Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=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.[CH3:57][C:58]([NH2:62])([CH2:60][CH3:61])[CH3:59]>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:62][C:58]([CH2:60][CH3:61])([CH3:59])[CH3:57])=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: CCC(C)(C)N
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(F)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C)(C)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Reaction time: 16 h
Yield: 20.8 %

Procedure:
To a stirred solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (59 mg, 0.19 mmol), HATU (91.20 mmol, 0.24 mmol) and DIPEA (49 mg, 0.38 mmol) in 6 mL of DMF, 2-methylbutan-2-amine (21.60 mg, 0.24 mmol) was added in one portion at room temperature. Then the reaction mixture was stirred for 16 hours. The solvent was evaporated at 70° C. under reduced pressure and the residue was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions were: 15% acetonitrile/75% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 70% acetonitrile/30% water (0.1% trifluoroacetic acid, v/v) in a linear fashion after 9 min.) to give 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-N-tert-pentyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (15 mg, 20.7%) as a white solid. MS: (M+H)+=381; 1H NMR (300 MHz, DMSO): δ 12.82 (s, 1H), 9.07 (s, 1H), 8.47-8.37 (m, 2H), 7.81 (s, 1H), 7.70 (dd, 1H, J=9.6, 2.1 Hz), 7.17 (t, 1H, J=2.1 Hz), 4.15 (s, 3H), 1.89 (q, 2H, J=7.6 Hz), 1.46 (s, 6H), 0.87 (t, 3H, J=7.5 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([N:22]([CH3:39])[C:23](=[O:38])[CH2:24][N:25]3[C:30]4[CH:31]=[C:32]([Cl:36])[C:33]([Cl:35])=[CH:34][C:29]=4[O:28][CH2:27][C:26]3=[O:37])[CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:40]([S:42](Cl)(=[O:44])=[O:43])[CH3:41].C(N(CC)CC)C>ClCCl>[Cl:36][C:32]1[C:33]([Cl:35])=[CH:34][C:29]2[O:28][CH2:27][C:26](=[O:37])[N:25]([CH2:24][C:23]([N:22]([CH:14]([C:11]3[CH:12]=[CH:13][C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][S:42]([CH2:40][CH3:41])(=[O:44])=[O:43])[CH:3]=4)=[CH:9][CH:10]=3)[CH2:15][N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)[CH3:39])=[O:38])[C:30]=2[CH:31]=1
Reactant: CCS(=O)(=O)Cl
Reactant: CN(C(=O)CN1C(=O)COc2cc(Cl)c(Cl)cc21)C(CN1CCOCC1)c1ccc(-c2cccc(N)c2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1cccc(-c2ccc(C(CN3CCOCC3)N(C)C(=O)CN3C(=O)COc4cc(Cl)c(Cl)cc43)cc2)c1
Reaction time: 0.2 h
Yield: 33.3 %

Procedure:
To a solution of N-[1-(3′-amino-4-biphenylyl)-2-(4-morpholinyl)ethyl]-2-(6,7-dichloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-N-methylacetamide (70.1 mg, 0.12 mmol) in dichloromethane (1 mL) was added ethanesulfonyl chloride (32 mg, 0.24 mmol). Triethylamine (50 mg, 0.50 mmol) was added and the resultant mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by Gilson preparative HPLC (Sunfire Prep C18, 30×150 mm, 50 mL/min, A: acetonitrile with 0.1% TFA B: water with 0.1% TFA, A: 30 to 60% over 12 min, UV detection at 214 nm) to give 26.4 mg (33%) of the title compound as off white solid. MS (ES) m/e 661.2 [M+H]+.
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2([CH3:19])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:9][N:8]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:19][C:13]1([C:10]2[CH:11]=[CH:12][C:7]([NH2:6])=[N:8][CH:9]=2)[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: COc1ccc(CNc2ccc(C3(C)CCOCC3)cn2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(c2ccc(N)nc2)CCOCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 89.7 %

