Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.[K]>CN(C)C=O>[C:7]1([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:17]2[C:13](=[O:23])[C:14]3[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:16]2=[O:18])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClCCCCCc1ccccc1
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCCc1ccccc1
Yield: 91.1 %

Procedure:
To a stirred solution of 24.0 g (0.131 mole) of 1-chloro-5-phenylpentane (Columbia Organics, Camden, S.C.) in 150 mL of dimethylformamide was added 24.3 g (0.131 mole) of potassium phthalimide (Aldrich) and the reaction mixture was heated at reflux under a nitrogen atmosphere for 15 hr. The solvent was evaporated under reduced pressure to heave a viscous, oily residue. The residue was triturated with 200 mL of water and then the mixture was extracted with four 200-mL portions of methylene chloride. The combined methylene chloride extracts were washed with two 200 mL portions of 2N sodium hydroxide solution, twice with 200 mL portions of water and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 35.0 g (91%) of title compound as a viscous oil. A sample of this viscous oil was further purified by high pressure liquid chromatography (Waters Associates Prep LC/System 500A, PrepPak® 500 silica gel; ethyl acetate-hexanes, 1:10). Fractions containing title compound were combined and the solvents were evaporated under reduced pressure to give purified title compound as a colorless, viscous oil.
Reaction SMILES: C[O-].[Na+].C([O:12][CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]([CH3:25])[CH:23]=O)=[O:15])(=O)C1C=CC=CC=1.O>ClCCl>[OH:12][C:13]1[C:14](=[O:15])[C:16]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:22]([CH3:23])[CH:25]=1
Reactant: CN(C=O)c1ccccc1C(=O)COC(=O)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cn1cc(O)c(=O)c2ccccc21

Procedure:
Sodium methoxide (17.75 g) was added to a stirred solution of 2-[2-(N-methylformamido) phenyl]-2-oxoethyl benzoate, obtained as described in Example 2a-d, (186 g) in dichloromethane (1300 ml) at 0° under nitrogen resulting in an exotherm to 25 to 30°. The mixture was recooled at 0° and a second portion of sodium methoxide (17.75 g) added resulting in a further exotherm and the resultant mixture stirred for 1 hour. Sodium methoxide (35.5 g) was then again added in two equal portions and the resultant mixture stirred at 0 to 10° for 1 hour. Water (1860 ml) was added over 70 minutes maintaining the temperature below 6°. The phases were separated and the dichloromethane phase was extracted with aqueous sodium hydroxide (0.5M, 930 ml). The combined aqueous phase and extract were washed with dichloromethane (930 ml) and then cooled to 0°. Hydrochloric acid ( 5M, 300 ml) was added dropwise to pH 3 to 4 followed by aqueous sodium hydroxide (5M, 38 ml) and then aqueous sodium bicarbonate (1M, 250 ml) to pH 8. The resultant solid was collected by filtration and washed with water (3×200 ml) to give 3-hydroxy-1-methyl-4-quinolone, m.p. 239°-241°.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([F:10])[C:7]3[O:11][C:12]4[C:17]([C@@:18]5([CH2:23][CH2:22][O:21][C:20]([NH2:24])=[N:19]5)[C:6]=3[CH:5]=2)=[CH:16][C:15]([NH2:25])=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([C:33](O)=[O:34])=[N:31][CH:32]=1.C(N(CC)CC)C.CCCP(=O)=O>CCOC(C)=O>[NH2:24][C:20]1[O:21][CH2:22][CH2:23][C@:18]2([C:6]3[CH:5]=[C:4]([CH:1]4[CH2:3][CH2:2]4)[N:9]=[C:8]([F:10])[C:7]=3[O:11][C:12]3[C:17]2=[CH:16][C:15]([NH:25][C:33](=[O:34])[C:30]2[CH:29]=[CH:28][C:27]([Cl:26])=[CH:32][N:31]=2)=[CH:14][CH:13]=3)[N:19]=1
Reactant: NC1=N[C@@]2(CCO1)c1cc(N)ccc1Oc1c2cc(C2CC2)nc1F
Reactant: O=C(O)c1ccc(Cl)cn1
Agent: CCCP(=O)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: NC1=N[C@@]2(CCO1)c1cc(NC(=O)c3ccc(Cl)cn3)ccc1Oc1c2cc(C2CC2)nc1F
Reaction time: 0.02 h
Yield: 12.2 %

