Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:24]=3[CH2:33][N:34]3[C@@H:38]([CH3:39])[C@@H:37]([C:40]4[CH:45]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:43]=[C:42]([C:50]([F:53])([F:52])[F:51])[CH:41]=4)[O:36][C:35]3=[O:54])[C:17]([O:21][CH3:22])=[CH:18][C:19]=2[F:20])[CH2:10][CH2:9]1)=[O:7])(=O)C.C[O-].[Na+].O>CO>[F:53][C:50]([F:51])([F:52])[C:42]1[CH:41]=[C:40]([C@H:37]2[O:36][C:35](=[O:54])[N:34]([CH2:33][C:24]3[CH:25]=[C:26]([C:29]([F:31])([F:32])[F:30])[CH:27]=[CH:28][C:23]=3[C:16]3[CH:15]=[C:14]([CH:11]4[CH2:10][CH2:9][N:8]([C:6](=[O:7])[CH2:5][OH:4])[CH2:13][CH2:12]4)[C:19]([F:20])=[CH:18][C:17]=3[O:21][CH3:22])[C@H:38]2[CH3:39])[CH:45]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:43]=1
Reactant: COc1cc(F)c(C2CCN(C(=O)COC(C)=O)CC2)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(F)c(C2CCN(C(=O)CO)CC2)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 2-{4-[2′-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-fluoro-6-methoxy-4′-(trifluoromethyl)biphenyl-3-yl]piperidin-1 -yl}-2-oxoethyl acetate (24 mg, 0.031 mmol) in MeOH (1 mL) under N2 was added sodium methoxide (6.66 mg, 0.031 mmol) The resultant mixture was stirred at room temperature for 15 min. Water (10 mL) was added and the mixture was extracted with EtOAc (3×10 mL). The combined organic fractions were washed with brine (10 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-100% EtOAC/hexanes) to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-5′-(1-glycoloylpiperidin-4-yl)-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one as a yellow gum. LCMS=737.1 (M+1)+. 1H NMR (CDCl3, 500 MHz, mixture of atropisomers) δ 7.87 (s, 1 H), 7.69 (s, 2 H), 7.68-7.60 (m, 2 H), 7.34-7.30 (m, 1 H), 6.96-6.91 (m, 1 H), 6.72 (d, J=11.9 Hz, 1 H), 5.44 (d, J=7.8 Hz, 1 H), 4.90 (d, J=15.8 Hz, 1 H), 4.78-4.70 (m, 1 H), 4.18-4.13 (m, 2 H), 3.78 (s, 3H), 3.62-3.54 (m, 1 H), 3.15-3.05 (m, 2 H), 2.82-2.73 (m, 1 H), 1.96-1.84 (m, 2 H), 1.70-1.52 (m, 4 H), 0.43-0.39 (m, 3 H).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:16]=[CH:15][C:10]([C:11](OC)=[O:12])=[CH:9][C:8]=2[O:17][CH3:18])[CH:5]=[CH:4][CH:3]=[N:2]1.CCCCCC>C1COCC1>[N:1]1([CH2:6][C:7]2[CH:16]=[CH:15][C:10]([CH2:11][OH:12])=[CH:9][C:8]=2[O:17][CH3:18])[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: COC(=O)c1ccc(Cn2cccn2)c(OC)c1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc(CO)ccc1Cn1cccn1
Temperature: -70 °C
Reaction time: 3.5 h

