Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:16]=[CH:15][C:6]([O:7][CH:8]([CH2:12][CH2:13][CH3:14])[C:9]([OH:11])=O)=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18])#[N:2].ON1C2C=CC=CC=2N=N1.C1C=CC2N(O)N=NC=2C=1.CN(C)CCCN=C=NCC.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1.Cl.[CH3:72][O:73][C:74]1[CH:85]=[C:84]2[C:77]([NH:78][CH:79]=[C:80]2[CH2:81][CH2:82][NH2:83])=[CH:76][CH:75]=1>CN(C=O)C>[CH3:72][O:73][C:74]1[CH:85]=[C:84]2[C:77](=[CH:76][CH:75]=1)[NH:78][CH:79]=[C:80]2[CH2:81][CH2:82][NH:83][C:9](=[O:11])[CH:8]([O:7][C:6]1[CH:15]=[CH:16][C:3]([C:1]#[N:2])=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:5]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCC(Oc1ccc(C#N)c(C(F)(F)F)c1)C(=O)O
Reactant: COc1ccc2[nH]cc(CCN)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCCC(Oc1ccc(C#N)c(C(F)(F)F)c1)C(=O)NCCc1c[nH]c2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The compound was prepared in the following manner. To 0.25 gm (0.87 mmol) of 2-(4-cyano-3-trifluoromethyl-phenoxy)-pentanoic acid in dimethylformamdie “DMF” (15 mL) were added 0.14 gm (1.09 mmol) of 1-Hydroxy-benzotriazole HOBT, 0.2 gm (1.09 mmol) of (3-(dimethylamino)propyl)ethylcarbodiimide EDCl, 0.23 gm (2.39 mmol) N-methyl morpholine, and approximately 246 mg of 5-methoxytryptamine hydrochloride (1.09 mmol). The resultant mixtures were stirred at room temperature for approximately 18 hours. The reactions were quenched with sodium bicarbonate (20 mL) and extracted with ethyl acetate (3 times 20 mL). The solvent was removed in vacuo to obtain oils that were then purified by HPLC.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:15]([CH:16]3[CH2:18][CH2:17]3)[C:14]3[C:19]([C:23](OC)=[O:24])=[CH:20][CH:21]=[CH:22][C:13]=3[N:12]=2)[CH3:10])[C:3]=1[C:27]#[N:28].N[C@H](C1N(C2CC2)C2C(C([NH:46][C:47]([CH3:50])([CH3:49])[CH3:48])=O)=CC=CC=2N=1)C>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:15]([CH:16]3[CH2:18][CH2:17]3)[C:14]3[C:19]([C:23]([NH:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:24])=[CH:20][CH:21]=[CH:22][C:13]=3[N:12]=2)[CH3:10])[C:3]=1[C:27]#[N:28]
Reactant: C[C@H](N)c1nc2cccc(C(=O)NC(C)(C)C)c2n1C1CC1
Reactant: COC(=O)c1cccc2nc([C@H](C)Nc3ncnc(N)c3C#N)n(C3CC3)c12
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2cccc(C(=O)NC(C)(C)C)c2n1C1CC1

