Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[C:15]2[C:16]([N+:20]([O-])=O)=[N:17][NH:18][CH:19]=2)[CH:5]=[C:4]([F:23])[C:3]=1[S:24]([NH:27][C:28]1[N:29]=[CH:30][S:31][CH:32]=1)(=[O:26])=[O:25].[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:20][C:16]1[C:15]([C@H:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C@@H:9]2[O:8][C:6]2[CH:5]=[C:4]([F:23])[C:3]([S:24]([NH:27][C:28]3[N:29]=[CH:30][S:31][CH:32]=3)(=[O:25])=[O:26])=[C:2]([F:1])[CH:7]=2)=[CH:19][NH:18][N:17]=1
Reactant: O=[N+]([O-])c1n[nH]cc1[C@H]1CCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2cscn2)c(F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1n[nH]cc1[C@H]1CCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2cscn2)c(F)c1
Reaction time: 2 h
Yield: 92.8 %

Procedure:
To a solution of the 2,6-difluoro-4-{[(1S*,2R*)-2-(3-nitro-1H-pyrazol-4-yl)cyclohexyl]oxy}-N-(1,3-thiazol-4-yl)benzenesulfonamide (167 mg, 0.343 mmol) prepared in Example 116c in ethanol (4.0 mL) and water (2.0 mL), ammonium chloride (92.0 mg, 1.72 mmol) and an iron powder (57.6 mg, 1.03 mol) were added, and the reaction solution was stirred for 2 hours under heated reflux. After allowing to cool, the reaction solution was filtered through celite, the filtrate was vacuum concentrated, and the residue was purified with silica gel chromatography (dichloromethane/methanol=93:7) to yield the title compound (145 mg, 92%) as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:28]=[CH:27][C:5]([CH2:6][O:7][CH2:8][C@@H:9]2[CH2:11][C@@H:10]2[CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([CH2:24][O:25][CH3:26])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[C:4]([F:29])[CH:3]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[Br-].[C:65]([O:69][C:70](=[O:73])[CH2:71][Zn+])([CH3:68])([CH3:67])[CH3:66]>C1COCC1.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:29][C:4]1[CH:3]=[C:2]([CH2:71][C:70]([O:69][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:73])[CH:28]=[CH:27][C:5]=1[CH2:6][O:7][CH2:8][C@@H:9]1[CH2:11][C@@H:10]1[CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[CH:22][C:21]([CH2:24][O:25][CH3:26])=[CH:20][N:19]=2)[CH2:14][CH2:13]1
Reactant: COCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(Br)cc3F)CC2)nc1
Reactant: CC(C)(C)OC(=O)C[Zn+]
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
Solvent: C1CCOC1
Product: COCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(CC(=O)OC(C)(C)C)cc3F)CC2)nc1
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 97.7 %

