Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[N:10]([CH:22]=[N:23][N:24]=3)[C:11](SC)=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:31]1([CH2:37][C@H:38]([NH2:41])[CH2:39][NH2:40])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[N:10]([CH:22]=[N:23][N:24]=3)[C:11]([NH:40][CH2:39][C@@H:38]([NH2:41])[CH2:37][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1
Reactant: CSc1nc(-c2ccncc2)c(-c2ccc(F)cc2)c2nncn12
Reactant: NC[C@@H](N)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N[C@H](CNc1nc(-c2ccncc2)c(-c2ccc(F)cc2)c2nncn12)Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 8-(4-fluorophenyl)-5-methylthio-7-(4-pyridyl)-1,2,4-triazolo[4,3-c]pyrimidine (1.0 g, 3.0 mmole), potassium carbonate (1.5 g) and (2S)-3-phenylpropane-1,2-diamine (540 mg, 3.6 mmole) in 50 ml of DMF was stirred at room temperature (RT) for 48 hours. The reaction solution was poured into water (200 mL), and the resulting precipitate was filtered and washed with water. The crude product was purified by flash chromatography (3%-15% MeOH/NH3 in DCM) to provide 1-(8-(4-fluorophenyl)-7-(4-pyridyl)-1,2,4-triazolo[4,3-c]pyrimidin-5-yl)amino-2(S)-amino-3-phenylpropane was obtained as white solid; MS: m/z (M+H)+ 440.1; C25H22FN7 requir. 439.5.
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([O:18][CH:19]([C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:29])([F:28])[F:27])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl.[Cl:42]C1C=CC=CC=1C(OC1CNC1)C1C=CC(Cl)=CC=1>>[ClH:42].[F:28][C:26]([F:27])([F:29])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH:19]([O:18][CH:16]1[CH2:17][NH:14][CH2:15]1)[C:30]1[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=1
Reactant: Clc1ccc(C(OC2CNC2)c2ccccc2Cl)cc1
Reactant: FC(F)(F)Oc1ccc(C(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2ccccc2C(F)(F)F)cc1
Agent: Cl
Product: FC(F)(F)Oc1ccc(C(OC2CNC2)c2ccccc2C(F)(F)F)cc1

Procedure:
This material was prepared from 1-benzhydryl-3-[2-(trifluoromethyl)-4′-(trifluoromethoxy)benzyhydryloxy]azetidine (140) (4.8 mmol) using the procedure described for compound (9) (1.32 g, 65%).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][C:7]2[N:12]=[C:11]([C:13]([OH:15])=O)[CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.Cl.[F:19][C:20]([F:30])([F:29])[C@@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)[NH2:22]>>[F:30][C:20]([F:19])([F:29])[C@H:21]([NH:22][C:13]([C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:17][CH:16]=2)[N:12]=1)=[O:15])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: O=C(O)c1cccc(Cc2ccc(F)cc2)n1
Reactant: N[C@H](c1ccccn1)C(F)(F)F
Agent: Cl
Product: O=C(N[C@H](c1ccccn1)C(F)(F)F)c1cccc(Cc2ccc(F)cc2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(4-fluorobenzyl)picolinic acid (Example 277 a) and (R)-2,2,2-trifluoro-1-(pyridin-2-yl)ethanamine hydrochloride (CAN 1228565-87-4) as starting materials. MS (EI): m/e=390.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:20])=[C:16](Cl)[N:17]=2)[C:12](=[O:21])[C:11]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10]1.[C:27]([O:31][C:32]([N:34]1[CH2:38][CH2:37][CH:36]([OH:39])[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28].C1CCN2C(=NCCC2)CC1.[H-].[Na+]>CN(C=O)C>[C:27]([O:31][C:32]([N:34]1[CH2:38][CH2:37][CH:36]([O:39][C:16]2[N:17]=[C:18]3[C:13]([C:12](=[O:21])[C:11]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10][N:9]3[C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[CH:14][C:15]=2[F:20])[CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(Cl)c(F)cc2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(OC3CCN(C(=O)OC(C)(C)C)C3)c(F)cc2c1=O
Temperature: 25 °C
Yield: 53 %

