Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH:9]([CH2:37][CH2:38][CH2:39][O:40][Si](C(C)(C)C)(C)C)/[CH:10]=[CH:11]/[CH:12]=[C:13]1[C:17](=[O:18])[C:16]([S:19][CH3:20])=[CH:15][C:14]1([CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[O:21][Si](C)(C)C)(C(C)(C)C)(C)C.N1C=CC=CC=1.C(=O)([O-])O.[Na+]>C(#N)C>[OH:8][CH:9]([CH2:37][CH2:38][CH2:39][OH:40])/[CH:10]=[CH:11]/[CH:12]=[C:13]1[C:17](=[O:18])[C:16]([S:19][CH3:20])=[CH:15][C:14]1([OH:21])[CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CSC1=CC(CCCCOc2ccccc2)(O[Si](C)(C)C)C(=C/C=C/C(CCCO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: c1ccncc1
Product: CSC1=CC(O)(CCCCOc2ccccc2)C(=C/C=C/C(O)CCCO)C1=O
Yield: 83.3 %

Procedure:
To a solution of 660 mg of 5-[(E)-4,7-bis(t-butyldimethylsilyloxy)-2-heptenylidene]-2-methylthio-4-(4-phenoxybutyl)-4-trimethylsilyloxy-2-cyclopentenone obtained in Example 75 dissolved in 50 ml of acetonitrile was added 4 ml of pyridine, under ice-cooling and stirring. A hydrogen-pyridine solution (2 ml) was added, and the mixture was stirred at 0° C. for 24 hours. The reaction mixture was poured onto saturated aqueous sodium hydrogencarbonate, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed with saturated sodium chloride and dried over anhydrous magnesium sulfate. After filtration and concentration, the concentrate was subjected to silica gel column chromatography to give 320 mg (yield 83%) of 5-[(E)-4,7-dihydroxy-2-heptenylidene]-4-hydroxy-2-methylthio-4-(4-phenoxybutyl)-2-cyclopentenone.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([C:9]2[O:13][C:12]([C:14]([OH:16])=O)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.C(Cl)(=O)C(Cl)=O.[CH2:25]1[O:33][C:32]2[CH:31]=[CH:30][C:29]([CH:34]3[C:46]4[NH:45][C:44]5[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=5)[C:38]=4[CH2:37][CH2:36][NH:35]3)=[CH:28][C:27]=2[O:26]1.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[CH2:25]1[O:33][C:32]2[CH:31]=[CH:30][C:29]([CH:34]3[C:46]4[NH:45][C:44]5[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=5)[C:38]=4[CH2:37][CH2:36][N:35]3[C:14]([C:12]3[O:13][C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:18])[F:17])[CH:4]=4)=[CH:10][CH:11]=3)=[O:16])=[CH:28][C:27]=2[O:26]1
Reactant: c1ccc2c3c([nH]c2c1)C(c1ccc2c(c1)OCO2)NCC3
Reactant: O=C(O)c1ccc(-c2cccc(C(F)(F)F)c2)o1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(c1ccc(-c2cccc(C(F)(F)F)c2)o1)N1CCc2c([nH]c3ccccc23)C1c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 5-(3-trifluoromethylphenyl)furoic acid (256 mg, 1 mmol) in DCM (20 mL, anhydrous) was added oxalyl chloride (165 mg, 1.3 mmol), followed by two drops of DMF. The mixture was stirred at room temperature for 1 h. A solution of 1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline (292 mg, 1 mmol) (prepared according to the process as disclosed in WO97/43287, Intermediate 7, page 24) and triethylamine (0.4 mL) in DCM (10 mL, anhydrous) was added and the mixture was stirred at room temperature for 16 h, washed sequentially with aqueous NaHCO3, brine (2×), 1N HCl and brine (2×) and dried with MgSO4. After evaporation of the solvent, a white solid was obtained.
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:36])=[C:5]([C:27]([O:34]C)=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].[OH-].[Na+]>C(#N)C.O>[CH3:31][O:30][C:29]1[C:3](=[O:2])[C:4]([CH3:36])=[C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[C:11]([CH:20]=2)[C:12]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[O:13])[C:27](=[O:34])[C:28]=1[O:32][CH3:33]
Reactant: COc1c(C)c(Cc2ccc(-c3ccncc3)c(C(=O)N3CCOCC3)c2)c(OC)c(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(-c3ccncc3)c(C(=O)N3CCOCC3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.7 %

