Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([O:10][C:11]1[C:19]([Cl:20])=[CH:18][C:17]([Cl:21])=[CH:16][C:12]=1[C:13](Cl)=[O:14])(=[O:9])[CH3:8].Cl.C([O:25][C:26](=[O:36])[C@H:27]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[NH2:28])C>C(N(CC)CC)C>[C:7]([O:10][C:11]1[C:19]([Cl:20])=[CH:18][C:17]([Cl:21])=[CH:16][C:12]=1[C:13]([NH:28][C@H:27]([C:26]([OH:36])=[O:25])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:14])(=[O:9])[CH3:8]
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC(=O)Oc1c(Cl)cc(Cl)cc1C(=O)Cl
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1c(Cl)cc(Cl)cc1C(=O)N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
In one non-limiting example of a synthesis method for N-(2-hydroxy-3,5-dichlorobenzoyl)-L-phenylalanine, synthesis begins with reaction of 3,5-dichlorosalicylic acid with acetic anhydride to obtain 2-acetoxy-3,5-dichlorobenzoic acid which in turn is converted into the acid chloride by the action of oxalyl chloride. The 2-acetoxy-3,5-dichlorobenzoic acid chloride is then reacted in situ with phenylalanine ethyl ester hydrochloride, in the presence of triethylamine, to yield ethyl ester of N-(2-acetoxy-3,5-dichlorobenzoyl)-L-phenylalanine. The last step of the synthesis method introduces novel and highly specific hydrolysis of both ester functions of N-(2-acetoxy-3,5-dichloro benzoyl)-L-phenylalanine ethyl ester to obtain the OTA template, N-(2-hydroxy-3,5-dichlorobenzoyl)-L-phenylalanine (I) with 98% yield. This synthesis reaction is summarized in FIG. 2.
Reaction SMILES: CC([O-])(C)C.[K+].[Br:7][C:8]1[C:17]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)=[C:16]2[C:11]([CH:12]=[N:13][C:14](Cl)=[N:15]2)=[CH:10][CH:9]=1.[NH2:33][C:34]1[CH:39]=[CH:38][C:37]([S:40]([NH2:43])(=[O:42])=[O:41])=[CH:36][CH:35]=1.CC(O)=O>CC(O)C>[Br:7][C:8]1[C:17]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)=[C:16]2[C:11]([CH:12]=[N:13][C:14]([NH:33][C:34]3[CH:39]=[CH:38][C:37]([S:40](=[O:42])(=[O:41])[NH2:43])=[CH:36][CH:35]=3)=[N:15]2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2c(Br)ccc3cnc(Cl)nc23)CC1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCC(Oc2c(Br)ccc3cnc(Nc4ccc(S(N)(=O)=O)cc4)nc23)CC1
Temperature: 105 °C
Reaction time: 2.5 h
Yield: 36.9 %

Procedure:
Solid KOtBu (442 mg, 3.95 mmole) was added to a solution of tert-butyl 4-(7-bromo-2-chloroquinazolin-8-yloxy)piperidine-1-carboxylate (500 mg, 1.13 mmole) and 4-aminobenzenesulfonamide (777 mg, 4.62 mmole) in IPA (15 mL). The reaction was sealed and heated to 105° C. with stirring. After 2.5 hours, AcOH was added to the reaction to pH 4 and the reaction was evaporated to a solid. The crude product was dissolved in DMSO (15 mL) and purified by prep. HPLC to give 241 mg of product in 37% yield (417 mmole).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18]Br>C1(=O)CCCC1>[Br:14][CH2:15][CH2:16][CH:17]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:18]
Reactant: Oc1ccccc1
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C1CCCC1
Product: CC(CCBr)Oc1ccccc1
Yield: 49.3 %

