Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.S(Cl)([Cl:13])=O>>[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([Cl:13])=[O:10])[CH2:4][CH2:3]1
Reactant: C[C@H]1CC[C@H](C(=O)O)CC1
Reactant: O=S(Cl)Cl
Product: C[C@H]1CC[C@H](C(=O)Cl)CC1

Procedure:
Trans-4-methyl-cyclohexanecarbonyl chloride was prepared by heating to reflux trans-4-methyl-cyclohexanecarboxylic acid (5 g, 0.035 mmol) in thionylchloride (5.0 ml) for 2 h followed by purification of the corresponding acyl chloride under reduced pressure in a Kugel-Rhorr apparatus collecting the fraction distilling at 95° C. yielding 5.1 g of the desired material which was used in the next step without further purification. This acyl chloride (1.5 ml, aprox. 10 mmol) was dissolved along with 5-Bromo-3-isopropylamino-thiophene-2-carboxylic acid methyl ester (2 g, 7.12 mmol) in anhydrous dichloroethane (2 mL) and heated at 80° C. (closed vial) for 12 h. The solvents were evaporated, the resulting crude material was dissolved in methanol and left 30 min. at room temperature, concentrated and purified via flash chromatography on silica gel using a 5% EtOAc 95% hexanes mixture of eluents, in this manner 600 mg (21%) of 5-Bromo-3-[isopropyl-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester the was isolated. 1H NMR (CDCl3, 300 MHz): 6.78 (s, 1H), 4.93 (m, 1H), 3.69 (s, 3H), 2.00-1.20 (m, 8H), 1.14 (d, 3H), 0.93 (d, 3H), 0.81 (d, 3H), 0.72-0.70 (m, 2H).
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:13])=[CH:9][C:10]=2[Cl:12])[NH:5][C@@H:4]([C:14]([O:16]C)=[O:15])[CH2:3]1.C(N(CC)CC)C.[C:25]1(=[O:35])[O:30][C:28](=[O:29])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12>O1CCCC1.CN(C)C1C=CN=CC=1>[C:28]([C:27]1[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=1[C:25]([NH:1][C@@H:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:13])=[CH:9][C:10]=2[Cl:12])[NH:5][C@@H:4]([C:14]([OH:16])=[O:15])[CH2:3]1)=[O:35])([OH:30])=[O:29]
Reactant: COC(=O)[C@H]1C[C@H](N)c2c(Cl)cc(Cl)cc2N1
Reactant: O=C1OC(=O)c2ccccc21
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1C(=O)N[C@H]1C[C@H](C(=O)O)Nc2cc(Cl)cc(Cl)c21
Yield: 68.7 %

Procedure:
To a suspension of trans-4-amino-5,7-dichloro-2-methoxycarbonyl-1,2,3,4-tetrahydroquinoline (0.5 g, 1.6 mmol) in anhydrous tetrahydrofuran (50 ml) under an atmosphere of nitrogen was added dry triethylamine (0.49 ml, 3.5 mmol) and the mixture stirred until dissolution was complete. To this solution was added phthalic anhydride (0.28 g, 1.9 mmol) and 4-dimethylaminopyridine (5 mg) and the reaction mixture was stirred at room temperature for 3 hours. The mixture was then evaporated to dryness in vacuo and the residue was partitioned between ethyl acetate (100 ml) and water (200 ml). The organic layer was separated and washed successively with dilute hydrochloric acid (2×50 ml, 1M), water (1×50 ml) and brine (1×50 ml), then dried (MgSO4) and evaporated to give a solid which was recrystallised from ethyl acetate/hexane to give the title compound as colourless crystals (0.45 g), m.p. 241°-243° C.; δ (360 MHz, DMSO) 1.71 (1H, ddd, J=13.0, 12.5 and 4.1 Hz, CHACHBHCCHD), 2.45 (1H, dm, J=13.0 Hz, CHACHBHCCHD), 3.74 (3H, dd, J=12.6 and 4.1 Hz, CHACHBHCCHD), 5.19 (1H, m, CHACHBHCCHD), 6.68 (1H, d, J=2.0 Hz, 6-H or 8-H), 6.82 (1H, s, ArNH), 6.84 (1H, d, J=2.0 Hz, 6-H or 8-H), 7.54 (4H, m, ArH), 8.64 (1H, d, J=7.0 Hz, CHDNHCOCH2), 12.86 (1H, bs, CO2H); m/e (FAB+) 423 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].[SH:18][C:19]1[N:23]=[CH:22][NH:21][N:20]=1.CN(C)C=O>O>[NH2:1][C:2]1[CH:7]=[C:6]([S:18][C:19]2[N:23]=[CH:22][NH:21][N:20]=2)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Sc1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(Sc2nc[nH]n2)ccc1[N+](=O)[O-]

