Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:27])=[CH:16][C:17]=3[O:19][CH:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[N:12]=[CH:11][N:10]=2)=[C:6]2[O:28][CH2:29][O:30][C:5]2=[CH:4][CH:3]=1.C1(C)C=CC(S(O[CH2:41][C:42]([F:45])([F:44])[F:43])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:27][CH2:41][C:42]([F:45])([F:44])[F:43])=[CH:16][C:17]=3[O:19][CH:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[N:12]=[CH:11][N:10]=2)=[C:6]2[O:28][CH2:29][O:30][C:5]2=[CH:4][CH:3]=1
Reactant: CN1CCC(Oc2cc(O)cc3ncnc(Nc4c(Cl)ccc5c4OCO5)c23)CC1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCC(Oc2cc(OCC(F)(F)F)cc3ncnc(Nc4c(Cl)ccc5c4OCO5)c23)CC1
Temperature: 95 °C
Yield: 48.7 %

Procedure:
A mixture of 4-(6-chloro-2,3-methylenedioxyanilino)-7-hydroxy-5-(N-methylpiperidin-4-yloxy)quinazoline (0.1 g), 2,2,2-trifluoroethyl 4-toluenesulphonate (0.071 g), potassium carbonate (0.08 g) and DMF (2 ml) was stirred and heated to 95° C. for 24 hours. The mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic solution was washed with water and with brine, dried over magnesium sulphate and evaporated The residue was purified by column chromatography on silica using a 45:46:4 mixture of methylene chloride, ethyl acetate and methanol as eluent. There was thus obtained the title compound (0.058 g); NMR Spectrum: (CDCl3) 1.95-2.1 (m, 2H), 2.1-2.3 (m, 2H), 2.32 (s, 3H), 2.3-2.45 (m, 2H), 2.75 (m, 2H), 4.48 (m, 2H), 4.64 (m, 1H), 6.05 (s, 2H), 6.6 (d, 1H), 6.74 (d, 1H), 6.78 (d, 1H), 6.97 (d, 1H), 8.5 (s, 1H), 9.28 (s, 1H); Mass Spectrum: M+H+ 511 and 513.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][CH:7]([NH2:8])[CH:3]([CH2:4]2)[CH2:2]1.FC(F)(F)S(O[C:15]1[C:16]2[CH2:37][N:36]([CH3:38])[CH2:35][CH2:34][C:17]=2[N:18]=[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[CH:31][N:30]=[C:29]3[CH3:33])=[CH:24][CH:23]=2)[N:20]=1)(=O)=O>C(Cl)Cl>[CH:3]12[CH2:4][CH:5]([CH2:1][CH2:2]1)[CH2:6][C@H:7]2[NH:8][C:15]1[C:16]2[CH2:37][N:36]([CH3:38])[CH2:35][CH2:34][C:17]=2[N:18]=[C:19]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([N:28]3[CH:32]=[CH:31][N:30]=[C:29]3[CH3:33])=[CH:26][CH:27]=2)[N:20]=1
Reactant: NC1CC2CCC1C2
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(OS(=O)(=O)C(F)(F)F)n2)CN(C)CC3)cc1
Solvent: ClCCl
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(N[C@@H]4CC5CCC4C5)n2)CN(C)CC3)cc1
Temperature: 35 °C
Reaction time: 2 h
Yield: 54.8 %

Procedure:
exo-2-Aminonorbornane (20.24 μl, 0.17 mmol) was added to a solution of 6-methyl-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl trifluoromethanesulfonate (80 mg, 0.17 mmol, Example 9a) in DCM (10 mL). The reaction was stirred at 35° C. for 2 h. Solvent was evaporated and the crude mixture dissolved in MeOH/DMSO and purified on preparative HPLC to give N4-((2R)-bicyclo[2.2.1]heptan-2-yl)-6-methyl-N2-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (40.0 mg, 47.8%).
Reaction SMILES: SCCO.[CH3:5][N:6]([C@@H:19]1[C@@H:26]2[C@@H:22]([CH2:23][N:24]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[CH2:25]2)[CH2:21][CH2:20]1)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O.N12CCCN=C1CCCCC2.C([O-])(O)=O.[Na+]>CN(C)C=O>[CH3:5][NH:6][C@@H:19]1[C@@H:26]2[C@@H:22]([CH2:23][N:24]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:37])[F:38])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[CH2:25]2)[CH2:21][CH2:20]1
Reactant: CN([C@H]1CC[C@@H]2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@@H]21)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: OCCS
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CN[C@H]1CC[C@@H]2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@@H]21
Reaction time: 0.5 h

