Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:14])=[C:8]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:9]=1)(=[O:3])[CH3:2].[Br:15]Br.O>CO>[Br:15][CH2:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:14])=[C:8]([S:10]([NH2:13])(=[O:11])=[O:12])[CH:9]=1)=[O:3]
Reactant: CC(=O)c1ccc(C)c(S(N)(=O)=O)c1
Reactant: BrBr
Solvent: CO
Solvent: O
Product: Cc1ccc(C(=O)CBr)cc1S(N)(=O)=O
Reaction time: 1.5 h
Yield: 95.9 %

Procedure:
21.3 Grams (0.1M) of 5-acetyl-2-methylbenzenesulfonamide was dissolved in 180 g of methanol, while the resulting solution was kept at 35°-40° C., 16.0 g (0.1M) of bromine was added dropwise by taking 1.5 hours. The reaction mixture was stirred for 10 minutes after the dropwise addition, 80 g of water was added to the reaction mixture and the whole reaction mixture was stirred for further 30 minutes at room temperature. A part of methanol-water was removed by evaporation, then the crystals formed were collected by filtration, washed with water and dried to obtain 28.0 g of 5-bromoacetyl-2-methylbenzenesulfonamide in the form of white crystals. Melting point: 146.5°-147.5° C. Yield: 95.9%.
Reaction SMILES: [AlH](CC(C)C)CC(C)C.[F:10][C:11]1[CH:12]=[CH:13][C:14]2[C:15]3[CH2:24][CH2:23][NH:22][C:21](=O)[CH2:20][C:16]=3[NH:17][C:18]=2[CH:19]=1>C(Cl)Cl.C1COCC1>[F:10][C:11]1[CH:12]=[CH:13][C:14]2[C:15]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20][C:16]=3[NH:17][C:18]=2[CH:19]=1
Reactant: O=C1Cc2[nH]c3cc(F)ccc3c2CCN1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: Fc1ccc2c3c([nH]c2c1)CCNCC3
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a flask containing THF (10 mL) at −78° C. under argon was added a 1 M solution of iBu2AlH in CH2Cl2 (16.3 mL). After 5 min, a solution of 8-fluoro-2,3,5,6-tetrahydroazepino[4,5-b]indol-4(1H)-one (0. 175 g, 0.80 mmol) in THF (16 mL) was added. The reaction mixture was allowed to warm to rt, stirred for 48 h, cooled to 0° C., then quenched with MeOH (4.5 mL). It was partitioned between CH2Cl2 and aqueous 1 M KO2CC(OH)C(OH)CO2Na. The CH2Cl2 extracts were washed with brine, dried, filtered, and concentrated to give a solid. The solid was purified by silica chromatography (92.5:7.5 CH2Cl2/satd NH3 in MeOH) to give the free amine. A solution of this amine (0.094 g, 0.46 mmol) in dry MeOH (4.0 mL) at rt under argon was mixed with a solution of fumaric acid (0.027 g, 0.23 mmol) in dry MeOH (2.2 mL). The turbid solution was stirred overnight at rt. The MeOH was evaporated. The residue was dissolved in hot MeOH, and the salt was permitted to crystallize. The crystalline salt was collected: mp 266° C.; MS (ESI+) m/z 205.1; 1H NMR (CD3SOCD3, 300 MHz) δ 10.94 (1H), 7.34 (1H), 7.00 (1H), 6.77 (1H), 6.40 (1H), 3.11 (4H), 2.91 (4H); Anal. C, 63.90; H, 5.83; N, 10.63.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[C:12]2([CH2:16][CH2:15][O:14][CH2:13]2)[CH2:11][CH2:10][CH2:9]1.C(N(CC)CC)C.[C:24]1([C:30]2[O:34][C:33]([C:35]([N:37]3[CH2:40][CH:39]([O:41][C:42]4[CH:49]=[CH:48][C:45]([CH:46]=O)=[CH:44][CH:43]=4)[CH2:38]3)=[O:36])=[N:32][N:31]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Na].C([O-])(O)=O.[Na+]>ClCCl>[N:8]1([CH2:46][C:45]2[CH:44]=[CH:43][C:42]([O:41][CH:39]3[CH2:38][N:37]([C:35]([C:33]4[O:34][C:30]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[N:31][N:32]=4)=[O:36])[CH2:40]3)=[CH:49][CH:48]=2)[C:12]2([CH2:16][CH2:15][O:14][CH2:13]2)[CH2:11][CH2:10][CH2:9]1
Reactant: O=Cc1ccc(OC2CN(C(=O)c3nnc(-c4ccccc4)o3)C2)cc1
Reactant: C1CNC2(C1)CCOC2
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1nnc(-c2ccccc2)o1)N1CC(Oc2ccc(CN3CCCC34CCOC4)cc2)C1
Yield: 60.7 %

Procedure:
7-Oxa-1-azaspiro[4.4]nonane TFA salt (0.07 g, 0.29 mmol) was dissolved in dichloromethane (2 ml). Triethylamine (0.044 ml, 0.32 mmol) was added, followed by 4-(1-(5-phenyl-1,3,4-oxadiazole-2-carbonyl)azetidin-3-yloxy)benzaldehyde (0.101 g, 0.29 mmol) and finally sodium triacetoxyhydroborate (0.123 g, 0.58 mmol. The reaction mixture was then diluted with dichloromethane (10 ml) and shaken with NaHCO3 (sat. 3 ml). The two phases were separated by the use of a phase separator. Evaporation of the organic phase afforded a residue, which was purified by preparative reverse-phase HPLC at pH 10 to give 0.081 g (61%) of the desired product as a solid. 1H NMR (600 MHz, DMSO) δ 1.62-1.74 (m, 3H), 1.79-1.9 (m, 2H), 2.10 (dt, 1H), 2.37-2.45 (m, 1H), 2.54 (dd, 1H), 3.41 (d, 1H), 3.48 (d, 1H), 3.63 (d, 1H), 3.69 (q, 1H), 3.80 (d, 1H), 3.91 (td, 1H), 4.10 (dd, 1H), 4.56 (dd, 1H), 4.63 (ddd, 1H), 5.07-5.18 (m, 2H), 6.84 (d, 2H), 7.25 (d, 2H), 7.64-7.73 (m, 3H), 8.08 (dd, 2H). MS (APCI+) m/z 461.2 [M+H]+, LC purity: 97%
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:15][CH3:16])[CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:28][CH2:29][CH:30]=[C:31]1[C:37]2[CH:38]=[CH:39][CH:40]=[N:41][C:36]=2[CH2:35][O:34][C:33]2[CH:42]=[CH:43][C:44]([C:46]([OH:49])([CH3:48])[CH3:47])=[CH:45][C:32]1=2>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:15][CH3:16])[CH:9]2[CH2:14][CH2:13][N:12]([CH2:28][CH2:29][CH:30]=[C:31]3[C:37]4[CH:38]=[CH:39][CH:40]=[N:41][C:36]=4[CH2:35][O:34][C:33]4[CH:42]=[CH:43][C:44]([C:46]([OH:49])([CH3:48])[CH3:47])=[CH:45][C:32]3=4)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: CCN(c1ccc(Cl)cc1)C1CCNCC1
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Solvent: Cc1cccc(C)n1
Product: CCN(c1ccc(Cl)cc1)C1CCN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CC1
Temperature: 80 °C
Reaction time: 14 h
Yield: 33.8 %

Procedure:
To a solution of the (4-chloro-phenyl)-ethyl-piperidin-4-yl-amine (0.150 g, 0.63 mmol) in isopropanol was added 2,6-lutidine (0.24 mL, 2.1 mmol) and catalytic potassium iodide. This mixture was heated to 80° C., and treated with 2-[5-(3-Bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a, d]cyclohepten-7-yl]-propan-2-ol (0.221 g, 0.6 mmol), added in portions over 1 h. The solution was then stirred at 80° C. for an additional 14 h. The reaction was concentrated in vacuo, then purified by Isco flash chromatography (15% methanol/85% methylene chloride) to yield the title compound (0.108 g, 34%). 1H-NMR (CDCl3): δ 1.12 (t, 3H), 1.57 (s, 6H), 2.67–2.80 (m, 4H), 2.00 (m, 2H), 2.34–2.41 (m, 2H), 2.43–2.54 (m, 2H), 2.88 (d, 2H), 3.22 (q, 2H), 3.37–3.51 (m, 1H), 5.28 (bs, 2H), 6.12 (t, 1H), 6.60 (d, 2H), 6.80 (d, 1H), 7.13 (d, 2H), 7.21–7.30 (m, 2H), 7.45 (s, 1H), 7.56 (d, 1H), 8.48 (dd, 1H). ESI-MS m/z: 532 (M+1), retention time 2.47.