Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1.C[Si](C)(C)[C:19]([F:22])([F:21])[F:20].Cl>COCCOC.CCOC(C)=O.[F-].[Cs+]>[F:20][C:19]([F:22])([F:21])[CH:11]([C:10]1[CH:13]=[CH:14][C:7]([O:6][CH2:5][CH2:4][CH2:3][C:2]([F:15])([F:16])[F:1])=[CH:8][CH:9]=1)[OH:12]
Reactant: O=Cc1ccc(OCCCC(F)(F)F)cc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: Cl
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: OC(c1ccc(OCCCC(F)(F)F)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 123.4 %

Procedure:
To the solution of Intermediate 2A (26.7 g, 114 mmol) and trimethyl(trifluoromethyl)silane (16.9 g, 119 mmol) in anhydrous DME (112 mL) was added CsF (500 mg, 3.29 mmol). The reaction was stirred at rt for 16 h. To the mixture was added 4 N aq HCl (114 mL) and the reaction was stirred at rt for 2.5 h. The reaction was diluted with EtOAc (300 mL) and washed with water, sat'd aq NaHCO3, sat'd aq NaCl, dried over anhydrous MgSO4, filtered and concentrated to provide Intermediate 2B (42.5 g, 122%) as an oil. The crude product was used without further purification. LCMS Anal. Calc'd for C12H12F6O2 302.21, found [M−H] 301.2.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH2:8][CH2:7][C:6](=[O:9])[CH:5]=1)[CH3:2].C1C(=O)N([Br:17])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:17][C:5]1[C:6](=[O:9])[CH2:7][CH2:8][C:4]=1[O:3][CH2:1][CH3:2]
Reactant: CCOC1=CC(=O)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC1=C(Br)C(=O)CC1

Procedure:
3-Ethoxy-cyclopent-2-enone (Intermediate NINE1) (commercially available from Aldrich) (10.0 g, 77.6 mmol) in carbon tetrachloride (15 mL) at 0° C. was treated with NBS (15.3 g, ˜85 mmol) added portion-wise over 30 m. After 1 h at 0° C. the mixture was partitioned between CH2Cl2 and saturated NaHCO3. The aqueous layer was extracted with CH2Cl2. The pooled organic layers were washed with H2O (2×) and dried over MgSO4. The mixture was filtered and evaporated to dryness. The solid was recrystallized from pentane:ether to give 13.3 g of 2-bromo-3-ethoxy-cyclopent-2-enone (Intermediate NINE2).
Reaction SMILES: CC1C=CC(S(NCl)(=O)=O)=CC=1.[Br:13][C:14]1[C:19]([OH:20])=[CH:18][CH:17]=[CH:16][N:15]=1.[I-:21].[Na+].Cl>C(OCC)(=O)C.O.CN(C)C=O>[Br:13][C:14]1[C:19]([OH:20])=[CH:18][CH:17]=[C:16]([I:21])[N:15]=1
Reactant: [I-]
Reactant: Oc1cccnc1Br
Agent: Cc1ccc(S(=O)(=O)NCl)cc1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Oc1ccc(I)nc1Br
Reaction time: 0.17 h
Yield: 88.2 %

Procedure:
17.6 g of Chloramine T was added to a mixture of 10.9 g of 2-bromo-3-hydroxypyridine, 9.35 g of sodium iodide and 110 ml of N,N-dimethylformamide under stirring in an ice bath, followed by stirring at the same temperature for 30 minutes and then at room temperature for 10 minutes. Water, ethyl acetate and 11 ml of an aqueous 6N hydrochloric acid solution were added thereto, and the organic phase was washed with brine and the solvent was removed. The residue was subjected to silica gel column chromatography and eluted with 30% ethyl acetate/hexane, to give 16.5 g of the target compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([CH:9]=[O:10])[CH:5]=[CH:4][C:3]=1[OH:11].Br[CH2:13][CH2:14][CH2:15][C:16]([O:18]CC)=[O:17].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([CH:9]=[O:10])[CH:5]=[CH:4][C:3]=1[O:11][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: O=Cc1ccc(O)c(Cl)c1Cl
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OCCCC(=O)O)c(Cl)c1Cl

