Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[C:12]1[CH:13]=[C:14]([CH3:23])[C:15]([O:21][CH3:22])=[C:16]([CH:20]=1)[C:17]([OH:19])=[O:18].C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C>CCO.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.O>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[C:14]([CH3:23])[C:15]([O:21][CH3:22])=[C:16]([CH:20]=2)[C:17]([OH:19])=[O:18])[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: COc1c(C)cc(Br)cc1C(=O)O
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: [Na+]
Solvent: CCO
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(C)cc(-c2cccc(F)c2)cc1C(=O)O
Temperature: 100 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
To a solution of 3-fluorophenylboronic acid (0.75 g, 5.39 mmol, 1.1 eq), 5-bromo-2-methoxy-3-methyl-benzoic acid (1.2 g, 4.90 mmol, 1.0 eq) and Na2CO3 (1.56 g, 14.69 mmol, 3 eq) in a mixture of EtOH (6 mL), DMF (24 mL) and H2O (6 mL) was added Pd(PPh3)4 (300 mg, 0.26 mmol, 0.05 eq). The mixture was stirred at 100° C. overnight. Water was added, the reaction was filtered and the filtrate was extracted with EtOAc. The organic extract was discarded and the aqueous phase was acidified to pH 4-5 with 1M HCl and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo to provide the title compound as a white solid (1.09 g, 86%).
Reaction SMILES: [ClH:1].[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:20][C:21]3[CH:26]=[C:25]([O:27]C(OC)=O)[C:24]([CH3:32])=[CH:23][C:22]=3[F:33])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:34][CH3:35])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+].O.Cl>CO>[ClH:1].[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:20][C:21]3[CH:26]=[C:25]([OH:27])[C:24]([CH3:32])=[CH:23][C:22]=3[F:33])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:34][CH3:35])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc(OCc4ccccc4)c(OC)cc23)c(F)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc2c(Nc3cc(O)c(C)cc3F)ncnc2cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
A solution of 7-benzyloxy-4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-6-methoxyquinazoline hydrochloride (259 mg, 0.54 mmol), (prepared as described for the starting material in Example 12), in methanol (15 ml) containing 1M sodium hydroxide (1.6 ml) was stirred at ambient temperature for 1 hour. After addition of water (15 ml), concentrated hydrochloric acid (1 ml) was added and the mixture was stirred at ambient temperature for 15 minutes. After evaporation of methanol, the precipitate was filtered, washed with water and dried under vacuum to give 7-benzyloxy-4-(2-fluoro-5-hydroxy4-methylanilino)-6-methoxyquinazoline hydrochloride (192 mg, 80%).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([O:32]C)=[O:31])=[CH:24][CH:23]=3)[CH:15]=2)=[C:9]([CH3:34])[CH:8]=1)[CH3:2]>CO.O1CCCC1.[OH-].[Na+].C(OCC)(=O)C>[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:21][C:22]3[CH:23]=[CH:24][C:25]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:26][CH:27]=3)[CH:15]=2)=[C:9]([CH3:34])[CH:8]=1)[CH3:2]
Reactant: CCOCCOc1cc(C)c(-c2cccc(COc3ccc(CCC(=O)OC)cc3)c2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOCCOc1cc(C)c(-c2cccc(COc3ccc(CCC(=O)O)cc3)c2)c(C)c1
Yield: 74.6 %

Procedure:
Methyl 3-[4-[[4′-(2-ethoxyethoxy)-2′,6′-dimethylbiphenyl-3-yl]methoxy]phenyl]propanoate (0.12 g, 0.26 mmol) was dissolved in a mixed solution of methanol (2 mL) and tetrahydrofuran (4 mL), and 1 N aqueous sodium hydroxide solution (0.52 mL) was added at room temperature with stirring. The mixture was stirred at the same temperature for 2 hrs. After the completion of the reaction, the reaction mixture was diluted with ethyl acetate, washed successively with 1 N hydrochloric acid, water and saturated brine, dried and concentrated under reduced pressure. The residue was crystallized from hexane/ethyl acetate=4/1 to give the title compound (0.087 g, yield 75%) as colorless crystals.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][CH:11]([CH2:13][OH:14])[CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:4]1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:22][S:23]([O:1][CH2:2][CH:3]1[CH2:12][CH:11]([CH2:13][O:14][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:10][C:5]2([O:6][CH2:7][CH2:8][O:9]2)[CH2:4]1)(=[O:25])=[O:24]
Reactant: OCC1CC(CO)CC2(C1)OCCO2
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CC(COS(C)(=O)=O)CC2(C1)OCCO2
Reaction time: 8 h
Yield: 97 %

Procedure:
To a solution of 7,9-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]decane (6.3 g, 21 mmol) in dry dichloromethane (100 ml) with triethylamine (8.90 ml, 63.8 mmol) was added methanesulfonyl chloride (4.11 ml, 53.2 mmol) drop-wise at 0° C. The reaction was allowed to come to ambient temperature and stir overnight. The reaction was quenched with saturated sodium bicarbonate (50 ml) and allowed to stir for 15 min. After separation, the aqueous layer was extracted with dichloromethane (1×50 ml). The combined extracts were dried over potassium carbonate, filtered and concentrated to give a dark brown liquid (7.3 g, 97%).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl[CH2:17][CH2:18][N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.C([O-])([O-])=O.[K+].[K+].CCOCC>CN(C=O)C.O>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:17][CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCN1CCCC1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: c1ccc(Oc2ccc(OCCN3CCCC3)cc2)cc1
Yield: 92.9 %

Procedure:
A solution of 4-phenoxyphenol (0.56 g, 3.0 mmol), 1-(2-chloroethyl)-pyrrolidine HCl (0.51 g, 3.0 mmol) and powdered K2CO3 (1.2 g, 8.7 mmol) in 30 mL DMF was stirred at 80°-90° C. for 15 hours. The solution was cooled, poured into Et2O and water and the ether layer washed with water and brine, dried over Na2SO4 and concentrated in vacuo to give 0.79 g of a brown oil. The crude product was flashed chromatographed on silica gel using a gradient of 2:1 hexane/EtOAc to 100% EtOAc to provide the title compound (0.65 g, 76.5%) as a light yellow oil:
Reaction SMILES: [CH2:1](O)[C@H:2]1O[C@H:6]([O:8][C@:9]2(CO)[O:13][C@H:12](CO)[C@@H:11]([OH:16])[C@@H:10]2O)[C@H:5](O)[C@@H:4](O)[C@@H:3]1O.CO[C:26]1C=CC(C=O)=C[CH:31]=1.[CH2:34](O)[CH3:35]>>[CH2:26]([C@H:10]([C@@H:11]([OH:16])[CH3:12])[C:9]([O:8][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][CH2:34][CH3:35])=[O:13])[CH3:31]
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Reactant: COc1ccc(C=O)cc1
Reactant: CCO
Product: CCCCCCCCOC(=O)[C@H](CC)[C@H](C)O
Reaction time: 0.5 h

Procedure:
Twenty grams of bakers' yeast (Sigma Chemical Company, type II) are suspended in an aqueous solution containing 30 grams of sucrose in a conical flask, and the mixture is placed on an orbital shaker (220 rpm) at 30° C. for 30 minutes to initiate fermentation. Two grams of octyl 2-ethyl acetoacetate is dissolved in 2 ml of 95% ethanol, the resulting solution is added to the fermenting yeast, and shaking is resumed. The reaction is followed by TLC (staining with anisaldehyde) to monitor the consumption of starting material and the production of product alcohol. After approximately 48 hours the reaction is judged complete, and the reaction is terminated by removing from the shaker and adding 20-30 grams of Celite. The resulting suspension is suction filtered through a pad of Celite and the clear yellow filtrate is extracted with ethyl acetate (4×200 ml). The extracts are combined, dried over MgSO4, filtered, and rotary evaporated to leave 1.8 grams of octyl (2R,3S)-2-ethyl-3-hydroxybutyrate as a yellowish oil (>96% enantiomeric excess as judged by chiral chromatography).
Reaction SMILES: [N:1]1([C:6]([N:8]2[CH2:14][CH2:13][C:12]3[CH:15]=[CH:16][C:17]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:18][C:11]=3[CH2:10][CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:23]1([N:29]=[C:30]=[O:31])[CH2:28][CH2:27][CH:26]=[CH:25][CH2:24]1>>[CH:23]1([NH:29][C:30]([NH:22][S:19]([C:17]2[CH:16]=[CH:15][C:12]3[CH2:13][CH2:14][N:8]([C:6]([N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[O:7])[CH2:9][CH2:10][C:11]=3[CH:18]=2)(=[O:21])=[O:20])=[O:31])[CH2:28][CH2:27][CH:26]=[CH:25][CH2:24]1
Reactant: NS(=O)(=O)c1ccc2c(c1)CCN(C(=O)N1CCCC1)CC2
Reactant: O=C=NC1CC=CCC1
Product: O=C(NC1CC=CCC1)NS(=O)(=O)c1ccc2c(c1)CCN(C(=O)N1CCCC1)CC2

Procedure:
By the reaction of 2,3,4,5-tetrahydro-3-(1-pyrrolidinylcarbonyl)-1H-3-benzazepin-7-sulfonamide and 3-cyclohexen-1-ylisocyanate in a manner analogous to that described in Example 1, there is obtained 1-(3-cyclohexen-1-yl)-3-{[2,3,4,5-tetrahydro-3-(1-pyrrolidinylcarbonyl)-1H-3-benzazepin-7-yl]sulfonyl}urea, m.p. 211°-212° C.
Reaction SMILES: [CH3:1][C:2]1[O:12][C:5]2[CH2:6][N:7]([CH3:11])[CH2:8][CH:9]([OH:10])[C:4]=2[CH:3]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17](O)=[CH:16][C:15]=1[Cl:21]>>[ClH:21].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([O:10][CH:9]2[CH2:8][N:7]([CH3:11])[CH2:6][C:5]3[O:12][C:2]([CH3:1])=[CH:3][C:4]2=3)=[CH:16][C:15]=1[Cl:21]
Reactant: Cc1cc2c(o1)CN(C)CC2O
Reactant: Oc1ccc(Br)c(Cl)c1
Product: Cc1cc2c(o1)CN(C)CC2Oc1ccc(Br)c(Cl)c1
Product: Cl

Procedure:
The same method as in Example 47 was conducted using 2,6-dimethyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridin-4-ol (Reference Example 2) instead of 6-methyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridin-4-ol (Reference Example 1) and was conducted using 4-bromo-3-chlorophenol instead of 4-chloro-3-methylphenol to give the objective compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].CC(C)([O-:15])C.[K+].ClC[C:20]1[C:24]2[C:25]([CH3:30])=[CH:26][CH:27]=[C:28]([Cl:29])[C:23]=2[O:22][CH:21]=1>CN(C)C=O>[C:9]([O:8][C:6](=[O:7])[CH3:5])(=[O:15])[CH3:10].[Cl:29][C:28]1[C:23]2[O:22][CH:21]=[C:20]([CH:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:4]([O:3][CH2:1][CH3:2])=[O:11])[C:24]=2[C:25]([CH3:30])=[CH:26][CH:27]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1ccc(Cl)c2occ(CCl)c12
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OC(C)=O
Product: CCOC(=O)C(C(=O)OCC)c1coc2c(Cl)ccc(C)c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Malonic acid diethyl ester (8.5 g) was dissolved in dimethylformamide (75 mL) followed by addition of potassium tert-butoxide (5.9 g). After stirring for 15 min at room temperature, a solution of 3-chloromethyl-7-chloro-4-methylbenzofuran (3.8 g, prepared analogously to the 5-fluoro analogue as described in Example, 2) in dimethylformamide (25 mL) was added dropwise. After stirring for 2 hours the reaction mixture was poured onto ice-water. Standard work-up with acetyl acetate gave a yellow oil (10 g) of diethyl 2-(7-chloro-4-methylbenzofuran-3-yl)malonate, sufficiently pure for further synthesis.
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].[CH2:5]([N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19])[CH2:6][CH2:7][CH3:8]>>[N+:1]([C:16]1[CH:15]=[C:12]2[C:13](=[O:14])[N:9]([CH2:5][CH2:6][CH2:7][CH3:8])[C:10](=[O:19])[C:11]2=[CH:18][CH:17]=1)([O-:4])=[O:2].[N+:1]([C:15]1[CH:16]=[CH:17][CH:18]=[C:11]2[C:10]([N:9]([CH2:5][CH2:6][CH2:7][CH3:8])[C:13](=[O:14])[C:12]=12)=[O:19])([O-:3])=[O:2]
Reactant: CCCCN1C(=O)c2ccccc2C1=O
Reactant: O=[N+]([O-])O
Product: CCCCN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Product: CCCCN1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Temperature: 100 °C

