Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC([Si](C)(C)[O:6][CH2:7][CH2:8][C@@H:9]([C:21]([NH:23][C@H:24]([C:33]([O:35][CH3:36])=[O:34])[CH2:25][O:26][CH2:27][CH:28]([O:31][CH3:32])[O:29][CH3:30])=[O:22])[NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])(C)C.O.C1(C)C(S(O)(=O)=O)=CC=CC=1>CO>[CH3:32][O:31][CH:28]([O:29][CH3:30])[CH2:27][O:26][CH2:25][C@@H:24]([C:33]([O:35][CH3:36])=[O:34])[NH:23][C:21](=[O:22])[C@H:9]([CH2:8][CH2:7][OH:6])[NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: COC(=O)[C@H](COCC(OC)OC)NC(=O)[C@H](CCO[Si](C)(C)C(C)(C)C)NC(=O)OCc1ccccc1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: CO
Product: COC(=O)[C@H](COCC(OC)OC)NC(=O)[C@H](CCO)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 89.8 %

Procedure:
A solution of N-[O-[(1,1-dimethylethyl)-dimethylsilyl]-N-[(phenylmethoxy)carbonyl]-L-homoseryl]-O-(2,2-dimethoxyethyl)-L-serine, methyl ester [5.56 g, 10 mmol, prepared as described in Example 10(h)] in methanol (65 ml) was cooled to 0° C. (ice salt bath), treated with p toluenesulfonic acid monohydrate (386 mg, 2.0 mmol) and stirred at 0° C. for 1.5 hours. The reaction was quenched with sodium bicarbonate solution (198 mg. in 20 ml water), stirred for 5 minutes then evaporated to remove the methanol. The aqueous phase was extracted with ethyl acetate (2×200 ml) and the combined organic extract was washed with water (110 ml), 5% sodium bicarbonate (80 ml) and brine (80 ml), dried (anhydrous sodium sulfate), filtered, evaporated to dryness and dried in vacuo. The crude product was chromatographed on silica gel column (Merck), eluting the column with ethyl acetate:hexane (2:1) and ethyl acetate:methanol (98:2) to give 3.975 g of title product as a syrup. TLC (ethyl acetate:hexane, 4:1) Rf =0.17.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2([O:15][CH2:16][CH:17]([OH:20])[CH2:18][OH:19])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[N:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH:23]([Se](C=C)(=O)=O)=[CH2:24]>ClCCl>[O:20]1[CH2:24][CH2:23][O:19][CH2:18][CH:17]1[CH2:16][O:15][C:8]1([CH2:7][N:6]2[C:2]([CH3:1])=[CH:3][CH:4]=[N:5]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: Cc1ccnn1CC1(OCC(O)CO)CCCCCC1
Reactant: C=C[Se](=O)(=O)C=C
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccnn1CC1(OCC2COCCO2)CCCCCC1
Reaction time: 0.17 h

Procedure:
To a stirred solution of EXAMPLE 170C (315 mg) in dichloromethane (10 mL) was added NaH (80 mg) at 0° C. The mixture was stirred for 10 minutes. A solution of vinyl selenone (240 mg) in dichloromethane (5 mL) was added to the mixture and the mixture was stirred at room temperature for 3 hours. The mixture was quenched with aqueous NH4Cl, extracted with dichloromethane (2×200 mL), washed with water and brine, and dried over Na2SO4. Filtration and evaporation of the solvent gave the crude product which was purified by column eluted with 50% ethyl acetate in hexane) to provide the title compound.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=2)=[O:20])=[CH:14][CH:13]=1.[CH2:33]([N:36]=[C:37]=[O:38])[CH2:34][CH3:35]>N1C=CC=CC=1>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:19](=[O:20])[NH:18][C:15]2[CH:14]=[CH:13][C:12]([N:7]3[CH:6]=[N:5][C:4]4[C:8]3=[N:9][CH:10]=[N:11][C:3]=4[NH:2][C:37]([NH:36][CH2:33][CH2:34][CH3:35])=[O:38])=[CH:17][CH:16]=2)=[CH:23][C:24]=1[C:29]([F:31])([F:32])[F:30]
Reactant: Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: CCCN=C=O
Agent: Cl
Solvent: c1ccncc1
Product: CCCNC(=O)Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 63.6 %

Procedure:
In 10 mL of pyridine, 300 mg (0.62 mmol) of 1-[4-(6-aminopurin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea hydrochloride was dissolved, and 1.58 g (18.6 mmol) of propyl isocyanate was added thereto and the mixture solution was stirred at 50° C. for eight hours. The reaction solution was concentrated under reduced pressure, and then the residue was partitioned between ethyl acetate and water, and the organic layer was washed with a saturated sodium chloride solution, dried and concentrated. The residue was triturated with n-hexane:ethyl acetate=1:1, collected by filtration and vacuum dried to obtain 210 mg (64%) of 1-(9-(4-[3-(4-chloro-3-(trifluoromethyl)phenyl)ureido]phenyl)-9H-purin-6-yl)-3-propylurea (Table 1, Compound No. 119) as a white solid.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[O:3].Cl.[CH3:8][Si:9]([O:12][C:13](=[O:23])[C@H:14]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH2:15])([CH3:11])[CH3:10]>>[CH3:8][Si:9]([O:12][C:13](=[O:23])[C@H:14]([CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[NH:15][C:1](=[O:5])[C:2]([CH3:4])=[O:3])([CH3:10])[CH3:11]
Reactant: CC(=O)C(=O)Cl
Reactant: C[Si](C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Product: CC(=O)C(=O)N[C@@H](Cc1ccccc1)C(=O)O[Si](C)(C)C

Procedure:
A method of synthesizing pyruvyl-phenylalanine according to the invention comprises the steps of reacting sodium pyruvate with oxalyl chloride to yield pyruvyl chloride, then reacting pyruvyl chloride with a suspension of phenylalanine trimethylsilyl ester hydrochloride to yield pyruvyl-phenylalanine trimethylsilyl ester and then subjecting the pyruvyl-phenylalanine trimethylsilyl ester to hydrolysis to yield pyruvyl-phenylalanine. The pyruvyl-phenylalanine synthesized via the route set forth above serves as a pyruvyl-amino acid pyruvate precursor.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:7][CH:8]=1.[CH2:13]([O:17][C:18](=[O:29])[C@H:19]([CH3:28])[NH:20]C(=O)CC(C)CC)[CH:14]([CH3:16])[CH3:15]>>[CH2:13]([O:17][C:18](=[O:29])[C@H:19]([CH3:28])[NH:20][C:10](=[O:12])[CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([S:2][CH3:1])[CH:4]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: CSc1cccc(CC(=O)O)c1
Reactant: CCC(C)CC(=O)N[C@@H](C)C(=O)OCC(C)C
Product: CSc1cccc(CC(=O)N[C@@H](C)C(=O)OCC(C)C)c1

Procedure:
Following General Procedure I above, and using 3-methylthiophenylacetic acid (CAS# 18698-73-2) and alanine iso-butyl ester (prepared following General Procedure 3 above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[CH3:12][C:13]([C:16]1[CH:17]=[C:18]([CH:20]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:22]=1)[NH2:19])([CH3:15])[CH3:14]>>[CH3:15][C:13]([C:16]1[CH:17]=[C:18]([NH:19][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[OH:11])[CH:20]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:22]=1)([CH3:12])[CH3:14]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1
Product: CC(C)(C)c1cc(NC(=O)c2cc(Br)ccc2O)cc(C(C)(C)C)c1
Yield: 45.2 %

Procedure:
Using 5-bromosalicylic acid and 3,5-bis[(1,1-dimethyl)ethyl]aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([NH2:22])=[C:17]([CH:21]=1)[C:18]([OH:20])=[O:19].C(Cl)Cl>N1C=CC=CC=1>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([NH:22][S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])=[C:17]([CH:21]=1)[C:18]([OH:20])=[O:19]
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(O)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 115.8 %

Procedure:
2.0 g of 4-chlorobenzenesulfonic acid chloride are added to a solution of 3.8 g of 5-chloro-2-aminobenzoic acid [4-(3-chloro-5-trifluoromethylpyridyl-2-oxy)-anilide] in 8.6 ml of pyridine at 0° C. After the reaction mixture has been stirred for 16 hours at room temperature, 300 ml of methylene chloride are added and the resulting solution is then washed with 100 ml each of 1N HCl, H2O, saturated NaHCO3 solution and saturated NaCl solution. The organic phase is then dried with MgSO4 and concentrated by evaporation. The crude product obtained is purified by stirring in diethyl ether. In this manner 3.8 g of 5-chloro-2-[(4-chlorophenylsulfonyl)-amino]-benzoic acid [4-(3-chloro-5-trifluoromethylpyridyl-2-oxy)-anilide] are obtained in the form of white crystals (m.p. 191°-193° C.).
Reaction SMILES: Cl.[NH2:2][C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][C:5]([C:13]([O:15][CH3:16])=[O:14])([CH2:6]3)[CH2:4]1)[CH2:10]2.[C:17]([NH:27][C@H:28]([C:36](O)=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].CN1CCOCC1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[C:17]([NH:27][C@H:28]([C:36]([CH:4]1[C:3]2([NH2:2])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][C:5]1([C:13]([O:15][CH3:16])=[O:14])[CH2:6]3)[CH2:10]2)=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]
Reactant: COC(=O)C12CC3CC(CC(N)(C3)C1)C2
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)C12CC3CC(CC(N)(C3)C1C(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C2
Reaction time: 24 h

Procedure:
To 30 ml of a 1 N sodium hydroxide solution is added 4.95 g of L-phenylalanine. The solution is cooled and stirred in an ice bath and 5.4 ml of a 6.1 M solution of carbobenzoxychloride is added dropwise along with additional 1 N sodium hydroxide solution so that the pH remains at 11.0-11.5. The reaction mixture is washed with ether. The aqueous layer is acidified to pH 1.0 with 12 N hydrochloric acid, then the solution is extracted with ethyl acetate. The ethyl acetate extract is separated and is washed three times with water then dried over magnesium sulfate. The solvent is removed under vacuum. The residue crystallizes on rubbing with water to give N-carbobenzoxy-L-phenylalanine. 3.99 Grams of methyl 3-amino-1-adamantanecarboxylate hydrochloride and 4.78 g of carbobenzoxy-L-phenylalanine are dissolved in 40 ml methylene chloride. To this solution is added 1.8 ml of N-methylmorpholine followed immediately by 2.19 g of dicyclohexylcarbodiimide. The reaction mixture is allowed to stand for 24 hours at room temperature, then the treatment with carbobenzoxy-L-phenylalanine and dicyclohexylcarbodiimide is repeated. The reaction mixture is again allowed to stand for 24 hours at room temperature. The dicyclohexylurea is removed by filtration and washed with methylene chloride. The combined filtrates are washed twice with 0.5 M potassium bisulfate, water and 1 M solution of potassium bicarbonate and dried over magnesium sulfate. The dicloromethane is removed under vacuum and the residue is purified by low pressure chromatography on silica gel using mixtures of hexane and chloroform as eluting solvent to give methyl carbobenzoxy-L-phenylalanyl-3-amino-1-adamantanecarboxylate which has the following structural formula ##STR13## wherein Cbz represents carbobenzoxy.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N+:13]([O-])=O)[CH:10]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>CCOC(C)=O>[CH2:1]([N:8]1[CH2:9][CH:10]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH:11]([NH2:13])[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: NC1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 67.8 %

