Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH:19]1([CH2:22][NH:23][C:24](=[O:41])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[C:27](B3OC(C)(C)C(C)(C)O3)[CH:26]=2)[CH2:21][CH2:20]1>>[CH:19]1([CH2:22][NH:23][C:24]([C:25]2[CH:26]=[CH:27][C:28]([CH3:31])=[C:29]([C:2]3[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]4[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=4)=[O:7])=[CH:4][N:3]=3)[CH:30]=2)=[O:41])[CH2:21][CH2:20]1
Reactant: COc1ccc(NC(=O)c2ccc(Cl)nc2)cc1
Reactant: Cc1ccc(C(=O)NCC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Product: COc1ccc(NC(=O)c2ccc(-c3cc(C(=O)NCC4CC4)ccc3C)nc2)cc1

Procedure:
6-[5-Cyclopropylmethylcarbamoyl-2-methyl-phenyl]-N-(4-methoxyphenyl)-nicotinamide was prepared from 6-chloro-N-(4-methoxyphenyl)nicotinamide (Intermediate 2) and N-cyclopropylmethyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 10) using General Method B. LCMS: retention time 3.12 min, MH+ 416. NMR: δH [2H6]-DMSO 10.39,(1H, s), 9.21,(1H, d), 8.63,(1H, t), 8.41,(1H, dd), 7.96,(1H, s), 7.86,(1H, d), 7.79, (1H, d), 7.71,(2H, d), 7.44,(1H, d), 6.96,(2H, d), 3.76,(3H, s), 3.15,(2H, t), 2.41, (3H, s), 1.03,(1H, m), 0.43,(2H, m), 0.23,(2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:13][C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[N:6]=1)=[O:4].[H-].[Na+].Br[CH2:17][C:18]1[CH:22]=[C:21]([C:23]2[S:24][C:25]([Cl:28])=[CH:26][CH:27]=2)[O:20][N:19]=1>CN(C=O)C.O>[CH3:1][O:2][C:3]([C:5]1[N:13]([CH2:17][C:18]2[CH:22]=[C:21]([C:23]3[S:24][C:25]([Cl:28])=[CH:26][CH:27]=3)[O:20][N:19]=2)[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[N:6]=1)=[O:4]
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Reactant: COC(=O)c1nc2cccnc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1nc2cccnc2n1Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
100 mg (0.56 mmol) 3H-Imidazo[4,5-b]pyridine-2-carboxylic acid methyl ester were dissolved in 3 mL DMF. 22.6 mg (0.56 mmol) sodium hydride (60% in mineral oil) were added and the mixture was stirred 30 minutes at room temperature. 157.2 mg (0.56 mmol) 3-Bromomethyl-5-(5-Chloro-thiophen-2-yl)-isoxazole were added and the resulting mixture was stirred for 1 h at 80° C. The reaction mixture was cooled to room temperature and after the addition of a few drops of water concentrated under reduced pressure. HPLC-MS-analysis showed the presence of another isomer (ratio of isomers≈7:1). Final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.05% formic acid) gave pure 3-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-3H-imidazo[4,5-b]pyridine-2-carboxylic acid methyl ester as a brown amorphous solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:17]=[C:16]([CH2:18]OS(C)(=O)=O)[O:15][N:14]=3)=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.C(O)(C)C.[OH-].[NH4+:29]>O1CCCC1.C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:17]=[C:16]([CH2:18][NH2:29])[O:15][N:14]=3)=[CH:9][CH:8]=2)=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)OCc1cc(-c2ccc(-c3ccncc3)cc2)no1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: NCc1cc(-c2ccc(-c3ccncc3)cc2)no1
Temperature: 25 °C

