Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][NH:17][CH2:18][CH2:19][C:20](=[O:41])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[F:38])=[O:30])=[C:24]([O:39][CH3:40])[CH:23]=1)[C:6]([O:8]CC)=[O:7].[OH-].[Na+].Cl>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][NH:17][CH2:18][CH2:19][C:20](=[O:41])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[F:38])=[O:30])=[C:24]([O:39][CH3:40])[CH:23]=1)[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)c1ccc(OCCNCCC(=O)Cc2ccc(NC(=O)Nc3ccccc3F)c(OC)c2)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(CC(=O)CCNCCOc2ccc(C(=O)O)cc2OC)ccc1NC(=O)Nc1ccccc1F
Yield: 46.3 %

Procedure:
To a stirred solution of ethyl 3-methoxy-4-[2-[3-methoxy-4-[N′-(2-fluorophenyl)ureido]phenylacetyl]ethylaminoethoxy]benzoate (160 mg, 0.28 mmol) in THF (5 mL) was added 0.25 N NaOH (5 mL) and the resulting mixture was the heated under reflux overnight. The mixture was poured into 1 N HCl and the solid was collected. The crude solid was recrystallized from EtOH—CHCl3-n-hexane to give 70 mg (46%) 3-methoxy-4-[2-[3-methoxy-4-[N′-(2-fluorophenyl)ureido]phenylacetyl]ethylaminoethoxy]benzoic acid 258 as a yellow crystalline powder. mp 105-110° C.; IR (KBr) 1687 cm−1; 1H-NMR (DMSO-d6) d 1.00-1.10 (m, 3 H), 2.48 (s, 2H), 3.35-381 (m, 10 H), 4.13-4.14 (m, 2 H), 6.70-9.15 (series of m, 12 H); MS (FAB) m/z 540 (M++1); Anal. Calcd. for C28H30FN3O7.1/2H2O: C, 61.31; H, 5.82; N, 7.47. Found: C, 61.05; H, 5.82; N, 7.47.
Reaction SMILES: [C:1]1([C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:8]2[CH:12]=[C:11]([CH:13]3[CH:15]([C:16](O)=[O:17])[CH2:14]3)[N:10]=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC(OCC)=O.C([N:39](CC)CC)C>>[C:19]1([C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[CH:12]=[C:11]([CH:13]3[CH:15]([C:16]([NH2:39])=[O:17])[CH2:14]3)[N:10]=[CH:9]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)C1CC1c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CCOC(=O)Cl
Product: NC(=O)C1CC1c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1

Procedure:
According to the foregoing reaction scheme I 3-[1-(triphenylmethyl)-1H-imidazol4-yl]-cyclopropanecarboxylic acid (1), prepared as a racemic mixture of trans cyclopropanes using the method of Burger, et al., J. Med. Chem., (1970), 13: 33-35, is converted to an activated ester through the action of ethyl chloroformate and triethylamine. The activated ester is reacted in situ with amine (2) to provide the 3-[1-(triphenylmethyl)-1H-imidazol-4-yl]-cyclopropanecarboxamide (3). The trityl group can be removed with acid, preferably aqueous 2N HCl, to give 3-[1H-imidazol-4-yl]-cyclopropanecarboxamide (4).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[CH:5][C:4]=1[CH3:11])=[O:2].[CH2:12]([O:14][C:15](=[O:31])[CH2:16][CH2:17][C:18]1[C:23]([CH3:24])=[CH:22][C:21]([C:25](=[NH:28])[NH:26]O)=[CH:20][C:19]=1[CH2:29][CH3:30])[CH3:13]>>[CH2:12]([O:14][C:15](=[O:31])[CH2:16][CH2:17][C:18]1[C:23]([CH3:24])=[CH:22][C:21]([C:25]2[N:28]=[C:8]([C:6]3[S:7][C:3]([CH:1]=[O:2])=[C:4]([CH3:11])[CH:5]=3)[O:10][N:26]=2)=[CH:20][C:19]=1[CH2:29][CH3:30])[CH3:13]
Reactant: Cc1cc(C(=O)O)sc1C=O
Reactant: CCOC(=O)CCc1c(C)cc(C(=N)NO)cc1CC
Product: CCOC(=O)CCc1c(C)cc(-c2noc(-c3cc(C)c(C=O)s3)n2)cc1CC

Procedure:
The title compound is prepared according to Method A starting from 5-formyl-4-methyl-thiophene-2-carboxylic acid and 3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenyl]-propionic acid ethyl ester; LC-MS: tR=1.19 min; [M+1]+=413.15; 1H NMR (D6-DMSO) δ 1.20 (t, J=7.5 Hz, 3H), 1.22 (t, J=7.5 Hz, 3H), 2.40 (s, 3H), 2.44-2.50 (m, 2H), 2.65 (s, 3H), 2.73 (q, J=7.5 Hz, 2H), 2.93-3.00 (m, 2H), 4.11 (q, J=7.0 Hz, 2H), 7.71 (s, 1H), 7.72 (s, 1H), 8.07 (s, 1H), 10.17 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)=[CH:7][CH:6]=1.[H-].[Na+].[CH:26]1(Br)[CH2:30][CH2:29][CH2:28][CH2:27]1.O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:23])[CH:4]([CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)[C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)=[CH:9][CH:10]=1
Reactant: BrC1CCCC1
Reactant: COC(=O)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.8 %

Procedure:
To a mixture of 4-(2-quinolylmethoxy)phenylacetic acid methyl ester (6.36 g; 20.7 mmol) in DMF (10 ml) at 0° C. was added in portions sodium hydride (60% dispersion in mineral oil) (840 mg; 21 mmol). The mixture was stirred at room temperature for 1 hour. It was then recooled to 0° C. and cyclopentyl bromide (2.38 ml, 22.0 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 18 hours, and was then poured into water (50 ml). The product was extracted with ethyl acetate and purified by silica gel chromatography (hexane-ethyl acetate 3:1) to provide 5.5 g of 2-cyclopentyl-2-(4-(2-quinolylmethoxy)phenyl)acetic acid methyl ester.
Reaction SMILES: [O:1]([CH2:3][CH2:4][O:5][C:6]1[N:14]=[C:13]2[C:9]([NH:10][CH:11]=[N:12]2)=[C:8]([NH2:15])[N:7]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH:23]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25]>CN(C=O)C>[CH2:27]([O:26][C:24](=[O:25])[CH:23]([N:12]1[CH:11]=[N:10][C:9]2[C:13]1=[N:14][C:6]([O:5][CH2:4][CH2:3][O:1][CH3:2])=[N:7][C:8]=2[NH2:15])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:28]
Reactant: COCCOc1nc(N)c2[nH]cnc2n1
Reactant: CCOC(=O)C(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(c1ccccc1)n1cnc2c(N)nc(OCCOC)nc21

Procedure:
To a suspension of 2-methoxylethoxyadenine (500 mg, 2.39 mmol) in DMF (5 ml), was added K2CO3 (329 mg, 2.39 mmol) and ethyl α-bromophenylacetate (460 μl, 2.68 mmol). The reaction mixture was allowed to react at 70° C. for 2 h. The reaction mixture was washed with water and extracted by DCM. The organic later was dried over Na2SO4. The organic layer then was filtered, concentrated and purified by silica gel column, using dichlormethane and MeOH as the solvent in a linear gradient. 1H NMR (CDCl3): δ 1.31 (t, 3H), δ 3.45 (s, 3H), δ 3.78 (t, 2H), δ 4.29-4.33 (m, 2H), δ 4.51 (t, 2H), δ 5.83 (bs, 2H), δ 7.41-7.42 (m, 5H), δ 7.78 (s, 1H); MS: 372.1 (M+H)+, 370.1 (M−1).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:20])[C:6]1[CH:11]=[CH:10][C:9]([C:12]#[CH:13])=[CH:8][C:7]=1[CH2:14][N:15]([CH:17]1[CH2:19][CH2:18]1)[CH3:16])([CH3:3])[CH3:2].[CH3:21][O:22][C:23](=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=1.C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:1]([O:4][C:5](=[O:20])[C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:28]2[CH:29]=[CH:30][C:25]([CH2:24][C:23]([O:22][CH3:21])=[O:32])=[CH:26][CH:27]=2)=[CH:8][C:7]=1[CH2:14][N:15]([CH:17]1[CH2:19][CH2:18]1)[CH3:16])([CH3:3])[CH3:2]
Reactant: COC(=O)Cc1ccc(I)cc1
Reactant: C#Cc1ccc(C(=O)OC(C)C)c(CN(C)C2CC2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(C#Cc2ccc(C(=O)OC(C)C)c(CN(C)C3CC3)c2)cc1

Procedure:
Following General Procedure B and using 2-[(cyclopropyl-methyl-amino)methyl]-4-ethynyl-benzoic acid isopropyl ester (Intermediate 122, 0.09 g, 0.33 mmol), 4-iodophenyl acetic acid methyl ester (0.09 g, 0.33 mmol), triethyl amine (2 mL), copper(I)iodide (0.04 g, 0.21 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.1 g, 0.14 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 10-15% ethyl acetate in hexane as the eluent, the title compound was obtained as an oil. (0.1 g, 72%).