Procedure:
A mixture of 3.5 g. 2-amino-4-chloro-1-nitrobenzene, 5.5 g. of potassium carbonate, 4.0 g. of 3-mercapto-1,2,4-triazole in 30 ml. dimethylformamide is heated under nitrogen for 4 hours at 130°-140°C. The mixture is cooled, diluted with water and the pH adjusted to about 6. The crude product is filtered off and recrystallized from methanol, yielding 2-amino-1-nitro-4-(1,2,4-triazol-3-ylthio)benzene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11](=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:5]=[C:6]([F:10])[C:7]=1[O:8][CH3:9].C=O.[C:20](=O)([O-])[O-].[K+].[K+]>CO>[CH2:13]([CH:12]1[CH2:20][C:3]2[C:4](=[CH:5][C:6]([F:10])=[C:7]([O:8][CH3:9])[C:2]=2[Cl:1])[C:11]1=[O:17])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCCC(=O)c1cc(F)c(OC)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: [K+]
Solvent: CO
Product: CCCCC1Cc2c(cc(F)c(OC)c2Cl)C1=O
Temperature: 50 °C

Procedure:
A mixture of the crude 1-(3-chloro-5-fluoro-4-methoxyphenyl)-1-hexanone from step 1, methanol (8.7 mL), 37% aqueous formaldehyde (0.786 mL, 10.5 mmol), and potassium carbonate (1.2 g, 8.72 mmol) was stirred and heated in an oil bath at 50° C. for 7 hours. The mixture was evaporated under vacuum and the residue partitioned between EtOAc (100 mL) and water (100 mL) containing 2N HCl (10 mL). The organic phase was washed with brine (50 mL), dried over MgSO4, filtered, and evaporated under vacuum to an oil (1.86 g) consisting of predominantly 1-(3-chloro-5-fluoro-4-methoxyphenyl)-2-(methoxymethyl)-1-hexanone.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].C1COCC1.[NH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][OH:45])=[CH:39][CH:38]=1>CCOC(C)=O>[OH:45][CH2:44][CH2:43][C:40]1[CH:41]=[CH:42][C:37]([NH:36][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[C:16]([NH:20][C:21]([C:23]5[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=5)=[O:22])[CH:17]=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:30])=[CH:38][CH:39]=1
Reactant: Nc1ccc(CCO)cc1
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(CCO)cc3)c2)n(C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 20 %

