Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][N:11]=[C:10]2[NH:15][CH:16]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][C:28]([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([Cl:36])[CH:31]=2)=[O:29])[CH:22]=1)[CH2:17][N:18]([CH3:20])[CH3:19])=[O:4].C1COCC1.CC(O)C.[NH4+:46].[OH-]>O>[Cl:36][C:32]1[CH:31]=[C:30]([C:28]([NH:27][C:23]2[CH:22]=[C:21]([CH:16]([NH:15][C:10]3[C:9]4[C:14](=[C:5]([C:3]([NH2:46])=[O:4])[CH:6]=[CH:7][CH:8]=4)[N:13]=[CH:12][N:11]=3)[CH2:17][N:18]([CH3:20])[CH3:19])[CH:26]=[CH:25][CH:24]=2)=[O:29])[CH:35]=[CH:34][N:33]=1
Reactant: COC(=O)c1cccc2c(NC(CN(C)C)c3cccc(NC(=O)c4ccnc(Cl)c4)c3)ncnc12
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CC(Nc1ncnc2c(C(N)=O)cccc12)c1cccc(NC(=O)c2ccnc(Cl)c2)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a 40-mL vial with magnetic stirbar at 25° C. was added 4-(1-{3-[(2-Chloro-pyridine-4-carbonyl)-amino]-phenyl}-2-dimethylamino-ethylamino)-quinazoline-8-carboxylic acid methyl ester (0.25 g, 0.495 mmol, 1 eq.) and THF (5 mL) and iPrOH (5 mL). An approx. equal volume of concentrated aq. NH4OH solution (28-30% soln.) was then added and stirring continued overnight. The reaction mixture was heated at 50° C.×4 hours in order to drive the reaction to completion. H2O (25 mL) was added to the reaction mixture and a precipitate immediately began to form. The precipitate was collected and discarded, and the aqueous layer was evaporated under nitrogen affording the desired product, 0.23 g (96% yield).
Reaction SMILES: [N+]([C:4]1[NH:5][CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[N:8]=1)([O-])=O.[C:12]([O:16][CH2:17][CH:18]1[CH2:20][O:19]1)([CH3:15])([CH3:14])[CH3:13].C([O-])(=O)C.[Na+]>C(O)C>[C:12]([O:16][CH2:17][CH:18]1[O:19][C:4]2=[N:8][C:7]([N+:9]([O-:11])=[O:10])=[CH:6][N:5]2[CH2:20]1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OCC1CO1
Reactant: O=[N+]([O-])c1c[nH]c([N+](=O)[O-])n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OCC1Cn2cc([N+](=O)[O-])nc2O1
Yield: 21 %

Procedure:
2,4-Dinitro-1H-imidazole (10 g, 63.3 mmol), 2-tert-butoxymethyloxirane (27 ml, 189 mmol) and sodium acetate (5.19 g, 189 mmol) were suspended in ethanol (100 ml) followed by stirring under reflux for 17 hours. The reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. Water was added to the residue, and the resulting mixture was extracted with methylene chloride. The organic phase was dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=50/1) to afford 2-tert-butoxymethyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole (3.2 g, yield 21%) as a white powder.
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)[NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][C:17]([N:26]([CH3:28])[CH3:27])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=CC=1)([O-])=O.[NH:30]1[CH2:35][CH:34]=[C:33]([C:36]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[NH:38][CH:37]=2)[CH2:32][CH2:31]1>O1CCOCC1>[CH3:27][N:26]([CH3:28])[C:17]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:16][CH2:15][CH:14]([CH2:13][NH:12][C:11]([N:30]2[CH2:31][CH:32]=[C:33]([C:36]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[NH:38][CH:37]=3)[CH2:34][CH2:35]2)=[O:10])[CH2:19][CH2:18]1
Reactant: CN(C)C1(c2ccccc2)CCC(CNC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Solvent: C1COCCO1
Product: CN(C)C1(c2ccccc2)CCC(CNC(=O)N2CC=C(c3c[nH]c4ccccc34)CC2)CC1
Yield: 28.4 %

