Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:31][C@H:32]([OH:39])[C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[C:19]([O:26][CH2:27][CH:28]([CH3:30])[CH3:29])[CH:18]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:52][S:53]([NH2:56])(=[O:55])=[O:54].N1CCCN2CCCCCC=12.Cl>CN(C)C=O.O>[OH:39][C@H:32]([C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1)[CH2:31][N:8]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([NH:56][S:53]([CH3:52])(=[O:55])=[O:54])=[O:24])=[C:19]([O:26][CH2:27][CH:28]([CH3:29])[CH3:30])[CH:18]=2)=[CH:13][CH:12]=1)[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)COc1cc(-c2ccc(CCN(C[C@H](O)c3cccnc3)C(=O)OC(C)(C)C)cc2)ccc1C(=O)O
Reactant: CS(N)(=O)=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)COc1cc(-c2ccc(CCN(C[C@H](O)c3cccnc3)C(=O)OC(C)(C)C)cc2)ccc1C(=O)NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.4 %

Procedure:
To a solution of 4′-[2-[[tert-butoxycarbonyl][(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]ethyl]-3-isobutoxy-4-biphenylcarboxylic acid (170 mg) in N,N-dimethylformamide (1.70 ml) was added 1,1′-carbonylbis(1H-imidazole) (61.7 mg) and the mixture was stirred at room temperature for 1 hour under nitrogen atmosphere. To the reaction mixture were added methanesulfonamide (36.3 mg) and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (0.057 ml) and the mixture was stirred at 120° C. for 12 hours. After cooling to room temperature, to the reaction mixture was added water (10 ml) and the pH was adjusted to 5.98 with 0.1N hydrochloric acid. The mixture was extracted with ethyl acetate (twice), washed with water and brine and dried over magnesium sulfate. Filtration followed by evaporation under reduced pressure gave a crude produce which was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=1/1.5) and further purification by column chromatography on silica gel (eluent: chloroform/methanol=100/0 to 99/1) gave tert-butyl [(2R)-2-hydroxy-2-(3-pyridyl)ethyl][2-[3′-isobutoxy-4′-[[(methylsulfonyl)amino]carbonyl]-4-biphenylyl]ethyl]carbamate (63 mg) as a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH:11]=[C:10]([CH2:22][O:23]C(=O)C)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH:11]=[C:10]([CH2:22][OH:23])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2cc(COC(C)=O)nc(-c3cccc(Cl)c3)c2cc1OC
Agent: Cl
Product: COc1cc2cc(CO)nc(-c3cccc(Cl)c3)c2cc1OC
Yield: 197.1 %

Procedure:
15.67 g (0.042 M) of 1-(3-chlorophenyl)-3-(acetoxymethyl)-6,7-dimethoxy-isoquinoline (compound of Example 21) are refluxed in 160 ml of an aqueous 5% solution of hydrochloric acid for one hour. The crystals of the end-product are rapidly beginning to form from the initially clear solution. After ice-cooling the reaction mixture is filtered, the product is washed with 3×10 ml of water and dried at 90° to 100° C., giving 15.21 g of a crude product, m.p. 210° to 214° C. The crude product is purified by refluxing in 180 ml of 99.5% ethanol, the suspension is cooled and kept at +5° C. for 10 hours, then it is filtered, washed with 3×5 ml of ethanol and dried. Yield 12.67 g (82.4%), m. p. 219° to 221° C. d.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[CH2:14][CH2:13]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:11][CH:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[CH2:16][CH2:17]2)=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1cc(OC2CCN(C(=O)OCc3ccccc3)CC2)ccc1[N+](=O)[O-]
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1cc(OC2CCN(C(=O)OCc3ccccc3)CC2)ccc1N
Temperature: 0 °C
Yield: 77.6 %

