Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[NH:18])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.C(=O)(O)[O-].[Na+].Br[CH2:25][C:26](=[O:31])[C:27]([F:30])([F:29])[F:28].N1C=CNC1>C(O)(C)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=3)[CH2:25][C:26]([OH:31])([C:27]([F:30])([F:29])[F:28])[N:18]=2)=[N:6][CH:7]=1
Reactant: O=C(CBr)C(F)(F)F
Reactant: CSc1ccc(NC(=N)c2ccc(C)cn2)cc1
Agent: C1=CNCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CSc1ccc(N2CC(O)(C(F)(F)F)N=C2c2ccc(C)cn2)cc1

Procedure:
To a mixture of the amidine of step 2 (10 g, 52.41 mmol) and sodium bicarbonate (8.6 g, 103 mmol) in isopropanol (1200 ml), 3-bromo-1,1,1-trifluoroacetone (10 g, 52 mmol) was added. After heating at reflux for 22 hours, the reaction mixture was cooled and filtered. The residue was dissolved in methylene chloride and washed water than brine. The organic extracts were dried (MgSO4), filtered and concentrated. The crude mixture was purified by chromatography (silica gel, 100% ethyl acetate) to give. the desired dihydro-imidazole (5.1 g): Anal Calc'd. for C17H16N3SOF3: C, 55.58; H, 4.39; N, 11.44. Found: C, 55.54; H, 4.35; N, 11.20.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([C@@H:14]([CH3:19])[CH2:15][C:16]([OH:18])=O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(Cl)(=O)C(C)(C)C.C([Li])CCC.[C:32]1([C@H:38]2[CH2:42][O:41][C:40](=[O:43])[NH:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.O1CCNC1=O>O1CCCC1>[C:32]1([C@H:38]2[CH2:42][O:41][C:40](=[O:43])[N:39]2[C:16](=[O:18])[CH2:15][C@@H:14]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH3:19])[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C1N[C@@H](c2ccccc2)CO1
Reactant: C[C@@H](CC(=O)O)c1ccccc1
Agent: CC(C)(C)C(=O)Cl
Agent: O=C1NCCO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H](CC(=O)N1C(=O)OC[C@@H]1c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.4 %

Procedure:
Triethylamine (1.3 mL, 9.1 mmol) was added to (S)-3-phenylbutyric acid (1.0 g, 6.1 mmol) in anhydrous tetrahydrofuran (60 mL) at −78° C. followed by the dropwise addition of pivaloyl chloride (0.83 ml, 6.7 mmol) to give a white solid. The reaction was allowed to warm to room temperature for 10 minutes then cooled back down to −78° C. In a separate flask, n-butyllithium (4.6 mL, 11.6 mmol, 2.5 M F in hexanes) was added to (S)-(+)-4-phenyl-2-oxazolidinone (2.0 g, 12.2 mmol) in anhydrous tetrahydrofuran at −78° C. and allowed to stir for 10 minutes. The lithiated oxazolidinone was transfered via cannula to the mixed anhydride at −78° C. and stirring continued for 2 hours. The reaction was quenched with water (25 mL) and extracted with ethyl acetate. The combined extracts were washed with water, brine and dried over sodium sulfate. The crude product was purified by chromatography over silica gel eluted with 2:3 ethyl acetate/hexanes and the resulting solid was recrystallized from ethyl acetate/hexanes to afford (S)-4-phenyl-3-((S)-3-phenyl-butyryl)-oxazolidin-2-one (1.63 g, 88% yield).
Reaction SMILES: C([O:5][C:6](=[O:46])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([C:44]#[N:45])[CH:39]=2)[CH:16]2[CH2:21][CH2:20][N:19]([CH:22]([CH3:36])[CH2:23][CH2:24][NH:25][C:26](=[O:35])[C:27]3[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:34])[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)(C)(C)C.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:44]([C:40]1[CH:39]=[C:38]([CH:43]=[CH:42][CH:41]=1)[CH2:37][N:15]([CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([CH3:36])[CH2:23][CH2:24][NH:25][C:26](=[O:35])[C:27]2[C:28]([CH3:34])=[CH:29][CH:30]=[CH:31][C:32]=2[CH3:33])[CH2:18][CH2:17]1)[C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:46])=[O:5])=[CH:10][CH:11]=1)#[N:45]
Reactant: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(OCC(=O)OC(C)(C)C)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(OCC(=O)O)cc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52 %

