Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[N:27]1([CH2:33][C:34]2[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=2)[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:39][CH2:38][C:37]1[CH:36]=[CH:35][C:34]([CH2:33][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:41][CH:40]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: NCc1ccc(CN2CCOCC2)cc1
Product: O=C(N1CCc2ccc(Cl)c(NCc3ccc(CN4CCOCC4)cc3)c2CC1)C(F)(F)F
Yield: 67.1 %

Procedure:
Use a method similar to the General Procedure 1-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (400 mg, 0.94 mmol) with 4-(morpholin-4-ylmethyl)-benzylamine (291 mg, 1.41 mmol). Purify by chromatography on silica gel (80 g, pre-packed cartridge) eluting with hexane/EtOAc (1:0 to 2:1 gradient) to obtain 7-chloro-6-[4-(morpholin-4-ylmethyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (304 mg, 67%). MS (APCI+) m/z: 482 (M+H)÷.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[C@@H:7]([OH:8])[C:5](=[O:6])[O:4][CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].[H][H]>O1CCCC1.O>[CH3:1][C:2]([CH3:9])([CH2:3][OH:4])[C@@H:7]([OH:8])[CH2:5][OH:6]
Reactant: [H][H]
Reactant: CC1(C)COC(=O)[C@@H]1O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(CO)[C@@H](O)CO
Temperature: 0 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
Adapting a procedure or a variation thereof according to Blakemore et al., J. Org. Chem. 2005, 70, 5449-5460; Mandel et al., Org. Lett. 2004, 6(26), 4801-4803; Lavallée et al., Tetrahedron Lett. 1986, 27, 679-682; Shiina et al., Bull. Chem. Soc. Jpn. 2001, 74, 113-122; Ito et al., Synthesis 1993, 137-140; Callant et al., Tetrahedron: Asymmetry 1993, 4(2), 185-188; Dolle et al., J. Am. Chem. Soc. 1985, 107, 1691-1694; and Matsuo et al., Tetrahedron Lett. 1976, 17(23), 1979-1982, a dry 1,000 mL three-necked flask equipped with a magnetic stirring bar, addition funnel, and reflux condenser topped with rubber septa was charged under a nitrogen atmosphere with 7.8 g (60.0 mmol) of commercially available D-pantolactone. The material was dissolved in 100 mL of anhydrous tetrahydrofuran (THF) and the solution cooled to ca. 0° C. (ice bath). Sixty-five (65) mL (38.5 mmol) of a one molar (1.0 M) solution of lithium aluminum hydride (LAH) in THF was added dropwise and the reaction mixture stirred overnight with gradual warming to room temperature. (Note: To ensure complete global reduction of the lactone several authors recommend heating the reaction mixture to reflux for ca. two hours after the overnight reaction to complete the reduction.) The reaction mixture was again cooled to ca. 0° C. (ice bath) and 4.23 mL of water, 8.46 mL of an aqueous solution of sodium hydroxide (10 wt-%), and 4.23 mL of water were carefully added (Note: Initially, there is a vigorous evolution of hydrogen gas.) and the resulting colorless precipitate was filtered off The filter residue was washed with dichloromethane (DCM) and the combined filtrates were dried over anhydrous magnesium sulfate (MgSO4). After filtration and evaporation of the solvents under reduced pressure using a rotary evaporator, 6.6 g (82% yield) of the title compound (6) was obtained as a slightly yellow, viscous liquid that was of sufficient purity to be used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6): δ=0.768 (s, 3H), 0.777 (s, 3H), 3.15 (d, J=10.4 Hz, 1H), 3.21 (d, J=10.0 Hz, 1H), 3.22-32 (m, 2H), 3.44-3.52 (m, 1H), 4.20-4.40 (br. m, 3H) ppm. MS (ESI) m/z: 135.03 (M+H)+, 132.89 (M−H)−. The analytical data for the compound was consistent with the proposed structure and the data given in the literature.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](I)[C:5]([CH3:16])=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=1.[CH3:18][C:19]([OH:23])([C:21]#[CH:22])[CH3:20]>C(#N)C.[Cu]I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:22]#[C:21][C:19]([OH:23])([CH3:20])[CH3:18])[C:5]([CH3:16])=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=1
Reactant: Cc1c(I)cc(Cl)cc1NC(=O)OC(C)(C)C
Reactant: C#CC(C)(C)O
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: Cc1c(C#CC(C)(C)O)cc(Cl)cc1NC(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 91.8 %