Procedure:
Phenylmethyl 4-[(3-methyl-4-nitrophenyl)oxy]-1-piperidinecarboxylate (0.798 g, 2.15 mmol) was dissolved in 20 mL of MeOH with stirring. Nickel(II) chloride hexahydrate (0.256 g, 1.08 mmol) was added and the mixture was cooled to 0° C. Sodium borohydride (0.163 g, 4.31 mmol) was added, and the mixture was stirred for 20 min. Additional sodium borohydride (˜20 to 30 mg) was added, and the mixture was stirred for 10 min more. The reaction was quenched by the addition of approximately 15 mL of 2N sodium hydroxide solution. The mixture was poured into EtOAc and H2O, and the layers were separated. The organic layer was washed with brine, and the combined aqueous layers were extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford 0.568 g (78%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 7.40-7.23 (m, 5H), 6.61-6.43 (m, 3H), 5.04 (s, 2H), 4.37 (s, 2H), 4.27-4.17 (m, 1H), 3.74-3.57 (m, 2H), 3.27-3.12 (m, 2H), 1.97 (s, 3H), 1.86-1.73 (m, 2H), 1.52-1.39 (m, 2H).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].[OH-].[Na+].[CH3:9][C:10]1[CH:19]=[CH:18][C:13]([CH2:14][N:15]=[N+:16]=[N-:17])=[CH:12][C:11]=1[C:20]([Cl:24])=[C:21]([Cl:23])[Cl:22]>C(O)C>[NH2:2][C:1]1[N:15]([CH2:14][C:13]2[CH:18]=[CH:19][C:10]([CH3:9])=[C:11]([C:20]([Cl:24])=[C:21]([Cl:23])[Cl:22])[CH:12]=2)[N:16]=[N:17][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: N#CCC(N)=O
Reactant: Cc1ccc(CN=[N+]=[N-])cc1C(Cl)=C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(Cn2nnc(C(N)=O)c2N)cc1C(Cl)=C(Cl)Cl
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 41.3 %

Procedure:
To a hot (60° C.) solution of cyanoacetamide (1.09 g) in 30 ml of ethanol, 13 ml of a methanolic solution of NaOH (1N) was added and the resulting mixture was stirred at 60° C. for 20 minutes. At this point a solution of 4-methyl-3-(trichlorovinyl)benzyl azide (1.65 g) in 10 ml of ethanol was added and the reaction mixture stirred at 60° C. for an additional two hours. The precipitate was removed by filtration and rinsed with ethanol and ether. The filtrate was diluted with water (200 ml) and the resulting precipitate collected (1.56 g). The crude product was chromatographed on silica with 95:5 methylene chloride:methanol to give 889 mg of 5-amino-1-[4-methyl-3-(trichlorovinyl)benzyl]-1,2,3-triazole-4-carboxamide, m.p. 196°-197° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][S:5](=[O:38])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[N:6][C:7](=[O:31])[C:8]1[CH:13]=[C:12]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]3[O:26][CH:27]=[CH:28][C:29]=3[CH3:30])=[O:24])[CH:17]=2)[CH:11]=[N:10][CH:9]=1.[OH:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>CN(C=O)C>[OH:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][N:45]1[CH2:50][CH2:49][N:48]([CH2:2][CH2:3][CH2:4][S@:5](=[O:38])([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[N:6][C:7](=[O:31])[C:8]2[CH:13]=[C:12]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]4[O:26][CH:27]=[CH:28][C:29]=4[CH3:30])=[O:24])[CH:17]=3)[CH:11]=[N:10][CH:9]=2)[CH2:47][CH2:46]1
Reactant: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(=O)(CCCBr)c3ccccc3)c2)c1
Reactant: OCCOCCN1CCNCC1
Solvent: CN(C)C=O
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=[S@](=O)(CCCN3CCN(CCOCCO)CC3)c3ccccc3)c2)c1
Temperature: 80 °C

Procedure:
To the solution of N-[(3-bromopropyl)(oxido)phenyl--sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide (450 mg, 0.76 mmol) in anhydrous DMF (5 mL) was added dropwise 1-[2-(2-hydroxyethoxy)ethyl]piperazine. The resulting reaction solution was stirred and heated at 80° C. for 30 min. It was then partitioned between saturated aqueous NaHCO3 and EtOAc. The EtOAc layer was separated and washed with brine (1×). The aqueous NaHCO3 layer was extracted with CHCl3 (1×) and the extract was washed with brine (1×). The organic layers were combined and dried over anhydrous sodium sulfate. The organic solution was decanted, concentrated, and wrapped with silica gel. Column chromatography (MeOH-EtOAc from 1:10 to 1:6) rendered the title compound as white foam in amount of 500 mg (96%).
Reaction SMILES: C(OC([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:40]([CH3:42])[CH3:41])[C:24](=[O:39])[C:25]([F:38])([F:37])[C:26](=[O:36])[NH:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[O:21])[C:15]([C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=2)=[N:14][CH:13]=1)=O)C1C=CC=CC=1.Cl.ClCCl.CO>O.ClCCl.CO>[NH2:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:40]([CH3:42])[CH3:41])[C:24](=[O:39])[C:25]([F:37])([F:38])[C:26](=[O:36])[NH:27][CH2:28][CH2:29][N:30]2[CH2:31][CH2:32][O:33][CH2:34][CH2:35]2)=[O:21])[C:15]([C:43]2[CH:44]=[CH:45][C:46]([F:49])=[CH:47][CH:48]=2)=[N:14][CH:13]=1
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccc(F)cc2)ncc(NC(=O)OCc2ccccc2)c1=O)C(=O)C(F)(F)C(=O)NCCN1CCOCC1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CC(C)C(NC(=O)Cn1c(-c2ccc(F)cc2)ncc(N)c1=O)C(=O)C(F)(F)C(=O)NCCN1CCOCC1

Procedure:
2-[5-Benzyloxycarbonylamino-2-(4-fluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-N-[3,3-difluoro-1-isopropyl-2-oxo-3-[N-(2-morpholinoethyl)carbamoyl]propyl]acetamide. Using a procedure similar to that described in Example 1, except omitting the 10% hydrochloric acid wash, the ketone was prepared; chromatography solvent: dichloromethane:methanol (gradient, 96:4, 95:5); TLC: Rf =0.41, dichloromethane:methanol (95:5); MS: m/z=687(M+1). Analysis for C33H37F3N6O7.0.95 H2O: Calculated: C, 56;32; H, 5.57; N, 11.94; Found: C, 56.28; H, 5.63; N, 11.90.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([C:12]([F:15])([F:14])[F:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].O.CCOC(C)=O.C[C:24]([N:26](C)C)=O>[C-]#N.[Zn+2].[C-]#N.[Zn].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.[Pd+2].[Pd+2].C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[CH-]1C=CC=C1.[Fe+2]>[C:24]([C:2]1[CH:3]=[CH:4][C:5]([C:12]([F:15])([F:14])[F:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])#[N:26]
Reactant: COC(=O)c1cc(Cl)ccc1C(F)(F)F
Reactant: CC(=O)N(C)C
Agent: [Fe+2]
Agent: [Pd+2]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc(C#N)ccc1C(F)(F)F
Temperature: 85 °C
Reaction time: 12 h
Yield: 66.5 %

