Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([O:14][CH2:15][C:16]2[C:24]3[O:23][CH:22]=[CH:21][C:20]=3[CH:19]=[C:18](Br)[CH:17]=2)[C@@H:9]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:32][N:33]1[C:37]([Sn](CCCC)(CCCC)CCCC)=[CH:36][N:35]=[N:34]1>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([O:14][CH2:15][C:16]2[C:24]3[O:23][CH:22]=[CH:21][C:20]=3[CH:19]=[C:18]([C:37]3[N:33]([CH3:32])[N:34]=[N:35][CH:36]=3)[CH:17]=2)[C@@H:9]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnnn1C
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](OCc2cc(Br)cc3ccoc23)[C@@H]1c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: Cn1nncc1-c1cc(CO[C@H]2CCCN(C(=O)OC(C)(C)C)[C@H]2c2ccccc2)c2occc2c1
Temperature: 25 °C
Yield: 45.7 %

Procedure:
Bis(triphenylphosphine)palladium dichloride (5.0 mg) was added to a degassed solution of [2S,3S]-1-tert-butoxycarbonyl-2-phenyl-3-[(5-bromobenzofuran-7-yl)methyloxy]piperidine (111 mg), and 1-methyl-5-tributylstannanyl-1H-[1,2,3]triazole (165 mg) in dry toluene (5.0 ml) under a dry nitrogen atmosphere. The resulting solution was warmed to reflux for 18 hours. After this time the reaction was cooled to room temperature and the solvent removed under reduced pressure. The residue was partitioned between aqueous NaHCO3 solution (10 ml, sat) and ethyl acetate. The organic layer was washed with brine (10 ml), dried over MgSO4, filtered and the solvent removed under pressure. Purification by MPLC (1:1 ethyl acetate/n-hexane) afforded [2S,3S]-1-tert-butoxycarbonyl-2-phenyl-3-{[5-(1-methyl-1H-[1,2,3]triazol-5-yl)benzofuran-7-yl]methyloxy}piperidine as a yellow foam (51 mg). 1H NMR (360 MHz,CDCl3)δ1.45 (9H, s), 1.51-1.83 (5H, m), 2.73 (1H, t d, J=7.0, 3.0 Hz), 3.94 (1H, m), 3.96 (3H, s), 5.02 (2H, d, J=1.0 Hz), 5.76 (1H, br s), 6.84 (1H, d, J=1.0 Hz), 7.26 (4H, m), 7.55 (3H, m), 7.70 (2H, br s); MS m/z CI+ 489 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11]Br)=[CH:4][CH:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][C:14]1=[O:19].[H-].[Na+].C(OCC)(=O)C>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][N:13]2[CH2:18][CH2:17][O:16][CH2:15][C:14]2=[O:19])=[CH:4][CH:3]=1
Reactant: O=C1COCCN1
Reactant: BrCCCOc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1COCCN1CCCOc1ccc(Br)cc1
Temperature: 75 °C
Reaction time: 5 h
Yield: 31.2 %

Procedure:
To a mixture of 1-bromo-4-(3-bromopropoxy)benzene (300 mg, 1.02 mmol) and morpholin-3-one (100 mg, 1.02 mmol) in DMF (6 mL) was added NaH (365 mg, 1.10 mmol). The mixture was stirred at 75° C. for 5 hours. The mixture was poured into ethyl acetate and washed with water. The organic phase was dried over sodium sulfate, filtered, and concentrated to give the title compound (100 mg, 35%) as a yellow oil.
Reaction SMILES: [NH3:1].[C:2]12([C:12]3[CH:24]=[CH:23][C:15]([O:16][CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21])=[CH:14][CH:13]=3)[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2>C1C=CC=CC=1>[C:2]12([C:12]3[CH:24]=[CH:23][C:15]([O:16][CH2:17][CH2:18][CH2:19][C:20]([NH2:1])=[O:21])=[CH:14][CH:13]=3)[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2
Reactant: O=C(Cl)CCCOc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: N
Solvent: c1ccccc1
Product: NC(=O)CCCOc1ccc(C23CC4CC(CC(C4)C2)C3)cc1

Procedure:
A strong stream of dry ammonia is passed (for 15 minutes) into a solution of 16.5 g of 4-[4-(1-adamantyl)-phenoxy]-butyric acid chloride in 150 ml of absolute benzene under anhydrous conditions, whilst stirring. The product formed is now filtered off and washed with ether. Recrystallisation from a large amount of acetone yields pure 4-[4-(1-adamantyl)-phenoxy]-butyric acid amide of melting point 176°-177° C (needles).
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][C@@H:8]([N:11]([CH3:21])[C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C@H:7]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[CH2:6]1)(=[O:4])[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].[NH:36]1[CH2:40][CH2:39][CH2:38][C:37]1=[O:41].O>CN(C=O)C>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]([N:11]([C@@H:8]2[CH2:9][CH2:10][N:5]([C:1](=[O:4])[CH2:2][CH2:3][N:36]3[CH2:40][CH2:39][CH2:38][C:37]3=[O:41])[CH2:6][C@H:7]2[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[CH3:21])=[O:20])=[CH:18][CH:17]=1
Reactant: O=C1CCCN1
Reactant: C=CC(=O)N1CC[C@@H](N(C)C(=O)c2ccc(Cl)cc2)[C@H](c2ccc(Cl)c(Cl)c2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)c1ccc(Cl)cc1)[C@@H]1CCN(C(=O)CCN2CCCC2=O)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 110 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
To a solution of the compound obtained in Example 588 (0.050 mg) in DMF (1 mL) were added potassium carbonate (0.0166 mg) and 2-pyrrolidinone (0.0093 mL), and the mixture was stirred at 110° C. for 1 hr. To the reaction mixture was added water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH Chromatorex) (solvent gradient; 30→100% ethyl acetate/hexane) to give the title compound (37 mg, 63%) as a white powder.
Reaction SMILES: [N:1]1([C:7]([C:9]2[N:10]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([C:18](O)=[O:19])=[CH:13][CH:12]=3)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:26]1([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH:26]1([N:32]2[CH2:37][CH2:36][N:35]([C:18]([C:14]3[CH:15]=[C:16]4[C:11](=[CH:12][CH:13]=3)[N:10]([CH2:21][C:22]([F:24])([F:23])[F:25])[C:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])=[CH:17]4)=[O:19])[CH2:34][CH2:33]2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: C1CCC(N2CCNCC2)CC1
Reactant: O=C(O)c1ccc2c(c1)cc(C(=O)N1CCOCC1)n2CC(F)(F)F
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCOCC1)n2CC(F)(F)F)N1CCN(C2CCCCC2)CC1
Yield: 65 %

Procedure:
The title compound was synthesized in analogy to example 46, intermediate e), from 2-(morpholine-4-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indole-5-carboxylic acid and 1-cyclohexylpiperazine (commercially available), to give the desired product as a white solid (65%).
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[N:23][C:24]=3[NH2:26])[N:19]([C@H:27]3[CH2:32][CH2:31][C@H:30]([N:33]4[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]4)[CH2:29][CH2:28]3)[N:18]=2)=[CH:13][C:12]=1[O:40][CH3:41]>C(O)C>[NH2:26][C:24]1[N:23]=[CH:22][N:21]=[C:20]2[N:19]([C@H:27]3[CH2:32][CH2:31][C@H:30]([N:33]4[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH2:38]4)[CH2:29][CH2:28]3)[N:18]=[C:17]([C:14]3[CH:15]=[CH:16][C:11]([N:10]=[CH:1][C:2]4[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=4[OH:4])=[C:12]([O:40][CH3:41])[CH:13]=3)[C:25]=12
Reactant: O=Cc1ccccc1O
Reactant: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Solvent: CCO
Product: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N=Cc1ccccc1O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Salicylaldehyde (0.034 g, 0.000282 mol) and trans-3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.117 g, 0.000268 mol) were combined in absolute ethanol and stirred at ambient temperature for 48 hours. The reaction mixture was concentrated under reduced pressure and the residue dried overnight to yield trans-2-[(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)imino]methylphenol which was used without further purification. Trimethylsulfoxonium iodide (0.145 g, 0.00068 mol) was dissolved in anhydrous dimethylsulfoxide (2 mL) and a 60% dispersion of sodium hydride in parafine (0.027 g, 00068 mol) was added at once. After 10 min., the solution of trans-2-[(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)imino]methylphenol in anhydrous dimethylsulfoxide (2 mL) was added and the resulting mixture was stirred at ambient temperature under an atmosphere of nitrogen for 2.5 hours. The solution was poured into ice-cold water (50 mL) and extracted with dichloromethane (2×40 mL). The combined organic extracts were dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC (Hypersil C18, 8 μm, 25 cm; 10-60% acetonitrile-0.1M ammonium acetate over 25 min, 21 mL/min) to yield trans-3-[4-(2,3-dihydrobenzo[b]furan-3-ylamino)-3-methoxyphenyl]-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine diacetate (0.096 g, 0.000142 mol) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH2:26][CH2:27][NH2:28].CN1CCOCC1>C(Cl)(Cl)Cl>[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH2:26][CH2:27][NH:28][S:17]([C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([C:3]3[C:4]([CH3:7])=[N:5][NH:6][C:2]=3[NH2:1])[S:9][C:10]=2[CH:16]=1)(=[O:19])=[O:18]
Reactant: NCCc1cccs1
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)Cl)cc2s1
Solvent: CN1CCOCC1
Solvent: ClC(Cl)Cl
Product: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)NCCc3cccs3)cc2s1
Yield: 8.3 %

