Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:56])[N:20]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([O:45][CH2:46][CH2:47][O:48][Si:49]([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50])[CH:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>O.C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:56])[N:20]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([O:45][CH2:46][CH2:47][O:48][Si:49]([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:50])[CH3:51])[CH:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: O=C([O-])O
Reactant: CCCCc1nc(C)n(-c2cccc(OCCO[Si](C)(C)C(C)(C)C)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(-c2cccc(OCCO[Si](C)(C)C(C)(C)C)c2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (1.03 g), sodium hydrogen carbonate (1.55 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-({4-butyl-1-[3-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)phenyl]-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (1.13 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.45 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.42 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.95 g, 77%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([F:10])=[C:4](F)[N:3]=1.[NH2:12][C@@H:13]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:14][OH:15].C(N(CC)CC)C>CC#N.C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:12][C@@H:13]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:14][OH:15])[C:5]([F:10])=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CC(C)(C)[C@H](N)CO
Reactant: N#Cc1cc(F)c(F)nc1Cl
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)[C@@H](CO)Nc1nc(Cl)c(C#N)cc1F
Temperature: 80 °C
Yield: 72.2 %

Procedure:
A mixture of 2-chloro-5,6-difluoropyridine-3-carbonitrile (6.52 g, 34.13 mmol), (2S)-2-amino-3,3-dimethyl-butan-1-ol (4.00 g, 34.13 mmol) and triethylamine (9.51 mL, 68.26 mmol) in CH3CN (50 mL) and THF (50 mL) was heated at 80° C. for 4 hours. The mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The crude product was purified via silica gel chromatography (0-60% EtOAc/Hexanes gradient) to afford 6.7 g of the desired product as an off white solid: 1H NMR (400 MHz, CDCl3) δ 7.25 (d, J=9.7 Hz, 1H), 5.32 (m, 1H), 4.19-4.08 (m, 1H), 3.95-3.83 (m, 1H), 3.74-3.51 (m, 1H), 0.92 (s, 9H); LC/MS (60-90% ACN/water 5 min with 0.9% FA) m/z 272.02 (M+H), retention time 1.02 minutes.
Reaction SMILES: Cl.CO[C:4]([C@@H:6]1[C@H:10]([O:11]C(=O)C2C=CC([N+]([O-])=O)=CC=2)[CH2:9][CH2:8][NH:7]1)=[O:5].[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=O)=[CH:27][C:26]=1[S:34][C:35]([F:38])([F:37])[F:36].CN(C([O:46][N:47]1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O1CCOCC1.NO>[OH:11][C@@H:10]1[CH2:9][CH2:8][N:7]([C:29](=[O:31])[C:28]2[CH:32]=[CH:33][C:25]([O:24][CH3:23])=[C:26]([S:34][C:35]([F:38])([F:37])[F:36])[CH:27]=2)[C@@H:6]1[C:4]([NH:47][OH:46])=[O:5]
Reactant: COC(=O)[C@H]1NCC[C@H]1OC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1ccc(C(=O)O)cc1SC(F)(F)F
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)N2CC[C@@H](O)[C@H]2C(=O)NO)cc1SC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 4 %

Procedure:
To a stirred solution of (2S,3R)-3-(4-nitro-benzoyloxy)-pyrrolidine-2-carboxylic acid methy ester hydrochloride salt prepared by Method C followed by Method F (109 mg, 0.33 mmol), 4-methoxy-3-trifluoromethylsulfanyl-benzoic acid (76.6 mg, 0.30 mmol), in anhydrous dioxane (2.0 mL) was added HATU (136 mg, 0.36 mmol) and DIEA (205 μL, 1.2 mmol) with rapid stirring. The reaction mixture was stirred 2 h at rt then diluted with 50% aq. hydroxylamine (2.0 mL) and stirred an additional 17 h. The crude reaction mixture was purified by preparative reverse phase HPLC to furnish the product (2S,3R)-3-hydroxy-N-hydroxy-1-(4-methoxy-3-trifluoromethylsulfanyl-benzoyl)-pyrrolidine-2-carboxamide (4.0 mg, 4% yield). HPLC: Rt=4.050 min following Method HH; ES−MS: calcd. for C14H15F3N2O5S (380.07). Found: 379.0 [M−H].
Reaction SMILES: [CH3:1][C:2]([C:5]1[O:9][C:8]([CH2:10][S:11][C:12]2[S:16][C:15]([NH:17][C:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[O:19])=[N:14][CH:13]=2)=[N:7][CH:6]=1)([CH3:4])[CH3:3].[O:26]=[CH:27][CH:28]([CH2:30]O)[OH:29].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].ClCCCl>CO>[OH:29][CH:28]([CH2:27][OH:26])[CH2:30][N:23]1[CH2:22][CH2:21][CH:20]([C:18]([NH:17][C:15]2[S:16][C:12]([S:11][CH2:10][C:8]3[O:9][C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])=[CH:6][N:7]=3)=[CH:13][N:14]=2)=[O:19])[CH2:25][CH2:24]1
Reactant: CC(C)(C)c1cnc(CSc2cnc(NC(=O)C3CCNCC3)s2)o1
Reactant: O=CC(O)CO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CO
Product: CC(C)(C)c1cnc(CSc2cnc(NC(=O)C3CCN(CC(O)CO)CC3)s2)o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.3 %

