Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([S:15]([C:18]2[C:19]3[CH:20]=[CH:21][N:22]=[CH:23][C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:28]([O-:30])=[O:29].[Na+].C(OC(=O)C)(=O)C.N>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([S:15]([C:18]2[C:19]3[CH:20]=[CH:21][N:22]=[C:23]([N+:28]([O-:30])=[O:29])[C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCN(S(=O)(=O)c2cccc3cnccc23)CC1
Reactant: O=N[O-]
Agent: N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)OC(C)=O
Product: CC(C)(C)OC(=O)N1CCCN(S(=O)(=O)c2cccc3c([N+](=O)[O-])nccc23)CC1
Reaction time: 8 h

Procedure:
To a stirred solution of the isoquinoline from step A (1.17 g, 3.0 mmol) in anhydrous DMSO (12 mL) was added sodium nitrite (1.24 g, 18 mmol). To the mixture was added slowly over 30 min a solution of acetic anhydride (1.84 g, 18 mmol) in anhydrous DMSO (12 mL). The mixture was stirred overnight and TLC showed most starting material remained. More sodium nitrite (1.24 g, 18 mmol) and acetic anhydride (1.84 g, 18 mmol) in anhydrous DMSO (12 mL) was added and stirring was continued for about 1 h. During this period yellow solid precipitated and TLC showed a new product at Rf 0.5 (hexane/EtOAc 1:1). The mixture was poured into a saturated aqueous solution of sodium bicarbonate (100 mL) and extracted with EtOAc (100 mL×2). Chromatography on silica eluting with 20% EtOAc/Hexane gave an oil. (0.81 g, 62%). LCMS (+APCI) m/z 454 (M+H+NH3).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)=O.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.C(=O)([O-])O.[Na+]>C(O)C>[Br:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3]3[N:18]=[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]4[CH:2]=3)=[CH:6][CH:7]=2)=[CH:12][CH:13]=1
Reactant: O=C(CBr)c1ccc(-c2ccc(Br)cc2)cc1
Reactant: Nc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Brc1ccc(-c2ccc(-c3cn4ccccc4n3)cc2)cc1
Yield: 84 %

Procedure:
Dissolving 6.7 g (19 mmol) of 2-bromo-1-(4′-bromo-biphenyl-4-yl)-ethanone into 50 milliliter of ethanol, adding 2.1 g (22 mmol) of 2-aminopyridine and 5.0 g of sodium hydrogen carbonate, the resultant suspension was refluxed under heating for 7 hours. After completion of the reaction, separation with filtration was carried out and resultant crystals were washed with water and methanol, thereby obtaining yellow crystals of 2-(4′-bromo-biphenyl-4-yl)-imidazo [1,2-a] pyridine in an amount of 5.5 g (yield: 84%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]([CH3:12])[CH3:11])=[O:9])=[N:6][CH:7]=1.[OH:13]O>CC(O)=O>[Br:1][C:2]1[CH:7]=[N+:6]([O-:13])[C:5]([C:8]([N:10]([CH3:12])[CH3:11])=[O:9])=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)c1ccc(Br)cn1
Reactant: OO
Solvent: CC(=O)O
Product: CN(C)C(=O)c1ccc(Br)c[n+]1[O-]
Temperature: 78 °C
Reaction time: 14 h
Yield: 98 %

Procedure:
To a solution of 5-bromo-N,N-dimethylpyridine-2-carboxamide (730 mg, 3.19 mmol) in 10 mL of HOAc was added 1 ml of 35% H2O2. After stirring the mixture at 78° C. for 14 hours, it was cooled and concentrated under reduced pressure. The residue was made alkaline with excess solid Na2CO3 and diluted with 25 mL of CHCl3 with stirring. The inorganic salts were filtered off, and the organic layer was dried over Na2SO4. The solvent was evaporated under reduced pressure to provided the product (750 mg, 98%), which was used without further purification. MS (ESI, pos): 247.00.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]([F:27])([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:13][CH2:14][C:15]([O:17]C(C)(C)C)=[O:16].FC(F)(F)C(O)=O>C(Cl)Cl>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[C:12]([C:22]([O:24][CH2:25][CH3:26])=[O:23])([F:27])[CH2:13][CH2:14][C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)C(F)(CCC(=O)OC(C)(C)C)N1C(=O)c2ccccc2C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(F)(CCC(=O)O)N1C(=O)c2ccccc2C1=O

Procedure:
A solution of tert-butyl 4-(1,3-dioxoisoindolin-2-yl)-4-fluoro-4-ethoxycarbonylbutanoate (1.1 g, 3 mmol) and trifluoroacetic acid (5 mL) in methylene chloride (5 mL) is stirred for 18 hours and then with methylene chloride (50 mL) for 10 min. The organic layer is washed with water and brine (30 mL each), and dried over sodium sulfate. The solvent is removed in vacuo to yield 4-(1,3-dioxoisoindolin-2-yl)-4-(ethoxycarbonyl)-4-fluorobutanoic acid which can be purified by chromatography or used in the next step without further purification.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:14](=[O:16])[CH3:15])[N:4]2[C:8]3[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:7]=3[S:6][C:5]=12.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:25]=[CH:24][C:21](/[CH:22]=[CH:15]/[C:14]([C:3]2[N:4]3[C:5]([S:6][C:7]4[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]=43)=[N:1][CH:2]=2)=[O:16])=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(=O)c1cnc2sc3c(n12)CCCCC3
Product: O=C(/C=C/c1ccc(F)cc1)c1cnc2sc3c(n12)CCCCC3

Procedure:
This compound was prepared as in EXAMPLE 15 by condensation of 1-(6,7,8,9-tetrahydro-5H-cyclohept [d]imidazo[2,1-b]thiazol-3-yl ethanone (Formula N-4) with 4-fluorobenzaldehyde to provide 6,7,8,9-Tetrahydro-[2-(4-fluorophenyl)-E-ethenyl]-5H-cyclohept [d]imidazo[2,1-b]thiazol-3-yl methanone (Formula N-5, X=4-fluoro), 3.1 g, m.p. 187-188°.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:16][CH2:17][O:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N+:7]([O-])=[CH:6][C:5]=2[N:15]=1.[NH4+:29].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O>C(Cl)Cl>[NH2:29][C:6]1[C:5]2[N:15]=[C:2]([CH3:1])[N:3]([CH2:16][CH2:17][O:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:4]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: Cc1nc2c[n+]([O-])c3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Cc1nc2c(N)nc3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
A solution of tert-butyl 2-[2-(2-methyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate (11.21 g, 29.0 mmol) in 75 mL of CH2Cl2 was treated with 75 mL of concentrated NH4OH solution. The mixture was chilled in an ice water bath. To the rapidly stirred mixture was added solid p-toluenesulfonyl chloride (5.53 g, 29.0 mmol) over a 10 min period. The reaction mixture was then warmed to room temperature and treated with 75 mL of CH2Cl2 and 75 mL of water. The organic portion was then washed with 1% Na2CO3 solution (3×) and brine. The organic portion was dried over Na2SO4 and concentrated and triturated in ether to yield 7.13 g of tert-butyl 2-[2-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as a light green solid.
Reaction SMILES: [I:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[CH:4][CH:3]=1.[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([CH2:20][Mg]Cl)=[CH:18][CH:17]=1>>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](=[O:7])[CH2:20][C:19]2[CH:23]=[CH:24][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)=[CH:12][CH:13]=1
Reactant: CON(C)C(=O)c1ccc(I)cc1
Reactant: COc1ccc(C[Mg]Cl)cc1
Product: COc1ccc(CC(=O)c2ccc(I)cc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 65.5 %

Procedure:
4-Iodo-N-methoxy-N-methylbenzamide (3.4 g, 11.7 mmol) was added dropwise over 5 min (internal temperature kept below 5° C.) to a vigorously stirring solution of (4-methoxybenzyl)magnesium chloride (52 mL, 0.25M in 2-MeTHF, 13 mmol) at 0° C. under N2. After 10 min, a white precipitate was observed. After 5 hours of vigorous stirring at 0° C., the reaction was quenched with 1N HCl (50 mL). When the internal temperature returned to 0° C., the reaction was filtered, and the filter cake was washed with ethyl acetate (50 mL) (Note #1). The filter cake was dried under vacuum to give 2.7 g of 1-(4-iodophenyl)-2-(4-methoxyphenyl)ethanone as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.92 (d, 2H), 7.78 (d, 2H), 7.16 (d, 2H), 6.87 (d, 2H), 4.28 (s, 2H), 3.72 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.C(N(CC)CC)C.[C:18]([NH2:22])([CH3:21])([CH3:20])[CH3:19].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[C:18]([NH:22][C:8](=[O:10])[C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1ccnc(C(=O)O)c1
Reactant: CC(C)(C)N
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccnc(C(=O)NC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.6 %

Procedure:
4-Methylpyridine-2-carboxylic acid (500 mg, 3.65 mmol), triethylamine (1.27 g, 12.5 mmol, 1.75 mL) and tert-butylamine (267 mg, 3.65 mmol) were combined and stirred in dichloromethane (1 mL). 1-Propanephosphonic acid cyclic anhydride (4.82 g, 7.5 mmol, 4.5 mL, 50% solution in ethyl acetate) was added dropwise and the reaction stirred at room temperature for 1 hour. The reaction mixture was concentrated at reduced pressure and the resulting residue taken up in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic phase was dried over sodium sulfate and concentrated under vacuum to afford the title compound (376 mg). MS (ESI) m/z 193.4 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:31])OC3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[C:32]([C:34]1[CH:39]=[CH:38][C:37]([S:40]([NH2:43])(=[O:42])=[O:41])=[CH:36][CH:35]=1)#[N:33]>>[C:32]([C:34]1[CH:35]=[CH:36][C:37]([S:40]([NH:43][C:23]([NH:22][CH2:21][CH2:20][C:17]2[CH:18]=[CH:19][C:14]([N:4]3[C:5]([CH3:13])=[C:6]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:2]([CH3:1])=[N:3]3)=[CH:15][CH:16]=2)=[O:31])(=[O:42])=[O:41])=[CH:38][CH:39]=1)#[N:33]
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Reactant: N#Cc1ccc(S(N)(=O)=O)cc1
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3ccc(C#N)cc3)cc2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 22 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 4-cyanobenzenesulfonamide: 1H-NMR (CDCl3) δ 7.99 (2H, d, J=8.4 Hz), 7.72 (2H, d, J=8.4 Hz), 7.45-7.15 (9H, m), 6.16 (1H, br.s), 3.36-3.34 (2H, m), 2.77-2.73 (2H, m), 2.29 (3H, s), 2.21 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]([O:13][CH:14]([CH3:16])[CH3:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH3:18][O:19][C:20]1[CH:46]=[CH:45][C:23]([CH2:24][N:25]2[CH2:29][CH:28]([CH2:30][CH2:31]OS(C3C=CC(C)=CC=3)(=O)=O)[N:27]([CH3:43])[C:26]2=[O:44])=[CH:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:17])[CH:4]([O:13][CH:14]([CH3:15])[CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:31][CH2:30][CH:28]2[CH2:29][N:25]([CH2:24][C:23]3[CH:45]=[CH:46][C:20]([O:19][CH3:18])=[CH:21][CH:22]=3)[C:26](=[O:44])[N:27]2[CH3:43])=[CH:8][CH:7]=1
Reactant: COC(=O)C(Cc1ccc(O)cc1)OC(C)C
Reactant: COc1ccc(CN2CC(CCOS(=O)(=O)c3ccc(C)cc3)N(C)C2=O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(Cc1ccc(OCCC2CN(Cc3ccc(OC)cc3)C(=O)N2C)cc1)OC(C)C
Temperature: 55 °C
Yield: 84.8 %

Procedure:
3-(4-Hydroxy-phenyl)-2-isopropoxy-propionic acid methyl ester (1.7 g, 7.3 mmol), Toluene-4-sulfonic acid 2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethyl ester (3.4 g, 8.0 mmol), and Cs2CO3 (3.6 g, 11 mmol) were combined in 10 mL of DMF and heated at 55° C. for 18 h. After cooling, the mixture is diluted with 100 mL of water and extracted with 3×20 mL of ethyl acetate. The organics were dried, concentrated, and the residue is purified by flash chromatography using 7/3 ethyl actate/hexanes to give 3.0 g (86%) of the title compound as an oil. NMR
Reaction SMILES: [OH:1][C:2]1([C:8]2[CH:13]=[CH:12][C:11]3[O:14][CH2:15][O:16][C:10]=3[CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:17](Br)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O>[CH2:17]([N:5]1[CH2:6][CH2:7][C:2]([OH:1])([C:8]2[CH:13]=[CH:12][C:11]3[O:14][CH2:15][O:16][C:10]=3[CH:9]=2)[CH2:3][CH2:4]1)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCCc1ccccc1
Reactant: OC1(c2ccc3c(c2)OCO3)CCNCC1
Solvent: CC(C)=O
Product: OC1(c2ccc3c(c2)OCO3)CCN(CCc2ccccc2)CC1

Procedure:
2.2 g. 4-Hydroxy-4-(3.4-methylene dioxy phenyl)-piperidine are dissolved hot in 35 ml. acetone, the solution is mixed with 0.95 g β phenethyl bromide and the reaction mixture is refluxed.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:19]C)=[C:4]([Cl:18])[C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])[C:6]=2[CH:17]=1.Cl.N1C=CC=CC=1>>[Cl:1][C:2]1[C:3]([OH:19])=[C:4]([Cl:18])[C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])[C:6]=2[CH:17]=1
Reactant: COc1c(Cl)cc2c(-c3ccccc3F)noc2c1Cl
Agent: Cl
Solvent: c1ccncc1
Product: Oc1c(Cl)cc2c(-c3ccccc3F)noc2c1Cl
Temperature: 200 °C

Procedure:
10 g of 5,7-dichloro-3-(2-fluorophenyl)-6-methoxy-1,2-benzisoxazole is combined with 100 g pyridine hydrochloride and heated at 200° C. for 0.5 hours. The hot melt is quickly poured into stirred ice water and a resultant precipitate is filtered and dried for 48 hours in vacuo (64° C.). The solid is recrystallized from toluene affording 5,7-dichloro-3-(2-fluorophenyl)-6-hydroxy-1,2-benzisoxazole, mp 194°-196° C.
Reaction SMILES: [Cl:1][CH:2]1[CH:12]=[CH:11][CH:5]2[C:6]([O:8][C:9](=O)[CH:4]2[CH2:3]1)=[O:7].[CH3:13][NH2:14]>>[CH3:13][N:14]1[C:9](=[O:8])[C:4]2=[CH:3][C:2]([Cl:1])=[CH:12][CH:11]=[C:5]2[C:6]1=[O:7]
Reactant: CN
Reactant: O=C1OC(=O)C2CC(Cl)C=CC12
Product: CN1C(=O)c2ccc(Cl)cc2C1=O
Temperature: 150 °C
Yield: 95 %

Procedure:
An appropriately equipped glass reaction vessel was charged with 186.5 grams (1 mole) of 4-chlorotetrahydrophthalic anhydride and heated to 150° C. under nitrogen. Methylamine gas (32 grams, 1.03 mole) was then introduced to the reaction vessel subsurface over 30 minutes. The reaction mixture was then heated for 3 hours at 180° C. The product was then distilled to give N-methyl-4-chlorophthalimide in approximately 95% yield.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][CH2:12][CH2:13][O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[C:3]=1[C:25]([O:27]CC)=[O:26].[CH:30](/B(O)O)=[CH:31]\[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(COC)OC.[Li+].[OH-]>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(O)C>[C:15]1([O:14][CH2:13][CH2:12][CH2:11][N:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2](/[CH:30]=[CH:31]/[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[C:3]2[C:25]([OH:27])=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1c(Br)c2ccccc2n1CCCOc1cccc2ccccc12
Reactant: OB(O)/C=C/c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: COCCOC
Solvent: CCO
Product: O=C(O)c1c(/C=C/c2ccccc2)c2ccccc2n1CCCOc1cccc2ccccc12

Procedure:
A mixture of EXAMPLE 31C (100 mg), (E)-styrylboronic acid (39 mg), and bis(triphenylphosphine)palladium(II) dichloride (8 mg) in 7:3:3 dimethoxyethane:ethanol:1N aqueous LiOH (2 mL) was heated under microwave conditions (CEM Discover) at 130° C. for 30 minutes The mixture was quenched with 1NHCl and extracted with ethyl acetate. The extract was dried (Na2SO4), filtered, and concentrated. The concentrate was purified by reverse phaseHPLC (Zorbax SB-C18, 20-100% acetonitrile/water/0.1% trifluoroacetic acid) to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 13.59 (br, 1H), 8.24 (m, 1H), 8.15 (d, 1H), 7.94 (m, 1H), 7.87 (m, 1H), 7.69 (d, 1H), 7.59 (m, 2H), 7.53 (m, 2H), 7.46 (m, 1H), 7.40 (m, 3H), 7.28 (m, 3H), 7.21 (m 1H), 6.87 (d, 1H), 4.87 (t, 2H), 4.17 (t, 2H), 2.34 (m, 2H).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:13][N:8]2[C:9](=[O:12])[C:10]=1[OH:11])=O.[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:27][NH2:28]>>[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:27][NH:28][C:3]([C:5]1[N:6]=[C:7]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)=[CH:13][N:8]2[C:9](=[O:12])[C:10]=1[OH:11])=[O:2]
Reactant: COC(=O)c1nc2ccc(N3CCCCC3)cn2c(=O)c1O
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: O=C(NCc1ccc(Cl)c(Cl)c1)c1nc2ccc(N3CCCCC3)cn2c(=O)c1O

Procedure:
Using the product of Example 2.6, the procedure described in Example 6 was adapted (except only 1.3 eq. of 3,4-dichlorobenzylamine was used) to afford the desired compound.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([OH:22])=[C:14]([C:23](OCC)=[O:24])[C:13]1=[O:28].[NH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].CCN(C(C)C)C(C)C>O1CCOCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([OH:22])=[C:14]([C:23]([NH:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:24])[C:13]1=[O:28]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)c1c(O)c2ccccc2n(OCc2nc3ccccc3s2)c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CNC(=O)c1c(O)c2ccccc2n(OCc2nc3ccccc3s2)c1=O
Temperature: 100 °C
Yield: 43 %

Procedure:
To a stirring suspension of ethyl 1-(benzo[d]thiazol-2-ylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate (930 mg, 2.346 mmol), tert-butyl 2-aminoacetate (369 mg, 2.82 mmol) in dioxane (5 mL) was added DIPEA (410 μl, 2.346 mmol). Reaction mixture was heated at 100° C. for 12 h. Solvent from reaction mixture was distilled out to get crude product which was then column purified using 15% EtOAC in hexane to get titled product in 43% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][CH2:6][C:7]1[CH:8]=[C:9]([C:16](=[O:20])[C:17]([OH:19])=[O:18])[N:10]([CH3:15])[C:11]=1[C:12]([OH:14])=[O:13].Cl.[CH2:25](O)[CH3:26]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][CH2:6][C:7]1[CH:8]=[C:9]([C:16](=[O:20])[C:17]([O:19][CH2:25][CH3:26])=[O:18])[N:10]([CH3:15])[C:11]=1[C:12]([OH:14])=[O:13]
Reactant: Cn1c(C(=O)C(=O)O)cc(COc2cccc(Cl)c2)c1C(=O)O
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C(=O)c1cc(COc2cccc(Cl)c2)c(C(=O)O)n1C
Yield: 42 %

Procedure:
4-(m-Chlorophenoxy)methyl-5-hydroxycarbonyl-1-methyl-α-oxopyrrole-2-acetic acid (5.5 g, 16,3 mmol) is suspended in absolute ethanol (40 ml) and concentrated HCl (1.0 ml) is added. The mixture is heated to reflux for 35 minutes, then cooled and the product crystallizes. The solid is filtered and dried to give 2.51 g (42%) of pure ethyl 4-(m-chlorophenoxy)methyl-5-hydroxycarbonyl-1-methyl-α-oxopyrrole-2-acetate.
Reaction SMILES: CN1CCOCC1.[OH:8][C@@H:9]1[C@@H:14]([OH:15])[C@H:13]([OH:16])[C@@H:12]([CH2:17][OH:18])[O:11][C:10]1=[O:19].[CH3:20][Si:21]([CH3:24])([CH3:23])Cl>O1CCCC1>[CH3:20][Si:21]([CH3:24])([CH3:23])[O:8][C@@H:9]1[C@@H:14]([O:15][Si:21]([CH3:24])([CH3:23])[CH3:20])[C@H:13]([O:16][Si:21]([CH3:24])([CH3:23])[CH3:20])[C@@H:12]([CH2:17][O:18][Si:21]([CH3:24])([CH3:23])[CH3:20])[O:11][C:10]1=[O:19]
Reactant: C[Si](C)(C)Cl
Reactant: O=C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: C[Si](C)(C)OC[C@H]1OC(=O)[C@H](O[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@@H]1O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
To a solution of N-methylmorpholine (246.8 mL, 2.24 mol) and (3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-one 1a (50 g, 0.28 mol, bought from Aladdin) in anhydrous tetrahydrofuran (500 mL) was added dropwise trimethylchlorosilane (213 mL, 1.68 mol) over a period of 2 hours. The mixture was stirred at room temperature (rt) for 8 hours and quenched with 1 L of water. The resulting mixture was partitioned. The organic layer was washed with saturated aqueous dipotassium hydrogen phosphate (100 mL×8.3) and saturated aqueous sodium chloride (100 mL×8.3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=40/1 to give the title compound 1b as colorless oil (125.2 g, 100%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3) δ(ppm): 4.17 (m, 1H), 3.99 (d, 1H), 3.89 (t, 1H), 3.81 (m, 3H), 0.18 (s, 9H), 0.17 (s, 9H), 0.15 (s, 9H), 0.11 (s, 9H).
Reaction SMILES: O=[CH:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH:10][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)CCCC=O
Reactant: Nc1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)CCCCNc1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
To a solution of methyl 5-oxopentanoate (3.0 g, 23 mmol) in methylene chloride (75 mL) was added 2-aminopyridine (2.38 g, 25.3 mmol). The mixture was stirred at room temperature for 30 minutes. Then, the sodium triacetoxy borohydride (7.31 g, 34.5 mmol) was added and the mixture was stirred at room temperature for 4.5 hours. A saturated solution of sodium bicarbonate (40 mL) was added and the reaction mixture was extracted with ether (4×30 mL). The organic layer was washed with 0.1 N NaOH, water (2×40 mL), dried (MgSO4) and concentrated. The residue was purified by flash chromatography 1:1 (Acetone:methylene chloride) to obtain 2.31 g (48%) of the product. 1H NMR (CDCl3) 8.09-8.06 (m, 1H), 7.42-7.38 (m, 1H), 6.59-6.52 (m, 1H), 6.37 (d, J=9 Hz, 1H), 4.52 (br s, 1H), 3.68 (s, 3H), 3.29 (q, J=6 Hz, 2H), 2.40-2.31 (m, 2H), 1.8-1.61 (m, 4H).
Reaction SMILES: C[Al](C)C.[CH3:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[NH:10][N:9]([NH:14][C:15]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([O:29]C)=O)(=[O:20])=[O:19])=[O:16])[N:8]=1.[CH3:31][SH:32]>C1(C)C=CC=CC=1>[CH3:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[NH:10][N:9]([NH:14][C:15]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([S:32][CH3:31])=[O:29])(=[O:20])=[O:19])=[O:16])[N:8]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)NC(=O)NN1N=C(OC)C=C(C)N1
Reactant: CS
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COC1=NN(NC(=O)NS(=O)(=O)c2ccccc2C(=O)SC)NC(C)=C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trimethylaluminum (6.0 ml, 2M) was charged via syringe to 15 ml dry toluene under nitrogen atmosphere and 3.8 g N-[(4-methoxy-6-methyltriazin-2-yl)aminocarbonyl]-2-methoxycarbonylbenzenesulfonamide was added portionwise. After stirring at room temperature for one hour, methyl mercaptan (gas) was passed through the reaction mixture until the initial temperature rise subsided, whereupon the addition was discontinued. The reaction mixture was allowed to stir at room temperature for 1 hour, and quenched with 25 ml of 10% HCl. The resultant white suspension was filtered to give 2.9 g white solid which showed infrared absorption peaks at 1740, 1690 cm-1, consistent for N-[(4-methoxy-6-methyltriazin-2-yl)aminocarbonyl]-2-(methylthio)carbonylbenzenesulfonamide.
Reaction SMILES: [Cl:1][CH2:2]/[CH:3]=[CH:4]/[CH2:5]Cl.[C:7]([NH2:18])(=[O:17])[C:8]1[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:10](N)=[O:11].[K].O>CN(C=O)C>[Cl:1][CH2:2][CH:3]=[CH:4][CH2:5][N:18]1[C:7](=[O:17])[C:8]2[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10]1=[O:11]
Reactant: NC(=O)c1ccccc1C(N)=O
Reactant: ClC/C=C/CCl
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CC=CCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.5 %

Procedure:
Trans-1,4-dichloro-2-butene (1.14 ml, 10.8 mmol) was dissolved in DMF (27 ml) and purged with argon. Potassium pthalamide (1.00 g, 5.40 mmol) was added to the solution and the reaction was allowed to stir at room temperature overnight. The reaction was then poured into water (75 ml), which precipitated a white solid. This solid was collected by filtration and purified using silica gel chromatography (3:1 Hex: EtOAc) to afford a 76% yield (961 mg) of a white solid.