Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[CH2:9]([N+:16]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([C:30]([O:32][CH3:33])=[O:31])=[C:22]2[C:17]=1[CH:18]=[CH:19][CH:20]=[CH:21]2)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl-].[NH4+]>C(O)C.[Zn]>[CH2:9]([N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]([C:30]([O:32][CH3:33])=[O:31])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:29]1=2)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)c1c2ccccc2[n+](Cc2ccccc2)c2ccccc12
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: COC(=O)C1c2ccccc2N(Cc2ccccc2)c2ccccc21
Temperature: 80 °C
Yield: 23.5 %

Procedure:
To a stirring solution of compound 83 (1.05 g, 3.20 mmol) and ammonium chloride (2.67 g, 49.8 mmol) in ethanol (35 mL) was added zinc (2.67 g, 40.8 mmol) and the reaction mixture was heated at 80° C. for 30 minutes then filtered through a pad of Celite®. The solution was diluted with brine, extracted with EtOAc, and the combined organics were dried over, filtered and concentrated to afford compound 84 (0.248 g, 24%) as a white solid after purification by flash chromatography (10 to 40% EtOAc in hexanes). LRMS (ESI): (calc) 329.39 (found) 330.5 (MH)+
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:16])[CH:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)[CH3:5].Cl.NO.[O-]CC.[Na+].[O:24]1C=NN[S:25]1=O.S(Cl)(Cl)=O.C(=N)(N)CC>>[CH:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[CH:15][C:6]=1[CH:4]([C:3]1[NH:16][S:25](=[O:24])[O:1][N:2]=1)[CH3:5]
Reactant: CC(C(N)=NO)c1ccc2ccccc2c1
Reactant: O=S1NN=CO1
Agent: CCC(=N)N
Agent: CC[O-]
Agent: Cl
Solvent: O=S(Cl)Cl
Product: CC(C1=NOS(=O)N1)c1ccc2ccccc2c1

Procedure:
The monomethyl compound (5.07 g) was converted to the N'-hydroxy-2-(naphthalen-2-yl)propanimidamide following the procedure of Example 1, with hydroxylamine hydrochloride and sodium ethoxide at reflux for three days. The product (4.18 g) was converted to the oxathiadiazole-2-oxide following the procedure of Example 1. The addition of thionyl chloride to the propanimidamide was performed at 0° C. over a thirty minute period. The crude product was purified by flash chromatography through a silica gel column employing dichloromethane, 0.5% ethyl acetate/dichloromethane, 1% ethyl acetate and 2% ethyl acetate serial elution solvents. The product is a light yellow oil.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:19]=O>C1C=C2C(C=C(C([O-])=O)C=C2)=CC=1.C1C=C2C(C=C(C([O-])=O)C=C2)=CC=1.[Co+2].C(O)(=O)C>[C:1]([C:8]1[CH:9]=[C:10]([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])[CH:11]=[CH:12][CH:13]=1)(=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C(=O)O)c1cccc(Cc2ccccc2)c1
Reactant: O=O
Agent: [Co+2]
Agent: O=C([O-])c1ccc2ccccc2c1
Solvent: CC(=O)O
Product: CC(C(=O)O)c1cccc(C(=O)c2ccccc2)c1

Procedure:
To a 300 ml reaction vessel with a stirrer were fed 25 g of α-(3-benzylphenyl)propionic acid obtained in Experiment 5, 0.08 g of cobalt naphthenate and 100 ml of acetic acid as a solvent, and 150 ml/min of pure oxygen was fed into the vessel for 16 hours at a reaction temperature of 120 ° C. After the reaction, the solvent was removed by reduced-pressure distillation to obtain a solid substance. The solid substance was washed five times with 500 ml of water and it was dissolved in 500 ml of ether and washed three times again with water. After that, the ether was removed by reduced-pressure distillation and the product was finally recrystallized with a benzene/petroleum ether mixture to obtain 13.2 g of α-(3-benzoylphenyl)propionic acid (ketoprofen). The properties such as melting point and spectrum of the final product were the same as those of an authentic sample.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20](OCC)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH:26]([O:29][CH2:30][CH2:31][CH2:32][NH2:33])([CH3:28])[CH3:27]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([NH:33][CH2:32][CH2:31][CH2:30][O:29][CH:26]([CH3:28])[CH3:27])=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Reactant: CC(C)OCCCN
Product: CC(C)OCCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 3-isopropoxypropylamine employing methods similar to those described in Example 2 and was obtained as a white solid: 1H NMR (d6-DMSO) δ 11.73 (1H, br s), 10.71 (1H, br s), 10.23 (1H, br s), 8.17 (1H, br s), 7.28-7.24 (3H, m), 7.15-7.10 (2H, t, J=8.4 Hz), 4.00 (2H, s), 3.52-3.46 (1H, m), 3.39 (2H, t, J=6 Hz), 3.30-3.21 (2H, m), 1.68-1.62 (2H, m), 1.06 (6H, d, J=6.1 Hz); HRMS calcd for C22H24FN3O4+H+: 414.1829. Found 414.1810.
Reaction SMILES: [IH:1].[Cl:2][C:3]1[CH:20]=[CH:19][C:6]([CH:7]([NH:14][C:15](SC)=[NH:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>CC(O)(C)C>[IH:1].[Cl:2][C:3]1[CH:20]=[CH:19][C:6]([CH:7]([NH:14][C:15]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[NH:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: CSC(=N)NC(c1ccccc1)c1ccc(Cl)cc1
Reactant: C1CCNC1
Agent: I
Solvent: CC(C)(C)O
Product: N=C(NC(c1ccccc1)c1ccc(Cl)cc1)N1CCCC1

Procedure:
A mixture of 7.0 g (0.017 mole) of methyl N-(4-chlorobenzhydryl)carbamimidothioate hydroiodide and 2.85 g (0.04 mole) of pyrrolidine in 20 mls of t-BuOH is heated at reflux overnight. The t-BuOH is removed in vacuo and the crude guanidine hydroiodide is crystallized from methanol-ether. The crude product is recrystallized from methanol-t-butanol to yield pure N-(4-chlorobenzhydryl)-1-pyrrolidinecarboximidamide hydroiodide; mp 218°-220° (dec).
Reaction SMILES: [Na].[C:2]([NH:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[C:20]=1[CH2:21]Br>C(O)C.O1CCCC1>[C:2]([NH:5][C:6]([CH2:21][C:20]1[C:23]([N+:27]([O-:29])=[O:28])=[CH:24][CH:25]=[CH:26][C:19]=1[O:18][CH3:17])([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: COc1cccc([N+](=O)[O-])c1CBr
Agent: [Na]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1c(OC)cccc1[N+](=O)[O-])(NC(C)=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.8 %

Procedure:
Sodium metal (1.15 g) was dissolved in absolute ethanol (500 mL), and to the resulting solution was added diethyl 2-acetylaminomalonate (9.1 g). After 15 min at room temperature, a solution of 2-methoxy-6-nitrobenzyl bromide (J. Med. Chem. 1977, 20, 190-196) (8.6 g) in tetrahydrofuran (25 mL) was added over 2 min. After 16 h stirring at room temperature the mixture was evaporated. The residue was dissolved in a mixture of ethyl acetate and water. The ethyl acetate layer was separated and washed sequentially with water and brine before drying over anhydrous sodium sulfate. Evaporation was followed by silica gel chromatography eluting initially with dichloromethane, followed by ethyl acetate, to obtain diethyl 2-acetylamino-2-(2-methoxy-6-nitrobenzyl)malonate (10.8 g).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[Cl:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][C:29]([F:32])([F:31])[F:30])[C:18]([CH2:33][NH2:34])=[CH:17]2.C(N(CC)C(C)C)(C)C.C(O)C>>[Cl:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][C:29]([F:30])([F:31])[F:32])[C:18]([CH2:33][NH:34][C:2]1[N:10]=[CH:9][N:8]=[C:7]3[C:3]=1[N:4]=[CH:5][NH:6]3)=[CH:17]2
Reactant: Clc1ncnc2nc[nH]c12
Reactant: NCc1cc2cccc(Cl)c2nc1-c1ccccc1OC(F)(F)F
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)Oc1ccccc1-c1nc2c(Cl)cccc2cc1CNc1ncnc2[nH]cnc12
Temperature: 75 °C
Reaction time: 36 h

