Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:20][CH2:19][C:18]3[C@:13]([C:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)=[O:32])([CH2:14][C:15]4[CH:23]=[N:22][N:21]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[C:16]=4[CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1>C(#N)C>[F:30][C:27]1[CH:26]=[CH:25][C:24]([N:21]2[C:16]3[CH:17]=[C:18]4[C@:13]([C:31]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=5)=[O:32])([CH2:14][C:15]=3[CH:23]=[N:22]2)[CH2:12][N:11]([S:8]([C:5]2[CH:6]=[N:7][C:2]([N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:20][CH2:19]4)=[CH:29][CH:28]=1
Reactant: O=C(c1ccccn1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(Cl)nc1)C2
Reactant: C1CCNC1
Solvent: CC#N
Product: O=C(c1ccccn1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCCC3)nc1)C2
Yield: 27.3 %

Procedure:
A solution of (R)-(6-((6-chloropyridin-3-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone (100 mg, 0.182 mmol) and pyrrolidine (37.9 μl, 0.455 mmol) in acetonitrile (2 mL) was stirred in a sealed vial at 40° C. for 1 hour. The cooled reaction mixture was then purified directly by preparative HPLC (Waters, Acidic (0.1% Formic acid), Waters X-Select Prep-C18, 5 μm, 19×50 mm column, 5-95% acetonitrile in water) to afford (R)-(1-(4-fluorophenyl)-6-((6-(pyrrolidin-1-yl)pyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone as a white solid (29 mg). LCMS (Method F, ES-API): RT 2.48 min, m+H=585.3; 1H NMR (400 MHz, CDCl3): δ 8.63-8.61 (1H, m), 8.43 (1H, d, J=2.4 Hz), 7.89-7.87 (1H, m), 7.80 (1H, dt, J=7.6, 1.8 Hz), 7.58 (1H, dd, J=9.0, 2.4 Hz), 7.45-7.41 (3H, m), 7.28 (1H, s), 7.19-7.13 (2H, m), 6.47 (1H, d, J=2.1 Hz), 6.22 (1H, d, J=9.0 Hz), 5.46 (1H, dd, J=12.2, 2.1 Hz), 4.27 (1H, d, J=16.9 Hz), 3.83-3.79 (1H, m), 3.52-3.45 (4H, m), 2.90-2.76 (2H, m), 2.68 (1H, d, J=12.3 Hz), 2.51-2.45 (2H, m), 2.06-2.04 (4H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=2)=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:23][O:24][C:25](=[O:35])[CH2:26]P(OCC)(OCC)=O.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].COC1C=C(C(C2C=CC=C(OC)C=2)=CC#N)C=C(OC)C=1>>[CH3:23][O:24][C:25](=[O:35])[CH:26]=[C:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=1
Reactant: COc1cc(OC)cc(C(=O)c2ccc(OC)c(OC)c2)c1
Reactant: CCOP(=O)(CC(=O)OC)OCC
Agent: COc1cccc(C(=CC#N)c2cc(OC)cc(OC)c2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: COC(=O)C=C(c1cc(OC)cc(OC)c1)c1ccc(OC)c(OC)c1
Yield: 25.4 %

Procedure:
(3,4-dimethoxyphenyl)-(3,5-dimethoxyphenyl)methanone (0.50 g, 4.95 mmol), (diethoxyphosphoryl)acetic acid methyl ester (2.29 g, 9.90 mmol), and lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 9.90 ml, 9.90 mmol) were treated in the same manner as described above for the synthesis of 3-(3,5-dimethoxy-phenyl)-3-(3-methoxy-phenyl)-acrylonitrile. The crude yellowish oil was purified via preparative HPLC to give 3-(3,4-dimethoxy-phenyl)-3-(3,5-dimethoxy-phenyl)-acrylic acid methyl ester as a light yellow oil (0.45 g, 25%): 1HNMR (CDCl3) δ 6.89-6.72 (m, 2H, Ar), 6.49-6.36 (m, 4H, Ar), 6.28 (s, 1H, double bond proton), 3.92 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 3.75 (s, 6H, 2OCH3), 3.64 (s, 3H, OCH3); Anal. Calcd. For C20H22O6+1.06H2O: C, 63.60; H, 6.45. Found: C, 63.22; H, 5.88.
Reaction SMILES: [CH:1]([NH:4]C(C)C)(C)C.[Li]CCCC.C1COCC1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][C:25]#[N:26].ClC1C=CC=CC=1CSC#N>C1(C)C=CC=CC=1.O>[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:24]([C:1]#[N:4])[C:25]#[N:26]
Reactant: N#CCc1ccccn1
Reactant: CC(C)NC(C)C
Agent: N#CSCc1ccccc1Cl
Agent: [Li]CCCC
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: N#CC(C#N)c1ccccn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 63.4 %

Procedure:
To diisopropylamine (15.3 mL, 109 mmol) in toluene (500 mL), at 0-5° C., under nitrogen, was added drop wise over ˜½ hour 1.6M″ BuLi/THF (68.5 mL, 109 mmol). The reaction mixture was stirred for a further 15 minutes before the drop wise addition of 2-pyridylacetonitrile (5.55 mL, 49.6 mmol) over 1 hour. 2-Chlorobenzylthiocyanate (20.0 g, 109 mmol), described in the literature by Schlesinger J. Am. Chem. Soc. 1954, 76, 585, was then added in solution in toluene (100 mL) over a period of 1 hour. The reaction mixture was stirred for an additional 2 hours. Water was added and the layers were separated. The organic phase was extracted twice with 200 mL 2N NaOH. The combined aqueous phases were cooled down to 0° C and acidified to ˜pH 1. The precipitate obtained was filtered and dried to give the title compound as a pale tan solid (4.50 g, 63% yield). δH (DMSO-d6) 6.79 (1H, t), 7.09 (1H, d), 7.73 (1H, t), 7.79 (1H, dd), 12.95 (1H, br s).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:17]=[C:18]([C:23]3[S:27][C:26]([C:28]([OH:34])([CH3:33])[C:29]([F:32])([F:31])[F:30])=[N:25][CH:24]=3)[CH:19]=[C:20]([CH3:22])[CH:21]=2)[N:10]=1)C1C=CC=CC=1.C(O)C.C(O)(=O)C.[H][H]>[Pd].CO.C(OCC)(=O)C>[CH3:22][C:20]1[CH:21]=[C:16]([NH:15][C:11]2[N:10]=[C:9]([OH:8])[CH:14]=[CH:13][N:12]=2)[CH:17]=[C:18]([C:23]2[S:27][C:26]([C:28]([OH:34])([CH3:33])[C:29]([F:32])([F:30])[F:31])=[N:25][CH:24]=2)[CH:19]=1
Reactant: [H][H]
Reactant: Cc1cc(Nc2nccc(OCc3ccccc3)n2)cc(-c2cnc(C(C)(O)C(F)(F)F)s2)c1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(Nc2nccc(O)n2)cc(-c2cnc(C(C)(O)C(F)(F)F)s2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.1 %

Procedure:
Palladium on carbon (10 wt %) (50 mg, 0.05 mmol) was added to a flask that was evacuated and backfilled with argon (3×). A solution of 2-[5-(3-{[4-(benzyloxy)pyrimidin-2-yl]-amino}-5-methylphenyl)-1,3-thiazol-2-yl]-1,1,1-trifluoropropan-2-ol (Example 94B-1, 230 mg, 0.47 mmol) in a mixture of methanol (4 mL), ethanol (3 mL) and ethyl acetate (2 mL) was added followed by the addition of acetic acid (50 μL, 0.87 mmol). A hydrogen balloon was placed on top of the reaction and the reaction was evacuated/backfilled with hydrogen (5×). The reaction was stirred overnight at room temperature. The mixture was then filtered through celite, washing with methanol. The filtrate was concentrated under reduced pressure and purified by Chromatography on silica gel (30-100% ethyl acetate in hexanes) to provide 145 mg (0.367 mmol, 77%) of 2-({3-methyl-5-[2-(1,1,1-trifluoro-2-hydroxypropan-2-yl)-1,3-thiazol-5-yl]phenyl}amino)pyrimidin-4-ol as a white solid.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[I:16])([OH:8])[C:4]([F:7])([F:6])[F:5].[ClH:19].Cl[O-].[Na+]>CC(O)C>[Cl:19][I:16]1[C:10]2[CH:11]=[CH:12][C:13]([CH3:15])=[CH:14][C:9]=2[C:3]([C:4]([F:7])([F:6])[F:5])([C:2]([F:1])([F:17])[F:18])[O:8]1
Reactant: Cc1ccc(I)c(C(O)(C(F)(F)F)C(F)(F)F)c1
Reactant: Cl
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC(C)O
Product: Cc1ccc2c(c1)C(C(F)(F)F)(C(F)(F)F)OI2Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 76 %

Procedure:
Compound 2 (60 mg, 156 μmol) was dissolved in 2 mL propan-2-ol, 10 μL hydrochloric acid (37%) and 50 μL sodium hypochlorite solution (10-15% in water) were added. A white precipitate appeared instantaneously. The reaction mixture was stirred 5 min at room temperature. The solvent was removed under vacuum and the residue was purified over silica gel column using dichloromethane as eluant to give 50 mg (119 μmol, 76% yield) of a white solid.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH2:12])=[CH:4][CH:3]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O.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>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][C:23]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([NH2:12])=[CH:4][CH:3]=2)=[CH:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: Nc1ccc(Br)c2ccccc12
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(N)c3ccccc23)CC1
Temperature: 100 °C

Procedure:
A mixture of 4-bromonaphthalen-1-amine (1.0 g, 4.5 mmol), tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.7 g, 5.4 mmol), Pd(PPh3)4 (26.01 mg, 0.02 mmol) and Na2CO3 (3.34 g, 31.5 mmol) in 10 mL of DMF and 5 mL of water was degassed and purged with nitrogen. The reaction was heated at 100° C. for 5 h, and cooled to room temperature. The reaction mixture was partitioned between EtOAc and water. The combined organic extracts were dried (Na2SO4), concentrated in vacuo and purified by silica gel chromatography (MeOH/DCM: 5/95) to afford tert-butyl-4-(4-aminonaphthalen-1-yl)-5,6-dihydropyridine-1(2H)-carboxylate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.CC(C)([O-])C.[Na+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH:8]1([C:5]2[CH:6]=[CH:7][C:2]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[CH:3][CH:4]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: Brc1ccc(C2CCCCC2)cc1
Reactant: C1CNCCN1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: c1cc(N2CCNCC2)ccc1C1CCCCC1

Procedure:
A target compound (2.01 g, 8.224 mmol, 45.7%) was yielded in the same manner as Reference Example 10 by reacting 1-bromo-4-cyclohexylbenzene (3.34 mL, 18 mmol) with piperazine (2.01 g, 23.4 mmol), sodium t-butoxide (2.51 g, 26.1 mmol) and dichlorobis(tri-o-tolylphosphine)palladium(II) (424.4 mg, 0.54 mmol) and purifying by separation through column chromatography (CH2Cl2/MeOH, 1:1).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[N:8][N:9]([C:11]2[CH:16]=[C:15]([C:17](=[O:36])[NH:18][C:19]3[CH:24]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:22]=[C:21]([S:29](=[O:33])(=[O:32])[NH:30][CH3:31])[C:20]=3[O:34][CH3:35])[CH:14]=[CH:13][C:12]=2[CH3:37])[CH:10]=1)=[O:5])C.[Li+].[OH-].Cl>CO.O>[C:25]([C:23]1[CH:22]=[C:21]([S:29](=[O:33])(=[O:32])[NH:30][CH3:31])[C:20]([O:34][CH3:35])=[C:19]([NH:18][C:17]([C:15]2[CH:14]=[CH:13][C:12]([CH3:37])=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=[N:8]3)[CH:16]=2)=[O:36])[CH:24]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CCOC(=O)c1cn(-c2cc(C(=O)Nc3cc(C(C)(C)C)cc(S(=O)(=O)NC)c3OC)ccc2C)nn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CNS(=O)(=O)c1cc(C(C)(C)C)cc(NC(=O)c2ccc(C)c(-n3cc(C(=O)O)nn3)c2)c1OC
Reaction time: 8 h
Yield: 102.4 %

Procedure:
The above ester (230 mg, 0.434 mmol) was dissolved in 7 mL of MeOH. A solution of 250 mg (5.99 mmol) of LiOH in 2 mL of water was added at RT. The resulting mixture was stirred overnight, then acidified with 4N HCl and extracted with EtOAc (4×30 mL). The extracts were combined, dried over MgSO4, filtered and concentrated to provide 223 mg of 1-[5-(5-tert-Butyl-2-methoxy-3-methylsulfamoyl-phenylcarbamoyl)-2-methyl-phenyl]-1H-[1,2,3]triazole-4-carboxylic acid as a brown foam (>90% by LCMS).
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([OH:15])CO)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].I([O-])(=O)(=O)=O.[Na+]>O.C(OCC)C>[OH:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]=[O:15])=[CH:7][CH:6]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(O)c1ccc(CC(O)CO)cc1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CCOCC
Product: CC(C)(O)c1ccc(CC=O)cc1
Reaction time: 2 h

Procedure:
A biphasic mixture of 3-[4-(1-hydroxy-1-methylethyl)phenyl]propane-1,2-diol (5.44 g, 25.9 mmol) in water (85 mL) and diethyl ether (170 mL) was charged with sodium periodate (11.07 g, 51.7 mmol) and stirred vigorously for two hours. The reaction mixture was then partitioned between diethyl ether (50 mL) and saturated aqueous sodium thiosulfate (50 mL), and the layers were separated. The aqueous layer was extracted with diethyl ether (2×100 mL), and the combined organic layers were washed with brine (25 mL), dried over sodium sulfate, filtered, and concentrated. To remove water left over, the concentrated material was dissolved in dichloromethane (70 mL), washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated to yield the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[C:5]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][C:3]=1[C:20]([CH3:22])=[O:21].[C:23](OC(=O)C)(=O)[CH3:24].C([O-])(=O)C.[Na+].C(OCC)(=O)C>O>[CH3:23][C:24]1[O:1][C:2]2[CH:7]=[C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[C:5]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:4][C:3]=2[C:20](=[O:21])[CH:22]=1
Reactant: CC(=O)c1cc(Oc2ccccc2)c(NS(C)(=O)=O)cc1O
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(=O)c2cc(Oc3ccccc3)c(NS(C)(=O)=O)cc2o1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 24.9 %

Procedure:
There were mixed 3.21 g of methyl 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl ketone, 5.45 g of acetic anhydride and 4.1 g of sodium acetate. The mixture was stirred for 1.5 hours at 130°-140° C. The reaction mixture was cooled to room temperature. 200 ml of ethyl acetate and 100 ml of water were added thereto. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropyl ether to obtain 860 mg (yield: 25%) of 2-methyl-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one having a melting point of 186.5°-187° C.
Reaction SMILES: C1(C2N=[C:9]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])[O:10]C=2C2C=CC=CC=2)C=CC=CC=1.[C:23]1([C:29]([CH:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[OH:32])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(=O)OC(=O)CC1>>[C:20]([OH:22])(=[O:21])[CH2:19][CH2:18][C:9]([OH:30])=[O:10].[C:23]1([C:29]([CH:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[OH:32])=[O:30])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1.[C:23]1([C:29]([CH:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[OH:32])=[O:30])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(O)CCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: O=C(c1ccccc1)C(O)c1ccccc1
Agent: O=C1CCC(=O)O1
Product: O=C(O)CCC(=O)O

Procedure:
A process for the preparation of 4,5-diphenyloxazole-2-propanoic acid of formula I ##STR2## by esterification of benzoin with succinic anhydride to give benzoin hemisuccinate, and cyclization to (I) by direct addition of ammonium acetate or urea to the mixture containing the hemisuccinate,
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6]Cl.[N+:13]([C:16]1[O:20][C:19]([CH:21]=[CH:22][C:23]2[NH:24][CH:25]=[CH:26][N:27]=2)=[CH:18][CH:17]=1)([O-:15])=[O:14]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][N:27]1[CH:26]=[CH:25][N:24]=[C:23]1[CH:22]=[CH:21][C:19]1[O:20][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])c1ccc(C=Cc2ncc[nH]2)o1
Reactant: COc1ccc(CCl)cc1OC
Product: COc1ccc(Cn2ccnc2C=Cc2ccc([N+](=O)[O-])o2)cc1OC