Procedure:
To a flame dried flask containing (R)-4,5-Dihydro[3-[4-(4-pyridinyl)phenyl]-5-(hydroxymethyl)]isoxazole (440 mg, 1.73 mmol) in methylene chloride (20 mL) at 0° C. under an inert atmosphere is added triethylamine (0.36 mL, 2.60 mmol) and methanesulfonyl chloride (0.14 mL, 1.82 mmol). The reaction is slowly warmed to ambient temperature, stirred 3 hours, and quenched with water (25 mL). The organic phase is separated, washed with saturated NaHCO3 (25 mL) and saline (25 mL), dried over sodium sulfate and concentrated in vacuo to give crude (R)-4,5-dihydro[3-[4-(4-pyridinyl)phenyl]-5-[[(methylsulfonyl)oxy]methyl]isoxazole. The crude (R)-4,5-dihydro[3-[4-(4-pyridinyl)phenyl]-5-[[(methylsulfonyl)oxy]-methyl]isoxazole (580 mg, 1.73 mmol) is dissolved in tetrahydrofuran (4 mL), isopropanol (4 mL), and concentrated ammonium hydroxide (4 mL) in a thick wall resealable vessel and heated to 100-110° C. for 15 hours. The reaction is cooled to ambient temperature, diluted with ethyl acetate (50 mL), washed with saline (20 mL), dried over sodium sulfate and concentrated in vacuo to give crude (R)-4,5-dihydro[3-[4-(4-pyridinyl)phenyl]-5-(aminomethyl)isoxazole. The crude (R)-4,5-dihydro[3-[4-(4-pyridinyl)phenyl]-5-(aminomethyl)isoxazole (320 mg, 1.57 mmol) is dissolved in methylene chloride (15 mL) and cooled to 0° C. under an inert atmosphere. Pyridine (0.31 mL, 3.78 mmol) and acetic anhydride (0.15 mL, 1.57 mmol) are added to the cooled solution and stirred 20 hours at ambient temperature. The reaction is concentrated in vacuo, diluted with methylene chloride (50 mL), washed with saline (25 mL), dried over sodium sulfate, concentrated in vacuo and chromatographed on silica gel (230-400 mesh, 200 mL), eluting with chloroform/methanol (97/3). The appropriate fractions are combined (Rf =0.14, TLC, chloroform/methanol, 95/5) and concentrated in vacuo to give the title compound, mp 244-245° C.
Reaction SMILES: O=C(C)[CH2:3][CH2:4][CH2:5][C:6]#[N:7].[NH2:9][C:10]1[C:15]([CH:16]=O)=[CH:14][CH:13]=[CH:12][N:11]=1.N1CCC[C@H:19]1[C:20](O)=O>C(O)C>[N:11]1[C:10]2[C:15](=[CH:16][CH:19]=[CH:20][N:9]=2)[CH:14]=[CH:13][C:12]=1[CH2:3][CH2:4][CH2:5][C:6]#[N:7]
Reactant: Nc1ncccc1C=O
Reactant: CC(=O)CCCC#N
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: N#CCCCc1ccc2cccnc2n1

