Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:18][CH2:17]1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([Cl:44])[C:30]=1[OH:45].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:28].[Cl:28][C:29]1[CH:34]=[C:33]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][N:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)[CH2:18][CH2:17]2)[CH:32]=[C:31]([Cl:44])[C:30]=1[OH:45]
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](CN2CCCC2)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1N[C@H]1CC[C@H](CN2CCCC2)CC1

Procedure:
Following general procedure II, 1-{6-chloro-4-[trans-4-(pyrrolidin-1-ylmethyl)-cyclohexylamino]-1,5-naphthyridin-3-yl}ethanone (67 mg, 0.17 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (58 mg, 0.21 mmol) followed by formation of the dihydrochloride salt to afford the desired product (36 mg, 36%) as an off-white solid: 1H NMR (300 MHz, CD3OD) δ 9.15 (s, 1H), 8.47 (d, J=9.0 Hz, 1H), 8.34 (d, J=9.0 Hz, 1H), 8.12 (s, 2H), 5.75-5.67 (m, 1H), 3.72-3.65 (m, 2H), 3.17-3.06 (m, 4H), 2.76 (s, 3H), 2.48-2.40 (m, 2H), 2.20-1.99 (m, 6H), 1.73-1.61, (m, 2H), 1.47-1.36 (m, 2H); ESI MS m/z 513 [M+H]+; HPLC 95.7% (AUC), tR=10.21 min.
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[O:6])[CH:2]=[CH2:3].[Cl:7][C:8]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([NH2:21])(=[O:20])=[O:19])=[CH:9][Cl:10].N12CCCN=C1CCCCC2>C(Cl)Cl>[Cl:7][C:8]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([NH:21][C:5]([NH:4][CH2:1][CH:2]=[CH2:3])=[O:6])(=[O:19])=[O:20])=[CH:9][Cl:10]
Reactant: C=CCN=C=O
Reactant: NS(=O)(=O)c1ccccc1OC(Cl)=CCl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: C=CCNC(=O)NS(=O)(=O)c1ccccc1OC(Cl)=CCl

Procedure:
A solution of 3.3. g of allyl isocyanate in 10 ml of methylene chloride is added dropwise to a mixture of 10.7 g of 2-(1,2-dichlorovinyloxy)phenylsulfonamide and 6.1 g of 1,8-diazabicyclo[5.4.0]undec-7-ene in 100 ml of methylene chloride, with stirring. When the exothermic reaction has subsided, stirring of the reaction mixture is continued at 20° to 25° C. for a further hour and the solvent is then evaporated off. The residue is dissolved in 5% sodium carbonate solution. The solution is filtered and acidified with 10% hydrochloric acid, whereupon the product precipitates as crystals. After filtration and drying, 13.2 g of N-[2-(1,2-dichlorovinyloxy)phenylsulfonyl]-N'-allylurea are obtained. Melting point: 187°-188° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[OH:11].S(=O)(=O)(O)O.[CH3:17]O>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([O:7][CH3:17])=[O:6])[C:3]=1[OH:11]
Reactant: CO
Reactant: Cc1cccc(C(=O)O)c1O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(C)c1O

Procedure:
To a slurry of 3-methylsalicylic acid (200 g) in 600 ml of methanol at −15° is added 65.7 g of concentrated sulfuric acid. The mixture is treated at reflux temperature for 5 days. The reaction mixture is concentrated, and methyl4-butyl ether (500 mL) and water (250 mL) are added. The ether layer is separated, washed with bicarbonate solution and evaporated to dryness to give methyl 3-methylsalicylate an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1>>[F:18][C:19]([F:29])([F:30])[C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:25])=[CH:22][CH:21]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(C(F)(F)F)cc4)cc23)CC1
Yield: 57.8 %

Procedure:
Beginning with 12.0 mg (0.05 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 29.0 mg (0.15 mMol) 4-trifluoromethylbenzoic acid, 11.6 mg (58%) of the title compound were recovered.
Reaction SMILES: B(Br)(Br)Br.C(Cl)Cl.[CH3:8][N:9]([CH3:30])[C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[NH:16][C:17](=[O:29])[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([O:27]C)[CH:19]=1>C1C=CC=CC=1>[CH3:8][N:9]([CH3:30])[C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[NH:16][C:17](=[O:29])[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([OH:27])[CH:19]=1
Reactant: COc1cc(C(=O)N[C@@H]2CCCC[C@H]2N(C)C)ccc1[N+](=O)[O-]
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: c1ccccc1
Product: CN(C)[C@@H]1CCCC[C@H]1NC(=O)c1ccc([N+](=O)[O-])c(O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of boron tribromide (7.52 g.; 0.03 mole) in 20 ml. of CH2Cl2 was added to a solution of trans-N-[2-(dimethylamino)cyclohexyl]-3-methoxy-4-nitrobenzamide (1.93 g.; 0.006 mole) in 50 ml. of CH2Cl3 keeping the temperature at -50° to -70°. It was allowed to warm to room temperature and stirred overnight. The mixture was concentrated in vacuo at 30° to a small volume, ice-water was added followed by solid NaHCO3 to pH 8, then solid NaCl and extracted with ethyl acetate (5×100 ml). The extract was dried (MgSO4) and evaporated to give 0.657 g. of solid. The aqueous was extracted again with CHCl3 (4×100 ml.) to give 0.561 g. of solid. The last extraction was repeated to give 0.3 g. of solid. The three crops were crystallized from benzene to give 0.548 g. of orange prisms, m.p. 139°- 140°. The analytical sample melted at 138°-140° (efferv.). NMR analysis showed this product to contain ca. 30% of benzene. This impure titled product was heated at 120°-125° for 17 hours in a sublimation tube (the m.p. changed to 198°-199.5°) and was then sublimed at 170°-175° for 18 hours. The sublimate, orange prisms, melted at 202°-203.5°. uv λmax 238 nm nm (ε 11,600); 278 (7,900); 358 (2,350); 422 (2,850). ir NH/=CH/N+H/OH 3220, 3180, 3020, ~2900 broad, C=O 1655; C=C 1600; amide II/NO2 /C=C 1580, 1485, 1335; C--N/C--O 1260, 1240, 1220, 1155, 995. NMR in CDCl3 +d6DMSO (100 MHz) showed absence of benzene. Mass spectrum M+ 307.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH2:13][C@H:12]3[C@@H:7]([CH2:8][CH2:9][CH2:10][N:11]3[CH2:14][CH2:15][CH3:16])[CH2:6][C:5]=2[N:17]=1.[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.[C:23]([OH:30])(=[O:29])/[CH:24]=[CH:25]\[C:26]([OH:28])=[O:27]>CCOCC>[C:23]([OH:30])(=[O:29])/[CH:24]=[CH:25]\[C:26]([OH:28])=[O:27].[N:18]1([C:2]2[S:3][C:4]3[CH2:13][C@H:12]4[C@@H:7]([CH2:8][CH2:9][CH2:10][N:11]4[CH2:14][CH2:15][CH3:16])[CH2:6][C:5]=3[N:17]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CCCN1CCC[C@H]2Cc3nc(Br)sc3C[C@@H]21
Reactant: C1CCNC1
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCOCC
Product: CCCN1CCC[C@H]2Cc3nc(N4CCCC4)sc3C[C@@H]21

Procedure:
A reaction mixture, prepared from 6.6 g. of trans-(±)-2-bromo-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g]quinoline and 20 ml. of pyrrolidine, was heated to reflux temperature for about 18 hours and was then cooled. The volatile constituents were removed in vacuo and the resulting residue diluted with water. The aqueous mixture was made strongly basic with concentrated aqueous ammonium hydroxide. The alkaline layer was extracted several times with equal volumes of chloroform. The chloroform extracts were combined, and the combined extracts washed with water and with saturated aqueous sodium chloride and were then dried. The solvent was evaporated therefrom in vacuo. TLC (9:1 CHCl3 /MeOH+a trace of aqueous ammonium hydroxide) showed one spot, more polar than starting material. The residue was therefore dissolved in chloroform and the chloroform solution chromatographed over a florisil column using chloroform as the eluant. Seventeen hundredths grams of a light yellow glass were obtained by this procedure. The glass was dissolved in ether and 0.06 g. of maleic acid in ethereal solution added thereto. A solid maleate salt precipitated. The ether was removed by decantation and the solid salt recrystallized from a mixture of ethanol and ether. Five hundredths grams of trans-(±)-2-(1-pyrrolidinyl)-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g]quinoline maleate were obtained melting with decomposition at 184° C.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[CH:6]1([NH:12][C:13](=[O:24])[CH2:14][CH2:15][C:16](=O)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.Cl.O>CO>[NH2:5][C:3]([NH:2][N:1]=[C:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:15][CH2:14][C:13]([NH:12][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:24])=[S:4]
Reactant: O=C(CCC(=O)c1ccccc1)NC1CCCCC1
Reactant: NNC(N)=S
Agent: Cl
Solvent: CO
Solvent: O
Product: NC(=S)NN=C(CCC(=O)NC1CCCCC1)c1ccccc1
Yield: 69.2 %

