Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH3:2][CH:3]([CH3:10])[CH2:4][C:5](=O)[C:6]([OH:8])=[O:7].[NH2:11][C@H:12]([C:14]([NH:16][C@H:17]([C:28]([OH:30])=[O:29])[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)=[O:15])[CH3:13].C([BH3-])#N.[Na+]>O>[C:6]([CH:5]([NH:11][C@H:12]([C:14]([NH:16][C@H:17]([C:28]([OH:30])=[O:29])[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)=[O:15])[CH3:13])[CH2:4][CH:3]([CH3:10])[CH3:2])([OH:8])=[O:7]
Reactant: C[C@H](N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: CC(C)CC(=O)C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: CC(C)CC(N[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)C(=O)O

Procedure:
A solution of the sodium salt of 4-methyl-2-oxopentanoic acid (414 mg) and L-alanyl-L-tryptophan (150 mg) in water are adjusted to pH 7 with caustic and treated with sodium cyanoborohydride (103 mg) at room temperature for several days. The product is adsorbed on strong acid ion exchange resin and eluted with 2% pyridine in water. The product rich cuts are freeze dried affording 189 mg of fluffly white solid. The mass spectrum shows a molecular ion at 389 m/e and peaks at 187 m/e and 158 m/e for the fragments shown respectively: ##STR16## The nmr spectrum in D2O is consistent with structure.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[C:5](=[C:10]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8]C)=[O:7].COCCNC1C=CC=C(C(O)=O)C=1C(O)=O>>[Cl:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][NH:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:4]([C:3]([OH:23])=[O:2])[C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1cccc(NCc2cccc(Cl)c2)c1C(=O)OC
Agent: COCCNc1cccc(C(=O)O)c1C(=O)O
Product: O=C(O)c1cccc(NCc2cccc(Cl)c2)c1C(=O)O

Procedure:
3-(3-Chloro-benzylamino)-phthalic acid dimethyl ester (1.61 g, 4.8 mmol) was treated in the same manner as described above for the synthesis of 3-(2-methoxy-ethylamino)-phthalic acid. The product of the reaction, which contained a mixture of diacid and monomethyl esters, was used without further purification.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[F:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31].Cl.[OH:33][CH:34]1[CH2:37][NH:36][CH2:35]1.CN1CCCC1>C(O)C>[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20]([N:36]4[CH2:37][CH:34]([OH:33])[CH2:35]4)[C:21]=3[F:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31]
Reactant: OC1CNC1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(F)c32)c(F)cc1F
Agent: CN1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(O)C4)c(F)c32)c(F)cc1F
Temperature: 85 °C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
To 280 mg of N,N-dimethylformamide were added 125 mg 1-(6-amino-3,5-difluoropyridin-2-yl)-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 60 mg of 3-hydroxyazetidine hydrochloride, and 120 mg of N-methylpyrrolidine together with 3 drops of ethanol, and the mixture was stirred at 85° C. for 10 minutes. After adding 0.8 ml of ethanol, the solution was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 90 mg of the title compound as a pale yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:12][C:13](=[O:32])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH2:23][CH2:24][C:25]3[CH:26]=[C:27]([CH3:31])[CH:28]=[CH:29][CH:30]=3)[CH:15]=2)[CH2:10][CH2:9][C:8](=[CH2:11])[CH2:7][CH2:6]1)=[O:4].[OH:33]O.[OH-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1([NH:12][C:13](=[O:32])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH2:23][CH2:24][C:25]3[CH:26]=[C:27]([CH3:31])[CH:28]=[CH:29][CH:30]=3)[CH:15]=2)[CH2:10][CH2:9][CH:8]([CH2:11][OH:33])[CH2:7][CH2:6]1)=[O:4]
Reactant: C=C1CCC(NC(=O)c2ccc(OC)c(OCCc3cccc(C)c3)c2)(C(=O)OC)CC1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)C1(NC(=O)c2ccc(OC)c(OCCc3cccc(C)c3)c2)CCC(CO)CC1
Temperature: -25 °C
Reaction time: 8 h