Reaction SMILES: [Na].[CH2:2](O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[C:10]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:15]=1[OH:24])([CH3:13])([CH3:12])[CH3:11].C(OO)(C)(C)C.Cl>C(OO)(C)(C)C>[C:20]([C:16]1[CH:17]=[C:18]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8])[CH:19]=[C:14]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:15]=1[OH:24])([CH3:23])([CH3:22])[CH3:21]
Reactant: OCCCCCCO
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: CC(C)(C)OO
Agent: Cl
Agent: [Na]
Product: CC(C)(C)c1cc(CCCCCCO)cc(C(C)(C)C)c1O
Yield: 60.4 %

Procedure:
1.15 grams of metallic sodium (0.05 moles) was added to 59 grams of 1,6-hexanediol (0.5 moles) in a 250 ml. flask fitted with a water trap and the mixture was stirred until the sodium dissolved. The flask was purged with nitrogen and there was then added 20.6 grams of 2,6-di-tert.-butylphenol (0.1 moles) and 0.5 grams (0.0055 moles) of tert.-butyl hydroperoxide. The mixture was heated at 230° C. for 5.5 hours with 0.5 gram increments of tert.-butyl hydroperoxide being added after 1, 2.5, 3.5, and 4.5 hours. The mixture was allowed to cool and was then neutralized by the addition of 5 ml. of concentrated hydrochloric acid. Sodium chloride from the neutralization of the base was removed by filtration and the filtrate was distilled under vacuum. There was obtained 18.5 grams 6-(3,5-di-tert.-butyl-4-hydroxyphenyl)hexanol, 60.5% yield.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10]C)=[O:9])=[CH:4][N:3]=1.[OH-].[Li+]>CO.O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][N:3]=1
Reactant: COC(=O)c1cnc(N)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1ncc(C(=O)O)cn1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Methyl 2-aminopyrimidine-5-carboxylate (300 mg, 2.0 mmol) was diluted in methanol (5 mL) containing a few drops of water. Lithium hydroxide (122 mg, 5.1 mmol) was added, and the reaction mixture was stirred at 60° C. overnight. The mixture was concentrated under reduced pressure, then diluted in water and adjusted to pH 4 with 1 M HCl. 2-Aminopyrimidine-5-carboxylic acid precipitated as a white solid, which was isolated by vacuum filtration (244 mg, 90%): 1H NMR (DMSO-d6) δ: 12.73 (1H, br s), 8.63 (2H, s), 7.44 (2H, br s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[C@@H:4]1[CH2:8][CH:7]([CH3:9])[CH2:6][NH:5]1.C(=O)([O-])O.[Na+].Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:10])[C@@H:4]1[CH2:8][CH:7]([CH3:9])[CH2:6][N:5]1[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]
Reactant: COC(=O)[C@@H]1CC(C)CN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1CC(C)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
(2S)-4-Methylproline methyl ester (0.93 g (6.5 mmol), prepared as described in 2)) was dissolved in toluene (20 ml). To the solution were added an aqueous solution (20 ml) of sodium hydrogencarbonate (1.89 g, 22.5 mmol) and benzyl chloroformate (1.54 ml, 10.8 mmol), and the resulting mixture was stirred at room temperature overnight. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and the solvent was removed by distillation under reduced pressure, to give (2S)-1-benzyloxycarbonyl-4-methylproline methyl ester (1.78 g) as a pale yellow oil (yield 99%). All of the compound obtained above was dissolved in tetrahydrofuran (30 ml). To the resulting solution was added lithium borohydride (0.28 g, 13 mmol) in three portions, and the resulting mixture was stirred at room temperature. Ice was added to the mixture and the mixture was stirred for 1 hour. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel (eluent, ethyl acetate:hexane=2:5), to give the title compound (1.07 g) as a pale yellow oil (yield 66%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].O1CCCC1.[I-].C[S+](C)(C)=O.C(OC(=O)[N:28](C1C=C(C)C(/C=C/S(N2CCC3(N=C(C4CCC(C)CC4)NC3=O)CC2)(=O)=O)=C(C)C=1)C)(C)(C)C.[Cl-].[NH4+].C([O:68][C:69](=O)[N:70]([C:72]1[CH:77]=[C:76]([CH3:78])[C:75]([CH:79]2[CH2:81][CH:80]2[S:82]([N:85]2[CH2:102][CH2:101][C:88]3([N:92]=[C:91]([CH:93]4[CH2:98][CH2:97][CH:96]([CH3:99])[CH2:95][CH2:94]4)[NH:90][C:89]3=[O:100])[CH2:87][CH2:86]2)(=[O:84])=[O:83])=[C:74]([CH3:103])[CH:73]=1)[CH3:71])(C)(C)C>CN1CCN(C)C1=O.C(OCC)(=O)C>[CH3:78][C:76]1[CH:77]=[C:72]([N:70]([CH3:71])[C:69]([NH2:28])=[O:68])[CH:73]=[C:74]([CH3:103])[C:75]=1[C:79]([CH3:81])=[CH:80][S:82]([N:85]1[CH2:102][CH2:101][C:88]2([N:92]=[C:91]([CH:93]3[CH2:94][CH2:95][CH:96]([CH3:99])[CH2:97][CH2:98]3)[NH:90][C:89]2=[O:100])[CH2:87][CH2:86]1)(=[O:83])=[O:84]
Reactant: Cc1cc(N(C)C(=O)OC(C)(C)C)cc(C)c1C1CC1S(=O)(=O)N1CCC2(CC1)N=C(C1CCC(C)CC1)NC2=O
Reactant: Cc1cc(N(C)C(=O)OC(C)(C)C)cc(C)c1/C=C/S(=O)(=O)N1CCC2(CC1)N=C(C1CCC(C)CC1)NC2=O
Agent: C[S+](C)(C)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN1CCN(C)C1=O
Solvent: C1CCOC1
Product: CC(=CS(=O)(=O)N1CCC2(CC1)N=C(C1CCC(C)CC1)NC2=O)c1c(C)cc(N(C)C(N)=O)cc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 1 M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (0.31 mL, 0.306 mmol) was added to a mixture of trimethylsulfoxonium iodide (29 mg, 0.131 mmol) in 1,3-dimethyl-2-imidazolidinone (2 mL) at room temperature. The reaction solution was stirred at room temperature for 0.5 hour. A mixed solution of (3,5-dimethyl-4-{(E)-2-[2-(4-methyl-cyclohexyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-vinyl}-phenyl)-methyl-carbamic acid tert-butyl ester (50 mg, 0.0873 mmol) in 1,3-dimethyl-2-imidazolidinone (2 mL) was then added at room temperature, and the mixture was heated with stirring at 50° C. for 15 hours. After returning to room temperature, an aqueous ammonium chloride solution and ethyl acetate were added to the reaction solution. The organic layer and the aqueous layer were separated, and the aqueous layer was repeatedly extracted with ethyl acetate three times. The organic layers were combined, washed with water twice and saturated brine, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give a mixture of (3,5-dimethyl-4-{2-[2-(4-methyl-cyclohexyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-cyclopropyl}-phenyl)-methyl-carbamic acid tert-butyl ester. This mixture was used in the next reaction as such without further purification.
Reaction SMILES: C(NC[S:6][CH2:7][CH:8]([CH3:19])[C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])=[O:10])(=O)C.S>C(O)(=O)C.O>[SH:6][CH2:7][CH:8]([CH3:19])[C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])=[O:10]
Reactant: CC(=O)NCSCC(C)C(=O)N1CCC[C@H]1C(=O)O
Agent: S
Solvent: O
Solvent: CC(=O)O
Product: CC(CS)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
1-[3-(acetamidomethylthio)-2-methylpropanoyl]-L-proline (1.4 g.) and mercuric acetate (1.93 g.) are dissolved in a mixture of acetic acid (25 ml.) and water (25 ml.). After one hour stirring on the steam bath, hydrogen sulfide is bubbled through until no more precipitation of mercuric sulfide is observed. The mixture is filtered, the precipitate is washed with ethanol, and the filtrate is concentrated to dryness in vacuo to yield 1-(3-mercapto-2-methylpropanoyl)-L-proline. Rf : 0.35 (Silica gel, Benzene/Acetic acid 3:1); Rf : 0.5 (Silica gel, Methyl-ethylketone/Acetic acid/pyridine/water 14:1:2:1) identical to the compound of Example 34.
