Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[C:13]([C:14]#[N:15])=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:22][CH3:23])[CH:10]=2)[C:5]1=[O:24])C=C.C(N(CC)CC)C.C(O)=O>O1CCOCC1.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>[CH3:23][O:22][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[C:5](=[O:24])[NH:4][C:13]([C:14]#[N:15])=[C:12]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C=CCn1c(C#N)c(-c2ccccc2)c2cc(OC)ccc2c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O=CO
Product: COc1ccc2c(=O)[nH]c(C#N)c(-c3ccccc3)c2c1

Procedure:
Allyl ether 88 (0.5 g, 1.6 mmol) was dissolved in dioxane (10 mL). Triethylamine (0.55 mL, 4 mmol) and formic acid (0.12 mL, 3.2 mmol) were added and the reaction mixture purged with argon. Pd(PPh3)4 (91 mg, 0.08 mmol) was added and the mixture heat to 100 C under a stream of Ar for 1.5 h. A precipitate formed upon cooling. It was isolated by filtration to give 97 as a white solid.
Reaction SMILES: Cl.O1CCOCC1.[CH3:8][S:9][C:10]1[N:11]=[C:12]2[C:21]3[C:16](=[N:17][NH:18][C:19]=3[N:20]=1)[CH:15](C(O)=O)[CH2:14][N:13]2[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCOCC1>[CH3:8][S:9][C:10]1[N:11]=[C:12]2[C:21]3[C:16](=[N:17][NH:18][C:19]=3[N:20]=1)[CH2:15][CH2:14][N:13]2[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CSc1nc2c3c(n[nH]c3n1)C(C(=O)O)CN2c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: CSc1nc2c3c(n[nH]c3n1)CCN2c1ccccc1

Procedure:
4 M dioxane-HCl (300 mL) was added to crude 7-(methylthio)-5-phenyl-1,3,4,5-tetrahydro-1,2,5,6,8-pentaazaacenaphthylene-3-carboxylic acid (20 g) and the mixture was refluxed for 16 h. Upon completion of reaction after 16 h (monitored by LCMS), dioxane was removed under reduced pressure and saturated NaHCO3 solution (200 mL) was added. The reaction mixture was then extracted with dichloromethane (150 mL×3). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (using 0-10% tetrahydrofuran in dichloromethane) to provide 7-(methylthio)-5-phenyl-1,3,4,5-tetrahydro-1,2,5,6,8-pentaazaacenaphthylene as a white solid after recrystalized from ethyl acetate (4.2 g, 26.7% yield for three steps). 1H NMR (DMSO-d6, 400 MHz) δ 13.02 (s, 1H); 7.53-7.23 (m, 5H); 4.19 (t, J=6.4 Hz, 2H); 3.21 (t, J=6.4 Hz, 2H); 2.42 (s, 3H). LCMS [M+H]: 284 HPLC: 98.28% (254 nm)
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=1)[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Cl>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][O:28][C:27]3[CH:35]=[CH:36][CH:37]=[C:25]([O:24][CH3:23])[CH:26]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cccc(OCCCCCCl)c1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cccc(OCCCCCN2CCC(CNC(=O)c3cc(Cl)c(N)cc3OC)CC2)c1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 5-(3-methoxyphenoxy)pentyl chloride were reacted and treated in the same manner as in Example 168 to give 4-amino-5-chloro-2-methoxy-N-((1-(5-(3-methoxyphenoxy)pentyl)-piperidin-4-yl)methyl)benzamide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[CH2:13][CH2:14][CH2:15][OH:16])=[CH:4][CH:3]=1.[Cu](C#N)[C:18]#[N:19].O1CCOCC1>[C-]#N.C([N+](CC)(CC)CC)C.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O>[C:18]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[CH2:13][CH2:14][CH2:15][OH:16])=[CH:4][CH:3]=1)#[N:19]
Reactant: OCCCc1cnoc1-c1ccc(Br)cc1
Reactant: N#C[Cu]C#N
Agent: [Fe+2]
Agent: [Pd]
Agent: CC[N+](CC)(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2oncc2CCCO)cc1
Yield: 47 %

