Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[F:14][C:15]([F:21])([F:20])[S:16](Cl)(=[O:18])=[O:17]>ClCCl>[F:14][C:15]([F:21])([F:20])[S:16]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)(=[O:18])=[O:17]
Reactant: C1CNCCN1
Reactant: O=S(=O)(Cl)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(N1CCNCC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
To a solution of piperazine (1 g) and triethylamine (1.78 mL) in dichloromethane (20 mL) at 0° C. was added dropwise trifluoromethanesulfonyl chloride (1.24 mL). The reaction mixture was stirred at room temperature for 16 h and then quenched with water (20 mL) and extracted into dichloromethane (2×40 mL). The combined organic layers were washed with saturated aqueous brine solution (2×40 mL), dried (MgSO4) and concentrated to afford 1-trifluoromethanesulfonyl-piperazine as a pale yellow solid (1.92 g, 76%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[C:15]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[O:29][N:28]=[C:27]([OH:30])[CH:26]=2)=[CH:21][CH:20]=1)(=[O:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[C:15]([NH:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[O:29][N:28]([C:2]3[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=3[N+:12]([O-:14])=[O:13])[C:27](=[O:30])[CH:26]=2)=[CH:23][CH:24]=1)(=[O:17])[CH3:16]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: CC(=O)Nc1ccc(-c2cc(O)no2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)Nc1ccc(-c2cc(=O)n(-c3ccc(C(F)(F)F)cc3[N+](=O)[O-])o2)cc1
Reaction time: 5 h
Yield: 76.1 %

Procedure:
After mixing 6.4 g of 4-chloro-3-nitrobenzotrifluoride, 7.0 g of 5-(4-acetylaminophenyl)-3-hydroxyisoxazole, 4.5 g of potassium carbonate, and 50 ml of dimethyl sulfoxide, the reaction was performed for 5 hours at 70° C. After the reaction was over, the reaction mixture obtained was poured into water and crystals thus formed were recovered by filtration and recrystallized from a mixture of dimethylformamide and methanol to provide 8.8 g of the desired product with a yield of 75.9%. The melting point thereof was 238° C. to 239° C.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][S:6]([C:9]1[CH:14]=[C:13]([CH2:15][NH:16][C:17]([C:19]2[C:20]3[CH:27]=[N:26][N:25]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[C:21]=3[CH:22]=[N:23][CH:24]=2)=[O:18])[CH:12]=[CH:11][N:10]=1)(=[O:8])=[O:7])C.[NH3:36].CO>>[C:4]([CH2:5][S:6]([C:9]1[CH:14]=[C:13]([CH2:15][NH:16][C:17]([C:19]2[C:20]3[CH:27]=[N:26][N:25]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[C:21]=3[CH:22]=[N:23][CH:24]=2)=[O:18])[CH:12]=[CH:11][N:10]=1)(=[O:8])=[O:7])(=[O:3])[NH2:36]
Reactant: N
Reactant: CCOC(=O)CS(=O)(=O)c1cc(CNC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Solvent: CO
Product: NC(=O)CS(=O)(=O)c1cc(CNC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
In a sealed tube, a solution of [4-({[1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]amino}-methyl)-pyridine-2-sulfonyl]-acetic acid ethyl ester (40 mg, 0.08 mmol) in a 7 N solution of ammonia in methanol (345 μL, 2.41 mmol) was warmed at 100° C. After 6 hours, the mixture was cooled to room temperature, and the resulting precipitate collected by filtration. The solid was purified by reversed-phase HPLC(C18 column, flow rate=25 mL/minute) using a 20 minute gradient of 5-95% acetonitrile (0.1% TFA) in water (0.1% TFA). Desired fractions from the column were combined and neutralized with saturated aqueous sodium bicarbonate, concentrated and extracted with a 10% solution of methanol in dichloromethane (3×30 mL). The combined organic layer were dried over magnesium sulfate, filtered and concentrated. The solid was triturated with methanol (3×1 mL), filtered and dried to afford the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10]C)=[O:9])=[N:6][CH:7]=1.[CH2:12]([OH:15])[CH:13]=[CH2:14].[OH-].[K+:17]>>[K+:17].[CH2:12]([O:15][C:2]1[N:3]=[CH:4][C:5]([C:8]([O-:10])=[O:9])=[N:6][CH:7]=1)[CH:13]=[CH2:14]
Reactant: C=CCO
Reactant: COC(=O)c1cnc(Cl)cn1
Agent: [K+]
Agent: [OH-]
Product: C=CCOc1cnc(C(=O)[O-])cn1
Temperature: 95 °C
Reaction time: 0.17 h
Yield: 100.8 %

Procedure:
A mixture of methyl 5-chloropyrazine-2-carboxylate (1.7 g, 10 mmol) and allyl alcohol (10 mL, 147 mmol) was heated with stirring to 95° C. and then treated with pulverized potassium hydroxide (1.3 g, 23 mmol). Within 10 min, a thick paste developed. The heating was continued for 2 h. The reaction mixture was concentrated in vacuo to dryness, and the residue was further concentrated in vacuo to dryness from toluene (2×50 mL). The 5-allyloxy-pyrazine-2-carboxylic acid potassium salt (2.2 g) that was isolated was used without further purification and characterization.
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[N:16][OH:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])([O-])=O.[H-].[Na+].O>COCCOCCOC>[O:17]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:16]1
Reactant: CCOC(=O)C(=NO)c1ccccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOCCOC
Product: CCOC(=O)c1noc2ccccc12
Temperature: 0 °C
Reaction time: 6 h

Procedure:
20 g of 3A was dissolved in 100 ml of diglyme and the solution was added dropwise to a vigorously stirred mixture of 2.5 g of sodium hydride and 100 ml of diglyme, under nitrogen at room temperature. The mixture was heated slowly to and held at 150° C. for 6 hours, then cooled, mixed with 200 ml of water and extracted with ether. The extract was dried and stripped of solvent. The residue was distilled in a Kugelrohr apparatus (60° C./0.05 Torr); the resulting residue was dissolved in warm petroleum ether, the solution was chilled to 0° C., and the solid phase was collected and dried, to give ethyl 3-benzisoxazolylcarboxylate (3B), as a white solid, m.p.: 53°-55° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([C:19](O)=[O:20])[C:13]=3[N:12]=[C:11]2[C:22](=[O:33])[NH:23][CH:24]2[CH2:29][CH2:28][N:27]([CH:30]([CH3:32])[CH3:31])[CH2:26][CH2:25]2)=[CH:4][CH:3]=1.[CH3:34][O:35][CH:36]1[CH2:39][NH:38][CH2:37]1>>[CH:30]([N:27]1[CH2:26][CH2:25][CH:24]([NH:23][C:22]([C:11]2[N:10]([CH2:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([N:38]4[CH2:39][CH:36]([O:35][CH3:34])[CH2:37]4)=[O:20])[C:13]=3[N:12]=2)=[O:33])[CH2:29][CH2:28]1)([CH3:31])[CH3:32]
Reactant: COC1CNC1
Reactant: CC(C)N1CCC(NC(=O)c2nc3c(C(=O)O)cccc3n2CCc2ccc(Cl)cc2)CC1
Product: COC1CN(C(=O)c2cccc3c2nc(C(=O)NC2CCN(C(C)C)CC2)n3CCc2ccc(Cl)cc2)C1

Procedure:
1-[2-(4-Chloro-phenyl)-ethyl]-4-(3-methoxy-azetidine-1-carbonyl)-1H-benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide was prepared by a procedure according to example 22 starting from 50 mg (0.097 mmol) 1-[2-(4-Chloro-phenyl)-ethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid and 13.5 mg (0.015 mmol) 3-methoxy-azetidine. The title compound was obtained as its formiate in form a white amorphous solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([O:22][CH2:23][C:24]([O:26]C)=[O:25])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:28](=[O:30])[NH2:29])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([O:22][CH2:23][C:24]([OH:26])=[O:25])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:28](=[O:30])[NH2:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1cccc(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(Cn2c3cccc(OCC(=O)O)c3c3c(C(N)=O)cccc32)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 65.6 %