Reaction SMILES: [C:1]([O:5][C@@H:6]1[CH2:11][N:10]([C:12]([O:14][CH3:15])=[O:13])[C@H:9]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[O:17])[C@@H:8]([C:30]([O:32]C)=O)[CH2:7]1)([CH3:4])([CH3:3])[CH3:2].[OH:34][NH2:35].Cl.NO.C[O-].[Na+].Cl>CO>[C:1]([O:5][C@@H:6]1[CH2:11][N:10]([C:12]([O:14][CH3:15])=[O:13])[C@H:9]([C:16]([N:18]2[CH2:19][CH2:20][N:21]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:22][CH2:23]2)=[O:17])[C@@H:8]([C:30]([NH:35][OH:34])=[O:32])[CH2:7]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@H]1C[C@H](OC(C)(C)C)CN(C(=O)OC)[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)N1C[C@@H](OC(C)(C)C)C[C@H](C(=O)NO)[C@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
To a solution of dimethyl (2S,3S,5S)-5-tert-butoxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1,3-dicarboxylate (0.038 g, 0.000082 mol) in methanol (0.30 mL, 0.0074 mol) was added 1.640 M of N-hydroxyamine in methanol (1.004 mL), freshly made from the corresponding hydroxylamine HCl salt and sodium methoxide. The mixture was stirred at rt for 1 h then acidified with 1N HCl. The resulting mixture was applied directly on RP-HPLC to give the targeted product as a TFA salt (10 mg, 45%). MS (ESI): (M+H)+=463.2.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[NH2:6][C:7]1[C:15]2[O:14][CH2:13][CH2:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.[OH-].[Na+]>S(=O)(=O)(O)O>[NH2:6][C:7]1[C:15]2[O:14][CH2:13][CH2:12][C:11]=2[CH:10]=[C:9]([N+:1]([O-:4])=[O:2])[CH:8]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Nc1cccc2c1OCC2
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [Na+]
Product: Nc1cc([N+](=O)[O-])cc2c1OCC2
Reaction time: 2 h
Yield: 75.8 %

Procedure:
Potassium nitrate (8.6 g) was added portionwise over 1/2 h to a solution of 7-amino-2,3-dihydrobenzofuran (D3) (10 g) in concentrated sulphuric acid (75 ml) at 5°-10° C. The resulting solution was stirred for a further 2 h, then added to ice, basified with 40% NaOH, and extracted into ethyl acetate. The organic phase was dried (Na2SO4) and the solvent evaporated under reduced pressure to give the title compound (10.1 g, 76%) as a red/brown foam.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]([O:27][C:28]([N:30]1[CH2:34][CH2:33][C@@H:32]([NH2:35])[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C(N(C(C)C)CC)(C)C>CC(O)C>[C:23]([O:27][C:28]([N:30]1[CH2:34][CH2:33][C@@H:32]([NH:35][C:18]2[C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=[C:14]3[N:10]([S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])[CH:11]=[CH:12][C:13]=23)[CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC[C@@H](Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Temperature: 80 °C
Reaction time: 4 h
Yield: 83.9 %

Procedure:
A suspension of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (8.16 g, 24.2 mmol), (R)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester (5.00 g, 26.8 mmol), and diisopropylethylamine (5.14 ml, 29.5 mmol) in propan-2-ol (150 ml) was heated at 80° C. for 13 h. The mixture was then cooled to 25° C. and stirred for 4 h. The resulting yellow solid was collected by vacuum filtration, washed with heptanes (1×20 ml), and was air-dried to afford (R)-3-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester (9.90 g, 88%). LCMS (Method G, ESI): RT=1.19 min, m+H=488.3. This material was used in the next step below without additional purification or characterization.
Reaction SMILES: [CH3:1][C:2]1([C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=4)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH2:7][CH2:6][CH:5]([O:8]C=O)[CH2:4][CH2:3]1.[OH-].[Na+]>CO>[OH:8][CH:5]1[CH2:4][CH2:3][C:2]([C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:23]=[C:24]([O:32][CH3:33])[C:25]([O:30][CH3:31])=[C:26]([O:28][CH3:29])[CH:27]=4)[N:20]=3)[NH:15][CH:14]=2)=[O:12])([CH3:1])[CH2:7][CH2:6]1
Reactant: COc1cc(-c2cnc3[nH]cc(C(=O)C4(C)CCC(OC=O)CC4)c3n2)cc(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(-c2cnc3[nH]cc(C(=O)C4(C)CCC(O)CC4)c3n2)cc(OC)c1OC
Temperature: 50 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
A solution of formic acid 4-methyl-4-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-cyclohexyl ester (12 mg, 0.026 mmol) in MeOH (1 ml) was treated with 2N NaOH aq. (0.2 ml, 0.4 mmol) and allowed to stir at 50° C. for overnight. The reaction mixture was partitioned between EtOAc/sat. NH4Cl aq., and the organic layers were collected and concentrated. Silica gel chromatography using 0-10% {5% NH4OH:MeOH} in DCM as eluant gave 10 mg (89%) of (4-hydroxy-1-methyl-cyclohexyl)-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone as a white solid. M+H=426.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13]O)=[C:11]([C:15]([N:17]([CH2:39][CH:40]([CH3:42])[CH3:41])[C@H:18]2[CH2:23][C@@H:22]([C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])[CH2:21][N:20]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:19]2)=[O:16])[N:10]=[N:9]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:63]>ClCCl>[Br:63][CH2:13][C:12]1[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:9]=[N:10][C:11]=1[C:15]([N:17]([CH2:39][CH:40]([CH3:42])[CH3:41])[C@H:18]1[CH2:23][C@@H:22]([C:24]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:25])[CH2:21][N:20]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:19]1)=[O:16]
Reactant: CC(C)CN(C(=O)c1nnn(-c2ccccc2F)c1CO)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)CN(C(=O)c1nnn(-c2ccccc2F)c1CBr)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
To a solution (4 ml) of tert-butyl (3S,5R)-3-[{[1-(2-fluorophenyl)-5-(hydroxymethyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (410 mg) and triphenylphosphine (275 mg) in dichloromethane was added under ice-cooling carbon tetrabromide (350 mg), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (10:90-100:0) was concentrated under reduced pressure to give the object product (442 mg).
Reaction SMILES: C(Cl)CCl.[NH:5]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@H:6]([C:8]([OH:10])=O)[CH3:7].[CH3:18][O:19][C:20](=[O:26])[C@H:21]([CH:23]([CH3:25])[CH3:24])[NH2:22].C(N(CC)CC)C>C(Cl)(Cl)Cl>[NH:5]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@H:6]([C:8]([NH:22][C@H:21]([C:20]([O:19][CH3:18])=[O:26])[CH:23]([CH3:25])[CH3:24])=[O:10])[CH3:7]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@@H](N)C(C)C
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(C)C
Reaction time: 0.5 h

Procedure:
EDC (1.521 g, 7.93 mmol) was added to Boc-Ala (1.500 g, 7.93 mmol) in 25 mL chloroform at 0° C. and the mixture was allowed to stir 30 minutes. Valine methyl ester (1.329 g, 7.93 mmol), triethylamine (1.11 mL, 7.93 mmol) and 25 mL chloroform were combined in a separate 50-mL flask and stirred. This mixture was transferred to the solution of activated Boc-alanine and stirred at 0° C. for 3 h. The ice bath was removed and the reaction mixture stirred an additional 27 h. Three drops of acetic acid were added and the stirring continued for 15 minutes. The mixture was concentrates in vacuo and then redissolved in EtOAc (50 mL). The organic portion was washed with 10% NaHCO3 (2×25 mL), 1N HCl (2×25 mL), water (25 mL), dried over sodium sulfate, and concentrated in vacuo to 1.848 g (81%) of product. 1H NMR (CDCl3, 300 MHz) δ 6.68 (br d, J=5.4 Hz, 1H), 4.99 (br s, 1H), 4.53 (dd, J=4.8, 8.7 Hz, 1H), 4.19 (br t, J=7.5 Hz, 1H), 3.74 (s, 3H), 2.18 (septet, J=6.9 Hz, 1H), 1.45 (s, 9H), 0.93 (d, J=6.9 Hz, 3H), 0.90 (d, J=6.9 Hz, 3H).