Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:3]=1[NH2:4].[Br:12][C:13]1[CH:17]=[C:16]([C:18](O)=[O:19])[N:15]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[N:14]=1.N1C=CC=C(C)C=1.CS(Cl)(=O)=O>CC#N>[Br:12][C:13]1[CH:17]=[C:16]([C:18]([NH:4][C:3]2[C:5]([N+:9]([O-:11])=[O:10])=[CH:6][CH:7]=[CH:8][C:2]=2[CH3:1])=[O:19])[N:15]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[N:14]=1
Reactant: O=C(O)c1cc(Br)nn1-c1ncccc1Cl
Reactant: Cc1cccc([N+](=O)[O-])c1N
Agent: CS(=O)(=O)Cl
Solvent: Cc1cccnc1
Solvent: CC#N
Product: Cc1cccc([N+](=O)[O-])c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Reaction time: 0.17 h
Yield: 82.2 %

Procedure:
2-Methyl-6-nitroaniline (540 mg, 3.54 mmol), 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid (1 g, 3.54 mmol), CH3CN (0.3 M, 11.8 mL) and 3-picoline (0.69 mL, 7.08 mmol, 2.0 eq) were introduced to a 50 mL round flask and subjected to a reaction at room temperature. After 10 minutes, the reaction mixture thus obtained was added with methylsulfonylchloride (0.41 mL, 5.31 mmol, 1.5 eq.), subjected to a reaction at 30° C. for 24 hours, and followed by a further reaction at 40° C. for 24 hours. Upon completion of the reaction, CH3CN was removed from the reaction mixture under reduced pressure, and the residue was extracted with 1 M HCl (20 mL) and ethyl acetate (20 mL), and, then, extracted with NaHCO3 (20 mL) and ethyl acetate (20 mL), washed with brine (20 mL). The organic layer thus obtained was dried over MgSO4 and concentrated under reduced pressure. Subsequently, the residue was purified by silica gel column chromatography (MC:EA=9:1) to obtain the title compound (1.27 g, yield: 82%).
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]1.[NH2:7][CH2:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:16]=[C:17]3[C:22](=[N:23][CH:24]=2)[N:21]([C:25]([NH2:27])=[O:26])[CH2:20][CH2:19][CH2:18]3)[CH:12]=[N:13][CH:14]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[CH:1]1([C:4]([NH:7][CH2:8][C:9]2[CH:10]=[C:11]([C:15]3[CH:16]=[C:17]4[C:22](=[N:23][CH:24]=3)[N:21]([C:25]([NH2:27])=[O:26])[CH2:20][CH2:19][CH2:18]4)[CH:12]=[N:13][CH:14]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: NCc1cncc(-c2cnc3c(c2)CCCN3C(N)=O)c1
Reactant: O=C(O)C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)N1CCCc2cc(-c3cncc(CNC(=O)C4CC4)c3)cnc21
Reaction time: 8 h

Procedure:
To the cyclopropanecarboxylic acid (16 mg, 0.18 mmol) is added a solution of 6-(5-aminomethyl-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide (40 mg, 0.14 mmol) in DMF (1 mL) followed by HATU (100 mg, 0.26 mmol) in DMF (1 mL) followed by triethylamine (51 mg, 0.50 mmol). The mixture is stirred overnight. The mixture is concentrated in vacuo, dissolved in 2 mL of DMF, filtered and purified by reverse phase HPLC to afford the titled product.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([C@@H:26]([C:31](=[O:33])[NH2:32])[CH2:27][CH:28]([CH3:30])[CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([S:16]([N:15]([C@H:26]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:31]([NH2:32])=[O:33])[CH2:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)(=[O:17])=[O:18])=[CH:20][CH:21]=1
Reactant: CC(C)C[C@H](C(N)=O)N(CC1CCN(C(=O)OC(C)(C)C)CC1)S(=O)(=O)c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C[C@H](C(N)=O)N(CC1CCNCC1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