Procedure:
N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide (66 mg, 0.17 mmol, 1 eq) was combined with glyceraldehyde (69 mg, 0.77 mmol, 4.5 eq), sodium triacetoxyborohydride (163 mg, 0.77 mmol, 4.5 eq) and 1,2-dichloroethane (4 mL). The resulting suspension was stirred at rt for 4 h. Methanol (1 mL) was added and the reaction mixture was stirred at rt overnight, concentrated in vacuo and purified by preparative HPLC to provide 69 mg (59%) of (±)-1-(2,3-dihydroxypropyl)-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide as a white solid. MS: 455 [M+H]+; HPLC: 100% at 3.06 min (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]1[S:16][CH:17]=[C:18]([CH2:20][O:21][C:22]2[CH:23]=[C:24]([CH2:28][C:29]([O:31]C)=[O:30])[CH:25]=[CH:26][CH:27]=2)[N:19]=1.O1CCCC1.[OH-].[Na+].Cl>O.CO>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]1[S:16][CH:17]=[C:18]([CH2:20][O:21][C:22]2[CH:23]=[C:24]([CH2:28][C:29]([OH:31])=[O:30])[CH:25]=[CH:26][CH:27]=2)[N:19]=1
Reactant: COC(=O)Cc1cccc(OCc2csc(CCc3nc(-c4ccccc4)oc3C)n2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1CCc1nc(COc2cccc(CC(=O)O)c2)cs1
Temperature: 50 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
To a mixture of methyl 2-[3-[[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]-4-thiazolyl]methoxy]phenyl]acetate (0.31 g), tetrahydrofuran (3 mL) and methanol (3 mL) was added a 1N aqueous sodium hydroxide solution (3 mL) and the mixture was stirred at 50° C. for 1 hr. 1N Hydrochloric acid (3 mL) and water were added to the reaction mixture, and the precipitated crystals were collected by filtration and air-dried to give crystals (0.23 g, 77%) of 2-[3-[[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]-4-thiazolyl]methoxy]phenyl]acetic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 153-154° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])=[CH:2]1.Cl.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=1>>[C:27]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])=[CH:2]1)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=1
Reactant: COc1cc(C(=O)/C=C/c2c[nH]c3ccccc23)cc(OC)c1OC
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Product: COc1cc(C(=O)/C=C/c2cn(C(=O)c3cccnc3)c3ccccc23)cc(OC)c1OC
Yield: 19.7 %

Procedure:
Substantially the same procedure as in Example 59 was repeated using Compound 1 (1.43 g) obtained in Example 1 and nicotinoyl chloride hydrochloride (1.51 g) to give Compound 60 (0.37 g).
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([C:9]#[N:10])[C:6]([CH3:11])=[CH:5][CH:4]=1.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[F:31])=[C:17](B(O)O)[CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.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>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[F:31])=[C:17]([CH2:2][C:3]2[N:8]=[C:7]([C:9]#[N:10])[C:6]([CH3:11])=[CH:5][CH:4]=2)[CH:18]=1
Reactant: Cc1ccc(CCl)nc1C#N
Reactant: OB(O)c1cc(Cl)ccc1OCc1ccc(Cl)cc1F
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(Cc2cc(Cl)ccc2OCc2ccc(Cl)cc2F)nc1C#N
Yield: 64 %

