Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH:25]([CH3:27])[CH3:26]>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])=[CH:7][N:8]2[CH2:24][CH:25]([CH3:27])[CH3:26])=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)C(F)(F)F
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Cn1cc(C(=O)C(F)(F)F)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 114.9 %

Procedure:
A mixture of 1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone (200 mg, 0.81 mmol) and potassium carbonate (214 mg, 2.02 mmol) in N,N-dimethylformamide (2 mL) was stirred at 25° C. for 30 min. This mixture was then treated with 1-bromo-2-methylpropane (0.13 mL, 1.21 mmol) and heated at 60° C. for 5 h. At this time, the reaction was cooled to 25° C. and concentrated in vacuo. The residue was diluted with ethyl acetate (50 mL) and was washed with a saturated aqueous sodium bicarbonate solution (1×50 mL), water (2×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford 1-(6-chloro-1-isobutyl-1H-indol-3-yl)-2,2,2-trifluoro-ethanone (282.7 mg) as dark yellow solid which was used without further purification or characterization.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:27][C:28]2[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][CH:29]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]1[S:19][CH:20]([CH2:23][C:24]([OH:26])=O)[CH2:21][N:22]=1)=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C[N:40](C)CCCN=C=NCC.[NH4+].ON1C2C=CC=CC=2N=N1.CN(C)C=O>O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:27][C:28]2[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][CH:29]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]1[S:19][CH:20]([CH2:23][C:24]([NH2:40])=[O:26])[CH2:21][N:22]=1)=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: CS(=O)(=O)c1ccc(Oc2cc(OCc3ccccc3)c3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccc(Oc2cc(OCc3ccccc3)c3[nH]c(C4=NCC(CC(N)=O)S4)cc3c2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 60.1 %

Procedure:
A mixture of (2-{7-(benzyloxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (500 mg), 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide hydrochloride (356 mg), 1-hydroxybenzotriazole ammonium salt (283 mg) and N,N-dimethylformamide (20 mL) was stirred at room temperature for 14 hr. Water was added to the reaction solution, and the precipitated solid was collected by filtration, and washed successively with water, ethanol and diethyl ether. The obtained brown solid was recrystallized from ethanol to give the title compound (300 mg, yield 60%) as colorless crystals. melting point 134-135° C. MS 536 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[S:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:17]1[CH2:21][CH2:20][C@@H:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18]1.C1(C2C=CC=CC=2)C=CC=CC=1P(C(C)(C)C)C(C)(C)C.CC(C)([O-])C.[Na+]>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(C)C=CC=CC=1>[C:25]([O:24][C:23](=[O:29])[N:22]([C:2]1[CH:7]=[CH:6][C:5]([S:8](=[O:10])(=[O:9])[NH:11][C:12]2[S:16][N:15]=[CH:14][N:13]=2)=[CH:4][CH:3]=1)[C@@H:19]1[CH2:20][CH2:21][NH:17][CH2:18]1)([CH3:28])([CH3:26])[CH3:27]
Reactant: O=S(=O)(Nc1ncns1)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N(c1ccc(S(=O)(=O)Nc2ncns2)cc1)[C@@H]1CCNC1
Yield: 20.9 %

Procedure:
Prepared using general procedure 74. The reaction was set up with 4-bromo-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (750 mg, 2.34 mmol), (R)-tert-butyl pyrrolidin-3-ylcarbamate (436 mg, 2.34 mmol), Pd2(dba)3 (64 mg, 0.07 mmol), biphenyl-2-yldi-tert-butylphosphine (84 mg, 0.28 mmol), sodium tert-butoxide (630 mg, 6.6 mmol), and toluene (6.0 mL). Purification via silica gel chromatography using 10% MeOH in CH2Cl2 gave the desired pyrrolidine as an orange solid (213 mg, 0.49 mmol, 21% yield). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=326.3; tR=1.39 min.
Reaction SMILES: [ClH:1].[NH:2](C(OC(C)(C)C)=O)[C@H:3]([C:7]([N:9]1[CH2:35][CH2:34][CH2:33][C@H:10]1[C:11]([NH:13][C@H:14]([C:18]([C:20]([C:23]([C:26]([C:29]([F:32])([F:31])[F:30])([F:28])[F:27])([F:25])[F:24])([F:22])[F:21])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])=[O:8])[CH:4]([CH3:6])[CH3:5]>C(OCC)(=O)C>[NH2:2][C@H:3]([C:7]([N:9]1[CH2:35][CH2:34][CH2:33][C@H:10]1[C:11]([NH:13][C@H:14]([C:18]([C:20]([C:23]([C:26]([C:29]([F:32])([F:30])[F:31])([F:27])[F:28])([F:24])[F:25])([F:22])[F:21])=[O:19])[CH:15]([CH3:16])[CH3:17])=[O:12])=[O:8])[CH:4]([CH3:6])[CH3:5].[ClH:1]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Bubble HCl gas into a stirred solution of Boc-Val-Pro-Val-CF2CF2CF2CF3 (245 mg, 0.40 mmol) in ethyl acetate (50 mL) and cool in an ice water bath. Treat with hydrogen chloride gas for 4 minutes. Stir the reaction mixture for 1 hour and warm to ambient temperature. Concentrate the reaction mixture and azeotrope with CCl4. Place under a high vacuum to give the title compound.
Reaction SMILES: [S:1](=NC1C=CC=CC=1)=O.[CH:10]1[CH:15]=[C:14]([F:16])[C:13]([NH2:17])=[C:12]([NH2:18])[CH:11]=1>>[F:16][C:14]1[C:13]2[C:12](=[N:18][S:1][N:17]=2)[CH:11]=[CH:10][CH:15]=1
Reactant: Nc1cccc(F)c1N
Reactant: O=S=Nc1ccccc1
Product: Fc1cccc2nsnc12
Temperature: 110 °C

Procedure:
4-Fluoro-2,1,3-benzothiadiazole was synthesized according to the method in which N-thionylaniline (0.49 g, 3.5 mmol) was added to a solution of the 3-fluoro-O-phenylene diamine (200 mg, 1.6 mmol) in foluen (2 ml) The reaction mixture was heated at 100-120° C. for 4 hr. After the solvent was filtered off, the residue was dissolved in dichloromethane and the solution was washed with 10% HCl solution and water, successively. The organic layer was dried and evaporated to dryness. Purification by chromatography on a silica gel column with chloroform as an eluent gave 4-fluoro-2,1,3-benzothiadiazole as pal yellow oil. Confirmed data of the obtained chemical compound is shown as follows.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:17]=[CH:16][C:7](/[CH:8]=[C:9]2/[C:10](=[O:15])[NH:11][C:12](=[O:14])[S:13]/2)=[CH:6][CH:5]=1)[CH3:2].Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+].C(OC1C=CC(/C=C2/C(=O)N(CCC)C(=O)S/2)=CC=1)C>>[CH2:1]([O:3][C:4]1[CH:17]=[CH:16][C:7](/[CH:8]=[C:9]2/[C:10](=[O:15])[N:11]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:12](=[O:14])[S:13]/2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCOc1ccc(/C=C2\SC(=O)NC2=O)cc1
Agent: CCCN1C(=O)S/C(=C\c2ccc(OCC)cc2)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOc1ccc(/C=C2\SC(=O)N(CC(=O)OC(C)(C)C)C2=O)cc1

Procedure:
The title compound 28g was prepared from compound 2 (249 mg, 1.00 mmol), tert-butyl bromoacetate (215 mg, 1.10 mmol) and potassium carbonate (276 mg, 2.00 mmol) in a manner similar to that described for 28d in 99.0% (360 mg) yield as a pale-yellow solid.
Reaction SMILES: S1[CH2:6][CH:5]=[C:4]([C:7]2[CH:8]=[C:9]([C:13]3[CH:14]=[C:15]4[C:20](=[N:21][CH:22]=3)[N:19]([C:23]([NH2:25])=[O:24])[CH2:18][CH2:17][CH2:16]4)[CH:10]=[N:11][CH:12]=2)[CH2:3][CH2:2]1.O[O:27][S:28]([O-:30])=O.[K+]>O1CCOCC1.O>[O:27]=[S:28]1(=[O:30])[CH2:2][CH:3]=[C:4]([C:7]2[CH:8]=[C:9]([C:13]3[CH:14]=[C:15]4[C:20](=[N:21][CH:22]=3)[N:19]([C:23]([NH2:25])=[O:24])[CH2:18][CH2:17][CH2:16]4)[CH:10]=[N:11][CH:12]=2)[CH2:5][CH2:6]1
Reactant: NC(=O)N1CCCc2cc(-c3cncc(C4=CCSCC4)c3)cnc21
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)N1CCCc2cc(-c3cncc(C4=CCS(=O)(=O)CC4)c3)cnc21
Reaction time: 2 h
Yield: 101.8 %

