Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:3][C:4]1[C:9]([CH2:10][CH2:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)=[CH:8][CH:7]=[CH:6][N:5]=1.S(Cl)([Cl:30])=O>>[Cl:30][CH:2]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:3][C:4]1[C:9]([CH2:10][CH2:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: COC(=O)c1ccc(CCc2cccnc2CC(O)c2ccccc2)cc1
Reactant: O=S(Cl)Cl
Product: COC(=O)c1ccc(CCc2cccnc2CC(Cl)c2ccccc2)cc1
Reaction time: 1 h

Procedure:
Methyl 4-[2-(2-(2-hydroxy-2-(phenyl)ethyl)-3-pyridyl)ethyl]benzoate (0.47 g), 1.29 mmol) was cooled in an ice bath. Thionyl chloride (15 ml) was added and the reaction held at 0° C. for 1 hour. The reaction mixture was evaporated and azeotroped with toluene to give methyl 4-[2-(2-(2-chloro-2-(phenyl)ethyl)-3-pyridyl)ethyl]benzoate (0.549 g) which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:31])[C:10]([NH:12][CH2:13][C:14]1[S:18][CH:17]=[C:16]([N:19]2[C:23]([C:24](O)=[O:25])=[CH:22][C:21]([C:27]([F:30])([F:29])[F:28])=[N:20]2)[CH:15]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:33][CH2:34][C:35]1[CH:44]=[CH:43][CH:42]=[CH:41][C:36]=1[C:37]([O:39][CH3:40])=[O:38].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:31])[C:10]([NH:12][CH2:13][C:14]1[S:18][CH:17]=[C:16]([N:19]2[C:23]([C:24]([NH:33][CH2:34][C:35]3[CH:44]=[CH:43][CH:42]=[CH:41][C:36]=3[C:37]([O:39][CH3:40])=[O:38])=[O:25])=[CH:22][C:21]([C:27]([F:30])([F:28])[F:29])=[N:20]2)[CH:15]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccccc1CN
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCc1cc(-n2nc(C(F)(F)F)cc2C(=O)O)cs1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccccc1CNC(=O)c1cc(C(F)(F)F)nn1-c1csc(CNC(=O)[C@H](C)NC(=O)OC(C)(C)C)c1
Yield: 61 %

Procedure:
A solution of acid 7 (preparation described in scheme 2, example 1c, step 7) (140 mg, 0.303 mmol), methyl 2-(aminomethyl)benzoate hydrochloride (61.0 mg, 0.303 mmol), BOP (134 mg, 0.303 mmol) and triethylamine (0.127 mL, 0.908 mmol) in DMF (2 mL) was shaken for 16 hours at room temperature. It was then diluted with water (˜30 mL) and extracted into ethyl acetate (3×). The ethyl acetate was combined and washed with saturated NaHCO3, brine, dried over Na2SO4, filtered and concentrated. The crude was purified by silica gel chromatography using a 25S Biotage column with a gradient of 40-65% ethyl acetate in hexanes to give compound 15f (112.7 mg, 61.1% yield) as a white crusty solid. LRMS (ESI): calc. 609.2; found 632.1 (MNa)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[N:10][C:11](Cl)=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:13]=2)[CH:5]=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)CCC.[F-].[Cs+]>CN(C)C=O.C(OCC)(=O)C.[Cu]I.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:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[N:10][CH:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: COC(=O)c1cc(-c2cncc(Cl)c2)cnc1Cl
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2cncc(Cl)c2)cnc1-c1ccccn1
Temperature: 80 °C

