Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C@H:12]([CH3:13])[CH2:11][CH2:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.C(C1C=C(C(C)C)C=C(C(C)C)C=1S([N:41]=[N+:42]=[N-:43])(=O)=O)(C)C.C(O)(=O)C>C1COCC1>[N:41]([C@@H:10]1[CH2:11][C@@H:12]([CH3:13])[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]1=[O:14])=[N+:42]=[N-:43]
Reactant: C[C@@H]1CCC(=O)N1Cc1ccccc1
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C[C@@H]1C[C@@H](N=[N+]=[N-])C(=O)N1Cc1ccccc1
Temperature: -15 °C
Reaction time: 0.17 h

Procedure:
To a solution of 13-3 (2.2 g, 11.6 mmol) in THF (45 mL) at -78° C. was added a solution of LDA (6.39 mL, 12.8 mmol; 2M/THF, ethylbenzene). The mixture was warmed to -15° C. for 20 minutes, then recooled to -78° C., and 2,4,6-triisopropylbenzenesulfonyl azide (4.31 g, 13.9 mmol, prepared as described in Harmon, et al, J. Org. Chem. 1973, 38, 11-16. ) was added rapidly as a solution in 40 mL THF at -78° C. After 10 minutes, glacial acetic acid (2.67 mL, 47 mmol) was added, and the resultant viscous liquid mixture allowed to warm to ambient temperature and stir for 1 hour. The solvent was then evaporated, the residue dissolved in CHCl3, washed with NaHCO3 (sat.), and dried over magnesium sulfate. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 25% ethyl acetate/hexanes) to give 13-4 as a colorless oil.
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:8][C:7]([CH3:10])([CH3:9])[CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].S(Cl)([Cl:20])=O.[CH3:22]O>>[ClH:20].[CH3:22][O:5][C:3](=[O:4])[C@@H:2]1[CH2:6][C:7]([CH3:10])([CH3:9])[CH2:8][NH:1]1
Reactant: O=S(Cl)Cl
Reactant: CC1(C)C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CO
Product: COC(=O)[C@@H]1CC(C)(C)CN1
Product: Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of Boc-Pro(4,4-diMe)-OH (0.5 g, 2.06 mmol) in anhydrous methanol (8 ml) was added dropwise thionylchloride (448 g, 6.18 mmol) and the reaction was stirred for six hours at room temperature. The reaction mixture was concentrated to an amorphous solid (377 mg, 95%).
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=3[OH:19])[CH:14]=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C([O-])([O-])=O.[K+].[K+].Br[CH:27]([CH3:29])[CH3:28]>CN(C=O)C.CCOC(C)=O>[C:1]12([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=3[O:19][CH:27]([CH3:29])[CH3:28])[CH:14]=[O:15])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: CC(C)Br
Reactant: O=Cc1ccc(O)c(C23CC4CC(CC(C4)C2)C3)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(C=O)cc1C12CC3CC(CC(C3)C1)C2
Yield: 86 %

Procedure:
To a stirred suspension of 3-(1-admantyl)-4-hydroxybenzaldehyde (0.5 g, 1.95 mmol) and K2CO3 (0.276 g, 2 mmol) in anhydrous DMF (5 ml) was added 2-bromopropane (1 ml) and the mixture was reflux for 2 h. The reaction mixture was brought to room temperature and diluted to 50 ml with EtOAc and washed with H2O. The organic layer was separated, dried over MgSO4 and filtered. The filtrate was evaporated to dryness and the residue was crystallized from MeOH to give the title compound (0.25 g, 86%), as a colourless solid. 1H-NMR (CDCl3) 1.42 (d, 6H, J=6 Hz); 1.76 (broad s, 6H); 2.07 (broad s, 3H); 2.12 (s, 6H); 4.69-4.78 (m, 1H); 6.91 (d, 1H, J=8.44 Hz); 7.66 (dd, 1H, J=2.13, 8.45 Hz); 7.76 (d, 1H, J=2.11 Hz); 9.84 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].C(=O)([O-])[O-].[K+].[K+].S(OCC)(O[CH2:22][CH3:23])(=O)=O.[CH3:27][C:28](C)=O>O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:22][CH3:23])=[O:7])=[C:4]([O:11][CH2:27][CH3:28])[CH:3]=1
Reactant: CC(C)=O
Reactant: CCOS(=O)(=O)OCC
Reactant: O=C(O)c1ccc(Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1ccc(Cl)cc1OCC
Reaction time: 24 h

Procedure:
A mixture of 4-chlorosalicylic acid (10.0 g, 57.94 mmol) and potassium carbonate (80 g, 0.58 mol) and diethyl sulphate (18.76 g, 0.122 mol) in acetone (150 ml) is heated at reflux with stirring for 24 h. The suspension is cooled and diluted with water (200 ml). Extract with diethyl ether (2×) and wash the extracts with water (2×) and brine. The organic phase is dried over magnesium sulphate, filtered and evaporated to a brown oil. The oil is purified using the combiflash on a 120 g silica cartridge eluting with isohexane-ethyl acetate (0 to 25% over 30 min.) to give ethyl 4-chloro-2-ethoxybenzoate as a colourless oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[C:8]2[CH2:12][CH2:11][O:10][C:9]2=[O:13])C=CC=CC=1.[CH:26]([C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=1)=O.C(Cl)(Cl)Cl>CS(C)=O>[O:13]=[C:9]1[C:8](=[CH:26][C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)[CH2:12][CH2:11][O:10]1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: O=C1OCCC1=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Product: COC(=O)c1ccc(C=C2CCOC2=O)cc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A mixture of 40.00 g (0.12 mol) of 3-(triphenylphosphoranylidene)dihydro-2(3H)-furanone and 20.85 g (0.13 mol) of methyl 4-formylbenzoate in 240 ml of dimethyl sulfoxide is stirred at 80° C. for 18 hours. After cooling, 400 ml of chloroform are added, and the mixture is extracted five times with 200 ml of water. The organic phase is dried over magnesium sulfate and the solvent is distilled off under reduced pressure. The residue is stirred with diethyl ether and dried under reduced pressure at 40° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.[CH:10]([B-](F)(F)F)=[CH2:11].[K+].C(Cl)Cl>C(O)(C)C>[CH:10]([C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1)=[CH2:11]
Reactant: C=C[B-](F)(F)F
Reactant: OCc1ccc(Cl)nc1
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)O
Product: C=Cc1ccc(CO)cn1
Temperature: 80 °C
Yield: 54.4 %

Procedure:
A 100 mL sealed tube was charged with a solution of (6-chloropyridin-3-yl)methanol (0.5 g, 3.4 mmol, Org. Lett. 2005, p 2965-2967) dissolved in isopropanol (10 mL), potassium vinyltrifluoroborate (1 g, 7.63 mmol, Aldrich), [1,1,-bis(diphenyl phosphino)ferrocine]dichloro palladium(II) complex with DCM (0.277 g, 0.34 mmol, Aldrich) and TEA (0.92 mL, 6.8 mmol). The mixture was degassed with nitrogen then heated at about 80° C. for about 12 h. The reaction mixture was cooled to RT, filtered and washed with isopropanol (10 mL). The filtrate was evaporated to dryness under reduced pressure and the crude material obtained was purified by silica gel column chromatography using 30 to 40% of EtOAc in hexane as an eluent. Relevant fractions containing the target compound were combined and evaporated to dryness under reduced pressure to afford (6-vinylpyridin-3-yl)methanol as a dark brown liquid 0.25 g (53%), 1H NMR (400 MHz, DMSO): δ 8.479 (s, 1H), 7.704-7.688 (d, J=6.4 Hz, 1H), 7.471-7.456 (d, J=6.0 Hz, 1H), 6.827-6.806 (m, 1H), 6.212-6.177 (d, J=14 Hz, 1H), 5.439-5.417 (d, J=8.8 Hz, 1H), 5.300 (m, 1H), 4.524 (d, J=4.4 Hz, 2H), MS m/z: 136 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:12])=[C:9]([NH2:11])[CH:10]=1)[CH3:2].C(N(CC)CC)C.[C:20](Cl)([CH3:22])=[O:21]>C(Cl)Cl>[CH2:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:12])=[C:9]([NH:11][C:20](=[O:21])[CH3:22])[CH:10]=1)[CH3:2]
Reactant: CCOCc1ccc(C)c(N)c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCc1ccc(C)c(NC(C)=O)c1

Procedure:
N-(5-ethoxymethyl-2-methyl-phenyl)-acetamide VII-e was prepared as described for intermediate II-i using 5-ethoxymethyl-2-methyl-phenylamine I-e (5 g, 30.26 mmol), dry triethylamine (12.23 mL), DCM (60 mL) and AcCl (4.32 mL) to give the desired intermediate VII-e as a white solid (5.39 g, 86%). 1H NMR (300 MHz, CDCl3) δ 7.69 (s, 1H), 7.15 (d, J=7.7 Hz, 1H), 7.07 (d, J=8.2 Hz, 1H), 4.46 (s, 2H), 3.53 (q, J=7.0 Hz, 2H), 2.23 (s, 3H), 2.18 (s, 3H), 1.23 (t, J=7.0 Hz, 3H).
Reaction SMILES: F[C:2]1[C:7](/[CH:8]=[N:9]/[NH:10][C:11]2[C:16]([F:17])=[CH:15][C:14]([F:18])=[CH:13][C:12]=2[F:19])=[C:6](I)[CH:5]=[CH:4][N:3]=1.IC1C=CN=C2N(C3C(F)=CC(F)=CC=3F)N=CC=12.CC1(C)C(C)(C)[O:44][B:43](B2OC(C)(C)C(C)(C)O2)[O:42]1.C([O-])(=O)C.[K+].C(Cl)Cl>CS(C)=O>[F:19][C:12]1[CH:13]=[C:14]([F:18])[CH:15]=[C:16]([F:17])[C:11]=1[N:10]1[C:2]2=[N:3][CH:4]=[CH:5][C:6]([B:43]([OH:44])[OH:42])=[C:7]2[CH:8]=[N:9]1
Reactant: Fc1cc(F)c(N/N=C/c2c(I)ccnc2F)c(F)c1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: CC(=O)[O-]
Agent: Fc1cc(F)c(-n2ncc3c(I)ccnc32)c(F)c1
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: OB(O)c1ccnc2c1cnn2-c1c(F)cc(F)cc1F

Procedure:
To a 48 mL pressure bottle containing (E)-2-fluoro-4-iodo-3-((2-(2,4,6-trifluorophenyl)hydrazono)methyl)pyridine (230 mg, 0.582 mmol), were added Intermediate 77A (133 mg, 0.355 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (330 mg, 1.30 mmol), potassium acetate (350 mg, 3.57 mmol), and anhydrous DMSO (8 mL). The reaction mixture was purged with argon, treated with PdCl2(dppf).CH2Cl2(64 mg, 0.087 mmol), and heated to 85° C. for 1.25 h to give the desired intermediate. LC/MS (Condition B): ret. T=2.9 min, (M+H)+ 294.03.
Reaction SMILES: C(O)C.[N:4]1[C:12]([C:13](=[O:15])[CH3:14])=[C:11]2[C:7]([N:8]=[CH:9][NH:10]2)=[N:6][CH:5]=1.[BH4-].[Na+].Cl>O>[N:4]1[C:12]([CH:13]([OH:15])[CH3:14])=[C:11]2[C:7]([N:8]=[CH:9][NH:10]2)=[N:6][CH:5]=1
Reactant: CC(=O)c1ncnc2nc[nH]c12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(O)c1ncnc2nc[nH]c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.4 %

Procedure:
To an ethanol solution (80 ml) of 0.70 g of (purin-6-yl)ethanone was added 0.70 g of sodium borohydride and the resulting mixture was stirred at room temperature for 4 hours. The excessive reagent was decomposed by adding water and 4 N hydrochloric acid and distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluted by dichloromethane/methanol) to thereby give 0.57 g of the title compound as a white solid.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[N:21]([CH:22]=2)[CH2:20][CH2:19][O:18][C:17]2[C:12]3=[CH:13][C:14]([CH:23]([OH:25])[CH3:24])=[CH:15][CH:16]=2)=[N:7][CH:6]=[N:5]1)[CH3:3].[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[CH3:26][S:27]([O:25][CH:23]([C:14]1[CH:13]=[C:12]2[C:17]([O:18][CH2:19][CH2:20][N:21]3[C:11]2=[N:10][C:9]([C:8]2[N:4]([CH:2]([CH3:1])[CH3:3])[N:5]=[CH:6][N:7]=2)=[CH:22]3)=[CH:16][CH:15]=1)[CH3:24])(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)cn1CCO2
Solvent: ClCCl
Product: CC(OS(C)(=O)=O)c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)cn1CCO2
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
To a solution of 1-{4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaen-13-yl}ethan-1-ol (200 mg, 0.590 mmol) in DCM (20 mL) at 0° C. was added TEA (296 mg, 2.93 mmol) and MsCl (136 mg, 1.19 mmol). The reaction mixture was stirred 0° C. for 2 h and then allowed to warm to room temperature. The reaction was quenched with sat. NaHCO3 (10 mL) and the resultant mixture was further washed with brine (20 mL). The organic phase was then dried and concentrated to afford the crude product (246 mg, 100% yield) as a brown solid, which was directly used in next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([NH:12]S(C(C)(C)C)=O)[CH2:11][O:10][CH2:9]2)=[N:6][CH:7]=1.[ClH:19].O1CCOCC1>CO>[Cl-:19].[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([NH3+:12])[CH2:11][O:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: CC(C)(C)S(=O)NC1(c2ccc(Br)cn2)COC1
Reactant: Cl
Solvent: CO
Solvent: C1COCCO1
Product: [Cl-]
Product: [NH3+]C1(c2ccc(Br)cn2)COC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a methanol (15 ml) solution of N-(3-(5-bromopyridin-2-yl)oxetan-3-yl)-2-methylpropane-2-sulfinamide (850 mg, 2.55 mmol) that had been cooled to 0° C. is added 4N HCl in dioxane (1.3 ml, 5.2 mmol). The solution is stirred for 1 hour at 0° C. The volatiles were removed by rotary evaporation at low pressure. After several evaporation cycles using acetonitrile (3×10 ml) the title product is obtained (584 mg): m/z (Cl) 229, 231 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.Br.BrBr.[Br:22]C(Br)=O>C(O)(=O)C.ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:18])[CH:9]([C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)[Br:22])=[CH:6][CH:7]=1
Reactant: O=C(Br)Br
Reactant: CSc1ccc(CC(=O)c2ccc(F)cc2)cc1
Agent: Br
Agent: BrBr
Solvent: ClCCl
Solvent: CC(=O)O
Product: CSc1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Reaction time: 0.25 h

Procedure:
A 1 L three necked round bottomed flask equipped with reflux condenser, magnetic stir bar, thermometer adapter, and constant pressure addition funnel was charged with the intermediate from Step 2, (55.5 g, 0.21 mol), acetic acid (250 mL) and 33% HBr in acetic acid (120 mL). The solution was stirred and treated with bromine (11.1 mL, 0.21 mol) from the addition funnel at such a rate that the bromine color was discharged rapidly, ca. 15 minutes. After an additional 10 minutes at room temperature, the solution was filtered through a Buchner funnel and the filtrate concentrated in vacuo to give an orange solid. The crude bromoketone was dissolved in dichloromethane and washed with 1N NaHSO3, dried over anhydrous MgSO4, filtered and concentrated in vacuo to give 68.8 g of 1-(4-fluorophenyl)-2-(4-methylthiophenyl)-2-bromoethanone as a yellow solid which was used directly without further purification. The crude bromoketone was dissolved in 300 mL acetone and 150 mL of water and heated to reflux for 2.5 hours. The solution was concentrated in vacuo and the residue taken up in dichloromethane, washed with saturated aqueous sodium bicarbonate, brine, dried over anhydrous magnesium sulfate, filtered and reconcentrated in vacuo to give a light yellow solid that was crystallized from a mixture of dichloromethane and isooctane to provide 37.8 g (65%) of pure 1-(4-fluorophenyl)-2-(4-methylthiophenyl)-2-hydroxy-ethanone: mp 90°-92° C.
Reaction SMILES: [Br:1][CH2:2]/[CH:3]=[C:4](/[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1)\[CH3:5].[N+](=[CH:17][C:18](OCC)=O)=[N-].Cl[CH2:24]Cl>CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:17]([CH:5]1[CH:3]([CH2:2][Br:1])[C:4]1([CH3:24])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1)[CH3:18]
Reactant: C/C(=C\CBr)c1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: ClCCl
Agent: [Rh]
Solvent: CC(=O)O
Product: CCC1C(CBr)C1(C)c1cccc([N+](=O)[O-])c1
Yield: 11 %

Procedure:
To a solution of 1-[(E)-3-bromo-1-methyl-1-propenyl]-3-nitrobenzene (Preparation 4, 4 g, 15.6 mmol) in dichloromethane (5 ml) was added rhodium (II) acetate dimer (100 mg, 0.22 mmol). To the mixture was added dropwise at room temperature over 4.5 h a solution of ethyl diazoacetate (3.1 ml, 2.84 g, 25 mmol) in dichloromethane (15 ml). The mixture was filtered, concentrated in vacuo, and the residue purified by silica column (100 g) chromatography, eluting with 2:1 hexane/dichloromethane then dichloromethane. Product-containing fractions were combined and concentrated in vacuo, then purified further by preparative HPLC (Condition 1). Combination and evaporation of appropriate fractions gave the title compound as a colourless oil (0.5 g, 11%).
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6](=[O:16])[CH2:7][C:8]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])([CH3:10])[O:9][C:4]=2[C:3]=1[CH2:19][CH2:20][CH3:21].[CH3:22]OC(OC)OC.S(=O)(=O)(O)O>>[OH:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6](=[O:16])[CH2:7][C:8]([CH2:11][CH2:12][C:13]([O:15][CH3:22])=[O:14])([CH3:10])[O:9][C:4]=2[C:3]=1[CH2:19][CH2:20][CH3:21]
Reactant: COC(OC)OC
Reactant: CCCc1c(O)ccc2c1OC(C)(CCC(=O)O)CC2=O
Agent: O=S(=O)(O)O
Product: CCCc1c(O)ccc2c1OC(C)(CCC(=O)OC)CC2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the title compound of Example 3 (4.3 g, 14.7 mmole), 6 ml of trimethylorthoformate, and 1.4 ml of sulfuric acid was stirred at room temperature for two hours. The reaction mixture was poured onto stirred ice/water and extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate, and concentrated to an oil. The oil was purified by chromatography on silica gel, giving 3.7 g of the title compound as a crystalline solid, m.p. 101.5°-102.5° Structure assignment was consistent with nmr and infrared spectra. ##STR9##
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[H][H].S(C1C=CC(C)=CC=1)(O)(=O)=O.S(C1C=CC(C)=CC=1)(O)(=O)=O.O[CH2:39][C@H:40]1[CH2:44][CH2:43][C@@H:42]([CH2:45]O)[O:41]1>CN(C)C=O>[CH2:12]([O:11][C:3]([C:4]1([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:45][CH:42]2[O:41][CH:40]([CH2:44][CH2:43]2)[CH2:39]1)=[O:10])[CH3:13]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: [H][H]
Reactant: OC[C@@H]1CC[C@H](CO)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C(=O)OCC)CC2CCC(C1)O2
Temperature: 140 °C
Yield: 70.8 %

Procedure:
Sodium hydride (2.28 grams, 95 mmole) was added in portions to a stirred solution of diethyl malonate (15 mL, 99 mmole) in N,N-dimethylformamide (400 mL). The mixture was stirred for 45 minutes at which time evolution of hydrogen was complete. A solution of cis-2,5-bis(hydroxymethyl)tetrahydrofuran ditosylate (19.0 grams, 43 mmole) in N,N-dimethylformamide (400 mL) was then added dropwise. The mixture was heated in an oil bath at 140° C. overnight. After cooling to room temperature, the mixture was quenched by addition of saturated aqueous ammonium chloride solution and concentrated under vacuum. The residual oil was taken up in water and extracted with diethyl ether. The organic extract was washed with water and brine, dried over magnesium sulfate and concentrated to an oil. Distillation under vacuum afforded the title compound (7.8 grams, 71%) as a clear oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[C:10]([CH3:16])([CH3:15])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:15][C:10]1([CH3:16])[C:11](=[O:14])[CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(C)(C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CNCCC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The 3,3-dimethyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester thus prepared (450 mg, 1.97 mmol) was dissolved in methylene chloride (10 mL). Trifluoroacetic acid was added (305 uL) and the resulting solution stirred at room temperature 2 h. Additional trifluoroacetic acid was added (300 uL) and the reaction stirred at room temperature 3 days. The pale yellow solution was concentrated to afford an oily residue, which was triturated with ether. The solids were collected by suction filtration and dried in vacuo. 3,3-Dimethyl-piperidin-4-one was isolated and used as its trifluoroacetic acid salt (381 mg, 80%).
Reaction SMILES: O[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:15]([CH:17]1[O:19][CH2:18]1)Cl.[OH-:20].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(OCC)(=O)C>[O:19]1[CH2:18][CH:17]1[CH2:15][O:20][C:5]1[C:6]2[NH:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]=2[CH:2]=[CH:3][CH:4]=1
Reactant: ClCC1CO1
Reactant: Oc1cccc2[nH]c3ccccc3c12
Reactant: [OH-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: c1ccc2c(c1)[nH]c1c(OCC3CO3)cccc12
Temperature: 2.5 °C
Yield: 63.8 %

Procedure:
4-Hydroxy carbazole (60 g) obtained in step 1 was charged into a reactor containing water (90 ml). Epichlorohydrin (64.2 g) and tetrabutyl ammonium bromide (6.3 g) were then charged into the reactor under stirring. 50% Sodium hydroxide solution (78 g) was added slowly in 2-3 hours into the reaction mass at about 30° C. After completion of reaction, ethyl acetate (315 ml) and potable water (315 ml) were charged into the reaction mass. The lower aqueous layer was separated and discarded. The ethyl acetate layer was washed with potable water to obtain neutral pH and dried over anhydrous sodium sulphate. The ethyl acetate is distilled out under vacuum below 55° C. to about 100 ml. The reaction mass was chilled to 0-5° C. and filtered and dried at 50-60° C. to give the title compound (50 g) (64%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:14][CH2:15][CH3:16])[C:11]=1[S:12][CH3:13])[CH:7]=[O:8])[CH3:2].[OH:17]O.O>C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:14][CH2:15][CH3:16])[C:11]=1[S:12]([CH3:13])=[O:17])[CH:7]=[O:8])[CH3:2]
Reactant: CCOc1cc(C=O)cc(OCC)c1SC
Reactant: OO
Solvent: CC(=O)O
Solvent: O
Product: CCOc1cc(C=O)cc(OCC)c1S(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a solution of 3,5-diethoxy-4-methylsulfanyl-benzaldehyde (0.28 g, 1.16 mmol, 1.0 equiv) in conc. acetic acid (5 mL) was added a solution of 35% hydrogen peroxide in water (0.13 mL, 0.15 g, 1.50 mmol, 1.3 equiv). After stirring the solution for 2 h at rt the reaction mixture was extracted with ethyl acetate (3×50 mL) and the combined organic phases dried over MgSO4. The organic solvent was removed by evaporation under reduced pressure and the crude material purified with column chromatography on silica eluting with ethyl acetate (1% methanol) providing 0.25 g (84%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.50 (t, J=7.0 Hz, 6H), 3.11 (s, 3H), 4.15-4.26 (m, 4H), 7.07 (s, 2H), 9.93 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 14.50, 37.62, 65.34, 106.10, 125.13, 139.95, 159.53, 191.07. MS (ISP): 257.1 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([CH3:19])([CH3:18])[CH2:9]1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:30])[O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:9][C:10]3([CH3:19])[CH3:18])=[CH:24][CH:23]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: CC1(C)CN(Cc2ccccn2)c2ccc(O)cc21
Product: COc1ccc(NC(=O)Oc2ccc3c(c2)C(C)(C)CN3Cc2ccccn2)cc1

Procedure:
The title compound was synthesized from 1-(2-pyridylmethyl)-3,3-dimethylindolin-5-ol (20.0 mg, 0.09 mmol) using the same procedure employed for Example 2 (2), but with 4-methoxyphenylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (14.6 mg, 46%) having the following characteristics.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[C:19]([C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([O:28][CH3:29])=[O:27])[CH:18]=[CH:17]3)[C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[BH4-].[Na+]>O1CCCC1.CO>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[C:19]([C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([O:28][CH3:29])=[O:27])[CH:18]=[CH:17]3)[C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc2nc(-c3ccccc3C(=O)OC)ccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc2nc(-c3ccccc3C(=O)OC)ccc2c1
Yield: 83.2 %

Procedure:
440 mg (0.953 mmol) of methyl 2-{6-[(2-butyl-4-chloro-5-formyl-1H-imidazol-1-yl)methyl]quinolin-2-yl}benzoate obtained in Example 1 were dissolved in a mixed solvent of 10 ml of tetrahydrofuran and 10 ml of methanol and the mixture was stirred. 40 mg (1.0 mmol) of sodium borohydride were added thereto and allowed to react at room temperature for one hour. After the reaction mixture was concentrated under reduced pressure, dichloromethane was added to the residue and the mixture was washed with a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate followed by filtration. The filtrate was concentrated under reduced pressure to obtain 368 mg of methyl 2-{6-[(2-butyl-4-chloro-5-hydroxymethyl-1H-imidazol-1-yl)methyl]quinolin-2-yl}benzoate.