Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][OH:3].[OH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH3:12])=[CH:7][CH:6]=1.C(C1C=CC=CC=1)(=O)C>N1C=CC=CC=1>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[N:2][OH:3])[CH3:12])=[CH:7][CH:6]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(=O)c1ccccc1
Product: CC(=NO)c1ccc(O)cc1

Procedure:
1.1 equivalents of hydroxylamine hydrochloride are added to a solution of para-hydroxyacetophenone in pyridine (16% dilution). The reaction mixture is maintained at reflux until the starting acetophenone has disappeared, and is then poured into ice-cold water. The medium is extracted with ethyl acetate. After drying, the organic phase is removed and the corresponding oxime is obtained quantitatively. The elemental analysis is in accordance with the structure.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=3[N:10]=[C:9]2[CH:19]([F:21])[F:20])[N:5]=[C:4]([N:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)[N:3]=1.Cl.[CH:36]12[O:43][CH:40]([CH2:41][CH2:42]1)[CH2:39][NH:38][CH2:37]2.CCN(C(C)C)C(C)C>C1COCC1>[F:20][CH:19]([F:21])[C:9]1[N:8]([C:6]2[N:7]=[C:2]([N:38]3[CH2:37][CH:36]4[O:43][CH:40]([CH2:41][CH2:42]4)[CH2:39]3)[N:3]=[C:4]([N:22]3[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:26][CH2:27]3)[N:5]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=2[N:10]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCN(C(=O)OC(C)(C)C)CC2)n1
Reactant: C1CC2CNCC1O2
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCN(C(=O)OC(C)(C)C)CC2)nc(N2CC3CCC(C2)O3)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
A mixture of tert-butyl 4-{4-chloro-6-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-1,3,5-triazin-2-yl}-1-piperazinecarboxylate (550 mg, 1.11 mmol), 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (215 mg, 1.44 mmol) and DIPEA (0.77 mL, 4.44 mmol) in THF (20 mL) was stirred at room temperature overnight. The solvent was removed under vacuum and the residue diluted with water. The resulting precipitate was washed with water, dissolved in CH2Cl2, dried (Na2SO4) and recrystallized from CH2Cl2/MeOH to give 540 mg (85% yield) of tert-butyl 4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]-1-piperazinecarboxylate: mp (CH2Cl2/MeOH) 181-183° C.; 1H NMR (CDCl3) δ7.89 (dd, J=8.4, 0.6 Hz, 1H), 7.49 (t, JHF=53.6 Hz, 1H), 7.35 (t, J=8.2 Hz, 1H), 6.81 (d, J=7.6, 1H), 4.48 (d, J=8.0 Hz, 2H), 4.33 (dd, J=12.6, 8.9 Hz, 2H), 4.05 (s, 3H), 3.87 (br s, 4H), 3.53 (br s, 4H), 3.29 (ddd, J=32.8, 13.1, 1.6 Hz, 2H), 1.99 (dd, J=8.3, 4.4 Hz, 2H), 1.79 (m, 2H), 1.50 (s, 9H); Anal. Calcd. for C27H34F2N8O4.0.05H2O: C, 56.55; H, 6.0; N, 19.5. Found: C, 56.2; H, 6.0; N, 19.6.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]2[S:7][C:8]([C:10](O)([CH2:13][CH3:14])[CH2:11][CH3:12])=[CH:9][C:5]=2[CH:4]=1.[C:18]1([CH3:25])[C:23]([OH:24])=[CH:22][CH:21]=[CH:20][CH:19]=1.B(F)(F)F.CCOCC>>[CH2:11]([C:10]([C:20]1[CH:21]=[CH:22][C:23]([OH:24])=[C:18]([CH3:25])[CH:19]=1)([C:8]1[S:7][C:6]2[CH:16]=[CH:17][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[CH:9]=1)[CH2:13][CH3:14])[CH3:12]
Reactant: CCC(O)(CC)c1cc2cc(OC)ccc2s1
Reactant: Cc1ccccc1O
Agent: FB(F)F
Solvent: CCOCC
Product: CCC(CC)(c1ccc(O)c(C)c1)c1cc2cc(OC)ccc2s1
Yield: 77.9 %

