Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[C:13]2[O:12][C:11]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:10][CH2:9][C:8]=2[CH:7]=[CH:6][C:5]=1[OH:28])[CH2:2][CH3:3].[C:29](O)(=[O:31])[CH3:30]>[Cl-].[Zn+2].[Cl-]>[C:29]([C:6]1[C:5]([OH:28])=[C:4]([CH2:1][CH2:2][CH3:3])[C:13]2[O:12][C:11]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:10][CH2:9][C:8]=2[CH:7]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)O
Reactant: CCCc1c(O)ccc2c1OC(CCC(=O)OCC)(CCC(=O)OCC)CC2
Agent: [Cl-]
Agent: [Zn+2]
Product: CCCc1c(O)c(C(C)=O)cc2c1OC(CCC(=O)OCC)(CCC(=O)OCC)CC2
Reaction time: 6 h

Procedure:
To a solution of 790 mg (2.01 mmol) of the title product of Example 44 in 4 ml of acetic acid was added 547 mg (4.02 mmol) of anhydrous zinc chloride. The mixture was stirred for six hours at reflux, and then permitted to cool. The mixture was partitioned between ethyl acetate and dilute hydrochloric acid. The aqueous layer was further extracted with two portions of ethyl acetate. The combined organic extracts were washed successively with five portions of aqueous sodium bicarbonate, water, and then brine. The extracts were dried over sodium sulfate, filtered, and the solvent removed under reduced pressure. Chromatography of the residue over silica gel using 25% ethyl acetate/hexane as eluent gave the title compound, 230 mg.
Reaction SMILES: ClC1C=CC(C2(C[Br:17])CCC(CCC)O2)=CC=1.[CH3:18][C:19]([OH:33])([CH2:21][CH2:22][C:23]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)=[CH:24][CH3:25])[CH3:20].BrBr.N1C=CC=CC=1>ClCCl>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([C:23]2([CH:24]([Br:17])[CH3:25])[CH2:22][CH2:21][C:19]([CH3:20])([CH3:18])[O:33]2)=[CH:27][CH:28]=1
Reactant: CCCC1CCC(CBr)(c2ccc(Cl)cc2)O1
Reactant: CC=C(CCC(C)(C)O)c1ccc(Cl)cc1
Agent: BrBr
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(Br)C1(c2ccc(Cl)cc2)CCC(C)(C)O1
Yield: 94 %

Procedure:
By the method described in Example 1 for the preparation of 2-(4-chlorophenyl)-2-bromomethyl-5-prop-1-yltetrahydrofuran, 2-methyl-5-(4-chlorophenyl)hept-5-en-2-ol (3.2 g), bromine (2.35 g), and pyridine (1.18 g) in dry dichloromethane (40 ml) gave 2-(4-chlorophenyl-2-(1-bromoethyl)-5,5-dimethyltetrahydrofuran (4.4 g, 94%), a mixture of diastereomers, as an orange oil.
Reaction SMILES: Cl[CH:2]([SiH3:4])Cl.[S:5]([C:21]1[CH:26]=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:24]=[C:23]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:22]=1[OH:35])[C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:9]=[C:8]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:7]=1[OH:20].C(N(CC)CC)C>>[C:27]([C:25]1[CH:24]=[C:23]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:22]2[O:35][SiH:4]([CH3:2])[O:20][C:7]3[C:8]([C:16]([CH3:18])([CH3:17])[CH3:19])=[CH:9][C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:11][C:6]=3[S:5][C:21]=2[CH:26]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)c1cc(Sc2cc(C(C)(C)C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Reactant: [SiH3]C(Cl)Cl
Solvent: CCN(CC)CC
Product: C[SiH]1Oc2c(cc(C(C)(C)C)cc2C(C)(C)C)Sc2cc(C(C)(C)C)cc(C(C)(C)C)c2O1
Yield: 48.7 %

