Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:13]1[O:17][C:16]2[CH:18]=[C:19]([OH:22])[CH:20]=[CH:21][C:15]=2[O:14]1.O[CH2:24][N:25]1[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]2[C:26]1=[O:35]>C(Cl)(Cl)Cl.ClCCl>[OH:22][C:19]1[CH:18]=[C:16]2[O:17][CH2:13][O:14][C:15]2=[CH:21][C:20]=1[CH2:24][N:25]1[C:26](=[O:35])[C:27]2=[CH:34][CH:33]=[CH:32][CH:31]=[C:28]2[C:29]1=[O:30]
Reactant: Oc1ccc2c(c1)OCO2
Reactant: O=C1c2ccccc2C(=O)N1CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: O=C1c2ccccc2C(=O)N1Cc1cc2c(cc1O)OCO2
Yield: 54.9 %

Procedure:
p-Toluenesulfonic acid monohydrate (3.61 g, 19.0 mmol) was dried by azeotropic distillation in a chloroform solution (100 mL). The remaining solution (50 mL) was cooled, 9.14 g (66.2 mmol) sesamol, 10.01 g (57 mmol) N--(hydroxymethyl)-phthalimide, and 100 mL chloroform were added, and the resulting green solution was refluxed overnight. The black reaction mixture was cooled to ambient, diluted to 500 mL with chloroform, and washed three times with saturated sodium bicarbonate. The pooled aqueous phases were back extracted with ethyl acetate, which was combined with the chloroform solution and dried over sodium sulfate. The residue that resulted from evaporation of solvents on a rotary evaporator was taken up in dichloromethane and filtered through a short column of silica gel. A dichloromethane rinse of the silica gel was combined with the eluent and evaporated to yield 9.3 g of N--(2-hydroxy-4,5-methylenedioxybenzyl)-phthalimide as a yellow solid (55%), which exhibited one spot on TLC (Rf =0.6; dichloro-methane). IR: 1768 and 1699 cm-1. 1HNMR (200 MHz): δ 7.81-7.90 (2H, m); 7.70-7.79 (2H, m); 7.76 (1H, s); 6.86 (1H, s); 6.52 (1H, s); 5.88 (2H, s); and 4.73 ppm (2H, s).
Reaction SMILES: C1C2C(CO[C:16]([NH:18][C@H:19]([C:36]([O:38][CH3:39])=[O:37])[CH2:20][S:21][CH2:22][CH:23]([C:28](=[O:35])[C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[CH2:24][C:25]([OH:27])=[O:26])=[O:17])C3C(=CC=CC=3)C=2C=CC=1.[CH3:40][O:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[N:48]=C=O>>[CH3:40][O:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[NH:48][C:16]([NH:18][C@H:19]([C:36]([O:38][CH3:39])=[O:37])[CH2:20][S:21][CH2:22][CH:23]([C:28](=[O:35])[C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)[CH2:24][C:25]([OH:27])=[O:26])=[O:17]
Reactant: COC(=O)[C@H](CSCC(CC(=O)O)C(=O)c1cccnc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: COc1ccccc1N=C=O
Product: COC(=O)[C@H](CSCC(CC(=O)O)C(=O)c1cccnc1)NC(=O)Nc1ccccc1OC
Yield: 14 %

Procedure:
The title compound was prepared from 3-({(2R)-2-[(fluoren-9-ylmethoxy)carbonylamino]-2-(methoxycarbonyl)ethylthio}methyl)-4-oxo-4-(3-pyridyl)butanoic acid and 2-methoxyphenyl isocyanate as described in Example 16 in a 14% yield; ESMS, (M+1)+476.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:15])=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH:11]([CH3:13])[CH3:12])[C:6]=2[CH:14]=1.[C:16](Cl)(Cl)=[O:17].C1(C)C=CC=CC=1>C1(C)C=CC=CC=1>[F:15][C:3]1[C:2]([N:1]=[C:16]=[O:17])=[CH:14][C:6]2[N:7]([CH:11]([CH3:13])[CH3:12])[C:8](=[O:10])[S:9][C:5]=2[CH:4]=1
Reactant: CC(C)n1c(=O)sc2cc(F)c(N)cc21
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)n1c(=O)sc2cc(F)c(N=C=O)cc21

Procedure:
A solution of 5-amino-3-isopropyl-6-fluoro-2(3H)-benzothiazolone (5 g) in toluene (70 ml) was added to 1M phosgene/toluene, and the resultant solution was stirred at 90° to 95° C. for 1 hour, followed by concentration under reduced pressure. The residue was crystallized from n-hexane to give 6-fluoro-3-isopropyl-2(3H)-benzothiazolon-5-yl isocyanate (5.2 g). m.p., 149°-150° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>>[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]([C:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH:6]=3)=[CH:9]2)=[O:24])=[CH:21][CH:20]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CN1CC=C(c2c[nH]c3ccccc23)CC1
Product: COc1ccc(C(=O)n2cc(C3=CCN(C)CC3)c3ccccc32)cc1

Procedure:
(10.9 mg, 27%); from 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (Example 4e, 24.8 mg, 0.12 mmol) and 4-methoxybenzoyl chloride (35 uL, 0.24 mmol); HRMS-FAB+ for C22H22N2O2 : calculated MH+ : 347.17596; found: 347.17819.
Reaction SMILES: [Cl-].C(O[CH:6]1[C@H:11]([NH3+:12])[C@@H:10]([O:13][C:14](=[O:16])[CH3:15])[C@H:9]([O:17][C:18](=[O:20])[CH3:19])[C@@H:8]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[O:7]1)(=O)C.[CH3:26][N:27]=[C:28]=[S:29].C(N(CC)CC)C.C(O)(C(F)(F)F)=O>CC#N>[C:18]([O:17][C@@H:9]1[C@@H:8]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[O:7][C@H:6]2[C@H:11]([N:12]=[C:28]([NH:27][CH3:26])[S:29]2)[C@H:10]1[O:13][C:14](=[O:16])[CH3:15])(=[O:20])[CH3:19]
Reactant: CC(=O)OC[C@H]1OC(OC(C)=O)[C@H]([NH3+])[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CN=C=S
Agent: [Cl-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CNC1=N[C@@H]2[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O[C@@H]2S1
Temperature: 60 °C
Reaction time: 12 h
Yield: 159.5 %

Procedure:
To a solution of (3R,4R,5S,6R)-2,4,5-triacetoxy-6-(acetoxymethyl)-tetrahydro-2H-pyran-3-aminium chloride (100 g, 261 mmol) in CH3CN (1 L) was added methyl isothiocyanate (21 g, 287 mmol), triethylamine (29 g, 287 mmol). After stirred for 12 h at 60° C., the resulting solution was treated with TFA (110 g, 0.96 mol) at room temperature overnight, and then washed with saturated sodium bicarbonate (1 L). The organic layer was dried over magnesium sulfate and concentrated under vacuum to provide a residue, which was purified by silica gel column, eluted with 1% MeOH in dichloromethane to give compound 23 as a yellow oil (150 g, 87%). (ES, tri/z): [M+H]+ 360.9; 1H NMR (300 MHz, CDCl3) δ 6.31-6.33 (d, J=6.6 Hz, 1H), 5.41-5.48 (t, J=8.4 Hz, 1H), 4.97-5.00 (m, 1H), 4.31-4.37 (t, J=5.7 Hz, 1H), 4.21 (m, 2H), 3.97 (m, 1H), 2.99 (s, 3H), 2.00-2.20 (m, 9H).
Reaction SMILES: [N:1]1([C:7]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:8]=2[CH:9]=[O:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[BH4-].[Na+]>CO>[N:1]1([C:7]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:8]=2[CH2:9][OH:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1N1CCOCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1ccc(N2CCOCC2)c(CO)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 107.7 %

Procedure:
To a cooled (0° C.) solution of 2-morpholin-4-yl-5-nitro-benzaldehyde (0.8 g, 3.39 mmol) in MeOH (5 mL) is added NaBH4 (0.125 g, 3.39 mmol) and the reaction mixture is stirred at room temperature for 3 hours. After quenching the reaction with water, the solvent is removed in vacuo and the residue dissolved in ethyl acetate and washed with brine. The organic layer is dried over MgSO4, filtered and concentrated to afford the title compound (870 mg), which is used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2OCC[O:9]2)=[CH:4][C:3]=1[S:13][CH3:14].C(=O)(O)[O-].[Na+]>C(#N)C.C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][C:3]=1[S:13][CH3:14]
Reactant: CSc1cc(C2OCCO2)ccc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CSc1cc(C=O)ccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
To a solution of the product from Example 226B (1.4 g, 6.7 mmol) in acetonitrile (50 mL) was added 2.OM HCI (50 mL) and the reaction mixture was allowed to stir for 2 hours at room temperature. The reaction mixture was poured onto a mixture of ice and saturated aqueous sodium bicarbonate, diluted with ethyl acetate, and the layers were separated. The organic layer was dried (Na2SO4), concentrated, and purified by flash chromatography (hexanes/ethyl acetate 5:1) to provide 1,1 g of the title compound.
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]1[S:6][CH:7]=[CH:8][CH:9]=1.[C:12]1([N:18]=[N+:19]=[N-:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CN(C)CCN(C)CCN(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.[Cu]I>[C:12]1([N:18]2[CH:3]=[C:4]([C:5]3[S:6][CH:7]=[CH:8][CH:9]=3)[N:20]=[N:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: [N-]=[N+]=Nc1ccccc1
Reactant: C[Si](C)(C)C#Cc1cccs1
Agent: [Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CN(C)CCN(C)CCN(C)C
Solvent: C1CCOC1
Product: c1ccc(-n2cc(-c3cccs3)nn2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 47533.3 %

Procedure:
To a solution of trimethyl(thiophen-2-ylethynyl)silane (50 mg, 0.2777 mmol), phenyl azide (0.5 M solution, 1.1 ml, 0.555 mmol), and CuI (52.87 mg, 0.2777 mmol) in THF (1 ml) was added 1,1,4,7,7-pentamethyldiethlenetriamine (0.116 ml, 0.555 mmol) and 1M TBAF.3H2O (0.554 ml, 0.554 mmol). After stirring the reaction mixture for 20 hours at room temperature, it was quenched with saturated ammonium chloride solution and was extracted with ethyl acetate. The combined organic layers were washed with water, dried over anhydrous sodium sulfate and evaporated. The crude material was purified by column chromatography (100-200 mesh silica gel) using 5% ethyl acetate in hexane as eluant to yield 1-phenyl-4-(thiophen-2-yl)-1H-1,2,3-triazole (30 mg, 0.132 mol, yield 47.61%) with an HPLC purity of 97.64%. LC-MS [M+H] 228.2 (C12H9N3S+H, expected 228.05). The 1H-NMR spectra was in accordance with the chemical structure.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][CH:6]1[CH2:10][CH2:9][C:8]2([C:15]([CH3:17])([CH3:16])[CH2:14][CH2:13][CH2:12][C:11]2([CH3:19])[OH:18])[O:7]1.CN(C)C1C=CC=CC=1.OS(O)(=O)=O>CCOCC>[C:1]([O:18][C:11]1([CH3:19])[CH2:12][CH2:13][CH2:14][C:15]([CH3:17])([CH3:16])[C:8]21[O:7][CH:6]([CH3:5])[CH2:10][CH2:9]2)(=[O:3])[CH3:2]
Reactant: CC1CCC2(O1)C(C)(C)CCCC2(C)O
Reactant: CC(=O)Cl
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: CN(C)c1ccccc1
Product: CC(=O)OC1(C)CCCC(C)(C)C12CCC(C)O2
Reaction time: 48 h

Procedure:
5.9 g (0.079 M) of acetyl chloride were added over 30 minutes at 20° to a mixture of 2,6,10,10-tetramethyl-1-oxa-spiro[4.5]decan-6-ol -- isomer A; see Example 1 -- and 10.9 g of N,N-dimethylaniline. After having been kept for 2 days at room temperature the reaction mixture was heated to reflux during 3 hours, then cooled and treated with 50 ml of ether. The reaction mixture was then filtered and the clear filtrate thus obtained poured onto crushed ice and finally acidified with a 10% aqueous solution of H2SO4. The organic layer was then washed with NaHCO3 in water, dried, evaporated and subjected to a fractional distillation to give 2.5 g of a product having b.p. 90°-100°/0.1 Torr. After crystallisation in aqueous ethanol 1.9 g (75%) of the desired ester were isolated -- isomer A.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]2[O:6][CH2:7][C:8](=O)[NH:9][C:4]=2[CH:3]=1.[CH3:13][C:14](OC(C)=O)=[O:15]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:12]=[CH:11][C:5]2[O:6][CH2:7][CH2:8][N:9]([C:14](=[O:15])[CH3:13])[C:4]=2[CH:3]=1
Reactant: O=C1COc2ccc(Br)cc2N1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1CCOc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
6-Bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (7A) (2.5 g, 11.7 mmol) was taken up in DCM (100 mL) and treated with TEA (4.07 mL, 29.2 mmol) followed by Ac2O (2.75 mL, 29.2 mmol). 4-DMAP (0.285 g, 2.34 mmol) was added and the reaction mixture was stirred at rt overnight. The reaction mixture was concentrated under reduced pressure and purified by column chromatography on silica gel eluting with a gradient of 0 to 50% EtOAc in hexanes to provide 2.62 g (87%) of the desired compound 1-(6-bromo-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethanone (7B).
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:38])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:37])[C@H:13]([CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[NH:14]C(OCC1C=CC=CC=1)=O)[CH:2]([CH3:4])[CH3:3].C12(CC=O)CC3CC(CC(C3)C1)C2.O.C(=O)(O)[O-].[K+].ClC(OCC1C=CC=CC=1)=O>CO.C(OCC)C.[Pd].CCCCCC.C(OCC)(=O)C>[CH2:1]([NH:5][C:6](=[O:38])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:37])[C@H:13]([CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[NH2:14])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Solvent: CO
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)CNC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Reaction time: 16 h

Procedure:
A solution of 6.3 g (0.012 mol) of Nα -benzyloxycarbonyl-Nε -tert.butoxycarbonyl-L-lysyl-L-proline isobutylamide in 100 ml of methanol was hydrogenated for 3 hours in the presence of 0.6 g of 5% palladium/carbon. A solution of 2.2 g (0.012 mol) of adamantane acetaldehyde in 5 ml of methanol was added via a septum cap and the hydrogenation was continued for 16 hours. The catalyst was removed by filtration and the filtrate was evaporated. A solution of the residue in 70 ml of diethyl ether was treated with 60 ml of water containing 2.5 g (0.025 mol) of potassium bicarbonate. 1.85 ml (0.023 mol) of benzyl chloroformate were added and the mixture was stirred vigorously for 1 hour. The organic solution was separated washed with 5% citric acid solution, water, 5% sodium bicarbonate solution and brine, dried over magnesium sulphate and evaporated to give a foam. Chromatography on 150 g of silica gel using n-hexane/ethyl acetate (2:1) yielded 4.4 g (53%) of Nα -(1-adamantylethyl)-Nα -benzyloxycarbonyl)-Nε -tert.butoxycarbonyl-L-lysyl-L-proline isobutylamide as a foam; Rf-value [n-hexane/ethyl acetate (2:1)]: 0.49.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:24])[N:10]([CH2:22][OH:23])[CH:11]=[C:12]3[C:17]=2[NH:16][C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[S:13]3)=[CH:4][CH:3]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:24])[N:10]([CH2:22][O:23][C:25](=[O:27])[CH3:26])[CH:11]=[C:12]3[C:17]=2[NH:16][C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[S:13]3)=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=c1c(-c2ccc(Cl)cc2)c2c(cn1CO)Sc1ccccc1N2
Solvent: c1ccncc1
Product: CC(=O)OCn1cc2c(c(-c3ccc(Cl)cc3)c1=O)Nc1ccccc1S2
Yield: 58 %

Procedure:
To 1.0 g. of 4-(4-chlorophenyl)-2-(hydroxymethyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one (2.8 mmol.) in 8 ml. of pyridine was added 4 ml. of acetic anhydride (42.3 mmol.), and the resulting suspension was stirred at room temperature for about 1 hour. The resulting solution was then concentrated under a nitrogen atmosphere, and the residue was titurated with methanol to yield a yellow precipitate which was washed with methanol and then air-dried to yield 4-(4-chlorophenyl)-2-[(acetyloxy)methyl]-5H-pyrido[3,4-b][1,4]-benzothiazin-3(2H)-one as a yellow solid (0.65 g; 58% yield) having the structural formula, ##STR12## a melting point in the range of 119°-120° C. and the following elemental analysis:
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][C:23]=2[CH3:24])[C:20](=[O:25])[N:19](CC2C=CC(OC)=CC=2)[CH:18]=[CH:17]3)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[CH3:24][C:23]1[CH:22]=[C:21]2[C:16]([CH:17]=[CH:18][NH:19][C:20]2=[O:25])=[CH:15][C:14]=1[O:13][C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: COc1ccc(Cn2ccc3cc(O[C@H]4CCN(C(=O)OC(C)(C)C)C4)c(C)cc3c2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(=O)[nH]ccc2cc1O[C@H]1CCNC1
Temperature: 150 °C
Yield: 87.3 %

Procedure:
0.54 g (1.2 mmol) (S)-3-[2-(4-Methoxy-benzyl)-7-methyl-1-oxo-1,2-dihydro-isoquinolin-6-yloxy]-pyrrolidine-1-carboxylic acid tert-butyl ester were dissolved in 2.7 g (23 mmol) trifluoroacetic acid. After 1 h at room temperature the mixture was heated for 2 h in a microwave oven at 150° C. Then the excess trifluoroacetic acid was distilled off in vacuo and the residue was diluted with 10 ml 1 M hydrochloric acid. The aqueous phase was washed with methylene chloride twice and then it was freeze dried to give 0.256 g 7-Methyl-6-((S)-pyrrolidin-3-yloxy)-2H-isoquinolin-1-one as the hydrochloride. Rt=0.90 min (Method B). Detected mass: 245.2 (M+H+).
Reaction SMILES: O.O.[Sn](Cl)Cl.[F:6][C:7]1[C:12]([F:13])=[CH:11][C:10]([N+:14]([O-])=O)=[CH:9][C:8]=1[C@:17]12[CH2:25][O:24][C@H:23]([CH2:26][F:27])[C@H:22]1[CH2:21][S:20][C:19]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[N:18]2.[OH-].[Na+]>C(O)C>[NH2:14][C:10]1[CH:11]=[C:12]([F:13])[C:7]([F:6])=[C:8]([C@:17]23[CH2:25][O:24][C@H:23]([CH2:26][F:27])[C@H:22]2[CH2:21][S:20][C:19]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[N:18]3)[CH:9]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc([N+](=O)[O-])cc(F)c3F)CO[C@H](CF)[C@H]2CS1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(N)cc(F)c3F)CO[C@H](CF)[C@H]2CS1
Reaction time: 16 h

Procedure:
Tin(II) chloride dihydrate (2.06 g) was added to a suspension of tert-butyl ((4aS,5S,7aS)-7a-(2,3-difluoro-5-nitrophenyl)-5-(fluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)carbamate, obtained in Preparation Example 2-(29), (1.17 g) in ethanol (20 ml) at RT. The mixture was stirred for 16 h at the same temperature (the solid gradually dissolved and the reaction color became yellow). The resultant mixture was poured into 2N sodium hydroxide solution and the organic was extracted with EtOAc. The organic layer was washed sequentially with water and brine, then dried over MgSO4. The solid was removed by filtration, and the filtrate was concentrated in vacuo. The crude mixture was purified by silica gel column chromatography (gradient from 20% to 60% EtOAc in heptane) acetate to afford the targeted compound (1.09 g) as a pale yellow solid. 1H-NMR (400 MHz, CDCl3) δ (ppm): 1.51 (s, 9H), 2.69-2.73 (m, 1H), 3.07-3.15 (m, 2H), 3.69 (bs, 2H), 3.84-3.85 (m, 1H), 4.49-4.67 (m, 4H), 6.34-6.36 (m, 1H), 6.44 (ddd, J=11.2, 6.4, 2.8 Hz, 1H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[F:23][C:24]([F:45])([F:44])[C:25]([C:28]1[O:32][N:31]=[C:30]([NH:33][C:34](=O)[O:35]C2C=CC(Cl)=CC=2)[CH:29]=1)([CH3:27])[CH3:26].C(OCC)C>C1COCC1.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([NH:19][C:34]([NH:33][C:30]2[CH:29]=[C:28]([C:25]([CH3:27])([CH3:26])[C:24]([F:45])([F:44])[F:23])[O:32][N:31]=2)=[O:35])[CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(c1cc(NC(=O)Oc2ccc(Cl)cc2)no1)C(F)(F)F
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C(F)(F)F)on4)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 55 %

Procedure:
To a stirred solution of 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline described in Example 115B (144 mg, 0.46 mmol) in anhydrous THF (5.6 mL), was added 4-chlorophenyl 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate described in Example 259A (161 mg, 0.46 mmol) and 4-(dimethylamino)pyridine (31 mg, 0.25 mmol). The mixture was stirred at rt for 15 h. To the suspension was added diethyl ether. Sonication and filtration afforded 1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea (134 mg, 55%) as a colorless solid. 1H NMR (300 MHz, DMSO-d6) δ 9.77 (s, 1H), 9.04 (s, 1H), 8.70 (s, 1H), 7.86 (s, 1H), 7.28-7.54 (m, 5H), 6.89 (s, 1H), 3.99 (s, 6H), 1.54 (s, 6H); LC-MS (ESI) m/z 534 (M+H)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=O)[C:5]=1[C:6]([O:8]C)=O.[N+:16]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])#[C-]>CN(C=O)C.CCOC(C)=O>[Cl:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:8])[NH:16][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14]2
Reactant: COC(=O)c1c(Cl)cccc1C=O
Reactant: [C-]#[N+]CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2cccc(Cl)c2c(=O)[nH]1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 14.6 %

Procedure:
To a solution of NaH (652.8 mg, 16.32 mmol) in DMF (20 mL) was added methyl 2-chloro-6-formylbenzoate (2.7 g, 13.6 mmol) and ethyl 2-isocyanoacetate (1.55 g, 13.6 mmol) in DMF (5 mL) at 40° C. over a 20 minute period. The reaction mixture was stirred at 20° C. for an additional 30 minutes. The reaction mixture was subsequently diluted with EtOAc (100 mL) and washed with saturated aqueous Na2CO3. The organic phase was concentrated in vacuo. The crude product was purified by column chromatography eluting with a gradient of EtOAc (0-90%) and PE to give the title compound (0.5 g, 15.6%). ESI-MS m/z [M+H]+ 252.1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=O)[N:13]=1.[NH:19]([C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([OH:25])=[O:24])[NH2:20]>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[OH:9])[N:19]([C:21]2[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=2[C:23]([OH:25])=[O:24])[N:20]=1
Reactant: NNc1ccccc1C(=O)O
Reactant: O=c1nc(-c2ccccc2O)oc2ccccc12
Solvent: CCO
Product: O=C(O)c1ccccc1-n1nc(-c2ccccc2O)nc1-c1ccccc1O

Procedure:
4.8 g of 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one and 3.5 g of 2-hydrazinobenzoic acid are boiled under reflux for 4 h in 10 ml of ethanol. The mixture is cooled, poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is crystallized from ethyl acetate/hexane. After drying, 2-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid is obtained as colorless crystals of m.p. 132-138° C.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[CH3:24][C:25]1[N:26]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[CH:27]=[C:28]([Sn](C)(C)C)[N:29]=1.CC1N(COCC[Si](C)(C)C)C([Sn](C)(C)C)=CN=1>O1CCOCC1.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>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:22]=[CH:23][C:2]([C:28]5[N:29]=[C:25]([CH3:24])[N:26]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[CH:27]=5)=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][CH:16]=[N:17]1)([CH3:21])[CH3:20]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: Cc1nc([Sn](C)(C)C)cn1COCC[Si](C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1ncc([Sn](C)(C)C)n1COCC[Si](C)(C)C
Solvent: C1COCCO1
Product: Cc1nc(-c2ccc3c(c2)OCCn2cc(-c4ncnn4C(C)C)nc2-3)cn1COCC[Si](C)(C)C
Temperature: 120 °C
Reaction time: 0.58 h
Yield: 59 %

Procedure:
A mixture of 9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 194 (300 mg, 0.8 mmol), Pd(PPh3)4 (93 mg, 0.08 mmol), a mixture of 2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-4-(trimethyl stannyl)-1H-imidazole and 2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-5-(trimethyl stannyl)-1H-imidazole (600 mg, 1.6 mmol) in dioxane (2 mL) was bubbled with N2 for about 2 min and then it was stirred at 120° C. for 35 min under the microwave irradiation. It was filtered, concentrated and purified by prep-TLC (EtOAc) to give 2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-9-(2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (238 mg, 59%). LC-MS m/z 506 [M+H+]