Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:7][CH2:6][NH:5][C:4]1=[O:8].[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:17][CH2:18][CH2:19]Cl)=[CH:12][CH:11]=1>CN(C=O)C>[F:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]([C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[CH2:17][CH2:18][CH2:19][N:3]2[CH2:7][CH2:6][NH:5][C:4]2=[O:8])=[CH:14][CH:15]=1
Reactant: O=C1NCCN1
Reactant: Fc1ccc(C(CCCCl)c2ccc(F)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1NCCN1CCCC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a suspension of sodium hydride (0.72 g, 18 mmol) in DMF (20.0 mL) was added a solution of imidazolidin-2-one (1) (2.5 g, 30.0 mmol, Aldrich) in DMF (10.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 45 minutes and then a solution of 4,4-bis(4-fluorophenyl)butyl chloride (2) (5.6 g, 10 mmol) in DMF (10.0 mL) was added. Then the mixture was stirred at 60° C. for 4 hours. After this period, the mixture was cooled to room temperature and quenched with water (20 mL). The mixture was extracted with ethyl acetate (100 mL×3). The organic layer was dried with anhydrous Na2SO4 and concentrated to give a crude sample. The crude sample was purified by column chromatography using ethyl acetate/hexane gradient as an eluent to give the title compound 3. MS: m/z 331. 1H NMR (CDCl3): δ 7.16 (m, 4H), 6.96 (t, J=8 Hz, 4H), 4.36 (br, 1H), 3.91 (t, J=8 Hz, 1H), 3.38 (m, 2H), 3.32 (m, 2H), 3.21 (t, J=8 Hz, 2H), 2.00 (dd, J=8, 12 Hz, 2H), 1.45 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH2:12])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH2:13](OC(OCC)OCC)C>C(O)=O>[N:1]1[C:2]2[C:3](=[N:4][CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=2)[NH:12][CH:13]=1
Reactant: CCOC(OCC)OCC
Reactant: COC(=O)c1cnc(N)c(N)c1
Solvent: O=CO
Product: COC(=O)c1cnc2[nH]cnc2c1
Temperature: 90 °C
Yield: 33 %

Procedure:
A stirred mixture of methyl 5,6-diaminonicotinate (1.69 g, 10.12 mmol) from Step 1 of this Example, formic acid (0.5 mL), and triethylorthoformate (25 mL) was heated at 90° C. for 2.5 h. The reaction mixture was cooled to rt and then the precipitated solid was collected by filtration and dried to afford methyl 3H-imidazo[4,5-b]pyridine-6-carboxylate (588 mg, 33%) as a cream solid which did not require further purification. The filtrate was concentrated under reduced pressure, and the residue purified by silica gel flash chromatography eluting with 100% DCM to 10% MeOH in DCM to afford additional methyl 3H-imidazo[4,5-b]pyridine-6-carboxylate (550 mg, 31%) as a cream solid. 1H NMR (300 MHz, DMSO-d6) δ 13.33 (br s, 1H), 8.95 (d, J=1.5 Hz, 1H), 8.64 (s, 1H), 8.50 (d, J=1.5 Hz, 1H), 3.91 (s, 3H). LCMS (ESI) m/z 178 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[CH2:10][C:11](=[O:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][C:11](=[O:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: CC(=O)CCl
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)COc1ccc(Cl)cc1
Yield: 97.5 %

Procedure:
4-Chlorophenol (10 g), chloroacetone (10.8 g), anhydrous potassium carbonate (12.9 g) and potassium iodide (1.3 g) were added to acetone (100 ml) and heated under reflux for 6 hours. The reaction mixture was filtered and the filtrate was concentrated to obtain 4-chlorophenoxyacetone (14 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3C=NC=N3)[C:11]3=[C:19]([CH3:23])[N:20]=[C:21]([CH3:22])[N:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:24]([NH:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32]N)=[CH:30][CH:29]=1)(=[O:26])[CH3:25].C(N(CC)CC)C>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([NH:14][CH2:32][C:31]3[CH:30]=[CH:29][C:28]([NH:27][C:24](=[O:26])[CH3:25])=[CH:35][CH:34]=3)[C:11]3=[C:19]([CH3:23])[N:20]=[C:21]([CH3:22])[N:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1nc(C)n2nc(-c3ccc(Br)cc3)nc(-n3cncn3)c12
Reactant: CC(=O)Nc1ccc(CN)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc(CNc2nc(-c3ccc(Br)cc3)nn3c(C)nc(C)c23)cc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
2-(4-Bromophenyl)-5,7-dimethyl-4-(1H-1,2,4-triazol-1-yl)imidazo[5,1-f][1,2,4]-triazine (3.7 mg, 10 mmol) is treated in dioxane (100 μl) with 4-acetylamino-benzylamine (3.3 mg, 20 mmol) and triethylamine (4 μl). The mixture is heated at 80° C. with shaking for 12 h, filtered and washed with DMSO (2×100 μl). The combined filtrates are purified chromatographically by preparative LC-MS.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:18]1[C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:22][N:21]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:20](=[O:39])[CH:19]=1.CCOC(C)=O>C1COCC1.[Cl-].[Na+].O>[C:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([O:1][C:18]2[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:22][N:21]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)[C:20](=[O:39])[CH:19]=2)[CH2:7][CH2:6]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: COc1ccc(Cn2nc(-c3ccccc3)c(Cl)cc2=O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(Cn2nc(-c3ccccc3)c(OC3CCN(C(=O)OC(C)(C)C)CC3)cc2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
To a mixture of tert-butyl 4-hydroxypiperidine-1-carboxylate (121 mg, 0.60 mmol) in THF (3 mL) at room temperature under argon was added NaH (24 mg, 0.60 mmol). After stirring at room temperature under argon for 30 minutes, 5-chloro-2-(4-methoxybenzyl)-6-phenylpyridazin-3(2H)-one (163 mg, 0.50 mmol) was added. The resulting reaction mixture was stirred at room temperature for three days. EtOAc (10 mL) and brine (10 mL) were added to the reaction mixture. Layers were separated. Organic layer were washed with water (15 mL), and brine (15 mL). Organic phase was dried (MgSO4), filtered and concentrated. The crude product was dissolved in a small amount of DCM (˜2 ml) and loaded onto a 40 g ISCO silica gel column which was eluted with a 20 min gradient from 0% to 100% EtOAc/Hexanes. 138.9 mg (56.3%) of tert-butyl-4-(1-(4-methoxybenzyl)-6-oxo-3-phenyl-1,6-dihydropyridazin-4-yloxy)piperidine-1-carboxylate was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.43 (s, 9H) 1.62-1.82 (m, 2H) 1.80-1.98 (m, 2H) 3.16-3.57 (m, J=5.27, 5.27 Hz, 4H) 3.76 (s, 1H) 4.35-4.64 (m, 1H) 5.26 (s, 2H) 6.21 (s, 1H) 6.84 (d, J=8.79 Hz, 2H) 7.33-7.53 (m, 5H) 7.64 (dd, J=6.81, 3.30 Hz, 2H). MS (ESI) 492 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](C)([C:14](O)=O)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.[ClH:18]>CO>[ClH:18].[CH3:1][O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]1)=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)O)CC1
Agent: Cl
Solvent: CO
Product: COC(=O)N1CCC(C)CC1
Reaction time: 18 h

Procedure:
To a stirred solution of 4-methyl-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (1.00 g, 4.10 mmol) in MeOH (2 mL) is added HCl (5 ml, 4 M in dioxane). After 18 h, the mixture is evaporated to dryness, the residue is dissolved in MeOH (3 mL), and the stirred solution is treated with Et2O (45 ml). The resulting solid is filtered and dried to give the title compound.
Reaction SMILES: [OH:1]O.[CH2:3]([S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([NH2:20])(=[O:19])=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)(=O)C>[CH2:3]([S:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([NH2:20])(=[O:19])=[O:18])=[O:1])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: NS(=O)(=O)c1ccccc1SCc1ccccc1
Reactant: OO
Solvent: CC(=O)O
Product: NS(=O)(=O)c1ccccc1S(=O)Cc1ccccc1
Reaction time: 5 h
Yield: 94.6 %

Procedure:
102 ml of 30% hydrogen peroxide solution are added dropwise at a temperature of +10° C. to a solution of 219 g of 2-benzylthiophenylsulfonamide obtained in accordance with Example P1 in 500 ml of concentrated acetic acid. The reaction mixture is then stirred for 5 hours at a temperature of +25° C., the product slowly crystallising out. After separating off the crystals, washing with water and drying, 219 g (94.6%) of 2-benzylsulfinylphenylsulfonamide are obtained in the form of colourless crystals having a melting point of from +206° to +209° C.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][N:11]2[C:14]2[C:15]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)=[N:16][C:17]3[C:22]([N:23]=2)=[CH:21][C:20]([C:24]([O:26]C)=[O:25])=[CH:19][CH:18]=3)=[CH:6][CH:5]=1>CO.O>[F:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][N:11]2[C:14]2[C:15]([C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)=[N:16][C:17]3[C:22]([N:23]=2)=[CH:21][C:20]([C:24]([OH:26])=[O:25])=[CH:19][CH:18]=3)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCc4ccc(F)cc43)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCc4ccc(F)cc43)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
Sodium hydroxide (52.0 mg, 1.30 mmol) was added to a solution of methyl 3-(7-fluoro-1,2,3,4-tetrahydroquinolin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylate (140 mg, 0.32 mmol) in methanol (30 mL) and water (1.0 mL). The reaction was stirred overnight at room temperature and then concentrated in vacuo, dissolved in water (30 mL), and adjusted to pH 5 with aqueous hydrochloric acid (3 N) to give a precipitate, which was collected by filtration to afford 3-(7-fluoro-1,2,3,4-tetrahydroquinolin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid as a light yellow solid (100 mg, 74%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22](=[O:35])[CH:23]([NH:27]C(=O)OC(C)(C)C)[CH:24]([CH3:26])[CH3:25])[CH2:17][CH2:16]1)=[N:11][C:10]([C:36]1[CH:41]=[C:40]([Cl:42])[C:39]([OH:43])=[C:38]([Cl:44])[CH:37]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[ClH:45]>>[ClH:42].[ClH:45].[C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([NH:21][C:22](=[O:35])[CH:23]([NH2:27])[CH:24]([CH3:26])[CH3:25])[CH2:17][CH2:16]1)=[N:11][C:10]([C:36]1[CH:37]=[C:38]([Cl:44])[C:39]([OH:43])=[C:40]([Cl:42])[CH:41]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1NC1CCC(NC(=O)C(NC(=O)OC(C)(C)C)C(C)C)CC1
Agent: Cl
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1N[C@H]1CC[C@H](NC(=O)C(N)C(C)C)CC1

Procedure:
Following general procedure IV-2, tert-butyl 1-(4-(3-acetyl-6-(3,5-dichloro-4-hydroxy-phenyl)-1,5-naphthyridin-4-ylamino)cyclohexylamino)-3-methyl-1-oxobutan-2-ylcarbamate (0.19 mmol) was reacted with HCl (5 mL, 2 M in ether) to afford the desired product (55 mg, 47% over two steps) as an off-white solid: 1H NMR (500 MHz, CD3OD) δ 9.14 (s, 1H), 8.45 (d, J=9.0 Hz, 1H), 8.33 (d, J=9.0 Hz, 1H), 8.10 (s, 2H), 5.67-5.53 (m, 1H), 3.91-3.80 (m, 1H), 3.62 (d, J=6.0 Hz, 1H), 2.76 (s, 3H), 2.49-2.40 (m, 2H), 2.25-2.10 (m, 3H), 1.81-1.54 (m, 4H), 1.07 (dd, J=9.0, 6.9 Hz, 6H); ESI MS m/z 544 [M+H]+; HPLC 99.0% (AUC), tR=10.15 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[CH:16]=[CH:15][C:14]4[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=4[C:12]=3[NH:11][C:10](=[O:22])[C:9]2=[O:23])[CH:5]=[CH:6][CH:7]=1.[I:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][C:32](Cl)=[O:33]>>[I:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][C:32]([NH:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[CH:16]=[CH:15][C:14]4[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=4[C:12]=3[NH:11][C:10](=[O:22])[C:9]2=[O:23])[CH:5]=[CH:6][CH:7]=1)=[O:33]
Reactant: Nc1cccc(-n2c(=O)c(=O)[nH]c3c4ccccc4ccc32)c1
Reactant: O=C(Cl)Cc1ccccc1I
Product: O=C(Cc1ccccc1I)Nc1cccc(-n2c(=O)c(=O)[nH]c3c4ccccc4ccc32)c1
Yield: 11 %

Procedure:
4-(3-Aminophenyl)-1,4-dihydrobenzo[f]quinoxaline-2,3-dione (30 mg, 0.1 mmol) and 2-iodophenylacetylchloride were used in a process similar to Example 9 to give the titled compound as a yellow crystal (6 mg, yield 11%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][NH:12][C:11]3=[O:15])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH2:16]([O:18][C:19](=[O:27])[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1Br)[CH3:17].CN[C@@H]1CCCC[C@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH2:16]([O:18][C:19](=[O:27])[C:20]1[CH:21]=[CH:22][N:23]=[CH:24][C:25]=1[N:12]1[CH2:13][CH2:14][N:10]([C:7]2[CH:8]=[CH:9][C:4]3[N:3]=[CH:2][S:1][C:5]=3[CH:6]=2)[C:11]1=[O:15])[CH3:17]
Reactant: O=C1NCCN1c1ccc2ncsc2c1
Reactant: CCOC(=O)c1ccncc1Br
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CCOC(=O)c1ccncc1N1CCN(c2ccc3ncsc3c2)C1=O
Yield: 39.5 %

Procedure:
1-Benzothiazol-6-yl-imidazolidin-2-one (I-84b: 0.25 g, 1.1 mmol) was reacted with 3-bromo-isonicotinic acid ethyl ester (0.28 g, 1.2 mmol), 1,4-dioxane (30 mL), copper iodide (0.065 g, 0.3 mmol), trans N,N′-dimethyl-cyclohexane-1,2-diamine (0.048 g, 0.3 mmol) and potassium phosphate (0.81 g, 2.8 mmol) to afford the crude product. Purification by column chromatography on silica gel (100% CHCl3) afforded 160 mg of the product (38.2% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH:11][CH2:12][C:13]([OH:15])=[O:14].C1C(O)=CC=C(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)C=1>O>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH:10]=[N:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: O=C(O)CNCCc1ccc(O)cc1O
Agent: OC[C@H]1O[C@@H](Oc2ccc(O)cc2)[C@H](O)[C@@H](O)[C@@H]1O
Solvent: O
Product: O=C(O)CN=CCc1ccc(O)cc1O

Procedure:
Ingredients. (1) Water 97.5 (2) Resacetophenone 1.5 (3) Glycine 1.0. Procedure. The mixture of all ingredients is heated at 90 to 95 C for 2 hours. A solution of N-[(2,4-dihydroxyphenyl)ethylidene]glycine in water is obtained. It is then hydrogenated over Ni catalyst, filtered, and then acidified to pH 6.5. [RS]-N-[(2,4-dihydroxyphenyl)ethyl]glycine is thus obtained, which is then resolved into the corresponding [R] and [S] optical isomers. Both the [R,S] and [R] and [S] compounds thus obtained are esterified with methanol/thionyl chloride method to the corresponding methyl esters, which are used directly in cosmetic compositions of the present invention.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])[CH2:18][CH2:17]2)=[O:15])=[C:8]([N+:30]([O-:32])=[O:31])[CH:7]=1.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:13][O:12][C:11]1[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:44]2[CH2:43][CH2:42][N:41]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=3[O:34][CH3:33])[CH2:46][CH2:45]2)=[CH:7][C:8]([N+:30]([O-:32])=[O:31])=[C:9]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])[CH2:18][CH2:17]2)=[O:15])[CH:10]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: COc1cc(C(=O)N2CCN(c3ccccc3OC)CC2)c([N+](=O)[O-])cc1OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(C(=O)N2CCN(c3ccccc3OC)CC2)c([N+](=O)[O-])cc1OCCCN1CCN(c2ccccc2OC)CC1
Reaction time: 16 h
Yield: 93 %

Procedure:
To a stirred suspension of [4-(3-bromopropyloxy)-5-methoxy-2-nitrophenyl][4-(2-methoxyphenyl)piperazino]methanone (9) (500 mg, 1.65 mmol), 1-(2-methoxyphenyl)piperazine (316 mg 15.6 mmol) and K2CO3 (816 mg 26.6 mmol) in acetone (30 mL) and the stirring was continued for 16 h. The acetone was evaporated in vacuum and the aqueous layer was washed with ethyl acetate and extracted with ethyl acetate and washed with brine, dried over Na2SO4 and evaporated in vacuum to afford the crude product to (5-methoxy-4-3-[4-(2-methoxyphenyl)-piperazino]propoxy-2-nitrophenyl)[4-(2-methoxyphenyl)piperazino]methanone (10) in 93% yield (670 mg, 85% yield). 1H NMR (CDCl3): δ 1.60-2.15 (m, 2H), 2.98-3.12 (t, 2H, J=7.31 Hz), 3.18-3.36 (m, 8H), 3.38-3.60 (m, 10H), 3.85 (m, 3H), 3.95 (s, 3H), 4.00-4.15 (m, 3H) 6.85-7.00 (m, 8H), 7.20-7.40 (m, 1H), 7.70-7.80 (d, 1H, J=6.81 Hz); FABMS: 619 (M+H)+.
Reaction SMILES: C1(=O)N(N([C:11](=[O:22])[CH2:12][S:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)CC([O-])=O)C(=O)CC1.[NH2:25][C@@H:26]([C:28]([NH:30][CH2:31][C:32]([NH:34][CH2:35][C:36]([OH:38])=[O:37])=[O:33])=[O:29])[CH3:27].C(OCC)C>C(O)C.O>[C:14]([S:13][CH2:12][C:11]([NH:25][C@@H:26]([C:28]([NH:30][CH2:31][C:32]([NH:34][CH2:35][C:36]([OH:38])=[O:37])=[O:33])=[O:29])[CH3:27])=[O:22])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C[C@@H](N)C(=O)NCC(=O)NCC(=O)O
Reactant: O=C([O-])CN(C(=O)CSC(=O)c1ccccc1)N1C(=O)CCC1=O
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: C[C@@H](NC(=O)CSC(=O)c1ccccc1)C(=O)NCC(=O)NCC(=O)O
Yield: 44.6 %

Procedure:
To a solution of 1 g of succinimidyl-N-(S-benzoylmercaptoacetyl)glycinate in 25 ml of anhydrous ethanol at 70° C. is added in one portion a solution of 203 mg of D-alanylglycylglycine in 10 ml of water at 70° C. The reaction mixture is refluxed for 1 hour and the solvents are evaporated under reduced pressure. The residue is agitated with 5 portions of 25 ml acetone, which is isolated by filtration. The combined filtrates are treated with diethylether until precipitation is complete. The precipitate is filtered off, washed with diethylether and dried over P2O5 under vacuum to obtain 170 mg (47,7%) of S-benzoylmercaptoacetyl-D-alanylglycylglycine as a white powder, m.p. 167°-170° C.
