Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].Br[C:17]1[C:18]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:19]=2[S:20](=[O:30])[C:21]=1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1>CN(C=O)C>[CH3:36][O:35][C:32]1[CH:33]=[CH:34][C:18]2[C:17]([O:1][C:2]3[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=3)=[C:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[S:20](=[O:30])[C:19]=2[CH:31]=1
Reactant: COc1ccc(C2=C(Br)c3ccc(OC)cc3S2=O)cc1
Reactant: COC(=O)/C=C/c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc(OC2=C(c3ccc(OC)cc3)S(=O)c3cc(OC)ccc32)cc1
Temperature: 80 °C
Yield: 97.6 %

Procedure:
To a solution of (E)-methyl 3-(4-hydroxyphenyl)acrylate (190 mg, 1.07 mmol) in DMF (5 mL) was added sodium hydride (60% suspension in oil, 42.7 mg, 1.07 mmol). The resulting mixture was allowed to stir for 10 min at room temperature after which 3-bromo-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene 1-oxide (300 mg, 0.82 mmol) was added, as a solid. The reaction was heated to 80° C. for 18 h and upon completion was cooled to room temperature, quenched with water and diluted with DCM. The organic phase was collected (phase separator) and concentrated in vacuo to afford the crude product which was purified by column chromatography (SiO2, 0-80% EtOAc/Heptane) to afford (E)-methyl 3-(4-((6-methoxy-2-(4-methoxyphenyl)-1-oxidobenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (370 mg, 0.80 mmol, 97% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm=7.75 (d, J=9.09 Hz, 2H), 7.65 (d, J=15.66 Hz, 1H), 7.54 (d, J=2.02 Hz, 1H), 7.43-7.52 (m, J=9.09 Hz, 2H), 7.07-7.16 (m, J=8.59 Hz, 2H), 6.98-7.07 (m, 1H), 6.93 (d, J=9.09 Hz, 3H), 6.35 (d, J=16.17 Hz, 1H), 3.91 (s, 3H), 3.82 (d, J=1.52 Hz, 6H). LC/MS (m/z, MH+): 463.4.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]=1[C:10]1[CH:11]=[CH:12][C:13]([O:19][CH3:20])=[C:14]([N+:16]([O-])=O)[CH:15]=1>C(O)(=O)C.[Zn]>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]=1[C:10]1[CH:11]=[CH:12][C:13]([O:19][CH3:20])=[C:14]([NH2:16])[CH:15]=1
Reactant: COc1ccc(-c2nc3cccnc3[nH]2)cc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: COc1ccc(-c2nc3cccnc3[nH]2)cc1N
Reaction time: 3 h
Yield: 11.4 %

Procedure:
5-(3H-Imidazo[4,5-b]pyridin-2-yl)-2-methoxy-nitrobenzene (7.0 g, 26 mmol) was dissolved in 200 mL acetic acid, and zinc powder (35 g, 535 mmol) was added in portions. The zinc was added at such a rate as to keep the temperature of the reaction mixture under 40° C. After complete addition, the reaction mixture was stirred for 3 hours and filtered to give solid. The solids wee washed with water and acetic acid. The filtrate was rotary evaporated in vacuo, and the residue was partitioned between 1 M NaOH and chloroform. The aqueous layer was extracted several times with chloroform, and the combined organic layers were dried over magnesium sulfate, filtered, and rotary evaporated to give 0.71 g of 5-(3H-imidazo[4,5-b]pyridin-2-yl)-2-methoxy-phenylamine as a tan solid. 1H-NMR (CDCl3): δ 8.06 (dd, 1H), 7.66 (dd, 1H), 7.41 (s, 1H), 7.35 (dd, 1H), 6.91 (dd, 1H), 6.64 (d, 1H), 3.67 (s, 3H) ppm. Anal. (C13H12N4O1) C,H,N values were within 0.4% of the theoretical values.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([OH:10])[N:7]([CH3:11])[N:6]=1)=[O:4].[CH3:12][C:13]1[O:17][N:16]=[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[C:14]=1[CH2:24]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([O:10][CH2:24][C:14]2[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:16][O:17][C:13]=2[CH3:12])[N:7]([CH3:11])[N:6]=1)=[O:4]
Reactant: COC(=O)c1cc(O)n(C)n1
Reactant: Cc1onc(-c2ccccn2)c1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCc2c(-c3ccccn3)noc2C)n(C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.9 %

