Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])[C:6]#[N:7])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH2:32]1[O:34][C@@H:33]1[CH2:35]O.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>C1COCC1>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH3:12])[C:10]=1[O:11][CH2:35][CH:33]1[CH2:32][O:34]1)[C:6]#[N:7])[CH3:2]
Reactant: CCc1cc(C#N)cc(C)c1O
Reactant: OC[C@@H]1CO1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCc1cc(C#N)cc(C)c1OCC1CO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.8 %

Procedure:
To a solution of 3-ethyl-4-hydroxy-5-methyl-benzonitrile (5.06 g, 31.4 mmol) in THF (80 mL), PPh3 (9.06 g, 34.5 mmol) and (R)-glycidol (2.29 mL, 34.5 mmol) are added. The mixture is cooled to 0° C. before DEAD in toluene (15.8 mL, 34.5 mmol) is added. The mixture is stirred for 18 h while warming up to rt. The solvent is evaporated and the crude product is purified by CC on silica gel eluting with heptane:EA 7:3 to give 3-ethyl-5-methyl-4-oxiranylmethoxy-benzonitrile (5.85 g) as a yellow oil; LC-MS: tR=0.96 min; [M+42]+=259.08. b) The above epoxide is dissolved in 7 N NH3 in methanol (250 mL) and the solution is stirred at 65° C. for 18 h. The solvent is evaporated to give crude (S)-4-(3-amino-2-hydroxypropoxy)-3-ethyl-5-methylbenzonitrile (6.23 g) as a yellow oil; LC-MS: tR=0.66 min; [M+1]+=235.11.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[O:19]C(C)(C)C(C)(C)[O:16]3)=[CH:11][CH:10]=2)[N:7]=[C:6](C)[CH:5]=1)[CH3:2].I[C:26]1[C:34]2[C:29](=[N:30][CH:31]=[N:32][C:33]=2[NH2:35])[N:28]([C@H:36]2[CH2:41][CH2:40][C@H:39]([N:42]3[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]3)[CH2:38][CH2:37]2)[N:27]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[C:15]([OH:19])(=[O:16])[CH3:12].[CH2:1]([O:3][C:4]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([C:26]3[C:34]4[C:29](=[N:30][CH:31]=[N:32][C:33]=4[NH2:35])[N:28]([C@H:36]4[CH2:41][CH2:40][C@H:39]([N:42]5[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]5)[CH2:38][CH2:37]4)[N:27]=3)=[CH:11][CH:10]=2)[N:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1cc(C)nn1-c1ccc(C2OC(C)(C)C(C)(C)O2)cc1
Reactant: CN1CCN([C@H]2CC[C@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(=O)O
Product: CCOc1ccnn1-c1ccc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)cc1
Temperature: 25 °C

Procedure:
A mixture of 5-ethoxy-3-methyl-1-[4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl]-1H-pyrazole (0.062 g, 0.00019 mol), trans-3-iodo-1-[4-(4-methylpiperazino)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.070 g, 0.000159 mol), tetrakis-(triphenylphosphine)palladium (0.011 g, 0.0000095 mol) and sodium carbonate monohydrate (0.049 g, 0.000398 mol) was heated in a mixture of ethylene glycol dimethyl ether (5 mL) and water (3 mL) at 80° C. for 16 hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature and solvents were removed under the reduced pressure. The residue was purified by preparative HPLC (Hypersil C18, 8 μm, 25 cm; 10-60% acetonitrile-0.1M ammonium acetate over 25 min, 21 mL/min) to yield trans-3-[4-(5-ethoxy-1H-1-pyrazolyl)phenyl]-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine acetate (0.037 g, 0.000064 mol) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:26]=[N:25][C:24]2[NH:23][CH2:22][CH2:21][O:20][C:19]=2[CH:18]=1.Br[C:28]1[CH:33]=[CH:32][CH:31]=C[C:29]=1[S:34]([NH:37][C@H:38]([CH3:41])[CH2:39][OH:40])(=[O:36])=[O:35]>>[O:20]1[CH2:21][CH2:22][NH:23][C:24]2[N:25]=[CH:26][C:17]([C:3]3[CH:4]=[CH:5][C:6]([C:8]4[C:29]([S:34]([NH:37][C@H:38]([CH3:41])[CH2:39][OH:40])(=[O:35])=[O:36])=[CH:28][CH:33]=[CH:32][CH:31]=4)=[CH:7][C:2]=3[F:1])=[CH:18][C:19]1=2
Reactant: C[C@H](CO)NS(=O)(=O)c1ccccc1Br
Reactant: CC1(C)OC(c2ccc(-c3cnc4c(c3)OCCN4)c(F)c2)OC1(C)C
Product: C[C@H](CO)NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc3c(c2)OCCN3)c(F)c1

Procedure:
The title compound was prepared in a manner similar to that described in Example 444 using 7-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine and (R)-2-bromo-N-(1-hydroxypropan-2-yl)benzenesulfonamide. MS (ESI): mass calcd. for C22H22FN3O4S, 443.13; m/z found, 444.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.16-8.10 (m, 1H), 7.82-7.79 (m, 1H), 7.74-7.71 (m, 1H), 7.70-7.64 (m, 1H), 7.61-7.57 (m, 1H), 7.54-7.46 (m, 1H), 7.40-7.33 (m, 3H), 4.40-4.36 (m, 2H), 3.75-3.69 (m, 2H), 3.48-3.33 (m, 2H), 3.24-3.16 (m, 1H), 1.05-1.01 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[C:11]([F:23])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[CH2:24]([CH:26]1[CH2:29][CH:28]([C:30](Cl)=[O:31])[CH2:27]1)[CH3:25].C(C1CC(C(Cl)=O)C1)CCCCCCC>>[CH2:24]([CH:26]1[CH2:29][CH:28]([C:30]([O:8][C:7]2[CH:6]=[CH:5][C:4]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[C:11]([F:23])[CH:10]=3)=[CH:3][C:2]=2[F:1])=[O:31])[CH2:27]1)[CH3:25]
Reactant: CCCCCCCOc1ccc(-c2ccc(O)c(F)c2)cc1F
Reactant: CCC1CC(C(=O)Cl)C1
Agent: CCCCCCCCC1CC(C(=O)Cl)C1
Product: CCCCCCCOc1ccc(-c2ccc(OC(=O)C3CC(CC)C3)c(F)c2)cc1F
Yield: 91.8 %

Procedure:
Except that 0.60 g of the crude 3,3'-difluoro-4-hydroxy-4'-heptyloxybiphenyl obtained in Example 6-(c) was used in place of 0.7 g of the crude 3,3'-difluoro-4-hydroxy-4'-decyloxybiphenyl and 0.3 g of 3-ethylcyclobutanecarboxylic acid chloride obtained in Example 13-(d) in place of 0.5 g of the 3-octylcyclobutanecarboxylic acid chloride used in Example 9-(g) and purification was carried out by way of column chromatography on silica gel (eluent: hexane/benzene=2/1), the operation was performed in the same manner as in Example 9-(g) to obtain 0.74 g (yield 90.6%) of 3,3'-difluoro-4-heptyloxybiphenyl-4'-yl 3-ethylcyclobutanecarboxylate.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:33][NH:32][C:31](=[O:34])[C:4]=2[C:5]([NH:23][C:24]2[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=2)=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[NH:15]C(=O)OC(C)(C)C.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>C(Cl)Cl>[C:37]([OH:39])([C:36]([F:41])([F:40])[F:35])=[O:38].[NH2:15][C@H:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C@H:9]1[NH:8][C:7]1[N:6]=[C:5]([NH:23][C:24]2[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=2)[C:4]2[C:31](=[O:34])[NH:32][CH2:33][C:3]=2[C:2]=1[Cl:1]
Reactant: Cc1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)c(Cl)c3c2C(=O)NC3)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3N)c(Cl)c3c2C(=O)NC3)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
To a solution of tert-butyl (1S,2R)-2-(7-chloro-3-oxo-4-(m-tolylamino)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (20 mg, 0.041 mmol) in DCM (0.8 mL) was added trifluoroacetic acid (0.31 mL). The reaction mixture was stirred at RT for 1 h, then concentrated to a brown residue which was diluted in MeOH (2 mL) and purified via preparative HPLC to give a TFA salt of the title compound as a fluffy white solid (12.3 mg, 61.9%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.85 (s, 1H), 8.36 (s, 1H), 7.83 (br s, 3H), 7.39-7.57 (m, 2H), 7.12-7.32 (m, 1H), 6.84 (d, J=7.6 Hz, 1H), 6.22 (d, J=6.8 Hz, 1H), 4.19-4.43 (m, 3H), 3.71 (br s, 1H), 2.32 (s, 3H), 1.37-1.99 (m, 8H). [M+H] calc'd for C20H24ClN5O, 386. found, 386.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)([CH3:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(C1(C2C=CC(OC)=C(C=2)[CH:30]=[O:31])CC1)#N>>[C:1]1([C:7]#[C:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([CH:13]=2)[CH:30]=[O:31])([CH3:11])[CH3:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(C(C)(C)C#Cc2ccccc2)cc1
Reactant: COc1ccc(C2(C#N)CC2)cc1C=O
Product: COc1ccc(C(C)(C)C#Cc2ccccc2)cc1C=O

