Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C@@H:6]([CH2:13][CH3:14])[N:5]([CH:15]([CH3:17])[CH3:16])[C:4]=2[N:3]=1.[C:18]1(C)C=CC(S(OC)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:18])[C:7](=[O:12])[C@@H:6]([CH2:13][CH3:14])[N:5]([CH:15]([CH3:16])[CH3:17])[C:4]=2[N:3]=1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: CC[C@@H]1C(=O)Nc2cnc(Cl)nc2N1C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C(C)C
Yield: 84.6 %

Procedure:
The crude compound (7R)-2-chloro-7-ethyl-8-isopropyl-5,7-dihydropteridin-6-one 22c (12.10 g, 47.50 mmol) was dissolved in 180 mL of acetone followed by the addition of methyl p-toluenesulfonate (13.28 g, 71.30 mmol) and potassium carbonate (13.11 g, 95 mmol). The reaction solution was heated to reflux for 3 hours with stirring and filtered. The filtrate was concentrated under reduced pressure, added with 100 mL of water and extracted with dichloromethane (100 mL×3). The combined organic phase was washed with saturated sodium chloride solution (100 mL), then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (7R)-2-chloro-7-ethyl-8-isopropyl-5-methyl-7H-pteridin-6-one 22d (10.80 g, yield: 84.7%) as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N:37]1[CH2:42][CH2:41][N:40]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]3[CH2:21][CH2:20][C:19]4[C:14](=[CH:15][C:16]([C:22]5[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=5)=[CH:17][CH:18]=4)[CH:13]=3)=[O:11])=[CH:5][CH:4]=2)[CH2:39][CH2:38]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CC3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(Cc2ccc(NC(=O)C3=Cc4cc(-c5ccc(C)cc5)ccc4CC3)cc2)CC1
Temperature: 25 °C
Reaction time: 13 h
Yield: 67.5 %

Procedure:
In DMF (3 ml) was dissolved N-[4-(chloromethyl)phenyl]-7-(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (150 mg), and to the solution were added 1-(2-methoxyphenyl)piperazine (97 mg) and potassium carbonate (268 mg). The mixture was stirred at room temperature for 13 hours, and to the mixture was added water (50 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropylether to give N-[4-[1-(2-methoxyphenyl)-4-piperazinylmethyl]phenyl]-7-(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (Compound 41) (142 mg) as colorless crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.C(N1CCN(C2C=C(N[C:29]([C:31]3[C:32]4[N:33]=[CH:34][CH:35]=[N:36][C:37]=4[C:38]([C:41]4[CH:46]=[C:45]([O:47][CH3:48])[CH:44]=[CH:43][C:42]=4[Cl:49])=[CH:39][CH:40]=3)=[O:30])C=CC=2)CC1)C>>[CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:29]([C:31]2[C:32]3[N:33]=[CH:34][CH:35]=[N:36][C:37]=3[C:38]([C:41]3[CH:46]=[C:45]([O:47][CH3:48])[CH:44]=[CH:43][C:42]=3[Cl:49])=[CH:39][CH:40]=2)=[O:30])=[CH:8][CH:7]=1
Reactant: CN(C)CCOc1ccc(N)cc1
Reactant: CCN1CCN(c2cccc(NC(=O)c3ccc(-c4cc(OC)ccc4Cl)c4nccnc34)c2)CC1
Product: COc1ccc(Cl)c(-c2ccc(C(=O)Nc3ccc(OCCN(C)C)cc3)c3nccnc23)c1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 4-(2-dimethylamino-ethoxy)-phenylamine (Step 5.1) and 8-(2-chloro-5-methoxy-phenyl)-quinoxaline-5-carboxylic acid (Example 63). Title compound: ESI-MS: 476.9 [M]+; tR=3.43 min (System 3).
Reaction SMILES: [CH:1]([C:3]1[C:8](=[O:9])[C:7]2[CH:10]=[C:11]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:12]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][C:6]=2[O:5][CH:4]=1)=O.[Br-].[CH2:27]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CC(C)([O-])C.[K+]>>[C:28]1([CH:27]=[CH:1][C:3]2[C:8](=[O:9])[C:7]3[CH:10]=[C:11]([O:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:12]([NH:14][S:15]([CH3:18])(=[O:16])=[O:17])=[CH:13][C:6]=3[O:5][CH:4]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CS(=O)(=O)Nc1cc2occ(C=O)c(=O)c2cc1Oc1ccccc1
Reactant: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Product: CS(=O)(=O)Nc1cc2occ(C=Cc3ccccc3)c(=O)c2cc1Oc1ccccc1

Procedure:
3-Formyl-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one was reacted with benzyltriphenylphosphonium bromide in the presence of potassium tertbutoxide to obtain 3-(2-phenylvinyl)-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:10][C:11]([O:13]CC)=[O:12])[C:6](=[O:9])[C:7]=1[Br:8].[OH-].[Na+].C(OCC)(=O)C>O1CCOCC1>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:10][C:11]([OH:13])=[O:12])[C:6](=[O:9])[C:7]=1[Br:8]
Reactant: CCOC(=O)Cn1ncc(Br)c(Br)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(O)Cn1ncc(Br)c(Br)c1=O
Yield: 96 %

Procedure:
Ethyl 2-(4,5-dibromo-6-oxopyridazin-1(6H)-yl)acetate (6.01 g, 17.7 mmol) in 1,4-dioxane (60 mL) was stirred with 1 M aqueous sodium hydroxide (53.1 mL, 53.1 mmol) at room temperature for 1 hour. After completion of the reaction, the reaction solution was mixed with ethyl acetate and extracted with 1 M aqueous sodium hydroxide twice. The resulting aqueous layer was acidified to pH 1 with 1 M hydrochloric acid and extracted with ethyl acetate twice. The resulting organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give the desired product (5.30 g, 88% yield).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]3[CH:11]=[CH:12][C:13]4[S:19][CH2:18][CH2:17][C:16]([C:20]([O:22]C)=[O:21])=[CH:15][C:14]=4[CH:24]=3)=[CH:4][C:3]=2[O:2]1.[OH-].[Na+]>C(O)C.C1COCC1.Cl>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]3[CH:11]=[CH:12][C:13]4[S:19][CH2:18][CH2:17][C:16]([C:20]([OH:22])=[O:21])=[CH:15][C:14]=4[CH:24]=3)=[CH:4][C:3]=2[O:2]1
Reactant: COC(=O)C1=Cc2cc(-c3ccc4c(c3)OCO4)ccc2SCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)C1=Cc2cc(-c3ccc4c(c3)OCO4)ccc2SCC1
Reaction time: 64 h
Yield: 88.8 %

Procedure:
To a solution of methyl 7-(3,4-methylenedioxyphenyl)-2,3-dihydro-1-benzothiepine-4-carboxylate (0.6 g) in ethanol/THF (10/10 ml) was added at room temperature 1N sodium hydroxide solution (2 ml), and the mixture was stirred for 64 hours. To the mixture was added iN hydrochloric acid (3 ml), and the mixture was concentrated. The resulting solid was collected by filtration, which was washed with water, 2-propanol and diisopropylether to give pale yellow powder of 7-(3,4-methylenedioxyphenyl)-2,3-dihydro-1-benzothiepine-4-carboxylic acid (510.6 mg).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([C:13]#[N:14])[CH:11]=2)[N:6]=[CH:5][CH:4]=1.CO.[F:19][C:20]1[CH:26]=[C:25]([CH3:27])[C:24]([OH:28])=[CH:23][C:21]=1[NH2:22]>C(O)(C)C>[ClH:2].[C:13]([C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][C:9]=1[O:15][CH3:16])[N:6]=[CH:5][CH:4]=[C:3]2[NH:22][C:21]1[CH:23]=[C:24]([OH:28])[C:25]([CH3:27])=[CH:26][C:20]=1[F:19])#[N:14]
Reactant: Cc1cc(F)c(N)cc1O
Reactant: COc1cc2nccc(Cl)c2cc1C#N
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: COc1cc2nccc(Nc3cc(O)c(C)cc3F)c2cc1C#N
Yield: 48.9 %

