Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[NH2:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH2:27][N:26]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:25][CH2:24]2>CC#N>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([NH:20][C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH2:27][N:26]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:25][CH2:24]3)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)ccc2C1
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CC#N
Product: CCCCN1C(=O)C(Nc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)C3)=C(c2ccccc2)S1(=O)=O
Temperature: 160 °C

Procedure:
A mixture of 2-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (1.000 g, 3.336 mmol), tert-butyl 6-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.828 g, 3.336 mmol) and TEA (0.460 ml, 3.33 gmmol) in dry MeCN (5 ml) was heated in a microwave reactor at 120° C. for 35 mins, 140° C. for 20 mins and 160° C. for 45 mins.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][NH:6][C:5]2=O.C1(P(Cl)([Cl:21])=O)C=CC=CC=1.C(OC(C)C)(C)C>>[Cl:21][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([I:1])[CH:3]=2)[N:8]=[CH:7][N:6]=1
Reactant: O=P(Cl)(Cl)c1ccccc1
Reactant: O=c1[nH]cnc2ccc(I)cc12
Solvent: CC(C)OC(C)C
Product: Clc1ncnc2ccc(I)cc12
Temperature: 150 °C

Procedure:
A mixture of 6-iodoquinazolin-4(3H)-one (Intermediate 11, 100 mg, 0.37 mmol) and phenylphosphonic dichloride (1.5 mL) was heated at 150° C. for one h. After cooling the reaction mixture in an ice bath, isopropyl ether was added. The resultant crystalline precipitate was collected by filtration, and was then stirred with saturated aqueous sodium bicarbonate solution. The solution was extracted with three portions of ethyl acetate, and the combined extracts were dried (magnesium sulfate) and concentrated under reduced pressure to give the crude product. Purification by preparative thin layer chromatography (silica gel, 5% and 10% ethyl acetate/hexanes) afforded the desired product. LC/MS 291 (M+1).
Reaction SMILES: [CH:1]([C:3]1[O:7][CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=1)=[O:2].P(OCC)(OCC)(O[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O.ClC1C=CC(CC2C=C(C=O)SC=2)=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CC#N.C(O)(C)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:20]([C:5]1[CH:4]=[C:3]([CH:1]=[O:2])[O:7][CH:6]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOP(=O)(OCC)OCc1ccccc1
Reactant: CC1(C)OB(c2coc(C=O)c2)OC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=Cc1cc(Cc2ccc(Cl)cc2)cs1
Solvent: CC(C)O
Solvent: CC#N
Product: O=Cc1cc(Cc2ccccc2)co1
Yield: 40.8 %

Procedure:
The title compound was synthesized from 5-formylfuran-3-boronic acid pinacol ester (878 mg, 3.95 mmol), and benzyl diethyl phosphate (1.25 g, 5.14 mmol) using the same conditions used to synthesize 4-(4-chlorobenzyl)thiophene-2-carbaldehyde, with the exception that triphenylphosphine and Pd(OAc)2 were dissolved in 2:1 CH3CN/isopropyl alcohol. Purification by flash chromatography yielded 4-benzyl-furan-2-carbaldehyde as a white solid (300 mg, 41%). 1H NMR (400 MHz, CDCl3) δ ppm 9.56 (s, 1H) 7.29-7.38 (m, 3H) 7.24-7.28 (m, 2H) 7.17 (d, J=3.5 Hz, 1H) 6.19 (d, J=3.6 Hz, 1H) 4.07 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[C:15]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:19][C:18]([C:21](Cl)=[O:22])=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:16][CH:17]=1)=[O:22]
Reactant: COc1ccc2[nH]cc(CCN)c2c1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2[nH]cc(CCNC(=O)c3ccc(-c4ccccc4)cc3)c2c1
Yield: 63.9 %

