Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[O:5][C:6]1[C:15]2[N:14]=[CH:13][CH:12]=[N:11][C:10]=2[C:9]([O:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:8]2[C:30](=[O:42])[N:31]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[C:32](=[O:33])[C:7]=12)C.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CN(C1C=CN=CC=1)C.O>[CH:17]([O:16][C:9]1[C:10]2[N:11]=[CH:12][CH:13]=[N:14][C:15]=2[C:6]([OH:5])=[C:7]2[C:32](=[O:33])[N:31]([CH2:34][C:35]3[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=3)[C:30](=[O:42])[C:8]=12)([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)Oc1c2c(c(OC(c3ccccc3)c3ccccc3)c3nccnc13)C(=O)N(Cc1ccc(F)cc1)C2=O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1c2c(c(OC(c3ccccc3)c3ccccc3)c3nccnc3c2O)C(=O)N1Cc1ccc(F)cc1
Reaction time: 18 h
Yield: 94.3 %

Procedure:
Carbonic acid 9-benzhydryloxy-7-(4-fluoro-benzyl)-6,8-dioxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoxalin-5-yl ester ethyl ester 244 (500 mg, 0.87 mmol) was dissolved in THF (9 mL, 0.1 M) along with DMAP (211 mg, 1.73 mmol, 2 equiv.). A solution of K2CO3 (1.20 g, 8.66 mmol, and 10 equiv.) was dissolved separately in H2O (6 mL) before being transferred to the reaction mixture. The reaction was allowed to stir for 18 hours and quenched with HCl (20 mL, 1 N) and extracted with ethyl acetate (2×30 mL). The organic layer was washed with saturated NH4Cl solution (25 mL), brine solution (25 mL) and dried over Na2SO4 and concentrated in vacuo to yield 5-benzhydryloxy-7-(4-fluoro-benzyl)-9-hydroxy-pyrrolo[3,4-g]quinoxaline-6,8-dione 245 (94%, 413 mg, 0.82 mmol). 1H NMR (300 MHz) CDCl3 δ 9.08 (d, J=1.5 Hz, 1 H), 8.92 (d, J=1.5 Hz, 1H), 7.67 (s, 1 H), 7.67-7.42 (dd, J1=1.5 Hz, J2=8.4 Hz, 4 H), 7.43-7.48 (m, 2 H), 7.19-7.27 (m, 7 H), 7.03-7.20 (m, 1 H), 4.86 (s, 2 H). MS: 528.0 (M+23). TLC Rf: 0.2 Hexanes/Ethyl acetate (8/2)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][C:3]=1[NH2:9].C(=O)([O-])[O-].[Na+].[Na+].[C:16](Cl)(Cl)=[S:17]>C(Cl)Cl>[Cl:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([N:9]=[C:16]=[S:17])=[CH:4][N:5]=1
Reactant: S=C(Cl)Cl
Reactant: Nc1cnc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: S=C=Nc1cnc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring slurry of 4,6-dichloropyridin-3-amine (2.00 g, 12 mmol) and sodium carbonate (3.4 g, 32 mmol) in 10 mL DCM was added thiophosgene (1.2 mL, 16 mmol). The orange mixture was sealed and allowed to stir at ambient temperature overnight. The reaction mixture was filtered, rinsing with DCM, and the filtrate concentrated in vacuo to give 2,4-dichloro-5-isothiocyanatopyridine as an orange solid. MS (ESD m/z: calculated: 203.9; Observed: 204.9 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:9][CH2:8][CH2:7][C:6]=1OS(C(F)(F)F)(=O)=O)=[O:4].[CH2:18]([Sn](CCCC)(CCCC)C=C)[CH2:19]CC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH2:9][CH2:8][CH2:7][C:6]=1[CH:18]=[CH2:19])=[O:4]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CC1=C(C(=O)OC)CCC1
Temperature: 50 °C
Yield: 59 %

Procedure:
Palladium (II) acetate (0.095 g) was added to a solution of the product from step 27a (1.62 g, 5.9 mmol), tributyl(vinyl)tin (1.72 mL, 5.9 mmol), and triphenylphosphine (0.215 g, 0.82 mmol) in THF (20 mL) under a nitrogen atmosphere. The reaction was heated to 50° C. for 3 h, cooled to room temperature and concentrated. The residue was purified by FCC on silica gel eluting ethyl ether:hexanes (2:98) to give 2-vinyl-cyclopent-1-enecarboxylic acid methyl ester (0.53 g, 59%) as an oil.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7]1[CH:48]=[CH:47][C:10]([CH2:11][N:12]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[C:13]2[N:18]=[C:17]([C:19]3[C:20]([NH:28][C:29]4[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=4)=[N:21][CH:22]=[C:23]([C:25]([CH3:27])=[CH2:26])[CH:24]=3)[N:16]=[C:15]([CH3:37])[N:14]=2)=[CH:9][CH:8]=1.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)(Cl)Cl>[N:1]([C:25]([C:23]1[CH:24]=[C:19]([C:17]2[N:16]=[C:15]([CH3:37])[N:14]=[C:13]([N:12]([CH2:11][C:10]3[CH:9]=[CH:8][C:7]([O:6][CH3:5])=[CH:48][CH:47]=3)[CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)[N:18]=2)[C:20]([NH:28][C:29]2[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)=[N:21][CH:22]=1)([CH3:27])[CH3:26])=[N+:2]=[N-:3]
Reactant: C=C(C)c1cnc(Nc2ccc(OC)nc2)c(-c2nc(C)nc(N(Cc3ccc(OC)cc3)Cc3ccc(OC)cc3)n2)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)(C)N=[N+]=[N-])cnc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.3 %

Procedure:
A slurry of sodium azide (0.075 g, 1.160 mmol) and N,N-bis(4-methoxybenzyl)-4-(2-(6-methoxypyridin-3-ylamino)-5-(prop-1-en-2-yl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.171 g, 0.290 mmol) in CHCl3 (1 mL) at −15° C. was treated with a solution of trifluoroacetic acid (0.223 mL, 2.90 mmol) in CHCl3 (1 mL) added via syringe over 10 min. The cooling reaction mixture was allowed to gradually warm to room temperature and stirred overnight. The reaction was sealed and heated at 60° C. After 2 h, the reaction was poured onto ice and basified with 10N NaOH. The reaction was partitioned between water and DCM. The aqueous layer was extracted with DCM (3×), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 4-(5-(2-azidopropan-2-yl)-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.184 g, 0.291 mmol, 100% yield). m/z (ESI, +ve ion) 633 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 11.67 (br. s., 1H); 8.90 (d, J=2.7 Hz, 1H); 8.38 (d, J=2.5 Hz, 1H); 8.26 (d, J=2.5 Hz, 1H); 7.91 (dd, J=8.8, 2.7 Hz, 1H); 7.18-7.26 (m, 4H); 6.81-6.94 (m, 4H); 6.73 (d, J=8.8 Hz, 1H); 4.90 (s, 2H); 4.81 (s, 2H); 3.94 (s, 3H); 3.82 (s, 3H); 3.78 (s, 3H); 2.59 (s, 3H); 1.64 (s, 6H).
Reaction SMILES: [O:1]([C:8]1[CH:23]=[CH:22][C:11]([O:12][C:13]([CH3:21])([C:17]([F:20])([F:19])[F:18])[C:14]([OH:16])=[O:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH2:26])=[N-]>CCOCC>[O:1]([C:8]1[CH:23]=[CH:22][C:11]([O:12][C:13]([CH3:21])([C:17]([F:18])([F:19])[F:20])[C:14]([O:16][CH3:26])=[O:15])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=[N+]=[N-]
Reactant: CC(Oc1ccc(Oc2ccccc2)cc1)(C(=O)O)C(F)(F)F
Solvent: CCOCC
Product: COC(=O)C(C)(Oc1ccc(Oc2ccccc2)cc1)C(F)(F)F

Procedure:
A solution of (±)-2-(4-phenoxyphenoxy)-3,3,3-trifluoro-2-methylpropionic acid (6.4 g.) in ether is treated with an excess of ethereal diazomethane at 0° C. The solution is evaporated and the residue distilled to give (±)-methyl 2-(4-phenoxyphenoxy)-3,3,3-trifluoro-2-methylpropionate (3.3 g.), b.p. 187° C. at 0.1 mm. pressure.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH2:24]([O:26][C:27](=[O:31])[C@H:28]([CH3:30])O)[CH3:25].CO>C(OCC)(=O)C>[CH2:24]([O:26][C:27](=[O:31])[C@H:28]([O:23][C:21]1[CH:20]=[CH:19][C:16]2[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]=2[CH:22]=1)[CH:10]=[C:9]([C:8]1[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][N:7]=1)[N:18]=3)[CH3:30])[CH3:25]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(O)cc1OCC2
Reactant: CCOC(=O)[C@H](C)O
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)[C@@H](C)Oc1ccc2c(c1)OCCn1cc(-c3ncnn3C(C)C)nc1-2

Procedure:
Following the procedure of Example 426, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ol 490 and ethyl-L-lactate were reacted and the crude product was subjected to flash chromatography (SiO2, gradient 0-10% methanol in ethyl acetate) to give (R)-2-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy]-propionic acid ethyl ester as a yellow (315 mg, 66%). LCMS: RT=3.44 min, [M+H]+=412
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[C:16]([Cl:18])[N:17]=2)[C:12]([NH2:14])=[O:13])[CH2:5][CH2:4]1.[C:19]([C:21]1[C:22]([CH3:30])=[C:23]([C:27](O)=[O:28])[NH:24][C:25]=1[CH3:26])#[N:20]>>[Cl:18][C:16]1[CH:15]=[C:11]([CH:10]=[C:9]([N:6]2[CH2:5][CH2:4][CH:3]([NH:2][C:27]([C:23]3[NH:24][C:25]([CH3:26])=[C:21]([C:19]#[N:20])[C:22]=3[CH3:30])=[O:28])[CH2:8][CH2:7]2)[N:17]=1)[C:12]([NH2:14])=[O:13]
Reactant: NC(=O)c1cc(Cl)nc(N2CCC(N)CC2)c1
Reactant: Cc1[nH]c(C(=O)O)c(C)c1C#N
Agent: Cl
Product: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(N)=O)cc(Cl)n3)CC2)c(C)c1C#N

Procedure:
Title compound was synthesized by an analogous method to Example 18 by coupling 2-(4-aminopiperidin-1-yl)-6-chloroisonicotinamide hydrochloride (Intermediate 70) with 4-cyano-3,5-dimethyl-1H-pyrrole-2-carboxylic acid (commercially available).
Reaction SMILES: C(O)C.[Na].[CH2:5]([O:7][C:8](=[O:23])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[C:12]=1[C:18]([CH:20]1[CH2:22][CH2:21]1)=O)[CH3:6]>C(OCC)(=O)C>[CH2:5]([O:7][C:8]([C:9]1[O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[C:12]=2[C:18]=1[CH:20]1[CH2:22][CH2:21]1)=[O:23])[CH3:6]
Reactant: CCOC(=O)COc1cccc(O)c1C(=O)C1CC1
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1oc2cccc(O)c2c1C1CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 84.2 %

Procedure:
To an anhydrous ethanol (2 ml) was added sodium (50 mg) at 0° C. under argon atmosphere. After 10 minutes, (2-cyclopropanecarbonyl-3-hydroxy-phenoxy)-acetic acid ethyl ester (380 mg) was added to the reaction mixture and the reaction mixture was stirred overnight at 0° C. The reaction was quenched with 2 N hydrochloric acid (5 ml) and stirred for 30 minutes yielding a white precipitate. The mixture was diluted with ethyl acetate (10 ml), washed with water (5 ml) and brine (5 ml), dried over anhydrous sodium sulfate, concentrated in vacuo. The residue was purified by silica gel column chromatography developed by hexane-ethyl acetate yielding 3-cyclopropyl-4-hydroxy-benzofuran-2-carboxylic acid ethyl ester (298 mg) as a white solid. FAB-MS: m/z 246 (M+); 1H-NMR (CDCl3): δ 0.99-1.05 (2H, m), 1.17-1.24 (2H, m), 1.45 (3H, t, J=7.26 Hz), 2.26-2.35 (1H, m), 4.45 (2H, q, J=7.26 Hz), 6.27 (1H, s), 6.71 (1H, dd, J=0.99 Hz, 8.25 Hz), 7.09 (1H, dd, J=0.99 Hz, 8.25 Hz), 6.41 (2H, d, J=8.25 Hz), 7.29 (1H, dd, J=8.25 Hz, 8.25 Hz).
Reaction SMILES: [Br:1][CH:2]([Br:15])[C:3]1[N:8]=[C:7]([CH:9](Br)Br)[N:6]=[C:5]([CH:12]([Br:14])[Br:13])[N:4]=1.[I-].[Na+].S(=O)(O)[O-].[Na+]>CC(C)=O.C(O)(=O)C>[Br:14][CH:12]([Br:13])[C:5]1[N:4]=[C:3]([CH:2]([Br:1])[Br:15])[N:8]=[C:7]([CH3:9])[N:6]=1
Reactant: BrC(Br)c1nc(C(Br)Br)nc(C(Br)Br)n1
Agent: O=S([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: Cc1nc(C(Br)Br)nc(C(Br)Br)n1
Temperature: 0 °C

