Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:31])=[C:6]([CH:30]=1)[CH2:7][C:8]1[CH:13]([C:14]([OH:16])=[O:15])[N:12]2[C:17](=[O:29])[C@@H:18]([NH:19][C:20](=[O:28])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@H:11]2[S:10][CH:9]=1.ClC1C=CC=C(C(OO)=[O:40])C=1>C(O)(C)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:31])=[C:6]([CH:30]=1)[CH2:7][C:8]1[CH2:9][S:10](=[O:40])[C@@H:11]2[CH:18]([NH:19][C:20](=[O:28])[CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:17](=[O:29])[N:12]2[C:13]=1[C:14]([OH:16])=[O:15]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)O)C(Cc3cc(F)ccc3O)=CS[C@H]12
Solvent: CC(C)O
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)O)=C(Cc3cc(F)ccc3O)CS(=O)[C@H]12
Reaction time: 2 h

Procedure:
A solution of 2.0 g of 3-(5-fluor-2-hydroxy-benzyl)7β-phenylacetylamino-ceph-2-em-4ξ-carboxylic acid in 10 ml of isopropanol is treated at 0°-5° in small amounts with 1.2 g of 3-chloro-perbenzoic acid and stirred for 2 hours. The reaction mixture is concentrated to half-volume and diluted with 10 ml of diethyl ether. The crystalline precipitate that forms is filtered off and recrystallised from methyl acetate to yield the 3-(5-fluoro-2-hydroxy-benzyl)-7-phenylacetylamino-ceph-3-em-4-carboxylic acid 1-oxide, which melts at 183°-185°; thin-layer chromatogram (silica gel) Rf = 0.48 (system: n-butanol/acetic acid/water 75:7.5:21), Rf = 0.64 (system: n-butanol/ethanol/water 40:10:50) and Rf = 0.77 (system: chloroform/methanol 1:1).
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:13])[CH2:9][C:10](=O)[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:14]>>[C:1]1([NH:7][C:8](=[O:13])/[CH:9]=[C:10](\[NH2:14])/[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)CC(=O)Nc1ccccc1
Reactant: N
Product: C/C(N)=C/C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-Phenyl-3-ketobutanamide (0.35 g, 2.0 mmole) was dissolved in ethanolic ammonia (15 ml, 0.105M) and stirred overnight at room temperature. The solution was evaporated to yield N-phenyl-3-aminocrotonamide which was used directly. The crude residue was taken up in ethanol (30 ml) and 2-chlorobenzaldehyde (0.28 g, 2 mmole) and methyl 4-[2-(2,4,5-trimethylimidazol-1-yl)ethoxy]-3-ketobutanoate (0.53 g, 2 mmole) were added. The mixture was heated at reflux for 8 hours then cooled and the solution evaporated to dryness under reduced pressure. The residue was chromatographed on silica eluting with ethyl acetate containing an increasing proportion of up to 10% diethylamine. The fractions containing the product were combined and evaporated to yield the title compound (0.56 g, 51%). m.p. 135°-140° C. Found: C, 65.06; H, 6.14; N, 9.86. C30H33ClN4O4.1/2H2O requires C, 65.09; H, 6.10; N, 10.12%.
Reaction SMILES: P(=[S:5])([O-])([O-])[O-].[Na+].[Na+].[Na+].Cl.[C:10]([O:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20](=[NH:23])[CH2:21][Cl:22])[CH2:16][CH2:15]1)(=[O:12])[NH2:11].Cl>O>[ClH:22].[C:10]([O:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20](=[NH:23])[CH2:21][SH:5])[CH2:16][CH2:15]1)(=[O:12])[NH2:11]
Reactant: N=C(CCl)N1CCC(OC(N)=O)CC1
Reactant: [O-]P([O-])([O-])=S
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N=C(CS)N1CCC(OC(N)=O)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 97.8 %

Procedure:
4.95 g of trisodium phosphorothioate were added to an ice-cooled solution of 6.40 g of 2-(4-carbamoyloxypiperidin-1-yl)-2-iminoethylchloride hydrochloride in 32 ml of water, and the mixture was stirred at room temperature for 2.5 hours. 28 ml of 1N hydrochloric acid were then added, and the mixture was heated at 60° C. for 30 minutes. The reaction mixture was worked up in the same manner as in Example 1(2), giving 6.20 g of 2-(4-carbamoyloxypiperidin-1-yl)-2-iminoethylmercaptan hydrochloride.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].C(O[C@@H](CCN[C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])C(=O)OC1C(F)=C(F)C(F)=C(F)C=1F)(=O)C1C=CC=CC=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:38]([O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: O=C(NCC[C@H](OC(=O)c1ccccc1)C(=O)Oc1c(F)c(F)c(F)c(F)c1F)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)Oc1ccccc1[N+](=O)[O-]
Yield: 26.3 %

Procedure:
To a stirring solution of 3′,4′,3′″,4′″-tetra-dehydro-3,2′,6′,2′″,6′″-penta-Cbz-neomycin (4, 190 mg, 0.156 mmol) in DMF (2 mL) was added succinimidyl benzoyloxy(2-Cbz-aminoethyl)carbamate (3, 81 mg, 0.18 mmol) and the reaction was stirred under a nitrogen atmosphere. DIPEA (67 μL, 0.38 mmol) was added and the reaction was stirred for 2 days. The reaction mixture was purified on a 2-inch reverse-phase HPLC column, followed by treatment with sat. aq. NaHCO3 to remove the benzoyl protecting group to yield a crude, which was purified on a 1-inch reverse-phase column to yield (5) (60 mg, 0.041 mmol, 26.3% yield): MS m/z (M+Na)+ calc. 1475.5, obs. 1475.4.
Reaction SMILES: [F:1][C@@H:2]1[C@@H:6]([CH2:7]O)[O:5][C@@H:4]([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:3]1.[N+:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Se:27]C#N)([O-:20])=[O:19].O1CCCC1.C(P(CCCC)CCCC)CCC>C(OCC)(=O)C>[F:1][C@@H:2]1[C@@H:6]([CH2:7][Se:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N+:18]([O-:20])=[O:19])[O:5][C@@H:4]([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:3]1
Reactant: Cc1cn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: N#C[Se]c1ccccc1[N+](=O)[O-]
Agent: CCCCP(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cn([C@H]2C[C@H](F)[C@@H](C[Se]c3ccccc3[N+](=O)[O-])O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78 %

Procedure:
3'-Deoxy-3'-fluorothymidine (2.04 g, 8.34 mM) and o-nitrophenylselenocyanate (2.10 g, 9.20 mM) were placed in a flask under nitrogen. Tetrahydrofuran (dry) (50 mL) was added followed by 2.2 mL (8.83 mM) of tri-n-butylphosphine. The mixture was stirred at room temperature for 1.5 hours, diluted with 200 mL of ethyl acetate and washed with 200 mL of sat. sodium bicarbonate followed by 200 mL of brine. The extract was dried over magnesium sulfate and concentrated under reduced pressure to a yellow oil (6.3 g). Chromatographic purification of the yellow oil on silica gel with hexane:ethyl acetate (4:1 v/v) as eluent gave 2.79 g (6.51 mM; 78%) of 3',5'-di-deoxy-3'-fluoro-5'-[(2-nitrophenyl)selenyl]thymidine as an amorphous yellow solid.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+].[CH3:7][O:8][C:9](=[O:26])[C@@H:10]1CC(=O)C[N:11]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].[Cl-].[NH4+]>C(OCC)C.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:7][O:8][C:9](=[O:26])[C@@H:10]1[CH2:3][C:2](=[CH2:5])[CH2:1][N:11]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: COC(=O)[C@@H]1CC(=O)CN1C(=O)OCc1ccccc1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: CCOCC
Product: C=C1C[C@@H](C(=O)OC)N(C(=O)OCc2ccccc2)C1
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 72.6 %

Procedure:
Potassium t-butoxide (1.41 g, 12.6 mmol) was suspended in diethyl ether (100 ml). To the suspension was added methyltriphenylphosphonium bromide (4.80 g, 13.4 mmol), and the resulting mixture was stirred at 5° C. for 15 minutes. To the mixture was added (S)-1-benzyloxycarbonyl-4-oxoproline methyl ester (2.50 g, 9.0 mmol) in diethyl ether (30 ml), and the resulting mixture was stirred at 35° C. for 3 hours. At the end of this time, the reaction mixture was added to a saturated solution of ammonium chloride (50 ml) under ice cooling, and then partitioned. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel (eluent, ethyl acetate:hexane=1:3), to give the title compound (1.80 g) as a pale yellow oil (yield 72%).
Reaction SMILES: [CH:1]1([CH:4]([O:12][CH2:13][CH:14](OCC)OCC)[CH2:5]/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])[CH2:3][CH2:2]1.C(OC[C@H](OCC=[N:37][OH:38])CC=C)C1C=CC=CC=1.C(OC(OCC)CO[C@H](CC=C)COCC1C=CC=CC=1)C.C(OC[C@@H]1OCC2=NOC[C@@H]2C1)C1C=CC=CC=1>>[CH:1]1([CH:4]([O:12][CH2:13][CH:14]=[N:37][OH:38])[CH2:5]/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])[CH2:3][CH2:2]1
Reactant: CCOC(COC(C/C=C/C(=O)OC)C1CC1)OCC
Reactant: C=CC[C@H](COCc1ccccc1)OCC=NO
Agent: C=CC[C@H](COCc1ccccc1)OCC(OCC)OCC
Agent: c1ccc(COC[C@H]2C[C@H]3CON=C3CO2)cc1
Product: COC(=O)/C=C/CC(OCC=NO)C1CC1

Procedure:
Methyl (2E)-5-cyclopropyl-5-(2,2-diethoxyethoxyl)pent-2-enoate (C34) was converted to the product using the method described for synthesis of 2-{[(2R)-1-(benzyloxy)pent-4-en-2-yl]oxy}-N-hydroxyethanimine (C3) in the section “Alternate conversion of C2 to C4.” The product was obtained as an oil: 1H NMR analysis indicated a roughly 1:1 mixture of geometric isomers around the oxime. Yield: 3.50 g, 15.4 mmol, 73%. 1H NMR (400 MHz, CDCl3) δ 7.73 and 7.47 (2 br s, total 1H), [7.49 (dd, J=5.8, 5.6 Hz) and 6.90 (dd, J=3.7, 3.6 Hz), total 1H], 6.99-7.09 (m, 1H), 5.87-5.93 (m, 1H), [4.54 (dd, half of ABX pattern, J=16.1, 3.6 Hz), 4.37 (dd, half of ABX pattern, J=16.0, 3.7 Hz), 4.28 (dd, half of ABX pattern, J=12.8, 5.5 Hz) and 4.14 (dd, half of ABX pattern, J=12.7, 5.8 Hz), total 2H], 3.74 and 3.74 (2 s, total 3H), 2.71-2.81 (m, 1H), 2.51-2.57 (m, 2H), 0.80-0.90 (m, 1H), 0.63-0.72 (m, 1H), 0.48-0.57 (m, 1H), 0.38-0.47 (m, 1H), 0.06-0.13 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]=O)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[C:19]1(C)C=CC=CC=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]=[CH2:19])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1
Reactant: O=Cc1ccc(OCc2ccccc2)cn1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: C=Cc1ccc(OCc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
In a two liter 3-neck round bottom flask fitted with a mechanical stirrer, thermometer and a water-cooled reflux condenser was placed 23.4 g. (0.11 mole) of 5-benzyloxypyridine-2-carbaldehyde, 78.5 g. (0.22 mole) of methyltriphenylphosphonium bromide and 26.5 g. (0.66 mole) of sodium hydroxide pellets in 250 ml. of toluene and 665 ml. of water. The reaction mixture was stirred at room temperature for 15 hours. The toluene layer was separated and saved. The aqueous layer was washed with toluene and the combined toluene layers are filtered through a 4"×6" pad of silica gel to remove triphenylphosphate. The pad was successively washed with toluene, then ether/hexane (3.2) to remove the desired product. The organic solutions were combined, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give 5-benzyloxy-2-vinylpyridine as a yellow oil (20.5 g., 73.7%); NMR (CDCl3) 8.15 (m, 1H, H6), 7.16 (s, 5H, C6H 5 --), 7.00 (m, 2H, H3 and H4), 6.67 (d of d, 1H, oletin H), 5.95 (d of d, 1H, oletin H), 5.15 (d of d, 1H, oletin H) and 4.90 (3, 2H, CH2).
Reaction SMILES: [CH3:1][C:2](O)([CH2:7][CH2:8][CH:9]=[CH2:10])[CH2:3][C:4](O)=[O:5].C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+]>>[CH3:10][C:9]1[CH:3]2[CH:2]([CH2:7][CH:8]=1)[CH2:1][C:4]2=[O:5]
Reactant: C=CCCC(C)(O)CC(=O)O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Product: CC1=CCC2CC(=O)C12

Procedure:
2.07 g (0.013 moles) of 3-methyl-3-hydroxy-hept-6-enoic acid, 15 ml of acetic anhydride and 3 g of potassium acetate are charged into a 50 ml flask equipped with a reflux condenser fitted with a CaCl2 tube.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:23][C:22]=1[OH:36].[F-].[Cs+]>COCCOC.CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:36][C:22]1[CH:23]=[CH:24][C:25]([C:2]2[CH:10]=[C:9]3[C:5](/[C:6](=[CH:12]/[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=4)/[C:7](=[O:11])[NH:8]3)=[CH:4][CH:3]=2)=[CH:26][C:21]=1[O:20][CH3:19]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Reactant: O=C1Nc2cc(Br)ccc2/C1=C/c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: COCCOC
Product: COc1cc(-c2ccc3c(c2)NC(=O)/C3=C\c2ccccn2)ccc1O
Temperature: 25 °C
Yield: 19 %

Procedure:
A solution of Example 2A (80 mg, 0.26 mmol), 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (78 mg, 0.31 mmol), Pd(PPh3)4 (30 mg, 0.026 mmol), and CsF (43 mg, 0.29 mmol) in DME/methanol (2:1) was stirred at 80° C. for 18 hours, cooled to room temperature, concentrated, and extracted with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by HPLC (Zorbax C-18 column) with 10-100% acetonitrile/water to provide the desired product (17 mg, 18%). MS (DCI/NH3) m/z 345.1 (M+H)+; 1H NMR (300 MHz, CD3OD) δ8.92 (d, 1H, J=5.5 Hz), 8.82 (d, 1H, J=7.8 Hz), 8.25 (s, 1H), 7.89 (m, 1H), 7.71 (s, 1H), 7.62 (m, 1H), 7.41 (m, 1H), 7.24 (d, 1H, J=1.7 Hz), 7.14 (dd, 1H, J=8.1, 2.0 Hz), 7.08 (dd, 1H, J=5.8, 2.1 Hz), 6.99 (d, 1H, J=8.1 Hz), 3.98 (s, 3H); Anal. Calcd. for C21H16N2O3.1.5CF3CO2H: C, 73.24; H, 4.68; N, 8.13. Found: C, 56.40; H, 3.57; N, 5.005.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].Cl[CH2:11][C:12]([N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:13].C(=O)([O-])O.[Cs+]>CN1C(=O)CCC1>[C:4]([O:6][CH2:11][C:12]([N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:13])(=[O:5])/[CH:3]=[CH:2]/[C:1]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)/C=C/C(=O)O
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)CCl
Agent: O=C([O-])O
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COC(=O)/C=C/C(=O)OCC(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Yield: 33.6 %

Procedure:
Following general procedure A, methyl hydrogen fumarate (MHF) (0.50 g, 3.84 mmol) dissolved in NMP was reacted at ca. 55° C. with tert-butyl (2S)-1-(2-chloroacetyl)pyrrolidine-2-carboxylate (0.82 g, 4.60 mmol) in the presence of CsHCO3 (0.89 g, 4.61 mmol) to provide 0.44 g (34% yield) of the title compound (20) as a white solid after purification by mass-guided preparative HPLC and lyophilization. 1H NMR (CDCl3, 400 MHz, all rotamers): δ 6.97-6.90 (m, 2H), 4.91-4.55 (m, 2H), 4.44-4.29 (m, 1H), 3.80 (s, 3H), 3.61-3.58 (m, 2H), 2.23-2.03 (br m, 4H), 1.54-1.46 (s, 9H). MS (ESI): m/z 342.16 (M+H)+, 364.09 (M+Na+)+.
Reaction SMILES: [Cl-].[Na+].[OH:3][C:4]1[C:11]([CH3:12])=[CH:10][C:7]([CH:8]=[O:9])=[C:6]([CH3:13])[CH:5]=1.[N+:14]([O-])([OH:16])=[O:15]>S(=O)(=O)(O)O>[OH:3][C:4]1[C:11]([CH3:12])=[CH:10][C:7]([CH:8]=[O:9])=[C:6]([CH3:13])[C:5]=1[N+:14]([O-:16])=[O:15]
Reactant: Cc1cc(C=O)c(C)cc1O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Product: Cc1cc(C=O)c(C)c([N+](=O)[O-])c1O
Reaction time: 0.5 h

Procedure:
To a −10° C. (ice and sodium chloride) solution of 4-hydroxy-2,5-dimethylbenzaldehyde (1.0 g, 6.65 mmol) in concentrated sulfuric acid (10 mL) was added dropwise 70% (concentrated) nitric acid (0.598 g, 6.65 mmol) in 2 mL concentrated sulfuric acid. The reaction stirred for approximately 30 minutes. The reaction was then poured onto crushed ice. The precipitate was collected and washed with water. The solid was then dried on a high vacuum pump to yield a white solid. Microanalysis (C9H9N1O4): calculated: C=55.39, H=4.65, N=7.18; found: C=55.60, H=4.65, N=7.02. MS: M+−1=194.1 Da.
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.[C:6]([NH:10][S:11]([C:14]1[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1)(=[O:13])=[O:12])([CH3:9])([CH3:8])[CH3:7]>>[CH:1]1([NH:5][S:20]([C:16]2[CH:15]=[C:14]([S:11]([NH:10][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=2)(=[O:22])=[O:21])[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(S(=O)(=O)Cl)c1
Reactant: NC1CCC1
Product: CC(C)(C)NS(=O)(=O)c1cccc(S(=O)(=O)NC2CCC2)c1

Procedure:
Using a procedure similar to that described in Preparation E, 4 ml of cyclobutylamine was added to 1 gram (3.9 mmole) of 3-tert-butylsulfamoyl-benzenesulfonyl chloride to give 813 mg of the titled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6](Cl)=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][N:14]([CH3:19])[CH2:15][CH2:16][CH2:17][SH:18].[OH-].[K+].CS(C)=O>C(OCC)C.O>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([S:18][CH2:17][CH2:16][CH2:15][N:14]([CH3:19])[CH3:13])=[CH:7][CH:8]=2)[N:3]=1
Reactant: CN(C)CCCS
Reactant: Nc1ccc2ccc(Cl)nc2n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOCC
Product: CN(C)CCCSc1ccc2ccc(N)nc2n1
Temperature: 90 °C
Yield: 77 %

Procedure:
A mixture composed of 2-amino-7-chloro-1,8-naphthyridine (8 g), 3-dimethylaminopropanethiol (11.4 g), potassium hydroxide pellets (85% pure; 6.26 g) and dimethyl sulphoxide (87 cc) is heated to 90° C. for 3 hours 30 minutes. The reaction mixture is then poured into water (1500 cc) and extracted with methylene chloride (5×400 cc). The organic extracts are combined and washed with distilled water (400 cc), dried over magnesium sulphate and concentrated to dryness at 40° C. under reduced pressure (4 kPa). The residue obtained is treated with ethyl ether (100 cc). The insoluble product is separated by filtration, washed with ethyl ether (10 cc) and dried at 40° C. under reduced pressure (0.07 kPa). 2-Amino-7-(3-dimethylaminopropylthio)-1,8-naphthyridine (9 g), m.p. 164° C., is obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](OC(C)(C)C)=O)[C@@H:10]([CH2:21][CH2:22][O:23][CH3:24])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:46]([O:50][C:51]([NH:53][C@@H:54]([CH2:57][S:58][C:59]([C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1)([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)C=O)=[O:52])([CH3:49])([CH3:48])[CH3:47]>C(Cl)Cl.ClC(Cl)C>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C@@H:54]([NH:53][C:51]([O:50][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:52])[CH2:57][S:58][C:59]([C:66]2[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=2)([C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=2)[C:60]2[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=2)[C@@H:10]([CH2:21][CH2:22][O:23][CH3:24])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H](C=O)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COCC[C@H]1CN(Cc2ccccc2)CCN1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCC[C@H]1CN(Cc2ccccc2)CCN1C[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 1 h

Procedure:
4-Benzyl-1-tert-butoxycarbonyl-2(S)-(2-methoxyethyl)piperazine from Example 7, step C (1.17 g, 3.50 mmol) was dissolved in methylene chloride (20 mL). To this solution was added trifluoroacetic acid (10 mL) and the reaction stirred at 20° C. for 1 h. The volatiles were removed in vacuo and the residue taken up in dichloroethane (40 mL). Triethylamine was added to attain pH 7. To this solution was added crushed molecular seives (1 g), sodium triacetoxyborohydride (1.2 g, 5.3 mmol) and the reaction cooled to -15° C. with ice-methanol. A solution of 2(R)-tert-butoxycarbonylamino-3-triphenylmethylthiopropanal (1.72 g, 3.85 mmol) in dichloroethane (15 mL) was added slowly dropwise. The reaction was stirred at 20° C. overnight then quenched with saturated sodium bicarbonate. The organic phase was washed with saturated sodium chloride solution, and dried over magnesium sulfate. The crude product (2.52 g) was chromatographed on silica gel with 30% ethyl acetate in hexane using medium pressure liquid chromatography (MPLC). The title compound (Rf 0.21) was isolated as a gum (0.906 g). NMR (CHCl3, 300 MHz) δ 7.2-7.4 (20H, m), 4.70 (1H, d, J=8 Hz), 3.63 (1H, br s), 3.50 (1H, d, J=13 Hz), 3.36 (1H, d, J=13 Hz), 3.2-3.35 (5H, m), 2.75 (1H, m), 2.0-2.6 (10H, m), 1.75 (2H, m), 1.42 (9H, s). A diastereomeric minor product (Rf 0.14) was also isolated (0.065 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH:14]=[O:15])=[CH:11][C:10]([C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)=[O:17])=[C:9]2[CH3:29])=[C:4]([C:30]([F:33])([F:32])[F:31])[CH:3]=1.P([O-])(O)(O)=[O:35].[Na+].CC(=CC)C.Cl([O-])=O.[Na+].S([O-])(O)=O.[Na+].Cl>C(O)(C)(C)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9]([CH3:29])=[C:10]([C:16](=[O:17])[NH:18][C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)[CH:11]=[C:12]2[CH2:13][C:14]([OH:35])=[O:15])=[C:4]([C:30]([F:32])([F:31])[F:33])[CH:3]=1
Reactant: O=P([O-])(O)O
Reactant: Cc1c(C(=O)Nc2ccc(S(C)(=O)=O)cc2)cc(CC=O)n1-c1ccc(Cl)cc1C(F)(F)F
Agent: CC=C(C)C
Agent: Cl
Agent: O=S([O-])O
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1c(C(=O)Nc2ccc(S(C)(=O)=O)cc2)cc(CC(=O)O)n1-c1ccc(Cl)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.1 %

Procedure:
To a solution of the above 1-[4-chloro-2-(trifluoromethyl)phenyl]-2-methyl-N-[4-(methylsulfonyl)phenyl]-5-(2-oxoethyl)-1H-pyrrole-3-carboxamide (0.85 g, 1.7 mmol) in tert-butanol (14 mL)-water (3.4 mL), sodium dihydrogenphosphate (0.40 g, 2.6 mmol), 2-methyl-2-butene (0.77 mL, 6.8 mmol) and sodium chlorite (0.85 g, 5.1 mmol) were added, and the mixture was stirred at room temperature for 1 hour. A 10% aqueous sodium hydrogensulfite solution and 1M hydrochloric acid were added to the mixture to stop the reaction, and the mixture was extracted with dichloromethane. The obtained organic layer was washed with saturated brine, and after the solution was dried with sodium sulfate, it was filtered and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give (1-[4-chloro-2-(trifluoromethyl)phenyl]-5-methyl-4-{[4-(methylsulfonyl)phenyl]carbamoyl}-1H-pyrrol-2-yl)acetic acid (0.50 g, 57%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([N:14]=CN(C)C)[C:11]([C:19]#[N:20])=[N:10][C:9]=1[C:21]1[CH:26]=[CH:25][C:24](=[O:27])[N:23]([CH:28]([CH3:30])[CH3:29])[N:22]=1.[OH-].[Na+]>O.Cl.O1CCOCC1>[NH2:14][C:12]1[C:11]([C:19]#[N:20])=[N:10][C:9]([C:21]2[CH:26]=[CH:25][C:24](=[O:27])[N:23]([CH:28]([CH3:30])[CH3:29])[N:22]=2)=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])[N:13]=1
Reactant: CC(C)n1nc(-c2nc(C#N)c(N=CN(C)C)nc2-c2ccccc2Br)ccc1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)n1nc(-c2nc(C#N)c(N)nc2-c2ccccc2Br)ccc1=O
Temperature: 22.5 °C
Reaction time: 18 h
Yield: 64.9 %

Procedure:
A solution of N′-[6-(2-bromophenyl)-3-cyano-5-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-pyrazinyl]-N,N-dimethylimidoformamide (285 mg) in a mixture of water (2 ml) and 4N hydrogen chloride in dioxane (6 ml) was stirred at 20-25° C. for 18 hours. After addition of water (18 ml), the mixture was neutralized with 1N aq. NaOH to give a solid. The solid was collected by filtration and purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (50:50 v/v) to give 3-amino-5-(2-bromophenyl)-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-pyrazinecarbonitrile as a solid (163 mg).