Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[C:18]([C:20]1[CH:21]=[CH:22][C:23]([C:26](O)=[O:27])=[N:24][CH:25]=1)#[N:19]>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:15])([F:14])[C@:8]([C:4]2[CH:3]=[C:2]([NH:1][C:26]([C:23]3[CH:22]=[CH:21][C:20]([C:18]#[N:19])=[CH:25][N:24]=3)=[O:27])[CH:7]=[CH:6][CH:5]=2)([CH3:17])[N:9]=1
Reactant: C[C@]1(c2cccc(N)c2)N=C(N)OCC1(F)F
Reactant: N#Cc1ccc(C(=O)O)nc1
Product: C[C@]1(c2cccc(NC(=O)c3ccc(C#N)cn3)c2)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(3-amino-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-4) and 5-cyano-pyridine-2-carboxylic acid following procedure I yielded the title compound as an off-white solid. MS (ISP): m/z=372.1 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[CH2:11][NH:12][CH:13]1[C:22]2[N:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:16][CH2:15][CH2:14]1)[C:6]#[N:7].[Cl:23][C:24]1[CH:25]=[C:26]([CH3:32])[C:27]([CH:30]=O)=[N:28][CH:29]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:23][C:24]1[CH:25]=[C:26]([CH3:32])[C:27]([CH2:30][N:12]([CH2:11][C:10]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[CH2:2][OH:1])[CH:13]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:16][CH2:15][CH2:14]2)=[N:28][CH:29]=1
Reactant: N#Cc1ccc(CNC2CCCc3cccnc32)c(CO)c1
Reactant: Cc1cc(Cl)cnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(Cl)cnc1CN(Cc1ccc(C#N)cc1CO)C1CCCc2cccnc21

Procedure:
Using General Procedure B: Reaction of 3-hydroxymethyl-4-[(5,6,7,8-tetrahydro-quinolin-8-ylamino)-methyl]-benzonitrile in CH2Cl2 with 5-chloro-3-methyl-pyridine-2-carbaldehyde and NaBH(OAc)3 gave 4-{[(5-chloro-3-methyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-3-hydroxymethyl-benzonitrile as a colorless oil. 1H NMR (CDCl3) δ 1.59 (m, 1H), 2.03 (m, 2H), 2.14 (m, 1H), 2.19 (s, 3H), 2.63 (m, 1H), 2.77 (m, 1H), 3.65 (d, 1H, J=12.0 Hz), 3.73-3.83 (m, 3H), 4.20 (d, 2H, J=12.0 Hz), 4.37 (d, 1H, J=12.0 Hz), 7.03 (dd, 1H, J=7.5, 3.0 Hz), 7.15-7.46 (m, 4H), 7.65 (s, 1H), 8.28 (s, 1H), 8.34 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[O:5][C:6]2=[O:11].[H-].[Na+].[CH3:15]I>CN(C)C=O>[CH3:15][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[O:5][C:6]2=[O:11]
Reactant: CI
Reactant: O=C1OC(=O)c2c(O)cccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc2c1C(=O)OC2=O
Reaction time: 0.25 h
Yield: 46.8 %

Procedure:
To a solution of 4-hydroxy-isobenzofuran-1,3-dione (195 mg, 1.2 mmol) in anhydrous N,N-dimethylformamide (4 ml) under nitrogen was added sodium hydride (61 mg, 1.56 mmol). The solution was stirred for 15 minutes and then methyl iodide (0.37 ml, 6.0 mmol) was added. The reaction was stirred for 48 hours and then quenched with saturated ammonium chloride. The mixture was concentrated in vacuo, diluted in ethyl acetate (20 ml) and the organic phase washed with 1N hydrochloric acid (5 ml) and brine (3×5 ml). The organic layer was dried (MgSO4) and concentrated in vacuo. To the crude solid was added methanol causing a precipitate to form. The flask was cooled in an ice bath for 2 hours and the solid filtered off, washed with methanol and dried in vacuo which afforded 0.1 g (47%) of 4-methoxy-isobenzofuran-1,3-dione as a solid.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[C:5]([NH:9]/[C:10](=[CH:15]/[C:16]([O:18]C)=O)/[C:11]([O:13][CH3:14])=[O:12])=[CH:4][NH:3]1.C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>>[O:1]=[C:2]1[NH:3][C:4]2[C:16](=[O:18])[CH:15]=[C:10]([C:11]([O:13][CH3:14])=[O:12])[NH:9][C:5]=2[C:6](=[O:8])[NH:7]1
Reactant: COC(=O)/C=C(/Nc1c[nH]c(=O)[nH]c1=O)C(=O)OC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: COC(=O)c1cc(=O)c2[nH]c(=O)[nH]c(=O)c2[nH]1
Temperature: 220 °C
Reaction time: 3 h
Yield: 63.3 %

Procedure:
In a 2 liter-4 neck flask fitted with a reflux condenser was placed dimethyl (2E)-2-[(2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)amino]-2-butenedioate (Intermediate 1.1) (38.5 g; 0.14 mol; 1 eq.) dowtherm(R) A (1 L)(phenyl ether-biphenyl eutectic). The suspension was stirred with a mechanical stirrer under argon and heated to 220° C. The reaction was monitored by HPLC/LC/MS. After 3 hours the reaction was stopped by cooling followed by the addition of 300 mL of petroleum ether. The resulting precipitate was filtered and washed with DMF (2×100 mL). Methyl 2,4,8-trioxo-1,2,3,4,5,8 hexahydropyrido[3,2-d]pyrimidine-6-carboxylate (21.02 g; 62%) (Intermediate 1.2) was isolated as a yellow powder in 100% HPLC purity.
Reaction SMILES: C(N(CC)CC)C.C([SiH](CC)CC)C.[CH3:15][O:16][C:17](=[O:62])[CH:18]([C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([NH:44][C:45]([NH:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])=[N:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH:39]=1)[O:19][P:20]([C@@H:23]([NH:27]C(OCC1C=CC=CC=1)=O)[CH:24]([CH3:26])[CH3:25])([OH:22])=[O:21]>C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:15][O:16][C:17](=[O:62])[CH:18]([C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([NH:44][C:45]([NH:54][C:55]([O:57][C:58]([CH3:59])([CH3:61])[CH3:60])=[O:56])=[N:46][C:47]([O:49][C:50]([CH3:52])([CH3:53])[CH3:51])=[O:48])[CH:39]=1)[O:19][P:20]([C@@H:23]([NH2:27])[CH:24]([CH3:26])[CH3:25])([OH:22])=[O:21]
Reactant: COC(=O)C(OP(=O)(O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)c1cccc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC[SiH](CC)CC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(OP(=O)(O)[C@@H](N)C(C)C)c1cccc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1
Reaction time: 0.42 h
Yield: 114.9 %

Procedure:
To a solution of palladium(II) acetate (184 mg, 0.82 mmol) in 13 mL of CH2Cl2 was added triethylamine (0.24 mL, 1.72 mmol) and triethylsilane (1.80 mL, 11.3 mmol). After stirring the resulting black slurry for 25 minutes, 2-(3-(N′,N″-di(t-butoxycarbonyl)guanidino)phenyl)-2-((1R)-(1-(benzyloxycarbonyl)amino-2-methylpropyl)(hydroxy)phosphinoyloxy)ethanoic acid methyl ester (2.93 g, 4.23 mmol) in methylene chloride (3 mL) was added. The reaction mixture was stirred at ambient temperature for 5.5 hours at which point the reaction was concentrated in vacuo, dissolved in methanol, and filtered. The filtrate was concentrated in vacuo and placed in vacuo overnight to provide 2.7143 g (116%) of 2-(3-(N′,N″-di(t-butoxycarbonyl)guanidino)phenyl)-2-((1R)-(1-amino-2-methylpropyl)-(hydroxy)phosphinoyloxy)ethanoic acid methyl ester as an impure white foam.
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[S:14]([CH2:20][CH2:21][C:22]([OH:24])=O)[CH2:15][CH2:16][C:17]([OH:19])=[O:18]>C(C(C)=O)C(C)C>[S:14]([CH2:15][CH2:16][C:17]([O:19][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][NH2:6])=[O:18])[CH2:20][CH2:21][C:22]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][NH2:6])=[O:24]
Reactant: NCCCCCCO
Reactant: O=C(O)CCSCCC(=O)O
Agent: CS(=O)(=O)O
Solvent: CC(=O)CC(C)C
Product: NCCCCCCOC(=O)CCSCCC(=O)OCCCCCCN
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
8.1 g of methanesulfonic acid (manufactured by Wako Pure Chemical Industries, Ltd.) was added dropwise, under an atmosphere of nitrogen and at 70° C., to 9.4 g of 6-amino-1-hexanol (manufactured by Tokyo Chemical Industry Co., Ltd.). After stirring for 10 minutes, 7.1 g of 3,3′-thiodipropionic acid (manufactured by Wako Pure Chemical Industries, Ltd.) was added, and the resulting mixture was heated to 120° C. and then stirred at 110° C. for 7 hours. Following completion of the reaction, the reaction mixture was cooled to room temperature and then added gradually to 50 mL of methyl isobutyl ketone (manufactured by Wako Pure Chemical Industries, Ltd.). After stirring for 2 hours, the precipitated crystals were collected by filtration and washed with acetone, yielding the methanesulfonate salt of di(6-aminohexyl) 3,3′-thiodipropionate.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[F-].[K+].[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1>C(#N)C>[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][O:10][C:8]2[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([OH:1])[CH:9]=2)=[CH:16][CH:15]=1
Reactant: O=Cc1ccc(O)cc1O
Reactant: ClCc1ccc(Cl)cc1
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1ccc(OCc2ccc(Cl)cc2)cc1O
Temperature: 90 °C

