Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][CH2:8]2)([O-])=O.C(OCC)(=O)C>C(O)C.[Pd]>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][CH2:8]2
Reactant: O=[N+]([O-])c1cccc2c1CCC2
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1cccc2c1CCC2
Yield: 86.7 %

Procedure:
In a 500 mL Parr shaker vessel, 4-nitroindane (10 g, 61 mmol) was dissolved in 50 mL ethanol. A slurry of 10% Pd/C (1 g) in ethanol was added. The mixture was then placed on a Parr shaker under a hydrogen atmosphere (50 psi) for 1 hour, at which point t.l.c. (20% ethyl acetate in hexanes) showed that all the starting material had disappeared. To work up the reaction, the mixture was filtered twice through Celite, washing with a large amount of ethanol, and once through filter paper. The ethanol was evaporated under reduced pressure, and the crude product purified by flash chromatography over silica gel (10% ethyl acetate in hexanes) to give 8 as a viscous, faintly colored oil (7.04 g, 86% yield): 1H NMR (400 MHz, DMSO-D6) δ 1.95 (m, 2H) 2.61 (t, J=7.3 Hz, 2H) 2.76 (t, J=7.5 Hz, 2H) 4.77 (s, 2H) 6.36 (d, J=7.8 Hz, 1H) 6.42 (d, J=6.8 Hz, 1H) 6.80 (t, J=7.6 Hz, 1H).
Reaction SMILES: Br[CH:2]([CH2:18][CH3:19])[C:3]([C:5]1[CH:14]=[CH:13][C:12]([O:15]C)=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:17])[NH:10]2)=[O:4].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1.O>[O:23]1[CH2:24][CH2:25][N:20]([CH:2]([CH2:18][CH3:19])[C:3]([C:5]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]3[C:6]=2[CH2:7][CH2:8][C:9](=[O:17])[NH:10]3)=[O:4])[CH2:21][CH2:22]1
Reactant: CCC(Br)C(=O)c1ccc(OC)c2c1CCC(=O)N2
Reactant: C1COCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCC(C(=O)c1ccc(O)c2c1CCC(=O)N2)N1CCOCC1

Procedure:
g of 5-(α-bromobutyl)-8-hydroxy-3,4-dihydrocarbostyril (IV) was suspended in 30 ml of benzene, and 4.2 ml of morpholine (III) was added to the suspension followed by allowing the mixture to react for 4 hours while heating under refluxing. The reaction mixture was filtered and the filtrate was washed with water followed by concentration under reduced pressure to remove any remaining water. The resulting residue was dissolved in 50 ml of isopropanol, and the solution was adjusted to a pH of 2-3 with concentrated hydrochloric acid. The viscous precipitate formed upon ice-cooling was separated and dissolved in acetone by heating. After allowing the solution to cool, the precipitate formed was dissolved in 30 ml of water and adjusted to a pH of 7.5-8 with sodium bicarbonate. The precipitate formed upon ice-cooling was filtered and dissolved in 10 ml of a 47% aqueous hydrobromic acid followed by concentration under reduced pressure. The residue thus obtained was washed with 10 ml of ethanol and recrystallized from ethanol to obtain 2.8 g of white amorphous 5-(α-morpholinobutyryl)-8-hydroxy-3,4-dihydrocarbostyril (IIb) hydrobromide monohydrate. The structure of the material thus obtained was confirmed by NMR and IR spectra and elemental analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])=[CH:17][N:18]([CH3:20])[CH3:19])=[CH:6][CH:7]=1
Reactant: COC(OC)N(C)C
Reactant: CC(C)(C)C(=O)Cc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: CN(C)C=C(C(=O)C(C)(C)C)c1ccc(Cl)cc1
Temperature: 103 °C
Reaction time: 5 h

