Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][N:13]2[C:22](=[O:23])[C:21]3[N:20]([CH2:24][C:25]#[C:26][CH3:27])[C:19](Br)=[N:18][C:17]=3[N:16]([CH3:29])[C:14]2=[O:15])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:36]1[CH2:41][CH2:40][CH2:39][C@@H:38]([NH2:42])[CH2:37]1>C(C(C)=O)C(C)C>[CH3:27][C:26]#[C:25][CH2:24][N:20]1[C:19]([N:36]2[CH2:37][C@H:38]([NH2:42])[CH2:39][CH2:40][CH2:41]2)=[N:18][C:17]2[N:16]([CH3:29])[C:14]([N:13]([CH2:12][C:4]3[N:3]=[C:2]([CH3:1])[C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[N:5]=3)[C:22](=[O:23])[C:21]1=2)=[O:15]
Reactant: N[C@@H]1CCCNC1
Reactant: CC#CCn1c(Br)nc2c1c(=O)n(Cc1nc(C)c3ccccc3n1)c(=O)n2C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CC#CCn1c(N2CCC[C@@H](N)C2)nc2c1c(=O)n(Cc1nc(C)c3ccccc3n1)c(=O)n2C
Temperature: 95 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
1-[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromoxanthine (20 gm) and methyl isobutyl ketone (MIBK 200 mL) were charged into a 1000 mL round bottomed flask equipped with a mechanical stirrer. Potassium carbonate (18.3 gm) and (R)-piperidine-3-amine (11.5 gm) were added to the reaction mixture at 30° C. The reaction mixture was heated to 95° C. and maintained at that temperature for 8 hours. The reaction mixture was cooled to 30° C. and filtered and washed with MIBK (40 mL). The filtrate was charged into another flask and added 10% aqueous acetic acid solution and stirred for one hour at 30° C. The aqueous layer was separated and washed with 60 mL of dichloromethane. The aqueous layer was charged into another flask and 200 mL of dichloromethane and 100 mL of aqueous sodium hydroxide solution (16 gm of sodium hydroxide in 100 mL of water) was added drop-wise at 30° C. The mixture was stirred for one hour at 30° C. and the organic layer was separated and the aqueous layer was extracted with 100 ml of dichloromethane. Combined the organic layers and evaporated under vacuum at below 45° C. Toluene (100 mL) was added to the residue and stirred for 3 hours at 30° C. Filtered the compound and washed with Toluene (40 mL) and dried the compound at below 60° C. under vacuum to give 16.8 gm of Linagliptin. Purity: 98.91%, PXRD pattern: FIG. 2.
Reaction SMILES: BrCCBr.C[Si](Cl)(C)C.[C:10]([N:17]1[CH2:20][CH:19](I)[CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].Br[C:23]1[C:28]([Br:29])=[CH:27][CH:26]=[CH:25][N:24]=1.C(Cl)Cl>CC(N(C)C)=O.[Zn].[Cu]I>[Br:29][C:28]1[C:23]([CH:19]2[CH2:20][N:17]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:18]2)=[N:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: Brc1cccnc1Br
Agent: [Cu]I
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Solvent: BrCCBr
Product: CC(C)(C)OC(=O)N1CC(c2ncccc2Br)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87.5 %

