Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:16]([O:17][CH3:18])=[CH:15][C:13]([NH2:14])=[C:12]([Cl:19])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[C:21](Cl)([O:23]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C>ClCCl>[C:4]([Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([Cl:19])[C:13]([N:14]=[C:21]=[O:23])=[CH:15][C:16]=1[O:17][CH3:18])([CH3:3])[CH3:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: COc1cc(N)c(Cl)cc1CO[Si](C)(C)C(C)(C)C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(N=C=O)c(Cl)cc1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 263.5 %

Procedure:
A solution of 4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-chloro-5-methoxyaniline (intermediate 39; 300 mg, 1 mmol) in 4 ml of dichloromethane was cooled externally with an ice bath while dropping a solution of triphosgene (108 mg; 0.36 mmol) in 5 ml of dichloromethane. Triethylamine (0.28 ml; 2.01 mmol) was added slowly and the system stirred at room temperature for 3 hr. Half of the solvent is then evaporated in vacuo and 25 ml of pentane added. The white precipitate of ureas was filtered and the filtrate evaporated to dryness giving 311 mg of the title compound that were used without further purification in the next step.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[CH:8]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[NH:10][C:11]=1[CH3:12].CN(C)[CH:19]=[O:20].[OH-].[Na+]>>[CH:19]([C:8]1[C:7]([CH3:6])=[C:11]([CH3:12])[NH:10][C:9]=1[C:13]([O:15][CH3:16])=[O:14])=[O:20]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cc(C)c(C)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1[nH]c(C)c(C)c1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
15.0 g (0.0979 mole) of phosphorus oxychloride were dropwise added to a solution of 13.7 g (0.0898 mole) of methyl 4,5-dimethylpyrrole-2-carboxylate in 13 ml (0.17 mole) of dimethylformamide over a period of 1.3 hours with ice-cooling, and the resulting mixture was stirred at room temperature for 0.5 hour and then at 90-100° C. for 0.5 hour. The hot reaction mixture thus obtained was poured into ice-water and dissolved. The solution was adjusted to pH 5-6 with a 10% aqueous solution of sodium hydroxide. The solids precipitated were collected by filtration and then dissolved in 600 ml of ethyl acetate. The filtrate was extracted twice with 200 ml each of ethyl acetate. The combined extracts were washed with water and dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was washed with a mixture of hexane and ethyl acetate and collected by filtration to give 10.6 g (0.0583 mole) of methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate as a brown powder.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[C:2]#[CH:3].[N:7]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[N:12]=1)=[N+:8]=[N-:9].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>CC(O)(C)C.O.C([O-])(O)=O.[Na+]>[Br:17][C:13]1[N:12]=[C:11]([CH2:10][N:7]2[CH:3]=[C:2]([C:1]([O:5][CH3:6])=[O:4])[N:9]=[N:8]2)[CH:16]=[CH:15][CH:14]=1
Reactant: [N-]=[N+]=NCc1cccc(Br)n1
Reactant: C#CC(=O)OC
Agent: O=C([O-])O
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: COC(=O)c1cn(Cc2cccc(Br)n2)nn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl propiolate (641 μL, 7.63 mmol) and 2-(azidomethyl)-6-bromopyridine (1.25 g, 5.87 mmol) were combined in t-BuOH (9.0 mL) and water (5.0 mL). A solution of CuSO4.5H2O (73 mg, 0.29 mmol) in water (2.0 mL) was added, followed by sodium ascorbate (232 mg, 1.17 mmol) in water (2.0 mL). The reaction was stirred at room temperature for 18 h, during which time it became a yellow suspension. The suspension was diluted with saturated NaHCO3 and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The crude solid was purified by flash chromatography (40-100% EtOAc/hexanes) to afford the title compound as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:9]=[C:10]([C:13]([OH:15])=O)[S:11][CH:12]=2)[N:4]([CH3:16])[N:3]=1.[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:9]=[C:10]([C:13]([NH:17][C@@H:18]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)[CH2:19][N:20]3[C:28](=[O:29])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21]3=[O:30])=[O:15])[S:11][CH:12]=2)[N:4]([CH3:16])[N:3]=1
Reactant: N[C@@H](Cc1cccc(F)c1)CN1C(=O)c2ccccc2C1=O
Reactant: Cc1c(Cl)nn(C)c1-c1csc(C(=O)O)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Cl)nn(C)c1-c1csc(C(=O)N[C@@H](Cc2cccc(F)c2)CN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(3-chloro-1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (291 mg, 1.13 mmol) [prepared according to the procedure of Example 176], 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (409 mg, 1.22 mmol) [prepared according to the procedure of Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-3-fluoro-L-phenylalanine (5.03 g, 17.8 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (654 mg, 1.39 mmol) in chloroform (10 mL). DIEA (1 mL, 5.73 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (427 mg, 0.76 mmol, 67%): LC-MS (ES) m/z=537 (M+H)+.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:18]=[C:17]([Cl:19])[C:16]([O:20][CH3:21])=[C:15]([Cl:22])[C:10]=1[C:11]([O:13][CH3:14])=[O:12])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][C:9]1[CH:18]=[C:17]([Cl:19])[C:16]([O:20][CH3:21])=[C:15]([Cl:22])[C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1c(NC(=O)OC(C)(C)C)cc(Cl)c(OC)c1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1c(N)cc(Cl)c(OC)c1Cl
Yield: 87 %

Procedure:
A solution o#methyl 2-(tert-butoxycarbonylamino)-4,6-dichloro-5-methoxybenzoate (2.3 g, 6.6 mM) and trifluoroacetic acid (6.0 g, 53 mM) in methylene chloride (23 mL) was stirred at room temperature for 1.5 hr. The reaction mixture was then washed with saturated aqueous sodium bicarbonate, drie (MgSO4), filtered and concentrated to obtain (87%) the title compound as a yellow oil; MS(CI): 250 (M+H).
Reaction SMILES: [CH2:1]1[C@H:5]2[CH2:6][NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10](=[S:11])[N:4]2[CH2:3][CH2:2]1.[C:16]1([CH3:40])[CH:21]=[CH:20][C:19]([C:22]2[CH:39]=[CH:38][CH:37]=[CH:36][C:23]=2[C:24]([NH:26][C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=2)=[O:25])=[CH:18][CH:17]=1>>[C:16]1([CH3:40])[CH:17]=[CH:18][C:19]([C:22]2[CH:39]=[CH:38][CH:37]=[CH:36][C:23]=2[C:24]([NH:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([N:7]3[C:8]4[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=4[C:10](=[S:11])[N:4]4[CH2:3][CH2:2][CH2:1][C@H:5]4[CH2:6]3)=[O:32])=[CH:29][CH:28]=2)=[O:25])=[CH:20][CH:21]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)O)cc2)cc1
Reactant: S=C1c2ccccc2NC[C@@H]2CCCN12
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N3C[C@@H]4CCCN4C(=S)c4ccccc43)cc2)cc1
Yield: 59.4 %

Procedure:
The same procedures used in Example 25 were repeated using (11aS)-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-thione prepared in Reference Example 32 and 4-[[2-(4-tolyl)benzoyl]amino]benzoic acid to thus give the title compound. Yield 59.4%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([S:15]([CH3:18])(=O)=O)[N:3]=1.[CH2:19](S)C.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([S:15][CH2:18][CH3:19])[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: CCS
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: CCSc1nc(N)nc(-c2ccco2)c1C#N

