Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH:3]([O:5][CH2:6][CH3:7])=[O:4].[C:8]1(/[C:14](/[CH2:21][C:22](OCC)=[O:23])=[CH:15]\[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CCOCC>[OH:23][CH:22]=[C:21](/[C:14](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[CH:15]/[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)/C=C(/CC(=O)OCC)c1ccccc1
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)/C=C(/C(=CO)C(=O)OCC)c1ccccc1
Reaction time: 12 h
Yield: 97 %

Procedure:
A stirred mixture of NaH (158.4 mg, 6.6 mmol) and ethyl formate (1.07 ml, 13.2 mmol) in Et2O (5 ml) were refluxed under argon for 15 min. Diethyl (2Z)-3-phenylpent-2-ene-1,5-dioate in Et2O (5 ml) was added dropwise to the above solution over 5 min at rt. The reaction was heated to retlux for 12 hours. The heterogeneous yellow mixture was diluted with Et2O (100 ml), washed with sat. NH4Cl (40 ml), half sat. NH4Cl (40 ml), brine (20 ml), dried with Na2SO4, filtered, and concentrated under reduced pressure. The product diethyl (3E)-2-(hydroxymethylene)-3-phenylpent-3-ene-1,5-dioate was obtained in 97% yield and could be used without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[CH2:9]([NH2:11])[CH3:10]>C1COCC1>[CH2:9]([NH:11][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[CH3:10]
Reactant: CCN
Reactant: O=Cc1ccccn1
Solvent: C1CCOC1
Product: CCNCc1ccccn1

Procedure:
prepared by reaction of pyridine-2-carboxaldehyde with 2M ethylamine in THF.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[C:25]([Cl:27])[C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:8]=1)=[O:5].O1CCOCC1.Br[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=1.C([O-])([O-])=O.[K+].[K+]>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.O>[Cl:1][C:2]1[CH:26]=[C:25]([Cl:27])[C:24]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=2)=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=[C:9]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:8]=1)=[O:5]
Reactant: CCOC(=O)c1cc(NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)c(Cl)cc2Cl)n(-c2ccccc2)n1
Reactant: Brc1ccccn1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cc(NC(=O)c2cc(-c3ccccn3)c(Cl)cc2Cl)n(-c2ccccc2)n1
Yield: 21 %

Procedure:
To the solution of ethyl 5-(2,4-dichloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylate in dioxane (Preparation 4, 675 mg, 1.27 mmol) was added water (2.2 mL), 2-bromopyridine (302 mg, 1.91 mmol) and K2CO3 (352 mg, 2.546 mmol). The reaction was degassed for 10 minutes before the addition of tetrakis(triphenylphosphine)palladium(0) (147 mg, 0.127 mmol) and heating at reflux for 2 hours. The reaction was cooled and concentrated in vacuo. The residue was purified using silica gel chromatography eluting with 20-50% EtOAc in heptanes to afford the title compound (128 mg, 21%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:15]([OH:17])=[O:16])[C:3]=1[Cl:18].S(Cl)(Cl)=O.O.[OH-].[Na+].[CH2:26](O)[CH3:27]>>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:15]([O:17][CH2:26][CH3:27])=[O:16])[C:3]=1[Cl:18]
Reactant: Nc1nc(-c2ccc(Cl)cc2)nc(C(=O)O)c1Cl
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1nc(-c2ccc(Cl)cc2)nc(N)c1Cl

Procedure:
To a solution of 6-amino-5-chloro-2-(4-chlorophenyl)-4-pyrimidinecarboxylic acid (i.e. the product of Example 4, Step C) (20.0 g, 70.4 mmol) in ethanol (70 mL) was added thionyl chloride (5.14 mL, 70.4 mmol) while maintaining the temperature below 15° C. using an ice bath. The reaction mixture was then heated at reflux overnight. Water was added. Then with external cooling aqueous sodium hydroxide (50%) was added to adjust the pH to 7. The resulting solid was isolated by filtration and dried to afford the title product, a compound of the present invention, as a light beige solid (20.1 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1)=O)[CH3:2].[CH:18]1([O:23][NH2:24])[CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)C>[CH2:1]([O:3][C:4](=[O:17])/[C:5](=[N:24]/[O:23][CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)/[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1)[CH3:2]
Reactant: NOC1CCCC1
Reactant: CCOC(=O)C(=O)c1ccc(S(C)(=O)=O)cc1
Solvent: CCO
Product: CCOC(=O)/C(=N/OC1CCCC1)c1ccc(S(C)(=O)=O)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 20.8 %