Procedure:
2-Mercaptoethanol (0.056 mL, 0.793 mmol) was added dropwise to a mixture of N-methyl-2-nitro-N-((3aR,4S,6aS)-2-(4-(trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-yl)benzenesulfonamide (235 mg, 0.440 mmol) from Example 300 and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.166 mL, 1.101 mmol) in N,N-dimethylformamide (1 mL) at room temperature. The reaction mixture was stirred for 30 minutes, and 1 N NaHCO3 solution was added, The mixture was extracted with dichloromethane, and the separated the organic layer was concentrated. The resultant crude material was purified using a SF15-12 g cartridge (Analogix®, Burlington, Wis.) with a gradient of 0-5.5% methanol (2 N NH3)/dichloromethane over 20 minutes to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.17 (d, J=8.1, 2H), 7.94 (d, J=8.2, 2H), 4.93-4.86 (m, 1H), 3.34 (dd, J=9.8, 3.3, 1H), 3.14 (dd, J=9.7, 3.2, 1H), 3.06 (dd, J=9.7, 8.2, 1H), 2.65 (q, J=5.7, 1H), 2.57-2.46 (m, 1H), 2.29 (s, 3H), 2.25 (ddd, J=8.6, 5.0, 2.5, 1H), 1.86 (ddd, J=12.0, 8.6, 6.1, 1H), 1.80-1.72 (m, 1H), 1.61-1.32 (m, 1H), 1.32-1.19 (m, 2H); MS (ESI+) m/z 349 (M+H)+.
Reaction SMILES: [C:1]([CH:5]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[O:6][C:7]1[C:12]([CH2:13][CH:14]=[CH2:15])=[CH:11][C:10]([CH2:16][N:17]2[C:21]3=[N:22][C:23]([CH3:27])=[CH:24][C:25]([CH3:26])=[C:20]3[N:19]=[C:18]2[CH2:28][CH3:29])=[CH:9][C:8]=1[Cl:30])([O:3]C)=[O:2].[OH-].[Na+].Cl>CO>[C:1]([CH:5]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[O:6][C:7]1[C:12]([CH2:13][CH:14]=[CH2:15])=[CH:11][C:10]([CH2:16][N:17]2[C:21]3=[N:22][C:23]([CH3:27])=[CH:24][C:25]([CH3:26])=[C:20]3[N:19]=[C:18]2[CH2:28][CH3:29])=[CH:9][C:8]=1[Cl:30])([OH:3])=[O:2]
Reactant: C=CCc1cc(Cn2c(CC)nc3c(C)cc(C)nc32)cc(Cl)c1OC(C(=O)OC)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=CCc1cc(Cn2c(CC)nc3c(C)cc(C)nc32)cc(Cl)c1OC(C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.3 %

Procedure:
To a magnetically stirred solution of 0.230 g (0.46 mmol) of the product of Step D in 5.0 mL methanol was added 0.5 mL of a 5.0N solution of sodium hydroxide and the reaction was stirred at room temperature 3 hours. The reaction mixture was adjusted to pH=6 with 1.0N hydrochloric acid and then concentrated in vacuo. The residue was then purified on a silica gel flash chromatography column eluted with CHCl3MeOH--NH4OH (80:15:1). Evaporation of the purified fractions and drying in vacuo afforded 0.181 g (81%) of the title compound.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[C:8]([C:12]2[C:17]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:16][CH:15]=[CH:14][C:13]=2[OH:24])[CH:9]=[CH:10][CH:11]=1)([O:3][CH2:4][CH3:5])=[O:2].[C:25]12([C:35]3[CH:42]=[CH:41][C:38]([CH2:39]I)=[CH:37][C:36]=3[O:43][CH3:44])[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH2:26]1)[CH2:32]2.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C(C)C>[C:1]([C:6]1[CH:7]=[C:8]([C:12]2[C:17]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:16][CH:15]=[CH:14][C:13]=2[O:24][CH2:39][C:38]2[CH:41]=[CH:42][C:35]([C:25]34[CH2:34][CH:29]5[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]5)[CH2:26]3)[CH2:32]4)=[C:36]([O:43][CH3:44])[CH:37]=2)[CH:9]=[CH:10][CH:11]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)Cc1cccc(O)c1-c1cccc(C(=O)OCC)c1
Reactant: COc1cc(CI)ccc1C12CC3CC(CC(C3)C1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)Cc1cccc(OCc2ccc(C34CC5CC(CC(C5)C3)C4)c(OC)c2)c1-c1cccc(C(=O)OCC)c1
Yield: 62 %