Procedure:
To a solution of COMPOUND 143 in CH2Cl2 (2 mL) was added anisole (0.1 mL, 0.92 mmol) followed by TFA (2 mL) and the solution was stirred at room temperature for 90 minutes to afford COMPOUND 149 as a white solid (200 mg, 52%) after a basic work-up and purification. 1H NMR (CD3OD) δ 1.29 (d, 3H, J=6.3 Hz), 1.76-1.89 (m, 5H), 2.07-2.28 (m, 1H), 2.28 (s, 6H), 2.86-3.03 (m, 2H), 3.19-3.27 (m, 3H), 3.37-3.51 (m, 2H), 3.67-3.75 (m, 1H), 4.19 (s, 2H), 4.24 (s, 2H), 6.76 (s, 4H), 7.02 (d, 2H, J=7.5 Hz), 7.11-7.16 (m, 1H), 7.36-7.41 (m, 1H), 7.48-7.55 (m, 3H). 13C NMR (CD3OD) δ 12.82, 18.45, 27.43, 31.16, 36.74, 46.73, 49.61, 50.48, 56.06, 59.61, 67.86, 112.19, 115.51, 118.98, 119.18, 127.52, 128.96, 129.51, 130.55, 130.77, 132.17, 134.23, 137.73, 142.53, 142.92, 152.96, 172.43, 176.24. ES-MS m/z 569 (M+H). Anal. Calcd. for C34H40N4O4.0.6CH2Cl2: C, 67.06; H, 6.70; N, 9.04. Found. C, 66.95; H, 6.64; N, 8.91.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([S:13][CH2:14][C:15]([NH:17][CH2:18][C@@H:19]3[O:24][CH2:23][CH2:22][N:21]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=4)[CH2:20]3)=[O:16])[S:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[C:34](OC(=O)C)(=[O:36])[CH3:35].O>N1C=CC=CC=1>[NH:1]([C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([S:13][CH2:14][C:15]([NH:17][CH2:18][C@@H:19]3[O:24][CH2:23][CH2:22][N:21]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=4)[CH2:20]3)=[O:16])[S:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1)[C:34]([CH3:35])=[O:36]
Reactant: Nc1cccc(-c2csc(SCC(=O)NC[C@H]3CN(Cc4ccc(Cl)c(Cl)c4)CCO3)n2)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1cccc(-c2csc(SCC(=O)NC[C@H]3CN(Cc4ccc(Cl)c(Cl)c4)CCO3)n2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the resultant product (262 mg) of Example 9 in pyridine (2 mL) was added dropwise acetic anhydride (57 μL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent. The solvent was evaporated from the eluent to give the title compound (279 mg) as a white amorphous solid.
Reaction SMILES: [C:1]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Br:14]NC(=O)CCC(N)=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[CH:8][CH:9]=1
Reactant: NC(=O)CCC(=O)NBr
Reactant: Cc1ccc(C(=O)C(C)(C)C)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)C(=O)c1ccc(CBr)cc1

Procedure:
To a suspension of 28.5 g. (1.17 g. atoms) magnesium turnings in 150 ml. tetrahydrofuran under a nitrogen atmosphere there is added 10 ml. of 4-bromotoluene (1.17 mole) in 650 ml. dry tetrahydrofuran, the reaction is started and the remainder of the bromotoluene solution is added dropwise at a rate that maintains a moderate reflux. After the addition is complete, the mixture is refluxed for an additional 1 1/2 hours. The resulting Grignard solution is added dropwise to a cold solution of 128.0 g. pivaloyl chloride (1.06 mole) in 500 ml. dry tetrahydrofuran at a rate that maintains the temperature at 0° to -5°C. The solution is stirred for an additional 1 1/2 hours at 0° and then at room temperature for 18 hours. The mixture is then cooled to 0° and hydrolyzed by the addition of 100 ml. 2N hydrochloric acid. The layers are separated and 200 ml. of ether is added to the organic phases which is then washed respectively with 100 ml. 2N hydrochloric acid, 100 ml. 10% sodium bicarbonate solution and 100 ml. saturated sodium chloride. The resulting layer is dried over anhydrous sodium sulfate, filtered, and the solvent is removed in vacuo to give p-pivaloyl toluene (b.p. 80°-84°C./0.7 mm,nD21 1.5108). A mixture of 156.3 g. (0.886 mole) of the resulting p-pivaloyl toluene is then added to 157.8 g. (0.886 mole) N-bromosuccinamide, 4.0 g. (0.016 mole) benzoyl peroxide and 150 ml. carbon tetrachloride and heated at reflux for 18 hours. The mixture is cooled and filtered and the resulting precipitate is washed with carbon tetrachloride. The solvents are removed in vacuo and the resulting oil is distilled in vacuo to give α-bromo-p-pivaloyl toluene (b.p. 124°-132°C./0.7 mm, nD22 1.5546-V.P.C. 96% monobromo 4%-dibromo).
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([CH2:12][CH2:13][CH:14]=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]1([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]1([C:7]2[CH:11]=[C:10]([CH2:12][CH2:13][CH2:14][N:25]3[CH2:26][CH2:27][N:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:23][CH2:24]3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CCCc1cc(-c2ccccc2)no1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: c1ccc(-c2cc(CCCN3CCN(c4ccccc4)CC3)on2)cc1
Yield: 67.3 %

Procedure:
About 2 min after dissolving 3-(3-phenylisoxazol-5-yl)propanal (10 mg, 0.05 mmol) and 1-phenylpiperazine (7.6, 0.05 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (32 mg, 0. 15 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 16 hr and followed the same processes as in Example 1 to obtain 11.7 mg (67.3%) of the target compound.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[CH2:20]([O:22][C:23]([C:25]1[C:26](=[O:45])[C:27]2[CH:32]=[N:31][C:30](S(C)(=O)=O)=[N:29][C:28]=2[N:37]([CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)[CH:38]=1)=[O:24])[CH3:21]>>[CH2:20]([O:22][C:23]([C:25]1[C:26](=[O:45])[C:27]2[CH:32]=[N:31][C:30]([NH:18][C:15]3[CH:14]=[CH:13][C:12]([CH:9]4[CH2:8][CH2:7][N:6]([C:4](=[O:5])[CH2:3][N:2]([CH3:19])[CH3:1])[CH2:11][CH2:10]4)=[CH:17][CH:16]=3)=[N:29][C:28]=2[N:37]([CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)[CH:38]=1)=[O:24])[CH3:21]
Reactant: CCOC(=O)c1cn(C2CCCCC2)c2nc(S(C)(=O)=O)ncc2c1=O
Reactant: CN(C)CC(=O)N1CCC(c2ccc(N)cc2)CC1
Product: CCOC(=O)c1cn(C2CCCCC2)c2nc(Nc3ccc(C4CCN(C(=O)CN(C)C)CC4)cc3)ncc2c1=O

Procedure:
Using the procedure outlined in Example 1(g) the title compound was prepared from 4-[1-(2-dimethylamino-acetyl)-piperidin-4-yl]-phenylamine (from Example 70(B)), 73 mg, 0.28 mmol) and 8-cyclohexyl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 17(e), 100 mg, 0.26 mmol). The title compound was obtained as a white solid (40 mg, 25%). 1H NMR (400 MHz, CDCl3) δ (ppm): 9.21 (s, 1H), 8.99 (s, 1H), 8.41 (s, 1H), 7.47 (d, J=8.5 Hz, 2H), 7.13 (d, J=8.5 Hz, 2H), 4.96 (m, 3H), 4.31 (q, J=7.1 Hz, 2H), 3.00 (m, 4H), 2.77 (m, 1H), 2.30 (s, 6H), 1.93 (m, 6H), 1.64 (m, 5H), 1.42 (m, 2H), 1.34 (t, J=7.1 Hz, 3H), 1.18(m, 1H).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)#[N:4].Cl[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:18][N+:17]=1[O-].P(Cl)(Cl)Cl>CN(C)C=O.C(OCC)(=O)C>[OH:14][C:9]1[NH:10][C:11]2[C:7]([C:8]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[CH:18][N:17]=1)=[CH:6][C:5]([C:3]#[N:4])=[CH:13][CH:12]=2
Reactant: [O-][n+]1cc(CN2CCOCC2)ccc1Cl
Reactant: N#Cc1ccc2c(c1)CC(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: ClP(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc2[nH]c(O)c(-c3ccc(CN4CCOCC4)cn3)c2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 44.5 %

Procedure:
To a suspension of sodium hydride (105 mg, 2.62 mmol, 60% in oil) in N,N-dimethylformamide (2 mL) was added 5-cyanooxindole (310 mg, 1.96 mmol). The mixture was stirred at room temperature for 10 min. To the obtained yellowish solution was added 2-chloro-5-(morpholin-4-ylmethyl)pyridine 1-oxide (299 mg, 1.31 mmol) and the mixture was heated under nitrogen at 130° C. for 30 min. The dark reaction mixture was allowed to cool and the solvent was removed in vacuo. The residue was partitioned between a 2 M aqueous solution of HCl and ethyl acetate. The aqueous layer was carefully saturated with NaHCO3 (s) and extracted twice with ethyl acetate. The two last organic layers were combined, dried (Na2SO4) and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (50 mL) and a concentrated solution of phosphorus trichloride (0.5 mL, 5.7 mmol) in ethyl acetate (3 mL) was added. A yellowish precipitate was formed. The mixture was stirred at room temperature overnight and then heated at 60° C. for 30 min and finally at reflux for 10 min. The mixture was allowed to cool and was then diluted with ethyl actetate and washed with a saturated aqueous NaHCO3 solution. The aqueous layer was extracted repeatedly with ethyl acetate. The combined organic layers were dried (Na2SO4) and the solvent was removed in vacuo. The residue was purified on a silica gel column using chloroform/ethyl acetate, (9:1), as the eluent affording 195 mg (45% yield) of the title compound as a yellow solid: mp 228-230° C.; 1H NMR (DMSO-d6, 400 MHz) δ 14.79 (br s, 1 H), 10.87 (s, 1 H), 8.10 (s, 1 H), 7.91 (s, 1 H), 7.84 (d, J=9 Hz, 1 H), 7.79 (dd, J=9, 1 Hz, 1 H), 7.28 (d, J=8 Hz, 1 H), 7.00 (d, J=8 Hz, 1 H), 3.58 (t, J=4 Hz, 4 H), 3.39 (s, 2 H), 2.38 (br s, 4 H); 13C NMR (DMSO-d6, 100 MHz) δ 168.6, 148.4, 142.0, 136.9, 135.9, 125.2, 124.0, 122.3, 121.0, 118.7, 118.3, 108.7, 101.2, 84.4, 66.1, 58.3, 52.8; MS (ESP) m/z 335 (M++1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.Cl.[OH:12][CH:13]1[CH2:16][NH:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:15]2[CH2:16][CH:13]([OH:12])[CH2:14]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Reactant: OC1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CC(O)C2)nc1

Procedure:
2-Bromo-5-nitropyridine (406 mg, 2 mmol), 3-hydroxyazetidine hydrochloride (199 mg, 2 mmol), and finely ground potassium carbonate (828 mg, 6 mmol) were heated to 80° C. in 20 mL anhydrous DMF for 5 hrs. The mixture was diluted with EtOAc, extracted with H2O and dried over MgSO4. The EtOAc layer was filtered, evaporated to dryness and used without further purification. ES-MS calcd for C8H9N3O3 (m/e) 195.18, obsd 196.2 (M+H).
Reaction SMILES: [N:1]([N+]([O-])=O)=[O:2].[CH2:6]([N:11]([CH:18]([OH:33])[C@H:19]1[O:25][C@:23]([CH2:26][CH2:27][CH2:28][CH3:29])([OH:24])[C@H:22]([OH:30])[C@@H:21]([OH:31])[C@@H:20]1[OH:32])[C:12](=[O:17])[NH:13][CH2:14][CH2:15][Cl:16])[CH2:7][CH:8]([CH3:10])[CH3:9]>O1CCCC1.C(O)(=O)C>[CH2:6]([N:11]([CH:18]([OH:33])[C@H:19]1[O:25][C@:23]([CH2:26][CH2:27][CH2:28][CH3:29])([OH:24])[C@H:22]([OH:30])[C@@H:21]([OH:31])[C@@H:20]1[OH:32])[C:12](=[O:17])[N:13]([CH2:14][CH2:15][Cl:16])[N:1]=[O:2])[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: O=N[N+](=O)[O-]
Reactant: CCCC[C@]1(O)O[C@H](C(O)N(CCC(C)C)C(=O)NCCCl)[C@@H](O)[C@H](O)[C@H]1O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCC[C@]1(O)O[C@H](C(O)N(CCC(C)C)C(=O)N(CCCl)N=O)[C@@H](O)[C@H](O)[C@H]1O
Yield: 60.4 %

