Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([CH2:7][C@H:8]([NH:12][C:13]([CH2:15][NH2:16])=[O:14])[C:9]([OH:11])=[O:10])=[CH:5][CH:6]=1.[C:17](Cl)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O.CC(O)C.C(NCC)C>[NH:16]([C:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH2:15][C:13]([NH:12][C@H:8]([C:9]([OH:11])=[O:10])[CH2:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)=[O:14]
Reactant: NCC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCNCC
Solvent: CC(C)O
Solvent: O
Product: O=C(CNC(c1ccccc1)(c1ccccc1)c1ccccc1)N[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 1 h
Yield: 64.6 %

Procedure:
Production of compound (22) was conducted in substantially the same manner as in step 1 of Example 6. That is, Gly-Phe (manufactured and sold by PEPTIDE INSTITUTE INC., Japan, 1.1 g, 5 mmol) was dissolved in a mixture of 2 ml of H2O, 2 ml of 2-propanol and 1.5 ml of diethylamine, to obtain a solution. To the obtained solution was portionwise added trityl chloride (1.8 g, 6.5 mmol), followed by stirring for one hour. To the resultant reaction mixture was added H2O, to thereby generate a precipitate. The generated precipitate was collected, washed with water and then dissolved into 5 ml of acetic acid, to thereby obtain an acidic solution. The obtained acidic solution was evaporated to dryness under reduced pressure, to thereby obtain 1.5 g of Trt-Gly-Phe.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:20][O:19][C:11]1[CH:10]=[C:9]([C:4]2[C:3]([CH2:2][N:21]3[CH2:26][CH2:25][N:24]([CH2:2][C:3]4[C:4]([C:9]5[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=5)=[N:5][CH:6]=[CH:7][CH:8]=4)[CH2:23][CH2:22]3)=[CH:8][CH:7]=[CH:6][N:5]=2)[CH:14]=[C:13]([O:15][CH3:16])[C:12]=1[O:17][CH3:18]
Reactant: C1CNCCN1
Reactant: COc1cc(-c2ncccc2CCl)cc(OC)c1OC
Product: COc1cc(-c2ncccc2CN2CCN(Cc3cccnc3-c3cc(OC)c(OC)c(OC)c3)CC2)cc(OC)c1OC

Procedure:
3-Chloromethyl-2-(3,4,5-trimethoxyphenyl) pyridine (241 mg) and piperazine (35 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [K].[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH2:18][C:17](=[O:19])[C:16]2[C:11](=[C:12]([C:20]([OH:22])=[O:21])[CH:13]=[CH:14][CH:15]=2)[N:10]=1.[CH2:23](Br)[CH:24]=[CH2:25].CN(C)C=O>O>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH2:18][C:17](=[O:19])[C:16]2[C:11](=[C:12]([C:20]([O:22][CH2:25][CH:24]=[CH2:23])=[O:21])[CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: C=CCBr
Reactant: O=C(O)c1cccc2c1N=C(c1ccccc1Cl)CC2=O
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1cccc2c1N=C(c1ccccc1Cl)CC2=O
Reaction time: 6 h

Procedure:
To 7 grams of the potassium salt of 2-(2-chlorophenyl)-4-quinolone-8-carboxylic acid were added 2 ml of allyl bromide and 200 ml of dimethyl formamide, the mixture was stirred at 70° to 80° C. for 6 hours, and poured into water. The mixture was extracted with chloroform, the solvent was removed from the extract, and the residue was recrystallized from acetone to give 5.6 grams of the title compound, pale yellow needles, melting point 121° C.
Reaction SMILES: [C:1]1([C:7]([CH3:12])=[CH:8]C(O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:20])C=CC=CC=1.C([N:32]([CH2:35]C)CC)C>C1C=CC=CC=1>[CH3:12][C:7]1[C:1]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:35](=[O:20])[NH:32][CH:8]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)CC
Reactant: CC(=CC(=O)O)c1ccccc1
Solvent: c1ccccc1
Product: Cc1c[nH]c(=O)c2ccccc12
Temperature: 25 °C
Yield: 62.9 %

Procedure:
A solution of 3-phenyl-but-2-enoic acid (16.2 g), diphenylphosphoryl azide (27.5 g), and triethylamine (10.1 g) in benzene (100 mL) was stirred for 1 h. After filtration through a silica gel plug washing with benzene and concentration, the residue was dissolved in diphenylmethane (80 mL) and refluxed for 3 h. After cooling to rt, solids were collected through a plug washing with benzene and dried to give 10 g (63%) of the desired 4-methyl-2H-isoquinolin-1-one as a solid. 1H NMR (400 MHz, CD3OD) δ ppm 2.30 (s, 3H), 7.00 (s, 1H), 7.54 (m, 1H), 7.77 (m, 2H), 8.33 (d, J=7.34 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[N:10][C:9]([C:12](O)=[O:13])=[CH:8][CH:7]=1)=[O:5])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>C(COC)OC.O>[OH:13][CH2:12][C:9]1[N:10]=[N:11][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1ccc(C(=O)O)nn1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCOCC1
Solvent: COCCOC
Product: CCOC(=O)c1ccc(CO)nn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 45.5 %

Procedure:
435 mg of 6-(ethoxycarbonyl)pyridazine-3-carboxylic acid was dissolved in 11.0 mL of dimethoxyethane, and 0.424 mL of 4-methylmorpholine and 0.531 ml, of isobutyl chloroformate were added thereto at 0° C. After stirring at 0° C. for 2 hours, a suspension of 294 mg of sodium borohydride in water (2.50 mL) was added to the reaction liquid, followed by further stiffing at 0° C. for 20 minutes. To the reaction liquid was added water, followed by extraction with ethyl acetate, and the organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=97:3 to 90:10) to obtain 184 mg of ethyl 6-(hydroxymethyl)pyridazine-3-carboxylate.
Reaction SMILES: NC1C=C(C(C2C=C3C(C(C=CC4C=CC=CC=4)=NN3COCC[Si](C)(C)C)=CC=2)=C)C=CC=1.[C:35]([NH:38][C:39]1[CH:40]=[C:41]([C:45]([C:47]2[CH:55]=[C:54]3[C:50]([C:51]([CH:64]=[CH:65][C:66]4[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=4)=[N:52][N:53]3COCC[Si](C)(C)C)=[CH:49][CH:48]=2)=[CH2:46])[CH:42]=[CH:43][CH:44]=1)(=[O:37])[CH3:36]>C(OCC)(=O)C.CCCCCC>[C:35]([NH:38][C:39]1[CH:40]=[C:41]([C:45]([C:47]2[CH:55]=[C:54]3[C:50]([C:51]([CH:64]=[CH:65][C:66]4[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=4)=[N:52][NH:53]3)=[CH:49][CH:48]=2)=[CH2:46])[CH:42]=[CH:43][CH:44]=1)(=[O:37])[CH3:36]
Reactant: C=C(c1cccc(NC(C)=O)c1)c1ccc2c(C=Cc3ccccc3)nn(COCC[Si](C)(C)C)c2c1
Agent: C=C(c1cccc(N)c1)c1ccc2c(C=Cc3ccccc3)nn(COCC[Si](C)(C)C)c2c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C=C(c1cccc(NC(C)=O)c1)c1ccc2c(C=Cc3ccccc3)n[nH]c2c1

Procedure:
6-(1-(3-Aminophenyl)-vinyl)-3-styryl-1-[2-trimethylsilanyl-ethoxymethyl]-1H-indazole was converted to 6-(1-(3-acetamido-phenyl)-vinyl)-3-styryl-1-[2-trimethylsilanyl-ethoxymethyl]-1H-indazole as described for Example 12(a): Rf sm 0.42, p 0.26 (ethyl acetate-hexane 4:6); FTIR (thin film) 3305, 3059, 2952, 1667, 1608, 1585, 1555, 1486, 1448, 1433, 1369, 1306, 1249, 1076, 912, 859, 836, 748, 693 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.98 (d, 1H, J=8.5 Hz), 7.7-7.4 (m, 9H), 7.35 (m, 2H), 7.26 (dd, 1H, J=1.3, 8.4 Hz), 7.16 (bd, 1H, J=7.8 Hz), 5.75 (s, 2H), 5.62 (s, 1H), 5.61 (s, 1H), 3.66 (t, 2H, J=8.2 Hz), 2.16 (s, 3H), 0.98 (t, 2H, J=8.2 Hz), −0.02 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 169.8, 150.9, 144.6, 143.5, 142.8, 142.0, 139.4, 138.6, 132.9, 130.3, 129.3, 127.9, 125.6, 124.2, 123.7, 122.0, 121.3, 121.0, 117.1, 110.8,68.0,25.8, 19.1, 0.0; HRMS (FAB) [M+Na]/z Calc'd 532.2396, found 532.2410.