Procedure:
Dissolve methyl 5-chloro-2-(trifluoromethyl)benzoate (500 mg, 2.1 mmol), zinc (II) cyanide (197 mg, 1.68 mmol), zinc (55 mg, 0.84 mmol), di-palladium (II) tris(dibenzylideneacetone) (192 mg, 0.21 mmol), and diphenylphosphino ferrocene (233 mg, 0.42 mmol) in dimethylacetamide (20 mL). Heat the reaction mixture to 85° C., and stir for 12 hours. Pour the resulting mixture into water, and extract with EtOAc (2×100 mL). Dry the combined organics over sodium sulfate; filter; collect the filtrate; and concentrate the filtrate under reduced pressure. Purify the residue by silica gel chromatography eluting with 50:1 petroleum ether:EtOAc to give the title compound (320 mg, 66.5% yield) as a white solid. 1H NMR (300 MHz, CDCl3,) δ 8.09 (s, 1H), 7.90 (s, 2H), 3.80 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[CH:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])=[C:4]([F:17])[CH:3]=1.[C:18]([CH2:20][C:21](OCC)=[O:22])#[N:19].N1CCCCC1.O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:21](=[O:22])[C:20]([C:18]#[N:19])=[C:11]([C:12]([F:15])([F:14])[F:13])[CH:10]=[N:9]2)=[C:4]([F:17])[CH:3]=1
Reactant: CCOC(=O)CC#N
Reactant: O=C(C=NNc1ccc(Cl)cc1F)C(F)(F)F
Solvent: C1CCNCC1
Solvent: c1ccncc1
Solvent: O
Product: N#Cc1c(C(F)(F)F)cnn(-c2ccc(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
After 1.0 g of 3, 3, 3-trifluoro-2-oxopropanal 1-(4-chloro-2-fluorophenylhydrazone) was dissolved in 10 mL of pyridine, 0.8 mL of ethyl cyanoacetate and 0.5 mL of piperidine were added to the pyridine solution, which was followed by stirring for 3 days at room temperature. After pouring into water, the reaction solution was extracted with ethyl acetate. After the organic layer was washed with aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate and concentrated, the residue was subjected to silica gel column chromatography (eluent: ethyl acetate/hexane =4/1), and thin-layer chromatography (eluent: ethyl acetate/hexane =5/1) to afford 0.28g of 2-(4-chloro-2-fluorophenyl)-4-cyano-5-trifluoromethylpyridazin-3-one (The present compound 1-1).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:13]=[C:14]([C@@H:18]2[C@@H:23]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[N:22]([C@@H:31]([CH2:34][CH3:35])[CH2:32][OH:33])[C:21](=[O:36])[C@@H:20]([CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:19]2)[CH:15]=[CH:16][CH:17]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[C:14]([C@@H:18]2[C@@H:23]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[N:22]([C@@H:31]([CH2:34][CH3:35])[CH:32]=[O:33])[C:21](=[O:36])[C@@H:20]([CH2:37][C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])[CH2:19]2)[CH:15]=[CH:16][CH:17]=1
Reactant: CC[C@@H](CO)N1C(=O)[C@@H](CC(=O)OC(C)(C)C)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC[C@@H](C=O)N1C(=O)[C@@H](CC(=O)OC(C)(C)C)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of oxalyl chloride (0.261 mL, 2.99 mmol) in DCM (5.87 mL) at −60° C. was added a solution of DMSO (0.512 mL, 5.98 mmol) in DCM (5.87 mL) under N2. After being stirred for 20 min, a solution of tert-butyl 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-2-oxopiperidin-3-yl)acetate (1.01 g, 1.99 mmol, Example 21, Step B) in DCM (5.87 mL) was added, and the resulting solution was stirred for 15 min. To this solution was added triethylamine (1.39 mL, 9.97 mmol). After being stirred at −60° C. for 5 min, the reaction was allowed to warm to rt, and quenched (H2O). The solution was extracted (3×DCM) and washed (H2O and sat. aq. NaCl solution). The combined organic layers were washed with sat. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give the title compound.
Reaction SMILES: [Mg].Br[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH2:8])=[CH:5][CH:4]=1.[CH3:11][C:12]1([CH3:37])[CH2:36][O:35][C:15]2([CH2:32][CH2:31][C@:30]34[O:33][C@:17]3([CH2:18][CH2:19][C@@H:20]3[C:29]4=[CH:28][CH2:27][C@@:25]4([CH3:26])[C@H:21]3[CH2:22][CH2:23][C:24]4=[O:34])[CH2:16]2)[O:14][CH2:13]1.[Cl-].[NH4+]>O1CCCC1.BrCCBr.[Cu]Cl>[CH3:11][C:12]1([CH3:37])[CH2:13][O:14][C:15]2([CH2:32][CH2:31][C:30]3[C@@:17]([OH:33])([CH2:18][CH2:19][C@@H:20]4[C:29]=3[C@@H:28]([C:3]3[CH:10]=[CH:9][C:6]([CH:7]=[CH2:8])=[CH:5][CH:4]=3)[CH2:27][C@@:25]3([CH3:26])[C@H:21]4[CH2:22][CH2:23][C:24]3=[O:34])[CH2:16]2)[O:35][CH2:36]1
Reactant: C=Cc1ccc(Br)cc1
Reactant: CC1(C)COC2(CC[C@]34O[C@]3(CC[C@@H]3C4=CC[C@]4(C)C(=O)CC[C@@H]34)C2)OC1
Agent: Cl[Cu]
Agent: [Cl-]
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: C=Cc1ccc([C@H]2C[C@]3(C)C(=O)CC[C@H]3[C@@H]3CC[C@@]4(O)CC5(CCC4=C32)OCC(C)(C)CO5)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.2 %

