Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:45])[C@H:9]([CH2:41][CH:42]([CH3:44])[CH3:43])[NH:10][C:11](=[O:40])[CH:12]([CH2:21][P:22]([CH2:25][CH2:26][CH2:27][CH2:28][N:29]2[C:37](=[O:38])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]2=[O:39])([OH:24])=[O:23])[CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+](=[CH2:48])=[N-].C(O)(=O)C>ClCCl>[C:1]1([NH:7][C:8](=[O:45])[C@H:9]([CH2:41][CH:42]([CH3:43])[CH3:44])[NH:10][C:11](=[O:40])[CH:12]([CH2:21][P:22]([CH2:25][CH2:26][CH2:27][CH2:28][N:29]2[C:37](=[O:38])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]2=[O:39])([O:24][CH3:48])=[O:23])[CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)C[C@H](NC(=O)C(CCc1ccccc1)CP(=O)(O)CCCCN1C(=O)c2ccccc2C1=O)C(=O)Nc1ccccc1
Reactant: C=[N+]=[N-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COP(=O)(CCCCN1C(=O)c2ccccc2C1=O)CC(CCc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)Nc1ccccc1
Reaction time: 0.17 h

Procedure:
A mixture of dichloromethane (100 mL) and (2-(((4-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)butyl)hydroxyphosphinyl)methyl)-4-phenylbutanoyl)-L-leucine N-phenylamide (2.00 g, 3.17 mmol) from Example 1 was warmed to give a clear solution which was then cooled in an ice bath. Diazomethane (0.3M solution in ether) was added until the yellow color persisted and the solution was stired 10 min longer. Glacial acetic acid (0.080 mL, 84 mg, 1.4 mmol) was added to give a colorless solution which was concentrated under vacuum. Methanol (100 mL) was added and the solution was evaporated again and dried under vacuum to give 2.09 g of crude product which was used in the next reaction without further purification.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][CH2:11][CH2:12][N:13]=2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[NH:13][CH:12]=[CH:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: CSc1ccc(C2=NCCN2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CSc1ccc(-c2ncc[nH]2)cc1
Temperature: 70 °C

Procedure:
To a solution of 2-(4-(methylthio)phenyl)-4,5-dihydro-1H-imidazole (2-Im-1, 9.6 g, 1.0 eq) in 100 mL of DMSO, DIB (1.1 eq) and K2CO3 (1.1 eq) were added. The mixture was heated to 70° C. overnight, then extracted with EtOAc and the organic layer was concentrated to provide 2-(4-(methylthio)phenyl)-1H-imidazole (compound 3-Im-1).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]([O:28][C:29]([F:32])([F:31])[F:30])[CH:12]=[C:13]3[C:18]=2[O:17][CH:16]([C:19]([F:22])([F:21])[F:20])[C:15]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:14]3)O1.[OH:34]O.[OH-].[Na+].Cl>C1COCC1.[Cl-].[Na+].O>[OH:34][C:9]1[CH:10]=[C:11]([O:28][C:29]([F:30])([F:31])[F:32])[CH:12]=[C:13]2[C:18]=1[O:17][CH:16]([C:19]([F:21])([F:20])[F:22])[C:15]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:14]2
Reactant: OO
Reactant: CCOC(=O)C1=Cc2cc(OC(F)(F)F)cc(B3OC(C)(C)C(C)(C)O3)c2OC1C(F)(F)F
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C1=Cc2cc(OC(F)(F)F)cc(O)c2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 91 %

