Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[CH:19][CH:18]=[C:17]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>C1COCC1.CCO.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[CH:19][CH:18]=[C:17]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[N:16]=2)=[CH:11][CH:10]=1
Reactant: COc1ccc(-c2ccc(-c3ccc(F)cc3)nc2-c2ccc(OCc3ccccc3)cc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(-c3ccc(F)cc3)nc2-c2ccc(O)cc2)cc1
Reaction time: 4 h
Yield: 89.1 %

Procedure:
The 2-(4-benzyloxyphenyl)-3-(4-methoxyphenyl)-6-(4-fluorophenyl)pyridine (1.2 g, 2.6 mmol) was dissolved in 50 mL of THF/ EtOH (1:1), 5% Pd/ C (0.3 g, 0.14 mmol Pd) added, and the reaction mixture hydrogenated at 40 psi for 4 h at rt. The reaction mixture was filtered and concentrated to give 0.86 g (90% yield) of white foam: mp 143°-145° C.; 1H NMR (CDCl3) d 3.83 (s, 3H, OCH3), 4.78 (s, 1H, ArOH), 6.72-6.75 (d, 2H, J=8 Hz, ArH), 6.84-6.87 (d, 2H, J=8 Hz, ArH), 7.14-7.27 (m, 4H, ArH), 7.37-7.40 (d, 2H, J=8 Hz, ArH), 7.69-7.73 (m, 2H, ArH), 8.10-8.15 (m, 2H, ArH); MS(FD) 371(M+). Anal. Calcd for C24H18 NO2F: C, 77.61; H, 4.89; N, 3.77. Found: C, 77.88; H, 5.12; N, 3.51.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][N:4]=1.S(=O)(=O)(O)O.[N+:18]([O-])([OH:20])=[O:19]>O>[CH3:1][NH:2][C:3]1[C:8]([N+:18]([O-:20])=[O:19])=[CH:7][C:6]([C:9]([F:12])([F:10])[F:11])=[CH:5][N:4]=1
Reactant: O=[N+]([O-])O
Reactant: CNc1ccc(C(F)(F)F)cn1
Agent: O=S(=O)(O)O
Solvent: O
Product: CNc1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 86.6 %

Procedure:
To a mixture of N-methyl-(5-trifluoromethyl-pyridin-2-yl)-amine (17.3 g) and sulfuric acid (100 ml), nitric acid (12.3 g) was added drop-wise, and stirred with heating at 80° C. for 2 hours. The mixture was cooled to room temperature, and then the reaction mixture was poured into water. The precipitate was collected by filtration, washed with water, and dried under reduced pressure to give 18.8 g of N-methyl-(3-nitro-5-trifluoromethyl-pyridin-2-yl)-amine.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20]([O:22][C:23](=[O:54])[CH2:24][C:25]1([CH2:28][CH2:29][CH:30](/[CH:45]=[CH:46]/[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[OH:53])[CH2:31][C:32]2[CH:44]=[CH:43][C:35]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[CH:34][CH:33]=2)[CH2:27][CH2:26]1)[CH3:21]>C(#N)C>[CH2:20]([O:22][C:23](=[O:54])[CH2:24][C:25]1([CH2:28][CH2:29][CH:30](/[CH:45]=[CH:46]/[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[O:53][CH2:8][C:7]2[CH:10]=[CH:11][C:4]([O:3][C:2]([F:13])([F:12])[F:1])=[CH:5][CH:6]=2)[CH2:31][C:32]2[CH:33]=[CH:34][C:35]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[CH:43][CH:44]=2)[CH2:26][CH2:27]1)[CH3:21]
Reactant: CCOC(=O)CC1(CCC(/C=C/c2ccccc2O)Cc2ccc(C(=O)OC(C)(C)C)cc2)CC1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CC1(CCC(/C=C/c2ccccc2OCc2ccc(OC(F)(F)F)cc2)Cc2ccc(C(=O)OC(C)(C)C)cc2)CC1

Procedure:
118 mg (0.46 mmol) of 4-trifluoromethoxybenzyl bromide and 98 mg (0.71 mmol) of anhydrous potassium carbonate are added to a solution of 170 mg (0.36 mmol) of tert-butyl 4-[(3E)-2-{2-[1-(2-ethoxy-2-oxoethyl)cyclopropyl]ethyl}-4-(2-hydroxyphenyl)but-3-en-1-yl]benzoate in 3 ml of dry acetonitrile, and the mixture is heated under reflux for 12 hours. The mixture is then concentrated to dryness. The residue is taken up in ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate. The organic phase is concentrated. The crude product obtained is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 5:1). This gives 155 mg (67% of theory) of a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[NH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>ClCCl>[Cl:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Clc1c[nH]c2ccncc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)n1cc(Cl)c2cnccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 128.9 %

Procedure:
To a stirred solution of 3-chloro-1H-pyrrolo[3,2-c]pyridine (1 g, 6.55 mmol) in dichloromethane (10 mL), triethylamine (2.3 ml, 16.38 mmol) was added. The mixture was cooled to 0° C. and benzyl chloroformate (2.3 mL, 50% solution in dichloromethane, 9.83 mmol) was added drop wise. After complete addition, the reaction mixture was stirred at room temperature for about 1 hour. On completion, the reaction was quenched by addition of saturated aq. sodium bicarbonate solution and the organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to afford benzyl 3-chloro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (2.42 g, 100%) as viscous liquid.
Reaction SMILES: C([O:14][C:15]([C:17]1([O:20]/[N:21]=[C:22](/[C:62]2[N:63]=[C:64]([NH:67]C(OC(C)(C)C)=O)[S:65][CH:66]=2)\[C:23]([NH:25][C@@H:26]2[C:29](=[O:30])[N:28]([S:31]([OH:34])(=[O:33])=[O:32])[C@@H:27]2[CH2:35][N:36]2[N:40]=[C:39]([CH2:41][N:42](C(OC(C)(C)C)=O)[CH2:43][CH:44]3[CH2:47][N:46](C(OC(C)(C)C)=O)[CH2:45]3)[CH:38]=[N:37]2)=[O:24])[CH2:19][CH2:18]1)=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:67][C:64]1[S:65][CH:66]=[C:62](/[C:22](=[N:21]/[O:20][C:17]2([C:15]([OH:16])=[O:14])[CH2:18][CH2:19]2)/[C:23]([NH:25][C@@H:26]2[C:29](=[O:30])[N:28]([S:31]([OH:34])(=[O:32])=[O:33])[C@@H:27]2[CH2:35][N:36]2[N:40]=[C:39]([CH2:41][NH:42][CH2:43][CH:44]3[CH2:47][NH:46][CH2:45]3)[CH:38]=[N:37]2)=[O:24])[N:63]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2Cn2ncc(CN(CC3CN(C(=O)OC(C)(C)C)C3)C(=O)OC(C)(C)C)n2)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(/C(=N/OC2(C(=O)O)CC2)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2Cn2ncc(CNCC3CNC3)n2)cs1