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:15]([O:17]CC2C=CC(OC)=CC=2)=[O:16])[CH2:4]1)=O.FC(F)(F)C(O)=O.[F:40][C:41]1[CH:46]=[CH:45][C:44]([C:47](=[O:57])[CH2:48][CH2:49][CH2:50][CH:51]2[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)=[CH:43][CH:42]=1>>[F:40][C:41]1[CH:46]=[CH:45][C:44]([C:47](=[O:57])[CH2:48][CH2:49][CH2:50][CH:51]2[CH2:56][CH2:55][N:54]([CH2:1][C@@H:3]3[C@@H:7]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH2:6][N:5]([C@H:14]([CH:27]4[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]4)[C:15]([OH:17])=[O:16])[CH2:4]3)[CH2:53][CH2:52]2)=[CH:43][CH:42]=1
Reactant: O=C(CCCC1CCNCC1)c1ccc(F)cc1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCCC1CCN(C[C@H]2CN([C@@H](C(=O)O)C3CCCCC3)C[C@@H]2c2ccccc2)CC1)c1ccc(F)cc1
Yield: 55.5 %

Procedure:
The title compound was prepared from 2-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, 4-(methoxy)benzyl ester (40 mg, 0.092 mmol, Aldehyde 5) and 4-(4-(4-fluorophenyl)-4-oxo-butyl)piperidine trifluoroacetate (43 mg, 0.119 mmol from Step D) using the procedure described in Example 26, Step F to provide 28 mg (56%) of the title compound. 1H NMR (500 MHz, CD3OD) δ1.15-1.5 (m, 9H), 1.58-2.05 (m, 10H), 2.33-2.35 (m, 1H), 2.49-2.52 (m, 1H), 2.7-2.8 (m, 2H), 2.92-2.94 (m, 1H), 2.95-2.98 (t, 2H, J=7), 3.1-3.13 (m, 1H), 3.3-4.8 (m, 6H), 7.18-7.21 (m, 2H) 7.26-7.29 (m, 1H), 7.31-7.34 (m, 4H), 8.01-8.5 (m, 2H). ESI-MS: 549 (M+H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([OH:15])=O)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.S(Cl)(Cl)=O.CN(C)C=O.[Br:25][C:26]1[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=1>N1C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:32][C:29]4[CH:28]=[CH:27][C:26]([Br:25])=[CH:31][N:30]=4)=[O:15])[CH2:11][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Nc1ccc(Br)cn1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Br)cn1)C1(c2ccc3c(c2)OCO3)CC1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
1-Benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid (2.38 g, 11.5 mmol) was placed in an oven-dried flask under nitrogen. Thionyl chloride (2.5 mL) and N,N-dimethylformamide (0.3 mL) were added and the solution was allowed to stir for 30 minutes at 60° C. The excess thionyl chloride was removed under vacuum and the resulting solid was suspended in 7 mL of anhydrous pyridine. This solution was then slowly added to a solution of 5-bromo-pyridin-2-ylamine (2.00 g, 11.6 mmol) suspended in 10 mL of anhydrous pyridine. The resulting mixture was allowed to stir for 15 hours at 110° C. The mixture was then evaporated to dryness, suspended in 100 mL of dichloromethane, and washed with three 25 mL portions of 1N NaOH. The organic layer was dried over sodium sulfate, evaporated to near dryness, and then purified by silica gel column chromatography utilizing dichloromethane as the eluent to yield the pure product (3.46 g, 83%) ESI-MS m/z calc. 361.2, found 362.1 (M+1)+; Retention time 3.40 minutes. 1H NMR (400 MHz, DMSO-d6) δ 1.06-1.21 (m, 2H), 1.44-1.51 (m, 2H), 6.07 (s, 2H), 6.93-7.02 (m, 2H), 7.10 (d, J=1.6 Hz, 1H), 8.02 (d, J=1.6 Hz, 2H), 8.34 (s, 1H), 8.45 (s, 1H).
Reaction SMILES: C(O)(C)C.[CH3:5][O:6][C:7]([C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)=[O:8].Cl(O)(=O)(=O)=O>[Ir](Cl)Cl.CC1C(C)=C(C)C(C)=C1C.O>[CH3:5][O:6][C:7]([C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][CH2:15][NH:16]2)=[CH:11][CH:10]=1)=[O:8]
Reactant: COC(=O)c1ccc2cccnc2c1
Agent: Cl[Ir]Cl
Agent: CC1=C(C)C(C)C(C)=C1C
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(C)O
Solvent: O
Product: COC(=O)c1ccc2c(c1)NCCC2
Temperature: 85 °C
Reaction time: 17 h

Procedure:
1,2,3,4-Tetrahydro-quinoline-7-carboxylic acid methyl ester was obtained as follows: To a solution of his (pentamethyl-cyclopentadiene iridium dichloride) (32 mg, 0.02 equiv.) in a degassed mixture of isopropanol (9.5 ml) and water (0.5 ml) was added quinoline-7-carboxylic acid methyl ester (374 mg, 2.00 mmol) and perchloric acid (70% in water, 0.02 ml, 0.1 equiv.). The mixture was stirred at 85° C. for 17 hours, then the solvents were evaporated. The residue was purified by flash chromatography (heptane/ethyl acetate gradient), yielding 1,2,3,4-tetrahydro-quinoline-7-carboxylic acid methyl ester as a white solid, 305 mg (80%). MS (ISP): m/e=192.4 (M+H+); δII (300 MHz; CDCl3) 7.23 (1H, d), 7.13 (1H, s), 6.98 (1H, d), 3.86 (3H, s), 2.52 (2H, m), 3.32 (2H, t), 2.79 (2H, t), 1.94 (2H, m).
Reaction SMILES: N1C2C(=NC=CC=2)N([O:10][C:11]([C:13]2[C:17]([CH3:18])=[C:16](/[CH:19]=[C:20]3\[C:21](=[O:41])[NH:22][C:23]4[C:28]\3=[CH:27][C:26]([S:29]([CH2:32][C:33]3[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:40])(=[O:31])=[O:30])=[CH:25][CH:24]=4)[NH:15][C:14]=2[CH3:42])=O)N=1.[N:43]1[CH:48]=[CH:47][C:46]([CH2:49][CH2:50][NH2:51])=[CH:45][CH:44]=1>CC(N(C)C)=O>[N:43]1[CH:48]=[CH:47][C:46]([CH2:49][CH2:50][NH:51][C:11]([C:13]2[C:17]([CH3:18])=[C:16](/[CH:19]=[C:20]3\[C:21](=[O:41])[NH:22][C:23]4[C:28]\3=[CH:27][C:26]([S:29]([CH2:32][C:33]3[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:40])(=[O:31])=[O:30])=[CH:25][CH:24]=4)[NH:15][C:14]=2[CH3:42])=[O:10])=[CH:45][CH:44]=1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)On1nnc2cccnc21
Reactant: NCCc1ccncc1
Solvent: CC(=O)N(C)C
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NCCc1ccncc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [1,2,3]triazolo[4,5-b]pyridin-3-yl ester (100 mg, 0.162 mmol) in DMA (2 mL) was added 2-pyridin-4-yl-ethylamine (39 mg, 2 eq.). The mixture was stirred at rt for 18 hours. The reaction was concentrated, diluted with DCM, washed with sat. NaHCO3 and water, concentrated and triturated with ethanol to give the titled compound as a yellow solid.
Reaction SMILES: [I-].[N:2]1([C:12]([N:14]2[CH:18]=[CH:17][N+](C)=[CH:15]2)=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.ClCCl.N1CC[CH:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:25]C1>C(N(CC)CC)C>[N:2]1([C:12]([N:14]2[CH2:15][CH2:25][CH:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:17][CH2:18]2)=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: C[n+]1ccn(C(=O)N2CCCc3ccccc32)c1
Reactant: CCOC(=O)C1CCNCC1
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CCN(C(=O)N2CCCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
16.5 g of 1-(3,4-dihydroquinolin-1(2H)-ylcarbonyl)-3-methyl-1H-imidazol-3-ium iodide, 224 ml of dichloromethane and 8.45 g of ethyl isonipecotate, followed by 31.22 ml of triethylamine, are introduced into a 500 ml round-bottomed flask. The reaction medium is stirred at ambient temperature for 20 hours. The solvent is evaporated under reduced pressure and the residue is taken up in ethyl acetate and then washed with water. The organic phase is dried over sodium sulfate and the solvent is evaporated under reduced pressure to result in 15.2 g of ethyl 1-(3,4-dihydroquinolin-1(2H)-ylcarbonyl)piperidine-4-carboxylate.
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[C:12]([O:20][CH:21]([O:24][C:25](ON1C(=O)CCC1=O)=[O:26])[CH2:22][CH3:23])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CC(OC)(C)C.CC(C)=O.O>[C:12]([O:20][CH:21]([O:24][C:25]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:26])[CH2:22][CH3:23])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CCC(OC(=O)ON1C(=O)CCC1=O)OC(=O)c1ccccc1
Solvent: O
Solvent: COC(C)(C)C
Solvent: CC(C)=O
Product: CCC(OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1)OC(=O)c1ccccc1

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (472 mg, 3.0 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]propyl benzoate (602 mg, 2.0 nmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 32 (679 mg, 93% yield) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.80-0.95 (br. m, 2H), 0.96 (t, J=7.6 Hz, 3H), 1.15-1.38 (br. m., 3H), 1.60-1.74 (m, 2H), 1.82-1.91 (m, 4H), 2.08 (tt, J=12.0, 3.2 Hz, 1H), 2.76-2.87 (br. m, 2H), 6.78 (t, J=5.6 Hz, 1H), 7.48-7.56 (br. m, 3H), 7.67 (tt, J=7.6, 1.2 Hz, 1H), 7.90-7.95 (m, 2H), 11.96 (br. s, 1H). MS (ESI) m/z 386.12 (M+Na)+; 362.14 (M−H)−.
