Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH:24]=[N:23][N:22]([CH:25]([CH3:29])[C:26](=[O:28])[CH3:27])[C:21]4=[O:30])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([BH-](C(CC)C)C(CC)C)(CC)C.[K+].O>CN(C=O)C.O1CCCC1>[OH:28][CH:26]([CH3:27])[CH:25]([N:22]1[C:21](=[O:30])[N:20]([C:17]2[CH:16]=[CH:15][C:14]([N:11]3[CH2:10][CH2:9][N:8]([C:5]4[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=4)[CH2:13][CH2:12]3)=[CH:19][CH:18]=2)[CH:24]=[N:23]1)[CH3:29]
Reactant: CC(=O)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(O)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O
Temperature: -10 °C

Procedure:
A mixture of (±)-2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2-(1-methyl-2-oxopropyl)-3H-1,2,4-triazol-3-one (0.06 mol) in DMF (500 ml) was cooled to −10° C. and then stirred under N2 flow. Potassium tri-sec-butylborohydride, 1M solution in tetrahydrofuran (150 ml) was added dropwise. The mixture was allowed to warm to room temperature slowly and then poured out into water. The precipitate was filtered off, washed with CH3OH and crystallized from CH3OH. The precipitate was filtered off and dried. The residue was purified by HPLC over CHIRALPAC AD (eluent:ethanol). Two pure fractions were collected and their solvents were evaporated. Each residue was triturated in CH3OH. The precipitate was filtered off and dried, yielding 7.3 g [S-(R*,R*)]-2,4-dihydro-2-(2-hydroxy-1-methylpropyl)-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-3H-1,2,4-triazol-3-one. (interm. 1a) [α]20D=−10.81° (c=50.43 mg/5 ml DMF).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](/[C:10](=[CH:18]\[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)/C(OC(C)(C)C)=O)=[O:9].C1(C)C=CC(S(O)(=O)=O)=CC=1>NC(N)=S.C1(C)C=CC=CC=1>[C:22]1([CH3:25])[CH:23]=[CH:24][C:19]([C@H:18]2[CH2:10][C:8](=[O:9])[C:3]3[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=3)[O:1]2)=[CH:20][CH:21]=1
Reactant: Cc1ccc(/C=C(/C(=O)OC(C)(C)C)C(=O)c2ccccc2O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: NC(N)=S
Solvent: Cc1ccccc1
Product: Cc1ccc([C@H]2CC(=O)c3ccccc3O2)cc1
Yield: 83.9 %

Procedure:
Prepared according to general procedure using (E)-tert-butyl 2-(2-hydroxyphenylcarbonyl)-3-p-tolylprop-2-enoate (54 mg, 0.16 mmol), thiourea catalyst III (11 mg, 0.016 mmol) in 1.6 mL toluene for 36 h at −25° C. and p-toluenesulfonic acid (15 mg, 0.08 mmol) for 25 h. Purification via column chromatography with 10% EtOAc/hexanes afforded 32 mg (83%) of 10 as a white solid in 90% ee. Analytical data match those reported in the literature.6
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[N:17][N:16]4[C:19]([C:22]5[CH:23]=[C:24]([NH:28][C:29]([NH:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[O:30])[CH:25]=[CH:26][CH:27]=5)=[CH:20][N:21]=[C:15]4[CH:14]=3)[CH:10]=[N:9]2)[CH2:7][NH:6][CH2:5]1)#[N:2].[CH3:37][C:38]1[O:42][N:41]=[CH:40][C:39]=1[S:43](Cl)(=[O:45])=[O:44]>>[C:1]([CH2:3][C:4]1([N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[N:17][N:16]4[C:19]([C:22]5[CH:23]=[C:24]([NH:28][C:29]([NH:31][CH2:32][C:33]([F:35])([F:36])[F:34])=[O:30])[CH:25]=[CH:26][CH:27]=5)=[CH:20][N:21]=[C:15]4[CH:14]=3)[CH:10]=[N:9]2)[CH2:5][N:6]([S:43]([C:39]2[CH:40]=[N:41][O:42][C:38]=2[CH3:37])(=[O:45])=[O:44])[CH2:7]1)#[N:2]
Reactant: N#CCC1(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CNC1
Reactant: Cc1oncc1S(=O)(=O)Cl
Product: Cc1oncc1S(=O)(=O)N1CC(CC#N)(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)C1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 73, Step 4 starting from N-[3-(7-{1-[3-(cyanomethyl)azetidin-3-yl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea and 5-methylisoxazole-4-sulfonyl chloride. LCMS (M+H)+: m/z=641.2.
Reaction SMILES: [C:1]1([C:7]2O[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]3[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:22][C:23]1[C:33]2[C:34]3[C:26]([CH:27]=[CH:28][C:29]=3[CH:30]=[CH:31][CH:32]=2)=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[Br:22][C:23]1[CH:24]=[CH:25][C:26]2=[C:34]3[C:33]=1[CH:32]=[CH:31][CH:30]=[C:29]3[C:28]1[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]3=[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:27]=12
Reactant: c1ccc(-c2oc(-c3ccccc3)c3ccccc23)cc1
Reactant: Brc1ccc2c3c(cccc13)C=C2
Solvent: Cc1ccccc1
Product: Brc1ccc2c3c(cccc13)-c1c-2c(-c2ccccc2)c2ccccc2c1-c1ccccc1
Temperature: 80 °C
Yield: 78.3 %

Procedure:
5 g (18.5 mmol) of diphenylisobenzofuran and 4.3 g (18.5 mmol) of 5-bromoacenaphthylene in toluene were agitated for 24 hours at the reflux temperature. The solvent was distilled off in vacuum, after which the residue was dissolved in 500 ml of acetic acid. An aqueous 40% hydrobromic acid solution, 50 cm3, was added to the solution, which was heated at 80° C. for one hour. After cooling to room temperature, the precipitate was collected by filtration. This was purified by silica gel chromatography using a mixture of toluene and hexane as an extracting solvent, yielding 7 g of 3-bromo-7,12-diphenylbenzo[k]fluoranthene having a yellowish white color.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]([CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)[CH2:7][C:8]([OH:10])=[O:9])=[O:5])[CH3:3].[C:20]1([CH2:26][C:27](=O)[C:28]([OH:30])=[O:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([BH3-])#N.[Na+]>[OH-].[K+]>[C:28]([CH:27]([NH:1][C@H:2]([C:4]([N:6]([CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)[CH2:7][C:8]([OH:10])=[O:9])=[O:5])[CH3:3])[CH2:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([OH:30])=[O:29]
Reactant: C[C@H](N)C(=O)N(CC(=O)O)C1Cc2ccccc2C1
Reactant: O=C(O)C(=O)Cc1ccccc1
Agent: [BH3-]C#N
Agent: [K+]
Agent: [Na+]
Product: C[C@H](NC(Cc1ccccc1)C(=O)O)C(=O)N(CC(=O)O)C1Cc2ccccc2C1
Reaction time: 8 h
Yield: 19.2 %

Procedure:
L-Alanyl-N-(indan-2-yl)glycine (1.0 g) and 6.0 g of phenylpyruvic acid are dissolved in 50 ml of 70% aqueous potassium hydroxide. Sodium cyanoborohydride (1.0 g) is added to this solution. After allowing the mixture to stand at room temperature overnight, the solvent is distilled off under reduced pressure, the residue is dissolved in 2 ml of water, made absorbed on a Dowex 50 (H+) [trade name of ion-exchange resin] column and eluted with 2% pyridine. The solvent is distilled off under reduced pressure, the residue is purified by silica gel column chromatography using acetonitrile-methanol (4:1) as the developer to give 0.3 g of N-(1-carboxy-2-phenylethyl)-L-alanyl-N-(indan-2-yl)glycine as colorless powder.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[O:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=1>C(O)CCC>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:12][CH2:11][CH2:3][CH2:2][CH3:7])=[C:3]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:16][C:14]=3[N:15]=2)[CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)c(-c2nc3cc(-c4ccccc4)ccc3o2)c1
Solvent: CCCCO
Product: CCCCOc1ccc([N+](=O)[O-])cc1-c1nc2cc(-c3ccccc3)ccc2o1

Procedure:
Prepared by the method of Example 44a), from 2-(2-fluoro-5-nitrophenyl)-5-phenylbenzoxazole (200 mg, 0.6 mmol) in butanol (2 ml) the subtitle compound was obtained (195 mg, 87%). 1H NMR (DMSO) δ 8.87(d, 1H), 8.45(dd, 1H), 8.08(d, 1H), 7.85(d, 1H), 7.70(m, 3H), 7.51(t, 3H), 7.40(t, 1H), 4.35(t, 2H), 1.83(q, 2H), 1.57(m, 2H), 1.01(t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27]C)[CH:22]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH2:29][CH3:30])[NH:11]1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH2:29][CH3:30])[NH:11]1
Reactant: CCc1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c2nc(Cc3cccc(OC)c3)nc(=O)c1-2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCc1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c2nc(Cc3cccc(O)c3)nc(=O)c1-2
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.7 %

Procedure:
To a stirred solution of 80 mg (0.17 mmol) of 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one in 1 mL of CH2Cl2 was added 1 mL (1 mmol) of 1 M boron tribromide in CH2Cl2. The solution was stirred 1 h at ambient temperature and then cooled to 0° C. The reaction was quenched with 4 mL of 1 M aq. HCl. The mixture was poured into water and extracted with 1:1 tetrahydrofuran-EtOAc. The organic extract was washed with brine, dried (MgSO4), and concentrated under reduced pressure to afford 77 mg (100%) of 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(3-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one as an off-white solid. Mass Spec.: 449 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([CH:7]=[CH2:8])=[CH:3]1.[CH:9]([C:12]([CH3:22])([N:15]1[C:19](=[O:20])[CH:18]=[CH:17][C:16]1=[O:21])[C:13]#[N:14])([CH3:11])[CH3:10]>C(Cl)(Cl)Cl>[CH:9]([C:12]([CH3:22])([N:15]1[C:19](=[O:20])[CH:18]2[CH2:8][CH2:7][CH:4]3[CH2:5][CH2:6][N:2]([CH3:1])[C:3]3=[C:17]2[C:16]1=[O:21])[C:13]#[N:14])([CH3:11])[CH3:10]
Reactant: CC(C)C(C)(C#N)N1C(=O)C=CC1=O
Reactant: C=Cc1ccn(C)c1
Solvent: ClC(Cl)Cl
Product: CC(C)C(C)(C#N)N1C(=O)C2=C3C(CCC2C1=O)CCN3C
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.5 %

Procedure:
A mixture of 1-methyl-3-vinylpyrrole (9.50 g, 0.089 mol), α-isopropyl-α-methyl-2,5-dioxo-3-pyrroline-1-acetonitrile (17.0 g, 0.089 mol) and chloroform is stirred overnight at room temperature and concentrated in vacuo to an amber oil residue. The residue is flash chromatographed (silica gel, gradient elution: 50% hexanes: methylene chloride to ether) to afford the title product as an orange glass (13.0 g, 48.8%), identified by 1HNMR spectroscopy.
Reaction SMILES: [NH:1]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:2]([C:18](OC)=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[H-].C([Al+]CC(C)C)C(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.CCCCCC>[NH:1]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:2]([CH:18]=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9]
Reactant: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](C=O)CCCCNC(=O)OCc1ccccc1
Reaction time: 0.25 h
Yield: 102.1 %

Procedure:
To a solution of 0.975 g of Boc-Lys(Cbz)-OMe in 25 ml of dichloromethane at −78° C. under a nitrogen atmosphere was added 6 ml of a 1M diisobutylaluminiumhydride solution in hexane. After 15 min the reaction was completed, the reaction mixture poured into 150 ml of 2% citric acid solution and filtered. The organic layer was separated, washed with water and brine, dried (magnesium sulfate) and concentrated. The residue was coevaporated with toluene to give 0.92 g of Boc-Lys(Cbz)-H. This aldehyde (0.89 g) was dissolved in 1.4 ml of toluene and 0.90 g of 2-(trimethylsilyl)oxazole (prepared according to: Edwards, P. D., Wolanin, D. J., Andisik D. W., and Davis W., J. Med. Chem. 38, 76 (1995)) was added and heated at 80° C. After 60 h the reaction mixture was concentrated, the residue dissolved in 5 ml of tetrahydrofuran, treated with 3 ml of a 3M tetrabutylammonium fluoride in tetrahydrofuran solution and stirred at room temperature for 2 h. The mixture was concentrated dissolved in ethyl acetate, washed with 3% aqueous sodium hydrogencarbonate solution and brine, dried (magnesium sulfate) and evaporated. Purification by column chromatography on silica gel eluting with a gradient of ethyl acetate/dichloromethane=2/1 (v/v) to ethyl acetate afforded an oil that was rechromatographed on silica gel eluting with a gradient of ethyl acetate/heptane=1/1 (v/v) to ethyl acetate/heptane=1/3 (v/v) to give 0.22 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1.[CH2:11]([NH:13][CH2:14][C:15](O)=[O:16])[CH3:12].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:11]([N:13]1[CH2:14][C:15](=[O:16])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:9]1=[S:10])[CH3:12]
Reactant: Fc1ccc(N=C=S)cc1
Reactant: CCNCC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCN1CC(=O)N(c2ccc(F)cc2)C1=S
Yield: 55.5 %

Procedure:
The title compound was prepared by the procedure described in Example 16 using 7.65 g of 4-fluorophenyl-isothiocyanate, 9.32 g of N-ethyl glycine, 10 g of triethyl amine, and 250 mL of chloroform. Purification was achieved through crystallization from ethanol. The title compound (6.6 g) was obtained as a pink solid, m.p. 149°-151° C. Anal. Calcd. for. C11H11F N2O S: C, 55.45; H, 4.65; N, 11.76. Found: C, 55.31; H, 4.51; N, 10.82. Mass spectrum (EI, M.+) m/z 238.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][C@@H:6]([C:24]1[CH:25]=[N:26][C:27]([CH3:30])=[N:28][CH:29]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]2[CH2:22][CH2:21][CH2:20][CH2:19][NH:18][C:17]=2[N:23]=1)C.[OH-].[Na+]>C(O)C>[CH3:30][C:27]1[N:26]=[CH:25][C:24]([C@@H:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]3[CH2:22][CH2:21][CH2:20][CH2:19][NH:18][C:17]=3[N:23]=2)[CH2:5][C:4]([OH:31])=[O:3])=[CH:29][N:28]=1
Reactant: CCOC(=O)C[C@H](CCCCCCc1ccc2c(n1)NCCCC2)c1cnc(C)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ncc([C@@H](CCCCCCc2ccc3c(n2)NCCCC3)CC(=O)O)cn1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a solution of 8-14 (0.50 g, 1.36 mmol) in ethanol (10 mL) was added 1N NaOH (1.5 mL), and the mixture stirred at 50° C. for 30 minutes, then concentrated. The residue was chromatographed on silica gel (25:10:1:1 to 15:10:1:1 EtOAc/EtOH/NH4OH/H2O) to give 8-15 as a yellow solid.
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:9][C:10]1[N:15]=[C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)[N:13]=[C:12]([C:24](=[NH:27])[NH:25]O)[N:11]=1.C1(C)C=CC=CC=1.Cl>N1C=CC=CC=1.C(Cl)Cl>[NH2:9][C:10]1[N:15]=[C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)[N:13]=[C:12]([C:24]2[N:27]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[O:8][N:25]=2)[N:11]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: N=C(NO)c1nc(N)nc(Nc2cccc(F)c2)n1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1nc(-c2nc(N)nc(Nc3cccc(F)c3)n2)no1
Temperature: 25 °C
Reaction time: 3 h
Yield: 17 %

Procedure:
Ethyl chlorooxoacetate (0.12 g, 0.84 mmol) was added to a mixture of (4-amino-6-[(3-fluorophenyl)amino]-N-hydroxy-1,3,5-triazine-2-carboximidamide (prepared in an analogous manner to Intermediate 97, 0.20 g, 0.76 mmol) in pyridine (0.12 mL) and toluene (4 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h and at 110 C for 3 h. The mixture was then cooled at room temperature; DCM (20 mL) and 1M aq. HCl (50 mL) were added. The phases were separated and the aqueous phase was extracted with DCM (2×20 mL). The organic extracts were combined, dried over sodium sulfate, and concentrated. The crude residue was washed with diethyl ether. The organic filtrate was concentrated and purified by flash chromatography to afford the title compound as a yellow solid (45 mg, 17%). Method D HPLC-MS: MH+ requires m/z=346 Found: m/z=346, Rt=2.70 min (40%).
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]=[C:4](SC)[CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH2:22]([NH2:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]=[C:4]([NH:30][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCCc1ccccc1
Reactant: CSC1=Nc2ccccc2C(=O)N(C)C1c1ccccc1
Product: CN1C(=O)c2ccccc2N=C(NCCc2ccccc2)C1c1ccccc1
Temperature: 240 °C
Reaction time: 1 h

Procedure:
A mixture of 7.41 g (0.025 m) of 3,4-dihydro-4-methyl-2-methylthio-3-phenyl-5H-1,4-benzodiazepine-5-one and 12.11 g (0.100 m) of phenethylamine is heated in an oil bath for 6 hours. The temperature of the oil bath is slowly raised to 240° C and held there for 1 hour. After cooling to room temperature, the residual oil is crystallized from ether to give the crude product, 3,4-dihydro-4-methyl-2-phenethylamino-3-phenyl-5H-1,4-benzodiazepine-5-one. Recrystallization from ethyl and ethyl acetate-ether gives a pure product, 3,4-dihydro-4-methyl-2-phenethylamino-3-phenyl-5H-1,4-benzodiazepine-5-one, a while solid, m.p. 173° - 174.5° C.
Reaction SMILES: [CH:1]([O:4][C:5]([CH:7]1[CH:19]([CH2:20][O:21][CH3:22])[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:16]=3)[NH:11][C:10]=2[CH2:9][NH:8]1)=[O:6])([CH3:3])[CH3:2].C(N(CC)CC)C.ClOC(C)(C)C>C(Cl)Cl>[CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[CH:16][C:15]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:14][CH:13]=3)=[O:6])([CH3:3])[CH3:2]
Reactant: COCC1c2c([nH]c3ccc(OCc4ccccc4)cc23)CNC1C(=O)OC(C)C
Agent: CC(C)(C)OCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCc1c(C(=O)OC(C)C)ncc2[nH]c3ccc(OCc4ccccc4)cc3c12
Temperature: -15 °C
Reaction time: 0.17 h
Yield: 32 %

Procedure:
A solution is prepared from 3.3 g (8.5 mmol) of 6-benzyloxy-4-methoxymethyl-l,2,3,4-tetrahydro-β-carboline-3-carboxylic acid isopropyl ester in 150 ml of methylene chloride, combined under argon with 3.9 ml of triethylamine, and cooled to -15° C. At this temperature, a solution of 3.2 ml (25.6 mmol) of tert-butyl hypochlorite in 50 ml of methylene chloride is added dropwise without delay to this solution. After the adding step is completed, the mixture is stirred for another 10 minutes, combined with 2.6 ml of triethylamine, and agitated for 2 hours at room temperature. Subsequently, the mixture is concentrated to one-half thereof and extracted once by shaking with dilute ammonia solution. The organic phase is dried, filtered, and concentrated. The residue is chromatographed over silica gel with methylene chloride:acetone =4:1 as the eluent. Recrystallization from ethyl acetate gives 1.1 g (35% yield) of 6-benzyloxy-4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester, mp 150°-151° C.
Reaction SMILES: [ClH:1].[NH:2]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]3[N:21]=[CH:20][NH:19][C:17]3=2)[N:12]=[C:11]([CH3:22])[CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:23][S:24]C1C=C(C=CC=1)N>CN(C)C=O>[ClH:1].[CH3:23][S:24][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[NH:2][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]3[N:21]=[CH:20][NH:19][C:17]3=2)[N:12]=[C:11]([CH3:22])[CH:10]=1
Reactant: Cc1cc(Nc2ccccc2)c2c(ccc3nc[nH]c32)n1
Reactant: CSc1cccc(N)c1
Agent: Cl
Solvent: CN(C)C=O
Product: CSc1cccc(Nc2cc(C)nc3ccc4nc[nH]c4c23)c1

Procedure:
A mixture of 21.7 g. (0.1 m.) of the compound of Example I, C., 13.9 g. (0.1 m.) of 3-methylmercaptoaniline and 250 ml. of dimethylformamide was refluxed overnight with stirring. It was chilled, filtered, washed with ether and air-dried to give 29 g. m.p. 310°-313°C.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:11][C:10]2[C:5](=[CH:6][C:7]([C:12]#[N:13])=[CH:8][CH:9]=2)[CH:4]2[O:14][CH:3]12.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH:27]=[CH:26][C:25](=[O:28])[NH:24]2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH:27]=[CH:26][C:25]([O:28][CH:4]3[C:5]4[C:10](=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[CH:6]=4)[O:11][C:2]([CH3:1])([CH3:15])[CH:3]3[OH:14])=[N:24]2)=[CH:21][CH:22]=1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: O=c1ccn(-c2ccc(Cl)cc2)[nH]1
Product: CC1(C)Oc2ccc(C#N)cc2C(Oc2ccn(-c3ccc(Cl)cc3)n2)C1O

Procedure:
Following the procedure in Example 1, using (±)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-cyclopropa[a]naphthalene-6-carbonitrile and 1-(4-chloro-phenyl)-1,2-dihydro-pyrazol-3-one as starting materials, the title compounds were prepared as white solids.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][C:6]1=[O:11].C(N(CC)C(C)C)(C)C.[F:21][C:22]1[CH:23]=[C:24]([N+:29]([O-:31])=[O:30])[CH:25]=[CH:26][C:27]=1F.FC(F)(F)C(O)=O.C(N(CC)C(C)C)(C)C>C(#N)C>[F:21][C:22]1[CH:23]=[C:24]([N+:29]([O-:31])=[O:30])[CH:25]=[CH:26][C:27]=1[N:8]1[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][O:2][CH3:1])[C:6](=[O:11])[CH2:7]1
Reactant: COCCN1CCNCC1=O
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COCCN1CCN(c2ccc([N+](=O)[O-])cc2F)CC1=O

Procedure:
1-(2-Methoxyethyl)-2-oxopiperazine (4TFA salt, 13.5 g) was dissolved in acetonitrile (200 ml), and N,N-diisopropylethylamine (22.6 ml) followed by 3,4-difluoronitrobenzene (2.2 ml) were added. The mixture was heated to reflux for 18 hours. Solvent was evaporated, and the residue chromatographed on silica, using as eluant a gradient increasing in polarity from 0 to 4% methanol in dichloromethane. Relevant fractions were combined and evaporated to give a solid containing some N,N-diisopropylethylamine trifluoroacetate. The solid was purified by dissolving in ethyl acetate and washing well with water. Evaporation of the organic layer gave 3-fluoro-4-(4-{2-methoxyethyl}-3-oxopiperazin-1-yl)nitrobenzene as a solid (4.07 g).
Reaction SMILES: [CH:1]1([CH3:24])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([O:10][C:11](=[O:23])[CH:12]([N:18]2[CH:22]=[CH:21][CH:20]=[CH:19]2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:2]1.[Cl:25][C:26]([Cl:31])([Cl:30])[C:27](Cl)=[O:28]>C(Cl)(Cl)Cl>[CH:1]1([CH3:24])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:8])[CH3:9])[CH:3]([O:10][C:11](=[O:23])[CH:12]([N:18]2[CH:19]=[CH:20][CH:21]=[C:22]2[C:27](=[O:28])[C:26]([Cl:31])([Cl:30])[Cl:25])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:2]1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: CCOC(=O)C(C(=O)OC1CC(C)CCC1C(C)C)n1cccc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(C(=O)OC1CC(C)CCC1C(C)C)n1cccc1C(=O)C(Cl)(Cl)Cl
Yield: 94.8 %

Procedure:
To a solution of 2-(pyrrol-1-yl)malonic acid ethyl (-)-menthyl ester (64.0 g) in chloroform (80 ml) was added trichloroacetyl chloride (69.0 g), and the resulting mixture was refluxed for 7 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was washed with 5% aqueous sodium carbonate solution and then with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was chromatographed on silica gel using n-hexane/ethyl acetate (50:1) as the eluent. Fractions containing the title compound were pooled and evaporated under reduced pressure to give the title compound (87.0 g, 94.9%) as a colorless oil.