Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:15]=[C:16]([CH:29]2[CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30]2)[CH:17]=[C:18]([N:21]([CH3:28])[CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:19]=1[CH3:20])=[O:13].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:31]1[CH2:30][CH:29]([C:16]2[CH:17]=[C:18]([N:21]([CH3:28])[CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:19]([CH3:20])=[C:14]([CH:15]=2)[C:12]([NH:11][CH2:10][C:3]2[C:4](=[O:9])[NH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])=[O:13])[CH2:32]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3CN(C(=O)OC(C)(C)C)C3)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c(CNC(=O)c2cc(C3CNC3)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 2.7 %

Procedure:
To a stirred solution of tert-butyl 3-(3-{[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]carbamoyl}-4-methyl-5-[methyl(oxan-4-yl)amino]phenyl)azetidine-1-carboxylate (29 mg, 1.29 mmol) in DCM (4 ml) was added TFA (1 ml) and the solution was stirred at room temperature for 90 min after which the solvent was evaporated and saturated aqueous NaHCO3 was added until pH7-8. The aqueous phase was extracted with a 1:1 mixture IPA:CHCl3 (2×50 ml), and the combined organic phases washed with brine (30 ml, dried with Na2SO4, filtered and evaporated. The residue was purified by preparative HPLC to afford the title compound as a white solid (15 mg, 42%). LC-MS 100%, m/z=439.3, 1H NMR (500 MHz, MeOD) δ 7.19 (d, J=1.4 Hz, 1H), 7.10 (d, J=1.5 Hz, 1H), 6.12 (s, 1H), 4.46 (s, 2H), 4.41-4.27 (m, 2H), 4.26-4.13 (m, 3H), 3.93 (d, J=11.4 Hz, 2H), 3.36 (td, J=11.3, 3.3 Hz, 2H), 3.06 (dq, J=14.6, 5.0 Hz, 1H), 2.65 (s, 3H), 2.39 (s, 3H), 2.26 (s, 3H), 2.24 (s, 3H), 1.75-1.60 (m, 4H).
Reaction SMILES: [CH:1]1([C:6]([OH:8])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)(Cl)=O.[H-].[Na+].[C:15]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>C1COCC1>[CH2:20]([O:19][C:17](=[O:18])[CH:16]([C:6]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:8])[C:15]([O:23][CH2:24][CH3:25])=[O:22])[CH3:21]
Reactant: O=C(O)C1CCCC1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C(C(=O)OCC)C(=O)C1CCCC1
Temperature: 25 °C
Yield: 100.9 %

Procedure:
Cyclopentanecarboxylic acid (10.0 g, 87.7 mmol) was heated under reflux with thionyl chloride (13 mL, 176 mmol). After 2 hrs the thionyl chloride was distilled under reduced pressure to give the crude acid chloride (9.8 g, 74.2 mmol) as a liquid. In another vessel, 50% sodium hydride (4.28 g, 89.09 mmol) was taken up in THF (100 mL) and diethyl malonate (11.88 g, 74.24 mmol) was added dropwise at 0° C. Into this mixture the previously-prepared acid chloride (9.8 g, 74.2 mmol) was added dropwise at 0° C. and the reaction mixture was stirred at r.t. for an hour. The reaction was quenched with cold water and extracted with ethyl acetate. The combined organic layer was washed with water, sodium bicarbonate solution, brine solution, dried over sodium sulfate, filtered and concentrated to afford 2-cyclopentanecarbonyl malonic acid diethyl ester (19.2 g, 85.5%) as a liquid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1.[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24].C(N(CC)CC)C>CCOCC>[CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)[C:23](=[O:24])[C:22]1[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=1[Cl:20]
Reactant: COC(=O)CCCCCCCNc1cccc(Cl)c1
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(=O)CCCCCCCN(C(=O)c1ccccc1Cl)c1cccc(Cl)c1

