Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]3[O:28][C:29]4[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=4[CH:31]=3)=[O:26])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[O:28]1[C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[CH:31]=[C:27]1[C:25]([NH:24][C:21]1[CH:22]=[CH:23][C:18]([C:15]2[CH:16]=[CH:17][C:12]([S:9]([NH:8][CH2:7][C:6]([OH:36])=[O:5])(=[O:10])=[O:11])=[CH:13][CH:14]=2)=[CH:19][CH:20]=1)=[O:26]
Reactant: CC(C)(C)OC(=O)CNS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3cc4ccccc4o3)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CNS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3cc4ccccc4o3)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
N-({4′-[(1-benzofuran-2-ylcarbonyl)amino]-1,1′-biphenyl-4-yl}sulfonyl)glycine t-butyl ester (75 mg) was dissolved in a 95% solution of TFA in methylene chloride (5 mL). The solution was stirred at room temperature for 4 h and the solvent was removed under vacuum. The crude product was triturated with hexane/ethyl acetate (95:5) three times. The product was lyophilized with benzene to give 56 mg of N-({4′-[(1-benzofuran-2-ylcarbonyl)amino]-1,1′-biphenyl-4-yl}sulfonyl)glycine. LCMS MH+ (m/z) 451. 1H NMR (300 MHz, DMSO-d6): δ 10.54 ppm (s, 1H), 7.95-7.54 ppm (m, 11H), 7.34 ppm (dd, 1H, J1=7.5 Hz, J2=7.5 Hz), 7.20 ppm (dd, 1H, J1=7.5 Hz, J2=7.5 Hz), 3.42 ppm (d, 2H J=6.3 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([C:23](=[O:31])[C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)[C@@H:15]([CH3:32])[CH2:14]2)[C:9](=[O:12])[CH2:10][CH3:11])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:36][CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40].C(O)C>CN(C=O)C>[CH2:42]([O:41][C:39](=[O:40])[CH2:38][CH2:37][CH2:36][O:30][C:27]1[CH:26]=[CH:25][C:24]([C:23]([N:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@H:13]([N:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:9](=[O:12])[CH2:10][CH3:11])[CH2:14][C@@H:15]2[CH3:32])=[O:31])=[CH:29][CH:28]=1)[CH3:43]
Reactant: CCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Reactant: CCOC(=O)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)CCCOc1ccc(C(=O)N2c3ccccc3[C@H](N(C(=O)CC)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Reaction time: 0.5 h

Procedure:
(±)-Cis-4-(4-{4-[(4-chloro-phenyl)-propionyl-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-butyric acid ethyl ester was prepared from (±)-cis-N-(4-chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-propionamide. (±)-Cis-N-(4-chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]-propionamide (140 mg, 0.31 mmol) was dissolved in DMF (5 mL) at room temperature. Sodium hydride (60% in oil, 32 mg, 0.81 mmol) was added and the mixture allowed to stir 30 min. Ethyl 4-bromobutyrate (207 mg, 1.06 mmol) was added and the reaction was allowed to stir over night. Ethanol was added and the reaction was concentrated in vacuo. The crude residue was purified by silica gel chromatography (80/20 hexanes/ethyl acetate—50/50 hexanes ethyl acetate gradient) to afford the product (171 mg, 0.304 mmol, 98%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:11]=[CH:12][C:13]([OH:21])=[N:14][C:15]=1[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18].[CH:22]1([CH:25]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH2:38]O)[CH:33]=2)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:24][CH2:23]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C1COCC1>[CH:22]1([CH:25]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH2:38][O:21][C:13]3[CH:12]=[CH:11][C:10]([C:3]4[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=4[F:1])=[C:15]([CH2:16][C:17]([CH3:18])([CH3:20])[CH3:19])[N:14]=3)[CH:33]=2)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:24][CH2:23]1
Reactant: CCOC(=O)CC(c1ccnc(CO)c1)C1CC1
Reactant: COc1ccc(F)c(-c2ccc(O)nc2CC(C)(C)C)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)CC(c1ccnc(COc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1)C1CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 77.8 %

Procedure:
Under a nitrogen atmosphere, to a solution of 5-(2-fluoro-5-methoxyphenyl)-6-neopentylpyridin-2-ol (100 mg) and ethyl 3-cyclopropyl-3-(2-(hydroxymethyl)pyridin-4-yl)propanoate (94 mg) in THF (3.0 mL) were added 1,1′-(azodicarbonyl)dipiperidine (140 mg) and tributylphosphine (136 μL), and the mixture was stirred at room temperature for 14 hr. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (140 mg) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([SH:25])[CH:18]=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22]>>[NH2:1][C:2]1[CH:3]=[C:4]([C:5](=[O:7])[S:25][C:17]2[CH:16]=[C:15]([O:14][CH3:13])[C:20]([O:21][CH3:22])=[C:19]([O:23][CH3:24])[CH:18]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COc1cc(S)cc(OC)c1OC
Reactant: COc1ccc(C(=O)O)cc1N
Product: COc1ccc(C(=O)Sc2cc(OC)c(OC)c(OC)c2)cc1N
Yield: 47 %

Procedure:
Using 3-amino-4-methoxybenzoic acid and 3,4,5-trimethoxyphenylmercaptan as materials, compound 5 is synthesized following a similar method as in Example 28. Yield: 47%.
Reaction SMILES: Br[CH2:2][C:3](OCC)([O:9][CH2:10][CH3:11])[C:4](=O)[CH2:5][C:6]#[N:7].[NH2:15][NH2:16]>>[C:6]([CH2:5][C:4]1[C:3]([O:9][CH2:10][CH3:11])=[CH:2][NH:16][N:15]=1)#[N:7]
Reactant: NN
Reactant: CCOC(CBr)(OCC)C(=O)CC#N
Product: CCOc1c[nH]nc1CC#N

Procedure:
Heterocyclic molecules are also derived from the above polyfunctional small molecules, which behave similarly. For example, 5-bromo-4,4-diethoxy-3-oxovaleronitrile is reacted with hydrazine, forming (via hydrazone formation, cyclization and ethanol elimination) 3-cyanomethyl-4-ethoxypyrazole; and acetimido 3-bromo-2,2-diethoxypropionate is cyclized on warming to produce 3-methyl-5-(2-bromo-1,1-diethoxyethyl)-1,2,5-oxadiazole. The latter is deketalized by warming in 95% formic acid to produce the corresponding 3-methyl-5-(2-bromoacetyl)-1,2,5-oxadiazole.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[C:10]([CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[CH:11]=[CH:12][C:7]=2[O:6][CH2:5][C:4]2[CH:18]=[CH:19][S:20][C:3]1=2.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>N1C=CC=CC=1>[CH3:21][S:22]([O:17][CH2:16][CH2:15][CH2:14][CH2:13][C:10]1[CH:11]=[CH:12][C:7]2[O:6][CH2:5][C:4]3[CH:18]=[CH:19][S:20][C:3]=3[C:2](=[O:1])[C:8]=2[CH:9]=1)(=[O:24])=[O:23]
Reactant: O=C1c2cc(CCCCO)ccc2OCc2ccsc21
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCCCc1ccc2c(c1)C(=O)c1sccc1CO2
Reaction time: 8 h
Yield: 10.8 %

Procedure:
A chilled stirring solution of 9.5 g of 4-(4,10-dihydro-10-oxothieno[3,2-c][1]benzoxepin-8-yl)butanol in 200 ml of sieve dried pyridine was treated dropwise with 3.80 g of methanesulfonyl chloride and the addition funnel was rinsed with a few ml of methylene chloride. The stirring solution was allowed to equilibrate to room temperature overnight with the bath in place. The resulting solution was poured into 750 ml of water and was allowed to stand for 15 min. The solids were collected by filtration, and dried in vacuo overnight at 42° C. Concentration of the mother liquor produced additional solids which were combined with the first crop and dried to give a total of 9.09 g of crude material. A 2.0 g portion of the product was recrystallized from hexane/ethyl acetate to give 1.3 g of 4-(4,10-dihydro-10-oxothieno[3,2-c][1]benzoxepin-8-yl)butanol methanesulfonate, m.p. 97-98° C.
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[N+:19]([O-:21])=[O:20])[C:9](=[O:22])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](N)=[CH:27][CH:26]=1.C([O-])(=O)C.[K+]>CO>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([NH:1][C:4]2[C:17]3[C:16](=[O:18])[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][C:14]=4[N+:19]([O-:21])=[O:20])[C:9](=[O:22])[C:8]=3[CH:7]=[CH:6][CH:5]=2)=[CH:27][CH:26]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C1c2cccc([N+](=O)[O-])c2C(=O)c2c1cccc2[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CO
Product: COc1ccc(Nc2cccc3c2C(=O)c2c(cccc2[N+](=O)[O-])C3=O)cc1
Reaction time: 8 h
Yield: 81.3 %

Procedure:
A mixture of 50 g of 1,8-dinitro-anthraquinone (82% strength), 150 g of p-anisidine and 21.5 g of anhydrous potassium acetate is heated at 95° - 100° C (duration approx. 5 hours), with vigorous stirring, until no further starting material is present, according to thin layer chromatography. The mixture is diluted with 150 ml of methanol over the course of 30 minutes at 50° - 60° C and is stirred overnight until cold and the reaction product is filtered off, washed with a solution of 30 g of p-anisidine in 30 ml of methanol and finally with 200 ml of methanol and hot water, and dried at 80° C. 51 g of 1-p-anisidino-8-nitro-anthraquinone are obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][C:10]2([O:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]1([OH:25])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1>C1C=CC=CC=1>[C:15]1([O:25][CH2:11][C:10]2([OH:12])[CH2:13][CH2:14][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9]2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: Oc1cccc2ccccc12
Reactant: c1ccc(CN2CCC3(CO3)C2)cc1
Solvent: c1ccccc1
Product: OC1(COc2cccc3ccccc23)CCN(Cc2ccccc2)C1
Temperature: 115 °C
Reaction time: 2 h
Yield: 60.6 %

Procedure:
A mixture of 18.9 g (0.1 mole) of 5-benzyl-1-oxa-5-azaspiro[2.4]heptane and 15.6 g (0.11 mole) of 1-naphthol was heated to 115° C. to form a homogenous melt, which was stirred with a magnetic stirrer for 2 hours. Upon cooling, a paste-like material formed. The reaction mixture was dissolved in benzene, filtered and ligroin added to the filtrate until cloudy. The suspension was warmed to solution and allowed to stand in the refrigerator overnight. The precipitate was collected by filtration to give 20.2 g (60%) of crude material. A portion of this solid was recrystallized from 190 ethanol to give a white crystalline solid, m.p. 129.5°-130° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[CH3:11].CN(C=O)C.C(Cl)(=O)C([Cl:20])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:20])=[O:7])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C(=O)O)ccc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)Cl)ccc1Cl
Temperature: 25 °C

Procedure:
To a suspension of 52.55 g (0.31 mol) of 4-chloro-3-methyl-benzoic acid in CH2Cl2 (1.2 L) with DMF (1 mL) at 0° C. under N2 with an outlet sparging through 2.5 N sodium hydroxide was added 29.56 mL (0.339 mol) of oxalyl chloride. The mixture was allowed to warm to room temperature over a 3 h period. The reaction mixture was concentrated and taken forward crude.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:26])[N:6]([CH2:20][C:21]([O:23]CC)=[O:22])[C:7]([CH3:19])=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]([CH3:18])[CH3:17])(=[O:3])[CH3:2].[OH-].[Na+]>C(O)C>[C:1]([C:4]1[C:5](=[O:26])[N:6]([CH2:20][C:21]([OH:23])=[O:22])[C:7]([CH3:19])=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]([CH3:18])[CH3:17])(=[O:3])[CH3:2]
Reactant: CCOC(=O)Cn1c(C)cc(-c2ccccc2C(C)C)c(C(C)=O)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)c1c(-c2ccccc2C(C)C)cc(C)n(CC(=O)O)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 3-acetyl-4-(2-isopropylphenyl)-6-methyl-1-ethoxycarbonylmethyl-2-pyridinone from step 3 of Example XX (0.20 g, 0.56 mmol) in ethanol (4 mL) was added aqueous NaOH (0.62 mL of a 1.0 N solution, 0.62 mmol). The resulting solution was stirred at ambient temperature for 2 h and the solvent was removed in vacuo. The residue was partitioned between EtOAc and 1.0 N aqueous HCl. The organic phase was separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound (HPLC RT=18.11 min, method B).
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.C([O-])(=O)C.[NH4+].[N+:17]([CH2:20][CH3:21])([O-:19])=[O:18]>>[N+:17]([C:20]([CH3:21])=[CH:7][C:6]1[CH:1]=[CH:2][C:3]2[O:11][CH2:10][O:9][C:4]=2[CH:5]=1)([O-:19])=[O:18]
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CC(=Cc1ccc2c(c1)OCO2)[N+](=O)[O-]
Temperature: 105 °C
Yield: 40 %

Procedure:
5.00 g (33.3 mmol) piperonal (Aldrich, Milwaukee, Wis.), 12.8 g (167 mmol) ammonium acetate (Fluka), and 50 g (670 Mmol) nitroethane, 98% (Aldrich) were combined in a 100 ml round bottom flask equipped with magnetic stirrer and nitrogen inlet. The reaction mixture was heated to 105° C. for 90 minutes and the solvent was removed under vacuum to give a dark yellow liquid which was recrystallized from cold methyl alcohol three times to give a yellow crystalline solid in 40% yield. 1H NMR spectra is shown in FIG. 1.
Reaction SMILES: [Cl:1]Cl.[C:3]([O:12][CH3:13])(=[O:11])[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[OH:6]>C(Cl)(Cl)Cl>[Cl:1][C:9]1[CH:10]=[C:4]([C:3]([O:12][CH3:13])=[O:11])[C:5]([OH:6])=[CH:7][CH:8]=1
Reactant: ClCl
Reactant: COC(=O)c1ccccc1O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(Cl)ccc1O

Procedure:
A 85.2 g quantity of chlorine gas was absorbed in a mixture of 152 g (1.0 mole) of methyl salicylate and 500 ml of chloroform at less than 20° C. over a period of 6 hours while the mixture was stirred. The resulting reaction mixture was washed with water and the chloroform was removed. The residue was subjected to fractional distillation at reduced pressure to provide 152 g (81.5%) of a fraction at 117° to 120° C. and 8 mmHg., M.P. 51° C.
Reaction SMILES: [I:1][C:2]1[C:10]2[CH:9]=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1.[H-].[Na+].[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[C:13]1([S:19]([N:4]2[C:5]3[N:6]=[CH:7][N:8]=[CH:9][C:10]=3[C:2]([I:1])=[CH:3]2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Ic1c[nH]c2ncncc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1cc(I)c2cncnc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5-Iodo-7H-pyrrolo[2,3-d]pyrimidine (39, 0.569 g, 2.32 mmol) was added to 10.0 mL of N,N-dimethylformamide in a round bottom flask. Sodium hydride (0.102 g, 2.55 mmol) was added and the reaction stirred at room temperature for 10 minutes, then benzenesulfonyl chloride (40, 326 μL, 2.55 mmol) was added. The reaction was stirred at room temperature overnight, then poured into aqueous saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate adsorbed onto silica. The desired compound was isolated by silica gel column chromatography, eluting with 0.5-6% methanol in dichloromethane. Appropriate fractions were combined and concentrated under vacuum. Toluene was added to the residue, then concentrated under vacuum and the resulting solid was washed with hexane and collected by filtration to provide the desired compound (41, 439 mg). 1H NMR consistent with the compound structure.
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:6]([CH3:7])[N:5]([CH2:8][CH2:9][C:10]#[N:11])[C@H:4]([CH2:12][OH:13])[CH2:3]1.C(N(CC)[C:17](=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1[CH3:25])C>>[CH3:1][C@H:2]1[C@@H:6]([CH3:7])[N:5]([CH2:8][CH2:9][C:10]2[NH:11][C:17](=[O:26])[C:18]3[C:19]([CH:25]=2)=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)[C@H:4]([CH2:12][OH:13])[CH2:3]1
Reactant: C[C@@H]1C[C@@H](CO)N(CCC#N)[C@@H]1C
Reactant: CCN(CC)C(=O)c1cccc(C)c1C
Product: Cc1cccc2c(=O)[nH]c(CCN3[C@H](CO)C[C@@H](C)[C@H]3C)cc12

Procedure:
In the same manner as in Example 1b (a) and using ethyl (2S,4R,5R)-4,5-dimethylpyrrolidine-2-carboxylate described in Tetrahedron Lett., Vol. 34, No. 3, pp. 537–540 (1993), ethyl (2S,4R,5R)-1-tert-butoxycarbonyl-4,5-dimethylpyrrolidine-2-carboxylate is obtained. In the same manner as in Example 1b (b) and using ethyl (2S,4R,5R)-1-tert-butoxycarbonyl-4,5-dimethylpyrrolidine-2-carboxylate, (2S,4R,5R)-1-tert-butoxycarbonyl-4,5-dimethyl-2-hydroxymethylpyrrolidine is obtained. In the same manner as in Example 1b (c) and using (2S,4R,5R)-1-tert-butoxycarbonyl-4,5-dimethyl-2-hydroxymethylpyrrolidine, (2S,4R,5R)-4,5-dimethyl-2-hydroxymethylpyrrolidine hydrochloride is obtained. In the same manner as in Example 1b (d) and using (2S,4R,5R)-4,5-dimethyl-2-hydroxymethylpyrrolidine hydrochloride, 3-[(2S,4R,5R)-4,5-dimethyl-2-hydroxymethylpyrrolidin-1-yl]propionitrile is obtained. In the same manner as in Example 1b (e) and using 3-[(2S,4R,5R)-4,5-dimethyl-2-hydroxymethylpyrrolidin-1-yl]propionitrile and N,N-diethyl-2,3-dimethylbenzamide, 3-(2-[(2S,4R,5R)-4,5-dimethyl-2-hydroxymethylpyrrolidin-1-yl]ethyl)-5-methyl-2H-isoquinolin-1-one is obtained.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH2:14])[CH:8]=1.[O:16]([C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH:14][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:24][CH:25]=2)[CH:8]=1
Reactant: COC(=O)CCc1cccc(CN)c1
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Agent: Cl
Product: COC(=O)CCc1cccc(CNCc2ccc(Oc3ccccc3)cc2)c1

Procedure:
The title compound of Step A was prepared from 3-(3-aminomethyl-phenyl)-propionic acid methyl ester hydrochloride salt, of Preparation 44, and 4-phenoxybenzaldehyde using the method described in Example 12z, Step A. 1H NMR (400 MHz, CDCl3) δ 7.37-6.95 (m, 13H), 3.82 (s, 2H), 3.79 (s, 2H), 3.64 (s, 3H), 2.93 (t, 2H), 2.63 (t, 2H); MS 376 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:31]1([S:37](Cl)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:37]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:39])=[O:38])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:22][CH:23]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3ccccn3)cc2)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-c3ccccn3)cc2)S(=O)(=O)c2ccccc2)c1

Procedure:
The title compound of Step B was prepared from {3-[(4-pyridin-2-yl-benzylamino)-methyl]-phenoxy}-acetic acid acid tert-butyl ester of Step A and benzenesulfonyl chloride following the method described in Example 3, Step B 1H NMR (400 MHz, CDCl3) δ 8.67 (d, 1H), 7.86 (m, 4H), 7.77-7.51 (m, 5H), 7.24 (m, 1H), 7.11 (m, 3H), 6.76 (dd, 1H), 6.64 (d, 1H), 6.59 (d, 1H), 4.38 (s, 2H), 4.35 (s, 2H), 4.30 (s, 2H), 1.48 (s, 9H); MS 545 (M+1).
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[O:17]>C1COCC1>[Br:12][C:13]1[CH:14]=[C:15]([CH:16]([OH:17])[CH2:2][C:1]#[N:3])[CH:18]=[CH:19][CH:20]=1
Reactant: CC#N
Reactant: O=Cc1cccc(Br)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CCC(O)c1cccc(Br)c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a −78° C. solution of acetonitrile (1.05 mL, 20 mmol) in anhydrous THF (25 mL) under argon, was added lithium diisopropylamide (11 mL of a 2 M solution in THF, 22 mmol) dropwise. The resulting mixture was stirred at −78° C. for 15 min. A solution of 3-bromobenzaldehyde (7) (2.78 g, 15 mmol) in anhydrous THF (10 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature, then concentrated under reduced pressure and diluted with EtOAc (75 mL). The solution was washed with water (50 mL) and brine (50 mL), dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (20 to 100% EtOAc-hexanes gradient) gave 3-(3-bromophenyl)-3-hydroxypropanenitrile (120) as a light yellow oil. Yield (2.75 g, 81%): 1H NMR (400 MHz, DMSO-d6) δ 7.60 (t, J=1.6 Hz, 1H), 7.46 (ddd, J=7.6, 2.0, 1.2 Hz, 1H), 7.40 (dd, J=7.6, 2.0 Hz, 1H), 7.31 (t, J=7.6 Hz, 1H), 6.05 (d, J=4.8 Hz, 1H), 2.94-2.80 (m, 2H).
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][CH2:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[NH:11][C:10]1=[O:20])=[O:5])C.[OH-].[Na+]>CO.O1CCCC1>[C:4]([CH2:6][CH2:7][CH2:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[NH:11][C:10]1=[O:20])([OH:5])=[O:3]
Reactant: CCOC(=O)CCCn1c(=O)[nH]c(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCCn1c(=O)[nH]c(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.2 %

Procedure:
A mixture of 1-(3-ethoxycarbonylpropyl)-2,4(1H,3H)-quinazolinedione (552 mg) and 1N sodium hydroxide (6.0 ml) in methanol-tetrahydrofuran (26 ml, 3.3:1 V/V) was stirred for 3 hours at room temperature. After evaporation of the organic solvents, the mixture was adjusted to pH 4~5 with 1N hydrochloric acid to give precipitates. Collected precipitates were washed in turn with water and ethanol to give 1-(3-carboxypropyl)-2,4(1H,3H)-quinazolinedione (393 mg) as a powder.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:44]=[CH:43][C:8]([CH2:9][N:10]([CH2:35][C:36]([O:38]C(C)(C)C)=[O:37])[C:11](=[O:34])[C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:33])[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=3[C:29]([F:32])([F:31])[F:30])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)=[NH:4].CCN(C(C)C)C(C)C.[C:54]1([CH3:65])[CH:59]=[CH:58][C:57]([C:60]#[C:61][C:62](Cl)=O)=[CH:56][CH:55]=1>CC(=O)OCC>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][C:19]([NH:18][C:15]2[CH:16]=[CH:17][C:12]([C:11]([N:10]([CH2:35][C:36]([OH:38])=[O:37])[CH2:9][C:8]3[CH:43]=[CH:44][C:5]([C:3]4[N:4]=[C:62]([C:61]#[C:60][C:57]5[CH:58]=[CH:59][C:54]([CH3:65])=[CH:55][CH:56]=5)[O:1][N:2]=4)=[CH:6][CH:7]=3)=[O:34])=[CH:13][CH:14]=2)=[O:33])=[C:22]([C:29]([F:32])([F:31])[F:30])[CH:23]=1
Reactant: Cc1ccc(C#CC(=O)Cl)cc1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(C(=N)NO)cc3)cc2)c(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)O)Cc3ccc(-c4noc(C#Cc5ccc(C)cc5)n4)cc3)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19 %

Procedure:
Prepared using General Procedures 20 and 8. To a stirred solution of tert-butyl 2-(N-(4-(N-hydroxycarbamimidoyl)benzyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)acetate INT-33 (200 mg, 0.325 mmol) in dioxanes (4 mL) was added DIEA (85 μL, 0.488 mmol) then 3-(p-tolyl)propioloyl chloride (60 mg, 0.36 mmol). The reaction mixture was stirred at room temperature for 30 mins then at 120° C. for 3 h. The reaction mixture was allowed to cool to room temperature, diluted with EA (100 mL) and washed with brine (100 mL). The organics were concentrated and the residue diluted with DCM (5 mL) and TFA (2 mL) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo and purified by preparative HPLC to afford 44 mg (19%) of 2-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(5-(p-tolylethynyl)-1,2,4-oxadiazol-3-yl)benzyl)benzamido)acetic acid 471 as an off-white powder. LCMS-ESI (m/z) calculated for C37H29F3N4O6: 682; found 683 [M+H]+, tR=8.49 min (Method 9).