Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[N:15]=[C:14]([C:16]2[N:20]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([C:29]3[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=3[CH3:36])=[C:18]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH:17]=2)[CH:13]=[CH:12][N:11]=1>CN(C=O)C>[NH2:9][C:10]1[N:15]=[C:14]([C:16]2[N:20]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([C:29]3[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=3[CH3:36])=[C:18]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH:17]=2)[C:13]([I:1])=[CH:12][N:11]=1
Reactant: CCOC(=O)c1cc(-c2ccnc(N)n2)n(COCC[Si](C)(C)C)c1-c1cc(Cl)ccc1C
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2nc(N)ncc2I)n(COCC[Si](C)(C)C)c1-c1cc(Cl)ccc1C
Temperature: 60 °C
Yield: 79.3 %

Procedure:
N-iodosuccinimide (356 mg, 1.58 mmol) was added to a solution of ethyl 5-(2-aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxylate (700 mg, 1.44 mmol) in DMF (15 mL). The reaction mixture was heated at 60° C. for 4 h, allowed to cool to room temperature, concentrated and then diluted with EtOAc (30 mL). The organic phase was washed with sodium sulfite, water, brine, dried over sodium sulphate, and evaporated to afford the title compound as yellow solid (0.70 g, 79%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]([NH:28][NH2:29])=[O:27])=[CH:21][CH:20]=2)=[O:17])=[CH:4][CH:3]=1.[C:30](OCC)(OCC)(OCC)[CH3:31].CS(O)(=O)=O.O1CCCC1>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:25][C:26]3[O:27][C:30]([CH3:31])=[N:29][N:28]=3)=[CH:23][CH:24]=2)=[O:17])=[CH:4][CH:3]=1
Reactant: Cn1ncc(/C=C/C(=O)Nc2ccc(CC(=O)NN)cc2)c1-c1ccc(F)cc1
Reactant: CCOC(C)(OCC)OCC
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nnc(Cc2ccc(NC(=O)/C=C/c3cnn(C)c3-c3ccc(F)cc3)cc2)o1
Yield: 47.1 %

Procedure:
A mixture of (2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-N-[4-(2-hydrazino-2-oxoethyl)phenyl]acrylamide (0.50 g), triethyl orthoacetate (0.63 g), methanesulfonic acid (0.025 g), and tetrahydrofuran (10 mL) was heated under reflux for 1 hr. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give (2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-N-{4-[(5-methyl-1,3,4-oxadiazol-2-yl) methyl]phenyl}acrylamide as pale-yellow crystals (0.25 g, yield 46%) from a fraction eluted with ethyl acetate-methanol (100:0-20:1, v/v). Recrystallization thereof from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 151-152° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]3[NH:15][CH:16]=[N:17][C:18]=3[C:19]3[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=3)=[CH:13][C:8]=2[N:7]([CH2:26][CH3:27])[C:6]1=[O:28])[CH3:4].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[CH2:29]([N:15]1[C:14]([C:12]2[CH:11]=[CH:10][C:9]3[N:5]([CH2:3][CH3:4])[C:6](=[O:28])[N:7]([CH2:26][CH3:27])[C:8]=3[CH:13]=2)=[C:18]([C:19]2[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=2)[N:17]=[CH:16]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCn1c(=O)n(CC)c2cc(-c3[nH]cnc3-c3cccc(C)c3)ccc21
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(=O)n(CC)c2cc(-c3c(-c4cccc(C)c4)ncn3Cc3ccccc3)ccc21
Reaction time: 0.25 h
Yield: 21.3 %

Procedure:
To a slurry of sodium hydride (254 mg of a 60% dispersion in mineral oil, 6.4 mmol) in DMF (79 mL) was added 1,3-diethyl-5-(5-m-tolyl-3H-imidazol-4-yl)-1,3-dihydro-benzoimidazol-2-one (prepared as described above, 2.0 gm, 5.8 mmol). The resulting mixture was stirred for 15 minutes, then benzyl bromide (0.76 mL, 6.4 mmol) was added all in one portion. The reaction was stirred for an additional 30 minutes, and was then quenched with water. The aqueous mixture was extracted with ethyl acetate, and the combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to afford a yellow oil. The oil was purified by flash chromatography eluting with ethyl acetate to afford 540 mg of the title compound as the less polar constituent. MS (M+1)=437.0
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:14][CH3:15])=[C:4]([CH:8]([OH:13])S([O-])(=O)=O)[CH:5]=[CH:6][CH:7]=1.Cl>C1COCC1>[Br:1][C:2]1[C:3]([CH2:14][CH3:15])=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH:8]=[O:13]
Reactant: CCc1c(Br)cccc1C(O)S(=O)(=O)[O-]
Agent: Cl
Solvent: C1CCOC1
Product: CCc1c(Br)cccc1C=O
Temperature: 25 °C
Yield: 81.8 %

