Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[Na+].[CH:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:25])[N:22]([CH3:24])[CH3:23])[CH:17]=[N:18][CH:19]=3)[CH:12]=2)[N:7]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[N:6]=1)=[O:4]>O.O1CCOCC1.[N+]([O-])([O-])=O.[Ag+]>[CH3:23][N:22]([CH3:24])[C:21](=[O:25])[NH:20][C:16]1[CH:15]=[C:14]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[N:6]=[C:5]3[C:3]([OH:1])=[O:4])[CH:19]=[N:18][CH:17]=1
Reactant: [OH-]
Reactant: CN(C)C(=O)Nc1cncc(-c2ccc3c(c2)c(C=O)nn3C2CCCCO2)c1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CN(C)C(=O)Nc1cncc(-c2ccc3c(c2)c(C(=O)O)nn3C2CCCCO2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
A solution of sodium hydroxide (0.173 g, 4.33 mmol) in water (5 mL) was added to a solution of silver nitrate (0.367 g, 2.16 mmol) in water (5 mL) to give a brown precipitate. 3-(5-(3-formyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl) pyridin-3-yl)-1,1-dimethylurea (CXXIII) (0.340 g, 0.86 mmol) was dissolved in 1,4-dioxane (10 mL) and added to the reaction which was stirred overnight at room temperature. The solution was diluted with water and then extracted with diethyl ether. The aqueous layer was separated and carefully brought to pH=3 with aqueous HCl. The aqueous layer was then extracted with 10% iPrOH/chloroform. The combined organic layers were then dried (Na2SO4), filtered and concentrated to give 5-(5-(3,3-dimethylureido)pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylic acid (CXXIV) as a brownish white solid (246 mg, 0.60 mmol, 70% yield). 1H NMR (DMSO-d6) δ ppm 13.26 (br. s, 1H), 8.87 (s, 1H), 8.63 (s, 1H), 8.41 (s, 1H), 8.34 (s, 1H), 8.03 (d, J=7.1 Hz, 1H), 7.86 (dd, J=7.2, 1.3 Hz, 1H), 6.06 (dd, J=8.0, 4.0 Hz, 1H), 3.92 (m, 1H), 3.80 (m, 1H), 2.98 (s, 6H), 2.42-2.39 (m, 1H), 2.03-2.02 (m, 2H), 1.79-1.77 (m, 1H) 1.61 (m, 2H); ESIMS found for C21H23N5O4 m/z 410.0 (M+H).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1.[CH3:13]C([O-])(C)C.[K+].IC>C1COCC1>[I:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:12])=[CH:8][CH:9]=2)[N:4]([CH3:13])[N:3]=1
Reactant: CC(C)(C)[O-]
Reactant: N#Cc1ccc2c(I)n[nH]c2c1
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: Cn1nc(I)c2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 3-iodo-1H-indazole-6-carbonitrile (2.0 g, 7.43 mmol), t-BuOK (1.2 g, 10.4 mmol) in THF (50 mL), iodomethane (1.2 g, 10.4 mmol) in THF (5 mL) was added dropwise at 0° C. under ice-water bath. The resulting mixture was stirred overnight at room temperature. Two isomers, which are methylated at N-1 and N-2 position respectively, were formed. The excess solvent was removed under reduced pressure, the residue was dissolved in EtOAc (100 mL), washed with brine (2×10 mL), the combined organics were dried over Na2SO4. After removal of drying agent and concentration, the crude mixture (1.6 g) was used in the next step without further purification. MS: (M+H)+=411;
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[S:12](Cl)(=[O:14])=[O:13].CCN(C(C)C)C(C)C.[CH3:25][N:26]([CH3:31])[CH2:27][CH2:28][CH2:29][NH2:30].Cl>C(Cl)Cl>[CH3:25][N:26]([CH3:31])[CH2:27][CH2:28][CH2:29][NH:30][S:12]([C:3]1[S:4][C:5]2[N:6]=[CH:7][NH:8][C:9](=[O:11])[C:10]=2[C:2]=1[CH3:1])(=[O:14])=[O:13]
Reactant: Cc1c(S(=O)(=O)Cl)sc2nc[nH]c(=O)c12
Reactant: CN(C)CCCN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c(S(=O)(=O)NCCCN(C)C)sc2nc[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.7 %

