Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:20]4[CH:21]=[C:22]([CH3:27])[C:23]([O:25][CH3:26])=[CH:24][C:19]=4[O:18][CH2:17]3)[C:9]2=[O:28])C=CC=CC=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH3:26][O:25][C:23]1[C:22]([CH3:27])=[CH:21][C:20]2[C:10]3([CH2:17][O:18][C:19]=2[CH:24]=1)[C:11]1[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:8][C:9]3=[O:28]
Reactant: COc1cc2c(cc1C)C1(CO2)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(cc1C)C1(CO2)C(=O)Nc2ccccc21
Yield: 86.1 %

Procedure:
A stirred solution of 1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (7.2 g, 16.1 mmol), triethylsilane (15 mL) and trifluoroacetic acid (50 mL) was refluxed for 14 h. The solution was concentrated in vacuo and precipitated from hexanes to afford 6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (3.9 g, 86%) as a colorless solid: mp>250° C.; 1H NMR (300 MHz, DMSO-d6) δ10.54 (s, 1H), 7.23-7.14 (m, 1H), 7.03 (d, J=6.9 Hz, 1H), 6.95-6.86 (m, 2H), 6.58 (s, 1H), 6.41 (s, 1H), 4.68 (ABq, 2H), 3.73 (s, 3H), 1.91 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ179.2, 160.4, 158.9, 142.2, 133.4, 129.1, 124.4, 124.2, 122.7, 120.3, 118.5, 110.2, 94.3, 80.1, 58.0, 56.0, 16.0; MS (ES+) m/z 282.2 (M+1).
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([I:29])[CH:24]=1)(C(OCC)=O)[C:12]([O:14]CC)=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4].C(O)C.Cl>O>[C:3]([O:7][C:8]([NH:10][C@H:11]([C:12]([OH:14])=[O:13])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([I:29])[CH:24]=1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)C(Cc1cccc(I)c1)(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(I)c1)C(=O)O
Temperature: 25 °C

Procedure:
240 ml of a 1N sodium hydroxide solution are added to a suspension of 30.3 g (62 mmol) of diethyl[(tert-butoxycarbonyl)amino](3-iodobenzyl)malonate (Example 7D) in 440 ml of a mixture of ethanol and water (3:1). After 3 h under reflux and after cooling to RT, the pH of the reaction mixture is adjusted with concentrated hydrochloric acid to approx. pH 2. The reaction mixture is concentrated in vacuo. The residue is taken up in MTBE and water. The aqueous phase is extracted three times with MTBE. The combined organic phases are dried over sodium sulfate, filtered and concentrated. The residue is purified by RP-HPLC (acetonitrile/water gradient).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].Br[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:35][CH3:36]>>[CH3:24][O:23][C:20]1[N:19]=[C:18]([O:25][CH3:26])[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[O:35][CH3:36])=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][N:21]=1
Reactant: COc1ncc(-c2cccc(-n3cnc(C(=O)N(C)OC)c3)c2)c(OC)n1
Reactant: COc1ccccc1Br
Product: COc1ncc(-c2cccc(-n3cnc(C(=O)c4ccccc4OC)c3)c2)c(OC)n1

Procedure:
This compound is prepared by method C using compound 12m and 2-bromoanisole
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]([CH3:18])[CH3:17])[C:6]=2[N:19]=1.[NH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:22]=1[O:30][CH3:31]>C(O)C.O.Cl>[F:14][C:9]1([F:15])[CH2:8][N:7]([CH:16]([CH3:18])[CH3:17])[C:6]2[N:19]=[C:2]([NH:20][C:21]3[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:22]=3[O:30][CH3:31])[N:3]=[CH:4][C:5]=2[N:11]([CH3:12])[C:10]1=[O:13]
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CC(C)N1CC(F)(F)C(=O)N(C)c2cnc(Cl)nc21
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C(C)C)CC(F)(F)C(=O)N2C
Yield: 55.8 %

