Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][N:16]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[Cl:37])[C:17]([CH:19]1[C:24](=O)[C@@:23]2([CH3:29])[C:26]([CH3:28])([CH3:27])[C@@H:20]1[CH2:21][CH2:22]2)=[O:18])=O)(C)(C)C>ClCCl>[Cl:37][C:31]1[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:30]=1[N:16]1[C:17](=[O:18])[C:19]2[C@@H:20]3[C:26]([CH3:27])([CH3:28])[C@@:23]([CH3:29])([CH2:22][CH2:21]3)[C:24]=2[NH:15]1
Reactant: CC(C)(C)OC(=O)NN(C(=O)C1C(=O)[C@]2(C)CC[C@H]1C2(C)C)c1ccc(F)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(F)cc3Cl)c(=O)c12
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Trifluoroacetic acid (50 mL) was added in two portions to a cooled (0° C.) solution of N′-(2-chloro-4-fluoro-phenyl)-N′-((1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl)-hydrazinecarboxylic acid tert-butyl ester (14.8 g, 33.7 mmol) in dichloromethane (50 mL). The mixture was stirred at 0° C. for 5 min and then the cooling bath was removed and the reaction mixture was allowed to warm to room temperature and stir for 4 h. Volatiles were evaporated under reduced pressure and dichloromethane (250 mL) was added. The solution was washed with water (4×125 mL), and brine (125 mL), dried (magnesium sulfate), filtered, and evaporated. The flask containing the product was covered in foil and the solid was dried overnight under high vacuum to give (4S,7R)-2-(2-chloro-4-fluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (11.4 g, 105% of the expected amount). This material was used in subsequent reactions without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][C:27](O)=[O:28])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.CN(C=O)C>C1COCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:12][CH2:13][CH:14]([C:17]3[CH:18]=[CH:19][C:20]4[CH2:23][CH2:24][CH2:25][CH2:26][C:27](=[O:28])[C:21]=4[CH:22]=3)[CH2:15][CH2:16]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCC(c3ccc(CCCCC(=O)O)cc3)CC2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2CCC(c3ccc4c(c3)C(=O)CCCC4)CC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.9 %

Procedure:
To a solution of 5-[4-[1-(4-methylphenylsulfonyl)piperidin-4-yl]phenyl]pentanoic acid (0.50 g) in THF (10 ml) were added at room temperature oxalyl chloride (0.21 ml) and a drop of DMF, and the mixture was stirred for 1 hour. Under reduced pressure, the mixture was concentrated, and the residue was dissolved in dichloromethane (10 ml). To the mixture was added at 0° C. aluminum chloride (0.35 g), and the mixture was stirred at 0° C. for 30 minutes and then at room temperature for 5 minutes. The mixture was added to ice/water, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, saturated sodium bicarbonate solution and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated, and the residue was purified with column chromatography (ethyl acetate/hexane=1:2) to give colorless crystals of 3-[1-(4-methylphenylsulfonyl)piperidin-4-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one (0.32 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@H:22]4[NH:27]C(=O)OC(C)(C)C)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].Cl>O1CCOCC1>[NH2:27][C@H:22]1[C:23]2[C:19](=[C:18]([C:15]3[N:14]=[C:13]([C:5]4[CH:6]=[CH:7][C:8]([O:9][CH:10]([CH3:12])[CH3:11])=[C:3]([CH:4]=4)[C:1]#[N:2])[O:17][N:16]=3)[CH:26]=[CH:25][CH:24]=2)[CH2:20][CH2:21]1
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4NC(=O)OC(C)(C)C)no2)cc1C#N
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4N)no2)cc1C#N
Temperature: 55 °C
Yield: 80.9 %

Procedure:
To (R)-tert-butyl 4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-ylcarbamate (12.8 g, 27.8 mmol) in dioxane (200 mL) was added 4N HCl in dioxane (69 mL). The solution was heated to 55° C. for 1 h, and product precipitated. Dioxane was removed and the resulting solid suspended in ether and collected. The material was recrystallized from MeOH (200 mL) to produce 8.11 g (81%) of (R)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 49 as the HCl salt. LCMS-ESI (m/z): calcd for: C21H20N4O2: 360.4; found 383.2 [M+Na]+, tR=2.49 min. Elemental Analysis and NMR spectra determined for C21H21N4O2Cl*0.5H2O; C calculated=62.14%; found=62.25%. H calculated=5.46%; found=5.30%. N calculated=13.80%; found=13.84%. Cl calculated=8.73%; found=8.34%. 1H NMR (400 MHz, DMSO) δ 8.71 (s, 3H), 8.49 (d, J=2.3, 1H), 8.39 (dd, J=9.0, 2.3, 1H), 8.11 (d, J=7.6, 1H), 7.91 (d, J=7.6, 1H), 7.55 (t, J=8.5, 2H), 4.97 (hept, J=6.1, 1H), 4.80 (s, 1H), 3.47 (ddd, J=17.4, 8.7, 5.3, 1H), 3.23 (ddd, J=17.4, 8.6, 6.4, 1H), 2.55 (ddd, J=13.7, 8.3, 3.2, 1H), 2.22-1.97 (m, 1H), 1.38 (d, J=6.0, 6H). 13C NMR (101 MHz, CDCl3) δ 173.28, 167.98, 162.53, 143.69, 141.29, 134.59, 133.80, 128.93, 128.11, 127.55, 122.72, 115.87, 115.24, 114.91, 102.46, 72.54, 54.38, 31.51, 29.91, 21.47. Chiral HPLC of the free base: (R)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxy benzonitrile was eluted using 15% i-PrOH in hexanes plus 0.3% DEA: >99.9% ee, tR=30.80 min. (S)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxy-benzonitrile 50 was prepared in an analogous fashion from (S)-tert-butyl 4-cyano-2,3-dihydro-1H-inden-1-ylcarbamate: >99.9% ee, tR for (S)-enantiomer=28.58 min.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH2:15]([O:22][C:23](=[O:36])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:37]([O:41][C:42](=[O:47])[NH:43][CH2:44][CH2:45]O)([CH3:40])([CH3:39])[CH3:38]>C1COCC1>[CH2:15]([O:22][C:23](=[O:36])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:45][CH2:44][NH:43][C:42]([O:41][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:47])=[CH:31][CH:30]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(NCCCCc1ccc(O)cc1)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCOc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
Diisopropylazodicarboxylate (132 mL) was added dropwise over 45 minutes to a stirring mixture of [4-(4-hydroxyphenyl)butyl]carbamic acid benzyl ester (50 g, 0.167 mol), (2-hydroxyethyl)carbamic acid tert-butyl ester (103.4 mL, 0.668 mol), and THF (150 mL) with ice-methanol bath cooling from 15 to 35° C. When the exothermic reaction ceased, the cooling bath was removed, and the reaction was allowed to stir at room temperature overnight. The solvent was evaporated at reduced pressure, and the residue was applied to a 1 kg column of silica gel and eluted with methylene chloride. The chromatography was repeated twice. The residue after evaporation was washed with hexanes (1.5 L), and the resulting solid was re-crystallized from a mixture of hexanes and methylene chloride (4:1, 1 L) to afford 54 g (73%) of the pure product as a white solid. A second crop yielded an additional 10 g (13%) of the product. 1H NMR (300 MHz, CDCl3) δ 1.45 (s, 9H), 1.56 (m, 4H), 2.56 (t, 2H), 3.20 (m, 2H), 3.50 (m, 2H), 3.98 (t, 2H), 4.75 (br s, 1H), 5.00 (br s, 1H), 5.09 (s, 2H), 6.80 (d, 2H), 7.06 (d, 2H), 7.34 (m, 5H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][NH:6][C:7]1[CH:12]=[C:11](F)[C:10]([Br:14])=[CH:9][C:8]=1[N+:15]([O-:17])=[O:16])[CH3:2].[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[C:10]([Br:14])=[CH:9][C:8]=1[N+:15]([O-:17])=[O:16])[CH3:2]
Reactant: CCOC(=O)CNc1cc(F)c(Br)cc1[N+](=O)[O-]
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1cc(-n2ccnc2)c(Br)cc1[N+](=O)[O-]
Yield: 90.3 %

