Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([CH:10]1[NH:14][C:13]2([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[NH:12][C:11]1=[O:27])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:28](Cl)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[NH4+].[Cl-]>C1COCC1>[CH2:28]([N:12]1[C:13]2([CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:18][CH2:19]2)[NH:14][CH:10]([CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:11]1=[O:27])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: ClCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)NC(=O)C(Cc1ccccc1)N2
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)NC(Cc1ccccc1)C(=O)N2Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
NaH (1.26 g, 52.5 mmol) was added to a solution of tert-butyl 3-benzyl-2-oxo-1,4,8-triazaspiro[4,5]decane-8-carboxylate (12.1 g, 35 mmol) in THF (250 ml) at RT. After stirring for 1 h at 0° C., benzyl chloride (4.9 g, 38.5 mmol) was added dropwise, and the mixture was allowed to warm to RT and heated under reflux for 60 h. Subsequently, benzyl chloride (2.4 g, 19 mmol) was again added, and the mixture was heated under reflux for a further 16 h. The reaction mixture was treated with saturated aqueous NH4Cl solution (20 ml) and extracted with EA (3×50 ml). The combined organic phase was dried over Na2SO4 and filtered and the solvent was removed by distillation. Workup was carried out by means of column chromatography to give tert-butyl 1,3-dibenzyl-2-oxo-1,4,8-triazaspiro[4,5]decane-8-carboxylate in a yield of 13.5 g (88% of theory).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](O)=[O:4].[NH2:8][CH2:9][C:10]1[N:15]=[C:14]([C:16]2[S:17][C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[C:20](=[O:22])[N:21]=2)[CH:13]=[CH:12][CH:11]=1.CS(Cl)(=O)=O>N1C=CC=CC=1>[F:1][C:2]([F:7])([F:6])[C:3]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([C:16]2[S:17][C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[C:20](=[O:22])[N:21]=2)[N:15]=1)=[O:4]
Reactant: O=C(O)C(F)(F)F
Reactant: NCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: O=C(NCc1cccc(-c2nc(=O)c3ccccc3s2)n1)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.6 %

Procedure:
2-[6-(Aminomethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one trifluoroacetic acid salt (350 mg, 0.91 mmol) was dissolved in pyridine (10 ml), and methanesulfonyl chloride (576 mg, 5.04 mmol) was added thereto. The reaction mixture was stirred at room temperature for 3 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with hexane-ethyl acetate (1:1, v/v) were collected, concentrated and recrystallized from hexane-tetrahydrofuran to give the titled compound (228 mg, 68%) as pale yellow crystals.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:11][NH:10][CH2:9][C:7]=2[N:8]=1.Br[C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)=[O:20])[CH:14]=1>>[F:31][C:28]([F:29])([F:30])[C:25]1[CH:24]=[CH:23][C:22]([NH:21][C:19]([C:15]2[CH:14]=[C:13]([N:10]3[CH2:11][C:6]4[CH:5]=[N:4][C:3]([S:2][CH3:1])=[N:8][C:7]=4[CH2:9]3)[CH:18]=[CH:17][N:16]=2)=[O:20])=[CH:27][CH:26]=1
Reactant: CSc1ncc2c(n1)CNC2
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)c1cc(Br)ccn1
Product: CSc1ncc2c(n1)CN(c1ccnc(C(=O)Nc3ccc(C(F)(F)F)cc3)c1)C2

Procedure:
In a manner similar to that describe in Example 126, 2-(methylthio)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine and 4-Bromo-N-(4-(trifluoromethyl)phenyl)picolinamide were converted to the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]Br)=[CH:4][CH:3]=1.NC(N)=[S:16].N.Cl>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][SH:16])=[CH:4][CH:3]=1
Reactant: NC(N)=S
Reactant: Clc1ccc(CCCCCBr)cc1
Agent: Cl
Agent: N
Solvent: CCO
Product: SCCCCCc1ccc(Cl)cc1
Yield: 63649.6 %

Procedure:
24.2 g (92.6 mmol) 5-(4-chlorophenyl)-pentyl bromide 60 in 60 ml ethanol was added to a solution of 10.6 g (0.139 mmol) thiourea in 40 ml ethanol. It was heated for 5 h to reflux, allowed to cool, admixed with 50 ml concentrated ammonia solution and again heated for 3 h to reflux. After cooling it was acidified to pH 1 with ca. 30 ml concentrated HCl and extracted twice with 150 ml ether. It was washed with saturated NaCl solution, dried over sodium sulfate and the solvent was removed on a rotary evaporator, 19.0 g (95%) 79 was obtained. A mixture of 5.00 g (16.3 mmol) 79, 2.25 g (16.3 mmol) potassium carbonate, 3.50 g (16.3 mmol) 6 and 50 ml dimethylformamide was stirred for 12 h at room temperature. It was admixed with water and extracted with ether. The ether phase was washed with water, dried over sodium sulfate and concentrated by evaporation. 7.1 g yellow oil which yielded 5.06 g (71%) of the ethyl ester of 27 after flash chromatography (toluene/heptane 1:2).
Reaction SMILES: Br[C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][CH:9]=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.[CH3:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C)C=O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([C:9]2[C:8]3[C:17]4=[C:16]5[C:5](=[CH:6][CH:7]=3)[CH:4]=[CH:3][CH:2]=[C:15]5[CH:14]=[CH:13][C:12]4=[CH:11][CH:10]=2)=[CH:21][CH:20]=1
Reactant: Brc1ccc2ccc3cccc4ccc1c2c34
Reactant: Cc1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2ccc3ccc4cccc5ccc2c3c45)cc1
Temperature: 120 °C
Reaction time: 5 h
Yield: 85.7 %

Procedure:
A mixed solution of 45.0 g of 1-bromopyrene, 21.7 g of 4-methylphenylboronic acid, 34.0 g of tripotassium phosphate, 10.3 g of tetrabutylammonium bromide, 0.71 g of palladium acetate and 1.6 L of dimethylformamide was heated and stirred under a nitrogen gas stream at 120° C. for 5 hours. The solution was cooled to room temperature and 1.6 L of water was poured into the solution, followed by stirring at room temperature for 0.5 hours. The precipitated solid was collected by filtration and then washed twice with 200 ml of water. The resulting solid was dissolved in 500 ml of dichloromethane, dried over magnesium sulfate and then filtered through Celite. The filtrate was evaporated and the residue was washed twice with 200 ml of methanol, and then the precipitated solid was collected by filtration and vacuum-dried to obtain 40.0 g of 1-(4-methylphenyl)pyrene.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[C:13]1[S:17][C:16]([N:18]([CH3:29])[CH:19]2[CH2:24][C:23]([CH3:26])([CH3:25])[NH:22][C:21]([CH3:28])([CH3:27])[CH2:20]2)=[N:15][N:14]=1.Cl.N1C=CC=CC=1.C(=O)(O)[O-].[Na+].N>CO.C(Cl)Cl>[CH3:29][N:18]([CH:19]1[CH2:24][C:23]([CH3:26])([CH3:25])[NH:22][C:21]([CH3:28])([CH3:27])[CH2:20]1)[C:16]1[S:17][C:13]([C:4]2[CH:5]=[C:6]3[C:11](=[CH:12][C:3]=2[OH:2])[N:10]=[CH:9][CH:8]=[CH:7]3)=[N:14][N:15]=1
Reactant: COc1cc2ncccc2cc1-c1nnc(N(C)C2CC(C)(C)NC(C)(C)C2)s1
Agent: Cl
Agent: N
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CO
Product: CN(c1nnc(-c2cc3cccnc3cc2O)s1)C1CC(C)(C)NC(C)(C)C1
Temperature: 160 °C
Yield: 82.7 %

Procedure:
A mixture of 5-(7-methoxyquinolin-6-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine (30 mg, 0.073 mmol) and pyridine hydrochloride (126 mg, 1.093 mmol) was heated in a microwave at 160° C. for 30 minutes. The resulting solid was dissolved into methanol and concentrated onto a mixture of silica gel (500 mg) and sodium bicarbonate (14.6 mmol, 122 mg) and subjected to flash column chromatography (4 g silica gel, 1-17% 1.4 N ammonia in MeOH gradient in DCM over 30 column volumes) to provide 6-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)quinolin-7-ol as a yellow solid (24 mg, 83%). MS=398.3 (M+1). 1H NMR (400 MHz, METHANOL-d4) ppm 8.67 (d, J=3.0 Hz, 1H), 8.49 (s, 1H), 8.29 (d, J=7.6 Hz, 1H), 7.36 (s, 1H), 7.28 (dd, J=8.3, 4.3 Hz, 1H), 4.55 (t, J=12.1 Hz, 1H), 3.13 (s, 3H), 1.90 (dd, J=12.6, 3.0 Hz, 2H), 1.62-1.78 (m, 2H), 1.46 (s, 6H), 1.33 (s, 6H).
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:24][CH2:23][C@@H:22]5[CH2:25][N:26](C(OCC)=O)[CH2:27][C@H:21]45)=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[N:6]=[CH:5][CH:4]=[CH:3]1.C(O)(=O)C>Br.CO>[N:20]1([C:17]2[CH:18]=[CH:19][C:14]([C:11]3[CH:12]=[CH:13][C:8]([N:7]4[C:2](=[O:1])[CH:3]=[CH:4][CH:5]=[N:6]4)=[CH:9][CH:10]=3)=[CH:15][CH:16]=2)[CH2:24][CH2:23][C@@H:22]2[CH2:25][NH:26][CH2:27][C@H:21]12
Reactant: CCOC(=O)N1C[C@H]2CCN(c3ccc(-c4ccc(-n5ncccc5=O)cc4)cc3)[C@H]2C1
Agent: Br
Solvent: CC(=O)O
Solvent: CO
Product: O=c1cccnn1-c1ccc(-c2ccc(N3CC[C@@H]4CNC[C@@H]43)cc2)cc1
Temperature: 67.5 °C
Yield: 116.1 %

Procedure:
A mixture of the product of Example 1E (7.50 g, 17.42 mmol) in 33% HBr in acetic acid (37 mL, 205.57 mmol, 11.8 equivalents) was heated to 65-70° C. for at least 6 hours while monitored by HPLC analysis for completion. When reaction is complete, the mixture is cooled to not more than 45° C. and is diluted with MeOH (111 mL). The mixture was cooled to 20-25° C., the product is collected by filtration and is washed with fresh MeOH (50 mL). The wet cake is dried in the vacuum oven at not more than 55° C. to provide the title compound (7.25 g, 94.8%).
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.Cl.C(N(CC)CC)C.Cl[CH2:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][C:31]=1[CH2:32]Cl)[NH2:28].[N:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41]2[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:44](=O)[NH:43][N:42]=2)=[CH:36][CH:35]=1.CN(C)C(=O)N(C)C.N>O.ClCCl>[CH3:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][C:31]=1[CH3:32])[NH:28][C:44]1[C:45]2[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:41]([CH2:40][C:37]2[CH:38]=[CH:39][N:34]=[CH:35][CH:36]=2)=[N:42][N:43]=1
Reactant: Nc1ccc(CCl)c(CCl)c1
Reactant: O=c1[nH]nc(Cc2ccncc2)c2ccccc12
Agent: Cl
Agent: N
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCN(CC)CC
Solvent: CN(C)C(=O)N(C)C
Solvent: ClCCl
Product: Cc1ccc(Nc2nnc(Cc3ccncc3)c3ccccc23)cc1C
Temperature: 200 °C

Procedure:
A mixture of 1.80 g (12.68 mmol) phosphorus pentoxide, 1.73 g (12.6 mmol) triethylamine hydrochloride, and 1.529 g (12.6 mmol) 3,4-dichloromethylaniline is heated and stirred in a nitrogen atmosphere at 200° C. until a homogeneous melt has formed. To the melt, 1 g (4.2 mmol) of 4-(4-pyridylmethyl)-1(2H)-phthalazinone (for preparation see German Auslegeschrift no. 1 061 788 [published 23.07.1959]) is added and the mixture stirred for 4 h at 200° C. After slight cooling, 4 ml tetramethylurea is added to the reaction mixture, followed by 2 ml water at about 120° C. The solution obtained is then distributed between dichloromethane and a mixture of 20 ml water and 5 ml conc. ammonia, and the organic phase dried over anhydrous sodium sulfate, filtered and evaporated under vacuum. Double recrystallization of the residue from acetonitrile and drying under HV (8 h, 120° C.) yields title compound; m.p. 180-181° C.; ESI-MS: (M+H)+=341.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[CH2:10][CH:9]([CH3:11])[O:8][CH:7]([CH2:12][N:13]2C(=O)C3=CC=CC=[C:15]3[C:14]2=[O:23])[CH2:6]1.O.NN>C(O)C>[C:14]([NH:13][CH2:12][CH:7]1[O:8][CH:9]([CH3:11])[CH2:10][N:5]([CH2:4][C:3]2[CH:24]=[CH:25][CH:26]=[CH:27][C:2]=2[Cl:1])[CH2:6]1)(=[O:23])[CH3:15]
Reactant: CC1CN(Cc2ccccc2Cl)CC(CN2C(=O)c3ccccc3C2=O)O1
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(=O)NCC1CN(Cc2ccccc2Cl)CC(C)O1
Reaction time: 0.25 h
Yield: 74.8 %

Procedure:
A mixture of N-[[4-(2-chlorobenzyl)-6-methyl-2-morpholinyl]methyl]phthalimide (26 g), 100% hydrazine hydrate (4.2 g), and ethanol (20 ml) is refluxed with stirring for 15 minutes. After the insoluble materials are filtered off, the filtrate is diluted with water and extracted with chloroform. The organic layer is washed successively with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and filtered. Acetic anhydride (14.7 g) is added to the filtrate, and the mixture is stirred at 25° C. for 2 hours. The reaction mixture is washed successively with aqueous sodium hydroxide solution, water and saturated aqueous sodium chloride solution, and dried over magnesium sulfate. After removal of the solvent under reduced pressure, the residue is chromatographed on silica gel with ethyl acetate to give the title compound (15 g) as an oil.
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[NH:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[F:22][C:23]([F:35])([F:34])[C:24]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>CN(C)C=O.O>[N:1]1[C:6]2[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[N:10]([C:26]([C:25]3[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:24]=3[C:23]([F:35])([F:22])[F:34])=[O:27])[CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccc(F)cc1C(F)(F)F
Reactant: c1cnc2c(c1)CNc1ccccc1N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccc(F)cc1C(F)(F)F)N1Cc2cccnc2Nc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.1 %

Procedure:
To a solution of 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine of Example 1, Step B (10.6 g, 53.8 mmol) in dimethylformamide (125 mL) under nitrogen was added potassium carbonate (22.4 g, 162 mmol). The mixture was cooled and treated dropwise with a solution of crude 2-trifluoromethyl-4-fluorobenzoyl chloride of Step A (81 mmol) in dimethylformamide (25 mL). After stirring at room temperature for 2 hours, the mixture was diluted with water and extracted with dichloromethane. The organic extracts were dried over magnesium sulfate and evaporated to dryness. The crude material was dissolved in dichloromethane and purified by flash chromatography (on silica Merck-60, hexane-ethyl acetate 80:20) to provide the pure title compound (6.9 g) which was crystallized by sonication from ethanol-hexane, m.p. 183-185° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:19])C(=O)C1>CN(C=O)C.O>[Br:19][C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=[CH:7][C:8]=1[NH2:11]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(N)c(Br)c1

Procedure:
To a solution of 4-tert-butyl-phenylamine (447 g, 3 mol) in DMF (500 mL) was added dropwise NBS (531 g, 3 mol) in DMF (500 mL) at room temperature. Upon completion, the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, brine, dried over Na2SO4 and concentrated. The crude product was directly used in the next step without further purification.
Reaction SMILES: O.O.Cl[Sn]Cl.[NH2:6][C:7]1[N:8]=[CH:9][C:10]([C:27]2[CH:37]=[CH:36][C:30]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])=[CH:29][CH:28]=2)=[N:11][C:12]=1[C:13]1[O:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-])=O)=[N:16][N:17]=1.C(=O)([O-])O.[Na+]>CCOC(C)=O.ClCCl>[NH2:6][C:7]1[N:8]=[CH:9][C:10]([C:27]2[CH:37]=[CH:36][C:30]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])=[CH:29][CH:28]=2)=[N:11][C:12]=1[C:13]1[O:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH2:24])=[N:16][N:17]=1
Reactant: CN(C)C(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4ccccc4[N+](=O)[O-])o3)n2)cc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4ccccc4N)o3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.9 %

Procedure:
SnCl2.2H2O (151.6 mg, 0.6720 mmol) was added to a solution of 4-[5-amino-6-[5-(2-nitrophenyl)-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]-N,N-dimethyl-benzamide (58 mg, 0.1344 mmol) in EtOAc (3 mL) and dichloromethane (1 mL) at room temperature and the resulting solution stirred overnight at room temperature. The reaction mixture was poured carefully onto saturated aqueous sodium hydrogen carbonate solution (5 mL) and the layers separated. The aqueous layer extracted further with dichloromethane (2×15 mL) and the combined organics dried over MgSO4 and concentrated in vacuo to leave a yellow solid. This was purified using by reverse phase preparative HPLC [Waters Sunfire C18, 10 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The product fractions were freeze dried to give the product as a yellow solid (17.2 mg, 34% yield); 1H NMR (400.0 MHz, DMSO) d 2.98 (m, 6H), 6.78 (t, 1H), 6.88 (br s, 1H), 7.34 (m, 1H), 7.55 (m, 2H), 7.79 (br s, 2H), 7.85 (m, 1H), 8.18 (m, 2H) and 8.99 (s, 1H) ppm; MS (ES+) 402.26
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][C:24]=1[N+:25]([O-])=O)[NH:7][C:8](=[O:21])[C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)([O-])=O.[CH3:28][O:29][C:30]1[CH:37]=[C:36]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)[CH:35]=[CH:34][C:31]=1[CH:32]=O>>[CH3:28][O:29][C:30]1[CH:37]=[C:36]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)[CH:35]=[CH:34][C:31]=1[C:32]1[NH:25][C:24]2[CH:23]=[CH:22][C:6]([NH:7][C:8](=[O:21])[C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)=[CH:11][CH:10]=3)=[CH:5][C:4]=2[N:1]=1
Reactant: COc1cc(N2CCOCC2)ccc1C=O
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccc(N2CCOCC2)cc1
Product: COc1cc(N2CCOCC2)ccc1-c1nc2cc(NC(=O)c3ccc(N4CCOCC4)cc3)ccc2[nH]1

Procedure:
Compound 424 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(4-morpholinobenzoyl)aniline and 2-methoxy-4-morpholinobenzaldehyde. [M+H]+ calcd for C29H31N5O4: 514.25; found: 514.05.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C@@H:4]([C:5]#[C:6][C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11].[CH2:30](O)[C:31]([CH3:34])([CH3:33])[CH3:32]>>[CH3:1][C:2]1([CH3:29])[C@@H:4]([C:5]#[C:6][C:7]([O:9][CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11]
Reactant: CC(C)(C)CO
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1C#CC(=O)O
Product: CC(C)(C)COC(=O)C#C[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.8 %

Procedure:
Using the procedure of Step A of Example 15, 3.89 g of (S)α-cyano-3-phenoxy-benzyl(1R,cis)2,2-dimethyl-3-(2-carboxyethynyl)-cyclopropane-carboxylate and 1 g of neopentyl alcohol were reacted and the mixture was stirred at room temperature for 4 hours and was filtered. The filtrate was washed with N hydrochloric acid, with water, dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with an 8-2 cyclohexane-ethyl acetate mixture to obtain 3.8 g of (S)α-cyano-3-phenoxy-benzyl(1R,cis)2,2-dimethyl-3-[2-neopentyloxycarbonyl-ethynyl]-cyclopropane-carboxylate melting at 67° C.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([CH2:7][C:8]2[C:9]3[N:13]([CH:14]=[C:15]([C:17]4[CH:18]=[CH:19][C:20](O)=[CH:21][CH:22]=4)[N:16]=2)[C:12]([OH:24])=[C:11]([CH2:25][C:26]2[CH:27]=[CH:28][C:29](O)=[CH:30][CH:31]=2)[N:10]=3)=[CH:5][CH:6]=1.[CH2:33]1N(CCO)CCN(CCS(O)(=O)=O)C1.[Cl-].[K+].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.CCC(COC(C(N(CC[NH+](C)C)C)=O)(C1C=CC=CC=1)C1C=CC=CC=1)CC.[Cl-]>OCC(CO)O>[CH2:25]([C:11]1[N:10]=[C:9]2[C:8]([CH2:7][C:4]3[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=3)=[N:16][C:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:14][N:13]2[C:12]=1[O:24][CH3:33])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=S(=O)(O)CCN1CCN(CCO)CC1
Reactant: Oc1ccc(Cc2nc3c(Cc4ccccc4)nc(-c4ccc(O)cc4)cn3c2O)cc1
Agent: CCC(CC)COC(C(=O)N(C)CC[NH+](C)C)(c1ccccc1)c1ccccc1
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: [Cl-]
Solvent: OCC(O)CO
Product: COc1c(Cc2ccccc2)nc2c(Cc3ccccc3)nc(-c3ccccc3)cn12

Procedure:
Chemiluminescence of P450 altered coelenterazine or coelenterazine derivatives was determined immediately following addition of 80 microliter of 37.5 mM Hepes pH7.4; 625 mM KCl; 0.125 mM EDTA pH 8.0; 0.25% Triton X-100; 0.125% Mazu; 1.25% Glycerol; 0.25 mg/mL gelatin to the P450 reactions. Renilla luciferase (1.2 ng/mL) (purchased from Chemicon) was added for detection of bioluminescence of P450 altered coelenterazine or coelenterazine derivatives.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][NH2:12].C(N(C(C)C)C(C)C)C.[C:22](Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>O1CCCC1>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][NH:12][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: NNc1ccc([N+](=O)[O-])cc1Br
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)NNc1ccc([N+](=O)[O-])cc1Br
Yield: 60.7 %

Procedure:
To a stirred and chilled (0°) solution containing 200 g (0.86 mol) of 2-bromo-4-nitrophenylhydrazine (m.p. 143°-145°) and 116.8 g (0.9 mol) of ethyldiisopropylamine in 1000 ml of tetrahydrofuran was added dropwise 108.5 g (0.9 mol) of pivaloyl chloride. The reaction mixture was stirred at ambient temperature for 1 hour and then concentrated to dryness under reduced pressure. The residue was treated with water, filtered and recrystallized from ethanol to give 165 g (52%) of product as a light yellow solid; m.p. 145° C.
Reaction SMILES: [C:1](/[C:3](=[N:10]\[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[I:19])/[C:4]([NH:6][CH2:7][CH2:8][CH3:9])=[O:5])#[N:2].[Cl-].[Al+3].[Cl-].[Cl-].C(OCC)(=O)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1>[NH2:2][C:1]1[C:17]2[C:12](=[C:13]([I:19])[C:14]([F:18])=[CH:15][CH:16]=2)[N:11]=[N:10][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH3:9])=[O:5]
Reactant: CCCNC(=O)/C(C#N)=N/Nc1cccc(F)c1I
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCNC(=O)c1nnc2c(I)c(F)ccc2c1N
Temperature: 60 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
To a 1 L, 3-necked flask equipped with a mechanical stirrer charged with (2E)-2-cyano-2-[(3-fluoro-2-iodophenyl)hydrazono]-N-propylacetamide (43.9 g, 117 mmol) in anhydrous toluene (Aldrich, 600 mL) under N2 was added portion-wise aluminum chloride (Aldrich, 46.8 g, 352 mmol) over 20 minutes. The mixture was heated to 60° C. with vigorous stirring for 2 hours and then cooled to ˜15° C. Ethyl acetate (30 mL) was carefully added while maintaining the internal temperature between 20-25° C. Additional ethyl acetate (900 mL) was then added, followed by careful addition of Rochelle's salt (saturated aqueous potassium sodium tartrate, 500 mL). Upon addition of the first 50 mL, the temperature rose from 20 to 36° C. The reaction was heated with stirring at 60° C. for 30 minutes. The aqueous layer contained a thick white precipitate and the organic layer slowly solubilized the brownish yellow solid. Note: If a non-white (brown/yellow) solid still existed at the aqueous/organic interface, the hot extraction was repeated. The mixture was placed in a separatory funnel and the aqueous layer was removed. The organic layer was washed with Rochelle's salt (500 mL) and brine, dried over magnesium sulfate, filtered and concentrated to give 38 g of product (86.5%). Further purification by trituration with ethyl acetate/hexanes was carried out when appropriate. An analytically pure sample was obtained by recrystallization from ethyl acetate. 1H NMR (300 MHz, CDCl3) δ 8.54 (br, 1H), 7.84 (dd, J=5.3, 9.2 Hz, 1H), 7.39 (dd, J=7.0, 9.2 Hz, 1H), 3.47 (apparent q, J=7.0 Hz, 2H), 1.68 (apparent sextet, J=7.0 Hz, 2H), 1.03 (t, J=7.4 Hz, 3H). MS APCI, m/z=375 (M+H). HPLC 2.13 min.