Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:8](=[N:10][OH:11])[NH2:9])=[CH:4][CH2:3]1.[C:12](O[C:17](=[O:20])[CH2:18][CH3:19])(=O)[CH2:13][CH3:14].[C:21]([OH:26])(=[O:25])[C:22]([OH:24])=[O:23]>C(O)C>[C:21]([O-:26])(=[O:25])[C:22]([O-:24])=[O:23].[CH3:1][NH+:2]1[CH2:7][CH2:6][C:5]([C:8]2[N:9]=[C:12]([CH2:13][CH3:14])[O:11][N:10]=2)=[CH:4][CH2:3]1.[CH3:1][NH+:2]1[CH2:7][CH2:6][C:5]([C:8]2[N:10]=[C:17]([CH2:18][CH3:19])[O:20][N:9]=2)=[CH:4][CH2:3]1
Reactant: CN1CC=C(C(N)=NO)CC1
Reactant: O=C(O)C(=O)O
Reactant: CCC(=O)OC(=O)CC
Solvent: CCO
Product: CCc1nc(C2=CC[NH+](C)CC2)no1
Product: O=C([O-])C(=O)[O-]

Procedure:
A solution of 1-methyl-1,2,5,6-tetrahydropyridin-4-carboxamide oxime (200 mg; 1.0 mmol) in propionic anhydride (5 ml; 39 mmol) was stirred at 80° C. for 20 hours. After evaporation in vacuo, the residue was dissolved in aqueous sodium hydroxide (4N) (5 ml) and extracted with ether (4×25 ml). The combined ether phases were dried (MgSO4), filtered, and evaporated in vacuo. To a solution of the residue in ethanol (5 ml) a solution of oxalic acid (90 mg; 1.0 mmol) in ethanol (5 ml) was added. Crystallization with ether gave the title compound. M.P 190°-191° C.
Reaction SMILES: ClCCCC([O:11]C(=O)C)CCCCC.BrCC#C[C@@H](OC(=O)C)CCCCC.C([O:32][C@@H:33]([CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[C:34]#[C:35][CH2:36][N:37]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][C:46]([O:48]CC)=[O:47])[C:38]#[N:39])(=O)C>>[OH:32][C@H:33]([CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[C:34]#[C:35][CH2:36][N:37]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][C:46]([OH:48])=[O:47])[C:38]#[N:39].[OH:32][C@H:33]([CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[C:34]#[C:35][CH2:36][N:37]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][C:46]([OH:48])=[O:47])[C:38]([NH2:39])=[O:11]
Reactant: CCCCCC(CCCCl)OC(C)=O
Reactant: CCCCC[C@@H](C#CCN(C#N)CCCCCCC(=O)OCC)OC(C)=O
Agent: CCCCC[C@@H](C#CCBr)OC(C)=O
Product: CCCCC[C@@H](O)C#CCN(C#N)CCCCCCC(=O)O
Product: CCCCC[C@@H](O)C#CCN(CCCCCCC(=O)O)C(N)=O

Procedure:
The synthesis of this compound is carried out as described in Example 1 except that, in Step a, the 1-chloro-4-acetoxynonane is replaced by an equimolar amount of 1-bromo-4(S)-acetoxy-2-nonyne (Example K). The product of Step A is thus ethyl 7-[N-(4(S)-acetoxy-2-nonynyl)cyanamido]heptanoate. The subsequent steps yield 7-[N-(4(S)-hydroxy-2-nonynyl)-cyanamido]heptanoic acid (B) and 7-[1-(4(S)-hydroxy-2-nonynyl)ureido]heptanoic acid (C). The product of Step C is hydrogenated over a platinum on charcoal catalyst to afford 7-[1-(4(S)-hydroxy-nonyl)ureido]heptanoic acid.
Reaction SMILES: [OH-:1].[Na+].[CH3:3][C:4]([CH3:44])([O:6][C:7]([NH:9][C@H:10]([C:18]([NH:20][C@H:21]([C:26](NC(CC1CCCCC1)C(=O)C(=O)CCC)=[O:27])[CH2:22][CH:23]([CH3:25])[CH3:24])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])[CH3:5]>CO>[C:4]([O:6][C:7]([NH:9][C@H:10]([C:18]([NH:20][C@H:21]([C:26]([OH:1])=[O:27])[CH2:22][CH:23]([CH3:25])[CH3:24])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])([CH3:44])([CH3:3])[CH3:5]
Reactant: CCCC(=O)C(=O)C(CC1CCCCC1)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)O
Reaction time: 1 h

Procedure:
Sodium hydroxide (1N; 12 ml, 12 mmol) was added to a 40 ml methanol solution of (S)-<α-[[(1,1-dimethylethoxy)carbonyl]amino]cyclohexanepropanoic acid, methyl ester (3.92 g, 10 mmol) and a chromatography check after one hour revealed total disappearance of starting material. The solvents were removed on rotary evaporator. The resulting white solid was suspended in 10 ml of water and 50 ml of ethyl acetate, acidified to pH=3.5 using 1N hydrochloric acid and the two layers separated. The aqueous layer was reextracted with ethyl acetate (3×30 ml), combined organic extracts dried over sodium sulfate and concentrated to give 3.54 g of the title E compound.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[C:11]([OH:22])=[N:10][C:8]=2[N:9]=1.[CH2:23](I)[CH3:24]>CN(C)C=O>[NH2:3][C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[C:11](=[O:22])[N:10]([CH2:23][CH3:24])[C:8]=2[N:9]=1
Reactant: CCI
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(O)nc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(N)nc21
Temperature: 50 °C
Reaction time: 3.5 h
Yield: 55.4 %

Procedure:
To a suspension of NaH (60% in mineral oil, 27 mg) in 5 mL of dimethylformamide was added 2-amino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidin-7(8H)-one (172 mg, 0.56 mmol) from Example 11. The mixture was heated at 50° C. for 1 hour resulting in a clear solution. Ethyl iodide (60 μL, 0.75 mmol) was added, and the solution was stirred at 50° C. for 3.5 hours, cooled to room temperature, and poured into 30 mL of ice water. The resulting precipitate was removed by filtration and partitioned between ethyl acetate and water. The organic layer was separated and dried over MgSO4, filtered, and concentrated in vacuo. Flash chromatography, eluting with ethyl acetate, provided 104 mg (55%) of 2-amino-6-(2,6-dichlorophenyl)-8-ethyl-pyrido[2,3-d]pyrimidin-7(8H)-one; mp 207-209° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([NH:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)=[O:16])=[CH:12][C:11]([C:31]([CH3:34])([CH3:33])[CH3:32])=[N:10]2)=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[CH3:44][O:45][CH2:46][CH2:47]C(Cl)=O.C1C[O:54]CC1>>[C:31]([C:11]1[CH:12]=[C:13]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=3)=[CH:20][CH:19]=2)=[O:16])[N:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:47](=[O:54])[CH2:46][O:45][CH3:44])=[CH:4][CH:5]=2)[N:10]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: COCCC(=O)Cl
Reactant: C1CCOC1
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccncc3)cc2)n(-c2ccc(CN)cc2)n1
Solvent: CCN(C(C)C)C(C)C
Product: COCC(=O)NCc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccncc3)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
To a solution of 1-[2-(4-aminomethyl-phenyl)-5-tert-butyl-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yloxy)phenyl]urea (400 mg, 0.88 mmol) in THF (20 mL) was added N,N-diisopropylethylamine (0.23 mL, 1.31 mmol). A solution of 3-methoxypropionyl chloride (95 mg, 0.88 mmol) in THF (1 mL) was added to the solution at 0° C. under N2 and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated at reduced pressure and dissolved in EtOAc (100 mL). The solution was washed with water and brine, dried over Na2SO4, and concentrated at reduced pressure. The residue was purified by MPLC (50:50 hexanes/EtOAc) to give 240 mg (52%) of the desired product. 1H-NMR (DMSO-d6) δ 9.16 (s, 1H), 8.42 to 8.40 (m, 4H), 7.50 to 7.37 (m, 6H), 7.08 (d, J=8.7 Hz, 2H), 6.85 (d, J=6.0 Hz, 2H), 6.34 (s, 1H), 4.33 (d, J=6.0 Hz, 2H), 3.86 (s, 2H), 3.26 (s, 3H), 1.25 (s, 9H); MS LC-MS [M+H]+=529, RT=2.29 min.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[C:19]([C:21]3[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]4[CH:32]=[N:33][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:36]=4)[N:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:30][C:27]([F:28])([F:29])[C:25]1[CH:24]=[C:23]([C:31]2[CH:32]=[N:33][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:36]=2)[N:22]=[C:21]([C:19]2[CH:18]=[CH:17][N:16]=[C:15]([C:11]3[CH:10]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=3)[CH:20]=2)[N:26]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)nc4)cc(C(F)(F)F)n3)ccn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)nc4)cc(C(F)(F)F)n3)ccn2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 79.5 %

Procedure:
To a cooled and stirred solution of 3-{4-[4-trifluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonic acid tert-butylamide (0.71 g) in dichloromethane (12 ml) was added TFA (12 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N Na2CO3 solution (25 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by crystallization (ethyl acetate/heptane) yielded the title compound as a white solid (0.51 g, 49%). MS (ISP) 526.2 [(M+H)+]; mp 258° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8]/[CH:9]=[CH:10]/[CH:11]=[CH:12]/[CH2:13]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P([N:31]=[N+:32]=[N-:33])(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[N:31]([CH2:13]/[CH:12]=[CH:11]/[CH:10]=[CH:9]/[CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[N+:32]=[N-:33]
Reactant: OC/C=C/C=C/CCc1ccccc1
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=NC/C=C/C=C/CCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
(2E,4E)-7-Phenylhepta-2,4-dien-1-ol (6.8 g) was dissolved in dry toluene (130 ml) and cooled in an ice-salt bath. Diphenyl phosphorazidate (7.83 ml) was added, followed by dropwise addition of DBU (6.53 ml) in dry toluene (15 ml). The mixture was stirred for 15 h while warming to room temperature. Solvents were evaporated and the residue was partitioned between diethyl ether and 1N NaOH. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by column chromatography yielded a colorless liquid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4](=[O:14])[NH:5][C:6]([CH:10]2[CH2:13][CH2:12][CH2:11]2)=[CH:7][C:8]=1[CH3:9].[NH2:15][CH2:16][C:17]1[C:18](=[O:28])[NH:19][C:20]([CH3:27])=[CH:21][C:22]=1[CH:23]1[CH2:26][CH2:25][CH2:24]1.[CH3:29][C:30]([O:33][C:34](O[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:35])([CH3:32])[CH3:31].C(N(CC)CC)C>C1COCC1.CN(C=O)C>[CH:10]1([C:6]2[NH:5][C:4](=[O:14])[C:3]([CH2:2][NH:1][C:34](=[O:35])[O:33][C:30]([CH3:32])([CH3:31])[CH3:29])=[C:8]([CH3:9])[CH:7]=2)[CH2:11][CH2:12][CH2:13]1.[CH:23]1([C:22]2[CH:21]=[C:20]([CH3:27])[NH:19][C:18](=[O:28])[C:17]=2[CH2:16][NH:15][C:37](=[O:38])[O:39][C:40]([CH3:41])([CH3:42])[CH3:43])[CH2:24][CH2:25][CH2:26]1
Reactant: Cc1cc(C2CCC2)c(CN)c(=O)[nH]1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Cc1cc(C2CCC2)[nH]c(=O)c1CN
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C2CCC2)[nH]c(=O)c1CNC(=O)OC(C)(C)C
Product: Cc1cc(C2CCC2)c(CNC(=O)OC(C)(C)C)c(=O)[nH]1
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 9.5 %
Yield: 20 %

Procedure:
To an ice bath cooled solution of 3-(aminomethyl)-6-cyclobutyl-4-methyl-2(1H)-pyridinone and 3-(aminomethyl)-4-cyclobutyl-6-methyl-2(1H)-pyridinone (3.5 g, 18 mmol) in THF (10 mL) and DMF (10 mL) were added Boc2O (4.68 g, 21.8 mmol) and triethylamine (5.4 g, 54 mmol). The contents were then stirred for 30 min. at 30° C. The reaction was quenched by addition of ice water, during which time precipitation occurred. The reaction mixture was filtered and dried to give a mixture of the crude products. The crude products were separated by HPLC to give 1,1-dimethylethyl [(6-cyclobutyl-4-methyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]carbamate (2.1 g, 20%) and 1,1-dimethylethyl [(4-cyclobutyl-6-methyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]carbamate (1 g, 9.5%). Data for 1,1-dimethylethyl [(6-cyclobutyl-4-methyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]carbamate: 1H NMR (400 MHz, DMSO-d6) δ 11.28 (br s, 1H), 6.49 (br s, 1H), 5.86 (br s, 1H), 3.85 (br s, 2H), 1.97-2.14 (m, 7H), 1.87-1.94 (m, 1H), 1.72-1.77 (m, 1H), 1.28 (s, 9H).
Reaction SMILES: [O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8][CH:7]=1.[C:15]([C:19]1[CH:23]=[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[NH:21][N:20]=1)([CH3:18])([CH3:17])[CH3:16].N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([N:21]2[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:23][C:19]([C:15]([CH3:16])([CH3:18])[CH3:17])=[N:20]2)=[CH:8][CH:7]=1
Reactant: OB(O)c1ccc(-c2nnco2)cc1
Reactant: CCOC(=O)c1cc(C(C)(C)C)n[nH]1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1cc(C(C)(C)C)nn1-c1ccc(-c2nnco2)cc1
Yield: 80.8 %

Procedure:
A mixture of 4-(1,3,4-oxadiazol-2-yl)phenylboronic acid (303 mg, 1.60 mmol) and powdered 4A molecular sieves (300 mg) in CH2Cl2 (6 mL) was heated to reflux for 2 h. Ethyl 3-tert-butyl-1H-pyrazole-5-carboxylate (310 mg, 1.6 mmol), pyridine (0.13 mL, 1.6 mmol) and copper (II) acetate (290 mg, 1.6 mmol) were added and the reaction mixture was refluxed for 24 h. The reaction was filtered and the solid was washed with EtOAc (40 mL) and MeOH (40 mL). The combined filtrate and washings were concentrated in vacuo and partitioned between EtOAc (40 mL) and water (20 mL). The organics were washed with water (20 mL), satd aq NaHCO3 (20 mL), water (20 mL), and brine (20 mL), dried (Na2SO4) and concentrated in vacuo. The oily residue was chromatographed to provide ethyl 1-(4-(1,3,4-oxadiazol-2-yl)phenyl)-3-tert-butyl-1H-pyrazole-5-carboxylate (440 mg, > 100% yield) as a visocus oil contaminated with the starting ester. The mixture was used without further purification.
Reaction SMILES: [F:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16]C)=[O:15])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:3]1.CO.O.[OH-].[Li+]>O1CCCC1>[C:21]([O:20][C:18]([N:4]1[CH2:5][CH2:6][CH:7]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([OH:16])=[O:15])=[CH:12][CH:13]=2)[CH:2]([F:1])[CH2:3]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: COC(=O)c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)C(F)C1
Reaction time: 3 h
Yield: 90 %

Procedure:
tert-Butyl 3-fluoro-4-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate described in Production Example 6-3 (402 mg, 1.19 mmol) was dissolved in tetrahydrofuran (18 mL), methanol (6 mL), and water (4 mL), then a 2 M aqueous lithium hydroxide solution (4.17 mL, 8.34 mmol) was added at room temperature, and then the mixture was stirred for 3 hours. Tetrahydrofuran and methanol were evaporated under vacuum and 1 M hydrochloric acid was added to the residual solution for neutralization. The aqueous layer was extracted with ethyl acetate four times, and the organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated and the resultant residue was purified with silica gel column chromatography (n-heptane:ethyl acetate=4:1-1:4) to obtain the title compound (347 mg, 90%).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:20])=[C:10]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]=2[F:13])[C:6](=[O:21])[C:5]([C:22]([OH:24])=[O:23])=[CH:4]1)[CH3:2].Br[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)=[O:28]>>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:20])=[C:10]([N:14]3[CH2:15][CH2:16][N:17]([CH2:26][C:27]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)=[O:28])[CH2:18][CH2:19]3)[C:11]=2[F:13])[C:6](=[O:21])[C:5]([C:22]([OH:24])=[O:23])=[CH:4]1)[CH3:2]
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)c(F)c21
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(CC(=O)c4ccc(F)cc4)CC3)c(F)c21

Procedure:
1-Ethyl-6,8-difluoro-7-{4-[2-(4-fluorophenyl)-2-oxoethyl]-1-piperazinyl}-4-oxo-1,4-dihydro-3-quinoline-carboxylic acid was prepared from 1-ethyl-6,8-difluoro-4-oxo-7-(1-piperazinyl)-1,4-dihydro-quinoline-3-carboxylic acid (0.50 g, 1.48 mmole) and 2-bromo-4′-fluoroacetophenone (0.40 g, 1.86 mmole) by a method similar to that described for Example 4 (64% yield). Mp: 170° C. (dec). 1H NMR (DMSO-d6) δ 1.44 (t, 3H, J=7.0), 2.70 and 3.3 (two m, 8H), 3.94 (s, 2H), 4.58 (q, 2H, J=7.0), 7.37 (n, 2H), 7.90 (d, 1H, J=11.8), 8.11 (m, 2H), 8.92 (s, 1H), 14.92 (br s, 1H). Anal. Calcd. for C24H22F3N3O4•0.5 H2O: C, 59.75; H, 4.80; N, 8.71. Found: C, 59.39; H, 4.66; N, 8.62.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][C:16](Br)=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[C:29]1[C:30]([NH2:44])=[N:31][CH:32]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>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.COCCOC.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][C:16]([C:33]3[CH:32]=[N:31][C:30]([NH2:44])=[C:29]([C:21]4[S:20][C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[N:22]=4)[CH:34]=3)=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)s2)CC1
Reactant: CC1(C)OB(c2cnc(N)c(-c3nc4ccccc4s3)c2)OC1(C)C
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: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3cnc(N)c(-c4nc5ccccc5s4)c3)s2)CC1
Temperature: 100 °C

Procedure:
A solution of 4-(5-bromothiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.079 g, 0.229 mmol), 3-benzothiazol-2-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridin-2-ylamine (BB8) (0.105 g, 0.298 mmol), potassium carbonate (0.101 g, 0.732 mmol), and Pd(PPh3)4 (0.018 g, 0.016 mmol) in previously degassed DME/H2O (4:1) (4.0 mL) was placed in a microwave tube and evacuated and charged with N2 (2×). The reaction mixture was heated in the microwave reactor to 100° C. for 30 min. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified on prep-TLC eluting with 3% 7M NH3 in MeOH/DCM yielding 4-[5-(6-amino-5-benzothiazol-2-ylpyridin-3-yl)-thiazol-2-yl]-piperazine-1-carboxylic acid tert-butyl ester, MS (ES+): m/z=495.06 [MH+]. To a solution of this compound in DCM (1.0 mL) was added 1M HCl in ether (2.0 mL, 2.0 mmol), and the mixture was stirred at room temperature overnight. The solid that formed was filtered off and purified on the MDP. To a solution of the material thus obtained in DCM (1.0 mL) was added 1M HCl in ether (1.0 mL, 1.0 mmol). The precipitate was filtered off and dried in vacuo, yielding the title compound as yellow solid. 1H NMR (400 MHz, CD3OD): δ=2.95-3.00 (m, 4H), 3.46-3.53 (m, 4H), 7.40 (s, 1H), 7.42-7.48 (m, 1H), 7.53 (dd, J=15.3, 1.1 Hz, 1H), 7.98-8.05 (m, 2H), 8.07 (d, J=2.3 Hz, 1H), 8.23 (d, J=2.3 Hz, 1H). MS (ES+): m/z=395.06 (55) [MH+]. HPLC: tR=2.11 min (ZQ2, polar—5 min).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]([S:25][CH2:26][CH3:27])=[CH:4][CH2:3]1.C[C:30]1(C)[C:39]2C=CC(C#CC3C=CC(C(OCC)=O)=CC=3)=C[C:34]=2C(=O)[CH2:32][CH2:31]1>>[CH3:28][C:2]1([CH3:1])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:23][CH:24]=3)=[CH:7][C:6]=2[C:5]([S:25][CH2:26][C:27]2[CH:34]=[CH:39][CH:30]=[CH:31][CH:32]=2)=[CH:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(SCC)=CCC3(C)C)cc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(=O)CCC3(C)C)cc1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(SCc2ccccc2)=CCC3(C)C)cc1

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-ethylthionaphth-3-yl)ethynyl]benzoate (Compound 151), 500 mg (1.44 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl]benzoate (Compound 2) was converted into the title compound (colorless crystals, recrystallized from methyl alcohol) using 268 mg (1.42 mmol) of titanium tetrachloride, 184 mg (1.49 mmol) of benzyl mercaptan and 271 mg (2.82 mmol) of triethylamine.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[S:10][C:11]=1[CH3:12].C(=O)([O-])[O-].[K+].[K+].O1CCO[CH2:26][CH2:25]1>O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:25]([C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[S:10][C:11]=1[CH3:12])=[CH2:26]
Reactant: COC(=O)c1cc(-c2c(Br)cnn2C)c(C)s1
Reactant: C1COCCO1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C=Cc1cnn(C)c1-c1cc(C(=O)OC)sc1C
Yield: 81 %

Procedure:
A solution of methyl 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylate (200 mg, 0.64 mmol)[prepared in Example 99], potassium carbonate (438 mg, 3.17 mmol), bis(tri-t-butylphosphine)palladium(0) (324 mg, 0.64 mmol) and 2,4,6-trivinylcycloboroxane-pyridine complex (77 mg, 0.32 mmol) in 1,4-dioxane (5.3 ml) and H2O (1 ml) was stirred at 80° C. in a sealed tube for 12 h. The reaction contents were partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (10-50% EtOAc in hexanes) affording methyl 4-(4-ethenyl-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylate (135 mg, 0.515 mmol, 81% yield) as a yellow oil: LCMS (ES) m/z=250 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].[CH3:13]C([O-])(C)C.[Na+].C(OCC)=O.Cl>O1CCOCC1.O>[CH3:9][O:8][C:6]1[CH:7]=[C:2]2[C:3]([C:10]([OH:12])=[CH:11][CH:13]=[N:1]2)=[CH:4][CH:5]=1
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc(C(C)=O)c(N)c1
Agent: Cl
Agent: [Na+]
Solvent: CCOC=O
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc2c(O)ccnc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(2-amino-4-methoxyphenyl)ethanone [J Med Chem, 32(4):807-826 (1989)] (7.32 g, 44.3 mmol) in dioxane (150 mL), NaOt-Bu (9.8 g, 102 mmol) was added and stirred at RT for 30 min. The color changed from lime green to dark green. Ethyl formate (23.64 mL, 292 mmol) was added with an additional 20 mL dioxane. The reaction mixture was stirred at RT 18 h after which the mixture was poured into water (20 mL) and the pH adjusted to 7 with 2N HCl. The solution was evaporated a little. The red solid was filtered and rinsed with water. The solid was triturated with 1:1 EtOAc:hexanes and then filtered to give the title compound as a brown solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[N:21]=[C:22]=[S:23]>CCOCC>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[NH:21][C:22]([N:10]1[CH2:9][CH2:8][N:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)[CH2:12][CH2:11]1)=[S:23]
Reactant: S=C=Nc1c(Cl)cccc1Cl
Reactant: c1cnc(N2CCNCC2)cn1
Solvent: CCOCC
Product: S=C(Nc1c(Cl)cccc1Cl)N1CCN(c2cnccn2)CC1
Reaction time: 0.25 h

Procedure:
To a solution of 4.92 g. of 1-(2-pyrazinyl)piperazine in 50 ml. of anhydrous ether is added dropwise a solution of 6.12 g. of 2,6-dichlorophenyl isothiocyanate in 50 ml. of anhydrous ether over 10 minutes. The mixture is stirred for 15 minutes and the resulting solid collected. This solid is dissolved with heat in a mixture of 200 ml. of acetone and 150 ml. of methanol and then cooled. The resulting solid is collected giving 5.29 g. of the desired product as white crystals, m.p. 225°-227° C.