Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:6][CH:5]([CH2:7][N:8]2[C:16]3[CH:15]=[CH:14][N:13]=[C:12]([O:17][CH3:18])[C:11]=3[C:10](I)=[CH:9]2)[CH2:4][O:3]1.CC1(C)C(C)(C)OB([C:29]2[CH:34]=[CH:33][C:32]([S:35]([NH2:38])(=[O:37])=[O:36])=[CH:31][CH:30]=2)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.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>[CH3:1][C:2]1([CH3:20])[O:6][CH:5]([CH2:7][N:8]2[C:16]3[CH:15]=[CH:14][N:13]=[C:12]([O:17][CH3:18])[C:11]=3[C:10]([C:29]3[CH:34]=[CH:33][C:32]([S:35]([NH2:38])(=[O:37])=[O:36])=[CH:31][CH:30]=3)=[CH:9]2)[CH2:4][O:3]1
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)OC1(C)C
Reactant: COc1nccc2c1c(I)cn2CC1COC(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)cn2CC1COC(C)(C)O1
Temperature: 130 °C
Reaction time: 1 h
Yield: 24.8 %

Procedure:
To a solution of 1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-iodo-4-methoxy-1H-pyrrolo[3,2-c]pyridine (120 mg) in DMF (3 mL)/water (0.30 mL) were added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (131 mg), tetrakis(triphenylphosphine)palladium(0) (35.7 mg) and potassium carbonate (85.4 mg). The reaction mixture was stirred under microwave irradiation at 130° C. for 1 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (32.0 mg).
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][CH:8]([O:10]C(=O)C)[CH3:9])(=[O:6])[O:4][CH3:5].Cl.C(OC)(=O)C.CO>CO>[CH3:1][O:2][P:3]([CH2:7][CH:8]([OH:10])[CH3:9])(=[O:6])[O:4][CH3:5]
Reactant: COP(=O)(CC(C)OC(C)=O)OC
Agent: Cl
Solvent: CO
Solvent: COC(C)=O
Product: COP(=O)(CC(C)O)OC
Yield: 75 %

Procedure:
100 g of 2-acetoxy-2-methylethane-phosphonic acid dimethyl ester are heated for about 5 hours to 65°-75°C in 200 ml of methanol containing 1 wt.% of HCl. A mixture of methyl acetate/methanol is removed continuously by distillation over a column. The residue is fractionated in high vacuum. 60 g of 2-hydroxy-2-methyl-ethane-phosphonic acid dimethyl ester (b.p.: 125°-127°C/1.5 torr) are obtained, corresponding to a yield of 76% of the theoretical.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][N:3]=1.OC(C(F)(F)F)=O.Cl[C:36]1[CH:37]=[CH:38][C:39]2[N:40]([C:42]([C:49]3[CH:54]=[CH:53][N:52]=[CH:51][CH:50]=3)=[C:43]([NH:45][C:46](=[O:48])[CH3:47])[N:44]=2)[N:41]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>[Pd+2].ClC1C=C[C-](P(C2C=CC=CC=2)C2C=CC=CC=2)C=1Cl.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:36]2[CH:37]=[CH:38][C:39]3[N:40]([C:42]([C:49]4[CH:54]=[CH:53][N:52]=[CH:51][CH:50]=4)=[C:43]([NH:45][C:46](=[O:48])[CH3:47])[N:44]=3)[N:41]=2)=[CH:6][C:7]=1[NH:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=1)(=[O:10])=[O:11]
Reactant: CC(=O)Nc1nc2ccc(Cl)nn2c1-c1ccncc1
Reactant: CC1(C)OB(c2cnc(Cl)c(NS(=O)(=O)c3ccc(F)cc3)c2)OC1(C)C
Agent: [Fe+2]
Agent: [Pd+2]
Agent: Clc1cc[c-](P(c2ccccc2)c2ccccc2)c1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(NS(=O)(=O)c4ccc(F)cc4)c3)nn2c1-c1ccncc1
Temperature: 90 °C
Yield: 26.2 %