Procedure:
To a mixture of 325 mg of ethyl 1-(2,4-difluorophenyl)-6-fluoro-7-chloro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate, 325 mg of 1-t-butoxycarbonyl-3hydroxypyrrolidine, 194 mg of DBU and 3 ml of DMF was added 46 mg of 55% sodium hydride while the former was stirred at room temperature. After the resultant mixture was stirred for 1.5 hours at room temperature, the reaction mixture was treated in a similar manner to Example 1-(1), whereby 240 mg of ethyl 7-(1-t-butoxycarbonyl-3-pyrrolidinyloxy)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate was obtained.
Reaction SMILES: C([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:62]/[O:63]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)/[C:27]([NH:29][CH:30]2[C:60](=[O:61])[N:32]3[C:33]([C:44]([O:46]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:45])=[C:34](/[CH:37]=[CH:38]/[CH2:39][O:40][C:41](=[O:43])[CH3:42])[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl>C(O)=O>[NH2:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:62]/[OH:63])/[C:27]([NH:29][CH:30]2[C:60](=[O:61])[N:32]3[C:33]([C:44]([OH:46])=[O:45])=[C:34](/[CH:37]=[CH:38]/[CH2:39][O:40][C:41](=[O:43])[CH3:42])[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1
Reactant: CC(=O)OC/C=C/C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Agent: Cl
Solvent: O=CO
Product: CC(=O)OC/C=C/C1=C(C(=O)O)N2C(=O)C(NC(=O)/C(=N\O)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.1 %

Procedure:
A mixture of diphenylmethyl 7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-[(E)-3-acetoxy-1-propenyl)-3-cephem-4-carboxylate (1.98 g, 1.75 mmol) in formic acid (20 ml) was stirred for 2 hr at room temperature. Conc. hydrochloric acid (0.16 ml, 1.92 mmol) was added to the mixture and the mixture was stirred for 1 hr at room temperature. Filtration, and concentration of the filtrate, followed by trituration with IPE gave 975 mg of the crude product. Chromatography on a column of reversed phase silica gel and elution with 10% MeOH in water and concentration of the fraction containing the desired product gave 418 mg (51%) of the title compound as an amorphous powder. IR νmax (KBr) cm-1 1765, 1730, 1650. UV λmax (pH 7 phosphate buffer) nm (ε) 290 (23400). 1H NMR (DMSO-d6) δ 2.03 (3H, s, OAC), 3.65 (2H, ABq, 2-H), 4.61 (2H, ABq, CH2OAc), 5.15 (1H, d, J=5 Hz, 6-H), 5.75 (1H, dd, J=5 & 8 Hz, 7-H), 6.15 (1H, m, vinyl-H), 6.65 (1H, s, thiazole), 6.85 (1H, d, J=15 Hz, vinyl-H), 7.05 (2H, s, NH2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10](/[CH:18]=[N:19]/[S:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21])=[CH:11][C:12]2[N:13]([CH:15]=[CH:16][N:17]=2)[CH:14]=1.[CH3:26][Mg]Br.[NH4+].[Cl-]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([CH:18]([NH:19][S:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21])[CH3:26])=[CH:11][C:12]2[N:13]([CH:15]=[CH:16][N:17]=2)[CH:14]=1
Reactant: C[Mg]Br
Reactant: CC(C)(C)S(=O)/N=C/c1cc2nccn2cc1-c1ccc(Cl)cc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC(NS(=O)C(C)(C)C)c1cc2nccn2cc1-c1ccc(Cl)cc1Cl

Procedure:
To a solution of 2-methyl-propane-2-sulfinic acid 1-[6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridin-7-yl]-meth-(E)-ylideneamide (20 mg, 0.045 mmol) in anhydrous THF (0.5 mL) was added methylmagnesium bromide (3 M solution in Et2O, 0.045 mL, 0.14 mmol) at RT. The reaction mixture was stirred for 3 h30 then poured into a saturated solution of NH4Cl in water and extracted with AcOEt. The organic layer was dried over Na2SO4, filtered and evaporated to dryness to give the crude 2-methyl-propane-2-sulfinic acid {1-[6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridin-7-yl]-ethyl}-amide intermediate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C([Li])(C)(C)C.[S:19](Cl)([Cl:22])(=[O:21])=[O:20]>CCOCC.C(OCC)(=O)C>[C:4]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=[C:2]([S:19]([Cl:22])(=[O:21])=[O:20])[CH:3]=1
Reactant: Brc1cccc(-c2ccccc2)c1
Reactant: O=S(=O)(Cl)Cl
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=S(=O)(Cl)c1cccc(-c2ccccc2)c1
Temperature: -78 °C
Yield: 49.5 %

Procedure:
3-Bromobiphenyl (1.5 g, 6.4 mmol) was dissolved in ether (15 ml) and cooled to -78° C. t-Butyllithium (1.7 M solution in hexane, 3.8 ml, 6.4 mmol) was added dropwise under constant stirring and an argon atmosphere. The resultant reaction mixture was stirred at -10° C. to -5° C. for 6 h. The reaction mixture was cooled to -78° C. and sulfuryl chloride (0.64 ml, 6.4 mmol) was added dropwise. After completion of the addition, the reaction mixture was allowed to attain ambient temperature slowly and stirred for 1 h. The reaction mixture was diluted with ethyl acetate (50 ml), washed with water and the organic layer dried over anhydrous MgSO4. Removal of the solvent under reduced pressure gave crude product, which was purified by column chromatography, using hexane followed by 5% ethyl acetate in hexane as eluent, to give 3-biphenylsulfonyl chloride as an oil (0.8 g, 49% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([O:10][C:11]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([C:22]2[N:23]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:24]3[C:29]([CH:30]=2)=[CH:28][C:27]([CH:31]=O)=[CH:26][CH:25]=3)=[C:16]2[C:12]=1[CH2:13][NH:14][C:15]2=[O:40])(=[O:9])=[O:8].[NH:41]1[CH2:45][CH2:44][CH2:43][CH2:42]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([O:10][C:11]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([C:22]2[N:23]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:24]3[C:29]([CH:30]=2)=[CH:28][C:27]([CH2:31][N:41]2[CH2:45][CH2:44][CH2:43][CH2:42]2)=[CH:26][CH:25]=3)=[C:16]2[C:12]=1[CH2:13][NH:14][C:15]2=[O:40])(=[O:8])=[O:9]
Reactant: COc1cc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(=O)(=O)c1ccccn1)CNC2=O
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: COc1cc(-c2cc3cc(CN4CCCC4)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(=O)(=O)c1ccccn1)CNC2=O
Yield: 31.8 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-(2-pyridinesulfonyloxy)-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (0.332 g, 0.589 mmol) was dissolved in acetonitrile (10.0 mL), and the solution was treated with pyrrolidine (0.983 mL, 11.8 mmol), acetic acid (0.674 mL, 11.8 mmol) and sodium triacetoxyborohydride (0.375 g, 1.77 mmol), followed by purification of the residue by flash column chromatography (chloroform/methanol=85/15) to obtain 4-(2-pyridinesulfonyloxy)-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-(pyrrolidin-1-ylmethyl)indol-2-yl]isoindolinone (0.116 g, 32%).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([NH:12][C:13](=[O:18])[O:14][CH2:15][CH2:16]Cl)=[CH:7][C:6]=1[NH:19][C:20](=[O:25])[O:21][CH2:22][CH2:23]Cl.Cl>O1CCOCC1>[CH3:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([N:12]2[CH2:16][CH2:15][O:14][C:13]2=[O:18])=[CH:7][C:6]=1[N:19]1[CH2:23][CH2:22][O:21][C:20]1=[O:25]
Reactant: COc1c(C)cc(NC(=O)OCCCl)cc1NC(=O)OCCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1c(C)cc(N2CCOC2=O)cc1N1CCOC1=O
Temperature: 45 °C
Reaction time: 2 h