Procedure:
To a solution of methyl 5′,6-dichloro-3,3′-bipyridine-5-carboxylate (12-2, 7.6 g, 26.8 mmol, 1.0 equiv) in dimethylformamide (107 mL) was added 2-tri-n-butylstannylpyridine (13.8 g, 37.6 mmol, 1.4 equiv), cesium fluoride (12.2 g, 81.0 mmol, 3.0 equiv), copper (I) iodide (1.0 g, 5.4 mmol, 0.2 equiv), and tetrakis(triphenylphosphine)palladium(0) (3.1 g, 2.7 mmol, 0.1 equiv) and the system was heated to 80° C. for 2 h. The reaction mixture was cooled and diluted with ethyl acetate (300 mL) and the reaction mixture was filtered through a pad of celite. The reaction mixture was washed with water (3×100 mL) and brine (1×100 mL), dried over magnesium sulfate and concentrated. The residue was purified via normal phase chromatography (10 to 100% EtOAc in hexanes, silica) followed by chiral normal phase chromatography (Chiracel OD, 10 cm column, hexanes:IPA [1:1], flow rate 150 mL/min) to afford the desired product (12-3) as a white solid after concentration. ESI+MS [M+H]+ C17H12ClN3O2 calc'd 326.1. found 326.0.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[O-]CCCC.[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[C:15]1([N:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Brc1ccccc1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Product: c1ccc(-n2c3ccccc3c3ccccc32)cc1
Temperature: 60 °C

Procedure:
2.5 g of carbazole, 2 g of bromobenzene and 0.064 g of a palladium acetate catalyst were dissolved in 40 mL of toluene, and the resulting solution was heated to 60° C. Subsequently, a solution of 1.5 g of sodium butoxide and 0.385 g of tri-tert-butylphosphine dissolved in toluene was slowly added dropwise. The mixture was refluxed at a steady 100° C. After completion of the reaction, the reaction mixture was extracted with dichloromethane and distilled water, and the solvent was dried. The resulting solid was filtered and purified, yielding a 9-phenyl carbazole compound as an intermediate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[CH2:16][CH2:17][NH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:20]1[CH:25]=[CH:24][C:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)C>CN1CCCC1=O.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[CH2:16][CH2:17][NH:18][C:20]1[CH:25]=[CH:24][C:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:22][N:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCc1cc(Br)ccc1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)c1ccc(NCCc2cc(Br)ccc2OCc2ccccc2)nc1
Temperature: 120 °C
Yield: 21.1 %

Procedure:
A mixture of 2-(2-aminoethyl)-4-bromophenyl benzyl ether (3 g), tert-butyl 2-chloro-5-pyridinecarboxylate (2.1 g) (prepared from the acid by standard procedures), and potassium carbonate (1.4 g) in N-methylpyrrolidone (20 ml) was heated at 120° C. for 16 hours. To the reaction mixture was added diethyl ether (200 ml) and water (200 ml), the layers separated, the organic layer washed with water, dried (MgSO4), filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with dichloromethane/ethyl acetate mixtures (100:0, 95:5) to give tert-butyl 2-[N-(2-benzyloxy-5-bromophenethyl)amino]-5-pyridinecarboxylate (1.0 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([O:19][S:20]([CH3:23])(=[O:22])=[O:21])=[C:14](Br)[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([O:19][S:20]([CH3:23])(=[O:22])=[O:21])=[C:14]([C:29]1[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=1)[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Oc1c(Br)ccc2cc(OCc3ccccc3)ccc12
Reactant: OB(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CS(=O)(=O)Oc1c(-c2ccc(F)cc2)ccc2cc(OCc3ccccc3)ccc12
Temperature: 100 °C
Yield: 98 %

Procedure:
Combine methanesulfonic acid 6-benzyloxy-2-bromo-naphthalen-1-yl ester (10.0 g, 24.4 mmol), 4-fluorophenylboronic acid (10.2 g, 729 mmol), sodium carbonate (7.8 g, 73.6 mmol) and tetrakistriphenylphosphine palladium (2.8 g, 2.4 mmol) in a mixture of toluene (300 mL), ethanol (60 mL) and water (40 mL). Heat the mixture at 100° C. for 12 hours. Cool and filter the suspension through a pad of celite. Evaporate the solvent in vacuo. Wash the residue with sodium bicarbonate solution and brine. Dry with magnesium sulfate and concentrate in vacuo. Purify the residue over silica gel, eluting the material with a step gradient of methanol/dichloromethane (0 to 10%), to obtain 10.1 g (98%) of methanesulfonic acid 6-benzyloxy-2-(4-fluoro-phenyl)-naphthalen-1-yl ester.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)#[CH:18]>>[F:25][C:21]1[CH:20]=[C:19]([C:17]#[C:18][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)[CH:24]=[CH:23][CH:22]=1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Reactant: C#Cc1cccc(F)c1
Product: O=c1[nH]c2nccc(C#Cc3cccc(F)c3)c2c2ccccc12
Yield: 71 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 160 using Compound 83 (100 mg, 0.43 mmol) and 1-ethynyl-3-fluoro-benzene (78 mg, 0.65 mmol) to provide 166 (96 mg, 70% yield) as a white solid. LC-MS (M+H=315, obsd.=315).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:11][C@@H:12]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:13])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:31](Br)[C:32]#[CH:33]>CC(C)=O>[CH3:13][C@H:12]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:11][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([O:1][CH2:33][C:32]#[CH:31])[CH:10]=2)[CH:6]=[N:7]1
Reactant: C[C@@H](Cn1ncc2ccc(O)cc21)NC(=O)OCc1ccccc1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCOc1ccc2cnn(C[C@H](C)NC(=O)OCc3ccccc3)c2c1
Yield: 73.6 %

Procedure:
A solution of the product from Step A (2.88 g, 8.86 mmol) in acetone (100 mL) was degassed with reduced pressure and nitrogen. Powdered potassium carbonate (1.35 g, 9.75 mmol) and propargyl bromide (80% by weight in toluene, 0.99 mL, 8.86 mmol) were added the mixture was refluxed for 24 hours. The cooled reaction mixture was filtered and the filtrate was evaporated to a yellow oil (3.15 g) which was purified by chromatography (silica, 20% to 50% ethyl acetate in hexane) to give a white solid (2.37 g, 74%): mp 104-106° C.; LC/MS (+APCI) m/z 364 (M+H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:26])[NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:13][N:12]=1)[OH:10])(C)(C)C.[ClH:28].O1CCOCC1>CCOC(C)=O>[ClH:28].[ClH:28].[NH2:7][CH2:8][CH:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:26])=[CH:13][N:12]=1)[OH:10]
Reactant: CC(C)(C)OC(=O)NCC(O)c1ccc(C(=O)NCc2ccccc2)cn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: NCC(O)c1ccc(C(=O)NCc2ccccc2)cn1
Reaction time: 8 h

Procedure:
[2-(5-Benzylcarbamoyl-pyridin-2-yl)-2-hydroxy-ethyl]-carbamic acid tert-butyl ester (47.0 mg, 0.129 mmol) was dissolved into 2 mL of EtOAc and 4.0 N HCl in dioxane (1.0 mL, 4 mmol) was added. The reaction was allowed to stir overnight. The resulting precipitate was triturated with 3×5 mL of THF and concentrated on a rotary evaporator to dryness to give 43 mg of 6-(2-amino-1-hydroxy-ethyl)-N-benzyl-nicotinamide 2HCl.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([OH:13])=O)=[CH:8][C:7]=2[CH:14]=1)#[N:2].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([NH:28][S:29]([CH2:32][CH2:33][CH2:34][CH3:35])(=[O:31])=[O:30])[C:24]([O:26][CH3:27])=[O:25])=[CH:18][CH:17]=1>>[CH2:32]([S:29]([NH:28][CH:23]([CH2:22][C:19]1[CH:18]=[CH:17][C:16]([NH:15][C:11]([C:9]2[O:10][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:14][C:7]=3[CH:8]=2)=[O:13])=[CH:21][CH:20]=1)[C:24]([O:26][CH3:27])=[O:25])(=[O:31])=[O:30])[CH2:33][CH2:34][CH3:35]
Reactant: N#Cc1ccc2oc(C(=O)O)cc2c1
Reactant: CCCCS(=O)(=O)NC(Cc1ccc(N)cc1)C(=O)OC
Product: CCCCS(=O)(=O)NC(Cc1ccc(NC(=O)c2cc3cc(C#N)ccc3o2)cc1)C(=O)OC
Yield: 36.3 %