Procedure:
Using the general synthetic procedure for (S)-methyl 2-(1-(6-amino-5-cyanopyrimidin-4-ylamino)ethyl)-1-cyclopropyl-1H-benzo[d]imidazole-7-carboxylate in example 47, 2-((1S)-1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-N-tert-butyl-1-cyclopropyl-1H-benzimidazole-7-carboxamidewas prepared using (S)-2-(1-amino ethyl)-N-tert-butyl-1-cyclopropyl-1H-benzo[d]imidazole-7-carboxamide: 1H NMR (400 MHz, MeOH-d4) δ 8.03 (1H, s), 7.68 (1H, d, J=8.0 Hz), 7.38 (1H, d, J=8.0 Hz), 7.27 (1H, t, J=8.0 Hz), 6.04 (1H, q, J=8.0 Hz), 3.55-3.43 (1H, m), 3.03-2.96 (1H, m), 1.73 (3H, d, J=4.0 Hz), 1.53 (9H, s), 1.40-1.30 (1H, m), 1.30-1.15 (2H, m), 1.10-0.93 (1H, m); LC-MS (ESI) m/z 419.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]=[O:11].[NH2:12][C:13]1[C:14]2[S:21][CH:20]=[CH:19][C:15]=2[N:16]=[CH:17][N:18]=1>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH:12][C:13]1[C:14]2[S:21][CH:20]=[CH:19][C:15]=2[N:16]=[CH:17][N:18]=1)=[O:11]
Reactant: O=C=Nc1c(Cl)cccc1Cl
Reactant: Nc1ncnc2ccsc12
Solvent: CC#N
Product: O=C(Nc1c(Cl)cccc1Cl)Nc1ncnc2ccsc12
Yield: 229.1 %

Procedure:
2,6-Dichlorophenyl isocyanate (0.075 g) was added to a mixture of 4-aminothieno[3,2-d]pyrimidine (Tetrahedron, 1971, 27, 487; 0.201 g) and acetonitrile (16 ml) and the resultant mixture was stirred at ambient temperature for 16 hours. The precipitate was isolated and washed in turn with diethyl ether and methanol. There was thus obtained the title compound (0.31 g); NMR Spectrum: (DMSOd6) 7.25 (t, 1H), 7.45 (d, 1H), 7.55 (d, 1H), 7.95 (d, 1H), 8.4 (s, 1H), 8.8 (s, 1H), 11.7 (br s, 1H); Mass Spectrum: M+H+ 339 and 341; Elemental Analysis: Found C, 45.8; H 2.4; N, 16.5; C13H8Cl2N4OS requires C, 46.03; H, 2.38; N, 16.52%.
Reaction SMILES: Cl[C:2]1C=C2C(C=CC(C)=N2)=C(C2C=CC(Cl)=CC=2)[C:3]=1C=C.FC(F)(F)S(O[C:28]1[C:37]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=2)=[C:36]2[C:31]([CH:32]=[CH:33][CH:34]=[N:35]2)=[CH:30][C:29]=1[CH3:45])(=O)=O>>[Cl:44][C:41]1[CH:42]=[CH:43][C:38]([C:37]2[C:28]([CH:2]=[CH2:3])=[C:29]([CH3:45])[CH:30]=[C:31]3[C:36]=2[N:35]=[CH:34][CH:33]=[CH:32]3)=[CH:39][CH:40]=1
Reactant: Cc1cc2cccnc2c(-c2ccc(Cl)cc2)c1OS(=O)(=O)C(F)(F)F
Reactant: C=Cc1c(Cl)cc2nc(C)ccc2c1-c1ccc(Cl)cc1
Product: C=Cc1c(C)cc2cccnc2c1-c1ccc(Cl)cc1

Procedure:
Compound 4E was prepared following the procedure used to prepare compound 1G of Example 1, except that 8-(4-chlorophenyl)-6-methylquinolin-7-yl trifluoromethanesulfonate (4D) was used instead of compound 1F. LCMS-ESI+ (m/z): 280.2, 282.2 (M+H)+.
Reaction SMILES: [C:1]([P:4](=[O:11])([O:8]CC)[O:5][CH2:6][CH3:7])(=[O:3])[CH3:2].[I-].[Na+:13]>CC(CC)=O>[C:1]([P:4](=[O:8])([O-:11])[O:5][CH2:6][CH3:7])(=[O:3])[CH3:2].[Na+:13]
Reactant: CCOP(=O)(OCC)C(C)=O
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCOP(=O)([O-])C(C)=O

Procedure:
A solution of diethyl acetylphosphonate (5 g, 0.028 mol) and oven-dried sodium iodide (4.2 g, 0.028 mol) in molecular sieve dried ethyl methyl ketone (75 ml) was stirred and refluxed for 16 hours.
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]2[CH2:21][CH2:20][O:19][CH:18]([C:22]3[N:23]=[C:24]([Cl:27])[S:25][CH:26]=3)[CH2:17]2)[CH3:15])=[CH:9][CH:8]=1)([O:3]C)=[O:2].[OH-].[Na+].Cl.C(Cl)Cl>CO>[C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]2[CH2:21][CH2:20][O:19][CH:18]([C:22]3[N:23]=[C:24]([Cl:27])[S:25][CH:26]=3)[CH2:17]2)[CH3:15])=[CH:9][CH:8]=1)([OH:3])=[O:2]
Reactant: COC(=O)COc1ccc(CC(C)N2CCOC(c3csc(Cl)n3)C2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CC(Cc1ccc(OCC(=O)O)cc1)N1CCOC(c2csc(Cl)n2)C1

Procedure:
0.55 g (0.0013 mol) of N-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-(2-chloro-thiazole-4-yl)morpholine are stirred in 4 ml of methanol and 4 ml of 1N sodium hydroxide solution at room temperature for 10 minutes. The mixture is then neutralised with 4 ml of 1N hydrochloric acid, and the product is obtained by extraction with methylene chloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][CH2:24][C:25]([F:28])([F:27])[F:26])[C:8]([F:11])=[CH:9][CH:10]=1.Cl[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32].C(N(CC)CC)C.[H-].[Na+]>C(Cl)Cl.CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][C:13]=2[CH2:22][N:23]([C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])[CH2:24][C:25]([F:28])([F:26])[F:27])[C:8]([F:11])=[CH:9][CH:10]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)Cc1ccc(F)c(-c2ccc(C(F)(F)F)cc2CNCC(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(F)c(-c2ccc(C(F)(F)F)cc2CN(CC(F)(F)F)C(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
{6-Fluoro-2′-[(2,2,2-trifluoro-ethylamino)-methyl]-4′-trifluoromethyl-biphenyl-3-yl}acetic acid methyl ester (0.26 g, 0.62 mmol), benzyl chloroformate (0.13 mL, 0.93 mmol), and triethylamine (0.13 mL, 0.93 mmol) were combined in CH2Cl2 (2.1 mL), and the reaction was stirred at room temperature for 2 hours. Analytical LCMS indicated that starting material was still present, so additional benzyl chloroformate (0.13 mL, 0.93 mmol), and triethylamine (0.13 mL, 0.93 mmol) were added, and the reaction was stirred for 1 hour. Starting material was still present, so an aqueous work-up was performed, and the residue was dissolved in DMF and cooled to 0° C. Sodium hydride (60% in mineral oil; 0.030 g, 0.75 mmol) was added, followed by benzyl chloroformate (0.13 mL, 0.93 mmol), and the reaction was stirred for 20 minutes. The mixture was worked up with CH2Cl2 and H2O, and the organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography to give the title compound.
Reaction SMILES: CC([O-])(C)C.[K+].CC(O)(C)C.[CH2:12]([O:14][C:15]1[CH:16]=[C:17]([C:23](=[O:29])[CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH3:13].[H][H]>CC1C=CC(C(C)C)=CC=1.CC1C=CC(S([N-][C@H]([C@@H](N)C2C=CC=CC=2)C2C=CC=CC=2)(=O)=O)=CC=1.Cl[Ru+].CC(O)C>[CH2:12]([O:14][C:15]1[CH:16]=[C:17]([C@@H:23]([OH:29])[CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH3:13]
Reactant: CCOc1cc(C(=O)CS(C)(=O)=O)ccc1OC
Reactant: [H][H]
Agent: Cl[Ru+]
Agent: CC(C)(C)[O-]
Agent: Cc1ccc(S(=O)(=O)[N-][C@@H](c2ccccc2)[C@@H](N)c2ccccc2)cc1
Solvent: CC(C)O
Solvent: Cc1ccc(C(C)C)cc1
Solvent: CC(C)(C)O
Product: CCOc1cc([C@@H](O)CS(C)(=O)=O)ccc1OC
Reaction time: 1 h
Yield: 52.2 %

