Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([C:18]3[O:22][C:21]([CH:23]=O)=[CH:20][CH:19]=3)=[CH:7][CH:8]=2)[N:3]=1.II.[NH3:27]>C1COCC1>[Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)[C:9]2[C:4](=[CH:5][C:6]([C:18]3[O:22][C:21]([C:23]#[N:27])=[CH:20][CH:19]=3)=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=Cc1ccc(-c2ccc3c(N4CCOCC4)nc(Cl)nc3c2)o1
Reactant: N
Agent: II
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2ccc3c(N4CCOCC4)nc(Cl)nc3c2)o1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a 50 mL round bottom flask, 5-(2-chloro-4-morpholino-quinazolin-7-yl)furan-2-carbaldehyde (0.48 g, 0.0014 mol; prepared in a similar method to that described in Example 10) and THF (10 mL) were added. To the same flask, iodine (0.39 g, 0.00154 mol) and 30% aqueous ammonia (9.6 mL) were added. The reaction mixture was stirred at 25° C. The light brown reaction mixture turned yellow after 3 h. The reaction was quenched by adding ethyl acetate (100 mL) and 10% aqueous sodium thiosulfate (40 mL) and stirred for 5 min. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure to get the crude product. The crude product was purified using column chromatography (60-120 silica gel, 10-50% ethyl acetate in hexane) to yield the desired product as a off white solid [0.31 g, 65%]. 1H NMR (300 MHz, CDCl3): δ 8.11 (s, 1H), 7.92 (d, J=9.0 Hz, 1H), 7.78 (d, J=9.0 Hz, 1H), 7.24 (d, J=3.6 Hz, 1H), 6.95 (d, J=3.6 Hz, 1H), 3.95 (s, 8H). LC-MS (ESI): Calculated mass: 340.0; Observed mass: 341.0 (RT: 1.55 min).
Reaction SMILES: [NH4+].O.O.O.O.O.O.O.O.O.O.O.O.[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[Al+3:24].[OH:25][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:35]=1[N:34]=[CH:33][CH:32]=[CH:31]2.[OH-].[Na+]>O>[CH:28]1[CH:27]=[C:26]([O-:25])[C:35]2[N:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH:29]=1.[CH:28]1[CH:27]=[C:26]([O-:25])[C:35]2[N:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH:29]=1.[CH:28]1[CH:27]=[C:26]([O-:25])[C:35]2[N:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH:29]=1.[Al+3:24]
Reactant: Oc1cccc2cccnc12
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [NH4+]
Solvent: O
Product: [O-]c1cccc2cccnc12
Yield: 91.3 %

Procedure:
As in Example 1, 22.7 g of ammonium alum and 21.8 g of 8-hydroxyquinoline were added to 150 g of water and the mixture was neutralized by dropwise addition of 6.5 g of a 33% solution of sodium hydroxide with stirring and allowed to react. The solid formed was washed with water and dried to give 21 g of Alq3. The raw material Alq3 thus prepared was refined in the metallic apparatus for refining by sublimation illustrated in FIG. 1 to give 11 g of refined Alq3.
Reaction SMILES: C1(O)C=CC=CC=1.[F:8][C:9]([F:27])([F:26])[C:10]1[N:14]2[CH:15]=[C:16]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[CH:17]=[CH:18][C:13]2=[N:12][N:11]=1.BrC1C=N[C:32]2N([C:35]([CH:38]([CH3:40])C)=[N:36][N:37]=2)C=1.C([O-])([O-])=O.[Cs+].[Cs+].C(#N)CCC>>[N:37]1[CH:32]=[CH:40][CH:38]=[C:35]([O:25][C:22]2[CH:21]=[CH:20][C:19]([C:16]3[CH:17]=[CH:18][C:13]4[N:14]([C:10]([C:9]([F:8])([F:26])[F:27])=[N:11][N:12]=4)[CH:15]=3)=[CH:24][CH:23]=2)[N:36]=1
Reactant: CC(C)c1nnc2ncc(Br)cn12
Reactant: Oc1ccc(-c2ccc3nnc(C(F)(F)F)n3c2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCC#N
Solvent: Oc1ccccc1
Product: FC(F)(F)c1nnc2ccc(-c3ccc(Oc4cccnn4)cc3)cn12
Temperature: 140 °C

Procedure:
In a sealable flask, a suspension of the phenol, 4-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)phenol, prepared as described in Example 1 (47 mg, 0.17 mmol), heteroaryl chloride (39 mg, 0.34 mmol), Cs2CO3 (111 mg, 0.34 mmol), and butyronitrile (1 mL) is heated to 140° C. overnight. The reaction is concentrated and purified by RP-HPLC to afford the desired product, 6-(4-(pyridazin-3-yloxy)phenyl)-3-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][CH:6]([O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>>[CH3:5][CH:6]([O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([Cl:3])=[O:19])=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCC(C)Oc1ccc(C(=O)O)cc1
Product: CCCCCCC(C)Oc1ccc(C(=O)Cl)cc1
Yield: 93 %

Procedure:
Thionyl chloride (51.2 g, 0.43 mol) was added to optically active p-(1-methyl-heptyloxy)benzoic acid (90.0 g, 0.36 mol), followed by refluxing the mixture for about 2 hours, thereafter completely removing excess thionyl chloride by distillation under reduced pressure to obtain optically active p-(1-methyl-heptyloxy)benzoic acid chloride (90.0 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]2[CH2:22][CH2:21][C@:20]([CH2:30][CH2:31][N:32](C)[C:33](=O)OC(C)(C)C)([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[O:19][C:18]2=[O:41])[CH3:16])=[CH:11][CH:10]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]2[CH2:22][CH2:21][C@@:20]([C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)([CH2:30][CH2:31][NH:32][CH3:33])[O:19][C:18]2=[O:41])[CH3:16])=[CH:11][CH:10]=1
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCN(C)C(=O)OC(C)(C)C)(c2ccc(F)cc2)OC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(F)cc3F)cc2)C(=O)O1
Yield: 21.3 %

Procedure:
A solution of tert-butyl 2-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl(methyl)carbamate (73 mg, 0.13 mmol) in TFA/CH2Cl2 (20%, 6 mL) was stirred at 0° C. for 1 h. After the material was consumed, the solution was concentrated to give residue, which was purified by preparative TLC followed by preparative HPLC to give (R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-(methylamino)ethyl)-1,3-oxazinan-2-one (13 mg, 21%). LC-MS Method 3 tR=1.10, min, m/z=469; 1H NMR (CDCl3): 1.50 (d, 3H), 2.25 (m, 4H), 2.37 (m, 1H), 2.60 (m, 3H), 2.81 (m, 1H), 2.98 (m, 2H) 6.85 (m, 2H), 7.00 (m, 4H), 7.18 (m, 2H), 7.28 (m, 3H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([S:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N+:31]([O-:33])=[O:32])=[CH:13][N:14]2[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:10][CH:9]=1)(C)(C)C.CCCCCCC.C(OCC)(=O)C.C(OCC)(=O)C>C(N(CC)CC)C>[N+:31]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[S:24][C:12]1[C:11]2[C:15](=[CH:16][C:8]([NH2:7])=[CH:9][CH:10]=2)[N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:13]=1)([O-:33])=[O:32]
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(Sc3ccccc3[N+](=O)[O-])cn(Cc3ccccn3)c2c1
Solvent: CCCCCCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Nc1ccc2c(Sc3ccccc3[N+](=O)[O-])cn(Cc3ccccn3)c2c1
Yield: 64.9 %

