Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O=[C:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]1[C:30]([O:32][CH2:33][CH3:34])=[O:31].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:19][C:18]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 67.9 %

Procedure:
Trifluoromethanesulfonic anhydride (15.5 mL, 92.0 mmol) was added over approximately 0.1 h, via syringe, to a stirred solution of the product of step B (33.8 g, 84.0 mmol) and N,N-diisopropylethylamine (17.6 mL, 101.0 mmol) in methylene chloride (300 mL) at −78° C. After allowing to warm to ambient temperature overnight, the reaction mixture was quenched with saturated aqueous sodium bicarbonate, poured into water and extracted three times with methylene chloride. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient elution; 0–20% ethyl acetate/hexanes as eluent) gave the title compound as an amber colored oil (23.0 g).
Reaction SMILES: [CH2:1]([Zn]CC)C.ICI.[CH3:9][C:10]1([CH3:31])[C:14]([CH3:16])([CH3:15])[O:13][B:12](/[CH:17]=[CH:18]/[CH2:19][NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:11]1>ClCCl>[CH3:16][C:14]1([CH3:15])[C:10]([CH3:31])([CH3:9])[O:11][B:12]([CH:17]2[CH2:1][CH:18]2[CH2:19][NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:13]1
Reactant: CC1(C)OB(/C=C/CNC(=O)OCc2ccccc2)OC1(C)C
Reactant: CC[Zn]CC
Solvent: ICI
Solvent: ClCCl
Product: CC1(C)OB(C2CC2CNC(=O)OCc2ccccc2)OC1(C)C
Temperature: -15 °C
Reaction time: 1 h
Yield: 67.1 %

Procedure:
A solution of diethylzinc (7.57 mL, 7.57 mmol) in dichloromethane (10 mL) was stirred at −78° C. under nitrogen as a solution of diiodomethane (1.22 mL, 15.1 mmol) in dichloromethane (10 mL) was added. The resulting mixture was stirred at −15° C. under nitrogen for 1 h to give a white milky suspension. A solution of (E)-benzyl (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)carbamate (1.2 g, 3.78 mmol) in dichloromethane (10 mL) was added. The reaction mixture was stirred at rt for 1 h. and was then quenched with 1HCl. The dichloromethane layer was separated. The aqueous layer was extracted with dichloromethane (2×20 mL). The combined organic layers were washed with aqueous sodium bicarbonate (2×20 mL) and brine (20 mL), dried over magnesium sulfate, and concentrated. The residue was purified by silica gel chromatography using 0-30% EtOAc/hexane as the eluent to give benzyl ((2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)methyl)carbamate as a colorless oil (0.84 g, 60%). 1H NMR (400 MHz, METHANOL-d4) d 7.42-7.22 (m, 5H), 5.07 (s, 2H), 3.12-2.84 (m, 2H), 1.20 (s, 12H), 1.17-1.12 (m, 1H), 0.71-0.60 (m, 1H), 0.58-0.44 (m, 1H), −0.28 (dt, J=9.5, 5.8 Hz, 1H). M+1=332.2.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6](=[O:13])[N:5]2[CH2:14][CH2:15][CH2:16][CH:4]2[C:3]1=[O:17].[N+:18]([O-])([O-:20])=[O:19].[K+]>S(=O)(=O)(O)O>[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][C:11]([N+:18]([O-:20])=[O:19])=[CH:12][C:7]=2[C:6](=[O:13])[N:5]2[CH2:14][CH2:15][CH2:16][CH:4]2[C:3]1=[O:17]
Reactant: CN1C(=O)C2CCCN2C(=O)c2ccccc21
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CN1C(=O)C2CCCN2C(=O)c2cc([N+](=O)[O-])ccc21
Reaction time: 2 h