Procedure:
To a stirred suspension of 5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-sulfonyl chloride (1.0 g, 12 mmol) in DCM (10 mL) at 0° C. was added Hünig's base (0.79 mL, 4.5 mmol) followed by N1,N1-dimethylpropane-1,3-diamine (0.52 mL, 4.2 mmol) and the solution stirred at ambient temperature for 2 hours. The suspension was adjusted to pH 8 with 2N hydrochloric acid, the precipitate collected by filtration, washed with water, diethyl ether and dried under vacuum to give the product as off-white solid (1.12 g, 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][NH:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>O1CCCC1.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][NH:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCOC(=O)CCNCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CNCCC(=O)O)c[nH]c34)no2)cc1Cl
Temperature: 20 °C
Reaction time: 6 h
Yield: 65.8 %

Procedure:
To a solution of ethyl N-{[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]methyl}-β-alaninate (D72) (176 mg) in tetrahydrofuran (10 mL) and methanol (5 mL) stirred at 20° C. was added a solution of sodium hydroxide (36 mg) in water (5 mL) in one charge. The reaction mixture was stirred at 20° C. for 6 hours. The reaction mixture was concentrated to about 5 mL and then H2SO4 (0.1 M) solution was added dropwise until no further white precipitate was formed. The solid was filtered and washed with EtOAc. The solid was collected and then was suspended in methanol (5 mL). The mixture was acidified with HCl (1 M) solution to pH around 1 to form a clear solution. After most of the solvent was evaporated off, the residue was freeze-dried to afford N-{[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]methyl}-β-alanine (E46) (109 mg) as a hydrochloride salt. δH (DMSO-d6, 400 MHz): 1.38 (6H, d), 2.72 (2H, t), 3.16 (2H, t), 4.41 (2H, s), 4.90-4.93 (1H, m), 7.33 (1H, t), 7.48 (1H, d), 7.76 (1H, d), 8.02 (1H, d), 8.09 (1H, d), 8.23 (1H, dd), 8.40 (1H, d), 8.81 (1H, br), 11.36 (1H, s). MS (ES): C23H23ClN4O4 requires 454; found 366.1 (M—NHC2H4COOH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH2:9]([O:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1)[CH3:10]>>[CH2:9]([O:11][C:12]1[CH:13]=[CH:14][C:15]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)=[CH:16][CH:17]=1)[CH3:10]
Reactant: CCOc1cccc(B(O)O)c1
Reactant: Clc1ccnc(Cl)n1
Product: CCOc1ccc(-c2ccnc(Cl)n2)cc1

Procedure:
2,4 dichloropyrimidine was coupled with 3-ethoxyphenylboronic acid following procedure A. LC-MS showed the product had the expected M+H+ of 235.
Reaction SMILES: C(OC([NH:11][CH:12]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C:22](=[O:40])[C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:39])[C:31]3[CH:36]=[C:35]([Cl:37])[CH:34]=[C:33]([Cl:38])[CH:32]=3)=[CH:25][CH:24]=2)[CH2:13]1)=O)C1C=CC=CC=1.[H][H]>C(O)(=O)C>[NH2:11][CH:12]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C:22](=[O:40])[C:23]2[CH:24]=[CH:25][C:26]([NH:29][C:30](=[O:39])[C:31]3[CH:36]=[C:35]([Cl:37])[CH:34]=[C:33]([Cl:38])[CH:32]=3)=[CH:27][CH:28]=2)[CH2:13]1
Reactant: [H][H]
Reactant: O=C(NC1Cc2ccccc2N(C(=O)c2ccc(NC(=O)c3cc(Cl)cc(Cl)c3)cc2)C1)OCc1ccccc1
Solvent: CC(=O)O
Product: NC1Cc2ccccc2N(C(=O)c2ccc(NC(=O)c3cc(Cl)cc(Cl)c3)cc2)C1
Yield: 63.3 %

Procedure:
To 3-benzyloxycarbonylamino-1-[4-(3,5-dichlorobenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline (3.3 g) are added acetic acid (40 ml) and 10% Pd--C (0.4 g) and the reaction mixture is subjected to catalytic reduction at ordinary temperature under atmospheric pressure of hydrogen. One hour thereafter, the catalyst is removed by filtration and the filtrate is concentrated. The resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=20:1), and recrystallized from ethanol to give 3-amino-1-[4-(3,5-dichlorobenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline (1.6 g) as white powder, m.p. 207°-210° C.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N:17]1CCC[C:18]1=[O:22]>>[CH2:9]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:18]([NH2:17])=[O:22])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CN1CCCC1=O
Reactant: c1ccc(CNCc2ccccc2)cc1
Product: NC(=O)N(Cc1ccccc1)Cc1ccccc1
Yield: 62 %

Procedure:
As described in Example 6, but using a 20strength solution of dibenzylamine in N-methylpyrrolidone instead of dodecylamine at a temperature of 70 C, N,N dibenzylurea was obtained in a yield of 62% of theory after recrystallizing from water/acetone.
Reaction SMILES: [Cl:1][C:2]([C:7]([CH3:10])([CH3:9])[CH3:8])=[CH:3][C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.O.[CH3:16]O>>[Cl:1][C:2]([C:7]([CH3:10])([CH3:9])[CH3:8])=[CH:3][C:4]([O:6][CH3:16])=[O:5]
Reactant: CC(C)(C)C(Cl)=CC(=O)O
Reactant: CO
Solvent: O
Solvent: O=S(Cl)Cl
Product: COC(=O)C=C(Cl)C(C)(C)C
Yield: 87 %

Procedure:
To a solution of 3-chloro-4,4-dimethylpent-2-enoic acid (0.8 g, 4.92 mmol) in methanol (20 mL) was added thionyl chloride (0.714 mL, 9.846 mmol) drop wise under stirring at ice cold temperature. The reaction mixture was refluxed for 2 h and attained to rt. The mixture was poured into ice cooled water and stirred for 15 min. The solution was extracted with chloroform (3×100 mL) and the combined organic layer was washed with water, brine, dried over sodium sulfate and filtered. Solvent was evaporated and the residue was chromatographed over silica gel column using hexane-ethyl acetate (95:5) as eluents to give the product as a pale green color oil (750 mg, 87%). 1H NMR (400 MHz, CDCl3): δ 6.08 (1H, s), 3.75 (3H, s), 1.24 (9H, s).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([F:24])[C:8]=1[N:9]1[CH2:14][CH2:13][CH:12]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)=[O:16])[CH2:11][CH2:10]1.CCN(C(C)C)C(C)C.[C:34]([CH2:36][C:37](O)=[O:38])#[N:35].CCN=C=NCCCN(C)C>C(Cl)Cl>[C:34]([CH2:36][C:37]([NH:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([F:24])[C:8]=1[N:9]1[CH2:10][CH2:11][CH:12]([C:15]([N:17]2[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]2)=[O:16])[CH2:13][CH2:14]1)=[O:38])#[N:35]
Reactant: CN1CCN(C(=O)C2CCN(c3c(N)cncc3F)CC2)CC1
Reactant: N#CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCN(C(=O)C2CCN(c3c(F)cncc3NC(=O)CC#N)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
To a solution of [1-(3-amino-5-fluoro-4-pyridyl)-4-piperidyl]-(4-methylpiperazin-1-yl)methanone hydrochloride 17b (300 mg, 0.8383 mmol) and DIPEA (541.8 mg, 730.2 μL, 4.192 mmol) in DCM (8 mL) was added cyanoacetic acid 7 (106.9 mg, 1.257 mmol). The reaction mixture was cooled on an ice bath and EDCI (241.0 mg, 1.257 mmol) was then added. The mixture was stirred at room temperature overnight, then heated under reflux for 4 h. The reaction mixture was cooled to room temperature and diluted with DCM (30 mL), washed with water (2×10 ml), then saturated sodium hydrogen carbonate solution (10 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo to afford the desired product 8a as an orange foam (292 mg, 90%). MS (ES+) 389.2.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH:5]([OH:9])[CH:6]([CH3:8])[CH3:7])[CH2:3][OH:4].[CH2:11](Cl)[CH:12]=[C:13]([CH3:15])[CH3:14]>>[CH3:14][C:13]([CH3:15])=[CH:12][CH2:11][O:4][CH2:3][C:2]([CH3:10])([CH3:1])[CH:5]([OH:9])[CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)C(O)C(C)(C)CO
Reactant: CC(C)=CCCl
Product: CC(C)=CCOCC(C)(C)C(O)C(C)C
Yield: 92 %

