Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCOC(C)=O>CN(C=O)C>[CH2:20]([NH:27][C:8]1[C:9](=[O:10])[N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[S:6](=[O:19])(=[O:18])[C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)N1C(=O)C(NCc2ccccc2)=C(c2ccccc2)S1(=O)=O
Temperature: 120 °C
Yield: 51.3 %

Procedure:
A mixture of 2-tert-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.150 g, 0.500 mmol) and benzylamine (0.110 ml, 1.001 mmol) in DMF (2 ml) was heated in the microwave reactor at 120° C. for 15 mins. EtOAc was added, the mixture was washed with brine and evaporated to dryness. The residue was purified by silica gel column chromatography (Horizons Biotage) using 15-20% EtOAc in petroleum ether 40-60° C. as eluent to give the title compound (0.095 g, 51%) as a solid. 1H NMR (500 MHz CDCl3): δ 7.50-7.38 (m, 5H), 7.34-7.25 (m, 3H), 7.06-6.98 (m, 2H), 5.55 (bs, 1H), 4.02 (d, 2H), 1.77 (9H, s); 13C NMR (125 MHz, CDCl3): δ 159.8, 136.8, 133.0, 131.9, 129.8, 129.0, 128.7, 128.2, 127.6, 124.8, 108.2, 61.6, 48.4, 27.9; Mass Spectrum M+H+ 371.
Reaction SMILES: Cl.Cl.[C:3]1([S:9]([N:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[C:15]=3[C:14]([CH3:27])=[CH:13]2)(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:28]([O:32][C:33]([NH:35][CH2:36][CH:37]([C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=1)[C:38](O)=[O:39])=[O:34])([CH3:31])([CH3:30])[CH3:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:28]([O:32][C:33](=[O:34])[NH:35][CH2:36][CH:37]([C:41]1[CH:42]=[CH:43][C:44]([Cl:47])=[CH:45][CH:46]=1)[C:38]([N:24]1[CH2:25][CH2:26][N:21]([C:20]2[C:15]3[C:14]([CH3:27])=[CH:13][N:12]([S:9]([C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=4)(=[O:10])=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:22][CH2:23]1)=[O:39])([CH3:31])([CH3:29])[CH3:30]
Reactant: Cc1cn(S(=O)(=O)c2ccccc2)c2ncnc(N3CCNCC3)c12
Reactant: CC(C)(C)OC(=O)NCC(C(=O)O)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1cn(S(=O)(=O)c2ccccc2)c2ncnc(N3CCN(C(=O)C(CNC(=O)OC(C)(C)C)c4ccc(Cl)cc4)CC3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
The 7-benzenesulfonyl-5-methyl-4-piperazin-1-yl-7H-pyrrolo[2,3-d]pyrimidine bis-hydrochloride (200 mg, 0.465 mmol) and 3-tert-butoxycarbonylamino-2-(4-chlorophenyl)-propionic acid (146 mg, 0.488 mmol) were dissolved/suspended in 2.0 mL of DMF at room temperature and treated with TEA (259 μL, 1.86 mmol). The HBTU (194 mg, 0.511 mmol) was added in one sum, and the reaction was allowed to stir overnight at room temperature to completion. The reaction was partitioned between ethyl acetate and diluted NaHCO3 solution. The aqueous was extracted with ethyl acetate, and the organics were combined. The organic was washed with water, then brine, separated, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by chromatography (silica gel eluted with 70:30 ethyl acetate:hexanes) to afford the pure [3-[4-(7-benzenesulfonyl-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-2-(4-chlorophenyl)-3-oxo-propyl]-carbamic acid tert-butyl ester as colorless gel (295 mg, 99%). 1H NMR (CDCl3, 400 MHz) δ 8.44 (s, 1H), 8.16 (d, J=8.4 Hz, 2H), 7.59 (t, J=7.2 Hz, 1H), 7.49 (appt, J=7.6 Hz, 2H), 7.31 (m, 3H), 7.20 (d, J=8.0 Hz, 2H), 5.12 (m, 1H), 4.09 (m, 1H), 3.92 (m, 1H), 3.60 (m, 1H), 3.56-3.46 (m, 4H), 3.38 (d, J=10.4 Hz, 2H), 3.32 (m, 1H), 2.90 (m, 1H), 2.29 (s, 3H), 1.41 (s, 9H). LCMS (APCI+) m/z 639 [M+H]+; Rt=3.70 min.
Reaction SMILES: B1([O-])OO1.[OH2:5].[OH2:6].[OH2:7].O.[Na+].[SH:10][C:11]1[CH2:16][O:15][CH2:14][CH2:13][C:12]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(O)(=O)C>[CH2:20]([O:19][C:17]([C:12]1[CH2:13][CH2:14][O:15][CH2:16][C:11]=1[S:10]([OH:7])(=[O:6])=[O:5])=[O:18])[CH3:21]
Reactant: O
Reactant: CCOC(=O)C1=C(S)COCC1
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(S(=O)(=O)O)COCC1
Temperature: 52.5 °C
Reaction time: 3 h
Yield: 219.9 %

Procedure:
Sodium perborate tetrahydrate (24.5 g) was added to acetic acid (130 ml) and the mixture was heated to 50-55° C. Thereto was added dropwise a solution of ethyl 5-sulfanyl-3,6-dihydro-2H-pyran-4-carboxylate (10.0 g) in acetic acid (30 ml) over 2 h. The mixture was stirred at 50-55° C. for 3 h, and the reaction mixture was concentrated under reduced pressure. To the residue was added acetonitrile (230 ml) and the mixture was stirred at room temperature for 2 days, and the resultant insoluble material was removed off by filtration and washed with acetonitrile (70 ml). The filtrate and washing were combined and the mixture was concentrated under reduced pressure. The residue was dissolved in acetonitrile (160 ml) and the mixture was stirred at room temperature for 6 h. The obtained insoluble material was removed off by filtration, and the filtrate was concentrated under reduced pressure. To the residue was added diisopropyl ether (100 ml), and the precipitated insoluble material was filtered off to give 4-(ethoxycarbonyl)-5,6-dihydro-2H-pyran-3-sulfonic acid as a pale-yellow oil (27.6 g) containing an inorganic product.
Reaction SMILES: Cl.Br[C:3]1[C:4]([F:10])=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1.[CH2:11]([Sn](CCCC)(CCCC)C=C)[CH2:12]CC>O1CCOCC1.CCOC(C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[F:10][C:4]1[C:3]([CH:11]=[CH2:12])=[CH:8][N:7]=[C:6]([NH2:9])[CH:5]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Nc1cc(F)c(Br)cn1
Agent: [Pd]
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C=Cc1cnc(N)cc1F
Temperature: 120 °C

Procedure:
5-Bromo-4-fluoro-pyridin-2-ylamine mono HCl salt (xvii) (368 mg, 1.62 mmol), tributyl(vinyl)stannane (0.52 mL, 1.78 mmol) and palladium tetrakis(triphenylphosphine) (19 mg, 0.016 mmol) in dioxane (6 mL) under argon were heated under microwave irradiation at 120° C. for 45 min. Were then added tributyl(vinyl)stannane (0.2 mL, 0.685 mmol) and palladium tetrakis(triphenylphosphine) (7 mg, 0.006 mmol) and the RM was placed under argon and heated once more under microwave irradiation at 120° C. for 45 min. The RM was diluted with EtOAc and washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by chromatography with hexane and EtOAc to yield the title product as a yellow solid (tR 1.76 min (conditions 8), MH+=139).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[C:23]([Br:25])[CH:22]=[CH:21][C:20]=2[O:26][CH2:27][C:28]([F:31])([F:30])[F:29])/[C:9]1=[O:32])=O)(C)(C)C.[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:35]=1[CH:41]=[N:42][C:43]([O:45][Si](C)(C)C)=[CH2:44]>C1(C)C=CC=CC=1.ClCCl>[F:29][C:28]([F:31])([F:30])[C:27]([OH:45])=[O:26].[Br:25][C:23]1[CH:22]=[CH:21][C:20]([O:26][CH2:27][C:28]([F:29])([F:31])[F:30])=[C:19]([CH:18]2[CH2:44][C:43](=[O:45])[NH:42][CH:41]([C:35]3[CH:36]=[C:37]([Cl:40])[CH:38]=[CH:39][C:34]=3[Cl:33])[C:10]32[C:11]2[C:16](=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[NH:8][C:9]3=[O:32])[CH:24]=1
Reactant: C=C(N=Cc1cc(Cl)ccc1Cl)O[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1C(=O)/C(=C\c2cc(Br)ccc2OCC(F)(F)F)c2ccc(Cl)cc21
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(O)C(F)(F)F
Product: O=C1CC(c2cc(Br)ccc2OCC(F)(F)F)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(Cl)ccc2Cl)N1
Yield: 18.5 %