Procedure:
To a solution of 6-(Chloromethyl)-3-methyl-2-pyridinecarbonitrile (132.5 mg) in dry toluene (4 ml) and ethanol (4 ml) was added (5-chloro-2-{[(4-chloro-2-fluorophenyl)methyl]oxy}phenyl)boronic acid (250 mg), potassium carbonate (330 mg) and tetrakis(triphenylphosphine)palladium(0) (92 mg) and the mixture stirred under reflux for 2.5 hours. Solvent was removed in vacuo and water (20 ml) and ether (20 ml) added. Insoluble solid was filtered over Celite and washed with ether. The aqueous layer was further extracted with ether (15 ml) and the combined extracts washed with brine (10 ml), dried (MgSO4) and concentrated in vacuo. The residue was purified by mass-directed autopreparation to afford the title compound (204 mg, 64%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27]([C:29]4[S:30][CH:31]=[CH:32][CH:33]=4)=[O:28])[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:38].[NH:39]1[CH2:44][CH2:43][CH:42]([NH:45]C(=O)OC(C)(C)C)[CH2:41][CH2:40]1>>[NH2:45][CH:42]1[CH2:43][CH2:44][N:39]([C:16]2[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27]([C:29]4[S:30][CH:31]=[CH:32][CH:33]=4)=[O:28])[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]3[CH:12]=[CH:11][C:10](=[O:38])[N:9]([C:3]4[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[C:14]=3[N:15]=2)[CH2:40][CH2:41]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Cc1ccc(NC(=O)c2cccs2)cc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Product: Cc1ccc(NC(=O)c2cccs2)cc1-c1nc(N2CCC(N)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
The title compound was prepared as described in Example 2 from N-{3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylphenyl}-2-thiophenecarboxamide and 1,1-dimethylethyl 4-piperidinylcarbamate: LC-MS m/z 573 (M+H)+, 1.90 min (ret time).
Reaction SMILES: [F:1][C:2]1([F:39])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([C:15]3[CH:16]=[C:17]([CH:32]=[CH:33][C:34]=3[CH3:35])[CH2:18][N:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)=[CH:12][CH:13]=2)[N:8]([CH3:36])[S:7]1(=[O:38])=[O:37].C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[F:39][C:2]1([F:1])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([C:15]3[CH:16]=[C:17]([CH2:18][N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:32]=[CH:33][C:34]=3[CH3:35])=[CH:12][CH:13]=2)[N:8]([CH3:36])[S:7]1(=[O:38])=[O:37]
Reactant: Cc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc2c(n1)N(C)S(=O)(=O)N2CC1CC1(F)F
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(CN2CCNCC2)cc1-c1ccc2c(n1)N(C)S(=O)(=O)N2CC1CC1(F)F
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Tert-butyl 4-(3-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridin-5-yl}-4-methylbenzyl)piperazine-1-carboxylate (43-1) (3.3 g, 5.7 mmol, 1.0 eq) was dissolved in DCM (40 mL) and TFA (4.4 mL, 56.7 mmol, 10 eq) was added and the reaction mixture stirred at ambient temperature for 45 minutes. Toluene (10 mL) was added and the reaction mixture was concentrated. The residue was dissolved in EtOAc (100 mL) and then washed with sodium bicarbonate (3×20 mL), water (20 mL) and brine (20 mL), dried over MgSO4, filtered and concentrated to afford 1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-5-[2-methyl-5-(piperazin-1-ylmethyl)phenyl]-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridine 2,2-dioxide (43-2) as a tan solid. No further purification was necessary. HRMS m/z (M+H) 463.1925 found, 463.1926 required.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:13]1[N:14]=[N:15][CH:16]=[C:17]2[C:21]([CH3:22])=[C:20]([CH3:23])[N:19]([CH2:24][C@H:25]3[CH2:27][C@@H:26]3[CH3:28])[C:18]=12.O>O1CCCC1>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][C:13]2[N:14]=[N:15][CH:16]=[C:17]3[C:21]([CH3:22])=[C:20]([CH3:23])[N:19]([CH2:24][C@H:25]4[CH2:27][C@@H:26]4[CH3:28])[C:18]=23)=[CH:4][CH:3]=1
Reactant: OCc1ccc(F)cc1
Reactant: Cc1c(C)n(C[C@H]2C[C@@H]2C)c2c(Cl)nncc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C)n(C[C@H]2C[C@@H]2C)c2c(OCc3ccc(F)cc3)nncc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
A solution of p-fluorobenzyl alcohol (1.45 g, 11.5 mmol) in tetrahydrofuran (2 ml) was added dropwise to a solution of sodium hydride (0.26 g, 10.8 mmol) in tetrahydrofuran (6 ml) and the mixture was stirred at room temperature for 30 minutes. A solution of 7-chloro-2,3-dimethyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrolo[2,3-d]pyridazine (2.50 g, 10.0 mmol) in tetrahydrofuran (13 ml) was added dropwise to the reaction mixture and the mixture was heated under reflux for 3 hours. After this time the reaction mixture was poured into iced water and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated in vacuo. Hexane was added to the residue, and the precipitate was collected by filtration and then recrystallized from a mixture of ethyl acetate and hexane to afford the title compound (2.25 g, 66.4%) as pale brown crystals.
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][NH:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[C:6]1([C:4]2[O:13][C:1](=[O:12])[CH2:2][N:3]=2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(O)CNC(=O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: O=C1CN=C(c2ccccc2)O1
Temperature: 90 °C

