Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[C:6]([CH3:8])[O:5][N:4]=1.[C:9]([N:13]1[C:17](=[O:18])[C:16]([NH:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:15]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[S:14]1(=[O:33])=[O:32])([CH3:12])([CH3:11])[CH3:10]>>[C:9]([N:13]1[C:17](=[O:18])[C:16]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([CH2:2][C:3]3[CH:7]=[C:6]([CH3:8])[O:5][N:4]=3)[CH2:22][CH2:21]2)=[C:15]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[S:14]1(=[O:33])=[O:32])([CH3:12])([CH3:10])[CH3:11]
Reactant: Cc1cc(CBr)no1
Reactant: CC(C)(C)N1C(=O)C(NC2CCNCC2)=C(c2ccccc2)S1(=O)=O
Product: Cc1cc(CN2CCC(NC3=C(c4ccccc4)S(=O)(=O)N(C(C)(C)C)C3=O)CC2)no1
Yield: 17 %

Procedure:
The title compound was prepared as described for Example 104 from 3-(bromomethyl)-5-methylisooxazole and 2-tert-butyl-5-phenyl-4-(piperidin-4-ylamino)isothiazol-3(2H)-one 1,1-dioxide (Example 75) to give the title compound (0.021 g, 17%) as a solid. 1H NMR (500 MHz CDCl3): δ 7.52-7.48 (m, 2H), 7.48-7.42 (m, 3H), 5.92 (s, 1H), 5.18 (d, 1H), 3.40 (s, 2H), 2.98-2.88 (m, 1H), 2.70-2.62 (m, 2H), 2.40 (s, 3H), 1.74 (m, 9H), 1.79-1.60 (m, 4H), 1.42-1.32 (m, 2H); 13C NMR (125 MHz CDCl3): δ 169.7, 161.7, 159.9, 134.2, 131.8, 130.1, 128.9, 125.3, 106.9, 101.8, 61.8, 53.4, 52.0, 50.1, 32.5, 27.8, 12.5; Mass Spectrum M+H+ 459.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:16]Br)=[CH:11][C:10]=1[CH2:26][OH:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:28][C:29]([CH3:42])([CH3:41])[CH2:30][C:31]1[CH:32]=[C:33]([CH2:37][C:38]([OH:40])=[O:39])[CH:34]=[CH:35][CH:36]=1.[CH:43](N(CC)C(C)C)(C)C>CS(C)=O.C(OCC)(=O)C>[CH3:43][O:39][C:38](=[O:40])[CH2:37][C:33]1[CH:34]=[CH:35][CH:36]=[C:31]([CH2:30][C:29]([NH:28][CH2:16][C@@H:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:10]([CH2:26][OH:27])[CH:11]=2)[O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])([CH3:42])[CH3:41])[CH:32]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c(CO)c1
Reactant: CC(C)(N)Cc1cccc(CC(=O)O)c1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)Cc1cccc(CC(C)(C)NC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(OCc3ccccc3)c(CO)c2)c1
Temperature: 90 °C
Reaction time: 28 h
Yield: 50 %