Procedure:
The diastereoisomer mixture of (4-dimethylamino-4-phenylcyclohexylmethyl)-carbamic acid-4-nitro-phenyl ester (825.5 mg, 2.08 mmole) was added to a solution of 3-(1,2,3,6-tetrahydropyridine-4-yl)-1H-indole (411.8 mg, 2.08 mmole) in dioxane (10 ml). The reaction mixture formed a clear, reddish-brown solution above 60° C. The solution was boiled under reflux for 12 hours. The solution was worked up by distilling off the solvent in vacuo. The residue contained, apart from nitrophenol, also the two diastereoisomers of 4-(1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide. The diastereoisomers were separated and purified by flash chromatography on silica gel (120 g). Methanol (2000 ml) was used as eluent. The non-polar diastereoisomer (351 mg, m.p. 204°-206° C., 37%) and the polar diastereoisomer of 4-(1H-indol-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide (270 mg, m.p. 112°-115° C., 28%) were thereby obtained as pale yellow solids.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.N1CCC[C@H]1C(O)=O.[SH:21][CH2:22][CH:23]([CH2:38][SH:39])[C:24](C1(C=CC=CC1)C[C@@H](C(O)=O)N)=[O:25]>>[SH:21][CH2:22][CH:23]([CH2:38][SH:39])[C:24]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:25]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: N[C@@H](CC1(C(=O)C(CS)CS)C=CC=CC1)C(=O)O
Agent: O=C(O)[C@@H]1CCCN1
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)O)C(CS)CS

Procedure:
By substituting L-phenylalanine for the L-proline in the procedure of Example 3B, and then submitting the product to the procedure of Example 4, 1-[2-acetylthiomethyl)-3-acetylthiopropanoyl]-L-phenylalanine and 1-[2-(mercaptomethyl)-3-mercaptopropanoyl]-L-phenylalanine are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH2:16][CH2:15][C:14]3[N:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:8]=2[CH:17]=1)([O-])=O>[Pd].CO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[CH2:16][CH2:15][C:14]3[N:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:8]=2[CH:17]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)-c1cccnc1CC2
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)-c1cccnc1CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 9-nitro-5,6-dihydro-benzo[f]quinoline (1.90 g), 10% palladium on carbon (0.20 g), and methanol (10 mL) is shaken under hydrogen atmosphere (3 bar) at room temperature for 3 h. The catalyst is then separated by filtration and the filtrate is concentrated to give an oil that is submitted to the next reaction without further purification. Yield: 1.67 g (crude); Mass spectrum (ESI+): m/z=197 [M+H]+.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:26](=[O:27])[N:6]2[C:7]([C:23]([O-:25])=[O:24])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([C:19](=[O:22])[CH2:20][CH3:21])[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].C(=O)([O-])O.[Na+].[C:34]([O:40][CH2:41]I)(=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36].C(OCC)(=O)C>CN(C=O)C>[OH:1][C@@H:2]([C@H:4]1[C:26](=[O:27])[N:6]2[C:7]([C:23]([O:25][CH2:41][O:40][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])=[O:24])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([C:19](=[O:22])[CH2:20][CH3:21])[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CC(C)(C)C(=O)OCI
Reactant: CCC(=O)c1ncn2cc(C3=C(C(=O)[O-])N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(=O)c1ncn2cc(C3=C(C(=O)OCOC(=O)C(C)(C)C)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Reaction time: 1.5 h

Procedure:
Sodium(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-propionylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (75.8 mg) was dissolved in 7 ml of DMF. Sodium hydrogencarbonate (4.9 mg) and 0.038 ml of pivaloyloxymethyl iodide were added to the solution in an argon atmosphere at −30° C. The mixture was stirred for 1.5 hr. Ethyl acetate (50 ml) was added to the reaction solution. The mixture was washed three times with 30 ml of semisaturated brine. The organic layer was dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated to 5 ml under the reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:methanol=30:1) to give 62.3 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([Cl:16])=[C:13]([OH:15])[CH:14]=2)[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27]>CC(C)=O>[Cl:16][C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:4]2[N:3]=[C:2]([NH2:1])[CH:7]=[CH:6][N:5]=2)=[CH:14][C:13]=1[O:15][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27]
Reactant: Nc1ccnc(Nc2ccc(Cl)c(O)c2)n1
Reactant: CC(C)=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CC(C)=CCOc1cc(Nc2nccc(N)n2)ccc1Cl
Yield: 43 %

Procedure:
Following the general procedure for O-alkylation of 2-R-5-(heteroaryl-2-ylamino)phenol, 5-(4-aminopyrimidin-2-ylamino)-2-chlorophenol (56 mg, 0.24 mmol) and Cs2CO3 (77 mg, 0.24 mmol) in acetone (3.0 mL) was treated with 4-bromo-2-methyl-2-butene (27 μL, 0.24 mmol) at room temperature. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 6/4) in 43% yield (31 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([NH:9][CH2:10][CH2:11][N:12]2[C:17](=[O:18])[CH:16]=[CH:15][C:14]([C:19]([OH:21])=[O:20])=[CH:13]2)=[O:8])[CH:2]=1.S(Cl)(Cl)=O.N1C=CC=[CH:28][CH:27]=1>>[CH2:27]([O:20][C:19]([C:14]1[CH:15]=[CH:16][C:17](=[O:18])[N:12]([CH2:11][CH2:10][NH:9][C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[O:8])[CH:13]=1)=[O:21])[CH3:28]
Reactant: O=C(O)c1ccc(=O)n(CCNC(=O)c2cccnc2)c1
Reactant: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(=O)n(CCNC(=O)c2cccnc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a 10 ml round bottomed flask fitted with a magnetic stirrer bar, reflux condensor, and nitrogen inlet was added 1,6-dihydro-1-[2-(3-pyridinylcarbonylamino)ethyl]-6-oxo-3-pyridinecarboxylicacid (0.14 g, 0.49 mmol) and thionyl chloride (3.0 ml). The mixture was heated for 1 hour at reflux, cooled to room temperature, and concentrated. The residue was suspended in absolute ethanol (7.0 ml) and 4-dimethylaminopyridine (1 mg). Pyridine (0.12 ml, 1.47 mmol) was added with stirring at room temperature. After 16 hours, the mixture was concentrated. Purification via medium liquid chromotography (silica gel, 5-10% methanol/dichloromethane) gave the desired ester, MP: 240°-242° C.
Reaction SMILES: Br[C:2]1[CH:18]=[C:17]2[C:5]([CH2:6][CH2:7][C@@:8]32[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]3)=[CH:4][CH:3]=1.[N:19]1[CH:24]=[C:23](B(O)O)[CH:22]=[N:21][CH:20]=1.COCCOC>O>[F:14][C:13]1([F:15])[CH2:12][O:11][C:10]([NH2:16])=[N:9][C@@:8]21[C:17]1[C:5](=[CH:4][CH:3]=[C:2]([C:23]3[CH:24]=[N:19][CH:20]=[N:21][CH:22]=3)[CH:18]=1)[CH2:6][CH2:7]2
Reactant: NC1=N[C@@]2(CCc3ccc(Br)cc32)C(F)(F)CO1
Reactant: OB(O)c1cncnc1
Solvent: COCCOC
Solvent: O
Product: NC1=N[C@@]2(CCc3ccc(-c4cncnc4)cc32)C(F)(F)CO1
Yield: 19 %