Reaction SMILES: CN(C)CCCOC1C=CC(C2SC(NC3C=CC=CC=3)=NC=2)=CC=1.[Br:26][C:27]1[CH:28]=[C:29]([C:33]2[S:37][C:36]([NH:38][C:39]3[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=3)=[N:35][CH:34]=2)[CH:30]=[CH:31][CH:32]=1.Cl.Cl[CH2:48][CH2:49][N:50]([CH2:53][CH3:54])[CH2:51][CH3:52]>>[Br:26][C:27]1[CH:28]=[C:29]([C:33]2[S:37][C:36]([NH:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH2:48][CH2:49][N:50]([CH2:53][CH3:54])[CH2:51][CH3:52])=[CH:41][CH:40]=3)=[N:35][CH:34]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: Oc1ccc(Nc2ncc(-c3cccc(Br)c3)s2)cc1
Reactant: CCN(CC)CCCl
Agent: CN(C)CCCOc1ccc(-c2cnc(Nc3ccccc3)s2)cc1
Agent: Cl
Product: CCN(CC)CCOc1ccc(Nc2ncc(-c3cccc(Br)c3)s2)cc1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
The title compound is prepared as described in Example 8 for {5-[4-(3-dimethylamino-propoxy)-phenyl]-thiazol-2-yl}-phenyl-amine but starting from 4-[5-(3-bromo-phenyl)-thiazol-2-ylamino]-phenol and using (2-chloroethyl)-diethylamine hydrochloride. After stirring the reaction mixture for 30 min at 70° C., purification of the crude material by silica gel column chromatography (CH2Cl2/MeOH, 95/5 then 90/10) affords the title compound: ES-MS: 447.9 [M+2]+; single peak at tR=3.77 min (System 2); Rf=0.14 (CH2Cl2/MeOH, 90/10).
Reaction SMILES: CN(C)C=O.C(Cl)(=O)C(Cl)=O.[O:12]=[C:13]1[C:18]([C:19]([OH:21])=O)=[CH:17][C:16]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[N:15][NH:14]1.[Cl:28][C:29]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:30]=1[CH2:31][NH2:32]>ClCCl.C(N(CC)CC)C>[Cl:28][C:29]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:30]=1[CH2:31][NH:32][C:19]([C:18]1[C:13](=[O:12])[NH:14][N:15]=[C:16]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH:17]=1)=[O:21]
Reactant: NCc1ccc(Cl)cc1Cl
Reactant: O=C(O)c1cc(-c2ccncc2)n[nH]c1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(Cl)cc1Cl)c1cc(-c2ccncc2)n[nH]c1=O
Temperature: 19 °C
Reaction time: 3 h

Procedure:
0.02 cm3 of dimethylformamide and then 0.12 cm3 of oxalyl chloride were added to 0.3 g of 3-oxo-6-(pyridin-4-yl)-2,3-dihydropyridazine-4-carboxylic acid prepared as described in patent FR 2 481 284, dissolved in 10 cm3 of dichloromethane. The reaction medium was stirred for 3 hours at 19° C. A further 0.12 cm3 of oxalyl chloride was then added and the mixture was stirred for a further one hour at 19° C. The reaction mixture was then poured onto a solution of 10 cm3 of dichloromethane containing 0.19 cm3 of triethylamine and 0.21 cm3 of 2,4-dichlorobenzylamine. The reaction medium was stirred for 12 hours at 19° C. and then filtered through a sinter funnel, rinsed with 10 cm3 of dichloromethane 10 cm3 of distilled water and with 10 cm3 of aqueous normal hydrochloric acid solution. After drying (10 kPa; 20° C.), 0.25 g of N-(2,4-dichlorobenzyl)-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carboxamide was obtained in the form of a white solid melting at 233° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.Cl.Cl.[CH3:37][N:38]1[CH2:43][CH2:42][N:41]([C:44]2[CH:45]=[C:46]3[C:50](=[CH:51][CH:52]=2)[CH2:49][NH:48][CH2:47]3)[CH2:40][CH2:39]1.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]([OH:11])=[C:6]([C:7]([N:48]2[CH2:47][C:46]3[C:50](=[CH:51][CH:52]=[C:44]([N:41]4[CH2:40][CH2:39][N:38]([CH3:37])[CH2:43][CH2:42]4)[CH:45]=3)[CH2:49]2)=[O:9])[CH:10]=1
Reactant: CN1CCN(c2ccc3c(c2)CNC3)CC1