Procedure:
To a solution of (3-bromo-2-ethylphenyl)(hydroxy)methanesulfonate (5.26 g, 16.59 mmol) in THF (25 mL) was added HCl (16.59 mL, 49.8 mmol). The mixture was stirred for an hour at rt. THF was removed under the reduced pressure. Residue was dissolved in EtOAc (50 mL) then washed with brine (10 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under the reduced pressure and dried in vacuum to give 3-bromo-2-ethylbenzaldehyde (2.89 g) as pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:25]#[N:26])[N:8]=[C:9]2[O:12][C@H:13]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]2)=[CH:4][CH:3]=1.[NH2:27][NH2:28].O>CO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:25]([NH:27][NH2:28])=[NH:26])[N:8]=[C:9]2[O:12][C@H:13]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:14]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(C#N)cc3ccc(Cl)cc23)C1
Reactant: NN
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(C(=N)NN)cc3ccc(Cl)cc23)C1

Procedure:
To a mixture of (S)-tert-butyl 3-((7-chloro-3-cyanoisoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate (300 mg, 1.61 mmol) in MeOH (4 mL) was added NH2NH2.H2O (5 mL). The resulting mixture was heated to reflux for 2 hours. The solvents were removed in vacuo to give the title compound, which was used without further purification. ESI-MS m/z [M+H]+ 406.1.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:12][CH:13]=[CH2:14])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:15](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[CH3:15][O:1][C:2]1[C:3]([CH2:12][CH:13]=[CH2:14])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: C=CCc1c(O)cccc1C(=O)OC
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: C=CCc1c(OC)cccc1C(=O)OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 93 %

Procedure:
To methyl 3-hydroxy-2-prop-2-en-1-ylbenzoate (10.3 g, 53.6 mmol, M. A. Eissenstat et al., J. Med. Chem. 1995, 38, 3094-3105) and cesium carbonate (26.2 g, 80.4 mmol) in DMF (100 ml) was added methyl iodide (15.2 g, 102.2 mmol). The reaction mixture was stirred at room temperature for 18 h, then filtered and concentrated. The residue was partitioned between ethyl acetate (250 mL) and water (100 mL). The layers were separated, the organic layer was washed with 5% lithium chloride (2×100 mL) and brine (100 mL), dried over sodium sulfate, and concentrated to provide methyl 3-(methyloxy)-2-prop-2-en-1-ylbenzoate (10.3 g, 93% yield) as a pale yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.41 (m, 1H), 7.24 (m, 1H), 7.02 (m, 1H), 6.97 (m, 1H), 4.97 (m, 2H), 3.88 (s, 3H), 3.85 (s, 3H), 3.73 (m, 2H).
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].OC1C=CC(C[CH2:20][C:21]([O:23][CH3:24])=O)=CC=1>>[O:23]1[CH2:24][CH:21]1[CH2:20][O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccccc1O
Reactant: COC(=O)CCc1ccc(O)cc1
Product: COC(=O)c1ccccc1OCC1CO1

Procedure:
The procedure of Example VII for producing methyl 3-[4-(2,3-epoxypropoxy)phenyl]propionate was repeated in all essential details, except methyl salicylate was substituted for methyl 3-(4-hydroxyphenyl)propionate. The boiling point of the product was 148° (p=75μ). The NMR spectrum was consistent with the assigned structure and the elemental analysis with the formula C11H12O4.
Reaction SMILES: [C:1]([C:4]1[CH:40]=[CH:39][C:7]([CH:8]=[CH:9][C:10]([NH:12][CH2:13][C:14]([N:16]([C:18]2[C:19]([Cl:38])=[C:20]([C:34]([Cl:37])=[CH:35][CH:36]=2)[CH2:21][O:22][C:23]2[CH:24]=[CH:25][CH:26]=[C:27]3[C:32]=2[N:31]=[C:30]([CH3:33])[CH:29]=[CH:28]3)[CH3:17])=[O:15])=[O:11])=[CH:6][CH:5]=1)([OH:3])=O.Cl.[CH2:42]([NH2:44])[CH3:43].C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O>[Cl:38][C:19]1[C:18]([N:16]([C:14](=[O:15])[CH2:13][NH:12][C:10](=[O:11])[CH:9]=[CH:8][C:7]2[CH:6]=[CH:5][C:4]([C:1](=[O:3])[NH:44][CH2:42][CH3:43])=[CH:40][CH:39]=2)[CH3:17])=[CH:36][CH:35]=[C:34]([Cl:37])[C:20]=1[CH2:21][O:22][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:32]=1[N:31]=[C:30]([CH3:33])[CH:29]=[CH:28]2
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(C(=O)O)cc4)c3Cl)c2n1
Reactant: CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4ccc(C)nc34)c2Cl)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 86.9 %

Procedure:
To a mixture of 8-[3-[N-(4-carboxycinnamoylglycyl)-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline (100 mg), ethylamine hydrochloride (16.9 mg) and N,N-dimethylformamide (2 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (32.2 mg) and 1-hydroxybenzotriazole (30.4 mg), and the mixture was stirred for 6 hours at ambient temperature. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by preparative thin-layer chromatography (methylene chloride—methanol) to give 8-[2,6-dichloro-3-[N-[4-(ethylcarbamoyl)cinnamoylglycyl]-N-methylamino]benzyloxy]-2-methylquinoline (91 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N+:3]=1[O-].[C:10]([O:13]C(=O)C)(=[O:12])[CH3:11]>>[CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][O:13][C:10](=[O:12])[CH3:11])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc[n+]([O-])c(C)c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OCc1ccnc(C)c1
Temperature: 25 °C
Yield: 15 %

Procedure:
2,4-Dimethyl-pyridine 1-oxide (24.6 g, 0.2 mol) was stirred in acetic anhydride (200 ml) in an oil bath (140-150° C.) for 4 hr. After cooling to room temperature, the mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, ether:hexane (2:1)) to afford 5.1 g (15%) of acetic acid 2-methyl-pyridin-4-ylmethyl ester as a colorless oil. 1H NMR (200 MHz, CDCl3) δ 2.15 (3H, s), 2.56 (3H, s), 5.08 (2H, s), 7.05 (1H, d, J=5.0 Hz), 7.11 (1H, s), 8.48 (1H, d, J=5.0 Hz).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.I[CH2:9][C:10]([O-:12])=[O:11].[Na+].[H-].[Na+].O>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH:4]([O:7][CH2:9][C:10]([OH:12])=[O:11])[CH2:3][CH2:2]1
Reactant: O=C([O-])CI
Reactant: OC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)COC1CCOCC1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A solution of tetrahydro-2H-pyran-4-ol (286 μl, Acros) in tetrahydrofuran (4 ml) was added with sodium iodoacetate (624 mg), and successively added with sodium hydride (198 mg) as several portions at 0° C., and the mixture was stirred at the same temperature for 45 minutes, and then further stirred at room temperature for 23 hours. The reaction mixture was cooled again to 0° C., and then carefully added with water and then with chloroform, and the organic layer was separated. The aqueous layer was acidified (pH 4) with 1 N hydrochloric acid, and extracted three times with chloroform, and the combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated under reduced pressure to obtain the title compound (43.4 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:13][C@:12]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[CH:16]=2)([CH3:14])[N:11]([CH2:23][C:24]#[C:25][C:26]2[CH:27]=[C:28]3[CH2:43][C@@:33]4([C:41]5[C:36](=[N:37][CH:38]=[CH:39][CH:40]=5)[NH:35][C:34]4=[O:42])[CH2:32][C:29]3=[N:30][CH:31]=2)[C:10](=[O:44])[C:5]21[CH2:9][CH2:8][CH2:7][CH2:6]2.C(O)(C(F)(F)[F:48])=O>C(#N)C.[Ag]F>[F:21][C:19]1[CH:20]=[C:15]([C@@:12]2([CH3:14])[N:11]([CH2:23][C:24]#[C:25][C:26]3[CH:27]=[C:28]4[CH2:43][C@@:33]5([C:41]6[C:36](=[N:37][CH:38]=[CH:39][CH:40]=6)[NH:35][C:34]5=[O:42])[CH2:32][C:29]4=[N:30][CH:31]=3)[C:10](=[O:44])[C:5]3([CH2:6][CH2:7][CH2:8][CH2:9]3)[N:4]([CH2:3][CH2:2][F:48])[CH2:13]2)[CH:16]=[C:17]([F:22])[CH:18]=1
Reactant: C[C@@]1(c2cc(F)cc(F)c2)CN(CCCl)C2(CCCC2)C(=O)N1CC#Cc1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Reactant: O=C(O)C(F)(F)F
Agent: F[Ag]
Solvent: CC#N
Product: C[C@@]1(c2cc(F)cc(F)c2)CN(CCF)C2(CCCC2)C(=O)N1CC#Cc1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21

