Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH2:12])[CH:5]=[CH:4][CH:3]=1.[CH3:13][N:14]([CH3:23])[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1>C(O)C>[CH3:13][N:14]([CH3:23])[C:15]1[CH:22]=[CH:21][C:18]([CH:19]2[NH:12][C:10]3[C:11]4[C:6]([CH:7]=[CH:8][CH:9]=3)=[CH:5][CH:4]=[CH:3][C:2]=4[NH:1]2)=[CH:17][CH:16]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: Nc1cccc2cccc(N)c12
Solvent: CCO
Product: CN(C)c1ccc(C2Nc3cccc4cccc(c34)N2)cc1
Yield: 65.7 %

Procedure:
A solution of 3.2 g (0.02 mole) of 1,8-diaminonaphthalene and 3.0 g (0.02 mole) of p-dimethylaminobenzaldehyde in 35 ml of ethanol was refluxed for 2 hours. After cooling, the resulting precipitate was filtered and recrystallized from ethanol. There were obtained 3.8 g of 2-(p-dimethylaminophenyl)-2,3-dihydroperimidine as colorless crystals, m.p. 165°-166° C. (Compound No. 18).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=1)([O-])=O.[OH-].[Na+]>CCOC(C)=O>[C:9]1([N:6]2[CH:7]=[CH:8][C:4]([NH2:1])=[CH:5]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])c1ccn(-c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Nc1ccn(-c2ccccc2)c1
Reaction time: 3 h
Yield: 93.7 %

Procedure:
A mixture of 3-nitro-1-phenyl-1H-pyrrole (410 mg, 2.18 mmol) and SnCL2 dihydrate (2.00 g, 8.86 mmol) in EtOAc (15 mL) was stirred at 80 C for 3 h. Aqueous 1N NaOH was added to bring pH to 12. The mixture was filtered through celite. The organic phase was separated, washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give 1-phenyl-1H-pyrrol-3-amine as a solid (323 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C(O[CH:16](N(C)C)[N:17]([CH3:19])[CH3:18])(C)(C)C>>[CH3:16][N:17]([CH:19]=[CH:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:10])[CH3:18]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CC(=O)c1ccc(Cl)cc1
Product: CN(C)C=CC(=O)c1ccc(Cl)cc1

Procedure:
1-(4-Chloro-phenyl)-ethanone (49 mg, 0.3 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 28a) to give crude title compound (87 mg) as a yellow solid which was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2.[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC=CC=1.C(OCC)(=O)C>[Br:12][CH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2
Reactant: Cc1ccc2nccnc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: BrCc1ccc2nccnc2c1

Procedure:
A mixture of 6-methylquinoxaline (1.5 g, 10.4 mmol), N-bromosuccinimide (2.2 g, 12.5 mmol) and benzoylperoxide (0.30 g, 1.25 mmol) in benzene (35 mL) was stirred rapidly and heated to reflux for 5 h. Upon cooling, the mixture was diluted with ethyl acetate (25 mL), washed with IN sodium hydroxide solution (50 mL) and saturated sodium chloride solution (50 mL). The organic layer was dried (MgSO4) and evaporated to a crystalline solid (2.5 g, 77% desired product, 23% α,α-dibrominated product as determined by 1H NMR). The mixture was used in subsequent reactions.
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH2:19][CH:20]1[CH2:22][O:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C1(C)C=CC(S(O)(=O)=[O:30])=CC=1>C(O)(=O)C>[CH2:1]([O:17][CH2:18][CH2:19][CH:20]([OH:30])[CH2:22][OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCOCCC1CO1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCCOCCC(O)CO
Reaction time: 0.5 h

