Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]1=[O:17].[NH:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[C:27]([C:29]1[CH:34]=[CH:33][C:32]([O:35][C:36]2[C:41](Cl)=[N:40][CH:39]=[CH:38][N:37]=2)=[CH:31][CH:30]=1)=[O:28].C([O-])(=O)C.[K+].O1CCOCC1.O>C(Cl)Cl.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[NH:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[C:27]([C:29]1[CH:34]=[CH:33][C:32]([O:35][C:36]2[C:41]([C:5]3[CH2:6][CH2:7][N:2]([CH3:1])[C:3](=[O:17])[CH:4]=3)=[N:40][CH:39]=[CH:38][N:37]=2)=[CH:31][CH:30]=1)=[O:28]
Reactant: CN1CCC(B2OC(C)(C)C(C)(C)O2)=CC1=O
Reactant: O=C(c1ccc(Oc2nccnc2Cl)cc1)c1nc2ccccc2[nH]1
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: CN1CCC(c2nccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)=CC1=O
Temperature: 100 °C

Procedure:
1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridin-2(1H)-one (0.365 g, 1.539 mmol), (1H-benzo[d]imidazol-2-yl)(4-(3-chloropyrazin-2-yloxy)phenyl)methanone (0.540 g, 1.539 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.076 g, 0.108 mmol), potassium acetate (0.453 g, 4.62 mmol), and 9:1 dioxane-H2O (7.5 mL) were combined in a sealed tube and heated at 100° C. for 3 h. The cooled reaction was diluted with CH2Cl2 and washed with water; the aqueous layer was back-extracted with CH2Cl2 (1×). The organic extracts were combined, dried (MgSO4), filtered, and concentrated in vacuo. Flash column chromatography (1% to 5% MeOH/CH2Cl2) provided a crude crop of the desired product. Further trituration with MeOH afforded 4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)-1-methyl-5,6-dihydropyridin-2(1H)-one as a yellow amorphous solid. [M+1]=426.8. IC50 (uM) +++++.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[C:15](Cl)(=[O:17])[CH3:16]>C(Cl)Cl>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:15](=[O:17])[CH3:16])[CH2:4][CH2:3]1
Reactant: OC1CCNCC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(O)CC1
Temperature: -78 °C
Yield: 79.1 %

Procedure:
4-hydroxypiperidine (0.534 g, 5.3 mmol) was dissolved in methylene chloride (50 mL). The solution was cooled to −78° C. and triethylamine (1.10 mL, 7.95 mmol) was added. Acetyl chloride (0.33 mL, 4.77 mmol) was added dropwise to the mixture. The mixture was warmed to r.t., concentrated under reduced pressure and purified using silica gel chromatography (50% ethyl acetate in hexanes) to give the title compound (0.540 g, 80%) as an oil.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[N:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)[CH:9]=1)=[N+]=[N-].O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1>[CH3:19][S:16]([C:13]1[CH:12]=[CH:11][C:10]([N:8]2[CH:9]=[C:5]([CH2:4][NH2:1])[CH:6]=[N:7]2)=[CH:15][CH:14]=1)(=[O:17])=[O:18]
Reactant: CS(=O)(=O)c1ccc(-n2cc(CN=[N+]=[N-])cn2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)(=O)c1ccc(-n2cc(CN)cn2)cc1
Reaction time: 8 h

Procedure:
To a solution of 4-azidomethyl-1-(4-methanesulfonyl-phenyl)-1H-pyrazole (1.90 g, 7.12 mmol, 1.00 equiv) in 1,4-dioxane (10 mL) was added water (1 mL) and triphenylphosphine resin (2.8 g, 3 mol/g, 200-400 mesh, 1.2 equiv). The suspension was stirred overnight. Filtration and concentration afforded C-[1-(4-methanesulfonyl-phenyl)-1H-pyrazol-4-yl]-methylamine as a colorless solid. LCMS: (MH)+=252.1 (0.55 min). This compound was utilized in the following Example 22.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][N:6]([CH2:8][CH2:9][C@H:10]([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:7])[CH3:2].[C:19]1([C:25]2[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][N:6]([CH2:8][CH2:9][C@H:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[O:17][C:28]1[CH:29]=[CH:30][C:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:26][CH:27]=1)[CH3:7])[CH3:2]
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)CN(C)CC[C@H](O)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CN(C)CC[C@@H](Oc1ccc(-c2ccccc2)cc1)c1ccccc1
Yield: 22 %

Procedure:
prepared by Mitzunobu reaction (analogously to Example 8C, Step 1) of [S]-(−)-N-(3-hydroxy-3-phenylpropyl)sarcosine ethyl ester (from step 1) with 4-phenylphenol (Aldrich)—yield 22%; [α]D25+22.3° (c 8.1, CHCl3). See Reaction 26, FIG. 3.
Reaction SMILES: [NH+]1C=CNC=1.N1([C:11]2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:14]=3[S:13](=[O:25])(=[O:24])[N:12]=2)C=CN=C1.[CH3:26][CH:27]([NH2:31])[CH:28]([CH3:30])[CH3:29]>>[CH3:26][CH:27]([NH:31][C:11]1[NH:16][C:15]2[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:14]=2[S:13](=[O:24])(=[O:25])[N:12]=1)[CH:28]([CH3:30])[CH3:29]
Reactant: O=[N+]([O-])c1ccc2c(c1)S(=O)(=O)N=C(n1ccnc1)N2
Reactant: CC(C)C(C)N
Agent: c1c[nH+]c[nH]1
Product: CC(C)C(C)NC1=NS(=O)(=O)c2cc([N+](=O)[O-])ccc2N1

Procedure:
3-(Imidazol-1-yl)-7-nitro-4H-1,2,4-benzothiadiazine 1,1-dioxide imidazolium salt was treated with 1,2-dimethylpropylamine according to the general procedure Method B to give the title compound; m.p. 308-311° C.; IR (KBr): 3294, 3199, 3101, 2965, 1636, 1600, 1566, 1538, 1497, 1485, 1349, 1252, 1166, 1153, 1107 cm−1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH:11]1[CH2:17][CH:16]2[N:18]([CH3:19])[CH:13]([CH2:14][CH2:15]2)[CH2:12]1)=O.[ClH:20].[NH2:21][OH:22].C([O-])(=O)C.[NH4+]>C(O)C.O>[ClH:20].[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[C:9](/[CH:11]1[CH2:17][CH:16]2[N:18]([CH3:19])[CH:13]([CH2:14][CH2:15]2)[CH2:12]1)=[N:21]\[OH:22]
Reactant: CN1C2CCC1CC(C(=O)c1ccc(F)cc1F)C2
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CN1C2CCC1CC(/C(=N/O)c1ccc(F)cc1F)C2

Procedure:
A mixture of (2,4-difluorophenyl)(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)methanone (20 g), hydroxylamine hydrochloride (10.6 g) and ammonium acetate (18.7 g) was heated in 67.5 ml of refluxing ethanol-water (3.2 mixture) for 19 hours. The mixture was concentrated to approximately half of its original volume, and the precipitated solid (21.3 g) was collected.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[C:8]([O:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:9]=2)[CH2:4][O:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[OH:3][CH2:4][C:5]1[C:10]([CH2:2][OH:1])=[CH:9][C:8]([O:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[C:7]([O:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:6]=1
Reactant: CC(C)(C)OC(=O)NCCOc1cc2c(cc1OCCNC(=O)OC(C)(C)C)C(=O)OC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCOc1cc(CO)c(CO)cc1OCCNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
A solution of compound 26 (5.00 g, 11.0 mmol) in THF (50 mL) was charged with lithium aluminum hydride (1 M solution in diethyl ether, 33.2 mL, 33.2 mmol) at 0° C. The resulting reaction mixture was stirred at 0° C. for 1 h and quenched with ice-cold water at 0° C. The reaction mixture was diluted with chloroform (300 mL) and filtered through a Celite pad, and the Celite pad was washed with chloroform (2×300 ml). The filtrate was concentrated under vacuum to afford 27 (4.50 g, 90%) as a colorless gum: 1H NMR (400 MHz, DMSO-d6) δ 6.99 (s, 2H), 6.90 (t, J=5.9 Hz, 2H), 4.97 (brs, 2H), 4.44 (s, 4H), 3.92 (t, J=5.6 Hz, 4H), 3.30-3.22 (m, 4H), 1.38 (s, 18H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([NH2:35])=[N:5][C:6]2([C:21]1[CH:26]=[CH:25][C:24]([O:27]C)=[C:23]([C:29]2[CH:34]=[N:33][CH:32]=[CH:31][N:30]=2)[CH:22]=1)[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1.B(Br)(Br)Br.O.N>C(Cl)Cl>[NH2:35][C:4]1[C:3]2[C:7](=[CH:8][CH:9]=[CH:10][C:2]=2[F:1])[C:6]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([C:29]3[CH:34]=[N:33][CH:32]=[CH:31][N:30]=3)[CH:22]=2)([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([C:17]([F:20])([F:18])[F:19])[CH:12]=2)[N:5]=1
Reactant: COc1ccc(C2(c3ccnc(C(F)(F)F)c3)N=C(N)c3c(F)cccc32)cc1-c1cnccn1
Agent: BrB(Br)Br
Agent: N
Solvent: O
Solvent: ClCCl
Product: NC1=NC(c2ccnc(C(F)(F)F)c2)(c2ccc(O)c(-c3cnccn3)c2)c2cccc(F)c21
Temperature: 0 °C
Reaction time: 1 h
Yield: 33.2 %

Procedure:
To a solution of 4-fluoro-1-(4-methoxy-3-(pyrazin-2-yl)phenyl)-1-(2-(trifluoromethyl) pyridin-4-yl)-1H-isoindol-3-amine (0.65 g, 1.36 mmol) in DCM (12.5 ml), boron tribromide (0.718 ml, 4.20 mmol) was added dropwise at 0° C. The mixture was stirred at 0° C. for 1 hour and then allowed to reach room temperature. Water (5 ml) was added and the pH was adjusted to approx 8 with aqeuous conc. NH3. The organic phase was separated and aqueous phase was extracted with DCM (20 mL). The combined organic phases were passed through a phase separator (Sorbent) and concentrated under reduced pressure. The residue was purified twice by preparative chromatography to give the title compound (210 mg, 32%).
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C@@H:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][CH2:12][CH2:11]4)[C@@H:6]1[CH2:5][CH2:4][C@@H:3]2[NH2:20].C(O)(=O)C.C([BH3-])#N.[Na+].[CH:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CO.O1CCCC1>[CH2:29]([NH:20][C@H:3]1[CH2:4][CH2:5][C@H:6]2[C@H:7]3[C@H:17]([CH2:18][CH2:19][C@:2]12[CH3:1])[C@:15]1([CH3:16])[C@H:10]([CH2:11][CH2:12][CH2:13][CH2:14]1)[CH2:9][CH2:8]3)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: C[C@]12CCCC[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](N)CC[C@@H]12
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C[C@]12CCCC[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](NCc3ccccc3)CC[C@@H]12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
5α-Androstan-17β-amine (10.946 g), glacial acetic acid (2.39 g), sodium cyanoborohydride (0.50 g), benzaldehyde (0.84 g) and tetrahydrofuran (50 ml) were added to methanol (25 ml). The resulting mixture was stirred at room temperature for 48 hours. Excess solvent was removed under reduced pressure. Water was added and made basic (pH 9) with 50% aqueous NMaOH. The mixture was extracted with ether (3X). The combined extracts were dried, filtered and concentrated to a solid. The solid was mixed with 20 g of flash silica gel and dissolved in ethyl acetate. The solvent was removed at reduced pressure and the silica gel was poured on top of the chromatographic column. The compound was eluted with 5% triethylamine-ethylacetate. 6 fractions (200 ml) were collected. An oil was obtained and was dissolved in hot methanol. The solution was cooled giving colorless crystals, mp 85.5°-87.5° C. (PLA2, diabetes)
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][N:18]=2)[C:12]([O:14][CH3:15])=[O:13])=[C:5]([F:19])[CH:4]=1>CO.[Pt](=O)=O>[ClH:2].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH:11]([C:12]([O:14][CH3:15])=[O:13])[CH2:16][CH2:17][NH:18]2)=[C:5]([F:19])[CH:4]=1
Reactant: COC(=O)c1ccnc(-c2ccc(Cl)cc2F)c1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: COC(=O)C1CCNC(c2ccc(Cl)cc2F)C1
Reaction time: 1 h
Yield: 201.2 %

Procedure:
Methyl 2-(4-chloro-2-fluorophenyl)isonicotinate hydrochloride (7.26 g, 24.03 mmol) was dissolved in MeOH (100 mL) and platinum(IV) oxide (0.546 g, 2.40 mmol) added. The resulting mixture was hydrogenated in a Büchi hydrogenator at room temperature and 5 bar for 1 h. The catalyst was filtered off and washed with MeOH and the eluate evaporated yielding methyl 2-(4-chloro-2-fluorophenyl)piperidine-4-carboxylate hydrochloride (7.45 g, quant.) as a brown solid. MS m/z 272 (M+H)+
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][O:24][CH3:25])=[C:18]([O:26][CH2:27][O:28][CH3:29])[CH:17]=2)=[CH:10][CH:9]=1)=O)C.[NH2:31][NH2:32]>CCO>[CH3:29][O:28][CH2:27][O:26][C:18]1[CH:17]=[C:16]([CH:15]=[CH:14][C:11]2[CH:10]=[CH:9][C:8]([C:6]3[CH2:5][C:4](=[O:3])[N:31]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[N:32]=3)=[CH:13][CH:12]=2)[CH:21]=[CH:20][C:19]=1[O:22][CH2:23][O:24][CH3:25]
Reactant: CCOC(=O)CC(=O)c1ccc(C=Cc2ccc(OCOC)c(OCOC)c2)cc1
Reactant: NN
Solvent: CCO
Product: COCOc1ccc(C=Cc2ccc(C3=NN(c4ccccc4)C(=O)C3)cc2)cc1OCOC

Procedure:
A solution of 3-{4-[2-(3,4-bis-methoxymethoxy-phenyl)-vinyl]-phenyl}-3-oxo-propionic acid ethyl ester (400 mg) and hydrazine (excess) in EtOH (30 mL) was stirred at 90° C. for 5 hours. Evaporation and purification by flash chromatography eluted with 5-10% MeOH in DCM gave 5-{4-[2-(3,4-bis-methoxymethoxy-phenyl)-vinyl]-phenyl}-2-phenyl-2,4-dihydro-pyrazol-3-one as a yellow oil (260 mg). 1H NMR (CDCl3, 300 MHz): 7.95 (d, J=8.7 Hz, 2H), 7.62 (d, J=8.7 Hz, 2H), 7.40-7.00(m, 7H), 6.90 (d, 1H), 6.58 (d, J=12.0 Hz, 1H), 6.50 (d, J=12.0 Hz, 1H) 5.21, 5.07(2s, 4H, MOM), 3.78(s, 2H), 33.51, 3.41 (2s, 6H, MOM) ppm. 13C NMR (CDCl3, 75 MHz 170.65, 154.82, 147.23, 147.15, 140.38, 138.53, 131.56, 129.84, 129.68, 129.29, 128.88, 126.17, 125.69, 123.72, 119.42, 117.83, 116.67, 56.69, 56.52, 40.03 ppm. MS: 459 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:10])[C@H:7]([CH3:9])[NH2:8])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C([O-])=O.[CH2:17]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([CH2:33][CH2:34][CH2:35][CH2:36][C:37](=O)[C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:29][CH2:28]1)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])(=O)C.[Na+].C([BH3-])#N.[Na+]>C(O)C.O.C(O)(=O)C>[C:1]([O:5][C:6](=[O:10])[C@H:7]([CH3:9])[NH:8][C@@H:37]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:36][CH2:35][CH2:34][CH2:33][CH:30]1[CH2:31][CH2:32][N:27]([C:25]([O:24][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:26])[CH2:28][CH2:29]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Reactant: CCOC(=O)C(=O)CCCCC1CCN(C(=O)OCc2ccccc2)CC1
Agent: CC(=O)[O-]
Agent: O=C([O-])C(=O)[O-]
Agent: [BH3-]C#N
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)[C@@H](CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@@H](C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.5 %

Procedure:
A mixture of 5 g of L-alanine tert-butyl ester.oxalate, 11 g of ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-oxohexanoate, 1.6 g of sodium acetate, 1.2 g of acetic acid and 100 ml of ethanol is stirred at room temperature for 1 hour, and a solution of 1.9 g of sodium cyanoborohydride in 100 ml of ethanol is added dropwise to the mixture over a period of 4 hours. After stirring at room temperature overnight, 500 ml of water is added to the reaction mixture, and the mixture is extracted with 300 ml of ethyl acetate. The extract is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is separated and purified by silica gel column chromatography (hexane:acetone=4:1), whereby the first fraction yields 1.7 g of N-[(R)-5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl]-L-alanine tert-butyl ester as a colorless oil.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:18]3[S:25][C:24]([C:26]#[N:27])=[CH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:13][CH2:12]1)=[O:10])(C)(C)C.[ClH:37]>C(Cl)Cl.O1CCOCC1>[ClH:35].[ClH:37].[NH2:7][CH:8]([CH2:28][C:29]1[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=1)[C:9]([N:11]1[CH2:12][CH2:13][N:14]([C:17]2[C:18]3[S:25][C:24]([C:26]#[N:27])=[CH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:15][CH2:16]1)=[O:10]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3cc(C#N)sc23)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: N#Cc1cc2ncnc(N3CCN(C(=O)C(N)Cc4ccc(Cl)cc4)CC3)c2s1
Temperature: 25 °C
Reaction time: 10 h
Yield: 44 %

Procedure:
To a solution of {1-(4-chlorobenzyl)-2-[4-(6-cyanothieno[3,2-d]pyrimidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester in DCM (4 mL) was added HCl in Dioxane (4M, 1 mL). The mixture was stirred at room temperature for 10 hours. The solvent was removed and the residue was subject to purification by HPLC to afford the product 4-{4-[2-Amino-3-(4-chlorophenyl)-propionyl]-piperazin-1-yl}-thieno[3,2-d]pyrimidine-6-carbonitrile dihydrochloride (12 mg, 44%). MS (ESI+) [M+H]+ 427.
Reaction SMILES: [N:1]1([C@@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][O:24][C:25]1[CH:26]=[CH:27][C:28]2[CH:32]=[C:31]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][N:42]4[CH2:46][CH2:45][CH2:44][CH2:43]4)=[CH:35][CH:34]=3)[S:30][C:29]=2[CH:47]=1.[Br-].[Al+3].[Br-].[Br-]>S(Cl)(Cl)=O.CN(C=O)C>[N:1]1([C@@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([C:32]3[C:28]4[CH:27]=[CH:26][C:25]([O:24][CH3:23])=[CH:47][C:29]=4[S:30][C:31]=3[C:33]3[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][N:42]4[CH2:46][CH2:45][CH2:44][CH2:43]4)=[CH:35][CH:34]=3)=[O:19])=[CH:16][CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc2cc(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Reactant: O=C(O)c1ccc(O[C@@H]2CCCC[C@H]2N2CCCCC2)cc1
Agent: [Al+3]
Agent: [Br-]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc2c(C(=O)c3ccc(O[C@@H]4CCCC[C@H]4N4CCCCC4)cc3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
1.698 g (5.60 mmol) of 4-[[trans-2-(1-piperidyl)cyclohexyl]oxy]benzoic acid (Part C) was dissolved in 30 mL of thionyl chloride at room temperature. To this was added 434 μL (5.60 mmol) of DMF as a catalyst. The mixture was stirred for 3 days at room temperature. The thionyl chloride was removed under reduced pressure and the residue was treated with dry benzene to remove azeotropically the residual thionyl chloride and then placed under high vacuum. The crude acid chloride was suspended in 50 mL of anhydrous dichloroethane, and to this was added 1.799 g (5.09 mmol) of 6-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene (Example 1, Part B). After cooling the slurry to 0° C., aluminum bromide (6.79 g, 25.4 mmol) was added, producing a dark red mixture. The ice bath was removed and the reaction mixture was stirred at room temperature for 6 h. The mixture was poured into 100 mL of cooled (0° C.) 2.0 N NaOH. The aqueous layer was extracted with EtOAc (3×400 mL). The combined organic layers were washed with 300 mL of brine, dried over MgSO4, and concentrated under reduced pressure. The crude product was purified using PrepLC (8% of (10% concd NH4OH in MeOH) in CH2Cl2).
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C:19]1[C:28]2[N:29]=[C:30]([CH2:37][CH2:38][CH2:39][CH3:40])[N:31]([CH2:32][CH2:33][CH2:34][CH2:35][NH2:36])[C:27]=2[C:26]2[N:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:20]=1>>[NH2:18][C:19]1[C:28]2[N:29]=[C:30]([CH2:37][CH2:38][CH2:39][CH3:40])[N:31]([CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:13](=[O:15])[C:12]3[CH:11]=[CH:10][C:9]([C:1](=[O:8])[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:17][CH:16]=3)[C:27]=2[C:26]2[N:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:20]=1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCN
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2)cc1
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCNC(=O)c1ccc(C(=O)c2ccccc2)cc1
Yield: 18 %

Procedure:
Using the general method of Example 112 Part B, 4-benzoylbenzoic acid (72 mg, 0.32 mmole) was reacted with 4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine (100 mg, 0.32 mmol) to provide 30 mg of N1-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-4-benzoylbenzamide as a white solid. Mass-spec (M+1=521.31).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([F:13])([F:12])[O:9]C(F)(F)[C:7]=2[CH:16]=1.[C-:17]#[N:18].[Na+]>CS(C)=O>[F:13][C:10]1([F:12])[O:11][C:6]2[CH:5]=[CH:4][C:3]([CH2:2][C:17]#[N:18])=[CH:16][C:7]=2[O:9]1
Reactant: [C-]#N
Reactant: FC1(F)Oc2ccc(CCl)cc2C(F)(F)O1
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCc1ccc2c(c1)OC(F)(F)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.5 %

Procedure:
A mixture of 6-chloromethyl-2,2,4,4-tetrafluoro-4H-benzo[1,3]dioxine (6.2 g) and NaCN (2.07 g, 42.3 mmol) in DMSO (50 mL) was stirred at room temperature for 2 h. The reaction mixture was poured into ice and extracted with EtOAc (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4, and evaporated to give a crude product, which was purified by silica gel column (Petroleum Ether/EtOAc 10:1) to give (2,2-difluoro-benzo[1,3]dioxol-5-yl)-acetonitrile (4.5 g, 68% over 3 steps). 1H NMR (CDCl3, 300 MHz) δ 7.57-7.60 (m, 2H), 7.20 (d, J=8.7 Hz, 1H), 3.82 (s, 2H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[S:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[CH2:11]([Li])[CH2:12][CH2:13][CH3:14]>[Cl-].[Zn+2].[Cl-].C1COCC1>[O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[NH:8]1[C:9]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:2]=[CH:7]1.[S:6]1[CH:10]=[CH:9][N:8]=[CH:7]1
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [Zn+2]
Agent: c1cocn1
Solvent: C1CCOC1
Product: c1ccc2[nH]ccc2c1

Procedure:
Alternatively, iodo indole 5 is reacted with an alkyl halide, for example as propyl or butyl iodide, bromide, or chloride in the presence of a base, for example sodium hydride or potassium tert-butoxide, more preferably potassium tert-butoxide, in an organic solvent, for example THF, DMF or DMSO, preferrably DMSO, at a temperature from room temperature to about 100° C., to yield iodo alkyl 9. An Oxazole or a thiazole in an organic solvent, for example dialkyl ether or THF, at a temperature from about 0 to about −78° C. is reacted with a base, preferably butyl lithium and optionally left stirring for from about 15 to about 60 min. Zinc chloride is then added and the mixture is allowed to warm to 0–30° C., at which time iodo alkyl 9 is added, followed by tetrakis triphenylphosphine palladium. The mixture is then optionally left stirring at a temperature from room temperature to about 80° C. to yield oxazole/thiazole indole 10.The hydrolysis of 10 by methods known to those skilled in the art yields oxazole/thiazole acid 11. Oxazole/thiazole acid 11 is coupled to amine (VIII) using methods known to those skilled in the art.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:18]=[C:17]([C:19]([OH:21])=O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.Cl.[OH:24][C:25]1[C:34]([CH3:35])=[CH:33][CH:32]=[C:31]2[C:26]=1[CH2:27][CH2:28][NH:29][CH2:30]2>>[CH3:1][N:2]([CH3:22])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:18]=[C:17]([C:19]([N:29]3[CH2:28][CH2:27][C:26]4[C:31](=[CH:32][CH:33]=[C:34]([CH3:35])[C:25]=4[OH:24])[CH2:30]3)=[O:21])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:7][CH:8]=1
Reactant: Cc1ccc2c(c1O)CCNC2
Reactant: CN(C)c1ccc(-c2nc(C(=O)O)c3ccccc3n2)cc1
Agent: Cl
Product: Cc1ccc2c(c1O)CCN(C(=O)c1nc(-c3ccc(N(C)C)cc3)nc3ccccc13)C2
Yield: 39 %

Procedure:
Reaction of 2-(4-(dimethylamino)phenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 36 (39% yield) as a brown solid. 1H NMR (300 MHz, CDCl3) δ2.25 and 2.28 (2s, 3H), 2.81 and 3.03 (2t, 2H), 3.12 (s, 6H), 3.61 and 4.21 (2t, 2H), 4.50 and 5.08 (2s, 2H), 4.69 and 4.77 (2s, 1H), 6.36-7.09 (m, 4H), 7.48-7.56 (m, 1H), 7.88-7.98 (m, 2H), 8.20-8.23 (m, 1H), 8.56-8.61 (m, 2H); MS (ESI) m/z 439 ([M+H]+).