Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]#[C:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)(=O)=O.[CH3:16][NH2:17]>>[CH3:16][NH:17][CH2:6][CH2:7][C:8]#[C:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CN
Reactant: CS(=O)(=O)OCCC#Cc1ccccn1
Product: CNCCC#Cc1ccccn1
Temperature: 45 °C
Yield: 39 %

Procedure:
4-(Pyridin-2-yl)but-3-ynyl methanesulfonate (2.90 g, 12.87 mmol) was dissolved in methylamine 40% in aqueous solution (20 mL) and stirred for 3 hoursunder nitrogen at 45° C. The reaction mixture was cooled with ice, quenched with water and extracted with DCM. The organic phases were washed with brine, dried over MgSO4 and concentrated. The crude residue was purified over silicagel chromatography (prepacked 70 g silicagel column, DCM/MeOH: from 90/10 to 90/10 with 1% of TEA as eluent) to afford 817 mg N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (Yield: 39%) as a brown oil
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([NH:13]/[N:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]=[CH:25][N:24]([C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=3)[N:23]=2)=[CH:18][CH:17]=1)=[S:12])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:45][CH2:46]Cl>CC(=O)CC.C(Cl)Cl>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:46][CH2:45][S:12]/[C:11]/1=[N:13]/[N:14]=[CH:15]\[C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:26]=[CH:25][N:24]([C:27]3[CH:28]=[CH:29][C:30]([O:33][C:34]([F:37])([F:35])[F:36])=[CH:31][CH:32]=3)[N:23]=2)=[CH:20][CH:21]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1NC(=S)N/N=C/c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCC(C)=O
Product: CC(C)c1ccccc1N1CCS/C1=N/N=C\c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 90 °C
Yield: 61.2 %

Procedure:
To (E)-N-(2-isopropylphenyl)-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)hydrazinecarbothioamide (214 mg, 0.407 mmol) and potassium carbonate (225 mg, 1.63 mmol) in butanone (4 ml) was added 1-bromo-2-chloroethane (70.0 mg, 0.489 mmol). The reaction was heated to 90° C. overnight. The reaction was determined to be complete by LCMS. The reaction mixture was cooled, diluted with DCM and washed with water. The aqueous layer was extracted with DCM. The organic layers were filtered through a phase separator and concentrated. Separation by flash column chromatography and drying the recovered solid at 55° C. under vacuum provided the title compound as a white solid (137 mg, 0.249 mmol, 61%): mp 193-196° C.; 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.22 (s, 1H), 8.17 (d, J=8.4 Hz, 2H), 7.80 (ddd, J=9.5, 6.9, 4.9 Hz, 4H), 7.43-7.33 (m, 4H), 7.31-7.21 (m, 2H), 4.05 (td, J=9.4, 7.1 Hz, 1H), 3.97-3.87 (m, 1H), 3.42-3.33 (m, 1H), 3.33-3.24 (m, 1H), 3.12 (heptet, J=6.8 Hz, 1H), 1.27 (d, J=6.8 Hz, 3H), 1.22 (d, J=6.9 Hz, 3H); ESIMS m/z 552 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:12]1([C@@H:18](O)[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[O:1]=[C:2]1[CH:3]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:9]=[CH:10][N:11]1[C@@H:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:19]
Reactant: C[C@H](O)c1ccccc1
Reactant: COC(=O)c1ccnc(O)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)c1ccn([C@H](C)c2ccccc2)c(=O)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.4 %