Procedure:
A solution of 40 g of [2-(hexadecyloxy)ethyl] oxirane in 270 ml of glacial acetic acid containing 0.265 g of p-toluenesulfonic acid was stirred at reflux for 4.5 hours. The acetic acid was removed, the residue dissolved in toluene the toluene removed and this residue dissolved in 300 ml of methanol. A solution of 17.9 g of sodium hydroxide in 18.5 ml of water was added, the mixture was stirred 1/2 hour and the solvent removed. The solid was dissolved in a mixture of ether and water. The ether layer was washed twice with saline, dried and filtered. The filtrate was warmed to dissolve the solid which formed, then concentrated to about 400 ml and allowed to stand at room temperature. Petroleum ether was added and the resulting solid collected, giving 32 g of the desired compound, mp 60°-61° C.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]3[C:24]([Cl:25])=[C:23]([Cl:26])[N:22]=[C:21]([NH:27][CH3:28])[N:20]=3)[CH2:15][CH2:14]2)[CH2:7][CH2:6]1.C(N(CC)CC)C.[O-:36][C:37]#[N:38].[K+]>CO>[Cl:25][C:24]1[C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH2:12][CH2:11][C@H:8]3[CH2:9][CH2:10][C@H:5]([NH:4][C:37]([NH2:38])=[O:36])[CH2:6][CH2:7]3)[CH2:18][CH2:17]2)=[N:20][C:21]([NH:27][CH3:28])=[N:22][C:23]=1[Cl:26]
Reactant: N#C[O-]
Reactant: CNc1nc(Cl)c(Cl)c(N2CCN(CC[C@H]3CC[C@H](N)CC3)CC2)n1
Agent: Cl
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CO
Product: CNc1nc(Cl)c(Cl)c(N2CCN(CC[C@H]3CC[C@H](NC(N)=O)CC3)CC2)n1

Procedure:
0.6 g (1.3 mmol) trans-(4-{4-[2-(4-amino-cyclohexyl)-ethyl]-piperazin-1-yl}-5,6-dichloro-pyrimidin-2-yl)-methyl-amine trihydrochlorid was suspended in methanol. Triethylamine (0.36 ml, 2.6 mmol) was added followed by the addition potassium cyanate (0.26 g, 3.12 mmol). The mixture was refluxed for 10 hours. The solvent was removed in vacuo. The residue was triturated with water, and the precipitate was filtered to give the title compound (0.42 g 75%) MS (EI): 431.2 (MH+). 1H NMR (300 MHz, DMSO-d6 (TMS)+1 drop of cc. DCl, (ppm)): 0.91-1.12 m (2H); 1.15-1.36 m (3H); 1.56-1.92 m (6H); 2.76 s (3H); 3.00-3.21 m (4H); 3.30-3.61 m (5H); 4.15-4.31 m (2H).
Reaction SMILES: Cl[C:2]1(Cl)[C:6](Cl)=[C:5](Cl)[C:4](Cl)=[C:3]1Cl.[C:12]1(C)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:17]=[CH:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH2:13]=[CH:12][CH2:17][CH2:2][CH2:6][CH2:5][CH:4]=[CH2:3]
Reactant: Cc1ccccc1
Reactant: ClC1=C(Cl)C(Cl)(Cl)C(Cl)=C1Cl
Product: C=CCCCC
Product: C=CCCCCC=C

Procedure:
A copolymer of 1-hexene and 1,7-octadiene (molar charge ratio 90:10) was synthesized according to the general procedure in Example I. It had an inherent viscosity of 3.5 dl./g. and 25 percent gel. A solution of 43.3 grams of this copolymer and 95 grams of hexachlorocyclopentadiene in 750 ml. toluene containing finely dispersed gel was heated at 110° C. for 24 hours. After cooling, the reaction mixture was precipitated in excess methanol. The yield of the product was 51.5 grams, inherent viscosity 1.5 dl./g., gel 16 percent. An acetone-extracted sample contained 14.1 percent chlorine, indicating that about 70 percent of the double bonds in the original copolymer had reacted with hexachlorocyclopentadiene.
Reaction SMILES: C(OCC)(=O)C.[N+:7]([C:10]1[CH:20]=[CH:19][CH:18]=[CH:17][C:11]=1[O:12][CH2:13][CH2:14][C:15]#[N:16])([O-])=O.[H][H]>[Pd]>[NH2:7][C:10]1[CH:20]=[CH:19][CH:18]=[CH:17][C:11]=1[O:12][CH2:13][CH2:14][C:15]#[N:16]
Reactant: [H][H]
Reactant: N#CCCOc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: N#CCCOc1ccccc1N
Reaction time: 4 h
Yield: 98 %

Procedure:
To palladium (0.00748 g, 0.0702 mmol) in a 50 mL flask with stirbar was added ethyl acetate (11.7 g, 133 mmol) under nitrogen, and then nitrile 83 (0.675 g, 3.51 mmol) was added (FIG. 18). The flask was fitted with a balloon containing hydrogen, and the nitrogen inlet was removed. The reaction was stirred vigorously for 4 hours, and then was filtered through celite, washing with ethyl acetate. The product 84 required no further purification, 98% yield. 1H NMR (500 MHz, CDCl3) δ 6.85-6.77 (m, 1H), 6.74-6.62 (m, 3H), 4.08 (t, J=6.1 Hz, 2H), 3.94-3.74 (m, 2H), 2.72 (t, J=6.1 Hz, 2H). LRMS m/z Calcd. for C9H10N2O: 162.07931, found: 163.1 [M+1].
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1>CN(C)C=O.COC1C=CC(CN)=CC=1.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][NH:7][CH2:6][C:9]4[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Agent: COc1ccc(CN)cc1
Solvent: CCO
Solvent: CN(C)C=O
Product: COc1ccc(CNC[C@@H](O)COc2ccc(-c3noc4cc(F)ccc34)cc2)cc1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 4-methoxybenzylamine in ethanol, essentially as described above in Example 70. Purity by LC/MS=100%, [M+H]+=423.
Reaction SMILES: [C:1]([O:5][C:6](=[O:47])[CH2:7][C@H:8]([N:31](CC1C=CC=CC=1)[C@@H](C1C=CC=CC=1)C)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].CC(O)=O>CCOC(C)=O.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6](=[O:47])[CH2:7][C@H:8]([NH2:31])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCCCCCCOc1ccc(-c2ccc(CC[C@H](CC(=O)OC(C)(C)C)N(Cc3ccccc3)[C@H](C)c3ccccc3)cc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCCCCCCOc1ccc(-c2ccc(CC[C@@H](N)CC(=O)OC(C)(C)C)cc2)cc1
Reaction time: 15 h
Yield: 160.5 %

Procedure:
To a stirred solution of (R)-3-[benzyl-((R)-1-phenylethyl)amino]-5-(4′-heptyloxy-biphenyl-4-yl)pentanoic acid tert-butyl ester (2.82 g, 4.45 mmol) in EtOAc (50 ml) were added AcOH (2.5 ml) and Pd(OH)2 on carbon (Pd(OH)2 ca. 20 wt %, 1.07 g), and then the mixture was set under H2 atmosphere. After being stirred for 15 h, the mixture was filtered through a pad of Celite and washed with MeOH. The filtrate and washings were combined, and concentrated in vacuo to give (R)-3-amino-5-(4′-heptyloxybiphenyl-4-yl)pentanoic acid tert-butyl ester (crude, 3.14 g) which was used for the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O>>[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Cc1ccccc1B(O)O
Reactant: Brc1ccc2cc[nH]c2c1
Product: Cc1ccccc1-c1ccc2cc[nH]c2c1

