Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[CH:3]=1.[C:13]1([SH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[K+]>CN(C=O)C.O.[Cu-]=O>[CH3:8][C:6]1[CH:7]=[C:2]([S:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=[C:4]([CH3:12])[C:5]=1[C:9](=[O:11])[CH3:10]
Reactant: CC(=O)c1c(C)cc(I)cc1C
Reactant: Sc1ccccc1
Agent: O=[Cu-]
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1c(C)cc(Sc2ccccc2)cc1C
Yield: 65.5 %

Procedure:
A mixture of 1-(4-iodo-2,6-dimethylphenyl)ethanone (1.5 g, 5.5 mmol, 1.0 equiv), benzenethiol (0.60 mL, 8.2 mmol, 1.5 equiv), copper(I) oxide (39.2 mg, 0.3 mmol, 0.05 equiv), and potassium hydroxide (614.1 mg, 11.0 mmol, 2.0 equiv) in DMF (4.4 mL) and H2O (1.1 mL) was heated at reflux for 20 h. The mixture was quenched with H2O (10 mL) and extracted with ether (2×20 mL). The organic layer was collected, dried over MgSO4(s), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (3.0% EtOAc in hexanes as eluant) to provide 1-(2,6-dimethyl-4-(phenylthio)phenyl)ethanone (931 mg, 3.6 mmol) as yellow oil in 66% yield: 1H NMR (CD3OD, 500 MHz) δ 7.34-7.35 (m, 5 H), 6.97 (s, 2 H), 2.46 (s, 3 H), 2.17 (s, 6 H); ESI-MS: m/z 257.0 (M+H)+.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30]C(=O)OC(C)(C)C)[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.[OH:38][C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][C:44]=1[CH3:45].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.CCOC(C)=O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[NH2:30][C:26]1([C:23]2[CH:24]=[CH:25][C:20]([C:19]3[N:5]4[C:6]5[CH:18]=[CH:17][CH:16]=[N:15][C:7]=5[NH:8][C:9]5[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=5[C:4]4=[N:3][C:2]=3[C:41]3[CH:42]=[CH:43][C:44]([CH3:45])=[C:39]([OH:38])[CH:40]=3)=[CH:21][CH:22]=2)[CH2:27][CH2:28][CH2:29]1
Reactant: Cc1ccc(B(O)O)cc1O
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(Br)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(-c2nc3n(c2-c2ccc(C4(N)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)cc1O
Temperature: 160 °C
Yield: 2.3 %

Procedure:
A mixture of tert-butyl {1-[4-(2-bromo-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (50 mg, 0.09 mmol), (3-hydroxy-4-methylphenyl)boronic acid (27 mg, 0.18 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (6.3 mg, 0.01 mmol) and K3PO4 (72 mg, 0.27 mmol) in DMF/water (0.9 mL, 6:1, v/v) was heated at 160° C. under microwave irradiation for 1 hour. After cooling to room temperature, the mixture was diluted with EtOAc and washed with water (×3). The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by HPLC. The fraction was evaporated and the residue was dissolved in methanol (10 mL) and 4M HCl in dioxane (10 mL). After overnight reaction, the mixture was evaporated and the residue was purified by HPLC to give the titled compound as a white solid (1 mg, 2%). LCMS: 486 [M+H].
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)[OH:5].C(N(CC)CC)C.Cl[C:24]([O:26][CH3:27])=[O:25]>O1CCCC1>[CH3:15][O:14][C:8]1[CH:7]=[C:6]([CH:4]([OH:5])[CH2:3][CH2:2][NH:1][C:24]([O:26][CH3:27])=[O:25])[CH:11]=[CH:10][C:9]=1[O:12][CH3:13]
Reactant: COc1ccc(C(O)CCN)cc1OC
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)NCCC(O)c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
3-amino-1-(3,4-dimethoxyphenyl)-1-propanol (1.27 g, 6.02 mM), triethylamine (0.84 g, 8.30 mM), and methyl chloroformate (0.59 g, 6.25 mM) were dissolved in dried tetrahydrofuran (80 ml) and stirred at room temperature for 5.5 hours. The solution obtained was poured into ice water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, then the solvent was removed in vacuo to obtain a crude product of 1-(3,4-dimethoxyphenyl)-3-(methoxycarbonylamino)-1-propanol as a yellow oil. Next, the crude product was dissolved in dried benzene (5 ml). The mixture was dropped into a solution of sodium hydride (60%) (0.24 g, 6.04 mM) in dried benzene (40 ml) at room temperature, water was added into the reaction solution and the mixture stirred at that temperature for 24 hours, which was then extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate, then the solvent was removed in vacuo to obtain a crude product as a brown solid. The crude product was washed with ether to obtain the above-described compound 0.86 g (yield 63.1%) as a light brown solid.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH:5]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([S:21][CH3:22])[N:16]=1)[C:6]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)=O)C.COC(=O)C(C1C=CC(F)=CC=1)C(=O)C1C=C[N:32]=CC=1.C(O)C>N1C=CC=CC=1>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[NH:32][O:3][C:4](=[O:23])[C:5]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]([S:21][CH3:22])[N:16]=2)=[CH:9][CH:10]=1
Reactant: CCOC(=O)C(C(=O)c1ccc(F)cc1)c1ccnc(SC)n1
Reactant: COC(=O)C(C(=O)c1ccncc1)c1ccc(F)cc1
Solvent: CCO
Solvent: c1ccncc1
Product: CSc1nccc(-c2c(-c3ccc(F)cc3)[nH]oc2=O)n1