Procedure:
A 1.0M t-BuOK solution in 2-methyl-2-propanol (0.220 mL, 0.220 mmol) was diluted into 2-propanol (12 mL). To the resulting solution was added RuCl(p-cymene)[(S,S)-Ts-DPEN] (28 mg, 0.044 mmol) and 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanone (1.2 g, 4.4 mmol). The mixture was hydrogenated at 50° C. under 450 psig hydrogen gas for 16 h. Then, the mixture was evaporated. The residue was dissolved in CH2Cl2 (50 mL), and this solution was washed with 1N NaOH (2×50 mL), water (50 mL) and brine (50 mL). The organic phase was evaporated and the residue was loaded directly onto a silica gel column, using a hexanes-ethyl acetate gradient. The appropriate fractions were pooled and evaporated. The residue was slurried with MTBE (20 mL) for 1 h and filtered. The filter was washed with MTBE (5 mL) and the solids were dried under vacuum to afford (R)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanol as a white solid (0.63 g, 52% yield); achiral HPLC (Hypersil BDS C8, 5.0 μm, 250×4.6 mm, 1.5 mL/min, 278 nm, 90/10 gradient to 80/20 0.1% aqueous TFA/MeOH over 10 min then gradient to 10/90 0.1% aqueous TFA/MeOH over the next 15 min): 11.38 (99.7%); chiral HPLC (Chiralpak AD-H 5.0 μm Daicel, 250×4.6 mm, 1.0 mL/min, 280 nm, 85:15 heptane-i-PrOH): 17.77 (9.1%), 20.14 (90.9%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][N:8]=2)[CH2:3][CH2:2]1.[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19]Cl.[I-].[K+].C(=O)([O-])[O-].[K+].[K+].[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34]>C(O)CCC.C(#N)C>[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34].[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34].[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19][N:1]1[CH2:2][CH2:3][CH:4]([C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][N:8]=2)[CH2:5][CH2:6]1
Reactant: c1ccc2c(C3CCNCC3)noc2c1
Reactant: CN(C)CCCl
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCCCO
Solvent: CC#N
Product: CN(C)CCN1CCC(c2noc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.6 %

Procedure:
A suspension of 4.5 g of 3-(4-piperidyl)-1,2-benzisoxazole, 2.6 g of 2-dimethylaminoethyl chloride, 3.0 g of potassium iodide and 5.0 g of potassium carbonate in 100 ml of butanol was heated under reflux for 2 hrs, cooled to room temperature and filtered. The filtrate was washed with water and extracted with ether (3 times). The ether extracts were dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to give an oil. The soil was dissolved in 10 ml of acetonitrile and 3.2 g of fumaric acid was added. The reaction mixture was stirred for 2 hrs, filtered and the filter cake was recrystallized three times from ethanol-ether to give 2.2 g (19.8%) of product, mp, 215°-217°.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][C:12]1[CH:16]=[CH:15][S:14][C:13]=1[C:17]([O:19][CH3:20])=[O:18]>C1(C)C=CC=CC=1.CO>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:11][C:12]1[CH:16]=[CH:15][S:14][C:13]=1[C:17]([O:19][CH3:20])=[O:18])([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: COC(=O)c1sccc1N
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1sccc1Nc1ccccc1[N+](=O)[O-]

Procedure:
The title compound was prepared using the process of Example 1(a) but with 2-fluoro-nitrobenzene and methyl 3-aminothiophene-2-carboxylate (U.K. Pat. No. 837,086) as starting materials, m.p. 184° C., (toluene/MeOH, 2:1).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][NH:8][C:9](=[O:20])[NH:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=O)=[O:5])[CH3:2].Cl.[NH:22]1[C:26]2([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH2:25][NH:24]/[C:23]/1=[N:32]\[C:33]([C:35]1[C:40]([NH2:41])=[N:39][C:38]([NH2:42])=[C:37]([Cl:43])[N:36]=1)=[O:34]>>[CH2:1]([O:3][C:4](=[O:5])[CH2:6][CH2:7][NH:8][C:9]([NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:13]([C:14]([N:29]2[CH2:30][CH2:31][C:26]3([NH:22]/[C:23](=[N:32]/[C:33]([C:35]4[C:40]([NH2:41])=[N:39][C:38]([NH2:42])=[C:37]([Cl:43])[N:36]=4)=[O:34])/[NH:24][CH2:25]3)[CH2:27][CH2:28]2)=[O:16])[CH:12]=1)=[O:20])[CH3:2]
Reactant: CCOC(=O)CCNC(=O)Nc1cccc(C(=O)O)c1
Reactant: Nc1nc(N)c(C(=O)/N=C2\NCC3(CCNCC3)N2)nc1Cl
Agent: Cl
Product: CCOC(=O)CCNC(=O)Nc1cccc(C(=O)N2CCC3(CC2)CN/C(=N\C(=O)c2nc(Cl)c(N)nc2N)N3)c1

Procedure:
The title compound was prepared from 3-[3-(2-ethoxycarbonyl-ethyl)-ureido]-benzoic acid (Int. F) and 3,5-diamino-6-chloro-pyrazine-2-carboxylic acid [1,3,8-triaza-spiro[4.5]dec-(2E)-ylidene]-amide hydrochloride using an analogous method to Example 1; LC-MS Rt 0.81 mins; 587.4 and 589.3 [M+H]+, Method 2minLC_v003.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:23])[N:9]3[CH2:22][CH2:21][CH2:20][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](=[N:18][OH:19])[NH2:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:24][CH2:25][C:26](OC(=O)CCl)=O>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:23])[N:9]3[CH2:22][CH2:21][CH2:20][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:17]=[C:26]([CH2:25][Cl:24])[O:19][N:18]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: NC(=NO)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Reactant: O=C(CCl)OC(=O)CCl
Solvent: CN(C)C=O
Product: O=C1c2c(Cl)cccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCCN12
Reaction time: 2 h
Yield: 75.4 %

Procedure:
A suspension of 7.07 g (21.3 mmol) of (S)-8-chloro-9-oxo-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxamidoxime in 50 ml of N,N-dimethylformamide was treated with 4.0 g (23.4 mmol) of chloroacetic anhydride. The yellow solution obtained was stirred at 105° for 2 hrs. and then completely freed from the solvents. The oily product was chromatographed over silica gel with methylene chloride/methanol 9:1 as the eluent and the oily product obtained was recrystallized from ethyl acetate/ether. The mother liquor was concentrated, the residue was again chromatographed over silica gel with acetonitrile as the eluent and the additional portion of product obtained was recrystallized from ethyl acetate/ether. There were obtained a total of 6.27 g (75%) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one as white crystals; m.p. 184°-186° and [α]D20 =+36.1° (MeOH, c=1%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=[C:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17][CH2:16]1.CC1CCCO1.C(O)(=O)C.[Na].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[OH-].[Na+].[ClH:53]>O>[ClH:53].[ClH:53].[ClH:53].[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17][CH2:16]2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CN1CCC(=O)CC1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC1CCCO1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)CN1CCC(N2CCN(Cc3ccccc3)CC2)CC1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
6.85 kg (38.9 mol) 1-benzyl-piperazine (N) were metered into a mixture of 10.00 kg (54.0 mol) ethyl (4-oxo-piperidin-1-yl)-acetate (K), 42 L 2-methyltetrahydrofuran and 11.81 kg (196.7 mol) acetic acid at 20° C. and rinsed with 10.6 L of 2-methyltetrahydrofuran, before the reaction mixture was stirred for one to two hours at 20° C. Then the mixture was metered into the mixture of 12.39 kg (58.5 mol) sodium-triacetoxyborohydride and 36.8 L 2-methyltetrahydrofuran at 20° C., during which time the temperature was allowed to rise to 40° C. After the addition had ended the mixture was rinsed with 15.8 L of 2-methyltetrahydrofuran and the reaction mixture was stirred for at least 1 hour at 40° C. If necessary, further sodium triacetoxyborohydride was added before stirring was continued overnight at 25° C. Once the reaction of the 1-benzylpiperazine was complete the mixture was cooled to 20° C., 52.6 L of water were metered in and the pH was adjusted to 9.0 with 27.3 kg sodium hydroxide solution (50%). After phase separation the organic phase was washed with 26.3 L water and evaporated down completely in vacuo. The residue was taken up in 134 L ethanol and combined with 15.6 kg of 10 molar ethanolic hydrochloric acid (159.4 mol, at least 37.2 wt.-%) at boiling temperature, before the mixture was refluxed for a further 1 hour, with stirring. After cooling to 2° C. and stirring for 1 hour the product was separated off, washed with 31.6 L cold ethanol and dried.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:10]=[CH:11][C:12]([O:18][CH3:19])=[C:13]([CH:17]=2)[C:14]([OH:16])=O)[S:3]1.[F:20][C:21]([F:31])([F:30])[C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1.P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>CN(C=O)C>[F:20][C:21]([F:30])([F:31])[C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:27][C:14](=[O:16])[C:13]2[CH:17]=[C:9]([CH:8]=[C:4]3[S:3][C:2](=[O:1])[NH:6][C:5]3=[O:7])[CH:10]=[CH:11][C:12]=2[O:18][CH3:19])=[CH:24][CH:23]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: COc1ccc(C=C2SC(=O)NC2=O)cc1C(=O)O
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(C=C2SC(=O)NC2=O)cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Yield: 83.9 %

Procedure:
To a solution of 5-(2,4-dioxothiazolidin-5-ylidene)methyl-2-methoxybenzoic acid (1.00 g) and 4-trifluoromethylbenzylamine (627 mg) in DMF (10 ml), diethyl cyanophosphate (615 mg) and triethylamine (370 mg) were added at room temperature in an argon atmosphere under stirring, and the mixture was stirred for 5 hours as it was. The reaction liquor was poured into ice water and the crystals deposited were collected by filtration, washed with water, and then dried to obtain 1.31 g (84%) of aimed compound as crystals. Further, these were recrystallized from ethanol to obtain purified aimed compound as yellow prismatic crystals. Melting point 210.0~211.5° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][C:10](=[O:25])/[C:11](/[C:15]2[N:16]=[C:17]([N:20]=CN(C)C)[S:18][CH:19]=2)=[N:12]\[O:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)=O.O.C(=O)([O-])O.[Na+]>CO.C(OCC)(=O)C>[C:1]1([CH2:7][CH2:8][NH:9][C:10](=[O:25])/[C:11](/[C:15]2[N:16]=[C:17]([NH2:20])[S:18][CH:19]=2)=[N:12]\[O:13][CH3:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CO/N=C(\C(=O)NCCc1ccccc1)c1csc(N=CN(C)C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=CO
Solvent: CCOC(C)=O
Product: CO/N=C(\C(=O)NCCc1ccccc1)c1csc(N)n1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 57.5 %

Procedure:
(Z)-N-(2-Phenylethyl)-2-(2-dimethylaminomethylidenaminothiazol-4-yl)-2-methoxyiminoacetamide (130 mg, 0.36 mmol) was dissolved in 4 ml of methanol, followed by the addition of 0.5 ml of formic acid and 1 ml of water. The mixture so obtained was stirred at 60° C. for 3 hours and 30 minutes. The reaction mixture was then added with 20 ml of a saturated aqueous solution of sodium hydrogencarbonate and 20 ml of ethyl acetate. The resulting mixture was then allowed to separate into an organic phase and an aqueous phase. The aqueous phase was further extracted twice with 10 ml portions of ethyl acetate. All the organic phases were combined, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, whereby 63 mg of the title compound were obtained (yield: 57.9%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]2[CH2:14][O:15][C:16](=[O:26])[N:17]([C:18]3[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:25])[C:12]=2[CH:11]=[C:10]([C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH:35]([CH3:37])[CH3:36])[CH2:31][CH2:30]2)=O)[CH:9]=1.B>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]2[CH2:14][O:15][C:16](=[O:26])[N:17]([C:18]3[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:25])[C:12]=2[CH:11]=[C:10]([CH2:27][N:29]2[CH2:34][CH2:33][N:32]([CH:35]([CH3:37])[CH3:36])[CH2:31][CH2:30]2)[CH:9]=1
Reactant: CC(C)N1CCN(C(=O)c2cc(-c3ccccc3Cl)c3c(c2)N(c2c(Cl)cccc2Cl)C(=O)OC3)CC1
Agent: B
Solvent: C1CCOC1
Product: CC(C)N1CCN(Cc2cc(-c3ccccc3Cl)c3c(c2)N(c2c(Cl)cccc2Cl)C(=O)OC3)CC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-7-[(4-isopropylpiperazin-1-yl)carbonyl]-1,4-dihydro-2H-3,1-benzoxazin-2-one (31 mg, 0.055 mmol, 1 eq) in THF (0.1 mL) at 0° C. under nitrogen was added a solution of borane in THF (0.1 mL of a 1M solution, 0.1 mmol, 1.8 eq). The mixture was stirred 5 min at 0° C. and then the cooling bath was removed. The mixture was brought to and maintained at reflux for 2 h (twice added 0.1 mL of THF due to solvent loss). The mixture was cooled. To the reaction was added 6N aqueous HCl (0.1 mL) and the mixture was heated in a 70° C. oil bath for 15 min. The mixture was cooled and diluted with CH2Cl2 and aqueous NaHCO3. Aqueous 2N NaOH was added to increase basicity. Mixed and separated the layers. The aqueous layer was back extracted 2× with CH2Cl2. The organic extracts were combined, dried over anhydrous Na2SO4, filtered and concentrated. The product was purified by flash column chromatography on silica gel giving 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-7-[(4-isopropylpiperazin-1-yl)methyl]-1,4-dihydro-2H-3,1-benzoxazin-2-one. Mass spectrum ESI) 544.2 (M+1); 546.2 (M+3).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[NH:13]1[CH2:18][CH2:17][CH:16]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH2:15][CH2:14]1.[OH-].[Na+].[Br-].C([NH3+])CCC>O.C1(C)C=CC=CC=1>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:13]2[CH2:18][CH2:17][CH:16]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:15][CH2:14]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: C1CC(C2CCNCC2)CCN1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Agent: CCCC[NH3+]
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(N2CCC(C3CCNCC3)CC2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 18 h
Yield: 93.9 %

Procedure:
A mixture of 4-fluoro-2-methoxy-1-nitrobenzene (1.02 g, 5.97 mmol), [4,4′]bipiperidinyl (3.6 g, 14.9 mmol), 2N sodium hydroxide (30 mL), toluene (15 mL) and n-butylammonium bromide (96 mg, 0.30 mmol) is vigorously stirred at 80° C. for 18 hours. After 10 mL of water is added, the mixture is filtrated. The residue is washed with water and then dried to give 1-(3-methoxy-4-nitro-phenyl)-[4,4′]bipiperidine (1.79 g, 94% yield) as yellow solids.