Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][NH:14][CH3:15])[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:23][CH2:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[CH2:30][CH2:29][CH2:28]2.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][N:14]([CH2:23][CH2:24][C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[CH2:30][CH2:29][CH2:28]3)[CH3:15])[C:8]([NH2:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CNCCCC(C(N)=O)(c1ccccc1)c1ccccc1
Reactant: BrCCc1ccc2c(c1)CCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCCC(C(N)=O)(c1ccccc1)c1ccccc1)CCc1ccc2c(c1)CCC2

Procedure:
A mixture containing 2,2-diphenyl-5-methylaminopentanamide (0.3 g--see Preparation 3), 5-(2-bromoethyl)indane (0.24 g--see Preparation 6), anhydrous potassium carbonate (0.5 g) and acetonitrile (10 ml) was heated under reflux for 16 hours. The mixture was partitioned between dichloromethane (30 ml) and 10% aqueous sodium carbonate (30 ml), the layers separated and the aqueous layer extracted with dichloromethane (2×20 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromotography on silica eluting with dichloromethane containing methanol (0% up to 6%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a foam, yield 0.23 g.
Reaction SMILES: BrCCl.[CH3:4][O:5][C:6]([CH:8]1[CH:13]=[CH:12][C:11]2[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:10]=2[O:9]1)=O.[Li]CCCC.CCCCCC>C1COCC1.O>[F:18][C:15]1[CH:16]=[CH:17][C:10]2[O:9][CH:8]([CH:6]3[CH2:4][O:5]3)[CH:13]=[CH:12][C:11]=2[CH:14]=1
Reactant: COC(=O)C1C=Cc2cc(F)ccc2O1
Agent: ClCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: Fc1ccc2c(c1)C=CC(C1CO1)O2
Temperature: 22.5 °C
Yield: 91 %

Procedure:
2.5 g of bromochloromethane (19 mmol) were added at room temperature to a solution of 2.0 g of crude 6-Fluoro-1-benzopyran-2-carboxylic acid methyl ester (9.5 mmol) in 40 ml of THF. The solution was then cooled to −80/−85° C. and 7.8 ml of 2.5 M n-BuLi in hexane (19.5 mmol) were slowly added to maintain the internal temperature between −75° C. and −80° C. The reaction progress was monitored by TLC. A 1 M solution of BH3 in THF (10 ml, 10 mmol) was then slowly added to maintain the internal temperature between −70° C. and −80° C. The reaction progress was monitored by TLC. The mixture was hydrolyzed by the addition of water (15 ml) at 0° C. and the phases separated. A 30% aqueous solution of sodium hydroxide was then added to the organic layer and the mixture warmed up to reflux for 2 h until 2-Chloro-1-(6-fluoro-1-benzopyran-2-yl)-ethanol had disappeared. The biphasic mixture was cooled to 20-25° C., the phases separated. The organic layer was washed with water (5 ml) and concentrated until dryness to give 6-Fluoro-2-oxiranyl-1-benzopyran as a mixture of the 4 diastereoisomers [(R,S);(S,R):(R,R);(S,S)]=52:48 (1.7 g, 91% yield).
Reaction SMILES: [C:1]([C@@H:3]([NH:5][C:6](=[O:12])OC(C)(C)C)[CH3:4])#[N:2].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:28]=[CH:29][CH:30]=1)[O:18][C:19]1[CH:27]=[CH:26][C:22](C(O)=O)=[CH:21][CH:20]=1>>[C:1]([C@@H:3]([NH:5][C:6](=[O:12])[C:22]1[CH:21]=[CH:20][C:19]([O:18][C:17]2[CH:28]=[CH:29][CH:30]=[C:15]([O:14][CH3:13])[CH:16]=2)=[CH:27][CH:26]=1)[CH3:4])#[N:2]
Reactant: C[C@@H](C#N)NC(=O)OC(C)(C)C
Reactant: COc1cccc(Oc2ccc(C(=O)O)cc2)c1
Product: COc1cccc(Oc2ccc(C(=O)N[C@@H](C)C#N)cc2)c1
Yield: 46.8 %

Procedure:
General procedure D was used to deprotect 0.62 mmols of 4 and immediately coupled to 0.62 mmols of 28 using general procedure F. After flash chromatography, 0.29 mmols (0.087 g) of the title product was recovered. 1H NMR (500 MHz, CDCl3) δ 7.77 (d, J=8.9, 2H), 7.27 (dd, J=6.7, 9.6, 1H), 7.00 (d, J=8.9, 2H), 6.83 (d, J=8.0, 1H), 6.73 (dd, J=2.4, 8.3, 1H), 6.64-6.55 (m, 2H), 5.13 (dq, J=7.2, 14.5, 1H), 3.78 (s, 3H), 1.65 (d, J=7.2, 3H). 13C NMR (126 MHz, CDCl3) δ 166.03, 161.07, 156.72, 130.44, 129.26, 128.99, 126.89, 119.48, 117.83, 111.97, 110.17, 105.93, 77.29, 77.04, 76.78, 55.41, 36.33, 19.46, 18.59.
Reaction SMILES: Cl.[Br:2][C:3]1[S:4][C:5]2[CH2:6][NH:7][CH2:8][CH2:9][C:10]=2[N:11]=1.Cl[CH2:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([CH:22]2[CH2:25][CH2:24][CH2:23]2)[CH2:18][CH2:17]1)=[O:15].C([O-])([O-])=O.[K+].[K+]>CC#N>[Br:2][C:3]1[S:4][C:5]2[CH2:6][N:7]([CH2:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:25][CH2:24][CH2:23]4)[CH2:18][CH2:17]3)=[O:15])[CH2:8][CH2:9][C:10]=2[N:11]=1
Reactant: O=C(CCl)N1CCN(C2CCC2)CC1
Reactant: Brc1nc2c(s1)CNCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(CN1CCc2nc(Br)sc2C1)N1CCN(C2CCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-bromo-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine hydrochloride (3.03 g, 11.86 mmol), 1-(chloroacetyl)-4-cyclobutylpiperazine (2.57 g, 11.86 mmol), K2CO3 (4.91 g, 35.58 mmol) and KI (166 mg, 1 mmol) in CH3CN (20 ml) is stirred at rt overnight. The solvent is removed in vacuo and the residue is partitioned between water (20 mL) and EtOAc (20 mL). The layers are separated and the aqueous layer is extracted with EtOAc (3×30 mL). The combined extracts are washed with brine (50 μL), dried and evaporated. The resulting oil is purified by flash column with DCM/MeOH/NH4OH (100:5:0.5) to give the title compound as a light yellow solid. MS (M+1): 398.9; 1H NMR (δ, CDCl3): 3.72 (s, 2H), 3.56-3.65 (m, 4H), 3.41 (s, 2H), 2.81-2.95 (m, 4H), 2.67-2.76 (m, 1H), 2.27-2.32 (m, 4H), 1.65-2.08 (m, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][C:14](N)=[C:15]([Br:19])[C:16]=3[C:17]=2[N:18]=1)=[O:5])[CH3:2].N(OCCC(C)C)=O>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([Br:19])[C:16]=3[C:17]=2[N:18]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2[nH]c3ccc(N)c(Br)c3c2n1
Agent: CC(C)CCON=O
Solvent: CCO
Product: CCOC(=O)c1ncc2[nH]c3cccc(Br)c3c2n1

Procedure:
A suspension of 1 g of 8-amino-9-bromo-5H-pyrimido[5,4-b]indole-2-carboxylic acid ethyl ester in 70 ml of ethanol is combined with 1.8 ml of isoamyl nitrite. The mixture is refluxed for one hour and then concentrated. Yield: 0.2 g of 9-bromo-5H-pyrimido[5,4-b]indole-2-carboxylic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=O)=O)=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.CCCCCCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[C:4]([C:12]([F:15])([F:13])[F:14])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1C(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Solvent: O
Product: FC(F)(F)c1cc(Br)ccc1S
Temperature: 2.5 °C
Yield: 97.7 %

Procedure:
4-Bromo-2-trifluoromethyl-benzenesulfonyl chloride (375 g, 1.16 mol) was dissolved in toluene (1.5 L) and a solution of triphenylphosphine (994 g, 3.79 mol) in toluene (1.5 L) was added at 5-10° C. within 45 min. The yellow suspension was stirred at 0-5° C. for min, then water (360 mL) was added at 5-12° C. (strongly exothermic) and the resulting colorless suspension was stirred for 20 min at room temperature. After filtration, the precipitate was washed with toluene (1 L). The combined organics were extracted with a potassium hydroxide solution (1M in water, 2.8 L). During extraction, 3 layers were formed. The upper layer was discarded, the other two were washed with toluene (1 L). The aqueous phase was acidified to pH 3-4 by addition of citric acid (280 g, 1.46 mol). After addition of n-heptane (1 L), the precipitate was filtered off and washed with n-heptane (500 mL). The layers of the combined filtrate were separated and the aqueous phase was extracted with n-heptane (1.5 L). The combined organic extracts were dried over sodium sulfate. Silica gel (250 g) was then added, the slurry was stirred for 10 min at room temperature, filtered and the filtered silica gel washed with n-heptane (1 L). The combined filtrate was concentrated and dried in vacuo at 45° C. to afford 291.2 g (98%) of the title compound as a colorless liquid that was used without further purification in the next step. MS (EI): m/z=256.9, 254.9 [M+H]+. 1H NMR (CDCl3, 400 MHz): δ 3.76 (q, J=2.8 Hz, 1H), 7.26 (d, J=8.3 Hz, 1H), 7.48 (dd, J=2.0 Hz, 8.5 Hz, 1H), 7.75 (d, J=1.9 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[C:19]([N:20]4[C:29]5[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=5)[CH2:23][CH2:22][CH2:21]4)=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:32]([O:34]C)=[O:33])[CH:16]=4)[N:11]=3)=[CH:7][C:6]=2[CH:36]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[C:19]([N:20]4[C:29]5[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=5)[CH2:23][CH2:22][CH2:21]4)=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:32]([OH:34])=[O:33])[CH:16]=4)[N:11]=3)=[CH:7][C:6]=2[CH:36]=1
Reactant: COC(=O)c1ccc2nc(-c3cc4cc(F)ccc4o3)c(N3CCCc4cc(OC)ccc43)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc2c(c1)CCCN2c1nc2cc(C(=O)O)ccc2nc1-c1cc2cc(F)ccc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
To a solution of methyl 2-(5-fluoro-1-benzofuran-2-yl)-3-(6-methoxy-1,2,3,4-tetrahydroquinolin-1-yl)quinoxaline-6-carboxylate (40 mg, 0.083 mmol) in methanol (20 mL) and water (three drops) was added sodium hydroxide (16.5 mg, 0.41 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (30 mL), adjusted to pH 5 with hydrogen chloride (3 N) to give the precipitation, which was collected by filtration to afford 2-(5-fluoro-1-benzofuran-2-yl)-3-(6-methoxy-1,2,3,4-tetrahydroquinolin-1-yl)quinoxaline-6-carboxylic acid as a light yellow solid (23 mg, 44%).
Reaction SMILES: Cl[Si:2]([CH3:10])([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1.[Li]>[CH3:9][Si:2]([CH3:10])([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[OH:18]
Reactant: O=Cc1ccccc1
Reactant: C[Si](C)(Cl)c1ccccc1
Agent: [Li]
Solvent: C1CCOC1
Product: C[Si](C)(c1ccccc1)C(O)c1ccccc1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 79.1 %

Procedure:
A 38 cm fragment of lithium wire (3.2 mm diameter, 45 mg/cm, 1% sodium content, 0.244 mmole) was cut into 2 mm pieces with a razor blade in a glove bag that had been purged with argon. The fragments were placed in an oven-dried 250 mL round bottom flask and sealed under argon. Then 50 mL of dry THF was added and the mixture was stirred at -10° C. After 10 min. 17.3 mL (100 mmole) of chlorodimethylphenylsilane was added and the mixture was stirred at -10° C. under argon for 36-48 h, until metallation was complete. The cold, dark red solution was transferred by canula to a solution of 6.1 mL (60 mmole) of benzaldehyde in 100 mL of dry THF that had been cooled to -78° C. under argon. The solution was stirred at -78° C. for 45 min and allowed to warm to 0° C. for 30 min. Then it was recooled to -78° C. and quenched by addition of 10 mL of glacial acetic acid in 25 mL of dry THF. The pale yellow solution was partitioned between ether and saturated NH4Cl solution and the ether layer was washed with KHCO3, and brine, dried over MgSO4, and concentrated. The residue was purified by flash chromatography on silica gel (6 cm×30 cm) using 10% ether hexane to afford 11.50 g (79%) of the title compound as a colorless oil. Mass Spectrum (FAB) m/e 243 (M+H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[C:19](=[O:23])[CH2:18][CH2:17][CH2:16]2.[BH4-].[Na+]>C(O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]([OH:23])[CH2:18][CH2:17][CH2:16]2
Reactant: O=C1CCCc2cc(OCc3ccc4ccccc4n3)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC1CCCc2cc(OCc3ccc4ccccc4n3)ccc21
Temperature: 25 °C
Yield: 97.7 %

Procedure:
A mixture of 3,4-dihydro-6-(2-quinolylmethoxy)-1(2H)-naphthalenone (1.82 g, 6 mmol), prepared as in step 2, and sodium borohydride (230 mg, 6 mmol) in ethanol (15 mL) was refluxed for 30 minutes. The reaction was allowed to warm to ambient temperature and was then quenched with saturated NH4Cl. Extraction with ethyl acetate and purification on a silica gel column eluting with 9:1 CH2Cl2 -ethyl acetate afforded 1.79 g of 1,2,3,4-tetrahydro-6-(2-quinolylmethoxy)-1-naphthalenol.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:13]([CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][C:20]([OH:22])=O)[C@@H:12]([OH:23])[CH2:11][C@H:10]1[OH:24].C(N(CC)CC)C.C(OC(Cl)=O)C.[CH:39]1[C:44]([OH:45])=[CH:43][C:42]2[C:46]([CH2:49][CH2:50][NH2:51])=[CH:47][NH:48][C:41]=2[CH:40]=1.Cl>C(Cl)Cl.C(OCC)(=O)C>[OH:45][C:44]1[CH:43]=[C:42]2[C:41](=[CH:40][CH:39]=1)[NH:48][CH:47]=[C:46]2[CH2:49][CH2:50][NH:51][C:20](=[O:22])[CH2:19][CH2:18][CH2:17]/[CH:16]=[CH:15]\[CH2:14][C@H:13]1[C@@H:12]([OH:23])[CH2:11][C@@H:10]([OH:24])[C@@H:9]1/[CH:8]=[CH:7]/[C@@H:6]([OH:25])[CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@H]1O
Reactant: NCCc1c[nH]c2ccc(O)cc12
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)NCCc2c[nH]c3ccc(O)cc23)[C@@H](O)C[C@H]1O
Temperature: 0 °C
Yield: 67.9 %

Procedure:
A solution of the protected prostaglandin F2α (500 mg, 0.825 mmol) in CH2Cl2 (4.5 mL) was treated with triethylamine (290 μL, 2.06 mmol) with stirring and cooled to 0° C. Ethylchloroformate (87 μL, 0.907 mmol) was then added and after 15 minutes the reaction was warmed to room temperature. Serotonin hydrochloride (211 mg, 0.99 mmol) was added and stirred for 16 hours. The reaction was then diluted with ethyl acetate and washed with HCl (1 N), saturated sodium bicarbonate, and brine. The organic portion was dried (MgSO4), filtered and concentrated in vacuo. The residue was diluted with methanol and pyridinium p-toluenesulfonate (PPTs) (100 mg) was added and the solution was stirred for 24 hours. The solvent was then removed in vacuo, and the residue was diluted with ethyl acetate and washed with HCl (1 N), saturated sodium bicarbonate, and brine. The organic portion was dried (MgSO4), filtered and concentrated in vacuo. Flash column chromatography (silica gel, 19:1 ethyl acetate:methanol) gave (Z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-((E)-(S)-3-hydroxy-oct-1-enyl)-cyclopentyl]-hept-5-enoic acid [2-(5-hydroxy-1H-indol-3-yl)-ethyl]-amide (Compound 3) (287 mg, 68%).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[C:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[N:15][C:10]=2[CH2:9][O:8][C:7]2[CH:16]=[CH:17][C:18]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:19][C:6]1=2.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH:32]2[CH3:37])=[CH:27][CH:26]=1.[I-].[K+]>C(O)(C)C>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([N:31]2[CH2:36][CH2:35][N:34]([CH2:2][CH2:3][CH:4]=[C:5]3[C:11]4[CH:12]=[CH:13][CH:14]=[N:15][C:10]=4[CH2:9][O:8][C:7]4[CH:16]=[CH:17][C:18]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:19][C:6]3=4)[CH2:33][CH:32]2[CH3:37])=[CH:29][CH:30]=1
Reactant: CC1CNCCN1c1ccc(Cl)cc1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Product: CC1CN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CCN1c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 68.2 %

Procedure:
A solution of 2-[5-(3-Bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.24 g, 0.64 mmol) in isopropanol (5 mL) was treated with 1-(4-Chloro-phenyl)-2-methyl-piperazine (0.25 g, 1.2 mmol) and catalytic potassium iodide. The solution was stirred at 80° C. for 5 hr, and evaporated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate→87:10:3 ethyl acetate/methanol/triethylamine) to yield 0.22 g (69%) of the title compound, 1H-NMR (CDCl3) δ: 1.00 (3H, m), 1.60 (6H, s), 2.20–2.70 (8H, m), 3.10 (2H, m), 3.75 (1H, m), 5.30 (2H, brs), 6.12 (1H, t), 6.87(4H, d), 7.18–7.32 (3H, m), 7.45 (1H, s), 7.70 (1H, d), 8.55 (1H, d).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[N:18]=[C:17]([N:19]([CH3:26])[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:16]=[C:15]([NH2:27])[N:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[OH:28]C1N=CC(C(O)=O)=CC=1.S(Cl)(Cl)=O.NC1N=C(N(C)C2C=CC=CC=2)N=C(C(=N)NO)N=1.NC1N=C(N(C)C2C=CC=C(C)C=2)N=C(C(NO)=N)N=1>>[NH2:27][C:15]1[N:16]=[C:17]([N:19]([CH3:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:18]=[C:13]([C:10]2[N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([OH:28])=[N:7][CH:6]=3)[O:12][N:11]=2)[N:14]=1
Reactant: O=C(O)c1ccc(O)nc1
Reactant: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(Cl)nc3)n2)n1
Agent: CN(c1ccccc1)c1nc(N)nc(C(=N)NO)n1
Agent: Cc1cccc(N(C)c2nc(N)nc(C(=N)NO)n2)c1
Solvent: O=S(Cl)Cl
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(O)nc3)n2)n1

Procedure:
Prepared according to the method described for Intermediate 135 above from 6-Hydroxypyridine-3-carboxylic acid (0.556 g, 4 mmol, thionyl chloride (1.2 mL, 16 mmol) and 4-amino-N-hydroxy-6-[methyl(phenyl)amino]-1,3,5-triazine-2-carboximidamide (prepared in an analogous manner to Intermediate 1, 0.52 g, 2 mmol). Method B HPLC-MS: MH+ requires m/z=363 Found: m/z=363, Rt=1.52 min (87%).
Reaction SMILES: [OH:1][CH:2]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:3][CH2:4][N:5]1[C:9](=[O:10])[CH2:8][S:7][CH:6]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19]C)=[O:18].OC1(CCN2C(=O)CSC2CCCCCCC(OC)=O)CCCCC1>>[OH:1][C:2]1([CH2:3][CH2:4][N:5]2[C:9](=[O:10])[CH2:8][S:7][CH:6]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CCCCCC(O)CCN1C(=O)CSC1CCCCCCC(=O)OC
Agent: COC(=O)CCCCCCC1SCC(=O)N1CCC1(O)CCCCC1
Product: O=C(O)CCCCCCC1SCC(=O)N1CCC1(O)CCCCC1

Procedure:
This compound is prepared essentially by the same method as described in Example 1, Step C, except that the methyl 7-[3-(3-hydroxyoctyl)-4-oxo-2-thiazolidinyl]heptanoate is replaced by methyl 7-{3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl}heptanoate. Chromatographic purification of the crude product resulting from this method gives the title compound as a tlc homogeneous, viscous oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:5][CH:4]([C:6]([OH:8])=[O:7])[CH2:3]1.[CH3:9][C:10](O)([CH3:12])[CH3:11].C1CCC(N=C=NC2CCCCC2)CC1>ClCCl.CN(C)C1C=CN=CC=1>[O:1]=[C:2]1[CH2:5][CH:4]([C:6]([O:8][C:10]([CH3:12])([CH3:11])[CH3:9])=[O:7])[CH2:3]1
Reactant: CC(C)(C)O
Reactant: O=C1CC(C(=O)O)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1CC(=O)C1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 60 %

Procedure:
Into a 2000-mL 4-necked round-bottom flask was placed a solution of 3-oxocyclobutane-1-carboxylic acid (114 g, 999.13 mmol, 1.00 equiv) in dichloromethane (400 mL), 2-methylpropan-2-ol (102 g, 1.38 mol, 1.37 equiv), N,N-dimethylpyridin-4-amine (67.2 g, 550.06 mmol, 0.55 equiv), followed by the addition of a solution of N—(N-cyclohexylcarboximidoyl)cyclohexanamine (226.6 g, 1.10 mol, 1.10 equiv) in dichloromethane (300 mL) dropwise with stirring at room temperature over 25 min. The resulting solution was stifled overnight at room temperature. The solids were filtered out and the filtrate was washed with 2×500 mL of HCl (1 M) and 1×500 mL of saturated aqueous NaHCO3, and concentrated under vacuum. The residue was diluted with 500 mL of hexane. The mixture was decolorized by 50 g of active carbon and stirring for 3 minutes. The solids were filtered out and the filtrate was concentrated under vacuum to afford 102 g (60%) of tert-butyl 3-oxocyclobutane-1-carboxylate as a light yellow liquid.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:13]1[CH:17]=[CH:16][CH:15]=[N:14]1>>[N:13]1([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH:17]=[CH:16][CH:15]=[N:14]1
Reactant: Oc1cccc2ccc(Cl)nc12
Reactant: c1cn[nH]c1
Product: Oc1cccc2ccc(-n3cccn3)nc12

Procedure:
A mixture of 2-chloro-quinolin-8-ol 3 (80 mg, 0.447 mmol) and pyrazole (152 mg, 2.233 mmol) was heated at 175° C. in a steel autoclave for 48 h. The crude product was then purified by column chromatography on silica (ethyl acetate/hexane, 1:1) to give 2-pyrazol-1-yl-quinolin-8-ol (compound ID 964) I1 as a white solid (68 mg, 72%).
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:18]1CCO[CH:19]1[C:23]1[C:31]2[O:30][C:29]([CH3:33])([CH3:32])[CH:28]([C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=3)[C:27]=2[C:26]([CH3:41])=[C:25]([N:42]2[CH2:47][CH2:46][N:45]([C:48]3[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][CH:49]=3)[CH2:44][CH2:43]2)[C:24]=1[CH3:56]>CC(C)=O.O>[CH3:55][O:54][C:51]1[CH:50]=[CH:49][C:48]([N:45]2[CH2:46][CH2:47][N:42]([C:25]3[C:24]([CH3:56])=[C:23]([CH:19]=[O:18])[C:31]4[O:30][C:29]([CH3:33])([CH3:32])[CH:28]([C:34]5[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=5)[C:27]=4[C:26]=3[CH3:41])[CH2:43][CH2:44]2)=[CH:53][CH:52]=1
Reactant: COc1ccc(N2CCN(c3c(C)c(C4OCCO4)c4c(c3C)C(c3ccc(C)cc3)C(C)(C)O4)CC2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(N2CCN(c3c(C)c(C=O)c4c(c3C)C(c3ccc(C)cc3)C(C)(C)O4)CC2)cc1
Yield: 80.4 %

Procedure:
Pyridinium p-toluenesulfonate (20 mg, 80 mmol) was added to a solution of 1-(7-(1,3-dioxolan-2-yl)-2,2,4,6-tetramethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl)-4-(4-methoxyphenyl)piperazine (1.41 g, 2.67 mmol) obtained in Example 93 in acetone (15 ml) and water (1 ml) and the mixture was refluxed for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The organic extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was crystallized from hexane-ethyl acetate to obtain 1.04 g (yield 81%) of the title compound. mp. 175–177° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH2:15][C:16]([OH:18])=O)[CH:12]=[CH:13][CH:14]=1)=[O:4].[F:23][C:24]([F:34])([F:33])[C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1.C(Cl)CCl.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C.O>[O:18]=[C:16]([NH:30][CH2:29][C:28]1[CH:27]=[CH:26][C:25]([C:24]([F:23])([F:33])[F:34])=[CH:32][CH:31]=1)[CH2:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][CH2:7][C:6]1[CH:19]=[CH:20][CH:21]=[CH:22][C:5]=1[C:3]([O:2][CH3:1])=[O:4]
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1ccccc1COc1cccc(CC(=O)O)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: ClCCCl
Product: COC(=O)c1ccccc1COc1cccc(CC(=O)NCc2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(3-{[2-(Methoxycarbonyl)benzyl]oxy}phenyl)acetic acid (60 mg, 0.2 mmol) was dissolved in DCM (2 ml). 4-(Trifluoromethyl)benzylamine (42 mg, 0.24 mmol) was added, then EDC (46 mg, (0.24 mmol) was added and then DMAP (29.3 mg, 0.24 mmol) was added. The mixture was stirred at room temperature overnight. 1% Hydrochloric acid (1 ml) and water (1 ml) were added to the mixture. The two phases were separated by using a Whatman Filter Tube. The obtained organic portion was evaporated in vacuum and 82 mg solid product was left. It was then used directly in next step.