Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15]/[C:16](=[C:23]2\[C:24](=[O:32])[NH:25][C:26]3[C:31]\2=[CH:30][CH:29]=[CH:28][CH:27]=3)/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)=O)(C)(C)C.C(OCC)(=O)C.Cl>ClCCl.CCOCC>[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15]/[C:16](=[C:23]2\[C:24](=[O:32])[NH:25][C:26]3[C:31]\2=[CH:30][CH:29]=[CH:28][CH:27]=3)/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCOCC
Product: Nc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
1.7 g (4 mmol) of (Z)-3-[1-(4-tert.butoxycarbonylamino-phenylamino)-1-phenyl-methylidene]-2-indolinone are suspended in 15 ml of dichloromethane and after the addition of 35 ml of ethyl acetate/hydrogen chloride for 18 hours at ambient temperature and stirred for 2 hours at 40° C. After cooling the mixture is diluted with ether and the precipitate is suction filtered. The residue is divided between sodium chloride solution and methylene chloride, the organic extracts are dried and concentrated by evaporation.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][CH2:7][C:8]([O:10]CC)=[O:9])=O.[OH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][C:18]=1[CH3:26].[OH-].[K+].Cl>CO.O>[OH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:25])/[CH:24]=[CH:1]/[C:3]2[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=2)[O:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:19][C:18]=1[CH3:26]
Reactant: CC(=O)c1ccc(O)c(C)c1
Reactant: CCOC(=O)COc1cccc(C=O)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(C(=O)/C=C/c2cccc(OCC(=O)O)c2)ccc1O
Temperature: 0 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
Ethyl 2-(3-formylphenoxy)acetate (20.8 g, 0.1 mol, Alfa Aesar) and 4′-hydroxy-3′-methylacetophenone (15.0 g, 0.1 mol, Indofine) were dissolved in 150 mL of methanol and 50 mL of water. The solution was cooled with an ice-water bath, to which was added potassium hydroxide (21.0 g, 0.375 mol). The reaction mixture was stirred overnight. The resulted mixture was poured on to 600 mL of ice-water, acidified to pH=4-5 with 1 N HCl, and extracted with ethyl acetate (4×200 mL). The combined organic layers were washed with water and brine (200 mL each), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The obtained oil was dried under high-vacuum, 20 g (64%) of a solid was obtained as the desired (E)-2-(3-(3-(4-hydroxy-3-methylphenyl)-3-oxoprop-1-enyl)phenoxy)acetic acid.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN([CH2:12][CH2:13]N(C)C)C.Cl[CH:18]([CH2:20][CH:21](Cl)[CH3:22])[CH3:19].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[C:1]1([CH:18]([CH2:20][CH:21]([C:13]2[CH:12]=[CH:3][CH:2]=[CH:1][CH:6]=2)[CH3:22])[CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CC(Cl)CC(C)Cl
Reactant: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(CC(C)c1ccccc1)c1ccccc1
Reaction time: 0.33 h

Procedure:
A mixture of phenyl magnesium bromide (1.25 mL of 0.96 M THF solution, 1.2 mmol) and TMEDA (181.1 μL, 1.2 mmol) was added to a solution of 2,4-dichloropentane (70.5 mg, 0.5 mmol) and FeCl3 (0.5 mL of 0.1 M THF solution, 0.05 mmol) in THF (0.5 mL) at 50° C. over an hour through a syringe pump. The resulting mixture was stirred at the temperature for 20 minutes and saturated ammonium chloride aqueous solution was added thereto to terminate the reaction, followed by diluting with 3 mL of ethyl acetate. The dilution was filtered through a packed silica gel (eluent: ethyl acetate) followed by concentration under reduced pressure. 1H NMR analysis indicates that the desired product was obtained in almost quantitative yield. Purification by recycling GPC gave the pure compound in a yield of 71%.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH3:51][N:52]([CH:63]1[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]1)[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[C:59]([F:62])([F:61])[F:60]>CN(C=O)C.O>[CH3:51][N:52]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[C:59]([F:62])([F:60])[F:61])[CH:63]1[CH2:68][CH2:67][N:66]([C:16](=[O:18])[CH2:15][NH:14][C:12]([C:9]2[CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:11][N:10]=2)=[O:13])[CH2:65][CH2:64]1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)on1
Reactant: CN(c1ccccc1C(F)(F)F)C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ccccc1C(F)(F)F)C1CCN(C(=O)CNC(=O)c2cc(-c3ccccc3)on2)CC1
Reaction time: 8 h
Yield: 14.7 %

Procedure:
To a stirred solution of [(5-phenyl-isoxazole-3-carbonyl)-amino]-acetic acid (0.0576 g, 0.00021 mol) in DMF (1 mL), was added DIPEA (0.1317 g, 0.0010 mol), HOBt (0.035 g, 0.00025 mol) and EDCI.HCl (0.049 g, 0.00025 mol) at ambient temperature. After 2 minutes methyl-piperidin-4-yl-(2-trifluoromethyl-phenyl)-amine hydrochloride (0.06 g, 0.00021 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product extracted with ethyl acetate. The ethyl acetate layer was collected and washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC [(column-Zorbax SB C18-21.2×150 mm, mobile phase-0.1% TFA in water (A)/acetonitrile (B), gradient: (Time): (% B)-0:30; 2:50; 8:80)]) to afford 0.015 g (15%) of 5-phenyl-isoxazole-3-carboxylic acid (2-{4-[methyl-(2-trifluoromethyl-phenyl)-amino]-piperidin-1-yl}-2-oxo-ethyl)-amide. LCMS: 487.19 (M+1)+, 98.16%, 1H NMR (DMSO-d6): δ 8.58 (t, 1H), 7.94 (m, 2H), 7.7 (m, 2H), 7.56 (m, 3H), 7.34 (m, 2H), 4.3 (m, 1H), 4.15 (d, 2H), 3.8 (d, 1H), 3.0 (m, 2H), 2.6 (s, 3H), 1.7 (m, 2H), 1.4 (m, 1H), 1.3 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:14]=[C:15]([OH:23])[C:16]3[CH:17]=[CH:18][CH:19]=[N:20][C:21]=3[CH:22]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].O[C@H:25]([C@H:27]1[CH2:31][N:30]([C@@H](C2C=CC=CC=2)C)[C:29](=[O:40])[CH2:28]1)[CH3:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:22]=[C:21]3[C:16]([CH:17]=[CH:18][CH:19]=[N:20]3)=[C:15]([O:23][C@@H:25]([C@H:27]3[CH2:31][NH:30][C:29](=[O:40])[CH2:28]3)[CH3:26])[CH:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: C[C@H](O)[C@@H]1CC(=O)N([C@H](C)c2ccccc2)C1
Reactant: COc1cc(-c2cc(O)c3cccnc3c2)cc(OC)c1OC
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(-c2cc(O[C@H](C)[C@H]3CNC(=O)C3)c3cccnc3c2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 19.3 %

Procedure:
80 mg of 7-(3,4,5-Trimethoxyphenyl)quinolin-5-ol, 62 mg of (R)-4-((S)-1-hydroxyethyl)-1-((R)-1-phenylethyl)pyrrolidin-2-one and 142 mg of triphenylphosphine was dissolved in 5 mL of DCM. 125.5 mg of DBAD was added and the mixture stirred for 6 h at room temperature. The mixture was diluted with DCM and extracted with 1N NaOH and water. The organic phase was concentrated in vacuo and purified via flash chromatography (10 SiO2; cyclohexane→cyclohexane: ethylacetate: MeOH 58:40:2). Product containing fractions were concentrated, dissolved in 1.5 mL of TFA and heated 75 min at 150° C. in the microwave. The mixture was purified with HPLC (XbridgeC18, MeOH/water, TFA) to yield after lyophilisation 21 mg of Example 2 as solid.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([CH:17]=O)[C:8]2=[O:19])=[CH:4][CH:3]=1.[S:22]1[CH2:26][C:25](=[O:27])[NH:24][C:23]1=[O:28]>C1(C)C=CC=CC=1.N1CCCCC1.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([CH:17]=[C:26]3[S:22][C:23](=[O:28])[NH:24][C:25]3=[O:27])[C:8]2=[O:19])=[CH:20][CH:21]=1
Reactant: O=Cc1cc2ccccc2n(Cc2ccc(Cl)cc2)c1=O
Reactant: O=C1CSC(=O)N1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: O=C1NC(=O)C(=Cc2cc3ccccc3n(Cc3ccc(Cl)cc3)c2=O)S1
Yield: 68 %

Procedure:
1.50 g of 1-(4-chlorobenzyl)-2-oxo-1,2-dihydroquinolin-3-carboxaldehyde and 0.826 g of 2,4-thiazolidinedione were suspended in 30 ml of toluene, and five drops of piperidine and five drops of acetic acid were added, followed by heating and refluxing for 6 hours. The resultant was allowed to cool to precipitate a solid. The precipitated solid was collected by filtration and dried, giving 1.36 g of 5-[1-(4-chlorobenzyl)-2-oxo-1,2-dihydroquinolin-3-ylmethylidene]thiazolidine-2,4-dione as a yellow powder (68% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:16][N:17]3[C:21]4=[N:22][C:23]([CH3:27])=[CH:24][C:25]([CH3:26])=[C:20]4[N:19]=[C:18]3[CH2:28][CH3:29])[CH:12]=2)[CH:7]=1)[CH3:2].CC(C)([O-])C.[K+].[CH2:37]1[CH2:41]O[CH2:39][CH2:38]1.ClC/C=C\CCl>C1COCC1.CN1C(=O)N(C)CCC1>[CH2:1]([O:3][C:4]([C:5]1([C:6]2[CH:15]=[CH:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([CH2:16][N:17]4[C:21]5=[N:22][C:23]([CH3:27])=[CH:24][C:25]([CH3:26])=[C:20]5[N:19]=[C:18]4[CH2:28][CH3:29])[CH:12]=3)[CH:7]=2)[CH2:39][CH:38]=[CH:37][CH2:41]1)=[O:30])[CH3:2]
Reactant: CCOC(=O)Cc1ccc2cc(Cn3c(CC)nc4c(C)cc(C)nc43)ccc2c1
Reactant: C1CCOC1
Agent: CC(C)(C)[O-]
Agent: ClC/C=C\CCl
Agent: [K+]
Solvent: CN1CCCN(C)C1=O
Product: CCOC(=O)C1(c2ccc3cc(Cn4c(CC)nc5c(C)cc(C)nc54)ccc3c2)CC=CC1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of the product of Step 3, above (52) (95 mg, 0.24 mmol), in THF/DMPU (1 ml/0.25 ml) at -78° C., was added 1.0M solution of potassium t-butoxide in THF (0.24 ml, 0.24 mmol). The solution was stirred for 15 minutes at -78° C. and cis-1,4-dichlorobut-2-ene (0.025 ml, 0.24 mmol) was added. The reaction mixture was stirred at -78° C. for 10 minutes and a second equivalent of 1.0M potassium t-butoxide solution was added. The reaction mixture was warmed to -50° C. for 15 minutes, the cooling bath was removed and the mixture was stirred at ambient temperature for 15 minutes. The reaction was then heated to 80° C. for 2 hours. The reaction was cooled to ambient temperature, quenched with concentrated acetic acid, diluted with EtOAc and extracted from brine. The combined organics were then dried over MgSO4, filtered and concentrated to dryness. The crude material was then chromatographed on silica gel using 50% EtOAc in hexanes as the eluant to yield the title compound (53) (35 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH3:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[C:15]([C:20]([OH:22])=O)[CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:24].CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.[OH:47][CH2:48][CH2:49][N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1>CN(C=O)C.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH3:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[C:15]([C:20]([N:53]2[CH2:54][CH2:55][N:50]([CH2:49][CH2:48][OH:47])[CH2:51][CH2:52]2)=[O:22])[CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:24]
Reactant: Cn1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2ccc(C(=O)O)cc21
Reactant: OCCN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2ccc(C(=O)N3CCN(CCO)CC3)cc21
Reaction time: 0.5 h
Yield: 62.4 %

Procedure:
In a similar manner to Step 1 of Example 20, Compound 158 (20.0 mg, 0.0587 mmol) was dissolved in DMF (1 mL), and the solution was treated with EDCI (23 mg, 0.12 mmol), HOBT monohydrate (7.9 mg, 0.059 mmol) and 1-(2-hydroxyethyl)piperazine (31 mg, 0.24 mmol). The mixture was added with water and ethyl acetate, and then extracted with 1 mol/L hydrochloric acid. The aqueous layer was added with sodium carbonate to adjust the pH to 9 and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in chloroform, and the solution was added with hexane and stirred for 30 minutes. The solid was collected by filtration, washed with hexane and dried under reduced pressure to obtain Compound 160 (16.6 mg, yield 62%).
Reaction SMILES: [Na].C([O:5][CH2:6][CH3:7])(=O)C.[CH:8](OCC)=O.[NH2:13][C:14]1[NH:18][N:17]=[C:16]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[C:15]=1[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1>C1(C)C=CC=CC=1.C(O)C>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:15]2[C:16]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[N:17][N:18]3[CH:8]=[CH:7][C:6](=[O:5])[NH:13][C:14]=23)=[CH:26][CH:27]=1
Reactant: Nc1[nH]nc(-c2ccncc2)c1-c1ccc(F)cc1
Reactant: CCOC=O
Reactant: CCOC(C)=O
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=c1ccn2nc(-c3ccncc3)c(-c3ccc(F)cc3)c2[nH]1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of sodium (28 mg), ethyl acetate (0.12 ml) and ethyl formate (0.10 ml) in dry toluene (0.5 ml) was stirred at ambient temperature for 14 hours under nitrogen. To the mixture was added 5-amino-4-(4-fluorophenyl)-3-(pyridin-4-yl)pyrazole (150 mg) in dry ethanol (1.5 ml) and the mixture was refluxed for 7 hours. The reaction mixture was cooled and the separated solid was collected and dried. The solid was dissolved in water (15 ml) and the solution was washed with ether. The aqueous solution was neutralized with diluted hydrochloric acid. The separated solid was collected, washed with water and dried to give 4,5-dihydro-3-(4-fluorophenyl)-5-oxo-2-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine (62 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)=[CH:14][C:13]=2[OH:29])=[O:10])=[CH:4][CH:3]=1.[CH3:30][O:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[OH:29][C:13]1[CH:14]=[C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[CH:16]=[CH:17][C:12]=1[NH:11][C:9](=[O:10])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:36]2[CH:35]=[CH:34][CH:33]=[C:32]([O:31][CH3:30])[CH:37]=2)=[CH:3][CH:4]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: O=C(Cc1ccc(Br)cc1)Nc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1O
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
Product: COc1cccc(-c2ccc(CC(=O)Nc3ccc(Oc4ccc(C(F)(F)F)cc4)cc3O)cc2)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
To 120 mg (0.1 mmol) of above resin-bound 2-(4-bromo-phenyl)-N-[2-Hydroxy-4-(4-trifluoromethyl-phenoxy)-phenyl]-acetamide in 2.0 mL of DME were added 46.0 mg (0.3 mmol) of 3-methoxyphenylboronic acid, 30 mg (0.03 mmol) of Pd(PPh3)4, and 0.3 mL (0.6 mmol) of 2N Na2CO3 solution. The mixture was heated to 80° C. for 12 h. The resin was washed with H2O, DMF, MeOH, DCM three times of each and cleaved with TMSBr/TFA/DCM (1:1:5) at rt for 4 h. The residue obtained after removing the solvent was purified by chromatography (100% methylene chloride) to give 25 mg (50%) of the title compound. LC/MS (m/z) 494 (M+1)+.
Reaction SMILES: C[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:15])=[CH:7][C:8]([C:12]([OH:14])=O)=[N:9]2)=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[CH2:37]([O:39][C:40]([N:42]1[CH2:47][CH2:46][N:45]([C:48]([CH:50]([NH2:60])[CH2:51][CH2:52][C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])=[O:49])[CH2:44][CH2:43]1)=[O:41])[CH3:38]>C(Cl)Cl.CN(C=O)C.C(Cl)Cl>[CH2:37]([O:39][C:40]([N:42]1[CH2:43][CH2:44][N:45]([C:48]([CH:50]([NH:60][C:12]([C:8]2[CH:7]=[C:6]([OH:15])[C:5]3[C:10](=[CH:11][CH:2]=[CH:3][CH:4]=3)[N:9]=2)=[O:14])[CH2:51][CH2:52][C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])=[O:49])[CH2:46][CH2:47]1)=[O:41])[CH3:38]
Reactant: CCOC(=O)N1CCN(C(=O)C(N)CCC(=O)OC(C)(C)C)CC1
Reactant: Cc1ccc2c(O)cc(C(=O)O)nc2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)N1CCN(C(=O)C(CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)c3ccccc3n2)CC1
Reaction time: 0.17 h

Procedure:
To a suspension of 7-methyl-4-hydroxy-2-carboxyquinoline (0.81 g, 4 mmol) in methylene chloride:DMF (4:1, 25 mL) was added 1-hydoxybenzotriazole (HOBT) (0.64 g, 4.8 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (1.09 g, 4.8 mmol) and the reaction mixture was stirred for 10 minutes. A solution of 4-ethoxycarbonyl-1-(1-amino-3-(1,1-dimethylethoxycarbonyl)propyl)carbonylpiperazine (1.37 g, 4 mmol) in methylene chloride (10 mL) was added to the reaction mixture and the resulting mixture was stirred at ambient temperature for 6 hours. The solvent was evaporated in vacuo and the resulting residue was partitioned in ethyl acetate and water. The organic layers were combined and washed with water, brine and concentrated to afford an off-white foam, 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-4-hydroxyquinoline; (1.44 g, 68%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[S:13][C:14]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[F:21][C:18]1[CH:19]=[CH:20][C:14]2[S:13][C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)=[N:16][C:15]=2[CH:17]=1.[S:13]1[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=[CH:12]1
Reactant: Brc1ccccn1
Reactant: C#CCCc1nc2cc(F)ccc2s1
Product: Fc1ccc2sc(CCC#Cc3ccccn3)nc2c1
Product: c1ccc2scnc2c1

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (220 mg, 1.39 mmol) and 2-but-3-ynyl-5-fluoro-benzo[d]thiazole (286 mg, 1.39 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1 to 98:2) to yield 38 mg-(0.13 mmol, 100%) of 5-fluoro-2-(4-pyridin-2-yl)but 3-ynyl)benzo[d]thiazole as an orange solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:21][OH:22])[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[I:32])[C:27]#[N:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)C(N=NC(N(C)C)=O)=O>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:21][O:22][C:24]1[CH:25]=[C:26]([C:27]#[N:28])[CH:29]=[CH:30][C:31]=1[I:32])[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)CC(=O)OCc1ccccc1
Reactant: N#Cc1ccc(I)c(O)c1
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](COc1cc(C#N)ccc1I)CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10.16 g (32.8 mmol) of benzyl (3R)-3-t-butoxycarbonylamino-4-hydroxybutanoate was dissolved in 100 ml of toluene. 10.5 g (42.7 mmol) of 3-hydroxy-4-iodobenzonitrile, 11.2 g (42.7 mmol) of triphenylphosphine and 7.4 g (42.7 mmol) of N,N,N′,N′-tetramethylazodicarboxamide were added to the obtained solution under cooling with ice, and they were stirred at room temperature overnight.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:26])[C:8]([CH2:24][CH3:25])=[C:9]([C:22]#[N:23])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[NH:21][N:20]=[N:19][N:18]=2)=[CH:13][CH:12]=1)=[O:5])[CH3:2].[H-].[Na+].Br[CH2:30][CH:31]([CH3:33])[CH3:32]>CN(C=O)C.[Cl-].[Na+].O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:26])[C:8]([CH2:24][CH3:25])=[C:9]([C:22]#[N:23])[C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([C:17]2[N:18]([CH2:30][CH:31]([CH3:33])[CH3:32])[N:19]=[N:20][N:21]=2)=[CH:15][CH:16]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccc(-c3nnn[nH]3)cc2)c(C#N)c(CC)n1C