Procedure:
To 6-[5-(3,6-dihydro-2H-thiopyran-4-yl)-pyridin-3-yl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide (57 mg, 0.16 mmol) in 2 mL of 1:1 dioxane/H2O is added oxone (266 mg, 0.32 mmol). The mixture is stirred for 2 h. The mixture is quenched by addition of sodium sulfite and concentrated. The residue is suspended into MeOH and filtered. The filtrate is concentrated and purified via the Preparative HPLC (5%-70% CH3CN/H2O) to give 62.6 mg of the titled product.
Reaction SMILES: [F:1][C:2]([Si](C)(C)C)([F:4])[F:3].C(=O)([O-])[O-].[Cs+].[Cs+].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[C:23]([CH3:43])([CH3:42])[CH2:24][C:25](=[O:41])[C:26]([NH:28][C:29]1[CH:30]=[CH:31][C:32]2[C:37](=[O:38])[O:36][N:35]=[C:34]([CH3:39])[C:33]=2[CH:40]=1)=[O:27].[SiH4]>CN(C=O)C.C(OCC)(=O)C>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[C:23]([CH3:43])([CH3:42])[CH2:24][C:25]([OH:41])([C:2]([F:4])([F:3])[F:1])[C:26]([NH:28][C:29]1[CH:30]=[CH:31][C:32]2[C:37](=[O:38])[O:36][N:35]=[C:34]([CH3:39])[C:33]=2[CH:40]=1)=[O:27]
Reactant: Cc1noc(=O)c2ccc(NC(=O)C(=O)CC(C)(C)c3cc(F)ccc3Br)cc12
Reactant: C[Si](C)(C)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [SiH4]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1noc(=O)c2ccc(NC(=O)C(O)(CC(C)(C)c3cc(F)ccc3Br)C(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.7 %

Procedure:
0.23 ml (1.25 mmol) of trifluoromethyl(trimethyl)silane and 256 mg (0.79 mmol) of cesium carbonate are added at 0° C. to a solution of 290 mg (0.63 mmol) of 6-[4-(2-bromo-5-fluorophenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-one in 7 ml of DMF. After 24 hours, the same amount of silane and base are added and stirred for another 24 hours at room temperature. The batch is diluted with 150 ml of ethyl acetate, washed with water and saturated NaCl, dried (Na2SO4) and concentrated by evaporation in a vacuum. Purification by column chromatography of the residue on silica gel yields 230 mg of product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:10]2[CH2:11][C:12](=O)[N:13]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[CH3:22])[C:9]2=[N:8][C:7]=1[C:24]([F:27])([F:26])[F:25])=[O:5])[CH3:2].P(Cl)(Cl)([Cl:30])=O>>[CH2:1]([O:3][C:4]([C:6]1[N:10]2[CH:11]=[C:12]([Cl:30])[N:13]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[CH3:22])[C:9]2=[N:8][C:7]=1[C:24]([F:27])([F:26])[F:25])=[O:5])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(C(F)(F)F)nc2n1CC(=O)N2c1c(C)cc(C)cc1C
Product: CCOC(=O)c1c(C(F)(F)F)nc2n(-c3c(C)cc(C)cc3C)c(Cl)cn12