Procedure:
Phenol 25 (0.656 g., 2.00 mmol, 1 equiv.; from Example 18) is dissolved in 15 mL of methyl isobutyl ketone. 4-[1-Adamantyl]-3-methoxybenzyl iodide (18b) (0.766 g., 2.00 mmol, 1 equiv.) and potassium carbonate (1.00 g., 7.2 mmol, 3.6 equiv.) are added and the mixture is heated to reflux for 5 hours. The solvents are evaporated and the residue is dissolved in methylene chloride. This solution is washed with water and brine, then dried (MgSO4), and concentrated. The crude material is chromatographed on silica gel using 50% CH2Cl2 /hexane to afford 3'-carboethoxy-2-[4-(1-adamantyl)-3-methoxyphenyl]methoxy-[1,1'-biphenyl]-6-acetic acid, ethyl ester (29d) (0.725 g., 1.24 mmol, 62%): 1H NMR (300 MHz, CDCl3) δ 8.06 (dd, J=2, 8 Hz, 1H, ArH), 7.98 (s, 1H, ArH), 7.50-7.47 (m, 2H, ArH), 7.33-6.97 (m, 4H, ArH), 6.69 (dd, J=2, 8 Hz, 1H, ArH), 6.57 (d, J=2 Hz, 1H, ArH), 4.97 (s, 2H, ArCH2O), 4.38 (q, J=7 Hz, 2H, CO2CH2), 4.03 (q, J=7 Hz, 2H, CO2CH2), 3.59 (s, 3H, CH3O), 3.41 (s, 2H, ArCH2CO2), 2.03 (s, 9H, adamantyl), 1.75 (s, 6H, adamantyl), 1.40 (t, J=7 Hz, 3H, CO2CH2CH3), 1.16 J=7 Hz, 3 Hz, CO2CH2CH3); 13C NMR (75 MHz, CDCl3) δ 171.48 (C=O), 166.54 (C=O), 158.84, 156.13, 137.62, 137.33, 135.74, 134.91, 134.21, 131.31, 131.05, 130.44, 128.82, 128.33, 128.14, 126.27, 122.82, 118.09, 111.49, 109.54, 69.75, 60.97, 60.77, 54.82, 40.55, 39.23, 37.13, 36.80, 29.09, 14.38, 14.12.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([CH2:31][CH3:32])[C:23](=[O:30])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:16]=3)=[CH:11][CH:10]=2)[S:3]1.O=C1NC(=O)C(CC2C=CC(C3C=CC=C(CC4C=CC=CC=4C(NCC)=O)C=3)=CC=2)S1>C1COCC1>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([CH2:31][CH3:32])[C:23](=[O:30])[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:16]=3)=[CH:13][CH:14]=2)[S:3]1
Reactant: CCN(Cc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1)C(=O)c1ccccc1
Agent: CCNC(=O)c1ccccc1Cc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1
Solvent: C1CCOC1
Product: CCN(Cc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1)C(=O)c1ccccc1

Procedure:
In a manner similar to that of Example 1(g), starting with 300 mg (0.7 mmol) of N-[4′-(2,4-dioxothiazolidin-5-ylidenemethyl)biphenyl-3-ylmethyl]-N-ethylbenzamide in 10 ml THF, 150 mg (50%) of N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl-N-ethylbenzamide, with a melting point of 157° C., are obtained.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1.[C:30](Cl)(Cl)=[O:31].C1(C)C=CC=CC=1>>[N:27]([C:26]1[CH:28]=[CH:29][C:23]([O:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)=[CH:24][CH:25]=1)=[C:30]=[O:31]
Reactant: O=C(Cl)Cl
Reactant: Nc1ccc(OCCOCCOCCOCCOCCOC2CCCCO2)cc1
Solvent: Cc1ccccc1
Product: O=C=Nc1ccc(OCCOCCOCCOCCOCCOC2CCCCO2)cc1
Reaction time: 3 h

