Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[NH:8][C:7]([C:11]2[CH:12]=[C:13]([CH:22]=[CH:23][C:24]=2[Cl:25])[CH2:14][NH:15]C(=O)C(F)(F)F)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].O>C1COCC1>[C:1]([N:5]1[C:9](=[O:10])[NH:8][C:7]([C:11]2[CH:12]=[C:13]([CH2:14][NH2:15])[CH:22]=[CH:23][C:24]=2[Cl:25])=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1nc(-c2cc(CNC(=O)C(F)(F)F)ccc2Cl)[nH]c1=O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)n1nc(-c2cc(CN)ccc2Cl)[nH]c1=O
Yield: 100.6 %

Procedure:
The title compound was prepared according to the procedure described in Intermediate-66 by using N-(3-(1-tert-butyl-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-4-chlorobenzyl)-2,2,2-trifluoroacetamide (Example-120, 0.400 g, 1.062 mmol), KOH (0.119 g, 2.12 mmol), water (5 mL) and THF (5.0 mL) to afford 0.300 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[CH3:22][C:23]([O:26][C:27]([NH:29][C@H:30]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)[C:31](O)=[O:32])=[O:28])([CH3:25])[CH3:24].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl.CN(C)C=O>[F:41][C:38]1[CH:39]=[CH:40][C:35]([CH2:34][C@@H:30]([NH:29][C:27](=[O:28])[O:26][C:23]([CH3:24])([CH3:22])[CH3:25])[C:31](=[O:32])[NH:1][C:2]2[CH:3]=[C:4]3[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]4=[C:7]([C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=5)[NH:8][C:9]([CH:10]=2)=[C:5]34)=[CH:36][CH:37]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(F)cc1)C(=O)O
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(F)cc1)C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 88.3 %

Procedure:
Preparation of example 152 from the title compound of Example 7 (hydrochloride) (40 mg, 0.128 mmol), (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-3-(4-fluorophenyl)propanoic acid (54 mg,0.192 mmol), triethylamine (0.054 m L, 0.384 m mol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (73 mg, 0.192 mmol) in CH2Cl2 (0.4 mL) and N,N-dimethylformamide (0.4 mL) was carried out analogously to Example 11. Silica gel chromatography (eluted with 1:1 hexane:acetone), also in an analogous manner, afforded the title compound (61 mg, 0.113 mmol) as a yellow powder in 88% yield.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C@@H:16]([CH2:20][C@H:21]3[CH2:25][CH2:24][C:23](=[O:26])[CH2:22]3)[C:17](O)=[O:18])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:33][C:34]1[CH:38]=[CH:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[N:35]=1.Cl>ClCCl.C(OCC)(=O)C.N1C=CC=CC=1.CN(C=O)C>[CH:1]1([C:4]2[CH:5]=[C:6]([C@@H:16]([CH2:20][C@H:21]3[CH2:25][CH2:24][C:23](=[O:26])[CH2:22]3)[C:17]([NH:33][C:34]3[CH:38]=[CH:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[N:35]=3)=[O:18])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)n1ccc(N)n1
Reactant: O=C1CC[C@H](C[C@@H](C(=O)O)c2ccc(S(=O)(=O)C3CC3)c(C3CC3)c2)C1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1ccc(NC(=O)[C@H](C[C@H]2CCC(=O)C2)c2ccc(S(=O)(=O)C3CC3)c(C3CC3)c2)n1
Reaction time: 1 h
Yield: 85.6 %

