Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:21]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=2[F:30])=[CH:20][C:19]([F:31])=[CH:18][C:3]=1[O:4][C:5]1[C:6]([CH3:17])=[C:7]([NH:11][S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])[CH:8]=[CH:9][CH:10]=1.[CH:32]1([S:35](Cl)(=[O:37])=[O:36])[CH2:34][CH2:33]1>N1C=CC=CC=1>[CH2:15]([S:12]([NH:11][C:7]1[C:6]([CH3:17])=[C:5]([CH:10]=[CH:9][CH:8]=1)[O:4][C:3]1[CH:18]=[C:19]([F:31])[CH:20]=[C:21]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=2[F:30])[C:2]=1[NH:1][S:35]([CH:32]1[CH2:34][CH2:33]1)(=[O:37])=[O:36])(=[O:13])=[O:14])[CH3:16]
Reactant: CCS(=O)(=O)Nc1cccc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2N)c1C
Reactant: O=S(=O)(Cl)C1CC1
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1cccc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2NS(=O)(=O)C2CC2)c1C
Reaction time: 16 h
Yield: 68.5 %

Procedure:
185 mg N-(3-{2-amino-5-fluoro-3-[(2-fluoro-4-iodophenyl)amino]phenoxy}-2-methylphenyl)ethanesulfonamide (0.33 mmol, 1 eq.) were dissolved in 3 mL pyridine, and treated with 49 mg cyclopropyl sulfonyl chloride (0.33 mmol, 1 eq.) and stirred at it for 16 h. Further 15 mg cyclopropyl sulfonyl chloride were added and stirring was continued for 4 h. Additional 15 mg cyclopropyl sulfonyl chloride were added and stirring was continued overnight. The reaction mixture was quenched with water, diluted with toluene and concentrated in vacuo. The residue was portioned between water and ethyl acetate, the aqueous layer reextracted with ethyl acetate, the combined organic layers dried, filtered and concentrated in vacuo. Flash column chromatography provided 150 mg of the target compound (64% yield).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C1N2CCN(CC2)C1.CO.[C:20]([O:24][CH2:25][CH3:26])(=[O:23])[CH:21]=[CH2:22]>>[CH2:25]([O:24][C:20](=[O:23])[C:21]([CH:8]([OH:9])[C:7]1[C:2]([CH3:1])=[N:3][CH:4]=[CH:5][CH:6]=1)=[CH2:22])[CH3:26]
Reactant: C=CC(=O)OCC
Reactant: Cc1ncccc1C=O
Agent: C1CN2CCN1CC2
Solvent: CO
Product: C=C(C(=O)OCC)C(O)c1cccnc1C
Temperature: 45 °C
Reaction time: 72 h
Yield: 62 %

Procedure:
To 2-methylpyridine-3-carbaldehyde (5 g, 0.04 mol) in ethyl acrylate (10 mL) were added DABCO (1 g, 0.01 mol) and methanol (1 mL). The reaction mixture was stirred at 45° C. for 3 days. The reaction mixture was then concentrated and purified by column chromatography (SiO2, 60-100% EtOAc/DCM) to give the title compound (62%) as a colourless oil. δH (DMSO-d6) 8.32 (dd, J 4.8, 1.7 Hz, 1H), 7.51 (dd, J 7.7, 1.7 Hz, 1H), 7.17 (dd, J 7.7, 4.8 Hz, 1H), 6.28 (t, J 1.3 Hz, 1H), 5.91 (t, J 1.6 Hz, 1H), 5.78 (d, J 5.0 Hz, 1H), 5.62 (d, J 5.0 Hz, 1H), 4.10-4.00 (m, 2H), 3.29 (s, 3H), 1.10 (t, J 7.0 Hz, 3H). LCMS (ES+) 222 (M+H)+, RT 1.11 minutes.
Reaction SMILES: [H-].[Na+].[CH3:3][C@@:4]1([C:20]([F:23])([F:22])[F:21])[CH2:19][N:7]2[C:8](=[O:18])[CH:9]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:11]=[C:6]2[NH:5]1.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:3][C@@:4]1([C:20]([F:23])([F:21])[F:22])[CH2:19][N:7]2[C:8](=[O:18])[CH:9]=[C:10]([N:12]3[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)[N:11]=[C:6]2[N:5]1[C:24]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:31]
Reactant: C[C@@]1(C(F)(F)F)Cn2c(nc(N3CCOCC3)cc2=O)N1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@]1(C(F)(F)F)Cn2c(nc(N3CCOCC3)cc2=O)N1C(=O)c1ccccc1