Procedure:
The compound of step 1 of example 56 (500 mg, 1.14 mmol) was dissolved in THF (5 ml) and cooled to −25° C. Borane-tetrahydrofuran complex (2.29 ml of a 1 M solution in THF, 2.29 mmol) was added and the mixture was kept overnight at 0° C. Hydrogen peroxide (2.5 ml, 30% in water) and sodium hydroxide (2.5 ml, 20% in water) were added sequentially and stirring was continued at room temperature. The mixture was partitioned between water and EA, the aqueous phase extracted with EA, and the combined organic phases were dried over sodium sulfate and evaporated to dryness. The residue was purified by silica gel chromatography (HEP/EA gradient) to yield the title compound.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:15](=[N:18][C:19]#[N:20])OC)[N:9]=1)[C:2]([NH2:4])=[NH:3].[CH3:21][NH2:22]>O>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:15]([NH:22][CH3:21])=[N:18][C:19]#[N:20])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: CN
Reactant: COC(=NC#N)NCCSCc1csc(NC(=N)N)n1
Solvent: O
Product: CNC(=NC#N)NCCSCc1csc(NC(=N)N)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 2-guanidino-4-[2-(3-cyano-2-methylisoureido)ethylthiomethyl]thiazole (1.88 g.) and 30% w/v aqueous methylamine (6.0 ml.) was stirred together at room temperature. After 1 hour 40 minutes water (20 ml.) was added, and stirring was continued for 15 minutes. The white solid (1.265 g.) was collected, washed with water (3 ml.) and dried in vacuo overnight. Recrystallization from aqueous dimethylformamide gave 2-guanidino-4-[2-(2-cyano-3-methylguanidino)ethylthiomethyl]thiazole, m.p. 160°-161.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C:13]([OH:15])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:17][NH:18][O:19][CH3:20].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:20][O:19][N:18]([CH3:17])[C:13]([C@H:10]1[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1)=[O:15]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C(=O)O)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of (S)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (430 mg, 2.0 mmol) in CH2Cl2 (20 mL) was added CDl (356 mg, 2.2 mmol). The mixture was stirred at room temperature for 20 minutes, N,O-dimethylhydroxylamine hydrochloride (234 mg, 2.4 mmol) and DIPEA (258 mg, 2.6 mmol) were then added subsequently at 0° C. The mixture was stirred at 0° C. for 0.5 hour, then warmed up and stirred at ambient temperature overnight. The mixture was washed with HCl (1 N), saturated aqueous NaHCO3 and water, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound for the next step.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:19][NH2:20].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O.C(N(CC)CC)C.ClC1C=C(C=CC=1OC)CN>[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:19][NH:20][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: COc1ccc(CN)cc1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(SC)nc1NCc1ccc(OC)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 95.7 %

Procedure:
To a solution of 4-chloro-5-ethoxycarbonyl-2-methylthiopyrimidine (25.33 g) in N,N-dimethylformamide (85 ml) are added a solution of 3-chloro-4-methoxybenzylamine (19.62 g) in N,N-dimethylformamide (15 ml) and triethylamine (16.7 ml) under ice-cooling. The mixture is stirred at room temperature for 20 minutes, and thereto is added 3-chloro-4-methoxybenzylamine (940 mg), and the mixture is further stirred for 15 minutes. To the mixture is further added said amine (940 mg), and the mixture is stirred for 15 minutes. The reaction mixture is poured into a mixture of ice water and citric acid, and the mixture is extracted with ethyl acetate. The extract is washed successively with a 10% aqueous citric acid solution, water and brine, and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, and the residue is washed with n-hexane to give 4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonyl-2-methylthiopyrimidine (38.34 g), m.p. 86° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:26]=[CH:27][CH:28]=1)[C:7]([C:9]1[CH:10]=[C:11]([CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:12]2[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]2)=[O:8])([O-])=O.[H][H]>O1CCOCC1CCO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:26]=[CH:27][CH:28]=1)[C:7]([C:9]1[CH:10]=[C:11]([CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:12]2[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]2)=[O:8]
Reactant: [H][H]
Reactant: CCOC(=O)CCCc1cc(C(=O)c2cccc([N+](=O)[O-])c2)c2ccccn12
Agent: [Pd]
Agent: OCCC1COCCO1
Product: CCOC(=O)CCCc1cc(C(=O)c2cccc(N)c2)c2ccccn12
Yield: 100.8 %

