Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:30])/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)[C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=CC=1)([O-])=O.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][CH2:38][CH2:39][CH2:40][NH2:41])[CH:32]=1>O1CCCC1>[CH3:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]([C:23]2[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=2)=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:41][CH2:40][CH2:39][CH2:38][CH2:37][C:33]2[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=2)=[O:30])=[CH:21][CH:20]=1
Reactant: NCCCCc1cccnc1
Reactant: Cc1ccc(C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccc(C)cc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(C(=C/C=C/C(=O)NCCCCc2cccnc2)c2ccc(C)cc2)cc1
Yield: 72 %

Procedure:
As before in Example 134, a solution of (E)-5,5-bis(4-methylphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester (2.5 g) and 3-pyridinebutanamine (1.08 g) in tetrahydrofuran (25 mL) was stirred overnight at room temperature and then worked up in the usual way. The amide was purified by HPLC (ethyl acetate) and then was crystallized two times from ether to give 1.85 g of (E)-5,5-bis(4-methylphenyl)-N-[4-(3-pyridinyl)butyl]-2,4-pentadienamide, mp 144.5°-145.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:4][C:3]=1[NH:21][C:22]([C:24]1[C:25]([NH2:32])=[N:26][C:27]([S:30][CH3:31])=[N:28][CH:29]=1)=[O:23].C(N(C(C)C)CC)(C)C.Cl[C:43](Cl)([O:45]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCOCC1.CCOC(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:18])([F:19])[F:17])[CH:11]=2)=[CH:4][C:3]=1[N:21]1[C:22](=[O:23])[C:24]2[C:25](=[N:26][C:27]([S:30][CH3:31])=[N:28][CH:29]=2)[NH:32][C:43]1=[O:45]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CSc1ncc(C(=O)Nc2cc(NC(=O)c3cccc(C(F)(F)F)c3)ccc2C)c(N)n1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncc2c(=O)n(-c3cc(NC(=O)c4cccc(C(F)(F)F)c4)ccc3C)c(=O)[nH]c2n1
Temperature: 100 °C
Reaction time: 12 h
Yield: 54.9 %

Procedure:
To a stirred solution of 4-amino-2-methylsulfanyl-pyrimidine-5-carboxylic acid [2-methyl-5-(3-trifluoromethyl-benzoylamino)-phenyl]-amide (286 mg, 0.62 mmol) and diisopropylethylamine (864 μL, 4.96 mmol) in dioxane (10 mL) is added a solution of triphosgene (184 mg, 0.62 mmol) in dioxane (2 mL) at 0° C., and the mixture is stirred for 12 h at 100° C. The reaction mixture is diluted with EtOAc (50 mL), and washed with saturated NaHCO3 solution. The organic layer is dried over MgSO4, filtered, concentrated under reduced pressure, and crystallized from MeOH to give N-[4-Methyl-3-(7-methylsulfanyl-2,4-dioxo-1,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-3-yl)-phenyl]-3-trifluoromethyl-benzamide (166 mg, 55%) as a white crystalline solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([O:14][CH2:15][CH3:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].Br[CH2:19][CH:20]=[C:21]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH2:25][CH2:24][C:23]2[CH:32]=[CH:33][CH:34]=[CH:35][C:22]1=2.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C1C=CC=CC=1>[CH:32]1[C:23]2[CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:21](=[CH:20][CH2:19][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][CH:5]([O:14][CH2:15][CH3:16])[C:4]([O:3][CH2:1][CH3:2])=[O:17])=[CH:12][CH:11]=3)[C:22]=2[CH:35]=[CH:34][CH:33]=1
Reactant: BrCC=C1c2ccccc2CCc2ccccc21
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CCOC(=O)C(Cc1ccc(OCC=C2c3ccccc3CCc3ccccc32)cc1)OCC
Temperature: 100 °C

Procedure:
A mixture of ethyl2-ethoxy-3-(4-hydroxyphenyl)-propionate (2.38 g, 0.01 mol), 5-(2-bromo-1-ethylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (2.75 g, 0.01 mol) and potassium carbonate (5.14 g, 0.03 mol) in dimethylformamide (30 ml) was heated at 100° C. for 20 h. The reaction mixture was diluted with benzene (80 ml), washed with 5% aqueous citric acid (3×25 ml) and with saturated NaHCO3 (25 ml), dried (MgSO4) and evaporated. The residue (4.88 g) was purified by column chromatography on silica gel (benzene eluent) to yield the title compound; 2.3 g (53.7%).
Reaction SMILES: Cl.[CH3:2][CH:3]([CH3:8])[CH2:4][C:5](O)=[O:6].[NH2:9][C@@H:10]([CH2:28][O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[CH:16][CH:15]=1)=[O:12]>>[CH2:30]([O:29][CH2:28][C@H:10]([NH:9][C:5](=[O:6])[CH2:4][CH:3]([CH3:8])[CH3:2])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[CH:16][CH:15]=1)=[O:12])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: CC(C)CC(=O)O
Agent: Cl
Product: CC(C)CC(=O)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 53.8 %

Procedure:
Proceeding as in Example 1, but substituting 3-methylbutanoic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 233, (S)—N-(3-(benzyloxy)-1-(4-(4-fluorophenoxy)phenylamino)-1-oxopropan-2-yl)-3-methylbutanamide (3 mg, 53.8%). MS (EI) for C27H29FN2O4. found 465.5 (MH+).
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:8]([O:11][CH3:12])([O:9][CH3:10])[CH2:7][CH2:6][N:5](C(OCC)=O)[CH2:4]1.[OH-].[K+]>CC(O)C>[CH3:1][O:2][CH:3]1[C:8]([O:11][CH3:12])([O:9][CH3:10])[CH2:7][CH2:6][NH:5][CH2:4]1
Reactant: CCOC(=O)N1CCC(OC)(OC)C(OC)C1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: COC1CNCCC1(OC)OC
Temperature: 10 °C
Yield: 75.4 %

Procedure:
A mixture of 117.7 parts of ethyl 3,4,4-tri-methoxy-1-piperidinecarboxylate, 267.3 parts of potassium hydroxide and 720 parts of 2-propanol was stirred and refluxed for 4 hours. The reaction mixture was evaporated. 900 Parts of water were added to the residue and the whole was stirred in a boiling water-bath. The last traces of 2-propanol were removed by evaporation on a Rotavapor. After cooling to 10° C., the product was extracted twice with 280 parts of 1,1'-oxybisethane. The extracts were dried, filtered and evaporated, yielding 62.9 parts (75.4%) of 3,4,4-trimethoxypiperidine as a residue (intermediate 65).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([S:18]([O-:20])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1.[Na+].Br[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[NH:25][CH:26]=[N:27]2>CS(C)=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([S:18]([C:23]2[N:31]=[CH:30][N:29]=[C:28]4[C:24]=2[N:25]=[CH:26][NH:27]4)(=[O:20])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1
Reactant: O=S([O-])c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Reactant: Brc1ncnc2nc[nH]c12
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=S(=O)(c1ccc2cc(-c3ccc(F)cc3)ccc2c1)c1ncnc2[nH]cnc12
Temperature: 80 °C
Reaction time: 22 h
Yield: 25 %

Procedure:
A mixture of sodium 6-(4-fluorophenyl)naphthalene-2-sulfinate [prepared according to the method of Example 10(a) Steps 1-2] (104 mg, 0.34 mmol) and 6-bromopurine (70 mg, 0.35 mmol) in dimethylsulfoxide (4 mL) was stirred at 80° C. (oil bath temperature) under nitrogen for 22 hours. The cooled reaction mixture was diluted with water (20 mL), the preciptate formed collected under suction, washed with water and dried in vacuo. Purification by flash chromatography, eluting with 5% methanol in dichloromethane, gave the title compound as a white solid (33 mg, 25%). 1H NMR (500 MHz, DMSO-d6) δ 14.06 (1H, br s), 9.04 (1H, s), 8.92 (1H, s), 8.86 (1H, s), 8.38 (1H, s), 8.35 (1H, d, J 8.7 Hz), 8.23 (1H, d, J 8.7 Hz), 8.05 (2H, m), 7.92 (2H, m), 7.38 (2H, m); m/z (ES+) 405 [MH+].
Reaction SMILES: CNCCC(OC1C=CC(C(F)(F)F)=CC=1)C1C=CC=CC=1.[Cl:23][CH2:24][CH2:25][C@@H:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[OH:27].[F:34][C:35]1[CH:36]=[C:37](O)[CH:38]=[CH:39][CH:40]=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(OCC)C>[F:34][C:35]1[CH:40]=[C:39]([CH:38]=[CH:37][CH:36]=1)[O:27][C@@H:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:25][CH2:24][Cl:23]
Reactant: Oc1cccc(F)c1
Reactant: O[C@@H](CCCl)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: CNCCC(Oc1ccc(C(F)(F)F)cc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: Fc1cccc(O[C@H](CCCl)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 15.7 %

Procedure:
Following a similar procedure for the chiral synthesis of fluoxetine [Srebnik, M. et al., J. Org. Chem. 53(13), 2916-20 (1988), hereby incorporated by reference herein], a solution of (S)-(−)3-chloro-1-phenyl-1-propanol (4.00 g, 23.4 mmol), 3-fluorophenol (2.63 g, 23.4 mmol), and diethyl azodicarboxylate (4.00 g, 23.4 mmol) were dissolved in THF (200 mL). The mixture was cooled to 0° C. and triphenylphosphine (6.77 g, 25.8 mmol, 1.1 equiv) was added slowly over 10 min. The reaction mixture was then stirred at room temperature for 18 h. The THF was subsequently evaporated under vacuum to afford a gel which was washed with pentane (3×50 mL). The pentane washings were filtered and the filtrate was evaporated under vacuum to give a clear oil. This oil was dissolved in diethyl ether (150 mL) and washed with 1% HCl-satd. NaCl (25 mL), 0.1N NaOH-satd. NaCl (2×25 mL), and finally H2O (2×25 mL). The organic layer was then dried (anh. Na2SO4), filtered, and evaporated to dryness under vacuum to give an orange oil. The crude product was chromatographed on silica gel (25×180 mm, gravity column), elution with 40:1 hexane-EtOAc, to provide 971 mg (15.7%) of product as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[O:11]1[CH2:16][CH2:15][CH:14]([CH2:17]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:17][CH:14]2[CH2:15][CH2:16][O:11][CH2:12][CH2:13]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: Cc1ccc(S(=O)(=O)OCC2CCOCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(Cl)ccc1OCC1CCOCC1
Temperature: 75 °C
Yield: 85.9 %

Procedure:
A mixture of 5-chlorosalicylaldehyde (5.0 g, 32 mmol), toluene-4-sulfonic acid tetrahydro-pyran-4-ylmethyl ester (8.6 g, 32 mmol) and K2CO3 (9.5 g, 68.8 mmol) in DMF (50 mL) was heated at 75° C. overnight. After cooled to room temperature, the mixture was poured into water. The aqueous phase was extracted with EtOAc twice. The combined organic phases were washed with water and brine, dried and concentrated. The residue was purified by column chromatography to give the title compound (7.0 g).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[NH2:21][C:22]1[N:27]=[CH:26][C:25]([C:28]([N:30]2[CH2:35][CH2:34][N:33](C(O)=O)[CH2:32][CH2:31]2)=[O:29])=[CH:24][CH:23]=1>>[CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]([N:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)=[O:29])=[CH:26][N:27]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: Nc1ccc(C(=O)N2CCN(C(=O)O)CC2)cn1
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CCNCC4)cn3)nc2n1C1CCCC1
Yield: 41 %

