Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH2:16])=O.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:16]
Reactant: COc1ccc2ncc(C(N)=O)c(Cl)c2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2ncc(C#N)c(Cl)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
To a solution of 4-chloro-6-(methyloxy)-1,5-naphthyridine-3-carboxamide (647 mg, 2.7 mmol) in anhydrous DCM (2 mL) with triethyamine (2 mL) at 0° C. was added trifluororacetic anhydride (1 mL) slowly. The resulting solution was warmed up to 25° C. and stirred for 1 h. The mixture was partitioned between CHCl and H2O. The aqueous layer was extracted several times with CHCl. The organic fractions were combined, concentrated and purified with column chromatography (silica, 0-25% ethyl acetate/hexane) affording the title compound as an off-white solid (540 mg, 91%): LC/MS (ES) m/e 220 (M+H)+.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([C:13]([OH:15])=[O:14])[C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=1)[CH2:2][CH3:3].C(OC(=O)C)(=O)C.C([O-])(=O)C.[Na+]>>[CH2:1]([C:4]1[CH:5]=[C:6]2[C:13](=[O:14])[O:15][C:10](=[O:12])[C:7]2=[N:8][CH:9]=1)[CH2:2][CH3:3]
Reactant: CCCc1cnc(C(=O)O)c(C(=O)O)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CCCc1cnc2c(c1)C(=O)OC2=O

Procedure:
2 g of 5-propylpyridine-2,3-dicarboxylic acid together with 25 ml of acetic anhydride and 2 g of anhydrous sodium acetate are heated for 1 hour at 70° C. After removal of the acetic anhydride by evaporation, the residue is partitioned between water and chloroform and the organic phase is dried over MgSO4 and then concentrated by evaporation. The residue is crystallised from ether/hexane, affording 5-propylpyridine-2,3-dicarboxylic anhydride with a melting point of 42°-44° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH:12]=1)(=O)=O.[CH:22]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)([CH3:24])[CH3:23].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:22]([C:25]1[CH:30]=[C:29]([C:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH:12]=2)[CH:28]=[CH:27][CH:26]=1)([CH3:24])[CH3:23]
Reactant: CC(C)c1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)c1cccc(C2=CCN(C(=O)OC(C)(C)C)CC2)c1

Procedure:
A mixture of tert-butyl 4-[(trifluoromethyl)sulfonyl]oxy-3,6-dihydropyridine-1(2H)-carboxylate (11.0 g, 0.0332 mol), (3-isopropylphenyl)boronic acid (5.44 g, 0.0332 mol) and potassium phosphate (21.1 g, 0.0996 mol) in tetrahydrofuran (150.0 mL, 1.849 mol) was degassed for 15 min, then tetrakis(triphenylphosphine)palladium(0) (2 g, 0.002 mol) was added and the resulting mixture was refluxed overnight. After evaporation of most of THF, the residue was diluted with water, extracted with EtOAc. The combined organic layers were washed with brine, dried and evaporated to dry. The residue was applied on silica gel column, eluting with 0 to 20% EtOAc in hexane (9.1 g, 91%). MS (ESI): (M−Bu) 246.1.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[C:24]([O:25][CH3:26])=[CH:23][C:8]2[S:9][C:10]([CH:21]=[O:22])=[C:11]([O:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:7]=2[CH:6]=1>CO>[CH3:3][O:4][C:5]1[C:24]([O:25][CH3:26])=[CH:23][C:8]2[S:9][C:10]([CH2:21][OH:22])=[C:11]([O:12][C:13]3[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)[C:7]=2[CH:6]=1
Reactant: COc1ccc(Oc2c(C=O)sc3cc(OC)c(OC)cc23)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(Oc2c(CO)sc3cc(OC)c(OC)cc23)cc1