Procedure:
A mixture of 2,3-dichloro-4-formylphenol (5.73 g., 0.03 mole), ethyl 4-bromobutyrate (11.7 g., 0.06 mole) and potassium carbonate (8.28 g., 0.06 mole) in dimethylformamide (25 ml.) is heated at 50°-60° C. for 11/2 hours. Water (50 ml.) is added and the mixture is extracted with ether. The ether extract is dried and evaporated. To the residue is added a solution composed of 48 ml. of 40% sodium bisulfite and 12 ml. of alcohol. The precipitated 4isulfite addition compound then is washed with alcohol and ether. The solid is suspended in water heated in a steam bath. An oily layer of the free aldehyde is formed. The hot water then is decanted and the oily layer is extracted with ether and the ether evaporated. The residue is heated to 80° C. in a mixture of potassium hydroxide (2.8 g.), methanol (30 ml.) and water (5 ml.), the resulting solution is evaporated to dryness and the residue dissolved in water. Upon acidification a solid separates. The solid is crystallized from benzene to obtain 2.9 g. of 4-(2,3-dichloro-4-formylphenoxy)butyric acid, M.P. 147°-148° C.
Reaction SMILES: ClCC[CH2:4][CH2:5][CH:6]([S:14][CH:15]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[N:22]=1)CCCCCl)C1C=CC=C(C)N=1.ClC1C=CC=C(C(OO)=[O:36])C=1.[CH2:39]([Cl:41])Cl>>[Cl:41][CH2:39][CH2:4][CH2:5][CH2:6][S:14]([CH2:15][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[N:22]=1)=[O:36]
Reactant: ClCCl
Reactant: Cc1cccc(C(CCCCCl)SC(CCCCCl)c2cccc(C)n2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: Cc1cccc(CS(=O)CCCCCl)n1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
To a solution of 4-chlorobutyl(6-methyl-2-pyridyl)methyl sulphide (9.2 g) in methylene chloride (140 cc), an 82.5% strength solution of meta-chloroperbenzoic acid (8.2 g) in methylene chloride (90 cc) is added dropwise in the course of 1 hour 30 minutes at a temperature in the region of 15° C. The mixture is stirred for 16 hours at a temperature in the region of 20° C. and then poured into neutral silica gel (225 g; 0.063-0.200 mm) contained in a column 4.3 cm in diameter. The column is eluted successively with methylene chloride (2.5 liters), a mixture (500 cc) of methylene chloride and ethyl acetate (50:50 by volume), ethyl acetate (500 cc) and a mixture (1.25 liters) of ethyl acetate and methanol (90:10 by volume), collecting 250-cc fractions. Fractions 15 to 19 are combined and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 50° C. 2-[(4-Chlorobutyl)sulphinylmethyl]-6-methylpyridine (8.8 g) is thereby obtained in the form of a yellow oil, and this is used without further purification in the subsequent syntheses.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7](O)=[O:8])[CH:2]=1.Cl.[NH2:17][OH:18]>>[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([NH:17][OH:18])=[O:8])[CH:2]=1
Reactant: O=C(O)c1cccc(-c2ccccc2)c1
Reactant: NO
Agent: Cl
Product: O=C(NO)c1cccc(-c2ccccc2)c1

Procedure:
Using the procedure of Example 1 part (b), but using 3-biphenyl carboxylic acid and hydroxylamine hydrochloride, the desired compound was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](O)=[N:7][C:6]([NH:13][C:14]1[CH:18]=[C:17]([CH3:19])[NH:16][N:15]=1)=[CH:5]2.O=P(Cl)(Cl)[Cl:22]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([Cl:22])=[N:7][C:6]([NH:13][C:14]1[CH:18]=[C:17]([CH3:19])[NH:16][N:15]=1)=[CH:5]2
Reactant: Cc1cc(Nc2cc3cc(Br)ccc3c(O)n2)n[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(Nc2cc3cc(Br)ccc3c(Cl)n2)n[nH]1

Procedure:
Similar procedure as described in example 9B was used, starting from 6-Bromo-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-ol and POCl3 to give (6-Bromo-1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS: m/e 337 (MH+).
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:14][CH2:13][S:12][CH:11]2[C:15](O)=[O:16])(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:27])=O.CN(C=O)C>C(Cl)Cl>[C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:14][CH2:13][S:12][CH:11]2[C:15]([Cl:27])=[O:16])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1
Temperature: -10 °C
Yield: 100 %

Procedure:
Intermediate VIII (Scheme 3), e.g., 3-(biphenyl-4-ylsulfonyl)-1,3-thiazolidine-2-carboxylic acid (1.747 g, 5 mmol) was dissolved in DCM (20 mL). The resulting solution was cooled down to −10° C. and oxalyl chloride (0.645 mL, 7.5 mmol) was added slowly. DMF (0.1 mL) was added carefully. The reaction mixture was allowed to warm to RT over 1 h and stirred an additional hour at RT. As the reaction was complete, the solvents were evaporated. Toluene was added and evaporated to remove residual oxalyl chloride. This process was repeated twice, affording intermediate XXX, e.g., 3-(biphenyl-4-ylsulfonyl)-1,3-thiazolidine-2-carbonyl chloride as a yellow solid (1.839 g, quantitative yield). α-Aminophenylacetic acid (831 mg, 5.5 mmol) was dissolved in water (20 mL). TEA (2.77 mL, 20 mmol) was added carefully. THF (25 mL) was added to reaction mixture. The reaction mixture was cooled to 0° C. Acid chloride previously prepared XXX, e.g. 3-(biphenyl-4-ylsulfonyl)-1,3-thiazolidine-2-carbonyl chloride dissolved in THF (25 mL) was added dropwise. The reaction mixture was stirred 15 min at 0° C. and overnight at RT. Solvents were concentrated and the resulting aqueous fraction was acidified with HCl 5N and extracted with 3 portions of EtOAc. Combined organic phases were dried over MgSO4, filtrated and evaporated. The crude product was recrystallized in acetone/Et2O mixture, affording carboxylic acid Ia, e.g., ({[3-(biphenyl-4-ylsulfonyl)-1,3-thiazolidin-2-yl]carbonyl}amino)(phenyl)acetic acid in 97% purity by HPLC (943 mg, 39% yield).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[O:9])[CH2:7]Br)=[CH:4][CH:3]=1.CN(C)[CH:14]=[O:15].N1(C2[CH2:27][CH2:26][S:25][CH2:24][CH:23]=2)CCCC1>O>[F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[O:9])[CH2:7][CH:23]2[C:14](=[O:15])[CH2:27][CH2:26][S:25][CH2:24]2)=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: C1=C(N2CCCC2)CCSC1
Solvent: O
Product: O=C(CC1CSCCC1=O)c1ccc(F)cc1
Reaction time: 6 h

Procedure:
A solution of 21.7 g (0.10 mole) of 4-fluorophenacyl bromide in 50 ml. of dimethylformamide is added dropwise to a cold stirred solution of 16.9 g (0.10 mole) of 5,6-dihydro-4-(1-pyrrolidinyl)-2H-thiopyran [Example 1 (a)], and 100 ml. of dimethylformamide under nitrogen. After 6 hours at ambient temperature, the mixture is diluted with water and extracted with chloroform. The chloroform solution is washed with water, dried over magnesium sulfate and concentrated to an oil. Crystallization and recrystallization from ethanol gives off-white crystals of 3-(4-fluorophenacyl)-2,3,5,6-tetrahydrothiopyran-4-one, m.p. 111.5° to 113.5°C.
Reaction SMILES: Cl[CH2:2][CH:3]=O.[NH2:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:9]=1.Cl.N>CCOCC.O>[C:17]1([N:10]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:8]3[CH2:7][CH2:6][NH:5][CH2:2][CH2:3][C:9]2=3)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCCc1cn(-c2ccccc2)c2ccccc12
Reactant: O=CCCl
Agent: Cl
Agent: N
Solvent: CCOCC
Solvent: O
Product: c1ccc(-n2c3c(c4ccccc42)CCNCC3)cc1

Procedure:
55.6 ml chloroacetaldehyde (45% in water) are added dropwise to 87.2 g 3-(2-aminoethyl)-1-phenylindole, 400 ml 2N hydrochloric acid and 2.5 liters water at 50°. The mixture is heated for 1 hour at 95°, treated once more with 55.6 ml chloroacetaldehyde and heated for a further 45 minutes. The mixture is then cooled to 0°, made alkaline with conc. ammonia and shaken with ether. The organic phase is dried over sodium sulphate, and purified with animal charcoal, and concentrated. The residue 1-chloromethyl-1,2,3,4-tetrahydro-9-phenylpyrido[3,4-b]indole is converted into the hydrochloride, m.p. 174°-180° (from ethanol/ether).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][C:29]=1[O:36][CH3:37]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][C:29]=4[O:36][CH3:37])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COc1cc(C#N)ccc1OCCCBr
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C#N)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 68.2 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.0 g, 13.6 mmoles), K2CO3 (2.8 g), 4-(3-bromopropoxy)-3-methoxybenzonitrile (4.0 gm, 14.8 mmoles) in acetonitrile (70 ml) was heated at reflux for 3 hr. At the end of the reaction, the solvent was removed on a rotary evaporator. The organic material was extracted into dichloromethane (250 ml) and the inorganics were filtered off. The dichloromethane solution was concentrated to a crude oil. The purification was done by flash chromatography over a silica gel column (SiO2, 55 gm; eluted with dichloromethane, 600 ml; 1% methanol in dichloromethane, 600 ml). The material thus obtained was crystallized from a small amount of dichloromethane. Recrystallization from ethanol (25 ml) provided 3.8 gm (68%) of 4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxybenzonitrile as white crystals, m.p.=107°-108° C.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[C:11]([O:13][CH2:14]/[CH:15]=[C:16](/[C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)\[C:17]2[CH:22]=[CH:21][C:20]([C:23]#[C:24][CH2:25][N:26]3CCO[CH2:28][CH2:27]3)=[CH:19][CH:18]=2)[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.C([N:42]1[CH:46]=CC=N1)C#C.[O:47]1CCC[CH2:48]1>C(N(CC)CC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:1][C:2]1[CH:12]=[C:11]([O:13][CH2:14]/[CH:15]=[C:16](/[C:32]2[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=2)\[C:17]2[CH:22]=[CH:21][C:20]([C:23]#[C:24][CH2:25][N:26]3[CH:27]=[CH:28][CH:46]=[N:42]3)=[CH:19][CH:18]=2)[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([O:47][CH3:48])=[O:8]
Reactant: Cc1ccc(/C(=C/COc2ccc(OCC(=O)O)c(C)c2)c2ccc(C#CCN3CCOCC3)cc2)cc1
Reactant: C#CCn1cccn1
Reactant: C1CCOC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(OC/C=C(/c2ccc(C)cc2)c2ccc(C#CCn3cccn3)cc2)cc1C
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A solution of methyl (Z)-[2-methyl-4-[3-(4-iodophenyl)-3-(4-methylphenyl)]allyloxy]-phenoxy]acetate (310 mg, 0.587 mmol; example 3) in a mixture of tetrahydrofuran (9 mL) and triethylamine (9 mL) was degassed and 1-propargyl-1H-pyrazole (124 mg, 1.17 mmol) was added in argon atmosphere. The solution was cooled down; tetrakis(triphenylphosphine)palladium (54 mg, 0.046 mmol) and copper(I) iodide (17.8 mg, 0.094 mmol) were added. The reaction mixture was stirred at ambient temperature for 4 days, subsequently evaporated in vacuo and the residue was dissolved in ethyl acetate (20 mL). The solution was washed with water (3×15 mL), dried with anhydrous magnesium sulphate and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 7:3) yielding methyl (Z)-[2-methyl-4-[3-(4-methylphenyl)-3-[4-(3-pyrazol-1-ylpropynyl)phenyl]allyloxy]phenoxy]acetate.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[CH2:9]([NH:16][C:17](=[O:24])[C@H:18]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH2:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.Cl[CH2:33][C:34](=[O:47])[CH2:35][C:36]12[CH2:45][CH:40]3[CH2:41][CH:42]([CH2:44][C:38]([CH3:46])([CH2:39]3)[CH2:37]1)[CH2:43]2.CC12CC3CC(CC(CC(O)=O)(C3)C1)C2>C1COCC1>[O:47]=[C:34]([CH2:35][C:36]12[CH2:45][CH:40]3[CH2:41][CH:42]([CH2:44][C:38]([CH3:46])([CH2:39]3)[CH2:37]1)[CH2:43]2)[CH2:33][N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([N:16]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:17](=[O:24])[C@H:18]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH2:19])=[O:5]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccccc1
Reactant: CC12CC3CC(C1)CC(CC(=O)CCl)(C3)C2
Agent: CC12CC3CC(C1)CC(CC(=O)O)(C3)C2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)CC12CC3CC(CC(C)(C3)C1)C2
Yield: 78.9 %

Procedure:
Using the procedure described in Example 5, a solution of L-proline-L-isoleucine benzylamide (162 mg, 0.51 mmol), and triethylamine (358 uL, 5.0 eq), in THF (2 mL), was treated with 246 mg (1.0 eq) of 1-chloro-2-oxo-3-(3-methyl-adamantan-1-yl) -propane (prepared from 3-methyl-1-adamantaneacetic acid using the procedure described in example 1) to provide 210 mg (78%) of L-isoleucine, N-[1-(2-oxo-3-(3-methyl-adamantan-1-yl)-propyl)-L-prolyl] benzylamide as a colorless residue.
Reaction SMILES: [H-].[Na+].C[O:4][C:5]1[CH2:10][CH2:9][NH:8][C:7](=[O:11])[CH:6]=1.[CH2:12](I)[CH3:13]>CN(C)C=O>[CH2:12]([N:8]1[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][C:7]1=[O:11])[CH3:13]
Reactant: CCI
Reactant: COC1=CC(=O)NCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1CCC(=O)CC1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 78 %

Procedure:
Sodium hydride (in the form of a 60% dispersion in oil) (447 mg) is suspended in N,N-dimethylformamide (10 ml), and thereto is added dropwise a solution of 4-methoxy-5,6-dihydro-2(1H)-pyridone (1.29 g) in N,N-dimethylformamide (30 ml). The mixture is stirred under ice-cooling for 30 minutes, and thereto is added dropwise ethyl iodide (0.97 ml). The mixture is stirred under ice-cooling for 30 minutes and further at room temperature for 2.5 hours. The reaction mixture is poured onto water and extracted with chloroform. The extract is washed with a saturated sodium chloride solution and dried. After evaporating the solvent, the residue is dissolved in ethanol (120 ml) and thereto is added 10% hydrochloric acid (60 ml), and the mixture is allowed to stand at 25° C. for 5 hours. After distilling off the solvent under reduced pressure, the residue is dissolved in chloroform, washed with 5% aqueous sodium hydrogen carbonate solution and water, and then dried. The solvent is distilled off to give 1-ethyl-2,4-dioxopiperidine (1.12 g, 78%).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([C@H:25]([NH2:29])[C:26]([OH:28])=[O:27])[CH2:11][C:12]([NH:14][C@H:15]([C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])[CH2:16][SH:17])=[O:13]>CC(C)=O.O>[NH2:29][C@H:25]([C:26]([OH:28])=[O:27])[CH2:10][CH2:11][C:12]([NH:14][C@H:15]([C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])[CH2:16][S:17][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:13]
Reactant: O=C(Cl)c1ccccc1
Reactant: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Solvent: CC(C)=O
Solvent: O
Product: N[C@@H](CCC(=O)N[C@@H](CSC(=O)c1ccccc1)C(=O)NCC(=O)O)C(=O)O
Temperature: 25 °C
Yield: 78 %