Procedure:
N-[5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(4-pyridyl)benzoyl]morpholine (102 mg, 0.2037 mmol) was dissolved in a mixed solvent of acetonitrile (15 ml) and water (5 ml), then CAN (279 mg, 0.5091 mmol) was added thereto at room temperature and the mixture was stirred for 3 hours. The reaction solution was poured into water, neutralized with 1N aqueous solution of sodium hydroxide and extracted with ethyl acetate. The extract was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by silica gel column chromatography (methylene chloride:methanol=95:5) to give the title compound (60 mg, 0.1298 mmol, 63%).
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][N:13]([CH2:15][C@H:16]([OH:21])[C:17]([F:20])([F:19])[F:18])[C:12](=[O:22])[C@@H:11]([NH:23]C(=O)OC(C)(C)C)[CH2:10]1>C(OCC)(=O)C>[NH2:23][C@H:11]1[CH2:10][C@@H:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[CH2:14][N:13]([CH2:15][C@H:16]([OH:21])[C:17]([F:20])([F:18])[F:19])[C:12]1=[O:22]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](c2cccc(F)c2F)CN(C[C@H](O)C(F)(F)F)C1=O
Solvent: CCOC(C)=O
Product: N[C@H]1C[C@@H](c2cccc(F)c2F)CN(C[C@H](O)C(F)(F)F)C1=O
Temperature: 23 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl {(3S,5S)-5-(2,3-difluorophenyl)-2-oxo-1-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]piperidin-3-yl}carbamate (39 mg, 0.089 mmol) in ethyl acetate (5 mL), pre-cooled to 0° C. was sparged with HCl gas for ˜1 min. The ice-bath was removed and the acidic solution was allowed to warm to 23° C. as stirring was continued for 2 h. The mixture was then concentrated to dryness to afford the title compound as a hydrochloride salt. MS: m/z=339.1 (M+1).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9](/[C:11](=[N:15]/[O:16][CH2:17][CH2:18][Cl:19])/[C:12]([OH:14])=[O:13])[N:10]=1)=[O:4].[Cl:20]N1C(=O)CCC1=O>>[Cl:1][CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]([Cl:20])=[C:9](/[C:11](=[N:15]/[O:16][CH2:17][CH2:18][Cl:19])/[C:12]([OH:14])=[O:13])[N:10]=1)=[O:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(CCl)Nc1nc(/C(=N/OCCCl)C(=O)O)cs1
Product: O=C(CCl)Nc1nc(/C(=N/OCCCl)C(=O)O)c(Cl)s1