Procedure:
23.3 gm (0.13 mol) of hippuric acid, 93.05 gm of acetic anhydride, and 50 ml of toluene were charged into a 500 ml eggplant-type flask, and heated on an oil bath at a temperature of 90° C. for 10 minutes to dissolution, followed by immediate quenching the resultant solution. The produced liquid was kept at -20° C. on a dry ice-methanol bath.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](O)=[O:28])=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:1][N:2]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:18])=[O:28])=[CH:22][CH:21]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Product: O=C(Cc1ccc(F)cc1)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-(4-fluorophenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.30 (dd, J=7.9, 1.3 Hz, 1H), 8.02-8.05 (m, 1H), 7.97-8.01 (m, 1H), 7.91 (td, J=7.5, 1.3 Hz, 1H), 7.40-7.43 (m, 2H), 7.16-7.20 (m, 2H), 3.78-3.83 (m, 4H), 3.70 (s, 2H), 3.04-3.13 (m, 4H); MS (ESI−) M/Z 381 (M−H)−.
Reaction SMILES: [OH-].[Na+].[CH2:3](O)C.[SH:6][C:7]1[N:8]=[N:9][C:10]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:12]=1.CI>O>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]2[N:12]=[C:7]([S:6][CH3:3])[N:8]=[N:9][C:10]=2[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[CH:18][CH:17]=1
Reactant: COc1ccc(-c2nnc(S)nc2-c2ccc(OC)cc2)cc1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CI
Product: COc1ccc(-c2nnc(SC)nc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Eight grams (0.20 mole) of sodium hydroxide were dissolved in 600 ml. of ethanol. The resulting solution was cooled to ambient temperature and 67.0 grams (0.20 mole) of 3-mercapto-5,6-bis(4-methoxyphenyl)-1,2,4-triazine were added. Methyl iodide, 67 g. (0.47 mole), was added to the reaction mixture and the mixture immediately became a slurry. Three hundred milliliters of ethanol were added to the slurry and stirring was continued for about 3 hours. One hundred milliliters of water were added to the reaction mixture and the solid product was collected by filtration. The yield of 5,6-bis(4-methoxyphenyl)-3-methylthio-1,2,4-triazine, m.p. about 152°-155° C., was 67.3 g.
Reaction SMILES: [NH2:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][C:3]1=[O:13].[C:14]1(=O)[CH2:17][CH2:16][CH2:15]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH:14]1([NH:1][N:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([OH:12])=[CH:4][C:3]2=[O:13])[CH2:17][CH2:16][CH2:15]1
Reactant: O=C1CCC1
Reactant: Nn1c(=O)cc(O)c2ccccc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=c1cc(O)c2ccccc2n1NC1CCC1
Reaction time: 48 h
Yield: 59.9 %

Procedure:
A solution of 1-amino-4-hydroxyquinolin-2(1H)-one (0.516 g, 2.9 mmol) and cyclobutanone (1.05 g, 15.0 mmol) in acetic acid (0.90 g, 15.0 mmol) and methanol (20 mL) was treated portion wise with sodium cyanoborohydride (0.94 g, 15.0 mmol), stirred for 48 hours and concentrated. The residue was treated with 0.5 M aqueous sodium bicarbonate, acidified to pH 2 with 1 M hydrochloric acid and extracted with ethyl acetate. The ethyl acetate was washed with brine, dried over sodium sulfate, filtered and concentrated, The crude material was chromatographed on silica gel eluting with 3:2 hexane/ethyl acetate to give 1-(cyclobutylamino)-4-hydroxyquinolin-2(1H)-one (0.400 g, 60%). MS (ESI+) m/z 231 (M+H)+. 1H NMR (300 MHz, DMSO-d6) δ 1.52 (m, 1H) 1.63 (m, 1H) 1.96 (m, 4H) 3.64 (m, 1H) 5.91 (s, 1H) 6.26 (d, J=6.62 Hz, 1H) 7.20 (t, J=8.09 Hz, 1H) 7.61 (m, 1H) 7.84 (m, 2H) 11.42 (s, 1H).
Reaction SMILES: [NH2:1][C@@H:2]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)[CH2:3][OH:4].C(N(CC)CC)C.[Cl:25][C:26]1[S:30][C:29]([S:31](Cl)(=[O:33])=[O:32])=[CH:28][CH:27]=1>C(Cl)Cl>[C:14]([O:13][C:11]([N:8]1[CH2:7][CH2:6][CH:5]([CH:2]([NH:1][S:31]([C:29]2[S:30][C:26]([Cl:25])=[CH:27][CH:28]=2)(=[O:33])=[O:32])[CH2:3][OH:4])[CH2:10][CH2:9]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC([C@H](N)CO)CC1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(CO)NS(=O)(=O)c2ccc(Cl)s2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 58.3 %

