Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=C1NC[C@@H](C2C=CC([Cl:22])=C([C:13]3[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=3)C=2)C1.Cl.Cl.[NH2:25][CH2:26][C@@H:27]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[C:34](Br)[CH:33]=1)[CH2:28][C:29]([OH:31])=[O:30]>>[ClH:22].[NH2:25][CH2:26][C@@H:27]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)[CH:33]=1)[CH2:28][C:29]([OH:31])=[O:30]
Reactant: NC[C@H](CC(=O)O)c1ccc(Cl)c(Br)c1
Reactant: O=C1C[C@H](c2ccc(Cl)c(-c3ccc(C(=O)O)cc3)c2)CN1
Agent: Cl
Product: NC[C@H](CC(=O)O)c1ccc(Cl)c(-c2ccc(C(=O)O)cc2)c1

Procedure:
(4R)-4-(3-Bromo-4-chlorophenyl)pyrrolidin-2-one (0.5 g, 0.55 mmol) and 4-methoxycarbonylphenyl boronic acid (0.144 g, 0.55 mmol) were mixed in DMF (2 mL). The mixture was degassed by alternately applying a vacuum and flushing with nitrogen gas. Palladium acetate (0.025 g, 0.11 mmol) and tetrabutylammonium bromide (0.053 g, 0.165 mmol) were added followed by potassium phosphate (0.35 g, 1.65 mmol). The mixture was stirred overnight at 90° C. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), washed with 10% aqueous HCl solution then brine, and concentrated in vacuo to provide 4-[5-((3R)-5-oxopyrrolidin-3-yl)-2-chlorophenyl]benzoic acid. 4-[5-((3R)-5-Oxopyrrolidin-3-yl)-2-chlorophenyl]benzoic acid was then treated with HCl as described for the preparation of (3R)-4-amino-3-(3-bromo-4-chlorophenyl)butanoic acid hydrochloride to provide the title compound (24). MS (ESI) m/z 334.07 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[OH:24].C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: Oc1ccccc1Cl
Reactant: NC(=O)c1cc(-c2ccc(CBr)cc2)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)c1cc(-c2ccc(COc3ccccc3Cl)cc2)no1
Temperature: 90 °C
Yield: 79.3 %

Procedure:
To a mixture of 3-(4-bromomethyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 14; 40 mg, 0.142 mmol) in CH3CN (2 mL) were added 2-chlorophenol (22 μL, 0.22 mmol) and K2CO3 (40 mg, 0.29 mmol). The mixture was heated at 90° C. for 4 h and then evaporated to dryness. The residue was purified by chromatography (66-75% EtOAc/hexanes) to give 3-[4-(2-chloro-phenoxymethyl)-phenyl]-isoxazole-5-carboxylic acid amide (37 mg, 79%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.39 (br. s., 1H), 8.01 (br. s., 1H), 7.94 (d, J=8.1 Hz, 2H), 7.61 (d, J=9.5 Hz, 3H), 7.44 (dd, J=8.1, 1.5 Hz, 1H), 7.19-7.35 (m, 2H), 6.92-7.01 (m, 1H), 5.29 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([N+:16]([O-])=O)[C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6].[H][H]>C(O)C.[Pd]>[NH2:16][C:10]1[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:3]([O:2][CH3:1])[C:13]([O:14][CH3:15])=[CH:12][CH:11]=1
Reactant: CCOC(=O)c1c([N+](=O)[O-])ccc(OC)c1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1c(N)ccc(OC)c1OC

Procedure:
Ethyl 2,3-dimethoxy-6-nitrobenzoate (200 g, 0.979 mole) was dissolved in ethanol (2 L) containing 5% palladium on carbon and hydrogenated until the theoretical amount of hydrogen was absorbed. Filtration and removal of the solvent in vacuo provided the product as a yellow oil, 220.6 g (98.0%).
Reaction SMILES: IC.[C:3]([NH:6][CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[NH:23])[NH:21][OH:22])=[C:16]([F:24])[CH:15]=2)[CH2:9]1)(=[O:5])[CH3:4].[C:25](N=C(N(C)C)N(C)C)(C)(C)C>CN(C=O)C>[C:3]([NH:6][CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[NH:23])[NH:21][O:22][CH3:25])=[C:16]([F:24])[CH:15]=2)[CH2:9]1)(=[O:5])[CH3:4]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C(=N)NO)c(F)c2)C(=O)O1
Reactant: CN(C)C(=NC(C)(C)C)N(C)C
Solvent: CI
Solvent: CN(C)C=O
Product: CONC(=N)c1ccc(N2C[C@H](CNC(C)=O)OC2=O)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Iodomethane (0.02 ml, 0.39 mmol) was added to a solution of 5-(S)-acetamidomethyl-3-[4′-(N-hydroxyamidino)-3′-fluorophenyl]oxazolidine-2-one (0.080 g, 0.26 mmol) and tert-butyl-1,1,3,3-tetramethylguanidine (0.058 ml, 0.39 mmol) in DMF (1.0 ml), and the mixture was stirred at r.t. overnight. Solvent was removed under vacuum, and the crude product purified by silica gel PTLC (10% methanol in DCM). HPLC: Rt 3.6 min. MS (m/z): [M+H]+=325.
Reaction SMILES: C(OC(=O)C)(=O)C.[C:8]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=1)(=[O:10])[CH3:9].[CH2:19]([O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[N+:35]([O-:37])=[O:36])[CH:30]=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)(Cl)Cl>[C:8]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=[CH:30][C:29]2[CH:32]=[CH:33][C:34]([N+:35]([O-:37])=[O:36])=[C:27]([O:26][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:28]=2)[N:13]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)Nc1cccc(C)n1
Reactant: O=Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1cccc(C=Cc2ccc([N+](=O)[O-])c(OCc3ccccc3)c2)n1
Temperature: 180 °C
Yield: 23.1 %

Procedure:
A mixture of acetic anhydride (6 ml), 2-acetamido-6-methylpyridine (8.00 g) and 3-benzyloxy-4-nitrobenzaldehyde (13.7 g), was heated at 180° C. for 22 hours with stirring. After cooling, the reaction mixture was dissolved in chloroform (150 ml). The solution was washed with aqueous potassium carbonate, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (640 g) by eluting with chloroform and washed with a mixture of ethyl acetate and diisopropyl ether to give 2-acetamido-6-[2-(3-benzyloxy-4-nitrophenyl)vinyl]pyridine (4.80 g).
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[S:21][C:22](S(C)(=O)=O)=[N:23][N:24]=4)[CH:18]=3)[N:13]([S:29]([C:32]3[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=3)(=[O:31])=[O:30])[CH:12]=2)[CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[C:39]([O:43][C:44]([NH:46][C@@H:47]1[CH2:51][CH2:50][NH:49][CH2:48]1)=[O:45])([CH3:42])([CH3:41])[CH3:40]>O1CCOCC1>[CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[S:21][C:22]([N:49]5[CH2:50][CH2:51][C@@H:47]([NH:46][C:44](=[O:45])[O:43][C:39]([CH3:41])([CH3:40])[CH3:42])[CH2:48]5)=[N:23][N:24]=4)[CH:18]=3)[N:13]([S:29]([C:32]3[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=3)(=[O:30])=[O:31])[CH:12]=2)[CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cccc(OC(C)C)n3)c3cc(-c4nnc(S(C)(=O)=O)s4)ccc32)cc1
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cccc(OC(C)C)n3)c3cc(-c4nnc(N5CC[C@@H](NC(=O)OC(C)(C)C)C5)s4)ccc32)cc1
Yield: 74.6 %

Procedure:
A yellow solution of 2-(3-(6-isopropoxypyridin-2-yl)-1-tosyl-1H-indol-5-yl)-5-(methylsulfonyl)-1,3,4-thiadiazole (107.4 mg, 0.189 mmol) and (3R)-(+)-3-(tert-butoxycarbonylamino)pyrrolidine (TCI America, Portland, Oreg.; 141 mg, 0.755 mmol) in dioxane (1.0 mL) was heated in an open microwave vial at 90° C. for 2 days. Chromatographic purification of the resulting dry residue (silica gel, 0-100% EtOAc/Hex) furnished (R)-tert-butyl 1-(5-(3-(6-isopropoxypyridin-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-thiadiazol-2-yl)pyrrolidin-3-ylcarbamate (95 mg, 0.141 mmol, 75%) as an off-white solid: MS (ESI, pos. ion) m/z: 675.1 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 8.78 (d, J=1.0 Hz, 1H), 8.02-8.08 (m, 2H), 7.94-7.99 (m, 1H), 7.82 (d, J=8.4 Hz, 2H), 7.61 (t, J=7.8 Hz, 1H), 7.28 (d, J=7.4 Hz, 1H), 7.24 (d, J=8.4 Hz, 2H), 6.63 (d, J=8.2 Hz, 1H), 5.57 (spt, J=6.2 Hz, 1H), 4.66-4.84 (m, 1H), 4.41 (br. s., 1H), 3.83 (dd, J=10.6, 6.1 Hz, 1H), 3.67-3.73 (m, 1H), 3.59-3.67 (m, 1H), 3.48-3.55 (m, 1H), 3.45 (dd, J=10.6, 4.1 Hz, 1H), 2.34 (s, 3H), 1.46 (s, 9H), 1.45 (br. s., 3H), 1.44 (br. s., 3H).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH3:50][C:51](=[O:54])[CH:52]=[CH2:53]>CC([O-])=O.CC([O-])=O.[Pd+2].O>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2](/[CH:53]=[CH:52]/[C:51](=[O:54])[CH3:50])=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: C=CC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Product: CC(=O)/C=C/c1cc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cnc1N1CC[C@@H](O)C1
Temperature: 130 °C
Reaction time: 6 h

Procedure:
(R)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 2.2, 250 mg, 0.560 mmol), Pd(OAc)2 (3.77 mg, 0.017 mmol), tri-o-tolylphosphine (20.46 mg, 0.067 mmol), but-3-en-2-one (55.1 μL, 0.672 mmol) and TEA (102 μL, 0.728 mmol) were added to a MW vial, which was sealed and purged with argon. DMF (1.87 mL) was added and the RM was stirred at 130° C. for 6 h. Additional but-3-en-2-one (22.96 μL, 0.280 mmol) was then added and mixture was stirred at 130° C. for 16 h. The RM was poured into water (25 mL) and extracted with DCM (3×20 mL). The combined extracts were dried over MgSO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (RediSep® Silica gel column, 12 g, cyclohexane/EtOAc-EtOH+0.1% NH4OH (9:1) from 40% to 75% EtOAc-EtOH+0.1% NH4OH (9:1)). Fractions containing pure product were combined and the solvent was evaporated off under reduced pressure to give a residue which was azeotroped with xylene and triturated in cyclohexane to yield the title compound as a yellow solid. UPLC-MS (Condition 1) tR=2.39 min, m/z=436.0 [M+H]+, m/z=434.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.82-1.91 (m, 1H) 1.91-2.00 (m, 1H) 2.35 (s, 3H) 3.43 (d, J=11.25 Hz, 1H) 3.59-3.67 (m, 1H) 3.78-3.88 (m, 2H) 4.34 (br. s, 1H) 4.99 (d, J=3.18 Hz, 1H) 6.61 (d, J=15.89 Hz, 1H) 7.36 (d, J=8.31 Hz, 2H) 7.81-7.93 (m, J=16.14, 9.29 Hz, 3H) 8.29 (d, J=2.20 Hz, 1H) 8.71 (d, J=2.45 Hz, 1H) 10.21 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH:11]([N:14]([CH2:16][CH2:17][O:18][CH3:19])[CH3:15])[CH2:12][CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[NH2:20].Cl[C:22]1[N:27]=[C:26]([NH:28][C@@H:29]2[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]2[NH:35][S:36]([CH3:39])(=[O:38])=[O:37])[C:25]([Cl:40])=[CH:24][N:23]=1>>[Cl:40][C:25]1[C:26]([NH:28][C@@H:29]2[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]2[NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[N:27][C:22]([NH:20][C:4]2[CH:5]=[CH:6][C:7]3[CH2:13][CH2:12][CH:11]([N:14]([CH2:16][CH2:17][O:18][CH3:19])[CH3:15])[CH2:10][CH2:9][C:8]=3[C:3]=2[O:2][CH3:1])=[N:23][CH:24]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: COCCN(C)C1CCc2ccc(N)c(OC)c2CC1
Product: COCCN(C)C1CCc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)c(OC)c2CC1
Yield: 42.5 %

Procedure:
In an analogous manner to Experimental 691, part c, 1-methoxy-N*7*-(2-methoxyethyl)-N*7*-methyl-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine and N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide were combined to yield N-[(1R,2R)-2-(5-Chloro-2-{1-methoxy-7-[(2-methoxy-ethyl)-methyl-amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino}-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (185 mg, 42.5% yield) as a brown foam. 1H-NMR (CDCl3) δ 7.94 (s, 1H), 7.89 (d, J=7.8 Hz, 1H), 6.88 (d, J=8.2 Hz, 1H), 5.41 (m, 1H), 3.91 (m, 1H), 3.73 (s, 1H), 3.45 (m, 2H), 3.32 (m, 5H), 2.78 (m, 7H), 2.30-2.08 (m, 7H), 1.83 (br s, 2H), 1.33 (m, 7H). LC/MS (ESI+)=581 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.ClC(OCC(C)C)=O.[N:22]1([C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[NH:33][C:32](=[O:37])[CH2:31]3)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([N:25]1[CH2:26][CH2:27][N:22]([C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[NH:33][C:32](=[O:37])[CH2:31]3)[CH2:23][CH2:24]1)=[O:8]
Reactant: O=C1Cc2cc(N3CCNCC3)ccc2N1
Reactant: COc1ccc(C(=O)O)cc1OC
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N2CCN(c3ccc4c(c3)CC(=O)N4)CC2)cc1OC
Yield: 42.2 %

Procedure:
3,4-Dimethoxybenzoic acid (2.6 g) and 1.65 g of 1,8-diazabicyclo[5,4,0]undecene-7 were added to 100 ml of DMF and to the mixture was added dropwise 1.5 ml of isobutyl chloroformate with ice-cooling externally with stirring. After completion of addition, the mixture was stirred for 30 minutes. To the mixture was added 40 ml of DMF solution containing 2.16 g of 5-(1-piperazinyl)oxindol and the mixture was stirred at room temperature for 5 hours. After completion of reaction, the solvent was removed by distillation. The residue was extracted with 300 ml of chloroform and the extract was washed with a diluted aqueous solution of sodium hydrogencarbonate, water, diluted hydrochloric acid and water, successively. Chloroform was removed by distillation and the residue was recrystallized from methanol to give 1.6 g of 5-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]oxindol.
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[C:7](=[C:8]([O:16][CH3:17])[CH:9]=[C:10]([C:13]([OH:15])=O)[CH:11]=3)[CH:6]=[CH:5]2)[CH2:3][CH2:2]1.[O:18]=[C:19]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:34]3[NH:35][C:36]([C:39]([NH2:41])=[O:40])=[N:37][N:38]=3)[CH:32]=2)[O:27][C:21]2([CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:20]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.O>[CH:1]1([N:4]2[C:12]3[C:7](=[C:8]([O:16][CH3:17])[CH:9]=[C:10]([C:13]([N:24]4[CH2:23][CH2:22][C:21]5([CH2:20][C:19](=[O:18])[C:33]6[C:28](=[CH:29][CH:30]=[C:31]([C:34]7[NH:35][C:36]([C:39]([NH2:41])=[O:40])=[N:37][N:38]=7)[CH:32]=6)[O:27]5)[CH2:26][CH2:25]4)=[O:15])[CH:11]=3)[CH:6]=[CH:5]2)[CH2:2][CH2:3]1
Reactant: COc1cc(C(=O)O)cc2c1ccn2C1CC1
Reactant: NC(=O)c1nnc(-c2ccc3c(c2)C(=O)CC2(CCNCC2)O3)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4nnc(C(N)=O)[nH]4)ccc2O3)cc2c1ccn2C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-cyclopropyl-4-methoxy-1H-indole-6-carboxylic acid (54 mg) and 5-[4-oxo-spiro(chroman-2,4′-piperidin)-6-yl]-4H-1,2,4-triazole-3-carboxamide (102 mg) in DMF (4 mL) were added TEA (77 uL), HOBT (42 mg), and WSC (53 mg) at room temperature and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into H2O, extracted with CHCl3, dried over sodium sulfate, filtered, and concentrated in reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of CHCl3/MeOH (1:0-10:1) as eluent to give the title compound as a colorless solid. 1H-NMR (400 MHz, CDCl3) δ: 8.78-8.60 (1H, m), 8.40-8.25 (1H, m), 7.29 (1H, s), 7.15 (1H, d, J=8.0 Hz), 7.09 (1H, d, J=4.0 Hz), 6.57 (1H, s), 6.52 (1H, d, J=4.0 Hz), 4.30-4.17 (1H, m), 3.95 (3H, s), 3.62-3.38 (3H, m), 3.38-3.32 (1H, m), 2.85 (2H, s), 2.28-1.70 (4H, m), 1.06-1.04 (2H, m), 1.00-0.97 (2H, m); MS [M+H]+=541.
Reaction SMILES: C(C(C)=O)C(C)C.[C:8]1([CH:14](Br)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31][O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[N+:39]([O-:41])=[O:40])[CH2:25][CH2:24]1>C(N(CC)CC)C>[C:8]1([CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:22][CH:23]2[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][CH2:31][O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[N+:39]([O-:41])=[O:40])[CH2:27][CH2:28]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=[N+]([O-])c1ccccc1OCCCN1CCC(O)CC1
Reactant: BrC(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(=O)CC(C)C
Product: O=[N+]([O-])c1ccccc1OCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reaction time: 15 h
Yield: 76 %

Procedure:
Into 270 ml of methyl isobutyl ketone were dissolved 32.1 g of diphenylmethyl bromide, 28.0 g of 4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine and 30.4 g of triethylamine. The resultant solution was heated under reflux with stirring for 15 hours. After cooling, the reaction solution was washed with water, and the solvent was removed under reduced pressure. The residue was eluted with methanol-chloroform (1:50) by silica gel column chromatography to give 33.9 g of oily 4-diphenylmethoxy-1-[3-(2-nitrophenoxy)propyl]piperidine.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=1[CH3:15].Cl[C:17]([O:19][CH3:20])=[O:18]>CC(C)=O>[OH:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:17](=[O:18])[O:19][CH3:20])=[C:9]([CH3:15])[CH:10]=1
Reactant: Cc1cc(O)ccc1N
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)Nc1ccc(O)cc1C
Reaction time: 3 h
Yield: 100 %

Procedure:
12.0 g of potassium carbonate were added to a solution of 100 g of 4-amino-3-methylphenol in 400 ml of acetone cooled in an ice-water bath, followed by the addition of 80 ml of methyl chloroformate at the same temperature. The resulting mixture was stirred at the same temperature for 3 hours, at the end of which time the reaction mixture was filtered. The resulting filtrate was concentrated under reduced pressure to give 151 g (yield 100%) of the title compound as an amorphous powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([S:8][CH3:9])=[CH:4][N:3]=1.N1C=CC=CC=1.[Br:16]Br>C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:7]([Br:16])=[N:6][C:5]([S:8][CH3:9])=[CH:4][N:3]=1
Reactant: CSc1cnc(N)cn1
Reactant: BrBr
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CSc1cnc(N)c(Br)n1
Reaction time: 0.5 h
Yield: 71967.6 %

Procedure:
To a solution of the compound obtained in Example 34 (1) (100 mg) in chloroform (18 ml), pyridine (56.0 mg) was added and then a solution of bromine (113 mg) in chloroform (18 ml) was added dropwise at 15 to 30° C. over 1 hour under light-shielding and the mixture was stirred at the same temperature for 30 minutes. After completion of the reaction, the reaction solution was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was separated using silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain 112 g (72%) of the desired product as a white powder.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH2:7][O:8][NH2:9])=[CH:4][CH:3]=1.[C:10]([C:13]1[C:14](=[O:29])[CH2:15][CH:16]([CH:23]2[CH2:28][CH2:27][CH2:26][S:25][CH2:24]2)[CH2:17][C:18]=1[O:19][C:20](=[O:22])[CH3:21])(=O)[CH3:11]>C(O)C>[C:20]([O:19][C:18]1[CH2:17][CH:16]([CH:23]2[CH2:28][CH2:27][CH2:26][S:25][CH2:24]2)[CH2:15][C:14](=[O:29])[C:13]=1[C:10](=[N:9][O:8][CH2:7][C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:11])(=[O:22])[CH3:21]
Reactant: CC(=O)OC1=C(C(C)=O)C(=O)CC(C2CCCSC2)C1
Reactant: NOCc1ccc(Cl)s1
Solvent: CCO
Product: CC(=O)OC1=C(C(C)=NOCc2ccc(Cl)s2)C(=O)CC(C2CCCSC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.34 g (2.0 mmol) of (5-chlorothien-2-yl)methoxyamine is added to a stirred solution of 0.59 g (2.0 mmol) of 2-acetyl-3-acetyloxy-5-(tetrahydro-2H-thiopyran-3-yl)-cyclohex-2-en-1-one in 10 ml of absolute ethanol. After stirring overnight at room temperature, the reaction mixture is concentrated under reduced pressure. The resulting residue is diluted with 25 ml of dichloromethane and washed twice with 10 ml of saturated sodium chloride solution. The washed extract is then dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The product can then be purified by column chromatography employing tetrahydrofuran-hexane (1:2 by volume) as eluent to afford the title compound.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[CH:3]=1.C([Li])CCC.CCCCCC.CN(C)[CH:27]=[O:28].[Cl-].[Na+]>C1COCC1>[CH3:13][O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([CH:27]=[O:28])[CH:11]=[CH:10]2
Reactant: COc1ccc2cc(Br)ccc2c1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc2cc(C=O)ccc2c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a solution of 2-bromo-6-methoxynaphthalene (4.00 g, 16.87 mmol) in 100 mL of anhydrous THF under nitrogen atmosphere at -78° C. was added a 1.6M solution of n-butyllithium in hexane (10.6 mL, 16.96 mmol). The reaction mixture turned into a yellow suspension 5 minutes after the addition of butyllithium. The suspension was stirred at -78° C. for 1 hour and then warmed to -23° C. Anhydrous N,N-dimethylformamide (4.0 mL, 51.7 mmol) was added. The reaction mixture was stirred at -23° C. for 30 minutes. Saturated sodium chloride solution (50 mL) was added to quench the reaction. The organic layer was collected and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were dried with anhydrous magnesium sulphate, filtered, and concentrated under reduced pressure. The residue oil was chromatographed by 10% ethyl acetate in hexanes on silica gel to give 2.86 g (91%) of 6-methoxy-2-naphthaldehyde as a white solid. 1HNMR (300 MHz, CDCl3) δ10.10 (1H, s), 8.26 (1H, s), 7.95-7.78 (3H, m), 7.28-7.18 (2H, m), 3.97 (3H, s).
Reaction SMILES: [S:1]([N:11]=[N+:12]=[N-:13])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]#[CH:22].N1C(C)=CC=CC=1C>C(Cl)(Cl)Cl.[Cu]I>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[N:13]=[N:12][N:11]([S:1]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=2)(=[O:2])=[O:3])[CH:22]=1
Reactant: C#Cc1ccccc1Cl
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: [Cu]I
Solvent: Cc1cccc(C)n1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccccc3Cl)nn2)cc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A solution of tosyl azide (16) (1.0 equiv) in CHCl3 (0.5M) cooled to 0° C. was treated with 2-chlorophenyl acetylene (15) (1.2 equiv), 2,6-lutidine (1.2 equiv) and CuI (0.1 equiv). The resulting mixture was stirred at 0° C. for 24 h, quenched with 10% HCl, the layers separated and the aqueous one washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (Hexane/AcOEt 5:1, 3:1 and 1:1) to provide 4-(2-chlorophenyl)-1-tosyl-1H-1,2,3-triazole (17) as a pale yellow crystalline solid.
Reaction SMILES: C([O:4][CH:5]1[CH:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[N:12]=[C:11]2Br)[CH2:8][CH:7]([CH2:22][O:23]C(=O)C)[CH:6]1[O:27]C(=O)C)(=O)C.[CH:31]([NH2:34])([CH3:33])[CH3:32]>C(O)C>[Cl:19][C:17]1[C:16]([Cl:20])=[CH:15][C:14]2[N:10]([CH:9]3[CH:5]([OH:4])[CH:6]([OH:27])[CH:7]([CH2:22][OH:23])[CH2:8]3)[C:11]([NH:34][CH:31]([CH3:33])[CH3:32])=[N:12][C:13]=2[CH:18]=1
Reactant: CC(=O)OCC1CC(n2c(Br)nc3cc(Cl)c(Cl)cc32)C(OC(C)=O)C1OC(C)=O
Reactant: CC(C)N
Solvent: CCO
Product: CC(C)Nc1nc2cc(Cl)c(Cl)cc2n1C1CC(CO)C(O)C1O
Reaction time: 24 h
Yield: 57 %

Procedure:
(±)-(1R*, 2S*, 3S*, 5S*)-3-(Acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (750 mg, 1.44 mmole) was refluxed in ethanol (10 mL) with isopropylamine (1.22 mL, Aldrich) under nitrogen for 18 hours. A second portion of isopropylamine (1.22 mL) was added and reflux continued for an additional 24 hours. Volatiles were evaporated, the residue was redissolved in ethanol, 1N sodium hydroxide (1.44 mL) was added, and volatiles were reevaporated. The residue was chromatographed on a silica gel column. Title compound was eluted with 10% methanol-chloroform as a colorless glass. The glass was crystallized from ethyl acetate-hexanes to give (±)-(1R*, 2S*, 3S*, 5S*)-5-[5,6-dichloro-2-(isopropylamino)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol as white crystals (305 mg, 57%); m.p. 213°-214° C.; 1H-NMR(DMSO-d6) identical with that of the enantiomer described in Example 75.