Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][C:10]1[C:30]([C:31]#[C:32][CH2:33][NH:34][C:35](=[O:40])[C:36]([F:39])([F:38])[F:37])=[CH:29][N:13]([C@@H:14]2[O:28][C@H:18]([CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[C@@H:16]([OH:17])[CH2:15]2)[C:12](=[O:41])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.C(OC(=O)C)(=O)C.C([O-])(O)=O.[Na+].[CH3:58][S:59]([CH3:61])=O>>[C:1]([NH:9][C:10]1[C:30]([C:31]#[C:32][CH2:33][NH:34][C:35](=[O:40])[C:36]([F:37])([F:38])[F:39])=[CH:29][N:13]([C@@H:14]2[O:28][C@H:18]([CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:22])[CH3:23])[C@@H:16]([O:17][CH2:58][S:59][CH3:61])[CH2:15]2)[C:12](=[O:41])[N:11]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(C)=O
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(C#CCNC(=O)C(F)(F)F)c(NC(=O)c3ccccc3)nc2=O)C[C@@H]1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CSCO[C@H]1C[C@H](n2cc(C#CCNC(=O)C(F)(F)F)c(NC(=O)c3ccccc3)nc2=O)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 50 %

Procedure:
The starting material (13) (2.85 g, 4.79 mmol) was dissolved in dry DMSO (40 ml) under N2 atmosphere. Acetic acid (2.7 ml, 47.9 mmol) and acetic anhydride (14.4 ml, 143.7 mmol) were added sequentially and slowly to the starting material, which was then stirred for 18 h at room temperature. Saturated NaHCO3 (150 ml) solution was carefully added to the reaction mixture. The aqueous layer was extracted with EtOAc (3×150 ml). The organic layers were combined, dried (MgSO4), filtered and evaporated to yield an orange liquid that was subsequently azeotroped with toluene (4×150 ml) until material solidified. Crude residue purified on silica gel (petroleum ether:EtOAc 3:1 to 2:1) to yield a yellow crystalline solid (14) (1.58 g, 50%). 1H NMR (d6 DMSO): δ 0.00 (s, 6H, CH3), 0.78 (s, 9H, tBu), 1.99 (s, 3H, CH3), 2.09 (m, 1H, H-2′), 2.28 (m, 1H, H-2′), 3.66 (d, 1H, J=11.5, 2.9 Hz, H-5′), 3.74 (dd, 1H, J=11.3, 2.9 Hz, H-5′), 3.99 (m, 1H, H-4′), 4.09 (m, 1H, CH2NH), 4.29 (m, 1H, H-3′), 4.61 (s, 2H, CH2S), 6.00 (m, 1H, H-1′), 7.37 (m, 2H, Ph), 7.50 (m, 2H, Ph), 7.80 (d, 1H, J=7.55 Hz, HAr), 7.97 (s, 1H, H-6), 9.79 (br t, 1H, NHCH2), 12.64 (br s, 1H, NH). Mass (−ve electrospray) calcd for C29H37F3N4O6SSi 654.79. found 653.2.
Reaction SMILES: [C:1]([OH:5])(=O)[C:2]#[CH:3].N1(C(N2C=CN=C2)=O)C=CN=C1.[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C:26](=[O:38])[CH2:27][C:28]1[NH:32][C:31]2[CH2:33][CH2:34][CH:35]([CH3:37])[CH2:36][C:30]=2[N:29]=1>>[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C:26]([C:27]1[CH:3]=[CH:2][C:1](=[O:5])[N:29]2[C:30]3[CH2:36][CH:35]([CH3:37])[CH2:34][CH2:33][C:31]=3[NH:32][C:28]=12)=[O:38]
Reactant: CC1CCc2[nH]c(CC(=O)c3ccc(F)cc3F)nc2C1
Reactant: C#CC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Product: CC1CCc2[nH]c3c(C(=O)c4ccc(F)cc4F)ccc(=O)n3c2C1

Procedure:
The compound is prepared as described in example 11 with 138 mg (1.97 mmol) of propiolic acid, 383.6 mg (2.37 mmol) of 1-(1H-imidazol-1-ylcarbonyl)-1H-imidazole and 382 mg (1.31 mmol) of 1-(2,4-difluorophenyl)-2-(5-methyl-4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)ethanone (example LIV). The isomers are isolated after purification over preparative HPLC (Daicel Chiralpak AD, eluent: iso-hexane-ethanol v/v 60:40):
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][N:8]=2)[S:5][CH:6]=1.[H-].[Na+].Cl[C:19]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:8]=2)[S:5][CH:6]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Brc1csc(-c2n[nH]c3ncccc23)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1csc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ncccc23)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-(4-bromothiazol-2-yl)-1H-pyrazolo[5,4-b]pyridine (161 mg, 0.5727 mmol) in DMF (3 mL) was cooled to 0° C. then sodium hydride (27.49 mg, 0.6872 mmol) was added in one portion. Stirred at 0° C. for 30 mins before (chloro-diphenyl-methyl)benzene (167.6 mg, 0.6013 mmol) was added. Ice-bath removed and stirred at room temperature for 2 h. Quenched with water, diluted with EtOAc. Organic layer then collected, washed with brine, dried (MgSO4), filtered and concentrated in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]([C:15]2[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:16]=2[F:25])[C:13]2[C:12](=[O:26])[CH2:11][NH:10][CH2:9][C:8]=2[NH:7][C:6]=1[CH3:27])=[O:4].[O:28]1[CH:30]([CH2:31][O:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)[CH2:29]1.Cl>CO>[CH3:1][O:2][C:3]([C:5]1[CH:14]([C:15]2[C:16]([F:25])=[C:17]([F:24])[C:18]([F:23])=[C:19]([F:22])[C:20]=2[F:21])[C:13]2[C:12](=[O:26])[CH2:11][N:10]([CH2:29][CH:30]([OH:28])[CH2:31][O:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)[CH2:9][C:8]=2[NH:7][C:6]=1[CH3:27])=[O:4]
Reactant: COc1ccc(OCC2CO2)cc1
Reactant: COC(=O)C1=C(C)NC2=C(C(=O)CNC2)C1c1c(F)c(F)c(F)c(F)c1F
Agent: Cl
Solvent: CO
Product: COC(=O)C1=C(C)NC2=C(C(=O)CN(CC(O)COc3ccc(OC)cc3)C2)C1c1c(F)c(F)c(F)c(F)c1F
Yield: 55.1 %

Procedure:
1,4,5,6,7,8-Hexahydro-2-methyl-5-oxo-4-(2,3,4,5,6-pentafluorophenyl)-1,7-naphthyridine-3-carboxylic acid methyl ester (5.0 g), 2.3 g of 1,2-epoxy-3-(4-methoxyphenoxy)propane and 125 ml of methanol were combined and refluxed for 18 hours. The solution was saturated with hydrogen chloride, then the methanol was evaporated in vacuo. The residue was crystallized from ethyl acetate. Recrystallization from acetonitrile afforded 4 g of the title compound as the hydrochloride, salt, m.p. 222° C. dec.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=[O:15])=[CH:4][CH:3]=1.[F:16][C:17]([F:31])([F:30])[C:18]1[CH:19]=[C:20]([CH:27]=[CH:28][CH:29]=1)[CH2:21][C:22]1[O:23][CH:24]=[N:25][N:26]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([C:24]2[O:23][C:22]([CH2:21][C:20]3[CH:27]=[CH:28][CH:29]=[C:18]([C:17]([F:30])([F:31])[F:16])[CH:19]=3)=[N:26][N:25]=2)[OH:15])=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Reactant: FC(F)(F)c1cccc(Cc2nnco2)c1
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1nnc(Cc2cccc(C(F)(F)F)c2)o1