Procedure:
To a solution of ethyl 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylate prepared as in Step 1 (600 mg, 1.24 mmole) in THF (20. mL) was added 30% H2O2 (192uL, 1.86 mmole) and aqueous NaOH (500 uL-2.5 N, 1.25 mmole) at 0° C. and the mixture was allowed to warm to room temperature. After stirring for 3.5 hrs, the mixture was acidified with 1N HCl, brine (50 mL) was added and the mixture was extracted with EtOAc (200 mL). The extract was dried over MgSO4, filtered and concentrated in vacuo to give a yellow crystalline solid. The crude product was purified by silica chromatography (0%-25% EtOAc in hexanes) to give 422 mg (91% yield) of the product as an off-white solid: EIHRMS m/z 372.0421 (M+, C14H10F6O5, Calc'd 372.0432).
Reaction SMILES: Cl.[F:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][C@H:8]2[CH2:12][NH:11][C@H:10]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)=[CH:18][CH:17]=3)=[O:14])[CH2:9]2)=[CH:5][CH:4]=1.[N:32]1[N:33]([CH2:37][C:38](O)=[O:39])[N:34]=[CH:35][CH:36]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[N:32]1[N:33]([CH2:37][C:38]([N:11]2[CH2:12][C@H:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([F:2])=[CH:31][CH:30]=3)[CH2:9][C@H:10]2[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)=[O:14])=[O:39])[N:34]=[CH:35][CH:36]=1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(F)cc2)CN1
Reactant: O=C(O)Cn1nccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(F)cc2)CN1C(=O)Cn1nccn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.3 %

Procedure:
A round bottom flask was charged with (2S,4R)-4-(4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide hydrochloride (150 mg, 0.37 mmole, 1 eq), prepared as in Reference 6, 2H-1,2,3-triazole-2-ylacetic acid (51 mg, 0.40 mmole, 1.1 eq), HATU (152 mg, 0.40 mmole, 1.1 eq) and DMF (1 mL). DIEA (195 μL, 1.11 mmole, 3 eq) was added and the mixture stirred at ambient temperature for 18 hours. The reaction mixture was partitioned between ethyl acetate and deionized water. The aqueous layer was separated and extracted twice with ethyl acetate. The combined organics were washed with 5% lithium chloride (3×5 mL), 1N sodium bicarbonate (2×5 mL) and then deionized water (2×5 mL) and concentrated in vacuo. Product was purified from the residue via flash chromatography (silica, 5% MeOH, 95% EtOAc). Clean fractions were combined and concentrated in vacuo to afford Compound 50, (2S,4R)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-4-(4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (171 mg, 89% yield), as a white solid. Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 9.97 (s, 1H), 7.80 (s, 2H), 7.58-7.51 (m, 2H), 7.34-7.07 (m, 6H), 7.04-6.90 (m, 4H), 5.48 (q, 2H), 4.53-4.46 (m, 1H), 3.85-3.76 (m, 1H), 2.77-2.61 (m, 3H), 2.03-1.86 (m, 2H). MS (EI) for C28H25F2N5O3. found 517.9 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[C:13]([CH3:19])=[N:14][N:15]([CH3:18])[C:16]=3[CH3:17])[N:7]([CH2:20][CH2:21][CH2:22][C:23](OCC)=[O:24])[C:6]=2[C:5]([CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:4][CH:3]=1.[BH4-].[Li+].O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[C:13]([CH3:19])=[N:14][N:15]([CH3:18])[C:16]=3[CH3:17])[N:7]([CH2:20][CH2:21][CH2:22][CH2:23][OH:24])[C:6]=2[C:5]([CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCn1c(Nc2c(C)nn(C)c2C)nc2c(Cl)ccc(C(CC)CC)c21
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCC(CC)c1ccc(Cl)c2nc(Nc3c(C)nn(C)c3C)n(CCCCO)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.7 %

