Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([N:21]1[CH2:22][CH2:23][N:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N+:9]([O-:11])=[O:10])[CH2:19][CH2:20]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.1 %

Procedure:
Benzyl bromide (3.1 mL, 26 mmol) was added to a mixture of 1-(2-nitrophenyl)piperazine (4.91 g, 24 mmol) and potassium carbonate (8.2 g, 59 mmol) in dimethylformamide (30 mL) and the mixture was stirred at room temperature for 2 h. The solvent was evaporated under reduced pressure and the residue was azeotroped with xylene. The residue was diluted with ethyl acetate, washed with brine (×3), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/Hexane (60:40) to give the title compound as an orange oil (4.0 g, 57%). δH (250 MHz, CDCl3) 7.75 (1H, dd, J 1.6, 8.1 Hz), 7.46 (1H, dt, J 1.6, 7.3 Hz), 7.34-7.24 (5H, m), 7.12 (1H, dd, J 7.1, 8.3 Hz), 7.01 (1H, dt, J 1.2, 8.3 Hz), 3.57 (2H, s), 3.10-3.05 (4H, m), and 2.63-2.58 (4H, m).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[CH3:9].[Br:10]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[CH2:9][Br:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(Br)cccc1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1c(Br)cccc1Br
Temperature: 25 °C
Yield: 99.7 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer, reflux condenser and nitrogen inlet was purged with nitrogen and charged with 2,6-dibromotoluene (2.50 g, 10.0 mmol), N-bromosuccinimide (1.78 g, 10.0 mmol) and carbon tetrachloride (40 mL). The solution was heated to 80° C. (oil bath temperature), and 2,2′-azobisisobutyronitrile (164 mg, 1.00 mmol) was added. The resulting mixture was refluxed for 14 h. After that time, the mixture was cooled to room temperature and filtered. The filter cake was washed with carbon tetrachloride (2×20 mL). The filtrate was diluted with ethyl acetate (200 mL) and washed with water (40 mL), saturated aqueous sodium bicarbonate (40 mL) and brine (40 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford a quantative yield (3.28 g) of 1,3-dibromo-2-(bromomethyl)benzene as a yellow solid: mp 77-78° C.; 1H NMR (300 MHz, CDCl3) d 7.55 (d, 2H, J=8.1 Hz), 7.07 (t, 1H, J=8.1 Hz), 4.83 (s, 2H)
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH2:8]([O:10][CH:11]([O:16][CH2:17][CH3:18])[CH2:12][CH2:13][CH2:14][NH2:15])[CH3:9].C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1>[CH2:17]([O:16][CH:11]([O:10][CH2:8][CH3:9])[CH2:12][CH2:13][CH2:14][NH:15][C:1](=[O:3])[CH3:2])[CH3:18]
Reactant: CCOC(CCCN)OCC
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: CCOC(CCCNC(C)=O)OCC