Procedure:
2-(2-Chloroacetamidothiazol-4-yl)-2-(Z)-(2-chloroethoxyimino)acetic acid and N-chlorosuccinimide are reacted in the procedure of Reference Example 37 to give 2-(2-chloroacetamido-5-chlorothiazol-4-yl)-2(Z)-(2-chloroethoxyimino)acetic acid.
Reaction SMILES: [C:1]1([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([N:10]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[N:25]=[C:24]([N:26]3[CH2:31][CH2:30][CH2:29][CH:28]([NH:32]C(=O)OCC4C=CC=CC=4)[CH2:27]3)[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)[CH2:11]1)=[O:9].Cl>CO.C(OCC)(=O)C.[Pd]>[NH2:32][CH:28]1[CH2:29][CH2:30][CH2:31][N:26]([C:24]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[C:16]([NH:15][CH:12]3[CH2:13][CH2:14][N:10]([C:8](=[O:9])[CH2:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=4[C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[CH2:11]3)[N:25]=2)[CH2:27]1
Reactant: O=C(NC1CCCN(c2nc(NC3CCN(C(=O)Cc4ccccc4-c4ccccc4)C3)nc3ccccc23)C1)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: NC1CCCN(c2nc(NC3CCN(C(=O)Cc4ccccc4-c4ccccc4)C3)nc3ccccc23)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Benzyl (1-(2-(1-(2-biphenyl-2-ylacetyl)pyrrolidin-3-ylamino)quinazolin-4-yl)piperidin-3-yl)carbamate (570 mg) synthesized in the same manner as the method described in Example 1 was dissolved in methanol (6 mL), followed by addition of a solution (0.25 mL) of 4 M HCl in ethyl acetate and 10% Pd—C (100 mg), and the mixture was stirred at room temperature under hydrogen atmosphere for 3 days. The catalyst was removed by filtration, then the filtrate was concentrated, made basic with saturated aqueous sodium hydrogencarbonate, and then extracted with chloroform, and the organic layer was dried with anhydrous magnesium sulfate. The desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, then the residue was purified by silica gel column chromatography (chloroform/methanol=3:1), and the resulting compound was solidified in hexane to obtain the title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:13]=[CH:12][C:6]([NH:7][CH2:8][CH:9]([CH3:11])[CH3:10])=[CH:5][CH:4]=1)[CH3:2].[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)=[CH2:15]>N1C=CC=CC=1>[CH2:1]([C:3]1[CH:13]=[CH:12][C:6]([N:7]([CH2:8][CH:9]([CH3:10])[CH3:11])[S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH:14]=[CH2:15])=[CH:17][CH:18]=2)(=[O:24])=[O:23])=[CH:5][CH:4]=1)[CH3:2]
Reactant: C=Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCc1ccc(NCC(C)C)cc1
Solvent: c1ccncc1
Product: C=Cc1ccc(S(=O)(=O)N(CC(C)C)c2ccc(CC)cc2)cc1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-ethyl-N-isobutylaniline (400 mg, 2.256 mmol) in pyridine (5 mL) stirred in air at room temperature was added 4-vinylbenzene-1-sulfonyl chloride (760 mg, 3.75 mmol) in one charge. The reaction mixture was stirred at 20° C. for 30 minutes then stood for 16 hours. The solvent was evaporated in vacuo (Vaportec V10) to give the crude product, which was then purified by silica (Si) chromatography (0-50% ethyl acetate-cyclohexane gradient). The appropriate fractions were combined and evaporated in vacuo to give the required product, 940 mg, as a colourless gum. LCMS [LCMS1] Rt 1.44 min, m/z (ES+) 344 (M+H).
Reaction SMILES: C[N:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([N+]([O-])=O)[C:3]1=O.[CH2:15]([N:22]1[CH2:27]CC(=O)[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N>CO>[CH2:15]([N:22]1[CH2:23][CH2:24][C:3]2[N:2]=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:5][C:4]=2[CH2:27]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cn1cc([N+](=O)[O-])cc([N+](=O)[O-])c1=O
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: N
Solvent: CO
Product: O=[N+]([O-])c1cnc2c(c1)CN(Cc1ccccc1)CC2
Yield: 49.7 %

Procedure:
A mixture of 1-methyl-3,5-dinitro-2-pyridone (1.2 g, 6.0 mmol), 1-benzyl-4-piperidone (1.12 g, 5.9 mmol) and ammonia solution in methanol (2.0 M, 60 mL) was refluxed for 3 h. The solvent was removed in vacua and the residue was dissolved in ethyl acetate. The soluble portion was flash chromatographed over silica gel (eluent: 90:10 v/v ethyl acetate-hexane) to give a yellow solid (0.79 g, 49.7% yield).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([CH2:20][NH2:21])=[CH:15][CH:14]=[CH:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl.N1C=CC=CC=1>[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([CH2:20][NH:21][S:23]([CH3:22])(=[O:25])=[O:24])=[CH:15][CH:14]=[CH:13]3)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCc1cccc2cc(S(=O)(=O)c3ccccc3)ccc12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)NCc1cccc2cc(S(=O)(=O)c3ccccc3)ccc12
Temperature: 25 °C