Procedure:
A sealable vial was charged with N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide (81 mg, 196 μmol), N-(6-chloro-3-(pyridin-4-yl)imidazo[1,2-b]pyridazin-2-yl)acetamide-TFA salt (47.0 mg, 163 μmol), sodium carbonate (69 mg, 653 μmol) and dichloro 1,1′-bis(diphenylphosphino)ferrocene palladium(II) (9.1 mg, 16 μmol). The vial was sealed with a septum cap and 1,4-dioxane (2 mL) and water (0.2 mL) were added under positive N2 flow. The mixture was sparged for 10 min with N2 and heated at 90° C. for 18 h. The solution was cooled to rt and concentrated for purification by MPLC (CombiFlash® Companion®, Teledyne Isco, Lincoln, Nebr.). The residue was taken up in minimal CH2Cl2/MeOH and absorbed onto a 25 g silica loading cartridge and passed through a Redi-Sep® pre-packed silica gel column (80 g) (Teledyne Isco, Lincoln, Nebr.) using a gradient of 1% MeOH in CH2Cl2 to 10% MeOH in CH2Cl2 to afford the title compound, N-(6-(6-chloro-5-(4-fluorophenylsulfonamido)pyridin-3-yl)-3-(pyridin-4-yl)imidazo[1,2-b]pyridazin-2-yl)acetamide (23 mg, 26% yield) as a yellow solid. LCMS (ESI positive ionization) m/z: 538.0 (M+1); 1H NMR (400 MHz, MeOH-d6) δ ppm 2.27 (s, 3H) 7.95-8.07 (m, 2H) 8.21 (dd, J=61.57, 9.54 Hz, 2H) 8.63-8.71 (m, 3H) 8.76-8.81 (m, 2H) 8.82-8.86 (m, 2H) 8.87-8.92 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:11]([C:21]([F:24])([F:23])[F:22])=[N:10][C:9]=2[C:25]2[CH:30]=[CH:29][C:28]([S:31](C)(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:4][CH:3]=1.C([Mg]Br)CCC.C(B(CC)CC)C.[NH2:48]OS(O)(=O)=O.C([O-])(=O)C.[Na+]>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:11]([C:21]([F:24])([F:23])[F:22])=[N:10][C:9]=2[C:25]2[CH:30]=[CH:29][C:28]([S:31]([NH2:48])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:4][CH:3]=1
Reactant: NOS(=O)(=O)O
Reactant: C[Si](C)(C)CCOCn1c(C(F)(F)F)nc(-c2ccc(S(C)(=O)=O)cc2)c1-c1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: CCB(CC)CC
Agent: CCCC[Mg]Br
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(C(F)(F)F)nc(-c2ccc(S(N)(=O)=O)cc2)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the protected sulfone imidazole from step 1 (1.1 g, 2.0 mmol) in THF (15 ml) at 0° C. under an argon atmosphere, n-butyl magnesium bromide (n-BuMgBr) (2M solution in THF, 4.5 ml) was added and the temperature warmed to 25° C. over 30 minutes. Triethylborane (Et3B) (1M solution in THF, 9 ml) was added and the reaction was heated to reflux for 48 hours. The reaction mixture was cooled to 25° C. and a mixture of hydroxylamine-O-sulfonic acid (NH2OSO3H) (2 g) and sodium acetate (2 g) in water (8 ml) was added and rapidly stirred at 25° C. for 16 hours. Water (50 ml) was added and the product was extracted with ethyl acetate, dried (Na2SO4), and evaporated. The residue was purified by chromatography on silica gel using mixtures of ethyl acetate and toluene as the eluent to give 500 mg (45%) of the desired protected sulfonamide. The product was used directly in the next step.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH2:13])[CH:11]=2)[N:6]=[CH:5][N:4]=1.C(N(CCC)CCC)CC.N1C=CC=CC=1.[CH2:30]([CH:32]([CH2:36][CH3:37])[C:33](Cl)=[O:34])[CH3:31]>C(OCC)(=O)C>[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:33](=[O:34])[CH:32]([CH2:36][CH3:37])[CH2:30][CH3:31])[CH:11]=2)[N:6]=[CH:5][N:4]=1
Reactant: CCC(CC)C(=O)Cl
Reactant: Nc1ccc2ncnc(N)c2c1
Agent: CCCN(CCC)CCC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCC(CC)C(=O)Nc1ccc2ncnc(N)c2c1
Reaction time: 3 h
Yield: 46.4 %

