Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([OH:20])[C:5]=1[O:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].[CH2:30](I)[CH3:31]>C(#N)C>[F:23][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([O:20][CH2:30][CH3:31])[C:5]=1[O:21][CH3:22]
Reactant: COc1c(OC(F)F)ccc(-c2ccc3c(c2)COC3=O)c1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1c(-c2ccc3c(c2)COC3=O)ccc(OC(F)F)c1OC
Temperature: 70 °C
Yield: 57.1 %

Procedure:
To a stirring solution of 5-(4-(difluoromethoxy)-2-hydroxy-3-methoxyphenyl)isobenzofuran-1(3H)-one (80 mg, 0.25 mmol) in acetonitrile (10 mL) was added potassium carbonate (103.5 mg, 0.75 mmol) and ethyl iodide (0.1 mL, 0.75 mmol) and the resultant reaction mixture was heated to 70° C. for 3 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-30% ethyl acetate in pet ether) to afford title compound as a solid (50 mg, 58%).
Reaction SMILES: [CH:1]1([CH:6]=[C:7]([C:22]2[NH:30][C:25]3=[N:26][CH:27]=[CH:28][CH:29]=[C:24]3[CH:23]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH2:17][CH2:18][O:19][CH2:20][CH3:21])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].CO>[CH:1]1([CH2:6][CH:7]([C:22]2[NH:30][C:25]3=[N:26][CH:27]=[CH:28][CH:29]=[C:24]3[CH:23]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH2:17][CH2:18][O:19][CH2:20][CH3:21])(=[O:15])=[O:16])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOCCS(=O)(=O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3[nH]2)cc1
Agent: [Pd]
Solvent: CO
Product: CCOCCS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cccnc3[nH]2)cc1
Temperature: 50 °C
Yield: 75.2 %

Procedure:
A mixture of 2-{2-cyclopentyl-1-[4-(2-ethoxy-ethanesulfonyl)-phenyl]-vinyl}-1H-pyrrolo[2,3-b]pyridine (900 mg, 2.12 mmol) and 10% palladium on activated carbon (270 mg) in methanol (300 mL) was heated at 50° C. under hydrogen (50 psi) for 16 h. The mixture was cooled to 25° C., the solids filtered off, washed with ethyl acetate and concentrated in vacuo. Purification using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-{2-cyclopentyl-1-[4-(2-ethoxy-ethanesulfonyl)-phenyl]-ethyl}-1H-pyrrolo[2,3-b]pyridine (680 mg, 75%): LC/MS m/e calcd for C24H30N2O3S [M+H]+ 427.58, observed 427.4; 1H NMR (400 MHz, CD3OD) δ ppm 8.08-8.15 (m, 1H), 7.86-7.94 (m, 3H), 7.62 (d, J=8.3 Hz, 2H), 7.07 (dd, J=7.7, 4.9 Hz, 1H), 6.41 (s, 1H), 4.34 (t, J=7.8 Hz, 1H), 3.75 (t, J=5.8 Hz, 2H), 3.48 (t, J=5.7 Hz, 2H), 3.28 (q, J=7.0 Hz, 2H), 2.26-2.35 (m, 1H), 2.07-2.20 (m, 1H), 1.62-1.89 (m, 5H), 1.46-1.57 (m, 2H), 1.19-1.33 (m, 2H), 0.86 (t, J=6.9 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([OH:13])=O)=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.Cl.[CH2:53]([O:55][C:56](=[O:59])[CH2:57][NH2:58])[CH3:54]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([NH:58][CH2:57][C:56]([O:55][CH2:53][CH3:54])=[O:59])=[O:13])=[CH:6][CH:7]=1
Reactant: CC(C)(CC(=O)O)Nc1ccc(Cl)cc1
Reactant: CCOC(=O)CN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)CC(C)(C)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
To a solution of 3-(4-chlorophenylamino)-3-methylbutanoic acid (1 g, 4.7 mmol) in CH2Cl2 (20 mL), was added BOP (2.07 g, 4.7 mmol), DIPEA (1.63 mL, 9.4 mmol) and glycine ethyl ester hydrochloride (0.79 g, 4.7 mmol). The mixture was stirred at rt overnight. The reaction was quenched with aq. NaHCO3, extracted with CH2Cl2, and the combined organic extracts were dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography using 0-30% EtOAc in hexanes as eluent to give ethyl 2-(3-(4-chlorophenylamino)-3-methylbutanamido)acetate (1.34 g, 96% yield) as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:27])[CH2:11][CH2:12][C:13]1[N:14]=[C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([OH:26])[CH:19]=2)[O:16][CH:17]=1)[CH3:2].Br[CH:29]([CH3:31])[CH3:30].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:27])[CH2:11][CH2:12][C:13]1[N:14]=[C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH:29]([CH3:31])[CH3:30])[CH:19]=2)[O:16][CH:17]=1)[CH3:2]
Reactant: CC(C)Br
Reactant: CCOc1ccccc1C(=O)CCc1coc(-c2ccc(OC)c(O)c2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOc1ccccc1C(=O)CCc1coc(-c2ccc(OC)c(OC(C)C)c2)n1
Reaction time: 8 h

Procedure:
A 5.0 g quantity of 1-(2-ethoxyphenyl)-3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]propan-1-one obtained in Example 101 was dissolved in 50 ml of dimethylformamide, 3.35 g of 2-bromopropane and 5.63 g of potassium carbonate were added thereto, and stirring was conducted overnight at room temperature. Water was added to the obtained mixture, ethyl acetate extraction was performed, followed by drying over anhydrous magnesium sulfate and distilling the solvent off. The residue was subjected to silica gel column purification (n-hexane:ethyl acetate=4:1), and the obtained crude crystals were recrystallized using ethanol, thereby yielding 2.99 g of white powdery 1-(2-ethoxyphenyl)-3-[2-(3-isopropoxy-4-methoxyphenyl)oxazol-4-yl]propan-1-one.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[CH2:37]([O:36][C:34]([N:2]1[CH2:6][CH2:5][C@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1)=[O:35])[CH3:38]
Reactant: CCOC(=O)Cl
Reactant: O=C(N[C@H]1CCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Agent: Cl
Product: CCOC(=O)N1CC[C@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (S)-pyrrolidin-3-ylamide hydrochloride (example A143) and ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19](O)=O)=[CH:11][CH:10]=1)#[N:8].C[N:23](C=O)C>ClCCCl>[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH2:23])=[CH:11][CH:10]=1)#[N:8]
Reactant: N#Cc1ccc(CCCCC(=O)O)cc1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Product: N#Cc1ccc(CCCCCN)cc1
Temperature: 10 °C
Reaction time: 0.08 h

Procedure:
Oxalyl chloride (43.0 mL, 0.492 mol) was added dropwise to a suspension of 5-(p-cyanophenyl)pentanoic acid in 100 mL of dry 1,2-dichloroethane at 23° C. under a nitrogen atmosphere. After 5 min, 50 mL of DMF was added. After 30 min, the reaction was concentrated in vacuo. The residue was dissolved in anhydrous THF (150 mL) under a nitrogen atmosphere. Azidotrimethylsilane (14.6 mL, 0.110 mL) was added dropwise at 23° C. After 5 min, the reaction was warmed to achieve reflux for 1 hour. The reaction was cooled to 10° C. and concentrated HCl (20 mL) was added over 1 min. The cooling bath was removed and stirring was continued for 15 min. The reaction was concentrated in vacuo and the residue was partitioned between ethyl acetate (200 mL) and water (200 mL). The aqueous layer was basified with 1N NaOH (250 mL) and extracted with ethyl acetate (2×200 mL). The organic layer was washed with water (100 mL) followed by brine (100 mL), and dried (Na2SO4). After concentration in vacuo, the residue was diluted with ethyl acetate:methanol (150 mL:5 mL) and treated with anhydrous HCl in dioxane (6.9N) at 0° C. The resultant precipitate was filtered, washed with ethyl acetate then ether. The solid was dried (atmospheric pressure; 55° C.) to afford 14.3 g: m.p. 155°-160° C.
Reaction SMILES: O.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.CN(C)C=O.C(Cl)(=O)C([Cl:21])=O>C1(C)C=CC=CC=1>[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([Cl:21])=[O:12])=[CH:5][CH:4]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 90 %

Procedure:
Into a 1-L three-neck flask equipped with a mechanical stirrer, an addition funnel, and a nitrogen bubbler vented to a water scrubber was placed 60.0 g (0.389 mol) of 4-fluorophenylacetic acid, 0.18 g, 0.002 mol) of N,N-dimethylformamide and 250 g of toluene. The addition funnel was charged with 50.4 g (0.397 mol) of oxalyl chloride and added to the reaction mixture over a 10 minute period resulting in gas evolution (4.7° C. exotherm was observed). The reaction mixture was stirred at ambient temperature for 2.5 hours (gas evolution complete) and the head space of the reaction flask was sparged with nitrogen for 10 minutes before storing the material. HPLC assay of the solution indicated that 19.1 wt % of the solution was 4-fluoroacetyl chloride, thus affording a 99% yield. Purification of crude 4-fluorophenylacetyl chloride by vacuum distillation (57-58° C., 0.15 mm Hg) affords 4-fluorophenylacetyl chloride as a clear liquid in 90% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])[CH3:2].[NH2:13][C:14]1[C:15]([C:20]([NH2:22])=[O:21])=[N:16][CH:17]=[CH:18][CH:19]=1>>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH:13][C:14]1[C:15]([C:20]([NH2:22])=[O:21])=[N:16][CH:17]=[CH:18][CH:19]=1)=[O:7])[CH3:2]
Reactant: NC(=O)c1ncccc1N
Reactant: CCOc1ccccc1C(=O)Cl
Product: CCOc1ccccc1C(=O)Nc1cccnc1C(N)=O

Procedure:
The title compound was prepared from 2-ethoxybenzoyl chloride and 3-aminopyridine-2-carboxamide (J. Chem. Soc., 1956, 1045) following the procedure of Preparation 7 and was obtained as an off-white solid (100%), m.p. 172-177° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[N:5][N:6]([CH3:8])[CH:7]=1.[CH2:9]([S-:11])[CH3:10].[Na+]>CN(C)C=O>[CH2:9]([S:11][CH2:2][C:3]1[CH:4]=[N:5][N:6]([CH3:8])[CH:7]=1)[CH3:10]
Reactant: Cn1cc(CCl)cn1
Reactant: CC[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCSCc1cnn(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
A mixture of 4-(chloromethyl)-1-methyl-1H-pyrazole (2.0 g, 15 mmol) (prepared according to Intermediate 5 Step A) and sodium ethanethiolate (2.6 g, 31 mmol) in N,N-dimethylformamide (20.0 mL) was stirred at room temperature overnight. The reaction mixture was quenched with brine and extracted with EtOAc (3×). The combined extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to give an oil residue which was purified by combi-flash chromatography eluted with 20% EtOAc in hexane to give 1.9 g (79% yield) of the desired product. LC-MS found: 157.1 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=1.[O-:15][C:16]#[N:17].[Na+].FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:16]([NH2:17])=[O:15])[CH:9]=1
Reactant: N#C[O-]
Reactant: Cn1cccc1Cc1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccccc1
Product: Cn1cccc1Cc1cccc(NC(N)=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
To a stirred solution of 4.4 g (23 mmol) of 1-methyl-2-(3'-aminobenzyl)pyrrole in 400 ml of benzene there were added 3.08 g (47 mmol) of sodium cyanate followed by the dropwise addition of a solution of 3.65 ml (47 mmol) of trifluoroacetic acid in 300 ml of benzene. When the addition was completed, the reaction mixture was stirred at room temperature for 1 hour further and then poured into 500 ml of saturated sodium carbonate solution. The organic phase was separated and the aqueous layer extracted with ethyl acetate (3×500 ml). The combined extracts were washed with water (1×500 ml), dried and evaporated under reduced pressure. The residue was purified by column chromatography on 500 g of silica gel, using methylene chloride-acetone (80:20) as eluant, thus obtaining 5.1 g (90%) of the title compound, 1-methyl-2-(3'-ureidobenzyl)pyrrole, which was recrystallized from acetone-hexane.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[N:24]=[C:25]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[O:38][C:39]([F:42])([F:41])[F:40])[O:26][C:27]=3[C:28]([F:31])([F:30])[F:29])=[O:22])=[CH:16][N:15]=2)[CH2:9]1)=[O:7])(C)(C)[CH3:2].FC(F)(F)C(O)=O.ClC(OCC)=O.C(N(CC)CC)C>>[CH2:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[N:24]=[C:25]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[O:38][C:39]([F:42])([F:41])[F:40])[O:26][C:27]=3[C:28]([F:29])([F:30])[F:31])=[O:22])=[CH:16][N:15]=2)[CH2:9]1)=[O:7])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2ccc(NC(=O)c3nc(-c4ccccc4OC(F)(F)F)oc3C(F)(F)F)cn2)C1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N1CC[C@H](Nc2ccc(NC(=O)c3nc(-c4ccccc4OC(F)(F)F)oc3C(F)(F)F)cn2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 42.7 %

Procedure:
To a flask containing (S)-3-(5-{[2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole-4-carbonyl]-amino}-pyridin-2-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester (150 mg, 0.249 mmol) was added trifluoroacetic acid (5 mL). When all the starting material was consumed, as indicated by TLC, the reaction mixture was concentrated to dryness. The residue was dissolved in dichloromethane (10 mL) and then cooled to 0° C. Ethyl chloroformate (24 μL, 0.249 mmol) and triethylamine (75.5 mg, 0.747 mmol) were added dropwise, and the reaction mixture was stirred for 2 h at room temperature and then concentrated. The crude product was purified by flash chromatography (Merck silica gel 60, 230-400 mesh, gradient elution with 0%-100% ethyl acetate in hexane) to give (S)-3-(5-{[2-(2-trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole-4-carbonyl]-amino}-pyridin-2-ylamino)-pyrrolidine-1-carboxylic acid ethyl ester (61 mg, 42.7% yield) as a light yellow solid. LCMS for C24H21F6N5O5 calculated (m/e) 573.46, found 574.15 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:19])=[O:18])=[CH:13][CH:12]=2)O)=[CH:4][CH:3]=1.C(N(S(F)(F)[F:32])CC)C.C(=O)([O-])O.[Na+]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([F:32])[C:11]2[CH:16]=[CH:15][C:14]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc(C(O)Cc2ccc(F)cc2)cc1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)c1ccc(C(F)Cc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-(4-Fluorophenyl)-1-[4-(phenylsulfonyl)phenyl]ethanol (Example 118, 100 mg, 0.28 mmol) was dissolved in dichloromethane (5 mL) and (diethylamino)sulfur trifluoride (0.05 mL, 0.32 mmol) added. The reaction was stirred at room temperature for 30 minutes. Saturated sodium hydrogencarbonate was added and the products extracted into ethyl acetate. The organic layer was dried over MgSO4 and evaporated. The residue was triturated with diethyl ether/isohexane to give the title compound as a beige solid. δH (360 MHz, CDCl3): 7.94-7.90 (4H, m), 7.58-7.48 (3H, m), 7.35 (2H, d, J=8.5 Hz), 7.08-7.00 (2H, m), 6.96-6.90 (2H, m), 5.69-5.53 (1H, m), 3.21-2.99 (2H, m).
Reaction SMILES: [C:1]([C:5]1[CH:20]=[CH:19][C:8]([C:9]([NH:11][C:12]2[C:13]([NH2:18])=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>C(Cl)Cl.CCOCC.O1CCCC1>[C:1]([C:5]1[CH:20]=[CH:19][C:8]([C:9]([NH:11][C:12]2[C:13]([NH:18][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][C:22]([Cl:21])=[CH:23][CH:24]=3)=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(C(=O)Nc2ccccc2N)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C(=O)Nc2ccccc2NC(=O)c2ccc(Cl)cc2)cc1
Reaction time: 0.5 h
Yield: 66.4 %

Procedure:
To a solution of N1-(4-tert-butylbenzoyl)-1,2-benzenediamine (100 mg, 0.37 mmol) in 3 mL methylene chloride was added 4-chlorobenzoyl chloride (95 μL, 0.74 mmol) and excess potassium carbonate. The mixture was stirred 30 min then a 1:1 solution of tetrahydrofuran and 5 N NaOH was added. The resultant mixture was stirred an additional 20 min and diluted with ether. The mixture was washed twice with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was sonicated with hexane causing a precipitate to form which was collected by filtration and dried under vacuum to yield 100 mg (66%) of the title compound.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].FC(F)(F)C(O)=O.[NH2:22][C:23]1[C:24]([C:28]2[N:32]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[C:35]([Br:40])[CH:34]=3)[C:31](=[O:41])[O:30][N:29]=2)=[N:25][O:26][N:27]=1.[CH2:42]([N:45]([S:53]([N:56]([CH2:60][CH:61]=[CH2:62])[CH2:57][CH:58]=O)(=[O:55])=[O:54])[C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])[CH:43]=[CH2:44].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[CH2:42]([N:45]([S:53](=[O:55])(=[O:54])[N:56]([CH2:60][CH:61]=[CH2:62])[CH2:57][CH2:58][NH:22][C:23]1[C:24]([C:28]2[N:32]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[C:35]([Br:40])[CH:34]=3)[C:31](=[O:41])[O:30][N:29]=2)=[N:25][O:26][N:27]=1)[C:46](=[O:52])[O:47][C:48]([CH3:49])([CH3:51])[CH3:50])[CH:43]=[CH2:44]
Reactant: C=CCN(CC=O)S(=O)(=O)N(CC=C)C(=O)OC(C)(C)C
Reactant: Nc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: C=CCN(CCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1)S(=O)(=O)N(CC=C)C(=O)OC(C)(C)C
Temperature: -5 °C
Reaction time: 0.17 h
Yield: 14.8 %

Procedure:
To a 50-mL flask was added sodium triacetoxyborohydride (1.06 g, 5.0 mmol, 1.0 equiv.), trifluoroacetic acid (TFA, 2.0 mL, 26 mmol) and tetrahydrofuran (THF, 1.0 mL) at ambient temperature. This mixture was cooled to −5° C. under N2 and stirred at 0-5° C. for 10 min. To this solution was added 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (0.171 g, 5.0 mmol; Step D) and tert-butyl allyl{[allyl(2-oxoethy)amino]sulfonyl}carbamate (0.398 g, 2.5 mmol, 0.5 equiv.) in THF (1.5 mL) drop-wise at 0-5° C. over 5 min. The resulting reaction mixture was stirred under N2 at 0-5° C. At 20 min, 40 min, and 2.5 h time points, a solution of tert-butyl allyl{[allyl(2-oxoethy)amino]sulfonyl}carbamate (0.040 g, 0.125 mmol, 0.25 equiv.) in THF (0.20 mL) was added drop-wise at 0-5° C. At 2.5 h, a solution of sodium triacetoxyborohydride (0.211 g, 1.0 mmol, 0.2 equiv.) in trifluoroacetic acid (TFA, 1.5 mL, 9.5 mmol) was added at 0-5° C. The reaction was warmed to room temperature and stirred overnight. The reaction mixture was then poured into an ice-cold saturated solution of sodium carbonate (50 mL) and extracted with dichloromethane (3×20 mL). The combined dichloromethane extracts were washed with brine, dried over sodium sulfate, and concentrated. The residue was then purified on silica gel (0-75% ethyl acetate/hexane gradient elution) to give the desired product (0.239 g, 74.2%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.07 (m, 1H), 7.71 (m, 1H), 7.58 (t, 1H, J=8.7 Hz), 6.62 (m, 1H), 5.77 (m, 2H), 5.19 (m, 4H), 4.17 (m, 2H), 3.89 (m, 2H), 3.44 (m, 2H), 3.38 (m, 2H), 1.42 (s, 9H); C23H27BrFN7O7S (MW 644.47), LCMS (EI) m/e 544/546 (M+-Boc+H).
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7](O)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].B.C1COCC1>C1COCC1.[Cl-].[Na+].O>[C:10]([NH:1][C@H:2]([CH2:7][OH:8])[CH2:3][CH:4]([CH3:5])[CH3:6])([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: B
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: 23 °C
Reaction time: 3 h
Yield: 89.1 %