Procedure:
Utilizing the procedure of Example 1, this compound is prepared from 5.7 grams (0.05 mole) dichloromethylsilane, 22.1 grams (0.05 mole) 2,2'-thiobis(4,6-di-t-butylphenol), and 10.1 grams (0.10 mole) triethylamine. Recrystallization twice from acetone-toluene gives 11.8 grams (48% yield) of white crystals, mp 178°-180° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][C:14]([CH3:20])=[CH:15][CH:16]=3)[N:11]=[C:10]2[CH:21]([NH:23][CH3:24])[CH3:22])=[CH:5][CH:4]=1.[C:25]([C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26]>>[C:25]([C:29]1[CH:34]=[CH:33][C:32]([S:35]([N:23]([CH:21]([C:10]2[N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[C:18](=[O:19])[C:17]3[C:12](=[CH:13][C:14]([CH3:20])=[CH:15][CH:16]=3)[N:11]=2)[CH3:22])[CH3:24])(=[O:37])=[O:36])=[CH:31][CH:30]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CNC(C)c1nc2cc(C)ccc2c(=O)n1-c1ccc(OC)cc1
Product: COc1ccc(-n2c(C(C)N(C)S(=O)(=O)c3ccc(C(C)(C)C)cc3)nc3cc(C)ccc3c2=O)cc1

Procedure:
In a similar manner as described above in Paragraph A, 3-(4-methoxyphenyl)-7-methyl-2-(1-methylaminoethyl)-3H-quinazolin-4-one, as prepared above in Example 5, was condensed with 4-tert-butylbenzenesulfonyl chloride to yield 4-tert-butyl-N-{1-[3-(4-methoxyphenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-N-methylbenzenesulfonamide; MS (ESI) 520 (MH+).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7][NH:8][C:9](=[O:20])[C:10]1[CH:15]=[C:14]([NH2:16])[C:13]([Cl:17])=[CH:12][C:11]=1[O:18][CH3:19])[CH2:4][CH3:5])[CH3:2].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:1]([N:3]([CH2:6][CH2:7][NH:8][C:9](=[O:20])[C:10]1[CH:15]=[C:14]([N:16]([S:29]([CH3:28])(=[O:31])=[O:30])[S:29]([CH3:28])(=[O:31])=[O:30])[C:13]([Cl:17])=[CH:12][C:11]=1[O:18][CH3:19])[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)CCNC(=O)c1cc(N)c(Cl)cc1OC
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)CCNC(=O)c1cc(N(S(C)(=O)=O)S(C)(=O)=O)c(Cl)cc1OC

Procedure:
To a solution of N-(diethylaminoethyl)-5-amino 4-chloro-2-methoxybenzamide (1.1 g) and triethylamine (815 mg) in dry methylene chloride (11 ml) is added dropwise a solution of methanesulfonyl chloride (882 mg) in dry methylene chloride (5ml) under ice-cooling and stirring and the resultant mixture is stirred at room temperature for 30 minutes. The reaction mixture is mixed with aqueous sodium hydrogen-carbonate and the methylene chloride layer is separated. The organic layer is washed with water, dried over anhydrous sodium sulfate and concentrated. The intermediary N-(diethylaminoethyl)-5-bis(methanesulfonyl)amino-4-chloro-2-methoxybenzamide obtained as a residue is mixed with 10 % aqueous sodium hydroxide (18ml) and methanol (2 ml) and heated at 50° C. for 30 minutes. The reaction mixture is acidified with conc. hydrochloric acid, neutralized with aqueous sodium hydrogencarbonate, salted out with brine, and shaken with methylene chloride. The organic layer is dried over anhydrous sodium sulfate, and concentrated. The residue is chromatographed on a column of alumina, which is eluted with methylene chloride. The eluate is concentrated and the residue is washed with ethyl acetate - isoproyl ether to give N-(diethylaminoethyl)-4-chloro-5-methanesulfonamido-2-methoxybenzamide (993 mg) as crystals melting at 123° to 123.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[CH:3]=1.Cl[CH2:14][CH2:15][O:16][CH3:17]>[OH-].[Na+].O>[CH3:17][O:16][CH2:15][CH2:14][O:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([C:9](=[O:11])[CH3:10])=[C:6]([CH3:8])[CH:7]=1
Reactant: CC(=O)c1c(C)cc(O)cc1C
Reactant: COCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCCOc1cc(C)c(C(C)=O)c(C)c1
Temperature: 140 °C
Yield: 61.3 %

Procedure:
A pressure glass vessel charged with 1-(4-hydroxy-2,6-dimethylphenyl)ethanone (500 mg, 3.1 mmol, 1.0 equiv) and 1-chloro-2-methoxyethane (0.28 mL, 3.1 mmol, 1.0 equiv) in 50% aqueous NaOH solution (5.0 mL) was heated at 140° C. for 16 h. The residue was diluted with H2O (20 mL) and extracted with EtOAc (3×30 mL). The organic layer was separated, dried with MgSO4, and concentrated under reduced pressure to give 1-(4-(2-methoxyethoxy)-2,6-dimethylphenyl)ethanone (430.9 mg, 1.9 mmol) as yellow oil in 64% yield: 1H NMR (CDCl3, 500 MHz) δ 6.58 (s, 2H), 4.09-4.10 (m, 2H), 3.72-3.74 (m, 2H), 3.44 (s, 3H), 2.45 (s, 3H), 2.23 (s, 6H); ESI-MS: m/z 223.6 (M+H)+.
Reaction SMILES: [C:1]1([N:7]2[C:11]([SH:12])=[N:10][N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]1([N:7]2[C:11]([S:12][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])=[N:10][N:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Sc1nnnn1-c1ccccc1
Reactant: OCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: OCCCCCCCCCCCCSc1nnnn1-c1ccccc1
Yield: 77 %

Procedure:
1-Phenyl-1H-tetrazole-5-thiol, 12-bromododecan-1-ol and anhydrous potassium carbonate were mixed together in acetone for 18 hrs at room temperature to provide 12-(1-phenyl-1H-tetrazol-5-ylsulfanyl)-dodecan-1-ol in 77% yield following work up and recrystallisation. Ammonium molybdate (VI) tetrahydrate in 35% H2O2 were added to a stirred solution of the solid in THF IMS (500 ml) at 10° C. and stirred at room temperature for 20 hrs. Work-up and crystallisation gave a white solid (m.p.: 56-58° C.), 12-(1-phenyl-1H-tetrazol-5-sulfonyl)-dodecan-1-ol in 95% yield. N-Bromosuccinimide was added to a solution of the alcohol and triphenylphosphine in dichloromethane and the reaction stirred at room temperature for 75 min. Work-up and purification by chromatography provided a white solid (m.p.: 63-65° C.), 5-(12-bromo-dodecane-1-sulfonyl)-1-phenyl-1H-tetrazole in 72% yield.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])[CH3:2].CCN(C(C)C)C(C)C.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([C:28](=[O:32])[C:29](Cl)=[O:30])=[CH:20]1>CN(C=O)C>[CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][C:29](=[O:30])[C:28]([C:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[NH:19][CH:20]=1)=[O:32])[CH3:2]
Reactant: CCc1ccccc1N
Reactant: O=C(Cl)C(=O)c1c[nH]c2ccccc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1ccccc1NC(=O)C(=O)c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.8 %

