Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][C@H:4]([NH2:8])[C:5]([OH:7])=[O:6].[Cl:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:11]=1[C:12](Cl)=[O:13]>[OH-].[Na+].C1COCC1>[Cl:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:11]=1[C:12]([NH:8][C@@H:4]([CH2:3][CH:2]=[CH2:1])[C:5]([OH:7])=[O:6])=[O:13]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: C=CC[C@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CC[C@H](NC(=O)c1c(Cl)cccc1Cl)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a mixed solvent of 2N aqueous sodium hydroxide solution (27.4 ml) and THF (55 ml), L-allylglycine (5.22 g) was dissolved, and 2,6-dichlorobenzoyl chloride (7.79 ml) was added dropwise thereto, followed by stirring the resulting mixture at room temperature for 1 hour. After concentrating the reaction solution to remove methanol, water (100 ml) was added thereto and the resulting mixture was washed with ether. Aqueous layer was acidified by adding 3N hydrochloric acid in small portions thereto, and extracted 3 times with ethyl acetate. Organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was recrystallized from hexane/ethyl acetate mixed solvent to obtain (S)-2-(2,6-dichlorobenzamido)pent-4-enoic acid (11.65 g). NMR (HL, CDCl3): δ 2.66-2.73 (1H, m), 2.80-2.86 (1H, m), 4.99 (1H, td, J=7.6, 5.6 Hz), 5.18-5.25 (2H, m), 5.76-5.86 (1H, m), 6.39 (1H, brd, J=7.6 Hz), 7.25-7.34 (3H, m) (2) Under an argon atmosphere, a solution of (S)-2-(2,6-dichlorobenzamido)pent-4-enoic acid (11.46 g) in methanol (120 ml) was cooled to 0° C. Thionyl chloride (5.22 ml) was added dropwise to the solution while keeping the reaction temperature not higher than 10° C., and thereafter the resulting mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, and sodium hydrogen carbonate was added thereto in small portions to neutralize it. After concentrating the reaction solution to remove methanol, aqueous layer was extracted twice with ethyl acetate. Organic layers were washed 3 times with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was recrystallized from hexane/ethyl acetate mixed solvent to obtain (S)-2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (11.68 g). NMR (H1, CDCl3): δ 2.62-2.69 (1H, m), 2.76-2.83 (1H, m), 3.79 (3H, s), 4.96 (1H, td, J=7.8, 5.4 Hz), 5.14-5.21 (2H, m), 5.72-5.82 (1H, m), 6.42 (1H, brd, J=6.8 Hz), 7.25-7.34 (3H, m)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:19]([NH:21][NH2:22])=[O:20])=[CH:11][C:12]3[NH:16][CH:15]=[N:14][C:13]=3[C:17]=2[F:18])=[C:4]([CH3:23])[CH:3]=1.[CH:24](OCC)(OCC)OCC.CC1C=CC(S(O)(=O)=O)=CC=1.O>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:19]3[O:20][CH:24]=[N:22][N:21]=3)=[CH:11][C:12]3[NH:16][CH:15]=[N:14][C:13]=3[C:17]=2[F:18])=[C:4]([CH3:23])[CH:3]=1
Reactant: CCOC(OCC)OCC
Reactant: Cc1cc(Cl)ccc1Nc1c(C(=O)NN)cc2[nH]cnc2c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: Cc1cc(Cl)ccc1Nc1c(-c2nnco2)cc2[nH]cnc2c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.7 %

Procedure:
6-(4-Chloro-2-methyl-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid hydrazide 20b (0.048 g, 0.144 mmol) is suspended in 3 mL absolute EtOH and HC(OEt)3 (0.60 mL, 3.54 mmol) is added followed by catalytic pTsOH.H2O. The reaction mixture is heated to reflux under N2. After 2 hours, the reaction mixture is cooled to room temperature and concentrated under reduced pressure. Purification by flash column chromatography (97:3 ethyl acetate:MeOH) provides 36 mg (73%) desired product as a light yellow solid. LC/MS ESI (+) m/z 344, 346 (M+ Cl pattern) detected; 1H NMR (400 MHz, DMSO-d6) δ13.10 (bs, 1H), 9.39 (s, 1H), 8.49 (s, 1H), 8.10 (bs, 1H), 7.78 (bs, 1H), 7.20 (d, 1H), 7.00 (dd, 1H), 6.41 (bs, 1H), 2.18 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[N:4][C:5]([NH2:9])=[C:6]([NH2:8])[CH:7]=1.[C:11](O)(=O)[CH2:12][CH2:13][CH2:14][CH3:15].[OH-].[Na+]>O.C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]2[NH:8][C:11]([CH2:12][CH2:13][CH2:14][CH3:15])=[N:9][C:5]2=[N:4][C:3]=1[CH3:10]
Reactant: Cc1nc(N)c(N)cc1Br
Reactant: CCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1nc2nc(C)c(Br)cc2[nH]1
Temperature: 110 °C
Reaction time: 3 h
Yield: 81.9 %

Procedure:
9.0 g (44.6 mmole) of the compound obtained in step 3 and 5.5 g (58 mmole) of valeric acid were mixed with 30 ml of polyphosphoric acid and stirred for 3 hours at 110° C. The reaction solution was dissolved in a mixture of 50 ml of cold water and 50 ml of THF and the resulting solution was neutralized to Ph 8 with cold 40% aqueous NaOH solution with stirring vigorously and extracted with ethyl acetate (50 ml×3). Thereafter, the organic layer was dried over Na2SO4, concentrated under reduced pressure and recrystallized from hexane-methylene chloride to obtain 9.8 g of the title compound (yield 82%).
Reaction SMILES: [C:1]([CH:4]1[N:12](C(OC(C)(C)C)=O)[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[CH2:5]1)(=[O:3])[NH2:2].[C:20]([OH:26])([C:22]([F:25])([F:24])[F:23])=[O:21]>C(Cl)Cl>[F:23][C:22]([F:25])([F:24])[C:20]([OH:26])=[O:21].[NH:12]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[CH2:5][CH:4]1[C:1]([NH2:2])=[O:3]
Reactant: CC(C)(C)OC(=O)N1c2ncccc2CC1C(N)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)C1Cc2cccnc2N1
Reaction time: 8 h
Yield: 90.2 %

Procedure:
To a solution of tert-butyl 2-carbamoyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (100 mg, 380 μmol, Eq: 1.00) in DCM (3 mL) was added TFA (2 mL, 26.0 mmol, Eq: 68.3) and the resulting mixture was stirred overnight. The reaction mixture was concentrated in vacuo and azeotroped with DCM (2×10 mL). The resulting residue was triturated with ether to give 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid amide, trifluoroacetate salt as an off-white solid (95 mg)
Reaction SMILES: Br[C:2]1[C:3]([NH:10][C@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17](=[O:21])[CH2:18][C:19]#[N:20])[CH2:12]2)=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.[CH3:22][Si:23]([CH3:42])([CH3:41])[CH2:24][CH2:25][O:26][CH2:27][N:28]1[C:32]2=[N:33][CH:34]=[C:35]([Sn](C)(C)C)[N:36]=[C:31]2[CH:30]=[CH:29]1.BrC1N=C2C=CN(COCC[Si](C)(C)C)C2=NC=1>>[CH3:9][S:8][C:5]1[N:4]=[C:3]([NH:10][C@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17](=[O:21])[CH2:18][C:19]#[N:20])[CH2:12]2)[C:2]([C:35]2[N:36]=[C:31]3[CH:30]=[CH:29][N:28]([CH2:27][O:26][CH2:25][CH2:24][Si:23]([CH3:42])([CH3:41])[CH3:22])[C:32]3=[N:33][CH:34]=2)=[CH:7][N:6]=1
Reactant: C[Si](C)(C)CCOCn1ccc2nc([Sn](C)(C)C)cnc21
Reactant: CSc1ncc(Br)c(N[C@H]2CCCN(C(=O)CC#N)C2)n1
Agent: C[Si](C)(C)CCOCn1ccc2nc(Br)cnc21
Product: CSc1ncc(-c2cnc3c(ccn3COCC[Si](C)(C)C)n2)c(N[C@H]2CCCN(C(=O)CC#N)C2)n1

Procedure:
The 3-[(S)-3-(5-bromo-2-methylsulfanyl-pyrimidin-4-ylamino)-piperidin-1-yl]-3-oxo-propionitrile from above (226 mg, 609 μmol) was cross-coupled with 5-(2-trimethylsilanyl-ethoxymethyl)-2-trimethylstannanyl-5H-pyrrolo[2,3-b]pyrazine prepared from 2-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (200 mg, 0.61 mmol) and tetrakistriphenylphosphine palladium (0) (35 mg, 0.03 mmol) in a manner similar to step 3, Example 76 to give 3-((S)-3-{2-methylsulfanyl-5-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidin-4-ylamino}-piperidin-1-yl)-3-oxo-propionitrile (−40 mg). MS (ES+): 539.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:13]=[CH:12][O:11][CH:10]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][O:24][CH2:25][C:26](O)=[O:27])=[C:17]([C:30]([O:32]C)=[O:31])[CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][O:24][CH2:25][C:26]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[C:3]([C:9]3[CH:13]=[CH:12][O:11][CH:10]=3)[CH:4]=2)=[O:27])=[C:17]([CH:16]=1)[C:30]([OH:32])=[O:31]
Reactant: Nc1ccc(F)c(-c2ccoc2)c1
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Product: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1ccc(F)c(-c2ccoc2)c1

Procedure:
Using the same method as in Example 15-(i), 4-fluoro-3-(furan-3-yl)aniline was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-([(2-([4-fluoro-3-(furan-3-yl)phenyl]amino)-2-oxoethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 52%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>CN(C)C=O.O>[CH3:24][C:23]([CH3:26])([O:22][C:20]([CH2:19][NH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1)=[O:21])[CH3:25]
Reactant: Nc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)CNc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.6 %

Procedure:
To a solution of 2-aminonaphthalene (985 mg, 6.8 mmol) in N,N-dimethylformamide (DMF) (50 mL) was added potassium carbonate (1.806 g, 13.6 mmol) and tert-butyl bromoacetate (1.4 mL, 9.9 mmol). The resulting reaction mixture was stirred at ambient temperature. After 24 hours, the reaction mixture was diluted with water (200 mL), then extracted by ethyl acetate (150 mL). The organic layer was separated and washed with water (3×100 mL), then dried over sodium sulfate. The solvent was evaporated in vacuo to afford a product as ann yellow oil. Purification of product by flash column on silica gel afforded 2-((1,1-dimethylethoxycarbonyl)methyl)aminonaphthalene (1.2 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:3][CH2:2]1.Br[CH2:15][C:16]#[N:17]>>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][CH:4]1[CH2:5][CH2:6][N:1]([CH2:15][C:16]#[N:17])[CH2:2][CH2:3]1
Reactant: c1ccc(CC2CCNCC2)nc1
Reactant: N#CCBr
Product: N#CCN1CCC(Cc2ccccn2)CC1

Procedure:
The title compound is synthesized by coupling of 2-Piperidin-4-ylmethyl-pyridine (commercially available from Array Biopharma) and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+=216.2.
Reaction SMILES: [CH3:1][N:2]([S:6][N:7]([CH3:11])[C:8]([F:10])=[O:9])[C:3](F)=[O:4].[C:12]1([OH:22])[C:21]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=2[CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:12]1([O:22][C:3](=[O:4])[N:2]([CH3:1])[S:6][N:7]([CH3:11])[C:8]([F:10])=[O:9])[C:21]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: CN(SN(C)C(=O)F)C(=O)F
Reactant: Oc1cccc2c1CCCC2
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN(SN(C)C(=O)Oc1cccc2c1CCCC2)C(=O)F

Procedure:
5,6,7,8-Tetrahydronaphthyl-N-methyl-N-(N'-methyl-N'-fluoroformylaminosulfenyl)carbamate was prepared by the procedure of Example IX by reacting 9.21 g of bis-(N-methyl-N-fluorocarbonylamino)sulfide with 7.41 g of 5,6,7,8-tetrahydro-1-naphthol in 300 ml of toluene with 5.05 g of triethylamine as acid acceptor to yield 9.5 g of an oil.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6](=[O:13])[N:7]2[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]2)=O.C(O)(=O)C.[C:23]([O:31][CH2:32][CH3:33])(=[O:30])[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>C1C=CC=CC=1>[C:23]([C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:1][C:3]1[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6](=[O:13])[N:7]2[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]2)([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCOC(=O)c1cc(C=O)c2ccccn2c1=O
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CCOC(=O)C(=Cc1cc(C(=O)OCC)c(=O)n2ccccc12)C(=O)OCC
Temperature: 25 °C
Yield: 81.6 %

Procedure:
A 100 ml round-bottom flask equipped with a Dean-Stark trap was charged with 50 ml benzene, ethyl 1-formyl-4-oxo-4H-quinolizine-3-carboxylate (8) (1.22 g, 5 mmol), acetic acid (5 g, 83 mmol), NH4OAc (5 g, 65 mmol), and diethyl malonate (2.3 g, 9 mmol). The reaction mixture was refluxed for 48 h. The reaction mixture was cooled to room temperature and washed three times with 50 ml water. The solvent was evaporated in vacuo and the crude product was purified by flash chromatography (ethyl acetate) to yield ethyl 1-(2,2-dicarboethoxyvinyl)-4-oxo-4H-quinolizine-3-carboxylate (12) as a yellow powder (1.58 g, 82%). M.p. 149-151° C. 1H NMR (δ, CDCl3): 1.31 (t, J=7 Hz, 3H), 1.36 (t, J=7 Hz, 3H), 1.42 (t, J=7 Hz, 3H), 4.34 (q, J=7 Hz, 2H), 4.36 (q, J=7 Hz, 2H), 4.41 (q, J=7 Hz, 2H), 7.34 (dd, J=7 Hz, J=7 Hz, 1H), 7.82 (dd, J=8 Hz, 1H), 7.96 (d, J=8 Hz, 1H), 8.05 (s, 1H), 8.60 (s, 1H), 9.50 (d, J=7 Hz). MS: m/z 387.1331; required for C20H21NO7: 387.1318.
Reaction SMILES: Cl[C:2]1[CH:19]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:20])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=3.[CH3:21][C:22]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[C:23]=1[NH2:24]>CC(O)C>[CH3:16][O:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][C:9]=1[O:17][CH3:18])[C:6]1=[CH:19][C:2](=[N:24][C:23]3[C:25]([CH3:30])=[CH:26][C:27]([CH3:29])=[CH:28][C:22]=3[CH3:21])[NH:3][C:4](=[O:20])[N:5]1[CH2:14][CH2:13]2
Reactant: COc1cc2c(cc1OC)-c1cc(Cl)nc(=O)n1CC2
Reactant: Cc1cc(C)c(N)c(C)c1
Solvent: CC(C)O
Product: COc1cc2c(cc1OC)-c1cc(=Nc3c(C)cc(C)cc3C)[nH]c(=O)n1CC2
Temperature: 25 °C

Procedure:
2-Chloro-9,10-dimethoxy-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-4-one, prepared according to Preparation 1, (38.5 g, 0.13 mol) and 2,4,6-trimethylaniline (52.7 g, 0.39 mol) in propan-2-ol (31) was stirred and heated at reflux, under nitrogen, for 24 h. After cooling to room temperature, the solution was evaporated in vacuo and the residue was purified by column chromatography on silica gel, eluting with CH2Cl2/MeOH, initially 98:2, changing to 96:4 once the product began to elute from the column. The title compound was obtained with a slight impurity, just above the product on tic). Yield 34.6 g, 67%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C:13]1[CH:35]=[CH:34][C:16]([O:17][CH:18]([CH3:33])[C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)=O)=[CH:15][CH:14]=1)[CH:6]=[N:5]2.C1COCC1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:42]>O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C:13]1[CH:35]=[CH:34][C:16]([O:17][CH:18]([CH3:33])[C:19](=[S:42])[NH:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)=[CH:15][CH:14]=1)[CH:6]=[N:5]2
Reactant: CC(Oc1ccc(Oc2cnc3cc(F)ccc3n2)cc1)C(=O)Nc1ccc(OC(F)(F)F)cc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: C1CCOC1
Solvent: O
Product: CC(Oc1ccc(Oc2cnc3cc(F)ccc3n2)cc1)C(=S)Nc1ccc(OC(F)(F)F)cc1
Reaction time: 2 h

Procedure:
A mixture of 2.0 g (4.1 mmol) of 2-(4-((6-fluoro-2-quinoxalinyl)oxy)phenoxy)-N-(4-(trifluoromethoxy)phenyl)propanamide and 40 ml of dry THF in a 100 ml flask was placed in a water-filled ultrasonic bath. Phosphorous pentasulfide (0.22 g) was added and the mixture sonicated while maintaining the reaction temperature below 40° C. by occasional addition of ice to the water bath. Additional P2S5 (1.76 g) was added in portions at 20 minute intervals over the next hour. Sonication was continued for an additional 2 hours and the mixture then filtered and the solid washed well with methylene chloride. The combined filtrates were treated with charcoal, filtered and evaporated to dryness. The residue was purified first by chromatography over silica gel, eluting with CH2Cl2, and then by preparative scale HPLC, eluting with 85:15 hexane: acetone. This left 1.1 g (53 percent of theoretical) of the above-named product as a yellow glassy solid. (Compound 34)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11](Cl)=[C:12]([F:17])[CH:13]=2)[N:8]([CH:19]2[CH2:21][CH2:20]2)[CH:7]=1)=[O:5])[CH3:2].[C:22]([NH:25][CH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[CH2:32][NH:31][CH2:30]2)(=[O:24])[CH3:23].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([N:31]3[CH2:30][C:29]4[C:33](=[CH:34][CH:35]=[C:27]([CH2:26][NH:25][C:22](=[O:24])[CH3:23])[CH:28]=4)[CH2:32]3)=[C:12]([F:17])[CH:13]=2)[N:8]([CH:19]2[CH2:21][CH2:20]2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: CC(=O)NCc1ccc2c(c1)CNC2
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(C2CC2)c2nc(N3Cc4ccc(CNC(C)=O)cc4C3)c(F)cc2c1=O
Yield: 56.1 %

Procedure:
A mixture of 310 mg of 1-cyclopropyl-6-fluoro-7- chloro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester, 745 mg of 5-acetamidomethylisoindoline, 0.56 ml of triethylamine, and 5 ml of anhydrous chloroform was heated at 60°-70° C. for 0.5 hours while stirring. The resulting reaction mixture was diluted with 25 ml of chloroform. The mixture was washed with 5% acetic acid and brine in this order, dried over anhydrous sodium sulfate, and condensed. The residue was crystallized by the addition of ethylether. The crystals were collected by filtration and recrystallized from a mixed solvent of chloroform, methanol, and ethanol to obtain 260 mg of 7-(5- acetamidomethyl-2-isoindolinyl)-1-cyclopropyl-6-fluoro-1,4- dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester.
Reaction SMILES: [Cl:1][C@H:2]1[CH2:6][N:5](C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)[C@@H:4]2[C@@H:24]([OH:27])[CH2:25][O:26][C@H:3]12.Cl[C@H]1CN(C(OCC2C=CC=CC=2)=O)[C@@H]2[C@@H](O)CO[C@H]12.[H][H]>[Pd].C(O)C>[Cl:1][C@H:2]1[CH2:6][NH:5][C@@H:4]2[C@@H:24]([OH:27])[CH2:25][O:26][C@H:3]12
Reactant: [H][H]
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)N1C[C@H](Cl)[C@H]2OC[C@H](O)[C@H]21
Agent: [Pd]
Agent: O=C(OCc1ccccc1)N1C[C@H](Cl)[C@H]2OC[C@H](O)[C@H]21
Solvent: CCO
Product: O[C@H]1CO[C@H]2[C@@H]1NC[C@@H]2Cl
Reaction time: 0.58 h

Procedure:
(3R,3aR,6S,6aS)-(9H-Fluoren-9-yl)methyl 6-chloro-3-hydroxytetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate (70). Ethanol (8.5 mL) was added dropwise to a mixture of 10% palladium on charcoal (55 mg) and alcohol (68) (550 mg, 1.85 mmol) under an atmosphere of argon. The argon was replaced by hydrogen then the suspension was stirred for 1 hour 35 minutes before filtering the mixture through celite in vacuo. The filter cake was washed with ethanol (45 mL) then the solvents removed in vacuo from the filtrate. The residue was azeotroped with toluene (3×5 mL) to obtain (3R,3aR,6S,6aS)-6-chlorohexahydro-2H-furo[3,2-b]pyrrol-3-ol (69) which was used without further purification.
Reaction SMILES: [NH:1]=[C:2]1[N:6]([C:7]2[S:8][CH:9]=[C:10]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[N:11]=2)[C:5]([CH3:21])([CH3:20])[CH2:4][O:3]1.[CH2:22]([N:24](CC)CC)C.N#CBr>O1CCCC1>[C:16]([C:15]1[CH:14]=[CH:13][C:12]([C:10]2[N:11]=[C:7]([N:6]3[C:5]([CH3:21])([CH3:20])[CH2:4][O:3]/[C:2]/3=[N:1]\[C:22]#[N:24])[S:8][CH:9]=2)=[CH:19][CH:18]=1)#[N:17]
Reactant: CCN(CC)CC
Reactant: CC1(C)COC(=N)N1c1nc(-c2ccc(C#N)cc2)cs1
Agent: N#CBr
Solvent: C1CCOC1
Product: CC1(C)CO/C(=N\C#N)N1c1nc(-c2ccc(C#N)cc2)cs1
Reaction time: 8 h
Yield: 7.5 %

Procedure:
4-[2-(2-Imino-4,4-dimethyl-1,3-oxazolidin-3-yl)-1,3-thiazol-4-yl]benzonitrile (0.250 g, 0.83 mmol), prepared in Example 63, was dissolved in tetrahydrofuran (2 mL) followed by triethylamine (0.139 mL, 1 mmol) and cyanogen bromide (0.21 g, 2 mmol). The mixture was stirred overnight, filtered and the tetrahydrofuran was removed in vacuo. Purification by normal phase HPLC on a phenomenex cyano column eluting with hexane/1,2-dimethoxyethane (9:1 to 1:9) gave the title compound (0.020 g, 7%). HRMS: calcd for C16H13N5OS+H+, 324.09136; found (ESI, [M+H]+), 324.0919; HPLC purity 100% at 210-370 nm, 9.3 min; 100% at 246 nm, 9.3 min; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([CH3:11])([OH:10])[C:4]#[C:5][Si](C)(C)C.[H-].[Na+].[N+:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)([O-:18])=[O:17]>CN(C=O)C>[N+:16]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([O:10][C:3]([CH3:11])([C:2]([F:13])([F:12])[F:1])[C:4]#[CH:5])=[O:24])=[CH:26][CH:27]=1)([O-:18])=[O:17]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CC(O)(C#C[Si](C)(C)C)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CC(C)(OC(=O)c1ccc([N+](=O)[O-])cc1)C(F)(F)F
Reaction time: 0.5 h

Procedure:
A solution of crude 1,1,1-trifluoro-2-methyl-4-(trimethylsilyl)but-3-yn-2-ol from Step 1 (˜20.2 mmol) in DMF (10 mL) was added dropwise to a suspension of NaH (60% disp., 850 mg, 21.2 mmol) in DMF (25 mL) at 0° C. The mixture was allowed to reach room temperature, stirred for 30 min. and recooled to 0° C. A solution of 4-nitrobenzoyl chloride (3.94 g, 21.2 mmol) in DMF (10 mL) was added dropwise and the resulting mixture was stirred at room temperature. After 30 min., the mixture was poured in 1:1 25% NH4OAc/H2O and extracted with Et2O (3×). The combined organic layers were washed with H2O (3×) and brine, dried (Na2SO4) and concentrated. The residue was subjected to chromatography on silica gel (toluene/hexane 40:60 to 60:40) affording the title compound. 1H NMR (400 MHz, acetone-d6): 8.44 (d, 2H), 8.28 (d, 2H), 3.65 (s, 1H), 2.09 (s, 3H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:10][O:9][CH2:8][C@H:7]([O:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C@@H:6]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])[C@H:5]([CH3:21])[O:4][C:3]1=[O:22].[OH:23][C:24]1[C:25]([C:32](O)=[O:33])=[N:26][CH:27]=[CH:28][C:29]=1[O:30][CH3:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>C(Cl)Cl>[CH2:12]([O:11][C@@H:7]1[C@@H:6]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])[C@H:5]([CH3:21])[O:4][C:3](=[O:22])[C@@H:2]([NH:1][C:32](=[O:33])[C:25]2[C:24]([OH:23])=[C:29]([O:30][CH3:31])[CH:28]=[CH:27][N:26]=2)[CH2:10][O:9][CH2:8]1)[CH:13]([CH3:14])[CH3:15]
Reactant: COc1ccnc(C(=O)O)c1O
Reactant: CC(C)CO[C@H]1[C@H](C)OC(=O)[C@@H](N)COC[C@@H]1OCC(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccnc(C(=O)N[C@H]2COC[C@H](OCC(C)C)[C@@H](OCC(C)C)[C@H](C)OC2=O)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.1 %

Procedure:
To a mixture of (3S,7S,8S,9S)-3-amino-7,8-diisobutoxy-9-methyl-1,5-dioxonan-2-one (170 mg, 0.536 mmol), 3-hydroxy-4-methoxypicolinic acid (136 mg, 0.803 mmol) and HATU (336 mg, 0.857 mmol) in a vial was added CH2Cl2 (3 mL), followed by 4-methylmorpholine (0.353 mL, 3.21 mmol), and the resulting suspension was stirred at room temperature for 3 h. The resulting orange solution was directly purified by flash chromatography (SiO2) to afford the title compound as a white solid (176 mg, 70%): 1H NMR (400 MHz, CDCl3) δ11.95 (s, 1H), 8.68 (d, J=8.0 Hz, 1H), 8.00 (d, J=5.2 Hz, 1H), 6.87 (d, J=5.2 Hz, 1H), 5.10-5.00 (m, 1H), 4.97 (dt, J=12.6, 6.3 Hz, 1H), 4.10-4.01 (m, 1H), 3.94 (s, 3H), 3.87-3.78 (m, 2H), 3.71 (dd, J=8.4, 6.1 Hz, 1H), 3.66-3.57 (m, 1H), 3.38-3.28 (m, 2H), 3.28-3.17 (m, 3H), 1.90-1.76 (m, 2H), 1.45 (t, J=5.8 Hz, 3H), 0.98-0.88 (m, 12H); 13C NMR (101 MHz, CDCl3) δ 170.33, 168.95, 155.38, 148.76, 140.66, 130.23, 109.58, 84.84, 83.75, 80.60, 77.74, 75.32, 73.97, 73.23, 56.11, 52.19, 29.13, 28.89, 19.60, 19.48, 19.47, 19.39, 18.66; ESIMS m/z 469.4 ([M+H]+).