Procedure:
A solution of 6-oxo-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid ethyl ester (3.04 g, 6.137 mol) in phosphorus oxychloride (70 mL) was heated at 150° C. for 72 h. The excess of phosphorus oxychloride was removed under reduced pressure, the residue was dissolved in saturated aqueous solution of sodium bicarbonate (100 mL) and extracted with ethyl acetate (5×50 mL). The combined organic extracts were dried with MgSO4. The solvent was removed under reduced pressure and the crude product was dried under pump vacuum overnight. Yield—1.192 g (38%). LC/MS: tR=2.17 min., MS: [M+H]=400.
Reaction SMILES: Cl[CH2:2][C@@H:3]([C:5]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:7]([F:14])[C:6]=1[F:15])[OH:4].CC(N=NC(C#N)(C)C)(C#N)C>>[F:11][C:10]1[C:5]([C@@H:3]([OH:4])[CH3:2])=[C:6]([F:15])[C:7]([F:14])=[C:8]([F:13])[C:9]=1[F:12]
Reactant: O[C@@H](CCl)c1c(F)c(F)c(F)c(F)c1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: C[C@H](O)c1c(F)c(F)c(F)c(F)c1F
Temperature: 60 °C
Reaction time: 1 h
Yield: 14.1 %

Procedure:
To this was added 2.47 g of (R)-(-)-2-chloro-1-(pentafluorophenyl)ethanol obtained in the method of Example 8, and was stirred for one hour at 60° C. to allow reaction to take place. After addition of 20 mg of AIBN, the reaction mixture was further stirred for three hours at 60° C. The subsequent distillation under reduced pressure gave 0.30 g of (S)-(-)-1-(pentafluorophenyl)ethanol.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](I)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH:11]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)=[CH2:12]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:11][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(I)c1
Reactant: C=Cc1ccncc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: O=[N+]([O-])c1cccc(C=Cc2ccncc2)c1
Temperature: 100 °C
Yield: 66.3 %

Procedure:
A mixture of 3.0 g (20 mmol) of 3-nitroiodobenzene, 3.5 mL (25 mmol) of TEA, 0.045 g (0.20 mmol) of palladium(II) acetate and 2.77 g (25.0 mmol) of 4-vinylpyridine was suspended in 4 mL of dry acetonitrle in a pyrex sealed tube and heated to 100° C. for 48 h. The mixture was cooled to rt and was quenched with 200 mL of 10% hydrochloric acid. The resulting yellow solid was isolated by filtration and partitioned between 250 mL of EtOAc and 250 mL of 1 N aqueous sodium hydroxide. The organic phase was dried over MgSO4 and concentrated to give 3.0 g (66%) of 4-[2-(3-nitrophenyl)ethenyl]-pyridine as a yellow solid: 1H NMR (DMSO-d6): δ 3.0-4.6 (br s, 1H), 7.71-7.78 (m, 2H), 8.07 (d, J=15.8 Hz, 1H), 8.13-8.16 (m, 3H), 8.24 (d, J=8.0 Hz, 1H), 8.56 (s, 1H), 8,84 (d, J=5.7 Hz, 2H); ESI−MS m/z 227 (M+1)+. A portion (1.3 g, 7.1 mmol) of this solid was dissolved in 100 mL of EtOAc, and 0.5 g of 10% palladium on charcoal was added. The mixture was hydrogenated on a Parr apparatus at 40 psi for 1.5 h. Another 0.5 g batch of 10% palladium on charcoal was added and the mixture was subjected to further hydrogenation for 1 h. The palladium catalyst was removed by filtration through a pad of celite, and the filtrate was concentrated to give 1.13 g (100%) of 3-(4-pyridinyl)ethylaniline: 1H NMR (DMSO-d6): δ 2.69 (m, 2H), 2.80 (m, 2H), 4.9 (bs, 2H), 6.33 (d, J=7.7 Hz, 2H), 6.38 (s, 1H), 6.86 (t, J=7.7 Hz, 1H), 7.20 (d, J=5.8 Hz, 2H), 8.41 (d, J=5.8 Hz, 2H). Conversion of 3-[2-(4-pyridinyl)ethyl]-aniline to 4-2-pyridin-4-yl-ethyl)-1H-indole-2,3-dione was accomplished according to Procedure A in 24% overall yield: 1H NMR (DMSO-d6): δ 2.80 (m, 2H), 3.10 (m, 2H), 6.70 (d, J=8.0 Hz, 1H), 6.81 (d, J=8.0 Hz, 1H), 7.24 (m, 2H), 7.40 (t, J=8.0 Hz, 1H), 8.42 (bs, 2H), 11.00 (s, 1H). Conversion of 4-(2-pyridin-4-yl-ethyl)-1H-indole-2,3dione to the title compound was accomplished according to Procedure G in 40% overall yield: 1H NMR (DMSO-d6): δ 2.98 (t, J=7.9 Hz, 2H), 3.30 (m, 2H, underneath water peak), 6.78 (d, J=7.7 Hz, 1H), 6.88 (d, J=7.6 Hz, 1H), 7.17 (t, J=7.6 Hz, 1H), 7.25 (s, 2H), 7.29 (d, J=6.0 Hz, 2H), 7.37 (d, J=8.8 Hz, 2H), 7.66 (d, J=8.8 Hz, 2H), 8.47 (d, J=6.0 Hz, 2H), 11.13 (s, 1H), 12.98 (s, 1H); APCI−MS m/z 420 (M−1)−. Anal. Calcd for C21H19N5O3S.0.15 HCl: C, 55.93, H, 4.43; N, 15.53; S, 7.11. Found C, 56.05, H, 4.36; N, 15.38; S, 7.18.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[S:31][CH:32]=[C:33]([CH:35]=[O:36])[N:34]=3)[C@H:14]2[CH3:37])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:40][Mg+].[Br-]>CCOCC>[F:39][C:2]([F:1])([F:38])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[S:31][CH:32]=[C:33]([CH:35]([OH:36])[CH3:40])[N:34]=3)[C@H:14]2[CH3:37])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1-c1nc(C=O)cs1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: CCOCC
Product: CC(O)c1csc(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1

Procedure:
To a −40° C. solution of 2-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethyl)phenyl]-1,3-thiazole-4-carbaldehyde (Example 133) (43.9 mg, 0.075 mmol) in Et2O (7.5 mL) was added MeMgBr (30 μL of a 3M solution in Et2O, 0.10 mmol). The reaction was monitored closely by TLC and additional MeMgBr was added dropwise until nearly all starting aldehyde was consumed. At this point, the reaction was quenched by pouring it into saturated NH4Cl (15 mL). The mixture was extracted with EtOAc (50 mL) and the organic layer was washed with water and brine (15 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (5 to 50% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[4-(1-hydroxyethyl)-1,3-thiazol-2-yl]-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one. Rf=0.17 (40% EtOAc/hexanes). LCMS=599.1 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.70-7.86 (m, 6H), 7.31-7.32 (m, 1H), 5.53-5.55 (m, 1H), 5.35-5.41 (m, 1H), 5.06 (m, 1H), 4.57-4.62 (m, 1H), 3.88 (m, 1H), 1.61-1.63 (m, 3H), 0.69 (d, J=6.7 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3](Cl)=[O:4].[NH2:17][C:18]1[C:19]([O:29][CH3:30])=[CH:20][CH:21]=[C:22]2[C:27]=1[O:26][CH2:25][CH2:24][C:23]2=[O:28].C(N(CC)CC)C.Cl>ClCCl>[CH3:30][O:29][C:19]1[C:18]([NH:17][C:3](=[O:4])[C:2]([CH3:16])([CH3:1])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[C:27]2[C:22]([C:23](=[O:28])[CH2:24][CH2:25][O:26]2)=[CH:21][CH:20]=1
Reactant: COc1ccc2c(c1N)OCCC2=O
Reactant: CCCCCCCCCCC(C)(C)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCC(C)(C)C(=O)Nc1c(OC)ccc2c1OCCC2=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.7 %

Procedure:
127 mg of 2,2-dimethyldodecanoyl chloride was added to a solution of 98 mg of 8-amino-7-methoxy-4-chromanone and 0.07 ml of triethylamine in 2 ml of dichloromethane, and the mixture was stirred at room temperature for 12 hr. 15 ml of 2N hydrochloric acid was added thereto, and the mixture was extracted with ethyl acetate (25 ml×2). The extract was washed with 25 ml of brine, dried over anhydrous magnesium sulfate, filtered, concentrated and purified by silica gel column chromatography (hexane/ethyl acetate=3:2) to give 198 mg of the intended title compound.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[NH:12][CH:13]([C:21]4[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=4)[CH:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:5]([C:6]=23)=[N:4][NH:3]1.C(O)(=O)C.[NH:33]1[CH2:36][CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CO>[N:33]1([CH2:25][C:24]2[CH:27]=[CH:28][C:21]([CH:13]3[NH:12][C:7]4[C:6]5[C:5](=[N:4][NH:3][C:2](=[O:1])[C:11]=5[CH:10]=[CH:9][CH:8]=4)[CH:14]3[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:22][CH:23]=2)[CH2:36][CH2:35][CH2:34]1
Reactant: C1CNC1
Reactant: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=c1[nH]nc2c3c(cccc13)NC(c1ccc(CN3CCC3)cc1)C2c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.2 %