Procedure:
3-(5-Methoxy-benzo[b]thiophen-2-yl)-pentan-3-ol (2.16 g, 8.63 mmol), o-cresol (4.66 g, 43.1 mmol), and BF3-Et2O (1.64 mL, 12.9 mmol) are reacted analogous to Example 1C to afford the title compound (2.29 g, 78%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:9]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[C:10]2[C:15]([C:16]=1[NH2:17])=[CH:14][C:13]([C:18]([F:21])([F:20])[F:19])=[CH:12][CH:11]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([C:8]1[N:9]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[C:10]2[C:15]([C:16]=1[N:17]=[C:33]=[O:35])=[CH:14][C:13]([C:18]([F:21])([F:20])[F:19])=[CH:12][CH:11]=2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)c1c(N)c2cc(C(F)(F)F)ccc2n1C(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1c(N=C=O)c2cc(C(F)(F)F)ccc2n1C(=O)OCc1ccccc1

Procedure:
To a solution of 3-amino-1-benzyloxycarbonyl-5-trifluoromethylindole-2-carboxylic acid tert-butyl ester 5D (1.78 g, 4.10 mmol) in anhydrous toluene (40 mL) was added triphosgene (0.42 g, 1.41 mmol) and triethylamine (0.83 g, 8.22 mmol). The reaction mixture was heated under reflux for 2 hours. Toluene (50 mL) was added and the organic layer was washed with water and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure to provide 1-benzyloxycarbonyl-3-isocyanato-5-trifluoromethylindole-2-carboxylic acid tert-butyl ester 5E which was used in the next step without further purification.
Reaction SMILES: [CH:1]1[C:15]2=[C:16]3[C:7](=[C:8]([CH:17]=[O:18])[C:9]4[C:14]2=[CH:13][CH:12]=[CH:11][CH:10]=4)[CH2:6][CH2:5][C:4]3=[CH:3][CH:2]=1>C1(C)C=CC=CC=1.CCCCCC>[CH:1]1[C:15]2=[C:16]3[C:7](=[C:8]([CH:17]=[O:18])[C:9]4[C:14]2=[CH:13][CH:12]=[CH:11][CH:10]=4)[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1
Reactant: O=Cc1c2c3c(cccc3c3ccccc13)CC2
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: O=Cc1c2c3c(cccc3c3ccccc13)C=C2
Yield: 35.8 %

Procedure:
Using the dehydrogenation procedure outlined in Example 7B, 4,5-dihydro-acephenanthrylene-6-carbaldehyde (J. P. Hoeffinger, P. Jacquignon, and N. P. Buu-Hoi, Bull. Soc. Chim. Fr. 974 (1970)) gave a 35.8% yield of 6-acephenanthrylenecarbaldehyde, mp 161°-163° (dec), (C, H), (PhCH3 /hexane).
Reaction SMILES: [C:1](OC(=NC(C)C)NC(C)C)([CH3:4])([CH3:3])[CH3:2].Cl.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]2[C:29]([C:30]([OH:32])=[O:31])=[CH:28][N:27]=[C:26]([Cl:33])[CH:25]=2)=[C:19]([Cl:34])[CH:18]=1>C1COCC1.CCOC(C)=O>[C:1]([O:31][C:30](=[O:32])[C:29]1[C:24]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([Br:16])=[CH:18][C:19]=2[Cl:34])=[CH:25][C:26]([Cl:33])=[N:27][CH:28]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)c1cnc(Cl)cc1Nc1ccc(Br)cc1Cl
Reactant: CC(C)N=C(NC(C)C)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cnc(Cl)cc1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 107.3 %

Procedure:
2-tert-Butyl-1,3-diisopropylisourea (8.04 g, 40.1 mmol) was added to a mixture of 4-(4-bromo-2-chlorophenylamino)-6-chloronicotinic acid hydrochloride salt (24) (2.91 g, 7.31 mmol) in THF (165 mL). After stirring for 2 hours at room temperature and 30 minutes at reflux, the reaction mixture was cooled to room temperature and diluted with EtOAc. The organic layer was washed with 10% K2CO3 and brine, dried (Na2SO4) and concentrated. The resulting residue was dissolved in CH2Cl2 and filtered. The filtrate was concentrated and purified by flash column chromatography using the Biotage system (CH2Cl2) to give the desired product (40) (3.28 g, 78%).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([OH:13])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1.C1C=CC=CC=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O>O>[ClH:11].[Cl:12][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[Cl:11])[CH:4]([OH:13])[CH2:3][NH:2][CH2:25][C:24]1[CH:27]=[CH:28][CH:29]=[C:22]([O:21][CH3:20])[CH:23]=1
Reactant: COc1cccc(C=O)c1
Reactant: NCC(O)c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: O
Solvent: c1ccccc1
Product: COc1cccc(CNCC(O)c2ccc(Cl)c(Cl)c2)c1

