Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[N:5]=[N:6][C:7]2[C:12]([C:13]=1Cl)=[CH:11][CH:10]=[CH:9][CH:8]=2.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(O)C=CC=CC=1>C(Cl)(Cl)Cl>[CH2:15]([N:22]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[N:5][C:4]=2[CH:3]=[CH:2]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClCCc1nnc2ccccc2c1Cl
Reactant: NCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: Oc1ccccc1
Product: c1ccc(Cn2ccc3nnc4ccccc4c32)cc1

Procedure:
3-(2-Chloroethyl)-4-chlorocinnoline (2 g, 0.0088 mol), benzylamine (4 g, 0.037 mol) and phenol (2 g, 0.0212 mol) were heated in an oil bath at 160° for 20 hours. The reaction had not gone to completion so the temperature was raised to 190° for a further 6 hours. The reaction mixture was dissolved in chloroform (300 ml) and extracted with 2N sodium hydroxide (3×100 ml). The chloroform extracts were washed with water (100 ml), dried over magnesium sulphate, filtered and evaporated under reduced pressure to give an oil. The oil was purified by chromatography using chloroform as eluant. The fractions containing the product were combined and evaporated to dryness to give a brown solid. Recrystallization from isopropyl alcohol gave the title compound, 0.5 g, m.p. 190-192°.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10](OC(=O)C)(=[O:12])[CH3:11].[N:17]1([CH2:22][C:23]([NH:25][C@@H:26]([CH2:44][CH2:45][CH2:46][NH2:47])[C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)=[CH:32][CH:31]=2)=[O:28])=[O:24])[CH:21]=[N:20][CH:19]=[N:18]1>C1COCC1>[N:17]1([CH2:22][C:23]([NH:25][C@@H:26]([CH2:44][CH2:45][CH2:46][NH:47][C:10](=[O:12])[CH3:11])[C:27]([NH:29][C:30]2[CH:31]=[CH:32][C:33]([O:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)=[CH:34][CH:35]=2)=[O:28])=[O:24])[CH:21]=[N:20][CH:19]=[N:18]1
Reactant: CC(=O)OC(C)=O
Reactant: NCCC[C@H](NC(=O)Cn1cncn1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCCC[C@H](NC(=O)Cn1cncn1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reaction time: 2 h
Yield: 27.1 %