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((4-(((tert-butoxycarbonyl)((1-(tert-butoxycarbonyl)azetidin-3-yl)methyl)amino)methyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidine-1-sulfonic acid (130 mg, 0.122 mmol), TFA (0.56 mL, 7.32 mmol), and DCM (1.5 mL). 6.3 mg. LCMS: Rt=0.47 min, m/z=599.3 (M+1). Method 2m_acidic_polar. 1H NMR (400 MHz, D2O) δ 7.82 (s, 1H), 7.10 (s, 1H), 5.61 (d, J=5.9 Hz, 1H), 5.01 (q, J=5.6 Hz, 1H), 4.95-4.85 (m, 2H), 4.36 (s, 2H), 4.26-4.15 (m, 2H) 4.11-3.97 (m, 2H), 3.46-3.30 (m, 3H), 1.26 (s, 2H), 1.20-1.05 (m, 2H).
Reaction SMILES: O1CCOCC1.Br[C:8]1[CH:9]=[C:10]([CH3:15])[C:11]([NH2:14])=[N:12][CH:13]=1.[I-:16].[Na+].CC(C)(N)C(C)(C)N>[Cu](I)I.O>[I:16][C:8]1[CH:9]=[C:10]([CH3:15])[C:11]([NH2:14])=[N:12][CH:13]=1
Reactant: [I-]
Reactant: Cc1cc(Br)cnc1N
Agent: I[Cu]I
Agent: CC(C)(N)C(C)(C)N
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(I)cnc1N
Temperature: 110 °C
Yield: 92.7 %

Procedure:
To dioxane (10 mL) was added 5-bromo-3-methylpyridin-2-amine (2 g, 10.6 mmol), sodium iodide (3.2 g, 21.4 mmoL), copper iodide (0.190 g, 1.06 mmol) and the solution degassed followed by addition of tetramethylethane-1,2-diamine (0.803 mL, 1.06 mmol) this mixture heated at 110° C. overnight. After cooling water was added and extracted the crude product with ethyl acetate. The residue was purified by column chromatography to give 5-iodo-3-methylpyridin-2-amine as a beige solid (2.3 g, 93%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4](/[N:12]=[C:13]2\C(Cl)=NSS\2)[CH:3]=1.[CH2:19]([NH2:24])[CH2:20][CH2:21][CH2:22][NH2:23].N#N>C1COCC1.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([C:6](=[O:8])[N:23]3[CH2:22][CH2:21][CH2:20][CH2:19][NH:24][C:13]3=[N:12]2)=[CH:10][CH:11]=1
Reactant: NCCCCN
Reactant: COC(=O)c1ccc(Br)cc1/N=c1/ssnc1Cl
Agent: N#N
Solvent: O
Solvent: C1CCOC1
Product: O=c1c2ccc(Br)cc2nc2n1CCCCN2
Temperature: 25 °C

Procedure:
To a stirred solution of (E)-methyl 4-bromo-2-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)benzoate (100 mg, 0.27 mmol, 1 eq) in THF was added butane-1,4-diamine (0.027 mL, 0.27 mmol, 1 eq) dropwise under N2 and the reaction was heated at reflux for 3 hours. After it was cooled to rt, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the desired product, which was purified by silica gel chromatography. MS (ESI): 294, 296 (MH+).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH:16][CH3:17])[C:5]2[N:6]([CH:8]=[C:9]([C:11](OCC)=[O:12])[N:10]=2)[CH:7]=1.[NH3:18]>>[Br:1][C:2]1[N:3]=[C:4]([NH:16][CH3:17])[C:5]2[N:6]([CH:8]=[C:9]([C:11]([NH2:18])=[O:12])[N:10]=2)[CH:7]=1
Reactant: N
Reactant: CCOC(=O)c1cn2cc(Br)nc(NC)c2n1
Product: CNc1nc(Br)cn2cc(C(N)=O)nc12
Yield: 40 %

Procedure:
A suspension of 0.470 g (1.57 mmol) of ethyl 6-bromo-8-methylaminoimidazo[1,2-a]pyrazine-2-carboxylate, obtained according to the process described in Example 3, in 50 ml of concentrated aqueous ammonia solution, is brought to reflux for 4 hours. After the mixture is cooled, the precipitate is drained, washed and dried. 0.160 g (Yld=40%) of 6-bromo-8-methylaminoimidazo[1,2-a]pyrazine-2-carboxamide (m.p. 312° C.) is obtained.
Reaction SMILES: [C:1]([CH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[F:16])[N:8]=1)#[N:2].[C:17](=O)([O:20]C)[O:18][CH3:19].C[O-].[Na+].Cl>C1(C)C=CC=CC=1>[C:1]([CH:3]([C:4]1[S:5][CH:6]=[C:7]([C:9]2[C:10]([F:16])=[CH:11][CH:12]=[CH:13][C:14]=2[F:15])[N:8]=1)[C:17]([O:18][CH3:19])=[O:20])#[N:2]
Reactant: COC(=O)OC
Reactant: N#CCc1nc(-c2c(F)cccc2F)cs1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)C(C#N)c1nc(-c2c(F)cccc2F)cs1
Temperature: 0 °C
Yield: 67 %