Procedure:
To a stirring solution of 2-ethyl-aniline (74 μL, 0.6 mmol) and DIEA (110 μL, 0.6 mmol) in DMF (1 mL) was added a solution of (1H-indol-3-yl)-oxo-acetyl chloride (62 mg, 0.3 mmol) in DMF (1 mL). The reaction was stirred at room temperature for 2 hours, then filtered and purified by HPLC (10-99% CH3CN/H2O) to yield the product N-(2-ethyl-phenyl)-2-(1H-indol-3-yl)-2-oxo-acetamide (34 mg, 39%). HPLC ret. time 3.50 min, 10-99% CH3CN, 5 min run; 1H NMR (400 MHz, DMSO-d6) δ 12.33 (s, 1H), 10.14 (s, 1H), 8.79 (d, J=3.2 Hz, 1H), 8.30 (m, 1H), 7.57 (m, 2H), 7.33-7.21 (m, 5H), 2.67 (q, J=7.6 Hz, 2H), 1.17 (t, J=7.6 Hz, 3H); ESI-MS m/z 293.1 (MH+).
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C(N(C(C)C)C(C)C)C.[Cl:33][C:34]1[CH:35]=[CH:36][C:37]([O:43][CH3:44])=[C:38]([CH:42]=1)[C:39](Cl)=[O:40]>C1C=CC=CC=1>[Cl:33][C:34]1[CH:35]=[CH:36][C:37]([O:43][CH3:44])=[C:38]([CH:42]=1)[C:39]([N:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:40]
Reactant: CCOC(=O)CCCCCNc1ccccc1-c1ccccc1
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccccc1
Product: CCOC(=O)CCCCCN(C(=O)c1cc(Cl)ccc1OC)c1ccccc1-c1ccccc1
Yield: 90 %

Procedure:
8.0 g of ethyl 6-(biphenyl-2-yl)aminocaproate and 3.3 g of ethyldiisopropylamine in 50 ml of benzene are reacted with a solution of 5.3 g of 5-chloro-2-methoxybenzoyl chloride in 20 ml of benzene, analogously to Example 47a), to obtain, as reaction product, 11.1 g (90% of theory) of ethyl 6-[5-chloro-2-methoxy-N-(biphenyl-2-yl)benzamido]caproate as a viscous non-distillable oil. The saponification of this ester yields 7.0 g (67% of theory) of 6-[5-chloro-2-methoxy-N-(biphenyl-2-yl)benzamido]-caproic acid, MP 164° to 165°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.Cl[C:16]([O:18][CH3:19])=[O:17]>C1(C)C=CC=CC=1>[CH3:19][O:18][C:16]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[O:17]
Reactant: COC(=O)Cl
Reactant: Nc1ccc(C2=NNC(=O)CC2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)Nc1ccc(C2=NNC(=O)CC2)cc1
Yield: 42.1 %

Procedure:
6.0 g (31.7 millimoles) of 6-(p-aminophenyl)-4,5-dihydro-3(2H)-pyridazinone and 3.3 g (34.9 millimoles) of methyl chloroformate in 100 ml of absolute toluene are kept for 6 hours at 80° C. The product is filtered off at 10° C., washed first with toluene and then with water, and recrystallized from dimethylformamide/water. 3.3 g (42% of theory) of 4,5-dihydro-6-(p-methoxycarbonylaminophenyl)-3(2H)-pyridazinone are obtained as beige crystals, of melting point 246°-247° C. (with decomposition).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5](OC)=O.[CH3:15][NH:16][CH2:17][CH2:18][NH2:19]>>[CH3:15][N:16]1[CH2:17][CH2:18][N:19]=[C:5]1[C:4]1[CH:9]=[CH:10][CH:11]=[C:2]([CH3:1])[C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: CNCCN
Reactant: COC(=O)c1cccc(C)c1[N+](=O)[O-]
Product: Cc1cccc(C2=NCCN2C)c1[N+](=O)[O-]
Temperature: 190 °C
Yield: 75 %

Procedure:
A solution of methyl 3-methyl-2-nitrobenzoate (3.0 g, 15.4 mmol) in N-methylethylene diamine (5 g, 68 mmol) was heated at reflux for 1.5 hour, at which point the solvent was removed at 130° C. under reduced pressure. The residue was then heated at 190° C. for 1.25 hour before being cooled on ice to give the title compound of Step A (75% pure) as a brown oil.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:5][CH2:6][CH2:7][C:8](=[O:14])[CH2:9][C:10](OC)=[O:11].O.Cl.[CH:23]([OH:26])([CH3:25])[CH3:24]>>[CH3:3][C:4]([CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:5][CH2:6][CH2:7][C:8](=[O:14])[CH2:9][C:10]([O:26][CH:23]([CH3:25])[CH3:24])=[O:11]
Reactant: COC(=O)CC(=O)CCC=C(C)CCC=C(C)C
Reactant: CC(C)O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(C)=CCCC(C)=CCCC(=O)CC(=O)OC(C)C

