Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-]CC.[Na+].[C:5]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:6][SH:7].[Cl:12][C:13]1[C:18]([C:19](OCC)=[O:20])=[C:17](Cl)[C:16]([CH3:25])=[C:15]([CH3:26])[N:14]=1.Cl>C(O)C>[Cl:12][C:13]1[C:18]2[C:19]([OH:20])=[C:6]([C:5]([O:9][CH2:10][CH3:11])=[O:8])[S:7][C:17]=2[C:16]([CH3:25])=[C:15]([CH3:26])[N:14]=1
Reactant: CCOC(=O)c1c(Cl)nc(C)c(C)c1Cl
Reactant: CCOC(=O)CS
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1sc2c(C)c(C)nc(Cl)c2c1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.5 %

Procedure:
A 20% solution (1.73 g, 5.08 mmol) of sodium ethoxide in ethanol was diluted with ethanol (5 mL), and ethyl thioglycolate (610 mg, 5.08 mmol) was added. Ethyl 2,4-dichloro-5,6-dimethylpyridine-3-carboxylate (630 mg, 2.54 mmol) was added to the mixture, and the mixture was stirred at room temperature for 18 hr. 2N Hydrochloric acid (3 mL) was added to the reaction mixture and the mixture was partitioned between brine and ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The obtained solid was washed with diisopropyl ether-hexane, and dried under reduced pressure to give the title compound (374 mg, 52%) as a white powder.
Reaction SMILES: [CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:9]([C:13]1([OH:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N+:34]([O-])=O.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.OS([O-])(=O)=O.[K+]>C1COCC1.O>[NH2:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[O:19][C:13]1([CH:9]([N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]([OH:12])=[O:11])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: O=C(O)C(N(Cc1ccccc1)Cc1ccccc1)C1(O)CCCCC1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccccc1OC1(C(C(=O)O)N(Cc2ccccc2)Cc2ccccc2)CCCCC1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 90.9 %

Procedure:
2-(dibenzylamino)-2-(1-hydroxycyclohexyl)acetic acid (0.70 g, 1.98 mmol, Eq: 1.00) and 1-fluoro-2-nitrobenzene (293 mg, 219 μl, 2.08 mmol, Eq: 1.05) were dissolved in THF (10 mL) and a solution of potassium bis(trimethylsilyl)amide 0.5 M in toluene (8.71 mL, 4.36 mmol, Eq: 2.2) was added. The mixture was heated to 60° C. After 1 h the mixture was cooled to RT and 0.2 mL 1-fluoro-2-nitrobenzene and an additional 9 mL of potassium bis(trimethylsilyl)amide (0.5 M in toluene) were added and the mixture stirred at 60° C. for 90 min. The mixture was diluted with H2O, acidified with sat. KHSO4, and extracted with EtOAc. The combined extracts were washed with H2O, brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography to afford 2-(1-(2-aminophenoxyl)cyclohexyl)-2-(dibenzylamino)acetic acid as a light brown oil (0.80 g, 85%). MS m/z 475.1 (MH+)
Reaction SMILES: C([O:3][C:4]([C:6]1([C:10]2[CH:11]=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[C:13]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[C:14]([Cl:16])[CH:15]=2)[CH2:9][CH2:8][CH2:7]1)=[O:5])C.O.[OH-].[Li+]>CO.C1COCC1.O>[Cl:16][C:14]1[CH:15]=[C:10]([C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][CH2:9]2)[CH:11]=[C:12]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:28]=2)[C:13]=1[O:17][CH2:18][C:19]([F:21])([F:22])[F:20]
Reactant: CCOC(=O)C1(c2cc(Cl)c(OCC(F)(F)F)c(-c3ccc(C(F)(F)F)cc3)c2)CCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1(c2cc(Cl)c(OCC(F)(F)F)c(-c3ccc(C(F)(F)F)cc3)c2)CCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
A mixture of ethyl-1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclo butane carboxylate (400 mg, 0.83 mmol) and lithium hydroxide monohydrate (0.2 g, 8.3 mmol) in a MeOH/THF/Water solvent mixture (10 ml/10 ml/10 ml) was stirred for 3 h at room temperature. Upon completion of the reaction, the volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by column chromatography to give 1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclobutane carboxylic acid in 88% yield (0.21 g). 1H-NMR (CDCl3, 400 MHz): 7.72 (d, 2H); 7.65 (d, 2H), 7.39 (s, 1H); 7.26 (s, 1H); 3.98 (q, 2H); 2.86 (m, 2H); 2.52 (m, 2H); 2.16 (m, 1H), 1.91 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:15]2[CH:20]=[C:19](O)[CH:18]=[C:17]([O:22][CH2:23][CH3:24])[CH:16]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[N:2].C([C:27]1[CH:32]=[CH:31][C:30]([NH:33]C(C2C=C(OS(C(F)(F)F)(=O)=O)C=C(OCC)C=2)C(OC)=O)=[CH:29][CH:28]=1)#N.NC1C=C(B(O)O)C=CC=1>>[NH2:33][C:30]1[CH:29]=[C:28]([C:19]2[CH:18]=[C:17]([O:22][CH2:23][CH3:24])[CH:16]=[C:15]([CH:10]([NH:9][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)[C:11]([O:13][CH3:14])=[O:12])[CH:20]=2)[CH:27]=[CH:32][CH:31]=1
Reactant: CCOc1cc(O)cc(C(Nc2ccc(C#N)cc2)C(=O)OC)c1
Reactant: CCOc1cc(OS(=O)(=O)C(F)(F)F)cc(C(Nc2ccc(C#N)cc2)C(=O)OC)c1
Agent: Nc1cccc(B(O)O)c1
Product: CCOc1cc(-c2cccc(N)c2)cc(C(Nc2ccc(C#N)cc2)C(=O)OC)c1

Procedure:
Analogously to Example 155, from methyl (RS)-(4-cyano-phenylamino)-(3-ethoxy-5-hydroxy-phenyl)-acetate via methyl (RS)-(4-cyano-phenylamino)-(3-ethoxy-5-trifluoromethanesulphonyloxy-phenyl)-acetate by reaction with 3-aminophenylboronic acid there was obtained the compound methyl (RS)-(3′-amino-5-ethoxy-biphenyl-3-yl)-(4-cyano-phenylamino)-acetate, which was converted into methyl (RS)-(3′-amino-5-ethoxy-biphenyl-3-yl)-(4-carbamimidoyl-phenylamino)-acetate hydrochloride; MS: 419 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:16][C:17]2[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.C[Si]([N:30]=[C:31]=[O:32])(C)C>CC(O)C>[CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:16][C:17]2[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:31]([NH2:30])=[O:32])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(CN(CCCCN)Cc2ncccc2C(C)C)c(C)c1
Reactant: C[Si](C)(C)N=C=O
Solvent: CC(C)O
Product: Cc1cnc(CN(CCCCNC(N)=O)Cc2ncccc2C(C)C)c(C)c1
Yield: 64.6 %

Procedure:
To a solution of N1-(3,5-Dimethyl-pyridin-2-ylmethyl)-N1-{3-isopropyl-pyridin-2-ylmethyl}-butane-1,4-diamine (78 mg, 0.23 mmol) in 2-propanol (2 mL) was added trimethylsilyl-isocyanate (32 μL, 0.24 mmol). The resultant solution was stirred at room temperature overnight then concentrated. Purification of the crude material by radial chromatography on silica gel (1 mm plate, 20:1:1 CH2Cl2-MeOH—NH4OH) provided 57 mg (64%) of the free base of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6](Cl)[N:5]=[C:4]([C:10]#[N:11])[C:3]=1[Cl:12].[Cl:13][C:14]1[CH:19]=[CH:18][C:17](B2OCCCO2)=[C:16]([F:26])[C:15]=1[O:27][CH3:28].[F-].[K+].C(#N)C>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>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[C:15]([O:27][CH3:28])[C:16]=2[F:26])[N:5]=[C:4]([C:10]#[N:11])[C:3]=1[Cl:12]
Reactant: COc1c(Cl)ccc(B2OCCCO2)c1F
Reactant: N#Cc1nc(Cl)c(F)c(N)c1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1c(Cl)ccc(-c2nc(C#N)c(Cl)c(N)c2F)c1F
Temperature: 75 °C
Yield: 57.2 %

Procedure:
A mixture of 4-amino-3,6-dichloro-5-fluoropicolinonitrile (0.37 g, 1.80 mmol), 2-(4-chloro-2-fluoro-3-methoxyphenyl)-1,3,2-dioxaborinane (0.549 g, 2.24 mmol) and KF (0.209 g, 3.59 mmol) was taken into acetonitrile (6.75 mL) and water (2.25 mL). The mixture was stirred and sparged with a nitrogen atmosphere. Pd(PPh3)2Cl2 (63 mg, 0.1 mmol) was added, and the mixture was again sparged with nitrogen. The solution was then heated to 75° C. under nitrogen for 2 h. Upon cooling down, a precipitate formed and was collected by filtration, washed with water and dried under vacuum to give the product (0.34 g) as an off-white solid. The aqueous phase was extracted with EtOAc (3×), and the combined organic extracts were washed with brine, dried, and concentrated. Purification by silica gel chromatography gave additional product (0.12 g) as a white solid. Total yield 78%. 1H NMR (400 MHz, DMSO-d6) δ 7.50 (dd, J=8.5, 1.4 Hz, 1H), 7.45 (s, 2H), 7.33 (dd, J=8.5, 7.2 Hz, 1H), 3.94 (s, 3H); 13C {1H} NMR (101 MHz, DMSO-d6) δ 152.97 (d, J=253.2 Hz), 145.73 (d, J=260.8 Hz), 143.82 (d, J=13.7 Hz), 141.83 (d, J=14.7 Hz), 138.45 (d, J=14.8 Hz), 133.93-132.79 (m), 128.93 (d, J=3.3 Hz), 127.74 (s), 126.37-125.10 (m), 122.08 (dd, J=13.6, 3.9 Hz), 119.34 (d, J=4.5 Hz), 114.99 (s), 61.61 (s); 19F NMR (376 MHz, DMSO-d6) δ −129.00 (dd, J=28.2, 7.0 Hz, 1F), −133.76 (d, J=28.2 Hz, 1F); ESIMS m/z 330.1 ([M+H]+).
Reaction SMILES: [N:1]1[C:14]2[CH:13]=[CH:12][C:11]3[C:6](=[CH:7]C=C[CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[O:15]=I(OI(=O)=O)=O.[C:22]([OH:25])(=O)[CH3:23]>>[N:1]1[C:14]2[C:5](=[C:6]3[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:23][C:22](=[O:25])[C:7]3=[O:15])[CH:4]=[CH:3][CH:2]=1
Reactant: [O-][I+2]([O-])O[I+2]([O-])[O-]
Reactant: CC(=O)O
Reactant: c1ccc2c(c1)ccc1ncccc12
Product: O=C1C=Cc2ccc3ncccc3c2C1=O

Procedure:
Following the procedure described in Example 608, Part A, 37.5 g (0.153 mole) of commercial 1-azaphenanthrene, 55 g (0.165 mole) of iodine pentoxide in 600 ml glacial acetic acid were refluxed 2 hours. Identical workup yielded 8.4 g, m.p. 215°-16°.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][C:5]=1[Cl:17].[Cl:18]OC(C)(C)C>ClCCl>[Br:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:6]([Cl:18])[C:5]=1[Cl:17].[Br:1][CH2:2][CH2:3][C:4]1[C:5]([Cl:17])=[CH:6][C:7]([NH:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:8]([Cl:18])[CH:9]=1
Reactant: CCOC(=O)CNc1ccc(CCBr)c(Cl)c1
Reactant: CC(C)(C)OCl
Solvent: ClCCl
Product: CCOC(=O)CNc1cc(Cl)c(CCBr)cc1Cl
Product: CCOC(=O)CNc1ccc(CCBr)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of ethyl N-[4-(2-bromoethyl)-3-chlorophenyl]aminoacetate (79 mg) in dichloromethane (2 ml) was added tert-butyl hypochlorite (31 μl) under ice-cooling, and the mixture was stirred for 6 hours at room temperature. The solvent was removed in vacuo, and purification of the residue by flash column chromatography on silica gel (eluent: hexane/ethyl acetate=15/1) gave ethyl N-[4-(2-bromoethyl) -2,3-dichlorophenyl]aminoacetate (31 mg) as a high-polar regioisomer and ethyl N-[4-(2-bromoethyl)-2,5-dichlorophenyl]aminoacetate (34 mg) as a low-polar regioisomer.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([OH:6])[CH2:3]1.C(N(CC)C(C)C)(C)C.[CH:16]1([S:19](Cl)(=[O:21])=[O:20])[CH2:18][CH2:17]1.O>O1CCCC1>[CH:16]1([S:19]([N:2]2[CH2:5][CH:4]([OH:6])[CH2:3]2)(=[O:21])=[O:20])[CH2:18][CH2:17]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: OC1CNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(C1CC1)N1CC(O)C1
Reaction time: 16 h

Procedure:
To a solution of azetidin-3-ol hydrochloride (1.00 g, 9.13 mmol) (purchased from Matrix) and N,N-diisopropylethylamine (4.77 mL, 27.4 mmol) in tetrahydrofuran (100 mL) at 0° C. was added cyclopropanesulfonyl chloride (0.930 mL, 9.13 mmol) and the reaction was stirred for 16 hours. Water was added and the product was extracted with ethyl acetate. The combined extracts were washed with 1N HCl, saturated sodium bicarbonate, and brine, dried over sodium sulfate, decanted and concentrated to afford a yellow oil used without further purification (1.04 g, 64%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[C:6]([C:8]([NH2:10])=O)[O:5][N:4]=1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:7]=[C:6]([C:8]#[N:10])[O:5][N:4]=1
Reactant: COc1cc(C(N)=O)on1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1cc(C#N)on1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 79.4 %

Procedure:
3-Methoxy-5-isoxazolecarboxamide (J. Chem Soc. 1968, 172) (1.0 g, 7.0 mmol) was dissolved in dichloromethane (20 mL), cooled to 0° C. then pyridine (1.1 mL, 14 mmol) and trifluoroacetic anhydride (1.0 mL, 7.4 mmol) were added and the reaction was stirred at 0° C. for 40 minutes. The mixture was diluted with dichloromethane (10 mL) and then washed with 5% aqueous citric acid solution (3×20 mL). The combined organic extracts were dried (Na2SO4), and the solvent was removed in vacuo to give the title compound as a yellow oil (0.69 g).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([Br:18])=[C:13]2[N:12]=[CH:11][C:10]=1[C:19]([OH:21])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:22][C:23]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([Br:18])=[C:13]2[N:12]=[CH:11][C:10]=1[C:19]([N:26]1[CH2:27][CH2:28][C:23]([F:22])([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:24][CH2:25]1)=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC1(c2ccccc2)CCNCC1
Reactant: O=C(O)c1cnc2c(Br)cnn2c1NCc1ccccc1
Product: O=C(c1cnc2c(Br)cnn2c1NCc1ccccc1)N1CCC(F)(c2ccccc2)CC1
Yield: 86.1 %

Procedure:
In the same manner as in Example 21, step 5 and using 7-benzylamino-3-bromopyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.500 g, 1.44 mmol) obtained in Example 22, step 3 and 4-fluoro-4-phenylpiperidine (WO2002/13824, 0.340 g, 1.73 mmol), the title compound (0.630 g, 86%) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[C:10]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][N:20]2[CH2:19][CH2:18][N:17]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:22][CH2:21]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: BrCc1cccc(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(Br)c2)CC1
Temperature: 25 °C
Yield: 89.7 %

Procedure:
A solution of 3-bromobenzyl bromide (6 g) and Boc-piperazine (4.06 g) in acetonitrile (30 mL) was treated with triethylamine (3.36 mL). The resulting mixture was heated at reflux for 16 hours. After cooling to room temperature, the reaction mixture was treated with saturated sodium bicarbonate solution (20 mL), and then extracted with ethyl acetate (2×30 mL). The organic phases were combined, dried (MgSO4) and concentrated under vacuum. The residue was purified by chromatography on silica (100 g) eluting with ethyl acetate/cyclohexane to give the title compound (6.95 g). LC/MS: m/z, 355, 357 (M+H), 2.40 min.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:17]1[C:18]([N:35]2[CH2:40][CH2:39][CH2:38][C@@H:37]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:36]2)=[C:19]2[C:25]([NH:26][C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=3)=[CH:24][NH:23][C:20]2=[N:21][CH:22]=1.CC#N.O>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>[C:27]([NH:26][C:25]1[C:19]2[C:20](=[N:21][CH:22]=[C:17]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:18]=2[N:35]2[CH2:40][CH2:39][CH2:38][C@@H:37]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:46])([CH3:45])[CH3:47])[CH2:36]2)[NH:23][CH:24]=1)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)c4cccnc4)c23)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(-c3ccccc3)cnc3[nH]cc(NC(=O)c4cccnc4)c23)C1
Temperature: 150 °C
Yield: 60.3 %

Procedure:
Phenylboronic acid (28.4 mg, 0.233 mmol), PS-palladium tetrakis (88.2 mg, 0.00970 mmol, 0.10 mmol/1 g) and 2N sodium carbonate (194 μL, 0.388 mmol) were added to (R)-tert-butyl 1-(5-bromo-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (100 mg, 0.194 mmol; Example 1A, Step 1) in degassed dioxane (1 mL). The reaction was heated to 150° C. for 1 hour under microwave irradiation. Phenylboronic acid (28.4 mg, 0.233 mmol) and 2N sodium carbonate (194 μL, 0.388 mmol) were added, and the reaction was heated to 150° C. for an additional 2 hours under microwave irradiation and then cooled down and filtered. The filtrate was diluted with DCM, dried with MgSO4, filtered, and concentrated. The resulting residue was purified by reverse phase chromatography (Biotage Horizon, C-18 25M+, 10-90% CH3CN/water) to yield (R)-tert-butyl 1-(3-(nicotinamido)-5-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (60 mg, 60% yield) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17](=O)[NH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:19]([O:21][CH3:22])=[O:20])[CH:14]=3)[NH:9]2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:25].CN(C)C1C=CC=CC=1>>[Cl:25][C:17]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[N:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:19]([O:21][CH3:22])=[O:20])=[CH:12][CH:11]=2
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc2c(c1)NC(=O)C(c1ccc(F)cc1)N2
Solvent: CN(C)c1ccccc1
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask, was placed methyl 2-(4-fluorophenyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (1.2 g, 4.00 mmol, 1.00 equiv), POCl3 (12.2 g, 80.26 mmol, 20.00 equiv), N,N-dimethylbenzenamine (4.9 g, 40.50 mmol, 10.00 equiv). The resulting solution was stirred for overnight at 110° C. in an oil bath. The resulting mixture was concentrated under vacuum and diluted with 50 mL of water. The pH value of the aqueous solution was adjusted to 7 with sodium bicarbonate (4 mol/L). The resulting mixture was concentrated under vacuum and purified by silica gel chromatography with ethyl acetate/petroleum ether (1:40).
Reaction SMILES: O.[NH2:2][C:3]1[N:8]=[C:7](Cl)[CH:6]=[C:5]([OH:10])[N:4]=1.[CH:11]1([NH2:14])[CH2:13][CH2:12]1>C(O)C>[NH2:2][C:3]1[N:8]=[C:7]([NH:14][CH:11]2[CH2:13][CH2:12]2)[CH:6]=[C:5]([OH:10])[N:4]=1
Reactant: NC1CC1
Reactant: Nc1nc(O)cc(Cl)n1
Solvent: O
Solvent: CCO
Product: Nc1nc(O)cc(NC2CC2)n1

Procedure:
2-Amino-4-chloro-6-hydroxypyrimidine monohydrate (5.0 g) was refluxed in ethanol (150 mL) with cyclopropylamine for 12 h. The mixture was evaporated in vacuo, codistilled with ethanol (3×50 mL), adsorbed from methanol on silica gel and applied on a column of silica gel (200 mL) in chloroform. Elution with chloroform-ethanol gradient afforded crystalline product which was filtered from ether and dried in vacuo to afford 2-amino-4-cyclopropylamino-6-hydroxypyrimidine, m.p.229° C. Yield, 3.0 g. For C7H10N4O (166.18) calculated 50.59% C, 6.07% H, 33.71% N; found 50.49% C, 6.25% H, 33.61% N. 1H NMR (DMSO): 9.73 brs, 1H (OH); 6.55 bs, 2H (NH); 6.08 brs, 2H (NH2); 4.66 s, 1H (H-5); 2.30 m, 1H and 0.62 m, 2H and 0.40, m, 2H (C—CH2, N—CH).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:27]=[C:26]([C:28]([CH3:31])([CH3:30])[CH3:29])[Se:25][C:24]=1[C:32]([NH2:34])=[O:33].CN(C=O)C.[OH-].[Na+]>>[CH3:16][O:15][CH2:14][CH2:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:17][CH2:18][CH2:19][O:20][CH3:21])[N:5]=[CH:4][N:3]=[C:2]2[NH:22][C:23]1[CH:27]=[C:26]([C:28]([CH3:31])([CH3:29])[CH3:30])[Se:25][C:24]=1[C:32]([NH2:34])=[O:33]
Reactant: CC(C)(C)c1cc(N)c(C(N)=O)[se]1
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OCCOC
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COCCOc1cc2ncnc(Nc3cc(C(C)(C)C)[se]c3C(N)=O)c2cc1OCCOC

Procedure:
The reaction of 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline with 3-amino-5-tert-butylselenophene-2-carboxamide in the presence of DMF/NaOH as described in Example 1 gave title compound as a pale yellow color solid, mp 198-204° C. IR (KBr) vmax 3430, 3162, 2961, 1627, 1576, 1474, 1463, 1386, 1321, 1242, 1131, 1092, 937, 859 cm−1; 1H NMR (400 MHz, CDCl3): δ 12.63 (1H, s, exchangeable with D2O), 8.67 (1H, s), 8.64 (1H, s), 7.66 (2H, br s, exchangeable with D2O), 7.40 (1H, s), 7.28 (1H, s), 4.25-4.33 (4H, m), 3.75-3.80 (4H, m), 3.37 (3H, s), 3.36 (3H, s), 1.41 (9H, s); 13C NMR (100 MHz, CDCl3): δ 168.2, 167.4, 153.9, 153.8, 153.0, 148.6, 147.0, 146.0, 120.8, 112.1, 108.7, 108.6, 101.5, 70.0 (2C), 68.2, 68.0, 58.4, 58.3, 36.5, 32.2; LC-MS (positive ion mode): m/z 521, 523 (M+H)+.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([N:16]2[CH:20]=[C:19]([C:21]([OH:23])=O)[CH:18]=[N:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:46][CH2:47][C:48]([N:50]1[CH2:55][CH2:54][CH:53]([O:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=2[Cl:63])[CH2:52][CH2:51]1)=[O:49]>CN(C=O)C.O>[Cl:63][C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][C:57]=1[O:56][CH:53]1[CH2:52][CH2:51][N:50]([C:48](=[O:49])[CH2:47][NH:46][C:21]([C:19]2[CH:18]=[N:17][N:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:20]=2)=[O:23])[CH2:55][CH2:54]1
Reactant: O=C(O)c1cnn(-c2ccccc2)c1
Reactant: NCC(=O)N1CCC(Oc2ccccc2Cl)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCC(Oc2ccccc2Cl)CC1)c1cnn(-c2ccccc2)c1
Reaction time: 0.03 h
Yield: 46.9 %

Procedure:
DIPEA (223 mg, 0.3 mL, 1.72 mmol) was added to a stirred solution of 1-phenyl-1H-pyrazole-4-carboxylic acid (65 mg, 0.34 mmol) in DMF (5 mL) followed by HOBt (51 mg, 0.38 mmol) and EDCI (165 mg, 0.86 mmol). After 2 minutes of stirring, 2-amino-1-[4-(2-chloro-phenoxy)-piperidin-1-yl]-ethanone hydrochloride salt (116 mg, 0.38 mmol) (prepared according to Step 1 and 5 of the General Scheme) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (using 60-120 silica gel and 70% EtOAc in hexane as eluent) to afford 70 mg (46.35% yield) of 1-phenyl-1H-pyrazole-4-carboxylic acid {2-[4-(2-chloro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 439.15, 95.23%. 1H NMR (300 MHz, CDCl3): δ 8.4 (s, 1H), 8.06 (s, 1H), 7.76 (d, 2H), 7.54 (t, 2H), 7.42 (m, 2H), 7.2 (d, 1H), 7.1 (t, 1H), 7.0 (t, 2H), 4.7 (t, 1H), 4.4-4.2 (m, 2H), 4.1 (m, 1H), 3.8-3.5 (m, 2H), δ 3.5 (m, 1H), 2.1-1.8 (m, 4H).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].[F:45][C:46]1[CH:47]=[C:48]([CH:52]=[CH:53][CH:54]=1)[C:49](O)=[O:50]>CN(C=O)C.O>[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([C:49](=[O:50])[C:48]2[CH:52]=[CH:53][CH:54]=[C:46]([F:45])[CH:47]=2)[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1cccc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc(F)c2)CC1
Reaction time: 8 h
Yield: 107.5 %

Procedure:
HOBt (290 mg, 2.14 mmol), DIEA (461 mg, 3.5 mmol), EDCI.HCl (410 mg, 2.14 mmol) followed by piperazine-1-carboxylic acid tert-butyl ester (398 mg, 2.14 mmol) were added to a stirred solution of 3-fluorobenzoic acid (250 mg, 1.78 mmol) in DMF (3 mL). The reaction mixture was stirred overnight and then diluted with cold water. The product was extracted with ethyl acetate and the organic layer was washed with brine solution, dried over Na2SO4, and concentrated under reduced pressure to afford 590 mg (92%) of 4-(3-fluoro-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester.