Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[N:13][C:14]([C:25]3[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=3)=[N:15][C:16]([N:17]3[CH2:23][CH:22]4[O:24][CH:19]([CH2:20][CH2:21]4)[CH2:18]3)=[C:11]2[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.CN.C(N1C2=NC(C3C=C[C:73]([N:76]=[C:77]=[O:78])=CC=3)=NC(N3CC4OC(CC4)C3)=C2C=N1)C1C=CC=CC=1>ClCCl.O1CCCC1>[CH2:1]([N:8]1[C:12]2=[N:13][C:14]([C:25]3[CH:26]=[CH:27][C:28]([NH:29][C:77]([NH:76][CH3:73])=[O:78])=[CH:30][CH:31]=3)=[N:15][C:16]([N:17]3[CH2:18][CH:19]4[O:24][CH:22]([CH2:21][CH2:20]4)[CH2:23]3)=[C:11]2[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C=Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(Cc4ccccc4)c3n2)cc1
Reactant: Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(Cc4ccccc4)c3n2)cc1
Agent: CN
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(Cc4ccccc4)c3n2)cc1

Procedure:
A solution of 4-(1-benzyl-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline (22 mg, 0.05 mmol) in a mixture of dichloromethane (3 mL) and tetrahydrofuran (2 mL) was treated with triphosgene (8 mg, 0.03 mmol) as a solution in dichloromethane (1 mL). After the passage of 5 minutes, the appropriate nucleophile—in the case, 2.0 M methylamine solution in tetrahydrofuran (1 mL)—was added to the 3-(1-benzyl-6-(4-isocyanatophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (“isocyanate”) mixture. The reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography using a Phenomenex Prodigy 21 mm×250 mm column, running a gradient elution of 5% acetonitrile/95% of 0.1% aqueous trifluoroacetic acid to 100% acetonitrile to provide 1-{4-[1-benzyl-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl}-3-methylurea. MS (ES+): 470.0 (M+H)+
Reaction SMILES: ClC1C=CC(C(Cl)=O)=CC=1.Cl[C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[C:19]1[C:24]([C:25]2[NH:26][CH:27]=[CH:28][N:29]=2)=[CH:23][N:22]=[C:21]([NH:30][CH2:31][CH2:32][NH:33][C:34]2[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][N:35]=2)[N:20]=1>>[Cl:18][C:16]1[CH:17]=[CH:12][C:13]([C:19]2[C:24]([C:25]3[NH:26][CH:27]=[CH:28][N:29]=3)=[CH:23][N:22]=[C:21]([NH:30][CH2:31][CH2:32][NH:33][C:34]3[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][N:35]=3)[N:20]=2)=[CH:14][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Agent: O=C(Cl)c1ccc(Cl)cc1
Product: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3)n2)nc1

Procedure:
[4-(4-chlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine was prepared from 4-chlorobenzoyl chloride using the general method for [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:10]=1.I[CH2:22][CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH:23]1([CH2:22][CH:15]([C:11]2[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=2)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CCOC(=O)Cc1cccnc1
Reactant: ICC1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C(CC1CCCC1)c1cccnc1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
LDA (50.1 mL of a 1.5 mmol mL-1 solution in c-C6H12, 7.6 mmol) was added to a stirred solution of ethyl 3-pyridylacetate (1.15 g, 6.9 mmol) in anhydrous THF-HMPA (3:1, 260 mL) at −78° C. After 30 min, iodomethylcyclopentane (1.46 g, 6.9 mmol) was added, then stirring was continued at −78° C. for 4.5 h. The mixture was allowed to warm to 20° C., before being stirred for 16 h. The reaction mixture was carefully quenched with saturated aqueous NH4Cl (20 mL), then H2O (100 mL) was added. The mixture was extracted with EtOAc (3×50 mL), then the extracts were dried (Na2SO4). Filtration, solvent evaporation, and column chromatography (n-C6H4-EtOAc) furnished ethyl 3-cyclopentyl-2-pyridin-3-ylpropionate: m/z (ES+)=248.3 [M+H]+. Step 2: A stirred solution of this compound (0.73 g, 3.0 mmol) in THF (3 mL) was treated with 2M NaOH (3 mL, 6.0 mmol). After 16 h at 20° C., the organic solvent was removed under reduced pressure, then the pH of the remaining solution was adjusted to 6.5, before being extracted with EtOAc. The EtOAc extracts were dried (Na2SO4), filtered, and concentrated to give the title compound: m/z (ES+)=220.2 [M+H]+. Preparation 3: (E)-3-Cyclopentyl-2-(6-methylsulfanylpyridin-3-yl)acrylic Acid
Reaction SMILES: C(Cl)Cl.C(Cl)(Cl)Cl.[C:8](#[N:10])[CH3:9].O1[CH2:15][CH2:14][CH2:13][CH2:12]1.C([N:18]([CH2:21]C)[CH2:19][CH3:20])C>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH:8]1([N:10]=[C:21]=[N:18][CH:19]2[CH2:20][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:9]1
Reactant: C1CCOC1
Reactant: CCN(CC)CC
Reactant: CC#N
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: C(=NC1CCCCC1)=NC1CCCCC1