To a solution of 4-{[N-((1R)-1-carbamoyl-3-methyl-butyl)-N-(4-chlorobenzenesulfonyl)amino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester (Example 92, 2.6 grams, 5.2 mmol) in CH2Cl2 (25 mL) was added trifluoroacetic acid (10 mL). The reaction was stirred at rt for 1 h and then was concentrated to give a white solid (1.6 grams, 84%). MS(ESI), (M+H)+402.15; 1H NMR (DMSO-d6, 500 MHz), δ7.87 (d, 2H, J=8.5), 7.66 (d, 2H, J=8.6), 7.41 (s, 1H), 7.04 (s, 1H), 4.17 (t, 1H, J=7.3), 3.40-3.50 (m, 1H), 3.20-3.25 (m, 1H), 3.03-3.10 (m, 1H), 2.65-2.80 (m, 2H), 1.85-2.00 (m, 1H), 1.20-1.85 (m, 2H), 1.45-1.60 (m, 1H), 1.30-1.40 (m, 1H), 1.10-1.30 (m, 4H), 0.75-0.90 (m, 1H), 0.82 (d, 3H, J=7.3), 0.80 (d, 3H, J=7.0).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)[C:3]([NH:5][C@H:6]([CH2:10][S:11][S:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:7]([OH:9])=[O:8])=[O:4].C(N(C(C)C)C(C)C)C.[C:36](OC(=O)C)(=[O:38])[CH3:37]>C(Cl)Cl>[C:36]([NH:1][C@@H:2]([CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)[C:3]([NH:5][C@H:6]([CH2:10][S:11][S:12][C:13]([CH3:14])([CH3:16])[CH3:15])[C:7]([OH:9])=[O:8])=[O:4])(=[O:38])[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)SSC[C@@H](NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@H](CSSC(C)(C)C)C(=O)O
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of (S)-2-((S)-2-amino-3-(1H-indol-3-yl)propanamido)-3-(tert-butyldisulfanyl)propanoic acid (H-Trp-D-Cys(StBu)-OH) (Compound SP643) (870 mg, 2.20 mmol) in methylene chloride (4.4 mL) was mixed with N-ethyldiisopropylamine (DIPEA) (1.15 mL, 6.60 mmol) and acetic anhydride (208 μL, 2.20 mmol) with stirring at room temperature, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was purified by reverse-phase silica gel column chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution) to afford (S)-2-((S)-2-acetamido-3-(1H-indol-3-yl)propanamido)-3-(tert-butyldisulfanyl)propanoic acid (Ac-Trp-D-Cys(StBu)-OH) (Compound SP644) (960 mg, 2.20 mmol, 100%).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]([CH:32]=[CH:33][CH:34]=1)[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:31])=[C:16]([NH:18][C:19](=[O:30])[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[CH:17]=1)=[O:10])(=[O:4])=[O:3].[H-].[Na+].[CH3:37]I.O>CN(C=O)C>[CH3:37][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[C:6]1[CH:7]=[C:8]([CH:32]=[CH:33][CH:34]=1)[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:31])=[C:16]([NH:18][C:19](=[O:30])[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[CH:17]=1)=[O:10]
Reactant: COc1ccc(C(=O)Nc2cc(NC(=O)c3cccc(NS(C)(=O)=O)c3)ccc2C)cc1OC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(=O)Nc2cc(NC(=O)c3cccc(N(C)S(C)(=O)=O)c3)ccc2C)cc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of N-[5-(3-methanesulphonylaminobenzamido)-2-methylphenyl]-3,4-dimethoxybenzamide (0.3 g) in DMF (5 ml) was added portionwise to a stirred mixture of sodium hydride (0.025 g) in DMF (5 ml). The resultant mixture was stirred at ambient temperature for 40 minutes. Methyl iodide (0.088 g) was added and the mixture was stirred at ambient temperature for 3 hours. The mixture was poured into water (150 ml). The resultant precipitate was isolated, washed in turn with water and diethyl ether and dried under vacuum at 60° C. There was thus obtained the title compound (0.18 g); m.p. 168-169° C.; NMR Spectrum: (DMSOd6) 2.19 (s, 3H), 2.99 (s, 3H), 3.82 (s, 6H), 7.07 (d, 1H), 7.21 (d, 1H). 7.59 (m, 5H), 7.79 (s, 1H), 7.87 (d, 1H), 7.93 (s, 1H), 9.75 (br s, 1H), 10.25 (br s, 1H); Mass Spectrum: M+H+ 498.