Procedure:
To a solution of ethyl 4-{4-chloro-7-(1-ethylpropyl)-2-[(1,3,5-trimethyl-1H-pyrazol-4-yl)amino]-1H-benzimidazol-1-yl}butanoate (240 mg, 0.52 mmol) in tetrahydrofuran (3 mL) was added lithium borohydride (34 mg, 1.57 mmol) portionwise at 0° C. The mixture was warmed to room temperature and stirred for 16 hr. Water was added and the mixture was extracted with ethyl acetate. Organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 0-10% methanol/ethyl acetate gradient mixture. The filtrate was concentrated in vacuo to give the title compound (74 mg, 0.17 mmol, 34%) as a colorless amorphous.
Reaction SMILES: [N+](=[CH:3][Si](C)(C)C)=[N-].[F:8][C:9]1[CH:10]=[C:11]([NH:20][C:21]([C@@H:23]2[N:32]([C:33]([C@@H:35]3[CH2:38][C@H:37]([CH2:39][C:40]([OH:42])=[O:41])[CH2:36]3)=[O:34])[CH2:31][CH2:30][C:29]3[N:28]=[C:27]([O:43][CH3:44])[CH:26]=[CH:25][C:24]2=3)=[O:22])[CH:12]=[C:13]2[C:17]=1[C:16]([CH3:19])([CH3:18])[CH2:15][CH2:14]2.O.C(OCC)(=O)C>C1COCC1.CO>[F:8][C:9]1[CH:10]=[C:11]([NH:20][C:21]([C@@H:23]2[N:32]([C:33]([C@@H:35]3[CH2:38][C@H:37]([CH2:39][C:40]([O:42][CH3:3])=[O:41])[CH2:36]3)=[O:34])[CH2:31][CH2:30][C:29]3[N:28]=[C:27]([O:43][CH3:44])[CH:26]=[CH:25][C:24]2=3)=[O:22])[CH:12]=[C:13]2[C:17]=1[C:16]([CH3:19])([CH3:18])[CH2:15][CH2:14]2
Reactant: COc1ccc2c(n1)CCN(C(=O)[C@H]1C[C@@H](CC(=O)O)C1)[C@H]2C(=O)Nc1cc(F)c2c(c1)CCC2(C)C
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C[C@H]1C[C@@H](C(=O)N2CCc3nc(OC)ccc3[C@@H]2C(=O)Nc2cc(F)c3c(c2)CCC3(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.2 %

Procedure:
(Diazomethyl)trimethylsilane (0.6M hexane solution) (0.392 mL, 0.24 mmol) was added to a mixture of (cis-3-(((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6 (5H)-yl)carbonyl)cyclobutyl)acetic acid (60 mg, 0.12 mmol) in THF (1 mL) and MeOH (1 mL) at 5° C., and the mixture was stirred at room temperature for 2 hr. To the reaction mixture were added water and ethyl acetate, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 5→50% ethyl acetate/hexane) to give the title compound (50 mg, 0.095 mmol, 81%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH:10]([C:14](N2CCOC2=O)=[O:15])[CH2:11][CH:12]=O)[O:6][CH2:5][CH2:4][O:3]1.[CH2:22]([O:24][C:25](=[O:38])[CH2:26][C@H:27]([NH2:37])[C:28]1[CH:36]=[CH:35][C:31]2[CH2:32][CH2:33][O:34][C:30]=2[CH:29]=1)[CH3:23].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CCN(CC)CC>ClC(Cl)C.C(OCC)(=O)C>[CH2:22]([O:24][C:25](=[O:38])[CH2:26][C@@H:27]([C:28]1[CH:36]=[CH:35][C:31]2[CH2:32][CH2:33][O:34][C:30]=2[CH:29]=1)[N:37]1[CH2:12][CH2:11][CH:10]([CH2:9][CH2:8][CH2:7][C:2]2([CH3:1])[O:6][CH2:5][CH2:4][O:3]2)[C:14]1=[O:15])[CH3:23]
Reactant: CCOC(=O)C[C@H](N)c1ccc2c(c1)OCC2
Reactant: CC1(CCCC(CC=O)C(=O)N2CCOC2=O)OCCO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@@H](c1ccc2c(c1)OCC2)N1CCC(CCCC2(C)OCCO2)C1=O
Reaction time: 48 h

Procedure:
A mixture of 2-5 (440 mg, 1.6 mmol), 3-6 (400 mg, 1.5 mmol), Na(OAc)3BH (469 mg, 2.25 mmol) and NEt3 (0.41 mL, 3.0 mmol) in dichloroethane (10 mL) was stirred for 48 h. The mixture was diluted with ethyl acetate, washed with sat. NaHCO3, brine, and dried over MgSO4. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 50:35:14:1 hexanes/chloroform/ethyl acetate/MeOH) to give 4-1 as a white solid.
Reaction SMILES: C(OC([N:8]1[CH:13]([C:14]2[NH:15][C:16]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:29]5[CH:34]=[CH:33][C:32]([C:35]6[NH:36][C:37]([CH:40]7[CH2:46][C:43]8([CH2:45][CH2:44]8)[CH2:42][N:41]7[C:47](=[O:57])[CH:48]([NH:52][C:53]([O:55][CH3:56])=[O:54])[CH:49]([CH3:51])[CH3:50])=[N:38][CH:39]=6)=[CH:31][CH:30]=5)[CH:25]=4)[CH:20]=3)=[CH:17][N:18]=2)[CH:12]2[CH2:58][CH:9]1[CH2:10][CH2:11]2)=O)(C)(C)C.Cl.[CH:60]1([CH:63]([NH:67][C:68]([O:70][CH3:71])=[O:69])[C:64]([OH:66])=O)[CH2:62][CH2:61]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CO.C(Cl)Cl>[CH3:56][O:55][C:53](=[O:54])[NH:52][CH:48]([C:47]([N:41]1[CH:40]([C:37]2[NH:36][C:35]([C:32]3[CH:33]=[CH:34][C:29]([C:24]4[CH:23]=[CH:22][C:21]5[C:26](=[CH:27][CH:28]=[C:19]([C:16]6[NH:15][C:14]([CH:13]7[CH:12]8[CH2:58][CH:9]([CH2:10][CH2:11]8)[N:8]7[C:64](=[O:66])[CH:63]([CH:60]7[CH2:61][CH2:62]7)[NH:67][C:68]([O:70][CH3:71])=[O:69])=[N:18][CH:17]=6)[CH:20]=5)[CH:25]=4)=[CH:30][CH:31]=3)=[CH:39][N:38]=2)[CH2:46][C:43]2([CH2:45][CH2:44]2)[CH2:42]1)=[O:57])[CH:49]([CH3:51])[CH3:50]
Reactant: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6C7CCC(C7)N6C(=O)OC(C)(C)C)[nH]5)ccc4c3)cc2)[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)O)C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CO
Product: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6C7CCC(C7)N6C(=O)C(NC(=O)OC)C6CC6)[nH]5)ccc4c3)cc2)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.6 %

Procedure:
To a slurry of 3-{5-[6-(4-{2-[5-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (0.05 g, 0.06 mmol) in MeOH (0.1 mL) was added HCl in dioxanes (4 M, 0.6 mL). The resulting solution was stirred at room temperature for 1 hour and the concentrated to dryness. Cyclopropyl-methoxycarbonylamino-acetic acid (0.02 g, 0.09 mmol, 1.5 equiv.) and CH2Cl2 (0.6 mL) were then added, followed by HATU (0.03 g, 0.08 mmol, 1.25 equiv.) and NMM (0.05 mL, 0.45 mmol, 5 equiv.). The resulting solution was stirred at room temperature for 18 hours. The reaction mixture was concentrated and purified by preparative HPLC (Gemini, 15-40% MeCN in H2O (0.1% formic acid)) and lyophilized to provide [1-(6-{5-[4-(6-{2-[2-(2-Cyclopropyl-2-methoxycarbonylamino-acetyl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.03 g, 49%) as a white powder. LCMS-ESI+: calc'd for C48H54N8O6: 838.4 (M+); Found: 839.9 (M+H+). 1H-NMR: 400 MHz, (CDCl3) δ: (mixture of rotomers) 8.22 (s, 2H), 7.81-7.96 (m, 10H), 7.63 (d, 1H), 7.29 (d, 1H), 5.18 (t, 1H), 4.56 (d, 1H), 3.96 (t, 1H), 3.74 (m, 1H), 3.51 (s, 6H), 3.12 (t, 1H), 2.48 (s, 1H), 1.93-2.29 (m, 6H), 1.58-1.77 (m, 5H), 0.85 (d, 3H), 0.80 (d, 3H), 0.58 (m, 4H), 0.34 (m, 1H), 0.26 (m, 1H), 0.03 (m, 1H), −0.12 (m, 1H).
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.CC[O-].[Na+].[Na].[C:16]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>O.C(O)C.CCOCC>[CH2:18]([CH:17]([C:2](=[O:4])[C:1]([O:8][CH2:9][CH3:10])=[O:7])[C:16]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCCC(=O)OCC
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: CCCCC(C(=O)OCC)C(=O)C(=O)OCC

Procedure:
100 ml of ether, then 13.55 ml of diethyl oxalate were added to a solution of sodium ethylate prepared by stirring 2.3 g of sodium and 150 ml of ethanol at 40° C. for one hour. The mixture was refluxed for 15 minutes, cooled down slightly and 50 ml of ethyl caproate were added. The mixture was stirred at reflux for 3 hours and at 30° C. to 35° C. for 16 hours. 50 ml of water were added and the aqueous phase was separated by decanting, washed twice with ether and acidified with 2N hydrochloric acid. Extraction was carried out 3 times with ether and the combined organic phases were washed with water, then with a saturated solution of sodium chloride, dried and evaporated to dryness to obtain 9.5 g of the desired product which was used as is for the following step.
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]1[NH:8][C:7](=[O:9])[C@@H:6]1[C@H:10]([O:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH3:11])=[CH2:4].CO[C:25](OC)([CH3:27])[CH3:26].B(F)(F)F.CCOCC>ClCCl>[O:9]=[C:7]1[N:8]2[C@H:5]([C:3](=[CH2:4])[CH2:2][O:1][C:25]2([CH3:27])[CH3:26])[C@H:6]1[C@H:10]([O:12][C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14])[CH3:11]
Reactant: C=C(CO)[C@H]1NC(=O)[C@@H]1[C@@H](C)OC(=O)OCc1ccccc1
Reactant: COC(C)(C)OC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: C=C1COC(C)(C)N2C(=O)[C@H]([C@@H](C)OC(=O)OCc3ccccc3)[C@@H]12

Procedure:
A solution of (3S,4S)-4-(1-hydroxymethylethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-2-azetidinone (3.7 g) and 2,2-dimethoxypropane (1.45 g) in dry dichloromethane (26 ml) was treated with boron trifluoride-etherate (0.14 ml) at room temperature for 1.5 hours. The reaction mixture was washed successively with saturated sodium bicarbonate (15 and water (20 ml×2), and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate in vacuo gave an oily residue, which was purified by silica gel chromatography to yield (6S,7S)-8-oxo-2,2-dimethyl-5-methylidene-7-(1-(R)-benzyloxycarbonyloxyethyl)-3-oxa-1-azabicyclo[4.2.0]octane.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[C:7]([N+:12]([O-])=O)[CH:8]=[N:9]2)=[CH:4][CH:3]=1>C1COCC1.CO.[Ni]>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[C:7]([NH2:12])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cnc2cc(Cl)ccc2c1Nc1ccc(F)cc1
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cnc2cc(Cl)ccc2c1Nc1ccc(F)cc1

Procedure:
1.3 g (4.09 mmol) (7-chloro-3-nitro-quinolinyl)-(4-fluoro-phenyl)-amine (Example 15c) in 60 ml THF/MeOH 2:1 and 0.6 g Raney-Ni are hydrogenated at rt for 2 h. The reaction solution is filtered on Hyflo® Super Cel diatomaceous earth and is evaporated to dryness. The raw product is dissolved in 30 ml ethyl acetate, and ca. 400 ml hexane are added. The title compound precipitates and is collected by filtration. Drying follows at 65° C. over night. mp: 198-200° C.; MS: 288 (M++1); HPLC: tret=8.38 min (Grad 1).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]([NH:5][C:6]1[S:10][N:9]=[C:8]([S:11][CH3:12])[C:7]=1[C:13]#[N:14])=[O:4].[OH:16]O>>[CH3:15][N:2]([CH3:1])[C:3]([NH:5][C:6]1[S:10][N:9]=[C:8]([S:11]([CH3:12])=[O:16])[C:7]=1[C:13]#[N:14])=[O:4]
Reactant: OO
Reactant: CSc1nsc(NC(=O)N(C)C)c1C#N
Product: CN(C)C(=O)Nc1snc(S(C)=O)c1C#N

Procedure:
In the manner of Example II, 7.9 g of 1,1-dimethyl-3-(4-cyano-3-(methylthio)-5-isothiazolyl)urea was oxidized with 3.7 ml of 30% hydrogen peroxide to give 7.0 g of 1,1-dimethyl-3-(4-cyano-3-(methylsulfinyl)-5-isothiazolyl)urea, m.p. 178°-179°. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH3:12].C([Li])CCC.CCCCCC.[C:24](=[O:26])=[O:25]>O1CCCC1.O>[CH3:12][C:3]1[C:4]2[O:9][CH2:8][CH2:7][O:6][C:5]=2[CH:10]=[CH:11][C:2]=1[C:24]([OH:26])=[O:25]
Reactant: O=C=O
Reactant: Cc1c(Br)ccc2c1OCCO2
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)ccc2c1OCCO2
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 77 %

Procedure:
In 300 ml of dry tetrahydrofuran, was dissolved 32.0 g of 6-bromo-5-methyl-1,4-benzodioxane and after cooling the solution to -78° C., 96.7 ml of n-butyl lithium (n-hexane solution)was added dropwise over 20 minutes or more. After stirring at the same temperature for 1.5 hours, the reaction mixture was poured onto crushed dry ice and dry ice was sublimated while stirring. Water was added to the -mixture and the tetrahydrofuran was removed under reduced pressure. The resulting alkaline aqueous solution was washed with methylene chloride and adjusted to pH 3 with a 5% hydrochloric acid, and the precipitated crystals were collected by filtration and dried to obtain 20.9 g of 5-methyl-1,4-benzodioxan-6-carboxylic acid (yield: 77%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:11][N:10]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=1.[Br:17]N1C(=O)CCC1=O>FC(F)(F)C(O)=O.C(OCC)(=O)C>[Br:17][C:8]1[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:10][O:11][C:7]=1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: CCOC(=O)c1cc(-c2ccccn2)on1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1noc(-c2ccccn2)c1Br
Yield: 69.1 %

