Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH3:29])([C:6]([NH:8][C@@H:9]1[C:15](=[O:16])[N:14]([CH2:17][CH2:18][O:19][CH3:20])[C:13]2[CH:21]=[CH:22][CH:23]=[CH:24][C:12]=2[C:11]2[CH:25]=[CH:26][CH:27]=[CH:28][C:10]1=2)=[O:7])[C:3]([OH:5])=O.[F:30][C:31]([F:38])([C:34]([F:37])([F:36])[F:35])[CH2:32][NH2:33]>>[OH:1][C:2]([CH3:29])([C:3]([NH:33][CH2:32][C:31]([F:38])([F:30])[C:34]([F:37])([F:36])[F:35])=[O:5])[C:6]([NH:8][C@@H:9]1[C:15](=[O:16])[N:14]([CH2:17][CH2:18][O:19][CH3:20])[C:13]2[CH:21]=[CH:22][CH:23]=[CH:24][C:12]=2[C:11]2[CH:25]=[CH:26][CH:27]=[CH:28][C:10]1=2)=[O:7]
Reactant: NCC(F)(F)C(F)(F)F
Reactant: COCCN1C(=O)[C@@H](NC(=O)C(C)(O)C(=O)O)c2ccccc2-c2ccccc21
Product: COCCN1C(=O)[C@@H](NC(=O)C(C)(O)C(=O)NCC(F)(F)C(F)(F)F)c2ccccc2-c2ccccc21

Procedure:
Using 2-hydroxy-N—[(S)-5-(2-methoxy-ethyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-2-methyl-malonamic acid and 2,2,3,3,3-pentafluoropropylamine, the title compound was prepared in the same manner as described for example 1c. White solid (78%). MS: m/e=530(M+H+).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:4]=[N:3]1.[CH3:14][Mg]Br.C(OCC)C.[Cl-].[NH4+]>C1COCC1>[OH:13][C:7]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1)([CH3:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(=O)c1cnn(C)c1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(O)c1cnn(C)c1
Reaction time: 1 h

Procedure:
Under an argon atmosphere, to a solution of 500 mg of ethyl (1-methyl-1H-pyrazol-4-yl)(oxo)acetate that had been cooled in a dry ice-acetone bath in 7.5 ml of THF was added 1.56 ml of a 3.0 M methyl magnesium bromide/diethyl ether solution, followed by stirring for 1 hour. To the reaction mixture was added a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 302 mg of ethyl 2-hydroxy-2-(1-methyl-1H-pyrazol-4-yl)propanoate.
Reaction SMILES: [ClH:1].[O:2]1[C:6]2([CH2:11][CH2:10][CH2:9][NH:8][CH2:7]2)[O:5][CH2:4][CH2:3]1.[CH2:12](O)C>[Pd]>[ClH:1].[CH3:12][CH:11]1[C:6]2([O:5][CH2:4][CH2:3][O:2]2)[CH2:7][NH:8][CH2:9][CH2:10]1
Reactant: C1CNCC2(C1)OCCO2
Reactant: CCO
Agent: [Pd]
Agent: Cl
Product: CC1CCNCC12OCCO2
Reaction time: 24 h
Yield: 99 %

Procedure:
A slurry of palladium on carbon (10%, 90 mg) in ethanol (10 mL) was added to a solution of (RS)-10-methyl-7-phenylmethyl)-1,4-dioxa-7-azaspiro[4.5]decane hydrochloride (Description 61, 750 mg, 2.65 mmol) in ethanol (30 mL) and the mixture was shaken under hydrogen (50 psi) for 24 hours. The mixture was filtered through Celite™ and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (510 mg, 99%). m/z (ES+) 158 (M+1).
Reaction SMILES: I[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.[CH3:18][C:19]([CH3:24])([CH3:23])[C:20]([NH2:22])=[O:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cu]I>[CH3:18][C:19]([CH3:24])([CH3:23])[C:20]([NH:22][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1)=[O:21]
Reactant: CC(C)(C)C(N)=O
Reactant: Cc1cc(N2CCCC2)c2ccc(I)cc2n1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(N2CCCC2)c2ccc(NC(=O)C(C)(C)C)cc2n1
Temperature: 150 °C
Yield: 56.2 %

Procedure:
A suspension of 0.338 mg (1 mmol) of 7-iodo-2-methyl-4-pyrrolidin-1-yl-quinoline, 0.81 g (8 mmol) of trimethylacetamide, 0.414 g (3 mmol) of potassium carbonate (water free) and 20 mg (0.1 mmol) of copper (I) iodide in DMF (10 ml) was heated at 150° C. (oil bath temperature) under an argon atmosphere for 20 h. The reaction mixture was partitioned between EtOAc and water, the layers were separated, the organic layer washed twice with water dried over sodium sulphate and concentrated in vacuo. The residue was applied to silica gel column with CH2Cl2/MeOH/NH4OH (20:1:0.2) as eluent. Combination of the purified fractions and concentration in vacuo gave 175 mg (50.4%) of the desired 2,2-dimethyl-N-(2-methyl-4-pyrrolidin-1-yl-quinolin-7-yl)-propionamide as light brown solid. ISP mass spectrum, m/e: 312.3 (M+1 calculated for C19H25N3O: 312).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[F:21])[C:11](=[O:22])[C:10]([C:23]#[N:24])=[C:9]([C:25]([F:29])([F:28])[CH2:26][CH3:27])[CH:8]=2)[O:5][CH:6]=1.[CH2:30]([S:32][C:33]1[CH:34]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:36]=[C:37]([CH:39]([CH3:41])[CH3:40])[CH:38]=1)[CH3:31].C([O-])([O-])=O.[K+].[K+]>COCCOC.CCOCC.O.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]>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[CH2:13][N:12]1[C:7]([C:4]2[O:5][CH:6]=[C:2]([C:35]3[CH:36]=[C:37]([CH:39]([CH3:41])[CH3:40])[CH:38]=[C:33]([S:32][CH2:30][CH3:31])[CH:34]=3)[CH:3]=2)=[CH:8][C:9]([C:25]([F:29])([F:28])[CH2:26][CH3:27])=[C:10]([C:23]#[N:24])[C:11]1=[O:22]
Reactant: CCSc1cc(B2OC(C)(C)C(C)(C)O2)cc(C(C)C)c1
Reactant: CCC(F)(F)c1cc(-c2cc(Br)co2)n(Cc2ccc(F)cc2F)c(=O)c1C#N
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: ClCCl
Solvent: COCCOC
Product: CCSc1cc(-c2coc(-c3cc(C(F)(F)CC)c(C#N)c(=O)n3Cc3ccc(F)cc3F)c2)cc(C(C)C)c1
Temperature: 80 °C
Yield: 44 %