Procedure:
1.33 (3H, t, J=7.4 Hz), 4.04 (2H, d, J=4.9 Hz), 4.30 (2H, q, J=7.4 Hz), 6.46 (1H, d, J=10.9 Hz), 8.44 (1H, d, J=7.3 Hz), 8.49 (1H, bs). 2) By using 3.36 g (10.5 mmol) of N-(4-bromo-5-fluoro-2-nitrophenyl)glycine ethyl ester, 2.86 g of imidazole and 20 ml of DMF, 3.50 g (90%) of N-[4-bromo-5-(1H-imidazol-1-yl)-2-nitrophenyl]glycine ethyl ester was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19](=O)[C:20]([F:23])([F:22])[F:21])[C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=O)=[CH:4][CH:3]=1.[NH2:25][NH2:26].O>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:11]3[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=3)=[N:25][NH:26][C:19]=2[C:20]([F:23])([F:22])[F:21])=[CH:4][CH:3]=1
Reactant: CSc1ccc(C(=O)C(C(=O)C(F)(F)F)c2ccc(F)cc2)cc1
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: CSc1ccc(-c2n[nH]c(C(F)(F)F)c2-c2ccc(F)cc2)cc1
Reaction time: 18 h
Yield: 89 %

Procedure:
Crude 2-(4-fluorophenyl)-1-[4-(methylthio)phenyl]-4,4,4-trifluoro-1,3-butanedione (Example 3, Step 2) (1.0 g) was reacted with anhydrous hydrazine (0.13 g) in glacial acetic acid. The mixture was held at 80°-110° C. for 18 hours and poured into water. The resulting solid precipitate was filtered, purified by HPLC and recrystallized from methylene chloride-hexane to give 4-(4-fluorophenyl)-3-[4-(methylthio)phenyl]-5-(trifluoromethyl)-1H-pyrazole as a solid (0.88 g, 89%): mp 189°-190° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][CH:13]=[CH:12]2.[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[S:28](Cl)(=[O:30])=[O:29]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:28]([C:22]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=2[F:20])(=[O:30])=[O:29])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][CH:13]=[CH:12]2
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Reactant: Nc1cnc(Oc2ccc3ncccc3c2)c(Cl)c1
Product: O=S(=O)(Nc1cnc(Oc2ccc3ncccc3c2)c(Cl)c1)c1ccc(F)cc1F