Procedure:
A 3-necked, 5-liter round-bottomed flask, equipped with a mechanical stirrer, was charged with 4,259 g (67.6 moles) of 99% nitric acid. To the flask was added 524.9 g (2.58 moles) N-butylphthalimide as a liquid at such a rate as to keep the reaction temperature under 40° C. The addition of the N-butylphthalimide was completed in about a half hour. The reaction was then heated for six hours to 50° C. in a temperature controlled water bath. The reaction product was then fed to a wiped film evaporator that was heated at 100° C. and under vacuum (30 mm). The bulk of the nitric acid was distilled off and the liquid product, i.e., 4-nitro-N-butylphthalimide and 3-nitro-N-butylphthalimide in a ratio of about 25:1, was isolated as a liquid which rapidly solidified to about 98% solids upon cooling in the collection vessel. Depending on the operation of the evaporator, the residual nitric acid in the product was less than 3% by weight, and was as low as 0.1% by weight.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[CH2:10][C:11]1[NH:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1>>[CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([CH2:10][C:11]2[NH:12][C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)[CH2:4][CH2:3]1
Reactant: ClCc1nc2ccccc2[nH]1
Reactant: CN1CCCNCC1
Product: CN1CCCN(Cc2nc3ccccc3[nH]2)CC1
Yield: 26 %

Procedure:
In the same manner as described in Reference Example 4, N-methylhomopiperazine (15 g) and 2-chloromethylbenzimidazole (10 g) are reacted, and the crude crystal thus obtained is recrystallized from toluene to give 2-(4-methyl-1-homopiperazinyl)methylbenzimidazole (3.81 g) as pale yellow prisms, m.p. 152°-155° C.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:19]([NH:21][NH:22][C:23](=[O:32])[NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:43](Cl)(=[O:47])[C:44](Cl)=[O:45]>ClCCl>[C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:19]([NH:21][N:22]1[C:44](=[O:45])[C:43](=[O:47])[N:24]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]1=[O:32])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)C[C@@H](C(=O)NNC(=O)NCc1ccccc1)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)C[C@@H](C(=O)NN1C(=O)C(=O)N(Cc2ccccc2)C1=O)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 0.94 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-2′-(benzyl)carbamoyl-4-methylvalerohydrazide in 10 ml of dichloromethane was cooled to 0° C. under a nitrogen atmosphere and treated with 0.4 ml of pyridine and 0.174 ml of oxalyl chloride. The mixture was stirred at 0° C. for 2 hours and then allowed to warm to room temperature overnight. The mixture was washed in sequence with 2M aqueous hydrogen chloride, water, 5% aqueous sodium hydrogen carbonate, and saturated aqueous sodium chloride. The organic fraction was dried over anhydrous magnesium sulphate and evaporated. The solid residue was recrystallized from ethyl acetate to give 0.69 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-N-(3-benzyl-2,4,5-trioxo-1-imidazolidinyl]-4-methylvaleramide in the form of a white solid.
Reaction SMILES: [SH:1][C:2]1[N:3]([CH3:12])[C:4](=[O:11])[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[OH-].[Na+].CN(C=O)C.[F:20][C:21]1[CH:36]=[CH:35][C:24]([C:25]([C:27]2[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=2)=[O:26])=[CH:23][CH:22]=1>C(O)C.O>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([C:27]2[CH:34]=[CH:33][C:30]([CH2:31][S:1][C:2]3[N:3]([CH3:12])[C:4](=[O:11])[C:5]4[S:10][CH:9]=[CH:8][C:6]=4[N:7]=3)=[CH:29][CH:28]=2)=[O:26])=[CH:35][CH:36]=1
Reactant: Cn1c(S)nc2ccsc2c1=O
Reactant: O=C(c1ccc(F)cc1)c1ccc(CBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: Cn1c(SCc2ccc(C(=O)c3ccc(F)cc3)cc2)nc2ccsc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
To a solution of 2-mercapto-3-methylthieno[3,2-d]-pyrimidin-4(3H)-one (1.0 g) and sodium hydroxide (205 mg) in 50% ethanol (12 ml)-DMF (20 ml) was added 4-(4-fluorobenzoyl)benzyl bromide (1.48 g) and the mixture was stirred at room temperature for 1 hour. This reaction mixture was poured in water and the resulting crystals were collected by filtration, rinsed with water and methanol, and recrystallized from methanol to provide the title compound as colorless solid (1.44 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:16])[CH:14]=[O:15])[CH:7]=[CH:6]2.[N+]1([O-:23])C=CC=CC=1.C(O)(=O)C.C(OO)(=O)C>C(OCC)(=O)C>[CH3:16][C@H:13]([C:14]([OH:23])=[O:15])[C:8]1[CH:7]=[CH:6][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:10]=2[CH:9]=1
Reactant: [O-][n+]1ccccc1
Reactant: COc1ccc2cc([C@H](C)C=O)ccc2c1
Agent: CC(=O)OO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Yield: 80.3 %

