Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.COCCOC[O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([C:23]([CH2:25][NH:26][CH2:27][C:28]1[CH:29]=[C:30]([C:34]3[CH:39]=[CH:38][C:37]([NH:40][C:41]4[CH:42]=[C:43]([CH:49]=[CH:50][CH:51]=4)[C:44]([O:46][CH2:47][CH3:48])=[O:45])=[CH:36][CH:35]=3)[CH:31]=[CH:32][CH:33]=1)=[O:24])[CH:17]=[CH:16]2>CO.O1CCCC1.C(OCC)(=O)C>[OH:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([C:23]([CH2:25][NH:26][CH2:27][C:28]1[CH:29]=[C:30]([C:34]3[CH:39]=[CH:38][C:37]([NH:40][C:41]4[CH:42]=[C:43]([CH:49]=[CH:50][CH:51]=4)[C:44]([O:46][CH2:47][CH3:48])=[O:45])=[CH:36][CH:35]=3)[CH:31]=[CH:32][CH:33]=1)=[O:24])[CH:17]=[CH:16]2
Reactant: CCOC(=O)c1cccc(Nc2ccc(-c3cccc(CNCC(=O)c4ccc5cc(OCOCCOC)ccc5c4)c3)cc2)c1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(Nc2ccc(-c3cccc(CNCC(=O)c4ccc5cc(O)ccc5c4)c3)cc2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 99.2 %

Procedure:
1 ml of concentrated sulfuric acid is added to a solution of 1.2 g (1.9 mmol) of ethyl 3-[3′-({[6-(2-methoxyethoxymethoxy)naphthalene-2-carbonyl]methylamino}methyl)biphenyl-4-ylamino]benzoate in 10 ml of methanol and 10 ml of tetrahydrofuran. The reaction medium is stirred at room temperature for 6 hours, diluted with ethyl acetate and washed with water. After extraction, the organic phase is dried over magnesium sulfate, filtered and concentrated under vacuum. The residue obtained is purified by chromatography on a column of silica eluted with a 60/40 heptane/ethyl acetate mixture. 1 g of ethyl 3-(3′-{[(6-hydroxynaphthalene-2-carbonyl) methylamino]methyl}biphenyl-4-ylamino)benzoate is obtained in the form of a beige-colored foam, in a yield of 80%.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[NH:22]1[CH2:25][CH:24]([C:26]2[C:27]([O:46][CH3:47])=[C:28]([CH:34]([NH:36][C:37]3[N:45]=[CH:44][N:43]=[C:42]4[C:38]=3[N:39]=[CH:40][NH:41]4)[CH3:35])[CH:29]=[C:30]([Cl:33])[C:31]=2[CH3:32])[CH2:23]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[C:1]([N:22]1[CH2:25][CH:24]([C:26]2[C:27]([O:46][CH3:47])=[C:28]([CH:34]([NH:36][C:37]3[N:45]=[CH:44][N:43]=[C:42]4[C:38]=3[N:39]=[CH:40][NH:41]4)[CH3:35])[CH:29]=[C:30]([Cl:33])[C:31]=2[CH3:32])[CH2:23]1)(=[O:3])[CH3:2].[C:17]([OH:19])([C:16]([F:21])([F:20])[F:15])=[O:18]
Reactant: CC(=O)OC(C)=O
Reactant: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(C)c1C1CNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(C)c1C1CN(C(C)=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Acetic anhydride (2.0 μL, 0.021 mmol) was added to a solution of N-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-9H-purin-6-amine bis(trifluoroacetate) (8.5 mg, 0.014 mmol, from Example 165) and DIPEA (0.015 mL, 0.085 mmol) in methylene chloride (0.5 mL) at 0° C. and then the reaction was stirred at room temperature for 30 minutes. The crude mixture was purified on prep-LCMS (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.05% trifluoroacetic acid, at flow rate of 30 mL/min) to afford the desired product as TFA salt. LCMS calculated for C20H24ClN6O2 (M+H)+: m/z=415.2. found: 415.1
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH2:18][CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:28][N:29]([CH3:39])[C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[CH2:18]([N:13]1[C:12]([C:33]2[CH:34]=[CH:35][C:30]([N:29]([CH3:39])[CH3:28])=[CH:31][CH:32]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)[CH3:19]