Procedure:
A 5 L 3-neck round bottom flask fitted with a magnetic stirrer under nitrogen was charged with zinc dust (138 g, preactivated according to the above Preparation 1, 2.11 mol, 2 eq.) and DMA (370 mL, anhydrous). 1,2-dibromoethane (13 mL, 0.158 mol, 0.15 eq, Aldrich) was then added over 5 min, followed by TMSCl (20 mL, 0.158 mol, 0.15 eq, Acros) over 5 min. The reaction mixture was stirred for 20 min at RT. A solution of N-Boc-3-iodoazetidine (2) (448 g, 1.583 mol, 1.5 eq, CNH Technologies) in DMA (925 mL, anhydrous) was added over 25 min keeping the internal temperature below 65° C. using a water bath. The suspension was stirred for 1 h at RT at which point it was degassed with nitrogen. Stirring was stopped and the suspension was allowed to stand. A 12 L 3-neck round bottom flask fitted with a mechanical stirrer was charged with 2,3-dibromopyridine (1) (250 g, 1.055 mol, 1.0 eq, Frontier Scientific), PdCl2dppf.CH2Cl2 (25.8 g, 31.65 mmol, 0.03 eq, Aldrich), CuI (12.5 g, 65.41 mmol, 0.062 eq, Aldrich), and DMA (925 mL, anhydrous). The solution was degassed with nitrogen. The clear zinc reagent solution above the residual solid zinc was poured into the 12 L flask under nitrogen. The brown solution was degassed with nitrogen and heated to 80° C. for 17 h at which point LCMS indicated complete conversion of 2,3-dibromopyridine (1). The reaction mixture was transferred to brine (2 L) in 22 L separatory funnel. Water (2 L) and EtOAc (4 L) were added and the layers were separated. The aqueous layer was extracted with EtOAc (2×3 L). The combined organics were washed with water (3×3 L) and brine (2 L), dried over sodium sulfate and evaporated. The resulting residue was purified by column chromatography (eluting with hexanes/ethyl acetate=9:1 to 5:1) to obtain 289 g of impure tert-butyl 3-(3-bromopyridin-2-yl)azetidine-1-carboxylate (3) which was distilled under high vacuum to remove the impurity (N-Boc-azetidine) to give 281 g of pure tert-butyl 3-(3-bromopyridin-2-yl)azetidine-1-carboxylate. Yield: 85%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11](C(O)=O)[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[F:25][C:26]([F:30])([F:29])[S:27]Cl>CCOCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([S:27][C:26]([F:30])([F:29])[F:25])[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1
Reactant: FC(F)(F)SCl
Reactant: COc1ccc(-c2cc(C(=O)O)[nH]c2-c2ccc(OC)cc2)cc1
Solvent: CCOCC
Product: COc1ccc(-c2cc(SC(F)(F)F)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 0.3 g (1 m mole) of 4,5-bis(4-methoxyphenyl)pyrrole-2-carboxylic acid in 5 ml ether/5 ml THF at -78° was added as a gas 0.3 g of trifluoromethanesulfenyl chloride. After 15 minutes, TLC showed no evidence of reaction, so a large excess of trifluoromethanesulfenyl chloride was added and the mixture was allowed to warm slowly to room temperature overnight, with a dry ice condenser attached for the first few hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by chromatography on 100 g Silic AR CC-7 to give after recrystallization from hexane 0.15 g (40%) of 4,5-bis(4-methoxyphenyl)-2-(trifluoromethylthio)pyrrole, identical to material obtained by Method A.
Reaction SMILES: [C:1]([C:4]1[C:5]([N:16]=[CH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][C:8]=1[CH3:9])(=[O:3])[CH3:2].[CH2:24](I)[CH3:25]>>[C:1]([C:4]1[C:5]([N:16]=[CH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([CH2:24][CH3:25])[C:8]=1[CH3:9])(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(C)[nH]c(-c2ccccc2)c1N=Cc1ccccc1
Reactant: CCI
Product: CCn1c(C)c(C(C)=O)c(N=Cc2ccccc2)c1-c1ccccc1

Procedure:
By procedure (a) of Example 49 and starting from the compound of Example 46 and ethyl iodide, the 4-acetyl-3-benzylideneamino-1-ethyl-5-methyl-2-phenylpyrrole is obtained, m.p. 139°-41° C. (from isopropanol/-water). This compound is hydrolyzed as in procedure (b) of Example ;49. Overall yield of the title compound: 54%, m.p. 107°-8° C.(from ethanol). 1-propylpyrrole
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([Cl:12])=[C:10]([F:11])[C:5]2=[N:4][CH:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17](B2OC(C)(C)C(C)(C)O2)=[CH:16][C:15]=1[C:29]1[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=1>>[Cl:12][C:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:17]3[CH:18]=[CH:19][C:14]([F:13])=[C:15]([C:29]4[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:16]=3)=[CH:3][N:4]=[C:5]2[C:10]=1[F:11]
Reactant: Fc1c(Cl)ccn2c(Br)cnc12
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccccc3C#N)c2)OC1(C)C
Product: N#Cc1ccccc1-c1cc(-c2cnc3c(F)c(Cl)ccn23)ccc1F
Yield: 70.3 %

