Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][CH:3]=1.O1CCCC1.C([Mg]Cl)(C)C.[CH2:19]([O:21][Si:22](OCC)([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])[CH3:20]>CCOCC>[CH2:19]([O:21][Si:22]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][CH:3]=1)[CH3:20]
Reactant: CCO[Si](OCC)(OCC)OCC
Reactant: Ic1ccc(I)cc1
Agent: CC(C)[Mg]Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCO[Si](OCC)(OCC)c1ccc(I)cc1
Temperature: -30 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
At first, a mixed solution of 1,4-diiodobenzene (15 g, 45.6 mmol) and a distilled tetrahydrofuran solution (dist.THF: 114 mL) was added dropwise with 2 mol/L of i-PrMgCl (24 mL (solvent: THF), 48 mmol) at −30° C. Then, the resultant mixture was stirred under a nitrogen atmosphere at −30° C. for 5.5 hours to obtain a reaction solution. Subsequently, the reaction solution was added dropwise (3 drops per second) using a cannula into a mixed solution of tetraethoxysilane (TEOS: 60.6 mL, 272 mmol) and dist.THF (90 mL), which was cooled to −30° C. Thereafter, the resultant mixed solution was stirred at −30° C. for one hour, and further stirred at room temperature for 44 hours to obtain a reaction mixture. After that, the obtained reaction mixture was added with ether (100 ml), and washed with distilled water (dist.H2O). Then, the aqueous layer was extracted with ether. The collected organic layers were washed with sat.NaCl, dried with MgSO4), filtered and concentrated to obtain a crude product. Thereafter, the crude product thus obtained was purified by distillation under a reduced pressure (1.5 mmHg, 120° C.), and thereby 4-(triethoxysilyl)iodobenzene was obtained (10.2 g, 61% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:24][O:25][C:26]1[C:27](=[O:50])[C:28]([CH3:49])=[C:29]([CH2:35][C:36]2[C:37]([O:45][C:46](=[O:48])[CH3:47])=[C:38]([CH:42]=[CH:43][CH:44]=2)[C:39](O)=[O:40])[C:30](=[O:34])[C:31]=1[O:32][CH3:33]>C(Cl)Cl>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:39](=[O:40])[C:38]2[CH:42]=[CH:43][CH:44]=[C:36]([CH2:35][C:29]3[C:30](=[O:34])[C:31]([O:32][CH3:33])=[C:26]([O:25][CH3:24])[C:27](=[O:50])[C:28]=3[CH3:49])[C:37]=2[O:45][C:46](=[O:48])[CH3:47])[CH:3]=1
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)O)c2OC(C)=O)=C(C)C1=O
Reactant: Nc1cccnc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)Nc3cccnc3)c2OC(C)=O)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 41.5 %

Procedure:
3-Aminopyridine (0.076 g, 0.802 mmol), triethylamine (0.081 g, 0.802 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.136 g, 0.802 mmol) were added to a methylene chloride solution (100 ml) of 3-(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 (chloroform:methanol=10:1) to obtain the titled compound (0.100 g, 0.222 mmol, 41%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.C(=O)(O)[O-].[Na+].Cl[C:16]([O:18][CH2:19][CH:20]1[C:32]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17]>O1CCOCC1.O.C1(C)C=CC=CC=1>[CH:31]1[C:32]2[CH:20]([CH2:19][O:18][C:16]([N:5]3[CH2:6][CH:2]([OH:1])[CH2:3][CH:4]3[C:7]([OH:9])=[O:8])=[O:17])[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]=2[CH:28]=[CH:29][CH:30]=1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)C1CC(O)CN1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C

