Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].C(N(CC)CC)C.CS(Cl)(=O)=O.[CH2:26]([N:28]([CH2:33][CH3:34])[CH2:29][CH2:30][NH:31][CH3:32])[CH3:27]>C(Cl)Cl>[CH2:26]([N:28]([CH2:33][CH3:34])[CH2:29][CH2:30][N:31]([CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])[CH3:32])[CH3:27]
Reactant: COC(=O)c1cc(C)cc(CO)c1
Reactant: CCN(CC)CCNC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)CCN(C)Cc1cc(C)cc(C(=O)OC)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice-cold, stirred solution of methyl 3-(hydroxymethyl)-5-methylbenzoate (200 mg, 1.19 mmol) and triethylamine (241 mg, 2.38 mmol) in methylene chloride (5 mL) is added methanesulfonyl chloride (191 mg, 1.67 mmol). The reaction mixture is stirred for 15 min, the precipitate that formed is removed by filtration, and N,N-diethyl-N′-methylethylenediamine (465 mg, 3.57 mmol) was added. The reaction mixture is stirred at room temperature for 2 h and then concentrated under reduced pressure. Purification by flash column chromatography (silica, 9:1 chloroform/methanol) gives the title compound. 1H NMR (300 MHz, CDCl3) δ 8.02 (s, 2H), 7.33 (s, 1H), 3.56 (s, 3H), 3.48 (s, 2H), 2.95 (m, 4H), 2.75 (m, 4H), 2.41 (s, 3H), 2.31 (s, 3H), 1.21 (m, 6H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9](C(O)=O)=[CH:10][C:5]=2[O:4][C:3]1=[O:14].C(Cl)(=O)[C:16]([Cl:18])=[O:17]>C(Cl)Cl.CN(C=O)C>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:16]([Cl:18])=[O:17])[CH:9]=[CH:10][C:5]=2[O:4][C:3]1=[O:14]
Reactant: Cn1c(=O)oc2cc(C(=O)O)ccc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1c(=O)oc2ccc(C(=O)Cl)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 3-methyl-2-oxo-2,3-dihydro-benzooxazole-6-carboxylic acid (1.0 g, [CAS Reg. No. 140934-94-7]) in CH2Cl2 (14 mL) were added two drops of DMF and oxalylchloride (0.71 mL). The mixture was stirred at room temperature for 1 hour and was then concentrated to dryness. 1,2-Dimethoxyethane (20 mL) was added and the solvent was evaporated again to give the crude acid chloride (3-methyl-2-oxo-2,3-dihydro-benzooxazole-6-carbonyl chloride). To a suspension of zinc powder (677 mg) in 1,2-dimethoxyethane (8 mL) was added tetrakis(triphenylphosphine)palladium(0) (60 mg). A suspension of the acid chloride in 1,2-dimethoxyethane (8 mL) was added. The mixture was cooled in an ice bath and a solution of 4-bromo-1-bromomethyl-2-chloro-benzene (1.47 g, [CAS Reg. No. 89720-77-4]) in 1,2-dimethoxyethane (10 mL) was slowly added over a period of 15 minutes. The mixture was stirred for 10 minutes at 0° C. and then for 2 hours at r.t. The reaction mixture was poured into ice and basified with sat. NaHCO3. The aqueous phase was then extracted two times with ethyl acetate and the organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. Ethyl acetate (20 mL) was added to the resulting precipitate and the suspension was stirred for 1 hour at r.t. The solid was filtered off and dried in vacuo. The title compound was obtained as an off-white solid (747 mg, 38%). MS (neg. ion, m/e)=380.2 [(M−H)−].