Procedure:
To a stirred 0° C. solution of 29 (0.95 g, 2.30 mmol) in 5:1 DCM/TEA (30 mL) was added a 20% phosgene/toluene solution (2.43 mL, 4.59 mmol). After stirring for 3 h the reaction was concentrated under reduced pressure and carried on without further purification.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][Si:31]([CH3:49])([CH3:48])[CH:32](I)[CH2:33][C:34]([F:46])([F:45])[C:35]([F:44])([F:43])[C:36]([F:42])([F:41])[C:37]([F:40])([F:39])[F:38])=[CH:20][N:19]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:1]([O:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[N:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][Si:31]([CH3:48])([CH3:49])[CH2:32][CH2:33][C:34]([F:45])([F:46])[C:35]([F:44])([F:43])[C:36]([F:41])([F:42])[C:37]([F:38])([F:39])[F:40])=[CH:20][N:19]=2)=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOc1ccc(-c2ncc(OCCCCCC[Si](C)(C)C(I)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cn2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCCCCCOc1ccc(-c2ncc(OCCCCCC[Si](C)(C)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of compound 51 (0.89 g, 1.06 mmol) in THF (20 ml) was added dropwise to a stirred suspension of lithium aluminiumhydride (80 mg, 2.11 mmol) in THF (20 ml) under an atmosphere of dry nitrogen. The reaction mixture was stirred at room temperature overnight, heated to reflux for 1 h, cooled, washed with water and the organic layer extracted into ethyl acetate/hexane (3 times). The combined organic extracts were washed with brine, dried (MgSO4), the solvent removed in vacuo and the residues purified by column chromatography [40 g silica gel eluted with hexane/ethyl acetate (9:1)] to yield a colorless solid, which was recrystallized from ethanol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([N:15]=C=O)([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.COC(C)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([NH2:15])([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(N=C=O)CCCN(C(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CC1(N)CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 812 mg (3.38 mmol) rac-3-isocyanato-3-methyl-piperidine-1-carboxylic acid tert-butyl ester in 17 ml THF were added 16.9 ml 2N NaOH and the emulsion stirred vigorously at ambient temperature for 20 h. The emulsion was diluted with tert-butyl methyl ether and extracted three times. The combined extracts were washed with brine to neutral pH, dried over sodium sulfate, filtered and evaporated. The crude product was purified by column chromatography on silica gel with a gradient of heptane and 10 to 100% ethyl acetate then with ethyl acetate/MeOH provided the title compound: 232 mg colourless oil which crystallized at ambient temperature MS (m/e): 215.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13](=[CH2:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2.C1(C(N)C2CCCCC2)CCCCC1>C(O)C>[CH3:17][C@H:13]([C:14]([OH:16])=[O:15])[C:8]1[CH:7]=[CH:6][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:10]=2[CH:9]=1
Reactant: C=C(C(=O)O)c1ccc2cc(OC)ccc2c1
Agent: NC(C1CCCCC1)C1CCCCC1
Solvent: CCO
Product: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Yield: 208.5 %

Procedure:
In a 200 ml-volume autoclave were charged 15.4 mg (0.02 moles) of the [2,2'-bis(diphenylphosphino)-6,6'-dimethylbiphenyl]ruthenium-diacetate as prepared in Example 1, 2.45 g (5 mmoles) of 6-methoxy-α-methylene-2-naphthaleneacetic acid, 0.98 g (5 mmoles) of dicyclohexylmethylamine, and 50 ml of ethanol. The mixture was subjected to hydrogenation at 15° C. under a hydrogen pressure of 100 kg/cm2 for 12 hours, and the solvent was removed from the reaction mixture by distillation to obtain 2.40 g of naproxen (i.e., 6-methoxy-α-methyl-2-naphthaleneacetic acid). The yield was 97%.
Reaction SMILES: [OH:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N+:13]([O-:15])=[O:14])=[N:3]1.[CH3:16][N:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:18](Cl)=[O:19]>>[N+:13]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:4]1[CH:5]=[CH:6][N:2]([O:1][C:18](=[O:19])[N:17]([CH3:16])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:3]=1)([O-:15])=[O:14]
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: O=[N+]([O-])c1ccccc1-c1ccn(O)n1
Product: CN(C(=O)On1ccc(-c2ccccc2[N+](=O)[O-])n1)c1ccccc1