Procedure:
A solution of 1.92 g of sodium hydride in 200 ml of isopropanol was added to a boiling mixture of 10 g of the product of Example 3 and 200 ml of isopropanol and the volume was held constant by replacing proportionately the distillate with isopropanol for 2 hours. After cooling, the mixture was poured into water and acidified with concentrated hydrochloric acid. The mixture was extracted with ethyl acetate and the extract was washed with water, dried over sodium sulfate and evaporated to dryness. The residue was chromatographed over silica and was eluted with a 9-1 petroleum ether (b.p.= 40°-75° C.)-ethyl ether mixture to obtain 7.05 g of isopropyl 7,11dimethyl-3-oxo-6,10-dodecadienoate in the form of an amber oil with a refractive index of nD24 = 1.467.
Reaction SMILES: [K+].[CH:2]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[S:7][C:6]=2[CH:5]=[C:4]([C:15]([O-:17])=O)[CH:3]=1.C(Cl)(=O)C([Cl:21])=O>C1C=CC=CC=1>[Cl:21][C:15]([C:4]1[CH:3]=[CH:2][C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[S:7][C:6]=2[CH:5]=1)=[O:17]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C([O-])c1ccc2c(c1)sc1ccccc12
Agent: [K+]
Solvent: c1ccccc1
Product: O=C(Cl)c1ccc2c(c1)sc1ccccc12
Reaction time: 0.5 h

Procedure:
To a suspension of 8.9 g. of dibenzothiophene-3-carboxylic acid potassium salt in 200 ml. of benzene was added dropwise with stirring over a period of 30 minutes, a solution of 6.4 g. of oxalyl chloride in 50 ml. of benzene. The mixture was stirred and refluxed for two hours. The mixture was filtered and the solvent was removed in vacuo on the steam bath. The residue, 3-chlorocarbonyldibenzothiphene (7.9 g.) was used directly in the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([S:10]([NH2:13])(=[O:11])=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: NS(=O)(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(S(N)(=O)=O)c1
Yield: 100.2 %

Procedure:
A solution of 1.5 g (7.42 mmol) of 3-nitrobenzenesulfonamide in 50 ml of EtOH containing 150 mg of 10% palladium on carbon was placed on a Parr hydrogenator under H2 for 1 h. The reaction was filtered through a pad of celite washing with EtOH, and the filtrate was concentrated in vacuo to give 1.28 g (100%) of 3-aminobenzenesulfonamide which was used immediately in the next reaction. The title compound was prepared as in example 21 from 3-aminobenzenesulfonamide using intermediate C. Recrystallization from MeOH/Et2O provided 1.46 g (67%) of title compound as an off-white solid: mp 240°-242° C.; 1H NMR (D2O, 300 MHz) δ 7.86 (d, 1 H, J=8.1 Hz), 7.75 (s, 1 H), 7.63 (t, 1 H, J=8.1 Hz), 7.51 (d, 1 H, J=8.1 Hz), 2.30 (s, 3 H).
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:16])[C:8]3[N:9]2[C:12](=[O:15])[NH:13][N:14]=3)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[NH:20]1[CH2:25][CH2:24][S:23][CH2:22][CH2:21]1>>[N+:17]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:20]1[CH2:25][CH2:24][S:23][CH2:22][CH2:21]1)[N:9]1[C:12](=[O:15])[NH:13][N:14]=[C:8]1[C:7](=[O:16])[NH:6]2)([O-:19])=[O:18]
Reactant: O=c1[nH]c2cc([N+](=O)[O-])c(F)cc2n2c(=O)[nH]nc12
Reactant: C1CSCCN1
Product: O=c1[nH]c2cc([N+](=O)[O-])c(N3CCSCC3)cc2n2c(=O)[nH]nc12

