Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:11])=[C:4]([NH2:10])[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].[CH:12]1([N:15]=[C:16]=S)[CH2:14][CH2:13]1.O1CCN(CCN=C=N)CC1.CC1C=CC(S(O)(=O)=O)=CC=1>N1C=CC=CC=1>[Br:1][C:2]1[C:3]2[N:11]=[C:16]([NH:15][CH:12]3[CH2:14][CH2:13]3)[NH:10][C:4]=2[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8]
Reactant: Nc1cc(Cl)c(Cl)c(Br)c1N
Reactant: S=C=NC1CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N=C=NCCN1CCOCC1
Solvent: c1ccncc1
Product: Clc1cc2[nH]c(NC3CC3)nc2c(Br)c1Cl
Yield: 34.7 %

Procedure:
3-Bromo-4,5-dichloro-1,2-phenylenediamine (5.12 g, 20.0 mmol), cyclopropyl isothiocyanate (2.18 g, 21.98 mmol), 1-cyclohexyl-3-(2-morpholinoethylcarbodiimide metho-p-toluenesulfonate (11.0 g, 25.97 mmol) and pyridine (75 mL) were used according to general procedure I. The product was recrystallized from 1,4-dioxane to afford 2.23 g (53%) of a white solid. MS (CI): m/z 319 amu. Anal. Calcd for C10H8BrCl2N3(0.35 C4H8O2): C, 38.92; H, 3.09; N, 11.94. Found: C, 39.17; H, 3.05; N, 11.94.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:30][O:31][C:32]1[C:33](=[O:56])[C:34]([CH3:55])=[C:35]([CH2:41][C:42]2[CH:43]=[CH:44][C:45]([O:51][C:52](=[O:54])[CH3:53])=[C:46]([CH:50]=2)[C:47](O)=[O:48])[C:36](=[O:40])[C:37]=1[O:38][CH3:39]>C(Cl)Cl>[CH3:30][O:31][C:32]1[C:33](=[O:56])[C:34]([CH3:55])=[C:35]([CH2:41][C:42]2[CH:43]=[CH:44][C:45]([O:51][C:52](=[O:54])[CH3:53])=[C:46]([CH:50]=2)[C:47]([NH:11][C:10]2[CH:12]=[CH:13][C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[CH:8][CH:9]=2)=[O:48])[C:36](=[O:40])[C:37]=1[O:38][CH3:39]
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(N4CCOCC4)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 26.9 %

Procedure:
4-Morpholinoaniline (0.286 g, 1.60 mmol), triethylamine (0.162 g, 1.60 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.271 g, 1.60 mmol) were added to a methylene chloride solution (20 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:2) and then recrystallized from ether to obtain the titled compound (0.077 g, 0.144 mmol, 27%).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C(N(CC)CC)C.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>C(Cl)(Cl)(Cl)Cl.O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl>[O:4]=[C:3]([CH:5]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=Cc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC(=O)C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
A solution of 6.6 ml (0.06 moles) of titanium tetrachloride in 30 ml of carbon tetrachloride was added dropwise with rapid stirring to 300 ml of cold (-50° ) tetrahydrofuran. The mixture was allowed to warm to 0° and a solution of 5.85 g (0.045 moles) of ethyl acetoacetate in 50 ml of tetrahydrofuran was added dropwise over about 20 minutes. After the mixture was stirred an additional 30 minutes, a solution of 25.2 ml (0.180 moles) of triethylamine in 50 ml of tetrahydrofuran was added dropwise over 45 minutes. After the mixture was stirred an additional 45 minutes, a solution of 4.8 g (0.045 moles) of benzaldehyde in 50 ml of tetrahydrofuran was added dropwise over 30 minutes. The reaction mixture was allowed to warm to room temperature and then stirred for 24 hours. Water (50 ml) was added and the resultant two-phase mixture was stirred for two hours. After the layers were separated, the aqueous layer was extracted with 50 ml of ethyl acetate. The ethyl acetate extract was combined with the initially separated organic layer, dried over sodium sulfate, filtered, and concentrated in vacuo to 9.8 g of an oil. Chromatography on silica gel gave 7.4 g of the title compound as a solid, m.p. ca. 49°. Structure assignment was supported by nmr and infrared spectra and by elemental analysis.
Reaction SMILES: [CH3:1][C:2]([N:10]1[N:14]=[N:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]([NH:47]C(OC(C)(C)C)=O)[CH2:23][C@H:24]([OH:46])[C@@H:25]([NH:33][C:34](=[O:45])[C@H:35]([C:41]([CH3:44])([CH3:43])[CH3:42])[NH:36][C:37]([O:39][CH3:40])=[O:38])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:17][CH:16]=2)=[N:11]1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].[ClH:55]>C(#N)C>[ClH:55].[CH3:3][C:2]([N:10]1[N:14]=[N:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][N:22]([NH2:47])[CH2:23][C@H:24]([OH:46])[C@@H:25]([NH:33][C:34](=[O:45])[C@H:35]([C:41]([CH3:43])([CH3:42])[CH3:44])[NH:36][C:37]([O:39][CH3:40])=[O:38])[CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:19][CH:20]=2)=[N:11]1)([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:1]
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2nnn(C(C)(C)c3ccccc3)n2)cc1)NC(=O)OC(C)(C)C)C(C)(C)C
Agent: Cl
Solvent: CC#N
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2nnn(C(C)(C)c3ccccc3)n2)cc1)C(C)(C)C