Procedure:
To a solution of ethyl 4-[1-(3-nitrobenzoyl)-indolizin-3-yl]butyrate (350 mg) in dioxane-ethanol (1:1; ml) was added 10% palladium on carbon (210 mg) and hydrogenated under 4 atm of hydrogen for 4 hours, and then filtered through a celite. Removal of the solvent gave ethyl 4-[1-(3-aminobenzoyl)indolizin-3-yl]butyrate (325 mg).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.CC1(C)COB([C:22]2[C:23]([CH3:37])=[C:24]([C:28]3[C:29]([C:35]#[N:36])=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[CH:25]=[CH:26][CH:27]=2)OC1>>[F:34][C:31]1[CH:30]=[C:29]([C:35]#[N:36])[C:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([C:2]3[N:6]4[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]4=[N:4][CH:3]=3)[C:23]=2[CH3:37])=[CH:33][CH:32]=1
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Reactant: Cc1c(B2OCC(C)(C)CO2)cccc1-c1ccc(F)cc1C#N
Product: Cc1c(-c2ccc(F)cc2C#N)cccc1-c1cnc2nc(C(F)(F)F)ccn12

Procedure:
3-Bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine was coupled with 3′-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-4-fluoro-2′-methylbiphenyl-2-carbonitrile as described in Example 65 to give 4-fluoro-2′-methyl-3′-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)biphenyl-2-carbonitrile as a white solid: δH (360 MHz, CDCl3) 1.94 (3H, s), 7.26 (1H, d, J 7), 7.40-7.51 (6H, m), 8.08 (1H, s), 8.35 (1H, d, J 7); m/z (ES+) 397 (M++H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=2)=[CH:9][C:5]2[O:6][CH2:7][CH2:8][C:4]=2[CH:3]=1.[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)Cl>[Cl:1][C:2]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:21]([C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[F:18])=[O:22])=[N:15][CH:16]=2)=[CH:9][C:5]2[O:6][CH2:7][CH2:8][C:4]=2[CH:3]=1
Reactant: Nc1ccc(-c2cc3c(cc2Cl)CCO3)cn1
Reactant: O=C(Cl)c1ccccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(-c2cc3c(cc2Cl)CCO3)cn1)c1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
To a solution of 5-(5-chloro-2,3-dihydrobenzo[3,4-b]furan-6-yl)-2-pyridylamine (151) (15 mg, 0.06 mmol) in 1 ml DCM was added 2-fluorobenzoyl chloride (11 μl, 0.088 mmol) followed by addition of DIEA (52 μl). The resulting solution was stirred at r.t. for overnight. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 1 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (120 μl) at r.t. for 2 h and before worked up with EA/aq. NaHCO3. Silica gel flash chromatography furnished N-[5-(5-chloro(2,3-dihydrobenzo[3,4-b]furan-6-yl))(2-pyridyl)](2-fluorophenyl)carboxamide (153) (14.7 mg, yield: 66.4%, purity>90%) as white solid.
Reaction SMILES: [C:1]([N:11]1[CH2:13][CH:12]1[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH3:15][C:16]1([CH3:24])[CH2:20][CH2:19][C:18]([CH3:22])([CH3:21])[CH:17]1[OH:23].B(F)(F)F.CCOCC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([NH:11][CH:12]([CH3:14])[CH2:13][O:23][CH:17]1[C:18]([CH3:22])([CH3:21])[CH2:19][CH2:20][C:16]1([CH3:24])[CH3:15])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CC1CN1C(=O)OCc1ccccc1
Reactant: CC1(C)CCC(C)(C)C1O
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: CC(COC1C(C)(C)CCC1(C)C)NC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
N-Cbz-2-Methyl aziridine and 2,2,5,5-tetramethyl-1-cyclopentanol are dissolved in CH2Cl2 at 0° C. under argon. Boron trifluoride etherate is added and the flask is stirred overnight. The contents are poured into saturated NaHCO3 and are extracted with ethyl acetate. The organic layer is dried over MgSO4 and evaporated to yield N-Cbz-1-(2-aminopropoxy)-2,2,5,5-tetramethylcyclopentane.
Reaction SMILES: [C:1]([C:3]1[CH:13]=[C:12]([NH:14][C:15](=[O:19])[CH:16]([CH3:18])[CH3:17])[CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]1[O:9][CH2:8]1)#[N:2].[C:20]([C:22]1([NH2:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)#[CH:21]>C(O)C>[C:1]([C:3]1[CH:13]=[C:12]([NH:14][C:15](=[O:19])[CH:16]([CH3:18])[CH3:17])[CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]([OH:9])[CH2:8][NH:28][C:22]1([C:20]#[CH:21])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)#[N:2]
Reactant: CC(C)C(=O)Nc1ccc(OCC2CO2)c(C#N)c1
Reactant: C#CC1(N)CCCCC1
Solvent: CCO
Product: C#CC1(NCC(O)COc2ccc(NC(=O)C(C)C)cc2C#N)CCCCC1

Procedure:
7.8 gm (0.03 mol) of 1-[2-cyano-4-(isobutyroyl-amino)-phenoxy]-2,3-epoxy-propane were dissolved in 80 ml of ethanol, and after addition of 7.5 gm (0.06 mol) of 1-ethinyl-cyclohexyl-amine the mixture was refluxed for one hour. The solvent was then distilled off, and the residue was acidified with dilute HCl. After extraction with ethyl acetate the aqueous phase was made alkaline by addition of NaOH, whereby basic components precipitated in oily form. They were taken up in ethyl acetate, the organic phase was washed with water, dried over MgSO4, evaporated and the solid residue was recrystallized twice from acetonitrile.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][N:18]([CH:19]([CH3:21])[CH3:20])[C:12]2=[N:11][C:10]=1[C:22](O)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[NH2:32][CH2:33][C:34]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:35]=1[C:36]([NH:38][CH3:39])=[O:37]>>[F:44][C:41]1[CH:42]=[CH:43][C:34]([CH2:33][NH:32][C:22]([C:10]2[N:11]=[C:12]3[N:18]([CH:19]([CH3:20])[CH3:21])[CH2:17][CH2:16][N:13]3[C:14](=[O:15])[C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:23])=[C:35]([C:36](=[O:37])[NH:38][CH3:39])[CH:40]=1
Reactant: CNC(=O)c1cc(F)ccc1CN
Reactant: CC(C)N1CCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCN2C(C)C
Yield: 73 %

Procedure:
Coupling of 6-(benzyloxy)-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylic acid (0.300 g, 0.91 mmol) and 2-(aminomethyl)-5-fluoro-N-methylbenzamide trifluoroacetate salt (0.210 g, 0.96 mmol) as described for the synthesis of intermediate 3 gave 0.328 g (72% yield) of the title amide as white crystals; mp 197-198° C. (ethyl acetate). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.23 (6H, d, J=6.8 Hz, 2×CH3), 2.98 (3H, d, J=5 Hz, NCH3), 3.66 (2H, t, J=9 Hz, CH2), 4.12 (2H, t, J=9 Hz, CH2), 4.43 (1H, m, CH), 4.48 (2H, d, J=6.3 Hz, NCH2), 5.09 (2H, s, OCH2), 7.05 (1H, m, aromatic), 7.13-7.17 (2H, m, aromatics), 7.3-7.35 (4H, m, NH and aromatics), 7.43-7.46 (2H, m, aromatics), 8.35 (1H, broad t, NH). Anal. Calcd for C26H28FN5O4: C, 63.27; H, 5.71; N, 14.19. Found: C, 63.06; H, 5.65; N, 14.02.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[N:6]1[CH2:10][C:9]2([CH:15]3[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]3)[CH2:11]2)[O:8][C:7]1=[O:18].[Br:19]N1C(=O)CCC1=O>CN(C)C=O.C(Cl)(Cl)Cl>[Br:19][C:5]1[S:1][C:2]([N:6]2[CH2:10][C:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[O:8][C:7]2=[O:18])=[N:3][CH:4]=1
Reactant: O=C1OC2(CN3CCC2CC3)CN1c1nccs1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C1OC2(CN3CCC2CC3)CN1c1ncc(Br)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.8 %