Reactant: CC(C)CBr
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(-c2ccc(-c3nnnn3CC(C)C)cc2)c(C#N)c(CC)n1C
Temperature: 0 °C

Procedure:
Into a round bottom flask containing a solution of 4-cyano-5-ethyl-1-methyl-3-[4-(1H-tetrazol-5-yl)-phenyl]-1H-pyrrole-2-carboxylic acid ethyl ester (0.150 g, 0.428 mmol, prepared in example E-242) in DMF (2 mL) cooled to 0° C. while stirring add NaH (0.019 g, 0.479 mmol, 60% in mineral oil). Let stir for 1 h, then add 1-bromo-2-methylpropane (0.052 mL, 0.479 mmol) and let stir overnight. Dilute the mixture with brine (20 mL) and extract the mixture with EtOAc (3×15 mL). Combine the organic layers and wash with brine (2×20 mL), aqueous NH4Cl (1×20 mL), aqueous NaHCO3 (1×20 mL) and water (1×20 mL). Dry the organic layer over anhydrous Na2SO4, filter, and concentrate under reduced pressure. Purify the residue via silica gel chromatography (eluent: 20 to 98% EtOAc in hexanes). Concentrate under reduced pressure the purified fractions and azeotroped with methylene chloride/hexanes. Place the residue under vacuum to provide the title compound as a colorless tar (0.011 g); mass spectrum (m/e): 407.3 (M+H)
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:13]([N:15]2[CH2:20][C:19](=O)[CH2:18][CH2:17][CH:16]2[CH2:22][NH:23][C:24]([C:26]2[CH:27]=[CH:28][CH:29]=[C:30]3[C:35]=2[N:34]=[CH:33][CH:32]=[CH:31]3)=[O:25])=[O:14])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[CH3:36][NH2:37]>>[CH3:1][C:2]1[S:3][C:4]([C:13]([N:15]2[CH2:20][CH:19]([NH:37][CH3:36])[CH2:18][CH2:17][CH:16]2[CH2:22][NH:23][C:24]([C:26]2[CH:27]=[CH:28][CH:29]=[C:30]3[C:35]=2[N:34]=[CH:33][CH:32]=[CH:31]3)=[O:25])=[O:14])=[C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:6]=1
Reactant: CN
Reactant: Cc1nc(-c2ccccc2)c(C(=O)N2CC(=O)CCC2CNC(=O)c2cccc3cccnc23)s1
Product: CNC1CCC(CNC(=O)c2cccc3cccnc23)N(C(=O)c2sc(C)nc2-c2ccccc2)C1

Procedure:
N-((1-(2-Methyl-4-phenylthiazole-5-carbonyl)-5-(methylamino)piperidin-2-yl)methyl)quinoline-8-carboxamide was prepared according to general procedure N using N-((1-(2-methyl-4-phenylthiazole-5-carbonyl)-5-oxopiperidin-2-yl)methyl)quinoline-8-carboxamide and methyl amine. (ESI) 500 (M+H).
Reaction SMILES: Br.[CH3:2][C:3]1[C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[N:5][C:6]2[C:11]([C:12]=1[C:13]([O:15]C)=[O:14])=[CH:10][C:9]([S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])=[C:8]([O:23]C)[CH:7]=2>C(O)(=O)C.O>[OH:23][C:8]1[CH:7]=[C:6]2[C:11]([C:12]([C:13]([OH:15])=[O:14])=[C:3]([CH3:2])[C:4]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:34])[F:32])[CH:26]=3)=[N:5]2)=[CH:10][C:9]=1[S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18]
Reactant: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2cc(OC)c(S(=O)(=O)C(C)C)cc12
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(-c2cccc(C(F)(F)F)c2)nc2cc(O)c(S(=O)(=O)C(C)C)cc2c1C(=O)O
Temperature: 25 °C
Yield: 94.1 %

Procedure:
Hydrobromic acid (80 mL, 1467 mmol) was added slowly to a solution of methyl 3-methyl-6-[(1-methylethyl)sulfonyl]-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (14.13 g, 29.3 mmol) in acetic acid (30 mL). The mixture was heated to reflux for 5 days. The mixture was cooled to room temperature and diluted with water. The solids were collected by filtration, washed with water, and dried to afford 7-hydroxy-3-methyl-6-[(1-methylethyl)sulfonyl]-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (12.5 g, 94% yield). 1H NMR (400 MHz, DMSO-d6) δ11.73 (br. s., 1H), 8.31 (s, 1H), 7.94-8.00 (m, 2H), 7.91 (d, J=7.78 Hz, 1H), 7.79 (t, J=7.65 Hz, 1H), 7.54 (s, 1H), 3.91 (dt, J=6.81, 13.74 Hz, 1H), 2.35 (s, 3H), 1.22 (s, 3H), 1.21 (s, 3H); MS (m/z) 454.1 (M+H+).