Procedure:
A small screw cap test tube was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 60, 300 mg, 0.746 mmol) and THF (7.5 mL). To the resulting solution was added 2-(4-amino-phenyl)-ethanol (120 mg, 0.875 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and the resulting suspension was filtered. The solids collected were washed with 0° C. iPrOH (5 mL) and set aside. The filtrate was concentrated in vacuo and the residue obtained was dissolved in EtOAc (5 mL). The resulting solution was triturated with Hexanes (˜50 mL) to yield a precipitate. This precipitate was then filtered and washed with 0° C. iPrOH (5 mL). The solids collected were combined with those previously set aside to afford the title compound in 20% yield (0.078 g, 0.149 mmol).
Reaction SMILES: C(=O)([O-])[O-].[NH4+:5].[NH4+].Cl[C:8]1[S:9][C:10]([N+:14]([O-:16])=[O:15])=[C:11]([Cl:13])[N:12]=1>C(#N)C>[NH2:5][C:8]1[S:9][C:10]([N+:14]([O-:16])=[O:15])=[C:11]([Cl:13])[N:12]=1
Reactant: [NH4+]
Reactant: O=[N+]([O-])c1sc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: Nc1nc(Cl)c([N+](=O)[O-])s1
Temperature: 0 °C
Reaction time: 48 h
Yield: 67.9 %

Procedure:
10.1 g (0.105 mol) of ammonium carbonate are added to a solution of 19.9 g (0.1 mol) of 2,4-dichloro-5-nitrothiazole in 200 ml of acetonitrile, while stirring, and stirring is continued at room temperature for two days. The mixture is then stirred into 1 l of ice-water and the precipitate is filtered off, washed with water and dried. To remove unreacted 2,4-dichloro-5-nitrothiazole, the product is stirred into about 100 ml of petroleum ether at room temperature, filtered off, washed with petroleum ether and dried. 12.2 g (68.0% of theory) of 2-amino-4-chloro-5-nitrothiazole of melting point 180° C. (decomposition) are obtained.
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[F:29])O)=[C:16]([F:30])[CH:15]=1.FC1C=CC(C(C2C=CC(F)=CC=2)C2C3C(=C(CSC)C=CC=3)NC=2)=CC=1.FC(F)(F)C(O)=O>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[F:29])[C:9]2[C:8]3[C:12](=[C:4]([CH2:3][S:2][CH3:1])[CH:5]=[CH:6][CH:7]=3)[NH:11][CH:10]=2)=[C:16]([F:30])[CH:15]=1
Reactant: CSCc1cccc2cc[nH]c12
Reactant: OC(c1ccc(F)cc1F)c1ccc(Cl)cc1F
Agent: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(F)cc3)c[nH]c12
Solvent: O=C(O)C(F)(F)F
Product: CSCc1cccc2c(C(c3ccc(F)cc3F)c3ccc(Cl)cc3F)c[nH]c12
Temperature: 80 °C
Reaction time: 48 h

Procedure:
The title compound was prepared starting from 750 mg (4.23 mmol) of the compound from Example 8A and 1.15 g (4.23 mmol) of the compound from Example 181A in analogy to the synthesis of the compound from Example 278. A difference was that stirring at 80° C. for two days was followed by addition of 0.33 ml (4.23 mmol) of trifluoroacetic acid and stirring for an additional 16 h. 65 mg (75% purity, 3% of theory) of the target compound were obtained.
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3]Cl.[CH2:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl>CN1CCCC1=O>[CH2:6]([NH:13][CH2:3][CH:2]([F:5])[F:1])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NCc1ccccc1
Reactant: FC(F)CCl
Agent: Cl
Solvent: CN1CCCC1=O
Product: FC(F)CNCc1ccccc1
Yield: 70.1 %

