Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:38]([O:42][C:43](=[O:51])[NH:44][CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)([CH3:41])([CH3:40])[CH3:39]>>[C:38]([O:42][C:43](=[O:51])[NH:44][CH:45]1[CH2:50][CH2:49][N:48]([C:32]([N:12]2[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=[C:11]2[C:8]2[CH:9]=[N:10][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:6][C:7]=2[O:35][CH2:36][CH3:37])=[O:33])[CH2:47][CH2:46]1)([CH3:41])([CH3:39])[CH3:40]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(NC(=O)OC(C)(C)C)CC1

Procedure:
In a manner analogous to the method described in example 3, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was reacted with piperidin-4-yl-carbamic acid tert-butyl ester (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C39H50Cl2N5O4 [(M+H)+] 722.3235, observed 722.3233.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[C:17]2[S:16][N:15]=[C:14](Cl)[C:13]=2[CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:20][CH2:21][CH2:22][CH2:23][NH2:24]>>[NH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:14]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([S:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:8])=[O:7])[C:17]=2[S:16][N:15]=1
Reactant: NCCCN
Reactant: CC(C)(C)NS(=O)(=O)c1cccc2c(Cl)nsc12
Solvent: O
Product: CC(C)(C)NS(=O)(=O)c1cccc2c(NCCCN)nsc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of N-tert-butyl-3-chlorobenzo[d]isothiazole-7-sulfonamide (260 mg, 0.85 mmol) in 1,3-diaminopropane (1 mL) was allowed to stir at room temperature for 3h. The dark brown reaction mixture was then poured over water (10 mL), extracted with ethyl acetate and the combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 3-(3-aminopropylamino)-N-tert-butylbenzo[d]isothiazole-7-sulfonamide (271 mg) as a pale yellow solid. 1H NMR (300 MHz, CD3OD): 8.17 (dd, 1H), 8.01 (dd, 1H), 7.55 (t, 1H), 3.58 (t, 2H), 2.81 (t, 2H), 1.86-1.95 (m, 2H), 1.17 ppm (s, 9H). MW=342 confirmed by LC-MS, tr=7.95 min (Method Y) MH+=343.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].OS(O)(=O)=O.[CH3:16][C:17]([CH3:19])=O>Cl.[O-]S([O-])(=O)=O.[Cu+2]>[CH3:16][C:17]1([CH3:19])[O:1][C@@H:2]2[C@@H:3]([C@@H:5]([OH:6])[C@@H:7]([CH2:9][OH:10])[O:8]2)[O:4]1
Reactant: CC(C)=O
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Agent: [Cu+2]
Agent: Cl
Agent: O=S(=O)(O)O
Product: CC1(C)O[C@H]2O[C@H](CO)[C@H](O)[C@H]2O1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
According to the reported procedures, (Suhara et al., J. Org. Chem. 2001, 66, 8760-8771) a suspension of D-xylose (50 g), anhydrous CuSO4 (70 g) and conc. H2SO4 (5 mL) in acetone (1 L) was stirred at room temperature for 24 h, followed by partial hydrolysis in aqueous HCl solution (110 mL, 0.1 M) at 40° C. for 2 h, to give 1,2-O-isopropylidene-α-D-xylofuranose (4, 61 g) as colorless syrup. Compound 4 (10 g, 52.6 mmol) was treated with pivaloyl chloride (6.6 g, 54.8 mmol) in pyridine (50 mL) at 0° C. for 8 h to give 1,2-O-isopropylidene-5-O-pivaloyl-α-D-xylofuranoside (13 g, 85% yield from D-xylose) as colorless oil. Pyridinium dichromate (PDC, 8.92 g, 23.7 mmol) and Ac2O (12.2 mL, 130 mmol) were added to the pivaloyl ester (10.8 g, 39.4 mmol) in CH2Cl2 (160 mL). The mixture was heated under reflux for 1.5 h, and then concentrated under reduced pressure. The residue was dissolved in EtOAc (30 mL), and filtered through a silica gel pad by elution with EtOAc. The filtrate was concentrated and coevaporated with toluene (2×) to remove Ac2O. The crude ketone product (10.2 g) was stirred with hydroxylamine hydrochloride (18.15 g, 260 mmol) in anhydrous pyridine (75 mL) at 60° C. for 24 h. The mixture was concentrated under reduced pressure, and the residue was dissolved in EtOAc. The organic layer was washed with water, and the aqueous layer was extracted with EtOAc (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated. The residual oil was purified by flash column chromatography on silica gel (EtOAc/hexane, 1:3) to afford the corresponding oxime (9.27 g, 82% yield for two steps) as a mixture of syn/anti isomers (70:30). Colorless oil; TLC (EtOAc/hexane, 1:4) Rf=0.4; [α]D20=+162.5 (c=1, CHCl3); IR (neat) 3501, 2988, 1769, 1292 cm−1; 1H NMR (600 MHz, CDCl3) (syn/anti isomers=7:3) δ 8.05 (0.3H, br s), 7.97 (0.7 H, br s), 5.98 (0.7 H, d, J=4.3 Hz), 5.96 (0.3 H, d, J=4.3 Hz), 5.27-5.25 (1 H, m), 4.99 (1 H, dd, J=4.2, 1.3 Hz), 4.97-4.96 (0.3 H, m), 4.55 (0.7H, dd, J=11.1, 2.6 Hz), 4.33 (0.3 H, dd, J=11.1, 2.6 Hz), 4.23-4.20 (1 H, m), 1.47 (3 H, s), 1.42 (3 H, s), 1.16 (9 H, s); 13C NMR (150 MHz, CDCl3) δ 178.1/1770.9, 158.4/157.3, 114.2/113.7, 105.0/104.8, 780.4/73.5, 75.8/750.6, 38.7/38.6, 27.7, 27.4, 27.3, 27.2, 27.19, 27.15; HRMS calc'd for C13H22NO6 (M++H): 288.1444, found: m/z 288.1452.
Reaction SMILES: C(C1C=C(OC)C(F)=C(C(O)C#N)C=1)C.[CH2:16]([O:18][C:19]1[C:20]([F:33])=[C:21]([CH:27]([OH:32])[C:28]([O:30][CH3:31])=[O:29])[CH:22]=[C:23]([CH2:25][CH3:26])[CH:24]=1)C>>[CH2:25]([C:23]1[CH:24]=[C:19]([O:18][CH3:16])[C:20]([F:33])=[C:21]([CH:27]([OH:32])[C:28]([O:30][CH3:31])=[O:29])[CH:22]=1)[CH3:26]
Reactant: CCOc1cc(CC)cc(C(O)C(=O)OC)c1F
Agent: CCc1cc(OC)c(F)c(C(O)C#N)c1
Product: CCc1cc(OC)c(F)c(C(O)C(=O)OC)c1

Procedure:
119C was prepared from 119B using a procedure similar to that used in the preparation of 118F. 1H NMR (400 MHz, CDCl3) δ ppm 1.21 (t, J=7.69 Hz, 3H) 2.59 (q, J=7.47 Hz, 2H) 3.76 (s, 3H) 3.87 (s, 3H) 5.38 (s, 1H) 6.65-6.85 (m, 2H).
Reaction SMILES: C[O:2][C:3](=[O:13])[C@H:4]([CH3:12])[NH:5][C:6](=[O:11])[CH2:7][CH:8]1[CH2:10][CH2:9]1>CO.ClCCl>[CH:8]1([CH2:7][C:6]([NH:5][C@H:4]([C:3]([OH:13])=[O:2])[CH3:12])=[O:11])[CH2:10][CH2:9]1
Reactant: COC(=O)[C@H](C)NC(=O)CC1CC1
Solvent: CO
Solvent: ClCCl
Product: C[C@H](NC(=O)CC1CC1)C(=O)O

Procedure:
Following General Procedure II-A above using N-(cyclopropylacetyl)-L-alanine methyl ester (from Step A), the title compound was prepared as an oil. The reaction was monitored by tlc on silica get (Rf=0.27 in 10% methanol/dichloromethane).