Procedure:
A mixture of [2-(benzyloxy)-5-((1R)-2-bromo-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl) phenyl]methanol (preparation 23), (3.4 g, 7.5 mmol), [3-(2-amino-2-methylpropyl)phenyl]acetic acid (preparation 146), (1.7 g, 7.5 mmol) and N,N-diisopropylethylamine (1.4 mL, 8 mmol) in dimethylsulfoxide (7.5 mL) was stirred at 90° C. for 28 hours. The reaction mixture was then cooled, diluted with ethyl acetate and washed with water. The organic solution was then dried over magnesium sulfate, concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with ethyl acetate:pentane, 66:33, to afford the title compound as a colourless oil in 50% yield, 2.2 g. 1H NMR (400 MHz, CDCl3) δ: 7.44-7.31 (6H, m), 7.30-7.19 (3H, m), 7.13-7.05 (2H, m), 6.80 (1H, d), 4.75-4.66 (3H, m), 3.68 (3H, s), 3.59 (2H, s), 2.90-2.72 (4H, m), 1.22-1.09 (6H, m), 0.70 (9H, s), −0.06 (3H, s), −0.28 (3H, s) ppm.
Reaction SMILES: C[Li].[C:3](OC)(=O)/[CH:4]=[CH:5]/[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].BrCBr.[C:18]([Mg]Cl)(C)(C)C.C([O:26][CH2:27][CH3:28])C>>[CH2:8]([C@@H:9]1[CH2:11][C@H:10]1[C:27]([OH:26])([CH3:28])[CH3:18])[CH2:7][CH2:6][CH2:5][CH2:4][CH3:3]
Reactant: CC(C)(C)[Mg]Cl
Reactant: CCCCCC/C=C/C(=O)OC
Reactant: CCOCC
Agent: [Li]C
Solvent: BrCBr
Product: CCCCCC[C@@H]1C[C@H]1C(C)(C)O
Reaction time: 18 h
Yield: 74 %

Procedure:
Prepared as described in Example 23 from methyl lithium 1.6 M in diethyl ether (7.4 ml, 12 mmol) and (E)-methyl non-2-enoate (Neofolione) (1 g, 6 mmol) in diethyl ether (10 ml) at −78° C., followed by dibromomethane (5×1 g, 30 mmol) and tert-butyl magnesium chloride 2M in diethyl ether (5×3 ml, 30 mmol) at 0°-5° C. Work-up after 18 h at 25° C. and bulb-to-bulb distillation under high vacuum gives 0.8 g (74%) of a colorless oil. 1H NMR (CDCl3): δ 0.15 (m, 1H), 0.45 (m, 1H), 0.7 (2 m, 2H), 1.15 (s, 3H), 1.2 (s, 3H), 1.2-1.4 (7H) ppm. 13C-NMR (CDCl3): δ 8.1 (t), 14.1 (q), 15.1 (d), 22.6 (t), 28.4 (q), 28.9 (q), 29.2 (t), 29.4 (t), 30.3 (d), 31.9 (t), 34.1 (t), 69.7 (s). MS (EI): m/z (%) 169 ([M-15]+, 19), 151 (3), 123 (4), 110 (11), 109 (12), 97 (14), 95 (37), 72 (88), 71 (89), 43 (100). IR (film): 3377 (br, OH), 2960 (m), 2922 (s), 2853 (m), 1464 (m), 1367 (m), 1229 (w), 1145 (m), 944 (m), 915 (m).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11]2[C:20]3[C:15](=[CH:16][C:17]([OH:21])=[CH:18][CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1.O.O.O.O.O.[OH-].C[N+](C)(C)C.[CH3:33][O:34][CH2:35][CH2:36]Br.Cl>CN(C=O)C.O>[ClH:1].[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH2:36][CH2:35][O:34][CH3:33])=[CH:18][CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1
Reactant: COCCBr
Reactant: Oc1ccc2c(N3CCc4ccc(Cl)cc43)ncnc2c1
Agent: C[N+](C)(C)C
Agent: Cl
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1ccc2c(N3CCc4ccc(Cl)cc43)ncnc2c1
Temperature: 50 °C
Reaction time: 36 h
Yield: 110.5 %