Procedure:
26 mmol of NaBH4 are added at room temperature to a solution of 24 mmol of the compound obtained in Step E of Example 1 in 100 ml of methanol. After 2 hours' reaction, one equivalent of NaBH4 is added to the reaction mixture. After 12 hours' reaction, the solution is concentrated and then diluted with ethyl acetate, washed with a 1N HCl solution, then with water and then with a saturated NaCl solution, subsequently dried over calcium sulphate, filtered and concentrated under reduced pressure. Chromatography over silica gel (dichloromethane/ethyl acetate: 95/5) enables 6.07 g of the expected product to be isolated.
Reaction SMILES: [CH2:1]1[O:3][CH:2]1[CH2:4]O.[Si](O[Si](C(C)(C)C)(C)C)(C(C)(C)C)(C)C.[N+]([C:24]1[NH:25][CH:26]=[C:27]([N+]([O-])=O)[N:28]=1)([O-])=O.[SiH3]OO.O1C=CCCC1>>[N:28]1[C:27]2=[CH:4][CH:2]=[CH:1][O:3][C:26]2=[N:25][CH:24]=1
Reactant: O=[N+]([O-])c1c[nH]c([N+](=O)[O-])n1
Reactant: OCC1CO1
Agent: C1=COCCC1
Agent: CC(C)(C)[Si](C)(C)O[Si](C)(C)C(C)(C)C
Agent: OO[SiH3]
Product: c1coc2ncnc-2c1

Procedure:
According to this process, the compound (B) obtained starting from glycidol and t-butyldimethylsilyl ether is reacted with 2,4-dinitroimidazole, and after protecting the hydroxy group of the resulted siloxy alcohol (C) with dihydropyran, the tetrahydropyranyl (THP) ether compound (D) is subjected to desilylation and cyclization to form imidazopyran skeleton (E) and then, the imidazopyran derivative (F) is obtained by removal of THP group.
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH:11]=[C:10]2[CH2:12][CH:13]=[CH:14][CH:15]=[C:9]2[O:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2)=[O:4].[OH:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C(OCC)(=O)C>[CH2:12]1[C:10]2=[CH:11][N:5]([C:3](=[O:4])[CH2:2][O:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:29][CH:30]=3)[C:6]3[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=3[O:8][C:9]2=[CH:15][CH:14]=[CH:13]1
Reactant: O=C(CBr)N1C=C2CC=CC=C2Oc2ccccc21
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OCC(=O)N2C=C3CC=CC=C3Oc3ccccc32)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 32.4 %