Procedure:
To a stirred mixture of tert-butyl 4-[(1S)-1-amino-2-hydroxyethyl]-1-piperidinecarboxylate (0.107 g, 0.44 mmol), triethylamine (0.046 g, 0.46 mmol) and methylene chloride (5 mL) cooled to 0° C., was added 5-chlorothiophene-2-sulfonyl chloride (0.095 g, 0.44 mmol) as a solution dissolved in 2 mL methylene chloride, dropwise by pipet. After 15 min, the ice bath was removed and the reaction allowed to attain 25° C. and stir overnight. The reaction was quenched by pouring it into saturated sodium bicarbonate solution (25 mL) and additional methylene chloride (15 mL). The organic phase was separated and washed sequentially with 1N HCl solution, H2O, brine and dried over MgSO4. The organic phase was filtered and evaporated to produce a crude oil that was flash chromatographed using ethyl acetate-hexane, 1-1 as eluent. This produced the title compound as a solid (0.109 g, 58%). MS (+APCI) 442.18 ([M+NH4]+); 386.08; 357.01; 325.07; 307.01; 285.06. Anal. Calc'd for C16H25ClN2O5S2: C, 45.22; H, 5.93; N, 6.59; Found: C, 45.31; H, 5.87; N, 6.44.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@H:13]([C:14]([OH:16])=O)[CH2:12][C:10](=[O:11])[CH2:9]1)=[O:7])([CH3:4])[CH3:3].CN(C(ON1N=NC2C=[CH:29][CH:30]=[N:31][C:26]1=2)=[N+](C)C)C.[F:34][P-](F)(F)(F)(F)F>C(Cl)Cl>[C:2]([O:5][C:6]([N:8]1[CH2:9][C:10](=[O:11])[CH2:12][C@H:13]1[C:14]([N:31]1[CH2:30][CH:29]([F:34])[CH2:26]1)=[O:16])=[O:7])([CH3:1])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)O
Reactant: F[P-](F)(F)(F)(F)F
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)N1CC(F)C1
Yield: 100 %

Procedure:
N-tert-Boc-4-oxo-L-proline (917 mg, 4 mmol), the title compound of Step 2 (446 mg, 4 mmol), and HATU (1.673 g, 4.4 mmol) were mixed under nitrogen in anhydrous methylene chloride. The solution was cooled in an ice bath before the addition of DIEA (1.4 mL, 8 mmol). The reaction mixture was allowed to warm to RT and stirred overnight. Saturated sodium bicarbonate was added, the phases were separated and the aqueous phase was extracted with methylene chloride. The combined organic portions were washed with brine and dried over magnesium sulfate. The crude product (2.11 g) was purified by chromatography (Biotage® Flash 40S, 95:5 EtOAc:MeOH) to give the title product as light pink foam (1.06 g, 92%). MS m/z 287.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[CH3:11].Cl[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15]>CC#N>[ClH:1].[Cl:1][C:2]1[C:10]2[C:5]([N:6]([CH2:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:15])[CH:7]=[CH:8][CH:9]=2)=[N:4][C:3]=1[CH3:11]
Reactant: O=C(CCl)c1ccccc1
Reactant: Cc1[nH]c2ncccc2c1Cl
Solvent: CC#N
Product: Cc1nc2n(CC(=O)c3ccccc3)cccc-2c1Cl
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 134.9 %

Procedure:
A solution of 200 mg (1.2 mmol) of 3-chloro-2-methyl pyrrolo-[2,3-b]pyridine and 204 mg (1,3 mmol) of 2-chloroacetophenon in 10 ml of CH3CN was refluxed for 48 h. The reaction mixture was cooled to room temperature and stirred for one hour. The precipitate was filtered off to give 260 mg (67%) of 3chloro-2-methyl-7-phenacylpyrrolo-[2,3-b]pyridinehydrochloride.