Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[C:2]1[C:10]1([NH:13]C(=O)OCC2C=CC=CC=2)[CH2:12][CH2:11]1.[H][H]>CO.[Pd+2]>[NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[C:2]1[C:10]1([NH2:13])[CH2:11][CH2:12]1
Reactant: O=C(NC1(c2nc3cnccc3[nH]2)CC1)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Solvent: CO
Product: NC1(c2nc3cnccc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 120.5 %

Procedure:
To a small RBF was added benzyl 1-(1H-imidazo[4,5-c]pyridin-2-yl)cyclopropylcarbamate (939 mg, 3.05 mmol) in methanol (13 ml). The flask was sealed with a septa and the solution was degassed and flushed with nitrogen several times. To the solution was then added 10% Palladium(II) on carbon (97 mg, 91 μmol), and a balloon of hydrogen was added to the top of the flask. The mixture was stirred overnight at room temperature. The mixture was pushed through a plug of celite in a Whatman Autovial (equipped with a 0.45 uM nylon membrane and a glass microfiber prefilter). Volatiles were removed giving 640 mgs (100% yield) of 1-(1H-imidazo[4,5-c]pyridin-2-yl)cyclopropanamine as a yellow solid. 1H NMR (400 MHz, CD3OD) δ ppm 1.67-1.72 (m, 2 H), 1.73-1.80 (m, 2 H), 7.92 (m, 1 H), 8.40 (d, J=7.0 Hz, 1 H), 9.05 (s, 1 H). LCMS rt=0.293 min., m/z 175.1 (M+H), 90.7% purity.
Reaction SMILES: [Mg].II.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([Mg]Br)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][C:19]=1[N+:26]([O-:28])=[O:27]>C1COCC1>[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]([C:8]2[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:6]([O:5][CH3:4])[CH:7]=2)[OH:23])=[CH:20][C:19]=1[N+:26]([O-:28])=[O:27]
Reactant: COc1ccc([Mg]Br)cc1OC
Reactant: COc1ccc(C=O)cc1[N+](=O)[O-]
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2ccc(OC)c([N+](=O)[O-])c2)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
Grignard reagent was prepared in an oven-dried three necked flask outfitted with a reflux condenser, dropping funnel, and magnetic stirrer. Approximately 3 mL of a solution of 3,4-bromoveratrole (3.5 g, 15.9 mmol) in THF (10 mL) was added to a mixture of magnesium turnings (0.4 g, 15.9 mmol) in THF (5 mL) with a small piece of iodine. As soon as the solution became colorless (heating sometimes necessary), the remaining 3,4-bromoveratrole solution was added dropwise to the solution under mild reflux. The resulting mixture was refluxed for 3 h then cooled to room temperature for 30 min. The (3,4-dimethoxyphenyl)magnesium bromide was then added slowly to a stirred solution of 4-methoxy-3-nitro-benzaldehyde (2.4 g, 13.3 mmol) in THF (10 mL) at 0° C. After complete addition, the solution was allowed to stir at room temperature for 1 h. The mixture was cooled to 0° C. and quenched with saturated NH4Cl solution (40 mL). The aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (2×30 mL), brine (30 mL) and dried (MgSO4). Solvent was removed and residue was purified by flash chromatography (silica gel, CH2Cl2:EtOAc 9:1) to give (4-methoxy-3-nitro-phenyl)-(3,4-dimethoxy-phenyl)-methanol as an oil (2.6 g, 63%): 1H NMR (CDCl3) δ 7.89 (d, J=2 Hz, 1H), 7.54-7.49 (dd, J=2, 8 Hz, 1H), 7.05 (d, J=8 Hz, 1H), 6.88-6.81 (m, 3H), 5.78 (d, J=3 Hz, 1H), 3.94 (s, 3H), 3.87 (s, 3H), 3.85 (s, 3H), 2.38 (d, J=3 Hz, 1H).
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][N:6]=1)=[O:4].[CH:11]1([C:14]([CH3:16])=[O:15])[CH2:13][CH2:12]1.C[O-].[Na+]>C1C=CC=CC=1>[CH:11]1([C:14](=[O:15])[CH2:16][C:3]([C:5]2[CH:10]=[CH:9][N:8]=[CH:7][N:6]=2)=[O:4])[CH2:13][CH2:12]1
Reactant: CC(=O)C1CC1
Reactant: COC(=O)c1ccncn1
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C(CC(=O)C1CC1)c1ccncn1