Procedure:
To a stirred solution of 2.00 g (9.3 mmol) of (S)-2-(6-methoxy-2-naphthyl)propionaldehyde in ethyl acetate (10 mL) cooled in a wet-ice bath (ca. 2° C.) was added concurrently 0.89 g (9.3 mmol) of pyridine N-oxide and 0.56 g (9.3 mmol) of acetic acid. To this solution was then added slowly dropwise 5.8 mL (14.0 mmol) of a 20.4 weight percent solution of peracetic acid in ethyl acetate, at a rate slow enough such that the reaction temperature did not exceed 10° C. (ca. 15 minutes). After the initial exotherm, the temperature returned to 2° C., and the reaction was maintained at this temperature for an additional 4 hours. The reaction solution was transferred into a separatory funnel, was diluted with ethyl acetate (15 mL), and was washed with a 0.1N aqueous solution of sodium thiosulfate (Na2S2 O3, 25 mL). The ethyl acetate layer was further washed with water (10 mL), and the combined water washes were back-extracted with ethyl acetate (10 mL). The combined ethyl acetate layers were extracted with two portions of a 5% aqueous solution of potassium hydroxide (KOH, 65 mL then 25 mL). The combined KOH solutions of potassium naproxenate were acidified to pH=1 with a 5% aqueous solution of hydrochloric acid, precipitating the naproxen acid. The mixture was cooled in a wet-ice bath, and then was vacuum filtered through a #1 Whatman filter. The filter cake was washed with cold water (20 mL) and the white solid thus obtained was dried in a vacuum oven 18 hours at 55° C. (25 mm Hg), giving 1.72 g (80.0%) of naproxen.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([NH2:20])[C:17]([NH2:21])=[CH:16][C:15]=2[C:22](=[O:33])[NH:23][C:24]2[CH:32]=[C:31]3[C:27]([CH:28]=[N:29][NH:30]3)=[CH:26][CH:25]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:34]([C:37]1[C:42]([CH3:43])=[CH:41][CH:40]=[CH:39][N:38]=1)=[C:35]=S>C(Cl)CCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]([C:22](=[O:33])[NH:23][C:24]3[CH:32]=[C:31]4[C:27]([CH:28]=[N:29][NH:30]4)=[CH:26][CH:25]=3)=[CH:16][C:17]3[N:21]=[C:35]([NH:34][C:37]4[C:42]([CH3:43])=[CH:41][CH:40]=[CH:39][N:38]=4)[NH:20][C:18]=3[CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(N)c(N)cc2C(=O)Nc2ccc3cn[nH]c3c2)CC1
Reactant: Cc1cccnc1N=C=S
Solvent: ClCCCl
Product: Cc1cccnc1Nc1nc2cc(C(=O)Nc3ccc4cn[nH]c4c3)c(N3CCN(C(=O)OC(C)(C)C)CC3)cc2[nH]1

Procedure:
4-[4,5-Diamino-2-(1H-indazol-6-ylcarbamoyl)-phenyl]piperazine-1-carboxylic acid tert-butyl ester (see Example 87) was reacted with 2-isothiocyanato-3-methylpyridine (0.3 mmol; prepared from 3-methylpyridin-2-ylamine following general procedure A) followed by cyclization using EDC as described in general procedure B to obtain 4-[6-(1H-indazol-6-ylcarbamoyl)-2-(3-methylpyridin-2-ylamino)-3H-benzimidazol-5-yl]-piperazine-1-carboxylic acid tert-butyl ester. MS: m/z 568 (M+H)+.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[CH3:5][S:6]([O:9][CH2:10][CH2:11][CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:22]2[C:23](=[O:37])[NH:24][C:25](=[O:36])[C:26]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[N+:33]([O-:35])=[O:34])=[CH:14]1)(=[O:8])=[O:7]>C(O)C>[CH3:5][S:6]([OH:9])(=[O:8])=[O:7].[C:2]([S:3][CH2:10][CH2:11][CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:22]2[C:23](=[O:37])[NH:24][C:25](=[O:36])[C:26]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[N+:33]([O-:35])=[O:34])=[CH:14]1)(=[NH:4])[NH2:1]
Reactant: NC(N)=S
Reactant: CS(=O)(=O)OCCCn1cc(C2=C(c3ccccc3[N+](=O)[O-])C(=O)NC2=O)c2ccccc21
Solvent: CCO
Product: CS(=O)(=O)O
Product: N=C(N)SCCCn1cc(C2=C(c3ccccc3[N+](=O)[O-])C(=O)NC2=O)c2ccccc21
Yield: 5.7 %

Procedure:
50 mg of thiourea were added to a solution, heated at reflux, of 150 mg of the product of Example 68 in 15 ml of ethanol. The mixture was heated for 1 hour and the solvent was then evaporated. The residue was chromatographed on silica gel with 20% methanol in dichloromethane to give 10 mg of 3-[1-[3-(amidinothio)propyl]-3-indolyl]-4-(2-nitrophenyl)-1H-pyrrole-2,5-dione methanesulphonate, m.p. 164°-165° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:13][S:12][C:11]=2[CH:22]=1.[NH:23]([CH2:27][CH2:28][OH:29])[CH2:24][CH2:25][OH:26]>>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:23]([CH2:27][CH2:28][OH:29])[CH2:24][CH2:25][OH:26])=[CH:22][C:11]=3[S:12][CH:13]=2)=[CH:16][CH:17]=1
Reactant: OCCNCCO
Reactant: Fc1ccc(-c2csc3cc(OCCCCBr)ccc23)cc1
Product: OCCN(CCO)CCCCOc1ccc2c(-c3ccc(F)cc3)csc2c1

Procedure:
In analogy to example 3.1, 6-(4-Bromo-butoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene and diethanolamine were converted to yield 2-[{4-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-(2-hydroxy-ethyl)-amino]-ethanol as white semisolid, MS: 404 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:6]([N:12]=1)=[N:7][CH:8]=[CH:9][C:10]=2[CH3:11])[CH3:2].ClC1C=CC=C(C(OO)=[O:21])C=1>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[NH:4][C:5]2[C:6]([N:12]=1)=[N+:7]([O-:21])[CH:8]=[CH:9][C:10]=2[CH3:11])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCc1nc2nccc(C)c2[nH]1
Solvent: ClC(Cl)Cl
Product: CCc1nc2c([nH]1)c(C)cc[n+]2[O-]
Yield: 96.6 %

Procedure:
A solution of 28 g (174 mmol) of 2-ethyl-7-methylimidazo[4,5-b]pyridine (described in European Patent Application #400,974, May 12, 1990) and m-chloroperbenzoic acid (80-90%, 44.6 g) in CHCl3 (300 mL) was heated at reflux for 0.5 hours. The mixture was concentrated and purified (SiO2, 100% CH2Cl2 gradient to 30% CH2Cl2 /MeOH) to give 29.8 g of the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]=[C:10]=[O:11])[N:3]=1.[C:12]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([NH2:26])(=[O:25])=[O:24])(=[O:14])[CH3:13]>C(#N)C>[C:12]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([NH:26][C:10]([NH:9][C:4]1[N:5]=[C:6]([Cl:8])[N:7]=[C:2]([Cl:1])[N:3]=1)=[O:11])(=[O:24])=[O:25])(=[O:14])[CH3:13]
Reactant: O=C=Nc1nc(Cl)nc(Cl)n1
Reactant: CC(=O)OCc1ccccc1S(N)(=O)=O
Solvent: CC#N
Product: CC(=O)OCc1ccccc1S(=O)(=O)NC(=O)Nc1nc(Cl)nc(Cl)n1
Reaction time: 16 h

Procedure:
A solution of 4,6-dichloro-1,3,5-triazin-2-yl isocyanate (0.87 g, 4.5 mmol) in acetonitrile (9 ml) was treated with 2-(acetoxymethyl)benzenesulfonamide (1.04 g, 4.5 mmol) and stirred for 16 hours. Volatiles were removed under vacuum to give a residue whose 'H NMR showed δ(CD3)2CO, 8.05-7.80 (m, 1H), 7.65-7.27 (m, 3H), 6.45 (brd s, 1H), 5.50 (s, 2H), 2.10 (s, 3H), consistent with the assigned structure.