Procedure:
A solution containing 3′-(thiazol-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one (2.80 g, 10.55 mmol) and N-bromosuccinimide (3.90 g, 21.86 mmole) in N,N-dimethylformamide (15 mL) were stirred at RT overnight. The mixture was diluted with chloroform, washed with saturated aqueous potassium carbonate and then with brine, dried through magnesium sulfate, and then the solvent was evaporated. The residue was purified by flash chromatography using a gradient of ammoniated methanol in chloroform to give the title compound as a pale solid (1.70 g), m/z 343, 345 (MH+).
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[CH2:6][CH2:5][CH2:4][N:3]1[C@@H:7]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:8]([NH:10][C@H:11]1[C@H:18]2[C@H:14]([CH2:15][NH:16][CH2:17]2)[CH2:13][CH2:12]1)=[O:9].[F:24][C:25]([F:35])([F:34])[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH:29]=O.C(O)(=O)C.C([BH3-])#N>ClCCl>[O:23]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C@@H:7]([CH2:19][CH:20]([CH3:21])[CH3:22])[C:8]([NH:10][C@H:11]1[C@H:18]2[C@H:14]([CH2:15][N:16]([CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[C:26]([C:25]([F:24])([F:34])[F:35])[CH:27]=3)[CH2:17]2)[CH2:13][CH2:12]1)=[O:9]
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: CC(C)C[C@@H](C(=O)N[C@@H]1CC[C@H]2CNC[C@H]21)N1CCCS1(=O)=O
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)N[C@@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)N1CCCS1(=O)=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(2S)-2-(1,1-Dioxidoisothiazolidin-2-yl)-4-methyl-N-[(3aS,4R,6aR)-octahydrocyclopenta[c]pyrrol-4-yl]pentanamide (204 mg, 0.594 mmol) and 3-(trifluoromethyl)benzaldehyde (0.158 mL, 1.188 mmol) were dissolved in dichloromethane (3 mL). Acetic acid (1 mL) was added. The reaction was stirred at ambient temperature for 20 min, then PS-cyanoborohydride (487 mg, 1.188 mmol) was added. The reaction was stirred at room temperature overnight, then filtered, and the solvent was removed in vacuo. The crude material was purified by silica gel chromatography using 1-10% methanol (2 N ammonia)/dichloromethane to the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.79 (d, J=7.0, 1H), 7.75 (d, J=10.3, 1H), 7.61-7.54 (m, 2H), 7.44 (t, J=7.7, 1H), 4.52 (dd, J=6.6, 8.9, 1H), 4.38 (dq, J=6.4, 12.6, 1H), 3.94 (dd, J=7.3, 16.2, 1H), 3.57 (dd, J=9.1, 13.5, 1H), 3.50-3.37 (m, 2H), 3.31-3.19 (m, 2H), 2.79 (ddd, J=3.0, 9.1, 19.0, 1H), 2.62-2.54 (m, 1H), 2.54-2.45 (m, 1H), 2.43-2.36 (m, 1H), 2.31-2.16 (m, 4H), 2.13-2.03 (m, 1H), 1.94-1.78 (m, 3H), 1.77-1.59 (m, 2H), 1.39 (dt, J=6.5, 19.8, 1H), 0.88 (d, J=6.6, 3H), 0.82 (dd, J=2.3, 6.5, 3H); MS (ESI+) m/z 502 (M+H)+.
Reaction SMILES: C1(C2C=CC=CC=2)C=CC=CC=1NC#CCC.[CH2:18]([NH:23][CH2:24][C:25]#[C:26][CH:27]([OH:40])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:19][CH:20]([CH3:22])[CH3:21].CO>[Pd].[Pt].C(O)C>[CH2:18]([NH:23][CH2:24][CH2:25][CH2:26][CH:27]([OH:40])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:19][CH:20]([CH3:21])[CH3:22]
Reactant: CC(C)CCNCC#CC(O)c1ccccc1-c1ccccc1
Agent: [Pd]
Agent: [Pt]
Agent: CCC#CNc1ccccc1-c1ccccc1
Solvent: CO
Solvent: CCO
Product: CC(C)CCNCCCC(O)c1ccccc1-c1ccccc1

Procedure:
The biphenylyl alkynylamine next is reduced to yield the corresponding biphenylyl alkylamine of the invention. Such exhaustive reduction typically is carried out by hydrogenation in the presence of a catalyst such as palladium or platinum. For example, a biphenylyl butynylamine such as N-isopentyl-4-hydroxy-4-(1,1'-biphenyl-2-yl)-2-butynylamine is dissolved in a suitable organic solvent such as methanol or ethanol and stirred for about two to four hours at about 20 to about 50° C. under a hydrogen atmosphere of about 20 to about 80 psi, in the presence of a hydrogenation catalyst such as palladium suspended on carbon. The reduced product, for instance N-isopentyl-4-hydroxy-4-(1,1'-biphenyl-2-yl)butylamine, is isolated by filtering the reaction mixture to remove the catalyst and then evaporating the reaction solvent from the filtrate. The amine thus formed can be further purified if desired by standard methods such as acid and base extraction, crystallization from solvents such as diethyl ether or Skelly-B, salt formation, chromatography and the like.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:37]=[CH:36][CH:35]=[CH:34][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:39][C:40](=[O:50])[C@H:41]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)O>>[CH2:1]([C:8]1[O:9][C:10]2[CH:37]=[CH:36][CH:35]=[CH:34][C:11]=2[C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C@@H:41]([CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:40]([OH:50])=[O:39])=[C:21]([C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)[CH:20]=2)=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Reactant: COc1ccc(-c2cc(-c3ccc(-c4c(Cc5ccccc5)oc5ccccc45)cc3)ccc2O)cc1
Product: COc1ccc(-c2cc(-c3ccc(-c4c(Cc5ccccc5)oc5ccccc45)cc3)ccc2O[C@@H](Cc2ccccc2)C(=O)O)cc1

Procedure:
The title compound was prepared from 4-(2-benzyl-benzofuran-3-yl)-4″-methoxy-[1,1′;3′,1″]terphenyl-4′-ol, and (S)-(−)-3-phenyllactic acid methyl ester, in substantially the same manner, as described in Example 1, steps g-h , and was obtained as a white solid, mp 73-75° C.; MS m/e 629 (M−H)+;
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([OH:22])[CH:16]=1.[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][O-:27].[Na+]>O1CCCC1.O>[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][O:27][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([OH:22])[CH:16]=1
Reactant: CN(C)CC[O-]
Reactant: Cc1ccc(Nc2c(C#N)cnc3cnc(F)cc23)cc1O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(Nc2c(C#N)cnc3cnc(OCCN(C)C)cc23)cc1O

Procedure:
To 160 mg of 6-fluoro-4-(3-hydroxy-4-methyl-phenylamino)-[1,7]naphthyridine-3-carbonitrile under an inert atmosphere was added 3 mL of 1 M sodium (2-dimethylamino-ethoxide) in tetrahydrofuran. After refluxing for 3 hours, the reaction was diluted with Water and the product extracted five times with chloroform. The crude product was purified by flash chromatography with 1% triethyl amine and 10% methanol/chloroform followed by recrystallized from chloroform/ether to give 106 mg of 6-(2-dimethylamino-ethoxy)-4-(3-hydroxy-4-methyl-phenylamino)-[1,7]naphthyridine-3-carbonitrile as a yellowish solid: melting point 100-180° C. (decomposed, effervescence); mass spectrum (m/e): M+H 419.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([NH2:10])[CH:4]=1.C(N(CC)CC)C.[C:18](OCC)(=[O:24])[C:19](OCC)=[O:20]>>[OH:20][C:19]1[C:18]([OH:24])=[N:10][C:5]2[C:6](=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: COc1ccc(N)c(N)c1
Solvent: CCN(CC)CC
Product: COc1ccc2nc(O)c(O)nc2c1
Temperature: 25 °C

Procedure:
A mixture consisting of 20 g. (0.114 mole) of 4-methoxy-o-phenylenediamine and 11 g. (0.114 mole) of triethylamine dissolved in 200 ml. of diethyl oxalate was refluxed overnight for a period of approximately 16 hours. Upon completion of this step, the reaction mixture was cooled to room temperature (~20° C.) and filtered to remove the desired product. After washing with ethanol, there were ultimately obtained 14.8 g. (68%) of pure 2,3-dihydroxy-6-methoxyquinoxaline, m.p. >300° C. Mass Spectrum: m/e, 192 (P).