Procedure:
Title compound 455 (0.890 g, 2.81 mmol) and the methyl 4-hydroxybenzoate (0.512 g, 3.37 mmol) were dissolved in acetonitile (10.0 mL) and the cesium carbonate (1.83 g, 5.62 mmol) was added. The reaction mixture was stirred at 100° C. in a sealed tube for 4 hours. The mixture was cooled down to room temperature and diluted with ethyl acetate. The organic layer was washed with water (2 times) and brine, dried over sodium sulfate, filtered and evaporated. The crude was purified by flash chromatography (30-40% ethyl acetate in hexanes) to afford title compound 456 (355 mg, 32%) as white foam. MS (m/z): 390.3 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[OH:11])([O-:3])=[O:2].[C:12]([O:16][C:17](=[O:31])[NH:18][CH2:19][CH:20](O)[CH2:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])([CH3:15])([CH3:14])[CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)(C)C)=O)=O)(C)(C)C>C1COCC1>[C:12]([O:16][C:17](=[O:31])[NH:18][CH2:19][CH:20]([O:11][C:5]1[CH:6]=[C:7]([F:10])[CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[CH2:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])([CH3:14])([CH3:15])[CH3:13]
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: CC(C)(C)OC(=O)NCC(O)CNC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(CNC(=O)OC(C)(C)C)Oc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Nitro-5-fluorophenol (8.4 g) and (3-tert-butoxycarbonylamino-2-hydroxy-propyl)-carbamic acid tert-butyl ester (17.0 g) were dissolved in THF (60 ml) and triphenylphosphine (21 g) and di-tert-butyl-azodicarboxylate (18.4 g) were added. The exothermic reaction was cooled in an ice bath. Then the mixture was stirred at room temperature overnight. It was concentrated in vacuo and the residue was dissolved in dichloromethane, washed with water and 1M NaOH. The organic layer was dried and concentrated in vacuo. The residue was purified by chromatography (silica/dichloromethane:methanol 25:1).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:32])[CH:12]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:31])([F:30])[CH:27]([F:29])[F:28])[CH:20]=2)[C:13]([O:15]CC)=[O:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[OH-].[Na+].Cl>C(O)C>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([OH:32])[CH:12]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:30])([F:31])[CH:27]([F:28])[F:29])[CH:20]=2)[C:13]([OH:15])=[O:14])=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(S(C)(=O)=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CS(=O)(=O)c1ccc(C(O)C(Cc2cccc(OC(F)(F)C(F)F)c2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl (2RS,3RS)-3-[4-(methylsulfonyl)phenyl]-3-hydroxy-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoate (2.55 g, 5.33 mmol) in ethanol (20 ml) was added 1N aqueous sodium hydroxide solution (10.7 ml, 10.7 mmol) and the mixture was stirred at room temperature for 1 hr. 1N Hydrochloric acid (30 ml) was added to acidify the reaction solution and the mixture was extracted with ethyl acetate (100 ml). The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give the objective substance (2.30 g, 96%) as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7]2)([O-:3])=[O:2].[CH3:13][S:14](Cl)(=[O:16])=[O:15].C(N(CC)CC)C.O>ClCCl>[CH3:13][S:14]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH2:7][CH2:8]1)(=[O:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc2c(c1)CCN2
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)N1CCc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
To a solution of 300 mg (1.83 mmol) of 5-nitroindoline in 20 mL of dichloromethane were added 141 μL (2.74 mmol) of methanesulfonyl chloride and 382 μL (2.74 mmol) of triethylamine, and the mixture was stirred for 2 hours at room temperature. 141 μL (2.74 mmol) of methanesulfonyl chloride and 255 μL (1.83 mmol) of triethylamine were further added to the reaction mixture, and the mixture was stirred for 2 hours at room temperature. Then, water was added to the reaction mixture and the mixture was extracted with dichloromethane. The organic layer was washed with saturated saline solution and dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was treated with diethyl ether, then, the precipitates were collected by filtration to give 410 mg (92%) of the title compound.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[C:5]1[N:10]=[C:9]([N:11]([CH2:14][C:15]2[S:19][C:18]([Cl:20])=[N:17][CH:16]=2)[CH2:12][CH3:13])[C:8]([N+:21]([O-:23])=[O:22])=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][N:2]([CH3:3])[C:5]1[N:10]=[C:9]([N:11]([CH2:14][C:15]2[S:19][C:18]([Cl:20])=[N:17][CH:16]=2)[CH2:12][CH3:13])[C:8]([N+:21]([O-:23])=[O:22])=[CH:7][CH:6]=1
Reactant: CCN(Cc1cnc(Cl)s1)c1nc(Cl)ccc1[N+](=O)[O-]
Reactant: CNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(Cc1cnc(Cl)s1)c1nc(N(C)C)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 32 %

Procedure:
1.15 g of 33% aqueous dimethylamine solution, 10 mL of N,N-dimethylformamide (DMF) and 2.80 g of 6-chloro-N-((2-chloro-thiazole-5-yl)methyl)-N-ethyl-3-nitropyridin-2-amine, prepared according to the example 1, in 5 mL of DMF were added into a 100 mL three-necked flask equipped with a magnetic stirrer, a condenser and a drying tube, under stirring at room temperature, 1.40 g of potassium carbonate was added in batches. Reacted at the room temperature until the reaction was complete. The reaction solution was treated by the method according to example 1 to obtain 0.92 g of 6-dimethylamino-N-((2-chlorothiazole-5-yl)methyl)-N-ethyl-3-nitropyridine-2-amine, the content of 98.0%, as a golden yellow solid in a yield of 31.4%, mp: 74.6-78.4° C., GC-MS (M+) (EI, 70 eV, m/z) calc: 341. found: 341. 1H NMR (CDCl3/TMS, 300 MHz) δ (ppm) 1.193 (t, J=7.2 Hz, 3H, CH3), 3.192 (s, 6H, 2*CH3), 3.216 (q, J=7.2 Hz, 2H, CH2), 4.811 (s, 2H, CH2), 6.022 (d, J=9.0 Hz, 1H, Py H), 7.458 (s, 1H, thiazole-H), 8.165 (d, J=9.0 Hz, 1H, Py H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:26][CH2:27][N:28]3[C@H:33]4[CH2:34][CH2:35][C@@H:29]3[CH2:30][CH:31]([N:36]3[C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=5[N:38]=[C:37]3[CH3:45])[CH2:32]4)[CH2:13][CH2:12][N:11]([CH:14]([CH3:25])[C:15]([O:17]CC3C=CC=CC=3)=[O:16])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[H][H]>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:26][CH2:27][N:28]3[C@H:33]4[CH2:34][CH2:35][C@@H:29]3[CH2:30][CH:31]([N:36]3[C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=5[N:38]=[C:37]3[CH3:45])[CH2:32]4)[CH2:13][CH2:12][N:11]([CH:14]([CH3:25])[C:15]([OH:17])=[O:16])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(C)C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(C)C(=O)O)CC1
Yield: 77.8 %

