Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[C@@H:12]([C:13]#[CH:14])[CH2:11][O:10]C1(C)C)(OC(C)(C)C)=O.[F:17][C:18]1[C:19](I)=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])/[C:21]/2=[CH:28]\[C:29]1[NH:30][CH:31]=[CH:32][C:33]=1[O:34][CH3:35].O>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.FC(F)(F)C(O)=O.C(Cl)Cl.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>[NH2:8][C@H:12]([CH2:11][OH:10])[C:13]#[C:14][C:19]1[C:18]([F:17])=[CH:26][CH:25]=[C:24]2[C:20]=1/[C:21](=[CH:28]/[C:29]1[NH:30][CH:31]=[CH:32][C:33]=1[O:34][CH3:35])/[C:22](=[O:27])[NH:23]2
Reactant: C#C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#C[C@H](N)CO)c21
Reaction time: 2 h

Procedure:
Using Method C above, (S)-N-Boc-2,2-dimethyl-4-ethynyl-oxazolidine (140 mg, 0.62 mmol) (Example 93A above) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (80 mg, 0.21 mmol) (Starting Material 6) using (Ph3P)4Pd (24 mg, 0.02 mmol) and a catalytic amount of Cul in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80° C. for 6 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4, concentrated and the residue was chromatographed on a silica gel column with a 0-50% THF in hexanes gradient. The intermediate that was obtained from this operation was directly dissolved in 5 mL of a 50% trifluoroacetic acid in CH2Cl2 solution that contained 0.5 mL of H2O at 0° C. and stirred for 2 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with ammonium hydroxide. The organic layer was dried over Na2SO4 and concentrated. (S)-(Z)-4-(3-Amino-4-hydroxy-1-butynyl)-1,3-dihydro-5-fluoro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one was obtained after silica gel column chromatography with 0-20% MeOH in CH2CO2 gradient and precipitation out of THF with excess of pentane. (Yield 22 mg, 31%).
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[Li].[CH2:6](Br)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>O1CCCC1.N>[CH2:1]([OH:4])[C:2]#[C:3][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH3:6]
Reactant: C#CCO
Reactant: CCCCCCCCCCCCCCCCBr
Agent: N
Agent: [Li]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCC#CCO
Reaction time: 1 h

Procedure:
A mixture of 56.1 g of propargyl alcohol in 100 ml of tetrahydrofuran and 15.6 g of lithium in 1 liter of ammonia containing a trace of ferric chloride is stirred for 1 hour. A 76.4 ml portion of hexadecyl bromide is added and the mixture refluxed for 8 hours then evaporated. The residue is dissolved in ether and washed with 10% hydrochloric acid, dried and purified by flash chromatography, to give 47.4 g of the desired compound as white platelets, mp. 60° C.
Reaction SMILES: C(C1C=CC([C@@H]2[C@]3(C4C(=CC=C(C(O)=O)C=4)NC3=O)C2)=CC=1)#N.C[O:25][C:26]([C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32](=[O:37])[C@@:31]12[CH2:39][C@@H:38]1[C:40]1[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=1)=[O:27].[OH-].[Li+]>CO.O>[F:46][C:43]1[CH:42]=[CH:41][C:40]([C@H:38]2[C@@:31]3([C:30]4[C:34](=[CH:35][CH:36]=[C:28]([C:26]([OH:27])=[O:25])[CH:29]=4)[NH:33][C:32]3=[O:37])[CH2:39]2)=[CH:45][CH:44]=1
Reactant: COC(=O)c1ccc2c(c1)[C@@]1(C[C@@H]1c1ccc(F)cc1)C(=O)N2
Agent: N#Cc1ccc([C@H]2C[C@]23C(=O)Nc2ccc(C(=O)O)cc23)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2c(c1)[C@]1(C[C@H]1c1ccc(F)cc1)C(=O)N2
Temperature: 25 °C
Reaction time: 14 h
Yield: 39.3 %