Procedure:
200 ml of sodium hydroxide solution (20% strength) were initially introduced and heated to 45° C. Subsequently, 59 g of bis(2-chloroethyl) (4-methoxy-5-methyl-1,3-phenylene)biscarbamate were added in portions and the mixture was diluted with 200 ml of dioxane. The mixture was after-stirred for a further 2 h at 45° C. After stirring overnight at room temperature, the mixture was poured onto ice, and the mixture was neutralized with hydrochloric acid. The precipitated product was filtered off with suction and dried overnight under reduced pressure.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH3:16])[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[NH4+].[NH4+].F[P-](F)(F)(F)(F)F.[N:30]1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[NH2:30][C:13](=[O:14])[C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:16]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])[O-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H](NC(=O)OCc1ccccc1)C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 121.5 %

Procedure:
A mixture of (2S)-2-[(benzyloxy)carbonyl]aminopropanoic acid (0.5 g, 0.002 mol), ammonium carbonate (0.43 g, 0.0045 mol), benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate (1.2 g, 0.0027 mol), N,N-diisopropylethylamine (980 μL, 0.0056 mol) in methylene chloride (3 mL) was stirred at RT overnight. The mixture was quenched with saturated NaHCO3 solution, and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was flash chromatographed on a silica gel column to afford the desired product (0.54 g). Analytical LCMS: (M+H)+=223.1.
Reaction SMILES: Cl[C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]2[CH:34]=[CH:33][S:32][CH:31]=2)=[O:29])=[CH:23][C:22]=1B1OC(C)(C)C(C)(C)O1>>[CH3:17][O:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[CH2:9][NH:8][C:6](=[O:7])[C:5]1[CH:18]=[CH:19][C:2]([C:22]2[CH:23]=[C:24]([NH:27][C:28]([C:30]3[CH:34]=[CH:33][S:32][CH:31]=3)=[O:29])[CH:25]=[CH:26][C:21]=2[CH3:20])=[N:3][CH:4]=1
Reactant: Cc1ccc(NC(=O)c2ccsc2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: COc1cccc(CNC(=O)c2ccc(Cl)nc2)c1
Product: COc1cccc(CNC(=O)c2ccc(-c3cc(NC(=O)c4ccsc4)ccc3C)nc2)c1

Procedure:
N-(3-Methoxybenzyl)-6-[5-(thiophen-3-ylcarbonylamino)-2-methyl-phenyl]-nicotinamide was prepared from 6-chloro-N-(3-methoxybenzyl)nicotinamide (Intermediate 3) and N-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]thiophene-3-amide (Intermediate 14) using General Method B. LCMS: retention time 3.27 min, MH+458. NMR: δH [2H6]-DMSO 10.12, (1H, s), 9.29, (1H, t), 9.15, (1H, d), 8.35-8.32, (2H, m), 7.86, (1H, s), 7.78, (1H, d), 7.68-7.65, (3H, s), 7.32-7.24, (2H, m), 6.94, (2H, m), 6.84, (2H, d), 4.51, (2H, d), 3.75, (3H, s), 2.32, (3H, s).
Reaction SMILES: [CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10](Br)[CH:9]=1)(=[O:5])=[O:4].CCO.[C:19]1(B(O)O)[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCOC(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>[CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([C:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=2)[CH:9]=1)(=[O:5])=[O:4]
Reactant: OB(O)C1=CCCCC1
Reactant: CNS(=O)(=O)CCc1ccc(N)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNS(=O)(=O)CCc1ccc(N)c(C2=CCCCC2)c1
Temperature: 80 °C
Yield: 69.2 %