Procedure:
A solution of benzyl 2-(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)propanoate (136 mg, 0.223 mmol) in 8 mL MeOH was stirred for 3 h under an atmospheric pressure of hydrogen and in the presence of catalytic 5% Pd/C. Filtration and evaporation afforded 2-(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)propanoic acid (90.0 mg, 78%) as a solid. 1H NMR (400 MHz, CDCl3), δ 7.69 (m, 1H), 7.40 (m, 1H), 7.26-7.12 (m, 4H), 7.09-6.95 (m, 2H), 5.37 (m, 1H), 3.85-3.55 (m, 5H), 2.81-1.77 (18H), 2.62 (s, 3H), 1.61-1.41 (3H); ESI-MS 517 (M−H).
Reaction SMILES: [NH2:1][C:2]1[N:17]=[CH:16][C:15]([Br:18])=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13])=[O:5].[CH2:19](OC(OCC)OCC)C>>[Br:18][C:15]1[CH:16]=[N:17][C:2]2[N:1]=[CH:19][N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[F:13])[C:4](=[O:5])[C:3]=2[CH:14]=1
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccccc1F
Reactant: CCOC(OCC)OCC
Product: O=c1c2cc(Br)cnc2ncn1-c1ccccc1F
Temperature: 130 °C
Reaction time: 15 h
Yield: 97 %

Procedure:
A mixture of 2-amino-5-bromo-N-(2-fluorophenyl)nicotinamide (100 mg, 0.32 mmol) and triethoxymethane (5 mL) was stirred at 130° C. for 15 h. The mixture was cooled to room temperature and extracted with ethyl acetate (10 mL*3), the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford 6-bromo-3-(2-fluorophenyl)pyrido[2,3-d]pyrimidin-4(3H)-one (100 mg, 97% yield), which was used for the next step without further purification. MS (M+H)+:320/322.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH:8]([CH2:11][OH:12])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>>[CH3:23][C:13]1[CH:18]=[CH:17][C:16]([S:19]([O:12][CH2:11][CH:8]2[CH2:7][C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[C:10]=3[O:9]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: OCC1Cc2cccc(Br)c2O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Yield: 80.5 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methanol (49.0 g, 0.214 mol) with p-toluenesulfonyl chloride (44.9 g, 0.235 mol) generally according to the procedure described for Intermediate 10 gave 66.00 g (80%) (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. Rf=0.44 (silica, ethyl acetate:hexanes 1:4); mp 120-122° C.; Anal. calcd. for C16H15BrO4S: C, 50.14; H, 3.94. Found: C, 48.47; H, 4.03.
Reaction SMILES: S([O:6][CH3:7])(OC)(=O)=O.CSC.C[O-].[Na+].[Cl:14][C:15]1[CH:35]=[CH:34][C:18]([CH2:19][C:20]2([C:23]([CH2:25][O:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)=O)[CH2:22][CH2:21]2)=[CH:17][CH:16]=1>C(#N)C.O>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([O:26][CH2:25][C:23]2([C:20]3([CH2:19][C:18]4[CH:17]=[CH:16][C:15]([Cl:14])=[CH:35][CH:34]=4)[CH2:22][CH2:21]3)[CH2:7][O:6]2)=[CH:32][CH:31]=1
Reactant: COS(=O)(=O)OC
Reactant: O=C(COc1ccc(Cl)cc1)C1(Cc2ccc(Cl)cc2)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CSC
Solvent: CC#N
Product: Clc1ccc(CC2(C3(COc4ccc(Cl)cc4)CO3)CC2)cc1
Temperature: 20 °C
Reaction time: 48 h
Yield: 80.2 %

