Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH:10](O)[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:6][CH:5]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[Br:48][C:49]1[CH:54]=[CH:53][C:52]([SH:55])=[CH:51][CH:50]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([S:55][C:52]2[CH:53]=[CH:54][C:49]([Br:48])=[CH:50][CH:51]=2)[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C(O)CC(C)C)cc1
Reactant: Sc1ccc(Br)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(CC(C)C)Sc2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(1-hydroxy-3-methyl-butyl)-benzoic acid methyl ester (1240 mg, 5.59 mmol) in toluene (10 mL) is added 1,1′-(azodicarbonyl)dipiperidine (ADDP, 2114 mg, 8.38 mmol) at 0° C., followed by the additions of tributylphosphine (2.09 mL, 8.38 mmol) and 4-bromo-thiophenol (1267 mg, 6.7 mmol). The reaction mixture is warmed up to room temperature and stirred overnight. The mixture is loaded on silica gel, eluted with hexanes with a gradient from 0% of ethyl acetate to 50% of ethyl acetate giving 4-[1-(4-bromo-phenylsulfanyl)-3-methyl-butyl]-benzoic acid methyl ester. 393 mg of the ester product is taken into ethanol (2 mL), treated with sodium hydroxide (5N aqueous, 1 mL) for 3 h at room temperature. The mixture is concentrated, diluted with ethyl acetate, acidified with 5 N HCl (1.1 mL), extracted with ethyl acetate. The organic layers are dried and concentrated giving 4-[1-(4-bromo-phenylsulfanyl)-3-methyl-butyl]-benzoic acid (379 mg).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Cl:43])[C:9]=1[C:10](=[O:42])[CH2:11][N:12]([CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:13]([C:15]1[CH:16]=[N:17][N:18]([C@H:24]2[CH2:29][CH2:28][C@H:27]([C:30]([O:32]CC)=[O:31])[C:26]([CH3:36])([CH3:35])[CH2:25]2)[C:19]=1[C:20]([F:23])([F:22])[F:21])=[O:14].C1COCC1>CCO>[Cl:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Cl:43])[C:9]=1[C:10](=[O:42])[CH2:11][N:12]([CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:13]([C:15]1[CH:16]=[N:17][N:18]([C@H:24]2[CH2:29][CH2:28][C@H:27]([C:30]([OH:32])=[O:31])[C:26]([CH3:36])([CH3:35])[CH2:25]2)[C:19]=1[C:20]([F:23])([F:22])[F:21])=[O:14]
Reactant: CCOC(=O)[C@H]1CC[C@H](n2ncc(C(=O)N(CC(=O)c3c(Cl)cncc3Cl)CC(C)(C)C)c2C(F)(F)F)CC1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)CN(CC(=O)c1c(Cl)cncc1Cl)C(=O)c1cnn([C@H]2CC[C@H](C(=O)O)C(C)(C)C2)c1C(F)(F)F
Temperature: 60 °C
Reaction time: 40 h
Yield: 86.7 %

Procedure:
NaOH (1.6 mL of a 1.0 M aqueous solution, 1.6 mmol) was added to a stirring solution of ethyl (1S,4S)-4-(4-((2-(3,5-dichloro-4-pyridinyl)-2-oxoethyl)(2,2-dimethylpropyl)carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)-2,2-dimethylcyclohexanecarboxylate (0.098 g, 0.16 mmol, from Step 2), THF (1.6 mL), and EtOH (1.6 mL), and then the reaction mixture was heated at 60° C. After stirring for 40 h, the reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was dissolved with water (10 mL), concentrated hydrochloric acid (10 drops) was added to the solution, the resulting heterogeneous mixture was filtered, the filter cake washed with water, dissolved with Et2O, the solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved with DCM, the solution was filtered, and the filtrate was concentrated under reduced pressure to give (1S,4S)-4-(4-((2-(3,5-dichloro-4-pyridinyl)-2-oxoethyl)(2,2-dimethylpropyl)carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)-2,2-dimethylcyclohexanecarboxylic acid (0.082 g, 88% yield) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](Br)=[C:11]([C:14]#[N:15])[N:10]([CH3:16])[C:9]2=[O:17])=[CH:4][CH:3]=1.[F-:18].[K+].O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([F:18])=[C:11]([C:14]#[N:15])[N:10]([CH3:16])[C:9]2=[O:17])=[CH:4][CH:3]=1
Reactant: [F-]
Reactant: Cn1c(C#N)c(Br)n(-c2ccc(Cl)cc2)c1=O
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cn1c(C#N)c(F)n(-c2ccc(Cl)cc2)c1=O