Procedure:
Treatment of 2,2,4-trimethylpentan-1,3-diol with prenyl chloride employing the alkylation reaction conditions described above provided 1-(3-methyl-2-butenyloxy)-2,2,4-trimethylpentan-3-ol in 92.0% yield (393.8 g, b.p.=82–84 C./0.8 mmHg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[C:15]1[O:16][CH2:17][CH:18]([C:20]([O:22][CH3:23])=[O:21])[N:19]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[C:15]1[O:16][CH:17]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[N:19]=1
Reactant: COC(=O)C1COC(c2ccc(OCc3ccsc3)cc2O)=N1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: COC(=O)c1coc(-c2ccc(OCc3ccsc3)cc2O)n1
Yield: 40.2 %

Procedure:
A mixture of methyl 2-[2-hydroxy-4-(3-thienylmethoxy)phenyl]-4,5-dihydrooxazole-4-carboxylate (1 g) and (2,3-dichloro-5,6-dicyanobenzoquinone (0.8 g) in toluene (100 mL) is stirred at reflux for 2 hours. The reaction is concentrated in vacuo and the residue passed through a pad of silica eluting with 20% ethyl acetate in cyclohexane. The eluant is concentrated in vacuo and the residue partitioned between ethyl acetate (100 mL) and 1N HCl (50 mL). The organic phase is washed with water (20 mL), dried over magnesium sulphate and concentrated in vacuo to give methyl 2-[2-hydroxy-4-(3-thienylmethoxy)phenyl]oxazole-4-carboxylate (400 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)[O:18][C:19]=2[CH3:20])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9].[OH:26][C:27]1[C:31]([CH:32]=[O:33])=[CH:30][N:29]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:28]=1.CN(C)C=O.[H-].[Na+]>O>[CH:32]([C:31]1[C:27]([O:26][CH2:2][C:3]2[CH:4]=[CH:5][C:6]([O:13][CH2:14][C:15]3[N:16]=[C:17]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[O:18][C:19]=3[CH3:20])=[C:7]([CH:12]=2)[C:8]([O:10][CH3:11])=[O:9])=[N:28][N:29]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:30]=1)=[O:33]
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Reactant: COC(=O)c1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 90 °C
Reaction time: 2 h
Yield: 78.4 %

Procedure:
To a mixture of methyl 5-(chloromethyl)-2-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzoate (1.16 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (0.50 g) and N,N-dimethylformamide (30 mL) was added sodium hydride (60% in oil, 0.12 g) at room temperature, and the mixture was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give methyl 5-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzoate as colorless crystals (1.07 g, yield 77%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 173-174° C.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:53])[CH:4]([N:12]1[C:18](=[O:19])[CH:17]([NH:20][C:21](=[O:48])[CH:22]([S:38]CC2C=CC(OC)=CC=2)[CH2:23][CH2:24][CH2:25][CH2:26][N:27]2[C:31](=[O:32])[C:30]3=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]3[C:28]2=[O:37])[CH2:16][C:15]2[CH:49]=[CH:50][CH:51]=[CH:52][C:14]=2[CH2:13]1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C([O-])(=O)C.[Hg+2].C([O-])(=O)C>[CH3:1][NH:2][C:3](=[O:53])[CH:4]([N:12]1[C:18](=[O:19])[CH:17]([NH:20][C:21](=[O:48])[CH:22]([SH:38])[CH2:23][CH2:24][CH2:25][CH2:26][N:27]2[C:28](=[O:37])[C:29]3=[CH:36][CH:35]=[CH:34][CH:33]=[C:30]3[C:31]2=[O:32])[CH2:16][C:15]2[CH:49]=[CH:50][CH:51]=[CH:52][C:14]=2[CH2:13]1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CNC(=O)C(Cc1ccccc1)N1Cc2ccccc2CC(NC(=O)C(CCCCN2C(=O)c3ccccc3C2=O)SCc2ccc(OC)cc2)C1=O
Agent: CC(=O)[O-]
Agent: [Hg+2]
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CNC(=O)C(Cc1ccccc1)N1Cc2ccccc2CC(NC(=O)C(S)CCCCN2C(=O)c3ccccc3C2=O)C1=O

Procedure:
Prepare by the method of Example 3.3 using 2-(4-(2-(p-methoxybenzylthio)-6-phthalimidohexanoyl-amino)-3-oxo-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl)-3-phenyl-propionic acid, N-methyl amide, mercury (II) acetate, anisole, and trifluoroacetic acid to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[C:5]1[CH:10]=[C:9]([C:11]2[CH2:15][CH2:14][CH2:13][C:12]=2[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=2[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:8]=[C:7]([NH:34][C:35](=[O:40])[CH2:36][CH2:37][CH2:38]Cl)[CH:6]=1)[CH3:2].[H-].[Na+].O>C1COCC1>[CH2:1]([O:3][C:4](=[O:41])[C:5]1[CH:10]=[C:9]([C:11]2[CH2:15][CH2:14][CH2:13][C:12]=2[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=2[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:8]=[C:7]([N:34]2[CH2:38][CH2:37][CH2:36][C:35]2=[O:40])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(NC(=O)CCCCl)cc(C2=C(c3cc(C(F)(F)F)ccc3OCc3ccccc3)CCC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C2=C(c3cc(C(F)(F)F)ccc3OCc3ccccc3)CCC2)cc(N2CCCC2=O)c1
Yield: 45.5 %

Procedure:
5-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-3-(4-chloro-butanoylamino) -benzoic acid ethyl ester (140 mg, 0.24 mmol) and NaH (10.5 mg, 0.26 mmol, 60% dispersion in oil) in THF (3 mL), were stirred at room temperature for 4 hrs. The reaction mixture was poured into water and extracted with ethyl acetate (10×3 mL), the combined organic layers were dried over MgSO4 and concentrated. Purification was carried out on a Biotage® using 40% of ethyl acetate in iso-hexane to give the required product as an orange oil (60 mg, 46%). 1H NMR (CDCl3): 1.26(3H,t,J=7.1), 2.01–2.18(4H,m), 2.52(2H,t,J=6.7), 2.88(2H,t,J=7.6), 2.97(2H,t,J=7.4), 3.44(2H,t,J=7.0), 4.26(2H,q,J=7.2), 5.06(2H,s), 6.96(1H,d,J=8.6), 7.18–7.58 (9H, m), 8.09(1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:3]=1[NH:4][C:5](=[N:19]O)[CH2:6][C:7]([NH:9][C:10]1[C:15]([Cl:16])=[CH:14][C:13]([Cl:17])=[CH:12][C:11]=1[Cl:18])=[O:8].C(OC(=O)C)(=O)C.CS(O)(=O)=O.C(N(C1CC(=O)N(C2C(Cl)=CC(Cl)=CC=2Cl)N=1)C1C=C([N+]([O-])=O)C=CC=1Cl)(=O)C.C(N(C1C=C(OC(=O)C)N(C2C(Cl)=CC(Cl)=CC=2Cl)N=1)C1C=C([N+]([O-])=O)C=CC=1Cl)(=O)C>O.C(O)(=O)C>[Cl:1][C:2]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:3]=1[NH:4][C:5]1[CH2:6][C:7](=[O:8])[N:9]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([Cl:17])=[CH:12][C:11]=2[Cl:18])[N:19]=1
Reactant: O=C(CC(=NO)Nc1cc([N+](=O)[O-])ccc1Cl)Nc1c(Cl)cc(Cl)cc1Cl
Agent: CC(=O)N(C1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1)c1cc([N+](=O)[O-])ccc1Cl
Agent: CC(=O)Oc1cc(N(C(C)=O)c2cc([N+](=O)[O-])ccc2Cl)nn1-c1c(Cl)cc(Cl)cc1Cl
Agent: CS(=O)(=O)O
Solvent: CC(=O)O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: O=C1CC(Nc2cc([N+](=O)[O-])ccc2Cl)=NN1c1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.9 %

Procedure:
In a 5 L three-necked flask, equipped with a stirrer, a reflux condenser, and a thermometer, were placed 226 g of 3-(2-chloro-5-nitroanilino)-3-oximino-N-(2,4,6-trichlorophenyl)propionamide, 2 L of glacial acetic acid, and 500 mL of acetic anhydride. The mixture was stirred at room temperature for 18 hours. The yellow color of the slurry turned almost colorless, and thin layer chromatography (TLC) showed that the O-acetyloximino derivative was the sole product. To the reaction mixture was added 50 g of methanesulfonic acid and the mixture was heated as quickly as possible to its boiling point, 117°-120° C., and kept under reflux for 10 minutes. TLC showed that the reaction was essentially complete at that time and gave a mixture of 3-(N-acetyl-2-chloro-5-nitroanilino)-1-(2,4,6-trichlorophenyl)-2-pyrazolin-5-one and 3-(N-acetyl-2-chloro-5-nitroanilino)-5-acetyloxy-1-(2,4,6-trichlorophenyl)pyrazole. At the end of the heating period, the reflux condenser was quickly replaced with a distillation head, and a water-aspirator vacuum was carefully applied to distill off the solvent as well as to cool down the mixture to 50°-60° C. The distillation of solvent was continued keeping the pot temperature at 50°-60° C. until no more distillate came off. The resulting dark greenish brown viscous oil was dissolved in 2 L of methanol with heat, and 500 mL of concentrated hydrochloric acid in water was added slowly through a dropping funnel. The mixture was heated under reflux for 1 hour, cooled to room temperature, and then allowed to stand at room temperature overnight. The solid was collected, washed with methanol and water, and dried. There was obtained 91 g (42%) of the desired 3-(2-chloro-5-nitroanilino)-1-(2,4,6-trichlorophenyl)-2-pyrazolin-5-one, having a melting point of 278°-280° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:20])[CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:20])[CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)N1CC(O)(c2ccc(F)c(F)c2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OC1(c2ccc(F)c(F)c2)CNC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.5 %

Procedure:
A mixture of tert-butyl 3-(3,4-difluorophenyl)-3-hydroxyazetidine-1-carboxylate (1.06 g, 3.72 mmol) and trifluoroacetic acid (3 ml) in dichloromethane (30 ml) was stirred at ambient temperature for 1.5 h. The solvent was evaporated and the crude product was purified on a Biotage Isolute SCX-3 SPE column (washed with methanol and eluted with methanol/triethylamine, 4:1) to give the title compound (0.52 g). MS m/z (rel. intensity, 70 eV) 185 (M+, 1), 156 (50), 141 (bp), 127 (58), 114 (90).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[C:24]([O:32][CH2:33][CH3:34])=[N:25][C:26]([O:29][CH2:30][CH3:31])=[N:27][CH:28]=3)=[N:9]2)=[CH:4][CH:3]=1.[N:35]1([C:41](=[O:49])[CH2:42][N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:46]3[CH2:47][CH2:48][N:43]([CH2:42][C:41]([N:35]4[CH2:36][CH2:37][O:38][CH2:39][CH2:40]4)=[O:49])[CH2:44][CH2:45]3)=[O:21])[C:10]([C:23]3[C:24]([O:32][CH2:33][CH3:34])=[N:25][C:26]([O:29][CH2:30][CH3:31])=[N:27][CH:28]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1ncc(C2=NC(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2C(=O)Cl)c(OCC)n1
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Product: CCOc1ncc(C2=N[C@@H](c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2C(=O)N2CCN(CC(=O)N3CCOCC3)CC2)c(OCC)n1

Procedure:
cis-4-[4,5-Bis-(4-chloro-phenyl)-2-(2,4-diethoxy-pyrimidin-5-yl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 8) was reacted with 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) to give cis-2-{4-[4,5-bis-(4-chloro-phenyl)-2-(2,4-diethoxy-pyrimidin-5-yl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-1-morpholin-4-yl-ethanone in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C34H40N7O5Cl2 [(M+H)+] 696.2463, observed 696.2463.