Procedure:
To a stirred solution of (3SR,4RS)-1-benzyl-3-(3,4-dichloro-phenyl)-4-nitro-pyrrolidine (15.0 g, 0.0427 mol) in EtOAc (200 ml) was added portionwise SnCl2.2H2O (43.36 g, 0.192 mol). The reaction mixture was then heated at reflux for 4 hours, cooled down to RT and a saturated aqueous solution of NaHCO3 (500 ml) was added. The salts were filtered off and the product extracted with EtOAc. The organic phases were then dried over Na2SO4, and concentration under vacuum gave 9.30 g (75%) of the title compound as a light yellow oil. The product was then used in the next step without further purification. ES-MS m/e: 321.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[C:3]#[C:4][C:5]#[C:6][CH2:7][N:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:10][NH2:11].C=O.[C:21]([BH3-])#N.[Na+]>C(O)C>[CH3:21][NH:11][CH2:10][CH2:9][N:8]([CH2:7][C:6]#[C:5][C:4]#[C:3][C:2]([CH3:17])([CH3:18])[CH3:1])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: [BH3-]C#N
Reactant: CCCCCN(CC#CC#CC(C)(C)C)CCN
Agent: C=O
Agent: [Na+]
Solvent: CCO
Product: CCCCCN(CC#CC#CC(C)(C)C)CCNC
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.6 %

Procedure:
In 1 ml of ethanol was dissolved 30 mg of N-(6,6-dimethyl-2,4-heptadiynyl)-N-pentylethylenediamine. Then 20 μl of 35% formalin and 8.3 mg of sodium cyanoborohydride were added to the solution. The mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with a mixture of ethyl acetate and 1N hydrochloric acid. The organic layer was fractionated, washed with saturated sodium bicarbonate aqueous solution and dried over anhydrous magnesium sulfate. The drying agent was filtered off and the solvent was then removed under reduced pressure. The residue was purified by silica gel column chromatography (Wako Gel C-200, 10 g, methylene chloride/methanol=50/1) to give 10 mg (yield: 32%) of the title compound as colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH2:12]O)[CH2:5][CH2:4][CH2:3]1.S(Cl)([Cl:16])=O>ClCCl>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH2:12][Cl:16])[CH2:5][CH2:4][CH2:3]1
Reactant: CN1CCCc2cccc(CO)c21
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CN1CCCc2cccc(CCl)c21
Temperature: 45 °C
Reaction time: 2 h

Procedure:
1-Methyl-8-hydroxymethyl-1,2,3,4-tetrahydroquinoline (0.89 g) was dissolved in dichloromethane (30 ml), and thionyl chloride (1.09 ml) was added thereto, and the mixture was stirred for 2 hours at 45° C. After distilling off the solvent, n-hexane was added to the residue, and the solvent was distilled off under reduced pressure to give 1-methyl-8-chloromethyl-1,2,3,4-tetrahydroquinoline (1.1 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])=[C:14]([CH3:22])[C:13]=2[CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>O1CCCC1.CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH:17]([OH:21])[CH:18]([CH3:19])[CH3:20])=[C:14]([CH3:22])[C:13]=2[CH:23]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)C(C)C)oc2ccc(OCc3ccccc3)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(C(O)C(C)C)oc2ccc(OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-[5-(Benzyloxy)-3-methyl-1-benzofuran-2-yl]-2-methylpropan-1-one (11.7 g) synthesized in the above-mentioned (1) was dissolved in a tetrahydrofuran (150 mL) and methanol (15 mL), and sodium borohydride (90%, 3.0 g) was added under ice-cooling. The ice bath was removed, the reaction mixture was stirred at room temperature for 2 hr. The mixture was ice-cooled again, water (10 mL) and 1N hydrochloric acid (100 mL) were carefully added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title object compound (11.3 g, quantitative) as a pale-yellow oil.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[NH2:22][C@@H:23]([CH2:27][CH2:28][S:29][CH3:30])[C:24]([NH2:26])=[O:25]>>[C:24]([C@@H:23]([NH:22][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[CH2:27][CH2:28][S:29][CH3:30])(=[O:25])[NH2:26]
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CSCC[C@H](N)C(N)=O
Agent: Cl
Product: CSCC[C@H](NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and (2S)-2-amino-4-(methylthio)-butanamide, monohydrochloride (CAN 14510-08-1) as starting materials. MS (EI): m/e=415.16 [M+H]+.
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:12]=[C:13]2[C:21](=[C:22]([C:33]3[CH:41]=[CH:40][C:36]4[O:37][CH2:38][O:39][C:35]=4[CH:34]=3)[C:23]=1[CH2:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:17]1[O:18][CH2:19][O:20][C:16]=1[CH:15]=[CH:14]2)=[O:10])C1C=CC=CC=1.[OH-].[Na+]>CO.O>[O:37]1[C:36]2[CH:40]=[CH:41][C:33]([C:22]3[C:23]([CH2:24][O:25][CH2:26][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)=[C:11]([C:9]([OH:10])=[O:8])[CH:12]=[C:13]4[C:21]=3[C:17]3[O:18][CH2:19][O:20][C:16]=3[CH:15]=[CH:14]4)=[CH:34][C:35]=2[O:39][CH2:38]1
Reactant: O=C(OCc1ccccc1)c1cc2ccc3c(c2c(-c2ccc4c(c2)OCO4)c1COCc1ccccc1)OCO3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc2ccc3c(c2c(-c2ccc4c(c2)OCO4)c1COCc1ccccc1)OCO3
Yield: 63.7 %