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]3[C:15]=2[CH2:16][N:17]([CH3:25])[C:18]3=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:32][C:33]1[N:38]=[C:37](Cl)[C:36]([Cl:40])=[CH:35][N:34]=1.O>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:22]=[CH:21][C:20]([NH:23][C:35]3[C:36]([Cl:40])=[CH:37][N:38]=[C:33]([Cl:32])[N:34]=3)=[C:19]3[C:15]=2[CH2:16][N:17]([CH3:25])[C:18]3=[O:24])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CN1Cc2c(N3CCN(C(=O)OC(C)(C)C)CC3)ccc(N)c2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CN1Cc2c(N3CCN(C(=O)OC(C)(C)C)CC3)ccc(Nc3nc(Cl)ncc3Cl)c2C1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 59.6 %

Procedure:
To a suspension of 4-(7-Amino-2-methyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (6.14 g, 18 mmol) and potassium carbonate (3.86 g, 4.76 mmol) in dimethylsulfoxide (60 mL), 2,4,5-trichloropyrimidine (3.1 mL, 27 mmol) is added and the mixture is stirred at 60° C. for 2 hours. To the mixture, 2,4,5-trichloro pyrimidine (1.0 mL, 9 mmol) is added. After stirring at 60° C. for 2 hours, 2,4,5-trichloropyrimidine (1.0 mL, 9 mmol) is added and the mixture is further allowed to stir at 60° C. for 10 hours. The mixture is cooled and then poured into iced water. The resulting brown solids are collected by filtration and washed with MeOH, and dried in vacuo at 50° C. to afford 4-[7-(2,5-Dichloro-pyrimidin-4-ylamino)-2-methyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-piperazine-1-carboxylic acid tert-butyl ester as brown solids (5.29 g) in 60% yield. Rf=0.28 (Hexane/AcOEt=111). 1H-NMR (400 MHz, CDCl3, δ, ppm): 1.50 (s, 9H), 2.99 (t, 4H), 3.23 (s, 3H), 3.59 (t, 4H), 4.40 (s, 2H), 7.18 (d, 1H), 8.21 (s, 1H), 8.67 (d, 1H), 11.0 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:9]([O:16]C)=[N:10][C:11]([O:14]C)=[N:12][CH:13]=2)=[CH:6][C:5]([F:18])=[CH:4][N:3]=1>CO>[ClH:1].[Cl:1][C:2]1[C:7]([C:8]2[C:9](=[O:16])[NH:10][C:11](=[O:14])[NH:12][CH:13]=2)=[CH:6][C:5]([F:18])=[CH:4][N:3]=1
Reactant: COc1ncc(-c2cc(F)cnc2Cl)c(OC)n1
Solvent: CO
Product: Cl
Product: O=c1[nH]cc(-c2cc(F)cnc2Cl)c(=O)[nH]1
Yield: 201.2 %

Procedure:
To a solution of 5-(2-chloro-5-fluoro-pyridin-3-yl)-2,4-dimethoxy-pyrimidine (Prep 70, 240 mg, 0.89 mmol) in MeOH (20 ml) 10% HClaq (15 ml) was added. After refluxing the mixture for 8 hours, the solvents were evaporated and the crude was triturated with ethyl acetate to give 249 mg of the title compound (97% yield)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:4][N:3]=1.[CH3:18][N:19]([CH3:28])[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[CH3:18][N:19]([CH3:28])[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][N:25]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)=[CH:4][N:3]=2)[CH2:24][CH2:23]1
Reactant: CN(C)CCN1CCNCC1
Reactant: FC(F)(F)c1ccc(-c2ccc(Cl)nc2)cc1
Product: CN(C)CCN1CCN(c2ccc(-c3ccc(C(F)(F)F)cc3)cn2)CC1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 1, starting from 2-chloro-5-(4-trifluoromethylphenyl)pyridine and (2-dimethylaminoethyl)piperazine.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:9]3[C:14]([C:15]=2[CH:16]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3)(=[O:3])[CH3:2].[H-].[Na+].Br[CH2:20][CH2:21][CH2:22][Cl:23]>CN(C=O)C>[Cl:23][CH2:22][CH2:21][CH2:20][N:8]1[C:7]2[CH:6]=[CH:5][C:4]([C:1](=[O:3])[CH3:2])=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2
Reactant: ClCCCBr
