Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:5]=2[N:6]=1.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.N1C=CC=CC=1>O>[N+:11]([C:8]1[CH:9]=[CH:10][C:4]2[S:3][C:2]([NH:1][C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:6][C:5]=2[CH:7]=1)([O-:13])=[O:12]
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1nc2cc([N+](=O)[O-])ccc2s1
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1nc2cc([N+](=O)[O-])ccc2s1)c1ccccc1
Temperature: 60 °C
Yield: 78.5 %

Procedure:
A mixture of 2-amino-5-nitrobenzothiazole (1.52 g, 7.8 mmol), benzoyl chloride (1.36 mL, 11.7 mmol) and pyridine (15 mL) was heated to 60° C. for 24 h. The mixture was poured into water (250 mL), and the resulting precipitate was separated by filtration to yield N-(5-nitrobenzothiazol-2-yl)benzamide (1:83 g, 6.12 mmol, 78%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][OH:12])[CH2:9][OH:10])=[CH:4][CH:3]=1.[C:13](OC=C)(=[O:15])[CH3:14]>>[C:13]([O:10][CH2:9][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[CH2:11][OH:12])(=[O:15])[CH3:14]
Reactant: OCC(CO)c1ccc(Br)cc1
Reactant: C=COC(C)=O
Product: CC(=O)OCC(CO)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 11 h
Yield: 65 %

Procedure:
To a solution of 2-(4-bromophenyl)propane-1,3-diol (9.01 g, 39.0 mmol) in vinyl acetate (100 ml) was added Lipase AK Amano (purchased from WAKO, 12.0 g) at room temperature. The mixture was stirred at room temperature for 11 hours and filtered through a pad of Celite to remove solid materials. After concentration, to the residue dissolved into ethanol (35 ml) and diisopropyl ether (200 ml) was added Lipase from porcine pancreas (type II, purchased from SIGMA, 22.2 g). The mixture was stirred at room temperature for 107 hours and filtered through a pad of Celite. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluant: hexane/ethyl acetate=2/1) to afford (−)-2-(4-bromophenyl)-3-hydroxypropyl acetate as colorless oil (6.88 g, 65%). [α]D=−11.2 (C=0.5, CHCl3).
Reaction SMILES: C[N:2](C)C=O.P(Cl)(Cl)(Cl)=O.[C:11]([C:14]1[N:15]=[C:16]([C@@H:19]2[CH2:23][C@@H:22]([O:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:21][N:20]2[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)=[O:30])[S:17][CH:18]=1)([OH:13])=O.O.N>O1CCCC1>[C:11]([C:14]1[N:15]=[C:16]([C@@H:19]2[CH2:23][C@@H:22]([O:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:21][N:20]2[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)=[O:30])[S:17][CH:18]=1)(=[O:13])[NH2:2]
Reactant: CN(C)C=O
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](c2nc(C(=O)O)cs2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: N
Solvent: C1CCOC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CS(=O)(=O)O[C@@H]1C[C@@H](c2nc(C(N)=O)cs2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 0.5 h

Procedure:
To a mixture of dimethylformamide (0.45 ml) and tetrahydrofuran (10 ml) was dropwise added phosphorus oxychloride (0.46 ml) at -5~5° C., and the mixture was stirred at the same temperature for 30 minutes. To the mixture was added a solution of (2S,4R)-2-(4-carboxythiazol-2-yl)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.54 g) in tetrahydrofuran (20 ml) at -5~5° C., followed by stirring at the same temperature for 30 minutes. The mixture was dropwise added to concentrated ammonia water (15 ml) at 0°-10° C. with stirring. The mixture was stirred at the same condition for 2 hours. Tetrahydrofuran was removed under reduced pressure to give a residue, which was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give (2S,4R)-2-(4-carbamoylthiazol-2-yl)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.4 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5]([Cl:8])=[N:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C.O>[CH2:16]([O:9][C:4]1[C:5]([Cl:8])=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cc(Br)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ncc(Br)cc1OCc1ccccc1
Reaction time: 8 h
Yield: 94.1 %

Procedure:
5-Bromo-2-chloro-pyridin-3-ol (500 mg, 2.399 mmol) and Cs2CO3 (1.2 g, 3.68 mmol) were combined in DMF (10 mL) at RT. To this was added benzyl bromide (0.34 mL, 2.86 mmol). After stirring overnight the mixture was diluted with H2O and extracted with Et2O (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated. Flash column (Biotage-SNAP-50 g, 0-10% EtOAc/hexanes) gave the title compound (674 mg, 94%) as a white solid. 1H NMR (500 MHz, CDCl3): δ 8.07 (d, J=2.0 Hz, 1 H); 7.53-7.35 (m, 6 H); 5.16 (s, 2 H). LC/MS (M+H)+ 298/300/302.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][CH2:10][C:11]([O:13]CC)=[O:12])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[OH-].[Na+].O.P(=O)(O)(O)O>CCCCCCC.O1CCCC1>[Br:1][C:2]1[C:3]([NH:9][CH2:10][C:11]([OH:13])=[O:12])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1
Reactant: CCOC(=O)CNc1ncc(Br)nc1Br
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: O=C(O)CNc1ncc(Br)nc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 2-(3,5-dibromopyrazin-2-ylamino)acetate (1 equiv), tetrahydrofuran and sodium hydroxide in water (1.1 equiv) were combined and stirred at room temperature overnight. The reaction mixture was treated with dilute phosphoric acid (1.9 equiv) and heptane. The organic layer was concentrated to about 75% of its original volume and further distilled with addition of heptane until the reaction mixture was 80° C. The solution was treated with seed and distillation with addition of heptane was continued until reaching 85° C. The slurry was cooled and filtered, and the solids washed with heptane and dried to obtain 2-((3,5-dibromopyrazin-2-yl)amino)acetic acid as a solid. MS (ESI) m/z 309.9 [M+1].
Reaction SMILES: C(C1C=CC=CC=1O)C.C1(O)C=CC=CC=1.C(C1C=C(O)C=CC=1)C.[CH2:26]([C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[CH3:27].C(C1C=CC=CC=1O)C.C1C=CC=CC=1.O>C1C=CC=CC=1>[CH:26]([C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)=[CH2:27]
Reactant: CCc1ccc(O)cc1
Agent: CCc1cccc(O)c1
Agent: CCc1ccccc1O
Solvent: O
Solvent: c1ccccc1
Solvent: Oc1ccccc1
Product: C=Cc1ccc(O)cc1

Procedure:
Crude ethylphenol consisting of 2.0% phenol and m- and p-cresols, 0.2% o-ethylphenol, 55.8% m-ethylphenol and 42.0% p-ethylphenol was dissolved in benzene, and dehydrogenated at a temperature of 600° C. and LHSV of 1.0 hr-1 under atmospheric pressure using the same catalyst as in Example 1, with the ethylphenol/benzene/water molar ratio being 1/1/12. The resulting product was allowed to stand at room temperature followed by separating the water. The crude vinylphenol so separated consisted of 39.0% benzene, 4.3% phenol and m- and p-cresols, 0.1% o-ethylphenol, 22.1% m-ethylphenol, 10.4% p-ethylphenol, traces of o-vinylphenol, 10.1% m-vinylphenol, 9.5% p-vinylphenol, 0.5% oligomers of vinylphenols and 4.0% water with the p-vinylphenol/(ethylphenols+ m-vinylphenol) molar ratio being 0.61. The crude vinylphenol was directly placed in a three necked glass reactor equipped with a stirrer, and heat polymerized at 140° C. for 4 hours to afford a crude p-vinylphenol polymer consisting of 1.2% oligomers of vinylphenols, 7.5% phenol and m- and p-cresols, 0.2% o-ethylphenol, 39.0% m-ethylphenol, 18.3% p-ethylphenol, 17.4% m-vinylphenol, and 16.4% p-vinylphenol polymer.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:28])[C:9]2[CH:27]=[CH:26][C:12]3[N:13]([CH3:25])[C:14]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=4)=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:29][S:30]([CH:33]([C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=1)[CH3:34])(=[O:32])=[O:31]>>[ClH:1].[CH3:29][S:30]([CH:33]([C:35]1[CH:36]=[CH:37][C:38]([NH:41][C:2]2[N:7]=[C:6]([N:8]([CH3:28])[C:9]3[CH:27]=[CH:26][C:12]4[N:13]([CH3:25])[C:14]([NH:16][CH2:17][C:18]5[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=5)=[N:15][C:11]=4[CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[CH:39][CH:40]=1)[CH3:34])(=[O:31])=[O:32]
Reactant: Cc1ccc(CNc2nc3cc(N(C)c4ccnc(Cl)n4)ccc3n2C)cc1
Reactant: CC(c1ccc(N)cc1)S(C)(=O)=O
Product: Cc1ccc(CNc2nc3cc(N(C)c4ccnc(Nc5ccc(C(C)S(C)(=O)=O)cc5)n4)ccc3n2C)cc1
Product: Cl

Procedure:
The title compound was prepared following the procedure of example one with N5-(2-Chloro-pyrimidin-4-yl)-1,N5-dimethyl-N2-(4-methyl-benzyl)-1H-benzoimidazole-2,5-diamine (98 mg, 0.25 mmol) and 4-(1-methanesulfonyl-ethyl)-phenylamine (50 mg, 0.25 mmol) as a white solid (151 mg, 97%). 1H NMR (300 MHz, d6-DMSO+NaHCO3) δ 9.20 (s, 1H), 7.76-7.79 (M, 3H), 7.38 (m, 1H), 7.21-7.29 (m, 5H), 7.08-7.13 (M, 3H), 6.83 (d, J=8.1 Hz, 1H), 5.64 (d, J=6.0 Hz, 1H), 4.54 (d, J=5.1 Hz, 2H), 4.39 (m, 1H), 3.57 (s, 3H), 3.43 (S, 3H), 2.76 (s, 3H), 2.26 (s, 3H), 1.59 (d, J=7.2 Hz, 3H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([N:6]2[C:14](=[O:15])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]2=[O:16])=[N:2]1.[CH3:17][C:18]1([CH3:35])[O:22][C@H:21]([CH2:23]OS(C2C=CC(Cl)=CC=2)(=O)=O)[CH2:20][O:19]1.CC(C)([O-])C.[Na+].O>O1CCOCC1>[CH3:17][C:18]1([CH3:35])[O:22][C@H:21]([CH2:23][N:1]2[CH:5]=[CH:4][C:3]([N:6]3[C:14](=[O:15])[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:7]3=[O:16])=[N:2]2)[CH2:20][O:19]1
Reactant: CC1(C)OC[C@@H](COS(=O)(=O)c2ccc(Cl)cc2)O1
Reactant: O=C1c2ccccc2C(=O)N1c1cc[nH]n1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)OC[C@@H](Cn2ccc(N3C(=O)c4ccccc4C3=O)n2)O1
Temperature: 103 °C
Yield: 74 %

Procedure:
A mixture of 2-(1H-pyrazol-3-yl)-isoindole-1,3-dione (5.00 g, 23.5 mmol), 4-chloro-benzenesulfonic acid (S)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl ester (8.00 g, 26.1 mmol), and sodium t-butoxide (2.78 g, 28.9 mmol) in 1,4-dioxane (50 mL) was refluxed (103° C.) for 24 h. Upon cooling to 25° C., water (55 mL) was added. The mixture became cloudy and crystallization was observed. Then, water (50 mL) was slowly added over 30 min. Subsequent filtration, washing with water, and suction drying provided 2-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-isoindole-1,3-dione (5.69 g, 74.1%) as an off-white solid: LR-ES-MS m/z calculated for C17H17N3O4 [M]+ 327, observed [M+H]+ 328.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:12]=[C:13]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[F:37])[N:14]([S:16]([C:19]2[CH:30]=[CH:29][C:22]([O:23][CH2:24][C:25]([O:27]C)=O)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:15]=1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:38][NH2:39]>CO>[F:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[C:13]1[N:14]([S:16]([C:19]2[CH:20]=[CH:21][C:22]([O:23][CH2:24][C:25]([NH:39][CH3:38])=[O:27])=[CH:29][CH:30]=2)(=[O:17])=[O:18])[CH:15]=[C:11]([CH2:10][N:8]([CH3:9])[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH:12]=1
Reactant: CN
Reactant: COC(=O)COc1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2-c2ccccc2F)cc1
Solvent: CO
Product: CNC(=O)COc1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2-c2ccccc2F)cc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
Methyl 2-(4-((4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-(2-fluorophenyl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)acetate 4e (100 mg, 0.19 mmol) was dissolved in 5 mL of a solution of methylamine in methanol (33%), and the reaction solution was heated up to 40° C. and stirred for 2 h. The reaction solution was concentrated under reduced pressure to obtain the title product tert-butyl ((5-(2-fluorophenyl)-1-((4-(2-(methylamino)-2-oxoethoxy)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 4f (100 mg, a yellow oil), which was used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[CH:14][NH:15]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Br:18]Br>>[Br:18][C:13]1[C:12]2[C:16](=[CH:17][C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[CH:10][CH:11]=2)[NH:15][CH:14]=1
Reactant: BrBr
Reactant: COc1ccc(-c2ccc3cc[nH]c3c2)cc1
Product: COc1ccc(-c2ccc3c(Br)c[nH]c3c2)cc1

Procedure:
The target compound was prepared as in Preparation Example 6 using 6-(4-methoxyphenyl)-1H-indole (500 mg, 2.24 mmol) and bromine (115 μL, 2.24 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1CC[CH2:17][CH2:16]1.O.ICC>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11](=[O:14])[CH:12]([CH2:16][CH3:17])[CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCI
Solvent: O
Product: CCC1CN(C(=O)OC(C)(C)C)CCC1=O
Temperature: 100 °C

Procedure:
A solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (5 g, 25.1 mmol), pyrollidine (5 mL) and p-toluenesulfonic acid (25 mg) in benzene (100 mL) was heated at reflux for 16 h with azeotropic distillation of water. The resulting enamine solution was cooled to rt and concentrated. The crude enamine was dissolved in acetonitrile (50 mL); iodoethane (4.67 g, 30.1 mmol.) was added and the mixture was heated at 100° C. for 0.5 h, cooled to rt and concentrated. The mixture was dissolved in ethyl acetate (200 mL), washed with 1 N hydrochloric acid, saturated aqueous sodium bicarbonate, and brine. The extract was dried over magnesium sulfate, filtered and concentrated. The crude compound was purified by silica gel chromatography (80% hexanes/20% ethyl acetate) to afford 3-ethyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (680 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1)[C:11]1[CH2:10][CH2:9][C@@H:8]([NH:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[CH2:7][C:6]2=1)#N.C(O)=[O:31]>O.CO>[F:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][N:12]1[C:11]2[CH2:10][CH2:9][C@@H:8]([NH:24][C:25](=[O:29])[CH:26]([CH3:27])[CH3:28])[CH2:7][C:6]=2[C:5]2[C:13]1=[CH:14][CH:15]=[C:3]([CH:1]=[O:31])[CH:4]=2
Reactant: CC(C)C(=O)N[C@@H]1CCc2c(c3cc(C#N)ccc3n2Cc2cccc(F)c2)C1
Reactant: O=CO
Solvent: CO
Solvent: O
Product: CC(C)C(=O)N[C@@H]1CCc2c(c3cc(C=O)ccc3n2Cc2cccc(F)c2)C1
Temperature: 90 °C
Yield: 89 %

Procedure:
Add Al—Ni catalyst [12635-27-7] (3.0 g) to a solution of (R)-N-(6cyano9-(3-fluorobenzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl)isobutyramide (Example 123) (2.50 g, 6.42 mmol) in formic acid (96%, 40 mL) and water (5 mL). Heat the reaction mixture to 90° C. for 18 h, then add 2 g fresh Al—Ni catalyst. Heat to reflux for 18 h, cool to 60° C., dilute with MeOH (30 mL), and resume heating. When reflux has begun, filter the reaction mixture while hot through filter paper. Concentrate the filtrate in-vacuo. Dilute the residue with water (30 mL) and saturated aqueous NaHCO3 (30 mL), then extract into EtOAc (3×150 mL). Dry the organics (MgSO4), filter, and concentrate to give 2.25g (89%) of the title compound as a brown solid. MS (ES): m/z 393 (M+1); HPLC (Method B): Rt=4.57 min (91%).
Reaction SMILES: O[C@H]1CCCC[C@@H]1N1C(=O)C2C(=C3C=CC=CC3=C(CN3CCC(C4C=CC=CN=4)(C#N)CC3)C=2)N=C1.[O:38]=[C:39]1[C:48]2[C:43](=[C:44]3[CH:54]=[CH:53][N:52]=[CH:51][C:45]3=[C:46]([CH:49]=O)[CH:47]=2)[N:42]=[CH:41][NH:40]1.[OH:55][C@H:56]1[CH2:61][CH2:60][CH2:59][CH2:58][C@@H:57]1N1C(=O)C2C(=C3C=CC=CC3=C(C=O)C=2)N=C1.[CH3:79][C:80]1[CH:85]=[CH:84][N:83]=[C:82]([C:86]2([C:92]#[N:93])[CH2:91][CH2:90][NH:89][CH2:88][CH2:87]2)[CH:81]=1.N1C=CC=CC=1C1(C#N)CCNCC1>>[OH:55][C@H:56]1[CH2:57][CH2:58][CH2:59][CH2:60][C@@H:61]1[N:40]1[C:39](=[O:38])[C:48]2[C:43](=[C:44]3[CH:54]=[CH:53][N:52]=[CH:51][C:45]3=[C:46]([CH2:49][N:89]3[CH2:90][CH2:91][C:86]([C:82]4[CH:81]=[C:80]([CH3:79])[CH:85]=[CH:84][N:83]=4)([C:92]#[N:93])[CH2:87][CH2:88]3)[CH:47]=2)[N:42]=[CH:41]1
Reactant: O=Cc1cc2c(=O)n([C@H]3CCCC[C@@H]3O)cnc2c2ccccc12
Reactant: O=Cc1cc2c(=O)[nH]cnc2c2ccncc12
Reactant: Cc1ccnc(C2(C#N)CCNCC2)c1
Agent: N#CC1(c2ccccn2)CCN(Cc2cc3c(=O)n([C@H]4CCCC[C@@H]4O)cnc3c3ccccc23)CC1
Agent: N#CC1(c2ccccn2)CCNCC1
Product: Cc1ccnc(C2(C#N)CCN(Cc3cc4c(=O)n([C@H]5CCCC[C@@H]5O)cnc4c4ccncc34)CC2)c1

Procedure:
The title compound was prepared by the procedure described for the synthesis of 1-({3-[(1S,2S)-2-Hydroxycyclohexyl]-4-oxo-3,4-dihydrobenzo[h]quinazolin-6-yl}methyl)-4-pyridin-2-ylpiperidine-4-carbonitrile in Example 2, substituting 34(1S,2S)-2-hydroxycyclohexyl]-4-oxo-3,4-dihydropyrido[3,4-h]quinazoline-6-carbaldehyde for 3-[(1S,2S)-2-hydroxycyclohexyl]-4-oxo-3,4-dihydrobenzo[h]quinazoline-6-carbaldehyde and 4-(4-methylpyridin-2-yl)piperidine-4-carbonitrile for 4-pyridin-2-ylpiperidine-4-carbonitrile. The resultant solid gave proton NMR spectra consistent with theory and a mass ion (ES+) of 509.0 for [M+H]+: 1H NMR (400 MHz, CD3OD) δ 9.89 (s, 1H), 9.07 (s, 1H), 8.88 (s, 1H), 8.72 (s, 1H), 8.63 (s, 1H), 8.49-8.43 (m, 1H), 7.54 (s, 2H), 7.25-7.13 (m, 1H), 5.09 (s, 2H), 4.16 (br s, 1H), 3.74-3.62 (m, 2H), 3.48-3.41 (m, 2H), 2.65-2.44 (m, 6H), 2.42 (s, 3H), 2.20 (br s, 1H), 2.03-1.93 (m, 1H), 1.88 (br s, 2H), 1.51 (br s, 3H).
Reaction SMILES: Cl.[O:2]=[C:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10].C(N(CC)CC)C.ClC1C(O[C:32](=[O:47])[CH2:33][N:34]2[CH2:38][CH:37]([C:39]3[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=3)[CH2:36][C:35]2=[O:46])=C(Cl)C(Cl)=C(Cl)C=1Cl.C(OCC)C>C(Cl)Cl>[Cl:45][C:42]1[CH:41]=[CH:40][C:39]([CH:37]2[CH2:38][N:34]([CH2:33][C:32]([N:14]3[CH2:15][CH2:16][N:11]([C:9](=[O:10])[CH2:8][N:4]4[CH2:5][CH2:6][CH2:7][C:3]4=[O:2])[CH2:12][CH2:13]3)=[O:47])[C:35](=[O:46])[CH2:36]2)=[CH:44][CH:43]=1
Reactant: O=C(CN1CC(c2ccc(Cl)cc2)CC1=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: O=C(CN1CCCC1=O)N1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(CN1CCCC1=O)N1CCN(C(=O)CN2CC(c3ccc(Cl)cc3)CC2=O)CC1
Reaction time: 16 h

Procedure:
To a suspension of 6.0 g (23.3 mmol) of 1-[2-(2-oxopyrrolidin-1-yl)-acetyl]-piperazine hydrochloride in 80 ml of methylene chloride there are added firstly 2.6 g (3.6 ml; 25.5 mmol) of triethylamine and then, dropwise, a solution of 13.7 g (23.3 mmol) of 2-[4-(p-chlorophenyl)-2-oxopyrrolidin-1-yl]-acetic acid pentachlorophenyl ester in 30 ml of methylene chloride. After being stirred at 20° for 16 hours, the suspension is filtered with suction. 6.16 g of a white crystalline mass are obtained. 110 ml of ethyl ether are stirred into the filtrate, whereby a further 6.51 g of precipitate can be formed and collected. The two portions are combined, triturated under 200 ml of ethyl ether and filtered with suction, and the resulting product is dissolved in 150 ml of hot glacial acetic acid, and warm water (50°) is added until the solution becomes cloudy. The whole is cooled to 20 °; after 3 hours, the resulting crystalline product is filtered off with suction and dried on a water bath. 1-[4-(p-chlorophenyl)-2-oxopyrrolidin-1-ylacetyl]-4-(2-oxopyrrolidin1-ylacetyl)-piperazine having a melting point of 224°-226° is obtained.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[N-:9]=[N+:10]=[N-:11].[Na+].[CH3:13]OC(OC)OC>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:13]=[N:11][N:10]=[N:9]2)=[CH:6][N:7]=1
Reactant: COC(OC)OC
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1ccc(F)nc1
Agent: [Na+]
Solvent: CC(=O)O
Product: Fc1ccc(-n2cnnn2)cn1
Temperature: 25 °C

Procedure:
6-fluoropyridin-3-amine (1.12 g, 10 mmol), sodium azide (0.98 g, 15 mmol) and trimethylorthoformate (1.7 g, 16 mmol) were added to acetic acid (20 mL), and stirred at room temperature over night. The reaction was heated to 120° C. reflux for 7 hours. The reaction was cooled down to room temperature, poured into ice water (50 mL), extracted with ethyl acetate (50 mL), second wash with sodium hydroxide (1N, 20 mL). The organic phase was dried by magnesium sulfate, filtered, concentrated and purified by column chromatography through a 80 gram Analogix™ silica gel cartridge eluting with 50% ethyl acetate/hexanes to give the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:3]=1[NH2:4].[NH:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18].C(N)CN.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.C1(C)C=CC=CC=1>[NH2:4][C:3]1[CH:5]=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:7]=[CH:8][C:2]=1[N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18]
Reactant: Nc1cc(C(F)(F)F)ccc1Br
Reactant: O=C1CCCN1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: NCCN
Solvent: Cc1ccccc1
Product: Nc1cc(C(F)(F)F)ccc1N1CCCC1=O
Temperature: 80 °C

Procedure:
A resealable tube was charged with 2-bromo-5-(trifluoromethyl)aniline (1.00 g, 4.16 mmol), 2-pyrrolidinone (0.425 g, 5.00 mmol), N,N′-ethylene diamine (0.037 g, 0.42 mmol), potassium carbonate (1.15 g, 8.32 mmol), copper iodide (0.80 mg, 0.42 mmol) and toluene (1.0 mL). The tube was sealed and the mixture was heated at 80° C. for 24 h. The resulting mixture was partitioned between ethyl acetate and water. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified via column chromatography on silica gel (gradient elution with 0-100% ethyl acetate-hexane) to afford 1-(2-amino-4-(trifluoromethyl)phenyl)pyrrolidin-2-one as a gray solid. MS m/z=245 [M+H]+. Calc'd for C11H11F3N2O: 244.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[C:12](=[N:14][OH:15])[CH3:13])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[NH2:17][NH:18][C:19]([NH2:21])=[S:20].C(O)(=O)C>CO.O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[N:17][NH:18][C:19]([NH2:21])=[S:20])[C:12](=[N:14][OH:15])[CH3:13])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: NNC(N)=S
Reactant: CC(=O)Nc1ccc(C(=O)C(C)=NO)cc1
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CC(=O)Nc1ccc(C(=NNC(N)=S)C(C)=NO)cc1
Yield: 68.2 %

Procedure:
4'-Acetamido-2-hydroxyiminopropiophenone (1.87 g) was added to a suspension of thiosemicarbazide (1 g) and acetic acid (0.1 ml) in a mixture of methanol (15 ml) and water (3 ml) and then heated at 100° for 39 hours with stirring. After cooling, the resultant precipitates were collected by filtration, washed with methanol, and then dried to give 1.7 g of 4'-acetamido-2-hydroxyiminopropiophenone thiosemicarbazone.
Reaction SMILES: [CH3:1][CH:2]([OH:9])[CH2:3][NH:4][CH2:5][CH:6]([OH:8])[CH3:7].[C:10](O)(=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>O>[CH3:1][CH:2]1[O:9][C:21]2([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH3:10])[O:8][CH:6]([CH3:7])[CH2:5][N:4]2[CH2:3]1
Reactant: CC(O)CNCC(C)O
Reactant: CCCCCCCCCCCC(=O)O
Solvent: O
Product: CCCCCCCCCCCC12OC(C)CN1CC(C)O2
Temperature: 180 °C
Reaction time: 1.33 h

Procedure:
To a 1 liter stirred reactor, equipped with a distillation column, condenser, and graduated receiver, the following constituents were added: 164.9 g of diisopropanol amine (DIPA, ChemCentral, Milwaukee, New Berlin, Wis.) and 201.5 g (98%) of lauric acid (Aldrich Chemical Co., Milwaukee, Wis.). The contents were heated to 180° C. under a nitrogen blanket. After 80 minutes, 17 ml of water had come overhead (1 equivalent). The batch temperature was held at 180° C. while the pressure was dropped to 320 Pa. The batch temperature was then raised to 195° C. During the pressure reduction and heat-up, unreacted DIPA (60 g) came overhead. A total of 199.4 g of amide acetal derived from lauric acid was then collected while the temperature was raised from 195 to 222° C. at a pressure of 320-466 Pa. This represents a 66.7% conversion of the lauric acid. Gas chromatography (GC) was used for the determination of diisopropanol amine (DIPA) and amide acetal content in the liquid samples. Liquid samples from the reactor and from the overhead receiver were analyzed for the presence of DIPA and amide acetal product using an internal standard GC method. The GC was calibrated using pure DIPA and amide acetal. Samples were removed, weighed, diluted with known amount of internal standard in methylene chloride, and then injected into the GC.