Procedure:
To 2 g of 2-cyanomethyl-4-(2,6-difluorophenyl)thiazole and 4.8 g of dimethyl carbonate was added 30 ml of toluene, 0.6 g of sodium methoxide was added, and the resulting mixture was stirred and heated to the reflux temperature for 4 hours. After cooling, the reaction mixture was poured into 100 ml of ice-cold water, 1N-HCl was added to acidify the aqueous layer, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure, and the residue obtained was purified by column chromatography (ethyl acetate/n-hexane=2/1) to give 1.67 g of methyl 2-cyano-2-{4-(2,6-difluorophenyl)thiazol-2-yl}acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:13](=[CH:14][N:15]([CH3:18])[N:16]=3)[CH:12]=[CH:11][CH:10]=2)=[C:5]([CH3:19])[CH:4]=1.[Li]CCCC.[CH3:25][O:26][CH2:27][C:28](=[O:33])[CH2:29][CH2:30][O:31][CH3:32]>C1COCC1.CCOC(C)=O>[CH3:25][O:26][CH2:27][C:28]([C:14]1[N:15]([CH3:18])[N:16]=[C:17]2[C:13]=1[CH:12]=[CH:11][CH:10]=[C:9]2[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH3:19])([OH:33])[CH2:29][CH2:30][O:31][CH3:32]
Reactant: COc1ccc(-c2cccc3cn(C)nc23)c(C)c1
Reactant: COCCC(=O)COC
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCC(O)(COC)c1c2cccc(-c3ccc(OC)cc3C)c2nn1C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 64.5 %

Procedure:
Indazole 4c (0.29 g, 0.79 mMol) was dissolved in 5 mL dry THF under a nitrogen atmosphere and cooled to −78° C. n-BuLi (0.4 mL of 2.5 M hexane solution, 1 mMol) was added dropwise via syringe, and stirred at −78° C. for 10 minutes. 1,4-dimethoxy-2-butanone (0.16 g, 1.18 mMol) was added dropwise at −78° C. and then the reaction mixture was allowed to warm to rt. The reaction mixture was diluted with EtOAc (50 mL) and washed successively with saturated ammonium chloride solution, brine and dried over magnesium sulfate. Evaporation of the solvent afforded crude material which was flash chromatographed on silica and eluted with hexane:EtOAc (3:1) which afforded 27c as an oil (0.196 g; 65%).
Reaction SMILES: [OH:1][C:2]1([CH2:9][N:10]2[CH2:15][CH2:14][C:13]3[NH:16][C:17]([CH:20]=O)=[C:18]([CH3:19])[C:12]=3[C:11]2=[O:22])[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[CH2:27]2>>[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[C:27]2=[CH:20][C:17]1[NH:16][C:13]2[CH2:14][CH2:15][N:10]([CH2:9][C:2]3([OH:1])[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]3)[C:11](=[O:22])[C:12]=2[C:18]=1[CH3:19]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CC1(O)CCN(C)CC1)CC2
Reactant: O=C1Cc2cc(F)ccc2N1
Product: Cc1c(C=C2C(=O)Nc3ccc(F)cc32)[nH]c2c1C(=O)N(CC1(O)CCN(C)CC1)CC2
Yield: 37.98 %

Procedure:
The title compound was prepared under the same conditions as described in Example 1 with 5-(4-hydroxy-1-methyl-piperidin-4-ylmethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-fluoro-1,3-dihydro-indol-2-one as starting materials to give 2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(4-hydroxy-1-methyl-piperidin-4-ylmethyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (16 mg, 37.98%) as an orange solid.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:17]3=[C:18]([CH3:22])[C:19]([OH:21])=[CH:20][N:16]3[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:23])[NH:6]2.[CH2:24]([CH:26]1[O:28][CH2:27]1)Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[C:10]([O:11][C:12]2[C:17]3=[C:18]([CH3:22])[C:19]([O:21][CH2:24][CH:26]4[CH2:27][O:28]4)=[CH:20][N:16]3[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:23])[NH:6]2
Reactant: Cc1cc2c(F)c(Oc3ncnn4cc(O)c(C)c34)ccc2[nH]1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc2c(F)c(Oc3ncnn4cc(OCC5CO5)c(C)c34)ccc2[nH]1
Temperature: 50 °C
Reaction time: 6 h
Yield: 80.6 %

Procedure:
A mixture of 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-ol (Example 1), (200 mg, 0.64 mmol), epichlorohydrin (297 mg, 3.21 mmol) and potassium carbonate (445 mg, 3.21 mmol) in DMF (1 ml) was stirred at 50° C. for 6 h. After cooling to RT and concentration in vacuo the crude material was purified by chromatography on silica gel eluting with 50% ethyl acetate in hexanes to afford the title compound (190 mg, 81%) as a yellowish solid. MS: (M+H)+=369.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([O:17][C:18]([NH:20][CH:21]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH2:35][CH3:36])[CH:27]=1)[CH2:22][C:23]([OH:25])=O)=[O:19])([CH3:16])([CH3:15])[CH3:14].Cl.[CH3:38][NH:39][O:40][CH3:41].CN1CCCCC1>C(Cl)Cl>[C:13]([O:17][C:18]([NH:20][CH:21]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH2:35][CH3:36])[CH:27]=1)[CH2:22][C:23]([N:39]([O:40][CH3:41])[CH3:38])=[O:25])=[O:19])([CH3:14])([CH3:15])[CH3:16]
Reactant: CCOc1cc(C(CC(=O)O)NC(=O)OC(C)(C)C)ccc1OC
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN1CCCCC1
Solvent: ClCCl
Product: CCOc1cc(C(CC(=O)N(C)OC)NC(=O)OC(C)(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
A mixture of carbonyldiimidazole (0.96 g, 5.9 mmol), 3-(tert-butoxycarbonylamino)-3-(3-ethoxy-4-methoxyphenyl)propionic acid (2.0 g, 5.9 mmol) and methylene chloride (25 mL) was stirred at room temperature for 1 hr and then cooled to 5° C. A solution of N,O-dimethylhydroxyamine hydrochloride (0.86 g, 8.85 mmol) and 1-methylpiperidine (0.87 g, 8.85 mmol) in methylene chloride (10 mL) was added slowly. The mixture was stirred at room temperature for 1 hr and then quenched with water (20 mL). The organic layer was separated and then was washed with 1N citric acid, water, and brine. The organic layer was dried and concentrated in vacuo to give an oil. This oil was purified by chromatography (silica gel, methylene chloride:ethyl acetate 8:2) to afford 3-(tert-butyloxycarbonylamino)-3-(3-ethoxy-4-methoxyphenyl)-N-methoxy-N-methylpropanamide as a white solid (1.76 g, 78%); 1H NMR (CDCl3) δ 6.86-6.78 (m, 3H), 6.07 (b, 1H), 5.01 (m, 1H), 4.10 (q, J=6.9 Hz, 2H), 3.84 (s, 3H), 3.50 (s, 3H), 3.10 (s, 3H), 3.02 (m, 2H), 2.84-2.75 (dd, J=5.3 and 15.2 Hz, 1H), 1.45 (t, J=7.1 Hz, 3H), 1.41 (s, 9H); 13C NMR (CDCl3) δ 171.81, 155.18, 148.39, 148.19, 134.82, 118.12, 111.41, 111.18, 79.27, 64.26, 61.19, 55.90, 51.25, 37.80, 31.87, 28.33, 14.73.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@@H:13]([CH2:24][C:25]([OH:27])=[O:26])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:12][C@@H:13]1[CH2:24][C:25]([O:27][CH3:28])=[O:26])=[O:18])([CH3:22])([CH3:23])[CH3:21]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C[C@@H]1CC(=O)O
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)C[C@H]1CN(C(=O)OCc2ccccc2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
To a solution of the compound of step 1 (2.52 g, 6.66 mmol) in 45 ml of acetone were added potassium carbonate (5.522 g, 39.96 mmol) and iodomethane (1.24 ml, 19.98 mmol) and the solution was stirred at room temperature overnight. The mixture was filtered and the filtrate was concentrated to dryness. The residue was dissolved in EA, washed twice with brine, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by chromatography on silica gel (cyclohexane/EA, 100:0, then 85:15) to give 2.334 g of the title compound as a colorless oil.
Reaction SMILES: [OH-].[K+].[OH:3][CH2:4][CH2:5][CH:6]([CH3:15])[CH2:7][CH2:8][CH2:9][C:10]([O:13][OH:14])([CH3:12])[CH3:11].[C:16](Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>O.CCCCC>[C:16]([O:14][O:13][C:10]([CH3:12])([CH3:11])[CH2:9][CH2:8][CH2:7][CH:6]([CH3:15])[CH2:5][CH2:4][OH:3])(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(CCO)CCCC(C)(C)OO
Reactant: CC(C)(C)C(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCCCC
Product: CC(CCO)CCCC(C)(C)OOC(=O)C(C)(C)C
Temperature: 30 °C
Reaction time: 1 h
Yield: 59.8 %

Procedure:
A jacketed reactor equipped with a mechanical stirrer, a thermometer and a dropping funnel was charged with 9.3 g (0.075 mole) of 45% KOH, 4.7 g of water and 11.3 g (0.058 mole) of 97.3% 7-hydroxy-1,1,5-trimethylheptyl hydroperoxide. To this vigorously stirred solution at 30° C. was slowly added 6.4 g (0.050 mole) of 94.3% pivaloyl chloride over a period of 20 minutes. The resulting mixture was then vigorously stirred for one hour at 30° C. after which it was cooled to 15° C. and 100 ml of pentane and 25 ml of water were added. After separating and discarding the aqueous phase the product solution was washed at 10° to 15° C. with 20 g of buffered sodium sulfite solution (consisting of 0.8 g of acetic acid, 1.2 g of sodium acetate, 2.0 g of sodium sulfite and 16 g of water), with 15 ml of water and then with 20 g of 7.7% sodium hydrogen carbonate solution. The resulting pentane solution was then dried over anhydrous MgSO4 and after separation of the spent desiccant by filtration the pentane was removed in vacuo at 0° to 10° C. leaving 8.2 g of liquid product. The assay of the product according to peroxyester active oxygen was 69.6% and the corrected yield was 41.7%. An infrared spectrum of the product showed a strong, broad OH band centered at 3400 to 3500 cm-1.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1.[Cl:17][C:18]1[CH:19]=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][C:23]=1Cl>CS(C)=O>[Cl:17][C:18]1[CH:19]=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][C:23]=1[O:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:15][CH:16]=1
Reactant: COC(=O)C(C)Oc1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COC(=O)C(C)Oc1ccc(Oc2ccc([N+](=O)[O-])cc2Cl)cc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
6.5 g of pulverised potassium hydroxide and 20 g of methyl 4-hydroxy-α-phenoxypropionate in 250 ml of dry dimethyl sulphoxide are charged at 0° C into a three-necked flask. With stirring, and at a temperature between 0° and 5° C, 19.5 g of 3,4-dichloro-nitrobenzene are added by small amounts and stirring is continued for 12 hours at room temperature. Thereafter the reaction mixture is poured into ice-water and extracted with ethyl acetate. The extract is dried over sodium sulphate and the solvent distilled off to yield an oily product which is then subjected to high vacuum distillation. The resultant substance, viz. methyl 4-(2'-chloro-4'-nitrophenoxy)-α-phenoxypropionate (yield 27 g), boils at 194° C/0.01 Torr (compound 1).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[O:15][CH2:16][CH2:17][CH3:18].[Li][CH2:20]CCC.CI>C1COCC1>[CH3:14][O:13][CH2:12][O:11][C:9]1[CH:8]=[CH:7][C:6]([O:15][CH2:16][CH2:17][CH3:18])=[C:5]([O:4][CH2:3][O:2][CH3:1])[C:10]=1[CH3:20]