Procedure:
Thiosemicarbazide (1.75 g, 19.2 mmol) was added to a solution of N-cyclohexyl-4-oxo-4-phenyl-butyramide (3.30 g, 11.7 mmol), prepared in the previous step, in 40 ml of methanol plus 3.2 ml of 1 N HCl plus 3.2 ml of water and the reaction stirred at room temperature for 21 hours. The solid formed was removed by filtration and dried to give 2.69 g of a white solid. The filtrate was concentrated under reduced pressure to remove the methanol. The residue was partitioned between methylene chloride and water. The organic layer was separated, wash ed multiple times with water, dried (MgSO4) and the solvent removed under reduced pressure to give 1.10 g of a white foam. The initial solid filtered from the reaction was dissolved in methylene chloride, washed multiple times with water, dried (MgSO4) and the solvent removed under reduced pressure to give a white foam. Both materials were combined and crystallized from methylene chloride-ethyl acetate to give the title compound (3.31 g, 69%) as a white solid, mp 89-92° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:14]O>S(=O)(=O)(O)O>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CO
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cccc([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 14 h

Procedure:
Combine (3-nitrophenyl)acetic acid (20.0 g, 110 mmol) and anhydrous methanol (125 mL). Add 7 drops of concentrated sulfuric acid. Heat to 50° C. After 14 hours, cool to ambient temperature. Evaporate in vacuo to give a residue. Partition the residue between water and diethyl ether. Separate the organic layer and extract with aqueous saturated sodium bicarbonate solution and aqueous saturated sodium chloride solution. Dry the organic layer over MgSO4 and filter. Slowly evaporate to give methyl (3-nitrophenyl)acetate. 1H NMR (CDCl3) δ8.17 (d, 1H, J=1.1 Hz), 8.14 (dd, 1H, J=1.0, 7.7 Hz), 7.63 (dd, 1H, J=1.1, 7.7 Hz), 7.52 (t, 1H, J=7.7 Hz), 3.75 (s, 2H), 3.73 (s, 3H).
Reaction SMILES: Cl(O)(=O)(=O)=O.[Cl:6][C:7]1[CH:8]=[C:9]([CH2:12]N2CCCC2)[NH:10][CH:11]=1.[OH-].[Na+].S(OC)(OC)(=O)=O.[C-:27]#[N:28].[Na+]>CS(C)=O>[Cl:6][C:7]1[CH:8]=[C:9]([CH2:12][C:27]#[N:28])[NH:10][CH:11]=1
Reactant: [C-]#N
Reactant: Clc1c[nH]c(CN2CCCC2)c1
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Agent: [OH-]
Solvent: COS(=O)(=O)OC
Solvent: CS(C)=O
Product: N#CCc1cc(Cl)c[nH]1
Temperature: 25 °C

Procedure:
An aqueous solution of 114.0 g. of the product of Example VI is converted into the free base form by addition of 10% aqueous sodium hydroxide solution. The solid that is thus precipitated is filtered, washed with water and dried to give 67.1 g. (0.364 mole) of free base. The free base is dissolved in 350 ml. of dry dimethyl sulfoxide and stirred in an ice bath while 45.9 g. (0.364 mole) of dimethyl sulfate is added dropwise. The whole is then stirred for a half hour and warmed to room temperature, whereupon 20.0 g. (0.41 mole) of freshly ground and dried sodium cyanide is added all at once. After the resulting solution has been stirred for 2 hours at ambient temperature, it is poured onto ice and this aqueous solution is extracted four times with 250 ml. of diethyl ether. The combined ether extracts are washed successively with brine, 3N hydrochloric acid solution, aqueous sodium bicarbonate solution, and brine, and are dried over sodium sulfate. Evaporation of the ether yields 4-chloropyrrole-2 -acetonitrile as a brown oil.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[N:13][C:14](=[O:16])[CH:15]=2)=[CH:7][CH:6]=1.S(O[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][O:34][C:35]([C:37]1[CH:38]([C:49]2[CH:54]=[CH:53][CH:52]=[C:51]([Cl:55])[C:50]=2[Cl:56])[C:39]([C:45]([O:47][CH3:48])=[O:46])=[C:40]([CH3:44])[NH:41][C:42]=1[CH3:43])=[O:36])(C1C=CC(C)=CC=1)(=O)=O>CN(C)C=O>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[NH:12][N:13]=[C:14]([O:16][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][O:34][C:35]([C:37]3[CH:38]([C:49]4[CH:54]=[CH:53][CH:52]=[C:51]([Cl:55])[C:50]=4[Cl:56])[C:39]([C:45]([O:47][CH3:48])=[O:46])=[C:40]([CH3:44])[NH:41][C:42]=3[CH3:43])=[O:36])[CH:15]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCOS(=O)(=O)c2ccc(C)cc2)C1c1cccc(Cl)c1Cl
Reactant: COc1ccc(C2=CC(=O)N=N2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCOc2cc(-c3ccc(OC)cc3)[nH]n2)C1c1cccc(Cl)c1Cl
Temperature: 80 °C
Yield: 59.5 %

