Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24]([SH:34])[NH:25][C:26]=2[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)=[CH:18][CH:17]=1.[H-].[Na+]>CN(C)C=O>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C:26]2[N:25]=[C:24]([S:34][C:2]3[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=3[N+:12]([O-:14])=[O:13])[NH:23][C:22]=2[C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=2)=[CH:32][CH:31]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: Sc1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Sc1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)[nH]1
Reaction time: 0.33 h
Yield: 89.1 %

Procedure:
Under agitation and a layer of argon, a solution of 3.77 g of 4-chloro-3-nitrotrifluoromethylbenzene in 50 ml of dimethylformamide is added dropwise to a solution of 4.82 g of 4,5-bis(4-chlorophenyl)-2-mercaptoimidazole and 0.45 g of sodium hydride (80% strength in white oil) in 100 ml of dimethylformamide. The mixture is stirred for 20 minutes, concentrated under vacuum, and the residue is distributed between water and ethyl acetate. The organic solution is dried over sodium sulfate and concentrated to dryness under vacuum. The residue is crystallized from methylene chloride/ether, thus obtaining 6.82 g of 4,5-bis(4-chlorophenyl)-2-(2-nitro-4-trifluoromethylphenylthio)imidazole, mp 264°-266°.
Reaction SMILES: N1C=CC=CC=1.[CH:7]1([CH:10]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:11](Cl)=[O:12])[CH2:9][CH2:8]1.[F:21][C:22]1[CH:38]=[CH:37][C:25]([O:26][C:27]2[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=2)[CH:30]([OH:33])[C:31]#[N:32])=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[CH:7]1([CH:10]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:11]([O:33][CH:30]([C:31]#[N:32])[C:29]2[CH:34]=[CH:35][CH:36]=[C:27]([O:26][C:25]3[CH:37]=[CH:38][C:22]([F:21])=[CH:23][CH:24]=3)[CH:28]=2)=[O:12])[CH2:9][CH2:8]1
Reactant: N#CC(O)c1cccc(Oc2ccc(F)cc2)c1
Reactant: O=C(Cl)C(c1ccc(Cl)cc1)C1CC1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: N#CC(OC(=O)C(c1ccc(Cl)cc1)C1CC1)c1cccc(Oc2ccc(F)cc2)c1

Procedure:
With stirring, 1 g of pyridine in 3 ml of toluene and 2.3 g of α-cyclopropyl-4-chlorophenylacetyl chloride in 3 ml of toluene are added successively at 0° to 10° C. to a solution of 2.43 g of 3-(4-fluorophenoxy)-α-cyanobenzyl alcohol in 20 ml of toluene. After stirring for 10 hours at room temperature, the reaction mixture is washed with water, 2 N hydrochloric acid and 3% sodium bicarbonate solution. The organic layer is dried over sodium sulfate and the toluene is distilled off, affording the compound of the formula ##STR4## with a refractive index of nD20 =1.5880.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][N:15]1[C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([OH:28])[C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][C:20]=2[C:29]([O:31]C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH-].[NH4+:35]>C1COCC1.C(OCC)(=O)C>[CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][N:15]1[C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([OH:28])[C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][C:20]=2[C:29](=[O:31])[NH2:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1Cc1ccccc1
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1Cc1ccccc1
Yield: 44 %

Procedure:
A solution of the 9-[(2-benzylphenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (166 mg, 0.39 mM) in 8 mL THF and 30 mL concentrated aqueous ammonium hydroxide was sonicated for 30 hours at 40-50° C. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 70 mg (44%) of the 9-[(2-benzylphenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a white solid. 1H NMR (CDCl3) δ8.0 (d, 1H, J=8 Hz), 7.4-7.0 (m, 12H), 6.8 (d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), 6.5 (m, 1H), 6.4 (m, 1H), 5.8 (s, 1H), 5.4 (s, 2H), and 4.2 (s, 2H). MS (ES) m/e 405, 407.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:34])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([NH2:33])=[CH:14][C:15]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:16]=2[CH:32]=1)([CH3:3])[CH3:2].[CH2:35]([S:38](Cl)(=[O:40])=[O:39])[CH2:36][CH3:37]>>[CH:1]([O:4][C:5](=[O:34])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([NH:33][S:38]([CH2:35][CH2:36][CH3:37])(=[O:40])=[O:39])=[CH:14][C:15]2[N:19]=[C:18]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:17]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:16]=2[CH:32]=1)([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)CCCCCOc1cc2c(cc1N)nc(-c1ccccc1)n2-c1ccccc1
Reactant: CCCS(=O)(=O)Cl
Product: CCCS(=O)(=O)Nc1cc2nc(-c3ccccc3)n(-c3ccccc3)c2cc1OCCCCCC(=O)OC(C)C

Procedure:
6-[(5-Amino-1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanoic acid isopropyl ester was reacted according to general operating instructions 13 with propanesulfonic acid chloride.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.O.[CH2:14]([NH2:16])[CH3:15]>CO>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:16][CH2:14][CH3:15])=[O:4]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CCN
Solvent: CO
Solvent: O
Product: CCNC(=O)c1ccccc1N
Reaction time: 1 h
Yield: 93.4 %

Procedure:
A round-bottomed flask was charged with isatoic anhydride (5.0 g, 0.030 mol), 200 mL water, and 5 mL of methanol. Ethylamine (2N in methanol, 18.4 mL, 0.036 mol) was added slowly to the reaction mixture. After 1 h, the reaction mixture was concentrated to 20 mL. The reaction mixture was acidified with 1N HCl and extracted with EtOAc. The aqueous layer was basified with 6N NaOH and extracted with EtOAc. The EtOAc layer was dried over Na2SO4, filtered, and concentrated to dryness to afford 2-amino-N-ethylbenzamide (4.6 g, 91%): Mass (M+H)+=165.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH3:21])[N:18]=[C:19]([CH3:20])[N:12]2[N:11]=1)[CH3:2].[Cl:22][S:23](O)(=[O:25])=[O:24]>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:23]([Cl:22])(=[O:25])=[O:24])=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH3:21])[N:18]=[C:19]([CH3:20])[N:12]2[N:11]=1)[CH3:2]
Reactant: CCOc1ccccc1-c1nn2c(C)nc(C)c2c(=O)[nH]1
Reactant: O=S(=O)(O)Cl
Product: CCOc1ccc(S(=O)(=O)Cl)cc1-c1nn2c(C)nc(C)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7.25 g (25.5 mmol) of 2-(2-ethoxyphenyl)-5,7-dimethyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one are initially charged, and 26.74 g (0.23 mol) of chlorosulphonic acid are added with ice-cooling. The mixture is stirred at room temperature overnight and poured into ice-water, and the crystals are filtered off with suction and dried in a vacuum desiccator.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:15])([CH3:14])[CH2:8][CH2:9][C:10]2=O)=[CH:5][C:4]=1[CH3:16].[CH:17]([Mg]Cl)([CH3:19])[CH3:18]>>[CH:17]([C:10]1[C:11]2[C:6](=[CH:5][C:4]([CH3:16])=[C:3]([O:2][CH3:1])[CH:12]=2)[C:7]([CH3:15])([CH3:14])[CH2:8][CH:9]=1)([CH3:19])[CH3:18]
Reactant: COc1cc2c(cc1C)C(C)(C)CCC2=O
Reactant: CC(C)[Mg]Cl
Product: COc1cc2c(cc1C)C(C)(C)CC=C2C(C)C
Yield: 97.9 %

Procedure:
Following General Procedure A, 7-methoxy-4,4,6-trimethyl-3,4-dihydro-2H-naphthalen-1-one (Compound 6, 1.0 g, 4.6 mmol) was reacted with a solution of 2M isopropylmagnesium chloride (12 mL, 22.9 mmol) to give 1.1 g (100%) of the title product as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[CH:4][CH:3]=1.[C:10]([S:14][C:15](=[O:20])[CH2:16][C:17](=[O:19])[CH3:18])([CH3:13])([CH3:12])[CH3:11]>>[C:10]([S:14][C:15](=[O:20])[CH:16]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[C:17](=[O:19])[CH3:18])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(=O)CC(=O)SC(C)(C)C
Reactant: BrCc1ccc(Br)cc1
Product: CC(=O)C(Cc1ccc(Br)cc1)C(=O)SC(C)(C)C