Procedure:
Prepared according to the procedure described in Example 19, Step 1, using 5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and 2-(3-trifluoromethyl-benzyl)-[1,3,4]oxadiazole.
Reaction SMILES: F[C:2](F)(F)[C:3](O)=O.[C:8]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[C:29](=[O:47])[N:30]([C:40]4[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=4)[N:31]=[CH:32][C:33]=3[N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)(=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10].CC(C)=O.C(I)C.C(N(CC)CC)C>ClCCl>[C:8]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[CH:23][C:24]([O:27][C:28]3[C:29](=[O:47])[N:30]([C:40]4[CH:41]=[CH:42][C:43]([CH3:46])=[CH:44][CH:45]=4)[N:31]=[CH:32][C:33]=3[N:34]3[CH2:39][CH2:38][N:37]([CH2:2][CH3:3])[CH2:36][CH2:35]3)=[CH:25][CH:26]=2)=[CH:17][CH:16]=1)(=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: Cc1ccc(-n2ncc(N3CCNCC3)c(Oc3ccc(-c4ccc(OC(=O)C(C)(C)C)cc4)cc3)c2=O)cc1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCI
Solvent: CC(C)=O
Product: CCN1CCN(c2cnn(-c3ccc(C)cc3)c(=O)c2Oc2ccc(-c3ccc(OC(=O)C(C)(C)C)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
360 mg (0.44 mmol) of the compound from Example 3 are introduced into 2.0 ml of acetone, and 0.046 ml (0.57 mmol) of ethyl iodide and 0.18 ml (1.32 mmol) of triethylamine are successively added. The mixture is stirred at room temperature overnight before being diluted with dichloromethane, washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and concentrated. The crude product is purified by filtration through a silica gel column (mobile phase: dichloromethane/methanol 95:5).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]=[CH:9][N:10](C)C)=[N:6][CH:7]=1.N1C=CC=CC=1.NOS(O)(=O)=O>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:10]=[CH:9][N:8]=2)[CH:7]=1
Reactant: CN(C)C=Nc1ccc(Br)cn1
Agent: NOS(=O)(=O)O
Solvent: c1ccncc1
Solvent: CO
Product: Brc1ccc2ncnn2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice-cooled, stirred solution of the crude product from Step A (3.94 g, 17.3 mmol) in methanol (30 mL) and pyridine (2.73 g, 35.6 mmol) was added hydroxylamine-O-sulfonic acid (2.54 g, 22.5 mmol). The reaction mixture was allowed to warm to room temperature and was stirred overnight. The volatiles were removed under reduced pressure, and the residue was partitioned between aqueous sodium bicarbonate solution and ethyl acetate. The aqueous layer was further extracted with ethyl acetate, and the combined organic layers were washed sequentially with water (100 mL) and saturated aqueous brine solution (100 mL), dried (magnesium sulfate) and concentrated in vacuo to yield a brown solid, which was recrystallized from dichloromethane to afford the title compound as an orange solid. LC/MS 197.9 and 199.9 (M+1).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[N:55]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1[O:64][CH3:65])=[C:56]=[O:57]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:56]([NH:55][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=2[O:64][CH3:65])=[O:57])[CH2:49][CH2:48]1
Reactant: COc1ccccc1N=C=O
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1NC(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 30 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 1-isocyanato-2-methoxybenzene as starting materials in 30% yield. LCMS for C32H34ClN8O3 (M+H)+: m/z=613.2.
Reaction SMILES: CO[CH:3]([O:13]C)[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][C:5]=1[F:12].[Cl:15][C:16]1[C:21]([Cl:22])=[CH:20][C:19]([NH2:23])=[C:18]([NH2:24])[CH:17]=1.C1(=O)C=CC(=O)C=C1>CO>[Cl:15][C:16]1[C:21]([Cl:22])=[CH:20][C:19]2[N:23]=[C:8]([C:7]3[CH:10]=[CH:11][C:4]([CH:3]=[O:13])=[C:5]([F:12])[CH:6]=3)[NH:24][C:18]=2[CH:17]=1
Reactant: COC(OC)c1ccc(C=O)cc1F
Reactant: Nc1cc(Cl)c(Cl)cc1N
Agent: O=C1C=CC(=O)C=C1
Solvent: CO
Product: O=Cc1ccc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.7 %

