Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O-:12])(=[O:11])[CH3:10].[NH4+].C(O)(=O)CC(O)=O>C(O)C>[C:9]([OH:12])(=[O:11])[CH:10]=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)[O-]
Agent: O=C(O)CC(=O)O
Agent: [NH4+]
Solvent: CCO
Product: O=C(O)C=Cc1ccccc1

Procedure:
β-substituted-β-amino-acids were prepared by refluxing the corresponding benzaldehyde derivatives with excess ammonium acetate (˜2 equiv.), and malonic acid (1 equiv.) in absolute ethanol until the reaction has completed (determined by TLC and NMR). Cinnamic acid derivative was produced as a side product. The reaction mixtures were then workup with standard procedures, e.g., as described in FIG. 4.
Reaction SMILES: [CH:1](NC1CCCCC1)(C)C.[Li]CCCC.[CH:16]1[C:27]2[CH2:26][C:25]3[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=3[O:23][CH:22]([C:32]([O:34][CH3:35])=[O:33])[O:21][C:20]=2[CH:19]=[CH:18][CH:17]=1.CI>O1CCCC1.CS(C)=O.C(Cl)Cl>[CH3:35][O:34][C:32]([C:22]1([CH3:1])[O:21][C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:27]=2[CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=2[O:23]1)=[O:33]
Reactant: CC(C)NC1CCCCC1
Reactant: COC(=O)C1Oc2ccccc2Cc2ccccc2O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Solvent: ClCCl
Product: COC(=O)C1(C)Oc2ccccc2Cc2ccccc2O1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 47.5 %

Procedure:
To a stirred solution of isopropyl cyclohexyl amine (2.92 ml, 0.0178 mol) in 15 ml of dry tetrahydrofuran (THF) under N2 at 0° C. is added n-BuLi (11.84 ml of 1.5 M in hexane). After stirring 15 minutes at 0° C., the solution is cooled to -65° C. and a solution of methyl 12H-dibenzo[d,g][1,3]dioxocin-6-carboxylate (4.0 g, 0.0148 mol) in 10 ml of THF is added dropwise over a period of 5 minutes. The solution is stirred at -65° C. for an additional 10 minutes and then added via syringe over a period of 2 minutes to a solution of methyl iodide (1.84 ml, 0.0246 mol) in 25 ml of dry dimethyl sulfoxide at room temperature After stirring for 30 minutes, the reaction mixture is diluted with 300 ml of CH2Cl2, washed with H2O, 1N HC1 and then brine, dried over MgSO4 and concentrated. The residue obtained is purified by dry column chromatography (elution with 1:4 ethyl acetate-hexanes) to afford 2 g of a yellow syrup. This material was subjected to HPLC purification (Waters 500, 2 columns, 4 cycles, elution with 1:7 ethylacetatehexanes) to afford 1.1 g (26 percent) of product as a clear sirup: IR (neat) 5.65, 6.3, 6.7, 6.85, 7.25 cm-1 ; 1H NMR (60 MHz, CDCl3) δ 1.36 (s, 3, CH3), 3.71 and 4.32 (2d, 2, CH2) 3.9 (s, 3, OCH3), 6.95-7.4 (m, 8, Ar--H).
Reaction SMILES: [OH:1][C:2]1[C:6]([CH:7]=[O:8])=[CH:5][N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[CH3:15][O:16][CH2:17]Cl.C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:15][O:16][CH2:17][O:1][C:2]1[C:6]([CH:7]=[O:8])=[CH:5][N:4]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:3]=1
Reactant: COCCl
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCOc1nn(-c2ccccc2)cc1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
A mixture of 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (1.88 g), chloromethyl methyl ether (0.835 mL), N,N-diisopropylethylamine (2.09 mL) and tetrahydrofuran (30 mL) was stirred at room temperature for 2 hrs. Saturated aqueous sodium hydrogen carbonate was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was washed with diisopropyl ether-hexane to give 3-(methoxymethoxy)-1-phenyl-1H-pyrazole-4-carbaldehyde as white crystals (1.34 g, yield 58%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 106-107° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:29]([Br:33])(Br)(Br)Br.OC[CH2:36][CH2:37][N:38]1[C:46]2[C:41](=[N:42][C:43]([O:47][CH3:48])=[CH:44][CH:45]=2)[CH2:40][C:39]1=[O:49]>ClCCl>[Br:33][CH2:29][CH2:36][CH2:37][N:38]1[C:46]2[C:41](=[N:42][C:43]([O:47][CH3:48])=[CH:44][CH:45]=2)[CH2:40][C:39]1=[O:49]
Reactant: BrC(Br)(Br)Br
Reactant: COc1ccc2c(n1)CC(=O)N2CCCO
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc2c(n1)CC(=O)N2CCCBr
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Under argon and in an anhydrous medium, 1.50 g (3.76 mmol) of 1,2-bis-diphenylphosphinoethane are added at 0° C. to a solution of 1.25 g (3.76 mmol) of carbon tetrabromide in 20 ml of dichloromethane. After 10 minutes at 0° C., 417 mg (1.88 mmol) of the compound obtained in Step D dissolved in 10 ml of dichloromethane are added to the mixture. The mixture is stirred for 30 minutes at 0° C., and then for 3 hours at room temperature. After hydrolysis of the reaction mixture, the organic phase is dried over magnesium sulphate, filtered and concentrated. Purification by flash chromatography over silica gel (eluant: petroleum ether/ethyl acetate, 8:2) yields the title compound in the form of a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:31]([C:32]4[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=4)[N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2].BrC1C=CC=CC=1C1N(C2C=CC([N+]([O-])=O)=CC=2)N=NN=1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([C:3]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:31]([C:32]4[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=4)[N:30]=[N:29][N:28]=3)=[CH:19][CH:20]=2)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1cc(OCc2ccc(-c3ccccc3-c3nnnn3-c3ccc([N+](=O)[O-])cc3)cc2)c2ccccc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1ccc(-n2nnnc2-c2ccccc2Br)cc1
Solvent: Cc1ccccc1
Product: CCc1cc(OCc2ccc(-c3ccccc3-c3nnnn3-c3ccc([N+](=O)[O-])cc3)cc2)c2c(n1)CCCC2
Temperature: 25 °C
Yield: 66.5 %

Procedure:
Tetrakis(triphenylphosphine)palladium (40 mg) was added to a suspension of compound A (200 mg) and 5-(2-bromophenyl)-1-(4-nitrophenyl)-1H-tetrazole (202 mg) in toluene (2 ml) ethanol (0.5 ml) and 2M aqueous sodium carbonate (0.58 ml). The mixture was degassed and placed under an atmosphere of argon, then heated under reflux for 12 hours. The resulting solution was cooled to ambient temperature, and dichloromethane (30 ml) and water (10 ml) were added. The organic layer was separated, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by flash chromatography, eluting with ethyl acetate/hexane (3:1 v/v), and the product triturated with ether/hexane to give 2-ethyl-4-[(2'-(1-(4-nitrophenyl)-1H-tetrazol-5-yl)biphenyl-4-yl)methoxy]-5,6,7,8-tetrahydroquinoline (134 mg) as a solid; NMR and m.p. similar to that obtained by procedure D.
Reaction SMILES: [C:1]([OH:32])(=[O:31])[CH2:2][CH2:3][C@H:4]([NH:8][C:9]([C:11]1[CH:30]=[CH:29][C:14]([NH:15][CH2:16][C:17]2[N:28]=[C:27]3[C:20]([N:21]=[C:22]([NH:24][C:25]3=[O:26])[NH2:23])=[N:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:10])[C:5]([OH:7])=[O:6]>[Rh].O>[C:1]([OH:32])(=[O:31])[CH2:2][CH2:3][C@H:4]([NH:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]([NH:15][CH2:16][CH:17]2[NH:28][C:27]3[C:25](=[O:26])[NH:24][C:22]([NH2:23])=[N:21][C:20]=3[NH:19][CH2:18]2)=[CH:29][CH:30]=1)=[O:10])[C:5]([OH:7])=[O:6]
Reactant: Nc1nc2ncc(CNc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)nc2c(=O)[nH]1
Agent: [Rh]
Solvent: O
Product: Nc1nc2c(c(=O)[nH]1)NC(CNc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)CN2
Yield: 75.3 %

Procedure:
Then, a suspension of 0.230 g of a 5% rhodium-activated carbon catalyst (containing the noble metal in an amount of 0.55% by weight based on the folic acid) in 25 ml of distilled water was added to the flask, and hydrogenation was carried out in the same manner as described in Example 1 to obtain 1.593 g (75.3% yield) of tetrahydrofolic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[S:14](=[O:16])(=[O:15])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[F:17][C:18]([F:23])([F:22])[C@@H:19]1[CH2:21][O:20]1>ClCCl>[F:17][C:18]([F:23])([F:22])[C@@H:19]([OH:20])[CH2:21][N:11]1[CH2:12][CH2:13][S:14](=[O:16])(=[O:15])[CH:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:10]1
Reactant: FC(F)(F)[C@@H]1CO1
Reactant: COc1cccc(C2CNCCS2(=O)=O)c1
Solvent: ClCCl
Product: COc1cccc(C2CN(C[C@H](O)C(F)(F)F)CCS2(=O)=O)c1
Reaction time: 8 h
Yield: 65.3 %

Procedure:
In a 25 mL round-bottomed flask was placed 2-(3-methoxyphenyl)-thiomorpholine-1,1-dioxide (252 mg, 1.04 mmol), followed by (S)-2-(trifluoromethyl)oxirane (129 mg, 1.15 mmol). The reaction mixture was stirred overnight. Reaction was not complete. An additional 100 mg of the (S)-2-(trifluoromethyl)oxirane was added followed by a small amount of dichloromethane. Reaction mixture was stirred at room temperature for an additional 2 h. The crude material was purified by flash chromatography (silica gel, 40 g, 10% to 40% EtOAc in hexanes) afforded (S)-1,1,1-trifluoro-3-[2-(3-methoxyphenyl)-1,1-dioxo-1λ6-thiomorpholin-4-yl]-propan-2-ol (240 mg) as a white foam. (M+H)+=354 m/e.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11]([C:13]2[NH:14][C:15]([CH2:19][CH3:20])=[C:16]([Cl:18])[N:17]=2)=[O:12])[C@H:6]([O:21][CH3:22])[CH2:5]1)(=[S:3])[NH2:2].Br[CH:24]([CH3:32])[C:25](=O)[CH2:26][C:27]([O:29][CH3:30])=[O:28]>>[Cl:18][C:16]1[N:17]=[C:13]([C:11]([NH:10][C@H:7]2[CH2:8][CH2:9][N:4]([C:1]3[S:3][C:24]([CH3:32])=[C:25]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[N:2]=3)[CH2:5][C@H:6]2[O:21][CH3:22])=[O:12])[NH:14][C:15]=1[CH2:19][CH3:20]
Reactant: COC(=O)CC(=O)C(C)Br
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(C(N)=S)C[C@H]2OC)nc1Cl
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(CC(=O)OC)c(C)s3)C[C@H]2OC)nc1Cl
Yield: 81.3 %

Procedure:
The same operation as in Example (22b) was performed using cis(±)-N-(1-carbamothioyl-3-methoxypiperidin-4-yl)-4-chloro-5-ethyl-1H-imidazole-2-carboxamide (40 mg, 0.12 mmol) obtained in Example (65c) and methyl 4-bromo-3-oxopentanoate obtained in Example (65a) (45 mg, 0.22 mmol), to obtain 44.5 mg of the title compound (84%).
Reaction SMILES: [NH2:1][C:2](=[N:5][C:6](=[O:9])[O:7][CH3:8])[O:3][CH3:4].NC(=NC(=O)OC)SC.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>C(Cl)Cl>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:28])[NH:1][C:2](=[N:5][C:6]([O:7][CH3:8])=[O:9])[O:3][CH3:4])=[CH:22][CH:21]=1
Reactant: COC(=O)N=C(N)OC
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: COC(=O)N=C(N)SC
Solvent: ClCCl
Product: COC(=O)N=C(NC(=O)Nc1ccc(Cl)cc1)OC
Reaction time: 8 h

Procedure:
To 13 parts of methyl N-(1-amino-1-methoxymethylene)carbamate, m.p. 36°-39.5°, prepared similar to the procedure in Example 3 for methyl N-(1-amino-1-methylthiomethylene)carbamate in 140 parts of methylene chloride is added 15 parts of p-chlorophenyl isocyanate. The reaction mixture is stirred overnight and the solution filtered to give 10 parts of methyl 4-(p-chlorophenyl)-N-methoxycarbonylallophanimidate melting at 170° dec.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[N:10]=[C:11](Cl)[C:12]2[CH:17]([C:18]([O:20][CH3:21])=[O:19])[CH2:16][CH2:15][C:13]=2[N:14]=1.C(O)=O>O1CCOCC1.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[NH2:8][C:9]1[N:10]=[CH:11][C:12]2[CH:17]([C:18]([O:20][CH3:21])=[O:19])[CH2:16][CH2:15][C:13]=2[N:14]=1
Reactant: COC(=O)C1CCc2nc(N)nc(Cl)c21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O=CO
Product: COC(=O)C1CCc2nc(N)ncc21
Temperature: 100 °C

Procedure:
Triethylamine (3.20 mL, 23.0 mmol) was added to a solution of methyl 2-amino-4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine-5-carboxylate (2.11 g, 9.27 mmol) in dioxane (42 mL) followed by formic acid (0.89 mL, 22.28 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (660 mg, 0.902 mmol). The reaction mixture was heated at 100° C. in a sealed tube overnight. The solvent was evaporated. The residue was purified by chromatography on silica (220 g+125 g cartridges) using CH2Cl2: MeOH 95:5 to afford the title compound which was used without further purification in the next step.
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:25](=[O:26])[N:5]2[C:6]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])=[CH:7][CH:8]([O:10][CH3:11])[S:9][C@H:4]12.C[Si](CC(N)=O)(C)C.N1C(C)=CC=CC=1C.P(Cl)(Cl)(Cl)=O.[CH:48]([NH:50][C:51]1[S:52][C:53]([Br:63])=[C:54]([C:56](=[N:60][O:61][CH3:62])[C:57](O)=[O:58])[N:55]=1)=[O:49]>C(OCC)(=O)C.CN(C)C=O>[CH:48]([NH:50][C:51]1[S:52][C:53]([Br:63])=[C:54]([C:56](=[N:60][O:61][CH3:62])[C:57]([NH:2][CH:3]2[C:25](=[O:26])[N:5]3[C:6]([C:12]([O:14][CH2:15][C:16]4[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=4)=[O:13])=[CH:7][CH:8]([O:10][CH3:11])[S:9][C@H:4]23)=[O:58])[N:55]=1)=[O:49]
Reactant: COC1C=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(N)[C@H]2S1
Reactant: CON=C(C(=O)O)c1nc(NC=O)sc1Br
Agent: C[Si](C)(C)CC(N)=O
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1cccc(C)n1
Solvent: CCOC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CC(OC)S[C@H]12)c1nc(NC=O)sc1Br
Yield: 88.9 %

Procedure:
A solution of 4-nitrobenzyl 7-amino-2-methoxy-3-cephem-4-carboxylate hydrochloride (2.0 g.), trimethylsilylacetamide (2.0 g.) and 2,6-lutidine (0.58 ml.) in dry ethyl acetate (60 ml.) and a solution of dimethylformamide (0.51 ml.), phosphoryl chloride (0.60 ml.) and 2-(2-formamido-5-bromothiazol-4-yl)-2-methoxyiminoacetic acid (syn isomer, 1.7 g.) in dry ethyl acetate (11.7 ml.) were treated in a similar manner to that of Example 1-(1) to give 4-nitrobenzyl 7-[2-(2-formamido-5-bromothiazol-4-yl)-2-methoxyiminoacetamido]-2-methoxy-3-cephem-4-carboxylate (syn isomer, 2.9 g.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([NH2:26])[CH:20]=[CH:19]2.C([O-])([O-])=O.[K+].[K+].[CH3:33][O:34][C:35]1[CH:43]=[CH:42][CH:41]=[CH:40][C:36]=1[C:37](Cl)=[O:38]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([NH:26][C:37](=[O:38])[C:36]1[CH:40]=[CH:41][CH:42]=[CH:43][C:35]=1[O:34][CH3:33])[CH:20]=[CH:19]2
Reactant: COc1cc2nccc(Oc3ccc4cc(N)ccc4c3)c2cc1OC
Reactant: COc1ccccc1C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc4cc(NC(=O)c5ccccc5OC)ccc4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 6-(6,7-dimethoxy-4-quinolyloxy)-2-naphthylamine (Step c, 34.6 mg, 0.1 mmol) and K2CO3 in dry CH2Cl2 (10 mL, Aldrich) was added 2-methoxybenzoyl chloride (25.5 mg, 0.15 mmol, Aldrich). The reaction was stirred at RT for 3 h. The volatile portion was removed in vacuo. To the residue was added 15 mL of MeOH and the mixture was stirred at RT for 30 min. The MeOH was removed in vacuo. The resulting residue was diluted in EtOAc (50 mL) and washed with water and brine. The organic phase was dried over MgSO4 and concentrated. The resulting brown residue was purified by silica gel column chromatography (EtOAc) to give the title compound as a white solid. MS (ESI, pos. ion) m/z: 481.4 (M+1). Mass Calc'd for C29H24N2O5: 480.17.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][C:12](=[O:17])[C:11]=2[CH:10]=[CH:9][CH:8]=1)(=O)=O.[CH3:20][N:21](C=O)C>C(Cl)Cl.[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:17]=[C:12]1[CH2:13][CH2:14][CH2:15][C:16]2[C:7]([C:20]#[N:21])=[CH:8][CH:9]=[CH:10][C:11]1=2
Reactant: CN(C)C=O
Reactant: O=C1CCCc2c(OS(=O)(=O)C(F)(F)F)cccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: ClCCl
Product: N#Cc1cccc2c1CCCC2=O
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A mixture of compound 5-oxo-5,6,7,8-tetrahydronaphthalen-1-yl trifluoromethanesulfonate (8.6 g, 30.8 mmol), Zn(CN)2(7.2 g, 61.6 mmol) and Pd(PPh3)4(0.8 g) in anhydrous DMF was stirred at 120° C. under N2 overnight. The reaction was cooled to ambient temperature, and then diluted with DCM. Filtered off solids and the orgainic filtrate was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified with silica gel cloumn chromatography to give 5-oxo-5,6,7,8-tetrahydronaphthalene-1-carbonitrile.
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[Cl:14][S:15]([C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1)(=[O:17])=[O:16].O.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:6]([N:5]1[CH:4]=[CH:3][N:24]([C:21]2[CH:22]=[CH:23][C:18]([S:15]([Cl:14])(=[O:16])=[O:17])=[CH:19][CH:20]=2)[C:25]1=[O:26])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: O=C=Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCCNCC(OC)OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CCCCCCn1ccn(-c2ccc(S(=O)(=O)Cl)cc2)c1=O
Reaction time: 0.33 h
Yield: 66.5 %

Procedure:
To the amine (38.6 mmol, 7.3 g) in methylene chloride (100 ml) at 0° C. was added 4-(chlorosulphonyl)phenyl isocyanate (38.6 mmol, 8.4 g). The reaction mixture was stirred for 20 mins until a clear solution had formed, and 1:1 water:trifluoroacetic acid (100 ml total) was added. Vigorous stirring was continued for 16 h., the layers separated, the organic layer was diluted with ethyl acetate (500 ml) and washed with saturated sodium bicarbonate solution (4×50 ml), brine (50 ml), dried with anhydrous magnesium sulphate, and concentrated in vacuo. Column chromatrography (eluant 3 hexane/1 ethyl acetate) yielded the title compound as pale yellow crystals (8.8 g, 67%).
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH3:21])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18]CC)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C.O>[Br:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH3:21])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([OH:18])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1c(Br)cccc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN1Cc2c(C(=O)O)ncn2-c2cccc(Br)c2C1=O

Procedure:
7.10 g (19 mmol) of ethyl 7-bromo-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepin-3carboxylate in 30 ml of ethanol are heated to boiling for 20 minutes with a solution of 1.13 g (28 mmol) of sodium hydroxide in 15 ml of water. The solution is thereafter neutralized with 7 ml of 4N hydrochloric acid and the ethanol is removed on a rotary evaporator. After cooling the separated solid is filtered off under suction. After drying at 85° in vacuo there is obtained 7-bromo-5,6-dihydro-5-methyl-6-oxo-4H-imidazo-[1,5-a][1,4]benzodiazepine-3-carboxylic acid.
Reaction SMILES: [Br:1][CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=[O:4].[NH2:29][C:30]1[N:31]=[CH:32][C:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[N:34][CH:35]=1.C(N(C(C)C)CC)(C)C>C(#N)CCC>[Br:1][CH:2]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13][CH2:12]2)=[CH:9][CH:10]=1)=[O:4].[C:18]([O:17][C:16]([NH:15][C:11]1([C:8]2[CH:7]=[CH:6][C:5]([C:3]3[N:29]=[C:30]4[CH:35]=[N:34][C:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:32][N:31]4[C:2]=3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:10][CH:9]=2)[CH2:14][CH2:13][CH2:12]1)=[O:22])([CH3:20])([CH3:19])[CH3:21]
Reactant: CCOC(=O)c1cnc(N)cn1
Agent: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCC#N
Product: CCOC(=O)c1cn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc2cn1
Temperature: 120 °C

Procedure:
To a mixture of crude tert-butyl (1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate [Int-1-A] (213 mg, 0.38 mmol, 1.0 eq), ethyl 5-aminopyrazine-2-carboxylate (CAS-Nr. 54013-06-8, 70.5 mg, 0.42 mmol, 1.1 eq.) and diisopropylethylamine (0.055 mL, 0.42 mmol, 1.1 eq) in 2.3 mL butyronitrile was added predried 3 Å mol sieves. The mixture was heated overnight at 120° C. The reaction mixture was partitioned between DCM/water and was filtered through a phase separator. The remaining volatile organic components were removed by the use of a rotary evaporator. In parallel we conducted the same experiment in the absence of diisopropylethylamine following the same protocol. The crude materials of both experiments were combined and purified via MPLC (Biotage Isolera, 25 g Snap-cartridge; eluent: hexane/ethyl acetate (1/1)→ethyl acetate) to deliver 69 mg (14%, yield based on combined amount of tert-butyl (1-{4-[bromo(phenyl)acetyl]-phenyl}cyclobutyl)carbamate) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:4]([NH:16][C:15]2[CH:17]=[CH:18][C:12]([Cl:11])=[CH:13][CH:14]=2)=[O:6])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: Nc1ncccc1C(=O)O
Reactant: Nc1ccc(Cl)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncccc1C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-aminonicotinic acid (5.3 g, 38 mmol) and 4-chloroaniline (4.9 g, 38 mmol) and DIEA (9 ml, 48 mmol) at 0° C. in CH2Cl2 was added EDC (9.5 g, 48 mmol) and HOBt (5.1 g, 38 mmol), the reaction was warmed to RT and stirred overnight. The solvent was evaporated under reduced pressure and quenched with 2N NaOH solution (60 ml) and stirred for 20 min. The precipitate was filtered to give the titled compound. MS (ES+): 248 (M+H)+; (ES−): 246 (M−H)−.
Reaction SMILES: C1(COC([NH:11][C@@H:12]([C:14]([N:16]([CH3:22])[CH2:17][C:18](OC)=[O:19])=[O:15])[CH3:13])=O)C=CC=CC=1.CO>C(Cl)Cl.[Pd]>[CH3:22][N:16]1[CH2:17][C:18](=[O:19])[NH:11][C@H:12]([CH3:13])[C:14]1=[O:15]
Reactant: COC(=O)CN(C)C(=O)[C@@H](C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: C[C@H]1NC(=O)CN(C)C1=O
Reaction time: 6 h
Yield: 94.9 %

Procedure:
To a slurry of three combined batches of methyl N-{[(phenylmethyl)oxy]carbonyl}-D-alanyl-N-methylglycinate (combined total 489.09 g, 1586 mmol) in DCM (210 mL) was added MeOH (1000 mL) and 10% Pd/C (50 g). The mixture was hydrogenated at 50 psi overnight, and then an additional portion of 10% Pd/C (5 g) was added. The mixture was hydrogenated at 50 psi for an additional 6 h, and was then filtered and washed with MeOH and DCM. The resulting clear liquid was evaporated to give a clear oil, which subsequently solidified upon standing to afford (3R)-1,3-dimethyl-2,5-piperazinedione (214.0 g, 95% yield) as a pale yellow tinted solid. LCMS: (M+H)+: 143.0.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:11][C:12]([NH2:14])=[O:13])=[CH:5][NH:6]2.C[O:16][C:17](=O)[C:18]([C:20]1[C:30]2=[C:31]3[C:26](=[CH:27][CH:28]=[CH:29]2)[CH2:25][CH2:24][CH:23]([CH3:32])[N:22]3[CH:21]=1)=O>>[CH3:32][CH:23]1[CH2:24][CH2:25][C:26]2[C:31]3=[C:30]([C:20]([C:18]4[C:17](=[O:16])[NH:14][C:12](=[O:13])[C:11]=4[C:4]4[C:3]5[C:7](=[CH:8][CH:9]=[CH:10][C:2]=5[F:1])[NH:6][CH:5]=4)=[CH:21][N:22]13)[CH:29]=[CH:28][CH:27]=2
Reactant: NC(=O)Cc1c[nH]c2cccc(F)c12
Reactant: COC(=O)C(=O)c1cn2c3c(cccc13)CCC2C
Product: CC1CCc2cccc3c(C4=C(c5c[nH]c6cccc(F)c56)C(=O)NC4=O)cn1c23

Procedure:
Beginning with (4-fluoroindol-3-yl)acetamide and (4-methyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxo-acetic acid methyl ester, the title compound was prepared essentially as described in Example 1.