Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:40]>ClCCl.C(O)C>[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:40])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Reactant: CCCCCCOC(=O)Cl
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OC)c4ccccc4)ccc3n2C)cc1
Yield: 54 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide-hydrochloride and n-hexyl chloroformate. Yield: 54% of theory, C34H40N6O5 (612.7) Rf value: 0.45 (silica gel; dichloromethane/ethanol=19:1) EKA mass spectrum: (M+H)+ =613
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[O:19][C:20]([CH2:30][CH3:31])=[C:21]([C:23]([O:25]CCCC)=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:32][CH2:33][CH3:34])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].CO>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[O:19][C:20]([CH2:30][CH3:31])=[C:21]([C:23]([OH:25])=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:32][CH2:33][CH3:34])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCCCOC(=O)c1nc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)oc1CC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCO[C@@H]1CN(c2nc(C(=O)O)c(CC)o2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 75.8 %

Procedure:
The same operation as in Example (91d) was performed using butyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl)-5-ethyl-1,3-oxazole-4-carboxylate obtained in Example (115c) (0.24 g, 0.48 mmol), 2 N lithium hydroxide (3 mL, 6 mmol), methanol (4 mL) and THF (6 mL), to obtain 160 mg of the title compound as a colorless solid (75%).
Reaction SMILES: CC(C)([O-])C.[K+].C1OCCOCCOCCOCCOCCOC1.[CH2:25]([N:27]([CH3:39])[CH:28]=[N:29][C:30]1[CH:35]=[C:34]([CH3:36])[C:33]([OH:37])=[CH:32][C:31]=1[CH3:38])[CH3:26].[CH3:40][O:41][N:42]=[C:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH:44]1Cl>CS(C)=O.O>[CH2:25]([N:27]([CH3:39])[CH:28]=[N:29][C:30]1[CH:35]=[C:34]([CH3:36])[C:33]([O:37][CH:44]2[CH2:45][CH2:46][CH2:47][CH2:48][C:43]2=[N:42][O:41][CH3:40])=[CH:32][C:31]=1[CH3:38])[CH3:26]
Reactant: CON=C1CCCCC1Cl
Reactant: CCN(C)C=Nc1cc(C)c(O)cc1C
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCN(C)C=Nc1cc(C)c(OC2CCCCC2=NOC)cc1C
Reaction time: 0.25 h
Yield: 31.1 %

Procedure:
At from 0 to 5° C., 239 mg (2.13 mmol) of potassium tert-butoxide and 26 mg 18-crown-6 (0.10 mmol) were added a little at a time and with stirring to 200 mg (0.97 mmol) of N-ethyl-N′-(4-hydroxy-2,5-dimethylphenyl)-N-methylformamidine (cf. WO 2007/031513) in 3 ml of DMSO, and stirring was continued for about 15 minutes. At from 0 to 5° C., a solution of 313 mg (1.94 mmol) of 2-chlorocyclohexanone O-methyl oxime in 0.5 ml of DMSO was added to this mixture with stirring, and stirring was continued for about 20 hours at from 20 to 25° C. With cooling and a little at a time, 50 ml of water were added, and the mixture was extracted with MTBE. The combined organic phases were dried and then freed from the solvent. Cheomatography on alumina using cyclohexane/MTBE mixtures gave 100 mg of the title compound.
Reaction SMILES: [C:1]([S:5]([N:7]=[C:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH2:9]1)=[O:6])([CH3:4])([CH3:3])[CH3:2].[CH3:22][Al](C)C.[Li]C.COCOC>C1(C)C=CC=CC=1>[CH3:2][C:1]([CH3:4])([S:5]([NH:7][C:8]1([CH3:22])[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH2:9]1)=[O:6])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCC(=NS(=O)C(C)(C)C)CC1
Reactant: C[Al](C)C
Agent: [Li]C
Solvent: Cc1ccccc1
Solvent: COCOC
Product: CC1(NS(=O)C(C)(C)C)CCC(NC(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 33 %

