Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH:21]=O)=[CH:16][CH:15]=3)=[C:8]2[C:4]=1[CH2:5][NH:6][C:7]2=[O:30])[CH3:2].[CH2:31]([CH2:33][NH2:34])[OH:32].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(#N)C>[CH2:1]([C:3]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH2:21][NH:34][CH2:33][CH2:31][OH:32])=[CH:16][CH:15]=3)=[C:8]2[C:4]=1[CH2:5][NH:6][C:7]2=[O:30])[CH3:2]
Reactant: NCCO
Reactant: CCc1ccc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CCc1ccc(-c2cc3cc(CNCCO)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Yield: 95.3 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-ethyl-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (68.0 mg, 0.168 mmol) was dissolved in acetonitrile (5.4 mL), and the solution was treated with ethanolamine (0.041 mL, 0.67 mmol), acetic acid (0.192 mL, 3.36 mmol) and sodium triacetoxyborohydride (71.0 mg, 0.336 mmol). The reaction mixture was added with 1 mol/L hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with sodium carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-ethyl-7-{1-(tert-butoxycarbonyl)-5-[(2-hydroxyethylamino)methyl]indol-2-yl}isoindolinone (72.0 mg, yield 95%).
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=2[NH:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BrH:17]>C(O)(=O)C.C(Cl)(Cl)(Cl)Cl>[C:1]1([C:7]2[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:8]=2[NH:9][C:10](=[O:12])[CH3:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Br
Reactant: CC(=O)Nc1ccccc1-c1ccccc1
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)Nc1ccc(Br)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
2-Phenyl-N-acetylaniline (6.21 g, 29.40 mmol) was dissolved in acetic acid (70 mL). Thereto was dropwise added under ice bath a separately prepared solution of hydrogen bromide (6.14 g, 38.42 mmol) dissolved in carbon tetrachloride (19.21 mL) and the mixture was stirred at room temperature overnight. The solution was concentrated under reduced pressure, to the residue was added water (20 mL) and subsequently ethanol (30 mL), and the mixture was stirred under ice bath for 1 hour. The precipitate was collected by filtration, washed with ethanol/water (=1:1), dried under reduced pressure to obtain 2-phenyl-4-bromo-N-acetylaniline (7.79 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(N(CC)CC)C>CN1C(=O)CCC1>[O:15]1[CH2:16][CH2:17][N:12]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=2)[NH2:7])[CH2:13][CH2:14]1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: Nc1cc(N2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 77 %

Procedure:
A solution of 5-chloro-2-nitroaniline (100 mg, 0.58 mmol) in NMP (4.5 mL) was treated with morpholine (75 mg, 0.86 mmol) in the presence of triethylamine (0.2 mL, 1.44 mmol). The reaction mixture was heated via microwave irradiation to 100° C. for 1 h and upon cooling, the solvent was removed by vacuum. Purification by flash column chromatography afforded the title compound in a 77% yield. 1H NMR: (400 MHz, DMSO-d6): δ 7.82 (d, 1H, J=9.6 Hz), 7.29 (bs, 2H), 6.39 (dd, 1H, J=2.8 and 9.6 Hz), 6.22 (d, 1H, J=2.4 Hz), 3.70 (m, 4H), 3.27 (m, 4H).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:19]3[C:27]([CH2:28][CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=[CH:24][C:20]=3[C:21](O)=[O:22])[CH:9]=2)[N:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[F:59][C@@H:60]1[CH2:64][CH2:63][NH:62][CH2:61]1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:2][C:3]1[C:12]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:19]3[C:27]([CH2:28][CH2:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[CH:26][CH:25]=[CH:24][C:20]=3[C:21]([N:62]3[CH2:63][CH2:64][C@@H:60]([F:59])[CH2:61]3)=[O:22])[CH:9]=2)[N:4]=1
Reactant: F[C@@H]1CCNC1
Reactant: CC(C)(C)CCc1cccc(C(=O)O)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CCc1cccc(C(=O)N2CC[C@@H](F)C2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-(2-amino-3-morpholinoquinolin-6-yl)-3-(3,3-dimethylbutyl)benzoic acid hydrochloride (168 mg, 0.357 mmol) and HATU (204 mg, 0.536 mmol) in DMF (5 mL) was stirred for 10 min at RT. (R)-(−)-3-fluoropyrrolidine hydrochloride (224 mg, 1.787 mmol) and 1,1′-dimethyltriethylamine (0.622 mL, 3.57 mmol) were added and the reaction mixture was allowed to stir overnight at RT. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was separated, dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by preparative HPLC (10-100% water with 0.1% TFA/CH3CN, 11 min). The obtained product was eluted on an SCX cartridge with MeOH followed by 2M NH3/MeOH. The basic fraction was concentrated to afford the titled compound as a white solid. MS (ESI, pos. ion) m/z: 505 (M+1).
Reaction SMILES: [N+](C1C=C(S([CH2:13][C@@H:14]2[CH2:16][O:15]2)(=O)=O)C=CC=1)([O-])=O.[CH3:17][C:18]1[NH:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][C:21]=2[OH:27].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:17][C:18]1[NH:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][C:21]=2[O:27][CH2:13][C@@H:14]1[CH2:16][O:15]1
Reactant: Cc1cc2cccc(O)c2[nH]1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)C[C@@H]2CO2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc2cccc(OC[C@@H]3CO3)c2[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 59 %

Procedure:
A mixture of (2S)-2{[(3-nitrophenyl)sulfonyl]methyl}oxirane (39 mg, 0.15 mmol), 2-methyl-1H-indol-7-ol (15 mg, 0.1 mmol), caesium carbonate (Cs2CO3) (65 mg, 0.2 mmol) in DMF (1.5 mL) was kept on stirring at room temperature for 5 h. The reaction mixture was partitioned between ethylacetate and water, organic layer dried over sodium sulphate (Na2SO4), filtered and concentrated. The residue was purified by silica gel flash chromatography to give subtitled compound (12 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:31](=[CH:32][C:33]=1[O:34][CH3:35])[CH:9]1[O:10][CH2:11][C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[CH:13]=[C:8]1[CH:7]=[C:6]2[C:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:47]=[CH:46][C:45]([O:48]O)=[CH:44][CH:43]=2)=[CH:38][CH:37]=1.[F:50][C:51]([F:67])([C:57]([F:66])([F:65])[C:58]([F:64])([F:63])[C:59]([F:62])([F:61])[F:60])[CH2:52][CH2:53][C:54](O)=[O:55].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:31](=[CH:32][C:33]=1[O:34][CH3:35])[CH:9]1[O:10][CH2:11][C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[CH:13]=[C:8]1[CH:7]=[C:6]2[C:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:47]=[CH:46][C:45]([O:48][C:54](=[O:55])[CH2:53][CH2:52][C:51]([F:50])([F:67])[C:57]([F:65])([F:66])[C:58]([F:63])([F:64])[C:59]([F:60])([F:62])[F:61])=[CH:44][CH:43]=2)=[CH:38][CH:37]=1
Reactant: COc1cc2c(cc1OC)C1OCC(c3ccccc3)(c3ccc(N4CCCC4)cc3)C=C1C=C2c1ccc(-c2ccc(OO)cc2)cc1
Reactant: O=C(O)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1cc2c(cc1OC)C1OCC(c3ccccc3)(c3ccc(N4CCCC4)cc3)C=C1C=C2c1ccc(-c2ccc(OC(=O)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.7 %

Procedure:
A solution of 8,9-dimethoxy-6-[4′-hydroxyoxybiphen-4-yl]-3-phenyl-3-(4-pyrrolidinophenyl)-3H-naphtho[1,2-b]pyran (0.95 g, 1.5 mmol) and 4,4,5,5,6,6,7,7,7-nonafluoroheptanoic acid (0.53 g, 1.8 mmol) in DCM (20 mL) containing 4-dimethylaminopyridine (0.02 g) and N,N′-dicyclohexylcarbodiimide (0.33 g, 1.6 mmol) under N2 was stirred at room temperature for 1 h. The resulting mixture was filtered through a short plug of silica using EtOAc (5% in DCM) as eluent. The solvent was removed under reduced pressure and the residue chromatographed on silica using EtOAc (0-25% gradient in toluene) as eluent. The solvent was removed under reduced pressure and the residue washed with toluene/hexanes to give the title compound (0.69 g, 51%) as a pale violet powder, mp 218-219° C. The liquors provided a further 0.16 g (12%) after evaporation and washing with acetone.
Reaction SMILES: [CH2:1]([CH:5]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:6]([O:8]CC1C=CC=CC=1)=[O:7])[CH:2]([CH3:4])[CH3:3].[H][H]>[Pd].CO>[CH2:1]([CH:5]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:6]([OH:8])=[O:7])[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)CC(CC(C)C)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)CC(CC(C)C)C(=O)O
Yield: 86.1 %

Procedure:
A mixture of 8.01 g (0.029 mol) of (2) and 1 g of 10% palladium on carbon in 50 mL of methanol was hydrogenated at room temperature under 4 atmospheres of hydrogen gas for 8 hr. After removal of the catalyst by filtration the filtrate was evaporated to dryness under reduced pressure to give 4.7 g (86% yield) of 2-isobutyl-3-(methoxycarbonyl)-propionic acid (3) as a colorless oil.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([NH:21][NH2:22])[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].[Cl:23][C:24]1[C:29]([CH:30]=O)=[C:28](Cl)[N:27]=[CH:26][N:25]=1>C1(C)C=CC=CC=1>[C:8]([O:12][C:13]([N:15]1[CH2:16][CH2:17][CH:18]([N:21]2[C:28]3=[N:27][CH:26]=[N:25][C:24]([Cl:23])=[C:29]3[CH:30]=[N:22]2)[CH2:19][CH2:20]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC(NN)CC1
Reactant: O=Cc1c(Cl)ncnc1Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Yield: 34 %

Procedure:
Triethylamine (19.5 mL, 140 mmol) was added to a stirred solution of 4-hydrazino-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 9; 15.0 g, 69.7 mmol) and 4,6-dichloro-pyrimidine-5-carbaldehyde (Intermediate 16; 12.34 g, 69.7 mmol) in toluene (100 mL) at room temperature under nitrogen and the resulting mixture was heated to reflux for 6 hours. The solvent was removed in vacuo and the crude reaction mixture was purified by column chromatography (silica gel, 100-200 mesh; 5% ethyl acetate/hexanes) to give 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (8.0 g, 34%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.43 (s, 9H), 1.97-2.00 (m, 2H), 2.19-2.29 (m, 2H), 2.90-3.00 (br s, 2H), 4.25-4.35 (m, 2H), 4.92-5.00 (m, 1H), 8.15 (s, 1H), 8.74 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 28.3, 31.1, 42.8, 55.3, 79.8, 113.8, 131.8, 152.4, 154.1, 154.4, 154.7. HRMS Calcd. for C15H21ClN5O2 (MH+): 338.1379. Found: 338.1377.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[C:14](=[O:18])[CH2:15][CH2:16][CH2:17][C:12]=3[N:11]=[C:10]2[CH:19]([CH3:21])[CH3:20])=[CH:4][CH:3]=1.ClCCl.[BH4-].[Na+]>CO>[I:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13]3[CH:14]([OH:18])[CH2:15][CH2:16][CH2:17][C:12]=3[N:11]=[C:10]2[CH:19]([CH3:21])[CH3:20])=[CH:6][CH:7]=1
Reactant: CC(C)c1nc2c(n1Cc1ccc(I)cc1)C(=O)CCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)c1nc2c(n1Cc1ccc(I)cc1)C(O)CCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.7 %

Procedure:
To Intermediate 87 (6.65 g) in a 250 mL round-bottom flask under nitrogen in Methanol (20 mL) and Dichloromethane (DCM) (20 mL) was added sodium borohydride (1.276 g) in three portions (effervescence) and the mixture stirred at room temperature under nitrogen for 16 h. The solvent was removed under vacuum and the residue was partitioned between ethyl acetate and water. The aqueous layer extracted well with ethyl acetate. The combined organics were dried (hydrophobic frit), filtered and evaporated to give the title compound 6.6 g as a white solid. LC/MS MH+397, Rt 2.61 min (5 min run).
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:9]=2)[N:4]2[C:16](/[CH:19]=[CH:20]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:18]=[C:3]12>[C].[Pd].C(O)(=O)C>[O:1]=[C:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([F:14])([F:13])[F:15])[CH:9]=2)[N:4]2[C:16]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:18]=[C:3]12
Reactant: CCOC(=O)/C=C/c1ccc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n12
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)CCc1ccc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Ethyl (E)-3-(4-oxo-7-trifluoromethyl-4,5-dihydropyrrolo[1,2-a]-quinoxalin-1-yl)acrylate as synthesized in Example 188, 182 mg, 5% palladium carbon 80 mg and acetic acid 6 mL were mixed and stirred under hydrogen atmosphere at room temperature for 16 hours. Filtering the reaction liquid through Celite, 50 mL of water was added to the filtrate and the precipitated crystals were recovered by filtration. The crystals were washed successively with water and diethyl ether, and dried in flowing air under heating to provide 120 mg of the title compound.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[C:19]1[CH:20]=[C:21]([CH:24]=[O:25])[O:22][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:19]2[CH:20]=[C:21]([CH:24]=[O:25])[O:22][CH:23]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=Cc1cc(Br)co1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
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: O=Cc1cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)co1
Temperature: 25 °C
Yield: 82.4 %

Procedure:
A solution of 3,5-bis(trifluoromethyl)phenylboronic acid (8.84 g), 4-bromo-2-furaldehyde (5.0 g), 2M aqueous sodium carbonate solution (71.4 mL), tetrakis(triphenylphosphine)palladium(0) (1.65 g) in 1,2-dimethoxyethane (300 ml) was stirred under an argon gas atmosphere at 90° C. for 16 hr. After cooling to room temperature, the reaction mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate 98:2-90:10) to give the title compound (7.26 g, yield 82%) as a white solid.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Sn](CCCC)(CCCC)CCCC)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].Br[C:31]1[N:32]=[C:33]([N:41]2[CH2:46][CH2:45][N:44]([CH2:47][CH3:48])[CH2:43][CH2:42]2)[C:34]2[C:39]([CH:40]=1)=[CH:38][CH:37]=[CH:36][CH:35]=2>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C.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>[CH2:47]([N:44]1[CH2:43][CH2:42][N:41]([C:33]2[C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:40]=[C:31]([C:14]3[CH:13]=[CH:12][C:11]([C@H:8]4[CH2:7][CH2:6][C@H:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:10][CH2:9]4)=[CH:16][CH:15]=3)[N:32]=2)[CH2:46][CH2:45]1)[CH3:48]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1[C@H]1CC[C@H](OC(C)=O)CC1
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: CCN1CCN(c2nc(-c3ccc([C@H]4CC[C@H](OC(C)=O)CC4)cc3)cc3ccccc23)CC1

Procedure:
Trans-4-(tributylstannylphenyl)cyclohexyl acetate (0.56 g) and 3-bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (0.46 g) were heated under reflux in the presence of tetrakistriphenylphosphinepalladium(0) (0.06 g) in xylene in nitrogen atmosphere overnight. After cooling, the reaction solution was diluted with ethyl acetate and filtered. The filtrate was extracted with 2N hydrochloric acid, and the resulting aqueous layer was washed with ethyl acetate. Then, it was adjusted to pH 10 by a 8N aqueous solution of sodium hydroxide, extracted with ethyl acetate, washed with a 10% aqueous solution of sodium carbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, to give a mixture (0.44 g) of 1-(4-ethylpiperazin-1-yl)-3-[4-(trans-4-acetoxycyclohexyl)phenyl]isoquinoline as a brown viscous oil and the starting material.
Reaction SMILES: [CH3:1][C:2]([CH3:49])([CH3:48])[C@H:3]([NH:43][C:44](=[O:47])[O:45][CH3:46])[C:4](=[O:42])[N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10](=[O:41])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]([C@@H:30]3[CH2:34][CH2:33][CH2:32][NH:31]3)=[O:29])=[CH:23][CH:22]=2)=[CH:14][CH:13]=1.[CH3:50][O:51][C:52]([NH:54][C@@H:55]([C@H:59]1[CH2:63][CH2:62][O:61][CH2:60]1)[C:56](O)=[O:57])=[O:53]>>[CH3:46][O:45][C:44]([NH:43][C@H:3]([C:4]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][N:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:29])[C@@H:30]3[CH2:34][CH2:33][CH2:32][N:31]3[C:56](=[O:57])[C@@H:55]([NH:54][C:52]([O:51][CH3:50])=[O:53])[C@H:59]3[CH2:63][CH2:62][O:61][CH2:60]3)=[CH:23][CH:22]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[CH:16][CH:17]=1)=[O:41])=[O:42])[C:2]([CH3:49])([CH3:48])[CH3:1])=[O:47]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)Nc1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3)cc2)c2ccccc2)cc1)C(C)(C)C
Reactant: COC(=O)N[C@H](C(=O)O)[C@H]1CCOC1
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)Nc1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3C(=O)[C@@H](NC(=O)OC)C(C)(C)C)cc2)c2ccccc2)cc1)[C@H]1CCOC1
Yield: 67 %

Procedure:
The product of Example 10A (0.035 g, 0.052 mmol) and (S)-2-(methoxycarbonylamino)-2-((R)-tetrahydrofuran-3-yl)acetic acid were processed as in Example 25B to give 0.030 g (67%) of the title compound as a thick oil. 1H NMR (500 MHz, DMSO-D6) δ ppm 0.91 (s, 9 H) 1.66 (ddd, J=20.03, 7.21, 7.10 Hz, 1 H) 1.77-1.88 (m, 6 H) 1.90-1.99 (m, 2 H) 2.06-2.14 (m, 2 H) 3.48 (s, 6 H) 3.54-3.65 (m, 4 H) 3.66-3.75 (m, 3 H) 3.78-3.85 (m, 1 H) 4.14-4.22 (m, 2 H) 4.38 (dd, J=8.09, 5.04 Hz, 2 H) 4.53 (s, 4 H) 6.51 (t, J=7.25 Hz, 1 H) 6.60 (d, J=8.09 Hz, 2 H) 6.99-7.06 (m, 3 H) 7.12 (d, J=7.48 Hz, 4 H) 7.45 (d, J=7.93 Hz, 4 H) 7.55 (d, J=7.93 Hz, 1 H) 9.93 (d, J=6.26 Hz, 2 H); MS ESI− m/z 852.5 (M−H)−.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([C:11]2[N:12]([CH3:18])[C:13]([NH:16][CH3:17])=[N:14][N:15]=2)[CH:8]=[CH:7][N:6]=1.CS(O[CH2:24][C:25]1[N:29]=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]#[N:37])[CH:31]=2)[O:27][N:26]=1)(=O)=O>CN(C=O)C>[CH3:3][O:4][C:5]1[CH:10]=[C:9]([C:11]2[N:12]([CH3:18])[C:13]([N:16]([CH2:24][C:25]3[N:29]=[C:28]([C:30]4[CH:31]=[C:32]([CH:33]=[CH:34][CH:35]=4)[C:36]#[N:37])[O:27][N:26]=3)[CH3:17])=[N:14][N:15]=2)[CH:8]=[CH:7][N:6]=1
Reactant: CS(=O)(=O)OCc1noc(-c2cccc(C#N)c2)n1
Reactant: CNc1nnc(-c2ccnc(OC)c2)n1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(-c2nnc(N(C)Cc3noc(-c4cccc(C#N)c4)n3)n2C)ccn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.1 %

Procedure:
Sodium hydride (0.013 g, 0.53 mmol) was added portionwise to a stirred solution of 5-(2-methoxypyridin-4-yl)-N,4-dimethyl-4H-1,2,4-triazol-3-amine (0.086 g; 0.39 mmol) in DMF (10 ml) at 0° C. The mixture was stirred for 30 minutes before [5-(3-cyanophenyl)-1,2,4-oxadiazol-3-yl]methyl methanesulfonate (0.1 g; 0.36 mmol) in DMF (1 ml) was added dropwise. The mixture was stirred at r.t. for 3 h before quenching with water (30 ml). The resulting mixture was extracted with EA (3×40 ml). The organics were combined, dried (Na2SO4) and evaporated to give a crude material, which was purified by prep. HPLC to give the title compound (0.061 g; 42.3%). 1H NMR: 8.49 (s, 1H), 8.33 (dd, 1H), 8.28 (d, 1H), 7.86 (dd, 1H), 7.67 (t, 1H), 7.24 (d, 1H), 7.02 (s, 1H), 4.60 (s, 2H), 3.97 (s, 3H), 3.70 (s, 3H), 3.08 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH3:15]>>[CH2:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH:5]1[CH2:1][CH2:2][NH:15][S:11]([C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=1)(=[O:13])=[O:12]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: N
Product: CC(C)(C)c1ccc(S(=O)(=O)NCCC2CCCCC2)cc1

Procedure:
The title compound was prepared according to example 1063B, replacing p-toluenesulfonyl chloride with p-tert-butylbenzenesulfonyl chloride to afford a white crystalline solid. MS (DCI/NH3) m/e 341 (M+NH4)+.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:14](=O)[CH:13]=[CH:12][NH:11][C:10]=3[S:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:14]1[CH:13]=[CH:12][N:11]=[C:10]2[S:9][CH:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:15]=12
Reactant: O=c1cc[nH]c2scc(-c3ccccc3)c12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccnc2scc(-c3ccccc3)c12

Procedure:
3-Phenyl-7H-thieno[2,3-b]pyridine-4-one (0.7 g, 4.29 mmol) was added to phosphorous oxychloride (10 ml) and heated to reflux for 4 hr. The solvent was removed to near dryness and the residue dissolved in DCM. The solution was washed with water followed by saturated sodium hydrogen carbonate and dried over magnesium sulfate. The solution was filtered through a pad of silica and solvents removed in vacuo to give 4-chloro-3-phenyl-thieno[2,3-b]pyridine. Yield=0.261g (25%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][C@H:13]([C:17]([OH:19])=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][C:21]1[CH:22]=[C:23]([N:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:28](Cl)=[O:29])[CH:24]=[CH:25][CH:26]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:28](=[O:29])[N:27]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([CH3:20])[CH:22]=2)[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C@H:13]([C:17]([OH:19])=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1CN(C(=O)OCc2ccccc2)CCN1
Reactant: Cc1cccc(N(C(=O)Cl)c2ccccc2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cccc(N(C(=O)N2CCN(C(=O)OCc3ccccc3)C[C@H]2C(=O)O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 116.2 %

Procedure:
A mixture of 264 mg (1 mmole) of (S)-4-(benzyloxycarbonyl)piperazine-2-carboxylic acid, 265 mg (1.1 mmole) of N-(3-methylphenyl)-N-phenylcarbamoyl chloride, 390 mg (3 mmole) of DIEA in 5 mL of DMF was stirred for 16 hr at room temperature. The solution was concentrated in vacuo and the residure was taken up in 50 mL of CH2CL2 and washed with 2×25 mL of 1N HCl. Concentration in vacuo gave 0.55 g of an oil, which was carried on in Step C.