Procedure:
To a stirred solution of 5-hydroxy-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester (400 mg, 2.6 mmol) and (5-methyl-3-pyridin-2-yl-isoxazol-4-yl)-methanol (500 mg, 2.6 mmol) in THF (10 mL) at 5° C. under argon was added triphenylphosphine (862 mg, 3.3 mmol), then diethyl azodicarboxylate (573 mg, 3.3 mmol) was added dropwise. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was then evaporated. Purification by chromatography (silica, dichloromethane:methanol=9:1) then purification using a 5×50 cm Chiralpak AD column at room temperature using an isopropanol:heptane (2:8) mobile phase with UV detection at 220 nM afforded the title compound (400 mg, 48%) as a white solid. MS: m/e=328.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])[CH3:3].[Cl-].[NH4+].C(Cl)CCl.C1C=CC2N(O)N=[N:29]C=2C=1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[NH2:29][C:14]([CH:9]1[CH2:10][O:11][CH2:12][CH2:13][N:8]1[C:6]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7])=[O:16]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCOCC1C(=O)O
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCOCC1C(N)=O

Procedure:
4-{[(1,1-Dimethylethyl)oxy]carbonyl}morpholine-3-carboxylic acid (0.5 g, 2.162 mmol), ammonium chloride (0.347 g, 6.49 mmol), EDC (0.622 g, 3.24 mmol), HOBt (0.993 g, 6.49 mmol) and DIPEA (1.699 mL, 9.73 mmol) were stirred in DMF (10 mL) at room temperature overnight. Saturated NaHCO3 was then added and the mixture was extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give the title compound as a yellow gum.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[N:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[S:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:26][C:27]1[N:28]=[C:29]([CH:32]=[CH:33][C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][C:35]=2[F:44])[O:30][CH:31]=1.[I-].[K+]>CC(=O)CC>[F:44][C:35]1[CH:36]=[C:37]([C:40]([F:43])([F:41])[F:42])[CH:38]=[CH:39][C:34]=1/[CH:33]=[CH:32]/[C:29]1[O:30][CH:31]=[C:27]([CH2:26][O:18][C:15]2[CH:16]=[CH:17][C:12]([C:9]3[S:10][CH:11]=[C:7]([CH2:6][N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)[N:8]=3)=[CH:13][CH:14]=2)[N:28]=1
Reactant: Oc1ccc(-c2nc(Cn3ccnc3)cs2)cc1
Reactant: Fc1cc(C(F)(F)F)ccc1C=Cc1nc(CCl)co1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCC(C)=O
Product: Fc1cc(C(F)(F)F)ccc1/C=C/c1nc(COc2ccc(-c3nc(Cn4ccnc4)cs3)cc2)co1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 33.4 %

Procedure:
A mixture of 0.129 g (0.50 mmol) 4-[4-(imidazol-1-ylmethyl)-thiazol-2-yl]-phenol and 0.10 g (0.30 mmol) cesium carbonate in 10 ml butanone was stirred at 60° C. for 30 min, then 0.153 g (0.50 mmol) 4-chloromethyl-2-[2-(2-fluoro-4-trifluoromethyl-phenyl)-vinyl]-oxazole and 0.083 g (0.50 mmol) potassium iodide were added and stirring at 60° C. continued over night. After evaporation, 15 ml water was added and the mixture extracted with two portions of 15 ml ethyl acetate. The combined organic layers were washed with 1N sodium hydroxide and water, dried over sodium sulfate and evaporated to give 241 mg raw material which was purified on silica. Elution with ethyl acetate/methanol 5:1 yielded 88 mg (33%) 2-[(E)-2-(2-Fluoro-4-trifluoromethyl-phenyl)-vinyl]-4-[4-(4-imidazol-1-ylmethyl-thiazol-2-yl)-phenoxymethyl]-oxazole as off-white crystals melting at 133-135° C.
Reaction SMILES: [N:1]1[CH:5]=[C:4]([CH2:6][NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)[NH:3][CH:2]=1.CO[C:21]([CH3:23])=[CH2:22].FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl>[N:1]1[CH:5]=[C:4]([CH2:6][N:7]([CH:21]([CH3:23])[CH3:22])[C:8]2[CH:9]=[CH:10][C:11]([O:14][C:15]([F:16])([F:17])[F:18])=[CH:12][CH:13]=2)[NH:3][CH:2]=1
Reactant: C=C(C)OC
Reactant: FC(F)(F)Oc1ccc(NCc2cnc[nH]2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CC(C)N(Cc1cnc[nH]1)c1ccc(OC(F)(F)F)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
To a solution of (3H-imidazol-4-ylmethyl)-(4-trifluoromethoxy-phenyl)-amine (0.39 g, 1.5 mmol) in 1,2-dichloroethane (5 ml) were added successively 2-methoxypropene (0.16 g, 2.25 mmol), trifluoroacetic acid (0.26 g, 2.25 mmol) and sodium triacetoxyborohydride (0.48 g, 2.25 mmol). After stirring the mixture overnight at 60° C. 1 M sodium hydroxide solution (5 ml) was added and the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography (heptane/ethyl acetate=1:1) to yield a white solid (0.24 g, 53%); MS (ISP): 300.1 ((M+H)+.).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:12]I)[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[Na].[Cl:15][C:16]1[CH:29]=[CH:28][C:19]([O:20][C:21]2[CH:26]=[CH:25][C:24]([SH:27])=[CH:23][CH:22]=2)=[CH:18][CH:17]=1.[H-].[Na+].Cl>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1([CH2:12][S:27][C:24]2[CH:25]=[CH:26][C:21]([O:20][C:19]3[CH:28]=[CH:29][C:16]([Cl:15])=[CH:17][CH:18]=3)=[CH:22][CH:23]=2)[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(CI)CCOCC1
Reactant: Sc1ccc(Oc2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(CSc2ccc(Oc3ccc(Cl)cc3)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
4-(Iodomethyl)tetrahydropyran-4-carboxylic acid ethyl ester (300 mg, 1 mmol) was added to a solution containing the sodium salt of 4-(4-chlorophenoxy)thiophenol (generated by the addition of sodium hydride powder (36 mg, 1.5 mmol) to a solution of 4-(4-chlorophenoxy)thiophenol (262 mg, 1.1 mmol) in N,N-dimethylformamide (2 mL) at 0° C. and stirring for 30 minutes). The mixture was warmed to room temperature over 5 minutes, stirred for an additional 20 minutes, cooled to room temperature, and 1M aqueous hydrochloric acid (5 mL) added. The mixture was then partitioned between ethyl acetate (100 mL) and 2M hydrochloric acid (25 mL). The aqueous layer was separated and washed with additional ethyl acetate (2×50 mL). The organic extracts were combined, washed with 1M sodium hydroxide (2×30 mL), dried over magnesium sulfate, concentrated in vacuo. Chromatography over silica gel, and eluting with 20% ethylacetate/hexanes, yielded pure 4-[4-(4-chlorophenoxy)phenylthiomethyl]-tetrahydropyran-4-carboxylic acid ethyl ester (370 mg, 91%), followed by impure 4-[4-(4-chlorophenoxy)phenylthiomethyl]tetrahydropyran-4-carboxylic acid ethyl ester (40 mg). IR (KBr) 1728 cm-1 ; 1HNMR (CDCl3) 1.23 (q, J=7.1 Hz, 3H), 1.56 (ddd, J=14.6, 10.9, 4.4, 2H), 1.63 (ddd, J=14.6, 5.7, 3.3, 2H), 3.13 (s, 2H), 3.51 (ddd, J=11.8, 11.1, 2.4 Hz, 2H), 3.80 (dt, J=11.8, 4.1 Hz, 2H), 4,07 (q, J=7.1 Hz, 2H), 6.91 (d, J=8.9 Hz, 2H), 6.92 (d, J=8.9 Hz, 2H), 7.29 (d, J=9.0 Hz, 2H), 7.39 (d, J=8.9 Hz, 2H); 13C NMR (CDCl3) δ 14.20 (q), 33.72 (t), 45.72 (t), 46.07 (s), 60.92 (t), 65.06 (t), 119.29 (d), 120.20 (d), 128.43 (s), 129.85 (d), 130.57 (s), 133.05 (s), 155.40 (s), 156.21 (s), 174.02 (s); EIHRMS Calcd. for C21H23SO4Cl (M+): 406.1006. Found: 406.1008. Anal. Calcd. for C21H23SO4Cl: C, 61.98; H, 5.70. Found: C, 61.86; H, 5.68.
Reaction SMILES: [S:1]([C:5]1[S:9][C:8]([C:10]#[N:11])=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].Cl.[NH2:13][OH:14].C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C>[OH:14][NH:13][C:10]([C:8]1[S:9][C:5]([S:1](=[O:4])(=[O:3])[NH2:2])=[CH:6][CH:7]=1)=[NH:11]
Reactant: NO
Reactant: N#Cc1ccc(S(N)(=O)=O)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N=C(NO)c1ccc(S(N)(=O)=O)s1
Yield: 57.5 %

Procedure:
A stirred mixture of 5-sulfamoyl-thiophene-2-carbonitrile [CAS-No. 519055-65-3] (0.31 g, 1.65 mmol), hydroxylamine hydrochloride (0.23 g, 3.31 mmol) and sodium carbonate (0.175 g, 1.65 mmol) in water (4.6 ml) and ethanol (1 ml) was heated under reflux conditions for 1.5 h. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with brine (100 ml), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (ethyl acetate/MeOH/hexane) to yield the title compound (0.21 g, 58%) as a white solid. MS (ISN) 220.1 [(M−H)−]; mp 189° C.
Reaction SMILES: [Si]([O:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[CH:18][CH:17]=[CH:16]2)=[CH2:10])(C(C)(C)C)(C)C.C1C(=O)N([Br:28])C(=O)C1>C1COCC1.O>[Br:28][CH2:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[CH:18][CH:17]=[CH:16]2)=[O:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(O[Si](C)(C)C(C)(C)C)c1cccc2cccnc12
Solvent: C1CCOC1
Solvent: O
Product: O=C(CBr)c1cccc2cccnc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
To a solution of 8-(1-((tert-butyldimethylsilyl)oxy)vinyl)quinoline (300 mg, 1.045 mmol) in THF (5 mL) and water (1 mL) was added NBS (203 mg, 1.149 mmol), and the resulting mixture was stirred at 25° C. for 30 min. The mixture was diluted with water (5 mL) and extracted in to EtOAc (2×5 mL). The combined extracts were dried over Na2SO4, filtered, and concentrated in vacuo to yield crude 2-bromo-1-(quinolin-8-yl)ethanone (200 mg) (used without further purification in subsequent transformations): 1H NMR (400 MHz, DMSO-d6) δ 8.99-8.98 (1H, m), 8.27-8.23 (1H, m), 8.17-8.15 (1H, m), 7.67-7.63 (1H, m), 5.18 (1H, s), 5.02 (1H, s), 2.78 (2H, s). m/z (ESI, +ve) 249.9 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:23][C:20]([F:21])([F:22])[C:17]1[CH:16]=[CH:15][C:14]([C:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=2)=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(C(F)(F)F)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1ccc(C2=CCNCC2)cc1
Reaction time: 4 h
Yield: 2121.9 %

Procedure:
A solution of 0.4 g (0.112 mmol) of 1-t-butoxycarbonyl-4-(4-trifluoromethyl phenyl)-1,2,3,6-tetrahydropyridine in 1 mL of TFA and 3 mL of CH2Cl2 was stirred at rt for 1 h. The reaction mixture was then concentrated. A mixture of the residue and 0.1 g of 10% Pd/C in 20 mL of MeOH was hydrogenated at 45 psi for 4 h. The reaction mixture was flitered though a plug of celite and concentrated to give 0.54 g of the title compound. 1H NMR (CDCl3) δ1.94 (m,2H), 2.06 (m, 2H), 3.00 (m, 1H), 3.11 (m, 2H), 3.49 (m, 2H), 7.45 (d, 2H, J=8 Hz), 7.62 (d, 2H, J=8 Hz)
Reaction SMILES: C(B(CC)CC)C.CCCCCCC.C(O)(=O)C(C)(C)C.[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[C:33]([CH3:35])[CH:32]=[C:31]([CH3:36])[C:30]=2/[CH:37]=[CH:38]/[CH:39]([OH:48])[CH2:40][C:41](=[O:47])[CH2:42][C:43]([O:45][CH3:46])=[O:44])=[CH:25][C:24]=1[CH3:49].[BH4-].[Na+]>CO.O1CCCC1>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[C:33]([CH3:35])[CH:32]=[C:31]([CH3:36])[C:30]=2/[CH:37]=[CH:38]/[CH:39]([OH:48])[CH2:40][CH:41]([OH:47])[CH2:42][C:43]([O:45][CH3:46])=[O:44])=[CH:25][C:24]=1[CH3:49]
Reactant: COC(=O)CC(=O)CC(O)/C=C/c1c(C)cc(C)cc1-c1ccc(F)c(C)c1
Agent: CC(C)(C)C(=O)O
Agent: CCB(CC)CC
Agent: [BH4-]
Solvent: CO
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: COC(=O)CC(O)CC(O)/C=C/c1c(C)cc(C)cc1-c1ccc(F)c(C)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Into a glass vessel under nitrogen at ambient temperature with stirring was charged a solution of triethylborane in heptane (49.4 ml, 52.5 mmole; 15 percent w/w) and pivalic acid (255 mg, 2.5 mmole). After 90 minutes, methyl (E)-7-(4'-fluoro-3,3',5-trimethyl[1,1'-biphenyl]-2-yl)-5-hydroxy-3-oxo-6-heptenoate (19.2 g, 50.0 mmole) was charged and then dry tetrahydrofuran (170 ml) was added. After 60 minutes, the solution was cooled to -78° C. and methanol (45 ml) was added dropwise. Sodium borohydride (1.42 g, 37.5 mmole) was carefully added in three equal portions at less than -70° C. The reaction mixture was stirred at -78° C. for 2 hours and additional sodium borohydride (472 mg, 12.5 mmole) was added. After 1 hour, the cold reaction mixture was quenched by addition to 30 percent aqueous hydrogen peroxide (200 ml) while maintaining the temperature below 25° C. After 1 hour, ethyl acetate (300 ml) and water (100 ml) were added. The phases were separated and the aqueous phase was washed with ethyl acetate (50 ml). The combined organic phases were washed with 0.5M aqueous hydrochloric acid (300 ml) and then water (3×300 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the product with 98.2 percent of the desired stereochemical conformation.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=2[CH2:21][NH:22][CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH2:26]([N:33]=[C:34]=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=2[CH2:21][N:22]([CH2:23][CH3:24])[C:34]([NH:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:35])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCNCc1ccc(C)cc1-c1cc(CC(=O)OCC)ccc1OC
Reactant: O=C=NCc1ccccc1
Product: CCOC(=O)Cc1ccc(OC)c(-c2cc(C)ccc2CN(CC)C(=O)NCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-5′-methyl-biphenyl-3-yl)-acetic acid ethyl ester and benzyl isocyanate.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[C:7]([C:10]1[CH:19]=[CH:18][C:13]2[NH:14][C:15](=[O:17])[S:16][C:12]=2[CH:11]=1)(=[O:9])[CH3:8].[CH3:20][O:21][CH2:22]Cl.CCOC(C)=O>CN(C)C=O>[C:7]([C:10]1[CH:19]=[CH:18][C:13]2[N:14]([CH2:20][O:21][CH3:22])[C:15](=[O:17])[S:16][C:12]=2[CH:11]=1)(=[O:9])[CH3:8]
Reactant: COCCl
Reactant: CC(=O)c1ccc2[nH]c(=O)sc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCn1c(=O)sc2cc(C(C)=O)ccc21
Yield: 75.4 %

Procedure:
Add cesium carbonate (1.5 Eq; 310.5 mmoles; 101.1 g) to a solution of 6-acetyl-3H-1,3-benzothiazol-2-one (40.0 g, 207 mmoles) in dimethylformamide (690 mL). Add chloromethyl methyl ether (1.3 Eq, 269 mmoles, 20.4 mL) dropwise and stir at room temperature for 18 hr. Transfer to a separatory funnel, add EtOAc (1 L), wash with water (2×200 mL), and then brine (200 mL). Back extract with DCM (300 mL). Dry the combined organic layers over Na2SO4, filter and concentrate. Slurry the concentrate in 200 ml hexanes/EtOAc (75:25), and filter to give 6-acetyl-3-(methoxymethyl)-3H-1,3-benzothiazol-2-one as a white solid (37.0 g, 156 mmoles, 75% yield). LCMS (low) rt=1.68 min., M+1=238.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2Cl)[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:9]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[NH:8][C:7]=1[CH3:29])=[O:5])[CH3:2].[Cl:30]C1C=CC=CC=1C=O.C(OC(=O)CC(C(OCC)=O)=O)C.C(OC(=O)/C=C(\N)/C)C>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:30])[CH:13]=2)[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:9]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[NH:8][C:7]=1[CH3:29])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(C(=O)OCC)C(c2ccccc2Cl)C(C(=O)OCC)=C(C)N1
Reactant: O=Cc1ccccc1Cl
Agent: CCOC(=O)/C=C(/C)N
Agent: CCOC(=O)CC(=O)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C1=C(C(=O)OCC)C(c2cccc(Cl)c2)C(C(=O)OCC)=C(C)N1

Procedure:
In the same way, 2-methyl-4-(2'-chlorophenyl)-1,4-dihydropyridine-3,5,6-tricarboxylic acid triethyl ester is prepared from 14 g of 2-chlorobenzaldehyde, 19 g of oxalacetic acid diethyl ester and 13 g of β-aminocrotonic acid ethyl ester in 60 ccs of ethanol.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:7][N:6]=1)=[O:4].[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:7]([Br:17])[N:6]=1)=[O:4]
Reactant: COC(=O)c1cnc(N2CCCCC2)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cnc(N2CCCCC2)c(Br)n1
Temperature: 60 °C

Procedure:
A mixture of 2 g (9 mmol) 5-piperidin-1-yl-pyrazine-2-carboxylic acid methyl ester and 1.69 g (9.4 mmol) N-bromosuccinimid in 30 mL CHCl3 was heated to 60° C. for 16 h. The mixture was concentrated and purified by flash column chromatography on silica eluting with a gradient formed from ethyl acetate and heptane to yield after evaporation of the product fractions 1.43 g (53%) of the title compound as white solid. m/z (ES+): 300.2 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[S:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=1)(=[O:25])=[O:24]>>[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[S:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([N:10]2[CH2:9][CH2:8][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:12][CH2:11]2)=[O:31])=[CH:28][CH:27]=1)(=[O:25])=[O:24]
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: O=C(O)c1ccc(S(=O)(=O)c2ccc3ccccc3c2)cc1
Product: O=C(c1ccc(S(=O)(=O)c2ccc3ccccc3c2)cc1)N1CCN(c2ccncc2)CC1
Yield: 32 %

Procedure:
Using an analogous procedure to that described in Example 1, N-(4-pyridyl)piperazine was reacted with 4-(2-naphthylsulphonyl)benzoic acid to give 1-[4-(2-naphthylsulphonyl)benzoyl]-4-(4-pyridyl)piperazine in 32% yield;
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][CH2:10][C:11](Cl)=[O:12].Cl.[CH3:15][NH:16][O:17][CH3:18]>ClCCl>[CH3:18][O:17][N:16]([CH3:15])[C:11](=[O:12])[CH2:10][O:9][CH3:8]
Reactant: CNOC
Reactant: COCC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(=O)N(C)OC
Temperature: 0 °C
Reaction time: 3 h

Procedure:
35.96 ml of triethylamine (258 mmol), followed by a solution of 14 g of methoxyacetyl chloride (Aldrich, 129 mmol) in 250 ml of dichloromethane, are added to a solution of N-methyl-O-methylhydroxylamine hydrochloride in 250 ml of dichloromethane cooled to 0° C. The mixture is stirred for 3 hours while allowing it to return to ambient temperature. A 1N solution of HClaq is added and then the organic phase is washed with water, dried over sodium sulphate, filtered, and concentrated under vacuum. 13.14 g of expected product are obtained in the form of an oil which is used without subsequent purification (crude yield=76%).
Reaction SMILES: [CH:1]1[C:13]2[C:12](=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C1([OH:21])C=CC=CC=1.O.C1(CC2C=CC=CC=2)C=CC=CC=1.SCCCS(O)(=O)=O>>[C:1]1(=[O:21])[C:13]2[C:5]([C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:4][CH:3]=[CH:2]1
Reactant: Oc1ccccc1
Reactant: O=C1c2ccccc2-c2ccccc21
Agent: O=S(=O)(O)CCCS
Solvent: c1ccc(Cc2ccccc2)cc1
Solvent: O
Product: O=C1C=CC=C2C1=Cc1ccccc12
Temperature: 53 °C

Procedure:
9-Fluorenone (3.65 g, 0.0200 mol. 1.00 equiv.), molten phenol (39.6 g, 0.420 mol, 20.8 equiv.), deionized water (0.055 g, 3.06 mmol, 0.151 equiv.) and diphenylmethane (32.83 g) is added to the reactor (reactor design 2). The reaction mixture is heated to 53° C. with stirring under a pad of nitrogen. 3-Mercaptopropanesulfonic acid (0.170 g, 1.10 mmol, 0.0537 equiv.) is added slowly over approximately 1 minute to the reaction mixture at 53° C. The reaction is monitored throughout the reaction period by collecting samples and analyzing by HPLC. The 9-fluorenone is found to be 49% consumed within 2 hours and 77% consumed within 4.5 hours. HPLC analysis (analytical method 3) gives the following relative area % analysis for the reaction products (fluorenone area not included) at 77% conversion: