Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:15](=[O:16])[CH:14]([NH:17]C(=O)OC(C)(C)C)[CH2:13][S:12][CH2:11][CH2:10]2)[CH:5]=[C:4]([Cl:25])[N:3]=1.Cl>O1CCOCC1>[ClH:1].[NH2:17][CH:14]1[CH2:13][S:12][CH2:11][CH2:10][N:9]([CH2:8][C:6]2[CH:5]=[C:4]([Cl:25])[N:3]=[C:2]([Cl:1])[CH:7]=2)[C:15]1=[O:16]
Reactant: CC(C)(C)OC(=O)NC1CSCCN(Cc2cc(Cl)nc(Cl)c2)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: NC1CSCCN(Cc2cc(Cl)nc(Cl)c2)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
230 mg of 36 (0.57 mmol) are taken up in a 25 ml round-bottomed flask and 3 ml of a solution of hydrogen chloride in dioxane (4M) are added. The mixture is stirred for 2 hours at room temperature under argon. After evaporating off the solvent, 290 mg of amine 37 are obtained in hydrochloride form, which product is used directly in the following step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][CH:5]1[C:9](=[O:10])[NH:8][C:7](=[O:11])[NH:6]1.Br[CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1.[O-]S([O-])(=O)=O.[Mg+2].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[CH2:4][CH:5]1[C:9](=[O:10])[N:8]([CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)[C:7](=[O:11])[NH:6]1
Reactant: BrCc1ccc2ccccc2c1
Reactant: COC(=O)CC1NC(=O)NC1=O
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CC1NC(=O)N(Cc2ccc3ccccc3c2)C1=O
Reaction time: 16 h
Yield: 53.4 %

Procedure:
A solution of (2,5-dioxo-imidazolidin-4-yl)-acetic acid methyl ester (6.48 g, 37.6 mmol) in DMF (250 mL) is treated with 2-(bromomethyl)-napthalene (9.15 g, 41.4 mmol), MgSO4 (4.53 g, 37.6 mmol) and then K2CO3 (15.61 g, 0.113 mol) at 0° C. The resultant mixture is warmed to room temperature and stirred under N2 for 16 hours. The reaction mixture is filtered, and then aqueous 1N HCl (300 mL) is added to the filtrate. The filtrate is extracted with Et2O and the organic layer dried. The solvent is removed to give a crude oil which is purified by flash chromatography using 2:1 hexanes:acetone to afford 6.27 g of (1-naphthalen-2-ylmethyl-2,5-dioxo-imidazolidin-4-yl)-acetic acid methyl ester (53%). Rf=0.32 (1:1 hexanes:acetone). 1H NMR.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[C:6]([F:9])[N:5]=[C:4]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])[CH:3]=1.[OH-].[NH4+:17].O>CN1C(=O)CCC1>[NH2:17][C:2]1[C:7]([F:8])=[C:6]([F:9])[N:5]=[C:4]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])[CH:3]=1
Reactant: CC(C)OC(=O)c1cc(F)c(F)c(F)n1
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)OC(=O)c1cc(N)c(F)c(F)n1
Reaction time: 8 h
Yield: 68 %

Procedure:
Isopropyl 4,5,6-trifluoropicolinate (17.52 g, 80 mmol) was dissolved in NMP (175 g) in a 500 mL flask equipped with a stirring bar. The mixture was blanketed with nitrogen and then ammonium hydroxide (10.70 g 176 mmol, 28% in water) was added to the flask dropwise at room temperature, and the reaction was stirred overnight. To the reaction was added water (190 mL) and the resulting slurry was cooled in an ice bath and stirred for 5 hours. The solid was collected by filtration and the cake washed with water. Vacuum drying provided the isopropyl 4-amino-5,6-difluoropicolinate as an off-white solid (11.7 g, 68% yield, 96% HPLC purity): mp 167-168° C.; 1H NMR (THF-d8, 300 MHz) δ 7.25 (d, 1H, J=6 Hz), 6.07 (s, 2H), 5.01 (m, 1H, J=6 Hz), 1.20 (d, 6H, J=6.3 Hz); 13C NMR (THF-d8, 75 MHz, 1H decoupled) δ 162.9 (s), 151.5 (dd, J=228 Hz, 12 Hz), 146.1 (dd, J=9 Hz, 6 Hz), 140.4 (dd, J=17 Hz, 5 Hz), 134.5 (dd, J=251 Hz, 32 Hz), 111.9 (m), 68.4 (s), 21.0 (s).
Reaction SMILES: [Na].[CH2:2]([N:9]1[CH:13]([C:14]([OH:16])=O)[CH2:12][CH2:11][S:10]1(=[O:18])=[O:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:19][CH:20]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:21]([OH:25])[C:22]([NH2:24])=[O:23].O[NH-].O=[N-]>>[NH2:24][C:22](=[O:23])[C:21](=[O:25])[CH:20]([NH:19][C:14]([CH:13]1[CH2:12][CH2:11][S:10](=[O:18])(=[O:17])[N:9]1[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)=[O:16])[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(O)C1CCS(=O)(=O)N1Cc1ccccc1
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Agent: [N-]=O
Agent: [NH-]O
Agent: [Na]
Product: NC(=O)C(=O)C(Cc1ccccc1)NC(=O)C1CCS(=O)(=O)N1Cc1ccccc1

Procedure:
Coupling of the sodium salt of 2-benzyl-1,1-dioxo-isothiazolidine-3-carboxylic acid with 3-amino-2-hydroxy-4-phenylbutanamide and oxidation of the resulting hydroxyamide intermediate to the corresponding ketoamide.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([O:21][CH3:22])[CH:13]=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[C:15]2[CH3:20])=[O:8].[CH3:23][CH:24]([CH3:34])[CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][NH:30][CH:29]([CH3:33])[CH2:28]1.C(N(CC)CC)C.O>C1C=CC=CC=1>[CH3:22][O:21][C:12]1[CH:13]=[C:14]2[C:19](=[C:10]([NH:9][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:30]3[CH2:31][CH2:32][N:27]([CH2:26][CH2:25][CH:24]([CH3:34])[CH3:23])[CH2:28][CH:29]3[CH3:33])[CH:11]=1)[N:18]=[CH:17][CH:16]=[C:15]2[CH3:20]
Reactant: COc1cc(NC(=O)CCCCCBr)c2nccc(C)c2c1
Reactant: CC(C)CCN1CCNC(C)C1
Solvent: O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COc1cc(NC(=O)CCCCCN2CCN(CCC(C)C)CC2C)c2nccc(C)c2c1
Yield: 44.3 %

Procedure:
A mixture of 6 g (0.0164 mole) of 6-bromo-N-(6-methoxy-4-methyl-8-quinolinyl)hexanamide, 3 g (0.017 mole) of 1-(3-methyl-butyl)-3-methylpiperazine and 3 ml of triethylamine in 100 ml of benzene was heated under reflux for 30 hr, allowed to cool and filtered to remove triethylamine hydrobromide. The filtrate was combined with 1 ml of triethylamine and heated under reflux for 28 hr. The cooled reaction mixture was combined with water and additional benzene. The benzene layer was separated, washed, dried and concentrated to dryness. The residue dissolved in ethyl acetate and chromatographed over 200 g of silica gel first with ethyl acetate, then with a 7% solution of methanol in ethyl acetate and finally with a 10% solution of methanol in ethyl acetate. Fractions containing product, Rf (15% methanol/ethyl acetate)=0.12, were combined and concentrated to afford 3.3 g (44%) of the desired product as an oil, which was used in the next step without further purification. The structure was confirmed by IR and NMR spectra.
Reaction SMILES: [CH:1]1[C:7]([F:8])=[C:6]([NH2:9])[NH:5][C:3](=[O:4])[N:2]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22])[C:15](Cl)=[O:16].O>N1C=CC=CC=1>[F:8][C:7]1[C:6]([NH:9][C:15](=[O:16])[C:14]2[CH:13]=[C:12]([O:11][CH3:10])[C:20]([O:21][CH3:22])=[C:19]([O:23][CH3:24])[CH:18]=2)=[N:5][C:3](=[O:4])[NH:2][CH:1]=1
Reactant: Nc1[nH]c(=O)ncc1F
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Solvent: c1ccncc1
Solvent: O
Product: COc1cc(C(=O)Nc2nc(=O)[nH]cc2F)cc(OC)c1OC
Yield: 90.4 %

Procedure:
To a suspension of 12.9 g of fluorocytosine in 78 ml of pyridine was added 23.1 g of 3,4,5-trimethoxybenzoyl chloride, and the mixture was reacted at 100° C. for 5 hours. After the completion of reaction, the reaction mixture was poured into 300 ml of water at room temperature with stirring. After stirring the resulting mixture for additional 3 hours, the precipitated crystals were collected by filtration, washed with water and then dried to obtain 29.2 g of 5-fluoro-N4 -(3,4,5-trimethoxybenzoyl)cytosine.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=O)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].S(Cl)([Cl:17])=O>>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([Cl:17])=[O:14])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1cccc(CC(=O)O)c1
Product: CC(=O)Oc1cccc(CC(=O)Cl)c1