Procedure:
This compound was prepared from Compound 67 in the same manner of Compound 2.
Reaction SMILES: S1C=CC=C1.[Li]CCCC.Br[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.[Li]C1C=CC=CN=1.[C:25]1(=[O:30])[CH2:29][CH2:28][CH:27]=[CH:26]1>C(OCC)C.[Cu](I)I.CCOC(C)=O>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH:27]1[CH2:28][CH2:29][C:25](=[O:30])[CH2:26]1
Reactant: Brc1ccccn1
Reactant: O=C1C=CCC1
Agent: I[Cu]I
Agent: [Li]CCCC
Agent: [Li]c1ccccn1
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: c1ccsc1
Product: O=C1CCC(c2ccccn2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.9 %

Procedure:
A solution of thiophene (0.50 g, 6.0 mmol), diethyl ether (50 mL), and n-BuLi (2.5 M, 2.20 mL, 5.50 mmol) was stirred at room temperature for 1 hour. The reaction mixture was cooled to <5° C. and copper iodide (1.05 g, 5.50 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 1 hour. In a separate flask, a solution of 2-bromopyridine (0.87 g, 5.50 mmol) in diethyl ether (50 mL) was cooled to <−70° C. and n-BuLi (2.5 M, 2.20 mL, 5.50 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 10 minutes. The 2-lithiopyridine reagent was added to the first reaction mixture via cannula and stirred at room temperature for 1 hour. To the reaction mixture was added 2-cyclopenten-1-one (0.45 g, 5.50 mmol) in diethyl ether (10 mL) and the reaction mixture was stirred for 1 hour. The reaction was poured into EtOAc (150 mL) and washed with brine (100 mL), dried (Na2SO4), filtered, and concentrated. The material was purified by flash column chromatography (20% EtOAc/hexanes), to provide the title compound (0.38 g, 43%). 1H NMR (CD3OD, 300 MHz) δ 2.10-2.19 (m, 1H), 2.13-2.66 (m, 5H), 3.56-3.68 (m, 1H), 7.27 (ddd, J=1.0, 5.1, 7.5 Hz, 1H), 7.38 (dd, J=1.02, 7.80 Hz, 1H), 7.76 (ddd, J=2.0, 7.80, 7.80 Hz, 1H), 8.47-8.50 (m, 1H); MS (DCI) m/z 162 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:19])[C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[NH2:18])=[CH:5][CH:4]=1.[N:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:34][CH2:33][CH:29]([C:30]([Cl:32])=[O:31])[CH2:28][CH2:27]2)=[CH:22][CH:21]=1>>[ClH:32].[F:17][C:16]1[C:11]([C:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:19])=[C:12]([NH:18][C:30]([CH:29]2[CH2:28][CH2:27][N:26]([C:23]3[CH:22]=[CH:21][N:20]=[CH:25][CH:24]=3)[CH2:34][CH2:33]2)=[O:31])[CH:13]=[CH:14][CH:15]=1
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Reactant: COc1ccc(NC(=O)c2c(N)cccc2F)cc1
Product: COc1ccc(NC(=O)c2c(F)cccc2NC(=O)C2CCN(c3ccncc3)CC2)cc1
Product: Cl
Yield: 65.3 %

Procedure:
Using the procedure described in Example 138, N-(4-methoxyphenyl)-2-amino-6-fluorobenzamide (1.8 mmol) and N-(4-pyridyl)isonipecotoyl chloride (3.6 mmol), purifying with RPHPLC Method A, yielded 570 mg (66%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1O.[CH3:9][O:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][C:12]=1[NH2:20]>>[NH2:20][C:12]1[CH:13]=[C:14]([C:15]2[O:17][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)[CH:18]=[CH:19][C:11]=1[O:10][CH3:9]
Reactant: Nc1ccccc1O
Reactant: COc1ccc(C(=O)O)cc1N
Product: COc1ccc(-c2nc3ccccc3o2)cc1N

Procedure:
Prepared by the method of Example 1a), from 2-aminophenol (326 mg, 2.9 mmol) and 4-methoxy-3-aminobenzoic acid (500 mg, 2.9 mmol) the subtitle compound was obtained, 97 mg (13%). 1H NMR (CDCl3) δ 7.66–7.45(m, 4H), 7.24(m, 2H), 6.82(d, J=8.3 Hz, 1H), 3.86(s, 3H). MS 241 m/z (M+H)+.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][CH:18]=1)(=O)C.CO.[OH-].[Na+]>C1COCC1.O>[I:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][OH:4])=[CH:22][CH:21]=1
Reactant: CC(=O)OCCCCCCCCCCCCc1ccc(I)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: OCCCCCCCCCCCCc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 0.1 %

Procedure:
12-(p-Iodophenyl)dodecyl acetate 34 (872 mg, 2.03 mol) was dissolved in THF (4 ml) and MeOH (4 ml) mixture, and a solution of NaOH (325 mg, 8.11 mmol) in H2O (1 ml) was added. The mixture was stirred at room temperature for 5 h, quenched with 1 N HCl to pH 7, diluted with NaHCO3 solution and extracted with EtOAc. The extract was dried over Na2SO4 and the solvent was evaporated. Silica gel chromatography of the residue in hexane-ethyl acetate (95:5, 90:10) yielded the product (682 mg, 87%) as a white solid.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH:5]1[CH:10]=[C:9]([O:11]C)[CH2:8][C:7]([O:13]C)=[CH:6]1.Cl>O1CCCC1.O>[CH3:1][NH:2][CH2:3][CH2:4][CH:5]1[CH2:6][C:7](=[O:13])[CH2:8][C:9](=[O:11])[CH2:10]1
Reactant: CNCCC1C=C(OC)CC(OC)=C1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CNCCC1CC(=O)CC(=O)C1
Temperature: 50 °C
Yield: 82.6 %

Procedure:
To a stirred solution of N-methyl-1,5-dimethoxycyclohexa-1,4-diene-3-ethylamine (5.5 g, 27.9 mmol) in 20 ml of tetrahydrofuran was added 10 ml of 6 N hydrochloric acid in one portion. The warm solution was heated for 15 min. at 50° C. and concentrated to give a light yellow oil. The crude oil was dissolved in 25 ml of water, and the solution was mixed with 50 g of Dowex 50X8 resin (previously washed with 2 N HCl and deionized water) in a sintered glass funnel. After a few minutes, the aqueous solution was drawn out by suction, and the resin rinsed with four 50 ml-portions of water, and then with eight 35 ml-portions of 2 M aqueous pyridine. Pyridine fractions 3-8 were pooled and concentrated to give 3.9 g of 5-[(2-methylamino)ethyl]-cyclohexane-1,3-dione. An analytical sample crystallized from water and had mp 171°-4° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([CH3:13])[C:8]1[CH:14]=[C:15]([O:24][CH2:25][C@@H:26]([NH:31]C(=O)OC(C)(C)C)[CH2:27][CH:28]([CH3:30])[CH3:29])[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[CH:17][C:7]2=1.Cl.O1CCOCC1.C([O-])(O)=O.[Na+]>CO.O>[NH2:31][C@@H:26]([CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:25][O:24][C:15]1[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:17][C:7]2[C:6]3[C:11](=[C:2]([CH3:1])[N:3]=[CH:4][CH:5]=3)[C:10](=[O:12])[N:9]([CH3:13])[C:8]=2[CH:14]=1
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)c(-c3ccccn3)cc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@@H](N)CC(C)C)c(-c3ccccn3)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.3 %

Procedure:
To a solution of (S)-tert-butyl (1-((4,6-dimethyl-5-oxo-9-(pyridin-2-yl)-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (35 mg, 0.068 mmol) in Methanol (4 mL) was added HCl in 1,4-dioxane (0.169 mL, 0.677 mmol) at 0° C. Then the reaction mixture was stirred at RT for 2 h. The volatiles were concentrated under reduced pressure. The residue so obtained was basified with saturated aqueous NaHCO3, diluted with water and extracted with DCM (3×5 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude product was purified by reverse phase prep HPLC (Sunfire C18 column (19.0×150 mm) 10.0 micron; mobile phase A: 10 mM ammonium acetate in water; mobile phase B: acetonitrile; flow rate: 16.0 mL) to afford (S)-8-((2-amino-4-methylpentyl)oxy)-4,6-dimethyl-9-(pyridin-2-yl)benzo[c][2,7]naphthyridin-5(6H)-one (10 mg, 0.024 mmol, 35% yield) as an off-white solid. LC/MS (ESI) m/e 417.6 [(M+H)+, calcd for C25H29N4O2 417.2]; LC/MS retention time (method E): tR=0.84 min; HPLC retention time (method A): tR=7.61 min; HPLC retention time (method B): tR=8.29 min; 1H NMR (400 MHz, METHANOL-d4). 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.70 (d, J=4.3 Hz, 1H), 8.64 (s, 1H), 8.58 (d, J=5.5 Hz, 1H), 8.21 (d, J=5.8 Hz, 1H), 8.04-7.94 (m, 1H), 7.93-7.86 (m, 1H), 7.46 (ddd, J=7.3, 5.0, 1.3 Hz, 1H), 7.18 (s, 1H), 4.32 (dd, J=9.5, 4.3 Hz, 1H), 4.13 (dd, J=9.4, 6.7 Hz, 1H), 3.84 (s, 3H), 3.36-3.34 (m, 1H), 3.11 (s, 3H), 1.86-1.70 (m, 1H), 1.53-1.32 (m, 2H), 0.97 (d, J=6.8 Hz, 3H), 0.93 (d, J=6.5 Hz, 3H).
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH:11][C:12]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=O)=[C:9]([C:21]#[N:22])[C:8]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:30]O.[OH-].[Na+]>C(O)C.O>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[N:22][C:21](=[O:30])[C:9]3=[C:8]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OO
Reactant: N#Cc1c(Cc2ccccc2)nn(C2CCCC2)c1NC(=O)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=c1nc(Cc2ccccc2)nc2n(C3CCCC3)[nH]c(Cc3ccccc3)c1-2
Temperature: 0 °C
Reaction time: 1 h
Yield: 22 %

Procedure:
To an ice-cooled solution of 1-cyclopentyl-3-phenylmethyl-4-cyano-5-(phenylmethylcarbonylamino)-1H-pyrazole (1.1 g, 2.8 mmol) in ethanol (30 ml) was added 30% H2O2 (2.5 ml), followed by NaOH (100 mg) dissolved in water (5 ml). The reaction mixture was stirred a such for 1 hour, then at room temperature for 1 hour, then it was heated on a steam bath for 3.5 hours and finally it was stirred at room temperature overnight. The reaction mixture was concentrated to dryness, and partitioned between water (25 ml) and CHCl3 (50 ml). The organic layer was separated, and concentrated in vacuo and the oily residue was crystallized from isopropanol to afford 234 mg (22%) of 1-cyclopentyl-3-phenylmethyl-6-(phenylmethyl)-pyrazolo[3,4-d]pyrimidin-4-one, as a white solid, m.p. 204°-206° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](CC#N)=[C:4]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:3]=1.[OH-:18].[K+].[CH2:20]([OH:22])[CH3:21]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:21][C:20]([OH:18])=[O:22])=[C:4]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:3]=1
Reactant: [OH-]
Reactant: CCO
Reactant: N#CCc1ccc(Br)cc1OC1CCCCC1
Agent: [K+]
Solvent: O
Product: O=C(O)Cc1ccc(Br)cc1OC1CCCCC1

Procedure:
A mixture of (4-bromo-2-cyclohexyloxyphenyl)acetonitrile (1.45 g) and potassium hydroxide (829 mg) in ethanol (17.4 ml) and water (5 ml) was refluxed for 22 hours. Ethanol was removed by evaporation under reduced pressure. To the residue were added water and a mixture of hexane and ethyl acetate (1:1). After separation, the aqueous layer was adjusted below pH 3 with concentrated hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, evaporated and dried in vacuo to give (4-bromo-2-cyclohexyloxyphenyl)acetic acid (1.34 g).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[Cl:21])=[O:12])[N:7]([C:22]2[CH:31]=[C:30]([CH:32]=[O:33])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:34][Mg]Cl>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[Cl:21])=[O:12])[N:7]([C:22]2[CH:31]=[C:30]([CH:32]([OH:33])[CH3:34])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(Cl)c2Cl)n(-c2cc(C=O)c3ccccc3c2)n1
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(O)c1cc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2cccc(Cl)c2Cl)cc2ccccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 41.9 %