Procedure:
Trans-4-hydroxyproline (5.0 g, 38.1 mmoles) is suspended in a mixture of dioxane (75 mL) and water (75 mL), and stirred briskly at ambient temperature. Sodium bicarbonate (8.0 g, 95.2 mmoles) is added. And the mixture is stirred until all solids dissolve. A solution of 9-fluorenylmethyl chloroformate (11.4 g, 44.0 mmoles) in toluene (25 mL) is added slowly dropwise. The mixture is then stirred for 16 hours. Water (50 mL) and saturated aqueous sodium bicarbonate (50 mL) are added to the reaction mixture, which is then poured into a separatory funnel and washed with diethyl ether (100 mL). The layers are separated, and the aqueous layer is titrated to a pH of about 2 (as determined using pH paper) with concentrated aqueous hydrochloric acid. Ethyl acetate (150 mL) is added to the acidic solution; the mixture is shaken well, and then poured into a separatory funnel. The layers are separated and the aqueous layer extracted again with ethyl acetate (150 mL). The combined ethyl acetate extracts are dried over anhydrous sodium sulfate, filtered and evaporated to a white glassy foam. The crude product is purified on silica gel (400 mL bed volume) eluting with ethyl acetate:acetic acid (100:2 [v/v], 1800 mL), then ethyl acetate:methanol:acetic acid (95:5:2 [v/v/v], 1000 mL). Fractions containing pure product by thin layer chromatography are pooled and evaporated to a clear colorless syrup. The syrup is co-evaporated three time with toluene (150 mL each) to remove residual acetic acid. The resulting amorphous white solid is dried well in vacuo. The yield is 12.0 g (89%).
Reaction SMILES: [Br:1][C:2]1[NH:6][C:5]([C@@H:7]2[CH2:11][CH2:10][CH2:9][N:8]2[C:12]([O:14]C(C)(C)C)=O)=[N:4][CH:3]=1.Cl.[CH3:20][O:21][C:22]([NH:24][C@@H:25]([CH:29]([CH3:31])[CH3:30])C(O)=O)=[O:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CO.C(OCC)(=O)C>[Br:1][C:2]1[NH:6][C:5]([C@@H:7]2[CH2:11][CH2:10][CH2:9][N:8]2[C:12](=[O:14])[C@@H:25]([NH:24][C:22](=[O:23])[O:21][CH3:20])[CH:29]([CH3:31])[CH3:30])=[N:4][CH:3]=1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(Br)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(Br)[nH]1)C(C)C
Temperature: 25 °C
Yield: 82.5 %

Procedure:
A solution of (S)-tert-butyl 2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (1.0 g, 3.2 mmol), 4M HCl solution in dioxanes (3.95 mL, 15.8 mmol) and methanol (4 mL) was stirred at room temperature for thirty minutes. The reaction was concentrated, suspended in dichloromethane, and thoroughly concentrated. This crude amine was dissolved in dimethylformamide (6.4 mL). To this solution were added (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (582 mg, 3.3 mmol), HATU (1.3 g, 3.3 mmol) and diisopropylethylamine (1.9 mL, 11.1 mmol). The reaction was stirred at room temperature for twenty minutes, and then diluted with ethyl acetate. The organic layer was washed with water and brine, dried (Na2SO4) and concentrated. The crude material was purified by flash column chromatography to yield methyl (S)-1-((S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (985 mg, 83%).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:16]3[C:11](=[C:12]([N+:17]([O-])=O)[CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][N:8]=2)=[CH:4][C:3]=1[C:22]([F:25])([F:24])[F:23].[NH4+].[Cl-]>CCO.O.[Fe]>[F:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=3[CH:10]=[CH:9][N:8]=2)=[CH:4][C:3]=1[C:22]([F:25])([F:23])[F:24]
Reactant: O=[N+]([O-])c1cccc2c(Oc3ccc(F)c(C(F)(F)F)c3)nccc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cccc2c(Oc3ccc(F)c(C(F)(F)F)c3)nccc12
Yield: 87.2 %