Procedure:
A solution of the product of Example 66, 1-(4-chlorophenyl)-5-bromo-4-cyano-3-methyl-1,3-dihydro-2H-imidazol-2-one (0.4 g, 1.3 mmol) and potassium fluoride (0.14 g, 2.66 mmol) in 100 mL of dry dimethyl sulfoxide was heated to 130° C. for two hours, then cooled and poured into 100 mL of water. The product was extracted into ethyl acetate, washed with saturated brine solution, dried, and concentrated to an oil. The oil was chromatographed through silica gel (25:75 ethyl acetate:petroleum ether). Collection of the appropriate fractions furnished 0.14 g of 1-(4-chlorophenyl)-4-cyano-5-fluoro-3-methyl-1,3-dihydro-2H-imidazol-2-one (m.p. 105° C.).
Reaction SMILES: [SH2:1].[CH3:2][C:3]1[CH:4]=[C:5]([O:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[CH:24]=2)(=[O:22])=[O:21])[CH:6]=[C:7]([O:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[CH:17][N:16]=[N:15][CH:14]=2)[CH:8]=1.C(N(CC)CC)C>N1C=CC=CC=1>[CH3:2][C:3]1[CH:4]=[C:5]([O:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29](=[S:1])[NH2:30])[CH:24]=2)(=[O:22])=[O:21])[CH:6]=[C:7]([O:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[CH:17][N:16]=[N:15][CH:14]=2)[CH:8]=1
Reactant: Cc1cc(OCCNc2ccnnc2)cc(OS(=O)(=O)c2cccc(C#N)c2)c1
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Cc1cc(OCCNc2ccnnc2)cc(OS(=O)(=O)c2cccc(C(N)=S)c2)c1
Yield: 87 %

Procedure:
Hydrogen sulfide was passed into a solution of 1.5 g (3.7 mmol) 3-cyanobenzenesulfonic acid-3-methyl-5-[2-(pyridazin-4-ylamino)-ethoxy]-phenyl ester (example 9) and 2.0 ml triethylamine in 20 ml pyridine until saturation (ca. 30 min). After 2 h at room temperature the solvent was removed in a vacuum, the residue was admixed with water, extracted with ethyl acetate, the solvent was removed in a vacuum, the residue was taken up in methanol and filtered over silica gel (dichloromethane: methanol=98:2). The solvent was removed in a vacuum and the title compound was obtained in a 87% yield as yellow crystals of Fp 76°-78° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:20])[CH:11]=[C:12]([C:15](OCC)=[O:16])[NH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:22][NH2:23]>>[CH2:1]([O:8][C:9]1[C:10](=[O:20])[CH:11]=[C:12]([C:15]([NH:22][NH2:23])=[O:16])[NH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(=O)c(OCc2ccccc2)c[nH]1
Reactant: NN
Solvent: O
Product: NNC(=O)c1cc(=O)c(OCc2ccccc2)c[nH]1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
A suspension of 5-(benzyloxy)-1,4-dihydro-4-oxo-2-pyridinecarboxylic acid, ethyl ester (7.1 g, 26 mmole) in 99% hydrazine hydrate (15 ml) was heated until most of the solid dissolved. The resulting mixture was stirred for 25 minutes at ambient temperature, the excess hydrazine was removed under high vacuum and the solid residue was treated with methanol. The volatiles were removed in vacuo (repeat methanol treatment and evaporation twice), the solid residue was washed with methanol, hexane, and dried to afford 6 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[I:11]([O-])(=O)=O.[K+].[I-].[K+]>S(=O)(=O)(O)O.O>[OH:1][C:2]1[C:7]([I:11])=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: [O-][I+2]([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(O)nc1
Agent: O=S(=O)(O)O
Agent: [I-]
Agent: [K+]
Solvent: O
Product: O=[N+]([O-])c1cnc(O)c(I)c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 236.3 %