Reaction SMILES: [NH3:1].[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]1[C:8]2[S:20][CH:19]=[CH:18][C:9]=2[N:10]=[C:11]([C:13](OCC)=[O:14])[N:12]=1>C(O)C>[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]1[C:8]2[S:20][CH:19]=[CH:18][C:9]=2[N:10]=[C:11]([C:13]([NH2:1])=[O:14])[N:12]=1
Reactant: N
Reactant: CCOC(=O)c1nc(-c2ccco2)c2sccc2n1
Solvent: CCO
Product: NC(=O)c1nc(-c2ccco2)c2sccc2n1
Yield: 67 %

Procedure:
Ammonia gas was bubbled through a hot solution of ethyl 4-(2-furyl)thieno[3,2-d]pyrimidine-2-carboxylate (0.156 g, 0.57 mmol) in ethanol (20 mL) for 3 h then the mixture cooled and the resulting white solid filtered to give the title compound (94 mg, 67%) as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[N:12]=[C:11]([CH2:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([C:53]([O:55]CC)=[O:54])[C:7](=[O:52])[N:8]2[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]2[N:29]=[N:30][N:31]([C:33]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:32]=2)=[CH:18][CH:17]=1)[CH3:2].[OH-].[Na+]>O1CCOCC1>[CH2:1]([C:3]1[N:12]=[C:11]([CH2:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([C:53]([OH:55])=[O:54])[C:7](=[O:52])[N:8]2[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]2[N:29]=[N:30][N:31]([C:33]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)([C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:32]=2)=[CH:20][CH:21]=1)[CH3:2]
Reactant: CCOC(=O)c1cc2c(CC)nc(CC)cc2n(Cc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCc1cc2c(cc(C(=O)O)c(=O)n2Cc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(CC)n1
Reaction time: 16 h
Yield: 46.6 %

Procedure:
Ethyl 5,7-diethyl-2-oxo-1-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1,2-dihydro-1,6-naphthyridin-3-carboxylate (0.41 g) was dissolved in dioxan (5 ml) containing aqueous 1M sodium hydroxide solution (0.55 ml) and the mixture was stirred for 16 hours. Volatile material was removed by evaporation and the residue was partitioned between ethyl acetate and water. The aqueous phase was separated, acidified to pH 4-5 with 1M aqueous citric acid solution and then extracted twice with dichloromethane. The combined extracts were dried (MgSO4) and the solvent was removed by evaporation. The residue was purified by flash chromatography, eluting initially with ethyl acetate/petroleum ether (2:1 v/v), followed by ethyl acetate and then methanol/ethyl acetate (1:9 v/v), to give 5,7-diethyl-2-oxo-1-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1,2-dihydro-1,6-naphthyridin-3-carboxylic acid (A) (0.184 g) as a solid; NMR (d6 -DMSO+d4 -acetic acid): 1.15(t,3H), 1.32 (t,3H), 2.68(q,2H), 3.22(q,2H), 5.66(s,2H), 6.8-7.9(complex m,24H), 9.06(s,1H), mass spectrum (+ve FAB, DMSO/NBA): 745(M+H)+ ; microanalysis, found: C, 66.9; H, 5.0; N, 10.0%; C46H38N6O3.1.7SiO2 requires: C, 67.0; H, 4.6; N, 10.2%.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:13])[CH3:12])[CH:7]=[CH:8][CH:9]=1.[CH2:14](I)[CH3:15].CN(C)C=O>O1CCCC1>[Br:3][C:4]1[CH:5]=[C:6]([N:10]([CH2:14][CH3:15])[C:11](=[O:13])[CH3:12])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)Nc1cccc(Br)c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCN(C(C)=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
820 mg (20.5 mmol, 1.1 eq) of 60% sodium hydride are added to a solution of 4.0 g (18.7 mmol, 1 eq) of N-(3-bromophenyl)acetamide and 1.80 mL (22.4 mmol, 1.2 eq) of ethyl iodide in 15 ml of tetrahydrofuran in the presence of 1.5 ml of dimethylformamide. The reaction medium is stirred at room temperature for 12 hours and then hydrolyzed with water and extracted with ethyl acetate. The organic phases are combined, washed with sodium chloride solution and dried over sodium sulfate. The solvents are evaporated off and the N-(3-bromophenyl)-N-ethylacetamide obtained in oil form is used in the following reaction without further purification.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Cl:23][C:24]1[CH:47]=[CH:46][C:27]([CH2:28][N:29]2[C:33]3([CH2:37][CH2:36][N:35]([CH:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)[C:34]3=[O:44])[CH2:32][C@@H:31]([OH:45])[CH2:30]2)=[CH:26][CH:25]=1.C(Cl)Cl.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:28][N:29]2[C:33]3([CH2:37][CH2:36][N:35]([CH:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)[C:34]3=[O:44])[CH2:32][C:31](=[O:45])[CH2:30]2)=[CH:46][CH:47]=1
Reactant: O=C1N(C2CCCCC2)CCC12C[C@@H](O)CN2Cc1ccc(Cl)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C1CN(Cc2ccc(Cl)cc2)C2(CCN(C3CCCCC3)C2=O)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Dess-Martin periodinane (0.19 g, 0.00044 mol) was added to a solution of (3R)-1-(4-chloro-benzyl)-7-cyclohexyl-3-hydroxy-1,7-diazaspiro[4.4]nonan-6-one (0.080 g, 0.00022 mol; prepared as in Example 32, derived from peak 2 of step 2) in DCM (2.0 mL, 0.031 mol). The resulting mixture was stirred for 3 h at RT. The mixture was then diluted with ethyl acetate and stirred with Na2S2O3 followed by saturated NaHCO3. Following separation of the organic and aqueous layers, the organic layer was dried and concentrated in vacuo to afford the desired product. LC/MS: 361.1 (M+1H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([C:21]([NH:23][CH:24]4[CH2:26][CH2:25]4)=[O:22])[CH:15]=3)=[CH:10][CH:9]=2)=[N:5][N:4]=1.[I-].[K+]>C(NCC)C>[CH:24]1([NH:23][C:21]([C:16]2[CH:15]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([C:6]4[O:7][C:3]([CH2:2][N:23]([CH2:24][CH3:25])[CH2:21][CH3:16])=[N:4][N:5]=4)=[CH:9][CH:10]=3)[C:19]([CH3:20])=[CH:18][CH:17]=2)=[O:22])[CH2:26][CH2:25]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CCl)o2)cc1
Agent: [I-]
Agent: [K+]
Solvent: CCNCC
Product: CCN(CC)Cc1nnc(-c2ccc(-c3cc(C(=O)NC4CC4)ccc3C)cc2)o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4′-[5-(Chloromethyl)-1,3,4-oxadiazol-2-yl]-N-cyclopropyl-6-methyl-1,1′-biphenyl-3-carboxamide (Intermediate 45) (37 mg) and potassium iodide (5 mg) were mixed in diethylamine (3 ml) and the reaction stirred at room temperature for 18 hours. The excess amine was evaporated under vacuum and the residue purified by bond-elut (silica), eluting with an ethyl acetate/cyclohexane gradient. After evaporation of the solvent this gave N-cyclopropyl-4′-{5-[(diethylamino)methyl]-1,3,4-oxadiazol-2-yl}-6-methyl-1,1′-biphenyl-3-carboxamide.