Procedure:
3-Bromo-7-chloro-8-fluoroimidazo[1,2-α]pyridine (70 mg, 0.28 mmol) was coupled with 2′-fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile (109 mg, 0.34 mmol), as described in Example 1, to afford the title compound as a white amorphous solid (72 mg, 71%): δH (400 MHz, DMSO) 7.11 (1H, t, J 7.0), 7.60-7.70 (2H, m), 7.78 (1H, s), 7.85-7.89 (3H, m), 7.93 (1H, s), 8.04 (1H, dd, J 0.8, 7.8), 8.52 (1H, dd, J 1.0, 7.2); m/z (ES+) 366 (100%, [MH]+).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][C:5]2[CH:8]=[C:9]([N:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]4[C:30]5[C:25](=[CH:26][CH:27]=[C:28]([C:31]([O:33]C)=[O:32])[CH:29]=5)[NH:24][CH:23]=4)[CH2:14][CH2:13]3)[CH:10]=[CH:11][C:4]=2[O:3]1>[OH-].[K+]>[O:1]=[C:2]1[CH:7]=[CH:6][C:5]2[CH:8]=[C:9]([N:12]3[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]4[C:30]5[C:25](=[CH:26][CH:27]=[C:28]([C:31]([OH:33])=[O:32])[CH:29]=5)[NH:24][CH:23]=4)[CH2:16][CH2:17]3)[CH:10]=[CH:11][C:4]=2[O:3]1
Reactant: COC(=O)c1ccc2[nH]cc(CCCCN3CCN(c4ccc5oc(=O)ccc5c4)CC3)c2c1
Agent: [K+]
Agent: [OH-]
Product: O=C(O)c1ccc2[nH]cc(CCCCN3CCN(c4ccc5oc(=O)ccc5c4)CC3)c2c1

Procedure:
1.8 g of methyl 3-{4-[4-(2-oxo-2H-1-benzopyran-6-yl)-1-piperazinyl]butyl}indole-5-carboxylate are boiled for 30 minutes with 100 ml of 2N ethanolic KOH and worked up in the customary manner and 3-{4-[4-(2-oxo-2H-1-benzopyran-6-yl)-1-piperazinyl]butyl}indole-5-carboxylic acid is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]1([NH:25][OH:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[N+:25]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[O-:26])=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Reactant: ONC1CCCCC1
Product: COc1cc(C=[N+]([O-])C2CCCCC2)ccc1OCc1ccccc1

Procedure:
The title compound was prepared according to the procedure described in Example 11 using 4-benzyloxy-3-methoxybenzaldehyde and N-cyclohexylhydroxylamine. The title compound was isolated in 97.9% yield as a solid, m.p. 154.1° C.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[CH:10]=[C:9]([NH:11]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:8]([F:31])=[CH:7][N:6]=1)C.OS(O)(=O)=O.CC#N>O>[NH2:11][C:9]1[C:8]([F:31])=[CH:7][N:6]=[C:5]([CH:4]=[O:3])[CH:10]=1
Reactant: CCOC(OCC)c1cc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)cn1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC#N
Product: Nc1cc(C=O)ncc1F
Yield: 89.9 %

Procedure:
Following the procedure for Example 12, 2-(diethoxymethyl)-5-fluoro-N-tritylpyridin-4-amine (457 mg, 1 mmol), conc H2SO4 (0.2 mL), CH3CN (5 mL) and H2O (5 mL) gave 4-amino-5-fluoropicolinaldehyde (126 mg, 87%) as a white solid: mp 133-135° C.; 1H NMR (400 MHz, CDCl3) δ 9.90 (s, 1H), 8.34 (d, J=2.7 Hz, 1H), 7.36 (d, J=7.5 Hz, 1H), 4.47 (br s, 2H); 19F NMR (376 MHz, CDCl3) δ −144.44; HRMS-ESI (P/z) [M+H]+ calcd for C6H5FN2O, 140.0386. found, 140.0384.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]=[C:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[CH3:2].[O-]CC.[Na+]>CS(C)=O>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[CH3:2]
Reactant: CCOC(=O)C=C1CCCCC1c1cccc(OC)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)CC1=C(c2cccc(OC)c2)CCCC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
Combine [2-(3-methoxy-phenyl)-cyclohexylidene]-acetic acid ethyl ester (839.4 mg, 3.06 mmol), sodium ethoxide (62.5 mg, 0.92 mmol), and DMSO (6.0 mL), stir, and heat at 100° C. After 2 hours, cool to ambient temperature and extract the organic layer with ethyl acetate. Wash the ethyl acetate layer 5× with brine and dry the organic layer over sodium sulfate, and concentrate in vacuo to yield the titled compound (769.6 mg, 92%) as a clear oil. TLC Rf=0.58 in 8:1 hexanes:ethyl acetate. 1H NMR (CDCl3): 7.21 (m, 1H), 6.75 (m, 3H), 4.11 (q, 2H, J=7.2 Hz), 3.79 (s, 3H), 2.91 (s, 2H), 2.28 (m, 2H), 2.12 (m, 2H), 1.72 (m, 4H), 1.24 (t, 3H, J=7.3 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:22]4[CH2:23][CH2:24][CH:18]3[CH2:19][N:20]([CH:25]3[CH2:28][O:27][CH2:26]3)[CH2:21]4)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:29]([O:32][CH2:33][C:34]1[C:35]([N:43]2[CH2:55][CH2:54][N:46]3[C:47]4[CH2:48][CH2:49][CH2:50][CH2:51][C:52]=4[CH:53]=[C:45]3[C:44]2=[O:56])=[N:36][CH:37]=[CH:38][C:39]=1B(O)O)(=[O:31])[CH3:30].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>O.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(#N)C>[C:29]([O:32][CH2:33][C:34]1[C:35]([N:43]2[CH2:55][CH2:54][N:46]3[C:47]4[CH2:48][CH2:49][CH2:50][CH2:51][C:52]=4[CH:53]=[C:45]3[C:44]2=[O:56])=[N:36][CH:37]=[CH:38][C:39]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:22]4[CH2:23][CH2:24][CH:18]3[CH2:19][N:20]([CH:25]3[CH2:28][O:27][CH2:26]3)[CH2:21]4)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)OCc1c(B(O)O)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: Cn1cc(Br)cc(Nc2ccc(N3C4CCC3CN(C3COC3)C4)cn2)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4C5CCC4CN(C4COC4)C5)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 25 °C
Yield: 42.4 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 152e (300 mg, 0.67 mmol), 3-(acetoxymethyl)-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)pyridin-4-ylboronic acid 113h (257 mg, 0.67 mmol), Pd(dppf)Cl2 (55 mg, 0.067 mmol), K3PO4 (284 mg, 1.34 mmol), sodium acetate (110 mg, 1.34 mmol), water (6 drops), and acetonitrile (20 mL). After three cycles of vacuum/argon flush, the mixture was stirred at reflux for 3 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 152f as a brown solid (200 mg, 42%). MS-ESI: [M+H]+ 705.4.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][NH:6][C:7](=[O:11])[CH2:8][CH2:9][CH3:10])C.Cl.CCOCC.O>C1COCC1>[O:3]=[CH:4][CH2:5][NH:6][C:7](=[O:11])[CH2:8][CH2:9][CH3:10]
Reactant: CCCC(=O)NCC(OCC)OCC
Agent: Cl
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCC(=O)NCC=O
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 55 %

Procedure:
A solution of N-(2,2-diethoxyethyl)butyramide (2.0 g, 0.0098 mol.)) in 10 mL of THF at 0° C. was added HCl (2N) in ether (4.9 mL, 1.0 eq) and water (0.34 mL, 2 eq). The solution was then stirred for 2 to 3 h at 0° C. the solvent was evaporated at room temperature and solid NaHCO3 was added, filtration and concentration to give after silica gel chromatography N-(2-oxoethyl)butyramide as a colorless oil (0.55 g g, 55% yield).
Reaction SMILES: [CH3:1][OH:2].[H-].[Na+].Br[C:6]1[CH:7]=[C:8]([CH:29]=[CH:30][N:31]=1)[C:9]([NH:11][C:12]1[S:13][C:14]2[C:20]([CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:19][CH:18]=[C:17]([O:27][CH3:28])[C:15]=2[N:16]=1)=[O:10]>O1CCOCC1>[CH3:1][O:2][C:6]1[CH:7]=[C:8]([CH:29]=[CH:30][N:31]=1)[C:9]([NH:11][C:12]1[S:13][C:14]2[C:20]([CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:19][CH:18]=[C:17]([O:27][CH3:28])[C:15]=2[N:16]=1)=[O:10]
Reactant: CO
Reactant: COc1ccc(C2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1cc(C(=O)Nc2nc3c(OC)ccc(C4CCOCC4)c3s2)ccn1
Temperature: 50 °C
Yield: 68.3 %

Procedure:
To a stirred solution of 0.09 ml (2.23 mmol) methanol in 5 ml dioxane at room temperature was added 49 mg (1.12 mmol) sodium hydride (55% dispersion in mineral oil) and the mixture heated at 50° C. for 1 hour. 100 mg (0.22 mmol) 2-bromo-N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-isonicotinamide was then added and the mixture heated at 50° C. for 16 h. The reaction mixture was then cooled to room temperature and poured onto water. The mixture was extracted three times with dichloromethane, and the combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (ethyl acetate) followed by trituration in ether and hexane afforded 60 mg (67%) 2-methoxy-N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-isonicotinamide as a white crystalline solid. ES-MS m/e (%): 398 ([M−H]−, 100).
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH3:13][C:14]1[CH:15]=[C:16]([OH:21])[CH:17]=[CH:18][C:19]=1[CH3:20].C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC=CC=1.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH3:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][C:19]=1[CH3:20])[O:21][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(O)cc1C
Reactant: CCOC(=O)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(Oc2ccc(C)c(C)c2)cc1
Temperature: 25 °C
Yield: 62.9 %

Procedure:
Ethyl 4-bromobenzoate (2.5 mmol), 3,4-dimethylphenol (3.5 or 5.0 mmol), molecular sieves (625 mg), Cs2CO3 (3.5 or 5.0 mmol), (CuOTf)2.PhH (0.0625 mmol, 5.0 mol % Cu), ethyl acetate (0.125 mmol, 5.0 mol %), and toluene (2.0 mL) were added to an oven-dried test tube which was then sealed with a septum, purged with argon, and heated to 110 C under argon until the aryl halide was consumed as determined by GC analysis. The reaction mixture was then allowed to cool to room temperature, diluted with Et2O and washed sequentially with 5% aqueous NaOH, water and brine. The organic layer was dried over Mg2SO4 and concentrated under vacuum to give the crude product. Purification by flash column chromatography (1% Et2O/pentane) gave the analytically pure product as a clear oil (425 mg, 63% yield). 1H NMR (300 MHz, CDCl3) δ 7.98 (d, J=8.6 Hz, 2H), 7.12 (d, J 8.0 Hz, 1H), 6.95 (d, J=8.6 Hz, 2H), 6.85 (d, J=2.4 Hz, 1H), 6.79 (dd, J=8.0 Hz, 2.3 Hz, 1H), 4.35 (q, J=7.0 Hz, 2H), 2.25 (s, 6H), 1.37 (t, J=7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 166.1, 162.2, 153.3, 138.5, 132.8, 131.5, 130.8, 124.4, 121.3, 117.4, 116.8, 60.7, 19.9, 19.1, 14.3; IR (neat): 2978, 2931, 1713, 1595, 1495, 1367, 1261, 1226, 1161, 1102 cm−1. Anal. Calcd for C17H18O3: C, 75.53; H, 6.71. Found: C, 75.77; H, 6.67.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].C([O:11][C:12](=O)[C:13](Br)([CH3:15])[CH3:14])C>C(O)C>[CH3:14][C:13]1([CH3:15])[NH:8][CH:1]2[CH:2]([CH2:3][CH2:4][CH2:5][CH2:6]2)[NH:7][C:12]1=[O:11]
Reactant: Nc1ccccc1N
Reactant: CCOC(=O)C(C)(C)Br
Solvent: CCO
Product: CC1(C)NC2CCCCC2NC1=O

Procedure:
5.4 parts of o-phenylene diamine are placed in a flask and ethyl-2-bromoisobutyrate added thereto with ethanol solvent. The reaction mixture is heated and 3,3-dimethyl-3,4-dihydroquinoxalin-2-one is recovered. Upon hydrogenation in the presence of catalyst, 3,3-dimethyl-decahydroquinoxalin-2-one is formed which, when used at 0.5 phr concentration in polypropylene in a manner analogous to that set forth in Example 1A hereinabove, provides stabilization for about 2000 hours (see Table I)
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:46][CH2:47][C:48]1[C:49]([OH:56])=[N:50][C:51]([CH3:55])=[CH:52][C:53]=1[CH3:54]>ClCCl>[OH:56][C:49]1[C:48]([CH2:47][NH:46][C:10](=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([CH:2]3[CH2:3][CH2:4][CH2:5][O:1]3)=[CH:14][CH:13]=2)=[C:53]([CH3:54])[CH:52]=[C:51]([CH3:55])[N:50]=1
Reactant: O=C(O)c1ccc(C2CCCO2)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(C3CCCO3)cc2)c(O)n1
Reaction time: 0.5 h
Yield: 21.4 %