Procedure:
To a solution of (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1R)-3-oxocyclopentyl]propionic acid (160 mg) in dichloromethane (5 mL) were added oxalyl chloride (0.04 mL) and a drop of DMF under ice-cooling, followed by stirring for 1 hour under ice-cooling. To the reaction mixture were sequentially added pyridine (0.04 mL) and tert-butyl 3-amino-1H-pyrazole-1-carboxylate (90 mg), followed by stirring at room temperature overnight. To the reaction mixture were added ethyl acetate (30 mL) and 1 M hydrochloric acid (30 mL), and the organic layer was sequentially washed with saturated aqueous sodium bicarbonate (30 mL) and saturated brine (30 mL). After drying over anhydrous magnesium sulfate, the solvent was then evaporated under reduced pressure to obtain tert-butyl 3-({(2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1R)-3-oxocyclopentyl]propanoyl}amino)-1H-pyrazole-1-carboxylate (197 mg) as a pale yellow amorphous substance. To a solution of tert-butyl 3-({(2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1R)-3-oxocyclopentyl]propanoyl}amino)-1H-pyrazole-1-carboxylate (190 mg) in ethyl acetate (5 mL) was added 4 M hydrogen chloride/ethyl acetate (5 mL) under ice-cooling, followed by stirring at room temperature overnight. The solvent was evaporated under reduced pressure, ethyl acetate (20 mL) and saturated aqueous sodium bicarbonate (20 mL) were added thereto, and the organic layer was washed with saturated brine (20 mL) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was then purified by silica gel column chromatography (ethyl acetate) to obtain (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1R)-3-oxocyclopentyl]-N-1H-pyrazol-3-yl propanamide (62 mg) as a colorless amorphous substance.
Reaction SMILES: [F:1][C:2]1([F:17])[CH:10](O)[C:9]2[NH:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][C:5]=2[CH2:4][CH2:3]1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[F:17][C:2]1([F:1])[CH2:10][C:9]2[NH:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][C:5]=2[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1cc2c([nH]1)C(O)C(F)(F)CC2
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc2c([nH]1)CC(F)(F)CC2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 59.4 %

Procedure:
Into a 500-mL 3-necked round-bottom flask was placed a solution of 113k (18 g, 73.40 mmol, 1.00 equiv) in dichloromethane (200 mL) and CF3COOH (41.9 g, 367.48 mmol, 5.00 equiv), followed by the addition of triethylsilane (25.6 g, 220.16 mmol, 3.00 equiv) dropwise with stirring at 0° C. over 20 min (FIG. 14). The resulting solution was stirred at room temperature for 4 h, adjusted pH to 7 with saturated aqueous sodium bicarbonate and extracted with 1×200 mL of dichloromethane. The combined organic layers were washed with 1×100 mL of water and 1×100 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC to afford 10 g (59%) of 113l as a white solid.
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][NH:9]3)=[CH:4][C:3]=2[O:2]1.[H-].[Na+].ClC(Cl)(Cl)S(O[CH2:26][C:27]([F:30])([F:29])[F:28])(=O)=O>CN(C)C=O>[CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]3[CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:4][C:3]=2[O:2]1
Reactant: O=S(=O)(OCC(F)(F)F)C(Cl)(Cl)Cl
Reactant: O=C(O)c1c[nH]c2cc3c(cc2c1=O)OCO3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1cn(CC(F)(F)F)c2cc3c(cc2c1=O)OCO3
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 15.6 (0.06 mole) of 6,7-methylenedioxy-4(1H)-quinolone-3-carboxylic acid (J. Med. Chem. 11, 160 (1968)) and 1.5 g. (0.062 mole) of sodium hydride powder in 250 ml. of dimethyl formamide was heated with stirring for 0.5 hour at 80°-90° C. 2,2,2-Trifluoroethyl trichloromethanesulfonate (17.5 g. 0.62 mole) was then added dropwise. The temperature was maintained at 80°-90° for an additional two hours. The cooled mixture was poured into ice water and the solid product was isolated by filtration. It was recrystallized from ethanol. This product was identical to that obtained from Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6][C:5]=2[CH:4]=1.[N:16]1[CH:21]=[CH:20][C:19]([CH2:22][Cl:23])=[CH:18][CH:17]=1.[ClH:24].[OH-].[Na+]>C1(C)C=CC=CC=1>[ClH:23].[ClH:24].[N:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:6]2([CH2:22][C:19]3[CH:20]=[CH:21][N:16]=[CH:17][CH:18]=3)[C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:15]=[CH:14][C:13]=3[C:12]3[C:7]2=[CH:8][CH:9]=[CH:10][CH:11]=3)=[CH:18][CH:17]=1
Reactant: COc1ccc2c(c1)Cc1ccccc1-2
Reactant: ClCc1ccncc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)C(Cc1ccncc1)(Cc1ccncc1)c1ccccc1-2

