Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:5]=1[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)=O)=[N+]=[N-].C(Cl)[Cl:22]>S(Cl)(Cl)=O>[Cl:22][C:6]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:1]=[C:4]2[C:5]=1[CH:16]=[CH:17][C:18]([F:20])=[CH:19]2
Reactant: ClCCl
Reactant: [N-]=[N+]=Nc1cc(F)ccc1C(=O)Nc1ccc(Cl)cc1
Solvent: O=S(Cl)Cl
Product: Fc1ccc2c(Cl)n(-c3ccc(Cl)cc3)nc2c1
Temperature: 0 °C
Yield: 95 %

Procedure:
2-Azido-N-(4-chloro-phenyl)-4-fluoro-benzamide (2.7 g, 1 mmol) was dissolved at ambient temperature in thionyl chloride (18.2 ml) under an argon atmosphere. The reaction mixture was heated under reflux conditions for 14 h and brought to dryness under reduced pressure. The residue was taken up in ice water/saturated aqueous NaHCO3 solution 1/1 and CH2Cl2. The layers were separated and the aqueous layer was extracted one more time with CH2Cl2. The combined extracts were washed with ice water/brine 1/1 and dried over Na2SO4. The solvent was removed under reduced pressure to give the title compound (2.47 g, 8.8 mmol; 95%) as yellow solid. MS: m/e=280.9 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][N:3]=1.[CH2:18]([N:20]([CH2:35][CH3:36])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=O)[NH:28][C:27]=1[CH3:34])=[O:25])[CH3:19]>>[CH2:35]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:5]3[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=3)[NH:12][C:11]2=[O:17])[NH:28][C:27]=1[CH3:34])=[O:25])[CH3:36]
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: Nc1ncc(-c2cccc3c2CC(=O)N3)cn1
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4cnc(N)nc4)c32)c1C

Procedure:
4-(2-Aminopyrimidin-5-yl)-1,3-dihydroindol-2-one (55 mg) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide (65 mg) to give the title compound.
Reaction SMILES: Cl.C([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[F:28])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:29][CH3:30])C1C=CC=CC=1>C(O)(C(F)(F)F)=O>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:14]2[C:13]3[C:18](=[CH:19][C:10]([OH:9])=[C:11]([O:29][CH3:30])[CH:12]=3)[N:17]=[CH:16][N:15]=2)=[C:22]([F:28])[CH:23]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCc1ccccc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Yield: 71.9 %

Procedure:
A solution of 7-benzyloxy-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline hydrochloride (892 mg, 2 mmol) in TFA (10 ml) was refluxed for 50 minutes. After cooling, the mixture was poured onto ice. The precipitate was collected by filtration, dissolved in methanol (10 ml) and basified to pH11 with aqueous ammonia. After concentration by evaporation, the solid product was collected by filtration, washed with water then ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline as a yellow solid (460 mg, 72%).
Reaction SMILES: CC1C(NC2CCNCC2)=NC2C(=CC=CC=2[C:19]2[NH:27][C:26]3[CH2:25][CH2:24][NH:23][C:22](=[O:28])[C:21]=3[CH:20]=2)N=1.CCN(C(C)C)C(C)C.CC(OC(C)=O)=O>C(Cl)Cl>[NH:27]1[C:26]2[CH2:25][CH2:24][NH:23][C:22](=[O:28])[C:21]=2[CH:20]=[CH:19]1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)OC(C)=O
Product: O=C1NCCc2[nH]ccc21
Temperature: 25 °C
Yield: 61.4 %

Procedure:
A mixture of 2-(2-methyl-3-(piperidin-4-ylamino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Ex. 53, 55 mg, 0.146 mmol) and DIPEA (76 μl, 0.438 mmol, EMD Biosciences, Rockland, Mass.) in DCM (5.8 mL) was set stirring at 25° C. before adding Ac2O (15.16 μl, 0.161 mmol, Sigma Aldrich) dropwise. The reaction was stirred for 30 min before concentrating under reduced pressure. The residue was taken up in DMSO, and purified by reverse-phase preparative HPLC (Phenomenex Gemini column, 10 micron, C18, 100 Å, 150×30 mm, 0.1% TFA in ACN/H2O, gradient 5% to 75%). Product-containing fractions were concentrated under reduced pressure and the residue was loaded onto a pre-washed (MeOH, 1 volume) functionalized Si-carbonate column (Silicyle) and allowed to percolate through to provide 2-(34(1-acetylpiperidin-4-yl)amino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (12.2 mg, 20.0%). 1H NMR (MeOH-d4) δ: 7.84-7.88 (m, 1H), 7.60-7.65 (m, 1H), 7.34-7.40 (m, 1H), 7.23 (s, 1H), 4.55-4.63 (m, 1H), 4.34-4.45 (m, 1H), 3.99-4.07 (m, 1H), 3.58-3.66 (m, 2H), 3.39-3.50 (m, 2H), 2.98-3.04 (m, 1H), 2.58 (s, 3H), 2.27-2.36 (m, 2H), 2.18-2.24 (m, 1H), 2.15 (s, 3H), 1.58-1.69 (m, 2H). m/z (ESI, −ve) 417.1 (M−H)−.
Reaction SMILES: [CH2:1](Br)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].[CH3:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)C>[CH2:12]([O:13][C:14]1[CH:15]=[C:16]([NH:20][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:2](=[O:3])[CH3:1])[CH:17]=[CH:18][CH:19]=1)[CH3:11]
Reactant: O=C(CBr)c1ccccc1
Reactant: CCOc1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1cccc(Nc2ccccc2C(C)=O)c1

