Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:7][C:8]2[CH:14]=[C:13]([CH2:15][N:16]([CH3:18])[CH3:17])[CH:12]=[CH:11][C:9]=2[CH:10]=1.[CH3:19][S:20][C:21](SC)=[CH:22][N+:23]([O-:25])=[O:24]>C(#N)C>[CH3:17][N:16]([CH2:15][C:13]1[CH:12]=[CH:11][C:9]2[CH:10]=[C:6]([CH2:5][S:4][CH2:3][CH2:2][NH:1][C:21]([S:20][CH3:19])=[CH:22][N+:23]([O-:25])=[O:24])[O:7][C:8]=2[CH:14]=1)[CH3:18]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: CN(C)Cc1ccc2cc(CSCCN)oc2c1
Solvent: CC#N
Product: CSC(=C[N+](=O)[O-])NCCSCc1cc2ccc(CN(C)C)cc2o1

Procedure:
A solution of 2-(2-aminoethylthiomethyl)-6-(dimethylaminomethyl)benzofuran (Example 1, Step E) (8.0 g., 0.0303 mole) and 1,1-bismethylthio-2-nitroethene (5.25 g., 0.0318 mole) in acetonitrile (80 ml.) is heated at 55° C. for 16 hours. The solvent is evaporated at reduced pressure. The residue is chromatographed on a column containing 175 g. of silica gel made up in chloroform. The product is eluted with 5% methanol in chloroform and is obtained as a light orange viscous oil weighing 6.1 g. (53%).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([CH3:42])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:15]=1)=[O:13])(C(C)(C)C)(C)C.Cl.[OH-].[Na+]>O1CCCC1>[OH:8][CH2:9][CH2:10][N:11]([CH3:42])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:15]=1)=[O:13]
Reactant: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(Cc2ccccc2-c2ccccc2)nc(O)c1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(CCO)C(=O)c1nc(Cc2ccccc2-c2ccccc2)nc(O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
To a stirred solution of 5-benzyloxy-2-biphenyl-2-ylmethyl-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-methyl-amide (132) (3 g, 4.967 mmol) in tetrahydrofuran (45 mL) was added 1N HCl (7.5 ml, 7.5 mmol) at room temperature and the mixture was stirred for 60 min at room temperature. After completion of the reaction, the mixture was neutralized with 1N sodium hydroxide aqueous solution, extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure to get a crude product which was purified by a normal silica column using 60% ethyl acetate in hexane to get 5-benzyloxy-2-biphenyl-2-ylmethyl-6-hydroxypyrimidine-4-carboxylic acid (2-hydroxyethyl)-methyl-amide (133) (1.7 g, 69.8%) as a white solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([CH3:15])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[Li+].CC([N-]C(C)C)C.C(NC(C)C)(C)C.C([Li])CCC.[CH2:36]=[O:37]>C1COCC1.O>[CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([CH2:15][CH2:36][OH:37])[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C=O
Reactant: CCCCOc1ccc(C(=O)O)c(C)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCCOc1ccc(C(=O)O)c(CCO)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 4-butoxy-2-methylbenzoic acid (2.5 g) in THF (15 mL) was added dropwise to a solution of LDA (freshly prepared from diisopropylamine (4.86 g) and n-butyllithium (32 mL; 1.5 M in hexane)) in THF (50 mL) at −78° C. After 10 minutes, paraformaldehyde (1.44 g) was added, and the mixture was allowed slowly to warm to room temperature. After 4 hours, water (10 mL) was added, and the volatile organic constituents were removed in a rotary evaporator. The residue was partitioned between water and diethyl ether. The aqueous phase was mixed with dichloromethane and cautiously acidified with hydrochloric acid at 0° C. Concentration of the organic phase afforded the desired product with the molecular weight of 238.29 (C13H18O4); MS (ESI): 239 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]([CH3:16])[C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[C:4]([Cl:17])[CH:3]=1.N1C=CN=C1.[CH3:23][C:24]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])[CH3:25].C([O-])(O)=O.[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:15]=[C:14]([CH3:16])[C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([O:13][Si:27]([C:24]([CH3:26])([CH3:25])[CH3:23])([CH3:29])[CH3:28])=[CH:11][N:12]=2)=[C:4]([Cl:17])[CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1cc(Br)cc(Cl)c1Oc1ccc(O)cn1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1cc(Br)cc(Cl)c1Oc1ccc(O[Si](C)(C)C(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.4 %

