Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:32])([F:31])[C:15]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])([OH:22])[CH2:16][N:17]3[CH:21]=[N:20][N:19]=[N:18]3)=[N:12][CH:13]=2)=C(F)C=1.BrC[C:38]1[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[C:40]([F:46])[CH:39]=1>>[F:30][C:24]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=1[C:15]([OH:22])([CH2:16][N:17]1[CH:21]=[N:20][N:19]=[N:18]1)[C:14]([C:11]1[N:12]=[CH:13][C:8]([O:7][CH2:6][C:38]2[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[C:40]([F:46])[CH:39]=2)=[CH:9][CH:10]=1)([F:32])[F:31]
Reactant: OC(Cn1cnnn1)(c1ccc(F)cc1F)C(F)(F)c1ccc(OCc2ccc(Cl)cc2F)cn1
Reactant: N#Cc1ccc(CBr)cc1F
Product: N#Cc1ccc(COc2ccc(C(F)(F)C(O)(Cn3cnnn3)c3ccc(F)cc3F)nc2)cc1F

Procedure:
Compound 10 was prepared in a similar manner to compound 1 from 4-(bromomethyl)-2-fluorobenzonitrile to afford a white solid (90 mg, 36%). 1H NMR (500 MHz, CDCl3): δ 8.73 (s, 1H), 8.23 (s, 1H), 7.70-7.67 (m, 1H), 7.56 (d, J=8.5 Hz, 1H), 7.38-7.36 (m, 2H), 7.32-7.29 (m, 3H), 6.78-6.74 (m, 1H), 6.71-6.68 (m, 1H), 5.50 (d, J=14.5 Hz, 1H), 5.17 (s, 2H), 5.15 (d, J=14.5 Hz, 1H). MS (ESI): m/z 503 [M++1]. HPLC: 95.84%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([OH:9])[N:3]=1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>C(#N)C>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[C:4](=[O:9])[N:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1nc(O)ncc1F
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Solvent: CC#N
Product: Nc1nc(=O)n(C(=O)OCc2ccccc2)cc1F
Temperature: 55 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
To a suspension of 4-amino-5-fluoro-pyrimidin-2-ol* (0.5 g. 3.87 mmol) in acetonitrile (CH3CN; 10 mL) was added N,O-bis(trimethylsilyl)acetamide (BSA; 1.42 mL, 5.81 mmol), and the mixture was heated to 55° C. for 1.5 h. The resulting solution was cooled to room temperature and to it was added benzyl chloroformate (1.38 mL, 9.67 mmol) causing a slight exotherm. After 10 minutes (min), a white precipitate formed that was allowed to stir at room temperature overnight. The solid was suction filtered and was washed with diethyl ether (Et2O; 2×10 mL), CH3CN (1×3 mL) and again with Et2O (2×10 mL) to give benzyl 4-amino-5-fluoro-2-oxopyrimidine-1(2H)-carboxylate (0.515 g, 50%) as a white solid: mp 212-215° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.35 (s, 1H), 8.07 (s, 1H), 8.04 (d, J=7.25 Hz, 1H), 7.48-7.45 (m, 2H), 7.41-7.34 (m, 3H), 5.32 (s, 2H); ESIMS m/z 264 ([M+H]+).
Reaction SMILES: Cl.[O:2]=[C:3]1[N:12]([CH2:13][CH2:14][CH2:15][N:16]([CH2:20][CH2:21][CH2:22][CH2:23][NH:24][CH2:25][CH2:26][CH2:27][N:28]2[C:37](=[O:38])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[NH:30][C:29]2=[O:39])[C:17](=[O:19])[CH3:18])[C:11](=[O:40])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4]1.[CH2:41](N(CC)CC)C.C=O.[BH4-].[Na+]>ClCCl.CO>[O:2]=[C:3]1[N:12]([CH2:13][CH2:14][CH2:15][N:16]([CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:25][CH2:26][CH2:27][N:28]2[C:37](=[O:38])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[NH:30][C:29]2=[O:39])[CH3:41])[C:17](=[O:19])[CH3:18])[C:11](=[O:40])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4]1
Reactant: CCN(CC)CC
Reactant: CC(=O)N(CCCCNCCCn1c(=O)[nH]c2ccccc2c1=O)CCCn1c(=O)[nH]c2ccccc2c1=O
Agent: C=O
Agent: Cl
Agent: [BH4-]
Solvent: CO
Solvent: ClCCl
Product: CC(=O)N(CCCCN(C)CCCn1c(=O)[nH]c2ccccc2c1=O)CCCn1c(=O)[nH]c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Hydrochloride acid salt of N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide (2 g, 3.5 mmol was dissolved in 80 mL dichloromethane and 10 mL, methanol. Triethylamine (0.45 g, 4.5 mmol) and paraformaldehyde (0.14 g, 4.5 mmol) was added thereto and stirred for 2 hours at room temperature. After concentration of the solvent, 40 mL methanol and sodium borohydride (0.76 g, 20.2 mmol) were added thereto and stirred for 15 hours. After removal of methanol by distillation under reduced pressure, silica gel column-chromatography of the remaining residue was performed to give the title compound of white solid (1.2 g, 62%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[CH:14][N:13]=[C:12]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:11]=3[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:38])[CH2:34][C:35](O)=[O:36])=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[F:25][C:26]1[CH:27]=[CH:28][C:29]([NH:32][C:33](=[O:38])[CH2:34][C:35]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C:16]4[CH:15]=[CH:14][N:13]=[C:12]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])[C:11]=4[CH:10]=[CH:9]3)=[CH:4][CH:3]=2)=[O:36])=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)Nc1nccc2c1ccn2-c1ccc(N)cc1
Reactant: O=C(O)CC(=O)Nc1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1nccc2c1ccn2-c1ccc(NC(=O)CC(=O)Nc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56524596 %

Procedure:
A solution of tert-butyl 1-(4-aminophenyl)-1H-pyrrolo[3,2-c]pyridin-4-ylcarbamate (27 mg, 0.083 mmol, Compound B of Example 1) in DMF (1 mL) was treated with 3-(4-fluorophenylamino)-3-oxopropanoic acid (25 mg, 0.13 nmol), DIPEA (21 μL, 0.13 mmol) and TBTU (40 mg, 0.13 mmol) and the mixture stirred at RT for 16 h. The mixture was concentrated in vacuo to remove the DMF and the residue was partitioned between EtOAc (2 mL) and saturated sodium bicarbonate solution (2 mL). The EtOAc phase was washed with 10% aqueous LiCl (2 mL), brine (2 mL), dried (MgSO4) and concentrated in vacuo. The crude product was purified using a Chromatotron (1 mm SiO2 GF rotor, 2-5% MeOH-CHCl3 gradient elution) to give the title compound (37 mg, 88%) as an off-white solid. LCMS (ESI+) m/z 504 (M+H)+; HPLC tR=3.49 min.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:7]=[CH:6][C:5]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](O)=[O:28])=[C:22]([F:30])[CH:21]=1)[CH3:2].[CH3:31][C:32]1[O:36][C:35]([C:37]2[CH:38]=[C:39]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=2)[NH2:40])=[N:34][N:33]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:7]=[CH:6][C:5]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:40][C:39]2[CH:41]=[C:42]([C:44]([F:45])([F:46])[F:47])[CH:43]=[C:37]([C:35]3[O:36][C:32]([CH3:31])=[N:33][N:34]=3)[CH:38]=2)=[O:28])=[C:22]([F:30])[CH:21]=1)[CH3:2]
Reactant: CCOc1cc(OCc2ccc(OC)cc2)ncc1-c1ccc(CC(=O)O)c(F)c1
Reactant: Cc1nnc(-c2cc(N)cc(C(F)(F)F)c2)o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1cc(OCc2ccc(OC)cc2)ncc1-c1ccc(CC(=O)Nc2cc(-c3nnc(C)o3)cc(C(F)(F)F)c2)c(F)c1
Reaction time: 2 h
Yield: 12.9 %

Procedure:
To a mixture of 2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (300 mg, 0.729 mmol), 3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)aniline (195 mg, 0.802 mmol), and Et3N (0.203 ml, 1.458 mmol) in DCM (15 ml) was added HATU (333 mg, 0.875 mmol) at 25° C. Then the mixture was stirred for 2 h, the mixture was concentrated to give the residue which was extracted with DCM (30 mL×2). The organic extract was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative TLC (DCM:MeOH=30:1, Rf=0.7) to yield 2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)phenyl)acetamide (60 mg, 0.094 mmol, 13% yield): 1H NMR (400 MHz, MeOD-d4) δ 8.52 (br. s., 1H), 7.99 (br. s., 1H), 7.95 (br. s., 1H), 7.42-7.39 (m, 2H), 7.30 (d, J=8.4 Hz, 3H), 6.89 (d, J=8.6 Hz, 3H), 6.52-6.50 (m, 1H), 5.11 (br. s., 2H), 4.64-4.62 (m, 2H), 4.31 (d, J=7.1 Hz, 2H), 2.63 (br. s., 3H), 1.38 (t, J=7.1 Hz, 3H); ES-LCMS m/z 637 (M+H).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH2:7]([N:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]([O:20][C:21]2[C:22]3[C:29]([C:30]4[CH:35]=[CH:34][C:33]([CH2:36][CH3:37])=[CH:32][CH:31]=4)=[C:28](I)[O:27][C:23]=3[N:24]=[CH:25][N:26]=2)[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[F:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1B(O)O>CS(C)=O.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>[CH2:7]([N:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]([O:20][C:21]2[C:22]3[C:29]([C:30]4[CH:35]=[CH:34][C:33]([CH2:36][CH3:37])=[CH:32][CH:31]=4)=[C:28]([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=4[F:39])[O:27][C:23]=3[N:24]=[CH:25][N:26]=2)[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCc1ccc(-c2c(I)oc3ncnc(O[C@@H]4CCCN(Cc5ccccc5)C4)c23)cc1
Reactant: OB(O)c1ccccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCc1ccc(-c2c(-c3ccccc3F)oc3ncnc(O[C@@H]4CCCN(Cc5ccccc5)C4)c23)cc1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
Add 0.68 ml of a 2 M aqueous sodium carbonate solution to a mixture of 365 mg (0.68 mmol) of 4-{[(3R)-1-benzylpiperidin-3-yl]oxy}-5-(4-ethylphenyl)-6-iodofuro[2,3-d]pyrimidine and 24 mg (0.03 mmol) of bis(triphenylphosphine)palladium(II) chloride in 15 ml of DMSO. Then add 118 mg (0.85 mmol) of (2-fluorophenyl)boronic acid and stir the mixture at 80° C. for 15 hours. Then filter the reaction mixture and purify directly by means of preparative RP-HPLC (gradient: water/acetonitrile). 291 mg (84% of theory) of the target compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12]OCC2)=[N:4][NH:5][C:6]=1[I:7].C1(C(=O)C)CC1>>[Cl:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12]2)=[N:4][NH:5][C:6]=1[I:7]
Reactant: Clc1c(C2CCOCC2)n[nH]c1I
Agent: CC(=O)C1CC1
Product: Clc1c(C2CC2)n[nH]c1I

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 294.4, except 1-cyclopropylethanone was used instead of 1-(tetrahydro-2H-pyran-4-yl)ethanone.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16]([P:19](Cl)(Cl)=[O:20])([CH3:18])[CH3:17]>>[CH:16]([P:19]1(=[O:20])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][N:8]1[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:18])[CH3:17]
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: CC(C)P(=O)(Cl)Cl
Product: CC(C)P1(=O)c2ccccc2CN1Cc1ccccc1
Yield: 12 %

Procedure:
The procedure of Example 1 was employed utilizing dibenzylamine and isopropyl phosphonic dichloride. The reaction of the dilithio compound and the isopropyl phosphonic dichloride was conducted at -65° C. The crude product produced as a result of the chromatographic separation was distilled at 160° C. and 0.2 mm to yield a colorless oil. The colorless oil was slurried in petroleum ether to yield 1-isopropyl-2-phenylmethyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (1.15 g, 12% yield) as a colorless solid having a melting point of 145°-147° C. and the following analysis:
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5](=[N:14]S(C2C=CC(C)=CC=2)(=O)=O)[N:6]([CH:8]([C:10](=O)[CH2:11][CH3:12])[CH3:9])[CH:7]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C1COCC1>[CH2:11]([C:10]1[N:14]=[C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:7][N:6]2[C:8]=1[CH3:9])[CH3:12]
Reactant: CCC(=O)C(C)n1cc(I)ccc1=NS(=O)(=O)c1ccc(C)cc1
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCc1nc2ccc(I)cn2c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.1 %

Procedure:
To a stirred solution of N-(5-iodo-1-(3-oxopentan-2-yl)pyridin-2(1H)-ylidene)-4-methylbenzenesulfonamide (4 g) in THF (50 ml) was added trifluoroacetic anhydride (10 ml) at 0° C., and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo, poured into saturated aqueous NaHCO3 solution and extracted with DCM. The extract was washed with brine, dried over Na2SO4, concentrated in vacuo, and purified by silica gel column chromatography (hexane/EtOAc) to afford the title compound (1.3 g) as a yellow solid.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[C:7]([C:13]([OH:15])=[O:14])=[N:8][CH:9]=[C:10]([F:12])[CH:11]=1.[CH3:16]O>>[F:5][C:6]1[C:7]([C:13]([O:15][CH3:16])=[O:14])=[N:8][CH:9]=[C:10]([F:12])[CH:11]=1
Reactant: O=C(O)c1ncc(F)cc1F
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ncc(F)cc1F
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To 10 mL of methanol was added dropwise 2.5 mL of thionylchloride under cooling in an ice bath over 30 minutes. To the reaction mixture was added 500 mg of 3,5-difluoropyridine-2-carboxylic acid, and warmed to room temperature, followed by stirring for 3 days. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. After filtration, it was concentrated under reduced pressure to obtain 496 mg of methyl 3,5-difluoropyridine-2-carboxylate.
Reaction SMILES: [CH3:1][Mg]Cl.[Br:4][C:5]1[CH:6]=[CH:7][C:8]([C:11](N(OC)C)=[O:12])=[N:9][CH:10]=1>C1COCC1>[Br:4][C:5]1[CH:6]=[CH:7][C:8]([C:11](=[O:12])[CH3:1])=[N:9][CH:10]=1
Reactant: CON(C)C(=O)c1ccc(Br)cn1
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(=O)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
Methylmagnesium chloride 3.0 M in THF (0.5 mL) was added dropwise to a mixture of 5-bromo-N-methoxy-N-methylpyridine-2-carboxamide (200 mg, 0.8 mmol) in tetrahydrofuran (10 mL) at 0° C. After stirring for 1 hr at room temperature, the reaction was quenched with 1 N NH4Cl and was extracted with EtOAc. The combined organic layer was washed with brine and dried over MgSO4, concentrated to give the crude product 1-(5-bromopyridin-2-yl)ethanone (0.15 g, 90%). LCMS calculated for C7H7BrNO (M+H)+: m/z=199.9, 201.9; found: 199.9, 201.9.
Reaction SMILES: O[CH:2]([C:4]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[CH3:3].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C1C=CC=CC=1>[CH:2]([C:4]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)=[CH2:3]
Reactant: CCOC(=O)C1(C(C)O)CCCCC1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: c1ccccc1
Product: C=CC1(C(=O)OCC)CCCCC1
Yield: 55 %

Procedure:
12 g (0.06 mole) of ethyl 1-(1-hyroxyethyl)-1-cyclohexyl-carboxylate were heated at 90° C. for 3 hours in 100 cm3 of benzene in the presence of 12 g of P2O5. The brown benzenic solution was washed in the cool with water, then distilled. The ethyl 1-vinyl-cyclohexyl-carboxylate was obtained with a yield of 55% (6 g) in the form of a colourless liquid.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[N:5]([CH2:9][C@@H:10]2[C@H:13]([NH:14][C:15](=[O:31])/[C:16](=[N:23]\[O:24][C:25]([CH3:30])([CH3:29])[C:26]([OH:28])=[O:27])/[C:17]3[N:18]=[C:19]([NH2:22])[S:20][CH:21]=3)[C:12](=[O:32])[N:11]2[S:33]([OH:36])(=[O:35])=[O:34])[CH2:4]1.Cl.[N:38]1([C:43](N)=[NH:44])C=CC=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:22][C:19]1[S:20][CH:21]=[C:17](/[C:16](=[N:23]/[O:24][C:25]([CH3:29])([CH3:30])[C:26]([OH:28])=[O:27])/[C:15]([NH:14][C@@H:13]2[C:12](=[O:32])[N:11]([S:33]([OH:36])(=[O:34])=[O:35])[C@@H:10]2[CH2:9][N:5]2[CH2:4][C@@H:3]([CH2:2][NH:1][C:43]([NH2:44])=[NH:38])[O:7][C:6]2=[O:8])=[O:31])[N:18]=1
Reactant: N=C(N)n1cccn1
Reactant: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1CN1C[C@@H](CN)OC1=O)c1csc(N)n1)C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1CN1C[C@@H](CNC(=N)N)OC1=O)c1csc(N)n1)C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 53.8 %

Procedure:
To a solution of 2-(((Z)-(2-(((2R,3S)-2-(((R)-5-(aminomethyl)-2-oxooxazolidin-3-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-1-(2-aminothiazol-4-yl)-2-oxoethylidene)amino)oxy)-2-methylpropanoic acid (30.1 mg, 0.055 mmol) and Pyrazole-1-carboxamidine hydrochloride (16.1 mg, 0.110 mmol) in DMF (548 μl) was added DIPEA (38.3 μl, 0.219 mmol). After 5 h of stirring at rt, the solution was concentrated in vacuo and purified by reverse phase prep HPLC (XSelect CSH, 30×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 60 mL/min), affording the title compound (17.5 mg, 49%) as a white powder. LCMS: Rt=0.30 min, m/z=592.2 (M+1) Method 2m_acidic; 1H NMR (400 MHz, D2O) δ 6.97 (s, 1H), 5.31 (d, J=5.9 Hz, 1H), 4.74 (dtd, J=9.3, 5.9, 3.2 Hz, 1H), 4.55 (ddd, J=9.2, 5.9, 3.1 Hz, 1H), 3.86 (t, J=9.3 Hz, 1H), 3.66 (dd, J=15.0, 9.5 Hz, 1H), 3.53 (dd, J=15.5, 3.2 Hz, 1H), 3.47-3.34 (m, 3H), 1.39 (s, 3H), 1.37 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:29])[C:8]([CH2:27][CH3:28])=[C:9]([C:25]#[N:26])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14](OS(C(F)(F)F)(=O)=O)=[CH:13][CH:12]=1)=[O:5])[CH3:2].[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:29])[C:8]([CH2:27][CH3:28])=[C:9]([C:25]#[N:26])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:13][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccc(OS(=O)(=O)C(F)(F)F)cc2)c(C#N)c(CC)n1C
Reactant: C1CCNC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(-c2ccc(N3CCCC3)cc2)c(C#N)c(CC)n1C
Temperature: 100 °C
Reaction time: 4 h
Yield: 71.8 %

Procedure:
Add 4-cyano-5-ethyl-1-methyl-3-(4-trifluoromethanesulfonyloxy-phenyl)-1H-pyrrole-2-carboxylic acid ethyl ester (0.3 g, 0.697 mmol, 1.0 eq, prepared in example E-97b or 97b), pyrrolidine (0.069 ml, 0.836 mmol, 1.2 eq), Pd(OAc)2 (4.69 mg, 0.0209 mmol, 0.03 eq), BINAP (19.53 mg, 0.0314 mmol, 0.045 eq) and cesium carbonate (0.318 g, 0.976 mmol, 1.4 eq) in toluene and heat at 100° C. with stirring. After 4 hours, stop reaction and let it cool down to room temperature. Partition the mixture between water and ethyl acetate. Separate the aqueous layer and extract it with ethyl acetate three times. Combine organic solution, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify the crude with flash chromatography eluting with 1:3 EtOAc/Hexane to provide 0.176 g (72%) of desired product as light yellow solid. Mass spectrum (m/e) 352.3 (M+1)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[N:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=2)[N:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C=NN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C=NN(c2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To the yellow colored suspension prepared by suspending the compound obtained in Step 4 (19.9 g, 65 mmol) in methanol (200 ml), 10% palladium on carbon (4.0 g) was added. The resulting mixture was subjected to vacuum outgassing and stirred at r.t., for 2 hrs in the flask connected with hydrogen bollum. The resulting mixture was filtered through celite 545 under redued pressure to remove the palladium on carbon. The filterate was concentrated under reduced pressure (reflux condenser, 10 torr, 40). The resulting pale brown colored residue was dissolved in isopropylalcohol (140 ml) and refluxed to dissolve completely. The resulting solution was stood at 0 for 2 hrs to cool, stirred for 30 min and filtered off under redued pressure. The resulting ivory crystalline solid was dried in vacuo to obtain the title compound (15.8 g, 88%).
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[F:20][CH:21]([F:32])[O:22][C:23]1[C:30]([CH3:31])=[CH:29][C:26]([CH:27]=O)=[CH:25][N:24]=1>>[F:32][CH:21]([F:20])[O:22][C:23]1[N:24]=[CH:25][C:26]([CH2:27][N:1]2[CH:2]([C:10]3[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=3[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]2=[O:8])=[CH:29][C:30]=1[CH3:31]
Reactant: Cc1cc(C=O)cnc1OC(F)F
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cnc(OC(F)F)c(C)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with 6-(difluoromethoxy)-5-methylnicotinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.86 min.; [M+H]+: 406.88 g/mol.
Reaction SMILES: C([O:3][C:4](=[O:16])[CH2:5][O:6][C:7]1[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[C:9]([F:15])[N:8]=1)C.C(O)C.[OH-].[Na+].Cl>O>[Cl:13][C:12]1[C:7]([O:6][CH2:5][C:4]([OH:16])=[O:3])=[N:8][C:9]([F:15])=[C:10]([Cl:14])[CH:11]=1
Reactant: CCOC(=O)COc1nc(F)c(Cl)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)COc1nc(F)c(Cl)cc1Cl

Procedure:
A mixture of 17 grams (0.06 mole) of ethyl-(3,5-dichloro-6-fluoro-2-pyridyloxy)acetate in 90 milliliters of commercial grade ethanol and 2.8 grams of sodium hydroxide in 25 milliliters of water was refluxed for ~20 minutes. Thereafter 5.9 cubic centimeters of concentrated hydrochloric acid was added thereto and the mixture stirred and cooled for 15 minutes. The mixture was filtered to recover the solid which precipitated and the solid was extracted exhaustively with boiling hexane followed by extraction with a hexane-benzene mixture. After drying, the (3,5-dichloro-6fluoro-2-pyridyloxy) acetic acid product was recrystallized from hexane and was recovered in a yield of ~6 grams and melted at 140°-144° C. Upon analysis, the product was found to have carbon, hydrogen, chlorine and nitrogen contents of 36.04, 2.11, 29.28 and 5.64 percent, respectively, as compared with the theoretical contents of 35.03, 1.67, 29.54 and 5.83 percent, respectively, calculated for the above-named compound.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]2[O:10][C:11]3([CH2:19][N:20]=2)[CH:16]2[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]2)[CH2:12]3)[CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[N:7]1[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=1[NH:8][C:9]1[O:10][C:11]2([CH2:19][N:20]=1)[CH:16]1[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]1)[CH2:12]2
Reactant: Brc1cccc(NC2=NCC3(CN4CCC3CC4)O2)n1
Agent: [Pd]
Solvent: CO
Product: c1ccc(NC2=NCC3(CN4CCC3CC4)O2)nc1
Yield: 18.6 %

Procedure:
To N-(6-bromopyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (291 mg, 0.86 mmol) in methanol (20 mL) was hydrogenated over 10% palladium on carbon (23 mg) in the Parr apparatus for 2 hours. The catalyst was removed by filtration and the filtrated concentrated in vacuo. The residue was purified by column chromatography (0.7% ammonium hydroxide/6.3% methanol/93% chloroform) to give racemic N-(pyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (41.3 mg, 0.16 mmol, 18.6 5 yield). 1H NMR (500 MHz, MeOD) δ ppm 8.13-8.33 (m, 1 H), 7.57-7.72 (m, 1 H), 6.83-7.04 (m, 2 H), 3.97 (d, J=10.07 Hz, 1 H), 3.66 (d, J=10.07 Hz, 1 H), 3.18-3.27 (m, 1 H), 3.03-3.14 (m, 1 H), 2.94 (t, J=7.63 Hz, 2 H), 2.70-2.90 (m, 2 H), 2.06-2.24 (m, 2 H), 1.57-1.87 (m, 3 H). MS (LC/MS) R.T.=1.76; [M+H]+=259.25.