Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C@H:2]1[C@H:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][NH:4][CH2:3]1.CCN(C(C)C)C(C)C.CS(O[C@H:29]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=2)[C:30]1=[O:42])(=O)=O>C(#N)C>[F:1][C@H:2]1[C@H:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C@@H:29]2[CH2:33][CH2:32][N:31]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)[C:30]2=[O:42])[CH2:3]1
Reactant: Cc1ccc(CN2CC[C@H](OS(C)(=O)=O)C2=O)cc1
Reactant: Oc1ccc([C@@H]2CCNC[C@H]2F)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(CN2CC[C@@H](N3CC[C@@H](c4ccc(O)cc4)[C@H](F)C3)C2=O)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 66.8 %

Procedure:
A solution of 4-((3S,4S)-3-fluoropiperidin-4-yl)phenol (7.10 g, 36.4 mmol, intermediate F) and DIEA (16 mL, 92 mmol) in 100 mL of acetonitrile was heated to 80° C. This solution was treated dropwise with a solution of (S)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl methanesulfonate (10.5 g, 37.0 mmol, intermediate J) in acetonitrile (80 mL) over a period of 4 hours. After the addition was completed, the reaction mixture was stirred at 80° C. for 16 h. The reaction mixture was then allowed to cool to rt, and the volume was reduced by rotary evaporation to 80 mL. A satd. NH4Cl solution (100 mL) was then added, and the layers were separated. The aqueous layer was extracted with DCM (2×100 mL) and the organic layers were combined, dried over Na2SO4 and concentrated in vacuo to give a crude product. The crude product was purified by silica gel chromatography (750 g of silica gel) eluting with a gradient of 0% to 20% of solvent B in solvent A, where Solvent B=20% methanol/DCM and solvent A=DCM. Fractions containing the product were combined. Evaporation of the solvents gave 9.3 grams of the desired product with 97% purity by LC/MS analysis (conditions B). The product thus obtained (8.5 g) was slurried in acetone:hexane (1:5, 200 mL) and the solid product was isolated by filtration and air dried. Careful SFC analysis showed the presence of a 2.1% impurity in the product. Using a Cell4 0.46×25 cm 5 μm column and eluting with 45% methanol in CO2 at 3 mL/min, the desired product eluted at 3.800 minutes and the undesired impurity eluted at 4.848 minutes. The product was then further purified by SFC Chromatography using a Cell4 3×25 cm 5 μm column at 150 mL/min injecting 1.5 mL of a 80 mg/mL solution. Concentration of the active fractions provided 7.82 grams (20.4 mmol, 56%) of >99.7% pure example 1 as a white powder. LC/MS (Conditions B), RT=2.512 min, (M+H)+=383.3. 19F NMR δ −182.83. 1H NMR (400 MHz, chloroform-d) δ 7.20-7.08 (m, 6H), 6.98-6.78 (m, 2H), 5.68 (s, 1H), 4.77-4.54 (m, 1H), 4.53-4.34 (m, 2H), 3.68 (t, J=8.8 Hz, 1H), 3.41-3.29 (m, 1H), 3.28-3.09 (m, 2H), 2.82 (d, J=10.8 Hz, 1H), 2.74-2.54 (m, 2H), 2.47 (td, J=9.9, 3.6 Hz, 1H), 2.34 (s, 3H), 2.19-1.94 (m, 2H), 1.92-1.80 (m, 2H). 13C NMR (101 MHz, chloroform-d) δ 172.4, 154.9, 137.5, 133.3, 133.0, 129.5, 128.7, 128.3, 115.5, 92.6, 90.8, 65.0, 54.4, 54.2, 48.7, 48.0, 47.8, 46.8, 43.7, 31.7, 31.6, 21.1, 19.6.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:14](B2OC(C)(C)C(C)(C)O2)=[CH:13][C:3]=1[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].Br[C:27]1[CH:28]=[C:29]([C:34]([F:37])=[CH:35][CH:36]=1)[C:30]([O:32][CH3:33])=[O:31].C(=O)([O-])[O-].[K+].[K+]>C(COC)OC>[C:8]([O:7][C:6]([NH:5][CH2:4][C:3]1[CH:13]=[C:14]([C:27]2[CH:28]=[C:29]([C:34]([F:37])=[CH:35][CH:36]=2)[C:30]([O:32][CH3:33])=[O:31])[CH:15]=[CH:16][C:2]=1[OH:1])=[O:12])([CH3:9])([CH3:10])[CH3:11]
Reactant: COC(=O)c1cc(Br)ccc1F
Reactant: CC(C)(C)OC(=O)NCc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)c1cc(-c2ccc(O)c(CNC(=O)OC(C)(C)C)c2)ccc1F
Temperature: 80 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
501 mg of t-butyl N-[2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]carbamate, 370 mg of methyl 3-bromo-6-fluorobenzoate, 80 mg of dichlorobistriphenyl phosphinoferrocene palladium and 500 mg of potassium carbonate were dissolved in 8 ml of dimethoxyethane and stirred overnight at 80° C. in a nitrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was evaporated. The residue was purified by silica gel column, to give 391 mg of the title compound in the 4:1 hexane-ethyl acetate fraction.
Reaction SMILES: [CH3:1][S:2][S:3][CH2:4][CH2:5][C:6]([OH:8])=O.ClC(OCC(C)C)=O.CN1CCOCC1.[NH2:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[N:31]=[CH:30][N:29]=[C:28]2[NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Br:42])[CH:37]=1>O1CCCC1.C(Cl)Cl.CO>[Br:42][C:38]1[CH:37]=[C:36]([NH:35][C:28]2[C:27]3[C:32](=[CH:33][CH:34]=[C:25]([NH:24][C:6](=[O:8])[CH2:5][CH2:4][S:3][S:2][CH3:1])[CH:26]=3)[N:31]=[CH:30][N:29]=2)[CH:41]=[CH:40][CH:39]=1
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reactant: CSSCCC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CO
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CSSCCC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 20 %

Procedure:
A solution of 1.5 grams of disulfide acid from Example 70 in 30 mL of tetrahydrofuran was cooled in an ice bath. A 1.28 mL portion of isobutyl chloroformate followed by a 1.08 mL portion of N-methyl morpholine were added. After stirring for 5 minutes at 0° C., 0.77 grams of 6-amino 4-(3-bromoanilino)quinazoline was added. The mixture was stirred for 3 hours at 0° C. and then allowed to warm to room temperature. The reaction was quenched with water and the tetrahydrofuran was evaporated under vacuum. Addition of methylene chloride followed by washing the methylene chloride layer with water and evaporation of the solvent gave a crude product. Silica gel chromatography with methanol in methylene chloride gave 0.22 grams light yellow solid of product.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([S:4]([NH:6][C:7]1(/[C:10](=[N:12]/[OH:13])/[NH2:11])[CH2:9][CH2:8]1)=[O:5])[CH3:3].[CH2:15](OC(OCC)OCC)C>CC(O)=O>[O:13]1[CH:15]=[N:11][C:10]([C:7]2([NH:6][S:4]([C:2]([CH3:14])([CH3:1])[CH3:3])=[O:5])[CH2:9][CH2:8]2)=[N:12]1
Reactant: CC(C)(C)S(=O)NC1(/C(N)=N/O)CC1
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: CC(C)(C)S(=O)NC1(c2ncon2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.6 %

Procedure:
(Z)-1-(1,1-dimethylethylsulfinamido)-N′-hydroxycyclopropanecarboximidamide (1.0 g, 4.6 mmol) in triethoxymethane (6.0 ml, 36 mmol) was treated with AcOH (6 ml) at rt. The reaction was allowed to stir at rt for 16 h. The reaction was concentrated to dryness azeotroping with toluene 3×. The resulting yellow oil which was purified on silica gel (Biotage, EtOAc/hexanes gradient (Rf ˜approximately 2 in 70% EtOAc/Hex) to give the expected product N-(1-(1,2,4-oxadiazol-3-yl)cyclopropyl)-2-methylpropane-2-sulfinamide (340 mg, 1.5 mmol, 33% yield) consistent by LCMS and NMR. LC-MS retention time: 1.06 min; m/z (MH+): 230. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 3u C18 2.0×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 1 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. 1H NMR (400 MHz, DMSO-d6) δ 9.44 (s, 1H), 6.36 (s, 1H), 1.57-1.51 (m, 1H), 1.45-1.32 (m, 3H), 1.15 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[CH3:17][N:18]1[C:22]([CH2:23][CH2:24][CH2:25]O)=[CH:21][C:20]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[N:19]1.CN(C)C(N=NC(N(C)C)=O)=O.C(P(CCCC)CCCC)CCC>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:25][CH2:24][CH2:23][C:22]3[N:18]([CH3:17])[N:19]=[C:20]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:35])([F:36])[F:34])=[CH:29][CH:28]=4)[CH:21]=3)[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: Cn1nc(-c2ccc(C(F)(F)F)cc2)cc1CCCO
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)Cn1ccc2ccc(OCCCc3cc(-c4ccc(C(F)(F)F)cc4)nn3C)cc21

Procedure:
In analogy to the procedure described for example 3 c], (6-hydroxy-indol-1-yl)-acetic acid ethyl ester (example 2 e]) was reacted with 3-[2-methyl-5-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-propan-1-ol in the presence of N,N,N′,N′-tetramethyl azodicarboxamide and tributylphosphine to give (6-{3-[2-methyl-5-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-propoxy}-indol-1-yl)-acetic acid ethyl ester as colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[C@H:7]([CH2:18][CH2:19][S:20][CH3:21])[NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[C:23]([O:40][CH:41]([CH2:49][O:50][C:51](=[O:67])[CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])[CH2:42][S:43][CH2:44][CH2:45][C:46](O)=[O:47])(=[O:39])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].O>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:22])[C@H:7]([CH2:18][CH2:19][S:20][CH3:21])[NH:8][C:9](=[O:17])[C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:46](=[O:47])[CH2:45][CH2:44][S:43][CH2:42][CH:41]([O:40][C:23](=[O:39])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:49][O:50][C:51](=[O:67])[CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])=[CH:14][CH:15]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)O)OC(=O)CCCCCCCCCCCCCCC
Reactant: CSCC[C@H](NC(=O)c1ccc(N)cc1)C(=O)OC(C)(C)C
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)Nc1ccc(C(=O)N[C@@H](CCSC)C(=O)OC(C)(C)C)cc1)OC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.8 %

Procedure:
To a solution of 4-aminobenzoylmethionine t-butyl ester (160 mg) in pyridine (5 ml), phospholic trichloride (0.022 ml) was added, followed by stirring at room temperature for 2 hours. After addition of 6,7-bis(palmitoyloxy)- 4-thiaheptanoic acid (164 mg) as obtained in Reference Example 4, the reaction mixture was stirred at room temperature for 24 hours. After addition of water, the reaction mixture was extracted with ethyl acetate. The extract was washed with a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:2) to yield the title compound (163 mg, yield 68%) as a colorless wax-like substance.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:12]O.S(=O)(=O)(O)O>>[Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:12])=[O:6]
Reactant: CO
Reactant: O=C(O)c1cccc(Br)c1F
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(Br)c1F
Temperature: 25 °C
Yield: 90.5 %

Procedure:
To a 100 mL round bottom flask was added 3-bromo-2-fluorobenzoic acid (10.4 g, 47.5 mmol), MeOH (100 mL, 2472 mmol) and sulfuric acid (6 mL, 113 mmol). The reaction mixture was refluxed for 1 hr. After cooling to rt, the MeOH was removed under reduced pressure and the acidic residue was poured into cold water and EtOAc, the layers were separated and the aqueous layer was extracted with EtOAc. The organic layers were combined, washed with brine, dried over NaSO4 and concentrated under reduced pressure to afford 10.02 g of methyl 3-bromo-2-fluorobenzoate. 1H-NMR (400 MHz, DMSO-d6) δ 7.95 (ddd, J=8.1, 6.4, and 1.7 Hz, 1H), 7.82-7.87 (m, 1H), 7.26 (t, J=7.9 Hz, 1H), and 3.86 (s, 3H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:11][O:12][C:13]1[C:18]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=2[O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:22]([NH2:24])=[O:23])=[CH:17][CH:16]=[CH:15][N:14]=1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C1COCC1>[CH3:11][O:12][C:13]1[C:18]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=2[O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:22]([NH:24][S:36]([CH3:35])(=[O:38])=[O:37])=[O:23])=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ncccc1-c1cc(C(N)=O)ccc1Oc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ncccc1-c1cc(C(=O)NS(C)(=O)=O)ccc1Oc1ccccc1
Reaction time: 0.5 h
Yield: 16.2 %

Procedure:
Lithium bis(trimethylsilyl)amide solution in THF (1 M, 0.78 mL, 0.78 mmol) was added to a solution of 3-(2-methoxypyridin-3-yl)-4-phenoxybenzamide (Preparation 19, 0.1 g, 0.31 mmol) in THF (4 mL) at room temperature and the reaction allowed to stir for 30 minutes. Methanesulfonyl chloride (0.088 g, 0.78 mmol) was added and the reaction was stirred at room temperature for 18 hours. The mixture was then partitioned between EtOAc (40 mL) and water (10 mL). The combined organics were dried over sodium sulfate and concentrated in vacuo to afford a brown solid. The crude product was purified by preparative HPLC to afford the title compound as a white solid (20 mg).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[CH2:12][O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:13]([Mg]Br)=[CH2:14]>O1CCCC1.[Cu]I>[CH2:1]([O:8][CH2:9][C@H:10]([OH:11])[CH2:12][CH:13]=[CH2:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C[Mg]Br
Reactant: c1ccc(COC[C@H]2CO2)cc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: C=CC[C@@H](O)COCc1ccccc1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a solution of (2R)-2-[(benzyloxy)methyl]oxirane (167 g, 1.02 mol) in tetrahydrofuran (2 L) was added copper(I) iodide (11.62 g, 61.02 mmol) at room temperature. The mixture was stirred for 5 minutes, then cooled to −78° C. A solution of vinylmagnesium bromide (1 M in tetrahydrofuran, 1.12 L, 1.12 mol) was added drop-wise over 1 hour while the reaction temperature was maintained below −70° C. Upon completion of the addition, the cooling bath was removed and the reaction mixture was left to stir at room temperature for 1 hour, then quenched by slow addition of aqueous ammonium chloride solution (200 mL). After dilution with additional aqueous ammonium chloride solution (1.5 L) and ethyl acetate (1.5 L), the aqueous layer was extracted with ethyl acetate (1 L) and the combined organic layers were washed with aqueous ammonium chloride solution (1.5 L), dried over magnesium sulfate, filtered, and concentrated in vacuo. Three batches of this reaction were carried out and combined to give the product as an orange oil. Yield: 600 g, 3.1 mmol, quantitative. 1H NMR (400 MHz, CDCl3) δ 7.28-7.40 (m, 5H), 5.78-5.90 (m, 1H), 5.08-5.17 (m, 2H), 4.57 (s, 2H), 3.86-3.94 (m, 1H), 3.53 (dd, J=9.6, 3.3 Hz, 1H), 3.39 (dd, J=9.6, 7.4 Hz, 1H), 2.26-2.34 (m, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N+:7]([C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1F)([O-:9])=[O:8].C(=O)(O)[O-].[Na+].[CH3:25][N:26]1[C:30]([OH:31])=[C:29]([C:32](=[O:41])[C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=2[Cl:40])[C:28]([CH3:42])=[N:27]1>C(C(C)=O)C.C(Cl)Cl>[CH3:25][N:26]1[C:30]([O:31][C:11]2[CH:12]=[CH:13][C:14]([N+:16]([O-:18])=[O:17])=[CH:15][C:10]=2[N+:7]([O-:9])=[O:8])=[C:29]([C:32](=[O:41])[C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=2[Cl:40])[C:28]([CH3:42])=[N:27]1
Reactant: Cc1nn(C)c(O)c1C(=O)c1ccc(Cl)cc1Cl
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: ClCCl
Product: Cc1nn(C)c(Oc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])c1C(=O)c1ccc(Cl)cc1Cl
Reaction time: 3 h
Yield: 70.1 %

Procedure:
In a four necked flask, 1.43 g of 1,3-dimethyl-4-(2,4-dichlorobenzoyl)-5-hydroxypyrazole was dissolved in 15 ml of methyl ethyl ketone and 1.38 g of anhydrous potassium carbonate was added to the solution and 0.93 g of 2,4-dinitrophenylfluoride was added dropwise to the mixture under stirring. After the addition, the reaction was carried out for 3 hours under refluxing. The reaction mixture was filtered and methyl ethyl ketone was distilled off to obtain the precipitate of the reaction product. The precipitate was dissolved in methylene chloride and the solution was mixed with a saturated aqueous solution of sodium bicarbonate. The organic phase was separated and methylene chloride was distilled off to obtain the solid product. The solid product was washed with benzene to obtain 1.58 g of 1,3-dimethyl-4-(2,4-dichlorobenzoyl)-5-(2,4-dinitrophenoxy) pyrazole having a melting point of 190° to 192° C.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([C@@H:10]3[O:22][C@H:21]([CH2:23][O:24]C(=O)C)[C@@H:16]([O:17]C(=O)C)[C@H:11]3[O:12]C(=O)C)[C:7]([Cl:9])=[N:8][C:4]=2[CH:3]=1>N.CO>[NH2:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([C@@H:10]3[O:22][C@H:21]([CH2:23][OH:24])[C@@H:16]([OH:17])[C@H:11]3[OH:12])[C:7]([Cl:9])=[N:8][C:4]=2[CH:3]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(Cl)nc3cc(N)ccc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: N
Solvent: CO
Product: Nc1ccc2c(c1)nc(Cl)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
A solution of 0.363 g (0.852 mmole) of 76 in 10 mL of NH3 /MeOH was stirred in a pressure bottle at room temperature for 5 hr. The reaction mixture was evaporated and coevaporated with MeOH (3×, bath temperature<40° C.). The residue was recrystallized from MeOH/Et2O to give 0.203 g (2 crops, 79%) of 78 as beige crystals. MP ~154° C. (dec.). MS (EI) m/e 299.0675 (10%, M+ =299.0673). 1H NMR (DMSO-d6): d 7.56 (d, 1, 7-H, J7-6 =8.5 Hz), 6.73 (d, 1, 4-H, J4-6 =2.0 Hz), 6.57 (dd, 1, 6-H), 5.77 (d, 1, 1'-H, J1'-2' =7 5 Hz), 5.39 (d, 1, 2'-OH, J2'-2'OH =6.5 Hz), 5.18 (d, 1, 3'-OH, J3'-3'OH =4.5 Hz), 5.11 (t, 1, 5'-OH, J5'-5'OH =5.0 Hz), 4.90 (s, 2, 5-NH2), 4.44 (m, 1, 2'-H, J2'-3' =6.0 Hz), 4.09 (m, 1, 3'-H, J3'-4' =2.5 Hz), 3.91 (m, 1, 4'-H, J4'-5' =3.5 Hz), 3.65 ("t", 2, 5'-H). 13C NMR (DMSO-d6): d 144.82 (C5), 142.77 (C3a), 138.25 (C2), 125.13 (C7a), 112.67 (C7), 112.22 (C6), 101.83 (C4), 88.81 (C1'), 85.48 (C4'), 70.89 (C2'), 69.61 (C3'), 61.31 (C5').
Reaction SMILES: [CH2:1]([C:5]1[N:10]2[CH:11]([CH3:15])[C:12](=[O:14])[NH:13][C:9]2=[N:8][C:7](=[O:16])[C:6]=1[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]2[N:34](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:33]=[N:32][N:31]=2)=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH3:4]>CC(O)=O.O>[CH2:1]([C:5]1[N:10]2[CH:11]([CH3:15])[C:12](=[O:14])[NH:13][C:9]2=[N:8][C:7](=[O:16])[C:6]=1[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]2[NH:34][N:33]=[N:32][N:31]=2)=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c(=O)nc2n1C(C)C(=O)N2
Solvent: O
Solvent: CC(=O)O
Product: CCCCc1c(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=O)nc2n1C(C)C(=O)N2
Yield: 76.6 %

Procedure:
A solution of 0.2 g of 5-butyl-3-methyl-6-[[2'-[N-triphenylmethyl-(1H-tetrazol-5-yl)]biphenyl-4-yl]methyl]imidazo[1,2-a]pyrimidin-2,7-dione in 6 ml of AcOH and 2 ml of H2O is stirred at room temperature for 5 h, then is evaporated under reduced pressure. The residue is taken up into H2O, adjusted to pH 8 with diluted NaOH and extracted with AcOet. The aqueous phase is acidified to pH 5 with AcOH, to separate a solid which is filtered off and washed with H2O, to obtain 0.1 g of a white solid (80% yield, m.p=192°-194° C. dec.).
Reaction SMILES: [Cl:1][C:2]1[C:12]([Cl:13])=[CH:11][CH:10]=[C:9]([Si:14]([CH3:17])([CH3:16])[CH3:15])[C:3]=1[C:4]([NH:6]CC)=[O:5].[CH3:18][N:19]([CH3:21])N>>[CH3:18][N:19]([CH3:21])[NH:6][C:4](=[O:5])[C:3]1[C:9]([Si:14]([CH3:17])([CH3:16])[CH3:15])=[CH:10][CH:11]=[C:12]([Cl:13])[C:2]=1[Cl:1]
Reactant: CCNC(=O)c1c([Si](C)(C)C)ccc(Cl)c1Cl
Reactant: CN(C)N
Product: CN(C)NC(=O)c1c([Si](C)(C)C)ccc(Cl)c1Cl
Yield: 81 %

Procedure:
The acid prepared in Example 203 was converted to the acid chloride by the procedure of example b. The acid chloride was reacted with 1,1-dimethylhydrazine using General Method E1 to afford the title compound. Purification by recrystallization from ether/hexanes gave 0.62 g of the title compound as off-white crystals in 81% yield. m.p. 144°-145° C.
Reaction SMILES: C(Cl)Cl.C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([C:17]1[CH:18]=[C:19]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)[C:20]([Cl:23])=[CH:21][CH:22]=1)=[O:16])(C)(C)C.FC(F)(F)C(O)=O>O>[NH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([C:17]1[CH:18]=[C:19]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)[C:20]([Cl:23])=[CH:21][CH:22]=1)=[O:16]
Reactant: CC(C)(C)OC(=O)NCCCNC(=O)c1ccc(Cl)c(-c2ccc(-c3ccccc3)cc2)c1
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: NCCCNC(=O)c1ccc(Cl)c(-c2ccc(-c3ccccc3)cc2)c1
Reaction time: 1 h
Yield: 73.5 %

Procedure:
To an oven dried 10 mL round bottom flask was added 5 mL of DCM, 10 mg (0.022 mmol) of 328, 1.5 mL trifluoroacetic acid (TFA), and 50 μL H2O. The solution was stirred for 1 hour and quenched with 1 mL of saturated NaHCO3. The product was taken up in 10 mL of DCM and washed with (3×5 mL) H2O and dried over Na2SO4. The organic solution was rotary evaporated to leave 5.9 mg of a pale yellow oil (73.6% yield). MS (ES+) m/z 365 (M+H); HPLC (214 nm), rt 7.06 min, 99.8%.
Reaction SMILES: Br[C:2]1[C:3]([F:25])=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15]4[N:16]([CH:21]([CH3:23])[CH3:22])[N:17]=[C:18]([CH3:20])[N:19]=4)=[CH:10]3)[C:6]=2[CH:24]=1.[CH:26]([N:29]1[CH2:34][CH2:33][CH:32]([SH:35])[CH2:31][CH2:30]1)([CH3:28])[CH3:27].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C>O1CCOCC1.C(Cl)Cl.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]>[F:25][C:3]1[C:2]([S:35][CH:32]2[CH2:33][CH2:34][N:29]([CH:26]([CH3:28])[CH3:27])[CH2:30][CH2:31]2)=[CH:24][C:6]2[C:7]3[N:11]([CH:10]=[C:9]([C:15]4[N:16]([CH:21]([CH3:23])[CH3:22])[N:17]=[C:18]([CH3:20])[N:19]=4)[N:8]=3)[CH2:12][CH2:13][O:14][C:5]=2[CH:4]=1
Reactant: CC(C)N1CCC(S)CC1
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(Br)c(F)cc2OCC3)n(C(C)C)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc(-c2cn3c(n2)-c2cc(SC4CCN(C(C)C)CC4)c(F)cc2OCC3)n(C(C)C)n1
Temperature: 120 °C

Procedure:
A mixture of 9-bromo-8-fluoro-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene from Example 8 (300 mg, 0.738 mmol), 1-isopropylpiperidine-4-thiol (176 mg, 1.107 mmol), Pd2(dba)3 (34 mg, 5 mol %), XantPhos (43 mg, 10 mol %) and DIPEA (0.52 mL, 2.95 mmol) in dioxane (10 mL) was purged with nitrogen and then heated at 120° C. for 1 h using microwave irradiation. The crude reaction mixture was diluted with DCM (100 mL) and purified by column chromatography (Si-PCC, gradient 0-10% MeOH in DCM followed by C18, gradient 20-55% MeOH in 0.5% TFA/H2O). The product containing fractions were combined and concentrated in vacuo and the resulting residue was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 0.5M NH3 in MeOH affording 209 as a white solid (217 mg, 61%). LCMS: RT 3.12 min [M+H]+ 485.1. 1H NMR (DMSO, 400 MHz): δ 8.49 (1H, d, J=8.69 Hz), 7.89 (1H, s), 7.01 (1H, d, J=10.14 Hz), 5.78-5.66 (1H, m), 4.57-4.46 (4H, m), 3.10-3.00 (1H, m), 2.78-2.69 (2H, m), 2.67-2.57 (1H, m), 2.24 (3H, s), 2.15 (2H, bt, J=10.98 Hz), 1.89 (2H, bd, J=12.50 Hz), 1.52-1.39 (8H, m), 0.90 (6H, d, J=6.56 Hz)