Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[CH:5]=[C:4]([Cl:11])[C:3]=1[Cl:12].C1COCC1.CCN(C(C)C)C(C)C.Cl[CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33]>CCOC(C)=O>[Cl:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])[C:6]=2[CH:5]=[C:4]([Cl:11])[C:3]=1[Cl:12]
Reactant: COCCOCCl
Reactant: Clc1cc2[nH]cnc2c(Cl)c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCOCn1cnc2c(Cl)c(Cl)c(Cl)cc21
Reaction time: 18 h

Procedure:
To a mixture of 4,5,6-trichloro-1H-benzoimidazole (0.098 g, 0.446 mmol) and THF (2.5 mL) was added DIPEA (0.155 mL, 0.892 mmol), followed by 1-chloromethoxy-2-methoxy-ethane (0.057 ml, 0.49 mmol) at 23° C. After stirring for 18 h, EtOAc was added. The organic layer was washed with saturated aqueous NaHCO3. The aqueous layer was further extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified (FCC) to yield the titled compound as a mixture of regioisomers (0.084 g, 61%). MS (ESI/CI): mass calcd. for C11H11Cl3N2O2, 308.0; m/z found, 309.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 8.59 (s, 1H), 8.58 (s, 1H), 8.09 (s, 1H), 8.04 (d, J=8.5 Hz, 1H), 5.84 (s, 2H), 5.71 (s, 2H), 3.59-3.57 (m, 2H), 3.56-3.53 (m, 2H), 3.42-3.38 (m, 4H), 3.18 (s, 3H), 3.17 (s, 3H).
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH:7]2[O:12][CH2:11][CH2:10][N:9]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:8]2)C(=O)C2=CC=CC=C12.O.NN>C(O)C>[NH2:5][CH2:6][CH:7]1[O:12][CH2:11][CH2:10][N:9]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8]1
Reactant: O=C1c2ccccc2C(=O)N1CC1CN(Cc2ccccc2)CCO1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCC1CN(Cc2ccccc2)CCO1

Procedure:
A mixture of 31.8 g of 2-chloromethyl-4-benzylmorpholine and 30.5 g of potassium phthalimide in 200 ml of dimethylformamide is refluxed for 4 hours and then poured into water. The precipitated crystals are collected by filtration and dried to give 40.2 g of 2-phthalimidomethyl-4-benzylmorpholine. To 400 ml of the ethanol solution of this product is added dropwise a solution of 12.3 g of hydrazine hydrate in 100 ml of ethanol. Further, the resultant mixture is refluxed for 30 minutes. After cooling, insoluble materials are filtered off and the filtrate is concentrated under reduced pressure to give 2-aminomethyl-4-benzylmorpholine as an oily substance. To the solution of 10.3 g of the obtained product in 400 ml of ethanol and 40 ml of water are added 11 g of concentrated hydrochloric acid and 1.1 g of 10% palladium-carbon and the mixture subjected to catalytic reduction at ordinary temperature and atmospheric pressure. After absorbing the theoretical volume of the hydrogen, the catalyst is filtered off and the filtrate is concentrated under reduced pressure. The obtained residue is treated with ethanol-acetone to give 2-(aminomethyl)morpholine dihydrochloride as white crystals, melting at 215°-218° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:14]2[N:18]=[C:17]([C:19]3[S:20][CH:21]=[C:22]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:23]=3[CH3:24])[O:16][N:15]=2)[CH:5]=[C:6]([CH3:13])[C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][O:11]1.C1COCC1.[NH3:34]>CO.[OH-].[Na+]>[NH2:34][CH2:12][CH:10]([OH:11])[CH2:9][O:8][C:7]1[C:2]([CH3:1])=[CH:3][C:4]([C:14]2[N:18]=[C:17]([C:19]3[S:20][CH:21]=[C:22]([CH2:25][CH:26]([CH3:27])[CH3:28])[C:23]=3[CH3:24])[O:16][N:15]=2)=[CH:5][C:6]=1[CH3:13]
Reactant: N
Reactant: Cc1cc(-c2noc(-c3scc(CC(C)C)c3C)n2)cc(C)c1OCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(-c2noc(-c3scc(CC(C)C)c3C)n2)cc(C)c1OCC(O)CN

Procedure:
A suspension of rac-3-(3,5-dimethyl-4-oxiranylmethoxy-phenyl)-5-(4-isobutyl-3-methyl-thiophen-2-yl)-[1,2,4]oxadiazole (382 mg, 0.959 mmol) in 7 N NH3 in MeOH (10 mL) and THF (5 mL) is stirred at 60° C. for 15 h. The mixture is diluted with 1M aq. NaOH (30 mL) and extracted with DCM (4×75 mL). The combined organic extracts are dried (Na2SO4), filtered and evaporated to give rac-1-amino-3-{4-[5-(4-isobutyl-3-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-propan-2-ol (419 mg) as a pale yellow solid; LC-MS: tR=0.90 min, [M+1]=416.42.
Reaction SMILES: [C:1]1([C:7]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[C:18]=1[NH2:24]>CO.C(O)(=O)C>[C:1]1([C:7]2[N:23]=[C:19]3[CH:20]=[CH:21][CH:22]=[N:17][C:18]3=[N:24][C:9]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Reactant: Nc1cccnc1N
Solvent: CC(=O)O
Solvent: CO
Product: c1ccc(-c2nc3cccnc3nc2-c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A solution of benzil (45.7 g, 217 mmol) and pyridine-2,3-diamine (23.7 g, 217 mmol) in methanol (514 ml) and acetic acid (57 ml) was heated at 160° C. for 10 mins using microwave radiation. The reaction mixture was concentrated in vacuo. To the crude residue in methanol (510 ml) was added activated charcoal (25 g) and the suspension was stirred at 60° C. for 1 h. The suspension was filtered hot, cooled and then was stirred in an ice bath. The solid was filtered, washed with cold methanol (50 ml) and dried in vacuo at 40° C. overnight to afford the title compound as pale brown crystals.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][NH:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>O1CCCC1.C(OCC)(=O)C.O>[O:13]=[C:8]1[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:12][CH2:11][CH2:10][N:9]1[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: O=C1NCCCC1c1ccccc1
Reactant: CCOC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CN1CCCC(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a suspension of the product from Example 91B (1.08 g, 6.16 mmol) in tetrahydrofuran (10 mL) at 0° C. was added potassium tert-butoxide (1.0 Min tetrahydrofuran) (6.78 mL, 6.78 mmol). After stirring for 20 minutes, ethyl 2-bromoacetate (0.750 mL, 6.78 mmol) was added, and the reaction was allowed to warm to room temperature. After stirring for 3 hours, the reaction was poured in ethyl acetate/water (1:1, 200 mL). The organic layer was washed with brine (100 mL), dried over magnesium sulfate and concentrated. Silica gel chromatography using a GraceResolv 80 g silica gel column (Grace Davison Discovery Sciences) eluting with a gradient of 25% ethyl acetate/hexanes to 85% ethyl acetate/hexanes (flow=40 mL/minute) over 30 minutes supplied the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.39-7.14 (m, 5H), 4.45 (d, J=17.2, 1H), 4.23 (q, J=7.1, 2H), 3.91 (d, J=17.2, 1H), 3.78-3.65 (m, 1H), 3.65-3.49 (m, 1H), 3.41 (dt, J=5.7, 11.3, 1H), 2.32-2.12 (m, 1H), 2.12-1.74 (m, 3H), 1.30 (t, J=7.2, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:7]=[CH:6][C:5]=1[NH:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24]Cl)[CH:19]=1.C(N(CC)CC)C.[CH3:35][CH:36]([OH:43])[CH2:37][NH:38][CH2:39][CH:40]([OH:42])[CH3:41].COC1C=C(C=CC=1OC)C(Cl)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:7]=[CH:6][C:5]=1[NH:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:38]([CH2:39][CH:40]([OH:42])[CH3:41])[CH2:37][CH:36]([OH:43])[CH3:35])[CH:19]=1
Reactant: CC(O)CNCC(C)O
Reactant: COC(=O)c1cc(N2CCCC2=O)ccc1NC(=O)c1cccc(CCl)c1
Agent: COc1ccc(C(=O)Cl)cc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(N2CCCC2=O)ccc1NC(=O)c1cccc(CN(CC(C)O)CC(C)O)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 47 %