Procedure:
(b′) A 3 L, 4-necked, round-bottomed flask, equipped with a mechanical stirrer, digital thermometer, reflux condenser, and nitrogen inlet-outlet, is charged with 953 g (1.05 L) of a toluene solution containing 1-(4-chlorophenyl)-3,3-dimethyl-2-butanone and 173 g (200 mL) of toluene; then add by pump 232 g (259 mL) of N,N-dimethylformamide dimethyl acetal. The solution is heated to an internal temperature at 97-109° C. (reflux) and stirred at this temperature for 5 hours. One hundred (100) mL of solvent is distilled off over a period of 0.5 hours. After distillation is stopped, the mixture is heated to an internal temperature at 107-114° C. (reflux). The mixture is stirred at this temperature for an additional 1 hour. Three more distillations follow in a similar procedure. Then the reaction mixture is cooled to an internal temperature at 20-25° C. over 1 hour, and stirred at this temperature for 1 hour, filtered over a pad of 70 g of Celite and the pad was washed with 300 mL of toluene. Filtrates are combined and concentrated under vacuum (30-80 torr) at an internal temperature at 25-40° C. (maximum jacket temperature 50° C.) to collect about 800 g or 925 mL of solvent to afford 275 g of crude 2-(4-chlorophenyl)-1-(dimethylamino)-4,4-dimethyl-1-pentene-3-one (Theoretical yield: 173.6 g). This crude product is dissolved in 440 mL (380 g) of toluene and the removal of excess N,N-dimethylformamide dimethyl acetal is confirmed by 1H NMR. The solution can be held at 21-23° C. under nitrogen and then used in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Oc1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of CH2Cl6 (60 mL) and 3,5-dichlorophenol (5.0 g 30 mmol) was added tert-butyldimethylsilyl chloride (5.54 g, 36 mmol), N,N-diisoprpylethylamine (8.0 mL, 46 mmol) and a catalytic amount of 4-dimethylaminopyridine. The initially exothermic solution was stirred at ambient temperature for 6 h then diluted with CH2Cl2 (40 mL). The mixture was washed consecutively with 10% aqueous HCl (50 mL), saturated aqueous NaHCO3 (50 mL), and brine (50 mL). the organic phase was dried over anhydrous MgSO4, filtered and concentrated in vacuo to provide 13 as a pale yellow liquied (8.8 g, 100%). 1H NMR (300 MHz, CDCl3) d 6.98 s, 1H), 6.72 (s, 2H), 0.98 (s, 9H), 0.22 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.CC(O)=O>ClCCCl>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: C1CCNCC1
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Fc1ccc(CN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.4 %

Procedure:
To a stirred solution of 4-fluorobenzaldehyde (500 mg, 4.0 mmol) in DCE (3 ml) at RT was added piperidine (309 mg, 3.6 mmol) followed by AcOH (242 mg, 4.0 mmol). The solution was stirred at RT for 2 h, and then STAB (1.3 g, 6.05 mmol) was added in one portion. The resulting mixture was stirred at RT overnight and then quenched with saturated NaHCO3 (10 ml). The organic layer was separated, dried (Na2SO4), filtered and concentrated at reduced pressure. Purification by silica flash column chromatography (eluting with DCM/MeOH/NH3 90:10:1) provided the title compound as colourless oil (650 mg, 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([NH:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[C:5]([N+:21]([O-])=O)=[CH:4][N:3]=1.Cl[Sn]Cl>CO>[NH2:21][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:10][CH2:11][C@H:12]([C:15]([NH:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]2)=[CH:7][C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(Cl)ncc2[N+](=O)[O-])CC1
Agent: Cl[Sn]Cl
Solvent: CO
Product: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(Cl)ncc2N)CC1

Procedure:
To a solution of cis-4-(2-chloro-5-nitropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide (400 mg, 1.174 mmol) in MeOH (2.3 mL) was added SnCl2 (890 mg, 4.69 mmol), and the mixture was stirred at reflux for 2 hours. The mixture was evaporated and partitioned between 10% IPA/DCM and saturated NaHCO3. The solids were removed by filtration through Celite® brand filter aid, and the organic layer was washed with water, saturated NaHCO3, dried over Na2SO4 and filtered. The mixture was purified via flash chromatography using a linear gradient of 0% to 10% of 1% NH4OH in MeOH in DCM. The title compound was collected as a white solid (160 mg, 44% yield).
Reaction SMILES: C(OCC)(=O)C.[ClH:7].[CH2:8]([O:10][C:11]([C@@H:13]([NH:32][C@@H:33]1[C:39](=[O:40])[N:38]([CH2:41][C:42]([O:44]C(C)(C)C)=[O:43])[C:37]2[CH:49]=[CH:50][CH:51]=[CH:52][C:36]=2[O:35][CH2:34]1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31])=[O:12])[CH3:9]>>[ClH:7].[CH2:8]([O:10][C:11]([C@@H:13]([NH:32][C@@H:33]1[C:39](=[O:40])[N:38]([CH2:41][C:42]([OH:44])=[O:43])[C:37]2[CH:49]=[CH:50][CH:51]=[CH:52][C:36]=2[O:35][CH2:34]1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31])=[O:12])[CH3:9]
Reactant: CCOC(=O)[C@H](CCCCCCCN1C(=O)c2ccccc2C1=O)N[C@H]1COc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](CCCCCCCN1C(=O)c2ccccc2C1=O)N[C@H]1COc2ccccc2N(CC(=O)O)C1=O
Reaction time: 3 h

Procedure:
A mixture of 5N hydrogen chloride-ethyl acetate solution (5 ml) and tert-butyl 3(S)-[1(S)-ethoxycarbonyl-8-phthalimidooctyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.1 g) is allowed to stand at room temperature for 3 hours. The mixture is diluted with petroleum ether (80 ml) to precipitate colorless powder, which is collected and dried in vacuo to give 3(S)-[1(S)-ethoxycarbonyl-8-phthalimidooctyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid.hydrochloride (0.067 g).
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1)([CH3:7])[C:3]([O:5][CH3:6])=[O:4].NN>C(O)C.[Pd]>[CH3:6][O:5][C:3](=[O:4])[C:2]([C:8]1[CH:9]=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=1)([CH3:7])[CH3:1]
Reactant: COC(=O)C(C)(C)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: COC(=O)C(C)(C)c1ccc(N)cc1
Temperature: 55 °C
Reaction time: 3 h
Yield: 98.7 %

Procedure:
To a solution of 4.68 g of methyl 2-methyl-2-(4-nitrophenyl)-propanoate in 200 mL of ethanol, under argon, is added 0.5 g of palladium-on-charcoal (10%). The suspension is heated at 55° C. and 28 mL of hydrazine are added dropwise at this same temperature, and heating is continued for 3 hours at 55° C. After cooling, the reaction medium is filtered through Celite and the filtrate is concentrated under reduced pressure to give 4 g of 2-(4-aminophenyl)-2-methylpropionic acid methyl ester in the form of a colourless oil, the characteristics of which are as follows:
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27]([OH:29])[CH3:28]>>[CH2:27]([O:29][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1)[CH3:28]
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.27 g of potassium carbonate and 3 ml of ethanol was stirred while heating at 60° C. for two hours and then at 90° C. for 2.5 hours. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. Water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.18 g of 2-(3-ethoxypyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 69”).
Reaction SMILES: [CH2:1]([S:8][CH2:9][C@H:10]([C:12]1[C:13]([CH3:24])=[N:14][O:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][C:36]([C:39]3([C:42]([NH:44][S:45]([CH3:48])(=[O:47])=[O:46])=[O:43])[CH2:41][CH2:40]3)=[CH:35][CH:34]=2)O1>>[CH2:1]([S:8][CH2:9][C@H:10]([C:12]1[C:13]([CH3:24])=[N:14][O:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([C:33]2[CH:34]=[CH:35][C:36]([C:39]3([C:42]([NH:44][S:45]([CH3:48])(=[O:47])=[O:46])=[O:43])[CH2:41][CH2:40]3)=[CH:37][CH:38]=2)=[CH:19][CH:18]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2ccc(C3(C(=O)NS(C)(=O)=O)CC3)cc2)OC1(C)C
Reactant: Cc1noc(-c2ccc(Br)cc2)c1[C@H](O)CSCc1ccccc1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)NS(C)(=O)=O)CC4)cc3)cc2)c1[C@H](O)CSCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using (S)-2-benzylsulfanyl-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-ethanol and N-{1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarbonyl}-methanesulfonamide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:24])=[C:4]([CH3:25])[CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[C:36]3[C:40](=[CH:41][CH:42]=2)[NH:39][CH:38]=[CH:37]3)O1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH:21]1([C:19]([N:16]2[CH2:17][CH2:18][C@@H:14]([CH2:13][C:12]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([C:34]5[CH:35]=[C:36]6[C:40](=[CH:41][CH:42]=5)[NH:39][CH:38]=[CH:37]6)=[CH:3][C:4]=4[CH3:25])[C:9](=[O:24])[NH:10][N:11]=3)[CH2:15]2)=[O:20])[CH2:23][CH2:22]1
Reactant: CC1(C)OB(c2ccc3[nH]ccc3c2)OC1(C)C
Reactant: Cc1cc(Br)ccc1-n1c(C[C@@H]2CCN(C(=O)C3CC3)C2)n[nH]c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(-c2ccc3[nH]ccc3c2)ccc1-n1c(C[C@@H]2CCN(C(=O)C3CC3)C2)n[nH]c1=O
Temperature: 150 °C
Yield: 53 %

Procedure:
A microwaveable vial was charged with 4-(4-bromo-2-methylphenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (100 mg, 0.247 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (60.0 mg, 0.247 mmol), PdCl2(dppf) (9.03 mg, 0.012 mmol), K2CO3 (85 mg, 0.617 mmol), 1,4-dioxane (3 mL) and water (1 mL). The reaction was purged with nitrogen, sealed and heated in a microwave reactor at 150° C. for 30 min (LCMS indicated complete conversion of starting material to desired product). The reaction mixture was concentrated under reduced pressure and the residue was dissolved in DMSO, filtered through a syringe filter and purified by reverse phase HPLC (Gilson, YMC-Pack ODS-A C18 5 μm 75×30 mm column, 10-90% MeCN/water+0.1% TFA, 3×1 mL injections). The appropriate fractions were concentrated to remove a majority of the MeCN, leaving an aqueous suspension of product. The precipitate was collected by filtration, rinsed with minimal water and dried to constant weight under vacuum to provide the title product (58 mg, 0.131 mmol, 53.2% yield) as a white solid. MS(ES)+ m/e 442.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.73 (d, J=4.04 Hz, 1H), 11.21 (br. s., 1H), 7.90 (s, 1H), 7.74 (br. s., 1H), 7.57-7.67 (m, 1H), 7.43-7.54 (m, 2H), 7.32-7.43 (m, 2H), 6.51 (d, J=2.27 Hz, 1H), 3.60-3.89 (m, 1H), 3.47-3.59 (m, 1H), 3.39-2.86 (m, 2H), 2.28-2.49 (m, 3H), 2.13-2.21 (m, 3H), 1.96 (d, J=9.35 Hz, 1H), 1.41-1.75 (m, 2H), 0.60-0.76 (m, 4H).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:7][OH:8])([CH2:5][OH:6])[NH2:4].[C:9]1(=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.O>C1(C)C=CC=CC=1>[CH2:2]([C:3]1([CH2:7][OH:8])[NH:4][C:9]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[O:6][CH2:5]1)[OH:1]
Reactant: NC(CO)(CO)CO
Reactant: O=C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: OCC1(CO)COC2(CCCCC2)N1

Procedure:
Tris-(hydroxymethyl)-aminomethane (24.23 grams; 0.2 mole) and cyclohexanone (19.63 grams; 0.2 mole) were refluxed overnight in 150 mls of toluene, using a water separator to remove approximately 3.6 mls of water. The toluene was then removed by distillation and the residue was recrystallized from acetone to obtain 32 grams (79.5% of theoretical; m.p. 117°-119° C.) of the desired compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:28]=[CH:27][C:26]([O:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:15])([F:16])[F:14])[CH:6]=2)=[CH:25][CH:24]=1
Reactant: Oc1ccc(F)cc1
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Product: N#Cc1ccc(N(CCOc2ccc(F)cc2)CC(F)(F)F)cc1C(F)(F)F

Procedure:
Synthesized as described in Example 1C using 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and 4-fluorophenol: MS (El) m/z 406 (M+, 54%), 295 ([M-C6H4FO]+, 82%), 281 (100%).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C@@H:11]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N:29]([CH3:40])[C:30]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[O:31])[CH:24]=2)=[CH:19][CH:18]=1)[C:12]([O:14]C)=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O1CCCC1.CO.O>C(O)(=O)C>[CH2:3]([O:10][C@@H:11]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N:29]([CH3:40])[C:30]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[O:31])[CH:24]=2)=[CH:19][CH:18]=1)[C:12]([OH:14])=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(C[C@H](OCc3ccccc3)C(=O)OC)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(C[C@H](OCc3ccccc3)C(=O)O)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.2 %

Procedure:
16 mg (0.4 mmol) of sodium hydroxide are added to a solution of 70 mg (0.42 mmol) of methyl (S)-2-benzyloxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoate in 2 ml of 9/1 tetrahydrofuran/methanol. The reaction mixture is stirred overnight at ambient temperature. The reaction is halted by the addition of 2 ml of water and 0.5 ml of acetic acid, and then extraction is carried out with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated and then the residue is chromatographed on silica gel (dichloromethane/methanol 90/10). 49 mg of 2(S)-benzyloxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic acid are obtained in the form of an oil. Yield=72%.
Reaction SMILES: Cl.[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([F:33])[CH:24]=2)[CH2:19][CH2:18][NH:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:34][N:35]=[C:36]=[O:37]>>[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:26]=[C:25]([F:33])[CH:24]=2)[CH2:19][CH2:18][N:17]([C:36]([NH:35][CH3:34])=[O:37])[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Fc1cc(CO[C@H]2CCNC[C@H]2C(c2ccccc2)c2ccccc2)cc(C(F)(F)F)c1
Reactant: CN=C=O
Agent: Cl
Product: CNC(=O)N1CC[C@H](OCc2cc(F)cc(C(F)(F)F)c2)[C@H](C(c2ccccc2)c2ccccc2)C1

