Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][O:14][CH:15]([F:17])[F:16])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1COCC1.C(OCC)(=O)C>[CH2:33]([NH:40][C:10](=[O:12])[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][O:14][CH:15]([F:17])[F:16])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](COC(F)F)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](COC(F)F)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
To a solution of (2R)-2-[(tert-butoxycarbonyl)amino]-3-(difluoromethoxy)propanoic acid (510 mg, 2.0 mmol) and triethylamine (607.1 mg, 6 mmol) in THF (10 mL) at −78° C., isobutyl chloroformate (348 mg, 2.55 mmol) was added dropwise. After 30 minutes, benzylamine (321.5 mg, 3.0 mmol) was added and the reaction mixture allowed to warm up to room temperature. The mixture then was diluted with ethyl acetate and washed with water, 0.5N HCl and Brine. The organic layer was dried over magnesium sulphate, concentrated, and triturated with ether-hexanes (1:3) to give tert-butyl {(1R)-2-(benzylamino)-1-[(difluoromethoxy)methyl]-2-oxoethyl}carbamate (345 mg, 50%) as a white solid. 1H NMR (300 MHz, CDCl3): δ(ppm) 7.40-7.80 (m, 5H), 6.60 (t, 1H), 6.22 (wt, 1H), 5.25 (w, 1H), 4.32-4.55 (m, 4H), 4.05 (dd, 1H) and 1.48 (s, 9H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([OH:13])=[CH:6][C:5]=1[CH3:14].[CH3:15]I.O>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([O:13][CH3:15])=[CH:6][C:5]=1[CH3:14]
Reactant: CI
Reactant: Cc1cc(O)c([N+](=O)[O-])cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C)c(Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
To a suspension of sodium hydride (1.2 mmol) in DMF (6 mL), 4-chloro 3-methyl 6-nitrophenol (1.0 mmol) was added at 0° C. The reaction mixture was stirred at 0° C. for 15 minute then methyliodide was added at 0° C. and the mixture was stirred for 4 hours at room temperature. Water (60 mL) was added and the mixture extracted with EtOAc (3×50 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography on silica using 5-8% EtOAc in hexane to give the title compound (87%) as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:16]([NH:18][C@H:19]([C:21]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:25](=[O:33])[C:24]5=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]5[N:22]=4)[CH3:20])=[N:15][CH:14]=[N:13][C:12]=3[N:11]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[CH:10]=2)[CH:5]=[C:6]([OH:8])[CH:7]=1.N1C=CC=CC=1.[S:52](Cl)(=[O:55])(=[O:54])[NH2:53].O>O1CCCC1>[OH:8][C:6]1[CH:7]=[C:2]([NH:1][S:52]([NH2:53])(=[O:55])=[O:54])[CH:3]=[C:4]([C:9]2[C:17]3[C:16]([NH:18][C@H:19]([C:21]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:25](=[O:33])[C:24]5=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]5[N:22]=4)[CH3:20])=[N:15][CH:14]=[N:13][C:12]=3[N:11]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:43])([CH3:45])[CH3:44])[CH:10]=2)[CH:5]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(N)cc(O)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: NS(=O)(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(O)cc(NS(N)(=O)=O)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.7 %

Procedure:
(S)-2-(1-((5-(3-Amino-5-hydroxyphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.08 mmol) was dissolved in 0.75 ml tetrahydrofuran. Pyridine (10 μl, 0.12 mmol) and sulfamoyl chloride (11 mg, 0.10 mmol) were added and the mixture was stirred at room temperature during 2 h. The reaction was poured into water and extracted twice with ethyl acetate. The organics were combined and washed with water, brine, dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue was purified using SP1® Purification System (0% to 100% hexane-ethyl acetate) to obtain 38 mg (66% yield) of the title compound.