Procedure:
A mixture of 2,4-dihydroxybenzaldehyde (6.62 g, 48 mmol, Fluka), potassium fluoride (5.57 g, 96 mmol, Aldrich) and 4-chlorobenzyl chloride (13.50 g, 84 mmol, Aldrich) in acetonitrile (50 mL) was heated at 90° C. for 24 hours. After cooling, the mixture was partitioned between ether (2×100 mL) and water (2×100 mL). Organic layers were washed with brine (100 mL), combined, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (Biotage 75S, hexanes, then hexanes-dichloromethane 1:1 as solvent) to give partial separation. Pure fractions of product were combined and concentrated and the residue crystallized from hexanes with traces of dichloromethane to give 4-(4-chloro-benzyloxy)-2-hydroxy-benzaldehyde as white crystals. (Yield 4.74 g). Mother liquor and impure fractions were combined and further purified by flash chromatography (Biotage 40L, same solvent as before) and pure fractions were combined and concentrated. The residue was re-crystallized to give second crop of 4-(4-chloro-benzyloxy)-2-hydroxy-benzaldehyde. (Yield 3.03 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:14].[H-].[Na+].Br[CH2:19][CH3:20]>CN(C)C=O>[CH2:19]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=2)[C:2]([CH3:15])([CH3:1])[C:3]1=[O:14])[CH3:20]
Reactant: CC1(C)C(=O)Nc2cc([N+](=O)[O-])ccc21
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1C(=O)C(C)(C)c2ccc([N+](=O)[O-])cc21
Temperature: 60 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
A solution of 3,3-dimethyl-6-nitro-1,3-dihydro-indol-2-one (6 g, 29.10 mmol) in anhydrous N,N-dimethylformamide (DMF) (35 ml) was treated with sodium hydride. The resulting suspension was stirred for 1 h at 60° C. A solution of bromo-ethane (2.17 mL, 3.17 g, 29.10 mmol) in DMF (10 ml) was added. The mixture was allowed to cool to room temperature and stirred for 1 h. After removal of the solvent the mixture was quenched with water (100 ml) and extracted with ethyl acetate (3×100 ml). The extract was dried over Na2SO4, evaporated and the crude product was purified by column chromatography on silica gel. Elution with ethyl acetate/n-heptane (1:3) yielded 5.94 g (87%) of a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[C:25]([CH3:26])=[CH:24][CH:23]=[C:22]3[CH3:27])[N:16]=2)[CH:3]=1.[CH2:28]1[CH2:32]O[CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](=[O:7])[CH2:30][CH2:29][C:28]2[CH:32]=[CH:4][CH:3]=[CH:2][CH:13]=2)=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[C:25]([CH3:26])=[CH:24][CH:23]=[C:22]3[CH3:27])[N:16]=2)[CH:3]=1
Reactant: C1CCOC1
Reactant: CON(C)C(=O)c1ccc(Cl)cc1Nc1cccc(-n2c(C)ccc2C)n1
Product: Cc1ccc(C)n1-c1cccc(Nc2cc(Cl)ccc2C(=O)CCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-chloro-2-[6-(2,5-dimethyl-pyrrol-1-yl)-pyridin-2-ylamino]-N-methoxy-N-methyl-benzamide (1.59 g) in THF (20 mL) was cooled in an ice bath, and phenethyl-Grignard solution (10 mL, 1 M in THF) added via syringe. The mixture was stirred overnight at RT, quenched with NH4Cl (aq), extracted with EtOAc, and adsorbed on silica. The product was chromatographed on silica (80 g) (hexane/EtOAc 100:0 to 50:50) (or using DCM/MeOH) to provide 1-{4-chloro-2-[6-(2,5-dimethyl-pyrrol-1-yl)-pyridin-2-ylamino]-phenyl}-3-phenyl-propan-1-one.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([OH:15])[CH2:9][CH2:10][C:11](OC)=[O:12])=[CH:4][C:3]=1[CH3:16]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:15][C:11](=[O:12])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[CH3:16]
Reactant: COC(=O)CC[C@@H](O)c1ccc(F)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc([C@H]2CCC(=O)O2)ccc1F
Temperature: 40 °C
Reaction time: 16 h
Yield: 112.5 %