Procedure:
A solution of 1,1-dimethylethyl (5-chloro-3-iodo-2-methylphenyl)carbamate (610 mg, 1.7 mmol), 2-methyl-3-butyn-2-ol (245 μl, 2.5 mmol), and triphenylphosphine (30 mg, 0.12 mmol) in acetonitrile (2 mL) was deoxygenated for 20 minutes. The solution was cooled to 0° C., followed by the addition of copper(I)iodide (12 mg, 0.07 mmol), and palladium(II)dichloride (13 mg, 0.06 mmol). The mixture was stirred at reflux for 1.5 hours, then cooled to room temperature and concentrated in-vacuo. The resultant residue was partitioned between water and ethyl acetate. The aqueous portion was extracted twice with ethyl acetate. The combined organic portions were washed with brine, dried over sodium sulfate, filtered and concentrated in-vacuo to afford a brown residue which was purified by column chromatography (silica gel, 20% ethyl acetate in hexanes). The product was collected to afford 504 mg, 1.56 mmol (94%) of 1,1-dimethylethyl [5-chloro-3-(3-hydroxy-3-methylbut-1-yn-1-yl)-2-methylphenyl]carbamate as a yellow solid. 1H NMR (400 MHz, CDCl3): 7.36 (d, 1H), 7.06 (d, 1H), 2.26 (s, 3H), 1.63 (s, 6H), 1.41 (s, 9H); MS (EI) for C17H22ClNO3: 324 (MH+).
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[F:27][C:28]([F:35])([F:34])[CH:29]([OH:33])[C:30](O)=[O:31]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:30](=[O:31])[CH:29]([OH:33])[C:28]([F:35])([F:34])[F:27])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: O=C(O)C(O)C(F)(F)F
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1)C(O)C(F)(F)F

Procedure:
The title compound, light yellow solid (91 mg, 81%), MS (ISP) m/z=453.3 [(M+H)+], mp 206° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and (RS)-3,3,3-trifluoro-2-hydroxy-propionic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](NC2N=CN=C(NC(C3CC3)=O)C=2)[C:5](=[O:21])[N:4]2[C:22]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)(C)[NH:23][C:24](=[O:25])[C:3]=12.[Br:34]C1C=C(F)C(C(OCC)=O)=NC=1>[Fe](Cl)(Cl)Cl.C(#N)C>[Br:34][C:6]1[C:5](=[O:21])[N:4]2[CH:22]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)[NH:23][C:24](=[O:25])[C:3]2=[C:2]([Cl:1])[CH:7]=1
Reactant: CCOC(=O)c1ncc(Br)cc1F
Reactant: CC1(c2cccc(F)c2)NC(=O)c2c(Cl)cc(Nc3cc(NC(=O)C4CC4)ncn3)c(=O)n21
Agent: Cl[Fe](Cl)Cl
Solvent: CC#N
Product: O=C1NC(c2cccc(F)c2)n2c1c(Cl)cc(Br)c2=O
Temperature: 90 °C

Procedure:
A mixture of 5-bromo-3-chloro-6-oxo-1H-pyridine-2-carboxamide (1, 0.4 g, 1.59 mmol), 3-fluorobenzaldehyde (2, 0.69 g, 5.57 mmol), acetonitrile (15 mL) and iron(III) chloride (1.81 g, 11.13 mmol) in a sealed tube was heated at 90° C. for 16 h. Once TLC showed consumption of the starting material, the mixture was cooled and filtered through a celite bed. The celite was washed with acetonitrile and the filtrate was concentrated under vacuum. The crude residue was subjected to flash column chromatography eluting with 35% ethyl acetate in hexane. The desired fractions were collected, concentrated and dried under high vacuum to afford 6-bromo-8-chloro-3-(3-fluorophenyl)-2,3-dihydroimidazo[1,5-c]pyridine-1,5-dione (3) as a yellow solid. Yield: 0.35 g, 61%; MS (ESI) m/z 357.20 [M+1]+.
Reaction SMILES: ClC1CCCC([C@@H](CC(OC(OCC)C[C@H](C2CCCC(Cl)C2)CC)OCC)CC)C1.C(N(C[C:38]1[C:39](=[O:51])[CH2:40][C@@H:41]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])[CH:42]=1)CC)C>CCCCCC.O1CCCC1>[O:43]([CH:41]1[CH2:40][C:39](=[O:51])[CH2:38][CH2:42]1)[Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45]
Reactant: CCN(CC)CC1=C[C@H](O[Si](C)(C)C(C)(C)C)CC1=O
Agent: CCOC(C[C@@H](CC)C1CCCC(Cl)C1)OC(C[C@@H](CC)C1CCCC(Cl)C1)OCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC1CCC(=O)C1
Temperature: -45 °C
Reaction time: 0.08 h