Procedure:
The compound obtained in Example 26 (28.8 mg) and methyl isocyanate (6.8 mg) were reacted and treated in the same manner as in the method described in Example 31 to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:24][C:25](O)([C:27]#[CH:28])[CH3:26].O>O1CCCC1>[Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([O:9][C:25]([CH3:26])([CH3:24])[C:27]#[CH:28])=[O:8]
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Reactant: C#CC(C)(C)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: C#CC(C)(C)OC(=O)c1cnc(Cl)c(Cl)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 19.4 %

Procedure:
5,6-Dichloronicotinic acid (1.92 g, 10.0 mmol) was slurried in 10 mL tetrahydrofuran to which carbonyldiimidazole (CDI) (1.78 g, 11.0 mmol) was added. The mixture was stirred at 40° C. for one hour to a uniform solution. 2-Methyl-3-butyn-2-ol (1.01 g, 12.0 mmol) was added via pipette and the solution refluxed overnight. The solution was poured into 4-5 volumes of water and extracted with Et2O (2×100 mL). The organics were washed with 2.0 N NaOH, dried over MgSO4, and concentrated to 1.2 g pale yellow oil. Crude product was chromatographed on medium column using silica gel (23-400 mesh) with descending solvent gradient from 100% petroleum ether to 50/50 pet. ether/ethyl acetate as the mobile phase. Elution and concentration gave (dimethyl)propargyl 5,6-dichloronicotinate (0.50 g) as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH2:5])[CH3:4].[C:6](O)(=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>>[CH3:4][CH:3]1[CH2:2][NH:1][C:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[N:5]1
Reactant: CC(N)CN
Reactant: CCCCCCCCC(=O)O
Product: CCCCCCCCC1=NC(C)CN1
Temperature: 170 °C

Procedure:
1,2-Diaminopropane 61.5 g (0.7 mole) was delivered to a reaction vessel and pelargonic acid 112 g (0.7 mole) was added slowly. The mixture was slowly heated to 170° C. while removing water of reaction. There was obtained 4-methyl-2-octyl-2-imidazoline. To it was added 42 g of paraformaldehyde with stirring. The mixture was heated to about 100° C. for 3 hours to produce N1 -hydroxymethyl-4-methyl-2-octyl-2-imidazoline.
Reaction SMILES: C(O)(=O)C(O)=O.[F:7][C:8]([F:21])([F:20])[C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=1)[O:12][CH:13]1[CH2:16][NH:15][CH2:14]1.C(N(CC)CC)C.[C:29]1([N:35]=[C:36]=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1.O>[C:29]1([NH:35][C:36]([N:15]2[CH2:16][CH:13]([O:12][C:11]3[CH:17]=[CH:18][CH:19]=[C:9]([C:8]([F:7])([F:20])[F:21])[CH:10]=3)[CH2:14]2)=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: FC(F)(F)c1cccc(OC2CNC2)c1
Reactant: O=C=Nc1ccccc1
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccccc1)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Reaction time: 16 h
Yield: 78.8 %

Procedure:
A stirred slurry of 6.2 g (0.02 mole) of 3-[3-(trifluoromethyl)phenoxy]azetidine oxalate in 60 ml of tetrahydrofuran was treated with 5 ml of triethylamine followed by 2.62 g (0.022 mole) of phenyl isocyanate and stirring continued for 16 hr. The reaction mixture was diluted with water until an oil separated which quickly solidified. The aqueous tetrahydrofuran was decanted and the solid residue recrystallized from ethanol-water to yield 5.3 g (80.1%) of white crystals, m.p. 137°-138° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[C:5](=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=1)[NH:6][C:7](=[O:17])[CH2:8][S:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.I([O-])(=O)(=O)=[O:25].[Na+].CC(C)=O>O>[CH3:1][O:2][C:3](=[O:23])[C:4]1[C:5](=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=1)[NH:6][C:7](=[O:17])[CH2:8][S:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:25]
Reactant: COC(=O)c1ccc(Cl)cc1NC(=O)CSCc1ccccc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1ccc(Cl)cc1NC(=O)CS(=O)Cc1ccccc1

Procedure:
2 g (5.7 mmol) of N-(benzylthio)acetyl-4-chloro-anthranilic acid methyl ester and 3.66 g (17.1 mmol) of sodium metaperiodate are dissolved in 12 ml of water and 48 ml of acetone and the resulting solution is stirred at reflux for 6 hours. The reaction mixture is allowed to cool, filtered and concentrated by evaporation. Chromatography of the crude product on silica gel with hexane/ethyl acetate yields N-(benzylsulfinyl)acetyl-4-chloro-anthranilic acid methyl ester in the form of a yellow oil interspersed with crystals.