Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C@H:11]([CH2:12][NH:13][C:14]2[CH:31]=[CH:30][C:17]([C:18](=[O:29])[NH:19][C@H:20]([C:26]([OH:28])=[O:27])[CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:16][CH:15]=2)[CH2:10][NH:9][C:8]2[N:7]=[C:6]([NH2:32])[NH:5][C:4](=[O:33])[C:3]1=2.[OH:34][CH:35]1[O:43][C@H:42]([CH2:44][OH:45])[C@@H:40]([OH:41])[C@H:38]([OH:39])[C@H:36]1[NH2:37]>>[OH:34][CH:35]1[O:43][C@H:42]([CH2:44][OH:45])[C@@H:40]([OH:41])[C@H:38]([OH:39])[C@H:36]1[NH2:37].[CH3:1][N:2]1[C@H:11]([CH2:12][NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:18](=[O:29])[NH:19][C@H:20]([C:26]([OH:28])=[O:27])[CH2:21][CH2:22][C:23]([O-:25])=[O:24])=[CH:30][CH:31]=2)[CH2:10][NH:9][C:8]2[N:7]=[C:6]([NH2:32])[NH:5][C:4](=[O:33])[C:3]1=2
Reactant: CN1c2c(nc(N)[nH]c2=O)NC[C@H]1CNc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1
Agent: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Product: CN1c2c(nc(N)[nH]c2=O)NC[C@H]1CNc1ccc(C(=O)N[C@@H](CCC(=O)[O-])C(=O)O)cc1
Yield: 132.5 %

Procedure:
9.19 g (20 mmol) of 5-methyl-(6R,S)-tetrahydrofolic acid were added portion-wise and completely dissolved in 60 ml of an aqueous solution of D-glucosamine (7.12 g, 40 mmol) stirred under nitrogen. The resulting solution (pH 6.53) was spray-dried, obtaining 16.9 g of the title product.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.Cl[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][C:23]([OH:25])=[O:24])=[C:14]([CH3:26])[N:13]=1.O1CCOCC1.Cl>CCOCC>[ClH:10].[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][N:2]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH2:22][C:23]([OH:25])=[O:24])=[C:14]([CH3:26])[N:13]=2)[CH3:1])=[CH:5][CH:6]=1
Reactant: Cc1nc(Cl)c2ccccc2c1CC(=O)O
Reactant: CNCc1ccc(Cl)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cc1nc(N(C)Cc2ccc(Cl)cc2)c2ccccc2c1CC(=O)O

Procedure:
N-Methyl-4-chlorobenzylamine (1.40 g., 9.0 mmol) and 1-chloro-3-methyl-4-isoquinoline acetic acid (770 mg., 3.0 mmol), prepared as in Example 8, were refluxed in 20 ml. p-dioxane for 16 hr. The cooled reaction mixture was partitioned between 200 ml ether and 50 ml 1 N sodium hydroxide. The ether rafinate was extracted with 2×30 ml 1 N sodium hydroxide. The combined basic phases were acidified to pH 6.5 with 6 N hydrochloric acid and extracted with 3×75 ml ethyl acetate. This organic phase was dried over magnesium sulfate, filtered, and vacuum evaporated to an oily residue. Chromatography of this on silica gel eluted with ethyl acetate gave an oil. The title compound was prepared from this oil by treatment with hydrochloric acid gas in ether, filtrate, and drying in vacuo; 52 mg. (4%), m/e 354.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:12])=[C:4]([C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)[CH:5]=O.[C:13](#[N:16])[CH:14]=[CH2:15]>>[C:13]([C:14]1[CH2:15][O:12][C:3]2[C:4]([CH:5]=1)=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:2]=2[F:1])#[N:16]
Reactant: C=CC#N
Reactant: COc1ccc(F)c(O)c1C=O
Product: COc1ccc(F)c2c1C=C(C#N)CO2
Yield: 13.6 %

