Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([O:11]CC)=O.[C:14](#[N:16])[CH3:15].Cl>C1COCC1.C(OCC)(=O)C>[O:11]=[C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=1)[CH2:15][C:14]#[N:16]
Reactant: CCOC(=O)c1ccccn1
Reactant: CC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#CCC(=O)c1ccccn1
Temperature: 65 °C
Yield: 100 %

Procedure:
To a mixture of sodium hydride (15 g, 60% in oil, 375 mmol) and ethyl 2-picolinate (50 g. 331 mmol) in anhydrous THF (250 mL) was added dropwise a solution of anhydrous acetonitrile (20 g, 487 mmol) in anhydrous THF (200 mL), at about 65° C. After complete addition the reaction mixture was heated at about 65° C., for about 5 h. After cooling to rt, ethyl acetate (500 mL) was added, followed by 1 M aqueous HCl (360 mL). The resulting layers were separated, and the aqueous layer was extracted with ethyl acetate (250 mL). The combined organic layers were washed with water (2×100 mL), dried (MgSO4), filtered, and concentrated in vacuo to give crude 3-oxo-3-(2-pyridyl)propanenitrile (48.6 g, 331 mmol, 100%), which was used as such in the next step. 1H-NMR (CDCl3, Bruker 400 MHz) 4.39 (2H, s); 7.58 (1H, m); 7.91 (1H, dt, J=2 Hz, 10 Hz); 8.11 (1H, dt, J=2 Hz, 10 Hz); 8.70 (1H, s).
Reaction SMILES: [Br:1][CH:2]1[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]([NH:7][C:8](=[O:9])[CH:3]12)=[O:6].N1C=CC=CC=1.[Cl:20][C:21]1[C:29]([Cl:30])=[CH:28][C:27]([Cl:31])=[CH:26][C:22]=1[C:23](Cl)=[O:24]>C1C=CC=CC=1>[Cl:20][C:21]1[C:29]([Cl:30])=[CH:28][C:27]([Cl:31])=[CH:26][C:22]=1[C:23]([N:7]1[C:8](=[O:9])[CH:3]2[CH:2]([Br:1])[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]1=[O:6])=[O:24]
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1Cl
Reactant: O=C1NC(=O)C2C1CCC(Br)C2Br
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: O=C(c1cc(Cl)cc(Cl)c1Cl)N1C(=O)C2CCC(Br)C(Br)C2C1=O
Temperature: 25 °C

Procedure:
3,4-Dibromohexahydrophthalimide (0.10 mole), benzene (300 ml) and pyridine (0.11 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,3,5-Trichlorobenzoyl chloride (0.10 mole) is then added dropwise to the flask with stirring at room temperature. After the addition is completed the reaction mixture is heated at reflux with continued stirring for a period of about 1 hour. After this time the reaction mixture is filtered and the filtrate is washed with water. The washed filtrate is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(2,3,5-trichlorobenzoyl)-3,4-dibromohexahydrophthalimide.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[C:12]([F:24])=[C:13]([NH:17][C:18](=[O:23])[O:19][CH2:20][CH:21]=[CH2:22])[CH:14]=[CH:15][CH:16]=2)=O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[NH2:33][C:34]([CH:36]1[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]1)=[S:35]>CN(C)C(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:35][C:34]([CH:36]3[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]3)=[N:33][C:9]=2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18]([O:19][CH2:20][CH:21]=[CH2:22])=[O:23])[C:12]=2[F:24])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Reactant: C=CCOC(=O)Nc1cccc(C(=O)Cc2ccnc(Cl)n2)c1F
Agent: O=C1CCC(=O)N1Br
Solvent: CC(=O)N(C)C
Product: C=CCOC(=O)Nc1cccc(-c2nc(C3CCN(C(=O)OC(C)(C)C)CC3)sc2-c2ccnc(Cl)n2)c1F
Temperature: 80 °C
Reaction time: 1 h
Yield: 57.1 %

Procedure:
To a solution of 2-propen-1-yl {3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-carbamate (1.43 g, 4.09 mmol) in N,N-dimethylacetamide (DMA) (15 mL) was added NBS (0.728 g, 4.09 mmol), and the reaction mixture was stirred for 1 h. 1,1-Dimethylethyl 4-(aminocarbonothioyl)-1-piperidinecarboxylate (0.999 g, 4.09 mmol) was added and the reaction mixture was heated to 80° C. for 25 min. The mixture was cooled, quenched with water (30 mL) and extract with EtOAc (3×). The extract was dried over Na2SO4, filtered and concentrated. The residue was purified using column chromatography (hexane/EtOAc, 0 to 100%) to give 1.34 g of the title compound. MS (ESI): 574.2 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]1([CH2:34][O:35][CH3:36])[CH2:33][O:32][CH2:31]1>C(#N)C>[CH3:21][O:20][C:3]1[C:2]([O:1][CH2:29][C:30]2([CH2:34][O:35][CH3:36])[CH2:33][O:32][CH2:31]2)=[C:7]([O:8][CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[O:14][CH2:13]2
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(OC)c1O
Reactant: COCC1(CBr)COC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCC1(COc2c(OC)ccc(-c3ccc4c(c3)COC4=O)c2OC)COC1
Temperature: 80 °C
Yield: 17.9 %

Procedure:
To a stirring solution of 5-(3-Hydroxy-2,4-dimethoxy-phenyl)-3H-isobenzofuran-1-one (80 mg, 0.279 mmol) in acetonitrile (10 mL) was added potassium carbonate (154 mg, 1.118 mmol) and 3-bromomethyl-3-methoxymethyl-oxetane (107 mg, 0.558 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-50% ethyl acetate in pet ether) to afford the title compound as a solid (20 mg, 18%).
Reaction SMILES: CC([S@]([NH:7][C@@H:8]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[CH2:9][CH:10]([CH3:12])[CH3:11])=O)(C)C.CO.[ClH:31]>CCOCC>[ClH:31].[CH3:11][CH:10]([CH3:12])[CH2:9][C@H:8]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[NH2:7]
Reactant: CC(C)C[C@@H](N[S@](=O)C(C)(C)C)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CC(C)C[C@@H](N)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 89 %

Procedure:
A round bottom flask was charged with (R)-2-methyl-N—((R)-3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butyl)propane-2-sulfinamide (47.5 g, 115.5 mmol) and methanol (300 mL). The mixture was cooled to 0° C. and 2.0N HCl in ether (150 mL) was added. The reaction was stirred for 20 minutes. The reaction was then concentrated under reduced pressure. Trituration with ether provided (R)-3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butan-1-amine hydrochloride (35.3 g, 89%), as a white solid. 1H NMR (400 MHz, CD3OD, δ): 0.95 (d, 3 H) 0.99 (d, J=6.44 Hz, 3 H) 1.38-1.51 (m, 1 H) 1.78-1.91 (m, 1 H) 1.92-2.03 (m, 1 H) 4.40 (dd, J=10.15, 5.66 Hz, 1 H) 7.56-7.63 (m, 2 H) 7.74-7.88 (m, 6 H). MS (M+1): 291.2. [α]D =−11.9, c=1.8 (MeOH).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][N:21](C3CCCCO3)[C:15]=2[CH:14]=1.[CH3:29][N:30]1[CH2:35][CH2:34][CH:33]([N:36]2[CH2:44][C:43]3[C:38](=[CH:39][CH:40]=[C:41](B4OC(C)(C)C(C)(C)O4)[CH:42]=3)[C:37]2=[O:54])[CH2:32][CH2:31]1>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:41]3[CH:42]=[C:43]4[C:38](=[CH:39][CH:40]=3)[C:37](=[O:54])[N:36]([CH:33]3[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]3)[CH2:44]4)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: CN1CCC(N2Cc3cc(B4OC(C)(C)C(C)(C)O4)ccc3C2=O)CC1
Reactant: COc1cc(OC)c(F)c(-c2cc3c(cn2)c(I)nn3C2CCCCO2)c1F
Product: COc1cc(OC)c(F)c(-c2cc3[nH]nc(-c4ccc5c(c4)CN(C4CCN(C)CC4)C5=O)c3cn2)c1F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 52, Step 8 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine and 2-(1-methylpiperidin-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one. LCMS (M+H)+=520.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:9][C:10]3[N:11]([CH:31]=2)[N:12]=[C:13]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:20][CH:19]=2)[C:14]=3[C:15]([NH2:17])=[O:16])[CH:5]=[CH:6][CH:7]=1.[C:32](Cl)(=[O:35])[CH:33]=[CH2:34]>>[C:32]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:9][C:10]3[N:11]([CH:31]=2)[N:12]=[C:13]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:20][CH:19]=2)[C:14]=3[C:15]([NH2:17])=[O:16])[CH:5]=[CH:6][CH:7]=1)(=[O:35])[CH:33]=[CH2:34]
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2cc(-c3cccc(N)c3)[nH]c12
Reactant: C=CC(=O)Cl
Product: C=CC(=O)Nc1cccc(-c2cn3nc(-c4ccc(Oc5ccccc5)cc4)c(C(N)=O)c3[nH]2)c1

Procedure:
The desired product was prepared from 2-(3-aminophenyl)-6-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-7-carboxamide and acryloyl chloride using the procedure similar to that for compound 8. 1H NMR (400 MHz, CD3OD-d4) δ 8.06 (s, 1H), 7.83 (s, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.52-7.38 (m, 5H), 7.15 (t, J=7.6 Hz, 1H), 7.09-7.05 (m, 4H), 6.49-6.37 (m, 2H) and 5.80 (dd, J=4.0, 8.8 Hz, 1H). MS (ESI) m/e [M+1]+ 463.9.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([OH:3])=O.CC(C)N=C=NC(C)C.O[NH:22][C:23](=[NH:35])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>C(Cl)Cl>[CH2:24]([C:23]1[N:22]=[C:1]([C:4]2[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=2)[O:3][N:35]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CCCCCCCCCCCC(=N)NO
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Product: CCCCCCCCCCCc1noc(-c2ccc(C=O)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
To a solution of 4-carboxybenzaldehyde (20.0 g, 133.2 mmol) in anhydrous DCM (500 mL) was added DIC (18.42 g, 146.5 mmol). The mixture was stirred at rt for 30 min then a solution of N-hydroxydodecanimidamide (31.41 g, 146.5 mmol) in anhydrous DCM (500 mL) was added in one portion. The resulting reaction mixture was stirred overnight at rt. The reaction was filtered, the collected solid washed with DCM and the solvent was concentrated in vacuo. The residue was heated at 115° C. for 5 h in a mixture of toluene (285 mL) and pyridine (115 mL). The solvents were evaporated off and the resulting residue was purified on column (SiO2, c-Hex/EtOAc 20/1) to give the title compound as a white solid (24.0 g, 55%). 1H NMR (CDCl3, 300 MHz) δ 10.1 (s, 1H), 8.18 (d, 2H, J=8.3 Hz), 7.94 (d, 2H, J=8.3 Hz), 2.33 (t, 2H, J=7.4 Hz), 1.74-1.58 (m, 2H), 1.43-1.18 (m, 16H), 0.87 (m, 3H). HPLC (Condition A), Rt: 5.83 min (HPLC purity: 99.6%).
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([CH2:9][C:10]([OH:12])=O)[CH2:4]1.[NH2:13][C@@H:14]([CH2:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)=[O:16]>>[CH2:34]([O:33][CH2:32][C@H:14]([NH:13][C:10](=[O:12])[CH2:9][N:5]1[CH2:6][CH2:7][CH2:8][CH:3]([CH3:2])[CH2:4]1)[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC1CCCN(CC(=O)O)C1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: CC1CCCN(CC(=O)N[C@@H](COCc2ccccc2)C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)C1
Yield: 42.8 %

Procedure:
Proceeding as in Example 1, but substituting 2-(3-methylpiperidin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 46, (2S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(3-methylpiperidin-1-yl)acetamido)propanamide (17.8 mg, 42.8%). 1H-NMR (400 MHz, DMSO-D6): σ 10.20 (s, 1H), 7.94 (d, 1H), 7.56 (d, 2H), 7.29 (m, 5H), 7.21 (m, 2H), 7.01 (m, 4H), 4.69 (m, 1H), 4.52 (s, 2H), 3.73 (m, 2H), 2.93 (m, 2H), 2.73 (m, 2H), 1.98 (s, 1H), 1.58 (m 5H), 0.81 (m, 4H). MS (EI) for C30H34FN3O4: 520.7 (MH+).
Reaction SMILES: CS(O[CH2:6][C@H:7]1[O:16][C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[O:9][CH2:8]1)(=O)=O.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])(O)=O.[Na+]>O1CCOCC1>[C:18]1([CH2:17][NH:24][CH2:6][C@@H:7]2[O:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[O:9][CH2:8]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CS(=O)(=O)OC[C@@H]1COc2cccnc2O1
Reactant: NCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: c1ccc(CNC[C@H]2COc3cccnc3O2)cc1

Procedure:
A mixture of intermediate (3) (0.041 mol), benzylamine (0.041 mol) and NaHCO3 (0.11 mol) in dioxane (100 ml) was stirred and refluxed for 48 hours. The solvent was evaporated. The residue was taken up in water and DCM. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 95/5). The desired fractions were collected, the solvent was evaporated, yielding (S)-2,3-dihydro-N-(phenylmethyl)-[1,4]dioxino[2,3-b]pyridine-3-methanamine (intermediate 55).
Reaction SMILES: CN(C)C=O.S(Cl)([Cl:8])=O.[CH3:10][C:11]1([CH3:23])[C@@H:13]([CH:14]([Br:19])[C:15]([Br:18])([Br:17])[Br:16])[C@H:12]1[C:20](O)=[O:21]>C(Cl)Cl>[CH3:10][C:11]1([CH3:23])[C@@H:13]([CH:14]([Br:19])[C:15]([Br:18])([Br:17])[Br:16])[C@H:12]1[C:20]([Cl:8])=[O:21]
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1C(Br)C(Br)(Br)Br
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)[C@H](C(=O)Cl)[C@@H]1C(Br)C(Br)(Br)Br
Reaction time: 2 h

Procedure:
A mixture of 0.2 ml of dimethylformamide, 8.5 ml of thionyl chloride and 179 ml of petroleum ether (b.p.=35°-75° C.) was heated to reflux and a mixture of 35.76 g of the product of Step A in 150 ml of methylene chloride was added thereto. The mixture was refluxed with stirring for 2 hours and was then cooled and evaporated to dryness. The residue was taken up in toluene and the mixture was evaporated to dryness under reduced pressure to obtain 38 g of raw (1R,cis) 2,2-dimethyl-3-(1',2',2',2'-tetrabromoethyl)-cyclopropane-1-carboxylic acid chloride with a melting point of 88° C. which was used as is for the next step.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3](=[N:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)[NH2:4].[CH3:16][O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=O)=[CH:20][CH:19]=1.N1C=CC=CC=1>O1CCOCC1>[CH3:16][O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]2[N:6]([C:7]3[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=3)[N:5]=[C:3]([C:2]([F:14])([F:15])[F:1])[N:4]=2)=[CH:20][CH:19]=1
Reactant: Cc1ccc(NN=C(N)C(F)(F)F)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: COc1ccc(-c2nc(C(F)(F)F)nn2-c2ccc(C)cc2)cc1
Reaction time: 1 h
Yield: 39 %

Procedure:
A mixture of 2,2,2-trifluoro-N′-(4-methylphenyl)ethanehydrazonamide (0.62 g, 2.85 mmol), 4-methoxybenzoyl chloride (584 mg, 3.43 mmol), and pyridine (0.277 mL, 3.43 mmol) in dioxane (6 mL) was refluxed with stirring for 1 hour. After cooling, the solvent was removed under reduced pressure. ethyl acetate-tetrahydrofuran (9:1) and water was poured into the residue and the organic layer was separated, washed with 0.1 N hydrochloric acid, water, and brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography (hexane-ethyl acetate 8:1-1:1). The desired product was recrystallized from hexane and dried in vacuo to give 5-(4-methoxyphenyl)-1-(4-methylphenyl)-3-(trifluoromethyl)-1H-1,2,4-triazole (370 mg, 38.9% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([CH2:18][CH3:19])[CH:12]=1)[CH:5]=[O:6].[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[N:26]1[C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:28]=[N:27]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][C:9]2[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[C:30]2[N:26]([CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25][O:20]3)[N:27]=[CH:28][CH:29]=2)=[CH:12][C:13]=1[CH2:18][CH3:19]
Reactant: CCc1cc(Oc2ccc(C=O)cc2Br)ccc1Cl
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CCc1cc(Oc2ccc(C=O)cc2-c2ccnn2C2CCCCO2)ccc1Cl
Temperature: 75 °C
Yield: 49.1 %

Procedure:
3-bromo-4-(4-chloro-3-ethylphenoxy)benzaldehyde (Preparation 9, 336 mg, 1.08 mmol), 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (300 mg, 1.08 mmol) and cesium carbonate (1.05 g, 3.24 mmol) were suspended in dioxane (4 mL) and water (2 mL). The suspension was degassed 40 minutes with nitrogen then tetrakis-triphenylphosphine palladium (62 mg, 0.054 mmol) was added and the reaction mixture was heated for 18 hours at 75° C. The solution was concentrated in vacuo to a quarter of its volume then diluted with water (20 mL) and extracted by ethyl acetate (3×20 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography eluting with a gradient from 15% diethyl ether in heptane to 50% diethyl ether in heptane to afford the title compound as a colourless oil (218 mg, 49%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[O:16][C:15](=[O:17])[C:14]4[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=4[N:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=1>>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([NH:22][C:15](=[O:17])[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[NH:12][C:11]([N:8]2[CH2:7][CH2:6][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:10][CH2:9]2)=[O:16])=[N:24][CH:25]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: O=c1oc(N2CCC3(CC2)OCCO3)nc2ccccc12
Product: O=C(Nc1ccc(Cl)cn1)c1ccccc1NC(=O)N1CCC2(CC1)OCCO2

Procedure:
Using a similar procedure to that described in example 51-D, 2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-4H-3,1-benzoxazin-4-one (1.30 g, 4.51 mmol) and 2-amino-5-chloropyridine (573 mg, 4.51 mmol) yielded, after recrystallization from EtOAc, 880 mg (47%) of the titled compound.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=2OS(C(F)(F)F)(=O)=O)[C:10]([O:12][CH3:13])=[O:11])[CH2:3][CH2:2]1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:8]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[CH:14]=[CH:15][C:16]=2[C:27]2[CH:28]=[C:29]([O:32][CH3:33])[CH:30]=[CH:31][C:26]=2[F:25])[CH2:3][CH2:2]1
Reactant: COc1ccc(F)c(B(O)O)c1
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C2=CCOCC2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C2=CCOCC2)c1
Temperature: 90 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
To a stirred solution of 66.46E (555 mg, 1.52 mmol) in DMF (10 mL) at 23° C. was added 2-fluoro-5-methoxyphenylboronic acid (512.3 mg, 3.0 mmol) (commercially available from Aldrich) and potassium carbonate (630.1 mg, 4.56 mmol) followed by tetrakis(triphenylphosphine)palladium(0) (176.8 mg, 0.15 mmol). The mixture was heated to 90° C. After 18 hours, LCMS showed the reaction was complete. The mixture was cooled to room temperature and diluted with water. After extracting three times with EtOAc, the mixture was concentrated in vacuo, and the residue was purified on silica gel (0-50% EtOAc in hexanes) to afford 66.46F (452.7 mg, 87% yield). MS ESI (pos.) m/e: 343.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:5]([CH2:11][CH:12]1[CH2:17][CH2:16][N:15](CC3C=CC=CC=3)[CH2:14][CH2:13]1)=[N:6]2.[O-2].[Ca+2].[H][H]>[Pd].CO>[F:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][N:4]2[C:3]3[C:7](=[N:8][CH:9]=[N:10][CH:2]=3)[N:6]=[C:5]2[CH2:11][CH:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)=[CH:27][CH:28]=1
Reactant: [H][H]
Reactant: Fc1ccc(Cn2c(CC3CCN(Cc4ccccc4)CC3)nc3ncnc(Cl)c32)cc1
Agent: [Pd]
Agent: [Ca+2]
Agent: [O-2]
Solvent: CO
Product: Fc1ccc(Cn2c(CC3CCNCC3)nc3ncncc32)cc1
Yield: 54 %

Procedure:
A mixture of 15 parts of 6-chloro-7-[(4-fluorophenyl)methyl]-8-[[1-(phenylmethyl)-4-piperidinyl]-methyl]-7H-purine. 5 parts of calcium oxide and 200 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was taken up in water. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia. (95:5→85:15 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 5.8 parts (54%) of 7-[(4-fluorophenyl)methyl]-8-(4-piperidinylmethyl)-7H-purine as a residue (compound 55).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=O.C[O:13][C:14](=[O:42])[C:15]1[CH:20]=[CH:19][C:18]([N:21]([CH:31]2[CH2:36][CH2:35][N:34]([CH:37]([CH3:41])[CH2:38][CH2:39][NH2:40])[CH2:33][CH2:32]2)[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[CH:24]=2)=[CH:17][CH:16]=1>>[C:29]([C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[CH2:22][N:21]([CH:31]1[CH2:32][CH2:33][N:34]([CH:37]([CH3:41])[CH2:38][CH2:39][NH:40][C:4](=[O:6])[C:3]2[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:2]=2[CH3:1])[CH2:35][CH2:36]1)[C:18]1[CH:17]=[CH:16][C:15]([C:14]([OH:42])=[O:13])=[CH:20][CH:19]=1)#[N:30]
Reactant: Cc1cccc(C)c1C(=O)O
Reactant: COC(=O)c1ccc(N(Cc2cccc(C#N)c2)C2CCN(C(C)CCN)CC2)cc1
Product: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(C(=O)O)cc2)CC1

Procedure:
Using general procedure F with 2,6-dimethylbenzoic acid (93 mg, 0.62 mmol) and 4-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(3-cyano-benzyl)-amino]-benzoic acid methyl ester (see EXAMPLE 107) (130 mg, 0.31 mmol) followed by general procedure K with the resulting ester afforded 4-((3-cyano-benzyl)-{1-[3-(2,6-dimethyl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-amino)-benzoic acid as a white solid (107 mg, 64% over 2 steps).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8](N)=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.CC[N:18](CC)CC>>[NH2:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][C:4]=2[C:3]=1[NH2:18]
Reactant: CCN(CC)CC
Reactant: Nc1ccc2c(c1)Cc1cc(N)ccc1-2
Product: Nc1ccc2c(c1N)Cc1ccccc1-2
Yield: 70 %

Procedure:
2″,7″-[Bis-(4′-O-demethylA4β-N-4-desoxypodophyllotoxin)] diamino flourene (8b) was prepared according to the procedure described for the earlier compounds, employing 2,7-diamino flourene (135 mg, 0.5 mmol), Bu4N+I−(185 mg, 0.5 mmol), Et3N (150 mg, 1.5 mmol) and 4′-O-demethyl-4β-bromo podophyllotoxin (462 mg, 1.0 mmol) to give the product in 70% yield. Spectral data: 1H NMR (CDCl3); 7.39-7.45 (d, 2H), 6.78 (S, 2H), 6.66 (S, 2H), 6.50 (S, 2H), 6.43-6.48 (d, 2H), 6.30 (S, 4H), 5.92-6.00 (ABq, 4H), 5.33 (S, 2H), 4.70 (br, 2H), 4.55-4.61 (d, 2H), 4.334.45 (t, 2H), 3.97-4.10(t,2H), 3.79 (S, 6H), 3.08-3.20 (dd, 2H), 2.90-3.08 (m, 2H); FAB MS: m/z 960 (M+); mp. 240-243° C.