Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Sb](F)(F)[F:19].C>C1(C)C(C)=CC=CC=1.CO>[C:1]1([N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([F:19])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Reactant: F[Sb](F)F
Agent: [Cl-]
Solvent: CO
Solvent: Cc1ccccc1C
Product: O=C(F)N(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
DPFC was prepared according to a published method of Metzger and Wilson (Biochem., 1964, Vol. 3, pp 926-931). Diphenylcarbamyl Chloride was obtained from Aldrich Chemical Co. Inc., Milwaukee, Wis., USA. DFPC was prepared from the chloride by reaction with 50% excess antimony trifluoride in hot xylene for one hour. The mixture was cooled to room temperature. Antimony halides were then precipitated with ether and the solution decolorized with charcoal, filtered and evaporated to dryness. The solids thus obtained were dissolved in Methanol, decolorized with charcoal, filtered and crystalized by cooling the solution to about 0° C. This process was repeated again and yielded white crystals with melting point of 81°-82° C.
Reaction SMILES: [CH:1]([C:3]1[O:7][CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=1)=[O:2].P(OCC)(OCC)(O[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O.C(C1OC(C=O)=CC=1)C1C=CC=CC=1>CC#N.C(O)(C)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:20]([C:5]1[CH:4]=[C:3]([CH:1]=[O:2])[O:7][CH:6]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC1(C)OB(c2coc(C=O)c2)OC1(C)C
Reactant: CCOP(=O)(OCC)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=Cc1ccc(Cc2ccccc2)o1
Solvent: CC#N
Solvent: CC(C)O
Product: O=Cc1cc(Cc2ccccc2)co1
Yield: 40.8 %

Procedure:
The title compound was synthesized from 5-formylfuran-3-boronic acid pinacol ester (878 mg, 3.95 mmol), and benzyl diethyl phosphate (1.25 g, 5.14 mmol) using the same conditions used to synthesize 5-benzyl-furan-2-carbaldehyde, with the exception that TPP and Pd(OAc)2 were dissolved in 2:1 CH3CN/isopropyl alcohol. Purification by flash chromatography yielded 4-benzyl-furan-2-carbaldehyde as a white solid (300 mg, 41%). 1H NMR (400 MHz, CDCl3) δ ppm 9.56 (s, 1 H) 7.29-7.38 (m, 3 H) 7.24-7.28 (m, 2 H) 7.17 (d, J=3.5 Hz, 1 H) 6.19 (d, J=3.6 Hz, 1 H) 4.07 (s, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]2[C:10]3([CH2:20][O:21][C:5]=2[CH:4]=1)[C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH:12][C:11]3=[O:19].C(#N)C>C(OC)(C)(C)C>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]2[C@:10]3([CH2:20][O:21][C:5]=2[CH:4]=1)[C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH:12][C:11]3=[O:19]
Reactant: COc1cc2c(cc1C)C1(CO2)C(=O)Nc2ccccc21
Solvent: CC#N
Solvent: COC(C)(C)C
Product: COc1cc2c(cc1C)[C@@]1(CO2)C(=O)Nc2ccccc21

Procedure:
6-Methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (2.16 g, 0.10 g per run) was resolved on a semi-prep chiral IA column with 10% acetonitrile in tert-butyl methylether. (3S)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was isolated as a crystalline colorless solid (0.96 g, 89% recovery): ee>99% (analytical chiralpak IA, 1:1 acetonitrile/tert-butyl methylether); mp>250° C.; 1H NMR (300 MHz, DMSO-d6) δ10.57 (s, 1H), 7.23 (ddd, J=7.6, 7.6, 1.3 Hz, 1H), 7.07 (d, J=6.8 Hz, 1H), 6.99-6.89 (m, 1H), 6.61 (s, 1H), 6.45 (s, 1H), 4.81-4.74 (m, 1H), 4.64 (d, J=9.2 Hz, 1H), 3.77 (s, 1H), 1.95 (s, 1H); 13C NMR (75 MHz, DMSO-d6) δ179.2, 160.4, 158.9, 142.2, 133.4, 129.1, 124.4, 124.2, 122.7, 120.3, 118.4, 110.2, 94.3, 80.1, 58.0, 56.0, 16.0; MS (ES+) m/z 282.0 (M+1).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].C(N(CC)CC)C.[Cl:36][CH2:37][C:38](Cl)=[O:39]>C1C=CC=CC=1>[CH3:8][C@@H:7]([C@@H:9]1[C@@:27]2([CH3:28])[CH2:26][CH2:25][C@@H:24]3[C@@:22]4([CH3:23])[CH2:21][CH2:20][C@H:18]([O:19][C:38]([CH2:37][Cl:36])=[O:39])[CH2:17][C:16]4=[CH:15][CH2:14][C@H:13]3[C@@H:12]2[CH2:11][CH2:10]1)[CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)CCl)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 80 °C
Yield: 66.1 %

Procedure:
A solution of cholesterol (1.93 g, 5 mmol) and triethylamine (0.51 g, 5 mmol) in benzene (25 mL) was added dropwise to an 8°-10° C. solution of chloroacetyl chloride (0.57 g, 5 mmol) in benzene (20 mL). The solution was heated under reflux at 80° C. for 24 hours, cooled to room temperature and worked up. Recrystallization (absolute EtOH) afforded the title compound (1.53 g, 66%) as a white solid (mp 160°-161° C.).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[N:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:39]=[CH:38][C:30]3[N:31]=[C:32]([NH:34][C:35](=[O:37])[CH3:36])[S:33][C:29]=3[CH:28]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.CS(C)=O.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>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([S:8]([C:4]2[N:3]=[C:2]([C:27]3[CH:39]=[CH:38][C:30]4[N:31]=[C:32]([NH:34][C:35](=[O:37])[CH3:36])[S:33][C:29]=4[CH:28]=3)[CH:7]=[CH:6][CH:5]=2)(=[O:10])=[O:9])=[CH:12][CH:13]=1
Reactant: CC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
Reactant: COc1ccc(S(=O)(=O)c2cccc(Cl)n2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: COc1ccc(S(=O)(=O)c2cccc(-c3ccc4nc(NC(C)=O)sc4c3)n2)cc1
Temperature: 95 °C
Reaction time: 8 h

Procedure:
2-Chloro-6-(4-methoxyphenylsulfonyl)pyridine (0.300 g, 1.06 mmol) was dissolved in 1,4-dioxane (6 mL) and then N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (0.4 g, 1 mmol), tetrakis(triphenylphosphine)palladium (0) (0.2 g, 0.1 mmol) and 2M sodium carbonate (1 mL, 2 mmol) were added to it. The flask was fit with a reflux condensor and placed into a pre-heated (95° C.) bath. The mixture was allowed to stir under inert atmosphere overnight. The mixture was allowed to cool to ambient temperature and diluted with DMSO. The crude was filtered and purified by reverse-phase HPLC. This gave N-(6-(6-(4-methoxyphenylsulfonyl)pyridin-2-yl)benzo[d]thiazol-2-yl)acetamide as an off-white solid. MS (ESI pos. ion) m/z: 440 (MH+). Calculated exact mass for C21H17N3O4S2: 439. 1H NMR (400 MHz, DMSO-d6): 8.53 (s, 1H), 8.15-8.24 (m, 2H), 8.02 (br s, 4H), 7.70 (d, J=7.53 Hz, 1H), 7.7.19 (d, J=7.53 Hz, 2H), 3.83 (s, 3H), 2.15 (s, 3H).
Reaction SMILES: O[C:2]1([C:9]([F:12])([F:11])[F:10])[CH:7]=[CH:6][C:5](=[O:8])[CH:4]=[CH:3]1.C(O)(=O)C.O>C(O)C.[Zn]>[F:10][C:9]([F:11])([F:12])[C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[CH:6][CH:7]=1
Reactant: O=C1C=CC(O)(C(F)(F)F)C=C1
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: Oc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 84.7 %

Procedure:
A solution of 200 mg (1.1 mmol) of 4-hydroxy-4-trifluoromethyl-2,5-cyclohexadien-1-one in 1 mL of absolute ethanol was treated successively with 147 mg (2.2 mmol) of zinc dust and 1 mL of a solution of 80% acetic acid--20% water. The mixture was heated to reflux for one hour, allowed to cool to room temperature, and poured into 20 mL of water. The resulting aqueous mixture was extracted with three 10 mL portions of diethyl ether. Combination, extraction with one 10 mL portion of 10% Na2CO3, drying (MgSO4), and concentration of the ether layers afforded a residue which was subjected to PTLC (one 2 mm silica gel plate eluted with dichloromethane), giving 151 mg (83% yield) of 4-trifluoromethylphenol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:21]([C:22]([O:24]C)=[O:23])=[C:20]3[C:15]([C:16]4[CH:28]=[CH:27][O:26][C:17]=4[CH2:18][O:19]3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[C:4](/[CH:29]=[CH:30]\[CH2:31][N:32]2[CH2:36][CH2:35][C@@H:34]([O:37]C(=O)C)[CH2:33]2)[CH:3]=1.O.[OH-].[Li+].C(O)=O>O.O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:21]([C:22]([OH:24])=[O:23])=[C:20]3[C:15]([C:16]4[CH:28]=[CH:27][O:26][C:17]=4[CH2:18][O:19]3)=[CH:14][CH:13]=2)(=[O:9])=[O:10])=[C:4](/[CH:29]=[CH:30]\[CH2:31][N:32]2[CH2:36][CH2:35][C@@H:34]([OH:37])[CH2:33]2)[CH:3]=1
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2/C=C\CN2CC[C@@H](OC(C)=O)C2)ccc2c1OCc1occc1-2
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: O=CO
Product: O=C(O)c1c(NS(=O)(=O)c2ccc(F)cc2/C=C\CN2CC[C@@H](O)C2)ccc2c1OCc1occc1-2
Yield: 4.8 %

Procedure:
A mixture of methyl 7-{4-fluoro-2-[(Z)-3-((R)-3-acetoxypyrrolidin-1-yl)prop-1-enyl]benzenesulfonylamino}-4H-furo[2,3-c]chromene-6-carboxylate (Intermediate 82, 0.092 g) and lithium hydroxide monohydrate (0.039 g) in water (2 mL) and dioxane (4 mL), was scaled in a microwave vial and irradiated in the microwave at 110° C. for 20 minutes. After cooling, the mixture was diluted with water (20 mL), acidified with formic acid to pH 4-5 and extracted into DCM. The organic layer was dried (MgSO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by HPLC (C6 Ph) eluting with a mixture of acetonitrile and water, containing 0.1% formic acid, with a gradient of 30-60%, to give 7-{4-fluoro-2-[(Z)-3-((R)-3-hydroxypyrrolidin-1-yl)-prop-1-enyl]-benzenesulfonylamino}-4H-furo[2,3-c]chromene-6-carboxylic acid (0.004 g).
Reaction SMILES: [Li+].[OH-].[NH2:3][C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:7]([CH2:14][C@@H:15]([O:35][C:36]([N:38]2[CH2:43][CH2:42][CH:41]([N:44]3[CH2:50][CH2:49][C:48]4[CH:51]=[CH:52][CH:53]=[CH:54][C:47]=4[NH:46][C:45]3=[O:55])[CH2:40][CH2:39]2)=[O:37])[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([N:24]3[CH2:29][CH2:28][CH:27]([C:30]([O:32]CC)=[O:31])[CH2:26][CH2:25]3)[CH2:20][CH2:19]2)=[O:17])=[CH:6][C:5]=1[Cl:56].Cl>O.C1COCC1>[NH2:3][C:4]1[C:9]([C:10]([F:12])([F:11])[F:13])=[CH:8][C:7]([CH2:14][C@@H:15]([O:35][C:36]([N:38]2[CH2:39][CH2:40][CH:41]([N:44]3[CH2:50][CH2:49][C:48]4[CH:51]=[CH:52][CH:53]=[CH:54][C:47]=4[NH:46][C:45]3=[O:55])[CH2:42][CH2:43]2)=[O:37])[C:16]([N:18]2[CH2:19][CH2:20][CH:21]([N:24]3[CH2:29][CH2:28][CH:27]([C:30]([OH:32])=[O:31])[CH2:26][CH2:25]3)[CH2:22][CH2:23]2)=[O:17])=[CH:6][C:5]=1[Cl:56]
Reactant: CCOC(=O)C1CCN(C2CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCC(C(=O)O)CC3)CC2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 7.2 mg (0.3 mmol) LiOH in 1 mL water was added to a solution of 140 mg (0.18 mmol) ethyl 1′-{(R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]-propionyl}-1,4′-bipiperidinyl-4-carboxylate in 1 mL THF and the reaction mixture was stirred for 3 h at RT. 1 mL HCl (1 M) was added and the crude product was purified by HPLC. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([O:12][C:13]([CH3:22])([CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH:14]=[CH2:15])(=[O:11])[CH3:10].[C:23](Cl)(=[O:32])[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1>C1COCC1>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([C:23](=[O:32])[CH2:10][C:9]([O:12][C:13]([CH3:22])([CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH:14]=[CH2:15])=[O:11])=[CH:25][CH:26]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: C=CC(C)(CCC=C(C)C)OC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC(C)(CCC=C(C)C)OC(=O)CC(=O)c1ccc(OC)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Lithium diisopropylamide (119.0 mL of a 2.0M solution, 0.238 mol) is placed into a 500 mL three-necked round-bottomed flask fitted with a magnetic stirrer, internal thermometer, argon inlet, and addition funnel. The flask is cooled to -78° C. 3,7-dimethyl-1,6-octadien-3-yl acetate (22.04 g, 0.112 mol) is dissolved in THF (5 mL) and the resulting solution added to the flask over 45 min. Once addition is complete, the mixture is stirred for an additional 15 min. before being treated with a solution of p-anisoyl chloride (35.00 g, 0.106 mol) dissolved in THF (30 mL) over 30 min. The mixture is warmed to -20° C. and stirred at that temperature for 18 h. After warming to 0° C., the mixture is quenched with 20% HCl (80 mL). The mixture is poured into a separatory funnel containing ether (150 mL) and water (250 mL). The aqueous layer is extracted with ether (150 mL). The mixture is poured into a separatory funnel containing ether (150 mL) and water (250 mL). The aqueous layer is extracted with ether (150 mL). The combined organic layers are washed with saturated NaHCO3 solution (2×100 mL), water (2×150 mL) and brine (150 mL), dried over MgSO4 and filtered. The solvent is removed by rotary evaporation to give an oil. The oil is purified by column chromatography (elution with 2% ethyl acetate/petroleum ether) to yield a colorless oil having 1H and 13C NMR spectra consistent with the desired product.
Reaction SMILES: [NH2:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2.[Cl:17][CH2:18][C:19](Cl)=O.[NH:22]1[CH2:27][CH2:26][C:25]2([C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][O:28]2)[CH2:24][CH2:23]1>>[ClH:17].[CH:12]1[C:7]2[CH2:6][CH2:5][C:4]3[CH:13]=[CH:14][CH:15]=[CH:16][C:3]=3[CH:2]([NH:1][CH2:18][CH2:19][N:22]3[CH2:27][CH2:26][C:25]4([C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[CH2:29][O:28]4)[CH2:24][CH2:23]3)[C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: c1ccc2c(c1)COC21CCNCC1
Reactant: NC1c2ccccc2CCc2ccccc21
Reactant: O=C(Cl)CCl
Product: Cl
Product: c1ccc2c(c1)CCc1ccccc1C2NCCN1CCC2(CC1)OCc1ccccc12

Procedure:
The title compound, m.p. 215° C. and MS: m/e=425.3 (M+H+), was prepared in accordance with the general method of example 1 from 5-amino-10,11-dihydro-5H-dibenzo[a,d]cycloheptene, chloroacetyl chloride, spiro[isobenzofuran-1(3H),4'piperidine] and Hcl.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:10][N:9]=[C:8](C(O)=O)[CH:7]=1.C1C=CC(P([N:28]=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.O>C1C=CC=CC=1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:10][N:9]=[C:8]([NH2:28])[CH:7]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1cc(-c2ccco2)on1
Solvent: O
Solvent: c1ccccc1
Product: Nc1cc(-c2ccco2)on1
Yield: 40 %

Procedure:
To a solution of 2.0 g of 5-furan-2-yl-isoxazole-3-carboxylic acid and 6.2 mL of TEA in benzene was added 3.61 mL of DPPA at room temperature. After refluxing for 1.5 hrs, 30 mL of distilled water was added and then the resulting solution was refluxed for an additional 30 min. The reaction solution was concentrated under reduced pressure, and the concentrate was purified by column chromatography on silica gel to obtain 0.6 g of 5-furan-2-yl-isoxazol-3-ylamine (Yield: 40%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH:10]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)[C:14](=[O:28])[CH2:13][CH2:12][CH2:11]1.Cl[CH2:30][CH:31]([OH:34])[CH2:32][OH:33]>>[OH:34][CH:31]([CH2:32][OH:33])[CH2:30][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH:10]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:25])[F:26])=[CH:19][CH:18]=2)[C:14](=[O:28])[CH2:13][CH2:12][CH2:11]1
Reactant: COc1cccc(O)c1C1CCCC(=O)N1Cc1ccc(OC(F)(F)F)cc1
Reactant: OCC(O)CCl
Product: COc1cccc(OCC(O)CO)c1C1CCCC(=O)N1Cc1ccc(OC(F)(F)F)cc1

Procedure:
Prepared according to the described general procedure 7 (GP7) by O-alkylation of 6-(2-hydroxy-6-methoxyphenyl)-1-(4-(trifluoromethoxy)benzyl)piperidin-2-one with commercially available 3-chloropropane-1,2-diol. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.73 min.; [M+H]+: 470.28 g/mol.
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:13]=[CH:14][C@@H:15]([C@H:17]([C@H:19]([C@@H:21]([CH2:23][OH:24])[OH:22])[OH:20])[OH:18])O.COS([O-])(=O)=O>O.S(=O)(=O)(O)O>[OH:1][CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([O:8][C@@H:23]2[O:24][C@H:15]([CH2:14][OH:13])[C@H:17]([OH:18])[C@H:19]([OH:20])[C@H:21]2[OH:22])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Agent: COS(=O)(=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O
Reaction time: 0.17 h

Procedure:
100 mmol/l of glucose, 20 mmol/l of galactose and 2 mg/ml of galactosidase are incubated at 35° C. in a mixture of water and MMIm MeSO4 for 24 h. The reaction is stopped by boiling for 10 minutes at 100° C., the reaction solution is filtered (Minisart RC 4 Sartorius injection filter) and the concentration of the reaction components at this time is determined chromatographically (Aminex HPX-87H cation exchange column from BioRad with corresponding preparatory column, 0.006 M sulphuric acid as eluent with a flux of 0.8 ml/min and a column temperature of 65° C. Detection is accomplished using UV at 208 nm and using the refractive index).
Reaction SMILES: [CH:1]1([C:4]2(O)[C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[O:8][C:7]3[CH:15]=[CH:16][CH:17]=[C:18]([O:19][CH3:20])[C:6]=3[CH2:5]2)[CH2:3][CH2:2]1.[BrH:22].O.[OH-].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Br:22][CH2:3][CH2:2][CH:1]=[C:4]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[O:8][C:7]2[CH:15]=[CH:16][CH:17]=[C:18]([O:19][CH3:20])[C:6]=2[CH2:5]1
Reactant: COc1cccc2c1CC(O)(C1CC1)c1cccnc1O2
Reactant: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1cccc2c1CC(=CCCBr)c1cccnc1O2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of the product of step 1 (4.3 g) in acetic acid (30 ml) was added 48% aqueous HBr (25 ml) at 10° C. The reaction mixture was warmed to room temperature, and stirred for 12 hours. Water and ethyl acetate were added to the reaction mixture and neutralized with dilute NaOH solution. The organic layer was separated and washed with saturated aqueous sodium chloride, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexane (1:4) to give 5-(3-bromopropylidene)-5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridine (5.6 g).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl-].[CH3:12][Zn+].O>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>[CH3:12][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: C[Zn+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ncccc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Under nitrogen atmosphere, 47.6 g of 2-chloro-3-nitropyridine was dissolved in 500 mL of tetrahydrofuran, and 150 mL of 2M methylzinc chloride in tetrahydrofuran and 6.9 g of tetrakis(triphenylphosphine)palladium(0) were added, and the reaction solution was stirred at 70° C. for 2 hours. The reaction solution was poured into cold water, extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to column chromatography (n-hexane:ethyl acetate=3:1) to obtain 35.4 g of 2-methyl-3-nitropyridine as a colorless oil. Then 35.4 g of 2-methyl-3-nitropyridine was dissolved in a mixed solution of 300 mL methanol/5 mL triethylamine, added with 5 g of 10% palladium on carbon, and stirred for 6 hours under hydrogen atmosphere and at normal temperature and pressure. The reaction solution was filtered thorough Celite, the solvent was evaporated, and 33.0 g of crudely produced 2-methyl-3-aminopyridine was obtained as a pale brown oil. Next, to 100 mL of a solution of 65 g of crude 3-amino-2-methylpyridine in dichloromethane were added 60 mL of pyridine and 71 mL of acetic anhydride at room temperature and stirred for 3 hours. The reaction solution was added with about 150 mL of silica gel powder, the solvent was evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate:methanol=100:3), to afford 74 g of the title compound as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11](I)=[CH:10][N:9]2[CH:15]=1)=[O:4].C([Mg]Cl)(C)C.CN([CH:26]=[O:27])C.[NH4+].[Cl-]>C1COCC1>[F:1][C:2]([F:17])([F:16])[C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([CH:26]=[O:27])=[CH:10][N:9]2[CH:15]=1)=[O:4]
Reactant: O=C(Nc1cn2cc(I)ccc2n1)C(F)(F)F
Reactant: CN(C)C=O
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=Cc1ccc2nc(NC(=O)C(F)(F)F)cn2c1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
2,2,2-Trifluoro-N-(6-iodo-imidazo[1,2-a]pyridin-2-yl)-acetamide (Stage 153.2, 1 g, 2.82 mmol) was dissolved in THF (15 mL) and cooled down to −40° C. under nitrogen atm. iPrMgCl in THF (2 M, 2.8 mL) was added dropwise. After 1 h stirring, cold DMF (0.65 mL, 8.46 mmol) in THF (1 mL) was added and the RM warmed up to −10° C. in 4 h. NH4Cl solution was added and the mixture was extracted 3 times with EtOAc. Combined organic layers were washed with brine and dried on Na2SO4. After evaporation of the solvent the crude was purified by preparative HPLC with acetonitrile/water (with 0.1% TFA) to afford the title compound (tR 0.88 min (conditions 2), (MH+=258).
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@@H:6]([C:15]([OH:17])=O)[CH2:5][O:4][CH2:3]1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.[CH2:35]([NH2:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@@H:6]([C:15]([NH:42][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:17])[CH2:5][O:4][CH2:3]1
Reactant: NCc1ccccc1
Reactant: O=C(O)[C@H]1COCC(=O)N1Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(NCc1ccccc1)[C@H]1COCC(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
(3R)-5-oxo-4-(phenylmethyl)-3-morpholinecarboxylic acid (3.67 g, 15.6 mmol) and 1-hydroxybenzotriazole (2.53 g, 18.7 mmol) in DCM (50 mL) cooled to 0° C. N-Methylmorpholine (8.50 mL, 77.3 mmol), benzylamine (1.87 mL, 17.2 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (3.26 g, 17.2 mmol) added sequentially. The reaction was stirred at rt overnight, washed with H2O (50 mL), 6N HCl (30 mL), H2O (50 mL) and dried over MgSO4 to provide the title compound of step C (5.09 g, 15.6 mmol, 100%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.59 (d, J=15.2 Hz, 1H), 3.82 (t, J=2.9 Hz, 1H), 3.86-3.97 (m, 2H), 4.07-4.17 (m, 2H), 4.23-4.34 (m, 2H), 5.30 (d, J=15.4 Hz, 1H), 7.17-7.22 (m, 5H), 7.24-7.32 (m, 5H), 8.60 (t, J=5.6 Hz, 1H).