Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[O:11]=[CH:12][C@@H]([C@H]([C@H](CO)O)O)O.P(OC[C@H](O)[C@H](O)C(=O)CO)(O)(O)=O.O=C[C@H]([C@@H]([C@@H](CO)O)O)O>C(O)C>[O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:12][OH:11])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)CO
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Agent: O=C(CO)[C@@H](O)[C@@H](O)COP(=O)(O)O
Agent: O=C[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CCO
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
The results presented in FIG. 3 show that in contrast to the control strain containing the shuttle vector alone (206C [pZB186]), the recombinant strain containing the added xylose isomerase, xylulokinase, L-arabinose isomerase, L-ribulokinase, L-ribulose 5-phosphate 4-epimerase, transaldolase and transketolase genes demonstrated growth on and ethanol production from xylose and arabinose, alone or in a combination as a carbon source. The recombinant strain produces ethanol from glucose as efficiently as the control strain at 94% of theoretical yield. The recombinant strain additionally produces ethanol from xylose, or arabinose, or xylose and arabinose at process yields of 91%, 55%, and 79% yield in 96 hours (47 hours for xylose only), respectively. Furthermore, in the presence of glucose and xylose and arabinose, the recombinant strain ferments all three sugars to ethanol at a process yield of 79% yield within 48 hours, thus providing the foundation for advanced process designs with cofermentation of mixed-sugar feedstocks. The recombinant strain produces ethanol from 2% xylose, 2% arabinose, 2% xylose and 2% arabinose, or 1% glucose, 2% xylose and 2% arabinose at 92%, 88%, 94% or 90% of theoretical consumed sugar yield, respectively. The control strain neither grew on nor produced ethanol from xylose, arabinose or xylose and arabinose.
Reaction SMILES: O.O.C([O-])(=O)C.[Li+].[Si:8]([O:15][C@@H:16]1[N:22]([C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])[C:21]2[CH:29]=[C:30]([O:35][Si](C(C)C)(C(C)C)C(C)C)[C:31]([O:33][CH3:34])=[CH:32][C:20]=2[C:19](=[O:46])[N:18]2[CH:47]=[C:48](/[CH:50]=[CH:51]/[CH3:52])[CH2:49][C@@H:17]12)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]>CN(C=O)C.C(OCC)(=O)C>[Si:8]([O:15][C@@H:16]1[N:22]([C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])[C:21]2[CH:29]=[C:30]([OH:35])[C:31]([O:33][CH3:34])=[CH:32][C:20]=2[C:19](=[O:46])[N:18]2[CH:47]=[C:48](/[CH:50]=[CH:51]/[CH3:52])[CH2:49][C@@H:17]12)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:9])[CH3:10]
Reactant: C=CCOC(=O)N1c2cc(O[Si](C(C)C)(C(C)C)C(C)C)c(OC)cc2C(=O)N2C=C(/C=C/C)C[C@H]2[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: CC(=O)[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1c2cc(O)c(OC)cc2C(=O)N2C=C(/C=C/C)C[C@H]2[C@@H]1O[Si](C)(C)C(C)(C)C
Reaction time: 4 h
Yield: 44.7 %

Procedure:
Lithium acetate dihydrate (0.31 g, 3.04 mmol, 1.0 eq) was added to a solution of the diazepine 11 (2.0 g, 3.04 mmol, 1.0 eq) in wet DMF (20 mL) at 25° C. and stirred for 4 hours. The reaction mixture was diluted with ethyl acetate (200 mL) and washed successively with 0.1M citric acid (50 mL, pH 3), water (50 mL) and brine (10 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 50/50 v/v n-hexane/EtOAc to 25/75 v/v n-hexane/EtOAc) to afford the product as a pale yellow solid (0.68 g, 45%). LC/MS (3.352 min (ES+)), m/z: 501.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.02 (s, 1H), 6.66 (m, 1H), 6.53 (s, 1H), 6.03 (d, 1H, J=15.5 Hz), 5.80 (s, 1H), 5.63 (d, 1H, J=8.9 Hz), 5.55 (m, 1H), 5.29 (m, 1H), 4.87 (m, 2H), 4.39 (dd, 1H, J=13.5, 4.2 Hz), 4.20 (dd, 1H, J=13.2, 5.7 Hz), 3.73 (s, 3H), 3.59 (m, 1H), 2.81 (dd, 1H, J=16.1, 10.5 Hz), 2.35 (d, 1H, J=15.7 Hz), 1.61 (d, 3H, J=6.4 Hz), 0.67 (s, 9H), 0.05 (s, 3H), 0.00 (s, 3H).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=2[S:17][CH3:18])[C:10]([O:12]C)=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.O.C(=O)([O-])[O-].[K+].[K+]>CO>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=2[S:17][CH3:18])[C:10]([OH:12])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1ccc(SC)c(OC2CCCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CSc1ccc(C(=O)O)cc1OC1CCCC1

Procedure:
A suspension of methyl 3-cyclopentyloxy-4-(methylthio)benzoate (0.8 g; that is prepared as described in Reference Example 54) in methanol (10 mL) and water (5 mL) is treated with potassium carbonate (0.48 g) and the mixture is heated at reflux for 7 hours. The mixture is concentrated, and the resulting residue is partitioned between diethyl ether (20 mL) and water (20 mL). The aqueous layer is separated, acidified to pH 1 by treatment with dilute hydrochloric acid (2N), and extracted with dichloromethane (2×25 mL). The combined organic extracts are dried and concentrated, to give 3-cyclopentyloxy-4-(methylthio)benzoic acid (0.7 g) in the form of a white solid m.p. 150°-152° C.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]3[C:10]([CH2:11][NH:12][CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[CH:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:35]1[CH:40]=[CH:39][N:38]=[CH:37][N:36]=1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]3[C:10]([CH2:11][N:12]([C:35]4[CH:40]=[CH:39][N:38]=[CH:37][N:36]=4)[CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[CH:14]1[CH2:15][CH2:16][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:18][CH2:19]1
Reactant: Clc1ccc2c(c1)CNCc1nnc(C3CCN(c4ccccn4)CC3)n1-2
Reactant: Clc1ccncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: Clc1ccc2c(c1)CN(c1ccncn1)Cc1nnc(C3CCN(c4ccccn4)CC3)n1-2
Temperature: 95 °C
Reaction time: 18 h
Yield: 13.4 %

Procedure:
A mixture of the amine from example 4 (500 mg, 1.3 mmol), potassium carbonate (480 mg, 3.5 mmol) and 4-chloropyrimidine (300 mg, 2.6 mmol) was stirred at 95° C. for 18 hours. The cooled reaction mixture was diluted with ethyl acetate and the solution was washed with brine (5×), then dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane:methanol (100:0 to 95:5) as eluant, and the product was triturated with diethyl ether to afford the title compound (80 mg).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[C:19]([CH3:20])=[C:18]([F:21])[C:17]([CH3:22])=[N:16]1)C1C=CC=CC=1>CO.[Pd]>[F:21][C:18]1[C:17]([CH3:22])=[N:16][N:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[OH:8])[C:19]=1[CH3:20]
Reactant: Cc1nn(-c2ccccc2OCc2ccccc2)c(C)c1F
Agent: [Pd]
Solvent: CO
Product: Cc1nn(-c2ccccc2O)c(C)c1F
Temperature: 25 °C
Yield: 100.2 %

Procedure:
416 mg of 1-(2-benzyloxyphenyl)-4-fluoro-3,5-dimethyl-1H-pyrazol was dissolved in 16 ml of methanol, and 42.6 mg of 10% palladium/carbon was added and stirred under hydrogen atmosphere at room temperature for a whole day and night. After the insoluble matter was filtered off, the filtrate was distilled off under reduced pressure and the resulting residue was purified using silica gel column chromatography (hexane:ethyl acetate=5:1) to yield 290 mg of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[N:9]([CH2:15][CH:16]([C:21]1([CH3:26])OCC[O:22]1)[C:17]([O:19][CH3:20])=[O:18])[C:8]2=[O:27])([CH3:4])([CH3:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[N:9]([CH2:15][CH:16]([C:21](=[O:22])[CH3:26])[C:17]([O:19][CH3:20])=[O:18])[C:8]2=[O:27])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(CN1C(=O)c2ccc(C(C)(C)C)cc2C1=O)C1(C)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COC(=O)C(CN1C(=O)c2ccc(C(C)(C)C)cc2C1=O)C(C)=O

Procedure:
Methyl 2-(5-t-butyl-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-3-oxo-butyrate was prepared (42 mg, 34%) in the same manner as described in the above example 6 (1) from methyl 3-(5-t-butyl-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.14 g, 0.34 mmol) and p-toluenesulfonic acid monohydrate (13 mg), and the obtained product was identified with the following NMR data.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH:15]1([C:18](Cl)=[O:19])[CH2:17][CH2:16]1>ClCCl>[CH:15]1([C:18]([N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)=[O:19])[CH2:17][CH2:16]1
Reactant: OC1CCNCC1
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C1CC1)N1CCC(O)CC1
Yield: 95.6 %

Procedure:
20 g of 4-hydroxypiperidine was dissolved in 400 ml of dichloromethane, to which 24 g of triethylamine was added. At -60° C., 100 ml of a dichloromethane solution containing 20.7 g of cyclopropanecarbonyl chloride was further added. After completion of the reaction, the reaction solution was extracted with chloroform under salting-out conditions and dried with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by the use of silica gel column chromatography (elution solvent: dichloroethane), thereby obtaining 32 g of the intended compound (yield 96%).
Reaction SMILES: N1CCCCC1.[CH2:7]([O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][C:13]=1[O:20][CH3:21])[C:8]#[C:9][CH3:10].C([CH2:25][C:26]([NH:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31]([OH:33])=[O:32])=[O:27])(O)=O.CC(O)=O>C1(C)C=CC=CC=1>[CH2:7]([O:11][C:12]1[CH:19]=[CH:18][C:15](/[CH:16]=[CH:25]/[C:26]([NH:28][C:29]2[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=2[C:31]([OH:33])=[O:32])=[O:27])=[CH:14][C:13]=1[O:20][CH3:21])[C:8]#[C:9][CH3:10]
Reactant: CC#CCOc1ccc(C=O)cc1OC
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CC#CCOc1ccc(/C=C/C(=O)Nc2ccccc2C(=O)O)cc1OC
Yield: 56.3 %

Procedure:
Piperidine (0.34 mL, 3.4 mmol) was added to a suspension of 4-(but-2-ynyloxy)-3-methoxybenzaldehyde (0.70 g, 3.4 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.70 g, 3.4 mmol) in toluene (10 mL) and treated according to Procedure 2, acidifying with 20% AcOH. (E)-2-{[3-(4-(But-2-ynyloxy)-3-methoxyphenyl)-1-oxo-2-propenyl]amino}benzoic acid (0.70 g, 61%) was obtained as a yellow crystalline solid; mp 194-195° C.; δH (400 MHz, DMSO-d6) 1.82 (s, 3H, CH3), 3.83 (s, 3H, OCH3), 4.77 (s, 2H, OCH2), 6.79 (d, J=15.6 Hz, 1H, CH═CHCO), 7.02 (d, J5′,6′=8.4 Hz, 1H, H5′), 7.14 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.23 (d, J5′,6′=8.4 Hz, 1H, H6′), 7.38 (s, 1H, H2′), 7.55 (d, J=15.6 Hz, 1H, CH═CHCO), 7.60 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 8.00 (d, J3,4=8.0 Hz, 1H, H3), 8.61 (d, J5,6=8.0 Hz, 1H, H6), 11.33 (s, 1H, NH), 13.59 (br s, 1H, CO2H); δC (100 MHz, DMSO-d6) 3.2, 55.7, 56.4, 74.6, 83.9, 110.7, 113.3, 116.8, 120.3, 120.4, 122.3, 122.8, 127.9, 131.2, 134.0, 141.1, 141.6, 148.6, 149.3, 164.2, 169.5; HRMS (ESI) calculated for C21H19NO6 [M+Na]+ 388.1155. found 388.1158; vmax 753, 1253, 1506, 1584, 1659, 2917, 3239, 3516 cm−1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([NH:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]1[NH:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([CH3:36])[CH:34]=2)[N:29]=[C:28]([C:37](O)=[O:38])[N:27]=1)=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:40][O:41][C:42]1[CH:48]=[CH:47][C:45]([NH2:46])=[CH:44][CH:43]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C.C(N(CC)CC)C.O>[C:1]([O:5][C:6]([NH:8][C:9]([NH:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]1[NH:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([CH3:36])[CH:34]=2)[N:29]=[C:28]([C:37]([NH:46][C:45]2[CH:47]=[CH:48][C:42]([O:41][CH3:40])=[CH:43][CH:44]=2)=[O:38])[N:27]=1)=[N:10][C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1ccc2nc(C(=O)O)nc(N[C@H]3CCCC[C@H]3NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2c1
Reactant: COc1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)c2nc(N[C@H]3CCCC[C@H]3NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c3cc(C)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.4 %

Procedure:
To a solution of 2.04 g of 4-{[(1S,2R)-2-({[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl}amino)cyclohexyl]amino}-6-methylquinazoline-2-carboxylic acid, 694 mg of 4-methoxyaniline, 1.08 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 762 mg of 1-hydroxybenzotriazole in 40 ml of N,N′-dimethylformamide, 1.57 ml of triethylamine was added, and then the mixture was stirred at room temperature for 24 hours. The reaction solution was mixed with water and then extracted with ethyl acetate. The organic layer was washed with water and saturated brine and then dried over magnesium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (chloroform) to obtain 2.08 g of the desirable compound as a white powder.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[N:14]=[C:15](OS(C(F)(F)F)(=O)=O)[C:16]4[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20][CH2:19][C:17]=4[N:18]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.[O:38]1[CH2:42][CH2:41][CH2:40][C@H:39]1[CH2:43][NH2:44]>CN(C=O)C>[O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[N:14]=[C:15]([NH:44][CH2:43][C@@H:39]4[CH2:40][CH2:41][CH2:42][O:38]4)[C:16]4[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20][CH2:19][C:17]=4[N:18]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(OS(=O)(=O)C(F)(F)F)c2C1
Reactant: NC[C@@H]1CCCO1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(NC[C@@H]3CCCO3)c2C1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
tert-Butyl 2-(4-(oxazol-5-yl)phenylamino)-4-(trifluoromethylsulfonyloxy)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (350 mg, 0.65 mmol, example 1b) was dissolved in DMF (2 mL). (S)-(tetrahydrofuran-2-yl)methanamine was added and the reaction mixture was stirred at 80° C. for 3 h. The solvent was evaporated under reduced pressure and the crude used in the subsequent step without purification. MS (ES+) m/z 493.3 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([NH2:9])[CH:5]=[CH:4][N:3]=1.[F:10][C:11]([F:16])([F:15])[C:12](O)=O>>[Cl:1][C:2]1[C:7]2[N:8]=[C:12]([C:11]([F:16])([F:15])[F:10])[NH:9][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccnc(Cl)c1N
Reactant: O=C(O)C(F)(F)F
Product: FC(F)(F)c1nc2c(Cl)nccc2[nH]1

Procedure:
A mixture of 400 mg (2.79 mmol) of 2-chloropyridine-3,4-diamine [H. Dvorakova et al., Collect. Czech. Chem. Commun., 58, 629 (1993)] and a few mL of trifluoroacetic acid was stirred at reflux overnight. The cooled solution was concentrated and then re-concentrated from ethanol. Flash chromatography of the residue on silica gel [0-10% of (9:1 methanol:concentrated ammonium hydroxide solution) in dichloromethane] yielded the title compound as a foam. LC-MS 222 (M+1).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:13]1([C:19]2[N:20]([CH2:30][C:31](O)=[O:32])[CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:23]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[C:13]1([C:19]2[N:20]([CH2:30][C:31]([N:4]3[CH2:5][CH2:6][N:1]([C:7]4[N:8]=[CH:9][CH:10]=[CH:11][N:12]=4)[CH2:2][CH2:3]3)=[O:32])[CH:21]=[C:22]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:23]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)Cn1cc(-c2ccccc2)nc1-c1ccccc1
Reactant: c1cnc(N2CCNCC2)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: O=C(Cn1cc(-c2ccccc2)nc1-c1ccccc1)N1CCN(c2ncccn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
40 mg 2-piperazin-1-yl-pyrimidine was added to 70 mg (2,4-diphenyl-imidazol-1-yl)-acetic acid, 80 mg TBTU, 50 μL TEA in 1 mL DMF. The reaction was stirred overnight at RT. The mixture was purified by HPLC to give 50 mg desired product.
Reaction SMILES: [C:1]12([CH2:11][OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Cl:13][C:14]1[C:15]([F:25])=[C:16]([CH:20]=[C:21]([F:24])[C:22]=1F)[C:17]([OH:19])=[O:18].CC(C)([O-])C.[K+]>CS(C)=O.CCOC(C)=O>[C:1]12([CH2:11][O:12][C:22]3[C:21]([F:24])=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[C:15]([F:25])[C:14]=3[Cl:13])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: O=C(O)c1cc(F)c(F)c(Cl)c1F
Reactant: OCC12CC3CC(CC(C3)C1)C2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C(O)c1cc(F)c(OCC23CC4CC(CC(C4)C2)C3)c(Cl)c1F
Reaction time: 0.5 h
Yield: 150.9 %

Procedure:
To a solution of 1-adamantylmethanol (309 mg) and 3-chloro-2,4,5-trifluoro-benzoic acid (391 mg) in DMSO (5.6 mL) at 14° C. (bath) was added potassium tert-butoxide (458 mg) gradually. The mixture was stirred at that temp for 30 min. Diluted with EtOAc, the contents were washed with 1:4 mixture of 1M HCl and 1M NaH2PO4 (3×) and brine, and dried (Na2SO4). After filtration and concentration, the product was obtained as white solid (1.00 g).
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]([S:19][CH3:20])[O:7][C@H:6]1[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=2)[CH:22]=1)(=[O:3])[CH3:2].Br[CH2:37][CH2:38][CH2:39][O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C([O-])([O-])=O.[K+].[K+]>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].CN(C=O)C.CCOCC>[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]([S:19][CH3:20])[O:7][C@H:6]1[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:37][CH2:38][CH2:39][O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:31][CH:30]=2)[CH:22]=1)(=[O:3])[CH3:2]
Reactant: BrCCCOCc1ccccc1
Reactant: CS[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(O)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CS[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(OCCCOCc4ccccc4)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
(2S,3S,4R,5S,6R)-2-(3-(4-hydroxybenzyl)-4-methylphenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyl triacetate (37, 2.01 g, 4.0 mmol), ((3-bromopropoxy)methyl)benzene (1.41 mL, 8.0 mmol), Bu4NI (148 mg, 0.40 mmol), and K2CO3 (2.76 g, 20 mmol) were combined in DMF (8 mL) under nitrogen and stirred overnight at room temperature. The reaction was diluted with Et2O, washed with saturated aqueous NaHCO3 and brine (with back extraction), dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (gradient 0-50% EtOAc/hexanes) to give alkylated product 47 as a glassy solid (2.36 g, 91% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.28-7.36 (m, 5 H), 7.10-7.18 (m, 2 H), 7.03 (s, 1 H), 6.97 (d, J=8.6 Hz, 2 H), 6.77-6.84 (m, 2 H), 5.33 (t, J=9.6 Hz, 1 H), 5.21 (t, J=9.6 Hz, 1 H), 5.12 (t, J=9.6 Hz, 1 H), 4.48-4.54 (m, 3 H), 4.38 (d, J=9.9 Hz, 1 H), 4.06 (t, J=6.3 Hz, 2 H), 3.83-3.96 (m, 2H), 3.66 (t, J=6.2 Hz, 2 H), 2.21 (s, 3 H), 2.17 (s, 3 H), 2.10 (s, 3H) 2.04-2.12 (m, 2 H), 2.01 (s, 3 H), 1.75 (s, 3 H); MS (ES+) [M+NH4]+=668.
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:19]/[C:20](/[C:29]([O:31][CH2:32]C)=[O:30])=[CH:21]\[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2F)[O:7][C@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2].[Br:39]C1C=CC(CC(=O)C(OC)=O)=CC=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:19]/[C:20](/[C:29]([O:31][CH3:32])=[O:30])=[CH:21]\[C:22]2[CH:27]=[CH:26][C:25]([Br:39])=[CH:24][CH:23]=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(=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
Reactant: COC(=O)C(=O)Cc1ccc(Br)cc1
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: COC(=O)/C(=C/c1ccc(Br)cc1)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: 34 %

Procedure:
The title compound was prepared as described for C4 using methyl 3-(4-bromophenyl)-2-oxopropanoate B18 (100 mg, 0.389 mmol), sodium hydride (10.27 mg, 0.428 mmol) and 2,3,4,6-tetra-O-acetyl-α-D-glucose bromide (160 mg, 0.389 mmol). The resulting compound was isolated in the form of white solid in 34% yield.
Reaction SMILES: [K].[NH:2]1[CH2:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Br)=[CH:12][CH:11]=1.CN(C)C=O>O>[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][N:4]2[C:5](=[O:7])[CH2:6][NH:2][C:3]2=[O:8])=[CH:12][CH:11]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: O=C1CNC(=O)N1
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CNC(=O)N1Cc1ccc(Cl)cc1
Temperature: 172.5 °C

Procedure:
Under a nitrogen atmosphere in a flame-dried flask, with magnetic stirring, the potassium salt of imidazolidine-2,4-dione (1.382 g, 10 mmol) and 4-chlorobenzyl bromide (2.055 g, 10 mmol) were combined with 15 mL of anhydrous N,N-dimethylformamide (DMF) and heated to 170-175° C. for 5 hours. The reaction was then cooled to room temperature and poured over 50 mL of water to produce a waxy white precicitate. Recrystallization from ethyl acetate hexanes produced the title product as a white crystalline solid, 0.775 g (34.5%)
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH:9]1([C:15]([O:17][CH3:18])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.Br[CH2:20][CH2:21][CH2:22][O:23][CH3:24]>O1CCCC1>[CH3:24][O:23][CH2:22][CH2:21][CH2:20][C:9]1([C:15]([O:17][CH3:18])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: COC(=O)C1CCCCC1
Reactant: COCCCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COCCCC1(C(=O)OC)CCCCC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a cooled (−78° C.) solution of lithium diisopropylamide (2.0 M, 12 mL) in tetrahydrofuran (10 mL) was added methyl cyclohexanecarboxylate (1.42 g) in tetrahydrofuran (10 mL). The mixture was stirred at −78° C. for 30 minutes and a solution of 1-bromo-3-methoxypropane (1.73 g) in tetrahydrofuran (10 mL) was added to the mixture. The mixture was stirred overnight and the temperature was allowed to warm up to room temperature. The mixture was quenched with aqueous NH4Cl and extracted with ethyl acetate (200 mL) and washed with water (3×), brine and dried over Na2SO4. Filtration and evaporation of the solvent gave the crude product which was used in the next reaction without further purification.