Procedure:
In a manner similar to the method described in Example 228d, E/Z-3-[5-bromo-2-(2,2,2-trifluoro-ethoxy)-benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (0.53 g, 1 mmol) was reacted with 1-(2,5-dichlorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in Example 159a (6 mmol) in toluene and then trifluoroacetic acid in dichloromethane to give title compound as a white solid (0.06 g).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:23][CH3:24])=[CH:4][C:5]2[O:10][CH2:9][N:8]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][CH:12]=3)[C:7](=[O:21])[C:6]=2[CH:22]=1.[OH-].[Na+]>O1CCOCC1.O>[F:1][C:2]1[C:3]([NH:23][CH3:24])=[CH:4][C:5]2[O:10][CH2:9][N:8]([C:11]3[CH:12]=[CH:13][C:14]([C:15]([OH:17])=[O:16])=[CH:19][CH:20]=3)[C:7](=[O:21])[C:6]=2[CH:22]=1
Reactant: CNc1cc2c(cc1F)C(=O)N(c1ccc(C(=O)OC)cc1)CO2
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CNc1cc2c(cc1F)C(=O)N(c1ccc(C(=O)O)cc1)CO2
Temperature: 25 °C
Reaction time: 4 h
Yield: 421.6 %

Procedure:
To methyl 4-(6-fluoro-7-(methylamino)-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)benzoate (0.05 g, 0.15 mmol) was dissolved in dioxan (2 ml) and to it was added sodium hydroxide (0.012 g, 0.3 mmol) in water (0.5 ml) and the mixture stirred for 4 hr at room temperature. The solvent was removed under vacuum and the residue acidified, extracted with ethyl acetate (2×10 ml), dried over anhydrous sodium sulfate and concentrated to provide 4-(6-fluoro-7-(methylamino)-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)benzoic acid (0.2 g, 41%). RP-HPLC: 1.8 min; ES-MS (M+H)+=317.0.
Reaction SMILES: CC(C)([O-])C.[K+].CN(C=O)C.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:15][CH:14]=1.[CH:24]1(Br)[CH2:28][CH2:27][CH2:26][CH2:25]1>O>[CH3:23][O:22][C:20](=[O:21])[CH:19]([C:16]1[CH:15]=[CH:14][C:13]([Cl:12])=[CH:18][CH:17]=1)[CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COC(=O)Cc1ccc(Cl)cc1
Reactant: BrC1CCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(c1ccc(Cl)cc1)C1CCCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of 3.65 g (32.5 mmol) of potassium tert-butoxide in 65 ml of abs. DMF was cooled to 0° C., and a solution of 5.0 g (27.08 mmol) of methyl 4-chlorophenylacetate in about 2 ml of abs. DMF was added dropwise. The mixture was stirred at 0° C. for 30 min, and 4.84 g (32.5 mmol) of cyclopentyl bromide were then slowly added dropwise. The reaction mixture was stirred at 0° C. for 1 h and then added to water and extracted with ethyl acetate. The organic phase was dried over sodium sulphate and concentrated under reduced pressure, and the residue was dried under high vacuum. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 100:1). This gave 6.28 g of the target compound (91.8% of theory).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1N)([O-:3])=[O:2].[CH3:11][O:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([C:21](Cl)=[O:22])=[CH:17][CH:16]=1)=[O:14].[N:24]1C=CC=CC=1>C1COCC1.C(=O)(O)[O-].[Na+].CCOC(C)=O>[CH3:11][O:12][C:13](=[O:14])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH2:24])=[O:22])=[CH:17][C:16]=1[C:5]1[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C(N)=O)cc1-c1ccccc1[N+](=O)[O-]
Yield: 78 %

Procedure:
A solution of 2-nitroaniline (0.41 g, 3.0 mmol) and methyl 4-chlorocarbonyl benzoate (0.65 g, 3.3 mmol) in THF (3.7 mL) and pyridine (0.8 mL) was stirred for 2 h at room temperature. The reaction was diluted with saturated sodium bicarbonate (10 mL) and EtOAc (15 mL), the phases separated and the aqueous phase extracted with EtOAc (2×10 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to afford (2-nitrophenyl)-terephthalamic acid methyl ester as a yellow solid (0.70 g, 78%). 1H NMR (CDCl3) δ3.97 (s, 3H), 7.25 (t, 1H, J=7.8 Hz), 7.74 (t, 1H, J=7.8 Hz), 8.04 (d, 2H, J=7.8 Hz), 8.20 (s, 1H (NH)), 8.20 (d, 2H, J=7.8 Hz), 8.3 (d, 1H, J=7.8 Hz), 8.99 (d, 1H, J=7.8 Hz).
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=2)[CH:7]([CH2:20][Cl:21])[CH2:6]1)[CH2:2][CH2:3][CH3:4].[F:22][C:23]([F:32])([F:31])[C:24]1[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=1.[H-].[Na+]>C(N1CCC(C2C=CC(N(C)C)=CC=2)C(CO)C1)CCC.CN(C=O)C>[ClH:21].[CH2:1]([N:5]1[CH2:10][CH2:9][C@@H:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=2)[C@H:7]([CH2:20][O:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([C:23]([F:22])([F:31])[F:32])[CH:25]=2)[CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCC(c2ccc(N(C)C)cc2)C(CCl)C1
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: CCCCN1CCC(c2ccc(N(C)C)cc2)C(CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCN1CC[C@@H](c2ccc(N(C)C)cc2)[C@H](COc2cccc(C(F)(F)F)c2)C1
Product: Cl

Procedure:
0.4 g of 1-butyl-3-chloromethyl-4-(4-dimethylaminophenyl) piperidine (18) in DMF (25 ml) (prepared from compound (12) by known procedures) was added to a 70° C. hot mixture of 3-trifluoromethylphenol (0.28 g) and NaH (0.09 g) in DMF (25 ml). Reaction time 2 h at 100° C. Evaporation with 3×100 ml toluene. The residue was extracted with NaOH (4N)-ether, the etheral layer separated and dried (MgSO4), purified on a silica gel column and precipitated with concentrated HCl from acetone. Yield 0.22 g of colorless crystals. M.p. 221°-223° C.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.CC(=CC)C.Cl([O-])=[O:19].[Na+].O.P([O-])(O)(O)=O.[Na+]>O.C(OCC)(=O)C.O1CCOCC1>[Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([OH:19])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(O)c1c(Cl)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 47.2 %

Procedure:
A mechanically stirred suspension of 15 g (83.5 mmol) of 2-chloroindole-3-carboxaldehyde [XXVI: R1 =R3 =H, X=Cl] (Schule, et al., Arch, Pharm. [Weinheim] 1972;305:523-533), 84 mL of 2-methyl-2-butene, and 200 mL of p-dioxane in an ice bath was treated with a solution of 40 g each of sodium chlorite and sodium dihydrogen phosphate monohydrate in 200 mL of water. The biphasic mixture was then stirred vigorously at 25° C. for 3.5 hours. An additional 16 g each of solid sodium chlorite and sodium dihydrogen phosphate monohydrate was added and the mixture was stirred for another 3.5 hours. The mixture was diluted with 350 mL of ethyl acetate and 200 mL of water. The layers were separated and the aqueous phase was extracted with 300 mL of ethyl acetate. The combined organic extracts were extracted with cold 2% aqueous NaOH (3×200 mL). The basic extracts were combined and acidified to pH 4 with 6N aqueous HCl. The precipitated solids were collected by filtration, washed well with water, and air dried overnight. The solids were dissolved in 150 mL of hot acetone and the solution was treated with 65 mL of hexane. After storage at 3° C. for 20 hours, the solids were collected by filtration, washed with cold acetone, and dried to leave 7.71 g of pure 2-chloroindole-3-carboxylic acid [XXVII: R1 =R3 =H, X=Cl] as an off-white solid; mp 181.5° C. (dec). Further processing of the filtrate as above afforded 2.41 g of a second crop; mp 179.5° C. (dec). Total yield 10.12 g (62%).
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:18][CH:17]=1.[OH2:28]>CC(N(C)C)=O>[CH2:12]([O:11][C:3](=[O:10])[C:4]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:28])[C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:18][CH:17]=1)([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:18][CH:17]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:13]
Reactant: CC(C)(C)C(=O)c1ccc(CBr)cc1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)C(Cc1ccc(C(=O)C(C)(C)C)cc1)(Cc1ccc(C(=O)C(C)(C)C)cc1)C(=O)OCC
Reaction time: 2 h

Procedure:
To a cold suspension of 4.66 g (0.194) mole of sodium hydride in 200 ml dimethylacetamide there is added dropwise 28.2 g (0.176 mole) diethyl malonate in 80 ml of dimethylacetamide maintaining the temperature between 0° and 5°C. Stirring is initiated for two hours at room-temperature and there is then added 40.8 g(0.16 mole) of α-bromo-p-pivaloyl toluene in 200 ml of dimethylacetamide maintaining the reaction temperature between 20° and 30°C. Stirring is continued overnight at room temperature. Water is then added and the excess dimethylacetamide is removed in vacuo, and the resulting residue is partitioned between petroleum ether and water. The layers are washed with water, and salt water, dried and evaporated in vacuo. The residue is then distilled in vacuo and crystallized from petroleum ether at -50°C to give bis-(p-pivaloylbenzyl)malonic acid diethyl ester, m.p. 65° to 67°C.
Reaction SMILES: [NH:1]([C:8]1[N:9]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[CH:14][C:13](/[CH:19]=[CH:20]/[C:21]([O:23]C)=[O:22])=[C:12]([CH3:25])[N:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CC#N.O>[NH:1]([C:8]1[N:9]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:10]2[N:11]=[C:12]([CH3:25])[C:13](/[CH:19]=[CH:20]/[C:21]([OH:23])=[O:22])=[CH:14][C:15]=2[C:16](=[O:18])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)/C=C/c1cc2c(=O)cc(Nc3ccccc3)n(-c3ccccc3)c2nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: Cc1nc2c(cc1/C=C/C(=O)O)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.4 %

Procedure:
To a suspension of 2-anilino-6-[(E)-3-methoxy-3-oxo-1-propenyl]-7-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (10 mg, 0.025 mmol) in CH3CN (2.0 mL) was added 1N NaOH (2.0 mL). The suspension was stirred at room temperature for 18 h. The mixture was diluted with water (10 mL) and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated in vacuo to afford (2E)-3-(7-anilino-2-methyl-5-oxo-8-phenyl-5,8-dihydro-1,8-naphthyridin-3-yl)-2-propenoic acid (6.2 mg, 63%): LCMS RT: 2.37 min, MHR: 398.3, Rf=0.51 (EtOAc).
Reaction SMILES: C(=O)=[O:2].O.[CH:5]1[C:19](I)=[C:18]([O-])[C:17](I)=[C:16]2[C:6]=1[C:7](C1C(Cl)=C(Cl)C(Cl)=C(Cl)C=1C([O-])=O)=[C:8]1[C:14]([O:15]2)=[C:13](I)[C:11](=O)[C:10](I)=C1.[Na+].[Na+].C(=O)=O>O>[CH2:8]=[CH:7][C:6]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:5]=1.[C:16]([O:15][CH2:14][CH2:13][CH2:11][CH3:10])(=[O:2])[CH:6]=[CH2:5]
Reactant: O=C([O-])c1c(Cl)c(Cl)c(Cl)c(Cl)c1-c1c2cc(I)c(=O)c(I)c-2oc2c(I)c([O-])c(I)cc12
Reactant: O=C=O
Agent: [Na+]
Solvent: O
Product: C=CC(=O)OCCCC
Product: C=Cc1ccccc1
Reaction time: 48 h

Procedure:
A process of microencapsulation using a CO2/water emulsification is described hereinbelow. About 4 wt % of a dye such as, for example, Acid Red 94, is incorporated into about 75 wt % of a latex, such as, for example, a styrenelbutylacrylate formed by either emulsion or dispersion polymerization. First, styrene/butyl acrylate monomers are polymerized via emulsion polymerization to form about 100 nm to about 200 nm particles. These particles are then placed on a freeze drier for about 48 hours. The latex particles are dispersed in de-ionized (DI) water using an ultrasonic bath. This solution is then transferred to a variable volume cell where the desired dye and about 1 wt % of a surfactant, such as, for example, polyethylene oxide/polypropylene oxide block copolymer (PLURONIC F108), are added to the latex dispersion. The cell is sealed and about 350 grams of supercritical CO2 is added. Once the supercritical CO2 is added, the cell is pressurized and a magnetic stirrer is used to emulsify the supercritical CO2 and water. The mixture is allowed to stir for approximately 10 hours. After the dye is incorporated into the latex, i.e. after about 12 hours, the CO2 is vented off slowly to minimize foaming. To remove any excess unreacted dye, the latex dye mixture is washed with absolute ethanol until the wash solution is colorless. These dyed latex particles are then re-dispersed in DI water and added to a reactor, such as a 4 liter glass bottom reactor, commercially available from Chemglass Life Sciences. Additionally, a wax may be added to the latex dye mixture. The mixture is then homogenized at high shear with a coagulating agent, such as for example, a polyaluminum chloride for about 20 minutes. The mixture is then aggregated for a predetermined time period until the particle size is sufficient for latex shell addition (such as from about 3.0 to about 7.0 μm).
Reaction SMILES: [O:1]=[C:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:12](Cl)(=[O:14])=[O:13])[CH:8]=2)[NH:3]1.C1COCC1.[CH2:21](CN)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[CH:30]([N:33](CC)C(C)C)(C)C>C(Cl)(Cl)Cl>[CH2:21]([N:33]([CH3:30])[S:12]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2](=[O:1])[C:10]2=[O:11])(=[O:14])=[O:13])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C1Nc2ccc(S(=O)(=O)Cl)cc2C1=O
Reactant: CCN(C(C)C)C(C)C
Reactant: NCCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CN(Cc1ccccc1)S(=O)(=O)c1ccc2c(c1)C(=O)C(=O)N2
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 3.3 %

Procedure:
To a black solution of 2,3-Dioxo-2,3-dihydro-1H-indole-5-sulfonylchloride (4.00 g, 16.3 mmol) in 1:1 THF:CHCl3 was added, drop-wise via syringe pump, a solution of N-benzylmethylamine (2.73 mL, 21.2 mmol, 1.3 eq) and N,N-diisopropylethylamine (5.68 mL, 32.6 mmol, 2 eq) in CHCl3 (32 mL) over a period of 1.25 hr. with cooling in an ice bath. After stirring for 50 min. the reaction was allowed to warm to room temperature and stirred for 30 minutes. The reaction was concentrated. The crude product was purified on Biotage KP silica gel eluting with 98/2 CHCl2/CH3OH to give the analytically pure sample of the title compound as a bright yellow solid (0.18 g, 15% yield). Anal. Calc'd for C16H14N2O4S: C, 58.17; H, 4.27; N, 8.48. Found: C, 57.88; H, 4.36; N, 8.40. MS: (API-ES−) m/z 329 [M−H]. m.p.: 183-185° C.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:29])=[C:9](B(O)O)[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25])=[O:5].[C:32]([C:35]1[S:36][CH:37]=[C:38](Br)[CH:39]=1)(=[O:34])[CH3:33]>CCCCCC.C(OCC)(=O)C>[C:32]([C:35]1[S:36][CH:37]=[C:38]([C:11]2[C:10]3[O:14][CH2:13][CH:12]([C:15]4[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=4)[C:9]=3[C:8]([CH3:29])=[C:7]([NH:6][C:4](=[O:5])[CH2:3][C:2]([CH3:1])([CH3:31])[CH3:30])[C:24]=2[CH3:25])[CH:39]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)c1cc(Br)cs1
Reactant: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1B(O)O)OCC2c1ccc(C(C)C)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)c1cc(-c2c(C)c(NC(=O)CC(C)(C)C)c(C)c3c2OCC3c2ccc(C(C)C)cc2)cs1
Yield: 62 %

Procedure:
Using (5-((3,3-dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl)boronic acid obtained in Example 116 and 2-acetyl-4-bromothiophene, the title compound was synthesized in the same manner as in Example 107. Yield: 62%. Melting point: 133-134° C. (hexane-ethyl acetate).