Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([CH3:25])=[C:15]([CH2:17][O:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[N:16]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C([Li])CCC.CN(C)[CH:33]=[O:34].O>O1CCCC1>[CH3:25][C:14]1[S:13][C:12]([C:4]2[CH:3]=[C:2]([CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=2)[CH:33]=[O:34])=[N:16][C:15]=1[CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1
Reactant: CN(C)C=O
Reactant: Cc1sc(-c2cc(Br)cc(C(F)(F)F)c2)nc1COC1CCCCO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1sc(-c2cc(C=O)cc(C(F)(F)F)c2)nc1COC1CCCCO1
Temperature: -78 °C
Reaction time: 1 h
Yield: 24.4 %

Procedure:
Under a nitrogen atmosphere at −78° C., to a solution (80 mL) of the compound (7.3 g, 17 mmol) obtained in Example 95a in tetrahydrofuran was added n-butyllithium (1.6M hexane solution, 16 mL, 25 mmol), and the mixture was stirred at the same temperature for 1 hr. Anhydrous N,N-dimethylformamide (2.6 mL, 33 mmol) was added to the reaction mixture, and the mixture was stirred overnight while allowing to spontaneously warm to room temperature from −78° C. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=80/20) to give the title compound (1.6 g, 24%) as an orange oil.
Reaction SMILES: [NH2:1][C:2]1[C:27]([N+:28]([O-])=O)=[CH:26][CH:25]=[C:24]2[C:3]=1[C:4](=[O:31])[O:5][C:6]12[C:19]2[CH:18]=[C:17]([F:20])[C:16]([OH:21])=[CH:15][C:14]=2[O:13][C:12]2[C:7]1=[CH:8][C:9]([F:23])=[C:10]([OH:22])[CH:11]=2.Cl>>[NH2:1][C:2]1[C:27]([NH2:28])=[CH:26][CH:25]=[C:24]2[C:3]=1[C:4](=[O:31])[O:5][C:6]12[C:7]2[CH:8]=[C:9]([F:23])[C:10]([OH:22])=[CH:11][C:12]=2[O:13][C:14]2[C:19]1=[CH:18][C:17]([F:20])=[C:16]([OH:21])[CH:15]=2
Reactant: Nc1c([N+](=O)[O-])ccc2c1C(=O)OC21c2cc(F)c(O)cc2Oc2cc(O)c(F)cc21
Agent: Cl
Product: Nc1ccc2c(c1N)C(=O)OC21c2cc(F)c(O)cc2Oc2cc(O)c(F)cc21
Yield: 78.7 %

Procedure:
4-Amino-5-nitro-2′,7′-difluoro-3′,6′-dihydroxy-spiro [isobenzofuran-1(3H),9′-[9H]xanthen]-3-one (1.3 g, 3.0 mmol) was added to an aqueous solution of Na2S and NaSH, and the mixture was refluxed for 24 hours. The reaction mixture was cooled, and adjusted to pH 3 with hydrochloric acid, and precipitates were collected by filtration. The obtained product was dried and purified by silica gel chromatography to obtain the title compound (0.94 g, 78%).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[O:13]1[CH2:17][CH2:16][CH2:15][CH:14]1[C:18](O)=[O:19].C(N(CC)CC)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[Li+].[OH-]>C(Cl)Cl.O>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:18]([CH:14]3[CH2:15][CH2:16][CH2:17][O:13]3)=[O:19])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(O)C1CCCO1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)C1CCCO1
Temperature: 25 °C
Reaction time: 7 h
Yield: 80.7 %

Procedure:
A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol), tetrahydrofuran-2-carboxylic acid (252 mg, 2.17 mmol), triethylamine (606 μL, 4.35 mmol), and BOP—Cl (203 mg, 2.17 mmol) in CH2Cl2 (10 mL) was stirred at room temperature for 7 hours. 2M LiOH (5 mL) was then added to the mixture and stirred at room temperature for 30 minutes. Water (25 mL) was then added to the mixture and stirred for an additional 30 minutes. The solid formed was filtered, washed with water (3×5 mL) and dried to provide N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)tetrahydrofuran-2-carboxamide (230 mg, 80.6% yield) as a solid.
Reaction SMILES: [CH2:1]([OH:10])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][OH:9].[CH3:11][C:12](C)([O-])[CH3:13].[K+].[I-].[K+].C(Br)C=C>C1COCC1>[CH2:13]([CH:1]([OH:10])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][OH:9])[CH:12]=[CH2:11]
Reactant: OCCOCCOCCO
Reactant: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCC(O)COCCOCCO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Allyl-triethylene glycol was prepared according to the literature method with modifications (Setz O, et al. Angew Chem Int Ed Engl. 1995, 34, 803-805). Thus, the mixture of triethylene glycol (11.83 g, 78.8 mmol), potassium t-butoxide (4.42 g, 39.4 mmol) and potassium iodide (0.65 g, 3.94 mmol) in THF (500 mL) was stirred at room temperature for 0.5 h, into which was added dropwise allyl bromide (4.767 g, 39.4 mmol) in THF (120 mL) over a period of 1.5 h. After continuing to be stirred at room temperature for 36 h, the mixture was filtered through a celite pad. The crude product, obtained after removal of solvents under vacuum, was purified by a silica gel column chromatography eluting with hexane/ethyl acetate (1:1) to afford the product (4.9 g, 25.8 mmol, 65% yield) with chemical structure confirmed by 1H NMR and MS.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[N:5]([C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[CH:11][NH:12]2)=[C:6]=[S:7]>C(Cl)Cl>[NH2:3][CH2:2][CH2:1][NH:4][C:6](=[S:7])[NH:5][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[CH:11][NH:12]2
Reactant: NCCN
Reactant: S=C=Nc1cccc2[nH]ccc12
Solvent: ClCCl
Product: NCCNC(=S)Nc1cccc2[nH]ccc12
Reaction time: 1 h
Yield: 91.2 %

Procedure:
Ethylenediamine (0.289 mL, 4.33 mmol) is added to a solution of 4-isothiocyanatoindole (0.150 g, 0.866 mmol) in methylene chloride (10 mL). The clear solution becomes cloudy within a few seconds with the formation of a white precipitate. The reaction mixture is stirred for one hour followed by the removal of most of the methylene chloride by rotary evaporation. The mixture is filtered and the white precipitate is dried to afford 0.185 g of 4-[N'-(2-aminoethyl)thioureido]indole (91% yield).
Reaction SMILES: [N:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH:4]=[N:3][C:2]=1[C:14]([NH:16][NH2:17])=[O:15].[N:18]([O-])=O.[Na+].N([O-])=O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.O>[N:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH:4]=[N:3][C:2]=1[C:14]([N:16]=[N+:17]=[N-:18])=[O:15]
Reactant: NNC(=O)c1ncc2[nH]c3ccccc3c2n1
Reactant: O=N[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: [N-]=[N+]=NC(=O)c1ncc2[nH]c3ccccc3c2n1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Under heating, 0.3 g of 5H-pyrimido[5,4-b]indole-2-carboxylic acid hydrazide (Example 5) is dissolved in a mixture of 6 ml of glacial acetic acid and 2.4 ml of water. Then, a solution of 0.33 g of sodium nitrite in 1 ml of water is added gradually thereto at 0° C. After adding the nitrite, the mixture is stirred for another 4 hours at 0° C., thereafter rendered alkaline with sodium carbonate solution, and the thus-crystallized 5H-pyrimido[5,4-b]indole-2-carboxylic acid azide is vacuum-filtered. The yield is 0.3 g.
Reaction SMILES: CC([O-])(C)C.[K+].[Cl:7][C:8]1[C:9]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:11]([OH:16])=[C:12]([CH:15]=1)[CH:13]=[O:14].[F:21][C:22]([F:37])([S:33](F)(=[O:35])=[O:34])[C:23]([F:32])([F:31])[C:24]([F:30])([F:29])[C:25]([F:28])([F:27])[F:26]>C1COCC1>[F:37][C:22]([F:21])([S:33]([O:16][C:11]1[CH:10]=[C:9]([C:17]([F:18])([F:19])[F:20])[C:8]([Cl:7])=[CH:15][C:12]=1[CH:13]=[O:14])(=[O:35])=[O:34])[C:23]([F:31])([F:32])[C:24]([F:30])([F:29])[C:25]([F:28])([F:27])[F:26]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: O=Cc1cc(Cl)c(C(F)(F)F)cc1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=Cc1cc(Cl)c(C(F)(F)F)cc1OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 0.07 h

Procedure:
A 1.04 M THF solution of t-BuOK (4.9 mL, 5.1 mmol) was added to a 0° C., THF solution (4 mL) of 5-chloro-2-hydroxy-4-(trifluoromethyl)benzaldehyde (1.0 g, 4.6 mmol). After 4 min, neat 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (1.7 mL, 9.3 mmol) was added and the ice bath was removed. After 1 h at room temperature, AcOH (1 mL) was added and the resulting mixture was concentrated. The resulting material was diluted with DCM and 1M aqueous HCl, the layers were separated, and the organic layer was washed with 1 M NaHCO3, dried (Na2SO4), and concentrated to yield the title compound that was used without further purification.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.F[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[CH3:1][S:2][C:3]1[CH:4]=[C:5]([S:9][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CSc1cccc(S)c1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CSc1cccc(Sc2ccc(C=O)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 33 %

Procedure:
A solution of 3-(methylthio)benzenethiol (19.9 g, 127.3 mmol), prepared as indicated in Rumpf, P., Bull. soc. chim. (1940), 7, pp. 632-4, in acetonitrile (60 mL) was treated with 4-fluorobenzaldehyde (13.4 mL, 127 mmol) followed by potassium carbonate (19.4 g, 140 mmol). After stirring at ambient temperature for 18 hours the suspension was diluted with water (200 mL) and extracted with ethyl acetate (3-fold 300 mL). The combined organic extracts were washed with brine (2-fold 100 mL) and dried (magnesium sulphate) and the solvent removed in vacuo to give a colourless oil. The crude oil was purified by flash column chromatography on silica gel eluting with heptane:ethyl acetate (1:0 changing to 9:1, by volume) to give the title compound as a colourless oil, 33% yield, 10.8 g.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH2:13][CH:14]2[CH2:16][CH2:15]2)(=[O:12])=[O:11])[CH2:7][N:6]1[C:17](=S)[CH2:18][C:19](=O)[CH3:20])=[O:4].[C:23]1([CH2:29][CH2:30][NH:31][NH2:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH2:13][CH:14]2[CH2:16][CH2:15]2)(=[O:12])=[O:11])[CH2:7][N:6]1[C:17]1[N:31]([CH2:30][CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:32]=[C:19]([CH3:20])[CH:18]=1)=[O:4]
Reactant: NNCCc1ccccc1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)CC2CC2)CN1C(=S)CC(C)=O
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)CC2CC2)CN1c1cc(C)nn1CCc1ccccc1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-4-cyclopropylmethanesulfonyl-1-(3-oxo-thiobutyryl)-pyrrolidine-2-carboxylic acid methyl ester (example 445c) was reacted with 1-(2-phenylethyl)hydrazine (CAS Reg. No. 51-71-8) to give the title compound as brown solid. MS (ESI): m/z=432.6 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[S:9][C:10]([C:14]([OH:16])=O)=[C:11]([CH3:13])[N:12]=2)[C:4](=[O:17])[CH:3]=1.[CH:18]1([CH:21]([NH2:23])C)[CH2:20][CH2:19]1>>[CH:18]1([CH2:21][NH:23][C:14]([C:10]2[S:9][C:8]([N:5]3[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][C:4]3=[O:17])=[N:12][C:11]=2[CH3:13])=[O:16])[CH2:20][CH2:19]1
Reactant: CC(N)C1CC1
Reactant: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)O
Product: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)NCC1CC1
Yield: 76 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use 2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid in place of 4-methyl-2-(2-oxo-4-phenylpyridin-1(2H)-yl)thiazole-5-carboxylic acid to react with cyclopropylethanamine, the title compound was obtained as a colorless solid in 76% yield: mp 240-242° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 11.56 (br s, 1H), 8.58 (d, J=8.0 Hz, 1H), 8.26 (t, J=5.6 Hz, 1H), 6.25 (dd, J=8.0, 2.5 Hz, 1H), 5.81 (d, J=2.5 Hz, 1H), 3.05 (m, 2H), 2.51 (s, 3H), 1.05-0.92 (m, 1H), 0.43-0.36 (m, 2H), 0.20-0.15 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 167.9, 161.8, 161.6, 153.9, 149.7, 132.6, 124.0, 104.3, 98.0, 43.9, 17.4, 11.4, 3.7; MS (ES+) m/z: 306.2 (M+1).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[CH3:7][NH2:8].[Br:9][C:10]1[CH:32]=[CH:31][C:13]2[N:14]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:15]([C:17]3[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=3[C:19]([NH:21]O)=[NH:20])=[N:16][C:12]=2[CH:11]=1>C1COCC1.N1C=CC=CC=1>[CH3:7][NH:8][C:2]([C:1]1[O:5][N:21]=[C:19]([C:18]2[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=2[C:15]2[N:14]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:13]3[CH:31]=[CH:32][C:10]([Br:9])=[CH:11][C:12]=3[N:16]=2)[N:20]=1)=[O:3]
Reactant: CC(C)(C)n1c(-c2ccccc2C(=N)NO)nc2cc(Br)ccc21
Reactant: CN
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CNC(=O)c1nc(-c2ccccc2-c2nc3cc(Br)ccc3n2C(C)(C)C)no1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
To a solution of oxalyl chloride (0.17 mL, 1.99 mmol) in anhydrous THF (20 mL) is added methylamine 2.0M in THF (0.99 mL, 1.99 mmol) at 0° C. The solution is stirred at 0° C. to room temperature for 0.5 hours and added to a stirred solution of 2-(5-bromo-1-tert-butyl-1H-benzimidazol-2-yl)-N-hydroxy-benzamidine (350 mg, 0.9 mmol) in anhydrous pyridine (5 mL). The reaction mixture is stirred at room temperature for 1 hour and then heated to 50° C. and stirred for 16 hours. The reaction mixture is cooled to room temperature and concentrated in vacuo. Dichloromethane is added and the organics washed sequentially with saturated NaHCO3 (20 mL) solution and H2O (20 mL) then dried (Na2SO4), filtered and concentrated. Purification via flash chromatography (25 g silica gel, 50-60% EtOAc/heptane) affords 3-[2-(5-bromo-1-tert-butyl-1H-benzimidazol-2-yl)-phenyl]-[1,2,4]oxadiazole-5-carboxylic acid methylamide (150 mg, 37%)
Reaction SMILES: Cl[C:2]1[N:3]=[N+:4]([O-:15])[C:5]2[CH:14]=[C:13]3[C:9]([CH2:10][CH2:11][CH2:12]3)=[CH:8][C:6]=2[N:7]=1.CCN(CC)CC.[CH3:23][O:24][CH2:25][CH2:26][CH2:27][N:28]([CH3:32])[CH2:29][CH2:30][NH2:31]>COCCOC>[CH3:23][O:24][CH2:25][CH2:26][CH2:27][N:28]([CH3:32])[CH2:29][CH2:30][NH:31][C:2]1[N:3]=[N+:4]([O-:15])[C:5]2[CH:14]=[C:13]3[C:9]([CH2:10][CH2:11][CH2:12]3)=[CH:8][C:6]=2[N:7]=1
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)CCC3
Reactant: COCCCN(C)CCN
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: COCCCN(C)CCNc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Yield: 74 %

Procedure:
A solution of chloride 21 (1.62 g, 7.3 mmol), Et3N (2.0 mL, 14.0 mmol) and N1-(3-methoxypropyl)-N1-methyl-1,2-ethanediamine (274) (1.24 g, 8.8 mmol) in DME (50 mL) was heated at reflux temperature for 18 h. The solution was cooled, the solvent evaporated and the residue partitioned between dilute aqueous NH3 solution (50 mL) and DCM (50 mL). The aqueous layer was extracted with DCM (4×120 mL), the combined organic fraction dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-15%) of MeOH/DCM, to give 1-oxide 32 (1.79 g, 74%) as a yellow solid: mp 41-42° C.; 1H NMR δ 8.07 (s, 1H, H-9), 7.39 (s, 1H, H-5), 5.83 (br s, 1H, NH), 3.55 (dt, J=5.9, 5.5 Hz, 2H, NCH2), 3.43 (t, J=6.3 Hz, 2H, OCH2), 3.33 (s, 3H, OCH3), 3.01 (t, J=7.4 Hz, 2H, H-8), 2.99 (t, J=7.8 Hz, 2H, H-6), 2.64 (t, J=5.9 Hz, 2H, NCH2), 2.50 (t, J=7.2 Hz, 2H, NCH2), 2.27 (s, 3H, NCH3), 2.14 (p, J=7.4 Hz, 2H, H-7), 1.76 (tt, J=7.2, 6.4 Hz, 2H, CH2); 13C NMR δ 158.7, 154.5, 148.8, 143.2, 129.8, 120.5, 114.7, 70.8, 58.6, 55.8, 54.4, 41.6, 38.6, 33.1, 32.3, 27.4, 25.7; MS (APCI) m/z 332 (MH+, 100%). Anal. calcd for C17H25N5O2: C, 61.6; H, 7.6; N, 21.1. Found: C, 61.4; H, 7.4; N, 21.4%.
Reaction SMILES: C(Cl)Cl.[CH3:4][C:5]([CH3:7])=[O:6].[CH:8]1C=C[CH:11]=[CH:10][CH:9]=1.C[N:15](C)C=O>C(Cl)(Cl)Cl>[C:5]([C:7]1[CH:11]=[CH:10][CH:9]=[CH:8][N:15]=1)(=[O:6])[CH3:4]
Reactant: CN(C)C=O
Reactant: CC(C)=O
Reactant: c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(=O)c1ccccn1

Procedure:
To a solution of 22.5 g (187 mmoles) 2-acetylpyridine dissolved in 350 ml of purified chloroform was added 25 g (93 mmoles) of TeCl4. The reaction solution was refluxed for 10 hours under an argon atmosphere, a red-brown solid forming. The reaction solution was filtered and the solid washed with chloroform and air dried to give 32 g of red-brown solid (m.p.: gums 85° C., murky red melt by 110° C.). This product is insoluble in CHCl3, CH2Cl2, acetone and benzene, but soluble in dimethylformamide. Elemental analysis confirmed the presence of the title compound.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5]C=CC=1.[CH2:8]1[O:10][C@H:9]1[CH2:11]Cl.[OH-:13].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[CH2:11]([O:7][CH2:1][CH:6]1[O:13][CH2:5]1)[CH:9]1[O:10][CH2:8]1
Reactant: ClC[C@H]1CO1
Reactant: Oc1ccccc1
Reactant: [OH-]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Product: C(OCC1CO1)C1CO1
Temperature: 70 °C
Reaction time: 2 h
Yield: 27.2 %

Procedure:
The starting phenol derivative (1.01 g) of the following formula: ##STR29## the same R-(-)-epichlorohydrin (2.01 g) as used in Preparation 2 and benzyltriethylammonium chloride (16 mg) are mixed and heated at 70° C., and thereto is added dropwise 24 wt. % aqueous sodium hydroxide (650 mg). The mixture is stirred at 70° C. for 2 hours. The reaction mixture is cooled to room temperature and extracted three times with chloroform. The extract is dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue is recrystallized from hexane to give S isomer of glycidyl ether (380 mg) of the following formula: ##STR30##
Reaction SMILES: O[O:2][S:3]([O-:5])=O.[K+].[F:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=1[C@H:15]1[CH2:21][N:20]([CH2:22][CH2:23]SC)[C:19](=[O:26])[C@H:18]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:17][CH2:16]1.[CH3:35]O>O>[F:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=1[C@H:15]1[CH2:21][N:20]([CH2:22][CH2:23][S:3]([CH3:35])(=[O:5])=[O:2])[C:19](=[O:26])[C@H:18]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])[CH2:17][CH2:16]1
Reactant: O=S([O-])OO
Reactant: CSCCN1C[C@H](c2cccc(F)c2F)CC[C@@H](NC(=O)OC(C)(C)C)C1=O
Reactant: CO
Agent: [K+]
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(CCS(C)(=O)=O)C1=O
Reaction time: 18 h

Procedure:
Oxone ® (16.1 mg, 0.11 mmol) was added to a solution of tert-butyl (3R,6S)-6-(2,3-difluorophenyl)-1-[2-(methylthio)ethyl]-2-oxoazepan-3-ylcarbamate (22 mg, 0.053 mmol) in methanol (2 mL) and water (2 mL). After 6 h excess oxone (32 mg, 0.22 mmol) was added. After 18 h, the reaction was quenched with aqueous sodium sulfite solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium carbonate (3×), saturated brine, dried over magnesium sulfate, filtered and concentrated to give the title compound. MS 447 (M+1).
Reaction SMILES: [H-].[Na+].[CH2:3]([NH:10][C:11]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:23][C:24]1[N:29]=[CH:28][C:27]([S:30]([N:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)(=[O:32])=[O:31])=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+]>CCCCCC.CN(C)C=O>[ClH:23].[CH2:3]([NH:10][C:11]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([OH:22])=[C:16]2[C:24]1[CH:25]=[CH:26][C:27]([S:30]([N:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)(=[O:32])=[O:31])=[CH:28][N:29]=1)=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CN1CCN(S(=O)(=O)c2ccc(Cl)nc2)CC1
Reactant: O=C1Cc2cc(C(=O)NCc3ccccc3)ccc2N1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CN1CCN(S(=O)(=O)c2ccc(-c3c(O)[nH]c4ccc(C(=O)NCc5ccccc5)cc34)nc2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 15.7 %

Procedure:
Sodium hydride (0.033 g of 60% dispersion in paraffin, 0.84 mmol) was washed with hexane, dried in vacuo and suspended in N,N-dimethylformamide (1 mL). N-Benzyl-2-oxoindoline-5-carboxamide (0.110 g, 0.41 mmol) and 1-[(6-chloropyridin-3-yl)sulfonyl]-4-methylpiperazine (0.170 g, 0.62 mmol; described in: Thunus L. Annuale Pharmacetiques Francisies, 1977, 35, 197-203) were dissolved in N,N-dimethylformamide (5 mL) and added to the suspension of sodium hydride. The reaction mixture was stirred at room temperature for 10 min and subsequently heated for 1 h at 90° C. After cooling to room temperature, a saturated aqueous sodium hydrogen carbonate solution was added (4 mL). Silica gel (8 mL) was added and the solvent was removed in vacuo. The residue was purified on a silica gel column using a gradient of chloroform/methanol mixtures, (40:1 to 1:1 and 2% triethylamine), as the eluent. The base was dissolved in a mixture of chloroform (5 mL) and methanol (5 mL). Hydrogen chloride (3 mL, 1 M in diethyl ether) was added and stirring was continued for 10 min. The precipitate was washed with diethyl ether and dried in vacuo at 60° C. to give 0.035 g (16% yield) of the title compound: 1H NMR (D2O, 400 MHz) δ 7.79 (m, 1H), 7.42 (m, 4H), 7.37 (m, 1H), 7.24 (m, 1H), 7.14 (m, 2H), 6.80 (m, 1H), 6.68 (m, 1H), 4.50 (s, 2H), 3.77 (m, 2H), 3.60 (m, 2H), 3.22 (m, 2H), 2.91 (m, 5H); MS (ES) m/z 506 (M++1).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3([C:16]([OH:18])=O)[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[NH:34]1[CH2:38][CH2:37][C@@:36]2([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=3[C:40](=[O:47])[O:39]2)[CH2:35]1>>[C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3([C:16]([N:34]4[CH2:38][CH2:37][C@@:36]5([C:42]6[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=6[C:40](=[O:47])[O:39]5)[CH2:35]4)=[O:18])[CH2:14][CH2:15]3)=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1O[C@]2(CCNC2)c2ccccc21
Reactant: O=C(O)C1(c2ccc(-c3ccccc3)nc2)CC1
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Product: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(-c5ccccc5)nc4)CC3)C2)c2ccccc21

Procedure:
1-(6-Phenylpyridin-3-yl)cyclopropanecarboxylic acid was then coupled with (1S)-(+)-10-camphorsulfonic acid salt of (1R)-3H-spiro-[2-benzofuran-1,3′-pyrrolidin]-3-one using procedures analogous to those of Example 83 to afford (1R)-1′-{[1-(6-Phenylpyridin-3-yl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one. MS (ESI): (M+H)+=411.1
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[N:15]=[CH:14][C:13]2[NH:12][C:11]3[N:16]=[CH:17][C:18]([C:20]4[CH:25]=[CH:24][C:23]([CH2:26][N:27]5[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]5)=[CH:22][CH:21]=4)=[CH:19][C:10]=3[C:9]=2[CH:8]=1)(C)C.C(=O)([O-])[O-].[K+].[K+]>CO.C(Cl)Cl>[C:6]([C:7]1[N:15]=[CH:14][C:13]2[NH:12][C:11]3[N:16]=[CH:17][C:18]([C:20]4[CH:21]=[CH:22][C:23]([CH2:26][N:27]5[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]5)=[CH:24][CH:25]=4)=[CH:19][C:10]=3[C:9]=2[CH:8]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: C#Cc1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 6-((trimethylsilyl)ethynyl)-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (120 mg, 0.3 mmol) and potassium carbonate (170 mg, 1.2 mmol) in methanol (2 mL) was stirred at ambient temperature for 1 h. The reaction mixture was diluted with DCM (20 mL) and methanol (2 mL) and washed with water (15 mL). The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford a brown residue that was taken to the next step without purification.