Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([NH:23][C:24]([NH2:26])=[NH:25])[CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1.CN(C)[CH:29]=[C:30]([CH3:38])[C:31](=O)[C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([NH:23][C:24]2[N:26]=[C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:30]([CH3:38])=[CH:29][N:25]=2)[CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1
Reactant: CCOC(=O)C(=O)C(C)=CN(C)C
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Solvent: O=[N+]([O-])O
Product: CCOC(=O)c1nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)ncc1C

Procedure:
The title compound was prepared from N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (298 mg, 0.8 mmol) and ethyl 4-dimethylamino-3-methyl-2-oxo-but-3-enoate (185 mg, 1.0 mmol) using in analogous manner the procedure described in example 139. Obtained as a white solid (30 mg, 8%). MS ISP (m/e): 368.2 [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.45 (s, 1H), 7.83 (d, 1H), 7.63 (s, 1H), 7.31 (s, 1H), 7.17 (d, 1H), 7.02 (dd, 1H), 6.87 (s, 1H), 4.46 (q, 2H), 3.89 (s, 3H), 2.41 (s, 3H), 2.30 (s, 3H), 1.44 (t, 3H).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([NH:13][C@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:15]2=[O:26])=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Cl:27][C:28]1[CH:33]=[N:32][C:31](Cl)=[CH:30][N:29]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:2][C:3]1[C:4]([NH:13][C@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([CH:20]3[CH2:21][CH2:22][N:23]([C:31]4[CH:30]=[N:29][C:28]([Cl:27])=[CH:33][N:32]=4)[CH2:24][CH2:25]3)[C:15]2=[O:26])=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C1[C@@H](Nc2ncc(C(F)(F)F)cc2Cl)CCCN1C1CCNCC1
Reactant: Clc1cnc(Cl)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1[C@@H](Nc2ncc(C(F)(F)F)cc2Cl)CCCN1C1CCN(c2cnc(Cl)cn2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 42.2 %

Procedure:
A flask was charged with (S)-3-(3-chloro-5-(trifluoromethyl)pyridin-2-ylamino)-1,4′-bipiperidin-2-one hydrochloride (0.075 g, 0.18 mmol), 2,5-dichloropyrazine (0.030 g, 0.20 mmol), Hunig's base (0.095 mL, 0.54 mmol), and DMF (3 mL). The reaction was stirred at 100° C. overnight. The organic solvents were removed under reduced pressure. The residue was purified using silica gel column chromatography with 50-100% ethyl acetate in hexanes to provide (S)-3-(3-chloro-5-(trifluoromethyl)pyridin-2-ylamino)-1′-(5-chloropyrazin-2-yl)-[1,4′-bipiperidin]-2-one (0.037 g, 0.076 mmol, 42% yield) as yellow solid. Mass spectrum (apci) m/z=489.2 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([CH3:15])=[C:8]([CH2:12][C:13]#[N:14])[CH:9]=[CH:10][CH:11]=1.[N-:21]=[N+:22]=[N-:23].[Na+].[Cl-].[NH4+].C(OCC)(=O)C>CN(C=O)C.CCCCCC>[CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([CH3:15])=[C:8]([CH:9]=[CH:10][CH:11]=1)[CH2:12][C:13]1[NH:23][N:22]=[N:21][N:14]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cccc(C)c1COc1cccc(CC#N)c1C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cccc(C)c1COc1cccc(Cc2nnn[nH]2)c1C
Temperature: 90 °C