Procedure:
The free base obtained from 70.0 g. of rac.-α-(aminomethyl)-3,4-dichlorobenzyl alcohol hydrochloride is heated at reflux in 1 l. of benzene with 40.8 g. of 3-methoxybenzaldehyde using a water-separator for 2 hours until no more water is released. After concentration and dissolving in 1 l. of methanol, the product is reduced with 30 g. of sodium borohydride below 5°, evaporated and extracted with methylene chloride and water. The methylene chloride extract, acidified with ethanolic hydrogen chloride, crystallizes with ethyl acetate and, after recrystallization from methanol-ether, yields rac.-3,4-dichloro-α-{[(3-methoxybenzyl)amino]methyl}benzyl alcohol hydrochloride, m.p. 198°-200°. The free base recrystallized from methanol-petroleum ether has a m.p. of 94°-95°.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[O:14])[CH2:9][CH:8]2[CH2:24][CH:25]=[O:26])=[CH:4][CH:3]=1.[CH3:29][Mg]Br.[NH4+].[Cl-]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[O:14])[CH2:9][CH:8]2[CH2:24][CH:25]([OH:26])[CH3:29])=[CH:27][CH:28]=1
Reactant: O=CCC1CN(C(=O)COc2ccc(Cl)cc2)CCN1Cc1ccc(F)cc1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)CC1CN(C(=O)COc2ccc(Cl)cc2)CCN1Cc1ccc(F)cc1
Yield: 89.5 %

Procedure:
To a solution of 4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-3-((formyl)methyl)piperazine (0.31 g, 0.77 mmol) in anhydrous THF (20 mL) was added methyl magnesium bromide (0.26 mL, 0.77 mmol, 3.0 M solution in ether). The resultant mixture was stirred overnight at ambient temperature. At that time the mixture was poured into 5% aqueous NH4Cl solution and extracted with two portions of ether. The combined organic extracts were washed with brine, then dried over MgSO4, filtered and concentrated in vacuo to afford a yellow oil. Purification by flash column chromatography on silica gel afforded 0.29 g of 4-(4-fluorobenzyl)-1-((4-chlorophenoxy)methyl)carbonyl-3-(2-hydroxypropyl)piperazine, as a clear, colorless oil, which was converted to its hydrochloride salt; NMR (CDCl3) 7.6 (m, 2), 7.2 (m, 4), 6.9 (m, 2), 4.7 (m, 2), 4.4-3.0 (m, 10), 2.4-1.4 (m, 2), 1.3-1.0 (m, 3) ppm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH2:4][N:5](S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)[CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].C1(S)C=CC=CC=1.C(OCC)(=O)C>C(#N)C>[CH3:1][O:2][C:3](=[O:37])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([C:13]2[CH:14]=[C:15]([O:23][CH3:24])[C:16]([O:21][CH3:22])=[C:17]([O:19][CH3:20])[CH:18]=2)[CH:8]=1
Reactant: COC(=O)CN(Cc1ccnc(-c2cc(OC)c(OC)c(OC)c2)c1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)CNCc1ccnc(-c2cc(OC)c(OC)c(OC)c2)c1

Procedure:
N-(2-Nitrobenzenesulfonyl)-N-[[2-(3,4,5-trimethoxy-phenyl)pyridin-4-yl]methyl]glycine methyl ester (11.35 g) was dissolved in acetonitrile (30 mL), and to the solution potassium carbonate (3.39 g) was added. Thiophenol (2.37 g) was then added to the mixture, and the resultant mixture was stirred overnight at room temperature. Ethyl acetate was added to the reaction mixture, and the resultant mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate, water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was then purified by column chromatography on silica gel (chloroform:methanol=20:1) to obtain the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([C:10]([CH3:13])([CH3:12])[CH3:11])=[N:5][N:6]([CH2:8]Cl)[CH:7]=1.[F:14][C:15]([F:24])([F:23])[CH2:16][CH2:17][CH:18]([C:21]#[N:22])[C:19]#[N:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:2][C:3]1[C:4]([C:10]([CH3:13])([CH3:12])[CH3:11])=[N:5][N:6]([CH2:8][C:18]([CH2:17][CH2:16][C:15]([F:14])([F:23])[F:24])([C:19]#[N:20])[C:21]#[N:22])[CH:7]=1
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: CC(C)(C)c1nn(CCl)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1nn(CC(C#N)(C#N)CCC(F)(F)F)cc1Cl
Yield: 30 %

Procedure:
0.98 g of 4-chloro-3-t-butyl-1-(chloromethyl)-1H-pyrazole hydrochloride and 0.65 g of (3,3,3-trifluoropropyl) malononitrile were dissolved in 12 ml of N,N-dimethylformamide. 1.11 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.40 g of [(4-chloro-3-t-butyl-1H-pyrazole-1-yl)methyl](3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (13), hereinafter) shown by below formula.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[NH:13]1[CH:17]=[CH:16][N:15]=[CH:14]1>O1CCOCC1>[N:13]1([CH2:2][CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: c1c[nH]cn1
Reactant: BrCCc1c[nH]c2ccccc12
Solvent: C1COCCO1
Product: c1ccc2c(CCn3ccnc3)c[nH]c2c1

Procedure:
A solution of 3-(2-bromo-ethyl)-1H-indole (1.12 g, 5 mmol) and imidazole (0.68 g, 10 mmol) in abs. dioxane (10 ml) was stirred at 80° C. for 4 h until according to TLC educt was no longer present. The solvent was then removed i. vac., CHCl3 (100 ml) was added to the residue and the mixture was washed twice with water. The organic phase was dried over Na2SO4 and concentrated i. vac. and the residue which remained was purified by flash chromatography with CHCl3/MeOH (20:1). Yield: 507 mg (Ind-71, 48%), colourless solid
Reaction SMILES: C([O:3][C:4]1[CH2:13][C:12]2[C:11]([NH2:14])=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6][CH:5]=1)C.Cl.C(=O)(O)[O-].[Na+]>O1CCCC1>[NH2:14][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[CH2:13][C:4](=[O:3])[CH2:5][CH2:6]2
Reactant: CCOC1=CCc2cccc(N)c2C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1cccc2c1CC(=O)CC2
Temperature: 40 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a stirred solution of 7-ethoxy-5,8-dihydronaphthalen-1-ylamine (1.07 g, 5.65 mmol) in tetrahydrofuran (30 mL) was added solution of aqueous 2N HCl (10 mL), and stirred at 40° C. for 1 hour. The mixture was neutralized with addition of sodium bicarbonate, and the product was extracted with ethyl acetate. The organic layer was washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 8-amino-3,4-dihydro-1H-naphthalen-2-one (0.71 g, 78% yield).
Reaction SMILES: [CH2:1]([S:7]([NH2:10])(=[O:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-].[Na+].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1.Cl>CC(C)=O>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:10][S:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])(=[O:9])=[O:8])=[O:22])=[CH:16][CH:15]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CCCCCCS(N)(=O)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCCCCCS(=O)(=O)NC(=O)Nc1ccc(Cl)cc1
Reaction time: 3 h
Yield: 87.6 %

Procedure:
The general method of procedure A was followed with hexanesulfonamide (10 g), acetone (200 ml), 1N sodium hydroxide (60 ml), and 4-chlorophenyl isocyanate (8.8 g) in acetone (50 ml). After three hours of stirring, 1N HCl (60 ml) was added followed by removal of acetone and collection of solid from the water. The solid was washed with water and dried at 65° C. under vacuum to provide 16 g of product.
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:27])[CH2:15][S:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[CH:19][CH:18]=3)=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[C:35](Cl)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]>CC(C)=O>[C:35]([N:5]1[CH2:6][CH2:7][N:2]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:27])[CH2:15][S:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[CH:19][CH:18]=3)=[CH:10][CH:9]=2)[CH2:3][CH2:4]1)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]
Reactant: O=C(CSc1ccnc2ccccc12)c1ccc(N2CCNCC2)cc1
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(C)(C)C(=O)N1CCN(c2ccc(C(=O)CSc3ccnc4ccccc34)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.9 %