Procedure:
A mixture of 0.5 g (0.0017 mole) of 2-chloro-7,7-difluoro-9-isopropyl-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-292b) and 0.35 g (0.002 mole) of 4-amino-3-methoxy-benzoic acid in 20 mL of ethanol-water-hydrochloric acid (20:80:1) was refluxed for 18 hours, then cooled and partially concentrated under reduced pressure. The resulting solid was collected by filtration, washed with 0.5M hydrochloric acid and water and dried to give 0.40 g of 4-(7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-292).
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]2[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:15]=2[Cl:21])=[CH:9][CH:8]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[Br:20][C:18]1[CH:17]=[CH:16][C:15]([Cl:21])=[C:14]([CH:19]=1)[CH2:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][OH:4])=[CH:8][CH:9]=1
Reactant: CC(=O)OCCc1ccc(Cc2cc(Br)ccc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: OCCc1ccc(Cc2cc(Br)ccc2Cl)cc1
Yield: 76 %

Procedure:
4-(5-bromo-2-chlorobenzyl)phenethyl acetate (intermediate BG) (400 mg, 1.09 mmol) and potassium carbonate (481 mg, 3.48 mmol) were stirred at room temperature in a mixture of 3 mL methyl alcohol and 0.5 mL water for 3 h. Solvents were evaporated and the residue taken up in 25 mL ether was washed with water (5 mL) and brine (20 mL), dried (Na2SO4), filtered and evaporated. Purification on silica gel using an ISCO column with 15:1 hexane:EtOAc gave intermediate BH (271 mg, yield 76%). 1H NMR (300 MHz, CDCl3): δ 7.27-7.07 (m, 7H), 4.02 (s, 2H), 3.84 (m, 2H), 2.86 (m, 3H); LC-ESI-MS (m/z): 325 (M+H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Na].Cl.[C:19]1([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O>[C:19]1([CH:25]2[CH2:26][CH2:27][N:28]([C:2]3[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])(=[O:10])=[O:9])=[CH:4][CH:3]=3)[CH2:29][CH2:30]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)CCNS(=O)(=O)c1ccc(F)cc1
Reactant: c1ccc(C2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(O)CCNS(=O)(=O)c1ccc(N2CCC(c3ccccc3)CC2)cc1
Temperature: 130 °C

Procedure:
A stirred mixture of 3-[4-fluoro-(benzenesulfonyl amino)]-propionic acid, sodium salt (0.248 g, 0.00100 mol), 4-phenyl-piperidine hydrochloride (0.218 g, 0.00110 mol), and sodium carbonate (0.317 g, 0.00299 mol) in dry dimethyl sulfoxide (3 mL) was heated in a sand bath (130° C.) under nitrogen for 22 hours. The mixture was cooled and partitioned between ethyl acetate and 1 M hydrochloric acid. The aqueous layer was extracted with additional ethyl acetate. The organics were combined, washed with saturated sodium chloride, dried (MgSO4), and rotary evaporated. The residue was dissolved in dichloromethane and chromatographed on silica gel (14 g, 230-400 mesh) eluting with dichloromethane-methanol (15:1, 10×15 mL). Fractions containing product were combined, rotary evaporated and rechromatographed to give the title compound as a peach-colored solid; yield 0.082 g (21%), mp=145-147° C.
Reaction SMILES: [C:1]([O:20][CH2:21][CH:22]1[CH2:26][CH:25]([CH2:27]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:24]=[CH:23]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:39]#[N:40].[Na+]>CN(C)C=O>[C:1]([O:20][CH2:21][CH:22]1[CH2:26][CH:25]([CH2:27][C:39]#[N:40])[CH:24]=[CH:23]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2C=CC(COC(c3ccccc3)(c3ccccc3)c3ccccc3)C2)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCC1C=CC(COC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 70 °C
Reaction time: 48 h
Yield: 97.1 %