Procedure:
Lithium wire (1% Na) (68 mg, 9.7 mg-atom) was added in 0.3-cm pieces to a stirred, cooled (0° C. internal) solution of 4,4′-di-t-butylbiphenyl (2.66 g, 10.0 mmol) and 5 mg of 2,2′-bipyridyl in 20 mL of dry tetrahydrofuran (THF) under argon. The mixture was titrated to a red endpoint with n-BuLi (2.5 M in hexane, 0.12 mL) and stirred for 15 hours to form a deep blue-green solution of lithium 4,4′-di-t-butylbiphenyl. The solution was cooled to −45° C. (internal), and a solution of (R)-1-(3-chloro-1-cyclohexyl)propyl(1-ethoxyethyl)ether (1.12 g, 4.5 mmol) in 9.0 mL of dry hexane was added dropwise. After 5 minutes, a solution of 0.25 M lithium (2-thienyl)cyanocuprate in THF (20 mL) was added dropwise. After 10 minutes, a solution of (R)-2-((diethylamino)methyl)-4-(t-butyldimethylsiloxy)-2-cyclopentenone (1.12 g, 3.77 mmol) in 20 mL of dry THF was added dropwise. The solution was allowed to warm to −20° C. and was quenched into a rapidly stirred mixture of diethyl ether and saturated aqueous NH4Cl. After four hours, the layers were separated and the aqueous solution was extracted with ethyl acetate. The combined organic solutions were dried (MgSO4), filtered and concentrated and the crude product was purified by chromatography on silica to give 0.95 g (57.5%) of (3R,4R)-2-methylene-3-[(3′R)-3′-(1-ethoxy)ethoxy)-3′-cyclohexyl-1′-propyl]-4-(t-butyldimethylsiloxy)cyclopentan-1-one. NMR (CDCl3) δ0.06 (s, 3H), 0.08 (s, 3H), 0.87 (s, 9H), 0.8-1.9 (m, 15H), 1.17 and 1.20 (2 overlapping t, J=7, 3H), 1.29 and 1.30 (2 overlapping d, J=5.3, 3H), 2.30 (A of ABX, Jab=18.0, Jax=4.6, 1H), 2.62 (B of ABX, Jab=17.8, Jbx=5.8, 1H), 2.65 (br s, 1H), 3.30 (br q, J=4, 1H), 3.55 (m, J=6, 2H), 4.12 (pent, J=5.2, 1H), 4.68 (2 overlapping q, J=5.2, 1H), 5.29, 5.32 (both s, 2:3 ratio, total 1H), 6.08 (s, 1H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13](B1OC(C)(C)C(C)(C)O1)=[CH:12][CH:11]=2.[OH:26][NH:27][C:28](=[O:45])[C@:29]([CH3:44])([S:40]([CH3:43])(=[O:42])=[O:41])[CH2:30][CH2:31][N:32]1[CH:37]=[CH:36][C:35](I)=[CH:34][C:33]1=[O:39].O>O1CCOCC1.[Pd]>[OH:26][NH:27][C:28](=[O:45])[C@:29]([CH3:44])([S:40]([CH3:43])(=[O:42])=[O:41])[CH2:30][CH2:31][N:32]1[CH:37]=[CH:36][C:35]([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[NH:9][C:8]([CH3:7])=[CH:16]3)=[CH:34][C:33]1=[O:39]
Reactant: Cc1cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2[nH]1
Reactant: C[C@@](CCn1ccc(I)cc1=O)(C(=O)NO)S(C)(=O)=O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc2cc(-c3ccn(CC[C@](C)(C(=O)NO)S(C)(=O)=O)c(=O)c3)ccc2[nH]1
Temperature: 80 °C
Yield: 21.4 %