Reactant: CC(=O)c1ccc2[nH]c3ccccc3c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2c(c1)c1ccccc1n2CCCCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Acetylcarbazole (1.0 g, 0.0048 mol) was dissolved in dry DMF (20 mL) and NaH (50% in oil) (0.13 g, 0.0053 mol) was added. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was added dropwise to a solution of 1-bromo-3-chloropropane (0.83 g, 0.0053 mol) in DMF (20 mL). The resulting mixture was stirred under a N2 atmosphere for 60 h. The solvent was removed in vacuo, and the residue was purified on a silica gel column (Eluent: CH2Cl2). This afforded the title comoound 0.70 g (51%) as a solid. M.p. 109-111° C.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:7]=1[F:13])=[O:5]>O1CCOCC1.O1CCCC1.C(OCC)(=O)C>[Br:1][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:7]=1[F:13])=[O:5]
Reactant: CC(=O)c1ccc(Br)cc1F
Reactant: BrBr
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: O=C(CBr)c1ccc(Br)cc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Bromine (0.54 mL, 10.6 mmol) was added dropwise to a cold (0° C.) solution of 4-bromo-2-fluoroacetophenone (2.30 g, 10.6 mmol) in dioxane (80 mL) and tetrahydrofuran (80 mL). The mixture was stirred for 1 h at 0° C. and warmed to RT for 15 h. The mixture was diluted with ethyl acetate, washed with saturated NaHCO3 solution, 5% sodium thiosulfate solution and brine prior to drying (Na2SO4). 2-Bromo-1-(4-bromo-2-fluorophenyl)ethanone (D1) was isolated as a colorless film which solidified upon further concentration under high vacuum. This solid was dissolved into anhydrous acetonitrile (50 mL) and treated with N-Boc-L-proline (2.28 g, 10.6 mmol) and diisopropylethylamine (1.85 mL, 10.6 mmol). After being stirred for 3 h at RT, the solvent was removed in vacuo and the residue was partitioned into ethyl acetate and water. The organic phase was washed with 0.1N hydrochloric acid, saturated NaHCO3 solution and brine prior to drying (Na2SO4), filtration, and concentration. This residue was taken up in xylenes (50 mL) and treated to solid NH4OAc (4.1 g, 53.0 mmol). The mixture was heated at 140° C. for 2 hr in a thick-walled, screw-top flask before it was cooled to ambient temperature, diluted with ethyl acetate and washed with saturated NaHCO3 solution and brine prior to drying (Na2SO4) and concentration. Purification of the residue by Biotage™ flash chromatography on silica gel (65M column, preequilibration with 16% B for 1800 mL followed by gradient elution with 16% B to 16% B for 450 mL, 16% B to 50% B for 2199 ml and finally 50% B to 100% B for 2199 mL) afforded title compound (D5) (3.61 g, 83%) as a brownish/caramel-colored oil. A small portion (40 mg) of the title compound was further purified by preparative HPLC (20% B to 100% B over 14 min where B is 10 mM NH4OAc in 10:90 H2O/ACN and A is 10 mM NH4OAc in 95:5 H2O/CAN using a Phenomenex-Gemini 30×100 mm S10 column flowing at 40 mL/min) to afford pure title compound (31.8 mg) as a white solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]3[N:16]4[N:17]=[C:18]([C:21]5[CH:22]=[N:23][N:24]([CH2:26][CH2:27]O)[CH:25]=5)[CH:19]=[CH:20][C:15]4=[N:14][CH:13]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:29]([N:31](CC)[CH2:32][CH3:33])[CH3:30].S(Cl)(C)(=O)=O.N1CCCC1>C1COCC1.C(Cl)Cl>[N:31]1([CH2:27][CH2:26][N:24]2[CH:25]=[C:21]([C:18]3[CH:19]=[CH:20][C:15]4[N:16]([C:12]([CH2:11][C:7]5[CH:6]=[C:5]6[C:10](=[CH:9][CH:8]=5)[N:1]=[CH:2][CH:3]=[CH:4]6)=[CH:13][N:14]=4)[N:17]=3)[CH:22]=[N:23]2)[CH2:32][CH2:33][CH2:30][CH2:29]1