Reaction SMILES: [CH3:1][N:2]([C-:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1)[CH3:3].[CH-:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1.[Fe+2:14].B(F)(F)F.CCOCC.[Li]CCCC.[P:29](Cl)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1.CCOCC>[C:36]1([P:29]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:5]2[C-:4]([N:2]([CH3:3])[CH3:1])[CH:8]=[CH:7][CH:6]=2)[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1.[CH-:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1.[Fe+2:14]
Reactant: CN(C)[c-]1cccc1
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: [Fe+2]
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(C)[c-]1cccc1P(c1ccccc1)c1ccccc1
Yield: 76.7 %

Procedure:
A solution of 11 (229 mg, 1.00 mmol) in THF (10 mL) was sequentially treated with BF3.OEt2 (0.13 mL, 1.05 mmol), n-BuLi (0.45 mL, 2.45 M, 1.10 mmol) and Ph2PCl (0.22 mL, 1.20 mmol). Standard workup followed by column chromatography of the pre-adsorbed product (silica gel, Et2O) gave an orange solid. Recrystallization from Et2O afforded 12f (317 mg, 77%) as orange needles in two crops; mp 146-148° C. (Et2O); IR (KBr) vmax 3090, 3050, 2952, 2840, 2780, 1494 cm−1; 31P NMR (121.5 MHz, CDCl3) −20.37; 1H NMR (600 MHz, CDCl3) 7.55-7.52 (m, 2H), 7.39 (m, 3H), 7.28 (m, 5H), 4.20 (s, 1H), 4.13 (s, 5H), 4.10 (t, 1H, J=2.4 Hz), 3.50 (s, 1H), 2.69 (s, 6H) ppm; 13C NMR (150.9 MHz, CDCl3) 139.8 (d, J=11.0 Hz), 137.9 (d, J=10.6 Hz), 135.3 (d, J=22.6 Hz), 132.4 (d, J=18.1 Hz), 129.0, 128.1 (d), 128.0 (d), 127.8, 119.0 (d, J=18.1 Hz), 68.7, 68.5 (d, J=3.0 Hz), 65.9 (d, J=10.6 Hz), 65.2, 60.1, 45.5 ppm; EIMS [m/z (%)] 413 (M+, 100); HRMS (EI) calcd for C24H24NP56Fe: 413.0995. Found 413.0991. Anal. Calcd for C24H24NPFe: C, 69.75; H, 5.85. Found: C, 69.87; H, 5.94.
Reaction SMILES: C([O-])(=O)C.[Na+].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[O:17]1[CH2:21][CH2:20][O:19][CH:18]1[C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][OH:25]>C(Cl)Cl.CCOCC>[O:17]1[CH2:21][CH2:20][O:19][CH:18]1[C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=[O:25]
Reactant: OCc1ccccc1C1OCCO1
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: O=Cc1ccccc1C1OCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of sodium acetate (6.56 g, 0.08 mol) and pyridinium chlorochromate (17.2 g, 0.08 mol) in dry methylene chloride (200 ml) was cooled in an ice bath under a nitrogen atmosphere and treated with a solution of 2-(2-dioxolanyl)benzyl alcohol (9.6 g, 0.053 mol) in methylene chloride (25 ml) over a 15 minute period. The reaction was stirred at room temperature for 2 hours and diluted with ether (200 ml). The solid was collected and washed with ether, and the filtrate was washed with 5% NaHCO3 and brine and dried. The solution was evaporated to give the title aldehyde; 7.8 g (82%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.C(N(CC)CC)C.O>C1COCC1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:7]
Reactant: C1COCCN1
Reactant: O=C(Cl)CCCCBr
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: O=C(CCCCBr)N1CCOCC1
Reaction time: 3.5 h
Yield: 88 %

Procedure:
Under a nitrogen atmosphere, 5-bromovaleryl chloride (4.0 mL, 30 mmol) was added dropwise to a solution of morpholine (3.13 mL, 36 mmol) and triethylamine (6.25 mL, 45 mmol) in anhydrous THF (200 mL), and the reaction was stirred for 3.5 hours. Water (100 mL) was added, and the resulting solution was extracted with ethyl acetate (250 mL+150 mL). The combined extracts were washed with aqueous hydrogen chloride (100 mL of 1 N), water (60 mL), and brine (100 mL); dried over magnesium sulfate; filtered; concentrated under reduced pressure; and further dried under high vacuum to provide 6.60 g of 4-(5-bromopentanoyl)morpholine as a yellow oil.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH2:5][C:6]1[CH:25]=[CH:24][C:9]([O:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1>CN(C)C=O.CO>[CH3:1][NH:2][C:3]([NH:5][C:6]1[CH:25]=[CH:24][C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[CH2:16][CH2:17]2)=[CH:8][CH:7]=1)=[O:4]
Reactant: CN=C=O
Reactant: Nc1ccc(OCC2CCN(c3ccncc3)CC2)cc1
Solvent: CO
Solvent: CN(C)C=O
Product: CNC(=O)Nc1ccc(OCC2CCN(c3ccncc3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.7 %

Procedure:
Methyl isocyanate (0.18 g) was added to a stirred solution of 4-[(4-aminophenoxy)methyl]-1-[4-pyridyl]piperidine (see Preparation 4) (0.57 g) in dimethylformamide (10 ml) and the mixture was stirred at room temperature for 3 hours and then diluted with methanol (2 ml). The solid was filtered off and crystallised from methanol to give the title compound, (0.32 g), m.p. 222°-224°.
Reaction SMILES: C(O[C:6](=[O:39])[NH:7][CH:8]([CH2:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[CH:32]=1)[CH:9]([OH:29])[CH2:10][NH:11][C:12]1([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Br:28])[CH:23]=2)[CH2:21][CH2:20][C:15]2([O:19][CH2:18][CH2:17][O:16]2)[CH2:14][CH2:13]1)(C)(C)C.[CH3:40]N1CCOCC1.C(O)(=O)C.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>FC(F)(F)C(O)=O.C(Cl)Cl>[Br:28][C:24]1[CH:23]=[C:22]([C:12]2([NH:11][CH2:10][CH:9]([OH:29])[CH:8]([NH:7][C:6](=[O:39])[CH3:40])[CH2:30][C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[CH:32]=3)[CH2:13][CH2:14][C:15]3([O:19][CH2:18][CH2:17][O:16]3)[CH2:20][CH2:21]2)[CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1cc(F)cc(F)c1)C(O)CNC1(c2cccc(Br)c2)CCC2(CC1)OCCO2
Reactant: CN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NC(Cc1cc(F)cc(F)c1)C(O)CNC1(c2cccc(Br)c2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound 17 was dissolved in 1 mL (1:1) trifluoroacetic acid (TFA) and CH2Cl2. The reaction stirred at room temperature for 2 h and concentrated under reduced pressure. The residue was dissolved in 4 mL CH2Cl2 and N-Methylmorpholine (NMM) (3.12 mmol). The reaction was stirred at 0° C. Acetic Acid (0.76 mmol) was added slowly to the reaction mixture and the mixture stirred at 0° C. for five min. Then 1-Hydroxylbenzotriazole hydrate (HOBt) (0.76 mmol) and 1-Ethyl-3-(3′-Dimethylaminopropyl)carbodiimide Hydrochloride (EDC.HCl) (0.76 mmol) were added sequentially. The reaction was stirred at room temperature for two h. CH2Cl2 was removed by reduced pressure and the residue dissolved in EtOAc. The organic layer was rinsed with a saturated NaHCO3 solution three times and once with Brine. The organic layer was dried with MgSO4, filtered and concentrated under reduced pressure. Compound 22 was purified by preparative HPLC.