Procedure:
Step (b) DIEA (0.10 mL, 0.57 mmol) and acetic anhydride (0.025 mL, 0.27 mmol) was added to (S)-2-(2-(1H-1,2,4-triazol-1-yl)acetamido)-5-amino-N-(4-(4-fluorophenoxy)phenyl)pentanamide (115 mg, 0.269 mmol) in THF (5 mL). The reaction mixture was stirred for 2 hours and then concentrated. Product was purified from the residue by reverse phase HPLC to give Compound 254, (S)-2-(2-(1H-1,2,4-triazol-1-yl)acetamido)-5-acetamido-N-(4-(4-fluorophenoxy)phenyl)pentanamide (34 mg, 0.073 mmol, 27%) as an off-white solid. 1H-NMR (400 MHz, DMSO-d6): 10.21 (s, 1H), 8.75-8.73 (m, 1H), 8.47 (s, 1H), 7.85-7.82 (m, 1H), 7.63-7.58 (m, 2H), 7.24-7.18 (m, 2H), 7.04-6.92 (m, 4H), 4.99 (s, 2H), 4.46-4.38 (m, 1H), 3.12-3.01 (m, 2H), 1.80 (s, 3H), 1.79-1.37 (m, 4H). MS (EI) for C23H25FN6O4. found 469.1 (MH+).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:12]=[C:11]([C:13]3[C:14]([C:22]4[N:23]=[C:24]([CH3:27])[S:25][CH:26]=4)=[N:15][N:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])CCC.C(Cl)(Cl)(Cl)[Cl:34]>O1CCCC1>[Cl:34][C:21]1[N:16]2[N:15]=[C:14]([C:22]3[N:23]=[C:24]([CH3:27])[S:25][CH:26]=3)[C:13]([C:11]3[CH:10]=[CH:9][N:8]=[C:7]([NH:6][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[CH:12]=3)=[C:17]2[CH:18]=[CH:19][CH:20]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: Cc1nc(-c2nn3ccccc3c2-c2ccnc(NC3CCCC3)c2)cs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1nc(-c2nn3c(Cl)cccc3c2-c2ccnc(NC3CCCC3)c2)cs1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A solution of N-cyclopentyl-4-[2-(2-methyl-1,3-thiazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyridinamine (138 mg, 0.37 mmol) in tetrahydrofuran (10 mL) was cooled to −78° C. n-Butyl lithium (1.6M in hexanes, 0.75 mL, 1.22 mmol) was added dropwise. After stirring at −78° C. for 20 minutes, carbon tetrachloride (1 mL) was added to the solution. The reaction was stirred for another 20 minutes at −78° C. and subsequently quenched with water. The reaction mixture was warmed to room temperature and extracted with ethyl acetate. The organics were combined and washed with water, brine and dried over magnesium sulfate. Filtration and concentration, followed by flash chromatography (1:19 methanol/dichloromethane) gave 4-[7-chloro-2-(2-methyl-1,3-thiazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyridinamine as a brown oil.
Reaction SMILES: [CH2:1]=[C:2]([CH:10]([OH:15])[C:11]([Cl:14])([Cl:13])[Cl:12])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4].[C:16](OC(=O)C)(=[O:18])[CH3:17].CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.C([O-])(=O)C.[Na+]>C([O-])(=O)C.[Na+].C(O)(=O)C>[CH2:1]=[C:2]([CH:10]([O:15][C:16](=[O:18])[CH3:17])[C:11]([Cl:14])([Cl:13])[Cl:12])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4]
Reactant: C=C(C(=O)OCCCC)C(O)C(Cl)(Cl)Cl
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: C=C(C(=O)OCCCC)C(OC(C)=O)C(Cl)(Cl)Cl
Temperature: 120 °C
Yield: 91.4 %

Procedure:
To 1173.0 g of butyl 2-methylene-3-hydroxy-4,4,4-trichlorobutyrate (91% pure) charged in a 2-liter, 3-neck round bottom flask equipped with a mechanical stirrer, thermometer, and a condenser were added 520.0 g of acetic anhydride and 7.0 g of sodium acetate. The reaction mixture was heated at 120° C. for three hours. Unreacted acetic to anhydride and formed acetic acid were stripped off under vacuum at <80° C./0.6 mm Hg. After cooling to room temperature, the solid sodium acetate that had settled to the bottom of the flask was separated. 1236.1 g of acetylated product was obtained, 91.3% purity (GC analysis), 91.4% yield. The product structure was confirmed by NMR spectroscopy.
Reaction SMILES: C([NH:9][C:10]([NH:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][C:22]([C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:26][CH:25]=2)=[O:23])[CH2:15][CH2:14]1)=[O:11])(=O)C1C=CC=CC=1.[OH-].[Na+].C(O)C>O>[NH:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24]([C:22](=[O:23])[CH2:21][CH2:20][CH2:19][N:16]2[CH2:15][CH2:14][CH:13]([NH:12][C:10]([NH2:9])=[O:11])[CH2:18][CH2:17]2)=[CH:25]1
Reactant: O=C(NC(=O)c1ccccc1)NC1CCN(CCCC(=O)c2c[nH]c3ccccc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NC(=O)NC1CCN(CCCC(=O)c2c[nH]c3ccccc23)CC1

Procedure:
1-Benzoyl-3-[1-(4-[3-indolyl]-4-oxobutyl)piperid-4-yl]urea free base (2.9g), sodium hydroxide (0.54g), ethanol (15ml) and water (5ml) were refuxed for two hours and then poured into cold water, the precipitated solid was filtered off and crystallised from ethanol to give 1-[1-(4-[3-indolyl]-4-oxobutyl)piperid-4-yl]urea.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]([CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=1)[S:5]([CH3:8])(=[O:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].[C:26]([O:30][C:31]([N:33]1[CH2:40][CH:39]2[O:41][CH:35]([CH2:36][NH:37][CH2:38]2)[CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>C(#N)C>[C:26]([O:30][C:31]([N:33]1[CH2:34][CH:35]2[O:41][CH:39]([CH2:38][N:37]([CH2:2][CH2:3][N:4]([CH2:9][CH2:10][O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=3)[S:5]([CH3:8])(=[O:7])=[O:6])[CH2:36]2)[CH2:40]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CS(=O)(=O)N(CCBr)CCOc1ccc(C#N)cc1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C1)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC2CN(CCN(CCOc3ccc(C#N)cc3)S(C)(=O)=O)CC(C1)O2

Procedure:
To a suspension of N-(2-bromoethyl)-N-[2-(4-cyanophenoxy)ethyl]methane-sulfonamide (6 g, 0.019 mol; see Preparation C above) and anhydrous potassium carbonate (3.6 g, 0.026 mol) in dry acetonitrile (100 mL) was added 9-oxa-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (4.35 g, 0.019 mol; see WO 01/28992), and the resultant mixture was then stirred at 50-55° C. overnight. After completion of the reaction (as determined by TLC), the mixture was filtered and concentrated. The crude product was further purified by column chromatography (silica gel: 60-120 mesh, eluent: chloroform-methanol, 99:1). Yield: 4.2 g (46%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:33])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([C:20]2[S:21][C:22]([CH2:26][N:27]3[CH2:32][CH2:31][S:30][CH2:29][CH2:28]3)=[CH:23][C:24]=2[Cl:25])=[O:19])=[CH:4][CH:3]=1.S([O-])(O[O-])(=O)=[O:35].[K+].[K+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:33])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([C:20]2[S:21][C:22]([CH2:26][N:27]3[CH2:28][CH2:29][S:30](=[O:35])[CH2:31][CH2:32]3)=[CH:23][C:24]=2[Cl:25])=[O:19])=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(Cl)cc1)c1cc(Cl)ccc1NC(=O)c1sc(CN2CCSCC2)cc1Cl
Reactant: O=S(=O)([O-])O[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(Nc1ccc(Cl)cc1)c1cc(Cl)ccc1NC(=O)c1sc(CN2CCS(=O)CC2)cc1Cl
Reaction time: 0.08 h
Yield: 57.5 %

Procedure:
To a suspension of N-(4-chlorophenyl)-2-[((3-chloro-5-(thiomorpholin-4-yl)methylthiophen-2-yl)carbonyl)amino]-5-chlorobenzamide (0.1 g, 0.2 mmol) in methanol (20 mL) at 0° C. was added a solution of potassium peroxymonosulfate (0.13 g, 0.2 mmol) in water (5 mL). After 5 minutes, the reaction was quenched by addition of aqueous 5% sodium bisulfite solution. The mixture was extracted with methylene chloride/methanol, and the organic phase dried over Na2SO4 and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 0.064 g (62% yield) of N-(4-chlorophenyl)-2-[((3-chloro-5-(1-(oxo)thiomorpholin-4-yl)methylthiophen-2-yl)carbonyl)amino]-5-chlorobenzamide, as a pale yellow powder; NMR (DMSO-d6/TFA) 11.2 (s, 1), 10.7 (s, 1), 8.3 (d, 1), 7.9 (s, 1), 7.7 (m, 2), 7.6 (m, 1), 7.4 (m, 3) 4.7 (s, 2), 3.7 (m, 2), 3.5 (m. 2), 2.9 (br s, 4) ppm.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:12])OCCl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][C:14]1[C:35]([Cl:36])=[CH:34][C:17]([C:18]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[CH2:23][CH2:22]2)=[O:19])=[C:16]([O:37][CH3:38])[CH:15]=1>C(O)C>[NH2:13][C:14]1[C:35]([Cl:36])=[CH:34][C:17]([C:18]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH:28]3[CH2:29][CH2:30][N:31]([C:8](=[O:12])[NH:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:32][CH2:33]3)[CH2:23][CH2:22]2)=[O:19])=[C:16]([O:37][CH3:38])[CH:15]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NC1CCN(CC2CCNCC2)CC1
Reactant: O=C(Nc1ccccc1)OCCl
Solvent: CCO
Product: COc1cc(N)c(Cl)cc1C(=O)NC1CCN(CC2CCN(C(=O)Nc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 7 h
Yield: 81 %

Procedure:
To a solution of chloromethyl N-phenylcarbamate (220 mg), which is prepared by the method disclosed in Synth. Commun., 1996, 26, 4253, in ethanol (20 ml) is added dropwise a solution of 4-amino-5-chloro-2-methoxy-N-[1-(4-piperidinylmethyl)-4-piperidinyl]benzamide (910 mg) in ethanol (10 ml) at room temperature, and the mixture is stirred at room temperature for 7 hours. The mixture is concentrated to dryness under reduced pressure, and the residue is dissolved in chloroform, washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (eluent; chloroform:methanol=30:1) to give the desired compound (480 mg) as white amorphous.
Reaction SMILES: [CH2:1]([C:3]1[CH:19]=[CH:18][C:6]([CH2:7][NH:8][C:9]2[CH:17]=[CH:16][C:12]3[N:13]=[CH:14][NH:15][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1)[CH3:2].[N:20]1[S:21][N:22]=[C:23]2[CH:28]=[CH:27][C:26]([CH2:29]Br)=[CH:25][C:24]=12.C([O-])([O-])=O.[K+].[K+]>>[CH2:1]([C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]([CH2:29][C:26]2[CH:27]=[CH:28][C:23]3[C:24]([CH:25]=2)=[N:20][S:21][N:22]=3)[C:9]2[CH:17]=[CH:16][C:12]3[NH:13][CH:14]=[N:15][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: BrCc1ccc2nsnc2c1
Reactant: CCc1ccc(CNc2ccc3nc[nH]c3c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1ccc(CN(Cc2ccc3nsnc3c2)c2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized starting from N-(4-ethylbenzyl)benzimidazol-5-amine (251 mg; 1 mmol; 1 eq.), (benzo-[c][1,2,5]-thiadiazol-6-yl)methylbromide (252 mg; 1.1 mmol; 1.1 eq.) and K2CO3 (152 mg; 1.1 mmol; 1.1 eq.) according to method 6; Yield: 0.115 g (28.8%); MS m/z: 400.2 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 1.14 (t, 3H, 3J=7.6 Hz); 2.55 (q, 2H, 3J=7.6 Hz); 4.73 (s, 2H); 4.87 (s, 2H); 6.77-6.81 (m, 2H); 7.15 (d, 2H, 3J=7.9 Hz); 7.22 (d, 2H, 3J=7.9 Hz), 7.34 (d, 1H, 3J=8.5 Hz); 7.69 (dd, 1H, 4J=1.5 Hz, 3J=9.2 Hz); 7.85 (s, 1H); 7.90 (s, 1H); 8.05 (d, 1H, 3J=8.9 Hz), 11.93 (br s, 1H); HPLC (METHOD [A]): rt 17.72 min (96.4%)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=2[F:19])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:21][C:22]1[N:23]=[C:24]([CH3:30])[NH:25][C:26]=1[C:27](O)=[O:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:21][C:22]1[N:23]=[C:24]([CH3:30])[NH:25][C:26]=1[C:27]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=2[F:19])[C:4]=1[F:20])=[O:28]
Reactant: N#Cc1ccc(Oc2c(Cl)ccc(CN)c2F)c(F)c1
Reactant: Cc1nc(Cl)c(C(=O)O)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3ccc(C#N)cc3F)c2F)[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 22.1 %

Procedure:
To a solution of 4-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-3-fluorobenzonitrile (40.0 mg, 0.136 mmol), 4-chloro-2-methyl-1H-imidazole-5-carboxylic acid (21.79 mg, 0.136 mmol) and HATU (51.6 mg, 0.136 mmol) in DMF (3 ml) was added diisopropylethyl amine (0.047 ml, 0.271 mmol) and the reaction mixture was stirred at rt for 15 minutes. The reaction mixture was purified via reverse phase HPLC and neutralized to give 4-chloro-N-({4-chloro-3-[(4-cyano-2-fluorophenyl)oxy]-2-fluorophenyl}methyl)-2-methyl-1H-imidazole-5-carboxamide (13 mg, 0.030 mmol, 22% yield) 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.73 (d, 1H), 7.47 (d, 1H), 7.29-7.42 (m, 2H), 6.87 (t, 1H), 4.52-4.73 (m, 2H), 2.34 (s, 3H). LC-MS (ES+) m/z 437.11, [M+H].
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:41]=[CH:42][CH:43]=1)[C:8]([NH:10][C:11]1[S:12][C:13]2[CH2:40][CH2:39][CH2:38][CH2:37][C:14]=2[C:15]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)=[O:17])=[O:9])(=[O:4])=[O:3].Cl.[NH2:45][CH2:46][CH2:47][CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50].C(N(CC)CC)C>ClCCl>[CH2:52]([O:51][C:49](=[O:50])[CH2:48][CH2:47][CH2:46][NH:45][S:2]([C:5]1[CH:6]=[C:7]([CH:41]=[CH:42][CH:43]=1)[C:8]([NH:10][C:11]1[S:12][C:13]2[CH2:40][CH2:39][CH2:38][CH2:37][C:14]=2[C:15]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)=[O:17])=[O:9])(=[O:4])=[O:3])[CH3:53]
Reactant: CCOC(=O)CCCN
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(S(=O)(=O)Cl)c4)sc4c3CCCC4)cc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCCNS(=O)(=O)c1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.1 %

Procedure:
A mixture of 600 mg of methyl 4-[2-(4-{[(2-{[3-(chlorosulfonyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate, 394 mg of ethyl 4-aminobutyrate hydrochloride, 0.27 mL of triethylamine, and 6.0 mL of dichloromethane was stirred at room temperature for 2 hours. The reaction mixture was purified by silica gel column chromatography (hexane-chloroform) to obtain 442 mg of methyl 4-{2-[4-({[2-({3-[(4-ethoxy-4-oxobutyl)sulfamoyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoate as a pale yellow solid.
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9](=[O:18])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.COC(=O)[C@@H]1CCCN1C(=O)CC1C=CC=CC=1>>[C:12]1([CH2:11][CH2:10][C:9]([N:5]2[CH2:6][CH2:7][CH2:8][C@H:4]2[CH2:3][OH:2])=[O:18])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)[C@@H]1CCCN1C(=O)CCc1ccccc1
Agent: COC(=O)[C@@H]1CCCN1C(=O)Cc1ccccc1
Product: O=C(CCc1ccccc1)N1CCC[C@H]1CO

Procedure:
Instead of N-(3-phenylpropionyl)-proline methyl ester, (a) N-phenylacetyl-proline methyl ester (Compound No. 2), (b) N-(4-phenyl-n-butyryl)-proline methyl ester (Compound No. 6) and (c) N-(5-phenyl-n-valeryl)-proline methyl ester were used as starting compounds and treated by the procedures described above to obtain the following end compounds as oil: ##STR11##
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].Br[CH2:13][CH2:14]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:8]1[C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([C:9](=[O:11])[CH3:10])[C:2]=2[O:1][CH2:14][CH2:13]1
Reactant: BrCCBr
Reactant: CC(=O)c1cccc(O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1cccc2c1OCCO2

Procedure:
Prepared by reacting 1-(2,3-dihydroxy-phenyl)-ethanone with 1,2-dibromoethane in the presence of potassium carbonate in N,N-dimethylformamide at 100° C.
Reaction SMILES: [CH:1]1[C:18]2=[C:19]3[C:8]([C:9]4[C:20]5[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=5)[CH:12]=[CH:11][CH:10]=4)=[CH:7][CH:6]=[C:5]2[C:21](O[C:24](=[O:25])[C:3](=[C:4]23)[CH:2]=1)=[O:22].[NH2:26][CH2:27][CH2:28][OH:29].N1C=CN=C1.C(C(N1C(=O)C2C3C4C(=CC=2)C2C5C(C=CC=2)=CC=CC=5C=4C=CC=3C1=O)CCCCCC)CCCCC>>[OH:29][CH2:28][CH2:27][N:26]1[C:24](=[O:25])[C:3]2[C:4]3[C:19]4[C:18](=[CH:1][CH:2]=2)[C:17]2[C:20]5[C:13]([CH:14]=[CH:15][CH:16]=2)=[CH:12][CH:11]=[CH:10][C:9]=5[C:8]=4[CH:7]=[CH:6][C:5]=3[C:21]1=[O:22]
Reactant: NCCO
Reactant: O=C1OC(=O)c2ccc3c4cccc5cccc(c6ccc1c2c63)c54
Agent: CCCCCCC(CCCCCC)N1C(=O)c2ccc3c4cccc5cccc(c6ccc(c2c36)C1=O)c54
Agent: c1c[nH]cn1
Product: O=C1c2ccc3c4cccc5cccc(c6ccc(c2c36)C(=O)N1CCO)c54

Procedure:
190 mg (0.56 mmol) of perylene-3,4-dicarboxylic anhydride are reacted with 0.85 ml (1.40 mmol) of 2-aminoethanol and 1.18 g of imidazole under an argon inert atmosphere for 96 h as in 2c, and the reaction product is worked up and dried in a drying cabinet. To remove unreacted starting material, it is boiled in 10 per cent potassium carbonate solution and washed with hot water until the filtrate run-off is colourless. The brown-red product is dried in a drying cabinet at 120° C. and then recrystallized by extraction with toluene. Yield 50 mg (23%), m.p. >260° C. UV (CHCl3): λmax =489 nm, 509. Fluorescence (CHCl3, exc. 489 nm) λmax (Irel =546 nm (1), 579 (sh, 0.46).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([NH:18]C(=O)OC(C)(C)C)[CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=2)[CH2:4][CH2:3]1.N1(C2C=C(NC(=O)OC(C)(C)C)C=C(C(F)(F)F)C=2)CCOCC1>>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[C:10]([NH2:18])[CH:11]=[C:12]([C:14]([F:17])([F:15])[F:16])[CH:13]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2cc(NC(=O)OC(C)(C)C)cc(C(F)(F)F)c2)CC1
Agent: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)cc(C(F)(F)F)c1
Product: CN1CCN(c2cc(N)cc(C(F)(F)F)c2)CC1

Procedure:
Utilising the procedure described in Example 90c, but employing [3-(4-methyl-1-piperazinyl)-5-(trifluoromethyl)phenyl]-carbamic acid, 1,1-dimethylethyl ester (Example 94a) in lieu of [3-(4-morpholinyl)-5-(trifluoromethyl)phenyl]-carbamic acid, 1,1-dimethylethyl ester, afforded the title compound as oil. 1H-NMR (400 MHz, DMSO-d6): 2.20 (s, 3H), 2.42 (m, 4H), 3.07 (m, 4H), 3.32 (br s, 2H), 5.34 (s, 1H) and 6.31 (s, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].[F-].[Cs+].S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:17][C@H:18]1[O:20][CH2:19]1)(=O)=O.O>CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:17][C@H:18]1[O:20][CH2:19]1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Reactant: O=[N+]([O-])c1ccccc1O
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1OC[C@@H]1CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
2-Nitrophenol (0.92 g, 6.6 mmol) was dissolved in 5 ml anhydrous DMF. Cesium fluoride (3.02 g, 19.9 mmol) was added to the reaction. The reaction mixture was stirred for 1 hour at room temperature and (S)-glycidyl nosylate (1.71 g, 6.6 mmol) was added. The reaction was stirred for 16 hours at room temperature. Water (150 ml) was added, and the solution was extracted with ethylacetate. The organic phase was dried over MgSO4 and evaporated. The residue was purified with column chromatograph using ethylacetate:hexane (50:50) solvent to give (S)-glycidyl o-nitrophenyl ether (1.21 g, 90% yield, m.p. 46-47° C.) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([CH:10]=[O:11])=[CH:8][CH:7]=[CH:6][N:5]2[CH:12]=1.[K+].[Br-:14]>>[Br:14][C:12]1[N:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH:10]=[O:11])[C:4]2=[N:3][C:2]=1[CH3:1]
Reactant: Cc1cn2cccc(C=O)c2n1
Reactant: [Br-]
Agent: [K+]
Product: Cc1nc2c(C=O)cccn2c1Br

