Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[NH2:7])([O-:3])=[O:2].[CH3:15][S:16](Cl)(=[O:18])=[O:17].C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([NH:7][S:16]([CH3:15])(=[O:18])=[O:17])[CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1)([O-:3])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 52.8 %

Procedure:
3-Nitro-5-trifluoromethylaniline (0.8 g; 4 mmol) was suspended in pyridine (5 mL), methanesulfonylchloride (0.6 mL; 8 mmol) was added at 0° C. and the mixture stirred for 5 hours at room temperature. A solution of sodium bicarbonate was then added to the reaction mixture and the precipitate obtained was washed with diluted hydrochloric acid and dried. 0.6 g (2.11; 52.8% yield) of N-(3-nitro-5-trifluoromethyl-phenyl)-methylsulfonamide were obtained as solid.
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:11]2[CH2:12][CH2:13][C:14]3([CH3:18])[O:16][O:17][C@:10]42[C@H:5]([C@@H:6]([CH3:20])[C@@H:7]([OH:19])[O:8][C@@H:9]4[O:15]3)[CH2:4][CH2:3]1.[CH3:21][N:22]=[C:23]=[O:24]>C(Cl)Cl>[CH3:1][C@H:2]1[C@@H:11]2[CH2:12][CH2:13][C:14]3([CH3:18])[O:16][O:17][C@:10]42[C@H:5]([C@@H:6]([CH3:20])[C@@H:7]([OH:19])[O:8][C@@H:9]4[O:15]3)[CH2:4][CH2:3]1.[CH3:21][NH:22][C:23](=[O:8])[O-:24]
Reactant: CN=C=O
Agent: C[C@H]1[C@@H](O)O[C@@H]2OC3(C)CC[C@H]4[C@H](C)CC[C@@H]1[C@@]24OO3
Solvent: ClCCl
Product: CNC(=O)[O-]

Procedure:
A solution of dihydroqinghaosu (284 mg, 1 mmol) in dry CH2Cl2 (6 ml) and methyl isocyanate (63 mg, 1.1 mmol) was refluxed for ca. 2 days. The solution was filtered and evaporated in vacuo at 40° C. to give a solid, which was chromatographed on a silica-gel column with petroleumether/AcOEt 8:2. The fraction obtained was evaporated to give a white powder (217.6 mg).
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].C(N(CC)CC)C.[F:11][C:12]([F:32])([F:31])[C:13]([N:15]([CH2:24][P:25]([O:29]Cl)([O:27]Cl)=[O:26])[CH2:16][C:17]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:18])=[O:14].[CH:33]([NH2:36])([CH3:35])[CH3:34]>O1CCCC1.CCOCC>[F:11][C:12]([F:32])([F:31])[C:13]([N:15]([CH:24]([NH:36][CH:33]([CH3:35])[CH3:34])[P:25]([OH:29])([O:27][S:3][CH2:1][CH3:2])=[O:26])[CH2:16][C:17]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:18])=[O:14]
Reactant: CC(C)N
Reactant: CCCCOC(=O)CN(CP(=O)(OCl)OCl)C(=O)C(F)(F)F
Reactant: CCS
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCOC(=O)CN(C(=O)C(F)(F)F)C(NC(C)C)P(=O)(O)OSCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 4 %

Procedure:
A solution of ethanethiol (2.9 ml, 0.04 mole) and triethylamine (5.6 ml, 0.04 mole) in tetrahydrofuran (50 ml.) was added to n-butyl N-trifluoroacetyl-N-(dichlorophosphonomethyl)glycinate (14.3 g, 0.04 mole) in 250 ml. of ether at 0° C. After three hours, the solution was filtered and the filtrate was added to a cooled (0° C.) solution of isopropylamine (6.8 ml, 0.08 mole) in 50 ml. of tetrahydrofuran. After stirring for 16 hours at 25° C., the solution was filtered and the filtrate concentrated in vacuo. The residual oil was dissolved in 100 ml. methylene chloride and washed with 3% hydrochloric acid, 3% ammonium hydroxide and saturated sodium chloride solution. Concentration in vacuo afforded an oil which was chromatographed on silica gel eluting with ethyl acetate-cyclohexane (1:1) to afford n-butyl N-trifluoroacetyl-N-(isopropylamino(ethylthio)phosphonomethyl)glycinate (0.7 g) as a white solid, m.p. 64°-65° C.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([CH2:15][O:16]C(=O)C)[O:8][C@H:7]([O:20][C:21]2[CH:26]=[CH:25][C:24](Br)=[CH:23][C:22]=2[CH3:28])[C@H:6]1CC([O-])=O)(=O)C.[CH3:33][NH:34][C:35]([C:37]1[CH:38]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH:40]=[CH:41][CH:42]=1)=[O:36].C(=O)([O-])[O-:53].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:33][NH:34][C:35](=[O:36])[C:37]1[CH:38]=[CH:39][CH:40]=[C:41]([C:24]2[CH:25]=[CH:26][C:21]([O:20][C@@H:7]3[C@@H:6]([OH:53])[C@@H:5]([OH:4])[C@H:10]([OH:11])[C@@H:9]([CH2:15][OH:16])[O:8]3)=[C:22]([CH3:28])[CH:23]=2)[CH:42]=1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)OC[C@H]1O[C@H](Oc2ccc(Br)cc2C)[C@@H](CC(=O)[O-])[C@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: CNC(=O)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1cccc(-c2ccc(O[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]3O)c(C)c2)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
Under nitrogen atmosphere, the mixture of [(2R,3S,4S,5R,6R)-4,5-diacetoxy-6-(acetoxymethyl)-2-(4-bromo-2-methyl-phenoxy)tetrahydropyran-3-yl]acetate (0.517 g, 1 mmol), 3-(N-methylaminocarbonyl)phenylboronic acid pinacol ester (0.392 g, 1.5 mmol), cesium carbonate (0.977 g, 3 mmol) and tetrakis(triphenylphosphine)palladium (0.116 g, 0.1 mmol) in dioxane/water (15 mL/3 mL) was heated at 80° C. with stirring for 1 h under a nitrogen atmosphere. After cooling to RT, the mixture was filtered through silica gel column to remove the metal catalyst and salts with hexane/ethyl acetate combinations as eluent. The filtrate was concentrated, and then dried in vacuo. The residue was diluted with 15 mL of methanol containing a catalytic amount of sodium methoxide (0.02 M) and the mixture was stirred at RT overnight. H+ exchange resin (DOWEX 50WX4-100) was added to neutralize the mixture. The resin was filtered off and the filtrate was concentrated. The resulting residue was purified by silica gel chromatography with CH2Cl2/MeOH combinations as eluent, giving the title compound (0.260 g) in 64% yield for two steps. 1H NMR (300 MHz, METHANOL-d4) δ ppm 7.94 (t, J=1.65 Hz, 1H), 7.57-7.72 (m, 2H), 7.33-7.50 (m, 3H), 7.23 (d, J=8.52 Hz, 1H), 5.48 (d, J=1.92 Hz, 1H), 4.00 (dd, J=1.79, 3.43 Hz, 1H), 3.83-3.94 (m, 1H), 3.60-3.76 (m, 3H), 3.46-3.58 (m, 1H), 2.87 (s, 3H), 2.24 (s, 3H). MS (ESI): found: [M+H]+, 404.2.
Reaction SMILES: [CH3:1][C:2]1C=C[N:5]=[CH:4][N:3]=1.[Mn]([O-])(=O)(=O)=O.[K+].[OH-:14].[K+].[CH2:16]([OH:18])[CH3:17]>O>[N:3]1[CH:2]=[CH:1][C:17]([C:16]([OH:14])=[O:18])=[N:5][CH:4]=1
Reactant: [OH-]
Reactant: Cc1ccncn1
Reactant: CCO
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)c1ccncn1
Temperature: 75 °C