Procedure:
An amount of 2 g (20 mmol) of 2,2-difluoro-1-chloroethane and 4.5 g (41 mmol) of benzylamine are heated in 62 g of N-methylpyrrolidone in an autoclave at an internal temperature of 120° C. for 16 hours. Subsequently, 50 g of 1N hydrochloric acid are added and the solvent is removed under vacuum. The residue is taken up in 50 ml of water and 50 ml of dichloromethane and adjusted to pH 8 with solid sodium hydrogencarbonate. The phases are subsequently separated and the aqueous phase is again extracted with 20 ml of dichloromethane. The organic phase is distilled. An amount of 2.4 g of N-benzyl-2,2-difluoroethanamine is obtained, which corresponds to a yield of 66.2%, based on 2,2-difluoro-1-chloroethane used.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([O-])(O)=O.[Na+].[CH3:19][C:20](N(C)C)=O.C(I)C>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:19][CH3:20])=[O:5]
Reactant: CC(=O)N(C)C
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCI
Solvent: ClCCl
Product: CCOC(=O)c1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
To a dry 100 mL 3-necked flask equipped with a magnetic stirrer and a nitrogen inlet were added 3.00 g of 2-fluoro-4-nitrobenzoic acid, 3.00 g of NaHCO3, and 20 mL of anhydrous dimethylacetamide. The suspension was treated with 3.50 mL of ethyl iodide and stirred at RT under N2 for 18 h. The reaction mixture was filtered to remove solids and the filtrate concentrated in vacuo to give an orange residue which was dissolved in 100 mL of CH2Cl2. The solution was washed with saturated aqueous NaHCO3 (3×50 mL), water (1×60 mL), and dried over anhydrous Na2SO4. Removal of drying agent by filtration and passage through a silica gel plug (3×5 cm) gave a light yellow solution which was concentrated in vacuo to afford 3.10 g (90%) of ethyl 2-fluoro-4-nitrobenzoate as a light yellow crystalline solid, m.p. 70-73° C.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][NH:6][C:7]([C:9]1[C:10](=[O:22])[S:11][C:12]2[C:17]([C:18]=1[OH:19])=[CH:16][C:15]([Cl:20])=[CH:14][C:13]=2Br)=[O:8])C.[F:24][C:25]([F:40])([F:39])[C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1>COCCOC.C1(P([Pd-4](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)C=CC=CC=1>[F:24][C:25]([F:39])([F:40])[C:26]1[CH:27]=[C:28]([C:13]2[CH:14]=[C:15]([Cl:20])[CH:16]=[C:17]3[C:12]=2[S:11][C:10](=[O:22])[C:9]([C:7]([NH:6][CH2:5][C:4]([OH:3])=[O:23])=[O:8])=[C:18]3[OH:19])[CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCOC(=O)CNC(=O)c1c(O)c2cc(Cl)cc(Br)c2sc1=O
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: O=C(O)CNC(=O)c1c(O)c2cc(Cl)cc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2sc1=O
Yield: 74.5 %

Procedure:
[(8-Bromo-6-chloro-4-hydroxy-2-oxo-2H-thiochromene-3-carbonyl)-amino]-acetic acid ethyl ester (22(d)) (500 mg, 1.2 mmol) was dissolved in DME-aqueous sodium carbonate (2M) (7 mL: 1.5 mL). To the solution was added 3,5-bis-trifluoromethyl-phenyl boronic acid (372 mg, 1.44 mmol) and tetrakis(triphenylphosphino) palladium(0) (275 mg, 0.24 mmol). The mixture was heated to reflux for six hours, cooled and concentrated. The residue was triturated with hot methanol (20 mL) and filtered to provide the title compound (470 mg.) MS ESI(−) m/e: 524.114, 526.018 (M−1).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][OH:41])=[CH:33][CH:32]=2)=[C:28]([CH:42]([CH3:44])[CH3:43])[NH:27][N:26]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:52][S:53](Cl)(=[O:55])=[O:54].Cl>ClCCl>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][O:41][S:53]([CH3:52])(=[O:55])=[O:54])=[CH:33][CH:32]=2)=[C:28]([CH:42]([CH3:44])[CH3:43])[NH:27][N:26]=1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCO)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCOS(C)(=O)=O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole (0.77 g) in dichloromethane (5 mL) were added triethylamine (0.26 mL) and methanesulfonylchloride (0.12 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-isopropyl-4-({4-[3-(methanesulfonyloxy)propoxy]phenyl}methyl)-1H-pyrazole (0.85 g). The obtained 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-isopropyl-4-({4-[(3-(methanesulfonyloxy)propoxy]phenyl}-methyl)-1H-pyrazole (0.2 g) was dissolved in a mixed solvent of acetonitrile (1.5 mL) and ethanol (1.5 mL). To the solution were added 2-[2-amino-2-(methyl)propionylamino]ethanol (0.25 g) and a catalytic amount of sodium iodide, and the mixture was stirred at 60° C. for 4 days. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=20/1-10/1) to give 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-(3-[1-(2-hydroxyethylcarbamoyl)-1-(methyl)ethylamino]propoxy)phenyl)methyl]-5-isopropyl-1H-pyrazole (0.13 g). This material was dissolved in methanol (3 mL). To the solution was added sodium methoxide (28% methanol solution, 0.05 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give the title compound (93 mg).
Reaction SMILES: [CH:1]([C:3]1[CH:16]=[CH:15][C:6]([CH:7]=[C:8]2[S:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])=[CH:5][CH:4]=1)=O.[F:17][C:18]([F:28])([F:27])[C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([NH2:26])[CH:20]=1>>[O:13]=[C:11]1[NH:10][C:9](=[O:14])[C:8](=[CH:7][C:6]2[CH:15]=[CH:16][C:3]([C:1]3[NH:26][C:21]4[CH:20]=[C:19]([C:18]([F:17])([F:27])[F:28])[CH:24]=[CH:23][C:22]=4[N:25]=3)=[CH:4][CH:5]=2)[S:12]1
Reactant: Nc1ccc(C(F)(F)F)cc1N
Reactant: O=Cc1ccc(C=C2SC(=O)NC2=O)cc1
Product: O=C1NC(=O)C(=Cc2ccc(-c3nc4ccc(C(F)(F)F)cc4[nH]3)cc2)S1