Procedure:
A solution of ethyl 5-(pyridin-2-yl)isoxazole-3-carboxylate (212 mg, 0.972 mmol) and N-bromosuccinimide (432 mg, 2.43 mmol) in trifluoroacetic acid (6 mL) was heated to 150° C. for 30 minutes via microwave. Concentration under reduced pressure afforded a yellow oil which was diluted with ethyl acetate (80 mL), washed with a saturated aqueous solution of sodium bicarbonate (20 mL), washed with brine (20 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure followed by purification by flash silica gel chromatography using a 1:3 mixture ethyl acetate and hexane afforded ethyl 4-bromo-5-(pyridin-2-yl)isoxazole-3-carboxylate (0.217 g, 0.672 mmol, 69% yield). The product had an HPLC retention. time=2.65 min.—Column: YMC S5 COMBISCREEN® 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=299.02. 1H NMR (400 MHz, CDCl3) δ ppm 1.48 (t, J=7.15 Hz, 3H), 4.52 (q, J=7.28 Hz, 2H), 7.43-7.48 (m, 1H), 7.90 (td, J=7.78, 1.76 Hz, 1H), 8.11 (d, J=8.03 Hz, 1H), and 8.84 (d, 1H).
Reaction SMILES: [CH:1]([S:5]([C:8]1[N:12]=[CH:11][NH:10][N:9]=1)(=[O:7])=[O:6])([CH2:3][CH3:4])[CH3:2].[CH2:13]([N:16]([CH2:20][CH:21]=[CH2:22])[C:17](Cl)=[O:18])[CH:14]=[CH2:15].O1CCCC1>C(N(CC)CC)C>[CH2:13]([N:16]([CH2:20][CH:21]=[CH2:22])[C:17]([N:10]1[CH:11]=[N:12][C:8]([S:5]([CH:1]([CH2:3][CH3:4])[CH3:2])(=[O:6])=[O:7])=[N:9]1)=[O:18])[CH:14]=[CH2:15]
Reactant: CCC(C)S(=O)(=O)c1nc[nH]n1
Reactant: C=CCN(CC=C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCN(CC=C)C(=O)n1cnc(S(=O)(=O)C(C)CC)n1

Procedure:
A mixture of 9.5 g. 3-sec.butylsulphonyl-1,2,4-triazole, 7.97 g. diallylcarbamoyl chloride, 50 ml. dry tetrahydrofuran and 7.5 ml. dry triethylamine was refluxed under anhydrous conditions for 5 hours. The reaction mixture was worked up by a method analogous to that described in Example 1 to give an oil which was not distilled but was heated under reduced pressure. (95°C/0.1 mm.) for 4 hours to remove traces of volatile material. The resulting product, 1-diallylcarbamoyl-3-sec.butylsulphonyl-1,2,4-triazole, was obtained as an oil, nD26 1.5174. (98.9% 1-isomer by GLC assay). Elemental analysis satisfactory.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:12][C@H:13]([N:20]=[C:21]=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:21]([NH:20][C@@H:13]([CH3:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:22]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: C[C@H](N=C=O)c1ccccc1
Product: C[C@H](NC(=O)Nc1ccc([N+](=O)[O-])cc1O)c1ccccc1
Yield: 76.7 %

Procedure:
(S)-N-(2-Hydroxy-4-nitrophenyl)-N′-(methylbenzyl)urea was prepared from 2-hydroxy 4-nitro aniline (308 mg, 2.0 mmol) and (S)-methyl benzyl isocyanate (2 mmol) according to the procedure in General Method A. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound (462 mg, 76%). EI-MS m/z 300(M−H)−
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Cl)=[N:6][CH:5]=1.CS(C)=O.[N-:17]=[N+:18]=[N-:19].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:17]=[N+:18]=[N-:19])=[N:6][CH:5]=1
Reactant: COC(=O)c1ccc(CCl)nc1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(CN=[N+]=[N-])nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
Add 6-chloromethyl-nicotinic acid methyl ester (9.1 g, 40.98 mmol) and dimethylsulfoxide (100 mL) into a flask and cool to 0° C. Add sodium azide (4 g, 61.47 mmol) and sodium carbonate (13 g, 122.9 mmol) to the reaction mixture. Let the mixture slowly warm to room temperature. Stir for 1 hr at room temperature. Add water (100 mL) to the mixture. Extract with diethyl ether (100 mL×3). Wash the organic layer with water and brine. Dry with sodium sulfate. Remove solvent under reduced pressure to give the product (6.8 g, 86% yield) as light yellow oil. MS (m/z): 193.3 (M+1).