Procedure:
A mixture of 3-[5-(4-bromophenyl)-4-isoxazolyl]propan-1-ol (1.10 g), copper cyanide (1.41 g), tris(dibenzylideneacetone)dipalladium (130 mg), 1,1′-bis(diphenylphosphino)ferrocene (314 mg), tetraethylammonium cyanide (553 mg) and 1,4-dioxane (20 ml) was refluxed for 3.5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and 3-[5-(4-cyanophenyl)-4-isoxazolyl]propan-1-ol (418 mg, yield 52%) was obtained as pale yellow crystals from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 82–83° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7](Cl)[N:6]=[CH:5]2.[NH2:15][C:16]1[CH:27]=[CH:26][C:19]([C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:18][CH:17]=1>C(O)(C)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([NH:15][C:16]1[CH:27]=[CH:26][C:19]([C:20]([NH:22][CH:23]([CH3:24])[CH3:25])=[O:21])=[CH:18][CH:17]=1)[N:6]=[CH:5]2
Reactant: COc1cc2nc(Cl)ncc2cc1Br
Reactant: CC(C)NC(=O)c1ccc(N)cc1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: COc1cc2nc(Nc3ccc(C(=O)NC(C)C)cc3)ncc2cc1Br
Temperature: 100 °C

Procedure:
To a 0.25M suspension of 6-bromo-2-chloro-7-methoxyquinazoline in isopropanol was added 4-amino-N-isopropylbenzamide (1.0 eq). The reaction mixture was heated to 100° C. in an oil bath for 14 h. Reaction mixture was diluted with ethyl acetate and filtered to collect desired product. ES/MS m/z 415/417 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[N:14]([C:19](=[O:22])[CH:20]=[CH2:21])[CH2:15][CH2:16]C=C)([CH3:4])([CH3:3])[CH3:2]>ClCCl.C1CCC([P+](C([P+](C2CCCCC2)(C2CCCCC2)C2CCCCC2)C2C=CC=CC=2)(C2CCCCC2)C2CCCCC2)CC1.Cl[Ru]Cl.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[C:1]([O:5][C:6](=[O:23])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[N:14]1[C:19](=[O:22])[CH:20]=[CH:21][CH2:16][CH2:15]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCCN(C(=O)C=C)[C@@H]1CCCC[C@H]1NC(=O)OC(C)(C)C
Agent: Cl[Ru]Cl
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1N1CCC=CC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
Bis(tricyclohexylphosphine)benzylidene ruthenium(IV)dichloride (13 mg, 16 μmol) was added to a solution of trans-[2-(acryloyl-but-3-enyl-amino) -cyclohexyl]-carbamic acid tert-butyl ester (50 mg, 0.16 mmol) and tetraisopropyl orthotitanate (8.8 mg, 31 μmol) in dichloromethane (2.5 ml), and the reaction mixture was stirred for 1 h at room temperature. The solvent was then evaporated and the residue chromatographed (SiO2, heptane-ethyl acetate gradient) to produce the title compound (44 mg, 96%). Off-white solid, MS (ISP) 295.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:22]2[CH:37]=[CH:36][C:25]([C:26]([NH:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])=[C:24]([F:38])[CH:23]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([O:14][Si](C(C)(C)C)(C)C)[CH2:9]2)=[CH:6][N:7]=1.C(=O)(O)[O-].[Na+].C(O)(C(F)(F)F)=O>Cl.C1COCC1.CO>[NH2:1][C:2]1[C:3]([C:22]2[CH:37]=[CH:36][C:25]([C:26]([NH:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])=[C:24]([F:38])[CH:23]=2)=[N:4][C:5]([C@@H:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([OH:14])[CH2:9]2)=[CH:6][N:7]=1
Reactant: CC(C)(C)[Si](C)(C)OC1CCCC(c2cnc(N)c(-c3ccc(C(=O)NCc4ccccc4)c(F)c3)n2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ncc([C@@H]2CCC[C@H](O)C2)nc1-c1ccc(C(=O)NCc2ccccc2)c(F)c1
Reaction time: 2 h

Procedure:
A mixture of 4-(3-amino-6-(3-((tert-butyldimethylsilyl)oxy)cyclohexyl)pyrazin-2-yl)-N-benzyl-2-fluorobenzamide (61 mg, 0.114 mmol) in 6N HCl (0.29 mL),THF (0. 57 mL) and MeOH (0.285 mL) was stirred for 2 h. Solid sodium bicarbonate was added to neutralize the reaction mixture. Solvent was evaporated and 25% of the residue was dissolved in DMSO, and purified with auto-prep to provide 15 mg of desired cis racemate compound as a TFA salt. LCMS (m/z): 421.3 (MH+), 0.74 min. 1H NMR (400 MHz, MeOD-d4) δ ppm 7.82-7.69 (m, 2H) 7. 62-7. 45 (m, 2H) 7.37-7.12 (m, 5H) 4.52 (s, 2H) 3.66-3.52 (m, 1H) 2.75-2.60 (m, 1H) 2.11-2.01 (m, 1H) 1.97-1.70 (m, 3H) 1.52-1.29 (m, 3H) 1.24-1.08 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][CH:12]=[CH:13][CH3:14])[C:7]([O:15][CH3:16])=[C:6]([O:17][CH3:18])[CH:5]=1>CCOC(C)=O>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:7]([O:15][CH3:16])=[C:6]([O:17][CH3:18])[CH:5]=1
Reactant: CC=CCCc1cc(C(=O)OC)cc(OC)c1OC
Solvent: CCOC(C)=O
Product: CCCCCc1cc(C(=O)OC)cc(OC)c1OC
Reaction time: 2.5 h

Procedure:
3,4-Dimethoxy-5-pentylbenzoic acid methyl ester was prepared 3,4-dimethoxy-5-pent-3-enylbenzoic methyl ester by following Method H using EtOAc as a solvent. The reaction was conducted for 2.5 h under hydrogen atmosphere. The product, obtained in quantitative yield, was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.CC(C)([O-])C.[Na+]>>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][CH:5]=1
Reactant: C1COCCN1
Reactant: COc1cccc(Br)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: COc1cccc(N2CCOCC2)c1
Yield: 95.9 %

Procedure:
According to the general procedure B, 3-bromoanisole (82 mg, 0.44 mmol) reacted with morpholine (36 mg, 0.41 mmol) using 1 mol % of catalyst and sodium tert-butoxide (42 mg, 0.44 mmol) at 100° C. for 21 h to give the title compound (76 mg, 96%) as an oil: 1H-NMR (300 MHz, CDCl3): δ 7.21 (t, 1H, J=8.1 and 8.7 Hz), 6.57-6.45 (m, 3H), 3.87 (t, 4H, J=4.5 and 5.1 Hz), 3.81 (s, 3H), 3.17 (t, 4H, J=4.5 and 5.1 Hz). 13C{1H}-NMR (100 MHz, CDCl3): δ 160.00, 152.67, 129.83, 108.43, 104.68, 102.18, 66.86, 55.15, 49.25. GC/MS(EI): m/z 193 (M+).
Reaction SMILES: [C:1]1([S:7]([C:10]([CH:16]2[CH2:28][CH2:27][C:26]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([Cl:29])[CH:24]=4)[NH:19][C:18]=3[CH2:17]2)([F:15])[C:11]([NH:13][CH3:14])=[O:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.[C:37]([O:41][C:42](=O)[O:43]C(C)(C)C)([CH3:40])([CH3:39])[CH3:38]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:37]([O:41][C:42]([N:19]1[C:18]2[CH2:17][CH:16]([C:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:8])=[O:9])([F:15])[C:11](=[O:12])[NH:13][CH3:14])[CH2:28][CH2:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[C:23]([Cl:29])[CH:24]=2)=[O:43])([CH3:40])([CH3:39])[CH3:38]
Reactant: CNC(=O)C(F)(C1CCc2c([nH]c3ccc(Cl)cc23)C1)S(=O)(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)C(F)(C1CCc2c(n(C(=O)OC(C)(C)C)c3ccc(Cl)cc23)C1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.5 %

