Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]([CH3:26])([CH3:25])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[CH2:24][CH2:23][C@@:17]3([NH:21][C:20](=[O:22])[O:19][CH2:18]3)[CH2:16]2)=[CH:11][CH:10]=1.[O-]S([O-])(=O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CO.O.S([O-])([O-])(=O)=O.[Cu+2].[OH-].[OH-].[Pd+2]>[CH3:25][CH:2]([CH3:26])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:15]2[CH2:24][CH2:23][C@@:17]3([NH:21][C:20](=[O:22])[O:19][CH2:18]3)[CH2:16]2)=[CH:13][CH:14]=1
Reactant: CC(C)(O)CCCCCCc1ccc([C@@H]2CC[C@]3(COC(=O)N3)C2)cc1
Agent: [Cu+2]
Agent: [Pd+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)CCCCCCc1ccc([C@@H]2CC[C@]3(COC(=O)N3)C2)cc1
Temperature: 100 °C
Yield: 54.5 %

Procedure:
To a slurry of silica gel (1 g) and copper sulfate hydrate (1 g) in toluene (10 mL) was added (5R,7R)-7-(4-(7-hydroxy-7-methyloctyl)phenyl)-3-oxa-1-azaspiro[4.4]nonan-2-one (230 mg, 0.640 mmol). The reaction mixture was heated to 100° C. After 2 days Na2SO4 (approx. 500 mg) was added. After an additional 1 day at 100° C. the reaction mixture was cooled to room temperature and filtered, rinsing with EtOAc. The resulting alkene was added to a slurry of palladium hydroxide on carbon (4.49 mg, 0.032 mmol) in MeOH (10.00 mL). Hydrogen was bubbled through the solution for 5 min and an atmosphere of hydrogen was maintained via balloon. After 15 h the reaction mixture was filtered and concentrated in vacuo. The crude alkane was purified by chromatography on silica gel (EtOAc/Hep) to provide (5R,7R)-7-(4-(7-methyloctyl)phenyl)-3-oxa-1-azaspiro[4.4]nonan-2-one (120 mg, 0.349 mmol, 54.6% yield) as a colorless solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7]2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:21](I)[CH2:22][CH2:23][CH3:24]>CN(C=O)C>[CH2:21]([N:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7]2)[CH2:3][CH2:2]1)[CH2:22][CH2:23][CH3:24]
Reactant: c1ccc2c(c1)CCC21CCNCC1
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCN1CCC2(CCc3ccccc32)CC1
Yield: 53.1 %

Procedure:
In the same way as that described in Example 1, step 5, the title compound was prepared using spiro[indane-1,4'-piperidine] (77 mg, 0.41 mmol), DMF (10 ml), potassium carbonate (68 mg, 0.49 mmol), and n-butyl iodide (0.05 ml, 0.45 mmol). The crude residue was chromatographed using 5:95 methanol: dichloromethane, to give 1'-n-butylspiro[indane-1,4'-piperidine] (53 mg, 53%) as a beige solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][CH:14]1[CH2:16][CH2:15]1.[CH3:17][N:18]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:37]3[CH:38]=[N:39][N:40]([CH3:42])[CH:41]=3)[CH:24]=2)[C:19]1=[O:43].C([O-])(O)=O.[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:14]1([CH2:13][O:12][C:3]2[CH:4]=[CH:5][C:6]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:7][C:2]=2[C:26]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:37]4[CH:38]=[N:39][N:40]([CH3:42])[CH:41]=4)[CH:24]=3)[C:19](=[O:43])[N:18]([CH3:17])[CH:27]=2)[CH2:16][CH2:15]1
Reactant: Cn1cc(-c2ccc3c(=O)n(C)cc(B4OC(C)(C)C(C)(C)O4)c3c2)cn1
Reactant: CS(=O)(=O)c1ccc(OCC2CC2)c(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2ccc3c(=O)n(C)cc(-c4cc(S(C)(=O)=O)ccc4OCC4CC4)c3c2)cn1
Yield: 34.9 %

Procedure:
A mixture of 2-bromo-1-(cyclopropylmethoxy)-4-methanesulfonylbenzene (20.8 mg, 0.068 mmol), 2-methyl-6-(1-methylpyrazol-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one (30 mg, 0.08 mmol), NaHCO3 (14.28 mg, 0.17 mmol), and Pd(dppf)Cl2 (10 mg, 0.014 mmol) in dioxane (2.0 mL) and H2O (0.5 mL) was microwaved under N2 at 100° C. for 30 min. Purification by preparative HPLC gave the title compound (11 mg, 28%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 8.48 (d, J=8.4 Hz, 1H), 7.98-8.04 (m, 1H), 7.89 (d, J=2.4 Hz, 1H), 7.68 (s, 1H), 7.63 (s, 1H), 7.58-7.62 (m, 1H), 7.19-7.21 (m, 1H), 7.11-7.15 (m, 1H), 7.09 (s, 1H), 3.93 (s, 3H), 3.83-3.91 (m, 2H), 3.66 (s, 3H), 3.12 (s, 3H), 0.94-1.04 (m, 1H), 0.30-0.40 (m, 2H), 0.00-0.12 (m, 2H). LCMS: 464.1 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:19]3[CH:23]=[CH:22][O:21][CH:20]=3)=[C:11]([CH2:13][C:14]([O:16]CC)=[O:15])[N:12]=2)=[CH:4][CH:3]=1.CO.[OH-].[Na+]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:19]3[CH:23]=[CH:22][O:21][CH:20]=3)=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1nc(-c2ccc(F)cc2)oc1-c1ccoc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)Cc1nc(-c2ccc(F)cc2)oc1-c1ccoc1
Yield: 85 %

Procedure:
6.30 g of ethyl 2-[2-(4-fluorophenyl)-5-(3-furyl)-4-oxazolyl]acetate, 70 ml of methanol, 7 ml of water and 1.5 g of sodium hydroxide are treated in the same manner as described in Example 16. 4.88 g of 2-[2-(4-fluorophenyl)-5-(3-furyl)-4-oxazolyl]acetic acid are obtained. Yield: 85%
Reaction SMILES: [C:1]1([CH2:7][CH:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][CH:11]1[C:15](=[O:16])[C:14]([OH:17])=[C:13]([CH3:18])[O:12]1.B(O)(O)O>>[OH:9][CH:8]([C:13]1([CH3:18])[C:14](=[O:17])[C:15]([OH:16])=[C:11]([CH3:10])[O:12]1)[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1=C(O)C(=O)C(C)O1
Reactant: O=CCc1ccccc1
Agent: OB(O)O
Product: CC1=C(O)C(=O)C(C)(C(O)Cc2ccccc2)O1
Temperature: 80 °C
Reaction time: 3 h
Yield: 23 %

Procedure:
To a mixture of 6 g (0.05 mole) phenylacetaldehyde and 1.28 g (0.01 mole) of 2.5-dimethyl-4-hydroxy-3-(2H)-furanone was added 60 mg of boric acid and the mixture was stirred at 80°C for 3 hours. After working up the reaction mixture as described earlier, 0.57 g (23%) of the title compound was obtained, with melting point 157.5°-159°C.
Reaction SMILES: [CH3:1][CH:2]([CH2:12][CH3:13])[CH2:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1.[Cl:14][C:15]1[CH:31]=[CH:30][C:18]2[CH2:19][CH2:20][N:21]([C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[CH2:22][CH2:23][C:17]=2[C:16]=1OS(C(F)(F)F)(=O)=O.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:31]=[CH:30][C:18]2[CH2:19][CH2:20][N:21]([C:24](=[O:29])[C:25]([F:26])([F:28])[F:27])[CH2:22][CH2:23][C:17]=2[C:16]=1[NH:9][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][CH:2]([CH3:1])[CH2:12][CH3:13])=[CH:11][CH:10]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: CCC(C)Cc1ccc(CN)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCC(C)Cc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Temperature: 95 °C
Yield: 58.4 %

Procedure:
Under a nitrogen atmosphere, add 4-(2-methyl-butyl)-benzylamine (450 mg, 2.54 mmol), 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (720 mg, 1.7 mmol), palladium(II) acetate (40 mg, 0.17 mmol), BINAP (222 mg, 0.34 mmol) and cesium carbonate (1.4 g, 4.3 mmol) to toluene (20 mL). Heat the mixture at 95° C. for 12 h. Cool the mixture to room temperature and apply the mixture to a silica gel column eluting with hexane/EtOAc (10:1) to provide 7-chloro-6-[4-(2-methyl-butyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (450 mg, 59%). MS (ES+) m/z: 453 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH3:25])[N:11]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][N:14]=2)=[CH:4][CH:3]=1.FC1C=CC(C2N=CN(C3CCN([CH2:52][C:53]4[CH:57]=[CH:56][O:55][N:54]=4)CC3)C=2C2C=CN=C(NC)N=2)=CC=1.CO>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH3:25])[N:11]([CH:19]3[CH2:24][CH2:23][N:22]([CH2:52][C:53]4[CH:57]=[CH:56][O:55][N:54]=4)[CH2:21][CH2:20]3)[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][N:14]=2)=[CH:6][CH:7]=1
Reactant: Cc1nc(-c2ccc(F)cc2)c(-c2ccncn2)n1C1CCNCC1
Reactant: CNc1nccc(-c2c(-c3ccc(F)cc3)ncn2C2CCN(Cc3ccon3)CC2)n1
Solvent: ClCCl
Solvent: CO
Product: Cc1nc(-c2ccc(F)cc2)c(-c2ccncn2)n1C1CCN(Cc2ccon2)CC1

Procedure:
Compound 14 was prepared from 4-[4-(4-fluorophenyl)-2-methyl-1-piperidin-4-yl-1H-imidazol-5-yl]pyrimidine (C31) according to the general procedure for the synthesis of 4-{4-(4-fluorophenyl)-1-[1-(isoxazol-3-ylmethyl)piperidin-4-yl]-1H-imidazol-5-yl}-N-methylpyrimidin-2-amine (5) in Example 5, except that extractions were carried out with dichloromethane, and the eluant employed for chromatography was 5% methanol in dichloromethane. The product was obtained as a solid. Yield: 10 mg, 0.024 mmol, 23%. LCMS m/z 419.6 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.95-2.00 (m, 2H), 2.15 (ddd, J=11.8, 11.8, 2.0 Hz, 2H), 2.27-2.37 (m, 2H), 2.65 (s, 3H), 3.01 (br d, J=11.6 Hz, 2H), 3.67 (s, 2H), 4.48 (tt, J=12.4, 4.0 Hz, 1H), 6.39 (d, J=1.7 Hz, 1H), 6.96 (dd, J=8.8, 8.8 Hz, 2H), 7.12 (dd, J=5.3, 1.5 Hz, 1H), 7.29 (dd, J=8.8, 5.4 Hz, 2H), 8.38 (d, J=1.7 Hz, 1H), 8.55 (d, J=5.3 Hz, 1H), 9.30 (d, J=1.4 Hz, 1H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C(Cl)Cl.[OH:8][C:9]1[C:18]([OH:19])=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1>C(OCC)C>[N+:1]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[C:18]([OH:19])[C:9]=1[OH:8])([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: Oc1cc2ccccc2cc1O
Solvent: ClCCl
Solvent: CCOCC
Product: O=[N+]([O-])c1c(O)c(O)cc2ccccc12

Procedure:
Fuming nitric acid (4.2 ml) was added to methylene chloride (50 ml) and the resulting solution diluted with diethyl ether (100 ml): Then 3-methylbuthylnitrite (1.9 ml) was added and this final solution added at 25-30° C. to a solution of 2,3-dihydroxynaphthalene (16.0 g) in ether (100 ml).The reaction mixture was washed with water, extracted into potassium bicarbonate (1 M), acidified and finally extracted into ether. After column chromatography (SiO2, toluene-ethyl acetate-acetic acid 18:1:1) the product was crystallized from toluene. Yield: 1.5 g, melting point 141-143° C.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([S:10]([CH2:13][CH2:14][CH2:15][OH:16])(=[O:12])=[O:11])[CH2:6][CH2:5]1.Cl[C:18]1[CH:19]=[CH:20][C:21]2[N:22]([N:24]=[CH:25][N:26]=2)[N:23]=1.[Cl-].[Na+]>CN(C)C=O.O1CCCC1>[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([S:10]([CH2:13][CH2:14][CH2:15][O:16][C:18]2[CH:19]=[CH:20][C:21]3[N:22]([N:24]=[CH:25][N:26]=3)[N:23]=2)(=[O:12])=[O:11])[CH2:6][CH2:5]1
Reactant: CN1CCN(S(=O)(=O)CCCO)CC1
Reactant: Clc1ccc2ncnn2n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN1CCN(S(=O)(=O)CCCOc2ccc3ncnn3n2)CC1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 60.6 %

Procedure:
In 10 ml of dimethylformamide was suspended 0.21 g of 60% sodium hydride in oil followed by addition of 1.12 g of 3-(1-methyl-4-piperazinylsulfonyl)-1-propanol and the mixture was stirred under reduced pressure at room temperature for 75 minutes. Then, 0.773 g of 6-chloro[1,2,4]triazolo[1,5-b]pyridazine was added and the mixture was further stirred at room temperature for 1.5 hours. Following addition of 40 ml of ice water, the reaction mixture was saturated with sodium chloride. The aqueous layer was extrated with tetrahydrofuran and the extrat was dried over magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was subjected to silica gel column chromatography, elution being carried out with dichloromethane-methanol (10:1). The fractions containing the desired product were pooled and concentrated to provide 1.032 g of the title compound. m.p. 140°-141° C.
Reaction SMILES: C([N:5]1[C:9]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](=[O:21])[N:13]([CH2:22][CH2:23][O:24][CH3:25])[N:12]=2)=[CH:8][C:7]([CH3:26])=[N:6]1)(C)(C)C>C(O)=O.O>[CH3:25][O:24][CH2:23][CH2:22][N:13]1[N:12]=[C:11]([NH:10][C:9]2[NH:5][N:6]=[C:7]([CH3:26])[CH:8]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]1=[O:21]
Reactant: COCCn1nc(Nc2cc(C)nn2C(C)(C)C)c2ccccc2c1=O
Solvent: O
Solvent: O=CO
Product: COCCn1nc(Nc2cc(C)n[nH]2)c2ccccc2c1=O
Yield: 93.5 %

Procedure:
4-(2-tert-Butyl-5-methyl-2H-pyrazol-3-ylamino)-2-(2-methoxy-ethyl)-2H-phthalazin-1-one (0.36 g, 1.0 mmol) was dissolved in formic acid (20 ml) and heated at reflux for 4 h. The resulting raw product was dissolved in H2O and dichloromethane, after evaporation of formic acid. Addition of NaHCO3 resulted in precipitation of a solid, which was collected by filtration. Subsequent washing with H2O, dichloromethane and diethyl ether and drying in vacuum at 40° C. yielded the desired product 2-(2-Methoxyethyl)-4-(5-methyl-2H-pyrazol-3-ylamino)-2H-phthalazin-1-one (example O-1) (0.28 g, 94%). 1H-NMR: (400 MHz, D6-DMSO) 9.21 (1H, s), 8.43 (1H, d), 8.29 (1H, d), 8.14 (1H, s), 7.84–7.94 (2H, m), 6.28 (1H, s), 4.23 (2H, t), 3.73 (2H, t), 3.33 (3H, s), 2.23 (3H, s); MS (ESI+)=300.3 (M+H)+
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][OH:7].N1C=CC=CC=1.[S:14](Cl)(Cl)(=[O:16])=[O:15].Cl.N1C=CC=CC=1>ClCCl.C(=O)=O.CC(C)=O>[S:14]1(=[O:16])(=[O:15])[N:1]2[CH2:5][CH2:4][CH2:3][C@H:2]2[CH2:6][O:7]1
Reactant: OC[C@@H]1CCCN1
Reactant: O=S(=O)(Cl)Cl
Agent: Cl
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: O=S1(=O)OC[C@@H]2CCCN21
Temperature: -40 °C
Yield: 72.7 %

Procedure:
To a solution of (S)-pyrrolidin-2-yl-methanol (25.0 g, 0.247 mol) in dichloromethane (165 ml) was added pyridine (41 ml, 0.508 mol). The solution was stirred while being cooled in dry ice/acetone bath until the temperature of the mixture was below −68° C. Sulfuryl chloride (20 ml, 0.247 mol) was added over 45 minutes while maintaining the reaction temperature below −60° C. The reaction temperature was allowed to warm to −40° C. and held for two hours while pyridine hydrochloride precipitates. The reaction mixture was allowed to warm to ambient temperature and was stirred for an additional 50 minutes. The reaction mixture was poured onto ice water (300 ml). The organic layer was separated and the aqueous phase was extracted with dichloromethane (150 ml). The combined organic layers are washed with 1N HCl (100 ml), water (100 ml) and saturated NaCl (100 ml) and then dried over Na2SO4. After evaporation of the solvent, the crude product (32.4 g in the form of a orange resin) was purified by flash chromatography over silica gel (eluent:cyclohexane/ethyl acetate 6:4) to afford 29.3 g (72.7% of theory) of (S)-tetrahydro-pyrrolo[1,2-c][1,2,3]oxathiazole 1,1-dioxide as a white solid m.p. 46-50° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([OH:22])=[CH:16][C:15]=1[C:23]1[CH:28]=[CH:27][C:26]([C:29](O)=[O:30])=[CH:25][C:24]=1[O:32][CH3:33])[CH:8]1[CH2:34][C:35]3[C:40]([CH:7]21)=[CH:39][CH:38]=[CH:37][CH:36]=3)(=[NH:3])[NH2:2].[CH:41]1([NH2:47])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1>>[CH:41]1([NH:47][C:29]([C:26]2[CH:27]=[CH:28][C:23]([C:15]3[CH:16]=[C:17]([OH:22])[C:18]([O:20][CH3:21])=[CH:19][C:14]=3[CH:9]3[CH:8]4[CH2:34][C:35]5[C:40]([CH:7]4[C:6]4[C:11](=[CH:12][CH:13]=[C:4]([C:1](=[NH:2])[NH2:3])[CH:5]=4)[NH:10]3)=[CH:39][CH:38]=[CH:37][CH:36]=5)=[C:24]([O:32][CH3:33])[CH:25]=2)=[O:30])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1
Reactant: NC1CCCCC1
Reactant: COc1cc(C2Nc3ccc(C(=N)N)cc3C3c4ccccc4CC23)c(-c2ccc(C(=O)O)cc2OC)cc1O
Product: COc1cc(C2Nc3ccc(C(=N)N)cc3C3c4ccccc4CC23)c(-c2ccc(C(=O)NC3CCCCC3)cc2OC)cc1O

Procedure:
Example 238 was prepared according to the protocol described for example 235 from 2′-(2-Carbamimidoyl-5,6a,7,11b-tetrahydro-6H-indeno[2,1-c]quinolin-6-yl)-5′-hydroxy-2,4′-dimethoxy-biphenyl-4-carboxylic acid (example 235 step a) and cyclohexylamine. Mass Spectrum: 617 (M+1).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[Br:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH2:18]2.N1CCCCC1>C(O)C>[Br:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[C:18]2=[CH:11][C:8]1[NH:9][CH:10]=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:7]=1[CH3:13]
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Reactant: O=C1Cc2cc(Br)ccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(CCC(=O)O)c[nH]c1C=C1C(=O)Nc2ccc(Br)cc21
Yield: 64.4 %

Procedure:
4-(2-Carboxyethyl)-2-formyl-3-methylpyrrole (90 mg), 106 mg 5-bromo-2-oxindole, and 75 μL piperidine in 2 mL ethanol were heated to 95° C. for 5 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 2 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven to give 120 mg (64%) of the title compound as a brown solid.
Reaction SMILES: Cl.[CH3:2][C:3]([N:8]1[CH:12]=[N:11][CH:10]=[N:9]1)([CH3:7])[C:4]([OH:6])=O.[NH2:13][C@@H:14]([CH2:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)=[O:16]>>[CH2:34]([O:33][CH2:32][C@H:14]([NH:13][C:4](=[O:6])[C:3]([CH3:2])([N:8]1[CH:12]=[N:11][CH:10]=[N:9]1)[CH3:7])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)(C(=O)O)n1cncn1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: CC(C)(C(=O)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1)n1cncn1
Yield: 36 %

Procedure:
Proceeding as in Example 1, but substituting 2-methyl-2-(1H-1,2,4-triazol-1-yl)propanoic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 255, (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-methyl-2-(1H-1,2,4-triazol-1-yl)propanamido)propanamide (93.3 mg, 36%). 1H-NMR (400 MHz, CDCl3): δ 8.45 (s, 1H), 8.30 (s, 1H), 8.07 (s, 1H), 7.42 (d, 2H), 7.39-7.24 (m, 7H), 7.11 (d, 1H), 7.05-6.91 (m, 5H), 4.65-4.59 (m, 2H), 4.50 (d, 1H), 4.00 (dd, 1H), 3.58-3.52 (m, 1H), 1.92 (s, 3H), 1.90 (s, 3H). MS (EI) for C28H28FN5O4 found 518 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([S:17][C:18]4[CH:27]=[CH:26][C:21]5[N:22]=[C:23]([NH2:25])[S:24][C:20]=5[CH:19]=4)=[N:15][N:16]=3)[N:13]=2)[CH:5]=[CH:6][CH:7]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([S:17][C:18]4[CH:27]=[CH:26][C:21]5[N:22]=[C:23]([NH:25][C:28](=[O:30])[CH3:29])[S:24][C:20]=5[CH:19]=4)=[N:15][N:16]=3)[N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc2ccc(Sc3nnc4ccc(-c5cccc(F)c5)nn34)cc2s1
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2ccc(Sc3nnc4ccc(-c5cccc(F)c5)nn34)cc2s1

Procedure:
The N-(6-{[6-(3-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-1, benzothiazol-2-yl)acetamide can be prepared according to the method described in Example 18b, but using 100 mg of 6-{[6-(3-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-1,3-benzothiazol-2-amine in 5 cm3 of pyridine and 0.318 cm3 of acetic anhydride at 50° C. for 4 h. 54 mg of N-(6-{[6-(3-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-1,3-benzothiazol-2-yl)acetamide are thus obtained in the form of a white powder, the characteristics of which are as follows:
Reaction SMILES: B.CSC.[CH3:5][C:6]([CH3:13])([CH2:10][O:11][CH3:12])[CH2:7][CH:8]=[CH2:9].[OH-:14].[Na+].OO>CCCCCC.O.C(O)C>[CH3:5][C:6]([CH3:13])([CH2:10][O:11][CH3:12])[CH2:7][CH2:8][CH2:9][OH:14]
Reactant: [OH-]
Reactant: C=CCC(C)(C)COC
Agent: B
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CSC
Solvent: CCCCCC
Product: COCC(C)(C)CCCO
Reaction time: 2 h

Procedure:
Borane-methyl sulphide complex (2.76 ml., 2M solution in tetrahydrofuran, Aldrich) was added to 4,4-dimethyl-5-methoxypent-1-ene (1.9 g.) in dry hexane (50 ml.) under nitrogen at 0°. The mixture was stirred at 20° for 2 hours and ethanol (15 ml.) was added. 2N Aqueous sodium hydroxide solution (6.0 ml.) was then added. The mixture was cooled to 0° and hydrogen peroxide (5.3 ml., 30% aqueous solution) was added dropwise. The mixture was refluxed for 1 hour, cooled and poured into iced water (100 ml.). The aqueous mixture was extracted with diethyl ether. The ethereal extracts were washed with water and dried over anhydrous magnesium sulphate. The solvent was removed in vacuo and 4,4-dimethyl-5-methoxypentan-1-ol was obtained as a colourless oil (1.12 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([NH:13][C:14](=[O:19])[CH2:15][CH2:16][CH2:17]Cl)=[N:10][N:9]=2)=[CH:4][CH:3]=1.N1CCCCC1.O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3=[N:13][C:14](=[O:19])[CH2:15][CH2:16][CH2:17][N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(CCCCl)Nc1nnc(-c2ccc(Br)cc2)s1
Solvent: O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: O=C1CCCN2N=C(c3ccc(Br)cc3)SC2=N1

Procedure:
A mixture of N-[5-(4-bromophenyl)-1,3,4-thiadiazol-2-yl]-4-chlorobutan-amide (1.44 g, 0.004 mol) and piperidine (0.7 g, 0.8 ml, 0.008 mol) in toluene (50 ml) was heated under reflux for 3 h. The reaction mixture was cooled, poured into water and stirred. Toluene was separated dried and evaporated to give a crude product which was purified by repeated silica gel and neutral alumina column chromatography eluting with EtOAc/hexane (50:50 v/v) and CHCl3/hexane (80:20 v/v); mp 204-7° C., m/e 324, 78% (consistent with molecular formula C12H10BrN3OS, calcd. 324.20) 1H NMR CDCl3): δ 2.32-2.40 (m, 2H, —CH2), 2.76 (t, J=7.5 Hz, 2H, —CH2), 4.29 (t, J=7.5 Hz, 2H, —CH2), 7.62-7.84 (dd, J=8.5 Hz, 4H, ArH). 13C NMR: δ 18.3, 31.2, 47.9, 125.0, 128.7, 129.5, 132.3, 157.5, 162.9, 173.7.
Reaction SMILES: Cl([O-])=O.[Na+].P([O-])(O)(O)=[O:6].[Na+].[CH2:11]([N:13]1[C:17]([CH:18]=[O:19])=[C:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[NH:33][S:34]([C:37]([F:40])([F:39])[F:38])(=[O:36])=[O:35])=[CH:23][CH:22]=2)[C:15]([CH2:41][CH2:42][CH3:43])=[N:14]1)[CH3:12].CC(=CC)C>O.C(O)(C)(C)C.C1COCC1>[CH2:11]([N:13]1[C:17]([C:18]([OH:6])=[O:19])=[C:16]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[NH:33][S:34]([C:37]([F:38])([F:40])[F:39])(=[O:35])=[O:36])=[CH:25][CH:26]=2)[C:15]([CH2:41][CH2:42][CH3:43])=[N:14]1)[CH3:12]
Reactant: CCCc1nn(CC)c(C=O)c1Cc1ccc(-c2ccccc2NS(=O)(=O)C(F)(F)F)cc1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CCCc1nn(CC)c(C(=O)O)c1Cc1ccc(-c2ccccc2NS(=O)(=O)C(F)(F)F)cc1
Reaction time: 3 h
Yield: 56.3 %

Procedure:
A solution of sodium chlorite (0.4 g) and sodium dihydrogen orthophosphate (2.56 g) in water (5 ml) was added to a solution of the product of Example 88 (430 mg) and 2-methyl-2-butene (4.5 ml, 2M solution in THF) in t-butanol (5 ml) and THF (10 ml) and the resulting mixture stirred for 3 h. Solvent was removed in vacuo, the residue taken up in dichloromethane (10 ml) and washed with water (10 ml). 2N Sodium hydroxide (10 ml) was added to the organic solution and the organic layer removed. 2N Hydrochloric acid (~11 ml) was added to the aqueous phase which was then extracted with ethyl acetate (2×15 ml). The dried organic extracts were evaporated in vacuo to give a yellow gummy solid which was recrystaltised from System D (1:1) to give the title compound as a white solid (250 mg) m.p. 68°-72° C.
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[C@@H:5]([OH:8])[C@H:4]([OH:9])[C@@H:3]([OH:10])[C@@H:2]1O>O>[OH:10][C@@H:3]1[C@@H:4]([OH:9])[C@H:5]([OH:8])[C:6](=[O:7])[CH:1]=[CH:2]1
Reactant: O=C1C[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O
Solvent: O
Product: O=C1C=C[C@H](O)[C@@H](O)[C@@H]1O
Yield: 41.4 %

Procedure:
1.64 g of 2-deoxy-scyllo-inosose synthesized according to the method described in WO 2006/112000 and 5 mL of an ion exchange resin IR120B were added to 13.6 mL of water, and the resulting mixture was heated at reflux for 20 hours. After the completion of the reaction, the ion exchange resin was filtered and the filtrate was concentrated under a reduced pressure. The condensation residue was purified with silica gel column (ethyl acetate), whereby 604 mg (yield: 41%) of (4S,5R,6S)-4,5,6-trihydroxy-2-cyclohexene-1-one was obtained.