Procedure:
To a mixture of 4,6-diaminoquinazoline hydrochloride (1.97 g), tripropylamine (2.60 g) and dry pyridine (20 ml) in an ice-bath was added dropwise during 10 minutes 2-ethylbutyryl chloride (1.75 g). The mixture was stirred for 3 hours at the same temperature. Crushed ice was added to the reaction mixture. The mixture was stirred for 5 minutes and concentrated under reduced pressure. After the addition of water (50 ml), sodium hydrogen carbonate (3.36 g) was added in small portions to the residue to give precipitates which were separated by filtration, washed with water and dried. The crude crystals were dissolved in a mixture of chloroform and methanol under heating. After insoluble materials were removed by filtration, the filtrate was concentrated under reduced pressure to give a residue, which was suspended in ethyl acetate. After stirring under heating, the suspension was filtered to give crystalline 4-amino-6-(2-ethylbutyramido)quinazoline (1.20 g).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:28](=[O:35])[N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[CH2:10][C:11]1[CH:12]=[C:13]([C:17](=[CH2:27])[CH2:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])[CH:14]=[CH:15][CH:16]=1)=O)(C)(C)C.C(O)(=O)C.[CH:40]1[C:52]2[CH:51]([CH2:53][O:54][C:55]([O:57]N3C(=O)CCC3=O)=O)[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:44]=2[CH:43]=[CH:42][CH:41]=1>O.O1CCOCC1>[CH:45]1[C:50]2[CH:51]([CH2:53][O:54][C:55]([NH:8][C@H:9]([C:28](=[O:35])[N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[CH2:10][C:11]3[CH:12]=[C:13]([C:17](=[CH2:27])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:14]=[CH:15][CH:16]=3)=[O:57])[C:52]3[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:49]=2[CH:48]=[CH:47][CH:46]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: C=C(CCC(=O)OC(C)(C)C)c1cccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N2CCCCC2)c1
Solvent: CC(=O)O
Solvent: C1COCCO1
Solvent: O
Product: C=C(CCC(=O)O)c1cccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)N2CCCCC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl (S)-4-(3-(2-((tert-butoxycarbonyl)amino)-3-oxo-3-(piperidin-1-yl)propyl)phenyl)pent-4-enoate (Compound SP420) (0.50 g, 1.03 mmol) was suspended in acetic acid (7.0 ml, 122.28 mmol) and water (7.0 ml), and the suspension was stirred with heating at reflux for 8 hours. The same reaction was additionally carried out four times. The reaction solutions were combined and concentrated under reduced pressure, and the resulting residue was suspended in a 10% aqueous sodium carbonate solution (38 ml). A solution of N-(9-fluorenylmethoxycarbonyloxy)-succinimide (1.65 g, 4.89 mmol) in 1,4-dioxane (19.0 ml) was added and the mixture was stirred at room temperature for 1 hour. The reaction solution was washed with diethyl ether, made acidic by adding acetic acid and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting residue was purified by column chromatography (hexane:ethyl acetate=100:0-50:50) to afford the title compound SP421 (0.78 g, 27.5%).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH2:18][C:19]2(SC2C=CC=CC=2)[S:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@H:15]2[C@@:6]1([F:39])[C@:7]1([CH3:38])[C:12]([CH2:13][CH2:14]2)=[CH:11][C:10](=[O:37])[CH:9]=[CH:8]1)(=[O:3])[CH3:2]>C(C1C=CC=CC=1CC)C>[C:1]([O:4][C@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH:18]=[C:19]2[S:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@H:15]2[C@@:6]1([F:39])[C@:7]1([CH3:38])[C:12]([CH2:13][CH2:14]2)=[CH:11][C:10](=[O:37])[CH:9]=[CH:8]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1C[C@@]2(C)[C@@H](CCC2(Sc2ccccc2)Sc2ccccc2)[C@@H]2CCC3=CC(=O)C=C[C@]3(C)[C@@]12F
Agent: CCc1ccccc1CC
Product: CC(=O)O[C@H]1C[C@]2(C)C(Sc3ccccc3)=CC[C@H]2[C@@H]2CCC3=CC(=O)C=C[C@]3(C)[C@@]12F
Yield: 116.2 %