Procedure:
2-Hydroxy-5-nitropyridine (7.0 g, 50 mmol) was suspended in 100 mL of 20% sulfuric acid and then treated with potassium iodate (4.2 g, 19.6 mmol) dissolved in 10 mL of water. The mixture was heated to 100° C. and potassium iodide (8.0 g, 48.2 mmol) dissolved in 20 mL of water was added dropwise over one h. The reaction mixture turns a purplish-red and a precipitate forms. After 0.5 h, the reaction mixture is cooled and filtered. The solid is stirred for 15 min with 10% sodium meta-bisulfite solution, filtered, washed with water and dried at 80° C. overnight on a vacuum pump to give the desired compound 765A (12.32 g, 92%) as a yellow solid. The product was characterized by 1H NMR.
Reaction SMILES: [CH:1]([S:4][CH2:5][CH2:6][N:7]([C:9]([O:11][C@@H:12]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:13]([O:15]CC1C=CC=CC=1)=[O:14])=[O:10])[CH3:8])([CH3:3])[CH3:2].[OH-].[K+]>C(O)C>[CH:1]([S:4][CH2:5][CH2:6][N:7]([C:9]([O:11][C@@H:12]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:13]([OH:15])=[O:14])=[O:10])[CH3:8])([CH3:3])[CH3:2]
Reactant: CC(C)SCCN(C)C(=O)O[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)SCCN(C)C(=O)O[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 1 h
Yield: 99.4 %

Procedure:
To a solution of benzyl 2(S)-[N-(2-isopropylthioethyl)-N-methylaminocarbonyloxy]-3-phenylpropionate (623 mg) in ethanol (10 ml) was added 1N potassium hydroxide (3 ml) at ambient temperature, and the mixture was stirred at the same temperature for 1 hour. The solution was concentrated in vacuo, and the residue was partitioned between water (20 ml) and diethyl ether (20 ml). The aqueous layer was separated and acidified to pH 2 with 10% hydrochloric acid, and the product was extracted with chloroform (20 ml×2). The extract was washed with water (30 ml) and dried over magnesium sulfate. Evaporation of the solvent gave 2(S)-[N-(2-isopropylthioethyl)-N-methylaminocarbonyloxy]-3-phenylpropionic acid (485 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].C[Si]([N:14]=[C:15]=[O:16])(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:15]([NH2:14])=[O:16])[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: Nc1cc(F)cc(F)c1
Solvent: ClCCl
Product: NC(=O)Nc1cc(F)cc(F)c1
Reaction time: 8 h
Yield: 37.6 %

Procedure:
To a stirred solution of 3,5-difluoroaniline (4.0 g, 31 mmol, 1.00 equiv) in CH2Cl2 (50 mL) under argon at room temperature was added dropwise trimethylsilyl isocyanate (3.56 g, 30.90 mmol, 1.00 equiv). The reaction mixture was stirred overnight and quenched by the dropwise addition of CH3OH (50 mL). The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography using CHCl3/CH3OH (10:1 to 7:1) as eluent to yield the title compound (2.0 g, 38%) as a white solid. 1H-NMR (400 MHz, DMSO-d6): δ ppm 8.96 (s, 1H), 7.16-7.10 (m, 2H), 6.72-6.66 (m, 1H), 6.07 (br s, 2H).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]([OH:11])=O)[CH:4]=1)[CH3:2].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:18]=[C:19]([CH:32]=[CH:33][CH:34]=1)[C:20]([C:22]1[CH:30]=[C:29]2[C:25]([CH2:26][C:27](=[O:31])[NH:28]2)=[CH:24][CH:23]=1)=[O:21]>C1COCC1>[O:31]=[C:27]1[CH2:26][C:25]2[C:29](=[CH:30][C:22]([C:20]([C:19]3[CH:18]=[C:17]([NH:16][C:9]([C:5]4[CH:4]=[C:3]([CH2:1][CH3:2])[N:7]([CH3:8])[N:6]=4)=[O:11])[CH:34]=[CH:33][CH:32]=3)=[O:21])=[CH:23][CH:24]=2)[NH:28]1
Reactant: CCc1cc(C(=O)O)nn1C
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4)c2)nn1C
Temperature: 79 °C
Reaction time: 3 h
Yield: 62.1 %