Procedure:
The resulting compound was then reacted with a compound of formula X--R20, wherein X represents a halogen atom, in an organic solvent, e.g., methylene chloride, chloroform, acetonitrile, tetrahydrofuran, etc., in the presence of an organic base, e.g., pyridine, 4-dimethylamino pyridine, triethylamine, etc., or reacted with a compound of the formula HO-R20 and a catalyst such as dicyclohexylcarbodiimide in the presence of 4-dimethylaminopyridine to obtain the compound of formula (V').
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[CH:3]=1.C(O)(=O)C>CO.[Rh]>[CH:2]1([C:1]([OH:12])=[O:11])[CH2:10][CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3]1
Reactant: O=C(O)c1cccc(C(=O)O)c1
Agent: [Rh]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(O)C1CCCC(C(=O)O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
To a suspension of isophthalic acid (500 g, 3 mol) in methanol (2.8) was added 5% Rhodium-on-alumina catalyst (50 g) and acetic acid (150 ml). The reaction mixture was shaken under hydrogen (50 psi) at room temperature overnight. The mixture was filtered through celite. To this solution was added fresh 5% Rhodium-on-alumina catalyst (25 g), and the mixture was shaken under 50 psi of hydrogen for another 24 hours. The final reaction mixture was filtered through celite. The solution was concentrated under vacuum to give 493 g of the title compound as a white powder (96.3% yield). m.p. 163-165° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[S:11][C:12]([Cl:15])=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19].C=O.[C:25](O)(=O)C.C([BH3-])#N.[Na+]>CO.O>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:9][C:10]2[S:11][C:12]([Cl:15])=[CH:13][CH:14]=2)[CH3:25])[CH:5]=[CH:4][C:3]=1[NH:16][C:17](=[O:22])[C:18]([F:19])([F:20])[F:21]
Reactant: O=C(Nc1ccc(NCc2ccc(Cl)s2)cc1Cl)C(F)(F)F
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN(Cc1ccc(Cl)s1)c1ccc(NC(=O)C(F)(F)F)c(Cl)c1
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a mixture of N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-2,2,2-trifluoroacetamide (3.28 g, 8.88 mmol), 37% aqueous formaldehyde (5 mL), and acetic acid (3 mL), sodium cyanoborohydride (NaBH3CN) (1.1 g) in methanol (10 mL) was added dropwise with stirring during 30 minutes. The reaction mixture was allowed to stand at room temperature for 2 hours and poured into water. After the oil solidified, it was filtered, washed with water and dried in vacuo to give 3.26 g of pale yellow-brown solid. Yield 95%. 1H NMR (DMSO-d6): 2.97 (s, 3H, NMe), 4.72 (s, 2H), 6.82 (m, 1H), 6.91 (m, 2H), 6.97 (d, 1H), 7.21 (d, 1H), 10.92 (br. s, 1H, NHCO). LC/MS (m/z) 382.0 (M+); RT=3.66, (UV, ELSD) 85%, 98%.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH2:15][N:14]([C:16](=[C:33]([CH3:42])[CH2:34][S:35][C:36]2[N:40]([CH3:41])[N:39]=[N:38][N:37]=2)[C:17]([O:19]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:18])[C:13]1=[O:43])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.CCCCCC>C1(OC)C=CC=CC=1>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH2:15][N:14]([C:16](=[C:33]([CH3:42])[CH2:34][S:35][C:36]2[N:40]([CH3:41])[N:39]=[N:38][N:37]=2)[C:17]([OH:19])=[O:18])[C:13]1=[O:43])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(CSc1nnnn1C)=C(C(=O)OC(c1ccccc1)c1ccccc1)N1CC(NC(=O)COc2ccccc2)C1=O
Solvent: CCCCCC
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(CSc1nnnn1C)=C(C(=O)O)N1CC(NC(=O)COc2ccccc2)C1=O
Reaction time: 0.25 h

Procedure:
The product from Example 13 above was dissolved in 1 ml of anisole. At 0° 1 ml of trifluoracetic acid was added. After 15 minutes at 0°, hexane was added. The solvents were removed under reduced pressure. Ether was added to the residue. The resulting slurry was filtered to provide 210 mg (53% from bromo derivative) of the title product: nmr (CDCl3) δ 2.10 and 2.27 (s, 3, CH3), 3.92 (s, 3, N--CH3), 4.3 (m, 2, --CH2S), 3.50 (m, 2, C4 --H), 5.00 (m, 1, C3 --H), 4.50 (s, 2, side chain CH2) and 7.2 (b, ArH).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:14][CH2:15][C:16]([OH:18])=O)=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.P(C#N)(OCC)(OCC)=O.Cl.[NH:30]1[CH2:35][CH2:34][S:33](=[O:37])(=[O:36])[CH2:32][CH2:31]1.C(N(CC)CC)C>O.CN(C)C=O>[NH2:1][C:2]1[S:3][C:4]([CH2:14][CH2:15][C:16]([N:30]2[CH2:35][CH2:34][S:33](=[O:37])(=[O:36])[CH2:32][CH2:31]2)=[O:18])=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=2)[N:6]=1
Reactant: Nc1nc(-c2ccc(Cl)cc2)c(CCC(=O)O)s1
Reactant: O=S1(=O)CCNCC1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1nc(-c2ccc(Cl)cc2)c(CCC(=O)N2CCS(=O)(=O)CC2)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3-[2-amino-4-(4-chlorophenyl)-5-thiazolyl]propionic acid (2.67 g), diethyl cyanophosphate (1.69 g), thiomorpholine-1,1-dioxide hydrochloride (1.62 g), triethylamine (2.9 ml) and N,N-dimethylformamide (40 ml) was stirred at room temperature for 3 hrs. The reaction mixture as poured into water, extracted with ethyl acetate, washed with 0.1N aqueous sodium hydroxide solution and water, dried over anhydrous magnesium sulfate and concentrated. The precipitated solid was collected by filtration to give 4-{3-[2-amino-4-(4-chlorophenyl)-5-thiazolyl]propanoyl}thiomorpholine-1,1-dioxide as a colorless powder. Recrystallization from ethanol-isopropyl ether gave colorless prism crystals. melting point: 220–222° C.
Reaction SMILES: C([O:8][C@H:9]1[CH2:12][C@H:11]([C:13]2[N:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:16]3[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=3[N:14]=2)[CH2:10]1)C1C=CC=CC=1.C1CCCCC=1.CC1C=C2N=C3C(=NC(NC3=O)=O)N(C[C@H](O)[C@H](O)[C@H](O)CO)C2=CC=1C>C(O)C.[Pd]>[OH:8][C@H:9]1[CH2:10][C@H:11]([C:13]2[N:17]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[C:16]3[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=3[N:14]=2)[CH2:12]1
Reactant: CC(C)(C)OC(=O)n1c2ccccc2nc1[C@H]1C[C@H](OCc2ccccc2)C1
Agent: [Pd]
Agent: Cc1cc2nc3c(=O)[nH]c(=O)nc-3n(C[C@H](O)[C@H](O)[C@H](O)CO)c2cc1C
Solvent: CCO
Solvent: C1=CCCCC1
Product: CC(C)(C)OC(=O)n1c2ccccc2nc1[C@H]1C[C@H](O)C1
Temperature: 65 °C

Procedure:
A mixture of tert-butyl 2-(trans-3-(benzyloxy)cyclobutyl)-1H-benzo[d]imidazole-1-carboxylate (0.47 g, 1.23 mmol), cyclohexene (0.080 g, 0.91 mmol), and 20 wt % Pd (dry basis) on carbon, Degussa type E101 NE/W (2.45 g) in ethanol (5 mL) under argon was heated to 65° C. for 6 h, cooled to RT, and filtered through Celite®. The filtrate was concentrated in vacuo and the resulting oil was purified by silica gel chromatography to give tert-butyl 2-(trans-3-hydroxycyclobutyl)-1H-benzo[d]imidazole-1-carboxylate (0.31 g, 1.09 mmol, 88% yield) as a white solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8]([NH2:10])=[S:9].Br[CH2:12][C:13](=O)[C:14]([OH:16])=[O:15]>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8]1[S:9][CH:12]=[C:13]([C:14]([OH:16])=[O:15])[N:10]=1
Reactant: NC(=S)NCc1ccco1
Reactant: O=C(O)C(=O)CBr
Product: O=C(O)c1csc(NCc2ccco2)n1
Yield: 98.2 %

Procedure:
2-[(Furan-2-ylmethyl)-amino]-thiazole-4-carboxylic acid (220 mg) was prepared according to General Procedure B using furan-2-ylmethyl-thiourea (156 mg) and 3-bromo-2-oxo-propionic acid (167 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13]([CH:15]1[CH2:17][CH2:16]1)=[O:14])=[C:5]2[C:18]1[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1.[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH:15]1([C:13]([C:6]2[C:7]([CH3:12])=[N:8][C:9]3[C:4]([C:5]=2[C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[CH:3][C:2]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:11][CH:10]=3)=[O:14])[CH2:17][CH2:16]1
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccc(S(C)(=O)=O)cc2)c1C(=O)C1CC1
Reactant: C1CCNCC1
Product: Cc1nc2ccc(N3CCCCC3)cc2c(-c2ccc(S(C)(=O)=O)cc2)c1C(=O)C1CC1
Yield: 39 %