Procedure:
To a solution (1R,2S) and (1S,2R)-methyl-2-(4-fluorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-5′-carboxylate (80 mg) (prepared as in Example 139) in methanol (1 mL) and water (0.1 mL) was added lithium hydroxide (10 mg) at room temperature. The mixture was stirred for 14 hours at room temperature. HPLC monitored the reaction finished. The solvent was removed under reduced pressure. Purification by preparative HPLC gave the title compound as white solid (30 mg). LC/MS m/e calcd. for C17H12FNO3: 297, observed (M+H)+: 298.2 LC/MS m/e calcd for C17H12FNO3297.08, observed (M−H)+: 296.1; 1HNMR (400 MHz, DMSO-d6) δppm 1.99 (dd, J=9.09, 4.80 Hz, 1 H) 2.35 (dd, J=8.08, 4.80 Hz, 1 H), 3.11 (t, J=8.46 Hz, 1 H) 6.65 (d, J=1.52 Hz, 1 H) 6.94 (d, J=8.08 Hz, 1 H) 7.14 (t, J=8.84 Hz, 2 H) 7.34 (dd, J=8.34, 5.56 Hz, 2 H) 7.72 (dd, J=8.08, 1.52 Hz, 1 H) 10.97 (s, 1 H) 12.36 (br. s., 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5](I)=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1.C([Sn](CCCC)(CCCC)[C:22]1[CH:27]=[CH:26][N:25]=[N:24][CH:23]=1)CCC.[F-].[Cs+]>C(#N)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([C:22]2[CH:27]=[CH:26][N:25]=[N:24][CH:23]=2)=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnnc1
Reactant: Oc1cc(Cl)c(-c2ccc(F)cc2)cc1I
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC#N
Product: Oc1cc(Cl)c(-c2ccc(F)cc2)cc1-c1ccnnc1
Temperature: 50 °C
Yield: 31.6 %

Procedure:
2-Chloro-4′-fluoro-5-iodobiphenyl-4-ol (Preparation 72, 553 mg, 1.59 mmol) and 4-(tributylstannyl)pyridazine (703 mg, 1.90 mmol) were dissolved in degassed acetonitrile (8 mL). Caesium fluoride (482 mg, 3.17 mmol) was added and the mixture further degassed. Tetrakistriphenylphosphinepalladium (0) (183 mg, 0.16 mmol) and copper (I) iodide (91 mg, 0.48 mmol) were added and the reaction heated at 50° C. for 2 hours. The reaction mixture was cooled and filtered through celite, washing with ethyl acetate. The organic solution was washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by trituration with hot ethyl acetate to give the title compound (151 mg, 32%) as a beige solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.[Cl:11][C:12]1[CH:17]=[C:16](B2OC(C)(C)C(C)(C)O2)[CH:15]=[CH:14][N:13]=1.C(N(CC)CC)C>C(Cl)Cl.CO.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:16]2[CH:15]=[CH:14][N:13]=[C:12]([Cl:11])[CH:17]=2)[N:3]=1
Reactant: CC1(C)OB(c2ccnc(Cl)c2)OC1(C)C
Reactant: Clc1n[nH]c2ccccc12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Clc1cc(-n2nc(Cl)c3ccccc32)ccn1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 3-chloroindazole (1 g, 6.6 mmol) in methylene chloride (25 mL) and methanol (25 mL) were added 2-chloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridine (3.6 g, 15 mmol) and copper(II) acetate (1.4 g, 7.5 mmol), followed by triethylamine (2 mL, 15 mmol). The resulting mixture was vigorously stirred at room temperature for 20 h. The reaction was filtered and the gray solid was discarded. The blue filtrate was concentrated in vacuo and the residue was dissolved in methylene chloride and washed with saturated sodium bicarbonate and brine and dried over MgSO4. Flash chromatography of the crude product mixture with 25:10:65 and 35:10:55 EtOAc-CH2Cl2-Hexane gave the title compound as a white solid. MS (ES+): 264.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[Cl-].[F:11][C:12]1[CH:13]=[CH:14][C:15]([O:38][CH2:39][O:40][CH3:41])=[C:16]([CH:37]=1)[CH2:17][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C(#N)C.C1C=CC=CC=1.C(O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[F:11][C:12]1[CH:13]=[CH:14][C:15]([O:38][CH2:39][O:40][CH3:41])=[C:16]([CH2:17][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[CH:37]=1
Reactant: COCOc1ccc(F)cc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(F)cc1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COCOc1ccc(F)cc1CCc1ccc(F)cc1
Temperature: 60 °C
Reaction time: 20 h
Yield: 85.3 %

Procedure:
950 mg of 4-fluorobenzaldehyde, 3860 mg of 5-fluoro-2-methoxymethoxybenzyltriphenylphosphonium chloride (prepared as described in Preparation 8) and 1.26 ml of DBU were allowed to react together in 60 ml of acetonitrile, subsequently treated, and purified by silica gel column chromatography, using a 9:1 by volume mixture of hexane and ethyl acetate as the eluent, in the same manner as described in Preparation 2, to give 2030 mg of an oily substance. 1980 mg of this oily substance were dissolved in 12 ml of a 1:2 by volume mixture of benzene and ethanol, and then 155 mg of tris-(triphenylphosphine)rhodium(I) chloride were added to the resulting solution. The mixture was then stirred under a hydrogen atmosphere at atmospheric pressure and at 60° C. for 20 hours. At the end of this time, the reaction solution was filtered with diatomaceous earth. The filtrate was concentrated by evaporation under reduced pressure, and purified by silica gel column chromatography, using a 9:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1816 mg (yield 87%) of the title compound as an oily substance.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.Cl[C:15]([O:17][CH:18]([Cl:20])[CH3:19])=[O:16]>C(Cl)Cl>[C:15](=[O:16])([O:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[O:17][CH:18]([Cl:20])[CH3:19]
Reactant: CC(Cl)OC(=O)Cl
Reactant: OC1CCCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(Cl)OC(=O)OC1CCCCC1
Reaction time: 0.17 h

Procedure:
A solution of 1.83 g of cyclohexanol and 1.45 g of pyridine in 30 ml of methylene chloride is cooled to -78° C. and 2.0 ml of 1-chloroethyl chloroformate is added dropwise, while stirring, over 10 minutes. Thereafter, the cold bath is removed and the mixture is stirred at room temperature for 16 hours, washed with three 30-ml portions of saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure to give 3.31 g (88% in yield) of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2](=[O:42])[CH2:3][C:4]1[C:5]([CH2:10][CH2:11][C:12]2[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][N:15]=[C:14]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([CH:29]4[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]4)=[CH:25][CH:24]=3)[N:13]=2)=[N:6][CH:7]=[N:8][CH:9]=1.FC(F)(F)C(O)=O.C1CCCCC1>C(Cl)Cl.CO.C(OCC)C>[NH:32]1[CH2:31][CH2:30][CH:29]([C:26]2[CH:27]=[CH:28][C:23]([NH:22][C:14]3[N:13]=[C:12]([CH2:11][CH2:10][C:5]4[C:4]([CH2:3][C:2]([NH2:1])=[O:42])=[CH:9][N:8]=[CH:7][N:6]=4)[C:17]([C:18]([F:21])([F:19])[F:20])=[CH:16][N:15]=3)=[CH:24][CH:25]=2)[CH2:34][CH2:33]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ncncc4CC(N)=O)n3)cc2)CC1
Solvent: CCOCC
Solvent: CO
Solvent: ClCCl
Product: NC(=O)Cc1cncnc1CCc1nc(Nc2ccc(C3CCNCC3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 23 h
Yield: 55.5 %

