Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:14]([F:23])=[C:15]([CH:20]=[CH:21][CH:22]=1)[C:16]([O:18]C)=O)(=[O:11])=[O:10].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:34][C:35]1[N:40]=[C:39]([CH3:41])[CH:38]=[CH:37][N:36]=1>C1COCC1>[Cl:34][C:35]1[N:40]=[C:39]([CH2:41][C:16]([C:15]2[C:14]([F:23])=[C:13]([NH:12][S:9]([C:3]3[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=3[F:1])(=[O:10])=[O:11])[CH:22]=[CH:21][CH:20]=2)=[O:18])[CH:38]=[CH:37][N:36]=1
Reactant: Cc1ccnc(Cl)n1
Reactant: COC(=O)c1cccc(NS(=O)(=O)c2cc(F)ccc2F)c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Cc1ccnc(Cl)n1)c1cccc(NS(=O)(=O)c2cc(F)ccc2F)c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 33.2 %

Procedure:
To a solution of methyl 3-(2,5-difluorophenylsulfonamido)-2-fluorobenzoate (44 g, 128 mmol (from a compilation of batches prepared as described above) in dry THF (500 mL) at −10° C., LiHMDS (1M in THF, 448 mmol, 448 mL) was added dropwise and the solution was allowed to stir for 1 h at 0° C. A solution of 2-chloro-4-methylpyrimidine (19.4 g, 154 mmol) in THF (50 mL) was then added dropwise to the solution of ester and base at 0° C. over 20 min. The solution was allowed to stir 1 h at rt. TLC showed the reaction was complete. The reaction was quenched by addition of the saturated aqueous NH4Cl (300 mL) at 0° C. The reaction mixture was extracted with EtOAc (500 mL×3). The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by flash column on silica gel, eluting with DCM. This solution was evaporated to obtain a solid. The orange solid was triturated with a small amount of EtOAc and filtered, rinsing with diethyl ether to give the title compound (18.6 g, 33.2% yield). 1H NMR (400 MHz, CDCl3) δ ppm 13.70-13.74 (br, 1H), 8.59 (d, J=5.29 Hz, 0.3H), 8.42 (d, J=5.51 Hz, 1H), 7.75-7.79 (m, 0.3H), 7.51-7.66 (m, 3.6H), 7.12-7.28 (m, 6.6H), 6.91 (d, J=5.51 Hz, 1H), 6.03 (s, 1H), 4.37 (s, 0.6H). MS (ES+): 442 [M+H]+
Reaction SMILES: FC1C=C(C=CC=1F)C(Cl)=O.C[C:13]1(C)[C:26]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH:19][C:18]=2[CH:17]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:16][NH:15][CH2:14]1>>[CH2:30]([O:29][C:27]([CH:17]1[C:18]2[NH:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[C:26]=2[CH2:13][CH2:14][NH:15][CH2:16]1)=[O:28])[CH3:31]
Reactant: CCOC(=O)C1CNCC(C)(C)c2c1[nH]c1ccccc21
Agent: O=C(Cl)c1ccc(F)c(F)c1
Product: CCOC(=O)C1CNCCc2c1[nH]c1ccccc21

Procedure:
In a manner similar to that described in Step B, but using 3,4-difluorobenzoyl chloride and ethyl 1,1-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-5-carboxylate which was prepared in a similar manner as described in Step A, the following compound was prepared:
Reaction SMILES: [OH-].[Na+].S(O)(O)(=O)=O.[NH2:8][CH2:9][C:10]#[N:11].CCOCC.[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][N:26]=1)[C:21](Cl)=[O:22]>O.C(OCC)(=O)C>[C:10]([CH2:9][NH:8][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][N:26]=[C:18]([F:17])[CH:19]=1)#[N:11]
Reactant: N#CCN
Reactant: O=C(Cl)c1ccnc(F)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O
Product: N#CCNC(=O)c1ccnc(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
2.4 g (0.056 mol) of sodium hydroxide was dissolved in 24 ml of water. 3.6 g (0.017 mol) of aminoacetonitrile sulfate was added to the solution. 30 ml of ether containing 3.0 g (0.017 mol) of 2-fluoroisonicotinoyl chloride was added dropwise to the solution while the temperature was kept below 5° C. The mixture was stirred at room temperature for 2 h to conduct a reaction. Water and ethyl acetate were added to the mixture to conduct extraction. The organic layer was washed with a saturated aqueous common salt solution and dried over anhydrous sodium sulfate. The solvent was distilled. The resulting crude crystalls were recrystallized from a solvent mixture of n-hexane and ethyl acetate to obtain 2.3 g (yield: 75.3%) of white crystal having a melting point of 124° to 125° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[F:12][CH:13]([F:22])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([C:7]([C:19]2[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH:13]([F:12])[F:22])=[CH:21][CH:20]=2)=[O:8])[CH:10]=1
Reactant: O=C(Cl)c1cc(Br)ccc1Cl
Reactant: FC(F)COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccc(OCC(F)F)cc1)c1cc(Br)ccc1Cl
Temperature: 0 °C
Yield: 100.3 %

Procedure:
Under Ar protection, 5-bromo-2-chloro-benzoyl chloride 12n (37.7 g, 148.6 mmol) was dissolved in 350 mL dichloromethane and 2,2-difluoroethoxybenzene 12c (25 g, 158.6 mmol) was added and stirred until dissolved, and cooled to 0° C., followed by addition of AlCl3 (19.1 g, 142.4 mmol) in batch. The reaction mixture was stirred for 2 hours at 0° C., then poured into 300 mL ice water and stirred for 30 minutes and partitioned. The aqueous layer was extracted with dichloromethane (100 mL). The organic layer was combined and partitioned after methanol (50 mL), dichloromethane (100 mL) and water (200 mL) were added. The organic layer was washed with saturated NaCl solution (200 mL) and combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (5-bromo-2-chloro-phenyl)-[4-(2,2-difluoroethoxy)phenyl]methanone 12o (56 g, yellow grease), yield: 99.0%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:21]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][C:30]([OH:32])=[O:31])=[CH:25][C:24]=2[O:33][CH3:34])=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[C:16]([CH3:35])[NH:17]2)(=[O:11])=[O:10].[Cl:36]N1C(=O)CCC1=O>CN(C)C=O>[Cl:36][C:15]1[C:14]2[C:18](=[CH:19][CH:20]=[C:21]([O:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][C:30]([OH:32])=[O:31])=[CH:25][C:24]=3[O:33][CH3:34])[C:13]=2[NH:12][S:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])(=[O:11])=[O:10])[NH:17][C:16]=1[CH3:35]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1cc(CC(=O)O)ccc1Oc1ccc2[nH]c(C)cc2c1NS(=O)(=O)c1ccc(Cl)cc1Cl
Solvent: CN(C)C=O
Product: COc1cc(CC(=O)O)ccc1Oc1ccc2[nH]c(C)c(Cl)c2c1NS(=O)(=O)c1ccc(Cl)cc1Cl
Reaction time: 0.67 h

Procedure:
A room temperature solution of 1 (14 mg, 0.026 mmol) and N-chlorosuccinimide (4 mg, 0.029 mmol) dissolved in N,N-dimethylformamide (1 mL) was stirred for 40 min., after which time HPLC indicated no 1 remained. The reaction was partitioned between ethyl acetate and 10% sodium thiosulfate aqueous solution. The organic separation was washed twice with water then brine. The organic layer was stirred over magnesium sulfate, filtered and the filtrate concentrated in vacuo on a rotary evaporator to afford a colorless solid. The product was isolated by semi-preparative reversed phase HPLC to afford a colorless solid. LC-MS ESI (neg.) m/z: 567.1 (M−H). 1H NMR (400 MHz) (d6-DMSO) δ 11.41 (s, 1H); 9.66 (br s, 1H); 7.64 (d, J=8 Hz, 1H); 7.52 (s, 1H); 7.18 (d, J=8.0 Hz, 1H); 6.86 (s, 1H); 6.61 (d, J=8.0 Hz, 1H); 6.35 (d, J=8.0 Hz, 1H); 6.23 (d, J=8.0 Hz, 1H); 3.66 (s, 3H); 3.51 (s, 2H); 2.38 (s, 3H) ppm.
Reaction SMILES: [C:1]([C:9]1[CH:24]=[CH:23][C:12]([CH:13]=[CH:14][C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:26]1[CH:27]=[C:28]([O:34][CH3:35])[C:29]([O:32][CH3:33])=[CH:30][CH:31]=1>>[C:1]([C:9]1[CH:24]=[CH:23][C:12](/[C:13](/[C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=2)=[CH:14]\[C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1ccc(C=CC(=O)N2CCOCC2)cc1
Reactant: COc1ccc(Br)cc1OC
Product: COc1ccc(/C(=C/C(=O)N2CCOCC2)c2ccc(C(=O)c3ccccc3)cc2)cc1OC

Procedure:
This compound was obtained analogous to Example 23 by reacting 4-benzoylcinnamic acid morpholide and 4-bromoveratrole.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].[CH3:18][N:19]1[C:23]([Sn](CCCC)(CCCC)CCCC)=[CH:22][C:21]([C:37]([F:40])([F:39])[F:38])=[N:20]1>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:23]1[N:19]([CH3:18])[N:20]=[C:21]([C:37]([F:40])([F:39])[F:38])[CH:22]=1)[CH:9]=2)=[O:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C(F)(F)F)nn1C
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2sc1=O
Product: COC(=O)c1c(O)c2ccc(-c3cc(C(F)(F)F)nn3C)cc2sc1=O

Procedure:
4-Hydroxy-7-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester was prepared from 7-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester under conditions analogous to Example 44(a) using 1-Methyl-5-tributylstannanyl-3-trifluoromethyl-1H-pyrazole. The crude material was used in the next step without purification.
Reaction SMILES: C(O[C:9]1[CH:10]=[CH:11][C:12]([C@@H](O[Si](C(C)(C)C)(C)C)CNCCCCCCOCC(F)(F)C2C=CC=CC=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[NH:17]1[C:18]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[CH:15][C:16]1=[O:19]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CNCCCCCCOCC(F)(F)c1ccccc1)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=c1ccc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
To a solution of Intermediate 72 (6.4 g, 9.63 mmol) in tetrahydrofuran (60 mL) was added tetra-n-butyl ammonium fluoride (5.02 g, 19.26 mmol). The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. Purification by column chromatography using methylene chloride/methanol (from 95:5 to 85:15) as eluent gave 8-(benzyloxy)-5-((1R)-2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino)}-1-hydroxy ethy)quinolin-2(1H)-one (1.1 g, 20%) as oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][NH:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[F:17][C:18]([F:33])([F:32])[C:19]1[C:27]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=2[N:21]([CH2:28][C:29](O)=[O:30])[N:20]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][N:12]([C:29](=[O:30])[CH2:28][N:21]4[C:22]5[CH2:23][CH2:24][CH2:25][CH2:26][C:27]=5[C:19]([C:18]([F:32])([F:17])[F:33])=[N:20]4)[C:11]=3[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Reactant: O=C(O)Cn1nc(C(F)(F)F)c2c1CCCC2
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
Product: O=C(Cn1nc(C(F)(F)F)c2c1CCCC2)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
To a mixture of 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine (0.023 g, 0.11 mmol), 2-[3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-1-yl]acetic acid (0.027 g, 0.11 mmol) and NEt3 (0.050 mL, 0.36 mmol) in DMF (0.6 mL) was added HATU (0.050 g, 0.13 mmol). The mixture was stirred at rt for 30 min. It was then quenched with water. The mixture was partitioned between IPA/CHCl3 (1:2, 50 mL) and sat. NaHCO3 (30 mL). The organic layer was separated, dried over Na2SO4, concentrated in vacuo, and purified by reverse phase HPLC to afford the desired product (0.027 g, 55%). 1H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 7.42 (dd, J=8.8, 4.4 Hz, 2H), 7.17 (dd, J=9.2, 8.0 Hz, 2H), 5.15 (s, 2H), 3.87 (m, 2H), 2.82 (t, J=6.2 Hz, 2H), 2.61 (m, 4H), 2.11 (m, 2H), 1.87 (m, 2H), 1.79 (m, 2H); MS: (ES) m/z calculated for C22H21F4N5O [M+H]+ 448.1, found 448.1.
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[C:7]([C:8](Cl)=[O:9])=[CH:6][N:5]([CH3:11])[N:4]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[C:15]=1[CH:22]1[CH2:24][CH:23]1[CH:25]([NH:27][O:28][CH3:29])[CH3:26].C1N2CCN(CC2)C1>C(#N)C>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[C:15]=1[C@@H:22]1[CH2:24][C@H:23]1[CH:25]([N:27]([O:28][CH3:29])[C:8]([C:7]1[C:3]([CH:2]([F:12])[F:1])=[N:4][N:5]([CH3:11])[CH:6]=1)=[O:9])[CH3:26]
Reactant: CONC(C)C1CC1c1c(Cl)cc(Cl)cc1Cl
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: CON(C(=O)c1cn(C)nc1C(F)F)C(C)[C@@H]1C[C@H]1c1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (24 mg; 0.12 mmol) in acetonitrile (1 ml) was added dropwise to a stirred mixture of N-{1-[2-(2,4,6-trichlorophenyl)-cyclopropyl]-ethyl}-O-methyl-hydroxylamine (24 mg; 0.08 mmol), prepared as described in example P16 and DABCO (14 mg; 0.12 mmol) in acetonitrile (1 ml) at ambient temperature. The reaction mixture was stirred for 2 hours at ambient temperature. The solvent was removed in vacuo and the residue was purified by flash chromatography over silica gel (4 g) (eluent: n-hexane/ethyl acetate 1:2).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:14][C@H:13]([OH:15])[C@@H:12]([N:16]=[N+:17]=[N-:18])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>CN(C=O)C.CCOC(C)=O>[C:3]([O:7][C:8]([N:10]1[CH2:14][C@H:13]([O:15][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C@@H:12]([N:16]=[N+:17]=[N-:18])[CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1C[C@H](N=[N+]=[N-])[C@@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CO[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
96.1 A suspension of 210 mg NaH (55% in mineral oil) in 3 ml DMF was treated at 0° C. with 1.0 g (3S,4S)-3-azido-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester in 6 ml DMF. The reaction mixture was stirred at 0° C. for 90 min, then it was cooled to 0° C. A solution of 0.53 ml ethyl bromoacetate was added dropwise. The reaction mixture was slowly warmed to r.t., stirred overnight, then heated for 1 hr at 50° C. After cooling to r.t. the mixture was taken up in EtOAc and washed with H2O. The combined organics were dried over MgSO4, filtrated and concentrated. The crude product was purified by column chromatography (silica gel; cyclohexane->cyclohexane/EtOAc 3:2) to give 584 mg (3S,4S)-3-azido-4-ethoxycarbonylmethoxy-pyrrolidine-1-carboxylic acid tert-butyl ester as yellow liquid. MS 315.2 ([M+H]+)
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:13]1([S:19]([NH2:22])(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>ClCCl.C(OCC)(=O)C.O.CS(C)=O>[Cl:12][C:11]1[C:2]([NH:22][S:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:21])=[O:20])=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Clc1nc2ccccc2nc1Cl
Reactant: NS(=O)(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: O=S(=O)(Nc1nc2ccccc2nc1Cl)c1ccccc1
Temperature: 150 °C
Reaction time: 15 h

Procedure:
A flask was charged with 2,3-dichloroquinoxaline (3.5 g, 18 mmol), 85 mL of dimethylsulfoxide, benzene sulfonamide (2.8 g, 18 mmol), and cesium carbonate (5.8 g, 18 mmol). The reaction mixture was stirred under an N2 atmosphere for 15 h at 150° C., after which time, it was transferred to a separatory funnel and 100 mL of water were added. Concentrated HCl was then added in order to acidify the reaction mixture to pH<2. The aqueous layer was subsequently washed three times with 90 mL ethyl acetate. The ethyl acetate layers were then washed two times with 150 mL water, three times with 100 mL brine and then dried over sodium sulfate. The ethyl acetate was removed on a rotary-evaporator. A slurry was formed by adding ethyl acetate and dichloromethane to the dried crude product, filtration yielded N-(3-chloroquinoxalin-2-yl)-benzenesulfonamide which was used without further purification. MS (EI) m/z C14H10ClN3O2S: 319.9 (MH+).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:44]=[CH:43][C:12]([O:13][CH2:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[C:29]([CH3:31])[C:28]([OH:32])=[CH:27][C:26]=4[CH3:33])=[CH:20][C:19]=3[N:34]([CH3:42])C(=O)OC(C)(C)C)=O)=[CH:11][CH:10]=2)[S:3]1.[ClH:45].O1CCOCC1.Cl.C(OCC)(=O)C>C(#N)C.O>[ClH:45].[OH:32][C:28]1[C:29]([CH3:31])=[CH:30][C:25]([O:24][C:21]2[CH:22]=[CH:23][C:18]3[N:17]=[C:15]([CH2:14][O:13][C:12]4[CH:43]=[CH:44][C:9]([CH2:8][CH:4]5[S:3][C:2](=[O:1])[NH:6][C:5]5=[O:7])=[CH:10][CH:11]=4)[N:34]([CH3:42])[C:19]=3[CH:20]=2)=[C:26]([CH3:33])[CH:27]=1
Reactant: Cc1cc(Oc2ccc(NC(=O)COc3ccc(CC4SC(=O)NC4=O)cc3)c(N(C)C(=O)OC(C)(C)C)c2)c(C)cc1O
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(Oc2ccc3nc(COc4ccc(CC5SC(=O)NC5=O)cc4)n(C)c3c2)c(C)cc1O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of t-butyl N-{2-[4-(2,4-dioxothiazolidine-5-ylmethyl)phenoxyacetylamino]-5-(4-hydroxy-2,5-dimethylphenoxy)phenyl}-N-methylcarbamate (0.71 g) and 4N hydrogen chloride/dioxane (10 ml) was stirred at room temperature for 17 hours. The solvent of the reaction mixture was evaporated to dryness. To the residue was added ethyl acetate and insoluble product was isolated by filtration and subjected to reversed-phase high performance liquid chromatography using acetonitrile/water=9/11 as the eluant and then treated with 4N hydrogen chloride/ethyl acetate to give the title compound (0.41 g).
Reaction SMILES: [N:1]1[N:2]2[CH2:16][CH2:15][CH2:14][C:3]2=[CH:4][C:5]=1[NH:6]C(=O)OC(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[N:1]1[N:2]2[CH2:16][CH2:15][CH2:14][C:3]2=[CH:4][C:5]=1[NH2:6]
Reactant: CC(C)(C)OC(=O)Nc1cc2n(n1)CCC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cc2n(n1)CCC2
Reaction time: 5 h

Procedure:
To a solution of 162b (45 mg, 0.20 mmol) in dichloromethane (1.5 mL) was added trifluoroacetic acid (1 mL) at room temperature. The solution was stirred for 5 h. It was then concentrated under reduced pressure to afford 162c which was used in the next step without further purification. MS-ESI: [M+H]+ 124.3
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:25]>O1CCOCC1>[ClH:25].[ClH:25].[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc3ccccc3n2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc2nc(NC3CCNCC3)ccc2c1

Procedure:
A solution of 4-(quinolin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.00 g, 3.05 mmol) in 4 M HCl in dioxane (100 mL) was stirred at rt for 1 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 228.6 [M+H]+.
Reaction SMILES: C(OC([NH:8][C:9]([C:11]1[CH:53]=[CH:52][C:14]([C:15]([NH:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][N:23]([CH:26]([C:44]3[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=3)[CH2:27][C:28]([O:30]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:29])[C:22](=[O:50])[C:21]2=[O:51])=[O:16])=[CH:13][CH:12]=1)=[NH:10])=O)(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[C:9]([C:11]1[CH:12]=[CH:13][C:14]([C:15]([NH:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][N:23]([CH:26]([C:44]3[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=3)[CH2:27][C:28]([OH:30])=[O:29])[C:22](=[O:50])[C:21]2=[O:51])=[O:16])=[CH:52][CH:53]=1)(=[NH:8])[NH2:10]
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(C(=O)NCCN2CCN(C(CC(=O)OC(c3ccccc3)c3ccccc3)c3cccnc3)C(=O)C2=O)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)c1ccc(C(=O)NCCN2CCN(C(CC(=O)O)c3cccnc3)C(=O)C2=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.8 %