Procedure:
The title compound was prepared from 8-fluoro-7-nitro[1,2,4]triazolo[4,3-a]quinoxaline-1,4(2H,5H)-dione and thiomorpholine by a method analogous to the method described in example 11. M.p. 230° C. decomp.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[CH3:16][O:17][C:18]1[CH:29]=[CH:28][CH:27]=[CH:26][C:19]=1[CH2:20][CH:21]([C:23]([OH:25])=[O:24])[NH2:22]>>[C:23]([CH:21]([NH:22][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:20][C:19]1[CH:26]=[CH:27][CH:28]=[CH:29][C:18]=1[O:17][CH3:16])([OH:25])=[O:24]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: COc1ccccc1CC(N)C(=O)O
Product: COc1ccccc1CC(Nc1nc2ccc(Cl)cc2cc1C(=O)O)C(=O)O

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 2-methoxy-DL-phenylalanine to provide the title compound in good yield.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:18]=[CH:17][C:16]=1[OH:28].[CH2:29](Br)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].C(=O)([O-])[O-].[K+].[K+]>[Cu].CN(C=O)C>[CH2:29]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:18]=[CH:17][C:16]=1[OH:28])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: COC(=O)CCCc1ccc(O)c(-c2cc(CCCC(=O)OC)ccc2O)c1
Reactant: CCCCCCCBr
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(CCCC(=O)OC)cc1-c1cc(CCCC(=O)OC)ccc1O
Yield: 89.3 %

Procedure:
To 5 ml of a DMF solution containing 200 mg (0.5181 mmol) of 2,2'-dihydroxy-5,5'-bis (3-methoxycarbonylpropyl) biphenyl and 0.840 ml (5.181 mmol) of heptyl bromide, there were added 85.8 mg (0.6217 mmol) of anhydrous potassium carbonate and a small amount of copper powder and the resulting mixture was agitated for 5 hours at room temperature. The reaction mixture was filtered by suction through Celite to remove the solid matter and the filtrate was washed with ethyl acetate. After the solvent in the filtrate was evaporated off under reduced pressure, the evaporated residue was dissolved in chloroform. This solution was washed with dilute hydrochloric acid, dilute aqueous sodium bicarbonate, water and aqueous sodium chloride solution in this sequence and was dried by adding anhydrous sodium sulfate. The residue obtained after the solvent had been evaporated off was purified by silica gel column chromatography (with 15 g of WAKO-gel C-200, eluent: toluene and toluene/ethyl acetate of 50/) to obtain 224 mg (0.4628 mmol, 89%) of 2-heptyloxy-2'-hydroxy-5,5'-bis (3-methoxycarbonylpropyl) biphenyl as an oily product. 1H-NMR (CDCl3) δ (ppm): 0.85 (3H, t, CH3), 1.0-2.2 (14H, m, 7CH2), 2.35 (4H, t, 2CH2), 2.64 (4H, t, 2CH2), 3.66 (6H, s, 2CH3), 4.01 (2H, s, CH2), 6.61 (1H, s, OH), 6.8-7.3 (6H, m, arom-H) MS (FAB): 483 (M-H)-
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:26]=[CH:25][C:11]([C:12]([NH:14][C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[CH:17][CH:16]=2)=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O.[NH2:28][NH2:29]>CCO>[CH2:1]([O:7][C:8]1[CH:26]=[CH:25][C:11]([C:12]([NH:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([NH:28][NH2:29])=[O:20])=[CH:17][CH:16]=2)=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1ccc(C(=O)Nc2ccc(C(=O)OC)cc2)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCCCCCOc1ccc(C(=O)Nc2ccc(C(=O)NN)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 80 %