Reactant: CCn1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Reactant: CN(C)c1ccc(B(O)O)cc1
Product: CCn1nc2c(c1-c1ccc(N(C)C)cc1)CCNCC2
Yield: 40.4 %

Procedure:
The title compound (57 mg) was prepared according to Example 263 using 205 mg of 2-ethyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 193, Step A) and 115 mg of 4-dimethylaminophenylboronic acid. MS (ESI): exact mass calculated for C17H24N4, 284.20. found, m/z 285.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.87-7.85 (m, 2H), 7.65-7.63 (m, 2H), 4.67 (br s, 2H), 4.06 (q, J=9.0 Hz, 2H), 4.00-3.62 (m, 2H), 3.36 (s, 6H), 3.32-3.29 (m, 2H), 3.18-2.81 (m, 2H), 1.31 (t, J=9.0 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:15]([CH:22]([CH3:24])[CH3:23])[N:16]=[C:17]([CH2:19][O:20][CH3:21])[N:18]=1)[N:7]=3.[CH3:27][C:28]([OH:45])([CH3:44])[CH2:29][N:30]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[N:31]1.C(Cl)Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.COCCOC>[CH:22]([N:15]1[C:14]([C:8]2[N:7]=[C:6]3[C:5]4[CH:25]=[CH:26][C:2]([C:33]5[CH:32]=[N:31][N:30]([CH2:29][C:28]([CH3:44])([OH:45])[CH3:27])[CH:34]=5)=[CH:3][C:4]=4[O:13][CH2:12][CH2:11][N:10]3[CH:9]=2)=[N:18][C:17]([CH2:19][O:20][CH3:21])=[N:16]1)([CH3:24])[CH3:23]
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COCc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)C)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Solvent: O
Product: COCc1nc(-c2cn3c(n2)-c2ccc(-c4cnn(CC(C)(C)O)c4)cc2OCC3)n(C(C)C)n1
Temperature: 140 °C
Yield: 34.9 %

Procedure:
A mixture of 8-bromo-2-(2-isopropyl-5-methoxymethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene (100 mg, 0.24 mmol), 2-methyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propan-2-ol (127 mg, 0.48 mmol), PdCl2(dppf).DCM (9.8 mg, 0.012 mmol), cesium carbonate (234 mg, 0.72 mmol), DME (1.6 mL), water (0.27 mL) and IMS (0.5 mL) was degassed and then heated at 140° C. for 20 min using microwave irradiation. The reaction mixture was partitioned between DCM and water, the aqueous extracted twice with DCM and the combined organic extracts washed with brine then dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to RPHPLC (C18 column, gradient 5 to 95% methanol in water+0.1% HCO2H) to give 302 as a white solid (40 mg, 35%). LCMS: RT=3.77 min, [M+H]+ 478. 1H NMR 400 MHz (DMSO-d) δ: 8.37 (1H, d, J=8.38 Hz), 8.17 (1H, s), 7.94 (2H, d, J=7.28 Hz), 7.40 (1H, dd, J=8.37, 1.80 Hz), 7.28 (1H, d, J=1.77 Hz), 5.89-5.88 (1H, m), 4.74 (1H, s), 4.53 (4H, m), 4.38 (2H, s), 4.04 (2H, s), 3.32 (3H, s), 1.49 (6H, d, J=6.60 Hz), 1.10 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[O:11][CH:12]=[C:13]([CH2:15][OH:16])[N:14]=2)=[C:4]([F:17])[CH:3]=1.CC(C)([O-])C.[Na+].Cl[C:25]1[N:26]=[N:27][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][N:35]2[CH:39]=[CH:38][N:37]=[N:36]2)=[CH:29][CH:30]=1.C(OCC)(=O)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[O:11][CH:12]=[C:13]([CH2:15][O:16][C:25]3[N:26]=[N:27][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][N:35]4[CH:39]=[CH:38][N:37]=[N:36]4)=[CH:29][CH:30]=3)[N:14]=2)=[C:4]([F:17])[CH:3]=1
Reactant: OCc1coc(C=Cc2ccc(Cl)cc2F)n1
Reactant: Clc1ccc(CCCCn2ccnn2)nn1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1cc(Cl)ccc1C=Cc1nc(COc2ccc(CCCCn3ccnn3)nn2)co1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
{2-[2-(4-Chloro-2-fluoro-phenyl)-vinyl]-oxazol-4-yl}-methanol (0.100 g, 0.40 mmol) is dissolved in anhydrous tetrahydrofuran (THF) (3 ml) followed by addition of sodium tert-butoxide (NaOtBu) (0.043 g, 0.43 mmol). After stirring for 15 min at r.t. 3-chloro-6-(4-[1,2,3]triazol-1-yl-butyl)-pyridazine (0.075 g, 0.32 mmol) is added slowly and stirred for further 4 h at 60° C. Ethyl acetate (20 ml) is added, the mixture is washed with saturated ammonium chloride (NH4Cl), dried over MgSO4 and concentrated in vacuo. After flash column chromatography (ethyl acetate/methanol 98:2) 3-{2-[2-(4-chloro-2-fluoro-phenyl)-vinyl]-oxazol-4-ylmethoxy}-6-(4-[1,2,3]triazol-1-yl-butyl)-pyridazine is isolated as a colorless solid. Yield 0.105 g (73%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:16])[CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[CH:5]=[CH:6][CH:7]=1.Cl.[N-:18]=[N+:19]=[N-].[Na+].C([O-])(O)=O.[Na+]>C1COCC1.O>[N:1]([C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:16])[CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[CH:5]=[CH:6][CH:7]=1)=[N+:18]=[N-:19]
Reactant: CCN(CC)CC(=O)Nc1cccc(N)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)CC(=O)Nc1cccc(N=[N+]=[N-])c1
Temperature: 25 °C
Yield: 96.4 %

Procedure:
N-(3-Aminophenyl)-2-(diethylamino)acetamide 5 (0.52 g, 2.35 mmol) was dissolved in THF (6 ml), and cooled in an ice bath. The resulting stirred mixture was treated sequentially with concentrated aqueous HCl (1.08 ml, 12.92 mmol), then with tBuONO (0.61 g, 5.87 mmol). The reaction was stirred in an ice bath for 1.5 hours and after that time NaN3 (0.46 g, 7.05 mmol) was added, followed by careful addition of water, until the reaction ceased to effervesse. The reaction was allowed to warm to room temperature and stirred overnight. The mixture was carefully neutralised with saturated aqueous NaHCO3 solution and THF was evaporated in vacuo. The aqueous solution was extracted three times with EtOAc (75 ml), dried (MgSO4), filtered and the solvent evaporated in vacuo, to give N-(3-azidophenyl)-2-(diethylamino)acetamide 6 as a dark brown oil (0.56 g, 85%) without requiring any further purification; Rf 0.24 [10% MeOH in DCM]; IR (film): 3279.67, 2934.63, 2110.57, 1687.86, 1515.73 cm−1; δH (CDCl3, 400 MHz) 9.43 (1H, s, NH), 7.41 (1H, m, ArH), 7.30-7.23 (2H, m, 2×ArH), 6.76 (1H, td, J1=8.0, J2=2.0 Hz, ArH), 3.13 (2H, s, CH2), 2.64 (4H, m, 2×CH2), 1.08 (6H, m, 2×CH3); δC (CDCl3, 100 MHz) 170.25 (C═O), 140.95 (Ar—C), 139.18 (Ar—C), 130.14 (Ar—CH), 115.60 (Ar—CH), 114.48 (Ar—CH), 109.96 (Ar—CH), 58.11 (CH2), 48.92 (2×CH2), 12.40 (2×CH3); LC-MS (5 min) m/z 248.49 [C12H17N5O+H]+ (25), 220.07 [(C12H17N5O+H)-28]+ (40) Rt 2.05 min; HRMS m/z calc. C12H18N5O [M+H]+248.1506. found [M+H]+ 247.1498.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[N:9]/[OH:10])=[CH:4][C:3]=1[CH3:11].[Cl:12][C:13]1[CH:18]=[C:17]([C:19]([C:21]([F:24])([F:23])[F:22])=[CH2:20])[CH:16]=[C:15]([Cl:25])[C:14]=1[F:26].Cl([Na])=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:20][C:19]([C:17]3[CH:16]=[C:15]([Cl:25])[C:14]([F:26])=[C:13]([Cl:12])[CH:18]=3)([C:21]([F:24])([F:23])[F:22])[O:10][N:9]=2)=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(/C=N/O)ccc1Br