Procedure:
A stirred mixture of 1.4 g. of methyl-4-pyrimidinecarboxylate, 1.7 g. of cyclopropylmethyl ketone, 1.2 g. of sodium methoxide and 40 ml. of benzene is heated under reflux for 4 hours. The mixture is diluted with 40 ml. of water and the benzene phase is removed. The aqueous mixture is made weakly acidic with dilute hydrochloric acid and extracted with chloroform. The cloroform solution is dried over magnesium sulfate and concentrated under reduced pressure to give light brown crystals, which are recrystallized from hexane to provide straw-colored crystals, melting point 81°-84°C.
Reaction SMILES: [C:1]12([NH:11][Si:12](Cl)([CH3:14])[CH3:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:16][C:17]1[CH-:18][C:19]2[C:24]([C:25]=1[CH3:26])=[CH:23][CH:22]=[CH:21][CH:20]=2.[Li+]>C1COCC1>[CH3:16][C:17]1[CH:18]([Si:12]([NH:11][C:1]23[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]4)[CH2:2]2)[CH2:8]3)([CH3:13])[CH3:14])[C:19]2[C:24]([C:25]=1[CH3:26])=[CH:23][CH:22]=[CH:21][CH:20]=2
Reactant: Cc1[cH-]c2ccccc2c1C
Reactant: C[Si](C)(Cl)NC12CC3CC(CC(C3)C1)C2
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1=C(C)C([Si](C)(C)NC23CC4CC(CC(C4)C2)C3)c2ccccc21
Reaction time: 8 h

Procedure:
(1-adamantylamino)chlorodimethylsilane (5.48 g, 0.0225 moles) was stirred in THF (100 mL) as lithium 2.3-dimethylindenide (3.40 g, 0.0225 moles) in THF (25 mL) was added dropwise. This mixture was allowed to stir for 8 hours. After the reaction period the volatiles were removed and the residue extracted and filtered using hexane. Removal of the hexane resulted in the isolation of the desired product as a solid. (7.69 g, 97.0 percent).
Reaction SMILES: ClC1C=CC([C@@H]2CN(C3N=NC(Cl)=CC=3)C[C@H]2C(OC)=O)=CC=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C@@H:31]2[CH2:35][N:34]([C:36]3[CH:41]=[CH:40][C:39](=[O:42])[NH:38][N:37]=3)[CH2:33][C@H:32]2[C:43]([O:45]C)=[O:44])=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C@@H:31]2[CH2:35][N:34]([C:36]3[CH:41]=[CH:40][C:39](=[O:42])[NH:38][N:37]=3)[CH2:33][C@H:32]2[C:43]([OH:45])=[O:44])=[CH:27][CH:26]=1
Reactant: COC(=O)[C@@H]1CN(c2ccc(=O)[nH]n2)C[C@H]1c1ccc(Cl)cc1
Agent: COC(=O)[C@@H]1CN(c2ccc(Cl)nn2)C[C@H]1c1ccc(Cl)cc1
Product: O=C(O)[C@@H]1CN(c2ccc(=O)[nH]n2)C[C@H]1c1ccc(Cl)cc1
Yield: 70 %