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[OH:7][C@@:8]([CH3:16])([C:12]([F:15])([F:14])[F:13])[C:9](O)=[O:10].[Br:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[C:29]([Cl:34])[CH:28]=2)(=[O:26])=[O:25])=[CH:20][CH:19]=1.O>ClCCl.CN(C=O)C>[Br:17][C:18]1[CH:19]=[CH:20][C:21]([S:24]([C:27]2[CH:33]=[CH:32][C:30]([NH:31][C:9](=[O:10])[C@:8]([OH:7])([CH3:16])[C:12]([F:15])([F:14])[F:13])=[C:29]([Cl:34])[CH:28]=2)(=[O:26])=[O:25])=[CH:22][CH:23]=1
Reactant: Nc1ccc(S(=O)(=O)c2ccc(Br)cc2)cc1Cl
Reactant: C[C@@](O)(C(=O)O)C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@](O)(C(=O)Nc1ccc(S(=O)(=O)c2ccc(Br)cc2)cc1Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.9 %

Procedure:
Oxalyl chloride (0.029 ml) was added to a stirred suspension of (R)-(+)-2-hydroxy-2-methyl-3,3,3-trifluoropropanoic acid (Method 9) (0.047 g) in dichloromethane (3 ml) containing DMF (1 drop). The mixture was stirred at ambient temperature for 30 minutes and was then added to a solution of 4-(4-bromophenylsulphonyl)-2-chloroaniline (Method 12) (0.104 g) in dichloromethane (3 ml) and stirred a further 1 hour. Water (10 ml) was added and the mixture was extracted with dichloromethane (3×20 ml). The organic extracts were combined, washed with brine then dried. Volatile material was removed by evaporation and the residue was purified by flash chromatography on silica gel eluting with 1% methanol/dichloromethane to give the title compound (0.049 g) as a foam. NMR (CDCl3): 1.78 (s, 3H), 7.65 (d, 2H), 7.8 (m, 3H), 8.0 (s, 1H), 8.6 (d, 2H), 9.3 (s, 1H);MS: 485 (M+).
Reaction SMILES: O=[C:2]1[C@H:6]([CH2:7][NH:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][N:4]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:3]1.Cl.[NH2:27][OH:28].C([O-])(=O)C.[Na+]>CO>[OH:28]/[N:27]=[C:2]1\[CH2:3][N:4]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:5][C@H:6]\1[CH2:7][NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CC(=O)[C@H](CNC(=O)OCc2ccccc2)C1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C/C(=N\O)[C@H](CNC(=O)OCc2ccccc2)C1
Reaction time: 3 h

Procedure:
Dissolve 1,1-dimethylethyl(4R)-3-oxo-4-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1-pyrrolidinecarboxylate (0.87 g, 2.49 mmol) in 5:1 MeOH/H O (10 mL). Add in hydroxylamine HCl (0.177 g, 2.54 mmol) and sodium acetate (2.04 g, 24.9 mmol). The mixture was heated to reflux and allowed to stir 3 hours. After the reaction was complete the solution was concentrated under reduced pressure and extracted with CHCl3 (3×). The organic layer was washed with 0.5 M HCl and brine. The solution was dried over Na2SO4, and evaporated to yield an oil. (0.90 g, quant). LCMS: m/z 364.6 (MH+).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[O:9][C:10]([CH:13]3[CH2:15][CH2:14]3)=[N:11][N:12]=2)=[CH:6][N:5]=[C:4]([S:16][CH3:17])[N:3]=1.C([N:20](CC)CC)C.C(Cl)(Cl)Cl>C1COCC1>[NH2:20][C:2]1[C:7]([C:8]2[O:9][C:10]([CH:13]3[CH2:15][CH2:14]3)=[N:11][N:12]=2)=[CH:6][N:5]=[C:4]([S:16][CH3:17])[N:3]=1
Reactant: CSc1ncc(-c2nnc(C3CC3)o2)c(Cl)n1
Reactant: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CSc1ncc(-c2nnc(C3CC3)o2)c(N)n1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
4-Chloro-5-(5-cyclopropyl[1,3,4]oxadiazol-2-yl)-2-methylthiopyrimidine (13 mg, 0.050 mmol) [Compound (AC) in which Q is a chlorine atom, R2B is methylthio, and —X—Y—Z— is —O—C(c-C3H5)═N—] obtained in Reference Example 3 was dissolved in THF (0.50 mL), then triethylamine (0.007 mL) and a chloroform solution (1.0 mol/L, 0.10 mL) of R1—H [wherein R1 is the same as that defined above: Compound (B)] were added thereto, followed by stirring at 60° C. for 12 hours with hermetic sealing. After completion of the reaction was confirmed by thin-layer chromatography, the reaction mixture was concentrated and dried. The residue was dissolved in chloroform (0.60 mL), then benzoyl chloride polymer-bound [about 2.5 mmol/g, 23 mg, Canadian Journal of Chemistry, vol. 55, p. 3351 (1977)], and poly(4-vinylpyridine) (23 mg) were added thereto, followed by further stirring at room temperature for 12 hours. The resin was filtered off from the reaction mixture, and the filtrate was concentrated and dried to give 4-amino-5-(5-cyclopropyl[1,3,4]oxadiazol-2-yl)-2-methylthiopyrimidine [Compound (AD) in which —X—Y—Z— is —O—C(c-C3H5)═N—].