Reactant: CCCOc1ccc(OCOC)cc1OCOC
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CCCOc1ccc(OCOC)c(C)c1OCOC
Temperature: -78 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A solution of 4b (165 mg, 0.64 mmol) in anhydrous THF (520 μL) was added dropwise to a solution of nBuLi (2.5 M in hexanes, 390 mL, 0.97 mmol) in anhydrous THF (420 μL) at room temperature. After 1 hour, the solution was cooled to −78° C. and methyl iodide (160 μL, 2.58 mmol) was added. The resulting solution was warmed to room temperature over 12 hours, and the reaction was quenched by the addition of saturated aqueous NH4Cl. Water (5 mL) was added and the solution was extracted with CH2Cl2 (3×10 mL). Combined organic fractions were dried (Na2SO4), filtered, and concentrated. The residue was purified via column chromatography (SiO2, 6:1 Hexane:EtOAc) to afford 5b as a yellow oil (166 mg, 95%): 1H NMR (CDCl3, 500 MHz) 6.66 (d, J=9.0 Hz, 1H), 6.60 (d, J=9.0 Hz, 1H), 5.02 (s, 2H), 5.00 (s, 2H), 3.80-3.77 (m, 2H), 3.49 (s, 3H), 3.47 (s, 3H), 2.14 (d, J=7.1 Hz, 3H), 1.73-1.69 (m, 2H), 0.94 (t, J=7.5 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 148.5, 148.5, 147.3, 145.6, 126.7, 123.0, 112.8, 110.8, 110.4, 99.2, 57.7, 57.6, 21.2, 10.9, 10.0; IR (film) νmax 2957, 2924, 2853, 1738, 1597, 1487, 1468, 1391, 1335, 1231, 1157, 974, 798 cm−1; HRMS (ESI+) m/z: [M+H]+ calcd for C14H22O5, 271.1545; found, 271.1558.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[CH3:23])[C:5](O)=[O:6].CN(C)C=O.C(Cl)(=O)C([Cl:32])=O>C1(C)C=CC=CC=1>[CH3:1][O:2][N:3]=[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[CH3:23])[C:5]([Cl:32])=[O:6]
Reactant: CON=C(C(=O)O)c1ccccc1COc1ccc(Cl)cc1C
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CON=C(C(=O)Cl)c1ccccc1COc1ccc(Cl)cc1C
Reaction time: 1 h

Procedure:
To a mixture of 52.24 g (0.150 mol, E/Z=3.5/96.5) of α-methoxyimino-2-(4-chloro-2-methylphenoxymethyl)phenylacetic acid produced in accordance with Example 5-(2), 0.57 g (0.0078 mol) of dimethylformamide and 203 g of toluene was added dropwise 25.9 g (0.204 mol) of oxalyl chloride over 3 hours while keeping at 60°-65° C., and the reaction was subsequently allowed to proceed at the same temperature for 1 hours and then 80° C. for 2 hours, which afforded 265 g of a toluene solution of α-methoxyimino-2-(4-chloro-2-methylphenoxymethyl)phenylacetyl chloride.