Procedure:
To a solution of methyl 2-hydroxyisonicotinate (459 mg, 3 mmol) and (S)-1-phenylethanol (366 mg, 3 mmol) in tetrahydrofuran (30 mL) was added dropwise a solution of tributylphosphine (909 mg, 4.5 mmol) in tetrahydrofuran (10 mL). The reaction solution was stirred at 0° C. for 0.5 hours. To the above solution was added 1,1′-(Azodicarbonyl)-dipiperidine (1134 mg, 4.5 mmol). The reaction mixture was stirred at 0° C. for 0.5 hours. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=1:1) to give (R)-methyl 2-oxo-1-(1-phenylethyl)-1,2-dihydropyridine-4-carboxylate as a white solid (451 mg, 58%).
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][CH2:6][S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:30](=[O:32])[CH3:31])[CH:24]=2)[CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:15])=[N:10][CH:9]=1)C.C1(CN(C2C=CC(F)=C(F)C=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.NC1C=C(NC(=O)C)C=CC=1.C1(C=O)CCCC1.C(OC(=O)CCSC1SC(N)=NC=1)C>>[C:30]([NH:29][C:25]1[CH:24]=[C:23]([N:16]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][CH2:6][CH2:5][C:4]([OH:33])=[O:3])=[CH:9][N:10]=2)[CH:28]=[CH:27][CH:26]=1)(=[O:32])[CH3:31]
Reactant: CCOC(=O)CCSc1cnc(NC(=O)N(CC2CCCC2)c2cccc(NC(C)=O)c2)s1
Agent: CC(=O)Nc1cccc(N)c1
Agent: CCOC(=O)CCSc1cnc(N)s1
Agent: O=C(O)Cc1csc(NC(=O)N(CC2CCCC2)c2ccc(F)c(F)c2)n1
Product: CC(=O)Nc1cccc(N(CC2CCCC2)C(=O)Nc2ncc(SCCC(=O)O)s2)c1

Procedure:
The title compound was prepared via 3-{2-[3-(3-acetylamino-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-propionic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using N-(3-amino-phenyl)-acetamide, cyclopentanecarbaldehyde and 3-(2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][N:4]=[C:3]1[SH:13].O.[CH3:15]I>[OH-].[Na+].CCO>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][N:4]=[C:3]1[S:13][CH3:15]
Reactant: CI
Reactant: Cn1c(S)nnc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CSc1nnc(-c2ccccc2)n1C
Reaction time: 0.25 h

Procedure:
To a solution of 4-methyl-5-phenyl-4H-1,2,4-triazole-3-thiol (2.00 g, 10 mmol) in NaOH 1.0 M in H2O (21 ml, 21 mmol) was added a solution of CH3I (0.98 mL, 16 mmol) in 6 mL EtOH. The reaction became cloudy and then clear. After 15 min, a white solid precipitated out of the reaction. The reaction was filtered, rinsing with water. The solid was collected and dried in vacuo to give 4-methyl-3-(methylthio)-5-phenyl-4H-1,2,4-triazole as a white solid. MS m/z=206 [M+H]+. Calc'd for C10H11N3S: 205.3.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:18]2[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH:19]=2)[CH:3]=1.C([Mg]Cl)(C)C.C([Li])(C)(C)C.[S:36]1[CH2:41][CH2:40][C:39](=[O:42])[CH2:38][CH2:37]1.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[CH3:24][C:21]1([CH3:25])[CH2:22][CH2:23][C:18]([C:4]2[CH:3]=[C:2]([C:39]3([OH:42])[CH2:40][CH2:41][S:36][CH2:37][CH2:38]3)[CH:7]=[CH:6][C:5]=2[NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[CH:19][CH2:20]1
Reactant: CC1(C)CC=C(c2cc(Br)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Reactant: O=C1CCSCC1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)CC=C(c2cc(C3(O)CCSCC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 64.9 %

Procedure:
To a solution of 4-cyano-1H-imidazole-2-carboxylic acid [4-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (as prepared in Example 1, step (g), 120 mg, 0.300 mmol) in 4 mL of THF at −78° C. under Ar was added isopropylmagnesium chloride (165 μL, 0.331 mmol, 2.0 M in THF). The resulting mixture was warmed to RT and stirred for 5 min, cooled to −78° C. again. To the mixture was added tert-butyllithium (530 μL, 0.902 mmol, 1.7 M in pentane) and the resulting mixture was stirred at −78° C. for 10 min. A solution of tetrahydro-thiopyran-4-one (175 mg, 1.50 mmol) in 1 mL of THF was then added, and the reaction was warmed to RT and stirred for 0.5 h under Ar. The mixture was treated with 2 mL of saturated NH4Cl followed by 20 mL of EtOAc, washed with brine (10 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (1-2% MeOH/DCM) gave 85.0 mg (65%) of the title compound as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 12.62 (s, 1H), 9.72 (s, 1H), 8.32 (d, 1H, J=8.6 Hz), 7.74 (d, 1H, J=2.3 Hz), 7.42 (dd, 1H, J=8.6, 2.3 Hz), 7.33 (d, 1H, J=2.3 Hz), 5.78 (m, 1H), 3.12-3.33 (br s, 2H), 2.46-2.54 (m, 2H), 2.26-2.33 (m, 2H), 2.16-2.22 (m, 2H), 2.00-2.13 (m, 4H), 1.79 (s, 1H), 1.59 (t, 2H, J=6.3 Hz), 1.10 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C24H28N4O2S, 437.2 (M+H). found 437.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14]2[NH:18][C:17]3[CH:19]=[C:20]([C:23]4[CH:32]=[N:31][C:30]5[C:25](=[CH:26][CH:27]=[C:28](B(O)O)[CH:29]=5)[N:24]=4)[CH:21]=[CH:22][C:16]=3[N:15]=2)[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:37]1[NH:41][C:40]([C@@H:42]2[CH2:47][C@@H:46]3[C@@H:44]([CH2:45]3)[N:43]2[C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[N:39][CH:38]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O.CO.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14]2[NH:18][C:17]3[CH:19]=[C:20]([C:23]4[CH:32]=[N:31][C:30]5[C:25](=[CH:26][CH:27]=[C:28]([C:37]6[NH:41][C:40]([C@@H:42]7[CH2:47][C@@H:46]8[C@@H:44]([CH2:45]8)[N:43]7[C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[N:39][CH:38]=6)[CH:29]=5)[N:24]=4)[CH:21]=[CH:22][C:16]=3[N:15]=2)[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1nc2ccc(-c3cnc4cc(B(O)O)ccc4n3)cc2[nH]1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1ncc(I)[nH]1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1ncc(-c2ccc3nc(-c4ccc5nc([C@@H]6C[C@H]7C[C@H]7N6C(=O)OC(C)(C)C)[nH]c5c4)cnc3c2)[nH]1
Temperature: 120 °C
Reaction time: 2 h
Yield: 39.5 %

Procedure:
Pd(OAc)2 (2.67 mg, 0.012 mmol) was added to a degassed solution of 2-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)quinoxalin-6-ylboronic acid (56 mg, 0.119 mmol), (1R,3S,5R)-tert-butyl 3-(5-iodo-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (66.9 mg, 0.178 mmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (9.76 mg, 0.024 mmol) and K2CO3 (49.3 mg, 0.356 mmol) in THF (1 mL) and water (0.25 mL) and the mixture was stirred at 120° C. for 2 h. The reaction was diluted with MeOH, filtered and purified by prep HPLC (H2O-MeOH with 10 mM NH4OAc buffer) to yield (1R,3S,5R)-tert-butyl 3-(5-(2-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)quinoxalin-6-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (32 mg, 0.047 mmol) as yellow solid. LC-MS retention time 1.89 min; m/z 675 [M+H]+. (Column PHENOMENEX® Luna 3.0×50 mm S10. Solvent A=95% water/5% methanol/10 mM ammonium acetate. Solvent B=5% water/95% methanol/10 mM ammonium acetate. Flow Rate=4 mL/min. Start % B=0. Final % B=100. Gradient Time=2 min. Wavelength=220). 1H NMR (400 MHz, MeOD) δ ppm 9.44 (s, 1H), 8.45 (br s, 1H), 8.39 (s, 1H), 8.23 (d, J=8.8 Hz, 1H), 8.18 (d, J=8.5 Hz, 1H), 8.13 (d, J=8.8 Hz, 1H), 7.69-7.76 (m, 1H), 7.64 (s, 1H), 4.69-4.78 (m, 1H), 4.49-4.57 (m, 1H), 3.56-3.70 (m, 2H), 2.50-2.73 (m, 2H), 2.31-2.47 (m, 2H), 1.67-1.86 (m, 2H), 1.31 (br s, 18H), 0.82-0.95 (m, 2H), 0.54-0.75 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][NH:9][CH:10]=1)=[O:5])[CH3:2].Cl[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CCCCCCC.C(OCC)(=O)C>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: Clc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(-c2ccccn2)c1

Procedure:
A solution of 1H-pyrazol-4-carboxylic acid ethyl ester (1.25 g, 8.9 mmol), 2-chloropyridine (2.02 g, 17.8 mmol) and cesium carbonate (8.7 g, 26.75 mmol) in DMF (26.8 ml) was irradiated under microwave conditions at 180° C. for 10 min. The reaction mixture was extracted with diethylether, and the combined organic phases were washed with water and brine. The product was obtained after silica gel chromatography using a heptane/ethyl acetate gradient as white solid (0.81 mg, 42%). MS: M=218.2 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:20]1[C:21](=[O:38])[O:22]/[C:23](=[CH:27]\[C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][CH:29]=2)/[C:24]=1[O:25][CH3:26].O1CCOCC1.C1COCC1>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>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:20]2[C:21](=[O:38])[O:22]/[C:23](=[CH:27]\[C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=[CH:30][CH:29]=3)/[C:24]=2[O:25][CH3:26])=[CH:4][CH:3]=1
Reactant: COC1=C(Br)C(=O)O/C1=C\c1cccc2ccccc12
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: O
Product: COC1=C(c2ccc(Cl)cc2)C(=O)O/C1=C\c1cccc2ccccc12
Temperature: 90 °C
Yield: 69 %

Procedure:
A stirred mixture of 4-chlorophenylboronic acid (259 mg, 166 mmol), K3PO4 (962 mg, 4.53 mmol) and Pd(PPh3)4 (52 mg, 45.3 μmol) under N2 is treated sequentially with of 3-bromo-4-methoxy-5-[(Z)-1-naphthylmethylidene]furan-2(5H)-one (500 mg, 1.51 mmol) and 9.3 mL of a 2:1 v/v mixture of dioxane/THF, heated at 90° C. until the disappearance of starting material by thin layer chromatography, cooled to room temperature, diluted with water and extracted with EtOAc. The extracts are combined, dried over MgSO4 and concentrated in vacuo. The resultant residue is purified by flash chromatography (silica gel, 25% EtOAc in hexanes as eluent) to afford the title product as a yellow solid, 380 mg (69% yield), identified by NMR and mass spectral analyses.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)([CH2:13][CH2:14][OH:15])[CH2:9]1)=[O:7].ClCCl.N1C=CC=CC=1.[C:40](OC(=O)C)(=[O:42])[CH3:41]>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)([CH2:13][CH2:14][O:15][C:40](=[O:42])[CH3:41])[CH2:9]1)=[O:7]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(C(=O)N2CCC(CCO)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCC(CCOC(C)=O)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reaction time: 2 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine (4.5 g, 9.9 mmol) and dichloromethane/pyridine (70 mL, 6/1). Add acetic anhydride (1.04 mL, 11.0 mmol) and 4-dimethylaminopyridine (50 mg, 0.41 mmol). After 2 hours, concentrate the reaction mixture in vacuo to obtain a residue. Dissolve the residue in ethyl acetate and extract with 1M hydrochloric acid solution (2×200 mL), saturated sodium bicarbonate solution, and saturated sodium chloride solution. Dry the organic layer over MgSO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with ethyl acetate to give 1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-acetoxyethyl)pyrrolidine: Rf=0.38 (silica gel, ethyl acetate). Elemental Analysis calculated for C24H27Cl2NO6: C 58.07; H 5.48; N 2.82; Found: C, 57.67; H, 5.46; N, 2.84.
Reaction SMILES: [C:1]1([S:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].ClCCl.[Br:16]Br>O>[Br:16][C:4]1[CH:5]=[CH:6][C:1]([S:7][CH3:8])=[CH:2][CH:3]=1
Reactant: CSc1ccccc1
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CSc1ccc(Br)cc1
Temperature: 5 °C
Reaction time: 4 h

Procedure:
A one-liter four-necked flask equipped with a stirrer, thermometer, dropping funnel and Liebig condenser was charged with 124.2 g (1.00 mole) of thioanisole, and 0.13 g (0.001 mole) of aluminum chloride and 200 g of dichloromethane, and 160 g (1.0 mole) of bromine was added dropwise with stirring at 5° C. over 4 hours. Thereafter, the reaction was further allowed to proceed for 2 hours. After completion of the reaction, 50 g of water was added, and phase separation was effected, whereby a 4-bromothioanisole-containing organic layer was obtained. The dichloromethane was distilled off from the organic layer obtained, whereby 203.1 g of crude 4-bromothioanisolve was obtained. The purity of the thus-obtained crude 4-bromothioanisole was 90.1% as determined by gas chromatography.
Reaction SMILES: N#N.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[C:32]([O:35][CH2:36][C:37]1[O:41][N:40]=[C:39]([CH3:42])[C:38]=1Br)(=[O:34])[CH3:33].CCN(CC)CC.[CH3:51][C:52]1([CH3:59])[C:56]([CH3:58])([CH3:57])[O:55][BH:54][O:53]1>O1CCOCC1.CC#N.CC#N.Cl[Pd]Cl>[C:32]([O:35][CH2:36][C:37]1[O:41][N:40]=[C:39]([CH3:42])[C:38]=1[B:54]1[O:55][C:56]([CH3:58])([CH3:57])[C:52]([CH3:59])([CH3:51])[O:53]1)(=[O:34])[CH3:33]
Reactant: CC(=O)OCc1onc(C)c1Br
Reactant: CC1(C)OBOC1(C)C
Agent: Cl[Pd]Cl
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: N#N
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)OCc1onc(C)c1B1OC(C)(C)C(C)(C)O1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
To a 500 mL flask (under N2 (g)) was added dichlorobis(acetonitrile)palladium(II) (0.551 g, 2.12 mmol) and dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (3.50 g, 8.53 mmol). To the solids was sequentially added a solution of (4-bromo-3-methylisoxazol-5-yl)methyl acetate (24.8 g, 106 mmol) in 1,4-dioxane (65 mL), Et3N (44.3 mL, 318 mmol), and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (24 mL, 160 mmol). The flask was sequentially evacuated and purged under N2 and this process was repeated three times. The reaction mixture was heated to 110° C. (under a constant stream of N2 (g)) and allowed to stir for ˜4 h. LC-MS analysis at this point showed complete conversion of the starting bromo-isoxazole. The reaction mixture was cooled to room temperature and EtOAc (100 mL) was added. After 15 min of stirring, the suspension was filtered over a pad of Celite. The filter cake was washed with EtOAc (3×100 mL), concentrated in vacuo, and the solvent was switched using 1,4-Dioxane (2×50 mL). The borate ester with used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([F:16])[CH2:13][C@H:12]1[C:17]([NH2:19])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([F:16])[CH2:13][C@H:12]1[C:17]#[N:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)[C@@H]1C[C@H](F)CN1C(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)OCc1ccccc1

Procedure:
Benzyl-(2S,4S)-2-aminocarbonyl-4-fluoropyrrolidine-1-carboxylate in dichloromethane was treated at 0° C. with Et3N (2.1 eq.) and trifluoroacetic anhydride was added dropwise.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][O:7][CH2:8][C:9]3[C:10]=2[C:11]=1[CH:12]=[CH:13][CH:14]=3.[CH3:15][C@@H:16]1[CH2:21][NH:20][CH2:19][CH2:18][NH:17]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:15][C@H:16]1[NH:17][CH2:18][CH2:19][N:20]([C:2]2[CH:3]=[CH:4][C:5]3[CH2:6][O:7][CH2:8][C:9]4[C:10]=3[C:11]=2[CH:12]=[CH:13][CH:14]=4)[CH2:21]1
Reactant: C[C@@H]1CNCCN1
Reactant: Brc1ccc2c3c(cccc13)COC2
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(c2ccc3c4c(cccc24)COC3)CCN1

Procedure:
A mixture of 6-bromo-1H,3H-naphtho[1,8-cd]pyran (0.30 g, 1.2 mmol), 2-(R)-methylpiperazine (0.145 g, 1.44 mmol), tris(dibenzylideneacetone)dipalladium(0) (55 mg, 0.06 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (56 mg, 0.09 mmol) and sodium tert-butoxide (0.162 g, 1.68 mmol) in toluene (5 mL) was heated under reflux for 2 h. The solvent was evaporated in vacuo and the crude mixture purified by column chromatography on silica gel, eluting with dichloromethane/methanol (9:1), to yield (3R)-3-methyl-1-(1H,3H-naphtho[1,8-cd]pyran-6-yl)piperazine as an orange solid.
Reaction SMILES: [CH3:1][N:2]1[C:6](B(O)O)=[CH:5][C:4]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[N:3]1.[NH2:15][C:16]1[N:21]=[C:20]([NH:22][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])=[O:24])[CH:19]=[CH:18][C:17]=1Br.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.CCO.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>[NH2:15][C:16]1[N:21]=[C:20]([NH:22][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])=[O:24])[CH:19]=[CH:18][C:17]=1[C:6]1[N:2]([CH3:1])[N:3]=[C:4]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=1
Reactant: Nc1nc(NC(=O)c2ccccc2F)ccc1Br
Reactant: Cn1nc(-c2ccco2)cc1B(O)O
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: CCO
Solvent: COCCOC
Product: Cn1nc(-c2ccco2)cc1-c1ccc(NC(=O)c2ccccc2F)nc1N
Temperature: 110 °C
Yield: 28.6 %

Procedure:
The boronic acid 91 (19.2 mg, 0.1 mmol) and 61 (31 mg, 0.1 mmol) was dissolved in 1 mL dimethoxyethane and 1 mL EtOH. The 0.5 ml of 2 M Na2CO3 was added and the mixture was bubbled with Ar for 1 min before add tetrakis(triphenylphosphine)-pallacium(0) (Pd(Ph3P)4, 11 mg, 0.01 mmol). The reaction was heated at 110° C. for 30 min under microwave initiator. The reaction mixture was worked-up with EtOAc extraction and product was purified by HPLC and afforded 100 (10.8 mg, 29%) as white solid. LC-MS: calcd. for C20H16FN5O2: 378 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20](OC1C=CC=CC=1)=[O:21].[CH3:29][C:30]1[O:34][N:33]=[C:32](C(Cl)=O)[CH:31]=1>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20]([C:32]1[CH:31]=[C:30]([CH3:29])[O:34][N:33]=1)=[O:21]
Reactant: Cc1cc(C(=O)Cl)no1
Reactant: Cn1c(Nc2ccc(I)cc2F)c(C(=O)Oc2ccccc2)c(=O)n(C)c1=O
Product: Cc1cc(C(=O)c2c(Nc3ccc(I)cc3F)n(C)c(=O)n(C)c2=O)no1

Procedure:
The title compound was synthesized following a similar procedure described in the synthesis of compound 2A by reaction of Example 1 and 5-methylisoxazole-3-carbonyl chloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.42 (s, 2 H) 3.13 (s, 2 H) 3.19 (s, 2 H) 6.13-6.29 (m, 1 H) 7.08 (t, J=8.59 Hz, 1 H) 7.47 (dd, J=8.46, 1.89 Hz, 1 H) 7.68 (dd, J=9.98, 1.89 Hz, 1 H) 10.47 (s, 1 H) [M+H] calc'd for C17H14FIN4O4, 485; found, 485.