Procedure:
A mixture of 329 g of phenol, 484 g of dry potassium carbonate, 756 g of 1,4-dibromobutane and 1,000 ml of cyclopentanone was refluxed for 24 hours, while stirring. The solid constituents were filtered off and the filtrate was then concentrated under reduced pressure; the oily residue was taken up in 1,500 ml of methylene chloride, and the solution was extracted with 10×200 ml of 15% strength by weight aqueous sodium hydroxide solution. The organic phase was then extracted with twice 300 ml of water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Distillation of the residue gave, at 92°-98° C./0.4 mbar, 395 g of colorless 1-bromo-3-phenoxybutane, which solidified in the receiver; melting point 33°-36° C.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][C:15]([CH3:20])(C(=O)C)[C:14]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)=[N:13]2)=[O:11])=[CH:5][CH:4]=1.ClC1C=[C:33](C=CC=1)[C:34]([O:36]O)=[O:35]>C(Cl)Cl.C(OCC)C>[F:1][C:2]([F:28])([F:29])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([N:12]2[CH2:16][C:15]([CH3:20])([O:36][C:34](=[O:35])[CH3:33])[C:14]([C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=3)=[N:13]2)=[O:11])=[CH:7][CH:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)C1(C)CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C1c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)OC1(C)CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C1c1ccc(Cl)cc1
Reaction time: 72 h

Procedure:
To 2.0 g (4.7 mmole) of N-(4-trifluoromethylphenyl)-3-(4-chlorophenyl)-4-methyl-4-acetyl-4,5-dihydro-1H-pyrazole-1-carboxamide (Example 13a) in 10 ml of methylene chloride was added 2 g (9.8 mmole) of 85% 3-chloroperoxybenzoic acid (MCPBA). After standing for 72 hours at room temperature an additional 0.6 g of MCPBA was added and the reaction was let stand an additional 72 hours. The reaction mixture was diluted with diethyl ether, washed with dilute aqueous sodium bisulfite, dilute aqueous sodium bicarbonate, and brine. The resulting solution was dried over anhydrous magnesium sulfate, filtered, concentrated in vacuo, and crystallized from diethyl ether and hexanes to yield the title compound, a white solid, mp 92°-96° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1/[CH:7]=[CH:8]/[C:9]1[C:17]2[C:12](=[CH:13][C:14]([CH:18]=O)=[CH:15][CH:16]=2)[N:11]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[N:10]=1.[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][C:27]1=[O:35].N1CCCCC1>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1/[CH:7]=[CH:8]/[C:9]1[C:17]2[C:12](=[CH:13][C:14](/[CH:18]=[C:28]3/[C:27](=[O:35])[NH:26][C:34]4[C:29]/3=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:15][CH:16]=2)[N:11]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[N:10]=1
Reactant: O=Cc1ccc2c(/C=C/c3ccccn3)nn(C3CCCCO3)c2c1
Reactant: O=C1Cc2ccccc2N1
Solvent: C1CCNCC1
Solvent: CO
Product: O=C1Nc2ccccc2/C1=C\c1ccc2c(/C=C/c3ccccn3)nn(C3CCCCO3)c2c1
Temperature: 60 °C
Yield: 17.9 %

Procedure:
To a solution of (E)-3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-carbaldehyde (25 mg, 0.0749 mmol), oxindole (10 mg, 0.0749 mmol), and MeOH (1 mL) was added piperidine (1 uL) and the reaction heated to 60° C. for 3 hours. The reaction was cooled to room temperature and the product yellow solid was precipitated with MeOH (1 mL) and then filtered to give 11 mg. The filtrate was purified by column chromatography (silica gel, 99:1 to 98:2 CH2Cl2/MeOH) to give an additional 6 mg of product (17 mg total, 50%). 1H NMR (400 MHz, CDCl3) δ 8.69-8.62 (m, 1H), 8.14 (d, J=8.3 Hz, 1H), 8.00-7.91 (m, 3H), 7.77 (d, J=8.1 Hz, 1H), 7.72 (t, J=8.3 Hz, 1H), 7.63 (d, J=16.9 Hz, 1H), 7.53 (m, 2H), 7.44 (b.s., 1H), 7.25-7.17 (m, 2H), 6.92-6.86 (m, 2H), 5.77 (d, J=10.6 Hz, 1H), 4.09 (d, J=9.6 Hz, 1H), 3.84-3.74 (m, 1H), 2.67-2.53 (m, 1H), 2.24-2.13 (m, 2H), 1.85-1.66 (m, 3H); MS ESI 449.2 [M+H]+, calcd for [C28H24N4O2+H]+ 449.20.
Reaction SMILES: [Br-:1].[Br-].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:16][CH2:15][CH:14]([N+:17]3[CH:21]=[CH:20][N:19]([CH2:22][CH2:23][CH2:24][N+:25]4[CH:29]=[CH:28][N:27]([CH:30]5[CH2:34][CH2:33][N:32]([C:35]6[CH:40]=[CH:39][C:38]([N+:41]([O-])=O)=[CH:37][CH:36]=6)[CH2:31]5)[CH:26]=4)[CH:18]=3)[CH2:13]2)=[CH:8][CH:7]=1)([O-])=O>O.C(O)C.[Pd]>[Br-:1].[Br-:1].[NH2:3][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:16][CH2:15][CH:14]([N+:17]3[CH:21]=[CH:20][N:19]([CH2:22][CH2:23][CH2:24][N+:25]4[CH:29]=[CH:28][N:27]([CH:30]5[CH2:34][CH2:33][N:32]([C:35]6[CH:36]=[CH:37][C:38]([NH2:41])=[CH:39][CH:40]=6)[CH2:31]5)[CH:26]=4)[CH:18]=3)[CH2:13]2)=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(N2CCC(n3cc[n+](CCCn4cc[n+](C5CCN(c6ccc([N+](=O)[O-])cc6)C5)c4)c3)C2)cc1
Agent: [Pd]
Agent: [Br-]
Solvent: O
Solvent: CCO
Product: Nc1ccc(N2CCC(n3cc[n+](CCCn4cc[n+](C5CCN(c6ccc(N)cc6)C5)c4)c3)C2)cc1