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, ethanethiol and DBU in DME. EI-MS m/e (%): 246 (M+, 49), 245 ([M—H]+, 100).
Reaction SMILES: [CH:1]([C:3]1[CH:25]=[CH:24][C:6]([O:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1)=O.[S:26]1[CH2:30][C:29](=[O:31])[NH:28][C:27]1=[O:32].C([O-])(=O)C.[NH2+]1CCCCC1.O>C1(C)C=CC=CC=1>[C:19]([O:18][C:17]([NH:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][O:7][C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[C:30]3[S:26][C:27](=[O:32])[NH:28][C:29]3=[O:31])=[CH:25][CH:24]=2)=[CH:15][CH:14]=1)=[O:23])([CH3:22])([CH3:20])[CH3:21]
Reactant: O=C1CSC(=O)N1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCOc2ccc(C=O)cc2)cc1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(CCOc2ccc(C=C3SC(=O)NC3=O)cc2)cc1
Temperature: 25 °C
Yield: 72.6 %

Procedure:
A solution of 3.41 g (10 mmole) tert-butyl N-{4-[2-(4-formylphenoxy)ethyl]phenyl}carbamate and 1.29 g (11 mmole) 2,4-thiazolidinedione in toluene containing a catalytic amount of piperidinium acetate was refluxed in a Dean-Stark water trap for 3 hours. The reaction was followed by TLC and more 2,4-thiazolidinedione was added during the reaction time. The solution was cooled to room temperature filtered and the precipitate was refluxed in methanol. Another filtration gave 3.2 g (yield 72.6%) 5-(4-[2-(4-tert-butyloxycarbonylaminophenyl)ethoxy]benzylidene)thiazolidine-2,4-dione as a light yellow, solid substance.
Reaction SMILES: C([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[Cl:27][C:28]1[N:35]=[CH:34][CH:33]=[CH:32][C:29]=1[C:30]#[N:31].Cl.C(OCC)(=O)C>C(OCC)C>[ClH:27].[C:30]([C:29]1[C:28]([N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:26])[S:12][CH:13]=2)=[N:35][CH:34]=[CH:33][CH:32]=1)#[N:31]
Reactant: N#Cc1cccnc1Cl
Reactant: CCCCCCCNCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ncccc1C#N

Procedure:
A compound obtained using 2-({4-[2-(heptylamino)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester synthesized in Example 303-2 and 2-chloronicotinonitrile as starting materials and by operations similar to those of Example 303-3 and 303-4 was dissolved in diethyl ether, and reacted with 4 mol/L hydrochloric acid-ethyl acetate to give the title compound.
Reaction SMILES: [C:1]1([C@@H:7]([NH2:16])[C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH:24]([C:27]1[CH:32]=[C:31]([CH:33]([CH3:35])[CH3:34])[CH:30]=[C:29]([CH:36]([CH3:38])[CH3:37])[C:28]=1[S:39](Cl)(=[O:41])=[O:40])([CH3:26])[CH3:25]>ClCCl>[NH2:16][C@H:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C@H:8]([NH:9][S:39]([C:28]1[C:29]([CH:36]([CH3:37])[CH3:38])=[CH:30][C:31]([CH:33]([CH3:35])[CH3:34])=[CH:32][C:27]=1[CH:24]([CH3:26])[CH3:25])(=[O:41])=[O:40])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N[C@H](c1ccccc1)[C@H](N)c1ccccc1
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1cc(C(C)C)c(S(=O)(=O)N[C@H](c2ccccc2)[C@H](N)c2ccccc2)c(C(C)C)c1
Temperature: 5 °C
Reaction time: 4 h
Yield: 96.7 %

Procedure:
(1R,2R)-1,2-Diphenyl-ethane-1,2-diamine (1.0 g) was dissolved in dichloromethane (20 mL), and then triethylamine (0.66 mL) added and the mixture was cooled to 5° C. (internal). 2,4,6-Triisopropyl-benzenesulfonyl chloride (1.21 g) was dissolved in dichloromethane (10 mL) and then added to the diamine mixture over 30 minutes, while maintaining the temperature between 7-10 ° C. The cooling bath was removed and the resulting mixture was stirred at 25° C. for 4 hours and the solvent was evaporated. The resulting residue was suspended in hexanes (100 mL) and washed with warm water (42° C., 3×100 mL). The hexane layer was separated, dried over Na2SO4, filtered, and evaporated to provide the product (1.85 g). 1HNMR (400 MHz, CDCl3): δ(ppm) 7.20-7.15 (m, 3H), 7.05-6.94 (m, 7H), 6.84-6.80 (m, 2H), 6.09 (br-s,1H), 4.49 (d, 1H), 3.99-3.91 (m, 3H), 2.87-2.79 (m, 1H), 1.21 (d, 6H), 1.17 (d, 6H), 1.08 (d, 6H). LC/MS: 479 (m/z).
Reaction SMILES: [NH:1]([C:7]([O:9][CH2:10][CH:11]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[C@H:2]([C:4](O)=[O:5])[CH3:3].CN1CCOCC1.ClC(OCC(C)C)=O.[F:39][C:40]1[CH:45]=[C:44]([NH:46][C:47]2[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=2)[C:43]([NH2:54])=[CH:42][CH:41]=1.[NH4+].[Cl-]>C(Cl)Cl>[F:39][C:40]1[CH:41]=[CH:42][C:43]([NH:54][C:4](=[O:5])[C@@H:2]([NH:1][C:7](=[O:8])[O:9][CH2:10][CH:11]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:18]3[C:23]2=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:3])=[C:44]([NH:46][C:47]2[CH:48]=[CH:49][C:50]([F:53])=[CH:51][CH:52]=2)[CH:45]=1
Reactant: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: Nc1ccc(F)cc1Nc1ccc(F)cc1
Agent: CC(C)COC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)Nc1ccc(F)cc1Nc1ccc(F)cc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a −10° C. solution (NaCl-ice bath) of Fmoc-L-Ala-OH (4.45 g, 14.30 mmol) and N-methylmorpholine (1.573 mL, 14.30 mmol) in DCM (34.1 mL) was added isobutyl chloroformate (1.782 mL, 13.62 mmol). The resulting cloudy colorless mixture was stirred at −10° C. for 30 min. To the mixture was then added a solution of 5-fluoro-N1-(4-fluorophenyl)benzene-1,2-diamine (1.500 g, 6.81 mmol) in DCM (12.75 mL). The resulting mixture was stirred at −10° C. for 1 h, to which the cold mixture was added satd. aq. NH4Cl solution (100 mL). The precipitate was collected by filtration and washed with water (100 mL) to give (S)-(9H-fluoren-9-yl)methyl 1-(4-fluoro-2-(4-fluorophenylamino)phenylamino)-1-oxopropan-2-ylcarbamate as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 9.42 (1H, s), 7.89 (2H, d, J=7.6 Hz), 7.63-7.78 (3H, m), 7.22-7.46 (6H, m), 6.96-7.14 (4H, m), 6.83 (1H, dd, J=11.2, 2.7 Hz), 6.67 (1H, td, J=8.5, 2.8 Hz), 4.11-4.33 (4H, m), 1.28 (3H, d, J=7.0 Hz); LC-MS (ESI) m/z 514.2 [M+H]+. The off-white solid was carried on crude without purification.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].[C:9](=[N:22][NH2:23])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[C:10]1([C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:22][NH:23][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[CH3:8])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1ccncc1Br
Reactant: NN=C(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccncc1NN=C(c1ccccc1)c1ccccc1
Yield: 59.9 %

Procedure:
3-Bromo-4-methyl-pyridine (1.0 g, 5.81 mmol) in 5 mL dry toluene was treated with benzophenone hydrazone (1.25 g, 6.39 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (335 mg, 0.58 mmol), and sodium tert-butoxide (840 mg, 8.72 mmol). The mixture was degassed with argon for 15 minutes. Added Pd(II)(OAc)2 (130 mg, 0.58 mmol) and stirred at 90° C. for 14 hours. Extracted using EtOAc/H2O (3×200 mL EtOAc, lx 100 mL H2O, 1×100 mL brine). Dried using Na2SO4 and then purified by flash chromatography (silica, 10-50% EtOAc/Hexane) to afford 3-(2-(diphenylmethylene)hydrazinyl)-4-methylpyridine (1.00 g, 3.48 mmol, 60%). 1H NMR (300 MHz, DMSO-d6) δ 8.79 (s, 1H), 7.97 (d, 1H), 7.67-7.52 (m, 6H), 7.45-7.36 (m, 5H), 7.06 (d, 1H), 1.91 (s, 3H); LC-MS (ESI) m/z 488 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12](=[O:13])[C:6]=2[CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:15]=[CH:14][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12](=[O:13])[C:6]=2[CH:5]=1
Reactant: [H][H]
Reactant: O=C1CCCCc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)C(=O)CCCC2