Procedure:
To a solution of (R)-methyl 4-(4-fluoro-3-methyl-phenyl)-4-hydroxy-butanoate (289 mg) in 20 mL DCM was added 4 drops TFA at room temperature and the resulting solution warmed to 40° C. After stirring for 16 h the reaction was cooled to room temperature and concentrated under reduced pressure. The product was isolated by flash column chromatograph eluting with 0% to 30% ethyl acetate/hexane gradient solvent to give 279 mg of (R)-5-(4-fluoro-3-methyl-phenyl)-dihydro-furan-2-one as a colorless oil.
Reaction SMILES: [C:1]1([CH:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[NH:8][C:9](=[O:23])[CH2:10][N:11]2[C:16]3[CH:17]=[CH:18][CH:19]=[C:20]([OH:21])[C:15]=3[O:14][CH2:13][C:12]2=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][C:38]([O:40][CH3:41])=[O:39].O>CN(C=O)C>[C:24]1([CH:7]([NH:8][C:9]([CH2:10][N:11]2[C:16]3[CH:17]=[CH:18][CH:19]=[C:20]([O:21][CH2:37][C:38]([O:40][CH3:41])=[O:39])[C:15]=3[O:14][CH2:13][C:12]2=[O:22])=[O:23])[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)CBr
Reactant: O=C(CN1C(=O)COc2c(O)cccc21)NC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1cccc2c1OCC(=O)N2CC(=O)NC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56 %

Procedure:
N-diphenylmethyl-2-(8-hydroxy-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-4-yl)acetamide (735 mg) was dissolved in DMF (30 ml), and the resultant solution was stirred at room temperature. Potassium carbonate (785 mg) and methyl bromoacetate (0.35 ml) were added to the solution, and the mixture was stirred at room temperature for 18 hours. Water (25 ml) was added to the reaction solution, and the mixture was then extracted with ethyl acetate. The resultant organic layer was washed with saturated saline, dried over sodium sulfate, and concentrated. The resultant residue was recrystallized from ethyl acetate/n-hexane to obtain the object compound (492 mg, yield 56%)
Reaction SMILES: C([O:3][C:4](=[O:14])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH:13]=[N:12][N:11]=[N:10]1)C.[OH-].[Na+]>CO>[N:9]1([CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:14])=[O:3])[CH:13]=[N:12][N:11]=[N:10]1
Reactant: CCOC(=O)CCCCn1cnnn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCCCn1cnnn1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
2.12 g of 5-(tetrazol-1-yl)-valeric acid ethyl ester are dissolved in 5 ml of methanol, and 4.28 ml of a methanolic NaOH solution (3N) are added thereto. After stirring for 2.5 hours at room temperature, the solvent is distilled off and the residue is taken up in water. After washing with ethyl acetate, the aqueous phase is acidified (pH 3) and extracted twice with ethyl acetate. After drying and concentrating by evaporation, the pure title compound is obtained.
Reaction SMILES: Br[C:2]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:5]2[N:6]([CH3:24])[C:7]([CH2:9][CH2:10][N:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:13][CH2:12]3)=[N:8][C:4]=2[CH:3]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:17]([N:14]1[CH2:15][CH2:16][N:11]([CH2:10][CH2:9][C:7]2[N:6]([CH3:24])[C:5]3[C:25]4[C:30]([CH:2]=[CH:3][C:4]=3[N:8]=2)=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:12][CH2:13]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cn1c(CCN2CCN(Cc3ccccc3)CC2)nc2cc(Br)c3ccccc3c21
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cn1c(CCN2CCN(Cc3ccccc3)CC2)nc2ccc3ccccc3c21
Reaction time: 6 h
Yield: 58.4 %

Procedure:
3.9 cc of toluene containing 2.62 g (0.013 mole) of (CH3OCH2CH2O)2NaAlH2 is added to a solution of 4.13 g (0.0089 mole) of the compound of Example 16 in 80 cc of toluene and the obtained mixture is refluxed with stirring under argon atmosphere. After 6 hours, when the reaction, which is followed by thin layer chromatography, is completed, 100 cc of 5% NaOH is added to the mixture and the toluene phase is separated and washed with a saturated NaCl solution. Upon evaporating the solvent, a crude product is obtained which is recrystallized from ethyl acetate:hexane 1:1, yielding 2 g of the compound of the title. M.p. 144°-46° C.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)=O.[CH2:20]([O:22][C:23]([C:25]1[N:26]=[CH:27][NH:28][C:29]=1[NH2:30])=[O:24])[CH3:21]>C(O)(=O)C>[CH2:20]([O:22][C:23]([C:25]1[N:26]=[CH:27][N:28]2[C:3]([C:2]([F:19])([F:18])[F:1])=[CH:4][C:5]([C:7]3[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=3)=[N:30][C:29]=12)=[O:24])[CH3:21]
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)c1nc[nH]c1N
Solvent: CC(=O)O
Product: CCOC(=O)c1ncn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Yield: 43.5 %

Procedure:
A mixture of 4,4,4-trifluoro-1-(4-trifluoromethyl-phenyl)-butane-1,3-dione (10.0 g, 35.2 mmol) and 5-amino-1H-imidazole-4-carboxylic acid ethyl ester (5.0 g, 32.2 mmol) in acetic acid (120 mL) was refluxed for 24 h and evaporated. The crude product was further purified by column chromatography on silica gel (ethyl acetate/heptane) and crystallization (diethyl acetate/hexane) to yield 4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine-8-carboxylic acid ethyl ester (5.65 g, 43%) as a yellow solid. MS (EI) 403.1 [(M)+]; mp 243° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:13]([C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][N:22]=2)[C:17]([OH:19])=[O:18])[N:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]1COCC1>>[CH2:1]([O:8][C:9]1[N:13]([C:14]2[CH:15]=[C:16]([C:17]([O:19][CH3:23])=[O:18])[CH:20]=[CH:21][N:22]=2)[N:12]=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: O=C(O)c1ccnc(-n2nccc2OCc2ccccc2)c1
Product: COC(=O)c1ccnc(-n2nccc2OCc2ccccc2)c1
Reaction time: 0.5 h

Procedure:
A solution of compound 2-(5-(benzyloxy)-1H-pyrazol-1-yl)isonicotinic acid (32 mg, 011 mmol, 1.0 eq.) in THF was added CH2N2 (˜10 eq.), the mixture was stirred for 30 min; the solvent was removed to obtain the desired product (25 mg). 1H NMR (400 MHz, CDCl3): δ 3.88 (3H, s), 5.18 (2H, s), 5.69 (1H, s), 7.28-7.39 (5H, m), 7.51 (1H, s), 7.69 (1H, d, J=4.4 Hz), 8.28 (1H, s), 8.65 (1H, s). [M+H] Calc'd for C17H15N3O3, 310; Found, 310.
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:11](=[O:13])[O:10][C:9]([C:14]3[C:15](F)=[N:16][CH:17]=[CH:18][CH:19]=3)=[N:8][C:7]=2[CH:6]=[C:5]([O:21][CH3:22])[CH:4]=1)[CH3:2].C(N(CC)CC)C.[CH3:30][N:31]([CH3:37])[C@H:32]1[CH2:36][CH2:35][NH:34][CH2:33]1>O1CCOCC1>[CH3:30][N:31]([CH3:37])[C@H:32]1[CH2:36][CH2:35][N:34]([C:15]2[C:14]([C:9]3[O:10][C:11](=[O:13])[C:12]4[C:3]([CH2:1][CH3:2])=[CH:4][C:5]([O:21][CH3:22])=[CH:6][C:7]=4[N:8]=3)=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:33]1
Reactant: CCc1cc(OC)cc2nc(-c3cccnc3F)oc(=O)c12
Reactant: CN(C)[C@H]1CCNC1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCc1cc(OC)cc2nc(-c3cccnc3N3CC[C@H](N(C)C)C3)oc(=O)c12
Reaction time: 8 h
Yield: 75.1 %