Reaction SMILES: CO[C:3]1[C:4](=[O:10])[C:5](=[O:9])[C:6]=1[O:7][CH3:8].[NH2:11][C:12]1[C:13]([F:31])=[C:14]([CH:28]=[CH:29][CH:30]=1)[C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])=[O:16]>CO>[F:31][C:13]1[C:12]([NH:11][C:3]2[C:4](=[O:10])[C:5](=[O:9])[C:6]=2[O:7][CH3:8])=[CH:30][CH:29]=[CH:28][C:14]=1[C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])=[O:16]
Reactant: COc1c(OC)c(=O)c1=O
Reactant: CC(C)OC(=O)[C@@H]1CCCN1C(=O)c1cccc(N)c1F
Solvent: CO
Product: COc1c(Nc2cccc(C(=O)N3CCC[C@H]3C(=O)OC(C)C)c2F)c(=O)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 32.6 %

Procedure:
1.80 g (0.01 mol; 2.0 eq) of 3,4-dimethoxy-3-cyclobutene-1,2-dione were added to a solution of 1.87 g (0.08 mol; 1.0 eq) of isopropyl (S)-1-(3-amino-2-fluorobenzoyl)pyrrolidine-2-carboxylate in 45 ml of methanol. The reaction medium was stirred at ambient temperature for 24 hours. The solvent was evaporated off and the residue was chromatographed on silica gel (200 g prepacked column, eluent 20/80 then 0/100 heptane/ethyl acetate). 1.32 g of isopropyl (S)-1-[2-fluoro-3-(2-methoxy-3,4-dioxocyclobut-1-enylamino)benzoyl]pyrrolidine-2-carboxylate were obtained in the form of a light yellow amorphous solid. Yield=51%.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[O:16])=[CH:13][N:12]=[C:11]([NH:25][CH:26]2[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]2)[N:10]=1.C(N(CC)CC)C.Cl[C:40]([O:42][CH3:43])=[O:41]>ClCCl>[CH3:43][O:42][C:40]([N:28]1[CH2:29][CH2:30][CH2:31][CH:26]([NH:25][C:11]2[N:10]=[C:9]([NH2:8])[C:14]([C:15](=[O:16])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])=[CH:13][N:12]=2)[CH2:27]1)=[O:41]
Reactant: COC(=O)Cl
Reactant: COc1ccccc1C(=O)c1cnc(NC2CCCNC2)nc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N1CCCC(Nc2ncc(C(=O)c3ccccc3OC)c(N)n2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
To a solution of [4-amino-2-(piperidin-3-ylamino)-pyrimidin-5-yl]-(2-methoxy-phenyl)-methanone trifluoroacetic acid salt (42 mg, Example 53) in dichloromethane (3 mL) were added triethylamine (48 mg, Aldrich) and methyl chloroformate (6.1 mg, Aldrich) at 0° C. After stirring for 1 hour at 0° C., the reaction mixture was concentrated in vacuo and crude product was purified on silica gel with 95:5 of dichloromethane/methanol to give 3-[4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid methyl ester (20.5 mg). MS (M+H)+, 386. CDK4 IC50=0.459 μM; CDK1 IC50=0.469 μM; CDK2 IC50=0.713 μM; HCT 116 IC90=6.437 μM.
Reaction SMILES: [OH:1][C@H:2]1[C@H:6]([O:7][C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[N:16]=[C:15]([C:18]2[N:22]4[CH:23]=[CH:24][C:25]([O:27][CH2:28][CH2:29][O:30][CH3:31])=[CH:26][C:21]4=[N:20][CH:19]=2)[CH:14]=[CH:13]3)[CH2:5][N:4](C(OCC2C=CC3C(=CC=CC=3)C=2)=O)[CH2:3]1.CCO.Cl>[Pd].C1COCC1>[CH3:31][O:30][CH2:29][CH2:28][O:27][C:25]1[CH:24]=[CH:23][N:22]2[C:18]([C:15]3[CH:14]=[CH:13][C:12]4[C:17](=[C:8]([O:7][C@@H:6]5[CH2:5][NH:4][CH2:3][C@H:2]5[OH:1])[CH:9]=[CH:10][CH:11]=4)[N:16]=3)=[CH:19][N:20]=[C:21]2[CH:26]=1
Reactant: COCCOc1ccn2c(-c3ccc4cccc(O[C@@H]5CN(C(=O)OCc6ccc7ccccc7c6)C[C@H]5O)c4n3)cnc2c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: COCCOc1ccn2c(-c3ccc4cccc(O[C@@H]5CNC[C@H]5O)c4n3)cnc2c1
Reaction time: 2 h
Yield: 20.2 %

Procedure:
A 25 mL flask was charged with (trans)-naphthalen-2-ylmethyl 3-hydroxy-4-(2-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)quinolin-8-yloxy)pyrrolidine-1-carboxylate (0.100 g, 0.165 mmol), EtOH (1.6 mL), THF (1.6 mL), 2 N HCl (0.2 mL) and 10% Degussa type Pd/C (0.018 g, 0.017 mmol), and the reaction was placed under a balloon of H2 and stirred for 2 hours. The reaction was filtered (GF/F paper), the filter paper was washed with 2 N HCl and THF, the aqueous phase was washed with DCM, neutralized with saturated NaHCO3, and then extracted with DCM. The organic layer was dried and condensed to afford 14 mg of the desired product. MS APCI (+) m/z 421.2 (M+1) detected.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([C:14]2[S:15][C:16]([C:19]3[C:23]([CH3:24])=[C:22]([C:25]([F:28])([F:27])[F:26])[O:21][N:20]=3)=[CH:17][CH:18]=2)=[O:13])[CH2:7]1)=O)C.[NH3:29]>>[CH3:24][C:23]1[C:19]([C:16]2[S:15][C:14]([C:12]([N:8]3[CH2:9][CH2:10][CH2:11][C@H:6]([C:4]([NH2:29])=[O:3])[CH2:7]3)=[O:13])=[CH:18][CH:17]=2)=[N:20][O:21][C:22]=1[C:25]([F:27])([F:28])[F:26]
Reactant: N
Reactant: CCOC(=O)[C@H]1CCCN(C(=O)c2ccc(-c3noc(C(F)(F)F)c3C)s2)C1
Product: Cc1c(-c2ccc(C(=O)N3CCC[C@H](C(N)=O)C3)s2)noc1C(F)(F)F
Yield: 86 %

Procedure:
A solution of (S)-1-[5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carbonyl]-piperidine-3-carboxylic acid ethyl ester (Example 65, 88 mg, 0.20 mmol) in 7N methanolic ammonia (5 mL) was heated at 60° C. in a sealed vial for 48 hr. After this time the reaction mixture was evaporated and triturated and filtered with the aid of water. The filtered solids were air dried to afford product as a colorless solid (67 mg, 86%). LC/MS 5.52 min, [M+1]+ 388.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH2:26][C:27]1[C:28]([F:44])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:38]#[N:39])[C:30]([Cl:33])=[CH:31][CH:32]=1.[CH3:45][S:46][CH2:47][CH2:48][CH2:49][O:50][C:51]1[CH:52]=[C:53]2[C:57](=[CH:58][CH:59]=1)[NH:56][C:55]([C:60](O)=[O:61])=[CH:54]2.CCN(C(C)C)C(C)C>O.CCOC(C)=O.CN(C=O)C>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][NH:25][C:60]([C:55]2[NH:56][C:57]3[C:53]([CH:54]=2)=[CH:52][C:51]([O:50][CH2:49][CH2:48][CH2:47][S:46][CH3:45])=[CH:59][CH:58]=3)=[O:61])=[C:28]([F:44])[C:29]=1[O:34][C:35]1[CH:36]=[C:37]([C:38]#[N:39])[CH:40]=[C:41]([Cl:43])[CH:42]=1
