Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>CN(C=O)C>[C:3]1([C:9]2[CH:10]=[N:11][N:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:13]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc(-c2cn[nH]c2)cc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cc(-c2ccccc2)cn1
Reaction time: 1 h

Procedure:
To a slurry of 3.0g (0.075 mol) of sodium hydride in 30 mL of DMF at room temperature was added 10g (0.069 mol) of 4-phenyl-1H-pyrazole of example 1. The mixture was stirred 1 hr and 7.8 mL (0.07 mol) of ethyl bromoacetate was added with cooling. The reaction was stirred 3 hr at room temperature, briefly at 100° C. and was poured onto ice. The product was filtered off, rinsed with water, dried, and washed with hexane to yield 14.0g of ethyl 4-phenyl-1H-pyrazole-1-acetate.
Reaction SMILES: C(O[K])(C)(C)C.[C:7]([O:11][C:12](=[O:18])[N:13]([CH2:15][CH2:16][OH:17])[CH3:14])([CH3:10])([CH3:9])[CH3:8].F[C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=[O:23]>O1CCOCC1>[C:7]([O:11][C:12](=[O:18])[N:13]([CH2:15][CH2:16][O:17][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=[O:23])[CH3:14])([CH3:10])([CH3:8])[CH3:9]
Reactant: O=Cc1ccccc1F
Reactant: CN(CCO)C(=O)OC(C)(C)C
Agent: CC(C)(C)O[K]
Solvent: C1COCCO1
Product: CN(CCOc1ccccc1C=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 28.6 %

Procedure:
tBuOK (2.69 g; 24 mmol; 1.2 eq.) was added portionwise to a solution of (2-hydroxy-ethyl)-methyl-carbamic acid tert-butyl ester (3.5 g; 20 mmol; 1 eq.) and 2-fluoro-benzaldehyde (2.97 g; 24 mmol; 1.2 eq.) in 1,4-dioxane (30 mL) and the reaction mixture was stirred at room temperature for 20 minutes. After dilution with EA, the solution was washed with water (2×) then brine, dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (15% to 50% EA in cyclohexane) afforded the title compound (1.6 g, 29%) as a colourless oil. HPLC (max plot) 89.3%; Rt 4.21 min.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1[CH:10]=[CH:11][C:12](=[O:16])[CH2:13][CH2:14][CH3:15].[OH:17]C1(C)CC(O)CC(C)(C)C1C=CC(O)C>>[OH:17][C:2]1([CH3:1])[CH2:7][CH2:6][CH2:5][C:4]([CH3:8])([CH3:9])[CH:3]1[CH:10]=[CH:11][CH:12]([OH:16])[CH2:13][CH2:14][CH3:15]
Reactant: CC(O)C=CC1C(C)(C)CC(O)CC1(C)O
Reactant: CCCC(=O)C=CC1=C(C)CCCC1(C)C
Product: CCCC(O)C=CC1C(C)(C)CCCC1(C)O

Procedure:
The entitled compound was prepared from 1-(2,6,6-trimethylcyclohex-1-enyl)hex-1-en-3-one in the same manner as in Example 1-(4), (5), and (6).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[CH:5][C:6]2[S:10][CH:9]=[N:8][C:7]=2[CH:11]=1.I[C:15]1[C:16]([NH:29][CH:30]2[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31]2)=[N:17][C:18]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:19][C:20]=1[O:21][CH3:22].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)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.[Cu]I>[CH3:22][O:21][C:20]1[N:19]=[C:18]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:17]=[C:16]([NH:29][C@@H:30]2[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31]2)[C:15]=1[C:9]1[S:10][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:12])[F:13])=[CH:11][C:7]=2[N:8]=1
Reactant: FC(F)(F)c1ccc2scnc2c1
Reactant: COc1nc(N2CCOCC2)nc(NC2CCCN(C(=O)OC(C)(C)C)C2)c1I
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1nc(N2CCOCC2)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1-c1nc2cc(C(F)(F)F)ccc2s1
Temperature: 85 °C

Procedure:
Into a 25-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of 5-(trifluoromethyl)-1,3-benzothiazole (100 mg, 0.49 mmol, 1.80 equiv) in N,N-dimethylformamide (5.0 mL), tert-butyl 3-[[5-iodo-6-methoxy-2-(morpholin-4-yl)pyrimidin-4-yl]amino]piperidine-1-carboxylate (140.2 mg, 0.27 mmol, 1.00 equiv), Cesium Carbonate (534.3 mg, 6.00 equiv), Tetrakis(triphenylphosphine)palladium (57.8 mg, 0.05 mmol, 0.18 equiv), and Copper (I) iodide (9.5 mg, 0.05 mmol, 0.18 equiv). The resulting mixture was heated for 2.5 h at 85° C. in an oil bath, cooled down, quenched by the addition of 15 mL of water and then extracted with ethyl acetate (4×15 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous sodium sulfate. After filtration and concentration under reducing pressure, the residue was purified by chromatography on a silica gel column eluting with petroleum ether/ethyl acetate (10:1-3:1) to afford the title compound as a gray white solid. MS m/z [M+H]+ (ESI): 595
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH:18]([OH:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:15])=[CH:9][CH:8]=1)(OC)=[O:2].[NH3:26]>CO>[C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH:18]([OH:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:15])=[CH:9][CH:8]=1)(=[O:2])[NH2:26]
Reactant: N
Reactant: COC(=O)COc1ccc(CC(C)NCC(O)c2ccccc2)cc1
Solvent: CO
Product: CC(Cc1ccc(OCC(N)=O)cc1)NCC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of N-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-phenylethanamine (0.5 g) in methanol (10 ml) was treated with a solution of 0.880 ammonia (40 ml), the resulting mixture boiled for 11/2 hours then stirred at ambient temperature for 18 hours. The resulting white precipitate was filtered off to yield the title compound (0.17 g) m.p. 158°-162°, as an 82:18 mixture of diastereoisomers.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:10]=2)[CH:2]=1.Cl.[CH:25]([O:28][C:29](=[O:36])[C@H:30]([CH2:32][CH2:33][S:34][CH3:35])[NH2:31])([CH3:27])[CH3:26]>>[CH:25]([O:28][C:29](=[O:36])[C@H:30]([CH2:32][CH2:33][S:34][CH3:35])[NH:31][C:13](=[O:14])[C:12]1[CH:16]=[CH:17][C:9]([CH2:8][O:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:10][C:11]=1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([CH3:27])[CH3:26]
Reactant: CSCC[C@H](N)C(=O)OC(C)C
Reactant: O=C(O)c1ccc(COc2cccnc2)cc1-c1ccccc1
Agent: Cl
Product: CSCC[C@H](NC(=O)c1ccc(COc2cccnc2)cc1-c1ccccc1)C(=O)OC(C)C

Procedure:
The desired compound was prepared by coupling of 4-(3-pyridyloxymethyl)-2-phenylbenzoic acid, prepared as in Example 228D with methionine isopropyl ester hydrochloride, prepared as in Example 229B using the procedure of Example 186C. 1H NMR (300 MHz, CD3OD) δ 8.70 (d, 1H), 8.46 (d, 1H), 8.31 (ddd, 1H), 8.01 (dd, 1H), 7.58 (m, 3H), 7.33-7.47 (m, 5H), 5.45 (s, 2H), 5.00 (heptet, 1H), 4.44 (m, 1H), 2.00-2.24 (m, 2H), 2.01 (s, 3H), 1.96 (m, 1H), 1.77 (m, 1H), 1.24 (d, 3H), 1.22 (d, 3H). MS (CI NH3) m/e 479 (M+H)+, 451, 419, 320, 288, 192. Anal calcd for C27H31ClN2O4S (+0.60 H2O): C, 61.67; H, 6.17; N, 5.33. Found: C, 61.67; H, 6.17; N, 5.33.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([OH:12])[C:10]#[CH:11].[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.O>[CH2:9]([O:12][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]#[CH:11]
Reactant: BrCc1ccccc1
Reactant: C#CCO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: C#CCOCc1ccccc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Tetrabutylammonium bromide (19.34 g, 600 mmol) was added to a solution of benzylbromide (71.3 ml, 600 mmol) and propargyl alcohol (35.5 ml, 600 mmol) in 270 ml of toluene and the mixture was heated to 50° C. A solution of sodium hydroxide (24 g, 600 mmol) in 55 ml of water was then added dropwise over a period of 1 hour and stirring was continued for another 3 hours. The reaction mixture was then cooled to 25° C. and transferred into a separatory funnel. The aqueous layer was removed and the organic layer was washed three times with 150 ml of brine. Residual water was removed by repeated azeotropic distillation using toluene. A pale yellow liquid was obtained. Yield: 81.9 g (93.4 %).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[CH3:7][N:6]1[C:2]([C:21]2[CH:22]=[CH:23][C:18]([C:17]([F:28])([F:27])[F:16])=[CH:19][CH:20]=2)=[C:3]([C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)[N:4]=[CH:5]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Product: Cn1cnc(-c2cc(C#N)ccn2)c1-c1ccc(C(F)(F)F)cc1
Yield: 93 %

Procedure:
The title compound was prepared in 93% yield from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile and 4-(trifluoromethyl)phenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C17H11F3N4, 329. Found, 329.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[CH:5]2.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=O)[CH:13]=1.C([SiH](CC)CC)C>ClCCl.FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[C:5]2[CH2:18][C:14]1[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cc2cc(Br)ccc2[nH]1
Reactant: O=Cc1cccnc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1[nH]c2ccc(Br)cc2c1Cc1cccnc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
A solution of 5-bromo-2-methyl-1H-indole (J. Chem. Soc., 1428 (1965)) (2.0 g) and 3-pyridinecarboxaldehyde (1.02 g) in dry dichloromethane (20 ml) was added dropwise over 10 minutes to a stirred solution of triethylsilane(3.30 g) in trifluoroacetic acid (20 ml) at 0° C. The solution was stirred at 0° C. for 30 minutes and then evaporated under vacuum, keeping the temperature below 35° C. The residue was dissolved in dichloromethane, and the solution was washed with 2N sodium hydroxide, water and dried (MgSO4). The solution was evaporated and the residue was chromatographed on silica gel, using dichloromethane/methanol (50:1) as eluent. The product fractions were combined and evaporated, and the residue was crystallised from ether to give the title compound (2.15 g), m.p. 188°-190° C. Found: C,59.62; H,4.43; N,9.26. C15 H13BrN2 requires: C,59.82; H,4.35; N,9.30%.
Reaction SMILES: [BH4-].[Na+].[C:3]([O:6][CH:7]1[CH2:19][CH2:18][C:10]2([CH2:15][CH2:14][CH:13]([CH:16]=[O:17])[CH2:12][CH2:11]2)[CH2:9][CH2:8]1)(=[O:5])[CH3:4].[Cl-].[NH4+]>CO>[OH:17][CH2:16][CH:13]1[CH2:12][CH2:11][C:10]2([CH2:9][CH2:8][CH:7]([O:6][C:3](=[O:5])[CH3:4])[CH2:19][CH2:18]2)[CH2:15][CH2:14]1
Reactant: CC(=O)OC1CCC2(CCC(C=O)CC2)CC1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CC(=O)OC1CCC2(CCC(CO)CC2)CC1
Reaction time: 2 h
Yield: 110.2 %

Procedure:
Sodium borohydride (0.110 g) was added, at 0° C. and under nitrogen atmosphere, to a solution of 1.35 g of 9-acetoxy-3-formyl-spiro[5.5]undecane (IV) in 50 ml of methanol. After 2 hrs, 10 ml. of a saturated aqueous ammonium chloride solution were added and the resulting mixture evaporated under reduced pressure. The residue, dissolved in 150 ml. of ethyl acetate, was washed with water to neutral pH; the organic layer, dried over anhydrous sodium sulfate, was evaporated under reduced pressure to give 1.50 g of 9-hydroxymethyl-3-acetoxy-spiro[5.5]undecane used as such in the following step. TLC: Rf=0.35 (SiO2 plates, diethylether/n-hexane 55/45). 1H-NMR (300 MHz, CDCl3, ppm from TMS): 4.73 (1H, hept), 3.47 (2H, d), 2.03 (3H, s) 1.90-0.95 (17H, m).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](I)[O:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1)=[O:5])[CH3:2].CC1(C)C(C)(C)OB([C:39]2[CH:44]=[CH:43][N:42]=[C:41]3[NH:45][CH:46]=[CH:47][C:40]=23)O1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:39]2[CH:44]=[CH:43][N:42]=[C:41]3[NH:45][CH:46]=[CH:47][C:40]=23)[O:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1)=[O:5])[CH3:2]
Reactant: CC1(C)OB(c2ccnc3[nH]ccc23)OC1(C)C
Reactant: CCOC(=O)c1nc(I)oc1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nc(-c2ccnc3[nH]ccc23)oc1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Yield: 82 %

Procedure:
To a mixture of tert-butyl 4-(4-(4-(ethoxycarbonyl)-2-iodooxazol-5-yl)phenyl)piperazine-1-carboxylate (0.080 g, 0.15 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (0.093 g, 0.38 mmol) and sodium carbonate (0.048 g, 0.45 mmol) in toluene (0.81 ml), ethanol (0.49 ml) and water (0.23 ml) was added bis(triphenylphosphine)palladium (II) chloride (0.005 g, 0.007 mmol) and the resulting mixture irradiated in the microwave at 120° C. for 60 minutes. The reaction mixture was diluted with EtOAc and washed with H2O. The organic phase was passed through a MP-SH cartridge, dried over MgSO4 and the solvent removed in vacuo. The residue was purified by silica gel column chromatography using a 0-100% EtOAc in hexane gradient to afford tert-butyl 4-(4-(4-(ethoxycarbonyl)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)oxazol-5-yl)phenyl)piperazine-1-carboxylate (0.070 g, 0.123 mmol, 81%) as a yellow solid. 1H NMR (CDCl3) δ 1.46 (3H, t), 1.49 (9H, s), 3.31 (4H, m), 3.61 (4H, m), 4.47 (2H, q), 7.00 (2H, d), 7.24 (1H, m), 7.55 (1H, m), 7.90 (1H, d), 8.18 (2H, d), 8.46 (1H, d), 10.68 (1H, br s). LCMS (3) Rt: 2.63 min; m/z (ES+) 518.
Reaction SMILES: [C:1]1([C:7]2[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[C:10]([C:23]3[CH:24]=[C:25]4[C:30](=[CH:31][CH:32]=3)[CH:29]=[C:28]([O:33][CH2:34][C:35]([O:37]C)=[O:36])[CH:27]=[CH:26]4)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].C1COCC1.CO>O>[C:1]1([C:7]2[N:11]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][CH:18]=3)[C:10]([C:23]3[CH:24]=[C:25]4[C:30](=[CH:31][CH:32]=3)[CH:29]=[C:28]([O:33][CH2:34][C:35]([OH:37])=[O:36])[CH:27]=[CH:26]4)=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)COc1ccc2cc(-c3ccc(-c4ccccc4)n3Cc3ccc(C(F)(F)F)cc3)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)COc1ccc2cc(-c3ccc(-c4ccccc4)n3Cc3ccc(C(F)(F)F)cc3)ccc2c1
Yield: 81.3 %

Procedure:
In a similar manner as described in step 2 of Example 6, the title compound was prepared from methyl [(6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]acetate (0.20 g, 0.38 mmol), prepared in the previous step, and 1N NaOH (0.58 mL, 0.58 mmol) in 1.67:1.67:1 THF:MeOH:water (39 mL). Purification on a Biotage Horizon™ system with a KP-Sil Flash 25+M column (40 g Silica Gel, 60 Å) using 25% EtOAc in hexane with 1% formic acid as the eluent gave [(6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]acetic acid as an off-white solid (0.155 g, 79%), mp 154–156° C. Elemental Analysis for C30H22F3NO3.0.02 H2O Calc'd: C, 71.80; H, 4.43; N, 2.79. Found: C, 71.96; H, 4.55; N, 2.61.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:19])[C:9]2[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[C:11]([F:17])[C:10]=2[F:18])=[CH:6][N:5]=[C:4]([NH:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([NH:27][S:28]([CH2:31][CH2:32][CH2:33]Cl)(=[O:30])=[O:29])[CH2:23][CH2:22]2)[N:3]=1.CC(C)([O-])C.[K+].[I-].[K+]>O1CCCC1>[NH2:1][C:2]1[C:7]([C:8]([C:9]2[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[C:11]([F:17])[C:10]=2[F:18])=[O:19])=[CH:6][N:5]=[C:4]([NH:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([N:27]3[CH2:33][CH2:32][CH2:31][S:28]3(=[O:30])=[O:29])[CH2:23][CH2:22]2)[N:3]=1
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(N[C@H]2CC[C@H](NS(=O)(=O)CCCCl)CC2)nc1N
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(N[C@H]2CC[C@H](N3CCCS3(=O)=O)CC2)nc1N

Procedure:
The chloride (530 mg, 1.02 mmol, Example 293) was dissolved in tetrahydrofuran (8 mL). To it was added potassium t-butoxide (395 mg, 3.53 mmol, Aldrich) and potassium iodide (10 mg). The mixture was heated at reflux for 3 hours and the reaction was quenched with 0.5N hydrochloric acid (1 mL). The mixture was extracted with ethyl acetate (3×10 mL) and the extracts were combined and dried with sodium sulfate. Removal of solvent gave the crude which was chromatographed (5% methanol/dichloromethane) to give a pale yellow solid. 412 mg, 85%. MS (ES) MH+=482. CDK4 IC50=0.005 μM; CDK1 IC50=0.028 μM; CDK2 IC50=0.008 μM; HCT 116 IC90=0.320 μM.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:12]([OH:14])=O)=[N:7][C:8]=1[N+:9]([O-:11])=[O:10].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[F:47][C:48]1[CH:49]=[C:50]([C@@H:59]([C:61]2[C:66]([F:67])=[CH:65][CH:64]=[CH:63][N:62]=2)[NH2:60])[CH:51]=[CH:52][C:53]=1[O:54][C:55]([F:58])([F:57])[F:56]>CN(C=O)C.CCCCCC.O.CCOC(C)=O>[F:47][C:48]1[CH:49]=[C:50]([C@@H:59]([C:61]2[C:66]([F:67])=[CH:65][CH:64]=[CH:63][N:62]=2)[NH:60][C:12](=[O:14])[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:8]([N+:9]([O-:11])=[O:10])[N:7]=2)[CH:51]=[CH:52][C:53]=1[O:54][C:55]([F:58])([F:57])[F:56]
Reactant: N[C@@H](c1ccc(OC(F)(F)F)c(F)c1)c1ncccc1F
Reactant: COc1ccc(C(=O)O)nc1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(C(=O)N[C@@H](c2ccc(OC(F)(F)F)c(F)c2)c2ncccc2F)nc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 5-methoxy-6-nitropicolinic acid (200 mg, 0.001 mol) in DMF was added EDCI.HCl (231.6 mg, 0.0012 mol, Molekula, India) followed by HOBt (164.7 mg, 0.0012 mol, Spectrochem, India), DIPEA (521.87 mg, 0.0040 mol, Spectrochem, India) and (S)-(3-fluoro-4-(trifluoromethoxy) phenyl) (3-fluoropyridin-2-yl) methanamine hydrochloride (349.83 mg, 0.0010 mmol, Intermediate 6) at 0° C. The reaction mixture was stirred at room temperature overnight. After completion of the reaction (monitored by TLC, 50% EtOAc in hexane), water (20 mL) was added to the reaction mixture, and the aqueous solution was extracted with EtOAc (20 mL×2). The combined organic layers were washed with water (100 mL×2). The organic layer was dried and concentrated providing a residue which was purified by silica gel (60-120 mesh) column chromatography eluting with 40-50% EtOAc in petroleum ether to give the title compound as a solid. 1H-NMR (400 MHz, DMSO-d6): δ 9.46 (d, J=7.6 Hz, 1H), 8.53 (d, J=4.4 Hz, 1H), 8.34 (d, J=8.4 Hz, 1H), 8.12 (d, J=8.8 Hz, 1H), 7.83 (t, J=9.6 Hz, 1H), 7.58-7.55 (m, 3H), 7.35 (d, J=8.4 Hz, 1H), 6.57 (d, J=7.2 Hz, 1H), 4.04 (s, 3H). MS (ESI, positive ion) m/z: 485 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:30]([F:33])([F:32])[F:31])[O:13][N:12]=[C:11]([C:14]3[CH:28]=[CH:27][C:17]([C:18]([NH:20][C:21]4[CH:22]=[N:23][CH:24]=[N:25][CH:26]=4)=[O:19])=[C:16]([CH3:29])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(N(CC)CC)C.Cl[C:42]([O:44][CH3:45])=[O:43]>CN(C)C1C=CN=CC=1.O1CCCC1>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:30]([F:31])([F:33])[F:32])[O:13][N:12]=[C:11]([C:14]3[CH:28]=[CH:27][C:17]([C:18]([N:20]([C:21]4[CH:26]=[N:25][CH:24]=[N:23][CH:22]=4)[C:42](=[O:43])[O:44][CH3:45])=[O:19])=[C:16]([CH3:29])[CH:15]=3)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: COC(=O)Cl
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Nc1cncnc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)N(C(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C)c1cncnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.1 %

Procedure:
In a solution of 0.25 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole-3-yl]-2-methyl-N-(5-pyrimidinyl)benzoic acid amide synthesized in Step 1 of Synthetic Example 14, 0.15 g of triethylamine and a catalytic amount of 4-(dimethylamino)pyridine in 4 mL of tetrahydrofuran, 0.15 g of methyl chloroformate was added, and stirred at room temperature for 16 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure, 10 mL of ethyl acetate was added and insoluble material was filtered off. The solvent was distilled off under reduced pressure and the residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (1:1) to obtain 0.14 g of the aimed product as white crystal.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8](C(C)=C)[C:7]1=[O:18].Cl>C(O)C.O.ClCCl>[CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]1=[O:18]
Reactant: C=C(C)n1c(=O)n(CCC(=O)OC)c2ccccc21
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: COC(=O)CCn1c(=O)[nH]c2ccccc21
Temperature: 60 °C
Yield: 86.4 %

Procedure:
To a stirred solution of 3-(3-Isopropenyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-propionic acid methyl ester (4.8 g, 18.4 mmol) in ethanol (30 ml) and water (30 ml) was added 37% hydrochloric acid (24 ml). The resulting solution was warmed to 60° C. for twenty minutes and cooled. The reaction was diluted with dichloromethane and water. The layers were separated and the organic phase was dried (Na2SO4), filtered and concentrated to give 3.5 g (86%) of the desired product as an oil which solidified on standing. Used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[CH:6][CH:7]=1.[CH3:9][C:10]1[CH:11]=[CH:12][C:13]([S:16](Cl)(=[O:18])=[O:17])=[N:14][CH:15]=1>>[C:2]1([CH3:1])[CH:7]=[CH:6][C:5]([NH:8][S:16]([C:13]2[CH:12]=[CH:11][C:10]([CH3:9])=[CH:15][N:14]=2)(=[O:18])=[O:17])=[CH:4][CH:3]=1
Reactant: Cc1ccc(N)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)nc1
Product: Cc1ccc(NS(=O)(=O)c2ccc(C)cn2)cc1

Procedure:
prepared by reaction of p-tolylamine with 5-methyl-pyridine-2-sulfonyl chloride
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:14])[CH:9]=[C:10]([CH3:13])[CH:11]=2)[CH:6]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:5]1)(=[O:3])[CH3:2].Cl.[CH3:21][CH2:22]O>CCO>[C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:14])[CH:9]=[C:10]([CH3:13])[CH:11]=2)[CH:6]([CH2:15][CH2:16][C:17]([O:19][CH2:21][CH3:22])=[O:18])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CC(CCC(=O)O)c2c(C)cc(C)cc21
Reactant: CCO
Agent: Cl
Product: CCOC(=O)CCC1CN(C(C)=O)c2cc(C)cc(C)c21

Procedure:
1-Acetyl-3-(2-carboxyethyl)-4,6-dimethylindoline (3.4 g) was dissolved in EtOH (50 ml) and 10N HCl-EtOH (3.9 ml) was added, which was followed by refluxing for 30 min. EtOH was evaporated under reduced pressure and AcOEt (100 ml) was added. After washing with water, the mixture was dried over anhydrous sodium sulfate. AcOEt was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHCl3/MeOH=50/1−10/1) to give 3.3 g of 1-acetyl-3-(2-ethoxycarbonylethyl)-4,6-dimethylindoline.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[F:20][CH:21]([F:32])[O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>>[F:20][CH:21]([F:32])[O:22][C:23]1[CH:24]=[CH:25][C:26]([NH:29][C:30](=[O:31])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[CH:12][N:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)=[CH:27][CH:28]=1
Reactant: NC(=O)c1[nH]c2cnccc2c1-c1ccc(N)cc1
Reactant: O=C=Nc1ccc(OC(F)F)cc1
Product: NC(=O)c1[nH]c2cnccc2c1-c1ccc(NC(=O)Nc2ccc(OC(F)F)cc2)cc1

Procedure:
87 mg of solid yellow 3-{4-[3-(4-difluoromethoxyphenyl)ureido]phenyl}-1H-pyrrolo[2,3-c]pyridine-2-carboxamide are prepared as described in Example 1 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide and 4-difluoromethoxyphenyl isocyanate.