Procedure:
To 4-(6-chloro-2,3-dihydro-indol-1-yl)-quinazolin-7-ol (125 mg, 0.42 mmol; from Example 65) in DMF (2 mL) was added H2O (50 μL), K2 CO3 (s) (116 mg, 0.84 mmol), and tetramethylammonium hydroxide pentahydrate (15 mg, 0.08 mmol) followed by 2-bromoethyl methyl ether (43 μL, 0.46 mmol). The mixture was stirred at 50° C. under N2(g) for 24 hours before another aliquot (43 μL) of 2-bromoethyl methyl ether was added. Stirring at 50° C. was continued for another 36 hours before extractive workup and chromatography analogous to that described in Example 1 followed by conversion to the HCl salt as outlined for Example 2 afforded 91 mg (61%) of product. (M.P. 213°-216° C. (dec); LC-MS: 356 (MH+); anal. RP18-HPLC RT: 4.73 min.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]([CH3:17])[CH3:16])[CH:10]=2)=[N:6][CH:7]=1.[CH3:18][I:19]>CCOCC>[I-:19].[Cl:1][C:2]1[CH:7]=[N:6][C:5]([O:8][C:9]2[CH:10]=[C:11]([N+:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[CH:13][CH:14]=2)=[N:4][CH:3]=1
Reactant: CN(C)c1cccc(Oc2ncc(Cl)cn2)c1
Reactant: CI
Solvent: CCOCC
Product: C[N+](C)(C)c1cccc(Oc2ncc(Cl)cn2)c1
Product: [I-]
Yield: 46.8 %

Procedure:
A solution of 5-chloro-2-(3-dimethylaminophenoxy)pyrimidine (3.75 g) and methyl iodide (4.50 g) in ether (25 ml) was stirred at room temperature for one week. Filtration of the ether solution gave 2.75 g (47%) of the title compound, mp 155° C.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:11])[CH2:9][CH3:10].[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[CH2:22][O:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1.O>C(Cl)Cl>[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[CH2:22][O:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:8](=[O:11])[CH2:9][CH3:10])=[CH:26][CH:25]=1
Reactant: Nc1ccc(OCc2nc3ccccc3s2)cc1
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCC(=O)Nc1ccc(OCc2nc3ccccc3s2)cc1
Reaction time: 3 h
Yield: 91 %

Procedure:
0.09 ml of triethylamine and 0.06 ml of propionyl chloride were added to a solution of 149.1 mg of 4-(benzothiazol-2-ylmethoxy)aniline [prepared as described in step (a) above] in 6 ml of methylene chloride cooled in an ice-water bath, and the resulting mixture was stirred at the same temperature for 3 hours. At the end of this time, water was added to the reaction mixture and the resulting mixture was extracted with methylene chloride. The extract was washed with water, dried over anhydrous sodium sulfate and the solvent was then removed under reduced pressure. The resulting residue was purified by column chromatography through silica gel using a 1:2 by volume mixture of hexane and ethyl acetate to give 165.5 mg of the title compound (yield 91%) as a solid having a melting point of 182° C.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][CH:4]2[C:12](=[O:13])[O:11][C:9](=[O:10])[CH:5]2[CH2:6][C:7]=1[CH3:8]>[Pt](=O)=O.O1CCCC1>[CH3:1][CH:2]1[CH:7]([CH3:8])[CH2:6][C:5]2[C:9]([O:11][C:12](=[O:13])[C:4]=2[CH2:3]1)=[O:10]
Reactant: CC1=C(C)CC2C(=O)OC(=O)C2C1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Product: CC1CC2=C(CC1C)C(=O)OC2=O
Reaction time: 8 h

Procedure:
A mixture of 4,5-dimethyl-4-cyclohexene-1,2-dicarboxylic anhydride (10 g; 0.0555 mol), platinum dioxide (150 mg) and tetrahydrofuran (100 ml) was hydrogenated at room temperature for 8 hours, followed by removal of insoluble materials by filtration. The filtrate was concentrated under reduced pressure to give the objective compound quantitatively. IR νmaxfilm (cm-1): 1860, 1760.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].O1[CH2:40][CH2:39]OCC1.O.[OH-].[Na+].[CH2:44](O)[CH3:45]>>[C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:15]4[CH2:45][CH2:44][N:19]([CH2:39][CH3:40])[CH2:18][CH2:16]4)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)n3)sc2c1-c1ccc(Cl)cc1
Reactant: C1COCCO1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCN1CCN(c2nccc(-c3nc4cc(C)c([C@H](OC(C)(C)C)C(=O)O)c(-c5ccc(Cl)cc5)c4s3)n2)CC1
Temperature: 90 °C

Procedure:
(S)-Methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyrimidin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (10 mg), dioxane (500 μL), and H2O (200 μL) were added. The reaction was heated to 90° C. for 1 h. Ethanol (absolute, 500 μL) and 5 M aq NaOH (500 μL) were added and the reaction was heated to 90° C. for 30 min. The reaction was cooled to 23° C. and directly purified by reverse phase HPLC (5-100% ACN/H2O+0.1% TFA) giving the title compound. 1H NMR (400 MHz, CD3OD) δ 8.62 (d, J=5.0 Hz, 1H), 7.91 (s, 1H), 7.74-7.49 (m, 5H), 5.24 (s, 1H), 3.37-3.28 (m, 8H), 3.24 (q, J=7.4 Hz, 2H), 2.62 (s, 3H), 1.38 (t, J=7.3 Hz, 2H), 0.97 (s, 9H). LCMS-ESI+: calc'd for C30H35ClN5O3S [M+H+]: 580.2, 582.2; Found: 580.4, 582.2 (M+H+).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH:17][C:18]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([O:26]CC3C=CC(OC)=CC=3)[CH:21]=2)=[O:19])[S:9][C:10]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1.C1(OC)C=CC=CC=1.C(=O)([O-])O.[Na+]>FC(F)(F)C(O)=O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH:17][C:18]([C:20]2[CH:25]=[CH:24][NH:23][C:22](=[O:26])[CH:21]=2)=[O:19])[S:9][C:10]=1[C:11]1[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=1
Reactant: COc1ccc(COc2cc(C(=O)Nc3nc(-c4ccco4)c(-c4ccncc4)s3)ccn2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1nc(-c2ccco2)c(-c2ccncc2)s1)c1cc[nH]c(=O)c1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 67.8 %

Procedure:
Compound 106 (2.10 g, 4.33 mmol) and anisole (4.72 mL, 43.4 mmol) were suspended in trifluoroacetic acid (7 mL), followed by stirring at 65° C. for 30 minutes. A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture to adjust the pH to 8, and the precipitated solid was collected by filtration. The resulting solid was purified through silica gel column chromatography (chloroform:methanol=4:1) to afford the entitled Compound 112 (1.07 g, 68%).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:32])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1.CS(Cl)(=O)=O.C(N(CC)CC)C.[Br-:45].[Li+]>O1CCCC1.O>[Br:45][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:32])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: [Br-]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)Nc2cccc(CO)c2)cc1
Agent: CS(=O)(=O)Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)Nc2cccc(CBr)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-[3-(hydroxymethyl)phenyl]-4-(tetradecyloxy)benzamide and 3.47 g of methanesulfonyl chloride in 200 ml of tetrahydrofuran is added 3.07 g of triethylamine followed by stirring at ambient temperature for 2 hours. Also added is 21.93 g of lithium bromide followed by stirring at ambient temperature for an additional 3 hours. The mixture is poured into water and extracted with ether. The organic layer is washed with a mixture of brine and saturated sodium bicarbonate then dried. The solvent is removed under vacuum and the residue crystallized from carbon tetrachloride:hexanes to give the desired product as a white solid, m.p. 116°-118° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9][CH2:8][C:6]=2[N:7]=1.[CH3:20][CH2:21][N:22](C(C)C)[CH:23]([CH3:25])[CH3:24].CC[O:31]C(C)=O>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:21][CH2:20][O:31][CH2:24][C@@H:23]2[CH3:25])[C:5]2[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCc2nc(Cl)nc(Cl)c2C1
Reactant: CCN(C(C)C)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H]1COCCN1c1nc(Cl)nc2c1CN(C(=O)OC(C)(C)C)CC2
Temperature: 35 °C
Reaction time: 48 h

Procedure:
To a solution of tert-butyl 2,4-dichloro-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (1.00 g, 3.29 mmol) and DIPEA (1.21 mL, 6.97 mmol) at room temperature (20° C.) was added 3-S-methyl morpholine (0.54 g, 5.33 mmol). The reaction mixture was heated to 35° C. and stirred for 48 h. The reaction was diluted with DCM and Sat. NaHCO3. The organic layer was rinsed (brine), dried (anhydrous Na2SO4) and concentrated in vacuo. The desired product was isolated by flash chromatography (silica, 50 g, 0-50% EtOAc in petroleum ether (40-60) over 25 min) as a white solid (0.71 g, 1.92 mmol, 59% yield).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([OH:8])=O.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)[N:28]=[N:27]C=2C=1.O.NN>ClCCl>[O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([NH:27][NH2:28])=[O:8]
Reactant: O=C(O)[C@H]1CCCO1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NN
Solvent: O
Solvent: ClCCl
Product: NNC(=O)[C@H]1CCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.6 %

Procedure:
To a round-bottom flask was added a solution of (R)-tetrahydrofuran-2-carboxylic acid (3.00 g, 25.8 mmol, 1.00 equiv) in dichloromethane (60 mL). EDC.HCl (7.37 g, 38.5 mmol, 1.50 equiv), HOBt (5.24 g, 38.8 mmol, 1.50 equiv), and hydrazine hydrate (2.60 g, 51.9 mmol, 2.00 equiv) were added to the reaction. The resulting solution was stirred overnight at 25° C. The solids were removed with filtration. The filtrate was concentrated in vacuo to yield 2.00 g (59%) of (R)-tetrahydrofuran-2-carbohydrazide as a yellow oil.
Reaction SMILES: Br[C:2]1[C:3]([CH3:10])=[N:4][CH:5]=[C:6]([CH3:9])[C:7]=1[NH2:8].[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH:12]=[CH2:13].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC>CN(C=O)C.O.C(O[Pd]OC(=O)C)(=O)C>[NH2:8][C:7]1[C:6]([CH3:9])=[CH:5][N:4]=[C:3]([CH3:10])[C:2]=1/[CH:13]=[CH:12]/[C:11]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: Cc1cnc(C)c(Br)c1N
Reactant: C=CC(=O)OCC
Agent: CC(=O)O[Pd]OC(C)=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1c(C)ncc(C)c1N
Temperature: 150 °C
Yield: 90.8 %

Procedure:
A mixture of 3-bromo-2,5-dimethylpyridin-4-amine (5.0 g, 25 mmol), ethyl acrylate (5.0 g, 50 mmol), diacetoxypalladium (1.12 g, 5.0 mmol), PPh3 (3.28 g, 12.5 mmol), and NEt3 (7.6 g, 75 mmol) in DMF (50 mL) was heated in a microwave reactor at 150° C. for 2 h. The reaction mixture was cooled, diluted with water (100 mL), and extracted with DCM (250 mL×3). The combined organic layers were washed with saturated sodium chloride solution (100 mL×3), dried with sodium sulfate, concentrated, and purified by column chromatography to give 5.0 g of the product as a yellow solid. MS (ESI): m/z 221.2 [M+H]+.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH3:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:11]=1.[C:26](=O)([O:29]C)[O:27][CH3:28]>C1COCC1>[F:24][C:22]([F:25])([F:23])[C:19]1[CH:18]=[CH:17][C:16]([C:12]2[CH:11]=[C:10]([CH2:9][C:26]([O:27][CH3:28])=[O:29])[CH:15]=[CH:14][N:13]=2)=[CH:21][CH:20]=1
Reactant: COC(=O)OC
Reactant: Cc1ccnc(-c2ccc(C(F)(F)F)cc2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)Cc1ccnc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 0 °C
Yield: 70.8 %

Procedure:
A solution of LDA (2M in THF/heptane/ethyl benzene, 44 ml, 88 mmol) was added dropwise to a stirred solution of 4-methyl-2-[4-(trifluoromethyl)phenyl]pyridine (10.5 g, 44 mmol) in dry THF (300 ml) under N2, such that the internal temperature remained <−70° C. After 1 hour at this temperature, dimethyl carbonate (8.9 ml, 106 mmol) was added. After 30 minutes the cooling bath was removed. When the internal temperature had reached −20° C. the reaction was transferred to a cold bath at −10° C., and then allowed to warm slowly to 0° C. After 1 hour at 0° C. the reaction was quenched with aqueous NH4Cl (half saturated, 100 ml). The reaction mixture was concentrated in vacuo. The residue was diluted with H2O (200 ml) and extracted with EtOAc (2×200 ml). The combined extracts were washed with brine (×1), then dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica, eluting with 10-30% EtOAc/isohexane to give the ester (9.2 g, 71%) as a pale yellow liquid. 1H NMR (400 MHz, CDCl3) δ: 3.72 (2H, s), 3.75 (3H, s), 7.24 (1H, dd, J 1.4, 5.0), 7.72 (3H, t, J 8.4), 8.11 (2H, d, J 8.2), 8.68 (1H, d, J 5.0).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:16]([N:20]1[CH:24]=[CH:23][N:22]=[N:21]1)[CH2:17][C:18]#[CH:19].C(NC(C)C)(C)C.C(OCC)(=O)C>C1COCC1.[Cu](I)I>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:19]#[C:18][CH2:17][CH2:16][N:20]2[CH:24]=[CH:23][N:22]=[N:21]2)=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCCn1ccnn1
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cn1
Agent: I[Cu]I
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(C#CCCn2ccnn2)cn1
Yield: 69.6 %

Procedure:
(5-Iodo-pyridin-2-yl)-carbamic acid tert-butyl ester (3.45 g, 10.77 mmol) was dissolved in anhydrous THF (30 ml) under an argon atmosphere and treated with (PPh3)2Pd(II)Cl2 (0.6 g, 0.86 mmol) and copper iodide (0.2 g, 1.1 mmol). To this mixture a solution of 1-but-3-inyl-1H-[1,2,3]triazole (2.1 g, 17.24 mmol) in anhydrous THF (20 ml) is added dropwise at 0° C. followed by diisopropyl-amine (7.6 mL, 53.88 mmol). After stirring for 6 h at room temperature ethyl acetate (100 mL) was added, the mixture was washed with water, brine and dried over sodium sulfate. After removal of the solvents the crude product was purified by column chromatography on silica gel (dichloro methane/methanol 98:2) yielding [5-(4-[1,2,3]triazol-1-yl-but-1-ynyl)-pyridin-2-yl]-carbamic acid tert-butyl ester as light yellow solid (2.35 g, 70%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:14]=[CH:13][C:7]([CH2:8][NH:9][C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1.[CH3:15]I.O>O1CCCC1.C(Cl)Cl>[F:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]([CH3:15])[C:10](=[O:12])[CH3:11])=[CH:13][CH:14]=1
Reactant: CC(=O)NCc1ccc(F)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N(C)Cc1ccc(F)cc1
Yield: 62.2 %