Procedure:
To 950 mg (2.18 mmol) of (RS,SR)-2-benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-2-fluoro-N-methyl-acetamide (from example 56) in 10 mL of CH2Cl2 at RT were added 0.60 mL (4.36 mmol, 2 eq) of Et3N, 27 mg (0.22 mmol, 0.1 eq) of DMAP and 571 mg (2.62 mmol, 1.2 eq) of carbonic acid di-tert-butyl ester. The reaction mixture was stirred at RT for 2 hours and extracted with 1M HCl. The organic phases were dried over Na2SO4, filtered and evaporated. Column chromatography afforded 682 mg (59%) of (RS,SR)-2-(benzenesulfonyl-fluoro-methylcarbamoyl-methyl)-6-chloro-1,2,3,4-tetrahydro-carbazole-9-carboxylic acid tert-butyl ester as white solid, MS: 552 (MNH4+).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([I:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:12]1[C@H:19]2[C@H:15]([O:16][C:17]([CH3:21])([CH3:20])[O:18]2)[C@@H:14]([CH2:22][OH:23])[O:13]1.[OH-].[K+].[O-:26][Mn](=O)(=O)=O.[K+].OO>O>[NH2:1][C:2]1[N:10]=[C:9]([I:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:12]1[C@H:19]2[C@@H:15]([O:16][C:17]([CH3:20])([CH3:21])[O:18]2)[C@H:14]([C:22]([OH:26])=[O:23])[O:13]1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CO)O[C@H]2n1cnc2c(N)nc(I)nc21
Agent: OO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC1(C)O[C@@H]2[C@@H](O1)[C@H](C(=O)O)O[C@H]2n1cnc2c(N)nc(I)nc21
Temperature: 7.5 °C
Yield: 70 %

Procedure:
To a stirred solution of 1.6 g (3.7 mmol) of [(1R,2R,4R,5R)-4-(6-amino-2-iodopurin-9-yl)-7,7-dimethyl-3,6,8-trioxabicyclo[3.3.0]oct-2-yl]methan-1-ol (6.6) in 200 mL of H2O was added 0.60 g of KOH and, dropwise, a solution of 1.70 g (10.8 mml) of KMnO4 in 50 mL of H2O. The mixture was set aside in the dark at room temperature for 225 hours. The reaction mixture was then cooled to 5-10° C. and decolorized by a solution of 4 mL of 30% H2O2 in 16 mL of water, while the temperature was maintained under 10° C. using an ice-salt bath. The mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to about 10 mL and then acidified to pH 4 with 2N HCl. The resulting precipitate was filtered off and washed with ether to yield 6.7 (70%) after drying as a white solid, m.p. 187-190° C. 1H NMR (300 MHz, DMSO-d6) δ 8.11 (s, 1H, H-8), 7.62 (s, 2H, NH2), 7.46 (s, 1H, COOH), 6.22 (s, 1H, H-1′), 5.42 (d, J=5.71 Hz, 1H, H-2′), 5.34 (d, J=6.16 Hz, 1H, H-3′), 4.63 (s, 1H, H-4′), 1.46 and 1.30 (s, 3H, C(CH3)2).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[O:4].[OH:15][CH:16]([CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1.C(=O)([O-])O.[Na+]>C(O)C>[OH:15][CH:16]([CH:24]1[CH2:29][CH2:28][N:27]([CH2:2][C:3]([C:5]2[CH:14]=[CH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=2)=[O:4])[CH2:26][CH2:25]1)[C:17]1[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=1
Reactant: OC(c1ccc(F)cc1)C1CCNCC1
Reactant: O=C(CBr)c1ccc2ccccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=C(CN1CCC(C(O)c2ccc(F)cc2)CC1)c1ccc2ccccc2c1