Procedure:
The title compound was prepared from [6-Bromo-4-(4-methanesulfonyl-phenyl)-2-methyl-quinolin-3-yl]-cyclopropyl-methanone [example 50] and piperidine according to the procedure of example 51. Yield: 39%; MS: m/z=449 (M+H).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:12]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]2[CH:24]=[CH:25][C:26]([Br:28])=[CH:27][C:14]=2[N:13]=1)[CH:9]([CH3:11])[CH3:10])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:17]([N:16]1[C:15]2[CH:24]=[CH:25][C:26]([Br:28])=[CH:27][C:14]=2[N:13]=[C:12]1[CH:8]([NH2:7])[CH:9]([CH3:10])[CH3:11])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)C(NC(=O)OC(C)(C)C)c1nc2cc(Br)ccc2n1Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(N)c1nc2cc(Br)ccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of [1-(1-Benzyl-5-bromo-1H-benzimidazol-2-yl)-2-methyl-propyl]-carbamic acid tert-butyl ester in DCM (2 ml), was added trifluoroacetic acid (0.5 ml). The reaction mixture was stirred at room temperature for 30 minutes. The solvent was removed in vacuo to give the free amine product.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH:11]=O)[CH:6]=[CH:7][CH:8]=1.[C:15]1([C@H:25]([NH2:27])[CH3:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>O.C(O)(=O)C.ClCCl>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][NH:27][C@@H:25]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[CH3:26])[CH:6]=[CH:7][CH:8]=1
Reactant: O=CCCc1cccc(C(F)(F)F)c1
Reactant: C[C@@H](N)c1cccc2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: C[C@@H](NCCCc1cccc(C(F)(F)F)c1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 2.12 g of 3-(3-trifluoromethylphenyl)propanal synthesized in the Step 2, 2.0 ml of (R)-1-(1-naphthyl)ethylamine, 3.42 g of sodium triacetoxyborohydride, and 150 ml of dry dichloromethane was added 0.750 ml of glacial acetic acid, and the mixture was stirred at room temperature for 5 hours. After 100 ml of water had been added and the mixture had been stirred for 3 hours, 100 ml of 2M sodium hydroxide aqueous solution was added, and the resultant was separated into an aqueous layer and an organic layer. The aqueous layer was extracted with dichloromethane, and the extract was combined with the separated organic layer, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified with column chromatography (silica gel/hexane:ethyl acetate of 4:1 to 1:1) and then concentrated to afford 3.41 g of (R)—N-(3-(3-trifluoromethylphenyl)propyl)-1-(1-naphthyl)ethylamine as an oil. The compound was dissolved in 10 ml of dichloromethane, 5 ml of 4M hydrochloric acid/dioxane and 20 ml of toluene were added, and the mixture was concentrated under reduced pressure to pureness. The residue was recrystallized from 40 ml of ethanol and 200 ml of heptane to afford 1.71 g of the captioned compound.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:5][C:6](=[O:25])[C:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH3:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18])[CH3:4].C(O)(=O)C>C(O)C>[CH2:3]([O:5][C:6](=[O:25])[CH:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH3:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18])[CH3:4]
Reactant: CCOC(=O)C(=Cc1ccc(NC)cc1[N+](=O)[O-])C(=O)OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(Cc1ccc(NC)cc1[N+](=O)[O-])C(=O)OCC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91 %

Procedure:
Sodium borohydride (NaBH4) (0.2 g, 5.8 mmol) was added to a slurry of the cinnamic ester (2) (3.4 g, 10.5 mmol) in 100 mL of absolute ethanol and the reaction allowed to stir at room temperature for 1.5 hours. Acetic acid (0.5 mL) was added and the mixture concentrated. The residue was dissolved in 250 mL of CHCl3 and was washed with 100 mL of saturated sodium bicarbonate (NaHCO3) solution, and H2O (100 mL). The organic phase was separated, dried (Na2SO4) and concentrated to produce 3.1 g of an orange solid. An analytical sample was obtained by crystallization from methanol(MeOH)-water, m.p. 75°-77° C.
Reaction SMILES: [K+].[N:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[C:18]([O-:20])=[O:19])=[CH:4][CH:3]=1.CN(C=O)C.Cl[CH2:27][N:28]([CH3:39])[S:29]([C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=1)(=[O:31])=[O:30].O>C1COCC1>[CH3:27][N:28]([CH2:39][O:19][C:18]([C:10]1[NH:11][C:12]2[C:17]([C:9]=1[NH:8][C:5]1[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:20])[S:29]([C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=1)(=[O:30])=[O:31]
Reactant: O=C([O-])c1[nH]c2ccccc2c1Nc1ccncc1
Reactant: Cc1ccc(S(=O)(=O)N(C)CCl)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)N(C)COC(=O)c2[nH]c3ccccc3c2Nc2ccncc2)cc1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 23.2 %