Procedure:
A mixture of 2-(3-(2,6-Dimethylbenzyloxy)-2-methylphenyl)acetonitrile (Step E, 2.70 g, 10.19 mmol), sodium azide (0.795 g, 12.23 mmol) and ammonium chloride (0.653 g, 12.22 mmol) in dry DMF (20 ml) was heated under argon at 90° C. for 16 hours or until all the starting material is consumed, the reaction mixture was cooled, diluted with water and extracted with EtOAc (30 ml×4). The combined organic layer was washed with brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (chloroform:methanol 92.5:7.5) to give semi solid product. The semi solid was stirred with 1:2 ethyl acetate:hexane (15 ml) for 10 minutes, and filtered to give product as a white solid.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:7]=[CH:6]2)=[CH2:2].Br[CH:20]([C:25]1[CH:26]=[C:27]([Cl:33])[C:28]([F:32])=[C:29]([Cl:31])[CH:30]=1)[C:21]([F:24])([F:23])[F:22].N1C=CC=CC=1C1C=CC=CN=1>ClC1C=CC=CC=1Cl.Cl[Cu]>[Cl:31][C:29]1[CH:30]=[C:25]([CH:20]([C:21]([F:24])([F:23])[F:22])/[CH:2]=[CH:1]/[C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:7]=[CH:6]3)[CH:26]=[C:27]([Cl:33])[C:28]=1[F:32]
Reactant: C=Cc1ccc2c(ccn2C(=O)OC(C)(C)C)c1
Reactant: Fc1c(Cl)cc(C(Br)C(F)(F)F)cc1Cl
Agent: Cl[Cu]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: Clc1ccccc1Cl
Product: CC(C)(C)OC(=O)n1ccc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc21
Temperature: 150 °C

Procedure:
To a stirred solution of tert-butyl 5-vinyl-1H-indole-1-carboxylate (0.65 g, 2.67 mmol), in 1,2-dichlorobenzene (10.0 mL) was added 5-(1-bromo-2,2,2-trifluoroethyl)-1,3-dichloro-2-fluorobenzene (1.74 g, 5.37 mmol), CuCl (53 mg, 0.537 mmol) and 2,2-bipyridyl (167 mg, 1.07 mmol). The resultant reaction mixture was degassed with argon for 30 min and heated to 150° C. for 2 h. The reaction mixture was cooled to ambient temperature and filtered, and the filtrate concentrated under reduced pressure. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 2% ethyl acetate/petroleum ether) to afford the title compound as a light brown gummy material (0.25 g, 10%): 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J=8.0 Hz, 1H), 7.60 (m, 2H), 7.39 (m, 3H), 6.69 (d, J=16.0 Hz, 1H), 6.55 (d, J=10.5 Hz, 1H), 6.36 (dd, J=16.0, 8.0 Hz, 1H), 4.10 (m, 1H), 1.65 (s, 9H); ESIMS m/z 485.91 ([M−H]−); IR (thin film) 1165, 854 cm−1.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])=[NH:4].[C:14](OC(=O)C)(=O)[CH3:15]>C(O)(=O)C>[CH3:14][C:15]1[O:1][N:2]=[C:3]([C:5]2[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=2)[C:8]([OH:10])=[O:9])[N:4]=1
Reactant: N=C(NO)c1cccc(C(=O)O)c1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Cc1nc(-c2cccc(C(=O)O)c2)no1
Temperature: 118 °C

Procedure:
A mixture of 614 g (3.41 mol) of 3-(N-hydroxycarbamimidoyl)benzoic acid, 756 ml (8.0 mol) of acetic anhydride and 2 l of acetic acid is heated at a temperature of 118° C. for 14 hours. The reaction mixture is cooled to 6° C. and filtered with suction. The residue is taken up in 2 l of water, filtered off with suction and washed well with water. The residue is recrystallised from ethanol/water: 3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoic acid as colourless crystals; m.p. 225° C.; ESI 205 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=1)#[N:2].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.[F:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([C:52]2[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=2)(N)[C@@H:44]([NH2:50])[CH2:45][O:46]COC)=[CH:39][CH:38]=1>C1(C)C=CC=CC=1>[C:9]([C:7]1[CH:6]=[CH:5][N:4]=[C:3]([C:1]2[NH:50][C@@H:44]([CH2:45][OH:46])[C:43]([C:40]3[CH:41]=[CH:42][C:37]([F:36])=[CH:38][CH:39]=3)([C:52]3[CH:53]=[CH:54][C:55]([F:58])=[CH:56][CH:57]=3)[N:2]=2)[CH:8]=1)#[N:10]
Reactant: N#Cc1ccnc(C#N)c1
Reactant: COCOC[C@H](N)C(N)(c1ccc(F)cc1)c1ccc(F)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: Cc1ccccc1
Product: N#Cc1ccnc(C2=NC(c3ccc(F)cc3)(c3ccc(F)cc3)[C@H](CO)N2)c1
Reaction time: 48 h
Yield: 21.2 %