Procedure:
A mixture of 4-chloro-6-cyano-7-methoxyquinoline hydrochloride (500 mg, 2 mmol), (prepared by an analogous procedure to that described for the starting material in Example 1 but using methanol instead of 2-methoxyethanol), and 2-fluoro-5-hydroxy-4-methylaniline (141 mg, 1 mmol), (prepared as described for the starting material in Example 1), in isopropanol (10 ml) was heated at reflux for 4 hours. The mixture was allowed to cool, the solid product was collected by filtration, washed with acetone and dried to give 6-cyano-4-(2-fluoro-5-hydroxy-4-methylanilino)-7-methoxyquinoline hydrochloride (176 mg, 54%) as a light brown solid.
Reaction SMILES: [N+:1]([CH:4]([N+:6]([O-:8])=[O:7])[CH3:5])([O-:3])=[O:2].[OH-].[K+].[C:11]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])(=[O:14])[CH:12]=[CH2:13].CO>O>[N+:1]([C:4]([N+:6]([O-:8])=[O:7])([CH3:5])[CH2:13][CH2:12][C:11]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:14])([O-:3])=[O:2]
Reactant: C=CC(=O)OCCCCCC
Reactant: CC([N+](=O)[O-])[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCCOC(=O)CCC(C)([N+](=O)[O-])[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.4 %

Procedure:
Dinitroethane (2.4 g, 0.02 mol) and potassium hydroxide (1.2 g, 0.022 mol) were dissolved in 50 mL of water to form a first solution. 50 mL of water was added to the first solution to dissolve a salt remaining in the first solution to form a second solution. Hexyl acrylate (8.8 mL, 0.05 mol) was mixed with 50 mL of methanol, and then the mixture was slowly added to the second solution to form a third solution. The third solution was stirred at room temperature for 4 hours. The reaction product was extracted by diethyl ether, and was then distilled under reduced pressure to obtain yellow liquid hexyl 4,4-dinitropentanoate (4.5 g, yield: 81%).
Reaction SMILES: [N+:1]([C:4]1[C:5](Cl)=[C:6]([C:10]([Cl:14])=[C:11]([Cl:13])[CH:12]=1)[C:7]([OH:9])=[O:8])([O-:3])=[O:2].ClC1C=CC=CC=1C[NH2:20].Cl>C1(C)C=CC=CC=1>[NH2:20][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:12][C:11]([Cl:13])=[C:10]([Cl:14])[C:6]=1[C:7]([OH:9])=[O:8]
Reactant: NCc1ccccc1Cl
Reactant: O=C(O)c1c(Cl)c(Cl)cc([N+](=O)[O-])c1Cl
Agent: Cl
Solvent: Cc1ccccc1
Product: Nc1c([N+](=O)[O-])cc(Cl)c(Cl)c1C(=O)O