Procedure:
A solution of 3-nitro-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-one (CAS #7507-93-9, 2 g, 9.75 mmol), palladium (413 mg, 10% on carbon, 0.4 mmol) in methanol (25 ml) under the hydrogen atmosphere (60 PSI) was stirred at room temperature for 16 hrs. The mixture was filtered through a layer of diatomaceous earth, washed with methanol and concentrated under reduced pressure to provide the title compound. 1H NMR (CDCl3) δ 1.77-1.84 (m, 4H), 2.67-2.73 (m, 2H), 2.82 (t, J=6.10 Hz, 2H), 6.75 (dd, J=8.14, 2.71 Hz, 1H), 6.99 (d, J=8.48 Hz, 1H), 7.05 (d, J=2.71 Hz, 1H). MS (M+H)+ m/z 175.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@H:3]1[NH:11][C:12](=[O:16])[CH2:13][CH2:14][CH3:15].CO[C:19]([CH3:21])=[CH2:20].CS(O)(=O)=O>C(Cl)Cl>[CH3:20][C:19]1([CH3:21])[N:11]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])[C@H:3]2[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=3[CH2:10][C@H:2]2[O:1]1
Reactant: C=C(C)OC
Reactant: CCCC(=O)N[C@H]1c2ccccc2C[C@H]1O
Agent: CS(=O)(=O)O
Solvent: ClCCl
Product: CCCC(=O)N1[C@H]2c3ccccc3C[C@H]2OC1(C)C
Reaction time: 0.33 h

Procedure:
N-(1S, 2R)-(2-Hydroxyindan-1-yl)-butyramide (XV, 2.2 g) and 2-methoxypropene (5 mL) were combined with CH2Cl2 (70 mL) at rt, and methanesulfonic acid (0.05 mL) was added. After 20 min at rt, the reaction mixture was partitioned between half-saturated NaHCO3 (30 mL) and CH2Cl2 (2×30 mL). The combined organic layers were dried dried (MgSO4), filtered, and concentrated under reduced pressure to give an oil as product: MH+260.1.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][C:9](=[O:19])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:21][CH2:22][CH2:23][CH2:24][C:25]([CH2:32][CH3:33])([CH3:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27]>C(=O)([O-])[O-].[Ag+2].CN(C)C=O>[CH2:32]([C:25]([CH3:31])([CH2:24][CH2:23][CH2:22][CH2:21][O:19][C:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:12]=[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:10]=1)[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:33]
Reactant: O=c1cc(-c2ccccc2)cc(-c2ccccc2)[nH]1
Reactant: CCOC(=O)C(C)(CC)CCCCBr
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(CC)CCCCOc1cc(-c2ccccc2)cc(-c2ccccc2)n1
Temperature: 100 °C

Procedure:
The procedure in Example 5 is followed but using 4,6-diphenyl-2-pyridinone (3 g), ethyl 6-bromo-2-ethyl-2-methylhexanoate (6.44 g) [prepared according to the method of K. E. MOELLER, Brenstoff-Chem., 47, 10 (1966)], silver carbonate (1.68 g) and dimethylformamide (110 cc). The reaction mixture is heated at 100° C. for 121 hours. The product is purified by chromatography under pressure on silica gel (30-60 mm; eluent: n-hexane-ethyl acetate 9-1). (yellow oil)
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]#[C:3][CH3:4].ClC(OCC(C)C)=O.CN1CCOCC1.[NH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[CH:28][C:27]([C:33]#[N:34])=[C:26]2[NH:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[C:38]([Cl:43])[CH:37]=1>C1COCC1>[Cl:43][C:38]1[CH:37]=[C:36]([NH:35][C:26]2[C:25]3[C:30](=[CH:31][CH:32]=[C:23]([NH:22][C:1](=[O:6])[C:2]#[C:3][CH3:4])[CH:24]=3)[N:29]=[CH:28][C:27]=2[C:33]#[N:34])[CH:41]=[CH:40][C:39]=1[F:42]
Reactant: CC#CC(=O)O
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1ccc(F)c(Cl)c1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 24.4 %

Procedure:
Dissolved 336 mg (4.00 mmol) 2-butynoic acid in 20 ml of THF and chilled to 0° C. under N2. Added 520 μl (4.00 mmol) isobutyl chloroformate and 440 μl (4.00 mmol) N-methylmorpholine and stirred for 10 minutes. Added a solution of 500 mg (1.60 mmol) 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-3-quinolinecarbonitrile, stirred for 15 minutes at 0° C. and then at 25° C. overnight. Stripped solvent, washed with water, collected and dried in vacuo. Recrystallized from ethyl acetate, giving 148 mg of a yellow solid: mass spectrum (electrospray m/e): M+H=379.1, 381.1.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=O)[CH2:8][CH:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:10][C:5]=2[O:4][CH:3]=1.[C:18]([NH:21][NH2:22])([NH2:20])=[NH:19].[ClH:23].Cl.O>C(O)C>[ClH:23].[NH:21]([N:22]=[C:7]1[C:6]2[C:2]([CH3:1])=[CH:3][O:4][C:5]=2[CH2:10][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8]1)[C:18]([NH2:20])=[NH:19]
Reactant: N=C(N)NN
Reactant: Cc1coc2c1C(=O)CC(c1ccccc1)C2
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1coc2c1C(=NNC(=N)N)CC(c1ccccc1)C2
Yield: 39.4 %

Procedure:
A mixture of 3-methyl-6-phenyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.18 g), aminoguanidine hydrochloride (0.092 g), concentrated hydrochloric acid (0.04 ml), water (0.040 ml) and ethanol (20 ml) was refluxed for 30 minutes. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethanol to give 4-guanidinoimino-3-methyl-6-phenyl-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 31) (0.10 g) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[CH2:8][CH2:7][CH2:6]2.C([O-])(=O)C.[Na+].Cl.[NH2:20][OH:21]>C(O)C.O.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[N:20][OH:21])[CH2:8][CH2:7][CH2:6]2
Reactant: NO
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc2c(c1)CCCC2=NO

Procedure:
Dissolve 100 g (0.57 mol) of 6-methoxy-1-tetralone in 2.5 liters of a mixture of ethanol/water: 80/20. There are then added, at ambient temperature, 85 g (1.04 mol) of sodium acetate and 43 g (0.62 mol) of hydroxylamine hydrochloride. Heat the suspension at reflux for 4 hours. Dilute the mixture with 5 liters of water and extract with ethyl ether, wash with water, dry over magnesium sulphate and filter. After evaporating off the solvent, 99 g of a beige solid are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[NH2:33].C(OC(N1CCN(C2C=CC(C(=O)NC3C=CC=C(C(C)(C)C)C=3)=CC=2)CC1)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:21])[NH:33][C:24]3[CH:25]=[CH:26][C:27]4[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:23]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)O)cc2)CC1
Agent: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)Nc3cccc(C(C)(C)C)c3)cc2)CC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)Nc3ccc4ccccc4c3)cc2)CC1

Procedure:
4-[4-(Naphthalen-2-ylcarbamoyl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester was synthesized from 4-(4-carboxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester and naphthalen-2-ylamine in a manner similar to the one described in the synthesis of 4-[4-(3-tert-butyl-phenylcarbamoyl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester, above. LCMS calcd for C26H29N3O3 (m/e) 431, obsd 432 (M+H).