Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:8]1[CH:17]=[N:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[C@H:20]1[CH2:24][CH2:23][O:22][CH2:21]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:2]1([NH:1][C:8]2[CH:17]=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][C@@H:20]4[CH2:24][CH2:23][O:22][CH2:21]4)[CH:14]=3)[N:9]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc2nc(Nc3ccccc3)cnc2c1
Reactant: O[C@H]1CCOC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1ccc(Nc2cnc3cc(O[C@@H]4CCOC4)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a THF solution at 0° C. under argon is added 2-anilino-6-quinoxalinol (0.23 g, 0.97 mmol), (S)-(+)-3-hydroxytetrahydrofuran (0.086 mL, 1.3 mmol), and triphenylphosphine (0.31 g, 1.2 mmol). DEAD (0.18 mL, 1.2 mmol) is added portionwise. The reaction is allowed to warm to room temperature and stirred for 1.5 hours. The mixture is concentrated and partitioned between EtOAc and H2O. The organic layer is washed with H2O, brine, dried (MgSO4), and concentrated. The resulting yellow oil is chromatographed (50% EtOAc/hexanes) and taken up in Et2O/IPA. HCl/Et2O solution is added dropwise and the resulting red-orange powder is dried in vacuo. The powder is free-based by stirring in MeOH with washed (3×H2O, 5×MeOHM basic ion exchange resin. The mixture is stirred 30 minutes, filtered, concentrated, and recrystallized from EtOAc/hexanes to provide, in two crops, the product (m.p. 173-175° C.). Anal. Calcd. for C18H17N3O2: C, 70.35; H, 5.57; N, 13.67; Found: C, 70.19; H, 5.60; N, 13.66.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Cl[CH2:18][C:19]1[N:23]=[C:22]([C:24]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=2[F:34])[O:21][N:20]=1>>[F:34][C:25]1[CH:26]=[CH:27][C:28]([C:30]([F:31])([F:32])[F:33])=[CH:29][C:24]=1[C:22]1[O:21][N:20]=[C:19]([CH2:18][N:3]2[C:4]3[C:9](=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=3)[CH:10]=[C:2]2[CH3:1])[N:23]=1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: Fc1ccc(C(F)(F)F)cc1-c1nc(CCl)no1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(C(F)(F)F)ccc2F)n1

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 120) and 3-(chloromethyl)-5-[2-fluoro-5-(trifluoromethyl)phenyl]-1,2,4-oxadiazole: 1H NMR (400 MHz, CDCl3) δ 8.33 (m, 1H), 7.85 (m, 1H), 7.69 (d, J=8.6 Hz, 1H), 7.56 (d, J=8.6 Hz, 1H), 7.39 (d, J=9.3 Hz, 1H), 6.65 (s, 1H), 5.50 (s, 2H), 2.68 (s, 3H); MS (ES) m/z 469 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([Cl:18])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([CH:27]3[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]3)([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[OH:20])[CH:8]=2)[N:3]=1.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34].C(Cl)(=O)C.CCN(CC)CC>C(Cl)Cl>[C:33]([N:23]1[CH2:24][CH2:25][CH2:26][CH:21]([C:19]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[N:3]=[C:2]([Cl:1])[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:10]3[Cl:18])([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[OH:20])[CH2:22]1)(=[O:34])[CH3:35].[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]