Procedure:
In a manner analogous to that described in Example 1, the cross-coupling reaction of (R)-6-bromo-5′,5′-difluoro-2,3,5′,6′-tetrahydrospiro[indene-1,4′-[1,3]oxazin]-2′-amine (intermediate A6.5) with pyrimidin-5-ylboronic acid in a 3:1-mixture of 1,2-dimethoxyethane and water as the solvent yielded the title compound (19% yield) as an off-white solid. MS (ISP): m/z=317.0 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[CH3:22][N:23]1[CH:27]=[C:26]([S:28](Cl)(=[O:30])=[O:29])[N:25]=[CH:24]1>>[CH3:22][N:23]1[CH:27]=[C:26]([S:28]([N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)(=[O:30])=[O:29])[N:25]=[CH:24]1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Product: Cn1cnc(S(=O)(=O)N2CCC3(CC2)CSC2=C(O3)c3ccccc3C(=O)C2=O)c1

Procedure:
Compound 79 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 1-methyl-1H-imidazole-4-sulfonyl chloride and conditions outlined in procedure P. M.p.=256-257° C.; 400 MHz 1H NMR (CDCl3) δ: 8.06-8.03 (m, 1H), 7.64-7.56 (m, 2H), 7.53-7.45 (m, 3H), 3.84-3.78 (m, 5H), 3.30-3.22 (m, 2H), 2.93 (s, 2H), 2.22-2.13 (m, 2H), 2.0-1.90 (m, 2H); LCMS: 446 [M+H].
Reaction SMILES: [Cl:1][C:2](Cl)(Cl)[S:3]Cl.[CH3:7][C:8]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[C:9]=1[C:10]([NH2:12])=[NH:11].[OH-].[Na+]>ClCCl.O>[Cl:1][C:2]1[S:3][N:12]=[C:10]([C:9]2[C:8]([CH3:7])=[CH:16][C:15]([CH3:17])=[CH:14][C:13]=2[CH3:18])[N:11]=1
Reactant: Cc1cc(C)c(C(=N)N)c(C)c1
Reactant: ClSC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C)c(-c2nsc(Cl)n2)c(C)c1
Reaction time: 1 h
Yield: 99.1 %

Procedure:
2.2 g of trichloromethanesulfenyl chloride are introduced into a solution of 2 g of 2,4,6-trimethyl benzamidine in 16 ml of dichloromethane under an inert atmosphere at about -20° C., followed by the slow addition of 2 g of NaOH dissolved in 3.2 ml of water at about -10° C. After 1 hour at about -5° C., the precipitate formed is isolated and the organic phase is separated and washed with 6 ml of water. After being dried over K2CO3, it is concentrated under reduced pressure to give 2.8 g of the desired product in the form of an oil, which may be used without purification.
Reaction SMILES: [Br:1][CH2:2][C:3]1[C:11]2[C:10](=[O:12])[C:9]([C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])=[CH:8][N:7]([CH2:18][C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:6]=2[S:5][C:4]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[N+:33]([O-])([O-:35])=[O:34].[Na+].O>CS(O)(=O)=O.C(OCC)(=O)C>[Br:1][CH2:2][C:3]1[C:11]2[C:10](=[O:12])[C:9]([C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])=[CH:8][N:7]([CH2:18][C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[C:6]=2[S:5][C:4]=1[C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1
Reactant: O=[N+]([O-])[O-]
Reactant: CC(C)C(=O)c1cn(Cc2c(F)cccc2F)c2sc(-c3ccccc3)c(CBr)c2c1=O
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)C(=O)c1cn(Cc2c(F)cccc2F)c2sc(-c3ccc([N+](=O)[O-])cc3)c(CBr)c2c1=O
Temperature: 11 °C
Reaction time: 2 h
Yield: 59.5 %

