Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3](=[O:31])[N:4]([CH2:19][C:20]2[CH:30]=[CH:29][C:23]3[O:24][C:25]([F:28])([F:27])[O:26][C:22]=3[CH:21]=2)[C:5](=[O:18])[N:6]([C:8]2[CH:9]=[C:10]([NH:14][C:15](=[O:17])[CH3:16])[CH:11]=[CH:12][CH:13]=2)[N:7]=1.CN([CH:35]=[O:36])C.C[O-].[Na+]>[NH4+].[Cl-]>[F:27][C:25]1([F:28])[O:24][C:23]2[CH:29]=[CH:30][C:20]([CH2:19][N:4]3[C:3](=[O:31])[C:2]([O:36][CH3:35])=[N:7][N:6]([C:8]4[CH:9]=[C:10]([NH:14][C:15](=[O:17])[CH3:16])[CH:11]=[CH:12][CH:13]=4)[C:5]3=[O:18])=[CH:21][C:22]=2[O:26]1
Reactant: CC(=O)Nc1cccc(-n2nc(Br)c(=O)n(Cc3ccc4c(c3)OC(F)(F)O4)c2=O)c1
Reactant: CN(C)C=O
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Product: COc1nn(-c2cccc(NC(C)=O)c2)c(=O)n(Cc2ccc3c(c2)OC(F)(F)O3)c1=O
Temperature: 0 °C
Yield: 63 %

Procedure:
According to Scheme 2 Step 4: A mixture of N-(3-(6-bromo-4-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)methyl)-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide (250 mg, 0.51 mmol), DMF (6 mL) was stirred at 0° C. under nitrogen atmosphere. A sodium methoxide solution 2M (303 μL, 0.61 mmol) was added dropwise and the mixture was stirred at 0° C. during 15 min. The reaction mixture was diluted with 100 mL of a saturated solution of NH4Cl and the aqueous layer was extracted twice with 100 mL of CH2Cl2. The organic layers were combined and successively dried over MgSO4, filtered and concentrated under reduced pressure to afford a brown solid. The crude solid was purified by flash chromatography with silica gel (Merck Flashmart prepacked column 15 g SiO2) using CH2Cl2/MeOH 98/2 as eluant to afford a beige solid. The solid was washed with diethylether and filtered to afford N-(3-(4-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)methyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide 5(C) (141 mg, 63%) as a white solid.
Reaction SMILES: [OH:1][C@@H:2]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)[CH3:3].[CH3:16][S:17](Cl)(=[O:19])=[O:18].CCN(CC)CC>C(Cl)Cl>[CH3:16][S:17]([O:1][C@@H:2]([CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1)[CH3:3])(=[O:19])=[O:18]
Reactant: CC(C)OC(=O)N1CCC([C@@H](C)O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCC([C@@H](C)OS(C)(=O)=O)CC1
Yield: 102.8 %

Procedure:
1-Methylethyl 4-{(1R)-1-[(methylsulfonyl)oxy]ethyl}-1-piperidinecarboxylate (0.7 g, 100%) was prepared as a light yellow oil from 1-methylethyl 4-[(1R)-1-hydroxyethyl]-1-piperidinecarboxylate (0.5 g, 2.32 mmol), methanesulfonyl chloride (0.22 mL, 2.79 mmol), Et3N (0.49 mL, 3.48 mmol) and CH2Cl2 (30 mL) in a manner similar to Example 150, Step 1. The crude material was used without further purification. 1H NMR (400 MHz, CDCl3): δ 4.88 (septet, 1H, J=6.2 Hz), 4.70-4.55 (m, 1H), 4.30-4.10 (m, 2H), 2.99 (s, 3H), 2.75-2.60 (m, 2H), 1.80-1.60 (m, 3H), 1.38 (d, 3H, J=6.3 Hz), 1.35-1.15 (m, 8H).
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17]3)[CH:13]=[CH:12][N:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.Cl.C(Cl)(Cl)Cl>ClCCl.CS(C)=O>[C:1]1([NH:7][C:8]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:20][CH2:19][C:18](=[O:21])[CH2:17]3)[CH:13]=[CH:12][N:11]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Nc1ccccc1)c1cc(N2CCC(O)C2)ccn1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1CCN(c2ccnc(C(=O)Nc3ccccc3)c2)C1
Reaction time: 0.08 h
Yield: 50 %

Procedure:
A solution of 4-(3-Hydroxypyrrolidin-1-yl)-pyridine-2-carboxylic acid phenylamide (259 mg, 0.92 mmol) in dichloromethane (5 mL) and dimethylsulfoxide (2.5 mL) was cooled in an ice bath. Diisopropylethylamine (0.48 mL, 2.8 mmol) was added and stirred for 5 minutes. A solution of sulfur trioxide-pyridine complex (0.44 g, 2.8 mmol) in DMSO (2.5 mL) was added dropwise. The reaction was stirred at 0° C. for 3 hours. To the reaction was added 1 M hydrochloric acid (6 mL) and chloroform. The layers were separated. The aqueous layer was treated with saturated aqueous sodium bicarbonate until pH=6. Extraction twice with chloroform gave a crude residue. Purification by chromatography on silica gel (12 g) eluted with chloroform:methanol 39:1 gave the title compound (133 mg, 0.46 mmol, 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]([CH2:8][C:9]2[N:14]=[C:13]([C:15]([OH:17])=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH:7]=1.ClC(Cl)(Cl)C(=N)O[C:23]([CH3:26])([CH3:25])[CH3:24]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][C:23]([CH3:26])([CH3:25])[CH3:24])=[C:6]([CH2:8][C:9]2[N:14]=[C:13]([C:15]([OH:17])=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Reactant: O=C(O)c1cccc(Cc2cc(Cl)ccc2O)n1
Solvent: ClCCl
Product: CC(C)(C)Oc1ccc(Cl)cc1Cc1cccc(C(=O)O)n1
Temperature: 25 °C
Reaction time: 44 h
Yield: 24 %

Procedure:
To a solution/suspension of 6-[(5-chloro-2-hydroxyphenyl)methyl]-2-pyridine-carboxylic acid (308 mg) in dry dichloromethane (12 ml) was added t-butyl 2,2,2-trichloroacetimidate (1.67 ml) and boron trifluoride-diethyl etherate (0.05 ml) and the mixture stirred under argon at ambient temperature for 44 hours. Dichloromethane (15 ml) was added and the mixture washed with saturated sodium bicarbonate solution (15 ml). The aqueous layer was extracted with dichloromethane (2×15 ml) and the combined organic extracts washed with brine (25 ml), dried (MgSO4) and concentrated in vacuo. The residue was purified by mass-directed autopreparation to afford the title compound (91 mg, 24%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]([C:14]1[C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][CH:15]=1)O)[CH:6]=[CH:5]2>C(O)=O.[Zn]>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][C:14]1[C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][CH:15]=1)[CH:6]=[CH:5]2
Reactant: COc1cc2nccc(C(O)c3ccc4cc(Br)ccc4c3)c2cc1OC
Agent: [Zn]
Solvent: O=CO
Product: COc1cc2nccc(Cc3ccc4cc(Br)ccc4c3)c2cc1OC

Procedure:
To a solution of (6-bromo-naphthalen-2-yl)-(6,7-dimethoxy-quinolin-4-yl)-methanol (Step e, 0.55 g, 1.3 mmol) in formic acid (10 mL), was added Zn dust (500 mg, 7.6 mmol). The suspension was heated at reflux for 6 h and the solvent was removed in vacuo. The resulting residue was worked up with 1N NaOH and extracted with CH2Cl2 3×. The combined organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude was purified with silica gel column chromatography (40-65% EtOAc/Hexane) to give the titled compound. MS (ESI, pos. ion) m/z: 408.1 (M+1).
Reaction SMILES: [CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].CN(C=[O:31])C.O=O>Cl[Pd]Cl.Cl[Cu].O>[Br:19][C:15]1[CH:14]=[C:13]([C@@H:11]([N:7]2[CH2:6][CH2:5][C@@:4]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)([CH2:1][C:2](=[O:31])[CH3:3])[O:9][C:8]2=[O:10])[CH3:12])[CH:18]=[CH:17][CH:16]=1
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2cccc(Br)c2)C(=O)O1
Reactant: CN(C)C=O
Agent: Cl[Cu]
Agent: Cl[Pd]Cl
Agent: O=O
Solvent: O
Product: CC(=O)C[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2cccc(Br)c2)C(=O)O1
Reaction time: 8 h
Yield: 86 %

Procedure:
(R)-6-allyl-3-((S)-1-(3-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (55 mg, 0.13 mmol), PdCl2 (6 mg, 0.3 equiv.), and CuCl (26 mg, 2.3 equiv.) were mixed with DMF (2 mL) and water (˜250 μL). A balloon of oxygen was attached to the flask and the mixture was stirred vigorously overnight. LC-MS found the reaction completed. The mixture was quenched by satd aq NH4Cl solution (2 mL), diluted with EtOAc (20 mL), washed by brine (7 mL), dried over Na2SO4. After filtration and concentration, the residue was purified by preparative HPLC to afford (S)-3-((S)-1-(3-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-oxopropyl)-1,3-oxazinan-2-one (49 mg, 86% yield). LC-MS (3 min) tR=1.76 min, m/z=434, 436 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:23]=[CH:24]/[C:25]([NH:27][O:28]C2CCCCO2)=[O:26])[CH:5]=[N:6][C:7]=1[NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[CH2:11][CH2:10]1.[ClH:35]>CCO>[ClH:1].[ClH:35].[Cl:1][C:2]1[CH:3]=[C:4](/[CH:23]=[CH:24]/[C:25]([NH:27][OH:28])=[O:26])[CH:5]=[N:6][C:7]=1[NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[CH2:11][CH2:10]1
Reactant: Cc1ccc(CN2CCC(Nc3ncc(/C=C/C(=O)NOC4CCCCO4)cc3Cl)CC2)cc1
Agent: Cl
Solvent: CCO
Product: Cc1ccc(CN2CCC(Nc3ncc(/C=C/C(=O)NO)cc3Cl)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2E)-3-(5-chloro-6-{[1-(4-methylbenzyl)-4-piperidyl]amino}-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (470 mg) in EtOH(2 ml) was treated with 2N HCl in EtOH (2.42 ml) and was stirred at 25° C. for 1 hour. The precipitate was collected, washed with EtOH, dried under reduced pressure to give (2E)-3-(5-chloro-6-{[1-(4-methylbenzyl)-4-piperidyl]amino}-3-pyridyl)-N-hydroxyacrylamide dihydrochloride (308 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:18](B4OC(C)(C)C(C)(C)O4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.Cl[C:37]1[CH:38]=[CH:39][C:40]2[O:53][CH2:52][N:43]3[C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][C:49]=4[C:50]([Cl:51])=[C:42]3[C:41]=2[N:54]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.CCOC(C)=O.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]>[Cl:51][C:50]1[C:49]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[N:43]2[CH2:52][O:53][C:40]3[CH:39]=[CH:38][C:37]([C:18]4[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][C:10]5[O:9][C:8]([C:5]6[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=6)=[C:12]([C:13]([NH:15][CH3:16])=[O:14])[C:11]=5[CH:17]=4)=[N:54][C:41]=3[C:42]=12
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: Clc1ccc2c(n1)-c1c(Cl)c3ccccc3n1CO2
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: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3c(Cl)c5ccccc5n3CO4)cc12
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a degassed solution of 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (110 mg, 0.22 mmol), 2,12-dichloro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole (64 mg, 0.22 mmol) and K3PO4 (176 mg, 0.66 mmol) in dioxane/H2O (0.8 mL/0.2 mL) was added Pd2(dba)3 (10 mg, 0.01 mmol) and X-Phos (10 mg, 0.02 mmol) under N2. The mixture was heated to 80° C. and then stirred for 1 hour. The reaction mixture was cooled to RT, diluted with EtOAc and filtered. The filtrate was washed with H2O, brine, dried over Na2SO4. After concentrated, the resulting residue was purified using prep-TLC (petroleum ether:EtOAc=1:1) to provide the desired product of compound 55 (60 mg, yield: 43.2%). 1H-NMR (CDCl3, 400 MHz) δ 8.13 (s, 1H), 7.94˜7.98 (m, 2H), 7.65 (d, J=8.0 Hz, 1H), 7.58 (s, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.28˜7.31 (m, 2H), 7.11˜7.20 (m, 3H), 5.85˜5.95 (br s, 3H), 3.32 (s, 3H), 2.96 (d, J=4.8 Hz, 3H), 2.72 (s, 3H). MS (M+H)+: 631.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([N:7]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=2)[C:8]([C:10]2[N:14]=[CH:13][NH:12][N:11]=2)=[O:9])[CH2:3][CH2:2]1.[H-].[Na+].CI.[C:31](=O)([O-])O.[Na+]>CN(C=O)C>[CH3:31][N:12]1[CH:13]=[N:14][C:10]([C:8]([N:7]([CH:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:24])[F:25])[CH:17]=2)=[O:9])=[N:11]1
Reactant: O=C([O-])O
Reactant: O=C(c1nc[nH]n1)N(Cc1cccc(OC(F)(F)F)c1)C1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cnc(C(=O)N(Cc2cccc(OC(F)(F)F)c2)C2CCOCC2)n1
Reaction time: 0.17 h

Procedure:
To a solution of N-(tetrahydro-2H-pyran-4-yl)-N-[3-(trifluoromethoxy)benzyl]-1H-1,2,4-triazole-3-carboxamide (138 mg) in DMF (2 mL), sodium hydride (60%, 18 mg) was added and the resulting mixture was stirred for 10 minutes; thereafter, methyl iodide (35 μL) was added and the resulting mixture was stirred overnight at room temperature. To the reaction mixture, a saturated aqueous solution of sodium hydrogencarbonate was added and extraction was conducted with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography (NH silica gel cartridge; hexane/ethyl acetate=1:0 to 1:3) to give the titled compound (75 mg).
Reaction SMILES: [CH2:1]([CH:17]1[C:21](=[O:22])[CH2:20][CH2:19][C:18]1=[O:23])[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].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH2:32][CH2:33][CH2:34][C:35](=[O:38])[CH:36]=[CH2:37])[CH:29]=[CH:30][CH:31]=1>[OH-].[K+]>[CH2:1]([C:17]1([CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33][CH2:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([O:25][CH3:24])[CH:27]=2)[C:18](=[O:23])[CH2:19][CH2:20][C:21]1=[O:22])[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: CCCCCCCCCCCCCCCCC1C(=O)CCC1=O
Reactant: C=CC(=O)CCCc1cccc(OC)c1
Agent: [K+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCCCC1(CCC(=O)CCCc2cccc(OC)c2)C(=O)CCC1=O
Yield: 73.7 %

Procedure:
Reflux a mixture of 2-cetylcyclopentane-1,3-dione (10.1 g), 6-m-methoxyphenylhex-1-en-3-one (6.0 g) and 0.02% methanolic potassium hydroxide solution (120 cc) for 26 hours and then cool. Dissolve the residue obtained after removal of solvent under reduced pressure in a mixture of benzene (50 cc) and ether (50 cc), and wash the solution in turn with sodium carbonate solution, 10% aqueous sulfuric acid and water. Remove the solvent by evaporation under reduced pressure to obtain as residue crude 2-cetyl-2-(6-m-methoxyphenyl-3-oxohexyl)-1,3-cyclopentanedione (11.4 g).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[O:14]C.C(O)C>C(Cl)Cl>[OH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[OH:14]
Reactant: COc1ccc(F)cc1OC
Agent: BrB(Br)Br
Solvent: CCO
Solvent: ClCCl
Product: Oc1ccc(F)cc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 104.1 %

Procedure:
A 1 M solution of boron tribromide in methylene chloride (500 mL, 0.50 mole) was cooled to -78 ° C. To this solution was added in a dropwise manner a solution of 46 g (0.30 mole) of 1,2-dimethoxy-4-fluorobenzene in 100 mL of methylene chloride. Upon completion of addition, the mixture was allowed to warm to ambient temperature at which it stirred for about 16 hours. At the conclusion of this period the reaction mixture was cooled to 0° C., and ethanol was added to the reaction mixture. The solvents were evaporated under reduced pressure, leaving 40 g of 1,2-dihydroxy-4-fluorobenzene as a residue. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([O:4][CH:5]([CH3:20])[CH2:6][C:7]([CH2:18]Br)=[CH:8][CH:9]([NH:15][CH:16]=[O:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:3])[CH3:2].[P:21]([O:30]C(C)C)([O:26][CH:27]([CH3:29])[CH3:28])[O:22][CH:23]([CH3:25])[CH3:24]>>[C:1]([O:4][CH:5]([CH3:20])[CH2:6][C:7]([CH2:18][P:21]([O:26][CH:27]([CH3:29])[CH3:28])([O:22][CH:23]([CH3:25])[CH3:24])=[O:30])=[CH:8][CH:9]([NH:15][CH:16]=[O:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:3])[CH3:2]
Reactant: CC(C)OP(OC(C)C)OC(C)C
Reactant: CCOC(=O)C(C=C(CBr)CC(C)OC(C)=O)NC=O
Product: CCOC(=O)C(C=C(CC(C)OC(C)=O)CP(=O)(OC(C)C)OC(C)C)NC=O
Reaction time: 18 h