Reactant: OC(c1cccnc1)(c1ccc2nc(Cl)c(-c3ccccc3)c(Cl)c2c1)C1CCCNC1
Solvent: CC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(=O)N1CCCC(C(O)(c2cccnc2)c2ccc3nc(Cl)c(-c4ccccc4)c(Cl)c3c2)C1
Reaction time: 8 h

Procedure:
A mixture of 2,4-dichloro-3-phenylquinolin-6-yl)(piperidin-3-yl)pyridin-3-ylmethanol•TFA (19 mg, 0.027 mmol, Example 93), acetyl chloride (10 mg, 0.13 mmol), and Et3N (0.030 mL, 0.22 mmol) in CH2Cl2 (1 mL) was stirred overnight and concentrated. The residue was purified by reverse phase HPLC (water/acetonitrile/0.1% TFA) to provide the title compound as a white solid. 1H NMR (400 MHz, MeOH-d4) δ 9.06-9.14 (m, 1H), 8.67-8.77 (m, 3H), 8.02-8.20 (m, 2H), 7.96 (dd, J=5.56, 8.08 Hz, 1H), 7.46-7.58 (m, 3H), 7.30-7.38 (m, 2H), 4.48-4.63 (m, 1H), 3.94 (d, J=13.14 Hz, 0.6H), 3.65 (d, J=9.60 Hz, 0.4H), 2.88-3.16 (m, 2H), 2.45-2.67 (m, 1H), 2.10 (s, 2H), 1.90 (s, 1H), 1.49-1.88 (m, 4H); MS m/e 506.1 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:18]([NH:21][NH:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:20])[CH3:19].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[C:12]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][C:9]([N:21]([CH:18]([CH3:20])[CH3:19])[NH:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:11])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)CC(c1ccccc1)c1ccccc1
Reactant: CC(C)NNC(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)CC(c1ccccc1)c1ccccc1
Yield: 27.3 %

Procedure:
A solution of 3,3-diphenylpropionic acid (127 mg, 0.56 mmoles) and benzoic acid N′-isopropyl-hydrazide (100 mg, 0.56 mmoles) in DMF (5 mL) was treated with triethylamine (0.23 mL, 1.68 mmol), HOBT (91 mg, 0.67 mmoles) and EDCI (129 mg, 0.67 mmol) at room temperature for 18 h. The reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with water, dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate/hexanes gradient to afford the product as a solid (59 mg, 27%). LC-MS m/e 387.26 (M+H+)
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[C:9]([C:11]1[N:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][CH:12]=1)#[N:10]>CC(C)=O>[C:9]([C:11]1[N:16]=[CH:15][C:14]([C:17]([O:19][CH3:1])=[O:18])=[CH:13][CH:12]=1)#[N:10]
Reactant: N#Cc1ccc(C(=O)O)cn1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1ccc(C#N)nc1
Yield: 80.2 %

Procedure:
Potassium carbonate (6.1 g, 43.9 mmol) and methyl iodide (21 mL, 338 mmol) were added sequentially to a solution comprising 6-cyanopyridine-3-carboxylic acid (5 g, 33.8 mmol) in acetone (300 mL). The mixture was heated at reflux for 15 hours and concentrated under reduced pressure. The residue was partioned between ether and saturated sodium bicarbonate. The organic layer was washed with water, dried (MgSO4), filtered and concentrated under reduced pressure to provide methyl 6-cyanopyridine-3-carboxylate (4.4 g, 27.1 mmol) as a tan solid. 1H-NMR (300 Mhz, DMSO-d6): 3.9 (s, 3H), 8.2 (d, 1H, J=7.5 Hz), 8.5 (d, 1H, J=7.5 Hz), 9.2 (s, 1H).
Reaction SMILES: Cl.[Br:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][CH3:15])[CH2:10][CH2:9]1.[F:16][C:17]1[CH:18]=[C:19]([S:24](Cl)(=[O:26])=[O:25])[CH:20]=[CH:21][C:22]=1[F:23]>>[Br:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([N:14]([CH3:15])[S:24]([C:19]2[CH:20]=[CH:21][C:22]([F:23])=[C:17]([F:16])[CH:18]=2)(=[O:26])=[O:25])[CH2:12][CH2:13]1
Reactant: CN[C@H]1CC[C@H](OCCCCBr)CC1
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1
Agent: Cl
Product: CN([C@H]1CC[C@H](OCCCCBr)CC1)S(=O)(=O)c1ccc(F)c(F)c1

Procedure:
In analogy to example 11.9, trans-[4-(4-Bromo-butoxy)-cyclohexyl]-methyl-amine hydrochloride and 3,4-difluoro-benzenesulfonyl chloride (with 2.1 eq N,N-diisopropylethylamine) were reacted to yield trans-N-[4-(4-Bromo-butoxy)-cyclohexyl]-3,4-difluoro-N-methyl-benzenesulfonamide which was used directly in the next steps see Example 12.55-12.56 and 12.65 and 12.66.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1)[CH2:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][N:15]=1)[C:9]([O:11][CH3:12])=[O:10]>C(O)(=O)C.[Pt](=O)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:18]=1)[CH2:5][CH:6]1[CH2:7][CH:8]([C:9]([O:11][CH3:12])=[O:10])[CH2:13][CH2:14][NH:15]1
Reactant: COC(=O)c1ccnc(Cc2cc(F)cc(C(F)(F)F)c2)c1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: COC(=O)C1CCNC(Cc2cc(F)cc(C(F)(F)F)c2)C1
Reaction time: 0.75 h
Yield: 89.6 %

Procedure:
To a solution of methyl 2-(3-fluoro-5-(trifluoromethyl)benzyl)isonicotinate (4.5 g, 14.37 mmol) in acetic acid (50 mL) was added platinum(IV) oxide (0.36 g, 1.59 mmol) and the resulting mixture hydrogenated at 5 bar in a Büchi hydrogenator for 3 h 45 min. The reaction mixture was filtered through a diatomeous earth filter carton and the catalyst washed with methanol. The solvents were evaporated, the residue dissolved in DCM and washed with 10% Na2CO3. After phase separation the aqueous layer was extracted with DCM. The combined organic layers were dried over MgSO4 and evaporated. Methyl 2-(3-fluoro-5-(trifluoro-methyl)benzyl)piperidine-4-carboxylate (4.11 g, 90%) was isolated as a pale yellow oil that partially solidified upon standing. MS m/z 320 (M+H)+
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].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.[CH3:53][C@H:54]1[O:59][C@@H:58]([CH3:60])[CH2:57][NH:56][CH2:55]1.[C:61]([N:64]1[CH2:69][CH2:68][N:67]([C:70]2[CH:75]=[CH:74][C:73](OS(C(F)(F)F)(=O)=O)=[CH:72][CH:71]=2)[CH2:66][CH2:65]1)(=[O:63])[CH3:62]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:60][C@H:58]1[O:59][C@@H:54]([CH3:53])[CH2:55][N:56]([C:73]2[CH:72]=[CH:71][C:70]([N:67]3[CH2:66][CH2:65][N:64]([C:61](=[O:63])[CH3:62])[CH2:69][CH2:68]3)=[CH:75][CH:74]=2)[CH2:57]1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: CC(=O)N1CCN(c2ccc(OS(=O)(=O)C(F)(F)F)cc2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)N1CCN(c2ccc(N3C[C@@H](C)O[C@@H](C)C3)cc2)CC1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
To a mixture of cesium carbonate (25.32 g), palladium(II) acetate (0.624 g) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (2.59 g) in toluene (110 ml) was successively added cis-2,6-dimethylmorpholine (8.21 ml) and trifluoromethanesulfonic acid 4-(4-acetylpiperazin-1-yl)phenyl ester (20 g) in stream of nitrogen. The mixture was stirred at ambient temperature for 30 minutes and at 100° C. for further 12 hours. After cooling to room temperature, water was added to the reaction mixture. The resulting precipitates were filtered, washed with water and dried. The residue was purified by silica gel chromatography (50:1 dichloromethane-methanol elution) to give 1-[4-[4-(cis-2,6-dimethylmorpholin-4-yl)phenyl]piperazin-1-yl]ethanone (7.78 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([OH:15])=O)[S:10][C:11]=1[CH3:12].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)[CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[O:15])[S:10][C:11]=1[CH3:12]