Procedure:
[3-(2-Nitro-phenylsulfanyl)-1-pyridin-2-ylmethyl-1H-indol-6-yl]-carbamic acid tert-butyl ester (Example 2, step iv; 3.4 g, 6.3 mmol) was deprotected to give, after column chromatography (heptane/ethyl acetate 2:8→ethyl acetate, containing some triethylamine), the title compound (1.54 g). 1H-NMR (CDCl3) δ 8.62 (bd, 1H, J=5.0 Hz), 8.26 (dd, 1, J=8.0 and 1.5 Hz), 7.61 (dt, H, J=7.5 and 2.0 Hz), 7.34 (s, 1H), 7.25-7.30 (m, 2H), 7.22 (ddd, 1H, J=7.5, 5.0 and 1.0 Hz), 7.16 (ddd, 1H J=8.0, 7.0 and 1.0 Hz), 7.05 (dd, 1H, J=8.0 and 1.0 Hz), 6.86 (d, 1H, J=8.0 Hz), 6.63 (d, 1H, J=1.5 Hz), 6.60 (dd, 1H, J=8.0 and 1.5 Hz), 5.41 (s, 2H), 3.70 (bs, 2H).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([CH3:32])([CH3:31])[CH2:11][N:12]1[C:16]2=[N:17][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:20]=[C:15]2[CH:14]=[C:13]1[C:26]([O:28][CH2:29][CH3:30])=[O:27])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][CH2:9][C:10]([CH3:31])([CH3:32])[CH2:11][N:12]1[C:16]2=[N:17][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:20]=[C:15]2[CH:14]=[C:13]1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)n(CC(C)(C)CNC(=O)OC(C)(C)C)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1ccc2cc(C(=O)OCC)n(CC(C)(C)CN)c2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.2 %

Procedure:
To a solution of diethyl 1-{3-[(tert-butoxycarbonyl)amino]-2,2-dimethylpropyl}-1H-pyrrolo[2,3-b]pyridine-2,6-dicarboxylate (4.20 g, 9.39 mmol) in CH2Cl2 (20 mL) is added TFA (10 mL). The mixture is stirred at room temperature for 4 hr. The solvent is evaporated and the residue is partitioned between ethyl acetate and saturated NaHCO3 solution. The layers are separated and the aqueous layer is further extracted with ethyl acetate. The combined organic phases are washed with brine, and are dried (Na2SO4) and concentrated in vacuo to afford the title compound (3.30 g, quantitative). LCMS: 348.79 (M+H+).
Reaction SMILES: O[CH2:2][CH2:3][O:4][CH2:5][C:6]([CH2:13][O:14][CH2:15][CH2:16]O)([CH2:8][O:9][CH2:10][CH2:11]O)[CH3:7].[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>N1C=CC=CC=1>[S:24]([CH2:16][CH2:15][O:14][CH2:13][C:6]([CH2:5][O:4][CH2:3][CH2:2][S:24]([C:21]1[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=1)(=[O:26])=[O:25])([CH2:8][O:9][CH2:10][CH2:11][S:24]([C:21]1[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=1)(=[O:26])=[O:25])[CH3:7])([C:21]1[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=1)(=[O:26])=[O:25]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(COCCO)(COCCO)COCCO
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)CCOCC(C)(COCCS(=O)(=O)c2ccc(C)cc2)COCCS(=O)(=O)c2ccc(C)cc2)cc1
Reaction time: 15 h
Yield: 50 %

Procedure:
A solution of 1,1,1-tris(hydroxyethoxymethyl)ethane (6.7 g, 0.026 mol) in 35 mL of anhydrous pyridine was cooled to -10° C. Then solid p-toluenesulfonyl chloride (16.6 g, 0.087 mol) was added in portions over 1.5 hrs. The mixture was kept at -10° C. for 15 hrs. The resulting slurry was partitioned between dichloromethane (100 mL) and water (50 mL) and the layers were separated. The organic layer was washed with water (50 mL), dried over anhydrous sodium sulfate and evaporated to give a crude gum. This material was purified over silica gel using 1% methanol/dichloromethane as eluant to give 1,1,1-tris(tosylethoxymethyl)ethane (8.9 g, 0.013 mol, 47%).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[CH2:10]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([N:27]2[CH2:32][CH2:31][NH:30][C@@H:29]([CH3:33])[CH2:28]2)=[N:19][N:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([N:27]2[CH2:32][CH2:31][N:30]([C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=3)[C@@H:29]([CH3:33])[CH2:28]2)=[N:19][N:18]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C[C@H]1CN(c2nnc(Cc3ccccc3)c3ccccc23)CCN1
Reactant: N#Cc1ccc(Cl)nc1
Product: C[C@H]1CN(c2nnc(Cc3ccccc3)c3ccccc23)CCN1c1ccc(C#N)cn1
Yield: 23 %

Procedure:
Following the above procedure, 6-chloro-nicotinonitrile (50 mg, 0.36 mmol, 1.2 eq) and 1-benzyl-4-((S)-3-methyl-piperazin-1-yl)-phthalazine (100 mg, 0.31 mmol, 1.0 eq) afford the title compound as a white solid (30 mg, 23% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:4]([C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][N:12]=2)[N:3]=1.Cl[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=1.C1(P(C2CCCCC2)C2(C(C)C)CC(C(C)C)=CC(C(C)C)=C2C2C=CC=CC=2)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)(C)C.O>[Cl:17][C:16]1[C:11]([N:4]2[C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:6][C:2]([NH:1][C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=3)=[N:3]2)=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: COC(=O)c1cc(N)nn1-c1ncccc1Cl
Agent: CC(C)C1=CC(C(C)C)=C(c2ccccc2)C(C(C)C)(P(C2CCCCC2)C2CCCCC2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: COC(=O)c1cc(Nc2ccc(C(F)(F)F)cn2)nn1-c1ncccc1Cl
Temperature: 100 °C
Reaction time: 24 h
Yield: 29 %

Procedure:
1.90 g (7.52 mmol) of methyl 3-amino-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylate 1.50 g (8.27 mmol) of 2-chloro-5-trifluoromethylpyridine, 0.275 g (0.3 mmol) of tris(dibenzylacetone)dipalladium, 0.286 g (0.60 mmol) of 2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl and 3.12 g (22.5 mmol) of potassium carbonate were initially charged in 190 ml of tert-butanol, and the reaction mixture was stirred at 100° C. for 24 hours. After cooling, the mixture was poured into water and extracted repeatedly with ethyl acetate, and the extracts were dried over magnesium sulphate. The solvent was distilled off under reduced pressure and the residue was chromatographed on silica gel, which gave 950 mg (29% of theory) of methyl 1-(3-chloropyridin-2-yl)-3-{[5-(trifluoromethyl)pyridin-2-yl]amino}-1H-pyrazole-5-carboxylate. (logP: 3.14; MH+: 398.0); 1H-NMR (400 MHz, CD3CN, δ, ppm): 3.74 (s, 3H), 7.26 (m, 1H), 7.37 (s, 1H), 7.66 (m, 1H), 7.95 (m, 1H), 8.25 (d, 1H), 8.56 (m, 2H).)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([O:13][CH2:14]/[CH:15]=[C:16](\I)/[CH3:17])=[N:9]2)=[CH:4][CH:3]=1.[CH3:19][O:20][C:21](=[O:24])[NH:22][CH3:23].P([O-])([O-])([O-])=O.[K+].[K+].[K+].CNCCNC>C1(C)C=CC=CC=1.[Cu](I)I>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([O:13][CH2:14]/[CH:15]=[C:16](\[N:22]([CH3:23])[C:21](=[O:24])[O:20][CH3:19])/[CH3:17])=[N:9]2)=[CH:4][CH:3]=1
Reactant: C/C(I)=C/COc1ccn(-c2ccc(Cl)cc2)n1
Reactant: CNC(=O)OC
Agent: I[Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)N(C)/C(C)=C\COc1ccn(-c2ccc(Cl)cc2)n1

Procedure:
1.50 g (4.00 mmol) 1-(4-chlorophenyl)-3-[(Z)-3-iodobut-2-enoxy]pyrazole, 0.43 g (4.81 mmol) N-methylcarbamic acid methyl ester (9), 76 mg (0.4 mmol) copperiodide, 1.27 g (6.00 mmol) potassium phosphate and 71 mg (0.80 mmol) N,N′-dimethylethylene diamine in 14 ml toluene have been stirred for 1.5 d at 100° C. After removal of the solvents in vacuo the crude product has been purified by chromatography on 50 g silica with MTBE/hexane (1:3). Yield 0.67 g. 1H-NMR (CDCl3): δ=1.90 (s); 3.05 (s); 3.70 (s); 4.68 (m); 5.63 (m); 5.90 (d); 7.35 (m); 7.55 (m); 7.68 (d).
Reaction SMILES: [Cl:1][C:2]([Cl:21])([Cl:20])[CH2:3][O:4][C:5]([CH2:7][O:8][N:9]=[C:10]([C:16](=O)[CH2:17]Cl)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:6].[NH2:22][C:23]([NH2:25])=[S:24].C([O-])(=O)C.[Na+]>C(O)C.O>[NH2:25][C:23]1[S:24][CH:17]=[C:16]([C:10](=[N:9][O:8][CH2:7][C:5]([O:4][CH2:3][C:2]([Cl:21])([Cl:20])[Cl:1])=[O:6])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:22]=1
Reactant: CCOC(=O)C(=NOCC(=O)OCC(Cl)(Cl)Cl)C(=O)CCl
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(=NOCC(=O)OCC(Cl)(Cl)Cl)c1csc(N)n1
Temperature: 40 °C
Reaction time: 5 h
Yield: 51.1 %

Procedure:
A mixture of ethyl 2-(2,2,2-trichloroethoxycarbonylmethoxyimino)-4-chloro-3-oxobutyrate (20 g), thiourea (3.9 g) and sodium acetate (4.2 g) in ethanol (50 ml) and water (50 ml) was stirred at 40° C. for 5 hours. After removal of the solvent from the reaction mixture, the residue was triturated with diisopropyl ether. The precipitates were collected by filtration and washed with diisopropyl ether to give ethyl 2-(2-aminothiazol-4-yl)-2-(2,2,2-trichloroethoxycarbonylmethoxyimino)acetate (syn isomer) (10.6 g), mp 138°-141° C.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH2:9][C:10]([NH:29][C:30]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:31])([CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[C:42](=[O:49])([O:46][CH2:47]I)[S:43][CH2:44][CH3:45]>O.C(Cl)Cl>[C:42](=[O:49])([S:43][CH2:44][CH3:45])[O:46][CH2:47][O:35][C:34](=[O:36])[CH2:33][CH2:32][C:30](=[O:31])[NH:29][C:10]([CH2:9][CH2:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])([CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14]
Reactant: CCSC(=O)OCI
Reactant: CC(C)(C)OC(=O)CCC(CCC(=O)OC(C)(C)C)(CCC(=O)OC(C)(C)C)NC(=O)CCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCSC(=O)OCOC(=O)CCC(=O)NC(CCC(=O)OC(C)(C)C)(CCC(=O)OC(C)(C)C)CCC(=O)OC(C)(C)C
Reaction time: 0.33 h
Yield: 71.9 %

Procedure:
To a mixture of acid 73 (519 mg, 1.01 mmol) in H2O (3 mL) and CH2Cl2 (3 mL) was added NaHCO3 (176 mg, 2.09 mmol) and TBAHSO4 (342 mg, 1.01 mmol). After stirring for 20 min, S-ethyl O-iodomethyl carbonothioate (192 mg, 0.77 mmol) in CH2Cl2 (1 mL) was added. The biphasic reaction was stirred vigorously for 3 h and was diluted with water and CH2Cl2. The layers were separated and the organic layer was washed with H2O, 0.5 N HCl solution, saturated NaHCO3 solution, saturated NaCl solution, dried over MgSO4, filtered and concentrated to dryness. The crude product was triturated with Et2O and the solids were removed by filtration and rinsed with small portions of Et2O. After concentration, the combined filtrates were purified by flash chromatography on a Biotage™ flash chromatography system, using a gradient of 20-60% EtOAc in CH2Cl2 as eluent, to furnish compound 74 (351 mg, 72%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.33 (t, J=7.4 Hz, 3H), 1.44 (s, 27H), 1.94-1.98 (m, 6H), 2.20-2.24 (m, 6H), 2.43 (t, J=6.9 Hz, 2H), 2.70 (t, J=6.9 Hz, 2H), 2.89 (q, J=7.4 Hz, 2H), 5.81 (s, 2H), 5.98 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:32])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([OH:31])[CH2:20][O:21][CH:22]2CC3C(=CC=CC=3)C2)[CH2:14][CH2:13]1.[F:33][C:34]([F:44])([F:43])[C:35]1[CH:42]=[CH:41][C:38](CO)=[CH:37][CH:36]=1>CC(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:32])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([OH:31])[CH2:20][O:21][CH2:22][C:38]2[CH:41]=[CH:42][C:35]([C:34]([F:44])([F:43])[F:33])=[CH:36][CH:37]=2)[CH2:14][CH2:13]1
Reactant: Cc1cccc(C)c1NC(=O)CN1CCN(CC(O)COC2Cc3ccccc3C2)CC1
Reactant: OCc1ccc(C(F)(F)F)cc1
Solvent: CC(C)O
Product: Cc1cccc(C)c1NC(=O)CN1CCN(CC(O)COCc2ccc(C(F)(F)F)cc2)CC1

Procedure:
Compound 17 was prepared in a similar manner to compound 7, substituting the commercially available 4-trifluoromethyl-benzylalcohol for 2-propanol in part C. MS (M+1)=480.37
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([N:14]2[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[N:15]2)[CH:11]=[CH:10][CH:9]=1.[Br:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH4+].[Cl-]>CN(C=O)C>[Br:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[N:13]=[C:12]([N:14]3[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[N:15]3)[CH:11]=[CH:10][CH:9]=2)=[CH:31][CH:30]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3O)n2)c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3OCc3ccc(Br)cc3)n2)c1C(F)(F)F
Reaction time: 1.5 h

Procedure:
To a solution of the title compound from Example 1 Step B (682 mg, 1.81 mmol) in DMF (10 mL) were added 4-bromobenzyl bromide (678 mg, 2.71 mmol) and cesium carbonate (1.77 g, 5.42 mmol). After 1.5 h, the reaction mixture was poured into sat. aq. NH4Cl and extracted with EtOAc. The organic phase was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 25% EtOAc in hexanes, then 25 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 548.0 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.13 (s, 1H), 8.08 (d, J=8.0 Hz, 1H), 7.95 (dd, J=7.5, 1.5 Hz, 1H), 7.88 (t, J=8.0 Hz, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.48 (d, J=8.0 Hz, 2H), 7.39-7.36 (m, 1H), 7.23 (d, J=8.0 Hz, 2H), 7.12 (t, J=7.5 Hz, 1H), 7.03 (d, J=7.5 Hz, 1H), 5.10 (s, 2H), 4.39 (q, J=7.0 Hz, 2H), 1.39 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([C:13]2[CH:35]=[CH:34][C:16]([O:17][CH2:18][C:19]([O:21][CH2:22][CH2:23][S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)(=[O:26])=[O:25])=[O:20])=[C:15]([O:36][CH2:37][C:38]([O:40][CH2:41][CH2:42][S:43]([C:46]3[CH:51]=[CH:50][C:49]([CH3:52])=[CH:48][CH:47]=3)(=[O:45])=[O:44])=[O:39])[CH:14]=2)(=[O:12])=[O:11])=[C:5]([N+:53]([O-])=O)[CH:4]=1>[Pt]=O>[NH2:53][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[NH:9][S:10]([C:13]1[CH:35]=[CH:34][C:16]([O:17][CH2:18][C:19]([O:21][CH2:22][CH2:23][S:24]([C:27]2[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=2)(=[O:25])=[O:26])=[O:20])=[C:15]([O:36][CH2:37][C:38]([O:40][CH2:41][CH2:42][S:43]([C:46]2[CH:51]=[CH:50][C:49]([CH3:52])=[CH:48][CH:47]=2)(=[O:44])=[O:45])=[O:39])[CH:14]=1)(=[O:11])=[O:12]
Reactant: COc1ccc(NS(=O)(=O)c2ccc(OCC(=O)OCCS(=O)(=O)c3ccc(C)cc3)c(OCC(=O)OCCS(=O)(=O)c3ccc(C)cc3)c2)c([N+](=O)[O-])c1
Agent: O=[Pt]
Product: COc1ccc(NS(=O)(=O)c2ccc(OCC(=O)OCCS(=O)(=O)c3ccc(C)cc3)c(OCC(=O)OCCS(=O)(=O)c3ccc(C)cc3)c2)c(N)c1

Procedure:
2(4-Tolylsulfonyl)ethyl 4-(4-methoxy-2-nitro-phenyl)aminosulfonyl-2-(2-[4-tolylsulfonyl]ethoxycarbonylmethoxy)phenoxyacetate (Intermediate A17, 6.6 g, 0.0080 mol) was hydrogenated using platinum oxide as catalyst. The mixture was filtered and concentrated. After drying at high vacuum, the residual product, title compound, weighed 5.9 g (93%).
Reaction SMILES: [OH:1][OH:2].[C:3]1(=[O:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>O>[CH2:6]1[CH2:7][CH2:8][C:3]([O:1][O:2][C:3]2([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)([OH:9])[CH2:4][CH2:5]1
Reactant: OO
Reactant: O=C1CCCCC1
Solvent: O
Product: OC1(OOC2(O)CCCCC2)CCCCC1
Reaction time: 8 h

Procedure:
In a 200 ml, 3-neck round-bottom flask equipped with a magnetic stirring bar, two addition funnels, and a thermometer, was placed 20.45 ml. of 30% hydrogen peroxide. One addition funnel was charged with 41.3 ml. of distilled cyclohexanone and the other with 82.6 ml of water. The contents of the two addition funnels were discharged gradually and constantly into the stirred round-bottom flask whose contents were kept at a constant temperature of about 25°-26° C. No exothermicity was noted. After both addition funnels were emptied into the round-bottom flask stirring was continued overnight.
Reaction SMILES: [CH3:1][Zn]C.[CH3:4][O:5][C:6]1[C:26]([O:27][CH3:28])=[C:25]([O:29][CH3:30])[CH:24]=[C:23]([CH3:31])[C:7]=1[C:8]([C:10]1[C:11]([O:21][CH3:22])=[N:12][CH:13]=[C:14](Br)[C:15]=1[C:16]([F:19])([F:18])[F:17])=[O:9].O>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:4][O:5][C:6]1[C:26]([O:27][CH3:28])=[C:25]([O:29][CH3:30])[CH:24]=[C:23]([CH3:31])[C:7]=1[C:8]([C:10]1[C:11]([O:21][CH3:22])=[N:12][CH:13]=[C:14]([CH3:1])[C:15]=1[C:16]([F:19])([F:18])[F:17])=[O:9]
Reactant: C[Zn]C
Reactant: COc1cc(C)c(C(=O)c2c(OC)ncc(Br)c2C(F)(F)F)c(OC)c1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C)c(C(=O)c2c(OC)ncc(C)c2C(F)(F)F)c(OC)c1OC
Temperature: 25 °C
Reaction time: 192 h
Yield: 97.1 %

Procedure:
3.80 ml (3.80 mmol) of dimethylzinc (1.0 mol/l hexane solution) was dropwise added at 0° C. to a solution having 0.60 g (1.29 mmol) of 3-(2,3,4-trimethoxy-6-methylbenzoyl)-5-bromo-4-trifluoromethyl-2-methoxypyridine obtained in Step (d) and 0.10 g (0.09 mmol) of tetrakis(triphenylphosphine)palladium dissolved in 10 ml of tetrahydrofuran, and the temperature was increased naturally, followed by stirring at room temperature for 8 days. Water was added to terminate the reaction, and tetrahydrofuran was distilled off under reduced pressure. After extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 0.50 g (yield: 96%) of 3-(2,3,4-trimethoxy-6-methylbenzoyl)-4-trifluoromethyl-2-methoxy-5-methylpyridine.