Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7]4=[C:8]([C:17](=[O:21])[NH:18][C:19](=[S:20])[N:6]4[C:5]=2[CH:4]=1)[CH:9]=[CH:10][CH:11]=3.[OH-].[K+].[CH3:26]C(C)=O.CI>O>[CH3:26][S:20][C:19]1[N:6]2[C:7]3[C:12]([S:13][C:14]4[CH:15]=[CH:16][C:3]([C:2]([F:1])([F:22])[F:23])=[CH:4][C:5]=42)=[CH:11][CH:10]=[CH:9][C:8]=3[C:17](=[O:21])[N:18]=1
Reactant: CC(C)=O
Reactant: O=c1[nH]c(=S)n2c3c(cccc13)Sc1ccc(C(F)(F)F)cc1-2
Agent: [K+]
Agent: [OH-]
Solvent: CI
Solvent: O
Product: CSc1nc(=O)c2cccc3c2n1-c1cc(C(F)(F)F)ccc1S3
Reaction time: 18 h

Procedure:
10-Trifluoromethyl-1H-pyrimido[5,4,3-kl]phenothiazine-3-one-1(2H)-thione (53.6 g., 0.152 mol.) was added to a stirred solution of 8.95 g. (0.160 mol.) of potassium hydroxide in 1680 ml. of acetone and 720 ml. of water. After all the solid had dissolved and a clear yellow solution formed, 22.8 g. (10 ml., 0.160 mol.) of methyl iodide was added in one portion. The reaction mixture was stirred at 25° for 18 hours, diluted with 1000 ml. of water and chilled in an ice-bath for several hours. The resulting light yellow solid was collected by filtration and washed with water to give 1-methylmercapto-10-trifluoromethyl-3H-pyrimido[5,4,3-kl]phenothiazine-3-one, m.p. 229°-231° (ethanol).
Reaction SMILES: [C:1]([C:4]([CH3:29])([CH2:16][CH2:17][CH2:18][CH:19]([O:25]C(=O)C)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])(=[O:3])[CH3:2].C(C(CCCC(OC(=O)C)CCCCC)CCCCCCC(OCC)=O)(=O)C>>[C:1]([C:4]([CH3:29])([CH2:16][CH2:17][CH2:18][CH:19]([OH:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2]
Reactant: CCCCCC(CCCC(C)(CCCCCCC(=O)OCC)C(C)=O)OC(C)=O
Agent: CCCCCC(CCCC(CCCCCCC(=O)OCC)C(C)=O)OC(C)=O
Product: CCCCCC(O)CCCC(C)(CCCCCCC(=O)O)C(C)=O

Procedure:
By following the hydrolytic procedure described in Example 1, Step D, but substituting an equimolar amount of ethyl 8-acetyl-8-methyl-12-acetoxyheptadecanoate for the ethyl 8-acetyl-12-acetoxyheptadecanoate of the example, there is obtained 8-acetyl-8-methyl-12-hydroxyheptadecanoic acid as a colorless viscous oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:5][O:6][C:7]1[CH:20]=[C:11]2[N:12]([CH2:16][C:17]([OH:19])=O)[CH2:13][CH2:14][CH2:15][N:10]2[C:9](=[O:21])[N:8]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:5][O:6][C:7]1[CH:20]=[C:11]2[N:12]([CH2:16][C:17](=[O:19])[N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:13][CH2:14][CH2:15][N:10]2[C:9](=[O:21])[N:8]=1
Reactant: C1CCNC1
Reactant: O=C(O)CN1CCCn2c1cc(OCc1ccc(F)c(F)c1)nc2=O
Product: O=C(CN1CCCn2c1cc(OCc1ccc(F)c(F)c1)nc2=O)N1CCCC1

Procedure:
The title compound was prepared by a procedure similar to that described for E13 starting from 2-(8-((3,4-difluorobenzyl)oxy)-6-oxo-2,3,4,6-tetrahydro-1H-pyrimido[1,6-a]pyrimidin-1-yl)acetic acid and pyrrolidine.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][O:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:7][CH:6]=1)C=C.[C:18]1(OC2C=CC=CC=2)[CH:23]=CC=C[CH:19]=1>>[CH2:23]([C:10]1[CH:9]=[C:8]([CH2:11][O:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:7]=[CH:6][C:5]=1[OH:4])[CH:18]=[CH2:19]
Reactant: C=CCOc1ccc(COCC(=O)OC)cc1
Reactant: c1ccc(Oc2ccccc2)cc1
Product: C=CCc1cc(COCC(=O)OC)ccc1O
Temperature: 200 °C

Procedure:
A mixture of methyl 4-allyloxyphenylmethyloxyacetate (2.00 g) and diphenyl ether (14 ml) was heated at 200° C. in an atmosphere of argon for 9 hours. The mixture was cooled to ambient temperature and purified by flash column chromatography on silica gel using a 4:1 (v/v) mixture of hexane and ethyl acetate as eluent to give methyl (3-allyl-4-hydroxyphenyl)methyloxyacetate (435 mg) as a colourless oil; NMR(CDCl3): 3.38(2H,d), 3.75(3H,s), 4.07(2H,s), 4.52(2H,s), 5.12(2H,m), 6.00(1H,m), 6.78(1H,m) and 7.08(2H,m); m/z 236(M).
Reaction SMILES: C([O:3][C:4](=[O:12])[CH:5]([CH2:9][CH:10]=[CH2:11])[CH2:6][CH:7]=[CH2:8])C.[OH-].[Na+]>CO.O>[CH2:6]([CH:5]([CH2:9][CH:10]=[CH2:11])[C:4]([OH:12])=[O:3])[CH:7]=[CH2:8]
Reactant: C=CCC(CC=C)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=CCC(CC=C)C(=O)O
Temperature: 25 °C
Reaction time: 15 h
Yield: 54.2 %

Procedure:
To a stirred solution of 2-allylpent-4-enoic acid ethyl ester (prepared above, 9.0 g, 54 mmol) in 50 mL of methanol and 2 mL of water was added sodium hydroxide (2.5 g, 63 mmol, available from EMD). The solution was stirred for 15 hours, then heated at reflux temperature for 2 hours. After cooling the reaction mixture to room temperature, solvent was removed at reduced pressure. To the residue were added 75 mL of diethyl ether and 10 mL of concentrated hydrochloric acid. The mixture was stirred at room temperature for 10 minutes, then the layers were separated and the diethyl ether layer was dried over magnesium sulfate. After filtration to remove the magnesium sulfate, solvent was removed at reduced pressure to leave 4.1 g of 2-allylpent-4-enoic acid as a colorless oil whose structure was confirmed by NMR analyses.
Reaction SMILES: [CH3:1][C:2]1[C:11]([S:12]([N:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.CCOCC>[Br:18][CH2:1][C:2]1[C:11]([S:12]([N:15]([CH3:17])[CH3:16])(=[O:13])=[O:14])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc(S(=O)(=O)N(C)C)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc(S(=O)(=O)N(C)C)c1CBr

Procedure:
A mixture of 25.7 g of the product from Example 10, 17.8 g of N-bromosuccinimide, and 1.0 g benzoyl peroxide in 350 ml carbon tetrachloride was stirred at reflux temperature for 3.5 hours and then at room temperature overnight. The by-product succinimide was removed by filtration and the filtrate concentrated in vacuo to afford an oil which was dissolved in ether and washed with two portions of water. Drying and evaporation of the ether layer afforded a viscous yellow oil which was shown by 1H NMR analysis to consist of the title compound and unreacted starting material in a ratio of approximately 2:1. This mixture was carried directly on to the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:26](=[O:27])[C:11]3=[CH:12][NH:13][C:14]([CH3:25])=[C:15]([C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19](O)=[O:20])[C:10]3=[N:9]2)=[CH:4][CH:3]=1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>CN(C)C(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:26](=[O:27])[C:11]3=[CH:12][NH:13][C:14]([CH3:25])=[C:15]([C:16]4[CH:24]=[CH:23][CH:22]=[C:18]([C:19]([N:28]5[CH2:32][CH2:31][CH2:30][CH2:29]5)=[O:20])[CH:17]=4)[C:10]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1[nH]cc2c(=O)n(-c3ccc(Cl)cc3)nc-2c1-c1cccc(C(=O)O)c1
Reactant: C1CCNC1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: Cc1[nH]cc2c(=O)n(-c3ccc(Cl)cc3)nc-2c1-c1cccc(C(=O)N2CCCC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.4 %

