Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:38])[C@@:4](N)([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:5][C@H:6]([OH:29])[C@@H:7](C(OC(C)(C)C)=O)[CH2:8][C:9]([CH3:21])([CH3:20])[CH2:10][CH2:11][O:12]CC1C=CC=CC=1.C(NC(=O)[C@H](C)C[C@H:47](O)[C@@H:48]([NH:71][C:72]([O:74][C:75]([CH3:78])([CH3:77])[CH3:76])=[O:73])[CH2:49]C(C)(C)CC(N1C2C(=CC=CC=2)CC(COCC=C)C1)=O)CCC.C(NC(=O)[C@H](CC(C)=C)C[C@@H]1[O:94]C(C)(C=C=O)N(OC(C)(C)C)[C@H]1CC(C)(C)CCOCC1C=CC=CC=1)CCC.C(NC(=O)[C@H](C(C)C)C[C@H](O)[C@@H](NC(OC(C)(C)C)=O)CC(C)(C)CC(N1C2C=CC=CC=2SC(C(NCC)=O)C1)=O)CCC>>[CH3:1][NH:2][C:3](=[O:38])[C@H:4]([CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:5][C@@H:6]1[O:29][C:48]([CH3:49])([CH3:47])[N:71]([C:72]([O:74][C:75]([CH3:76])([CH3:78])[CH3:77])=[O:73])[C@H:7]1[CH2:8][C:9]([CH3:20])([CH3:21])[CH2:10][C:11]([OH:12])=[O:94]
Reactant: C=CCOCC1Cc2ccccc2N(C(=O)CC(C)(C)C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@@H](C)C(=O)NCCCC)C1
Reactant: C=C(C)C[C@H](C[C@@H]1OC(C)(C=C=O)N(OC(C)(C)C)[C@H]1CC(C)(C)CCOCc1ccccc1)C(=O)NCCCC
Reactant: CNC(=O)[C@@](N)(Cc1ccccc1)C[C@H](O)[C@H](CC(C)(C)CCOCc1ccccc1)C(=O)OC(C)(C)C
Agent: CCCCNC(=O)[C@@H](C[C@H](O)[C@H](CC(C)(C)CC(=O)N1CC(C(=O)NCC)Sc2ccccc21)NC(=O)OC(C)(C)C)C(C)C
Product: CNC(=O)[C@H](Cc1ccccc1)C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC(C)(C)CC(=O)O

Procedure:
starting from 505 mg of 2(R)-benzyl-9-benzyloxy-5(S)-tert-butoxycarbonyl-amino-4(S)-hydroxy-7,7-dimethyl-nonanoic acid (N-methyl)amide via 3-[N-tert-butoxycarbonyl-4(S)-(4-benzyloxy-2,2-dimethylbutyloxy-2,2-dimethyl-1,3-oxazolidin-5(S)-yl]-2(R)-benzyl-propionic acid (N-methyl)amide (Rf (A)=0.43; FAB-MS:(M+H)+ =567) and 3-[N-tert-butoxycarbonyl-4(S)-(2,2-dimethyl-4-hydroxybutyloxy-2,2-dimethyl-1,3-oxazolidin-5(S)-yl]-2(R)-benzylpropionic acid (N-methyl)amide (Rf (B)=0.14; FAB-MS:(M+H)+ =477) in a manner analogous to that described in Examples 74a,74b and 74c), as the pure diastereomer: Rf (L)=0.17; FAB-MS:(M+H)+ =491.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Mg]Br.[CH:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.FC(F)(F)C1C=C(Cl)C=CC=1C(O)C1C=CC=CC=1>>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:13]([OH:22])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1
Reactant: FC(F)(F)c1ccccc1[Mg]Br
Reactant: COc1ccc(C=O)cc1
Agent: OC(c1ccccc1)c1ccc(Cl)cc1C(F)(F)F
Product: COc1ccc(C(O)c2ccccc2C(F)(F)F)cc1

Procedure:
This material was prepared from 2-(trifluoromethyl)phenylmagnesium bromide (16 mmol) and p-anisaldehyde (1.86 mL, 15 mmol) using the procedure described for compound (96) (4.34 g, 100%).
Reaction SMILES: [CH:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])OCC.B(F)(F)F.CCOCC.[Br:20][C:21]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]2[C:22]=1[CH2:23][CH2:24][C:25]2=[O:32].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:9]([O:8][CH:1]([O:5][CH2:6][CH3:7])[CH:24]1[CH2:23][C:22]2[C:26](=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:21]=2[Br:20])[C:25]1=[O:32])[CH3:10]
Reactant: COc1ccc(Br)c2c1C(=O)CC2
Reactant: CCOC(OCC)OCC
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(OCC)C1Cc2c(Br)ccc(OC)c2C1=O
Temperature: 0 °C

Procedure:
Triethyl orthoformate (16.5 ml) was cooled to -30° C. and 15.0 ml BF3.Et2O in 50 ml methylene chloride was added. The reaction was warmed to 0° C. for 15 min, and then cooled to -78° C. To the reaction was added 12.05 g of the product from Example 34 in 50 ml methylene chloride, followed by dropwise addition of 19.4 ml diisopropyl ethyl amine. The reaction was then warmed to -15° C. for 2 h, then quenched in 5% NaHCO3 solution and extracted with methylene chloride. The organic extracts were washed with brine, dried (MgSO4), and the solvent removed. The crude product was triturated with cold hexane, and the crystalline product collected to yield 14.60 g of a white solid, mp: 76°-8° C. NMR (CDCl3) δ 1.05 (t, 3H), 1.27 (t, 3H), 3.03 (m, 2 H), 3.30 (m, 1H), 3.43-3.80 (m, 4H), 3.95 (s, 3H), 5.00 (d, 1H), 6.71 (d, 1H), 7.63 (d, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([NH2:30])=[C:13]2[C:17]=1[N:16]=[C:15]1[N:18]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])[CH2:19][CH2:20][CH2:21][N:14]21.C(N(CC)CC)C.CC(C)([O-])C.[K+]>O1CCCC1.CO>[Cl:8][C:9]1[C:17]2[N:16]=[C:15]3[N:18]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=4[Cl:29])[CH2:19][CH2:20][CH2:21][N:14]3[C:13]=2[C:12]([N:30]2[CH2:2][CH2:3][CH2:4][C:5]2=[O:6])=[CH:11][CH:10]=1
Reactant: O=C(Cl)CCCCl
Reactant: Nc1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C1CCCN1c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 31.5 %

Procedure:
4-Chlorobutanoyl chloride (88.2 mg, 0.626 mmol) was added to a stirred solution of 9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-amine (Example 100, 230 mg, 0.626 mmol) and triethylamine (0.18 mL) in tetrahydrofuran (6.0 mL) at 0° C., and the mixture was stirred at 0° C. for 2 hr. Methanol (1.0 mL) and potassium t-butoxide (351 mg, 3.13 mmol) were added to the mixture, and the mixture was stirred at 60° C. for 16 hr. The mixture was concentrated in vacuo, diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 80-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/diisopropyl ether to give the title compound as a colorless crystal (85.8 mg, 0.197 mmol, 31%).
Reaction SMILES: [Cl:1][C:2]1[C:7](B2OC(C)(C)C(C)(C)O2)=[CH:6][N:5]=[C:4]2[N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:18]=[CH:19][C:3]=12.Br[C:29]1[CH:30]=[C:31]([CH:35]([OH:41])[C:36]([N:38]([CH3:40])[CH3:39])=[O:37])[CH:32]=[N:33][CH:34]=1>C1COCC1.C(#N)C.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[Cl:1][C:2]1[C:7]([C:29]2[CH:30]=[C:31]([CH:35]([OH:41])[C:36]([N:38]([CH3:39])[CH3:40])=[O:37])[CH:32]=[N:33][CH:34]=2)=[CH:6][N:5]=[C:4]2[N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:26])[CH3:27])[CH:18]=[CH:19][C:3]=12
Reactant: CN(C)C(=O)C(O)c1cncc(Br)c1
Reactant: CC1(C)OB(c2cnc3c(ccn3COCC[Si](C)(C)C)c2Cl)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: [CH]1[CH][CH][C]([PH+](c2ccccc2)c2ccccc2)[CH]1
Solvent: ClCCl
Solvent: CC#N
Solvent: C1CCOC1
Product: CN(C)C(=O)C(O)c1cncc(-c2cnc3c(ccn3COCC[Si](C)(C)C)c2Cl)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
A mixture of 4-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (1.3 g, 3.3 mmol), 2-(5-bromo-pyridin-3-yl)-2-hydroxy-N,N-dimethyl-acetamide (0.8 g, 3.3 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (133 mg, 0.2 mmol) in THF/Acetonitrile/saturated NaHCO3 (20 ml/20 ml/20 ml) was stirred at 70° C. overnight. The mixture was allowed to cool down to room temperature and then extracted with ethyl acetate (2×). The combined organic layers were extracted with brine, dried with Na2SO4, decanted, and concentrated to dryness. Silica chromatography of the crude using a gradient of ethyl acetate and hexane afforded 2-{5-[4-chloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine-5-yl]pyridine-3-yl}-2-hydroxy-N,N-dimethyl-acetamide (1.3 g, 85% yield). 1H NMR (500 MHz, DMSO-d6) δ 0.05 (s, 9H), 0.92 (t, 2H), 2.95 (d, 6H), 3.62 (t, 2H), 5.68 (s, 1H), 6.77 (s, 1H), 7.96, (s, 1H), 7.98 (s, 1H), 8.41 (s, 1H), 8.71 (s, 1H), 8.72 (s, 1H). MS: m/z 461.3 (M+H+).
Reaction SMILES: Br[C:2]1[S:14][C:5]2[NH:6][C:7](=[O:13])[C:8]([C:11]#[N:12])=[C:9]([OH:10])[C:4]=2[C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(NCC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:45]([OH:53])(=[O:52])[CH2:46][CH2:47][CH2:48][CH2:49][C:50]#[CH:51]>CN(C=O)C.[Cu]I>[C:11]([C:8]1[C:7](=[O:13])[NH:6][C:5]2[S:14][C:2]([C:51]#[C:50][CH2:49][CH2:48][CH2:47][CH2:46][C:45]([OH:53])=[O:52])=[C:3]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:4]=2[C:9]=1[OH:10])#[N:12]
Reactant: N#Cc1c(O)c2c(-c3ccccc3)c(Br)sc2[nH]c1=O
Reactant: C#CCCCCC(=O)O
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: N#Cc1c(O)c2c(-c3ccccc3)c(C#CCCCCC(=O)O)sc2[nH]c1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-Bromo-4-hydroxy-6-oxo-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridine-5-carbonitrile (150 mg, 0.45 mmol) in 4.5 mL DMF was added diethylamine (0.48 mL, 4.5 mmol), followed by copper(I) iodide (trace), Pd(PPh3)Cl2 (10 mg, 0.015 mmol), and triphenylphosphine (36 mg, 0.12 mmol). The resulting mixture was stirred at rt for 5 min, after which hept-6-ynoic acid (0.19 mL, 1.5 mmol) was added. The reaction was then heated to 120° C. using microwave for 25 min, filtered, concentrated and purified by reverse phase HPLC. MS (ESI) m/e 393 (M+H)+; 1H NMR (400 MHz, DMSO-d6): δ ppm 1.28–1.56 (m, 4H), 2.12–2.30 (m, 4H), 7.20–7.35 (m, 5H).
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].[OH-].[Na+].Cl[C:7]1[N:12]=[C:11]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:19](=[O:20])[C:10]2=[N:9][C:8]=1[C:21]#[N:22]>C1COCC1>[CH2:1]([S:3][C:7]1[N:12]=[C:11]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:19](=[O:20])[C:10]2=[N:9][C:8]=1[C:21]#[N:22])[CH3:2]
Reactant: N#Cc1nc2c(nc1Cl)-c1ccccc1C2=O
Reactant: CCS
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCSc1nc2c(nc1C#N)C(=O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
To a mixture of ethanethiol (62 μl, 0.84 mmol) and 1N NaOH (0.5 ml, 0.5 mmol) in THF (2.1 ml) 9 (101 mg, 0.42 mmol) was added. The mixture was stirred at room temperature for 30 min then the solvent was evaporated under reduced pressure. The residue was dissolved in H2O (4 ml) and extracted with CH2Cl2 (2×4 ml). The collected organic phases were dried over Na2SO4, filtered and evaporated. The crude was purified by flash chromatography (CH2Cl2) affording 23 (98 mg, 87%) as orange solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC#N.[OH2:24]>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C@H:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[CH:15]=2)[C@@H:12]([OH:24])[CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc(Br)c2)CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC[C@H](c2cccc(Br)c2)[C@@H](O)C1

Procedure:
The title compound is prepared analogously as described for the title B compound in Example 1 from the title A compound, 4-(3-bromo-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester: MS 356.2/358.1 [M+H]+; retention time 6.59 min (HPLC, Nucleosil C18; 5→100% CH3CN in H2O within 8 min).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C1CCN2C(=NCCC2)CC1.[Cl:23][C:24]1[CH:25]=[C:26]([NH:34][C:35](OC2C=CC=CC=2)=[O:36])[C:27](=[CH:32][CH:33]=1)[C:28]([O:30][CH3:31])=[O:29].Cl>O1CCCC1.O>[Cl:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]([NH:34][C:35]([NH:11][S:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=2)(=[O:9])=[O:10])=[O:36])[CH:25]=1
Reactant: NS(=O)(=O)c1cccc(O)c1
Reactant: COC(=O)c1ccc(Cl)cc1NC(=O)Oc1ccccc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(Cl)cc1NC(=O)NS(=O)(=O)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59 %

Procedure:
Following the Synthesis Method (B), 938 mg (5.42 mmol) of 3-hydroxybenzenesulfonamide was dissolved in 40 ml of tetrahydrofuran, then 892 μl (5.96 mmol) of 1,8-diazabicyclo[5,4,0]-7-undecene (hereinafter referred to as DBU) was added dropwise. The reaction solution was stirred at room temperature for 15 minutes, then 1.66 g (5.42 mmol) of methyl 4-chloro-2-N-phenoxycarbonylanthranilate was added and the mixture was stirred at room temperature overnight. An excess amount of water was poured into the reaction solution, then the mixture was made acidic with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The crude product thus obtained was purified by silica gel column chromatography (0% to 5% methanol/dichloromethane) to obtain 1.23 g (yield 59%) of methyl 4-chloro-2-{[(3-hydroxybenzenesulfonylamino)carbonyl]amino}benzoate. Properties: colorless amorphous, PMR (δ ppm, DMSO-d6): 3.91 (3H, s), 7.02 (1H, m), 7.09 (1H, m), 7.34 (1H, t), 7.57 (2H, m), 7.89 (1H, d), 8.38 (1H, d), 10.94 (1H, s). Next, the 1.23 g (3.2 mmol) of the compound thus obtained was dissolved in 20 ml of methanol, then 10 ml of 2N sodium hydroxide aqueous solution was added dropwise. The reaction solution was stirred at room temperature for 15 minutes, then an excess amount of water was added and the mixture was made acidic with hydrochloric acid. This was then stirred to cause crystals to precipitate which were then obtained by filtration and dried to obtain carboxylic acid. The product thus obtained was dissolved in 50 ml of tetrahydrofuran (hereinafter referred to as THF), then 434 mg (2.68 mmol) of CDI was added under ice cooling and the mixture was stirred for 30 minutes. The reaction solution was diluted with ethyl acetate, washed with water and saturated saline, and dried over anhydrous magnesium sulfate, then concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:2) to obtain 230 mg (yield 20%: 2 steps) of the above-identified compound. Properties: colorless crystal, Melting point: >200° C. (decomposition), PMR (δ ppm, DMSO-d6): 7.12 (2H, s), 7.24 (1H, d), 7.48 (1H, t), 7.58 (2H, s), 7.85 (1H, d), 10.28 (1H, s), 11.63 (1H, s).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:41])[N:10]([C@H:12]([C:14](=[O:40])[NH:15][C:16]1[C:17](=[O:39])[N:18]([CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[C:28]([C:30](=[O:38])[C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH:29]=2)[C:19](Br)=[CH:20][CH:21]=1)[CH3:13])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:42]1(B(O)O)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:8][C:9](=[O:41])[N:10]([C@H:12]([C:14](=[O:40])[NH:15][C:16]1[C:17](=[O:39])[N:18]([CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[C:28]([C:30](=[O:38])[C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH:29]=2)[C:19]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:20][CH:21]=1)[CH3:13])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: C[C@@H](C(=O)Nc1ccc(Br)n(Cc2cncc(C(=O)c3ccc(F)cc3)c2)c1=O)N(C)C(=O)OCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: C[C@@H](C(=O)Nc1ccc(-c2ccccc2)n(Cc2cncc(C(=O)c3ccc(F)cc3)c2)c1=O)N(C)C(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
A mixture of ((S)-1-{6-bromo-1-[5-(4-fluoro-benzoyl)-pyridin-3-ylmethyl]-2-oxo-1,2-dihydro-pyridin-3-ylcarbamoyl}-ethyl)-methyl-carbamic acid benzyl ester (1D) (79 mg, 0.13 mmol) and phenyl boronic acid (19 mg, 0.15 mmol) in 8 mL of toluene, 3 mL of ethanol and Na2CO3 (0.5 mL, 0.5 mmol, 1 M aqueous solution) is degassed under vacuum. PdCl2(PPh3)2 (5 mg, 0.006 mmol) is added to the mixture. The reaction mixture is stirred at 80° C. for 1 hour, cooled to room temperature and diluted with 20 mL of EtOAc. The organic phase is washed with 2×5 mL of water and concentrated. The crude product is purified by chromatography (heptane 60%, EtOAc 40%) to give ((S)-1-{1-[5-(4-fluoro-benzoyl)-pyridin-3-ylmethyl]-2-oxo-6-phenyl-1,2-dihydro-pyridin-3-ylcarbamoyl}-ethyl)-methyl-carbamic acid benzyl ester (1E) (72 mg, yield 91%) as a light yellow solid. MS (ESI) m/e 619 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH:12]=[O:13])=[C:7]([OH:14])[CH:6]=[CH:5]2.[O-:15]Cl=O.[Na+].[OH-].[Na+]>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:15])=[O:13])=[C:7]([OH:14])[CH:6]=[CH:5]2
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1c(O)ccc2cc(Br)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1c(O)ccc2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.4 %

Procedure:
To a ice-cooled mixture of 6-Bromo-2-hydroxy-1-naphthaldehyde (24.0 g) and aqueous NaH2PO4 solution (3.2 g in 30 mL of water) in DMSO (160 mL) was added dropwise a solution of NaClO2 (80%; 15.1 g) in water (150 mL) over 1 h. After being stirred for 5 h at room temperature, a solution of NaClO2 (80%; 2.16 g) in water (20 mL) was added, and the reaction mixture was further stirred for 2 h at room temperature. The mixture was alkalized with 1N-NaOH, and the precipitate was filtered off. The filtrate was washed with AcOEt and iPr2O, and then the aqueous phase was acidified with conc. HCl. The precipitate was filtered, washed with water, and dried in vacuo to give the title compound (22.3 g) as a brown powder.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:23])[C:5]1[CH:10]=[C:9]([C:11]2[CH:19]=[C:18]3[C:14]([C:15](I)=[N:16][NH:17]3)=[CH:13][CH:12]=2)[C:8]([CH3:21])=[C:7]([F:22])[CH:6]=1)[CH3:2].CC1(C)C(C)(C)OB([C:32]2[CH2:33][CH2:34][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:36][CH:37]=2)O1.C(=O)([O-])O.[Na+]>C(O)(C)C.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>[CH2:1]([NH:3][C:4]([C:5]1[CH:6]=[C:7]([F:22])[C:8]([CH3:21])=[C:9]([C:11]2[CH:19]=[C:18]3[C:14]([C:15]([C:32]4[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH:33]=4)=[N:16][NH:17]3)=[CH:13][CH:12]=2)[CH:10]=1)=[O:23])[CH3:2]
Reactant: CCNC(=O)c1cc(F)c(C)c(-c2ccc3c(I)n[nH]c3c2)c1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
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: CC(C)O
Product: CCNC(=O)c1cc(F)c(C)c(-c2ccc3c(C4=CCN(C(=O)OC(C)(C)C)CC4)n[nH]c3c2)c1
Temperature: 150 °C
Reaction time: 0.42 h
Yield: 66.5 %

Procedure:
A mixture of N-ethyl-3-fluoro-5-(3-iodo-1H-indazol-6-yl)-4-methylbenzamide (Intermediate 19, 2.34 g), 1,1-dimethylethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate (1.71 g), aqueous sodium hydrogen carbonate (1M, 11.1 ml) and tetrakis(triphenylphosphine)palladium(0) (129 mg) in isopropanol (10 ml) was divided into three portions then stirred in sealed vials at 150° C. for 25 min in a microwave oven. The reaction mixtures were combined, the solvent was removed under vacuum and the residue was partitioned between ethyl acetate and water. The organic layer was separated using a hydrophobic filter tube, the solvent was evaporated and the residue was purified by chromatography on a silica column eluting with an ethyl acetate:cyclohexane gradient, to give the title compound as a yellow foam (1.76 g).
Reaction SMILES: C([O:8][CH:9]([CH2:36][O:37][C:38]1C=CC(F)=[CH:40][CH:39]=1)[CH2:10][CH2:11][CH:12]1[N:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25]CC2C=CC=CC=2)=[O:24])[C:15](=[O:33])[CH2:14][S:13]1(=O)=O)C1C=CC=CC=1.C(OC(COCCC)CCC1N(CCCCCCC(OCC2C=CC=CC=2)=O)C(=O)CS1)C1C=CC=CC=1>>[OH:8][CH:9]([CH2:36][O:37][CH2:38][CH2:39][CH3:40])[CH2:10][CH2:11][CH:12]1[N:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:15](=[O:33])[CH2:14][S:13]1
Reactant: O=C(CCCCCCN1C(=O)CS(=O)(=O)C1CCC(COc1ccc(F)cc1)OCc1ccccc1)OCc1ccccc1
Agent: CCCOCC(CCC1SCC(=O)N1CCCCCCC(=O)OCc1ccccc1)OCc1ccccc1
Product: CCCOCC(O)CCC1SCC(=O)N1CCCCCCC(=O)O

Procedure:
This compound is prepared essentially by the method described in Example 5, Step E, except that the benzyl 7-{2[3-benzyloxy-4-(4-fluorophenoxy)butyl]-1,1,4-trioxo-3-thiazolidinyl}heptanoate is replaced by benzyl 7-[2-(3-benzyloxy4-propoxybutyl)-4-oxo-3-thiazolidinyl]heptanoate. This method provides the title compound as a viscous, pale yellow oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[N:16][C:17]([NH:20][C:21]3[C:22]4[N:23]([CH:54]=[CH:55][N:56]=4)[CH:24]=[C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([N:33]5[N:42]=[CH:41][C:40]6[C:35](=[C:36]([F:47])[CH:37]=[C:38]([C:43]([CH3:46])([CH3:45])[CH3:44])[CH:39]=6)[C:34]5=[O:48])[C:28]=4[CH2:49][O:50][C:51](=[O:53])[CH3:52])[CH:26]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:43]([C:38]1[CH:39]=[C:40]2[C:35](=[C:36]([F:47])[CH:37]=1)[C:34](=[O:48])[N:33]([C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([C:25]3[CH:26]=[C:21]([NH:20][C:17]4[N:16]=[CH:15][C:14]([CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)=[CH:19][CH:18]=4)[C:22]4[N:23]([CH:54]=[CH:55][N:56]=4)[CH:24]=3)[C:28]=1[CH2:49][O:50][C:51](=[O:53])[CH3:52])[N:42]=[CH:41]2)([CH3:44])([CH3:45])[CH3:46]
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cn3)c3nccn3c2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C4CCNCC4)cn3)c3nccn3c2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the solution of 6-{6-[2-acetoxymethyl-3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)phenyl]-imidazo[1,2-a]pyridin-8-ylamino}-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (280 mg, 0.3689 mmol) in DCM (8 mL) was added TFA (1.4 mL) and the solution was stirred at room temperature for one hour. TLC showed a complete reaction. The solution was poured onto water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the crude product used directly to the next step (260 mg). LC-MS: 660 [M+1]+, tR=1.270 min.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[C:11](=[O:19])[NH:12][NH:13][C:14]=2[C:15]([F:18])([F:17])[F:16])=[CH:5][CH:4]=1)[CH3:2].[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].N1C=CN=C1.O>CN(C)C=O.C(OCC)(=O)C>[Si:20]([O:19][C:11]1[C:10]([CH2:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)=[C:14]([C:15]([F:17])([F:18])[F:16])[NH:13][N:12]=1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CCc1ccc(Cc2c(C(F)(F)F)[nH][nH]c2=O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1ccc(Cc2c(O[Si](C)(C)C(C)(C)C)n[nH]c2C(F)(F)F)cc1
Reaction time: 3 h

Procedure:
1,2-Dihydro-4-((4-ethylphenyl)methyl)-5-(trifluoromethyl)-3H-pyrazol-3-one (4) (prepared by the method described in J. Med. Chem 1996, 39, 3920-3928) (15.0 g; 55.6 mmol) was dissolved in dimethylformamide (150 ml) and cooled to 0° C. t-Butyldimethylsilyl chloride (9.3 g; 61.1 mmol) was added in portions, and then, imidazole (4.2 g; 61.1 mmol) was added in portions. Then, the resulting mixture was back to ambient temperature, then the mixture was stirred for 3 hours. Water was added to the reaction solution, for extraction twice with ethyl acetate. The organic phase was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated, to give the desired compound (21.4 g; 55.6 mmol). (100%)