Procedure:
tert-Butyl 4-(4-((4-(2-(5-(2-amino-2-oxoethyl)pyrimidin-4-yl)ethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I114) (0.076 g, 0.13 mmol) was dissolved in DCM (5 mL) under an atmosphere of nitrogen. Trifluoroacetic acid (0.298 mL, 3.89 mmol) was added to the solution and the reaction was stirred at room temperature for 23 hours. Volatiles were removed in vacuo, EtOAc (70 mL) and 2 M aq. NaOH (70 mL) were added to the residue and the layers were separated. The aqueous layer was extracted with EtOAc (2×70 mL), the combined organics were washed with brine (2×50 mL), dried (MgSO4), filtered and concentrated in vacuo to give a pale yellow gum. Methanol (˜5 mL) and cyclohexane (˜15 mL) were added to the product, some of the volatiles were removed in vacuo (˜50%) which gave a yellow oil that separated from the solvent solution and was carefully transferred to a new flask with a pipette. The removed solution was concentrated in vacuo and then further dried under high-vacuum to give a pale yellow gum. Diethyl ether (5 mL) and methanol (1 mL) were added and the solution was concentrated in vacuo. The process was repeated twice with diethyl ether to give the title compound (29) (35 mg, 56% yield) as a pale yellow solid; 1H NMR (400 MHz, d4-MeOD) δ 8.91 (s, 1H), 8.53-8.50 (m, 2H), 7.52 (d, J=8.2 Hz, 2H), 7.21-7.16 (m, 2H), 3.70 (s, 2H), 3.42-3.34 (m, 4H), 3.27-3.20 (m, 2H), 2.84 (td, J=12.5, 2.6 Hz, 2H), 2.70 (tt, J=12.2, 3.9 Hz, 1H), 1.89 (d, J=13.7 Hz, 2H), 1.72 (ddd, J=16.4, 12.9, 4.0 Hz, 2H). LCMS Method C: rt 4.46 min; m/z 486.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([CH:14]=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.ClC1C=CC([C@H]2CC[C@H](C(O)=O)CC2)=CC=1.CO.[S:34](S([O-])=O)([O-:37])(=[O:36])=[O:35].[Na+].[Na+]>CCOC(C)=O.O>[S:34](=[O:35])([OH:37])[OH:36].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:9][CH2:10][C@H:11]([CH:14]=[O:15])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=S([O-])S(=O)(=O)[O-]
Agent: O=C(O)[C@H]1CC[C@H](c2ccc(Cl)cc2)CC1
Agent: O=C[C@H]1CC[C@H](c2ccc(Cl)cc2)CC1
Agent: O=C[C@H]1CC[C@H](c2ccc(Cl)cc2)CC1
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: O=S(O)O
Temperature: 51 °C
Reaction time: 0.75 h

Procedure:
A stirred solution of trans-4-(4-chlorophenyl)cyclohexanecarbaldehyde (compound of formula (IVa) (approximately 9.33 g, 41.9 mmol, assuming quantitative conversion for preparation from trans-4-(4-chlorophenyl)cyclohexanecarboxylic acid) in EtOAc (100 mL) was charged with MeOH (40 mL), water (10 mL) and sodium metabisulfite (4.38 g, 0.55 eq). The resulting slurry was heated to 51° C., and stirred at this temperature for 45 min, the slurry was cooled to 20° C. over 1 hr then held for 30 min. The slurry was filtered and the cake washed with EtOAc (2×20 mL). The product was de-liquored then dried further in a 45° C. oven under reduced pressure to yield the title compound as a colourless solid (11.04 g, 81%). 1H NMR (400 MHz, d6-DMSO) δH 1.10-1.43 (4H, m, CH-alkyl), 1.70-1.80 (3H, m, CH-alkyl), 1.87-1.94 (1H, m, CH-alkyl), 2.12-2.21 (1H, m, CH-alkyl) 2.37-2.47 (1H, m, OH), 3.67 (1H, m, H-6), 4.79 (1H, m, H-9), 7.20-7.34 (4H, m, H-1 and H-2).
Reaction SMILES: [C:1]1([C:7]2[NH:12][C:11](=O)[CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)([Br:16])=O.C(=O)([O-])[O-].[Na+].[Na+]>O>[Br:16][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:12]=1
Reactant: O=c1cccc(-c2ccccc2)[nH]1
Reactant: O=P(Br)(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Brc1cccc(-c2ccccc2)n1
Temperature: 100 °C
Yield: 75.7 %

Procedure:
A mixture of 6-phenyl pyridone (3 g, 17.5 mmol; prepared according to Example 5) and phosphoryl bromide (7.2 g, 25.0 mmol) is heated to 100° C. for 5 h. The cooled mixture is poured into water (40 mL) and the pH is adjusted to 9 by addition of saturated aqueous sodium carbonate. Then the layers are separated and the aqueous layer is extracted with ethyl acetate (50 mL). The combined organic layers are dried with anhydrous magnesium sulphate and the solvent is evaporated in vacuo. The crude product is crystallized from aqueous ethanol. Subsequent purification by flash chromatography (silica gel, hexane/ethyl acetate 9/1 v/v) gives 2-bromo-6-phenyl pyridine (3.1 g, 76% of th.) as light brown crystals with mp 50° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10](F)=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7])([O-:3])=[O:2].[NH:14]1[CH2:16][CH2:15]1.O>CS(C)=O>[N:14]1([C:10]2[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([CH:9]=2)[C:6]([NH2:8])=[O:7])[CH2:16][CH2:15]1
Reactant: NC(=O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: C1CN1
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1cc(N2CC2)ccc1[N+](=O)[O-]
Temperature: -5 °C
Yield: 47 %