Procedure:
(4-Methylsulfonyl-phenyl)-oxo-acetic acid ethyl ester (218 mg, 0.85 mmol) was stirred in ethanol (1.7 mL) and warmed in a 70° C. oil bath. O-Cyclopentyl-hydroxylamine (prepared as in Example 1, 146 mg, 1.06 mmol) was added. After 2 h, the reaction mixture was allowed to cool and concentrated in vacuo. Purification by flash column chromatography (Merck silica gel 60, 40-63 □m; 30% ethyl acetate/hexanes to 75% ethyl acetate/hexanes) afforded (E)-cyclopentyloxyimino-(4-methanesulfonyl-phenyl)-acetic acid ethyl ester (60 mg, 21%) as a clear, colorless film containing an unidentified impurity: LC-MS (ESI) m/e calcd for C16H21NO5S [M+] 339.11, found 340 [M+H+].
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([NH:17][C:18](=[O:27])[C@H:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:20])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]([CH3:16])[CH2:13][CH2:14][CH3:15])=[CH:6][CH:5]=1.[C:28]([NH:35][C@H:36]([C:41](O)=[O:42])[C@H:37]([CH2:39][CH3:40])[CH3:38])([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C([O-])(O)=O.[Na+]>ClCCl>[CH3:38][C@@H:37]([CH2:39][CH3:40])[C@H:36]([NH:35][C:28](=[O:29])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[C:41]([NH:1][CH2:2][C@@H:3]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][CH:12]([CH3:16])[CH2:13][CH2:14][CH3:15])=[CH:8][CH:9]=1)[NH:17][C:18](=[O:27])[C@H:19]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH3:20])=[O:42]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCCC(C)COc1ccc([C@H](CN)NC(=O)[C@@H](C)c2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(C)COc1ccc([C@H](CNC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)CC)NC(=O)[C@@H](C)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 60.1 %

Procedure:
A stirred solution of (2S)-N-((1R)-2-amino-1-(4-(2-methylpentyloxy)phenyl)ethyl)-2-phenylpropanamide (200 mg, 0.543 mmol), prepared according to the procedure described in example 5, in dichloromethane (4 mL) was cooled to 0° C. To this solution, Boc-L-isoleucine (188 mg, 0.814 mmol), N,N-diisopropylethylamine (0.569 mL, 3.26 mmol) and HATU (310 mg, 0.814 mmol) were added. The ice-water bath was removed and reaction mixture was stirred at room temperature for 3 h. The mixture was transferred to a separatory funnel containing saturated aqueous NaHCO3 solution (60 mL). The aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (30→40% ethyl acetate in hexanes) to afford t-butyl (2S,3S)-3-methyl-1-((2R)-2-(4-(2-methylpentyloxy)phenyl)-2-((S)-2-phenylpropanamido)ethylamino)-1-oxopentan-2-ylcarbamate (190 mg, 60% yield) as a colorless solid: LRMS (ESI) m/e 582.4 [(M+H)+, calcd for C34H52N3O5 582.4].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O.[H][H].C(O)C>C1(C)C=CC=CC=1.[Pd]>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: O=[N+]([O-])c1cnc2ccccc2c1NCCCCO
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Nc1cnc2ccccc2c1NCCCCO
Reaction time: 1 h
Yield: 105.6 %

Procedure:
Catalyst (5% Pd/C) was added to a suspension of 4-[(3-nitroquinolin-4-yl)amino]butan-1-ol (18.2 g, 69.6 mmol) in toluene (450 mL) in a Parr vessel. The vessel was placed on a shaker and pressurized with hydrogen. The next day ethanol (60 mL) and additional catalyst were added and the vessel was again pressurized with hydrogen. After 1 hour analysis by TLC indicated that all of the starting material had been consumed. The reaction mixture was filtered through a layer of CELITE filter aid and then concentrated under reduced pressure to provide 17 g of 4-[(3-aminoquinolin-4-yl)amino]butan-1-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.O.[NH3:29]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:29])=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Cl
Reactant: N
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(N)=O
Reaction time: 18 h
Yield: 101.2 %

Procedure:
In a mixture of 3.0 g of concentrated ammonia water and 15 ml of tetrahydrofuran, a solution of 3.0 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methylbenzoyl chloride in 20 ml of tetrahydrofuran was added dropwise, after the completion of the addition, continued to stir further for 18 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in 50 ml of ethyl acetate, washed with 50 ml of water, dehydrated and dried with saturated sodium chloride aqueous solution and anhydrous sodium sulfate in that order, and the solvent was distilled off under reduced pressure to obtain 2.9 g of the aimed product as orange crystal.
Reaction SMILES: [CH2:1]([S:3]([CH2:6][CH2:7][CH2:8][C:9]12[CH2:16][CH2:15][C:12]([C:17]([O:19]C)=[O:18])([CH2:13][CH2:14]1)[CH2:11][CH2:10]2)(=[O:5])=[O:4])[CH3:2].[OH-].[K+].Cl>CO.O>[CH2:1]([S:3]([CH2:6][CH2:7][CH2:8][C:9]12[CH2:10][CH2:11][C:12]([C:17]([OH:19])=[O:18])([CH2:13][CH2:14]1)[CH2:15][CH2:16]2)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)CCCC12CCC(C(=O)OC)(CC1)CC2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCS(=O)(=O)CCCC12CCC(C(=O)O)(CC1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sulfone 11-7 (3.1 g, 10 mmol) was dissolved in 9:1 MeOH/water (50 mL) and treated with potassium hydroxide (3 g). The solution was stirred at room temperature overnight, then the mixture was acidified with 1 N HCl and extracted four times with 50 mL of methylene chloride. The organic layer was dried over anhydrous sodium sulfate and evaporated to afford 4-[3-(ethylsulfonyl)propyl]bicyclo[2.2.2]octane-1-carboxylic acid (11-8) which was used without purification in the next step. 1H NMR (500 MHz, CDCl3): δ 3.03 (2H, q, J=7 Hz), 2.94 (2H, dd, J=7.5 Hz), 1.84 (8H, m), 1.45 (8H,m), 1.30 (2H, m) ppm.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[NH:11][CH:10]([C:12]([OH:14])=O)[CH2:9][S:8]2)[CH:2]=1.[N:15]1([CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:19]=[CH:18][N:17]=[CH:16]1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.C(CC(OC)=O)C>C(OCC)(=O)C.CN(C)C=O>[N:15]1([CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][N:26]([C:12]([CH:10]3[CH2:9][S:8][CH:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[NH:11]3)=[O:14])[CH2:25][CH2:24]2)[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: c1cn(CCCN2CCNCC2)cn1
Reactant: O=C(O)C1CSC(c2cccnc2)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCCC(=O)OC
Solvent: CN(C)C=O
Product: O=C(C1CSC(c2cccnc2)N1)N1CCN(CCCn2ccnc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.7 %

Procedure:
To a solution of 2-(3-pyridyl)thiazolidine-4-carboxylic acid 630 mg, 1-[3-(1-imidazolyl)propyl]piperazine 580 mg, 1-hydroxybenztriazole 410 mg and N,N-dimethylformamide 15 ml was added dicyclohexylcarbodiimide 620 mg under ice-cooling and then stirred overnight at room temperature. Ethyl acetate 100 ml was added to the solution, the resultant unsoluble matter filtered off and the solution washed with saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride in succession. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, ethyl acetate added to the residue, the unsoluble matter filtered off and the solution concentrated to dryness under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography (eluent: 20% methanol - ethyl acetate) to give an oily product. This was dissolved in ethyl acetate 30 ml, 2N hydrogen chloride - dioxane 4 ml added and the precipitated powder filtered off to give 620 mg of 1-[3-(1-imidazolyl)propyl]-4-[2-(3-pyridyl)thiazolidine-4-ylcarbonyl]piperazine.4 hydrochloride.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([CH2:11][C:12]([NH2:14])=[O:13])[CH2:4][CH2:3]1.[BH4-].[Na+].O>C(O)C>[OH:1][CH:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([CH2:11][C:12]([NH2:14])=[O:13])[CH2:4][CH2:3]1
Reactant: NC(=O)CC1CCC(=O)c2sccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(=O)CC1CCC(O)c2sccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
Twenty-seven g (0.129 M) of 4,5,6,7-Tetrahydro-7-oxobenzo[b]thien-4-ylacetamide is dissolved in absolute ethanol (270 ml) and treated with sodium borohydride (4.9 g, 0.129 M). The mixture is stirred at room temperature overnight, water (250 ml) is added and stirring continued for 2 hours. The bulk of the ethanol is evaporated and the precipitated solid is filtered off, washed twice with water (total 50 ml) and air dried to afford the title compound (13.73 g, 50.4% yield) as an off white solid, m.p. 175° C. to 179° C. dec.
Reaction SMILES: [CH2:1]([C:3]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:20][CH:19]=2)[C:6]2[CH:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8][CH2:9][CH2:10][C:5]=2[N:4]=1)[CH3:2].[C:37](OC(=O)C)(=[O:39])[CH3:38].C(=O)([O-])O.[Na+].C(Cl)(Cl)Cl>O>[CH2:1]([C:3]1[N:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])=[CH:22][CH:23]=2)[C:6]2[CH:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]([C:37](=[O:39])[CH3:38])[CH2:9][CH2:10][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCOC(=O)C1NCCc2nc(CC)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c21
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)C1c2c(nc(CC)n2Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)CCN1C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
A mixture of ethyl 2-ethyl-3-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (2.26 g), acetic anhydride (0.94 g), sodium hydrogen carbonate (2.33 g), chloroform (18 ml) and water (18 ml) is stirred overnight at room temperature. The organic layer is separated, washed with brine, dried, and evaporated. The residue is purified by silica gel column chromatography (solvent; chloroform/methanol) to give ethyl 2-ethyl-5-acetyl-3-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (2.10 g) as a white foam.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.[CH3:13][CH:14]([CH3:24])[CH2:15][CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)O.B(F)(F)F.CCOCC>O1CCOCC1>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[C:3]=1[CH:16]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:15][CH:14]([CH3:24])[CH3:13]
Reactant: CC(C)CC(O)c1ccccc1
Reactant: O=c1cc(O)c2ccccc2o1
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)CC(c1ccccc1)c1c(O)c2ccccc2oc1=O
Temperature: 25 °C
Yield: 20.1 %

Procedure:
To a time-dried flask containing a near-solution of 650 mg of 4-hydroxycoumarin and 800 mg of 3-methyl-1-phenylbutan-1-ol of Preparation 16 in 25 mL of dioxane under an argon atmosphere is added 2.5 mL of boron trifluoride etherate. The resulting yellow solution is left to stir at room temperature. After 3 days the volatiles are removed and the residue is partioned between diethyl ether and 1N sodium hydroxide. The basic aqueous phase is washed with diethyl ether and acidified to pH=1 with 6N hydrochloric acid. The resulting precipitant is repeatedly extracted with dichloromethane (methanol-chloroform Co-solvents). The combined dichloromethane extracts are washed once with dilute sodium bicarbonate to remove most of the unreacted 4-hydroxycoumarin, then brine, dried (magnesium sulfate), and finally concentrated under reduced pressure. The residue is adsorbed onto silica and flash column chromatographed with 30% to 40% ethyl acetate in hexane to yield 248 mg of the title product as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][C:15](=O)[CH3:16])[C:9](=[O:18])[CH2:8][CH2:7]2)([O-:3])=[O:2].[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CO.C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][CH:15]([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[CH3:16])[C:9](=[O:18])[CH2:8][CH2:7]2)([O-:3])=[O:2]
Reactant: C1CCNC1
Reactant: CC(=O)CN1C(=O)CCc2cc([N+](=O)[O-])ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: CC(CN1C(=O)CCc2cc([N+](=O)[O-])ccc21)N1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6-nitro-1-(2-oxopropyl)-3,4-dihydroquinolin-2(1H)-one (500 mg, 2.01 mmol) and pyrrolidine (333 μL, 4.03 mmol) in 10 mL 1,2-dichloroethane (DCE) was treated with acetic acid (228 μL, 4.03 mmol) followed by sodium triacetoxyborohydride (1.27 g, 6.03 mmol). The suspension was stirred at room temperature overnight then quenched with 10 mL 1N NaOH. The mixture was diluted with 15 mL H2O then extracted with 2×100 mL CH2Cl2. The combined organic fractions were rinsed with 50 mL H2O, dried over MgSO4, filtered and concentrated to give a yellow residue which was subjected to flash chromatography on silica gel using 5% 2M NH3 in MeOH/CH2Cl2. A yellow oil was obtained (595 mg, 97.5%). 1H-NMR (CDCl3) δ: 8.13 (dd, J=2.7, 9.0 Hz, 1H), 8.07 (d, J=2.7 Hz, 1H), 7.21 (d, J=9.0 Hz, 1H), 4.21 (dd, J=8.7, 14.1 Hz, 1H), 4.02 (dd, J=5.4, 14.4 Hz, 1H), 3.00 (t, J=7.2 Hz, 2H), 2.91-2.62 (m, 7H), 1.92-1.90 (m, 4H), 1.00 (d, J=6.3 Hz, 3H).
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][O:12][CH2:13]Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[N:24]=[CH:23][N:22]=[C:21]2[C:17]=1[NH:18][CH:19]=[N:20]2.C(N(CC)CC)C.Cl.C(N(CC)CC)C>CN(C)C=O>[Cl:15][C:16]1[N:24]=[CH:23][N:22]=[C:21]2[C:17]=1[N:18]=[CH:19][N:20]2[CH2:13][O:12][CH2:11][CH2:10][O:9][C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCCOCCl)c1ccccc1
Reactant: Clc1ncnc2nc[nH]c12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(OCCOCn1cnc2c(Cl)ncnc21)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Following substantially the procedure of Schaeffer, et al. supra but with minor modifications, 1-benzoyloxy-2-chloromethoxyethane (4.4 g) was added with stirring to a dry solution of 6-chloropurine (3.1 g) and triethylamine (6.5 ml) in dimethylformamide (50 ml). The reaction was exothermic, immediately precipitating triethylamine hydrochloride. The reaction mixture was stirred at room temperature for 24 hours and filtered. The filtrate was evaporated on a rotary evaporator at 70° C. The remaining thick amber oil was dissolved in the minimum amount of benzene and purified by column chromatography using a silica gel column. Benzene elution removed a trace of an unidentified material. Elution with ether first removed a small amount of ethylene glycol monobenzoate and then 6-chloro-9-(2-benzoyloxyethoxymethyl)purine. Recrystallization from ether gave a white material, m.p. 108.5°-111° C.
Reaction SMILES: C1C=CC2N(O)N=[N:7]C=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.CCN(C(C)C)C(C)C.[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][CH:43]([C:46]2[CH:51]=[CH:50][C:49]([NH:52][C:53]3[N:58]=[C:57]([CH2:59][CH2:60][C:61]4[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=4[C:67]4([C:70]([OH:72])=O)[CH2:69][CH2:68]4)[C:56]([C:73]([F:76])([F:75])[F:74])=[CH:55][N:54]=3)=[CH:48][CH:47]=2)[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34].C(=O)([O-])[O-].[NH4+].[NH4+]>C1COCC1.CN(C=O)C>[C:70]([C:67]1([C:62]2[CH:63]=[CH:64][CH:65]=[CH:66][C:61]=2[CH2:60][CH2:59][C:57]2[C:56]([C:73]([F:75])([F:74])[F:76])=[CH:55][N:54]=[C:53]([NH:52][C:49]3[CH:48]=[CH:47][C:46]([CH:43]4[CH2:44][CH2:45][N:40]([C:38]([O:37][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:39])[CH2:41][CH2:42]4)=[CH:51][CH:50]=3)[N:58]=2)[CH2:68][CH2:69]1)(=[O:72])[NH2:7]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4C4(C(=O)O)CC4)n3)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4C4(C(N)=O)CC4)n3)cc2)CC1
Temperature: 40 °C
Reaction time: 72 h
Yield: 44.2 %

Procedure:
HOBt (99 mg, 0.73 mmol), EDCl.HCl (140 mg, 0.73 mmol) and DIPEA (0.42 mL, 2.43 mmol) were added to a stirred solution of 1-(2-(2-(2-((4-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxylic acid (A5) (297 mg, 0.486 mmol) in dry THF (6 mL) and dry DMF (1 mL) under an atmosphere of nitrogen. After 10 minutes ammonium carbonate (234 mg, 2.43 mmol) was added in one portion and the resulting solution was stirred at 40° C. for 72 hours. The volatiles were removed in vacuo and EtOAc (50 mL) and saturated NaHCO3 (50 mL) were added to the residue. After separating the organic layer, the aqueous phase was extracted with EtOAc (2×50 mL). The organic extracts were combined, washed with brine and dried over MgSO4. The volatiles were removed under reduced pressure and the residue was purified by silica gel column chromatography (Biotage Isolera, SiO2 cartridge, 0-60% EtOAc in petroleum benzine 40-60° C.) to give the title compound A6 as a yellow solid (131 mg, 44%); 1H NMR (400 MHz, d6-DMSO) δ 10.15 (s, 1H), 8.67 (s, 1H), 7.67 (d, J=8.5 Hz, 2H), 7.32 (dd, J=13.9, 5.0 Hz, 3H), 7.26-7.14 (m, 3H), 6.98 (s, 1H), 5.99 (s, 1H), 4.05 (dd, J=15.7, 8.8 Hz, 2H), 3.13 (dd, J=25.3, 9.9 Hz, 4H), 2.93-2.70 (m, 2H), 2.63 (t, J=12.2 Hz, 1H), 1.74 (d, J=12.5 Hz, 2H), 1.41 (s, 13H), 0.97 (s, 2H). LCMS-A: rt 6.720 min; m/z 610 [M+H]+.