Procedure:
A solution of 2,4,6-tris(dibromomethyl)-s-triazine (15 g, 23.3 mmol) in acetone (100 mL) was added to a solution of sodium iodide (150 g, 1.0 mol) in acetic acid (50 mL) and acetone (500 mL). After 10 minutes at room temperature the reaction mixture was added to sodium bisulfite (25 g) in ice water (1000 mL). The aqueous layer was extracted with ether (3×100 mL). The ether layer was dried (MgSo4), filtered, and concentrated to dryness. The crude product was crystallized first from EtOH and then from cyclohexane to give the title compound (mp 87-88.5° C.). 1H NMR (CDCL3) δ2.51 (s, 3H, CH3), 6.86 (s, 2H, CH).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:19]=[C:18]([NH:20]/[C:21](/[NH:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[N:22]\[C:23](=[O:34])[C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[NH:17][N:16]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:36]([NH:35]/[C:21](/[NH:20][C:18]1[NH:17][N:16]=[C:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[OH:8])[CH:19]=1)=[N:22]/[C:23](=[O:34])[C:24]1[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:28][CH:29]=1)([CH3:39])([CH3:37])[CH3:38]
Reactant: [H][H]
Reactant: CC(C)(C)N/C(=N/C(=O)c1ccc(C(F)(F)F)cc1)Nc1cc(-c2ccccc2OCc2ccccc2)n[nH]1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)N/C(=N/C(=O)c1ccc(C(F)(F)F)cc1)Nc1cc(-c2ccccc2O)n[nH]1
Yield: 43.7 %

Procedure:
(Z)—N-(((3-(2-(Benzyloxy)phenyl)-1H-pyrazol-5-yl)amino)(tert-butylamino)methylene)-4-(trifluoromethyl)benzamide (190 mg) was dissolved in methanol (10 mL) and the solution was degassed with nitrogen. To the solution was added 10% palladium on carbon (38 mg, 0.1 equiv). The resulting mixture was subjected to hydrogen gas at 30 psi pressure in a Parr shaker. The reaction was checked periodically for completion. Upon reaction completion, the mixture was filtered through celite, and the filtrate was concentrated in vacuo to provide the crude product, which was purified by silica chromatography (9:1 to 55:45 hexanes:EtOAc) to provide the title compound (69 mg, 44% yield). 1HNMR (400 MHz, DMSO-d6) δ 12.79 (bm, 2H), 10.32 (bs, 1H), 9.05 (s, 1H), 8.28 (d, 2H), 7.82 (d, 2H), 7.61 (d, 1H), 7.19 (t, 1H), 6.95 (d, 1H), 6.86 (t, 1H), 6.53 (s, 1H), 4.06 (m, 1H), 3.14 (s, 1H), 1.56 (s, 9H); MS (EI+) m/z: 446.00, 467.97; HPLC (Method B): 6.15 min
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[N:17]=[C:16]([C:18]3[C:23]([CH3:24])=[N:22][CH:21]=[CH:20][N:19]=3)[CH:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)C.C(OC(=O)C1C=CC(NC2N=C(C3C=NC=CC=3)C=CN=2)=CC=1)C>>[CH3:24][C:23]1[C:18]([C:16]2[CH:15]=[CH:14][N:13]=[C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([C:4]([OH:25])=[O:3])=[CH:6][CH:7]=3)[N:17]=2)=[N:19][CH:20]=[CH:21][N:22]=1
Reactant: CCOC(=O)c1ccc(Nc2nccc(-c3nccnc3C)n2)cc1
Agent: CCOC(=O)c1ccc(Nc2nccc(-c3cccnc3)n2)cc1
Product: Cc1nccnc1-c1ccnc(Nc2ccc(C(=O)O)cc2)n1

Procedure:
4-[4-(3-methylpyrazin-2-yl)-pyrimidin-2-ylamino]-benzoic acid ethyl ester prepared in Preparation 14 was used instead of 4-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzoic acid ethyl ester according to the similar procedure to Preparation 19 to give the titled compound as yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)[CH:3]=1.CCCCCC.C([Li])CCC.[B:28](OC)([O:31]C)[O:29]C.S(=O)(=O)(O)O>C1COCC1>[CH2:15]([C:12]1[CH:13]=[CH:14][C:9]([CH2:8][C:4]2[CH:3]=[C:2]([B:28]([OH:31])[OH:29])[CH:7]=[CH:6][CH:5]=2)=[CH:10][CH:11]=1)[CH3:16]
Reactant: COB(OC)OC
Reactant: CCc1ccc(Cc2cccc(Br)c2)cc1
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCc1ccc(Cc2cccc(B(O)O)c2)cc1
Reaction time: 0.33 h
Yield: 31.6 %

Procedure:
In a nitrogen stream, a solution of 1-bromo-3-(4-ethylbenzyl)benzene (2.19 g, 7.96 mmol) in THF (20 mL) was cooled to −78° C., and an n-butyllithium hexane solution (2.44 M, 3.42 mL) was added dropwise thereto and the mixture solution was stirred at the same temperature for 20 minutes. After addition of trimethyl borate (2.68 mL, 23.87 mmol), the reaction mixture was stirred at the temperature for five minutes and at room temperature for 12.5 hours. After cooling the reaction mixture in an ice bath, concentrated sulfuric acid (10 mL) was added dropwise thereto and the mixture solution was stirred at the same temperature for one hour. The mixture was extracted with ether and the organic layer was washed with water and then dried over sodium sulfate. To a white solid obtained by distilling the solvent under reduced pressure was added hexane-ethyl acetate (10:1)(5 mL), the mixture was filterated and then the obtained solid was washed with hexane-ethyl acetate (10:1). The obtained white powder was dried under reduced pressure to obtain the title compound (604.2 mg, 32%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:13](=[O:14])[N:12]([CH2:15][CH:16]([OH:21])[C:17]([F:20])([F:19])[F:18])[C:11]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)=[N:10]2)[CH:5]=[N:6][CH:7]=1.[F:29][C:30]([F:41])([F:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:11]2[N:12]([CH2:15][CH:16]([OH:21])[C:17]([F:20])([F:19])[F:18])[C:13](=[O:14])[N:9]([CH2:8][C:4]3[CH:5]=[N:6][CH:7]=[C:2]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[C:30]([F:41])([F:40])[F:29])[CH:3]=3)[N:10]=2)=[CH:23][CH:24]=1
Reactant: O=c1n(Cc2cncc(Br)c2)nc(-c2ccc(Cl)cc2)n1CC(O)C(F)(F)F
Reactant: OB(O)c1ccccc1C(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: C1COCCO1
Product: O=c1n(Cc2cncc(-c3ccccc3C(F)(F)F)c2)nc(-c2ccc(Cl)cc2)n1CC(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
72 mg (0.15 mmol) of the compound from Example 28A and 43 mg (0.23 mmol) of 2-(trifluoro-methyl)phenylboronic acid were dissolved in 2 ml of dioxane. For 10 min, a stream of argon was passed through this solution, and 8.7 mg (0.008 mmol) of tetrakis(triphenylphosphine)palladium(0) were then added under argon. The mixture was heated to the boil, and 0.15 ml (0.30 mmol) of a 2 N aqueous sodium carbonate solution was added under argon. The mixture was stirred under reflux for 20 h. After cooling to RT, the mixture was diluted with 10 ml of water and extracted twice with in each case 15 ml of ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified chromatographically [Method 19]. This gave 36 mg (44% of theory) of the target compound.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[N:21][C:20]=1[N:25]1[CH2:30][CH2:29][N:28]([C:31]2[N:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[N:19]1[CH:24]=[CH:23][CH:22]=[N:21][C:20]=1[N:25]1[CH2:26][CH2:27][N:28]([C:31]2[N:36]=[CH:35][C:34]([NH:37][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][C:9]=3[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:33][CH:32]=2)[CH2:29][CH2:30]1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: Nc1ccc(N2CCN(c3ncccn3)CC2)nc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(N2CCN(c3ncccn3)CC2)nc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (100 mg, 0.39 mmol) in methylene chloride (15 mL) was added 6-(4-pyrimidin-2-yl-piperazin-1-yl)-pyridin-3-ylamine (100 mg, 0.39 mmol) and diisopropylethylamine (0.35 mL, 1.90 mmol). To this solution was added bromo-tris-pyrrolidino-phosphoniumhexafluorophosphate (PyBrOP) in one portion (280 mg, 0.59 mmol). The mixture was stirred at room temperature overnight. The residue was purified by HPLC to yield 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(4-pyrimidin-2-yl-piperazin-1-yl)-pyridin-3-yl]-amide as a light yellow powder. The NMR spectrum obtained on the sample is compatible with its structure. LCMS calcd for C24H20F3N7O2 (m/e) 495, obsd 496 (M+H).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][NH:21][CH2:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[CH3:30][O:31][CH2:32][CH2:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][N:21]([C:36](=[O:37])[CH2:35][O:34][CH2:33][CH2:32][O:31][CH3:30])[CH2:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2]
Reactant: COCCOCC(=O)Cl
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CNCC3)cc1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C(=O)COCCOC)CC3)cc1

Procedure:
Compound ez was prepared according to the procedure described in Example 5 by reacting (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)phenyl)urea with 2-(2-methoxyethoxy)acetyl chloride. LC-MS: m/z=+513 (M+H)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([O:23][C:24](=[O:47])[CH:25]([CH2:44][CH2:45]O)[N:26]([CH3:43])[S:27]([C:30]1[CH:35]=[CH:34][C:33]([O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH:21]=[CH2:22].C(Br)(Br)(Br)[Br:49].O>O1CCCC1>[CH2:20]([O:23][C:24](=[O:47])[CH:25]([CH2:44][CH2:45][Br:49])[N:26]([CH3:43])[S:27]([C:30]1[CH:35]=[CH:34][C:33]([O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH:21]=[CH2:22]
Reactant: BrC(Br)(Br)Br
Reactant: C=CCOC(=O)C(CCO)N(C)S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: C=CCOC(=O)C(CCBr)N(C)S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Yield: 86.1 %

Procedure:
After triphenylphosphine (4.72 g, 18.0 mmol) was added to a solution of (±)-2-(2-hydroxyethyl)-N-methyl-N-(4-phenoxybenzenesulfonyl)glycine allyl ester (6.08 g, 15.0 mmol), the product of Example 41(2), in tetrahydrofuran (45 ml), a solution of carbon tetrabromide (5.97 g, 18.0 mmol) in tetrahydrofuran (20 ml) was added over 20 minutes to the solution with ice-cooling and with stirring. The mixture was stirred at room temperature for 1 hour. To the reaction mixture, water was added and this was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=5/1 as the eluant to afford the desired compound (6.05 g, yield 86%) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.[CH3:15][C@@H:16]([CH2:19][CH3:20])[CH2:17]O.S(=O)(=O)(O)O.OC1C=CC(C(O)=O)=CC=1>C(Cl)(Cl)Cl.C1C=CC=CC=1>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14][CH2:15][C@@H:16]([CH3:17])[CH2:19][CH3:20])=[O:13])[CH:6]=[CH:5]2
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Reactant: CC[C@H](C)CO
Agent: O=C(O)c1ccc(O)cc1
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Product: CC[C@H](C)COC(=O)c1ccc2cc(O)ccc2c1
Temperature: 25 °C
Yield: 93 %

Procedure:
In a flask equipped with a Dean-Stark trap 6.78 g (0.036 mole) 6-hydroxyl-2-naphthaleneformic acid, 4.76 g (0.054 mole) (S)-2-methyl-1-butanol, 0.2 ml sulfuric acid and 15 ml anhydrous benzene were charged and refluxed for about 15 hours until all the 4-hydroxybenzoic acid was dissolved. The esterification reaction mixture was cooled to room temperature, extracted with ethyl ether, and washed with 5% (w/w) sodium hydrogen carbonate aqueous solution. The ethyl ether layer was collected, concentrated, and purified with column chromatography (ethyl acetate/n-hexane) to obtained light yellow solid. Yield: 93%. The optical rotation: [α]25D =+2.97 (c=1.0 g/dl, chloroform).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)=[N:8][CH:9]=1)([O-])=O>CO.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[C:12]([O:20][CH3:21])[C:13]([O:18][CH3:19])=[C:14]([O:16][CH3:17])[CH:15]=2)=[N:8][CH:9]=1
Reactant: COc1cc(-c2ccc([N+](=O)[O-])cn2)cc(OC)c1OC
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(-c2ccc(N)cn2)cc(OC)c1OC
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
To a solution of 5-nitro-2-(3,4,5-trimethoxyphenyl)-pyridine (1.50 g, 5.17 mmol) in methanol-ethyl acetate (1:4, 50 mL) was added 10% palladium on charcoal (158.6 mg), and the resulting mixture was stirred at 45° C. for 2 hours and 30 minutes under hydrogen. Insoluble materials were removed by filtration through Celite, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to yield the title compound as colorless needles (melting point: 153.5-155.5° C. )(1.25 g, yield: 93%).