Procedure:
3.2 g (0.0044 mol) of derivative (4) above dissolved in a mixture of 60 ml of water/300 ml of ethanol were hydrogenated in the presence of palladium-on-charcoal under a hydrogen pressure of 9 bar and at 75° C. After filtering off the catalyst, the expected derivative (5) was isolated in the form of the hydrobromide. 3.4 g of white powder were obtained; 94% yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:13]=O)=[N:4][CH:5]=[C:6]([N:8]([CH3:12])[CH2:9][CH2:10][CH3:11])[N:7]=1.[CH2:15]([NH:22][CH2:23][C@@H:24]([OH:28])[CH2:25][O:26][CH3:27])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(#N)C.C(O)(=O)C>[CH2:15]([N:22]([CH2:13][C:3]1[C:2]([Cl:1])=[N:7][C:6]([N:8]([CH3:12])[CH2:9][CH2:10][CH3:11])=[CH:5][N:4]=1)[CH2:23][C@@H:24]([OH:28])[CH2:25][O:26][CH3:27])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCCN(C)c1cnc(C=O)c(Cl)n1
Reactant: COC[C@H](O)CNCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CCCN(C)c1cnc(CN(Cc2ccccc2)C[C@@H](O)COC)c(Cl)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73.7 %

Procedure:
To a solution of 3-chloro-5-[methyl(propyl)amino]pyrazine-2-carbaldehyde (427 mg), (2R)-1-(benzylamino)-3-methoxypropan-2-ol (469 mg) and acetic acid (343 μL) in acetonitrile (10 mL) was added sodium triacetoxyborohydride (636 mg), and the mixture was stirred at room temperature for 1.5 hr. To the reaction mixture was added dropwise a saturated sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient: 5→50% ethyl acetate/hexane) to give the title compound (579 mg, 74%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4](=[CH:7][CH:8]=[CH:9][CH:10]=1)[O:5][CH3:6].C([O-])([O-])=O.[K+].[K+].[C:17]1([CH:23]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:24]2[CH2:27][CH:26](S(C)(=O)=O)[CH2:25]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>C(#N)C>[CH:23]([N:24]1[CH2:27][CH:26]([N:2]([C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=2[O:5][CH3:6])[CH3:1])[CH2:25]1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CNc1ccccc1OC
Reactant: CS(=O)(=O)C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1ccccc1N(C)C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 80 °C
Yield: 25.9 %

Procedure:
To a solution of 0.65 g of N-methyl o-anisidine in 15 mL of acetonitrile, was added 0.280 g of K2CO3, followed by 0.650 g of 1-(diphenylmethyl)-3-methane sulfonyl azetidine. The reaction mixture was heated at 80° C. for 1 h then at 50° C. overnight. Water was added and the mixture was extracted with ether. The organic phase was dried and the solvent was removed under vacuo. The product was filtered through 100 mL of silica gel, eluting a with 15% ethyl acetate/hexanes then 25% ethyl acetate/hexanes to give 0.200 g of the desired product: mp 91-95° C. MS (ES) m/z (relative intensity): 356 (M++H).
Reaction SMILES: CO[C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][OH:20])[CH2:14][CH2:13]2)=[O:11])=[N:6][CH:5]=1>CO.C(CN)O>[OH:11][CH2:10][CH2:7][NH:6][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][OH:20])[CH2:16][CH2:17]2)=[O:11])=[N:6][CH:5]=1
Reactant: COC(=O)c1ccc(C(=O)N2CCN(CCO)CC2)nc1
Solvent: CO
Solvent: NCCO
Product: O=C(NCCO)c1ccc(C(=O)N2CCN(CCO)CC2)nc1
Yield: 79 %

