Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:33][C:34]4[CH:43]=[C:42]5[C:37]([CH:38]=[CH:39][N:40]=[CH:41]5)=[CH:36][CH:35]=4)=[N:18][CH:19]=[C:20]([CH2:22][N:23]4[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24]4)[CH:21]=3)[N:10]=2)=CC=1.S(O)(C(F)(F)F)(=O)=O.FC(C(O)=O)(F)F>>[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[C:17]([NH:33][C:34]3[CH:43]=[C:42]4[C:37]([CH:38]=[CH:39][N:40]=[CH:41]4)=[CH:36][CH:35]=3)=[N:18][CH:19]=[C:20]([CH2:22][N:23]3[CH2:24][CH2:25][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:27][CH2:28]3)[CH:21]=2)[N:10]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3Nc3ccc4ccncc4c3)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(N)nc(-c2cc(CN3CCN(S(C)(=O)=O)CC3)cnc2Nc2ccc3ccncc3c2)n1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
To a 25 mL, round-bottomed flask was added N-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-yl)isoquinolin-7-amine (150 mg, 0.201 mmol) and 5% TfOH-TFA (5 mL). The reaction mixture was stirred at 70° C. for 30 minutes and cooled to room temperature.After removal of TFA in high vacuum, the residue was treated with saturated NaHCO3, the obtained suspension was filtered to provide the crude product as a yellow solid. After air drying, the solid was treated with MeOH-DCM-ether and filtered to provide N-(3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-yl)isoquinolin-7-amine (100 mg, 98% yield) as a yellow solid. m/z (ESI positive ion): 506 (M+H)+. 1H NMR (400 MHz, DMSO-d6): δ ppm 2.88 (s, 3H) 3.09-3.16 (m, 4H) 3.29-3.36 (m, 7H) 3.56 (s, 2H) 7.74 (d, J=5.67 Hz, 1H) 7.83 (br s, 1H) 7.93 (d, J=8.80 Hz, 2H) 8.07 (dd, J=8.90, 2.05 Hz, 1H) 8.36 (d, J=5.67 Hz, 1H) 8.40 (d, J=2.15 Hz, 1H) 8.79 (d, J=2.35 Hz, 1H) 8.87 (d, J=1.56 Hz, 1H) 9.21 (s, 1H) 12.42 (s, 1H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].OS(O)(=O)=O.[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([NH2:19])[CH3:18])=[CH:13][CH:12]=1.[OH-].[Na+]>>[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([NH2:19])[CH3:18])=[CH:13][C:12]=1[N+:1]([O-:4])=[O:2]
Reactant: CC(N)c1ccc(F)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(N)c1ccc(F)c([N+](=O)[O-])c1
Yield: 98 %

Procedure:
Fuming HNO3 (0.48 ml, 10.8 mmol) was added carefully to ice bath cooled concentrated H2SO4 (3.6 ml, 68.2 mmol). To the mixture was added 1-(4-fluorophenyl)ethanamine (1.0 g, 7.2 mmol) dropwise. The reaction mixture was stirred with cooling for 50 minutes. The reaction mixture was poured into ice and basified with 3M NaOH solution (24 ml, 72.00 mmol) to about pH8.0. The alkaline solution was extracted with DCM twice. The combined organic layer was dried over Na2SO4 and evaporated to afford title compound (1.3 g, yield: 96%). 1H-NMR (400 MHz, CDCl3) δ 1.41 (d, 6H) 4.25 (q, 1H) 7.21-7.26 (m, 1H) 7.67 (ddd, 1H) 8.10 (dd, 1H)
Reaction SMILES: [SH:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10](=[O:18])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl[CH2:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[N:23]([CH3:25])[CH3:24]>>[CH3:24][N:23]([CH3:25])[C:22]1[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=1[CH2:20][S:1][C:2]1[N:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:10](=[O:18])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CN(C)c1ccccc1CCl
Reactant: O=c1c2ccccc2nc(S)n1-c1ccccc1
Product: CN(C)c1ccccc1CSc1nc2ccccc2c(=O)n1-c1ccccc1
Yield: 26.9 %

Procedure:
The title compound was prepared in a yield of 26.9%, using 2-mercapto-3-phenyl-4(3H)-quinazolinone in place of 3- isobutyl-2-mercapto-4(3H)-quinazolinone and 2-chloromethyl-N,N-dimethylaniline in place of 2-choromethylpyridine hydrochloride.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(=O)([O-])O.[Na+].C1(C)C=CC=CC=1.[C:25]([NH:33][CH:34]1[CH:43]=[CH:42][CH:41]=[CH:40][C:35]1(Br)[C:36]([O:38]C)=[O:37])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>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.O.C(O)C>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:42]2[CH:41]=[CH:40][C:35]([C:36]([OH:38])=[O:37])=[C:34]([NH:33][C:25](=[O:32])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:43]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)C1(Br)C=CC=CC1NC(=O)c1ccccc1
Reactant: CC(=O)c1ccc(B(O)O)cc1
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: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CC(=O)c1ccc(-c2ccc(C(=O)O)c(NC(=O)c3ccccc3)c2)cc1
Temperature: 160 °C
Reaction time: 0.08 h

Procedure:
51 mg of 4-acetylphenylboronic acid, 61 mg of sodium hydrogen carbonate and 12 mg of tetrakis(triphenylphosphine)palladium(0) were added to a mixed solution of 2.0 mL of toluene, 0.6 mL of ethanol and 0.4 mL of water containing 70 mg of methyl 2-(benzamido)-1-bromobenzoate, and stirred under pressure at 160° C. for 5 minutes. After the reaction mixture was cooled to room temperature, insoluble were removed by filtration, ethyl acetate and 0.5 mol/L hydrochloric acid were added and a solid substance was separated by filtration. The obtained solid substance was added to a mixed solution of 1.0 mL of 2.0 mol/L aqueous sodium hydroxide and 5.0 mL of ethanol and stirred at room temperature for 1 hour and 30 minutes. 0.6 mol/L hydrochloric acid and ethyl acetate were added to the reaction mixture. The organic layer was separated, and the solvent was evaporated under reduced pressure to obtain 50 mg of 4-(4-acetylphenyl)-2-(benzamido)benzoic acid as white solid.
Reaction SMILES: C(N=C=O)(=O)C1C=CC=CC=1.NC1ON=C(C)N=1.NC1SC(SCC2C3C(=CC=CC=3)C=CC=2)=NN=1.[N+](C1C=CC(C2ON=C(C(F)(F)F)N=2)=CC=1)([O-])=O.NC1C=CC=CC=1.[Cl:62][C:63]1[C:72]2[C:67](=[CH:68][CH:69]=[CH:70][CH:71]=2)[C:66]([N+:73]([O-])=O)=[CH:65][CH:64]=1>>[NH2:73][C:66]1[C:67]2[C:72](=[CH:71][CH:70]=[CH:69][CH:68]=2)[C:63]([Cl:62])=[CH:64][CH:65]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c2ccccc12
Agent: Cc1noc(N)n1
Agent: Nc1nnc(SCc2cccc3ccccc23)s1
Agent: O=C=NC(=O)c1ccccc1
Solvent: Nc1ccccc1
Product: Nc1ccc(Cl)c2ccccc12

Procedure:
The following intermediate anilines and aromatic amines were prepared in a manner similar to that described in the indicated publication. and were then reacted with the appropriate benzoyl isocyanate according to the procedure employed in Example II above: 5-amino-3-methyl-1,2,4-oxadiazole described in U.S. Pat. No. 3,917,478 (Compound 82); 2-amino-5-(l-naphthyl) methylthio-1,3,4-thiadiazole described in German Patent 1,079.060 (Compound 38); 5-(4-nitrophenyl)-3-trifluoromethyl-1,2,4-oxadiazole described in U.S. Pat. No. 3,917,478 (Compound 50) in which the reduction conditions of Example I, Part B above were used to prepare the corresponding aniline; 1-chloro-4-nitronaphthalene described in Bassilios, Bull. Soc. Chim. Fr., 1951, 651 in which catalytic reduction (Example I. Part B above) afforded 1-amino-4-chloronaphthalene (Compound 40); l-chloro-4-nitronaphthalene was converted into l-amino-4-(2,4-dimethylphenoxy) naphthalene according to U.S. patent application Ser. No. 495,331, filed May 20, 1983 (Compound 42); 9-nitroanthracene was reduced using the procedure described in Example I. Part B above (Compound 44); l-amino-4-chloro-5,6,7,8-tetrahydronaphthalene described in Press and Hoffman, Org. Prep. Proc. Int., 1982. 14,204 and Simonetta Beltrane. Gazz. Chim. Ital., 1958, 88,769 (Compound 70); 3,5-dichloro-4-[4-chloro-l-naphthoxy)butoxy] aniline and 4-[l-(l-naphthyl)ethoxy] aniline described in U.S. patent application Ser. No. 430,368, filed Sep. 30, 1982 (Compounds 66 and 81); 1,1-bis-(4-chlorophenyl)methylamine and alpha-methyl-4-chlorobenzylamine described in Cram and Guthrie, J. Am. Chem. Soc., 1966, 88, 5760 (Compounds 83 and 84): and alpha-amino-4-chlorophenylacetonitrile described in Stevens et al., J. Chem. Soc., 1931, 2568 (Compound 86). Compounds 51 and 52 were prepared from commercially available anilines or amines according to the procedure employed in Example II above.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[CH2:9]1.[Br:25][C:26]1[N:31]=[C:30]([C:32](O)=[O:33])[CH:29]=[CH:28][C:27]=1[F:35]>CCOC(C)=O>[Br:25][C:26]1[N:31]=[C:30]([C:32]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C@@H:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([N:14]3[C:15](=[O:24])[C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:22]3=[O:23])[CH2:9]2)=[O:33])[CH:29]=[CH:28][C:27]=1[F:35]
Reactant: Nc1cnccc1C1CCCC(N2C(=O)c3ccccc3C2=O)C1
Reactant: O=C(O)c1ccc(F)c(Br)n1
Solvent: CCOC(C)=O
Product: O=C(Nc1cnccc1[C@@H]1CCC[C@H](N2C(=O)c3ccccc3C2=O)C1)c1ccc(F)c(Br)n1

Procedure:
Following Method 9, 2-(3-(3-aminopyridin-4-yl)cyclohexyl)isoindoline-1,3-dione and 6-bromo-5-fluoropicolinic acid were coupled and following addition of EtOAc and washing with H2O, NaCl(sat.) and drying over MgSO4, 6-bromo-N-(4-((1R,3S)-3-(1,3-dioxoisoindolin-2-yl)cyclohexyl)pyridin-3-yl)-5-fluoropicolinamide was obtained. LCMS (m/z): 523.2/525.2 (MH+); LC Rt=3.31 min.
Reaction SMILES: O1CCCC1.C(N(CC)CC)C.C1(=O)OC(=O)CC1.Cl.C[O:22][C:23](=[O:45])[C@H:24]([CH2:26][C:27]1[CH:34]=[C:32]([I:33])[C:31]([O:35][C:36]2[CH:43]=[C:41]([I:42])[C:40]([OH:44])=[C:38]([I:39])[CH:37]=2)=[C:29]([I:30])[CH:28]=1)[NH2:25]>>[NH2:25][C@H:24]([C:23]([OH:45])=[O:22])[CH2:26][C:27]1[CH:28]=[C:29]([I:30])[C:31]([O:35][C:36]2[CH:37]=[C:38]([I:39])[C:40]([OH:44])=[C:41]([I:42])[CH:43]=2)=[C:32]([I:33])[CH:34]=1
Reactant: COC(=O)[C@@H](N)Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1
Agent: Cl
Agent: O=C1CCC(=O)O1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N[C@@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(=O)O
Temperature: 4 °C
Reaction time: 8 h

Procedure:
In 150 ml of dried tetrahydrofuran 1.65 g (0.002 mol) of thyroxine methyl ester hydrochloride was dissolved. To the resulting solution 300 μl (0.0021 mol) of triethyl amine and 200 mg. (0.0022 mol) of succinic anhydride were added. The mixture was stirred at 4° C. overnight to effect reaction.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:18]([NH:26][C:27]1[CH:39]=[C:38](Br)[CH:37]=[CH:36][C:28]=1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:18]([NH:26][C:27]1[CH:39]=[C:38]([O:9][C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=2)[CH:37]=[CH:36][C:28]=1[C:29]([O:31][C:32]([CH3:34])([CH3:35])[CH3:33])=[O:30])(=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Oc1cc(F)cc(F)c1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1NC(=O)c1ccccc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(Oc2cc(F)cc(F)c2)cc1NC(=O)c1ccccc1
Temperature: 25 °C
Yield: 89.7 %

Procedure:
29 mg of 3,5-difluorophenol, 79 mg of tripotassium phosphate, 4.7 mg of 2-(di-tert-butylphosphino)-2′, 4′, 6′-triisopropylbiphenyl and 6.8 mg of tris(dibenzylideneacetone)dipalladium(0) were added to 1.4 mL of toluene solution containing 70 mg of tert-butyl 2-(benzamido)-4-bromobenzoate at room temperature, and the resulting mixture was heated to reflux under nitrogen atmosphere for 3 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% citric acid aqueous solution were added and insoluble were removed by filtration. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [PSQ100B (spherical) manufactured by Fuji Silysia Chemical Ltd, eluent; hexane:ethyl acetate=10:1] to obtain 71 mg of tert-butyl 2-(benzamido)-4-(3,5-difluorophenoxy)benzoate as colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12]([CH:15]=O)=[C:11]([CH3:17])[NH:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].Cl.[NH2:19][C:20]1[C:21]([OH:35])=[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([OH:34])=[O:33])[CH:27]=2)[CH:23]=[CH:24][CH:25]=1.C([O-])(=O)C.[Na+].Cl>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[CH:15][NH:19][C:20]3[C:21]([OH:35])=[C:22]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([OH:34])=[O:33])[CH:27]=4)[CH:23]=[CH:24][CH:25]=3)[C:11]([CH3:17])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Nc1cccc(-c2cccc(C(=O)O)c2)c1O
Reactant: Cc1ccc(-n2[nH]c(C)c(C=O)c2=O)cc1C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC1=NN(c2ccc(C)c(C)c2)C(=O)C1=CNc1cccc(-c2cccc(C(=O)O)c2)c1O
Reaction time: 1 h
Yield: 75.5 %

Procedure:
A solution of 1-(3,4-dimethylphenyl)-3-methyl-5-oxo-3-pyrazolin-4-carbaldehyde (10 mg, 0.043 mmol) and 3′-amino-2′-hydroxybiphenyl-3-carboxylic acid hydrochloride (11 mg, 0.042 mmol) in ethanol (1 mL) was shaken with 0.2M aq. sodium acetate (0.25 mL, 0.05 mmol) for 1 h. 0.06M aq. hydrochloric acid (3 mL) was added and shaking continued for 1 h. The solid was filtered, washed with water and dried under reduced pressure to afford the title compound (14 mg, 74%) as a cream-coloured powder. 1H NMR (300 MHz, d6-DMSO) δ 13.08 (br s, 1H), 11.79 (d, J=13.8 Hz, 1H), 9.56 (s, 1H), 8.71 (d, J=13.2 Hz, 1H), 8.14 (s, 1H), 7.97 (d, J=7.8 Hz, 1H), 7.83-7.80 (m, 3H), 7.71 (d, J=8.2 Hz, 1H), 7.62 (t, J=7.8 Hz, 1H), 7.16-7.11 (m, 3H), 2.31 (s, 3H), 2.26 (s,3H), 2.22 (s, 3H).
Reaction SMILES: C(O[C:4](=[O:13])[C:5]1[CH:10]=[C:9]([NH2:11])[N:8]=[C:7]([NH2:12])[CH:6]=1)C.[CH3:14][NH2:15]>CO>[NH2:11][C:9]1[CH:10]=[C:5]([CH:6]=[C:7]([NH2:12])[N:8]=1)[C:4]([NH:15][CH3:14])=[O:13]
Reactant: CN
Reactant: CCOC(=O)c1cc(N)nc(N)c1
Solvent: CO
Product: CNC(=O)c1cc(N)nc(N)c1
Temperature: 70 °C
Reaction time: 24 h

Procedure:
A mixture of 0.270 g 2,6-diaminoisonicotinic acid ethyl ester and 5 ml of a 2M solution of methylamine in methanol was stirred at 70° C. for 24 h. The solvent were evaporated and the residue was triturated with ethyl acetate to yield 0.214 g of the title compound as light brown solid. MS (ISP) M+H+=167.4
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:9]2)=[N:4][CH:3]=1.[NH2:18][C:19]1[O:20][C:21]2[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][C:22]=2[N:23]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[O:15]1[CH2:16][CH2:17][N:12]([C:8]2[N:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[N:4]=[CH:3][C:2]([C:25]2[CH:26]=[CH:27][C:21]4[O:20][C:19]([NH2:18])=[N:23][C:22]=4[CH:24]=2)=[CH:11]3)[CH2:13][CH2:14]1
Reactant: Nc1nc2cc(B(O)O)ccc2o1
Reactant: Brc1cnc2ccc(N3CCOCC3)nc2c1
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: C1COCCO1
Solvent: O
Product: Nc1nc2cc(-c3cnc4ccc(N5CCOCC5)nc4c3)ccc2o1
Yield: 67.2 %

Procedure:
A mixture of 7-bromo-2-morpholino-1,5-naphthyridine (F-32) (180 mg, 0.6 mmol, 1.0 eq), 2-aminobenzo[d]oxazol-5-ylboronic acid (131 mg, 0.73 mmol, 1.2 eq), Pd(PPh3)4 (71 mg, 0.06 mmol, 0.1 eq), and Na2CO3 (195 mg, 1.8 mmol, 3.0 eq) were dissolved in a mixture of 1,4-dioxane (10 mL) and water (10 mL). The resulting mixture was degassed and back-filled with argon three times and heated at reflux under an argon atmosphere for 2 h. The reaction was complete based on TLC analysis. The mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (3-5% MeOH-DCM) to afford 5-(6-morpholino-1,5-naphthyridin-3-yl)benzo[d]oxazol-2-amine (73) (140 mg, 67.2% yield). 1H NMR (400 MHz, DMSO-d6) δ: 8.93 (s, 1H), 8.10 (m, 2H), 7.66 (s, 1H), 7.53 (s, 2H), 7.45 (m, 3H), 3.74 (m, 8H); ESI-MS m/z: 348.11 [M+H]1.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[O:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:28][O:29][C:30]1[CH:31]=[N:32][CH:33]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:35]=1>>[CH3:28][O:29][C:30]1[CH:35]=[C:34]([C:2]2[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]3[O:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)[CH:33]=[N:32][CH:31]=1
Reactant: COc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3o2)CC1
Product: COc1cncc(-c2nc(N3CCOCC3)c3oc(CN4CCN(S(C)(=O)=O)CC4)cc3n2)c1

Procedure:
2-Chloro-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinofuro[3,2-d]pyrimidine (Example 153) was reacted with 3-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine via General Procedure E to give, after purification by reverse HPLC, 29 mg of 239. MS (Q1) 489 (M+).
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:18]2[CH:22]=[C:21]([C:23]3[C:24]4[CH:31]=[CH:30][N:29](COCC[Si](C)(C)C)[C:25]=4[N:26]=[CH:27][N:28]=3)[CH:20]=[N:19]2)[CH2:7][N:6]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][C:9]=2[F:17])[CH2:5]1)#[N:2].Cl.[F:41][C:42]([F:47])([F:46])[C@H:43]([NH2:45])[CH3:44]>>[C:1]([CH2:3][C:4]1([N:18]2[CH:22]=[C:21]([C:23]3[C:24]4[CH:31]=[CH:30][NH:29][C:25]=4[N:26]=[CH:27][N:28]=3)[CH:20]=[N:19]2)[CH2:7][N:6]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH:45][C@H:43]([CH3:44])[C:42]([F:47])([F:46])[F:41])=[O:14])=[CH:10][C:9]=2[F:17])[CH2:5]1)#[N:2]
Reactant: C[C@@H](N)C(F)(F)F
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(c5ccc(C(=O)O)cc5F)C4)c3)ncnc21
Agent: Cl
Product: C[C@@H](NC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ncnc5[nH]ccc45)cn3)C2)c(F)c1)C(F)(F)F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 5, Step 3 starting from 4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-3-fluorobenzoic acid and (2R)-1,1,1-trifluoropropan-2-amine hydrochloride. LCMS (M+H)+: m/z=513.2. 1H NMR (400 MHz, DMSO-d6): δ 12.66 (br, 1H), 9.11 (s, 1H), 8.86 (s, 1H), 8.64 (d, J=8.9 Hz, 1H), 8.58 (s, 1H), 7.80 (br, 1H), 7.71 (s, 1H), 7.69 (dd, J=4.0, 1.6 Hz, 1H), 7.26 (br, 1H), 6.78 (t, J=8.7 Hz, 1H), 4.89-4.78 (m, 1H), 4.71 (d, J=7.7 Hz, 2H), 4.45 (dd, J=9.4, 1.8 Hz, 2H), 3.78 (s, 2H), 1.35 (d, J=7.0 Hz, 3H).
Reaction SMILES: [CH2:1]([CH:3]1[C:8]([C:9]2[CH:24]=[CH:23][C:12]3[N:13]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=4)[O:15][C:11]=3[CH:10]=2)=[N:7][NH:6][C:5](=[O:25])[CH2:4]1)[CH3:2].[CH2:26]([N:28]([CH:32]([CH3:34])[CH3:33])[CH2:29][CH2:30]O)[CH3:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1>CC(=O)OCC.C1COCC1>[CH2:1]([CH:3]1[C:8]([C:9]2[CH:24]=[CH:23][C:12]3[N:13]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH2:27][CH2:26][N:28]([CH2:29][CH3:30])[CH:32]([CH3:34])[CH3:33])=[CH:18][CH:17]=4)[O:15][C:11]=3[CH:10]=2)=[N:7][NH:6][C:5](=[O:25])[CH2:4]1)[CH3:2]
Reactant: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(O)cc3)oc2c1
Reactant: CCN(CCO)C(C)C
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(OCCN(CC)C(C)C)cc3)oc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
40 mg (119 μmol) 5-ethyl-6-[2-(4-hydroxy-phenyl)-benzoxazol-6-yl]-4,5-dihydro-2H-pyridazin-3-one, 31 mg (238 μmol) 2-(ethyl-isopropyl-amino)-ethanol, 66 mg (251 μmol) triphenylphosphine and 5 ml THF are placed under protective gas. At 0° C., 58 mg (251 μmol) of DBAD are added and then the mixture is stirred overnight at RT. Then it is diluted with EA and extracted with 10% sodium carbonate solution. The organic phase is stirred with 15 mL of 4N HCl for 5 min and then extracted twice with diethyl ether. The acid H2O phase is made basic with sodium carbonate solution and extracted 3 times with DCM. The organic phase is washed with saturated saline solution and then the solv. is eliminated i.V. The residue is recrystallised with cyclohexane/EA.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.Br[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH2:21][CH2:22][CH2:23][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)(=[O:20])=[O:19])=[CH:14][CH:13]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:24]1([CH2:23][CH2:22][CH2:21][S:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:1][C:2]3[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][N:3]=3)=[CH:13][CH:14]=2)(=[O:19])=[O:20])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Nc1ncc([N+](=O)[O-])cn1
Reactant: O=S(=O)(CCCN1CCCC1)c1ccc(Br)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Nc1cnc(Nc2ccc(S(=O)(=O)CCCN3CCCC3)cc2)nc1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of 2-amino-5-nitropyrimidine (840 mg, 6.0 mmol) in 50 mL anhydrous 1,4-dioxane were added 1-[3-(4-bromo-benzenesulfonyl)-propyl]-pyrrolidine (2.9 g, 8.7 mmol), Xantphos, (690 mg, 1.2 mmol), Pd2(dba)3 (559 mg, 0.61 mmol) and Cs2CO3 (5.8 g, 18 mmol). The reaction mixture was stirred at 100° C. for 5 h under argon. The solvent was removed under reduced pressure. The resulting solution was extracted with CHCl3 (3×50 mL) and sat. NaHCO3 (50 mL). The organic layer was separated, washed with brine, dried over Na2SO4 and filtered. The organic solvent was removed and the crude product was purified by silica gel column with 20% CH3OH/CHCl3 as an eluent. The precipitated yellow solid was isolated by washed with acetone and dried in vacuo (1.2 g, 52%). The above product was hydrogenated in 100 mL methanol/ethyl acetate (v/v: 1:1) using Pd/C (10%, 1 g) for 2 h. The palladium catalyst was removed by filtration, and the solvent was evaporated. The pale yellow solid was isolated by washed with acetone/methanol (v/v 5:1) and dried in vacuo (550 mg, 49%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[S:5][C:6]=1[Cl:7].[CH3:12][N:13]1[C:17](B2OC(C)(C)C(C)(C)O2)=[C:16]([CH3:27])[CH:15]=[N:14]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:7][C:6]1[S:5][C:4]([C:8]([O:10][CH3:11])=[O:9])=[CH:3][C:2]=1[C:17]1[N:13]([CH3:12])[N:14]=[CH:15][C:16]=1[CH3:27]
Reactant: COC(=O)c1cc(Br)c(Cl)s1
Reactant: Cc1cnn(C)c1B1OC(C)(C)C(C)(C)O1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(-c2c(C)cnn2C)c(Cl)s1
Temperature: 85 °C
Yield: 24.4 %

Procedure:
To a 350 mL sealed flask reactor was added methyl 4-bromo-5-chloro-2-thiophenecarboxylate (409 mg, 1.60 mmol) [prepared according to the procedure of Example 95], 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (388 mg, 1.75 mmol) [prepared according to the procedure of Preparation 17], K2CO3 (676 mg, 4.89 mmol) and Pd(PtBu3)2 (32 mg, 0.06 mmol) in 1,4-Dioxane (6 mL) and water (1.5 mL). The reaction was heated at 85° C. for 3 hours. The reaction was partitioned between CHCl3/H2O and the pH of the aqueous layer was adjusted to ˜3 with 6N HCl. The separated organic layer was dried with Na2SO4, adsorbed onto silica and purified via column chromatography (10-65% EtOAc/Hexanes) affording the title compound (106 mg, 0.39 mmol, %); LC-MS (ES) m/z=271 (M+H)+.