Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)[C:7]([CH:10]=O)=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].S(=O)(O)[O-].[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[CH2:31][CH:32](C([O-])=O)[C:33]([O:35]CC)=[O:34]>>[CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)[C:7](/[CH:10]=[C:32](\[CH2:31][C:27]2[S:26][CH:30]=[CH:29][CH:28]=2)/[C:33]([OH:35])=[O:34])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)C(Cc1cccs1)C(=O)[O-]
Reactant: CCCCc1ncc(C=O)n1Cc1ccc(C(=O)O)cc1
Agent: O=S([O-])O
Product: CCCCc1ncc(/C=C(\Cc2cccs2)C(=O)O)n1Cc1ccc(C(=O)O)cc1

Procedure:
Alternately, 4-[(2-n-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoic acid or the bisulfite addition compound of 4-[(2-n-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoic acid and (2-thienylmethyl)propanedioic acid, mono-ethyl ester are reacted to give (E)-α-[[2-butyl-1-[(4carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene]-2-thiophene propanoic acid by heating the two substrates in toluene at reflux under reduced pressure and in the presence of piperidine as catalyst followed by hydrolysis of the intermediate ester ethyl (ethyl (E)-α-[[2-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene]-2-thiophenepropanoate). In this preparation, 4-[(2-n-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoic acid or the bisulfite addition compound of 4-[(2-n-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoic acid, (2-thienylmethyl)propanedioic acid, mono-ethyl ester, and toluene are charged to a glass lined steel vessel and are initially heated to 55-60° C. to afford a homogenous solution. The catalyst (66 mol % piperidine) is added and the reaction is heated to reflux (70-75° C.) under reduced pressure. Reflux conditions are maintained for 20-35 hours and additional (2-thienylmethyl)-propanedioic acid, mono-ethyl ester is added. Once the reaction is complete, water and aqueous sodium hydroxide are added to the vessel and the reaction mixture heated at reflux under atmospheric conditions for 1-3 hours. The reaction is deemed complete when the level of ethyl (E)-α-[[2-butyl-1-[(4-carboxyphenyl)-methyl]-1H-imidazol-5-yl]methylene]-2-thiophene propanoate is less than 2.0%. The reaction is cooled to 45-50° C. and the aqueous and organic phases separated. The toluene phase is discarded. Ethanol is added to the aqueous phase and the solution is acidified with aqueous hydrochloric acid until a pH of 5.0 to 5.4 is achieved, maintaining the temperature at 50-55° C. The product slurry is cooled and allowed to stir at 10-15° C. for 2 hours. The product is isolated by centrifugation, washed and stored. Thereafter, pharmaceutically acceptable salts may be prepared as described above.
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:15][C:16]1[CH:21]=[N:20][C:19]([Br:22])=[CH:18][N:17]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.C(O)(=O)C.ClCCl>[C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:14]=[CH:13][C:10]([CH2:11][NH:15][C:16]2[CH:21]=[N:20][C:19]([Br:22])=[CH:18][N:17]=2)=[CH:9][CH:8]=1
Reactant: Nc1cnc(Br)cn1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: Brc1cnc(NCc2ccc(-c3ccccc3)cc2)cn1
Yield: 38.6 %

Procedure:
4-Phenylbenzaldehyde (0.3 g, 1.65 mmol) and 2-amino-5-bromopyrazine (0.24 g, 1.37 mmol) were treated with Na(OAc)3BH (0.44 g, 2.06 mmol) in dichloroethane (7.0 mls) and acetic acid (0.25 mls) for 18 hours at room temperature. The mixture was diluted with dichloromethane, washed with 1.0 N NaOH, washed with brine, dried over MgSO4, and concentrated. Chromatography (SiO2, EtOAc: Hex, 1:1) gave 0.18 g of N-(biphenyl-4-ylmethyl)-5-bromopyrazin-2-amine.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11](O)=O)=[CH:5][CH:4]=1)#[N:2].[C:14]1([N:20]([CH2:32][CH2:33][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:21](=[O:31])[C:22]2[CH:27]=[CH:26][C:25]([NH:28][CH3:29])=[C:24]([NH2:30])[CH:23]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl.CO>[C:14]1([N:20]([CH2:32][CH2:33][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:21]([C:22]2[CH:27]=[CH:26][C:25]3[N:28]([CH3:29])[C:11]([CH2:10][NH:9][C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=4)=[N:30][C:24]=3[CH:23]=2)=[O:31])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CNc1ccc(C(=O)N(CCCC(=O)OC(C)(C)C)c2ccccc2)cc1N
Reactant: N#Cc1ccc(NCC(=O)O)cc1
Solvent: ClCCl
Solvent: CO
Product: Cn1c(CNc2ccc(C#N)cc2)nc2cc(C(=O)N(CCCC(=O)OC(C)(C)C)c3ccccc3)ccc21
Yield: 65 %

Procedure:
Prepared analogously to Example 25c from N-(4-cyanophenyl)glycine and 3-amino-4-methylaminobenzoic acid-N-phenyl-N-(3-tert-butyloxycarbonylpropyl)amide. Yield: 65% of theory; Rf value: 0.17 (silica gel; dichloromethane/methanol=19:1).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[CH:9]\[CH2:10][OH:11])=[CH:4][CH:3]=1.[CH3:19][C:20]1[CH:30]=[C:29](OC/C=C(/C2C=CC(C#CCN3CCOCC3)=CC=2)\C2C=CC=CC=2)[CH:28]=[CH:27][C:21]=1[O:22][CH2:23][C:24]([OH:26])=[O:25].[C:56]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.O1CCCC1>[I:1][C:2]1[CH:3]=[CH:4][C:5](/[C:8](/[C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)=[CH:9]\[CH2:10][O:11][C:29]2[CH:28]=[CH:27][C:21]([O:22][CH2:23][C:24]([O:26][CH3:56])=[O:25])=[C:20]([CH3:19])[CH:30]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(/C(=C/CO)c2ccc(I)cc2)cc1
Reactant: Cc1cc(OC/C=C(\c2ccccc2)c2ccc(C#CCN3CCOCC3)cc2)ccc1OCC(=O)O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(/c2ccc(C)cc2)c2ccc(I)cc2)cc1C
Temperature: 0 °C
Reaction time: 48 h

Procedure:
The above allyl alcohol (420 mg, 1.2 mmol), methyl (4-hydroxy-2-methylphenoxy)acetate (0.259 mg, 1.32 mmol; example 2) and triphenylphosphine (378 mg, 1.44 mmol) were dissolved in a mixture of anhydrous toluene (20 mL) and tetrahydrofuran (7 mL). The solution was cooled to 0° C., kept under nitrogen and a degassed solution of diisopropyl azodicarboxylate (0.28 mL, 1.44 mmol) in anhydrous tetrahydrofuran (2.5 mL) was added dropwise over 10 min. The reaction mixture was allowed to warm up to the ambient temperature with the bath and then was stirred for 48 h. The solvents were evaporated in vacuo and the residue was submitted to flash column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 4:1) affording methyl (Z)-[4-[3-(4-iodophenyl)-3-(4-methylphenyl)allyloxy]-2-methylphenoxy]acetate as solidifying yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]4[N:19]([CH:20]([CH3:22])[CH3:21])[N:18]=[CH:17][N:16]=4)[N:14]=[C:7]3[C:6]=2[CH:23]=1.[N:24]1(C([O-])=O)[CH:28]=[CH:27][CH:26]=[N:25]1>>[CH:20]([N:19]1[C:15]([C:13]2[N:14]=[C:7]3[C:6]4[CH:23]=[C:2]([C:27]5[CH:28]=[N:24][NH:25][CH:26]=5)[CH:3]=[CH:4][C:5]=4[O:11][CH2:10][CH2:9][N:8]3[CH:12]=2)=[N:16][CH:17]=[N:18]1)([CH3:22])[CH3:21]
Reactant: O=C([O-])n1cccn1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(Br)ccc1OCC2
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(-c3cn[nH]c3)ccc1OCC2

Procedure:
Following Example 182, 10-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 187 was coupled with tert-butyl 444, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate to give 160. MS: 362.3. 1H NMR (400 MHz, DMSO) δ 8.57 (t, J=4.0, 1H), 7.99-7.94 (m, 4H), 7.56 (dt, J=11.2, 5.6, 1H), 7.06 (t, J=8.6, 1H), 5.81 (p, J=6.6, 1H), 4.53 (d, J=9.5, 4H), 1.53 (d, J=6.6, 7H).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[C:6]([N+:12]([O-:14])=[O:13])[CH:7]=[CH:8]2)=[N:3]1.[CH2:15]1[C:20](=[O:21])[N:19]([Br:22])[C:17](=[O:18])[CH2:16]1>C(Cl)(Cl)(Cl)Cl>[Br:22][CH2:11][C:10]1[N:2]([CH3:1])[N:3]=[C:4]2[C:9]=1[CH:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[CH:5]2.[C:17]1(=[O:18])[NH:19][C:20](=[O:21])[CH2:15][CH2:16]1
Reactant: Cc1c2ccc([N+](=O)[O-])cc2nn1C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Cn1nc2cc([N+](=O)[O-])ccc2c1CBr
Product: O=C1CCC(=O)N1
Temperature: 80 °C
Reaction time: 8 h
Yield: 283.7 %

Procedure:
To a solution of 2,3-dimethyl-6-nitro-2H-indazole (3.00 g, 15.69 mmol) in CCl4 (500 mL) was added AlBN (0.51 g, 3.14 mmol) and NBS (3.06 g, 17.26 mmol). The mixture was heated to 80° C. for 5 hours then stirred at rt overnight. Approximately half of the solvent was removed in vacuo, and the mixture was filtered. The filtrate was conc. in vacuo, and the crude product was purified by silica gel column chromatography eluting with ethyl acetate and hexane to afford 3-(bromomethyl)-2-methyl-6-nitro-2H-indazole with some succinimide present (4.41 g, 104% TY). 1H NMR (300 MHz, CDCl3) δ 8.68 (d, J=2.1 HZ, 1H), 7.98 (dd, J=9.3, 2.1 Hz, 1H), 7.74 (d, J=9.3 Hz, 1H), 4.87 (s, 2H), 4.28 (s, 3H). MS (ES+, m/z) 270, 272 (M+H).
Reaction SMILES: O.O=[C:3]([C:7]([OH:9])=[O:8])[C:4]([OH:6])=[O:5].[C:10]1([NH:16][NH2:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)C.O>[C:10]1([NH:16][N:17]=[C:3]([C:7]([OH:9])=[O:8])[C:4]([OH:6])=[O:5])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NNc1ccccc1
Reactant: O=C(O)C(=O)C(=O)O
Solvent: CCO
Solvent: O
Product: O=C(O)C(=NNc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
To a vigorously stirred solution of ketomalonic acid monohydrate (29.33 g) in ethanol (140 mL) and water (300 mL) at ambient temperature was added phenylhydrazine (23.3 g) dropwise over a 40 minute period. The resultant slurry was stirred overnight at ambient temperature. The solid was separated by filtration, washed sucessively with cold water (100 mL) and ethanol (25 mL) and air dried. Subsequent drying was performed at 75° C. overnight in a vacuum oven to give the title compound as a yellow solid (42.38 g). 1H (300 MHz, DMSO-d6): d 7.12(t, 1H), 7.35-7.48(m, 4H); m.p.: 155°-157° C. (dec).
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:22][O:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH2:31].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:22][O:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:17](=[O:18])[CH2:16][O:15][C:14]1[CH:13]=[CH:12][C:11]([C:1]23[CH2:10][CH:5]4[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]4)[CH2:8]2)[CH2:2]3)=[CH:21][CH:20]=1
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: COC(=O)c1ccccc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1NC(=O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reaction time: 8 h
Yield: 36.9 %

Procedure:
To a mixture of [4-(1-adamantyl)phenoxy]acetic acid (85.9 mg, 0.30 mmol), 2-amino-benzoic acid methyl ester (0.07 mL, 0.54 mmol), N-(3-dimethylaminopropyl)-N′-ethyl carbodiimide HCl (EDC) (103.5 mg, 0.54 mmol) and 1-hydroxybenzotriazole (HOBt) (73.0 mg, 0.54 mmol) in DMF (3.6 mL) was added N,N-diisopropylethylamine, redistill (DIPEA) (69.8 mg, 0.10 mL, 0.54 mmol). The mixture was stirred overnight, and then partitioned between ethyl acetate and 10% HCl. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel flash column chromatography (n-Hexane:Ethyl acetate:MeEOH=12:3:1) to give 2-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-benzoic acid methyl ester as a white solid (46.4 mg, 3.69% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4](Cl)[N:3]=1.[CH2:10]([NH2:14])[CH2:11][CH2:12][CH3:13]>O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:14][CH2:10][CH2:11][CH2:12][CH3:13])[N:3]=1
Reactant: Nc1nc(N)nc(Cl)n1
Reactant: CCCCN
Solvent: O
Product: CCCCNc1nc(N)nc(N)n1
Yield: 96 %

Procedure:
A mixed solution of 14.5 g (0.1 mol) of 2,4-diamino-6-chloro-1,3,5-triazine prepared in the (a), 100 mL of water and 29.2 g (0.4 mol) of butylamine was heated while stirring, followed by being finally reacted for 6 hours at reflux temperature. After cooling reaction liquid, a product was filtered, followed by washing with a large quantity of water and then with toluene. The product was dried at 70° C. in vacuo for 6 hours to obtain 17.5 g (a yield of 96%) of the above-identified compound. Melting point: 167° C.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[CH:30]([CH2:32][CH2:33][CH:34]([OH:36])[CH3:35])[CH3:31].O>CN(C)C=O>[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[C:30]([CH2:32][CH2:33][C:34](=[O:36])[CH3:35])=[CH2:31]
Reactant: CC(O)CCC(C)c1ccc(Cl)cc1Cl
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: O
Product: C=C(CCC(C)=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
A mixture of pyridinium dichromate (49 g) and 2-(2,4-dichlorophenyl)hexan-5-ol (16 g) in dry dimethylformamide (100 ml) was stirred overnight at room temperature then poured into water and extracted with ether. The extracts were washed successively with dilute hydrochloric acid and water, then dried over magnesium sulphate and concentrated under reduced pressure to give almost pure 2-(2,4-dichlorophenyl)hex-1-en-5-one (14.5 g, 91%) as a yellow oil, 1H n.m.r. (CDCl3): δ2.18 (3H,s), 2.4-3.0 (4H,m), 5.15 (1H,s), 5.41 (1H,s), 7.2-7.6 (3H, m).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@:9]1([CH3:17])[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:51][O:52][C@@H:53]([C@@H:71]1[CH2:75][CH2:74][CH2:73][N:72]1[C:76](=[O:95])[CH2:77][C@@H:78]([O:93][CH3:94])[C@@H:79]([N:84]([CH3:92])[C:85](=[O:91])[C@H:86]([CH:88]([CH3:90])[CH3:89])[NH2:87])[C@@H:80]([CH3:83])[CH2:81][CH3:82])[C@@H:54]([CH3:70])[C:55]([NH:57][C@H:58]([C:66]([O:68][CH3:69])=[O:67])[CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)=[O:56]>ClCCl.CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@:9]1([C:14]([NH:87][C@H:86]([C:85]([N:84]([CH3:92])[C@@H:79]([C@@H:80]([CH3:83])[CH2:81][CH3:82])[C@H:78]([O:93][CH3:94])[CH2:77][C:76]([N:72]1[CH2:73][CH2:74][CH2:75][C@H:71]1[C@H:53]([O:52][CH3:51])[C@@H:54]([CH3:70])[C:55]([NH:57][C@H:58]([C:66]([O:68][CH3:69])=[O:67])[CH2:59][C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1)=[O:56])=[O:95])=[O:91])[CH:88]([CH3:89])[CH3:90])=[O:16])[CH3:17])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@]1(C)C(=O)O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](N)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](NC(=O)[C@@]1(C)CCCCN1C(=O)OC(C)(C)C)C(C)C
Reaction time: 0.25 h
Yield: 48.1 %