Procedure:
A solution of (6S)-3-{3-[(8R)-6-(2-chloroethyl)-8-(3,5-difluorophenyl)-8-methyl-10-oxo-6,9-diazaspiro[4.5] dec-9-yl]prop-1-yn-1-yl}-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one from Step A (67 mg, 0.11 mmol) and silver(I)fluoride (140 mg, 1.1 mmol) in acetonitrile (3 ml) was heated at 100° C. for 90 min The mixture was diluted with TFA (0.5 mL), filtered, and purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The desired fractions were poured onto saturated NaHCO3 (10 mL) and extracted with CH2Cl2 (3×10 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to yield the title compound. MS: m/z=600 (M+1). HRMS: m/z=600.2604 (M+1); calculated m/z=600.2581 (M+1) for C34H34F3N5O2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:42])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][C:14]=2[CH2:28][N:29]2[C@@H:33]([CH3:34])[C@@H:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[O:31][C:30]2=[O:41])[CH:7]=1)[CH3:2].Br[C:44]1[S:45][CH:46]=[CH:47][N:48]=1>>[CH2:1]([O:3][C:4](=[O:42])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:44]3[S:45][CH:46]=[CH:47][N:48]=3)=[CH:15][C:14]=2[CH2:28][N:29]2[C@@H:33]([CH3:34])[C@@H:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[O:31][C:30]2=[O:41])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1
Reactant: Brc1nccs1
Product: CCOC(=O)Cc1cccc(Oc2ccc(-c3nccs3)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 19, Step 3, using the following starting materials: {3-[2-((4S,5R)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-phenyl}-acetic acid ethyl ester and 2-bromothiazole.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:17]([C:20]2[CH:21]=[CH:22][C:23]([NH2:26])=[N:24][CH:25]=2)(=[O:19])=[O:18])[CH:5]=[CH:6][C:7]=1B1OC(C)(C)C(C)(C)O1.Cl[C:28]1[N:33]=[CH:32][C:31]([C:34]([OH:43])([C:39]([F:42])([F:41])[F:40])[C:35]([F:38])([F:37])[F:36])=[CH:30][N:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC>O>[NH2:26][C:23]1[N:24]=[CH:25][C:20]([S:17]([C:4]2[CH:5]=[CH:6][C:7]([C:28]3[N:29]=[CH:30][C:31]([C:34]([OH:43])([C:35]([F:36])([F:37])[F:38])[C:39]([F:41])([F:42])[F:40])=[CH:32][N:33]=3)=[C:2]([CH3:1])[CH:3]=2)(=[O:18])=[O:19])=[CH:21][CH:22]=1
Reactant: Cc1cc(S(=O)(=O)c2ccc(N)nc2)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: OC(c1cnc(Cl)nc1)(C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(S(=O)(=O)c2ccc(N)nc2)ccc1-c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1
Temperature: 100 °C
Yield: 25.3 %