Procedure:
To a stirred solution of 4-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (150 mg, 0.41 mmol) in dry dichloromethane (20 mL) and MeOH (2 mL) was added acetic acid (120 mg) followed by azetidine (70 mg, 1.23 mmol). After the addition, the mixture was stirred at room temperature overnight. Then sodium triacetoxyborohydride (131 mg, 0.62 mmol) was added at 0° C. After the addition, the mixture was stirred at this temperature for 5 hr. DCM was removed under reduced pressure. The residue was washed with ethyl acetate/methanol (10/1) and filtered. The filtrate was concentrated to give the crude product, which was purified by column chromatography (silica gel, dichloromethane/methanol=100:1 to 15:1) to give the title compound (84 mg, yield 51%) as yellow solid. LC-MS (ESI) m/z: 409 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[C:3]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:4]=2[C:5]([C:13]([F:16])([F:15])[F:14])=[N:6][C:7]=1[C:8](OCC)=[O:9].[NH2:26][CH2:27][C:28]([OH:30])=[O:29].[O-]CC.[Na+].Cl>CCOC(C)=O.O.CN(C=O)C>[OH:1][C:2]1[C:3]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:4]=2[C:5]([C:13]([F:14])([F:15])[F:16])=[N:6][C:7]=1[C:8]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:9]
Reactant: CCOC(=O)c1nc(C(F)(F)F)c2c(-c3ccccc3)noc2c1O
Reactant: NCC(=O)O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CNC(=O)c1nc(C(F)(F)F)c2c(-c3ccccc3)noc2c1O
Temperature: 25 °C
Yield: 57.1 %

Procedure:
Ethyl 7-hydroxy-3-phenyl-4-(trifluoromethyl)isoxazolo[4,5-c]pyridine-6-carboxylate (58 mg, 0.17 mmol), glycine (247 mg, 3.30 mmol), and sodium ethoxide (168 mg, 2.47 mmol) were added to 6 mL of DMF and the mixture was refluxed for 2 h. After the mixture cooled to room temperature, water (50 mL) and EtOAc (50 mL) were added. The mixture was stirred vigorously and 4M hydrochloric acid was added until pH was 3. The aqueous layer was extracted with additional EtOAc and the combined organic layer was dried over MgSO4 and concentrated. The residue was taken up in saturated sodium bicarbonate solution (20 mL) and washed with hexanes and EtOAc. The aqueous layer was acidified to pH 3 with 4M hydrochloric acid and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give a crude solid, which was purified by flash chromatography (0-100% EtOAc/hexanes+2% acetic acid) to give 37 mg of the title compound. MS: (−) m/z 380.19 (M−1).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.Cl.[F:30][CH2:31][CH2:32][NH2:33].C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.CCN(C(C)C)C(C)C>>[F:30][CH2:31][CH2:32][NH:33][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:28])([F:26])[F:27])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12]
Reactant: NCCF
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCCF)ccc21
Yield: 28.4 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-fluoro-ethyl)-amide (31 mg) was prepared by following General Procedure N starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100 mg), 2-fluoroethylamine hydrochloride (24 mg), DPPA (53 uL), and DIEA (43 uL). LC/MS: m/z 454.8. 1H NMR (DMSO-d6, 400 MHz): δ 12.37 (bs, 1H), 8.67 (s, 1H), 8.10 (s, 1H), 7.90 (s, 1H), 7.79 (d, 1H), 7.71 (d, 1H), 7.49 (d, 1H), 7.34 (d, 1H), 4.61 (t, 1H), 4.49 (t, 1H), 3.62 (bs, 3H), 3.58-3.48 (m, 2H).