Procedure:
4-Methylpyrimidine (1.00 g, 10.6 mmol) was diluted in water (90 mL). Potassium permanganate (4.20 g, 26.5 mmol) and potassium hydroxide (4.20 g, 74.8 mmol) were added, and the mixture was heated at 75° C. for 1.5 h. Ethanol was added dropwise, and the precipitate was removed by filtration through Celite. The filtrate was concentrated under reduced pressure, diluted in water, and treated with a concentrated HCl solution until acidic. The title compound precipitated as a fine powder, which was collected by vacuum filtration and dried in a vacuum oven (770 mg, 58%): 1H NMR (DMSO-d6) δ: 13.92 (1H, br s), 9.35 (1H, d), 9.05 (1H, d), 7.99 (1H, dd).
Reaction SMILES: C([N:8]1[C:20]2[CH:19]=[CH:18][C:17]([Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([Si:31]([CH:38]([CH3:40])[CH3:39])([CH:35]([CH3:37])[CH3:36])[CH:32]([CH3:34])[CH3:33])[CH:13]=2)C1C=CC=CC=1.C1COCC1.O=O>CS(C)=O>[CH:38]([Si:31]([CH:32]([CH3:34])[CH3:33])([CH:35]([CH3:37])[CH3:36])[C:12]1[CH:11]=[CH:10][C:9]2[NH:8][C:20]3[C:15]([C:14]=2[CH:13]=1)=[CH:16][C:17]([Si:21]([CH:25]([CH3:27])[CH3:26])([CH:28]([CH3:30])[CH3:29])[CH:22]([CH3:23])[CH3:24])=[CH:18][CH:19]=3)([CH3:40])[CH3:39]
Reactant: CC(C)[Si](c1ccc2c(c1)c1cc([Si](C(C)C)(C(C)C)C(C)C)ccc1n2Cc1ccccc1)(C(C)C)C(C)C
Agent: O=O
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC(C)[Si](c1ccc2[nH]c3ccc([Si](C(C)C)(C(C)C)C(C)C)cc3c2c1)(C(C)C)C(C)C
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 52.1 %

Procedure:
A 500 ml dry round bottom flask was charged with 9-benzyl-3,6-bis-triisopropylsilanyl-9H-carbazole 4 (23.0 g, 0.04 mol) and the oil was suspended in 100 ml DMSO. The suspension was cooled in an ice water bath (˜15° C.) and 1M KOBu-t in THF (240 ml, 0.24 mol) was added via a syringe under nitrogen. Oxygen started to bubble in the mixture and the nitrogen line was suppressed. While the oxygen bubbling was taking place, the mixture was left to warm up to ˜20° C. and cooling continued with only water. The oxygen bubbling continued until the starting material (TLC) disappeared, i.e., after ˜30 min. Water was added to the mixture and the mixture was extracted with 5×200 ml ethylacetate. To remove the benzoic acid organic layer, the mixture was washed with sat. NaHCO3, followed by brine washing. The organic layer was then dried over Na2SO4, filtered, concentrated, and purified over a 330 g SiO2 column with hexane and hexane:ethylacetate (95:5) eluents. Appropriate fractions were collected to yield a white solid of 3,6-bis-triisopropylsilanyl-carbazole 5 10.0 g (54%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]=[C:12](Cl)Cl.[CH2:15]([NH2:19])[CH2:16][CH2:17][NH2:18]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]=[C:12]1[NH:19][CH2:15][CH2:16][CH2:17][NH:18]1
Reactant: NCCCN
Reactant: O=[N+]([O-])c1ccc(Cl)c(N=C(Cl)Cl)c1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Cl)c(N=C2NCCCN2)c1
Temperature: 7.5 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
(2-Chloro-5-nitrophenyl)carbonimidic dichloride (35.5 g, 140 mmol) was dissolved in tetrahydrofuran (135 mL). The solution was added dropwise within 30 min to a solution of 1,3-propanediamine (58 mL, 700 mmol) in tetrahydrofuran (335 mL) which was kept at 5-10° C. The reaction mixture was stirred for 1 h at 5-10° C. another 2 hr at room temperature. The suspension was filtered, and washed with tetrahydrofuran. The filtrate was concentrated in vacuo. The residue was taken up in water, filtered, and washed with water and diisopropyl ether. After drying at 50° C. under vacuum, the title compound (35.0 g, 137.4 mmol, 98%) was obtained as yellow crystals.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH2:12][OH:13])[CH:6]=1)[CH2:3][NH2:4].[C:14]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](=O)[CH3:32])=[CH:26][CH:25]=1)([O:16]CC1C=CC=CC=1)=[O:15].O>C1(C)C(C)=CC=CC=1>[C:14]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH:31]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH2:12][OH:13])[CH:6]=2)[CH3:32])=[CH:26][CH:25]=1)([OH:16])=[O:15]
Reactant: CC(=O)Cc1ccc(C(=O)OCc2ccccc2)cc1
Reactant: NCC(O)c1ccc(O)c(CO)c1
Solvent: Cc1ccccc1C
Solvent: O
Product: CC(Cc1ccc(C(=O)O)cc1)NCC(O)c1ccc(O)c(CO)c1
Reaction time: 3 h

Procedure:
2-Hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethanamine (1.09 g) and 1-(4-carbobenzyloxyphenyl)propan-2-one (1.6 g) were refluxed in xylene in a Dean and Stark apparatus until the theoretical amount of water had been collected. The solvent was removed, ethanol added and the mixture hydrogenated at 70 psi and 50° for 3 hours using 10% Pd/c as catalyst. Filtration of the catalyst and evaporation of the solvent gave the title compound as a foam τ(d6DMSO) 8.95 (3H, d, J=7 Hz), 6.8-7.4 (5H, m), 5.5 (2H, s+1H, t), 3.65 (5H, broad), 2.3-3.3 (5H, m), 2.0 (2H, d, J=8 Hz).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][C:11]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:10]2=[O:19])=[CH:5][CH:4]=1)[CH3:2].O=C(Cl)[O:22][C:23](Cl)(Cl)Cl.[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=1>>[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH:34][C:23]([N:16]2[CH2:17][CH2:18][C:11]3([C:10](=[O:19])[N:9]([C:6]4[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=4)[CH2:13][CH2:12]3)[CH2:14][CH2:15]2)=[O:22])=[CH:31][CH:30]=1
Reactant: NCc1ccc(F)cc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CCc1ccc(N2CCC3(CCNCC3)C2=O)cc1
Product: CCc1ccc(N2CCC3(CCN(C(=O)NCc4ccc(F)cc4)CC3)C2=O)cc1

Procedure:
This material was prepared in analogy to example 251 step B) from 2-(4-Ethyl-phenyl)-2,8-diaza-spiro[4.5]decan-1-one, diphosgene and 4-Fluoro-benzylamine. MS (ESI): 410.4 (MH+).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[CH2:9][C@H:8]([S:10][C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][N:6]1[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=1)=[O:31])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.N>N1C=CC=CC=1>[NH2:1][CH2:4][C@@H:5]1[CH2:9][C@H:8]([S:10][C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:7][N:6]1[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=1)=[O:31]
Reactant: [N-]=[N+]=NC[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: c1ccncc1
Product: NC[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 123.9 %

Procedure:
A solution of (2S,4S)-2-azidomethyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (5.18 g) and triphenylphosphine (3.75 g) in pyridine (15 ml) was stirred at ambient temperature for 1 hour. To a reaction mixture was added conc. ammonia water (1.2 ml) with stirring at ambient temperature and the mixture was allowed to stand overnight at the same temperature. The solution was evaporated in vacuo to give a residue. The residue was chromatographed on silica gel (100 g) eluting with a mixture of chloroform and methanol (9:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-2-aminomethyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (6.13 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6]2.[C:17]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([C:21]1[CH:22]=[CH:23][C:24]([CH2:25][N:8]2[C:9]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)[CH:6]=[C:7]2[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:27][CH:28]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CCOC(=O)c1cc2cc(OC)ccc2[nH]1
Reactant: CC(C)(C)c1ccc(CBr)cc1
Product: CCOC(=O)c1cc2cc(OC)ccc2n1Cc1ccc(C(C)(C)C)cc1

Procedure:
The title compound was prepared from ethyl 5-methoxy-1H-indole-2-carboxylate and 4-(tert-butyl) benzyl bromide in substantially the same manner, as described in step 1 of Example 1. The product was obtained as a solid. Mass spectrum (ESI, [M−H]−) m/z 364. 1H NMR (400 MHz, DMSO-d6) δ 7.48 (d, 1H, J=9.20 Hz), 7.27 (s, 1H), 7.24 (d, 2H, J=7.18 Hz), 7.16 (d, 1H, J=2.44 Hz), 6.96-6.92 (m, 3H), 5.77 (s, 2H), 4.28 (q, 2H), 3.76 (s, 3H), 1.28 (s, 3H), and 1.20 ppm (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=O)[NH:5][CH:4]=1.O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:6]1[C:7]2[C:12](=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[C:3]([O:2][CH3:1])=[CH:4][N:5]=1
Reactant: COc1ccc2c(=O)[nH]cc(OC)c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(Cl)ncc(OC)c2c1
Yield: 27.5 %

Procedure:
A solution of 4,6-dimethoxyisoquinolin-1(2H)-one (4 g, 19.49 mmol) in POCl3 (40 mL) was refluxed for 18 h. The solvent was evaporated under reduced pressure and the residue was diluted with cold water. The aqueous solution was basified by solid sodium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography (20% ethyl acetate in pet ether) to get desired compound (1.2 g, 27.5%) as pale yellow solid. 1H NMR (400 MHz, CDCl3): δ ppm 8.16-8.13 (d, J=12 Hz, 1H), 7.74 (s, 1H), 7.44-7.43 (d, J=4 Hz, 1H), 7.30-7.27 (d, J=12 Hz, 1H), 7.26 (s, 1H), 4.05 (s, 3H), 3.97 (s, 3H); MS: MS m/z 224.2 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([O:9][CH2:10][C@H:11]([OH:14])[CH2:12][OH:13])=[O:8])=[CH:5][CH:4]=1.O([Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])S(C(F)(F)F)(=O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][CH2:10][C@H:11]([O:14][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:12][O:13][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])=[O:8])=[CH:15][CH:16]=1
Reactant: COc1ccc(C(=O)OC[C@H](O)CO)cc1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C(=O)OC[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a 1.0 L RB flask containing (R)-2,3-dihydroxypropyl 4-methoxybenzoate (4.800 g, 21.2 mmol; according to the procedure described in Corey, E. J.; Guzman-Perez, A.; and Noe, M. C. J. Am. Chem. Soc. 1995, 117, 10805-10816) was added DCM (100 mL ) and the mixture was allowed to stir at 0° C. for 5 minutes. At this time, TEA (8.87 ml, 63.7 mmol) was added and the reaction was allowed to stir for 5 min before the dropwise addition of tert-butyldimethylsilyl triflate (10.2 ml, 44.6 mmol) via syringe. The reaction was allowed to stir for 1 h and then quenched by pouring into HCl (0.1 N, 100 mL). The aqueous layer was extracted with DCM (2×75 mL). The combined organics were washed with HCl (0.1 N, 2×150 mL), sodium bicarbonate (1×150 mL, sat), brine, dried sodium sulfate. The concentrated solution was passed through a plug of silica gel to and concentrated to give the title compound as a colorless oil.
Reaction SMILES: [OH:1][CH:2]([CH:4]1[CH2:9][CH2:8][C:7]([CH3:10])=[CH:6][CH2:5]1)[CH3:3].C(O)(=O)C.C(O[N:20]=[O:21])CCC.[ClH:22]>O>[Cl:22][C:7]1([CH3:10])[CH2:8][CH2:9][CH:4]([CH:2]([OH:1])[CH3:3])[CH2:5][C:6]1=[N:20][OH:21]
Reactant: CC1=CCC(C(C)O)CC1
Reactant: Cl
Reactant: CCCCON=O
Solvent: O
Solvent: CC(=O)O
Product: CC(O)C1CCC(C)(Cl)C(=NO)C1
Temperature: 0 °C

Procedure:
To a mixture of 21.0 g. (0.133 mole) of 4-(1-hydroxyethyl)-1-methyl-cyclohexene, 23 mg. glacial acetic acid and 26 ml. n-butylnitrite at 0° C. there is added dropwise a solution of 5 ml. concentrated hydrochloric acid and 5 ml. glacial acetic acid. After two additional hours while maintaining the temperature at 0° C., 500 ml. water is added and the solution is extracted with diethyl ether. These ether extracts are washed with water and brine and dried over magnesium sulfate. The magnesium sulfate is removed by filtration and the solution evaporated to give 2-chloro-5-(1-hydroxyethyl)-2-methyl-cyclohexanone oxime. To this compound is added 12.0 g. anhydrous sodium acetate and 50 ml. glacial acetic acid. This mixture is heated at 100° for one hour and poured into 250 ml. water. After sitting for several hours, the aqueous solution is extracted several times with ether and the combined ether extracts are washed with brine and sodium bicarbonate, dried over magnesium sulfate, filtered and evaporated to give 1,3-dimethyl-2-oxabicyclo[2,2,2]octan-6-one-oxime.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:23])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=O)=[CH:13][C:12]=1[O:21][CH3:22].[CH3:24][O:25][C@@H:26]1[CH2:30][NH:29][C@H:28]([CH2:31][O:32][C:33]2[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=2)[CH2:27]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:23])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([N:29]2[CH2:30][C@@H:26]([O:25][CH3:24])[CH2:27][C@H:28]2[CH2:31][O:32][C:33]2[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=2)=[O:20])=[CH:13][C:12]=1[O:21][CH3:22]
Reactant: COC(=O)c1ccc(OC[C@@H]2C[C@H](OC)CN2)cc1
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC[C@@H]2C[C@H](OC)CN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3Cl)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 86.6 %

Procedure:
A mixture of 4-[N′-(2-chlorophenyl)ureido]-3-methoxyphenylacetic acid (398 mg, 1.19 mmol), methyl 4-[(2S,4S)-4-methoxy-2-pyrrolidinyl]methoxybenzoate (317 mg, 1.19 mmol), EDC.HCl (342 mg, 1.79 mmol), HOBT (242 mg, 1.79 mmol) and Et3 N (0.83 ml, 5.95 mmol) in DMF (5 ml) was stirred at room temperature for 13 h. The mixture was poured into ice water and extracted with EtOAc. The combined extracts were washed with ice water and brine. After dried over Na2SO4, the extracts were concentrated in vacuo. The residue was chromatographed on silica gel [50 g, CHCl3/Aectone (10/1)CHCl3/MeOH (20/1)], to give methyl 4-[(2S,4S)-1-[4-[N′-(2-chlorophenyl)ureido]-3-methoxyphenylacetyl]-4-methoxy-2-pyrrolidinyl]methoxybenzoate (600 mg, 87%) as a colorless amorphous solid 1H-NMR (CDCl3) δ 1.99–2.06 (m, 1H), 2.34 (d, J=13.9 Hz, 1H), 3.30 (s, 3H), 3.59 (d, J=7.4 Hz, 1H), 3.62 (d, J=3.2 Hz, 2H), 3.83 (s, 3H), 3.88 (s, 3H), 4.00–4.18 (m, 3H), 4.42–4.51 (m, 2H), 6.82–7.07 (m, 7H), 7.28 (d, J=8.3 Hz, 1H), 7.35 (dd, J=7.9, 1.5 Hz, 1H), 7.94–8.00 (m, 3H), 8.18(d, J=8.3 Hz, 1H); MS (ESI) m/z 582 (M++1), 584 (M++3).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([NH:8][CH2:9][C:10]2([C:25]([F:28])([F:27])[F:26])[C:15]3[CH:16]=[C:17]([C:20]([NH:22]C)=O)[CH:18]=[CH:19][C:14]=3[NH:13][C:12](=[O:24])[O:11]2)=[O:7])=[CH:4][CH:3]=1.[N-:31]=[N+:32]=[N-:33].[Na+].[Cl-].[NH4+].O>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH2:9][C:10]2([C:25]([F:26])([F:27])[F:28])[C:15]3[CH:16]=[C:17]([C:20]4[NH:33][N:32]=[N:31][N:22]=4)[CH:18]=[CH:19][C:14]=3[NH:13][C:12](=[O:24])[O:11]2)=[O:7])=[CH:29][CH:30]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CNC(=O)c1ccc2c(c1)C(CNC(=O)c1ccc(F)cc1)(C(F)(F)F)OC(=O)N2
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1Nc2ccc(-c3nnn[nH]3)cc2C(CNC(=O)c2ccc(F)cc2)(C(F)(F)F)O1
Temperature: 110 °C
Reaction time: 12 h

Procedure:
N-{[6-cyano-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-4-yl]methyl}-4-fluorobenzamide (30 mg, 0.076 mmol) synthesized in Example 159, sodium azide (24.8 mg, 0.38 mmol) and ammonium chloride (20.4 mg, 0.38 mmol) were dissolved in DMF (0.5 mL), and the solution was stirred for 12 hours under heating at 110° C. Water was added to the solution and the solution was extracted twice with ethyl acetate-ethanol, and the resulting organic layer was dried over magnesium sulfate. After the drying agent was removed by filtration, the solvent was evaporated under reduced pressure. The residue was purified by reverse-phase HPLC, whereby the objective compound (3.4 mg, 10%) was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6](I)[CH:5]=1.[C:13]1([O:19][CH2:20][C:21]#[CH:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:8][CH:9]=1)[NH:10][C:21]([CH2:20][O:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:22]2)=[O:12]
Reactant: C#CCOc1ccccc1
Reactant: COC(=O)c1ccc(N)c(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2[nH]c(COc3ccccc3)cc2c1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
Resin bound 4-amino-3-iodo-benzoic acid methyl ester was suspended in DMF and treated with 15.6 g of phenyl propargylether, 60 ml of triethylamine and catalytic amounts of Cul and bis(triphenylphosphine)palladium(II) chloride. The resin was shaken for 6 h at 50° C. and washed subsequently with DMF, isopropanol/water and diethylether.