Procedure:
N-(2-(5-Methoxy-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide was obtained following Method C starting from 2-(5-methoxy-1H-indol-3-yl)ethanamine (0.100 g, 0.515 mmol), biphenyl-4-carbonyl chloride (0.120 g; 0.541 mmol), and triethylamine (0.087 mL; 0.616 mmol) in dichloromethane (5 mL). Flash chromatography on silica gel (eluent with 10% ethyl acetate in dichloromethane) furnished 0.122 g (64%) of N-(2-(5-Methoxy-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide as a white solid.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:19]=[C:18]3[C:13]([C:14](=[O:25])[C:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][NH:17]3)=[CH:12][C:11]=2[F:26])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S(O[CH2:43][CH2:44][F:45])(=O)=O)=CC=1>CN(C)C=O>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:19]=[C:18]3[C:13]([C:14](=[O:25])[C:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][N:17]3[CH2:43][CH2:44][F:45])=[CH:12][C:11]=2[F:26])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Reactant: CCOC(=O)c1c[nH]c2nc(N3CCN(C(C)=O)CC3)c(F)cc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CCF)c2nc(N3CCN(C(C)=O)CC3)c(F)cc2c1=O
Temperature: 50 °C
Yield: 77.6 %

Procedure:
Ethyl 7-(4-acetyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (7.2 g) and anhydrous potassium carbonate (4.1 g) are added to dimethylformamide (60 ml). The mixture is heated at 50° C. for 30 minutes with stirring. 2-Fluoroethyl p-toluenesulfonate (6.5 g) is added to the mixture, and the mixture is heated at 70°-80° C. with stirring. After the reaction is completed, the insoluble substance is removed by filtration. The filtrate is concentrated to dryness under reduced pressure, and the precipitate is collected by filtration. The precipitate is recrystallized from acetone to give 6.3 g of ethyl 7-(4-acetyl-1-piperazinyl)-6-fluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (m.p. 183°-185° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:34](=[O:37])[CH2:35][CH3:36])[C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH:19]=[CH:20][C:21]([OH:23])=[O:22])[CH:17]=3)[N:12]([C:24](=[O:32])[C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C@@H:11]([CH3:33])[CH2:10]2)=[CH:4][CH:3]=1.Br[C:39]1C=C2C(=CC=1)N(C(=O)C1C=CC(F)=CC=1)[C@@H](C)C[C@H]2N(C1C=CC(Cl)=CC=1)C(=O)CC.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC)(=O)C=C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:39][O:22][C:21](=[O:23])[CH:20]=[CH:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:24](=[O:32])[C:25]1[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=1)[C@@H:11]([CH3:33])[CH2:10][C@H:9]2[N:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:34](=[O:37])[CH2:35][CH3:36]
Reactant: CCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(F)cc2)c2ccc(Br)cc21
Reactant: CCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(F)cc2)c2ccc(C=CC(=O)O)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C=CC(=O)OC
Solvent: CN(C)C=O
Product: CCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(F)cc2)c2ccc(C=CC(=O)OC)cc21
Temperature: 80 °C
Yield: 44 %

Procedure:
(±)-Cis-3-[4-[(4-chloro-phenyl)-propionyl-amino]-1-(4-fluoro-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-6-yl]-acrylic acid was made from (±)-cis-N-[6-bromo-1-(4-fluoro-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-N-(4-chloro-phenyl)-propionamide. To a solution of (±)-cis-N-[6-bromo-1-(4-fluoro-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-N-(4-chloro-phenyl)-propionamide (250 mg, 0.47 mmol), TEA (0.2 ml, 1.4 mmol), palladium acetate (11 mg, 0.047 mmol), 1,3-Bis(diphenylphosphino)propane (39 mg, 0.094 mmol), in 10 ml DMF was added 0.13 ml methyl acrylate (1.41 mmol). The resulting reaction mixture was heated to 80° C. overnight. The mixture was filtered through celite and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography, eluting with ethyl acetate-hexane (2:3) to give (±)-cis-3-[4-[(4-chloro-phenyl)-propionyl-amino]-1-(4-fluoro-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-6-yl]-acrylic acid methyl ester (110 mg, 44%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:13]([CH2:14][OH:15])=[C:12]([C:16]([F:19])([F:18])[F:17])[S:11][N:10]=1.[F:20][C:21]1[CH:22]=[C:23]([CH2:29][CH:30]([CH3:36])[C:31]([O:33]CC)=[O:32])[CH:24]=[C:25]([F:28])[C:26]=1O>>[F:20][C:21]1[CH:22]=[C:23]([CH2:29][CH:30]([CH3:36])[C:31]([OH:33])=[O:32])[CH:24]=[C:25]([F:28])[C:26]=1[O:15][CH2:14][C:13]1[C:9]([C:3]2[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[F:1])=[N:10][S:11][C:12]=1[C:16]([F:19])([F:17])[F:18]
Reactant: CCOC(=O)C(C)Cc1cc(F)c(O)c(F)c1
Reactant: Cc1ccc(-c2nsc(C(F)(F)F)c2CO)c(F)c1
Product: Cc1ccc(-c2nsc(C(F)(F)F)c2COc2c(F)cc(CC(C)C(=O)O)cc2F)c(F)c1

Procedure:
The title compound was prepared according to the procedure described in Example 1 starting following Step 5 and 6 coupling (3-(2-fluoro-4-methylphenyl)-5-(trifluoromethyl)isothiazol-4-yl)methanol and ethyl 3-(3,5-difluoro-4-hydroxyphenyl)-2-methylpropanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (300 MHz, CD3OD) δ 7.29 (t, J=7.8 Hz, 1H), 7.10 (d, J=7.5 Hz, 1H), 7.07 (d, J=11.4 Hz, 1H), 6.73 (d, J=9.7 Hz, 2H), 5.13 (s, 2H), 2.94-2.85 (m, 1H), 2.54-2.44 (m, 2H), 2.44 (s, 3H), 1.09 (d, J=6.3 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C22H17F6NO3S, 488.1 (M−H). found 488.1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[Cl:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1
Reactant: Clc1cc2c(cc1N1CCCCC1)OCC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: Clc1cc2ccoc2cc1N1CCCCC1

Procedure:
A solution of 2.37 g (10.0 mmole) of 5-chloro-6-(piperidin-1-yl)-2,3-dihydrobenzofuran and 2.27 g (10.0 mmole) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in 200 ml of dioxane is boiled under reflux for 12 hours. The reaction mixture is cooled and filtered and the filtrate is concentrated in a vacuum rotary evaporator. The residue is chromatographed over silica gel using methylene chloride as eluant (Rf =0.63). In that manner, 5-chloro-6-(piperidin-1-yl)-benzofuran is obtained in the form of an oil which distills at 96°-97°/1.5 torr.
Reaction SMILES: [CH2:1]([C@@:4]1([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22](=[O:25])[N:21]([CH3:26])[CH:20]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=C.C1C[O:37]CC1.O>CCOC(C)=O.O=[Os](=O)(=O)=O>[F:33][C:30]1[CH:31]=[CH:32][C:27]([C@:4]2([CH2:1][CH2:2][OH:37])[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]3[CH:14]=[CH:15][C:16]([C:19]4[CH:24]=[CH:23][C:22](=[O:25])[N:21]([CH3:26])[CH:20]=4)=[CH:17][CH:18]=3)[CH3:12])[CH2:6][CH2:5]2)=[CH:28][CH:29]=1
Reactant: C1CCOC1
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(=O)n(C)c3)cc2)C(=O)O1
Agent: O=[Os](=O)(=O)=O
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H](c1ccc(-c2ccc(=O)n(C)c2)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (0.064 g, 0.144 mmol, 1.0 equiv) in THF-H2O (1:1, 6 mL) were added NalO4 (0.145 g, 0.678 mmol, 4.7 equiv) and OsO4 (2.5 wt. % solution in t-BuOH, 0.048 g, 0.0047 mmol, 0.033 equiv), and the mixture was stirred at rt for 1 h. The mixture was diluted with EtOAc, dried over Na2SO4, and concentrated under reduced pressure. The residue was dissolved in MeOH (3 mL) and NaBH4 (0.100 g) was added. After the mixture was stirred for 0.5 h at rt, acetone was added. The solvents were removed in vacuo, the residue was treated with saturated brine, extracted with CH2Cl2, and dried over Na2SO4. After the solvent was evaporated, the residue was purified by reversed-phase HPLC (SunFire™ Prep C18 OBD™ 5 μm 19×50 mm column, 10%→90% CH3CN/H2O, 0.1% CF3COOH over 8 min and then 90% CH3CN/H2O, 0.1% CF3COOH over 2 min, flow rate 20 mL/min) to afford (S)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one. LC-MS Method 1 tR=1.21 min, m/z=451 (M+1); 1H NMR (400 MHz, CD3OD) δ 7.80 (m, 1H), 7.69 (d, J=9.4 Hz, 1H), 7.22-7.19 (m, 4H), 7.00-6.92 (m, 4H), 6.52 (d, J=9.4 Hz, 1H), 5.45 (q, J=7.0 Hz, 1H), 3.60-3.52 (m, 1H), 3.52 (s, 3H), 3.24-3.18 (m, 1H), 3.02-2.98 (m, 1H), 2.39-2.35 (m, 1H), 2.23-2.12 (m, 2H), 2.01 (t, J=7.3 Hz, 2H), 1.43 (d, J=7.0 Hz, 3H); 19F NMR (376 MHz, CD3OD) δ −117.19 (m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[C:18]([N:22]1[C:26]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)=[CH:25][C:24]([CH:34]=O)=[N:23]1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([N:22]1[C:26]([C:27]2[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=2)=[CH:25][C:24]([CH2:34][NH:17][CH2:16][CH2:15][N:12]2[CH2:11][CH2:10][N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH2:14][CH2:13]2)=[N:23]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1ccc(-c2cc(C=O)nn2C(C)(C)C)cc1
Reactant: COc1ccc(N2CCN(CCN)CC2)cc1
Product: COc1ccc(N2CCN(CCNCc3cc(-c4ccc(C)cc4)n(C(C)(C)C)n3)CC2)cc1
Yield: 95.9 %

Procedure:
Compound 45 was prepared using the same method as that Example 1 except that 4-(4-methoxyphenyl)piperazin-1-ylethylamine and 1-t-butyl-5-(4-methylphenyl)pyrazole-3-carbaldehyde were used.
Reaction SMILES: C([NH:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16]Cl)=[C:7]([O:19][CH2:20][C:21]2[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[CH:22]=2)[CH:6]=1)(=O)C.N1CCCCC1.[CH2:37]([CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)[CH2:38][CH3:39]>>[NH2:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][N:43]2[CH2:44][CH2:45][CH:40]([CH2:37][CH2:38][CH3:39])[CH2:41][CH2:42]2)=[C:7]([O:19][CH2:20][C:21]2[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[CH:22]=2)[CH:6]=1
Reactant: COc1cc(COc2cc(NC(C)=O)c(Cl)cc2C(=O)CCCCCl)cc(OC)c1
Reactant: CCCC1CCNCC1
Solvent: C1CCNCC1
Product: CCCC1CCN(CCCCC(=O)c2cc(Cl)c(N)cc2OCc2cc(OC)cc(OC)c2)CC1

Procedure:
Proceeding as in Example 4, Step (c), but replacing 1-(4-acetylamino-5-chloro-2-methoxyphenyl)-5-chloropentan-1-one with 1-[4-acetylamino-5-chloro-2-(3,5-dimethoxybenzyloxy)phenyl]-5-chloropentan-1-one and piperidine with 4-(prop-1-yl)piperidine, gave 1-[4-amino-5-chloro-2-(3,5-dimethoxybenzyloxy)-phenyl]-5-[4-(prop-1-yl)piperidin-1-yl]pentan-1-one, m.p. 119-120° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C@@H:13]3[CH2:21][C:16]4([O:20][CH2:19][CH2:18][O:17]4)[CH2:15][N:14]3[C:22](=[O:32])[C@@H:23]([NH:27][C:28](=[O:31])[O:29][CH3:30])[CH:24]([CH3:26])[CH3:25])=[N:10][CH:9]=2)=[CH:4][CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:57]1[CH:58]=[C:59]2[C:79](=[CH:80][CH:81]=1)[C:63]1[NH:64][C:65]([C@@H:67]3[CH2:71][CH2:70][CH2:69][N:68]3[C:72]([O:74][C:75]([CH3:78])([CH3:77])[CH3:76])=[O:73])=[N:66][C:62]=1[CH:61]=[CH:60]2.C([O-])([O-])=O.[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].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.O1CCOCC1.CS(C)=O>[CH3:30][O:29][C:28]([NH:27][C@@H:23]([CH:24]([CH3:26])[CH3:25])[C:22]([N:14]1[C@H:13]([C:11]2[NH:12][C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:57]4[CH:58]=[C:59]5[C:79](=[CH:80][CH:81]=4)[C:63]4[NH:64][C:65]([C@@H:67]6[CH2:71][CH2:70][CH2:69][N:68]6[C:72]([O:74][C:75]([CH3:77])([CH3:78])[CH3:76])=[O:73])=[N:66][C:62]=4[CH:61]=[CH:60]5)=[CH:3][CH:4]=3)=[CH:9][N:10]=2)[CH2:21][C:16]2([O:20][CH2:19][CH2:18][O:17]2)[CH2:15]1)=[O:32])=[O:31]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2ccc3cc(Br)ccc3c2[nH]1
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc(Br)cc3)[nH]1)OCCO2)C(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc(-c4ccc5c(ccc6nc([C@@H]7CCCN7C(=O)OC(C)(C)C)[nH]c65)c4)cc3)[nH]1)OCCO2)C(C)C
Temperature: 95 °C
Reaction time: 4 h

Procedure:
Methyl (S)-1-((S)-8-(5-(4-bromophenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamate (100 mg, 0.197 mmol), bis(pinacolato)diboron (51 mg, 0.2 mmol), potassium acetate (58 mg, 0.591 mmol), and Pd(dppf)Cl2 (15 mg, 0.02 mmol) were all weighed out in a glass pressure vessel and anhydrous 1,4-Dioxane (1 mL) was added. The mixture was bubbled with nitrogen gas for about 5 min. The vessel was then capped and sealed and heated in an oil bath at 95° C. overnight with continuous stirring. The reaction vessel was cooled down to room temperature and (S)-tert-butyl 2-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate (83 mg, 0.29 mmol), 2M K2CO3 (296 uL), and Pd(PPh3)4 (23 mg, 0.02 mmol) were all added along with 1 mL of DMSO or 1,4-dioxane and the mixture was bubbled with nitrogen gas for 5 minutes. The vessel, again, was capped, sealed and placed in an oil bath at 100° C. for 4 hours.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([CH3:27])([CH3:26])[C:24]#[N:25])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:28])[CH3:9])=[CH:4][CH:3]=1.[O:29]=[C:30]1[NH:35][CH:34]=[C:33](B(O)O)[CH:32]=[CH:31]1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:26][C:23]([CH3:27])([CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:28])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:33]3[CH:32]=[CH:31][C:30](=[O:29])[NH:35][CH:34]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1)[C:24]#[N:25]
Reactant: O=c1ccc(B(O)O)c[nH]1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccccc2)OC1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: C[C@@H](c1ccc(-c2ccc(=O)[nH]c2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccccc2)OC1=O
Temperature: 90 °C
Yield: 94.3 %

Procedure:
To a solution of 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile (208 mg, 0.47 mmol) in 1,4-dioxane (5 mL) were added 6-oxo-1,6-dihydropyridin-3-ylboronic acid (98 mg, 1.5 equiv), 2.0 M aq Cs2CO3 solution (500 μL), and Pd(dppf)Cl2 (20 mg, 0.06 equiv). The mixture was degassed and refilled with N2 gas 3 times, before being heated to 90° C. (oil bath) for 3 h. LC-MS found the reaction was complete. The mixture was cooled to rt, diluted with EtOAc (25 mL), and washed with water (10 mL). The aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layers were washed with water (10 mL) and brine (8 mL), and dried over Na2SO4. After filtration and concentration, the residue was purified by chromatography (12-g silica gel cartridge, 0˜10% MeOH in CH2Cl2, major UV peak) to afford 2,2-dimethyl-3-((R)-2-oxo-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-6-yl)propanenitrile (202 mg, 94%) as a brown oil. LC-MS Method 1 tR=1.34 min, m/z=456 (M+1); 1H NMR (CDCl3) 8.01 (d, 1H), 7.80 (s, 1H), 7.36 (dt, 6H), 7.19 (d, 2H), 6.98 (m, 3H), 5.65 (d, 1H), 2.98 (d, 1H), 2.50 (m, 2H), 2.32 (m, 1H), 2.17 (s, 2H), 1.57 (d, 3H), 1.40 (s, 3H), 1.32 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([F:27])=[C:11]([NH:13][C:14](=[O:26])[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[CH:12]=2)=[C:4]([C:30]#[N:31])[CH:3]=1.[S-:32][C:33]#[N:34].[K+].BrBr>C(O)(=O)C>[NH2:34][C:33]1[S:32][C:3]2[C:4]([C:30]#[N:31])=[C:5]([O:6][C:7]3[CH:8]=[CH:9][C:10]([F:27])=[C:11]([NH:13][C:14](=[O:26])[CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=4)[CH:12]=3)[CH:28]=[CH:29][C:2]=2[N:1]=1
Reactant: N#Cc1cc(N)ccc1Oc1ccc(F)c(NC(=O)Cc2cccc(C(F)(F)F)c2)c1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: N#Cc1c(Oc2ccc(F)c(NC(=O)Cc3cccc(C(F)(F)F)c3)c2)ccc2nc(N)sc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.7 %

Procedure:
To a solution of N-[5-(4-amino-2-cyanophenoxy)-2-fluorophenyl]-2-[3-(trifluoromethyl)phenyl]acetamide (1.15 g, 2.68 mmol) in acetic acid (40 mL) was added potassium thiocyanate (1.22 g, 12.6 mmol), and the mixture was stirred at room temperature for 10 min. A solution of bromine (652 mg, 4.08 mmol) in acetic acid (6.5 mL) was added dropwise to the obtained solution over 10 min. After the completion of the dropwise addition, the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with acetic acid (50 mL), and insoluble material was filtered off and washed with acetic acid, the filtrate and washings were combined and the mixture was concentrated under reduced pressure. The obtained residue was suspended in ethyl acetate (120 mL)/tetrahydrofuran (12 mL), and the suspension was washed successively with saturated aqueous sodium hydrogen carbonate solution (120 mL) and saturated brine (120 mL), and dried over anhydrous magnesium sulfate. Insoluble material was filtered off, the filtrate was purified by basic silica gel column chromatography (eluate: ethyl acetate), and the obtained solution was concentrated under reduced pressure to give the title compound (1.13 g, 87%) as a beige powder.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[C:13]([O:15]C)=O)=[CH:4][C:3]=1[CH3:19].[CH3:20][S:21]([NH:24][C:25]1[CH:40]=[CH:39][C:28]2[NH:29][C:30]([CH2:35][C:36](O)=[O:37])=[N:31][S:32](=[O:34])(=[O:33])[C:27]=2[CH:26]=1)(=[O:23])=[O:22].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.Cl>CN(C)C=O>[F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]2[C@@H:8]3[C@@H:9]([CH2:10][CH2:11][CH2:12]3)[C:13]([OH:15])=[C:35]([C:30]3[NH:29][C:28]4[CH:39]=[CH:40][C:25]([NH:24][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:26][C:27]=4[S:32](=[O:33])(=[O:34])[N:31]=3)[C:36]2=[O:37])=[CH:4][C:3]=1[CH3:19]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: COC(=O)[C@@H]1CCC[C@@H]1NCc1ccc(F)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1cc(CN2C(=O)C(C3=NS(=O)(=O)c4cc(NS(C)(=O)=O)ccc4N3)=C(O)[C@@H]3CCC[C@@H]32)ccc1F
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirred solution of methyl (1R,2S)-2-[(4-fluoro-3-methylbenzyl)amino]cyclopentanecarboxylate (120 mg, 0.45 mmol) and (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 150 mg, 0.45 mmol) in anhydrous N,N-dimethylformamide (4 mL) under a nitrogen atmosphere, N-methylmorpholine (0.15 mL, 1.40 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (86 mg, 0.45 mmol) were added sequentially. The mixture was stirred at 25° C. for 2.5 h, and then poured into 1.0 M aqueous hydrochloric acid solution and extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous brine solution, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to afford the amide intermediate, which was used directly in the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:12])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:12][C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[N:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Cl)nc(Cl)c1
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(Cl)nc(N2CCCCC2)c1
Yield: 99.6 %

Procedure:
A solution of methyl 2,6-dichloroisonicotinate (1 g, 4.85 mmol), piperidine (0.61 g, 7.28 mmol), K2CO3 (1.38 g, 9.7 mmol) in acetonitrile (20 mL) was heated at 90° C. for 20 h. After completion of reaction, reaction mass was filtered, filtrate concentrated and purified by column to obtain pure methyl 2-chloro-6-(piperidin-1-yl)isonicotinate (1.23 g, 90%).