Procedure:
Using the same general procedure as employed in Example 1, the captioned compound was prepared from 3,4-dimethoxybenzyl chloride (as prepared from the corresponding alcohol) in lieu of the 2,3-dimethoxybenzyl chloride intermediate of Example 1.
Reaction SMILES: [NH2:1][C@H:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH:21]1([C:27](Cl)=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][C@H:2]([NH:1][C:27]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:28])[C:3]1=[O:20]
Reactant: O=C(Cl)C1CCCCC1
Reactant: CN1C(=O)[C@@H](N)N=C(c2ccccc2)c2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1C(=O)[C@@H](NC(=O)C2CCCCC2)N=C(c2ccccc2)c2ccccc21
Reaction time: 0.17 h

Procedure:
Equimolar amounts of 3(S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, cyclohexane carboxylic acid chloride and triethylamine were mixed in CH2Cl2 at room temperature and stirred 10 minutes. Flash chromatography of the reaction solution on silica gel (10% Et2O in CH2Cl2) provided the title compound as a white solid after removal of the solvent: m.p. 212°-214° C.
Reaction SMILES: [OH:1][C@H:2]1[C:10]2[C:5](=[C:6]([C:11]3[N:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=4)[C:21]#[N:22])[O:13][N:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.N1C=CC=CC=1.[C:34](Cl)(=[O:36])[CH3:35]>C(Cl)Cl>[C:34]([O:1][C@H:2]1[C:10]2[C:5](=[C:6]([C:11]3[N:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([C:21]#[N:22])[CH:23]=4)[O:13][N:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1)(=[O:36])[CH3:35]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4O)no2)cc1C#N
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)O[C@@H]1CCc2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cccc21
Temperature: 25 °C
Reaction time: 96 h
Yield: 91.7 %

Procedure:
To a flask containing (R)-5-(3-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 5 (36 mg, 0.10 mmol) in DCM (1 mL) was added pyridine (24 μL, 0.3 mmol) and acetyl chloride (21 μL, 0.3 mmol). The reaction was stirred at room temperature for 4 days. The crude reaction mixture was washed with saturated sodium bicarbonate, dried over magnesium sulfate, and purified by chromatography (EA/hexane) to give 37 mg (92%) of (R)-4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl acetate 13 as a white solid. LCMS-ESI (m/z) calculated for C23H21N3O4: 403.2. found 426.1 [M+Na]+, tR=4.19 min. 1H NMR (400 MHz, CDCl3) δ 8.37 (d, J=2.1, 1H), 8.27 (dd, J=8.9, 2.2, 1H), 8.10 (dd, J=7.7, 0.9, 1H), 7.53 (d, J=7.4, 1H), 7.35 (t, J=7.7, 1H), 7.06 (d, J=9.0, 1H), 6.21 (dd, J=7.2, 3.7, 1H), 4.73 (hept, J=6.1, 1H), 3.44 (ddd, J=17.5, 8.3, 6.3, 1H), 3.26 (ddd, J=17.6, 8.7, 4.8, 1H), 2.52 (tdd, J=14.9, 7.9, 6.3, 1H), 2.21-2.06 (m, 1H), 2.02 (s, 3H), 1.41 (d, J=6.1, 6H).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH2:10])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:11][C:12]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:13]=1[C:14](Cl)=[O:15].C(N(CC)CC)C>C(Cl)Cl>[C:1]([C:5]1[S:9][C:8]([NH:10][C:14](=[O:15])[C:13]2[CH:17]=[C:18]([C:21]([F:22])([F:23])[F:24])[CH:19]=[CH:20][C:12]=2[F:11])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nnc(N)s1
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1nnc(NC(=O)c2cc(C(F)(F)F)ccc2F)s1
Temperature: 25 °C
Yield: 92.1 %