Procedure:
5.4 g of 2-bromo-2'-acetonaphthone, 4.6 of 4-(α-hydroxy-p-fluorobenzyl)piperidine and 10 g of sodium hydrogencarbonate were refluxed in ethanol solvent for 2.5 h. After completion of the reaction, the product was treated by an ordinary process. The obtained oily product was purified according to silica gel column chromatography to obtain 5 g of 2-[4-(α-hydroxy-p-fluorobenzyl)piperidinyl]-2'-acetonaphthone; 1 g of this product was stirred together with 1.0 g of acetic anhydride and 0.1 g of dimethylaminopyridine in pyridine solvent at room temperature for 5 h. After completion of the reaction, the oily product was purified according to silica gel column chromatography and converted into its hydrochloride, which was recrystallized from ethyl acetate and methanol.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)[CH2:3][NH:4][C:5]1[S:6][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13]3)=[CH:8][N:9]=1.N1C=CC=CC=1.[C:37](OC(=O)C)(=[O:39])[CH3:38]>C(Cl)Cl>[O:19]=[C:14]1[CH2:13][C:12]2[C:16](=[CH:17][CH:18]=[C:10]([C:7]3[S:6][C:5]([NH:4][CH2:3][C@@H:2]([NH:1][C:37](=[O:39])[CH3:38])[CH2:20][C:21]4[CH:22]=[CH:23][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:26]=4)=[N:9][CH:8]=3)[CH:11]=2)[NH:15]1
Reactant: N[C@H](CNc1ncc(-c2ccc3c(c2)CC(=O)N3)s1)Cc1ccc(C(F)(F)F)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N[C@H](CNc1ncc(-c2ccc3c(c2)CC(=O)N3)s1)Cc1ccc(C(F)(F)F)cc1
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
To a 25 mL round-bottom flask was added Example 42 (30 mg, 69 μmol), pyridine (27 mg, 347 μmol), acetic anhydride (14 mg, 139 μmol), and 2 mL of DCM. After 30 minutes, LC-MS showed that the reaction was complete. The reaction mixture was concentrated and dissolved in 2 mL of MeOH, then purified by preparative LC to give N—((S)-1-(5-(2-oxoindolin-5-yl)thiazol-2-ylamino)-3-(4-(trifluoromethyl)-phenyl)propan-2-yl)acetamide (26 mg, 79% yield). MS m/z: 475 (M+1). 1H NMR (400 MHz, CD3OD) δ ppm 1.89 (s, 3H), 2.90 (dd, J=13.99, 9.29 Hz, 1H), 3.08 (dd, J=13.99, 5.18 Hz, 1H), 3.46-3.53 (m, 1H), 3.60 (s, 2H), 3.61-3.67 (m, 1H), 4.41-4.48 (m, 1H), 6.96 (d, J=8.22 Hz, 1H), 7.38 (dd, J=8.12, 1.86 Hz, 1H), 7.46-7.51 (m, 3H), 7.63 (d, J=8.02 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:23]=[C:11]3[N:12]=[C:13]([Cl:22])[CH:14]=[C:15]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[N:10]3[N:9]=2)=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[CH3:43][O:44][CH2:45][CH2:46][NH2:47]>C1(C)C=CC=CC=1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[Cl:22][C:13]1[CH:14]=[C:15]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:10]2[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:47][CH2:46][CH2:45][O:44][CH3:43])=[CH:3][CH:4]=3)[CH:23]=[C:11]2[N:12]=1
Reactant: Clc1cc(N2CCOCC2)n2nc(-c3ccc(Br)cc3)cc2n1
Reactant: COCCN
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: COCCNc1ccc(-c2cc3nc(Cl)cc(N4CCOCC4)n3n2)cc1
Yield: 58 %