Procedure:
A solution of 6.36 g 3-acetoxyphenylacetic acid and 10 ml of thionyl chloride was refluxed for one hour. The solvent was removed on a rotary evaporator, 15 ml of dry benzene was added and re-evaporated to yield crude 3-acetoxyphenylacetyl chloride. To a cooled solution of the acid chloride in 35 ml benzene was added dropwise a solution 8.9 g of octyl amine and 10 ml of ether. The reaction mixture was stirred at room temperature for three hours, the solids filtered, and the filtrate transferred to a separatory funnel and extracted with 50 ml of 1 N HCl, 50 ml of H2O and 50 ml of brine. The resulting organic solution was dried (MgSO4), filtered, and evaporated to yield 10.14 g of a mixture containing octyl 3-acetoxyphenylacetamide.
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)=O.[N+:12]([CH3:15])([O-])=O>>[NH2:12][CH2:15][CH2:1][C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=Cc1cc2ccccc2[nH]1
Reactant: C[N+](=O)[O-]
Product: NCCc1cc2ccccc2[nH]1

Procedure:
A process disclosed in U.S. patent application Ser. No. 10/302,636 for making 4-{3-[1-benzhydryl-5-chloro-2-(2-{[3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid may be summarized as follows: methyl-4-iodobenzoate is reacted with allyl alcohol to provide 4-(3-Oxo-propyl)-benzoic acid methyl ester, which is then reacted with 5-chloro-2-methylindole to yield 4-[3-(5-chloro-2-methylindol-3-yl)propyl]benzoic acid methyl ester; this product is reacted with benzhydryl bromide to produce 4-[3-(1-benzhydryl-5-chloro-2-methylindol-3-yl)propyl]benzoic acid methyl ester, which is then reacted with benzoyl peroxide to produce the 2-formyl indole; the 2 formyl indole is then reacted with nitromethane followed by Zn(Hg)/HCl to form the 2-(2-aminoethyl) indole; this amine is then reacted with [(3,4-dichlorophenyl)-methyl]sulfonyl chloride to produce 4-{3-[1-benzhydryl-5-chloro-2-(2-{[3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid methyl ester, which is then hydrolyzed to form 4-{3-[1-benzhydryl-5-chloro-2-(2-{[3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid. In this process, chromatography is used to separate some of the compounds made in the aforesaid reactions. It would be desirable to have a process for making the product that does not require the use of chromatography.
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[CH:3]=[CH:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].N[C@H]1CCCC[C@H]1O>C(Cl)(Cl)Cl>[CH3:1][CH:2]([CH3:12])/[CH:3]=[CH:4]/[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: CC(C)C=CCCCCC(=O)O
Agent: N[C@H]1CCCC[C@H]1O
Solvent: ClC(Cl)Cl
Product: CC(C)/C=C/CCCCC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
The obtained 8-methyl-6-nonenoic acid (isomer ratio trans:cis=29:1, 408 mg, 2.40 mmol) was again dissolved in chloroform (10 ml), and a solution of cis-2-aminocyclohexanol (249 mg, 2.16 mmol) in chloroform (5 ml) was added dropwise at room temperature. The reaction mixture was concentrated under reduced pressure, the residue was again dissolved in chloroform (3 ml), and hexane (12 ml) was added dropwise. The reaction mixture was stirred overnight at room temperature, and the precipitated crystals were collected by filtration. Hexane (15 ml) was added to the obtained crystal, and the mixture was washed three times with 10% aqueous citric acid solution (10 ml) and once with saturated brine (10 ml), and dried over anhydrous magnesium sulfate. Magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to give trans-8-methyl-6-nonenoic acid (250 mg, 1.47 mmol, purity 98.8%, yield 35.1%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([N:23]([CH2:25][CH2:26][CH2:27][C:28]2[CH:38]=[CH:37][C:31]([C:32]([O:34]CC)=[O:33])=[CH:30][CH:29]=2)[CH3:24])=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[OH-].[Na+].Cl>C1COCC1.C[C@H]1O[C@H]2[C@H](O)[C@@H](O)[C@H](OC3C4C(=CC5OCOC=5C=4)[C@@H](C4C=C(OC)C(O)=C(OC)C=4)[C@@H]4[C@@H]3COC4=O)O[C@@H]2CO1.C1COP(NCCCl)(=O)N(CCCl)C1.[NH2-].[NH2-].Cl[Pt+2]Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([N:23]([CH2:25][CH2:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:37][CH:38]=2)[CH3:24])=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11]
Reactant: CCOC(=O)c1ccc(CCCN(C)C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1
Agent: Cl[Pt+2]Cl
Agent: COc1cc([C@@H]2c3cc4c(cc3C(O[C@@H]3O[C@@H]5CO[C@@H](C)O[C@H]5[C@H](O)[C@H]3O)[C@H]3COC(=O)[C@H]23)OCO4)cc(OC)c1O
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc(CC(=O)N(C)CCCc2ccc(C(=O)O)cc2)ccc1NC(=O)Nc1ccccc1C
Yield: 27.7 %

