Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH3:9])=[C:4]([Cl:10])[N:3]=1.C(N(CC)CC)C.[CH2:18]([NH:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21]>C(#N)C.O.Cl>[CH2:18]([N:22]([C:6]1[C:5]([CH3:9])=[C:4]([Cl:10])[N:3]=[C:2]([CH3:1])[N:7]=1)[CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21]
Reactant: Cc1nc(Cl)c(C)c(Cl)n1
Reactant: CCCCNCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: CCCCN(CC)c1nc(C)nc(Cl)c1C
Yield: 64.3 %

Procedure:
A mixture of 2,5-dimethyl-4,6-dichloro-pyrimidine (0.999 g, 5.64 mmol) in 5 ml of acetonitrile was treated with triethylamine (0.571 g, 5.65 mmol) and N-butyl-ethyl-amine (0.570 g, 5.65 mmol) and heated at reflux overnight. The mixture was cooled, diluted with water and dilute hydrogen chloride, and extracted with ethyl acetate. The organic layer was neutralized with saturated potassium carbonate, washed with brine, dried and concentrated to give 0.877 g (64%) of title compound as a yellow oil. 1H NMR (CDCl3) δ 0.90 (t, 3H), 1.15 (t, 3H), 1.22–1.36(m, 2H), 1.5–1.6(m, 2H), 2.20 (s, 3H), 2.45 (s, 3H), 3.25–3.48 (m, 4H) ppm.
Reaction SMILES: NC1C=CC(C)=C([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([Cl:23])[CH:17]=3)[N:12]=[CH:11][N:10]=2)C=1.ClC1C=C(C2(N)C=C(Cl)N=CN2)C=CC=1F.[CH3:41][C:42]1[CH:48]=[CH:47][C:46]([N+:49]([O-:51])=[O:50])=[CH:45][C:43]=1N.Cl>C(O)CCC.CCOC(C)=O>[Cl:23][C:18]1[CH:17]=[C:16]([N:15]([C:48]2[CH:47]=[C:46]([N+:49]([O-:51])=[O:50])[CH:45]=[CH:43][C:42]=2[CH3:41])[C:13]2[CH:14]=[C:9]([NH2:8])[N:10]=[CH:11][N:12]=2)[CH:21]=[CH:20][C:19]=1[F:22]
Reactant: Cc1ccc(N)cc1Nc1cc(Nc2ccc(F)c(Cl)c2)ncn1
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Agent: Cl
Agent: NC1(c2ccc(F)c(Cl)c2)C=C(Cl)N=CN1
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: Cc1ccc([N+](=O)[O-])cc1N(c1ccc(F)c(Cl)c1)c1cc(N)ncn1
Temperature: 120 °C

Procedure:
Synthesis of N-(5-Amino-2-methylphenyl)-N′-(3-chloro-4-fluorophenyl)-pyrimidine-4,6-diamine (Int-F) A mixture of 4-(3-chloro-4-fluorophenyl)-6-chloropyrimidin-4-ylamine (IR-4) (1.2 g, 4.6 mmol), 2-methyl-5-nitroaniline (0.85 g, 5.5 mmol) and 1 mL of concentrated HCl in 10 mL of n-butanol was heated at 120° C. for 16 h. With stirring, 5 mL of EtOAc was added to the reaction mixture. The light yellow colored product that precipitated was filtered and dried under vacuum to give N-(3-chloro-4-fluorophenyl)-N-(2-methyl-5-nitrophenyl)pyrimidine-4,6-diamine. MS (APCI) (m/z): 374/376 (M+1). A mixture of N-(3-chloro-4-fluorophenyl)-N-(2-methyl-5-nitrophenyl)pyrimidine-4,6-diamine (0.55 g, 1.5 mmol) and iron powder (35 mesh, 0.5 g, 5 eq) in 5 mL of HOAc and 2 mL of MeOH was heated at reflux for 2 h. The solvent was removed in vacuo and the dark colored residue was mixed with 150 mL of CH2Cl2 and 15 mL of sat. K2CO3 solution and was stirred at room temperature for 30 min. The organic layer was dried (MgSO4), was concentrated, and was then purified by flash chromatography (silica gel, MeOH/NH4OH/CH2Cl2) to afford 0.115 g of N-(5-amino-2-methylphenyl)-N′-(3-chloro-4-fluorophenyl)pyrimidine-4,6-diamine as a light colored solid. (Int-F) MS (m/z): 344/346 (M+1).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:18]=[C:19]([NH:36][C:37]4[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=4)[C:40]([NH2:42])=[O:41])[C:20]4[CH:25]=[CH:24][N:23](S(C5C=CC(C)=CC=5)(=O)=O)[C:21]=4[N:22]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[OH-].[K+]>CO>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]3[N:18]=[C:19]([NH:36][C:37]4[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=4)[C:40]([NH2:42])=[O:41])[C:20]4[CH:25]=[CH:24][NH:23][C:21]=4[N:22]=3)=[CH:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ccc(Nc3nc(Nc4cccc(C(N)=O)c4)c4ccn(S(=O)(=O)c5ccc(C)cc5)c4n3)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)N1CCN(c2ccc(Nc3nc(Nc4cccc(C(N)=O)c4)c4cc[nH]c4n3)cc2)CC1
Temperature: 60 °C
Yield: 49.8 %