Procedure:
6-[1-(2-hydroxyethyl)piperazin-4-yl-carbonyl]nicotinic acid methyl ester (2 g) was dissolved in methanol (20 ml) and with the addition of ethanolamine (2 ml), the mixture was heated to reflux for 8 hours and concentrated under reduced pressure. The concentrated residue was dissolved in isopropanol (14 ml), and with the addition of isopropyl ether to precipitate. After 2-hours stirring, the filtered solid was recrystallized with ethyl acetate and hexane to give a desired compound of 1.74 g (yield: 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:13]3[O:18][CH2:17][CH2:16][NH:15][CH2:14]3)[NH:11][CH:12]=2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[C:24](Cl)[N:23]=[C:22]([NH2:27])[N:21]=1.CCN(C(C)C)C(C)C>C(O)C>[Cl:19][C:20]1[CH:25]=[C:24]([N:15]2[CH2:16][CH2:17][O:18][CH:13]([C:10]3[NH:11][CH:12]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=3)[CH2:14]2)[N:23]=[C:22]([NH2:27])[N:21]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: Clc1ccc(-c2c[nH]c(C3CNCCO3)n2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Nc1nc(Cl)cc(N2CCOC(c3nc(-c4ccc(Cl)cc4)c[nH]3)C2)n1
Yield: 46.1 %

Procedure:
A solution of 2-[4-(4-chlorophenyl)-1H-imidazol-2-yl]morpholine (322 mg, 1.22 mmol), 4,6-dichloro-2-pyrimidinamine (200 mg, 1.220 mmol) and Hunig's base (531 μL, 3.05 mmol) in ethanol (6.1 mL) was heated at 85° C. overnight. The mixture was evaporated and chromatographed (PE-EtOAc, 2:3) to afford the title compound (220 mg). LC-MS (ES) m/z=391 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].CI.[C:15](OCC)(=O)C>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH3:15]
Reactant: CCOC(C)=O
Reactant: Brc1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1ccc2c(Br)cccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 4-bromoindole (5 g, TCI) in DMF (30 ml) was added with 60% sodium hydride (1.14 g) under ice cooling and stirred for 10 minutes. The mixture was added dropwise with methyl iodide (3.18 ml, TCI), stirred for 10 minutes, then warmed to room temperature and further stirred for 30 minutes. The reaction mixture was poured into ice water and added with ethyl acetate (300 ml) for extraction. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate, saturated aqueous ammonium chloride and saturated brine and dried, and then the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Quad, hexane:ethyl acetate=10:1) to obtain the title compound (Intermediate 51, 4.95 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:7]([CH3:20])([CH3:19])[CH:6]=[C:5]2[CH3:21].C([Li])(C)(C)C.[B:27](OC)([O:30]C)[O:28]C>C1COCC1>[C:15]([O:14][C:12]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([B:27]([OH:30])[OH:28])=[CH:11][CH:10]=2)[C:5]([CH3:21])=[CH:6][C:7]1([CH3:20])[CH3:19])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: COB(OC)OC
Reactant: CC1=CC(C)(C)N(C(=O)OC(C)(C)C)c2ccc(Br)cc21
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC1=CC(C)(C)N(C(=O)OC(C)(C)C)c2ccc(B(O)O)cc21
Yield: 43.8 %

Procedure:
A 25 mL r.b. flask, equipped with a magnetic stirring bar, was charged with Compound 8 (3.765 g, 10.67 mmol) under N2. The oil was dissolved in 11 mL THF (anhydrous) and cooled to −78° C. tert-Butyllithium (12.6 mL, 21.4 mmol, 1.70 M) was added by syringe over a period of 10 min (maintaining temperature below −70° C.) turning the reaction mixture from pale yellow to bright yellow. The reaction was allowed to continue at −75° C. until all of the starting material had been consumed as judged by TLC (15% ethyl acetate/hexane). Trimethyl borate (1.22 g, 1.33 mL, 11.7 mmol, 1.1 equiv) was added by syringe over 5-10 minutes (temperature between −70° C. and −65° C.). The reaction was monitored by TLC. Upon completion, the product mixture was quenched with saturated NH4Cl (200 mL). Addition of ethyl acetate (200 mL) partitioned the mixture into 2 phases. The organic phase was washed with saturated NH4Cl (100 mL) and brine (100 mL). The combined aqueous layers were extracted with ethyl acetate (100 mL). The organic layers were combined and dried (Na2SO4). The crude mixture was applied to a small column containing 200 mL silica and 15% ethyl acetate/hexane. The higher Rf impurities were eluted with 2 L of 10% ethyl acetate/hexane. The boronic acid, Compound 9, was eluted with 500 mL ethyl acetate followed by 750 mL ethanol to provide 1.483 g (44%) of Compound 9. Data for Compound 9: 1H NMR (400 MHz, acetone-d6) 7.73 (d, J=1.2, 1H), 7.66 (dd, J=8, 1.2, 1H), 7.13 (d, J=8, 1H), 5.49 (s, 1H), 2.01 (d, J=1.6, 3H), 1.50 (s, 9H), 1.46 (s, 6H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:5]=[C:6]2[CH:12]=[CH:11][NH:10][C:7]2=[N:8][CH:9]=1.[CH3:13][Si:14]([CH2:17][CH2:18][O:19][CH2:20]Cl)([CH3:16])[CH3:15]>CCCCCC.CN(C)C=O>[Br:3][C:4]1[N:5]=[C:6]2[CH:12]=[CH:11][N:10]([CH2:20][O:19][CH2:18][CH2:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[C:7]2=[N:8][CH:9]=1
Reactant: Brc1cnc2[nH]ccc2n1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: C[Si](C)(C)CCOCn1ccc2nc(Br)cnc21
Temperature: 2.5 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
Sodium hydride (60% in mineral oil, 0.800 g, 20 mmol) was washed with hexane then taken up in 30 mL of N,N-dimethylformamide and cooled to 0-5° C. 2-Bromo-5H-pyrrolo[2,3-b]pyrazine (3.0 g, 15 mmol) was added, then SEMCl (3.5 mL, 20 mmol). The mixture was stirred at room temperature for 3 h, then concentrated. Column chromatography afforded 3.25 g (65%) of 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine.
Reaction SMILES: F[C:2]1([C:12]([F:15])([F:14])[F:13])[C:7](F)([F:8])[O:6]C(F)=C(F)[O:3]1.[F:16][C:17]([F:21])=[C:18]([F:20])[F:19]>FC(F)(C(F)(F)F)C(OOC(=O)C(F)(F)C(F)(F)F)=O.C(C(Cl)(F)F)(Cl)(Cl)F>[F:16][C:17]1([F:21])[C:18]([F:20])([F:19])[O:3][C:2]([C:12]([F:15])([F:14])[F:13])=[C:7]([F:8])[O:6]1
Reactant: FC(F)=C(F)F
Reactant: FC1=C(F)OC(F)(C(F)(F)F)C(F)(F)O1
Agent: O=C(OOC(=O)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Solvent: FC(F)(Cl)C(F)(Cl)Cl
Product: FC1=C(C(F)(F)F)OC(F)(F)C(F)(F)O1
Reaction time: 0.03 h

Procedure:
A 240 mL s.s-lined tube was charged with 5.0 g (21 mmol) of monomer 14, 50 mL of CFCl2CF2Cl, 5 mL of cold 3% perfluoropropionyl peroxide catalyst in CFCl2CF2Cl, and 30 g (0.30 mol) of tetrafluoroethylene. The tube was agitated as the mixture warmed; at 20° C., a rapid exotherm carried to 55° C. while the pressure fell to 0 psig. The solid, white polymeric product was heated under vacuum to constant weight, 29.2 g. Analysis of the volatiles by GC indicated the presence of about 1.5 g (30%) of recovered monomer 14. For the polymer, DSC on reheat showed a broad mp, Tonset 271° C., Tpeak 297° C. TGA: 2% weight loss to 400° C., 3.5% weight loss to 440° C. Thus, copolymerization of 14 with TFE occurs readily to give very stable copolymer. A film pressed at 330° C. and 1800 psi for 2 min was clear and tough. ##STR36##
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.ClC1C=C(C=CC=1)C(OO)=[O:15]>ClCCl>[NH:1]1[C:5]2=[N+:6]([O-:15])[CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1cnc2[nH]ccc2c1
Solvent: ClCCl
Product: [O-][n+]1cccc2cc[nH]c21
Temperature: 25 °C