Procedure:
The title compound (0.51 g, 70%) was prepared from the product of Step A, methyl (3S,4R)-4-(4-chlorophenyl)-1-(6-oxo-1,6-dihydropyridazin-3-yl)pyrrolidine-3-carboxylate (0.76 g, 2.28 mmol) according to the same procedure as in Step C of Preparation 17.
Reaction SMILES: [C:1]([C:5]1[CH2:18][C:17](=[O:19])[C:8]2[N:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]3=[CH:11][S:12][C:7]=2[C:6]=1[C:20]([O:22]CC)=[O:21])([O:3]C)=[O:2].Cl>[OH-].[Na+].C(O)C>[O:19]=[C:17]1[C:8]2[N:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]3=[CH:11][S:12][C:7]=2[C:6]([C:20]([OH:22])=[O:21])=[C:5]([C:1]([OH:3])=[O:2])[CH2:18]1
Reactant: CCOC(=O)C1=C(C(=O)OC)CC(=O)C2=C1SC=C1C=CC=CN12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1=C(C(=O)O)C2=C(C(=O)C1)N1C=CC=CC1=CS2
Temperature: 60 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
A mixture of 12 g of 3-carbomethoxy-4-carbethoxy-1-oxo-pyrido[2,1-C][1,4]benzothiazine in 270 ml 0.5N NaOH and 60 ml ethanol was stirred at 60° C. for 2 hrs. It was then acidified with 1N HCl, filtered, the precipitate washed with water and dried to give 8.5 g crude solid which was purified by dissolving in IN NaOH, and crystallizing out by addition of IN HCl. It was then filtered, washed with water and ether to give 7.8 g product, m.p. 222° C. (decomposition).
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[C:9]([CH3:11])[O:10][C:6]=2[CH:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=1.Br[C:18]1[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][N:19]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.[Cu]I>[CH3:11][C:9]1[O:10][C:6]2[CH:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=[C:2]([O:1][C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][N:19]=3)[C:7]=2[CH:8]=1
Reactant: CS(=O)(=O)c1ccc(Br)nc1
Reactant: CCOC(=O)c1cc(O)c2cc(C)oc2c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cn2)c2cc(C)oc2c1
Temperature: 100 °C
Yield: 97.4 %

Procedure:
A mixture of ethyl 4-hydroxy-2-methyl-1-benzofuran-6-carboxylate (500 mg, 2.27 mmol), 2-bromo-5-methanesulfonyl pyridine (590 mg, 2.57 mmol), Cs2CO3 (1.1 g, 4.12 mmol) and CuI (100 mg, 1 mmol) in DMF (20 mL) was heated to 100° C. for 4 hours. The solvent was removed under reduced pressure. The residue was poured into water (20 mL) and extracted with EtOAc (50 mL×2). The combined organic layer was washed with brine (20 mL×2), dried over Na2SO4 and concentrated. The product was purified via gradient silica gel chromatography on silica gel using EtOAc/Hex (10/90 to 30/70) to afford the title compound (830 mg, 88%) as a white solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.42 (t, J=7.16 Hz, 3 H) 2.48 (s, 3 H) 3.01-3.19 (m, 3 H) 4.41 (q, J=7.16 Hz, 2 H) 6.23 (d, J=0.94 Hz, 1 H) 7.02-7.18 (m, 2 H) 7.64 (d, J=1.13 Hz, 1 H) 7.85-7.96 (m, 1 H) 8.02-8.10 (m, 1 H); (ESI, pos): 376.
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1)(=O)=O.[I-:17].[K+]>CN(C)C=O>[I:17][CH:6]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1
Reactant: [I-]
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(I)C1
Temperature: 100 °C

Procedure:
A mixture of tert-butyl 3-[(methylsulfonyl)oxy]-1-azetidinecarboxylate (prepared as described in Synlett 1998, 379; 5.0 g, 19.9 mmol), and potassium iodide (16.5 g, 99.4 mmol) in N,N-dimethylformamide (25 ml), was heated at 100° C. for 42 h. The cooled mixture was partitioned between water and ethyl acetate, and the layers separated. The organic phase was dried over MgSO4, concentrated under reduced pressure and the residue azeotroped with xylene. The crude product was purified by flash column chromatography (dichloromethane as eluant) to give the title compound, 3.26 g; 1H NMR (300 MHz, CDCl3) δ=1.43 (s, 9H), 4.28 (m, 2H), 4.46 (m, 1H), 4.62 (m, 2H); LRMS (TSP) 284 (MH)+
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]#[N:11])[CH:8]=2)[CH2:3][CH2:2]1.C1C(=O)N([Br:19])C(=O)C1.C(=O)(O)[O-].[Na+]>CC#N>[Br:19][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][C:7]=1[C:10]#[N:11])[NH:1][CH2:2][CH2:3]2
Reactant: N#Cc1ccc2c(c1)NCC2
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: N#Cc1cc2c(cc1Br)CCN2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 58.4 %

Procedure:
A solution of 2,3-dihydro-1H-indole-6-carbonitrile (2.5 g, 17.34 mmol) in MeCN (69 mL) was cooled to 0° C. and treated with NBS (3310 mg, 17.7 mmol). The light red reaction mixture was stirred at room temperature for 20 minutes, and was then poured into saturated aqueous sodium bicarbonate (200 mL). The product was extracted with ethyl acetate (2×200 mL), and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified using flash chromatography eluting with heptanes/ethyl acetate (95:5 to 60:40) to give the title compound (2.26 g, 58%) as a white solid. MS (ES−): 219.0, 221.0 (79Br M+H, 81Br M+H).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([OH:10])=[O:9])[CH:3]1[CH2:11][C:12]#[C:13][CH2:14][CH3:15].N1C=CC=C[CH:17]=1>[Pd]>[CH3:15][CH2:14]/[CH:13]=[CH:12]\[CH2:11][C@H:3]1[C:2](=[O:1])[CH2:6][CH2:5][C@@H:4]1[CH2:7][C:8]([O:10][CH3:17])=[O:9]
Reactant: c1ccncc1
Reactant: CCC#CCC1C(=O)CCC1CC(=O)O
Agent: [Pd]
Product: CC/C=C\C[C@H]1C(=O)CC[C@@H]1CC(=O)OC
Yield: 98 %

Procedure:
Four hundred mg. of the methyl ester of 3-oxo-2-(2-pentynyl)-cyclopentaneacetic acid dissolved in 10 ml. of pyridine is added to 100 mg of 5% palladium on barium sulfate, and the resulting mixture is hydrogenated at room temperature and pressure. Forty-four milliliters of hydrogen is absorbed in 90 minutes, then the reaction stops completely. After filtering off the catalyst, the solvent is evaporated. The remaining oil is dissolved in ether-hexane 1:1 and washed with 1N HCl, aqueous saturated sodium bicarbonate and finally water. After drying (MgSO4), the solvent is evaporated and 392 mg. of methyl cis-jasmonate is obtained. Yield 98%. Spectral properties are in agreement with the above structure and published spectral data. The product shows one spot on thin layer chromatography. Methyl cis-jasmonate was also characterized as its semicarbazone, m.p. 118°-119° C (Lit. 115°-117° C).
Reaction SMILES: [C:1]([NH:18][C@H:19]([C:23]([OH:25])=[O:24])[CH2:20][CH2:21][CH3:22])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].S(Cl)(Cl)=O.[CH3:30]O>C(OC(=O)C)C>[NH:18]([C:1]([O:3][CH2:4][CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]2[C:17]1=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:2])[C@H:19]([C:23]([O:25][CH3:30])=[O:24])[CH2:20][CH2:21][CH3:22]
Reactant: CO
Reactant: CCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: CCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC

Procedure:
To a chilled solution of the commercially available Fmoc-norvaline (25 g, 73.75 mmol) in anhydrous methanol (469 ml) was added thionyl chloride (53.76 ml, 737.5 mmol) over one hour. TLC in ethylacetate taken an hour later confirmed the completion of the reaction (Rf=0.85). The reaction mixture was concentrated and the remaining residue was dissolved in ethylacetate. The organic layer was washed with several 200 ml portions of saturated sodium bicarbonate followed by brine. The organic layer was dried, filtered and concentrated to afford Fmoc-norVal-OMe) as a white solid (26.03 g) in quantitative yield. NMR δ ppm (CD3OD): 7.7 (m, 2H), 7.6 (m, 2H), 7.4 (m, 2H), 7.3 (m, 2H), 4.3 (m, 2H), 4.1 (m, 2H), 3.7 (s, 3H), 1.7 (m, 1H), 1.6 (m, 1H), 1.4 (m, 2H), 0.95 (t, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2].[Br:30][C:31]1[CH:32]=[C:33]([CH:39]=[C:40]([OH:42])[CH:41]=1)[C:34]([N:36]([CH3:38])[CH3:37])=[O:35].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CC(C)=O.O.Cl>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:42][C:40]2[CH:39]=[C:33]([C:34](=[O:35])[N:36]([CH3:38])[CH3:37])[CH:32]=[C:31]([Br:30])[CH:41]=2)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Reactant: CN(C)C(=O)c1cc(O)cc(Br)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(C(=O)N(C)C)c2)c1CCC(=O)OCC
Temperature: 70 °C
Yield: 79.2 %

Procedure:
To a solution of 4-[3-(6-bromo-hexyl)-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (3.48 g, 7.4 mmol), 3-bromo-5-hydroxy-N,N-dimethyl-benzamide (1.5 g, 6.17 mmol) in N,N-dimethylformamide (30 mL) and acetone (60 mL) was added potassium carbonate (8.51 g, 61.7 mmol). The resulting suspension was heated to 70° C. for 24 h. Then the reaction mixture was cooled to room temperature and diluted with water and 10% aq. HCl. The organic compound was extracted into ethyl acetate and the combined organic extracts were washed with water and brine solution. The organic extracts were dried over anhydrous sodium sulfate and removal of the solvent under reduced pressure gave the crude product which was purified on ISCO™ column (120 g) using 50% ethyl acetate in hexanes as eluting solvent to give the title compound (3.1 g, 80%) as colorless oil.
Reaction SMILES: N1C=CC=CC=1.Cl.[CH3:8][NH:9][O:10][CH3:11].[CH3:12][C:13]1[C:17]([C:18](Cl)=[O:19])=[C:16]([CH3:21])[O:15][N:14]=1>ClCCl.C([O-])(O)=O.[Na+].C1(C)C=CC=CC=1>[CH3:11][O:10][N:9]([CH3:8])[C:18]([C:17]1[C:13]([CH3:12])=[N:14][O:15][C:16]=1[CH3:21])=[O:19]
Reactant: CNOC
Reactant: Cc1noc(C)c1C(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CON(C)C(=O)c1c(C)noc1C
Temperature: 25 °C
Yield: 98.9 %

Procedure:
659 μl (8.15 mmol) of pyridine are added to a suspension of 343.07 mg (3.45 mmol) of N,O-dimethylhydroxylamine hydrochloride in 10 mL of dichloromethane. The mixture is stirred at room temperature until fully dissolved. A solution of 526.32 mg (3.13 mmol) of 3,5-dimethylisoxazole-4-carbonyl chloride in 5 mL of dichloromethane is then added. After stirring for 1 hour at room temperature, the reaction mixture is taken up in saturated aqueous NaHCO3 solution and stirred for a few minutes, and the phases are separated by settling. The organic phase is dried over magnesium sulfate and evaporated to dryness. The residue obtained is taken up in toluene and evaporated, the operation being repeated a second time. 570 mg of N-methoxy-N-methyl-3,5-dimethylisoxazole-4-carboxamide are then obtained, corresponding to the following characteristics:
Reaction SMILES: Br[C:2]1[C:7]2[CH2:8][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][CH2:11][O:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.CC(C)([O-])C.[Na+].O1CCOCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.O>[N:20]1([C:2]2[C:7]3[CH2:8][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][CH2:11][O:12][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1CCOc2cccc(Br)c2C1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOc2cccc(N3CCOCC3)c2C1
Yield: 78.5 %

Procedure:
A solution of tert-butyl 6-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (150 mg, 0.457 mmol), morpholine (0.120 ml, 1.37 mmol), X-phos (13.0 mg, 0.0274 mmol), tris(dibenzylideneacetone)dipalladium(0) (82.4 mg, 0.00900 mmol), sodium tert-butoxide (65.8 mg, 0.684 mmol) and dioxane (3 ml) was stirred under an argon atmosphere for 2 hr at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (120 mg, 78.4%) as an oil.
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3](Cl)=[O:4].[NH:10]1[CH2:16][CH2:15][CH2:14][C@H:11]1[CH2:12][OH:13].C([O-])(=O)C.[Na+]>CC(C)=O.O>[Br:1][CH:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([N:10]1[CH2:16][CH2:15][CH2:14][C@H:11]1[CH2:12][OH:13])=[O:4]
Reactant: CC(C)CC(Br)C(=O)Cl
Reactant: OC[C@@H]1CCCN1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)CC(Br)C(=O)N1CCC[C@H]1CO
Reaction time: 2 h

Procedure:
A solution of (±)-2-bromo-4-methyl-pentanoyl chloride, 21 g (0.099 mol), in 25 ml of acetone is added dropwise with stirring to a solution of 10 g (0.099 mol) of L-prolinol and 16.2 g (0.197 mol) of sodium acetate in a mixture of 150 ml of acetone and 75 ml of water at 0°-5° C. The mixture is stirred and allowed to reach room temperature over two hours, the solvent is evaporated in vacuo and the residue is suspended in 300 ml of chloroform and washed with water, 2×300 ml. The chloroform layer is separated, dried over sodium sulfate, evaporated in vacuo, and the residue is purified by chromatography using silica gel and eluting with dichloromethane-methanol (95:5) to give (2S)-1-(2-bromo-4-methyl-1-oxopentyl)2-pyrrolidinemethanol (2 position on side chain is R,S mixture), 21 g; mp 79°-82°; [α]D25 -54.0° (c 0.6, methanol).
Reaction SMILES: [C:1]1([NH:7][C:8]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([N+:19]([O-])=O)=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[Cl-].[NH4+]>C(O)C.[Fe]>[C:1]1([NH:7][C:8]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([NH2:19])=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Nc1ccccc1)n1ccc2cc([N+](=O)[O-])ccc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc2c(ccn2C(=O)Nc2ccccc2)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 22 %

Procedure:
5-Nitroindole-1-carboxylic acid phenylamide (3.53 g, 12.3 mmol) was dissolved in ethanol (250 ml); water (50 ml), electrolytic iron powder (2.75 g, 49.2 mmol), ammonium chloride (5.26 g, 98.4 mmol) were added thereto; and the reaction mixture was heated and stirred at 80° C. for 2 hours. After cooling to room temperature, the reaction mixture was filtered off; insoluble portions were washed with ethyl acetate; and the filtrate was concentrated under reduced pressure. The residue was partitioned between water and a solvent mixture of ethyl acetate and tetrahydrofuran; and the organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was solidified by diethyl ether; the crystals were suspended in diethyl ether, filtered off, washed with diethyl ether, and dried to yield the title compound as pale red powder (681 mg, 2.71 mmol, 22.0%). The mother liquor was concentrated under reduced pressure, which was then treated by the similar methods to yield the title compound (590 mg, 2.35 mmol, 19.1%) as pale red powder (secondary crystals).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(N(CC)CC)C.O1CCCC1.[C:21](Cl)(=[O:25])[CH:22]([CH3:24])[CH3:23]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CC(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.6 %

Procedure:
In a 500 mL three-neck flask were put 16 g (90 mmol) of 4-bromoaniline, 11 g (108 mmol) of triethylamine, and 250 mL of tetrahydrofuran (THF), and the mixed solution was stirred. To this mixed solution, a mixed solution of 9.6 g (90 mmol) of isobutyryl chloride and 50 mL of THF was added dropwise under cooling with ice, and the mixture was stirred at room temperature for 12 hours. After the stirring, this mixture was dissolved in chloroform, and washed with water and a saturated aqueous solution of sodium hydrogen carbonate. After the washing, anhydrous magnesium sulfate was added to the organic layer for drying. The resulting mixture was subjected to gravity filtration, and the filtrate was concentrated to give a solid. This solid was washed with hexane to give 18 g of a white solid of N-(4-bromophenyl)isobutyramide in a yield of 82%. The reaction scheme of Step 1 is shown in (b-1) below.