Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][N:7]=1)=[O:4].[C:13]([O-:16])(=[O:15])[CH3:14].[Na+]>CN(C)C=O.C(OCC)(=O)C>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[CH2:2][O:16][C:13](=[O:15])[CH3:14])=[N:7][CH:8]=1
Reactant: O=C(CCl)Nc1ccc(Cl)cn1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)OCC(=O)Nc1ccc(Cl)cn1
Temperature: 60 °C
Reaction time: 5 h
Yield: 89.4 %

Procedure:
2-Cloro-N-(5-chloropyridin-2-yl)acetamide (30.68 g) obtained in Reference Example 20(1) is dissolved in N,N-dimethylformamide (500 ml), thereto is added sodium acetate (24.55 g) and the mixture is stirred at 60° C. for 5 hours. The reaction solution is diluted with ethyl acetate, washed successively with water and saturated brine. The solution is dried over magnesium sulfate, treated with activated charcoal, and the filtrate is concentrated under reduced pressure. The resulting residue is suspended in n-hexane and the resulting crystals are collected by filtration, washed with n-hexane, and dried to give N-(5-chloropyridin-2-yl)-2-acetoxyacetamide (30.58 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[O:8][C@@H:7]1[C:9]([OH:11])=O)=[O:5])[CH3:2].[CH3:12][O:13][C@@H:14]([C@@H:21]([NH2:26])[CH2:22][CH:23]([CH3:25])[CH3:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:12][O:13][C@@H:14]([C@@H:21]([NH:26][C:9]([C@H:7]1[O:8][C@@H:6]1[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:11])[CH2:22][CH:23]([CH3:24])[CH3:25])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)[C@H]1O[C@@H]1C(=O)O
Reactant: CO[C@H](c1ccccc1)[C@@H](N)CC(C)C
Product: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)[C@H](OC)c1ccccc1

Procedure:
The procedures of Example 1a were repeated employing (2S,3S)-3-ethoxycarbonyloxirane-2-carboxylic acid and 1-(S)-[α-(R)-methoxybenzyl]-3-methylbutylamine (its preparation is described in the after-mentioned Reference Example 2) to prepare the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Al+3].[Cl-].[Cl-].[Cl-].[Cl:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[O:24][CH3:25].Cl>ClCCCl.CCCCCC>[Cl:23][C:22]1[C:17]([Cl:16])=[C:18]([O:24][CH3:25])[CH:19]=[CH:20][C:21]=1[C:4]([C:3]1[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:2]=1[F:1])=[O:5]
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: COc1cccc(Cl)c1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCC
Solvent: ClCCCl
Product: COc1ccc(C(=O)c2ccc(F)cc2F)c(Cl)c1Cl
Temperature: 43 °C
Reaction time: 0.5 h

Procedure:
To a solution of 52.23 g of 2,4-difluorobenzoylchloride in 200 ml of 1,2-dichloroethane, 40 g of AlCl3 is added over a 30 minute period. A solution of 48.3 g of 2,3-dichloroanisole in 100 ml 1,2-dichloroethane is added dropwise. There is a slow evolution of gas and the temperature rises to approximately 30° C. The reaction mixture is warmed to 43° C. and the gas continues to evolve for approximately 30 minutes. The mixture is poured over concentrated HCl and ice. The organic layer is separated and the aqueous layer is extracted two times with CHCl3. The combined organic layers are washed with water, dried (Na2SO4) and evaporated to give an oil. Trituration with hexane yields 2,3-dichloro-4-methoxy-2',4'-difluorobenzophenone which is recrystallized from ether, mp 139°-141° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][NH2:12])=[CH:7][CH:6]=1)[CH3:2].[F:14][C:15]([F:22])([F:21])[C:16](=O)[CH2:17][C:18]#[N:19]>>[NH2:19][C:18]1[N:11]([C:8]2[CH:9]=[CH:10][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:13])=[CH:6][CH:7]=2)[N:12]=[C:16]([C:15]([F:22])([F:21])[F:14])[CH:17]=1
Reactant: N#CCC(=O)C(F)(F)F
Reactant: CCOC(=O)c1ccc(NN)cc1
Product: CCOC(=O)c1ccc(-n2nc(C(F)(F)F)cc2N)cc1
Yield: 90.6 %

Procedure:
Using the same method as Example QQ, 4-hydrazinobenzoic acid ethyl ester (From Example A82, 3.0 g, 16.6 mmol) and commercially available 1N NH 4,4,4-trifluoro-3-oxobutyronitrile (3.4 g, 24.9 mmol) were combined to afford ethyl 4-[5-amino-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzoate (4.5 g, 91% yield), which was used to the next reaction without further purification.
Reaction SMILES: C(OC1C=CC([C@@H]2C[C@H]2N)=CC=1)C1C=CC=CC=1.[Br:19][C:20]1[CH:25]=[CH:24][C:23]([C@@H:26]2[CH2:28][C@H:27]2[N+:29]([O-])=O)=[CH:22][CH:21]=1>>[Br:19][C:20]1[CH:21]=[CH:22][C:23]([C@@H:26]2[CH2:28][C@H:27]2[NH2:29])=[CH:24][CH:25]=1
Reactant: O=[N+]([O-])[C@@H]1C[C@H]1c1ccc(Br)cc1
Agent: N[C@@H]1C[C@H]1c1ccc(OCc2ccccc2)cc1
Product: N[C@@H]1C[C@H]1c1ccc(Br)cc1
Yield: 10 %

Procedure:
This compound was synthesized using the same methodology described in Intermediate D, using as starting material 1-bromo-4-[(trans)-2-nitrocyclopropyl]benzene. 10% yield. 1HNMR (CD3OD): 1.45 (m, 2H), 2.61 (m, 1H), 2.86 (m, 1H), 6.98 (d, 2H), 7.11 (d, 2H). MS (M+H): 211.9
Reaction SMILES: [CH:1]12[N:8]([C:9]([C:11]3[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=3[O:19][CH3:20])=[O:10])[CH2:7][CH:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.C1(C2C=CC=CC=2)C=CC=CC=1C(N1C2C(CCNC2)C1)=O.Cl[C:44]1[O:45][C:46]2[CH:52]=[CH:51][CH:50]=[CH:49][C:47]=2[N:48]=1.ClC1C=NC2C(=CC=CC=2)N=1>>[O:45]1[C:46]2[CH:52]=[CH:51][CH:50]=[CH:49][C:47]=2[N:48]=[C:44]1[N:3]1[CH2:4][CH2:5][CH:6]2[CH:1]([N:8]([C:9]([C:11]3[C:12]([O:19][CH3:20])=[CH:13][CH:14]=[CH:15][C:16]=3[O:17][CH3:18])=[O:10])[CH2:7]2)[CH2:2]1
Reactant: Clc1nc2ccccc2o1
Reactant: COc1cccc(OC)c1C(=O)N1CC2CCNCC21
Agent: Clc1cnc2ccccc2n1
Agent: O=C(c1ccccc1-c1ccccc1)N1CC2CCNCC21
Product: COc1cccc(OC)c1C(=O)N1CC2CCN(c3nc4ccccc4o3)CC21

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting the trifluoro acetic acid salt of (3,8-diaza-bicyclo[4.2.0]oct-8-yl)-(2,6-dimethoxy-phenyl)-methanone (Intermediate 4) for biphenyl-2-yl-(3,8-diaza-bicyclo[4.2.0]oct-8-yl)methanone and 2-chlorobenzoxazole for 2-chloro quinoxaline. MS (ESI) mass calcd. for C22H23N3O3, 393.45; m/z found, 394.0 [M+H]+. 1H NMR (CDCl3): 7.54-7.26 (m, 3H), 7.24-7.10 (m, 2H), 7.08-7.02 (m, 0.6H), 6.80-6.73 (m, 0.4H), 6.33-6.22 (m, 1H), 4.74-4.64 (m, 1H), 4.14-3.56 (m, 5H), 3.50-3.35 (m, 1H), 2.99-2.85 (m, 1H), 2.72-2.56 (m, 1H), 2.36-2.20 (m, 5H), 2.03-1.78 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][OH:15])[CH:11]=[C:10]([CH2:16][N:17]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[S:18]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:9]=2)=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:43][S:44](Cl)(=[O:46])=[O:45].Cl>CCOC(C)=O>[CH3:43][S:44]([O:15][CH2:14][C:12]1[CH:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:9]=[C:10]([CH2:16][N:17]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)[S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH:11]=1)(=[O:46])=[O:45]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)N(Cc2ccc(F)cc2)Cc2cc(CO)cc(-c3ccc(F)cc3)c2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)N(Cc2ccc(F)cc2)Cc2cc(COS(C)(=O)=O)cc(-c3ccc(F)cc3)c2)cc1
Reaction time: 1 h

Procedure:
To a solution of N-((4′-fluoro-5-(hydroxymethyl)biphenyl-3-yl)methyl)-N-(4-fluorobenzyl)-4-methylbenzenesulfonamide (100 mg, 0.203 mmol) and Et3N (0.15 mL) in EtOAc (5 mL) at −30° C. was added methanesulfonyl chloride (25 mg, 0.218 mmol) in EtOAc (10 mL) slowly with stirring. After 1 h, a small amount of 1N aq HCl and EtOAc were added to the reaction mixture. The EtOAc layer was separated, dried over MgSO4 and concentrated in vacuo to obtain the product as a viscous material. It was enough pure to use for next step without any further purification. MS (ESI): (M+H)+=572.18.
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH:14]1(Br)[CH2:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>>[CH:14]1([O:1][C:2]2[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:17][CH2:16][CH2:15]1
Reactant: COc1ccc(C#N)c(O)c1OC
Reactant: BrC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(C#N)c(OC2CCC2)c1OC
Temperature: 80 °C
Reaction time: 4 h
Yield: 75.3 %

Procedure:
2-Hydroxy-3,4-dimethoxybenzonitrile (6.65 g, 0.037 mol) was added to a suspension of cyclobutyl bromide (5.01 g, 0.037 mol) and potassium carbonate (5.11 g, 0.037 mol) in dimethylformnamide (65 ml) and the reaction stirred at 80° C. for 4 hours. On cooling, the mixture was concentrated under reduced pressure and the residue partitioned between water (50 ml) and ethyl acetate (50 ml). The aqueous layer was extracted with further ethyl acetate (100 ml) and the combined organic extracts dried (MgSO4), filtered and evaporated under reduced pressure to give the subtitle compound as a brown oil (6.50 g, 75%). Rf 0.63 (dichloromethane). MS m/z 251 (MNH4)+.
Reaction SMILES: Cl.[C:2]([C:4]1[C:5]([S:18][CH2:19][CH2:20][NH:21][CH2:22][C@H:23]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=2)[CH2:24][CH:25]=[CH2:26])=[C:6]([C:14]([O:16]C)=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)#[N:3].Cl.N1C=CC=CC=1>>[C:2]([C:4]1[C:5]([S:18][CH2:19][CH2:20][NH:21][CH2:22][C@H:23]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=2)[CH2:24][CH:25]=[CH2:26])=[C:6]([C:14]([OH:16])=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)#[N:3]
Reactant: C=CC[C@H](CNCCSc1c(C#N)cc2ccccc2c1C(=O)OC)c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: c1ccncc1
Product: C=CC[C@H](CNCCSc1c(C#N)cc2ccccc2c1C(=O)O)c1ccc(Cl)c(Cl)c1
Temperature: 180 °C
Yield: 99.3 %

Procedure:
An evenly distributed mixture of methyl 3-cyano-2-[(2-{[(2S)-2-(3,4-dichlorophenyl)pent-4-enyl]amino}ethyl)thio]-1-naphthoate hydrochloride (Intermediate 5, 150 mg, 0.28 mmol) and pyridine hydrochloride (487 mg, 4.20 mmol) was heated at 180° C. for 5 min, cooled, and partitioned between ethyl acetate and water. The organic layer was washed with 1 N HCl and brine, dried (Na2SO4), and evaporated to dryness to give 135 mg (100% yield) of the title compound which was used without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@H:4]1[CH2:16][C:15]2[C:14]3[C:13]([O:17][CH:18]4[CH2:23][CH2:22][CH:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]4)=[N:12][CH:11]=[N:10][C:9]=3[S:8][C:7]=2[CH2:6][CH2:5]1.C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-:44][Cr](O[Cr]([O-])(=O)=O)(=O)=O>CN(C=O)C>[C:27]([O:26][C:25]([NH:24][CH:21]1[CH2:20][CH2:19][CH:18]([O:17][C:13]2[C:14]3[C:15]4[CH2:16][C@@H:4]([CH2:3][C:2]([OH:44])=[O:1])[CH2:5][CH2:6][C:7]=4[S:8][C:9]=3[N:10]=[CH:11][N:12]=2)[CH2:23][CH2:22]1)=[O:31])([CH3:28])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)NC1CCC(Oc2ncnc3sc4c(c23)C[C@@H](CCO)CC4)CC1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCC(Oc2ncnc3sc4c(c23)C[C@@H](CC(=O)O)CC4)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
To a solution of tert-butyl N-(4-[[(12S)-12-(2-hydroxyethyl)-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-3-yl]oxy]cyclohexyl)carbamate (172 mg, 0.38 mmol, 1.00 equiv) in 4 mL of DMF was added PDC (847 mg, 2.25 mmol, 6.00 equiv) and the resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of water and extracted with 4×50 mL of chloroform/isopropanol (3:1). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1) to provide 2-[(12S)-3-[(4-[[(tert-butoxy)carbonyl]amino]cyclohexyl)oxy]-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-12-yl]acetic acid (148 mg, 83%) as an off-white solid. MS: m/z 462 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[H-].[Na+].[Br:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>C1COCC1>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:1]2[CH:5]=[CH:4][CH:3]=[CH:2]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: c1cc[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(Br)cc1)n1cccc1
Reaction time: 8 h
Yield: 15.7 %

Procedure:
Pyrrole (1.05 mL, 15.0 mmol) was added to a slurry of sodium hydride (0.71 g, 60% in mineral oil, 17.8 mmol) in dry THF (10 mL) at room temperature. 4-Bromobenzene sulfonyl chloride (1.5 g, 6.0 mmol) dissolved in dry THF (5 mL) was added dropwise. The reaction mixture was stirred overnight. The reaction was quenched with saturated ammonium chloride and diluted with ethyl acetate. The layers were separated and the organic layer was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product. The crude product was purified via Isco chromatography (the Redisep™ column, silica, gradient 5-50% ethyl acetate in hexane) to give 1-[(4-bromophenyl)sulfonyl]-1H-pyrrole (0.27 g, 16%). MS (ESI) m/z 286. HPLC purity 100.0% at 210-370 nm, 9.9 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [OH-].[Na+].[Cl:3][O-].[Na+].[OH:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10]>>[Cl:3][C:13]1[CH:12]=[C:8]([C:9]([OH:11])=[O:10])[C:7]([OH:6])=[N:15][CH:14]=1
Reactant: [O-]Cl
Reactant: O=C(O)c1cccnc1O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc(Cl)cnc1O
Reaction time: 4 h

Procedure:
To an agitated solution of 216.0 g (5.4 mole) of sodium hydroxide pellets in 2.25 liters of 5% (1.51 moles) sodium hypochlorite solution was added 150.0 g (1.08 mole) of 2-hydroxynicotinic acid. Temperature of the mixture was 20°-32° C. After 4 hr mass spectrographic analysis showed some starting 2-hydroxynicotinic acid was present. An additional liter of 5% (0.67 moles) of sodium hypochlorite solution was added and stirring was continued overnight. Starting 2-hydroxynicotinic acid was no longer present. Slow acidification with 690 ml of concentrated of the reaction mixture under agitation over a 1.25 hr period resulted in conversion to a mass of porous fluffy salt crystals. As more acid was added severe bubbling occurred and half of the reactor contents had to be removed. Both portions were completely acidified, the total of additional acid being 100 ml concentrated hydrochloric acid. The mixture was filtered on a large sintered glass funnel and crystals became gooey and difficult to handle. Once the filter cake had reached a mud-like stage, it was slurried in 500 ml of 6N hydrochloric acid and refiltered. The filter cake was rinsed with 350 ml of water and subjected to vacuum for several hours. The filter cake was rinsed first with 300 ml of 1:1 isopropyl ether/isopropyl alcohol then with 300 ml of 3:1 isopropyl ether/isopropyl alcohol and subjected to vacuum filtration for several hours. The crystals were desicated under vacuum using a heat lamp. The weight of dry crystals was 84.5 g (45.1%). However 1HNMR analysis indicated that the product contained 10-12% impurity≠(3,5-dichloro-2-hydroxypyridine). See Example 3 for the method of computing impurity. The original filtrate also contained this impurity.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[C:24](=[S:34])(Cl)[O:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1.C(N(CC)CC)C>C1COCC1>[F:23][C:2]([F:1])([F:22])[O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:21]=[CH:20][C:18]([NH:19][C:24](=[S:34])[O:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)=[CH:17][CH:16]=3)=[N:11]2)=[CH:8][CH:9]=1
Reactant: Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: Fc1ccc(OC(=S)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Fc1ccc(OC(=S)Nc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)cc1
Reaction time: 2 h
Yield: 16.8 %

Procedure:
Into a 25 mL round-bottomed flask were added 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)aniline (200 mg, 0.624 mmol), O-4-fluorophenyl carbonochloridothioate (238 mg, 1.249 mmol), and triethylamine (0.348 mL, 2.498 mmol) in THF (5 mL). The solution was stirred under ambient conditions for 2 h before the solvent was removed under reduced pressure. The crude product was added to a silica gel column and was eluted with EtOAc/hexanes gradient to afford the title compound (50 mg, 0.105 mmol, 17%) as a yellow solid: mp 164-169° C.; 1H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1H), 8.19-8.04 (m, 6H), 7.97 (br s, 1H), 7.66-7.57 (d, J=8.24 Hz, 2H), 7.33-7.19 (m, 4H); ESIMS m/z 475 (M+1).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:5]([Cl:16])=[CH:4][CH:3]=1.[Cl:17][C:18]1[C:19](B(O)O)=[CH:20][C:21]([F:24])=[N:22][CH:23]=1.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.CCOC(C)=O.C(=O)(O)[O-].[Na+].Cl[Pd]Cl>[Cl:16][C:5]1[CH:4]=[CH:3][C:2]([C:19]2[C:18]([Cl:17])=[CH:23][N:22]=[C:21]([F:24])[CH:20]=2)=[N:7][C:6]=1[NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: OB(O)c1cc(F)ncc1Cl
Reactant: Clc1ccc(Br)nc1NCC1CCOCC1
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: ClCCl
Product: Fc1cc(-c2ccc(Cl)c(NCC3CCOCC3)n2)c(Cl)cn1
Temperature: 25 °C
Yield: 55.8 %

Procedure:
A mixture of 6-bromo-3-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine (F, 200 mg, 0.654 mmol), 5-chloro-2-fluoropyridin-4-ylboronic acid (230 mg, 1.309 mmol), PdCl2 (dppf). CH2Cl2 adduct (53.4 mg, 0.065 mmol) in DME (3 mL) and 2M aqueous sodium carbonate (3 mL, 6.00 mmol) was heated in a sealed tube at about 103° C. for 16 hr. The reaction mixture was cooled to ambient temperature, diluted with EtOAc (˜100 mL) and saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed with saturated aqueous sodium bicarbonate solution (2×), dried over sodium sulfate, filtered off and concentrated in vacuo. The resulting residue was purified by column chromatography [ISCO, SiO2, 25 g, EtOAc/heptane=0/100 to 30/70]. Fractions were combined and concentrated in vacuo providing 5,5′-dichloro-2′-fluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridin-6-amine (130 mg) as a nearly colorless liquid. LCMS (m/z): 356.1 [M+H]+; Retention time=1.10 min.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:13]=[CH:12][S:11][C:4]=2[NH:5][C:6](=[O:10])[C:7]=1[C:8]#[N:9].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:2]2[C:3]3[CH:13]=[CH:12][S:11][C:4]=3[NH:5][C:6](=[O:10])[C:7]=2[C:8]#[N:9])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#Cc1c(Cl)c2ccsc2[nH]c1=O
Product: CC(C)(C)OC(=O)N1CCN(c2c(C#N)c(=O)[nH]c3sccc23)CC1

Procedure:
Compounds of structure (III) with R2 as carbonitrile, and R1 and R3 as defined above were also prepared from intermediate 4-chloro-6-oxo-6,7-dihydro-thieno[2,3-b]pyrdine-5-carbonitrile, depicted by formula (50). Intermediate 4-chloro-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carbonitrile, depicted by formula (50), was reacted with tert-butyl-1-piperazine carboxylate to yield 4-(5-cyano-6-oxo-6,7-dihydro-thieno[2,3-b]-pyridine-4-yl)-piperazine-1-carboxylic acid tert-butyl ester, depicted by formula (53). This intermediate was either reacted with an appropriate halide (R1—X) or boronic acid (R1—B(OH)2) to yield an intermediate of structure (54), which was deprotected and reacted with an appropriate acid chloride (R3—COCl) or acid (R3—COOH) to yield target compounds of structure (III) with R2 as carbonitrile, and R1 and R3 as defined above, as shown in Scheme 28.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:31])[CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:13]([C:32]([OH:34])=[O:33])[CH2:12]1)=O)C1C=CC=CC=1.C(O)CCC.C(O)(=O)C.O>CO.[Pd]>[C:32]([OH:34])(=[O:33])[CH3:13].[C:25]1([CH:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:17]([N:14]2[CH2:15][CH2:16][NH:11][CH2:12][C@H:13]2[C:32]([OH:34])=[O:33])=[O:31])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(O)[C@@H]1CN(C(=O)OCc2ccccc2)CCN1C(=O)C(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCCCO
Product: O=C(O)[C@@H]1CNCCN1C(=O)C(c1ccccc1)c1ccccc1
Reaction time: 4 h

Procedure:
A solution of 785 mg (1.71 mmole) of (S)-4-(benzyloxycarbonyl)-1-(diphenylacetyl)piperazine-2carboxylic acid (from Step A) in 25 ml of methanol was treated with 800 mg of 10% Pd/C and the mixture was hydrogenated at 40 psi at 25° C. with rocking for 4 hours. The mixture was filtered and the catalyst was washed with 4×30 ml of acetic acid. All organic phases were combined, concentrated in vacuo, redissolved in 100 ml of water and reconcentrated in vacuo to leave 404 mg (73%) of waxy solid which was homogeneous by TLC (4:1:1 n-butyl alcohol-acetic acid-water, Rf =0.55).
Reaction SMILES: C([O:3][C:4]([CH2:6][S:7][C:8](=[N:15][OH:16])[C:9]([N+:12]([O-])=O)([CH3:11])[CH3:10])=O)C.[OH-].[NH4+].N>O>[N:15](=[C:8]1[C:9]([CH3:11])([CH3:10])[NH:12][C:4](=[O:3])[CH2:6][S:7]1)[OH:16]
Reactant: CCOC(=O)CSC(=NO)C(C)(C)[N+](=O)[O-]
Agent: N
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CC1(C)NC(=O)CSC1=NO
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 12 g. of 1-ethoxycarbonylmethylthio-2-nitro-2-methylpropionaldoxime and 150 ml of ammonium hydroxide was charged into a pyrex pressure bottle and stirred at room temperature for three days. The excess ammonia and water was stripped from the reaction mixture under reduced pressure. The solid crystalline residue was washed with a small amount of cold water and dried. The residue was then recrystallized from acetonitrile to yield 4 g of 2-Oximino-3,3-dimethyltetrahydro-1,4-thiazin-5-one, m.p. 234°-236° C. The nmr and infrared spectra supported the proposed structure.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]=2)O1.O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+]>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.O>[N+:8]([C:5]1[N:6]=[CH:7][C:2]([C:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc([N+](=O)[O-])nc2)CC1
Temperature: 80 °C
Reaction time: 15 h
Yield: 13.8 %

Procedure:
In a 50 mL round-bottomed flask, 5-bromo-2-nitropyridine (3.28 g, 16.2 mmol, Eq: 1) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (5 g, 16.2 mmol, Eq: 1.00) were combined with dioxane (80.0 ml) to give a light yellow solution. Cs2CO3 (10.5 g, 32.3 mmol, Eq: 2) and 3 mL H2O were added. The solution was degassed with Ar before bis(triphenylphosphine)palladium(ii) dichloride (1.13 g, 1.62 mmol, Eq: 0.1) was added. The reaction mixture was heated to 80° C. and stirred for 15 h. The reaction mixture was poured into 300 mL H2O and extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine and dried over MgSO4. The crude reaction mixture was concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 220 g, 10% to 100% EtOAc/Hex gradient) to give a dark brown impure solid. The solid was triturated with Et2O to afford tert-butyl 4-(6-nitropyridin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (685 mg, 69%) as a tan solid. LC/MS-ESI observed [M+H]+ 306.