Procedure:
There was dissolved, in toluene (3 mL), 2-(4-bromo-phenyl)-5-chloro-7-morpholin-4-yl-pyrazolo[1,5-a]pyrimidine (59.3 mg, 0.151 mM) in an argon gas atmosphere, then there were added, to the resulting solution, a solution of sodium t-butoxide (58.0 mg, 0.604 mM), tris(dibenzylidene acetone) di-palladium (6.9 mg, 0.0076 mM) and tri-t-butyl phosphine (11.0 μL, 0.0453 mM) in toluene (0.556 mL) and 2-methoxy-ethylamine (26.3 μL, 0.302 mM) and the resulting mixture was stirred at 80° C. for 4 hours and a half. This reaction liquid was diluted with a saturated aqueous common salt solution and then extracted with ethyl acetate. The extracts thus obtained were combined, dried over anhydrous sodium sulfate, then the solvent was distilled off and the resulting residue was purified by the silica gel column chromatography (ethyl acetate//hexane=1:4 to 2:3) to thus give the title compound (34.2 mg, yield: 58%).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][CH2:9][CH2:10][S:11]([N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@@H:16]([C:27]([NH:29][O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:28])[CH2:15]1)(=[O:13])=[O:12]>CC(O)=O>[C:1]([NH:8][CH2:9][CH2:10][S:11]([N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@@H:16]([C:27]([NH:29][O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:28])[CH2:15]1)(=[O:13])=[O:12])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)ONC(=O)[C@H]1CN(S(=O)(=O)CCN)CCN1C(=O)OC(C)(C)C
Solvent: CC(=O)O
Product: CC(=O)NCCS(=O)(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)NOC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
Acetic anhydride (36 mg) was added to a solution of (2R)-4-(2-aminoethanesulfonyl)-N-tert-butoxy-1-tert-butoxycarbonyl-2-piperazinecarboxamide (130 mg) in AcOH (2 ml). The reaction mixture was stirred at ambient temperature for 3 hours. The mixture was concentrated in vacuo, and the residue was partitioned between AcOEt and saturated aqueous NaHCO3 solution. The organic layer was washed with saturated aqueous NaCl solution, dried over MgSO4, and concentrated in vacuo to give 142 mg of (2R)-4-[2-(acetylamino)ethanesulfonyl]-N-tert-butoxy-1-tert-butoxycarbonyl-2-piperazinecarboxamide.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2.[N:12]1([CH2:18][CH2:19][NH:20][C:21]([C:23]2[S:31][C:30]3[C:25](=[N:26][CH:27]=[CH:28][C:29]=3Cl)[CH:24]=2)=[O:22])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[N:12]1([CH2:18][CH2:19][NH:20][C:21]([C:23]2[S:31][C:30]3[C:25](=[N:26][CH:27]=[CH:28][C:29]=3[NH:11][C:7]3[CH:8]=[C:9]4[C:4](=[CH:5][CH:6]=3)[NH:3][C:2]([CH3:1])=[CH:10]4)[CH:24]=2)=[O:22])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C(NCCN1CCCCC1)c1cc2nccc(Cl)c2s1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)NCCN5CCCCC5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 2-methyl-1H-indol-5-ylamine and 7-chloro-thieno[3,2-b]pyridine-2-carboxylic acid (2-piperidin-1-yl-ethyl)-amide by a procedure analogous to Example 1C. MS: 434 (MH+); HPLC Rf: 3.82 min.; HPLC purity 99%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][N:10]=[C:11]([C:14]#[N:15])[C:12]#[N:13])[CH:5]=[CH:6][C:7]=1[F:8].FC1C=C(C=CC=1F)N.C(#N)CC#N.O.[NH2:31][NH2:32]>>[NH2:15][C:14]1[C:11](=[N:10][NH:9][C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)[C:12]([NH2:13])=[N:32][N:31]=1
Reactant: NN
Reactant: N#CC(C#N)=NNc1ccc(F)c(F)c1
Agent: Nc1ccc(F)c(F)c1
Solvent: O
Solvent: N#CCC#N
Product: NC1=NN=C(N)C1=NNc1ccc(F)c(F)c1
Yield: 38 %

Procedure:
This compound was prepared using 103 mg (0.5 mmol) of 2-[(3,4-difluorophenyl)-hydrazono]malononitrile, which was derived from 3,4-difluoroaniline (99 μL, 1.0 mmol) and malononitrile (1.5 mmol) as described in Example 8, and hydrazine hydrate. Precipitate formed in the reaction tube approximately 5 min after the addition of hydrazine hydrate. The resulting solid was isolated by filtration, washed with ethanol, and dried to yield 45 mg (38%) of the title compound as a yellow solid. 1H NMR (ppm, DMSO-d6): 6.18 (br s, 4H), 7.28-7.55 (m, 2H), 7.70-7.82 (m, 1H), 10.80 (br s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:18][CH2:17][C@@H:16]([O:19]S(C)(=O)=O)[C:15]2=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][C:26]1[N:30]([C:31]2[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=2)[N:29]=[N:28][N:27]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.O.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:18][CH2:17][CH:16]([O:19][C:34]3[CH:35]=[CH:36][C:31]([N:30]4[C:26]([CH3:25])=[N:27][N:28]=[N:29]4)=[CH:32][CH:33]=3)[C:15]2=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CC[C@@H](OS(C)(=O)=O)C2=O)CC1
Reactant: Cc1nnnn1-c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nnnn1-c1ccc(OC2CCN(C3CCN(C(=O)OC(C)(C)C)CC3)C2=O)cc1
Temperature: 70 °C
Yield: 49.4 %

Procedure:
To a solution of (R)-tert-butyl-4-(3-(methylsulfonyloxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (Preparation D; 1.03 g, 2.84 mmol) and 4-(5-methyl-1H-tetrazol-1-yl)phenol (500 mg, 2.84 mmol) in DMSO (10 mL) was added K2CO3 (1.18 g, 8.51 mmol). The reaction was heated to 70° C. for 12 hours and then diluted with water (10 mL) and EtOAc (10 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (2×15 mL). The combined organic layers were dried with MgSO4 and concentrated in vacuo. The material was purified by silica gel chromatography eluting with 1:1 hexanes/EtOAc to EtOAc to yield tert-butyl-4-(3-(4-(5-methyl-1H-tetrazol-1-yl)phenoxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (621 mg, 52%) as an off white solid.