Procedure:
To a stirred solution of ethyl 4-[3-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenyl acetyl-N-methylamino]-1propyl]benzoate (500 mg, 0.966 mmol) in THF (8 mL) was added 0.25 N NaOH (8 mL), and the mixture was heated under reflux overnight. The resulting solution was poured into ice-1 N HCl (100 mL) and the solid was collected with suction. The solid was dissolved in CHCl3 (100 mL) and dried over MgSO4. After removal of the solvent, the residue was chromatographed on silica gel with CHCl3-MeOH (10:1 to 5:1, v/v) to give 131 mg (28%) 4-[3-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl-N-methylamino]-1-propyl]benzoic acid 269 as a pale yellow amorphous solid. 1H-NMR (DMSO-d6) δ 1.68–1.80 (m, 2 H), 2.24 (s, 3 H), 2.57 (m, 2 H), 2.81 and 2.97 (s, each, total 3 H), 3.33 (m, 2 H), 3.57–3.61 (m, 2 H), 3.84 (s, 3 H), 6.71 (dd, J=29.8, 8.3 Hz, 1H), 6.87 (d, J=11.2 Hz, 1H), 6.93 (t, J=7.3 Hz, 1H), 7.15 (m, 2H), 7.28 (m, 2 H), 7.79 (d, J=8.3 Hz, 1 H), 7.84–7.87 (m, 2 H), 8.02 (d, J=8.3 Hz, 1 H), 8.49 (d, J=7.3 Hz, 1 H), 8.58 (d, J=4.9 Hz, 1 H); MS (FAB) m/z 490 (M++1); Anal. Calcd for C28H31N3O5.1/2H2O: C, 67.45; H, 6.47; N, 8.43. Found: C, 67.27; H, 6.51; N, 8.02.
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]([CH3:32])[C@@H:5]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[C:14]([CH3:16])[C:13]([CH:17]([CH2:22][CH2:23][CH3:24])[C:18]([O:20]C)=[O:19])=[C:12]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)[N:11]=2)[CH2:6]1>CO>[CH3:32][N:4]([CH3:3])[C@H:5]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[C:14]([CH3:16])[C:13]([CH:17]([CH2:22][CH2:23][CH3:24])[C:18]([OH:20])=[O:19])=[C:12]([C:25]3[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=3)[N:11]=2)[CH2:6]1
Reactant: CCCC(C(=O)OC)c1c(C)nc(N2CC[C@@H](N(C)C)C2)nc1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(N2CC[C@H](N(C)C)C2)nc1-c1ccc(C)cc1
Temperature: 100 °C
Yield: 15.2 %

Procedure:
A solution of sodium hydroxide 5N (0.5 mL) was added to a mixture of methyl 2-(2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (0.053 g; 0.116 mmol) in methanol (1.5 mL). The mixture was heated in a sealed tube at 100° C. for 18 h and then concentrated under reduced pressure. The residue was dissolved in water and the pH of the solution was adjusted between 3 and 4 by addition of a solution of hydrochloric acid 6N. The aqueous layer was extracted with ethyl acetate and concentrated under reduced pressure. Purification by preparative HPLC (HPLC method 5) furnished 0.007 g (14%) of the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.Br[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1>[Cu]>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: Brc1ccc2ccccc2c1
Agent: [Cu]
Product: O=[N+]([O-])c1ccc(-c2ccc3ccccc3c2)cc1