Procedure:
To a solution of compound S (37.60 g, 125 mmol) and triethylamine (42 mL, 301 mmol) in anhydrous 1,4-dioxane (800 mL) was added dropwise (S)-(−)-3-(dimethylamino)-pyrrolidine (17.1 g, 150 mmol) at room temperature under Ar. The resulting mixture was stirred for 8 hours. The solution was concentrated, and diluted with water (200 mL) and EtOAc (50 mL). The resulting solution was basified to pH 9 with saturated sodium bicarbonate and then extracted with ethyl acetate (3×300 mL). The organic layers were combined and washed with water, brine, and dried over anhydrous Na2SO4 followed by the removal of EtOAc in vacuo. The crude product was purified by column chromatography (Chromatrex NH-DM2035, Fuji Sislysia Chemical Co. Ltd.) using a gradient of 20-25% ethyl acetate/hexanes to yield compound 132 (37.03 g, 73%) as a yellow amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([O-:28])=[O:27])=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.[Na+].C(O)C.S(O[CH:46]([CH3:52])[C:47]([O:49][CH2:50][CH3:51])=[O:48])(C1C=CC(C)=CC=1)(=O)=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([O:28][CH:46]([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH3:52])=[O:27])=[CH:29][CH:30]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)OS(=O)(=O)c1ccc(C)cc1
Reactant: O=C([O-])c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(C)OC(=O)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1

Procedure:
To a warm mixture of 7 g. sodium 4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoate in 100 ml. ethanol is added 4.7 g. ethyl α-tosyloxypropionate. After 17 hours at reflux, the cooled solution is diluted with an equal volume of water and the resultant precipitate is filtered. After washing with cold ethanol and drying, the product is crystallized from acetonitrile to yield 1-(ethoxycarbonyl)ethyl 4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoate as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:15])=O>>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(F)c(F)cc1Cl
Product: O=C(Cl)c1cc(F)c(F)cc1Cl
Yield: 90 %

Procedure:
2-Chloro-4,5-difluorobenzoic acid (19.2 g, 0.1 mol) was mixed with thionyl chloride (50 ml) and heated to reflux for 3 hours. The reaction mixture was evaporated to dryness, and the residue dissolved in methylene chloride. Solvent was removed in vacuo, and the procedure repeated once with methylene chloride and once with benzene. The material (19 g, 0.09 mol, 90% yield) was used without further purification.
Reaction SMILES: [C:1]1([C@H:11]([N:13]([CH2:21][CH:22]2[CH:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:25][NH:24][CH2:23]2)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1>[C:34]1([N:24]2[CH2:25][CH:26]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:22]([CH2:21][N:13]([C@@H:11]([C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)[CH3:12])[C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:19])[CH3:17])[CH2:23]2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Clc1ccccc1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CNCC1c1ccccc1)C(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C[C@H](c1cccc2ccccc12)N(CC1CN(c2ccccc2)CC1c1ccccc1)C(=O)OC(C)(C)C
Temperature: 135 °C
Yield: 33.6 %

Procedure:
In accordance with the techniques of “Journal of Organic Chemistry”, 2001, vol. 66, p. 1403-1412, a mixture of 215 mg of tert-butyl [(1R)-1-(1-naphthyl)ethyl][(4-phenylpyrrolidin-3-yl)methyl]carbamate, 113 mg of chlorobenzene and 3 ml of toluene was mixed with 231 mg of potassium tert-butoxide and heated at 135° C. for 36 hours in a sealed tube. The organic layer was washed with 1 M hydrochloric acid, and the organic layer was dried with anhydrous sodium sulfate and concentrated under a reduced pressure. The thus obtained residue was purified by a silica gel column chromatography (chloroform-methanol) to obtain 85 mg of tert-butyl [(1,4-diphenylpyrrolidin-3-yl)methyl][(1R)-1-(1-naphthyl)ethyl]carbamate as a colorless oily substance. The thus obtained compound was dissolved in 2 ml of ethyl acetate, mixed with 1 ml of 4 M hydrogen chloride/ethyl acetate and stirred at room temperature for 6 hours. The reaction solution was concentrated under a reduced pressure, and the thus precipitated solid was collected by filtration to obtain 30 mg of (1R)—N-[(1,4-diphenylpyrrolidin-3-yl)methyl]-1-(1-naphthyl)ethanamine dichloride as a purple solid.