Procedure:
To a solution of (S)-3-cyclopropyl-1-fluoro-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazine]-2′,7-diamine (0.0864 g, 0.254 mmol) and 5-chloro-2-pyridinecarboxylic acid (0.044 g, 0.279 mmol) in EtOAc (2 mL) was added triethylamine (0.106 ml, 0.762 mmol). The mixture was stirred for one minute and propylphosphonic anhydride solution, 50 wt. % in ethyl acetate (0.302 ml, 0.508 mmol) was added. Stirring continued for 1 h. The reaction was quenched with saturated NaHCO3 and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered, concentrated and chromatographed on silica gel using 0-5% MeOH/DCM and repurified by HPLC to afford (S)—N-(2′-amino-3-cyclopropyl-1-fluoro-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazin]-7-yl)-5-chloropicolinamide as a white solid (0.015 g, 0.031 mmol, 12.31% yield). MS m/z=480.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH3:14])[CH:3]=[CH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1.C(Cl)(=O)C(Cl)=O.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=1>CCOC(C)=O.CN(C=O)C>[CH3:14][C:2]([CH3:1])([CH3:15])/[CH:3]=[CH:4]/[C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([O:23][CH3:22])[CH:25]=2)=[O:11])=[CH:12][CH:13]=1
Reactant: COc1cccc(N)c1
Reactant: CC(C)(C)C=Cc1ccc(C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cccc(NC(=O)c2ccc(/C=C/C(C)(C)C)cc2)c1
Reaction time: 1 h

Procedure:
To a cooled (0° C.) and well stirred suspension of 4-(3,3-dimethyl-but-1-enyl)-benzoic acid (1.5 g, 7.34 mMol) in a mixture of EtOAc and DMF (1:1, 25 mL) is added oxalyl chloride (0.364 g, 4.04 mMol) slowly drop-wise and the mixture is agitated for one hour. m-Anisidine (1.36 g, 11.01 mMol) is then added in EtOAc (5 mL) and the mixture is stirred for 6.0 hours before being quenched with saturated potassium carbonate solution. The precipitate is filtered, washed with water and vacuum dried to obtain the title compound.
Reaction SMILES: CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:14][N+:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:16]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[Br:37][C:38]1[CH:43]=[CH:42][C:41]([C:44](=[O:51])[C:45]#[C:46][CH2:47][CH2:48][CH2:49][CH3:50])=[CH:40][CH:39]=1>O>[CH2:24]([O:23][C:21]([C:17]1[CH:18]=[CH:19][C:20]2[N:15]([N:14]=[C:46]([CH2:47][CH2:48][CH2:49][CH3:50])[C:45]=2[C:44](=[O:51])[C:41]2[CH:42]=[CH:43][C:38]([Br:37])=[CH:39][CH:40]=2)[CH:16]=1)=[O:22])[CH3:25]
Reactant: CCCCC#CC(=O)c1ccc(Br)cc1
Reactant: CCOC(=O)c1ccc[n+](N)c1
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1nn2cc(C(=O)OCC)ccc2c1C(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.6 %