Procedure:
A dry flask was charged with 5-Ethyl-1-methyl-1H-pyrazole-3-carboxylic acid (0.159 g, 1.03 mmol) and thionyl chloride (5 mL) and allowed to stir at 79° C. for 3 h. The thionyl chloride was then removed by concentration in vacuo. The crude acid chloride was cooled to room temperature, and then dissolved in THF (10 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 0.260 g, 1.03 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux overnight. The reaction mixture was then allowed to cool to room temperature and filtered. The solid residue was washed with 0° C. THF and collected to afford the 5-Ethyl-1-methyl-1H-pyrazole-3-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide as a solid (0.248 g, 0.64 mmol, 62%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[F:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][N:21]=1.[Cl-].[NH4+].[O:29]1CCC[CH2:30]1>>[F:19][C:20]1[CH:25]=[C:24]([CH2:26][CH2:30][OH:29])[CH:23]=[CH:22][N:21]=1
Reactant: C1CCOC1
Reactant: Cc1ccnc(F)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: OCCc1ccnc(F)c1
Temperature: -80 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
To a solution of anhydrous diisopropylamine (18.5 mL, 0.13 mol) in anhydrous tetrahydrofuran (160 mL) was added dropwise at −80° C., under argon, a 1.3 M n-butyllithium solution in hexane (100 mL, 0.13 mol). The mixture was stirred at −80° C. for 1 h before addition dropwise of a solution of 2-fluoro-4-picoline (41) (9.00 g, 6.30 mmol) in anhydrous tetrahydrofuran (60 mL). The mixture was stirred at −80° C. for 1 h once again before addition dropwise of a p-formaldehyde (16.6 g, 0.55 mol) suspension in anhydrous tetrahydrofuran (100 mL). The mixture was stirred at −80° C. for 1 h and then at room temperature for 12 h. A saturated aqueous ammonium chloride solution (450 mL) was added to the mixture. The solution was decanted and the aqueous layer was extracted with dichloromethane (4×200 mL). The organic layers were combined, dried on magnesium sulfate, filtered and evaporated under vacuum. The residue obtained was chromatographed (Al2O3, CH2Cl2/EtOH, 99/1, v/v) to give compound 42 (7.25 g, 51.4 mmol) as an orange-coloured oil. Yield 57%; Rf (Al2O3, CH2Cl2/EtOH, 99/1, v/v) 0.32; IR (CCl4) ν 1046, 1149, 1278, 1413, 1613, 2800-3000, 3100-3600, 3634 cm−1; 1H NMR (200 MHz, CDCl3) δ 2.87 (t, 2H, J=6.3 Hz), 3.87 (t, 2H, J=6.3 Hz), 6.82 (s, 1H), 7.07 (d, 1H, J=5.2 Hz), 8.01 (d, 1H, J=5.2 Hz); MS m/z 141 (M+, 23), 111 (100), 91 (34), 83 (14), 64 (10), 57 (12).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:13])[CH:11]=2)[C:6]([CH2:14]Br)=[N:5]1)(=[O:3])[CH3:2].Cl.Cl.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:13])[CH:11]=2)[C:6]([CH2:14][N:29]2[CH2:28][CH2:27][N:26]([C:23]3[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=3)[CH2:31][CH2:30]2)=[N:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)n1nc(CBr)c2ccc(F)cc21
Reactant: COc1ccc(N2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(N2CCN(Cc3nn(C(C)=O)c4cc(F)ccc34)CC2)cc1
Temperature: 20 °C
Reaction time: 16 h
Yield: 53.3 %