Procedure:
Step b) Add acetyl chloride (9.28 g, 118 mmol) to a mixture of triethylamine (16.0 g, 158 mmol) and 4-fluorobenzylamine (9.90 g, 78.8 mmol) in 200 mL of ethyl acetate at 0° C. and stir for 12 hours. Add 100 mL of water to the mixture. Extract aqueous layer with ethyl acetate (3×100 mL). Combine organic layers and wash with brine then dry over anhydrous Na2SO4 Remove solvent under reduced pressure to give N-(4-fluorobenzyl)acetamide (13.5 gm) in 100% yield as a yellow oil. Add NaH (6.5 g, 162 mmol) to N-(4-fluorobenzyl)-acetamide (13.5 g, 80.8 mmol) in 200 mL of tetrahydrofuran at 0° C. and stir for 4 hours. Then add methyl iodide (22.9 g, 161.6 mmol) to the above mixture and stir for 12 hours. Pour mixture into 200 mL of water. Extract aqueous layer with methylene chloride (3×200 mL). Combine organic layers and wash with brine then dry over anhydrous Na2SO4. Remove solvent under reduced pressure. Purify the residue by column chromatography (silica gel, 5% acetone in hexanes, 50% acetone in hexanes) to give N-(4-fluorobenzyl)-N-methylacetamide (9.1 gm) in 64% yield as a yellow oil. Add Lawesson reagent (20.3 g, 50.3 mmol) to N-(4-fluorobenzyl)-N-methylacetamide (9.1 g, 50.3 mmol) in 200 mL of toluene and heat to 100° C. for three hours. Remove solvent under reduced pressure. Purify the residue with a column chromatography (silica gel, 2% methylene chloride in hexanes, 100% methylene chloride) to give N-(4-fluorobenzyl)-N-methylthioacetamide (5.6 g) 56.5% as a yellow solid: MS 198 (MH+).
Reaction SMILES: [F:1][C:2]1[C:3]([OH:8])=[N:4][O:5][C:6]=1[CH3:7].O[CH2:10][C@@H:11]([N:13]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]1=[O:23])[CH3:12]>>[F:1][C:2]1[C:3]([O:8][CH2:12][C@@H:11]([N:13]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:23])[CH3:10])=[N:4][O:5][C:6]=1[CH3:7]
Reactant: Cc1onc(O)c1F
Reactant: C[C@@H](CO)N1C(=O)c2ccccc2C1=O
Product: Cc1onc(OC[C@H](C)N2C(=O)c3ccccc3C2=O)c1F

Procedure:
Using 4-fluoro-5-methylisoxazol-3-ol and 2-[(1S)-2-hydroxy-1-methylethyl]-1H-isoindole-1,3(2H)-dione, and in the same manner as in Example 1, step B, the title compound was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[CH2:9])[CH:5]=[CH:4][C:3]=1F.[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=[O:14].O.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>C(#N)C>[Br:1][C:2]1[CH:7]=[C:6]([C:8](=[CH2:9])[CH2:10][CH:13]([OH:14])[C:12]([O:16][CH2:17][CH3:18])=[O:15])[CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)c1ccc(F)c(Br)c1
Reactant: CCOC(=O)C=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Solvent: O
Product: C=C(CC(O)C(=O)OCC)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a solution of 2-bromo-1-fluoro-4-(prop-1-en-2-yl)benzene (12.3 g, 62.2 mmol, 1.0 equiv) in acetonitrile (124 mL, 0.5 M) are added ethyl glyoxalate (38.1 g, 37 mL, 187 mmoles, 3 equiv) and ytterbium trifluoromethanesulfonate, hydrate (7.72 g, 12.4 mmoles, 0.2 equiv). The mixture is stirred overnight at room temperature. The mixture is concentrated under reduced pressure and diluted with diethyl ether. The resulting solution is washed twice with water. The organic layer is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified via flash column chromatography on silica gel (330 g) in two batches using a gradient of 0-100% ethyl acetate/hexanes to yield the title compound (87% yield): 1H NMR (CDCl3, 400 MHz): δ 7.53 (t, 1H, J=1.9 Hz), 7.41-7.37 (dt, 1H), 7.33-7.30 (dt, 1H), 7.18 (t, 1H, J=7.6 Hz), 5.37 (s, 1H), 5.22 (s, 1H), 4.26-4.21 (m, 1H), 4.17-3.99 (m, 2H), 2.99 (dd, J=14.8, 4.8 Hz), 2.83-2.72 (m, 2H), 1.23 (t, 3H, J=7.6 Hz).