Procedure:
To a DMF (50 mL) solution of 6-(4-bromo-2-chloro-6-methylphenoxy)pyridin-3-ol (5.00 g) were added imidazole (1.41 g) and TBDMSCl (2.87 g) at room temperature. After stirring at room temperature for 5 hours, to the reaction mixture was added saturated aqueous NaHCO3, and extracted with AcOEt. The organic layer was washed with water, saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=9/1 to 2/1) to give 2-(4-bromo-2-chloro-6-methylphenoxy)-5-{[tert-butyl(dimethyl)silyl]oxy}pyridine as a colorless oil (6.16 g).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9](C)[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[NH:25]1[CH2:30][CH2:29][CH:28]([C:31]([O:33][CH3:34])=[O:32])[CH2:27][CH2:26]1>O1CCOCC1.CS(C)=O.CO>[OH:23][C:20]([C:17]1[CH:16]=[CH:15][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([N:25]3[CH2:30][CH2:29][CH:28]([C:31]([O:33][CH3:34])=[O:32])[CH2:27][CH2:26]3)[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=2)=[O:24])=[CH:19][CH:18]=1)([CH3:22])[CH3:21]
Reactant: COC(=O)C1CCNCC1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Solvent: C1COCCO1
Solvent: CS(C)=O
Solvent: CO
Product: COC(=O)C1CCN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3ccnn23)CC1
Temperature: 25 °C
Yield: 11.4 %

Procedure:
A solution of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 500 mg, 1.51 mmol) and methyl piperidine-4-carboxylate (390 mg, 3.05 mmol) in Dioxane (15 mL) was stirred at 100° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC, 30-40% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (75 mg, 28%). 1H NMR (DMSO-d6) δ: 10.89 (s, 1H), 8.09 (d, J=2.3 Hz, 1H), 8.00 (d, J=8.6 Hz, 2H), 7.60 (d, J=8.6 Hz, 2H), 7.44 (s, 1H), 6.35 (d, J=2.3 Hz, 1H), 5.18 (s, 1H), 4.29-4.44 (m, 2H), 3.65 (s, 3H), 3.17 (d, J=5.3 Hz, 2H), 2.67-2.82 (m, 1H), 1.98-2.11 (m, 2H), 1.70-1.88 (m, 2H), 1.46 (s, 6H). ESI-MS: m/z 438.0 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[CH:7]=[C:8]2[C:13](=[C:14]([C:16]#[C:17][CH2:18][CH2:19][OH:20])[CH:15]=1)[O:12][C:11](=[O:21])[C:10]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)=[CH:9]2>C1COCC1>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[C:14]([CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH:15]=1)[O:12][C:11](=[O:21])[C:10]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)=[CH:9]2
Reactant: COc1ccc(-c2cc3cc(C#CCCO)cc(C#CCCO)c3oc2=O)cc1
Solvent: C1CCOC1
Product: COc1ccc(-c2cc3cc(CCCCO)cc(CCCCO)c3oc2=O)cc1

Procedure:
6,8-Bis-(4-hydroxy-but-1-ynyl)-3-(4-methoxy-phenyl)-chromen-2-one is hydrogenated in THF on Pd/activated charcoal until the reaction is completed. The catalyst is filtered off, the solvent removed in vacuo and the crude product is filtered through silica gel with THF/toluene (3:2) and recrystallized from toluene. 6,8-Bis-(4-hydroxy-butyl)-3-(4-methoxy-phenyl)-chromen-2-one is obtained as a colourless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[N+:21]([CH3:24])([O-:23])=[O:22].C([O-])(=O)C.[NH4+]>O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12](/[CH:13]=[CH:24]/[N+:21]([O-:23])=[O:22])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1ccc(OCc2ccccc2)cc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 97.9 %

Procedure:
To a mixture of 4-benzyloxy benzaldehyde (50 g, 0.24 mol) and acetic acid (200 mL) were added nitromethane (64 mL, 1.2 mol) and ammonium acetate (36 g, 0.47 mol), which was stirred for 90 minutes at 100° C. The reaction mixture was cooled to room temperature, and water (1 L) was added at the same temperature. The deposited solids were filtered to obtain the title compound (60 g).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].ClC(Cl)(Cl)C(=N)O[C:16]([CH3:19])([CH3:18])[CH3:17].B(F)(F)F.CCOCC.C(=O)(O)[O-].[Na+]>C1COCC1.C1CCCCC1>[CH3:1][C:2]1[C:3]([O:11][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:4][CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Reactant: Cc1c(O)cccc1[N+](=O)[O-]
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1c(OC(C)(C)C)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 2-methyl-3-nitrophenol K1 (1.1 g; 7.18 mmol) in THF (13 mL) was added cyclohexane (27 mL; a solution was maintained). tert-Butyl trichloroacetimidate K2 (5.36 mL; 28.73 mmol) was added followed by a catalytic amount of boron trifluoride etherate (143.8 mL; 1.14 mmol) and the reaction was stirred at room temperature for 15 h. The reaction was incomplete (by analytical HPLC) and an additional amount of tert-butyl trichloroacetimidate (1.4 mL; 7.51 mmol) was added (reaction remains in solution). The reaction was complete after stirring at room temperature for 5 h. Solid sodium bicarbonate was added, and the mixture was filtered, rinsed with dichlormethane and evaporated to dryness to provide a white solid. The solid was triturated with dichloromethane, the white solid filtered and discarded (=trichloroacetimide). The filtrate was concentrated and loaded onto a flash column for purification (hexane:EtOAc 9:1) to provide the pure 2-methyl-3-tert-butoxynitrobenzene K3 (1.17 g; 78%). Homogeneity by HPLC (TFA) @ 220 nm:96%
Reaction SMILES: [F:1][C:2]([F:15])([C:11]([F:14])([F:13])[F:12])[C:3]([F:10])([F:9])[C:4](=[CH2:8])[C:5](O)=[O:6].[NH2:16][C:17]([NH2:19])=[O:18].C(OC(=O)C)(=O)C>C(O)C>[F:1][C:2]([F:15])([C:11]([F:14])([F:13])[F:12])[C:3]([F:10])([F:9])[CH:4]1[CH2:8][NH:19][C:17](=[O:18])[NH:16][C:5]1=[O:6]
Reactant: C=C(C(=O)O)C(F)(F)C(F)(F)C(F)(F)F
Reactant: NC(N)=O
Solvent: CCO
Solvent: CC(=O)OC(C)=O
Product: O=C1NCC(C(F)(F)C(F)(F)C(F)(F)F)C(=O)N1
Temperature: 100 °C
Reaction time: 0.67 h
Yield: 63.8 %

Procedure:
A mixture of α-heptafluoropropylacrylic acid (240 mg; 1.0 mmole), urea (64 mg; 1.1 mmoles) and acetic anhydride (0.6 ml) was heated at 100° C. with stirring for 40 minutes. Then, ethanol (3 ml) was added to the reaction mixture to give 180 mg (yield: 64%) of 5-heptafluoropropyldihydrouracil as colorless crystals. m.p.: 223°-224 (decomp.).
Reaction SMILES: COC1C=CC(C[O:10][C:11]2[CH:12]=[C:13]([C:21]3[C:22]4[CH:31]=[CH:30][O:29][C:23]=4[C:24](=[O:28])[N:25]([CH3:27])[CH:26]=3)[CH:14]=[C:15]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:16]=2)=CC=1>CC(O)=O>[OH:10][C:11]1[CH:12]=[C:13]([C:21]2[C:22]3[CH:31]=[CH:30][O:29][C:23]=3[C:24](=[O:28])[N:25]([CH3:27])[CH:26]=2)[CH:14]=[C:15]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:16]=1
Reactant: COc1ccc(COc2cc(-c3cn(C)c(=O)c4occc34)cc(S(C)(=O)=O)c2)cc1
Solvent: CC(=O)O
Product: Cn1cc(-c2cc(O)cc(S(C)(=O)=O)c2)c2ccoc2c1=O
Temperature: 25 °C
Yield: 78.3 %

Procedure:
A solution of 4-[3-[(4-methoxyphenyl)methoxy]-5-methylsulfonylphenyl]-6-methylfuro[2,3-c]pyridin-7-one (370 mg, 0.84 mmol) in AcOH (6 mL) was heated to 100° C. for 12 h. After cooling to rt, the reaction mixture was evaporated to dryness in vacuo. The resulting residue was diluted with water and extracted with EtOAc (20 ml×3); the combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The resulting solid was suspensed in a 1:1 mixture of EtOAc and hexanes, sonicated for 1 min, and filtered. The filter cake was collected to afford the title compound (210 mg, 78%) as a gray solid. LCMS (M+H)+=320.
Reaction SMILES: [NH2:1][C@@:2]([CH3:14])([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13])[CH2:3][OH:4].C([O-])([O-])=O.[K+].[K+].[N:21]#[C:22]Br.O>C1COCC1.C(OCC)(=O)C>[Cl:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH2:6][CH2:5][C@@:2]1([CH3:14])[CH2:3][O:4][C:22]([NH2:21])=[N:1]1
Reactant: N#CBr
Reactant: C[C@@](N)(CO)CCc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@]1(CCc2ccccc2Cl)COC(N)=N1
Reaction time: 18 h
Yield: 32.9 %

Procedure:
To a stirred mixture of (S)-2-amino-4-(2-chloro-phenyl)-2-methyl-butan-1-ol (0.190 g, 0.89 mmol) and K2CO3 (0.155 g, 1.12 mmol) in THF (10 ml) under an argon atmosphere was added a solution of cyanogen bromide (0.119 g, 1.12 mmol) in THF (1 ml). The mixture was stirred for 18 hours, then water and ethyl acetate were added. The organic layer was washed with water, dried over MgSO4 and evaporated over Isolute® Flash-NH2 silica gel. Chromatography (column: Isolute® Flash-NH2 from Separtis; eluent: ethyl acetate/MeOH=90:10) yielded the title compound as off-white solid, (0.070 g, 33%); MS (ISP): 239.2; 241.2 ((M+H)+.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8](O)[C@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:4][C:3]=1[F:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:56][S:57][C:58]1[N:63]=[C:62]([C:64]2[CH:69]=[CH:68][NH:67][C:66](=[O:70])[CH:65]=2)[CH:61]=[CH:60][N:59]=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:67]2[CH:68]=[CH:69][C:64]([C:62]3[CH:61]=[CH:60][N:59]=[C:58]([S:57][CH3:56])[N:63]=3)=[CH:65][C:66]2=[O:70])[C@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:4][C:3]=1[F:22]
Reactant: CSc1nccc(-c2cc[nH]c(=O)c2)n1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1[C@H](O)c1ccc(Cl)c(F)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CSc1nccc(-c2ccn([C@@H](c3ccc(Cl)c(F)c3)[C@H]3CCCN3C(=O)OC(C)(C)C)c(=O)c2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of (R)-tert-butyl 2-((R)-(4-chloro-3-fluorophenyl)(hydroxy)methyl)pyrrolidine-1-carboxylate (0.662 g, 2.01 mmol) and triphenylphosphine (0.658 g, 2.51 mmol) in THF (40 mL) was placed in an ice bath, and diisopropyl azodicarboxylate (0.518 mL, 2.51 mmol) was added. The cold bath was removed after 10 minutes, and the reaction mixture was stirred at room temperature for 10 minutes. 4-(2-(Methylthio)pyrimidin-4-yl)pyridin-2(1H)-one (0.22 g, 1.00 mmol) was added, and the reaction was left at room temperature for 1 hour. The reaction mixture was concentrated, and the crude product was purified via column chromatography, eluting with hexanes/ethyl acetate (1:1) to give (R)-tert-butyl 2-((S)-(4-chloro-3-fluorophenyl)(4-(2-(methylthio)pyrimidin-4-yl)-2-oxopyridin-1(2H)-yl)methyl)pyrrolidine-1-carboxylate (contaminated with large amounts of PPh3O). m/z (APCI-pos) (M+1)-Boc=431.2, 433.2.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([C:12]([NH:14][C:15]2[CH:16]=[C:17]([CH:34]=[CH:35][CH:36]=2)[O:18][C:19]2[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:28]C(=O)OCC)=S)=[N:23][CH:24]=2)=[O:13])[CH:9]=[CH:10][CH:11]=1)([CH3:5])[CH3:4])#[N:2].C(O)C.Cl.NO.C([N:46](CC)C(C)C)(C)C>CO>[NH2:46][C:26]1[N:25]=[C:22]2[CH:21]=[CH:20][C:19]([O:18][C:17]3[CH:16]=[C:15]([NH:14][C:12](=[O:13])[C:8]4[CH:9]=[CH:10][CH:11]=[C:6]([C:3]([C:1]#[N:2])([CH3:5])[CH3:4])[CH:7]=4)[CH:36]=[CH:35][CH:34]=3)=[CH:24][N:23]2[N:28]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)NC(=S)Nc1ccc(Oc2cccc(NC(=O)c3cccc(C(C)(C)C#N)c3)c2)cn1
Agent: Cl
Agent: NO
Solvent: CO
Solvent: CCO
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(N)nn4c3)c2)c1
Temperature: 60 °C
Yield: 76 %

Procedure:
To a solution of the above-mentioned crude product, ethyl ({5-[3-({[3-(1-cyano-1-methylethyl)phenyl]carbonyl}amino)phenoxy]pyridin-2-yl}carbamothioyl)carbamate, in methanol (100 mL)/ethanol (100 mL) were added hydroxylamine hydrochloride (4.84 g, 69.6 mmol) and N,N-diisopropylethylamine (14.6 mL, 83.5 mmol), and the mixture was stirred with heating at 60° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, water (100 mL) was added to the residue, and the mixture was extracted with ethyl acetate (150 mL, 2×50 mL). The combined organic layer was washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, hexane/ethyl acetate=30/70→0/100), and fractions containing the desired product were concentrated under reduced pressure to give the title compound (3.65 g, 76%) as a pale-yellow amorphous solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[SH:7][CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14].[C:18]([C:20]1[C:21](OS(C(F)(F)F)(=O)=O)=[C:22]([C:30]([O:32][CH3:33])=[O:31])[C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2)#[N:19].CC1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)=CC=1>C1(C)C=CC=CC=1.CCOCC.C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:13]([O:12][C:11]([NH:10][CH2:9][CH2:8][S:7][C:21]1[C:20]([C:18]#[N:19])=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]=1[C:30]([O:32][CH3:33])=[O:31])=[O:17])([CH3:14])([CH3:16])[CH3:15]
Reactant: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)c(C#N)cc2ccccc12
Reactant: CC(C)(C)OC(=O)NCCS
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccc(P(c2ccc(C)cc2)c2ccc3ccccc3c2-c2c(P(c3ccc(C)cc3)c3ccc(C)cc3)ccc3ccccc23)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1c(SCCNC(=O)OC(C)(C)C)c(C#N)cc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
To a suspension (vacuum degassed 3 times) of potassium carbonate (110 mg, 0.78 mmol) in toluene (5 mL) under nitrogen was added tert-butyl 2-mercaptoethylcarbamate (131 μL, 0.78 mmol) followed by stirring at ambient temperature for 1 h. To this suspension was added by cannula a solution (vacuum degassed 3 times) of methyl 3-cyano-2-{[(trifluoromethyl)-sulfonyl]oxy}-1-naphthoate (Intermediate 1, 200 mg, 0.56 mmol), (R)-Tol-BINAP (44.1 mg, 0.07 mmol), and palladium(II) acetate (14 mg, 0.06 mmol) in toluene (10 mL). The resulting suspension was stirred at 80° C. for 20 h, cooled, (reduced volume by ½ under reduced pressure, diluted with ether (12 ml) and methylene chloride (6 ml), washed organic layer with 20% K2CO3 (2×15 ml), water and brine, dried over Na2SO4, filtered, and evaporated to dryness. The residue was precipitated from 10% ethyl acetate in hexanes to give 150 mg of the title compound. An additional 40 mg (88% overall yield) of the title compound was isolated from the mother liquor by chromatography on silica gel in 20% ethyl acetate/hexanes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:10](=[O:17])[C@@H:9]([CH2:18][C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[N:29])[CH:23]=3)=[O:20])[O:8][C@H:7]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])[C:6]=2[CH:37]=1.[N-:38]=[N+:39]=[N-:40].[Na+].O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]([CH3:14])([CH3:15])[CH3:16])[C:10](=[O:17])[C@@H:9]([CH2:18][C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]4[NH:40][N:39]=[N:38][N:29]=4)[CH:23]=3)=[O:20])[O:8][C@H:7]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])[C:6]=2[CH:37]=1
Reactant: CC(C)(C)CN1C(=O)[C@@H](CC(=O)Nc2cccc(C#N)c2)O[C@H](c2ccccc2Cl)c2cc(Cl)ccc21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)CN1C(=O)[C@@H](CC(=O)Nc2cccc(-c3nnn[nH]3)c2)O[C@H](c2ccccc2Cl)c2cc(Cl)ccc21
Yield: 50.9 %

Procedure:
A solution of 0.2 g of trans-7-chloro-5-(2-chlorophenyl)-3-(3-cyanophenylaminocarbonylmethyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine and 80 mg of sodium azide in 5 ml of dimethylformamide was stirred at 90° C. for 60 hours. After water was added, the mixture was washed with water, after which the solvent was removed and the residue was subjected to silica gel column chromatography to yield 0.11 g of a crystal.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[N:20][C:19]([OH:30])=[N:18]2)=[CH:13][CH:12]=1.Cl[CH2:32][C:33]1[N:37]=[CH:36][O:35][N:34]=1>CN(C)C=O.O.C(OCC)(=O)C>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([N:17]2[C:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[N:20][C:19]([O:30][CH2:32][C:33]3[N:37]=[CH:36][O:35][N:34]=3)=[N:18]2)=[CH:15][CH:16]=1
Reactant: COc1ccc(-c2nc(O)nn2-c2ccc(OC)cc2)cc1
Reactant: ClCc1ncon1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2nc(OCc3ncon3)nn2-c2ccc(OC)cc2)cc1
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 43.1 %

Procedure:
Potassium carbonate (279 mg, 2.02 mmol) and potassium iodide (335 mg, 2.02 mmol) was added to a solution of 1,5-bis(4-methoxyphenyl)-1H-1,2,4-triazol-3-ol (200 mg, 0.673 mmol) in dimethylformamide (2 mL). After 5 minutes stirring, 3-(chloromethyl)-1,2,4-oxadiazole (239 mg, 2.02 mmol) was added to the mixture and the mixture was heated at 100° C. for 1 hour. After cooling, ethyl acetate and water were poured into the mixture. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by preparative-TLC (toluene-ethyl acetate 4:1). The desired product was triturated with isopropylether, isolated by filtration, and dried in vacuo to give 3-({[1,5-bis(4-methoxyphenyl)-1H-1,2,4-triazol-3-yl]oxy}methyl)-1,2,4-oxadiazole (110 mg, 43.1% yield).
Reaction SMILES: [CH:1]1([C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[N+:15]([O-])([OH:17])=[O:16].O>C(OC(=O)C)(=O)C>[CH:1]1([C:5]2[CH:6]=[CH:7][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:13][C:14]=2[N+:15]([O-:17])=[O:16])[CH2:2][CH2:3][CH2:4]1
Reactant: COC(=O)c1ccc(C2CCC2)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COC(=O)c1ccc(C2CCC2)c([N+](=O)[O-])c1
Temperature: 30 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
To a solution of methyl 4-cyclobutylbenzoate (compound 168.1, 3.80 g, 20.0 mmol, 1.00 equiv) in acetic anhydride (12 mL) 0° C. was added dropwise fuming HNO3 (5 mL, 97%). The resulting mixture was stirred at 30° C. in an oil bath. After 2 h, 30 mL of water was carefully added and the mixture was extracted with 2×30 mL of ethyl acetate. The combined organic layers were washed with aqueous saturated NaHCO3 (note: gas evolution), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:25) as eluent to furnish 3.00 g (64%) of the title compound as a light yellow oil.