Procedure:
A mixture of 4-dimethoxymethyl-3-fluorobenzaldehyde (321 mg, 1.62 mmol), 4,5-dichloro-1,2-phenylenediamine (283 mg, 1.60 mg) and 1,4-benzoquinone (173 mg, 1.60 mmol) in methanol (10 mL) was heated to reflux for 2 h. The solvent was removed under reduced pressure. To the residue were added tetrahydrofuran (15 mL) and hydrochloric acid (1 mol/L; 1.6 mL), and the mixture was stirred at room temperature for 16 h. Water was added and the precipitated products were collected by filtration, followed by trituration with ether to afford 5,6-dichloro-2-(3-fluoro-4-formylphenyl)benzimidazole (132 mg, 26%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.[CH2:19]([S:21][C:22]1([CH2:33][CH2:34]O)[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([F:31])[CH:29]=2)[NH:24][C:23]1=[O:32])[CH3:20]>>[CH2:19]([S:21][C:22]1([CH2:33][CH2:34][N:16]2[CH2:15][CH2:14][N:13]([CH:10]3[C:11]4[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=4)[CH2:7][CH2:8][CH2:9]3)[CH2:18][CH2:17]2)[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([F:31])[CH:29]=2)[NH:24][C:23]1=[O:32])[CH3:20]
Reactant: COc1ccc2c(c1)C(N1CCNCC1)CCC2
Reactant: CCSC1(CCO)C(=O)Nc2ccc(F)cc21
Product: CCSC1(CCN2CCN(C3CCCc4ccc(OC)cc43)CC2)C(=O)Nc2ccc(F)cc21
Temperature: 110 °C

Procedure:
A mixture of 8.1 g (0.0328 mole) of 1-(7-methoxy-1,2,3,4-tetrahydro-1-naphthyl)piperazine and 6.7 g (0.0164 mole) of 3-(ethylthio)-5-fluoro-3-(2-hydroxyethyl)-1,3-dihydro-2(2H)-indolone is heated to 110° C. for 1 hour.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9]([OH:13])(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[OH:22]>C(O)(=O)C>[OH:13][C:9]1([C:19]2[CH:20]=[C:15]([CH3:14])[C:16]([OH:22])=[CH:17][C:18]=2[CH3:21])[C:10](=[O:11])[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[C:7]1=[O:8]
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Reactant: Cc1ccc(C)c(O)c1
Solvent: CC(=O)O
Product: Cc1cc(C2(O)C(=O)c3ccccc3C2=O)c(C)cc1O
Yield: 8.2 %

Procedure:
To a solution of ninhydrin (1.00 g, 5.6 mmol) in glacial acetic acid (20 ml) was added 2,5-dimethyl phenol (0.68 g, 5.6 mmol), followed by heating for 24 hrs under reflux. The reaction mixture was concentrated in a vacuum, and extracted with ethylacetate. The concentrated organic layer was purified using column chromatography (ethylacetate:hexane=1:6 to 1:4) to afford the title compound (0.13 g, 8%).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH2:23][CH2:24][CH3:25])=[CH:11][C:6]=2[O:5][C:4]([C:26]([OH:28])=[O:27])=[CH:3]1.C(=O)(O)[O-].[Na+:33]>O>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH2:23][CH2:24][CH3:25])=[CH:11][C:6]=2[O:5][C:4]([C:26]([O-:28])=[O:27])=[CH:3]1.[Na+:33]
Reactant: CCCc1ccccc1OCCCOc1ccc2c(=O)cc(C(=O)O)oc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCCc1ccccc1OCCCOc1ccc2c(=O)cc(C(=O)[O-])oc2c1

Procedure:
A mixture of 11.11 parts of 4-oxo-7-(3-[2-propylphenoxy]propoxy)-4H-1-benzopyran-2-carboxylic acid and 2.4 parts of sodium bicarbonate in 200 parts of water was heated to effect solution. The solution was filtered and freeze dried to yield 11.5 parts of sodium 4-oxo-7-(3-[2-propylphenoxy]propoxy)-4H-1-benzopyran-2-carboxylate.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([N:11]=[N+:12]=[N-:13])[C@@H:9]([O:14]C(=O)C)[C@@H:8]([CH2:18][O:19]C(=O)C)[O:7][C@H:6]1[S:23][C@@H:24]1[O:37][C@H:36]([CH2:38][O:39]C(=O)C)[C@H:31]([O:32]C(=O)C)[C@H:30]([N:43]=[N+:44]=[N-:45])[C@H:25]1[O:26]C(=O)C)(=O)C.C(Cl)Cl.C[O-].[Na+].CCCCCCC.CCOC(C)=O>CO>[N:11]([C@H:10]1[C@@H:9]([OH:14])[C@@H:8]([CH2:18][OH:19])[O:7][C@@H:6]([S:23][C@@H:24]2[O:37][C@H:36]([CH2:38][OH:39])[C@H:31]([OH:32])[C@H:30]([N:43]=[N+:44]=[N-:45])[C@H:25]2[OH:26])[C@@H:5]1[OH:4])=[N+:12]=[N-:13]
Reactant: CC(=O)OC[C@H]1O[C@@H](S[C@@H]2O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@H](N=[N+]=[N-])[C@H]2OC(C)=O)[C@H](OC(C)=O)[C@@H](N=[N+]=[N-])[C@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CO
Solvent: CCOC(C)=O
Product: [N-]=[N+]=N[C@H]1[C@@H](O)[C@@H](CO)O[C@@H](S[C@@H]2O[C@H](CO)[C@H](O)[C@H](N=[N+]=[N-])[C@H]2O)[C@@H]1O
Yield: 75.6 %

Procedure:
Compound 10 (160 mg, 0.00024 mol) was dissolved in dry MeOH (2.6 mL) and dry CH2Cl2 (1.6 mL), and NaOMe (1M, 24 μL, 24 μmol) was added. The reaction was monitored by TLC (heptane:EtOAc 1:1 and D:M 5:1). When the reaction was complete, the mixture was neutralized with Duolite C436 until pH 7, filtered and washed with MeOH. The filtered solution was concentrated under reduced pressure. The residue was purified by flash chromatography (Eluent: CH2Cl2:MeOH, 5:1) to give pure 11 (74.1 mg, 75%). 1H NMR in CDCl3 δ 4.72 (d, 2H, J=9.7 Hz, H-1, H-1′), 3.95 (br s, 2H, H-4, H-4′), 3.84 (t, 2H, J=9.8 Hz, H-2, H-2′), 3.74 (dd, 2H, J=11.47 Hz, 7.23 Hz, H-6, H-6′), 3.64 (dd, 2H, J=11.48 Hz, 4.72 Hz, H-6, H6′), 3.60-3.55 (ddd, 2H, 7.15 Hz, 4.67 Hz, 0.93 Hz, H-5, H-5′), 3.36 (dd, 2H, J=10 Hz, 3.05 Hz, H-3, H-3′).
Reaction SMILES: Br[CH2:2]/[C:3](/[C:11]([O:13][CH3:14])=[O:12])=[CH:4]\[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[S:15]([O-:18])([O-:17])=[O:16].[Na+:19].[Na+].[Br-].[Na+].[K+].[Br-]>CO>[Na+:19].[C:11](/[C:3](=[CH:4]/[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)/[CH2:2][S:15]([O-:18])(=[O:17])=[O:16])([O:13][CH3:14])=[O:12]
Reactant: O=S([O-])[O-]
Reactant: COC(=O)/C(=C/c1ccccc1)CBr
Agent: [Br-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: COC(=O)/C(=C/c1ccccc1)CS(=O)(=O)[O-]
Temperature: 50 °C
Reaction time: 0.75 h

Procedure:
To a 12L, 3-neck round bottom flask fitted with a mechanical stirrer, thermometer and an addition funnel was added the resultant product from Example 3B (400 g, 1.57 mol) and methanol (4L). The mixture was warmed to 50° C. and a solution of sodium sulfite (199 g, 1.57 mol) dissolved in water (4L) was added over 75 min while the internal temperature of the flask was maintained at 50° C. After the addition was complete, the clear solution was allowed to stir at 50° C. for an additional 45 min. The reaction mixture in solution was taken to the next step without additional purification. The compound can be isolated by concentration to an amorphous powder, which is contaminated with an equivalent of sodium bromide: IR (KBr) 1711, 1628, 1215 cm-1 ; 1H NMR (DMSO D-6) delta 3.70 (s, 3H), 3.77 (s, 2H), 7.33-7.41 (m, 3H), 7.48 (s, 1H), 7.87-7.89 (m, 2H); 13C NMR (75 MHz, DMSO D-6) delta 49.88, 51.93, 127.36, 128.33, 128.91, 129.82, 134.75, 139.06, 168.60.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[NH2:13][C:14]1[CH:15]=[C:16]([CH:32]=[CH:33][CH:34]=1)[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[C:21]([OH:28])[C:20]=1[CH2:29][CH2:30][CH3:31].[C:35]([O:46][CH3:47])(=[O:45])[C:36]1[CH:44]=[CH:43][CH:42]=[C:38]([C:39](O)=[O:40])[CH:37]=1.C(N(CC)CC)C>ClCCl>[CH3:47][O:46][C:35](=[O:45])[C:36]1[CH:44]=[CH:43][CH:42]=[C:38]([C:39]([NH:13][C:14]2[CH:34]=[CH:33][CH:32]=[C:16]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[C:21]([OH:28])[C:20]=3[CH2:29][CH2:30][CH3:31])[CH:15]=2)=[O:40])[CH:37]=1
Reactant: COC(=O)c1cccc(C(=O)O)c1
Reactant: CCCc1c(OCc2cccc(N)c2)ccc(C(C)=O)c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1c(OCc2cccc(NC(=O)c3cccc(C(=O)OC)c3)c2)ccc(C(C)=O)c1O
Reaction time: 5 h
Yield: 77.1 %

Procedure:
Add ethyldimethylaminopropylcarbodiimide hydrochloride (2.47 g, 12.9 mmol) to a solution of 1-[4-(3-amino-benzyloxy)-2-hydroxy-3-propyl-phenyl]-ethanone (1.54 g, 5.14 mmol) and methyl hydrogen isophthalate (1.11 g, 6.17 mmol) in dichloromethane (40 mL) at 0° C. Add triethylamine (3.59 mL, 25.7 mmol) and stir at room temperature for 72 hours. At 5 hours, add additional methyl hydrogen isophthalate (200 mg). Stir overnight. Wash the mixture twice with 2N hydrochloric acid, saturated sodium bicarbonate, brine, dry, and concentrate. Triturate the residue with 1:1 hexanes: dichloromethane, and filter to afford the title compound as an off-white powder (1.83 g, 77%): 1H NMR (CDCl3) δ 0.97 (t, 3H), 1.59 (sextet, 2H), 2.56 (s, 3H), 2.72 (t, 2H), 3.98 (s, 3H), 5.20 (s, 2H), 6.49 (d, 1H), 7.25 (m, 1H), 7.42 (t, 1H), 7.56-7.64 (m, 3H), 7.79 (s, 1H), 7.89 (s, 1H), 8.15 (d, 1H), 8.24 (d, 1H), 8.48 (s, 1H), 12.75 (s, 1H).
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[Cl:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[C:14](=[O:29])[CH2:15][C:16]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)=[N:17]2.ClC1C=C2C(C(=O)CC(C3C=CC(C)=CC=3)=N2)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Cl:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[C:14]([O:29][CH2:2][C:3]([N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4])=[CH:15][C:16]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)=[N:17]2
Reactant: O=C(CBr)N1CCOCC1
Reactant: Cc1ccc(C2=Nc3cccc(Cl)c3C(=O)C2)cc1
Agent: Cc1ccc(C2=Nc3cc(Cl)ccc3C(=O)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Cc1ccc(-c2cc(OCC(=O)N3CCOCC3)c3c(Cl)cccc3n2)cc1
Temperature: 20 °C
Yield: 13.6 %