Procedure:
Prepared by Procedure I and Scheme T using 6-bromo-1H-indole and 2-methylphenylboronic acid: ESMS m/e: 207.9 (M+H)+.
Reaction SMILES: N.Cl[C:3]1[N:8]2[C:9]([CH2:12][CH2:13][CH3:14])=[N:10][CH:11]=[C:7]2[CH:6]=[C:5]([Cl:15])[N:4]=1.NC1N2C(CCC)=NC=C2C=C(Cl)N=1.[CH4:30].[OH2:31]>C1CCCCC=1.CO>[Cl:15][C:5]1[N:4]=[C:3]([O:31][CH3:30])[N:8]2[C:9]([CH2:12][CH2:13][CH3:14])=[N:10][CH:11]=[C:7]2[CH:6]=1
Reactant: O
Reactant: CCCc1ncc2cc(Cl)nc(Cl)n12
Reactant: C
Agent: CCCc1ncc2cc(Cl)nc(N)n12
Agent: N
Solvent: CO
Solvent: C1=CCCCC1
Product: CCCc1ncc2cc(Cl)nc(OC)n12
Reaction time: 1.5 h

Procedure:
To 25 ml of methanol saturated with ammonia gas was added with stirring 1.00 g (4.35 mmole) of 5,7-dichloro-3-(n-propyl)imidazo[1,5-c]pyrimidine (from Example 36). Stirring was continued at 20° C. for 1.5 hours, at which time the mixture was poured into 50 ml of water and extracted with four 35 ml portions of chloroform. The combined extracts were washed twice with 50 ml portions of water, once with 35 ml of saturated aqueous sodium chloride solution and dried over magnesium sulfate. Concentration provided a residue which was triturated with diethyl ether to provide a yellow solid which was mostly 5-amino-7-chloro-3-(n-propyl)imidazo[1,5-c]pyrimidine. The ether solution was evaporated to provide a yellow solid. The solid was dissolved in cyclohexene, treated with decolorizing charcoal and cooled. The small amount of precipitate formed was 5-amino-7-chloro-3-(n-propyl)-imidazo[1,5-c]pyrimidine. Evaporation of the cyclohexane gave yellow solid 7-chloro-5-methoxy-3-(n-propyl)imidazo[1,5-c]pyrimidine, m.p. 76°- 77° C. Analysis: Calculated for C10H12ClN3O: %C, 53.2; %H, 5.4; %N, 18.6; Found; %C, 52.9; %H, 5.4; %N, 18.1 .
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12](=[O:26])[C:13]2[C:14]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:15][CH:16]=[CH:17][CH:18]=2)=[C:6]([F:27])[CH:5]=1.[H][H]>CO.C(OCC)(=O)C.[Pt](=O)=O>[CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12](=[O:26])[C:13]2[C:14]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:15][CH:16]=[CH:17][CH:18]=2)=[C:6]([F:27])[CH:5]=1
Reactant: [H][H]
Reactant: COC(=O)c1ccc(/C=C/C(=O)c2cccnc2Nc2ccccc2)c(F)c1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(CCC(=O)c2cccnc2Nc2ccccc2)c(F)c1
Yield: 96.3 %

Procedure:
A solution of 3-fluoro-4-[(E)-3-oxo-3-(2-phenylamino-pyridin-3-yl)-propenyl]-benzoic acid methyl ester (890 mg, 2.36 mmol) in methanol (59.1 mL) and ethyl acetate (59.1 mL) at 25° C. was treated with platinum(IV) oxide (26.8 mg, 118 μmol). The reaction was stirred under a balloon of hydrogen gas for 18 h. At this time, the reaction was filtered through a pad of Celite® and was rinsed with a solution of 10% methanol/methylene chloride (3×75 mL). The filtrate was concentrated in vacuo to afford 3-fluoro-4-[3-oxo-3-(2-phenylamino-pyridin-3-yl)-propyl]-benzoic acid methyl ester (860 mg, 96.2%) as a dark green solid. The material was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:26])[CH2:13][C:14]([OH:16])=O)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].Cl.[CH3:28][O:29][NH2:30].CN1CCCCC1.CCOCC>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:26])[CH2:13][C:14]([NH:30][O:29][CH3:28])=[O:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CON
Reactant: CCOc1cc(C(CC(=O)O)N2Cc3ccccc3C2=O)ccc1OC
Agent: Cl
Solvent: CN1CCCCC1
Solvent: ClCCl
Solvent: CCOCC
Product: CCOc1cc(C(CC(=O)NOC)N2Cc3ccccc3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.4 %