Procedure:
To a solution of BOC-Leu-OH (15.09 g, 65 mmol, 1 equiv) in THF (150 mL) at 0° C. was added BH3•THF (163 mL of a 1.0 M solution in THF, 163 mmol, 2.51 equiv). The reaction mixture was stirred at 23° C. for 3 h and then cooled to 0° C. Brine (100 mL) was added carefully, and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography (gradient elution, 25→35% EtOAc in hexanes) to afford BOC-L-Leucinol as a colorless oil (12.59 g, 89%): IR (cm−1) 3434, 1699, 1256, 739; 1H NMR (CDCl3) δ 0.93 (dd, 6H, J=6.6, 1.5), 1.29-1.31 (m, 2H), 1.45 (s, 9H), 1.60-2.05 (m, 2H), 3.47-3.53 (m, 1H), 3.65-3.72 (m, 2H), 4.56 (s, br, 1H); Anal. (C11H23NO3) C, H, N.
Reaction SMILES: C1(C)C=CC(S(O[C:11]2[N:16]=[C:15]([NH:17][C:18]([O:20][CH3:21])=[O:19])[N+:14]([O-:22])=[C:13]([NH:23][C:24]([O:26][CH3:27])=[O:25])[CH:12]=2)(=O)=O)=CC=1.[NH:29]1[CH2:34][CH2:33][CH:32]=[CH:31][CH2:30]1>C(Cl)(Cl)Cl.C(Cl)Cl>[N:29]1([C:11]2[N:16]=[C:15]([NH:17][C:18]([O:20][CH3:21])=[O:19])[N+:14]([O-:22])=[C:13]([NH:23][C:24]([O:26][CH3:27])=[O:25])[CH:12]=2)[CH2:30][CH:31]=[CH:32][CH2:33][CH2:34]1
Reactant: COC(=O)Nc1cc(OS(=O)(=O)c2ccc(C)cc2)nc(NC(=O)OC)[n+]1[O-]
Reactant: C1=CCNCC1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COC(=O)Nc1cc(N2CC=CCC2)nc(NC(=O)OC)[n+]1[O-]

Procedure:
1.0 g of dimethyl 6-[(p-tolylsulfonyl)oxy]-2,4-pyrimidinedicarbamate-3-oxide is dissolved in 20 ml of chloroform and the solution is heated at reflux with 1 ml of 1,2,5,6-tetrahydropyridine. The cooled mixture is diluted with methylene chloride and washed with water. The organic phase is dried over sodium sulfate and concentrated. The residue is recrystallized from methylene chloride and methanol, there being obtained pure dimethyl 6-[3,6-dihydro-1(2H)-pyridyl]-2,4-pyrimidinedicarbamate-3-oxide of melting point 185°-187°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:15][O:16][C:17](=[O:28])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:1]([O:5][C:6](=[O:14])[C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][C:17]([O:16][CH3:15])=[O:28])=[CH:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1ccc(O)cc1
Reactant: COC(=O)CCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)CCCCCCCCCOc1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Yield: 89.8 %

Procedure:
4-Hydroxy-benzoic acid tert-butyl ester (500 mg, 2.57 mmol) and 10-bromodecanoic acid methyl ester (683 mg, 2.57 mmol) were dissolved in acetonitrile, and K2CO3 (712 mg, 5.15 mmol) was added. The mixture was refluxed under nitrogen for 16 h, and cooled to rt. The solids were filtered off, and the filtrate concentrated under vacuum. The resulting residue was dissolved in AcOEt (50 ml) and water (25 mL). The phases were separated and the organic phase was dried over MgSO4 and concentrated to yield a colorless oil (874 mg, 90% yield).