Procedure:
To a stirred solution of tert-butyl 4-(tert-butylsulfinylimino)cyclohexylcarbamate (0.6 g, 1.9 mmol) in 40 mL of toluene at −78° C. was added, under a nitrogen atmosphere, a solution of Me3Al 2M in toluene (2 mL, 4 mmol). The mixture was stirred for 20 minutes at −78° C., then a solution of MeLi, 3M in dimethoxymethane (2.8 mL, 8.4 mmol), was added slowly and the reaction mixture was stirred at −78° C. for 4 hours. The reaction was quenched by adding 2 mL of water and the solvents evaporated under reduced pressure. The residue was passed through a pad of silica gel (200-300 mesh, eluting with a mixture of petroleum ether and ethyl acetate (4:1, v/v) to give tert-butyl 4-(1,1-dimethylethylsulfinamido)-4-methylcyclohexylcarbamate (0.21 g, 33%) as crude yellow oil which was used for the next step without further purification. MS: (M+H)+=333.2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][CH2:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2].[N+:27](C1C=CC(C2CCC3C(=CC=C(O)C=3)O2)=CC=1)([O-:29])=[O:28]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][CH:16]([C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)[CH2:15][CH2:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(C2CCc3cc(O)ccc3O2)cc1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Product: O=[N+]([O-])c1ccc(C2CCc3cc(Oc4ccc([N+](=O)[O-])cn4)ccc3O2)cc1

Procedure:
5-Nitro-2-[2-(4-nitrophenyl)chroman-6-yloxy]pyridine was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 2-(4-nitrophenyl)chroman-6-ol. 1H NMR (300 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 2.9 Hz), 8.60 (dd, 1H, J 9.1, 2.9 Hz), 8.29 (d, 2H, J 6.9 Hz), 7.76 (d, 2H, J 6.9 Hz), 7.21 (d, 1H, J 9.1 Hz), 6.98-7.02 (m, 3H), 5.35 (dd, 1H, J 9.9, 2.2 Hz), 2.96-3.05 (m, 1H), 2.73-2.78 (m, 1H), 2.24-2.29 (m, 1H), 1.96-2.04 (m, 1H).
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].C([O-])(=O)C.[Na+].[C:10]([C:13]1[C:14]([CH2:20][S:21][C:22]2[CH2:26][C:25]([CH3:28])([CH3:27])[O:24][N:23]=2)=[C:15]([CH3:19])[S:16][C:17]=1[CH3:18])(=O)[CH3:11].O>C(O)C>[CH3:27][C:25]1([CH3:28])[O:24][N:23]=[C:22]([S:21][CH2:20][C:14]2[C:13]([C:10](=[N:4][O:3][CH3:2])[CH3:11])=[C:17]([CH3:18])[S:16][C:15]=2[CH3:19])[CH2:26]1
Reactant: CC(=O)c1c(C)sc(C)c1CSC1=NOC(C)(C)C1
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CON=C(C)c1c(C)sc(C)c1CSC1=NOC(C)(C)C1
Reaction time: 5 h
Yield: 36 %

Procedure:
0.57 g (6.8 mmoles) of O-methylhydroxylamine hydrochloride and 0.56 g (6.8 mmoles) of sodium acetate were added to a solution of 1.0 g (3.4 mmoles) of 3-(4-acetyl-2,5-dimethylthiophen-3-ylmethylthio)-5,5-dimethyl-2-isoxazoline dissolved in 50 ml of ethanol. The mixture was stirred for 5 hours under refluxing, to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 0.4 g (36.4%) of 5,5-dimethyl-3-[2,5-dimethyl-4-(1-methoxyiminoethyl)-thiophen-3-ylmethylthio]-2-isoxazoline as a yellow oily substance.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH2:29][C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1)[C:25]([O:27][CH3:28])=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:28][O:27][C:25](=[O:26])[C@@H:24]([NH:23][C:21]([O:20][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:22])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])=[CH:32][CH:31]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
Trifluoromethanesulfonic anhydride (0.85 mL, 5.1 mmol) was added to a solution of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxyphenyl)propanoate (1 g, 3 mmol) (Aldrich, Cat 469106) and triethylamine (1 mL, 10 mmol) in methylene chloride (30 mL) at −78° C. The reaction was stirred for 1 h. at −78° C. Saturated NaHCO3 was added and the reaction was extracted with dichloromethane. The organic phase was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by Flash chromatography on a silica gel column (EtOAc:Hexane, 1:3 to 1:1) to obtain (S)-2-tert-butoxycarbonylamino-3-(4-trifluoromethanesulfonyloxy-phenyl)-propionic acid methyl ester (1.2 g, 80%) as light yellow oil. Analytical LCMS (M+H-Boc)+: m/z=327.9.
Reaction SMILES: [C:1](OC(OC(C)(C)C)=O)(OC(C)(C)C)=[O:2].[NH2:16][C:17]1[C:18]([CH3:29])=[C:19]([CH:25]=[CH:26][C:27]=1[CH3:28])[C:20]([N:22]([CH3:24])[CH3:23])=[O:21].C(N(CC)C1C=CN=CC=1)C>C(Cl)Cl>[CH3:23][N:22]([CH3:24])[C:20]([C:19]1[C:18]([CH3:29])=[C:17]([N:16]=[C:1]=[O:2])[C:27]([CH3:28])=[CH:26][CH:25]=1)=[O:21]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Cc1ccc(C(=O)N(C)C)c(C)c1N
Agent: CCN(CC)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(C(=O)N(C)C)c(C)c1N=C=O

Procedure:
A solution of di-tert-butyl dicarbonate (0.081 g) in methylene chloride (1.6 ml) and a solution of 3-amino-N,N,2,4-tetramethylbenzamide (J. Chem. Soc., Perkin Trans, I. 1973, 1-4; 0.072 g) in methylene chloride (1.0 ml) were added in turn to a solution of 4-diethylaminopyridine (0.004 g) in methylene chloride (0.4 ml). The resultant mixture was stirred at ambient temperature for 20 minutes. There was thus obtained a solution of 3-(N,N-dimethylcarbamoyl)-2,6-dimethylphenylisocyanate which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([N:14]=[C:15]=[O:16])(=[O:13])=[O:12])=[O:4].[NH2:17][C:18]1[N:22]=[C:21]([O:23][CH3:24])[N:20]([CH3:25])[N:19]=1.C1N2CCN(CC2)C1>C(Cl)Cl>[CH3:24][O:23][C:21]1[N:20]([CH3:25])[N:19]=[C:18]([NH:17][C:15]([NH:14][S:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:3]([O:2][CH3:1])=[O:4])(=[O:12])=[O:13])=[O:16])[N:22]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: COc1nc(N)nn1C
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(OC)n(C)n1
Reaction time: 72 h
Yield: 72.9 %

Procedure:
To a solution of 2-(methoxycarbonyl)benzenesulfonylisocyanate (80%, 1.41 g, 4.7 mmol) in methylene chloride (10 ml) at room temperature under nitrogen was added 3-amino-5-methoxy-1-methyl-1H-1,2,4-triazole (0.50 g, 3.9 mmol). DABCO (catalytic amount) was added, and the reaction mixture was stirred for 3 days. Isolation of the product by filtration and washing with methylene chloride gave 1.05 g of a white powder, m.p. 177°-180°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([C:17]3[C:18]([CH2:32][CH3:33])=[C:19]([CH2:23][N:24]4[CH2:27][CH:26]([C:28]([O:30]C)=[O:29])[CH2:25]4)[CH:20]=[CH:21][CH:22]=3)=[N:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>C(O)(C)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([C:17]3[C:18]([CH2:32][CH3:33])=[C:19]([CH:20]=[CH:21][CH:22]=3)[CH2:23][N:24]3[CH2:25][CH:26]([C:28]([OH:30])=[O:29])[CH2:27]3)=[N:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCc1c(CN2CC(C(=O)OC)C2)cccc1-c1nnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCc1c(CN2CC(C(=O)O)C2)cccc1-c1nnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Temperature: 25 °C
Reaction time: 0.85 h