Procedure:
20 g (196 mmol) of acetic anhydride in 100 ml of benzene are added drop by drop, at reflux, to a stirred suspension of 32 g (198 mmol) of 4,4-diethoxybutylamine and 24 g (174 mmol) of potassium carbonate in 600 ml of benzene. The mixture is heated to reflux for 15 min. and cooled, the precipitate is filtered and the filtrate is evaporated to dryness. The residual oil is treated with vegetable charcoal in 300 ml of diethyl ether and, after filtration and evaporation of the filtrate in vacuo, 37.3 g of oily product are obtained. n20D =1.4472.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)(=[O:7])[CH3:6].[OH-].[Na+]>>[C:5]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([N+:1]([O-:4])=[O:2])=[CH:18][C:11]=2[CH2:10][CH2:9]1)(=[O:7])[CH3:6]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)N1CCc2ccccc2CC1
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)N1CCc2ccc([N+](=O)[O-])cc2CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a cooled solution of HNO3 (70%) at 10° C., 3-acetyl-2,3,4,5-tetrahydro-1H-3-benzazepine (6.8 g, preparation reported in WO 02/40471) was added portionwise over 20 min. After addition mixture was allowed to warm at rt. and stirred for further 4 h. Mixture was poured into ice and pH adjusted to 11 using NaOH (conc) then was extracted with DCM. The organic layer was collected and the aqueous phase extracted twice with DCM. The combined DCM layers were concentrated to provide the target compound (7.74 g), which was used in further conversions without any purification.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:9]2[CH2:10][CH2:11][CH2:12][C:8]=2[C:7]([C:13](=[NH:15])[NH2:14])=[N:6]1.C[O:21][C:22](=O)[C:23]([CH3:30])([CH3:29])[CH:24]([C:27]#[N:28])[C:25]#[N:26]>C(O)(C)(C)C>[NH2:26][C:25]1[C:24]2[C:23]([CH3:30])([CH3:29])[C:22](=[O:21])[NH:28][C:27]=2[N:15]=[C:13]([C:7]2[C:8]3[CH2:12][CH2:11][CH2:10][C:9]=3[N:5]([CH2:4][C:3]3[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=3[F:1])[N:6]=2)[N:14]=1
Reactant: N=C(N)c1nn(Cc2ccccc2F)c2c1CCC2
Reactant: COC(=O)C(C)(C)C(C#N)C#N
Solvent: CC(C)(C)O
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4c3CCC4)nc(N)c21

Procedure:
300 mg (1.15 mmol) of 1-(2-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboximidamide was dissolved with 2 ml tert.-butanol, 287 mg (1.38 mmol) of methyl-3,3-dicyano-2,2-dimethylpropanoate in 2 ml tert.-butanol and 181 mg (1.61 mmol) of potassium tert.-butylate was added and it was heated under reflux for 72 h. It was evaporated to dryness and the residue was mixed with water/isopropanol (v/v=3:1). The solid was filtered off and dried under high vacuum. 385 mg (80% of theor.) of the target compound was obtained.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH:16]=1)[C:11]([OH:13])=[O:12].C1(N=C=NC2CCCCC2)CCCCC1.O[N:40]1[C:44](=[O:45])[CH2:43][CH2:42][C:41]1=[O:46]>CCOCC>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH:16]=1)[C:11]([O:13][N:40]1[C:44](=[O:45])[CH2:43][CH2:42][C:41]1=[O:46])=[O:12]
Reactant: O=C(O)c1cc(OC2CCCCO2)cc(OC2CCCCO2)c1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Product: O=C(ON1C(=O)CCC1=O)c1cc(OC2CCCCO2)cc(OC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 40 h
Yield: 89.8 %

Procedure:
A mixture of 3,5-bis[(tetrahydro-2H-pyran-2-yl)oxy]benzoic acid (5.00 g, 15.5 mmol), 1,3-dicyclohexylcarbodiimide (3.72 g, 18.1 mmol) and N-hydroxysuccinimide (2.08 g, 18.0 mmol) in tetrahydroftiran (100 mL) was stirred at room temperature for 40 h. Ether (100 mL) was added and the mixture was stirred for 20 min. The white solid was filtered off and discarded. The solvent was evaporated from the filtrate, and the residue was coated onto silica gel and chromatographed (50-75% ethyl acetate/hexanes) to give 1-[[3,5-bis[(tetrahydro-2H-pyran-2-yl)oxy]benzoyl]oxy]-2,5-pyrrolidinedione (5.84 g, 90%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=O)=[C:24]([CH:28]=[CH2:29])[N:23]=[C:22]3[O:30][CH2:31][CH3:32])=[C:16]([F:33])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:34][OH:35].N1C=CC=CC=1>O>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[N:34][OH:35])=[C:24]([CH:28]=[CH2:29])[N:23]=[C:22]3[O:30][CH2:31][CH3:32])=[C:16]([F:33])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C=Cc1nc(OCC)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2F)c1C=O
Reactant: NO
Solvent: O
Solvent: c1ccncc1
Product: C=Cc1nc(OCC)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2F)c1C=NO
Reaction time: 8 h
Yield: 91.4 %