Procedure:
A glass microwave reaction vessel was charged with 5-((3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)-2-pyridinamine (278 mg, 0.74 mmol), 2-(2-chloropyrimidin-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (139 mg, 0.49 mmol, Intermediate D), (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium (20 mg, 0.025 mmol, Strem Chemical Inc, Newburyport, Mass.), cesium carbonate (484 mg, 1.49 mmol, Sigma-Aldrich, St. Louis, Mo.), DME (1.2 mL), and water (0.1 mL). The reaction mixture was purged with nitrogen for several minutes, and then stirred and heated in an Emrys Optmizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 100° C. for 45 min. The organic layer was taken and the solvent was removed under vacuum. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a silica gel column (12 g), eluting with a gradient of DCM to 2% 2M NH3.MeOH in DCM, to provide 2-(2-(4-((6-amino-3-pyridinyl)sulfonyl)-2-methylphenyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol (61 mg) as an off-white solid.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]2OCO[C:10]=12)[CH:6]=O.C([O-])(=O)C.[NH4+].[N+:19]([CH3:22])([O-:21])=[O:20]>C(O)(=O)C>[N+:19]([CH:22]=[CH:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:3][CH:4]=1)([O-:21])=[O:20]
Reactant: COc1cc(C=O)cc2c1OCO2
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 133.7 %

Procedure:
Under N2, 3-Methoxy-4,5-methylenedioxybenzaldehyde (928 g, 97%, w., 5 mol), Acetic acid (2.5 L), followed by ammonium acetate (664 g, 8.5 mol) and HOAc (1 L) were added to a 22-L 4-necked flask equipped with a an overhead stirrer, a thermometer and a refluxing condenser. The mixture was stirred at room temperature for 10 minutes. Nitromethane (1350 mL, 25 mol) and acetic acid (1 L) were subsequently added. The mixture was heated and stirred at 95° C. for 6 hours. The reaction was monitored with HPLC [HPLC conditions: Zorbax Rx-C8 (25 cm×4.6 mm); column temperature 35° C.; gradient elution from 5:95 to 90:10-acetonitrile:water (0.1% phosphoric acid) in 15 minutes; flow-1.5 mL/min.; UV detection at 230 nm. Retention time: 3-Methoxy-4,5-methylenedioxybenzaldehyde-9.7 min.; 4-Methoxy-6(2-nitrovinyl)-1,3-Benzodioxole-11.8 min.]. After the reaction was completed, the mixture was cooled down to room temperature and filtered. The yellow solid was washed with acetic acid (2×500 mL) and water (2×1000 mL) and the product was dried under vacuum for 3 days to give 997 g of product. (yield 89%) 1H NMR(CDCl3/300 MHz) 7.90(d, J=15.0 Hz, 1H), 7.48(d, J=15.0 Hz, 1H), 6.74(m, 2H), 6.08(s, 2H), 3.95(s, 3H) ppm.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][N:24]([C:27]3[C:28]([CH3:41])=[C:29]([CH3:40])[C:30]4[O:34][C:33]([CH3:36])([CH3:35])[C:32](=[O:37])[C:31]=4[C:38]=3[CH3:39])[CH2:23][CH2:22]2)=[CH:17][CH:16]=1>CCCCCC>[F:10][C:9]([F:12])([F:11])[O:8][C:5]1[CH:6]=[CH:7][C:2]([C:32]2([OH:37])[C:31]3[C:38]([CH3:39])=[C:27]([N:24]4[CH2:25][CH2:26][N:21]([C:18]5[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=5)[CH2:22][CH2:23]4)[C:28]([CH3:41])=[C:29]([CH3:40])[C:30]=3[O:34][C:33]2([CH3:35])[CH3:36])=[CH:3][CH:4]=1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(=O)C(C)(C)O4)CC2)cc1
Solvent: CCCCCC
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)(c3ccc(OC(F)(F)F)cc3)C(C)(C)O4)CC2)cc1
Yield: 82 %

