Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:5]=[N:6][C:7]=1Br.O1CCC[CH2:14]1.C[Mg]Br>C1COCC1.C1(C)C=CC=CC=1.[Ni](Cl)Cl.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:5]=[N:6][C:7]=1[CH3:14]
Reactant: C1CCOC1
Reactant: COC(=O)c1cnc(Br)c(Br)c1
Agent: Cl[Ni]Cl
Agent: C[Mg]Br
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cnc(C)c(Br)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 43.6 %

Procedure:
To a solution of methyl 5,6-dibromopyridine-3-carboxylate (0.5122 g; 1.737 mmol) in tetrahydrofuran (10.0 mL; 123 mmol) at 0° C. (using an oven-dried flask) was added 1,3-bis(diphenylphosphino)propane nickel(II) chloride (98.0 mg; 0.179 mmol). After 5 minutes, methylmagnesium bromide (1.4 mol/L) in THF:toluene (1:3) (1.6 mL; 2.2 mmol) was added dropwise. After addition was complete, the reaction mixture was stirred at room temperature. After 8 hours, methylmagnesium bromide (1.4 mol/L) in THF:toluene (1:3) (1.0 mL) was added and the reaction stirred at room temperature overnight. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with ethyl acetate. The organic portion was dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (25 g silica, solvent gradient: 0-30% ethyl acetate in dichloromethane) to yield 174.1 mg (44%) of the title compound. LCMS (ESI): M+H=230.2; 1H NMR (400 MHz, DMSO) δ 8.93 (d, J=1.4 Hz, 1H), 8.39 (d, J=1.4 Hz, 1H), 3.89 (s, 4H), 2.67 (s, 4H).
Reaction SMILES: [CH2:1]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:17]N=O)(C)(C)C.ON1C(=O)C2=CC=CC=C2C1=O.S(=O)(=O)(O)O.[OH-].[Na+].C1(=NO)CCCCCCCCCCC1.[N+](C1CCCCCCCCCCC1)([O-])=O>C(O)(=O)C>[C:1]1(=[O:17])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)ON=O
Reactant: C1CCCCCCCCCCC1
Agent: O=C1c2ccccc2C(=O)N1O
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])C1CCCCCCCCCCC1
Solvent: CC(=O)O
Product: O=C1CCCCCCCCCCC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Cyclododecane (1.66 g; 9.88 mmol), t-butylnitrite (2 mmol), N-hydroxyphthalimide (0.4 mmol), and acetic acid (2 ml) were placed in a flask and were stirred at 80° C. in an atmosphere of argon gas for 1 hour. The mixture was further treated with fuming sulfuric acid having a concentration of 5% by weight (100 mg) with stirring at 70° C. for 15 minutes under anhydrous conditions. The reaction mixture was neutralized with sodium hydroxide and was analyzed to find that cyclododecanone oxime, nitrocyclododecane, and cyclododecanone were formed in yields of 48%, 6%, and 3%, respectively.
Reaction SMILES: [Na+].[CH:2]1([C:8]2[CH:13]=[CH:12][C:11]([S:14]([O-:17])(=O)=[O:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.P(Cl)(Cl)(Cl)(Cl)[Cl:19]>>[CH:2]1([C:8]2[CH:13]=[CH:12][C:11]([S:14]([Cl:19])(=[O:17])=[O:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=S(=O)([O-])c1ccc(C2CCCCC2)cc1
Agent: [Na+]
Product: O=S(=O)(Cl)c1ccc(C2CCCCC2)cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
The sodium salt prepared in Example I (420 gm, 1.6M) is intermittently mixed with phosphorous pentachloride (160 gm, 0.77M) in a three liter multi-necked flask and slowly warmed to 70° C. in an oil bath. The liquified reaction mass is aged at 70° C. for 8 hours, then cooled to room temperature and carefully poured over one kilogram of cracked ice. A solid precipitate is removed by filtration and the aqueous phase is extracted with methylene chloride three times, each time using 300 milliliters of MeCl. The combined organic phases are dried and concentrated using a rotary evaporator. 4-cyclohexylbenzenesulfonyl chloride (338 gm, 81% of theoretical yield) was recovered as a crude product.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)[CH2:3][C:4]([OH:6])=[O:5].[Br:17]Br>C(Cl)Cl>[Br:17][C:13]1[CH:12]=[CH:11][C:10]([O:14][CH3:15])=[CH:9][C:8]=1[CH2:7][C:2]([CH3:16])([CH3:1])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: COc1cccc(CC(C)(C)CC(=O)O)c1
Reactant: BrBr
Solvent: ClCCl
Product: COc1ccc(Br)c(CC(C)(C)CC(=O)O)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
To a solution of 3,3-dimethyl-4-(3-methoxyphenyl)butanoic acid (6.7 g, 0.03 mol) in DCM (100 mL) at 0° C. was added a solution of bromine (1.55 mL, 0.03 mol) in DCM (13 mL) dropwise. After addition the solution was stirred at 0° C. for 1 h then the solution was washed with water (3×100 mL), dried (Na2SO4) and evaporated. The product (8.45 g, 94%) was isolated as a brown oil and used without further purification. 1H NMR (360 MHz, CDCl3) δ 1.12 (6H, s), 2.36 (2H, s), 2.98 (2H, s), 3.80 (3H, s), 6.65 (1H, dd, J=8.7 and 3.1 Hz), 6.85 (1H, d, J=3.1 Hz), 7.43 (1H, d, J=8.7 Hz).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[Cl:12][C:13]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:14]=1[CH:15]=[CH:16][N+]([O-])=O.[N+:25]([CH2:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])#[C-:26]>C1COCC1>[Cl:12][C:13]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:14]=1[C:15]1[CH:16]=[CH:26][NH:25][C:27]=1[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]
Reactant: O=[N+]([O-])C=Cc1ccc(Cl)cc1Cl
Reactant: [C-]#[N+]CC(=O)OCc1ccccc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(OCc1ccccc1)c1[nH]ccc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 15 %

Procedure:
DBU (1 eq) was added to a stirred solution of 2,4-Dichloronitrostyrene (1) (1 eq) and benzyl 2-isocyanoacetate (0.9 eq) in THF at −78° C. under N2. The reaction was allowed to warm to room temperature over 2 h. The reaction could be followed by TLC eluting with CHCl3 (Rf0.3). After stirring for an additional 12 h, the reaction was diluted with CH2Cl2 and EtOAc. The organic mixture washed with 0.1 N HCl, water, sat. aq. NaHCO3, brine, dried (Na2SO4), filtered and concentrated under reduced pressure to an oil. The crude product was purified using silica column chromatography eluting with CHCl3 to obtain pure phenylmethyl 3-(2,4-dichlorophenyl)pyrrole-2-carboxylate (2) (15% yield).
Reaction SMILES: [O:1]=[C:2]1[C:15]2[C:14]3[S:13][C:12]4=[CH:16][CH2:17][CH2:18][CH:19]=[C:11]4[CH:10]=[C:9]([C:20]([O:22]C)=[O:21])[C:8]=3[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.[OH-].[K+].Cl>O>[O:1]=[C:2]1[C:15]2[C:14]3[S:13][C:12]4=[CH:16][CH2:17][CH2:18][CH:19]=[C:11]4[CH:10]=[C:9]([C:20]([OH:22])=[O:21])[C:8]=3[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1
Reactant: COC(=O)C1=CC2=CCCC=C2Sc2c1ccc1c2C(=O)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C1=CC2=CCCC=C2Sc2c1ccc1c2C(=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 1-oxo-2,3,9,10-tetrahydro-1H-benz[b]indeno[5,4-f]thiepin-6-carboxylate (160 mg, 0.5 mmole) was added to 4.1 ml of the potassium hydroxide solution described above and the mixture was stirred at room temperature under argon for 8 hours. Water (2 ml) was added and then 10% hydrochloric acid (0.3 ml) was added to precipitate the title compound 126 mg (81%), m.p. 298°-302° (dec.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Br.Br[CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1>>[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([CH2:18][N:13]2[CH:14]=[C:10]([C:9]#[C:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=3)[N:11]=[C:12]2[CH3:15])[CH:20]=1
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Reactant: BrCc1cccnc1
Agent: Br
Product: Cc1cc(C#Cc2cn(Cc3cccnc3)c(C)n2)ccn1

Procedure:
The title compound, MS: m/e=288.9 (M+H30), was prepared in accordance with the general method of example 1 from 2-methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 3-(bromomethyl)pyridine hydrobromide.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:20])=[C:6]([CH:19]=1)[C:7]([NH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=[O:8].[C:21]1(=[O:27])[NH:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>[Cu]I.O1CCOCC1>[Cl:20][C:5]1[CH:4]=[CH:3][C:2]([N:26]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]2=[O:27])=[CH:19][C:6]=1[C:7]([NH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=[O:8]
Reactant: O=C(NCCc1ccccc1Cl)c1cc(Br)ccc1Cl
Reactant: O=C1CCCCN1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C(NCCc1ccccc1Cl)c1cc(N2CCCCC2=O)ccc1Cl
Temperature: 25 °C
Yield: 1.2 %

Procedure:
A mixture of 5-bromo-2-chloro-N-[2-(2-chloro-phenyl)-ethyl]-benzamide (200 mg, 0.536 mmol), δ-valerolactam (106 mg, 1.07 mmol), potassium carbonate (156 mg, 1.13 mmol), dioxane (1 ml, purged with nitrogen), and copper (I) iodide (5 mg) in an oven-dried round bottom flask equipped with a reflux condenser under a nitrogen atmosphere was heated in an oil bath at 120–125)C. After 21 hours the mixture was cooled to room temperature, filtered through a pad of silica gel and concentrated under reduced pressure to give 50 mg of crude product. Purification by preparative HPLC (Shimadsu LC-8A preparative liquid chromatograph) eluting with a gradient of 0.1% aqueous formic acid in acetonitrile provided 2.5 mg of the title compound as a colorless amorphous solid. Mass Spectrum (ES+) 391.6; LC retention time=2.3 minutes (using the LC/MS and method outlined for the examples in Table 1).
Reaction SMILES: Cl[CH2:2][C@@H:3]([OH:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[N-:11]=[N+:12]=[N-:13].[Na+]>CN(C)C=O>[N:11]([CH2:2][C@@H:3]([OH:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+:12]=[N-:13]
Reactant: CCOC(=O)C[C@H](O)CCl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@H](O)CN=[N+]=[N-]
Reaction time: 2 h

Procedure:
To a mixture of ethyl (S)-4-chloro-3-hydroxybutyrate (1 93 g, 1.16 mol, optical purity:98.5% ee) and N,N-dimethylformamide (1.4 Lit.) is added sodium azide (151 g, 2.32 mol) and the mixture was stirred at 100°-110° C. for 2 hours. After cooling N,N-dimethylformamide was distilled off and to the residue was added water (1 Lit.). The mixture was extracted with ethyl acetate and the extract was dried over magnesium sulfate. By distillation off ethyl acetate under vacuo, there is obtained ethyl (S)-4-azido-3-hydroxybutyrate as a crude product (206 g). Then the crude product was dissolved in methanol (1 Lit.) and to it 5% palladium-carbon (10 g) was added. The mixture was stirred for 17 hours at room temperature under a hydrogen atmosphere. After the reaction was over, palladium-carbon was filtered off and the solvent was distilled off under vacuo. The resulting product was recrystallized from acetone-water to give (S)-4-hydroxy-2-pyrrolidone (99 g, 0.98 mol, yield:84%) as a colorless crystalline solid. Optical purity:98.3% ee, Specific rotation:[α]D22 -57.6°(c=1.00, H2O).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([OH:11])=O)[CH:7]=1.Cl.[F:27][C:28]1([F:33])[CH2:31][CH:30]([NH2:32])[CH2:29]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:24])(=[O:25])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([NH:32][CH:30]2[CH2:31][C:28]([F:33])([F:27])[CH2:29]2)=[O:11])[CH:7]=1
Reactant: NC1CC(F)(F)C1
Reactant: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)O)c1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)NC2CC(F)(F)C2)c1
Reaction time: 3 h

Procedure:
To the mixture of 2-(5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetic acid (1.09 g, 3 mmol) and 3,3-difluorocyclobutyl amine hydrochloride (1 g, 7 mmol) in DMF (10 ml), added PyBOP (1.56 g, 3 mmol) then triethyl amine (1.8 ml, 12 mmol). Stirring was kept for 3 hours. Diluted with EtOAc, washed with 1N HCl, water and brine. Dried over anhydrous sodium sulfate. Concentrated, the residue was dissolved in DMSO and purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column). The title compound was obtained as light yellow powder. MS calcd for (C19H20BF2N3O5S): 451.12. MS found (ESI negative): (M−H)−=450.1. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.79 (s, 1H), 9.15 (s, 1H), 8.48 (d, J=6.4 Hz, 1H), 7.43 (d, J=8.8 Hz, 1H), 7.39 (d, J=2 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 7.09 (dd, J=8.4 Hz, 1H), 6.40 (d, J=2 Hz, 1H), 6.35 (dd, J=8.4 Hz, 1H), 5.92 (s, 2H), 4.85 (s, 2H), 4.05 (m, 1H), 3.75 (s, 2H), 2.89 (m, 2H), 2.59 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH:17]([NH2:20])([CH3:19])[CH3:18]>C(O)(C)C>[CH:17]([NH:20][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][O:8][C:4]=2[N:5]=[CH:6][N:7]=1)([CH3:19])[CH3:18]
Reactant: CC(C)N
Reactant: Clc1ncnc2occ(-c3ccccc3)c12
Solvent: CC(C)O
Product: CC(C)Nc1ncnc2occ(-c3ccccc3)c12
Reaction time: 20 h

Procedure:
Into a 50 mL round bottom flask was placed 4-chloro-5-phenylfuro[2,3-d]pyrimidine, isopropanol (25 mL), and isopropylamine (1.5 g, 25 mmol). The flask was equipped with a magnetic stir bar, a reflux condenser, and argon balloon and the reaction was brought to reflux with stirring for 20 hours.
Reaction SMILES: C([N:4]1[C:13]2[CH:12]=[CH:11][C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:8]=2[C:7]2[N:17]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[N:18]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:6]=2[CH2:5]1)(=O)C>CCO.Cl>[F:31][C:28]1[CH:29]=[CH:30][C:25]([N:17]2[C:7]3[C:8]4[CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:12][C:13]=4[NH:4][CH2:5][C:6]=3[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:18]2)=[CH:26][CH:27]=1
Reactant: CCOC(=O)c1nn(-c2ccc(F)cc2)c2c1CN(C(C)=O)c1ccc([N+](=O)[O-])cc1-2
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1nn(-c2ccc(F)cc2)c2c1CNc1ccc([N+](=O)[O-])cc1-2
Temperature: 80 °C
Yield: 85 %

Procedure:
The material from step 1 of Example 24 (5 g, 0.0117 mol) was suspended in 100 mL absolute EtOH and 60 mL 1N HCl. The mixture was then heated to 80° C. for 18 hours. The heating was then terminated and the compound filtered upon cooling, to give the pure desired product as an orange solid. 3.8 g. (MW=382.35, 85% yield). LC/MS m/z=383.4 (m+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[CH:24][C:23]([CH2:26][O:27][CH3:28])=[CH:22][N:21]=3)[CH2:16][CH2:15]2)[CH:5]=[C:4]([F:29])[C:3]=1[CH2:30][C:31](O)=[O:32].Cl.[NH:35]1[CH2:38][CH:37]([OH:39])[CH2:36]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:15][CH2:16][N:17]([C:20]3[N:21]=[CH:22][C:23]([CH2:26][O:27][CH3:28])=[CH:24][N:25]=3)[CH2:18][CH2:19]2)[CH:5]=[C:4]([F:29])[C:3]=1[CH2:30][C:31]([N:35]1[CH2:38][CH:37]([OH:39])[CH2:36]1)=[O:32]
Reactant: OC1CNC1
Reactant: COCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3cc(F)c(CC(=O)O)c(F)c3)CC2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3cc(F)c(CC(=O)N4CC(O)C4)c(F)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {2,6-difluoro-4-[2-((1S,2R)-2-{1-[5-(methoxymethyl)pyrimidin-2-yl]piperidin-4-yl}cyclopropyl)ethoxy]phenyl}acetic acid (1.00 g, 2.17 mmol) in 8 ml anhydrous DMF at RT was added azetidin-3-ol hydrochloride (0.475 g, 4.33 mmol) and N,N-diisopropylethylamine (1.84 ml, 10.8 mmol). 0-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.65 g, 4.33 mmol) was added and the mixture stirred at RT overnight. The mixture was filtered and purified by reverse-phase HPLC column chromatography (SunFire Prep C18 OBD Sum 19×100 mm column; 35-75% acetonitrile in 0.1% formic acid in water gradient) to afford the title compound. 1H NMR (CD3OD): δ 8.26 (s, 2H), 6.57 (d, J=9.4 Hz, 2H), 4.69 (t, J=12.5 Hz, 2H), 4.57-4.59 (m, 1H), 4.45-4.49 (m, 1H), 4.27 (s, 2H), 4.18-4.22 (m, 1H), 4.01-4.09 (m, 3H), 3.75-3.78 (m, 1H), 3.47 (s, 2H), 3.34 (s, 3H), 2.86-2.93 (m, 2H), 2.09-2.12 (m, 1H), 1.82-1.88 (m, 2H), 1.56-1.58 (m, 1H), 1.31-1.35 (m, 2H), 1.16-1.18 (m, 1H), 0.95-0.97 (m, 1H), 0.59-0.68 (m, 2H), −0.04 (m, 1H). LC/MS (m/z): 517.5 (M+H)+. Human EC50: 1.6 nM
Reaction SMILES: [C:1]([NH:5][C:6](=[O:43])[NH:7][C:8]1[C:9]([C:22]2[C:23]([Cl:42])=[C:24]([NH:29][C:30](=[O:41])[C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=3)[CH:25]=[CH:26][C:27]=2[Cl:28])=[CH:10][C:11]2[CH:16]=[N:15][C:14](S(C)(=O)=O)=[N:13][C:12]=2[N:21]=1)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:55]([N:57]([CH2:68][CH3:69])[CH2:58][CH2:59][O:60][C:61]1[CH:66]=[CH:65][C:64]([NH2:67])=[CH:63][CH:62]=1)[CH3:56]>CN(C=O)C>[C:1]([NH:5][C:6](=[O:43])[NH:7][C:8]1[C:9]([C:22]2[C:23]([Cl:42])=[C:24]([NH:29][C:30](=[O:41])[C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=3)[CH:25]=[CH:26][C:27]=2[Cl:28])=[CH:10][C:11]2[CH:16]=[N:15][C:14]([NH:67][C:64]3[CH:63]=[CH:62][C:61]([O:60][CH2:59][CH2:58][N:57]([CH2:68][CH3:69])[CH2:55][CH3:56])=[CH:66][CH:65]=3)=[N:13][C:12]=2[N:21]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)Nc1nc2nc(S(C)(=O)=O)ncc2cc1-c1c(Cl)ccc(NC(=O)c2cccc(C(F)(F)F)c2)c1Cl
Reactant: CCN(CC)CCOc1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1ccc(Nc2ncc3cc(-c4c(Cl)ccc(NC(=O)c5cccc(C(F)(F)F)c5)c4Cl)c(NC(=O)NC(C)(C)C)nc3n2)cc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
This compound is prepared using a similar procedure to the one described above except that in step D the following procedure is used. To a solution of N—{3-[7-(3-tert-butyl-ureido)-2-methanesulfonyl-pyrido[2,3-d]pyrimidin-6-yl]-2,4-dichloro-phenyl}-3-trifluoromethyl-benzamide (50 mg, 0.08 mmol) in DMF (2 ml) is added p-toluenesulfonic acid (15 mg, 0.08 mmol) and 4-(2-diethylamino-ethoxy)-phenylamine (21 mg, 0.1 mmol). The reaction is stirred at 80° C. for 4 hours. The crude product is purified by RP-HPLC to give the title compound as yellow solid: 1H NMR 400 MHz (DMSO) δ 10.46 (s, 1H), 10.09 (s, 1H), 9.30 (s, 1H), 9.05 (s, 1H), 8.28 (s, 1H), 8.24 (d, 1H, J=7.6 Hz), 8.05 (m, 2H), 7.95 (m, 3H), 7.76 (m, 3H), 7.67 (d, 2H, J=8.8 Hz), 4.24 (t, 2H, J=4.6 Hz), 3.45 (m, 2H), 3.15 (m, 4H), 1.39 (s, 9H), 1.18 (t, 6H, J=7.2 Hz); MS m/z 783.3 (M+1).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH:2]([CH:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][C@H:22]2[CH2:27][CH2:26][C@H:25]([C:28]3[CH:33]=[CH:32][C:31]([CH2:34][N:35]([CH3:37])[CH3:36])=[CH:30][CH:29]=3)[CH2:24][CH2:23]2)=[O:20])=[CH:14][CH:13]=1.C(OCC)C>C(O)C>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][C@H:22]2[CH2:23][CH2:24][C@H:25]([C:28]3[CH:29]=[CH:30][C:31]([CH2:34][N:35]([CH3:36])[CH3:37])=[CH:32][CH:33]=3)[CH2:26][CH2:27]2)=[O:20])=[CH:14][CH:13]=1.[C:6]([CH:4]([CH:2]([C:1]([O-:10])=[O:9])[OH:3])[OH:5])([O-:8])=[O:7]
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: CN(C)Cc1ccc([C@H]2CC[C@H](OC(=O)Cc3ccc(Cl)cc3)CC2)cc1
Agent: CN(C)Cc1ccc([C@H]2CC[C@H](OC(=O)Cc3ccc(Cl)cc3)CC2)cc1
Solvent: CCO
Solvent: CCOCC
Product: O=C([O-])C(O)C(O)C(=O)[O-]
Reaction time: 8 h

Procedure:
First 0.15 g (0.001 mol) of anhydrous tartaric acid and then 0.39 g (0.001 mol) of trans-O-(4-chlorophenylacetyl)-4-(4-dimethylaminomethylphenyl)-cyclohexanol are dissolved in 7 ml of absolute ethanol. Diethyl ether is then added to the clear solution until it becomes slightly cloudy and it is then left to stand for 8 hours at +4° C. The crystalline product precipitated is suction filtered, washed with diethyl ether and dried. Melting point: 169-171° C. Yield: 0.46 g (86% of theory) C27H34ClNO8 (536.02) Calculated: C 60.50 H 6.39 N 2.61 Cl 6.61 Found: 60.37 6.38 2.65 6.73
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20]([O:22]CC)=[O:21].[OH-].[Li+]>C(O)C.O>[O:1]=[C:2]1[C:6]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20]([OH:22])=[O:21]
Reactant: CCOC(=O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Temperature: 80 °C

Procedure:
The product from Example 21B (0.92 g, 2.84 mmol) was dissolved in ethanol (20 mL). A solution of lithium hydroxide (0.57 g, 23.8 mmol) in water (5 mL) was added, and the reaction was heated to 80° C. for 2 hours. The reaction mixture was cooled to room temperature, concentrated, neutralized with 2 N HCl, and then diluted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and then concentrated to give the title compound. MS (DCI+) m/z 296.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N+:5]([O-])=[CH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:2].[OH-].[Na+].O=P(Cl)(Cl)[Cl:19]>C(Cl)(Cl)Cl>[Cl:19][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[C:4]([O:3][CH2:1][CH3:2])[N:5]=1
Reactant: CCOc1cc2ccccc2c[n+]1[O-]
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCOc1cc2ccccc2c(Cl)n1
Temperature: 120 °C
Yield: 40 %

Procedure:
3-Ethoxyisoquinoline N-oxide (1.15 g, 6.1 mmol) was taken up in POCl3 (5 mL) at rt and then heated to 120° C. under an atmosphere of Ar for 2 h. Following cooling to rt, the reaction was diluted with CHCl3 and poured into icewater (20 mL) and the resulting solution was placed in an ice bath and treated with 10M NaOH until pH 10 with vigorous stirring. Following extraction with CHCl3, the combined organics were washed with brine and dried over anhydrous MgSO4. Following concentration in vacuo, purification on SiO2 (3-15% EtOAc/hex) afforded 0.51 g (40%) of 1-chloro-3-ethoxyisoquinoline. LCMS found 208.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)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>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:13]2[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=2)=[CH:4][N:3]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Nc1ccc(Br)cn1
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: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Nc1ccc(-c2ccc(F)cc2)cn1
Temperature: 25 °C
Yield: 61.3 %

Procedure:
To a mixture of 2-amino-5-bromopyridine 1 (1.80 g, 10.4 mmol) in 104 ml toluene and 24 ml ethanol (EtOH) was added 4-fluorophenyl boronic acid (1.75 g, 12.5 mmol) followed by 10 ml of 2.0 M aqueous Na2CO3. The reaction was degassed with nitrogen and Pd(PPh3)4 (0.60 g, 0.52 mmol) was added in one portion and the reaction was heated to reflux for 26 hours. The reaction was then cooled to ambient temperature and diluted with 50 ml water. The layers were separated and the aqueous layer was extracted with ethyl acetate (EtOAc) (2×100 mL). The organic layers were combined, washed with saturated aqueous NaHCO3, dried over MgSO4 and concentrated to a brown oil. Automated purification on a silica gel ISCO column (120 g column, 2.5% MeOH—CH2Cl2) gave 1.20 g (60%) of 2-amino-5-(4-fluorophenyl)pyridine as a yellow solid.