Procedure:
2-(4-((1R,2R)-2-(((4-bromo-2-fluorobenzyl)oxy)methyl)cyclopropyl)piperidin-1-yl)-5-(methoxymethyl)pyrimidine (Step B product, 1.0 g, 2.15 mmol) was dissolved in anhydrous THF (3 ml). The mixture was stirred for 5 min and TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.099 g, 0.108 mmol) and X-PHOS (0.103 g, 0.215 mmol) were added, followed by (2-(tert-butoxy)-2-oxoethyl)zinc(II) bromide (0.5 M solution in ether, 12.92 ml, 6.46 mmol). The mixture was heated at 60° C. overnight. The reaction mixture was quenched with aqueous NH4Cl, and the aqueous layer was extracted with EtOAc. The organic extracts were washed with brine, dried, and evaporated to give the crude product, which was purified by flash column (25 g SNAP, 5˜30% EtOAc in hexane) to afford 1.05 g (98%) of the desired product. Rf was 0.3 @ 20% EtOAc in hexanes (blue spot on CAM stain).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[CH:12]1(O)[CH2:16][CH2:15][CH:14]=[CH:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(Cl)Cl>[CH:16]1([O:8][C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[N+:9]([O-:11])=[O:10])[CH2:15][CH2:14][CH:13]=[CH:12]1
Reactant: OC1C=CCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(F)cc1OC1C=CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-fluoro-2-nitrophenol (1.48 g), 2-cyclopenten-1-ol (662 mg) and triphenylphosphine (2.47 g) in THF (25.0 ml) diethylazodicarboxylate (1.48 ml) was added at 0° C. After stirring at room temperature overnight the reaction mixture was diluted with methylene chloride and washed with 10% aq. KHSO4. The organic layer was passed through a hydrophobic frit and concentrated in vacuo. The residue was purified by chromatography to give the desired product.
Reaction SMILES: [OH:1][C@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH:10]=[C:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.Cl>N1C=CC=CC=1>[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30]([O:1][C@H:2]2[CH2:21][CH2:20][C@@:19]3([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]4[C@@H:18]3[CH2:17][CH2:16][C@@:15]3([CH3:23])[C@H:8]4[CH2:9][CH:10]=[C:11]3[C:12](=[O:14])[CH3:13])[CH2:3]2)(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)C1=CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)C1=CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](OS(=O)(=O)c5ccc(C)cc5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
3β-Hydroxy-5α-pregn-16-en-20-one (10 g.) in pyridine (50 ml.) was treated with toluene-p-sulphonyl chloride (10 g.), and the solution was stirred at room temperature overnight and then poured into dilute hydrochloric acid. The precipitate was extracted into chloroform, and the extract was washed with dilute hydrochloric acid and with water, dried over sodium sulphate and evaporated to an oil which crystallised on standing. Recrystallisation from ethyl acetate/petrol gave 3β-toluene-p-sulphonyloxy-5α-pregn-16-en-20-one (13.3g) as off-white prisms, m.p. 146°-148° , [α]D + 24.0°, λmax. (EtOH) 226.5 nm (ε 18,600), 240 nm (infl.) (ε 9550), 272.5 nm (ε 518).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:13][C:14]([NH2:16])=[NH:15])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.C1(C2(CC(N)=N)CCCC2)C=CC=CC=1.[C:33]([O:37][C:38](=[O:53])/[C:39](/O)=[C:40](\[O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)/[C:41](O)=[O:42])([CH3:36])([CH3:35])[CH3:34].C[O-].[Na+]>CO.C(OCC)(=O)C.CCCCCC>[C:33]([O:37][C:38]([C:39]1[C:40]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[C:41]([OH:42])[N:16]=[C:14]([CH2:13][C:8]2([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:15]=1)=[O:53])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)/C(O)=C(\OCc1ccccc1)C(=O)O
Reactant: N=C(N)CC1(c2ccc(Cl)cc2)CCCC1
Agent: C[O-]
Agent: Cl
Agent: N=C(N)CC1(c2ccccc2)CCCC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1
Temperature: 0 °C
Yield: 91 %

Procedure:
To a stirred solution of 2-[1-(4-chlorophenyl)-cyclopentyl]-acetamidine; hydrochloride (322) (3.1 g, 11.34 mmol) in methanol (25 mL) was added (E,Z)-2-benzyloxy-3-hydroxy-but-2-enedioic acid 4-tert-butyl ester 1-methyl ester (4) (4.19 g, 13.61 mmol) and cooled to 0° C. To this reaction mixture was then added sodium methoxide (25% in methanol) (7.4 mL, 34.03 mmol) and stirred at room temperature for 16 h (TLC; ethyl acetate:hexane=1:1, Rf=0.5). The reaction mixture was diluted with ethyl acetate (300 mL), washed with water (60 mL) and brine (60 mL) and dried and concentrated in vacuo to get crude mass which was purified by CombiFlash eluted with gradient polarity mobile phase (hexane to 50% ethyl acetate in hexane) to get pure 5-benzyloxy-2-[1-(4-chlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester (323) (5.1 g, 91%) as a light brown solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=O)=[CH:4][C:3]=1[CH2:12][O:13]C.[Cl:15][C:16]1[CH:17]=[C:18]([C:23](=[N:25]O)[NH2:24])[CH:19]=[N:20][C:21]=1[Cl:22]>>[Cl:22][C:21]1[C:16]([Cl:15])=[CH:17][C:18]([C:23]2[N:25]=[C:12]([C:3]3[CH:2]=[CH:11][C:10]([C:2]4[CH:11]=[CH:10][CH:5]=[CH:4][C:3]=4[CH3:12])=[C:5]([CH2:6][O:8][CH3:9])[CH:4]=3)[O:13][N:24]=2)=[CH:19][N:20]=1
Reactant: COCc1cc(C(=O)OC)ccc1Br
Reactant: NC(=NO)c1cnc(Cl)c(Cl)c1
Product: COCc1cc(-c2nc(-c3cnc(Cl)c(Cl)c3)no2)ccc1-c1ccccc1C