Procedure:
To a suspension of methyl 4-{[4-(hexyloxy)benzoyl]amino}benzoate (856 mg, 2.41 mmol) in EtOH (10 mL) was added hydrazine hydrate (1.8 mL). After stirring for 15 h at reflux, the reaction mixture was cooled to rt and a white solid precipitated out. Filtration, washing with EtOH (1×2 mL) and water (2×2 mL), and drying under vacuo at rt for 72 hrs gave 681 mg of the title compound (80%) as a white solid in 99.7% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [ClH:1].C([O:9][C:10]1[CH:11]=[CH:12][C:13]([C@@H:21]([OH:35])[CH2:22][NH:23][C@H:24]([CH3:34])[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[C:14]2[C:19]=1[NH:18][C:17](=[O:20])[CH:16]=[CH:15]2)C1C=CC=CC=1.O1CCCC1>[Pd].O>[ClH:1].[OH:9][C:10]1[CH:11]=[CH:12][C:13]([C@@H:21]([OH:35])[CH2:22][NH:23][C@H:24]([CH3:34])[CH2:25][C:26]2[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)=[C:14]2[C:19]=1[NH:18][C:17](=[O:20])[CH:16]=[CH:15]2
Reactant: COc1ccc(C[C@@H](C)NC[C@H](O)c2ccc(OCc3ccccc3)c3[nH]c(=O)ccc23)cc1
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C[C@@H](C)NC[C@H](O)c2ccc(O)c3[nH]c(=O)ccc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.1 %

Procedure:
A mixture of 3.5 g of 8-benzyloxy-5-{(1R)-1-hydroxy-2-[N-((1R)-2-(p-methoxyphenyl)-1-methylethyl)amino]ethyl}carbostyril hydrochloride, 240 mg of 10% palladium-charcoal, 100 ml of tetrahydrofuran and 10 ml of water is shaken at room temperature at an atmospheric pressure under a hydrogen atmosphere for 2 hours. Insoluble materials are collected by filtration and washed with an aqueous 10% ethanol solution. The filtrate and washings are combined, and the combined solution is concentrated under reduced pressure to remove solvent. The residue is crystallized with a mixture of ethanol, water and isopropyl ether, and crystalline precipitates are collected by filtration. 2.38 g of 8-hydroxy-5-{(1R)-1-hydroxy-2-[N-((1R)-2-(p-methoxyphenyl)-1-methylethyl)amino]ethyl}carbostyril hydrochloride are obtained as colorless crystals. Yield: 83%
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.[C:11](O)(=[O:14])[CH:12]=[CH2:13]>>[CH3:8][C:6]1([CH3:9])[CH2:7][C:2]2[NH:1][C:11](=[O:14])[CH2:12][CH2:13][C:3]=2[C:4](=[O:10])[CH2:5]1
Reactant: CC1(C)CC(=O)C=C(N)C1
Reactant: C=CC(=O)O
Product: CC1(C)CC(=O)C2=C(C1)NC(=O)CC2

Procedure:
Prepared analogously to Example G from 1-amino- 5,5-dimethyl-cyclohexen-3-one and acrylic acid at 140° C. for 3 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]=[CH:6][C:5]2=O.S(O)(O)(=O)=O.[CH3:18][NH:19][NH2:20].C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([OH:8])=[C:4]([C:5]2[N:19]([CH3:18])[N:20]=[CH:7][CH:6]=2)[CH:3]=1
Reactant: CNN
Reactant: O=c1ccoc2ccc(Cl)cc12
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cn1nccc1-c1cc(Cl)ccc1O
Temperature: 25 °C

Procedure:
To a suspension of 6-chlorochromone (2.00 g, 0.011 mol) in ethanol (35 mL) was added methylhydrazine sulfate (1.85 g, 0.013 mol) and triethylamine (2.0 mL, 0.014 mol) and the mixture was heated at reflux for 18 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo and the resulting residue purified by silica gel chromatography eluting with 0 to 100% EtOAc in hexane to yield two regioisomeric products in a 1:4 ratio, the title compound being the minor regiosiomer.