Procedure:
To a solution of methyl 1-{[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-yl)-2-ethylphenyl]methyl}-3-azetidinecarboxylate (2.78 g, 5.32 mmol) in Isopropanol (20.00 mL) and Water (10 mL) was added sodium hydroxide (0.638 g, 15.96 mmol). The mixture was stirred at rt for 51 mins. Stirring was stopped and the solution was concentrated under the reduced pressure. The residue was adjusted to pH value around 6 with HCl (1.0 M) solution, 1-(3-(5-(3-chloro-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2-ethylbenzyl)azetidine-3-carboxylic acid (2.33 g) was collected by filtering and dried in vacuum as yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]2[CH:20]=[C:19](Cl)[CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:29](B(O)O)[CH3:30].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[F-].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]2[CH:20]=[C:19]([CH2:29][CH3:30])[CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCB(O)O
Reactant: COC(=O)c1ccc(Cl)cc1Nc1cc(C(C)(C)C)nn1-c1ccccc1C
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCc1ccc(C(=O)OC)c(Nc2cc(C(C)(C)C)nn2-c2ccccc2C)c1
Temperature: 110 °C
Yield: 78.2 %

Procedure:
To a mixture of methyl 2-{[3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}-4-chlorobenzoate (Example 242, 50 mg, 0.13 mmol), ethylboronic acid (18.56 mg, 0.26 mmol), Pd2(dba)3 (5.8 mg, 0.006 mmol), tris(tert-butyl)phosphine (2.54 mg, 0.013 mmol), and potassium fluoride (14.6 mg, 0.25 mmol) was added dioxane (1 mL). The resulting solution was degassed under argon for 30 min and then heated to 110° C. for 16 h. The reaction mixture was then cooled to rt. The residue was diluted with ethyl acetate and filtered through a silica gel plug. The solvent was removed under reduced pressure, and the crude product was purified by HPLC purification using gradient elution from 30 to 100% acetonitrile in water to afford 39.8 mg (81%) of the title compound. 1H NMR (300 MHz, CD2Cl2) δ 9.23 (s, 1H), 7.74 (d, 1H), 7.23-7.29 (m, 4H), 7.03 (s, 1H), 6.57 (d, 1H), 6.09 (s, 1H), 3.69 (s, 3H), 2.55 (q, 2H), 2.06 (s, 3H), 1.30 (s, 9H), 1.15 (t, 3H). ES-MS m/z 392.2 (MH+); HPLC RT (min) 4.65.
Reaction SMILES: C(S[C:9]1[NH:10][CH:11]=[C:12]([C:14]2[CH:19]=[C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:17]([OH:24])=[C:16]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:15]=2)[N:13]=1)C1C=CC=CC=1.ClC1C=CC=C(C(OO)=O)C=1>C(Cl)(Cl)Cl>[C:25]([C:16]1[CH:15]=[C:14]([C:12]2[N:13]=[CH:9][NH:10][CH:11]=2)[CH:19]=[C:18]([C:20]([CH3:21])([CH3:22])[CH3:23])[C:17]=1[OH:24])([CH3:26])([CH3:27])[CH3:28]
Reactant: CC(C)(C)c1cc(-c2c[nH]c(SCc3ccccc3)n2)cc(C(C)(C)C)c1O
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1cc(-c2c[nH]cn2)cc(C(C)(C)C)c1O