Procedure:
From 4b (yield: 68%); mp 137-139° C.; IR (KBr) 1695, 1541 cm−1; 1H NMR (400 MHz, CDCl3) δ 2.55 (s, 3H), 7.08 (t, 1H, J=7 Hz), 7.87 (d, 1H, J=7 Hz), 8.30 (d, 1H, J=7 Hz), 10.72 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 13.7, 94.6, 112.3, 123.3, 126.8, 128.4, 143.6, 143.7, 188.3; MS m/z 240 (M++2, 66), 238 (M+, 67), 212 (98), 210 (100), 131 (77), 104 (73), 78 (33), 51 (40).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.[CH2:14]([O:21][CH2:22][C:23](O)=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH3:1][O:2][C:3](=[O:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:23](=[O:24])[CH2:22][O:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][CH:7]=1
Reactant: O=C(O)COCc1ccccc1
Reactant: COC(=O)COc1ccc(N)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COC(=O)COc1ccc(NC(=O)COCc2ccccc2)cc1
Reaction time: 12 h
Yield: 68.7 %

Procedure:
To a mixture of (4-aminophenoxy)-acetic acid methyl ester 3 (20 g, 110.5 mmol) and benzyloxy acetic acid (20.4 g, 123 mmol) in anhydrous dichloromethane (200 ml) under nitrogen atmosphere was added dropwise a solution of 1,3-dicyclohexyl carbodiimide (63.2 g, 306 mmol) in anhydrous dichloromethane (80 ml) then stirred at room temp. for 12 hours. The solids were filtered off, the dichloromethane was washed with 5% sodium bicarbonate solution (100 ml), water (100 ml) added, and the solids dried over sodium sulphate and distilled to get crude 49. Crude 49 was purified by column chromatography on silica gel using benzene as eluant to get pure 49 (25 g, 68.9%) as a white powder with an m.p. between 76-77.5° C.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15]3[C:16]([NH2:21])=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N=CO[CH2:25][NH:26][C:27](=[O:30])[O:28][CH3:29].C(O)(=O)C>ClC(Cl)Cl>[C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[NH:21][C:25]3=[N:26][C:27](=[O:30])[O:28][CH3:29])[CH2:10][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)NCOC=N
Reactant: Nc1ccccc1NC1CCN(Cc2ccccc2)CC1
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COC(=O)N=c1[nH]c2ccccc2n1C1CCN(Cc2ccccc2)CC1

Procedure:
A mixture of 5 parts of N-[1-(phenylmethyl)-4-piperidinyl]-1,2-benzenediamine, 2.35 parts of methyl (iminomethoxymethyl)carbamate, 5 parts of acetic acid and 75 parts of trichloromethane is stirred and refluxed for 48 hours. The reaction mixture is evaporated and the residue is taken up in water. The solution is neutralized with ammonium hydroxide solution. The precipitated product is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 1.75 parts of methyl {1,3-dihydro-1-[1-(phenylmethyl)-4-piperidinyl]-2H-benzimidazol-2-ylidene}carbamate; mp. 169.7° C.