Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:22][NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>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>[CH2:15]([O:14][C@@H:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([NH:23][CH3:22])[CH:25]=2)=[CH:3][CH:4]=1)[C:10]([O:12][CH3:13])=[O:11])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CNc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: COC(=O)[C@H](Cc1ccc(Br)cc1)OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CNc1cccc(-c2ccc(C[C@H](OCc3ccccc3)C(=O)OC)cc2)c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
635 mg (0.55 mmol) of tetrakis(triphenylphosphine)palladium are added to a solution of 4 g (11 mmol) of methyl (S)-3-(4-bromophenyl)-2-benzyloxypropionate and 4 g (17 mmol) of methyl[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine in 25 ml of dimethylformamide. 10 ml of a 2M potassium phosphate solution are added and the reaction mixture is stirred at 70° C. for 1 hour. The reaction is halted by the addition of 50 ml of water and then extraction is carried out with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated and then the residue is chromatographed on silica gel (heptane/ethyl acetate 80/20). 2.6 g of methyl (S)-2-benzyloxy-3-[3′-(methylamino)biphenyl-4-yl]propanoate are obtained in the form of an oil. Yield=61%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl.Cl.[CH:15]1[C:27]2[CH:26]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C>ClCCl.CN(C1C=CN=CC=1)C>[CH:24]1[C:25]2[CH:26]([N:28]3[CH2:33][CH2:32][N:31]([C:10]([C:6]4[CH:5]=[C:4]5[C:9](=[CH:8][CH:7]=4)[NH:1][CH:2]=[CH:3]5)=[O:12])[CH2:30][CH2:29]3)[C:27]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]=2[CH:21]=[CH:22][CH:23]=1
Reactant: c1ccc2c(c1)-c1ccccc1C2N1CCNCC1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc2[nH]ccc2c1)N1CCN(C2c3ccccc3-c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Indole-5-carboxylic acid (17 mg, 0.11 mmole) and N-9-fluorenyl-piperazine dihydrochloride (32 mg, 0.1 mmole) were dissolved in 5 ml dichloromethane. To this solution was added triethylamine (2 eq. to neutralize HCl salt), catalytic DMAP and EDCI (33 mg, 0.11 mmole). The resulting mixture was stirred at room temperature overnight and was then worked up by washing sequentially with 1N HCl, saturated sodium bicarbonate, and saturated sodium chloride. The product was then purified by flash chromatography on silica gel (40:1 CHCl3/MeOH). 1H NMR (300 Mhz, CDCl3) δ 8.38 (s, 1H), 7.72-7.60 (m, 5H), 7.40-7.18 (m, 7H), 6.55 (d, 1H), 4.88 (s,1H), 3.60 (bs, 4H), 2.62 (bs, 4H).
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[C@H:3]([CH3:5])[OH:4].C([O-])(O)=O.[Na+].[CH2:14]([O:20][C:21](N1C=CC=CC1=O)=[O:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>O.C1COCC1>[OH:4][C@@H:3]([CH3:5])[C@@H:2]([NH:1][C:21]([O:20][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:22])[C:6]([OH:8])=[O:7]
Reactant: CCCCCCOC(=O)n1ccccc1=O
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCOC(=O)N[C@@H](C(=O)O)[C@H](C)O
Reaction time: 15 h
Yield: 87.3 %