Procedure:
2,4-Dicyanopyridine (601 mg) and ytterbium trifluoromethanesulfonate (289 mg) were added to a solution of (2R)-1,1-bis(4-fluorophenyl)-3-(methoxymethoxy)-1,2-propanediamine (1.50 g) in toluene (30 mL), and the mixture was refluxed under stirring for 2 days. The reaction mixture was concentrated in vacuo, and then the residue was dissolved in tetrahydrofuran (20 mL). 6N Hydrochloric acid (10 mL) was added to the solution, and then the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated in vacuo, and then the residue was purified by silica gel column chromatography (C-300; hexane: ethyl acetate=2:1) to give the objective compound (385 mg).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([NH:17][CH2:18][CH2:19][CH3:20])[C:14]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH3:30])=[CH:23][CH:22]=3)=[N:13]2)=[O:11])=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:39](Cl)(=[O:42])[CH2:40][CH3:41]>C(OCC)(=O)C>[F:32][C:2]([F:1])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([N:17]([C:39](=[O:42])[CH2:40][CH3:41])[CH2:18][CH2:19][CH3:20])[C:14]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][CH3:30])=[CH:25][CH:26]=3)=[N:13]2)=[O:11])=[CH:5][CH:4]=1
Reactant: CCCNC1CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C1c1ccc(OCCC)cc1
Reactant: CCC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCOc1ccc(C2=NN(C(=O)Nc3ccc(C(F)(F)F)cc3)CC2N(CCC)C(=O)CC)cc1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 22 %

Procedure:
To 2 g (4.5 mmole) of N-(4-trifluoromethylphenyl)-3-(4-propoxyphenyl)-4-(N-propylamino)-4,5,-dihydro-1H-pyrazole-1-carboxamide Example (586) dissolved in 25 ml of ethyl acetate and cooled to -5° C., was added 0.8 g (9 mmole) of pyridine and, finally, 0.8 g (9 mmole) of propionyl chloride was added. After 30 minutes, the reaction mixture was washed with water and brine, concentrated in vacuo, and chromatographed over silica gel using hexanes and ethyl acetate to yield 0.5 g of the desired compound, mp 152°-154° C.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([C@@H:12]3[CH:17]4[CH2:18][CH2:19][CH:14]([CH2:15][CH2:16]4)[N:13]3[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[N:5][C:4]=2[CH:3]=1.[CH3:27][C:28]1[C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30](C(OC(C)(C)C)=O)[N:29]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[CH3:27][C:28]1[NH:29][N:30]=[CH:31][C:32]=1[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([C@@H:12]3[CH:17]4[CH2:18][CH2:19][CH:14]([CH2:15][CH2:16]4)[N:13]3[C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])=[N:5][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C2CCC(CC2)[C@H]1c1nc2cc(Br)sc2c(=O)[nH]1
Reactant: Cc1nn(C(=O)OC(C)(C)C)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1[nH]ncc1-c1cc2nc([C@@H]3C4CCC(CC4)N3C(=O)OC(C)(C)C)[nH]c(=O)c2s1
Temperature: 100 °C
Reaction time: 3 h
Yield: 76.6 %