Reactant: OCCn1cc(-c2ccc3ncc(Cc4ccc5ncccc5c4)n3n2)cn1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: C1CCNC1
Product: c1cnc2ccc(Cc3cnc4ccc(-c5cnn(CCN6CCCC6)c5)nn34)cc2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 2-[4-(3-quinolin-6-ylmethyl-imidazo[1,2-b]pyridazin-6-yl)-pyrazol-1-yl]-ethanol (Example 210, 74 mg, 0.200 mmol), triethylamine (61 μL, 0.440 mmol) and mesylchloride (33 μL, 0.420 mmol) in THF (10 mL) was stirred at rt for 24 h. Pyrrolidine (6 eq.) was then added and the mixture was stirred at 60° C. for 48 h. The mixture was diluted with DCM and washed with NaHCO3 10% and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (CombiFlash® Companion System®, with a 4 g RediSep® silica gel column, DCM/(MeOH+NH3)=95:5→80:20) to afford the title compound (tR 2.70 min (conditions 3), MH+=424.3)
Reaction SMILES: C(O[C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][C:13]([CH3:28])=[C:14]2NC(=O)C)[CH2:6]1)(=O)C.[OH2:29].Cl.C(CC(C)(C)C)(C)C.C(OCC)(=O)C>C1COCC1>[CH3:28][C@H:13]1[CH2:12][C@H:11]2[C@H:10]3[C@H:19]([CH2:18][CH2:17][C@:15]2([CH3:16])[C:14]1=[O:29])[C@:20]1([CH3:23])[C:7]([CH2:6][CH2:5][CH2:22][CH2:21]1)=[CH:8][CH2:9]3
Reactant: O
Reactant: CC(=O)NC1=C(C)C[C@H]2[C@@H]3CC=C4C[C@@H](OC(C)=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)CC(C)(C)C
Solvent: C1CCOC1
Product: C[C@H]1C[C@H]2[C@@H]3CC=C4CCCC[C@]4(C)[C@H]3CC[C@]2(C)C1=O

Procedure:
The crude methyl enamide acetate (3, 1.94 g) was refluxed in 100 ml each of THF and water with 10 ml of concentrated HCl for 31/2 hours. Following the usual work-up the crude hydroxy methyl ketones (5 and 6) were converted to the 3-acetates. Silica gel thin layer chromatography using isooctane-ethyl acetate (21:4) roughly showed a 3:1 mixture of polar (Rf 0.17) and mobile (Rf 0.21) products, representing a mixture of the 16α-methyl and 16β-methyl-17-ones, respectively. Crystallization of the original 3-hydroxy mixture gave 425 mg of pure 16β-methyl-5-androsten-17-one (6), mp 168°-170°. The mother liquor residue (660 mg) represented a mixture of 16-α and 16β-methyl-3-hydroxy-17-ones (5 and 6).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:18][CH3:19])=[CH:5][C:6]2[C:15]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[C:9](=[O:16])[NH:8][C:7]=2[CH:17]=1.[CH3:20][N:21]([CH2:23][CH2:24]Cl)[CH3:22]>>[CH3:20][N:21]([CH3:22])[CH2:23][CH2:24][N:12]1[CH2:11][C:10]2[C:9](=[O:16])[NH:8][C:7]3[CH:17]=[C:3]([O:2][CH3:1])[C:4]([O:18][CH3:19])=[CH:5][C:6]=3[C:15]=2[CH2:14][CH2:13]1
Reactant: COc1cc2[nH]c(=O)c3c(c2cc1OC)CCNC3
Reactant: CN(C)CCCl
Product: COc1cc2[nH]c(=O)c3c(c2cc1OC)CCN(CCN(C)C)C3

Procedure:
In the same way as described in example 10, 0.02 m of 1,2,3,4-tetrahydro-8,9-dimethoxybenzo[c][2,7]naphthyridin-5(6H)-one was alkylated with dimethylamino ethyl chloride. Crystallization from acetonitrile gave analytical material, mp 160°-164° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:6]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[CH:5][CH:4]=1.[OH:23][C:24]1[CH:25]=[C:26]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C(#N)C>[CH3:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:7]1[N:8]=[C:3]([CH2:2][O:23][C:24]2[CH:25]=[C:26]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=2)[CH:4]=[CH:5][C:6]=1[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[F:22]
Reactant: COc1ccc(F)c(-c2ccc(CCl)nc2CC(C)(C)C)c1
Reactant: CCOC(=O)CCc1cc(O)cc(OC)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)CCc1cc(OC)cc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1
Yield: 94.7 %

Procedure:
To a solution of 6-(chloromethyl)-2-(2,2-dimethylpropyl)-3-(2-fluoro-5-methoxyphenyl)pyridine (300 mg) in acetonitrile (10 mL) were added ethyl 3-(3-hydroxy-5-methoxyphenyl)propanoate (270 mg) and cesium carbonate (510 mg), and the mixture was heated under reflux for 15 hr. Ethyl acetate was added to the reaction mixture, and the insoluble material was filtered off. The solvent in the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (450 mg) as a colorless oil.
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O+](C)C.[CH2:10]([N:14]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:17]([C:24](=[S:26])[NH2:25])[N:16]=[C:15]1[N:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1)[C:11]#[C:12][CH3:13]>ClCCl>[CH2:10]([N:14]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:17]([C:24]([S:26][CH3:6])=[NH:25])[N:16]=[C:15]1[N:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[CH2:29][CH2:28]1)[C:11]#[C:12][CH3:13]
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(C(N)=S)c1C(=O)OCC
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(C(=N)SC)c1C(=O)OCC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.235 of trimethyl oxonium tetrafluoroborate was added to a 20-ml dichloromethane solution of 0.58 g of t-butyl 4-[1-(2-butynyl)-5-ethoxycarbonyl-4-thiocarbamoyl-1H-imidazol-2-yl]piperazine-1-carboxylate, and the mixture was stirred at room temperature for 18 hours. 50 ml of dichloromethane was added to the solution, and the mixture was washed with 20 ml of a saturated sodium bicarbonate solution. The mixture was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 0.55 g of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([Cl:11])[N:5]=[C:4]([CH2:12][CH3:13])[N:3]=1.CO.[H][H].[CH:18]1([NH2:21])[CH2:20][CH2:19]1>[Ni].C(O)(C)C.CCOC(C)=O>[NH2:8][C:7]1[C:6]([Cl:11])=[N:5][C:4]([CH2:12][CH3:13])=[N:3][C:2]=1[NH:21][CH:18]1[CH2:20][CH2:19]1
Reactant: CCc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Reactant: NC1CC1
Reactant: [H][H]
Agent: [Ni]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: CO
Product: CCc1nc(Cl)c(N)c(NC2CC2)n1
Yield: 65.8 %

Procedure:
A mixture of 4,6-dichloro-5-nitro-2-ethylpyrimidine (0.5 g), Raney nickel (ca. 0.5 g) and MeOH (5 ml) was shaken in a hydrogen atmosphere at 1-2 p.s.i until reduction of the nitro group was complete. The mixture was filtered, evaporated to a black gum, taken up in a mixture of cyclopropylamine (5 ml, ca. 100 mmol) and isopropyl alcohol (5 ml) and heated in a bomb at 110° for 4 hours. The reaction mixture was then filtered, evaporated to dryness under reduced pressure and the pure product was isolated by preparative tlc using four 20×20 cm×1000μ silica gel GF plates developed with 1:1 EtOAc:hexanes; 315 mg of product was obtained. Yield: 64%. NMR (CDCl3, δ from TMS): 0.47(m) and 0.76(m) cyclopropyl methylenes, 1.24 (t, CH3), 2.69 (q, CH2CH3), 2.86 (m, CH), 3.47 (br s, NH2), 5.47 (br s, NH).