Procedure:
A stirred solution of 2-nitro-5-fluorobenzamide (Orrin, Eur. Pat. Appl. 19,388; Chem. Abstr. 1981, 94, 156538h) (480 mg, 2.61 mmol) in dry DMSO (2 mL) was treated with aziridine (0.54 mL, 10.4 mmol) at room temperature under N2 for 48 h, then poured into cold water (50 mL). Prolonged cooling at −5° C. gave a crystalline product that was collected and filtered throuhg a column of silica gel in EtOAc to give 11 (256 mg, 47%), mp (EtOAc) 172-174° C. 1H NMR [(CD3)2SO] δ8.01 & 7.61 (2xs, 2H, CONH2), 7.93 (d, J=8.9 Hz, 1H, H-3), 7.17 (dd, J=8.8, 2.4 Hz, 1H, H-4), 7.09 (d, J=2.3 Hz, 1H-6), 2.24 (s, 4H, aziridine-H ). Anal. Calcd. for C9H9N3O3: 52.17;H, 4.38; N, 20.29 Found: C, 52.29;H, 4.27; N, 20.25%.
Reaction SMILES: [Na:1].[CH2:2]1[O:4][CH2:3]1.[C:5]([OH:10])(=[O:9])[C:6]([CH3:8])=[CH2:7].[CH2:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19]([OH:24])(=[O:23])[C:20]([CH3:22])=[CH2:21].[C:25]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])(=[O:28])[CH:26]=[CH2:27].C(OCCCC)(=O)CS.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+]>O>[CH:11]([CH2:7][C:6](=[CH2:8])[C:5]([OH:10])=[O:9])=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:25]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])(=[O:28])[CH:26]=[CH2:27].[Na:1].[CH2:3]1[O:4][CH2:2]1.[C:19]([OH:24])(=[O:23])[C:20]([CH3:22])=[CH2:21]
Reactant: C=Cc1ccccc1
Agent: C=C(C)C(=O)O
Agent: C=CC(=O)OCCCC
Agent: CCCCOC(=O)CS
Solvent: C1CO1
Solvent: O
Product: C=C(CC=Cc1ccccc1)C(=O)O
Temperature: 75 °C
Reaction time: 0.25 h

Procedure:
To a reaction vessel equipped with a stirrer and a thermometer, 683 parts of water, 11 parts of sodium salt of the sulfuric acid ester of methacrylic acid ethylene oxide adduct (ELEMINOL RS-30, available from Sanyo Chemical Industries, Ltd.), 139 parts of styrene, 138 parts of methacrylic acid, 110 parts of butyl acrylate, 12 parts of butyl thioglycolate and 1 part of ammonium persuiphate were poured, and the components were stirred at 400 rpm for 15 minutes to obtain a white emulsion. The white emulsion was heated, the system temperature was raised to 75° C. and the reaction was performed for 5 hours. Next, 30 parts of an aqueous solution of 1% ammonium persulphate was added thereto, and the reaction mixture was aged at 75° C. for 5 hours to obtain an aqueous dispersion of a Vinyl resin (copolymer of styrene-methacrylic acid-butyl acrylate-sodium salt of the sulfuric acid ester of methacrylic acid ethylene oxide adduct). This aqueous dispersion was taken as particulate dispersion 1. The volume average particle diameter of the particulate dispersion 1 measured by a laser diffraction particle size distribution analyzer (LA-9201 available from Shimadzu Corporation) was 120 nm. A part of the particulate dispersion 1 was dried, and the resin therein was isolated. The glass transition temperature (Tg) of the resin was 42° C. and the mass average molecular mass of the resin was 30,000.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.Br[C:11]([CH3:18])([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>C(OCC)(=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:11]([CH3:18])([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:4]([CH3:9])[CH:3]=1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Cc1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C(C)(C)Oc1ccc(F)cc1C