Procedure:
A mixture of 5-oxo-hexanenitrile (8-1) (5 ml, 43.8 mmol), 2-amino-3-formylpyridine (7 g, 57 mmol), proline (5.3 g, 43.8 mmol) and ethanol (100 mL) was heated at reflux for 12 hours. Following evaporation of the solvent, the residue was chromatographed (silica gel, ethyl acetate) to give 8-2 as a white solid.
Reaction SMILES: BrCCBr.[Mg].[CH3:6][N:7]1[CH2:12][CH2:11][CH:10](Cl)[CH2:9][CH2:8]1.[Br:14][C:15]1[CH:16]=[C:17]2[CH2:26][CH2:25][N:24]3[C:18]2=[C:19]([CH:32]=1)[CH:20]=[N:21][C:22]1[CH:30]=[C:29]([Br:31])[CH:28]=[CH:27][C:23]=13.[OH-].[NH4+]>O1CCCC1.ClCCl>[Br:14][C:15]1[CH:16]=[C:17]2[CH2:26][CH2:25][N:24]3[C:18]2=[C:19]([CH:32]=1)[CH:20]([CH:10]1[CH2:11][CH2:12][N:7]([CH3:6])[CH2:8][CH2:9]1)[NH:21][C:22]1[CH:30]=[C:29]([Br:31])[CH:28]=[CH:27][C:23]=13
Reactant: Brc1cc2c3c(c1)CCN3c1ccc(Br)cc1N=C2
Reactant: CN1CCC(Cl)CC1
Agent: [Mg]
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: BrCCBr
Product: CN1CCC(C2Nc3cc(Br)ccc3N3CCc4cc(Br)cc2c43)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1,2-Dibromoethane (0.5 ml) was added to a refluxing slurry of magnesium chips (6 gm) in tetrahydrofuran (70 ml) to initiate a Grignard reaction. A solution of N-methyl-4-chloropiperidine (35 ml) in tetrahydrofuran (100 ml) was added rapidly. The reaction mixture was refluxed for 2 hours, during which a white precipitate formed. The mixture was cooled to room temperature and transferred to a flask containing 4,9-dibromo-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepine (20 gm) in tetrahydrofuran (200 ml) in one portion at ice-temperature. After 1 hour of stirring, the mixture was poured into ice-water/concentrated hydrochloric acid (600 ml:35 ml), and stirred for 15 minutes. The acid solution was slowly added to a stirred mixture prepared from dichloromethane (1 L) and an ammonium hydroxide solution (40 ml). The organic solution was separated, washed with water (500 ml) and brine (2×500 ml) and dried over anhydrous magnesium sulfate. The solution was filtered and concentrated to an oil (26 gm).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:26]([O:28]C)=[O:27])[C:5]([CH3:25])=[C:6]([CH:24]=1)[O:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:10][CH2:9]1.[OH-].[Na+].Cl>O1CCCC1.CO.O>[CH2:17]([O:16][C:14]([N:11]1[CH2:10][CH2:9][CH:8]([O:7][C:6]2[C:5]([CH3:25])=[C:4]([CH:3]=[C:2]([Cl:1])[CH:24]=2)[C:26]([OH:28])=[O:27])[CH2:13][CH2:12]1)=[O:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)c1cc(Cl)cc(OC2CCN(C(=O)OCc3ccccc3)CC2)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(OC2CCN(C(=O)OCc3ccccc3)CC2)cc(Cl)cc1C(=O)O
Temperature: 45 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
To a solution of benzyl 4-(5-chloro-3-(methoxycarbonyl)-2-methylphenoxy)piperidine-1-carboxylate (0.68 g, 1.627 mmol) in tetrahydrofuran (5 mL) and methanol (15 mL) was added 3 N NaOH (2.71 mL, 8.14 mmol). The reaction mixture was stirred for 1 h, then heated at 45° C. for 3 h. The volatiles were removed in vacuo to give an aqueous residue, which was diluted with water (25 mL) and cooled (ice bath). The mixture was acidified to pH˜3-4 with 1 M HCl and stirred for 15 min. The solids were filtered, washed with water, and dried under high vacuum overnight to give 3-((1-((benzyloxy)carbonyl)piperidin-4-yl)oxy)-5-chloro-2-methylbenzoic acid (0.52 g, 1.223 mmol, 75% yield). 1H NMR δ 1.54-1.72 (m, 2H), 1.83-1.98 (m, 2H), 2.29 (s, 3H), 3.38 (br. s., 2H), 3.58-3.70 (m, 2H), 4.72 (tt, 1H), 5.09 (s, 2H), 7.24-7.46 (m, 7H), 13.28 (br. s., 1H). MS(ES) [M+H]+ 404.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:12]#[N:13])=[C:9]([CH3:11])[N:10]=2)[CH:7]=1.Cl.CCOC(C)=O.P(S)(OCC)(OCC)=[S:22]>CO.C(OC(C)C)(C)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:12](=[S:22])[NH2:13])=[C:9]([CH3:11])[N:10]=2)[CH:7]=1
Reactant: Cc1nc2ccc(Br)cn2c1C#N
Reactant: CCOP(=S)(S)OCC
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Product: Cc1nc2ccc(Br)cn2c1C(N)=S
Temperature: 60 °C
Reaction time: 3 h
Yield: 86.9 %