Procedure:
A mixture of 3-(3-ethoxy-4-methoxyphenyl)-3-(1-oxoisoindolinyl)propanoic acid (500 mg, 1.41 mmol) and N,N′-carbonyldiimidazole (250 mg, 1.54 mmol) in methylene chloride (30 mL) under nitrogen was stirred at room temperature for 30 minutes. To the solution was added O-methyl hydroxylamine hydrochloride (175 mg, 2.09 mmol) followed by the addition of 1-methyl piperidine (0.26 mL, 2.14 mmol). The mixture was stirred at room temperature for 2 hours and then was heated to reflux for 14 hours. The cooled reaction mixture was washed with hydrochloric acid (1N, 25 mL), saturated sodium bicarbonate (25 mL), brine (25 mL), and then dried over sodium carbonate and sodium sulfate. Removal of solvent in vacuo gave a solid which was stirred with ether (10 mL) for 30 minutes. This suspension was filtered and the solid was washed with ether (2×10 mL) to give 3-(3-ethoxy-4-methoxyphenyl)-N-methoxy-3-(1-oxoisoindolinyl)-propionamide as a white solid (360 mg, 67% yield): mp, 138.0-139.5° C.; 1H NMR (CDCl3) δ1.41 (t, J=6.9 Hz, 3H, CH3), 2.95 (dd, J=4.6, 14.5 Hz, 1H, CHH), 3.53 (dd, J=11.2, 14.5 Hz, 1H, CHH), 3.62 (s, 3H, CH3), 3.84 (s, 3H, CH3), 4.02 (q, J=6.9 Hz, 2H, CH2), 4.23 (d, J=17.1 Hz, 1H, NCHH), 4.46 (d, J=17 Hz, 1H, NCHH), 5.49 (dd, J=4.4, 10.3 Hz, 1H, NCH), 6.78-6.99 (m, 3H, Ar,), 7.27-7.51 (m, 3H, Ar), 7.78 (dd, J=7.4 Hz, 1H, Ar), 10.08 (br s, 1H, NH); 13C NMR (CDCl3) δ14.66, 37.52, 49.48, 54.94, 5.91, 64.01, 64.41, 111.37, 112.12, 119.26, 122.75, 123.54, 128.04, 131.38, 131.68, 132.58, 141.44, 148.56, 149.15, 167.81, 169.47. Anal. Calcd for C21H24N2O5: C, 65.61; H, 6.29; N, 7.29. Found: C, 65.23; H, 6.52; N, 6.88.
Reaction SMILES: [CH2:1]=[O:2].[CH3:3][C:4]1[CH:8]=[C:7]([CH3:9])[NH:6][C:5]=1[CH:10]=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12]1=[O:20].C(N(CC)CC)C>CN(C)C=O.O>[CH3:3][C:4]1[CH:8]=[C:7]([CH3:9])[NH:6][C:5]=1/[CH:10]=[C:11]1\[C:12](=[O:20])[N:13]([CH2:1][OH:2])[C:14]2[C:19]\1=[CH:18][CH:17]=[CH:16][CH:15]=2
Reactant: Cc1cc(C)c(C=C2C(=O)Nc3ccccc32)[nH]1
Reactant: C=O
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C)c(/C=C2\C(=O)N(CO)c3ccccc32)[nH]1
Reaction time: 1 h
Yield: 98.4 %