Procedure:
4-(2-Bromoacetyl)morpholine (7.9 g) in 2-butanone (50 cc) is added to a stirred suspension of a mixture (10 g) of 5-chloro-2-(4-methylphenyl)-4-quinolone and 7-chloro-2-(4-methylphenyl)-4-quinolone and anhydrous potassium carbonate (10.2 g) in 2-butanone (250 cc). The mixture is heated to reflux for 15 hours and cooled to room temperature (approximately 20° C.), the insoluble matter is removed by filtration and the 2-butanone is evaporated off under reduced pressure. The residue is taken up with water (200 cc) and the aqueous phase is extracted with methylene chloride (3×100 cc). The organic phase is separated after settling has taken place, dried and evaporated under reduced pressure. After the residue has been chromatographed twice on silica gel, the first time using a chloroform/ethyl acetate mixture (70:30 by volume) and the second time using a chloroform/ethyl acetate mixture (80:20 by volume) as eluant, the solid obtained is recrystallized in ethyl acetate. 4-{[ 5-chloro-2-(4-methylphenyl)-4-quinolyl]oxyacetyl}morpholine (2 g), m.p. 170 ° is thereby obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10][C:9]2([CH3:19])[CH3:18])=[O:5].[CH:20]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1)=[O:21]>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.CN(C)C=O>[C:26]([C:25]1[CH:30]=[CH:31][C:22]([C:20](=[O:21])[CH2:2][CH2:3][C:4]([C:6]2[CH:15]=[CH:14][C:13]3[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10][C:9]([CH3:19])([CH3:18])[C:8]=3[CH:7]=2)=[O:5])=[CH:23][CH:24]=1)([O:28][CH3:29])=[O:27]
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)CCCl)ccc21
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)CCC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Reaction time: 1 h
Yield: 45.5 %

Procedure:
5.6 g (0.02 mole) of 6-(3-chloropropionyl)-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnapthalene and 3.3 were stirred for 1 hour at room temperature. Thereafter, a solution of 3.6 g (0.025 mole) of methyl 4-formylbenzoate and 1 g of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride in 10 ml of dimethylformamide was added dropwise. Stirring was continued for 1 hour, after which the mixture was poured onto ice/water and extracted twice with ethyl acetate, and the combined organic extracts were washed several times with water, dried over magnesium sulfate and evaporated down. 3.7 g of 1-(4-carbomethoxyphenyl)-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-butane-1,4-dione of melting point 139°-141° C. were obtained from the residue (6.4 g) after recrystallization from ethanol. 2-(4-Carbomethoxyphenyl)-5-(5,6,7,8-tetrahy-dro-5,5,8,8-tetramethyl-2-naphthalenyl)-thiophene:
Reaction SMILES: [Se:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH3:6][O:7][C:8]([C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1)=[O:9].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[Se:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:14]([C:13]1[CH:12]=[CH:11][C:10]([C:8]([O:7][CH3:6])=[O:9])=[CH:18][CH:17]=1)=[O:15]
Reactant: c1cc[se]c1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COC(=O)c1ccc(C(=O)c2ccc[se]2)cc1
Yield: 43 %

Procedure:
Selenophene (61) (5.0 g, 0.038 mole) and 4-methoxycarbonyl benzoyl chloride (62) (8.34 g, 0.042 mole) were dissolved in 50 ml of 1, 2-dichloroethane, and then anhydrous aluminum chloride (AlCl3) (10.19 g, 0.076 mole) was added. The mixture was heated under refluxing for 30 min, cooled, and quenched with 250 ml of icewater to stop the reaction. The organic layer was sequentially washed with water, 5% sodium carbonate solution, and water till neutral, then dried over MgSO4 and filtered. The solvent of the filtrate was evaporated under a reduced pressure, and the residue was subjected to a column chromatography (silica gel, chloroform), and then recrystallized from n-hexane to afford compound 63 in yellow crystals (4.78 g).