Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH2:25][C:24]3[N:26]4[C:17](=[CH:18][N:19]=[C:20]4[CH:21]=[CH:22][CH:23]=3)[C:16]2=[O:27])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:28]>C(O)C>[ClH:28].[ClH:28].[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH2:25][C:24]3[N:26]4[C:17](=[CH:18][N:19]=[C:20]4[CH:21]=[CH:22][CH:23]=3)[C:16]2=[O:27])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2Cc3cccc4ncc(n34)C2=O)CC1
Agent: Cl
Solvent: CCO
Product: O=C1c2cnc3cccc(n23)CN1CC1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
To a solution prepared by dissolving 3.71 g (10.0 mM) of 4,5-dihydro-4-(1-tert-butoxycarbonylpiperidin-4-ylmethyl)-3H-1,4,8b-triazaacenaphthylen-3-one in 50 ml of ethanol was added 4.11 ml of 12N-hydrochloric acid at room temperature. This mixture was stirred at room temperature for 1 hour and the resulting precipitate was recovered by filtration. The precipitate was rinsed with a small amount of ether and dried in vacuo to provide 3.24 g (yield 94.2%) of the title compound as white powders.
Reaction SMILES: [C:1]1(=[O:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:14](=O)([O-])[O-:15].[K+].[K+].C=O>C(#N)C.O>[OH:15][CH2:14][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:1]1=[O:13]
Reactant: O=C1CCCCCCCCCCC1
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C1CCCCCCCCCCC1CO
Temperature: 40 °C
Reaction time: 4 h

Procedure:
To a solution of cyclododecanone (1) (5.0 g, 27.47 mmol, 1 equiv) and potassium carbonate (0.06 g, 0.41 mmol, 0.015 equiv) in acetonitrile (20 mL) and water (2 mL) was added formaldehyde (37% in water) (4.2 mL, 52.20 mmol, 1.9 equiv) at 40° C. dropwise. The reaction was stirred at 40° C. for 4 hours, then cooled to room temperature and extracted with diethyl ether (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, concentrated under reduced pressure. The crude product was purified on an AnaLogix system using a gradient of 0 to 30% ethyl acetate in heptanes to give the desired product as a clear oil, which slowly solidifies to a white solid (2.5 g, 43% yield).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([Cl:19])=[C:9]([CH:18]=1)[C:10]([NH:12][C:13]1[NH:14][CH:15]=[CH:16][N:17]=1)=[O:11].C(N(CC)CC)C.[C:27](Cl)(=[O:31])[CH:28]([CH3:30])[CH3:29]>C1COCC1>[Cl:19][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][NH:3][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])=[CH:18][C:9]=1[C:10]([NH:12][C:13]1[NH:14][CH:15]=[CH:16][N:17]=1)=[O:11]
Reactant: CC(C)C(=O)Cl
Reactant: NCc1ccc(Cl)c(C(=O)Nc2ncc[nH]2)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2ncc[nH]2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.5 %

Procedure:
To a suspension of 5-(aminomethyl)-2-chloro-N-(1H-imidazol-2-yl)benzamide dihydrochloride (50 mg, 0.154 mmol, 1.0 equiv) in THF (0.77 mL), add triethylamine (80 μL, 0.57 mmol, 3.7 equiv) and isobutyryl chloride (16.3 μL, 0.154 mmol, 1.0 equiv), and stir the reaction mixture for 1 h at room temperature. Concentrate the reaction mixture under reduced pressure, triturate the crude solids with a mixture of water (10 mL), hexanes (10 mL), and diethyl ether (10 mL), isolate the white solid by filtration and dry in a 40° C. vacuum oven to give the title compound (19 mg, 38% yield): 1H NMR (DMSO-d6, 400 MHz): δ 11.74 (br s, 2H), 8.30 (t, 1H, J=6.0 Hz), 7.42 (d, 1H, J=8.0 Hz), 7.36 (d, 1H, J=2.0 Hz), 7.26 (dd, 1H, J=8.0, 2.0 Hz), 6.73 (br s, 2H), 4.22 (d, 2H, J=5.9 Hz), 2.37 (septet, 1H, J=6.6 Hz), 0.97 (d, 6H, J=6.8 Hz). MS (m/z) (35Cl/37Cl) 321/323 (M+1).
Reaction SMILES: OC[C@@H](NC(C1C=NC(N2CCCC2)=C(OCCC)N=1)=O)CC(C)C.[CH3:26][O:27][CH2:28][CH2:29][O:30][C:31]1[N:36]=[C:35]([C:37]([OH:39])=O)[CH:34]=[N:33][C:32]=1[N:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1.[CH3:46][O:47][C:48](=[O:55])[C@H:49]([CH2:51][CH:52]([CH3:54])[CH3:53])[NH2:50]>>[CH3:46][O:47][C:48](=[O:55])[C@@H:49]([NH:50][C:37]([C:35]1[CH:34]=[N:33][C:32]([N:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)=[C:31]([O:30][CH2:29][CH2:28][O:27][CH3:26])[N:36]=1)=[O:39])[CH2:51][CH:52]([CH3:54])[CH3:53]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: COCCOc1nc(C(=O)O)cnc1N1CCCCC1
Agent: CCCOc1nc(C(=O)N[C@H](CO)CC(C)C)cnc1N1CCCC1
Product: COCCOc1nc(C(=O)N[C@@H](CC(C)C)C(=O)OC)cnc1N1CCCCC1

Procedure:
In analogy to the procedure described for the synthesis of 6-propoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid ((S)-1-hydroxymethyl-3-methyl-butyl)-amide (example 10, step d) the title compounds was prepared from 6-(2-methoxy-ethoxy)-5-piperidin-1-yl-pyrazine-2-carboxylic acid and (S)-leucine methyl ester (commercially available). m/z (ES+): 409.3 (M+H).
Reaction SMILES: [CH2:1]([CH:8]([CH2:11][N:12]([CH3:14])[CH3:13])[CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.[F:30][C:31]([F:40])([F:39])[C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1.O.O.[C:43]([OH:48])(=[O:47])[C:44]([OH:46])=[O:45]>CCOCC>[C:43]([OH:48])(=[O:47])[C:44]([OH:46])=[O:45].[CH3:13][N:12]([CH2:11][CH:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][O:10][C:35]1[CH:36]=[CH:37][C:32]([C:31]([F:40])([F:39])[F:30])=[CH:33][CH:34]=1)[CH3:14]
Reactant: CN(C)CC(CO)Cc1ccccc1
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(O)C(=O)O
Solvent: CCOCC
Solvent: O
Product: CN(C)CC(COc1ccc(C(F)(F)F)cc1)Cc1ccccc1

Procedure:
A mixture of 2-benzyl-3-dimethylaminopropanol (4.2 g), dicyclohexylcarbodiimide (4.6 g) and cuprous chloride (0.2 g) is maintained at 80° for 40 hours. 4-Trifluoromethylphenol (5.0 g) is added, and the mixture maintained at 130° for 12 hours. The reaction mixture is cooled and ether (100 ml) is added. The insoluble material is filtered off and the filtrate extracted with 2N hydrochloric acid (3×100 ml). The acidic solutions are combined and made basic by the addition of concentrated aqueous ammonia. The aqueous solution is extracted with ether (3×150 ml), and the combined extracts dried over magnesium sulfate and evaporated under reduced pressure to give the ether as a yellow oil. This material is converted to the oxalate salt by dissolving in ether and adding the calculated quantity of oxalic acid dihydrate in ether. Filtration gives N,N-dimethyl-2-benzyl-3-(4-trifluoromethylphenoxy)propylamine oxalate, m.p. 147°-149°.
Reaction SMILES: [F:1][C:2]1[C:3]([C:23]2[N:27]=[CH:26][N:25](C3CCCCO3)[N:24]=2)=[CH:4][C:5]([CH3:22])=[C:6]([C:8]2[N:13]=[C:12]3[N:14]([CH:19]([CH3:21])[CH3:20])[C:15](=[O:18])[CH2:16][NH:17][C:11]3=[N:10][CH:9]=2)[CH:7]=1.C(N1C2=NC([Sn](C)(C)C)=CN=C2NCC1=O)(C)C.BrC1C(C)=CC(C2N=CN(C3CCCCO3)N=2)=C(F)C=1>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[F:1][C:2]1[C:3]([C:23]2[N:27]=[CH:26][NH:25][N:24]=2)=[CH:4][C:5]([CH3:22])=[C:6]([C:8]2[N:13]=[C:12]3[N:14]([CH:19]([CH3:21])[CH3:20])[C:15](=[O:18])[CH2:16][NH:17][C:11]3=[N:10][CH:9]=2)[CH:7]=1
Reactant: Cc1cc(-c2ncn(C3CCCCO3)n2)c(F)cc1-c1cnc2c(n1)N(C(C)C)C(=O)CN2
Agent: Cl[Pd]Cl
Agent: CC(C)N1C(=O)CNc2ncc([Sn](C)(C)C)nc21
Agent: Cc1cc(-c2ncn(C3CCCCO3)n2)c(F)cc1Br
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc[nH]n2)c(F)cc1-c1cnc2c(n1)N(C(C)C)C(=O)CN2
Temperature: 140 °C
Yield: 52 %

Procedure:
7-(5-Fluoro-2-methyl-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)phenyl)-1-isopropyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one. 1-Isopropyl-7-(trimethylstannyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (300 mg, 0.84 mmol), 3-(4-bromo-2-fluoro-5-methylphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazole (428 mg, 1.26 mmol) and bis(triphenylphosphine)palladium(II)dichloride (56 mg, 0.08 mmol) were combined in N,N-dimethylformamide (5 mL). The mixture was degassed and heated at 140° C. under nitrogen for 3 h. After being cooled to room temperature, the reaction mixture was filtered and the filtrate was partitioned between ethyl acetate (15 mL) and water (15 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (10 mL×2). The combined organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure and purified by preparative TLC (15% methanol in dichloromethane) to give the title compound (200 mg, yield 52%) as a solid.
Reaction SMILES: [Cl:1]C1C=CC(O)=CC=1.ClC1C=C(O)C=CC=1Cl.[CH3:18][N:19]1[C:24]([N:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][O:34][C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[CH:36]=3)[CH2:27][CH2:26]2)=[CH:23][C:22](=[O:43])[N:21]([CH3:44])[C:20]1=[O:45]>>[ClH:1].[CH3:18][N:19]1[C:24]([N:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][O:34][C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[CH:36]=3)[CH2:27][CH2:26]2)=[CH:23][C:22](=[O:43])[N:21]([CH3:44])[C:20]1=[O:45]
Reactant: Oc1ccc(Cl)cc1
Agent: Cn1c(N2CCN(CCCOc3ccc(Cl)c(Cl)c3)CC2)cc(=O)n(C)c1=O
Agent: Oc1ccc(Cl)c(Cl)c1
Product: Cl

Procedure:
The same treatment as in Example 3 was effected except that 4-chlorophenol was replaced with 3,4-dichlorophenol, thereby obtaining 10.5 g of the crystals of 1,3-dimethyl-6-[4-(3-[3,4-dichlorophenoxy]propyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: [CH2:1]([C@H:4]1[C@@H:8]([OH:9])[CH2:7][O:6][C:5]1=[O:10])[CH:2]=[CH2:3].N1C=CN=C1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>CN(C)C=O>[CH2:1]([C@H:4]1[C@@H:8]([O:9][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:7][O:6][C:5]1=[O:10])[CH:2]=[CH2:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CC[C@@H]1C(=O)OC[C@@H]1O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C=CC[C@@H]1C(=O)OC[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
The hydroxy lactone of Example 8 (6.0 g, 42.2 mmol) was dissolved in dry dimethylformamide (10 ml) under nitrogen. Imidazole (4.78 g, 70.2 mmol) and then tert-butyldimethylsilyl chloride (7.05 g, 46.80 mmol) were added. The mixture was stirred at room temperature overnight and then partitioned between water (50 ml) and heptane (2×30 ml). The heptane extracts were dried (MgSO4), filtered and evaporated to give the crude product (10.5 g). This was crystallised from heptane (40 ml) at −15° C. to give the title compound as a white solid (7.60 g, 29.6 mmol, 70%); m.p. 48° C. (onset by DSC); Found: C, 61.1; H, 9.5. C13H24O3Si requires C, 60.9; H, 9.4%; vmax (Nujol) 1763 and 1644 cm−1; [α] +88.0° (c=1.0, CH2Cl2); 1HNMR(400 MHz, CDCl3) δ ppm5.94-5.80 (1 H, m), 5.18-5.06(2 H, m), 4.53 (1 H, t, J 3.5), 4.26 (1 H, dd, J 10,3), 4.17 (1 H, d, J 10), 2.60-2.35 (3 H, m), 0.89 (9 H, s), 0.10 (3 H, s) and 0.08 (3 H, s); m/z (GCMS, EI) 199 (M-tBu, 4%) and 117 (100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][NH:10][N:9]=2)=[CH:4][C:3]=1[CH2:13][NH:14][C:15](=[O:18])[O:16][CH3:17].Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]([F:31])([F:30])[F:29])[CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][N:10]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]([F:29])([F:30])[F:31])[CH:22]=3)[N:9]=2)=[CH:4][C:3]=1[CH2:13][NH:14][C:15](=[O:18])[O:16][CH3:17]
Reactant: COC(=O)NCc1cc(-c2cc[nH]n2)ccc1Cl
Reactant: FC(F)(F)Oc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)NCc1cc(-c2ccn(Cc3cccc(OC(F)(F)F)c3)n2)ccc1Cl
Temperature: 100 °C

Procedure:
A mixture of methyl N-[[2-chloro-5-(1H-pyrazol-3-yl)phenyl]methyl]carbamate (i.e. the product of Step B, Example 4) (0.2 g, 0.75 mmol), 1-(bromomethyl)-3-(trifluoromethoxy)benzene (0.765 g, 3.0 mmol) and potassium carbonate (−325 mesh, 0.829 g, 6.0 mmol) in N,N-dimethylformamide (4 mL) was heated at 100° C. overnight and then concentrated under reduced pressure. The resulting residue was purified by medium pressure liquid chromatography (0 to 100% gradient of ethyl acetate in hexanes as eluant) to provide the title compound, a compound of the present invention, as a solid (0.178 g).
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:5].C(=O)([O-])[O-].[Ca+2].[OH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>C(O)C>[OH:25][CH:26]1[CH2:31][CH2:30][N:29]([C:2]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:3]=2[C:4]([C:6]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=2)=[O:5])[CH2:28][CH2:27]1
Reactant: O=C(c1ccc(Cl)cc1)c1cc([N+](=O)[O-])ccc1Cl
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCO
Product: O=C(c1ccc(Cl)cc1)c1cc([N+](=O)[O-])ccc1N1CCC(O)CC1
Yield: 69.6 %

Procedure:
Proceeding as indicated in example 2, with 0.0506 mole (15 g) of 2,4'-dichloro-5-nitro-benzophenone, 0.076 mole (10.5 g) of calcium carbonate and 0.076 mole (76.8 g) of 4-hydroxypiperidine, in 100 cm3 of ethanol, 12.7 g (Yield: 70%) of the expected product are obtained after re-crystallization in ethyl acetate. M.P. 142° C.
Reaction SMILES: [S:1]1[C:9]2[CH:8]([OH:10])[CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.[Br:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](F)=[CH:14][CH:13]=1>>[Br:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([O:10][CH:8]2[CH2:7][NH:6][CH2:5][C:4]3[CH:3]=[CH:2][S:1][C:9]2=3)=[CH:14][CH:13]=1
Reactant: OC1CNCc2ccsc21
Reactant: Fc1ccc(Br)c2ccccc12
Product: Brc1ccc(OC2CNCc3ccsc32)c2ccccc12

Procedure:
The same method as in Example 1 was conducted using 4,5,6,7-tetrahydrothieno[3,2-c]pyridin-7-ol (Reference Example 13) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 1-bromo-4-fluoronaphthalene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH:9]=[O:10])=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[CH:4][N:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[C:7]([CH2:8][CH2:9][OH:10])=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[CH:4][N:3]=1
Reactant: O=CCc1c(Cl)ncnc1-c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCCc1c(Cl)ncnc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.9 %

Procedure:
To a stirred solution of 2-(4-chloro-6-phenylpyrimidin-5-yl)acetaldehyde (450 mg) in dry methanol (10 mL), sodium borohydride (110 mg) was slowly added under nitrogen atmosphere at 0° C. The reaction mixture was stirred at room temperature for 2 hours and solvents were removed under reduced pressure. The resulting oil was diluted with dichloromethane (50 mL), washed with 10% NaHCO3 (10 mL) and brine (10 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to give a residue which was purified by column chromatography using MeOH/CHCl3 (0.2:9.8) as eluent to afford 2-(4-chloro-6-phenylpyrimidin-5-yl)ethanol (340 mg) as colorless oily liquid. 1H NMR (DMSO-d6): δ 2.89-2.94 (t, 2H), 3.53-3.58 (t, 2H), 4.81-4.85 (t, 1H), 7.50-7.61 (m, 5H), 8.92 (s, 1H).
Reaction SMILES: [I:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[CH2:15](O)[CH3:16].OS(O)(=O)=O>C1(C)C=CC=CC=1>[CH2:15]([O:13][C:12](=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][I:1])[CH3:16]
Reactant: CCO
Reactant: O=C(O)CCCCCCCCCCI
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCCCCCCCCI

Procedure:
11-Iodo-undecanoic acid ethyl ester was synthesized according to Bergbreiter, J. Org. Chem., 40/6 (1975) 779. Briefly, 246.6 g 11-Iodo undecanoic acid, 440 ml dry ethanol, 440 ml dry toluol and 5 ml H2SO4 (98%) were combined. The mixture was distilled whereby about 400 ml aceotrope was removed at 75° C. or 76° C., respectively. Then 15 g K2CO3 was added and after 5 min the mixtures was filtered and finally distilled at a bath temperature of 115° C. The resulting brown oil was purified by filtration through a frit filled with silica gel (eluent: acetic acid ethyl ester/petrol ether 1:7). The final product was characterized by 1H-NMR and thin layer chromatography.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8](O/C(/C(OCC)=O)=C\C2C=CC=CC=2F)[O:7][C@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2].[F:39][C:40]1[CH:41]=[C:42]([CH2:46][C:47](=[O:53])[C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH:43]=[CH:44][CH:45]=1.[H-].[Na+].[Br-].C(O[C@@H]1[C@@H](OC(=O)C)[C@@H](OC(=O)C)[C@@H](COC(=O)C)O[C@@H]1O)(=O)C>>[C:1]([O:4][C@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:53]/[C:47](/[C:48]([O:50][CH2:51][CH3:52])=[O:49])=[CH:46]\[C:42]2[CH:43]=[CH:44][CH:45]=[C:40]([F:39])[CH:41]=2)[O:7][C@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(=O)Cc1cccc(F)c1
Reactant: CCOC(=O)/C(=C/c1ccccc1F)O[C@H]1O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)OC[C@H]1O[C@H](O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Br-]
Agent: [H-]
Product: CCOC(=O)/C(=C/c1cccc(F)c1)O[C@H]1O[C@@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 79 %

Procedure:
The title compound was prepared as described for C4 by using ethyl 3-(3-fluorophenyl)-2-oxopropanoate B5 (100 mg, 0.476 mmol), sodium hydride (13 mg, 0.523 mmol) and 2,3,4,6-tetra-O-acetyl-α-D-galactose bromide (196 mg, 0.476 mmol). The compound was isolated in the form of white solid in 79% yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]2[O:26][C:13]3([CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[N:12]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:11](=[O:34])[C:10]=2[CH:35]=1.Cl.COC(=O)/C=C/C1C=C2C(=CC=1)OC1(CCNCC1)CC2=O>>[CH3:1][O:2][C:3](=[O:36])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]2[O:26][C:13]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[N:12]([CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:11](=[O:34])[C:10]=2[CH:35]=1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)N(Cc1ccccc1)C1(CCN(C(=O)OC(C)(C)C)CC1)O2
Agent: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCNCC1)O2
Agent: Cl
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)N(Cc1ccccc1)C1(CCNCC1)O2
Yield: 97.5 %

Procedure:
(E)-3-{1′-Tert-butoxycarbonyl-3,4-dihydro-3-benzyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid methyl ester (900 mg, 1.83 mmol) was deprotected with HCl according to the procedure for preparation of Intermediate 1, Step C, giving (E)-3-{3,4-dihydro-3-benzyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid methyl ester (700 mg) as its hydrochloride salt.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:21])=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13].[N:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:21][C:35]2[CH:36]=[CH:37][N:32]=[CH:33][CH:34]=2)=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1)=[O:13]
Reactant: OB(O)c1ccncc1
Reactant: COc1c(C)c(Cc2ccc(O)c(C(=O)N3CCOCC3)c2)c(OC)c(OC)c1OC
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1c(C)c(Cc2ccc(Oc3ccncc3)c(C(=O)N3CCOCC3)c2)c(OC)c(OC)c1OC
Yield: 29.3 %

Procedure:
N-[5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-hydroxybenzoyl]morpholine (0.150 g, 0.348 mmol) was dissolved in methylene chloride (3.5 ml) and after adding thereto in sequence copper acetate (0.070 g, 0.383 mmol), 4-pyridylboronic acid (0.086 g, 0.696 mmol), Molecular Sieves 4A (0.150 g), triethylamine (0.088 g, 0.870 mmol) and pyridine (0.069 g, 0.870 mmol), the solution was stirred at room temperature for 12 hours. The reaction solution was filtered and the filtrate was poured into water and then extracted with methylene chloride. The extract was washed with saturated brine, then dried and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=9:1) to obtain the titled compound (0.052 g, 0.102 mmol, 29%).
Reaction SMILES: [CH2:1]([O:28][CH2:29]Cl)[CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[CH:16]([CH2:17][CH2:18][CH2:19][CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].[N:31]1([CH2:36][CH2:37][OH:38])[CH:35]=[CH:34][N:33]=[CH:32]1.C(O[K])(C)(C)C>O1CCCC1>[CH2:1]([O:28][CH2:29][O:38][CH2:37][CH2:36][N:31]1[CH:35]=[CH:34][N:33]=[CH:32]1)[CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[CH:16]([CH2:17][CH2:18][CH2:19][CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3]
Reactant: CC(CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4CCCC[C@]4(C)[C@H]3CC[C@]12C)COCCl
Reactant: OCCn1ccnc1
Agent: CC(C)(C)O[K]
Solvent: C1CCOC1
Product: CC(CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4CCCC[C@]4(C)[C@H]3CC[C@]12C)COCOCCn1ccnc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 75.2 %

Procedure:
Under ice cooling, 43.7 g of chloromethyl cholestanyl ether (24) was added to a mixture of 11.2 g of 2-(1H-imidazol-1-yl)ethanol (23), 11.2 g of t-butoxypotassium, and 100 g of tetrahydrofuran. Then the mixture was stirred at room temperature for 10 hours. Subsequent standard aqueous work-up and purification by silica gel column chromatography gave 38.5 g of 1-[2-(cholestanyloxymethoxy)ethyl]imidazole (Quencher 5). Yield 75%.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].O.[OH-].[Ca+2].[OH-].[H][H]>>[OH:12][CH2:11][C@@H:9]([C@H:7]([C@@H:5]([C@@H:3]([CH2:2][OH:1])[OH:4])[OH:6])[OH:8])[OH:10]
Reactant: [H][H]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO

Procedure:
As shown in the drawing, a glucose-water feed solution at 10 is mixed with an alkaline promotor material at 11 such as calcium hydroxide. The resulting mixture is pressurized and passed with hydrogen from 12 through preheater 14 to fixed-bed catalytic reactor 16 for hydrogenation reaction to produce mainly sorbitol. The promotor material added at 11 should be sufficient to control pH of feedstream to range of 7-14 to prevent leaching damage to the catalyst in reactor 16. The catalyst is preferably a reduced and stabilized nickel on silica-alumina support, and usually contains 50-66 W % nickel. Catalyst particle size of 0.060 to 0.250 inch can be used. The reaction conditions which can be used in reactor 16 are 130°-180° C. temperature, 500-2000 psig hydrogen partial pressure, and 0.5-3.5 Vf/hr/Vc space velocity to achieve at least about 90 W % conversion of the glucose feed to sorbitol solution.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[O:5][C:6]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:7]=1[CH:8]=[O:9].CC(C)=[O:21].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[O:5][C:6]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:7]=1[C:8]([OH:21])=[O:9]
Reactant: CC(C)=O
Reactant: O=Cc1cc(F)ccc1Oc1ccc(Cl)c(Cl)c1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(F)ccc1Oc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Alternatively, a solution of 4.28 g (15 mmol) of 2-(3,4-dichloro-phenoxy)-5-fluorobenzaldehyde (Preparation no. 5) in 25 mL of acetone was cooled to 5-10° C. and treated via syringe with 5.8 mL (15.6 mmol) of 2.67 M Jones reagent*. After 1 hr at this temperature, the reaction was quenched with 8 mL of isopropanol, allowed to warm to 25° C., and filtered through a pad of d.e. The filtrate was concentrated in vacuo to approximately ¼ volume, diluted with water and extracted several times with CHCl3. The organic layers were washed with water, then with saturated NaCl and finally dried over MgSO4 and concentrated to provide 2-(3,4-dichlorophenoxy)-5-fluoro-benzoic acid as a tan solid, 4.19 g. 1H-nmr (CDCl3, 400 MHz, δ): 7.78 (dd, 1H), 7.38 (d, 1H), 7.27 (m, 1H), 6.98 (m, 2H), 6.81 (dd, 1H).