Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]1[S:11][C:10]([S:12]([NH:15][C:16]([NH:18][C:19]2[N:24]=[C:23]([C:25]([O:27][CH3:28])=[O:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=2)=[O:17])(=[O:14])=[O:13])=[CH:9][C:8]=1[CH3:33])(=O)C.[H-].[Na+]>CO>[CH3:28][O:27][C:25]([C:23]1[CH:22]=[C:21]([C:29]([F:31])([F:30])[F:32])[CH:20]=[C:19]([NH:18][C:16](=[O:17])[NH:15][S:12]([C:10]2[S:11][C:7]([CH2:6][CH2:5][OH:4])=[C:8]([CH3:33])[CH:9]=2)(=[O:14])=[O:13])[N:24]=1)=[O:26]
Reactant: COC(=O)c1cc(C(F)(F)F)cc(NC(=O)NS(=O)(=O)c2cc(C)c(CCOC(C)=O)s2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(C(F)(F)F)cc(NC(=O)NS(=O)(=O)c2cc(C)c(CCO)s2)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 0.100 g methyl 6-[({[5-(2-acetoxyethyl)-4-methyl-2-thienyl]sulfonyl}carbamoyl)amino]-4-(trifluoromethyl)pyridine-2-carboxylate in 1.5 ml methanol was added 0.02 g sodium hydride 55% in oil. The resulting solution was stirred at room temperature for 18 h. The reaction mixture was partitioned between 10% citric acid and ethyl acetate. The phases were separated and the organic phase was washed with brine and evaporated to yield the title compound as white foam. MS (ISN) M−H+=466.3
Reaction SMILES: [CH2:1]([N:5]1[C:10]([N:11]([C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[CH:16]=2)C(=O)C)=[C:9]([CH2:23][CH3:24])[C:8](=[O:25])[NH:7][C:6]1=[O:26])[CH:2]=[CH:3][CH3:4].C[O-].[Na+]>CO>[CH2:1]([N:5]1[C:10]([NH:11][C:15]2[CH:16]=[C:17]([CH3:22])[CH:18]=[C:19]([CH3:21])[CH:20]=2)=[C:9]([CH2:23][CH3:24])[C:8](=[O:25])[NH:7][C:6]1=[O:26])[CH:2]=[CH:3][CH3:4]
Reactant: CC=CCn1c(N(C(C)=O)c2cc(C)cc(C)c2)c(CC)c(=O)[nH]c1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC=CCn1c(Nc2cc(C)cc(C)c2)c(CC)c(=O)[nH]c1=O
Reaction time: 4 h
Yield: 72.8 %

Procedure:
To a stirred solution of N-(3-but-2-enyl-5-ethyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yl)-N-(3,5-dimethyl-phenyl)-acetamide (110) (90 mg, 0.25 mmol) in methanol (3 mL), was added sodium methoxide (73 mg, 1.35 mmol). After 4 hr., the mixture was neutralized with excess. NH4Cl and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexane (1:1)) to afford 57 mg (72%) of a white solid. m.p. 190-192° C.; 1H-NMR (200 MHz, CDCl3) δ 1.00 (3H, t, J=7.5 Hz), 1.68-1.70 (3H, m), 2.28-2.37 (8H, m), 4.31-4.33 (2H, m), 5.44 (1H, s), 5.51-5.58 (2H, m), 6.39 (2H, s), 6.66 (1H, s), 8.72 (1H, s); m/z (EI) 313 (M+).