Reactant: C=C(c1cc(Cl)c(F)c(Cl)c1)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)ccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed dichloromethane (10 mL), (E)-N-[(4-bromo-3-methylphenyl)methylidene]hydroxylamine (50 mg, 0.23 mmol, 1.00 equiv), 1,3-dichloro-2-fluoro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (60 mg, 0.23 mmol, 1.00 equiv), chlorosylsodium (5 mL). The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with 50 mL of DCM. The resulting mixture was washed with 3×10 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 82 mg (75%) of 3-(4-bromo-3-methylphenyl)-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazole as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[CH:11]([CH3:30])[C:12]([OH:29])([C:17]1[CH:18]=[CH:19][C:20]2[O:25][CH2:24][C:23](=[O:26])[N:22]([CH3:27])[C:21]=2[CH:28]=1)[C:13]([F:16])([F:15])[F:14].Cl.C[O:33][C:34](=[O:39])[CH2:35][CH2:36][CH2:37][NH2:38]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:38][CH2:37][CH2:36][CH2:35][C:34]([OH:33])=[O:39])=[O:7])=[CH:4][C:3]=1[CH:11]([CH3:30])[C:12]([OH:29])([C:17]1[CH:18]=[CH:19][C:20]2[O:25][CH2:24][C:23](=[O:26])[N:22]([CH3:27])[C:21]=2[CH:28]=1)[C:13]([F:14])([F:15])[F:16]
Reactant: COC(=O)CCCN
Reactant: CC(c1cc(C(=O)O)ccc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Agent: Cl
Product: CC(c1cc(C(=O)NCCCC(=O)O)ccc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F

Procedure:
In analogy to Example 19, step 2, 4-chloro-3-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-propyl]-benzoic acid (Example 19, step 1) was coupled with methyl-4-aminobutyrate hydrochloride. The product of this reaction was hydrolyzed in analogy to Example 2, to give the title compound as a colorless solid. MS (m/e, ISP neg. ion)=527.2 [M−H+].
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][OH:8])=[CH:5][CH:4]=[N:3]1.Cl[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(P(C(C)(C)C)C1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1)(C)(C)C>C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:6]([CH2:7][O:8][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=2)=[CH:5][CH:4]=[N:3]1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: Cn1nccc1CO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccc2ccccc2c1-c1cccc2ccccc12)C(C)(C)C
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cn1nccc1COc1ccc(C(F)(F)F)cn1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 67.6 %

Procedure:
Under a nitrogen atmosphere, a mixture of (1-methyl-1H-pyrazol-5-yl)methanol (200 mg), 2-chloro-5-(trifluoromethyl)pyridine (389 mg), palladium(II) acetate (40 mg), cesium carbonate (870 mg), rac-2-(di-t-butylphosphino)-1,1′-binaphthyl (71 mg) and toluene (9.0 mL) was stirred at 100° C. for 2.5 hours. Thereafter, the reaction solution was diluted with diethyl ether, and was then filtrated with Celite. The filtrate was concentrated under a reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane:ethyl acetate=85:15 to 50:50), so as to obtain the title compound (310 mg) in the form of a light yellow oily substance.
Reaction SMILES: [CH:1]1([N:4]2[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][C:6]([C:14]([F:17])([F:16])[F:15])=[N:5]2)[CH2:3][CH2:2]1.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1>CCCCCC>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]([OH:24])[C:7]2[C:6]([C:14]([F:17])([F:16])[F:15])=[N:5][N:4]([CH:1]3[CH2:3][CH2:2]3)[C:8]=2[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:21][CH:20]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cc(C(F)(F)F)nn1C1CC1
Solvent: CCCCCC
Product: CCOC(=O)c1c(C(O)c2ccc(Cl)cc2)c(C(F)(F)F)nn1C1CC1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 40.2 using ethyl 1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxylate (Step 44.1) and 4-chlorobenzaldehyde. tR: 1.29 min (LC-MS 2); ESI-MS: 389 [M+H]+ (LC-MS 2); Rf=0.12 (hexane/15% EtOAc).
Reaction SMILES: C(#N)C.N1C=CC=CC=1.F.[CH3:11][O:12][C:13]([C:15]1[CH2:29][C@@H:28]([O:30][Si](C(C)(C)C)(C)C)[C@H:27](/[CH:38]=[CH:39]/[C@@H:40]([O:48][Si](C(C)(C)C)(C)C)[CH2:41][C@H:42]([CH3:47])[CH2:43][CH2:44][CH2:45][CH3:46])[C:16]=1[S:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[O:14]>N1C=CC=CC=1>[CH3:11][O:12][C:13]([C:15]1[CH2:29][C@@H:28]([OH:30])[C@H:27](/[CH:38]=[CH:39]/[C@@H:40]([OH:48])[CH2:41][C@H:42]([CH3:47])[CH2:43][CH2:44][CH2:45][CH3:46])[C:16]=1[S:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[O:14]
Reactant: CCCC[C@@H](C)C[C@@H](/C=C/[C@@H]1C(SCCCCCC(=O)OC)=C(C(=O)OC)C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: F
Solvent: CC#N
Solvent: c1ccncc1
Product: CCCC[C@@H](C)C[C@H](O)/C=C/[C@@H]1C(SCCCCCC(=O)OC)=C(C(=O)OC)C[C@H]1O
Reaction time: 15 h
Yield: 79 %

Procedure:
To a solution of ice-cooled acetonitrile (1 mL) and pyridine (10 mL) was added a hydrogen fluoride-pyridine (0.1 mL). To this solution was added methyl (11R,12S,13E,15S,17R)-9-methoxycarbonyl-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate (67 mg, 0.097 mmol) in pyridine (0.1 mL). The ice bath was removed and the solution was agitated for 15 hours while returning it to room temperature. The reaction solution was poured into a mixture of ethyl acetate and saturated aqueous sodium hydrogencarbonate. The desired product was extracted from this mixed solution with ethyl acetate. The extract was washed with brine, then dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, then was purified by silica gel column chromatography (40 to 50% ethyl acetate/hexane) to obtain methyl (11R,12S,13E,15S,17R)-9-methoxycarbonyl-11,15-dihydroxy-17,20-dimethyl-7-thiaprosta-8,13-dienoate (35 mg, 78%).
Reaction SMILES: Br[C:2]1[C:3]([F:21])=[C:4]([F:20])[C:5]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(N(CC)C(C)C)(C)C.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.[CH2:73]([SH:80])[C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1>O1CCOCC1.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]>[CH2:73]([S:80][C:2]1[C:3]([F:21])=[C:4]([F:20])[C:5]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])[C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1
Reactant: COC(=O)c1cc(Br)c(F)c(F)c1Nc1ccccc1Cl
Reactant: SCc1ccccc1
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
Product: COC(=O)c1cc(SCc2ccccc2)c(F)c(F)c1Nc1ccccc1Cl
Temperature: 100 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of methyl 5-bromo-3,4-difluoro-2-((2-chlorophenyl)amino)benzoate (12.98 g, 34.47 mmol) in anhydrous 1,4-dioxane (30 mL) was added N,N-diisopropylethylamine (8.86 g, 68.94 mmol). Then Pd2(dba)3 (1.63 g, 1.78 mmol) followed by Xantphos (2.06 g, 3.56 mmol) and BnSH (4.48 g, 36.19 mmol) was added under nitrogen atmosphere. The mixture was stirred overnight at 100° C. under N2 atmosphere and then allowed to warm to ambient temperature. The reaction was quenched with water (150 mL) and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with water (100 mL) and brine (100 mL) sequentially, dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 50:1, v/v) to give the desired product (white solid, 12.44 g, 86.0% yield). 1H NMR (400 MHz, CDCl3): δ 9.19 (s, 1H), 7.79 (dd, 1H), 7.41 (dd, 1H), 7.24 (m, 5H), 7.18 (m, 1H), 7.00 (m, 1H), 6.87 (m, 1H), 4.08 (s, 2H), 3.90 (s, 3H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[CH:10][CH:9]=1)#[N:6]>C(OC(=O)C)(=O)C>[C:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[C:10]([N+:1]([O-:4])=[O:2])[CH:9]=1)#[N:6]
Reactant: CC(=O)Nc1ccc(CC#N)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(CC#N)cc1[N+](=O)[O-]
Temperature: -10 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
Concentrated nitric acid (10 mL, >69% pure) was added to acetic anhydride (100 mL) cooled to −10° C. The solution was treated portionwise with N-[4-(cyanomethyl)phenyl]acetamide (5.0 g, 28.7 mmol) at a rate which maintained an internal temperature below −5° C. The solution was stirred for 1 hour while warming to room temperature. The solution was poured into an ice/water mixture and extracted several times with ethyl acetate. The combined extracts were washed with 10% Na2CO3 and brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel with 1:1 hexanes/ethyl acetate to provide 4.82 g (77%) of N-[4-(cyanomethyl)-2-nitrophenyl]acetamide.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][C:5](=[O:8])[NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[N:21][CH:20]=[CH:19][N:18]=1>C(O)(C)C.C(Cl)(Cl)Cl>[N+:23]([C:22]1[C:17]([N:1]2[CH2:7][CH2:6][C:5](=[O:8])[NH:4][CH2:3][CH2:2]2)=[N:18][CH:19]=[CH:20][N:21]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1nccnc1Cl
Reactant: O=C1CCNCCN1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: O=C1CCN(c2nccnc2[N+](=O)[O-])CCN1
Reaction time: 20 h

Procedure:
To a solution of hexahydro-1H-1,4-diazepin-5-one (1.14 g, 10 mmol) and triethylamine (1.01 g, 10 mmol) in isopropanol (30 ml) cooled in an ice bath, was added over 30 minutes a solution of 2-chloro-3-nitropyrazine (1.59 g, 10 mmol) in chloroform (20 ml). After addition was complete, the reaction mixture was allowed to warm to 20°-25° and was stirred at this temperature for 20 hours. Solvents were removed under reduced pressure and the residue was partitioned between a saturated aqueous solution of sodium chloride and ethyl acetate. The ethyl acetate extract was dried over anhydrous sodium sulfate, filtered and concentrated to an oil. Flash chromatography over silica gel and elution with 2% methanol -98% chloroform gave pure 1-(3-nitro-2-pyrazinyl)hexahydro-1H-1,4-diazepin-5-one. ##STR3##
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.O=[C:18]([C:24](OCC)=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(O)C>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([N:8]2[C:24](=[O:25])[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:1][C:2]3[CH:7]=[CH:6][CH:5]=[N:4][C:3]2=3)=[CH:10][CH:11]=1
Reactant: COc1ccc(Nc2ncccc2N)cc1
Reactant: CCOC(=O)C(=O)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)c1nc2cccnc2n(-c2ccc(OC)cc2)c1=O
Temperature: 25 °C
Yield: 37.1 %

Procedure:
5.2 g (24 mmol) of 3-amino-2-(4-methoxyphenyl)aminopyridine was dissolved in ethanol (150 mL), and 4.6 g (27 mmol) of diethyl ketomalonate was added thereto. The mixture was heated to reflux for 9 hours while stirring. After confirming the completion of the reaction, the reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure. The residue thus obtained was purified by column chromatography (developing solvent:ethyl acetate:hexane=1:2), to obtain 2.9 g (yield: 37%) of ethyl 4-(4-methoxyphenyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine-2-carboxylate as yellow crystals.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[C:31]([N+:32]([O-:34])=[O:33])=[CH:30][CH:29]=[CH:28][N:27]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[C:31]([N+:32]([O-:34])=[O:33])=[CH:30][CH:29]=[CH:28][N:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4ncccc4[N+](=O)[O-])cc3CC[C@@H]12
Yield: 65.2 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-3-nitropyridine (73 mg, 0.46 mmol) and 1.5 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (90% ethyl acetate/hexanes eluent) to give 95 mg (65%) of the title compound as an amorphous foam. mp 80°-84°. FDMS: m/e=383. α[D]589 =+73.78 (c=0.49, chloroform).