Procedure:
5 g of phenacyl bromide and 3.78 g of m-phenetidine are stirred at 50° C. for 2.5 h in 50 ml of ethanol in the presence of 5.85 g of powdered Na2CO3. The mixture is then cooled and concentrated in an RE. The residue is partitioned between water and methylene chloride and the aqueous phase is extracted twice with methylene chloride. The combined organic phases are dried over Na2SO4 and concentrated. The residue is slurried with ether and the crystals are filtered off, 2'-(3-ethoxyphenylamino)acetophenone being obtained. Further product is again obtained from the mother liquor after addition of petroleum ether.
Reaction SMILES: Br[C:2]1[C:3]([N+:18]([O-:20])=[O:19])=[C:4]2[O:8][C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])=[N:6][C:5]2=[C:13]([C:15]([OH:17])=[O:16])[CH:14]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[C:9]([C:7]1[O:8][C:4]2[C:5](=[C:13]([C:15]([OH:17])=[O:16])[CH:14]=[C:2]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:3]=2[N+:18]([O-:20])=[O:19])[N:6]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)c1nc2c(C(=O)O)cc(Br)c([N+](=O)[O-])c2o1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)c1nc2c(C(=O)O)cc(-c3ccccc3)c([N+](=O)[O-])c2o1
Temperature: 85 °C
Reaction time: 22 h
Yield: 140.6 %

Procedure:
6-Bromo-2-tert-butyl-7-nitro-1,3-benzoxazole-4-carboxylic acid (I-222) (2.15 g, 6.27 mmol), phenylboronic acid (1.53 g, 12.53 mmol) and aqueous 2 M sodium carbonate solution (20 ml) were suspended in toluene (40 ml) and ethanol (30 ml). Tetrakis(triphenylphosphine)palladium(0) (724 mg, 0.63 mmol) was added at room temperature to the suspension. The mixture was stirred at 85° C. for 22 hours, then cooled to room temperature. The reaction liquid was fractionated with ethyl acetate and aqueous 1 M hydrochloric acid solution. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was removed by filtration, the solvent was evaporated away and the resulting residue was purified by middle-pressure liquid chromatography (eluent, chloroform:methanol=9:1) to obtain the entitled compound (3.00 g) as a brown gel. This was used in the next reaction as such.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][C:26](=[O:30])[C:25]1=[O:31].Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH3:18][C:17]1([CH3:19])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=2)[NH:9][CH:8]1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([N:27]2[CH2:28][CH2:29][N:24]([CH3:23])[C:25](=[O:31])[C:26]2=[O:30])[CH:3]=1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(Br)c1
Reactant: CN1CCNC(=O)C1=O
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CS(C)=O
Product: CN1CCN(c2cccc(C3Nc4ccc(C(=O)O)cc4CC3(C)C)c2)C(=O)C1=O
Temperature: 120 °C
Reaction time: 16 h
Yield: 79.9 %