Procedure:
A solution of 11β-(acetyloxy)-17,17-bis(phenylthio)-9-fluoroandrosta-1,4-diene-3-one (2.3 g) in diethylbenzene (150 ml) is heated in a bath at 190° C for 60 minutes. The solution is then cooled in an ice bath and the separated title compound is isolated by filtration and washed with hexane to afford 2.15 g of the title compound, melting point 229°-231° C.
Reaction SMILES: C[Mg]Cl.Cl[C:5]1[C:10]([N:11]=[C:12]=[S:13])=[CH:9][CH:8]=[C:7]([Cl:14])[N:6]=1.[C:15](=O)([O-])[O-].[Na+].[Na+].O>C1COCC1.CN(C=O)C>[Cl:14][C:7]1[N:6]=[C:5]2[S:13][C:12]([CH3:15])=[N:11][C:10]2=[CH:9][CH:8]=1
Reactant: S=C=Nc1ccc(Cl)nc1Cl
Reactant: O=C([O-])[O-]
Agent: C[Mg]Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1nc2ccc(Cl)nc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 0° C. solution of methylmagnesium chloride 3.0 M in THF (99 mL, 298 mmol) in 100 mL THF under argon was added a solution of 2,6-dichloro-3-isothiocyanatopyridine (43.6 g, 213 mmol) in 100 mL THF slowly dropwise via addition funnel over 2 h. The resulting reaction mixture was allowed to stir 1 h, then was quenched by careful slow addition of sat'd aq. NH4Cl. The reaction mixture was allowed to warm to ambient temperature, and was transferred to a separatory funnel with 200 mL EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give a thick oil. The oil was taken up in 200 mL DMF and treated with sodium carbonate (34 g, 319 mmol). The reaction flask was fitted with an air cooled reflux condenser and the reaction mixture was heated to 90° C. under nitrogen. After 1 h, the reaction mixture was cooled slightly and poured into a stirring mixture of ice and water. The resulting slurry (total volume about 1.5 L) was stirred rapidly for 30 min, then filtered through a frit, rinsing with water, then dried in air and in vacuo to give 5-chloro-2-methylthiazolo[5,4-b]pyridine as a tan solid. MS (ESI) m/z: calculated: 184.0; Observed: 185.0 (M++1).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([C:10](=[CH:16][NH:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9])=[CH:6][N:5]=[C:4]([Cl:26])[C:3]=1[F:27].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:26][C:4]1[C:3]([F:27])=[C:2]2[C:7]([C:8](=[O:9])[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][N:17]2[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])=[CH:6][N:5]=1
Reactant: CCOC(=O)C(=CNc1ccc(F)cc1F)C(=O)c1cnc(Cl)c(F)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2c(F)c(Cl)ncc2c1=O
Temperature: 0 °C

Procedure:
4.26 g (10 mmol) of ethyl 2-(4,6-dichloro-5-fluoronicotinoyl)-3-(2,4-difluorophenyl)amino-acrylate are stirred with 1.65 g (12 mmol) of potassium carbonate in 28 ml of DMF at 100° C. for four hours. Ice-water is added to the mixture and the product is isolated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[O:10][C:11]([C:18]([OH:20])=O)=[C:12]([C:14]([F:17])([F:16])[F:15])[N:13]=1.[CH3:21][O:22][CH2:23][CH2:24][N:25]([CH3:33])[C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][N:27]=1>>[CH3:21][O:22][CH2:23][CH2:24][N:25]([CH3:33])[C:26]1[N:27]=[CH:28][C:29]([NH:32][C:18]([C:11]2[O:10][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])=[N:13][C:12]=2[C:14]([F:15])([F:16])[F:17])=[O:20])=[CH:30][CH:31]=1
Reactant: COc1ccccc1-c1nc(C(F)(F)F)c(C(=O)O)o1
Reactant: COCCN(C)c1ccc(N)cn1
Product: COCCN(C)c1ccc(NC(=O)c2oc(-c3ccccc3OC)nc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 1 above, 2-(2-methoxy-phenyl)-4-trifluoromethyl-oxazole-5-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 2-(2-methoxy-phenyl)-4-trifluoromethyl-oxazole-5-carboxylic acid and N2-(2-methoxy-ethyl)-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C21H21F3N4O4 (m/e) 450, obsd 451 (M+H).
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[N+](=C)=[N-]>>[C:1]([O:12][C:5]([CH3:6])=[CH2:4])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][C:2]([CH3:3])=[CH2:1])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Agent: C=[N+]=[N-]
Product: C=C(C)OC(=O)c1ccc(C(=O)OC(=C)C)cc1