Procedure:
Aqueous formaldehyde (15.0 g of 38% solution, 190 mmol) was added to a stirred solution of 3-(3,5-dimethyl-1H-pyrrol-2-ylmethylidene)-1,3-dihydro-indol-2-one (23.8 g, 100 mmol) and triethylamine (15.0 g, 150 mmol) in dimethylformamide (200 mL). After 1 h, the solution was diluted with water and the precipitate was filtered off, washed with water, and dried to give 26.4 g of the title compound, mp 196–200° C. HPLC Rt 5.71 min. 1H NMR (CDCl3) δ 2.34 (s, 6H), 3.14 (t, 1H), 5.44 (d, 2H), 5.98 (d, 1H), 7.08 (m, 2H), 7.18 (m, 1H), 7.36 (s, 1H), 7.48 (dd, 1H) and 13.0 (br s, 1H). Anal. Calcd for C16H16N2O2: C, 71.62; H, 6.01; N, 10.44. Found: C, 71.33; H, 6.09; N, 10.43. A sample was recrystallized from ethyl acetate; mp 200–202° C.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9]Br.ClC1C=CC(C2C=CC=CC=2)=CC=1.C(OCCCC1C=CC=CC=1)(=O)CC([O-])=[O:27]>>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:27]
Reactant: BrCCc1ccccc1I
Reactant: O=C([O-])CC(=O)OCCCc1ccccc1
Agent: Clc1ccc(-c2ccccc2)cc1
Product: OCCc1ccccc1I

Procedure:
The title compound was synthesized by a sequence similar to that for Example 87 except that 2-(2-iodophenyl)ethyl bromide and commercially available diethyl phenethyl malonate were used in lieu of the 4-chlorobiphenyl and phenylpropyl malonate respectively. The final product was recrystallized from chloroform to give a fluffy, white solid (mp: melts/softens over a broad range starting at 50° C.; the bulk of the sample melts at 189°-190° C.).
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([S:9]([C:12]1[CH:13]=[CH:14][C:15](C)=[C:16]([NH:18][C:19]2[O:20][C:21]([C:24]3[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=3)=[CH:22][N:23]=2)[CH:17]=1)(=[O:11])=[O:10])[CH3:8].[C:32]1(B(O)O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.ClCCl.[CH2:44]([O:46]CC)C>CC([O-])=O.CC([O-])=O.[Cu+2]>[CH2:7]([S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:46][CH3:44])=[C:16]([NH:18][C:19]2[O:20][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:25]=3)=[CH:22][N:23]=2)[CH:17]=1)(=[O:11])=[O:10])[CH3:8]
Reactant: CCS(=O)(=O)c1ccc(C)c(Nc2ncc(-c3cccc(O)c3)o2)c1
Reactant: CCOCC
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCS(=O)(=O)c1ccc(OC)c(Nc2ncc(-c3cccc(Oc4ccccc4)c3)o2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
Pyridine (5 eq.) was added to a mixture of the title compound of Example 158 (100 mg, 0.27 mmol, 1 eq.), Cu(OAc)2 (1 eq.), phenylboronic acid (2 eq.), powered 4A molecular sieves, and dichloromethane (5 mL). After stirring at RT overnight, the reaction was diluted with diethyl ether and washed with 6N HCl solution. The aqueous layer was separated, made basic with 5N NaOH solution, and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure. Purification by thin layer chromatography gave the title compound (22 mg, 18%) as an off-white solid. 1H NMR (400 MHz, d6-DMSO): δ 9.82 (s, 1H), 8.80 (d, J=2.1, 1H), 7.62 (s, 1H), 7.62 (s, 1H), 7.53–7.42 (m, 5H), 7.30–7.27 (m, 2H), 7.22–7.17 (m, 1H), 7.09 (d, J=8.0, 2H), 6.95 (d, J=7.6, 1H), 3.98 (s, 3H), 3.22 (q, J=7.3, 2H), 1.13 (t, J=7.3, 3H). MS (ES+, m/z)=451 (m+H)+.
Reaction SMILES: [C:1]1([C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:10][CH2:11]Br)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:19]12[NH:25][CH:22]([CH2:23][CH2:24]1)[CH2:21][CH2:20]2>COCCO>[C:1]1([C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:10][CH2:11][N:25]2[CH:19]3[CH2:24][CH2:23][CH:22]2[CH2:21][CH2:20]3)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CC(CCBr)(c1ccccc1)c1ccccc1
Reactant: C1CC2CCC1N2
Solvent: COCCO
Product: N#CC(CCN1C2CCC1CC2)(c1ccccc1)c1ccccc1

