Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[C:9]([CH3:11])[O:10][C:6]=2[CH:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=1.Br[C:18]1[CH:23]=[N+:22]([O-:24])[C:21]([C:25]([N:27]([CH3:29])[CH3:28])=[O:26])=[CH:20][CH:19]=1>>[CH3:28][N:27]([CH3:29])[C:25]([C:21]1[N+:22]([O-:24])=[CH:23][C:18]([O:1][C:2]2[C:7]3[CH:8]=[C:9]([CH3:11])[O:10][C:6]=3[CH:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=2)=[CH:19][CH:20]=1)=[O:26]
Reactant: CN(C)C(=O)c1ccc(Br)c[n+]1[O-]
Reactant: CCOC(=O)c1cc(O)c2cc(C)oc2c1
Product: CCOC(=O)c1cc(Oc2ccc(C(=O)N(C)C)[n+]([O-])c2)c2cc(C)oc2c1

Procedure:
The title compound was synthesized in a similar fashion as described for Intermediate 252d, by reacting ethyl 4-hydroxy-2-methylbenzofuran-6-carboxylate and 5-bromo-N,N-dimethylpyridine-2-carboxamide 1-oxide. LC-MS (ESI, pos): 386.00.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:31])[C:13]([CH3:30])([CH3:29])[CH:14]([CH2:27][CH3:28])[NH:15][C:16](=[O:26])[C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][C:18]=2[F:25])[CH2:8][CH2:7]1)[CH3:2].[OH:33][CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:31])[C:13]([CH3:30])([CH3:29])[CH:14]([CH2:27][CH3:28])[NH:15][C:16](=[O:26])[C:17]2[CH:22]=[CH:21][C:20]([C:23]([N:37]3[CH2:38][CH2:39][CH:34]([OH:33])[CH2:35][CH2:36]3)=[NH:24])=[CH:19][C:18]=2[F:25])[CH2:10][CH2:11]1)[CH3:2]
Reactant: CCOC(=O)CC1CCN(C(=O)C(C)(C)C(CC)NC(=O)c2ccc(C#N)cc2F)CC1
Reactant: OC1CCNCC1
Product: CCOC(=O)CC1CCN(C(=O)C(C)(C)C(CC)NC(=O)c2ccc(C(=N)N3CCC(O)CC3)cc2F)CC1
Yield: 26 %

Procedure:
The same procedure as in Example 45 was performed with ethyl-N-(N-(4-cyano-2-fluorobenzoyl)-β-ethyl-α,α-dimethyl-β-alanyl)-4-piperidineacetate (1.4 g, 3.1 mmol) by using 4-hydroxypiperidine (3.1 g) as an amine to yield the titled compound (440 mg, 26%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:31](O)=[O:32])[CH2:10][S:11][C:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>CCOCC>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH:31]=[O:32])[CH2:10][S:11][C:12]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@H](C=O)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -45 °C
Yield: 93 %

Procedure:
The Weinreb amide of N-t-butoxycarbonyl-S-tritylcysteine, prepared above, (406 mg, 0.8 mmol) was dissolved in anhydrous ether (5 ml) and cooled to -45° C. Lithium aluminium hydride (1 ml of a 1N solution in ether, 1 mmol) was then added keeping the temperature below -35° C., after addition the solution was then allowed to warm to 5° C. The solution was then cooled to -45° C. and sodium sulfate decahydrate (1.25 g) added and the cooling bath removed. After 1. hour the solution was filtered through celite and the solvent removed under reduced pressure to yield the aldehyde (332 mg, 93%) as a white foam.
Reaction SMILES: [N:1]1[N:2]([C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=2)[N:3]=[N:4][CH:5]=1>C(O)C.[Pd]>[N:1]1[N:2]([C:6]2[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=2)[N:3]=[N:4][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(-n2ncnn2)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(-n2ncnn2)cc1
Yield: 114 %

Procedure:
4-(Tetrazol-2-yl)nitrobenzene (0.83 g, 4.3 mmol) and Pd/C (300 mg) in ethanol (50 ml) were hydrogenated at rtp for 3 days. The suspension was filtered through celite, evaporated under reduced pressure to afford a white solid (790 mg, 100%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([NH:11][C:12]1[CH:41]=[CH:40][C:15]([C:16]([NH:18][CH2:19][C:20]2[C:21]([NH:33][CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[C:22]3[CH:30]=[N:29][N:28]([CH2:31][CH3:32])[C:23]3=[N:24][C:25]=2[CH2:26][CH3:27])=[O:17])=[CH:14][CH:13]=1)=[O:10].[CH3:42][NH:43][CH2:44][CH2:45][OH:46].C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:31]([N:28]1[C:23]2=[N:24][C:25]([CH2:26][CH3:27])=[C:20]([CH2:19][NH:18][C:16](=[O:17])[C:15]3[CH:40]=[CH:41][C:12]([NH:11][C:9](=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:43]([CH2:44][CH2:45][OH:46])[CH3:42])=[CH:13][CH:14]=3)[C:21]([NH:33][CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[C:22]2[CH:30]=[N:29]1)[CH3:32]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(NC(=O)CCCCCCCBr)cc1
Reactant: CNCCO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(NC(=O)CCCCCCCN(C)CCO)cc1
Temperature: 85 °C

Procedure:
4-[(8-Bromooctanoyl)amino]-N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}benzamide (100 mg, 0.16 mmol, e.g. which can optionally be as prepared in Intermediate 11) was dissolved in N,N-dimethylformamide (4 ml). To one-quarter of this solution, i.e. containing 4-[(8-bromooctanoyl)amino]-N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}benzamide (25 mg, 0.04 mmol) in N,N-dimethylformamide (1 ml), was added 2-(methylamino)ethanol (0.0064 ml (6.4 microliters), 0.08 mmol, 2 equivalents, commercially available e.g. from Aldrich) followed by N,N-diisopropylethylamine (0.04 ml, about 6 equivalents). The reaction mixture was heated at 85° C. for 16 hours. The solvent was evaporated and the residue was purified by eluting through a 5 g silica SPE cartridge, with dichloromethane containing 20% methanol and 1% triethylamine as the eluent, to give the title compound (18.7 mg), in the form of a cream foam, initially thought to be in the form of the “free base”. LCMS showed MH+=622; TRET=2.20 min. However, later re-inspection of the 1H NMR spectrum suggests that the product was isolated as a salt e.g. a mono-salt (presumed to be a hydrobromide salt), e.g. from the signals of protons adjacent to the (2-hydroxyethyl)(methyl)amino group.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[C:12]([NH2:17])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18]([O:22][C:23]([NH:25][CH2:26][C:27](O)=[O:28])=[O:24])([CH3:21])([CH3:20])[CH3:19].Cl.C(N=C=NC(C)(C)CC)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[C:18]([O:22][C:23](=[O:24])[NH:25][CH2:26][C:27](=[O:28])[NH:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[N:9][N:8]2[CH2:7][CH2:6][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Nc1cccc2c1cnn2CCN1CCCC1
Agent: CCN=C=NC(C)(C)CC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)Nc1cccc2c1cnn2CCN1CCCC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1-(2-Pyrrolidin-1-yl-ethyl)-1H-indazol-4-ylamine (1.00 g, 4.34 mmol), tert-butoxycarbonylamino-acetic acid (0.836 g, 4.77 mmol), ethyldimethylpropylcarbodiimide hydrochloride (1.00 g, 5.24 mmol), N-hydroxybenzotriazole (0.707 g, 5.24 mmol) and N-methyl morpholine (1.10 g, 10.9 mmol) were dissolved in 30 mL of DMF, and stirred at room temperature for 6 hours. The mixture was concentrated under reduced pressure and the residue purified by flash chromatography to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.41 (s, 9H), 1.62 (m, 4H), 2.44 (m, 4H), 2.86 (t, 2H, J=6.78), 3.86 (d, 2H, J=6.11), 4.47 (t, 2H, J=6.78), 7.08–7.65 (m, 4H), 8.24 (s, 1H), 9.97 (s, 1H); MS (DCI/NH3) m/z 388 [M+H]+.
Reaction SMILES: [OH:1][C@@H:2]([CH3:15])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:4].[C:16]([NH:26][C@H:27]([C:31](O)=[O:32])[CH:28]([CH3:30])[CH3:29])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.ClCCl>[C:16]([NH:26][C@H:27]([C:31]([O:1][C@@H:2]([CH3:15])[C:3]([O:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)=[O:4])=[O:32])[CH:28]([CH3:30])[CH3:29])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: COc1ccc(COC(=O)[C@H](C)O)cc1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(COC(=O)[C@H](C)OC(=O)[C@@H](NC(=O)OCc2ccccc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-methoxybenzyl (S)-(+)-2-hydroxypropionate (7.6 g, 36 mmole), N-CBZ-L-valine (10.05 g, 40 mmole) and DMAP (0.98 g, 8 mmole) in 150 ml dichloromethane was added a solution of DCC (8.3 g, 40 mmole) and the mixture was stirred overnight at room temperature. The mixture was cooled to about 5° C. and the urethane was filtered. The filtrate was evaporated and the product was isolated by silica gel column chromatography. Yield: 14.4 g=90%
Reaction SMILES: [C:1]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=1)(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].Cl[C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][N:17]=1>>[F:22][C:21]1[C:16]([C:5]#[C:4][CH2:3][CH2:2][C:1]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[O:6])=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: Fc1cccnc1Cl
Reactant: C#CCCC(=O)Oc1cccc(Cl)c1
Product: O=C(CCC#Cc1ncccc1F)Oc1cccc(Cl)c1
Yield: 13.1 %

Procedure:
According to the protocol described in Example 237(B), the reaction between 3-chlorophenyl pent-4-ynoate (580 mg, 2.80 mmol) and 2-chloro-3-fluoropyridine (370 mg, 2.80 mmol) afforded 111 mg of 3-chlorophenyl 5-(3-fluoropyridin-2-yl)pent-4-ynoate (Yield: 13%) as yellow-oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[N+:23]([O-])=O)=[N:3]1>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:23][C:14]1[CH:15]=[C:16]([C:19]([F:21])([F:22])[F:20])[CH:17]=[CH:18][C:13]=1[NH:12][C:4]1[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:6][N:2]([CH3:1])[N:3]=1
Reactant: CCOC(=O)c1cn(C)nc1Nc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1cn(C)nc1Nc1ccc(C(F)(F)F)cc1N

Procedure:
Ethyl 1-methyl-3-(2-nitro-4-trifluoromethylanilino)pyrazole-4-carboxylate (9.2 g) was hydrogenated at 60 p.s.i. in a mixture of ethyl acetate (200 ml) and ethanol (50 ml) over 10% palladium on charcoal (1.0 g). The catalyst was removed by filtration, the solvent evaporated and the residue crystallised from carbon tetrachloride to give the title compound m.p. 162° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH2:19][O:20][CH2:21][CH2:22][NH:23][CH2:24][C:25](OCC)=[O:26])=[C:9]1[C:30]([O:32][CH2:33][CH3:34])=[O:31].[NH3:35]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH2:19][O:20][CH2:21][CH2:22][NH:23][CH2:24][C:25]([NH2:35])=[O:26])=[C:9]1[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCOC(=O)CNCCOCC1=C(C(=O)OCC)C(c2ccccc2Cl)C(C(=O)OC)=C(C)N1
Reactant: N
Solvent: CCO
Product: CCOC(=O)C1=C(COCCNCC(N)=O)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Ethyl N-(2-{[4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl]methoxy}ethyl)aminoacetate (2.50 g) in a mixture of ethanol (40 ml) and 0.880 aqueous ammonia (30 ml) was stirred at room temperature for four days and then evaporated. The residue was partitioned between ethyl acetate and water and the organic layer washed with water, dried (MgSO4), and evaporated. The residue was chromatographed on silica (t.l.c. grade Merck Kieselgel 60H, [Trade Mark] 30 g) eluting with dichloromethane plus 0-5% methanol. Appropriate fractions were combined and evaporated. The residue was triturated with ethyl acetate and the resulting solid collected, washed with ethyl acetate, and dried to give the title compound (1.23 g), m.p. 126°-129°.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[NH:13][C:12](=[O:14])[CH2:11][N:10]=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[CH:21]=1.[CH2:22](Br)[C:23]#[CH:24]>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]([CH2:24][C:23]#[CH:22])[C:12](=[O:14])[CH2:11][N:10]=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[CH:21]=1
Reactant: O=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCN1C(=O)CN=C(c2ccccc2)c2cc(Cl)ccc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3.76 g of 50% sodium hydride in mineral oil were added to 250 ml. of dimethylforamamide cooled to about 0° C. The temperature of the suspension was maintained at about 0° C., while a solution of 27.05 g (0.1 mol) of 7-chloro-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one in 50 ml. of dimethylformamide was added dropwise to it. The resulting mixture was stirred for 2 hours, and then 10 ml. of propargyl bromide were added dropwise while maintaining the temperature at 10°-15° C. The reaction mixture was stirred for about 4 hours and then poured over ice. The product was filtered and dissolved in chloroform; and the chloroform solution was separated from the aqueous layer, and dried over sodium sulphate. The chloroform was evaporated off from the solution and the residue was dissolved in the minimum quantity of a 7:3 (by volume) mixture of benzene and ethyl acetate. This solution was chromatographed on a column of silica gel and eluted with a 7:3 (by volume) mixture of benzene and ethyl acetate. The portion of eluate containing the desired product, as determined by thin-layer chromatography, was collected and evaporated under reduced pressure. The residue was recrystallized from a 1:1 (by volume) mixture of benzene and hexane, giving 16 g of the pure desired product with a melting point of 141°-143° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18]([CH:20]1[O:22][CH2:21]1)Cl>>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([O:9][CH2:18][CH:20]2[O:22][CH2:21]2)=[CH:7][CH:8]=1
Reactant: ClCC1CO1
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: FC(F)(F)c1ccc(OCC2CO2)cc1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
A mixture of 4-trifluoromethyl phenol (2 g), K2CO3 (2.04 g) and epichlorohydrin (10 mL) was stirred at 120° C. for 4 hrs. After completion of reaction, the solid was filtered, filtrate was Diluted with water (50 mL) and extracted with ethylacetate (3×25 mL). Organic layer was washed with Distilled water (3×100 mL) and concentrated to an oil, which was purified on silica gel column using hexane:ethylacetate (9:1) as eluant, to given required compound 2.42 g (90%) yield.
Reaction SMILES: O[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-:11].[Cs+].[Cs+]>C1COCC1>[OH:11][C:8]1[CH:9]=[CH:2][CH:3]=[CH:4][C:5]=1[CH:6]=[O:7]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc(O)cc1
Agent: [Cs+]
Solvent: C1CCOC1
Product: O=Cc1ccccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
1170 mg of 4-hydroxybenzaldehyde and 6800 mg of cesium carbonate are added to a solution containing 650 mg of dendritic core obtained in the preceding stage in 20 mL of THF. The mixture is stirred at RT overnight, and the salts are eliminated by centrifugation. The resulting solution is then concentrated under reduced pressure and precipitated with an ether/pentane mixture (1/1) in order to produce a white powder with a yield of 82%.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:14]=[C:13]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[CH2:12][N:11]1[C:23]([N:25]([CH3:32])[CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:24])(C(C)(C)C)(C)C.CC(O)=O.C(O[C:46]1(O[Si](C)(C)C)[CH2:48][CH2:47]1)C.[BH3-]C#N.[Na+].FC(F)(F)C(O)=O>CO>[CH:46]1([N:29]2[CH2:28][CH2:27][CH:26]([N:25]([CH3:32])[C:23]([N:11]3[CH2:12][C:13]([C:15]4[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=4[F:22])=[CH:14][C@@:10]3([CH2:9][OH:8])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:24])[CH2:31][CH2:30]2)[CH2:48][CH2:47]1
Reactant: CN(C(=O)N1CC(c2cc(F)ccc2F)=CC1(CO[Si](C)(C)C(C)(C)C)c1ccccc1)C1CCNCC1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)N1CC(c2cc(F)ccc2F)=C[C@@]1(CO)c1ccccc1)C1CCN(C2CC2)CC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To 30 mg (0.055 mmol) of amine 7-2 in MeOH was added 30 μL (0.55 mmol) of HOAc, 33 μL (0.17 mmol) of (1-ethoxycyclopropoxy)trimethylsilane, 10 mg (0.17 mmol) of NaCNBH3 and 100 mg of 4 Å molecular sieves. The mixture was then heated at 100° C. for 10 min in a microwave reactor. After cooling to room temperature, ˜500 μL of trifluoroacetic acid was added and the mixture was stirred for 1 h. The reaction was partitioned between EtOAc and saturated NaHCO3, the layers were separated, the organic phase was washed with water, brine, dried over MgSO4, and concentrated by rotary evaporation. The residue was purified by column chromatography on silica gel with 20:1:1 EtOH/NH4OH/H2O in EtOAc to provide 15-1 as a white solid. Data for 15-1: 1HNMR (500 MHz, CDCl3) δ 7.4-7.2 (m, 5H), 7.1-6.9 (m, 3H), 6.3 (s, 1H), 5.45 (m, 1H), 4.8 (m, 1H), 4.6 (m, 1H), 4.4 (m, 1H), 4.0 (m, 1H), 3.75 (m, 1H), 3.15 (m, 2H), 2.9 (s, 3H), 2.3 (m, 2H), 1.9-1.6 (m, 5H), 0.5-0.4 (m, 4H) ppm. HRMS (ES) calc'd M+H for C27H31F2N3O2: 468.2457. Found: 468.2438. Resolution of the enantiomers was carried out chromatographically using a Chiralpak AD© 10×50 cm column with 15% isopropanol in hexanes (with 0.1% diethylamine) at 150 mL/min. Analytical HPLC analysis of the eluent on a 4×250 mm Chiralpak AD® column with 15% isopropanol in hexanes (with 0.1% diethylamine) at 1 mL/min indicated that inactive enantiomer has Rt=7.05 min and the active enantiomer has Rt=8.17 min.
Reaction SMILES: [C:1]([O:5][CH:6]([C:12]1[C:21]([CH3:22])=[C:20](C)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].BrC1C2C(=CC=CC=2)C(C2C=CC(Cl)=CC=2)=C(C(OC(C)(C)C)C(OC)=O)C=1C.[NH2:60][C:61]1[N:66]=[CH:65][C:64](B(O)O)=[CH:63][N:62]=1>>[NH2:60][C:61]1[N:66]=[CH:65][C:64]([C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)=[C:12]([CH:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:7]([OH:9])=[O:8])[C:21]=2[CH3:22])=[CH:63][N:62]=1
Reactant: Nc1ncc(B(O)O)cn1
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)c(C)c2ccccc2c1-c1ccc(Cl)cc1
Agent: COC(=O)C(OC(C)(C)C)c1c(C)c(Br)c2ccccc2c1-c1ccc(Cl)cc1
Product: Cc1c(C(OC(C)(C)C)C(=O)O)c(-c2ccc(Cl)cc2)c2ccccc2c1-c1cnc(N)nc1

Procedure:
2-(4-(2-Aminopyrimidin-5-yl)-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (145) was prepared in a manner similar to 2-tert-butoxy-2-(1-(4-chlorophenyl)-3,4-dimethylnaphthalen-2-yl)acetic acid of Example 125, except using methyl 2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate as the starting material and 2-aminopyrimidine-5-yl-boronic acid pinacolate ester in the Suzuki reaction, giving the title compound (mono trifluoroacetic acid salt form).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([F:38])([F:37])[F:36])[CH:29]=3)=[C:20]([C:39]([F:42])([F:41])[F:40])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:44]>C(O)C>[ClH:44].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([F:36])([F:37])[F:38])[CH:29]=2)=[C:20]([C:39]([F:40])([F:41])[F:42])[CH:19]=1)([CH2:13][OH:12])[CH2:9][OH:10]
Reactant: CC(C)(C)OC(=O)NC1(CCc2ccc(OCCCc3cccc(OC(F)(F)F)c3)c(C(F)(F)F)c2)COC(C)(C)OC1
Agent: Cl
Solvent: CCO
Product: NC(CO)(CO)CCc1ccc(OCCCc2cccc(OC(F)(F)F)c2)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Compound 58-4 (790 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated, and the residue was washed, with diethyl ether to give the object product (590 mg) as a white powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1.[CH2:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)[CH3:21].C(=O)([O-])[O-].[K+].[K+].Cl>[Cu]>[F:17][C:16]([F:19])([F:18])[C:4]1[CH:3]=[C:2]([O:29][C:26]2[CH:27]=[CH:28][C:23]([O:22][CH2:20][CH3:21])=[CH:24][CH:25]=2)[CH:7]=[CH:6][C:5]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: FC(F)(F)c1cc(Br)ccc1OCc1ccccc1
Reactant: CCOc1ccc(O)cc1
Agent: [Cu]
Agent: Cl
Agent: O=C([O-])[O-]
Product: CCOc1ccc(Oc2ccc(OCc3ccccc3)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 41.8 %

Procedure:
Then, 5.10 g of 4-bromo-2-trifluoromethyl-1-benzyloxybenzene, 2.34 g of p-ethoxyphenol, 2.13 g of potassium carbonate, 100 mg of copper and 200 mg of cuprous chloride were charged into a reaction vessel, and stirred at 130° C. to 140° C. for 5 hours. The reaction solution was cooled to room temperature, poured into ice-water and then acidified by adding 10% hydrochloric acid. The solution was extracted twice with 100 ml of diethyl ether. Then, the ether layers were combined, washed with water, dried over anhydrous magnesium sulfate and concentrated to give a crude product. This crude product was subjected to silica gel chromatography to give 2.50 g of 2-trifluoromethyl-4-(4-ethoxyphenoxy)-1-benzyloxybenzene, (yield, 41%).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[CH2:6][CH2:5]1)[C:2]#[CH:3].I[C:20]1[N:21]=[C:22]([NH2:38])[C:23]2[N:24]=[CH:25][N:26]([C:36]=2[N:37]=1)[C@@H:27]1[O:35][C@H:32]([CH2:33][OH:34])[C@@H:30]([OH:31])[C@H:28]1[OH:29]>>[O:12]([C:10]([N:7]1[CH2:6][CH2:5][CH:4]([CH2:1][C:2]#[C:3][C:20]2[N:21]=[C:22]([NH2:38])[C:23]3[N:24]=[CH:25][N:26]([C:36]=3[N:37]=2)[C@@H:27]2[O:35][C@H:32]([CH2:33][OH:34])[C@@H:30]([OH:31])[C@H:28]2[OH:29])[CH2:9][CH2:8]1)=[O:11])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C#CCC1CCN(C(=O)Oc2ccccc2)CC1
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Product: Nc1nc(C#CCC2CCN(C(=O)Oc3ccccc3)CC2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
Batch: AB-9-97. Phenyl 4-(prop-2-ynyl)piperidine-1-carboxylate, batch JR28-11 (0.329 g, 1.352 mmol) was added to a solution of 2-iodoadenosine (0.513 g, 1.305 mmol) according to general procedure 2. Yield: 54.5 mg, 82%. 1H NMR (CD3OD) δ 8.30 (s, 1H), 7.38-7.06 (3×m, 5H), 5.94 (d, 1H), 4.71 (m, 1H), 4.32-4.17 (2×m, 7H), 3.92-3.72 (2×d, 2H), 3.10-2.90 (2×bt, 4H), 2.48 (d, 5H), 1.93 (2×m, 5H). m/z MH+=509.18. HPLC rt=5.3 min.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([F:10])([F:9])[F:8].C([N-]C(C)C)(C)C.[Li+].[CH2:19]=[O:20].Cl>C(OCC)(=O)C.O1CCCC1>[Br:1][C:2]1[CH:6]=[C:5]([CH2:19][OH:20])[S:4][C:3]=1[C:7]([F:10])([F:9])[F:8]
Reactant: C=O
Reactant: FC(F)(F)c1sccc1Br
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCc1cc(Br)c(C(F)(F)F)s1
Temperature: -10 °C
Reaction time: 1 h
Yield: 19.5 %

Procedure:
To a tetrahydrofuran solution (5.0 mL) of 3-bromo-2-(trifluoromethyl)thiophene (500 μL, 2.08 mmol), lithium diisopropylamide (2.06 mL, 2.29 mmol) was added under nitrogen atmosphere at −40° C., and the resultant mixture was stirred for 30 minutes. To the reaction solution, paraformaldehyde (68.8 mg, 2.29 mmol) was added and the resultant mixture was stirred for 30 minutes, followed by raising the temperature of the mixture to −10° C. The mixture was stirred at −10° C. for 4 hours and at 0° C. for 1 hour. After completion of the reaction, a 1 M hydrochloric acid was added to the reaction solution and extraction from the resultant mixture with ethyl acetate was performed. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (106 mg, yield 20%).