Reactant: CSCCCOc1ccc2[nH]c(C(=O)O)cc2c1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CSCCCOc1ccc2[nH]c(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)cc2c1
Reaction time: 2 h
Yield: 50 %

Procedure:
HATU (0.061 g, 0.161 mmol) was added as a solid to a DMF (1 mL) solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.050 g, 0.161 mmol), 5-{[3-(methylthio)propyl]oxy}-1H-indole-2-carboxylic acid (0.043 g, 0.161 mmol) and DIPEA (0.028 mL, 0.161 mmol). After stirring for 2 hours the reaction mixture was poured into EtOAc and water and the layers separated. The organic layer was dried over MgSO4, filtered and the solvent evaporated. The residue was dissolved in MeOH and purification was accomplished by reverse-phase HPLC (water/acetonitrile with 0.1% TFA) to afford the title compound (0.045 g, 50%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.45 (s, 1H), 8.96 (t, 1H), 7.80 (s, 1H), 7.43-7.54 (m, 3H), 7.37 (t, 1H), 7.28 (d, 1H), 7.01-7.10 (m, 2H), 6.82 (dd, 1H), 4.54 (d, 2H), 4.00 (t, 2H), 2.61 (t, 2H), 2.04 (s, 3H), 1.89-2.01 (m, 2H). LCMS: m/z 558.1 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:26][CH:27]([CH3:29])[CH3:28])=[C:13]([C:15]2[NH:25][C:18]3=[N:19][C:20]([CH2:23]Cl)=[CH:21][CH:22]=[C:17]3[N:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:30]#[N:31].[K+].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:26][CH:27]([CH3:29])[CH3:28])=[C:13]([C:15]2[NH:25][C:18]3=[N:19][C:20]([CH2:23][C:30]#[N:31])=[CH:21][CH:22]=[C:17]3[N:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: CC(C)Oc1ccc(OCc2ccccc2)cc1-c1nc2ccc(CCl)nc2[nH]1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1ccc(OCc2ccccc2)cc1-c1nc2ccc(CC#N)nc2[nH]1
Yield: 52.1 %

Procedure:
A solution of 2-[5-(benzyloxy)-2-isopropoxyphenyl]-5-(chloromethyl)-3H-imidazo[4,5-b]pyridine (0.11 g) and potassium cyanide (30 mg) in N,N-dimethylformamide (5 ml) was stirred at 60° C. for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated. The residue was purified by preparative HPLC, and saturated aqueous sodium hydrogencarbonate solution was added to the obtained fraction to neutralize the mixture. The mixture was extracted with dichloromethane, and the extract was concentrated to give the title compound (56 mg, yield 52%) as colorless crystals. purity 90%. M+H: 399.
Reaction SMILES: N#N.C(N[C@@H](C(NCCCC1C=CC=CC=1)=[O:9])C)C.FC1C(OC(=O)[C@H](CC2C=CC(OCC3C=CC=CC=3)=CC=2)NC(OCC2C=CC=CC=2)=O)=C(F)C(F)=C(F)C=1F.C(N(C(C)C)CC)(C)C.[CH2:70]([O:77][C:78]([NH:80][C@H:81]([C:97]([N:99]([CH2:114][CH3:115])[C@@H:100]([C:102]([NH:104][CH2:105][CH2:106][CH2:107][C:108]1[CH:113]=[CH:112][CH:111]=[CH:110][CH:109]=1)=[O:103])[CH3:101])=[O:98])[CH2:82][C:83]1[CH:88]=[CH:87][C:86]([O:89][CH2:90][C:91]2[CH:96]=[CH:95][CH:94]=[CH:93][CH:92]=2)=[CH:85][CH:84]=1)=[O:79])[C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1>O1CCCC1.CN(C)C=O>[NH:80]([C:78]([O:77][CH2:70][C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1)=[O:79])[C@H:81]([C:97]([N:99]([CH2:114][CH3:115])[C@@H:100]([C:102]([NH:104][CH2:105][CH2:106][CH2:107][C:108]1[CH:109]=[CH:110][CH:111]=[CH:112][CH:113]=1)=[O:103])[CH3:101])=[O:98])[CH2:82][C:83]1[CH:88]=[CH:87][C:86]([O:89][C:90]([C:91]2[CH:92]=[CH:93][CH:94]=[CH:95][CH:96]=2)=[O:9])=[CH:85][CH:84]=1
Reactant: CCN[C@H](C)C(=O)NCCCc1ccccc1
Reactant: CCN(C(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OCc1ccccc1)[C@H](C)C(=O)NCCCc1ccccc1
Agent: N#N
Agent: O=C(N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)Oc1c(F)c(F)c(F)c(F)c1F)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCN(C(=O)[C@H](Cc1ccc(OC(=O)c2ccccc2)cc1)NC(=O)OCc1ccccc1)[C@H](C)C(=O)NCCCc1ccccc1

Procedure:
A solution of N2 -ethyl-N-(3-phenylpropyl)-D-alaninamide (2.71 g.), N-benzyloxycarbonyl-O-benzyl-L-tyrosine pentafluorophenyl ester (5.71 g.) and diisopropylethylamine (1.29 g.) in tetrahydrofuran (65 ml.) was stirred overnight at room temperature. Dimethylformamide (10 ml.) and more N-benzyloxycarbonyl-O-benzyl-L-tyrosine pentafluorophenyl ester (5.71 g.) were added, stirring was continued over the weekend, and the mixture was concentrated. A solution of the residual syrup in ethyl acetate was washed with water, dilute hydrochloric acid, aqueous sodium chloride, aqueous sodium hydroxide (1N, 20 ml.) and aqueous sodium chloride again, then dried and stripped of ethyl acetate. High pressure liquid chromatography of the residue (9.2 g.) on silica gel (350 g.) using hexane-ethyl acetate (55:45) as the eluant (200 ml./min.) afforded in the fractions having a k' value range of 2.5-4.5 (N-benzyloxycarbonyl-O-benzyl-L-tyrosyl)-N2 -ethyl-N-(3-phenylpropyl)-D-alaninamide as a syrup which crystallized (2.291 g.).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]2[C@H:16]([CH2:25][NH:26][C@@H:10]1[CH:11]([O:14]2)[O:12][CH3:13])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[CH2:32]([O:39][C:40](Cl)=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(OCC)C>[CH2:32]([O:39][C:40]([N:26]1[CH2:25][C@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:15]2[C@H:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C@H:10]1[CH:11]([O:14]2)[O:12][CH3:13])=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COC1O[C@H]2[C@H](OCc3ccccc3)[C@@H]1NC[C@@H]2OCc1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: COC1O[C@H]2[C@H](OCc3ccccc3)[C@@H]1N(C(=O)OCc1ccccc1)C[C@@H]2OCc1ccccc1
Reaction time: 2 h

Procedure:
To the crude amine (15), in a solution of diethyl ether:saturated sodium bicarbonate (3:2, 20 ml), was added benzylchloroformate (0.2 ml, 1.2 mmol). The reaction was then stirred, at such a rate as to make it one phase, for 2 hours. The aqueous phase was then separated and washed with diethyl ether (3×10 ml). The combined ethereal layers were then dried (sodium sulphate) and the solvent removed in vacuo. Purification by flash chromatography (0-50%, diethyl ether/hexane) then yielded methyl N-benzyloxycarbonyl-3,5-di-O-benzyl-2,6-deoxy-2,6-imino-L-gulofuranoside (16), as a colorless oil (200 mg, 67% from azidotriflate). νmax (CHCl3): 1685, 750, 700 cm-1.