Reactant: O=C(O)c1cc(Cl)c(O)cc1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc3c(c2)CN(C(=O)c2cc(Cl)c(O)cc2O)C3)CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 5-chloro-2,4-dihydroxy-benzoic acid (176 mg, 0.93 mmol) in DMF (5 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (179 mg, 0.93 mmol) then HOBt (126 mg, 0.93 mmol). After 45 min, the solution of the activated acid was added to a mixture 5-(4-methyl-piperazin-1-yl)-2,3-dihydro-1H-isoindole dihydrochloride (290 mg, 0.78 mmol) and triethylamine (0.28 mL, 2 mmol) then the mixture was stirred at r.t. for 3 h. The solvent was removed in vacuo then the residue was partitioned between ethyl acetate and water (×3). Each extract was washed with saturated sodium bicarbonate solution and brine then dried (MgSO4), combined and concentrated. Some insoluble material remained and this was dissolved in 1N hydrochloric acid and methanol then combined with the organic extracts. The pH was adjusted to 14 with solid sodium hydroxide and the mixture allowed to stand overnight. The pH was adjusted to 7 with 1N hydrochloric acid and the resulting precipitate was filtered off then subjected to purification by preparative HPLC to afford the title compound as a red solid. This was converted to its hydrochloride salt by treatment with 4M HCl in dioxane, concentration in vacuo and trituration with ether which gave a brown solid (91 mg, 27%). 1H NMR (DMSO-d6) 11.10 (1H, br.s), 10.50 (1H, br.s), 7.26-7.15 (2H, m), 7.02-6.93 (2H, m), 6.69 (1H, s), 4.72-4.61 (4H, m), 3.78-3.72 (2H, m), 3.45 (2H, br.s), 3.12 (4H, br.s), 2.78 (3H, s). MS: [M+H]+ 386/388.
Reaction SMILES: Cl.[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])(=[O:15])=[O:14])[CH2:10][NH:9]1)=[O:7])#[N:3].[CH3:23][O:24][CH2:25][C:26](O)=[O:27]>>[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])(=[O:14])=[O:15])[CH2:10][N:9]1[C:26](=[O:27])[CH2:25][O:24][CH3:23])=[O:7])#[N:3]
Reactant: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1
Reactant: COCC(=O)O
Agent: Cl
Product: COCC(=O)N1C[C@H](S(=O)(=O)c2ccccc2Cl)C[C@H]1C(=O)NCC#N

Procedure:
L11. (2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid cyanomethyl-amide hydrochloride from experiment K1 was coupled with methoxy-acetic acid in analogy to experiment A1 to give (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-(2-methoxy-acetyl)-pyrrolidine-2-carboxylic acid cyanomethyl-amide as a colorless foam. MS: 400.1 [M+H]+.
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:6]=[C:5]2[CH2:16][CH2:17][CH2:18][C:4]=12.[CH3:19][NH:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([NH2:30])=[O:29])=[CH:23][CH:22]=1>CN1C(=O)CCC1>[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:4]3=[C:3]([N:20]([CH3:19])[C:21]3[CH:22]=[CH:23][C:24]([CH2:27][C:28]([NH2:30])=[O:29])=[CH:25][CH:26]=3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Reactant: CNc1ccc(CC(N)=O)cc1
Agent: Cl
Solvent: CN1CCCC1=O
Product: CN(c1ccc(CC(N)=O)cc1)c1cc(-c2cccc(Cl)c2)nc2c1CCC2
Yield: 15.3 %

Procedure:
A mixture of 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.060 g, 0.20 mmol) and 2-(4-(methylamino)phenyl)acetamide (0.066 g, 0.40 mmol) in NMP (3 mL) was microwaved for 3 h at 140° C. After this time, the mixture was purified by silica gel chromatography followed by preparative HPLC to afford the title compound (0.012 g, 15%) as a white solid. MW=391.89. 1H NMR (DMSO-d6, 500 MHz) δ 14.18 (br s, 1H), 8.10 (s, 1H), 7.94 (d, J=7.5 Hz, 1H), 7.70-7.66 (m, 2H), 7.55 (br s, 7.37-7.27 (m, 5H), 6.92 (br s, 1H), 3.57 (s, 3H), 3.01 (t, J=7.1 Hz, 2H), 1.96-1.85 (m, 4H); ESI MS m/z 392 [M+H]+.