Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:11]([OH:13])=O)[C:7](=[O:20])[CH:6]=1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:48][C:49]1[CH:53]=[CH:52][N:51]([CH2:54][C:55]([CH3:58])([OH:57])[CH3:56])[N:50]=1>ClCCl>[Cl:1][C:2]1[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:11]([NH:48][C:49]2[CH:53]=[CH:52][N:51]([CH2:54][C:55]([OH:57])([CH3:56])[CH3:58])[N:50]=2)=[O:13])[C:7](=[O:20])[CH:6]=1
Reactant: COc1cccc(OC2=CC(=O)N([C@@H](CC3CCCC3)C(=O)O)C2)c1Cl
Reactant: CC(C)(O)Cn1ccc(N)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1cccc(OC2=CC(=O)N([C@@H](CC3CCCC3)C(=O)Nc3ccn(CC(C)(C)O)n3)C2)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.6 %

Procedure:
A solution of (S)-2-[4-(2-chloro-3-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclopentyl-propionic acid (200 mg, 0.53 mmol) in dichloromethane (10 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (90 mg, 0.58 mmol) and 1-hydroxybenzotriazole (75 mg, 0.55 mmol). The reaction mixture was stirred at 25° C. for 2 h followed by the addition of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 94 mg, 0.61 mmol). The reaction mixture was stirred for 18 h at 25° C., under nitrogen. The reaction mixture was diluted with dichloromethane, washed with 2N aqueous hydrochloric acid, saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g; 0% to 10% methanol/dichloromethane) to afford (S)-2-[4-(2-chloro-3-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (147 mg, 54%) as a light yellow solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.04 (br. s., 3H) 1.06 (br. s., 3H) 1.08-1.95 (m, 11H) 3.89 (br. s., 2H) 3.90 (s, 3H) 4.21 (d, J=18.4 Hz, 1H) 4.59 (d, J=18.4 Hz, 1H) 4.67 (s, 1H) 4.80 (s, 1H) 4.81-4.87 (m, 1H) 6.45 (d, J=2.1 Hz, 1H) 7.09 (d, J=8.2 Hz, 1H) 7.13 (d, J=8.5 Hz, 1H) 7.41 (t, J=8.5 Hz, 1H) 7.53 (d, J=2.1 Hz, 1H) 10.80 (s, 1H).
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:9]([O:21][CH3:22])[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:38](=[O:39])[C:37]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:36]2[C:35]1=[O:44])(OCC)=O.CCOCC>O.C(#N)C>[C:35]1(=[O:44])[N:1]([CH:2]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:9]([O:21][CH3:22])[CH:8]=2)[CH2:3][C:4]([OH:6])=[O:5])[C:38](=[O:39])[C:37]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:36]12
Reactant: COc1cc(C(N)CC(=O)O)ccc1OCc1ccccc1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC#N
Solvent: O
Product: COc1cc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)ccc1OCc1ccccc1
Reaction time: 1 h
Yield: 75.6 %

Procedure:
To a stirred solution of 3-amino-3-(4'-benzyloxy-3'-methoxyphenyl)propionic acid (1.505 g, 5.00 mmol) and sodium carbonate (0.572 g, 5.40 mmol) in a mixture of 75 mL of water and 175 mL of acetonitrile (mixture was warmed gently to dissolve solid) was added N-carbethoxyphthalimide (1.096 g, 5.00 mmol). The mixture was stirred for 1 hour, then partially concentrated in vacuo to remove the acetonitrile. A small amount of solid formed which was removed by filtration. The pH of the solution was adjusted to 1 with 4N Hydrochloric acid, a gum formed. To the stirred mixture was added 1 mL of ether and the mixture was then stirred overnight. The resulting slurry was filtered and the solid dried to afford 1.63 g (75%) of 3-phthalimido-3-(4'-benzyloxy-3'-methoxyphenyl)propionic acid as a white powder; 1H NMR (DMSO-d6) δ 12.43 (br s, 1 H, COOH), 8.0-7.8 (m, 4 H, Ar), 7.60-7.25 (m, 5 H), 7.15-6.85 (m, 3 H, Ar), 5.25 (dd, 1 H, J=9, 6.6 Hz), 5.05 (s, 2 H, OCH2), 3.76 (s, 3 H, OMe), 3.52 (dd, 1 H, J=9, 16.5 Hz), 2.29 (dd, 1 H, J=6.6, 16.5 Hz); 13C NMR (DMSO-d6) δ 171.7, 167.6,148.9, 147.3, 137.0, 134.6, 131.7, 131.0, 128.3, 127.7, 127.6, 123.1, 119.1, 113.3, 111.3, 69.8, 55.5, 50.1, 36.0. Anal. Calcd for C25H21N1O6. Theory: C, 69.66 ; H, 4.91; N, 3.25. Found: C, 69.50; H, 4.85; N, 3.22.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH:13]1([C:18]([OH:20])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1.[CH2:21]([O:28][C:29](=[O:36])[C:30]([CH2:32][CH2:33][O:34][CH3:35])=[CH2:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl>O1CCCC1>[CH2:21]([O:28][C:29](=[O:36])[CH:30]([CH2:32][CH2:33][O:34][CH3:35])[CH2:31][C:13]1([C:18]([OH:20])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C=C(CCOC)C(=O)OCc1ccccc1
Reactant: O=C(O)C1CCCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COCCC(CC1(C(=O)O)CCCC1)C(=O)OCc1ccccc1
Temperature: -73 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
n-Butyl lithium (2.5M in hexane, 18.16 ml, 45.4 mmole) was added dropwise under nitrogen to a stirred solution of diisopropylamine (4.59, 45.4 mmole) in dry tetrahydrofuran (20 ml) keeping the temperature between -40° and -20° C. Stirring was continued at -20° C. for half an hour and cyclopentane carboxylic acid (2.59 g, 22.7 mmole) in dry tetrahydrofuran (10 ml) was added over five minutes, keeping the temperature at -20° C. The mixture was allowed to attain room temperature over one and a half hours, stirred for a further one hour and then cooled to -73° C. 2-(2-Methoxyethyl)propenoic acid benzyl ester (5.0 g, 22.7 mmole) in dry tetrahydrofuran (10 ml) was added dropwise keeping the temperature below -70° C. After two hours at -77° C., the mixture was quickly warmed to 0° C., acidified with 5N hydrochloric acid, and extracted with hexane. The hexane extract was washed (×7) with a mixture of water and saturated aqueous sodium bicarbonate (1:1 by volume) to remove unreacted cyclopentane carboxylic acid. The extract was washed with water, dried (MgSO4) and evaporated under vacuum to give a pale yellow oil (6.3 g) which was chromatographed on silica gel (600 g). Gradient elution starting with a mixture of ethyl acetate and hexane (3:7 by volume) changing to neat ethyl acetate gave the required product as a colourless oil (4.0 g, 53%). Found: C,68.39 ; H,7.99. C19H26O5 requires C,68.24; H,7.84%. On prolonged standing the material solidified and when recrystallized from hexane gave a white solid, m.p. 41°-2° C.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6](N1CCN(C2C=CC(F)=CC=2)CC1)=[O:7].C(N1C=CN=C1)(N1C=CN=C1)=O.CN(CCN)C.[CH3:40][O:41][C:42]1[CH:43]=[C:44]([N:50]2[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)[CH:45]=[CH:46][C:47]=1[O:48][CH3:49].[ClH:56]>O1CCCC1>[ClH:56].[CH3:40][O:41][C:42]1[CH:43]=[C:44]([N:50]2[CH2:51][CH2:52][N:53]([C:6]([NH:5][CH2:4][CH2:3][N:2]([CH3:21])[CH3:1])=[O:7])[CH2:54][CH2:55]2)[CH:45]=[CH:46][C:47]=1[O:48][CH3:49]
Reactant: CN(C)CCNC(=O)N1CCN(c2ccc(F)cc2)CC1
Reactant: COc1ccc(N2CCNCC2)cc1OC
Agent: CN(C)CCN
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1ccc(N2CCN(C(=O)NCCN(C)C)CC2)cc1OC

Procedure:
This compound was prepared according to the procedure used to synthesize the compound of Example 11. A mixture of 1.6 g (0.01 mole) of 1,1'-carbonyldiimidazole, 0.87 g (0.01 mole) of unsym-dimethylethylenediamine, and 2.2 g (0.01 mole) of 1-(3,4-dimethoxyphenyl)piperazine in a total volume of 50 ml of tetrahydrofuran gave an oil as residue. The hydrochloride was formed in ethereal hydrogen chloride and the collected solid was recrystallized twice from methanolethyl ether to yield 2.3 g (57%) of the title compound as an off-white solid, m.p. 208°-210° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[N:6]=[C:5]([N:16]2[CH2:21][CH2:20][CH:19]([C:22](O)=[O:23])[CH2:18][CH2:17]2)[N:4]=1.C(O)(C(F)(F)F)=O.[F:32][C:33]([F:43])([F:42])[C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36][NH2:37].Cl.C(N=C=NCCCN(C)C)C>CN(C1C=CN=CC=1)C.ClCCl>[CH3:1][NH:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[N:6]=[C:5]([N:16]2[CH2:17][CH2:18][CH:19]([C:22]([NH:37][CH2:36][C:35]3[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=3[C:33]([F:32])([F:42])[F:43])=[O:23])[CH2:20][CH2:21]2)[N:4]=1
Reactant: NCc1ccccc1C(F)(F)F
Reactant: CNc1nc(N2CCC(C(=O)O)CC2)nc(N2CCN(C)CC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1nc(N2CCC(C(=O)NCc3ccccc3C(F)(F)F)CC2)nc(N2CCN(C)CC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.5 %

Procedure:
A solution of 1-[4-(methylamino)-6-(4-methyl-1-piperazinyl)-1,3,5-triazin-2-yl]-4-piperidinecarboxylic acid as the TFA salt (44.7 mg, 0.100 mmol, 1.00 equiv), 2-trifluoromethyl benzylamine (26.6 mg, 0.150 mmol, 1.50 equiv) and DMAP (3.3 mg, 0.26 equiv) in dichloromethane (1 ml) was cooled in an ice bath. 1-Ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (EDCI, 32 mg, 0.17 mmol, 1.7 equiv) was added. The reaction mixture was stirred at room temperature for 2 h. The solution was diluted with dichloromethane (1 ml) and washed with saturated sodium bicarbonate and water. The solvent was removed, and the residue was purified by reverse-phase HPLC to give the title compound (66 mg, 82.5% yield). MS (ES+): m/e 493.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][N:3]=1.[CH:16]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([CH3:18])[CH3:17]>>[ClH:1].[ClH:1].[CH:16]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[N:3]=[CH:4][C:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)[CH2:21][CH2:20]1)([CH3:18])[CH3:17]
Reactant: N#Cc1ccc(-c2ccc(Cl)nc2)cc1
Reactant: CC(C)N1CCNCC1
Product: CC(C)N1CCN(c2ccc(-c3ccc(C#N)cc3)cn2)CC1
Product: Cl

Procedure:
The title compound was prepared by a similar procedure to that described in Example 1, starting from 2-chloro-5-(4-cyanophenyl)pyridine and 1-isopropylpiperazine.
Reaction SMILES: [Br:1][C:2]1[C:6]2[C:7]([NH2:12])=[N:8][CH:9]=[C:10](I)[C:5]=2[S:4][CH:3]=1.[CH2:13]([O:15][CH:16]([O:28][CH2:29][CH3:30])/[CH:17]=[CH:18]/B1OC(C)(C)C(C)(C)O1)[CH3:14].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[Br:1][C:2]1[C:6]2[C:7]([NH2:12])=[N:8][CH:9]=[C:10](/[CH:18]=[CH:17]/[CH:16]([O:28][CH2:29][CH3:30])[O:15][CH2:13][CH3:14])[C:5]=2[S:4][CH:3]=1
Reactant: CCOC(/C=C/B1OC(C)(C)C(C)(C)O1)OCC
Reactant: Nc1ncc(I)c2scc(Br)c12
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(/C=C/c1cnc(N)c2c(Br)csc12)OCC
Temperature: 25 °C
Yield: 75 %

Procedure:
A mixture of Example 21A (200 mg, 0.56 mmol), 2-[(1E)-3,3-diethoxy-1-propenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (175 mg, 0.67 mmol), Pd(PPh3)4 (40 mg, 0.03 mmol) and Na2CO3 (120 mg, 1.13 mmol) in 1,2-dimethoxyethane (10 mL) and water (5 mL) was heated in an 85° C. oil bath for 15 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The mixture was extracted with dichloromethane and the extract was dried (MgSO4), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel to provide the desired product (150 mg, 75%). 1H NMR (DMSO-d6, 400 MHz) δ 8.02 (s, 1H), 7.88 (s, 1H), 6.74 (d, 1H), 6.09 (dd, 1H), 5.09 (d, 1H), 3.62 (m, 2H), 3.48 (m, 2H), 1.15 (t, 6H); MS m/e 357.1, 359.1 (M+H)+.
Reaction SMILES: C[OH:2].NC1C=CN=CC=1.[CH2:10]([O:17][CH2:18][C@@H:19]1[O:21][CH2:20]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C]=O.[CH3:24][O:25][C:26](C)(C)C>>[CH3:24][O:25][C:26](=[O:2])[CH2:20][C@@H:19]([OH:21])[CH2:18][O:17][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: c1ccc(COC[C@H]2CO2)cc1
Reactant: COC(C)(C)C
Reactant: CO
Agent: Nc1ccncc1
Agent: [C]=O
Product: COC(=O)C[C@@H](O)COCc1ccccc1
Temperature: 25 °C
Yield: 95 %

Procedure:
In a 50 mL-volumetric autoclave were added deaerated methanol (10 mL) and t-butyl methyl ether (10 mL), and thereto were added 4-aminopyridine (47 mg, 0.5 mmol) and (R)-benzylglycidyl ether (3.3 g, 20 mmol, >99% ee). Then to the mixture was added crystalline dicobaltoctacarbonyl complex (171 mg, 0.5 mmol). After covering the autoclave with a cap, carbon monoxide (1 MPa) was introduced therein and the mixture was reacted at 40° C. for 6 hours. After cooling to room temperature, the solvent was removed in vacuo. The residue was subjected to Kugelrohr distillation to give (R)-4-benzyloxy-3-hydroxybutanoic acid methyl ester (4.3 g, 95%, >99% ee) as a colorless oil.
Reaction SMILES: [C:1]1([C:15](O)=[C:11]([N+:12]([O-:14])=[O:13])[CH:10]=[C:6]([N+:7]([O-:9])=[O:8])[CH:5]=1)[N+:2]([O-:4])=[O:3].P([O-])([O-])(O)=O.[NH4+:22].[NH4+].S1(CCCC1)(=O)=O>O>[CH:5]1[C:1]([N+:2]([O-:4])=[O:3])=[C:15]([NH2:22])[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:6]=1[N+:7]([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1
Reactant: [NH4+]
Agent: O=P([O-])([O-])O
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: Nc1c([N+](=O)[O-])cc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 20 h
Yield: 93 %

Procedure:
Picric acid (10.0 g, 43.8 mmol), diammonium hydrogen phosphate (11.6 g, 87.6 mmol) and dry sulfolane (40 ml) are placed in a glass-lined, stainless steel reactor to form a 1.1M concentration reaction slurry. The reactor is sealed and the reaction slurry is stirred with heating for 2 hr as the temperature increases from 25 to 175° C. (20 psi pressure). The temperature is maintained at 175° C. and stirring is continued for an additional 20 hr. The cooled reaction mixture is mixed with water (400 ml) and the insoluble material is collected, washed with water and dried to produce picramide in 93% yield (Table 2, entry 5).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([CH3:16])[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=1)=[O:5].[CH2:17]([N:19]1[C:31]2[CH:30]=[CH:29][C:28]([C:32](O)=[O:33])=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH3:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[C:14]([C:11]1[CH:10]=[CH:9][C:8]([CH2:7][NH:6][C:4](=[O:5])[CH:3]([CH3:16])[CH2:2][NH:1][C:32]([C:28]2[CH:29]=[CH:30][C:31]3[N:19]([CH2:17][CH3:18])[C:20]4[C:25]([C:26]=3[CH:27]=2)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:33])=[CH:13][CH:12]=1)#[N:15]
Reactant: CC(CN)C(=O)NCc1ccc(C#N)cc1
Reactant: CCn1c2ccccc2c2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c2ccccc2c2cc(C(=O)NCC(C)C(=O)NCc3ccc(C#N)cc3)ccc21
Yield: 69.2 %

Procedure:
A solution (2.5 mL) of the compound obtained in Step 2 (112 mg, 0.52 mmol), 9-ethyl-9H-carbazole-3-carboxylic acid (123 mg, 0.52 mmol), HATU (255 mg, 0.67 mmol) and TEA (0.216 mL, 1.55 mmol) in DMF was stirred at room temperature for 16 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent; ethyl acetate) to give the title compound (158 mg, 0.360 mmol, 69.9%) as a white powder.
Reaction SMILES: C(O[C:4](=[O:28])/[CH:5]=[CH:6]/[N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)[C:8]1=[O:27])C.[O:29]([CH3:31])[Na].CN(C=[O:36])C>>[CH3:31][O:29][CH:6]([N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)[C:8]1=[O:27])[CH2:5][C:4]([OH:28])=[O:36]
Reactant: CN(C)C=O
Reactant: CO[Na]
Reactant: CCOC(=O)/C=C/n1c(=O)n(Cc2cccc3ccccc23)c2ccccc21
Product: COC(CC(=O)O)n1c(=O)n(Cc2cccc3ccccc23)c2ccccc21
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of (E)-3-(3-Naphthalen-1-ylmethyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-acrylic acid ethyl ester (0.1 g, 0.27 mmol) in DMF (1 mL) was added NaOCH3 (1.1 mL, 0.5 M in MeOH). The reaction mixture was stirred at 60° C. for 2 h (due to poor solubility, the reaction was heated). The reaction mixture was concentrated. The reaction mixture was diluted with 1N HCl and then extracted with CH2Cl2. The organic phase was dried over Na2SO4 and concentrated. Since LCMS indicated that there was a small amount of the product in methyl ester form, the resulting residue was diluted with methanol and treated with 2N NaOH for 30 min. The mixture was acidified by adding 1N HCl and extracted with CH2Cl2. The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 95:5 CH2Cl2:MeOH as an eluent to afford 39 mg of the title compound as an off-white solid. LCMS (ESMS): m/z 377.31 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH:12]1([OH:16])[CH2:15][CH2:14][CH2:13]1.[OH-].[K+].Cl>CS(C)=O.O>[Br:1][C:2]1[C:3]([O:16][CH:12]2[CH2:15][CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Reactant: OC1CCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1cnc(OC2CCC2)c(Br)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.7 %

Procedure:
5-Bromo-6-chloronicotinic acid (CAN 29241-62-1; 3 g, 12.7 mmol) was dissolved in DMSO (30 mL); cyclobutanol (1.19 g, 1.29 ml, 16.5 mmol) and potassium hydroxide (powder) (2.14 g, 38.1 mmol) were added and the reaction mixture was stirred at room temperature for 5 h. More cyclobutanol (0.5 mL) and KOH (1 g) was added and the reaction mixture was stirred at room temperature for another 2 days. Water (30 mL) was added and the mixture was acidified (cooling) with 5 mL 37% HCl in water (pH=2). The suspension was filtered and washed with water. The cake was dried in vacuo to obtain the title compound (3.1 g, 88.7%) as white solid; MS (ESI) 270.2 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH:7]=[CH:8][CH2:9][OH:10])=[CH:5][CH:4]=1.[CH2:13](I)[CH3:14]>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH:7]=[CH:8][CH2:9][O:10][CH2:13][CH3:14])=[CH:5][CH:4]=1
Reactant: CCI
Reactant: COc1ccc(C=CCO)cc1
Product: CCOCC=Cc1ccc(OC)cc1
Yield: 80 %

Procedure:
Reaction of p-methoxycinnamyl alcohol with ethyl iodide in the same manner as described under Example III gave an 80% yield of ethyl p-methoxycinnamyl ether after molecular distillation (vacuum, 105° C): λmaxCCl4 6.1, 6.6, 6.75, 8.0, 8.55, 8.92, 9.55, 10.15, 10.8, and 12.05 μ.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].C(=O)([O-])[O-].[K+].[K+].[C:21]([N:31]1[CH2:49][CH2:48][CH2:47][C@H:32]1[C:33]([NH:35][C:36]([C:44](O)=[O:45])=[CH:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:34])([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>C(OCC)(=O)C>[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH:6][C:44](=[O:45])[C:36](=[CH:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[NH:35][C:33](=[O:34])[C@@H:32]1[CH2:47][CH2:48][CH2:49][N:31]1[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(O)C(=Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)C(=Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1

Procedure:
A mixture of 0.759 g (0.0036 mole) of L-phenylalanine methyl ester hydrochloride and 40 ml of ethyl acetate was cooled in an ice-bath and 15 ml of cold 505 potassium carbonate solution was added. The mixture was equilibrated, and the ethyl acetate layer was separated and dried over anhydrous Na2SO4 at 0°. To the solution 1.129 g (0.003 mole) of the azlactone of N-carbobenzoxy-L-prolyl-dehydrophenylalanine was added. The reaction mixture was then refluxed for 8 hours, cooled and washed with N-hydrochloric acid, saturated sodium bicarbonate solution, saturated sodium chloride solution and dried over anhydrous Na2SO4. The solvent was evaporated in vacuo and the residual crystals were recrystallized from ethyl acetate/petroleum ether giving 1.473 g (88%) of N-carbobenzoxy-L-prolyl-dehydrophenylalanyl-L-phenylalanine methyl ester, mp 161°-163.5°, RfA 0.95, [α]D26 =-94.3° (c, 1% in EtOH); ir (CHCl3) 1735 (C=) 1690-1670 (C=O), 1630 cm-1 (C=C); NMR (CDCl3) δ1.5-2.4 (m, 4H, Pro ring), 3.0-3.33 (m, 2H, --CHCH2Ph), 3.33-3.57 (m, 2H, Pro ring) 3.63 (s, 3H, --COOCH3), 4.17-4.53 (m, 1H, --CH-CH2Ph), 4.67-5.0 (m, 1H, Pro ring), 5.02 (br.s., 2H>NOCOCH2Ph) 6.83-7.47 (m, 11H, ArH and PhCH=C<), 7.9-8.1 ppm (b, 2 H, NH, exchange by D2O).
Reaction SMILES: I.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([NH:16][C:17](SC)=[NH:18])[CH:7]=[CH:8][C:9]=1[N:10]1[CH:14]=[N:13][C:12]([CH3:15])=[N:11]1.[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([C:30]1[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[C:32]([F:41])[CH:31]=1)[C:27](O)=O.[NH2:42][NH2:43]>>[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([C:27]1[NH:43][N:42]=[C:17]([NH:16][C:6]2[CH:7]=[CH:8][C:9]([N:10]3[CH:14]=[N:13][C:12]([CH3:15])=[N:11]3)=[C:4]([O:3][CH3:2])[CH:5]=2)[N:18]=1)[C:30]1[CH:35]=[CH:34][C:33]([O:36][C:37]([F:38])([F:39])[F:40])=[C:32]([F:41])[CH:31]=1
Reactant: NN
Reactant: COc1cc(NC(=N)SC)ccc1-n1cnc(C)n1
Reactant: O=C(O)C(CCCCCl)c1ccc(OC(F)(F)F)c(F)c1
Agent: I
Product: COc1cc(Nc2n[nH]c(C(CCCCCl)c3ccc(OC(F)(F)F)c(F)c3)n2)ccc1-n1cnc(C)n1

Procedure:
Methyl 3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenylcarbamimidothioate, hydroiodide (0.250 g, 0.617 mmol), from preparation F) and 6-chloro-2-(3-fluoro-4-(trifluoromethoxy)phenyl)hexanoic acid (0.304 g, 0.925 mmol, from preparation AY) were coupled and then reacted with hydrazine (0.078 mL, 2.47 mmol) using a procedure analogous to Step A of Example 13. After an aqueous workup, 5-(5-chloro-1-(3-fluoro-4-(trifluoromethoxy)phenyl)pentyl)-N-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-1H-1,2,4-triazol-3-amine was obtained as a brown residue. The crude product was used in the next step without purification. LC-MS (M+H)+ 554.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[N+:6]([O-:8])[CH:7]=1.[N+:10]([O-])([OH:12])=[O:11]>S(=O)(=O)(O)O>[Br:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[CH:4][C:5]([CH3:9])=[N+:6]([O-:8])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(Br)c[n+]1[O-]
Agent: O=S(=O)(O)O
Product: Cc1cc([N+](=O)[O-])c(Br)c[n+]1[O-]
Temperature: 90 °C
Yield: 78 %

Procedure:
A solution of 5-bromo-2-methyl-pyridine N-oxide (536 mg, 2.85 mmol) in concentrated sulfuric acid (3.0 mL) was added dropwise a solution of fuming nitric acid (2.4 mL) in concentrated sulfuric acid (3.2 mL) at 0° C. The reaction mixture was heated at 90° C. for 1.5 h. The reaction mixture was cooled to rt and poured into ice (50 g). The mixture was extracted with CH2Cl2 (3×20 mL). The combined extracts were washed with a saturated aqueous sodium chloride solution (1×20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford 5-bromo-2-methyl-4-nitro-pyridine N-oxide as a yellow solid (520 mg, 78%) which was used without further purification