Procedure:
To a solution of 3-(2-(4-(4-acetylpiperazin-1-yl)phenylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)benzamide (40 mg, 0.064 mmol) in MeOH (3 mL), aq. 1N KOH (1.0 mL, 1.0 mmol) was added. The mixture was heated at 60° C. for 3 h. It was concentrated in vacuo. The residue was acidified with HOAc (1 mL) before being purified by HPLC to give 3-(2-(4-(4-acetylpiperazin-1-yl)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)benzamide (15 mg), MS 471.1 (M+H); UV 207.3, 284.1, 311.5 nm; and 3-(2-(4-(piperazin-1-yl)phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)benzamide (5 mg), MS 429.1 (M+H); UV 202.6, 279.3 nm.
Reaction SMILES: C([CH:7]([NH2:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])CCCCC.[CH:15]([OH:17])=O>>[CH2:7]([N:14]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:15]=[O:17])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCC(N)CCCCCC
Reactant: O=CO
Product: CCCCCCCN(C=O)CCCCCC

Procedure:
20.0 g (100 mmol) of 1-hexylheptylamine are heated under reflux with 20.0 g (400 mmol) of 92 percent formic acid for 1 hour. The excess formic acid is distilled off over a 10 cm Vigreux column and the reaction product which remains is subjected to fractional distillation in vacuo. Yield 18.1 g (79%)--boiling point 165° C. (1 mm Hg)-nD 20=1.4577. The reaction product contains a small content of bisformamide which can be removed by distillation only with difficulty but does not interfere in the further reactions.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[N:15]([CH2:19][CH2:20][O:21][CH3:22])[C:16]([CH3:18])=[N:17][C:13]=2[CH:12]=[C:11]([C:23]([OH:25])=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][NH:27][CH2:28][CH2:29][OH:30]>>[CH2:1]([O:8][C:9]1[C:14]2[N:15]([CH2:19][CH2:20][O:21][CH3:22])[C:16]([CH3:18])=[N:17][C:13]=2[CH:12]=[C:11]([C:23]([N:27]([CH2:28][CH2:29][OH:30])[CH3:26])=[O:25])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNCCO
Reactant: COCCn1c(C)nc2cc(C(=O)O)cc(OCc3ccccc3)c21
Product: COCCn1c(C)nc2cc(C(=O)N(C)CCO)cc(OCc3ccccc3)c21
Yield: 99 %

Procedure:
The title compound was prepared as a white amorphous in 99% yield from 7-(benzyloxy)-1-(2-methoxyethyl)-2-methyl-1H-benzimidazole-5-carboxylic acid (5.00 g, 14.7 mmol, Step 5 of Example 1) and 2-(methylamino)ethanol (1.21 g, 16.2 mmol) by the same manner in Step 13 of Example 1.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[N:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:4][NH:3]1.Br[CH2:26][C:27]1[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=1)[C:30]([O:32][CH3:33])=[O:31].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:33][O:32][C:30]([C:29]1[CH:28]=[C:27]([CH:36]=[CH:35][CH:34]=1)[CH2:26][N:3]1[C:2](=[O:1])[C:6]2([CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]2)[N:5]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:4]1)=[O:31]
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)c1
Temperature: 65 °C
Yield: 57.8 %

Procedure:
A mixture of tert-butyl 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (2 g, 6.02 mmol, 1 equiv), methyl 3-(bromomethyl)benzoate (1.38 g, 6.02 mmol, 1 equiv) and potassium carbonate (1.25 g, 9.03 mmol, 1.5 equiv) in N,N-dimethylformamide was heated at 65° C. for 16 h. Upon cooling the mixture was partitioned between ethyl acetate and water. The organic layer was further washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified using the Biotage flash chromatography system (SNAP 50 g cartridge, Rf=0.5, gradient—10%-50% ethyl acetate in hexanes) to afford tert-butyl 3-(3-(methoxycarbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate as a white solid (1.67 g, 58%); MS for C27H33N3O5 m/z 479.24 (M+H)+.
Reaction SMILES: C1CO[C:3]2([CH2:8][CH2:7][N:6]([C:9]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][CH:20]=3)[NH:17][C:16](=[O:21])[CH2:15][CH2:14]4)=[O:10])[CH2:5][CH2:4]2)[O:2]1.Cl.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>O1CCOCC1.O.CO>[O:2]=[C:3]1[CH2:8][CH2:7][N:6]([C:9]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])[CH2:15][CH2:14]3)=[O:10])[CH2:5][CH2:4]1
Reactant: O=C1CCc2cc(C(=O)N3CCC4(CC3)OCCO4)ccc2N1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: O=C1CCN(C(=O)c2ccc3c(c2)CCC(=O)N3)CC1
Temperature: 100 °C

Procedure:
46 Grams of 6-(4,4-ethylenedioxy-1-piperidylcarbonyl)3,4-dihydrocarbostyril was dispersed in 400 ml of dioxane and 150 ml of water, then 15 ml of concentrated hydrochloric acid was added thereto and the whole mixture was heated at 100° C. for 7 hours with stirring. After the reaction mixture was allowed to stand for cooling, then was made alkaline by adding sodium carbonate, and the solvent was removed by evaporation. The residue thus obtained was extracted with chloroform, and the extract was dried with anhydrous sodium carbonate, and the solvent was removed by evaporation. The residue thus obtained was purlfied by means of a silica gel column chromatography (eluent:dichloromethane:methanol=10:1) to yield 37.6 g of 6-(4-oxo-1-piperidylcarbonyl)-3,4-dihydrocarbostyril.
Reaction SMILES: [CH2:1]([S:7][C:8]1[C:9](=[O:16])[O:10][C:11]([CH3:15])=[CH:12][C:13]=1[OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH:17]O>C(O)(=O)C>[CH2:1]([S:7]([C:8]1[C:9](=[O:16])[O:10][C:11]([CH3:15])=[CH:12][C:13]=1[OH:14])=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: OO
Reactant: CCCCCCSc1c(O)cc(C)oc1=O
Solvent: CC(=O)O
Product: CCCCCCS(=O)c1c(O)cc(C)oc1=O
Temperature: 25 °C

Procedure:
3-n-Hexylthio-4-hydroxy-6-methyl-2-pyrone (9.1 g., 0.040 mol), 30% hydrogen peroxide (4.85 g., 0.0440 mol), and 40 ml. glacial acetic acid were combined and stirred at room temperature over night. The clear solution was poured into 200 ml. ice water and the resulting white precipitate was collected and dried in vacuo: m.p. 59°-60°C. The solid was recrystallized from n-hexane to recover 8.0 g. (77%) of the desired compound as white crystalline platelets, m.p. 59°-60°C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:14].O.[O-]S(OOS([O-])(=O)=O)(=O)=O.[Na+].[Na+]>CC(C)=O>[CH2:1]([N:8]1[CH2:12][CH:11]2[O:14][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1=CCN(Cc2ccccc2)C1
Reactant: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: c1ccc(CN2CC3OC3C2)cc1
Yield: 25.7 %

Procedure:
To a solution of 15.9 g (0.1 mol) of 1-benzyl-3-pyrroline, 12.0 g (0.12 mol) of 98% sulfuric acid, 15.0 g of water, and 60.0 g of acetone in a Pyrex round flask reactor, 47.6 g (0.20 mol) of Na2S2O8 (sodium peroxydisulfate produced by Mitsubishi Gas Chemical Industry Co., Ltd.) was added with stirring and allowed to react for 10 hours at room temperature with irradiation by 500 W Xe lamps (UXL-500D xenon lamp produced by Ushio). After completion, acetone was evaporated under reduced pressure, neutralized by NaOH (aq), and extracted with toluene and water. After the solvent was evaporated under reduced pressure, 4.5 g of 1-benzyl-3,4-epoxypyrrolidine (yield 23.3%) was obtained and 11.9 g (yield 75.0%) of 1-benzyl-3-pyrroline was recovered.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C:19]1[C:20](=[O:33])[N:21]([CH2:30][CH2:31][CH3:32])[C:22](=[O:29])[N:23]([CH2:26][CH2:27][CH3:28])[C:24]=1[NH2:25].CCN=C=NCCCN(C)C>CO>[NH2:25][C:24]1[N:23]([CH2:26][CH2:27][CH3:28])[C:22](=[O:29])[N:21]([CH2:30][CH2:31][CH3:32])[C:20](=[O:33])[C:19]=1[NH:18][C:13](=[O:15])[C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:17][CH:16]=1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: CO
Product: CCCn1c(N)c(NC(=O)c2ccc(OCc3ccccc3)cc2)c(=O)n(CCC)c1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 4-benzyloxy-benzoic acid (0.868 g, 3.8 mmol), 5,6-diamino-1,3-dipropyl-1H-pyrimidine-2,4-dione (1.0 g, 3.8 mmol), methanol (15 ml), EDCI (0.95 g, 4.9 mmol), was stirred for 20 hours at room temperature. The reaction mixture was concentrated and water was added to obtain the intermediate N-(6-amino-2,4-dioxo-1,3-dipropyl-1,2,3,4-tetrahydro-pyrimidin-5-yl)-4-benzyloxy-benzamide. It was dissolved in methanol (32 ml) and added 10% NaOH (24 ml). The mixture was heated at 80-90° C. for 3 hours. The mixture was cooled and solvent was removed. The residue was dissolved in water (20 ml) acidified with dil HCl to provide 8-(4-benzyloxy-phenyl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (1.2 g, 75%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][C:11](=[O:13])[NH:10][CH:9]2[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.[H-].[Na+].[C:27]1([CH2:37]Cl)[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1>CN(C)C=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][C:11](=[O:13])[N:10]([CH2:37][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[CH:29][CH:28]=3)[CH:9]2[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1
Reactant: ClCc1cccc2ccccc12
Reactant: O=C1NC(Cc2ccc(C(F)(F)F)cc2)C(c2ccc(F)cc2)O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1OC(c2ccc(F)cc2)C(Cc2ccc(C(F)(F)F)cc2)N1Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
To a solution of (4RS,5SR)-5-(4-fluorophenyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one (1 g, 2.95 mmol) in N,N-dimethylformamide (10 ml) was added 60% sodium hydride (142 mg, 3.54 mmol) and the mixture was stirred at room temperature for 15 min. To the reaction solution was added 1-naphthylmethyl chloride (480 ml, 3.25 mmol) and the mixture was stirred for 1 hr. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1). Recrystallization from diisopropyl ether-hexane gave (4RS,5SR)-5-(4-fluorophenyl)-3-(1-naphthalenylmethyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one (1.23 g, 87%).
Reaction SMILES: [C:1](=[O:36])([O:3][CH:4]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:35])[CH2:5][NH:6][C:7](=[O:28])[CH2:8][N:9]1[C:13](=[O:14])[N:12](/[CH:15]=[CH:16]/[C:17]([F:20])([F:19])[F:18])[C:11]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[N:10]1)[NH2:2]>CO.[Pt]>[C:1](=[O:36])([O:3][CH:4]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:35])[CH2:5][NH:6][C:7](=[O:28])[CH2:8][N:9]1[C:13](=[O:14])[N:12]([CH2:15][CH2:16][C:17]([F:20])([F:18])[F:19])[C:11]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[N:10]1)[NH2:2]
Reactant: NC(=O)OC(CNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(/C=C/C(F)(F)F)c1=O)c1ccccc1Cl
Agent: [Pt]
Solvent: CO
Product: NC(=O)OC(CNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(CCC(F)(F)F)c1=O)c1ccccc1Cl

Procedure:
A solution of 50 mg (92 μmol) of the compound of Example 58 in 20 ml of methanol was hydrogenated in a continuous-flow hydrogenation apparatus fitted with a 5% Pt/C cartridge (H-Cube, from Thales Nano, Budapest, Model HC-2-SS) at a flow rate of 1 ml/min, a temperature of 60° C. and at standard pressure. After the reaction had ended, the solution was freed from the methanol on a rotary evaporator and the residue was purified by preparative HPLC [Method 23]. This gave 22 mg (44% of theory) of the title compound.
Reaction SMILES: [OH-].[K+].C([O:7][C:8](=[O:23])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])(C)(C)C.Cl>O.CO>[OH:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]([OH:23])=[O:7]
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCCCCCCCCCCCO
Temperature: 25 °C

Procedure:
A solution of potassium hydroxide (8.60 g, 153 mmol) in water (100 mL) was added to a solution of the above ester (9.20 g, 30.6 mmol) in methanol (100 mL) and the resulting mixture was heated at 60 C for 2 days. The mixture was cooled to room temperature; then it was washed with hexanes (2×70 mL) and concentrated in vacuo. Concentrated hydrochloric acid (32%, 20 mL, 0.65 mol) was added dropwise and the mixture was extracted with ethyl acetate (2×150 mL). The combined organic layers were dried over anhydrous magnesium sulfate and evaporated to dryness to yield 14-hydroxy-tetradecanoic acid as white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[C:24]([F:28])([F:27])[CH:25]=[CH2:26].O>CN(C)C=O>[F:27][C:24]([F:28])=[CH:25][CH2:26][O:15][C:14]([CH:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]1)=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Reactant: C=CC(F)(F)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(C(=O)OCC=C(F)F)C1
Temperature: 60 °C
Reaction time: 4.5 h

Procedure:
To a solution of piperidine-1,3-dicarboxylic acid 1-tert-butyl ester (30.0 g) in N,N-dimethylformamide (300 ml) were added potassium carbonate (36.2 g) and 3-bromo-3,3-difluoropropene (16 ml), and the mixture was stirred at 60° C. for 4.5 hours. To the reaction mixture was added water, and the mixture was extracted with n-hexane/ethyl acetate (1/1) solution. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=10/1) to give the titled compound (33.5 g).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=[O:12])[CH:9]=2)[NH:4][N:3]=1.[CH2:13](O)[CH2:14][CH2:15][OH:16].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]3[O:16][CH2:15][CH2:14][CH2:13][O:12]3)[CH:9]=2)[NH:4][N:3]=1
Reactant: O=Cc1ccc2[nH]nc(Cl)c2c1
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Clc1n[nH]c2ccc(C3OCCCO3)cc12

Procedure:
2.2 g (12.2 mmol) 3-chloro-1H-indazole-5-carbaldehyde (Example 43A), 4.64 g (60.9 mmol) propane-1,3-diol and a trace amount of p-toluene sulfonic acid in toluene (60 ml) were heated to reflux for 12 h using a Dean-Stark trap. After cooling, the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water. The organic layer was dried with sodium sulfate, filtered and evaporated to dryness. The remaining solid (2.76 g, 91% of th.) was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[C:7]([C:17]3[NH:18][CH2:19][CH2:20][N:21]=3)[C:6]=2[C:22]=1[F:23].C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[C:7]([C:17]3[NH:21][CH:20]=[CH:19][N:18]=3)[C:6]=2[C:22]=1[F:23]
Reactant: Fc1ccc(-c2oc3ccc(Cl)c(F)c3c2C2=NCCN2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Product: Fc1ccc(-c2oc3ccc(Cl)c(F)c3c2-c2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.7 %

Procedure:
To a mixture of 2-(5-chloro-4-fluoro-2-(4-fluorophenyl)benzofuran-3-yl)-4,5-dihydro-1H-imidazole (0.65 g, 1.954 mmol) in DMSO (5 ml) in a 25 ml RB flask was added potassium carbonate (0.405 g, 2.93 mmol) and iodobenzene diacetate (0.755 g, 2.344 mmol). The reaction mixture was stirred at room temperature in darkness overnight. The reaction mixture was added water and extracted with ethyl acetate (3×25 ml). The combined organic extracts were dried over Na2SO4, filtered and concentrated. The crude product was purified by using 40 g combiflash silica column with 11% methanol in chloroform as an eluent. The desired fractions were collected and concentrated to give the titled product (0.25 g, 39%). 1H NMR (400 MHz, CDCl3): δ 9.45 (s, 1H), 7.92-7.89 (m, 2H), 7.36-7.30 (m, 2H), 7.26-7.21 (m, 2H), 7.11-7.07 (m, 2H).
Reaction SMILES: C[O:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[C:11]([C:12]3[CH:17]=[C:16]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:15]=[CH:14][C:13]=3[NH:22][CH2:23][C:24]3[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=3)=[CH:10][N:9]([CH3:32])[C:8]=12.Cl.O1CCOCC1>>[CH3:32][N:9]1[C:8]2[C:3](=[O:2])[NH:4][CH:5]=[CH:6][C:7]=2[C:11]([C:12]2[CH:17]=[C:16]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:15]=[CH:14][C:13]=2[NH:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:28]#[N:29])=[CH:30][CH:31]=2)=[CH:10]1
Reactant: COc1nccc2c(-c3cc(S(C)(=O)=O)ccc3NCc3ccc(C#N)cc3)cn(C)c12
Agent: Cl
Solvent: C1COCCO1
Product: Cn1cc(-c2cc(S(C)(=O)=O)ccc2NCc2ccc(C#N)cc2)c2cc[nH]c(=O)c21
Temperature: 70 °C
Yield: 15.4 %

Procedure:
The product from Example 46A (0.067 g, 0.15 mmol) and 4 M hydrogen chloride in dioxane (5 mL, 20.00 mmol) were combined and heated at 70° C. for 24 hours, cooled and concentrated Purification by reverse phase chromatography (C18, CH3CN/water (0.1% TFA), 10-100%) afforded the title compound (0.01 g, 15%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.97 (d, J=5.19 Hz, 1H) 7.80 (d, J=8.54 Hz, 2H) 7.45-7.61 (m, 5H) 6.87-6.95 (m, 1H) 6.54 (d, J=8.85 Hz, 1H) 6.48-6.53 (m, 1H) 6.23 (d, J=6.71 Hz, 1H) 4.48 (d, J=6.10 Hz, 2H) 4.14 (s, 3H) 3.07 (s, 3H). MS (ESI+) m/z 433 (M+H)+.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].C1(C)C=CC=CC=1.[OH:12][C:13]1[CH:33]=[CH:32][C:16]([CH2:17][NH:18][NH:19][C:20](=[O:31])[CH:21]([OH:30])[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[CH:15][C:14]=1[O:34][CH3:35].[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[CH3:35][O:34][C:14]1[CH:15]=[C:16]([CH:32]=[CH:33][C:13]=1[O:12][CH2:3][C:2]#[CH:1])[CH2:17][NH:18][NH:19][C:20](=[O:31])[CH:21]([OH:30])[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1
Reactant: C#CCBr
Reactant: COc1ccc(C(O)C(=O)NNCc2ccc(O)c(OC)c2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C#CCOc1ccc(CNNC(=O)C(O)c2ccc(OC)cc2)cc1OC
Reaction time: 16 h

Procedure:
A 80% propargyl bromide solution in toluene (2.1 g, 14.5 mmol) is added slowly at room temperature to a mixture of hydroxy-(4-methoxy-phenyl)-acetic acid N′-(4-hydroxy-3-methoxy-benzyl)-hydrazide (4.0 g, 12 mmol), 30% sodium hydroxide solution (3.5 ml, 14.5 mmol) and catalytic amounts of tetrabutylammonium bromide in 35 ml of dichloromethane. The reaction is stirred for 16 hours at +40° C. Subsequently the mixture is evaporated and the residue is diluted with water and dichloromethane. The phases are separated and the aqueous phase is extracted three times with dichloromethane. The combined organic phase is washed with brine, dried over sodium sulfate and evaporated. The remaining oil is purified by chromatography on silica gel (ethyl acetate/hexane 7:3) to obtain hydroxy-(4-methoxy-phenyl)-acetic acid N′-(3-methoxy-4-prop-2-ynyloxy-benzyl)-hydrazide.