Procedure:
Under N2 at 60° C. dissolve 3-(4-pyridinylamino)-1H-indole-2-carboxylic acid potassium salt (2.0 g, 6.89mmol) in a mixture of anhydrous THF and DMF (60:10 mL Cool to −5° C. add piperidinomethyl polystyrene HL resin (NOVA #01-64-0212, 30 mg) and follow with a solution of N-chloromethyl-N-methyl-4-methylbenzenesulfonamide (1.9 g, 8.34 mmol) in anhydrous THF (10 mL) dropwise. After 30 min, add water (100 mL) and then extract with dichloromethane (3×50 mL). Combine organic layers, wash with NaHCO3 (sat), water, brine, dry with MgSO4 and then concentrate. Purify the residue on an ISCO RediSep 35-gram silicagel cartridge, eluting with 50% heptane/ethyl acetate, ethyl acetate and then 10% methanol/ethyl acetate. Combine product containing fractions and concentrate to a solid (1.1 g). Wash the solid with methanol/ether, and dry to give the title compound as a white solid (720 mg): TLC (silica gel, EtOAc/MeOH, 8:2), Rf=0.49, 1H NMR (DMSO-d6) δ 11.47 (1H, s), 8.32 (1H, s), 8.09 (2H, d, J=5.7 Hz), 7.63 (2H, d, J=8.3 Hz), 7.48 (1H, d, J=8.3 Hz), 7.34 (2H, m), 7.14 (3H, m), 6.52 (2H, d, J=6.0 Hz), 5.61 (2H, s), 2.83 (3H, s), 2.05 (3H, s).
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[N:15]=[CH:16][N:17]([C:19]3[N:24]=[C:23]([CH3:25])[CH:22]=[C:21]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=4)[N:20]=3)[CH:18]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:25][C:23]1[CH:22]=[C:21]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:28][CH:27]=2)[N:20]=[C:19]([N:17]2[CH:18]=[C:14]([C:11]3[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=3)[N:15]=[CH:16]2)[N:24]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(-c3ccc(S(N)(=O)=O)s3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 19.6 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-5-{1-[4-methyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonamide (0.08 g) in dichloromethane (3 mL) was added TFA (3 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (3 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane and dried. Further purification by flash-chromatography on silica gel (ethyl acetate/hexane) and crystallization (diethyl ether) yielded the title compound as a white solid (0.014 g, 3%). MS (ISP) 466.1 [(M+H)+]; mp 277° C.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([N:6]([CH3:17])[S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[N+:20]([O-])([OH:22])=[O:21].O>C(O)(=O)C>[Br:1][C:2]1[CH:19]=[CH:18][C:5]([N:6]([CH3:17])[S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[C:4]([N+:20]([O-:22])=[O:21])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N(C)c2ccc(Br)cc2)cc1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)N(C)c2ccc(Br)cc2[N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 62.7 %

Procedure:
4′-Bromo-N-methyl-p-toluenesulfonanilide (0.90 g (2.65 mmol)) was dissolved in 5.0 ml of acetic acid. To this, 97% fuming nitric acid (0.64 ml (15.0 mmol)) was added dropwise, and the mixture was heated at 100° C. for 1.5 hours with stirring, followed by cooling to room temperature. Then, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate-hexane (1:3) as eluent, to give 0.64 g (63%) of the title compound as pale yellow crystals.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[N:8]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:7]=1.[CH2:21]1[N:26]([C:27]2[CH:28]=[CH:29][C:30]([NH2:33])=[N:31][CH:32]=2)[CH2:25][CH2:24][N:23]2[CH2:34][CH2:35][CH2:36][CH:22]12>>[CH:16]1([N:8]2[C:6]3[N:7]=[C:2]([NH:33][C:30]4[CH:29]=[CH:28][C:27]([N:26]5[CH2:25][CH2:24][N:23]6[CH2:34][CH2:35][CH2:36][CH:22]6[CH2:21]5)=[CH:32][N:31]=4)[N:3]=[CH:4][C:5]=3[CH:10]=[C:9]2[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Nc1ccc(N2CCN3CCCC3C2)cn1
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN5CCCC5C4)cn3)nc2n1C1CCCC1
Yield: 37.2 %

Procedure:
Following general N—C coupling procedure 1, 2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (100 mg, 0.34 mmole) was combined with 5-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pyridin-2-amine (74.6 mg, 0.34 mmole) which gave 7-cyclopentyl-2-(5-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pyridin-2-ylamino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (60 mg) in 37% yield.