Procedure:
To a suspension of 6-bromo-2-methylimidazo[1,2-a]pyridine-3-carbonitrile (6.2 g, 26.4 mmol) obtained above in MeOH (88 mL), were added 4N solution of hydrogen chloride in EtOAc (22 mL, 88.0 mmol) and O,O-diethyl hydrogen dithiophosphate (25 mL, 158 mol), and the mixture was stirred at 60° C. for 3 h. The mixture was allowed to cool to rt, and diluted with diisopropyl ether (100 mL). The resulting precipitate was collected by filtration and washed with diethyl ether to give the title compound (6.2 g, 77%) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH3:13])[C:3]([NH:5][C:6]1[N:7]=[N:8][C:9]([CH3:12])=[CH:10][CH:11]=1)=[O:4].[CH3:15][CH2:16][Mg+].[Br-]>>[CH2:15]([C:11]1[CH:10]=[C:9]([CH3:12])[N:8]=[N:7][C:6]=1[NH:5][C:3](=[O:4])[C:2]([CH3:14])([CH3:13])[CH3:1])[CH3:16]
Reactant: Cc1ccc(NC(=O)C(C)(C)C)nn1
Reactant: CC[Mg+]
Agent: [Br-]
Product: CCc1cc(C)nnc1NC(=O)C(C)(C)C
Yield: 17.4 %

Procedure:
Using a procedure analogous to Example 17A, 2,2-dimethyl-N-(6-methyl-pyridazin-3-yl)-propionamide (4.18 g, 21.65 mmol) and 3.0 M solution of EtMgBr (36 mL, 108.29 mmol) give the title compound (0.83 g, 3.76 mmol, 17%). 1H NMR (CDCl3): δ 1.24 (t, J=7.5 Hz, 3H), 1.37 (s, 9H), 2.62 (q, J=7.5 Hz, 2H), 2.66 (s, 3H), 7.23 (s, 1H), 8.50 (s, 1H) ppm. ES-MS (m/z): calcd for C12H19N3O (M+H)+: 222.3. found: 222.1.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][C:13]=2[Cl:23])[C:10]=1[CH3:11])=[O:5])C.[OH-].[Na+].Cl>C(O)C.O>[C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:21])([F:22])[F:20])=[CH:14][C:13]=2[Cl:23])[C:10]=1[CH3:11])([OH:5])=[O:3]
Reactant: CCOC(=O)c1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(C(=O)O)cnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Yield: 93.8 %

Procedure:
By the method of Example 5, Step B, 137.4 g (0.374 mole) of 4-ethoxycarbonyl-5-methyl-1-(2,6-dichloro-4-trifluoromethylphenyl)-1H-pyrazole dissolved in 767 mL of ethanol was reacted with 23.6 g (0.59 mole) of sodium hydroxide dissolved in 413 mL of water. After being neutralized with 180 mL of 10% hydrochloric acid, this reaction yielded 119 g of 4-carboxy-5-methyl-1-(2,6-dichloro-4-trifluoromethylphenyl)-1H-pyrazole. The nmr spectrum of this solid was consistent with the proposed structure.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[OH-].[K+].Cl[C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1.O>CS(C)=O>[N:15]1[CH:16]=[CH:17][N:18]=[CH:19][C:14]=1[O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: Clc1cnccn1
Reactant: Oc1cccc2[nH]ccc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: c1cc(Oc2cnccn2)c2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
A solution of 2.66 g of 4-hydroxyindole in 60 ml of DMSO is combined with 1.4 g of potassium hydroxide (pulverized) and stirred under an N2 atmosphere for one hour at room temperature. After adding 2.5 g of 2-chloropyrazine, the mixture is heated for 2 hours to 100° C., poured into water, and extracted with ethyl acetate. The residue from the organic phase is purified over silica gel, thus obtaining 2.95 g (70%) of 4-(2-pyrazinyloxy)indole, mp 192°-193° C.
Reaction SMILES: [OH:1][CH:2]([C:4]1[N:8]=[CH:7][N:6]([C:9]2[N:10]=[CH:11][C:12]([O:23][CH3:24])=[C:13]3[C:17]([C:18](=[O:22])[C:19]([OH:21])=O)=[CH:16][NH:15][C:14]=23)[N:5]=1)[CH3:3].[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[C:32]2[CH2:40][CH2:39][NH:38][CH2:37][C:33]=2[N:34]=[CH:35][N:36]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C.CO>[OH:1][CH:2]([C:4]1[N:8]=[CH:7][N:6]([C:9]2[N:10]=[CH:11][C:12]([O:23][CH3:24])=[C:13]3[C:17]([C:18](=[O:22])[C:19]([N:38]4[CH2:39][CH2:40][C:32]5[C:31]([C:26]6[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=6)=[N:36][CH:35]=[N:34][C:33]=5[CH2:37]4)=[O:21])=[CH:16][NH:15][C:14]=23)[N:5]=1)[CH3:3]
Reactant: c1ccc(-c2ncnc3c2CCNC3)nc1
Reactant: COc1cnc(-n2cnc(C(C)O)n2)c2[nH]cc(C(=O)C(=O)O)c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cnc(-n2cnc(C(C)O)n2)c2[nH]cc(C(=O)C(=O)N3CCc4c(ncnc4-c4ccccn4)C3)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.6 %

Procedure:
To a solution of 2-(7-(3-(1-hydroxyethyl)-1H-1,2,4-triazol-1-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (18 mg, 0.054 mmol), 4-(pyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (1.53 mg, 0.054 mmol) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (20.93 mg, 0.065 mmol) in DMF (1 mL) was added N,N-diisopropylethylamine (0.095 mL, 0.543 mmol). The mixture was stirred at room temperature for 2 hours, diluted with MeOH and purified by prep. HPLC to give 1-(7-(3-(1-hydroxyethyl)-1H-1,2,4-triazol-1-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(pyridin-2-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)ethane-1,2-dione (17 mg, 0.030 mmol, 54.8% yield). LCMS: m/z 526.2 (M+H)+, 1.54 min (method 8). 1H NMR (500 MHz, MeOD) d ppm 9.17 (s, 1H) 8.99-9.10 (m, 1H) 8.61-8.74 (m, 1H) 8.27-8.32 (m, 1H) 7.92-8.04 (m, 2H) 7.74-7.79 (m, 1H) 7.43-7.53 (m, 1H) 5.09 (q, J=6.41 Hz, 1H) 4.80-5.02 (m, 2H) 3.76-4.02 (m, 5H) 3.24-3.38 (m, 2H) 1.60-1.89 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][C:5](=O)[CH2:4][C:3]1=[O:9].[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([F:21])[C:19]=1[F:20])[CH:15]=O.[NH2:22][C:23]1[CH:27]=[CH:26][NH:25][N:24]=1>>[CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][C:5]2[NH:22][C:23]3=[CH:27][CH:26]=[N:25][N:24]3[CH:15]([C:14]3[CH:13]=[C:12]([F:11])[C:19]([F:20])=[C:18]([F:21])[CH:17]=3)[C:4]=2[C:3]1=[O:9]
Reactant: Nc1cc[nH]n1
Reactant: O=Cc1cc(F)c(F)c(F)c1
Reactant: CC1(C)CCC(=O)CC1=O
Product: CC1(C)CCC2=C(C1=O)C(c1cc(F)c(F)c(F)c1)n1nccc1N2