Procedure:
A solution of 4-fluoro-2-methylphenol (10 g, 79.28 mmol), ethyl 2-bromoisobutyrate (23.2 mL, 158.6 mmol), potassium carbonate (21.9 g, 158.6 mmol), and DMSO (80 mL) was stirred at room temperature for 72 hours. Water and ethyl acetate were added and the layers were separated. The aqueous phase was extracted with ethyl acetate (3×50 mL) and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude compound was purified by flash column chromatography on silica gel with hexanes and EtOAc (20%) to afford ethyl 2-(4-fluoro-2-methylphenoxy)-2-methylpropanoate. To a solution of ethyl 2-(4-fluoro-2-methylphenoxy)-2-methylpropanoate (13.3 g, 55.44 mmol) in tetrahydrofuran (40 mL) and methanol (10 mL) was added NaOH (6.66 g, 166.32 mmol) in water (14 mL) and stirred overnight. The volatiles were removed in vacuo and acidified with concentrated HCl. The milky white solution was extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated in vacuo to give 2-(4-fluoro-2-methylphenoxy)-2-methylpropanoic acid (658) as a yellow solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1/[CH:6]=[CH:7]/[C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=1.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH:26][C:27](=[O:50])[NH:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36](OC2C(F)=C(F)C(F)=C(F)C=2F)=[O:37])=[CH:31][CH:30]=1.CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH:26][C:27](=[O:50])[NH:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]([N:1]2[CH2:5][CH2:4][CH2:3][CH:2]2/[CH:6]=[CH:7]/[C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)=[O:37])=[CH:31][CH:30]=1
Reactant: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1
Reactant: CCOC(=O)c1ccc(/C=C/C2CCCN2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(/C=C/C2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)cc2)cc1
Reaction time: 15 h
Yield: 100 %

Procedure:
A mixture of ethyl (E)-4-[2-(2-pyrrolidinyl)ethenyl]benzoate (434 mg, 1.77 mmol), pentafluorophenyl 4-[N′-(2-methylphenyl)ureido]phenylacetate (797 mg, 1.77 mmol), Et3N (0.37 mL, 2.66 mmol) in DMF (15 mL) was stirred for 15 hr. The mixture was diluted with EtOAc (300 mL). The solution was washed with brine (2×200 mL), dried over MgSO4, and evaporated off in vacuo. The residue was chromatographed on silica-gel with CHCl3-EtOAc (4:1) as eluent to give 906 mg (q.y.) ethyl (E)-4-[2-[1-[4-[N′-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]ethenyl]benzoate as a brown oil. 1H-NMR (CDCl3) δ1.39 (3 H, t, J=7.3 Hz), 1.83-2.20 (4 H, series of m), 2.24 (3 H, d, J=4.9 Hz), 3.63 (4 H, m), 4.36 (2 H, q, J=7.3 Hz), 4.62 and 4.84 (total 1 H, m), 6.18-6.47 (2 H, m), 7.03-8.02 (14 H, series of m).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:7][CH:8]=[CH:9][N:10]=1)CCC.[Br:19][C:20]1[CH:25]=[CH:24][C:23](I)=[CH:22][C:21]=1[O:27][CH3:28].[F-].[K+]>O1CCOCC1.C(Cl)Cl.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(Cl)Cl>[Br:19][C:20]1[CH:25]=[CH:24][C:23]([C:6]2[S:7][CH:8]=[CH:9][N:10]=2)=[CH:22][C:21]=1[O:27][CH3:28]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: COc1cc(I)ccc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [F-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cc(-c2nccs2)ccc1Br
Yield: 71.7 %

Procedure:
A solution of PdCl2(dppf)-CH2Cl2 adduct (0.391 g, 0.479 mmol), 2-tributylstannylthiazole (3.01 ml, 9.59 mmol), 1-bromo-4-iodo-2-methoxybenzene (3.00 g, 9.59 mmol), and potassium fluoride (1.499 g, 38.3 mmol) in 10 mL dioxane was heated to 100° C. overnight. LC/MS showed mostly product, so the reaction mixture was diluted with DCM and washed with water. The organics were dried over MgSO4 and concentrated. Purification of the crude residue by silica gel column chromatography (0-100% EtOAc/heptane) gave 2-(4-bromo-3-methoxyphenyl)thiazole (1.858 g, 6.88 mmol, 71.7% yield). (M+H)+=271.2.