Procedure:
Pd EnCat™ (93 mg, 0.03 mmol) was added to a mixture of potassium carbonate (115 mg, 0.83 mmol), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (86 mg, 0.33 mmol), and (2R)-N-hydroxy-4-(4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (115 mg, 0.28 mmol) in dioxane:water (2.5 mL, 5:1 mixture). The reaction mixture was heated overnight at 80° C. The reaction was cooled to ambient temperature, filtered through a nylon filter and concentrated. The material was dissolved in a minimal amount of DMSO and loaded onto a 13g c18 column. The gradient was run from 25-45% acetonitrile in water. The desired material was concentrated yielding 25 mg (22%) of a light brown solid. LCMS m/z 418.5 (M+1) 1H NMR (400 MHz, DMSO-d6) δ ppm 1.58 (s, 3 H) 2.13-2.24 (m, 1 H) 2.32-2.46 (m, 1 H) 2.39 (s, 3 H) 3.12 (s, 3 H) 3.69-3.78 (m, 1 H) 4.06-4.16 (m, 1 H) 6.20 (s, 1 H) 6.65 (d, J=1.95 Hz, 1 H) 6.70 (dd, J=7.22, 1.95 Hz, 1 H) 7.31-7.39 (m, 2 H) 7.70 (d, J=7.22 Hz, 1 H) 7.79 (s, 1 H) 9.25 (br. s., 1 H) 11.11 (br. s., 1 H) 11.23 (br. s., 1 H)
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][N:7]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)[CH2:8][C:9]1[O:10][C:11]2[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:12]=2[CH:13]=1>N1C=CC=CC=1>[CH3:6][N:7]([CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([NH:27][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:25][CH:26]=1)[CH2:8][C:9]1[O:10][C:11]2[CH:17]=[C:16]([NH:18][S:2]([CH3:1])(=[O:4])=[O:3])[CH:15]=[CH:14][C:12]=2[CH:13]=1
Reactant: CN(CCc1ccc(N)cc1)Cc1cc2ccc(N)cc2o1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CN(CCc1ccc(NS(C)(=O)=O)cc1)Cc1cc2ccc(NS(C)(=O)=O)cc2o1

Procedure:
Methanesulphonyl chloride (0.21 g, 1.8 mmole) and N-methyl-N-(6-aminobenzofur-2-ylmethyl)-4-aminophenethylamine (see Preparation 2--0.24 g, 0.82 mmole) in pyridine (3 ml) when reacted together under conditions similar to those of Example 2, gave the title compound as an oil, yield 0.18 g.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[F:12].[NH2:13][CH2:14][C:15]([O-:17])=[O:16].[Na+:18]>CN(C=O)C.O>[Na+:18].[Br:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH:13][CH2:14][C:15]([O-:17])=[O:16])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(F)c(Br)cc1F
Reactant: NCC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C([O-])CNc1cc(Br)c(F)cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 8 h
Yield: 32.2 %

Procedure:
To a stirred solution of 1-bromo-2,5-difluoro-4-nitrobenzene (1.100 g, 4.622 mmol, as prepared above) in DMF (11.0 mL) at 70° C., was added, dropwise, a solution of sodium glycinate (0.451 g, 4.65 mmol, Aldrich, used as received) in water (5.0 mL). The resulting solution was stirred overnight at 70° C. The solution was cooled to room temperature and the bright orange solid was filtered, washed with cold acetone (10 mL) and dried under vacuum to give 0.469 g (35%) of the title compound as a bright orange powder; 1H NMR (DMSO-d6): δ 3.458 (d, 2H, J=3.9 Hz), 7.148 (d, 1H, J=6.0 Hz), 7.944 (d, 1H, J =9.3 Hz), 8.740 (s, 1H).
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:12]1=[O:26])C.[OH-].[Na+]>>[O:26]=[C:12]1[N:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:27])=[O:3])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)CCCCCCn1c(=O)n(-c2ccccc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCCCn1c(=O)n(-c2ccccc2)c2ccccc21

Procedure:
The product is produced as described in example 22 from 16 g. of 7-(2-oxo-3-phenyl-benzimidazolin-1-yl)-enanthic acid ethyl ester and 2.1 g. of NaOH.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[OH:21])[CH:6]=1.[BH4-].[Li+]>O1CCCC1>[C:25]([O:24][C:22](=[O:23])[N:12]([CH2:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([CH2:4][CH2:3][OH:2])[CH:6]=1)[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21])([CH3:26])([CH3:28])[CH3:27]
Reactant: COC(=O)Cc1cccc(CN(CCc2ccccc2O)C(=O)OC(C)(C)C)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CCc1ccccc1O)Cc1cccc(CCO)c1
Temperature: 60 °C
Yield: 96 %

Procedure:
A solution of [3-({tert-butoxycarbonyl-[2-(2-hydroxy-phenyl)-ethyl]-amino}-methyl)-phenyl]-acetic acid methyl ester (560 mg) in anhydrous tetrahydrofuran (20 mL) was treated with lithium borohydride (62 mg) and the mixture was heated at 60° C. for 5 hours under nitrogen. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and saturated aqueous brine, the organic layer was separated, dried and the solvent evaporated under reduced pressure. The residue was purified on silica, eluting with 40% ethyl acetate in isohexane to yield the sub-titled compound (500 mg).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:8]([C:12]([F:15])([F:14])[F:13])[O:9]2)=[CH:4][CH:3]=1.F[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][C:23]=1[F:31].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:31][C:23]1[CH:24]=[C:25]([N+:28]([O-:30])=[O:29])[CH:26]=[CH:27][C:22]=1[O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:8]([C:12]([F:15])([F:13])[F:14])[O:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1=Cc2ccc(O)cc2OC1C(F)(F)F
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2ccc(Oc3ccc([N+](=O)[O-])cc3F)cc2OC1C(F)(F)F
Temperature: 90 °C
Yield: 83.9 %

Procedure:
Ethyl 7-hydroxy-2-(trifluoromethyl)-2H-chromene-3-carboxylate from Example 1a, Step 1 (0.50 g, 1.73 mmole), 1,2-difluoro-4-nitrobenzene (0.30 g, 1.91 mmole), and cesium carbonate (0.62 g, 1.91 mmole) were mixed in DMF (2 mL). Copper (I) trifluoromethanesulfonate benzene complex (5 mg) was added to above mixture. The mixture was heated to 90° C. for 6 hour. LCMS indicated product formation and there was no starting material present. The reaction was quenched with sodium bicarbonate (sat.) and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous MgSO4. The filtrate was evaporated and dried in vacuo to afford a brown oil, which was purified by Biotage silica chromatography with 20% ethyl acetate in hexane to provide a light yellow oil (0.62 g, 84%): LCMS m/z 449.65 (M+Na). 1NMR (CDCl3/400 MHz) 8.05 (m, 2H), 7.70 (s, 1H), 7.24 (m, 1H), 7.17 (dd, 1H, J=8.8, 8 Hz), 6.66 (m, 1H), 6 65 (s, 1H), 5.69 (q, 1H, J=6.8 Hz), 4.30 (q, 2H, J=7.2 Hz), 1.33 (t, 3H, J=7.2 Hz).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@@H:4]([C@H:6]([C@@H:8]([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9])[OH:7])[OH:5].[C:14]([CH2:17][N:18]1[C:22](=[O:23])[C:21](=[CH:24][CH:25]=[CH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[S:20][C:19]1=[S:34])([OH:16])=[O:15].S1CC(=O)NC1=S.CO>O>[CH3:1][NH:2][CH2:3][C@@H:4]([C@H:6]([C@@H:8]([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9])[OH:7])[OH:5].[C:14]([CH2:17][N:18]1[C:22](=[O:23])/[C:21](=[CH:24]\[CH:25]=[CH:26]\[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])/[S:20][C:19]1=[S:34])([OH:16])=[O:15]
Reactant: Cc1ccccc1C=CC=C1SC(=S)N(CC(=O)O)C1=O
Agent: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=C1CSC(=S)N1
Solvent: CO
Solvent: O
Product: Cc1ccccc1/C=C/C=C1/SC(=S)N(CC(=O)O)C1=O
Temperature: 25 °C
Yield: 72.5 %

Procedure:
To a solution of 2.001 g of N-methyl-D-glucamine in 20 ml of water was added 3.194 g of 3-carboxymethyl-5-(2-methylcinnamylidene)rhodanine [prepared as described in Example 1 (35)], and the mixture was heated to dissolve the rhodanine derivative, and then 40 ml of methanol was added to the solution at the same temperature. The mixture was cooled to room temperature and the precipitated crystals were filtered. The resulting crystals were washed with 5 ml of mixture of water and methanol (1:2), and 5 ml of methanol, and dried under reduced pressure to obtain 3.73 g of the titled compound.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]4[O:22][C:21]([NH:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[N:20][N:19]=4)[CH:16]=3)[N:11]([S:29]([C:32]3[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=3)(=[O:31])=[O:30])[CH:10]=2)O1.Br[C:41]1[N:46]=[C:45]([CH:47]2[CH2:49][CH2:48]2)[CH:44]=[CH:43][N:42]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>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]>[CH:47]1([C:45]2[CH:44]=[CH:43][N:42]=[C:41]([C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:18]5[O:22][C:21]([NH:23][CH2:24][C:25]([F:27])([F:26])[F:28])=[N:20][N:19]=5)[CH:16]=4)[N:11]([S:29]([C:32]4[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=4)(=[O:31])=[O:30])[CH:10]=3)[N:46]=2)[CH2:49][CH2:48]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(-c4nnc(NCC(F)(F)F)o4)ccc32)cc1
Reactant: Brc1nccc(C2CC2)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nccc(C4CC4)n3)c3cc(-c4nnc(NCC(F)(F)F)o4)ccc32)cc1
Temperature: 100 °C