Procedure:
A solution of 177 mg (0.604 mmol) of 2-(4-amino-3-bromo-phenyl)-ethanesulfonic acid methylamide (as prepared in the previous step) in toluene (5 mL) and EtOH (2.5 mL) was treated with 83.7 mg (0.664 mmol) of cyclohex-1-enylboronic acid and 2.40 mL (4.83 mmol) of 2.0 M aqueous Na2CO3. The mixture was degassed via sonication, placed under Ar, treated with 67.3 mg (0.0604 mmol) of Pd(PPh3)4, and heated to 80° C. for 19 h. The mixture was diluted with EtOAc (15 mL) and washed with water (1×10 mL). The aqueous layer was extracted with EtOAc (1×10 mL), and the combined organic layers were dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 25-g Varian MegaBond Elut SPE column with 50% EtOAc-hexane afforded 123 mg (69%) of the title compound as a white solid: 1H-NMR (CD3CN; 400 MHz): δ 6.90 (dd, 1H, J=8.0, 2.0 Hz), 6.83 (d, 1H, J=2.0 Hz), 6.32 (d, 1H, J=8.0 Hz), 5.70-5.66 (m, 1H), 4.97-4.90 (m, 2H), 4.08-3.99 (br s, 2H), 3.24-3.17 (m, 2H), 2.91-2.84 (m, 2H), 2.66 (d, 3H, J=5.2 Hz), 2.24-2.15 (m, 4H), 1.82-1.74 (m, 2H), 1.74-1.66 (m, 2H).
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]#[C:19][CH3:20])=[CH:12][CH:11]=1)(=[O:9])=[O:8])C.[OH-].[Na+].Cl>C1COCC1.CO>[CH2:17]([O:16][C:13]1[CH:12]=[CH:11][C:10]([S:7]([NH:6][CH2:5][C:4]([OH:21])=[O:3])(=[O:9])=[O:8])=[CH:15][CH:14]=1)[C:18]#[C:19][CH3:20]
Reactant: CC#CCOc1ccc(S(=O)(=O)NCC(=O)OCC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC#CCOc1ccc(S(=O)(=O)NCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
To a solution of 0.30 g (0.965 mmol) of the product of Example 20 in 10 mL of THF/methanol (1:1) was added 4.8 mL of a 1.0N sodium hydroxide solution and the reaction was stirred overnight at room temperature and then acidified to pH 2 with 10% HCl solution. The resulting mixture was extracted with dichloromethane and the combined organics were dried over MgSO4, filtered and concentrated in vacuo to provide 0.238 g (83%) of the sulfonamide as a white solid. Electrospray Mass Spec 281.9 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:30])[N:15]([CH2:17][C:18]4[C:19]([CH3:29])=[N+:20]([O-])[C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=4)[N:16]=[C:10]3[C:9]=2[C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)=[CH:4][CH:3]=1.[C:37]([O:40]C(=O)C)(=[O:39])[CH3:38]>>[C:37]([O:40][CH2:29][C:19]1[C:18]([CH2:17][N:15]2[C:14](=[O:30])[N:11]3[CH:12]=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[C:9]([C:31]4[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=4)[C:10]3=[N:16]2)=[CH:23][CH:22]=[C:21]([C:24]([F:27])([F:26])[F:25])[N:20]=1)(=[O:39])[CH3:38]
Reactant: Cc1c(Cn2nc3c(-c4ccncc4)c(-c4ccc(Cl)cc4)ccn3c2=O)ccc(C(F)(F)F)[n+]1[O-]
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OCc1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn2c1=O
Temperature: 25 °C

Procedure:
A solution of 3-((7-(4-chlorophenyl)-3-oxo-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)methyl)-2-methyl-6-(trifluoromethyl)pyridine 1-oxide (60 mg, 0.12 mmol) in acetic anhydride (2 mL) in a sealed tube was stirred at 130° C. for 6 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc, washed with saturated aqueous NaHCO3, water, then saturated aqueous NaCl, dried (Na2SO4), filtered, and concentrated under reduced pressure to afford 45 mg of the crude product as a light brown foam. A portion of the product (15 mg) was purified using preparative reverse phase HPLC (Phenomenex Luna 5 μm C-18 21.2×100 mm column eluted with a linear gradient of 50% to 80% B over 8 min (A=0.1% trifluoroacetic acid, 90% water, 10% methanol and B=0.1% trifluoroacetic acid, 90% methanol, 10% water) with flow rate at 20 mL/min and UV detection at 220 nm). The desired fractions were concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with saturated aqueous NaHCO3 once, water twice, then saturated aqueous NaCl, dried over Na2SO4 and evaporated. The residue was dissolved in acetonitrile, frozen and lyophilized to afford 7.5 mg of the title compound as a yellow powder. HPLC/MS: retention time=2.90 min, [M+H]+=554.1.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([Br:22])[CH:16]=2)[CH2:9]1)(OC(C)(C)C)=O.C(=O)([O-])[O-].[K+].[K+].[CH2:29](Br)[CH:30]=[CH2:31]>CC(C)=O>[Br:22][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[O:21][CH2:31][CH:30]=[CH2:29])[CH2:14][C@H:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2ccc(O)c(Br)c2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(C[C@@H]2CNCCO2)cc1Br
Temperature: 55 °C
Reaction time: 16 h