Procedure:
A solution of compound A (17.9 g, 39.7 mmol), hydroxylamine (3.9 g, 119 mmol), pyridine (200 mL), and water (100 mL) were combined. After stirring overnight, water (50 mL) was added and the precipitate was filtered to yield compound B as an off-white solid (16.9 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[C:6]([O:13][CH3:14])[CH:5]=1>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([O:13][CH3:14])[CH:5]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(OC)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(N)c(OC)c1
Reaction time: 3 h

Procedure:
A 2-L, Parr high-pressure hydrogenation bottle (glass rated to 80 psi) was charged with Pd/C (10 wt % on Carbon, 5 g), ethyl acetate (800 mL) and 32 (120.5 g, 0.57 mol). The reaction mixture was charged with H2 (30 psi) on a Parr apparatus. Charging H2 was continued carefully several times until the pressure remained steady. This took approximately about 3 h. The reaction was shaken for an additional 0.5 h. After the hydrogenation, the reaction mixture was diluted with ethyl acetate to dissolve some of the precipitated product and directly passed through a short pad of Celite, and washed with ethyl acetate. The solvent was evaporated to yield 4-amino-3-methoxy-benzoic acid methyl ester 33 as a white solid. 1H NMR (400 MHz, CDCl3) δ: 7.55 (dd, 1H), 7.45 (d, 1H), 6.66 (d, 1H), 4.21 (s, 2H), 3.90 (s, 3H), 3.86 (s, 3H). MS (ES) m/z 182.1 (MH)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:2]=1.C([Li])(C)(C)C.N1([CH:26]=[O:27])CCCCC1>C1COCC1.CCCCC>[CH:26]([C:4]1[CH:5]=[CH:6][N:1]=[CH:2][C:3]=1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:27]
Reactant: O=CN1CCCCC1
Reactant: CC(C)(C)OC(=O)Nc1cccnc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(C)(C)OC(=O)Nc1cnccc1C=O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 60.3 %

Procedure:
A solution of tert-butyl pyridin-3-ylcarbamate (17.7 g, 91.1 mmol) in THF (300 mL) was cooled to −78° C. and treated with 1.70 M tert-butyllithium in pentane (129 mL). Upon completion of the addition, the reaction was stirred at −78° C. for an additional 15 min and then at −20° C. for 1.5 h. 1-piperidinecarboxaldehyde (30.4 mL, 0.273 mol) was added while the temperature was maintained below at −15° C., and then the mixture was allowed to stir at room temperature overnight. The solution was cooled to 0° C. and was quenched by the addition of 1 M HCl to bring the pH to 2. Solid Na2CO3 was then added to adjust the pH to 7. The solution was extracted with ethyl acetate three times, and the combined organic solutions were washed with water (3×) and brine. The organic layer was dried, filtered, and volatiles evaporated. The residue was purified by silica gel chromatography (50% ethyl acetate/hexanes) to give the desired product as a yellow solid (12.2 g, 60%). LCMS for C11H15N2O3(M+H)+: m/z=223.1.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[NH:5][C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.O(C1C=CC(C(C2C=CC(OC#N)=CC=2)(C)C)=CC=1)[C:22]#[N:23].O>C1COCC1.[Cl-].[Na+].O>[Br:3][C:4]1[N:5]([C:22]#[N:23])[C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: CC(C)(c1ccc(OC#N)cc1)c1ccc(OC#N)cc1
Reactant: COc1ccc(-c2c(Br)[nH]c3ccccc23)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2c(Br)n(C#N)c3ccccc23)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 87.7 %