Procedure:
The title compound was prepared from 1-hydroxy-3-(2-nitrophenyl)pyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (94%, oil).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:17][N:18]3[CH:22]=[CH:21][N:20]=[CH:19]3)[CH2:12][CH:11]([C:13](=O)[CH3:14])[O:10][N:9]2[CH3:16])=[CH:4][CH:3]=1.Cl.[NH2:24][OH:25].[OH-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:17][N:18]3[CH:22]=[CH:21][N:20]=[CH:19]3)[CH2:12][CH:11]([C:13](=[N:24][OH:25])[CH3:14])[O:10][N:9]2[CH3:16])=[CH:4][CH:3]=1
Reactant: CC(=O)C1CC(Cn2ccnc2)(c2ccc(Cl)cc2)N(C)O1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=NO)C1CC(Cn2ccnc2)(c2ccc(Cl)cc2)N(C)O1
Temperature: 25 °C
Yield: 50 %

Procedure:
Under a nitrogen atmosphere, a solution of 3.00 g (0.00938 mol) of 1-[3-(4-chlorophenyl)-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidin-5-yl]ethanone [isomer A (3, R1 =4-Cl, R2 =CH3)], 0.69 g (0.010 mol) of hydroxylamine hydrochloride and 0.60 g (0.015 mol) of sodium hydroxide in 75 ml of ethanol is refluxed for 1 hour, cooled to ambient temperature, neutralized with 0.1N hydrochloric acid, and extracted with chloroform (2×50 ml). The combined organic extract is washed with 50 ml of saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo to give a white solid. Crystallization from ethanol gives 1.57 g (50%) of compound 4, melting point 214°-216° C. (ethanol). Anal. Calcd. for C16H19ClN4O2 : C, 57.40; H, 5.72; Cl, 10.59; N, 16.73. Found: C, 57.24; H, 5.80; Cl, 10.70; N, 16.62.
Reaction SMILES: [Li].C[Cu]C.[CH3:5][Li].[CH2:7]1[O:14][C@@H:13]2[O:15][C@H:8]1[CH:9]=[CH:10][C:11]2=[O:12].[Cl-].[NH4+]>[Cu](I)I.CCOCC>[CH3:5][C@@H:9]1[C@H:8]2[CH2:7][O:14][C@H:13]([O:15]2)[C:11](=[O:12])[CH2:10]1
Reactant: [Li]C
Reactant: O=C1C=C[C@H]2CO[C@@H]1O2
Agent: C[Cu]C
Agent: I[Cu]I
Agent: [Cl-]
Solvent: CCOCC
Product: C[C@H]1CC(=O)[C@@H]2OC[C@H]1O2
Temperature: -20 °C
Yield: 84.2 %

Procedure:
To dimethyl copper lithium solution prepared by adding 66.6 g of copper iodide (350 mmol) to 500 ml of methyl lithium (1.4 N, 700 mmol) according to a general method, 50 ml of anhydrous ether solution in which 44.1 g of levoglucosenone (350 mmol) is dissolved were added dropwise at -60° C. Thereafter, the resultant solution was stirred at -60° C. for thirty minutes, and then its reaction temperature was raised to -20° C. Next, the reacted solution was poured into saturated ammonium chloride aqueous solution, followed by stirring at room temperature for an hour, The resultant solution was filtered to remove insoluble substances. Next, the organic solvent layer was separated from the obtained filtrate. The residual aqueous layer was extracted with methylene chloride to obtain an extract, This extract and the organic layer as separated before were combined. The organic layer thus combined was washed with a saturated aqueous sodium chloride solution, and dried with anhydrous magnesium sulfate. The resultant organic layer was further filtered, and the filtrate was concentrated. The obtained residue was distilled under reduced pressure, thereby yielding 41.9 g of 1,6-anhydro-3,4-dideoxy-4-C-methyl-β-D-erythrohexopyranose-2-ulose (yield: 84.3%). This product exhibited the following physical properties;
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[O:13][CH3:14].C([NH:22][CH2:23][CH2:24]O)(OC(C)(C)C)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:14][O:13][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:2]=1[O:1][CH2:24][CH2:23][NH2:22])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1ccc(O)c(OC)c1
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc(OCCN)c(OC)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 91.2 %