Procedure:
Under a nitrogen atmosphere, 1.37 g (1.84 mmol) of 1-{4-[2-(1-methyl-1-phenyl-ethyl)-2H-tetrazol-5-yl]-phenyl}-4(S)-hydroxy-2-(tert-butoxycarbonyl)amino-5(S)-N-(N-methoxycarbonyl-(L)-tert-leucyl)amino-6-phenyl-2-azahexane are stirred in 64 ml of acetonitrile and 64 ml of aqueous 2N HCl at room temperature for 6 days. The reaction mixture is filtered, and the filtrate is concentrated by evaporation under a high vacuum at room temperature and is finally lyophilised from dioxane to yield the title compound: HPLC20-100 : tRet =14.2; 1H-NMR (CD3OD) inter alia δ 8.10 (d, J=8, 2Harom), 7.8 (m, 1Harom), 7.53 (m, 2Harom), 7.32 (m, 3Harom), 7.17 (m, 6Harom), 2.23 (s, 2H3Ctetrazole-protecting group).
Reaction SMILES: [CH:1]1([CH2:4][O:5]/[N:6]=[C:7](/[C:13]2[N:14]=[C:15]([NH:18]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[S:16][CH:17]=2)\[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3][CH2:2]1.O>C(O)=O>[CH2:11]([O:10][C:8](=[O:9])/[C:7](/[C:13]1[N:14]=[C:15]([NH2:18])[S:16][CH:17]=1)=[N:6]\[O:5][CH2:4][CH:1]1[CH2:2][CH2:3]1)[CH3:12]
Reactant: CCOC(=O)/C(=N\OCC1CC1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O=CO
Solvent: O
Product: CCOC(=O)/C(=N\OCC1CC1)c1csc(N)n1
Yield: 93 %

Procedure:
Ethyl (Z)-2-cyclopropylmethoxyimino-2-(2-tritylaminothiazol-4-yl)acetate (2.39 g) was dissolved in 98% formic acid (18.7 ml), water (5.6 ml) was added, and the mixture vigorously stirred. After 6 h the solvents were evaporated, toluene added to the residue and the process repeated. This was done twice more. The residual solid was chromatographed on silica to give the title compound as a white solid (1.17 g), νmax (Nujol) 3440, 3250, 3120, 1720, and 1620 cm-1 ; δH (CDCl3) inter alia 1.35 (3H, t, J 7 Hz), 4.0 (2H, d, J 7 Hz), 4.37 (2H, q, J 7 Hz), 5.4 (2H, broad s, exch. D2O), and 6.67 (1H, s).
Reaction SMILES: [O:1]=[C:2]1[N:8]2[C@H:4]([O:5][C:6]([CH:9]=[CH2:10])=[CH:7]2)[CH2:3]1.[SH:11][CH2:12][CH2:13][OH:14].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>O1CCCC1.C(OCC)(=O)C>[OH:14][CH2:13][CH2:12][S:11][CH2:10]/[CH:9]=[C:6]1/[CH2:7][N:8]2[C@H:4]([O:5]/1)[CH2:3][C:2]2=[O:1]
Reactant: OCCS
Reactant: C=CC1=CN2C(=O)C[C@H]2O1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1C[C@H]2O/C(=C\CSCCO)CN12