Procedure:
To a stirred solution of compound from Step 2, toluene-4-sulfonic acid 4-trityloxymethyl-cyclopent-2-enylmethyl ester (21.3 g, 40.59 mmol) in dimethylformamide (150 mL) was added sodium cyanide (3.58 g, 73.18 mmol) at room temperature and the reaction was stirred at 70° C. for 48 h. After cooling, the reaction mixture was extracted with ethyl acetate (2×250 mL), washed with water (2×100 mL), brine (50 mL) and dried (MgSO4). After filtration, the filtrate was concentrated and the residue was purified on a silica gel column using ethyl acetate in hexanes (0 to 30%), which afforded 14.96 g (97.1%) of desired product, (4-trityloxymethyl-cyclopent-2-enyl)-acetonitrile, as a colorless solid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1[CH:15]=[C:16]([NH:25][C:26]2[N:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=2)[CH:17]=[C:18]([C:20]2[S:24][CH:23]=[N:22][CH:21]=2)[CH:19]=1.[Li+].CC([N-]C(C)C)C.[CH3:44][C:45]1([CH3:56])[CH2:50][C:49](=O)[CH2:48][CH2:47][CH:46]1[C:52]([O:54]C)=[O:53].[Li]>C1COCC1>[CH3:56][C:45]1([CH3:44])[CH2:50][C@:49]2([C:23]3[S:24][C:20]([C:18]4[CH:17]=[C:16]([NH:25][C:26]5[N:31]=[C:30]([C:32]([F:33])([F:35])[F:34])[CH:29]=[CH:28][N:27]=5)[CH:15]=[C:14]([CH3:13])[CH:19]=4)=[CH:21][N:22]=3)[CH2:48][CH2:47][C@H:46]1[C:52](=[O:53])[O:54]2
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncs2)c1
Reactant: COC(=O)C1CCC(=O)CC1(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc([C@@]34CC[C@@H](C(=O)O3)C(C)(C)C4)s2)c1
Temperature: -65 °C
Reaction time: 0.58 h
Yield: 4.9 %

Procedure:
A solution of N,N-Diisopropylamine (13.98 mL, 98 mmol) in THF (55 mL) was cooled to −78° C. n-butyllithium (1.6M in hexanes, 61.3 mL, 98 mmol) was added portionwise via syringe, maintaining an internal temperature lower than −65° C. The reaction mixture warmed to −60° C. and aged for 45 min. and then cooled back to −78° C. A solution of N-[3-methyl-5-(1,3-thiazol-5-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (INTERMEDIATE 4, 2.113 g, 6.28 mmol) in THF (55 mL) was transferred via cannula (using positive pressure) to the freshly made LDA over the course of 30 min, maintaining the internal temperature below −70° C. The reaction mixture was aged at −78° C. for 35 min, warmed to −50° C. and aged for another 15 min., then cooled to −70° C. A solution of methyl 2,2-dimethyl-4-oxocyclohexanecarboxylate (9.04 g, 49.1 mmol) in THF (50 mL) was transferred via cannula (using positive pressure) to the flask containing the lithium salt, over the course of 45 min, maintaining the internal temperature below −65° C. The reaction was aged at −65° C. for 20 min. The cold bath was removed and the reaction allowed to warm to rt. The solution was cooled to 0° C. and quenched using ethanol (1 mL) and water (1 mL). The mixture was diluted with EtOAc (1 L) and washed with saturated ammonium chloride (3 times, total volume of wash 1.5 L). The organic layer was concentrated under reduced pressure and purified by column chromatography on silica (0-30% EtOAc:Hexanes) to afford the title compound (149 mg, 0.8%) as a yellow solid. MS ESI: [M+H]+ m/z 489. 1H NMR (600 MHz, CDCl3) δ 8.66 (d, J=4.8, 1H), 7.89 (d, J=7.0, 2H), 7.39 (s, 1H), 7.29-7.22 (m, 1H), 7.11-7.01 (m, 2H), 2.40 (m, 1H) 2.39 (s, 3H), 2.29 (m, 2H), 2.15 (m, 2H), 2.05-1.90 (m, 2H), 1.24 (s, 3H), 1.15 (s, 3H). rhSYK activity=++
Reaction SMILES: OC(C(F)(F)F)=O.[F:8][C:9]([F:26])([F:25])[O:10][C:11]1[CH:12]=[C:13]([NH:17][C:18]([C@@H:20]2[CH2:24][CH2:23][CH2:22][NH:21]2)=[O:19])[CH:14]=[CH:15][CH:16]=1.C(N(CC)CC)C.[CH2:34]([O:41][C:42]([C:44]1[N:52]2[C:47]([CH:48]=[CH:49][CH:50]=[CH:51]2)=[C:46]([N:53]=[C:54]=[O:55])[CH:45]=1)=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.Cl>C1COCC1>[CH2:34]([O:41][C:42]([C:44]1[N:52]2[C:47]([CH:48]=[CH:49][CH:50]=[CH:51]2)=[C:46]([NH:53][C:54]([N:21]2[CH2:22][CH2:23][CH2:24][C@H:20]2[C:18](=[O:19])[NH:17][C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([O:10][C:9]([F:25])([F:8])[F:26])[CH:12]=2)=[O:55])[CH:45]=1)=[O:43])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C=Nc1cc(C(=O)OCc2ccccc2)n2ccccc12
Reactant: O=C(Nc1cccc(OC(F)(F)F)c1)[C@@H]1CCCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCc1ccccc1)c1cc(NC(=O)N2CCC[C@H]2C(=O)Nc2cccc(OC(F)(F)F)c2)c2ccccn12
Temperature: 25 °C

Procedure:
To a solution of (S)-pyrrolidine-2-carboxylic acid (3-trifluoromethoxy-phenyl)-amide TFA salt (328 mg, 0.845 mmol) and triethylamine (353 μl, 2.54 mmol) in THF (10 mL) was added the crude 1-isocyanato-indolizine-3-carboxylic acid benzyl ester (247 mg, 0.845 mmol, prepared as described in Scheme A6). The resulting mixture was stirred at RT under nitrogen over the week-end then poured into HCl 1N and extracted with EtOAc (×3). The combined organic extracts were washed with an aqueous saturated solution of NaHCO3, dried (Na2SO4), filtered and concentrated. The crude mixture was purified by flash column chromatography on silica gel (c-hexane/EtOAc 1:1 to c-hexane/EtOAc 3:7) to afford the desired compound. TLC, Rf (c-hexane/EtOAc 1:1)=0.3; MS (LC/MS): 567.3 [M+H]+ 565.2 [M−H]−; tR (HPLC conditions a): 4.16 min.
Reaction SMILES: [CH2:1]([C:4]1([CH3:30])[C:9]2[N:10]([CH2:18][C:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)(O)[CH3:20])[C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][C:16]=3[C:8]=2[CH2:7][N:6]([CH3:29])[CH2:5]1)[CH:2]=[CH2:3].C(=O)(O)[O-].[Na+]>Cl>[CH2:1]([C:4]1([CH3:30])[C:9]2[N:10]([CH:18]=[C:19]([C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[CH3:20])[C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][C:16]=3[C:8]=2[CH2:7][N:6]([CH3:29])[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCC1(C)CN(C)Cc2c1n(CC(C)(O)c1ccc(F)cc1)c1ccc(C)cc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCC1(C)CN(C)Cc2c1n(C=C(C)c1ccc(F)cc1)c1ccc(C)cc21

Procedure:
A solution of 1-(4-allyl-2,4,8-trimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2-(4-fluoro-phenyl)-propan-2-ol (300 mg, 0.738 mmol) in 6N HCl (10 mL) was stirred at 80° C. for 2 h. The progress of reaction mass was monitored by TLC and LCMS. The reaction mixture was basified with saturated sodium bicarbonate solution and extracted with EtOAc (3×25 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (1% MeOH-DCM) to yield 4-allyl-5-[2-(4-fluoro-phenyl)-propenyl]-2,4,8-trimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. The product is further purified by reverse phase HPLC followed by chiral HPLC separation to give enantiomers 274a and 274b. 1H NMR (CD3OD, HCl salt) δ (ppm): 7.62 (m, 2H), 7.27 (s, 1H), 7.20 (m, 2H), 7.04 (m, 3H), 6.78-6.82 (m, 1H), 5.18 (d, 2H), 4.78 (d, 1H), 4.37 (d, 1H), 3.58 (m, 2H), 3.18 (s, 3H), 2.40 (s, 3H), 2.38 (d, 2H), 1.82 (s, 3H), 1.58 (s, 3H).
Reaction SMILES: CS(O)(=O)=O.C1(C)C=CC=CC=1.[F:13][CH:14](F)[C:15](C(OC(C)(C)C)=O)([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[C:16](OCC)=[O:17]>O>[F:13]/[CH:14]=[C:15](\[CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)/[CH2:16][OH:17]
Reactant: CCOC(=O)C(CCc1ccc(F)cc1)(C(=O)OC(C)(C)C)C(F)F
Agent: CS(=O)(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: OC/C(=C/F)CCc1ccc(F)cc1
Reaction time: 4.5 h

Procedure:
Add methanesulfonic acid (47.7 kg, 496 mol) to a toluene solution of ethyl 2-(difluoromethyl)-2-(t-butoxycarbonyl)-4-(p-fluorophenyl)butyrate as prepared in Example 3.1 at a temperature of 40° C.-50° C. After 3 to 6 hours, cool the reaction to ambient temperature. Add toluene (91 kg) and water (421 kg) and stir for 30 minutes. Separate the aqueous layer. Add to the organic layer a 20% by weight solution of sodium chloride in water (420 kg) and stir for 30 minutes. Separate the layers to give the title compound as a solution in toluene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.[F:24][C:25]1[CH:30]=[C:29]([O:31][C:32]([F:35])([F:34])[F:33])[CH:28]=[CH:27][C:26]=1Br>>[F:24][C:25]1[CH:30]=[C:29]([O:31][C:32]([F:33])([F:34])[F:35])[CH:28]=[CH:27][C:26]=1[C:6]1[CH:5]=[CH:4][C:3]([C:17]2[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=2)=[C:2]([F:1])[CH:7]=1
Reactant: Fc1cc(OC(F)(F)F)ccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: Nc1cnc(-c2ccc(-c3ccc(OC(F)(F)F)cc3F)cc2F)cn1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 1 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 2-fluoro-4-(trifluoromethoxy)bromobenzene. MS (ESI): mass calcd. for C17H10F5N3O, 367.07; m/z found, 368.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 1H), 8.03-7.96 (m, 2H), 7.78 (m, 1H), 7.56-7.49 (m, 3H), 7.37 (d, J=8.2, 1H), 6.75 (s, 2H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][OH:10])[CH:6]=[CH:7][CH:8]=1.[N+:11]([C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=O)([O-:13])=[O:12]>>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([N+:9]([O-:10])=[CH:16][C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[N+:11]([O-:13])=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: OCc1cccc(NO)c1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Product: O=[N+]([O-])c1ccccc1C=[N+]([O-])c1cccc(CO)c1
Yield: 64 %

Procedure:
The reaction of hydroxylamine 91 (1.36 g, 10 mmol) with 2-nitrobenzaldehyde (59) (1.51 g, 10 mmol) afforded, after workup, a yellow oil. The crude product was recrystallized from acetone/petroleum ether to obtain 1.74 g (6.4 mmol, 64%) of 94 as a yellow crystalline solid: mp 97°-99° C.; IR (CH2Cl2) 3605, 1570, 1525, 1340, 1155 cm-1 ; 1H NMR (Me2SO-d6) δ 4.60 (d, J=5.6 Hz, 2H), 5.43 (t, J=5.6 Hz, 1H), 7.49-8.74 (m, 9H); 13C NMR (Me2SO-d6) δ 62.82, 119.85, 120.24, 124.84, 125.06, 128.85, 129.54, 129.79, 130.84, 131.28, 133.83, 144.86, 148.44, 148.55. Anal. Calcd for C14H12N2O4 : C, 61.76; H, 4.41. Found: C, 61.85; H, 4.58.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([N:11]([O:13][CH3:14])[CH3:12])(=[O:10])=[O:9])=[C:6]([OH:15])[C:5]([NH:16][C:17]2[C:20](=[O:21])[C:19](=[O:22])[C:18]=2OCC)=[CH:4][CH:3]=1.[O:26]1[CH2:30][CH2:29][CH2:28][CH:27]1[C@H:31]([NH2:34])[CH2:32][CH3:33]>CC#N>[Cl:1][C:2]1[C:7]([S:8]([N:11]([O:13][CH3:14])[CH3:12])(=[O:9])=[O:10])=[C:6]([OH:15])[C:5]([NH:16][C:17]2[C:20](=[O:21])[C:19](=[O:22])[C:18]=2[NH:34][C@@H:31]([CH:27]2[CH2:28][CH2:29][CH2:30][O:26]2)[CH2:32][CH3:33])=[CH:4][CH:3]=1
Reactant: CCOc1c(Nc2ccc(Cl)c(S(=O)(=O)N(C)OC)c2O)c(=O)c1=O
Reactant: CC[C@@H](N)C1CCCO1
Solvent: CC#N
Product: CC[C@@H](Nc1c(Nc2ccc(Cl)c(S(=O)(=O)N(C)OC)c2O)c(=O)c1=O)C1CCCO1
Temperature: 70 °C

Procedure:
To a stirred solution of 6-chloro-3-(2-ethoxy-3,4-dioxocyclobut-1-enylamino)-2-hydroxy-N-methoxy-N-methylbenzenesulfonamide (Intermediate A) (500 mg, 1.279 mmol) in MeCN was added TEA (1.783 ml, 12.79 mmol) and (R)-1-(tetrahydro-furan-2-yl)-propylamine (1 g, 7.74 mmol) (Intermediate DA). The reaction mixture was heated to 70° C. over night. The reaction mixture was evaporated to dryness. The residue was dissolved in DCM and washed with 0.1M aqueous HCl. The organic layer was dried over MgSO4, filtered and evaporated to dryness. The diastereomers were separated by Supercritical fluid chromatography according to the following conditions:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[OH-].[K+].[CH2:9](Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(OCC)C>[CH2:9]([N:4]1[CH:3]=[C:2]([Br:1])[CH:6]=[N:5]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: ClCc1ccccc1
Reactant: Brc1cn[nH]c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: CCOCC
Solvent: O
Product: Brc1cnn(Cc2ccccc2)c1
Reaction time: 8 h
Yield: 94.8 %

Procedure:
A 100 mL round bottom flask was charged with 4-bromopyrazole (4.41 g, 30 mmol), tetrabutylammonium bromide (484 mg, 1.5 mmol) and potassium hydroxide pellets (3.37 g, 60 mmol). After the mixture was sonicated for 15 min, benzyl chloride (5.2 mL, 45 mmol) was added dropwise and the resulting mixture was stirred overnight. Ethyl ether (20 mL), water (20 mL), and diluted hydrochloric acid (1 mL, 10%) were added under stirring. The organic layer was washed with water (2×20 mL) and dried over MgSO4. The solvent was removed under reduced pressure and the product was purified by flash chromatography on silica gel (hexane/ethyl acetate 10:1) to provide the desired product as a white solid (6.74 g, 95% yield). Mp 51-52° C. (lit. 44-45° C., See Jones, R. G. J. Am. Chem. Soc. 1949, 71, 3994). 1H NMR (400 MHz, CDCl3): δ 7.53 (s, 1H), 7.42-7.33 (m, 4H), 7.28-7.22 (m, 2H), 5.29 (s, 2H); 13C NMR (100 MHz, CDCl3): δ 140.4, 136.2, 129.8, 129.4, 128.8, 128.3, 93.9, 57.1.
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[NH2:24])[CH2:4][CH3:5])[CH3:2].[CH:25](OC)(OC)OC.C1(O)O[C@H](C)[C@@H](O)C[C@H]1O>C1(C)C=CC=CC=1>[CH2:1]([CH:3]([N:6]1[C:7]2[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[C:8]=2[N:24]=[CH:25]1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1N
Reactant: COC(OC)OC
Agent: C[C@H]1OC(O)[C@H](O)C[C@@H]1O
Solvent: Cc1ccccc1
Product: CCC(CC)n1cnc2c(Oc3c(C)cc(C)cc3C)nc(C)cc21
Yield: 96.8 %

Procedure:
A mixture of N4-(1-ethylpropyl)-6-methyl-2-(2,4,6-trimethylphenoxy)-pyridine-3,4-diamine (160 mg, 0.49 mmol), trimethyl orthoformate (62 mg, 0.59 mmol) and paratosylalcohol (p-TsOH) (10 mg) in 20 ml of toluene was heated at reflux under a Dean-Stark trap apparatus for 24 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give the title compound (160 mg, 97%) as a light brown oil. The oil was purified through silica gel column chromatography using 2% methanol (MeOH) in chloroform as eluent to give a tan solid. Mp 127–131° C. 1H NMR (CDCl3) δ 7.82 (s, 1H), 6.90 (s, 2H, 6.81) (s, 1H), 4.02 (m, 1H), 2.37 (s, 3H), 2.32 (s, 3H), 2.13 (s, 6H), 1.98 (m, 4H), 0.87 (t, 6H) ppm.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([S:8]([CH3:11])(=[O:10])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:15]1[N:20]2[C:21]([N+:24]([O-:26])=[O:25])=[CH:22][N:23]=[C:19]2[CH:18]=[CH:17][CH:16]=1.O>CN(C)C=O>[CH3:11][S:8]([N:5]1[CH2:6][CH2:7][CH:2]([O:1][C:15]2[N:20]3[C:21]([N+:24]([O-:26])=[O:25])=[CH:22][N:23]=[C:19]3[CH:18]=[CH:17][CH:16]=2)[CH2:3][CH2:4]1)(=[O:10])=[O:9]
Reactant: CS(=O)(=O)N1CCC(O)CC1
Reactant: O=[N+]([O-])c1cnc2cccc(Cl)n12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1CCC(Oc2cccc3ncc([N+](=O)[O-])n23)CC1
Yield: 54.7 %

Procedure:
To a solution of 4-hydroxy-1-methylsulfonylpiperidine (2.15 g, 12 mmoles) in dimethylformamide (3 ml) was added 60% sodium hydride in oil (0.48 g, 12 mmoles) with stirring under ice-cooling and the mixture was stirred at room temperature for 10 minutes. To the reaction mixture was added 5-chloro-3-nitroimidazo[1,2-a]pyridine (1.976 g, 10 mmoles) with stirring under ice-cooling and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The precipitate was filtered off, washed with water and dried to obtain 1.862 g of the desired product (54.7%, yellow solid). The organic layer was washed with water and dried over anhydrous magnesium sulfate. After the solventy was distilled off, the crude crystlals thus obtained were recrystallized from methylene-n-hexane to obtain 460 mg of the desired product (460 mg, tan solid).