Procedure:
To 10-methyl-2,3-dihydro-1H-pyrrolo[2,1-c][1,4]benzodiazapine-5,11(10H,11aH)-dione (5.7 g, 24.7 mmol) in concentrated sulfuric acid (60 ml) at 0° C. was added potassium nitrate (2.62 g, 25.9 mmol). After stirring for 2 h the mixture was dumped onto ice (500 g) and extracted with ethyl acetate (5×75 ml). The combined extracts were washed with water, dried over magnesium sulfate, filtered, and concentrated to a solid which was recrystallized from ethyl acetate-hexane (5.2 g, 77%), m.p. 160-162° C.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[C:12]([N:14]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:11]3[N:31]=[CH:32][C:33]([C:34]4[CH:35]=[N:36][C:37]([C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)=[CH:38][CH:39]=4)=[C:10]3[N:9]=2)[CH2:4][CH2:3]1.C1C=C(Cl)C=C(C(OO)=[O:54])C=1>C(Cl)Cl>[C:40]1([C:37]2[N:36]=[CH:35][C:34]([C:33]3[CH:32]=[N:31][N:11]4[C:12]([N:14]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:29])[CH3:30])[CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:20])([CH3:21])[CH3:22])=[CH:13][C:8]([CH:5]5[CH2:4][CH2:3][C:2]6([O:54][CH2:1]6)[CH2:7][CH2:6]5)=[N:9][C:10]=34)=[CH:39][CH:38]=2)[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(-c5ccccc5)nc4)c3n2)CC1
Solvent: ClCCl
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCC3(CC2)CO3)nc2c(-c3ccc(-c4ccccc4)nc3)cnn12
Temperature: 25 °C
Reaction time: 4 h
Yield: 34.9 %

Procedure:
To a solution of 5-(4-methylenecyclohexyl)-3-(6-phenylpyridin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (455 mg, 0.709 mmol) in DCM (4 mL) at 0° C. was added a solution of m-CPBA (191 mg, 0.850 mmol) in DCM (3 mL). The resulting mixture was warmed to rt and stirred for 4 h. All the volatiles were removed under reduced pressure and the residue was purified by a SiO2 column (0-20% EtOAc/Hexanes, Rf=0.25 in 20% EtOAc) to afford 3-(6-phenylpyridin-3-yl)-5-(1-oxaspiro[2.5]octan-6-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine as a pale yellow oil (163 mg). HPLC-MS TR=3.32 min (UV 254 nm, 5 min method); mass calculated for formula C36H51N5O3Si2 657.4, observed LCMS m/z 658.3 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][CH:7]([CH:14]1[O:19][CH2:18][C:17](=O)[N:16](C)[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([O-:3])=[O:2].[CH3:26]O.Cl>C1COCC1>[N+:1]([C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][CH:7]([CH:14]1[O:19][CH2:18][CH2:17][NH:16][CH:15]1[CH3:26])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([O-:3])=[O:2]
Reactant: CN1CC(C(Oc2ccccc2[N+](=O)[O-])c2ccccc2)OCC1=O
Reactant: CO
Agent: Cl
Solvent: C1CCOC1
Product: CC1NCCOC1C(Oc1ccccc1[N+](=O)[O-])c1ccccc1
Reaction time: 1 h

Procedure:
Into a solution of 12.3 g of 2-[α-(2-nitro-phenoxy)-benzyl]-4-methyl-morpholin-5-one in 350 ml of anhydrous THF there was slowly added dropwise 77 ml of a molar solution of BH3 in THF. After the addition, the mixture was refluxed for 6 hours. The excess of BH3 was eliminated with MeOH at room temperature, and dropwise addition was then made to the reaction mixture of 50 ml of 23% HCl and stirring carried out for 1 hour at 60° C. The whole was concentrated to a small volume and the residue diluted with water, thereafter alkalinizing with NaOH and extracting with CH2Cl2. After normal processing and crystallization from isopropyl ether, the 2-[α-(2-nitro-phenoxy)-benzyl]-3-methyl-morpholine, m.p. 78°-81° C. (8.1 g; 68%) was obtained.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[Cl:18][CH:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20](Cl)=[O:21]>C1COCC1>[Cl:18][CH:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20]([NH:8][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1)=[O:21]
Reactant: O=C(Cl)C(Cl)c1ccccc1
Reactant: Cc1cccc(N)n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(NC(=O)C(Cl)c2ccccc2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 124.4 %