Procedure:
Crude 3-fluoro-hydroxy-6-methoxybenzaldehyde (8.0 g) from above, acrylonitrile (13 mL; 193 mmol) and 1,4.diazadicyclo [2,2,2]octane (0.66 g; 5.9 mmol) were refluxed in a three-necked round-bottom flask (50 mL) under nitrogen for 4 h. Rotary-evaporation of the volatiles left a thick, red oil which was flash-chromatographed on a silica column eluted with methylene chloride/n-hexane (4:5). Concentration of relevant fractions gave an impure product (91% GC) which was crystallized form EtOAc to give 1.31 g of the title compound as colourless bars. Mp. 133°-135° C.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][C:15]([CH3:25])=[C:16]([CH2:18][CH2:19]OS(C)(=O)=O)[N:17]=2)=[CH:9][CH:8]=1>C1COCC1>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][C:15]([CH3:25])=[C:16]([CH2:18][CH2:19][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[N:17]=2)=[CH:9][CH:8]=1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCOS(C)(=O)=O
Reactant: CCNCC
Solvent: C1CCOC1
Product: CCN(CC)CCc1nc(-c2ccc(Br)cc2)oc1C
Temperature: 60 °C
Yield: 66.6 %

Procedure:
Add diethyl amine (0.488 g, 6.68 mmol) to a solution of methanesulfonic acid 2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyl ester (See Intermediate 13) (0.240 g, 0.668 mmol) in anhydrous THF (5 mL) in a sealed tube, and heat at 60° C. overnight. Add dichloromethane and wash the crude organic layer with saturated sodium chloride solution. Dry the organic extracts over Na2SO4, filter, and concentrate. Purify on silica gel eluting with 5% anmioniated methanol in dichloromethane to give {2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyl}-diethyl-amine (0.150 g, 67%): MS (nme): 337 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[C:5]([N+:11]([O-])=O)=[C:4]([CH:14]([CH3:16])[CH3:15])[CH:3]=1.C(N(CC)CC)C>O1CCCC1.[Pd]>[CH:8]([C:6]1[C:5]([NH2:11])=[C:4]([CH:14]([CH3:16])[CH3:15])[CH:3]=[CH:2][N:7]=1)([CH3:10])[CH3:9]
Reactant: CC(C)c1cc(Cl)nc(C(C)C)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)c1ccnc(C(C)C)c1N

Procedure:
5.0 g of 6-chloro-2,4-diisopropyl-3-nitropyridine are dissolved in 100 ml of tetrahydrofuran and, after the addition of 2.75 g of triethylamine and 7.5 g of 5% palladium/carbon catalyst, hydrogenated under normal pressure at from +20° C. to +25° C. The reaction mixture is filtered over diatomaceous earth and the filtrate is concentrated. The residue is purified by column chromatography on silica gel (eluant: ethyl acetate/hexane 1:3). 2,4-Diisopropyl-3-aminopyridine is obtained in the form of a waxlike solid, m.p. 35°-39° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]([OH:8])=O.CCN(CC)CC.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[F:43][C:44]([F:74])([F:73])[C:45]1[CH:46]=[C:47]([C:55]([CH3:72])([CH3:71])[C:56]([N:58]([CH3:70])[C@H:59]2[C@H:63]([C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[CH2:62][NH:61][CH2:60]2)=[O:57])[CH:48]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:50]=1>C1COCC1>[F:53][C:51]([F:52])([F:54])[C:49]1[CH:48]=[C:47]([C:55]([CH3:71])([CH3:72])[C:56]([N:58]([CH3:70])[C@H:59]2[C@H:63]([C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[CH2:62][N:61]([C:6]([C@@H:2]3[CH2:3][CH2:4][CH2:5][O:1]3)=[O:8])[CH2:60]2)=[O:57])[CH:46]=[C:45]([C:44]([F:43])([F:73])[F:74])[CH:50]=1
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CNC[C@H]1c1ccccc1
Reactant: O=C(O)[C@@H]1CCCO1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CN(C(=O)[C@@H]2CCCO2)C[C@H]1c1ccccc1
Reaction time: 48 h
Yield: 21.3 %

Procedure:
To a stirred solution of (S)-tetrahydro-furan-2-carboxylic acid (described in J. Med. Chem., 1995, 38(15, 2830) (5.0 mg, 0.043 mmol) in THF (2 ml) at RT were added Et3N (12 μl, 0.086 mmol), BOP (25 mg, 0.057 mmol) and rac-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-((3S,4R)-4-phenyl-pyrrolidin-3-yl)-isobutyramide (Intermediate VII-1) (20 mg, 0.043 mmol). Stirring was continued at 40° C. for 48 hours. Concentration and purification by preparative HPLC afforded 5.1 mg (25%) of the title compound.
Reaction SMILES: B1([O-])OO1.[OH2:5].[OH2:6].O.O.[Na+].[Cl:10][C:11]1[CH:12]=[C:13]([CH:15]=[C:16]([F:18])[CH:17]=1)[NH2:14].CC(OC)(C)C>C(O)(=O)C>[Cl:10][C:11]1[CH:12]=[C:13]([N+:14]([O-:6])=[O:5])[CH:15]=[C:16]([F:18])[CH:17]=1
Reactant: Nc1cc(F)cc(Cl)c1
Reactant: O
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CC(=O)O
Solvent: COC(C)(C)C
Product: O=[N+]([O-])c1cc(F)cc(Cl)c1
Temperature: 55 °C
Reaction time: 1 h
Yield: 18.2 %