Procedure:
The title compound was prepared following the procedure described in Step 3 of Intermediate-1 using 1-(4-fluoro-3-(trifluoromethyl)phenoxy)-5-nitroisoquinoline (830 mg, 2.35 mmol), iron powder (1.31 mg, 23.5 mmol), and NH4Cl (1.09 g, 18.8 mmol) in EtOH (8 mL) and water (2 mL) to afford 660 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 7.79 (d, J=6.0 Hz, 1H), 7.71-7.56 (m, 4H), 7.51 (d, J=8.1 Hz, 1H), 7.40 (t, J=8.1 Hz, 1H), 6.94 (d, J=7.2 Hz, 1H), 6.01 (s, 2H).
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH3:28])[O:14][CH2:13][N:12]([CH2:15][CH2:16][O:17][C:18]3[CH:27]=[CH:26][C:21]([NH:22]C(=O)C)=[CH:20][CH:19]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl>>[OH2:14].[ClH:1].[ClH:1].[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][O:17][C:18]3[CH:27]=[CH:26][C:21]([NH2:22])=[CH:20][CH:19]=3)[CH2:13][CH:28]=2)=[CH:7][CH:8]=1
Reactant: CC(=O)Nc1ccc(OCCN2CCC(C)(c3ccc(F)cc3)OC2)cc1
Agent: Cl
Product: Nc1ccc(OCCN2CC=C(c3ccc(F)cc3)CC2)cc1
Product: O

Procedure:
0.2 G. of 4'-{2-[6-(p-fluorophenyl)-dihydro-6-methyl-2H-1,3-oxazin-3(4H)-yl]ethoxy}acetanilide hydrochloride and 2 ml. of conc. hydrochloric acid are heated on the steam bath for 4 hours. The excess hydrochloric acid is evaporated under reduced pressure and the residue brought to crystallization with ethanol-acetic acid ethyl ester. The p-{2-[4-(p-fluorophenyl)-3,6-dihydro-1(2H)-pyridyl]ethoxy}aniline dihydrochloride hydrate obtained melts at 180°-183°C. after recrystallization from ethanol-acetic acid ethyl ester.
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[C:20](=[O:22])=[O:21].Cl.C([O:28]CCCC)CCC>CCCCCC>[CH:1]1[C:14]2[C:13](=[O:28])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[C:4]([C:20]([OH:22])=[O:21])=[CH:3][CH:2]=1
Reactant: O=C=O
Reactant: CCCCOCCCC
Reactant: c1ccc2c(c1)Cc1ccccc1S2
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Product: O=C(O)c1cccc2c(=O)c3ccccc3sc12

Procedure:
This compound was prepared by adding dropwise a solution of thioxanthene in n-butylether to a solution of n-butyllithium in hexane. The intermediate product was carbonated with dry ice and acidified with hydrochloric acid. The final product had a melting point of greater than 300° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[Br:12]N1C(=O)CCC1=O>C(#N)C.C(OCC)(=O)C>[Br:12][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]=1[NH2:8]
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Nc1c(Br)cc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 107.4 %

Procedure:
A mixture of 4-chloro-2-nitrobenzenamine (5.1 g, 30 mmol) and N-bromosuccinimide (6.2 g, 36 mmol) in acetonitrile (50 mL) was heated at reflux for overnight. It was cooled to room temperature and diluted with ethyl acetate (50 mL). The mixture was washed with saturated aqueous K2CO3 solution (100 mL×2). The organic phase was separated, dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to afford 109a as a yellow solid (8.1 g, 100%). LCMS: [M+H]+ 253. 1H NMR (500 MHz, CDCl3) δ 8.17 (d, J=2.5 Hz, 1H), 7.71 (d, J=2.5 Hz, 1H), 6.64 (s, 2H).
Reaction SMILES: Cl.[NH2:2][C:3]1([C:8]([O:10][CH3:11])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15].C([O-])(O)=O.[Na+].O>CN(C=O)C>[O:15]=[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:13][NH:2][C:3]1([C:8]([O:10][CH3:11])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COC(=O)C1(N)CCCC1
Reactant: O=C(CBr)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1(NCC(=O)c2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of methyl 1-aminocyclopentanecarboxylate hydrochloride (2.00 g, 11.1 mmol, described in Intermediate 25), 2-bromoacetophenone (2.44 g, 12.2 mmol), and NaHCO3 (2.34 g, 27.9 mmol) in DMF (20 mL) was stirred at ambient temperature for 5 h. H2O (25 mL) was added and the mixture was extracted with EtOAc (2×75 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The product-containing fractions were combined, adjusted to pH 10 by addition of saturated aqueous Na2CO3 and extracted with EtOAc (2×75 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound. MS: m/z=262 (M+1).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([OH:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:34]([C@@H:36]([O:38]C(=O)C)[CH3:37])=[O:35]>>[OH:38][C@@H:36]([CH3:37])[C:34]([N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([OH:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:6][CH2:7]1)=[O:35]
Reactant: O=C(NC1CCNCC1)c1c[nH]c2c(-c3cc(F)c(O)cc3OCC3CC3)ncnc12
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: C[C@H](O)C(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4cc(F)c(O)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-4-hydroxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A188) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:12]=[C:11](OS(C(F)(F)F)(=O)=O)[C:10]([CH2:21][CH3:22])=[C:9]([CH3:23])[N:8]=2)=[CH:4][CH:3]=1.[OH:24][B:25]1[C:29]2[CH:30]=[C:31]([NH2:34])[CH:32]=[CH:33][C:28]=2[CH2:27][O:26]1.CS(C)=O>O>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:12]=[C:11]([NH:34][C:31]3[CH:32]=[CH:33][C:28]4[CH2:27][O:26][B:25]([OH:24])[C:29]=4[CH:30]=3)[C:10]([CH2:21][CH3:22])=[C:9]([CH3:23])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCc1c(C)nc(-c2ccc(Cl)s2)nc1OS(=O)(=O)C(F)(F)F
Reactant: Nc1ccc2c(c1)B(O)OC2
Solvent: CS(C)=O
Solvent: O
Product: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Nc1ccc2c(c1)B(O)OC2
Temperature: 90 °C
Reaction time: 2 h
Yield: 51.9 %

Procedure:
A 8-mL vial was charged with [2-(5-chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]trifluoromethanesulfonate (20 mg, 0.052 mmol, 1.05 eq.), 1-hydroxy-3H-2,1-benzoxaborol-6-amine (7.5 mg, 0.05 mmol, 1 eq.) and DMSO (0.5 ml). The mixture was stirred at 90° C. under Ar for 2 hr. After cooling to room temperature, the mixture was added to water (5 ml). The precipitate was collected by filtration and washed with water. After dried, the mixture was purified by prep. TLC using 10% of ethyl acetate in dichloromethane as a mobile phase to give the title compound as a solid (10 mg, 52% yield). MW=385.68. 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J=7.2 Hz, 1H), 7.85 (s, 1H), 7.65 (d, J=4.0 Hz, 1H), 7.41 (d, J=7.2 Hz, 1H), 6.92 (d, J=4.0 Hz, 1H), 6.58 (brs, 1H), 5.15 (s, 1H), 2.65 (q, J=7.6 Hz, 2H), 2.50 (s, 3H), 1.25 (t, J=7.6 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:21]=[CH:20][C:14]([C:15](OCC)=[O:16])=[CH:13][CH:12]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:15]([C:14]2[CH:20]=[CH:21][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)=[O:16])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(Cl)n1
Reactant: CCOC(=O)c1ccc(OC)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Cc2cccc(Cl)n2)cc1
Temperature: 45 °C
Yield: 85.8 %

Procedure:
To a cold (0° C.) solution of 6-chloro-2-picoline (18.3 mL, 166.5 mmol) and ethyl 4-methoxybenzoate (30.0 g, 166.5 mmol) in tetrahydrofuran (300 mL) was added lithium bis(trimethylsilyl)amide (333 mL 1.0 M in tetrahydrofuran, 332.7 mmol) dropwise via a pressure equalizing funnel over 1 hour. Upon complete addition, the cold bath was removed and the resulting solution was heated at 45° C. for 15 hours. The mixture was cooled to room temperature, and the solution was concentrated. Methanol was added to quench the reaction, resulting in the formation of a yellow precipitate. The precipitate was collected by filtration and dried to give 2-(6-chloro-2-pyridinyl)-1-(4-methoxyphenyl)ethanone (37.4 g, 86%) as a yellow solid. 1H NMR (CDCl3): δ 7.99 (d, 2H), 7.57 (t, 1H), 7.22-7.19 (m, 2H), 6.90 (d, 2H), 4.39 (s, 2H), 3.83 (s, 3H); MS m/z 262 (M+1).
Reaction SMILES: [C:1]([C@H:4]1[C@@H:9]([NH2:10])[CH2:8][CH2:7][C@@H:6]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:5]1)(=[O:3])[CH3:2].[F:19][C:20]([F:35])([F:34])[C:21]1[CH:22]=[C:23]([CH:31]=[CH:32][CH:33]=1)[C:24]([NH:26][CH2:27][C:28](O)=[O:29])=[O:25].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[C:1]([C@H:4]1[C@@H:9]([NH:10][C:28](=[O:29])[CH2:27][NH:26][C:24](=[O:25])[C:23]2[CH:31]=[CH:32][CH:33]=[C:21]([C:20]([F:19])([F:35])[F:34])[CH:22]=2)[CH2:8][CH2:7][C@@H:6]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N
Reactant: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(=O)[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 45.4 %

Procedure:
Tert-butyl (1R,3R,4S)-3-acetyl-4-aminocyclohexylcarbamate (500 mg) dissolved in DMF (2 mL) prior to the addition of 2-(3-(trifluoromethyl)benzamido)acetic acid (626 mg), 4-methylmorpholine (1.1 mL), and BOP (1.3 g). The reaction was stirred for 12 h at rt and then partitioned between EtOAc and 1N HCl solution. The organic phases were combined, washed with saturated NaHCO3 and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford tert-butyl (1R,3R,4S)-3-acetyl-4-(2-(3-(trifluoromethyl)benzamido)acetamido)cyclohexylcarbamate (430 mg). MS found: (M+H)+=486.2.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=O)[CH3:2].CO.C([BH3-])#[N:13].[Na+].[OH-].[Na+]>N.C(O)(=O)C>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([NH2:13])[CH3:2])[CH:5]=1
Reactant: CC(=O)c1cccnc1
Reactant: [BH3-]C#N
Agent: N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CC(N)c1cccnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 44 %

Procedure:
3-Acetylpyridine (2.4 g, 20 mmol, Aldrich) was dissolved in 2M ammonia solution in methyl alcohol (50 mL, 100 mmol, Aldrich) and acetic acid (15 mL, J. T. Baker) was slowly added at 0 C. After stirring for 3 h at room temperature, the sodium cyanoborohydride (5.0 g, 80 mmol, Aldrich) was added to the solution at 0 C. The mixture was stiffed under nitrogen at room temperature for overnight then the reaction was cooled at ice bath and quenched with aqueous 5 N sodium hydroxide (30 mL, 150 mmol, J. T. Baker). The methyl alcohol was removed from the mixture via vacuo. The residue was extracted by diethyl ether (30 mL×4). The combined organic phases were dried over anhydrous magnesium sulfate and concentrated via vacuo to give crude 1-pyridin-3-yl-ethylamine as light yellow oil in 44% yield (1.07 g, 8.8 mmol).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=O)=[CH:4][C:3]=1[C:11]1[C:22](=[O:23])[N:21]([CH3:24])[C:14]2[N:15]=[C:16]([S:19][CH3:20])[N:17]=[CH:18][C:13]=2[CH:12]=1.[NH2:25]N.C[N:28]([CH:30](OC)OC)C>>[CH3:24][N:21]1[C:14]2[N:15]=[C:16]([S:19][CH3:20])[N:17]=[CH:18][C:13]=2[CH:12]=[C:11]([C:3]2[CH:4]=[C:5]([C:6]3[NH:8][CH:30]=[N:28][N:25]=3)[CH:9]=[CH:10][C:2]=2[CH3:1])[C:22]1=[O:23]
Reactant: NN
Reactant: CSc1ncc2cc(-c3cc(C(N)=O)ccc3C)c(=O)n(C)c2n1
Reactant: COC(OC)N(C)C
Product: CSc1ncc2cc(-c3cc(-c4nnc[nH]4)ccc3C)c(=O)n(C)c2n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
4-Methyl-3-(8-methyl-2-methylsulfanyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl)-benzamide (100 mg, 0.294 mmol) was taken up in 6 mL DMFDMA, and the reaction mixture was heated to reflux for 10 minutes, then cooled and concentrated under reduced pressure. The resulting residue was taken up in 10 mL HOAc, and hydrazine (0.24 g, 7.638 mmol) was added. The reaction mixture was stirred at room temperature for 20 minutes, and the resulting precipitate was collected by filtration and washed with water to give 60 mg of 8-methyl-2-methylsulfanyl-6-[2-methyl-5-(4H-[1,2,4]triazol-3-yl)-phenyl]-8H-pyrido[2,3-d]pyrimidin-7-one, MS (M+H)=365.
Reaction SMILES: [NH:1]([C:46]([O:48][CH2:49][CH:50]1[C:62]2[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=2)[C:56]2[C:51]1=[CH:52][CH:53]=[CH:54][CH:55]=2)=[O:47])[C@H:2]([C:14]([N:16]([CH3:45])[C@H:17]([C:25]([N:27]([CH3:44])[C@H:28]([C:36]([NH:38][C@H:39]([C:41]([OH:43])=[O:42])[CH3:40])=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:3][C:4](=[O:13])[O:5]CC1C=CC=CC=1.[H][H]>[Pd].CO>[NH:1]([C:46]([O:48][CH2:49][CH:50]1[C:62]2[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=2)[C:56]2[C:51]1=[CH:52][CH:53]=[CH:54][CH:55]=2)=[O:47])[C@H:2]([C:14]([N:16]([CH3:45])[C@H:17]([C:25]([N:27]([CH3:44])[C@H:28]([C:36]([NH:38][C@H:39]([C:41]([OH:43])=[O:42])[CH3:40])=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:26])[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:15])[CH2:3][C:4](=[O:5])[OH:13]
Reactant: C[C@H](NC(=O)[C@H](Cc1ccccc1)N(C)C(=O)[C@H](Cc1ccccc1)N(C)C(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C[C@H](NC(=O)[C@H](Cc1ccccc1)N(C)C(=O)[C@H](Cc1ccccc1)N(C)C(=O)[C@H](CC(=O)O)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Fmoc-Asp(OBn)-MePhe-MePhe-Ala-pip (Compound SP457) (8.06 g, 8.90 mmol) and 20% palladium on active carbon (1.61 g, 3.0 mmol) were added to methanol (50 ml) under a nitrogen atmosphere, the atmosphere in the reaction vessel was replaced with hydrogen gas, and the mixture was stirred at room temperature for 5 hours. The reaction solution was filtered through celite, and the organic layer was concentrated under reduced pressure to afford Fmoc-Asp-MePhe-MePhe-Ala-pip (Compound SP458) (4.79 g, 66%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[C:33]5[C:28](=[CH:29][C:30]([O:36]CC6C=CC=CC=6)=[C:31]([O:34][CH3:35])[CH:32]=5)[N:27]=[CH:26][CH:25]=4)=[C:19]([F:44])[CH:18]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.C1CC=CCC=1>CCO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[C:33]5[C:28](=[CH:29][C:30]([OH:36])=[C:31]([O:34][CH3:35])[CH:32]=5)[N:27]=[CH:26][CH:25]=4)=[C:19]([F:44])[CH:18]=3)=[O:15])[CH2:12][CH2:13]2)=[O:10])=[CH:4][CH:3]=1
Reactant: COc1cc2c(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ccnc2cc1OCc1ccccc1
Agent: [Pd]
Solvent: C1=CCC=CC1
Solvent: CCO
Product: COc1cc2c(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ccnc2cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a solution of cyclopropane-1,1-dicarboxylic acid [4-(7-benzyloxy-6-methoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide (4-fluoro-phenyl)-amide (1.18 g, 2.0 mmol) in EtOH (20 mL) was added 1,4-cyclohexadiene (2.0 mL, 20 mmol) and 10% Pd/C (300 mg). The reaction mixture was then heated to reflux and the stirring was continued for 2 h. It was cooled to room temperature, filtered through celite and washed with MeOH. The MeOH solution was then concentrated under reduced pressure. The residue was taken into EtOAc (200 mL). The EtOAc solution was washed with water, and dried over Na2SO4. Removal of the solvent under reduced pressure gave 900 mg (89%) of the crude product (90% purity by analytical HPLC), which was used in the next reaction without further purification.