Procedure:
To a solution of 3-[2-(4-chlorophenyl)-3,5-dihydro-6-methyl-3-oxo-2H-pyrazolo[4,3-c]pyridin-7-yl]benzoic acid (65 mg, 0.171 mmol) in anhydrous N,N-dimethylacetamide (2 ml) was added pyrrolidine (15.7 ml, 0.188 mmol), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (48.0 mg, 0.188 mmol), then, dropwise, anhydrous triethylamine (52.5 ml, 0.376 mmol). The mixture was stirred under nitrogen at room temperature for 18 h. The solvent was removed in vacuo and the residue was purified by flash chromatography (silica gel, 3-5% MeOH/CH2Cl2) to give 63.2 mg (85%) of the title compound as a yellow solid; mp 253-255° C.; 1H NMR (360 MHz, DMSO-d6) δ1.85 (4H, m), 2.29 (3H, s), 3.49 (4H, br q, J 6.9 Hz), 7.41 (2H, d, J 9.0 Hz), 7.55-7.59 (3H, m), 7.66 (1H, s), 8.12 (2H, d, J 9.0 Hz), 8.58 (1H, s), 12.49 (1H, br s); MS (ES+) m/z 433/435 [H]+. Anal. found: C, 63.85; H, 4.96; N, 12.33. C24H21ClN4O2.H2O requires: C, 63.93; H, 5.14; N, 12.42%.
Reaction SMILES: Cl.[S:2]1[C:6]2[CH2:7][CH2:8][CH2:9][C:5]=2[N:4]=[C:3]1[NH2:10].[C:11]12([C:21](Cl)=[O:22])[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C1COCC1>[S:2]1[C:6]2[CH2:7][CH2:8][CH2:9][C:5]=2[N:4]=[C:3]1[NH:10][C:21]([C:11]12[CH2:20][CH:15]3[CH2:14][CH:13]([CH2:19][CH:17]([CH2:16]3)[CH2:18]1)[CH2:12]2)=[O:22]
Reactant: Nc1nc2c(s1)CCC2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1nc2c(s1)CCC2)C12CC3CC(CC(C3)C1)C2

Procedure:
A mixture of 5,6-dihydro-4H-cyclopentathiazole-2-ylamine hydrochloride (400 mg, 2.27 mmol), 1-adamantanecarbonyl chloride (540 mg, 2.72 mmol), 4-dimethylaminopyridine (100 mg, 0.82 mmol) and triethylamine (632 μL, 4.54 mmol) in 30 mL of THF was processed according to the method of Example 1A to afford the title compound: MS (DCI/NH3) m/z 303 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[F:15][C:16]([F:25])([F:24])[C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:12]([NH2:14])=[O:13])=[CH:7][C:8]=1[C:9]([NH:21][C:20]1[CH:22]=[CH:23][C:17]([C:16]([F:15])([F:24])[F:25])=[CH:18][CH:19]=1)=[O:11]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1ccc(C(F)(F)F)cc1

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 4-trifluoromethylaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: [CH2:1]([C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[C:17]([O:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:16]=1)(=[O:21])[CH2:16][CH2:15][CH2:1][CH2:2][CH3:3]
Reactant: CCCCCCCCCCCCCCc1cccc(O)c1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCc1cccc(OC(=O)CCCCC)c1
Reaction time: 24 h
Yield: 195.2 %

Procedure:
To a solution of 10.73 g of 3-tetradecylphenol in 30 ml of pyridine was added 8.02 g of hexanoic anyhydride. The mixture was stirred 24 hours, then diluted with chloroform, washed with water, then saturated aqueous sodium bicarbonate, dried and the solvent evaporated, giving 14.01 g of the desired compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][CH2:17][NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[CH:6][C:5]=1[CH2:28][NH:29][CH2:30][CH2:31][CH3:32])([O-])=O.S1C=CC=C1.O=[Si]=O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][CH2:17][NH:18][S:19]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)(=[O:21])=[O:20])=[CH:6][C:5]=1[CH2:28][NH:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCNCc1cc(-c2ccccc2CCNS(=O)(=O)c2ccccc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=[Si]=O
Solvent: c1ccsc1
Solvent: CO
Product: CCCNCc1cc(-c2ccccc2CCNS(=O)(=O)c2ccccc2)ccc1N

Procedure:
A mixture of N-[2-(4′-nitro-3′-propylaminomethyl-biphenyl-2-yl)-ethyl]-benzenesulfonamide (0.00031 mol) in methanol (50 mL) was hydrogenated with 10% Pd/C (0.100 g) as a catalyst in the presence of thiophene solution (0.5 mL). After uptake of H2 gas (3 equiv.), the reaction mixture was filtered over Dicalite and the filtrate was evaporated to yield the title compound as a residue. (The compound was used without further purification, immediately in the next reaction step.)
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].[Si]([O:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:30](=[O:31])[C:29]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([C:39]4[C:40]([C:45]#[N:46])=[CH:41][CH:42]=[CH:43][CH:44]=4)=[CH:35][CH:34]=3)=[C:28]([CH2:47][CH2:48][CH3:49])[N:27]3[N:50]=[CH:51][N:52]=[C:26]23)=[CH:21][CH:20]=1)[CH3:18])(C(C)(C)C)(C)C>CS(C)=O>[OH:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:30](=[O:31])[C:29]([CH2:32][C:33]3[CH:34]=[CH:35][C:36]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=4[C:45]4[NH:46][C:4](=[O:7])[O:5][N:3]=4)=[CH:37][CH:38]=3)=[C:28]([CH2:47][CH2:48][CH3:49])[N:27]3[N:50]=[CH:51][N:52]=[C:26]23)=[CH:21][CH:20]=1)[CH3:18]
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(C(C)O[Si](C)(C)C(C)(C)C)cc2)c2ncnn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(-c2ccc(C(C)O)cc2)c2ncnn12
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 44.9 %

Procedure:
A mixture of hydroxylammonium chloride (0.83 g), sodium hydrogen carbonate (1.4 g) and dimethyl sulfoxide (10 mL) was stirred at 50° C. for 30 min, 4′-({4-[4-(1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)phenyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.49 g) was added, and the mixture was stirred at 90° C. for 20 hr. After allowing to cool to room temperature, the reaction mixture was extracted with ethyl acetate and water, and the organic layer was washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography, and dissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.16 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.13 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 N hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (15 mL). Tetrabutylammonium fluoride (1 M tetrahydrofuran solution, 2 mL) was added, and the mixture was stirred at 50° C. for 3 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.2 g, 44%).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[CH3:14][NH:15][CH3:16].[I-].[Na+]>C(#N)C.O1CCCC1.C(OCC)(=O)C>[CH3:14][N:15]([CH3:16])[CH2:2][CH2:3][O:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1
Reactant: Fc1ccc(CNOCCCl)cc1
Reactant: CNC
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)CCONCc1ccc(F)cc1
Temperature: 55 °C
Yield: 91 %

Procedure:
A solution of O-(2-chloroethyl)-N-(4-fluorobenzyl)-hydroxylamine (0.327 g, 1.6 mmol) in acetonitrile (2 ml) was treated with a solution of dimethylamine (16 mmol, 8 ml of a 2 M solution in tetrahydrofuran). Sodium iodide (0.06 g) was then added and the resulting mixture was sealed and heated at 55° C. for 16 h. The cooled mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate, brine and dried over anhydrous sodium sulphate. Evaporation of the solvent under reduced pressure yielded 0.310 g (91% yield) of the crude title hydroxylamine as a light brown oil which was used as such for the next step. 1HNMR 400 MHz (C6D6) δ (ppm): 2.19 (6H, s, NCH3), 2.47 (2H, t, J=6.1 Hz, CH2), 3.82 (2H, s, NCH2), 3.84 (2H, t, J=6.1 Hz, CH2), 6.9 (2H, m, aromatics), 7.11 (2H, m, aromatics).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]1[CH2:13][CH2:14][NH:15][CH2:16][CH:8]1[C:7](=[O:17])[NH:6]2.[CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)=[CH2:21].CO.Cl>C(O)C.C(O)(=O)C>[N:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH2:20][CH2:21][N:15]1[CH2:14][CH2:13][N:9]2[C:10]3[C:5]([NH:6][C:7](=[O:17])[CH:8]2[CH2:16]1)=[CH:4][C:3]([C:2]([F:18])([F:1])[F:19])=[CH:12][CH:11]=3
Reactant: O=C1Nc2cc(C(F)(F)F)ccc2N2CCNCC12
Reactant: C=Cc1ccccn1
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Solvent: CCO
Product: O=C1Nc2cc(C(F)(F)F)ccc2N2CCN(CCc3ccccn3)CC12
Yield: 71 %

Procedure:
A solution of 8.5 g. (0.03 mole) of 2,3,4,4a-tetrahydro-8-trifluoromethyl-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one and 17.5 g. (0.16 mole) of 2-vinylpyridine in 250 ml. of methanol containing 7 ml. acetic acid was heated under reflux for 20 hours. The reaction mixture was cooled, and the solvent was removed under reduced pressure. The residue was precipitated with 1 l. of water. The product was filtered and recrystallized from methanol-water to yield 10.1 g. of free base. 4.5 G. of this free base was dissolved in 150 ml. of absolute ethanol and treated with dry hydrogen chloride saturated ether solution. The product hydrochloride was filtered and recrystallized two times from methanol-ether to give 4 g. (71%) of the title compound as the dihydrochloride salt, m.p. 194°-196° C.
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:14]2[CH:15]=[C:16]([CH:27]=[CH:28][CH:29]=2)[NH:17][S:18]([CH2:21][C:22]([O:24]CC)=O)(=[O:20])=[O:19])[CH3:13])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH3:30]>>[CH2:1]([N:7]1[CH2:8][CH:9]2[CH:11]([C:10]2([C:14]2[CH:15]=[C:16]([CH:27]=[CH:28][CH:29]=2)[NH:17][S:18]([CH2:21][C:22]([NH2:30])=[O:24])(=[O:19])=[O:20])[CH3:13])[CH2:12]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: N
Reactant: CCCCCCN1CC2C(C1)C2(C)c1cccc(NS(=O)(=O)CC(=O)OCC)c1
Product: CCCCCCN1CC2C(C1)C2(C)c1cccc(NS(=O)(=O)CC(N)=O)c1
Yield: 53.5 %

Procedure:
A solution of ethyl 2-{[3-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)anilino]sulfonyl}acetate (Example 41, 0.13 g, 0.38 mmol) in ammonia (2M in methanol, 3.0 ml, 1.5 mmol) was heated to 60° C. for 12 h in a sealed tube. The mixture was cooled, concentrated in vacuo and then purified by chromatography on silica gel eluting with methanol:ethyl acetate (2:98) to give the product as a pale yellow foam (80 mg, 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(Cl)(=O)C(Cl)=O.[N+:21]([C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1)([O-:23])=[O:22].C(N(CC)CC)C>CN(C=O)C.ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][C:27]1[CH:28]=[CH:29][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][CH:26]=1)=[O:5]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c(Cl)c1
Reaction time: 1 h

Procedure:
A 200-mL round bottom flask was fitted with thermometer, magnetic stirrer, and reflux condenser with nitrogen bypass. The flask was charged with 0.94 g (4 mmol) of 2-chloro-4-(methylsulfonyl)benzoic acid, 2 drops of DMF, and 20 mL of dichloromethane. Oxalyl chloride (0.56 g, 4.4 mmol) was added dropwise and the mixture was stirred for 1 hr. A solution consisting of 0.62 g (4 mmol) of 4-nitrophenol, 0.44 g (4.4 mmol) of triethylamine and 5 mL of dichloromethane was added slowly. The mixture was stirred for 1 hr, diluted with 100 mL of dichloromethane, washed twice with 100 mL portions of dilute aqueous sodium bicarbonate, once with water, dried over magnesium sulfate, filtered, and volatiles removed under reduced pressure to give the title product as 1.30 g of off-white solid, m.p. 123-125° C. 1H NMR (CDCl3): δ 3.14 (s, 3), 7.48 (m, 2), 8.00 (m, 1), 8.14 (m, 1), 8.21 (m, 1), 8.36 (m, 2).
Reaction SMILES: [OH:1][C:2]1[C:7]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([O:17][CH3:18])=[C:12]([CH3:19])[CH:11]=2)=[C:6]([OH:21])[N:5]=[C:4]([S-:22])[N:3]=1.[Na+].[OH-].[Na+].I[CH3:27].Cl>O.CN1CCCC1=O>[OH:21][C:6]1[C:7]([NH:8][C:9](=[O:20])[C:10]2[CH:11]=[C:12]([CH3:19])[C:13]([O:17][CH3:18])=[C:14]([CH3:16])[CH:15]=2)=[C:2]([OH:1])[N:3]=[C:4]([S:22][CH3:27])[N:5]=1
Reactant: COc1c(C)cc(C(=O)Nc2c(O)nc([S-])nc2O)cc1C
Reactant: CI
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1c(C)cc(C(=O)Nc2c(O)nc(SC)nc2O)cc1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
19.1 g of sodium 4,6-dihydroxy-5-(4-methoxy-3,5-dimethyl-benzoylamino)-pyrimidine-2-thiolate in 190 ml of water and 80 ml of N-methylpyrrolidin-2-one were cooled to 0° C. With cooling, 5.9 g of sodium hydroxide were added, and the mixture was then stirred at 0° C. for 30 min. Then a solution of 3.7 ml of iodomethane in 4.3 ml of N-methylpyrrolidin-2-one was added. After completion of the reaction (2 h), the mixture was acidified with concentrated hydrochloric acid. The resulting precipitate was isolated by suction, washed with water and dried in vacuo. 10.1 g of the title compound were obtained.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][C:7]([NH:11][CH2:12][C:13]1[CH:14]=[C:15]2[C:24](=[C:25]3[C:30]=1[CH:29]=[CH:28][CH:27]=[CH:26]3)[CH:23]=[CH:22][C:21]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=1)([CH3:10])[CH2:8][OH:9])(=[O:4])=[O:3].[OH-:31].[Na+].[CH3:33]O.O>>[CH:20]1[C:21]2[CH:22]=[CH:23][C:24]3[C:15](=[CH:14][C:13]([CH2:12][NH:11][C:7]([CH3:10])([CH2:6][OH:5])[CH2:8][OH:9])=[C:30]4[C:25]=3[CH:26]=[CH:27][CH:28]=[CH:29]4)[C:16]=2[CH:17]=[CH:18][CH:19]=1.[OH:31][CH2:33][CH2:1][S:2]([O-:5])(=[O:3])=[O:4]
Reactant: [OH-]
Reactant: CO
Reactant: CC(CO)(COS(C)(=O)=O)NCc1cc2c3ccccc3ccc2c2ccccc12
Agent: [Na+]
Solvent: O
Product: CC(CO)(CO)NCc1cc2c3ccccc3ccc2c2ccccc12
Product: O=S(=O)([O-])CCO
Yield: 70.4 %

Procedure:
2-((6-chrysenylmethyl)amino)-2-methyl-1,3-propanediol methanesulfonate (1C, 10.0 g, 26.63 mmol) was neutralized with 1N NaOH (30 mL) in CH3OH/H2O (200/800 mL) as in procedure 1D. The white solid which formed was filtered, washed successively with warm H2O (3×500 mL), CH3OH (200 mL), and abs. Et2O (2×500 mL), sucked semi-dry and then resuspended in CH3OH (500 mL). To this was added a 0.43M aqueous solution of 2-hydroxyethanesulfonic acid (30 mL). Slight warming gave a solution which was then filtered. The solvent was removed by rotary evaporation to give a wet white solid. This was triturated with dry Et2O, filtered, and recrystallized 3× from EtOH/Et2O to give 8.8 g (70.4%) of 2-((6-chrysenylmethyl)amino)-2-methyl-1,3-propanediol 2-hydroxyethanesulfonate, mp 212°-213°, (C, H, N, S).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:20]2[CH:30]=[CH:29][C:23]([O:24][CH2:25][C:26]([OH:28])=O)=[C:22]([CH3:31])[CH:21]=2)([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:11][C:10]=1[CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:34][N:35](C)[O:36][CH3:37]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:20]2[CH:30]=[CH:29][C:23]([O:24][CH2:25][C:26]([N:35]([O:36][CH3:37])[CH3:34])=[O:28])=[C:22]([CH3:31])[CH:21]=2)([CH2:16][CH3:17])[CH2:18][CH3:19])=[CH:11][C:10]=1[CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CON(C)C
Reactant: CCC(CC)(c1ccc(OCC(=O)O)c(C)c1)c1ccc(OCc2ccccc2)c(C)c1
Agent: Cl
Product: CCC(CC)(c1ccc(OCC(=O)N(C)OC)c(C)c1)c1ccc(OCc2ccccc2)c(C)c1
Yield: 77.2 %

Procedure:
Using an analogous procedure to Example 1J, {4-[1-(4-benzyloxy-3-methyl-phenyl)-1-ethyl-propyl]-2-methyl-phenoxy}-acetic acid (1.46 g, 3.38 mmol) and N,O-dimethylmethylhydroxyamine hydrochloride (363 mg, 3.72 mmol) give the title compound (1.24 g, 2.61 mmol, 77%).