Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]([CH:16]([CH3:18])[CH3:17])[C:8](=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[OH:19][C:20]1[C:25]2[N:26]=[C:27]([NH:29][C:30](=[O:32])[CH3:31])[S:28][C:24]=2[CH:23]=[CH:22][CH:21]=1>>[C:30]([NH:29][C:27]1[S:28][C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([O:19][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]([CH:16]([CH3:18])[CH3:17])[C:8](=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:25]=2[N:26]=1)(=[O:32])[CH3:31]
Reactant: CCCCCCC(=O)N(CCCCCBr)C(C)C
Reactant: CC(=O)Nc1nc2c(O)cccc2s1
Product: CCCCCCC(=O)N(CCCCCOc1cccc2sc(NC(C)=O)nc12)C(C)C
Yield: 41.8 %

Procedure:
N-(5-Bromopentyl)-N-isopropylheptanamide (75 mg, 0.23 mmol) was alkylated with commercial N-(4-hydroxybenzo[d]thiazol-2-yl)acetamide (54 mg, 0.26 mmol) as described above to give analog 30 (43 mg, 42%) as a sticky solid. TLC: EtOAc/hexanes (1:4), Rf˜0.30; 1H NMR (300 MHz, 45/55 mixture of rotamers) δ 11.50 (br s, —NH, 1H), 7.37-7.42 (m, 1H), 7.18-7.26 (m, 1H), 6.84-6.88 (m, 1H), 4.58-4.78 and 4.00-4.10 (m, 1H for two rotamers), 4.02 (t, J=6.3 Hz, 2H), 3.12 (t, J=7.3 Hz, 2H), 2.22-2.45 (m, 5H), 1.82-1.92 (m, 2H), 1.44-1.70 (m, 4H), 1.20-1.40 (m, 8H), 1.11-1.19 (m, 6H), 0.82-0.95 (m, 3H); 13C NMR (75 MHz) δ 173.94, 172.78, 169.40, 169.36, 157.89, 151.62, 138.43, 138.32, 133.91, 133.87, 124.92, 124.85, 114.02, 113.87, 109.66, 108.35, 69.46, 69.08, 48.53, 48.33, 45.94, 43.61, 41.20, 34.26, 34.09, 31.91, 31.88, 31.39, 29.55, 29.45, 29.37, 29.30, 25.88, 25.77, 25.71, 24.43, 24.16, 23.55, 22.77, 21.59, 20.80, 14.28. HRMS (ESI-neg) calcd for C24H36N3O3S [M−1]− 446.2477. found 446.2434.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:27]([F:30])([F:29])[F:28])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[C:16]([C:23]([F:26])([F:25])[F:24])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=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.Cl.[NH:65]1[CH2:69][C:68](=[O:70])[NH:67][CH2:66]1>CN(C)C=O.[Cl-].[Na+].O>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:27]([F:29])([F:28])[F:30])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([N:65]4[CH2:69][C:68](=[O:70])[NH:67][CH2:66]4)=[O:19])=[C:16]([C:23]([F:24])([F:25])[F:26])[CH:15]=3)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: O=C1CNCN1
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C(F)(F)F
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
Solvent: O
Product: O=C1CN(C(=O)c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc2C(F)(F)F)CN1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(trifluoromethyl)benzoic acid (300 mg, 0.64 mmol, 1.00 equiv) in N,N-dimethylformamide (2 mL), HATU (483 mg, 1.27 mmol, 2.00 equiv), DIEA (164 mg, 1.27 mmol, 2.00 equiv), imidazolidin-4-one hydrochloride (155 mg, 1.26 mmol, 2.00 equiv). The resulting solution was stirred for 3 h at 20° C. The resulting solution was diluted with 50 mL of brine. The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined. The mixture was dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with PE/EA (10:1). This resulted in 320 mg (93%) of 1-([4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(trifluoromethyl)phenyl]carbonyl)imidazolidin-4-one as light yellow oil.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([NH:11]C=O)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[O:14][CH2:15][CH:16]([CH2:27][O:28]C(=O)C)[CH2:17][CH2:18][P:19]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])=[O:20].[NH3:32]>>[NH2:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[CH:5][N:6]2[O:14][CH2:15][CH:16]([CH2:27][OH:28])[CH2:17][CH2:18][P:19]([O:21][CH2:22][CH3:23])([O:24][CH2:25][CH3:26])=[O:20])=[C:2]([NH2:32])[N:10]=1
Reactant: CCOP(=O)(CCC(COC(C)=O)COn1cnc2c(Cl)nc(NC=O)nc21)OCC
Reactant: N
Product: CCOP(=O)(CCC(CO)COn1cnc2c(N)nc(N)nc21)OCC
Reaction time: 6 h
Yield: 45 %

Procedure:
6-Chloro 9-[2-(acetoxymethyl)-4-(diethoxyphosphoryl)-butoxy]-2-formamidopurine (0.110 g, 0.23 mmol) was dissolved in ethanolic ammonia solution (5 ml) and the resulting reaction mixture was kept at 110°0 C. for 6 hours. The solution was allowed to cool, the solvent was evaporated and the residue chromatographed on silica gel (eluting with chloroform 9:1) to yield the title compound (40 mg, 45%). 1H NMR: δH [(CD3)2SO] 1.22 (6H, t, (OCH2CH3)2), 1.76 (5H, m, CHCH2CH2P), 3.49 (2H, br.s, CH2OH), 3.99 (4H, m, (OCH2CH3)2), 4.25 (2H, m, NOCH2), 4.72 (1H, br.s, D2O exchangeable CH2OH), 5.9 (2H, br.s, D2O exchangeable, NH2), 6.79 (2H, br.s, D2O exchangable, NH2), 8.31 (1H, s, H-8).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:9]=[N:8][C:7]([S:10]([N:13]([CH2:49][CH2:50][C:51]([CH3:54])([CH3:53])[CH3:52])[C@@H:14]([C:17]3[S:21][C:20]([C@@H:22]([NH:27][C:28](=[O:48])[C@H:29]([CH:35]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[NH:30][C:31]([O:33][CH3:34])=[O:32])[C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:15][OH:16])(=[O:12])=[O:11])=[CH:6][N:5]2[CH:55]=1>CO.[Pd]>[CH3:52][C:51]([CH3:54])([CH3:53])[CH2:50][CH2:49][N:13]([S:10]([C:7]1[N:8]=[CH:9][C:4]2[N:5]([CH:55]=[CH:2][N:3]=2)[CH:6]=1)(=[O:12])=[O:11])[C@@H:14]([C:17]1[S:21][C:20]([C@@H:22]([NH:27][C:28](=[O:48])[C@H:29]([CH:35]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[NH:30][C:31]([O:33][CH3:34])=[O:32])[C:23]([F:26])([F:24])[F:25])=[CH:19][CH:18]=1)[CH2:15][OH:16]
Reactant: COC(=O)N[C@H](C(=O)N[C@H](c1ccc([C@@H](CO)N(CCC(C)(C)C)S(=O)(=O)c2cn3cc(Cl)nc3cn2)s1)C(F)(F)F)C(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)N[C@H](C(=O)N[C@H](c1ccc([C@@H](CO)N(CCC(C)(C)C)S(=O)(=O)c2cn3ccnc3cn2)s1)C(F)(F)F)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of Pd/C (25 mg, 0.235 mmol) in methanol (3 mL) under N2 was added N-[(1S)-1-{5-[(1R)-1-{[(2-chloroimidazo[1,2-a]pyrazin-6-yl)sulfonyl](3,3-dimethylbutyl)amino}-2-hydroxyethyl]thiophen-2-yl}-2,2,2-trifluoroethyl]-Nα-(methoxycarbonyl)-β-phenyl-L-phenylalaninamide (7.5 mg, 9.13 μmol). The resulting slurry was purged under vacuum and backfilled with H2 three times, after which the mixture was stirred for 16 hours at room temperature. Since LCMS showed only 50% conversion, the reaction mixture was transferred to a pressure flask and hydrogenated at 50 psi of H2 for 3 days, after which Pd/C (25 mg, 0.235 mmol) was added and the mixture was hydrogenated at 50 psi for 6 hours. The reaction mixture was filtered over a Celite pad, and the volatile components were evaporated under reduced pressure. The crude residue was purified by flash chromatography (Combiflash® Rf system; SiO2 4 grams Cat. No. 69-2203-304, solvent flow 18 mL/minute, elution gradient of 20-100% (EtOAc/hexanes). The fractions containing the desired product were pooled and evaporated under reduced pressure to afford the title material as a colorless oil. MS: m/z=787.2 ((MH+)).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[N+:12]([O-])([O-:14])=[O:13].[Na+].S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(Cl)Cl>[N+:12]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[C:4]=1[OH:9])([O-:14])=[O:13]
Reactant: O=[N+]([O-])[O-]
Reactant: Oc1ccccc1C(F)(F)F
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(C(F)(F)F)c1O
Reaction time: 24 h
Yield: 48 %

Procedure:
2-trifluoromethyphenol (3.00 g, 18.5 mmol) was dissolved in methylene chloride(40 mL) followed by the addition of sodium nitrate (1.73 g, 20.4 mmol). The addition of sulfuric acid (23 mL/3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2Cl2) gave the desired product(1.84 g, 47%). 1H NMR (CD3COCD3): d 8.35 (d, 1H), 7.95 (d, 1H), 7.13 (t, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:9]=2)[CH2:4][CH2:3]1.[C:16](Cl)(=[O:18])[CH3:17].[Cl-].[Al+3].[Cl-].[Cl-]>CCCCCC>[C:16]([C:6]1[CH:7]=[C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:9]=[C:10]2[C:5]=1[CH2:4][CH2:3][C:2]2([CH3:15])[CH3:1])(=[O:18])[CH3:17]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)c1ccc2c(c1)C(C)(C)CC2
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCC
Product: CC(=O)c1cc(C(C)(C)C)cc2c1CCC2(C)C
Temperature: 0 °C
Yield: 121.2 %

Procedure:
A solution of 1,1-dimethyl-6-t-butylindane (600 grams) and acetyl chloride (314 grams) is added over a 4 hour period at -10° C. to a slurry of aluminum chloride (534 grams), 1,1-dimethyl-6-t-butylindane (1420 grams) and n-hexane (400 grams). The resulting reaction mass is poured into 5 liters of ice water with vigorous stirring thereby forming 2 liquid layers. The bottom (aqueous) layer is discarded and the organic layer is washed twice with 2 liters of water. Distillation affords recovered 1,1-dimethyl-6-t-butylindane (1252 grams, 62% recovery) and 878 grams of 4-acetyl-6-t-butyl-1,1-dimethylindane (90% yield based on acetyl chloride, 95% yield based on consumed 1,1-dimethyl-6-t-butylindane.).
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:11])[C@H:8]([CH3:10])[NH2:9])([CH3:5])([CH3:4])[CH3:3].C(N(C(C)C)CC)(C)C.[CH:21](OCC)=[O:22]>C(Cl)Cl>[C:2]([O:6][C:7](=[O:11])[C@@H:8]([NH:9][CH:21]=[O:22])[CH3:10])([CH3:5])([CH3:4])[CH3:3]
Reactant: CCOC=O
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC=O)C(=O)OC(C)(C)C