Procedure:
The title compound was prepared by reacting 5-chloro-6-(quinolin-6-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 3) and 2,4-difluorobenzene-1-sulfonyl chloride.
Reaction SMILES: [Na].Br[C:3]1[N:4]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[C:5]2[C:10]([N:11]=1)=[C:9]([NH2:12])[N:8]=[C:7]([O:13][CH2:14][CH2:15][O:16][CH:17]([CH3:19])[CH3:18])[N:6]=2.[CH3:26][OH:27]>>[CH3:18][CH:17]([O:16][CH2:15][CH2:14][O:13][C:7]1[N:6]=[C:5]2[C:10]([N:11]=[C:3]([O:27][CH3:26])[N:4]2[CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)=[C:9]([NH2:12])[N:8]=1)[CH3:19]
Reactant: CC(C)OCCOc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Reactant: CO
Agent: [Na]
Product: COc1nc2c(N)nc(OCCOC(C)C)nc2n1C1CCCCO1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To methanol (120 ml) was added sodium (0.966 g). When the metal was dissolved, 8-bromo-2-({2-[(1-methylethyl)oxy]ethyl}oxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (5.69 g, 21.2 mmol) was added, heated to reflux and the solution stirred for 16 h, cooled to room temperature. The solvent was removed. Extracted with ethyl acetate after adding water, dried and concentrated to give the crude product which was purified through silica gel eluting with 2:1 ethyl acetate:petroleum ether to give the title compound (4.8 g).
Reaction SMILES: Cl[CH2:2][C:3]([C:6]1[N:10]([CH2:11][CH3:12])[C:9]2[CH:13]=[C:14]([Cl:18])[C:15]([Cl:17])=[CH:16][C:8]=2[N:7]=1)([OH:5])[CH3:4].[CH2:19]([SH:21])[CH3:20].C[O-].[Na+]>CO>[Cl:17][C:15]1[C:14]([Cl:18])=[CH:13][C:9]2[N:10]([CH2:11][CH3:12])[C:6]([C:3]([OH:5])([CH3:4])[CH2:2][S:21][CH2:19][CH3:20])=[N:7][C:8]=2[CH:16]=1
Reactant: CCn1c(C(C)(O)CCl)nc2cc(Cl)c(Cl)cc21
Reactant: CCS
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCSCC(C)(O)c1nc2cc(Cl)c(Cl)cc2n1CC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1-chloro-2-(5,6-dichloro-1-ethyl-1H-benzoimidazol-2-yl)-propan-2-ol (161 mg) in methanol (5 mL) at room temperature was added a solution of ethanethiol (37 mg) and sodium methoxide (0.144 mls of 25 wt % in MeOH). The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with NH4Cl (aq), extracted with EtOAc, and dried over Na2SO4. The crude product was purified by flash chromatography (10%-40% EtOAc/hexanes) to yield the title compound as an off-white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[C:7]([CH2:9][OH:10])[CH:8]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+].[CH3:20][O:21][C:22](=[O:27])[CH2:23][CH2:24][CH2:25]Br>C1COCC1>[CH3:20][O:21][C:22](=[O:27])[CH2:23][CH2:24][CH2:25][O:11][C:5]1[CH:4]=[C:3]([CH2:2][OH:1])[CH:8]=[C:7]([CH2:9][OH:10])[CH:6]=1
Reactant: OCc1cc(O)cc(CO)c1
Reactant: COC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)CCCOc1cc(CO)cc(CO)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 3,5-bis-hydroxymethylphenol (Felder, D.; Gutiérrez Nava, M.; del Pilar Carreon, M.; Eckert, J. F.; Luccisano, M.; Schell, C.; Masson, P.; Gallani, J. L.; Heinrich, B.; Guillon, D.; Nierengarten, J. F. Helv. Chimica Acta 2002, 85, 288) (200 mg), potassium iodide (50 mg) and potassium carbonate (540 mg) in THF (2.5 mL) was added 4-bromo-butyric acid methyl ester (400 μL). The reaction mixture was stirred for 20 h at room temperature then the unsoluble part was filtered off. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography (Merck SuperVarioFlash 30 g column, Si60 15-40 μm), using gradient elution with a mixture of MeOH (A)/DMC (B), (gradient: 100% B down to 5% A: 95% B) to give 4-(3,5-bis-hydroxymethyl-phenoxy)-butyric acid methyl ester (53.5 mg): LC/MS (Method A2: ES: m/z=255 MH+; m/z=237 (M+H−H2O)+; RT=2.5 min; 1H N.M.R. (400 MHz, DMSO-d6, δ in ppm): δ=1.96 (m, 2H); 2.47 (t, J=6.5 Hz, 2H); 3.61 (s, 3H); 3.96 (t, J=6.5 Hz, 2H); 4.43 (d, J=6.0 Hz, 4H); 5.11 (t, J=6.0 Hz, 2H); 6.71 (s, 2H); 6.82 (s, 1H).
Reaction SMILES: [OH:1][C@:2]1([C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32])[C@:18]2([CH3:19])[C@H:5]([C@H:6]3[C:15]([C@@H:16]([C:20]4[CH:25]=[CH:24][C:23]([CH:26]([OH:28])[CH3:27])=[CH:22][CH:21]=4)[CH2:17]2)=[C:14]2[C:9](=[CH:10][C:11](=[O:29])[CH2:12][CH2:13]2)[CH2:8][CH2:7]3)[CH2:4][CH2:3]1.[C:37]([O:41][C:42]([N:44]1[CH2:48][CH2:47][CH2:46][C@H:45]1[C:49](O)=[O:50])=[O:43])([CH3:40])([CH3:39])[CH3:38]>>[OH:1][C@:2]1([C:30]([F:35])([F:36])[C:31]([F:32])([F:33])[F:34])[C@:18]2([CH3:19])[C@H:5]([C@H:6]3[C:15]([C@@H:16]([C:20]4[CH:21]=[CH:22][C:23]([CH:26]([O:28][C:49]([C@@H:45]5[CH2:46][CH2:47][CH2:48][N:44]5[C:42]([O:41][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:43])=[O:50])[CH3:27])=[CH:24][CH:25]=4)[CH2:17]2)=[C:14]2[C:9](=[CH:10][C:11](=[O:29])[CH2:12][CH2:13]2)[CH2:8][CH2:7]3)[CH2:4][CH2:3]1
Reactant: CC(O)c1ccc([C@H]2C[C@@]3(C)[C@@H](CC[C@@]3(O)C(F)(F)C(F)(F)F)[C@@H]3CCC4=CC(=O)CCC4=C32)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Product: CC(OC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)c1ccc([C@H]2C[C@@]3(C)[C@@H](CC[C@@]3(O)C(F)(F)C(F)(F)F)[C@@H]3CCC4=CC(=O)CCC4=C32)cc1
Yield: 78 %