Procedure:
tert-Butyl (3S)-3-(6-Bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-2-azabicyclo[2.2.2]octane-2-carboxylate (190 mg), tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (266 mg), sodium carbonate (78 mg), 1,2-dimethoxyethane (3.0 mL) and water (1.5 mL) were placed in a flask, and the atmosphere in the flask was purged with argon. [1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane complex (1:1) (35 mg) was added, and the atmosphere in the flask was purged again with argon. The reaction system was stirred at 100° C. for 3 hr, and the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained pale-yellow solid was crystallized from methanol/ethyl acetate to give the title compound (146 mg) as a pale-yellow solid.
Reaction SMILES: C=O.[CH2:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[CH3:12][CH2:13][O-].[Na+].Cl>CN(C=O)C>[CH:3]1([CH2:9][CH:8]2[C:12]3[C:13](=[CH:11][CH:3]=[CH:4][CH:5]=3)[CH:6]=[CH:7]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: CC[O-]
Reactant: C1=Cc2ccccc2C1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: C1=CC(CC2C=Cc3ccccc32)c2ccccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 89 %

Procedure:
3.5 g of formalin (37% solution, 43.1 mmol) was added to a mixture of 10.0 g of indene (86.2 mmol) and 2.9 g of EtONa (43.1 mmol) in 100 mL of DMF. The reaction mixture was stirred at room temperature for 12 hours. A solution of HCl (1 M, 50 mL) was added. The mixture was extracted with CH2Cl2 (2×100 mL) and the organic phases combined, washed with a saturated solution of NaCl and then with water, dried over MgSO4, filtered and finally concentrated to yield bis(1-indenyl)methane as a viscous brown liquid (89% yield by GC). Vacuum distillation yielded the pure product as a yellow viscous oil (b.p. 160-180° C. at 1.2 mmHg, 3.65 g, 35% yield), which can be recrystallized from pentane.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][P:8]([CH3:12])(=[O:11])[O:9][CH3:10].C[O:14][C:15](=O)[CH2:16][CH2:17][CH:18]=[C:19]([Cl:21])[CH3:20].C(O)(=O)C>O1CCCC1>[CH3:6][O:7][P:8]([CH2:12][C:15](=[O:14])[CH2:16][CH2:17][CH:18]=[C:19]([Cl:21])[CH3:20])(=[O:11])[O:9][CH3:10]
Reactant: COC(=O)CCC=C(C)Cl
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)CCC=C(C)Cl)OC
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 66.7 %