Procedure:
NaH (18.35 mg, 0.76 mmol) was stirred in dry THF (1 ml) at 0° C. and 2-bromo-3-(4-methoxyphenyl)-1H-indole (210 mg, 0.69 mmol) dissolved in dry THF (4.5 ml) was added dropwise. The mixture was stirred at 0° C. for 5 min and then 2,2-bis-(4-cyanatophenyl)propane (251 mg, 0.90 mmol) dissolved in dry THF (4.5 ml) was added dropwise. Water was added and this mixture was stirred for 30 min Brine was added and the aqueous mixture was extracted with DCM. The solvent was concentrated and the crude product was purified on silica (EtOAc/n-Heptane 1:4). 198 mg 2-bromo-3-(4-methoxyphenyl)-1H-indole-1-carbonitrile was obtained.
Reaction SMILES: C(OC=CC[S:8]C)(=O)C.CO.[C]=O.[C:14]([O:17][CH:18]([CH2:23][CH2:24][S:25][CH3:26])[C:19]([O:21][CH3:22])=O)(=[O:16])[CH3:15]>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[C:14]([O:17][CH:18]([CH2:23][CH2:24][S:25][CH3:26])[C:19]([O:21][CH3:22])=[S:8])(=[O:16])[CH3:15]
Reactant: CSCC=COC(C)=O
Reactant: COC(=O)C(CCSC)OC(C)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [C]=O
Solvent: C1CCOC1
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=S)C(CCSC)OC(C)=O
Temperature: 100 °C
Yield: 19.5 %

Procedure:
0.5 mmoles 1-acetoxy-3-methylthiopropene (Z:E ratio 43:57) and 2.5 mmoles methanol were charged into a 71 cc stainless steel bomb equipped with a glass liner and a Teflon coated stir bar. Ten mole percent, based on 1-acetoxy-3-methylthiopropene, of a catalyst comprising bis(triphenylphosphine)dichloropalladium, (φ3P)2PdCl2, was added. Toluene was included as an internal standard. Five milliliters of tetrahydrofuran as a solvent were also included in the reaction system. The reaction mixture was charged under argon. The bomb was sealed and carbon monoxide at a pressure of 1000 psi (at room temperature) was charged to the bomb, and the bomb was heated to 100° C. and allowed to react for 92.5 hours with stirring. At the termination of the reaction, the reaction products were analyzed by gas chromatography and it was found that 2-acetoxy-4-(methylthio)butanoic acid, methyl ester was produced in a yield of 28.6 percent and that 2-acetoxy-4-(methylthio)thiobutanoic acid, methyl ester was produced in a yield of 19.5 percent, based on the 1-acetoxy-3-methylthiopropene reactant charged. Note that each of the products is hydrolyzable to methionine hydroxy analog.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[C:18]([Cl:19])=[CH:17][N:16]=[CH:15][C:14]=2[Cl:20])[CH2:9][CH2:8]1)=[O:6].[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([BH3-])#N.[Na+]>CO>[CH2:21]([NH:1][CH2:2][CH2:3][NH:4][C:5]([CH:7]1[CH2:8][CH2:9][N:10]([C:13]2[C:14]([Cl:20])=[CH:15][N:16]=[CH:17][C:18]=2[Cl:19])[CH2:11][CH2:12]1)=[O:6])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=Cc1ccccc1
Reactant: NCCNC(=O)C1CCN(c2c(Cl)cncc2Cl)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=C(NCCNCc1ccccc1)C1CCN(c2c(Cl)cncc2Cl)CC1
Reaction time: 2 h
Yield: 30 %

Procedure:
To a solution of N-(2-aminoethyl)-1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide E13 (50 mg, 0.16 mmol) in MeOH (5 mL) was added benzaldehyde (16 μL, 0.16 mmol). After stirring for 2 h, sodium cyanoborohydride (20 mg, 0.32 mmol) was added and the mixture was stirred for a further 20 h. The solvent was removed under reduced pressure, the residue was dissolved in EtOAc (20 mL), washed with a saturated solution of sodium hydrogencarbonate (25 mL), brine (25 mL), dried (MgSO4) and the solvent was removed under reduced pressure. The crude product was purified by preparative tlc on silica gel (CH2Cl2, MeOH, 9:1) to furnish the title compound as a colourless oil (19 mg, 30%), umax (CHCl3)/cm−1 3015, 2850, 1659, 1558, 1512, 1236, 1146, 1036, 934; m/z (ESI) C20H25Cl2N4O requires 407.1400, found [M+H]+ 407.1401.
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[N:8]=[CH:9][N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14](=[O:21])[N:13]([CH3:22])[CH2:12][C:11]=12)=[O:6])[C:2]#[CH:3].IN1C(=O)CCC1=O.[CH2:31]([NH:34][CH2:35][CH2:36][CH3:37])[CH2:32][CH3:33]>C(O)(=O)C>[CH2:31]([N:34]([CH2:3][C:2]1[O:6][C:5]([C:7]2[N:8]=[CH:9][N:10]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[C:14](=[O:21])[N:13]([CH3:22])[CH2:12][C:11]=23)=[N:4][CH:1]=1)[CH2:35][CH2:36][CH3:37])[CH2:32][CH3:33]
Reactant: CCCNCCC
Reactant: C#CCNC(=O)c1ncn2c1CN(C)C(=O)c1ccccc1-2
Agent: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: CCCN(CCC)Cc1cnc(-c2ncn3c2CN(C)C(=O)c2ccccc2-3)o1
Temperature: 25 °C
Reaction time: 46 h
Yield: 25.4 %

Procedure:
A solution of 2.94 g (0.010 mol) of 5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid prop-2-ynylamide in 60 ml of acetic acid was treated with 3.36 g (0.015 mol) of N-iodosuccinimide while gassing with argon. After stirring at room temperature for 46 hrs. the dark suspension obtained was completely freed from the solvents and dried azeotropically several times with toluene. The dark brown solid residue was dissolved in 100 ml of THF, treated with 13.7 ml (0.10 mol) of dipropylamine and stirred at room temperature for 3 hrs. The suspension obtained was completely freed from the solvents, the residue was partitioned between ethyl acetate and 1N aqueous hydrochloric acid and extracted. The aqueous-acidic phase was made basic and extracted with ethyl acetate. The organic phase was concentrated, the orange-brownish product was chromatographed over basic Alox (grade III) with dichloromethane/ethyl acetate 4:1 as the eluent and recrystallized from hot isopropyl ether. There was obtained 1.0 g (25%) of 3-(5-dipropylaminomethyl-oxazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as yellowish crystals; m.p. 133°-135°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10](=[O:32])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:13][CH:12]=1.[CH3:33][I:34]>>[I-:34].[CH3:33][N+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10](=[O:32])[C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:15][CH:16]=1
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)NCCc2ccccn2)cc1
Reactant: CI
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)NCCc2cccc[n+]2C)cc1
Product: [I-]
Yield: 90.7 %

Procedure:
The title compound is prepared by the procedure of Example 28 using 0.750 g of product from Example 58 and 12.13 g of methyl iodide. The residue is recrystallized from methyl alcohol to give 0.90 g of the desired product as colorless needles.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:15]#N)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[OH-:17].[Na+].Cl.[OH2:20]>O1CCOCC1.OO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:15]([OH:20])=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: O
Reactant: COc1ccc(C2(C#N)CCCCC2)cc1
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(C2(C(=O)O)CCCCC2)cc1
Yield: 71 %

Procedure:
A solution of 1-(4-methoxyphenyl)cyclohexanecarbonitrile (E2) (1.092 g, 5.07 mmol) in dioxane (6 ml) to a mixture of 2 M NaOH in water (150 ml) and 30% H2O2 in water (7.5 ml) was added and the resultant suspension was stirred under reflux for 4 days. The pH of the reaction medium was brought to pH 1 with conc. HCl (ca. 30 ml) and the obtained mixture was extracted with ethyl acetate (4×80 ml). The combined organic extract was washed with brine (50 ml) and dried (Na2SO4). The solvent was evaporated and the residue was chromatographed on silicagel (50 g) with benzene-ethyl acetate-acetic acid (9:1:0.15) as eluent affording the title compound (0.844 g, 71%) as a white solid. 1H NMR (CDCl3, HMDSO) δ: 1.05-1.91 (8H, m); 2.16-2.61 (2H, m); 3.76 (3H, s); 6.86 (2H, d, J=9.0 Hz); 7.34 (2H, d, J=9.0 Hz); 11.26 (1H, br s).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C@@H:6]([NH:15][C@H:16]([C:18]([N:20]1[C@H:29]([C:30]([OH:32])=[O:31])[CH2:28][C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH2:21]1)=[O:19])[CH3:17])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:5].[ClH:33].[OH-].[Mg+2:35].[OH-]>O>[CH3:1][CH2:2][O:3][C:4]([C@@H:6]([NH:15][C@H:16]([C:18]([N:20]1[C@H:29]([C:30]([OH:32])=[O:31])[CH2:28][C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH2:21]1)=[O:19])[CH3:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5].[Mg:35].[Cl-:33].[Mg+2:35].[Cl-:33]
Reactant: Cl
Agent: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Agent: [Mg+2]
Agent: [OH-]
Solvent: O
Product: [Cl-]
Product: [Mg]

Procedure:
In the liquid mixture, the 10.0 g of quinapril hydrochloride reacted with 1.23 g of magnesium hydroxide to produce 9.47 g of quinapril magnesium plus 1.00 g of magnesium chloride, plus 0.76 g of water. The liquid was then filtered to remove the excess magnesium hydroxide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH3:9].[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][Br:10]
Reactant: Cc1c(Cl)cccc1Br
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cccc(Br)c1CBr

Procedure:
2-bromo-6-chlorotoluene (20.55 g) and N-bromosuccinimide (19.6 g) were stirred together in carbon tetrachloride (100 ml) under reflux for 22 hours exposure to radiation from an infrared lamp. The resulting solution was cooled in ice, filtered and evaporated to yield the title product which was dissolved in petroleum ether (60-80). Part was recrystallised therefrom as pink needles (8.5 g) and part was recovered by evaporation as a dark orange solid (17.7 g) (total yield 26.2 g. 92%).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([C:19]1[CH:20]=[C:21]([C:28]2[CH:29]=[N:30][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:33]=2)[C:22]([OH:27])=[C:23]([CH:26]=1)[CH:24]=O)([CH3:18])([CH3:17])[CH3:16].[CH3:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.C(O)C.[ClH:48]>O1CCCC1>[ClH:48].[ClH:48].[C:15]([C:19]1[CH:20]=[C:21]([C:28]2[CH:29]=[N:30][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:32][CH:33]=2)[C:22]([OH:27])=[C:23]([CH2:24][N:42]2[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]2)[CH:26]=1)([CH3:16])([CH3:18])[CH3:17]
Reactant: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(C(F)(F)F)nc2)c1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CN1CCN(Cc2cc(C(C)(C)C)cc(-c3ccc(C(F)(F)F)nc3)c2O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 53 %

Procedure:
Sodium triacetoxyborohydride (0.30 g, 1.4 mmol) was added to a solution of 5-(tert-butyl)-2-hydroxy-3-(6-(trifluoromethyl)pyridin-3-yl)benzaldehyde (0.35 g, 1.1 mmol) and 1-methyl piperazine (0.14 mL, 1.3 mmol) in tetrahydrofuran (10 mL). The reaction mixture was stirred at room temperature under nitrogen for 16 hours. The reaction was partitioned between ethyl acetate (25 mL) and saturated aqueous sodium bicarbonate solution (25 mL). The organic phase was dried with sodium sulfate, filtered and concentrated under reduced pressure to give a yellow syrup. The product was purified using flash chromatography on silica eluting with a solvent gradient of 0 to 100% ethyl acetate in hexanes to give a yellow syrup which was dissolved in 1.25 M hydrochloric acid in ethanol (10 mL, 12.5 mmol). The mixture stood for 20 minutes and was then concentrated under reduced pressure to give a white solid which was triturated with diethyl ether (10 mL) and solid was filtered off to afford 4-(tert-butyl)-2-((4-methylpiperazin-1-yl)methyl)-6-(6-(trifluoromethyl)pyridin-3-yl)phenol dihydrochloride (0.26 g, 53% yield) as a white solid.