Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:21][C:10]3([CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]3)[CH2:9]2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[I:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][C:10]3([CH2:13][NH:12][CH2:11]3)[CH2:21]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC2(C1)CN(c1ccc(I)cc1)C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Ic1ccc(N2CC3(CNC3)C2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
tert-Butyl 6-(4-iodophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (2.14 g, 5.35 mmol) was dissolved in DCM (10 mL) and cooled to 0° C. TFA (5 mL) was added and then reaction was stirred at 0° C. for 30 min, warmed up to rt and stirred for 1 h. The mixture was concentrated under reduced pressure and purified using a Waters PoraPak Rxn CX 20 cc 2 g cartridge to give the title compound as a white solid (1.51 g, 94%). 1H NMR (400 MHz, CDCl3) 8 ppm 7.45 (d, J=8.5 Hz, 2H), 6.22 (d, J=8.5 Hz, 2H), 3.94 (s, 4H), 3.80 (s, 4H), 1.66 (br. s., 1H); MS ESI 301.0 [M+H]+, calcd for [C11H13IN2+H]+ 301.0.
Reaction SMILES: [Br-:1].[Li+].CS(O[CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=O)=O>O1CCCC1>[Br:1][CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: [Br-]
Reactant: CC(C)(C)OC(=O)NCCOS(C)(=O)=O
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCBr
Temperature: 23 °C
Reaction time: 18 h
Yield: 95.8 %

Procedure:
Lithium bromide (136 g, 1.56 mol.) was dissolved in tetrahydrofuran (600 mL) at 0° C. The mixture was allowed to warm to 23° C. and then tert-butyl 2-methylsulfonyloxyethylcarbamate (37.39 g, 156 mmol) was added dropwise. The mixture was stirred at 23° C. for 18 hours and concentrated in vacuo. The residue was dissolved in hexanes and the organic layer was washed with water and brine, dried (Na2SO4) and concentrated in vacuo to provide tert-butyl 2-bromoethylcarbamate (33.48 g, 96% yield) as a brown oil; MS (PB-PCI) C7H14BrNO2 m/e calc 224.10; found 225 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[C:23]1([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:32]2[CH2:33][CH2:34][N:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:30][CH2:31]2)=[O:22])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1nc2ccccc2nc1NC(=O)Oc1ccccc1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1nc2ccccc2nc1NC(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.5 %

Procedure:
Phenyl N-(2-methoxyquinoxalin-3-yl)carbamate (378 mg, 1.28 mmol) and 1-phenylpiperazine (208 mg, 1.28 mmol) were dissolved in anhydrous tetrahydrofuran and thereto DBU (195 mg, 1.28 mmol) was added. The mixture was stirred at room temperature for 2 hours, concentrated under the reduced pressure to remove the solvent, and purified by column chromatography to obtain the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[CH:6]([N:15]3[CH2:20][CH2:19][N:18]([C:21](SC)=[N:22][C:23]#[N:24])[CH2:17][CH2:16]3)[C:7]3[C:12]([CH2:13][S:14][C:4]=2[CH:3]=1)=[CH:11][CH:10]=[CH:9][N:8]=3.[O:29]1[C:33]2[CH:34]=[CH:35][C:36]([CH2:38][NH2:39])=[CH:37][C:32]=2[O:31][CH2:30]1>O.C(Cl)Cl>[O:29]1[C:33]2[CH:34]=[CH:35][C:36]([CH2:38][NH:39][C:21]([N:18]3[CH2:19][CH2:20][N:15]([CH:6]4[C:7]5=[N:8][CH:9]=[CH:10][CH:11]=[C:12]5[CH2:13][S:14][C:4]5[CH:3]=[C:2]([Cl:1])[CH:28]=[CH:27][C:5]4=5)[CH2:16][CH2:17]3)=[N:22][C:23]#[N:24])=[CH:37][C:32]=2[O:31][CH2:30]1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: CSC(=NC#N)N1CCN(C2c3ccc(Cl)cc3SCc3cccnc32)CC1
Solvent: ClCCl
Solvent: O
Product: N#CN=C(NCc1ccc2c(c1)OCO2)N1CCN(C2c3ccc(Cl)cc3SCc3cccnc32)CC1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
Methyl 4-(8-chloro-5,11-dihydro-[1]benzothiepino[4,3-b]pyridin-11-yl)-N-cyano-1-piperazine-carboximidothioate (184 mg, 0.428 mmol) was combined with 1 ,3-benzodioxol-5-ylmethylamine [piperonylamine] (1.07 ml, 8.56 mmol) in a 10 ml flask, and the mixture was stirred at 100° C. for three hours. The reaction mixture was cooled to room temperature and diluted with water and CH2Cl2. The layers were shaken together and separated, and the aqueous extract was extracted several times with CH2Cl2. The combined organic layers were washed with brine, dried (MgSO4), filtered through `Celite` and concentrated. The residue (over 2 g) was first filtered through a plug of silica gel and eluted with 15%acetone/CH2Cl2), and then further chromatographed more carefully and eluted with 2%EtOH/CH2Cl2, increasing gradually to 40%EtOH/CH2Cl2, to afford the pure product, 155 mg (68%); MS (FAB, M+H)=533.6.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=4)=[CH:22][CH:21]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:37][CH3:38])C1C=CC=CC=1.C(N(CC)CC)C.[H][H]>CN(C)C=O.[OH-].[Pd+2].[OH-]>[C:33]([C:30]1[CH:29]=[CH:28][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([O:19][C:13]3[C:12]4[C:17](=[CH:18][C:9]([OH:8])=[C:10]([O:37][CH3:38])[CH:11]=4)[N:16]=[CH:15][CH:14]=3)=[CH:21][CH:22]=2)=[CH:32][CH:31]=1)([CH3:36])([CH3:34])[CH3:35]
Reactant: COc1cc2c(Oc3ccc(Nc4ccc(C(C)(C)C)cc4)cc3)ccnc2cc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(Nc4ccc(C(C)(C)C)cc4)cc3)ccnc2cc1O
Yield: 62.4 %

Procedure:
[4-(7-Benzyloxy-6-methoxy-4-quinolyloxy)phenyl](4-tert-butylphenyl)amine (starting compound 2) (400 mg) was dissolved in N,N-dimethylformamide (10 ml) to prepare a solution. Triethylamine (2 ml) and 20% palladium hydroxide (0.58 g) were then added to the solution, and the mixture was stirred in a hydrogen atmosphere at room temperature overnight. The insolubles were removed by filtration, and the solvent was then removed by evaporation under the reduced pressure. Water and ethyl acetate were added to the crude, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and was dried over sodium sulfate. The solvent was removed by evaporation under the reduced pressure, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (205 mg, yield 62%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]([NH:24][O:25]C4CCCCO4)=[O:23])=[CH:17][CH:18]=3)[CH2:13]2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.Cl>[OH:25][NH:24][C:22]([C:16]1[CH:15]=[C:14]2[C:19]([CH2:20][CH2:21][N:12]([C:10]([NH:9][CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:11])[CH2:13]2)=[CH:18][CH:17]=1)=[O:23]
Reactant: O=C(NOC1CCCCO1)c1ccc2c(c1)CN(C(=O)NCCc1ccccc1)CC2
Agent: Cl
Solvent: CO
Product: O=C(NO)c1ccc2c(c1)CN(C(=O)NCCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.1 %

Procedure:
A mixture of 200 mg N2-(2-phenylethyl)-N7-(tetrahydro-2H-pyran-2-yloxy)-3,4-dihydroisoquinoline-2,7(1H)-dicarboxamide in 6 ml methanol and 6 ml 0.1 N aqueous hydrochloric acid is stirred overnight at ambient temperature. Subsequently, the reaction mixture is evaporated. The residue is dissolved in a mixture of water and acetonitrile and lyophilized. The crude product is further purified by silica gel flash chromatography. 98 mg of the title compound are obtained. MH+=340.1
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:9]2[N:10]([CH:15]=[CH:16][N:17]=2)[N:11]=[C:12]([Cl:14])[CH:13]=1)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[Cl:14][C:12]1[CH:13]=[C:8]([NH2:7])[C:9]2[N:10]([CH:15]=[CH:16][N:17]=2)[N:11]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)nn2ccnc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cc(Cl)nn2ccnc12
Yield: 110.4 %

Procedure:
A solution of (6-chloro-imidazo[1,2-b]pyridazin-8-yl)-carbamic acid tert-butyl ester (1.59 g, 5.91 mmol) in 30 mL of dichloromethane and 15 mL of trifluoroacetic acid was stirred for 5 h then concentrated to a yellow oil, which was treated (slowly) with 50 mL of a saturated aq. NaHCO3 solution. Undissolved solid was isolated by Buchner filtration, rinsing well with water and dried by sucking air through then in vacuo to afford 1.10 g (102% crude) of 6-chloro-imidazo[1,2-b]pyridazin-8-ylamine as a yellow solid that was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17]OS(C)(=O)=O)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)=[O:4].[C:23]([N:27]1[C:31](=[O:32])[CH2:30][CH:29]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][SH:40])=[CH:35][CH:34]=2)[S:28]1(=[O:42])=[O:41])([CH3:26])([CH3:25])[CH3:24]>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[CH:13][C:14]([CH2:17][S:40][CH2:39][C:36]3[CH:35]=[CH:34][C:33]([CH:29]4[S:28](=[O:41])(=[O:42])[N:27]([C:23]([CH3:25])([CH3:24])[CH3:26])[C:31](=[O:32])[CH2:30]4)=[CH:38][CH:37]=3)=[CH:15][CH:16]=2)=[CH:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1ccc(-c2ccc(COS(C)(=O)=O)cc2)cc1
Reactant: CC(C)(C)N1C(=O)CC(c2ccc(CS)cc2)S1(=O)=O
Product: COC(=O)c1ccc(-c2ccc(CSCc3ccc(C4CC(=O)N(C(C)(C)C)S4(=O)=O)cc3)cc2)cc1

Procedure:
This compound was prepared according to the procedure of Example 1.35, Step 4, using 4.17-A of Step 1 and 4.15-F of Example 4.15, Step 6 as the starting materials. LCMS found for C29H32NO5S2 (M+H)+: m/z=538.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2OCC[O:9]2)[S:5][C:6]=1[F:7].Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[S:5][C:6]=1[F:7]
Reactant: Fc1cc(C2OCCO2)sc1F
Agent: Cl
Solvent: C1CCOC1
Product: OCc1cc(F)c(F)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.5 %

Procedure:
A mixture of 2-(4,5-difluoro-2-thienyl)-1,3-dioxolane (586 mg), THF (10 ml) and 6 M HCl (1 ml) was stirred at ambient temperature for 1 h. The mixture was quenched with saturated NaHCO3 solution and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc). The resulting oil was dissolved in THF (10 ml), and NaBH4 (48.5 mg) and MeOH (0.1 ml) were added to the solution at room temperature. After the mixture was stirred at room temperature for 15 min, the mixture was poured into saturated NH4Cl solution and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (190 mg) as a mixture with (4-bromo-2-thienyl)methanol and (4-bromo-5-fluoro-2-thienyl)methanol.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]([NH2:11])=[N:7][CH:8]=[CH:9][CH:10]=2)[CH2:3][CH2:2]1.[C:12](N1C=CN=C1)(N1C=CN=C1)=[O:13]>O1CCOCC1.CCOC(C)=O>[CH:1]1([N:4]2[C:5]3[C:6](=[N:7][CH:8]=[CH:9][CH:10]=3)[NH:11][C:12]2=[O:13])[CH2:3][CH2:2]1
Reactant: Nc1ncccc1NC1CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=c1[nH]c2ncccc2n1C1CC1
Temperature: 60 °C

Procedure:
To a solution of N3-cyclopropylpyridine-2,3-diamine (1.0 g, 6.70 mmol) in dioxane (13.41 ml) was added 1,1′-carbonyldiimidazole (Acros Organics, 1.630 g, 10.05 mmol). The resulting mixture was heated to 60° C. for 2 h. The reaction mixture was diluted with EtOAc and washed with water. The organic layer was loaded onto a Biotage samplet and purified (0-100% EtOAc/hexane, 25G biotage column) to afford product that solidified upon rotovap. Material was advanced to the next step. M+1: 176.0.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1)([O-])=O.Cl.O>[Pd].CO>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1
Reactant: CN1CCC(c2n[nH]c3ccc([N+](=O)[O-])cc23)CC1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: CN1CCC(c2n[nH]c3ccc(N)cc23)CC1
Reaction time: 24 h
Yield: 103 %

Procedure:
A mixture of 5-nitro-3-(1-methylpiperidin-4-yl)-1H-indazole (287 mg, 1.1 mmol), 5N aqueous hydrochloric acid (0.5 mL), water (5 ml), and methanol (15 mL) was warmed to give a homogeneous solution. Palladium (86 mg, 5% on carbon) was added to the solution and the resulting mixture was stirred under an atmosphere of hydrogen gas for 24 hours. The palladium catalyst was filtered and the filtrate was concentrated in vacuo. The residue was slurried in methylene chloride and 5N aqueous sodium hydroxide then extracted with chloroform/isopropanol (3:1). The organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to give 261 mg of a light brown foam. Purification by radial chromatography (silica gel, 2000 micron rotor, methylene chloride:methanol:ammonium hydroxide, 100:10:1) gave 223 mg (87.8%) of a brown oil. The product was crystallized as the dihydrochloride salt. EA calculated for C13H20Cl2N4 : C, 51.49; H, 6.65; N, 18.48.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:14]([N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])C>ClCCl>[CH3:14][N:16]1[C:19]2[C:20](=[CH:5][CH:4]=[CH:9][CH:8]=2)[C:18]([C:10]2[C:11](=[O:12])[O:12][C:11](=[O:13])[C:10]=2[C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[CH:17]1
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc(C2=C(c3cccc([N+](=O)[O-])c3)C(=O)OC2=O)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 110.1 %

Procedure:
A solution of 1-methylindole-3-glyoxylyl chloride in dichloromethane (350 mL) was added to a solution of 3-nitrophenylacetic acid (8.5 g, 0.093 mL) and triethylamine (13 mL, 93 mmol) in dichloromethane (350 mL) at 0° C. The reaction mixture was then stirred at room temperature overnight and then concentrate under reduced pressure. The crude product was purified on a silica gel column with 6:1 hexane/ethyl acetate to afford 3-(1-methylindol-3-yl)-4-(3-nitrophenyl)furan-2,5-dione (9 g, 55%).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:8][C@@H:7]([N:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]=3[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:20]=3)=[CH:10]2)[CH2:6]1)=[O:4].Cl>C1COCC1>[NH2:18][C:17]1[C:12]2[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:20]=3)=[CH:10][N:9]([C@@H:7]3[CH2:6][C@H:5]([C:3]([OH:4])=[O:2])[CH2:8]3)[C:13]=2[N:14]=[CH:15][N:16]=1
Reactant: COC(=O)[C@H]1C[C@@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Agent: Cl
Solvent: C1CCOC1
Product: Nc1ncnc2c1c(-c1cccc(OCc3ccccc3)c1)cn2[C@H]1C[C@@H](C(=O)O)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
0.1 g (0.23 mmol) of cis-3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanecarboxylic acid methyl ester are dissolved in 1.8 ml of THF/1 M LiOH (1:1, v/v). After stirring at RT for 15 min, the pH of the solution is adjusted to pH=6 with 2N HCl and cis-3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanecarboxylic acid is obtained by filtering the suspension. Analytical HPLC: tR=6.61 min (Grad 2); ES-MS: m/eo=415.0.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[N:5][N:4]=[N:3]1.C([Li])CCC.[F:13][C:14]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:15]=1[C:16]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[F:25])=[O:17]>O1CCCC1>[F:13][C:14]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:15]=1[C:16]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[F:25])([OH:17])[CH2:7][C:6]1[N:2]([CH3:1])[N:3]=[N:4][N:5]=1
Reactant: Cc1ccc(C(=O)c2ccc(C)cc2F)c(F)c1
Reactant: Cc1nnnn1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C(O)(Cc2nnnn2C)c2ccc(C)cc2F)c(F)c1
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1,5-dimethyltetrazole (4.6 g, 4.7 mmoles) in tetrahydrofuran (40 mL) at -50° C. was added butyl lithium solution (21.4 mL of a 2.2M solution, 4.7 mmoles). After stirring for 10 minutes, a solution of 2,2'-difluoro-4,4'-dimethylbenzophenone in tetrahydrofuran (15 mL) was added. The solution was stirred for 2.5 hours during which time it was allowed to warm to -10° C. The reaction was quenched by adding 1N hydrochloric acid. The layers were separated and the aqueous layer was extracted with methylene chloride. The combined organic fractions were dried (MgSO4) and evaporated. The residue was triturated with diethyl ether and crystallized from isopropyl acetate to give 8.0 g of the title compound; m.p.=150°-151° C. MS: M+ =344.
Reaction SMILES: C([O:4][C@@H:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:6][CH2:7][C@@H:8]1[C@@H:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:11](=[O:23])[CH2:10][CH2:9]1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>>[OH:4][C@@H:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:6][CH2:7][C@@H:8]1[C@@H:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:11](=[O:23])[CH2:10][CH2:9]1
Reactant: CCCCC[C@@H](CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OC)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCC[C@H](O)CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OC

Procedure:
A solution of 2.26 g. of methyl 15(S)-acetoxy-9-oxoprostanoate (Example 52) in 300 ml. of absolute alcohol containing 790 mg. of potassium carbonate is stirred at ambient temperature for 72 hours then concentrated to near dryness under reduced pressure. The resulting mixture is extracted with ether. The combined extracts are washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness to give 1.83 g. of an oil. Purification by silica gel chromatography affords the subject compound as an oil; λ max. 2.92 (hydroxyl group), 5.74 μ (carbonyl groups); [α]D25 -23°C. (0.2% in CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH:21]=O)[CH:19]=2)[CH:14]=[N:13]1>>[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18](/[CH:21]=[C:6]3/[C:7](=[O:11])[NH:8][C:9]4[C:5]/3=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=4)[CH:19]=2)[CH:14]=[N:13]1
Reactant: O=Cc1ccc2cn[nH]c2c1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Product: O=C1Nc2cc(Cl)ccc2/C1=C\c1ccc2cn[nH]c2c1

Procedure:
The title compound was synthesized according to the method described for Example A11B except substituting 6-chlorooxindole (30 mg, 0.179 mmol) and 1H-indazole-6-carbaldehyde (29 mg, 0.197 mmol) to obtain 22 mg (42%) of a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 13.30 (s, 1H), 10.79 (s, 1H), 8.16 (s, 1H), 7.90-7.87 (m, 2H), 7.83 (s, 1H), 7.56 (d, J=8.00 Hz, 1H), 7.41 (d, J=8.80 Hz, 1H), 6.93-6.88 (m, 2H); MS ESI 296.0 [M+H]+, calcd for [C16H10ClN3O+H]+ 296.06.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:5]=[CH:6][C:7]2[C:16](=[O:17])[N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[CH:19]=3)[CH2:14][C@H:13]3[N:9]([CH2:10][CH2:11][CH2:12]3)[C:8]=2[N:31]=1)[CH3:2].C=O.[C:34](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[CH2:1]([NH:3][C:4]1[N:5]=[CH:6][C:7]2[C:16](=[O:17])[N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH:25]4[CH2:30][CH2:29][N:28]([CH3:34])[CH2:27][CH2:26]4)[CH:19]=3)[CH2:14][C@H:13]3[N:9]([CH2:10][CH2:11][CH2:12]3)[C:8]=2[N:31]=1)[CH3:2]
Reactant: CCNc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(OC3CCNCC3)c1)C2=O
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CCNc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(OC3CCN(C)CC3)c1)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
Compound 147 (100 mg, 0.237 mmol) obtained in Example 147 was dissolved in 1,2-dichloroethane (5 mL), and the mixture was stirred at room temperature for 2 hours after adding 37% formalin solution (0.0530 mL, 0.710 mmol) and sodium triacetoxyborohydride (150 mg, 0.710 mmol). Thereafter, a saturated aqueous sodium bicarbonate solution was added to the mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and crystallized from diethyl ether to give the title compound (Compound 148) (93.9 mg, 91%).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=1
Reactant: C1COCCN1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCCl)c34)cc2Cl)cn1
Product: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCN5CCOCC5)c34)cc2Cl)cn1
Yield: 17 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-{3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine (prepared as described in Example 16) and morpholine to give the title compound in 17% yield; NMR Spectrum: 2.45 (s, 3H), 2.50 (hidden by DMSO, 4H), 2.82 (t, 2H), 3.55-3.56 (m, 4H), 4.46 (t, 2H), 7.20 (d, 1H), 7.27 (s, 2H), 7.71 (d, 1H), 8.12 (s, 1H), 8.20 (s, 1H), 8.35 (s, 1H), 8.60 (br s, 1H); Mass Spectrum: 482 (MH+).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Cl[C:25]1[N:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=1>>[Cl:31][C:28]1[CH:27]=[N:26][C:25]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)=[O:11])=[N:30][CH:29]=1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Clc1cnc(Cl)nc1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(Cl)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2,5-dichloropyrimidine. ESI-MS (m/z): 426 [M+1]+.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[C:13]([OH:21])(=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].CI.Cl>O1CCCC1>[CH3:1][CH:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:13]([OH:21])=[O:20]
Reactant: CCCCCCC(=O)O
Reactant: CC(C)NC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CCCCCC(C)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cold (0° C.) solution of 100 ml. of dry tetrahydrofuran containing 11.8 ml. of dry diisopropylamine and 55 ml. of 1.6M n-butyl lithium was added 5.4 ml. of n-heptanoic acid and the mixture allow to stir at room temperature for one hour. The resulting solution was cooled to 0° C. and 7.2 ml. of methyl iodide was added. The reaction was stirred at room temperature under nitrogen for 1.5 hours, and was then poured into 10% hydrochloric acid and extracted with diethyl ether (3×100 ml.). The extracts were combined, washed with 10% hydrochloric acid, water, 20% sodium bisulfite and a brine solution and dried over magnesium sulfate. The solvent was removed in vacuo and the residue, 5.61 g., dissolved in methanol containing 5.1 g. of potassium hydroxide. After stirring overnight the mehtanol was removed and the residue dissolved in 150 ml. of water. The aqueous layer was washed with ether (2×100 ml.) and acidified with 10% hydrochloric acid. The product was extracted with ether, washed with a 20% sodium bisulfite solution and brine and dried over magnesium sulfate. Removal of the ether gave 5.0 g. of the product as a yellow liquid.