Procedure:
4-[2-[4-(1-Piperazinyl)phenyl]-2-oxoethylthio]-quinoline hydrochloride (Compound 51; 2.20 g, 4.66 mmol) was suspended in dry acetone (300 ml). Triethylamine (6.60 ml, 47.2 mmol) was added at -15° C. to the suspension and, after 30 minutes, pivaloylchloride (1.25 ml, 10.0 mmol) was added dropwise to the suspension. The reaction mixture was stirred at room temperature overnight and the solvent was removed under reduced pressure. The residue was chromatographed by silica gel chromatography (dichloromethane:methanol=20:1) to obtain 1.50 g of the titled compound (72.0%).
Reaction SMILES: [CH:1]([C@@H:3]1[CH:20]2[C@:15]([CH3:22])([CH2:16][CH2:17][C:18](=[O:21])[CH2:19]2)[C@@H:14]2[C@H:5]([C@H:6]3[C@@:10]([CH2:12][CH2:13]2)([CH3:11])[C:9](=[O:23])[CH2:8][CH2:7]3)[CH2:4]1)=[O:2].[O-:24][Mn](=O)(=O)=O.[K+]>>[C:1]([C@@H:3]1[CH:20]2[C@:15]([CH3:22])([CH2:16][CH2:17][C:18](=[O:21])[CH2:19]2)[C@@H:14]2[C@H:5]([C@H:6]3[C@@:10]([CH2:12][CH2:13]2)([CH3:11])[C:9](=[O:23])[CH2:8][CH2:7]3)[CH2:4]1)([OH:24])=[O:2]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: C[C@]12CCC(=O)CC1[C@@H](C=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [K+]
Product: C[C@]12CCC(=O)CC1[C@@H](C(=O)O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 0.08 h
Yield: 96 %

Procedure:
To a stirred suspension of 6α-formylandrostane-3,17-dione (1.77 g) in t-ButOH (35 mL) and 5% aqueous Na2HPO4 solution (21.5 mL), 1N aqueous KMnO4 (35 mL) was added. After 5 minutes at room temperature, the mixture was quenched by addition of 40% aqueous NaHSO3 solution. The suspension was filtered, washed with H2O and the filtrate was freeze-dried. The residue was taken up with H2O (50 mL) and extracted with EtOAc (4×70 mL). The combined organic extracts were dried over Na2SO4 and evaporated to dryness to give 6α-carboxyandrostane-3,17-dione (1.80 g, 96%). 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 11.99 (1H, bb), 2.46-0.73 (21H, m), 1.01 (3H, s), 0.79 (3H, s).
Reaction SMILES: C(O[C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[CH:12][C:13]#[N:14])=[O:5])C.Br.N[CH2:17][CH2:18][CH2:19][SH:20].C([O-])(=O)C.[Na+]>ClC1C=CC=CC=1Cl>[O:5]=[C:4]1[C:6]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:12]=[C:13]2[S:20][CH2:19][CH2:18][CH2:17][N:14]12
Reactant: CCOC(=O)C1CCCCC1=CC#N
Reactant: NCCCS
Agent: Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: Clc1ccccc1Cl
Product: O=c1c2c(cc3n1CCCS3)CCCC2

Procedure:
To 15 ml. of o-dichlorobenzene were added 5.8 g. of 2-cyanomethylene-cyclohexane-carboxylic acid ethyl ester, 6.5 g. of 3-aminopropanethiol hydrobromide and 3.1 g. of sodium acetate. Then, by treating the mixture as in Example 95, 800 mg. of 6-oxo-3,4,7,8,9,10-hexahydro-2H,6H-1,3-thiazino[3,2-b]isoquinoline was obtained.
Reaction SMILES: COC(=O)[O-].[CH3:6][N+:7]1(C)[CH2:11][CH2:10][CH2:9][CH2:8]1.[H+].[B-:14]([F:18])([F:17])([F:16])[F:15]>>[CH3:6][N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.[F:15][B-:14]([F:18])([F:17])[F:16]
Reactant: C[N+]1(C)CCCC1
Agent: COC(=O)[O-]
Agent: F[B-](F)(F)F
Agent: [H+]
Product: CN1CCCC1