Procedure:
The compound obtained in Example 16 (1 g) was dissolved in methanesulfonic acid (5 ml) with cooling at 10 to 12° C. and then treated dropwise with a solution of sodium nitrate (0.165 g) in methanesulfonic acid (2.5 ml). The mixture was stirred as it was for 2 hours, and then poured into a cool water, and the crystal precipitated was recovered by a filtration, washed with water and diisopropylether, dried in vacuo to obtain a crude crystal (1.04 g). This was suspended in ethyl acetate (15 ml) with stirring and then cooled on ice, and the crystal precipitated was recovered by a filtration, washed with a cool ethyl acetate to obtain the title compound (0.647 g, 59.5%).
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:30])[C:9]2[CH:14]=[C:13]([OH:15])[C:12]([OH:16])=[CH:11][C:10]=2[NH:17][C:18]([C:20]2[S:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[C:21]=2[Cl:29])=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:31][C:32]([CH3:37])([CH3:36])[C:33](Cl)=[O:34]>C(Cl)Cl.N1C=CC=CC=1>[C:1]1([NH:7][C:8](=[O:30])[C:9]2[CH:14]=[C:13]([OH:15])[C:12]([O:16][C:33]([C:32]([CH3:37])([CH3:36])[CH3:31])=[O:34])=[CH:11][C:10]=2[NH:17][C:18]([C:20]2[S:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[C:21]=2[Cl:29])=[O:19])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Nc1ccccc1)c1cc(O)c(O)cc1NC(=O)c1sc2ccccc2c1Cl
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)C(=O)Oc1cc(NC(=O)c2sc3ccccc3c2Cl)c(C(=O)Nc2ccccc2)cc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.6 %

Procedure:
To a solution of N-phenyl-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-4,5-dihydroxybenzamide (0.09 g, 0.21 mmol) in CH2Cl2 (1 mL) and pyridine.(1 mL) at 0° C. was added trimethylacetyl chloride (0.027 mL, 0.22 mmol). The solution was allowed to warm to ambient temperature with stirring. After 16 hours, the reaction mixture was partitioned between ethyl acetate and dilute HCl. The organic layer was dried over Na2SO4 and concentrated in vacuo. The resulting oil was purified by flash chromatography on silica gel to afford 0.038 g (40% yield) of N-phenyl-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-hydroxy4-((1,1-dimethylethyl)carbonyl)oxybenzamide as a white solid; NMR(DMSO-d6) 12.2 (s, 1), 10.8 (s, 1), 10.4 (s, 1), 8.3 (s, 1), 8.2 (d, 1), 8.0 (d, 1), 7.6-7.7 (m, 4), 7.4 (t, 2), 7.1 (t, 1), 1.3 (s, 9) ppm.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:10][C:5]2=[N:4][CH:3]=1.[S:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.CC([O-])=O.[K+].CN(C)C(=O)C>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:11]1([C:9]2[CH:8]=[CH:7][N:6]3[C:2]([C:21]4[S:17][CH:18]=[N:19][CH:20]=4)=[CH:3][N:4]=[C:5]3[CH:10]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Brc1cnc2cc(-c3ccccc3)ccn12
Reactant: c1cscn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: c1ccc(-c2ccn3c(-c4cncs4)cnc3c2)cc1
Temperature: 200 °C

Procedure:
A microwave vessel was charged with 3-bromo-7-phenylimidazo[1,2-a]pyridine (6-1, 0.050 g, 0.183 mmol), thiazole (0.065 ml, 0.92 mmol), tetrakis(triphenylphosphine)palladium(0) (0.011 g, 0.10 mmol) and KOAc (0.054 g, 0.55 mmol). N,N-dimethylacetamide, 1.5 ml, was added and the reaction was placed in the microwave reactor. The reaction was heated to 200° C. for 10 min. The reaction was diluted with water, and extracted 3× with DCM. The extracts were dried over Na2SO4, filtered and concentrated. The resulting residue was dissolved in DMSO and purified by reverse phase preparative HPLC. The resulting oil was triturated with ether, resulting in the rapid crystallization to a white solid. The solid was filtered and washed with ether. Afforded the pure title compound. 1H NMR (CDCl3) δ 9.11 (s, 1H), 8.47 (s, 1H), 8.37 (d, 1H, J=7.4 Hz), 8.20 (s, 1H), 8.00 (s, 1H), 7.73 (d, 2H, J=7.3 Hz), 7.57–7.52 (m, 4H). LCMS m/z (M+1) Calc: 278.1, found 278.1.
Reaction SMILES: [Cl:1][C:2]1[C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:11]([S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])[CH:10]=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].[OH-].[Na+].C(OCC)C>C(O)C>[Cl:1][C:2]1[C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:11]([S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])[CH:10]=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1ccc(S(=O)(=O)CC)c(OCCOC)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: CCS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1OCCOC
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.9 %