Procedure:
(5R)-7-Oxo-3-vinyl-4-oxa-1-azabicyclo[3.2.0] hept-2-ene (2.5 mmole) in dry tetrahydrofuran (20 ml) was treated with 2-mercaptoethanol (0.4 ml) and benzoyl peroxide (10 mg). The resulting mixture was stirred under dry nitrogen while being irradiated using a 200 W bulb placed 1" from the reaction vessel for a total time of 14 hours. The mixture was diluted with ethyl acetate (100 ml) and was washed with saturated sodium bicarbonate solution and saturated brine. The solution was dried (magnesium sulphate) and the solvent was evaporated under reduced pressure to give a yellow oil. The oil was chromatographed on silica gel (20 g) using graded elution from 1:4 to 1:1 ethyl acetate/petroleum ether (b.p. 60°-80°). The title compound was thus obtained as a colourless gum (45 mg), [α]D22 =+66.8° (c 1.0, CHCl3). νmax (CHCl3): 3370, 1795, 1695 cm-1. δ(CDCl3): 2.40 (1H, br.s, OH), 2.65 (2H, t, J 6 Hz), 2.95 (1H, d, J 16 Hz), 3.15-3.80 (6H, complex), 4.25-4.55 (2H, complex), 5.47 (1H, d, J 2 Hz). m/e: 138 (67%), 96 (100).
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][C:7](Br)=[CH:6][C:3]=1[C:4]#[N:5].[CH3:11][C@H:12]1[CH2:17][N:16]([CH2:18][B-](F)(F)F)[CH2:15][C@@H:14]([CH3:23])[O:13]1.[K+].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>O1CCOCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C:2]1[N:9]=[CH:8][C:7]([CH2:18][N:16]2[CH2:17][C@@H:12]([CH3:11])[O:13][C@@H:14]([CH3:23])[CH2:15]2)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(Br)cnc1N
Reactant: C[C@@H]1CN(C[B-](F)(F)F)C[C@H](C)O1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H]1CN(Cc2cnc(N)c(C#N)c2)C[C@H](C)O1
Temperature: 80 °C
Yield: 92.6 %

Procedure:
A suspension of 2-amino-5-bromonicotinonitrile (50 mg, 0.25 mmol), potassium (((2S,6R)-2,6-dimethylmorpholino)methyl)-trifluoroborate (219 mg, 0.51 mmol), cesium carbonate (247 mg, 0.76 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (36 mg, 0.076 mmol) and palladium(II) acetate (8.5 mg, 0.038 mmol) in dioxane (1 mL) and water (0.1 mL) was purged with nitrogen for 10 minutes, then sealed and heated at 80° C. for 15 hours. The reaction was filtered through Celite while still hot, cooled to room temperature, and diluted with water (10 mL). The resulting precipitate was filtered, washed with water (10 mL) and hexanes (10 mL), and dried under vacuum to give the title compound as a solid (57 mg, 92%). 1H NMR (400 MHz, DMSO-d6) δ 1.03 (d, J=6.3 Hz, 6H), 1.61 (t, J=10.7 Hz, 2H), 2.64 (d, J=10.7 Hz, 2H), 3.45-3.61 (m, 2H), 6.83 (s, 2H), 7.74 (d, J=2.3 Hz, 1H), 8.03-8.19 (m, 1H).
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([CH2:12][OH:13])[CH:9]=[CH:8][C:6]=2[N:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][S:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([CH:12]=[O:13])[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CSc1nc2ccc(CO)cc2s1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Solvent: ClCCl
Product: CSc1nc2ccc(C=O)cc2s1
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To a stirred mixture of (2-(methylthio)benzo[d]thiazol-6-yl)methanol (958 mg, 4.5 mmol) from Step 3 of Example 36 in CH2Cl2 (20 mL) at 0° C. under argon was added Dess-Martin periodinane (2.0 g, 5.0 mmol) portionwise. The mixture was stirred for 1 h and then diluted with CH2Cl2 (100 mL). To this mixture was added a 50/50 mixture of saturated aq sodium sulfite and saturated aq sodium bicarbonate (40 mL). This mixture was stirred for 10 min and then the CH2Cl2 layer was separated, washed with a saturated aq sodium bicarbonate (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 2-(methylthio)benzo[d]thiazole-6-carbaldehyde (937 mg, 99%) as a white solid. LCMS (ESI) m/z 210 (M+H)+.
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[C:18]([F:26])[CH:17]=3)[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>Cl>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[C:18]([F:26])[CH:17]=3)[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C1CC(=O)OC(CCc2ccc(C(=O)O)c(F)c2)(C2CCCC2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.6 %

Procedure:
Methyl 4-[2-(2-cyclopentyl-4,6-dioxotetrahydro-2H-pyran-2-yl)ethyl]-2-fluorobenzoate (example B(5)) (300 mg) was treated with 4N NaOH (10 ml) and stirred for 4 hrs at room temperature. The mixture was then acidified with 1N HCl (20 ml) and the product was extracted with ethyl acetate (2×20 ml). The combined organic layers were dried over magnesium sulfate and concentrated to a solid. The solid was recrystallised from diethyl ether to afford the title compound as a white solid (120 mg). 1H NMR (300 MHz, MeOD): δ 1.38-2.30 (m, 11H), 2.80-3.12 (m, 6H), 6.91 (d, J=7.19 Hz, 1H), 7.17 (m, 1H), 7.86 (d, J=719 Hz, 1H)
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]1[C@H:11]([CH3:12])[C@@H:10]([C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=2[C:23]2[CH:28]=[C:27](Br)[CH:26]=[CH:25][C:24]=2[O:30][CH3:31])[O:9][C:8]1=[O:32].[NH2:42][C:43]1[CH:48]=[C:47]([C:49]([O:51][CH3:52])=[O:50])[CH:46]=[CH:45][C:44]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].C(O)C>[Cl-].[Na+].O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[NH2:42][C:43]1[CH:48]=[C:47]([C:49]([O:51][CH3:52])=[O:50])[CH:46]=[CH:45][C:44]=1[C:27]1[CH:26]=[CH:25][C:24]([O:30][CH3:31])=[C:23]([C:14]2[CH:15]=[CH:16][C:17]([C:19]([F:21])([F:20])[F:22])=[CH:18][C:13]=2[C@H:10]2[O:9][C:8](=[O:32])[N:7]([CH2:6][C:5]3[CH:4]=[C:3]([C:2]([F:41])([F:40])[F:1])[CH:35]=[C:34]([C:36]([F:38])([F:39])[F:37])[CH:33]=3)[C@@H:11]2[CH3:12])[CH:28]=1
Reactant: COc1ccc(Br)cc1-c1ccc(C(F)(F)F)cc1[C@H]1OC(=O)N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reactant: COC(=O)c1ccc(B(O)O)c(N)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3[C@H]3OC(=O)N(Cc4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(N)c1
Temperature: 80 °C
Reaction time: 0.75 h

Procedure:
(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-5-[5′-bromo-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]-4-methyl-1,3-oxazolidin-2-one (358 mg, 0.545 mmol), [2-amino-4-(methoxycarbonyl)phenyl]boronic acid (214 mg, 1.1 mmol), dichloro bis(triphenylphosphine)palladium(II) (76.5 mg, 0.109 mmol), aqueous potassium carbonate (545 μL, 2M, 1.09 mmol) and ethanol (5 mL) were mixed and heated in a 80° C. oil bath. Aliquot at reaction time 2 hours and 3.5 hours indicated about 6% of unreacted starting material. Added more [2-amino-4-(methoxycarbonyl)phenyl]boronic acid (50 mg, 0.256 mmol) when reaction time was 3 hours 45 minutes. Aliquot did not show any further progress. Crude mixture was cooled and mixed with brine. Volatiles were removed from the crude under reduced pressure. The resulting mixture was treated with water followed by ethyl acetate extraction. The combined extracts were dried over Na2SO4, filtrated and concentrated under reduced pressure to afford a dark oil. The resulting oil was purified by flash chromatography (SiO2, Biotage 40+M cartridge, EtOAc/hexanes, gradient) followed by preparative TLC purification (SiO2, 10% ethyl acetate in dichloromethane) to afford methyl 2-amino-2″-{(4R,5R)-3-[3,5-bis(trifluoromethyl)benzyl]-4-methyl-2-oxo-1,3-oxazolidin-5-yl}-4′-methoxy-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate. LCMS calc.=726.18; found=727.29 (M+1)+.
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:44])[CH2:14][CH2:15][N:16]([CH2:28][CH2:29][C:30]([N:32]1[CH2:36][CH2:35][CH2:34][C@@H:33]1[C:37]([O:39]C(C)(C)C)=[O:38])=[O:31])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=1)=[O:7])(C)(C)C.[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48]>ClCCl.CCOCC>[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48].[C:37]([C@H:33]1[CH2:34][CH2:35][CH2:36][N:32]1[C:30](=[O:31])[CH2:29][CH2:28][N:16]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:20][CH:19]=1)[CH2:15][CH2:14][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[C:6]([OH:7])=[O:5])=[O:44])([OH:39])=[O:38]
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)CCN(CCC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C)Cc1ccc(C(F)(F)F)cc1
Solvent: CCOCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@H]1CCCN1C(=O)CCN(CCC(=O)N1CCC[C@@H]1C(=O)O)Cc1ccc(C(F)(F)F)cc1
Reaction time: 16 h
Yield: 75 %

Procedure:
To a stirred solution of 200 mg (0.32 mmol) (R)-1-[3-[[3-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-3-oxo-propyl]-(4-trifluoromethyl-benzyl)-amino]-propionyl]-pyrrolidine-2-carboxylic acid tert-butyl ester in 5 ml dichloromethane at 0° C. was added dropwise 1.0 ml trifluoroacetic acid and stirring continued for 16 h at room temperature. Concentration in vacuo and azeotroping three times with chloroform on a rotary evaporator afforded, after trituration in ether, 150 mg (75%) of the title compound as a yellow crystalline solid. MS m/e (%): 536 (M+Na+, 20), 514 (M+H+, 100).
Reaction SMILES: C1CO[C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22](O)[CH:21]=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1.ClC1N=C(NC2C=CC=C(O)C=2)C(F)=CN=1.[S:43]1[C:47]2C=CC=CC=2[C:45](CN)=[CH:44]1>>[S:43]1[C:44]2[CH:45]=[CH:21][CH:22]=[CH:23][C:24]=2[C:25]([CH2:20][NH:19][C:14]2[N:13]=[C:12]([NH:11][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([OH:2])[CH:4]=3)[C:17]([F:18])=[CH:16][N:15]=2)=[CH:47]1
Reactant: NCc1csc2ccccc12
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Agent: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Product: Oc1cccc(Nc2nc(NCc3csc4ccccc34)ncc2F)c1
Yield: 53 %

Procedure:
In a manner analogous to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine (50 mg, 0.21 mmol) and benzothiophen-3-ylmethylamine (100 mg, 0.61 mmol) gave N2-(benzothiophen-3-ylmethyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine (40 mg, 53%). 1H NMR (CDCl3): δ 4.82 (d, J=6.0 Hz, 2H), 6.45 (dd, J=8.1 Hz, 1H), 6.70 (m, 1H), 6.80 (d, J=8.4 Hz, 1H), 7.03 (t, J=8.1 Hz, 1H), 7.22 (m, 1H), 7.34 (s, 1H), 7.39-7.46 (m, 2H), 7.82 (m, 1H), 7.89-7.92 (m, 2H); 19F NMR (282 MHz, CDCl3): δ −170.02; LCMS: ret. time: 21.29 min.; purity: 92.97%; MS (m/e): 367.03 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([OH:13])=[C:9]([CH:12]=1)[CH:10]=[O:11])([CH3:4])([CH3:3])[CH3:2].CC(=CC)C.P([O-])(O)(O)=[O:20].[Na+].Cl([O-])=O.[Na+]>O1CCCC1.O.C(OCC)(=O)C.C(O)(C)(C)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([OH:13])=[C:9]([CH:12]=1)[C:10]([OH:20])=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(O)c(C=O)c1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1ccc(O)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 128.7 %

Procedure:
5-tert-Butyl-2-hydroxy-benzaldehyde (1.4 g, 6.0 mmol, prepared according to Smith W. E. J. Org. Chem. 1972, 37, 3972-3973) was taken up in 30 mL of a 2M solution of 2-methyl-2-butene in tetrahydrofuran. t-Butanol (30 mL) was added. Sodium dihydrogenphosphate (2.6 g, 18.8 mmol) and sodium chlorite (1.4 g, 12.3 mmol) were then added as a solution in 12 mL of water. The reaction mixture was stirred at room temperature for 2 h. It was diluted with ethyl acetate and washed with 1N hydrochloric acid. The aqueous layers were extracted three times with ethyl acetate. The combined organic layers were washed with a saturated solution of Na2S2O3, brine, and dried over anhydrous magnesium sulfate. The solids were filtered off, and the filtrate was concentrated to give 5-tert-butyl-2-hydroxy-benzoic acid (1.5 g, quant.), which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[C:16](B3OC(C)(C)C(C)(C)O3)[CH:17]=2)[C:11]([O:13]C)=[O:12])=[N:6][CH:7]=1.Br[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:29]=1[F:35].C(=O)([O-])[O-].[Cs+].[Cs+].O.CN(C)C=O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:34][C:30]1[C:29]([F:35])=[CH:28][CH:33]=[CH:32][C:31]=1[C:16]1[CH:17]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=2)[CH:9]=[C:10]([C:11]([OH:13])=[O:12])[CH:15]=1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cc(-c2ccc(C)cn2)c1
Reactant: Fc1cccc(Br)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)O)cc(-c3cccc(F)c3F)c2)nc1

Procedure:
In a 5 mL microwave vial, methyl 3-(5-methylpyridin-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (250 mg, 0.71 mmol), 1-bromo-2,3-difluorobenzene (273.2 mg, 1.416 mmol), cesium carbonate (1153 mg, 3.539 mmol), tetra-n-butylammonium iodide (261.4 mg, 0.7078 mmol), and POPd (35.51 mg, 0.07078 mmol) were dissolved in Water (0.5 mL, 30 mmol) and N,N-dimethylformamide (3 mL, 30 mmol). The reaction mixture was microwaved for 10 mins at 150 degrees. The reaction mixture was extracted with ethylacetate and washed repeatedly with brine. The solvent removed under reduced pressure and used in the next reaction without further purification.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH:10]([CH2:14][OH:15])[CH:9]1[C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:24](Cl)([C:27]1[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=1)(=[O:26])=[O:25]>[K]>[CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH:10]([CH2:14][O:15][S:24]([C:27]2[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH:9]1[C:16]1[C:17]([Cl:23])=[CH:18][CH:19]=[CH:20][C:21]=1[Cl:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC(CO)C(c2c(Cl)cccc2Cl)N1Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [K]
Product: Cc1ccc(S(=O)(=O)OCC2CC(=O)N(Cc3ccccc3)C2c2c(Cl)cccc2Cl)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 77.2 %

Procedure:
To 40 g of 1-benzyl-2-(2,6-dichlorophenyl)-3-hydroxymethyl-pyrrolidine-5-one in 67 ml of potassium dried pyridine at 5°-10° was added 23.3 g of tosyl chloride over 30 minutes. After the addition, the mixture was stirred for 3 hours at 15° and then for 13 hours ambient temperature. The reaction mixture was added dropwise to a stirred ice-water solution and then set at ambient temperature for 72 hours. The light yellow solid was collected by filtration and then air dried. Trituration with ether followed by filtration provided 44.5 g of colorless crystals, m.p. 110°-114°.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl:8][C:9]1[CH:10]=[C:11]([SH:16])[CH:12]=[C:13]([Cl:15])[CH:14]=1.CC(C)([O-])C.[K+].C(OCC)(=O)C>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].C1C=CC(P(C2C(OC3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=CC=3)=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:8][C:9]1[CH:10]=[C:11]([S:16][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:12]=[C:13]([Cl:15])[CH:14]=1
Reactant: Ic1cccnc1
Reactant: Sc1cc(Cl)cc(Cl)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Clc1cc(Cl)cc(Sc2cccnc2)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 717.1 %

Procedure:
A solution of 0.018 g (0.020 mmol) Pd2dba3 and 0.021 g (0.039 mmol) DPEphos in toluene (3 mL) was stirred under an argon atmosphere for 5 minutes. 3-Iodo-pyridine (0.100 g, 0.49 mmol), 3,5-dichlorobenzenethiol (0.087 g, 0.49 mmol) and 0.060 g (0.54 mmol) potassium t-butoxide were added and the reaction mixture was heated to 100° C. and held for 2 hours, then cooled. Ethyl acetate was added to the reaction mixture and the organic phase was washed with water, dried and concentrated. The crude product was purified using flash chromatography to give 0.90 g (72% yield) 3-(3,5-dichloro-phenylsulfanyl)-pyridine.