Procedure:
A suspension of the {9-[(3-methylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester (15.8 mg, 0.039 mM) and 0.04 mL (0.04 mM) of 1 N NaOH in 5 mL of ethanol was stirred for 24 h at 25° C. The resultant white precipitate was collected by filtration, washed with a small amount of EtOH, then dried in vacuo to afford 10 mg (62%) of the {9-[(3-methylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt as a white powder. 1H NMR (DMSO-d6) δ 7.55 (d, 1H, J=8 Hz), 7.5-7.0 (m, 9H), 6.85 (d, 1H, J=8 Hz), 6.55 (d, 1H, J=8 Hz), 5.6 (s, 2H), 4.35 (s, 2H), and 2.2 (s, 3H). IR (KBr, cm−1) 3390, 1656, 1613, 1595, 1573, 1498, 1455, 1408, 1325, 1332, and 719. MS (ES) m/e 387, 389.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][C:11]([C:12](O)=[O:13])=[C:10]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[NH2:38][C:39]1[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C)C=O>[CH2:22]([O:21][C:10]1[CH:9]=[C:8]([CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][C:11]=1[C:12]([NH:38][C:39]1[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=1)=[O:13])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1cccnc1
Reactant: O=C(O)c1cc(C(F)(F)F)c(CN2CCOCC2)cc1OCc1ccccc1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccnc1)c1cc(C(F)(F)F)c(CN2CCOCC2)cc1OCc1ccccc1
Reaction time: 2 h

Procedure:
To a solution of 4-(4-morpholinylmethyl)-2-[(phenylmethyl)oxy]-5-(trifluoromethyl)benzoic acid (may be prepared as described in Description 50; 120 mg, 0.30 mmol) in N,N-dimethylformamide (5 ml) was added diisopropylethylamine (0.11 ml, 0.61 mmol), 3-aminopyridine (42.8 mg, 0.46 mmol), 1-hydroxy-7-azabenzotriazole (53.7 mg, 0.40 mmol) and EDC (116 mg, 0.61 mmol). The solution was stirred for 2 hours, then the solvent was removed in vacuo. The yellow residue was purified by MDAP to give the title compound as a white solid. 106 mg.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:12])=[C:9]([CH3:11])[N:10]=2)[CH:7]=1.[F:13][C:14]1[CH:28]=[CH:27][C:17]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][NH:23][C:22](=[O:26])[CH:21]=2)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC>[Cu]I.O1CCOCC1>[CH3:11][C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([N:23]3[CH:24]=[CH:25][C:20]([O:19][CH2:18][C:17]4[CH:27]=[CH:28][C:14]([F:13])=[CH:15][CH:16]=4)=[CH:21][C:22]3=[O:26])=[CH:7][N:6]2[C:8]=1[CH3:12]
Reactant: O=c1cc(OCc2ccc(F)cc2)cc[nH]1
Reactant: Cc1nc2ccc(I)cn2c1C
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cn2c1C
Temperature: 110 °C
Yield: 30.2 %

Procedure:
To a mixture of 6-iodo-2,3-dimethylimidazo[1,2-a]pyridine (204 mg), 4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (150 mg), potassium carbonate (283 mg) and dioxane (15 ml) were added CuI (51 mg) and trans-N,N′-dimethyl-cyclohexane-1,2-diamine (38 mg), and the mixture was heated at 110° C. in a sealed tube for 16 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The residue was diluted with DCM, washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica gel column chromatography (MeOH/DCM) to afford the title compound (75 mg) as an off-white solid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][C:9](=[O:19])[CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C(OCC)C.O1CCOCC1>[NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][CH:9]([OH:19])[CH2:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:3]=[CH:2]1
Reactant: O=C(CCCc1ccccc1)CCCc1c[nH]cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: CCOCC
Product: OC(CCCc1ccccc1)CCCc1c[nH]cn1
Reaction time: 8 h

Procedure:
1 mmol of the compound obtained in Example 49 is introduced into a suspension of 10 mmol of lithium aluminium hydride in 30 ml of diethyl ether and 10 ml of dioxane and the mixture is stirred overnight. Hydrolysis is carried out with a 2N sodium hydroxide solution and the precipitate is washed with dichloromethane. The organic phases are combined and concentrated. The title compound is recrystallized in the hydrogenmaleate form from ethanol/diethyl ether.
Reaction SMILES: [CH:1]1([CH2:6][N:7]2[C:12](=[O:13])[C:11]([CH2:14]OS(C)(=O)=O)=[CH:10][C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=3)=[N:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH:1]1([CH2:6][N:7]2[C:12](=[O:13])[C:11]([CH2:14][N:33]3[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]3)=[CH:10][C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=3)=[N:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCNCC1
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC3CCCC3)n2)cc1F
Product: COc1ccc(-c2cc(CN3CCN(C)CC3)c(=O)n(CC3CCCC3)n2)cc1F
Yield: 61.4 %

Procedure:
Following the procedure of Example 1(10), 2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 61.4%).
Reaction SMILES: [OH:1][NH:2][C:3](=[O:19])[O:4][CH2:5][CH:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2.[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1.C(N(CC)CC)C.O>C(OCC)(=O)C>[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([O:1][NH:2][C:3](=[O:19])[O:4][CH2:5][CH:6]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]3[C:7]2=[CH:8][CH:9]=[CH:10][CH:11]=3)=[O:26])=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: O=C(NO)OCC1c2ccccc2-c2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NOC(=O)c1ccc(Cl)cc1)OCC1c2ccccc2-c2ccccc21

Procedure:
To a solution of (9H-fluoren-9-yl)methyl hydroxycarbamate (5.20 g, 20.4 mmol) in ethyl acetate (300 mL) at −10° C. is added 4-chlorobenzoyl chloride (3.56 g, 20.3 mmol). Triethylamine (3 mL, 21.3 mmol) is added dropwise keeping the internal temperature below −5° C. After 10 min water (100 mL) is added and the separated aqueous layer is
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])=O.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([NH:27][C:28]([NH2:30])=[S:29])[CH:18]=[CH:19][C:20]=1[N:21]1[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]1>C(OCC)C>[Cl:12][C:6]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=1[C:3]1[N:30]=[C:28]([NH:27][C:17]2[CH:18]=[CH:19][C:20]([N:21]3[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]3)=[C:15]([O:14][CH3:13])[CH:16]=2)[S:29][CH:2]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1Cl
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Solvent: CCOCC
Product: COc1cc(Nc2nc(-c3ccc(Cl)cc3Cl)cs2)ccc1-n1cnc(C)c1
Yield: 98.9 %

Procedure:
The title compound was prepared in analogy to example 1 step e) from 90 mg (0.33 mmol) 2-bromo-2′,4′-dichloroacetophenon and 79 mg (0.3 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea. The crude reaction was diluted with diethyl ether and the precipitate was filtered off and dried to yield 128 mg (99%) [4-(2,4-dichloro-phenyl)-thiazol-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine as a light yellow solid. MS ISP (m/e): 431.1/433.2 (100/65) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.78 (s, 1H), 9.28 (s, 1H), 7.99 (s, 1H), 7.97 (d, 1H), 7.74 (s, 1H), 7.67 (s, 1H), 7.55 (d, 1H), 7.53 (s, 1H), 7.50 (d, 1H), 7.25 (d, 1H), 3.88 (s, 3H), 2.34 (s, 3H).
Reaction SMILES: [C:1]([C:6]1[CH:18]=[C:17]([C:19]([CH2:22][CH3:23])([CH3:21])[CH3:20])[CH:16]=[CH:15][C:7]=1[O:8][CH:9]([CH2:13][CH3:14])[C:10](Cl)=[O:11])([CH2:4][CH3:5])([CH3:3])[CH3:2].[Cl:24][CH:25]([F:40])[C:26]([F:39])([F:38])[C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][C:31]=1[OH:37])=[O:28].N1C2C(=CC=CC=2)C=CC=1.Cl>O1CCOCC1>[Cl:24][CH:25]([F:40])[C:26]([F:38])([F:39])[C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:10](=[O:11])[CH:9]([O:8][C:7]2[CH:15]=[CH:16][C:17]([C:19]([CH2:22][CH3:23])([CH3:21])[CH3:20])=[CH:18][C:6]=2[C:1]([CH2:4][CH3:5])([CH3:3])[CH3:2])[CH2:13][CH3:14])=[CH:32][C:31]=1[OH:37])=[O:28]
Reactant: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Cl
Reactant: Nc1ccc(NC(=O)C(F)(F)C(F)Cl)c(O)c1
Agent: Cl
Solvent: c1ccc2ncccc2c1
Solvent: C1COCCO1
Product: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1ccc(NC(=O)C(F)(F)C(F)Cl)c(O)c1
Reaction time: 1.5 h

Procedure:
A solution of 33.85 g (0.1 mole) of 2-(2,4-di-tert-pentylphenoxy)butyryl chloride in 80 ml of dioxan was added to a solution of 26.85 g (0.1 mole) of 2-(3-chloro-2,2,3-trifluoropropionamido)-5-aminophenol and 23.7 ml (0.2 mole) of quinoline in 500 ml of dioxan at room temperature. The mixture was stirred for 90 minutes and left standing overnight. Next it was poured out in 2 l of icewater and 100 ml of concentrated hydrochloric acid. The sticky residue was extracted with ether, rinsed with water until free from acid, and dried. The solvent was evaporated and the residue recrystallized from hexane.
Reaction SMILES: [Cl:1][C:2]1[CH:39]=[CH:38][C:5]2[NH:6][C:7]([C@@H:9]([NH:11][C:12](=[O:37])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([N:21]4[CH2:25][CH2:24][CH2:23][C@H:22]4[CH2:26][CH2:27][NH:28]C(OC(C)(C)C)=O)=[O:20])=[C:15]([Cl:36])[CH:14]=3)[CH3:10])=[N:8][C:4]=2[CH:3]=1.FC(F)(F)C(O)=O.ClCCl.CO.N.ClCl>>[Cl:1][C:2]1[CH:39]=[CH:38][C:5]2[NH:6][C:7]([C@@H:9]([NH:11][C:12](=[O:37])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([N:21]4[CH2:25][CH2:24][CH2:23][C@H:22]4[CH2:26][CH2:27][NH2:28])=[O:20])=[C:15]([Cl:36])[CH:14]=3)[CH3:10])=[N:8][C:4]=2[CH:3]=1
Reactant: C[C@H](NC(=O)c1ccc(C(=O)N2CCC[C@H]2CCNC(=O)OC(C)(C)C)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: C[C@H](NC(=O)c1ccc(C(=O)N2CCC[C@H]2CCN)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 17 from N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethyl]-3-chloro-4-{(2S)-2-[2-(N-tert-butoxycarbonylamino)ethyl]pyrrolidin-1-ylcarbonyl}benzamide and trifluoroacetic acid. Yield: quantitative; Rf value: 0.10 (silica gel; dichloromethane/methanol/ammonia=9:1:0.1); C23H25Cl2N5O2 (474.39); mass spectrum: (M+H)+=474/476/478 (chlorine isotope).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[C@H:7]([CH2:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].[C:29]([O:46][CH:47]([CH2:55][O:56][C:57](=[O:73])[CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])[CH2:48][S:49][CH2:50][CH2:51][C:52](O)=[O:53])(=[O:45])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44].O>N1C=CC=CC=1.P(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:28])[C@H:7]([CH2:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:52](=[O:53])[CH2:51][CH2:50][S:49][CH2:48][CH:47]([O:46][C:29](=[O:45])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:55][O:56][C:57](=[O:73])[CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])=[CH:14][CH:13]=1)(=[O:10])=[O:11])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)CC[C@H](NS(=O)(=O)c1ccc(N)cc1)C(=O)OC(C)(C)C
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)O)OC(=O)CCCCCCCCCCCCCCC
Solvent: c1ccncc1
Solvent: O
Solvent: ClP(Cl)Cl
Product: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)Nc1ccc(S(=O)(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1)OC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a solution of 4-aminobenzenesulfonylglutamic acid di-t-butyl ester (189 mg) in pyridine (2.3 ml), phosphorus trichloride (0.023 ml) was added, followed by stirring at room temperature for 2 hours. To the mixture, 6,7-bis(palmitoyloxy)-4-thiaheptanoic acid as obtained in Reference Example 4 (150 mg) was added, followed by stirring at room temperature for 24 hours. After addition of water, the reaction mixture was extracted with ethyl acetate. The extract was washed with a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and dried over anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to yield the title compound (213 mg, yield 89%) as a wax-like substance.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][NH:8][CH2:9][CH2:10][CH2:11][NH2:12])[CH:4]=[N:3]1.[N+:13]([CH:16]=[C:17](SC)SC)([O-:15])=[O:14].CS>C(O)C>[CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][N:8]2[CH2:9][CH2:10][CH2:11][NH:12][C:17]2=[CH:16][N+:13]([O-:15])=[O:14])[CH:4]=[N:3]1
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: Cn1cc(CNCCCN)cn1
Agent: CS
Solvent: CCO
Product: Cn1cc(CN2CCCNC2=C[N+](=O)[O-])cn1
Yield: 70.1 %

Procedure:
A mixture of 16.8 g of N-(1-methyl-4-pyrazolylmethyl)-trimethylenediamine, 16.5 g of 1-nitro-2,2-bis(methylthio)ethylene and 200 ml of ethanol was heated under reflux until the generation of methylmercaptan ceased. The mixture was cooled, and the precipitated crystals were collected by filtration. Washing with methanol gave 16.6 g of the desired 1-(1-methyl-4-pyrazolylmethyl)2-(nitromethylene)tetrahydropyrimidine as pale yellow crystals.
Reaction SMILES: [Br:1]Br.[F:3][C:4]([F:14])([F:13])[S:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:12][C:9]1[CH:8]=[CH:7][C:6]([S:5][C:4]([F:13])([F:3])[F:14])=[CH:11][CH:10]=1
Reactant: BrBr
Reactant: Cc1ccc(SC(F)(F)F)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)Sc1ccc(CBr)cc1

Procedure:
Bromine (20.5 g, 0.13 mol) in 20 ml of carbon tetrachloride is added slowly to a solution of 4-trifluoromethylthiotoluene (29 g, 0.15 mol) in 90 ml of carbon tetrachloride heated to gentle reflux under a 275 W sunlamp. When the addition is complete, the solution is maintained at reflux for one hour. Most of the solvent is removed at atmospheric pressure, then the residue is vacuum distilled. The 15.5 g cut with boiling point 64°-77° C./0.6-0.8 mm is 92% monobromo compound by glc.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[C:6]([CH3:17])[C:5](=[O:18])[N:4]2[CH2:19][CH2:20][O:21][C:3]=12.[CH:22]1([S:26](Cl)(=[O:28])=[O:27])[CH2:25][CH2:24][CH2:23]1>N1C=CC=CC=1>[F:16][C:10]1[CH:11]=[C:12]([I:15])[CH:13]=[CH:14][C:9]=1[NH:8][C:7]1[C:2]([NH:1][S:26]([CH:22]2[CH2:25][CH2:24][CH2:23]2)(=[O:28])=[O:27])=[C:3]2[O:21][CH2:20][CH2:19][N:4]2[C:5](=[O:18])[C:6]=1[CH3:17]
Reactant: Cc1c(Nc2ccc(I)cc2F)c(N)c2n(c1=O)CCO2
Reactant: O=S(=O)(Cl)C1CCC1
Solvent: c1ccncc1
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2CCC2)c2n(c1=O)CCO2
Yield: 5.1 %

Procedure:
Using the same reaction conditions and workup as described for the preparation of Example 7A, 8-amino-7-(2-fluoro-4-iodo-phenylamino)-6-methyl-2,3-dihydro-oxazolo[3,2-a]pyridin-5-one (I-7f: 400 mg, 0.99 mmol) in pyridine (4 ml) was reacted with cyclobutanesulfonyl chloride (274 mg, 1.7 mmol) to afford the crude product. Purification by preparative HPLC afforded 26 mg of the product (5% yield).