Procedure:
Following Buchwald Method B, 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (205 mg, 0.7 mmol) and 4-(6-amino-pyridine-3-carbonyl)-piperazine-1-carboxylic acid tort-butyl ester (236 mg, 0.8 mmol), followed by deprotection using General Procedure A to give 7-cyclopentyl-2-[5-(piperazine-1-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (13 mg, 41%).
Reaction SMILES: [CH:1]1([C:7]2[C:8]([OH:37])=[CH:9][C:10]([CH3:36])=[C:11]([CH:13]([C:22]3[CH:27]=[C:26]([CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)[C:25]([OH:34])=[CH:24][C:23]=3[CH3:35])[C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([OH:21])[CH:15]=3)[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:38][S:39](Cl)(=[O:41])=[O:40].C(N(CC)CC)C>O1CCOCC1>[CH:28]1([C:26]2[C:25]([OH:34])=[CH:24][C:23]([CH3:35])=[C:22]([CH:13]([C:11]3[CH:12]=[C:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[C:8]([OH:37])=[CH:9][C:10]=3[CH3:36])[C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([OH:21])[CH:15]=3)[CH:27]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[CH3:38][S:39]([OH:41])(=[O:20])=[O:40]
Reactant: CS(=O)(=O)Cl
Agent: Cc1cc(O)c(C2CCCCC2)cc1C(c1ccc(O)c(O)c1)c1cc(C2CCCCC2)c(O)cc1C
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CS(=O)(=O)O

Procedure:
Bis(5 -cyclohexyl-4-hydroxy-2-methylphenyl)-3,4-dihydroxyphenylmethane(1.0 mole), naphthoquinone-1,2-diazido-5-sulfonyl chloride (2.0 moles) and methanesulfonyl chloride(0.5 moles) were dissolved in dioxane (4,000 g). To the resulting solution, dioxane (1,500 g) having triethylamine (500 g) dissolved therein was added dropwise over 40 minutes at a controlled temperature not higher than 35° C. The precipitating salt was separated by filtration and the thus recovered reaction product was washed and dried to yield a mixed ester of bis(5-cyclohexyl-4-hydroxy-2-methylphenyl)-3,4-dihydroxyphenylmethane with naphthoquinone-1,2-diazido-5-sulfonic acid and methanesulfonic acid; the average degree of esterification was 50% for the quinonediazidosulfonate ester and 12% for the methanesulfonate ester.
Reaction SMILES: FC1C=CC(NC(=O)NC2C=CC(C3C=C4C(CN([C@@H](C(C)C)C(O)=O)C4=O)=CC=3)=CC=2)=CC=1.C[O:36][C:37](=[O:70])[C@@H:38]([N:42]1[CH2:50][C:49]2[C:44](=[CH:45][C:46]([C:51]3[CH:56]=[CH:55][C:54]([NH:57][C:58]([NH:60][C:61]4[CH:66]=[C:65]([F:67])[CH:64]=[C:63]([F:68])[CH:62]=4)=[O:59])=[CH:53][CH:52]=3)=[CH:47][CH:48]=2)[C:43]1=[O:69])[CH:39]([CH3:41])[CH3:40]>>[F:68][C:63]1[CH:62]=[C:61]([NH:60][C:58](=[O:59])[NH:57][C:54]2[CH:53]=[CH:52][C:51]([C:46]3[CH:45]=[C:44]4[C:49]([CH2:50][N:42]([C@@H:38]([CH:39]([CH3:40])[CH3:41])[C:37]([OH:70])=[O:36])[C:43]4=[O:69])=[CH:48][CH:47]=3)=[CH:56][CH:55]=2)[CH:66]=[C:65]([F:67])[CH:64]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4cc(F)cc(F)c4)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(F)cc4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4cc(F)cc(F)c4)cc3)cc2C1=O
Yield: 94 %

Procedure:
The compound of example 30 was prepared analogous to compound of example 8 by hydrolysis of compound of example 29.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:39])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:20][C:3]=1[NH:4][C:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([Cl:18])=[CH:13][C:12]=2[Cl:19])[N:6]=1.[C:40]([C:43]1[CH:44]=[C:45]([N:49]2[C:53]([SH:54])=[N:52][N:51]=[N:50]2)[CH:46]=[CH:47][CH:48]=1)([OH:42])=[O:41].O>CN(C)C=O>[Cl:1][C:2]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:39])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:20][C:3]=1[NH:4][C:5]1[CH:9]([S:54][C:53]2[N:49]([C:45]3[CH:46]=[CH:47][CH:48]=[C:43]([C:40]([OH:42])=[O:41])[CH:44]=3)[N:50]=[N:51][N:52]=2)[C:8](=[O:10])[N:7]([C:11]2[C:12]([Cl:19])=[CH:13][C:14]([Cl:18])=[CH:15][C:16]=2[Cl:17])[N:6]=1
Reactant: O=C(O)c1cccc(-n2nnnc2S)c1
Reactant: CCCCCCCCCCCCCC(=O)Nc1ccc(Cl)c(NC2=NN(c3c(Cl)cc(Cl)cc3Cl)C(=O)C2)c1
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCCC(=O)Nc1ccc(Cl)c(NC2=NN(c3c(Cl)cc(Cl)cc3Cl)C(=O)C2Sc2nnnn2-c2cccc(C(=O)O)c2)c1
Reaction time: 0.5 h
Yield: 69 %

Procedure:
A mixture of 15.4 g of 3-(2-chloro-5-tetradecaneamidoanilino)-1-(2,4,6-trichlorophenyl)-2-pyrazolin-5-one and 5.4 g of 1-(3-carboxyphenyl)-5-mercaptotetrazole was dissolved in 100 ml of dimethylformamide (DMF), and a solution of 4.9 g of N-glucosuccinic acid imide in 20 ml of DMF was added dropwise thereto at room temperature. The resulting mixture was stirred for 30 minutes, and 500 ml of water was added thereto. The mixture was then extracted with ethyl acetate. The ethyl acetate was distilled away under reduced pressure, and the residue was precipitated from a mixed solvent of ethyl acetate and acetonitrile to obtain 14 g of 3-(2-chloro-5-tetradecaneamidoanilino)-1-(2,4,6-trichlorophenyl)-4-[1-(3-carboxyphenyl)-5-tetrazolylthio]-2-pyrazolin-5-one, m.p., 155°-165° C. Yield was 68%.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].C([Mg]Br)C.C([Cu])#N.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>O1CCCC1>[C:17]1([CH2:16][C:6]#[C:5][CH2:4][CH2:3][CH2:2][C:1]([OH:8])=[O:7])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: C#CCCCC(=O)O
Agent: N#C[Cu]
Agent: CC[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: O=C(O)CCCC#CCc1ccccc1
Temperature: 5 °C
Reaction time: 0.33 h

Procedure:
Hex-5-ynoic acid (0.1 mole) is added to a tetrahydrofuran solution of ethylmagnesium bromide (0.2 mole) maintained at 5° C. When the addition is complete, the solution is warmed to room temperature and CuCN (0.5 g) is added with stirring. After 20 minutes, a solution of benzylbromide (0.05 mole) in tetrahydrofuran is added dropwise over a one-half hour period. The reaction is maintained at room temperature until thin layer chromatography shows completion and then poured onto 1 N hydrochloric acid. This mixture is then extracted with ethyl ether and the ether layer separated. Removal of the ether gives a residue which is distilled under reduced pressure to afford the title product, 7-phenylhept-5-ynoic acid.
Reaction SMILES: [NH:1]([C:8]1[CH:9]=[C:10]2[C:15](=[O:16])[NH:14][C:12](=[O:13])[C:11]2=[CH:17][C:18]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26]C)=[C:22]([O:28]C)[CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>ClCCl>[NH:1]([C:8]1[CH:9]=[C:10]2[C:15](=[O:16])[NH:14][C:12](=[O:13])[C:11]2=[CH:17][C:18]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([OH:28])[CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(Nc2cc3c(cc2Nc2ccccc2)C(=O)NC3=O)cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1NC(=O)c2cc(Nc3ccc(O)c(O)c3)c(Nc3ccccc3)cc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 219 mg (0.56 mmol) of 4-anilino-5-(3,4-dimethoxy-anilino)-phthalimide in 5 ml of dichloromethane, a solution of 270 μl (2.8 mmol) boron tribromide in 3 ml of dichloromethane is added dropwise at RT. The reaction mixture is stirred for 5 hours at RT and then quenched with 5 ml of water, and the phases are separated. The water phase is extracted three times with ethyl acetate. The organic phases are combined and washed twice with water, dried over magnesium sulfate and concentrated by evaporation. Excluding light, the evaporation residue is chromatographed with ethylacetate/hexane2:1 on a silica gel column (precoated with 0.1 g of sodium ascorbate per g silica gel) that is cooled with ice-water (double jacket), and the productfractions are combined and concentrated by evaporation. Recrystallization from ethyl acetate/dichloromethane/hexane yields the title compound in theform of orange crystals, FAB-MS: 362 [M+ +H].
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:17]1[C:21](=[O:22])[CH2:20][CH2:19][C:18]1=[O:23].C1(N=C=NC2CCCCC2)CCCCC1>O1CCOCC1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([O:15][N:17]1[C:21](=[O:22])[CH2:20][CH2:19][C:18]1=[O:23])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1COCCO1
Product: O=C(CNC(=O)OCc1ccccc1)ON1C(=O)CCC1=O
Reaction time: 8 h
Yield: 52.5 %

Procedure:
N-Benzyloxycarbonylglycine (10.9 g, 52.2 mmol) and N-hydroxysuccinimide (6.0 g, 52.2 mmol), were dissolved in dioxane (100 ml) and cooled in a cold water bath. N,N'-Dicyclohexylcarbodiimide (10.8 g, 52.2 mmol) was added and the mixture was stirred overnight. The white precipitate which formed was filtered, washed and air-dried (11.8 g, 100% of dicyclohexylurea). The filtrate was evaporated to dryness under reduced pressure, and the residual solid (16.2 g) was crystallized from ethyl acetate (50 ml) to give 8.4 g (53%) of crystalline N-(N-benzyloxycarbonylglycyloxy)succinimide, m.p. 110.5°-112° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:19]=[CH:18][C:13]3[O:14][CH2:15][CH2:16][O:17][C:12]=3[CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([SH:22])[N:3]=1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)(O)[O-].[Na+].O>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:19]=[CH:18][C:13]3[O:14][CH2:15][CH2:16][O:17][C:12]=3[CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1c(N)nc(S)c(C#N)c1-c1ccc2c(c1)OCCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1c(N)nc(SCc2ccccc2)c(C#N)c1-c1ccc2c(c1)OCCO2

Procedure:
100 mg (0.32 mol) of 2-amino-6-sulfanyl-4-(2,3-dihydro-1,4-benzodioxin-6-yl)-3,5-pyridinedicarbonitrile [prepared analogously to Dyachenko et al., Russian Journal of Chemistry 33 (7), 1014–1017 (1997); 34 (4), 557–563 (1998)], 110 mg (0.64 mmol) of benzyl bromide and 108 mg (1.29 mmol) of sodium bicarbonate are stirred in 2 ml of DMF at room temperature for 5.5 h. Water is then added and the mixture is extracted three times with ethyl acetate. The combined organic phases are dried with magnesium sulfate and concentrated under reduced pressure. The residue is taken up in diethyl ether, giving, after reconcentration, a crystalline product.
Reaction SMILES: [CH3:1][N:2]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[S:3]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12]Br)=[CH:8][CH:7]=1)(=[O:5])=[O:4].[S:22]1[CH2:26][C:25](=[O:27])[NH:24][C:23]1=[O:28].C(OCC)(=O)C>CCCCCC>[CH3:1][N:2]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[S:3]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:26]2[S:22][C:23](=[O:28])[NH:24][C:25]2=[O:27])=[CH:8][CH:7]=1)(=[O:5])=[O:4]
Reactant: O=C1CSC(=O)N1
Reactant: CN(CCc1ccccc1)S(=O)(=O)c1ccc(CBr)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CN(CCc1ccccc1)S(=O)(=O)c1ccc(CC2SC(=O)NC2=O)cc1

Procedure:
By the method of Example 1, N-methyl-N-(2-phenylethyl)-4-(bromomethyl)benzenesulfonamide (10.6 mmol, 3.9 g) and thiazolidine-2,4-dione (11.7 mmol 1.4 g,), using 1:2 ethyl acetate:hexane as eluant, were converted to 3.3 g purified title product as a gum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:33][C:34]1[CH:39]=[CH:38][C:37]([NH:40]N)=[CH:36][CH:35]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:40][C:37]3[C:38]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:39][C:34]([CH3:33])=[CH:35][CH:36]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(NN)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(Cl)c3)CC2)c1
Agent: Cl
Product: Cc1ccc2[nH]c(-c3cccc(Cl)c3)c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(3-chlorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-methylphenylhydrazine hydrochloride: ESMS m/e: 528.2 (M+H)+.