Procedure:
To a suspension of 0.262 g of sodium hydride (55% dispersion in mineral oil) in 10 ml of N,N-dimethylformamide, 1.33 g (7 mmole) of 3-p-methoxyphenyl-5-pyrazolone was added portionwise with stirring under ice cooling. To the above mixture was added dropwise a solution of 3.05 g (5 mmole) of 1,4-dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-tosyloxyhexyl ester in 7 ml of N,N-dimethylformamide at 0° to 10° C. with stirring and then the mixture was heated at 80° C. for 3 hours. The resulting reaction mixture was poured into ice water, and the precipitate was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and then evaporated in vacuo to obtain an oily residue. The residue was purified by silica gel column chromatography using a mixed solution of chloroform-methanol (the ratio by volume of 100:1) as an eluent, and the fractions containing desired compound were collected and evaporated in vacuo to dryness to give white crystalline residue. The residue was recrystallized from a mixed solution of ethyl acetate-normal hexane to give 1.87 g (yield 59.0%) of the 1,4-dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-(5-p-methoxyphenyl-3-pyrazolyloxy)hexyl ester as colorless needles.
Reaction SMILES: Br.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[O:19][C:18]([NH2:20])=[N:17][N:16]=3)=[CH:11][CH:10]=2)[CH:3]=1.[CH3:21][O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][C:24]=1[C:32]([F:35])([F:34])[F:33]>N1C=CC=CC=1.CO>[CH3:21][O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:20][C:18]2[O:19][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][C:4]4[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=4)=[CH:14][CH:13]=3)=[N:16][N:17]=2)=[O:28])=[CH:25][C:24]=1[C:32]([F:33])([F:34])[F:35]
Reactant: COc1ccc(C(=O)Cl)cc1C(F)(F)F
Reactant: Nc1nnc(-c2ccc(Oc3cccnc3)cc2)o1
Agent: Br
Solvent: c1ccncc1
Solvent: CO
Product: COc1ccc(C(=O)Nc2nnc(-c3ccc(Oc4cccnc4)cc3)o2)cc1C(F)(F)F
Reaction time: 3 h
Yield: 16.2 %

Procedure:
5-[4-(Pyridin-3-yloxy)phenyl]-1,3,4-oxadiazol-2-amine hydrobromide salt (167.5 mg, 0.5 mmol) was suspended in 2 mL of anhydrous pyridine. Neat 4-methoxy-3-trifluoromethylbenzoyl chloride (179.0 mg, 0.75 mmol) was added directly into the solution. The reaction mixture formed an orange-red solution with a small amount of white precipitate. It was left to stir for 3 hours. Then it was diluted with ca. 1 mL of MeOH, filtered through 0.22 u syringe filter and purified by reverse phase preparative HPLC using acetonitrile/water mixture containing 0.01% of TFA. Fractions, containing the product, were combined and partitioned between ca. 40 mL of EtOAc and ca. 40 mL of saturated aqueous NaHCO3. The EtOAc layer was washed with brine, dried over anhydrous sodium sulfate and filtered. Solvent was removed in vacuo to give the title product as a yellow solid (37.0 mg). Yield 16.2%.
Reaction SMILES: OO[S:3]([O-:5])=[O:4].[K+].[CH3:7][O:8][CH2:9][CH2:10][O:11][CH2:12][O:13][CH:14]1[CH2:20][CH2:19][CH2:18]S[C:16]2[CH:21]=[C:22]([S:24]([NH2:27])(=[O:26])=[O:25])[S:23][C:15]1=2>O.CO>[CH3:7][O:8][CH2:9][CH2:10][O:11][CH2:12][O:13][CH:14]1[CH2:20][CH2:19][CH2:18][S:3](=[O:5])(=[O:4])[C:16]2[CH:21]=[C:22]([S:24]([NH2:27])(=[O:26])=[O:25])[S:23][C:15]1=2
Reactant: O=S([O-])OO
Reactant: COCCOCOC1CCCSc2cc(S(N)(=O)=O)sc21
Agent: [K+]
Solvent: CO
Solvent: O
Product: COCCOCOC1CCCS(=O)(=O)c2cc(S(N)(=O)=O)sc21
Temperature: 25 °C
Reaction time: 41 h

Procedure:
A solution of OXONE® (28.9 g, 0.047 mole) in water (200 ml) was added to a stirred suspension of 8-(2-methoxyethoxymethoxy)-5,6,7,8-tetrahydrothieno[3,2-b]thiepin-2-sulfonamide (14.0 g, 0.040 mole) in methanol (250 ml) and the mixture was stirred at ambient temperature for 41 hours. Methanol was evaporated under reduced pressure and the aqueous suspension was extracted with ethyl acetate (3×250 ml). The combined extracts were washed twice with water, dried over sodium sulfate and evaporated under reduced pressure to give 16.62 g (theory 15.42 g) of solvated oily product which was used in the next step without further purification.
Reaction SMILES: [OH-].[K+].[I:3]I.[NH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:15])[CH:12]=2)[CH:7]=[CH:6]1>CN(C=O)C.O>[I:3][C:7]1[C:8]2[C:13](=[CH:12][C:11]([C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:15])=[CH:10][CH:9]=2)[NH:5][CH:6]=1
Reactant: O=C(c1ccc2cc[nH]c2c1)N1CCOCC1
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccc2c(I)c[nH]c2c1)N1CCOCC1

Procedure:
Potassium hydroxide (422 mg, 7.543 mmol, 3.47 eq), iodine (1.103 g, 4.347 mmol, 2.0 eq) and (1H-indol-6-yl)(morpholino)methanone (500 mg, 2.173 mmol, 1.0 eq) in DMF (10 mL) were stirred at room temperature for 5 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2×15 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate and evaporated in vacuo. White solid. Yield: 600 mg (77% of theory)
Reaction SMILES: C([Li])(CC)C.C(O[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[CH2:16])=[CH:13][CH:12]=1)(C)(C)C.[O:19]1CC[CH2:21][CH2:20]1>>[CH3:21][C:20]([C:11]1[CH:12]=[CH:13][C:14]([CH:15]=[CH2:16])=[CH:17][CH:18]=1)=[O:19]
Reactant: C=Cc1ccc(OC(C)(C)C)cc1
Reactant: C1CCOC1
Agent: [Li]C(C)CC
Product: C=Cc1ccc(C(C)=O)cc1
Reaction time: 0.5 h

Procedure:
A 1-liter flask was charged with 500 ml of tetrahydrofuran as a solvent and 0.01 mol of sec-butyl lithium as an initiator. To the solution at −78° C. was added 30 g of p-tert-butoxystyrene. With stirring, polymerization reaction was effected for 30 minutes. The reaction solution turned red. For producing a branched polymer, 0.005 mol of p-methylcarbonylstyrene was added to the reaction solution whereupon reaction was effected for 5 minutes. Further 15 g of p-tert-butoxystyrene was added. With stirring, polymerization reaction was effected for 30 minutes. Polymerization was stopped by adding 0.1 mol of methanol to the reaction solution.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1[NH:7][C:8](=[O:11])[NH:9][CH:10]=1.[C:12](Cl)(=[O:15])[CH2:13][CH3:14]>Cl>[CH3:5][C:6]1[NH:7][C:8](=[O:11])[NH:9][C:10]=1[C:12](=[O:15])[CH2:13][CH3:14]
Reactant: Cc1c[nH]c(=O)[nH]1
Reactant: CCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCC(=O)c1[nH]c(=O)[nH]c1C

Procedure:
To 13.3 g (0.1 mole) of aluminum chloride under 150 ml of dry dichloromethane is added 4.9 g (0.05 mole) of 1,3-dihydro-4-methyl-2H-imidazol-2-one and, dropwise, 5.1 g (0.055 mole) of propionyl chloride. The mixture is stirred and heated to reflux temperature for 6 hours. The mixture is cooled and 2N hydrochloride acid (150 ml) is added dropwise. The resulting precipitate is collected, washed with water and dichloromethane and recrystallized from 50% aqueous ethanol to give the title compound, m.p. 270°-271° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7](Cl)=[O:8].[NH2:10][C:11]1[C:12]([I:29])=[C:13]([C:22]([NH:24][CH2:25][CH:26]([OH:28])[CH3:27])=[O:23])[C:14]([I:21])=[C:15]([C:19]=1[I:20])[C:16]([OH:18])=[O:17].CC(N(C)C)=O>O>[OH:28][CH:26]([CH3:27])[CH2:25][NH:24][C:22](=[O:23])[C:13]1[C:14]([I:21])=[C:15]([C:19]([I:20])=[C:11]([NH:10][C:7](=[O:8])[CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[C:12]=1[I:29])[C:16]([OH:18])=[O:17]
Reactant: CC(O)CNC(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I
Reactant: COCCOCC(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: O
Product: COCCOCC(=O)Nc1c(I)c(C(=O)O)c(I)c(C(=O)NCC(C)O)c1I
Temperature: 0 °C
Reaction time: 1 h

Procedure:
At a maximum of 10° C. (ice cooling), 16.5 ml. of methoxyethoxyacetyl chloride is added dropwise within 30 minutes with agitation to 30.8 g. (50 mmol) of 5-amino-(2-hydroxypropyl)2,4,6-triiodoisophthalamic acid in 60 ml. of dimethylacetamide. The mixture is stirred for 1 hour at 0° C. and then for 16 hours at room temperature. Thereafter, another 2 ml. of the acid chloride is added thereto, and the mixture is stirred at room temperature for 4 hours. Then, 10 ml. of water is added and the mixture is concentrated under vacuum. The residue is dissolved in 350 ml. of water and neutralized with 32% sodium hydroxide solution. The mixture is combined with another 5 ml. of 32% sodium hydroxide solution and then stirred for some time after adding 5 g. of active carbon. After the carbon has been removed, the mixture is acidified with concentrated hydrochloric acid, allowed to stand for a period of time and vacuum-filtered. The resulting precipitate is dried under vacuum. Yield: 21.3 g. (58%), m.p. 275° C., with decomposition.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][CH:17]=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:22][CH3:23].C(=O)([O-])[O-].C1(C)C=CC(S([CH2:37][C@H:38]2[NH:42][C:41](=[O:43])[CH2:40][CH2:39]2)(=O)=O)=CC=1>CN(C=O)C>[NH:18]1[C:19]2[C:15](=[CH:14][C:13]([O:12][C:6]3[C:5]4[C:10](=[CH:11][C:2]([O:1][CH2:37][C@H:38]5[NH:42][C:41](=[O:43])[CH2:40][CH2:39]5)=[C:3]([O:22][CH3:23])[CH:4]=4)[N:9]=[CH:8][N:7]=3)=[CH:21][CH:20]=2)[CH:16]=[CH:17]1
Reactant: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1O
Reactant: Cc1ccc(S(=O)(=O)C[C@@H]2CCC(=O)N2)cc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@@H]1CCC(=O)N1
Temperature: 100 °C
Yield: 30.4 %

Procedure:
To a solution of 7-hydroxy-4-(l H-indol-5-yloxy)-6-methoxyquinazoline (600 mg, 1.95 mmol), (prepared as described for the starting material in Example 107), in DMF (20 ml) was added powdered potassuim carbonate (540 mg, 3.9 mmol) and (5S)-5-(p-toluene-sulphonylmethyl)-2-pyrrolidinone (580 mg, 2.16 mmol). The reaction was then heated at 100° C. for 4 hours. The inorganic material was filtered off and the DMF removed by evaporation. The residue was then purified by chromatography eluting from methylene chloride to 12% methanol/88% methylene chloride (+1% ammonium hydroxide). The product was evaporated, triturated with ether, and filtered to give (5S)-4-(1H-indol-5-yloxy)-6-methoxy-7-(2-oxopyrrolidin-5-ylmethoxy)quinazoline (240 mg, 31%) as a white solid.