Procedure:
To a solution of 4-(tetrahydrofuran-2-yl)benzoic acid (95 mg, 0.5 mmol) in dichloromethane (20 mL) were added o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (380 mg, 1 mmol) and triethylamine (202 mg, 2 mmol). The mixture was stirred for 0.5 hour. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (120 mg, 0.8 mmol) was added and the mixture was stirred at room temperature for 4 hours. The mixture was washed with water (50 mL). The organic phase was separated and concentrated to give a residue. The residue was purified through column chromatography (silica gel, dichloromethane/methanol=20:1) and to afford N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(tetrahydrofuran-2-yl)benzamide (35 mg, 21%) as a white solid. LRMS (M+H+) m/z: calcd 326.16. found 326.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]1[CH:21]=[CH:22][C:23]([OH:53])=[C:24](/[CH:26]=[CH:27]/[CH:28]([CH2:41][CH2:42][C:43]2[CH:48]=[CH:47][C:46]([C:49]([O:51][CH3:52])=[O:50])=[CH:45][CH:44]=2)[CH2:29][CH2:30][C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=2)[CH:25]=1>C(#N)C>[F:19][C:20]1[CH:21]=[CH:22][C:23]([O:53][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=2)=[C:24](/[CH:26]=[CH:27]/[CH:28]([CH2:41][CH2:42][C:43]2[CH:48]=[CH:47][C:46]([C:49]([O:51][CH3:52])=[O:50])=[CH:45][CH:44]=2)[CH2:29][CH2:30][C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=2)[CH:25]=1
Reactant: COC(=O)c1ccc(CCC(/C=C/c2cc(F)ccc2O)CCc2ccc(C(=O)OC)cc2)cc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CCC(/C=C/c2cc(F)ccc2OCc2ccc(C(F)(F)F)cc2)CCc2ccc(C(=O)OC)cc2)cc1
Temperature: 60 °C

Procedure:
280 mg (1.2 mmol) of 1-(bromomethyl)-4-(trifluoromethyl)benzene and 162 mg (1.2 mmol) of anhydrous potassium carbonate are added to a solution of 279 mg (0.59 mmol) of methyl 4-[(4E)-5-(5-fluoro-2-hydroxyphenyl)-3-{2-[4-(methoxycarbonyl)phenyl]ethyl} pent-4-en-1-yl]benzoate in 6.5 ml of dry acetonitrile, and the mixture is then heated at 60° C. for 12 hours. The mixture is then filtered, and the filtrate is evaporated to dryness. The residue is purified by preparative HPLC. This gives 274 mg (0.43 mmol, 74% of theory) of a colorless oil.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[F:17][C:18]([F:41])([F:40])[C:19]1[CH:20]=[C:21]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:22][O:23][CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=O.O>C1COCC1>[F:17][C:18]([F:40])([F:41])[C:19]1[CH:20]=[C:21]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:22][O:23][CH2:24][C:25]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: O=C(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C=C(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
Ethyl diethoxyphosphorylacetate (30 mL, 150 mmol) was dropped into a suspension of sodium hydride (60% oily) (6.00 g, 150 mmol) in THF (300 mL) at room temperature during 30 minutes. After the dropping, the mixture was stirred at room temperature for 1 hour more, a solution of 2-(3,5-bis(trifluoromethyl)-benzyloxy)-1-phenylethanone (48.90 g, 135 mmol) in THF (100 mL) was dropped thereinto at room temperature during 30 minutes and the mixture was stirred for 1 hour more. The reaction mixture was added to water (1000 mL) followed by extracting with ethyl acetate. The organic layers were combined, washed with water and a saturated saline solution and dried over anhydrous sodium sulfate and the solvent was evaporated in vacuo. The residual oily product was purified by a silica gel column chromatography (n-hexane:ethyl acetate=9:1) to give ethyl 4-(3,5-bis(trifluoromethyl)-benzyloxy)-3-phenyl-2-butenoate (40.00 g, 69%) as an oily product. 1H-NMR (DMSO-d6) δ: 1.23 (t, J=7.1 Hz, 3H), 4.15 (q, J=7.1 Hz, 2H), 4.63 (s, 2H), 5.08 (s, 2H), 6.24 (s, 1H), 7.39-7.43 (m, 3H), 7.57-7.61 (m, 2H), 7.79 (s, 2H), 7.96 (s, 1H).