Procedure:
A mixture of 13.8 g of ethyl 1-aminopyridinium 3-carboxylate 2,4,6-trimethylbenzenesulphonate (compound A) (Synthesis 1977, page 1, TAMURA, et al.), 150 ml of dimethylformamide, 5.7 g of potassium carbonate and 10 g of the product of Step A of Example 1 were stirred for 3 hours at room temperature and then 6.9 g of compound A and 2.85 g of potassium carbonate were added. The mixture was stirred for 2 hours. Then 6.9 g of compound A and 2.85 g of potassium carbonate were added and the mixture was stirred for 2 hours at ambient temperature. The mixture was taken up in water and extracted with ethyl acetate. Separation was carried out by chromatography on silica (essence G: 80/ethyl acetate: 20) to obtain 7.38 g of the expected product (M.p.≤50° C.) and 8.25 g of the corresponding isomer of Example 16.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[C:4]([CH3:11])[N:3]=1.[NH2:12][C@H:13]([C:15]1[N:20]=[C:19]2[CH:21]=[CH:22][N:23]([CH3:24])[C:18]2=[CH:17][C:16]=1[N:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C@@H:27]([CH3:38])[CH2:26]1)[CH3:14].C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([NH:12][C@H:13]([C:15]2[N:20]=[C:19]3[CH:21]=[CH:22][N:23]([CH3:24])[C:18]3=[CH:17][C:16]=2[N:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[C@@H:27]([CH3:38])[CH2:26]2)[CH3:14])[C:5]([C:9]#[N:10])=[C:4]([CH3:11])[N:3]=1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1N1CCN(C(=O)OC(C)(C)C)[C@@H](C)C1
Reactant: Cc1nc(N)nc(Cl)c1C#N
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2N2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)c1C#N
Temperature: 85 °C
Yield: 89.7 %

Procedure:
To a 250 mL round-bottom flask were added 2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile (0.821 g, 4.87 mmol) and tert-butyl (S)-4-(5-((S)-1-aminoethyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)-2-methylpiperazine-1-carboxylate (1.40 g, 3.75 mmol) in DMSO (15 mL). Triethylamine (2.1 mL, 15 mmol) was added to the mixture, which was then heated to 85° C. for 2 hours. After cooling, the mixture was partitioned between saturated NaHCO3 and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over MgSO4, filtered, and concentrated. The crude product was purified by column chromatography (SiO2, 20-100% EtOAc/heptane gradient). The product-containing fractions were combined and then concentrated in vacuo to give the title compound as light-yellow oil (1.7 g, 90%). ESI-MS m/z [M+H]+ calc'd for C26H35N9O2, 506. found 506.
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]\[CH2:5]Cl.C[Si](C)(C)CCOC[N:13]1[C:17]2=[N:18][CH:19]=[CH:20][CH:21]=[C:16]2[CH2:15][C:14]1=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[NH:13]1[C:17]2=[N:18][CH:19]=[CH:20][CH:21]=[C:16]2[C:15]2([CH2:5][CH:4]=[CH:3][CH2:2]2)[C:14]1=[O:22]
Reactant: C[Si](C)(C)CCOCN1C(=O)Cc2cccnc21
Reactant: ClC/C=C\CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1Nc2ncccc2C12CC=CC2
Temperature: 45 °C
Reaction time: 1 h
Yield: 25.2 %

Procedure:
To a solution of cis-1,4-dichloro-2-butene (1.98 g, 15.8 mmol) and 1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (3.49 g, 13.2 mmol) in DMF (175 mL) was added cesium carbonate (10.7 g, 32.9 mmol). After 24 h the reaction mixture was partitioned between Et2O (200 mL) and H2O (200 mL). The aqueous layer was extracted further with Et2O (2×200 mL). The combined organic layers were washed with H2O (2×100 mL), then brine (100 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. To a solution of this material in dichloromethane (150 mL) was added trifluoroacetic acid (150 mL). After 1 h, the reaction was concentrated, dissolved in EtOH (150 mL) and 2N HCl (150 mL) was added. This mixture was heated at 45° C. for 48 h. The mixture was concentrated, diluted with saturated aqueous NaHCO3, and extracted with dichloromethane (2×). The combined organic layers were dried and concentrated. The crude product was purified by silica gel chromatography, eluting with a gradient of 0 to 5% methanol:dichloromethane to give the title compound (0.62 g). MS: m/z=187.1 (M+1).
Reaction SMILES: I.[CH2:2]([N:6]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[S:8][C:7]1=[NH:15])[CH2:3][CH2:4][CH3:5].[C:16]1([N:26]=[C:27](OCC)[CH2:28][CH3:29])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1>C(O)CCC>[CH2:2]([N:6]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[S:8]/[C:7]/1=[N:15]\[C:27](=[N:26][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)[CH2:28][CH3:29])[CH2:3][CH2:4][CH3:5]
Reactant: CCOC(CC)=Nc1cccc2ccccc12
Reactant: CCCCn1cc(C(C)(C)C)sc1=N
Agent: I
Solvent: CCCCO
Product: CCCCn1cc(C(C)(C)C)s/c1=N\C(CC)=Nc1cccc2ccccc12
Temperature: 85 °C
Reaction time: 48 h

Procedure:
To a 20-ml scintillation vial containing a magnetic stir bar were added the free base of Example 6A and the liquid imidate from Example 73A. Butanol was added to form a yellow solution. The reaction was heated to 85° C. in a heated shaker block and stirred for 48 h. The volatiles were removed by rotary evaporator to give a brown oil. Product purified by flash chromatography (silica gel: 5-40% ethyl acetate in hexanes) to give the title compound as a colorless oil. 1H NMR (DMSO-d6) δ0.96 (t, J=7.3 Hz, 3H), 1.04 (t, J=7.5 Hz, 3H),1.24 (s, 9H) 1.29-1.42 (m, 2H), 1.73-1.83 (m, 2H), 2.18 (q, J=7.5 Hz, 2H), 4.13 (t, J=7.1 Hz, 2H), 6.76 (dd, J=7.3, 1.2 Hz, 1H), 7.13 (s, 1H), 7.38-7.55 (m, 4H), 7.83-7.88 (m, 2H). MS (ESI+) m/z 394 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:6]([C:18]([NH:20][NH2:21])=[O:19])=[C:5]2[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.O.C1C[O:39][CH2:38]C1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:6]([C:18]1[O:19][C:38](=[O:39])[NH:21][N:20]=1)=[C:5]2[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NNC(=O)c1c(N2CCCCC2)nc2ccc(Cl)cc2c1-c1ccccc1
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: O=c1[nH]nc(-c2c(N3CCCCC3)nc3ccc(Cl)cc3c2-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-Chloro-4-phenyl-2-piperidin-1-yl-quinoline-3-carboxylic acid hydrazide (30 mg, 70.9 μmol, Eq: 1.00) and N,N′-carbonyldiimidazole (13.8 mg, 85.1 μmol, Eq: 1.2) were dissolved in THF (1 ml). Then triethylamine (10.0 mg, 13.8 μL, 99.2 μmol, Eq: 1.4) was added and the reaction mixture was stirred for 2 h at RT. Water was added and the mixture was extracted with ethyl acetate (3×). The combined extracts were washed with water and brine, dried with Na2SO4 and evaporated. The remaining residue was purified by column chromatography (silica gel, DCM/EtOAc 97:3) to afford the title compound as yellow solid (25 mg). MS (ESI): 407.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([N:19]3[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]3)(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:28]([NH2:34])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>C1COCC1.CO>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([N:19]3[CH2:24][CH2:23][CH:22]([NH:34][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:21][CH2:20]3)(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C1CCN(S(=O)(=O)c2ccc(CNC(=O)c3ccc(Cl)cc3)cc2)CC1
Reactant: CCCCCCN
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCNC1CCN(S(=O)(=O)c2ccc(CNC(=O)c3ccc(Cl)cc3)cc2)CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
4-chloro-N-{4-[(4-oxo-1-piperidinyl)sulfonyl]benzyl}benzamide 7d (500 mg, 1.23 mmol) was suspended in THF/methanol (10 ml/20 ml), N-hexylamine (149 mg, 1.48 mmol) and Cyanoborohydride-IRA400 (1.0 g, 3.0 mmol) were added and the reaction mixture was stirred at 50° C. overnight. Excess amine was scavenged with Ameba-PS (415 mg, 0.50 mmol) by shaking for 2 h. The resins were filtered off, solvent removed in vacuo and the obtained residue purified by column chromatography on silica gel using a step gradient of 2.5% methanol in DCM and 5% methanol in DCM. Fractions with Rf=0.28 (5% methanol in DCM,) were collected and evaporated to dryness (Note: Up to 1% conc. NH3 (13.5 M) may be added during the chromatography to reduce loss of material). The residue was dissolved in DCM (10 ml) and 1 N HCl in ether (3 ml) added. After aging at room temp for 1 h the precipitate was filtered off and dried in vacuo. The hydrochloric salt of sulfonamide 4-chloro-N-(4-{[4-(hexylamino)-1-piperidinyl]sulfonyl}benzyl)benzamide 7 was isolated as off-white powder (260 mg, 36%) in >95% purity. M/Z APCI 492.0 (M+1), 490.2 (M−1). 1H-NMR (DMSO-d6) (HCl salt) δ 9.39 (t, 1H, H—N5, 3J=5.92 Hz), 8.97 (m, br, 2H, H—N16), 7.99 (d, 2H, 3J=8.65 Hz, H—C2, 3), 7.75 (d, 2H, 3J=8.20 Hz, H—C8, 9), 7.61 (m, 4H, H—C1, 4, 7, 10), 4.61 (d, 2H, 3J=5.92 Hz, H—C6), 3.73* (d, 2H, 2J=11.84 Hz, Heq—C11, 15), 3.07 (m, br, 1H, H—C13), 2.83 (m, br, 2H, H—C17), 2.29* (m, 2H, Hax—C12, 14), 2.10* (d, br, 2H, 2J=11.90 Hz, Hax—C11, 15), 1.71-1.54* (m, 4H, Heq—C12, 14 and H—C18), 1.36-1.23 (m, 6H, H—C19, 20, 21), 0.89 (t, 3H, 3J=6.60 Hz, H—C22)
Reaction SMILES: [C:1]([Cl:6])(=[O:5])[C:2](Cl)=[O:3].[Br:7][C:8]1[CH:9]=C(C(O)=O)O[C:12]=1[Br:13].CN(C)C=O>ClCCl>[Br:7][C:8]1[CH:9]=[C:2]([C:1]([Cl:6])=[O:5])[O:3][C:12]=1[Br:13]
Reactant: O=C(O)c1cc(Br)c(Br)o1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(Br)c(Br)o1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Oxalyl chloride (10.4 ml, 0.12 mol) was added to a suspension of 4,5-dibromo-2-furoic acid (27 g, 0.1 mol) in dichloromethane (300 ml) containing dimethylformamide (0.1 ml). The mixture was stirred at room temperature for 4 h and then concentrated in vacuo. The residue was re-dissolved in dichloromethane and concentrated in vacuo; this was repeated to give the title compound which was used directly in the following step.
Reaction SMILES: F[C:2]([C:4]1[O:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]=1[C:15]([O:17][CH3:18])=[O:16])=[O:3].O/[N:20]=[C:21](/[C:23]1[CH:40]=[CH:39][C:26]([CH2:27][N:28]2[CH2:31][CH:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29]2)=[CH:25][CH:24]=1)\[NH2:22].C(N(C(C)C)CC)(C)C>C(#N)C>[C:35]([O:34][C:32]([CH:30]1[CH2:31][N:28]([CH2:27][C:26]2[CH:39]=[CH:40][C:23]([C:21]3[N:22]=[C:2]([C:4]4[O:8][N:7]=[C:6]([C:9]5[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=5)[C:5]=4[C:15]([O:17][CH3:18])=[O:16])[O:3][N:20]=3)=[CH:24][CH:25]=2)[CH2:29]1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(/C(N)=N/O)cc2)C1
Reactant: COC(=O)c1c(-c2ccccc2)noc1C(=O)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1c(-c2ccccc2)noc1-c1nc(-c2ccc(CN3CC(C(=O)OC(C)(C)C)C3)cc2)no1
Temperature: 25 °C
Yield: 62.5 %

