (95 mg, 0.9 mmol). The mixture was heated at 160° C. for 1 h in microwave oven. The mixture was evaporated under reduced pressure and the residue was purified with silica gel column chromatography (hexane/ethyl acetate/methanol, 10:0:0 to 0:10:1) to give tert-butyl (1-{4-[2-(2-aminopyridin-3-yl)-5-{3-[4-(dimethylcarbamoyl)piperidin-1-yl]phenyl}-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}cyclobutyl)carbamate. This compound was deprotected with methanol (15 mL) and 4M HCl in ethyl acetate (15 mL) for 18 h at rt. The mixture was solidified with diethyl ether and the solid was purified with HPLC and HCl was added to the fraction and evaporated then solidified with diethyl ether to give the titled compound (281 mg, 50%) as a white solid.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[N:15]=[CH:16][N:17]([C:19]3[N:24]=[C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=4)[CH:22]=[C:21]([C:32]([F:35])([F:34])[F:33])[N:20]=3)[CH:18]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:31][C:27]1[CH:26]=[C:25]([C:23]2[CH:22]=[C:21]([C:32]([F:34])([F:33])[F:35])[N:20]=[C:19]([N:17]3[CH:18]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=4)[N:15]=[CH:16]3)[N:24]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4cccc(Cl)c4)cc(C(F)(F)F)n3)cn2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4cccc(Cl)c4)cc(C(F)(F)F)n3)cn2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 10 %

Procedure:
To a cooled and stirred solution of 5-{1-[4-(3-chloro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.4 g) in dichloromethane (6 mL) was added TFA (6 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and purified by flash chromatography (heptane/ethyl acetate) and crystallization (dichloromethane/MeOH/hexane) to yield the title compound as a white solid (0.036 g, 5%). MS (ISP) 486.2 [(M+H)+]; mp 280° C.
Reaction SMILES: ClC(OCC(C)C)=O.[CH2:9]([O:16][C:17]([C:19]1([C:50]([OH:52])=O)[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[N:36]=[C:35]([C:37]4[CH:42]=[CH:41][C:40]([C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=5)=[C:39]([F:49])[CH:38]=4)[O:34][N:33]=3)=[CH:28][CH:27]=2)[CH2:21][CH2:20]1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN1CCOCC1.[NH2:60][N:61]1[CH2:66][CH2:65][CH2:64][CH2:63][CH2:62]1>O1CCCC1.O>[CH2:9]([O:16][C:17]([C:19]1([C:50](=[O:52])[NH:60][N:61]2[CH2:66][CH2:65][CH2:64][CH2:63][CH2:62]2)[CH2:20][CH2:21][N:22]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]3[N:36]=[C:35]([C:37]4[CH:42]=[CH:41][C:40]([C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=5)=[C:39]([F:49])[CH:38]=4)[O:34][N:33]=3)=[CH:30][CH:31]=2)[CH2:23][CH2:24]1)=[O:18])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: NN1CCCCC1
Reactant: O=C(O)C1(C(=O)OCc2ccccc2)CCN(Cc2ccc(-c3noc(-c4ccc(-c5ccccc5)c(F)c4)n3)cc2)CC1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: O
Product: O=C(NN1CCCCC1)C1(C(=O)OCc2ccccc2)CCN(Cc2ccc(-c3noc(-c4ccc(-c5ccccc5)c(F)c4)n3)cc2)CC1
Temperature: 5 °C
Reaction time: 0.75 h

Procedure:
Isobutyl chloroformate (0.158 mL, 0.0012 mol) is added to a solution of 1-{4-[5-(2-fluoro-biphenyl-4-yl)-[1,2,4]oxadiazol-3-yl]-benzyl}-piperidine-4,4-dicarboxylic acid benzyl ester (0.6 g, 0.0010 mol) and N-methyl morpholine (0.156 mL, 0.0015 mol) in tetrahydrofuran (20 mL) at 5° C. The reaction mixture is stirred at 5° C. for 45 minutes. 1-Amino piperidine (0.162 mL, 0.0015 mol) is added to the reaction mixture and is stirred for 30 minutes at 5° C. and then at room temperature for 45 minutes. Demineralized water (10 mL) is added to the reaction mixture, Organic layer is separated and dried over sodium sulphate. Removal of solvent under reduced pressure gives a viscous liquid, which is purified by column chromatography (silica gel 230-400 mesh, hexane:ethyl acetate 70:30) to get 1-{4-[5-(2-fluoro-biphenyl-4-yl)-[1,2,4]oxadiazol-3-yl]-benzyl}-4-(piperidine-1-ylcarbamoyl)-piperidine-4-carboxylic acid benzyl ester.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:8]1[C:16]2[C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[S:13][C:12]=2[C:11]([C:21]2[CH:33]=[CH:32][C:31]3[C:30]4[C:25](=[CH:26][C:27]([C:34]5[C:39]6[S:40][C:41]7[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=7[C:38]=6[CH:37]=[CH:36][CH:35]=5)=[CH:28][CH:29]=4)[NH:24][C:23]=3[CH:22]=2)=[CH:10][CH:9]=1.CC(C)([O-])C.[Na+].C1(C)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.[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C1(C)C=CC=CC=1>[CH:37]1[C:38]2[C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=3[S:40][C:39]=2[C:34]([C:27]2[CH:28]=[CH:29][C:30]3[C:31]4[C:23](=[CH:22][C:21]([C:11]5[C:12]6[S:13][C:14]7[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=7[C:16]=6[CH:8]=[CH:9][CH:10]=5)=[CH:33][CH:32]=4)[N:24]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:25]=3[CH:26]=2)=[CH:35][CH:36]=1
Reactant: Ic1ccccc1
Reactant: c1ccc2c(c1)sc1c(-c3ccc4c(c3)[nH]c3cc(-c5cccc6c5sc5ccccc56)ccc34)cccc12
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: Cc1ccccc1C
Product: c1ccc(-n2c3cc(-c4cccc5c4sc4ccccc45)ccc3c3ccc(-c4cccc5c4sc4ccccc45)cc32)cc1
Temperature: 120 °C
Reaction time: 5 h
Yield: 97.7 %

Procedure:
In a 200-mL three-neck flask were mixed 0.7 g (4.3 mmol) of iodobenzene, 1.7 g (3.2 mmol) of 2,7-di-(dibenzothiophen-4-yl)-9H-carbazole, 0.6 g (5.5 mmol) of sodium tert-butoxide, and 36 mg (0.1 mmol) of bis(dibenzylideneacetone)palladium(0), and the air in the flask was replaced with nitrogen. Then, 5 mL of dehydrated xylene was added to this mixture. After the mixture was degassed while being stirred under reduced pressure, 0.7 mL (0.3 mmol) of tri(tert-butyl)phosphine (10 wt % hexane solution) was added to the mixture. This mixture was stirred under a nitrogen atmosphere at 120° C. for 5 hours to be reacted. After the reaction, 300 mL of toluene was added to this reaction mixture solution, and this suspension was filtered through Florisil and Celite. The resulting filtrate was concentrated, followed by purification using silica gel column chromatography (the developing solvent was toluene). The fraction thus obtained was concentrated, acetone and methanol were added thereto, and the mixture was irradiated with ultrasonic waves. Then, recrystallization gave 1.9 g of a white powder in 93% yield. A reaction scheme of the above synthesis method is shown in the following (B-2).