Procedure:
To an ice-cooled solution of 6-methylpyridin-2-amine [CAS 1824-81-3] (5.22 g, 44.08 mmol) in 350 mL anhydrous THF was added diisopropylethylamine (15.36 mL, 88.16 mmol). Chloro(phenyl)acetyl chloride [CAS 2912-62-1] (10.0 g, 52.9 mmol) was added dropwise and the resulting mixture was stirred for 1 h while cooling was maintained. The mixture was partitioned between ethyl acetate and water and the organic phase was washed with brine. The organic phase was filtered through a Whatman filter and the volatile components were removed by the use of a rotary evaporator to give title compound (14.3 g) in ˜80% purity (LC-MS). The crude material was forwarded directly to the next step.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8](C(OC)=O)=[CH:7][C:5]=2[N:6]=1.[C:15]([O:18][CH2:19]C)(=[O:17])C>>[NH2:1][C:2]1[S:3][C:4]2[C:10]([C:15]([O:18][CH3:19])=[O:17])=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: COC(=O)c1ccc2sc(N)nc2c1
Reactant: CCOC(C)=O
Product: COC(=O)c1cccc2nc(N)sc12
Temperature: 30 °C

Procedure:
8.4 g of methyl 3-thioureido-benzoate are suspended in 120 ml of chlorobenzene, 2.2 ml of bromine in 30 ml of chlorobenzene are added at 0° C. in the course of 1 hour, while stirring as thoroughly as possible, and the mixture is then stirred to room temperature. It is then kept at 70° C. for 4 hours and subsequently cooled, a little diethyl ether is added and the precipitate is filtered off, mixed thoroughly with 70 ml of aqueous sodium bicarbonate solution, filtered off again and washed with water. 7.7 g (88%) of crude product of melting point 231-232° C. result. HPLC analysis shows a content of more than 83% of the pure title compound, in addition to 8-18% of isomeric methyl 2-amino-benzothiazole-5-carboxylate. Suspension in and brief heating at 70° C. with ethyl acetate, cooling to 30° C. and filtration give the pure title compound of melting point >250° C.
Reaction SMILES: [O:1]1[CH2:22][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:21])[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12]2)=[CH:7][CH:6]=1.[CH2:23]([NH2:25])[CH3:24].[ClH:26].CCO>CO>[ClH:26].[CH2:23]([NH:25][CH2:22][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:21])[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12]2)=[CH:7][CH:6]=1)[CH3:24]
Reactant: O=c1cc(-c2ccccc2)oc2cc(OCC3CO3)ccc12
Reactant: CCN
Agent: Cl
Solvent: CCO
Solvent: CO
Product: CCNCC(O)COc1ccc2c(=O)cc(-c3ccccc3)oc2c1
Yield: 36 %

Procedure:
According to Method B, the title compound was synthesized from the reaction of 7-(2,3-epoxypropoxy) flavone and 70% aqueous ethylamine followed by treatment with HCl/EtOH, as white prisms, m.p. 244°-46° (MeOH) in 36% yield. The free base was obtained after column purification as white crystals, m.p. 164°-65° (MeOH/ehter), yield 39%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[N:7]([CH2:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([CH:28]3[CH2:31][CH2:30][CH2:29]3)[CH2:24][CH2:23]1)=[O:21])[CH2:6][CH2:5]2.[CH2:32]([O:36]C=C)[CH2:33]CC.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:32]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[N:7]([CH2:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([CH:28]3[CH2:31][CH2:30][CH2:29]3)[CH2:24][CH2:23]1)=[O:21])[CH2:6][CH2:5]2)(=[O:36])[CH3:33]
Reactant: O=C(CN1CCc2cc(Br)ccc2C1c1ccccc1Cl)N1CCN(C2CCC2)CC1
Reactant: C=COCCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2c(c1)CCN(CC(=O)N1CCN(C3CCC3)CC1)C2c1ccccc1Cl
Temperature: 80 °C
Reaction time: 7 h

Procedure:
To a solution of 2-[6-bromo-1-(2-chloro-phenyl)-3,4-dihydro-1H-isoquinolin-2-yl]-1-(4-cyclobutyl-piperazin-1-yl)-ethanone (310 mg, 0.62 mmol) in dry DMF (5.0 ml) is added n-butylvinyl ether (310 mg, 3.98 mmol, 5.0 eq.), TEA (75 mg, 0.74 mmol, 1.2 eq.), 1,3-bis(diphenylphosphino)propane (7 mg, 0.0017 mmol, 0.0276 eq.), and palladium acetate (3.5 mg, 0.015 mmol, 0.025 eq.) under nitrogen. The resulting mixture is stirred at 80° C. for 7 hr. Water (20 ml) is added to quench the reaction, and the mixture is extracted with EtOAc (10 ml×3). The combined organic phase is washed with water, and treated with concentrated HCl (1.0 ml). The mixture is stirred at rt for 2 hr, and then basified with saturated sodium carbonate solution. The organic phase is collected, and the aqueous phase is extracted with EtOAc (10 ml×2). The combined organic phase is dried over sodium sulfate, and concentrated. The residue is purified by PTLC (EtOAc/4% TEA) to give the title compound. 1H NMR (300 MHz, CDCl3) δ 7.74 (1H, s), 7.59 (1H, dd), 7.41 (1H, dd), 7.10˜7.25 (3H, m), 6.72 (1H, d), 5.22 (1H, s), 3.81 (1H, m), 3.04˜3.52 (7H, m), 2.78˜2.98 (2H, m), 2.67 (1H, m), 2.55 (3H, s), 2.41 (1H, m), 2.27 (1H, m), 1.96˜2.14 (4H), 1.60˜1.92 (4H); MS (+VE) m/z 466.00 (M+).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1.Cl.[C:15](Cl)(Cl)=[S:16].C(=O)([O-])O.[Na+]>O1CCCC1>[N:9]([C:8]1[CH:10]=[CH:11][C:5]([O:4][CH2:3][C:2]([F:12])([F:13])[F:1])=[CH:6][CH:7]=1)=[C:15]=[S:16]
Reactant: Nc1ccc(OCC(F)(F)F)cc1
Reactant: S=C(Cl)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: FC(F)(F)COc1ccc(N=C=S)cc1
Temperature: -5 °C
Reaction time: 0.08 h

Procedure:
4-(2,2,2-Trifluoroethoxy)aniline (10 g) was dissolved in tetrahydrofuran (100 ml), 6M hydrochloric acid (9 ml) was added thereto, and the mixture was cooled to −5° C. A solution of thiophosgene (4.01 ml) in tetrahydrofuran (20 ml) was added dropwise thereto over 5 min, and the mixture was stirred at −5° C. for 10 min. Saturated aqueous sodium hydrogen carbonate solution (125 ml) was poured into the mixture, and the mixture was extracted twice with ethyl acetate (200 ml). The extracted layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the obtained brown crude product was purified by silica gel column chromatography, and the obtained pale-yellow solid was washed with hexane to give the title compound (10.7 g) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]([OH:17])=O)=[CH:13][O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.Cl.[CH3:51][C:52]1[CH:53]=[CH:54][C:55]([C:58]2([OH:63])[CH2:62][CH2:61][NH:60][CH2:59]2)=[N:56][CH:57]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]([N:60]3[CH2:61][CH2:62][C:58]([C:55]4[CH:54]=[CH:53][C:52]([CH3:51])=[CH:57][N:56]=4)([OH:63])[CH2:59]3)=[O:17])=[CH:13][O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(-c2nocc2C(=O)O)cc1Cl
Reactant: Cc1ccc(C2(O)CCNC2)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2nocc2C(=O)N2CCC(O)(c3ccc(C)cn3)C2)cc1Cl
Yield: 54.4 %