Procedure:
Dinitrogen trioxide gas (0.6 g) was introduced into a solution of 3-isopentyl-3-(n-butyl α-D-glucopyranose-6-yl)-1-(2-chloroethyl)urea (2.15 g, 5.23 mmol), synthesized in the above-mentioned way, in a mixture of tetrahydrofuran (50 ml) and acetic acid (8 ml) with well stirring at 0° to 5° C. After continuation of stirring for 2 hours, the resulting solution was vacuum-concentrated at 25° C. and purified by column chromatography (packing: Kiesel gel 60; eluent: chloroform/methanol 10:1), giving 1.44 g of 3-isopentyl-3-(n-butyl α-D-glucopyranose-6-yl)-1-(2-chloroethyl)-1-nitrosourea; yield 62.6%, m.p. 66°-68° C., [α]D20 +65.2° (C 1.0, methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:13][C:14](=[S:26])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[CH:18][CH:17]=2)[CH:5]=[C:6]([Cl:12])[C:7]=1[O:8][CH2:9][CH2:10][OH:11].[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>N1C=CC=CC=1.O1CCCC1.C(OCC)(=O)C>[C:23]([NH:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:14](=[S:26])[NH:13][C:4]2[CH:3]=[C:2]([Cl:1])[C:7]([O:8][CH2:9][CH2:10][O:11][C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:6]([Cl:12])[CH:5]=2)=[CH:17][CH:18]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)Nc1ccc(NC(=S)Nc2cc(Cl)c(OCCO)c(Cl)c2)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(NC(=S)Nc2cc(Cl)c(OCCOC(=O)c3ccccc3)c(Cl)c2)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To an ice cooled solution of N-(4-(3-[3,5-dichloro-4-(2-hydroxy-ethoxy)-phenyl]-thioureido}-phenyl)-acetamide (0.20 g) in pyridine (2 mL) and tetrahydrofuran (0.5 mL) is added benzoyl chloride (0.08 g) and the mixture is stirred at 0° C. for 1.5 hours. The mixture is then diluted with ethyl acetate, washed successively two times with 2% aqueous hydrochloric acid, once with saturated aqueous sodium chloride, then dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure the residue is chromatographed over silica gel (5% methanol in dichloromethane is used as the eluant) and product containing fractions are combined, evaporated under reduced pressure, and the residue is recrystallized from acetone-hexanes to provide the desired product as a white powder.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]1[CH:34]=[CH:33][C:14]2[N:15]=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[N:22][CH:23]=3)[S:17][C:13]=2[CH:12]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:35]I.O>CN(C=O)C>[C:3]([O:7][C:8]([N:10]([CH3:35])[C:11]1[CH:34]=[CH:33][C:14]2[N:15]=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[N:22][CH:23]=3)[S:17][C:13]=2[CH:12]=1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2nc3ccc(NC(=O)OC(C)(C)C)cc3s2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1ccc2nc(-c3ccc(CNC(=O)OC(C)(C)C)nc3)sc2c1
Temperature: 0 °C
Yield: 91.1 %

Procedure:
NaH (95%, 4.5 mg, 0.18 mmol) was added to a solution of tert-butyl (5-{6-[(tert-butoxycarbonyl)amino]-1,3-benzothiazol-2-yl}pyridin-2-yl)methylcarbamate (66 mg, 0.14 mmol) in DMF (2 mL). The mixture was cooled to 0° C. and MeI (10 μL, 0.16 mmol) was added. The reaction was stirred at rt on. Water was added and the mixture was extracted with EtOAc (3×) The combined organic phases were dried (MgSO4) and concentrated. Flash chromatography (Heptane/EtOAc gradient) gave the product (60 mg) as a white solid. MS m/z (M+H) 471.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]([NH:8][C:9]([NH2:11])=[S:10])=[N:6][CH:7]=1.[C:19]([N:22]1[CH2:27][CH2:26][CH:25]([C:28](=O)[CH2:29]Br)[CH2:24][CH2:23]1)(=[O:21])[CH3:20].CCN(C(C)C)C(C)C>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:5]([NH:8][C:9]2[S:10][CH:29]=[C:28]([CH:25]3[CH2:26][CH2:27][N:22]([C:19](=[O:21])[CH3:20])[CH2:23][CH2:24]3)[N:11]=2)=[N:6][CH:7]=1
Reactant: CC(=O)N1CCC(C(=O)CBr)CC1
Reactant: NC(=S)Nc1ncc(Br)cc1Oc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(=O)N1CCC(c2csc(Nc3ncc(Br)cc3Oc3ccccc3)n2)CC1
Temperature: 60 °C
Yield: 95 %

Procedure:
1-(5-bromo-3-phenoxypyridin-2-yl)thiourea (Example 1, Step E; 30.0 g, 92.5 mmol) and 1-(1-acetylpiperidin-4-yl)-2-bromoethanone (Example 2, Step C, 32.1 g, 130 mmol) were suspended in ethanol (400 mL) and DIEA (48.3 mL, 278 mmol) was added. The resulting mixture was heated to 60° C. for 4 hours and then at ambient temperature overnight. The reaction was concentrated to dryness, dissolved in CH2Cl2 and washed with saturated aqueous sodium bicarbonate, water, dried over Na2SO4, filtered and concentrated. The resulting material was purified on silica eluting with 3% MeOH/EtOAc to give 1-(4-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)piperidin-1-yl)ethanone (41.6 g, 95.0% yield) as a tan solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1.[Li]CCCC.[C:17]([Si:21]([CH3:44])([CH3:43])[O:22][C:23]1[N:28]=[CH:27][C:26]([C:29]2[CH:30](O)[O:31][C:32]3[C:37]([C:38]=2[CH3:39])=[CH:36][CH:35]=[C:34]([O:40][CH3:41])[CH:33]=3)=[CH:25][CH:24]=1)([CH3:20])([CH3:19])[CH3:18].Cl>O1CCCC1.C1(C)C=CC=CC=1.CCCCCC>[C:17]([Si:21]([CH3:44])([CH3:43])[O:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH:30]([C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][Cl:1])=[CH:6][CH:7]=3)[O:31][C:32]3[C:37]([C:38]=2[CH3:39])=[CH:36][CH:35]=[C:34]([O:40][CH3:41])[CH:33]=3)=[CH:27][N:28]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: COc1ccc2c(c1)OC(O)C(c1ccc(O[Si](C)(C)C(C)(C)C)nc1)=C2C
Reactant: ClCCOc1ccc(I)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)OC(c1ccc(OCCCl)cc1)C(c1ccc(O[Si](C)(C)C(C)(C)C)nc1)=C2C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
In a single neck, 100 mL round bottom flask was dissolved and stirred 1-(2-chloro-ethoxy)-4-iodo-benzene (530 mg, 1.88 mmol, 5.0 eq), in tetrahydrofuran (5 mL) under nitrogen, and the mixture cooled to −78° C. After 5 minutes of stirring, a hexane solution of n-BuLi (0.75 mL of 2.5 M, 1.88 mmol, 5.0 eq) was added via syringe. The reaction mixture was then stirred for 30 min at about −78° C. A tetrahydrofuran solution of 3-[6-(tert-butyl-dimethyl-silanyloxy)-pyridin-3-yl]-7-methoxy-4-methyl-2H-chromen-2-ol (150 mg, 0.376 mmol, 1 eq, in 2 mL), prepared as in Example 24, was then added, the cooling bath was removed and the reaction mixture was allowed to warm to room temperature overnight. After about 18 hours, the reaction was worked-up with addition of saturated ammonium acetate solution and extraction with ethyl ether. The combined organic extracts were washed with brine and water, dried with anhydrous sodium sulphate, filtered and evaporated to yield a sticky semisolid residue. To this solid was added 0.2 mL HCl in 10 mL toluene at room temperature. The mixture was stirred for 2 hours at room temperature. The reaction was worked-up with sodium bicarbonate washing and extraction with ethyl acetate three times. The combined organic extracts were washed with brine and water, dried with anhydrous sodium sulphate, filtered and evaporated to yield a brown oil. The title product was isolated as a white semisolid foam via chromatography on silica gel eluted with 1:1 hexanes:ethyl acetate as eluent.
Reaction SMILES: Br[CH:2]([CH2:8]Br)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:17]1[CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:8][NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]1=2
Reactant: Nc1ccccc1O
Reactant: CCOC(=O)C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1CNc2ccccc2O1
Temperature: 25 °C

Procedure:
To a solution of ethyl 2,3-dibromopropionate (8.05 g, 31.0 mmol, Aldrich) in acetone (35 mL) was added o-aminophenol (3.38 g. 31.0 mmol) and potassium carbonate (5.1 g, 36.9 mmol). The reaction mixture was stirred at reflux under a water condenser for 18 h. Upon cooling to room temperature, the reaction was concentrated in vacuo, and the residue was taken up in water (50 mL) and the product was extracted using EtOAc (3×75 mL). The organic fractions were combined, washed with saturated brine (15 mL), dried over sodium sulfate, and concentrated. Purification of the product by flash column chromatography (30% EtOAc/hexane) afforded the title compound as a yellow oil. MS m/z: 208 (M+1).