Procedure:
By following the same procedure (2nd step) of Example 1 except that 10.0 g of N,N-dimethylpyrrolidinium methyl carbonate thus obtained and 12.9 g of an aqueous solution of 42% HBF4 were used, 10.1 g (yield of 92.4% to N-methylpyrrolidine) of high-pure dimthylpyrrolidinium tetrafluoroborate was obtained.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7](Cl)=[O:8])=[CH:3][CH:2]=1.Cl.[CH3:12][NH:13][O:14][CH3:15].N1C=CC=CC=1>ClCCl>[CH3:15][O:14][N:13]([CH3:12])[C:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=1)=[O:8]
Reactant: CNOC
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
To a solution of 10.00 g of p-toluoyl chloride in 300 ml of dichloromethane, 6.94 g of N,O-dimethylhydroxyamine hydrochloride was added. The reaction solution was ice-cooled and 11.5 ml of pyridine was added dropwise. After the completion of dropwise addition, the mixture was stirred at room temperature for one hour and the solvent was evaporated under reduced pressure. The residue was combined with water, extracted with diethyl ether and then washed in turn with 10% hydrochloric acid, water and an aqueous saturated sodium hydrogen carbonate solution. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure to obtain 10.40 g of the desired compound as a colorless oily substance.
Reaction SMILES: [CH3:1][CH:2]([CH3:10])[C:3](=O)[C:4]([O:6]CC)=O.[F:11][C:12]1[CH:31]=[CH:30][CH:29]=[CH:28][C:13]=1[CH2:14][N:15]1[C:19]2=[N:20][CH:21]=N[CH:23]=[C:18]2[C:17]([C:24](=[NH:27])[NH:25][NH2:26])=[N:16]1.[CH2:32](O)C>>[F:11][C:12]1[CH:31]=[CH:30][CH:29]=[CH:28][C:13]=1[CH2:14][N:15]1[C:19]2=[N:20][CH:21]=[CH:32][CH:23]=[C:18]2[C:17]([C:24]2[N:25]=[N:26][C:3]([CH:2]([CH3:1])[CH3:10])=[C:4]([OH:6])[N:27]=2)=[N:16]1
Reactant: N=C(NN)c1nn(Cc2ccccc2F)c2ncncc12
Reactant: CCO
Reactant: CCOC(=O)C(=O)C(C)C
Product: CC(C)c1nnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1O

Procedure:
1.014 g (7.035 mmol) of ethyl 3-methyl-2-oxobutanoate in 15 ml of ethanol were initially introduced and heated to reflux. Then, 2.000 g (7.035 mmol) of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboximidohydrazide suspended in 20 ml of ethanol were added and the mixture was heated under reflux overnight. After cooling, the mixture was filtered off with suction, and the filtercake was washed with a little ethanol and dried under high vacuum. This gave 918 mg of the target compound (36% of theory).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[O:25][CH2:26][CH2:27][S:28][CH3:29])(=[O:5])[CH2:2][CH2:3][CH3:4].[OH2:30].Cl[O-].[Na+].[CH2:34](Cl)Cl>>[CH:26]([O:25][CH:10]([CH3:9])[CH3:11])([CH3:27])[CH3:34].[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[O:25][CH2:26][CH2:27][S:28]([CH3:29])=[O:30])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: ClCCl
Reactant: O
Reactant: CCCC(=O)c1cnc2c(OCCSC)cccc2c1Nc1ccc(C)cc1C
Agent: [Na+]
Agent: [O-]Cl
Product: CC(C)OC(C)C
Product: CCCC(=O)c1cnc2c(OCCS(C)=O)cccc2c1Nc1ccc(C)cc1C
Reaction time: 2 h
Yield: 91 %

Procedure:
3-butyryl-4-(2,4-dimethylphenylamino)-8-(2-methylthioethoxy)quinoline (0.34 g, 0.83 mmol) was dissolved in methylene chloride (4 ml). Water (2 ml) and sodium hypochlorite (5% in water) (1.39 ml) were added and the mixture was stirred for 2 h. Another portion of sodium hypochlorite (0.5 ml) was added and the stirring was continued for 2 h. The organic layer was dried over sodium sulfate and evaporated. Trituration with isopropyl ether gave 0.32 g (91%) of the title compound.