Procedure:
C-(6-Benzenesulfonyl-naphthalen-1-yl)-methylamine is dissolved in methylene chloride and pyridine, and the mixture is cooled in an ice bath. Methanesulfonyl chloride is added dropwise, and the reaction mixture is stirred at ice bath temperature, then allowed to warm to room temperature. The reaction mixture is quenched by addition of water and extracted with methylene chloride. The organic layer is washed with water, dried (MgSO4), filtered and concentrated under reduced pressure to give N-(6-benzenesulfonyl-naphthalen-1-ylmethyl)-methanesulfonamide.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:54][O:55][CH3:56])[C:27]([NH:29][CH:30]2[C:37](=[O:38])[N:36]3[CH:31]2[CH2:32][S:33][CH:34]([S:47][CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])[C:35]3(O)[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(I)(I)P(I)I.C(OCC)(=O)C>N1C=CC=CC=1>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:54][O:55][CH3:56])[C:27]([NH:29][CH:30]2[C:37](=[O:38])[N:36]3[CH:31]2[CH2:32][S:33][C:34]([S:47][CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])=[C:35]3[C:39]([O:41][C:42]([CH3:43])([CH3:45])[CH3:44])=[O:40])=[O:28])[N:25]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CSC1SCC2C(NC(=O)C(=NOC)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C(=O)N2C1(O)C(=O)OC(C)(C)C
Agent: IP(I)P(I)I
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)CSC1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)C(=NOC)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C2CS1
Reaction time: 1 h
Yield: 44.5 %

Procedure:
1.55 g of the product of Step A dissolved in 30 ml of pyridine and 1.4 g of diphosphorus tetraiodide were stirred under an inert atmosphere for 30 minutes and after a further 0.76 g of diphosphorus tetraiodide were added, the mixture was stirred for 1 hour. 100 ml of ethyl acetate were added followed by filtering and concentrating to dryness under reduced pressure at a temperature below 30° C. The residue was dissolved in ethyl acetate and the solution was filtered, washed first with 0.1N hydrochloric acid, then with a solution of sodium bicarbonate, and then with a sodium chloride solution, after which it was dried and concentrated to dryness. The residue was chromatographed on silica and eluted with a mixture of methylene chloride and acetone (10-0.75). After crystallization from ether, 675 mg of racemic 1,1-dimethylethyl 7-[2-(2-tritylaminothiazol-4-yl)-2-methoxyimino-acetamido]-3-(ethoxycarbonylmethylthio)-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylate melting at 212°-214° C. (decomposes) were obtained.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2COCC[Si](C)(C)C)=[CH:4][C:3]=1[CH:19]([C:21]1[N:25]2[N:26]=[C:27]([C:30]3[CH:31]=[N:32][N:33]([CH3:35])[CH:34]=3)[CH:28]=[CH:29][C:24]2=[N:23][CH:22]=1)O.FC1C(C(C2N3N=C(C4C=NN(C)C=4)C=CC3=NC=2)O)=CC2C(C=1)=NN(COCC[Si](C)(C)C)C=2.II.O[PH2]=O>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[CH2:19][C:21]1[N:25]2[N:26]=[C:27]([C:30]3[CH:31]=[N:32][N:33]([CH3:35])[CH:34]=3)[CH:28]=[CH:29][C:24]2=[N:23][CH:22]=1
Reactant: Cn1cc(-c2ccc3ncc(C(O)c4cc5cnn(COCC[Si](C)(C)C)c5cc4F)n3n2)cn1
Agent: Cn1cc(-c2ccc3ncc(C(O)c4cc5cn(COCC[Si](C)(C)C)nc5cc4F)n3n2)cn1
Agent: II
Agent: O=[PH2]O
Product: Cn1cc(-c2ccc3ncc(Cc4cc5cn[nH]c5cc4F)n3n2)cn1
Reaction time: 0.08 h

Procedure:
A mixture of (rac)-[6-fluoro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-5-yl]-[6-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-yl]-methanol and (rac)-[6-fluoro-2-(2-trimethylsilanyl-ethoxymethyl)-2H-indazol-5-yl]-[6-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-yl]-methanol (Stage 164.3, 400 mg, 0.810 mmol), iodine (617 mg, 2.431 mmol) and H3PO2 (1.326 mL of a 50% aqueous solution, 12.16 mmol) were introduced in a microwave tube and the mixture was subjected to MW-irradiation at 150° C. for 5 min. The solvent was removed and the residue was taken up with 1 N HCl and washed with EtOAc three times. The aqueous layer was basified with NaOH pellets and extracted with EtOAc/MeOH (9:1) three times. The organics were joined and washed with brine, dried over Na2SO4 and the solvent was removed. The residue was purified by MPLC with DCM and MeOH to give the title compound as a light yellow solid (tR 0.90 min (conditions 2), MH+=348, 1H-NMR in DMSO-d6: 13.00 (s, 1H); 8.40 (s, 1H); 8.05 (m, 2H); 7.75 (d, 1H); 7.55 (m, 2H); 7.32 (d, 1H)).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2([CH2:13][CH2:14][OH:15])[CH3:12].[Li]CCCC.[CH3:21][S:22]SC>O1CCCC1>[CH3:12][C:5]1([CH2:13][CH2:14][OH:15])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([S:22][CH3:21])[CH:3]=2)[O:8][CH2:7][CH2:6]1
Reactant: CSSC
Reactant: CC1(CCO)CCOc2ccc(Br)cc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1ccc2c(c1)C(C)(CCO)CCO2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 48.8 %