Procedure:
To a solution of methyl 4-((1H-pyrazol-1-yl)methyl)-3-methoxybenzoate (330 mg crude) in THF (6 ml) DIBAL-H 1M in Hexane (4.02 ml, 4.02 mmol) was added dropwise at −70° C. The reaction mixture was stirred at −70° C. for 3.5 h. The reaction mixture was quenched subsequently with ethyl acetate (2 ml) and saturated aqueous NH4Cl. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude (4-((1H-pyrazol-1-yl)methyl)-3-methoxyphenyl)methanol. MS [M+H]+=219.
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:7][CH2:6][CH2:5][C:4]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:3]1.CCN(C(C)C)C(C)C.[CH3:35][N:36]([CH3:42])[C@@H:37]1[CH2:41][CH2:40][NH:39][CH2:38]1>>[F:1][C:2]1([F:25])[CH2:7][CH2:6][CH2:5][C:4]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:39]4[CH2:40][CH2:41][C@@H:37]([N:36]([CH3:42])[CH3:35])[CH2:38]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:3]1
Reactant: O=C(NCC1(O)CCCC(F)(F)C1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: CN(C)[C@@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)[C@@H]1CCN(c2ccc3c(C(=O)NCC4(O)CCCC(F)(F)C4)c(Cl)ccc3n2)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (3,3-difluoro-1-hydroxy-cyclohexylmethyl)-amide, DIPEA and (R)-3-dimethylamino-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.73 (m, 1H), 7.85 (1H), 7.48 (m, 2H), 6.69 (1H), 4.66 (s, 1H), 3.89 (m, 1H), 3.70 (m, 1H), 3.45 (m, 1H), 3.26 (m, 2H), 2.85 (m, 1H), 2.54 (m, 4H), 2.22 (s, 6H), 2.15 (m, 1H), 2.06 (m, 2H), 1.85 (m, 3H), 1.74-1.76 (m, 5H). m/z: 467 [M+H]
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:5][CH:4]=[C:3]1[C:20]([OH:22])=[O:21].[I-].ClC1C=CC=C[N+]=1C.[C:32]1(=O)[CH2:37][CH2:36][CH2:35][CH2:34][C:33]1=[O:38].C(N(CC)CC)C>ClCCl>[O:1]=[C:2]1[N:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:6]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:5][CH:4]=[C:3]1[C:20]([O:22][C:37]1[CH2:36][CH2:35][CH2:34][C:33](=[O:38])[CH:32]=1)=[O:21]
Reactant: O=C1CCCCC1=O
Reactant: O=C(O)c1cnc(-c2cccnc2)n(-c2ccccc2)c1=O
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1C=C(OC(=O)c2cnc(-c3cccnc3)n(-c3ccccc3)c2=O)CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 1,6-dihydro-6-oxo-1-phenyl-2-(3-pyridinyl)-5-pyrimidinecarboxylic acid (i.e. the product from Example 7, Step C) (10.7 g, 36.3 mmol) in dichloromethane (150 mL) at ambient temperature was added 2-chloro-N-methylpyridinium iodide (also known as the Mukaiyama reagent) (14.8 g, 57.9 mmol) followed by cyclohexanedione (6.5 g, 58 mmol) and triethylamine (9.2 g, 91 mmol). The reaction mixture was left stirring at ambient temperature overnight, then diluted with dichloromethane, washed with water, brine and dried over anhydrous Na2SO4. The residue obtained after removal of the solvent under vacuum was purified by trituration with n-chlorobutane/petroleum ether mixtures to obtain 9.8 g of the title compound as a light brown solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[N+:21]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Zn].[NH4+].[Cl-]>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(Cl)cc2)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(Cl)cc2)cc1N

Procedure:
Prepared from (4′-chloro-3-nitro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example C2) by reduction with Zn/NH4Cl according to the general procedure G (method c). Obtained as a green solid (162 mg).
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][Si](C(C)(C)C)(C)C)=[CH:9][C:8]=1[CH2:21][CH:22]=[C:23]([CH2:27][CH2:28][CH:29]=[C:30]([CH3:37])[CH2:31][CH2:32][CH:33]=[C:34]([CH3:36])[CH3:35])[C:24]([OH:26])=[O:25])(C)(C)C.[F-].[K+].Br.Cl>CN(C=O)C>[CH3:35][C:34]([CH3:36])=[CH:33][CH2:32][CH2:31]/[C:30](/[CH3:37])=[CH:29]/[CH2:28][CH2:27]/[C:23](/[C:24]([OH:26])=[O:25])=[CH:22]/[CH2:21][C:8]1[CH:9]=[C:10]([OH:13])[CH:11]=[CH:12][C:7]=1[OH:6]
Reactant: CC(C)=CCCC(C)=CCCC(=CCc1cc(O[Si](C)(C)C(C)(C)C)ccc1O[Si](C)(C)C(C)(C)C)C(=O)O
Agent: Br
Agent: Cl
Agent: [F-]
Solvent: CN(C)C=O
Product: CC(C)=CCC/C(C)=C/CC/C(=C/Cc1cc(O)ccc1O)C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 87 %

Procedure:
To cleave off the tert.-butyidimethylsilyl groups, 0,10 g of [2′-(2,5-bis[(tert.-butyldimethylsilyl)oxy]phenyl)ethylidene]-6,10-dimethyl-5,9-undecadienic acid is dissolved in 10 ml of DMF together with 2 equivalents of anhydrous potassium fluoride and 0.2 equivalents of 48% aqueous HBr, followed by stirring at room temperature for 24 hours under an argon atmosphere. Then, 10 ml of 2.0 M aqueous HCl solution is added, and the reaction mixture is extracted three times with 15 ml each of ether. The combined organic phases are washed with 10 ml of saturated aqueous NaCl solution, dried over MgSO4 and concentrated under reduced pressure. Purification of the raw product is effected by column chromatography (mobile system heptane:ethyl acetate=1:1). The yield was 87% of ganomycin B.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29]3[CH:34]=[CH:33][C:32]([N:35](C(OC(C)(C)C)=O)[CH3:36])=[CH:31][CH:30]=3)=[CH:23][CH:22]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[ClH:44]>C(OCC)C>[ClH:44].[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29]3[CH:34]=[CH:33][C:32]([NH:35][CH3:36])=[CH:31][CH:30]=3)=[CH:23][CH:22]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCCOc2ccc(/C=C/c3ccc(N(C)C(=O)OC(C)(C)C)cc3)cc2)cc1
Agent: Cl
Solvent: CCOCC
Product: CNc1ccc(/C=C/c2ccc(OCCOCCOCCOS(=O)(=O)c3ccc(C)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
200 mg 2-[2-(2-{4-[(E)-2-{4-[(tert-butoxycarbonyl)(methyl)amino]phenyl}-vinyl]phenoxy}ethoxy)ethoxy]ethyl 4-methylbenzenesulfonate (2c) were dissolved in a 2M solution of HCl in diethyl ether. The mixture was stirred at room temperature for 72 h. The solvent was removed under reduced pressure. Diethyl ether was added and the precipitate was collected, washed with diethyl ether and dried under reduced pressure. 160 mg 2e were obtained as light yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:21][NH:22][O:23][CH3:24].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[CH3:24][O:23][N:22]([CH3:21])[C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CON(C)C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
2(S)-(tert-Butoxycarbonylamino)-3-phenylpropionic acid (39.80 g, 0.150 mol), N,O-dimethylhydroxylamine hydrochloride (21.95 g, 0.225 mol), EDC hydrochloride (31.52 g, 0.165 mol) and HOBT (20.25 g, 0.150 mol) were stirred in dry, degassed DMF (200 mL) at 20° C. under nitrogen. N-Methylmorpholine is added to obtain pH 7. The reaction was stirred overnight, the DMF distilled under high vacuum, and the residue partitioned between ethyl acetate and 2% potassium hydrogen sulfate. The organic phase was washed with saturated sodium bicarbonate, water, and saturated brine, and dried with magnesium sulfate. The solvent was removed in vacuo to give the title compound.
Reaction SMILES: [BH4-].[Na+].[I:3][C:4]1[CH:9]=[C:8]([Si:10]([CH3:13])([CH3:12])[CH3:11])[N:7]=[C:6]([O:14][CH3:15])[C:5]=1[CH:16]=[O:17]>CCO>[I:3][C:4]1[CH:9]=[C:8]([Si:10]([CH3:11])([CH3:13])[CH3:12])[N:7]=[C:6]([O:14][CH3:15])[C:5]=1[CH2:16][OH:17]
Reactant: COc1nc([Si](C)(C)C)cc(I)c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1nc([Si](C)(C)C)cc(I)c1CO
Reaction time: 1 h
Yield: 78.4 %

Procedure:
To a solution of NaBH4 (1.1 g, 26.4 mmol) in EtOH (100 mL) at −40° C. was slowly added a solution of 4-iodo-2-methoxy-6-trimethylsilanyl-3-pyridinecarboxaldehyde 1 (31.8 g, 94.9 mmol) in EtOH (50 mL). See Josien, H.; Ko, S.-B.; Bom, D.; Curran, D. P. Chem. Eur. J., 67 (1998). After stirring for 1 h, the reaction mixture was carefully quenched with brine and then extracted 3 times with Et2O. The combined organic extracts were dried over MgSO4. The solvent was removed under reduced pressure and the residue purified by flash chromatography (gradient hexane to hexane-EtOAc 91:9) to afford 2a (25.1 g, 78% yield) as a clear oil. 1H NMR (300 MHz, CDCl3) δ0.28 (s, 9H), 2.5 (bs, 1H), 4.01 (s, 3H), 4.8 (s, 2H), 7.5 (s, 1H); 13C NMR (75 MHz, CDCl3) δ−1.99, 53.78, 65.32, 11.65, 125.34, 133.19, 160.9, 165.81; IR (film, NaCl, cm−1) 3485, 2960, 1580, 1450, 1039, 839; LRMS (70 eV, EI) m/z (rel int %) 337 (M+), 322 (100), 306, 194, 180, 73. HRMS m/z calcd for C10H16NO2SiI (M+) 336.9996, found 337.000.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[S:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=3)=[N:10][C:9]=2[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=2)[CH:5]=[C:4]([CH3:28])[N:3]=1.ClC1C=CC=C(C(OO)=[O:37])C=1.[OH-].[Na+]>CN(C)C=O>[CH3:28][C:4]1[CH:5]=[C:6]([C:8]2[S:12][C:11]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([CH3:20])=[O:37])=[CH:17][CH:18]=3)=[N:10][C:9]=2[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=2)[CH:7]=[C:2]([CH3:1])[N:3]=1
Reactant: CSc1ccc(-c2nc(-c3cccc(C)c3)c(-c3cc(C)nc(C)c3)s2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1cccc(-c2nc(-c3ccc(S(C)=O)cc3)sc2-c2cc(C)nc(C)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of 5-(2,6-dimethyl-4-pyridyl)-4-(3-methylphenyl)-2-[4-(methylthio)phenyl]-1,3-thiazole (0.41 g, 1.0 mmol) in N,N-dimethylformamide (15 mL) was added m-chloroperbenzoic acid (0.25 g, 1.0 mmol), and the mixture was stirred for 1 hour at room temperature. A 8N aqueous sodium hydroxide solution was poured into the reaction mixture, and extracted with ethyl acetate. The extracted solution was washed with brine, dried, then, the solvent was distilled off. The residue was purified by column chromatography (filler: Chromatorex NH DM1020 (trade name, manufactured by Fuji Silysia Chemical Lte.), hexane-ethyl acetate=1:2), to obtain a title compound (0.41 g, yield 97%).
Reaction SMILES: Br.[C:2]1([C:8]2[N:9]=[C:10]3[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=[CH:12][N:11]3[CH:21]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([N:24](CC)CC)C.ClS(N=C=O)(=O)=O>C(#N)C>[C:22]([C:21]1[N:11]2[CH:12]=[CH:13][CH:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:10]2=[N:9][C:8]=1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)#[N:24]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1cccn2cc(-c3ccccc3)nc12
Agent: Br
Agent: O=C=NS(=O)(=O)Cl
Solvent: CC#N
Product: CCOC(=O)c1cccn2c(C#N)c(-c3ccccc3)nc12
Yield: 66.9 %

Procedure:
Ethyl 2-phenyl-imidazo[1,2-a]pyridine-8-carboxylate hydrogen bromide (1.96 g, 5.35 m mol), and triethylamine (0.55 g, 5.44 m mol) were added to acetonitrile (20 ml). To this solution was dropwise added a solution of chlorosulfonylisocyanate (ClSO2NCO) (0.8 ml, 9.19 m mol) in acetonitrile (5 ml) at an inner temperature of 0°-20° C. Then, the mixture was allowed to react at room temperature for an hour. After completion of the reaction, the mixture was concentrated under reduced pressure. The resulting concentrate to which water was added was extracted with dichloromethane, and the extract was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform) to give the object compound (1.06 g, yield 67.9%) as crystals. m.p. 87°-89° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])[N:3]=1.[CH3:19][C:20]1[N:21]=[CH:22][NH:23][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:8][C:6]1[CH:7]=[C:2]([N:23]2[CH:24]=[C:20]([CH3:19])[N:21]=[CH:22]2)[N:3]=[C:4]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])[N:5]=1
Reactant: Cc1c[nH]cn1
Reactant: C[C@H](Nc1nc(Cl)cc(Cl)n1)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cn(-c2cc(Cl)nc(N[C@@H](C)c3ccc(F)cc3)n2)cn1
Temperature: 100 °C
Reaction time: 17 h
Yield: 26.7 %

Procedure:
200 mg of (S)-4,6-dichloro-N-[1-(4-fluorophenyl)ethyl]pyrimidine-2-amine and 63 mg of 4-methylimidazole were dissolved in 2 ml of dimethylformamide, and 193 mg of potassium carbonate was added thereto, and the mixture was stirred at 100° C. for 17 hours. The reaction solution was diluted with water, and then subjected to extraction with ethyl acetate. The organic layer was washed in turn with water and brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 62 mg of the objective compound as a white solid.
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22]>S(=O)(=O)(O)O>[O:8]=[CH:6][C@@H:5]([C@H:4]([C@@H:3]([C@@H:2]([CH2:1][OH:23])[OH:7])[OH:22])[OH:21])[OH:20]
Reactant: OC[C@H]1O[C@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@@H](O)[C@@H]1O
Agent: O=S(=O)(O)O
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 100 °C

Procedure:
The 250 MHz proton NMR spectral patterns of the white powder thus obtained are identical with those of commercially available trehalose. The white powder is found negative in the Somogyi-Nelson reducing sugar test. Furthermore, the white powder is dissolved in 0.05 N sulfuric acid to make a 20 mM solution, heated at 100° C. for 15 hours in a closed container to give 37 mM glucose according to an HPLC measurement.
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][N:7]=[C:6]([NH2:11])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:12][CH2:13][C:14](=O)[CH2:15]Cl>COCCOC.CCO>[Cl:12][CH2:13][C:14]1[N:11]=[C:6]2[N:7]([CH:15]=1)[CH:8]=[CH:9][C:10]1[N:1]=[CH:2][CH:3]=[CH:4][C:5]2=1
Reactant: O=C(CCl)CCl
Reactant: Nc1nccc2ncccc12
Solvent: COCCOC
Solvent: CCO
Product: ClCc1cn2ccc3ncccc3c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.7 %

Procedure:
To a solution of 1,6-naphthyridin-5-amine (145 mg, 1 mmol) in 1,2-dimethoxyethane (5 mL) was added 1,3-dichloropropan-2-one (140 mg, 1.1 mmol). The solid dissolved immediately and a white precipitate was observed. The mixture was stirred at room temperature for 1 h, and then was cooled to 0° C. for 20 min. The resulting mixture was filtered to give a white solid. The precipitate was suspended in EtOH (40 mL) and heated at reflux. After refluxing for 2 h, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in water and saturated aqueous NaHCO3 solution was added to adjust the pH value to 7. A white suspension formed during the course of addition. The resulting mixture was stirred for 20 min and then filtered to give 2-(chloromethyl)imidazo[2,1-f][1,6]naphthyridine as a white solid (130 mg). MS (ESI): m/z 218 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[O:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])=[CH:11][N:12]=1.[Li+].[OH-].Cl>O1CCOCC1.O>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:10]1[O:9][C:8]([CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:21])=[O:2])=[N:12][CH:11]=1
Reactant: COC(=O)CCCCc1ncc(-c2ccccc2OC)o1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccccc1-c1cnc(CCCCC(=O)O)o1
Temperature: 25 °C
Reaction time: 21 h
Yield: 75.3 %

Procedure:
Dissolve 5-[5-(2-methoxy-phenyl)-oxazol-2-yl]-pentanoic acid methyl ester (2.47 g, 8.54 mmol) in 40 mL of dioxane and add a solution of LiOH (1.0344 g, 43.19 mmol) in 20 mL of water to the solution. Allow the reaction to stir at ambient temperature for 21 hours. Acidify the reaction with 5N HCl and concentrate the reaction mixture in vacuo to remove the dioxane. Extract the aqueous residue with EtOAc (3×). Dry the combined organic layers with MgSO4. Filter off the drying agent and concentrate in vacuo to afford a crude residue. Recrystallize the residue in EtOAc/hexanes to afford 1.7692 g of the titled product (75%): mass spectrum: m/z=276.1 (M+H).
Reaction SMILES: C[Si](C)(C)CC[C:5]1([C:36]([O-:38])=[O:37])[CH:10]([CH3:11])[N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:8]([NH2:22])=[C:7]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:6]1[C:28]1[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=1>O1CCCC1>[NH2:22][C:8]1[N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:10]([CH3:11])=[C:5]([C:36]([OH:38])=[O:37])[CH:6]([C:28]2[CH:29]=[CH:30][C:31]([C:34]#[N:35])=[CH:32][CH:33]=2)[C:7]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)C1=C(N)N(c2cccc(C(F)(F)F)c2)C(C)C(CC[Si](C)(C)C)(C(=O)[O-])C1c1ccc(C#N)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(N)N(c2cccc(C(F)(F)F)c2)C(C)=C(C(=O)O)C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 410 mg (0.72 mmol) of the compound of Example 58 in 1.4 ml absolute tetrahydrofuran are added 1.43 ml (1.43 mmol) of a 1 M solution of N,N-tributyl-1-butanaminiumfluoride in tetrahydrofuran under argon at 0° C. After 5 minutes at 0° C., the reaction mixture is stirred at room temperature overnight. The solvent is removed in vacuo and the residue is purified by column chromatography on silica with dichloromethane/methanol 100:1→100:6 mixtures as eluent. The product containing fractions are combined and concentrated in vacuo. The residue is dissolved in 250 ml ethyl acetate and washed three times with 10% citric acid solution and brine. The organic phase is dried with magnesium sulfate and concentrated in vacuo. Trituration of the residue in ethyl acetate affords the title product.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[C:10]([CH3:20])=[CH:11][CH:12]=[C:13]2[C:18]=1[O:17][CH2:16][CH2:15][C:14]2=[O:19].Cl[C:22](Cl)([O:24]C(=O)OC(Cl)(Cl)Cl)Cl.C(Cl)(Cl)(Cl)Cl>CCOCC>[CH3:20][C:10]1[C:9]([N:8]=[C:22]=[O:24])=[C:18]2[C:13]([C:14](=[O:19])[CH2:15][CH2:16][O:17]2)=[CH:12][CH:11]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1ccc2c(c1N)OCCC2=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccc2c(c1N=C=O)OCCC2=O
Temperature: 25 °C
Yield: 276.5 %

Procedure:
0.15 ml of triethylamine was added to a mixture of 180 mg of 8-amino-7-methyl-4-chromanone, 103 mg of triphosgene and 8 ml of carbon tetrachloride at room temperature with stirring, and the reaction was allowed to proceed under reflux for 6.5 hr. The reaction mixture was cooled to room temperature, ether was added thereto, and insolubles were removed by filtration. The filtrate was concentrated to give 195 mg of the intended title compound.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([C:19]([OH:21])=O)[N:14]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:24]([CH2:26][NH2:27])[OH:25].O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.C(OCC)(=O)C>[OH:25][CH2:24][CH2:26][NH:27][C:19]([C:15]1[N:14]=[C:13]([C:10]2[CH:9]=[CH:8][C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:23][CH:22]=3)=[CH:12][CH:11]=2)[CH:18]=[CH:17][N:16]=1)=[O:21]
Reactant: O=C(O)c1nccc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NCCO)c1nccc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Temperature: 25 °C

Procedure:
To a mixture of 4-[4-(4-fluorophenoxy)phenyl]pyrimidine-2-carboxylic acid (1.03 g, 3.1 mmol), ethanolamine (0.31 mL, 5.08 mmol), and 1-hydroxybenzotriazol hydrate (0.53 g, 3.46 mmol) in DMF (20 mL) under nitrogen at 0° C. was added 4-methylmorpholine (0.76 mL, 6.9 mmol), and 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride (0.68 g, 3.48 mmol). The mixture was allowed to warm to room temperature overnight. The reaction was diluted with ethyl acetate, washed 3 times with water, dried over sodium sulfate, filtered, and evaporated under reduced pressure to give the desired product as an oil. 1H NMR (CDCl3): δ 8.82 (d, J=5.7 Hz, 1H), 8.50 (bs, 1H), 8.10 (d, J=8.7 Hz, 2H), 7.71 (d, J=5.1 Hz, 1H), 7.08-7.03 (m, 6H), 3.88 (t, J=4.2 Hz, 2H), 3.70 (q, J=4.8 Hz, 2H), 3.25 (bs, 1H).