Procedure:
To a mixture of methyl 5-(fluorocarbonyl)-3-phenylisoxazole-4-carboxylate (99 mg, 0.397 mmol) and (Z)-tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate (121 mg, 0.397 mmol) in acetonitrile (2 mL) at rt was added diisopropylethylamine (0.083 mL, 0.477 mmol) and the reaction mixture was allowed to stir at rt over the weekend. The reaction mixture was partitioned between EtOAc (30 mL) and water (30 mL). The organic layer was washed with brine (20 mL), dried (MgSO4) and concentrated to afford a white solid that was chromatographed on a 12 gm Isco silica gel cartridge, eluting with a 0-100% EtOAc/Hex gradient. The essentially pure fractions containing product were concentrated to afford methyl 5-(3-(4-((3-(tert-butoxycarbonyl)azetidin-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)-3-phenylisoxazole-4-carboxylate (128 mg, 0.248 mmol, 62.4% yield) as a white solid. HPLC retention time=1.78 minutes (YMC Combi 4.6×30 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.1 TFA a 2 minute gradient. MS: (M+H)=517.22. 1H NMR (400 MHz, chloroform-d) d ppm 1.45 (s, 9H) 3.23-3.32 (m, 3H) 3.51-3.58 (m, 2H) 3.68 (s, 2H) 3.95 (s, 3H) 7.44 (d, J=8.0 Hz, 2H) 7.48-7.56 (m, 3H) 7.75 (dd, J=7.91, 1.63 Hz, 2H) 8.11 (d, J=8.3 Hz, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:4])([CH3:3])[CH3:2].S(Cl)(Cl)=O.[CH2:18]([NH:20][CH2:21][CH3:22])[CH3:19]>C(Cl)Cl>[CH2:18]([N:20]([CH2:21][CH3:22])[C:7](=[O:9])[C:6]1[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=1[C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:19]
Reactant: CC(C)(C)c1ccccc1C(=O)O
Reactant: CCNCC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccccc1C(C)(C)C
Temperature: 0 °C

Procedure:
A solution of 2-tert-butylbenzoic acid (4.0 g, 22.5 mmol) in thionyl chloride (8.2 mL, 112 mmol) was stirred at RT for 2 h, then was concentrated three times from carbon tetrachloride to remove all traces of excess thionyl chloride. A solution of diethylamine (4.93 g, 67.4 mmol) in CH2Cl2 (10 mL) was added dropwise over 10 min to an ice water-cooled solution of the crude acid chloride in CH2Cl2 (35 mL). Ten min after addition was complete, the reaction was partitioned between ether and 10% HCl. The ether phase was then washed with sat aq NaHCO3, then was dried (MgSO4), and concentrated to afford a quantitative yield of N,N-diethyl-2-tert-butyl-benzamide as an off-white solid. m.p. 38.5°-40.5° C.
Reaction SMILES: [C:1]([Si:5]([CH3:16])([CH3:15])[O:6][CH2:7][CH2:8][C@H:9]([OH:14])[C:10]([CH3:13])([OH:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].O.[C:18]1(C)[CH:23]=CC(S(O)(=O)=O)=C[CH:19]=1>COC(OC)(C)C>[C:1]([Si:5]([CH3:15])([CH3:16])[O:6][CH2:7][CH2:8][C@H:9]1[C:10]([CH3:11])([CH3:13])[O:12][C:18]([CH3:23])([CH3:19])[O:14]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(O)[C@@H](O)CCO[Si](C)(C)C(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COC(C)(C)OC
Product: CC1(C)O[C@@H](CCO[Si](C)(C)C(C)(C)C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 1503.3 %

Procedure:
Step E To a suspension of (S)-5-(tert-butyl-dimethyl-silanyloxy)-2-methyl-pentane-2,3-diol (6.8 g, 27 mmol) in 2,2-dimethoxypropane (35 mL) was added p-toluenesulfonic acid monohydrate (0.2 g). The reaction mixture was stirred at room temperature for 30 min. The mixture was partitioned between water and dichloromethane. The organic layer was separated, the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:20) to give tert-butyl-dimethyl-[2-((S)-2,2,5,5-tetramethyl-[1,3]dioxolan-4-yl)-ethoxy]-silane as a yellow oil (4.56 g, 58%).
Reaction SMILES: [N:1]([C:4]1[C:12]([CH2:13]/[CH:14]=[C:15](\[CH3:22])/[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:11]([O:23][CH3:24])[C:10]([CH3:25])=[C:9]2[C:5]=1[C:6](=[O:26])[O:7][CH2:8]2)=[C:2]=[O:3].[CH3:27][OH:28]>>[CH3:27][O:28][C:2]([NH:1][C:4]1[C:12]([CH2:13]/[CH:14]=[C:15](\[CH3:22])/[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:11]([O:23][CH3:24])[C:10]([CH3:25])=[C:9]2[C:5]=1[C:6](=[O:26])[O:7][CH2:8]2)=[O:3]
Reactant: COC(=O)CC/C(C)=C/Cc1c(N=C=O)c2c(c(C)c1OC)COC2=O
Reactant: CO
Product: COC(=O)CC/C(C)=C/Cc1c(NC(=O)OC)c2c(c(C)c1OC)COC2=O

Procedure:
A solution of methyl (E)-6-(1,3-dihydro-4-isocyanato-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate (1.0 g) in 10 ml methanol was heated to reflux for 4 hours and then evaporated to dryness. The residue was recrystallized from acetone/hexane to give 0.41 g of methyl (E)-6-(1,3-dihydro-4-methoxycarbonylamino-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate. The ester (0.35 g) and 0.05 g of LiOH-H2O in 9 ml 2:1 MeOH-H2O was heated at reflux for 4 hours. The mixture was acidified, extracted with ethyl acetate, and the organic layer was dried over MgSO4. The organic layer was concentrated and the residue was further purified by silica gel chromatography (eluant 60:40:2 hexane:ethyl acetate:acetic acid) to give 0.21 g of (E)-6-(1,3-dihydro-4-methoxycarbonylamino-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoic acid, mp 155°-158° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]1[S:10][C:9]([C:11]2[NH:15][C:14]3[CH:16]=[CH:17][CH:18]=[C:19]([C:20]([NH2:22])=[O:21])[C:13]=3[N:12]=2)=[CH:8][CH:7]=1.C=O.[C:25]([BH3-])#N.[Na+]>CO.O>[CH3:25][N:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]1[S:10][C:9]([C:11]2[NH:15][C:14]3[CH:16]=[CH:17][CH:18]=[C:19]([C:20]([NH2:22])=[O:21])[C:13]=3[N:12]=2)=[CH:8][CH:7]=1
Reactant: NC(=O)c1cccc2[nH]c(-c3ccc([C@H]4CCCN4)s3)nc12
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN1CCC[C@@H]1c1ccc(-c2nc3c(C(N)=O)cccc3[nH]2)s1
Reaction time: 8 h

Procedure:
A solution of EXAMPLE 16D (50 mg) in methanol (20 mL) was treated with 37 wt % formaldehyde in water (114 μL) and stirred overnight. Sodium cyanoborohydride (315 mg) was added, and the solution was stirred for 3 hours and concentrated. The concentrate was dissolved in methanol and TFA, and purified by HPLC (Zorbax C-8, 0.1% TFA/acetonitrile/water). 1H NMR (CD3OD) δ 2.30 (m, 2H), 2.47 (m, 1H), 2.74 (m, 1H), 2.94 (s, 3H), 3.31-3.40 (m, 1H), 3.88 (m, 1H), 4.81 (m, 1H), 7.40 (t, J=7.7 Hz, 1H), 7.51 (d, J=3.7 Hz, 1H), 7.73 (d, J=7.6 Hz, 1H), 7.86 (d, J=4.0 Hz, 1H), 7.95 (d, J=7.6 Hz, 1H).