Reaction SMILES: C1([C:7]2[S:11][C:10]([CH:12]=O)=[CH:9][CH:8]=2)C=CC=CC=1.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][N:28]([CH2:12][C:10]3[SH:11]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:7]=[CH:8][CH:9]=3)[CH2:27][CH2:26]2)[CH:20]=1)=[O:17]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=Cc1ccc(-c2ccccc2)s1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC3=CC=C[SH]3c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 5-phenyl-2-thiophenecarbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 419.1 (M+H)+.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[N:21]=[CH:22][N:23]([CH2:25][CH:26]=[CH2:27])[CH:24]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CON(C)[C:36](=[O:38])[CH3:37].[Cl-].[NH4+]>C1COCC1>[Si:1]([O:18][CH2:19][C:20]1[N:21]=[C:22]([C:36](=[O:38])[CH3:37])[N:23]([CH2:25][CH:26]=[CH2:27])[CH:24]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CON(C)C(C)=O
Reactant: C=CCn1cnc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCn1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)nc1C(C)=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
The compound (1.26 g) obtained in (1) was dissolved in THF (50 mL), and cooled to −78° C. while stirring under nitrogen stream. To the present solution was added dropwise n-butyl lithium (2.76 M hexane solution, 1.82 mL), followed by stirring at the same temperature for 30 minutes. Then, N-methoxy-N-methylacetamide (1.05 mL) was added, and stirring was continued for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution to terminate the reaction, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and subsequently the solvent was distilled off under reduced pressure. The resulting residue was purified by flash chromatography (ethyl acetate/hexane=5%→70%) using silica gel column (product name: Hi-Flash Column 3 L, manufactured by Yamazen Corporation) to afford the title compound (0.75 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[F:9].C([Li])CCCCC.[C:17]([N:24]1[CH2:28][CH2:27][C:26](=[O:29])[CH2:25]1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>C(OCC)C>[Cl:8][C:4]1[C:3]([F:9])=[C:2]([C:26]2([OH:29])[CH2:27][CH2:28][N:24]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:25]2)[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: Fc1c(Cl)cccc1Br
Agent: [Li]CCCCCC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cccc(Cl)c2F)C1
Yield: 66.6 %

Procedure:
Preparation according to Preparation 10: 1-Bromo-3-chloro-2-fluorobenzene (8 g, 38.3 mmol), dry diethyl ether (100 mL), n-hexyllithium (2.3 M in hexane, 16.64 ml, 38.3 mmol) and a solution of 1-N-boc-3-pyrrolidone (7.08 g, 38.3 mmol) in dry diethyl ether (50 mL). The crude product was purified by flash column chromatography (ethylacetate/isooctane, 1:9 to 1:1) to give the title compound (8.05 g, 66%). MS m/z (rel. intensity, 70 eV) 259 (20), 214 (42), 157 (26), 143 (23), 57 (bp).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH2:24]Cl)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[CH3:26][S:27][CH2:28][CH2:29][NH2:30].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH2:24][NH:30][CH2:29][CH2:28][S:27][CH3:26])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:11][CH:10]([CH2:16][CH:14]([CH2:13]3)[CH2:15]1)[CH2:9]2)=[O:5]
Reactant: CSCCN
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(NCCCl)ccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSCCNCCNc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Yield: 56.4 %

Procedure:
2-Chloro-5-[(2-chloroethyl)amino]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.200 g, Example 29c), 2-(methylthio)ethylamine (0.478 g), triethylamine (0.7 ml) and tetrahydrofuran (4 ml) were heated together in a sealed tube at 80° C. for 24 h. The mixture was cooled, poured into saturated aqueous sodium hydrogencarbonate solution and extracted into ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified on silica gel (eluant 19:1/dichloromethane:methanol) to afford the title compound as a gum (0.129 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][C@H:7]2[N:12]1[C:20](=[O:21])[NH:19][C:18]2[C:13]1=[N:14][C:15]([N:22]1[C:26]3[CH:27]=[C:28]([C:31](F)(F)F)[CH:29]=[CH:30][C:25]=3[N:24]=[CH:23]1)=[N:16][CH:17]=2.F[C:36]1C=CC=C2C=1OCC[C@H]2N1C(=O)NC2C1=NC(N1C3C=CC(C(F)(F)F)=CC=3N=C1)=NC=2.FC(F)(F)C1C=CC2N=CNC=2C=1>>[CH3:36][C:29]1[C:28]([CH3:31])=[CH:27][C:26]2[N:22]([C:15]3[N:14]=[C:13]4[C:18]([NH:19][C:20](=[O:21])[N:12]4[C@H:7]4[C:6]5[C:11](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=5)[O:10][CH2:9][CH2:8]4)=[CH:17][N:16]=3)[CH:23]=[N:24][C:25]=2[CH:30]=1
Reactant: O=c1[nH]c2cnc(-n3cnc4cc(C(F)(F)F)ccc43)nc2n1[C@@H]1CCOc2c(F)cccc21
Reactant: O=c1[nH]c2cnc(-n3cnc4ccc(C(F)(F)F)cc43)nc2n1[C@@H]1CCOc2c(F)cccc21
Agent: FC(F)(F)c1ccc2nc[nH]c2c1
Product: Cc1cc2ncn(-c3ncc4[nH]c(=O)n([C@@H]5CCOc6c(F)cccc65)c4n3)c2cc1C

Procedure:
9-((R)-8-Fluorochroman-4-yl)-2-(6-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)-7H-purin-8(9H)-one and 9-((R)-8-fluorochroman-4-yl)-2-(5-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)-7H-purin-8(9H)-one. The title compound was synthesized from 5-trifluoromethylbenzimidazole (US 2004/0087601) via the procedures described in Example 25. Purification by column chromatography (2% MeOH/DCM) eluted the 6-trifluoromethyl isomer first (1H-NMR (300 MHz, CDCl3) δ 8.8 (d, 2H), 8.4 (s, 1H), 7.9 (d, 1H), 7.6 (d, 2H), 7.0 (t, 1H), 6.7 (m, 2H), 5.9 (t, 1H), 4.7 (m, 1H), 4.4 (m, 1H), 3.0 (m, 1H), 2.4 (m, 1H).) followed by the 5-trifluoromethyl isomer (1H-NMR (300 MHz, CDCl3) δ 9.0 (s, 1H), 8.4 (s, 1H), 8.1 (s, 1H), 8.0 (d, 1H), 7.6 (d, 2H), 7.0 (m, 1H), 6.8 (m, 2H), 5.9 (t, 1H), 4.7 (m, 1H), 4.4 (m, 1H), 2.9 (m, 1H), 2.4 (m, 1H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Si:20]([O:27][C:28]1[CH:29]=[C:30]([CH:59]=[CH:60][C:61]=1[F:62])[C:31]([NH:33][NH:34][C:35](=[O:58])[C@H:36]([NH:47][C:48]1[CH:53]=[CH:52][C:51]([C:54]#[N:55])=[C:50](Cl)[C:49]=1C)[C@@H:37]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[CH3:38])=O)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].[CH2:63]([Cl:65])Cl>>[Si:40]([O:39][C@H:37]([CH3:38])[C@@H:36]([NH:47][C:48]1[CH:49]=[CH:50][C:51]([C:54]#[N:55])=[C:63]([Cl:65])[C:53]=1[CH3:52])[C:35]1[O:58][C:31]([C:30]2[CH:59]=[CH:60][C:61]([F:62])=[C:28]([O:27][Si:20]([C:23]([CH3:24])([CH3:25])[CH3:26])([CH3:21])[CH3:22])[CH:29]=2)=[N:33][N:34]=1)([C:43]([CH3:46])([CH3:44])[CH3:45])([CH3:42])[CH3:41]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(F)c(O[Si](C)(C)C(C)(C)C)c2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Reactant: ClCCl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(F)c(O[Si](C)(C)C(C)(C)C)c3)o2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl

Procedure:
Triphenylphosphine (1.0 g, 3.85 mmol) was dissolved in 25 mL of DCM followed by addition of 12 (977 mg, 3.85 mmol) and TEA (779 mg, 7.70 mmol) at 0° C. 3-(tert-butyldimethylsilyloxy)-N′-((2R,3S)-3-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)butanoyl)-4-fluorobenzohydrazide (1.25 g, 1.93 mmol) in 35 mL DCM was added to the pre-cooled solution mixture of PPh3/I2/TEA system and stir. The temperature was allowed to rise to room temperature and stirred for additional 10 min. The reaction was quenched with 100 mL saturated sodium thiosulfate and extracted with EtOAc. The crude mixture was chromatographed to give the product (1.10 g). 1H NMR (400 MHz, DMSO-d6, δ in ppm): 7.71 (m, 1H), 7.70 (d, J=9 Hz, 1H), 7.65 (m, 1H), 7.03 (d, J=9 Hz, 1H), 6.53 (d, J=9 Hz, 1H), 5.15 (d, J=9 Hz, 1H), 4.80 (m, 1H), 2.44 (s, 3H), 1.51 (d, J=6 Hz, 3H), 1.13 (s, 9H), 0.83 (s, 9H), 0.36 (s, 6H), 0.19 (s, 3H), 0.00 (s, 3H).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].O1CCCCC1[N:35]1[C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][CH:37]=[N:36]1.C([O-])([O-])=O.[Na+].[Na+].C(O)(C(F)(F)F)=O.N.CO>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.C(Cl)Cl.CCO.O.COCCOC>[Cl:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:21]=[C:2]([C:37]3[NH:36][N:35]=[CH:39][CH:38]=3)[C:3]([N:22]3[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]3)=[N:4][CH:5]=2)=[CH:11][CH:12]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@H](CO)C2)c(-c2ccn[nH]2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (S)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-(hydroxymethyl)pyrrolidin-1-yl)nicotinamide (Stage 10.1, 119 mg, 0.25 mmol), 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (139 mg, 0.5 mmol), Pd(PPh3)2Cl2 (0.018 g, 0.025 mmol), Na2CO3 (0.106 g, 1.000 mmol), DME (1.061 mL), water (0.303 mL) and EtOH (0.152 mL) were added to a MW vial which was sealed, evacuated/purged 3 times with argon then subjected to MW irradiation at 125° C. for 20 min. The RM was diluted with DME (2 mL) and stirred overnight with Si-Thiol (Silicycle 1.43 mmol/g, 0.105 g, 0.150 mmol). The mixture was centrifuged and the supernatant was filtered through a 0.45 μm PTFE filter and the solvent was evaporated off under reduced pressure. The crude product was purified by flash chromatography (RediSep® Silica gel column, 12 g, cyclohexane/EtOAc from 20% to 90% EtOAc) to afford the protected intermediate which was treated with a mixture of DCM (2.5 mL) and TFA (0.963 mL, 12.50 mmol) and stirred at RT for 2 h. The solvent was evaporated off under reduced pressure and the residue treated with a solution of 7 N NH3 in MeOH (2 mL, 14 mmol). The solvent was evaporated off under reduced pressure and the residue was purified by preparative SFC (Column DEAP, isocratic 28% in 9 min) to afford the title compound as a yellow oil. UPLC-MS (Condition 1) tR=1.87 min, m/z=464.1 [M+H]+, m/z=462.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.49-1.65 (m, 1H) 1.75-1.97 (m, 1H) 2.14-2.30 (m, 1H) 3.04 (dd, J=11.37, 6.97 Hz, 1H) 3.14-3.26 (m, 2H) 3.26-3.29 (m, 1H) 3.35-3.46 (m, 2H) 4.60 (t, J=5.14 Hz, 1H) 6.39 (d, J=1.96 Hz, 1H) 7.33 (d, J=9.05 Hz, 2H) 7.76 (br. s, 1H) 7.84-7.94 (m, 2H) 8.04 (d, J=2.45 Hz, 1H) 8.74 (s, 1H) 10.18 (s, 1H) 12.87 (br. s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([N:7]2[CH2:13][CH:12]3[O:14][CH:9]([CH2:10][CH:11]3O)[CH2:8]2)=[C:5]([N+:16]([O-:18])=[O:17])[CH:4]=[N:3]1.C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:31]=[N+:32]=[N-:33].[Na+]>C(Cl)Cl.CN(C=O)C>[N:31]([CH:11]1[CH2:10][CH:9]2[O:14][CH:12]1[CH2:13][N:7]([C:6]1[N:2]([CH3:1])[N:3]=[CH:4][C:5]=1[N+:16]([O-:18])=[O:17])[CH2:8]2)=[N+:32]=[N-:33]
Reactant: Cn1ncc([N+](=O)[O-])c1N1CC2CC(O)C(C1)O2
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1ncc([N+](=O)[O-])c1N1CC2CC(N=[N+]=[N-])C(C1)O2
Temperature: 0 °C
Reaction time: 18 h

Procedure:
3-(2-Methyl-4-nitro-pyrazol-3-yl)-8-oxa-3-azabicyclo[3.2.1]octan-6-ol (500 mg, 1.96 mmoL) was dissolved in DCM (15 mL) and triethylamine (0.41 mL, 2.95 mmol) was added. After cooling to 0° C., methanesulfonyl chloride (0.19 mL, 2.45 mmol) was added slowly and the reaction mixture was allowed to warm to room temperature and stirred for 18 hr. The mixture was diluted with DCM (10 mL), quenched with water (10 mL) and the aqueous layer extracted with DCM (3×20 mL). The combined organic layers were washed with brine (10 mL), passed through a phase separation cartridge and concentrated under reduced pressure to give a light brown solid. This solid (450 mg, 1.35 mmol) was dissolved in DMF (20 mL), sodium azide (450 mg, 6.8 mmol) was added and the mixture heated at 150° C. for 18 hr, behind