Procedure:
18.0 g (51.4 mmol) of ethyl 6-acetoxy-4-bromomethyl-2-formylamino-hept-3-enoate and 56.3 ml (205.6 mmol) of 90% triisopropyl phosphite are heated to 80° C. and and the mixture is stirred for 18 hours under a pressure of 100-150 mbar. Excess triisopropyl phosphite is removed by distillation and the residue is purified by chromatography on silica gel with ethyl acetate/isopropanol (7:2), giving ethyl 6-acetoxy-2-formylamino-4-diisopropylphosphonomethyl-hept-3-enoate as an orange oil. yield.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)=[O:10].Cl[C:23]1[C:28]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:26]=[CH:25][N:24]=1>>[S:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]([N:2]1[CH2:3][CH:4]2[CH:5]([CH2:6][N:7]([C:23]3[C:28]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:26]=[CH:25][N:24]=3)[CH2:8]2)[CH2:1]1)=[O:10]
Reactant: FC(F)(F)c1cccnc1Cl
Reactant: O=C(c1ccccc1-c1cccs1)N1CC2CNCC2C1
Product: O=C(c1ccccc1-c1cccs1)N1CC2CN(c3ncccc3C(F)(F)F)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 37 and 2-chloro-3-trifluoromethyl-pyridine. MS (ESI): mass calculated for C23H20F3N3OS, 443.49; m/z found 444.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.28 (dd, J=4.7, 1.4, 1H), 7.79 (dd, J=7.8, 1.8, 1H), 7.55-7.49 (m, 1H), 7.46-7.33 (m, 3H), 7.30-7.19 (m, 2H), 7.01 (br s, 1H), 6.71 (dd, J=7.7, 4.7, 1H), 3.98-2.54 (m, 10H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[C:7]2[N:14]([CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[C:15](=[O:27])[C:16]1[C:21](OC)=[C:20]([O:24][CH3:25])[CH:19]=[CH:18][C:17]=1I)([O-:3])=[O:2].C(Cl)(=O)[C:34](Cl)=[O:35].COC1C=C(C(I)=CC=1OC)C(O)=O.[N+](C1C=C2C(=CC=1)N=CC=C2NCCN(C)C)([O-])=O.C(N(CC)CC)C>C(Cl)Cl>[CH3:25][O:24][C:20]1[C:19]([O:35][CH3:34])=[CH:18][C:17]2[C:8]3[C:7](=[C:6]4[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=[CH:12][C:11]4=[N:10][CH:9]=3)[N:14]([CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[C:15](=[O:27])[C:16]=2[CH:21]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(I)c(C(=O)N(CCN(C)C)c2ccnc3ccc([N+](=O)[O-])cc23)c1OC
Agent: CN(C)CCNc1ccnc2ccc([N+](=O)[O-])cc12
Agent: COc1cc(I)c(C(=O)O)cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(=O)n(CCN(C)C)c3c4cc([N+](=O)[O-])ccc4ncc3c2cc1OC
Yield: 78 %

Procedure:
N-(6-Nitroquinolin-4-yl)-N-(N,N-dimethylaminoethyl)-2-iodo-5,6-dimethoxybenzamide (8c). Oxalyl chloride (1.5 g, 12.0 mmol) was added to a solution of 3,4-dimethoxy-6-iodobenzoic acid (985 mg, 3.2 mmol) in anhydrous methylene chloride (20 mL), and the stirred mixture was refluxed for 3 hours. The mixture was then concentrated to dryness under reduced pressure. The acid chloride was redissolved in 20 mL of anhydrous methylene chloride, and this solution was added to a solution of 7c (700 mg, 2.7 mmol) and triethylamine (2.0 g, 20.0 mmol) in methylene chloride (30 mL), and the resulting mixture was stirred at reflux for 2 hours. The reaction mix was cooled and washed with saturated sodium bicarbonate (3×75 mL), and extracted with 5% aqueous HCl (4×100 mL). The combined aqueous extracts were basified with 30% NaOH and then extracted with chloroform (3×100 mL). Combined organic extracts were then dried (MgSO4) and evaporated to give 1.15 g of the amide, in 78% yield; 1H NMR (CDCl3) δ 2.23 (s, 6H), 2.63 (m, 2H), 3.35 (s, 3H), 3.71 (s, 3H), 3.96 (m, 1H), 4.29 (m, 1H), 6.50 (s, 1H), 6.94 (s, 1H), 7.79 (d, 1H, J=5.2), 8.22 (d, 1H, J=9.2), 8.48 (d, 1H, J=9.2), 9.0 (d, 1H, J=5.2), 9.28 (s, 1H); 13C NMR (CDCl3) δ 45.5, 48.0, 55.6, 56.1, 56.8, 82.3, 110.7, 120.9, 121.5, 122.9, 123.4, 125.5, 132.2, 133.7, 145.9, 148.4, 149.1, 149.8, 151.5, 154.1, 169.7; IR (CHCl3) 1345, 1535, 1655.
Reaction SMILES: OC(C)(C)[C:3]#[C:4][C:5]1[CH:6]=[C:7]([O:11][CH2:12][C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH3:18])[CH:8]=[N:9][CH:10]=1.[H-].[Na+]>C1(C)C=CC=CC=1>[C:4]([C:5]1[CH:6]=[C:7]([O:11][CH2:12][C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH3:18])[CH:8]=[N:9][CH:10]=1)#[CH:3]
Reactant: CN1CCC[C@H]1COc1cncc(C#CC(C)(C)O)c1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C#Cc1cncc(OC[C@@H]2CCCN2C)c1
Yield: 101.7 %

Procedure:
To a stirred solution of 5-(3-hydroxy-3-methyl-1-butynyl)-3-(1-methyl-2(S) -pyrrolidinylmethoxy)pyridine (70 mg, 0.25 mmol) in toluene (3 mL) was added NaH (60% in mineral oil, 2 mg, 0.05 mmol). The reaction mixture was refluxed for 1 h, and then some toluene was distilled. After cooled, the mixture was treated with ice-cold water, and extracted with EtOAc (15 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by chromatography with CH2Cl2-MeOH (5:1) to give a light yellow oil (55 mg, 99%), [α]D−59 (c 1.4, CHCl3). 1H NMR (CDCl3) δ 8.32 (d, 1H, J=1.5 Hz), 8.29 (d, 1H, J=2.7 Hz), 7.28 (dd, 1H, J=2.7, 1.5 Hz), 4.01 (dd, 1H, J=9.3, 5.4 Hz), 3.93 (dd, 1H, J=9.3, 5.4 Hz), 3.20 (s, 1H), 3.16-3.09 (m, 1H), 2.73-2.63 (m, 1H), 2.48 (s, 3H), 2.32 (td, 1H, J=9.3, 7.2 Hz), 2.10-1.97 (m, 1H), 1.94-1.67 (m, 3H); 13C NMR (CDCl3) δ 154.38, 145.01, 138.27, 123.50, 119.26, 80.27, 71.12, 64.03, 57.67, 41.65, 28.47, 23.01.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N+:12]([O-])=O)[N:3]=1>CO.[Cl-].[Cl-].[Cl-].[Ti+3]>[CH3:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[NH2:12])[N:3]=1
Reactant: Cc1cnc2c([N+](=O)[O-])cccc2n1
Agent: [Ti+3]
Agent: [Cl-]
Solvent: CO
Product: Cc1cnc2c(N)cccc2n1
Reaction time: 1 h
Yield: 79 %

Procedure:
To a solution of 2-methyl-5-nitroquinoxaline (3.67 g) in MeOH (350 mL) was added dropwise a 20% aqueous titanium trichloride (92.9 g) at room temperature. After the addition, the mixture was further stirred for one hour, and concentrated under reduced pressure. The resultant was neutralized by addition of aqueous sodium carbonate solution, and the mixture was extracted four times with ethyl acetate (150 mL). The organic layers were combined, and dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform) to give 2-methyl-5-aminoquinoxaline (2.44 g,79%) as orange crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[F:11][C:12]([F:21])([F:20])[C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:19][C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([C:12]([F:11])([F:20])[F:21])[CH:14]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Temperature: 120 °C

Procedure:
A mixture of 1-chloro-4-nitrobenzene (11 g), 3-(trifluoromethyl)phenol (12 g), and potassium carbonate (21 g) in dimethyl formamide (175 mL) was heated at 120° C. for about 16 hours. The reaction mixture was cooled to room temperature and poured over ice-water. The mixture was filtered and the solid collected was washed with water and dried under vacuum (25 g).