Procedure:
The reaction described in Example 3 was repeated using 27.0 gm (0.162 moles) of terephthalic acid instead of azelaic acid. Infrared analysis of an aliquot of the product showed several materials present. Methylation of a representative portion of the product with diazomethane and analysis of the methylated product by GLC showed the product to be predominantly the half-ester with a smaller amount of the diisopropenyl ester. We anticipate that higher yields of diisopropenyl terephthalate can be obtained if the rate of reaction is increased by conducting it at higher temperatures and pressures. Pure diisopropenyl terephthalate was obtained by passing an aliquot of the above mixed reaction products through a short plug of Florisil (a magnesium silicate) and eluting with petroleum ether. The product crystallized in rhombic shaped plates from petroleum ether, m.p. 72°-73.5° C. Carbon and hydrogen analysis: calculated % C 68.29, % H 5.96; found % C 69.05, % H 5.58. Infrared examination of the crystals in carbon disulphide solution shows band maxima at 1737, 1263, 1210, 1110, 1092, 1017, 867, and 720 cm-1. NMR analysis in deuterochloroform shows absence of the ##STR1## proton signal in the chromatographed, recrystallized sample. The mass spectrum pattern of the unpurified product, m/e 189(100%), 161(50%), 132(10%), is indicative of the diisopropenyl ester. Reactants and products for this example are shown in Table I.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([NH2:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[N+:19]([C:22]1[CH:32]=[CH:31][CH:30]=[C:24]2[C:25]([O:27][C:28](=O)[C:23]=12)=[O:26])([O-:21])=[O:20]>C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:18]2[C:28](=[O:27])[C:23]3[C:24](=[CH:30][CH:31]=[CH:32][C:22]=3[N+:19]([O-:21])=[O:20])[C:25]2=[O:26])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: CCOc1cc(C(N)CS(C)(=O)=O)ccc1OC
Solvent: CC(=O)O
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)ccc1OC
Yield: 81 %

Procedure:
A stirred solution 1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethylamine (640 mg, 2.34 mmol) and 3-nitrophthalic anhydride (460 mg, 2.34 mmol) in acetic acid (10 mL) was heated at reflux for 15 h. The solvent was removed in vacuo to yield an oil. Chromatography of the resulting oil yielded 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-nitroisoindoline-1,3-dione as a yellow solid (850 mg, 81% yield): mp, 110.0-114.0° C.; 1H NMR (CDCl3); δ 1.47 (t, J=7.0 Hz, 3H, CH3), 2.90 (s, 3H, CH3), 3.71 (dd, J=4.3, 14.4 Hz, 1H, CHH), 3.85 (s, 3H, CH3), 4.10 (q, J=7.0 Hz, 2H, CH2), 4.58 (dd, J=10.7, 14.4 Hz, 1H, CHH), 5.93 (dd, J=4.2, 10.7 Hz, 1H, NCH), 6.84 (d, J=8.8 Hz, 1H, Ar), 7.11-7.15 (m, 2H, Ar), 7.89 (t, J=7.8 Hz, 1H, Ar), 8.08-8.13 (m, 2H, Ar); 13C NMR (CDCl3) δ 14.67, 41.56, 49.19, 53.97, 55.96, 64.56, 111.52, 112.51, 120.62, 123.44, 127.35, 128.65, 128.84, 133.73, 135.48, 145.24, 148.68, 149.92, 162.53, 165.33; Anal Calcd for C20H20NO8S: C, 53.57; H, 4.50; N, 6.23. Found: C, 53.54; H, 4.28; N, 6.32
Reaction SMILES: [CH:1]1C2C(COC(N[C@H](CO)CCC)=O)C3C(=CC=CC=3)C=2C=CC=1.[C:25]([NH:42][C@H:43]([C:47]([OH:49])=[O:48])[CH2:44][CH2:45][CH3:46])([O:27][CH2:28][CH:29]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]2[C:30]1=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:26].S(Cl)(Cl)=O>CO.C(OCC)(=O)C>[CH3:1][O:48][C:47](=[O:49])[C@H:43]([CH2:44][CH2:45][CH3:46])[NH:42][C:25]([O:27][CH2:28][CH:29]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:35]=2[C:36]2[C:41]1=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:26]
Reactant: CCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CCC[C@@H](CO)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Solvent: CO
Product: CCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC

Procedure:
FIG. 11 depicts a reaction scheme for the synthesis of 11-2b, 9-fluorenylmethoxy-carbonyl-norvalinol, a description of the synthesis of which follows. To a chilled solution of Fmoc-norvaline (25 g, 73.75 mmol) in anhydrous methanol (469 ml), was added thionyl chloride (53.76 ml, 737.5 mmol) over one hour. Thin layer chromatography in ethyl acetate after an hour confirmed the completion of the reaction (Rf=0.85). The reaction mixture was concentrated and the remaining residue was dissolved in ethyl acetate. The organic layer was washed with several 200 ml portions of saturated sodium bicarbonate followed by brine. The organic layer was dried and concentrated to afford the title compound 9-fluorenylmethoxy-carbonyl-norvaline methyl ester 11-2a as a white solid (26.03 g) in quantitative yield. NMR δ ppm (CD3OD): 7.7 (m, 2H), 7.6 (m, 2H), 7.4 (m, 2H), 7.3 (m, 2H), 4.3 (m, 2H), 4.1 (m, 2H), 3.7 (s, 3H), 1.7 (m, 1H), 1.6 (m, 1H), 1.4 (m, 2H), 0.95 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([NH2:12])[C:10]=2[CH:11]=1.[Cl:13][C:14]([Cl:19])([Cl:18])[C:15](Cl)=[O:16]>C(N(CC)CC)C>[Cl:13][C:14]([Cl:19])([Cl:18])[C:15]([NH:12][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:11]=[C:2]([CH3:1])[N:3]=[N:4]2)=[O:16]
Reactant: Cc1cc2c(N)cccc2nn1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cc2c(NC(=O)C(Cl)(Cl)Cl)cccc2nn1

Procedure:
The title compound was prepared using 3-methylcinnolin-5-amine (commercially available Maybridge), triethylamine, trichloroacetyl chloride and the procedure described in Example 1A.
Reaction SMILES: [Br:1][C:2]1[C:10]([Br:11])=[C:9]2[C:5]([CH2:6][CH:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8]2=[O:12])=[CH:4][C:3]=1[OH:19].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[Br:1][C:2]1[C:10]([Br:11])=[C:9]2[C:5]([CH2:6][CH:7]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:8]2=[O:12])=[CH:4][C:3]=1[O:19][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)CBr
Reactant: O=C1c2c(cc(O)c(Br)c2Br)CC1c1ccccc1
Product: CCOC(=O)COc1cc2c(c(Br)c1Br)C(=O)C(c1ccccc1)C2

Procedure:
Reaction of 6,7-dibromo-5-hydroxy-2-phenyl-1-indanone with ethyl bromoacetate according to the procedure of Example 1, STEP (a), affords the title compound.
Reaction SMILES: [ClH:1].C[O:3][C:4]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][C:5]=1[CH2:6][NH:7][C@H:8]1[CH2:13][CH2:12][CH2:11][NH:10][C@H:9]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.OC1C=CC(OC(F)(F)F)=CC=1C=O>>[ClH:1].[OH:3][C:4]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:26])[F:27])=[CH:20][C:5]=1[CH2:6][NH:7][C@H:8]1[CH2:13][CH2:12][CH2:11][NH:10][C@H:9]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccc(OC(F)(F)F)cc1CN[C@H]1CCCN[C@H]1c1ccccc1
Agent: Cl
Agent: O=Cc1cc(OC(F)(F)F)ccc1O
Product: Oc1ccc(OC(F)(F)F)cc1CN[C@H]1CCCN[C@H]1c1ccccc1

Procedure:
The title compound was prepared in a manner similar to the compound of Example 4 by replacing 2-methoxy-5-trifluoromethoxybenzaldehyde with 2-hydroxy-5-trifluoromethoxybenzaldehyde.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:17])[C:11]=2[CH:10]=[C:9]1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:21][O:22][C:23](=[O:32])[CH:24](Br)[CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28]>CN(C)C=O.C(OCC)(=O)C>[CH3:30][O:29][C:27](=[O:28])[CH2:26][CH2:25][CH:24]([O:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[C:9]([CH3:18])[N:8]2[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:23]([O:22][CH3:21])=[O:32]
Reactant: Cc1cc2c(O)cccc2n1Cc1ccccc1
Reactant: COC(=O)CCC(Br)C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CCC(Oc1cccc2c1cc(C)n2Cc1ccccc1)C(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
1-Benzyl-2-methyl-1H-indol-4-ol 3 (0.3 g 1.26 mmole) was dissolved in anhydrous dimethylformamide (20 mL). To the solution sodium hydride 60% in mineral oil (66 mg 1.65 mmole) was added. The mixture was stirred at room temperature for 1 h. To the mixture dimethyl-2-bromoglutarate (0.3 mL, 1.25 mmole) was added. The mixture was stirred at room temperature for 18 h. The reaction was diluted with ethyl acetate (300 mL) and washed with H2O (4×100 mL) and brine (1×100 mL). The organic layer was separated, dried with magnesium sulfate and concentrated. The residue was purified by column chromatography (6:1 Hexane:EtOAc) to afford 9 (0.49 g, 97%) as a white solid.