Procedure:
Using in the procedure of Example 1 benzoyl chloride in place of pivaloyl chloride, L-glutathione reduced (15.4 g) affords a crude white solid which is suspended in boiling acetone/water (3/1; 400 ml) for thirty minutes. After cooling at room temperature the white precipitate is collected by filtration and washed with acetone (20 ml). Under vacuum drying yields γ-L-glutamyl-S-benzoyl-L-cysteinyl-glycine (16 g yield=78%).
Reaction SMILES: [CH2:1]([NH:8][C@H:9](C)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([Li])CCC.[CH3:22][O:23][C:24]1[N:29]=[CH:28][C:27]([CH:30]=[CH:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:26][CH:25]=1.[NH4+].[Cl-]>C1COCC1.CCCCCC.CCOC(C)=O>[CH2:35]([O:34][C:32](=[O:33])[C@H:31]([CH3:17])[C@@H:30]([C:27]1[CH:28]=[N:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=1)[N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH3:36]
Reactant: [Li]CCCC
Reactant: CCOC(=O)C=Cc1ccc(OC)nc1
Reactant: C[C@@H](NCc1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](C)[C@@H](c1ccc(OC)nc1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of N-benzyl-(R)-α-methylbenzylamine (97.5 g, 462 mmol) in THF (750 mL) at 0° C. was added n-butyllithium (2.5M in hexanes; 178.5 mL, 446 mmol). The dark violet solution was stirred at 0° C. for 20 minutes, cooled to −78° C., and the ester 1-3 (63.7 g, 308 mmol) in THF (250 mL) was added over 60 minutes. The resulting solution was stirred at −78° C. for 1 hr, then cannulated into saturated NH4Cl and extracted with EtOAc, washed with water, then brine, dried and concentrated in vacuo to give an oil. Column chromatography (silica gel; hexane/EtOAc 9:1 then 4:1) gave 1–4 as an oil contaminated with N-benzyl-(R)-α-methylbenzylamine. This oil was taken up in 5% AcOH in water and extracted with diethyl ether (4×). The organic layers were dried over MgSO4 and the solvent removed to give the title compound 1–4.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:9]=[C:8]([CH2:10][CH2:11][CH3:12])[NH:7][C:6](=[O:13])[CH:5]=1.Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][C:4]1[N:9]=[C:8]([CH2:10][CH2:11][CH3:12])[N:7]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:20][CH:21]=2)[C:6](=[O:13])[CH:5]=1
Reactant: CCCc1nc(COC)cc(=O)[nH]1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCc1nc(COC)cc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 43.1 %

Procedure:
A mixture of 6-(methoxymethyl)-2-propylpyrimidin-4(3H)-one (17 g), 4′-(bromomethyl)biphenyl-2-carbonitrile (27 g) and potassium carbonate (25 g) in acetonitrile (300 mL) was stirred overnight at 50° C. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale yellow solid (15 g, 43%).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:12]([CH2:15][CH3:16])=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:17]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.ClC1C2N(C(CCC)=NN=2)C2C(N=1)=CC=CC=2.C1(N)CCCC1>>[CH:17]1([NH:23][C:2]2[C:3]3[N:4]([C:12]([CH2:15][CH3:16])=[N:13][N:14]=3)[C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: NC1CCCCC1
Reactant: CCc1nnc2c(Cl)nc3ccccc3n12
Agent: CCCc1nnc2c(Cl)nc3ccccc3n12
Agent: NC1CCCC1
Product: CCc1nnc2c(NC3CCCCC3)nc3ccccc3n12

Procedure:
The title compound was prepared essentially as described in Example 4 substituting 4-chloro-1-ethyl[1,2,4]triazolo[4,3-a]quinoxaline and cyclohexanamine for 4-chloro-1-propyl[1,2,4]triazolo [4,3-a]quinoxaline and cyclopentanamine respectively; mp 217°-220° C.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3]1[CH2:8][CH2:7][CH:6]=[CH:5][CH:4]=1.[C:10]1(=[O:16])[NH:14][C:13](=[O:15])[CH:12]=[CH:11]1>O1CCOCC1>[CH3:1][N:2]([CH3:9])[C:3]12[CH2:8][CH2:7][CH:6]([CH:5]=[CH:4]1)[CH:12]1[CH:11]2[C:10](=[O:16])[NH:14][C:13]1=[O:15]
Reactant: O=C1C=CC(=O)N1
Reactant: CN(C)C1=CC=CCC1
Solvent: C1COCCO1
Product: CN(C)C12C=CC(CC1)C1C(=O)NC(=O)C12

Procedure:
9 g (73 mmol) of 1-dimethylaminocyclohexa-1,3-diene and 6.4 g (66 mmol) of maleimide are stirred in 100 ml of absolute dioxane at room temperature overnight. The mixture is concentrated and the residue is recrystallized from isopropanol.