Procedure:
14.2 mg of sodium hydride are added to a solution of 150 mg of (2S)-2-methyl-7-morpholin-4-yl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]-pyrimidin-5-one (Example 1j), in 3 ml of tetrahydrofuran. After stirring for 25 minutes at a temperature in the region of 20° C., 0.092 ml of benzoyl chloride is added. The reaction medium is stirred for 1 hour at ambient temperature before the addition of 1.5 ml of a saturated solution of sodium bicarbonate and ethyl acetate. The organic phase is successively separated, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate, filtered, and then concentrated under reduced pressure. After purification by silica column chromatography (eluent: dichloromethane/methanol: 98/02), 49 mg of (2S)-2-methyl-7-(morpholin-4-yl)-1-(phenylcarbonyl)-2-(trifluoromethyl)-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)one are obtained in the form of a brown solid, the characteristics of which are the following:
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C:11]([C:12]([CH3:23])([CH3:22])[C:13](=[O:21])[CH2:14][CH2:15]1)=[CH:10][CH2:9]3.[OH2:24]>C1COCC1>[CH3:22][C:12]1([CH3:23])[C@@H:13]([OH:21])[CH2:14][CH2:15][C@@:16]2([CH3:17])[CH:11]1[C@@H:10]([OH:24])[CH2:9][C@@H:8]1[C@@H:18]2[CH2:19][CH2:20][C@@:3]2([CH3:4])[C@H:5]1[CH2:6][CH2:7][C@@H:2]2[OH:1]
Reactant: O
Reactant: CC1(C)C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](O)[C@@]3(C)CC[C@@H]12
Solvent: C1CCOC1
Product: CC1(C)C2[C@@H](O)C[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CC[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
To a stirred solution of 17β-hydroxy-4,4-dimethylandrost-5-en-3-one (408 mg) in THF (12 ml) at −15° C., under N2, was added 1M BH3.THF complex in THF (6.44 ml). The mixture was then stirred at RT overnight. H2O (5 ml) was cautiously added dropwise followed by NaBO3.4H2O (330 mg). After stirring at RT overnight, the mixture was filtered. The solid was washed with THF and then discarded. The liquid phases were separated and the aqueous layer was saturated with NaCl and extracted with THF (3×200 ml). The combined organic extracts were dried over NaCl and Na2SO4, filtered and evaporated to dryness. The crude product was purified by flash chromatography (SiO2, DCM/MeOH 97/3) to give 4,4-dimethylandrostan-3β,6α,17β-triol (137 mg, 32%).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[NH2:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[C:10]=1[C:11]([O:13][CH3:14])=[O:12].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O>[CH3:1][C:2]([CH3:7])([CH3:6])[C:3]([NH:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[O:4]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COC(=O)c1c(N)cccc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1c(O)cccc1NC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
Trimethylacetyl chloride (3.69 g) was added to a mixture of methyl 2-amino-6-hydroxybenzoate (prepared according to Comess et al, US2004 0167128, 3.99 g) and sodium bicarbonate (2.57 g) in ethyl acetate (77 mL) and water (18 mL). The reaction mixture was stirred at room temperature for 1 hour. A further amount of trimethylacetyl chloride (1.85 g) was added and the mixture was stirred for 1 hour. A further amount of trimethylacetyl chloride (0.920 g) was added and the mixture was stirred for 30 minutes. The mixture was diluted with ethyl acetate, the layers were separated and the organic layer was dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 5-25% to give methyl 2-(2,2-dimethylpropionylamino)-6-hydroxybenzoate (5.79 g) as a white solid.
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.[NH2:10][C:11]1[C:20]2[N:21]=[C:22]([CH2:32][CH3:33])[N:23]([CH2:24][C:25]3([OH:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:19]=2[C:18]2[N:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1.[N:34]1([C:40](Cl)=[O:41])[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>ClCCl>[NH2:10][C:11]1[C:20]2[N:21]=[C:22]([CH2:32][CH3:33])[N:23]([CH2:24][C:25]3([OH:31])[CH2:30][CH2:29][N:28]([C:40]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[O:41])[CH2:27][CH2:26]3)[C:19]=2[C:18]2[N:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CCc1nc2c(N)nc3cccnc3c2n1CC1(O)CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2c(N)nc3cccnc3c2n1CC1(O)CCN(C(=O)N2CCOCC2)CC1
Temperature: -5 °C
Reaction time: 48 h
Yield: 88.3 %

Procedure:
Under a nitrogen atmosphere triethylamine (1.39 mL, 10.0 mmol) was added to a suspension of 4-[(4-amino-2-ethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]piperidin-4-ol dihydrochloride (1.00 g, 2.50 mmol) in dichloromethane (25 mL). The mixture was cooled to −5° C. 4-Morpholinecarbonyl chloride (292 μL, 2.50 mmol) was added and the reaction mixture was allowed to slowly warm to ambient temperature. The reaction mixture was stirred at ambient temperature for 2 days and then at 30° C. for 2 days. More 4-morpholinecarbonyl chloride (30 μL) was added and the reaction mixture was stirred at 30° C. for 5 days. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between chloroform (150 mL) and saturated aqueous sodium carbonate (30 mL). The organic was washed with saturated aqueous sodium carbonate (20 mL) and brine (20 mL), dried over sodium sulfate, filtered, and then concentrated under reduced pressure to provide an off white solid. This material was triturated with acetonitrile, recrystallized from chloroform/hexanes, isolated by filtration, washed with hexanes, and dried under high vacuum at 130° C. to provide 0.97 g of 4-[(4-amino-2-ethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]-1-(morpholin-4-ylcarbonyl)piperidin-4-ol as a white powder, mp>255.0° C. Anal. Calcd for C22H29N7O3.0.25H2O C, 59.51; H, 6.70; N, 22.08. Found: C, 59.32; H, 6.36; N, 22.00.
Reaction SMILES: C([N:8]1[C:12]([NH:13][CH:14]2[CH2:19][CH2:18][CH:17]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:16][CH2:15]2)=[CH:11][N:10]=[N:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+].C(O)(=O)C>[C].[Pd].CO>[Si:21]([O:20][CH:17]1[CH2:18][CH2:19][CH:14]([NH:13][C:12]2[NH:8][N:9]=[N:10][CH:11]=2)[CH2:15][CH2:16]1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(Nc2cnnn2Cc2ccccc2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)OC1CCC(Nc2cnn[nH]2)CC1
Temperature: 60 °C
Reaction time: 16 h
Yield: 65.3 %

Procedure:
A mixture of 1-benzyl-N-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-1H-1,2,3-triazol-5-amine (11.10 g), 10% palladium-carbon (containing water by 50%, 6.66 g), ammonium formate (9.05 g), acetic acid (22 mL) and methanol (220 mL) was stirred at 60° C. for 16 hr under a nitrogen atmosphere. The reaction mixture was filtered, and the solvent was evaporated. The residue was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate-isopropyl alcohol (3:1). The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by basic silica gel chromatography [eluent: hexane/ethyl acetate=70/30→30/70 (volume ratio)] to give the title compound as a colorless oil (5.56 g, 65%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:16](=[O:17])[C:15]([CH3:19])([CH3:18])[NH:14][C:13]1([CH3:21])[CH3:20].[Cl:22]OC(C)(C)C>CO>[Cl:22][N:14]1[C:15]([CH3:19])([CH3:18])[C:16](=[O:17])[N:12]([CH2:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[C:13]1([CH3:21])[CH3:20]
Reactant: CC(C)(C)OCl
Reactant: COCCOCCOCCCN1C(=O)C(C)(C)NC1(C)C
Solvent: CO
Product: COCCOCCOCCCN1C(=O)C(C)(C)N(Cl)C1(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 95.5 %

Procedure:
A solution of 3-(3-(2-(2-methoxyethoxy)ethoxy)propyl)-2,2,5,5-tetramethylimidazolidin-4-one (182 g, 0.60 mmol) in methanol (10 mL) was cooled in ice water for 10 minutes, before neat tert-butyl hypochlorite (0.10 mL, 0.9 mmol, 1.5 equiv.) was added in one portion. High pressure liquid chromatography-mass spectroscopy analysis after 5 minutes showed all starting amine had been consumed. After 20 min, the mixture was concentrated in vacuo to an oil, which was absorbed on silica (1 g). Chromatography on silica (0-4% methanol in dichloromethane) afforded the title compound as a colorless oil (193 mg, 95%). 1H NMR (400 MHz, CDCl3) δ 3.66-3.62 (m, 4H), 361-3.58 (m, 2H), 3.56-3.53 (m, 2H), 3.51 (t, J=6.0 Hz, 2H), 3.38 (s, 3H), 3.35-3.30 (m, 2H), 1.96-1.88 (m, 2H), 1.45 (s, 6H), 1.33 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 172.6, 82.1, 71.9, 70.59, 70.54, 70.13, 68.6, 65.3, 59.0, 38.2, 29.1, 25.1, 23.5; LRMS (ESI/APCI) m/z 337 [M+H]+.
Reaction SMILES: [F:1][CH:2]([F:27])[N:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[N:14]=[N:15][N:16]([C:19]4[C:20]([F:25])=[N:21][CH:22]=[CH:23][CH:24]=4)[C:17]=3[CH3:18])[CH:9]=2)[C:4]1=[O:26].[H][H]>[C].[Pd].C(O)C>[F:27][CH:2]([F:1])[N:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[N:14]=[N:15][N:16]([C:19]4[C:20]([F:25])=[N:21][CH:22]=[CH:23][CH:24]=4)[C:17]=3[CH3:18])[CH:9]=2)[C:4]1=[O:26]
Reactant: Cc1c(-c2ccc3c(=O)n(C(F)F)ccc3c2)nnn1-c1cccnc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1c(-c2ccc3c(c2)CCN(C(F)F)C3=O)nnn1-c1cccnc1F
Yield: 28.4 %

Procedure:
After adding 20 mg of palladium carbon to 10 ml solution of ethanol with 7 mg of 4-(2-difluoromethyl-1-oxo-isoquinoline-6-yl)-1-(2-fluoropyridine-3-yl)-5-methyl-1H-[1,2,3]triazole, hydrogen was added under 4 atm of hydrogen pressure. 8 hours later, the reaction solution was filtrated and after distilling out the solvents of the filtrate under reduced pressure, the residues were separated and purified by thin-layer chromatography (chloroform/methanol=10/1) to obtain 2 mg of the above compound as a white solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:19])C=1>C(Cl)Cl>[N+:1]1([O-:19])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2ncccc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][n+]1cccc2ccccc21
Reaction time: 24 h
Yield: 90 %

Procedure:
To a 100 mL round bottom flask containing a solution of quinoline (12.2 mmol) in 50 mL of DCM was added 5.3 g of m-CPBA (30.6 mmol). The reaction mixture was stirred for 24 h. The reaction mixture was then diluted DCM (100 mL), washed with 5% NaOH (2×100 mL), dried (MgSO4), filtered, and concentrated in vacuo to give solid quinoline-N-oxide (90-95% yield).
Reaction SMILES: [Cl-].CC([O-])(C)C.[K+].[CH2:8]([CH:11]1[CH2:15][CH2:14][CH:13]([CH:16]2[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]2)[CH2:12]1)[CH2:9][CH3:10].C1[CH2:27][O:26][CH2:25]C1>>[CH3:25][O:26][CH:27]=[C:19]1[CH2:20][CH2:21][CH:16]([CH:13]2[CH2:14][CH2:15][CH:11]([CH2:8][CH2:9][CH3:10])[CH2:12]2)[CH2:17][CH2:18]1
Reactant: CCCC1CCC(C2CCC(=O)CC2)C1
Reactant: C1CCOC1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Product: CCCC1CCC(C2CCC(=COC)CC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
THF (100 ml) was added to methoxymethyltriphenylphophnium chloride (29.3 g) in a reaction vessel under an atmosphere of nitrogen, and the solution was cooled to −15° C. t-BuOK (10.5 g) in a THF (50 ml) solution was added, and the stirring was continued for another 1 hour. 4-(3-Propylcyclopentyl)-cyclohexanone (15.0 g) in a THF (50 ml) solution was added dropwise, and the stirring was continued for another 2 hours. The reaction mixture was warmed to room temperature and was extracted with toluene after the addition of water (200 ml) The resulting organic layer was washed with water and dried over anhydrous sulfate, and the toluene was concentrated to a volume of about 100 ml under reduced pressure. The concentrate was poured into n-hexane (500 ml) and solids deposited were filtered off. The solvent of the resulting solution was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (eluent: ethyl acetate/n-heptane=1/9 by volume) to give 1-methoxymethylene-4-(3-propylcyclopentyl)cyclohexane (17.0 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4](O)[CH2:3]1.[NH:13]1[CH:17]=[CH:16][N:15]=[CH:14]1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.CN(C)C(N=NC(N(C)C)=O)=O>C1(C)C=CC=CC=1.CCCCCCC>[CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)[CH2:3]1
Reactant: CC1(C)CC(O)c2ccccc21
Reactant: c1c[nH]cn1
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: CC1(C)CC(n2ccnc2)c2ccccc21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3,3-dimethyl-indan-1-ol (CAS#38393-92-9, 1.62 g, 1.0 mmol)] in toluene (30 mL) is added imidazole (1.36 g, 20.0 mmol) followed by tri-t-butylphosphine (2.5 mL, 10.1 mmol). The reaction is put at 0° C. and N,N,N′,N′-tetramethylazodicarboxamide (1.72 g, 10 mol) is then added. The reaction is permitted to stir for 10 minutes at 0° C. and then is heated at 60° C. over night. The next morning the reaction is diluted with heptane (30 mL) and filtered. The filtrate is extracted twice with 1 N aqueous HCl. The aqueous extracts are combined, washed with ethyl acetate and then basified (pH>10) by the careful addition of 5 N aqueous NaOH. The aqueous solution is then extracted three times with dichloromethane. The combined organic extracts are dried with Na2SO4. filtered and concentrated. The resulting residue is purified by semi-preparative reverse phase HPLC (15 to 85% acetonitrile/water w/0.1% NH4OH) to afford 1-(3,3-dimethyl-indan-1-yl)-1H-imidazole; HRMS: (ESI) m/z 213.1397 [(M+H)+; calcd for C14H17N2: 213.1392]; 1H NMR (400 MHz, CDCl3) δ ppm 1.28 (s, 3 H), 1.42 (s, 3 H), 2.11 (dd, J=12.9, 8.3 Hz, 1 H), 2.57 (dd, J=12.9, 7.6 Hz, 1 H), 5.72 (t, J=8.1 Hz, 1 H), 6.86 (s, 1 H), 7.01 (d, J=8.3 Hz, 1 H), 7.09 (s, 1 H), 7.19-7.29 (m, 2 H), 7.35 (t, J=7.5 Hz, 1 H), 7.62 (s, 1 H). The HCl salt of the title compound can be prepared by dissolution in diethyl ether followed by treatment with an excess of 1N HCl in diethyl ether. The resulting heterogeneous solution is concentrated to furnish the HCl salt of 1-(3,3-dimethyl-indan-1-yl)-1H-imidazole.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:21]2=[CH:22][CH:23]=[N:24][CH:25]=[C:20]2[C:5]2[C:6]([OH:19])=[CH:7][C:8]([CH:10]([CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:11])=[CH:9][C:4]=2[O:3]1.[ClH:27].[N:28]1([CH2:34][CH2:35][CH2:36][CH2:37][C:38](O)=[O:39])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C1(N=C=NC2CCCCC2)CCCCC1>>[ClH:27].[CH3:26][C:2]1([CH3:1])[C:21]2=[CH:22][CH:23]=[N:24][CH:25]=[C:20]2[C:5]2[C:6]([O:19][C:38](=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34][N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:7][C:8]([CH:10]([CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:11])=[CH:9][C:4]=2[O:3]1
Reactant: O=C(O)CCCCN1CCCCC1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Product: CCCCCC(C)C(C)c1cc(OC(=O)CCCCN2CCCCC2)c2c(c1)OC(C)(C)c1ccncc1-2

Procedure:
5,5-Dimethyl-8-(3-methyl-2-octyl)-10-[5-(piperidino)valeryloxy]-5H-[1]benzopyrano[3,4-d]pyridine hydrochloride is prepared according to the method of Example 29 by reacting equimolar quantities of 5,5-dimethyl-10-hydroxy-8-(3-methyl-2-octyl)-5H-[1]benzopyrano[3,4-d]pyridine and δ-piperidinovaleric acid hydrochloride in the presence of dicyclohexyl carbodiimide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][C:8](=[O:22])[CH2:9][C@H:10]([OH:21])[CH2:11][O:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.O>[C:1]([O:5][C:6](=[O:23])[CH2:7][C@@H:8]([OH:22])[CH2:9][C@H:10]([OH:21])[CH2:11][O:12][C:13](=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)C[C@H](O)COC(=O)c1ccccc1
Reactant: [H][H]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)C[C@@H](O)C[C@H](O)COC(=O)c1ccccc1
Temperature: 50 °C
Yield: 82.3 %

Procedure:
To (S)-6-benzoyloxy-3-oxo-5-hydroxyhexanoic acid tert-butylester (161 mg, 0.50 mmol) and RuBr2(S)-BINAP (4.4 mg, 0.0050 mmol) (BINAP was 2,2′-bisdiphenylphosphino-1,1′-binaphthyl), 2 mL of a methanol-water (10/1) solution was added to completely dissolve the (S)-6-benzoyloxy-3-oxo-5-hydroxyhexanoic acid tert-butylester and RuBr2(S)-BINAP in an argon atmosphere. Hydrogen replacement at −78° C. was performed three times. After the temperature of the resulting mixture had increased to 50° C., the mixture was allowed to react for twenty hours under a hydrogen pressure of 5.0 kg/cm2. After extraction of hydrogen, the mixture was condensed and purified by silica gel column chromatography. As a result, 133.4 mg (82%) of (3S, 5S)-6-benzoyloxy-3,5-dihydroxyhexanoic acid tert-butylester was obtained. The diastereomer ratio determined by high performance liquid chromatography (HPLC) analysis was (3R, 5S):(3S, 5S)=10.4/89.6.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23](O)=[O:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.[NH2:27][CH2:28][C:29](=[O:31])[CH3:30].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([NH:27][CH2:28][C:29](=[O:31])[CH3:30])=[O:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:6][CH:7]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(=O)O)(c2ccccc2)OC1=O
Reactant: CC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)CNC(=O)C[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.9 %

Procedure:
To a solution of 2-((S)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)acetic acid (200 mg, 0.5 mmol) in anhydrous CH2Cl2 (10 mL) was added 1-aminopropan-2-one (119 mg, 0.7 mmol), HOBt (195 mg, 1.44 mmol), EDCl (283 mg, 1.44 mmol) and DIEA (620 mg, 4.8 mol) at 0° C. The formed mixture was stirred overnight at ambient temperature under nitrogen. Then the reaction mixture was washed with 1N aq HCl and water. The organic phase was dried over Na2SO4, filtered and concentrated to afford the residue, which was purified by prep TLC to give 2-((S)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)-N-(2-oxopropyl)acetamide (118 mg, 50%). 1H NMR (400 MHz, CDCl3): δ=1.43 (d, 3H), 2.06 (s, 3H), 2.20 (m, 1H), 2.43 (m, 2H), 2.68 (m, 1H), 2.86 (m, 2H), 3.90 (m, 1H), 4.12 (m, 1H), 5.51 (m, 1H), 6.53 (m, 1H), 6.78 (m, 2H), 7.14 (m, 2H), 7.30 (m, 5H).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([O:11][CH2:12][CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])=[C:9]([O:23][CH3:24])[C:8]([Cl:25])=[C:7]([CH3:26])[C:6]=1[C:27](=[O:29])[CH3:28].[CH:30]1([NH2:35])[CH2:34][CH2:33][CH2:32][CH2:31]1>>[Cl:25][C:8]1[C:7]([CH3:26])=[C:6]([C:27](=[O:29])[CH3:28])[C:5]([O:4][CH2:3][CH2:2][NH:35][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[C:10]([O:11][CH2:12][CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])[C:9]=1[O:23][CH3:24]
Reactant: COc1c(Cl)c(C)c(C(C)=O)c(OCCBr)c1OCCC(C)c1ccc(F)cc1
Reactant: NC1CCCC1
Product: COc1c(Cl)c(C)c(C(C)=O)c(OCCNC2CCCC2)c1OCCC(C)c1ccc(F)cc1

Procedure:
Example 8a (100 mg, 0.21 mmol) was reacted with cyclopentylamine (6.0 eq.) as described under General Procedure G. The title compound was afforded as an oil (65 mg, 65%). 1H NMR (300 MHz, CDCl3) δ 7.17-7.13 (m, 2H), 6.99-6.93 (m, 2H), 4.07 (t, J=5.2 Hz, 2H), 3.92 (t, J=6.7 Hz, 2H), 3.81 (s, 3H), 3.06 (quintet, J=6.6 Hz, 1H), 3.01-2.93 (m, 1H), 2.81 (t, J=5.2 Hz, 2H), 2.46 (s, 3H), 2.16 (s, 3H), 2.03-1.96 (m, 2H), 1.84-1.76 (m, 2H), 1.68-1.49 (m, 4H), 1.33-1.23 (m, 2H), 1.27 (d, J=7.0 Hz, 3H).