Procedure:
In the same manner as in Example 1 (2), 5-cyano-2-benzofurancarboxylic acid (200 mg, 1.07 mmol) and methyl 3-(4-aminophenyl)-2-(n-butylsulfonylamino)propionate (371 mg, 1.18 mmol) were condensed to give 188 mg of methyl 2-(n-butylsulfonylamino)-3-[4-[(5-cyano-2-benzofuranyl)carbonylamino]phenyl]propionate as a yellow solid (36%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[NH:10]C(C1N=C2C=NC=CN2C=1I)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)C1C=CC=CN=1)CCC>O1CCOCC1.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>[CH2:1]([O:8][C:9](=[O:23])[NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(NC(=O)OCc1ccccc1)c1nc2cnccn2c1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Solvent: C1COCCO1
Product: NC(=O)OCc1ccccc1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a solution of [1-(3-iodo-imidazo[1,2-a]pyrazin-2-yl)-ethyl]-carbamic acid benzyl ester (1.6 g, 3.79 mmol) and 2-tributylstannanyl pyridine (4.1 g, 11.37 mmol) in 1,4-dioxane (20 mL) was added Pd(PPh3)4 (50 mg, 0.4 mmol) at rt. The reaction mixture was stirred overnight at 110° C. After completion of the reaction, the mixture was concentrated in vacuo. The crude product was purified by column chromatography using silica gel (100-200 mesh) and 0-40% acetone in hexane to provide [1-(3-pyridin-2-yl-imidazo 1,2-a]pyrazin-2-yl)-ethyl]-carbamic acid benzyl ester: LC-MS (ESI) m/z 374.1 [M+H]+.
Reaction SMILES: [N:1]12[CH2:7][C:4]([C:8]3[CH:9]=[CH:10][C:11](O)=[N:12][CH:13]=3)([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.P(Cl)(Cl)([Cl:17])=O.[OH-].[Na+]>>[Cl:17][C:11]1[N:12]=[CH:13][C:8]([C:4]23[CH2:7][N:1]([CH2:6][CH2:5]2)[CH2:2][CH2:3]3)=[CH:9][CH:10]=1
Reactant: Oc1ccc(C23CCN(CC2)C3)cn1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: Clc1ccc(C23CCN(CC2)C3)cn1
Temperature: 140 °C
Reaction time: 0.75 h
Yield: 91.4 %

Procedure:
0.37 g (1.94 mmol) of 5-(1-azabicyclo[2.2.1]hept-4-yl)pyridin-2-ol obtained in Example 4, in solution in 5.44 ml (58.35 mmol) of phosphorus oxychloride, is introduced into a sealed tube and the combined mixture is subsequently stirred at 140° C. for 45 minutes. The reaction mixture is subsequently brought back to ambient temperature, poured onto 200 g of crushed ice and stirred for 15 minutes. The medium is then very slowly adjusted to pH 10 with a concentrated sodium hydroxide solution. The combined mixture is subsequently extracted twice with chloroform and the organic phases are subsequently combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide 370 mg of the desired compound in the form of a brown powder.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@H:5]([C@@H:7]([CH3:9])[OH:8])[NH2:6].[N+:11]([C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1)([O-:13])=[O:12].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>ClCCl>[CH3:2][O:3][C:4](=[O:10])[C@H:5]([C@@H:7]([CH3:9])[OH:8])[NH:6][C:18](=[O:19])[C:17]1[CH:16]=[CH:15][C:14]([N+:11]([O-:13])=[O:12])=[CH:22][CH:21]=1
Reactant: COC(=O)[C@@H](N)[C@@H](C)O
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H](NC(=O)c1ccc([N+](=O)[O-])cc1)[C@@H](C)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 94.1 %

Procedure:
Dichloromethane (80 mL) was added to threonine methyl ester hydrochloride (3.39 g, 20 mmol), 4-nitrobenzoic acid (3.34 g, 20 mmol), WSC hydrochloride (3.83 g, 20 mmol), HOBt (2.87 g, 20 mmol) and N,N-diisopropylethylamine (2.58 g, 20 mmol), and the mixture was stirred at room temperature for three days. The reaction solution was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/2, 1/1, 1/2) to obtain 5.31 g of the title compound as a colorless solid (94%).
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[NH2:39][CH2:40][C:41]1[C:42]([OH:49])=[N:43][C:44]([CH3:48])=[N:45][C:46]=1[CH3:47]>ClCCl.C(N(CC)CC)C>[OH:49][C:42]1[C:41]([CH2:40][NH:39][C:12](=[O:14])[C:11]2[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:16][CH:15]=2)=[C:46]([CH3:47])[N:45]=[C:44]([CH3:48])[N:43]=1
Reactant: Cc1nc(C)c(CN)c(O)n1
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(C)c(CNC(=O)c2ccc(Oc3ccccc3)cc2)c(O)n1
Temperature: 25 °C
Yield: 21.5 %

Procedure:
A mixture of 4-phenoxybenzoic acid (92 mg, 0.43 mmol), 1-hydroxybenzotriazole (80 mg, 0.6 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (113 mg, 0.6 mmol), triethylamine (0.16 mL) and dichloromethane (15 mL) was stirred at 25° C. for half an hour. Then 5-(aminomethyl)-2,6-dimethylpyrimidin-4-ol (60 mg, 0.4 mmol) was added. The mixture was stirred at 25° C. for 12 hours and then concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give N-((4-hydroxy-2,6-dimethylpyrimidin-5-yl)methyl)-4-phenoxybenzamide as a white solid (30 mg, 21%). LRMS (M+H+) m/z: calcd 349.14. found 349. HPLC purity (214 nm): 98%. 1H NMR (300 MHz, d6-DMSO): δ 12.36 (s, 1H), 8.35 (t, J=4.5 Hz, 1H), 7.86 (d, J=8.4 Hz, 2H), 7.42 (t, J=8.4 Hz, 2H), 7.24-6.97 (m, 5H), 4.25 (d, J=4.5 Hz, 2H), 2.29 (s, 3H), 2.20 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:17]([NH:19][CH2:20][CH3:21])[CH3:18].C(O)=O>C1(C)C=CC=CC=1>[CH2:17]([N:19]([C:13]1[CH2:12][CH2:11][N:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:15][CH:14]=1)[CH2:20][CH3:21])[CH3:18]
Reactant: CCNCC
Reactant: O=C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Solvent: O=CO
Solvent: Cc1ccccc1
Product: CCN(CC)C1=CCN(c2ccc([N+](=O)[O-])cc2)CC1

Procedure:
5.0 g (22.7 mmol) of 1-(4-nitrophenyl)-4-piperidone, 16.0 g (220 mmol) of diethylamine and 5 ml of formic acid in 150 ml of toluene were refluxed with a water trap for 5 h. The solvent was removed under reduced pressure, and 4-(N,N-diethylamino)-1-(4-nitrophenyl)-1,2,3,6-tetrahydropyridine was obtained as crude product. 3.45 g (92.5 mmol) of sodium borohydride were added a little at a time to this crude product in 150 ml of ethanol at 10° C. The mixture was left to stir at room temperature for 3 h and then the solvent was removed under reduced pressure. The residue was partitioned between water and methylene chloride, and the organic phase was dried and concentrated under reduced pressure. This crude product was dissolved in a little isopropanol, and ethereal hydrogen chloride solution was added to give 5.5 g of 4-(N,N-diethylamino)-1-(4-nitrophenyl)piperidine hydrochloride, which was identical to the product from preparation 1. Melting point 183°- 184° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:11]=[CH:12][C:13]([C:16](OC)=[O:17])=[N:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].CC(C[AlH]CC(C)C)C>C1COCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:11]=[CH:12][C:13]([CH2:16][OH:17])=[N:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)c1cnc(Nc2ccc(Cl)c(Cl)c2)cn1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OCc1cnc(Nc2ccc(Cl)c(Cl)c2)cn1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 61 %

Procedure:
A suspension of methyl 5-((3,4-dichlorophenyl)amino)pyrazine-2-carboxylate (0.53 g, 1.778 mmol) in THF (18 mL) was cooled at −78° C. and 1M solution of DIBAL-H (5.33 ml, 5.33 mmol) in toluene was added. The mixture was stirred for 1.5 h while warming to room temperature. The reaction mixture was diluted with THF (20 mL) and quenched with Na2SO4.10H2O followed by a few drops of water. The mixture was stirred at room temperature for 18 h, then filtered through a pad of Celite topped with silica gel. The pad was washed with ethyl acetate and the filtrate concentrated. The residue was purified on silica gel using 40-100% ethyl acetate in hexanes. The desired fractions were concentrated to give (5-(3,4-dichlorophenylamino)pyrazin-2-yl)methanol as a yellow solid (0.293 g, 61%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.80 (1H, s), 8.02-8.34 (3H, m), 7.46-7.66 (2H, m), 5.36 (1H, t, J=5.77 Hz), 4.51 (2H, d, J=5.77 Hz). LCMS: R.T.=3.65; [M+H]+=269.96.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N+:8]([O-])=[CH:9]2)=[CH:4][C:3]=1[F:13].O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:9]1[C:10]2[C:5](=[CH:4][C:3]([F:13])=[C:2]([Cl:1])[CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: [O-][n+]1ccc2cc(F)c(Cl)cc2c1
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1cc2ccnc(Cl)c2cc1Cl
Temperature: 25 °C

Procedure:
2.6 g of 7-chloro-6-fluoro-isoquinoline 2-oxide (5) were heated in 40 ml of POCl3 at reflux for 4 h. After the mixture has cooled down to room temperature, it was poured on ice. The aqueous solution was extracted three times with dichloromethane. The combined organic layers were dried with magnesium sulfate and evaporated to yield 2.91 g of the title compound 6, which was used without further purification. Rt=2.34 min (Method A). Detected mass: 216.0 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][S:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]([O:25]C)=[O:24])[CH2:10]2)=[CH:5][C:4]=1[F:27])[CH3:2].CC(C)([O-])C.[K+]>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][S:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]([OH:25])=[O:24])[CH2:10]2)=[CH:5][C:4]=1[F:27])[CH3:2]
Reactant: CCc1ccc(C2CC(C(=O)OC)CN(C(=O)N3CCSCC3)C2)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCSCC3)C2)cc1F

Procedure:
According to General Method 4A, 1.2 g (3.0 mmol) of methyl 5-(4-ethyl-3-fluorophenyl)-1-(thiomorpholin-4-ylcarbonyl)piperidine-3-carboxylate were reacted with 3.4 g (30.4 mmol) of potassium tert-butoxide. Yield: 599 mg (50% of theory)
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([CH3:12])[CH:10]=2)[CH:5]=[C:4]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:16](O)=[O:17])[C:3]1=[O:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:48][C:49]1[CH:50]=[CH:51][C:52]([NH2:55])=[N:53][CH:54]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([CH3:12])[CH:10]=2)[CH:5]=[C:4]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:16]([NH:55][C:52]2[CH:51]=[CH:50][C:49]([CH3:48])=[CH:54][N:53]=2)=[O:17])[C:3]1=[O:23]
Reactant: Cc1ccc(N)nc1
Reactant: Cc1cc2c(cn1)cc(-c1cc(C(=O)O)ccc1C)c(=O)n2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccc(C)c(-c3cc4cnc(C)cc4n(C)c3=O)c2)nc1

Procedure:
A solution of 3-(1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-methylbenzoic acid 29 (50 mg, 0.17 mmol) in DMF (1 mL) is treated with HATU (97 mg, 0.255 mmol), 5-methylpyridin-2-amine (22 mg, 0.2 mmol) and DIPEA (0.089 mL, 0.51 mmol) at 80° C. for 2 h. The residue is purified by preparative LC/MS to give the desired product M6 as an off-white solid. 1H NMR (400 MHz, MeOH-d4) δ 9.12 (s, 1H), 8.26 (m, 1H), 8.22 (d, J=8.7 Hz, 1H), 8.16 (s, 1H), 8.07 (dd, J=8, 1.6 Hz, 1H), 8.02 (s, 1H), 7.94 (s, 1H), 7.86 (m, 1H), 7.57 (d, J=8 Hz, 1H), 3.85 (s, 3H), 2.87 (s, 3H), 2.46 (s, 3H), 2.35 (s, 3H); LC/MS (M+1, m/z): 399.2.