Procedure:
To a solution of 6-(4-bromo-furan-2-yl)-1-(2,4-difluoro-benzyl)-4-(1,1-difluoro-propyl)-2-oxo-1,2-dihydro-pyridine-3-carbonitrile (75 mg, 160 μmol) and 2-(3-ethylsulfanyl-5-isopropyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (73 mg, 240 μmol) in 1,2-dimethoxyethane (2.0 mL) was added K2CO3 (68 mg, 490 μmol) and H2O (200 μL). Dichloro[1,1′-bis(diphenylphosphino)ferrocene)palladium (II) dichloromethane adduct (11 mg, 15 μmol, ˜9 mol %) was added and the resulting dark mixture was sparged with nitrogen for ˜5 minutes. The reaction vial was sealed with a septum that had been pierced with a needle to allow for pressure release, and immersed in an oil bath heated to 80° C. After 5½ hours stirring at 80° C., heating was discontinued and the reaction was allowed to stir at ambient temperature for 16 hrs. The reaction mixture was then diluted with ether and H2O, the layers were separated, and the aqueous was extracted with ether (3×20 mL). The combined ether layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford a dark oil. The crude product was purified by silica gel column chromatography by adsorbing the material onto silica gel from a CH2Cl2 solution, loading the resulting solid onto the column and eluting with a gradient from 0% to 20% ethyl acetate/hexane to afford 1-(2,4-difluoro-benzyl)-4-(1,1-difluoro-propyl)-6-[4-(3-ethylsulfanyl-5-isopropyl-phenyl)-furan-2-yl]-2-oxo-1,2-dihydro-pyridine-3-carbonitrile (40 mg, 44% yield) as a brown foam. 1H-NMR (400 MHz, CDCl3): δ 7.85 (1H, d, J=0.8 Hz), 7.18-7.15 (2H, m), 7.12-7.03 (2H, m), 7.00 (1H, d, J=0.8 Hz), 6.87-6.79 (2H, m), 6.76 (1H, s), 5.56 (2H, s), 2.98 (2H, q, J=7.3 Hz), 2.90 (1H, heptet, J=7.1 Hz), 2.34 (2H, t of q, JH-H=7.6 Hz, JH-F=16.9 Hz), 1.34 (3H, t, J=7.3 Hz), 1.27 (6H, d, J=7.1 Hz), 1.13 (3H, t, J=7.3 Hz).
Reaction SMILES: C([O:4][C:5]1[C:15]2[CH2:14][CH2:13][CH2:12][C:11]([C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)=[CH:10][C:9]=2[CH:8]=[CH:7][C:6]=1[O:28][CH3:29])(C)C.[Cl-].[Al+3].[Cl-].[Cl-].O>ClCCl>[CH3:29][O:28][C:6]1[C:5]([OH:4])=[C:15]2[CH2:14][CH2:13][CH2:12][C:11]([C:16]3[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=3)=[CH:10][C:9]2=[CH:8][CH:7]=1
Reactant: COc1cc(C2=Cc3ccc(OC)c(OC(C)C)c3CCC2)cc(OC)c1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COc1ccc2c(c1O)CCCC(c1cc(OC)c(OC)c(OC)c1)=C2
Reaction time: 0.17 h
Yield: 41 %

Procedure:
41 (220 mg, 0.55 mmol) was dissolved in 15 mL of anhydrous dichloromethane under nitrogen at room temperature. Aluminium chloride (147 mg, 1.1 mmol) was added and the reaction mixture was stirred for 10 minutes. 10 mL of water was added and the product was extracted in dichloromethane (2×20 mL) and the combined organic phases were dried over anhydrous sodium sulfate, evaporated under reduced pressure purified by column chromatography. The product 3, 81 mg (41% yield) was obtained in 10% ethylacetate in hexanes. Rf: 0.54 (60:40 Hex:EA).
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]2[N:13]=[CH:14][CH:15]=[CH:16][C:4]=2[C:3]1=[O:17].[H-].[Na+].Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>CN(C)C=O>[C:25]([O:24][C:22]([CH2:21][N:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:2]([CH3:1])[C:3](=[O:17])[C:4]2[CH:16]=[CH:15][CH:14]=[N:13][C:5]1=2)=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CN1C(=O)c2cccnc2Nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)c2cccnc2N(CC(=O)OC(C)(C)C)c2ccccc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 43.8 %