Procedure:
To a suspension of (2S) alanine tert-butyl ester hydrochloride (3.63 g, 20 mmol) in a mixture of ethyl formate (10 mL) and DCM (5 mL) was added diisopropylethylamine (3.83 mL, 22 mmol) and the reaction mixture was refluxed overnight. The solvents were evaporated and the residue was then triturated in Et2O and filtrated. The filtrates were evaporated and the residue was filtered through a short pad of silica using ethyl acetate as eluent. Evaporation of the solvent afforded the sub-title compound as a colorless oil which crystallised upon standing (2.806 g, 81%): 1H NMR (400 MHz CDCl3) δ 1.43 (3H, d), 1.50 (9H, s), 4.55 (1H, m), 6.31 (1H, br s), 8.16 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[N:6]=[C:7]([N:9]=[C:10]=[O:11])[S:8][C:4]=2[CH:3]=1.[CH2:14]([NH:17][CH2:18][CH:19]=[O:20])[CH:15]=[CH2:16]>C1C=CC=CC=1>[CH2:14]([N:17]([CH2:18][CH:19]=[O:20])[C:10]([NH:9][C:7]1[S:8][C:4]2[CH:3]=[C:2]([Cl:1])[CH:13]=[CH:12][C:5]=2[N:6]=1)=[O:11])[CH:15]=[CH2:16]
Reactant: O=C=Nc1nc2ccc(Cl)cc2s1
Reactant: C=CCNCC=O
Solvent: c1ccccc1
Product: C=CCN(CC=O)C(=O)Nc1nc2ccc(Cl)cc2s1
Reaction time: 1 h

Procedure:
6-Chlorobenzothiazol-2-yl isocyanate dimer (0.1 mole), the dimethyl acetal of 2-allylaminoacetaldehyde (0.2 mole) and benzene (100 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is stirred at ambient temperatures for a period of about one hour. After this time the reaction mixture is filtered, and the filtrate is stripped of solvent to yield the desired product the dimethyl acetal of 2-[1-allyl-3-(6-chlorobenzothiazol-2-yl)ureido]acetaldehyde as the residue.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:5]=[C:4]([O:19]C)[CH:3]=1.Br[Zn][CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH:23]1([C:2]2[C:10]3[O:9][C:8]([C:11]4[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=4)=[N:7][C:6]=3[CH:5]=[C:4]([OH:19])[CH:3]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COc1ccc(-c2nc3cc(OC)cc(Br)c3o2)cc1
Reactant: Br[Zn]C1CCCC1
Product: Oc1ccc(-c2nc3cc(O)cc(C4CCCC4)c3o2)cc1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 35, from 7-bromo-5-methoxy-2-(4-methoxyphenyl)-1,3-benzoxazole, and bromo(cyclopentyl)zinc. The desired product was obtained as a white solid, m.p. 220-222° C.; MS m/e 296 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)=[CH:14][CH:13]=1.Cl.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([S:31](Cl)(=[O:33])=[O:32])[CH:26]=1>>[CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]([S:31]([C:27]1[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=1)(=[O:33])=[O:32])[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)=[CH:16][CH:17]=1
Reactant: COC(=O)CCCCCCNCc1ccc(-c2nccs2)cc1
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: Cl
Product: COC(=O)CCCCCCN(Cc1ccc(-c2nccs2)cc1)S(=O)(=O)c1cccnc1

Procedure:
The title compound of Step A was prepared from 7-(4-thiazol-2-yl-benzylamino)-heptanoic acid methyl ester, prepared in Step A of Example 11c, and pyridine-3-sulfonyl chloride hydrochloride, of Preparation 2, following the method of Example 1, Step B. 1H NMR (400 MHz, CDCl3) δ 9.06 (d, 1H), 8.80 (m, 1H), 8.09 (m, 1H), 7.91 (d, 2H), 7.86 (m, 1H), 7.46 (m, 1H), 7.34 (m, 3H), 4.39 (s, 2H), 3.62 (s, 3H), 3.15 (t, 2H), 2.21 (t, 2H), 1,48 (m, 2H), 1.37 (m, 2H), 1.14 (m, 4H); MS 474 (M+1)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([F:30])([F:29])[C:13]2[N:18]=[CH:17][C:16]([CH2:19][O:20][C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][N:22]=3)=[CH:15][CH:14]=2)[CH2:11][O:10]1.[NH:31]1[CH:35]=[N:34][N:33]=[N:32]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOCC>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:10])([CH2:11][N:31]1[CH:35]=[N:34][N:33]=[N:32]1)[C:12]([C:13]1[N:18]=[CH:17][C:16]([CH2:19][O:20][C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][N:22]=2)=[CH:15][CH:14]=1)([F:29])[F:30]
Reactant: N#Cc1ccc(OCc2ccc(C(F)(F)C3(c4ccc(F)cc4F)CO3)nc2)nc1
Reactant: c1nnn[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: N#Cc1ccc(OCc2ccc(C(F)(F)C(O)(Cn3cnnn3)c3ccc(F)cc3F)nc2)nc1
Temperature: 55 °C
Reaction time: 36 h

Procedure:
To a magnetically stirred mixture of 6-((6-((2-(2,4-difluorophenyl)oxiran-2-yl)difluoromethyl)pyridin-3-yl)methoxy)nicotinonitrile (BZ; 200 mg, 0.482 mmol) and 1H-tetrazole (67.5 mg, 0.963 mmol) in dry DMF (4.815 mL) was added K2CO3 (133 mg, 0.963 mmol) in a dry 25 mL vial under N2 atmosphere. The reaction mixture was stirred at 55° C. for 36 hours, then cooled to RT, and diluted with ice-water and ether. The layers were separated and the aq. layer was extracted again with ether (2×). The combined ether extracts were dried over sodium sulfate, filtered, and evaporated. The crude residue was purified on silica (40 gram column, gradient over 15 min to 40% EA/Hex, hold 10 min then 10 min at 80% EA/hex, monitor 240 and 254 nm). The respective product fractions were evaporated to afford the title compound contaminated with DMF. The material was diluted with water and extracted 3× with ether, the combined ether extracts were diluted with pet. ether and washed with sat'd NH4Cl (2×) and brine (1×), dried over MgSO4, filtered, and evaporated to afford 98. Yield=62 mg (25.2%) of a white foam. 1H NMR (400 MHz, CDCl3) δ 8.75 (s, 1H), 8.63 (d, J=1.3 Hz, 1H), 8.48 (dd, J=2.3, 0.8 Hz, 1H), 7.91 (dd, J=8.2, 2.1 Hz, 1H), 7.85 (dd, J=8.7, 2.4 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.56 (s, 1H), 7.35 (td, J=9.0, 6.5 Hz, 1H), 6.92 (dd, J=8.5, 0.8 Hz, 1H), 6.76 (ddd, J=12.0, 8.5, 2.5 Hz, 1H), 6.71-6.61 (m, 1H), 5.56 (d, J=14.3 Hz, 1H), 5.50 (s, 2H), 5.13 (dd, J=14.2, 1.1 Hz, 1H). 1H-decoupled 19F NMR (376 MHz, CDCl3) δ −103.83 (ddd, J=42.2, 17.0, 10.2 Hz), −104.20 (d, J=16.3 Hz), −104.89 (d, J=16.3 Hz), −107.90 −108.07 (m), −110.92 (dd, J=262.9, 42.2 Hz). MS (ESI): m/z 486.1 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=[CH:3]1.[Br:15]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:15][C:3]1[C:2](=[O:1])[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1cc[nH]c2c([N+](=O)[O-])cccc12
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c(Br)c[nH]c2c([N+](=O)[O-])cccc12
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
To a stirred mixture of 1,4-dihydro-4-oxo-8-nitroquinoline (10 g) in dimethylformamide (100 ml) was dropwise added N-bromosuccinimide (9.83 g) over the period of 2 minutes under ice-cooling, and the mixture was stirred for 30 minutes at 4° C. Water was added thereto under ice-cooling, and the mixture was stirred for 1 hour. The resulting precipitate was collected by filtration, and the residue was washed with water and hot ethanol to give 3-bromo-1,4-dihydro-8-nitro-4-oxoquinoline (12.12 g).
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[S:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][C:11]1([CH2:16][CH3:17])[O:15][CH2:14][CH2:13][O:12]1.[CH2:18](O)C.[OH-].[Na+].S([O-])(OC)(=O)=O>O>[CH3:18][S:8][C:6]1[N:5]=[C:4]([OH:9])[C:3]([CH2:10][C:11]2([CH2:16][CH3:17])[O:12][CH2:13][CH2:14][O:15]2)=[C:2]([NH2:1])[N:7]=1
Reactant: CCO
Reactant: CCC1(Cc2c(N)[nH]c(=S)[nH]c2=O)OCCO1
Agent: COS(=O)(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC1(Cc2c(N)nc(SC)nc2O)OCCO1
Temperature: 25 °C
Reaction time: 6 h
Yield: 67 %

Procedure:
To a slurry of 3.95 g (15.3 mmol) of 6-amino-5-(2-ethyl-1,3-dioxolan-2-ylmethyl)-2-thiouracil, 27 mL of ethanol, 3 mL of water and 3.06 mL of 5 M sodium hydroxide was added 1.93 g (15.3 mmol) of methyl sulfate. The reaction exothermed to 45° C. and became a solution. After stirring for 6 hours at ambient temperature, the precipitate was collected by filtration. The solids were washed with 15 mL of water and dried in vacuo (40° C., 10 torr) to yield 2.78 g (67%) of 2-(methylthio)-6-amino-5-(2-ethyl-1,3-dioxolan-2ylmethyl)-4-pyrimidinol as a white powder. nmr (500 MHz, dmso-d6) δ0.80 (t, J=7.4 Hz, 3H), 1.52 (q, J=7.4 Hz, 2H), 2.42 (s, 3H), 2.58 (s, 2H), 3.82 (m, 2H), 3.92 (m, 2H), 6.10 (s, 2H), 11.6 (bs, 1H)
Reaction SMILES: [CH:1]1([NH:7][C:8]([CH2:10][NH:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[N+:20]([O-])=O)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>O1CCCC1.[C].[Pd]>[NH2:20][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:12]=1[NH:11][CH2:10][C:8](=[O:9])[NH:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[C:16]#[N:17]
Reactant: N#Cc1ccc(NCC(=O)NC2CCCCC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Product: N#Cc1ccc(NCC(=O)NC2CCCCC2)c(N)c1
Yield: 99.8 %

Procedure:
4-(Cyclohexylcarbamoylmethylamino)-3-nitrobenzonitrile (3.64 g) was hydrogenated using 7.5% palladium carbon (1.1 g) in tetrahydrofuran (100 ml) at atmospheric pressure over 40 min. After completion of the reaction, the reaction mixture was filtered through celite, and the solvent was evaporated and the residue was dried under reduced pressure to give the title compound (3.274 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[N+:17]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.[Pt]=O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[NH2:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: COc1ccc(N)c(OCc2ccccc2)c1

Procedure:
A solution of 2-benzyloxy-4-methoxy-1-nitrobenzene (700 mg) in EtOAc (15 mL) is hydrogenated over platinum oxide (70 mg) at 20 psi for 1 h. The catalyst is filtered and the filtrate evaporated to give the title compound as an oil.
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:31]=[CH:30][C:8]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24](O)=[O:25])[CH2:19]3)[N:15]3[N:27]=[CH:28][CH:29]=[C:14]3[N:13]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].CN.C[CH2:35][N:36]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[OH:1][C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([NH:36][CH3:35])=[O:25])[CH2:19]3)[N:15]3[N:27]=[CH:28][CH:29]=[C:14]3[N:13]=2)=[O:10])=[CH:30][CH:31]=1)([CH3:3])[CH3:4]
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(N3CCC[C@@H](C(=O)O)C3)n3nccc3n2)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CNC(=O)[C@@H]1CCCN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3ccnn23)C1
Yield: 54.4 %

Procedure:
A solution of (R)-1-(5-(4-(2-hydroxypropan-2-yl)benzamido)pyrazolo[1,5-a]pyrimidin-7-yl)piperidine-3-carboxylic acid (Compound 84, 100 mg, 0.236 mmol), methylamine (15 mg, 0.472 mmol), EDCI (90 mg, 0.472 mmol), and HOBT (16 mg, 0.118 mmol) in DMF (4.22 mL) were stirred for 12 hours at room temperature. The reaction was complete as determined by LCMS analysis. The reaction mixture was then partitioned between ethyl acetate and water and the separated organic layer was dried over Mg2SO4, filtered, and concentrated under reduced pressure. Purification by preparatory HPLC, 20-40% (MeCN/H2O gradient+0.01% TFA) provided the titled compound as a yellow solid (56 mg, 53%). 1H NMR (DMSO-d6) δ: 10.90 (s, 1H), 8.10 (d, J=2.3 Hz, 1H), 8.00 (d, J=8.6 Hz, 2H), 7.55-7.65 (m, J=8.6 Hz, 2H), 7.40 (s, 1H), 6.36 (d, J=2.3 Hz, 1H), 4.35 (br. s., 3H), 3.25 (dd, J=12.3, 10.7 Hz, 1H), 3.05 (br. s., 1H), 2.55-2.64 (m, 3H), 1.93 (br. s., 1H), 1.79-1.88 (m, 1H), 1.73 (d, J=10.9 Hz, 2H), 1.45 (s, 6H). ESI-MS: m/z 437.0 (M+H)+.
Reaction SMILES: P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.C(N(C(C)C)CC)(C)C.[OH:27][C@@H:28]([C@H:30]1[C:51](=[O:52])[N:32]2[CH:33]([C:38]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][CH:43]=3)=[O:39])[C:34](=O)[C@H:35]([CH3:36])[C@H:31]12)[CH3:29].FC(F)(F)S(O)(=O)=O.[C:61]([O:64][CH2:65][CH2:66][N:67]1[CH2:73][CH2:72][CH2:71][N:70]([C:74]([C@@H:76]2[CH2:80][C@H:79]([SH:81])[CH2:78][N:77]2[C:82]([O:84][CH2:85][C:86]2[CH:91]=[CH:90][C:89]([N+:92]([O-:94])=[O:93])=[CH:88][CH:87]=2)=[O:83])=[O:75])[CH2:69][CH2:68]1)(=[O:63])[NH2:62]>C(#N)C>[C:61]([O:64][CH2:65][CH2:66][N:67]1[CH2:73][CH2:72][CH2:71][N:70]([C:74]([C@@H:76]2[CH2:80][C@H:79]([S:81][C:34]3[C@H:35]([CH3:36])[C@@H:31]4[C@@H:30]([C@H:28]([OH:27])[CH3:29])[C:51](=[O:52])[N:32]4[C:33]=3[C:38]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][CH:43]=3)=[O:39])[CH2:78][N:77]2[C:82]([O:84][CH2:85][C:86]2[CH:87]=[CH:88][C:89]([N+:92]([O-:94])=[O:93])=[CH:90][CH:91]=2)=[O:83])=[O:75])[CH2:69][CH2:68]1)(=[O:63])[NH2:62]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: NC(=O)OCCN1CCCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCCN(CCOC(N)=O)CC4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Reaction time: 1 h
Yield: 31.8 %

Procedure:
88 μl of diphenyl chlorophosphate and 74 μl of diisopropylethylamine were added dropwise, whilst ice-cooling, to a solution of 145 mg of 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylate in 2 ml of anhydrous acetonitrile, and the resulting mixture was stirred at the same temperature for 1 hour. 202 μl of diisopropylethylamine and a solution of 310 mg of (2S,4S)-2-[4-(2-carbamoyloxyethyl)-1-homopiperazinylcarbonyl]-4-mercapto-1-(4-nitrobenzyloxycarbonyl)pyrrolidine trifluoromethanesulfonate [prepared as described in step (1) above] in 2.0 ml of anhydrous acetonitrile were then added dropwise to the mixture, whilst ice-cooling, and the resulting mixture was allowed to stand overnight at the same temperature. At the end of this time, the reaction mixture was worked up and purified in a similar manner to that described in Example 32(2), to afford 107 mg of the title compound as a powder.