Procedure:
1H-Pyrrolo[2,3-b]pyridine 7-oxide 507 is prepared by reacting 7-azaindole 1 with an oxidizing agent (e.g. m-chloro-peroxybenzoic acid) in an appropriate solvent (e.g. dichloromethane). After stirring at room temperature for 30 minutes to one hour, compound 507 is collected by filtration.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:5][C:4]=1[N+:15]([O-:17])=[O:16])=O.[O:18]=[C:19]1[CH2:23][CH2:22][S:21][CH2:20]1>>[N+:15]([C:4]1[CH:5]=[C:6]([CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])[CH:7]=[CH:8][C:3]=1[CH:1]=[C:20]1[C:19](=[O:18])[CH2:23][CH2:22][S:21]1)([O-:17])=[O:16]
Reactant: COC(=O)C(C)c1ccc(C=O)c([N+](=O)[O-])c1
Reactant: O=C1CCSC1
Product: COC(=O)C(C)c1ccc(C=C2SCCC2=O)c([N+](=O)[O-])c1
Yield: 36.9 %

Procedure:
By using methyl 2-(4-formyl-3-nitrophenyl)propionate (360 mg) obtained in Example 54 and 3-oxothiolane (270 mg), the title compound (180 mg, 37%) was obtained in the same manner as that of Example 1.
Reaction SMILES: C(O[C:4](=O)[CH2:5][CH2:6][C:7]([N:9]1[CH:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][O:11][C:10]1=[O:21])=[O:8])C.BrC[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>C1COCC1>[CH2:12]([O:11][C:10](=[O:21])[CH:6]([C:7]([N:9]1[CH:13]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:12][O:11][C:10]1=[O:21])=[O:8])[CH2:5][CH2:4][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH3:13]
Reactant: CCOC(=O)CCC(=O)N1C(=O)OCC1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: C1CCOC1
Product: CCOC(=O)C(CCC(=O)OC(C)(C)C)C(=O)N1C(=O)OCC1Cc1ccccc1
Reaction time: 0.33 h

Procedure:
A solution of the compound of example 67 (5.0 g, 16.38 mmol) in anhydrous THF (160 mL) was cooled to −78° C. A solution of NaHDMS in THF (1M, 16.4 mL, 16.4 mmol) was injected over 10 minutes. The reaction mixture was stirred for an additional 20 minutes, after which time, a solution of tert-butyl bromoacetate in anhydrous THF (10 mL) was slowly injected. After stirring for 1 h at −78° C. and 3 h at −48° C., the reaction was quenched by the addition of a saturated ammonium chloride solution. The mixture was extracted several times with ethyl acetate. The recombined organic layer was successively extracted with brine, a saturated sodium hydrogen carbonate solution, brine and water. The solvent was evaporated following drying over sodium sulfate and filtration. The resultant crude product was flashed with 20% ethyl acetate in hexanes to give the product as a white solid. 1H-NMR(CDCl3, 400 MHz: 1.24(t, J=7.2, 3H); 1.44(s, 9H); 2.54(m, 2H); 2.77(m, 3H); 3.31(m, 1H); 4.14(m, 4H); 4.43(m, 1H); 4.69(m, 1H); 7.26(m 5H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.Br.Br.[OH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>CN(C)C=O>[OH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N:35]1[CH2:40][CH2:39][N:38]([CH2:2][CH2:3][CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=34)[S:6]2(=[O:18])=[O:17])[CH2:37][CH2:36]1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Reactant: Oc1ccccc1N1CCNCC1
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CCN(c2ccccc2O)CC1
Temperature: 20 °C
Yield: 55 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (7.02 g), triethylamine (10.5 cc) and 4-(2-hydroxyphenyl)piperazine dihydrobromide (8.5 g) in dimethylformamide (150 cc). The mixture is heated for 6 hours at boiling point, then cooled to a temperature of about 20° C. Stirring is maintained for 15 hours at this temperature. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with a mixture of dichloromethane and ethyl acetate (50-50 vol) as eluant, and recrystallization from acetonitrile (25 cc), 2-{3-[4-(2-hydroxyphenyl)-1-piperazinyl]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (5.8 g) is obtained, m.p. 128° C.