Procedure:
To a chilled (−78° C.) solution of 1 g (3.7 mmol) of 2-(6-bromo-4-methylchroman-4-yl)ethanol in 10 mL of dry tetrahydrofuran was added 3.25 mL (8 mmol) of a 2.5 M solution of n-BuLi in hexanes. After 10 minutes, 0.66 mL (7.4 mmol) of dimethyldisulfide was added and the reaction was warmed to room temperature. After 30 minutes, the reaction was cooled to −78° C., quenched with saturated aqueous ammonium chloride, warmed to room temperature and extracted with ethyl acetate. The combined organic fractions were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography eluting with ethyl acetate-hexanes (0-30% gradient) to afford 0.43 g (50%) of 2-(4-methyl-6-methylsulfanylchroman-4-yl)ethanol as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([C@@H:16]3[CH2:19][CH2:18][C@H:17]3[C:20]([O:22]C)=[O:21])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[C:25]1[S:26][C:27]2[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:28]=2[N:29]=1.[OH-].[Na+]>C(O)CCC>[Cl:34][C:32]1[CH:31]=[CH:30][C:28]2[N:29]=[C:25]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([C@@H:16]5[CH2:19][CH2:18][C@H:17]5[C:20]([OH:22])=[O:21])=[O:15])=[CH:10][CH:9]=4)=[CH:4][CH:3]=3)[S:26][C:27]=2[CH:33]=1
Reactant: Clc1ccc2nc(Cl)sc2c1
Reactant: COC(=O)[C@@H]1CC[C@H]1C(=O)c1ccc(-c2ccc(N)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Product: O=C(O)[C@@H]1CC[C@H]1C(=O)c1ccc(-c2ccc(Nc3nc4ccc(Cl)cc4s3)cc2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 10.8 %

Procedure:
To a solution of methyl trans-2-[(4′-amino-1,1′-biphenyl-4-yl)carbonyl]cyclobutanecarboxylate (100 mg, 0.32 mmol) in n-butanol (15 mL) was added 2,6-dichloro-1,3-benzothiazole (396 mg, 1.94 mmol), and the resulting reaction mixture was heated at 90° C. overnight. The mixture was evaporated to dryness and the residue was brought up in MeOH. Then 1 N aqueous NaOH (1.0 mL, 1.0 mmol) was added to the suspension, and the reaction mixture was stirred at 50° C. overnight. The reaction mixture was concentrated, and the residue was suspended in water. Concentrated HCl was added to adjust the acidity to pH 1, and the precipitate that formed was collected by filtration, washed with water and MeOH, and dried in a vacuum oven to give trans-2-({4′-[(6-chloro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclobutanecarboxylic acid (16 mg, 10%). LC-MS ret. time 3.69; m/z 463.1 (MH+); 1H NMR (400 MHz, DMSO-d6) δ 2.01-2.23 (m, 3H), 2.32 (m, 1H), 3.43 (m, 1H), 4.32 (m, 1H), 7.35 (m, 1H), 7.31 (m, 1H), 7.62 (d, 1H), 7.81 (m, 4H), 7.90 (d, 2H), 7.98 (m, 3H), 10.77 (s, 1H), 12.29 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]O)=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:42]I>C1(C)C=CC=CC=1>[I:42][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(CCCCCCCCO)cc1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(CCCCCCCCI)cc1
Temperature: 65 °C

Procedure:
To a stirred solution of 8-(4-methoxyphenyl)octan-1-ol (12.3 g, 52 mmol) in dry toluene (200 mL) under an argon atmosphere was added triphenylphosphine (17.8 g, 67.6 mmol) and imidazole (10.6 g, 156 mmol). After the imidazole had dissolved, I2 (17.1 g, 67.6 mmol) was added. The reaction was then heated at 65° C. for 30 minutes. Upon cooling to room temperature the reaction was concentrated to 1/4 volume. The remaining solution was diluted with Et2O and washed with H2O and brine and dried (MgSO4). The solvent was removed and the resulting residue was dissolved in CH2Cl2 and applied to a flash chromatography column (silica). Elution with 2% EtOAc in hexane provided the product as a colorless oil (slight contamination with triphenylphosphine): 1H NMR (250 MHz, CDCl3) δ7.08 (d, J=8.6 Hz, 2H, aryl), 6.82 (d, J=8.6 Hz, 2H, aryl), 3.78 (s, 3H, OCH3), 3.17 (t, J=7.4 Hz, 2H, I-CH2), 2.54 (t, J=7.6 Hz, 2H, benzylic), 1.85 (m, 2H, CH2), 1.60 (m, 2H, CH2), 1.31 (m, 8H, aliphatic); MS (CI): 364.2 (M+NH4).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.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]>[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10]
Reactant: COc1ccc(O)c(Br)c1
Reactant: OB(O)c1ccco1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(O)c(-c2ccco2)c1
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 56.6 %

Procedure:
2-Bromo-4-methoxyphenol (400 mg, 1.97 mmol), 2-furanylboronic acid (287 mg, 2.56 mmol), Pd(dppf)Cl2 (81 mg, 0.1 mmol) and sodium carbonate (626 mg, 5.91 mmol) were dissolved in DME:water=4 mL:2 mL, followed by stirring in microwave at 120° C. for 20 minutes. After the completion of the reaction, the reaction mixture was filtered using Celite. The filtrate was added with water, and extracted with ethyl acetate. The obtained organic layer was dried over magnesium sulfate, and purified by column chromatography (hexane:ethyl acetate=9:1) to obtain 2-(furan-2-yl)-4-methoxyphenol (212 mg, 57%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:25])[NH:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][C:19]3[O:22][CH2:23][O:24][C:18]=3[CH:17]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5])C.CO.[OH-].[K+].Cl>O>[CH2:23]1[O:22][C:19]2[CH:20]=[CH:21][C:16]([C:15]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[NH:8][C:7](=[O:25])[C:6]=3[C:4]([OH:5])=[O:3])=[CH:17][C:18]=2[O:24]1
Reactant: CCOC(=O)c1c(-c2ccc3c(c2)OCO3)c2ccccc2[nH]c1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1c(-c2ccc3c(c2)OCO3)c2ccccc2[nH]c1=O
Yield: 95.4 %

Procedure:
A mixture of 1,2-dihydro-4-(3,4-methylenedioxyphenyl)-2-oxo-3-quinoline carboxylic acid ethyl ester (40 g, 118.6 mmol), methanol (200 ml), water (300 ml) and potassium hydroxide (33.3 g, 593.5 mmol) was refluxed with heat for 40 hours. To the reaction mixture was added 110 ml of 6N-HCl to acidify the mixture to obtain a precipitated crystal by filtration. The crystal obtained was washed with diethylether to give 35 g (yield: 95.4%) of the title compound.
Reaction SMILES: [CH2:1]([N:4]([CH2:25][CH2:26][CH3:27])[C:5](=[O:24])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:9]([N+:21]([O-])=O)[CH:8]=1)[CH2:2][CH3:3].[H][H]>[Ni].CO>[CH2:25]([N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:24])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:9]([NH2:21])[CH:8]=1)[CH2:26][CH3:27]
Reactant: [H][H]
Reactant: CCCN(CCC)C(=O)Cc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Agent: [Ni]
Solvent: CO
Product: CCCN(CCC)C(=O)Cc1ccc(OCc2ccccc2)c(N)c1
Reaction time: 4.5 h
Yield: 73.7 %

Procedure:
In the presence of Raney nickel, 36.0 g of 2-(4-benzyloxy-3-nitrophenyl)acetic acid dipropylamide is hydrogenated in 600 ml of methanol until 6.7 l of hydrogen has been absorbed, which takes about 4.5 hours. The crude product obtained after removing the catalyst by filtration and after evaporation is chromatographed on silica gel with cyclohexane/ethyl acetate (1:1), thus obtaining 24.4 g of pure 2-(3-amino-4-benzyloxyphenyl)acetic acid dipropylamide as an oil.