Procedure:
Sodium perborate tetrahydrate (7.69 g, 50.0 mmol) was suspended in 30 mL of acetic acid, and this suspension was warmed to 55° C. 3-Chloro-5-fluoroaniline (1.46 g, 10 mmol) was dissolved in 20 mL of acetic acid and added within one hour. The reaction was stirred for 1 hour at 55° C. and then cooled to room temperature. 300 mL of TBME was added, and the reaction mixture was filtered. The organic layer was washed with brine, followed by 20 mL of aqueous Na2S2O3, followed by brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give a residue, which was purified by column chromatography (40 g SiO2; cyclohexane) to yield the title compound as a solid (320 mg, 18%). 1H-NMR (400 MHz; DMSO-d6): 8.20 (s, 1H), 8.18 (d, 1H), 8.07 (d, 1H).
Reaction SMILES: [C:1]12([C:11]3[CH:22]=[CH:21][C:14]([O:15][CH2:16][CH2:17][C:18](O)=[O:19])=[C:13]([CH3:23])[CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[C:1]12([C:11]3[CH:22]=[CH:21][C:14]([O:15][CH2:16][CH2:17][C:18]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[O:19])=[C:13]([CH3:23])[CH:12]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: Cc1cc(C23CC4CC(CC(C4)C2)C3)ccc1OCCC(=O)O
Reactant: C1COCCN1
Product: Cc1cc(C23CC4CC(CC(C4)C2)C3)ccc1OCCC(=O)N1CCOCC1
Yield: 91.1 %

Procedure:
The title compound was prepared from 3-(4-(adamantan-1-yl)-2-methylphenoxy)propanoic acid (0.2 g, 0.63 mmol) and morpholine (0.055 g, 0.63 mmol) according to the example 1, which was given 3-(4-(adamantan-1-yl)-2-methylphenoxy)-1-morpholinopropan-1-one as a white solid (0.22 g, 90.5% yield).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[C:10]([NH:11][CH2:12][C:13]3[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:20])=[CH:9][CH:8]=[CH:7][N:6]2[C:21]=1[CH3:22].[CH3:23][S-:24].[Na+]>C(#N)C>[CH3:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([CH3:19])[C:13]=1[CH2:12][NH:11][C:10]1[C:5]2[N:6]([C:21]([CH3:22])=[C:3]([CH2:2][S:24][CH3:23])[N:4]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: C[S-]
Reactant: Cc1cccc(C)c1CNc1cccn2c(C)c(CCl)nc12
Agent: [Na+]
Solvent: CC#N
Product: CSCc1nc2c(NCc3c(C)cccc3C)cccn2c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 24 %

Procedure:
2-chloromethyl-8-(2,6-dimethylbenzylamino)-3-methylimidazo[1,2-a]pyridine (0.2 g, 0.64 mmol) and sodium methanethiolate (0.1 g, 1.3 mmol) were added to acetonitrile (10 ml) and stirred for 4 h. at room temperature. The solvent was evaporated under reduced pressure and to the residue were added methylene chloride and water. The organic layer was separated, dried (Na2SO4) and evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel using diethyl ether:petroleum ether (1:2) as eluent and crystallization from diethyl ether:petroleum ether (1:2) gave 0.05 g (24%) of the desired product.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)#[N:2].Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][C:21]([CH3:32])=[C:22]([CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][C@H:27]3[CH3:31])[N:23]=2)=[CH:15][CH:14]=1>>[CH3:32][C:21]1[O:20][C:19]([C:16]2[CH:17]=[CH:18][C:13]([C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[CH:8]=3)=[CH:14][CH:15]=2)=[N:23][C:22]=1[CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][C@H:27]1[CH3:31]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCC[C@H]1C
Product: Cc1oc(-c2ccc(-c3cccc(C#N)c3)cc2)nc1CCN1CCC[C@H]1C

Procedure:
The title compound is prepared in a manner substantially analogous to example 133 starting from 3-Cyanobenzene boronic acid (211 mg, 1.43 mmol) and 2-(4-Bromo-phenyl)-5-methyl-4-[2-((R)-2-methyl-pyrrolidin-1-yl)-ethyl]-oxazole (100 mg, 0.287 mmol) to give 50 mg (47%). MS (m/e) 372.2 (M+1)
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:25]([CH:26]=[CH2:27])=[C:14]3[CH2:15][CH:16]([N:22]([CH3:24])[CH3:23])[C:17]4[CH2:18][O:19][CH:20]=[CH:21][C:12]([C:13]=43)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.O1CCCC1.[Pd]>[C:1]1([S:7]([N:10]2[C:25]([CH2:26][CH3:27])=[C:14]3[CH2:15][CH:16]([N:22]([CH3:23])[CH3:24])[C:17]4[CH2:18][O:19][CH:20]=[CH:21][C:12]([C:13]=43)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CC1=C2CC(N(C)C)C3=C2C(=CN1S(=O)(=O)c1ccccc1)C=COC3
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCC1=C2CC(N(C)C)C3=C2C(=CN1S(=O)(=O)c1ccccc1)C=COC3
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.4 %

Procedure:
Compound (54) 200.1 mg was dissolved in a mixture of methanol 8 ml and tetrahydrofuran 4 ml. 10% Pd/C 49.8 mg was added. The mixture was stirred under hydrogen atmosphere for 18 h at room temperature. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in chloroform:hexane (1:1) to give the titled compound as a colorless oil 198 mg. Yield 98%. This was treated with 1 eq. of oxalic acid to give the salt, which was recrystallized from ether-methanol to give colorless crystals, m.p. 193-194° C.(dec.).
Reaction SMILES: Cl.[N:2]1([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[CH:28]([OH:30])[CH3:29].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[OH:30][CH2:28][CH2:29][N:5]1[CH2:6][CH2:7][N:2]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][CH:18]=3)[N:9]=2)[CH2:3][CH2:4]1
Reactant: CC(O)Br
Reactant: FC(F)(F)c1ccc(-n2nc(N3CCNCC3)c3ccccc32)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCN1CCN(c2nn(-c3ccc(C(F)(F)F)cc3)c3ccccc23)CC1
Yield: 44.6 %

Procedure:
A stirred mixture of 5.5 g of 3-(1-piperazinyl)-1-[4(trifluoromethyl)phenyl]-1H-indazole hydrochloride, 2.3 g of bromoethanol, 2.5 g of potassium carbonate and 60 ml of dimethylformamide was heated, under nitrogen, at 70°-75° for 16 hours. The reaction mixture was poured into water and the aqueous mixture extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated to an oil. The oil was chromatographed on silica gel utilizing a Water's Model 500 High Pressure Liquid Chromatograph and eluting with dichloromethane/methanol (6%). Evaporation of the appropriate fractions gave an oil which solidified upon standing. Recrystallization of the solid from hexane (2×) gave 2.5 g (40%) of 3-[4-(2-hydroxyethyl)-1piperazinyl-]-1-[4-(trifluoromethyl)phenyl]-1H-indazole, mp 82°-84°.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[N+]([C:8]1[C:9]([N+]([O-])=O)=[C:10]([CH3:14])[CH:11]=[CH:12][CH:13]=1)([O-])=O>C1(C)C=CC=CC=1>[N+:1]([C:13]1[CH:12]=[CH:11][C:10]([CH3:14])=[CH:9][CH:8]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc([N+](=O)[O-])c1[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: Cc1ccc([N+](=O)[O-])cc1

Procedure:
Commercial aromatic nitration processes are generally operated with a mixed acid system comprising sulfuric and nitric acids. A substantial amount of nitric acid is typically lost in an economically and environmentally unsound manner in the spent acid of nitration. For example, conventional dinitrotoluene processes comprise reacting toluene in a first nitration stage to form mononitrotoluene and separating the organic product from the aqueous spent acid phase. The nitric acid in the spent acid phase is usually removed or recovered so that the remaining sulfuric acid can be reconcentrated and recycled. The crude mononitrotoluenes are then nitrated with fresh nitrating acid in a second nitration stage. The dinitrotoluene product is then separated from the aqueous spent acid phase which is recycled to a nitration stage.
Reaction SMILES: C(=O)(O)[O-:2].[Na+].Cl.NO.[CH3:9][C:10]1[N:15]=[C:14]([C:16]#[N:17])[CH:13]=[C:12]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[CH:11]=1>C(O)C>[CH3:9][C:10]1[N:15]=[C:14]([C:16]([NH2:17])=[O:2])[CH:13]=[C:12]([O:18][CH2:19][C:20]([F:23])([F:21])[F:22])[CH:11]=1
Reactant: O=C([O-])O
Reactant: Cc1cc(OCC(F)(F)F)cc(C#N)n1
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(OCC(F)(F)F)cc(C(N)=O)n1
Reaction time: 2 h
Yield: 101.7 %

Procedure:
To 6 ml of ethanol were added 0.54 g of sodium bicarbonate and 0.44 g of hydroxylamine hydrochloride, and the mixture was heated to reflux for 1 hour. After allowing to cool, 0.69 g of 6-methyl-4-(2,2,2-trifluoroethoxy)pyridine-2-carbonitrile was added at room temperature, and the mixture was stirred for 2 hours, and concentrated. To the residue was added water, the resultant solution was extracted with ethyl acetate three times, and the organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was washed with hexane three times to obtain 0.76 g of 6-methyl-4-(2,2,2-trifluoroethoxy)pyridine-2-carboxamide=oxime.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27]([F:31])[CH:26]([CH3:32])[CH2:25][CH:24]([O:33][CH3:34])[CH:23]2[O:35][C:19]([OH:39])([CH:20]([CH3:38])[CH2:21][CH:22]2[O:36][CH3:37])[C:18](=[O:40])[C:17](=[O:41])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:42])[O:9][CH:8]([C:43]([CH3:63])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([O:51][C:52]3[CH:61]=[CH:60][C:59]4[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=4)[CH:53]=3)[CH:47]([OH:62])[CH2:46]2)[CH:7]([CH3:64])[CH:6]([OH:65])[CH2:5][C:4]1=[O:66])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:71][CH:72]=[CH2:73].FC(F)(F)S(O)(=O)=O>C(Cl)Cl.C1CCCCC1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27]([F:31])[CH:26]([CH3:32])[CH2:25][CH:24]([O:33][CH3:34])[CH:23]2[O:35][C:19]([OH:39])([CH:20]([CH3:38])[CH2:21][CH:22]2[O:36][CH3:37])[C:18](=[O:40])[C:17](=[O:41])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:42])[O:9][CH:8]([C:43]([CH3:63])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([O:51][C:52]3[CH:61]=[CH:60][C:59]4[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=4)[CH:53]=3)[CH:47]([O:62][CH2:73][CH:72]=[CH2:71])[CH2:46]2)[CH:7]([CH3:64])[CH:6]([OH:65])[CH2:5][C:4]1=[O:66])[CH3:2]
Reactant: CCC1C=C(C)C(F)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc5ccccc5c4)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCCCC1
Solvent: ClCCl
Product: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)C(F)C(C)=CC(CC)C(=O)CC(O)C2C)C(OC)CC3C)CCC1Oc1ccc2ccccc2c1
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-20-fluoro-1,14-dihydroxy-12-[2'-(4"-(napth-2-yloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone in 33% methylene chloride/cyclohexane is added 1.5 equivalents of allyl trichloroacetimidate, and the reagents are allowed to mix for 5 minutes. A catalytic amount of trifluoromethanesulfonic acid is then added slowly via syringe and the mixture is stirred at room temperature. After 3 hours the reaction is quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate. The combined organics are washed with brine and dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel gives the title compound.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[F:18][C:19]1[C:24]([F:25])=[C:23]([F:26])[CH:22]=[CH:21][C:20]=1B(O)O>>[F:17][C:4]1[CH:3]=[C:2]([C:22]2[CH:21]=[CH:20][C:19]([F:18])=[C:24]([F:25])[C:23]=2[F:26])[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Reactant: OB(O)c1ccc(F)c(F)c1F
Product: Cc1c2n(c3c(-c4ccc(F)c(F)c4F)cc(F)cc13)CCNC2=O

Procedure:
The title compound, white solid (21 mg, 24%), MS (ISP) m/z=349.5 [(M+H)+], mp 130° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 2,3,4-trifluorophenylboronic acid (57.2 mg, 0.325 mmol).
Reaction SMILES: O=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[C:12]([CH2:15][C:16](=[O:18])[CH3:17])(=[O:14])[CH3:13]>>[CH3:7][O:6][C:5]1[C:8]([OH:9])=[CH:10][CH:11]=[C:3](/[CH:2]=[CH:13]/[C:12]([CH2:15][C:16](/[CH:17]=[CH:2]/[C:3]2[CH:4]=[C:5]([O:6][CH3:7])[C:8]([OH:9])=[CH:10][CH:11]=2)=[O:18])=[O:14])[CH:4]=1
Reactant: CC(=O)CC(C)=O
Reactant: COc1cc(C=O)ccc1O
Product: COc1cc(/C=C/C(=O)CC(=O)/C=C/c2ccc(O)c(OC)c2)ccc1O
Yield: 80 %

Procedure:
British patent No. 914 047 (publ. 28.12.62) describes the condensation of vanillin with acetylacetone in the presence of 2 mole equivalents of trialkyl borates and 0.35 molequivalents boric oxide to give curcumin with yields from 16-80% of the theory. Best results (80% yield) at room temperature were obtained in ethyl acetate as solvent with 2 molequivalents tri-isopropyl borate in the presence of 0.35 molequivalent of boric anhydride and 0.1 molequivalent butylamine (Pabon, H. J. J., Recueil 83, 379-386 [1964]). However, the purity of the curcumin is not mentioned.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:10]=3[C:9]=2[O:19][C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28](O)=[O:29])=[CH:22][CH:21]=2)=[C:4]([CH3:31])[CH:3]=1.[O:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]1[O:38][NH2:39].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:10]=3[C:9]=2[O:19][C:20]2[CH:21]=[CH:22][C:23](/[CH:26]=[CH:27]/[C:28]([NH:39][O:38][CH:33]3[CH2:34][CH2:35][CH2:36][CH2:37][O:32]3)=[O:29])=[CH:24][CH:25]=2)=[C:4]([CH3:31])[CH:3]=1
Reactant: COc1ccc2c(Oc3ccc(/C=C/C(=O)O)cc3)c(-c3ccc(F)cc3C)sc2c1
Reactant: NOC1CCCCO1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(Oc3ccc(/C=C/C(=O)NOC4CCCCO4)cc3)c(-c3ccc(F)cc3C)sc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
To a 30 mL screw cap vial, (E)-3-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (50 mg, 0.115 mmol) was dissolved in DMF (2 mL). The vial was charged with O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (27.0 mg, 0.230 mmol), HATU (65.6 mg, 0.173 mmol), and DIEA (0.060 mL, 0.345 mmol). The reaction mixture was stirred for 30 min at room temperature. The reaction was quenched with sat. NH4Cl and diluted with DCM. The organic phase was collected (phase separator) and concentrated by vacuum to afford to crude product. The crude material was purified by column chromatography (SiO2, 1-80% Heptanes/EtOAc) to afford (E)-3-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)acrylamide (53 mg, 0.099 mmol, 86% yield). 1H NMR (400 MHz, CD3OD) δ ppm=1.48-1.73 (m, 3H), 1.73-1.96 (m, 3H), 2.36 (s, 3H), 3.56-3.70 (m, 1H), 3.89 (s, 3H), 3.98-4.14 (m, 1H), 4.96 (br. s., 1H), 6.35 (d, J=15.66 Hz, 1H), 6.79-6.95 (m, 3H), 6.95-7.07 (m, 2H), 7.26-7.39 (m, 2H), 7.39-7.48 (m, 3H), 7.52 (d, J=16.17 Hz, 1H). LC/MS (m/z, MH+): 534.1.
Reaction SMILES: O=C1[S:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])O1.[C:12](#[N:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([C:12]2[S:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:19]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1nsc(=O)o1
Reactant: N#Cc1ccccc1
Product: CCOC(=O)c1nsc(-c2ccccc2)n1
Temperature: 25 °C
Yield: 3 %

Procedure:
A mixture of ethyl 2-oxo-1,3,4-oxathiazole-5-carboxylate (U.S. Publication No. 2005/0096362) (1.5 g, 8.56 mmol) and benzonitrile (4.37 ml, 42.8 mmol) in 1,2-dichrlotobenzene (15.42 ml, 137 mmol) was heated to 160° C. for 4 days. The reaction was then cooled down to RT and the solvent was evaporated by heated the reaction at 75° C. at maximum vacuum. The residue was purified on silica gel chromatography (100% CH2Cl2 to 3% EtOAc in CH2Cl2) to provide the title material (0.064 g, 3%). LC (Method B): 2.021 min. HRMS (ESI) calcd for C11H11N2O2S [M+H]+ m/z 235.0541. found 235. 1H NMR (CDCl3, 400 MHz) δ ppm: 8.01-8.09 (m, 1H), 7.49-7.59 (m, 2H), 4.56 (q, J=7.17 Hz, 1H), 1.50 (t, J=7.24 Hz, 1H).