Procedure:
In analogy to Example 5, 330 mg (0.65 mmol) of (8S,11R,13S,14S,17S)-17-hydroxy-11-[4-((RS)-1-hydroxyethyl)phenyl]-13-methyl-17-pentafluoroethyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one were converted using (S)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester and, after workup and purification, 356 mg (78%) of the title compounds were isolated as a colourless foam.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9]N)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[C:17](=O)[CH2:16][CH2:15]2>C(O)C.C(O)(=O)C>[F:11][C:12]1[CH:13]=[C:14]2[C:18]([CH2:17][C:16]3[C:3]4[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][C:4]=4[NH:9][C:15]=32)=[CH:19][CH:20]=1
Reactant: Cc1cc(C)cc(NN)c1
Reactant: O=C1CCc2cc(F)ccc21
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cc(C)c2c3c([nH]c2c1)-c1cc(F)ccc1C3
Temperature: 85 °C

Procedure:
To a solution of 3,5-dimethylphenylhydrazine (2.54 g, 14.7 mmol) and 5-fluoro-1-indanone (2.21 g, 14.7 mmol) in ethanol (24 mL) was added glacial acetic acid (3 drops). The solution was stirred at reflux (85° C.) for 15 minutes and cooled to room temperature. Ethanol was removed in vacuo and the resulting orange solid was dissolved in isopropanol (24 mL). Sulfuric acid (36N, 1.65 mL) was added via syringe and the mixture was stirred at reflux (90° C.) for 17 hours and subsequently cooled to room temperature. The solution was basified to pH 10 via addition of aqueous sodium hydroxide (2% by mass) resulting in the formation of a precipitate. The solid was collected by vacuum filtration to yield 47b in 76% crude yield (2.80 g, 11.2 mmol). Crude product was brought on to the next step without further purification. 1H NMR (400 MHz, CDCl3): δ 8.12 (s, 1H), 7.32-7.35 (dd, 1H, J=8.2, 5.2 Hz), 0.24-7.26 (m, 1H), 7.01-7.05 (m, 2H), 6.79 (s, 1H), 3.83 (s, 2H), 2.60 (s, 3H), 2.44 (s, 3H); 13C NMR (150 MHz, CDCl3): δ 160.7 (d, J=361.5), 150.0 (d, J=12.0 Hz), 140.9, 140.6, 131.8, 131.2, 128.9, 122.6, 122.3, 121.6 (d, J=4.5 Hz), 117.2 (d, J=13.5 Hz), 113.4 (d, J=25.5 Hz), 113.1 (d, J=25.5 Hz), 109.6, 31.7 (d, J=3.0 Hz), 21.8, 19.3; 19F NMR (CD3CD, 376 MHz): δ −117.9 (m).
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[N:3]=1.[CH3:20][N:21]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[O:9]([CH2:8][CH2:7][N:6]1[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[N:3]=[C:2]1[N:24]1[CH2:25][CH2:26][CH2:27][N:21]([CH3:20])[CH2:22][CH2:23]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CN1CCCNCC1
Reactant: Clc1nc2ccccc2n1CCOc1ccccc1
Agent: O=C(O)/C=C/C(=O)O
Product: CN1CCCN(c2nc3ccccc3n2CCOc2ccccc2)CC1
Yield: 52.6 %

Procedure:
In the same manner as described in Example 1 using 2-chloro-1-[2-(phenoxy)ethyl)benzimidazole (4.00 g), N-methylhomopiperazine (4.00 g) and fumaric acid (2.65 g), there are obtained crude crystals, which are recrystallized from ethanol to give 1-[2-(phenoxy)ethyl]-2-(4-methyl-1-homopiperazinyl)benzimidazole difumarate (3.50 g) as colorless needles, m.p. 167°-168° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[C:20]1([CH3:29])[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>>[C:20]1([CH3:29])[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:28])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[CH:12][N:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)=[CH:22][CH:21]=1
Reactant: NC(=O)c1[nH]c2cnccc2c1-c1ccc(N)cc1
Reactant: Cc1ccc(N=C=O)cc1
Product: Cc1ccc(NC(=O)Nc2ccc(-c3c(C(N)=O)[nH]c4cnccc34)cc2)cc1

Procedure:
76 mg of solid yellow 3-[4-(3-p-tolylureido)phenyl]-1H-pyrrolo[2,3-c]pyridine-2-carboxamide are prepared as described in Example 1 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide and p-tolyl isocyanate.
Reaction SMILES: ClCC([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[NH:13][C:12](=[O:15])[CH:11]=[CH:10]2)=O>N1C=CC=CC=1>[NH:13]1[C:14]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:12]1=[O:15]
Reactant: O=C(CCl)c1cccc2ccc(=O)[nH]c12
Solvent: c1ccncc1
Product: O=c1ccc2ccccc2[nH]1
Reaction time: 2.5 h

Procedure:
30 Grams of 8-chloroacetylcarbostyril was mixed with 300 ml of pyridine and stirred at 80°-90° C. for 2.5 hours under heating. Then the reaction mixture was ice-cooled and crystals formed were collected by filtration and washed with ether. Recrystallized from methanol to obtain 40.85 g of 8-(α-pyridiniumacetyl)carbostyril chloride 1/2-hydrate. Colorless needle-like crystals. Melting point: 261.5°-264.0° C. (decomposed).
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:16]3[CH:17]=[C:18]([CH:21]=[C:22]([F:24])[CH:23]=3)[C:19]#[N:20])[CH:8]=2)[NH:3]1.C([O-])(=O)C.[K+].[Br:30]Br>C(O)(=O)C>[Br:30][C:5]1[CH:6]=[C:7]([C:16]2[CH:17]=[C:18]([CH:21]=[C:22]([F:24])[CH:23]=2)[C:19]#[N:20])[CH:8]=[C:9]2[C:4]=1[NH:3][C:2](=[O:1])[C:10]12[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: N#Cc1cc(F)cc(-c2ccc3c(c2)C2(CCCCC2)C(=O)N3)c1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: N#Cc1cc(F)cc(-c2cc(Br)c3c(c2)C2(CCCCC2)C(=O)N3)c1
Reaction time: 1 h
Yield: 42.8 %

Procedure:
A mixture of 3-(1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-5-fluorobenzonitrile (0.40 g, 1.23 mmol) and potassium acetate (0.13 g, 1.3 mmol) in glacial acetic acid (3 mL) at room temperature was treated with a solution of bromine (1.05 eq, 0.21 g, 1.3 mmol) in a glacial acetic acid (3 mL). After stirring for 1 h the mixture was poured onto ice (20 g). The layers were separated and the aqueous layer was extracted with dichloromethane (2×10 mL). The organic layers were combined, washed sequentially with 10% aqueous sodium thiosulfate (20 mL), water (2×10 mL), saturated sodium bicarbonate (10 mL) and brine (15 mL) and dried over MgSO4. The solution was filtered, concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with 30% EtOAc/hexane) to give the title compound (0.21 g, 43%) as an oil which crystallized upon addition of 10% EtOAc/hexanes, mp 217° C. 1H NMR (CDCl3; 300 MHz) δ 1.56-2.04 (m, 10H), 7.33 (dddd, 1H, J=1.25, 2.3, 3.6 and 9.0 Hz), 7.45 (m, 1H), 7.47 (m, 2H), 7.54 (m, 1H), 7.60 (m, 1H). MS ((−)−ESI) m/z 399 [M−]. Anal. Calcd for C20H16BrFN2O1: C, 60.17; H, 4.04; N, 7.02. Found: C, 60.03; H, 4.08; N, 6.83.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH:7]1[CH:12]=[C:11]2[C:13]([O:15][C:16]([C:18]3=[CH:19][CH:20]=[CH:21][C:9](=[C:10]23)[CH:8]=1)=O)=[O:14].Cl.[NH2:23][OH:24]>>[CH:7]1[CH:12]=[C:11]2[C:13]([N:23]([OH:24])[C:16]([C:18]3=[CH:19][CH:20]=[CH:21][C:9](=[C:10]23)[CH:8]=1)=[O:15])=[O:14]
Reactant: NO
Reactant: O=C1OC(=O)c2cccc3cccc1c23
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C1c2cccc3cccc(c23)C(=O)N1O

Procedure:
To 400 g of an aqueous solution of 3% by weight sodium carbonate were added 24.0 g of 1,8-naphthalic acid anhydride and 10.0 g of hydroxylamine hydrochloride and they were reacted for 2 hours at 90° C. Then, 200 g of an aqueous solution of 10% by weight sodium carbonate was added to the mixture, after filtering away insoluble materials, 100 ml of concentrated hydrochloric acid was added to the mixture, and precipitates formed were collected and recrystallized from ethanol to provide N-hydroxy-1,8-naphthalimide.
Reaction SMILES: CN(C)C=O.Cl[CH2:7][CH2:8][CH2:9][N:10]1[C:23]2[CH:22]=[C:21]([S:24][CH3:25])[CH:20]=[CH:19][C:18]=2[S:17][C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2.[Cl:26][C:27]1[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:28]=1[C:29]([CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:30].C(=O)(O)[O-].[Na+]>O>[Cl:26][C:27]1[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:28]=1[C:29]([CH:31]1[CH2:32][CH2:33][N:34]([CH2:7][CH2:8][CH2:9][N:10]2[C:23]3[CH:22]=[C:21]([S:24][CH3:25])[CH:20]=[CH:19][C:18]=3[S:17][C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:35][CH2:36]1)=[O:30]
Reactant: CSc1ccc2c(c1)N(CCCCl)c1ccccc1S2
Reactant: O=C(c1ccc(Cl)cc1Cl)C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ccc2c(c1)N(CCCN1CCC(C(=O)c3ccc(Cl)cc3Cl)CC1)c1ccccc1S2
Reaction time: 5 h
Yield: 79.9 %

Procedure:
To 75 ml of dry dimethylformamide was added 2.0 g of 10-(3-chloropropyl)-2-methylthiophenothiazine, 1.7 g of 4-(2,4-dichlorobenzoyl)piperidine, and 5.0 g of sodium bicarbonate. The reaction mixture was stirred at 90° for five hours, poured into 200 ml of water, and extracted with ethyl acetate. This extract was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated to an oil. This oil was purified by high pressure liquid chromatography on a silica gel column, utilizing ethyl acetate/dichloromethane (1:2 by volume) as the eluent. Concentration of the appropriate fractions yielded 2.7 g of 4-(2,4-dichlorobenzoyl)-1-[3-(2-methylthio-10H-phenothiazin-10-yl)propyl]piperidine as an oil.