Procedure:
The title compound was prepared following the procedure of Example 5 from 1.8 g (9.2 mmole) of 2-methoxyfluorene, 3.0 g of 4-picolylchloride.HCl, 20 ml of 50% NaOH, 100 mg of cetyl Bu3PBr, and 30 ml of toluene by reaction at 50° for 6 hrs. The material was chramato-graphed to yield 1.6 g of product. δ: 3.37(s,4H), 3.89(s,3H), 6.52(broad,4H), 6.80(m,1H), 7.01(d,J=2.1 Hz,1H), 7.26(m,5H), 7.45(d,J=7.5 Hz,1H), 8.11(broad,4H).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16]([OH:18])=O)[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:22])=O.CN(C)C=O>C(Cl)Cl>[C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16]([Cl:22])=[O:18])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(C)c(-c2csc(C(=O)O)n2)s1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(C)c(-c2csc(C(=O)Cl)n2)s1
Reaction time: 2 h

Procedure:
2′-(Acetylamino)-4′-methyl-4,5′-bi-1,3-thiazole-2-carboxylic acid, Compound (4), (100 mg; 0.35 mmol; 1 eq.) is suspended in DCM (6 ml). Oxalyl chloride (92 μl; 1.06 mmol; 3 eq.) is added followed by anhydrous dimethylformamide (5.5 μl; 0.07 mmol; 0.20 eq.). After 2 hours, a sample is quenched with MeOH, showing that the reaction is complete. The solvents are evaporated affording 2′-acetylamino-4′-methyl-[4,5′]bithiazolyl-2-carbonyl chloride which is used in the next step without further purification. HPLC (method A), Rt: 1.90 min (purity: 92.0%).
Reaction SMILES: [F:1][CH:2]([F:35])[O:3][C:4]1[CH:5]=[C:6]([N:14]([CH2:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[C:15]2[CH:27]=[CH:26][C:18]([C:19]([O:21]C(C)(C)C)=[O:20])=[CH:17][CH:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12].FC(F)(F)C(O)=O>ClCCl>[F:35][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]([N:14]([CH2:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[C:15]2[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:26][CH:27]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12]
Reactant: CC(C)(C)OC(=O)c1ccc(N(Cc2cccnc2)c2ccc(OC(F)F)c(OC(F)F)c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(N(Cc2cccnc2)c2ccc(OC(F)F)c(OC(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 72.6 %

Procedure:
A solution consisting of 1.75 g (3.44 mmol) of tert-butyl N-(3,4-bis-difluoromethoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoate, 33.5 mL of dichloromethane and 8.4 mL of trifluoroacetic acid was stirred at room temperature for 5 hours. The solution was washed with 50 mL of H2O. Then 50 mL of H2O was added and the pH adjusted to 6 by the addition of 10% aqueous NaOH. The combined aqueous layers were extracted with 2×50 mL of dichloromethane. The combined dichloromethane extracts were evaporated and the remaining material was purified by flash chromatography over SiO2 using 10% MeOH in CH2Cl2 as eluant. The material was triturated with CH3CN to yield 1.09 g (73% yield) of the title compound as a white crystalline powder. [MW 436.359; ESMS m/z (M+H)+].
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[C:23]1[N:28]([CH3:29])[C:27](=[O:30])[CH:26]=[C:25]([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)[N:24]=1>O1CCCC1>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH2:11][N:12]([C:23]3[N:28]([CH3:29])[C:27](=[O:30])[CH:26]=[C:25]([C:31]4[CH:32]=[CH:33][N:34]=[CH:35][CH:36]=4)[N:24]=3)[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Reactant: Brc1ccc(C2CCNCC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(N2CCC(c3ccc(Br)cc3)CC2)nc(-c2ccncc2)cc1=O
Yield: 93.1 %