Procedure:
To a solution of #157 (109 mg, 0.448 mmol, 1 eq.) in dichloromethane (3 mL) and N,N-dimethylformamide (0.5 mL), was added diisopropylethylamine (0.234 mL, 1.34 mmol, 3 eq.) followed by HATU (205 mg, 0.538 mmol, 1.2 eq.). The reaction stirred for 15 minutes and #114 (284 mg, 0.448 mmol, 1 eq.) was added. After stirring at room temperature for 2 hours, the mixture was diluted with dichloromethane (10 mL), washed with 10% citric acid (3×5 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by silica gel chromatography (Gradient: 0 to 100% acetone in heptane) afforded #161 (185 mg, 48%). LC-MS (Protocol Q): m/z 858.3 [M+H+], retention time=2.25 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:11](#[N:13])[CH3:12]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:7]([OH:8])[CH2:12][C:11]#[N:13])[CH:9]=1
Reactant: CC#N
Reactant: Cc1ccc(Br)cc1C=O
Product: Cc1ccc(Br)cc1C(O)CC#N

Procedure:
Alkylation of 5-bromo-2-methylbenzaldehyde with acetonitrile following the method used in Example 114 gave 3-(5-bromo-2-methylphenyl)-3-hydroxypropanenitrile as a pale yellow oil. Yield (3.33 g, 86%): 1H NMR (400 MHz, DMSO-d6) δ 7.61 (d, J=2.0 Hz, 1H), 7.35 (dd, J=8.0, 2.0 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H), 5.96 (d, J=4.4 Hz, 1H), 5.04-5.00 (m, 1H), 2.88 (ABd, J=16.8, 4.4 Hz, 1H), 2.77 (ABd, J=16.8, 6.4 Hz, 1H), 2.23 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]([OH:26])[CH2:18][CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[CH:11][CH:10]=2)[CH:6]=CC=1)#N.[OH-:27].[Na+].[CH2:29]([OH:31])[CH3:30]>O>[C:29]([C:30]1[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]([OH:26])[CH2:18][CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[CH:11][CH:10]=2)[CH:4]=[CH:3][CH:1]=1)([OH:27])=[O:31]
Reactant: CCO
Reactant: [OH-]
Reactant: N#Cc1cccc(-c2ccc(OC[C@H](O)CCc3cccnc3)cc2)c1
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cccc(-c2ccc(OC[C@H](O)CCc3cccnc3)cc2)c1

Procedure:
A stirred solution of (2R)-1-(3'-cyanobiphenyl-4-yloxy)-4-(3-pyridyl)-2-butanol (0.60 g) and sodium hydroxide (0.696 g) in ethanol (8 ml) and water (2 ml) was heated at reflux for 10 hours. The mixture was concentrated and the residues dissolved in water and neutralised. The precipitate was filtered off and dried under vacuum to give the title compound as a white solid (0.616 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][Si](C(C)(C)C)(C)C)[CH2:13][C@H:12]1[CH2:24][O:25][C:26](=[O:28])[CH3:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(F)(F)F.CCOCC>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:12]1[CH2:24][O:25][C:26](=[O:28])[CH3:27])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccccc1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)OC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1

Procedure:
To a solution of (2S,4R)-1-benzyloxycarbonyl-2-acetoxymethyl-4-t-butyldimethylsilyloxypyrrolidine (42.23 g) in dry dichloromethane (422 ml), boron trifluoride etherate (103.54 g) was added at room temperature, and the resultant mixture was stirred at the same temperature for 4 hours. The reaction mixture was washed successively with aqueous sodium bicarbonate solution and water and dried over magnesium sulfate. Removal of the solvent gave (2S,4R)-1-benzyloxycarbonyl-2-acetoxymethyl-4-hydroxypyrrolidine.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[C:6]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:7][C:8]([NH:15][C:16]([C:18]2[CH:19]=[N:20][CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:23]=2)=[O:17])=[C:9]([CH:14]=1)[C:10]([O:12]C)=[O:11].C(Cl)(Cl)Cl>CO>[CH3:3][O:4][C:5]1[C:6]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:7][C:8]([NH:15][C:16]([C:18]2[CH:19]=[N:20][CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:23]=2)=[O:17])=[C:9]([CH:14]=1)[C:10]([OH:12])=[O:11]
Reactant: COC(=O)c1cc(OC)c(-c2ccccc2)cc1NC(=O)c1cncc(-c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc(C(=O)O)c(NC(=O)c2cncc(-c3ccccc3)c2)cc1-c1ccccc1
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
A 2 mol/L aqueous solution of sodium hydroxide (1.3 mL) was added to a methanol (2.2 mL) suspension of the obtained methyl 5-methoxy-4-phenyl-2-(5-phenylpyridine-3-carboxamido)-benzoate (0.11 g) at room temperature, followed by stirring at the same temperature for 30 minutes. Chloroform (3 mL) and methanol (2 mL) were added to the reaction mixture, followed by stirring at room temperature for 4 hours. The solvent was evaporated under reduced pressure, and ethanol and water were added to the obtained residue. After adjusting the pH to 1 with 6 mol/L hydrochloric acid, the solid substance was collected by filtration to obtain 88 mg of 5-methoxy-4-phenyl-2-(5-phenylpyridine-3-carboxamido)benzoic acid as a white solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[N:8][CH:9]=2)[CH:4]=[C:3]([C:11]([O-:13])=O)[N:2]=1.[NH2:14][NH2:15].Cl.[N:17]([O-])=O.[Na+].C([O-])(O)=O.[Na+]>O.C(O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[N:8][CH:9]=2)[CH:4]=[C:3]([C:11]([N:14]=[N+:15]=[N-:17])=[O:13])[N:2]=1
Reactant: O=C([O-])c1cc2ccncc2cn1
Reactant: O=N[O-]
Reactant: NN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: [N-]=[N+]=NC(=O)c1cc2ccncc2cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
A mixture of 2,7-naphthyridine-3-carboxylate (260 mg, 1.29 mmol), hydrazine (0.20 mL, 6.44 mmol) and ethanol was refluxed for 2 h and concentrated to dryness. The resulting residue was mixed with 2N HCl (1.3 mL, 2.60 mmol) and H2O (5 mL) and cooled with an ice bath. To the mixture was added a solution of NaNO2 (178 mg, 2.6 mmol in 1 mL H2O) dropwise, the mixture was stirred at 0° C. for 1 h. The mixture was then neutralized with saturated NaHCO3 and extracted with DCM. The DCM solution was washed with water, brine, dried and concentrated to give 2,7-naphthyridine-3-carbonyl azide as a pale yellow solid (244 mg, 95%). LRMS (M−N2+H+) m/z 172.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]1[C:12]([NH:14][C:15]1([C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=2)[CH2:17][CH2:16]1)=[O:13].O[Li:32].O>>[F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]1[C:12]([NH:14][C:15]1([C:18]2[CH:19]=[CH:20][C:21]([C:22]([O-:24])=[O:23])=[CH:26][CH:27]=2)[CH2:16][CH2:17]1)=[O:13].[Li+:32]
Reactant: [Li]O
Reactant: COC(=O)c1ccc(C2(NC(=O)[C@H]3CCCCN3Cc3cccc(F)c3)CC2)cc1
Solvent: O
Product: O=C([O-])c1ccc(C2(NC(=O)[C@H]3CCCCN3Cc3cccc(F)c3)CC2)cc1
Product: [Li+]

Procedure:
The title compound (E11) (61 mg) was prepared according to the general procedure for esters hydrolysis starting from (R)-methyl 4-(1-(1-(3-fluorobenzyl)piperidine-2-carboxamido)cyclopropyl)benzoate (D28) (62 mg). (LiOH H2O: 3 eq; reaction time: 3 hrs)
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@H:11]([C:16]([OH:18])=[O:17])[CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(Cl)(Cl)Cl.C(O)C(C)C>[CH2:2]([O:17][C:16](=[O:18])[C@H:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[NH:10][C:8](=[O:9])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH:1]([CH3:7])[CH3:6]
Reactant: CC(C)C[C@H](NC(=O)Cc1ccccc1)C(=O)O
Solvent: CC(C)CO
Solvent: ClC(Cl)Cl
Product: CC(C)COC(=O)[C@H](CC(C)C)NC(=O)Cc1ccccc1
Reaction time: 96 h

Procedure:
N-Phenylacetyl-L-leucine (0.0081 g, 0.038 mmol) was dissolved in 2.0 ML CHCl3 (EtOH free) and iso-butyl alcohol (0.055 mL) and treated with P-EPC (100 mg, 0.87 milliequivalents). The mixture was rotated for 4 days, filtered through a plug of cotton and the filtrate evaporated at reduced pressure to an oil which was sufficiently pure for testing.