Procedure:
To 11.3 g (0.03 mole) of the ethyl 2-chloro-3-(2-methoxyethoxy)-4-ethylsulfonylbenzoate in 100 mL of 96% ethanol was added dropwise 16 mL (1.2 eq) of 10% sodium hydroxide. After stirring at room temperature for 4 hours, 100 mL of diethyl ether was added and the organic phase was extracted with 50 mL of 5% NaOH. The aqueous phase was acidified with 10% HCl and extracted two times with 50 mL chloroform. The organic phase was dried with MgSO4 and concentrated under vacuum to yield 8.8 grams of 2-chloro-3-(2-methoxyethoxy)4-ethylsulfonylbenzoic acid as a viscous oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:16]=[CH:15][C:8]2[O:9][CH2:10][CH:11]([CH2:13][OH:14])[O:12][C:7]=2[C:6]=1[CH3:17])=[O:4].O.[OH-].[Ba+2].[OH-]>CO>[OH:14][CH2:13][CH:11]1[CH2:10][O:9][C:8]2[CH:15]=[CH:16][C:5]([C:3]([OH:4])=[O:2])=[C:6]([CH3:17])[C:7]=2[O:12]1
Reactant: COC(=O)c1ccc2c(c1C)OC(CO)CO2
Agent: [Ba+2]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c(C(=O)O)ccc2c1OC(CO)CO2
Yield: 79.9 %

Procedure:
To a round bottom flask equipped with magnetic stirring was added 3-hydroxymethyl-5-methyl-2,3-dihydrobenzo[1,4]dioxine-6-carboxylic acid methyl ester (6.40 g, 26.9 mmol), barium hydroxide monohydrate (25.44 g, 134.3 mmol), and methanol (108 mL). This mixture was stirred at room temperature for 24 hours. The methanol was evaporated. The resulting slurry was taken up in water and washed once with ether. The aqueous layer was acidified by pouring into iced concentrated HCl. This was extracted twice with ethyl acetate. The ethyl acetate extracts were combined, dried over magnesium sulfate, filtered and evaporated to give a yellow solid, 3-hydroxymethyl-5-methyl-2,3-dihydrobenzo[1,4]dioxine-6-caboxylic acid, (4.82 g, 21.5 mmol) in 80% yield. 1H-NMR (300 MHz, CD3COCD3) δ (ppm): 2.45 (s, 3H), 3.85 (m, 2H), 4.12 (m, 1H), 4.24 (m, 1H), 4.41 (m, 1H), 6.76 (d, 1H), 7.51 (d, 1H); TLC: Rf=0.32 (1:1 ethyl acetate/hexane).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([CH3:21])([CH3:20])[CH2:9]1)C1C=CC=CC=1>CO.[H][H].[OH-].[OH-].[Pd+2]>[C:15]([NH:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][C:10]1([CH3:20])[CH3:21])([O:17][CH2:18][CH3:19])=[O:16]
Reactant: [H][H]
Reactant: CCOC(=O)NC1CCN(Cc2ccccc2)CC1(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)NC1CCNCC1(C)C

Procedure:
A mixture of 20% Pd(OH)2 on carbon (0.3 g) and 1-benzyl-4-carbethoxyamino-3,3-dimethylpiperidine (1.3 g, 4.48 mmol) in methanol (15 ml) was stirred in hydrogen atmosphere (1 atm.) at 30° C. for 3 hr. The catalyst was filtered off, washed with methanol and filtrate was concentrated to dryness to afford 4-carbethoxyamino-3,3-dimethylpiperidine. Yield 0.8 g (90%), C10H20N2O2, m/z 201 (M+1).
Reaction SMILES: [C:1]([O:6][C@@H:7]1[C@@H:15]([CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)[CH2:14][O:13][CH2:12][C@H:11]([NH:27][C:28](=[O:38])[C:29]2[C:34]([OH:35])=[C:33]([O:36][CH3:37])[CH:32]=[CH:31][N:30]=2)[C:10](=[O:39])[O:9][C@H:8]1[CH3:40])(=[O:5])[CH:2]([CH3:4])[CH3:3].[C:41](Cl)(=[O:43])[CH3:42]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:6][C@@H:7]1[C@@H:15]([CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)[CH2:14][O:13][CH2:12][C@H:11]([NH:27][C:28](=[O:38])[C:29]2[C:34]([O:35][C:41](=[O:43])[CH3:42])=[C:33]([O:36][CH3:37])[CH:32]=[CH:31][N:30]=2)[C:10](=[O:39])[O:9][C@H:8]1[CH3:40])(=[O:5])[CH:2]([CH3:3])[CH3:4]
Reactant: COc1ccnc(C(=O)N[C@H]2COC[C@H](Cc3cccc4ccccc34)[C@@H](OC(=O)C(C)C)[C@H](C)OC2=O)c1O
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccnc(C(=O)N[C@H]2COC[C@H](Cc3cccc4ccccc34)[C@@H](OC(=O)C(C)C)[C@H](C)OC2=O)c1OC(C)=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 93.1 %

Procedure:
To a solution of (3S,6S,7R,8S)-3-(3-hydroxy-4-methoxypicolinamido)-6-methyl-8-(naphthalen-1-ylmethyl)-4-oxo-1,5-dioxonan-7-yl isobutyrate (80 mg, 0.145 mmol) and DMAP (28.4 mg, 0.232 mmol) in CH2Cl2 (1.45 mL) was added acetyl chloride (218 μL, 0.218 mmol) slowly and the resulting mixture was stirred at room temperature for 14 h. The reaction mixture was treated with Celite®, the solvent removed under reduced pressure, and the resulting adsorbed crude material was purified by flash chromatography (SiO2, 0→100% acetone/hexanes) to afford (3S,6S,7R,8S)-3-(3-acetoxy-4-methoxypicolinamido)-6-methyl-8-(naphthalen-1-ylmethyl)-4-oxo-1,5-dioxonan-7-yl isobutyrate as a white powder (80 mg, 93%): mp 104-108° C.; 1H NMR (400 MHz, CDCl3) δ 8.53 (d, J=8.2 Hz, 1H), 8.27 (d, J=5.4 Hz, 1H), 8.01-7.94 (m, 1H), 7.88-7.81 (m, 1H), 7.73 (d, J=8.2 Hz, 1H), 7.55-7.43 (m, 2H), 7.39 (dd, J=8.2, 7.0 Hz, 1H), 7.29 (dd, J=7.0, 1.2 Hz, 1H), 6.96 (d, J=5.4 Hz, 1H), 5.18-5.02 (m, 3H), 4.00 (dd, J=11.7, 7.4 Hz, 1H), 3.86 (s, 3H), 3.58 (d, J=4.2 Hz, 2H), 3.37 (dd, J=11.7, 7.2 Hz, 1H), 3.22 (dd, J=14.1, 3.1 Hz, 1H), 2.76-2.63 (m, 2H), 2.38 (s, 3H), 2.34-2.22 (m, 1H), 1.38 (d, J=5.7 Hz, 3H), 1.29 (d, J=3.7 Hz, 3H), 1.27 (d, J=3.7 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 176.38, 171.66, 168.84, 162.67, 159.42, 146.73, 141.03, 137.53, 134.77, 133.99, 131.98, 128.97, 127.78, 127.34, 126.01, 125.57, 125.39, 123.50, 109.95, 77.05, 74.20, 72.26, 71.84, 56.29, 51.51, 44.99, 34.38, 32.26, 20.73, 19.15, 19.08, 18.28; HRMS-ESI (m/z) [M+H]+ calcd for C32H37N2O9 expected, 593.2494. found, 593.2502.