Procedure:
Subsequently, 2-(3-chloromethyl-benzoylamino)-5-(2-oxo-pyrrolidin-1-yl)benzoic acid methyl ester (14 mg) was dissolved in anhydrous methylene chloride (5 ml). Triethylamine (7 mg: dissolved in 2 ml of anhydrous methylene chloride) and diisopropanolamine (compound B′) (10 mg: dissolved in 2 ml of anhydrous methylene chloride) were added dropwise to the solution at 0° C., and the mixture was stirred at room temperature for 24 hr. After the completion of the reaction, distilled water was added thereto at room temperature, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine, was dried over sodium sulfate, and was then concentrated under the reduced pressure. The residue was purified by column chromatography eluted with a chloroform-methanol system to give 2-(3-{[bis-(2-hydroxy-propyl)-amino]-methyl}-benzoylamino)-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid methyl ester (8.0 mg, yield 47%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[CH3:11]I.O>C1COCC1>[Br:8][C:6]1[CH:5]=[CH:4][N:3]([CH3:11])[C:2](=[O:1])[CH:7]=1
Reactant: CI
Reactant: Oc1cc(Br)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1ccc(Br)cc1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.6 %

Procedure:
To an ice-cold solution of 2-hydroxy-4-bromopyridine (1.0 g, 5.75 mmol) in THF (20.0 mL) was added NaH (60% suspension in mineral oil, 0.23 g, 5.75 mmol) portionwise. The reaction mixture was stirred at room temperature for 15 min followed by addition of methyl iodide (1.10 mL, 17.24 mmol). The resulting reaction mixture was stirred at room temperature for 16 h. After the completion of the reaction (TLC monitoring), the reaction mixture was cooled to 0° C., added water and extracted with EtOAc (3×50 mL). The combined organics was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to obtain the desired product (0.99 g, 92%). 1H NMR (400 MHz, DMSO-d6): δ 3.38 (s, 3H), 6.44 (dd, J=2.0 and 7.20 Hz, 1H), 6.69 (d, J=2.0 Hz, 1H) and 7.69 (d, J=7.20 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[NH:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12].N1C=CC=CC=1.[C:21](Cl)(Cl)=[O:22].[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[C:11]([C:3]1[NH:4][C:5]([C:7]([CH3:10])([CH3:8])[CH3:9])=[CH:6][C:2]=1[NH:1][C:21]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)=[O:22])([O:13][CH3:14])=[O:12]
Reactant: Cc1ccc(N)cc1
Reactant: COC(=O)c1[nH]c(C(C)(C)C)cc1N
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COC(=O)c1[nH]c(C(C)(C)C)cc1NC(=O)Nc1ccc(C)cc1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
To a solution of methyl 3-amino-5-tert-butylpyrrole-2-carboxylate (12 mg, 0.062 mmol) and anh. pyridine (0.25 mL, 3.06 mmol, 49.4 equiv) in anh. toluene (1 mL) was rapidly added phosgene (1.93M in toluene, 0.32 mL, 0.62 mmol, 10 equiv). After 30 min, the orange suspension was concentrated under reduced pressure, then successively charged with anh. toluene (1 mL) and concentrated (2×). Finally, toluene (2 mL) was added followed by p-toluidine (10 mg, 0.094 mmol). The mixture was heated at 90° C. for 3 h, then was concentrated under reduced pressure. The residue was purified by preparative TLC (2 plates, 20×20 cm×0.25 mm, 2% MeOH/CH2Cl2). The major UV-active band was isolated and the product was extracted from the silica using 5% MeOH/CH2Cl2 to give N-(2-carbomethoxy-5-tert-butyl-3-pyrrolyl)-N′-(4-methylphenyl)urea as a pale yellow amorphous solid (0.016 g, 80%): 1H NMR (d6-DMSO ) δ1.23 (s, 9H), 2.20 (s, 3H), 3.78 (s, 3H), 6.54 (d, J=3.0 Hz, 1H), 7.04 (d, J=8.5 Hz, 2H), 7.32 (d, J=8.5 Hz, 2H), 8.61 (s, 1H), 9.51 (s, 1H), 10.85 (br d, J=2.2 Hz, 1H); 13C NMR (MeOD, CDCl3, partial spectrum) δ19.7, 29.0 (3C), 31.5, 50.0, 97.4, 105.9, 119.6 (2C), 128.9 (2C), 132.2, 136.2, 147.6, 153.5, 161.9; FTIR (KBr) 3341 (s), 2947 (m), 1676 (s), 1583 (s), 1548 (s), 1456 (s), 1279 (s), 1208 (s), 1094 (s); cm−1; FAB-LRMS m/z (rel abundance) 330 (M+H, 47%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:17]([O-])=O)=[O:5])[CH3:2].[CH3:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:26][CH2:25][C:24]1[CH:27]=[CH:28][C:21]([CH3:20])=[CH:22][CH:23]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Reactant: Cc1ccc(CN)cc1
Product: CCOC(=O)c1cnc2c(N)cccc2c1NCc1ccc(C)cc1
Yield: 83 %

Procedure:
The compound prepared in Example 3 was reacted reacted with 4-methyl-benzylamine according to the method as described in Example 4 and the obtained compound was treated as described in Example 14 to prepare the title compound (yield 83%).
Reaction SMILES: ClCCl.[NH2:4][C:5]1[CH:32]=[CH:31][C:8]([CH2:9][N:10]2[C:19]3[C:14](=[C:15]([CH2:22][CH:23]4[S:27][C:26](=[O:28])[NH:25][C:24]4=[O:29])[CH:16]=[CH:17][C:18]=3[O:20][CH3:21])[CH2:13][CH2:12][C:11]2=[O:30])=[CH:7][CH:6]=1.N1C=CC=CC=1.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>O>[CH3:39][S:40]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]2[C:19]3[C:14](=[C:15]([CH2:22][CH:23]4[S:27][C:26](=[O:28])[NH:25][C:24]4=[O:29])[CH:16]=[CH:17][C:18]=3[O:20][CH3:21])[CH2:13][CH2:12][C:11]2=[O:30])=[CH:31][CH:32]=1)(=[O:42])=[O:41]
Reactant: COc1ccc(CC2SC(=O)NC2=O)c2c1N(Cc1ccc(N)cc1)C(=O)CC2
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(CC2SC(=O)NC2=O)c2c1N(Cc1ccc(NS(C)(=O)=O)cc1)C(=O)CC2
Yield: 92 %

Procedure:
To a dichloromethane (20 ml) solution of 1.00 g (0.00243 mM) of 5-[1-(4-aminobenzyl)-8-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl]thiazolidine-2,4-dione were successively added pyridine (2.0 ml) and 0.21 ml (0.0027 mM) of methanesulfonyl chloride under ice cooling with stirring. The mixture was stirred at the same temperature for 30 minutes, and water was added to stop the reaction. The resultant was washed (twice with water and once with saturated sodium chloride solution), dried (magnesium sulfate), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:ethyl acetate=1:10→1:1), giving 1.1 g (92% yield) of the target compound as a white amorphous solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[O:25]1[CH2:29][CH2:28][CH2:27][CH:26]1[CH2:30][NH2:31]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:31][CH2:30][CH:26]4[CH2:27][CH2:28][CH2:29][O:25]4)=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: NCC1CCCO1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NCC3CCCO3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (tetrahydrofuran-2-yl)methanamine 1H NMR (400 MHz, DMSO-d6) δ ppm 1.49-1.67 (m, 1 H) 1.75-1.89 (m, 2 H) 1.89-2.01 (m, 1 H) 2.44 (s, 3 H) 3.35-3.42 (m, 2 H) 3.65 (q, J=7.49 Hz, 1 H) 3.80 (q, J=6.82 Hz, 1 H) 4.00 (t, J=6.32 Hz, 1 H) 7.67 (d, J=7.83 Hz, 1 H) 7.74 (s, 1 H) 7.78 (br. s., 1H) 8.18 (br. s., 1 H) 8.43 (d, J=6.57 Hz, 2 H) 8.82 (t, J=5.31 Hz, 1 H) 8.93 (s, 1 H) 13.20 (br. s., 1 H). MS m/z [M+H]+ 404.2
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][CH2:11][C:12]2[S:16][C:15]([S:17](Cl)(=[O:19])=[O:18])=[CH:14][CH:13]=2)=[O:9])=[CH:4][CH:3]=1.[S:21]1[CH2:25][CH2:24][S:23][CH:22]1[C:26]1[CH:31]=[CH:30][C:29]([C:32]2[S:33][CH:34]=[C:35]([C:37]([NH:39][NH2:40])=[O:38])[N:36]=2)=[CH:28][CH:27]=1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][CH2:11][C:12]2[S:16][C:15]([S:17]([NH:40][NH:39][C:37]([C:35]3[N:36]=[C:32]([C:29]4[CH:28]=[CH:27][C:26]([CH:22]5[S:21][CH2:25][CH2:24][S:23]5)=[CH:31][CH:30]=4)[S:33][CH:34]=3)=[O:38])(=[O:19])=[O:18])=[CH:14][CH:13]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(S(=O)(=O)Cl)s1)c1ccc(Cl)cc1
Reactant: NNC(=O)c1csc(-c2ccc(C3SCCS3)cc2)n1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C(NCc1ccc(S(=O)(=O)NNC(=O)c2csc(-c3ccc(C4SCCS4)cc3)n2)s1)c1ccc(Cl)cc1
Yield: 80 %

Procedure:
A solution of sulfonyl chloride 1b (1.0 equivalents), 2-[4-(1,3-Dithiolan-2-yl)phenyl]-1,3-thiazole-4-carbohydrazide (1.1 equivalents), and pyridine (1.2-2 equivalents) in CHCl3 is heated to reflux for 2 h. Filtration over SiO2 (CH3CN) and evaporation yielded 80% of the desired sulfonyl hydrazide 1.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[C:21]1[NH:25][N:24]=[CH:23][CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl[CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[C:21]1[CH:22]=[CH:23][N:24]([CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:25]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCCN1CCOCC1
Reactant: Cc1nnc2ccc3c(cc(-c4ccn[nH]4)n3Cc3ccccc3)n12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1nnc2ccc3c(cc(-c4ccn(CCN5CCOCC5)n4)n3Cc3ccccc3)n12
Temperature: 70 °C

Procedure:
A mixture of 6-benzyl-1-methyl-7-(1H-pyrazol-5-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (4.2 mg, 0.013 mmol, from Example 62), 4-(2-chloroethyl)morpholine hydrochloride (7.1 mg, 0.038 mmol, Aldrich) and Cs2CO3 (21 mg, 0.064 mmol) in DMF (0.21 mL) was heated at 70° C. overnight. The product was purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH) and the major isomer was isolated. Yield: (2.4 mg, 42%).
Reaction SMILES: Cl/[C:2](/[CH3:13])=[CH:3]\[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5].[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[O:20](/[C:2](/[CH3:13])=[CH:3]\[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Oc1ccccc1
Reactant: C/C(Cl)=C/C(=O)Nc1ccccc1
Product: C/C(=C/C(=O)Nc1ccccc1)Oc1ccccc1

Procedure:
3-chlorocrotonanilide [formed from aniline and β-chloro-crotonyl chloride] was reacted with phenol in a basic media to obtain 3-phenoxy-crotonanilide melting at 145° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[C:13]([C:22]([NH:24][CH3:25])=[O:23])=[CH:12][C:11]2=[O:26])[CH2:4][CH2:3]1.[CH3:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH:31]=O.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH3:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][NH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[C:13]([C:22]([NH:24][CH3:25])=[O:23])=[CH:12][C:11]2=[O:26])[CH2:4][CH2:3]1
Reactant: CNC(=O)c1cc(=O)n(CCN2CCC(N)CC2)c2cc(OC)ccc12
Reactant: Cc1cccc(C=O)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNC(=O)c1cc(=O)n(CCN2CCC(NCc3cccc(C)c3)CC2)c2cc(OC)ccc12
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
370 μL of a methanol solution containing 14 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-N-methyl-2-oxo-1,2-dihydroquinolin-4-carboxamide and 10 μL of acetic acid were added to 3.6 mg of 3-methylbenzaldehyde, and stirred at room temperature for 1 min. To the reaction mixture, 120 μL, of a methanol solution containing 3.8 mg of sodium cyanoborohydride was added, and stirred at the same temperature overnight. After the solvent was removed under reduced pressure, ethyl acetate and aqueous saturated sodium hydrogen carbonate solution were added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; ethyl acetate: methanol=20:1], to give 7.6 mg of (1-(2-(4-(3-methylbenzylamino)piperidin-1-yl)ethyl)-7-methoxy-N-methyl-2-oxo-1,2-dihydroquinolin-4-carboxamide as a pale yellow foam.
Reaction SMILES: [CH2:1]([C:3]([OH:32])([CH2:30][CH3:31])[CH2:4][CH2:5]/[CH:6]=[C:7](/[C:9]1[S:13][C:12]([CH2:14][O:15][C:16]2[CH:17]=[C:18]([C:26](OC)=[O:27])[C:19](=[CH:24][CH:25]=2)[C:20](OC)=[O:21])=[CH:11][CH:10]=1)\[CH3:8])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)C>[OH:27][CH2:26][C:18]1[CH:17]=[C:16]([CH:25]=[CH:24][C:19]=1[CH2:20][OH:21])[O:15][CH2:14][C:12]1[S:13][C:9](/[C:7](/[CH3:8])=[CH:6]/[CH2:5][CH2:4][C:3]([CH2:30][CH3:31])([OH:32])[CH2:1][CH3:2])=[CH:10][CH:11]=1
Reactant: CCC(O)(CC)CC/C=C(\C)c1ccc(COc2ccc(C(=O)OC)c(C(=O)OC)c2)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CCC(O)(CC)CC/C=C(\C)c1ccc(COc2ccc(CO)c(CO)c2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
350 mg (0.76 mmol) of dimethyl 4-[5-((E)-5-ethyl-5-hydroxy-1-methylhept-1-enyl)-2-thienylmethoxy]phthalate are dissolved in 20 mL of anhydrous ethyl ether. 70 mg (1.8 mmol) of lithium aluminium hydride are added and the reaction medium is stirred at room temperature for 30 minutes. 400 mL of water are then added slowly and the medium is filtered. The filtrate is concentrated under reduced pressure and the residue obtained is then purified by chromatography on a column of silica (eluent: 70 ethyl acetate/30 heptane). A white solid (m.p.: 100-102° C.) is obtained (m=175 mg; Y=58%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[NH2:18][C:19]1[C:24]([CH3:25])=[CH:23][N:22]=[C:21]([OH:26])[N:20]=1>>[OH:26][C:21]1[N:20]=[C:19]([NH:18][C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:3]=2)[C:24]([CH3:25])=[CH:23][N:22]=1
Reactant: Cc1cnc(O)nc1N
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Product: Cc1cnc(O)nc1Nc1cc(C(F)(F)F)nc(-c2cccnc2)n1

Procedure:
The title compound was prepared from 4-chloro-2-(3-pyridinyl)-6-trifluoromethylpyrimidine (50 mg, 0.192 mmol) and 4-amino-2-hydroxy-5-methylpyrimidine (36 mg, 0.288 mmol) similar to Example 190 and was isolated as a solid. 1H NMR (CDCl3): 9.47 (brs, 1H), 8.59–8.54 (m, 2H), 7.28 (dd, J=8.1, 5.1 Hz, 1H), 6.59 (s, 1H), 5.18 (s, 2H), 1.70 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]([CH3:43])[CH2:3][CH2:4][N:5]([CH2:38][CH2:39][CH:40]([CH3:42])[CH3:41])[C:6]([C:8]1[CH:9]=[CH:10][C:11]2[N:15]=[C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=3)[N:13]([CH2:26][CH2:27][CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:12]=2[CH:37]=1)=[O:7]>C(OCC)(=O)C.CO.[Pd]>[NH2:23][C:20]1[CH:19]=[CH:18][C:17]([NH:16][C:14]2[N:13]([CH2:26][CH2:27][CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:34])[CH3:35])[C:12]3[CH:37]=[C:8]([C:6]([N:5]([CH2:4][CH2:3][CH:2]([CH3:43])[CH3:1])[CH2:38][CH2:39][CH:40]([CH3:41])[CH3:42])=[O:7])[CH:9]=[CH:10][C:11]=3[N:15]=2)=[CH:22][CH:21]=1
Reactant: CC(C)CCN(CCC(C)C)C(=O)c1ccc2nc(Nc3ccc([N+](=O)[O-])cc3)n(CCCNC(=O)OC(C)(C)C)c2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)CCN(CCC(C)C)C(=O)c1ccc2nc(Nc3ccc(N)cc3)n(CCCNC(=O)OC(C)(C)C)c2c1
Temperature: 20 °C
Reaction time: 15 h
Yield: 87 %

Procedure:
Tert-butyl 3-{6-{[bis(3-methylbutyl)amino]carbonyl}-2-[(4-nitrophenyl)amino]-1H-benzimidazol-1-yl}propylcarbamate (580 mg) in solution in a mixture of ethyl acetate/methanol 3:1 (40 ml), and 10% palladium on carbon (58 mg) are introduced into an autoclave. After stirring for 15 hours under a hydrogen atmosphere (3 bar) at a temperature of approximately 20° C., the catalyst is eliminated by filtration on celite and the filtrate is concentrated under reduced pressure at 40° C. in order to produce the expected compound in the form of a foam (480 mg; 87% yield).