Procedure:
To this aldehyde (150 mg, 0.312 mmol) in THF (5 mL) at 0° C. was added dropwise MeMgCl (0.37 mL, 82 mg, 1.09 mmol). The mixture was stirred at 0° C. for 1 h and then warmed to RT and stirred for 7 h. The mixture was treated with an additional batch of MeMgCl (0.2 mL, 0.6 mmol), stirred overnight at RT, treated with additional MeMgCl (0.3 mL, 0.9 mmol) and then quenched with H2O (25 mL) and diluted with EtOAc (25 mL) and 5% citric acid (10 mL). The organic phase was separated, washed with brine dried (Na2SO4), filtered, concentrated and purified to yield 1-(3-t-butyl-1-(4-(1-hydroxyethyl)naphthalen-2-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea (65 mg, 42% yield). 1H-NMR (300 MHz, DMSO-d6): δ 1.31 (s, 9H), 1.49 (d, J=6.2 Hz, 3H), 5.47-5.48 (m, 1H), 5.53-5.54 (m, 1H), 6.45 (s, 1H), 7.28-7.31 (m, 2H), 7.57-7.60 (m, 2H), 7.83 (s, 1H), 7.94 (s, 1H), 8.02-8.18 (m, 3H), 8.78 (s, 1H), 9.31 (s, 1H); MS (ESI) m/z: 499.0 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:13]=[CH:12][NH:11][CH:10]=2)[O:3]1.CC1(C)C(C)(C)OB(C2C=NNC=2)O1.[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([N:11]1[CH:12]=[CH:13][C:9]([B:4]2[O:3][C:2]([CH3:14])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:10]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC1(C)OB(c2cc[nH]c2)OC1(C)C
Reactant: BrCc1ccccc1
Agent: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: CC1(C)OB(c2ccn(Cc3ccccc3)c2)OC1(C)C

Procedure:
The title compound was prepared by substituting 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole for and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and benzyl bromide for EXAMPLE 4A in EXAMPLE 4B.
Reaction SMILES: C([Li:5])CCC.Cl[P:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.BrC(Br)CC[C].O>CCCCCC.O1CCCC1>[C:8]1([P:7]([Li:5])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: [Li]CCCC
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: [C]CCC(Br)Br
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: [Li]P(c1ccccc1)c1ccccc1
Reaction time: 15 h

Procedure:
Diphenylphosphino lithium was prepared by adding n-butyl lithium (12.5 ml, 1.6 molar, 0.02 mole) in hexane to a solution of chlorodiphenylphosphine (3.76 g, 0.02 mole) in tetrahydrofuran. The dibromopropyl carbon of step 2 was added and the mixture was stirred for 15 hours. Water (100 ml) was added and the mixture stirred for 15 hours. Water (100 ml) was added and the product filtered. After washing with tetrahydrofuran and drying at 55° C. and 0.1 mm Hg pressure for three hours, the product contained 1.24 wt. % phosphorus.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([CH:13]2[CH2:17][NH:16][C:15](=[O:18])[CH2:14]2)=[CH:7][C:6]=1[O:19][CH3:20])[CH3:4].[CH3:21]I>O1CCCC1.CN(C)C=O>[CH2:3]([C:5]1[C:6]([O:19][CH3:20])=[CH:7][C:8]([CH:13]2[CH2:17][N:16]([CH3:21])[C:15](=[O:18])[CH2:14]2)=[CH:9][C:10]=1[O:11][CH3:12])[CH3:4]
Reactant: CI
Reactant: CCc1c(OC)cc(C2CNC(=O)C2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCc1c(OC)cc(C2CC(=O)N(C)C2)cc1OC
Temperature: 25 °C
Yield: 86.4 %

Procedure:
3.12 g (78 mmol) of a sodium hydride dispersion (60% in oil) were added using a spatula and while stirring to a suspension of 8.85 g (35.5 mmol) of 4-(4-ethyl-3,5-dimethoxy-phenyl)-pyrrolidin-2-one in 250 ml of tetrahydrofuran and 2 ml of dimethylformamide and the mixture was stirred at room temperature for a further hour. Thereafter, the reaction mixture was treated with 3.52 ml (106.5 mmol) of methyl iodide and left to stir at room temperature for a further 16 hours. Subsequently, the reaction mixture was poured on to 400 ml of ice-water and extracted twice with 600 ml of ethyl acetate each time. The combined organic phases were washed twice with 300 ml of saturated sodium chloride solution each time, dried (MgSO4) and concentrated in a vacuum. The crude product was purified by column chromatography on silica gel (methylene chloride/methanol 39:1). 8.08 g (86%) of 4-(4-ethyl-3,5-dimethoxy-phenyl)-1-methyl-pyrrolidin-2-one were obtained as a beige solid.