Procedure:
202 g of 1-bromo-4-nitrobenzene and 207 g of 2-bromonaphthalene were subjected to Ullmann coupling using a copper catalyst. The product was purified by a column chromatography to obtain 2-(4-nitrophenyl)naphthalene. The product was reduced using a reduced iron to obtain 2-(4-aminophenyl)naphthalene (yield: 36%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1)#[CH:2].I[C:11]1[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=1[NH2:13]>>[C:6]1([CH3:9])[CH:7]=[CH:8][C:3]([C:1]2[NH:13][C:12]3[C:14]([CH:2]=2)=[CH:15][CH:16]=[CH:17][CH:11]=3)=[CH:4][CH:5]=1
Reactant: C#Cc1ccc(C)cc1
Reactant: Nc1ccccc1I
Product: Cc1ccc(-c2cc3ccccc3[nH]2)cc1
Yield: 74 %

Procedure:
The general procedure was used to convert 1-Ethynyl-4-methyl-benzene and 2-iodoaniline to the title product. Purification by flash chromatography gave the analytically pure product as a white solid, 74% yield. 1H NMR (300 MHz, DMSO) δ 11.47 (s, 1H), 7.74 (d, J=7.72, 2H), 7.50 (d, J=7.72, 2H), 7.38 (d, J=7.91, 1H), 7.25 (d, J=7.72, 2H), 7.11-7.06 (t, J=7.91, 1H), 7.01-6.96 (t, J=7.35, 1H), 6.83 (s, 1H), 2.34 (s, 3H). 13C NMR (75 MHz, DMSO) δ 138.63, 137.85, 137.60, 130.31, 129.55, 125.77, 122.17, 120.72, 120.14, 112.04, 98.89, 21.65. Anal. Calcd. for C15H13N: C, 86.92; H, 6.32; N, 6.67. Found C, 86.69; H, 6.24; N, 6.76. m.p.: 213-215° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][C:4]([CH2:28][C:29]#[N:30])([N:6]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]4[N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:18]=[CH:19][C:12]=34)[CH:8]=[N:7]2)[CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH-].[Na+]>C(Cl)Cl>[O:1]=[C:2]1[CH2:3][C:4]([CH2:28][C:29]#[N:30])([N:6]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]4[N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:27])[CH3:26])[CH:18]=[CH:19][C:12]=34)[CH:8]=[N:7]2)[CH2:5]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CC(O)C4)c3)ccnc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CC(=O)C4)c3)ccnc21
Reaction time: 0.25 h

Procedure:
To a solution of {3-hydroxy-1-[4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile (1.3 g, 3.1 mmol, a mixture of diastereomers from Step B) in methylene chloride (40 mL) was added Dess-Martin periodinane (1.63 g, 3.84 mmol). After stirring for 1 hour and 15 minutes, the reaction mixture was poured into 1N NaOH and extracted with three portions of DCM. The combined extracts were washed with 1N NaOH, then brine, dried over sodium sulfate, decanted and solvent was removed in vacuo. Flash chromatography on silica gel, eluting with an initial gradient from 0-30% EtOAc/Hexanes, then a rapid gradient up to 100% EtOAc afforded product (1.1 g, 85%). 1H NMR (300 MHz, CDCl3) δ 8.34 (d, J=5.0 Hz, 1H), 8.14 (s, 1H), 8.11 (s, 1H), 7.42 (d, J=3.7 Hz, 1H), 7.18 (d, J=5.0 Hz, 1H), 6.71 (d, J=3.7 Hz, 1H), 5.71 (s, 2H), 4.10-3.97 (m, 2H), 3.74-3.61 (m, 2H), 3.61-3.47 (m, 2H), 3.28 (s, 2H), 0.98-0.86 (m, 2H), −0.07 (s, 9H); LCMS (M+H)+: 422.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Br:10]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>CC(C)=O>[Br:10][CH2:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1].[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[CH3:9]
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: Cc1ccc(I)cc1F
Solvent: CC(C)=O
Product: Fc1cc(I)ccc1CBr
Yield: 73 %

Procedure:
Part C. To a solution of 2-fluoro-4-iodo-1-methylbenzene (50 g, 210 mmol) in anhydrous acetone (490 mL) was added N-bromosuccinimide (42 g, 230 mmol) and 2,2′-azobisiso-butyronitrile (100 mg, 0.60 mmol). The resulting solution was heated to reflux and maintained under reflux conditions for 5 h. The reaction was then cooled, concentrated, and filtered. The filtrate was concentrated, and the resulting dark red residue was purified by flash column chromatography (10% ethyl acetate in hexanes) to afford a 4:1 mixture (58 g) of 1-(bromomethyl)-2-fluoro-4-iodobenzene (49 g, 73%) and 2-fluoro-4-iodo-1-methylbenzene (9 g, 17%) as a red solid. 1H NMR (product) (CDCl3) δ 7.40-7.49 (m, 2H), 7.13 (t, 1H), 4.45 (s, 2H).
Reaction SMILES: [SH:1][CH2:2][CH:3]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5].SCC[C:24]([N:26]1CCC[C@H:27]1[C:28](O)=O)=[O:25]>>[CH2:27]([NH:26][C:24]([S:1][CH2:2][CH:3]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])=[O:25])[CH3:28]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)CCS
Reactant: O=C(O)[C@@H]1CCCN1C(=O)C(CS)Cc1ccccc1
Product: CCNC(=O)SCC(Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
By substituting 1-(3-mercapto-2-benzylpropanoyl)-L-proline for the 1-(3-mercaptopropanoyl)-L-proline in the procedure of Example 65, 1-[3-[[(ethylamino)carbonyl]thio]-2-benzylpropanoyl]-L-proline is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][N:17]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[F:18].Cl>CO.[Pt](=O)=O>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH:10]([C:11]([O:13][CH3:14])=[O:12])[CH2:15][CH2:16][NH:17]2)=[CH:4][C:3]=1[F:18]
Reactant: COC(=O)c1ccnc(-c2ccc(Cl)c(F)c2)c1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: COC(=O)C1CCNC(c2ccc(Cl)c(F)c2)C1
Reaction time: 1.5 h
Yield: 192 %

Procedure:
Methyl 2-(4-chloro-3-fluorophenyl)isonicotinate (1.473 g, 5.54 mmol) was suspended in MeOH (30 mL) and hydrogen chloride (1.25 M in MeOH, 9.86 mL, 11.09 mmol) was added dropwise during stirring. The solvent was evaporated after 15 min and the HCl salt redissolved in MeOH (10 mL) and platinum(IV) oxide (0.063 g, 0.28 mmol) added. The resulting mixture was hydrogenated in a Büchi hydrogenator at room temperature and 5 bar for 1.5 h. Platinum(IV) oxide (0.038 g, 0.17 mmol) was added and the hydrogenation continued for 1 h. The catalyst was filtered off and washed with MeOH. The solvent was evaporated in vacuo yielding methyl 2-(4-chloro-3-fluorophenyl)piperidine-4-carboxylate hydrochloride (1.639 g, 96%) as a white solid. MS m/z 272 (M+H)+
Reaction SMILES: [NH:1]([C:3]1[CH:12]=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[NH2:2].[C:13](O)(=O)[CH3:14]>>[CH3:13][C:14]1[N:4]2[C:5]3[C:10]([N:11]=[CH:12][C:3]2=[N:1][N:2]=1)=[CH:9][CH:8]=[CH:7][CH:6]=3
Reactant: CC(=O)O
Reactant: NNc1cnc2ccccc2n1
Product: Cc1nnc2cnc3ccccc3n12

Procedure:
A 5 g. portion of 2-hydrazinoquinoxaline was stirred at reflux temperature in acetic acid for 3 hours. The reaction mixture was then cooled, and was evaporated to dryness under vacuum. The product was found to melt at 210°-12° C. without purification, and was identified as 1-methyl-s-triazolo[ 4,3-a]quinoxaline by NMR analysis and elemental microanalysis, the results of which follow.
Reaction SMILES: [CH3:1][O:2][CH:3]=[CH:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.ClC1C=CC=C(C(OO)=[O:20])C=1>C(Cl)(Cl)Cl>[CH3:1][O:2][CH:3]=[CH:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]2[O:20][CH:8]2[CH:7]=1
Reactant: COC=CCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: COC=CCC1=CC2OC2C=C1
Reaction time: 40 h
Yield: 62.6 %

Procedure:
22.2 g of p-methoxyallylbenzene was dissolved in 200 ml of chloroform and to the mixture was added dropwise, while maintaining the temperature at 0° -5° C, 31.3 g of m-chloroperbenzoic acid dissolved in 1l of chloroform. The resulting mixture was allowed to stand at the same temperature for 40 hours. After the separated m-chlorobenzoic acid was filtered off, the filtrate was washed with 5% sodium hydroxide solution, then with water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain the residue, which was distilled under reduced pressure, there was obtained 15.4 g (yield 62.6%) of p-methoxyallylbenzene oxide having a boiling point of 90° C/2 mmHg.