Procedure:
A solution of 3-(3-chloro-4-methoxyphenyl)isoxazole-4-carboxylic acid (10 mg, 0.04 mmol), N-ethyl-N-isopropylpropan-2-amine (14 μL, 0.08 mmol, 2 equ.) and TBTU (15 mg, 0.046 mmol, 1.2 equ.) in DMF (0.3 mL) was added to 3-(5-methylpyridin-2-yl)pyrrolidin-3-ol dihydrochloride (10 mg, 0.04 mmol). After 1 h at rt the crude product was purified by RP-HPLC. The pure fractions were basified (NaHCO3) and extracted with ethyl acetate, dried (Na2SO4), evaporated and dried in vacuum to yield the title compound (9 mg). MS (ESI, pos. ion) m/z: calcd for C21H20ClN3O4: 413.1142, found 413.1143.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]([CH3:16])([C:10]1[NH:14][C:13](=[O:15])[O:12][N:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].CO.[C:20]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]([CH3:9])([C:10]1[N:14]([CH3:20])[C:13](=[O:15])[O:12][N:11]=1)[CH3:16])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1noc(=O)[nH]1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: C1CCOC1
Solvent: CO
Product: Cn1c(C(C)(C)NC(=O)OC(C)(C)C)noc1=O
Temperature: 2.5 °C
Reaction time: 16 h
Yield: 88.2 %

Procedure:
To a colorless solution of [1-methyl-1-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-ethyl]-carbamic acid tert-butyl ester (1.5 g, 6.17 mmol) in THF (30.0 mL) was added methanol (296 mg, 374 μl, 9.25 mmol) and triphenylphosphine (1.94 g, 7.4 mmol). The mixture was cooled to 0-5° C. and diisopropyl azodicarboxylate (1.5 g, 1.46 ml, 7.4 mmol) was added slowly over a period of 20 minutes at max: 5° C. The mixture was stirred for another 30 minutes at 0-5° C. and for 16 hours at room temperature. Solvents were removed in vacuo and the residue was purified by flash chromatography (silica gel, 70 g, 0% to 100% ethyl acetate in heptane) to give the title compound (1.4 g, 89%) as white solid; GC-MS (EI) 98%, 257.0 (M)+.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([OH:26])=[O:25])=[CH:19][CH:18]=1>CN(C)C=O.C(OCC)C>[OH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:25])=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)Cc1ccc(CO)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(Cc1ccc(CO)cc1)OCc1ccccc1
Reaction time: 3.5 h
Yield: 82.5 %

Procedure:
2.52 g (23.8 mmol) of sodium carbonate and 8.13 g (47.6 mmol) of benzyl bromide were added to a solution of 3.95 g (23.8 mmol) of 4-Hydroxymethylphenylacetic acid [prepared as described in step (i) above] in 40 ml of N,N-dimethylformamide, and the resulting mixture was stirred for 3.5 hours. At the end of this time, the reaction mixture was diluted with diethyl ether, and the diluted mixture was washed with water and then with a saturated aqueous solution of sodium chloride. The organic phase was dried over anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was purified by column chromatography through 200 g of silica gel, using a gradient elution method, with mixtures of methylene chloride and ethyl acetate in ratios ranging from 100:5 to 100:10 by volume as the eluent, to give 5.03 g (yield 82%) of the title compound as an oil.
Reaction SMILES: [CH2:1]([O:8][N:9]([C@H:22]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:25]([CH2:35][O:36][Si](C(C)(C)C)(C)C)[CH:24]=[C:23]1[CH2:44][CH2:45][N+:46]([O-:48])=[O:47])[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C>CO>[CH2:1]([O:8][N:9]([C@H:22]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:25]([CH2:35][OH:36])[CH:24]=[C:23]1[CH2:44][CH2:45][N+:46]([O-:48])=[O:47])[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:11])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](N(OCc2ccccc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])C(CC[N+](=O)[O-])=C[C@H]1CO[Si](C)(C)C(C)(C)C
Solvent: CO
Solvent: CC(=O)Cl
Product: CC(C)(C)OC(=O)N1C[C@H](N(OCc2ccccc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])C(CC[N+](=O)[O-])=C[C@H]1CO
Temperature: 0 °C
Reaction time: 3 h
Yield: 97.9 %

Procedure:
(2S,5R)-tert-butyl 5-(N-(benzyloxy)-2-nitrophenylsulfonamido)-2-((tert-butyldimethylsilyloxy)methyl)-4-(2-nitroethyl)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 220, 5 g, 7.07 mmol) was taken up in methanol (150 mL) cooled to 0° C. and acetyl chloride (0.075 mL, 1.06 mmol) added. The reaction mixture was stirred for 3 hours at 0° C. The solvent was removed in vacuo and the residue was taken up in EtOAc, washed with saturated sodium bicarbonate, dried over Na2SO4, filtered and concentrated to afford the title compound as an oil (4.1 g, 98%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:13][CH2:14][CH2:15][O:16][CH3:17].CC(OC(C)=O)=O.[N+:25]([O-])([OH:27])=[O:26]>CC(O)=O>[CH3:1][O:2][C:3]1[C:4]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:5][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:11]([N+:25]([O-:27])=[O:26])[CH:12]=1
Reactant: O=[N+]([O-])O
Reactant: COCCOc1cc(C(=O)OC)ccc1OC
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COCCOc1cc(C(=O)OC)c([N+](=O)[O-])cc1OC
Temperature: 50 °C
Yield: 56 %

Procedure:
According to the procedure described in Example 6A Step 2, to a solution of methyl 4-methoxy-3-(2-methoxyethoxyl)benzoate (5.6 g, 23.3 mmol) and Ac2O (12 mL) in AcOH (60 mL) was dropped fuming nitric acid (90%, 4 mL). The reaction was heated at 50° C. for 3 hours, and the residue was purified by silica gel chromatography with 0-15% EtOAc/hexane as eluants to afford methyl 4-methoxy-5-(2-methoxyethoxy)-2-nitrobenzoate as a solid (3.67 g, 56%). 1H NMR (300 MHz, DMSO-d6) δ 7.64 (s, 1H), 7.34 (s, 1H), 4.26 (m, 2H), 3.91 (s, 3H), 3.82 (s, 3H), 3.68 (m, 2H), 3.33 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[CH2:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)[CH:17]=1)=[O:14].[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:13](=[O:14])[CH2:12][C:7]2[C:8]3[C:3](=[C:2]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH:11]=[CH:10][CH:9]=3)[CH:4]=[CH:5][CH:6]=2)=[CH:17][C:18]=1[N:24]1[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]1
Reactant: OB(O)c1ccccc1
Reactant: COc1ccc(NC(=O)Cc2cccc3c(Br)cccc23)cc1N1CCN(C)CC1
Product: COc1ccc(NC(=O)Cc2cccc3c(-c4ccccc4)cccc23)cc1N1CCN(C)CC1

Procedure:
The title compound was prepared from 5-bromo-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]naphth-1-ylacetamide (E20) and phenylboronic acid using a similar procedure to Example 4 (39%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[OH-].[K+].[F:14][C:15]([F:19])=[C:16]([F:18])[F:17]>CN(C)C=O.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][C:16]([F:18])([F:17])[CH:15]([F:19])[F:14]
Reactant: FC(F)=C(F)F
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(OC(F)(F)C(F)F)c(F)c1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
7.0 Grams of 2-fluoro-4-nitrophenol was dissolved in 70 ml of N,N-dimethylformamide, and 1.0 g of potassium hydroxide was added thereto. Tetrafluoroethylene was blown into the resulting solution at an inner temperature of 100° C., after which stirring was continued for 6 hours at an inner temperature of 100° C. The reaction solution was poured into ice water and extracted with ether. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated. The residue obtained was subjected to column chromatography on silica gel with toluene as an eluent to obtain 6.97 g of 3-fluoro-4-(1',1',2',2'-tetrafluoroethoxy)nitrobenzene. 1H-NMR (CDCl3): δ(ppm) 7.10-8.2(3H), 5.59(1H, tt, J=53, 3 Hz)