Procedure:
21.8 ml of n-butyllithium solution (2.2M in hexane) are added dropwise at -65° C. to a solution of 5.58 g of methanephosphonic acid dimethyl ester in 160 ml of absolute tetrahydrofuran and the mixture is stirred at that temperature for 15 minutes. A solution of 4.05 g of the methyl ester obtained in Example (6d) in 10 ml of tetrahydrofuran is then added and the mixture is stirred at -65° C. for 1 hour. The solution is heated to -10° C., 2.80 ml of acetic acid are added and the mixture is concentrated. The residue is partitioned between ethene and water, the ether phase is separated, dried over magnesium sulphate and concentrated in vacuo. The residue is then purified by ball-tube distillation. 4.23 g of the title compound are obtained (bath temperature 180°-185° C., 1.5 torr).
Reaction SMILES: [CH2:1]([C@@:5]12[C@H:20]([CH2:21][CH2:22][CH3:23])[C:19](=[O:24])[CH:18]=[C:6]1[C:7]1[CH:8]=[CH:9][C:10]([O:14]COC)=[CH:11][C:12]=1[CH2:13]2)[CH2:2][CH2:3][CH3:4].Cl>CO.CCOC(C)=O>[CH2:1]([C@@:5]12[C@H:20]([CH2:21][CH2:22][CH3:23])[C:19](=[O:24])[CH:18]=[C:6]1[C:7]1[CH:8]=[CH:9][C:10]([OH:14])=[CH:11][C:12]=1[CH2:13]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[C@]12Cc3cc(OCOC)ccc3C1=CC(=O)[C@H]2CCC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCC[C@]12Cc3cc(O)ccc3C1=CC(=O)[C@H]2CCC
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A solution of (rac)-(1S,8aR)-8a-butyl-6-(methoxymethoxy)-1-propyl-8,8a-dihydrocyclopenta[a]inden-2(1H)-one (92 mg, 0.28 mmol) in methanol (1 mL) was treated with aqueous 2N HCl (0.42 mL, 0.84 mmol). The resulting mixture was stirred and gradually heated to 80° C. over 30 minutes, and then kept at 80° C. for an additional 30 minutes. After cooling, the mixture was diluted with EtOAc and washed with 5% NaHCO3. The aqueous portion was back-extracted with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by Biotage™ (Charlottesville, Va.) flash chromatography on a 12S (1.2×7.5 cm) silica gel column, eluting with 5:1 hexane-EtOAc, to give (rac)-(1S,8aR)-8a-butyl-6-hydroxy-1-propyl-8,8a-dihydrocyclopenta[a]inden-2(1H)-one as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH:13]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]([C:24](=[O:41])[C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:40])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[CH3:39])=[CH:27][CH:26]=2)[CH2:16][CH2:15][CH2:14]1)[CH2:3][CH2:4][CH2:5][O:6][CH:7]1[CH2:12]CCC[O:8]1.C(Cl)(=O)C>C(O)(=O)C>[CH3:1][N:2]([CH:13]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]([C:24](=[O:41])[C:25]2[CH:26]=[CH:27][C:28]([NH:31][C:32](=[O:40])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[CH3:39])=[CH:29][CH:30]=2)[CH2:16][CH2:15][CH2:14]1)[CH2:3][CH2:4][CH2:5][O:6][C:7](=[O:8])[CH3:12]
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N(C)CCCOC3CCCCO3)c3ccccc32)cc1
Solvent: CC(=O)O
Solvent: CC(=O)Cl
Product: CC(=O)OCCCN(C)C1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2)c2ccccc21
Reaction time: 8 h
Yield: 16.2 %

Procedure:
To 5-{N-methyl-N-[3-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propyl]amino}-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.4 g) is added a mixture of acetyl chloride (0.5 ml) and acetic acid (5 ml) at room temperature, and the mixture is stirred overnight. The reaction solution is concentrated and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=30:1), and further purified again by silica gel column chromatography (eluent; n-hexane:ethyl acetate=1:2) to give 5-[N-methyl-N-(3-acetyloxypropyl)amino]-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.06 g) as colorless amorphous.
Reaction SMILES: [C:1]([N:5]=[N:6][C:7](Cl)([CH2:9][C:10]([O:13][CH3:14])([CH3:12])[CH3:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:16]([O:21][OH:22])([CH2:19][CH3:20])([CH3:18])[CH3:17].[OH-].[K+].C(N=NC(O)(CC(OC)(C)C)C)(C)(C)C>>[C:1]([N:5]=[N:6][C:7]([O:22][O:21][C:16]([CH2:19][CH3:20])([CH3:18])[CH3:17])([CH2:9][C:10]([O:13][CH3:14])([CH3:12])[CH3:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(C)(C)CC(C)(Cl)N=NC(C)(C)C
Reactant: CCC(C)(C)OO
Agent: COC(C)(C)CC(C)(O)N=NC(C)(C)C
Agent: [K+]
Agent: [OH-]
Product: CCC(C)(C)OOC(C)(CC(C)(C)OC)N=NC(C)(C)C