Procedure:
A mixture of 6-chloropurine (0.1109 g, 0.7175 mmol), (8-chloro-2-(2-(trifluoro-methoxy)phenyl)quinolin-3-yl)methanamine (0.2531 g, 0.7175 mmol), and N,N-diisopropylethylamine (0.2500 mL, 1.435 mmol) in ethanol (4.221 mL, 0.7175 mmol) was stirred at 75° C. After 36 h, the mixture was removed from the heat and concentrated under reduced pressure. The residue was purified by flash column chromatography on a silica gel column using 50% of CH2Cl2:MeOH:NH4OH (89:9:1) in CH2Cl2 as eluent to give N-((8-chloro-2-(2-(trifluoromethoxy)phenyl)quinolin-3-yl)methyl)-9H-purin-6-amine as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.94 (1 H, s), 8.38 (1 H, s), 8.03-8.32 (3 H, m), 7.96-8.02 (1 H, m), 7.93 (1 H, dd, J=7.5, 0.9 Hz), 7.51-7.75 (5 H, m), 4.69 (2 H, br. s.); LC-MS (ESI) m/z 471.1 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:8][C:9]=1[CH2:10][CH2:11][OH:12])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:7]2[S:6][C:5]3[C:3](=[O:2])[O:12][CH2:11][CH2:10][C:9]=3[CH:8]=2)=[CH:14][CH:15]=1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1OCCc2cc(-c3ccc(Cl)cc3)sc21
Temperature: 80 °C
Yield: 42.9 %

Procedure:
Dissolve 5-(4-chloro-phenyl)-3-(2-hydroxy-ethyl)-thiophene-2-carboxylic acid methyl ester (3.4 g, 11.46 mmol) in toluene (60 mL) and add p-toluenesulfonic acid monohydrate (0.3 g, 1.58 mmol) and heat to 80° C. for one hour. Cool the mixture to room temperature and dilute with ethyl acetate (50 mL). Wash the solution with 1 N NaOH and extract the aqueous portion twice with ethyl acetate. Combine the organic fractions, dry over Na2SO4, filter, and concentrate. Triturate the solid with ether and then filter and dry under vacuum to give 1.3 g (43%) of the title compound. LC-MS/ES m/z (35Cl) 265.0 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])O[C:4](=[O:9])[CH:3]=1.[CH2:10]([NH2:13])[CH:11]=[CH2:12]>O>[CH2:10]([N:13]1[C:6]([CH3:8])=[CH:7][C:2]([OH:1])=[CH:3][C:4]1=[O:9])[CH:11]=[CH2:12]
Reactant: Cc1cc(O)cc(=O)o1
Reactant: C=CCN
Solvent: O
Product: C=CCn1c(C)cc(O)cc1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 68.1 %

Procedure:
4-hydroxy-6-methyl-2-pyrone (2 g, 16 mmol) was stirred in water (25 mL). Allylamine (1.2 ml, 16 mmol) was added to the reaction. The reaction was then heated to 100° C. at which point the reaction became homogeneous. The reaction was stirred at 100° C. for 2 h. The reaction was then allowed to cool to rt after which a white precipitate formed. The precipitate was isolated by suction filtration. After additional washing with water, 1.8 g (69%) of an off-white solid was obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]2[N:5]([N:9]=[C:10]([CH3:17])[C:11]=2C(OCC)=O)[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+]>S(=O)(=O)(O)O>[CH3:17][C:10]1[CH:11]=[C:4]2[C:3]([CH2:2][OH:1])=[CH:8][CH:7]=[CH:6][N:5]2[N:9]=1
Reactant: CCOC(=O)c1c(C)nn2cccc(CO)c12
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc2c(CO)cccn2n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
A mixture of ethyl 4-(hydroxymethyl)-2-methylpyrazolo[1,5-a]pyridine-3-carboxylate (41.0 g, 0.180 mol) and 40% aqueous sulfuric acid solution (350 mL) was stirred at 100° C. for 2 hr. The reaction mixture was basified with 10% aqueous sodium hydroxide solution, and extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give the title compound (28.0 g, yield 99%).
Reaction SMILES: [OH:1][CH2:2][C:3]([OH:5])=O.O.OC1C2N=NNC=2C=CC=1.Cl.C(N=C=NCCCN(C)C)C.FC(F)(F)C(O)=O.[N:36]1([C:42]2[N:50]=[C:49]([C:51]3[CH:52]=[N:53][C:54]([NH2:57])=[N:55][CH:56]=3)[N:48]=[C:47]3[C:43]=2[N:44]=[C:45]([N:63]2[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]2)[N:46]3[CH2:58][C:59]([F:62])([F:61])[F:60])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>C(N(CC)CC)C.CN(C)C=O>[NH2:57][C:54]1[N:55]=[CH:56][C:51]([C:49]2[N:48]=[C:47]3[C:43]([N:44]=[C:45]([N:63]4[CH2:68][CH2:67][N:66]([C:3](=[O:5])[CH2:2][OH:1])[CH2:65][CH2:64]4)[N:46]3[CH2:58][C:59]([F:60])([F:62])[F:61])=[C:42]([N:36]3[CH2:37][CH2:38][O:39][CH2:40][CH2:41]3)[N:50]=2)=[CH:52][N:53]=1
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3nc(N4CCNCC4)n(CC(F)(F)F)c3n2)cn1
Reactant: O=C(O)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ncc(-c2nc(N3CCOCC3)c3nc(N4CCN(C(=O)CO)CC4)n(CC(F)(F)F)c3n2)cn1
Reaction time: 4 h
Yield: 78.8 %

Procedure:
2-Hydroxyacetic acid (15 mg, 0.19 mmol), hydroxybenzotriazole hydrate (37 mg, 0.19 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (37 mg, 0.19 mmol), dimethylformamide (3 ml), and triethylamine (100 μl) were added to 5-[6-morpholin-4-yl-8-piperazin-1-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl]pyrimidin-2-amine trifluoroacetate (120 mg, 0.17 mmol) and the resulting mixture was stirred for 4 hours. The reaction mixture was partitioned with ethyl acetate and water, the organic layer was washed with saturated aqueous sodium bicarbonate solution and dried over magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform:methanol=19:1) to give the title compound (70 mg) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9](I)=[CH:8][C:6]=2[N:7]=1.[CH2:18]([OH:21])[C:19]#[CH:20].C(N(CC)CC)C>[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([C:20]#[C:19][CH2:18][OH:21])=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(I)cc2n1
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: OCC#Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reaction time: 240 h

Procedure:
A mixture of 2-chloro-6-iodo-4-morpholin-4-yl-thieno[3,2-d]pyrimidine 19, prepared according to Example 12, (1.57 g), propargyl alcohol (288 μL), copper iodide (39 mg), bis(triphenylphosphine)palladium(II) chloride (146 mg), triethylamine (25 ml), and tetrahydrofuran (30 ml) were stirred under nitrogen for 10 days. The reaction mixture was then partitioned between chloroform and brine, the combined organics were then dried (MgSO4). The solvents were removed in vacuo. The crude product was then purified using flash chromatography to yield 3-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-prop-2-yn-1-ol (1.2 g).
Reaction SMILES: C(OC(=O)[NH:10][C:11]12[CH2:18][CH:17]3[CH2:19][C:13]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:30][CH2:29][CH2:28][S:27]5(=[O:32])=[O:31])=[CH:22][CH:21]=4)([CH2:14][CH:15]1[CH2:16]3)[CH2:12]2)C1C=CC=CC=1>CO.[Pd]>[O:31]=[S:27]1(=[O:32])[CH2:28][CH2:29][CH2:30][N:26]1[C:23]1[CH:22]=[CH:21][C:20]([C:13]23[CH2:19][CH:17]4[CH2:16][CH:15]([CH2:14]2)[C:11]([NH2:10])([CH2:18]4)[CH2:12]3)=[CH:25][CH:24]=1
Reactant: O=C(NC12CC3CC1CC(c1ccc(N4CCCS4(=O)=O)cc1)(C3)C2)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NC12CC3CC1CC(c1ccc(N4CCCS4(=O)=O)cc1)(C3)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
A mixture of benzyl[2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl)hexahydro-2,5-methanopentalene-3a(1H)-yl]carbamate (0.8 g, 1.7 mmol) obtained in step I, Pd/C (10%, 0.4 g) in MeOH (17 mL) was stirred at room temperature under H2 atmosphere for 2 h. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to obtain 1-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]tricyclo[3.3.1.03,7]nonan-3-amine as an off-white solid (0.49 g) in 85% yield. m/z (M+1) 333; IR cm−1 3418, 1652, 1137, 772. 1H NMR (CDCl3) 300 MHz, δ 7.31 (d, J=8.8 Hz, 2H), 7.22 (d, J=8.8 Hz, 2H), 3.78 (t, J=6.6 Hz, 2H), 3.43 (t, J=7.4 Hz, 2H), 2.58-2.47 (m, 3H), 2.40-2.34 (m, 1H), 2.27-2.11 (m, 2H), 2.10-1.95 (m, 4H), 1.93-1.70 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]1[C:13]([CH3:42])([CH3:41])[C@H:14]2[C@:27]([CH3:30])([CH2:28][CH:29]=1)[C@@H:26]1[C@:17]([CH3:40])([C@@:18]3([CH3:39])[C@H:23]([CH2:24][CH2:25]1)[C@H:22]1[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]1([CH:37]=O)[CH2:20][CH2:19]3)[CH2:16][CH2:15]2)[C:5]([O:7]C)=[O:6].Cl.[NH2:44][CH2:45][CH2:46][C:47]([N:49]1[CH2:53][CH2:52][CH2:51][CH2:50]1)=[O:48]>>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]1[C:13]([CH3:42])([CH3:41])[C@H:14]2[C@:27]([CH3:30])([CH2:28][CH:29]=1)[C@@H:26]1[C@:17]([CH3:40])([C@@:18]3([CH3:39])[C@H:23]([CH2:24][CH2:25]1)[C@H:22]1[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]1([CH2:37][NH:44][CH2:45][CH2:46][C:47](=[O:48])[N:49]1[CH2:53][CH2:52][CH2:51][CH2:50]1)[CH2:20][CH2:19]3)[CH2:16][CH2:15]2)[C:5]([OH:7])=[O:6]
Reactant: C=C(C)[C@@H]1CC[C@]2(C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: NCCC(=O)N1CCCC1
Agent: Cl
Product: C=C(C)[C@@H]1CC[C@]2(CNCCC(=O)N3CCCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 72 %

Procedure:
The title compound was prepared in 72% yield following steps 5 and 6, using methyl 3-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-formyl-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate and 3-amino-1-(pyrrolidin-1-yl)propan-1-one hydrochloride as the reactant amine MS: m/e 687.5 (MH+), 1.76 min (method 2). 1H NMR (400 MHz, MeOD) δ ppm 0.91 (s, 3H) 0.96 (s, 3H) 1.05 (s, 3H) 1.09 (s, 3H) 1.17 (s, 3H) 1.73 (s, 3H) 0.85-1.85 (m, 20H) 1.87-1.96 (m, 2H) 2.01 (dt, J=13.36, 6.74 Hz, 2H) 2.04-2.12 (m, 1H) 2.16 (dd, J=17.07, 6.53 Hz, 1H) 2.48-2.57 (m, 1H) 2.81 (t, J=6.02 Hz, 2H) 2.88 (d, J=12.80 Hz, 1H) 3.33-3.43 (m, 3H) 3.43-3.52 (m, 4H) 4.65 (s, 1H) 4.76 (d, J=1.25 Hz, 1H) 5.35 (dd, J=6.02, 1.51 Hz, 1H) 7.22 (t, J=7.53 Hz, 1H) 7.64 (dd, J=9.79, 1.25 Hz, 1H) 7.75 (dd, J=8.03, 1.51 Hz, 1H). 19F NMR (376 MHz, MeOD) δ ppm −113.36 (s, 1 F).
Reaction SMILES: [N:1]1([C:6]2[N:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=O)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.[C:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(CC)CC>C(Cl)Cl.O>[N:1]1([C:6]2[N:11]=[CH:10][C:9]([CH2:12][C:13]([N:26]3[CH2:25][CH2:24][N:23]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:28][CH2:27]3)=[O:15])=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)Cc1ccc(-n2cnnn2)nc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)Cc2ccc(-n3cnnn3)nc2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of [6-(1H-tetrazol-1-yl)pyridin-3-yl]acetic acid (65 mg, 0.31 mmol), N-Boc-piperazine (88 mg, 0.47 mmol), HOBt (64 mg, 0.47 mmol), EDC (90 mg, 0.47 mmol) and Et3N (96 mg, 0.95 mmol) in DCM (2 mL) was stirred 12 hours at room temperature. Water was added and the mixture was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated and the residue was purified by prep-TLC to give tert-butyl 4-{[6-(1H-tetrazol-1-yl)pyridin-3-yl]acetyl}piperazine-1-carboxylate. MS m/z 374 (M+1)+. 1H-NMR (400 MHz, CDCl3) δ 9.45 (s, 1H), 8.33 (s, 1H), 7.98˜8.01 (m, 1H), 7.82˜7.85 (m, 1H), 3.73 (s, 2H), 3.56˜3.58 (m, 2H), 3.46˜3.47 (m, 2H), 3.36˜3.39 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1(C(C2C=CC=CC=2)=[NH:23])C=CC=CC=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:23][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: N#CC1(c2ccc(Br)cc2)CCOCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: N#CC1(c2ccc(N)cc2)CCOCC1
Temperature: 90 °C
Reaction time: 10 h
Yield: 70.4 %

Procedure:
To a solution of 4-(4-bromophenyl)tetrahydro-2H-pyran-4-carbonitrile (1.7 g) obtained in Step A of Example 150, diphenylmethanimine (1.4 g), tris(dibenzylideneacetone)dipalladium(0) (88 mg) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (130 mg) in toluene (50 mL) was added sodium 2-methylpropan-2-olate (920 mg) under nitrogen atmosphere, and the mixture was stirred at 90° C. for 10 hr. The reaction mixture was diluted with ethyl acetate, and the insoluble substance was removed by filtration through Celite. The filtrate was concentrated, and to a solution of the residue in methanol (10 mL) were added hydroxylamine hydrochloride (440 mg) and sodium acetate (530 mg). The mixture was stirred at room temperature for 30 min, and 0.1 M aqueous sodium hydroxide solution and ethyl acetate were added thereto. The solvent was evaporated under reduced pressure, and the reaction mixture was poured into water, and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (910 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[CH:4][CH:3]=1.N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>C(Cl)Cl>[C:26]([Si:23]([CH3:25])([CH3:24])[O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:11])=[CH:6][CH:7]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: O=C(CCc1ccc(O)cc1)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CCC(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared as described in General Method 5 using 4.53 g (20 mmol) of 3-(4-hydroxy-phenyl)-1-phenyl-propan-1-one from Example L, 1.64 g (24 mmol) of imidazole, 3.62 g (24 mmol) of t-butyldimethylsilyl chloride and 80 mL of CH2Cl2. The product was carried on crude to the next step (see Example TT).