Reaction SMILES: [Cl:1][C:2]1=[C:3]([Cl:9])[C:4]([O:6][C:7]1=[O:8])=[O:5].[Cl:10][CH:11]=[CH:12][CH2:13][NH:14][CH2:15][CH:16]=[CH:17][Cl:18]>C(Cl)Cl>[Cl:10][CH:11]=[CH:12][CH2:13][N:14]([CH2:15][CH:16]=[CH:17][Cl:18])[C:4](=[O:5])/[C:3](/[Cl:9])=[C:2](/[Cl:1])\[C:7]([OH:6])=[O:8]
Reactant: ClC=CCNCC=CCl
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Solvent: ClCCl
Product: O=C(O)/C(Cl)=C(/Cl)C(=O)N(CC=CCl)CC=CCl
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.1 %

Procedure:
Dichloromaleic anhydride (1.7 g, 0.01 mol) and 30 ml methylene chloride were stirred under a mild reflux. Bis-(3-chloroallyl)amine (1.7 g, 0.01 mol) was then added. The exothermic reaction yielded a clear solution. The solution was stirred at room temperature for 3 hours. The mixture was stripped, resulting in 3.3 g of the above-named product.
Reaction SMILES: [CH3:1][O:2][C:3]1[NH:7][N:6]=[C:5]([NH2:8])[CH:4]=1.Br[C:10]1[C:11](=[O:18])[N:12]([CH3:17])[CH:13]=[C:14]([Br:16])[CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.CCOC(C)=O.O>[Br:16][C:14]1[CH:15]=[C:10]([NH:8][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[NH:7][N:6]=2)[C:11](=[O:18])[N:12]([CH3:17])[CH:13]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: COc1cc(N)n[nH]1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cc(Nc2cc(Br)cn(C)c2=O)n[nH]1
Temperature: 100 °C
Yield: 12 %

Procedure:
A sealed tube was equipped with a magnetic stirrer and charged with 5-methoxy-1H-pyrazol-3-amine (1.9 g, 17 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (4.9 g, 18 mmol) and cesium carbonate (12 g, 37 mmol) in 1,4-dioxane (160 mL). After bubbling nitrogen through the solution for 30 min, Xantphos (1.1 g, 2 mmol) and tris(dibenzylideneacetone) dipalladium(0) (1.1 g, 1.2 mmol) were added, and the reaction mixture was heated to 100° C. for 16 hours. After this time, H2O (50 mL) and EtOAc (50 mL) were added. The aqueous layer was separated and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine (100 mL) and dried over sodium sulfate. The resulting solution was concentrated under reduced pressure to near dryness and the desired product fell out of solution. Filtering and washing with Et2O (10 mL) afforded 12% yield (590 mg) of crude 157a.
Reaction SMILES: [S:1]([Cl:3])Cl.[CH3:4][NH:5][C:6](=[O:20])[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(N(CC)CC)C>C(Cl)Cl>[Cl:3][S:1][N:5]([CH3:4])[C:6](=[O:20])[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: ClSCl
Reactant: CCCCCCCCCCCCOC(=O)NC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCOC(=O)N(C)SCl
Temperature: 5 °C
Reaction time: 2.3 h
Yield: 101.3 %

Procedure:
To a solution of 62 g (0.6 mole) of sulfur dichloride in 200 ml of methylene chloride cooled to 0° C. under a nitrogen atmosphere was added a solution made up of 97.4 g (0.4 mole) of n-dodecyl N-methylcarbamate, 44.5 g (0.44 mole) of triethylamine and 150 ml of methylene chloride. The addition took 2.3 hr while the temperature was maintained at -10° to 5° C. After stirring for one additional hour at 5° C. the mixture was filtered under a positive nitrogen atmosphere, and the filtrate was concentrated. Triethylamine hydrochloride was removed by extracting the product into 200 ml of hexane. After filtration, the hexane solution was concentrated to give 125.6 g n-dodecyl N-chlorothio-N-methylcarbamate.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)CCC.[CH3:19][CH:20]([CH3:26])[CH2:21][CH2:22][C:23](Cl)=[O:24]>C1COCC1>[CH3:19][CH:20]([CH3:26])[CH2:21][CH2:22][C:23]([C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)=[O:24]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: CC(C)CCC(=O)Cl
Solvent: C1CCOC1
Product: CC(C)CCC(=O)c1ccco1

Procedure:
A solution of 2-tributylstannylfuran (1 mmol), 4-methylvaleroyl chloride (1.1 mmol), and PdCl2 (PPh3)2 (0.05 mmol) in THF was stirred at 25° C. for 24 h. Extraction and chromatography gave 2-(4-methylvaleryl)furan.
Reaction SMILES: C[O:2][CH2:3][C:4]1[NH:5][C:6]([C:10]2[C:11]([CH3:33])=[CH:12][C:13]([CH3:32])=[C:14]([CH:31]=2)[C:15]([N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)=[O:16])=[C:7]([CH3:9])[N:8]=1.[Na+].[I-].C1OCCOCCOCCOCCOC1.B(Br)(Br)Br>ClCCl>[OH:2][CH2:3][C:4]1[NH:5][C:6]([C:10]2[C:11]([CH3:33])=[CH:12][C:13]([CH3:32])=[C:14]([CH:31]=2)[C:15]([N:17]2[CH2:18][CH2:19][CH:20]([C:23]3[CH:24]=[CH:25][C:26]([C:27]#[N:28])=[CH:29][CH:30]=3)[CH2:21][CH2:22]2)=[O:16])=[C:7]([CH3:9])[N:8]=1
Reactant: COCc1nc(C)c(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C)[nH]1
Agent: BrB(Br)Br
Agent: C1COCCOCCOCCOCCO1
Agent: [I-]
Solvent: ClCCl
Product: Cc1cc(C)c(-c2[nH]c(CO)nc2C)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Temperature: -30 °C
Reaction time: 15 h
Yield: 17.2 %

Procedure:
Into a 50-mL 3-necked round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a mixture of 4-(1-(5-(2-(methoxymethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile (compound 2, 30 mg, 0.068 mmol), NaI (20 mg, 0.13 mmol), 15-crown-5 (30 mg, 0.14 mmol) and dichloromethane (10 mL). The mixture was cooled to −30° C. and boron tribromide (70 mg, 0.28 mmol) was added. The resulting mixture was allowed to warm to room temperature and stirred for 15 h. The reaction mixture was carefully quenched by the addition of saturated aqueous sodium bicarbonate (10 mL) and the resulting mixture was extracted dichloromethane (2×20 mL). The combined organics was washed with saturated aqueous Na2S2O3 (2×20 mL), then dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and CH3CN (21% CH3CN up to 35% in 8 min, up to 100% in 2 min, down to 21% in 1 min); Detector, Waters 2489, 254&220 nm. The fractions containing pure compound were combined and lyophilized to yield the title compound as a white solid (5.0 mg, 17%). m/z (ES+) 429 (M+H)+. 1H NMR (400 MHz, CD3OD): δ 7.74-7.65 (m, 2), 7.48 (d, J=8.0 Hz, 2H), 7.38 (d, J=5.6 Hz, 1H), 7.29 & 7.16 (2 singlets, rotamers, Ar—H, 1H), ˜4.9 (1H obscured by water peak), 3.64 (app t, J=15.0 Hz, 1H), ˜3.35-3.21 (m, 1H partially overlapped with methanol solvent peak), 3.09-2.93 (m, 1H), 2.45 & 2.34 (2 singlets, rotamers, Ar—CH3, 3H), 2.29 (s, 3H), 2.24 (s, 3H), 2.09-1.97 (m, 1H), 1.92-1.71 (m, 2H), 1.70-1.55 (m, 1H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[S:17][C:18]([C@H:21]([C:29]5[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=5[Cl:36])[NH:22][S@@](C(C)(C)C)=O)=[CH:19][N:20]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.Cl.O1CCOCC1>CO>[NH2:22][C@@H:21]([C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=1[Cl:36])[C:18]1[S:17][C:16]([NH:15][C:13]([C:10]2([C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)[CH2:11][CH2:12]2)=[O:14])=[N:20][CH:19]=1
Reactant: CC(C)(C)[S@@](=O)N[C@H](c1cnc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)s1)c1ccc(F)cc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: N[C@H](c1cnc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)s1)c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((S)-(2-chloro-4-fluorophenyl)((R)-1,1-dimethylethylsulfinamido)methyl)thiazol-2-yl)cyclopropanecarboxamide (659 mg, 1.2 mmol) in MeOH (5 mL) was added 4M HCl in dioxane (1.8 mL, 7.2 mmol). The reaction mixture was stirred at room temperature for 1.5 h and evaporated to dryness. The crude product was dissolved in CH2Cl2. The organic layer was washed with aqueous NaHCO3 solution (50 mL×2), brine (50 mL×1), dried over MgSO4 and concentrated to provide (S)-N-(5-(Amino(2-chloro-4-fluorophenyl)methyl)thiazol-2-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide as a colorless solid that was used without further purification. 1H-NMR (400 MHz, CDCl3) δ 8.48 (br s, 1H), 7.63 (dd, J=6.1, 8.7 Hz, 1H), 7.18 (s, 1H), 7.08 (dd, J=2.6, 8.4 Hz, 1H), 6.99 (td, J=8.3, 2.6 Hz, 1H), 6.91-6.86 (m, 2H), 6.81 (d, J=7.9 Hz, 1H), 6.01 (s, 2H), 5.78 (s, 1H), 3.80 (s, 2H), 1.74-1.67 (m, 2H), 1.30-1.22 (m, 2H); HPLC ret. time 2.67 min, 10-99% CH3CN, 5 min run; ESI-MS 446.3 m/z (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:13]([C:16]1[CH:21]=[CH:20][C:19](O)=[CH:18][CH:17]=1)([O-:15])=[O:14]>C1COCC1.C(N(CC)CC)C.CN(C1C=CN=CC=1)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][C:19]2[CH:20]=[CH:21][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][CH:18]=2)=[O:9])=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Temperature: -30 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
8.77 g of 4-nitrobenzoic acid (52.5 mM) were dissolved in 400 ml of THF and 53.1 g of triethylamine (525.0 mM). The solution was cooled to −30° C. and 6.01 g of methansulfochloride (52.5 mM) were added dropwise. The mixture was stirred for 1 h at this temperature, then 6.95 g of 4-nitrophenol (50.0 mM) were added at once, followed by 250 mg of DMAP. The reaction mixture was stirred for 1 h at −30° C. and was allowed to warm to room temperature while stirred overnight. The next day, the reaction mixture was filtered, the cake was washed with THF and the filtrate was evaporated to dryness. The residue was purified by chromatography using silica gel and dichloromethane to give 11.0 g (38.2 mM, 76%) of 4-nitrophenyl 4-nitrobenzoate as white crystals.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]([OH:14])=[O:13])=[N:8][NH:9]2)=[CH:5][CH:4]=1>Br>[OH:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]([OH:14])=[O:13])=[N:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(C(=O)O)n[nH]c2c1
Agent: Br
Product: O=C(O)c1n[nH]c2cc(O)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-Methoxyindazole-3-carboxylic acid (1.015 g; manufactured by ChemPacific Corp.) was dissolved in hydrobromic acid (52 mL; manufactured by Kanto Chemical Co., Inc.), and the solution was stirred overnight at reflux. The solution was cooled to room temperature, and then the loss of raw materials and the presence of the title compound were confirmed using LCMS. The solvent was evaporated under reduced pressure, and thus a crude product (1.504 g) of the title compound was obtained.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH:8]=O)=[C:6]([CH3:10])[CH:5]=[C:4]([CH3:11])[C:3]=1[CH3:12].C([O-])([O-])=O.[K+].[K+].[F:19][C:20]([F:29])([F:28])/[CH:21]=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C=O)C>[CH3:10][C:6]1[CH:5]=[C:4]([CH3:11])[C:3]([CH3:12])=[C:2]2[C:7]=1[CH:8]=[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:21]([C:20]([F:19])([F:29])[F:28])[O:1]2
Reactant: Cc1cc(C)c(C=O)c(O)c1C
Reactant: CCOC(=O)/C=C/C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2c(C)cc(C)c(C)c2OC1C(F)(F)F
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of 6-hydroxy-2,4,5-trimethylbenzaldehyde (2.77 g, 17.1 mmoles) in 50 mL of dry DMF was added anhydrous K2CO3 (5.19 g, 37.6 mmoles), and ethyl 4,4,4-trifluorocrotonate (3.16 g, 18.8 mmoles). The mixture was stirred rapidly under a drying tube at 100° C. for 3 h. After cooling, the mixture was diluted with DMF, filtered, and evaporated. Chromatography of the residue over silica gel using DCM as eluent gave ethyl 5,7,8-trimethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylate, 3.75 g, as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C@@H:9]1[CH2:22][OH:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N+]1([O-])CCOCC1>C(Cl)Cl.CCCCCC.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C@H:9]1[CH:22]=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1CO
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To a solution of 77E (800 mg, 2.3 mmol) in DCM (15 mL) was added 4-methylmorpholine N-oxide (541 mg, 4.6 mmol, 2 equiv) followed by the addition of TPAP (177 mg, 0.5 mmol, 0.22 equiv). The mixture was stirred at rt for 3 h. The mixture was diluted with hexane (10 mL), loaded on a layer of silica gel and eluted with 25% EtOAc/hexane. The filtrate was concentrated to gave the desired product 77F (711 mg, 90%): Rf (30% EtOAc/hexane) 0.87; HPLC (Phenomenex Luna 5 u C18 4.6×50 mm, linear gradient over 4 min) retention time 4.1 min (100%); MS (ES) m/z 344.1 [M+1]+; HRMS calcd for C17H34NO4Si 344.2257, Found 344.2259.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CN=C1.[C:14]1([CH3:21])[C:19]([OH:20])=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[C:4]([Si:1]([CH3:3])([CH3:2])[O:20][C:19]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:21])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1ccccc1O
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1ccccc1O[Si](C)(C)C(C)(C)C
Reaction time: 3 h

Procedure:
tert-Butyldimethylsilyl chloride (83.6 g, 0.55 mol) and imidazole (78.69 g, 1.15 mol) were added to a solution of o-cresol (50 g, 0.46 mol) in dry DMF (200 mL). The reaction mixture was stirred for 3 h, treated with a 5% aqueous NaHCO3 solution, extracted with petroleum ether and concentrated to obtain the title compound as an oil. Yield: 102 g, (100%); 1H NMR (CDCl3): δ 0.20 (s, 6H, 2CH3), 1.0 (s, 9H, 3CH3), 2.2 (s, 3H, CH3), 6.75 (d, 1H, Ar), 6.85 (q, 1H, Ar), 7.18 (q, 1H, Ar), 7.25 (d, 1H, Ar).
Reaction SMILES: Cl[C:2]([CH3:8])([CH3:7])[CH:3]([N:5]=[O:6])[CH3:4].Cl.Cl.[NH2:11][CH2:12][CH:13]([O:23][NH2:24])[CH2:14][N:15]1[CH:19]=[CH:18][N:17]=[C:16]1[N+:20]([O-:22])=[O:21]>>[CH3:7][C:2]([CH3:8])([NH:24][O:23][CH:13]([CH2:14][N:15]1[CH:19]=[CH:18][N:17]=[C:16]1[N+:20]([O-:22])=[O:21])[CH2:12][NH:11][C:2]([CH3:8])([CH3:7])[C:3](=[N:5][OH:6])[CH3:4])[C:3](=[N:5][OH:6])[CH3:4]
Reactant: NCC(Cn1ccnc1[N+](=O)[O-])ON
Reactant: CC(N=O)C(C)(C)Cl
Agent: Cl
Product: CC(=NO)C(C)(C)NCC(Cn1ccnc1[N+](=O)[O-])ONC(C)(C)C(C)=NO

Procedure:
According to the General Reaction Scheme, N-(2,3-epoxypropyl)phthalimide (1) is reacted with 2-nitro-imidazole (2) to obtain 2-[2-Hydroxy-2-(2-nitro-1H-imidazol-1-yl)ethyl]-1H-isoindole-1,3(2H)-dione (3). This product is then reacted with N-hydroxyphthalimide, preferably in the presence of a tertiary amine such as triphenylphosphine, to obtain the intermediate of Formula II, 2-{2-(1,3-dioxoisoindolin-2-yl)-1-[(2-nitroimidazolyl)methyl]ethoxy}isoindoline-1,3-dione (4). This intermediate is then reacted with hydrazine to obtain 1-[3-amino-2-(aminooxy)propyl]-2-nitro-1H-imidazole dihydrochloride (5), which is then reacted with the compound of Formula III to yield the compound of Formula I. A preferred compound of Formula III is 3-chloro-3-methyl-2-nitrosobutane, which, when used contacted with 1-[3-amino-2-(aminooxy)propyl]-2-nitro-1H-imidazole dihydrochloride (5), yields 3,3,9,9-tetramethyl-6-[(2-nitro-1H-imidazol-1-yl)methyl]-5-oxa-4,8-diazaundecane-2,10-dione dioxime (7).
Reaction SMILES: [CH:1]1([C:4]2[NH:5][N:6]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:7](=[O:9])[CH:8]=2)[CH2:3][CH2:2]1.[F:16][C:17]([F:25])([F:24])[C:18](=[O:23])[C:19]([O:21][CH3:22])=[O:20]>C(Cl)(Cl)Cl>[CH3:22][O:21][C:19](=[O:20])[C:18]([OH:23])([C:17]([F:25])([F:24])[F:16])[C:8]1[C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:5][C:4]=1[CH:1]1[CH2:3][CH2:2]1
Reactant: O=c1cc(C2CC2)[nH]n1-c1ccccc1
Reactant: COC(=O)C(=O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COC(=O)C(O)(c1c(C2CC2)[nH]n(-c2ccccc2)c1=O)C(F)(F)F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a chloroform solution (5 ml) of 3-cyclopropyl-1-phenyl-5-pyrazolone (100 mg, 0.5 mmol), methyl trifluoropyruvate (78 mg, 0.5 mmol) was added at room temperature and the mixture was stirred at 80° C. for 2 hours. After removing the solvent under reduced pressure, the title compound was obtained as a colorless solid (178 mg).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([C:12]3([NH:15]C(=O)OC(C)(C)C)[CH2:14][CH2:13]3)=[CH:8][CH:7]=2)=[N:4][N:3]=[N:2]1.[ClH:23].C(OCC)(=O)C>C(OC(=O)C)C>[ClH:23].[NH:4]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]([C:12]3([NH2:15])[CH2:13][CH2:14]3)=[CH:10][CH:11]=2)=[N:1][N:2]=[N:3]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nnn[nH]3)cc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: NC1(c2ccc(-c3nnn[nH]3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the solution of tert-butyl (1-(4-(1H-tetrazol-5-yl)phenyl)cyclopropyl)carbamate (D16) (800 mg, 2.65 mmol) in ethylacetate (10 ml), 4N HCl/ethyl acetate solution (20 ml) was added and the mixture was stirred at room temperature for 1 hour, then cooled to 0° C. The solid was filtered and washed with ethylacetate to afford the title compound (D17) (510 mg) as a yellow solid.