Procedure:
The title compound was prepared following procedure described in Method B starting from Intermediate A1 and 5,6-dichloro-N′-hydroxypyridine-3-carboximidamide (WO2000015637). The title compound was obtained as a white powder. HPLC (Method A), Rt: 6.7 min (purity: 95.0%). UPLC/MS, M+(ESI): 426.1. 1H NMR (DMSO-d6, 300 MHz) δ 9.08 (d, J=2.1 Hz, 1H), 8.72 (d, J=2.1 Hz, 1H), 8.34 (d, J=1.8 Hz, 1H), 8.19 (dd, J=7.9, 1.8 Hz, 1H), 7.44 (d, J=7.9 Hz, 1H), 7.36 (m, 2H), 7.30 (m, 1H), 7.15 (d, J=7.1 Hz, 1H), 4.23 (d, J=12.7 Hz, 1H), 4.16 (d, J=12.7 Hz, 1H), 3.25 (s, 3H), 2.03 (s, 3H).
Reaction SMILES: [O:1]=[CH:2][CH:3]=[CH:4][C:5]1[CH:27]=[CH:26][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:10])=[CH:7][CH:6]=1.[BH4-].[Na+]>C(O)C>[OH:1][CH2:2][CH:3]=[CH:4][C:5]1[CH:27]=[CH:26][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:10])=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C=CC=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C=CCO)cc1
Reaction time: 0.08 h
Yield: 82.1 %

Procedure:
To a stirred solution of compound XVI (1.00 g, 2.79 mmol) in ethanol (15 ml) under nitrogen was added sodium borohydride (110 mg, 2.73 mmol). After 5 min, the reaction mixture was quenched with water and diluted with AcOEt. After separation the organic layer was successively washed with brine, dried over MgSO4, filtered, and concentrated. The crude residue was then purified by flash chromatography on silica gel (AcOEt/hexane:40/60) to afford the title compound XVIII (910 mg, 2.29 mmol, 82% yield) as a pale yellow solid (slightly contaminated with the diene). 1H NMR (300 MHz, CDCl3) δ(ppm): 9.20 (s, 1H), 7.90 (d, J=7.8 Hz, 2H), 7.75 (d, J=7.5 Hz, 1H), 7.43 (d, J=8.4 Hz, 2H), 7.32–7.08 (m, 3H), 6.94 (s, 1H), 6.65 (d, J=15.9 Hz, 1H), 6.45 (td, J=15.9, 5.4 Hz, 1H), 4.35 (d, J=5.4 Hz, 2H), 1.92 (s, 1H), 1.51 (s, 9H).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH2:9][C@@H:10]([O:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[C:24]#[N:25])[C:11]1[S:12][CH:13]=[CH:14][N:15]=1)([CH3:4])[CH3:3].[H-].[Na+].IC.[C:31](OCC)(=O)C>O1CCCC1.CCCC(C)C>[CH3:4][C:2]([O:5][C:6](=[O:26])[N:7]([CH2:8][CH2:9][C@@H:10]([O:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[C:24]#[N:25])[C:11]1[S:12][CH:13]=[CH:14][N:15]=1)[CH3:31])([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC[C@@H](Oc1cc(Cl)ccc1C#N)c1nccs1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCCC(C)C
Solvent: C1CCOC1
Product: CN(CC[C@@H](Oc1cc(Cl)ccc1C#N)c1nccs1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98 %

Procedure:
To a solution of [(3R)-3-(5-chloro-2-cyanophenoxy)-3-(2-thiazolyl)propyl]-carbamic acid 1,1-dimethylethyl ester (200 mg, 0.51 mmol) in dry tetrahydrofuran (10 ml), was added sodium hydride (56 mg, 60% dispersion in oil, 1.41 mmol) and stirred at room temperature for 15 minutes. Iodomethane (1.325 g, 0.58 ml, 4.7 mmol) was added. The reaction was stirred at room temperature for 18 h, quenched with saturated ammonium chloride solution and partitioned between ethyl acetate and water. The combined extracts were washed with water (3×25 ml) and saturated brine solution, dried (magnesium sulphate) and concentrated in vacuo to leave a crude yellow gum. Flash chromatography (silica, 25% ethyl acetate in isohexane) afforded 175 mg of an opaque oil (98%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:37][N:5]2[C:6]3[C:11]([N:12]([C:14](=[O:36])[C:15]4[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:35])[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[CH:17][CH:16]=4)[CH2:13][C@@H:4]2[CH2:3]1)=[CH:10][CH:9]=[CH:8][CH:7]=3.[C:38](O)(=[O:40])[CH3:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[C:38]([O:1][C@@H:2]1[CH2:37][N:5]2[C:6]3[C:11]([N:12]([C:14](=[O:36])[C:15]4[CH:16]=[CH:17][C:18]([NH:21][C:22](=[O:35])[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)=[CH:19][CH:20]=4)[CH2:13][C@@H:4]2[CH2:3]1)=[CH:10][CH:9]=[CH:8][CH:7]=3)(=[O:40])[CH3:39]
Reactant: O=C(Nc1ccc(C(=O)N2C[C@@H]3C[C@@H](O)CN3c3ccccc32)cc1)c1ccccc1-c1ccccc1
Reactant: CC(=O)O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)O[C@H]1C[C@H]2CN(C(=O)c3ccc(NC(=O)c4ccccc4-c4ccccc4)cc3)c3ccccc3N2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
To a solution of (2R,3aS)-2-hydroxy-5-[4-[(2-phenylbenzoyl)amino]benzoyl]-1,2,3,3a,4,5-hexahydro-pyrrolo[1,2-a]quinoxaline (0.8 g) prepared in Example 3, acetic acid (0.15 g) and triphenyl phosphine (0.64 g) in anhydrous tetrahydrofuran (5 ml), there was gradually dropwise added a solution of diisopropyl azodicarboxylate (0.49 g) in anhydrous tetrahydrofuran (2 ml) under ice-cooling. After stirring the reaction solution at room temperature for 2 hours, it was concentrated. The resulting residue was subjected to silica gel column chromatography and then eluted with hexane/ethyl acetate (1/1) to give 0.66 g (yield 76.0%) of the title compound as amorphous powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[C:8]([CH3:14])([CH3:13])[C:7](=[O:15])[C:6]([C:16](OCC)=[O:17])=[C:5]2[OH:21].C(N(C(C)C)C(C)C)C.Cl.[NH2:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>O1CCOCC1.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[C:8]([CH3:13])([CH3:14])[C:7](=[O:15])[C:6]([C:16]([NH:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:17])=[C:5]2[OH:21]
Reactant: CCOC(=O)C1=C(O)c2cc(F)c(F)cc2C(C)(C)C1=O
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(F)c(F)cc2C(C)(C)C1=O
Temperature: 80 °C
Yield: 42.5 %

Procedure:
To a mixture of ethyl 6,7-difluoro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalene-3-carboxylate (570 mg, 1924 μmol) in 1,4-dioxane (3848 μL) and N-ethyl-N-isopropylpropan-2-amine (1005 μL, 5772 μmol), was added tert-butyl 2-aminoacetate hydrochloride (484 mg, 2886 μmol). The reaction was then heated at 80° C. for 3 hours. The reaction mixture was then diluted with 100 mL of EtOAc, added to a separatory funnel, partitioned with NaHCO3 (saturated, aqueous), washed 2 times with 50 mL of NaHCO3 (saturated, aqueous), separated, dried over Na2SO4, and concentrated in vacuo to give the title compound (312 mg) as a white solid after flash chromatography. MS (m/z)=404(M+Na)+.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1B1OC(C)(C)C(C)(C)O1)(=[O:3])[CH3:2].Cl[C:37]1[CH:38]=[C:39]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([N:52]3[CH2:57][CH2:56][N:55]([CH:58]4[CH2:61][O:60][CH2:59]4)[CH2:54][CH2:53]3)=[CH:48][N:47]=2)[C:40](=[O:44])[N:41]([CH3:43])[N:42]=1.CC([O-])=O.[Na+]>CC#N.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]>[C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:37]1[CH:38]=[C:39]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([N:52]3[CH2:57][CH2:56][N:55]([CH:58]4[CH2:59][O:60][CH2:61]4)[CH2:54][CH2:53]3)=[CH:48][N:47]=2)[C:40](=[O:44])[N:41]([CH3:43])[N:42]=1)(=[O:3])[CH3:2]
Reactant: Cn1nc(Cl)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C5COC5)CC4)cn3)c(=O)n(C)n2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 110 °C
Yield: 73.6 %

Procedure:
A sealed tube was charged with the mixture of 4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 210d (420 mg, 0.9 mmol), 328c (300 mg, 0.78 mmol), Pd(dppf)Cl2 (66 mg, 0.078 mmol), K3PO4.3H2O(360 mg, 1.56 mmol), and NaOAc (130 mg, 1.56 mmol) in CH3CN(20 ml). The system was evacuated and then refilled with N2. And the reaction mixture was heated at 110° C. for 2 h. Then, the mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography eluting with 30:1 methylene chloride/methanol to afford 328d as a yellow solid (400 mg, 72%). MS: [M+H]+ 696.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[CH:29]=[C:28](O)[CH:27]=[CH:26]3)=[CH:19][CH:18]=1>ClCCl.N1C=CC=CC=1>[F:13][C:10]([F:11])([F:12])[S:7]([O:6][C:28]1[CH:27]=[CH:26][C:25]2[C:30](=[CH:31][CH:32]=[C:23]([C:20]3[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=3)[CH:24]=2)[CH:29]=1)(=[O:8])=[O:9]
Reactant: Oc1ccc2cc(-c3ccc(F)cc3)ccc2c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Oc1ccc2cc(-c3ccc(F)cc3)ccc2c1)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
Trifluoromethanesulfonic anhydride (1.3 mL, 7.74 mmol) was added over 5 minutes to a stirred solution of 6-(4-fluorophenyl)-2-naphthol (Step 1, 1.75 g, 7.35 mmol) in dichloromethane (25 mL) and pyridine (15 mL) at 0° C. under nitrogen. The reaction was stirred at 0° C. for 1 hour then allowed to warm to room temperature. The solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. The combined organic layers were washed with water and brine, dried over MgSO4 and evaporated in vacuo to give 6-(4-fluorophenyl)-2-naphthyl trifluoromethanesulfonate (2.34 g, 86%). 1H NMR (500 MHz, CDCl3) δ 8.03 (1H, s), 7.96 (2H, dd, J=9.1, 13.1 Hz), 7.81-7.77 (2H, m), 7.67-7.65 (2H, m), 7.41 (1H, dd, J=2.4, 9.0 Hz), 7.21-7.17 (2H, m).
Reaction SMILES: [CH3:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([C:10](Cl)=[O:11])[N:4]([CH2:13][CH2:14][CH3:15])[N:3]=1.[OH-].[NH4+:17]>CC(C)=O>[CH3:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([C:10]([NH2:17])=[O:11])[N:4]([CH2:13][CH2:14][CH3:15])[N:3]=1
Reactant: [NH4+]
Reactant: CCCn1nc(C)c([N+](=O)[O-])c1C(=O)Cl
Agent: [OH-]
Solvent: CC(C)=O
Product: CCCn1nc(C)c([N+](=O)[O-])c1C(N)=O
Yield: 79 %

Procedure:
A solution of 46 g (0.2 mol) of 3-methyl-4-nitro-1-n-propyl-pyrazole-5-carbonyl chloride [J. Med. Chem., 16 1346 (1973)] in 50 ml of acetone is added slowly to 250 ml of cold (5° C.) concentrated ammonium hydroxide. The mixture is filtered to give 33 g (79%) of 3-methyl-4-nitro-1-n-propylpyrazole-5-carboxamide, mp 136°-138° C. The amide (33 g, 0.15 mol) is stirred under reflux in 100 ml of phosphorus oxychloride for 2.5 hours and evaporated in vacuo. The residue is stirred in 250 ml of ice water to give, after filtering, 25.5 g (86%) of 5-cyano-3-methyl-4-nitro-1-n-propylpyrazole. This nitropyrazole (25 g, 0.013 mol) is dissolved in 350 ml of glacial acetic acid and treated at 95° C. portionwise with 12 g iron filings and 20 ml of water. After stirring under reflux three hours the mixture is filtered and the filtrate is concentrated in vacuo. The concentrate is extracted with methylene dichloride and the organic extract is treated with 20 ml of acetic anhydride and refluxed for two hours. The cooled mixure is stirred with saturated aqueous NaHCO3 solution, the organic layer is dried (MgSO4), and evaporated in vacuo to give 16.5 g of N-(5-cyano-3-methyl-1-n-propylpyrazol-4-yl)acetamide, mp 129°-131° C.
Reaction SMILES: [C:1]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([OH:36])=O)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(Cl)(=O)C([Cl:40])=O>O1CCCC1>[C:1]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([Cl:40])=[O:36])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC(=O)O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC(=O)Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 99.9 %

Procedure:
16-Hexadecanoyloxyhexadecanoic acid (7.73 g, 15.13 mmol) prepared as in (f) above was dissolved in tetrahydrofuran (140 ml) and oxalyl chloride (4.80 g, 37.83 mmol) was added dropwise. The mixture was stirred at room temperature for 3 days and then the solvent and unreacted oxalyl chloride were evaporated under reduced pressure to give 8.0 g (100%) of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+]>CC(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>[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: OB(O)c1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Nc1ccc(-c2ccccc2F)nn1
Temperature: 80 °C
Yield: 87.4 %

Procedure:
To a mixture of 6-chloropyridazin-3-amine (3.00 g, 23.1 mmol), 4-fluorophenylboronic acid (34.7 mmol), Na2CO3 (69.3 mmol) in 2-propanol (150 mL) and water (50 mL) that has been degassed with N2 (5 minutes) is added PdCl2(PPh3)2(1.15 mmol). The mixture is heated at 80° C. for 12 hours, concentrated under reduced pressure, added sat. aqueous NaHCO3 (100 mL) and extracted with EtOAc (3×100 mL). Organic layer is collected, dried over Na2SO4, filtered and concentrated to dryness. The crude product is purified via chromatography using a gradient of CH2Cl2 to 70% CH2Cl2:EtOAc:methanol (1:1:0.1) to afford the title compound (3.82 g, 87%) as a white solid: Rf 0.37 (1:1:0.1 CH2Cl2:EtOAc:methanol); LCMS (m/z)=190.2 [M+H]+, tR=0.44 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH2:7][CH2:6][C:5]2=[O:13].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[O:8][CH2:7][CH2:6][C:5]2=[O:13]
Reactant: O=C1CCOc2cc(O)c(F)cc21
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1CCOc2cc(OCc3ccccc3)c(F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
A mixture of 6-fluoro-7-hydroxychroman-4-one (the compound of Preparation 29, 0.93 g, 5.11 mmol), benzyl bromide (0.61 mL, 5.13 mmol), potassium carbonate (1.41 g, 10.2 mmol) in acetone (100 mL) was stirred at ambient temperature overnight. The mixture was cooled, filtered, and concentrated to a yellow solid. This residue was recrystallized from ethyl acetate/ether to give 1.02 g (73%) of 6-fluoro-7-benzyloxychroman-4-one in two crops as cream white crystals which had: mp 155-156° C.; NMR δ7.58 (d, J=11 Hz, 1 H), 7.46-7.33 (m, 5 H), 6.54 (d, J=6.7 Hz, 1 H), 5.16 (d, 2 H), 4.50 (t, J=6.4 Hz, 2 H), 2.75 (t, J=6.4 Hz, 2 H). Analysis calculated for C16H13FO2: C, 70.58; H, 4.81. Found: C, 70.45; H, 4.80.