Procedure:
N-BOC-(R)-2-(3-bromo-4-hydroxybenzyl)morpholine, example 4, intermediate (a) (70 mg, 0.19 mmol) was dissolved in acetone (1.5 mL), treated with potassium carbonate (78 mg, 0.56 mmol) and allyl bromide (68 mg, 1.86 mmol) added. The resulting reaction was shaken at 55° C. for 16 hrs. The reaction was filtered and concentrated under a flow of nitrogen. The crude residue was dissolved in tetrahydrofuran (8 mL) with polymer supported diphenylphosphine (0.5 g) and shaken for 4 hrs. The reaction was then filtered and concentrated under a high flow of nitrogen. The crude residue was dissolved in TFA (20% v/v solution in dichloromethane, 2.5 mL) and shaken for 3 hrs at room temperature. The reaction mixture was added directly to an SCX-2 column (2 g) and washed with dichloromethane (2 mL×2) and methanol (2 mL×2). The SCX-2 column was then washed with ammonia (2N in methanol, 3×2 mL). Combined ammonia washes were concentrated in vacuo to yield the desired morpholine example 19 as a colorless oil (35 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].C(N(CC)CC)C.[C:20]([C:22]1[C:27](F)=[CH:26][CH:25]=[CH:24][N:23]=1)#[N:21]>CN(C)C(=O)C>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][C:27]1[C:22]([C:20]#[N:21])=[N:23][CH:24]=[CH:25][CH:26]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: N#Cc1ncccc1F
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2cccnc2C#N)c(OC)c1
Temperature: 80 °C
Yield: 73.6 %

Procedure:
2,4-Dimethoxybenzylamine (3.29 g, 19.7 mmol) and triethylamine (1.99 g, 19.7 mmol) were added sequentially to a solution of 2-cyano-3-fluoropyridine (2.0 g, 16.4 mmol) (Sakamoto et. al., Chem. Pharm. Bull., 1985, 33, 565-71) in N,N-dimethylacetamide (29 mL). The reaction was heated at 80° C. for 4 h, quenched with water and extracted with diethyl ether (3×). The combined organic extracts were washed water, saturated brine, dried over magnesium sulfate and concentrated. The crude product was purified by flash chromatography (silica gel, 0-12% ethyl acetate (with 0.1 triethylamine) in dichloromethane gradient elution) to produce the title compound (3.25 g). MS 270.3 (M+1).
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:9](=[O:10])[CH2:8][N:7]([CH2:11][CH:12]([OH:21])[CH2:13][C:14](OCC(C)C)=[O:15])C1C(C)C)(=[O:3])[NH2:2]>CN(C)C=O.O>[OH:21][CH:12]1[CH2:11][N:7]([CH2:8][C:9]([NH:5][CH2:4][C:1]([NH2:2])=[O:3])=[O:10])[C:14](=[O:15])[CH2:13]1
Reactant: CC(C)COC(=O)CC(O)CN1CC(=O)N(CC(N)=O)C1C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)CNC(=O)CN1CC(O)CC1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 0 %

Procedure:
A solution of 11.8 g (34.3mol) of 2-methylpropyl 3-carbamoylmethyl-Beta-hydroxy-2-(l-methylethyl)-4-oxo-1-imidazolidinebutanoate in 90 ml of dimethylformamide and 10 ml of water was gently refluxed (external temp. 130° C.) for 24 hours. The solvent was evaporated under reduced pressure. The oily residue was taken up with 40 ml of ethanol and stirred at 0° C. for 30 minutes. The precipitate was collected and crystallized from ethanol/isopropanol 1:1 to give 2.5 g of the title compound as a white powder, m.p. 158°-160° C. Mass spectrum (E.I., 70 eV, 1.5 mA), m/z=197 (M+ --H2O), 180. IR spectrum (oil mull): 3420, 3320, 3220, 1680, 1655 and 1630 cm`31.