Procedure:
The 2-t-butylazo-2-(t-amylperoxy)-4-methoxy-4-methylpentane was prepared in 97% crude yield from 7.78 grams (0.0331 moles) of 2-t-butylazo-2-chloro-4-methoxy-4-methylpentane, 5.35 grams (0.0464 moles) of 90% t-amyl hydroperoxide and 7.92 grams (0.0353 moles) of 25% potassium hydroxide solution. The procedure was the same as that described in Example XX. The infrared spectrum of the product indicated there was a small amount of 2-t-butylazo-2-hydroxy-4-methoxy-4-methylpentane present in the product.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([C:8](=[O:12])[CH2:9][C:10]#[N:11])=[C:3]1[CH3:13].C1(C)C=CC=CC=1.[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(N(CC)CC)C>[CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([C:8](=[O:12])[CH:9]([C:28](=[O:29])[NH:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]#[N:11])=[C:3]1[CH3:13]
Reactant: Cc1cc(C(=O)CC#N)c(C)n1C
Reactant: O=C=Nc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)C(C#N)C(=O)Nc2ccccc2)c(C)n1C
Reaction time: 8 h

Procedure:
The suspension of 1.0 g of 1,2,5-trimethyl-β-oxo-3-pyrrolpropionitrile, 40 ml of toluene and 0.7 g of triethylamine is treated with 0.75 g of phenylisocyanate and warmed for 5 minutes on the steam cone until all is dissolved. After standing overnight, the precipitate formed is collected, taken up in methanol, and the solution added to the mixture of 3 ml of 5 N hydrochloric acid and 250 ml of water. The crude product formed is collected, washed with water, dissolved in 5% aqueous sodium hydroxide, filtered, and the alkaline filtrate acidified with 5 N hydrochloric acid. The precipitate is collected, washed with water, air-dried and recrystallized from ethanol, to yield the 1,2,5-trimethyl-β-oxo-α-phenylcarbamoyl-3-pyrrolpropionitrile melting at 158°-160°.
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][CH:7]=[C:6]([Br:12])[CH:5]=2.S(=O)(=O)(O)[OH:14].O1CCOCC1>O>[Br:12][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]([CH3:11])[C:2](=[O:14])[NH:3]2)=[CH:8][CH:7]=1
Reactant: Cc1c(Br)[nH]c2cc(Br)ccc12
Reactant: O=S(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: CC1C(=O)Nc2cc(Br)ccc21

Procedure:
To 2,6-dibromo-3-methyl-1H-indole (15.7 g) were added 3N aqueous sulfuric acid solution (100 ml) and dioxane (100 ml), and the mixture was refluxed for 5 hours. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate solution. This ethyl acetate solution was washed with water and an aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to give the title compound (11.2 g) as a brown crystal.
Reaction SMILES: [C:1]([N:5]1[CH2:9][CH2:8][NH:7][S:6]1(=[O:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].[N+:12]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1)([O-:14])=[O:13]>C(OCC)(=O)C.CCCCCC>[C:1]([N:5]1[CH2:9][CH2:8][N:7]([CH2:19][C:18]2[CH:21]=[CH:22][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=2)[S:6]1(=[O:10])=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CC(C)(C)N1CCNS1(=O)=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)N1CCN(Cc2ccc([N+](=O)[O-])cc2)S1(=O)=O
Yield: 70 %

Procedure:
The title compound was prepared in 70% yield from 2-tert-butyl-1,2,5-thiadiazolidine-1,1-dioxide [M. Preiss, Chem. Ber., 1978, 111, 1915] and 4-nitrobenzyl bromide following the procedure described for Example 1 (Method B, Step 1); mp 113° C. (ethyl acetate-hexane, 60:40); δH (360 MHz, CDCl3) 8.21 (2H, d, J=8.7 Hz, Ar--H), 7.58 (2H, d, J=8.7 Hz, Ar--H), 4.24 (2H, s, Ar--CH2 --), 3.40 (2H, t, J=6.2 Hz, --CH2 --), 3.17 (2H, t, J=6.2 Hz, --CH2 --), 1.44 (9H, t-Bu); m/z (EI) 313 (M+).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3](=[O:14])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1.[C:16]1(=O)[CH2:19][CH2:18][CH2:17]1.[Si]([C:25]#[N:26])(C)(C)C>C(OCC)(=O)C>[CH3:15][N:2]([CH3:1])[C:3](=[O:14])[CH2:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:16]2([C:25]#[N:26])[CH2:19][CH2:18][CH2:17]2)=[CH:11][CH:12]=1
Reactant: C[Si](C)(C)C#N
Reactant: CN(C)C(=O)CCCc1ccc(N)cc1
Reactant: O=C1CCC1
Solvent: CCOC(C)=O
Product: CN(C)C(=O)CCCc1ccc(NC2(C#N)CCC2)cc1
Temperature: 80 °C
Reaction time: 15 h
Yield: 56.5 %

Procedure:
A mixture of N,N-Dimethyl 4-(4-aminophenyl)butanamide (Formula 47) (74 mg, 0.36 mmol), cyclobutanone (54 mg, 0.78 mmol) and TMSCN (77 mg, 0.78 mmol) was heated to 80° C. and stirred for 15 h. To the medium was added ethyl acetate (2×20 mL) and then washed with water (2×20 mL). The organic layer was dried over MgSO4 and concentrated and the residue was purified with silica gel column chromatography (dichloromethane:acetone, 9:1) to give N,N-Dimethyl 4-[4-(1-cyanocyclobutylamino)phenyl]butanamide (Formula 48) (58 mg, 57%) as a white solid. 1NMR δ 7.07 (d, 2H, J=8.5 Hz), 6.59 (d, 2H, J=8.5 Hz), 3.94 (br s, 1H), 2.94 (s, 3H), 2.93 (s, 3H), 2.75-2.83 (m, 2H), 2.60 (t, 2H, J=7.6 Hz), 2.33-2.42 (m, 2H), 2.30 (t, 2H, J=7.6 Hz), 2.11-2.28 (m, 2H), 1.93 (p, 2H, J=7.6 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[N:6][CH:5]=[C:4]([NH2:9])[N:3]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>COC(OC)C>[NH2:1][C:2]1[C:7]([Br:8])=[N:6][CH:5]=[C:4]([NH:9][C:10](=[O:12])[CH3:11])[N:3]=1
Reactant: Nc1cnc(Br)c(N)n1
Reactant: CC(=O)OC(C)=O
Agent: COC(C)OC
Product: CC(=O)Nc1cnc(Br)c(N)n1

Procedure:
A mixture of 2,6-diamino-3-bromopyrazine (10.50 g, 0.056 mole) in dry 1,1-dimethoxyethane (168 ml) and acetic anhydride (7.91 ml, 8.56 g, 0.084 mole) was refluxed under nitrogen for 2.50 hrs. The cooled mixture was evaporated in vacuo. The residue was triturated with ether, filtered and dried in vacuo. Yield 10.31 g (80%), M.p. 218-221° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1.[H-].[Na+].I[CH3:15].CN([CH:19]=[O:20])C>>[CH3:15][O:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:20][CH3:19])=[O:8])=[CH:5][CH:4]=1
Reactant: CN(C)C=O
Reactant: CI
Reactant: O=C(O)c1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Product: COCc1ccc(C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 72 %

Procedure:
Under nitrogen atmosphere, a solution of 4-(hydroxymethyl)-benzoic acid (5.00 g) in DMF (200 mL) was cooled to 0° C., and thereto was added NaH (2.76 g, 60%). The mixture was stirred at the same temperature for 10 minutes, and stirred at room temperature for 20 minutes. The mixture was cooled to 0° C., and thereto were added DMF (100 mL) and iodomethane (18.7 g), and the mixuture was stirred at room temperature for 48 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (hexane/ethyl acetate=15/1) to give methyl 4-(methoxymethyl)benzoate (4.27 g, 72%).