Procedure:
the title compound (8 mg) was prepared from crude 2-(5-amino-3-methyl-1H-pyrazol-4-yl)-benzothiazole-6-sulfonyl chloride (75 mg, 0.23 mmol), 2-thiophen-2-ylethylamine (29 μL, 0.25 mmol) and PS-NMM (0.22 g, 0.45 mmol) in 4 mL of chloroform. MS (m/z, ES+): 420.4 (M+1, 100): 1H NMR (500 MHz, ppm, DMSO-d6): δ 11.8-12.2 (br s, 1H), 8.5 (s, 1H), 8.0 (d, 1H), 7.8 (m, 2H), 7.32 (d, 1H), 6.93 (dd, 1H), 6.86 (d, 1H), 6.0 (br s, 2H), 3.03 (q, 2H), 2.92 (t, 2H), 2.43 (br s, 3H). Yield=8%.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]2[CH2:6][CH2:7][CH:8]([C:10]([O:12][CH3:13])=[O:11])[O:9][C:4]=2[C:3]=1[CH2:16][CH2:17][CH3:18].Br[CH2:20][CH2:21][CH2:22][Cl:23].C(=O)([O-])[O-].[K+].[K+].C(C(C)=O)C>C(OCC)(=O)C>[Cl:23][CH2:22][CH2:21][CH2:20][O:1][C:2]1[CH:15]=[CH:14][C:5]2[CH2:6][CH2:7][CH:8]([C:10]([O:12][CH3:13])=[O:11])[O:9][C:4]=2[C:3]=1[CH2:16][CH2:17][CH3:18]
Reactant: CCCc1c(O)ccc2c1OC(C(=O)OC)CC2
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(OCCCCl)ccc2c1OC(C(=O)OC)CC2
Reaction time: 8 h

Procedure:
Methyl 3,4-dihydro-7-hydroxy-8-propyl-2H-1-benzopyran-2-carboxylate (10 g, 40 mmol), 1-bromo-3-chloropropane (75 g, 48 mmol), and potassium carbonate (828 g, 60 mmol) were added to 100 ml of methyl ethyl ketone, and the reaction mixture was heated to reflux and stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over magnesium sulfate, concentrated, and the crude product was chromatographed on silica gel using 20% ethyl acetate/80% hexane as eluant to give the product.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([S:19][CH2:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.S(=O)(=O)(O)O.[CH3:35]O>>[C:1]12([C:11]3[CH:12]=[C:13]([S:19][CH2:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([O:27][CH3:35])=[O:26])=[CH:23][CH:22]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: CO
Reactant: COc1ccc(SCc2ccc(C(=O)O)cc2)cc1C12CC3CC(CC(C3)C1)C2
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(CSc2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)cc1

Procedure:
5 g (12.3 mmol) of 4-[3-(1-adamantyl)-4-methoxyphenylthiomethyl]benzoic acid and 50 ml of methanol were introduced into a round-bottomed flask and 330 μl of concentrated sulfuric acid were added. The mixture was heated at reflux for eight hours and the reaction medium was then evaporated to dryness. The residue was taken up in water, neutralized with sodium bicarbonate and extracted with ethyl ether. The organic phase was separated out after settling had taken place, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a column of silica, eluted with a mixture of dichloromethane and hexane (40/60). After evaporation of the solvents, 4.1 g (79%) of methyl 4-[3-(1-adamantyl)-4-methoxyphenylthiomethyl]benzoate were recovered.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([NH:13][CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:10]=[C:9](Cl)[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH:1]1([NH:6][C:7]2[N:12]=[C:11]([NH:13][CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:10]=[C:9]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: Clc1cc(NC2CCCC2)nc(NC2CCCC2)n1
Product: c1c(NC2CCCC2)nc(NC2CCCC2)nc1N1CCNCC1
Yield: 81.9 %

Procedure:
2,4-Bis(cyclopentylamino)-6-chloropyrimidine is reacted with piperazine according to the method of Example 4. The title compound is obtained in a yield of 81.9%, m.p.:142°-148° C.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[C:17]1([C:23]#[CH:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>[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.O.C(N(CC)CC)C>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]([C:5]2[CH:15]=[CH:16][C:2]([C:24]#[C:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:3][CH:4]=2)=[O:7])=[CH:9][CH:10]=1
Reactant: C#Cc1ccccc1
Reactant: O=C(c1ccc(F)cc1)c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(c1ccc(F)cc1)c1ccc(C#Cc2ccccc2)cc1
Temperature: 23 °C
Reaction time: 16 h

Procedure:
4-Fluoro-4′-phenylethynylbenzophenone was synthesized by the cuprous iodide catalyzed coupling of 4-bromo-4′-fluorobenzophenone. More specifically, 4-bromo-4′-fluorobenzophenone (30 grams, 0.11 mol), phenylacetylene (11 grams, 0.11 mol), triphenylphosphine (0.2 gram), cuprous iodide (0.1 gram), bis(triphenylphosphine) palladium dichloride (0.1 gram) and 450 milliliters of triethylamine were charged to a 500 milliliter flask equipped with a mechanical stirrer, N2 inlet, and reflux condenser. The mixture was heated to reflux for 4 hours, cooled to 23° C., and stirred for an additional 16 hours. The mixture was then poured into water acidified with HCl and the precipitate was collected by filtration. Recrystallization from acetone gave 23 grams (75 percent yield) of the desired product.
Reaction SMILES: [OH-].[Na+].CO.[C:5]([NH:13][C:14]1[CH:23]=[C:22]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18]C)=[O:17])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O1CCCC1>[C:5]([NH:13][C:14]1[CH:23]=[C:22]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:21]=[CH:20][C:15]=1[C:16]([OH:18])=[O:17])(=[O:12])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(OCCCc2ccccc2)cc1NC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1cc(OCCCc2ccccc2)ccc1C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.090 mL of 2.0 mol/L aqueous sodium hydroxide was added dropwise to a mixed solution of 1 mL of methanol and 1 mL of tetrahydrofuran containing 45 mg of methyl 2-(benzamido)-4-(3-phenylpropoxy)benzoate while ice-cooled and stirred at room temperature for 14 hours and 30 minutes. 0.15 mL of 2.0 mol/L aqueous sodium hydroxide was added dropwise and stirred at the same temperature for 5 hours and 30 minutes. The solvent was evaporated under reduced pressure and water was added and pH was adjusted to pH 4.0 with 1.0 mol/L hydrochloric acid. A solid substance was separated by filtration to obtain 32 mg of 2-(benzamido)-4-(3-phenylpropoxy)benzoic acid as white solid.
Reaction SMILES: CO[C:3]([C:5]1[C:6](=[O:18])[O:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][C:11]([Cl:16])=[CH:10][C:9]=2[Cl:17])=[O:4].[Na+].[NH2:20][CH2:21][C:22]([O-:24])=[O:23]>COCCO>[Cl:16][C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([Cl:17])[CH:10]=1)[O:7][C:6](=[O:18])[C:5]([C:3]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:4])=[C:14]2[OH:15]
Reactant: COC(=O)c1c(O)c2cc(Cl)cc(Cl)c2oc1=O
Reactant: NCC(=O)[O-]
Agent: [Na+]
Solvent: COCCO
Product: O=C(O)CNC(=O)c1c(O)c2cc(Cl)cc(Cl)c2oc1=O
Yield: 86.9 %

Procedure:
A mixture of 6,8-dichloro-4-hydroxy-2-oxo-2H-chromene-3-carboxylic acid methyl ester (400 mg, 1.39 mmol) and glycine sodium salt (674 mg, 6.94 mmol) in 2-methoxyethanol (14 mL) was heated to reflux overnight. Reaction mixture was concentrated and dissolved in water (100 mL). The solution was acidified by 1 N aq HCl to pH=2-3. White precipitate was collected, rinsed with water and methanol and dried to give the title compound (401 mg). MS ESI(−) m/e: 332, 330 (M−1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N:15]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH:12]=[CH:11][C:10]=1[CH:25]=[CH:26][C:27]1[S:31][C:30]([CH:32]=O)=[CH:29][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]([C:36]1[C:37](=[C:44]([C:47]#[N:48])[C:45]#[N:46])[O:38][C:39]([CH3:43])([CH3:42])[C:40]=1[CH3:41])#[N:35].C([O-])(=O)C.[NH4+]>C(O)C.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N:15]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH:12]=[CH:11][C:10]=1[CH:25]=[CH:26][C:27]1[S:31][C:30]([CH:32]=[CH:41][C:40]2[C:39]([CH3:42])([CH3:43])[O:38][C:37](=[C:44]([C:45]#[N:46])[C:47]#[N:48])[C:36]=2[C:34]#[N:35])=[CH:29][CH:28]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCN(CCCCO)c1ccc(C=Cc2ccc(C=O)s2)c(OCc2ccccc2)c1
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCN(CCCCO)c1ccc(C=Cc2ccc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(C)C)s2)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 56.4 %

Procedure:
In 7 ml of ethanol and 2 ml of tetrahydrofuran were dissolved 218 mg (0.47 mmol) of 5-[2-[2-benzyloxy-4-[butyl(4-hydroxybutyl)amino]phenyl]vinyl]thiophene-2-carboaldehyde and 103 mg (0.52 mmol) of 2-(3-cyano-4,5,5-trimethyl-2(5H)-furanylidene)propanedinitrile. To this mixture was added 40 mg (0.52 mmol) of ammonium acetate, and the mixture was stirred at room temperature for 90 minutes. The precipitate was separated by filtration, purified by silica gel column chromatography and washed with methanol to give 171 mg of a dark brown crystal having a mp of 216-217° C. (yield: 56.4%).
Reaction SMILES: [OH:1][CH2:2][C@H:3]([CH3:23])[O:4][C:5]1[CH:6]=[C:7]([OH:22])[CH:8]=[C:9]([C:11]2[NH:12][C:13]([C:16]3[O:17][C@@H:18]([CH3:21])[CH2:19][N:20]=3)=[CH:14][CH:15]=2)[CH:10]=1.F[C:25]1[CH:30]=[CH:29][C:28]([S:31]([N:34]2[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]2)(=[O:33])=[O:32])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:21][C@@H:18]1[O:17][C:16]([C:13]2[NH:12][C:11]([C:9]3[CH:10]=[C:5]([CH:6]=[C:7]([O:22][C:25]4[CH:30]=[CH:29][C:28]([S:31]([N:34]5[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]5)(=[O:32])=[O:33])=[CH:27][CH:26]=4)[CH:8]=3)[O:4][C@@H:3]([CH3:23])[CH2:2][OH:1])=[CH:15][CH:14]=2)=[N:20][CH2:19]1
Reactant: CN1CCN(S(=O)(=O)c2ccc(F)cc2)CC1
Reactant: C[C@H]1CN=C(c2ccc(-c3cc(O)cc(O[C@@H](C)CO)c3)[nH]2)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H]1CN=C(c2ccc(-c3cc(Oc4ccc(S(=O)(=O)N5CCN(C)CC5)cc4)cc(O[C@@H](C)CO)c3)[nH]2)O1
Temperature: 100 °C
Reaction time: 4 h
Yield: 23.6 %

Procedure:
3-[(1S)-2-Hydroxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenol (40 mg, 0.13 mmol) synthesized in Example (117a) and 1-[(4-fluorophenyl)sulfonyl]-4-methylpiperazine (49 mg, 0.19 mmol) synthesized in Example (116a) were dissolved in N,N-dimethylformamide (2 mL), and potassium carbonate (52 mg, 0.38 mmol) was added, followed by stirring at 100° C. for 4 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, water (10 mL) was added, and extraction was carried out twice with ethyl acetate (10 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-5%) to afford the desired compound (17 mg, yield 25%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C([CH:11]([C:38](=[O:40])[NH2:39])[O:12][C:13]1[CH:14]=[C:15]([CH:35]=[CH:36][CH:37]=1)[C:16]([C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[C:21]([C:32]([OH:34])=[O:33])=[CH:20][N:19]=1)=[O:17])(C)C.N1[CH2:46][CH2:45][S:44][CH2:43][CH2:42]1>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:31][O:30][C:24]1[CH:23]=[C:22]2[C:27](=[CH:26][C:25]=1[O:28][CH3:29])[C:18]([C:16](=[O:17])[C:15]1[CH:35]=[CH:36][CH:37]=[C:13]([O:12][CH2:11][C:38](=[O:40])[N:39]3[CH2:46][CH2:45][S:44][CH2:43][CH2:42]3)[CH:14]=1)=[N:19][CH:20]=[C:21]2[C:32]([OH:34])=[O:33]
Reactant: C1CSCCN1
Reactant: COc1cc2c(C(=O)O)cnc(C(=O)c3cccc(OC(C(N)=O)C(C)C)c3)c2cc1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(C(=O)O)cnc(C(=O)c3cccc(OCC(=O)N4CCSCC4)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The resin bound activated ester (intermediate in the preparation of 1-[3-(Isopropyl-carbamoyl-methoxy)-benzoyl]-6,7-dimethoxy-isoquinoline-4-carboxylic acid; compound with trifluoro-acetic acid (Example 37)) (225 mg, 0.19 mmol) was combined with 3 ml of methylene chloride and 0.04 ml of thiomorpholine (0.4 mmol). The mixture was shaken for 15 minutes at room temperature. The mixture was filtered and the filter cake was washed with methylene chloride. The filtrate was evaporated to dryness. The residue was saponified by dissolving in 1 ml of methanol containing 0.5 ml of 1N sodium hydroxide solution and several drops of tetrahydrofuran. The mixture was stirred at room temperature for 4 hrs and then evaporated to dryness. The residue was purified through a reverse phase preparative HPLC to give 6,7-Dimethoxy-1-[3-(2-oxo-2-thiomorpholin-4-yl-ethoxy)-benzoyl]-isoquinoline-4-carboxylic acid; compound with trifluoro-acetic acid, as a fluffy solid (30 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[C:8]2[CH:7]=[C:6]([C:18]#[C:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+].Cl>CCO.C1COCC1>[CH3:1][C:2]1([CH3:31])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[C:8]2[CH:7]=[C:6]([C:18]#[C:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:29][CH:30]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C)s2)=CCC3(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 4-[5,6-dihydro-5,5-dimethyl-8-(5-methyl-2-thienyl)-2-naphthalenyl]ethynylbenzoate (Compound 33) (35.0 mg, 0.082 mmol) in 2 ml of EtOH and 1 ml THF at room temperature was added aqueous NaOH (1 ml, 1M, 1 mmol). The resulting solution was stirred at room temperature overnight and then acidified with 10% HCl. Extraction with EtOAc, followed by drying over Na2SO4, and removal of the solvents under reduced pressure afforded the title compound as a colorless solid. 1H NMR (d6-acetone): δ 8.03 (2H, d, J=8.6 Hz), 7.63 (2H, d, J=8.6 Hz), 7.54-7.48 (3H, m), 6.89 (1H, m), 6.18 (1H, t, J=4.7 Hz), 2.49 (3H, s), 2.35 (2H, d, J=4.7 Hz), 1.32 (6H, s).