Reaction SMILES: [N+:1]([O:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[O:9][CH2:8]1)([O-:3])=[O:2].[N+:18]([O-])([OH:20])=[O:19]>>[N+:1]([O:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:10]=2[O:9][CH2:8]1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: O=C1c2ccccc2OCN1CCO[N+](=O)[O-]
Product: O=C1c2cc([N+](=O)[O-])ccc2OCN1CCO[N+](=O)[O-]

Procedure:
50 ml of 100% fuming nitric acid were dropped into 50 g (0.21 mole) of 2,3-dihydro-3-(2'-nitrooxyethyl)-4H-1,3-benzoxazin-4-one, at a temperature of -10° C. At the end of the addition, the reaction mixture was stirred for minutes, then poured in ice and sequentially extracted with chloroform. The organic layer was washed with water, sodium hydroxide 0.1N and again with water, then dried over sodium sulphate and concentrated to dryness. The resulting oil was taken up with warm ethyl ether yielding 42.5 g of the title compound as white solid. m.p. 97°-99° C. (ethyl ether).
Reaction SMILES: [CH3:1][Si:2]([CH3:5])([CH3:4])Cl.[CH3:6][C:7]1([C:13]2([Li])C=CC=C2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>C1COCC1>[CH3:6][C:7]1([CH2:13][Si:2]([CH:5]2[CH:9]=[CH:8][CH:7]=[CH:6]2)([CH3:4])[CH3:1])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: C[Si](C)(C)Cl
Reactant: [Li]C1(C2(C)CCCCC2)C=CC=C1
Solvent: C1CCOC1
Product: CC1(C[Si](C)(C)C2C=CC=C2)CCCCC1
Yield: 57 %

Procedure:
Trimethylchlorsilane (29.1 g, 268 mmol) was slowly added to a solution of (1-methyl-cyclohexyl)cyclopentadienyllithium (43.34 g, 258 mmol) in THF (350 ml). After refluxing the mixture for 3,5 h, the solvent was removed in vacuo and the residue was distilled under reduced pressure to give (1-methylcyclohexyl)cyclopentadienyltrimethylsilane as yellow oil.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:10]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH3:21])[C:13]=2[CH3:22])=[O:11])=[N:6][CH:7]=[CH:8][CH:9]=1)([OH:3])=O.[CH:23]1([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([N:36]([CH2:39][CH3:40])[CH2:37][CH3:38])[CH:31]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C(OC(=O)C)(=O)C>[CH2:39]([N:36]([CH2:37][CH3:38])[C:32]1[CH:33]=[CH:34][C:35]([C:10]2([C:12]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]([CH3:21])[C:13]=3[CH3:22])[C:5]3[C:4](=[CH:9][CH:8]=[CH:7][N:6]=3)[C:1](=[O:3])[O:11]2)=[C:30]([O:29][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:31]=1)[CH3:40]
Reactant: Cc1c(C(=O)c2ncccc2C(=O)O)c2ccccc2n1C
Reactant: CCN(CC)c1cccc(OC2CCCCC2)c1
Solvent: CC(=O)OC(C)=O
Product: CCN(CC)c1ccc(C2(c3c(C)n(C)c4ccccc34)OC(=O)c3cccnc32)c(OC2CCCCC2)c1
Temperature: 25 °C
Yield: 75.3 %

Procedure:
Into 150 ml of acetic anhydride, 14.7 g of (1,2-dimethylindol-3-yl) (3-carboxypyridin-2-yl) ketone and 13.3 g of 1-cyclohexyloxy-3-diethylaminobenzene were added and the resultant mixture was stirred for 3 hours at 60° to 65° C. After cooling the reaction mixture to room temperature, the cooled mixture was treated by the same procedures as in Synthetic Example 7 and 19.7 g of the object compound was obtained as pale blue crystals (melting point: 161° to 165° C.).