Procedure:
A solution of (4-(4-bromophenyl)-piperidine hydrochloride (279 mg, 1.01 mmol) and triethylamine (554 mg, 5.47 mmol), 2-chloro-3-methyl-6-(pyridin-4-yl)-3H-pyrimidin-4-one (206 mg, 0.929 mmol) in tetrahydrofuran (20 mL) was stirred for 3 hr. The resulting solution was diluted with tetrahydrofuran and filtrated. After removal of the solvents under reduced pressure and the purification of the resulting residue by CHEM ELUT CE1010 (manufactured by VARIAN) eluting dichloromethane/ethanol (15/1, v/v) and wash with ethyl acetate afforded 2-(4-(4-Bromophenyl)-piperidin-1-yl)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one (368 mg, 93%) as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([Cl:15])[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].[C:16]([O:20][C:21]([N:23]1[CH2:27][C@H:26]([CH3:28])OS1(=O)=O)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C@H:26]([CH3:28])[CH2:27][NH:23][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[C:8]2[C:13]([CH:14]=1)=[C:12]([Cl:15])[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(Cl)cccc2[nH]1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Product: CCOC(=O)c1cc2c(Cl)cccc2n1[C@H](C)CNC(=O)OC(C)(C)C

Procedure:
The title compound, m.p.: 115–119° C., ISP-MS: m/e=381.3 (M+H+) and αD20=−8.0, was prepared in accordance with the general method of example 12b) from 4-chloro-1H-indole-2-carboxylic acid ethyl ester and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[NH:13][NH:12][C:11]2=[O:16])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]>C(Cl)Cl>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:11](=[O:16])[N:12]=[N:13][C:14]2=[O:15])=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(-n2c(=O)[nH][nH]c2=O)cc1
Solvent: ClCCl
Product: CC(=O)c1ccc(N2C(=O)N=NC2=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 36 %

Procedure:
To 4-(4-acetylphenyl)-1,2,4-triazolidine-3,5-dione (115 mg, 0.999 mmol) in CH2Cl2 (3.5 mL) was added SiO2-HNO3 (300 mg). The mixture was stirred at room temperature for 15 minutes, filtered, concentrated in vacuo and dried to give 4-(4-acetylphenyl)-3H-1,2,4-triazole-3,5(4H)-dione as a red solid (78 mg, 74%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH2:12]([N:15]1[CH:19]=[C:18]([CH2:20][C@@H:21]([NH2:25])[C:22]([OH:24])=[O:23])[N:17]=[CH:16]1)[CH:13]=[CH2:14].C(OCC)(=O)C.Cl>[OH-].[Na+]>[CH2:12]([N:15]1[CH:19]=[C:18]([CH2:20][C@@H:21]([NH:25][C:2]([O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:3])[C:22]([OH:24])=[O:23])[N:17]=[CH:16]1)[CH:13]=[CH2:14]
Reactant: C=CCn1cnc(C[C@@H](N)C(=O)O)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: C=CCn1cnc(C[C@@H](NC(=O)OCc2ccccc2)C(=O)O)c1
Temperature: 25 °C

Procedure:
3.53 ml (4.24 g, 24.84 mmol) of benzyl chloroformate were added to a solution of 4.85 g (24.84 mmol) of (R)-3-(1-allyl-1H-imidazol-4-yl)-2-aminopropionic acid (as described for the (S)-enantiomer in Bioorg. Med. Chem. 2006, 14, 5981-5988) in 13 ml of 2N sodium hydroxide solution while stirring at 0° C., and stirring was continued at this temperature with addition of a further 13 ml of 2N sodium hydroxide solution for 2 h, and the mixture was them warmed to RT. The reaction mixture was covered with a layer of ethyl acetate, and the pH was adjusted to 3 to 4 with 6N hydrochloric acid. The organic phase was separated off, and the aqueous phase was washed again with ethyl acetate and then freeze dried. The residue was mixed with THF and DMF until stirrable and was thoroughly stirred, and the suspension was filtered. The resulting solution was concentrated and reacted without further purification in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:15]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[O:16])[CH2:10][CH2:9]2)=[C:4]([F:28])[CH:3]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:43]=[CH:42][CH:41]=[CH:40][C:36]=2[C:37](O)=[O:38])[CH:30]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[OH-].[Na+]>C(O)C.CC(OC)(C)C.ClCCl.CN(C=O)C>[CH2:20]([N:17]([CH2:18][CH3:19])[C:15]([CH:14]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:37](=[O:38])[C:36]3[CH:40]=[CH:41][CH:42]=[CH:43][C:35]=3[C:31]3[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=3)=[CH:3][C:4]=2[F:28])[CH2:9][CH2:10]1)=[O:16])[CH3:21]
Reactant: CCN(CC)C(=O)C(c1ccccc1)N1CCN(c2ccc(N)cc2F)CC1
Reactant: O=C(O)c1ccccc1-c1cccnc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)C(c1ccccc1)N1CCN(c2ccc(NC(=O)c3ccccc3-c3cccnc3)cc2F)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 250 mL, round-bottomed flask under a positive pressure of nitrogen was equipped with a magnetic stirrer and charged with anhydrous DMF (70 mL) followed by 2-[4-(4-amino-2-fluoro-phenyl)-piperazin-1-yl]-N,N-diethyl-2-phenyl-acetamide (3.5 g, 9.1 mmol), 2-pyridin-3-yl-benzoic acid (1.9 g, 9.5 mmol), HATU (3.8 g, 10.0 mmol) and DIPEA (1.3 g, 10.0 mmol). The resulting brown colored reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was then concentrated on the rotary evaporator to yield an oil. To this oil was added, dichloromethane (100 mL) and 1N NaOH (50 mL). The biphasic solution was stirred for 0.5 h after which phases were separated. The aqueous layer was extracted with dichloromethane (2×25 mL). The organic layers were pooled, dried over anhydrous sodium sulfate, filtered and concentrated to yield a viscous brown oil. The oil was taken in ethanol (100 mL) and heated to ˜60° C. in a water bath for 1 h. The resulting mixture was diluted with MTBE (added with magnetic stirring in 25 mL portions, total 125 mL). The resulting suspension was stirred at 0° C. (ice/water bath) for 2 h. The product was collected by filtration through a medium porosity glass frit, washed with a mixture of EtOH/MTBE (1:1.25, 22.5 mL×2) and the filter-cake dried thoroughly under house vacuum to yield the title compound as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[N:56]1([CH2:62][CH2:63][NH2:64])[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1>CN(C=O)C>[N:56]1([CH2:62][CH2:63][NH:64][C:30]([C:26]2[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])(=[O:11])=[O:12])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])=[O:32])[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1
Reactant: NCCN1CCOCC1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NCCN1CCOCC1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
To a mixture of 5-[5-(2,6-Dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (100 mg, 0.19 mmol), HOBt (31 mg, 1.2 eq.), EDAC.HCl (44 mg, 1.2 eq.) and 2-morpholin-4-yl-ethylamine (62 mg, 2.5 eq.) in DMF (2 mL) was added TEA (0.066 mL, 2.5 eq.). After stirring at rt for 6 days, the reaction was concentrated, diluted with DCM, washed with sat. NaHCO3 and water, dried, concentrated and purified on a silica gel column to give the titled compound as a pale yellow waxy solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]([CH2:16][CH2:17][C:18]([OH:20])=O)[C:5]=2[CH:4]=1.O=S(Cl)[Cl:23]>CO.O>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]([CH2:16][CH2:17][C:18]([Cl:23])=[O:20])[C:5]=2[CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc2c(c1)C(CCC(=O)O)c1ccccc1-2
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1)C(CCC(=O)Cl)c1ccccc1-2
Reaction time: 2 h

Procedure:
3-(2-Methoxyfluoren-9-yl)propionic acid (1.6 g, 5.2 mmol) was charged with SOCl2 (20 mL, in excess) at room temperature. The reaction mixture was boiled for 2 hr. The reaction was monitored by TLC (silica RP-18, 70% methanol/water). The excess of thionyl chloride was removed under reduced pressure, the residue (an oil) was used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH2:9])=[C:4]([CH3:10])[C:3]=1[CH3:11].[CH3:12][N:13]=[C:14]=[S:15]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH:9][C:14](=[S:15])[NH:13][CH3:12])=[C:4]([CH3:10])[C:3]=1[CH3:11]
Reactant: CN=C=S
Reactant: Cc1c(Cl)nnc(NN)c1C
Solvent: ClCCl
Product: CNC(=S)NNc1nnc(Cl)c(C)c1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.8 %

Procedure:
(6-Chloro-4,5-dimethylpyridazin-3-yl)hydrazine (W3.006; 8.00 g) was dissolved in DCM (400 ml) and admixed with methyl isothiocyanate (3.39 g). Subsequently, the mixture was stirred at RT for 24 h and left to stand over the weekend. The precipitate was filtered off, washed with DCM and dried in a drying cabinet at 45° C. 11.25 g of the title compound were obtained.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[C:19](S(C)(=O)=O)[CH:18]=[C:17]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[N:16]=3)[CH:12]=[CH:11][CH:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:31]([OH:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C)C=O>[C:3]1([C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[C:19]([O:38][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:18]=[C:17]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[N:16]=3)[CH:12]=[CH:11][CH:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)c1cc(-c2ccccn2)nc(-c2cccc(-c3ccccc3)n2)c1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(COc2cc(-c3ccccn3)nc(-c3cccc(-c4ccccc4)n3)c2)cc1
Yield: 69.3 %

Procedure:
Sodium hydride (60% content, oil dispersion, 0.8 g) was added to a mixture of 6-phenyl-4'-methanesulfonyl-2,2':6',2"-terpyridine (4.67 g, 0.015 mol), benzyl alcohol (1.08 g, 0.010 mol) and N,N-dimethylformamide (0.1 liter) over a period of 10 minutes. The reaction solution was refluxed for 6 hours and then processed in the same manner as in Example 1, whereby 2.88 g of the above-entitled product (T-21) was obtained. Yield: 85%. m.p. 182° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][OH:11])[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=2[CH3:25])[N:15]=[C:14]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=2[CH3:33])[N:13]=1.C(N(CC)CC)C.[C:41](Cl)(=[O:44])[CH:42]=[CH2:43]>O1CCCC1>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][O:11][C:41](=[O:44])[CH:42]=[CH2:43])[CH:5]=[CH:4][C:3]=1[C:12]1[N:13]=[C:14]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=2[CH3:33])[N:15]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=2[CH3:25])[N:17]=1
Reactant: Cc1ccc(-c2nc(-c3ccc(C)cc3C)nc(-c3ccc(OCCO)cc3O)n2)c(C)c1
Reactant: C=CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC(=O)OCCOc1ccc(-c2nc(-c3ccc(C)cc3C)nc(-c3ccc(C)cc3C)n2)c(O)c1
Temperature: 27.5 °C
Yield: 88.8 %

Procedure:
22.1 g (0.05 mol) of 2-(2-hydroxy-4-hydroxyethoxy-phenyl)-4,6-bis(2,4-dimethylphenyl)-1,3,5-triazine (prepared as described in U.S. Pat. No. 3,244,708, Example 18), are dissolved in 300 ml of tetrahydrofurane at 40° C. and 21 ml (0.15 mol) of triethylamine are added. A solution of 5.05 ml (0.053 mol) of acrylic acid chloride in 20 ml THF is added dropwise with stirring and with cooling the reaction mixture to 25-30° C. After further stirring of two hours the precipitated ammonium salt is filtered off, the filtrate is evaporated and the residue recrystallized from toluene-hexane mixture to obtain 22 g (88.7% yield) of 2-(2-hydroxy-4-acryloyloxyethoxy-phenyl)-4,6-bis(2,4-dimethylphenyl)-1,3,5-triazine as slightly yellow crystals (compound No. 25), m.p. 128-129° C.