Reactant: N[C@@H](Cc1ccc(F)cc1)CN1C(=O)c2ccccc2C1=O
Reactant: Cc1sc(C(=O)O)cc1-c1c(Br)cnn1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1sc(C(=O)N[C@@H](Cc2ccc(F)cc2)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Br)cnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.8 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid (256 mg, 0.85 mmol), 2-[(2S)-2-amino-3-(4-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (1272 mg, 3.80 mmol) [prepared according to the procedure of Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-4-fluoro-L-phenylalanine (4.95 g, 17.5 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (485 mg, 1.03 mmol) in Chloroform (8.5 mL). DIEA (750 μL, 4.29 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (319 mg, 0.50 mmol, 71%): LC-MS (ES) m/z=583 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[NH:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=3)=[CH:17][C:11]=2[N:10]([CH3:29])[C:9]1=[O:30])(=[O:3])[CH3:2].[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38]Cl)=[CH:34][CH:33]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CC(=O)OCC.[Cl-].[Na+].O>[C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[N:15]([CH2:38][C:35]3[CH:36]=[CH:37][C:32]([Cl:31])=[CH:33][CH:34]=3)[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:26])([F:27])[F:28])[CH:19]=3)=[CH:17][C:11]=2[N:10]([CH3:29])[C:9]1=[O:30])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCn1c(=O)c2[nH]c(-c3cccc(OC(F)(F)F)c3)cc2n(C)c1=O
Reactant: ClCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)OCCCn1c(=O)c2c(cc(-c3cccc(OC(F)(F)F)c3)n2Cc2ccc(Cl)cc2)n(C)c1=O
Temperature: 85 °C
Yield: 38.7 %

Procedure:
To a solution of tert-butyl 3-(1-methyl-2,4-dioxo-6-(3-(trifluoromethoxy)phenyl)-1H-pyrrolo[3,2-d]pyrimidin-3(2H,4H,5H)-yl)propyl acetate (See Intermediate 1, 60 mg, 0.141 mmol) in DMF (2 mL) was added 1-chloro-4-(chloromethyl)benzene (45.4 mg, 0.282 mmol), followed by K2CO3 (58.5 mg, 0.423 mmol). The reaction was heated at 85° C. for 18 h, cooled to RT then diluted with EA (10 mL) and brine (5 mL). The organic layer was washed with aq. 1N LiCl (3×20 mL), dried over Na2SO4 and concentrated to a residue which was purified by chromatography PE/EA (5:1 to 2:1) to give 3-(5-(4-chlorobenzyl)-1-methyl-2,4-dioxo-6-(3-(trifluoromethoxy)phenyl)-1H-pyrrolo[3,2-d]pyrimidin-3(2H,4H,5H)-yl)propyl acetate (30 mg, 38.7% yield) as a solid. LCMS: MH+ 550 and TR=2.078 min.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:11][C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:9][N:8]=1)(=O)=O.[F:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=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>[CH2:19]([O:18][C:10]1[CH:11]=[C:12]([CH2:13][C:14]([CH3:15])([CH3:16])[CH3:17])[C:7]([C:30]2[CH:31]=[C:32]([O:35][CH3:36])[CH:33]=[CH:34][C:29]=2[F:28])=[N:8][CH:9]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COc1ccc(F)c(B(O)O)c1
Reactant: CC(C)(C)Cc1cc(OCc2ccccc2)cnc1OS(=O)(=O)C(F)(F)F
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: O
Solvent: Cc1ccccc1
Product: COc1ccc(F)c(-c2ncc(OCc3ccccc3)cc2CC(C)(C)C)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 93.6 %

Procedure:
Under an argon atmosphere, to a solution of 5-(benzyloxy)-3-neopentylpyridin-2-yl trifluoromethanesulfonate (3.35 g) in toluene (25 mL) were added (2-fluoro-5-methoxyphenyl)boronic acid (2.12 g), tetrakis(triphenylphosphine)palladium (0) (961 mg) and 2.0 M aqueous sodium carbonate solution (12.5 mL), and the mixture was stirred at 90° C. for 3 hr. Water was added at room temperature, and the mixture was filtered through celite. The filtrate was extracted with ethyl acetate, and the extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.95 g) as a pale-yellow oil.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]([C:8]2([CH3:13])[O:12][CH2:11][CH2:10][O:9]2)=[CH:6][N:7]=1.[N+:14]([C:17]1[NH:21][N:20]=[CH:19][CH:18]=1)([O-:16])=[O:15].[Br-].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:13][C:8]1([C:5]2[O:4][C:3]([CH2:2][N:20]3[CH:19]=[CH:18][C:17]([N+:14]([O-:16])=[O:15])=[N:21]3)=[N:7][CH:6]=2)[O:12][CH2:11][CH2:10][O:9]1
Reactant: CC1(c2cnc(CCl)o2)OCCO1
Reactant: O=[N+]([O-])c1ccn[nH]1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(c2cnc(Cn3ccc([N+](=O)[O-])n3)o2)OCCO1
Temperature: 25 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [5-(2-methyl-[1,3]dioxolan-2-yl)-oxazol-2-yl]-methanol (35 mg, 0.19 mmol) in dry CH2Cl2 (1.0 mL) was treated at 0° C. with Et3N (0.03 mL, 0.25 mmol) followed by DMAP (2.3 mg, 0.02 mmol) and Ms-Cl (0.02 mL, 0.23 mmol). After stirring at rt for 30 min, the reaction mixture was quenched with water (10 mL), extracted with CH2Cl2 (10 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give crude 2-chloromethyl-5-(2-methyl-[1,3]dioxolan-2-yl)-oxazole as a yellow oil. A solution of this crude 2-chloromethyl-5-(2-methyl-[1,3]dioxolan-2-yl)-oxazole (38 mg, 0.19 mmol) in acetone (1.0 mL) was treated with 5-nitro-1H-pyrazole (21 mg, 0.19 mmol) and TBA bromide (12 mg, 0.04 mmol) followed by K2CO3 (77 mg, 0.56 mmol). The reaction mixture was stirred at rt until completion. The solvent was removed under reduced pressure and water (10 mL) followed by EA (10 mL) were added. The aq. layer was extracted with EA (10 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (4:6 hept-EA) gave the title compound as a colorless oil. TLC: rf (4:6 hept-EA)=0.15. LC-MS-conditions 02: tR=0.83 min; [M+H]+=281.05.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C@@H:9]([OH:14])[C@H:8]([NH:15][C:16](=[O:32])[CH:17]([NH:24]C(=O)OC(C)(C)C)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:7]=2[CH:33]=1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[NH2:24][CH:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:16]([NH:15][C@@H:8]1[C:7]2[CH:33]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=2[O:11][C:10]([CH3:13])([CH3:12])[C@H:9]1[OH:14])=[O:32]
Reactant: CC(C)(C)OC(=O)NC(C(=O)N[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC(=O)C(N)c2ccccc2)[C@@H]1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution containing (3S-trans)-[2-[(6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl)amino]-2-oxo-1-phenylethyl]carbamic acid, 1,1-dimethylethyl ester (2.27 g, 5.03 mmol; the title compound of Example 1) in dichloromethane (20 mL) was added trifluoroacetic acid (5.0 mL) and the reaction mixture was stirred at room temperature for 16 hours. The volatile materials were removed under vacuum and the residue in chloroform was washed with sodium bicarbonate solution and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the residue was purified by flash chromatography (7.5% methanol in dichloromethane) to give two diastereomers. The faster moving material was triturated with ether to give (3S-trans)-α-amino-N-(6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl)benzeneacetamide, isomer A (620 mg, 35.2%) as a colorless solid, mp 243°-246° C. Analysis calculated for C20H21N3O3.0.3H2O: C, 67.32; H, 6.10; N, 11.78. Found: C, 67.50; H, 5.99; N, 11.65. [α]D =-17.2° (c=1, Dimethylformamide). The slower moving material was triturated with ether to give (3S-trans)-α-amino-N-(6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl)-benzeneacetamide, isomer B (940 mg, 53.4%) as a colorless solid, mp 109°-111° C. (with foaming). Analysis calculated for C20H21N3O3.0.45H2O: C, 66.82; H, 6.14; N, 11.69. Found: C, 67.14; H, 6.32; N, 11.14. [α]D=+29.2° (c=1, Dimethylformamide).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][C@H:20]3[CH3:25])[N:16]=[C:15]([NH:26][CH3:27])[N:14]=2)[CH:10]=[C:9]([F:28])[C:8]=1[C:29]#[N:30])(=O)=O.[O:33]1[CH:37]=[CH:36][CH:35]=[C:34]1B(O)O.C(Cl)Cl.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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]>[F:28][C:9]1[CH:10]=[C:11]([C:13]2[CH:18]=[C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][C@H:20]3[CH3:25])[N:16]=[C:15]([NH:26][CH3:27])[N:14]=2)[CH:12]=[C:7]([C:34]2[O:33][CH:37]=[CH:36][CH:35]=2)[C:8]=1[C:29]#[N:30]
Reactant: CNc1nc(-c2cc(F)c(C#N)c(OS(=O)(=O)C(F)(F)F)c2)cc(N2CCOC[C@H]2C)n1
Reactant: OB(O)c1ccco1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CNc1nc(-c2cc(F)c(C#N)c(-c3ccco3)c2)cc(N2CCOC[C@H]2C)n1
Yield: 23.9 %

Procedure:
A solution of 2-cyano-3-fluoro-5-{2-(methylamino)-6-[(3R)-3-methyl-4-morpholinyl]-4-pyrimidinyl}phenyl trifluoromethanesulfonate (374 mg, 0.786 mmol), 2-furanylboronic acid (176 mg, 1.572 mmol), PdCl2(dppf).CH2Cl2 adduct (32.1 mg, 0.039 mmol), and K3PO4 (500 mg, 2.358 mmol) in 1,4-dioxane (10 mL) was heated overnight at 100° C. in a sealed tube. The reaction mixture was allowed to cool, then was partitioned between EtOAc (50 mL) and water (50 mL). The aqueous layer was neutralized with 0.1 M HCl (pH paper) and extracted with EtOAc (3×50 mL). The combined organics were dried over Na2SO4, and concentrated. The residue was purified by RP-HPLC (15-50% CH3CN in water, 0.1% TFA). The product fractions were combined, basified with NaHCO3, extracted with EtOAc, dried, and concentrated to afford the title compound (74 mg) as a brown solid LC-MS (ES) m/z=394 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]([N:14]([C:24]([CH3:27])([CH3:26])[CH3:25])[O:15][CH:16]([C:18](=[O:23])[NH:19][CH2:20][CH2:21][OH:22])[CH3:17])[C:10]([CH3:13])([CH3:12])[CH3:11])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[C:28](Cl)(=[O:31])[CH:29]=[CH2:30].C(N(CC)CC)C>>[C:24]([N:14]([CH:9]([P:4]([O:5][CH2:6][CH3:7])([O:3][CH2:1][CH3:2])=[O:8])[C:10]([CH3:13])([CH3:12])[CH3:11])[O:15][CH:16]([CH3:17])[C:18]([NH:19][CH2:20][CH2:21][O:22][C:28](=[O:31])[CH:29]=[CH2:30])=[O:23])([CH3:26])([CH3:25])[CH3:27]
Reactant: C=CC(=O)Cl
Reactant: CCOP(=O)(OCC)C(N(OC(C)C(=O)NCCO)C(C)(C)C)C(C)(C)C
Solvent: CCN(CC)CC
Product: C=CC(=O)OCCNC(=O)C(C)ON(C(C(C)(C)C)P(=O)(OCC)OCC)C(C)(C)C

Procedure:
In analogy to Example 3C) are reacted 8.43 g (0.0205 mol) (1-{tert-butyl-[1-(2-hydroxy-ethylcarbamoyl)-ethoxy]-amino}-2,2-dimethyl-propyl)-phosphonic acid diethyl ester, 2.08 g (0.025 mol) acryloylchloride and 3.2 ml (0.025 mol) triethylamine to afford the title compound as two diastereomers: 4.79 g of a colorless oil and 3.5 g of a white solid, mp 95-98° C.