Procedure:
21 g (0.17 mol) of dimethyl sulphate are added dropwise with stirring at 20° C. to a solution of 10.5 g (0.17 mol) of dimethyl sulphide in 100 ml of acetonitrile. After standing for 2 days at 20° C., 9.2 g (0.17 mol) of sodium methoxide is added to this solution, the mixture is stirred for 30 minutes at 20° C. and then 29 g (0.09 mol) of 4-chlorophenoxymethyl 1-(4-chlorobenzyl)cycloprop-1-yl ketone are added. After stirring for 16 hours at 20° C., the reaction mixture is poured into water and the mixture is extracted with methylene chloride. The organic phase is washed with water, dried over magnesium sulphate and concentrated under reduced pressure. 25.2 g (80% of theory) of 2-(4-chlorophenoxymethyl)-2-[(4-chlorobenzyl)cycloprop-1-yl]-oxirane are obtained in the form of a colorless oil which is employed for further synthesis without additional purification. ##STR14##
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:31][CH2:30][CH2:29][C@@:16]3([C:20](=[O:21])[N:19]([C@H:22]4[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24][CH2:23]4)[CH2:18][CH2:17]3)[CH2:15]2)=[N:12][CH:13]=1.O[C@H]1CC[C@H](N2CC[C@:41]3([CH2:48][CH2:47][CH2:46][NH:45][CH2:44]3)C2=O)CC1.N1C=CC(B(O)O)=CC=1.C1(C)C=CC=CC=1.C(O)C>O.CN1C(=O)CCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N:12]1[C:11]([N:14]2[CH2:31][CH2:30][CH2:29][C@@:16]3([C:20](=[O:21])[N:19]([C@H:22]4[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24][CH2:23]4)[CH2:18][CH2:17]3)[CH2:15]2)=[CH:10][CH:9]=[C:8]([C:48]2[CH:47]=[CH:46][N:45]=[CH:44][CH:41]=2)[CH:13]=1
Reactant: O=C1N([C@H]2CC[C@H](O)CC2)CC[C@]12CCCN(c1ccc(Br)cn1)C2
Reactant: O=C1N([C@H]2CC[C@H](O)CC2)CC[C@]12CCCNC2
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: OB(O)c1ccncc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C1N([C@H]2CC[C@H](O)CC2)CC[C@]12CCCN(c1ccc(-c3ccncc3)cn1)C2
Temperature: 120 °C

Procedure:
Sodium carbonate (10.6 mg, 0.000100 mol) in water (0.10 mL) was added to a mixture of (5S)-7-(5-bromopyridin-2-yl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one (20.4 mg, 0.0000500 mol) which was prepared by using a procedure that was analogous to the one described for the synthesis of example 93 starting from (5S)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one in NMP (0.25 mL), 4-pyridinylboronic acid (9.22 mg, 0.0000750 mol) and tetrakis(triphenylphosphine) palladium(0) (1.7 mg, 0.0000015 mol) in toluene (200.0 μL, 0.001878 mol) and ethanol (100.000 μL, 1.71267E-3 mol). The resulting mixture was heated at 120° C. for 20 min. The mixture was filtered and the filtrate was diluted with methanol and adjusted to pH=2 with TFA. The resulting solution was purified by prep.-HPLC to give the desired product. LC-MS: 407.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].P(Br)(Br)[Br:14]>C1(C)C=CC=CC=1>[Br:14][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(CO)ccc1F
Reactant: BrP(Br)Br
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(CBr)ccc1F
Temperature: 25 °C
Yield: 81 %

Procedure:
(4-Fluoro-3-nitro-phenyl)-methanol (100 mg, 0.58 mmol) was dissolved in toluene (1 ml) under nitrogen. PBr3 (225 mg, 0.83 mmol) was added and the reaction was allowed to stir at room temperature. The solvent was removed under vacuum. The reaction mixture was partitioned between ethyl acetate and brine. The organic layer was washed with brine two additional times, dried over MgSO4, and the solvent removed to yield the title product as a yellow oil (110 mg (81%), 0.47 mmol). 1H NMR (DMSO-d6): δ=8.04 (s, 1H), 7.68 (d, J=7.5 Hz, 1H), 7.38 (d, J=7.5 Hz, 1H), 3.85 (d, J=4.5 Hz, 2H).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[O:24])[CH:15]=[CH:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[N:21][CH:22]=3)=[CH:8][CH:9]=[C:4]2[CH2:3][CH2:2]1.CO.[BH4-].[Na+]>C1COCC1>[NH:1]1[C:5]2=[N:6][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([OH:24])[CH:15]=[CH:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[N:21][CH:22]=3)=[CH:8][CH:9]=[C:4]2[CH2:3][CH2:2]1
Reactant: Cc1ncc(C=CC(=O)CCCCc2ccc3c(n2)NCC3)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ncc(C=CC(O)CCCCc2ccc3c(n2)NCC3)cn1
Yield: 96.2 %

Procedure:
A solution of the enone 23-8 (0.400 g, 1.24 mmol) in THF:MeOH (5 mL each) was treated with NaBH4 (0.047 g, 1.24 mmol). The reaction was quenched with acetone (2 mL), concentrated in vacuo, partitioned between water (5 mL) and chloroform (5 mL), and extracted with chloroform (4×10 mL). The organics were combined, dried (Na2SO4), and concentrated in vacuo to afford 0.387 g (96% yield) of 23-9.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].FC(F)(F)C1C=CC(S(NC2C=CC3C[C@@H]4[C@H](CCCN4C(=O)CC)CC=3C=2)(=O)=O)=CC=1.[F:39][C:40]([F:70])([F:69])[C:41]1[CH:46]=[CH:45][C:44]([S:47]([NH:50][C:51]2[CH:68]=[CH:67][C:54]3[CH2:55][C@@H:56]4[C@@H:61]([CH2:62][C:53]=3[CH:52]=2)[N:60]([C:63](=O)[CH2:64][CH3:65])[CH2:59][CH2:58][CH2:57]4)(=[O:49])=[O:48])=[CH:43][CH:42]=1.O>O1CCCC1>[F:70][C:40]([F:39])([F:69])[C:41]1[CH:42]=[CH:43][C:44]([S:47]([NH:50][C:51]2[CH:68]=[CH:67][C:54]3[CH2:55][C@@H:56]4[C@@H:61]([CH2:62][C:53]=3[CH:52]=2)[N:60]([CH2:63][CH2:64][CH3:65])[CH2:59][CH2:58][CH2:57]4)(=[O:48])=[O:49])=[CH:45][CH:46]=1
Reactant: CCC(=O)N1CCC[C@@H]2Cc3ccc(NS(=O)(=O)c4ccc(C(F)(F)F)cc4)cc3C[C@H]21
Agent: CCC(=O)N1CCC[C@@H]2Cc3cc(NS(=O)(=O)c4ccc(C(F)(F)F)cc4)ccc3C[C@H]21
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CCCN1CCC[C@@H]2Cc3ccc(NS(=O)(=O)c4ccc(C(F)(F)F)cc4)cc3C[C@H]21
Temperature: 10 °C
Reaction time: 0.08 h

Procedure:
To a suspension of 0.035 g of lithium aluminium hydride (0.922 mmol) in 2.5 ml tetrahydrofurane were added at 4° C. a solution of 0.2 g of the 1:1 mixture of trans-4-trifluoromethyl-N-(1-propionyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinolin-7-yl)benzenesulfonamide and trans-4-trifluoromethyl-N-(1-propionyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinolin-8-yl)-benzenesulfonamide (0.429 mmol) in 2.5 ml tetra-hydrofuran. After stirring for 5 minutes at 10° C., 1 mL water was cautiously added, the solvent evaporated and the residue treated with diethyl ether and water. The aqueous phase was reextracted with diethylether, and the combined organic layers dried over magnesium sulfate, filtered and the solvent evaporated under reduced pressure. The crude product was purified via preparative HPLC (compression column, Delta Pack 40 mm diameter) using a gradient consisting of methanol/water/0.1% acetic as eluent; fraction 3, m=31.9 mg (8-isomer), fraction. 4, m=22.4 mg, fractions. 5-7, m=22.5 mg (7-isomer),