Procedure:
15 Parts of 2,2-diphenyl-4-bromobutyronitrile are condensed with 12.9 parts of 7-azabicyclo[2.2.1]heptane by reflux in 100 parts by volume of ethylene glycol monomethyl ether. The reaction mixture is cooled and extracted with dilute hydrochloric acid. The aqueous hydrochloric acid extract is made basic with sodium hydroxide solution and extracted with ether. The ether extracts are dried over anhydrous sodium sulfate. Filtration and removal of the ether by evaporation at reduced pressure provides 2,2-diphenyl-4-(7-azabicyclo[2.2.1]hept-7-yl)butyronitrile, melting at 79°-81°. 4.9 Parts of this butyronitrile, 1.5 parts of sodium azide, 1.2 parts of ammonium chloride, and 0.023 part of lithium chloride are placed in 50 parts by volume of dimethylformamide and heated at 125° for 12 hours. The mixture is cooled and the solid is filtered from the dimethylformamide. The solid is washed with dimethylformamide and water. The dried solid is 5-{[1,1-diphenyl-3-(7-azabicyclo[2.2.1]hept-7 -yl)]propyl}-1H-tetrazole, melting at 284°-286°.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:16]([O:18]CC)=[CH2:17])CCC.CN(C=O)C.O1CCOCC1>CO.Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:4]1[CH:3]=[C:2]([C:16](=[O:18])[CH3:17])[N:6]2[C:5]=1[CH:10]=[CH:9][CH:8]=[N:7]2
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Brc1cnc2cccnn12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CO
Solvent: C1COCCO1
Product: CC(=O)c1cnc2cccnn12
Temperature: 100 °C
Reaction time: 1 h

Procedure:
3-Bromoimidazo[1,2-b]pyridazine (1.0 g, 5.05 mmol), tributyl(1-ethoxyvinyl)tin (3.41 mL, 10.1 mmol), and PdCl2(PPh3)2 (354 mg, 0.505 mmol), were added to a sealed tube. DMF (25.2 mL) was added and the reaction purged with nitrogen for 5 minutes. The reaction was heated at 100° C. for 18 h. The reaction was cooled to room temperature and quenched with aqueous saturated sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (×3) and the combined organic layers were dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was diluted with methanol (10 mL) and HCl in 1,4-dioxane (1.26 mL, 5.05 mmol, 4M) was added. The solution was stirred at room temperature for 1 h. The reaction was then quenched with aqueous saturated sodium bicarbonate and extracted with ethyl acetate (×3). The combined organic layers were dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography to afford the title compound. 1H NMR (500 MHz, CD3SOCD3) δ 8.76 (d, 1H); 8.55 (s, 1H); 8.31 (d, 1H); 8.49 (dd, 1H); 2.64 (s, 3H). LRMS (APCI) calc'd for (C8H7N3O) [M+H]+, 162.1. found 162.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].BrC[C:24]#[N:25].C(OCC)(=O)C>C(#N)C>[C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:24]#[N:25])[CH2:13][CH2:14]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCC1CCN(C#N)CC1
Reaction time: 3 h

Procedure:
Piperidin-4-ylmethyl-carbamic acid tert-butyl ester (4 g, 18.66 mmol) was suspended in 120 ml of acetonitrile. Dried potassium carbonate (2.837 g, 20.53 mmol) was added. A solution of bromoacetonitrile in (3.72 ml, 5 mmolar solution, 18.66 mmol) was added (argon atmosphere) and the mixture was stirred for 3 hours. After addition of aqueous FeSO4 solution and ethyl acetate, the separated solid was filtered and the organic layer separated, dried and evaporated.