Procedure:
To a mixture of 0.1 g of diphenylmethyl 3-[4-[2-(4-tert-butoxycarbonylamidinobenzoyl)aminoethyl]-2,3-dioxopiperazin-1-yl]-3-(pyridin-3-yl)propionate and 1 ml of anisole was added 2 ml of trifluoroacetic acid, and the resulting mixture was stirred at room temperature for 3 hours. Then, the solvent was distilled off under reduced pressure and 2 ml of ethyl acetate, 1 ml of water and 1 ml of acetonitrile were added to the residue. To the resulting mixture was added 0.023 g of sodium hydrogencarbonate, followed by stirring at room temperature for 10 minutes. Thereafter, the aqueous layer was separated and then concentrated to a volume of about 0.5 ml under reduced pressure. The resulting concentrate was purified by a reversed phase column chromatography (eluent: a 10% aqueous acetonitrile solution) to obtain 0.02 g of 3-[4-[2-(4-amidinobenzoyl)aminoethyl]-2,3-dioxopiperazin-1-yl]-3-(pyridin-3-yl)propionic acid as colorless crystals.
Reaction SMILES: [C:1]([C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:19]=[CH:18][C:11]([O:12][CH:13]([CH3:17])[C:14]([OH:16])=O)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2].[CH:22]1([N:28]=[C:29]=[N:30]C2CCCCC2)[CH2:27][CH2:26][CH2:25]C[CH2:23]1.NC1C=CC=C(C)N=1>ClCCl>[CH3:23][C:22]1[N:28]=[C:29]([NH:30][C:14](=[O:16])[CH:13]([O:12][C:11]2[CH:10]=[CH:9][C:8]([O:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:21][CH:20]=3)=[CH:19][CH:18]=2)[CH3:17])[CH:25]=[CH:26][CH:27]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC(Oc1ccc(Oc2ccc(C#N)cc2)cc1)C(=O)O
Agent: Cc1cccc(N)n1
Solvent: ClCCl
Product: Cc1cccc(NC(=O)C(C)Oc2ccc(Oc3ccc(C#N)cc3)cc2)n1
Temperature: 0 °C
Yield: 58.3 %

Procedure:
To 100 ml of dichloromethane solution containing 1.99 g of 2-[4-(4-cyanophenoxy)-phenoxy]-propionic acid, which was cooled with ice water, was added slowly 1,46 g of dicyclohexylcarbodiimide with stirring. After this mixture was stirred for 15 minutes, 0.76 g of 2-amino-6-methylpyridine was added thereinto with stirring. A temperature of reacting mixture was returned to room temperature with stirring. A precipitated solid was removed through filtration, and then the obtained solution was poured into 200 ml of chilled water. An organic layer was separated therefrom, and it was washed with dilute hydrochloric acid, saturated aqueous solution of sodium bicarbonate and saturated aqueous solution of sodium chloride in this order, from which the solvent was distilled away after drying. The residue was purified through a column-chromatography [silica gel, developed with benzene/ethyl acetate=10/1(V/V)] to give 1.53 g of the title compound having melting point of 109°-111° C.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:9].[CH3:10][C:11]1[CH:16]=[CH:15][N+:14]([CH2:17][CH2:18][OH:19])=[CH:13][CH:12]=1>C(O)C>[I-:9].[CH2:13]([N:14]([C:5]1[CH:6]=[CH:7][C:2](/[CH:1]=[CH:10]/[C:11]2[CH:16]=[CH:15][N+:14]([CH2:17][CH2:18][OH:19])=[CH:13][CH:12]=2)=[CH:3][CH:4]=1)[CH2:17][CH2:18][OH:19])[CH3:12]
Reactant: Cc1cc[n+](CCO)cc1
Reactant: O=Cc1ccccc1
Agent: [I-]
Solvent: CCO
Product: CCN(CCO)c1ccc(/C=C/c2cc[n+](CCO)cc2)cc1
Yield: 67 %

Procedure:
Following the procedure of Example 6, equimolar amounts of 4-N-ethyl-N-hydroxyethylamino)benzaldehyde, prepared according to Example 2, and 4-methyl-N-(2-hydroxyethyl)pyridinium iodide, prepared according to Example 4, were reacted in ethanol at reflux, overnight. Upon cooling, dye3 precipitated as a red solid and was collected by filtration, washed, and dried. Yield: 67%. 1H-NMR (DMSO)-d6): δ 1.0 (t, 3H), 3.3 (q, 2H), 3.40 (q, 2H), 3.50 (t, 2H), 3.80 (q, 2H), 4.40 (t, 2H), 4.70 (t, 1H), 5.2 (t, 1H), 6.7 (d, 2H), 7.1 (d, 1H), 7.80 (d, 2H), 7.90 (d, 1H), 8.10 (d, 2H), 8.70 (d, 2H) ppm. The elements analy. calcd. for C19H25IN2O2: C, 51.8; H, 5.7; N, 6.4; Found: C, 51.5; H, 5.7; N, 7.1. Td 270° C.