Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([O:25][C:26](=[O:28])[CH3:27])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2].C1C(=O)N([Cl:36])C(=O)C1>CC#N>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:25][C:26](=[O:28])[CH3:27])=[C:8]2[C:16]([Cl:36])=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2ccc(F)cc2)c1OC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1nc(C#N)c2c(c(Cl)cn2Cc2ccc(F)cc2)c1OC(C)=O
Temperature: 90 °C
Yield: 59.7 %

Procedure:
A mixture of 4-acetoxy-7-cyano-1-(4-fluoro-benzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (103 mg), NCS (38 mg) in MeCN (2 mL) in a closed vial was heated at 90° C. for 1 h. Then the solvent was removed, the residue was purified with column to give the desired product (67 mg). The title compound, ESI MS (m/z): 416 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([N+:28]([O-])=O)[C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)=[C:12]([O:26][CH3:27])[CH:11]=2)=[N:6][CH:7]=1.O.[Cl-].[NH4+]>O1CCCC1.CO.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2].[Zn]>[I:1][C:2]1[CH:3]=[C:4]([NH2:28])[C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)=[C:12]([O:26][CH3:27])[CH:11]=2)=[N:6][CH:7]=1
Reactant: COc1ccc(COc2ccc(CNc3ncc(I)cc3[N+](=O)[O-])cc2OC)cc1
Agent: [Fe+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(COc2ccc(CNc3ncc(I)cc3N)cc2OC)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.5 %

Procedure:
To a stirred suspension of 5-iodo-N-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-3-nitropyridin-2-amine (6.72 g, 13.25 mmol) in tetrahydrofuran (75 mL), methanol (25 mL), and water (25 ml) was added ammonium chloride (5.68 g, 106.0 mmol) and iron(II) sulfate heptahydrate (11.05 g, 39.76 mmol). The yellow mixture was treated with zinc (2.60 g, 39.76 mmol), and the resulting dark mixture was heated to reflux. After 3 h, the reaction mixture was allowed to cool to room temperature and was filtered through Celite with the aid of methanol. The filtrate was concentrated, and the residue was dissolved in chloroform. The solution was washed with water, filtered through Celite, dried over magnesium sulfate, filtered, and concentrated to provide 6.67 g (>100%) of 5-iodo-N2-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyridine-2,3-diamine as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CO[CH:30](OC)[N:31]([CH3:33])[CH3:32]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:25])([F:27])[F:26])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([N:20]=[CH:30][N:31]([CH3:33])[CH3:32])=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(N)=O
Reactant: COC(OC)N(C)C
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)N=CN(C)C
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
A mixture of 6.0 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-2-methyl benzoic acid amide synthesized in Step 1 of Synthetic Example 19 and 50 mL of N,N-dimethylformamide dimethylacetal were stirred at 120° C. for 1.5 hour. After the completion of the reaction, the solvent was distilled off under reduced pressure. The residual solid was washed with ethyl acetate-hexane mixture (1:20) to obtain 6.2 g of the aimed product as pale yellow crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11])[CH:6]=[O:7].[C:14]([Si:18]([CH3:21])([CH3:20])Cl)([CH3:17])([CH3:16])[CH3:15].N1C=CN=C1>CN(C)C=O>[Si:18]([O:11][C:10]1[C:9]([O:12][CH3:13])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:2][CH3:1])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:21])[CH3:20]
Reactant: COc1cc(C=O)cc(OC)c1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1cc(C=O)cc(OC)c1O[Si](C)(C)C(C)(C)C

Procedure:
Using the conditions described in Example 14c 2.05 g of 3,5-dimethoxy-4-hydroxybenzaldehyde were reacted with 2.05 g of tertbutyldimethylchlorosilane in the presence of 0.91 g of imidazole and 15 ml of absolute dimethylformamide. The crude product was purified by chromatography on silica gel [Kieselgel 60 (0.063-0.200 mm)] with petroleum ether/ether (1:1) whereupon 2.91 g of the title compound were obtained in the form of crystals melting at 68° C.
Reaction SMILES: [N:1]1([CH:6]([CH3:10])[C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:35]([O:37][C:38](=[O:46])[C:39]1[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=1)[CH3:36].CN1CCOCC1>CN(C=O)C.C(OCC)(=O)C>[N:1]1([CH:6]([CH3:10])[C:7]([NH:45][C:42]2[CH:41]=[CH:40][C:39]([C:38]([O:37][CH2:35][CH3:36])=[O:46])=[CH:44][CH:43]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CC(C(=O)O)N1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(NC(=O)C(C)N2CCCC2)cc1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To the 2-pyrrolidin-1-yl-propanoic acid (508 mg, 3.55 mmol) in DMF (10 mL), was added HATU (1.62 g, 4.26 mmol), 4-Amino-benzoic acid ethyl ester (645 mg, 3.90 mmol) and NMM (1.2 mL, 10.65 mmol) and stirred at 50° C. for 16 hours. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with 1 N HCl, saturated NaHCO3, water, brine and dried over MgSO4. Filtration and concentration gave ethyl 4-(2-(pyrrolidin-1-yl)propanamido)benzoate.
Reaction SMILES: C(OC([N:8]1[C@@H:12]([CH2:13][F:14])[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][C:24]([CH:27]([CH:29]([CH3:31])[CH3:30])[NH2:28])=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)[O:10]C1(C)C)=O)(C)(C)C.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>C(Cl)Cl>[OH:38][C:36]([C:35]([F:40])([F:39])[F:34])=[O:37].[NH2:8][C@H:12]([CH2:13][F:14])[C@@H:11]([C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:22]=[N:23][C:24]([CH:27]([CH:29]([CH3:31])[CH3:30])[NH2:28])=[CH:25][CH:26]=2)=[CH:19][CH:20]=1)[OH:10]
Reactant: CC(C)C(N)c1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]3CF)cc2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(N)c1ccc(-c2ccc([C@@H](O)[C@H](N)CF)cc2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (4R,5R)-4-Fluoromethyl-5-{4-[6-(isopropyl amino-methyl)-pyridin-3-yl]-phenyl}-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (100 mg, 0.218 mmol) in CH2Cl2 (0.17 mL) is added trifluoroacetic acid (0.4 mL) at 0° C. Reaction mixture is allowed to stir at room temperature for 2 hours. The volatiles are removed under reduced pressure and crude material is purified by column chromatography over basic alumina using 50% methanol in CH2Cl2 as eluent to afford title compound (70 mg, impure). LC-MS (m/z): [M+H]=318.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:39]1[CH:40]=[C:41]2[N:47]=[C:46]([CH2:48][CH2:49][CH:50]3[NH:56][C:55](=[O:57])[CH2:54][CH2:53][CH2:52][CH2:51]3)[NH:45][C:42]2=[N:43][CH:44]=1.C(=O)([O-])[O-].[Na+].[Na+]>O=O.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C(Cl)Cl>[N:11]1([S:8]([C:5]2[CH:6]=[CH:7][C:2]([C:39]3[CH:40]=[C:41]4[N:47]=[C:46]([CH2:48][CH2:49][CH:50]5[NH:56][C:55](=[O:57])[CH2:54][CH2:53][CH2:52][CH2:51]5)[NH:45][C:42]4=[N:43][CH:44]=3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:14][CH2:13][CH2:12]1
Reactant: O=S(=O)(c1ccc(Br)cc1)N1CCC1
Reactant: O=C1CCCCC(CCc2nc3cc(Br)cnc3[nH]2)N1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: ClCCl
Product: O=C1CCCCC(CCc2nc3cc(-c4ccc(S(=O)(=O)N5CCC5)cc4)cnc3[nH]2)N1
Temperature: 110 °C
Yield: 46.3 %

Procedure:
378 mg of 1-(4-bromo-benzenesulfonyl)-azetidine (compound C3) are dissolved in 10 ml of oxygen-free dioxane under an atmosphere of dry nitrogen. Subsequently, 383 mg of bis(pinacolato)diboron, 30 mg of Pd(Cl)2(dppf).CH2Cl2, 23 mg of DPPF (1,1′-bis(diphenylphosphino)-ferrocene), and 403 mg of potassium acetate are added. The reaction mixture is heated at 110° C. for 16 hours during which time the former yellowish suspension becomes black (LC-MS monitoring for boronic ester intermediate). Thereafter, 300 mg of 7-[2-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-one (compound C1), 2.70 ml of aqueous sodium carbonate solution (strength 2.0 M), and 66 mg of trans-dichloro-bis(tricyclohexyl-phosphine)-palladium(II) are added and the reaction mixture is heated at 110° C. for 72 hours. Subsequently, the mixture is diluted with 50 ml of water and extracted three times each with 100 ml of dichloromethane. The organic layer is separated, dried using Na2SO4 (solid) and concentrated in vacuo. The resulting crude material is purified by chromatography on flash silica gel (eluent gradient: dichloromethane/0-10 vol. % ethanol) to yield 187 mg of the title compound as an oil. ESI-MS: 454.2 (MH+). TLC: Rf=0.29 (dichloromethane/ethanol 10:1 parts by volume).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[C:2]#[CH:3].[N:7]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[N:12]=1)=[N+:8]=[N-:9].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>CC(O)(C)C.O.C([O-])(O)=O.[Na+]>[Br:17][C:13]1[N:12]=[C:11]([CH2:10][N:7]2[CH:3]=[C:2]([C:1]([O:5][CH3:6])=[O:4])[N:9]=[N:8]2)[CH:16]=[CH:15][CH:14]=1
Reactant: C#CC(=O)OC
Reactant: [N-]=[N+]=NCc1cccc(Br)n1
Agent: O=C([O-])O
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: COC(=O)c1cn(Cc2cccc(Br)n2)nn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl propiolate (641 μL, 7.63 mmol) and 2-(azidomethyl)-6-bromopyridine (1.25 g, 5.87 mmol) were combined in t-BuOH (9.0 mL) and water (5.0 mL). A solution of CuSO4.5H2O (73 mg, 0.29 mmol) in water (2.0 mL) was added, followed by sodium ascorbate (232 mg, 1.17 mmol) in water (2.0 mL). The reaction was stirred at room temperature for 18 h, during which time it became a yellow suspension. The suspension was diluted with saturated NaHCO3 and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The crude solid was purified by flash chromatography (40-100% EtOAc/hexanes) to afford the title compound as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH2:23])=[C:16]2[N:15]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:32]([NH:31][C:28]3[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=3)=[O:33])=[C:16]2[N:15]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(F)cc1)Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Reaction time: 1.5 h
Yield: 83.9 %

Procedure:
To a DCM (0.8 mL) solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (Preparation B; 25 mg, 0.079 mmol) was added 1-fluoro-4-isocyanatobenzene (13 mg, 0.095 mmol) at ambient temperature drop-wise, followed by addition of DIEA (0.028 mL, 0.16 mmol). The reaction was stirred for 90 minutes before it was concentrated and directly purified by column chromatography on silica, eluting with 3:1 EtOAc/hexanes to yield the final product as a solid (30 mg, 84% yield). MS (apci) m/z=453.2 (M+H).
Reaction SMILES: [Br:1]Br.Cl.[NH2:4][CH2:5][CH2:6][CH2:7][C:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[C:17]([O:18][CH3:19])[C:12]=2[O:11][CH2:10][CH:9]=1.ClCCl>C(N(CC)CC)C>[NH2:4][CH2:5][CH2:6][CH:7]=[C:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[C:17]([O:18][CH3:19])[C:12]=2[O:11][CH2:10][CH:9]1[Br:1]
Reactant: BrBr
Reactant: COc1cccc2c1OCC=C2CCCN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc2c1OCC(Br)C2=CCCN
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
3.02 kg of bromine is added during 35 minutes to a mixture of 4.83 kg of 4-(3-aminopropyl)-8-methoxy-2H-[1]-benzopyran hydrochloride and 58 l of dichloromethane at 16°-23°, and once addition is complete the reaction is stirred for 3.5 hours at room temperature. 5.8 kg of triethylamine is added to yield 4-(3-aminopropylidene)-3-bromo-8-methoxy-2H-[1]-benzopyran. The reaction is heated at 60° for 4 hours and then stirred overnight at room temperature. The mixture is washed five times with 12 l water each and 8 l of brine, dried with anhydrous sodium sulfate, filtered and the filtrate is evaporated at reduced pressure to give an oil. This is dissolved in 12 l of isopropanol, treated with 400 g of charcoal, and the mixture is filtered. The filtrate is cooled at 10°, treated with 1.8 l of 10N ethanolic hydrogen chloride and stirred for 1 hour at 5°-10°. The suspension is filtered; the product is washed three times with 4 l isopropanol each and dried 72 hours at 40°/400 Pa to give 7-methoxy-2,3,4a,5-tetrahydro-4H-[1]-benzopyrano[3,4-b]pyridine hydrochloride, m.p. 195°-198° (dec).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1CCC(N=C=NC2CCCCC2)CC1.[C:35](=[N:38]O)([NH2:37])[CH3:36].N1C=CC=CC=1>C(Cl)Cl.CCOC(C)=O>[C:4]([O:3][C:1](=[O:2])[NH:8][C@@H:9]([C:17]1[O:19][N:38]=[C:35]([CH3:36])[N:37]=1)[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(N)=NO
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1noc([C@@H](Cc2ccccc2)NC(=O)OC(C)(C)C)n1
Reaction time: 1 h
Yield: 98.6 %

Procedure:
To a solution of N-Boc-L-phenylalanine (2.0 g, 7.5 mmol) in CH2Cl2 (20 mL) at 0° C. was added DCC (780 mg, 3.8 mmol) in CH2Cl2 (20 mL) via cannula. The reaction mixture was stirred for 1 h, the precipitate filtered off, and the filterate concentrated to dryness. Acetamidoxime (195 mg, 2.64 mmol) and pyridine (20 mL) were added and the reaction mixture heated at reflux for 1.5 h and then at RT for 16 h. The reaction mixture was poured into EtOAc (50 mL) and washed with 10% citric acid (3×25 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. Purification by column chromatography (25% EtOAc/hex) furnished (R)-[1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-phenylethyl]carbamic acid tertbutyl ester (790 mg, 99% yield). 304.22, M+H.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[CH3:10].[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=C(S([O-])(=O)=O)C=2OC)CCCCC1.[Na+].O>[CH3:10][C:3]1[CH:4]=[C:5]([CH3:9])[CH:6]=[C:7]([CH3:8])[C:2]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH3:11]
Reactant: Cc1cc(C)c(Br)c(C)c1
Reactant: Cc1ccccc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1ccc(S(=O)(=O)[O-])c(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Product: Cc1cc(C)c(-c2ccccc2C)c(C)c1
Yield: 93.7 %

Procedure:
The general procedure described in Example 3 was used with 2-bromo-mesitylene (0.153 mL, 1.00 mmol), 2-methylphenylboronic acid (203 mg, 1.50 mmol), Pd(OAc)2 (4.5 mg, 0.020 mmol, 2 mol %), sodium 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl-3′-sulfonate (20.0 mg, 0.040 mmol, 4 mol %), K2CO3 (276 mg, 2.00 mmol), water (1.5 mL), 22 h, room temperature. The product was isolated as a colorless oil (197 mg, 94%). 1H NMR (400 MHz, CDCl3) δ: 7.30-7.19 (m, 3H), 7.05-7.00 (m, 1H), 6.92 (s, 2H), 2.30 (2, 3H), 1.99 (s, 3H), 1.89 (s, 6H). 13C NMR (125 MHz, CDCl3) δ: 140.9, 138.2, 136.4, 136.0, 135.9, 130.0, 129.2, 128.1, 127.1, 126.2, 21.4, 20.6, 19.9.
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:5]1([NH:39][CH2:40][CH2:41][NH:42][S:43]([CH3:46])(=[O:45])=[O:44])[CH2:4][CH2:3]2.[CH2:47](S(Cl)(=O)=O)C>>[CH2:46]([S:43]([NH:42][CH2:41][CH2:40][NH:39][C@:5]12[CH2:35][CH2:34][C@@H:33]([C:36]([CH3:38])=[CH2:37])[C@@H:6]1[C@@H:7]1[C@@:2]([CH3:1])([CH2:3][CH2:4]2)[C@@:19]2([CH3:20])[C@@H:10]([C@:11]3([CH3:32])[C@@H:16]([CH2:17][CH2:18]2)[C:15]([CH3:21])([CH3:22])[C:14]([C:23]2[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=2)=[CH:13][CH2:12]3)[CH2:9][CH2:8]1)(=[O:45])=[O:44])[CH3:47]
Reactant: CCS(=O)(=O)Cl
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCNS(C)(=O)=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NCCNS(=O)(=O)CC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(methylsulfonamido)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid using ethanesulfonyl chloride as the reagent in Step 1. The product was isolated as a white solid (8.7 mg, 56%). LCMS: m/e 665.46 (M+H)+, 2.29 min (method 11). 1H NMR (500 MHz, CHLOROFORM-d) δ 9.27 (br. s., 1H), 8.00 (d, J=7.1 Hz, 2H), 7.25 (d, J=7.1 Hz, 2H), 6.84 (br. s., 1H), 6.07 (br. s., 1H), 5.24 (d, J=6.3 Hz, 1H), 4.85 (s, 1H), 4.73 (s, 1H), 3.84-3.68 (m, 1H), 3.54 (d, J=14.8 Hz, 1H), 3.37-3.21 (m, 2H), 3.17 (q, J=7.4 Hz, 2H), 2.83-2.76 (m, 1H), 2.36-0.95 (m, 22H), 1.72 (s, 3H), 1.46 (t, J=7.4 Hz, 3H), 1.20 (s, 3H), 1.05 (s, 3H), 0.97 (s, 3H), 0.95 (s, 3H), 0.95 (s, 3H).
Reaction SMILES: C(=O)(O)[O-].[K+].[F:6][C:7]1[C:13](F)=[CH:12][C:10]([NH2:11])=[C:9]([N+:15]([O-:17])=[O:16])[CH:8]=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].O>CN(C=O)C>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:13]2[CH:12]=[C:10]([NH2:11])[C:9]([N+:15]([O-:17])=[O:16])=[CH:8][C:7]=2[F:6])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2cc(N)c([N+](=O)[O-])cc2F)CC1
Temperature: 60 °C
Yield: 71.6 %

Procedure:
2.4 g of potassium bicarbonate and 1 g of 4,5-difluoro-2-nitroaniline are added to a solution of 3.3 g of piperazine-1-carboxylic acid tert-butyl ester in 30 mL of anhydrous DMF. The reaction medium is heated at 60° C. using an oil bath for 30 minutes. The reaction medium is cooled to ambient temperature, then 150 mL of water are added thereto, and precipitation occurs. The precipitate is filtered off through sintered glass. The solid is dried in an oven at 50° C. 1.4 g of 4-(5-amino-2-fluoro-4-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester are obtained in the form of a yellow solid. 1H NMR (300 MHz, DMSO-d6, δ in ppm): 1.42 (s, 9H); 3.14 (m, 4H); 3.46 (m, 4H); 6.43 (d, J=8.0 Hz, 1H); 7.36 (broad s, 2H); 7.66 (d, J=14.5 Hz, 1H). EI mass spectrum: m/z=340 M+., m/z=284 (M−C4H+., m/z=264 (m/z=284−HF)+, m/z=57 C4H+ (base peak).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][C:4]=2[CH:3]=1.O.[NH2:22][NH2:23].C1C(O)=CC(C(O)=O)=C(O)C=1>O1CCOCC1>[NH:22]([C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][C:4]=2[CH:3]=1)[NH2:23]
Reactant: CCCCCCCC(=O)N1CCc2nnc(Cl)cc2C1
Reactant: NN
Agent: O=C(O)c1cc(O)ccc1O
Solvent: O
Solvent: C1COCCO1
Product: CCCCCCCC(=O)N1CCc2nnc(NN)cc2C1

Procedure:
11.5 g of 3-chloro-6-octanoyl-5,6,7,8-tetrahydropyrido(4,3-c]pyridazine, dissolved in 50 cc of dioxane, and 30 cc of hydrazine hydrate are stirred at a bath temperature of 100° for 16 hours, and the mixture is worked up as described in Example 17. The gentisinate of the title compound has a M.P. of 164°-166° (decomp., from methanol).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][C:3]=1[OH:18]>[OH-].[Na+].[Ni]>[N:12]1([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:2]=[C:3]([OH:18])[CH:4]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: Oc1cc(N2CCCCC2)c2ccccc2c1Cl
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Product: Oc1cc(N2CCCCC2)c2ccccc2c1
Yield: 55.9 %

Procedure:
1-Chloro-4-piperidino-2-naphthol (3.0 g;0.0115 mol), prepared as in 1(a) above, dissolved in 1.25M aqueous NaOH (100 ml) was stirred and heated to 75°-80° C. To the solution was added (50/50) Raney Nickel (14.0 g) portionwise over 1 hour. The mixture was stirred for 1.5 h, cooled then filtered through celite with washing (3×2M NaOH). The filtrate was neutralised with conc. HCl and extracted into CH2Cl2, dried and evaporated to yield crude 4-piperidino-2-naphthol (1.46 g;56%) as a red-orange oil. Purification by flash chromatography over silica (CH2Cl2) gave 4-piperidino-2-naphthol (of structure 4a below) as a red oil. ##STR16## (c) A mixture of 4-piperidino-2-naphthol (1.00 g; 0.0044 mol) , prepared as described in 1(b) above, 1,1-dianisylprop-2-yn-1-ol(1.18 g;0.0044 mol), acidic alumina Brockmann 1 (4 g) and toluene (40.0 ml) was heated and stirred for 1.5 h, cooled and filtered. The filtrate was washed with 2M NaOH then water, dried and evaporated to give a red gum. Purification of the gum by flash chromatography over silica (20% ethylacetate in hexane) affored an orange gum which upon trituration with pet. ether (40-60)/diethyl ether yielded 3,3-dianisyl-6-piperidino -3H-naphtho[2,1-b]pyran (of structure 5a below) as an off-white solid (5% yield), m.pt. 114°-119° C. ##STR17##
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Br[CH2:22][CH2:23][OH:24]>O>[OH:24][CH2:23][CH2:22][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCO)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
12.2 g (0.1 mol) of 4-hydroxybenzaldehyde, 16.6 g (0.12 mol) of potassium carbonate and 100 ml of N,N-dimethylformamide were put in a three-neck 300 ml-flask equipped with a thermometer and a stirrer and heated up to 60° C. To this mixture was dropwise added 25.0 g (0.2 mol) of 2-bromoethanol. The internal temperature rose up to 80° C. due to the reaction heat. Afterwards, the reaction system was heated and stirred at 100° C. for 2 hours. The reaction mixture was cooled to room temperature, poured into water and extracted with ethyl acetate. The resulting extract was dried with anhydrous sodium sulfate, and ethyl acetate was removed therefrom by distillation. The residue was subjected to silica gel column chromatography (using an eluent of ethyl acetate/n-hexane of 1/1) to obtain the intended 4-(2-hydroxyethoxy)benzaldehyde as an oily product. The yield of the product was 5.8 g (34.9%).