Procedure:
4,4-Dimethyl-1,3-cyclohexanedione, 3,4,5-trifluorobenzaldehyde and 3-aminopyrazole were processed as described in General Procedure A to provide the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:11][CH2:10][N:9](CC2C=CC=CC=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C1(C(=O)OCC)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1(C(=O)OCC)CCNCC1

Procedure:
To a solution of benzylpiperidine-4,4-dicarboxylic acid diethyl ester (21.5 g, 0.067 mol) in ethanol (300 mL) is added 5% Pd/C (25 g, 50% wet). The reaction mixture is stirred under 40 psi pressure of hydrogen for 3 hrs, then filtered through a celite bed and the filtrate is concentrated to give a crude viscous liquid which is purified by column chromatography (silica gel 230-400 mesh, methanol:dichloromethane 10:90) to furnish piperidine-4,4-dicarboxylic acid diethyl ester as pale yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([O:12][CH2:13][CH3:14])(=[O:11])[CH:9]=[CH2:10].[ClH:15]>C(O)C>[Cl:15][C:5]1[CH:6]=[CH:7][C:2]([NH:1][CH2:10][CH2:9][C:8]([O:12][CH2:13][CH3:14])=[O:11])=[CH:3][CH:4]=1
Reactant: C=CC(=O)OCC
Reactant: Cl
Reactant: Nc1ccccc1
Solvent: CCO
Product: CCOC(=O)CCNc1ccc(Cl)cc1

Procedure:
A mixture of aniline (1.4 ml), ethyl acrylate (3.4 ml), and conc. HCl (1.6 ml) in ethanol (17 ml) was heated to reflux for 24 h. Then the solvent was removed and the residue partitioned between an excess of ammonia solution and dichloromethane. The organic layer was separated, washed with brine, dried (MgSO4), and evaporated. The residue was purified by flash chromatography on silica gel (hexane/ethyl acetate 2:1) to provide ethyl N-(4-chlorophenyl)-3-aminopropionate (1.27 g) as yellowish oil.
Reaction SMILES: [CH:1]([NH:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([CH:17]2[CH2:20][C:19]([CH3:22])([CH3:21])[CH2:18]2)=[O:16])=[C:10]([OH:23])[CH:9]=1)=[O:7])([CH3:3])[CH3:2].C[O-].[Na+].[C:27]1([O-:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[Na+].C(Cl)(=O)C=CCC=C>>[CH:1]([NH:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([CH:17]2[CH2:20][C:19]([CH3:21])([CH3:22])[CH2:18]2)=[O:16])=[C:10]([O:23][C:27](=[O:33])[CH:28]=[CH:29][CH2:30][CH:31]=[CH2:32])[CH:9]=1)=[O:7])([CH3:3])[CH3:2]
Reactant: [O-]c1ccccc1
Reactant: CC(C)NCC(=O)c1ccc(OC(=O)C2CC(C)(C)C2)c(O)c1
Agent: C=CCC=CC(=O)Cl
Agent: C[O-]
Agent: [Na+]
Product: C=CCC=CC(=O)Oc1cc(C(=O)CNC(C)C)ccc1OC(=O)C1CC(C)(C)C1

Procedure:
Following a procedure similar to that described in Example 2A above when 3-hydroxy-4-(3,3-dimethylcyclobutanecarbonyloxy)phenyl isopropylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted with 2,5-hexadienoyl chloride there is obtained 3-(2,5-hexadienoyloxy)-4-(3,3-dimethylcyclobutanecarbonyloxy)phenyl isopropylaminomethyl ketone which reacts with hydrochloric acid to yield the hydrochloride salt. When this hydrochloride is reduced with sodium borohydride, using a procedure similar to that described above in Example 30C, there is obtained 3-(2,5-hexadienoyloxy)-4-(3,3-dimethylcyclobutanecarbonyloxy)-alpha-(isopropylaminomethyl)benzyl alcohol hydrochloride.
Reaction SMILES: [CH:1]([Si:4]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[O:5][CH2:6][C:7]1[S:8][C:9](B2OC(C)(C)C(C)(C)O2)=[CH:10][C:11]=1[CH3:12])([CH3:3])[CH3:2].Br[C:29]1[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH:1]([Si:4]([CH:22]([CH3:24])[CH3:23])([CH:25]([CH3:27])[CH3:26])[O:5][CH2:6][C:7]1[S:8][C:9]([C:29]2[CH:30]=[CH:31][C:32]([O:35][C:36]([F:37])([F:38])[F:39])=[CH:33][CH:34]=2)=[CH:10][C:11]=1[CH3:12])([CH3:2])[CH3:3]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)sc1CO[Si](C(C)C)(C(C)C)C(C)C
Reactant: FC(F)(F)Oc1ccc(Br)cc1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(-c2ccc(OC(F)(F)F)cc2)sc1CO[Si](C(C)C)(C(C)C)C(C)C

Procedure:
A mixture of triisopropyl{[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thien-2-yl]methoxy}silane (intermediate 116, 0.40 g) in 1,2-dimethoxyethane (12 ml) and water (6 ml) was treated with 4-bromo-trifluoromethoxybenzene (0.26 g), sodium carbonate (0.26 g) and tetrakis(triphenylphosphine)palladium (0) (0.120 g). The reaction mixture was stirred at reflux for 2 hours and then partitioned between water and ethyl acetate. The aqueous layer was separated and extracted with further ethyl acetate and then the organic solutions combined and dried over magnesium sulfate. The crude product was purified by Si SPE using dichloromethane as eluent to give the title compound as a yellow gum.
Reaction SMILES: Br[CH2:2][C:3]([CH2:5]Br)=[O:4].[C:7]1([OH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F-].[K+]>CN(C)C=O>[O:4]([CH2:8][C:7]([CH2:12][O:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:13])[C:3]1[CH:5]=[CH:11][CH:10]=[CH:9][CH:2]=1
Reactant: O=C(CBr)CBr
Reactant: Oc1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(COc1ccccc1)COc1ccccc1
Reaction time: 2 h
Yield: 50 %

Procedure:
Thus obtained bromomethyl ketone derivative (X, 12.9 g, 31.0 mmol) and phenol (3.23 g, 1.2 Eq) were dissolved in dimethylformamide (30 ml), KF(4.53 g, 2.5 Eq) was added, and the mixture was stirred for two hours to give phenoxymethyl ketone derivative (XIb). This compound was dissolved in methanol (40 ml)-THF (100 ml) and was reacted by adding NaBH4 (2.35 g)-methanol solution (40 ml) (−10□-room temperature, two hours). The reaction was stopped by acetic acid, and the reaction mixture was distilled under reduced pressure to remove methanol. The residue was extracted with ethyl acetate (50 ml×2), washed with water and aqueous sodium chloride solution, dried (anhydrous Na2SO4), concentrated under reduced pressure, and separated-purified by column chromatography (ethyl acetate-hexane, 1:7) to give a compound (XIIb, 6.50 g, Yield 50%) in a diastereomeric form of which amino group is protected by benzyloxycarbonyl.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28]([OH:30])=O)[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[CH2:33]([NH2:36])[CH2:34][CH3:35].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH2:33]([NH:36][C:28]([C:23]1[CH:24]=[N:25][C:26]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]1[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:31])([F:32])[F:1])=[CH:4][CH:5]=3)=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16])[CH:27]=2)=[O:30])[CH2:34][CH3:35]
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Reactant: CCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCNC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.8 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (100 mg, 0.23 mmol) was combined with propylamine (0.019 ml, 0.23 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53 mg, 0.27 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), and triethylamine (0.13 ml, 0.92 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 50 ml of dichloromethane, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide a residue. This material was purified by preparative thin-layer-chromatography on silica eluting with a 4:1 ethyl acetate-hexanes mixture. The product containing band was collected and eluted with 5% methanol in ethyl acetate to afford 47 mg of the title compound.