Procedure:
2-[4-[(2,4-Dioxothiazolidin-5-ylidene)methyl]phenyl]-5-trifluoromethylbenzimidazole was prepared from 5-(4-formylbenzylidene)-2,4-thiazolidinedione and 4-trifluoromethyl-1,2-phenylenediamine by following General Procedure 2.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:12]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:11]([OH:39])[C:10]1([OH:43])[CH2:40][CH2:41][CH3:42])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.CC(C)=O>[CH2:1]([O:8][CH:9]1[CH:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:12]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:11]([O:39][CH2:5][CH2:6][CH3:7])[C:10]1([O:43][C:1](=[O:8])[CH2:2][CH2:3][CH3:4])[CH2:40][CH2:41][CH3:42])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: CCCC1(O)C(O)C(OCc2ccccc2)C(OCc2ccccc2)C(OCc2ccccc2)C1OCc1ccccc1
Solvent: CCO
Solvent: CC(C)=O
Product: CCCOC1C(OCc2ccccc2)C(OCc2ccccc2)C(OCc2ccccc2)C(OCc2ccccc2)C1(CCC)OC(=O)CCC
Yield: 123.1 %

Procedure:
The allyl ether 21 (182 mg, 0.26 mmol) was dissolved in a mixture of 7 mL ethanol and 1 mL acetone and 18 mg Wilkinson catalyst (19 μmol) was added. The mixture was stirred in a hydrogen atmosphere for 3 days, before the solvents were removed under reduced pressure. The residue was chromatographed by preparative HPLC (95% MeOH, 40 mL/min, tRet=35.00 min) to give 26 as a colorless solid(108 mg, 0.16 mmol; 59.2% yield).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:24]([OH:26])=[O:25])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:23])[NH:19][N+:20]([O-:22])=[O:21])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.[NH:28]([C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])[C@@H:29]([C:31](O)=[O:32])[CH3:30]>CN(C=O)C.CCOC(C)=O>[NH:28]([C:34]([O:36][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:35])[C@@H:29]([C:31]([NH:1][C@H:2]([C:10]([NH:12][C@H:13]([C:24]([OH:26])=[O:25])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:23])[NH:19][N+:20]([O-:22])=[O:21])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:32])[CH3:30]
Reactant: N=C(NCCC[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)O)N[N+](=O)[O-]
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)O

Procedure:
2.69 Grams (5 m moles) of H-Phe-Arg(NO2)-CHA.HCl was dissolved in 10 ml of 1.5N-NEM/DMF, to this solution was added 1.73 g (5 m moles) of Z-D-Ala-SDP at 0° to 5° C., the reacted at room temperature for 18 hours. After the reaction was completed, the reaction mixture was diluted with 150 ml of AcOEt, the washed 3 times with 50 ml of cold 5%-hydrochloric acid and washed twice with 50 ml of an aqueous solution saturated with sodium chloride, then decolored and dried with activated carbon and anhydrous magnesium sulfate. After the drying, magnesium sulfate and activated carbon were removed by filtration, and the solvent was removed from the filtrate by evaporation under reduced pressure to obtain crude product of Z-D-Ala-Phe-Arg(NO2)-CHA, recrystallized from MeOH/AcOEt/n-hexane to obtain 2.8 g (80.0%) of Z-D-Ala-Phe-Arg(NO2)-CHA.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7](SC)=[N:6]2.CC1N=C(C2C=CC=CC=2)N2C=1C=NC(S(C)(=O)=O)=N2.[CH3:39][O:40][C:41]1[CH:42]=[C:43]([CH:45]=[C:46]([O:48][CH3:49])[CH:47]=1)[NH2:44]>C(O)C>[CH3:49][O:48][C:46]1[CH:45]=[C:43]([NH:44][C:7]2[N:8]=[CH:9][C:10]3=[C:2]([CH3:1])[N:3]=[C:4]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:5]3[N:6]=2)[CH:42]=[C:41]([O:40][CH3:39])[CH:47]=1
Reactant: COc1cc(N)cc(OC)c1
Reactant: CSc1ncc2c(C)nc(-c3ccccc3)n2n1
Agent: Cc1nc(-c2ccccc2)n2nc(S(C)(=O)=O)ncc12
Solvent: CCO
Product: COc1cc(Nc2ncc3c(C)nc(-c4ccccc4)n3n2)cc(OC)c1
Yield: 37.4 %

Procedure:
Applying the displacement procedure, using 5-methyl-2-(methylthio)-7-phenylimidazo[5,1-f][1,2,4]triazine (Intermediate 72) (50 mg, 0.17 mmol), 3,5-dimethoxyaniline (26.5 mg, 0.17 mmol) and ethanol (2.5 mL) to afford N-[3,5-bis(methyloxy)phenyl]-5-methyl-7-phenylimidazo[5,1-f][1,2,4]triazin-2-amine (23 mg) as a yellow solid. MS m/z 362 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:42]=[CH:43][C:44]=1[CH3:45])[CH2:7][O:8][CH:9]1[CH:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])=[CH:17][CH:16]=2)[CH2:13][CH2:12][N:11]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:10]1)(O)=[O:2].C(Cl)(=O)C([Cl:49])=O.CN(C)C=O>ClCCl>[Cl:49][C:1]([C:4]1[CH:5]=[C:6]([CH:42]=[CH:43][C:44]=1[CH3:45])[CH2:7][O:8][CH:9]1[CH:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])=[CH:17][CH:16]=2)[CH2:13][CH2:12][N:11]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:10]1)=[O:2]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc(C)c(C(=O)O)c2)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc(C)c(C(=O)Cl)c2)cc1
Reaction time: 1 h

Procedure:
The solution of 0.474 g of tert-butyl 3-(3-carboxy-4-methylbenzyloxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 12 ml of dichloromethane is admixed at 0° C. successively with 0.132 ml of oxalyl chloride and 0.005 ml of N,N-dimethylformamide. The reaction mixture is stirred over 1 hour and then concentrated by evaporation. The residue is dissolved once more in 20 ml of dichloromethane and concentrated by evaporation. This gives the crude title compound.