Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[CH:8]1[CH2:13][CH2:12][N:11](C(OCC2C=CC=CC=2)=O)[CH2:10][CH2:9]1>C(O)C.[Pd]>[NH:11]1[CH2:12][CH2:13][CH:8]([N:3]2[CH2:4][CH2:5][O:6][CH2:7][C:2]2=[O:1])[CH2:9][CH2:10]1
Reactant: O=C(OCc1ccccc1)N1CCC(N2CCOCC2=O)CC1
Agent: [Pd]
Solvent: CCO
Product: O=C1COCCN1C1CCNCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
Benzyl 4-(3-oxo-4-morpholinyl)piperidin-1-carboxylate (3.8 g) obtained in Example 7b) was dissolved in ethanol (50 mL), 10% palladium on carbon (containing 50% water; 0.38 g) was added thereto, and the mixture was stirred at room temperature for 15 hours under a hydrogen atmosphere. The reaction mixture was filtered and the solvent was distilled off under reduced pressure to obtain the title compound (2.2 g, quantitative) as a light yellow oil.
Reaction SMILES: [CH2:1]([C:4]([C@@H:6]([C@H:8]([C@H:19]([C@@H:21]([CH2:23][OH:24])[OH:22])[OH:20])[O:9][CH:10](OC(C)(C)C)[C:11]([OH:13])=[O:12])[OH:7])=[O:5])[CH:2]=[CH2:3]>[OH-].[Na+]>[CH2:1]([C:4]([C@@H:6]([C@H:8]([C@H:19]([C@@H:21]([CH2:23][OH:24])[OH:22])[OH:20])[O:9][CH2:10][C:11]([OH:13])=[O:12])[OH:7])=[O:5])[CH:2]=[CH2:3]
Reactant: C=CCC(=O)[C@H](O)[C@@H](OC(OC(C)(C)C)C(=O)O)[C@@H](O)[C@H](O)CO
Agent: [Na+]
Agent: [OH-]
Product: C=CCC(=O)[C@H](O)[C@@H](OCC(=O)O)[C@@H](O)[C@H](O)CO
Reaction time: 2 h
Yield: 113 %

Procedure:
Compound 7 (7.8 g) was dissolved in 2N NaOH solution and stirred for 2 hr. The reaction mixture was acidified with Dowex-H resin and the resin was removed by filtration. The filtrate was lyophilized to give 1-C-allyl-3-O-carboxymethylgalactose (7.0 g). 1N NMR (CD3OD): δ, 2.38-2.42, 2H; 3.28-3.31, m, 1H; 3.44-3.47, dd, 2H; 3.63-3.67,m, 2H; 3.98-4.02, m, 1H; 4.11-4.15,m, 1H; 4.22-4.25,m, 1H; 4.95-5.00, and 5.10-5.15,dd, 2H, CH2CH═CH2; 5.75-5.85, m, 1H, CH2CH═CH2: 13C NMR (CD3OD): 176.52 (COOH); 136.67, 116.89, 81.98, 79.79, 76.00, 73.50, 68.60, 68.56, 67.59, 62.05, 30.70: [α]D=+66.82 (c 0.214, methanol).
Reaction SMILES: C([S:4][CH:5]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6]1)(=O)C.C(=O)([O-])[O-].[K+].[K+].Cl>CO>[SH:4][CH:5]1[CH2:6][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8]1
Reactant: CC(=O)SC1CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(S)C1
Temperature: 50 °C
Reaction time: 2 h
Yield: 101.3 %

Procedure:
Mixture of tert-butyl 3-(acetylthio)azetidine-1-carboxylate (STEP C, 700 mg, 3.03 mmol), methanol (10 mL) and potassium carbonate (836 mg, 6.05 mol) was stirred at 50° C. for 2 h and cooled to room temperature. To the reaction mixture was added 2 mol/L hydrochloric acid for solution acidified (pH <4). The resulting solution was extracted with diethyl ether (30 mL×2). The organic layer was combined and washed with water (30 mL×2) and brine (30 mL). The extract was dried with magnesium sulfate and concentrated. Resulting crude product (581 mg) was used without further purification.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:20]=[CH:19][C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]=1[N+:21]([O-:23])=[O:22].S(OC)(O[CH3:28])(=O)=O.O>CN(C=O)C>[CH3:28][N:8]([S:9]([C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1)(=[O:11])=[O:10])[C:7]1[CH:19]=[CH:20][C:4]([CH3:3])=[C:5]([N+:21]([O-:23])=[O:22])[CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(C)c([N+](=O)[O-])c2)cc1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N(C)c2ccc(C)c([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Yield: 75.6 %

Procedure:
To a suspension of sodium hydride (60%, 0.14 g (3.50 mmol)) in DMF (3.0 ml), 4′-methyl-3′-nitro-p-toluenesulfonanilide (1.00 g (3.26 mmol)) was added with stirring at room temperature. To the resulting mixture, after 15 minutes' stirring at room temperature, dimethyl sulfate (0.34 ml (3.56 mmol)) was added dropwise. After one hours' stirring at room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution, successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. Diethyl ether was added to the residue, and the solid separated was filtered and washed to give 0.79 g (76%) of the title compound as pale yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([O:9]C)=[CH:4][C:3]=1[C:11](=O)[CH3:12].[C:14](O)(=O)C>[Zn]>[CH2:11]([C:3]1[CH:4]=[C:5]([OH:9])[C:6]([O:8][CH3:14])=[CH:7][C:2]=1[F:1])[CH3:12]
Reactant: CC(=O)O
Reactant: COc1cc(C(C)=O)c(F)cc1O
Agent: [Zn]
Product: CCc1cc(O)c(OC)cc1F
Reaction time: 8 h
Yield: 97 %

Procedure:
A solution of 1-(2-fluoro-4-hydroxy-5-methoxyphenyl)ethanone (18.0 g; 97.7 mmol; 1 eq; which may be prepared as hereinbefore described for D1) in glacial acetic acid (800 mL) is stirred at 70° C. before adding added zinc dust (63.9 g; 977 mmol; 10 eq). The resulting grey heterogeneous mixture is then heated at reflux and stirred overnight using a mechanical stirrer. After this period, zinc has aggregated and conversion rate reaches 90% according to the 1H NMR analysis of a crude aliquot. Therefore, the zinc metal is removed by filtration on a fritted glass and fresh zinc dust (6.4 g; 98 mmol) is added to the resulting limpid yellow filtrate. The solution is heated at reflux overnight until completion of the reaction. The solution is filtered on a fritted glass and basified until pH 11-12 is reached with a saturated aqueous solution of potassium carbonate (1.5 L) and with additional solid potassium carbonate if needed. The resulting aqueous layer is then extracted with ethyl acetate (1.0 L), dried over sodium sulphate or by azeotropic toluene distillation, filtered and concentrated under vacuum to afford the pure title compound (16.1 g; 94.7 mmol; 97%) as a pale yellow oil. It should be noted that the title compound is a volatile product and should be kept in the fridge under Argon away from light (darkens with oxygen and/or UV exposure).
Reaction SMILES: CO[C:3]([CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3([CH3:19])[O:18]CCO3)[CH:12]=2)[N:7]([CH2:20][CH3:21])[C:6]1=[O:22])=[O:4].[NH2:23][C:24]1[CH:25]=[C:26]([CH:37]=[CH:38][CH:39]=1)[C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=1)=[O:28]>>[C:33]1([CH3:36])[CH:32]=[CH:31][C:30]([NH:29][C:27]([C:26]2[CH:25]=[C:24]([NH:23][C:3]([CH:5]3[C:13]4[C:8](=[CH:9][CH:10]=[C:11]([C:14](=[O:18])[CH3:19])[CH:12]=4)[N:7]([CH2:20][CH3:21])[C:6]3=[O:22])=[O:4])[CH:39]=[CH:38][CH:37]=2)=[O:28])=[CH:35][CH:34]=1
Reactant: Cc1ccc(NC(=O)c2cccc(N)c2)cc1
Reactant: CCN1C(=O)C(C(=O)OC)c2cc(C3(C)OCCO3)ccc21
Product: CCN1C(=O)C(C(=O)Nc2cccc(C(=O)Nc3ccc(C)cc3)c2)c2cc(C(C)=O)ccc21

Procedure:
Prepared as in Example 1 from 1-ethyl-5-(2-methyl-[1,3]dioxolan-2-yl)-2-oxo-2,3-dihydro-1H-indole-3-carboxylic acid methyl ester and 3-amino-N-(p-tolyl)-benzamide. Purified by trituration in ethyl acetate hexanes. mp 168 dec.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][C:13]([NH:17][CH2:18][CH2:19][OH:20])=[N:14][CH:15]=3)[N:10]([CH3:21])[N:9]=2)=[CH:4][CH:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:24]=1[N:33]=[C:34]=[O:35]>>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:24]=1[NH:33][C:34](=[O:35])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][C:13]([NH:17][CH2:18][CH2:19][O:20][C:34](=[O:35])[NH:33][C:24]4[CH:25]=[C:26]([C:29]([F:31])([F:32])[F:30])[CH:27]=[CH:28][C:23]=4[F:22])=[N:14][CH:15]=3)[N:10]([CH3:21])[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: Cn1nc(-c2ccc(N)cc2)c2cnc(NCCO)nc21
Product: Cn1nc(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)c2cnc(NCCOC(=O)Nc3cc(C(F)(F)F)ccc3F)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-[3-(4-amino-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)-ethanol (25.4 mg, 0.1 mmol) in N-methylpyrrolidinine (0.5 mL) was added 2-fluoro-5-trifluoromethyl-phenyl isocyanate (22 mg, 0.11 mmol, 2.1 eq). The reaction mixture was stirred for 1 hour at room temperature while monitored by TLC. The mixture was then evaporated and the crude product was purified by preparative HPLC to give pure (2-fluoro-5-trifluoromethyl-phenyl)-carbamic acid 2-(3-{4-[3-(2-fluoro-5-trifluoromethyl-phenyl)-ureido]-phenyl}-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)-ethyl ester; 1H-NMR (DMSO): δ 3.71 (m, 2H), 3.81 (s, 3H), 4.34 (m, 2H), 7.41–7.60 (m, 4H), 7.92 (d, 2H, J=8.4 Hz), 8.11 (br s, 1H), 8.63 (s, 1H), 8.94 (s, 1 H), 9.15 (s, 1H), 9.36 (br s, 1H), 9.75 (br s, 1H); LC/MS (m/e)=695.2 (MH+).
Reaction SMILES: Cl[C:2](OC(Cl)(Cl)Cl)=[O:3].[F:9][C:10]1[CH:16]=[C:15]([Cl:17])[C:14]([O:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:13][C:11]=1[NH2:12]>C(OCC)(=O)C>[F:9][C:10]1[CH:16]=[C:15]([Cl:17])[C:14]([O:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:13][C:11]=1[N:12]=[C:2]=[O:3]
Reactant: Nc1cc(OC2CCCC2)c(Cl)cc1F
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C=Nc1cc(OC2CCCC2)c(Cl)cc1F

Procedure:
An ethyl acetate solution (5 ml) of trichloromethyl chloroformate (2.00 g, 10.0 mmol) was gradually dropwise added to an ethyl acetate solution (25 ml) of 2-fluoro-4-chloro-5-cyclopentyloxyaniline (2.30 g, 10.0 mmol) at room temperature. After addition, the whole was heated to remove ethyl acetate therefrom by distillation. As a result, 2-fluoro-4-chloro-5-cyclopentyloxyphenylisocyanate was obtained almost quantitatively.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:10]=2)=[CH:5][CH:4]=1)=O.[S:20]1[CH2:24][C:23](=[O:25])[NH:22][C:21]1=[O:26]>>[O:26]=[C:21]1[NH:22][C:23](=[O:25])[C:24](=[CH:1][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:10]=3)=[CH:5][CH:4]=2)[S:20]1
Reactant: O=C1CSC(=O)N1
Reactant: CCOC(=O)c1cccc(-c2ccc(C=O)cc2)c1
Product: CCOC(=O)c1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1
Yield: 80 %

Procedure:
In a manner similar to that of Example 1(f), by reacting 11.7 g (46 mmol) of ethyl 4′-formylbiphenyl-3-carboxylate with 5.4 g (46 mmol) of 2,4-thiazolidine dione, 13 g (83%) of the expected product are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[C:9]2[C:5]([C:6]([CH3:14])=[N:7][NH:8]2)=[CH:4][C:3]=1[Cl:15].[Cl:16][C:17]1[C:18]([N:23]2[C:27]([C:28](O)=O)=[CH:26][C:25]([C:31]([F:34])([F:33])[F:32])=[N:24]2)=[N:19][CH:20]=[CH:21][CH:22]=1.N1C=CC=CC=1.CS(Cl)(=O)=O>O1CCCC1>[Cl:15][C:3]1[CH:4]=[C:5]2[C:6]([CH3:14])=[N:7][NH:8][C:9]2=[C:10]2[C:2]=1[N:1]=[C:28]([C:27]1[N:23]([C:18]3[C:17]([Cl:16])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:24]=[C:25]([C:31]([F:34])([F:32])[F:33])[CH:26]=1)[O:12][C:11]2=[O:13]
Reactant: Cc1n[nH]c2c(C(=O)O)c(N)c(Cl)cc12
Reactant: O=C(O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1n[nH]c2c1cc(Cl)c1nc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)oc(=O)c12
Temperature: 0 °C
Reaction time: 48 h
Yield: 70.3 %

Procedure:
To a suspension of 540 mg (2.39 mmol) of 6-amino-5-chloro-3-methyl-1H-indazole-7-carboxylic acid in 22 mL of anhydrous tetrahydrofuran at 10° C., is added 698 mg (2.39 mmol) of 2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid followed by 963 μL (11.97 mmol) of pyridine. Then the suspension is cooled to 0° C. and 748 μL (9.57 mmol) of methanesulfonyl chloride are added dropwise. The mixture is stirred at ambient temperature for 48 hours. Then the solvent is evaporated and the residue is taken-up with acetone. After filtration, the filtrate is evaporated in vacuo. The residue obtained is purified by flash chromatography (SiO2, heptane/ethyl acetate 1:2) and affords 810 mg (1.68 mmol, 70%) of the product as a solid; LC/MS:481/483 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[C:30]([O:31][CH:32]3[CH2:36][CH2:35][O:34][CH2:33]3)=[CH:29][CH:28]=[CH:27][C:26]=2[F:37])[C:21]([Cl:38])=[CH:20][N:19]=1>>[Cl:38][C:21]1[C:22]([NH:24][C:25]2[C:30]([O:31][CH:32]3[CH2:36][CH2:35][O:34][CH2:33]3)=[CH:29][CH:28]=[CH:27][C:26]=2[F:37])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: Fc1cccc(OC2CCOC2)c1Nc1nc(Cl)ncc1Cl
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4c(F)cccc4OC4CCOC4)n3)cc2CC1

Procedure:
Title compound was prepared from 3-(2-Methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and (2,5-Dichloro-pyrimidin-4-yl)-[2-fluoro-6-(tetrahydro-furan-3-yloxy)-phenyl]-amine in an analogous manner to Example 1221d. Title compound was isolated as a white solid (60 mg, 42%). HPLC purity 99%, LCMS=528.17 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 11.79 (s, 1H), 7.92 (s, 1H), 7.42-7.38 (m, 2H), 7.24-7.19 (m, 2H), 6.95-6.91 (m, 2H), 6.77 (d, J=8.4 Hz, 1H), 4.92 (s, 1H), 3.87-3.80 (m, 8H), 3.45-3.40 (m, 7H), 2.90-2.80 (m, 3H), 2.65-2.55 (m, 1H), 2.30-2.24 (m, 1H), 2.22-2.10 m, 1H).
Reaction SMILES: C(OC([NH:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]([CH3:31])[CH:23]=2)=[O:21])[CH2:11]1)=O)(C)(C)C.[NH2:32][C:33]1[C:41]([Cl:42])=[CH:40][C:36]([C:37]([OH:39])=O)=[C:35]([O:43][CH3:44])[CH:34]=1>>[NH2:32][C:33]1[C:41]([Cl:42])=[CH:40][C:36]([C:37]([NH:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]([CH3:31])[CH:23]=3)=[O:21])[CH2:11]2)=[O:39])=[C:35]([O:43][CH3:44])[CH:34]=1
Reactant: Cn1cc(C(=O)NCCCCN2CC[C@@H](CNC(=O)OC(C)(C)C)C2)c2ccccc21
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Product: COc1cc(N)c(Cl)cc1C(=O)NC[C@@H]1CCN(CCCCNC(=O)c2cn(C)c3ccccc23)C1

Procedure:
N-(4-((3S)-3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)-butyl)-1-methyl-1 H-indole-3-carboxamide (1.94 g) as starting compound was reacted and treated in the same manner as in Example 67 using 4-amino-5-chloro-2-methoxybenzoic acid (0.67 g) to give N-(4-((3S)-3-(4-amino-5-chloro-2-methoxybenzoylaminomethyl)pyrrolidin-1-yl)butyl)-1-methyl-1 H-indole-3-carboxamide.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1.B([C:19]1[N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:21]=[CH:22][CH:23]=1)(O)O>>[CH3:13][C:7]1([CH3:14])[C:6]2[CH:15]=[C:2]([C:19]3[N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:21]=[CH:22][CH:23]=3)[CH:3]=[CH:4][C:5]=2[NH:11][C:10](=[O:12])[CH2:9][O:8]1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: CC1(C)OCC(=O)Nc2ccc(Br)cc21
Product: CC(C)(C)OC(=O)n1cccc1-c1ccc2c(c1)C(C)(C)OCC(=O)N2

Procedure:
tert-Butyl 2-(5,5-dimethyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-7-yl)-1H-pyrrole-1-carboxylate was prepared from 7-bromo-5,5-dimethyl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 2-borono-1H-pyrrole-1-carboxylic acid, 1-tert-butyl ester generally according to the procedure described in example 1. 1H-NMR (DMSO-d6) δ 9.96 (s, 1H), 7.32 (m, 1H), 7.23 (m, 1H), 7.15 (d, J=8.24 Hz, 1H), 7.07 (d, J=8.3 Hz, 1H), 6.25 (m, 2H), 4.23 (s, 2H), 1.55 (s, 6H), 1.36 (s, 9H); MS (ES) m/z 357 ([M+H]+, 100%).
Reaction SMILES: ClCC1C=CN=CN=1.Cl[CH2:10][C:11]1[CH:16]=[N:15][CH:14]=[CH:13][N:12]=1.[C:17]1(=[O:27])[NH:21][C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.[K]>>[N:12]1[CH:13]=[CH:14][N:15]=[CH:16][C:11]=1[CH2:10][N:21]1[C:17](=[O:27])[C:18]2[C:19](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:20]1=[O:22]
Reactant: ClCc1cnccn1
Reactant: O=C1NC(=O)c2ccccc21
Agent: ClCc1ccncn1
Agent: [K]
Product: O=C1c2ccccc2C(=O)N1Cc1cnccn1
Yield: 46 %

Procedure:
Following the procedure as described in step A of Preparation 14, making variations as required to replace 4-(chloromethyl)pyrimidine with 2-(chloromethyl)pyrazine (prepared according to R. W. Carling, et al., J. Med. Chem., (2004), Vol. 47, pp. 1807-1822) to react with potassium phthalimide, 2-(pyrazin-2-ylmethyl)isoindoline-1,3-dione was obtained as a colorless solid in 46% yield: mp 141-143° C.; 1H NMR (300 MHz, CDCl3) δ 8.65 (s, 1H), 8.47 (s, 2H), 7.90-7.87 (m, 2H), 7.76-7.73 (m, 2H), 5.05 (s, 2H); MS (ES+) m/z 240.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14]S(C2C=CC=CC=2)(=O)=O)=[C:6]([CH:13]=1)/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].Br.Br[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[N:30]=1)=[O:28]>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:13]=2)[NH:14][C:26]=1[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[N:30]=1)=[O:28]
Reactant: Cc1cccc(C(=O)CBr)n1
Reactant: COC(=O)/C=C/c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Agent: Br
Product: COC(=O)Cc1c(C(=O)c2cccc(C)n2)[nH]c2ccc(Cl)cc12

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 8 (Method A) from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (Example 36, step 3) and 2-bromoacetyl-6-methylpyridine hydrobromide (H. Erlenmeyer, J. Jenni, and B. Prijs, J. Med. Pharm. Chem., 1961, 3, 561-566).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][NH:13][CH3:14])[CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.[C:15]1([C:25](Cl)=[O:26])[C:24]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=2[CH:18]=[CH:17][CH:16]=1.O>C(Cl)Cl.[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:9][CH2:10][OH:11])[CH2:12][N:13]([CH3:14])[C:25]([C:15]2[C:24]3[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=3[CH:18]=[CH:17][CH:16]=2)=[O:26])=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1cccc2c1CCCC2
Reactant: CNCC(CCO)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CN(CC(CCO)c1ccc(Cl)cc1)C(=O)c1cccc2c1CCCC2
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 90.4 %

Procedure:
To a stirred cooled (0° C.) mixture of 3-(4-chloropenyl)-N-methyl-4-amino-1-butanol (0.706 g, 3.30 mmol) in DCM (25 mL) and 1N NaOH (4.13 mL) was added dropwise a solution of 5,6,7,8-tetrahydro-1-naphthalenecarbonyl chloride (0.643 g, 3.30 mmol) in DCM (10 mL). The mixture was stirred at 0° C. for 2.5 h, H2O and DCM were added and the mixture was extracted with DCM (2×20 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. Purification by chromatography (0%, 50%, 100% EtOAc in Et2O) provided the title compound (1.11 g, 90%) as a solid. MS m/z 372 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[C:19](Cl)[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[O:29]([CH2:36][C:37]#[C:38][CH2:39][OH:40])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C1(OCC#C)C=CC=CC=1.C=O.[H-].[Na+]>C1COCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[C:19]([O:40][CH2:39][C:38]#[C:37][CH2:36][O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-c2c(Cl)ncnc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: OCC#CCOc1ccccc1
Agent: C#CCOc1ccccc1
Agent: C=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCC#CCOc2ccccc2)cc1
Reaction time: 4 h
Yield: 41.1 %

Procedure:
To a mixture of 282 mg of 4-tert.-butyl-N-[6-chloro-5-(p-tolyl)4-pyrimidinyl]-benzene sulfonamide (Example 12c) and 1.10 g of 4-phenoxy-2-butyn-1-ol (prepared starting from phenyl-propargylether and para-formaldehyde following the procedure given in J. Chem. Soc. Perkin Trans. 1, 1991, 1721-1727) in 15 ml THF was added 271 mg of 55% NaH in mineral oil. The suspension was stirred for 4 h at reflux. The reaction mixture was cooled, diluted with 100 ml 10% aqueous citric acid and extracted 4 times with 50 ml of ethyl acetate. The combined organic phases were washed with water, dried over MgSO4 and evaporated. The crude product was purified by column chromatography on silica gel eluting with heptane:ethyl acetate 1:1 and precipitated from diethyl ether to give 151 mg of 4-tert.-butyl-N-[6-(4-phenoxy-2-butynyloxy)-5-(p-tolyl)4-pyrimidinyl]-benzene sulfonamide as a white powder. LC-MS: tR=6.34 min, [M+1]+=542.48, [M−1]−=540.15.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[C:16](=[CH:18][CH:19]=[C:20]([OH:36])[C:21]=1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])[OH:17].C(O)C.[OH-].[Na+:42].O>>[Na+:42].[C:20]1([C:21]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O-:35])=[O:34])=[C:15]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([O-:37])=[O:2])[C:16](=[CH:18][CH:19]=1)[OH:17])[OH:36].[Na+:42]
Reactant: COC(=O)CCCCCCCCCCCc1c(O)ccc(O)c1CCCCCCCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C([O-])CCCCCCCCCCCc1c(O)ccc(O)c1CCCCCCCCCCCC(=O)[O-]

Procedure:
Hydroquinone bislauric acid methyl ester prepared in Example 1 (2.8 g) was stirred in sodium hydroxide ethanol/water solution at room temperature for 12 hours. At first, the solution was cloudy. By the end of the reaction, the solution was clear. The crude product was extracted with n-butanol twice. After the solvent was rotevaporated, the remaining material was washed with ethanol. The white solid material was collected by filtration. NMR results showed that the material is the desired product. ##STR23##
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH2:26][CH2:27][C@H:28]([N:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[C:29]([O:31][CH3:32])=[O:30]>ClCCl>[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:26][CH2:27][C@H:28]([N:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[C:29]([O:31][CH3:32])=[O:30])(=[O:24])=[O:23])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)[C@H](CN)N1CCCCC1
Reactant: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CNS(=O)(=O)c1ccc(OCc2ccccc2)cc1)N1CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.6 %

Procedure:
1.2 ml (8.5 mmol) of triethylamine and then 800 mg (2.8 mmol) of 4-benzyloxybenzenesulfonyl chloride in 8 ml of dichloromethane are added to a solution of 670 mg (2.6 mmol) of methyl(S)-3-amino-2-piperidin-1-ylpropanoate in 10 ml of dichloromethane. The reaction medium is stirred at ambient temperature for 18 h, hydrolyzed and then diluted with dichloromethane. The product is extracted with dichloromethane. The organic phase is washed with water and then with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue obtained is purified by chromatography on silica gel, elution being carried out with a 70/30 heptane/ethyl acetate mixture. 940 mg (85%) of methyl(S)-3-(4-benzyloxybenzenesulfonylamino)-2-piperidin-1-ylpropanoate are obtained in the form of a white solid.