Procedure:
3.3 g of magnesium turnings are placed in 14 ml of absolute tetrahydrofuran under inert gas and one drop of 1,2-dibromoethane is added. After the reaction has started, a solution of 25 g of 4-bromostyrene in 137 ml of absolute tetrahydrofuran is slowly added dropwise so that the internal temperature remains in the range from 40 to 45° C. The reaction mixture is subsequently stirred for one hour until the magnesium has completely reacted. 2.26 g of copper(I) chloride are then added to the mixture. A solution of 8.5 g of 5,10-epoxy-5α,10α-estr-9(11)-ene-3,17-dione 3-(2,2-dimethylpropane-1,3-diyl) ketal (for preparation cf. Tetrahedron Lett. 26, 2069-2072 (1985)) in 137 ml of absolute tetrahydrofuran is slowly added dropwise. The reaction mixture is stirred for one hour at room temperature and then poured into saturated aqueous ammonium chloride solution. The aqueous phase is extracted with ethyl acetate and the organic phases are combined, washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. The product is filtered and concentrated under vacuum. Column chromatography on silica gel with a hexane/ethyl acetate mixture gives 6.76 g of the title compound as a colorless foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][NH2:13])[C:6]([O:14][CH3:15])=[N:5]2.[CH:16](OCC)(OCC)OCC>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:16]=[N:13][N:12]=[C:7]1[C:6]([O:14][CH3:15])=[N:5]2
Reactant: COc1nc2cc(Cl)ccc2nc1NN
Reactant: CCOC(OCC)OCC
Product: COc1nc2cc(Cl)ccc2n2cnnc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture consisting of 1.4 g. (0.0062 mole) of 6-chloro-2-hydrazino-3-methoxyquinoxaline and 20 ml. of triethyl orthoformate was heated with mechanical stirring in a preheated oil bath at 100° C. overnight (~16 hours). The resulting mixture was then cooled to room temperature, and the precipitate which formed was subsequently recovered by means of suction filtration and washed with ethanol to ultimately afford 1.0 g. (69%) of pure 7-chloro-4-methoxy-[1,2,4]triazolo[4,3,a]quinoxaline, m.p. 250°-252° C.
Reaction SMILES: C(Cl)(Cl)Cl.[CH3:5][C@@:6]12[O:13][C@@H:10]([CH2:11][CH2:12]1)[C:9](=[O:14])[CH2:8][C:7]2=[O:15].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[C:37]([Pb+3])[CH:36]=2)=[CH:31][CH:30]=1.Cl>C1(C)C=CC=CC=1>[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[C:37]([CH:8]3[C:9](=[O:14])[C@H:10]4[O:13][C@:6]([CH3:5])([CH2:12][CH2:11]4)[C:7]3=[O:15])[CH:36]=2)=[CH:33][CH:34]=1
Reactant: Cc1ccc(-c2ccc(Cl)cc2)cc1[Pb+3]
Reactant: C[C@]12CC[C@H](O1)C(=O)CC2=O
Agent: CC(=O)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2ccc(Cl)cc2)cc1C1C(=O)[C@@H]2CC[C@@](C)(O2)C1=O
Temperature: 25 °C
Yield: 41.8 %

Procedure:
To a mixture of chloroform (3.5 ml) and toluene (0.75 ml) is added (1R*,5S*)-1-methyl-8-oxa-bicyclo[3.2.1]octane-2,4-dione (0.25 g, 1.62 mmol) and N,N-dimethylaminopyridine (0.99 g, 8.11 mmol) under a nitrogen atmosphere with stirring. To this reaction mixture is then added 4′-chloro-4-methylbiphenyl-3-yllead triacetate (1.05 g, 1.78 mmol) in one portion, then the mixture heated at 80° C. for 1-2 hours. The reaction mixture is cooled to room temperature, acidified with dilute aqueous hydrochloric acid then filtered through diatomaceous earth to remove inorganic residues (subsequent washing with dichloromethane). Aqueous fractions are extracted with dichloromethane (2×10 ml), then all organic fractions are combined, dried over sodium sulfate and concentrated under vacuum to give crude product which is purified by flash chromatography (hexane/ethyl acetate) to give (1R*,5S*)-3-(4′-chloro-4-methylbiphenyl-3-yl)-1-methyl-8-oxabicyclo[3.2.1]octane-2,4-dione (0.240 g) as a white solid.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[C:22]=1I)=[O:4].[OH-].[K+].O.[CH3:29][S:30]SC>N1C=CC=CC=1.[Cu]>[F:1][C:2]([F:25])([F:24])[C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[C:22]=1[S:30][CH3:29])=[O:4]
Reactant: CSSC
Reactant: O=C(c1ccccc1)c1ccc2nc(NC(=O)C(F)(F)F)c(I)n2c1
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: CSc1c(NC(=O)C(F)(F)F)nc2ccc(C(=O)c3ccccc3)cn12
Temperature: 104 °C
Reaction time: 0.25 h
Yield: 81.4 %

Procedure:
The 2-trifluoroacetamido-3-iodo-6-benzoyl-imidazo[1,2-a]pyridine (1.00 g, 2.17 mmol) was dissolved in 20 ml of pyridine (predried over KOH and then molecular sieve 3A , 0.04% H2O) under argon atmosphere. Copper bronze (207 mg, 3.25 mmol) was added. To the golden suspension in brown solution was added methyldisulfide (160 μl, 2.17 mmol) via syringe. The reaction mixture was heated for 1 hour at 104° C. then 68 hours at 100° C. The evolution of the reaction was followed by NMR (in each case, a sample was taken, hydrolized and washed with ammonia/NH4Cl (1:9) before checking by NMR). When the reaction was complete, the reaction mixture was diluted in 3 L of EtOAc and stirred for 15 minutes. Two liters of NH4OH/NH4Cl 1:9 were added and the mixture was strongly stirred for 30 minutes in a 10 L funnel. The layers were separated and 2 L of NH4OH/NH4Cl (1:9) were added to the organic layer. The mixture was again stirred for 30 minutes and then left without stirring for 5 to 10 minutes. The layers were separated and the organic layer was washed with brine. The organic layers were removed in vacuo and the resulting brown solid was subjected to a vary rapid column chromatography (MeOH/CH2Cl2, 2:98) to give 670 mg (81%) of a yellow solid. NMR
Reaction SMILES: [SH:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].F[C:11]1[C:12]([CH:25]=[O:26])=[CH:13][C:14]2[C:15]([CH3:24])([CH3:23])[CH2:16][CH2:17][C:18]([CH3:22])([CH3:21])[C:19]=2[CH:20]=1>CN(C)C=O>[CH3:21][C:18]1([CH3:22])[CH2:17][CH2:16][C:15]([CH3:23])([CH3:24])[C:14]2[CH:13]=[C:12]([CH:25]=[O:26])[C:11]([S:1][C:2]3[N:7]=[CH:6][CH:5]=[CH:4][N:3]=3)=[CH:20][C:19]1=2
Reactant: Sc1ncccn1
Reactant: CC1(C)CCC(C)(C)c2cc(C=O)c(F)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)CCC(C)(C)c2cc(Sc3ncccn3)c(C=O)cc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 15.7 %

Procedure:
To a solution of 0.479 g (4.27 mmol) of 2-mercaptopyrimidine in 11 mL dimethylformamide was added 0.108 g (4.27 mmol) of 95% sodium hydride. After 20 minutes, 1.00 g (4.27 mmol) of 3-fluoro-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthaldehyde was added and the resulting solution was heated at reflux. After 18 hours, the reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The organic phase was washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The product was purified by flash chromatography on silica (15% ethyl acetate/hexane) to afford 0.219 g (16%) of 5,5,8,8-tetramethyl-3-(pyrimidin-2-yl-thio)-5,6,7,8-tetrahydro-2-naphthaldehyde (mp=143.2-145.8). Horner-Emmons olefination, followed by ester saponification gave 4-{(E)-2-[5,5,8,8-Tetramethyl-3-(mercaptopyrmidin-2-yl)-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoic acid 155 (mp=283-283.5). Substitution of 2-mercaptopyrimidine with 2-mercaptothiazole gave 4-{(E)-2-[5,5,8,8-Tetramethyl-3-(mercaptothiazol-2-yl)-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoic acid 154 (MH+=450).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[NH:12][C:11](C(O)=O)=[C:10]([CH2:16][C:17]([OH:19])=[O:18])[C:9]=2[CH3:20])=[O:7])=[CH:4][CH:3]=1.N1C2C(=CC=CC=2)C=CC=1.Cl>>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[NH:12][CH:11]=[C:10]([CH2:16][C:17]([OH:19])=[O:18])[C:9]=2[CH3:20])=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)c2ccc(Cl)cc2)[nH]c(C(=O)O)c1CC(=O)O
Agent: Cl
Solvent: c1ccc2ncccc2c1
Product: Cc1c(CC(=O)O)c[nH]c1C(=O)c1ccc(Cl)cc1

Procedure:
A solution of 1.4 g. (0.004 mole) of 5-(ρ-chlorobenzoyl)-4-methyl-2-carboxypyrrole-3-acetic acid in 25 ml. quinoline is heated overnight at 160° C. under nitrogen. The reaction is poured into ice acidified with hydrochloric acid. The mixture is extracted with chloroform, and the organic phase is extracted with a saturated solution of sodium bicarbonate. The basic solution is made acidic with dilute hydrochloric acid, and the resulting solid, 5-(ρ-chlorobenzoyl)-4-methylpyrrole-3-acetic acid, is filtered and purified by recrystallization from isopropyl alcohol, M.P. 145°-147° C.