Procedure:
To a stirred solution of 3-nitro-2,5,6-trichlorobenzoic acid (37.1 mmol, 10.0 g) in 150 mL of toluene, was added 2-chlorobenzylamine (81.6 mmol, 11.56 g). The reaction mixture was refluxed overnight, poured into dilute hydrochloric acid and vigorously stirred. The resulting solid was filtered. The product was dissolved in toluene and then precipitated with diethyl ether. Recrystallization of the product from methanol gave 3.4 g of 2-[2-chlorophenyl)methyl]amino-5,6-dichloro-3-nitrobenzoic acid; mp 168.5°-171° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[N:12][C:13]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[O:8]C.C1(S)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1.O>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[N:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc(-c2cnc(Nc3ccccc3)nc2)cc1F
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Oc1ccc(-c2cnc(Nc3ccccc3)nc2)cc1F
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
A mixture of 5-(3-fluoro-4-methoxyphenyl)-N-phenylpyrimidin-2-amine (Step 2, 0.066 g, 0.22 mmol), thiophenol (0.20 g, 1.0 mmol), and K2CO3 (0.15 g, 1.1 mmol) in NMP (2 mL) was heated at 120° C. for 20 h. The mixture was cooled to RT and diluted with H2O (4 mL). After stirring for 10 min, the resulting suspension was filtered, and the solid was further washed with H2O. The solid was washed with hexanes to provide the title compound as a brown solid. MS (ESI pos. ion) m/z: 282. Calc'd for C16H12FN3O: 281.10.
Reaction SMILES: [CH:1]([N:4]([CH2:21][CH2:22][NH:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1)=[O:25])[C:5]([C:7]1[N:8]=[C:9]([N:12]2[CH2:15][CH:14](OS(C)(=O)=O)[CH2:13]2)[S:10][CH:11]=1)=[O:6])([CH3:3])[CH3:2].[C:37]([O-:40])(=[S:39])[CH3:38].[K+]>CN(C)C=O>[C:37]([S:39][CH:14]1[CH2:15][N:12]([C:9]2[S:10][CH:11]=[C:7]([C:5](=[O:6])[N:4]([CH:1]([CH3:2])[CH3:3])[CH2:21][CH2:22][NH:23][C:24]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][C:31]([N+:34]([O-:36])=[O:35])=[CH:32][CH:33]=3)=[O:25])[N:8]=2)[CH2:13]1)(=[O:40])[CH3:38]
Reactant: CC([O-])=S
Reactant: CC(C)N(CCNC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(C(=O)N(CCNC(=O)OCc3ccc([N+](=O)[O-])cc3)C(C)C)cs2)C1
Temperature: 90 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
A solution of 1-(4-{N-isopropyl-N-[2-(p-nitrobenzyloxycarbonylamino)ethyl]-carbamoyl}-1,3-thiazol-2-yl)-3-methanesulfonyloxyazetidine (776 mg, 1.43 mmol) (obtained as described in Reference Example 60(4)) in dimethylformamide (23 ml) was added potassium thioacetate (982 mg, 8.60 mmol) at room temperature. The mixture was stirred in an oil bath (90° C.) for 4 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (1:2) as the eluant to afford 3-acetylthio-1-(4-{N-isopropyl-N-[2-(p-nitrobenzyloxycarbonylamino)ethyl]-carbamoyl}-1,3-thiazol-2-yl)azetidine (746 mg, yield 46%) as a pale brown solid.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.Cl[C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(O)C>CN(C)C=O>[CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=2)=[CH:7][CH:6]=1
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: CNCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CNCCc1ccc(Oc2ccc(C(N)=O)cn2)cc1
Temperature: 85 °C
Yield: 22.7 %

Procedure:
Combine 4-(2-methylamino-ethyl)-phenol (1.0 g, 6.6 mmol), 6-chloronicotinamide (1.0 g, 6.6 mmol), and cesium carbonate (4.3 g, 13.2 mmol) in N,N-dimethylformamide (30 mL), stir and heat at 85° C. for 18 hours. Cool to room temperature and evaporate on a rotary evaporator to yield the crude product (1.3 g). The crude product is purified by flash column chromatography on silica gel eluting with 1% conc. ammonium hydroxide/10% ethanol in chloroform then ethanol to yield 6-[4-(2-Methylamino-ethyl)-phenoxy]-nicotinamide (0.4 g, 1.5 mmol): 1H NMR (DMSO-d6, 300.00 MHz): 8.58 (d, 1H); 8.22 (dd, 1H); 7.26-7.23 (m, 2H); 7.05-7.02 (m, 3H); 3.32 (br, 2H); 2.69 (m, 5H); 2.29 (m, 4H) m/z=271.87 (M+1); HPLC=99% (5/95 to 95/5 ACN/(0.1% TFA in water) over 10 minutes, Zorbax SB-Phenyl 4.6 mm×15 cm×5 micron, λ=254 nM.
Reaction SMILES: [OH:1][CH:2]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[O:11][CH3:12]>N1C=CC=CC=1>[OH:1][CH:2]([CH:13]1[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[O:11][CH3:12]
Reactant: COc1cccc(C(O)c2ccncc2)c1OC
Solvent: c1ccncc1
Product: COc1cccc(C(O)C2CCNCC2)c1OC

Procedure:
In Scheme N, step b, the pyridine functionality of 4-[1-hydroxy-1-(2,3-dimethoxyphenyl)methyl]pyridine (10) is reduced to give 4-[1-hydroxy-1-(2,3-dimethoxyphenyl)methyl]piperidine (11) as described previously in Scheme F, step e.
Reaction SMILES: [S:1]1(=[O:11])(=[O:10])[C:5]2=[CH:6][S:7][CH:8]=[C:4]2[C:3](=[S:9])[NH:2]1.[CH2:12](O)C.[OH-].[Na+].IC>O>[CH3:12][S:9][C:3]1[C:4]2=[CH:8][S:7][CH:6]=[C:5]2[S:1](=[O:10])(=[O:11])[N:2]=1
Reactant: O=S1(=O)NC(=S)c2cscc21
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CI
Product: CSC1=NS(=O)(=O)c2cscc21

Procedure:
To a mixture of 0.9 g. (0.0044 mole) of thieno[3,4-d]isothiazole-3(2H)-thione 1,1-dioxide in 4 ml. of ethanol is added a solution of 0.35 g. (0.0044 mole) of 50% sodium hydroxide in 3 ml. of water. To this thick mixture is added 0.62 g. (0.0044 mole) of iodomethane. The mixture is heated under reflux for 5 minutes, and then filtered to give 0.35 g. of product. On cooling, a second crop of 0.1 g. of material is obtained. A small amount of the first crop is recrystallized from ethanol to afford an analytical sample, m.p. 184°-6° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19]([O:21][C:22](=[O:50])[CH2:23][C:24]1([CH2:27][CH2:28][CH:29](/[CH:41]=[CH:42]/[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[OH:49])[CH2:30][C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=2)[CH2:26][CH2:25]1)[CH3:20]>C(#N)C>[CH2:19]([O:21][C:22](=[O:50])[CH2:23][C:24]1([CH2:27][CH2:28][CH:29](/[CH:41]=[CH:42]/[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[O:49][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:30][C:31]2[CH:32]=[CH:33][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:39][CH:40]=2)[CH2:25][CH2:26]1)[CH3:20]
Reactant: BrCCCCCc1ccccc1
Reactant: CCOC(=O)CC1(CCC(/C=C/c2ccccc2O)Cc2ccc(C(=O)OC)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CC1(CCC(/C=C/c2ccccc2OCCCCCc2ccccc2)Cc2ccc(C(=O)OC)cc2)CC1

Procedure:
273 mg (1.2 mmol) of (5-bromopentyl)benzene and 222 mg (1.6 mmol) of anhydrous potassium carbonate are added to a solution of 350 mg (0.8 mmol) of methyl 4-[(3E)-2-{2-[1-(2-ethoxy-2-oxoethyl)cyclopropyl]ethyl}-4-(2-hydroxyphenyl)but-3-en-1-yl]benzoate in 10 ml of dry acetonitrile, and the mixture is heated under reflux for 12 hours. The mixture is then concentrated to dryness. The residue is taken up in ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate. The organic phase is concentrated. The crude product obtained is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 9:1). This gives 275 mg (58% of theory) of a solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH:4]([CH2:8][C:9]([C:11]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=1[O:19][CH3:20])=O)[C:5](=O)[CH3:6].[CH:22]1([CH2:28][NH2:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:1][O:2][C:3]([C:4]1[CH:8]=[C:9]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[O:19][CH3:20])[N:29]([CH2:28][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:5]=1[CH3:6])=[O:21]
Reactant: COC(=O)C(CC(=O)c1cc(OC)ccc1OC)C(C)=O
Reactant: NCC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)c1cc(-c2cc(OC)ccc2OC)n(CC2CCCCC2)c1C
Temperature: 25 °C

Procedure:
To a solution of 2 g of -[2-(2,5-Dimethoxy-phenyl)-2-oxo-ethyl]-3-oxo-butyric acid methyl ester in methanol was added 0.88 ml of cyclohexanemethylamine and 40 mg of p-toluene sulfonic acid. The reaction mixture was then heated at reflux for 2 days. After such time the reaction mixture was allowed to cool to room temperature before being concentrated in vacuo and purified by column chromatography to give 2.3 g of the title compound; MS (ISP) 372.2 (M+H)+.
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH:9]([CH3:12])[CH2:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][C:5]=2[S:4][CH:3]=1.[C:20](B1OC(C)(C)C(C)(C)O1)([CH3:22])=[CH2:21].C(=O)([O-])[O-].[K+].[K+].O>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:12][CH:9]1[CH2:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][C:5]2[S:4][CH:3]=[C:2]([C:20]([CH3:22])=[CH2:21])[C:11]=2[O:10]1
Reactant: CC1CN(C(=O)OC(C)(C)C)Cc2scc(Br)c2O1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: C=C(C)c1csc2c1OC(C)CN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Yield: 74 %

Procedure:
A mixed solution of tert-butyl 8-bromo-2-methyl-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (418 mg) obtained in Example 6, steps 1-6, isopropenylboronic acid pinacol ester (0.293 ml), dichlorobis(triphenylphosphine)palladium (42 mg) and potassium carbonate (498 mg) in DME-water (1:1, 10 mL) was stirred at 85° C. for 1 hr under a nitrogen stream. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and 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→12% ethyl acetate/hexane) to give the title compound (274 mg, 74%) as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])#[N:2]>[Pd].CO>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: N#Cc1cccc(C(=O)O)c1
Agent: [Pd]
Solvent: CO
Product: NCc1cccc(C(=O)O)c1

Procedure:
Commercially available 3-cyanobenzoic acid was hydrogenated in the presence of palladium on charcoal in methanol to yield 3-aminomethylbenzoic acid. This was reacted with Boc-ON to obtain Boc-aminomethylbenzoic acid and incorporated into the peptide by solid phase peptide synthesis methodology as described in Example 1 and isolated according to the procedures described in Example 2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:11](=[O:24])[CH:10]=[C:9]2[CH:25]=[O:26])[CH:5]=[CH:6][CH:7]=1.[F:27][C:28]([Si](C)(C)C)([F:30])[F:29].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:11](=[O:24])[CH:10]=[C:9]2[CH:25]([OH:26])[C:28]([F:30])([F:29])[F:27])[CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COc1ccc(COc2cn(-c3cccc(Br)c3)c(C=O)cc2=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(COc2cn(-c3cccc(Br)c3)c(C(O)C(F)(F)F)cc2=O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a semi-suspension of 1-(3-bromophenyl)-5-[(4-methoxybenzyl)oxy]-4-oxo-1,4-dihydropyridine-2-carbaldehyde (500 mg, 1.21 mmol) in THF (5 mL) at 0° C. was added (trifluoromethyl)trimethylsilane solution (5.3 mL of 0.5 mL solution in THF) followed by tetrabutylammonium fluoride solution (0.1 mL of a 1 M solution in THF). The reaction mixture was stirred at 0° C. for 1 h and then quenched by adding water. The quenched reaction mixture was then diluted with dichloromethane, washed with brine (1×), dried over Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography (24 g silica gel, linear gradient of 0 to 5% methanol in dichloromethane) afforded 1-(3-bromophenyl)-5-[(4-methoxybenzyl)oxy]-2-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-4(1H)-one.
Reaction SMILES: Cl[S:2](O)(=O)=O.[CH3:6][O:7][C:8](=[O:24])[CH:9]([CH:14]1[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[O:15]1)[C:10]([O:12][CH3:13])=[O:11]>>[CH3:13][O:12][C:10](=[O:11])[CH:9]([CH:14]1[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([SH:2])[CH:20]=2)[O:15]1)[C:8]([O:7][CH3:6])=[O:24]
Reactant: O=S(=O)(O)Cl
Reactant: COC(=O)C(C(=O)OC)C1CCc2ccccc2O1
Product: COC(=O)C(C(=O)OC)C1CCc2cc(S)ccc2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53 %

Procedure:
Chlorosulfonic acid (15 mL) was cooled to 0° C. Then compound 5B (5.5 g. 20.8 mmol) was added over 30 min. The mixture was stirred at RT for 3 h and was poured into ice (100 g). The cloudy solution was extracted with ether (2×100 mL). The extracts were dried with magnesium sulfate and concentrated to give the desired product (4.0 g, 53%) as a yellow oil. The crude product was used immediately for the next step without purification.