Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CON(C)[C:4](=[O:15])[CH:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:6].C(=O)=O.C(#N)C.C([Mg]Cl)(C)C.Br[Mg][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1>C1COCC1>[O:15]=[C:4]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)[C@@H:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:12])[CH3:13])[CH3:6]
Reactant: CON(C)C(=O)C(C)NC(=O)OC(C)(C)C
Reactant: Br[Mg]Cc1ccccn1
Agent: CC(C)[Mg]Cl
Agent: O=C=O
Solvent: CC#N
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Cc1ccccn1
Temperature: 25 °C

Procedure:
tert-Butyl 1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (50.0 g, 215 mmol) in THF (450 mL) was cooled to −40° C. (dry ice/acetonitrile) and slowly charged with isopropylmagnesium chloride (2.0M, 102.2 mL, 0.95 eq). After a clear solution was obtained (became clear at −20° C. and milky again at −40° C.), bromo(pyridin-2-ylmethyl)magnesium solution (see below for preparation) was added drop wise using cannula before warming to rt overnight. The reaction mixture was quenched with NH4Cl solution and extracted with EtOAc (500 mL×2). The combined organic layers were washed with water, brine, dried over sodium sulfate, and concentrated under high vacuum to give (S)-tert-butyl 3-oxo-4-(pyridin-2-yl)butan-2-ylcarbamate as a tan oil. Small scale reaction was purified by combiflash (EtOAc/hexane, up to 1/3) to give a red oil. Mass Spectrum (ESI) m/e=265 (M+1).
Reaction SMILES: [CH:1]12[N:7]([S:8]([CH2:11][C:12]3[C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([O:22][CH3:23])[C:15]([Br:24])=[CH:14][CH:13]=3)(=[O:10])=[O:9])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Na+].Br[C:27]1C=CC(CS([O-])(=O)=O)=C(C(OC)=O)C=1OC.C12NC(CC1)CCC2>>[CH:1]12[N:7]([S:8]([CH2:11][C:12]3[C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([O:22][CH3:23])[C:15]([Br:24])=[CH:14][CH:13]=3)(=[O:9])=[O:10])[CH:4]([CH2:3][CH2:2]1)[CH2:27][CH2:5][CH2:6]2
Reactant: COC(=O)c1c(CS(=O)(=O)N2C3CCC2CC3)ccc(Br)c1OC
Reactant: COC(=O)c1c(CS(=O)(=O)[O-])ccc(Br)c1OC
Agent: C1CC2CCC(C1)N2
Agent: [Na+]
Product: COC(=O)c1c(CS(=O)(=O)N2C3CCCC2CC3)ccc(Br)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 177, starting from methyl (4-bromo-3-methoxy-2-methoxycarbonylphenyl)-methanesulphonic acid sodium salt (Intermediate 148) and 8-azabicyclo[3.2.1]octane, as a white solid.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]#[N:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:13](OCC)(OCC)[O:14][CH2:15][CH3:16].C(OC(=O)C)(=O)C.C(OCC)(=O)C>CO>[CH2:15]([O:14][CH:13]=[C:10]([S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:8])=[O:9])[C:11]#[N:12])[CH3:16]
Reactant: CCOC(OCC)OCC
Reactant: N#CCS(=O)(=O)c1ccccc1
Solvent: CO
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CCOC=C(C#N)S(=O)(=O)c1ccccc1
Yield: 56.7 %

Procedure:
A solution of (phenylsulfonyl)acetonitrile (10.5 g, 0.089 mol) in triethyl orthoformate (21 mL, 0.14 mol) and acetic anhydride (21 mL, 0.2 mol) was heated at 160° C. with removal of ethyl acetate (35 mL). The dark oily residue was dissolved in methanol (60 mL) and the solution was concentrated and recrystallized from hexanes/ethyl acetate to yield (11.98 g, 78%) of the desired product.
Reaction SMILES: [NH2:1][OH:2].CC1CCCO1.[Na+].[Cl-].[C:11](#[N:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O>[C:11](=[N:1][OH:2])([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NO
Reactant: N#Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CC1CCCO1
Solvent: O
Product: NC(=NO)c1ccccc1
Temperature: 70 °C