Procedure:
To a stirred solution of ethyl 4-hydroxy-3-methoxybenzoate (1.46 g, 7.44 mmol), N-Boc ethanolamine (1.19 g, 7.38 mmol), PPh3 (2.53 g, 9.65 mmol) in THF (30 mL) was added DIAD (1.90 mL, 9.65 mmol), and the resulting mixture was then heated under reflux overnight. The mixture was evaporated to give a crude gum. The crude product was dissolved in CH2Cl2 (20 mL) and TFA (20 mL). The resulting mixture was stirred for 2.5 hr at room temp. The mixture was concentrated in vacuo and the residue was made basic with sat. NaHCO3 and extracted with CHCl3. The extract was washed with brine, dried over Na2SO4, and evaporated to give the 1.61 g (90% for 2 steps ) ethyl 3-methoxy-4-(2-aminoethoxy)benzoate as a yellow oil. 1H-NMR (CDCl3) d 1.39 (t, 3 H, J=7.3 Hz), 3.14-3.17 (m, 2 H), 3.92 (s, 3 H), 4.09-4.11 (m, 2 H), 4.36 (q, 2 H, J=7.3 Hz), 6.89 (d, 1 H, J=8.3 Hz), 7.56 (d, 1 H, J=2.0 Hz), 7.66 (dd, 1 H, J=2.0, 8.3 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC([N:38]1[CH:42]=[C:41]([CH2:43]O)[CH:40]=[N:39]1)=O)(C)(C)C>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:22]1[CH:23]=[CH:24][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:26][CH:27]=1)[CH2:43][C:41]1[CH:42]=[N:38][NH:39][CH:40]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1ccc(NC(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Reactant: CC(C)(C)OC(=O)n1cc(CO)cn1
Product: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Yield: 42.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 82 using 5-benzyloxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (5.94 g) and 1-(tert-butoxycarbonyl)-4-(hydroxymethyl)pyrazole (2.95 g) as starting materials, 5-benzyloxy-N-(4-isopropylphenyl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (3.00 g) was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]([C:12]3[CH:13]=[C:14]([NH:18][C:19]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)=[O:20])[CH:15]=[CH:16][CH:17]=3)=[N:9][NH:10][CH:11]=2)=[CH:3][CH:2]=1.C1COCC1.Cl[C:38]([O:40][CH2:41][CH3:42])=[O:39]>>[CH2:41]([O:40][C:38]([N:10]1[CH:11]=[C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[O:20])[CH:13]=2)=[N:9]1)=[O:39])[CH3:42]
Reactant: CCOC(=O)Cl
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)Nc1cccc(-c2n[nH]cc2-c2ccncc2)c1
Solvent: C1CCOC1
Product: CCOC(=O)n1cc(-c2ccncc2)c(-c2cccc(NC(=O)Nc3ccc(C(F)(F)F)cc3)c2)n1
Reaction time: 0.08 h
Yield: 77 %

Procedure:
To a suspension of 1-[3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-3-(4-trifluoromethyl-phenyl)-urea (100 mg, 0.236 mmol) (prepared as described in Example 6) in THF (10 mL) DIPEA (61 mg, 81 uL, 0.427 mmol) was added. The mixture was stirred for 5 minutes before adding ethyl chloroformate (31 mg, 27 uL, 0.283 mmol). After 2 hours the mixture was evaporated to dryness, taken up with ethyl acetate and washed three times with water. The organic phase was dried over Na2SO4, evaporated to dryness and triturated with diisopropyl ether to yield 4-pyridin-4-yl-3-{3-[3-(4-trifluoromethyl-phenyl)-ureido]-phenyl}-pyrazole-1-carboxylic acid ethyl ester (90 mg, 77%).