Procedure:
A solution of 4 (56 mg, 0.11 mmol) and NaOH (16 mg, 0.4 mmol) in MeOH/H2O (4:1, 2 mL) was heated at 70° C. for 12 h. The solvent was evaporated to dryness, and the residue was dissolved in water. The aqueous solution was acidified to pH 1-2 with 10% aqueous HCl solution and then extracted with ether (3×50 mL). The extract was washed with water and brine, and dried over MgSO4. The evaporation of solvent yielded 5 (32 mg, 70%) as a white powder. mp 219-221° C.; 1H NMR (DMSO-d6) δ 8.27 (s, 1H, H4), 7.70 (d, 1H, H5, J=8.7 Hz), 7.38 (d, 1H, H6, J=8.7 Hz), 7.17-7.25 (m, 5H, OCH2Ph), 6.89 (d, 1H, H5′, J=8.1 Hz), 6.79 (d, 1H, H2′, J=1.5 Hz), 6.65 (dd, 1H, H6′, J=1.5, 8.1 Hz), 6.06 (AB, 2H, 3′,4′-OCH2O—, Δδ=18.0 Hz, J=0.6 Hz), 5.85 (AB, 2H, 7,8-OCH2O—, Δδ=9.3 Hz, J=0.9 Hz), 4.53 (s, 2H, 2-CH2OCH2Ph), 4.24 (s, 2H, 2-CH2OBn); MS (FAB, positive) m/z 457 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C@H:17]2[CH2:19][C@H:18]2[CH2:20][CH2:21][O:22][C:23]2[C:28]([CH3:29])=[CH:27][C:26]([NH2:30])=[CH:25][N:24]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl[CH2:41][CH2:42][N:43]=[C:44]=[O:45].NC(N)=O.[H-].[Na+]>C1COCC1>[CH3:29][C:28]1[C:23]([O:22][CH2:21][CH2:20][C@@H:18]2[CH2:19][C@@H:17]2[CH:14]2[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[CH2:16][CH2:15]2)=[N:24][CH:25]=[C:26]([N:30]2[CH2:41][CH2:42][NH:43][C:44]2=[O:45])[CH:27]=1
Reactant: Cc1cc(N)cnc1OCC[C@@H]1C[C@@H]1C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: O=C=NCCCl
Agent: NC(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(N2CCNC2=O)cnc1OCC[C@@H]1C[C@@H]1C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of benzyl-4-((1R,2 S)-2-{2-[(5-amino-3-methylpyridin-2yl)oxy]ethyl}cyclopropyl)piperidine-1-carboxylate (39 mg, 0.106 mmol) in THF (2.5 ml) at RT under nitrogen was added DIPEA (0.037 ml, 0.213 mmol), followed by 2-chloroethyl isocyanate (0.014 ml, 0.160 mmol). And the resulting solution stirred at room temperature overnight. LC/MS showed clean conversion to the uncyclized urea intermediate. The mixture was cooled to 0° C. and NaH (8.51 mg, 0.213 mmol) was added. The mixture was removed from the ice bath after ca. 15 minutes. LC/MS at 1 h showed complete conversion to the desired product. Formic acid (50 μl) was added and the reaction mixture stirred for 30 minutes. The material was concentrated under reduced pressure and the residue was purified by RP HPLC on a Gilson, SunFire-5C18 OBD 19×150 mm column, eluting with a gradient of MeCN in water (0.1% HCOOH) from 10% to 100% over 8 minutes, hold at 100% for 1 minute, at 20 ml/min flow rate to afford the title compound. MS (ESI) m/z 479 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([O:9]C(C)(C)C)=[O:8])[CH2:5][N:4]([C:14]2[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=2)[C:3]1=[O:24]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:1][N:2]1[CH:6]([C:7]([OH:9])=[O:8])[CH2:5][N:4]([C:14]2[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=2)[C:3]1=[O:24]
Reactant: CN1C(=O)N(c2nccc(C(F)(F)F)n2)CC1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)N(c2nccc(C(F)(F)F)n2)CC1C(=O)O
Yield: 102.7 %

Procedure:
A solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (600 mg, 3 mmol) (prepared as described in step (iii) of Example 13, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) and 2-chloro-4-(trifluoromethyl)pyrimidine (547 mg, 3.00 mmol) in 1,4-dioxane (20 ml) was treated with cesium carbonate (1464 mg, 4.49 mmol), Xantphos™ (130 mg, 0.225 mmol) and tris(dibenzylideneacetone)dipalladium(0) (68.6 mg, 0.075 mmol) and the mixture was heated at reflux under argon for 6 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with water and brine and evaporated. The residue was purified by silica gel chromatography eluting with 0-100% ethyl acetate in isohexane to give 1,1-dimethylethyl 3-methyl-2-oxo-1-[4-(trifluoromethyl)-2-pyrimidinyl]-4-imidazolidinecarboxylate (506 mg, 49%). LC/MS [M+H]+=347. (ii) A solution of 1,1-dimethylethyl 3-methyl-2-oxo-1-[4-(trifluoromethyl)-2-pyrimidinyl]-4-imidazolidinecarboxylate (506 mg, 1.46 mmol) in TFA/DCM (1:2, 9 ml) was stirred at room temperature for 16 hours. The solution was evaporated and the residue was co-evaporated with toluene and dried to give crude 3-methyl-2-oxo-1-[4-(trifluoromethyl)-2-pyrimidinyl]-4-imidazolidinecarboxylic acid (assume ˜1.5 mmol) which was used in the next step. LC/MS [M+H]+=291.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19](I)[CH:18]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O.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>[Cl:16][C:17]1[CH:18]=[C:19]([C:13]2[CH:14]=[CH:15][C:10]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:11][CH:12]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: Clc1cccc(I)c1
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Clc1cccc(-c2ccc(-c3ccccc3)cc2)c1
Temperature: 25 °C
Yield: 83.8 %

Procedure:
A solution of [1,1′-biphenyl]-4-ylboronic acid (8.47 g, 42.8 mmol), 1-chloro-3-iodobenzene (10 g, 41.9 mmol), Pd(PPh3)4 (0.969 g, 0.839 mmol) and K2CO3 (17.4 g, 126 mmol) in toluene (270 ml) and water (90 ml) was refluxed under nitrogen for 4.5 h. After cooling to room temperature, the organic phase was separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine and water, dried over Na2SO4 and the solvent was evaporated. The residue was purified by column chromatography on silica gel with heptane/DCM (98/2, v/v) as eluent to yield 3-chloro-1,1′:4′,1″-terphenyl (9.3 g, 84%) as a white solid.