Procedure:
To a stirred mixture of D-threonine (0.150 g, 1.25 mmol) and NaHCO3 (0.158 g, 1.89 mmol) in H2O (3.5 mL), the crude mixture containing hexyl-2-pyridyl-carbonate and hexyl-2-oxopyridine-1-carboxylate (0.45 g, 1.89 mmol) in THF (3.5 mL) was added. After 15 h at rt, the crude mixture was rotary evaporated to remove the organics and subsequently extracted with Et2O (3×5 mL). The aqueous phase was acidified with 2.0 M HCl solution to pH 2-3 and subsequently extracted with EtOAc (3×10 mL). The organic fraction was dried over Na2SO4, filtered and concentrated to dryness to afford the title compound (0.27 g, 88%) as transparent oil, which was used in the next step without further purification. 1H NMR (DMSO-d6) δ 0.83-0.90 (m, 3H), 1.08 (d, J=6.3 Hz, 3H), 1.21-1.36 (m, 6H), 1.49-1.59 (m, 2H), 3.89-3.99 (m, 3H), 4.01-4.11 (m, 1H), 6.67 (d, J=9.0 Hz, 1H), 12.30 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[O:12][C:11]([CH3:13])=[C:10]([CH:14]([NH:19][C:20]3[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=3)[CH2:15][CH:16]([CH3:18])[CH3:17])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH3:29][NH:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34].Cl.C(N=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[O:12][C:11]([CH3:13])=[C:10]([CH:14]([NH:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([N:30]([CH3:29])[CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:25])=[CH:22][CH:21]=3)[CH2:15][CH:16]([CH3:17])[CH3:18])[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)CCNC
Reactant: Cc1oc(-c2ccnc(Cl)c2)cc1C(CC(C)C)Nc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1oc(-c2ccnc(Cl)c2)cc1C(CC(C)C)Nc1ccc(C(=O)N(C)CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
A solution of 4-({1-[5-(2-chloropyridin-4-yl)-2-methylfuran-3-yl]-3-methylbutyl}amino)benzoic acid (239 mg), ethyl 3-(methylamino)propanoate (94 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (138 mg), hydroxybenzotriazole monohydrate (110 mg) and triethylamine (100 μL) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure. To the residue were added ethanol (2 mL), tetrahydrofuran (2 mL) and 1N lithium hydroxide (1.2 and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (279 mg, 96%).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1.Cl[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:11]=[CH:10][C:8]([NH:9][C:13]2[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:7][CH:6]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: COCOc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCOc1ccc(Nc2ncccc2[N+](=O)[O-])cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 71.8 %

Procedure:
8.4 g (54.8 mmol) of 4-methoxymethyloxyaniline and 7.5 g (49 mmol) of 2-chloro-3-nitropyridine were dissolved in 35 ml of dimethylformamide. 7.6 g (55 mmol) of anhydrous potassium carbonate was added to the solution. The resulting solution was heated under stirring at 100° C. for 4 h. The reaction liquid was cooled to room temperature and an insoluble matter thus formed was removed by filtration. The solvent was distilled off under reduced pressure and the residue was dissolved in ethyl acetate. The solution was washed with an aqueous citric acid solution and then with water. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure and the residue was recrystallized from ethanol to obtain 9.68 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.[NH2:19][CH2:20][CH:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]1[CH3:31].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:19][CH2:20][CH:21]2[CH2:30][CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]2[CH3:31])[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: CN1c2ccccc2CCC1CN
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: CN1c2ccccc2CCC1CNc1nc(N)nc(-c2ccco2)c1C#N

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, 2-(aminomethyl)-1,2,3,4-tetrahydro-1-methyl-quinoline hydrochloride and DBU in DME. ES-MS m/e (%): 361 (M+H+, 100).
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]([NH:12][C:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][C:14]=2[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=2)=[O:23])=[O:11])[CH2:6][CH2:5]1.Br[CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38].C(N(CC)C(C)C)(C)C.[I-].[K+]>CN(C)C(=O)C.C(OCC)(=O)C>[CH3:40][O:39][C:37]([CH2:36][CH2:35][CH2:34][CH2:33][NH:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]([NH:12][C:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][C:14]=2[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=2)=[O:23])=[O:11])[CH2:6][CH2:5]1)=[O:38]
Reactant: N[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccccc23)CC1
Reactant: COC(=O)CCCCBr
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COC(=O)CCCCN[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccccc23)CC1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
Trans-3-(4-aminocyclohexylcarbonylamino)-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide dihydrochloride (300 mg) obtained in Example 219 is suspended in N,N-dimethylacetamide (5 ml), and thereto are added methyl 5-bromovalerate (106 μl), N,N-diisopropylethylamine (537 μl), and potassium iodide (111 mg), and the mixture is stirred at 100° C. for 24 hours. Methyl 5-bromovalerate (106 μl), N,N-diisopropylethylamine (537 μl) and potassium iodide (111 mg) are further added thereto, and the mixture is stirred at 100° C. for 12 hours. The reaction solution is diluted with ethyl acetate, and washed successively with a saturated aqueous sodium hydrogen carbonate solution, water, a saturated brine, and dried over sodium sulfate. The solvent is evaporated under reduced pressure, and the resulting residue is purified by NH-silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1, then ethyl acetate) to give trans-3-[4-(4-methoxycarbonylbutylamino)cyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)-benzofuran-2-carboxamide (101 mg).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:11]2[N:12]=[N:13][N:14]([CH3:16])[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH:17][CH2:18][C:19]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1.[H-].[Na+]>CN(C)C=O>[CH3:10][O:9][C:8]1[CH:7]=[CH:6][C:5]([C:11]2[N:12]=[N:13][N:14]([CH3:16])[N:15]=2)=[CH:4][C:3]=1[CH2:2][O:17][CH2:18][C:19]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Reactant: COc1ccc(-c2nnn(C)n2)cc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2nnn(C)n2)cc1COCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5-(3-(Bromomethyl)-4-methoxyphenyl)-2-methyl-2H-tetrazole (35.0 mg, 0.12 mmol) and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (40.0 mg, 0.14 mmol) were combined in dimethylformamide (1 mL) and cooled to 0° C. The reaction was treated with sodium hydride (3.2 mg, 0.14 mmol), stirred at 0° C. for 1 h, and at room temperature overnight. The solvents were removed in vacuo and the crude product purified by column chromatography on silica gel (30% ethyl acetate/hexanes) to afford 30 mg (50%). LC/MS (HPLC method 3): tR=3.29 min, 494.25 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:9]CC=C)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:13]1(C)[CH:18]=C(C)C=C(C)[CH:14]=1>>[CH3:8][C:6]1[C:5]([CH2:18][CH:13]=[CH2:14])=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc(C)cc(C)c1
Reactant: C=CCOc1cc(C)cc(C)c1
Product: C=CCc1c(C)cc(C)cc1O
Yield: 74 %

Procedure:
837 g of allyl 3,5-dimethylphenyl ether (B) were dissolved in 1 500 ml of mesitylene, and the solution was refluxed for two days. The solvent was removed in vacuo and the residue was taken up in tert-butyl methyl ether. The mixture was extracted repeatedly using sodium hydroxide solution, and the aqueous phases were combined and acidified with hydrochloric acid. The product which separates out was taken up in tert-butyl methyl ether, and the mixture was dried over magnesium sulphate, concentrated and distilled. A total of 619 g (74% of theory) of 3,5-dimethyl-2-(2-propen-1-yl)-phenol of a boiling point of 145° C. at 30 mbar and a melting point of 51° C. were obtained.
Reaction SMILES: C[O:2][C:3](=[O:38])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][CH:15]([C:19]3([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=4)[C:27]4[C:22](=[CH:23][C:24]([Cl:28])=[CH:25][CH:26]=4)[NH:21][C:20]3=[O:29])[CH2:14]2)=[O:12])=[CH:6][CH:5]=1.O.[OH-].[Li+]>O1CCCC1>[Cl:28][C:24]1[CH:23]=[C:22]2[C:27]([C:19]([CH:15]3[CH2:16][CH2:17][CH2:18][N:13]([C:11]([NH:10][C:7]4[CH:6]=[CH:5][C:4]([C:3]([OH:38])=[O:2])=[CH:9][CH:8]=4)=[O:12])[CH2:14]3)([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=3)[C:20](=[O:29])[NH:21]2)=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of rac-4-({3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carbonyl}-amino)-benzoic acid methyl ester (0.24 g, 0.44 mmol) (from Example 63 supra) in tetrahydro furan (2.5 mL) was added the suspension of lithium hydroxide monohydrate (0.18 g, 4.4 mmol) (Aldrich). The mixture was stirred at room temperature for overnight. The solvent was removed and the residue was partitioned between ethyl acetate and water. The aqueous layer was acidified to pH<5 with dilute HCl, then extracted with ethyl acetate several times. The combined organic layer was washed with water, brine, dried over MgSO4 and concentrated to give rac-4-({3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carbonyl}-amino)-benzoic acid as a white solid.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][OH:8].[O:9]1CCC[CH2:10]1.C([Li])CCC.CN(C)C=O>O.CO>[OH:8][CH2:7][C:3]1[S:4][CH:5]=[CH:6][C:2]=1[CH:10]=[O:9]
Reactant: C1CCOC1
Reactant: OCc1sccc1Br
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: O=Cc1ccsc1CO
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 35 %

Procedure:
To a stirred, chilled, (-70° C.) solution of 3-bromo-2-hydroxymethylthiophene (19.0 g) and tetrahydrofuran (250 ml) was added n-butyllithium (88 ml of a 2.5M solution in hexanes), under nitrogen, over 45 mins. The solution was stirred and chilled for 1 hr and was transferred via canula to a vessel containing a solution of N,N-dimethylformamide (7.9 g) and tetrahydrofuran (250 ml). The mixture was allowed to warm to ambient temperature overnight, with stirring. Methanol (20 ml) and water (200 ml) were added. The organic phase was removed in vacuo, and the residue was extracted with dichloromethane. The combined organic phase was washed with 5% sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by high performance liquid chromatography (silica gel, eluted with 40% ethyl acetate in hexane). The appropriate fractions were combined and evaporated to afford 3.5 g (35%) of 2-hydroxymethyl-3-thiophenecarboxaldehyde.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([CH3:9])[C:3]=1[CH:10](O)[C:11]([F:14])([F:13])[F:12].[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([CH3:9])[C:3]=1[CH:10]([N:20]1[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]1)[C:11]([F:14])([F:13])[F:12]
Reactant: Cn1ccc(=O)c(O)c1C(O)C(F)(F)F
Reactant: CN1CCNCC1
Product: CN1CCN(C(c2c(O)c(=O)ccn2C)C(F)(F)F)CC1
Yield: 29 %

Procedure:
In a similar manner, Apo7073 was prepared from 3-hydroxy-1-methyl-2-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-4(1H)-one (1.0 g, 4.5 mmol) and 1-methylpiperazine (1.0 mL, 9.0 mmol). The title compound Apo7073 (401 mg) was obtained after purification by Biotage reverse C18 column. Yield=29%; 1H NMR (400 MHz, DMSO-d6, 75° C.) δ (ppm): 7.63 (d, J=6.8 Hz, 1H), 6.21 (d, J=7.4 Hz, 1H), 4.94 (q, J=8.5 Hz, 1H), 3.86 (s, 3H), 3.05 (br. s., 4H), 2.92 (br. s., 4H), 2.64 (s, 3H); MS m/z 306 [M+1]+, 206 (100%).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1.P(Cl)(Cl)Cl>O>[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:21][C:12]([C:3]2[C:2]([OH:1])=[C:11]3[C:6]([CH:7]=[CH:8][CH:9]=[N:10]3)=[CH:5][CH:4]=2)=[O:14])=[CH:18][CH:17]=1
Reactant: O=C(O)c1ccc2cccnc2c1O
Reactant: NCc1ccc(Cl)cc1
Solvent: ClP(Cl)Cl
Solvent: O
Product: O=C(NCc1ccc(Cl)cc1)c1ccc2cccnc2c1O
Reaction time: 8 h
Yield: 21.3 %

Procedure:
A solution of 8-hydroxyquinoline-7-carboxylic acid (0.250 g) of Preparation 1 and 4-chlorobenzylamine (0.187 g) in 25 mL xylenes is heated to reflux. To this is added dropwise PCl3 (0.073 g). Refluxing is continued overnight. The reaction is then cooled and water is added to destroy excess PCl3. The resulting solid is collected and recrystallized from EtOAc/hexanes to yield 0.088 g of the title product as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[Cl:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([Cl:27])[C:20]=1[N:28]=[C:29]=[S:30]>>[Cl:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])[C:2]=1[NH:1][C:29](=[S:30])[NH:28][C:20]1[C:21]([Cl:27])=[CH:22][C:23]([O:25][CH3:26])=[CH:24][C:19]=1[Cl:18]
Reactant: COC(=O)c1ccc(Cl)c(N)c1NCCCO
Reactant: COc1cc(Cl)c(N=C=S)c(Cl)c1
Product: COC(=O)c1ccc(Cl)c(NC(=S)Nc2c(Cl)cc(OC)cc2Cl)c1NCCCO
Temperature: 25 °C
Reaction time: 24 h
Yield: 26.8 %

Procedure:
A mixture of methyl 3-amino-4-chloro-2-[(3-hydroxypropyl)amino]benzoate (500 mg, 1.93 mmol) and 1,3-dichloro-2-isothiocyanato-5-methoxybenzene (678 mg, 2.90 mmol) was stirred at room temperature for 1 day and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 30-70% ethyl acetate/n-hexane gradient mixture to give the title compound as a brown oil (255 mg, 0.517 mmol, 27%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH:18]C(=O)OC(C)(C)C)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[ClH:26]>O1CCOCC1>[ClH:26].[CH3:1][C:2]1[C:3]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH2:18])=[N:4][CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: Cc1cc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl N-[(1S,2S)-2-{[3-methyl-5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]carbamate (580 mg, 1.614 mmol) in 1,4-dioxane (5 ml) was added HCl in 1,4-dioxane (4M, 4 ml, 16.00 mmol). The reaction was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and azeotropically distilled with toluene to afford the title compound.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:51][C:52]1[CH:57]=[CH:56][C:55]([OH:58])=[CH:54][CH:53]=1)[C:6]([NH:8][CH:9]([CH2:43][C:44]1[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=1)[C:10]([N:12]1[CH2:17][CH:16]([CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)[NH:15][C:14](=[O:29])[CH:13]1[CH2:30][C:31]1[N:32]=[CH:33][N:34](CC2C=CC=CC=2)[CH:35]=1)=[O:11])=[O:7])(=[O:3])[CH3:2].C1CCCCC=1>C(O)C.C(O)(=O)C.[Pd]>[C:1]([NH:4][CH:5]([CH2:51][C:52]1[CH:57]=[CH:56][C:55]([OH:58])=[CH:54][CH:53]=1)[C:6]([NH:8][CH:9]([CH2:43][C:44]1[CH:45]=[CH:46][C:47]([F:50])=[CH:48][CH:49]=1)[C:10]([N:12]1[CH2:17][CH:16]([CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)[NH:15][C:14](=[O:29])[CH:13]1[CH2:30][C:31]1[N:32]=[CH:33][NH:34][CH:35]=1)=[O:11])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)NC(Cc1ccc(O)cc1)C(=O)NC(Cc1ccc(F)cc1)C(=O)N1CC(Cc2ccc3ccccc3c2)NC(=O)C1Cc1cn(Cc2ccccc2)cn1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Solvent: CC(=O)O
Product: CC(=O)NC(Cc1ccc(O)cc1)C(=O)NC(Cc1ccc(F)cc1)C(=O)N1CC(Cc2ccc3ccccc3c2)NC(=O)C1Cc1c[nH]cn1
Reaction time: 48 h

Procedure:
2-acetylamino-N-[2-[2-(1-benzyl-1H-imidazol-4-ylmethyl)-5-naphthalen-2-ylmethyl-3-oxo-piperazin-1-yl]-1-(4-fluorobenzyl)-2-oxo-ethyl]-3-(4-hydroxyphenyl)propionamide, 73, (0.22 g, 0.28 mmol) is dissolved in ethanol/acetic acid (4:1) (3 mL). Cyclohexene (3 mL) and Pd-black are added and the solution is refluxed with periodic replenishment of cyclohexene. The reaction is monitored by TLC and after 2 days is cooled and filtered through Celite to remove the catalyst. The filtrate is concentrated in vacuo to afford an oil which is purified by reverse phase C18 prep HPLC to afford the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:22])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[OH:21])=[CH:4][CH:3]=1.Br[CH2:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([OH:22])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[CH2:10][CH:9]2[O:21][CH2:24][C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)=[CH:6][CH:7]=1
Reactant: BrCc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)cc2)C(O)C1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to the procedure described under (c), by alkylating tert-butyl (3RS,4RS)-4-(4-chlorophenyl)-3,4-dihydroxy-piperidine-1-carboxylate with 2-bromomethylnaphthalene there was obtained tert-butyl (3RS,4RS)-4-(4-chlorophenyl)-4-hydroxy-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a light yellow oil; MS: 411, 413 [M-(C4H8)]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[C:14]([CH:16]1[CH2:18][CH2:17]1)#[CH:15]>C1(C)C=CC=CC=1.C(N(CC)CC)C.[Cu]I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=[C:4]([C:15]#[C:14][CH:16]2[CH2:18][CH2:17]2)[N:3]=1
Reactant: CCOC(=O)c1ccc(Cl)nc1Cl
Reactant: C#CC1CC1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#CC2CC2)nc1Cl
Yield: 31 %

Procedure:
Ethyl 2,6-dichloropyridine-3-carboxylate (2.0 g, 9.1 mmol), ethynylcyclopropane (1.6 mL of a 70% w/v solution in toluene, 13.63 mmol), copper(I) iodide (173 mg, 0.9 mmol), bis(triphenylphosphine) palladium(II) chloride (1.28 g, 1.82 mmol) were stirred in 40 mL triethylamine at room temperature for 24 h. The solvent was removed in vacuo and the residue was purified by column chromatography using 10-50% EtOAc/hexane to give the product (0.7 g, 31%) as a brown oil. m/z=250 (M+1).