Procedure:
To a 5 mL glass microwave tube containing 5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indol-5-yl)-N-(2,2,2-trifluoroethyl)-1,3,4-oxadiazol-2-amine (180 mg, 0.320 mmol) was added 2-bromo-4-cyclopropylpyrimidine (73.3 mg, 0.368 mmol) (CombiPhos Catalysts Inc.), potassium phosphate (204 mg, 0.960 mmol) (Sigma-Aldrich), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (9.16 mg, 0.019 mmol) (Strem), and Pd2(dba)3 (8.79 mg, 9.60 μmol) (Strem). The tube was purged with argon, the solids were treated with dioxane (2.0 mL) and water (0.200 mL), the tube was sealed, and the contents were heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 100° C. for 20 min. The mixture was treated with H2O and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by flash chromatography (20-100% EtOAc in Hex) affording 5-(3-(4-cyclopropylpyrimidin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(2,2,2-trifluoroethyl)-1,3,4-oxadiazol-2-amine as an amorphous beige solid. MS (ESI, pos. ion) m/z: 554.9 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.03 (s, 1H), 8.63-8.71 (m, 2H), 8.53 (s, 1H), 8.16 (d, J=8.8 Hz, 1H), 8.04 (m, J=8.4 Hz, 2H), 7.92 (d, J=7.2 Hz, 1H), 7.43 (m, J=8.2 Hz, 2H), 7.37 (d, J=5.1 Hz, 1H), 4.06-4.21 (m, 2H), 2.33 (s, 3H), 2.16-2.27 (m, 1H), 1.24 (br. s., 2H), 1.18 (d, J=6.7 Hz, 2H).
Reaction SMILES: Br[C:2]1[C:3]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:4][N:5]2[C:10]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)=[N:9][C:8]([S:17][CH3:18])=[N:7][C:6]=12.C(=O)([O-])[O-].[Na+].[Na+].[F:31][C:32]1[CH:37]=[C:36](B(O)O)[CH:35]=[CH:34][N:33]=1.C(OCC)(=O)C>O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:12]1([NH:11][C:10]2[N:5]3[N:4]=[C:3]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:2]([C:36]4[CH:35]=[CH:34][N:33]=[C:32]([F:31])[CH:37]=4)=[C:6]3[N:7]=[C:8]([S:17][CH3:18])[N:9]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: OB(O)c1ccnc(F)c1
Reactant: CSc1nc(NC2CCCC2)n2nc(-c3ccccc3)c(Br)c2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CSc1nc(NC2CCCC2)n2nc(-c3ccccc3)c(-c3ccnc(F)c3)c2n1
Temperature: 100 °C
Yield: 33.3 %

Procedure:
8—Bromo-N-cyclopentyl-2-(methylsulfanyl)-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4-amine (0.20 g, 0.50 mmol) was dissolved in N,N-dimthylformamide. To this solution was added dichlorobis(triphenylphosphine)palladium (II] (70 mg, 0.2 equiv), anhydrous sodium carbonate (105 mg, 2 equiv), 2-fluoro-4-pyridinylboronic acid (91 mg, 1.3 equiv) and a few drops of water. The reaction mixture was heated at 100° C. for 12 hours, at which time no starting material remained in the reaction mixture. Ethyl acetate and water were added to the reaction mixture. The phases were separated and the organic phase was washed with water, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (ethyl acetate:hexane 1:1) gave 70 mg (33%) of N-cyclopentyl-8-(2-fluoro-4pyridinyl)-2-(methylsulfanyl)-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4-amine as a white foam. 1H-NMR (CDCl3): δ 8.10 (d, 1H), 7.60 (m, 2H), 7.52 (m, 3H), 7.37 (m, 1H), 7.29 (s, 1H), 6.55 (d, 1H), 4.63 (m, 1H), 2.66 (s, 3H), 2.3–2.1 (m, 2H), 2.0–1.6 (m, 6H);F-NMR (CDCl3): δ −69.01; MS m/z 421 (M+1).