a blast shield. The mixture was allowed to cool to room temperature, the mixture partitioned between water (20 mL) and EtOAc (20 mL) and the aqueous layer extracted with EtOAc (3×25 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (10-50%, EtOAc/isohexane) gave 6-azido-3-(2-methyl-4-nitro-pyrazol-3-yl)-8-oxa-3-azabicyclo[3.2.1]octane as brown gum (25 mg, 68% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 4.65 (d, J=7.4 Hz, 1H), 4.34 (s, 1H), 4.28 (dd, J=8.0, 3.2 Hz, 1H), 3.82 (s, 3H), 3.75-3.70 (m, 2H), 2.83-2.73 (m, 1H), 2.64-2.49 (m, 2H), 2.20 (ddd, J=13.4, 7.3, 3.2 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:15]=1[C:16]([N:18]1[CH2:21][C:20]([C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][N:24]2[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])([OH:22])[CH2:19]1)=[O:17].ClC1C=C(C=CC=1)C(OO)=[O:41]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:11]=[N+:12]([O-:41])[CH:13]=[CH:14][C:15]=1[C:16]([N:18]1[CH2:21][C:20]([C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][N:24]2[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])([OH:22])[CH2:19]1)=[O:17]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C1(O)CN(C(=O)c2ccncc2Nc2ccc(I)cc2F)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C1(O)CN(C(=O)c2cc[n+]([O-])cc2Nc2ccc(I)cc2F)C1
Reaction time: 15 h
Yield: 69.4 %

Procedure:
1,1-Dimethylethyl (2S)-2-[1-({3-[(2-fluoro-4-iodophenyl)amino]pyridin-4-yl}carbonyl)-3-hydroxyazetidin-3-yl]piperidine-1-carboxylate (80 mg, 0.134 mmol), prepared using procedures similar to those described in Example 38, was dissolved in dichloromethane (3 mL) and treated with 3-chloroperoxybenzoic acid (73% pure; 32 mg, 0.135 mmol) at ambient for 7 hours. 3-chloroperoxybenzoic acid (73% pure; 32 mg, 0.135 mmol) was added and the mixture was stirred for 15 hours. The mixture was purified by column chromatography (silica gel, 0-10% ethanol in ethyl acetate) to give 1,1-dimethylethyl (2S)-2-[1-({3-[(2-fluoro-4-iodophenyl)amino]-1-oxidopyridin-4-yl}carbonyl)-3-hydroxyazetidin-3-yl]piperidine-1-carboxylate (57 mg, 0.093 mmol, 69% yield): 1H NMR (400 MHz, CDCl3): 9.38 (s, 1H), 8.00 (s, 1H), 7.68 (dd, 1H), 7.51 (dd, 1H), 7.46 (d, 1H), 7.19 (br d, 1H), 7.09 (t, 1H), 5.78 (br, 1H), 4.44-3.98 (m, 3H), 3.98-3.87 (m, 1H), 3.49-3.39 (m, 1H), 3.07-2.88 (m, 1H), 2.01-1.91 (m, 1H), 1.70-1.47 (m, 6H), 1.45 (s, 9H); MS (EI) for C25H30FIN4O5: 613 (MH+).
Reaction SMILES: [NH:1]([C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:6]2)[NH2:2].[F:20][CH:21]([F:27])[C:22](OCC)=O.FC(F)C(O)=O.O>CN1C(=O)N(C)CC1>[F:20][CH:21]([F:27])[C:22]1[N:4]2[C:5]3[CH:6]=[C:7]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:8](=[O:13])[NH:9][C:10]=3[CH:11]=[CH:12][C:3]2=[N:1][N:2]=1
Reactant: CCOC(=O)C(F)F
Reactant: NNc1ccc2[nH]c(=O)c(-c3ccccc3)cc2n1
Agent: O=C(O)C(F)F
Solvent: CN1CCN(C)C1=O
Solvent: O
Product: O=c1[nH]c2ccc3nnc(C(F)F)n3c2cc1-c1ccccc1
Temperature: 200 °C

Procedure:
A mixture of 6-hydrazino-3-phenyl-1,5-naphthyridin-2(1H)-one (7-2) (21 g, 83 mmol), ethyl difluoroacetate (31 g, 250 mmol), and difluoroacetic acid (200 mg, 2.08 mmol) in DMI (100 mL) was heated under microwave irradiation at 200° C. for 1 h. To the cooled mixture was added water, and the resulting solid was collected by filtration to give 1-(difluoromethyl)-8-phenyl[1,2,4]triazolo[4,3-a]-1,5-naphthyridin-7(6H)-one (10-1) as pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CN(C=O)C>CC(C)=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCCCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-(tert-butoxycarbonylamino)hexanoic acid (1 eq) in acetone (0.2 M) was added potassium carbonate (2 eq) and (bromomethyl)benzene (2 eq) in acetone (2 M). The reaction mixture was stirred at room temperature for 1 hour. Additional amount of DMF was then added to the reaction mixture to facilitate the dissolution of potassium carbonate. The reaction mixture was stirred at room temperature for another 30 minutes. The mixture was then diluted with ethyl acetate, and washed with 5% citric acid, water and brine. The organic layer was dried over anhydrous Na2SO4, and concentrated en vaccuo. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 10-40% EtOAc/Hex to give the product.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][CH:35]=1)[C:6]([C:8]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][N:11]=[C:10]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[N:9]=1)=[O:7])=O.[CH:36]1([NH2:40])[CH2:39][CH2:38][CH2:37]1.[BH3-]C#N.[Na+]>O1CCOCC1>[CH:36]1([NH:40][CH2:1][C:3]2[CH:4]=[C:5]([CH:33]=[CH:34][CH:35]=2)[C:6]([C:8]2[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][N:11]=[C:10]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)=[CH:24][CH:25]=3)[N:9]=2)=[O:7])[CH2:39][CH2:38][CH2:37]1
Reactant: CCOC(=O)c1cnc(Nc2ccc(N3CCN(C)CC3)cc2)nc1C(=O)c1cccc(C=O)c1
Reactant: NC1CCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc(Nc2ccc(N3CCN(C)CC3)cc2)nc1C(=O)c1cccc(CNC2CCC2)c1

Procedure:
A mixture of Example 158C (100 mg, 0.2 mmol), cyclobutanamine (30 mg, 0.4 mmol) and NaCNBH3 (13 mg, 0.2 mmol) in dioxane (5 mL) was heated at 70° C. for two days. The volatiles were removed, and the residue was purified by HPLC (Zorbax C-18, Mobile phase A: 0.1% TFA in H2O; B: 0.1% TFA in CH3CN; 0-100% gradient) to provide the title compound. MS (DCI/NH3) m/z 529 (M+H)+.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]([OH:13])(=[O:12])[CH2:8][CH2:9][CH:10]=[CH2:11].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.O>[C:7]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:12])[CH2:8][CH2:9][CH:10]=[CH2:11]
Reactant: C=CCCC(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A suspension of K2CO3 (4.17 g, 30.2 mmol) and pent-4-enoic acid (3.01 g, 29.2 mmol) in DMF (25 mL) was stirred at room temperature for 5 minutes. Benzyl bromide (3.55 mL, 29.3 mmol) was added from a syringe over 3 minutes, and the resulting white suspension was stirred at room temperature for 23 hours, then diluted with water (150 mL) and extracted with EtOAc (3×50 mL). The combined extract was washed with saturated brine (30 mL) and concentrated under vacuum to leave the title compound. 1H NMR (300 MHz, CD3OD) δ ppm 2.30-2.41 (m, 2H) 2.42-2.50 (m, 2H) 4.96 (dddd, J=10.2, 1.7, 1.4, 1.0 Hz, 1H) 5.03 (dq, J=17.3, 1.6 Hz, 1H) 5.11 (s, 2H) 5.82 (tdd, J=17.0, 10.4, 6.3 Hz, 1H) 7.25-7.38 (m, 5H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.CCCCCC.C([Li])CCC.[C:19]1(=[O:24])[O:23][CH2:22][CH2:21][CH2:20]1>CCOCC>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:22](=[O:23])[CH2:21][CH2:20][CH2:19][OH:24])[CH:3]=1
Reactant: Brc1cccnc1
Reactant: O=C1CCCO1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: O=C(CCCO)c1cccnc1
Yield: 76.5 %

Procedure:
A solution of 10.0 g (63.3 mmol) of 3-bromopyridine in 100 ml of ether was cooled to -78° C., to which 40 ml (64 mmol) of 1.6 M n-butyllithium hexane solution was added dropwise with stirring. After completion cf the addition, the mixture was stirred for further 15 minutes, to which the solution of 5.45 g (63.3 mmol) of γ-butyrolactone in 15 ml of ether was added dropwise, and stirred for further 1 hour at -78° C.-room temperature. To the reaction mixture an aqueous solution of ammonium chloride, and the resultant substance was extracted with ethyl acetate. The extract was washed with water and dried, and the solvent was evaporated off. The residue was purified with silica gel column chromatography (CHCl3 -MeOH (9:1)) and recrystallized from ethyl acetate-isopropyl ether, to give 8.0 g (77%) of 4-(3-pyridyl)-4-oxobutanol. m.p. 36°-37° C.