Procedure:
To an ice cold solution of N-(2,4-dimethoxybenzyl)-5-(4-methyltetrahydro-2H-pyran-4-yl)pyridin-2-amine (100 mg, 0.29 mmol) in DCM (6 mL) was added 10 mL 30% TFA in DCM solution. The resulting solution was stirred at 0° C. for 15 min. The solvent was removed via vacuum. The resulting residue was redissolved in ethyl acetate, and the organic solution was washed with 1M NaOH, brine, dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography on silicagel (ISCO) eluting with 0-100% ethyl acetate in heptane to give 5-(4-methyltetrahydro-2H-pyran-4-yl)pyridin-2-amine (50 mg, 0.26 mmol, 89% yield) as white color solid. LCMS (m/z): 193 (MH+), 0.35 min.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)=[CH:22][CH:21]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=3[F:19])[N:11]=2)=[CH:4][CH:3]=1.[C:36]([C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1)([CH3:39])([CH3:38])[CH3:37]>>[C:36]([C:40]1[CH:45]=[CH:44][C:43]([C:2]2[CH:35]=[CH:34][C:5]([CH2:6][C:7]3[N:8]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[S:30](=[O:31])(=[O:32])[NH:29][C:28](=[O:33])[CH2:27]5)=[CH:22][CH:21]=4)[CH:9]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=4[F:19])[N:11]=3)=[CH:4][CH:3]=2)=[CH:42][CH:41]=1)([CH3:39])([CH3:38])[CH3:37]
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(F)cc4F)nc3Cc3ccc(Br)cc3)cc2)S(=O)(=O)N1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Product: CC(C)(C)c1ccc(-c2ccc(Cc3nc(-c4ccc(F)cc4F)cn3-c3ccc(N4CC(=O)NS4(=O)=O)cc3)cc2)cc1

Procedure:
5-{4-[2-(4-Bromo-benzyl)-4-(2,4-difluoro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (prepared according to general procedures A, B and C subsequently) (56 mg, 0.1 mmol) was treated as described in general procedure G using 4-tert-butylphenylboronic acid (36 mg, 0.2 mmol) to give 5-{4-[2-(4′-tert-butyl-biphenyl-4-ylmethyl)-4-(2,4-difluoro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:21]=1[C:22](Cl)=[O:23].N1C=CC=CC=1>O1CCCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:22](=[O:23])[C:21]2[CH:25]=[C:26]([C:29]([F:30])([F:31])[F:32])[CH:27]=[CH:28][C:20]=2[F:19])[N:7]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(N)n(Cc2ccc(F)cc2)n1
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)c2cc(C(F)(F)F)ccc2F)n(Cc2ccc(F)cc2)n1
Temperature: 60 °C
Reaction time: 16 h
Yield: 65.9 %

Procedure:
To a solution of Example 30A (0.7 g, 2.6 mmol) in tetrahydrofuran (20 mL) were added 2-fluoro-5-(trifluoromethyl)benzoyl chloride (0.46 mL, 3.1 mmol, Aldrich) and pyridine (0.62 mL, 7.6 mmol). After stirring at 60° C. for 16 h, the reaction mixture was cooled and quenched with saturated NaHCO3 (20 mL). The aqueous layer was extracted with ethyl acetate (3×30 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, O-25% ethyl acetate in methylene chloride) to afford 0.75 g (67%) of the title compound. MS (ESI+) m/z 438 (M+H)+.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:30])[CH:20]=[C:21]([C:22]4[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>>[Cl:30][C:19]1[CH:20]=[C:21]([C:22]2[C:23]([CH3:29])=[CH:24][CH:25]=[CH:26][C:27]=2[CH3:28])[C:15]2[O:14][CH:13]([CH2:12][N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[CH2:17][C:16]=2[CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(-c4c(C)cccc4C)c3O2)cc1
Reactant: C1CCNC1
Product: Cc1cccc(C)c1-c1cc(Cl)cc2c1OC(CN1CCCC1)C2

Procedure:
The title compound was prepared (0.094 g, 73%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.15 g, 0.338 mmol) and pyrrolidine (0.48 g, 6.76 mmol). mp 245-247° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11](O)[C@@H:10]([N:14]=[N+:15]=[N-:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COCCN(S(F)(F)[F:27])CCOC>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([F:27])[C@@H:10]([N:14]=[N+:15]=[N-:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](N=[N+]=[N-])[C@@H](O)C1
Reactant: COCCN(CCOC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(F)[C@@H](N=[N+]=[N-])C1
Temperature: 25 °C
Reaction time: 22 h
Yield: 60.5 %

Procedure:
37.1 To stirred, cooled (−78° C.) solution of 695 mg (3S,4S)-3-azido-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (example 22.2) in 5 ml CH2Cl2 under an argon atmosphere were added 2.69 g bis(2-methoxyethyl)aminosulphur trifluoride (50% solution in THF). The dry ice bath was removed and the mixture was allowed to warm to r.t. and stirring was continued for 22 h. The mixture was poured into 10% aq. Na2CO3. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated. The crude product was purified by chromatography (silica gel; gradient: cyclohexane->cyclohexane/EtOAc 3:2) to give 424 mg (S)-3-azido-4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester as light yellow oil. MS 409.0 ([M+H]+)
Reaction SMILES: CI.[C:3](=O)([O-])[O-].[K+].[K+].[CH3:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=1[C@H:19]1[C@H:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:23]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@H:22]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C@@H:21]([CH2:49][O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[O:20]1>CN(C=O)C>[CH3:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([O:16][CH3:3])=[O:15])=[CH:12][C:11]=1[C@H:19]1[C@H:24]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@@H:23]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@H:22]([O:41][CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C@@H:21]([CH2:49][O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[O:20]1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(C(=O)O)cc1[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(C)c([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c1
Reaction time: 3 h
Yield: 84.9 %

Procedure:
Methyl iodide (0.17 ml) and potassium carbonate (0.4 g) were added to a solution of 4-methyl-3-[(2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-[(benzyloxy)methyl]-tetrahydro-2H-pyran-2-yl]benzoic acid (1.5 g) in DMF (10 ml) at room temperature and the mixture was stirred for three hours. The insoluble matter was separated by filtration and the filtrate was diluted with ethyl acetate. The diluted solution was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain methyl 4-methyl-3-[(2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-[(benzyloxy)methyl]-tetrahydro-2H-pyran-2-yl]benzoate (1.3 g).
Reaction SMILES: C(OC([N:6]1[CH2:22][CH2:21][C:10]2[C:11]3[CH:12]([CH2:19][CH3:20])[CH2:13][CH2:14][O:15][C:16]=3[CH:17]=[CH:18][C:9]=2[CH2:8][CH2:7]1)=O)C.[OH-].[K+]>CCO.Cl.O>[CH2:19]([CH:12]1[C:11]2[C:10]3[CH2:21][CH2:22][NH:6][CH2:7][CH2:8][C:9]=3[CH:18]=[CH:17][C:16]=2[O:15][CH2:14][CH2:13]1)[CH3:20]
Reactant: CCOC(=O)N1CCc2ccc3c(c2CC1)C(CC)CCO3
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCC1CCOc2ccc3c(c21)CCNCC3
Temperature: 120 °C
Yield: 55.2 %

Procedure:
Into a sealed tube, the product from step (i) (95 mg, 0.313 mmol) dissolved in EtOH (2 ml) and water (500 μl) was added. To this stirred solution, KOH (275 mg, 4.9 mmol) was added. The reaction mixture was heated to 120° C. for 24 hours. The reaction mixture was allowed to cool to room temperature and was diluted with 2M HCl (15 ml) and water (15 ml). The aqueous mixture was washed with EtOAc (2×). The aqueous layer was then basified with 2M NaOH to pH 10 and extracted with DCM (3×). The combined DCM extracts were washed with brine, dried over Na2SO4, and solvent evaporated in vacuo to give the title compound as a yellow oil (40 mg). 1H NMR (300 MHz, CDCl3) δ 6.86 (d, J=8.1 Hz, 1H); 6.57 (d, J=8.1 Hz, 1H); 4.22-4.17 (m, 1H); 4.12-4.03 (m, 1H); 3.00-2.84 (m, 8H); 2.83-2.72 (m, 1H); 2.06 (bs, 1H); 1.97-1.92 (m, 2H); 1.56-1.45 (m, 2H); 1.01 (t, J=6.0 Hz, 3H); MS: ESI (positive): 232 (M+H).
Reaction SMILES: [C:1]1([C:7]2[C:15]3[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][C:10]=3[N:9](COCC[Si](C)(C)C)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1([C:7]2[C:15]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[NH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(-c3ccccc3)nn(COCC[Si](C)(C)C)c2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(-c2n[nH]c3c2CCNC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 3-phenyl-1-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate (298 mg, 0.69 mmol) was dissolved in DCM (8 mL) with TFA (0.5 mL, 6.98 mmol) and was allowed to stir under N2 pressure at rt overnight. Solvent was removed and the residue partitioned between 2M Na2CO3 and DCM, then extracted with DCM three times. The combined organic layers were dried over Na2SO4 and concentrated. The resulting product was used as is in the next step.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[S:27][C:11]3[N:12]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:13]=[C:14]([C:17]([O:19]C)=O)[C:15](=[O:16])[C:10]=3[CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH:34][C:17]([C:14]2[C:15](=[O:16])[C:10]3[CH:9]=[C:8]([CH2:7][N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[S:27][C:11]=3[N:12]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:13]=2)=[O:19])=[CH:31][CH:30]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: COC(=O)c1nn(-c2ccccc2)c2sc(CN3CCOCC3)cc2c1=O
Product: O=C(NCc1ccc(Cl)cc1)c1nn(-c2ccccc2)c2sc(CN3CCOCC3)cc2c1=O
Temperature: 25 °C
Yield: 65 %

Procedure:
A solution of methyl 6-(4-morpholinylmethyl)-4-oxo-1-phenyl-1,4-dihydrothieno[2,3-c]pyridazine-3-carboxylate (0.29 g) in 4-chlorobenzylamine (2 mL) is heated to 190° C. for 30 min. The reaction mixture is cooled to ambient temperature, the solvent is removed in vacuo and Et2O (15 mL) is added to the residue. The resulting precipitate is filtered and rinsed with Et2O to afford 0.24 g (65%) of the title compound as a tan solid. Physical characteristics: m.p. 182-184° C.; 1H NMR (400 MHz, CDCl3) δ10.56, 7.71, 7.58, 7.42, 7.32, 4.69, 3.71, 3.65, 2.51; IR (diffuse reflectance) 1677, 1587, 1549, 1532, 1508, 1493, 1347, 1297, 1278, 1261, 1115, 1112, 799, 777, 701 cm1; MS (EI) m/z 494 (M+); HRMS (FAB) m/z 495.1265 (C25H23ClN4O3S+H). Anal. Found: C, 60.18; H, 4.79; N, 11.04.
Reaction SMILES: [F:1][C:2]1[C:21](F)=[CH:20][C:5]2=[N:6][C:7]3[N:8]([CH2:18][CH3:19])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.CS(O)(=O)=O.CS(O)(=O)=O.[NH2:33][C:34]1([CH3:38])[CH2:37][NH:36][CH2:35]1>>[NH2:33][C:34]1([CH3:38])[CH2:37][N:36]([C:21]2[C:2]([F:1])=[CH:3][C:4]3[C:5]([CH:20]=2)=[N:6][C:7]2[N:8]([CH2:18][CH3:19])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=2[CH:13]=3)[CH2:35]1
Reactant: CC1(N)CNC1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)cc3nc21
Agent: CS(=O)(=O)O
Product: CCn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CC(C)(N)C4)cc3nc21
Yield: 78.4 %

Procedure:
8-(3-Amino-3-methyl-1-azetidinyl)-1-ethyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid was prepared under the conditions described in Example 15, but starting with 1.52 g of 7,8-difluoro-1-ethyl-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine-3-carboxylic acid and 2.22 g of 3-amino-3-methylazetidine dimethanesulphonate, for 72 hours at approximately 20° C. and then 1 and a half hours at a temperature in the region of 90° C. The insoluble matter in the reaction mixture is drained at approximately 20° C., washed with twice 20 cm3 of water, recrystallized in 70 cm3 of dimethylformamide and washed with 40 cm3 of ethanol at approximately 75° C. 1.45 g of 8-(3-Amino-3-methyl-1-azetidinyl)-1-ethyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid, which decomposes at 334° C.
Reaction SMILES: [CH2:1]1[C@H:5]2[CH2:6][CH2:7][C@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C@H:4]2[CH2:3][NH:2]1.C(N(CC)CC)C.[F:24][C:25]([F:37])([F:36])[C:26]1[CH:27]=[C:28]([S:32](Cl)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>ClCCl>[F:37][C:25]([F:24])([F:36])[C:26]1[CH:27]=[C:28]([S:32]([N:2]2[CH2:3][C@@H:4]3[C@@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH2:7][CH2:6][C@@H:5]3[CH2:1]2)(=[O:33])=[O:34])[CH:29]=[CH:30][CH:31]=1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@@H]21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
tert-Butyl(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-ylcarbamate (0.71 g, 3.14 mmol) from Step B, triethylamine (0.656 mL, 4.71 mmol), and 3-(trifluoromethyl)benzene-1-sulfonyl chloride (0.552 mL, 3.45 mmol) were combined in dichloromethane (10.0 mL). The reaction was stirred at room temperature for 16 hours and quenched with saturated aqueous NaHCO3. The organic layer was separated and concentrated in vacuo. The resultant crude material was applied to a SF-25-60 g cartridge (Analogix®, Burlington, Wis.) and purified with a gradient of 0-2% methanol/dichloromethane over 20 minutes to give tert-butyl(3aR,4S,6aS)-2-(3-(trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-ylcarbamate: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.30 (s, 1H), 8.14 (d, J=7.8, 1H), 7.84 (d, J=7.8, 1H), 7.65 (t, J=7.8, 1H), 6.83-6.71 (m, 1H), 3.88-3.76 (m, 1H), 3.61 (dd, J=10.1, 3.3, 1H), 3.24 (dd, J=9.8, 8.1, 1H), 3.12 (d, J=5.6, 2H), 2.64-2.44 (m, 2H), 1.99-1.78 (m, 2H), 1.55 (tt, J=12.4, 7.7, 1H), 1.48 (s, 9H), 1.38-1.20 (m, 1H); MS (ESI−) m/z 433 (M−H)−.
Reaction SMILES: BrC1C2N3CCN(C)C(=O)C3=[C:10]([O:11][CH2:12][C:13]3C=CC=CC=3)[C:6]=2C(=O)N(CC2C=CC(F)=C(Cl)C=2)N=1.C([Sn](CCCC)(CCCC)C(OCC)=C)CCC.[O:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:58]([O:53][CH:54]=[CH:55][O:56][CH:6]=[CH:10][O:11][CH2:12][CH3:13])[CH3:57]
Reactant: C1COCCO1
Reactant: CN1CCn2c(c(OCc3ccccc3)c3c(=O)n(Cc4ccc(F)c(Cl)c4)nc(Br)c32)C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Product: CCOC=COC=COCC
Temperature: 100 °C

Procedure:
A mixture of 4-bromo-10-(benzyloxy)-2-(3-chloro-4-fluorobenzyl)-8-methyl-7,8-dihydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (1.00 g, 1.83 mmol), tributyl(1-ethoxyvinyl)tin (0.73 g, 2.01 mmol), and trans-dichlorobis(triphenylphosphine)palladium (II) (64 mg, 92 μmol) in dioxane (10 mL) was purged with nitrogen for 15 minutes. The reaction mixture was heated in a sealed tube at 100° C. overnight. The product mixture was filtered through a pad of Celite, and the filtrate concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a 1:1 mixture of ethyl acetate in chloroform. Collecting and concentration of appropriate fractions provided the intermediate ethoxyvinyl ether as off white solid. A solution of the ethoxyvinyl ether (0.70 g, 1.30 mmol) in acetone at room temperature was treated with hydrochloric acid (2 mL, 1 M) and stirred at the same temperature for 30 minutes. The resultant solution was concentrated under vacuum to provide the title ketone.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5](=[CH:10][CH:11]=1)[C:6](OC)=[O:7].O.[NH2:14][NH2:15]>CO>[F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:14][NH2:15])=[O:7])=[C:4]([OH:12])[CH:3]=1
Reactant: COC(=O)c1ccc(F)cc1O
Reactant: NN
Solvent: CO
Solvent: O
Product: NNC(=O)c1ccc(F)cc1O
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 4-fluorosalicylate (500 mg, 2.94 mmol, commercially available from e.g. Apollo, Alfa Aesar or ABCR) in methanol (15 ml) stirred under argon at room temp was added neat hydrazine monohydrate (0.722 ml, 14.69 mmol). The reaction mixture was stirred at 80° C. for 18 hr. The reaction mixture was concentrated in vacuo and partitioned between ethyl acetate (˜50 ml) and water (˜25 ml). The aqueous phase was extracted with ethyl acetate (2×25 ml) and the combined organic extracts washed with brine (25 ml), dried over sodium sulphate, evaporated in vacuo and dried (vacuum oven, 40° C., 24 hr) to afford the crude product as an off-white solid in 385 mg.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1.[NH2:26][CH2:27][CH2:28]O.B(F)(F)F>O1CCCC1>[O:1]1[C:2]2([CH2:3][CH2:4][N:5]([C:8]3[CH:13]=[CH:12][C:11]([N:14]4[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]4=[O:24])=[CH:10][C:9]=3[F:25])[CH2:6][CH2:7]2)[NH:26][CH2:27][CH2:28]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=O)CC3)c(F)c2)C(=O)O1
Reactant: NCCO
Agent: FB(F)F
Solvent: C1CCOC1
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)NCCO4)c(F)c2)C(=O)O1
Yield: 78 %

Procedure:
The title compound was prepared by reacting (S)-N-{3-[4-(4-oxo-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.0 mmol), 2-aminoethanol (1.0 mmol) and BF3.etherate (2.0 mmol) in tetrahydrofuran (10 ml) at a temperature 65° C. for 6 hours in 78% yield.
Reaction SMILES: [CH3:1][N:2]1[C@@:6]2([CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([NH:15][C:16](=[O:30])[CH2:17][NH:18][CH2:19][C:20]4[CH:29]=[CH:28][C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[CH:21]=4)[CH:12]=3)[CH2:7]2)[C:5](=[O:31])[NH:4][C:3]1=[O:32].[Cl:33][CH2:34][C:35]([CH3:40])([CH3:39])[C:36](Cl)=[O:37].C(N(CC)CC)C>C(Cl)Cl>[Cl:33][CH2:34][C:35]([CH3:40])([CH3:39])[C:36]([N:18]([CH2:17][C:16]([NH:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@@:6]1([C:5](=[O:31])[NH:4][C:3](=[O:32])[N:2]1[CH3:1])[CH2:14]2)=[O:30])[CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)=[O:37]
Reactant: CC(C)(CCl)C(=O)Cl
Reactant: CN1C(=O)NC(=O)[C@@]12Cc1ccc(NC(=O)CNCc3ccc4ccccc4c3)cc1C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1C(=O)NC(=O)[C@@]12Cc1ccc(NC(=O)CN(Cc3ccc4ccccc4c3)C(=O)C(C)(C)CCl)cc1C2

Procedure:
To a stirred solution of N-[(4S)-3-methyl-2,5-dioxo-1′,3′-dihydrospiro[imidazolidine-4,2′-inden]-5′-yl]-2-[(2-naphthylmethyl)amino]acetamide from Step C (19 mg, 0.044 mmol), in DCM (1 mL), at 0° C. was added 3-chloro-2,2-dimethylpropanoyl chloride (10 mg, 0.067 mmol) and triethylamine (9.0 mg, 0.089 mmol). After 1 hour the reaction mixture was applied directly to a silica gel column for purification, eluting with DCM:MeOH—99:1 to 96:4. Product containing fractions were pooled and concentrated in vacuo to give the title compound. MS: m/z=547 (M(35Cl)+1). HRMS: m/z=547.2103; calculated m/z=547.2107 for C30H32N4O5(35Cl)1.