Reaction SMILES: I.[NH:2]1[CH2:7][CH2:6][CH2:5][N:4]=[C:3]1[NH:8][NH2:9].Cl.[C:11](Cl)(=O)[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[N:15]1[CH:16]=[CH:17][C:12]([C:11]2[N:4]3[CH2:5][CH2:6][CH2:7][NH:2][C:3]3=[N:8][N:9]=2)=[CH:13][CH:14]=1
Reactant: NNC1=NCCCN1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Agent: I
Solvent: c1ccncc1
Product: c1cc(-c2nnc3n2CCCN3)ccn1
Yield: 13.3 %

Procedure:
A solution of 750 mg (3.1 mmol) (1,4,5,6-tetrahydro-pyrimidin-2-yl)-hydrazine hydroiodide (ref. Krezel, Izabella; Pharmazie; EN; 49; 1; 1994; 27-31) and 552 mg (3.1 mmol) isonicotinoyl chloride hydrochloride in 3 ml pyridine was heated at 120° C. over night. The reaction mixture was cooled and diluted with K2CO3(sat) and extracted with 3×10 ml chloroform. The combined organic extracts were dried and concentrated. Flashchromatography (CH2Cl2/MeOH 10:1) afforded 83 mg (18%) of a white solid. 1H NMR (CDCl3), d (ppm): 1.91 (m, 2 H) 3.24 (m, 2 H) 4.13 (m, 2 H) 7.67 (m, 2 H) 8.65 (m, 2 H).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1>>[N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([NH:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[O:17])[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1cccnc1
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cccnc1
Yield: 55.7 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 427 mg of 3-aminopyridine in place of the 2,4-difluoroaniline. 168 mg of 2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]-N-(pyridin-3-yl)acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1.[C:20](Cl)(=[O:22])[CH3:21]>N1C=CC=CC=1>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][O:10][C:6]2[C:7](=[O:9])[CH:8]=[C:3]([CH2:2][O:1][C:20](=[O:22])[CH3:21])[NH:4][CH:5]=2)=[CH:17][CH:16]=1
Reactant: COc1ccc(COc2c[nH]c(CO)cc2=O)cc1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: COc1ccc(COc2c[nH]c(COC(C)=O)cc2=O)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
2-(Hydroxymethyl)-5-[(4-methoxybenzyl)oxy]pyridin-4(1H)-one (3.21 g, 12.2 mmol) was dissolved in pyridine (60 mL), added acetyl chloride (1.44 g, 18.3 mmol) under ice-cold conditions, and the mixture was stirred at 60° C. overnight. Then, the reaction solution was concentrated in vacuo. Water was added under ice-cold conditions, and stirred at room temperature for 30 minutes. The deposited solid was filtered, washed with iced water and diethyl ether, concentrated in vacuo, and the title compound (3.56 g (yield 96%)) was obtained as brown powder crystal.
Reaction SMILES: N[C@@H]1CCCCN(C(NC2CCC2)=O)C1=O.CC(O[C:22](=[O:39])[NH:23][C@H:24]1[CH2:30][CH2:29][CH2:28][CH2:27][N:26]([C:31]([NH:33][CH:34]2[CH2:37][CH2:36][CH2:35]2)=[O:32])[C:25]1=[O:38])(C)C.C(O)(C(F)(F)F)=O.ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O.C(N(C(C)C)CC)(C)C.[Cl:69][C:70]1[CH:79]=[C:78]2[C:73]([C:74]([N:81]3[CH2:86][CH2:85][NH:84][CH2:83][CH2:82]3)=[CH:75][C:76]([NH2:80])=[N:77]2)=[CH:72][CH:71]=1>>[NH2:80][C:76]1[CH:75]=[C:74]([N:81]2[CH2:82][CH2:83][N:84]([C:22]([NH:23][C@H:24]3[CH2:30][CH2:29][CH2:28][CH2:27][N:26]([C:31]([NH:33][CH:34]4[CH2:35][CH2:36][CH2:37]4)=[O:32])[C:25]3=[O:38])=[O:39])[CH2:85][CH2:86]2)[C:73]2[C:78](=[CH:79][C:70]([Cl:69])=[CH:71][CH:72]=2)[N:77]=1
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCN(C(=O)NC2CCC2)C1=O
Agent: N[C@@H]1CCCCN(C(=O)NC2CCC2)C1=O
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(N2CCN(C(=O)N[C@H]3CCCCN(C(=O)NC4CCC4)C3=O)CC2)c2ccc(Cl)cc2n1

Procedure:
As described example 78, (3R)-3-amino-N-cyclobutylhexahydro-2-oxo-1H-azepine-1-carboxamide by de-protection of [(3S)-1-[(cyclobutylamino)carbonyl]hexahydro-2-oxo-1H-azepin-3-yl] carbamic acid-1,1-dimethylethyl ester with TFA, p-nitrophenyl chloroformate, diisopropyl(ethyl)amine, and 7-chloro-4-(1-piperazinyl)-2-quinolinamine are reacted to afford the product. 1HNMR (DMSO-d6): δ 1.24 (br. s, 1H), 1.5–1.9 (m, 7H), 2.2 (m, 2H), 2.99 (m, 4H), 3.6 (m, 4H), 4.17 (m, 1H), 4.52 (m, 1H), 4.66 (t, 1H), 6.14 (s, 1H, 6.42 (br. s, 1H), 6.8 (d, 1H), 7.1 (d, 1H), 7.39 (s, 1H), 7.76 (d, 1H), 9.3 (d, 1H).
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([CH:22]([F:24])[F:23])=[C:18]([F:25])[CH:17]=3)[O:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:27][C:28]1[N:29]=[C:30]2[S:37][CH:36]=[C:35]([CH3:38])[N:31]2[C:32](=[O:34])[CH:33]=1.O.OC1N=CN=C2C=1NC(S)=N2>>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([CH:22]([F:24])[F:23])=[C:18]([F:25])[CH:17]=3)[O:11][C:10](=[O:12])[C:9]([CH2:27][C:28]3[N:29]=[C:30]4[S:37][CH:36]=[C:35]([CH3:38])[N:31]4[C:32](=[O:34])[CH:33]=3)=[C:8]([OH:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CC(=O)OC(CCc2ccc(C(F)F)c(F)c2)(C2CCCC2)C1
Reactant: Cc1csc2nc(CCl)cc(=O)n12
Agent: Oc1ncnc2nc(S)[nH]c12
Solvent: O
Product: Cc1csc2nc(CC3=C(O)CC(CCc4ccc(C(F)F)c(F)c4)(C4CCCC4)OC3=O)cc(=O)n12

Procedure:
The title compound was prepared as described in Example B(54) where 6-Cyclopentyl-6-{2-[4-(difluoromethyl)-3-fluorophenyl]ethyl}-dihydro-2H-pyran-2,4(3H)-dione (described in Step 3 of Example B(69)) was used in place of 6-[2-(5-Chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione and 7-(Chloromethyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (prepared according to a reported procedure: Doria, G.; Passarotti, C.; Sala, R.; Magrini, R.; Sberze, P.; Tibolla, M.; Cesarani, R.; Arcari, G.; Castello, R.; Toti, D. Farmaco Ed. Sci. 1985, 40, 885) was used in place of 6-Hydroxy-8-mercaptopurine monohydrate.