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[NH:18][C:19]([C:21]1([C:24](=[O:33])[NH:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH2:23][CH2:22]1)=[O:20])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8](C(N)=O)[CH:7]=1.O.FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=O.[N:56]1C=CC=CC=1>CN(C)C=O>[NH2:56][C:8]1[CH:7]=[C:6]([O:5][C:4]2[CH:15]=[CH:16][C:17]([NH:18][C:19]([C:21]3([C:24]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)=[O:33])[CH2:22][CH2:23]3)=[O:20])=[C:2]([F:1])[CH:3]=2)[CH:11]=[CH:10][N:9]=1
Reactant: c1ccncc1
Reactant: NC(=O)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Reaction time: 8 h
Yield: 66 %

Procedure:
4-(3-Fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridine-2-carboxamide (101 mg) was dissolved in N,N-dimethylformamide (1.0 ml) under a nitrogen atmosphere, and water (0.01 ml), [bis(trifluoroacetoxy)iodo]benzene (109 mg) and pyridine (0.0541 ml) were added at room temperature in this order, followed by stirring overnight. Water (0.01 ml), [bis(trifluoroacetoxy)iodo]benzene (109 mg) and pyridine (0.0541 ml) were added at room temperature in this order, followed by further stirring for 24 hr. The reaction mixture was partitioned between ethyl acetate and a 1N aqueous solution of sodium hydroxide. The organic layer was separated, washed with brine, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate). Fractions containing the target compound were concentrated under reduced pressure, and the residue was dried under reduced pressure to provide the titled compound as white foam (62.2 mg, 66%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:40][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: NCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Cn1c(-c2ccc(Cl)cc2)nc2cccnc21)NCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
Under nitrogen bubbling, a mixture of 2-(4-chlorophenyl)-3H-imidazo [4,5-b]pyridine-3-acetic acid (4.0 g, 0.014 mole) and 1,1'-carbonyldiimidazole (2.27 g, 0.014 mole) in 150 ml of tetrahydrofuran was stirred at room temperature for 3 hours. Then, under nitrogen atmosphere, benzylamine (1.58 g, 0.0147 mole) was added and the reaction was allowed to stir at room temperature overnight. The tetrahydrofuran was evaporated, to give a solid. The solid was recrystallized from isopropyl alcohol, collected by filtration, washed with cold isopropyl alcohol and water, and dried under high vacuum at 50° C. overnight to give 3.43 g (65%) of title compound, mp 200°-200.5° C.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:3]1.[CH3:21][C:22]1[C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=[CH:24][N:23]=1.C1C=CC2N(O)N=NC=2C=1.O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:28]([OH:30])=[O:29].[CH3:1][C@@H:2]1[CH2:3][N:4]([S:8]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=2)(=[O:9])=[O:10])[CH2:5][CH2:6][N:7]1[C:28]([C:27]1[C:22]([CH3:21])=[N:23][CH:24]=[CH:25][CH:26]=1)=[O:29]
Reactant: Cc1ncccc1C(=O)O
Reactant: C[C@@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncccc1C(=O)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)C[C@H]1C
Product: O=CO
Yield: 122.3 %

Procedure:
To a solution of (3R)-3-methyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (Description 12) (80 mg, 0.259 mmol) in DMF (4 ml) was added 2-methyl-3-pyridinecarboxylic acid (35.6 mg, 0.259 mmol), HOBT.H2O (39.7 mg, 0.259 mmol), HBTU (98 mg, 0.259 mmol) and DIPEA (0.136 ml, 0.778 mmol) and the reaction mixture was stirred at room temperature for 1 h. The DMF was evaporated under vacuum, 5 ml of DCM added and then washed with saturated NaHCO3 solution (5 ml), dried on a phase separation cartridge and evaporated under vacuo. The crude material was dissolved in MeCN/DMSO 1:1 and purified by MDAP to give the title compound (75 mg).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:22])[NH:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[C:5]1=[O:21].[Br:23][C:24]1[CH:29]=[C:28]([CH2:30]Br)[CH:27]=[CH:26][N:25]=1.O.C(#N)C>CN(C)C=O>[CH3:3][C:4]1([CH3:22])[N:8]([CH2:30][C:28]2[CH:27]=[CH:26][N:25]=[C:24]([Br:23])[CH:29]=2)[C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[C:5]1=[O:21]
Reactant: CC1(C)NC(=O)N(c2ccc(OC(F)(F)F)cc2)C1=O
Reactant: BrCc1ccnc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC1(C)C(=O)N(c2ccc(OC(F)(F)F)cc2)C(=O)N1Cc1ccnc(Br)c1
Reaction time: 0.58 h
Yield: 11.6 %

Procedure:
0.023 g of sodium hydride is added to a solution of 0.081 g of 5,5-dimethyl-3-(4-trifluoromethoxyphenyl)imidazolidine-2,4-dione in 2 ml of anhydrous dimethylformamide, under an inert atmosphere of argon at a temperature in the region of 20° C. Stirring is continued at this temperature for 35 minutes. A solution of 0.071 g of 2-bromo-4-(bromomethyl)pyridine in 1 ml of anhydrous dimethylformamide is added, followed by addition of ice-cold water after reaction for 15 minutes. The reaction mixture is placed on a cartridge 16 mm in diameter packed with 5 g of octadecyl-grafted 40-60 μm silica conditioned successively with the mixture (water/acetonitrile) (5/95) (v/v) and then the mixture (water/acetonitrile) (95/5) (v/v). The elution was performed with a linear gradient of from 5% to 95% of acetonitrile over 30 minutes then with a mixture (water/acetonitrile) (5/95) (v/v) over 10 minutes, at a flow rate of 5 ml/minute. The fractions between 90 and 100 ml are concentrated under reduced pressure. 0.015 g of 5,5-dimethyl-1-(2-bromopyrid-4-ylmethyl)-3-(4-trifluoromethoxyphenyl)-imidazolidine-2,4-dione is thus obtained in the form of a white foam, the characteristics of which product are as follows:
Reaction SMILES: [CH3:1][C:2]([CH3:19])([O:4][C:5]([NH:7][CH:8]1[CH2:12][S:11][CH:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:9]1O)=[O:6])[CH3:3].C(Cl)Cl.CCN(CC)CC.S(Cl)(C)(=O)=O>CCOCC>[CH2:16]([O:15][C:13]([C:10]1[S:11][CH2:12][CH:8]([NH:7][C:5]([O:4][C:2]([CH3:1])([CH3:19])[CH3:3])=[O:6])[CH:9]=1)=[O:14])[CH3:17]
Reactant: CCOC(=O)C1SCC(NC(=O)OC(C)(C)C)C1O
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)C1=CC(NC(=O)OC(C)(C)C)CS1
Temperature: 0 °C

Procedure:
Into an ice cooled stirring solution containing the crude alcohol obtained in Step C, 75 ml of CH2Cl2, and 10.5 ml (74 mmole) of Et3N was added 2.9 ml (37 mmole) of mesyl chloride while maintaining the system under a positive argon atmosphere. The reaction was stirred an additional 5 minutes at 0° C. and then 3 hours at 25° C. The reaction was poured into a separatory funnel containing 200 ml Et2O and successively washed with 70 ml water, 1N HCl until the aqueous wash tested acidic; 15 ml water and 50 ml brine, and dried over MgSO4. Removal of the solvent at reduced pressure afforded 6.5 g of a brown oil which was purified by flash chromatography (eluting with 15% and then 20% EtOAc/Hexanes) to yield 3.97 g of product. This material exhibited the following optical rotation [α]Damb =+122.8° at a concentration of 0.5M in ethanol. The highest rotation observed for the R enantiomer under similar conditions was -128.1°.
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][C:22]([C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]([F:20])([F:19])[F:18])[CH:8]=1)=[O:5].[N:30]1([C:36](Cl)=[O:37])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[O:33]1[CH2:34][CH2:35][N:30]([C:36]([O:1][C:2]2[CH:24]=[CH:23][C:22]([C:25]3[CH:29]=[CH:28][S:27][CH:26]=3)=[CH:21][C:3]=2[C:4]([NH:6][C:7]2[CH:12]=[C:11]([C:13]([F:15])([F:14])[F:16])[CH:10]=[C:9]([C:17]([F:18])([F:19])[F:20])[CH:8]=2)=[O:5])=[O:37])[CH2:31][CH2:32]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(-c2ccsc2)ccc1O
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(-c2ccsc2)ccc1OC(=O)N1CCOCC1
Yield: 92.7 %

Procedure:
Using 2-hydroxy-5-(3-thienyl)-N-[3,5-bis(trifluoromethyl)phenyl]benzamide and morpholine-4-carbonyl chloride as the raw materials, the same operation as the Example 71 gave the title compound.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([N:13]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]([NH2:28])[CH:22]=1)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:11][OH:12])=[O:4].[C:40](O)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[N:43][CH:42]=1>>[NH2:28][C:23]1[CH:22]=[C:21]([S:18]([N:13]([CH2:14][CH:15]([CH3:16])[CH3:17])[CH:10]([CH2:11][OH:12])[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3]([CH:2]([NH:1][C:40](=[O:47])[C:41]2[CH:46]=[CH:45][CH:44]=[N:43][CH:42]=2)[CH2:29][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)=[O:4])(=[O:19])=[O:20])[CH:26]=[CH:25][C:24]=1[F:27]
Reactant: CC(C)CN([C@H](CO)CCCCNC(=O)[C@@H](N)Cc1ccc2ccccc2c1)S(=O)(=O)c1ccc(F)c(N)c1
Reactant: O=C(O)c1cccnc1
Product: CC(C)CN(C(CO)CCCCNC(=O)C(Cc1ccc2ccccc2c1)NC(=O)c1cccnc1)S(=O)(=O)c1ccc(F)c(N)c1

Procedure:
The title compound was prepared from (2S,5S)-2-amino-N-{5-[(3-amino4-fluoro-benzenesulfonyl)-isobutyl-amino]-6-hydroxy-hexyl}-3-naphthalen-2-yl-propionamide (example 81) as described in general procedure E using nicotinic acid. The final product was obtained in 35% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1B(O)O.O1CCOCC1.[Cl:18][C:19]1[C:31](I)=[CH:30][C:22]2[NH:23][C:24]([C:26]([F:29])([F:28])[F:27])=[N:25][C:21]=2[CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.O>[Cl:18][C:19]1[C:31]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[CH:30][C:22]2[NH:23][C:24]([C:26]([F:28])([F:29])[F:27])=[N:25][C:21]=2[CH:20]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: FC(F)(F)c1nc2cc(Cl)c(I)cc2[nH]1
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: C1COCCO1
Solvent: O
Product: FC(F)(F)c1nc2cc(Cl)c(-c3ccc(Cl)cc3Cl)cc2[nH]1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Compound number 260 (i.e., 6-chloro-5-(2,4-dichlorophenyl)-2-trifluoromethylbenzimidazole) was prepared as follows. A 100-mL round-bottom flask was purged and maintained with an inert atmosphere of nitrogen. (2,4-dichlorophenyl)boronic acid (229 mg, 1.20 mmol, 2.00 equiv), dioxane (30 mL), 5-chloro-6-iodo-2-(trifluoromethyl)-1H-1,3-benzodiazole (200 mg, 0.58 mmol, 1.00 equiv), sodium carbonate (191 mg), water (8 mL) and Pd(PPh3)4 (34.7 mg) was placed in the flask. The resulting solution was stirred overnight at 80° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:4). This resulted in 87.8 mg (42%) of 6-chloro-5-(2,4-dichlorophenyl)-2-trifluoromethylbenzimidazole as a white solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([OH:10])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].[CH2:13]([O:15][CH2:16]Cl)[CH3:14].O>CN(C=O)C>[CH2:13]([O:15][CH2:16][O:10][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH:2]=[CH:3][C:4]=2[CH:9]=1)[CH3:14]
Reactant: Oc1ccc2occc2c1
Reactant: CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCOc1ccc2occc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of benzofuran-5-ol (2) (257 mg, 1.92 mmol) in DMF (3 mL), NaH (81 mg, 1.92 mmol, 57% dispersion in oil) was added at 0° C. The reaction mixture was warmed to room temperature and stirred 1 hour. Chloromethyl ethyl ether (214 μL, 2.30 mmol) was then added drop wise to 0° C. and the mixture was stirred at room temperature for additional 1 hour. Water (10 mL) was added and the reaction mixture was extracted with ethyl acetate (2×50 mL). The organic extracts were washed with water, brine, dried over Na2SO4, and concentrated in vacuo. Purification of the crude product by flash column chromatography using 10% ethyl acetate in hexane afforded compound (3) (273 mg) as a colourless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]1[CH2:14][CH2:13][NH:12][C:11]1=[NH:15].CC(C)([O-])C.CC(C)([O-])C.CC(C)([O-])C.[Al+3].[Br:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>CN(C)C=O>[Br-:32].[CH2:37]([O:36][C:34]([CH2:33][N:12]1[CH:13]=[CH:14][N+:10]([C:3]2[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])=[C:11]1[NH2:15])=[O:35])[CH3:38]
Reactant: Cc1cc(C)c(N2CCNC2=N)c(C)c1
Reactant: CCOC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [Al+3]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cc[n+](-c2c(C)cc(C)cc2C)c1N
Product: [Br-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 1-(2,4,6-trimethyl-phenyl)-imidazolidin-2-ylideneamine (3.00 g, 0.0148 mol) and aluminum tri-tert-butoxide (1.0 g, 0.0041 mol) in dimethylformamide (15 mL) was added ethyl bromoacetate (1.65 mL, 2.48 g, 0.00148 mol). The reaction mixture was allowed to stir at room temperature for 1 h, after which LC-MS indicated a 4:1 ratio of desired product to starting material. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a pale orange-yellow solid, which was then treated twice with toluene to azeotropically remove any water. The solid was triturated with toluene, collected by filtration, and placed under high vacuum for 6 h. 1H NMR (CDCl3, 300 MHz) δ 7.01 (s, 2H), 4,87 (s, 2H), 4.29 (q, J=7 Hz, 2H), 3.96–3.89 (m, 4H), 2.32 (s, 3H), 2.25 (s, 6H), 1.34 (t, J=7 Hz, 3H). LC/MS: tR=0.92 min., (MH+)=290.43.
Reaction SMILES: [O:1]=[C:2]1[NH:16][C:5]2=[CH:6][C:7]3[CH:8]=[C:9]([C:13]([OH:15])=O)[NH:10][C:11]=3[CH:12]=[C:4]2[O:3]1.[F:17][C:18]1[CH:30]=[CH:29][C:21]([CH2:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:20][CH:19]=1>C(OCC)C>[F:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][CH:23]2[CH2:24][CH2:25][N:26]([C:13]([C:9]3[NH:10][C:11]4[CH:12]=[C:4]5[O:3][C:2](=[O:1])[NH:16][C:5]5=[CH:6][C:7]=4[CH:8]=3)=[O:15])[CH2:27][CH2:28]2)=[CH:29][CH:30]=1
Reactant: O=C(O)c1cc2cc3[nH]c(=O)oc3cc2[nH]1
Reactant: Fc1ccc(CC2CCNCC2)cc1
Solvent: CCOCC
Product: O=C(c1cc2cc3[nH]c(=O)oc3cc2[nH]1)N1CCC(Cc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from 2-oxo-1,5-dihydro-2H-oxazolo[4,5-f]indole-6-carboxylic acid and 4-(4-fluorobenzyl)piperidine [J. Med. Chem., 35, 4903, (1992)] according to the method described in Example 1/c. Mp.: 244-247° C. (diethyl ether).