Procedure:
Using the procedure from Example 1k set forth above, substitute 3-(4-fluorophenyl)-3-oxo-2-(2-methylsulfanyl-pyrimidin-4-yl)-propionic acid ethyl ester for 2-(4-fluorophenyl)-3-oxo-3-pyridin-4-yl-propionic acid methyl ester and ethanol for pyridine to produce the title compound.
Reaction SMILES: [F:1][C:2]([F:29])([CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][C@@H:5]1[C@@H:12]2[C@@H:8]([O:9][C:10](=[O:13])[CH2:11]2)[CH2:7][C@H:6]1[O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1.CC(C[AlH]CC(C)C)C.C(OCC)(=O)C>C1COCC1>[F:29][C:2]([F:1])([CH2:21][O:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][CH2:4][C@@H:5]1[C@@H:12]2[C@@H:8]([O:9][CH:10]([OH:13])[CH2:11]2)[CH2:7][C@H:6]1[O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1
Reactant: O=C1C[C@@H]2[C@@H](CCC(F)(F)COc3ccccc3)[C@H](OC3CCCCO3)C[C@@H]2O1
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC1C[C@@H]2[C@@H](CCC(F)(F)COc3ccccc3)[C@H](OC3CCCCO3)C[C@@H]2O1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
(3aR,4R,5R,6aS)-4-(3,3-Difluoro-4-phenoxybutyl)-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one, prepared in Step E, was dissolved in anhydrous THF (0.5 M) under nitrogen atmosphere and cooled to −78° C. A solution consisting of DIBAL-H (2 molar equivalents, 1 M in toluene) is added to the reaction mixture dropwise and stirred for 3 hours. Ethyl acetate (20 mL) is added and the mixture is stirred for an additional 5 minutes. The mixture is subsequently treated with 30% aqueous K, Na tartrate and stirred vigorously overnight. The layers are separated and the organic phase is filtered and concentrated under reduced pressure. The crude product is purified by flash chromatography on regular silica gel eluted with ethyl acetate-hexanes to afford the title intermediate.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].[F:7][C:8]1([F:42])[O:12][C:11]2[CH:13]=[CH:14][C:15]([C:17]3([C:20]([NH:22][C:23]4[N:24]=[C:25]([C:33]5[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=5)[C:36](Cl)=[O:37])[C:26]5[C:31]([CH:32]=4)=[CH:30][CH:29]=[CH:28][CH:27]=5)=[O:21])[CH2:19][CH2:18]3)=[CH:16][C:10]=2[O:9]1>ClCCl>[F:42][C:8]1([F:7])[O:12][C:11]2[CH:13]=[CH:14][C:15]([C:17]3([C:20]([NH:22][C:23]4[N:24]=[C:25]([C:33]5[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=5)[C:36]([O:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])=[O:37])[C:26]5[C:31]([CH:32]=4)=[CH:30][CH:29]=[CH:28][CH:27]=5)=[O:21])[CH2:18][CH2:19]3)=[CH:16][C:10]=2[O:9]1
Reactant: CN(C)CCO
Reactant: O=C(Cl)c1cccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)cc3ccccc23)c1
Solvent: ClCCl
Product: CN(C)CCOC(=O)c1cccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)cc3ccccc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To N,N-dimethylethanol amine (921 mg, 1.04 mL, 10.3 mmol) in dichloromethane (5 mL) was added a solution of 3-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoyl chloride in dichloromethane (5 mL). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with DCM (20 mL) and was washed with 1N HCl (20 mL) and saturated NaHCO3 (20 mL). The organics were dried over Na2SO4 and evaporated to yield 2-(dimethylamino)ethyl 3-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoate (1.30 g, 90%). ESI-MS m/z calc. 559.6. found 560.3 (M+1)+. Retention time 1.72 minutes.
Reaction SMILES: [CH3:1][N:2]([N:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19](=[O:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[F:26])[C:3](=[O:13])[CH2:4][NH:5]C(OC(C)(C)C)=O.[BrH:28]>CO>[BrH:28].[CH3:1][N:2]([N:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19](=[O:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[F:26])[C:3](=[O:13])[CH2:4][NH2:5]
Reactant: CN(C(=O)CNC(=O)OC(C)(C)C)n1cccc1C(=O)c1ccccc1F
Agent: Br
Solvent: CO
Product: CN(C(=O)CN)n1cccc1C(=O)c1ccccc1F
Temperature: 25 °C
Reaction time: 6 h
Yield: 95 %

Procedure:
A slurry prepared from 1-[N-methyl-(t-butoxycarbonylamino)acetamido]-2-(2-fluorobenzoyl)pyrrole (20 g, 53.2 mmol) and 100 ml of methanol solution containing 12 ml of 48% HBr (0.106 mol) was stirred at room temperature for 6 hours. The resultant solution was evaporated to a solid which was recrystallized from isopropanol-ether to give 18 g (95%) of powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH:13]([NH:20][C:21](=O)[CH2:22][O:23][CH3:24])[CH2:14][CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].B.CSC>O1CCCC1>[CH3:24][O:23][CH2:22][CH2:21][NH:20][CH:13]([C:9]1([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:10][CH2:11][CH2:12]1)[CH2:14][CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17]
Reactant: CCC(CC)CC(NC(=O)COC)C1(c2ccc(Cl)c(Cl)c2)CCC1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: CCC(CC)CC(NCCOC)C1(c2ccc(Cl)c(Cl)c2)CCC1
Reaction time: 168 h

Procedure:
Borane-methyl sulphide complex (2 ml) was added dropwise to a solution of the methoxyacetamide (5 g) prepared as described above in dry tetrahydrofuran (20 ml) at 0°-5° C. This mixture was left at ambient temperature for 7 days, then poured onto ice-water basified and extracted into ether, washed with water, dried and evaporated to dryness to give an oil. This oil was treated as above with more borane-methyl sulphide to give N-(2-methoxyethyl)-1-[1-(3,4-dichlorophenyl)cyclobutyl]-3-ethyl pentylamine (b.p. 189°-190° C./1.5 mm Hg) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13]>C1COCC1>[C:12]([NH:16][S:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromobenzenesulfonyl chloride (100.2 g) in THF (400 mL) was added t-butylamine (125 mL). An exothermic reaction results with gentle refluxing of the solvent. After 30 min, the bath was removed and the mixture was allowed to warm to r.t. Isopropyl acetate (400 mL) was added and the mixture was washed twice with water. The aqueous phase was back-extracted with ethyl acetate and the combined organics were dried (sodium sulfate) and concentrated to provide the title compound as a solid (112.9 g).
Reaction SMILES: C([C:5]1[N:10]=[C:9]([NH2:11])[C:8]([C:12]2[NH:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)=[CH:7][N:6]=1)(C)(C)C.N[C:22]1C(C2NC3C=CC=CC=3N=2)=CC=CN=1>>[CH:7]1[C:8]2[C:12]3[N:16]([CH:22]=[N:11][C:9]=2[N:10]=[CH:5][N:6]=1)[C:15]1[C:14](=[CH:20][CH:19]=[CH:18][CH:17]=1)[N:13]=3
Reactant: CC(C)(C)c1ncc(-c2nc3ccccc3[nH]2)c(N)n1
Reactant: Nc1ncccc1-c1nc2ccccc2[nH]1
Product: c1ccc2c(c1)nc1c3cncnc3ncn21

Procedure:
Preparation analogous to 7), using 26.7 g (100 mmol) of 2-(2-tert-butyl-4-aminopyrimidin-5-yl)benzimidazole (S55) (employed as equimolar mixture with 2-tert-butylbenzimidazole as obtained from synthesis 26)) instead of 100 mmol of the 2-(2-aminopyridin-3-yl)benzimidazole derivative. After crystallisation from methanol, the crude products are passed through a silica-gel column (heptane:ethyl acetate, 3:1 vv). The solids obtained in this way are freed from low-boiling components and non-volatile secondary components by sublimation (p about 1×10−5 mbar, T about 200-240° C.). Purity according to 1H-NMR typically >99.5%.
Reaction SMILES: Br[CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1)[C:3]([OH:5])=[O:4].[CH3:13][C:14]1[CH:15]=[C:16]([OH:21])[CH:17]=[CH:18][C:19]=1[CH3:20]>>[Cl:12][C:8]1[CH:7]=[C:6]([CH:2]([O:21][C:16]2[CH:17]=[CH:18][C:19]([CH3:20])=[C:14]([CH3:13])[CH:15]=2)[C:3]([OH:5])=[O:4])[CH:11]=[CH:10][CH:9]=1
Reactant: Cc1ccc(O)cc1C
Reactant: O=C(O)C(Br)c1cccc(Cl)c1
Product: Cc1ccc(OC(C(=O)O)c2cccc(Cl)c2)cc1C
Yield: 90.1 %

Procedure:
3-Chlorophenylacetic acid (20.90 g, 122.51 mmol) and NBS (23.50 g, 132.03 mmol) were dissolved in carbon tetrachloride (300 mL), then BPO (300 mg) was added, the resulting reaction was heated to reflux under a sunlamp for 5 hours, then cooled to room temperature, filtered and concentrated to give the desired α-bromo-3-chlorophenylacetic acid. 1.40 g of this α-bromo-3-chlorophenylacetic acid was reacted with 3,4-dimethylphenol (686 mg) according to the General procedure C to give 1.47 g of the desired title compound. Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ ppm 2.17 (s, 3 H) 2.21 (s, 3 H) 5.58 (s, 1 H) 6.65 (dd, J=8.20, 2.64 Hz, 1 H) 6.78 (d, J=2.64 Hz, 1 H) 7.01 (d, J=8.20 Hz, 1 H) 7.29-7.40 (m, 2 H) 7.42-7.52 (m, 1 H) 7.59 (s, 1 H).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:10]([CH2:19][N:20]2[CH2:42][CH2:41][C:23]3([NH:27][C:26](=[O:28])[N:25]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=4)[C:24]3=[O:40])[CH2:22][CH2:21]2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:39][S:36]([C:33]1[CH:32]=[CH:31][C:30]([CH2:29][N:25]2[C:24](=[O:40])[C:23]3([CH2:22][CH2:21][N:20]([CH2:19][C@@H:10]4[C@@H:11]([C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=5)[CH2:12][NH:8][CH2:9]4)[CH2:42][CH2:41]3)[NH:27][C:26]2=[O:28])=[CH:35][CH:34]=1)(=[O:37])=[O:38]
Reactant: CC(C)(C)OC(=O)N1C[C@H](CN2CCC3(CC2)NC(=O)N(Cc2ccc(S(C)(=O)=O)cc2)C3=O)[C@@H](c2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(CN2C(=O)NC3(CCN(C[C@H]4CNC[C@@H]4c4ccccc4)CC3)C2=O)cc1
Yield: 75.5 %

Procedure:
83 mg (0.139 mmol) of (3S,4S)-3-[3-(4-methanesulfonyl-benzyl)-2,4-dioxo-1,3,8-triaza-spiro[4.5]dec-8-ylmethyl]-4-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester was dissolved in 3 mL of DCM and 1 mL of TFA and the solution was stirred overnight. The mixture was then evaporated to dryness and the residue was redissolved in 2 mL of toluene and evaporated again at 40° C. The crude compound was then dissolved in 5 mL of 5% methanol in DCM and filtered through a ChemElute™ loaded with 1 mL of 2 M NaOH. The filtrate was evaporated to yield 3-(4-methanesulfonyl-benzyl)-8-((3R,4S)-4-phenyl-pyrrolidin-3-ylmethyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione (52.1 mg, 76%).
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C:21]1=[O:26])(=[O:19])=[O:18].[CH2:27]([O:34][C:35]([NH:37][C:38]1[CH:43]=[CH:42][N:41]([CH2:44][C:45](O)=[O:46])[C:40](=[O:48])[N:39]=1)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][N:23]([C:45](=[O:46])[CH2:44][N:41]2[CH:42]=[CH:43][C:38]([NH:37][C:35]([O:34][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:36])=[N:39][C:40]2=[O:48])[CH2:22][C:21]1=[O:26])(=[O:19])=[O:18]
Reactant: O=C1CNCCN1S(=O)(=O)c1nc2ccccc2s1
Reactant: O=C(O)Cn1ccc(NC(=O)OCc2ccccc2)nc1=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccn(CC(=O)N2CCN(S(=O)(=O)c3nc4ccccc4s3)C(=O)C2)c(=O)n1)OCc1ccccc1

Procedure:
The title compound was synthesized by the reaction of 1-(benzothiazole-2-sulfonyl)-piperazin-2-one trifluoroacetic acid salt with [4-N-(benzyloxycarbonyl)-cytosin-1-yl]-acetic acid as per the procedure of Example 52. 1H NMR (500 MHz; DMSO-d6) δ 10.79 (brs, 1H), 8.34 (m, 1H), 8.26 (m, 1H), 7.91 (d, 0.6H), 7.85 (d, 0.4H), 7.45˜7.30 (m, 5H), 7.10 (t, 1H), 5.18 (s, 2H), 4.82 (s, 1.2H), 4.72 (s, 0.8H), 4.45 (s, 0.8H), 4.28 (s, 1.2H), 4.22 (t, 1.2H), 4.07 (t, 0.8H), 3.99 (t, 1.2H), 3.86 (t, 0.8H).
Reaction SMILES: [C@:1]12([CH3:13])[C:7]([CH3:9])([CH3:8])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:10](Cl)=[O:11].[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:23]([OH:28])[C:24]([CH3:27])([CH3:26])[CH3:25])([O-:16])=[O:15]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C@:1]12([CH3:13])[C:7]([CH3:9])([CH3:8])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:10]([O:28][CH:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N+:14]([O-:16])=[O:15])[C:24]([CH3:25])([CH3:26])[CH3:27])=[O:11]
Reactant: CC(C)(C)C(O)c1ccccc1[N+](=O)[O-]
Reactant: CC1(C)C2CC[C@@]1(C)C(C(=O)Cl)C2
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(C)(C)C(OC(=O)C1CC2CC[C@]1(C)C2(C)C)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 84.6 %

Procedure:
Under a nitrogen atmosphere, (1S)-camphanic acid chloride (3.37 g, 15.6 mmol) was added to a solution of (RS)-1-(2-nitrophenyl)-2,2-dimethyl-1-propanol (2.71 g, 13 mmol) and DMAP (80 mg, 0.65 mmol) in anhydrous pyridine (50 mL). The mixture was stirred for 24 hours at room temperature. Solvent was removed in vacuo, and the residue was dissolved in ethyl acetate (50 mL), washed with 0.5 M HCl (20 mL) twice followed with saturated NaHCO3 solution (20 mL). The organic phase was dried over Na2SO4, concentrated in vacuo and purified by silica gel column chromatography to yield (RS)-1-(2-nitrophenyl)-2,2-dimethyl-1-propyl (1S)-camphanate (4.11 g, 81%, 1:1 mixture of diastereomers) as a yellow solid. 1H NMR (400 MHz, CDCl3) for diastereomers: δ 7.91 (m, 1H, Ph-H), 7.62 (m, 2H, Ph-H), 7.46 (m, 1H, Ph-H), 6.66 and 6.62 (2 s, 1H, Ph-CH), 2.38 (m, 1H), 2.10-1.9 (m, 2H), 1.71 (m, 1H), 1.13, 1.11, 1.08, 1.04, 1.03, 0.87 (6 s, 9H, CH3×3), 0.97 (s, 9H, (CH3)3C).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([O:11][CH3:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([O:24][CH3:25])[CH:23]=1)[C:18](Cl)=[O:19]>C(Cl)Cl>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([C:18]([C:8]2[CH:9]=[CH:10][C:5]([O:11][CH3:12])=[CH:6][CH:7]=2)=[O:19])[CH:21]=[C:22]([O:24][CH3:25])[CH:23]=1
Reactant: COc1ccccc1
Reactant: COc1cc(OC)cc(C(=O)Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2cc(OC)cc(OC)c2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 76.1 %

Procedure:
Aluminum chloride (2.20 g, 16.5 mmol) was added to a stirred mixture of anisole (1.63 ml, 15.0 mmol) in anhydrous methylene chloride (20 ml) in an ice bath. Then a solution of 3,5-dimethoxybenzoyl chloride (3.01 g, 15.0 mmol) in anhydrous methylene chloride (10 ml) was added. The mixture was allowed to warm up to rt, then refluxed overnight. After cooling down to rt, the mixture was poured to ice water (50 ml), stirred for 20 min., and extracted with methylene chloride (3-x 50 ml). The combined organic extracts were washed with sat. NaHCO3 (3×50 ml), H2O (2×50 ml), brine (50 ml), dried over MgSO4, filtered and concentrated in vacuo to an oil, which was purified via flash column chromatography (10% EtOAc in hexane) to give (3,5-dimethoxy-phenyl)-(4-methoxy-phenyl)-methanone as a yellow solid (3.11 g, 76%): mp, 90-92° C.; 1HNMR (CDCl3) δ 7.85 (d, J=8.0 Hz, 2H, Ar), 6.96 (d, J=9.0 Hz, 2H, Ar), 6.88 (d, J=2.3 Hz, 2H, Ar), 6.65 (d, J=2.4 Hz, 1H, Ar), 3.89 (s, 3H, OCH3), 3.83 (s, 6H, 2OCH3). The product was carried over to the next step.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1/[CH:11]=[CH:12]/[C:13]1[S:14][CH:15]=[C:16]([C:18]([O-:20])=[O:19])[N:17]=1.[OH-].[Na+]>C(O)C.O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1/[CH:11]=[CH:12]/[C:13]1[S:14][CH:15]=[C:16]([C:18]([OH:20])=[O:19])[N:17]=1
Reactant: O=C([O-])c1csc(/C=C/c2ccc3ccccc3n2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1csc(/C=C/c2ccc3ccccc3n2)n1
Temperature: 0 °C

Procedure:
2-[(E)-2-(2-Quinolinyl)ethenyl]-1,3-thiazole-4-carboxylate (0.137 g, 0.44 mmol; see step (vi) above) was suspended in ethanol (2 mL), NaOH (0.052 g, 1.32 mmol) in water (5 mL) was added and the solution was then refluxed for 2 h. The reaction was then hot-filtered and then cooled to 0° C., whereupon dilute HCl was added dropwise until the title compound precipitated as a yellow solid (0.103 g, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]([CH2:25][CH:26]([CH3:28])[CH3:27])[S:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C@@H:18]3[CH2:23][CH2:22][NH:21][CH2:20][C@H:19]3[OH:24])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:38]([Si:41](OS(C(F)(F)F)(=O)=O)([CH:45]([CH3:47])[CH3:46])[CH:42]([CH3:44])[CH3:43])([CH3:40])[CH3:39].O>C(Cl)Cl>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]([CH2:25][CH:26]([CH3:28])[CH3:27])[S:8]([C:11]2[CH:12]=[CH:13][C:14]([O:17][C@@H:18]3[CH2:23][CH2:22][NH:21][CH2:20][C@H:19]3[O:24][Si:41]([CH:45]([CH3:47])[CH3:46])([CH:42]([CH3:44])[CH3:43])[CH:38]([CH3:40])[CH3:39])=[CH:15][CH:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: CC(C)CN(Cc1ccc(Cl)cc1)S(=O)(=O)c1ccc(O[C@@H]2CCNC[C@H]2O)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)CN(Cc1ccc(Cl)cc1)S(=O)(=O)c1ccc(O[C@@H]2CCNC[C@H]2O[Si](C(C)C)(C(C)C)C(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
To a solution of N-(4-chloro-benzyl)-4-((+/−)trans-3-hydroxy-piperidin-4-yloxy)-N-isobutyl-benzenesulfonamide (202 mg, 447 μmol) in DCM (10 mL) was added triethylamine (187 μL, 1.34 mmol) followed by triisopropylsilyltrifluoromethanesulfonate (132 μL, 492 μmol) and the reaction was stirred at room temperature for 1 hour. To the reaction was added Et3N (187 μL, 1.34 mmol) followed by triisopropylsilyltrifluoromethanesulfonate (132 μL, 492 μmol) and reaction stirred for a further 30 minutes at room temperature. Water was added, and the mixture was extracted with DCM, filtered through a phase separator, concentrated then purified by silica gel column chromatography (0-10% MeOH in DCM) to give N-(4-chloro-benzyl)-N-isobutyl-4-((+/−)trans-3-triisopropylsilanyloxy-piperidin-4-yloxy)-benzenesulfonamide (189 mg, 70%). LCMS (m/z, Method A) ES+ 609 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:13])=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([NH:8][NH2:9])=[O:7].[CH2:14]1[C:23](=O)[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15]1.CCOCC>CO.C(O)(=O)C>[CH2:20]1[C:21]2[C:16](=[CH:15][CH:14]=[CH:23][CH:22]=2)[CH2:17][CH2:18][C:19]1=[N:9][NH:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[C:4]=1[CH3:13]
Reactant: O=C1CCc2ccccc2C1
Reactant: COc1cccc(C(=O)NN)c1C
Solvent: CO
Solvent: CCOCC
Solvent: CC(=O)O
Product: COc1cccc(C(=O)NN=C2CCc3ccccc3C2)c1C

Procedure:
3-Methoxy-2-methyl-benzoic acid hydrazide (1.0 g) and β-tetralone (0.9 g) were mixed in 4 mL of methanol with 1 drop of acetic acid at room temperature for 10 minutes. Approximately 10 mL of ether were added and the mixture was refrigerated. Crystals of 3-methoxy-2-methyl-benzoic acid (3,4-dihydro-1H-naphthalen-2-ylidene)-hydrazide formed, which were collected by filtration (0.85 g). 1H NMR (300 MHz, CDCl3) δ (ppm): 6.8-7.3 (m, 4H), 3.75+3.8 (2 s, 3H), 3.45+3.7 (2 s, 2H), 2.85 (t, 2H), 2.4 (t, 2H), 2.27+2.25 (2 s, 3H); multiple conformers; Rf=0.56 (3:1 ethyl acetate:hexane); m.p.=138° C.; m.p. of 3-methoxy-2-methyl-benzoic acid hydrazide=113-116° C.,