Procedure:
1-Acetyl-3-bromomethyl-6-fluoro-1-H-indazole (0.63 g, 2.33 mmol) in CH2Cl2 (10 mL) was treated with 4-methoxyphenylpiperazine dihydrochloride (0.593 g, 2.33 mmol) and Hunig's base (1.32 mL, 7.5 mmol) and the mixture stirred at 20° C. for 16 h. The mixture was poured into saturated aqueous sodium bicarbonate solution (25 mL) and extracted with CH2Cl2 (3×25 mL). The combined organic extracts were dried (MgSO4), concentrated and the residue purified by flash chromatography (25% EtOAc in hexane) to give the title compound as a white solid (475 mg, 53%); mp 94°-95° C. (from Et2O/hexane); 1H NMR (360 MHz, d6 -DMSO) δ8.12 (dd, J=8.4, 2.9 Hz, 1H, indazole), 8.00 (d, J=9.8 Hz, 1H, indazole), 7.34 (t, J=9.8 Hz, 1H, indazole), 6.87 (d, J=9.2 Hz, 2H, Ph), 6.80 (d, J=9.2 Hz, 2H, Ph), 3.93 (s, 2H, Ar--CH2N), 3.67 (s, 3H, OMe), 3.02 (m, 4H, piperazine), 2.70 (s, 3H, Ac), 2.63 (m, 4H, piperazine); MS (CI+) m/e 383 (M+H+); Anal. calcd for C21H23FN4O2 : C, 65.95; H, 6.06; N, 14.65. Found: C, 66.38; H, 5.79; N, 14.59.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[S:8][C:9]([CH3:11])=[CH:10][C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14].[I:15]N1C(=O)CCC1=O>B(F)(F)F.CCOCC.O>[I:15][C:10]1[C:6]2[C:5](=[O:12])[N:4]([CH3:13])[C:3](=[O:14])[N:2]([CH3:1])[C:7]=2[S:8][C:9]=1[CH3:11]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cc2c(=O)n(C)c(=O)n(C)c2s1
Agent: FB(F)F
Solvent: O
Solvent: CCOCC
Product: Cc1sc2c(c1I)c(=O)n(C)c(=O)n2C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of Step 4 intermediate (12.5 g, 59.52 mmol) in boron trifluoride diethyl etherate (300 ml) was added N-iodosuccinimide (19.9 g, 89.28 mmol) and the mixture was stirred for 3 h at room temperature under nitrogen atmosphere. The reaction mixture was diluted with water (100 ml), extracted with ethyl acetate (3×200 ml) and the combined organic layers were washed with water (2×150 ml), dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 2% ethyl acetate in chloroform to obtain 9.7 g of the product as a pale brown solid; 1H NMR (300 MHz, DMSO-d6) δ 2.37 (s, 3H), 3.21 (s, 3H), 3.42 (s, 3H); MS (m/z) 337.11 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[C:14]([N:20]3[CH2:25][CH2:24][C:23]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)([OH:26])[CH2:22][CH2:21]3)[C:15](=O)[O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].[OH2:36]>C(O)C.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]([OH:36])[CH:14]([N:20]3[CH2:25][CH2:24][C:23]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)([OH:26])[CH2:22][CH2:21]3)[CH2:15][O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O
Reactant: O=c1oc2cc(OCc3ccccc3)ccc2cc1N1CCC(O)(c2ccc(F)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: OC1c2ccc(OCc3ccccc3)cc2OCC1N1CCC(O)(c2ccc(F)cc2)CC1
Reaction time: 8 h
Yield: 60 %

Procedure:
To a slurry of 7-benzyloxy-3-[4-(4-fluorophenyl)-4-hydroxy-piperidine-1-yl]-chromenone (8.24 g, 18.5 mmol) in ethanol (400 mL) and tetrahydrofuran (600 mL) was added sodium borohydride (7.0 g, 185 mmol). The mixture was stirred overnight. Additional sodium borohydride (7.0 g) was added and the reaction mixture was stirred for 3 days. Water was added and the solvent was removed at reduced pressure at 45° C. The solids which formed were collected and washed well with water and then ether. The solid was further dried in vacuo overnight to give 5.01 g, 60% of 3R*4S*7-benzyloxy-3-[4-(4-fluorophenyl)-4-hydroxy-piperidin-1-yl]-chroman-4-ol which was suitable for use without further purification. A sample recrystallized from ethyl acetate/chloroform had mp. 194-195° C.; NMR δ7.56-7.30 (m, 8H), 7.06 (long range coupled t, J=8.7 Hz, 2H) 6.63 (dd, J=2.4, 8.5 Hz, 1H), 6.47 (d, J=2.4 Hz, 1H), 5.04 (s, 2H), 4.77 (d, J=4.5Hz, 1H), 4.37 (dd, J=3.5, 10.4Hz, 1H), 4.13 (t, J=10.4 Hz, 1H), 3.82 (brs, 1H), 3.11 (br d, J=11.2 Hz, 1H), 2.92-2.71 (m, 4H), 2.21-2.06 (m, 2H), 1.87-1.73 (m, 2H), 1.54 (s,1H).
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH2:14][CH:15]4[CH2:19][NH:18][CH2:17][CH:16]4[CH:20]=3)=[CH:10][CH:11]=2)[N:6]([CH3:21])[C:5]1=[O:22].CCN(C(C)C)C(C)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH2:14][CH:15]4[CH2:19][N:18]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:17][CH:16]4[CH:20]=3)=[CH:10][CH:11]=2)[N:6]([CH3:21])[C:5]1=[O:22]
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3=CC4CNCC4C3)nc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3=CC4CN(S(C)(=O)=O)CC4C3)nc21
Reaction time: 0.08 h

Procedure:
1-(2,2-Dimethylpropyl)-5-(1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrol-5-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (84, 100 mg, 0.30 mmol, 1.0 equiv), and DIPEA (0.16 mL, 0.91 mmol, 3.0 equiv) were added to anhydrous methylene chloride (3 mL). Stirred for 5 min and methanesulfonyl chloride (26.3 μL, 0.33 mmol, 1.1 equiv) was added. After stirring for 10 min at room temperature, LCMS showed consumption of starting material. Purification by reverse-phase HPLC (20-100% CH3CN:0.1% TFA in H2O) provided 10-1 as a pale yellow oil. MS m/z (M+H): calculated=405.1957; observed=405.1969.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16]C2C=CC=CC=2)[C@@H:13]([O:23][CH2:24]C2C=CC=CC=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:42]=[CH:43][C:44]4[O:48][CH2:47][CH2:46][C:45]=4[CH:49]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C:10]1([CH2:52][OH:53])CO)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:55](F)(F)[C:56](O)=O>ClCCl>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@@H:13]([O:23][CH2:24][C:56]2[CH:55]=[CH:52][CH:10]=[CH:9][CH:14]=2)[C@:12]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:42]=[CH:43][C:44]5[O:48][CH2:47][CH2:46][C:45]=5[CH:49]=4)[CH:34]=3)[O:11][C@@:10]1([CH2:52][OH:53])[CH2:32][O:31]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc4c(c3)CCO4)c2)OC(CO)(CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc5c(c4)CCO5)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Reaction time: 1.5 h
Yield: 100.9 %

Procedure:
[(3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-(2,3-dihydrobenzofuran-5-ylmethyl)phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol 5k (1.2 g, 1.63 mmol) was dissolved in 25 mL dichloromethane, followed by dropwise addition of trifluoroacetic acid (0.5 mL, 6.52 mmol). The reaction mixture was stirred for 1.5 hours. Thereafter, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system D to obtain the title compound [(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-(2,3-dihydrobenzofuran-5-ylmethyl)phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]methanol 5m (580 mg, white solid), yield: 50.4%. MS m/z (ESI): 722.3 [M+18]; 1H NMR (400 MHz, CD3OD): δ 7.48-7.39 (m, 3H), 7.35-7.23 (m, 10H), 7.21-7.11 (m, 3H), 6.97 (s, 1H), 6.90 (d, 1H), 6.84 (d, 2H), 6.57 (d, 1H), 4.83 (d, 4H), 4.44 (t, 2H), 4.23 (m, 2H), 4.07-4.00 (m, 3H), 3.95 (dd, 1H), 3.87 (d, 1H), 3.79 (d, 1H), 3.73-3.69 (m, 2H), 3.56 (d, 1H), 3.01 (t, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9](=O)[NH:10][C:4]=2[CH:3]=1.[NH:20]1[CH2:25][CH2:24][S:23][CH2:22][CH2:21]1.[OH-].[Na+]>[Ti](Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9]([N:20]3[CH2:25][CH2:24][S:23][CH2:22][CH2:21]3)=[N:10][C:4]=2[CH:3]=1
Reactant: O=C1Nc2cc(Br)ccc2N2CCc3cccc1c32
Reactant: C1CSCCN1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Brc1ccc2c(c1)N=C(N1CCSCC1)c1cccc3c1N2CC3
Temperature: 25 °C
Yield: 87.9 %

Procedure:
A mixture of 7.88 g (0.025 mole) of 9-bromo-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepin-6-one and 1200 ml of toluene was heated under nitrogen, with stirring, until a solution resulted. Then there was added 25.8 g (0.250 mole) of thiomorpholine, followed by 14.2 g (0.075 mole) of titanium tetrachloride. The mixture was heated under reflux for 3 hours, cooled to room temperature and treated with 500 ml of 2N sodium hydroxide solution. After stirring vigorously for 15 minutes, the layers were separated. The aqueous phase was extracted with 300 ml of toluene. The toluene layers were combined, washed once with 2N sodium hydroxide solution, twice with water, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was crystallized from 100 ml of hot methanol to give 8.8 g (88%) of product. Recrystallization from a hot solution of dichloromethane (50 ml, charcoal) to which methanol (100 ml) was added provided the analytical sample, mp 165°-167° C.