Procedure:
The title compound was prepared by the method of Preparation 11a using 1-bromo-4-bromomethylbenzene and 3-oxothiobutyric acid S-tert-butyl ester.
Reaction SMILES: [CH3:1][C@@H:2]([NH2:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[C:37]([N:45]1[C@H:49]([C:50](O)=[O:51])[CH2:48][S:47](=[O:54])(=[O:53])[CH2:46]1)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C)C=O>[C:37]([N:45]1[C@H:49]([C:50](=[O:51])[NH:10][C@H:2]([CH3:1])[C:3]2[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=2)[CH2:48][S:47](=[O:53])(=[O:54])[CH2:46]1)(=[O:44])[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: C[C@@H](N)c1ccc(O)cc1
Reactant: O=C(O)[C@@H]1CS(=O)(=O)CN1C(=O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)[C@@H]1CS(=O)(=O)CN1C(=O)c1ccccc1)c1ccc(O)cc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
1.00 g (7.29 mmole) of (R)-α-methyl-p-hydroxybenzylamine (prepared as described in Preparation 13), 1.12 g (7.29 mmole) of N-hydroxybenzotriazole monohydrate and 1.51 g (7.29 mmole) of dicyclohexylcarbodiimide were added in that order to a solution of 1.96 g (7.29 mmole) of (4R)-3-benzoyl-1,1-dioxothiazolidine-4-carboxylic acid (prepared as described in Preparation 12) in 100 ml of dimethylformamide cooled at 5° C., and then the mixture was stirred at a temperature between 3° and 6° C. for 30 minutes and then at room temperature for a further 23 hours. The reaction mixture was filtered, the insolubles were washed with 20 ml of ethyl acetate, and the filtrate and the washings were combined. 50 ml of ethyl acetate were added to the combined mixture, which was washed twice, each time with 50 ml of a 4% w/v aqueous solution of sodium bicarbonate, and the organic phase was separated and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by Lobar column chromatography through silica gel (Merck, Art-10402), eluted with a 2:1 by volume mixture of ethyl acetate and cyclohexane. The eluate was concentrated by evaporation under reduced pressure and the residue was lyophilized with a mixture of acetone and benzene to give 2.04 g (72.0%) of the title compound in the form of a colorless powder.
Reaction SMILES: Cl[O-].[Na+].C(=O)(O)[O-].[Na+].[CH2:9]([O:16][CH2:17][CH:18]([OH:28])[CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CC1(C)N([O])C(C)(C)CCC1>C1(C)C=CC=CC=1>[CH2:9]([O:16][CH2:17][C:18](=[O:28])[CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: OC(COCc1ccccc1)COCc1ccccc1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(COCc1ccccc1)COCc1ccccc1
Temperature: 22.5 °C
Reaction time: 0.25 h
Yield: 88.7 %

Procedure:
A mixture of sodium hypochlorite (100 ml, 13% w/v) and saturated sodium bicarbonate (25 ml) was added in one charge to a stirred solution of 1,3-dibenzyloxy-2-propanol (10 g) and 2,2,6,6-tetramethyl-1-piperidinyloxy free radical, (TEMPO) (0.3 g) in toluene (40 ml). The biphasic mixture was stirred at 20-25° C. for 15 minutes when HPLC analysis showed reaction to be complete. The reaction mixture was stirred for a total of 25 minutes at 23° C. The reaction mixture was separated and the organic extract was washed with 5% w/v sodium thiosulfate solution (40 ml) and separated. The organic extract was washed with 1% w/v sodium chloride solution (2×25 ml). The organic extract was then concentrated in vacuo to give an oil which crystallised on standing to give 8.8 g of 1,3-dibenzyloxy-2-propanone in 88.7% yield. The NMR spectrum of the product was concordant with a reference sample.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][CH:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH3:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]Cl>[I-].[K+].C1OCCOCCOCCOCCOCCOC1.C1(C)C=CC=CC=1>[CH3:7][C:8]([CH2:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:22]([CH3:23])[CH:21]=1)([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: Cc1cccc(CCl)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(Cc1cccc(C)c1)C(=O)OCC
Temperature: 85 °C
Yield: 65.9 %

Procedure:
500 ml of toluene, 207 g of ground potassium carbonate, 8 g of potassium iodide, 7 g of 18-crown-6 and 209 g of diethyl methylmalonate were initially introduced into a 2 l four-necked flask. The mixture was heated to 85° C. with stirring. 141 g of 3-methylbenzyl chloride were added dropwise in the course of half an hour and the mixture was then stirred at 90° C. for 8 hours. After cooling, the salts were removed by repeatedly shaking with water and the organic layer was distilled. 184 g of diethyl 2-methyl-2-(3-methylbenzyl)-malonate were obtained at a boiling point of 120° C. and a pressure of about 0.02 mbar. For hydrolysis, the ester was boiled under reflux with stirring for 16 hours with 60 g of NaOH, 170 ml of water and a spatula tip-full of tetradecyltrimethylammonium bromide, ethanol which formed in the meantime being distilled off. The dicarboxylic acid was liberated by acidifying with hydrochloric acid, separated off and heated in xylene for 4 hours under reflux for decarboxylation. The monocarboxylic acid was then esterified with ethanol (p-toluenesulfonic acid as catalyst, cyclohexane as entraining agent for water). 115 g of ethyl 2-(3-methylbenzyl)-propionate (boiling point 70°-73° C. at 0.03 mbar) were obtained. For hydrogenation, 21 g of LiAlH4 were dissolved or suspended in 800 ml of tetrahydrofuran in a 2 l four-necked flask under nitrogen. A mixture of 110 g of ethyl 2-(3-methylbenzyl)-propionate and 100 ml of tetrahydrofuran were then added dropwise with ice cooling. The mixture was then decomposed with ice and hydrochloric acid, extracted with ether and dried over K2CO3, and 75 g of 2-methyl-3-(3-methylphenyl)propan-1-ol (boiling point 68°-70° C. at 0.1 mbar) were obtained by distillation.
Reaction SMILES: [NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:20](O)=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].CN1CCOCC1.ClC(OCC)=O.S(O)(C1C=CC(C)=CC=1)(=O)=O.[NH2:57][C@H:58]([C:63]([O:65][CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)=[O:64])[CH2:59][CH:60]([CH3:62])[CH3:61]>O1CCCC1.CN(C)C=O>[NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:20]([NH:57][C@H:58]([C:63]([O:65][CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)=[O:64])[CH2:59][CH:60]([CH3:62])[CH3:61])=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10]
Reactant: CC(C)C[C@H](N)C(=O)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1
Agent: CCOC(=O)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OCc2ccccc2)C(=O)N[C@@H](CC(C)C)C(=O)OCc2ccccc2)cc1
Temperature: -5 °C
Reaction time: 0.08 h

Procedure:
In 500 ml of tetrahydrofuran is dissolved 46.2 g (100 millimoles) of Z-Arg(Tos)-OH, and 11 ml of N-methylmorpholine is added to the solution and the mixture is stirred at -5° C. for 5 minutes. Then, 9.6 ml of ethyl chloroformate is added to the mixture, and a cooled solution of 39.4 g (100 millimoles) of Tos-OH.H-Leu-OBzl and 11 ml of N-methylmorpholine in dimethylformamide is added to the above mixture. The resulting mixture is stirred at -5° to 0° C. for 4 hours and concentrated under reduced pressure. The residue is dissolved in 700 ml of ethyl acetate, and the solution is washed with 0.1 N aqueous hydrochloric acid, 1 N aqueous NaHCO3 and water and concentrated under reduced pressure. Ether is added to the residue and the formed precipitate is recovered by filtration to obtain 58 g of intended Z-Arg(Tos)-Leu-OBzl (the yield being 87%).
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][CH2:5][NH:6][C:7](=[O:38])[C:8]1[CH:13]=[CH:12][C:11]([O:14][C@H:15]([C:22]2[CH:23]=[N:24][C:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)=[CH:26][CH:27]=2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:10][CH:9]=1.[OH-].[Na+]>C(O)C>[F:36][C:34]([F:35])([F:37])[C:31]1[CH:30]=[CH:29][C:28]([C:25]2[N:24]=[CH:23][C:22]([C@@H:15]([O:14][C:11]3[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:39])=[O:2])=[O:38])=[CH:9][CH:10]=3)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:27][CH:26]=2)=[CH:33][CH:32]=1
Reactant: CCCCCC[C@H](Oc1ccc(C(=O)NCCC(=O)OC)cc1)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCC[C@H](Oc1ccc(C(=O)NCCC(=O)O)cc1)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1

Procedure:
or (S)-3-(4-{1-[6-(4-Trifluoromethyl-phenyl)-pyridin-3-yl]-heptyloxy}-benzoylamino)-propionic acid methyl ester is taken into ethanol (2 mL), treated with 5N NaOH (1 mL) for 2 h, concentrated, acidified with 5 N HCl, extracted with ethyl acetate, dried over sodium sulfate. Concentration gives (R) or (S)-3-(4-{1-[6-(4-Trifluoromethyl-phenyl)-pyridin-3-yl]-heptyloxy}-benzoylamino)-propionic acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[C:9]([NH:12][CH2:13][C:14]([OH:16])=[O:15])(=O)[CH3:10].C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C(OC)(C)(C)C.CC(C)=O>[CH3:10][C:9]1[O:16][C:14](=[O:15])/[C:13](=[CH:7]/[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)/[N:12]=1
Reactant: O=Cc1cccnc1
Reactant: CC(=O)NCC(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CC1=N/C(=C\c2cccnc2)C(=O)O1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Under nitrogen, acetone (40.0 l), followed by pyridine-3-carbaldehyde (20.0 kg, 186.9 mol), was added to N-acetylglycine (32.7 kg, 280.0 mol) and sodium acetate (15.3 kg, 186.9 mol). With stirring, acetic anhydride (40.0 l, 429.0 mol) was added. Within 30 min, the reaction mixture was heated to reflux temperature and then stirred under reflux for 1.5 h. This gave a thin reddish suspension. The suspension was cooled to 50° C., and methyl tert-butyl ether (80.0 l) was then added. Ice-water (<2° C., 200.0 l) was added as quickly as possible (<5 min), with stirring and cooling, and the mixture was then stirred at 5–10° C. for 1 h. The beige suspension was introduced into a centrifuge which had been inertized with nitrogen. The precipitate was centrifuged, washed with deionized water (80.0 l) and dried under reduced pressure at 40° C. Yield: 24.8 kg (131.9 mol, 70.6% of theory). M.p.: 173° C.; MS (DCl): m/z (%)=189 ([M+H+], 100); 1H-NMR (200 MHz, DMSO-d6): δ=2.40 (s, 3H), 7.28 (s, 1H), 7.53 (dd, 1H), 8.61 (d, 2H), 9.18 (brs, 1H); IR (KBr): ν=1799.9, 1777.4, 898.0 cm−1.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[OH-].[K+].Cl[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20].Cl>CS(C)=O>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([O:2][C:1]2[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=2)=[C:13]([N+:19]([O-:21])=[O:20])[CH:14]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Reactant: Oc1ccc(O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc(Cl)ccc1Oc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
A solution of hydroquinone (1.21 g, 0.011 mol) and potassium hydroxide (0.894 g, 0.0159 mol) in anhydrous dimethylsulfoxide (7 mL) was heated at 120° for 30 minutes under a nitrogen atmosphere. A solution of 2,5-dichloronitrobenzene (1.90 g, 0.0099 mol) in dimethylsulfoxide (3 mL) was added dropwise over a 30 minute period at 120° then let the reaction stir for 1 hour at the same temperature. The reaction was then cooled in an ice bath and poured into 30 mL of ice water. The mixture was acidified with concentrated hydrochloric acid to pH 1 and extracted with ethyl ether (2×50 mL). The combined ethereal extracts were washed with water (3×150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation under vacuum. Purification of the residue by silica gel chromatography using methylene chloride as eluent provided the product as a tan solid (1.34 g, 51%).
Reaction SMILES: [OH:1][CH2:2][CH:3]=[C:4]([CH2:6][CH2:7][CH:8]=[C:9]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH3:10])[CH3:5]>[Pd].C(O)C>[CH3:16][CH:14]([CH2:13][CH2:12][CH2:11][CH:9]([CH2:8][CH2:7][CH2:6][CH:4]([CH2:3][CH2:2][OH:1])[CH3:5])[CH3:10])[CH3:15]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCO
Agent: [Pd]
Solvent: CCO
Product: CC(C)CCCC(C)CCCC(C)CCO
Reaction time: 36 h
Yield: 93.6 %

Procedure:
A flask containing a stirring suspension of farnesol (5.7 ml, 22.5 mmol) and palladium on carbon (10% Pd, 1 g, 0.04 equ) in ethanol (15 ml) was evacuated, and then filled with hydrogen. The reaction mixture was then stirred under an atmosphere of hydrogen for 36 hours. After this time the reaction was filtered and the filtrate concentrated in vacuo to give hexahydrofarnesol (44) (4.81 g, 93%) as a colourless oil.
Reaction SMILES: Cl.F[C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[C:5]([CH3:15])[CH:4]=1.[Na].[CH2:17]([OH:19])[CH3:18]>>[CH2:17]([O:19][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[C:5]([CH3:15])[CH:4]=1)[CH3:18]
Reactant: CCO
Reactant: Cc1cc(F)nc(N2CCNCC2)c1
Agent: Cl
Agent: [Na]
Product: CCOc1cc(C)cc(N2CCNCC2)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
1-(6-Fluoro-4-methyl-2-pyridyl)piperazine hydrochloride (80 mg, 0.34 mmol) was dissolved in anhydrous ethanol (1.5 ml), sodium (50 mg, 1.96 mmol) was added and the mixture was stirred for five minutes at room temperature and then at 140° C. for one hour under microwave heating in a closed vial. The mixture was filtered through kieselguhr, the filtrate was concentrated under reduced pressure and the residue was treated with acetonitrile and then ethylacetate. The liquids were separated from solids by centrifugation and decanting and the combined supernatants were concentrated under reduced pressure to give 85 mg of a solid (quantitative). MS (multi-mode) m/z=222.2 [M+1]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH3:8])=[CH:5][CH:4]=[C:3]1[C:9]([C:11]1[N:15]2[CH2:16][CH2:17][CH:18]([C:19]([O:21][CH:22](C)[C:23]3C=CC=CC=3)=[O:20])[C:14]2=[CH:13][C:12]=1[CH3:30])=[O:10].B(Br)(Br)Br.C(O)C>C(Cl)Cl>[CH3:1][N:2]1[C:6]([S:7][CH3:8])=[CH:5][CH:4]=[C:3]1[C:9]([C:11]1[N:15]2[CH2:16][CH2:17][CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]2=[CH:13][C:12]=1[CH3:30])=[O:10]
Reactant: CSc1ccc(C(=O)c2c(C)cc3n2CCC3C(=O)OC(C)c2ccccc2)n1C
Agent: BrB(Br)Br
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C1CCn2c1cc(C)c2C(=O)c1ccc(SC)n1C
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 86.2 %

Procedure:
To a solution of (-)-α-methylbenzyl 5-(1-methyl-5-methylthiopyrrol-2-oyl)-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate (3.0 g, 7.1 mmol) in CH2Cl2 (80 ml) at -78° C. under N2 atmosphere was slowly added a 1.0M solution of boron tribromide in CH2Cl2 (15.6 ml, 15.6 mmol). The solution was stirred at -78° C. for 5 minutes and absolute ethanol (30 ml) was added slowly and warmed to room temperature then stirred at room temperature for 2 hours. The solution was washed with water (3×25 ml.) and brine (1×25 ml.), dried over anhydrous sodium sulfate, filtered and rotovapped at 20° C. to an orange solid and chromatographed on a flash silica gel column (5×15 cm) eluted with 50% ether/hexane. The resulting crude product was crystallized from hot EtOH to afford 2.12 g (86% yield) of (-)-ethyl 5-(1-methyl- 5-methylthiopyrrol-2-oyl)-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate. [α]D25 =-127.4 (CHCl3, C=1.06); m.p. 113°-115° C.