Procedure:
To a solution of 5-tert-butyl-1,3,4-thiadiazol-2-amine (1.57 g, 10 mmol) and 2-fluoro-5-(trifluoromethyl)benzoyl chloride (2.27 g, 10 mmol) in CH2Cl2 (45 mL) at 0° C. was added triethylamine (1.7 mL, 12 mmol) dropwise and the reaction mixture was allowed to warm to ambient temperature for 12 hours. The mixture was then washed with water, brine, dried with MgSO4, filtered, and concentrated under reduced pressure to afford 3.2 g of the title compound. MS (DCI/NH3) m/z 348 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([OH:26])=O)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[NH:27]1[CH2:32][CH2:31][CH2:30][CH:29]([C:33]#[N:34])[CH2:28]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([N:27]3[CH2:32][CH2:31][CH2:30][CH:29]([C:33]#[N:34])[CH2:28]3)=[O:26])[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: N#CC1CCCNC1
Reactant: O=C(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: N#CC1CCCN(C(=O)Cn2nc(-c3ccccc3)c3c(Cl)c(-c4ccccc4)nnc32)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 22.7 %

Procedure:
To a suspension of 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetic acid (100 mg, 0.27 mmol) in DMF (2 mL) were added piperidine-3-carbonitrile (33 mg, 0.30 mmol), diisopropylethylamine (DIPEA) (105 μL, 0.60 mmol) and 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (125 mg, 0.33 mmol). The solution obtained was stirred at room temperature for 18 h then diluted with EtOAc. The organic phase was washed with water and brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by preparative HPLC followed by a second chromatography purification (silica gel, gradient 1/1 ethyl acetate/isohexane) yielding Compound 58 as a solid (28 mg).
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[C:51]([C:58]5[CH:59]=[N:60][CH:61]=[CH:62][CH:63]=5)[CH:52]=[CH:53][CH:54]=4)[O:49][C:48]=3[C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C>>[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[C:51]([C:58]5[CH:59]=[N:60][CH:61]=[CH:62][CH:63]=5)[CH:52]=[CH:53][CH:54]=4)[O:49][C:48]=3[C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)=[CH:45][CH:46]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(-c5cccnc5)cccc4c3=O)cc2)CCC1
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(-c5cccnc5)cccc4c3=O)cc2)CCC1
Yield: 11 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, {1-[4-(4-oxo-2-phenyl-8-pyridin-3-yl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was reacted to give the title compound as a white solid (4 mg, 11%). 1H NMR (400 MHz, DMSO-d6): δ 8.90 (d, J=2.1 Hz, 1H), 8.59 (dd, J=4.8 and 1.6 Hz, 1H), 8.17-8.12 (m, 2H), 7.91 (dd, J=7.5 and 1.8 Hz, 1H), 7.60 (t, J=8.0 Hz, 1H), 7.52-7.48 (m, 1H), 7.36 (d, J=8.6 Hz, 2H), 7.31-7.20 (m, 5H), 7.13 (d, J=8.4 Hz, 2H), 4.05 (d, J=3.8 Hz, 2H), 2.41-2.32 (m, 2H), 2.17-2.08 (m, 2H), 2.03-1.91 (m, 1H), 1.69-1.57 (m, 1H). LCMS (Method E): RT=3.06 min, [M+H]+=445.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:19][CH:20]([CH3:22])[CH3:21].O>CN(C=O)C>[CH2:19]([O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1)[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)CBr
Reactant: O=C1CCc2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)COc1ccc2c(c1)C(=O)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
To a mixture of 6-hydroxy-2,3-dihydro-1H-inden-1-one (5.0 g, 33.8 mmol) in DMF (170 mL) was added K2CO3 (9.33 g, 67.5 mmol) and 1-bromo-2-methylpropane (5.50 mL, 50.6 mmol). The resulting orange mixture was stirred at r.t. overnight and was then heated to 60° C. for 2 days. The mixture was cooled to r.t., water was added and the mixture was extracted with EtOAc (×4). The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography using 0-20% EtOAc in heptane as eluent afforded 4.98 g (72% yield) of the title compound: 1H NMR (500 MHz, CDCl3) δ ppm 1.03 (d, 6H), 2.10 (dt, 1H), 2.69-2.75 (m, 2H), 3.04-3.11 (m, 2H), 3.75 (d, 2H), 7.17-7.22 (m, 2H), 7.37 (d, 1H); MS (ES+) m/z 205 [M+H]+.