Reaction SMILES: COC([C:5]1([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH2:9][CH2:8][C:7]([CH2:15][O:16][CH2:17][O:18][CH3:19])([CH2:10][O:11][CH2:12][O:13][CH3:14])[C:6]1=[O:20])=O.[OH-].[Na+].O>C(O)(C)C>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][CH:5]2[C:6](=[O:20])[C:7]([CH2:10][O:11][CH2:12][O:13][CH3:14])([CH2:15][O:16][CH2:17][O:18][CH3:19])[CH2:8][CH2:9]2)=[CH:27][CH:26]=1
Reactant: COCOCC1(COCOC)CCC(Cc2ccc(Cl)cc2)(C(=O)OC)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: COCOCC1(COCOC)CCC(Cc2ccc(Cl)cc2)C1=O
Temperature: 90 °C
Reaction time: 2 h

Procedure:
In isopropanol (5.5 mL), 1-(4-chlorobenzyl)-3,3-bis((methoxymethoxy)methyl)-2-oxocyclopentane carboxylic acid methyl ester (2.2895 g, 5.52 mmol) was dissolved, and a 2 M sodium hydroxide solution (5.5 mL) was added thereto. The mixture was stirred at 90° C. for 2 hours. Following the completion of the reaction, water was added, and the mixture was subjected to extraction using ethyl acetate. The organic layer was washed with saturated brine solution and water, and dried using anhydrous sodium sulfate. The solvent was distilled out, and the residue was purified using silica gel to obtain a target product.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH:5]=[CH:4][CH:3]1/[CH:7]=[CH:8]\[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].CC(C)=O.[Cr](O)(O)(=O)=O>S(=O)(=O)(O)O>[C:13]([CH2:12][CH2:11][CH2:10][CH2:9]/[CH:8]=[CH:7]\[CH:3]1[CH:4]=[CH:5][CH2:6][C:2]1=[O:1])([OH:15])=[O:14]
Reactant: O=C(O)CCCC/C=C\C1C=CCC1O
Agent: O=[Cr](=O)(O)O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: O=C(O)CCCC/C=C\C1C=CCC1=O

Procedure:
A solution of 3.2 g of 1-hydroxy-2-(6-carboxy-2-cis-hexenyl)cyclopent-3-ene (Example 55) in 60 ml. of reagent acetone is treated dropwise with a total of 6 ml of 8N chromic acid in sulfuric acid at 0° C. The oxidation is rather slow. The resulting mixture is dissolved in 200 ml. of water and the solution is extracted with six 50 ml. portions of ether. The combined ethereal extracts are dried over sodium sulfate and the solvent is evaporated at reduced pressure to yield the product as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.C1(=O)O[CH2:15][CH2:14][O:13]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)(Cl)Cl>[CH:7]1[C:8]2[C:3](=[C:2]([O:1][CH2:15][CH2:14][OH:13])[CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Oc1cccc2cnccc12
Reactant: O=C1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: OCCOc1cccc2cnccc12
Temperature: 155 °C
Yield: 67.5 %

Procedure:
A mixture of 5-hydroxyisoquinoline (2.05 g, 14.1 mmol), ethylene carbonate (1.43 g, 16.2 mmol), K2CO3 (0.97 g, 7.1 mmol) in DMF (6 mL) was heated at 155° C. for 1.5 h under stirring in a sealed tube. After cooling, the mixture was diluted with CHCl3 and filtered through a pad of Celite. The brownish filtrate was concentrated in vacuo, and the residue was purified by chromatography on silica gel using EtOAc as eluent to give 1.8 g (67%) of the title product as a beige oil which solidified on standing: mp 64-67° C.; HRMS m/z calcd for C11H11NO2 (M)+189.0790, found 189.0789. Anal. (C11H11NO2) C, H, N.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH3:16][N:17]1[C:22]2=[C:23]3[N:28]([C:29]([C:30]4[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=4)[C:33]#[N:34])=[C:21]2[C:20](=[O:39])[N:19]([CH3:40])[C:18]1=[O:41])[CH2:27][CH2:26][CH2:25][C:24]3=O.N1C(C)=CC=CC=1C>C(Cl)Cl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:24]1[C:23]2[N:28]([C:29]([C:30]3[CH:37]=[CH:36][CH:35]=[C:32]([C:33]#[N:34])[CH:31]=3)=[C:21]3[C:20](=[O:39])[N:19]([CH3:40])[C:18](=[O:41])[N:17]([CH3:16])[C:22]3=2)[CH2:27][CH2:26][CH:25]=1)(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cn1c(=O)c2c(-c3cccc(C#N)c3)n3c(c2n(C)c1=O)C(=O)CCC3
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: Cn1c(=O)c2c(-c3cccc(C#N)c3)n3c(c2n(C)c1=O)C(OS(=O)(=O)C(F)(F)F)=CCC3
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Trifluoromethanesulfonic anhydride (221 μL, 1.31 mmol) was added to an ice-cooled solution of 3-(1,3-dimethyl-2,4,10-trioxo-1,2,3,4,7,8,9,10-octahydropyrimido[4,5-a]indolizin-5-yl)benzonitrile (step 7) (350 mg, 1.01 mmol) and 2,6-lutidine (176 μL, 1.51 mmol) in DCM (5 mL). The solution was stirred at ice-bath temperature for 2 hours, further portions of 2,6-lutidine (88 μL, 0.78 mmol) and trifluoromethanesulfonic anhydride (85 μL, 0.50 mmol) were added. The reaction mixture was diluted with dichloromethane (40 mL) and was washed with water (2×20 mL) and sat. brine (1×20 mL). The organic phase was dried with magnesium sulfate and the solvent was removed under vacuum.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[CH3:17][O:18][C:19]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:20]=1[C:21](O)=O>>[CH3:17][O:18][C:19]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:20]=1[C:21]1[O:14][C:13]([C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:15][N:16]=1
Reactant: COc1ccc(C(=O)O)c(OC)c1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Product: COc1ccc(-c2nnc(-c3c(-c4ccccc4)noc3C)o2)c(OC)c1
Yield: 62 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) was converted using 2,4-dimethoxybenzoic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate=80:20 to 50:50, 207 mg, 62%) which was obtained as a white solid. MS: m/e=364.2 [M+H]+.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1([C:10]([O:12][CH3:13])=[O:11])[CH2:8][CH2:7][CH2:6][C:5]1=[O:9].[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.Cl>O.CO>[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[C:6]2[CH2:7][CH2:8][C:4]([CH3:3])([C:10]([O:12][CH3:13])=[O:11])[C:5]2=[O:9])=[CH:17][CH:16]=1
Reactant: COC(=O)C1(C)CCCC1=O
Reactant: O=Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)C1(C)CCC(=Cc2ccc(Cl)cc2)C1=O

Procedure:
To a solution of 3.4 g of sodium hydroxide in 770 ml of water were added 15 g of methyl 1-methyl-2-oxocylopentanecarboxylate (prepared in Reference Example 1 hereinafter) and a solution of 13.5 g of 4-chlorobenzaldehyde in 800 ml of methanol, and the mixture was stirred for 5 hours at room temperature. The reaction mixture was neutralized with diluted hydrochloric acid and the solvent was evaporated under reduced pressure. The residue was extracted with ethyl acetate. The organic layer was washed with water and dried. Ethyl acetate was evaporated under reduced pressure to obtain 25 g of an oily matter.
Reaction SMILES: [O:1]=[C:2]1[N:6]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])[C:5](=[O:12])[CH2:4][S:3]1.[Br:13][C:14]1[CH:31]=[CH:30][C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][C:24]([CH:28]=O)=[CH:25][CH:26]=3)[CH:21]=[N:20]2)=[C:16]([C:32]([F:35])([F:34])[F:33])[CH:15]=1>>[Br:13][C:14]1[CH:31]=[CH:30][C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][C:24](/[CH:28]=[C:4]4/[C:5](=[O:12])[N:6]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])[C:2](=[O:1])[S:3]/4)=[CH:25][CH:26]=3)[CH:21]=[N:20]2)=[C:16]([C:32]([F:33])([F:35])[F:34])[CH:15]=1
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(Br)cc2C(F)(F)F)c1
Reactant: CS(=O)(=O)NN1C(=O)CSC1=O
Product: CS(=O)(=O)NN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Br)cc3C(F)(F)F)c2)C1=O

Procedure:
N-[(5Z)-5-({1-[4-Bromo-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]methanesulfonamide was prepared from N-(2,4-dioxothiazolidin-3-yl)methanesulfonamide (from Example 360) and [4-bromo-2-(trifluoromethyl)benzyl]-1H-indazol-5-carbaldehyde following General Procedure E.
Reaction SMILES: [C:1]([C:4]1[C:16]([OH:17])=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14])=[C:6]([CH2:18][CH:19]=[CH2:20])[CH:5]=1)(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:29])C=1>C(Cl)Cl>[C:1]([C:4]1[C:16]([OH:17])=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14])=[C:6]([CH2:18][CH:19]2[O:29][CH2:20]2)[CH:5]=1)(=[O:3])[CH3:2]
Reactant: C=CCc1cc(C(C)=O)c(O)cc1OCCCCC#N
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(=O)c1cc(CC2CO2)c(OCCCCC#N)cc1O
Reaction time: 5 h

Procedure:
To a solution of 5.46 % of 5-[4-acetyl-5-hydroxy-2-allylphenoxy]pentanenitrile in 100 ml of methylene chloride were added 6.1 % of 85% meta-chloroperbenzoic acid. After stirring for 5 hours, the reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and a cold sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate, and concentrated in vacuo to approximately 35 ml. The solution was placed in a freezer overnight providing 4.08 g of the crystalline title product which were recovered by filtration, m.p. 86°-87° C.
Reaction SMILES: [CH3:1][O-:2].[K+].Cl[C:5]1[CH:25]=[CH:24][C:8]([C:9]([C:11]2[C:12]([CH3:23])=[C:13]([CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:14]=[CH:15][CH:16]=2)=[O:10])=[CH:7][CH:6]=1>CO>[CH3:1][O:2][C:5]1[CH:25]=[CH:24][C:8]([C:9]([C:11]2[C:12]([CH3:23])=[C:13]([CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:14]=[CH:15][CH:16]=2)=[O:10])=[CH:7][CH:6]=1
Reactant: Cc1c(CCCC(=O)O)cccc1C(=O)c1ccc(Cl)cc1
Reactant: C[O-]
Agent: [K+]
Solvent: CO
Product: COc1ccc(C(=O)c2cccc(CCCC(=O)O)c2C)cc1
Temperature: 25 °C
Yield: 72.3 %

Procedure:
17.5 g of 89% potassium methylate were added under an inert atmosphere to a suspension of 7.5 g of 4-(3'-p-chlorobenzoyl-2'-methyl-phenyl)-butyric acid (Example V) in 75 ml of methanol and was then heated at 120°-130° C for 17 hours under pressure. After cooling to room temperature, the mixture was rinsed with water and the methanol was eliminated under reduced pressure. The residue was dissolved in water, treated hot with activated carbon, iced and filtered. The filtrate was acidified to a pH of 1 with hydrochloric acid and the precipitate formed was recovered by filtration, was washed with water until the wash water was neutral and dried. The residue was crystallized from isopropyl ether to obtain 5.35 g of 4-(3'-p-methoxybenzoyl-2'-methyl-phenyl)-butyric acid in the form of colorless crystals melting at 100° C and then 115° C.