Procedure:
Using 1-bromo-4-(trifluoromethoxy)benzene and 4-(4-methoxyphenyl)-1-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-on-5-yl)piperazine obtained in Reference Example 13, the title compound was synthesized in the same manner as in Example 33. Yield 82%. mp. 175–176° C. (hexane).
Reaction SMILES: Br[C:2]1[N:3]([CH2:21][C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.ClCC(N(C)C)=O.C([O-])([O-])=O.[Na+].[Na+].[CH3:40][O:41][C:42]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][N:43]=1>O1CCOCC1>[CH:11]1([C:10]2[C:9]3[C:4](=[CH:5][C:6]([C:17]([O:19][CH3:20])=[O:18])=[CH:7][CH:8]=3)[N:3]([CH2:21][C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[C:2]=2[C:45]2[CH:44]=[N:43][C:42]([O:41][CH3:40])=[CH:47][CH:46]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COc1ccc(B(O)O)cn1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CC(=O)N(C)C)c2c1
Agent: CN(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(OC)nc3)n(CC(=O)N(C)C)c2c1
Temperature: 25 °C
Yield: 85 %

Procedure:
To a solution of methyl 2-bromo-3-cyclohexyl-1-[2-(dimethylamino)-2-oxoethyl]-1H-indole-6-carboxylate (1 eq), prepared as described in Example 3, Step 1, but using 2-chloro-N,N-dimethylacetamide in the alkylation step, in dioxane (0.06 M) was added bistriphenylphosphine-palladium dichloride (0.2 eq). The reaction mixture was left at RT under nitrogen atmosphere for 15 min, at that rime an aqueous solution of Na2CO3 (2 M), (2.93 eq) and 2-methoxy-5-pyridineboronic acid (2.5 eq) were added. The reaction mixture was heated to reflux for 2 h, then was cooled to RT and concentrated in vacuo. The residue was diluted with DCM, filtered and washed with water, brine, dried over Na2SO4, filtered and evaporated in vacuo to give the title compound (85%). 1H NMR (400 MHz; DMSO-d6, 300 K) δ 1.20-1.28 (m, 3H), 1.65-1.85 (m, 7H), 2.50-2.54 (m, 1H), 2.8 (s, 3H), 2.9 (s, 3H), 3.87 (s, 3H), 3.93 (s, 3H), 4.92 (s, 2H), 6.97 (d, J 8.4, 1H), 7.62 (d, J 8.8, 1H), 7.67 (d, J 8.8, 1H), 7.85 (d, J 8.4, 1H), 7.99 (s, 1H), 8.11 (s, 1H); MS (ES+) m/z 450 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]([NH2:10])=[N:8][CH:9]=1)([O-:3])=[O:2].Br[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([NH:10][C:7]2[N:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][N:6]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(Br)cc1
Reactant: Nc1ncc([N+](=O)[O-])cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Product: COc1ccc(Nc2ncc([N+](=O)[O-])cn2)cc1

Procedure:
In a dry 50 mL round bottom flask 5-nitro-pyrimidin-2-ylamine (1.16 g, 8.3 mmol, 1 equiv), 4-bromo anisole (1.3 mL, 10.4 mmol, 1.25 equiv), cesium carbonate (5.4 g, 16.6 mmol, 2 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (0.479 g, 0.83 mmol, 0.1 equiv) and tris(dibenzylideneacetone) dipalladium (0.304 g, 0.33 mmol, 0.04 equiv) were combined. Reactants were flushed with argon, diluted with dioxane (15 mL) and outfitted with reflux condenser. Reaction was heated to reflux for 18 hours. Reaction was then filtered hot and solvents were evaporated to provide dark solids. Silica gel chromatography (1:4 EtOAc/Hexanes) provided desired product. Yellow powder (0.6 g, 30% yield). Rf=0.39 (20% EtOAc/Hexanes).
Reaction SMILES: C(N1[C:12]2[C:7](=[CH:8]C=CC=2)[C:6](=O)C1=O)CC.[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[O:26].BrCC(C)C>>[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:6][CH:7]([CH3:12])[CH3:8])[C:20](=[O:25])[C:19]2=[O:26]
Reactant: CCCN1C(=O)C(=O)c2ccccc21
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Solvent: CC(C)CBr
Product: CC(C)CN1C(=O)C(=O)c2cc(Cl)ccc21

Procedure:
Was made in an analogous fashion to 1-propylindoline-2,3-dione from commercially available 5-chloroisatin (purchased from Fisher Scientific) and 1-bromo-2-methylpropane (purchased from Fisher Scientific). 1H NMR δ 7.57 (m, 2H), 6.87 (d, 1H), 3.54 (d, 2H), 2.12 (m, 1H), 1.00 (d, 6H).