Procedure:
A mixture of 2-(3-bromo-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (500 mg, 1.4 mmol), 1-methyl-piperazine-2,3-dione (267 mg, 2.1 mmol), copper(I) iodide (80 mg, 0.4 mmol), N,N-dimethylglycine hydrochloride (117 mg, 0.8 mmol) and potassium carbonate (769 mg, 5.6 mmol) in dimethyl sulfoxide (5 mL) was stirred at 120° C. for 16 h. Then the reaction mixture cooled to room temperature. The reaction mixture was extracted with ethyl acetate (2×150 mL), washed with water (2×50 mL) and saturated aqueous ammonium chloride solution (2×50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 3,3-dimethyl-2-[3-(4-methyl-2,3-dioxo-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (456 mg, 80%) as a white solid: LC/MS m/e calcd for C23H25N3O4 (M+H)+: 408.47, observed: 408.1.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6].C(=O)([O-])O.[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH:35]([C:37]1[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=1)=[CH2:36]>C(O)(=O)C>[O:11]([C:10]1[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[S:1][CH2:36][CH2:35][C:37]1[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(S)c1Oc1ccccc1
Reactant: C=Cc1ccncc1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: NS(=O)(=O)c1cc(C(=O)O)cc(SCCc2ccncc2)c1Oc1ccccc1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A mixture of 3-mercapto-4-phenoxy-5-sulfamylbenzoic acid (1.7 g), sodium hydrogen carbonate (1 g), sodium dithionite (1 g), 4-vinylpyridine (0.8 ml) and saturated aqueous sodium hydrogen carbonate (17 ml) is stirred at 70° C. for 4 hours. After cooling, pH of the mixture is adjusted to 4.5 by addition of acetic acid. The precipitated material is collected by filtration, washed with water, and recrystallized from aqueous ethanol to yield 4-phenoxy-3-(4-pyridylethylthio)-5-sulfamylbenzoic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([N+:27]([O-:29])=[O:28])[C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:12]([NH2:15])=[N:13][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30](O)(=O)[CH3:31]>CN(C)C=O.[Cl-].[Na+].O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:12]2[N:15]=[C:30]([CH3:31])[O:14][N:13]=2)[CH:16]=[C:17]([N+:27]([O-:29])=[O:28])[C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=NO)c1cc(OCc2ccccc2)c(OCc2ccccc2)c([N+](=O)[O-])c1
Reactant: CC(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(-c2cc(OCc3ccccc3)c(OCc3ccccc3)c([N+](=O)[O-])c2)no1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 3,4-bis-benzyloxy-N′-hydroxy-5-nitro-benzamidine (1.0 g, 2.54 mmol) in dimethylformamide (5 mL) at room temperature was added 1,1-carbonyldiimidazole (0.494 g, 3.048 mmol) in one portion and the mixture was stirred at room temperature for ninety minutes. Thereupon, acetic acid (0.184 g, 3.067 mmol) was added dropwise and the mixture was allowed to stir for two hours at room temperature, then at 155° C. for three hours. The mixture was allowed to cool to room temperature, and poured onto ice-water (100 mL). Brine (10 mL) was added and the resulting precipitate was removed by filtration, washed with water and dried in air. The solid was then dissolved in dichloromethane (20 mL) and a spatula tip of activated charcoal was added. After stirring for twenty minutes, the suspension was filtered through celite and the filtrate was evaporated to leave a yellow oil that solidified on standing. After recrystallisation from dichloromethane/petroleum ether, 3-(3,4-bis-benzyloxy-5-nitrophenyl)-5-methyl-[1,2,4]oxadiazole was obtained as a pale yellow solid (0.537 g, 51%).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([C:35]3[N:39]([CH3:40])[C:38]4[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=4[N:36]=3)[CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([C:35]3[N:39]([CH3:40])[C:38]4[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=4[N:36]=3)[CH:32]=[C:33]([CH3:34])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(C)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2c(C)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-butyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][CH2:13][C@H:12]([CH:15]=[CH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28]CC2C=CC=CC=2)[CH2:11][CH2:10]1.C(O)C>[Pd].C(OCC)(=O)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:10][CH2:11][C@H:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28])[CH2:13][CH2:14]1
Reactant: Fc1cccc([C@H]2CC[C@H](C=CCCCCCCCCCCCOCc3ccccc3)CC2)c1F
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: OCCCCCCCCCCCCC[C@H]1CC[C@H](c2cccc(F)c2F)CC1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
First, 10.9 g of 2,3-difluoro-1-[trans-4-{13-benzyloxy-1-tridecenyl}cyclohexyl]benzene, 1 g of 10% Pd-C, 50 ml of ethanol, and 50 ml of ethyl acetate were placed in a 500 ml autoclave. The mixture was stirred at room temperature for 5 days under a hydrogen pressure of 8 kg/cm2. A catalyst was filtered away and a filtrate was concentrated. Thereafter, the residue was purified by silica gel column chromatography (eluent: toluene/ethyl acetate=4/1) and recrystallized from acetone to obtain 5.7 g of 2,3-difluoro-1-[trans-4-(13-hydroxytridecyl)cyclohexyl]benzene (Y: 64%). The compound thus obtained had a purity of 97.2% by GC and 99.8% by HPLC.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[CH:10][C:5]2=[N:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:17]1([C:2]2[N:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:5]3=[N:4][CH:3]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1cnc2cnccn12
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: c1ccc(-c2cnc3cnccn23)cc1
Temperature: 80 °C
Yield: 87.7 %