Procedure:
In 10 ml of chloroform was dissolved 0.8 g of 2-benzylthio-4-(3,5-di-tert-butyl-4-hydroxyphenyl)imidazole and then 0.35 g of m-chloroperbenzoic acid was added to the solution at room temperature. After the reaction was over, the reaction mixture was washed with a diluted aqueous alkali solution, dried, and concentrated under reduced pressure. The residue formed was subjected to silica gel chromatography and eluted with chloroform. The fraction thus obtained was concentrated udner reduced pressure and the residue was recrystallized from cyclohexane to provide 0.3 g of 2-benzylsulfinyl)-4-(3,5-di-tert-butyl-4-hydroxyphenyl)imidazole.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)=[N:8][CH:9]=1)([O-])=O>C(O)(=O)C.CCOC(C)=O.[Zn]>[N:10]1([C:7]2[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH:14]=[N:13][N:12]=[N:11]1
Reactant: O=[N+]([O-])c1ccc(-n2cnnn2)nc1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1ccc(-n2cnnn2)nc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
5-Nitro-2-(1H-tetrazol-1-yl)pyridine (1020 mg, 5.31 mmol) was suspended in acetic acid (10 ml). Zinc (3472 mg, 53.1 mmol) was added slowly (exothermic reaction). The mixture was stirred at 50° C. for 1 hour, cooled, diluted with EtOAc. The mixture was filtered, rinsed with ethyl acetate. The filtrate was concentrated to dryness to give crude 6-(1H-tetrazol-1-yl)pyridin-3-amine: LC/MS: [(M+1-28)]+=135.1.9.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][CH2:13][C:14]([N:16]3[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17]3)=O)=[CH:9][C:4]=2[CH:3]=[CH:2]1.Cl.O.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:16]3[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17]3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: O=C(COCCc1ccc2occc2c1)N1CCC(O)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: OC1CCN(CCOCCc2ccc3occc3c2)C1
Temperature: 25 °C
Reaction time: 17 h
Yield: 72.6 %

Procedure:
In 14.0 mL of tetrahydrofuran was dissolved 1.39 g of 2-[2-(1-benzofuran-5-yl)ethoxy]-1-(3-hydroxy-1-pyrrolidinyl)-1-ethanone, and 14.4 mL of a 1 mol/L solution of a borane-tetrahydrofuran complex in tetrahydrofuran was added dropwise thereto under ice-cooling, after which the resulting mixture was stirred at room temperature for 17 hours. To the reaction mixture was added 8.0 mL of 6 mol/L hydrochloric acid, and the resulting mixture was heated under reflux for 1 hour. After the reaction mixture was cooled, water and ethyl acetate were added thereto and the pH was adjusted to 10 with a 2 mol/L aqueous sodium hydroxide solution, and then the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; chloroform:methanol=30:1 to 10:1) to obtain 0.96 g of 1-{2-[2-(1-benzofuran-5-yl)ethoxy]ethyl}-3-pyrrolidinol as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[F:26][C:27]1([C:31]([O:33][CH3:34])=[O:32])[CH2:30][NH:29][CH2:28]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:34][O:33][C:31]([C:27]1([F:26])[CH2:30][N:29]([C:20](=[O:21])/[CH:19]=[CH:18]\[N:15]2[CH:16]=[N:17][C:13]([C:5]3[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:23])([F:24])[F:1])[CH:4]=3)=[N:14]2)[CH2:28]1)=[O:32]
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: COC(=O)C1(F)CNC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1(F)CN(C(=O)/C=C\n2cnc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C1
Temperature: -60 °C
Reaction time: 0.75 h
Yield: 24 %

Procedure:
(Z)-3-(3-(3,5-Bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.20 g, 1.0 eq.) was dissolved in DCM (4 mL). The reaction mixture was cooled to −60° C., at which temperature methyl 3-fluoroazetidine-3-carboxylate hydrochloride (0.09 g, 1.2 eq.) and T3P (50% in EtOAc) (0.427 g, 1.2 eq.) were added, followed by DIPEA (0.146 g, 2 eq.). The clear reaction mixture was stirred at −60° C. for 45 min and concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product, which was purified by chromatography (20-30% ethyl acetate in hexane) to give (Z)-methyl-1-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)-3-fluoroazetidine-3-carboxylate. (40 mg; 24% yield). 1H NMR (400 MHz, CDCL3) δ 9.51 (S, 1H), 8.62 (s, 2H), 7.96 (s, 1H), 7.20-7.18 (d, J=10.8, 1H), 5.70-5.68 (d, J=10.8 Hz, 1H), 4.15-3.82 (m, 4H), 3.82 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)=[O:7].[CH2:23]([NH2:29])[C:24]1[O:28][CH:27]=[CH:26][CH:25]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C)C1C=CN=CC=1.CN(C=O)C>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH:29][CH2:23][C:24]1[O:28][CH:27]=[CH:26][CH:25]=1)=[O:14])=[O:7]
Reactant: NCc1ccco1
Reactant: O=C(COc1ccc(Cl)cc1Cl)Nc1cccc(C(=O)O)c1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Product: O=C(COc1ccc(Cl)cc1Cl)Nc1cccc(C(=O)NCc2ccco2)c1
Yield: 115 %

Procedure:
To solution of 3-[2-(2,4-dichloro-phenoxy)-acetylamino]-benzoic acid (100.3 mg, 0.3 mmol), furfuryl amine (58.3 mg, 0.06 ml, 0.6 mmol), 4-dimethylaminopyridine (73.4 mg, 0.6 mmol) and PyBOP (312.3 mg, 1.0-mmol) in DMF 5.0 mL was stirred. Reaction mixture was separated by EtoAC and brine. The organic phase was dried (MgSO4 anh) and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2:MeOH=10:1) to give 3-[2-(2,4-dichloro-phenoxy)-acetylamino]-N-furan-2-ylmethyl-benzamide as a white solid (144.6 mg, 90% yield).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[N:2]=1.S(Cl)(Cl)=O.Cl.[NH2:19][CH2:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[C:23](=[O:39])[N:24]([CH:31]1[CH2:36][CH2:35][C:34](=[O:37])[NH:33][C:32]1=[O:38])[C:25]2=[O:30].C(N(CC)CC)C>C1COCC1>[O:38]=[C:32]1[CH:31]([N:24]2[C:23](=[O:39])[C:22]3[C:26](=[CH:27][CH:28]=[CH:29][C:21]=3[CH2:20][NH:19][C:11]([C:3]3[N:2]=[CH:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[O:13])[C:25]2=[O:30])[CH2:36][CH2:35][C:34](=[O:37])[NH:33]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(O)c1cc2ccccc2cn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4cc5ccccc5cn4)c3C2=O)C(=O)N1
Yield: 76 %

Procedure:
A mixture of isoquinoline 3-carboxylic acid (0.39 g, 2.0 mmol) and thionyl chloride (10 mL) was heated to reflux for 1 hour. Excess thionyl chloride was removed under vacuum. To the acid chloride, was then added 4-aminomethyl-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione hydrochloride (0.65 g, 2.0 mmol), THF (30 mL) and triethylamine (0.61 g, 6.0 mmol), and the resulting mixture was stirred at reflux for 90 minutes. The solvent was evaporated and the crude residue was chromatographed using a methylene chloride-methanol gradient, eluting 0.67 g of the product with 96:4 methylene chloride-methanol, in 76% yield: mp 198-200° C.; 1H NMR (DMSO-d6) δ 2.07-2.11 (m, 1H), 2.53-2.66 (m, 2H), 2.85-2.97 (m, 1H), 5.02 (d, J=6.3 Hz, 2H), 5.19 (dd, J=12.6 Hz, d=5.3 Hz, 1H), 7.71-7.92 (m, 5H), 8.21 (d, J=7.8 Hz, 1H), 8.28 (d, J=7.8 Hz, 1H) 8.59 (s, 1H), 9.43 (s, 1H), 9.65 (t, J=6.3 Hz, 1H), 11.17 (s, 1H); 13C NMR (DMSO-d6) δ 22.0, 31.0, 38.5, 48.9, 120.0, 121.9, 127.2, 127.8, 128.0, 129.2, 129.3, 131.4, 131.6, 133.0, 134.8, 135.4, 139.2, 143.4, 151.7, 164.7, 167.0, 167.6, 169.9, 172.8; Anal. calcd for C24H18N4O5.0.5H2O: C, 63.85; H, 4.24; N, 12.41. Found: C, 63.85; H, 3.93; N, 12.31.