Procedure:
To 0.8 g (3.5 mmoles) of 5,6-dihydro-6-methyl-11H-pyrido[2,3-b][1,5]benzodiazepin-5-one in 75 ml of dimethylformamide was added 0.2 g (4.0 mmol) of 50% sodium hydride in oil, and the reaction mixture was stirred at 60° C. for 2 h. It was then cooled to room temperature and 0.78 g (4.0 mmoles) of t-butyl bromoacetate was added dropwise, and the reaction mixture was allowed to stir overnight. Excess sodium hydride was carefully quenched with water and the solvent was evaporated. The residue was dissolved in methylene chloride, washed with water and dried over anhydrous sodium sulfate. Evaporation of the solvent gave 2.0 g of crude product. Purification by column chromatography (silica gel) using 10% ethyl acetate/methylene chloride afforded 0.52 g of pure 5,6-Dihydro-11-(t-butoxycarbonyl)methyl-6-methyl-11H-pyrido[2,3-b][1,5]benzodiazepin-5-one, m.p. 64°-65° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:24][C@@H:25]1[C:31](=[O:32])[N:30]([CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:29]2[CH:41]=[CH:42][CH:43]=[CH:44][C:28]=2[O:27][CH2:26]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1C(=O)C2=CC=CC=C2[C:14]1=[O:23])=[O:5])[CH3:2].[OH2:45].NN>C(O)C>[C:37]([O:45][C:14]([NH:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]([NH:24][C@@H:25]1[C:31](=[O:32])[N:30]([CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:38])[CH3:39])=[O:35])[C:29]2[CH:41]=[CH:42][CH:43]=[CH:44][C:28]=2[O:27][CH2:26]1)[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:23])([CH3:40])([CH3:39])[CH3:38]
Reactant: CCOC(=O)[C@H](CCCCCCN1C(=O)c2ccccc2C1=O)N[C@H]1COc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Reactant: O
Agent: NN
Solvent: CCO
Product: CCOC(=O)[C@H](CCCCCCNC(=O)OC(C)(C)C)N[C@H]1COc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Reaction time: 8 h
Yield: 153.3 %

Procedure:
In 10 ml of ethanol is dissolved 0.7 g of tert-butyl 3(S)-[1(S)-ethoxycarbonyl-7-phthalimidoheptyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate obtained in Example 64, and hydrazine hydrate (0.29 g) is added to the solution. After standing overnight, the solution is concentrated under reduced pressure, diluted with 50 ml of water and extracted five times with 30 ml each of ethyl acetate. To the ethyl acetate layer are added 50 ml of water and 0.7 g of sodium bicarbonate and 0.38 g of di-tert-butyl dicarbonate is added dropwise to the resulting mixture with stirring. After the mixture is stirring at room temperature for 0.5 hour, the ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give 0.51 g of tert-butyl 3(S)-[7-tert-butoxycarbonylamino-1(S)-ethoxycarbonylheptyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate as a colorless oil.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[NH:5])#[N:2].Cl.C(CC(=N)OCC)#N.Br[CH:17]1[C:26](=O)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[O:19][CH2:18]1>C(O)C>[NH2:5][C:4]1[NH:6][C:26]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:19][CH2:18][C:17]=2[C:3]=1[C:1]#[N:2]
Reactant: O=C1c2ccccc2OCC1Br
Reactant: N#CCC(=N)N
Agent: CCOC(=N)CC#N
Agent: Cl
Solvent: CCO
Product: N#Cc1c(N)[nH]c2c1COc1ccccc1-2

Procedure:
To an ethanolic solution of 2-cyanoacetamidine prepared from ethyl 2-cyanoacetimidate hydrochloride (4.0 g) as in Reference Example 2 was added a solution of 3-bromo-4-chromanone (3.0 g) in ethanol dropwise under ice-cooling with stirring. The mixture was stirred at room temperature overnight and, then, concentrated under reduced pressure. The resulting crude product was dissolved in ethyl acetate. The ethyl acetate layer was washed with water, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Wakogel C-200, 200 g; eluent: 2% methanol/chloroform) and recrystallized from acetone/isopropyl ether to provide the title compound as light-brown crystals (0.31 g). m.p. 216-217° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[N:3]=1.[B-](F)(F)(F)[F:14].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CC#N>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[C:8]=2[F:14])[N:3]=1
Reactant: Oc1ccc2nc(Cl)ccc2c1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: Oc1ccc2nc(Cl)ccc2c1F
Temperature: 60 °C
Yield: 21 %

Procedure:
To a solution of 2-chloroquinolin-6-ol (Intermediate 2, 1.8 g, 85% pure, 8.5 mmol) in CH3CN (50 mL) was added Selectfluor (4.20 g, 12.0 mmol). The reaction mixture was heated at 60° C. overnight and concentrated. The residue was partitioned between water (50 mL) and EtOAc (100 mL). The aqueous phase was separated and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography to give 2-chloro-5-fluoroquinolin-6-ol using ethyl acetate and hexanes as solvents (0.4 g, 21% yield).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])#[N:2].Br[CH2:12][CH2:13][CH2:14]Br.C(=O)([O-])[O-].[K+].[K+].[Na+].[I-]>C(C(C)=O)C>[C:7]([O:6][C:4]([C:3]1([C:1]#[N:2])[CH2:14][CH2:13][CH2:12]1)=[O:5])([CH3:10])([CH3:9])[CH3:8]
Reactant: BrCCCBr
Reactant: CC(C)(C)OC(=O)CC#N
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)C1(C#N)CCC1
Temperature: 80 °C

Procedure:
A solution of tert-butyl 2-cyanoacetate (4.0 g, 28.3 mmol), 1,3-dibromopropane (6.29 g, 31.2 mmol) in methyl ethyl ketone (100 ml) was treated with potassium carbonate (11.75 g, 85 mmol). The reaction mixture was heated to 80° C. for 17 h and then NaI (catalyst) (0.21 g, 1.42 mmol) was added. The mixture was heated at 80° C. for 6 days and then allowed to cool to RT. The mixture was filtered through Celite® (filter material) and the filtrate was concentrated in vacuo. Purification by chromatography on silica eluting with 10% EtOAc in iso-hexane afforded the title product as a colourless oil; 1H NMR (400 MHz, CDCl3) δ 2.64 (4H, m), 2.22 (2H, m), 1.53 (9H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.F[B-](F)(F)F.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C[Si]([N-:36][Si](C)(C)C)(C)C.[Li+]>C1(C)C=CC=CC=1.C(OCC)C.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[NH2:36][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COc1ccc2ncc(Br)cc2c1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COc1ccc2ncc(N)cc2c1
Reaction time: 48 h

Procedure:
To a stirred mixture of 3-bromo-6-methoxyquinoline [synthesis given in Tetrahedron (1986), 42, 1475-1485] (2.38 g), tris(dibenzylideneacetone) dipalladium (0) (0.114 g) and tri t-butylphosphine tetrafluoroborate (0.116 g) in toluene (15 ml) under an atmosphere of nitrogen at ambient temperature was added a solution of lithium bistrimethylsilylamide (11.0 ml, 1.0M solution in hexanes). The mixture was stirred for 2 days and the brown suspension diluted with diethyl ether and extracted with 2M aqueous hydrochloric acid (twice) and the acidic fractions combined, washed with diethyl ether and made basic with 2M aqueous sodium hydroxide to give the required product as a brown solid that was used in the next Step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[O:21])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:35][O:36][CH2:37][CH:38]([NH2:40])[CH3:39]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:40][CH:38]([CH3:39])[CH2:37][O:36][CH3:35])=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][C:20]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[O:21])=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: COCC(C)N
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCOCC2)c1=O
Product: COCC(C)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCOCC2)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-[2-(4-morpholinyl)-2-oxoethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and (±)-1-(methyloxy)-2-propanamine employing methods similar to those those described in Example 9 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as an off-white rigid foam: 1H NMR (CDCl3) δ 10.01 (1H, d, J=8 Hz), 8.57 (1H, s), 7.15 (2H, dd, J=8.6, 5.5 Hz), 7.03 (3H, m), 4.98 (1H, d, J=17 Hz), 4.91 (1H, d, J=17 Hz), 4.34 (1H, m), 4.12 (2H, s), 3.73 (2H, m), 3.68 (2H, m), 3.56 (4H, m), 3.45 (2H, d, J=5 Hz), 3.39 (3H, s), 1.29 (3H, d, J=7 Hz); HRMS calcd for C26H29FN4O6+H+: 513.2149. Found: 513.2145.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:23][C:24]1[N:25]=[CH:26][NH:27][CH:28]=1)[C:3]([NH:5][C@@H:6]([CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C@@H:7]([OH:15])[CH2:8][C@@H:9]([CH:12]([CH3:14])[CH3:13])[CH:10]=[CH2:11])=[O:4].CCN(C(C)C)C(C)C.[CH2:38]([N:45]([CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[C:46]([NH:48][C@H:49]([C:57](O)=[O:58])[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:47])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(#N)C>[CH2:60]([N:45]([CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:46]([NH:48][C@H:49]([C:57](=[O:58])[NH:1][C@H:2]([C:3](=[O:4])[NH:5][C@@H:6]([CH2:16][CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1)[C@@H:7]([OH:15])[CH2:8][C@@H:9]([CH:12]([CH3:13])[CH3:14])[CH:10]=[CH2:11])[CH2:23][C:24]1[N:25]=[CH:26][NH:27][CH:28]=1)[CH2:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)=[O:47])[C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1
Reactant: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@@H](N)Cc1c[nH]cn1)C(C)C
Reactant: O=C(O)[C@H](Cc1ccccc1)NC(=O)N(Cc1ccccc1)Cc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)N(Cc1ccccc1)Cc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.7 %

Procedure:
100 mg (0.256 mmol) of (S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-imidazole-4-propionamide and 0.052 ml of Hunig base in 2 ml of acetonitrile were treated at room temperature with 100 mg of N-(dibenzylcarbamoyl)-3-phenyl-L-alanine and 113 mg of BOP and subsequently stirred at room temperature for 12 hours. Thereafter, the reaction solution was poured onto 1N hydrochloric acid/ice, extracted with ethyl acetate, the extracts were dried over sodium sulfate and the solvent was removed under reduced pressure. Chromatography of the residue on silica gel using a 10:1 mixture of methylene chloride and methanol as the eluting agent yielded 130 mg of 1,1-dibenzyl-3-[(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]urea in the form of an amorphous solid. MS: 761 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([OH:32])([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[CH:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[CH:10]=2)[N:5]=[C:4]([C:33]([F:36])([F:35])[F:34])[C:3]=1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[OH:32])[CH:10]=2)[N:5]=[C:4]([C:33]([F:35])([F:34])[F:36])[C:3]=1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(O)(c2cccnc2)c2ccc3nc(C(F)(F)F)c(-c4ccccc4)c(Cl)c3c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC(c1cccnc1)(c1ccc2nc(C(F)(F)F)c(-c3ccccc3)c(Cl)c2c1)C1CCNCC1
Reaction time: 3 h

Procedure:
A solution of tert-butyl 4-((4-chloro-3-phenyl-2-(trifluoromethyl)quinolin-6-yl)(hydroxy)(pyridin-3-yl)methyl)piperidine-1-carboxylate (313 mg, 0.520 mmol, Example 69) in DCM (6 mL) was treated with 1.8 mL of TFA, stirred for 3 hours, and concentrated. The residue was partitioned between saturated NaHCO3 aqueous solution and DCM. The organic layer was dried (Na2SO4), filtered and concentrated to dryness to provide the title compound as a light brown solid. 1H NMR (400 MHz, CDCl3) δ 8.86 (s, 1H), 8.55 (s, 1H), 8.44 (d, J=4.55 Hz, 1H), 8.21 (d, J=9.09 Hz, 1H), 7.89-7.96 (m, 2H), 7.46-7.53 (m, 4H), 7.23-7.32 (m, 2H), 3.23-3.36 (m, 2H), 2.77-2.91 (m, 3H), 1.66-1.86 (m, 4H).