Procedure:
Benzonitrile (50.0 g, 0.485 mol) was added to a 250 mL flask and heated to 70° C. with stirring. Deionized water (1.0 g) was added and the temperature was lined out at 70° C. Aqueous hydroxylamine (50%, 37.50 g, 34.8 ml, assay was 53.3%, 0.605 moles) was added via a syringe pump over 1.5 hours while maintaining the temperature at 70°±2° C. HPLC analysis indicated that the conversion of benzonitrile was >99% after about 2.5 hours of reaction time. The batch was heated for a total of 3.5 hours at 70° C., then was cooled to 60° C. The batch was transferred to a 500 mL flask with 2-methyltetrahydrofuran (208.98 g), followed by 20 wt % aqueous NaCl (40.0 g). The mixture was heated to 60° C., and the phases were separated at 60° C. to give a solution of benzamide oxime in 2-methyltetrahydrofuran (281.80 g) and aqueous waste (44.61 g). The 2-methyltetrahydrofuran solution assayed for 21.73 wt % benzamide oxime.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.Cl.[CH2:26]([O:28][C:29](=[O:40])[C@H:30]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1)[NH2:31])[CH3:27]>N1C=CC=CC=1>[CH2:26]([O:28][C:29](=[O:40])[C@H:30]([CH2:32][C:33]1[CH:34]=[CH:35][C:36]([OH:39])=[CH:37][CH:38]=1)[NH:31][C:1](=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1)[CH3:27]
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: O=C(O)c1cccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)c1cccnc1
Reaction time: 8 h

Procedure:
Nicotinic acid (12.3 g, 0.1 mol) was dissolved in dry pyridine (300 mL). The solution was cooled and dicyclohexylcarbodiimide (20.6 g, 0.1 mol) was added. After dissolution, tyrosine ethyl ester hydrochloride (24.6 g, 0.1 mol) was added and the solution was stirred overnight. The precipitated dicyclohexylurea (DCU) was removed by filtration. Additional DCU was removed by triturating the oil with hot water. The product was purified with acetone. Calculated for C17H18N2O4.1/2H2O: C,63.16; H,5.88; N,8.66. Found: C,63.10; H,5.96; N,8.59. The product can also be named N-[1-ethoxycarbonyl-2-(4'-hydroxyphenyl)ethyl]nicotinamide.
Reaction SMILES: CC1(C)S[C@@H]2[C@H](NC([C@H](N)C3C=CC=CC=3)=O)C(=O)[N:4]2[C@H]1C(O)=O.C[C@@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](NC(N)=N)[C@@H](O)[C@@H]2NC(N)=N)[C@H]([O:49][C@@H:50]2[O:55][C@@H:54]([CH2:56]O)[C@H:53](O)[C@@H:52](O)[C@@H:51]2[NH:60]C)[C@@]1(O)C=O.C([O-])(=O)CCCCCCC/C=C\CCCCCCCC.[Na+]>OCC(CO)O>[NH2:60][C@H:51]([C:50]([OH:55])=[O:49])[CH2:52][CH2:53][CH2:54][CH2:56][NH2:4]
Reactant: CN[C@@H]1[C@H](O[C@H]2[C@H](O[C@H]3[C@H](O)[C@@H](O)[C@H](NC(=N)N)[C@@H](O)[C@@H]3NC(=N)N)O[C@@H](C)[C@]2(O)C=O)O[C@@H](CO)[C@H](O)[C@H]1O
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)[O-]
Agent: [Na+]
Solvent: OCC(O)CO
Product: NCCCC[C@H](N)C(=O)O
Reaction time: 24 h

Procedure:
Glycerol stocks of the strains obtained in Example 3, in which fad genes were amplified, were thawed. And, 100 μL of each was evenly spread on an LB agar medium plate containing 50 mg/L ampicillin and 20 mg/L streptomycin and incubated at 37° C. for 24 hours. About ½ volume of bacterial cells on the obtained plate were inoculated into 5 mL of fermentation medium described below containing 50 mg/L ampicillin and 20 mg/L streptomycin in a test tube manufactured by AGC TECHNO GLASS CO., LTD. (diameter×length×thickness (mm)=25×200×1.2), and cultured using a reciprocal shaking culture apparatus at 37° C. for 72 hours. As a carbon source in a main culture, sodium oleate added with polyoxyethylene sorbitan monooleic acid ester (Tween 80: manufactured by NACALAI TESQUE, INC.) as an emulsification promoter to a final concentration of 0.5% (w/v) was used. As for a total amount of carbon sources, sodium oleate was 10 g/L. The medium composition used for the culture is shown below.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:6][C:5]2[CH:7]=[C:8]([CH2:11][CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][N:15]=3)[CH:9]=[CH:10][C:4]=2[O:3]1.CN(C)C=O.C(N(CC)CC)C.[CH3:34][O:35][N:36]([CH3:40])[C:37](Cl)=[O:38]>O>[CH3:1][C:2]1([CH3:21])[CH2:6][C:5]2[CH:7]=[C:8]([CH2:11][CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:37]([N:36]([O:35][CH3:34])[CH3:40])=[O:38])=[CH:16][N:15]=3)[CH:9]=[CH:10][C:4]=2[O:3]1
Reactant: CON(C)C(=O)Cl
Reactant: CC1(C)Cc2cc(CCOc3ccc(N)cn3)ccc2O1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CON(C)C(=O)Nc1ccc(OCCc2ccc3c(c2)CC(C)(C)O3)nc1
Temperature: 25 °C
Yield: 73.1 %

Procedure:
2.2 g of 2-[2-(2,3-dihydro-2,2-dimethyl-5-benzofuranyl)ethoxy]-5-aminopyridine was dissolved into 10 ml of N,N-dimethylformamide, and 0.9 g of triethylamine was added thereto. 1.2 g of N-methoxy-N-methylcarbamoyl chloride was slowly added dropwise thereto. After the mixture was stirred at room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. After the organic layer was washed with water, it was dried over anhydrous magnesium sulfate and ethyl acetate was dried off. The residue was subjected to silica gel column chromatography using ethyl acetate/n-hexane (2/3) as a developer to obtain 2.1 g of 1-{2-[2-(2,3-dihydro-2,2-dimethyl-5-benzofuranyl)ethyloxy]-5-pyridyl}-3-methoxy-3-methylurea.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:13]2[N:18]=[C:17]([CH3:19])[N:16]=[C:15]([NH2:20])[CH:14]=2)[C:9](F)=[N:10][CH:11]=1)=[CH2:5])C.[F:21][C:22]1[CH:23]=[C:24]([NH2:30])[CH:25]=[N:26][C:27]=1[O:28][CH3:29].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[NH2:20][C:15]1[N:16]=[C:17]([CH3:19])[N:18]=[C:13]([C:8]2[CH:7]=[C:6]([C:4](=[O:3])[CH3:5])[CH:11]=[N:10][C:9]=2[NH:30][C:24]2[CH:25]=[N:26][C:27]([O:28][CH3:29])=[C:22]([F:21])[CH:23]=2)[CH:14]=1
Reactant: COc1ncc(N)cc1F
Reactant: C=C(OCC)c1cnc(F)c(-c2cc(N)nc(C)n2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ncc(Nc2ncc(C(C)=O)cc2-c2cc(N)nc(C)n2)cc1F
Reaction time: 0.5 h
Yield: 32.1 %

Procedure:
A mixture of 6-(5-(1-ethoxyvinyl)-2-fluoropyridin-3-yl)-2-methylpyrimidin-4-amine (208 mg, 0.76 mmol) and 5-fluoro-6-methoxypyridin-3-amine (162 mg, 1.14 mmol) in 1.5 mL of THF at 0° C. was added sodium bis(trimethylsilyl)amide (1 M in THF) (2.28 mL, 2.28 mmol) dropwise at 0° C. and the dark red solution was stirred at this temperature for 30 min. It was quenched with 4 mL of 0.5 N HCl and stirred for 10 min. The mixture was basified with 1 N NaOH to pH of 8 and stirred with 10 mL of EtOAc for 5 min. The precipitated brown solid was filtered, washed with 2×2 mL of water followed by 2×2 mL of EtOAc. The brown solid was dried in a vacuum oven at 45° C. for 18 h to give 1-(5-(6-amino-2-methylpyrimidin-4-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)ethanone (90 mg, 32% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.93 (s, 1H), 8.90 (s, 1H), 8.50 (s, 1H), 8.37 (s, 1H), 8.24 (s, 1H), 7.10 (br., 2H), 6.93 (s, 1H), 3.95 (s, 3H), 2.60 (s, 3H), 1.58 (s, 3H). m/z (ESI, positive ion) 369.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16].C(=O)(O)[O-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])=[CH:4][CH:3]=1
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-bromo-1H-indole (2 g, 10.2 mmol) in THF (20 mL) at 0° C. was added 0.46 g of sodium hydride (12 mmol) in 3 portions. The mixture was stirred 30 min followed by addition of chlorotriisopropylsilane (2 g, 10.4 mmol). The reaction was allowed to warm to room temperature and stirring was continued overnight. The mixture was then poured into sat. aq. sodium bicarbonate and extracted with ethyl acetate. The organic phase was washed with brine, dried (magnesium sulfate) and concentrate under vacuum to afford the crude product as an orange oil that was purified by flash chromatography on silica gel using a 4:1 ethyl acetate/heptane mixture as the eluent. The purified product (2.8 g) was a light orange oil.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Br:9][CH2:10][S:11](Br)(=[O:13])=[O:12].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[Br:9][CH2:10][S:11]([CH:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])(=[O:13])=[O:12]
Reactant: C=CCCCCCC
Reactant: O=S(=O)(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCCCCCC=CS(=O)(=O)CBr
Reaction time: 0.25 h
Yield: 87.2 %

Procedure:
A mixture of 1-octene (2.82 g) and bromomethanesulfonyl bromide (6.0 g) in methylene chloride (4 mL) was irradiated at -20° C. with an ultraviolet lamp for 0.5 hours. A small amount of solid potassium carbonate was added and then removed by filtration. The reaction mixture was diluted with methylene chloride (50 mL), cooled in ice and treated with a solution of triethylamine (4.45 g) in 10 mL of methylene chloride. The reaction mixture was stirred for 0.25 hours and was washed with dilute HCl and water. The methylene chloride layer was separated, dried over anhydrous magnesium sulfate and the methylene chloride removed in vacuo to give 5.9 g (97% yield) of oily 1-octenyl bromomethyl sulfone which was characterized by IR and NMR spectroscopy.
Reaction SMILES: CC[N:3]=C=NCCCN(C)C.[CH2:12]([O:14][C:15](=[O:50])[CH2:16][CH:17]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:37]=3[F:44])=[C:32]([CH2:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH:31]=2)[CH:23]=1)[CH2:18][C:19](O)=[O:20])[CH3:13].C(N(CC)CC)C.O>CN(C=O)C>[NH2:3][C:19](=[O:20])[CH2:18][CH:17]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:37]=3[F:44])=[C:32]([CH2:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH:31]=2)[CH:23]=1)[CH2:16][C:15]([O:14][CH2:12][CH3:13])=[O:50]
Reactant: CCOC(=O)CC(CC(=O)O)c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1
Reactant: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(CC(N)=O)c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.2 %

Procedure:
Under a nitrogen atmosphere, WSC (53.6 mg) was added to a suspension of 5-ethoxy-3-(3-(((2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-yl)oxy)methyl)phenyl)-5-oxopentanoic acid (100 mg), 1-hydroxybenzotriazole monohydrate-ammonia complex (42.5 mg) and triethylamine (78 μL) in DMF (1 mL), and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (47.1 mg) as a colorless oil.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>>[CH2:1]([NH:9][C:10](=[O:12])[CH3:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NCCc1ccccc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)NCCc1ccccc1

Procedure:
In close analogy to the procedure described above, phenethylamine is reacted with acetic anhydride to provide the title compound.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25](Br)=[CH:24][N:23]=[C:22]([S:27][CH3:28])[N:21]=3)[C@H:14]2[CH3:29])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:32][C:33]1[C:37](B(O)O)=[C:36]([CH3:41])[O:35][N:34]=1.FC(F)(F)C1C=C([C@H]2OC(=O)N(CC3C(C4C(OC)=NC=C(C(C)C)C=4)=CN=C(S(C)(=O)=O)N=3)[C@H]2C)C=C(C(F)(F)F)C=1>>[F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:37]4[C:33]([CH3:32])=[N:34][O:35][C:36]=4[CH3:41])=[CH:24][N:23]=[C:22]([S:27][CH3:28])[N:21]=3)[C@H:14]2[CH3:29])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CSc1ncc(Br)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Reactant: Cc1noc(C)c1B(O)O
Agent: COc1ncc(C(C)C)cc1-c1cnc(S(C)(=O)=O)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Product: CSc1ncc(-c2c(C)noc2C)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5-bromo-2-(methylsulfanyl)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 8, 500 mg, 0.943 mmole) and 3,5-dimethylisoxazole-4-boronic acid, pinacol ester (231 mg, 1.037 mmol) were treated in a similar fashion to INTERMEDIATE 17 Step A or EXAMPLE 64 Step A to give the title compound after filtration of the reaction mixture, evaporation and silica gel purification of the crude isolate. LCMS (M+H)+: 547.2.
Reaction SMILES: [O:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH2:3][CH2:2]1.[NH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[N+:21]([O-:23])=[O:22].C(OCC)C>C(#N)C>[N+:21]([C:13]1[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=1[O-:11])([O-:23])=[O:22].[NH2:10][N+:6]1[CH:7]=[CH:8][C:9]2[O:1][CH2:2][CH2:3][C:4]=2[CH:5]=1
Reactant: c1cc2c(cn1)CCO2
Reactant: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: CC#N
Solvent: CCOCC
Product: N[n+]1ccc2c(c1)CCO2
Product: O=[N+]([O-])c1ccc([O-])c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 89 %

Procedure:
To a solution of 2,3-dihydrofuro[3,2-c]pyridine (23.8 g, 200 mmol) in acetonitrile (130 mL) was added 1-(aminooxy)-2,4-dinitrobenzene (55.0 g, 240 mmol), and the mixture was stirred at room temperature for 3 days. Diethyl ether was added, and the resulting precipitate was collected by filtration to give the title compound (57.0 g, yield 89%).
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[CH2:19][CH2:20][CH2:21]O)[NH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.C1(C)C=CC(S([Cl:38])(=O)=O)=CC=1>C(#N)C>[C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[CH2:19][CH2:20][CH2:21][Cl:38])[NH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)c1c[nH]c2cccc(CCCO)c12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CC#N
Solvent: c1ccncc1
Product: O=S(=O)(c1ccccc1)c1c[nH]c2cccc(CCCCl)c12
Reaction time: 264 h
Yield: 48 %

Procedure:
To a solution of 3-[3-(phenylsulfonyl)-1H-indol-4-yl]propan-1-ol (1.006 g, 3.19 mmol) in anhydrous acetonitrile (25 mL) at room temperature under nitrogen was added pyridine (0.65 mL, 7.97 mmol) followed by p-toluenesulfonyl chloride, and the reaction mixture stirred for 11 days. The reaction mixture was then concentrated to a small volume in vacuo, and the mixture partitioned between ethyl acetate (100 mL) and 1 N aqueous HCl (100 mL). The organic phase was separated, washed with water (2×100 mL) and brine (200 mL), dried (Na2SO4), filtered and concentrated in vacuo to afford a yellow syrup. Purification by flash chromatography (0 to 40% ethyl acetate/hexane) afforded 3-phenylsulfonyl-4-(3-chloro-propyl)-1H-indole as a colorless foam (0.51 g, 48%). MS (ES+) m/z 334 (M+H). Further elution afforded 3-[3-(phenylsulfonyl)-1H-indol-4-yl]propyl 4-methylbenzenesulfonate as a white foam (0.48 g, 32%). MS (ES+) m/z 469.7 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:20]([NH:22][C@H:23]([C:31]([C@:33]([C@H:38]([C@@H:40]([C@@H:42]([CH2:44][NH2:45])[OH:43])[OH:41])[OH:39])([OH:37])[C:34]([OH:36])=[O:35])=[O:32])[CH2:24][S:25][CH2:26][NH:27][C:28](=[O:30])[CH3:29])=[O:21])[CH2:10][CH:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:12](=[O:14])[OH:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH3:61][Si:62]([CH:65](O)[CH3:66])([CH3:64])[CH3:63]>CN(C)C=O>[CH3:61][Si:62]([CH2:65][CH2:66][O:35][C:34]([C@@:33]([C:31](=[O:32])[C@H:23]([CH2:24][S:25][CH2:26][NH:27][C:28](=[O:30])[CH3:29])[NH:22][C:20](=[O:21])[C@H:9]([CH2:10][CH:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:12](=[O:13])[OH:14])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])([C@H:38]([C@@H:40]([C@@H:42]([CH2:44][NH2:45])[OH:43])[OH:41])[OH:39])[OH:37])=[O:36])([CH3:64])[CH3:63]
Reactant: CC(=O)NCSC[C@H](NC(=O)[C@H](CC(OC(C)(C)C)C(=O)O)NC(=O)OC(C)(C)C)C(=O)[C@](O)(C(=O)O)[C@@H](O)[C@H](O)[C@H](O)CN
Reactant: CC(O)[Si](C)(C)C
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(=O)NCSC[C@H](NC(=O)[C@H](CC(OC(C)(C)C)C(=O)O)NC(=O)OC(C)(C)C)C(=O)[C@](O)(C(=O)OCC[Si](C)(C)C)[C@@H](O)[C@H](O)[C@H](O)CN
Reaction time: 0.33 h

Procedure:
To 5 mL of a solution containing 1 mmol of the above acid 5, anhydrous dimethylformamide, and 1 mmol of N-methylmorpholine maintained at 0°--5° C., 1 mmol of isobutylchloroformate is added, and the mixture is kept at this temperature for 20 minutes. To this solution is added a solution of 1 mmol of trimethylsilylethanol in 2 mL of anhydrous dimethylformamide (previously cooled to 0°--5° C.), and the solution is stirred for 1 hour at this temperature and allowed to come to room temperature. The solvent is removed in vacuo and the residue is dissolved in 20 mL of ethyl acetate and washed with water. The organic layer is dried and evaporated to give 6.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][C:12]=3[CH:25]=2)=[CH:4][C:3]=1[N+:26]([O-:28])=[O:27].CO.[ClH:31]>O1CCOCC1.C(OCC)C>[ClH:31].[N+:26]([C:3]1[CH:4]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][NH:14][CH2:13][C:12]=3[CH:25]=2)[CH:6]=[CH:7][C:2]=1[NH2:1])([O-:28])=[O:27]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(-c3ccc(N)c([N+](=O)[O-])c3)cc2C1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Solvent: C1COCCO1
Product: Nc1ccc(-c2ccc3c(c2)CNCCO3)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 72 %

Procedure:
1,1-dimethylethyl 7-(4-amino-3-nitrophenyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (example 8, step 1) (6.0 g, 15.6 mmol) was taken into warm methanol (50 mL) followed by addition of 4M hydrogen chloride in dioxane (50 mL) in portions and the warm solution was allowed to slowly cool to room temperature over 1 h. The mixture was diluted with ethyl ether (100 mL) and the yellow solid was collected by filtration and dried to give 2-nitro-4-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)aniline hydrochloride salt (3.61 g, 72% yield) as a yellow solid. 1H NMR (400 MHz, D2O): 7.79 (s, 1H), 7.44 (d, 1H), 7.29 (s, 1H), 7.26 (d, 1H), 7.02 (d, 1H), 6.82 (d, 1H), 4.34 (s, 2H), 4.32 (br m, 2H), 3.67 (br m, 2H).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=O)[C:2]2=O.COP([CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[CH3:26])=O)(=O)OC.O.[NH2:28][NH2:29]>>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]2[N:28]=[N:29][C:2]3[CH:1]4[CH2:7][CH:4]([C:3]=3[CH:16]=2)[CH2:5][CH2:6]4)=[C:20]([CH3:26])[CH:21]=1
Reactant: O=C1C(=O)C2CCC1C2
Reactant: COP(=O)(CC(=O)c1ccc(F)cc1C)OC
Reactant: NN
Solvent: O
Product: Cc1cc(F)ccc1-c1cc2c(nn1)C1CCC2C1

Procedure:
yellow oil. MS (EI): 254.2 (M+). Prepared from bicyclo[2.2.1]heptane-2,3-dione, [2-(4-Fluoro-2-methyl-phenyl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([C:14](=[O:16])[NH2:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].ClCCl>ClCCCl>[CH2:17]([N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH:10]1[C:14](=[O:16])[NH2:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCNC(C(N)=O)C1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)C(C(N)=O)C1
Reaction time: 18 h
Yield: 93.1 %

Procedure:
A solution of (RS)-1-(tert-butyloxycarbonyl)-3-carbamoylpiperazine (ref Bruce et al. Syn. Comm. 1995, 2673-84) (25 g, 0.109 mol) and benzaldehyde (11.1 ml, 0.109 mol) in 1,2-dichloroethane (550 ml) was stirred at room temperature for 1.5 h. Sodium triacetoxyborohydride (34.7 g, 0.163 mol) was added in one portion and the resultant stirred for a further 18 h. Dichloromethane (400 ml) was added and the mixture washed with saturated sodium hydrogen carbonate (600 ml). The organic layer was dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed on silica gel eluting with 10-70% ethyl acetate in hexane to afford the title compound as a colourless solid (32.4 g, 93%).