Procedure:
3-Bromoimidazo[1,2-a]pyrazine (1.66 g, 7.13 mmol, Intermediate 2), sodium carbonate (3.78 g, 35.6 mmol) and phenylboronic acid (1.043 g, 8.55 mmol) were dissolved in 1,2-dimethoxyethane (DME) (40 ml) and water (20 ml). Bis(triphenylphosphine)palladium (II) chloride (0.250 g, 0.356 mmol) was added and the biphasic solution heated at 80° C. for 16 h. The aqueous phase was extracted with ethyl acetate (3×100 ml) and the combined extracts washed with saturated sodium bicarbonate solution (100 ml), water (100 ml), brine (100 ml) and dried by passing through a hydromatrix cartridge (Varian). The filtrate was concentrated in vacuo to afford a crude oil (2.44 g). The crude product was purified by flash chromatography (Biotage SP4, 40+M, eluting with a 0-100% gradient of ethylacetate in hexane)—(the product elutes in 100% ethyl acetate), to afford 3-phenylimidazo[1,2-a]pyrazine (1.22 g, 6.25 mmol, 88% yield).
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][N:9]=[C:8]2[S:12]([CH2:14][C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]3)=[O:16])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Mn]([O-])(=O)(=O)=[O:29].[K+].C(Cl)(Cl)Cl>C(O)(=O)C.O>[C:1]1([N:7]2[CH:11]=[CH:10][N:9]=[C:8]2[S:12]([CH2:14][C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]3)=[O:16])(=[O:29])=[O:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O=C1CCc2cc(C(=O)CS(=O)c3nccn3-c3ccccc3)ccc2N1
Agent: [K+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C1CCc2cc(C(=O)CS(=O)(=O)c3nccn3-c3ccccc3)ccc2N1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3.79 Grams (10 mM) of 6-[2-(1-phenyl-2-imidazolyl)sulfinylacetyl]-3,4-dihydrocarbostyril was dissolved in a mixture of 240 ml of acetic acid with 100 ml of water, then 5.06 g (32 mM) of potassium permanganate was added thereto. This mixture was stirred at room temperature for 2 days. After the reaction was completed, chloroform was added to the reaction mixture and filtered with Celite (a trademark for distomaceous earth product, manufactured by Johns-Manville Proudcts Corp.). The filtrate was washed with water and dried with anhydrous magnensium sulfate. The residue obtained by removing the solvent was purified by means of a silica gel column chromatography (eluent: chloroform:methanol=30:1), and recrystallized from ethanol-chloroform to yield 0.6 g of 6-[2-(1-phenyl-2-imidazolyl)sulfonylacetyl]-3,4-dihydrocarbostyril. Light yellow granular substance. Melting point: 199°-201° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C(Br)C1C=CC=CC=1>[CH2:4]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:2]=1[Br:1])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:2]=1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Br
Agent: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccccc1)c1cc([N+](=O)[O-])ccc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 187.7 %

Procedure:
Under an atmosphere of argon, to a solution of 2-bromo-5-nitrobenzoic acid (5.14 g) in DMF, benzyl bromide (2.73 mL) and potassium carbonate (4.33 g) were added. The mixture was stirred for 30 minutes at room temperature. To the reaction mixture, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated. The residue was washed with hexane/ethyl acetate to give the title compound (6.59 g) having the following physical data.
Reaction SMILES: [CH2:1](OC(C1C=CC(C2C=CC(O)=CC=2)=CC=1)=O)[CH2:2]CCCCCCCC.[F:27][C:28]([F:38])([F:37])[C@H:29]([OH:36])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].C(C1C=CC(C2C=CC(O)=CC=2)=CC=1)CCCCCCCCC>>[F:27][C:28]([F:37])([F:38])[C@H:29]([OH:36])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:1][CH3:2]
Reactant: CCCCCCCCCCOC(=O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: CCCCCC[C@@H](O)C(F)(F)F
Agent: CCCCCCCCCCc1ccc(-c2ccc(O)cc2)cc1
Product: CCCCCCCC[C@@H](O)C(F)(F)F

Procedure:
Example 22 was repeated except that 4-decyloxycarbonyl-4'-hydroxybiphenyl and (R)-(+)-1,1,1-trifluoro-2-octanol were used in place of the 4-decyl-4'-hydroxybiphenyl and the (R)-(+)-1,1,1-trifluoro-2-decanol, respectively, to obtain the titled compound.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]([OH:14])=O.C(Cl)(=O)C([Cl:18])=O>C(Cl)Cl.CN(C=O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]([Cl:18])=[O:14]
Reactant: O=C(O)Cc1ccc2ccccc2c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)Cc1ccc2ccccc2c1
Reaction time: 1.5 h

Procedure:
To a stirred solution of 2-naphthylacetic acid (0.960 g, 5.15 mmol) in methylene chloride (10 mL) was added oxalyl chloride (0.58 mL, 6.7 mmol) and DMF (1 drop). After 1.5 hours, the solvent was evaporated to give 2-naphthylacetyl chloride. A solution of the 2-naphthylacetyl chloride in THF (3 mL), cooled to -78° C., was slowly cannulated into a stirred solution of the lithium salt of 4 -(S)-(+)-4-isopropyl-2-oxazolidinone (prepared by treating, at -78° C., a solution of 4 -(S)-(+)-4 -isopropyl-2-oxazolidinone (0.60 g, 5.2 mmol) in THF (4 mL) with a solution of butyllithium (1.6 M in hexane) for 15 min). After 2 hours, 10% citric acid and ethyl acetate were added. The organic phase was washed with NaHCO3 and brine, dried (MgSO4), and concentrated. Flash column chromatography of the residue (15% ethyl acetate/hexanes) gave 4 -(S)-4 -isopropyl-3-(2-naphthylacetyl)-2-oxazolidinone as a slightly yellow oil (0.91 g, 60%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][C:18]#N)[CH2:13][CH2:12]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C.Cl.CC[O:33]CC>C(Cl)Cl>[C:1]([O:5][C:6](=[O:20])[N:7]([CH3:8])[CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][CH:18]=[O:33])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(CC[C@H]1CC[C@H](CC#N)CC1)C(=O)OC(C)(C)C
Reactant: CCOCC
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: ClCCl
Product: CN(CC[C@H]1CC[C@H](CC=O)CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 10.14 g (36.17 mmol) of trans-[2-(4-cyanomethyl-cyclohexyl)-ethyl]-methyl-carbamic acid tert-butyl ester in 90 mL of CH2Cl2 were added 90 mL (108.5 mmol, 3 eq) of 1.2M DIBAH at −70-−78° C. The solution was stirred at that temperature for 4 h, 40 mL of 4M HCl were added carefully and the solution was slowly warmed to RT. Stirring was continued at RT for 10 min, and the substance was partioned between ether and 1M HCl. The organic phases were washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography with n-hexane: EtOAc 1:3 to yield 7.5 g (73%) of trans-methyl-{2-[4-(2-oxo-ethyl)-cyclohexyl]-ethyl}-carbamic acid tert-butyl ester.
Reaction SMILES: C1(C)C=CC(S(O[C@H:11]2[CH2:30][CH2:29][C@@:28]3([CH3:31])[C@@H:13]([CH2:14][CH2:15][C@@H:16]4[C@@H:27]3[CH2:26][CH2:25][C@@:24]3([CH3:32])[C@H:17]4[CH2:18][CH:19]=[C:20]3[C:21](=[O:23])[CH3:22])[CH2:12]2)(=O)=O)=CC=1.N1C(C)=CC(C)=CC=1C.Cl>>[CH3:22][C:21](=[O:23])[C:20]1[C@:24]2([CH3:32])[C@H:17]([C@H:16]3[C@H:27]([CH2:26][CH2:25]2)[C@:28]2([CH3:31])[C@H:13]([CH2:12][CH:11]=[CH:30][CH2:29]2)[CH2:14][CH2:15]3)[CH2:18][CH:19]=1
Reactant: CC(=O)C1=CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](OS(=O)(=O)c5ccc(C)cc5)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cl
Solvent: Cc1cc(C)nc(C)c1
Product: CC(=O)C1=CC[C@H]2[C@@H]3CC[C@H]4CC=CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 86.5 %

Procedure:
3β-Toluene-p-sulphonyloxy-5α-pregn-16-en-20-one (6 g.) was added to hot collidine (12 ml.), and the solution was then refluxed for 30 minutes. The solution was allowed to cool and then poured into cold dilute hydrochloric acid. The precipitate was filtered off, washed with water and dissolved in methylene chloride. The solution was dried over sodium sulphate and then filtered through a short column of silica gel (50 g.). The methylene chloride eluate (about 150 ml.) was evaporated to give 5α-pregna-2,16-dien-20-one (3.29 g.) as white crystals, m.p. 143°-145° , [α]D + 110.5° .