Procedure:
As described in example 3(b), the reaction is carried out with 10 g (35 mmol) of 8-(3-chlorophenylamino)-caprylic acid methyl ester, 6.2 g (35 mmol) of 2-chlorobenzoic acid chloride, 3.9 g (39 mmol) of triethylamine and 100 cc. of ether. Reaction time: 24 hours, reaction temperature: 25° C. The crude product is further purified chromatographically on silicic acid gel using chloroform as eluant.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:16]C(=O)C.O.S(=O)(=O)(O)O>C(O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:14])([F:15])[F:13])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH2:16]
Reactant: CC(=O)Nc1ccc2ccc(C(F)(F)F)cc2c1Cl
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: Nc1ccc2ccc(C(F)(F)F)cc2c1Cl
Temperature: 25 °C

Procedure:
A mixture of 1-chloro-7-trifluoromethyl-2-acetamidonaphthalene (700 mg, 2.43 mmol), water (3 mL) and concentrated sulfuric acid (3 mL in ethanol (6 mL) is heated to reflux temperature under a N2 atmosphere for 1 hour. After cooling to room temperature, the mixture is extracted with EtOAc. The extracts are washed with water, brine, dried (Na2SO4) and concentrated. Flash chromatography on silica gel (3:1 hexanes/EtOAc) gives 1-chloro-7-trifluoromethyl-2-aminonaphthalene as a white solid.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1.I[CH3:20]>CN(C)C=O>[F:3][C:4]1[CH:5]=[C:6]([N:10]([CH3:20])[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(Nc1cccc(F)c1)c1ccccn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)c1ccccn1)c1cccc(F)c1
Reaction time: 0.5 h
Yield: 51.7 %

Procedure:
To a suspension of 60% sodium hydride (1.76 g, 44 mmol) in dry dimethylformamide (50 mL) under nitrogen was added dropwise a solution of N-(3-fluorophenyl)-2-pyridinecarboxamide (6.87 g, 32 mmol), prepared by the process of Example 4, Step 1, in dimethylformamide (25 mL) over 30 minutes. After 30 minutes more, iodomethane (3.58 mL, 57 mmol) was added. The reaction mixture was quenched with water (500 mL), extracted with ether (3×400 mL) and further extracted with ethyl acetate (300 mL). After washing with brine the ethyl acetate layer was combined with the other organic extracts, which were dried and preadsorbed onto silica gel. Flash chromatography (250 g of silica gel gradient elution with 20-50% ethyl acetate in petroleum ether) was utilized to afford N-(3-fluorophenyl)-N-methyl-2-pyridinecarboxamide (3.81 g, 52%) m.p. 75°-78° C.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].C([Li])CCC.Cl[Sn:21]([CH3:24])([CH3:23])[CH3:22]>C1COCC1>[CH3:22][Sn:21]([CH3:24])([CH3:23])[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)Nc1ccsc1Br
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccsc1[Sn](C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of tert-butyl (2-bromo-3-thienyl)carbamate (4.81 g, 17.3 mmol) in THF (42 mL) was added 2.5 M n-butyllithium in hexanes (15.2 mL, 38.0 mmol) dropwise at −78° C. After stirring for 45 min, 1.0 M chlorotrimethylstannane in THF (19.0 mL, 19.0 mmol) was added. The resulting mixture was allowed to warm to room temperature. The reaction was quenched with brine (70 mL) and extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to give the desired product. 1H NMR (300 MHz, CDCl3) δ 7.49 (1H, d, J=4.8 Hz), 7.13 (1H, d, J=4.8 Hz), 6.39 (1H, brs), 1.50 (9H, s), 0.36 (9H, s) ppm.
Reaction SMILES: [ClH:1].Cl.C([O:7][CH:8](OCCCC)[C@H:9]([CH2:40][CH2:41][CH2:42][NH:43][C:44](=[NH:46])[NH2:45])[NH:10][C:11](=[O:39])[C@H:12]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[NH:13][C:14](=[O:31])[C@H:15]1[CH2:19][CH2:18][C:17](=[O:20])[N:16]1[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])CCC.[OH-].[Na+]>C(#N)C>[ClH:1].[CH2:24]([O:23][C:21]([N:16]1[C:17](=[O:20])[CH2:18][CH2:19][C@@H:15]1[C:14]([NH:13][C@H:12]([C:11]([NH:10][C@H:9]([CH:8]=[O:7])[CH2:40][CH2:41][CH2:42][NH:43][C:44](=[NH:45])[NH2:46])=[O:39])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:31])=[O:22])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCCCOC(OCCCC)[C@H](CCCNC(=N)N)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1C(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: N=C(N)NCCC[C@@H](C=O)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1C(=O)OCc1ccccc1
Yield: 75 %

Procedure:
After 1N hydrochloric acid aqueous solution (5 ml) was added to a solution of N-benzyloxycarbonyl-D-pyroglutamyl-L-phenylalanyl-L-argininal dibutylacetal hydrochloride (72 mg, 0.10 mmol) in acetonitrile (10 ml), the mixture was reacted at 36° C. for 1.5 hour with stirring. After completion of the reaction, pH of the reaction mixture was adjusted to 4.8 with 1N sodium hydroxide aqueous solution. The solvent was distilled off under reduced pressure and chloroform was added to the residue. Insoluble matters were removed by filtration. After the filtrate was concentrated, the residue was recrystallized from chloroform-hexane to give 44 mg (75%) of N-benzyloxycarbonyl-D-pyroglutamyl-L-phenylalanyl-L-argininal hydrochloride.
Reaction SMILES: [CH:1]1([CH:7]([NH:24][C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=2)[C:8]2[C:9]([CH2:22][CH3:23])=[N:10][N:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH3:21])[CH:14]=3)[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH2:56][CH2:57][CH:58]([CH3:63])[C:59]([O:61][CH3:62])=[O:60]>CN(C)C=O.O>[CH:1]1([CH:7]([NH:24][C:25]2[CH:33]=[CH:32][C:28]([C:29]([NH:56][CH2:57][CH:58]([CH3:63])[C:59]([O:61][CH3:62])=[O:60])=[O:30])=[CH:27][CH:26]=2)[C:8]2[C:9]([CH2:22][CH3:23])=[N:10][N:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH3:21])[CH:14]=3)[CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)C(C)CN
Reactant: CCOc1cccc(-n2cc(C(Nc3ccc(C(=O)O)cc3)C3CCCCC3)c(CC)n2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cccc(-n2cc(C(Nc3ccc(C(=O)NCC(C)C(=O)OC)cc3)C3CCCCC3)c(CC)n2)c1
Reaction time: 8 h
Yield: 13.6 %

Procedure:
4-({Cyclohexyl[1-(3-ethoxyphenyl)-3-ethyl-1H-pyrazol-4-yl]methyl}amino)benzoic acid (0.18 g) synthesized in the above-mentioned (2) was dissolved in N,N-dimethylformamide (3 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.11 g), 1-hydroxybenzotriazole.monohydrate (0.09 g) and methyl 3-amino-2-methylpropanoate (0.07 g) were added at room temperature, and the mixture was stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1, volume ratio) to give methyl 3-({[4-({cyclohexyl[1-(3-ethoxyphenyl)-3-ethyl-1H-pyrazol-4-yl]methyl}amino)phenyl]carbonyl}amino)-2-methylpropanoate (0.03 g) as a yellow oil. This was dissolved in ethanol (2.0 mL), 1N aqueous sodium hydroxide solution (0.5 mL) was added at room temperature, and the mixture was stirred at room temperature for 0.5 hr. Ethanol was evaporated under reduced pressure, and 1N hydrochloric acid (0.5 mL) was added to the residue. The precipitate was washed with water to give the title object compound (0.02 g, 9%) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH:11][C:12]([CH:14]([O:16]C(=O)C)[CH3:15])=[O:13])[NH:7][C:6](=[O:20])[CH2:5]2.O.[OH-].[Na+].Cl>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH:11][C:12](=[O:13])[CH:14]([OH:16])[CH3:15])[NH:7][C:6](=[O:20])[CH2:5]2
Reactant: CC(=O)OC(C)C(=O)Nc1cc2c(cc1F)CC(=O)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(O)C(=O)Nc1cc2c(cc1F)CC(=O)N2
Yield: 65.6 %

Procedure:
Acetic acid 1-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-ylcarbamoyl)-ethyl ester 8a (1.86 g, 6.4 mmol) was dissolved in 20 ml of methanol under stirring, and added with 10 ml of water and sodium hydroxide solution (10 ml, 0.7 mol/L) to the solution and stirred for 4 hours at room temperature. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was neutralized with hydrochloride acid (1 mol/L) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and dried to obtain N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-propionamide 8b (1.0 g, yield 70%) as a white solid.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][CH2:10][CH:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][CH:27]=1)=[O:25].Cl>O1CCCC1>[Br:32][C:29]1[CH:30]=[CH:31][C:26]([C:24](=[O:25])[CH2:23][C:11]([CH2:10][CH2:9][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:27][CH:28]=1
Reactant: CCOC(=O)C(CCc1ccccc1)C(=O)OCC
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CCc1ccccc1)(CC(=O)c1ccc(Br)cc1)C(=O)OCC
Temperature: 0 °C
Reaction time: 16 h
Yield: 60.5 %

Procedure:
To a 500 mL 3-neck round-bottom flask equipped with an argon inlet and an addition funnel, was added sodium hydride (95%, 1.40 g, 58.3 mmol) followed by tetrahydrofuran (30 mL). The resulting suspension was then cooled to 0° C. and diethyl 2-(2-phenylethyl)malonate (14.0 g, 53.0 mmol) in tetrahydrofuran (20 mL) was added dropwise over 20 minutes. The cooling bath was removed and the reaction mixture was allowed to warm to rt over 45 minutes. A solution of 2-bromo-1-(4-bromophenyl)ethanone (14.72 g, 58.26 mmol) in tetrahydrofuran (40 mL) was rapidly added and the resulting orange-red mixture was stirred at rt for 16 h. The mixture was carefully poured into 300 mL of 1N hydrochloric acid, and the resulting mixture was stirred for 10 minutes and extracted twice with ethyl acetate. The combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (Biotage flash 75, 10:90 ethyl acetate/hexane) to afford diethyl 2-[2-(4-bromophenyl)-2-oxoethyl]-2-(2-phenylethyl)malonate (14.8 g, 61%). LC-MS ret. time 3.89 min, m/z 461.2 (MH+); 1H NMR (300 MHz, CDCl3) δ 1.26 (t, 6H), 2.41–2.45 (m, 2H), 2.56–2.59 (m, 2H), 3.67 (s, 2H), 4.23 (q, 4H), 7.14–7.22 (m, 3H), 7.22 (d, 2H), 7.61 (d, 2H), 7.79 (d, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][OH:15])[CH2:9][CH2:8]1.[CH2:16]=[C:17]1[O:21][C:19](=[O:20])[CH2:18]1>C1(C)C=CC=CC=1>[C:19]([O:15][CH2:14][CH2:13][N:10]1[CH2:9][CH2:8][N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:12][CH2:11]1)(=[O:20])[CH2:18][C:17]([CH3:16])=[O:21]
Reactant: OCCN1CCN(c2ccccn2)CC1
Reactant: C=C1CC(=O)O1
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)OCCN1CCN(c2ccccn2)CC1
Yield: 78.3 %

Procedure:
To a solution of 4-(2-pyridyl)-1-piperazineethanol (4.65 g) in toluene (3 ml) was added dropwise diketene (2.26 g) under stirring at 70°-80° C. The mixture was further stirred at room temperature for an hour and purified by silica gel chromatography [eluent: dichloromethanemethanol (95:5)] to give 2-[4-(2-pyridyl)-1-piperazinyl]ethyl acetoacetate as an oil (5.12 g, 78.3%). IR(Neat): 1740, 1715 cm-1. NMR(CDCl3)δ: 2.26(3H, s), 2.47-2.79(6H, m), 3.40-3.64(6H, m), 4.27(2H, t, J=6), 6.43-6.69(2H, m), 7.24-7.56(1H, m), 8.02-8.18(1H, m).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14][CH2:13]1)([O-])=O.O>C(O)C.Cl>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][N:12]1[CH2:13][CH2:14][CH:15]([NH:18][C:19](=[O:26])[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:16][CH2:17]1
Reactant: O=C(NC1CCN(CCc2ccccc2[N+](=O)[O-])CC1)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1ccccc1CCN1CCC(NC(=O)c2ccccc2)CC1
Reaction time: 4 h
Yield: 42.4 %

Procedure:
A solution of 1-[2-(o-nitrophenyl)ethyl]-4-benzamidopiperidine (4.25 g.) in absolute ethanol (150 ml.) was added over 50 minutes to stirred stannous chloride (10.82 g.) in concentrated hydrochloric acid (12 ml.). and water (7.5 ml.) at 60°-70° C. After addition, the mixture was stirred at this temperature for 4 hours before cooling and evaporating the ethanol. Continuous extraction into chloroform of the neutralised (with 2N sodium hydroxide solution) aqueous fraction gave the title compound (1.65 g.). The aqueous layer after extraction was made alkaline with 2N sodium hydroxide solution and extracted with more chloroform to give a further batch of the title compound (2.36 g.). The total product was crystallised from ethanolic hydrogen chloride and ether to give the hydrochloride of the title compound (2.75 g.), m.p. 263.8° C. (Found: C, 60.3; H, 7.0; N, 10.5. C20H25N3O. 2HCl requires C, 60.6; H, 6.9; N, 10.60%).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([S:27][CH3:28])[N:8]2[C:14]3[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=3[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])=[N:11][CH2:10][C:9]=12)=O.[NH3:29].[K+].[Br-]>CO>[Cl:19][C:17]1[CH:16]=[CH:15][C:14]2[N:8]3[C:7]([S:27][CH3:28])=[N:6][C:5]([C:3]([NH2:29])=[O:2])=[C:9]3[CH2:10][N:11]=[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[C:13]=2[CH:18]=1
Reactant: COC(=O)c1nc(SC)n2c1CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2
Reactant: N
Agent: [Br-]
Agent: [K+]
Solvent: CO
Product: CSc1nc(C(N)=O)c2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
A mixture of 3 g (0.007 mole) of 8-chloro-6-(2-chlorophenyl)-1-methylthio-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid methyl ester and 60 ml of 25% solution of ammonia in methanol was heated at 130° in a steel bomb for 18 hrs. The contents of the bomb were evaporated at reduced pressure to give light tan crystals, which were recrystallized from methanol/methylene chloride to yield light tan prisms with mp 270°-274° (dec.). Uv λ max 217 mμ (ε=47,200) infl 242 (23,200) sh 270 (11,500), ir (KBr) 3365, 3250, 3215, 3150 cm-1 (NH2) 1675, 1650, 1590 (CON).
Reaction SMILES: [OH:1][CH:2]=[C:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14])[C:4]([O:6][CH3:7])=[O:5].[C:15](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>COCCOC>[CH3:15][O:1][CH:2]=[C:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(=CO)c1ccccc1C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: COS(=O)(=O)OC
Product: COC=C(C(=O)OC)c1ccccc1C
Temperature: 25 °C
Yield: 97 %

Procedure:
To a flask (1000 mL), 48 g of methyl 3-hydroxy-2-o-tolylacrylate, 54.4 g of potassium carbonate, and 500 mL of ethylene glycol dimethyl ether were added. The mixture was stirred at room temperature for an hour, and then 36 mL of dimethyl sulfate was added. The mixture was allowed to react for between 6 and 8 hrs with stiffing at room temperature. The reaction was monitored with thin layer chromatography (TLC) until the reactants were basically consumed. Subsequently, the mixture was filtered, the solvent was removed by vacuum distillation, the residue was washed with water (1000 mL), extracted with ethyl acetate (2×300 mL), dried with anhydrous sodium sulfate and concentrated under reduced pressure to yield a light yellow oily product with a yield of 97%.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]1([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:31])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ncc(N)n3)s2)OCCO1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3ncoc3-c3ccccc3)n2)s1

Procedure:
Following general procedure A followed by B, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:30][CH2:29][C@@:28]2([CH3:31])[C@@H:12]([CH2:13][CH2:14][C:15]3[C:16]4[C@:24]([CH3:32])([CH2:25][CH2:26][C:27]=32)[C@@H:19]([C@@H:20]([CH:22]=[O:23])[CH3:21])[CH2:18][CH:17]=4)[C:11]1([CH3:34])[CH3:33])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:35]1([Mg]Br)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[Cl-].[NH4+]>O1CCCC1>[C:1]([O:9][C@H:10]1[CH2:30][CH2:29][C@@:28]2([CH3:31])[C@@H:12]([CH2:13][CH2:14][C:15]3[C:16]4[C@:24]([CH3:32])([CH2:25][CH2:26][C:27]=32)[C@@H:19]([C@H:20]([CH3:21])[CH:22]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[OH:23])[CH2:18][CH:17]=4)[C:11]1([CH3:33])[CH3:34])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Br[Mg]c1ccccc1
Reactant: C[C@H](C=O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](OC(=O)c2ccccc2)C(C)(C)[C@@H]1CC3
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[C@H](C(O)c1ccccc1)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](OC(=O)c2ccccc2)C(C)(C)[C@@H]1CC3
Temperature: 25 °C
Reaction time: 3 h

Procedure:
ix)—A solution of the aldehyde 10 (2.0 g), obtained in the previous step, in dry tetrahydrofuran (17 ml) was added dropwise to a 1 M solution of phenylmagnesium bromide (13 ml) in tetrahydrofuran. The reaction mixture was stirred at room temperature for 3 h. A saturated aqueous solution of ammonium chloride was added and the product was extracted into ethyl acetate. The combined organic phases were washed with water, dried over sodium sulfate, and concentrated under reduced pressure to give (3β,5α,20S)-4,4,20-trimethyl-21-phenylpregna-8,14-diene-3,21-diol 3-benzoate (11) (3.0 g) which was used in the following step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Br:26])[C:5]2[N:10]=[C:9]([C:11]3[N:12]([C:17]4[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH:13]=[C:14]([Br:16])[CH:15]=3)[O:8][C:7](=[O:24])[C:6]=2[CH:25]=1.[CH3:27][NH:28][NH2:29].O1CCCC1>O>[Br:16][C:14]1[CH:15]=[C:11]([C:9]([NH:10][C:5]2[C:4]([Br:26])=[CH:3][C:2]([Br:1])=[CH:25][C:6]=2[C:7]([N:28]([CH3:27])[NH2:29])=[O:24])=[O:8])[N:12]([C:17]2[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:13]=1
Reactant: CNN
Reactant: O=c1oc(-c2cc(Br)cn2-c2ncccc2Cl)nc2c(Br)cc(Br)cc12
Solvent: C1CCOC1
Solvent: O
Product: CN(N)C(=O)c1cc(Br)cc(Br)c1NC(=O)c1cc(Br)cn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 0.50 g of 6,8-dibromo-2-[4-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrrol-2-yl]-4H-3,1-benzoxazine-4-one, 0.15 ml of methylhydrazine and 8 ml of tetrahydrofuran was stirred at room temperature for 20 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography to obtain 0.39 g of 4-bromo-N-[4,6-dibromo-2-(N-methylhydrazinocarbonyl)phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrrole-2-carboxamide of the formula: